WO2015066344A1

WO2015066344A1 - 5-ht2c receptor agonists and compositions and methods of use

Info

Publication number: WO2015066344A1
Application number: PCT/US2014/063191
Authority: WO
Inventors: Graeme Semple; Dominic P. Behan; Konrad Feichtinger; Alan GLICKLICH; Andrew J. Grottick; Maria Matilde Sanchez KAM; Michelle Kasem; Juerg Lehmann; Albert S. Ren; Thomas O. Schrader; William R. Shanahan; Amy Siu-Ting Wong; Xiuwen Zhu
Original assignee: Arena Pharmaceuticals, Inc.
Priority date: 2013-11-01
Filing date: 2014-10-30
Publication date: 2015-05-07

Abstract

Provided are 5-HT_2C receptor agonists. Also provided are methods for weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, and sex addiction), obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders (including insomnia, fragmented sleep architecture, and disturbances of slow-wave sleep), urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea. Also provided are compositions comprising a selective 5-HT_2C receptor agonist, optionally in combination with a supplemental agent, and methods for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising administering a selective 5-HT_2C receptor agonist, optionally in combination with a supplemental agent.

Description

5-HT_2C RECEPTOR AGONISTS AND COMPOSITIONS AND METHODS OF USE

Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer, and gallbladder disease.

Obesity is now a major healthcare issue in the Western World and increasingly in some third world countries. The increase in numbers of obese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people' s lives. Currently about 30% of the population of the USA is now considered obese.

Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m²). Thus, the units of BMI are kg/m² and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m², and obesity as a BMI greater than 30 kg/m² (see table below).

Classification Of Weight By Body Mass Index (BMI)

As the BMI increases there is an increased risk of death from a variety of causes that are independent of other risk factors. The most common diseases associated with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. The strength of the link between obesity and specific conditions varies. One of the strongest is the link with type 2 diabetes. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women (Seidell, Semin Vase Med 5:3-14 (2005)). Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.

There are problems however with the BMI definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% in males and greater than 30% in females.

Obesity considerably increases the risk of developing cardiovascular diseases as well. Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complications induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac insufficiency and of cerebral vascular accidents would decrease by 35%. The incidence of coronary diseases is doubled in subjects less than 50 years of age who are 30% overweight. The diabetes patient faces a 30% reduced lifespan. After age 45, people with diabetes are about three times more likely than people without diabetes to have significant heart disease and up to five times more likely to have a stroke. These findings emphasize the inter-relations between risks factors for diabetes and coronary heart disease and the potential value of an integrated approach to the prevention of these conditions based on the prevention of obesity (Perry, I. J., et al, BMJ 310, 560-564 (1995)).

Diabetes has also been implicated in the development of kidney disease, eye diseases and nervous system problems. Kidney disease, also called nephropathy, occurs when the kidney' s "filter mechanism" is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma. Finally, diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation' s leading causes of death.

The first line of treatment is to offer diet and life style advice to patients such as reducing the fat content of their diet and increasing their physical activity. However, many patients find this difficult and need additional help from drug therapy to maintain results from these efforts.

Most currently marketed products have been unsuccessful as treatments for obesity because of a lack of efficacy or unacceptable side-effect profiles. The most successful drug so far was the indirectly acting 5-hydro ytryptamine (5-HT) agonist d-fenfluramine (Redux™) but reports of cardiac valve defects in up to one third of patients led to its withdrawal by the FDA in 1998.

In addition, two drugs have been launched in the USA and Europe: orlistat (Xenical™), a drug that prevents absorption of fat by the inhibition of pancreatic lipase, and sibutramine (Reductil™), a 5- HT/noradrenaline re-uptake inhibitor. However, side effects associated with these products may limit their long-term utility. Treatment with Xenical is reported to induce gastrointestinal distress in some patients, while sibutramine has been associated with raised blood pressure in some patients.

Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in physical and in psychiatric disorders. 5-HT has been implicated in the regulation of feeding behavior. 5-HT is believed to work by inducing a feeling of satiety, such that a subject with enhanced 5-HT stops eating earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT on the 5-HT₂c receptor plays an important role in the control of eating and in the anti-obesity effect of d-fenfluramine. As the 5-HT_2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e.

paraventricular hypothalamic nucleus and dorsomedial hypothalamic nucleus, and predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral tissues, a selective 5-HT₂c receptor agonist can be a more effective and safe anti-obesity agent. Also, 5-HT_2C knockout mice are overweight with cognitive impairment and susceptibility to seizure. It is believed that the 5-HT₂c receptor may play a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, agonists can have anti-panic properties, and properties useful for the treatment of sexual dysfunction.

In sum, the 5-HT_2C receptor is a receptor target for the treatment of obesity and psychiatric disorders, and it can be seen that there is a need for selective 5-HT₂c agonists which safely decrease food intake and body weight.

The 5-HT₂c receptor is one of 14 distinct serotonin receptor subtypes. Two receptors that are closely related to the 5-HT_2C receptor are the 5-HT_2A and 5-HT_2B receptors, which share considerable sequence homology. It is believed that activation of central 5-HT_2A receptors is a cause for a number of adverse central nervous system effects of nonselective serotonergic drugs including changes in perception and hallucination. Activation of 5-HT_2B receptors located in the cardiovascular system is hypothesized to result in the heart valve disease and pulmonary hypertension associated with the use of fenfluramine and a number of other drugs that act via serotonergic mechanisms.

Lorcaserin (disclosed in PCT patent publication WO2003/086303) is an agonist of the 5-HT_2C receptor and shows effectiveness at reducing obesity in animal models and humans. In December 2009, Arena Pharmaceuticals submitted a New Drug Application, or NDA, for lorcaserin to the US Food and Drug Administration (FDA). The NDA submission is based on an extensive data package from lorcaserin' s clinical development program that includes 18 clinical trials totaling 8,576 patients. The pivotal phase 3 clinical trial program evaluated nearly 7,200 patients treated for up to two years, and showed that lorcaserin consistently produced significant weight loss with excellent tolerability. About two-thirds of patients achieved at least 5% weight loss and over one-third achieved at least 10% weight loss. On average, patients lost 17 to 18 pounds or about 8% of their weight. Secondary endpoints, including body composition, lipids, cardiovascular risk factors and glycemic parameters improved compared to placebo. In addition, heart rate and blood pressure went down. Lorcaserin did not increase the risk of cardiac valvulopathy. Lorcaserin improved quality of life, and there was no signal for depression or suicidal ideation. The only adverse event that exceeded the placebo rate by 5% was generally mild or moderate, transient headache. Based on a normal BMI of 25, patients in the first phase 3 trial lost about one-third of their excess body weight. The average weight loss was 35 pounds or 16% of body weight for the top quartile of patients in the second phase 3 trial.

As a part of the phase 3 clinical trial program, lorcaserin was evaluated in a randomized, placebo-controlled, multi-site, double-blind trial of 604 adults with poorly controlled type 2 diabetes mellitus treated with oral hyperglycemic agents ("BLOOM-DM"). Analysis of the overall study results showed significant weight loss with lorcaserin, measured as proportion of patients achieving > 5% or > 10% weight loss at 1 year, or as mean weight change (Diabetes 60, Suppl 1, 2011). Lorcaserin significantly improved glycemic control in the overall patient population. Accordingly, in addition to being useful for weight management, lorcaserin is also useful for the treatment of type 2 diabetes.

On June 27, 2012 the FDA provisionally approved lorcaserin (BELVIQ®), contingent upon a final scheduling decision by the Drug Enforcement Administration (DEA), as an adjunct to a reduced- calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m² or greater (obese), or 27 kg/m² or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes). On December 19, 2012 the DEA recommended that lorcaserin should be classified as a schedule 4 drug, having a low risk for abuse. The Office of the Federal Register filed for public inspection DEA's final rule placing BELVIQ into schedule 4 of the Controlled Substances Act. The scheduling designation was effective and BELVIQ was launched in the United States on June 7, 2013, 30 days after publication of the DEA's final rule in the Federal Register.

Tobacco use is the leading cause of preventable illness and early death across the globe.

According to the World Health Organization Fact Sheet (July 2013), 50% of all tobacco users die from a tobacco-related illness— this amounts to approximately six million people each year. It is estimated that greater than five million deaths per year result from direct tobacco use, with the remaining deaths resulting from exposure to second-hand smoke ( World Health Organization website. Fact Sheet No 339: Tobacco, www.who.int/mediacentre/factsheets/fs339/en/index.html. Updated July 2013. Accessed September 10, 2013). According to the Centers for Disease Control and Prevention (CDC), approximately 43.8 million adults in the United States (U.S.) are cigarette smokers. In the U.S., tobacco use is responsible for one in five deaths each year (World Health Organization website. Fact Sheet No 339: Tobacco, www.who.int/mediacentre/factsheets/fs339/en/index.html. Updated July 2013. Accessed September 10, 2013). Tobacco use is directly related to cardiovascular disease, lung and other cancers, and chronic lower respiratory diseases (chronic bronchitis, emphysema, asthma, and other chronic lower respiratory diseases) (Health Effects of Cigarette Smoking. Centers for Disease Prevention website.

www. cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/ Accessed September 10, 2013). These have held position as the top three leading causes of death in the U.S. since 2008, when chronic lower respiratory disease replaced cerebrovascular disease, which is also directly associated with tobacco use (Molgaard CA, Bartok A, Peddecord KM, Rothrock J. The association between cerebrovascular disease and smoking: a case-control study. N euro epidemiology. 1986;5(2):88-94).

A study which surveyed the smoking behavior of 2138 US smokers over 8 years beginning in 2002 found that approximately one-third of subjects reported making a quit attempt over the previous year, approximately 85% of the original cohort made at least one quit attempt over the survey period, and the average quit rate was 3.8% for the retained cohort. Therefore the vast majority of smokers make quit attempts, but continued abstinence remains difficult to achieve (Cummings KM, Cornelius ME, Carpenter MJ, et al. Abstract: How Many Smokers Have Tried to Quit? Society for Research on Nicotine and Tobacco. Poster Session 2. March 2013. POS2-65).

Existing smoking cessation treatments include CHANTIX (varenicline) and ZYBAN

(bupropion SR). However, the prescribing information for both CHANTIX and ZYBAN include black box warnings. The CHANTIX prescribing information carries a warning for serious neuropsychiatric events, to include symptoms of agitation, hostility, depressed mood changes, behavior or thinking that are not typical for the patient, and suicidal ideation or suicidal behavior (CHANTIX (varenicline) (package insert), New York, NY: Pfizer Labs, Division of Pfizer, Inc.; 2012). In addition, the warning notes that a meta-analysis found cardiovascular events were infrequent, but some were reported more frequently in individuals treated with CHANTIX; the difference was not statistically significant

(CHANTIX (varenicline) (package insert), New York, NY: Pfizer Labs, Division of Pfizer, Inc.; 2012). The ZYBAN prescribing information includes a similar black box warning for serious neuropsychiatric events during treatment as well as after discontinuation of treatment (ZYBAN (bupropion

hydrochloride) (package insert), Research Triangle Park, NC: Glaxo SmithKline; 2012). Additional warnings include monitoring of individuals using antidepressants as there is an increased risk of suicidal thinking and behavior in children, adolescents and young adults, and other psychiatric disorders (ZYBAN (bupropion hydrochloride) (package insert), Research Triangle Park, NC: Glaxo SmithKline; 2012).

Further, weight gain is a well-recognized side effect of quitting smoking. Smoking cessation leads to weight gain in about 80% of smokers. The average weight gain in the first year after quitting is 4-5 kg, most of which is gained during the first 3 months. This amount of weight is typically viewed as a modest inconvenience compared with the health benefits of smoking cessation, but 10-20% of quitters gain more than 10 kg. Furthermore, a third of all subjects stated that they were unable to lose the excess weight after resuming smoking, lending support to the hypothesis that multiple quit attempts lead to cumulative weight gain (Veldheer S, Yingst J, Foulds G, Hrabovsky S, Berg A, Sciamanna C, Foulds J. Once bitten, twice shy: concern about gaining weight after smoking cessation and its association with seeking treatment. Int J Clin Pract. (2014) 68:388-395).

Given these statistics, it is perhaps not surprising that 50% of female smokers and 25% of male smokers cite fear of post-cessation weight gain (PCWG) as a major barrier to quitting, and

approximately the same proportion cite weight gain as a cause of relapse in a previous quit attempt

(Meyers AW, Klesges RC, Winders SE, Ward KD, Peterson BA, Eck LH. Are weight concerns predictive of smoking cessation? A prospective analysis. J Consult Clin Psychol. (1997) 65: 448-452; Clark MM, Decker PA, Offord KP, Patten CA, Vickers KS, Croghan IT, Hays JT, Hurt RD, Dale LC. Weight concerns among male smokers. Addict Behav. (2004) 29:1637- 1641; Clark MM, Hurt RD, Croghan IT, Patten CA, Novotny P, Sloan J A, Dakhil SR, Croghan GA, Wos EJ, Rowland KM, Bernath A, Morton RF, Thomas SP, Tschetter LK, Garneau S, Stella PJ, Ebbert LP, Wender DB, Loprinzi CL. The prevalence of weight concerns in a smoking abstinence clinical trial. Addict Behav. (2006) 31:1144- 1152.; Pomerleau CS, Kurth CL. Willingness of female smokers to tolerate postcessation weight gain. J Subst Abuse. (1996) 8:371-378; Pomerleau CS, Zucker AN, Stewart AJ. Characterizing concerns about post cessation weight gain: results from a national survey of women smokers. Nicotine Tob Res. (2001 ) 3:51-60). Women, in particular, are reluctant to gain weight while quitting; about 40% state they would resume smoking if they gained any weight at all (Veldheer S, Yingst J, Foulds G, Hrabovsky S, Berg A, Sciamanna C, Foulds J. Once bitten, twice shy: concern about gaining weight after smoking cessation and its association with seeking treatment. Int J Clin Pract. (2014) 68:388-395; Pomerleau CS, Kurth CL. Willingness of female smokers to tolerate postcessation weight gain. J Sub st Abuse (1996) 8:371- 378; Pomerleau CS, Zucker AN, Stewart AJ. Characterizing concerns about post-cessation weight gain: results from a national survey of women smokers. Nicotine Tob Res. (2001) 3:51-60; T0nnesen P, Paoletti P, Gustavsson G, Russell MA, Saracci R, Gulsvik A, Rijcken B, Sawe U. Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society. Eur Respir J. ( 1999 ) 13:238-246).

Light and moderate smokers are generally considered to be more motivated to quit than heavy smokers, leaving an increasingly high proportion of 'hard-core' smokers who are less likely to stop smoking (Hughes JR. The hardening hypothesis: is the ability to quit decreasing due to increasing nicotine dependence? A review and commentary. Drug Alcohol Depend. (2011) 117:111-117). One of the factors commonly associated with weight-gain concern (WGC) is high nicotine dependence; thus, the prospect of quitting may be even more difficult for smokers who are both highly nicotine-dependent and weight concerned. In addition, somewhat paradoxically, heavy smokers tend to have higher body weights and a higher likelihood of obesity than lighter smokers, suggesting a more complex relationship between body weight and smoking (Chiolero A, Jacot-Sadowski I, Faeh D, Paccaud F, Cornuz J. Association of cigarettes smoked daily with obesity in a general adult population. Obesity ( Silver Spring) (2007) 15:1311-1318; John U, Hanke M, RumpfHJ, Thyrian JR. Smoking status, cigarettes per day, and their relationship to overweight and obesity among former and current smokers in a national adult general population sample. Int J Ob es (Lond). (2005) 29:1289-1294). Several studies have found that overweight and obese smokers exhibit higher levels of smoking-related weight-gain concern than normal weight smokers (Aubin H-J, Berlin I, Smadja E, West R. Factors associated with higher body mass index, weight concern, and weight gain in a multinational cohort study of smokers intending to quit. Int. J. Environ. Res. Public Health. (2009). 6:943-957; Levine MD, Bush T, Magnusson B, Cheng, Y, Chen X. Smoking-related weight concerns and obesity: differences among normal weight, overweight, and obese smokers using a telephone tobacco quitline. Nicotine Tob Res. (2013) 15:1136- 1140). Given the convergence of high nicotine dependence and high weight-gain concern in obese smokers, smoking cessation interventions that address post-cessation weight gain could be especially beneficial for this subpopulation.

Despite the existence of several therapies for smoking cessation, long-term success rates are low and major barriers to quitting remain. There is a significant unmet need for safe and effective therapies that address these barriers. There also remains a need for alternative compounds for the treatment of diseases and disorders related to the 5-HT₂c receptor. The compounds described herein satisfy this need and provide related advantages as well. The present disclosure satisfies this need and provides related advantages as well.

SUMMARY Provided are compounds selected from compounds of Formula I, and salts, hydrates, and solvates thereof:

Formula I

wherein:

X is selected from O and S; and

R¹ is selected from: C₁-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylthio, Ci-C₆ alkylsulfonyl, aryloxy, halogen, and Ci-C₆ haloalkyl.

Also provided herein are compounds selected from compounds of Formula XI, and salts, hydrates, and solvates thereof:

Formula XI

wherein:

X¹ is selected from O and S;

R¹¹ is selected from: C₁-C6 alkyl, optionally substituted with one or more substituents independently selected from: C₁-C6 alkoxy, C₁-C6 alkoxycarbonyl, and halogen;

R¹² and R^12b are each independently H, C3-C7 cycloalkyl or C₁-C6 alkyl, wherein the C3-C7 cycloalkyl and C₁-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C₁-C6 alkyl and C₁-C6 alkoxy;

R¹³ and R^13b are each independently H, C3-C7 cycloalkyl or C₁-C6 alkyl, wherein the C3-C7 cycloalkyl and C₁-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C₁-C6 alkyl and C₁-C6 alkoxy;

or R¹³ and R^13b taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring;

n is 0, 1, or 2;

wherein if n is 1, R¹⁴ is Ci-Ce alkyl,

and wherein if n is 2, each R¹⁴ is C₁-C6 alkyl bonded to the same carbon, or two R¹⁴ taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring; provided that if R^12a, R^12b, R^13a and R^13b are each H then n is 1 or 2.

Also provided are compounds selected from compounds of Formula XXI, and salts, hydrates, and solvates thereof:

Formula XXI

wherein:

each of R²⁵ and R²⁶ is independently hydrogen or Ci-C6 alkyl;

R²⁷ is hydrogen, Ci-C6 alkyl or C₃-C₇ cycloalkyl;

R²⁸ is hydrogen or Ci-C6 alkyl;

each of R²² and R²³ is independently hydrogen or Ci-C6 alkyl optionally substituted with one or more halogens;

or R²² and R²³ taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy;

R²⁴ is hydrogen, halogen, hydroxy, C₃-C₇ cycloalkyl, Ci-C6 alkoxy or Ci-C6 alkyl optionally substituted with Ci-C6 alkoxy; and

R²¹ is selected from the group consisting of:

hydrogen;

halogen;

C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C6 alkoxy, amino, heteroarylamino, arylamino, C₁-C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with Ci-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-C6 alkoxy, or C₃-C₇ cycloalkyl optionally substituted with Ci-C6 alkoxy;

aryl;

heteroaryl;

C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy;

amino;

C₁-C6 alkylamino optionally substituted with C₁-C6 alkoxy or with hydroxy; C₁-C6 dialkylamino optionally substituted with C₁-C6 alkoxy or with hydroxy; arylamino;

C₁-C6 alkoxy optionally substituted with one or more halogens;

hydroxy; -NHCO-Ci-Ce alkyl;

-NHCO(0)Ci-C₆ alkyl;

-OCO(NH)Ci-C₆ alkyl;

and

CN;

provided that if R²⁴ is hydrogen or halogen, at least one of R²¹, R²², R²³, R²⁵, R²⁶ R²⁷ and R²⁸ is other than hydrogen.

Also provided are compositions comprising a compound provided herein and a

pharmaceutically acceptable carrier.

Also provided are processes for preparing compositions, comprising admixing a compound provided herein and a pharmaceutically acceptable carrier.

Also provided are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.

Also provided are processes for preparing pharmaceutical compositions, comprising admixing a compound provided herein a pharmaceutically acceptable carrier.

Also provided are methods for decreasing food intake in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for inducing satiety in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the prevention of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for weight management in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are use of a compound provided herein for the manufacture of a medicament for decreasing food intake.

Also provided are use of a compound provided herein for the manufacture of a medicament for inducing satiety.

Also provided are use of a compound provided herein for the manufacture of a medicament for the treatment of obesity.

Also provided are use of a compound provided herein for the manufacture of a medicament for the prevention of obesity.

Also provided are use of a compound provided herein for the manufacture of a medicament for weight management. Also provided are compounds for use in a method for treatment of the human or animal body by therapy.

Also provided are compounds for use in a method for decreasing food intake.

Also provided are compounds for use in a method for inducing satiety.

Also provided are compounds for use in a method for the treatment of obesity.

Also provided are compounds for use in a method for the prevention of obesity.

Also provided are compounds for use in weight management.

Prior to the present discovery, it was unclear whether a selective serotonin 2C receptor agonist would be able to drive clinically meaningful smoking cessation in humans— much less for particular individuals or in specific dosing regimens.

Provided is a method for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist.

Also provided is a method for aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist.

Also provided is a method for aiding in smoking cessation and preventing associated weight gain in an individual attempting to cease smoking and prevent weight gain comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist.

Also provided is a method for controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist.

Also provided is a method of treatment for nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist.

Also provided is a method of reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist.

Also provided is a method for reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist.

Also provided is a method of reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco, aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product, aiding in smoking cessation and preventing associated weight gain, controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use, comprising:

selecting an individual with an initial BMI > 27 kg/m²; and

prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist for at least one year.

administering a selective 5-HT_2C receptor agonist to an individual;

monitoring the individual for BMI during said administration; and

discontinuing said administration if the BMI of the individual becomes < 18.5 kg/m² during said administration.

administering a selective 5-HT₂c receptor agonist to an individual with an initial BMI < 25 kg/m²;

monitoring the individual for body weight during said administration; and

discontinuing said administration if the body weight of the individual decreases by more than about 1 % during said administration.

administering a selective 5-HT₂c receptor agonist to an individual;

monitoring the individual for body weight during said administration; and

discontinuing said administration if the body weight of the individual decreases by more than about 1 kg during said administration.

Also provided is a composition comprising a selective 5-HT₂c receptor agonist and at least one supplemental agent.

Also provided is a selective 5-HT₂c receptor agonist for use in combination with a supplemental agent.

Also provided is a supplemental agent chosen from nicotine replacement therapies, for use in combination with a selective 5-HT₂c receptor agonist.

BRIEF DESCRIPTION OF FIGURES

Figure 1 shows a schematic of the study design used in the Phase 2 clinical trial described in Example 4.

Figures 2 and 3 show the baseline characteristics of subjects in the Phase 2 clinical trial.

Figure 4 shows the disposition of subjects from the Phase 2 clinical trial.

Figure 5 shows CO-confirmed 4-week CARs for Weeks 9 to 12 in the MITT population from the Phase 2 clinical trial, "n" in Figures 5-8 is the number of subjects that reported not smoking (not even a puff or other nicotine use) and exhibited an end-expiratory CO level of < 10 ppm.

Figure 6 shows CO-confirmed 4-week CARs for Weeks 5 to 8 in the MITT population.

Figure 7 shows CO-confirmed 4-week CARs for Weeks 5 to 12 in the MITT population.

Figure 8 shows CO-confirmed 4-week CARs for Weeks 3 to 12 in the MITT population.

Figure 9 shows the 7-day point prevalence smoking abstinence at Week 12 in the MITT population, "n" in Figure 9 is the number of subjects who were continuously abstinent for the 7-day period preceding a clinical visit and exhibited an end-expiratory CO level of < 10 ppm.

Figure 10 shows the change from baseline in number of cigarettes smoked at Week 12 in the MITT population.

Figure 11 shows the change from baseline in body weight (in kg) at Week 12 in the MITT population. Figure 12 shows the change from baseline in body weight (in kg) at Week 12 for responders in the MITT population. "Responders" in Figure 12 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of < 10 ppm. Figure 13 shows the change from baseline in body weight (in kg) at Week 12 by responder status in the MITT population. "Responders" in Figure 13 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of < 10 ppm.

Figure 14 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI in the MITT population.

Figure 15 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI in the MITT population.

Figure 16 shows the change from baseline in body weight (in kg) at Week 12 by baseline BMI and responder status in the MITT population. "Responders" in Figure 16 are subjects who had 4 weeks of continuous abstinence from Week 9 to Week 12 and exhibited an end-expiratory CO level of < 10 ppm. Figure 17 shows a summary of treatment-emergent adverse events in the Phase 2 clinical trial.

Figure 18 shows potency and efficacy of lorcaserin in human, rat, and monkey 5-HT_2A, 5-HT_2B, and 5- HT₂c receptors.

Figure 19 shows differences in exposure and 5-HT₂ receptor selectivity in humans and rats.

Figure 20 shows a general synthetic scheme for preparing compounds provided herein.

Figure 21a shows an exemplary synthetic scheme for preparing intermediates useful for preparing compounds provided herein.

Figure 21b shows an exemplary synthetic scheme for preparing compounds provided herein.

Figure 21c shows another exemplary synthetic scheme for preparing compounds provided herein. Figure 21d shows another exemplary synthetic scheme for preparing compounds provided herein.

Figure 22 shows another exemplary synthetic scheme for preparing compounds provided herein.

Figure 23 shows another exemplary synthetic scheme for preparing compounds provided herein.

Figure 24 shows an example of food intake 1 hour after dosing the 2^nd eluting enantiomer in example

1B.5 at 2.5, 5, 7.5, and 10 mg kg compared to the vehicle.

Figure 25 shows an example of food intake 1 hour after dosing the 2^nd eluting enantiomer in example

1B.9 at 10 mg/kg compared to the vehicle.

Figure 26 shows an example of a synthetic scheme for preparing compounds provided herein.

Figure 27 shows plots of (a) food intake vs. dose, and (b) % inhibition of food intake vs. dose, in rats for compound 215.

Figure 28 shows plots of (a) food intake vs. dose, and (b) % inhibition of food intake vs. dose, in rats for compound 250.

DETAILED DESCRIPTION

As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. As used herein, the term "agonist" refers to a moiety that interacts with and activates a receptor, such as the 5-HT₂c serotonin receptor, and initiates a physiological or pharmacological response characteristic of that receptor.

The term "composition" refers to a compound, including but not limited to, salts, hydrates, and solvates of a compound provided herein, in combination with at least one additional component.

The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, such as a compound as described herein; including but not limited to, salts, hydrates, and solvates of compounds provided herein, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

The term "individual" refers to a human. An individual can be an adult or prepubertal (a child) and can be of any gender. The individual can be a patient or other individual seeking treatment. The methods disclosed herein can also apply to non-human mammals such as livestock or pets.

As used herein, a "plurality of individuals" means more than one individual.

As used herein, "administering" means to provide a compound or other therapy, remedy or treatment. For example, a health care practitioner can directly provide a compound to an individual in the form of a sample, or can indirectly provide a compound to an individual by providing an oral or written prescription for the compound. Also, for example, an individual can obtain a compound by themselves without the involvement of a health care practitioner. Administration of the compound may or may not involve the individual actually internalizing the compound. In the case where an individual internalizes the compound, the body is transformed by the compound in some way.

As used herein, "prescribing" means to order, authorize or recommend the use of a drug or other therapy, remedy or treatment. In some embodiments, a health care practitioner can orally advise, recommend or authorize the use of a compound, dosage regimen or other treatment to an individual. In this case the health care practitioner may or may not provide a prescription for the compound, dosage regimen or treatment. Further, the health care practitioner may or may not provide the recommended compound or treatment. For example, the health care practitioner can advise the individual where to obtain the compound without providing the compound. In some embodiments, a health care practitioner can provide a prescription for the compound, dosage regimen or treatment to the individual. For example, a health care practitioner can give a written or oral prescription to an individual. A prescription can be written on paper or on electronic media such as a computer file, for example, on a hand-held computer device. For example, a health care practitioner can transform a piece of paper or electronic media with a prescription for a compound, dosage regimen or treatment. In addition, a prescription can be called in (oral) or faxed in (written) to a pharmacy or a dispensary. In some embodiments, a sample of the compound or treatment can be given to the individual. As used herein, giving a sample of a compound constitutes an implicit prescription for the compound. Different health care systems around the world use different methods for prescribing and administering compounds or treatments and these methods are encompassed by the disclosure.

A prescription can include, for example, an individual's name and/or identifying information such as date of birth. In addition, for example, a prescription can include, the medication name, medication strength, dose, frequency of administration, route of administration, number or amount to be dispensed, number of refills, physician name, and/or physician signature. Further, for example, a prescription can include a DEA number or state number.

A healthcare practitioner can include, for example, a physician, nurse, nurse practitioner, physician assistant, clinician, or other related healthcare professional who can prescribe or administer compounds (drugs) for weight management, decreasing food intake, inducing satiety, and treating or preventing obesity. In addition, a healthcare practitioner can include anyone who can recommend, prescribe, administer or prevent an individual from receiving a compound or drug including, for example, an insurance provider.

The term "prevent," "preventing," or "prevention", such as prevention of obesity, refers to the prevention of the occurrence or onset of one or more symptoms associated with a particular disorder and does not necessarily mean the complete prevention of a disorder. For example, weight gain may be prevented even if the individual gains some amount of weight. For example, the terms "prevent," "preventing," and "prevention" refer to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of the at least one symptom can also be considered prevention or prophylaxis.

For example,_the term "prevent," "preventing" or "prevention" may refer to prevention of weight gain associated with smoking cessation.

In some embodiments the salts, hydrates, and solvates described herein are pharmaceutically acceptable salts, hydrates, and solvates. It is understood that when the phrase "pharmaceutically acceptable salts, hydrates, and solvates" or the phrase "pharmaceutically acceptable salt, hydrate, or solvate" is used when referring to compounds described herein, it embraces pharmaceutically acceptable hydrates and/or solvates of the compounds, pharmaceutically acceptable salts of the compounds, as well as pharmaceutically acceptable hydrates and/or solvates of pharmaceutically acceptable salts of the compounds. It is also understood that when the phrase "pharmaceutically acceptable hydrates and solvates" or the phrase "pharmaceutically acceptable hydrate or solvate" is used when referring to compounds described herein that are salts, it embraces pharmaceutically acceptable hydrates and/or solvates of such salts. It is also understood by a person of ordinary skill in the art that hydrates are a subgenus of solvates. The term "prodrug" refers to an agent which must undergo chemical or enzymatic

transformation to the active or parent drug after administration, so that the metabolic product or parent drug can subsequently exhibit the desired pharmacological response.

The term "treat," "treating," or "treatment" includes the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, "treating" can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically. For example, the term "treating" in reference to a disorder can mean a reduction in severity of one or more symptoms associated with a particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder. For example, a method for treatment of obesity can result in weight loss; however, the weight loss does not need to be enough such that the individual is no longer obese. It has been shown that even modest decreases in weight or related parameters such as BMI, waist circumference and percent body fat, can result in improvement of health, for example, lower blood pressure, improved blood lipid profiles, or a reduction in sleep apnea. As another example, a method for treatment of an addiction can result in a reduction in the number, frequency, or severity of cravings, seeking behaviors, or relapses, or it can result in abstention.

As used herein the term "treat," "treating" or "treatment" refers to the administration of therapy to an individual who already manifests, or who has previously manifested, at least one symptom of a disease, disorder, condition, dependence, or behavior, such as at least one symptom of a disease or condition. For example, "treating" can include any of the following with respect to a disease, disorder, condition, dependence, or behavior: alleviating, abating, ameliorating inhibiting (e.g., arresting the development), relieving, or causing regression. "Treating" can also include treating the symptoms, preventing additional symptoms, preventing the underlying physiological causes of the symptoms, or stopping the symptoms (either prophylactically and/or therapeutically) of a disease, disorder, condition, dependence, or behavior, such as the symptoms of a disease or condition.

The term "weight management" refers to controlling body weight and in the context of the present disclosure is directed toward weight loss and the maintenance of weight loss (also called weight maintenance herein). In addition to controlling body weight, weight management includes controlling parameters related to body weight, for example, BMI, percent body fat and waist circumference. For example, weight management for an individual who is overweight or obese can mean losing weight with the goal of keeping weight in a healthier range. Also, for example, weight management for an individual who is overweight or obese can include losing body fat or circumference around the waist with or without the loss of body weight. Maintenance of weight loss (weight maintenance) includes preventing, reducing or controlling weight gain after weight loss. It is well known that weight gain often occurs after weight loss. Weight loss can occur, for example, from dieting, exercising, illness, drug treatment, surgery or any combination of these methods, but often an individual that has lost weight will regain some or all of the lost weight. Therefore, weight maintenance in an individual who has lost weight can include preventing weight gain after weight loss, reducing the amount of weight gained after weight loss, controlling weight gain after weight loss or slowing the rate of weight gain after weight loss. As used herein, "weight management in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from weight management treatment. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods disclosed herein.

"Weight management" also includes preventing weight gain, controlling weight gain, reducing weight gain, maintaining weight, or inducing weight loss. Weight management also refers to controlling weight (also called weight control) and/or controlling parameters related to weight, for example, BMI, percent body fat and/or waist circumference. In addition, weight management also includes preventing an increase in BMI, reducing an increase in BMI, maintaining BMI, or reducing BMI; preventing an increase in percent body fat, reducing an increase in percent body fat, maintaining percent body fat, or reducing percent body fat; and preventing an increase in waist circumference, reducing an increase in waist circumference, maintaining waist circumference, or reducing waist circumference

The term "decreasing food intake in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from decreasing food intake. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner' s expertise, but that includes the knowledge that the individual has a condition, for example, obesity, that is treatable by the methods disclosed herein. In some embodiments, an individual in need of decreasing food intake is an individual who is overweight. In some embodiments, an individual in need of decreasing food intake is an individual who is obese.

The term "satiety" refers to the quality or state of being fed or gratified to or beyond capacity. Satiety is a feeling that an individual has and so it is often determined by asking the individual, orally or in writing, if they feel full, sated, or satisfied at timed intervals during a meal. For example, an individual who feels sated may report feeling full, feeling a decreased or absent hunger, feeling a decreased or absent desire to eat, or feeling a lack of drive to eat. While fullness is a physical sensation, satiety is a mental feeling. An individual who feels full, sated or satisfied is more likely to stop eating and therefore inducing satiety can result in a decrease in food intake in an individual. As used herein, "inducing satiety in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from inducing satiety. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition, for example, obesity, that is treatable by the methods of the disclosure.

The term "treatment of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from treatment of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner' s expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods of the disclosure. To determine whether an individual is obese one can determine a body weight, a body mass index (BMI), a waist circumference or a body fat percentage of the individual to determine if the individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.

The term prevention of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from prevention of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner' s expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods disclosed herein. In some embodiments, an individual in need of prevention of obesity is an individual who is overweight (also called pre-obese). In some embodiments, an individual in need of prevention of obesity is an individual who has a family history of obesity. To determine whether an individual is overweight one can determine a body weight, a body mass index (BMI), a waist circumference or a body fat percentage of the individual to determine if the individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.

As used herein, an "adverse event" or "toxic event" is any untoward medical occurrence that may present itself during treatment. Adverse events associated with treatment may include, for example, headache, nausea, blurred vision, paresthesias, constipation, fatigue, dry mouth, dizziness, abnormal dreams, insomnia, nasopharyngitis, toothache, sinusitis, back pain, somnolence, viral gastroenteritis, seasonal allergy, or pain in an extremity. Additional possible adverse effects include, for example, gastrointestinal disorders (such as constipation, abdominal distension, and diarrhea), asthenia, chest pain, fatigue, drug hypersensitivity, fibromyalgia, temporomandibular joint syndrome, headache, dizziness, migraine, anxiety, depressed mood, irritability, suicidal ideation, bipolar disorder, depression, drug abuse, and dyspnea. In the methods disclosed herein, the term "adverse event" can be replaced by other more general terms such as "toxicity". The term "reducing the risk" of an adverse event means reducing the probability that an adverse event or toxic event could occur.

As used herein, the term "agonist" refers to a moiety that interacts with and activates a receptor, such as the 5-HT₂c serotonin receptor, and initiates a physiological or pharmacological response characteristic of that receptor.

The term "immediate-release dosage form" refers to a formulation which rapidly disintegrates upon oral administration to a human or other animal releasing an active pharmaceutical ingredient (API) from the formulation. In some embodiments, the T80 of the immediate-release dosage form is less than 3 hours. In some embodiments, the T80 of the immediate-release dosage form is less than 1 hour. In some embodiments, the T80 of the immediate-release dosage form is less than 30 minutes. In some embodiments, the T80 of the immediate-release dosage form is less than 10 minutes.

The term "T80 " refers to the time needed to achieve 80% cumulative release of an API from a particular formulation comprising the API.

The term "modified-release dosage form" refers to any formulation that, upon oral administration to a human or other animal, releases an API after a given time (i.e., delayed release) or for a prolonged period of time (extended release), e.g., at a slower rate over an extended period of time when compared to an immediate-release dosage-form of the API (e.g., sustained release).

As used herein, "nicotine replacement therapy" (commonly abbreviated to NRT) refers to the remedial administration of nicotine to the body by means other than a tobacco product. By way of example, nicotine replacement therapy may include transdermal nicotine delivery systems, including patches and other systems that are described in the art, for example, in U.S. Pat. Nos. 4,597,961, 5,004,610, 4,946,853, and 4,920,989. Inhaled nicotine (e.g., delivery of the nicotine through pulmonary routes) is also known. Transmucosal administration (e.g., delivery of nicotine to the systemic circulation through oral drug dosage forms) is also known. Oral drug dosage forms (e.g., lozenge, capsule, gum, tablet, suppository, ointment, gel, pessary, membrane, and powder) are typically held in contact with the mucosal membrane and disintegrate and/or dissolve rapidly to allow immediate systemic absorption. It will be understood by those skilled in the art that a plurality of different treatments and means of administration can be used to treat a single individual. For example, an individual can be simultaneously treated with nicotine by transdermal administration and nicotine which is administered to the mucosa. In some embodiments, the nicotine replacement therapy is chosen from nicotine gum (e.g., NICORETTE), nicotine transdermal systems such as nicotine patches (e.g., HABITROL and NICODERM), nicotine lozenges (e.g., COMMIT), nicotine microtabs (e.g., NICORETTE Microtabs), nicotine sprays or inhalers (e.g., NICOTROL), and other nicotine replacement therapies known in the art. In some embodiments, nicotine replacement therapy includes electronic cigarettes, personal vaporizers, and electronic nicotine delivery systems.

As used herein, "combination" as used in reference to drug combinations and/or combinations of a selective 5-HT₂c agonist with at least one supplemental agent refers to (1) a product comprised of two or more components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (2) two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; (3) a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or (4) any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

Combinations include without limitation a fixed-dose combination product (FDC) in which two or more separate drug components are combined in a single dosage form; a co-packaged product comprising two or more separate drug products in their final dosage forms, packaged together with appropriate labeling to support the combination use; and an adjunctive therapy in which a patient is maintained on a second drug product that is used together with (i.e., in adjunct to) the primary treatment, although the relative doses are not fixed, and the drugs or biologies are not necessarily given at the same time. Adjunctive therapy products may be co-packaged, and may or may not be labeled for concomitant use.

As used herein, "responder" refers to an individual who experiences continuous abstinence from tobacco use during a specified period of administration of a selective 5-HT₂c receptor agonist. In some embodiments, "responder" refers to an individual who reports no smoking or other nicotine use from Week 9 to Week 12 of administration of a selective 5-HT₂c receptor agonist and exhibits an end- expiratory exhaled carbon monoxide-confirmed measurement of < 10 ppm.

As used herein, "tobacco product" refers to a product that incorporates tobacco, i.e., the agricultural product of the leaves of plants in the genus Nicotiana. Tobacco products can generally be divided into two types: smoked tobacco including without limitation pipe tobacco, cigarettes (including electronic cigarettes) and cigars, as well as Mu'assel, Dokha, shisha tobacco, hookah tobacco, or simply shisha; and smokeless tobacco including without limitation chewing tobacco, dipping tobacco, also known as dip, moist snuff (or snuff), American moist snuff, snus, Iqmik, Naswar, Gutka,

Toombak, shammah, tobacco water, spit tobacco, creamy snuff or tobacco paste, dissolvable tobacco, and tobacco gum.

As used herein, "Fagerstrom test" refers to a standard test for nicotine dependence which is a test for assessing the intensity of nicotine addiction. See Heatherton, T. F., Kozlowski, L. T., Frecker, R. C, Fagerstrom, K. O. The Fagerstrom test for Nicotine Dependence: A revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991 ; 86: 1119-27. The test consists of a brief, self-report survey that measures nicotine dependence on a scale of 0-10, with 10 being the highest level of dependence. A score of 0-2 corresponds to very low dependence. A score of 3-4 corresponds to low dependence. A score of 5 corresponds to moderate dependence. A score of 6-7 corresponds to high dependence. A score of 8-10 corresponds to very high dependence.

Other methods may be utilized to assess the craving for nicotine, including but not limited to, the nicotine craving test specified by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R).

As used herein, "Mood and Physical Symptoms Scale" (MPSS) refers to a scale used to assess cigarette withdrawal symptoms (West R, Hajek P: Evaluation of the mood and physical symptoms scale (MPSS) to assess cigarette withdrawal. Psychopharmacology 2004, 177(1 -2): 195-199). The core elements of MPSS involve a 5-point rating of depressed mood, irritability, restlessness, difficulty concentrating and hunger and a 6-point rating of strength of urges to smoke and time spent with these urges.

As used herein, lorcaserin refers to (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-l/f-3- benzazepine. Similarly, lorcaserin hydrochloride refers to the hydrochloric acid salt of (R)-8-chloro-l - methyl-2,3,4,5-tetrahydro-l/f-3-benzazepine (see Statement on Nonproprietary Name Adopted by the USAN Council for Lorcaserin Hydrochloride).

The term "phentermine" refers to l, l-dimethyl-2-phenyl-ethylamine, including phentermine derivatives and pharmaceutically acceptable salts thereof, such as, but not limited to, chlorphentermine (2-(4-chloro-phenyl)-l,l-dimethyl-ethylamine) and the like. In one embodiment, phentermine is in the HC1 salt form of 1 , 1 -dimethyl-2-phenyl-ethylamine.

The term "amphetamine" refers to l-phenylpropan-2-amine and salts, hydrates, and solvates thereof.

The term "a substituted amphetamine" refers to a class of chemicals based on amphetamine with additional substitutions. Examples of substituted amphetamines include, but are not limited to: methamphetamine (iV-methyl-l -phenylpropan-2-amine); ephedrine (2-(methylamino)-l -phenylpropan- l-ol); cathinone (2 - amino -1-pheny 1- 1 -prop anone); MDMA (3,4-methylenedioxy-iV- methylamphetamine); and DOM (2,5-Dimethoxy-4-methylamphetamine); and salts, hydrates, and solvates thereof.

The term "a benzodiazepine" includes, but is not limited to alprazolam, bretazenil, bromazepam, brotizolam, chlordiazepoxide, cinolazepam, clonazepam, clorazepate, clotiazepam, cloxazolam, cyclobenzaprine, delorazepam, diazepam, estazolam, etizolam, ethyl, loflazepate, flunitrazepam, 5-(2-bromophenyl)-7-fluoro-l/f-benzo[e] [l,4]diazepin-2(3//)-one, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, phenazepam, pinazepam, prazepam, premazepam, pyrazolam, quazepam, temazepam, tetrazepam, and triazolam and salts, hydrates, and solvates thereof.

The term "an atypical benzodiazepine receptor ligand" includes, but is not limited to clobazam, DMCM, flumazenil, eszopiclone, zaleplon, Zolpidem, and zopiclone and salts, hydrates, and solvates thereof.

The term "marijuana" refers to a composition comprising one or more compound selected from tetrahydrocannabinol, cannabidiol, cannabinol, and tetrahydrocannabivarin and salts, hydrates, and solvates thereof.

The term "cocaine" refers to benzoylmethylecgonine and salts, hydrates, and solvates thereof.

The term "dextromethorphan" refers to (4bS,8aR,9S)-3-methoxy-l l-methyl-6,7,8,8a,9,10- hexahydro-5/f-9,4b-(epiminoethano)phenanthrene and salts, hydrates, and solvates thereof.

The term "eszopiclone" refers to (¾-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5/f- pyrrolo[3,4-¾]pyrazin-5-yl 4-methylpiperazine-l-carboxylate and salts, hydrates, and solvates thereof.

The term "GHB" refers to 4-hydroxybutanoic acid and salts, hydrates, and solvates thereof.

The term "LSD" refers to lysergic acid diethylamide and salts, hydrates, and solvates thereof. The term "ketamine" refers to 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone and salts, hydrates, and solvates thereof.

The term "a monoamine reuptake inhibitor" refers to a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters. Examples of monoamine reuptake inhibitors include alaproclate, citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine, pirandamine, RTI- 353, sertraline, zimelidine, desmethylcitalopram, desmethylsertraline, didesmethylcitalopram, seproxetine, cianopramine, litoxetine, lubazodone, SB-649,915, trazodone, vilazodone, vortioxetine, dextromethorphan, dimenhydrinate, diphenhydramine, mepyramine, pyrilamine, methadone, propoxyphene, mesembrine, roxindole, amedalin, tomoxetine, CP-39,332, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, reboxetine, talopram, talsupram, tandamine, viloxazine, maprotiline, bupropion, ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, ginkgo biloba, altropane, amfonelic acid, benzothiophenylcyclohexylpiperidine, DBL-583, difluoropine, l-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine, 4-{ 13-methyl-4,6-dioxa- l l ,12-diazatricyclo[7.5.0.0]tetradeca-l,3(7),8,10-tetraen-10-yl} aniline, iometopane, [(lR,2S,3S,5S)-3- (4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]-pyrrolidin-l-ylmethanone, vanoxerine, medifoxamine, Chaenomeles speciosa, hyperforin, adhyperforin, bupropion, pramipexole, cabergoline, venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, bicifadine, 4- indolylarylalkylamines, 1-naphthylarylalkylamines, amineptine, desoxypipradrol, dexmethylphenidate, difemetorex,diphenylprolinol, ethylphenidate, fencamfamine, fencamine, lefetamine, mesocarb, methylenedioxypyrovalerone, methylphenidate, nomifensine, methyl 2-cyclopentyl-2-(3,4- dichlorophenyl)acetate, oxolinic acid, pipradrol, prolintane, pyrovalerone, tametraline, l-[l-(3- chlorophenyl)-2-(4-methylpiperazin-l-yl)ethyl]cyclohexan-l-ol, nefopam, amitifadine, EB-1020, tesofensine, NSD-788, tedatioxetine, RG7166, Lu-AA37096, Lu-AA34893, NS-2360, bicifadine, SEP- 227162, SEP-225289, DOV-216,303, brasofensine, NS-2359, diclofensine, EXP-561, taxil, naphyrone, 5-APB, 6-APB, and hyperforin, and salts, hydrates, and solvates thereof.

The term "nicotine" refers to 3-(l-methylpyrrolidin-2-yl)pyridine.

The term "an opiate" includes, but is not limited to the following compounds and salts, hydrates, and solvates thereof: alfentanil, alphaprodine, anileridine, bezitramide, buprenorphine, butorphanol, dextropropoxyphene, carfentanil, codeine, diamorphine, dextromoramide, dezocine, poppy straw, dihydrocodeine, dihydroetorphine, diphenoxylate, ethylmorphine, etorphine, hydrochloride, fentanyl, hydrocodone, hydromorphone, isomethadone, levo-alphacetylmethadol, levomethorphan, levorphanol, meptazinol, metazocine, methadone, metopon, morphine, nalbuphine, opium, oripavine, oxycodone, oxymorphone, pentazocine, pethidine, phenazocine, piminodine, propoxyphene, racemethorphan, racemorphan, remifentanil, sufentanil, tapentadol, and thebaine.

For example, the term includes the following compounds and salts, hydrates, and solvates thereof: alfentanil, alphaprodine, anileridine, bezitramide, dextropropoxyphene, carfentanil, codeine, poppy straw, dihydrocodeine, dihydroetorphine, diphenoxylate, ethylmorphine, etorphine, hydrochloride, fentanyl, hydrocodone, hydromorphone, isomethadone, levo-alphacetylmethadol, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium, oripavine, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan, remifentanil, sufentanil, tapentadol, and thebaine.

The term "PCP" refers to l-(l-phenylcyclohexyl)piperidine and salts, hydrates, and solvates thereof.

The term "a substituted phenethylamine" includes, but is not limited to, the following compounds and salts, hydrates, and solvates thereof: 2-(4-bromo-2,5-dimethoxyphenyl)-iV-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-chloro-2,5-dimethoxyphenyl)-iV-[(2- methoxyphenyl)methyl]ethanamine, 2-(4-iodo-2,5-dimethoxyphenyl)-iV-[(2- methoxyphenyl)methyl]ethanamine, 4-bromo-2,5-dimethoxyphenethylamine, 1 -(4-chloro-2,5- dimethoxyphenyl)-2-aminoethane, 1 -(2,5-dimethoxy-4-methylphenyl)-2-aminoethane, 1 -(2,5- dimethoxy-4-ethylphenyl)-2-aminoethane, 4-fluoro-2,5-dimethoxyphenethylamine, 2,5-dimethoxy-4- iodophenethylamine, 2,5-dimethoxy-4-nitrophenethylamine, 2-(2,5-dimethoxy-4- propylphenyl)ethanamine, 2,5-dimethoxy-4-ethylthiophenethylamine, 2- [2,5-dimethoxy-4-(2- fluoroethylthio)phenyl]ethanamine, 2,5-dimethoxy-4-isopropylthiophenethylamine, 2,5-dimethoxy-4-w- propylthiophenethylamine, 2-[4-[(cyclopropylmethyl)thio]-2,5-dimethoxyphenyl]ethanamine, 2-[4- (butylthio)-2,5-dimethoxyphenyl]ethanamine, 6-hydroxydopamine, dopamine, epinephrine, mescaline, meta-octopamine, meta-tyramine, methylphenidate, w-methylphenethylamine, norepinephrine, para- octopamine, para-tyramine, phentermine, phenylephrine, salbutamol, and β-methylphenethylamine, and salts, hydrates, and solvates thereof.

The term "psilocybin" refers to [3-(2-dimethylaminoethyl)-l/f-indol-4-yl] dihydrogen phosphate, and salts, hydrates, and solvates thereof.

The term "an anabolic steroid" includes, but is not limited to, the following compounds and salts, hydrates, and solvates thereof: 1 -androstenediol, androstenediol, 1-androstenedione,

androstenedione, bolandiol, bolasterone, boldenone, boldione, calusterone, clostebol, danazol, dehydrochlormethyltestosterone, desoxymethyltestosterone, dihydrotestosterone, drostanolone, ethylestrenol, fluoxymesterone, formebolone, furazabol, gestrinone, 4-hydroxytestosterone, mestanolone, mesterolone, metenolone, methandienone, methandriol, methasterone, methyldienolone, methyl- 1 -testosterone, methylnortestosterone, methyltestosterone, metribolone, mibolerone, nandrolone, 19-norandrostenedione, norboletone, norclostebol, norethandrolone, oxabolone, oxandrolone, oxymesterone, oxymetholone, prasterone, prostanozol, quinbolone, stanozolol, stenbolone, 1 -testosterone, testosterone, tetrahydrogestrinone, and trenbolone.

As used herein, the term "greater than" is used interchangeably with the symbol > and the term

"less than" is used interchangeably with the symbol <. Likewise the term less than or equal to is used interchangeably with the symbol < and the term greater than or equal to is used interchangeably with the symbol >. When an integer is used in a method disclosed herein, the term "about" can be inserted before the integer. For example, the term "greater than 29 kg/m²" can be substituted with "greater than about 29 kg/m²".

As used in the present specification, the following abbreviations are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

PP Point prevalence

ppm parts per million

QD Once a day

SAE Serious Adverse Events

SE Standard Error

SBP Systolic blood pressure

TGA Thermogravimetric Analysis

wt Weight

PXRD X-ray powder diffraction

Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers.

Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

Each embodiment described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features unless specifically stated otherwise.

The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the invention(s), as described herein.

It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment.

Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. For example, a method that recites prescribing or administering a compound provided herein can be separated into two methods; one reciting prescribing a compound provided herein and the other reciting administering a compound provided herein. In addition, for example, a method that recites prescribing a compound provided herein and a separate method reciting administering a compound provided herein can be combined into a single method reciting prescribing and/or administering a compound provided herein. Γη addition, for example, a method that recites prescribing or administering a selective 5-HT₂c receptor agonist can be separated into two methods— one reciting prescribing a selective 5-HT₂c receptor agonist and the other reciting administering a selective 5-HT₂c receptor agonist. In addition, for example, a method that recites prescribing a selective 5-HT_2C receptor agonist and a separate method of the invention reciting administering a selective 5-HT_2C receptor agonist can be combined into a single method reciting prescribing and/or administering a selective 5-HT_2C receptor agonist.

CHEMICAL GROUP, MOIETY OR RADICAL

The term "C₁-C6 alkoxy" refers to a radical comprising a C₁-C6 alkyl group attached to an oxygen atom, wherein Ci-C6 alkyl has the same definition as found herein. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 to 2 carbons. Examples include, but are not limited to methoxy, ethoxy, M-propoxy, isopropoxy, w-butoxy, ieri-butoxy, isobutoxy, and sec-butoxy.

The term "aryl" refers to an aromatic ring radical containing 6 to 10 ring carbons. Examples include, but are not limited to, phenyl and naphthyl.

The term "Ci-C6 alkoxycarbonyl" refers to a radical comprising a Ci-C6 alkoxy group attached to a carbonyl, wherein Ci-C₆ alkoxy has the same definition as found herein. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,

butoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and ieri-butoxycarbonyl.

The term "Ci-C6 alkyl" refers to a straight or branched carbon radical containing 1 to 6 carbons.

Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 to 2 carbons. Examples of an alkyl group include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec-butyl, isobutyl, feri-butyl, pentyl, isopentyl, i-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH₃)CH₂CH₂CH₃], 2- methylbutyl [i.e., -CH₂CH(CH₃)CH₂CH₃], and n-hexyl.

The term "Ci-C₆ alkylsulfonyl" refers to a radical comprising a Ci-C₆ alkyl group attached to the sulfur of a sulfonyl group, wherein Ci-C₆ alkyl has the same definition as described herein.

Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, w-propylsulfonyl,

isopropylsulfonyl, w-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, and feri-butylsulfonyl.

The term "Ci-C6 alkylthio" refers to a radical comprising a Ci-C6 alkyl group attached to a sulfur atom, wherein Ci-C₆ alkyl has the same definition as described herein. Examples include, but are not limited to, methylthio, ethylthio, w-propylthio, isopropylthio, w-butylthio, sec-butylthio, isobutylthio, and ieri-butylthio.

The term "carbocyclic ring" refers to a saturated ring containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons.

The term "C₃-C₇ cycloalkyl" refers to a saturated ring radical containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "C₃-C₇ cycloalkyl-Ci-C6 alkylene" refers to a radical comprising a C₃-C₇ cycloalkyl group attached to a Ci-C₆ alkyl group, wherein the C₃-C₇ cycloalkyl and Ci-C₆ alkyl groups have the same definitions as described herein. Examples include, but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cyclopropylethyl.

The term "Ci-C6 haloalkyl" refers to a radical comprising a Ci-C6 alkyl group substituted with one or more halogens, wherein Ci-C₆ alkyl has the same definition as found herein. The Ci-C₆ haloalkyl may be fully substituted in which case it can be represented by the formula C_qL_2q+i, wherein L is a halogen and "q" is 1, 2, 3, 4, 5 or 6. When more than one halogen is present then they may be the same or different and selected from: fluorine, chlorine, bromine, and iodine. In some embodiments, haloalkyl contains 1 to 5 carbons. In some embodiments, haloalkyl contains 1 to 4 carbons. In some

embodiments, haloalkyl contains 1 to 3 carbons. In some embodiments, haloalkyl contains 1 to 4 carbons. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2-fluoropropan-2-yl, 1, 1-difluoropropyl, 1,3- difluoropropan-2-yl, (SJ-l-fluoropropan-2-yl, fRJ-l-fluoropropan-2-yl, l,l ,l-trifluoropropan-2-yl, and

1,1, 1,3,3,3 -hexafluoropropan-2-yl.

The term "heterocyclic ring" refers to a saturated ring containing 3 to 7 atoms, one or more of which are heteroatoms. In some embodiments one, two or three of the ring atoms are heteroatoms. In some embodiments, one, two or three of the ring atoms are heteroatoms each of which is independently

O, N or S.

The term "3- to 7-membered heterocycloalkyl" refers to a saturated ring radical containing 3 to 7 atoms, one or more of which are heteroatoms. In some embodiments one, two or three of the ring atoms are heteroatoms. In some embodiments, one, two or three of the ring atoms are heteroatoms each of which is independently O, N or S. Examples include aziridinyl, azetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, and morpholinyl.

The term "halogen" refers to a fluoro, chloro, bromo or iodo group.

The term "heteroaryl" refers to a ring system containing 5 to 10 ring atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic and at least one ring atom of the aromatic ring is a heteroatom selected from, for example: O, S and N, wherein N is optionally substituted with H, Ci-C₄ acyl, Ci-C₄ alkyl, or O (i.e., forming an iV-oxide) and S is optionally substituted with one or two oxygens. In some embodiments, the aromatic ring contains one heteroatom. In some embodiments, the aromatic ring contains two heteroatoms. In some embodiments, the aromatic ring contains three heteroatoms. Some embodiments are directed to 5-membered heteroaryl rings. Examples of a 5-membered heteroaryl ring include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, and thiadiazolyl. Some embodiments are directed to 6-membered heteroaryl rings. Examples of a 6- membered heteroaryl ring include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

The term "heteroaryl-Ci-C6 alkylene" refers to a radical comprising a heteroaryl group attached to a Ci-C₆ alkyl group, wherein the C₃-C₇ cycloalkyl and Ci-C₆ alkyl groups have the same definitions as described herein. Examples include, but are not limited to pyridinylmethyl, pyridinylethyl, pyridinylpropyl, pyridinylbutyl, pyridinylpentyl, pyridinylhexyl, and pyrazinylmethyl.

The term "phenyl" refers to the group -CeH₅.

The term "aryloxy" refers to a radical comprising an aryl group, attached to an oxygen, wherein aryl has the same definition as found herein. Examples include, but are not limited to, phenoxy and naphthyloxy.

The number of occurrences of a given substituent in a compound may be specified by a subscript (such as "n" and the like). The subscript may be a positive integer or it may be 0. A value of 0 for the subscript is intended to indicate that the substituent is absent.

In compounds of formula XI and formulae related thereto,

is used to denote a ring moiety wherein, for n=l, R¹⁴ as defined herein is bound to a carbon, which is any of the three saturated carbons of the seven-membered ring, or, for n=2, two R¹⁴ as defined herein are bound to the same carbon, which is any of the three saturated carbons of the seven-membered ring.

COMPOUNDS

Provided are certain heterocyclyl derivatives selected from compounds of Formula I and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula I

wherein:

X is selected from O and S; and

R¹ is selected from: Ci-C6 alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C₁-C6 alkoxy, Ci-C6 alkoxycarbonyl, Ci-C6 alkylthio, Ci-C6 alkylsulfonyl, aryloxy, halogen, and Ci-C6 haloalkyl.

Also provided herein are compounds selected from compounds of Formula XI, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula XI

wherein:

X¹ is selected from O and S;

R¹² and R^12b are each independently H, C₃-C₇ cycloalkyl or C₁-C6 alkyl, wherein the C₃-C₇ cycloalkyl and C₁-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, Ci-C6 alkyl and Ci-C6 alkoxy;

R¹³ and R^13b are each independently H, C₃-C₇ cycloalkyl or Ci-C6 alkyl, wherein the C₃-C₇ cycloalkyl and Ci-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, Ci-C6 alkyl and Ci-C6 alkoxy;

n is 0, 1, or 2;

wherein if n is 1, R¹⁴ is Ci-Ce alkyl,

and wherein if n is 2, each R¹⁴ is Ci-C6 alkyl bonded to the same carbon, or two R¹⁴ taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring;

provided that if R^12a, R^12b, R^13a and R^13b are each H then n is 1 or 2.

Also provided are certain compounds selected from compounds of Formula XXI and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula XXI wherein:

each of R and R is independently hydrogen or Ci-C6 alkyl;

R²⁷ is hydrogen, Ci-C6 alkyl or C₃-C₇ cycloalkyl; R²⁸ is hydrogen or C₁-C6 alkyl;

each of R²² and R²³ is independently hydrogen or C₁-C6 alkyl optionally substituted with one or more halogens;

or R²² and R²³ taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C₁-C6 alkyl, and C₁-C6 alkoxy;

R²⁴ is hydrogen, halogen, hydroxy, C₃-C₇ cycloalkyl, Ci-C₆ alkoxy or Ci-C₆ alkyl optionally substituted with C₁-C6 alkoxy; and

R²¹ is selected from the group consisting of:

hydrogen;

halogen;

Ci-C₆ alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C6 alkoxy, amino, heteroarylamino, arylamino, C₁-C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with Ci-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-C₆ alkoxy, or C₃-C₇ cycloalkyl optionally substituted with Ci-C₆ alkoxy;

aryl;

heteroaryl;

C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy;

amino;

Ci-C₆ alkoxy optionally substituted with one or more halogens;

hydroxy;

-NHCO-Ci-Ce alkyl;

-NHCO(0)Ci-C₆ alkyl;

-OCO(NH)Ci-C₆ alkyl;

and

CN;

All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., X, R¹, etc.) contained within the generic chemical formulae described herein, for example, Formulae I, II, III, XI, XXI, etc. are specifically embraced by the present invention(s) just as if each and every combination was individually and explicitly recited, to the extent that such combinations embrace compounds that result in stable compounds (i.e., compounds that can be isolated, characterized and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of uses and medical indications described herein, are also specifically embraced by the present invention(s) just as if each and every subcombination of chemical groups and subcombination of uses and medical indications was individually and explicitly recited herein.

In addition, some embodiments include every combination of one or more embodiments pertaining to the chemical groups represented by the variables and generic chemical formulae as described herein or every combination of one or more compounds disclosed herein together/in combination with every combination of one or more weight loss drug chosen from sodium/glucose cotransporter-2 (SGLT2) inhibitors, lipase inhibitors, monoamine reuptake inhibitors, anticonvulsants, glucose sensitizers, incretin mimetics, amylin analogs, GLP-1 analogs, Y receptor peptides, 5-HT₂c receptor agonists, opioid receptor antagonists, appetite suppressants, anorectics, and hormones and the like, either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited. In some embodiments, the weight loss drug is chosen from dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, empagliflozin, remogliflozin etabonate, orlistat, cetilistat, alaproclate, citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine, pirandamine, sertraline, zimelidine, desmethylcitalopram, desmethylsertraline, didesmethylcitalopram, seproxetine, cianopramine, litoxetine, lubazodone, trazodone, vilazodone, vortioxetine,

dextromethorphan, dimenhydrinate, diphenhydramine, mepyramine, pyrilamine, methadone, propoxyphene, mesembrine, roxindole, amedalin, tomoxetine, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, reboxetine, talopram, talsupram, tandamine, viloxazine, maprotiline, bupropion, ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, ginkgo biloba, altropane, difluoropine, iometopane, vanoxerine, medifoxamine, Chaenomeles speciosa, hyperforin, adhyperforin, bupropion, pramipexole, cabergoline, venlafaxine, desvenlafaxine, duloxetine, milnacipran, levomilnacipran, bicifadine, amineptine, desoxypipradrol, dexmethylphenidate, difemetorex, diphenylprolinol, ethylphenidate, fencamfamine, fencamine, lefetamine, mesocarb,

methylenedioxypyrovalerone, methylphenidate, nomifensine, oxolinic acid, pipradrol, prolintane, pyrovalerone, tametraline, nefopam, amitifadine, tesofensine, tedatioxetine, bicifadine, brasofensine, diclofensine, taxil, naphyrone, hyperforin, topiramate, zonisamide, metformin, acarbose, rosiglitazone, pioglitazone, troglitazone, exenatide, liraglutide, taspoglutide, obinepitide, pramlintide, peptide YY, vabicaserin, naltrexone, naloxone, phentermine, diethylpropion, oxymetazoline, benfluorex, butenolide cathine, phenmetrazine, phenylpropanolamine, pyroglutamyl-histidyl-glycine , amphetamine, benzphetamine, dexmethylphenidate, dextroamphetamine, methylenedioxypyrovalerone, glucagon, lisdexamfetamine, methamphetamine, methylphenidate, phendimetrazine, phenethylamine, caffeine, bromocriptine, ephedrine, pseudoephedrine, rimonabant, surinabant, mirtazapine, Dietex®, MG Plus Protein™, insulin, and leptin and pharmaceutically acceptable salts and combinations thereof. As used herein, "substituted" indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group. When a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1 , 2, or 3 substituents, a methylene group can be substituted by 1 to 4 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents, and the like. Likewise, "substituted with one or more substituents" refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.

Compounds provided herein can also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds provided herein.

It is understood and appreciated that compounds of Formula I or XI or XXI or other formulae used throughout this disclosure may have one or more chiral centers and therefore can exist as enantiomers and/or diastereoisomers. The invention(s) are understood to extend to and embrace all such enantiomers, diastereoisomers and mixtures thereof, including but not limited to racemates. It is understood that compounds of Formula I or XI or XXI or other formulae used throughout this disclosure represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise.

Formula I:

Provided are compounds of Formula I and pharmaceutically acceptable salts, hydrati solvates thereof:

Formula I

wherein:

X is selected from O and S; and

R¹ is selected from: Ci-C6 alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C₁-C6 alkoxy, Ci-C6 alkoxycarbonyl, Ci-C6 alkylthio, Ci-C6 alkylsulfonyl, aryloxy, halogen, and Ci-C6 haloalkyl. The Group R¹ In some embodiments, R¹ is selected from: C₁-C6 alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-C C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C₁-C6 alkoxy, C₁-C6 alkoxycarbonyl, C₁-C6 alkylthio, C₁-C6 alkylsulfonyl, aryloxy, halogen, and Ci-C₆ haloalkyl.

In some embodiments, R¹ is selected from: C₁-C6 alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-C C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.

In some embodiments, R¹ is selected from: butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, n-propyl, pyridinyl, and pyridinylmethyl; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.

In some embodiments, R¹ is selected from: (6-(trifluoromethyl)pyridin-3-yl)methyl, 1- ethoxypropan-2yl, 1 -methoxypropan-2-yl, 2-(ethylthio)ethyl, 2-(methylsulfonyl)ethyl, 2- (methylthio)ethyl, 2-chloroethyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-fluoroethyl, 3-fluoropropyl, 2- isopropoxyethyl, 2-methoxy-2-oxoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-phenoxyethyl, 2- propoxyethyl, 3-methoxypropyl, butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, propyl, pyridin-2-ylmethyl, and pyridin-3-yl.

In some embodiments, R¹ is (6-(trifluoromethyl)pyridin-3-yl)methyl.

In some embodiments, R¹ is l-ethoxypropan-2yl.

In some embodiments, R¹ is l-methoxypropan-2-yl.

In some embodiments, R¹ is 2-(ethylthio)ethyl.

In some embodiments, R¹ is 2-(methylsulfonyl)ethyl.

In some embodiments, R¹ is 2-(methylthio)ethyl.

In some embodiments, R¹ is 2-chloroethyl.

In some embodiments, R¹ is 2-ethoxyethyl.

In some embodiments, R¹ is 2-ethoxypropyl.

In some embodiments, R¹ is 2-fluoroethyl.

In some embodiments, R¹ is 3-fluoropropyl.

In some embodiments, R¹ is 2-isopropoxyethyl.

In some embodiments, R¹ is 2-methoxy-2-oxoethyl.

In some embodiments, R¹ is 2-methoxyethyl.

In some embodiments, R¹ is 2-methoxypropyl.

In some embodiments, R¹ is 2-phenoxyethyl.

In some embodiments, R¹ is 2-propoxyethyl.

In some embodiments, R¹ is 3-methoxypropyl.

In some embodiments, R¹ is butyl.

In some embodiments, R¹ is cyclopropyl. In some embodiments, R¹ is cyclopropylmethyl.

In some embodiments, R¹ is ethyl.

In some embodiments, R¹ is isopropyl.

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is propyl.

In some embodiments, R¹ is pyridin-2-ylmethyl.

In some embodiments, R¹ is pyridin-3-yl.

The Group X

In some embodiments, X is selected from

In some embodiments, X is O.

In some embodiments, X is S.

Compounds of Formula I that are compounds of Formula II

Also provided are compounds of Formula I wherein the compound of formula I is a compound of Formula II, and salts, hydrates, and solvates thereof:

Formula II

wherein R¹ is selected from: C₁-C6 alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: C₁-C6 alkoxy, C₁-C6 alkoxycarbonyl, C₁-C6 alkylthio, C₁-C6 alkylsulfonyl, aryloxy, halogen, and C₁-C6 haloalkyl.

Also provided are compounds of Formula II, and salts, hydrates, and solvates thereof:

Formula II

wherein R¹ is selected from: C₁-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.

Formula II wherein R¹ is selected from: butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, w-propyl, pyridinyl, and pyridinylmethyl; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.

Formula II

wherein R¹ is selected from: (6-(trifluoromethyl)pyridin-3-yl)methyl, l-ethoxypropan-2yl, 1- methoxypropan-2-yl, 2-(ethylthio)ethyl, 2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2-chloroethyl, 2- ethoxyethyl, 2-ethoxypropyl, 2-fluoroethyl, 2-fluoropropyl, 2-isopropoxyethyl, 2-methoxy-2-oxoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-phenoxyethyl, 2-propoxyethyl, 3-methoxypropyl, butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, propyl, pyridin-2-ylmethyl, and pyridin-3-yl.

Compounds of Formula I that are compounds of Formula III

Also provided are compounds of Formula I wherein the compound of formula I is a compound of Formula III, and salts, hydrates, and solvates thereof:

Formula III

wherein R¹ is selected from: Ci-C₆ alkyl optionally substituted with one or more substituents selected from: Ci-C6 alkoxy.

Also provided are compounds of Formula III, and salts, hydrates, and solvates thereof:

Formula III

wherein R¹ is selected from: Ci-C6 alkyl optionally substituted with one or more substituents selected from: methoxy.

Formula III

wherein R¹ is selected from: ethyl and methyl; each optionally substituted with one or more substituents selected from: methoxy. Also provided are compounds of Formula III, and salts, hydrates, and solvates thereof:

Formula III

wherein R¹ is selected from: 2-methoxyethyl and methyl.

In some embodiments, the salts, hydrates, and solvates of the compounds of Formula II or of Formula III, are pharmaceutically acceptable salts, hydrates, and solvates.

Some embodiments of the compounds of Formula I include every combination of one or more compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group shown in Table A.

Table A

8 -carboxamide Compound No. Chemical Structure Chemical Name

iV- (2-isopropoxyethyl) - 1, 2,3,4, 6,7-hexahydro-

17

[1,4] diazepino [6,7 , 1 -hi] indole- 8-carboxamide iV-(2-(ethylthio)ethyl)- 1, 2,3,4, 6,7-hexahydro-

18

[1,4] diazepino [6,7 , 1 -hi] indole- 8-carboxamide

7V-(1 -methoxypropan-2-yl)- 1, 2,3,4, 6,7-hexahydro-

19

[1,4] diazepino [6,7 , 1 -hi] indole- 8-carboxamide iV-(l-ethoxypropan-2-yl)- 1, 2,3,4, 6,7-hexahydro-

20

[1,4] diazepino [6,7 , 1 -hi] indole- 8-carboxamide

N- (2-methoxypropyl) - 1, 2,3,4, 6,7-hexahydro-

21

[1,4] diazepino [6,7 , 1 -hi] indole- 8-carboxamide iV-(2-ethoxypropyl)- 1,2,3,4,6,7-

22 hexahydro- [ 1,4] diazepino [6,7,1- hi] indole- 8 -carboxamide iV-(2-propoxyethyl)- 1,2,3,4,6,7-

23 hexahydro- [ 1,4] diazepino [6,7,1- hi] indole- 8 -carboxamide iV-(2-phenoxyethyl)- 1,2,3,4,6,7-

24 hexahydro- [ 1,4] diazepino [6,7,1- hi] indole- 8 -carboxamide

N-(2-methoxyethyl)- 1,2,3,4,6,7-

25 hexahydro- [ 1,4] diazepino [6,7,1- hi] indole- 8 -carbo thioamide iV-methyl- 1,2,3,4,6,7-

26 hexahydro- [ 1,4] diazepino [6,7,1- hi] indole- 8 -carbo thioamide Compound No. Chemical Structure Chemical Name

N-(2-fluoroethyl)- l,2,3,4,6,7-

27 hexahydro- [ 1,4] diazepino [6,7,1 - hi] indole- 8 -carboxamide

N-(3-fluoropropyl)- 1,2,3,4,6,7-

28 hexahydro- [ 1,4] diazepino [6,7,1 - hi] indole- 8 -carboxamide

N-butyl-l,2,3,4,6,7-hexahydro-

29 [1,4] diazepino [6,7 , 1 -hi] indole- 8 -carboxamide

Formula XI:

Provided are compounds of Formula XI and pharmaceutically acceptable salts, hydrati solvates thereof:

wherein:

X¹ is selected from O and S;

R¹¹ is selected from: Ci-C6 alkyl, optionally substituted with one or more substituents independently selected from: Ci-C6 alkoxy, Ci-C6 alkoxycarbonyl, and halogen;

R¹² and R^12b are each independently H, C₃-C₇ cycloalkyl or Ci-C6 alkyl, wherein the C₃-C₇ cycloalkyl and Ci-C₆ alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, Ci-C6 alkyl and Ci-C6 alkoxy;

n is 0, 1 , or 2;

wherein if n is 1 , R¹⁴ is Ci-Ce alkyl, and wherein if n is 2, each R is C₁-C6 alkyl bonded to the same carbon, or two R taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring;

provided that if R^12a, R^12b, R^13a and R^13b are each H then n is 1 or 2.

The Group R¹¹

In some embodiments, R¹¹ is Ci-C6 alkyl, optionally substituted with one or more substituents independently selected from: Ci-C6 alkoxy, Ci-C6 alkoxycarbonyl, and halogen.

In some embodiments, R¹¹ is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from: chloro, ethoxy, fluoro, isopropoxy, methoxy, methoxycarbonyl, and propoxy.

In some embodiments, R¹¹ is selected from: butyl, ethyl, isopropyl, methyl, and w-propyl; each optionally substituted with one or more substituents independently selected from: chloro, ethoxy, fluoro, isopropoxy, methoxy, methoxycarbonyl, and propoxy.

In some embodiments, R¹¹ is selected from: l-ethoxypropan-2yl, l-methoxypropan-2-yl, 2- chloroethyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-fluoroethyl, 3-fluoropropyl, 2-isopropoxyethyl, 2- methoxy-2-oxoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-propoxyethyl, 3-methoxypropyl, butyl, ethyl, isopropyl, methyl, and propyl.

In some embodiments, R¹¹ is selected from: ethyl and methyl each optionally substituted with more substituents independently selected from ethoxy and methoxy.

In some embodiments, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl

In some embodiments, R¹¹ is 1 -ethoxypropan-2yl.

In some embodiments, R¹¹ is 1 -methoxypropan-2-yl.

In some embodiments, R¹¹ is 2-chloroethyl.

In some embodiments, R¹¹ is 2-ethoxyethyl.

In some embodiments, R¹¹ is 2-ethoxypropyl.

In some embodiments, R¹¹ is 2-fluoroethyl.

In some embodiments, R¹¹ is 3-fluoropropyl.

In some embodiments, R¹¹ is 2-isopropoxyethyl.

In some embodiments, R¹¹ is 2-methoxy-2-oxoethyl.

In some embodiments, R¹¹ is 2-methoxyethyl.

In some embodiments, R¹¹ is 2-methoxypropyl.

In some embodiments, R¹¹ is 2-phenoxyethyl.

In some embodiments, R¹¹ is 2-propoxyethyl.

In some embodiments, R¹¹ is 3-methoxypropyl.

In some embodiments, R¹¹ is butyl.

In some embodiments, R¹¹ is ethyl.

In some embodiments, R¹¹ is isopropyl.

In some embodiments, R¹¹ is methyl. In some embodiments, R¹¹ is propyl.

In some embodiments, R¹¹ is C₁-C6 alkyl substituted with one or more substituents independently selected from halogen.

In some embodiments, R¹¹ is Ci-C₆ alkyl substituted with one or more fluorine.

In some embodiments, R¹¹ is 2,2-difluoroethyl.

In some embodiments, R¹¹ is 2,2,2-trifluoroethyl.

In some embodiments, R¹¹ is 3,3,3-trifluoropropyl.

In some embodiments, R¹¹ is 2,2,3,3,3-pentafluoropropyl.

The Group X¹

In some embodiments, X¹ is selected from O and S.

In some embodiments, X¹ is O.

In some embodiments, X¹ is S.

The Groups R^12aand R^12b

In some embodiments, R¹² and R^12b are each independently H, C₃-C₇ cycloalkyl or C₁-C6 alkyl, wherein the C₃-C₇ cycloalkyl and Ci-C₆ alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C₁-C6 alkyl and C₁-C6 alkoxy.

In some embodiments, R¹² and R^12b are each independently selected from: H, methyl, ethyl and propyl, wherein methyl, ethyl and propyl are each optionally substituted with one or more substituents independently selected from methoxy and fluorine.

In some embodiments, R¹² and R^12b are each independently selected from: H, methyl, ethyl, propyl, methoxymethyl, CF₃ and 2,2,2-trifluoroethyl.

In some embodiments, each of R¹² and R^12b is H.

In some embodiments, each of R¹² and R^12b is C₁-C6 alkyl.

In some embodiments, each of R¹² and R^12b is Ci-C₆ alkyl and is the same.

In some embodiments, each of R¹² and R^12b is methyl.

In some embodiments, each of R¹² and R^12b is ethyl.

In some embodiments, each of R¹² and R^12b is propyl.

In some embodiments, each of R¹² and R^12b is C₁-C6 alkyl substituted with one or more substituents independently selected from halogen and Ci-C₆ alkoxy.

In some embodiments, each of R¹² and R^12b is C₁-C6 alkyl substituted with one or more halogen

In some embodiments, each of R¹² and R^12b is CF₃.

In some embodiments, each of R¹² and R^12b is 2,2,2-trifluoroethyl.

IInn ssoommee eemmbbooddiimmeennttss,, eeaacchh ooff 1 R and R is C₁-C6 alkyl substituted with one or more substituents selected from C₁-C6 alkoxy

In some embodiments, each of R and R is methoxymethyl. In some embodiments, each of R and R is 2-methoxyethyl.

In some embodiments, each of R¹² and R^12b is 2-ethoxyethyl.

In some embodiments, each of R¹² and R^12b is C₃-C₇ cycloalkyl.

In some embodiments, each of R¹² and R^12b is C₃-C₇ cycloalkyl and is the same.

In some embodiments, one of R^12a and R^12b is H and the other is Ci-C₆ alkyl.

In some embodiments, one of R¹² and R^12b is H and the other is methyl.

In some embodiments, one of R^12a and R^12b is H and the other is ethyl.

In some embodiments, one of R¹² and R^12b is H and the other is propyl.

In some embodiments, one of R¹² and R^12b is H and the other is C₁-C6 alkyl substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.

In some embodiments, one of R¹² and R^12b is H and the other is Ci-C6 alkyl substituted with one or more halogen.

In some embodiments, one of R^12a and R^12b is H and the other is CR.

In some embodiments, one of R¹² and R^12b is H and the other is 2,2,2-trifluoroethyl.

In some embodiments, one of R¹² and R^12b is H and the other is Ci-C6 alkyl substituted with one or more substituents selected from Ci-C6 alkoxy.

In some embodiments, one of R^12a and R^12b is H and the other is methoxymethyl.

In some embodiments, one of R^12a and R^12b is H and the other is 2-methoxyethyl.

In some embodiments, one of R^12a and R^12b is H and the other is 2-ethoxyethyl.

In some embodiments, one of R^12a and R^12b is H and the other is C3-C7 cycloalkyl.

In some embodiments, one of R^12a and R^12b is H and the other is cyclopropyl.

In some embodiments, one of R^12a and R^12b is H and the other is cyclobutyl.

In some embodiments, one of R^12a and R^12b is H and the other is cyclopentyl.

In some embodiments, one of R^12a and R^12b is H and the other is cyclohexyl.

In some embodiments, one of R^12a and R^12b is H and the other is cycloheptyl.

In some embodiments, the carbon bearing R and R has (R) stereochemistry.

In some embodiments, the carbon bearing R¹² and R^12b has (S) stereochemistry.

The Groups R"" and IT*

In some embodiments, R¹³ and R^13b are each independently H, C3-C7 cycloalkyl or C₁-C6 alkyl, wherein the C₃-C₇ cycloalkyl and Ci-C₆ alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C₁-C6 alkyl and C₁-C6 alkoxy;

or R¹³ and R^13b taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring.

In some embodiments, R¹³ and R^13b are each independently selected from: H, methyl, and ethyl.

In some embodiments, each of R¹³ and R^13b is H.

In some embodiments, each of R¹³ and R^13b is C₁-C6 alkyl. In some embodiments, each of R and R is Ci-C₆ alkyl and is the same.

In some embodiments, each of R¹³ and R^13b is methyl.

In some embodiments, each of R¹³ and R^13b is ethyl.

In some embodiments, each of R¹³ and R^13b is propyl.

In some embodiments, each of R¹³ and R^13b is Ci-C₆ alkyl substituted with

substituents independently selected from halogen and Ci-C₆ alkoxy.

In some embodiments, each of R and R is C C₆ alkyl substituted with one or more halogen

In some embodiments, each of R and R is CF₃.

In some embodiments, each of R¹³ and R^13b is 2,2,2-trifluoroethyl.

In some embodiments, each of R¹³ and R^13b is Ci-C₆ alkyl substituted with one or more substituents selected from Ci-C6 alkoxy.

In some embodiments, each of R¹³ and R^13b is methoxymethyl.

In some embodiments, each of R¹³ and R^13b is 2-methoxyethyl.

In some embodiments, each of R¹³ and R^13b is 2-ethoxyethyl.

In some embodiments, each of R^lja and R^13b is C₃-C₇ cycloalkyl.

In some embodiments, each of R¹³ and R^13b is C₃-C₇ cycloalkyl and is the same.

In some embodiments, R^13a and R^13b taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring.

In some embodiments, R¹³ and R^13b taken together with the carbon they are bonded to form a

3- membered spirocyclic ring.

In some embodiments, R^lja and R^13b taken together with the carbon they are bonded to form a

4- membered spirocyclic ring.

In some embodiments, R^lja and R^ljb taken together with the carbon they are bonded to form a

5- membered spirocyclic ring.

In some embodiments, one of R^13a and R^13b is H and the other is C C₆ alkyl.

In some embodiments, one of R¹³ and R^13b is H and the other is methyl.

In some embodiments, one of R^13a and R^13b is H and the other is ethyl.

In some embodiments, one of R¹³ and R^13b is H and the other is propyl.

In some embodiments, one of R¹³ and R^13b is H and the other is Ci-C₆ alkyl substituted with one or more substituents independently selected from halogen and C C₆ alkoxy.

In some embodiments, one of R^lja and R^13b is H and the other is C C₆ alkyl substituted with one or more halogen.

In some embodiments, one of R^13a and R^13b is H and the other is CF₃.

In some embodiments, one of R^13a and R^13b is H and the other is 2,2,2-trifluoroethyl.

In some embodiments, one of R¹³ and R^13b is H and the other is Ci-C₆ alkyl substituted with one or more substituents selected from Ci-C6 alkoxy.

In some embodiments, one of R¹³ and R^13b is H and the other is methoxymethyl. In some embodiments, ^13a and R^13b is

In some embodiments, ^13a and R^13b is

In some embodiments, 13a„„J _D 13b ·

In some embodiments,

The variable n

In some embodiments, n is 0, 1, or 2.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

The Group R (when n is 1)

In some embodiments, R¹⁴ is Ci-C6 alkyl.

In some embodiments, R¹⁴ is methyl.

In some embodiments, R¹⁴ is ethyl.

In some embodiments, R¹⁴ is propyl.

In some embodiments, the carbon bearing R¹⁴ has (R) stereochemistry.

In some embodiments, the carbon bearing R¹⁴ has (S) stereochemistry.

The Group R (when n is 2)

In some embodiments, two R¹⁴ groups are each Ci-C6 alkyl bonded to the same carbon. In some embodiments, two R¹⁴ groups are each Ci-C6 alkyl bonded to the same carbon and are the same.

In some embodiments, two R¹⁴ groups are each methyl bonded to the same carbon.

In some embodiments, two R¹⁴ groups are each ethyl bonded to the same carbon.

In some embodiments, two R¹⁴ groups are each propyl bonded to the same carbon.

In some embodiments, two R¹⁴ taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring.

In some embodiments, two R¹⁴ taken together with the carbon they are bonded to form a

3- membered spirocyclic ring.

4- membered spirocyclic ring. In some embodiments, two R taken together with the carbon they are bonded to form a 5-membered spirocyclic ring.

Embodiments of Formula XI

In some embodiments, n is 0 and the compound of formula XI is selected from compounds of Formula Xlla-i, and salts, hydrates, and solvates thereof:

Formula Xlla-i

wherein:

R¹¹ is C₁-C6 alkyl optionally substituted with one or more substituents selected from: C₁-C6 alkoxy; and

one of R¹² and R^12b is H and the other is C₁-C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula Xlla-i, X¹ is O.

In some embodiments of formula Xlla-i, R¹¹ is selected from methyl, ethoxy ethyl and methoxyethyl.

In some embodiments of formula Xlla-i, R¹¹ is methyl.

In some embodiments of formula Xlla-i, R¹¹ is ethoxyethyl.

In some embodiments of formula Xlla-i, R¹¹ is methoxyethyl.

In some embodiments of formula Xlla-i, one of R¹² and R^12b is H and the other is selected from: methyl, ethyl, propyl, methoxymethyl, CF₃ and 2,2,2-trifluoroethyl.

In some embodiments of formula Xlla-i, one of R¹² and R^12b is H and the other is methyl. In some embodiments of formula Xlla-i, one of R^12a and R^12b is H and the other is ethyl. In some embodiments of formula Xlla-i, one of R¹² and R^12b is H and the other is propyl. In some embodiments of formula Xlla-i, one of R^12a and R^12b is H and the other is CF₃. In some embodiments of formula Xlla-i, one of R¹² and R^12b is H and the other is 2,2,2- trifluoroethyl.

In some embodiments of formula Xlla-i, one of R^12a and R^12b is H and the other is CH₂OMe. In some embodiments of formula Xlla-i, the carbon bearing R¹² and R^12b has (R) stereochemistry.

In some embodiments of formula Xlla-i, the carbon bearing R¹² and R^12b has (S) stereochemistry. In some embodiments, n is 0 and the compound of formula XI is selected from compounds of Formula Xlla-i, and salts, hydrates, and solvates thereof:

Formula Xlla-i wherein:

R¹² and R^12b are each Ci-C₆ alkyl optionally independently substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula Xlla-i, X¹ is O.

In some embodiments of formula Xlla-i, R¹¹ is selected from methyl, ethoxy ethyl, and methoxyethyl.

In some embodiments of formula Xlla-i, R¹¹ is methyl.

In some embodiments of formula Xlla-i, R¹¹ is ethoxyethyl.

In some embodiments of formula Xlla-i, R¹¹ is methoxyethyl.

In some embodiments of formula Xlla-i, R¹² and R^12b are each selected from: methyl, ethyl, propyl, methoxymethyl, CF₃ and 2,2,2-trifluoroethyl.

In some embodiments of formula Xlla-i, R¹² and R^12b are each methyl.

In some embodiments of formula Xlla-i, R¹² and R^12b are each ethyl.

In some embodiments of formula Xlla-i, R¹² and R^12b are each propyl. In some embodiments, n is 0 and the compound of formula XI is selected from compounds of

Formula Xllb-i, and salts, hydrates, and solvates thereof:

Formula XIIb-i

wherein:

one of R¹³ and R^13b is H and the other is C₁-C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula XIIb-i, X¹ is O.

In some embodiments of formula XIIb-i, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula XIIb-i, R¹¹ is methyl.

In some embodiments of formula XIIb-i, R¹¹ is ethoxyethyl.

In some embodiments of formula XIIb-i, R¹¹ is methoxyethyl.

In some embodiments of formula XIIb-i, one of R¹³ and R^13b is H and the other is selected from methyl and ethyl.

In some embodiments of formula XIIb-i, one of R¹³ and R^13b is H and the other is methyl. In some embodiments of formula XIIb-i, one of R^13a and R^13b is H and the other is ethyl. In some embodiments of formula XIIb-i, the carbon bearing R¹³ and R^13b has (R) stereochemistry.

In some embodiments of formula XIIb-i, the carbon bearing R¹³ and R^13b has (S) stereochemistry.

In some embodiments, n is 0 and the compound of formula XI is selected from compounds of Formula XIIb-i, and salts, hydrates, and solvates thereof:

Formula XIIb-i

wherein:

R¹¹ is Ci-C₆ alkyl optionally substituted with one or more substituents selected from: Ci-C₆ alkoxy; and

R¹³ and R^13b are each C₁-C6 alkyl optionally independently substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula XIIb-i, X¹ is O.

In some embodiments of formula XIIb-i, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl. In some embodiments of formula Xllb-i, R¹¹ is methyl.

In some embodiments of formula Xllb-i, R¹¹ is ethoxyethyl.

In some embodiments of formula Xllb-i, R¹¹ is methoxyethyl.

In some embodiments of formula Xllb-i, R¹³ and R^13b are each selected from methyl and ethyl. In some embodiments of formula Xllb-i, R¹³ and R^13b are each methyl.

In some embodiments of formula Xllb-i, R¹³ and R^13b are each ethyl.

In some embodiments, n is 1 and the compound of formula XI is selected from compounds of Formula XIIc, and salts, hydrates, and solvates thereof:

Formula XIIc

wherein

R¹¹ is C₁-C6 alkyl optionally substituted with one or more substituents selected from: Ci-C6 alkoxy; and

each of R^12a and R^12b is H; or one of R^12a and R^12b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.

In some embodiments, X¹ is O.

In some embodiments of formula XIIc, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula XIIc, R¹¹ is methyl.

In some embodiments of formula XIIc, R¹¹ is ethoxyethyl.

In some embodiments of formula XIIc, R¹¹ is methoxyethyl.

In some embodiments of formula XIIc, R¹⁴ is methyl.

In some embodiments of formula XIIc, the carbon bearing R¹⁴ has (R) stereochemistry.

In some embodiments of formula XIIc, the carbon bearing R¹⁴ has (S) stereochemistry.

In some embodiments of formula XIIc, each of R¹² and R^12b is H.

In some embodiments of formula XIIc, one of R^12a and R^12b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.

In some embodiments of formula XIIc, one of R¹² and R^12b is H and the other is selected from:

H, methyl, ethyl, propyl, methoxymethyl, CF₃ and 2,2,2-trifluoroethyl.

In some embodiments of formula XIIc, one of R¹² and R^12b is H and the other is methyl. In some embodiments of formula XIIc, one of R^12a and R^12b is H and the other is ethyl. In some embodiments of formula XIIc, one of R and R is H and the other is propyl,

In some embodiments of formula XIIc, one of R^12a and R^12b is H and the other is CF₃.

In some embodiments of formula XIIc, one of R^12a and R^12b is H and the other is 2,2,2- trifluoroethyl.

In some embodiments of formula XIIc, one of R^12a and R^12b is H and the other is CH₂OMe.

In some embodiments of formula XIIc, the carbon bearing R¹² and R^12b has (R)

stereochemistry.

In some embodiments of formula XIIc, the carbon bearing R¹² and R^12b has (S)

stereochemistry.

In some embodiments, n is 1 and the compound of formula XI is selected from compounds of Formula Xlld, and salts, hydrates, and solvates thereof:

Formula Xlld

wherein:

each of R^12a and R^12b is H; or one of R^12a and R^12b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula Xlld, X¹ is O.

In some embodiments of formula Xlld, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula Xlld, R¹¹ is methyl.

In some embodiments of formula Xlld, R¹¹ is ethoxyethyl.

In some embodiments of formula Xlld, R¹¹ is methoxyethyl.

In some embodiments of formula Xlld, R¹⁴ is methyl.

In some embodiments of formula Xlld, the carbon bearing R¹⁴has (R) stereochemistry. In some embodiments, the carbon bearing R¹⁴ has (S) stereochemistry.

In some embodiments of formula Xlld, each of R¹² and R^12b is H.

In some embodiments of formula Xlld, one of R^12a and R^12b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy. In some embodiments of formula Xlld, one of R and R is H and the other is selected from: H, methyl, ethyl, propyl, methoxymethyl, CF₃ and 2,2,2-trifluoroethyl.

_R12a _R12b

of formula Xlld, one of and is H and the other is methyl.

_R12a _R12b

of formula Xlld, one of and is H and the other is ethyl.

_R12a _R12b

of formula Xlld, one of and is H and the other is propyl.

_R12a _R12b

of formula Xlld, one of and is H and the other is CF₃.

_R12a _R12b

of formula Xlld, one of and is H and the other is 2,2,2- trifluoroethyl.

In some embodiments of formula Xlld, one of R^12a and R^12b is H and the other is CH₂OMe. In some embodiments of formula Xlld, the carbon bearing R¹² and R^12b has (R)

stereochemistry

IInn ssoommee embodiments of formula Xlld, the carbon bearing R and R has (S)

stereochemistry

In some embodiments, n is 1 and the compound of formula XI is selected from compounds of Formula Xlle, and salts, hydrates, and solvates thereof:

Formula Xlle

wherein:

In some embodiments of formula Xlle, X¹ is O.

In some embodiments of formula Xlle, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula Xlle, R¹¹ is methyl.

In some embodiments of formula Xlle, R¹¹ is ethoxyethyl.

In some embodiments of formula Xlle, R¹¹ is methoxyethyl.

In some embodiments of formula Xlle, R¹⁴ is methyl.

In some embodiments of formula Xlle, the carbon bearing R¹⁴ has (R) stereochemistry.

In some embodiments of formula Xlle, the carbon bearing R¹⁴ has (S) stereochemistry. In some embodiments of formula Xlle, each of R and R is H.

In some embodiments of formula Xlle, one of R^12a and R^12b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula Xlle, one of R¹² and R^12b is H and the other is selected from:

H, methyl, ethyl, propyl, methoxymethyl, CF₃ and 2,2,2-trifluoroethyl.

In some embodiments of formula Xlle, one of R¹² and R^12b is H and the other is methyl. In some embodiments of formula Xlle, one of R^12a and R^12b is H and the other is ethyl.

In some embodiments of formula Xlle, one of R¹² and R^12b is H and the other is propyl.

In some embodiments of formula Xlle, one of R^12a and R^12b is H and the other is CF₃.

In some embodiments of formula Xlle, one of R¹² and R^12b is H and the other is 2,2,2- trifluoroethyl.

In some embodiments of formula Xlle, one of R^12a and R^12b is H and the other is CH₂OMe. In some embodiments of formula Xlle, the carbon bearing R¹² and R^12b has (R)

stereochemistry.

In some embodiments of formula Xlle, the carbon bearing R¹² and R^12b has (S)

stereochemistry.

In some embodiments, n is 1 and the compound of formula XI is selected from compounds of Formula Xllf, and salts, hydrates, and solvates thereof:

Formula Xllf

wherein:

one of R¹³ and R^13b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.

In some embodiments of formula Xllf, X¹ is O.

In some embodiments of formula Xllf, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula Xllf, R¹¹ is methyl.

In some embodiments of formula Xllf, R¹¹ is ethoxyethyl. In some embodiments of formula Xllf, R¹¹ is methoxyethyl.

In some embodiments of formula Xllf, R¹⁴ is methyl.

In some embodiments of formula Xllf, the carbon bearing R¹⁴ has (R) stereochemistry.

In some embodiments of formula Xllf, the carbon bearing R¹⁴ has (S) stereochemistry.

In some embodiments of formula Xllf, one of R^13a and R^13b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula Xllf, one of R¹³ and R^13b is H and the other is selected from methyl and ethyl.

In some embodiments of formula Xllf, one of R¹³ and R^13b is H and the other is methyl. In some embodiments of formula Xllf, one of R^13a and R^13b is H and the other is ethyl.

In some embodiments of formula Xllf, the carbon bearing R¹³ and R^13b has (R) stereochemistry.

In some embodiments of formula Xllf, the carbon bearing R¹³ and R^13b has (S) stereochemistry.

In some embodiments, n is 1 and the compound of formula XI is selected from compounds of Formula Xllg, and salts, hydrates, and solvates thereof:

Formula Xllg

wherein:

In some embodiments of formula Xllg, X¹ is O.

In some embodiments of formula Xllg, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula Xllg, R¹¹ is methyl.

In some embodiments of formula Xllg, R¹¹ is ethoxyethyl.

In some embodiments of formula Xllg, R¹¹ is methoxyethyl.

In some embodiments of formula Xllg, R¹⁴ is methyl. In some embodiments of formula Xllg, the carbon bearing R has (R) stereochemistry. In some embodiments of formula Xllg, the carbon bearing R¹⁴has (S) stereochemistry. In some embodiments of formula Xllg, one of R^13a and R^13b is H and the other is Ci-C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C₆ alkoxy.

In some embodiments of formula Xllg, one of R¹³ and R^13b is H and the other is selected from methyl and ethyl.

In some embodiments of formula Xllg, one of R¹³ and R^13b is H and the other is methyl. In some embodiments of formula Xllg, one of R^13a and R^13b is H and the other is ethyl. In some embodiments of formula Xllg, the carbon bearing R¹³ and R^13b has (R) stereochemistry.

In some embodiments of formula Xllg, the carbon bearing R¹³ and R^13b has (S)

stereochemistry. In some embodiments of formula XII, n is 1 and the compound of formula XI is selected from compounds of Formula XlJh, and salts, hydrates, and solvates thereof:

Formula XlJh

wherein:

one of R¹³ and R^13b is H and the other is Ci-C6 alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C6 alkoxy.

In some embodiments of formula XlJh, X¹ is O.

In some embodiments of formula XlJh, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula XlJh, R¹¹ is methyl.

In some embodiments of formula XlJh, R¹¹ is ethoxyethyl.

In some embodiments of formula XlJh, R¹¹ is methoxyethyl.

In some embodiments of formula XlJh, R¹⁴ is methyl.

In some embodiments of formula XlJh, the carbon bearing R¹⁴has (R) stereochemistry. In some embodiments of formula XlJh, the carbon bearing R¹⁴has (S) stereochemistry. In some embodiments of formula XlJh, one of R and R is H and the other is C₁-C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy.

In some embodiments of formula Xllb, one of R¹³ and R^13b is H and the other is selected from methyl and ethyl.

In some embodiments of formula XlJh, one of R¹³ and R^13b is H and the other is methyl. In some embodiments of formula XIDi, one of R^13a and R^13b is H and the other is ethyl.

In some embodiments of formula XlJh, the carbon bearing R¹³ and R^13b has (R)

stereochemistry.

In some embodiments of formula XlJh, the carbon bearing R¹³ and R^13b has (S)

stereochemistry.

In some embodiments, n is 2 and the compound of Formula XI is selected from compounds of Formula XIIi, and salts, hydrates, and solvates thereof:

Formula XIIi

wherein:

R¹¹ is C₁-C6 alkyl optionally substituted with one or more substituents selected from: C₁-C6 alkoxy.

In some embodiments of formula XIIi, each R¹⁴ is the same.

In some embodiments of formula XIIi, the two R¹⁴ taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring.

In some embodiments of formula XIIi, the two R¹⁴ taken together with the carbon they are bonded to form a 3-membered spirocyclic ring.

In some embodiments of formula XIIi, the two R¹⁴ taken together with the carbon they are bonded to form a 4-membered spirocyclic ring.

In some embodiments of formula XIIi, the two R¹⁴ taken together with the carbon they are bonded to form a 5-membered spirocyclic ring.

In some embodiments of formula XIIi, each R¹⁴ is methyl.

In some embodiments of formula XIIi, each R¹⁴ is ethyl.

In some embodiments of formula XIIi, each R¹⁴ is propyl.

In some embodiments of formula XIIi, X¹ is O. In some embodiments of formula Xlli, R¹¹ is selected from methyl, ethoxyethyl and methoxyethyl.

In some embodiments of formula Xlli, R¹¹ is methyl.

In some embodiments of formula Xlli, R¹¹ is ethoxyethyl.

In some embodiments of formula Xlli, R¹¹ is methoxyethyl.

In some embodiments, the salts, hydrates, and solvates of the compounds of Formula XII, including Formulae Xlla-i, Xllb-i, and XIIc, Xlld, ΧΠε, Xllf, Xllg, Xllh and Xlli, are

pharmaceutically acceptable salts, hydrates, and solvates.

Some embodiments of Formula XI include every combination of one or more compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group shown in Table AA.

Table AA

Some embodiments of Formula XI include every combination of one or more compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group:

,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole-8-carboxarnide (compound 124):

7Y-methyl-6-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l- i;^']indole-8-carboxamide (compound 125):

4-ethyl-A^?-methyl-l,2 ,4,6 -hexahydro-[l,4]diazepino[6 J-i;]indole-8-carboxamide (compound 126):

^ 2-ethoxyethyl)-7 2,2,2 rifluoroemyl) ,23,4,6J-hexahydro 1,4]diazepino[6JJ-i;]indole-8-

A^?-butyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-i;^']indole-8-carboxamide

A^?-propyl-7-(2,2,2-trifluoroethyl)-l,2 ,4,6 -hexahydro-[l,4]diazepino[6 J-i;]indole-8-carboxamide

A^?-(2-methoxyethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-i;^']indole- carboxamide (compound 130):

A^?-(2-isopropoxyethyl)-7-(2,2,2-trifluoroethyl)-l,2 ,4,6 -hexahydro-[l,4]diazepino[6,7J- i;]ind

N-ethyl-7-(2,2,2-trifluoroethyl)-l, 2,3,4,6 ,7-hexahydro-[l,4]diazepino[6,7 ,1 - i;]indole-8-carboxamide

^ 2-fluoroemyl)-7-(2,2,2 rifluoroemyl) ,2,3,4,6,7-hexahydro 1,4]diazepino[6,7,l-/i;]indole-8- ):

iV-(2,2-difluoroethyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole- carboxamide (compound 134):

(R)-^ropyl-7-(2,2,2 rifluoroemyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l-/i;]indole-8- :

(S)-^ropyl-7 2,2,2 rifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l-/i;]indole-8- carboxamide (compound 136):

A^? -bis(2,2,2-trifluoroemyl)-l,2 ,4,6 -hexahydro-[l,4]diazepino[6 J- i;]indole-8-carboxam

V-(2,2,3,3,3-pentafluoropropyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- ']indole-8-carboxamide (compound 138):

7-emyl-A^?-(2-fluoroethyl)-l,23,4,6,7-hexahydro-[l,4]diazepino[6,7J- i;]indole-8-carboxamide

iV-(2,2-difluoroethyl)-7-ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7 ,l- i;]indole-8-carboxamide (compound 140):

In some embodiments, provided herein are intermediates disclosed in Figures 21a, 21b, 21c, 21d, 22, and 23, wherein the variables in the figures have the same definition as described herein.

Formula XXI:

Formula XXI wherein:

each of R²⁵ and R²⁶ is independently hydrogen or C₁-C6 alkyl;

R²⁷ is hydrogen, Ci-C₆ alkyl or C₃-C₇ cycloalkyl;

R²⁸ is hydrogen or C₁-C6 alkyl;

R²⁴ is hydrogen, halogen, hydroxy, C₃-C₇ cycloalkyl, Ci-C6 alkoxy or Ci-C6 alkyl optionally substituted with Ci-C₆ alkoxy; and

R²¹ is selected from the group consisting of:

hydrogen;

halogen;

Ci-C₆ alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C6 alkoxy, amino, heteroarylamino, arylamino, C₁-C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with Ci-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-C6 alkoxy, or C₃-C₇ cycloalkyl optionally substituted with Ci-C6 alkoxy;

aryl;

heteroaryl;

C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy;

amino;

C₁-C6 alkylamino optionally substituted with C₁-C6 alkoxy or with hydroxy;

C₁-C6 dialkylamino optionally substituted with C₁-C6 alkoxy or with hydroxy; arylamino;

C₁-C6 alkoxy optionally substituted with one or more halogens; hydroxy;

-NHCO-Ci-Ce alkyl; -NHCO(0)Ci-C₆ alkyl;

-OCO(NH)Ci-C₆ alkyl;

and

CN;

The Group R²¹

In some embodiments, R²¹ is selected from the group consisting of:

hydrogen;

halogen;

C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, Ci-C₆ alkoxy, amino, heteroarylamino, arylamino, C C6 dialkylamino, aryl, Ci-C6 alkoxycarbonyl, Ci-C6 alkylamino optionally substituted with C₁-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with Ci-

C6 alkoxy, or C₃-C₇ cycloalkyl optionally substituted with Ci-C6 alkoxy;

aryl;

heteroaryl;

C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy;

amino;

C₁-C6 alkylamino optionally substituted with C₁-C6 alkoxy or with hydroxy;

Ci-C₆ dialkylamino optionally substituted with Ci-C₆ alkoxy or with hydroxy;

arylamino;

C₁-C6 alkoxy optionally substituted with one or more halogens;

hydroxy;

-NHCO-Ci-Ce alkyl;

-NHCO(0)Ci-C₆ alkyl;

-OCO(NH)Ci-C₆ alkyl;

and

CN.

In some embodiments, R²¹ is selected from the group consisting of:

hydrogen;

halogen;

C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C₃-C₇ cycloalkyl optionally substituted with Ci-C₆ alkoxy;

and

C3-C7 cycloalkyl.

In some embodiments, R²¹ is hydrogen. In some embodiments, R is halogen. In some embodiments, R is chlorine. In some embodiments, R²¹ is bromine. In some embodiments, R²¹ is fluorine. In some embodiments, R²¹ is iodine.

In some embodiments, R²¹ is Ci-C₆ alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, C₁-C6 alkoxy, amino, heteroarylamino, arylamino, C₁-C6 dialkylamino, aryl, C₁-C6 alkoxycarbonyl, C₁-C6 alkylamino optionally substituted with alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with C₁-C6 alkoxy, or C3-C7 cycloalkyl optionally substituted with Ci-C₆ alkoxy.

In some embodiments, R²¹ is C₁-C6 alkyl.

In some embodiments, R²¹ is C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy.

In some embodiments, R²¹ is C₁-C6 alkyl optionally substituted with one or more substituents each of which is halogen. In some embodiments, R²¹ is Ci-C₆ alkyl optionally substituted with one or more substituents each of which is fluorine. In some embodiments, R²¹ is 3,3,3-trifluoropropyl.

In some embodiments, R²¹ is C₁-C6 alkyl optionally substituted with one or more substituents each of which is C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy.

In some embodiments, R²¹ is methyl. In some embodiments, R²¹ is ethyl. In some embodiments, R²¹ is propyl. In some embodiments, R²¹ is isobutyl.

In some embodiments, R²¹ is aryl.

In some embodiments, R²¹ is heteroaryl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is triazolyl. In some embodiments, the triazolyl is 1,2,4-triazol-l-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is pyrazolyl. In some embodiments, the pyrazol is pyrazol-l-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is pyrazolyl. In some embodiments, the pyrazol is pyrazol-3-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is pyrazolyl. In some embodiments, the pyrazol is pyrazol-4-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is pyrazolyl. In some embodiments, the pyrazol is pyrazol-5-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is imidazolyl. In some embodiments, the imidazol is imidazol-l-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is pyrrolyl. In some embodiments, the pyrrolyl is pyrrol-2-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is thiophenyl. In some embodiments, the thiophenyl is thiophen-3-yl.

In some embodiments, R²¹ is heteroaryl, wherein the heteroaryl is furanyl. In some embodiments, the furanyl is furan-2-yl. In some embodiments R is C₁-C6 alkyl substituted with C₁-C6 alkoxy. In some embodiments, R²¹ is methoxymethyl. In some embodiments, R²¹ is isopropoxymethyl.

In some embodiments, R is C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy.

In some embodiments, R²¹ is amino.

In some embodiments, R²¹ is C₁-C6 alkylamino optionally substituted with C₁-C6 alkoxy or with hydroxy.

In some embodiments, R²¹ is C₁-C6 dialkylamino optionally substituted with C₁-C6 alkoxy or with hydroxy.

In some embodiments, R²¹ is arylamino.

In some embodiments, R²¹ is C₁-C6 alkoxy optionally substituted with one or more halogens.

In some embodiments, R²¹ is hydroxyl.

In some embodiments, R²¹ is -NHCO-Ci-Ce alkyl.

In some embodiments, R²¹ is -NHCO(0)C C₆ alkyl.

In some embodiments, R²¹ is -OCO(NH)Ci-C₆ alkyl.

In some embodiments, R²¹ is CN.

The Groups R²² and R²³

In some embodiments, each of R²² and R²³ is independently hydrogen or C₁-C6 alkyl optionally substituted with one or more halogens.

In some embodiments, R²² is hydrogen.

In some embodiments, R²³ is hydrogen.

In some embodiments, each of R²² and R²³ is hydrogen.

In some embodiments, R²² is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines.

In some embodiments, R²³ is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines.

In some embodiments, each of R²² and R²³ is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines. In some embodiments, each of R²² and R²³ is methyl. In some embodiments, each of R 22 and R 23 is ethyl. In some embodiments, each of R 22 and R 23 is propyl. In some embodiments, each of R 22 and R 23 is isobutyl. In some embodiments, each of R 22 and R 23 is 2,2,2-trifluoroethyl.

In some embodiments, one of R²² and R²³ is hydrogen and the other is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines. In some embodiments, one of

R 22 and R 23 is hydrogen and the other is methyl. In some embodiments, one of R 2^{^}2 and R 2^{^}3 is hydro gen and the other is ethyl. In some embodiments, one of R²² and R²³ is hydrogen and the other is propyl. In some embodiments, one of R²² and R²³ is hydrogen and the other is isobutyl. In some embodiments, one of R²² and R²³ is hydrogen and the other is 2,2,2-trifluoroethyl. In some embodiments, one of R and R is hydrogen, the other is C₁-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines, and the carbon attached to R²² and R 23 has (R) stereochemistry. In some embodiments, one of R 22 and R 23 is hydrogen, the other is methyl, and the carbon attached to R²² and R²³ has (R) stereochemistry.

In some embodiments, one of R²² and R²³ is hydrogen, the other is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines, and the carbon attached to R²² and R 23 has (S) stereochemistry. In some embodiments, one of R 22 and R 23 is hydrogen, the other is methyl, and the carbon attached to R²² and R²³ has (S) stereochemistry.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a three-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a four-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a five-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a six-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a seven-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C6 alkyl, and Ci-C6 alkoxy.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a three-membered heterocyclic ring containing one heteroatom which is O, N or S.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a four-membered heterocyclic ring containing one heteroatom which is O, N or S.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a five-membered heterocyclic ring containing one or two heteroatoms each of which is independently O, N or S. In some embodiments, the five-membered heterocyclic ring contains one heteroatom which is O. In some embodiments, the five-membered heterocyclic ring contains one heteroatom which is N.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a six-membered heterocyclic ring containing one or two heteroatoms each of which is independently O, N or S. In some embodiments, the six-membered heterocyclic ring contains one heteroatom which is O. Γη some embodiments, the six-membered heterocyclic ring contains one heteroatom which is N. In some embodiments, the six-membered heterocyclic ring contains one heteroatom which is N and one heteroatom which is O. In some embodiments, the six-membered heterocyclic ring contains two heteroatoms each of which is N.

In some embodiments, R²² and R²³ taken together with the carbon they are bonded to form a seven-membered heterocyclic ring containing one or two heteroatoms each of which is independently O, N or S. In some embodiments, the seven-membered heterocyclic ring contains one heteroatom which is N. In some embodiments, the seven-membered heterocyclic ring contains two heteroatoms each of which is N.

The Groups R²⁵and R²⁶

In some embodiments, each of R²⁵ and R²⁶ is independently hydrogen or Ci-C6 alkyl.

In some embodiments, R²⁵ is hydrogen.

In some embodiments, R²⁶ is hydrogen.

In some embodiments, each of R²⁵ and R²⁶ is hydrogen.

In some embodiments, R²⁵ is Ci-C6 alkyl.

In some embodiments, R²⁶ is Ci-C₆ alkyl.

In some embodiments, each of R²⁵ and R²⁶ is Ci-C6 alkyl. In some embodiments, each of R²⁵ and R²⁶ is methyl.

In some embodiments, one of R²⁵ and R²⁶ s hydrogen and the other is Ci-C6 alkyl. In some embodiments, one of R²⁵ and R²⁶ is hydrogen and the other is methyl.

In some embodiments, one of R²⁵ and R²⁶ is hydrogen, the other is Ci-C₆ alkyl, and the carbon attached to R²⁵ and R²⁶ has (R) stereochemistry. In some embodiments, one of R²⁵ and R²⁶ is hydro gen, the other is methyl, and the carbon attached to R²⁵ and R²⁶ has (R) stereochemistry.

In some embodiments, one of R²⁵ and R²⁶ is hydrogen, the other is Ci-C6 alkyl, and the carbon attached to R²⁵ and R²⁶ has (S) stereochemistry. In some embodiments, one of R²⁵ and R²⁶ is hydro gen, the other is methyl, and the carbon attached to R²⁵ and R²⁶ has (S) stereochemistry.

The Group R²⁴

In some embodiments, R²⁴ is hydrogen, halogen, hydroxy, C₃-C₇ cycloalkyl, Ci-C6 alkoxy or

Ci-C₆ alkyl optionally substituted with Ci-C₆ alkoxy.

In some embodiments, R²⁴ is hydrogen.

In some embodiments, R²⁴ is halogen. In some embodiments, R²⁴ is bromine. In some embodiments, R²⁴ is chlorine. In some embodiments, R²⁴ is fluorine.

In some embodiments, R²⁴ is hydroxy.

In some embodiments, R²⁴ is C₃-C₇ cycloalkyl,

In some embodiments, R²⁴ is cyclopropyl,

In some embodiments, R²⁴ is Ci-C6 alkoxy. In some embodiments, R is methoxy.

In some embodiments, R²⁴ is C₁-C6 alkyl optionally substituted with Ci-Ce alkoxy.

In some embodiments, R²⁴ is methyl.

In some embodiments, R²⁴ is 2-ethoxyethyl.

The Group R²⁷

In some embodiments, R²⁷ is hydrogen, C₃-C₇ cycloalkyl or Ci-C6 alkyl.

In some embodiments, R²⁷ is hydrogen.

In some embodiments, R²⁷ is C₃-C₇ cycloalkyl.

In some embodiments, R²⁷ is cyclopropyl.

In some embodiments, R²⁷ is Ci-C₆ alkyl.

In some embodiments, R²⁷ is methyl.

In some embodiments, R²⁷ is Ci-C₆ alkyl, and the carbon attached to R²⁷ has (R) stereochemistry. In some embodiments, R^z/ is methyl, and the carbon attached to R^z/ has (R) stereochemistry.

In some embodiments, R²⁷ is Ci-C6 alkyl, and the carbon attached to R²⁷ has (S) stereochemistry. In some embodiments, R²⁷ is methyl, and the carbon attached to R²⁷ has (S) stereochemistry.

The Group R²⁸

In some embodiments, R²⁸ is hydrogen or Ci-C6 alkyl.

In some embodiments, R²⁸ is hydrogen.

In some embodiments, R²⁸ is Ci-C₆ alkyl.

In some embodiments, R²⁸ is methyl.

In some embodiments, R²⁸ is Ci-C6 alkyl, and the carbon attached to R²⁸ has (R) stereochemistry. In some embodiments, R²⁸ is methyl, and the carbon attached to R²⁸ has (R) stereochemistry.

In some embodiments, R²⁸ is Ci-C6 alkyl, and the carbon attached to R²⁸ has (S) stereochemistry. In some embodiments, R²⁸ is methyl, and the carbon attached to R²⁸ has (S) stereochemistry. In some embodiments the compounds of Formula XXI are selected from compounds of

Formula XXII, and salts, hydrates, and solvates thereof:

R is selected from the group consisting of

hydrogen;

halogen;

Ci-C₆ alkyl optionally substituted with one or more substituents each of which is independently halogen or C₃-C₇ cycloalkyl;

and

C3-C7 cycloalkyl;

R²² is hydrogen or Ci-C₆ alkyl optionally substituted with halogen;

R²³ is hydrogen or C₁-C6 alkyl optionally substituted with halogen;

22 23 22 wherein if each of R and R is C₁-C6 alkyl optionally substituted with halogen, then R and R²³ are the same;

or R²² and R²³ taken together with the carbon they are bonded to form a three-membered carbocyclic ring, a four-membered carbocyclic ring, a five-membered carbocyclic ring or a six- membered carbocyclic ring;

and R²⁴ is hydrogen, bromine or chlorine;

24 21 22 23

provided that if R is hydrogen, at least one of R , R , and R is other than hydrogen;

and provided that if R²⁴ is bromine or chlorine, R²¹ is other than hydrogen.

In some embodiments the compounds of Formula XXI are selected from compounds of Formula XXII, and salts, hydrates, and solvates thereof:

Formula XXII

wherein:

R²¹ is selected from the group consisting of

hydrogen;

halogen;

C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C3-C7 cycloalkyl;

and

C3-C7 cycloalkyl;

R²² is hydrogen or C₁-C6 alkyl optionally substituted with halogen;

R²³ is hydrogen or C₁-C6 alkyl optionally substituted with halogen;

22 23 23 wherein if each of R and R is C₁-C6 alkyl optionally substituted with halogen, then R and R²³ are the same; or R and R taken together with the carbon they are bonded to form a three-membered carbocyclic ring, a four-membered carbocyclic ring, a five-membered carbocyclic ring or a six- membered carbocyclic ring;

and R² is hydrogen;

21 22 23

provided that at least one of R , R , and R is other than hydrogen.

Formula XXII

wherein:

R²¹ is selected from the group consisting of

halogen;

Ci-Ce alkyl optionally substituted with one or more substituents each of which is independently halogen , or C₃-C₇ cycloalkyl;

and

C3-C7 cycloalkyl;

R²² is hydrogen or C₁-C6 alkyl optionally substituted with halogen;

R²³ is hydrogen or C₁-C6 alkyl optionally substituted with halogen;

and R²⁴ is bromine or chlorine.

In some embodiments the compounds of Formula XXII are selected from compounds of Formula XXIIa, and salts, hydrates, and solvates thereof:

Formula XXIIa

wherein: R is selected from the group consisting of

hydrogen;

halogen;

and

C3-C7 cycloalkyl;

R²² is hydrogen or Ci-C₆ alkyl optionally substituted with halogen;

and R²⁴ is hydrogen

provided that at least one of R²¹ and R²² is other than hydrogen.

Formula XXIIa

wherein:

R²¹ is selected from the group consisting of

halogen;

and

C3-C7 cycloalkyl;

R²² is hydrogen or C₁-C6 alkyl optionally substituted with halogen;

and R²⁴ is bromine or chlorine.

In some embodiments the compounds of Formula XXIIa are selected from compounds of Formula XXIIa-i, and salts, hydrates, and solvates thereof:

Formula XXIIa-i

wherein:

R is C₁-C6 alkyl optionally substituted with halogen;

R²¹ is selected from the group consisting of hydrogen;

halogen;

Ci-Ce alkyl optionally substituted with one or more substituents each of which is independently halogen or C₃-C₇ cycloalkyl;

and

C3-C7 cycloalkyl; and

R²⁴ is hydrogen.

In some embodiments of Formula XXIIa-i, R²² is Ci-C₆ alkyl optionally substituted with one or more substituents each of which is fluorine.

wherein:

R²² is C₁-C6 alkyl optionally substituted with halogen;

R²¹ is selected from the group consisting of

halogen;

C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or C₃-C₇ cycloalkyl;

and

C3-C7 cycloalkyl.

and

R²⁴ is bromine or chlorine.

In some embodiments of Formula XXIIa-i, R²² is C₁-C6 alkyl optionally substituted with one or more substituents each of which is fluorine.

In some embodiments the compounds of Formula XXIIa are selected from compounds of Formula XXIIa-ii, and salts, hydrates, and solvates thereof:

Formula XXIIa-ii

wherein:

R²² is C₁-C6 alkyl optionally substituted with halogen;

R²¹ is selected from the group consisting of

hydrogen;

halogen;

and

C3-C7 cycloalkyl; and

R²⁴ is hydrogen.

In some embodiments of Formula XXIIa-ii, R² is C₁-C6 alkyl optionally substituted with one or more substituents each of which is fluorine.

R is C₁-C6 alkyl optionally substituted with halogen;

R²¹ is selected from the group consisting of

halogen;

and

C3-C7 cycloalkyl; and

R²⁴ is bromine or chlorine.

In some embodiments of Formula XXIIa-ii, R²² is C₁-C6 alkyl optionally substituted with one or more substituents each of which is fluorine.

Formula XXII

wherein:

R²¹ is selected from the group consisting of

hydrogen;

halogen;

and

CVC₇ cycloalkyl;

R²² and R²³ are the same and each is hydrogen or Ci-C₆ alkyl optionally substituted with halogen;

and

R² is hydrogen;

provided that at least one of R²¹, R²² and R²³ is other than hydrogen. In some embodiments the compounds of Formula XXI are selected from compounds of

Formula XXII, and salts, hydrates, and solvates thereof:

R is selected from the group consisting of

halogen;

C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen or CVC₇ cycloalkyl;

and

C3-C7 cycloalkyl; R and R are the same and each is hydrogen or C₁-C6 alkyl optionally substituted with halogen;

and

R²⁴ is bromine or chlorine.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa- ii), R²¹ is selected from the group consisting of

hydrogen;

halogen;

and

C3-C7 cycloalkyl.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²¹ is selected from the group consisting of:

halogen;

and

C3-C7 cycloalkyl.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²¹ is bromine. In some embodiments, R²¹ is chlorine. In some embodiments, R²¹ is iodine. In some embodiments, R²¹ is fluorine. In some embodiments wherein R²¹ is fluorine in Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²² is other than hydrogen.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²¹ is methyl. In some embodiments, R²¹ is ethyl. In some embodiments, R²¹ is propyl. In some embodiments, R²¹ is isobutyl.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²¹ is hydrogen.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and

XXIIa-ii), R 2^Z2ⁱ is methyl. In some embodiments, R 22 is ethyl. In some embodiments, R 22 is propyl. In some embodiments, R²² is isobutyl. In some embodiments, R²² is 2,2,2-trifluoroethyl.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²² is hydrogen. In some embodiments of Formula XXI, including XXII, R is methyl. In some embodiments,

23 23 23

R" is ethyl. In some embodiments, R is propyl. In some embodiments, R is isobutyl. In some embodiments, R²³ is 2,2,2-trifluoroethyl.

In some embodiments of Formula XXI, including XXII, R²³ is hydrogen.

In some embodiments of Formula XXI, including XXII, each of R²² and R²³ is Ci-C6 alkyl optionally substituted with one or more halogens, such as one or more fluorines. In some embodiments of Formula XXI, including XXII, each of R²² and R²³ is methyl. In some embodiments of Formula

XXI, including XXII, each of R²² and R²³ is ethyl. In some embodiments of Formula XXI, including

XXII, each of R²² and R²³ is propyl. In some embodiments of Formula XXI, including XXII, each of R²² and R²³ is 2,2,2-trifluoroethyl.

In some embodiments of Formula XXI, including XXII, R² and R²³ taken together with the carbon they are bonded to form a three-membered carbocyclic ring. In some embodiments of Formula XXI, including XXII, R²² and R²³ taken together with the carbon they are bonded to form a four- membered carbocyclic ring. In some embodiments of Formula XXI, including XXII, R² and R²³ taken together with the carbon they are bonded to form a five-membered carbocyclic ring. In some embodiments of Formula XXI, including XXII, R²² and R²³ taken together with the carbon they are bonded to form a six-membered carbocyclic ring.

In some embodiments of Formula XXI, R is methyl.

In some embodiments of Formula XXI, R²⁵ is hydrogen.

In some embodiments of Formula XXI, R²⁷ is methyl.

In some embodiments of Formula XXI, R²⁷ is hydrogen.

In some embodiments of Formula XXI, R²⁶ is methyl.

In some embodiments of Formula XXI, R²⁶ is hydrogen.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²⁴ is hydrogen.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²⁴ is chlorine.

In some embodiments of Formula XXI, including XXII and XXIIa, (including XXIIa-i and XXIIa-ii), R²⁴ is bromine.

In some embodiments, the salts, hydrates, and solvates of the compounds of Formula XXII, including Formulae XXIIa, XXIIa-i, and XXIIa-ii, are pharmaceutically acceptable salts, hydrates, and solvates.

Some embodiments include every combination of one or more compounds and

pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group shown in Table AAA.

Table AAA

Compound Chemical Name

Chemical Structure

No. ethyl (7,7-dimethyl- 1,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i^']indol-

286 8-yl)carbamate

9-fluoro-7,7-dimethyl- 1,2,3,4,6,7-hexahydro-

287

[l,4]diazepino[6,7,l-¾i] indole

7,7-dimethyl-9-propyl- 1,2,3,4,6,7-hexahydro-

288 [l,4]diazepino[6,7,l-¾i] indole

289 ⁶5 2,3,4,6-tetrahydro-lH- spiro[[ 1 ,4]diazepino[6,7, 1 - /w^']indole-7,r-cyclopentane]

Some embodiments of Formula XXI include every combination of one or more compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof selected from the following group: 8-bromo-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- i;]indole-7,l'-cyclobutane] (compound

l)- 1,2, 3,4,6,7 -hexahydro-[l,4]diazepino[6,7,l- i;^']indole (compound 291):

trahydro-lH-spiro[[l,4]diazepino[6,7,l- i;^']indole-7,r-cyclobutane] (compound 292):

8-methyl-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- i;^']indole-7,r-cyclobutane] (compound 293): 2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole (compound 294):

8-(lH-imidazol-l-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/i;^'] indole (compound 295):

8-(lH-pyrrol-2-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- j ]indole (compound 296):

fluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole (compound 297):

8-(tliiophen-3-yl)-l,2,3,4,6,7-hexaliydro-[l,4]diazepino[6,7,l - j ]indole (compound 298): 3,4,6,7-hexahydro-[l,4]diazepino[6,7, l- i;^']indole (compound 299):

8-(lH-pyrazol-5-yl)-l,2,3,4,6,7-hexaliydro-[l,4]diazepino[6,7,l-/7 ]indole (compound 300):

8-(methoxymethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/i;^']indole (compound 301):

,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole (compound 302):

,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l - i;]indole (compound 303):

xahydro-[l,4]diazepino[6,7, l- i;^']indole (compound 304):

8-(lH-pyrazol-4-yl)- l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l- i;^']indole (compound 305):

Some embodiments of Formula XXI include 6,7-dimethyl- l,2,3,4,6,7-hexahydro- [6,7, l- i;^']indole (compound 306):

Additionally, individual compounds and chemical genera provided herein, including, isomers, diastereoisomers and enantiomers thereof, encompass all pharmaceutically acceptable salts, hydrates, and solvates, thereof. Further, mesoisomers of individual compounds and chemical genera provided herein encompass all pharmaceutically acceptable salts, solvates and particularly hydrates, thereof.

The compounds provided herein may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples. Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3^rd Edition, 1999 [Wiley]).

It is understood that the present invention(s) embrace, each isomer, each diastereoisomer, each enantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers and enantiomers (such as, by chiral HPLC,

recrystallization of diastereoisomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers can be accomplished by application of various methods which are well known to practitioners in the art.

Also provided are compounds for use in a method for treatment of the human or animal body by therapy.

Also provided are compounds for use in a method for decreasing food intake.

Also provided are compounds for use in a method for inducing satiety.

Also provided are compounds for use in a method for the treatment of obesity.

Also provided are compounds for use in a method for the prevention of obesity.

Also provided are compounds for use in weight management.

In some embodiments, the weight management further comprises a surgical weight loss procedure.

In some embodiments, the weight management comprises weight loss.

In some embodiments, the weight management comprises maintenance of weight loss.

In some embodiments, the weight management further comprises a reduced-calorie diet. In some embodiments, the weight management further comprises a program of regular exercise.

In some embodiments, the weight management further comprises both a reduced-calorie diet and a program of regular exercise.

In some embodiments, the individual in need of weight management is an obese patient with an initial body mass index > 30 kg/m².

In some embodiments, the individual in need of weight management is an overweight patient with an initial body mass index > 27 kg/m² in the presence of at least one weight related comorbid condition.

In some embodiments, the weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.

Also provided are compounds for use in the treatment of antipsychotic-induced weight gain.

Also provided are compounds for use in a method for the treatment of type 2 diabetes.

Also provided are compounds for use in a method for the treatment of type 2 diabetes in combination with one or more type 2 diabetes medications.

In some embodiments, the need for the one or more type 2 diabetes treatments is reduced.

In some embodiments, the need for the one or more type 2 diabetes treatments is eliminated.

Also provided are compounds for use in a method for the prevention of type 2 diabetes.

In some embodiments the need for other type 2 diabetes treatments is reduced.

In some embodiments the need for other type 2 diabetes treatments is eliminated.

Also provided are compounds for use in a method for the treatment of Prader-Willi syndrome.

Also provided are compounds for the treatment of addiction.

Also provided are compounds for the treatment of drug and alcohol addiction.

Also provided are compounds for the treatment of alcohol addiction. Also provided are compounds for the treatment of drug addiction.

In some embodiments, the drug is selected from amphetamine, a substituted amphetamine, a benzodiazepine, an atypical benzodiazepine receptor ligand, marijuana, cocaine, dextromethorphan, GHB, LSD, ketamine, a monoamine reuptake inhibitor, nicotine, an opiate, PCP, a substituted phenethylamine, psilocybin, and an anabolic steroid.

In some embodiments, the drug is nicotine.

In some embodiments, the drug is amphetamine.

In some embodiments, the drug is a substituted amphetamine.

In some embodiments, the drug is methamphetamine.

In some embodiments, the drug is a benzodiazepine.

In some embodiments, the drug is an atypical benzodiazepine receptor ligand.

In some embodiments, the drug is marijuana.

In some embodiments, the drug is cocaine.

In some embodiments, the drug is dextromethorphan.

In some embodiments, the drug is GHB.

In some embodiments, the drug is LSD.

In some embodiments, the drug is ketamine.

In some embodiments, the drug is a monoamine reuptake inhibitor.

In some embodiments, the drug is an opiate.

In some embodiments, the drug is PCP.

In some embodiments, the drug is a substituted phenethylamine.

In some embodiments, the drug is psilocybin.

In some embodiments, the drug is an anabolic steroid.

Also provided are compounds for aiding smoking cessation.

Also provided are compounds for the treatment of tobacco dependence.

Also provided are compounds for the treatment of nicotine dependence.

Also provided are compounds for the treatment of alcoholism.

Also provided are compounds for use in a method for the treatment of pathological gambling. Also provided are compounds for use in a method for the treatment of reward deficiency syndrome.

Also provided are compounds for use in a method for the treatment of sex addiction.

Also provided are compounds for use in a method for the treatment of an obsessive-compulsive spectrum disorder.

Also provided are compounds for use in a method for the treatment of an impulse control disorder.

for use in a method for the

for use in a method for the Also provided are compounds for use in a method for the

Also provided are compounds for use in a method for the

architecture.

Also provided are compounds for use in a method for the

wave sleep.

Also provided are compounds for use in a method for the

movement disorder.

Also provided are compounds for use in a method for the

disease

Also provided are compounds for use in a method for the

disease

Also provided are compounds for use in a method for the

INDICATIONS

Weight Management

FDA approved for weight loss, BELVIQ is used along with a reduced-calorie diet and increased physical activity for chronic weight management in adults who are: obese (BMI of 30 kg/m² or greater), or overweight (BMI of 27 kg/m² or greater) with at least one weight-related medical condition (for example, high blood pressure, high cholesterol, or type 2 diabetes) (www.belviq.com).

In some embodiments, an individual in need of weight management is an individual who is overweight. In some embodiments, an individual in need of weight management is an individual who has excess visceral adiposity. In some embodiments, an individual in need of weight management is an individual who is obese. To determine whether an individual is overweight or obese one can determine a body weight, a body mass index (BMI), a waist circumference or a body fat percentage of the individual to determine if the individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.

Determination of body weight can be through the use of a visual estimation of body weight, the use of a weight measuring device, such as an electronic weight scale or a mechanical beam scale. In some embodiments, an individual in need of weight management is an adult male with a body weight greater than about 90 kg, greater than about 100 kg, or greater than about 110 kg. In some

embodiments, an individual in need of weight management is an adult female with a body weight greater than about 80 kg, greater than about 90 kg, or greater than about 100 kg. In some embodiments, the individual is prepubertal and has a body weight greater than about 30 kg, greater than about 40 kg, or greater than about 50 kg.

Whether an individual is overweight or obese can be determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m²). Thus, the units of BMI are kg/m² and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. According to the classification from the World Health Organization (W.H.O.), overweight is defined as a BMI in the range 25-30 kg/m², and obesity as a BMI greater than 30 kg/m² (see below for a detailed W.H.O. BMI classification).

The International Classification of Adult Underweight, Overweight, and Obesity

According to BMI (World Health Organization)

The healthy range of BMI, and other measures of whether one is overweight or obese, can also be dependent on genetic or racial differences. For example, since Asian populations develop negative health consequences at a lower BMI than Caucasians, some nations have redefined obesity for their populations. For example, in Japan any BMI greater than 25 is defined as obese and in China any BMI greater than 28 is defined as obese. Similarly, different threshold values for body weight, waist circumference or body fat percentage can be used for different populations of individuals. The additional cut-off points included in the table above (for example, 23, 27.5, 32.5 and 37.5) were added as points for public health action. The WHO recommends that countries should use all categories for reporting purposes with a view to facilitating international comparisons.

Determination of BMI can be through the use of a visual estimation of BMI, the use of a height measuring device such as a stadiometer or a height rod and the use of a weight measuring device, such as an electronic weight scale or a mechanical beam scale. In some embodiments, the individual in need of weight management is an adult with a BMI of greater than about 25 kg/m², greater than about 26 kg/m², greater than about 27 kg/m², greater than about 28 kg/m², greater than about 29 kg/m², greater than about 30 kg/m², greater than about 31 kg/m², greater than about 32 d kg/m², greater than about 33 kg/m², greater than about 34 kg/m², greater than about 35 kg/m², greater than about 36 kg/m², greater than about 37 kg/m², greater than about 38 kg/m², greater than about 39 kg/m², or greater than about 40 kg/m². In some embodiments, the individual is prepubertal with a BMI of greater than about 20 kg/m , greater than about 21 kg/m², greater than about 22 kg/m², greater than about 23 kg/m², greater than about 24 kg/m², greater than about 25 kg/m², greater than about 26 kg/m², greater than about 27 kg/m², greater than about 28 kg/m², greater than about 29 kg/m², greater than about 30 kg/m², greater than about 31 kg/m², greater than about 32 kg/m², greater than about 33 kg/m², greater than about 34 kg/m², or greater than about 35 kg/m².

Determination of waist circumference can be through the use of a visual estimation of waist circumference or the use of a waist circumference measuring device such as a tape measure.

Determinations of the healthy range of waist circumference and percentage body fat in an individual are dependent on gender. For example, women typically have smaller waist circumferences than men and so the waist circumference threshold for being overweight or obese is lower for a woman. In addition, women typically have a greater percentage of body fat than men and so the percentage body fat threshold for being overweight or obese for a woman is higher than for a man. Further, the healthy range of BMI and other measures of whether one is overweight or obese can be dependent on age. For example, the body weight threshold for considering whether one is overweight or obese is lower for a child (prepubertal individual) than an adult.

In some embodiments, the individual in need of weight management is an adult male with a waist circumference of greater than about 100 cm, greater than about 110 cm, greater than about 120 cm, greater than about 110 cm or an adult female with a waist circumference of greater than about 80 cm, greater than about 90 cm, or greater than about 100 cm. In some embodiments, the individual is prepubertal with a waist circumference of about of greater than about 60 cm, greater than about 70 cm, or greater than about 80 cm.

Determination of body fat percentage can be through the use of a visual estimation of body fat percentage or the use of a body fat percentage measuring device such as bioelectric impedance, computed tomography, magnetic resonance imaging, near infrared interactance, dual energy X ray absorptiometry, use of ultrasonic waves, use of body average density measurement, use of skinfold methods, or use of height and circumference methods. In some embodiments, the individual in need of weight management is an adult male with a body fat percentage of greater than about 25%, greater than about 30%, or greater than about 35% or an adult female with a body fat percentage of greater than about 30%, greater than about 35%, or greater than about 40%. In some embodiments, the individual is prepubertal with a body fat percentage of greater than about 30%, greater than about 35%, or greater than about 40%.

In some embodiments, modifying the administration of the compound provided herein comprises prescribing or administering a weight loss drug or procedure to the individual to be used in combination with the compound provided herein.

Antipsychotic-induced Weight Gain

Antipsychotic-induced weight gain is a serious side effect of antipsychotic medication that can lead to increased morbidity, mortality, and non-compliance in patients. The mechanisms underlying weight gain resulting from antipsychotic drugs are not fully understood, although antagonism of the 5- HT₂c receptor is likely to contribute. Animal studies indicate that the drugs most likely to cause weight gain, clozapine and olanzapine, have direct effects on the neuropeptide Y-containing neurons of the hypothalamus; these neurons mediate the effects of the circulating anorexigenic hormone leptin on the control of food intake (Association Between Early and Rapid Weight Gain and Change in Weight Over One Year of Olanzapine Therapy in Patients with Schizophrenia and Related Disorders; Kinon, B. J. et al, Journal of Clinical Psychopharmacology (2005), 25(3), 255-258). Furthermore, significant overall weight gain has been found in schizophrenic or related disorder patients undergoing therapy with the 5- HT₂c-receptor antagonist, olanzapine (The 5-HT₂c Receptor and Antipsychotic-induced Weight Gain - Mechanisms and Genetics; Reynolds G. P. et al ; Journal of Psychopharmacology (2006), 20(4 Suppl), 15-8). Accordingly, 5-HT₂c-receptor agonists such as compounds provided herein are useful for treating antipsychotic-induced weight gain.

Diabetes

It is known that 5-HT₂c-receptor agonists significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes at concentrations of agonist that have no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass (Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways; Ligang, Z. et al, Cell Metab. 2007 November 7; 6(5): 398-405). As a part of a phase 3 clinical trial program, BELVIQ was evaluated in a randomized, placebo- controlled, multi-site, double-blind trial of 604 adults with poorly controlled type 2 diabetes mellitus treated with oral hyperglycemic agents ("BLOOM-DM")- Within the glycemic, lipid and blood pressure families, patients in the BELVIQ group achieved statistically significant improvements relative to placebo in HbAlc and fasting glucose. BELVIQ (10 mg BID) patients achieved a 0.9% reduction in HbAlc, compared to a 0.4% reduction for the placebo group (p < 0.0001) and a 27.4% reduction in fasting glucose, compared to a 11.9% reduction for the placebo group (p < 0.001). Among patients with type 2 diabetes, the use of medications to treat diabetes decreased in patients taking BELVIQ concurrently with mean improvement in glycemic control. In particular, mean daily doses of sulfonylureas and thiazolidinediones decreased 16-24% in the BELVIQ groups, and increased in the placebo group (Effect of Lorcaserin on the Use of Concomitant Medications for Dyslipidemia, Hypertension and Type 2 Diabetes during Phase 3 Clinical Trials Assessing Weight Loss in Patients with Type 2 Diabetes; Vargas, E. et al.; Abstracts of Papers, Obesity Society 30* Annual Scientific Meeting, San Antonio, Texas, Sept. 20-24 2012, (2012), 471-P). In studies that excluded patients with diabetes the population was insulin resistant, as indicated by baseline homeostasis model of assessment - insulin resistance (HOMA-IR) values greater than 1.5. Mean fasting glucose was statistically significantly decreased by BELVIQ (-0.2 mg/dL) compared to placebo (+0.6 mg/dL), and BELVIQ caused a small but statistically significant decrease in HbAlc. In one study, fasting insulin decreased significantly in the BELVIQ group (-3.3 μΐυ/mL) relative to placebo (-1.3 μΐυ/mL), resulting in significant improvement in insulin resistance (indicated by HOMA-IR) in the BELVIQ group (-0.4) compared with placebo (-0.2). Accordingly 5-HT₂c agonists such as compounds provided herein are useful for the prevention and treatment of type 2 diabetes.

Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a maternally imprinted human disorder resulting from a loss of paternal gene expression on chromosome 15ql 1-13 that is characterized by a complex phenotype including cognitive deficits, infantile hypotonia and failure to thrive, short stature, hypogonadism and hyperphagia which can lead to morbid obesity (Goldstone, 2004; Nicholls and Knepper, 2001). There is support in the literature for the use of 5-HT₂c-receptor agonists such as compounds provided herein for treating PWS (Mice with altered serotonin 2C receptor RN A editing display characteristics of Prader- Willi syndrome. Morabito, M.V. et al., Neurobiology of Disease 39 2010) 169-180; and Self -injurious behavior and serotonin in Prader-Willi syndrome. Hellings, J. A. and Warnock, J. K.

Psychopharmacology bulletin (1994), 30(2), 245-50).

Substance Abuse and other Addiction

Addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one' s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.

The power of external cues to trigger craving and drug use, as well as to increase the frequency of engagement in other potentially addictive behaviors, is also a characteristic of addiction, with the hippocampus being important in memory of previous euphoric or dysphoric experiences, and with the amygdala being important in having motivation concentrate on selecting behaviors associated with these past experiences. Although some believe that the difference between those who have addiction, and those who do not, is the quantity or frequency of alcohol/drug use, engagement in addictive behaviors (such as gambling or spending), or exposure to other external rewards (such as food or sex), a characteristic aspect of addiction is the qualitative way in which the individual responds to such exposures, stressors and environmental cues. A particularly pathological aspect of the way that persons with addiction pursue substance use or external rewards is that preoccupation with, obsession with and/or pursuit of rewards (e.g., alcohol and other drug use) persist despite the accumulation of adverse consequences. These manifestations can occur compulsively or impulsively, as a reflection of impaired control.

Agonists of the 5-HT₂c receptor such as the compounds provided herein are active in rodent models of substance abuse, addiction and relapse, and there is strong support in the literature that such agonists act via modulation of dopamine function.

1. Smoking & Tobacco Use

Tobacco use can lead to tobacco/nicotine dependence and serious health problems. Cessation can significantly reduce the risk of suffering from smoking-related diseases. Tobacco/nicotine dependence is a chronic condition that often requires repeated interventions.

2. Drug addiction

There is support in the literature for the use of 5-HT₂c-receptor agonists such as compounds provided herein for treating drug addiction (Novel Pharmacotherapeutic Approaches for the Treatment of Drug Addiction and Craving; Heidbreder et al, Current Opinion in Pharmacology (2005), 5(1), 107- 118).

3. Alcoholism

There is support in the literature for the use of 5-HT_2C-receptor agonists such as compounds provided herein for treating alcoholism (An Investigation of the Role of 5-HT₂c Receptors in Modifying Ethanol Self-Administration Behaviour, Tomkins et al. Pharmacology, biochemistry, and behavior (2002), 71(4), 735-44). 4. Pathological Gambling

There is support in the literature for the use of 5-HT₂c-receptor agonists such as compounds provided herein for treating pathological gambling. Marazziti, D. et al. found that the maximum binding capacity of the platelet 5-HT transporter pathological gambling patients was significantly lower than that of healthy subjects. Pathological gambling patients showed a dysfunction at the level of the platelet 5-HT transporter that would suggest the involvement of the 5-HT system in this condition. (Decreased Density of the Platelet Serotonin Transporter in Pathological Gamblers; Marazziti, D. et al, Neuropsychobiology (2008), 57(1-2), 38-43.)

5. Reward Deficiency Syndrome; Sex Addiction

The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms. The net effect of neurotransmitter interaction at the meso limbic brain region induces "reward" when dopamine (DA) is released from the neuron at the nucleus accumbens and interacts with a dopamine D2 receptor. "The reward cascade" involves the release of serotonin, which in turn at the hypothalamus stimulates enkephalin, which in turn inhibits GABA at the substania nigra, which in turn fine tunes the amount of DA released at the nucleus accumbens or "reward site." It is well known that under normal conditions in the reward site DA works to maintain our normal drives. In fact, DA has become to be known as the "pleasure molecule" and/or the "antistress molecule." When DA is released into the synapse, it stimulates a number a DA receptors (D1-D5) which results in increased feelings of well-being and stress reduction. A consensus of the literature suggests that when there is a dysfunction in the brain reward cascade, which could be caused by certain genetic variants (polygenic), especially in the DA system causing a hypodopaminergic trait, the brain of that person requires a DA fix to feel good. This trait leads to multiple drug-seeking behavior. This is so because alcohol, cocaine, heroin, marijuana, nicotine, and glucose all cause activation and neuronal release of brain DA, which could heal the abnormal cravings. Certainly after ten years of study we could say with confidence that carriers of the DAD2 receptor Al allele have compromised D2 receptors. Therefore lack of D2 receptors causes individuals to have a high risk for multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette' s Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In order to explain the breakdown of the reward cascade due to both multiple genes and environmental stimuli (pleiotropism) and resultant aberrant behaviors, Blum united this hypodopaminergic trait under the rubric of a reward deficiency syndrome. (Reward Deficiency Syndrome: a Biogenetic Model for the Diagnosis and Treatment of Impulsive, Addictive, and Compulsive Behaviors; Blum K. et al.; Journal of psychoactive drugs (2000), 32 Suppl, i-iv, 1-112.) Accordingly, compounds provided herein are useful for the treatment of reward deficiency syndrome, multiple addictive, impulsive and compulsive behavioral propensities, such as severe alcoholism, cocaine, heroin, marijuana and nicotine use, glucose bingeing, pathological gambling, sex addiction, ADHD, Tourette' s Syndrome, autism, chronic violence, posttraumatic stress disorder, schizoid/avoidant cluster, conduct disorder and antisocial behavior. In some embodiments, compounds provided herein are useful for the treatment of sex addiction. Obsessive-compulsive Spectrum Disorders; Impulse Control Disorders; Onychophagia

The morbidity of obsessive-compulsive spectrum disorders (OCSD), a group of conditions related to obsessive-compulsive disorder (OCD) by phenomenological and etiological similarities, is increasingly recognized. Serotonin reuptake inhibitors (SRIs) have shown benefits as first-line, short- term treatments for body dysmorphic disorder, hypochondriasis, onychophagia, and psychogenic excoriation, with some benefits in trichotillomania, pathological gambling, and compulsive buying.

(Obsessive-Compulsive Spectrum Disorders: a Review of the Evidence-Based Treatments. Ravindran A. V., et al., Canadian journal of psychiatry, (2009), 54(5), 331-43). Furthermore, impulse control disorders such as trichotillomania (hair-pulling), pathological gambling, pyromania, kleptomania, and intermittent explosive disorder, as well as onychophagia (nail-biting), are treated by administering a serotonin reuptake inhibitor such as clomipramine, fluvoxamine, fluoxetine, zimelidine, and sertraline or their salts. Significant improvement was noted with clomipramine in a 5-week trial (Method of Treating Trichotillomania and Onychophagia, Swedo, S. E. et al., PCT Int. Appl. (1992), WO 9218005 Al 19921029). Accordingly, compounds provided herein are useful for the treatment of body dysmorphic disorder, hypochondriasis, onychophagia, psychogenic excoriation, trichotillomania, pathological gambling, compulsive buying, pyromania, kleptomania, and intermittent explosive disorder. In some embodiments, compounds provided herein are useful for the treatment of onychophagia.

Sleep

There is support in the literature for the use of 5-HT₂c-receptor agonists such as compounds provided herein for treating insomnia, for increasing slow-wave sleep, for sleep consolidation, and for treating fragmented sleep architecture. (The Role of Dorsal Raphe Nucleus Serotonergic and Non- Serotonergic Neurons, and of their Receptors, in Regulating Waking and Rapid Eye Movement (REM) Sleep; Monti, J. M.; Sleep medicine reviews (2010), 14(5), 319-27). Furthermore, 5-HT₂c-receptor knockout mice exhibit more wakefulness and less slow wave sleep than do wild-types (Serotonin IB and 2C Receptor Interactions in the Modulation of Feeding Behaviour in the Mouse; Dalton, G. L. et al., Psychopharmacology (2006), 185(1), 45-57). However, the 5-HT₂c-receptor agonist, m- chlorophenylpiperazine (mCPP) has been shown to decrease slow-wave sleep in humans (Decreased Tryptophan Availability but Normal Post-Synaptic 5-HT2C Receptor Sensitivity in Chronic Fatigue Syndrome; Vassallo, C. M. et al, Psychological medicine (2001), 31(4), 585-91).

Urinary Incontinence The serotoninergic system has been widely implicated in the control of urinary bladder function. It has been demonstrated that preganglionic fibers and ganglionic serotoninergic neurons, expressing the 5-HT₃ and 5-HT₄ receptors, and the effector smooth muscle cells, expressing 5-HTi and 5-HT₂ receptors, are actively involved in the regulation of the bladder contractile activity in rabbits (Role of Serotonin Receptors in Regulation of Contractile Activity of Urinary Bladder in Rabbits;

Lychkova, A. E. and Pavone, L. M., Urology 2013 Mar;81(3):696). Furthermore, there is support in the literature for the use of 5-HT₂c-receptor agonists such as compounds provided herein for treating urinary incontinence (Discovery of a Novel Azepine Series of Potent and Selective 5-HT₂c Agonists as Potential Treatments for Urinary Incontinence; Brennan et al.; Bioorganic & medicinal chemistry letters (2009), 19(17), 4999-5003).

Psychiatric Disorders

There is support in the literature for the use of 5-HT_2C-receptor agonists such as compounds provided herein for and prodrugs thereof for treating psychiatric disorders (5-HT₂c Receptor Agonists as an Innovative Approach for Psychiatric Disorders; Rosenzweig-Lipson et al, Drug news & perspectives (2007), 20(9), 565-71 ; and Naughton et al, Human Psychopharmacology (2000), 15(6), 397-415).

1. Schizophrenia

The 5-HT₂c receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT_2C receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT_2C receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. The preclinical profile of 5-HT_2C agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of an tip sycho tic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT_2C agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low extrapyramidal side effects liability. These data are highly encouraging and suggest that 5-HT_2C agonists such as compounds provided herein are useful for the treatment of psychiatric disorders, such as schizophrenia (5 -HT₂c Agonists as Therapeutics for the Treatment of Schizophrenia. Rosenzweig-Lipson, S. et al, Handbook of Experimental Pharmacology (2012), 213 (Novel

Antischizophrenia Treatments), 147-165). 2. Eating Disorders

5-HT_2C receptor agonists such as compounds provided herein are useful for the treatment of psychiatric symptoms and behaviors in individuals with eating disorders such as, but not limited to, anorexia nervosa and bulimia nervosa. Individuals with anorexia nervosa often demonstrate social isolation. Anorexic individuals often present symptoms of being depressed, anxious, obsession, perfectionistic traits, and rigid cognitive styles as well as sexual disinterest. Other eating disorders include, anorexia nervosa, bulimia nervosa, binge eating disorder (compulsive eating) and ED-NOS (i.e., eating disorders not otherwise specified - an official diagnosis). An individual diagnosed with ED- NOS possess atypical eating disorders including situations in which the individual meets all but a few of the criteria for a particular diagnosis. What the individual is doing with regard to food and weight is neither normal nor healthy.

Alzheimer Disease

The 5-HT₂c receptor plays a role in Alzheimer Disease (AD). Therapeutic agents currently prescribed AD are cholinomimetic agents that act by inhibiting the enzyme acetylcholinesterase. The resulting effect is increased levels of acetylcholine, which modestly improves neuronal function and cognition in patients with AD. Although, dysfunction of cholinergic brain neurons is an early manifestation of AD, attempts to slow the progression of the disease with these agents have had only modest success, perhaps because the doses that can be administered are limited by peripheral cholinergic side effects, such as tremors, nausea, vomiting, and dry mouth. In addition, as AD progresses, these agents tend to lose their effectiveness due to continued cholinergic neuronal loss.

Therefore, there is a need for agents that have beneficial effects in AD, particularly in alleviating symptoms by improving cognition and slowing or inhibiting disease progression, without the side effects observed with current therapies. Therefore, serotonin 5-HT₂c receptors, which are exclusively expressed in brain, are attractive targets and agonists of 5-HT₂c receptors such as compounds provided herein are useful for the treatment of AD.

Sexual Dysfunction; Erectile dysfunction

Another disease, disorder or condition that can is associated with the function of the 5-HT₂c receptor is erectile dysfunction (ED). Erectile dysfunction is the inability to achieve or maintain an erection sufficiently rigid for intercourse, ejaculation, or both. An estimated 20-30 million men in the United States have this condition at some time in their lives. The prevalence of the condition increases with age. Five percent of men 40 years of age report ED. This rate increases to between 15% and 25% by the age of 65, and to 55% in men over the age of 75 years.

Erectile dysfunction can result from a number of distinct problems. These include loss of desire or libido, the inability to maintain an erection, premature ejaculation, lack of emission, and inability to achieve an orgasm. Frequently, more than one of these problems presents themselves simultaneously. The conditions may be secondary to other disease states (typically chronic conditions), the result of specific disorders of the urogenital system or endocrine system, secondary to treatment with pharmacological agents (e.g. antihypertensive drugs, antidepressant drugs, antipsychotic drugs, etc.) or the result of psychiatric problems. Erectile dysfunction, when organic, is primarily due to vascular irregularities associated with atherosclerosis, diabetes, and hypertension. There is evidence for use of a serotonin 5-HT₂c agonist for the treatment of sexual dysfunction in males and females. The serotonin 5-HT₂c receptor is involved with the processing and integration of sensory information, regulation of central monoaminergic systems, and modulation of neuroendocrine responses, anxiety, feeding behavior, and cerebrospinal fluid production (Tecott, L. H., et al. Nature 374: 542-546 (1995)). In addition, the serotonin 5-HT₂c receptor has been implicated in the mediation of penile erections in rats, monkeys, and humans. Accordingly 5-HT₂c agonists such as compounds provided herein are useful for the treatment of sexual dysfunction and erectile dysfunction.

Seizure Disorders

Evidence suggests a role for the monoamines, norepinephrine and serotonin, in the pathophysiology of seizure disorders (Electrophysiological Assessment of Monoamine Synaptic Function in Neuronal Circuits of Seizure Susceptible Brains; Waterhouse, B. D.; Life Sciences (1986), 39(9), 807-18). Accordingly, 5-HT_2C receptor agonists such as compounds provided herein, are useful for the treatment of seizure disorders.

Epilepsy is a syndrome of episodic brain dysfunction characterized by recurrent unpredictable, spontaneous seizures. Cerebellar dysfunction is a recognized complication of temporal lobe epilepsy and it is associated with seizure generation, motor deficits and memory impairment. Serotonin is known to exert a modulatory action on cerebellar function through 5-HT_2C receptors. (Down-regulation of Cerebellar 5-HT₂c Receptors in Pilocarpine-Induced Epilepsy in Rats: Therapeutic Role ofBacopa monnieri Extract; Krishnakumar, A. et al., Journal of the Neurological Sciences (2009), 284(1-2), 124- 128). Mutant mice lacking functional 5-HT2C-receptors are also prone to spontaneous death from seizures (Eating Disorder and Epilepsy in Mice Lacking 5-HT₂c Serotonin Receptors; Tecott, L. H. et al., Nature. 1995 Apr 6;374(6522):542-6). Furthermore, in a preliminary trial of the selective serotonin reuptake inhibitor citalopram as an add on treatment in non-depressed patients with poorly controlled epilepsy, the median seizure frequency dropped by 55.6% (The Anticonvulsant Effect of Citalopram as an Indirect Evidence of Serotonergic Impairment in Human Epilepto genesis; Favale, E. et al., Seizure. 2003 Jul; 12(5):316-8). Accordingly, 5-HT_2C receptor agonists such as compounds provided herein, are useful for the treatment of epilepsy. For example, 5-HT_2C receptor agonists such as compounds provided herein, are useful for the treatment of generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, or epilepsy partialis continua.

Dravet Syndrome, also known as severe myoclonic epilepsy of infancy (SMEI), is a catastrophic form of childhood epilepsy in which children are unresponsive to standard anti-epilepsy drugs. The average age of death is 4-6 years. If patients survive beyond this age they will be likely mentally retarded. Data from case studies over twenty years demonstrates that administering a low-dose of the indirectly-acting serotonin agonist fenfluramine stops patients with Dravet Syndrome fitting. Accordingly, 5-HT_2C receptor agonists such as compounds provided herein, are useful for the treatment of Dravet Syndrome. Movement Disorders

The basal ganglia are a highly interconnected group of subcortical nuclei in the vertebrate brain that play a critical role not only in the control of movements but also in some cognitive and behavioral functions. Several recent studies have emphasized that serotonergic pathways in the central nervous system (CNS) are intimately involved in the modulation of the basal ganglia and in the pathophysiology of human involuntary movement disorders. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of the basal ganglia. In fact, serotonergic terminals have been reported to make synaptic contacts with dopamine (DA)-containing neurons and γ-aminobutyric acid (GABA)-containing neurons in the striatum, globus pallidus, subthalamus and substantia nigra.

These brain areas contain the highest concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. Furthermore, in these structures a high expression of 5-HT different receptor subtypes has been revealed (Serotonin Involvement in the Basal Ganglia

Pathophysiology: Could the 5-HT₂c Receptor be a New Target for Therapeutic Strategies? Di Giovanni, G. et al, Current medicinal Chemistry (2006), 13(25), 3069-81). Accordingly, 5-HT_2C receptor agonists such as compounds provided herein, are useful for the treatment of movement disorders. In some embodiments, compounds provided herein are useful for the treatment of parkisonism. In some embodiments, compounds provided herein are useful for the treatment of movement disorders associated with antipsychotic drug use.

Hypertension

In clinical trials in patients without type 2 diabetes, 2.2% of patients on BELVIQ and 1.7% of patients on placebo decreased total daily dose of antihypertensive medications, while 2.2% and 3.0%, respectively, increased total daily dose. In patients without type 2 diabetes, numerically more patients who were treated with placebo initiated dyslipidemia and hypertension therapy as compared to those treated with BELVIQ. In patients with type 2 diabetes, 8.2% on BELVIQ and 6.0% of patients on placebo decreased total daily dose of antihypertensive medications, while 6.6% and 6.3%, respectively, increased total daily dose (Effect of Lorcaserin on the Use of Concomitant Medications for

Dyslipidemia, Hypertension and Type 2 Diabetes during Phase 3 Clinical Trials Assessing Weight Loss in Patients with Type 2 Diabetes; Vargas, E. et al.; Abstracts of Papers, Obesity Society 30* Annual Scientific Meeting, San Antonio, Texas, Sept. 20-24 2012, (2012), 471 -P). Accordingly, 5-HT_2C receptor agonists such as compounds provided herein, are useful for the treatment of hypertension.

Dyslipidemia

In clinical trials in patients without type 2 diabetes, 1.3% of patients on BELVIQ and 0.7% of patients on placebo decreased the total daily dose of medications used for treatment of dyslipidemia; 2.6% and 3.4%, respectively, increased use of these medications during the trials. In patients without type 2 diabetes, numerically more patients who were treated with placebo initiated dyslipidemia and hypertension therapy as compared to those treated with BELVIQ. In patients with type 2 diabetes, 5.5% of patients on BELVIQ BID and 2.4% of patients on placebo decreased the total daily dose of medications used for treatment of dyslipidemia; 3.1 % and 6.7%, respectively, increased use of these medications during the trials. (Effect of Lorcaserin on the Use of Concomitant Medications for Dyslipidemia, Hypertension and Type 2 Diabetes during Phase 3 Clinical Trials Assessing Weight Loss in Patients with Type 2 Diabetes; Vargas, E. et al.; Abstracts of Papers, Obesity Society 30* Annual Scientific Meeting, San Antonio, Texas, Sept. 20-24 2012, (2012), 471 -P). Accordingly, 5-HT_2C receptor agonists such as compounds provided herein, are useful for the treatment of dyslipidemia. Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease encompasses a range of liver diseases. Simple steatosis, or fatty liver, is now found in up to 31 % of adults and 16% of children. Of those with steatosis, approximately 5% will develop nonalcoholic steatohepatitis (NASH), in which steatosis is accompanied by inflammation and fibrosis. Up to 25% of NASH patients will progress to cirrhosis. NASH is the third leading indication for liver transplantation in the United States and will become the most common if current trends continue. Therefore, understanding its pathogenesis and treatment is of utmost importance. Overall reductions in body weight, through reduced-calorie intake and increased physical activity, are the current mainstays of NASH treatment (Dietary Treatment of Nonalcoholic

Steatohepatitis; Perito, E. R., et al.; Disclosures Curr Opin Gastroenterol, 2013; 29(2): 170- 176).

Accordingly, by virtue of their ability to decrease food intake and induce satiety, 5-HT₂c receptor agonists such as compounds provided herein, are useful for the treatment of nonalcoholic fatty liver disease.

Obesity-related Renal Disease

Obesity is established as an important contributor of increased diabetes mellitus, hypertension, and cardiovascular disease, all of which can promote chronic kidney disease. Recently, there is a growing appreciation that, even in the absence of these risks, obesity itself significantly increases chronic kidney disease and accelerates its progression. (Scope and mechanisms of obesity-related renal disease; Hunley, T. E. et al.; Current Opinion in Nephrology & Hypertension (2010), 19(3), 227-234). Accordingly, by virtue of their ability to treat obesity, 5-HT₂c receptor agonists such as compounds provided herein, are useful for the treatment of obesity-related kidney disease.

Catecholamine Suppression

Administering the selective 5-HT₂c receptor agonist lorcaserin to an individual causes a reduction of the individual's norepinephrine level independently of weight-loss. A fifty-six-day, double -blind, randomized, placebo-controlled, parallel-group study was conducted to assess the effects of lorcaserin hydrochloride administration to overweight and obese male and female patients. No significant weight loss was observed at 6 days in either the lorcaserin or placebo groups. Significantly greater weight loss was observed at 55 days in the lorcaserin group as compared to placebo. Mean concentrations and mean change from baseline in 24 h urine epinephrine and norepinephrine at Day 7 and Day 56 were assessed. At baseline, 24 h epinephrine and norepinephrine excretion did not differ between lorcaserin and placebo. There was a significant decrease in 24 h norepinephrine excretion in urine after 7 (p < 0.0001) and 56 days (p < 0.001). Accordingly, 5-HT₂c receptor agonists such as compounds provided herein are useful for the treatment of disorders ameliorated by reduction of an individual' s norepinephrine level, wherein said disorders include but are not limited to hypernorepinephrinemia, cardiomyopathy, cardiac hypertrophy, cardiomyocyte hypertrophy in post-myocardial infarction remodeling, elevated heart rate, vasoconstriction, acute pulmonary vasoconstriction, hypertension, heart failure, cardiac dysfunction after stroke, cardiac arrhythmia, metabolic syndrome, abnormal lipid metabolism, hyperthermia, Cushing syndrome, pheochromocytoma, epilepsy, obstructive sleep apnea, insomnia, glaucoma, osteoarthritis, rheumatoid arthritis, and asthma.

Also provided is a method for aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist. In some embodiments, aiding in the cessation of use of a tobacco product is aiding smoking cessation, and the individual attempting to cease use of the tobacco product is an individual attempting to cease smoking.

Also provided is a method for aiding in the cessation of use of a tobacco product and the prevention of associated weight gain comprising the step of: prescribing and/or administering an effective amount of a selective 5-HT₂c receptor agonist to an individual attempting to cease use of the tobacco product. In some embodiments, aiding in the cessation of use of a tobacco product is aiding smoking cessation, and the individual attempting to cease use of the tobacco product is an individual attempting to cease smoking.

Also provided is a method for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist.

Also provided is a method for controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist.

Also provided is a method of treatment for nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist. Also provided is a method of reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising the step of:

prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist.

Methods of Formulating or Manufacturing Pharmaceutical Products

In some embodiments, prior to administering the selective 5-HT₂c receptor agonist, the method further comprises the steps of:

providing a plurality of potential selective 5-HT₂c receptor agonists,

testing the plurality of potential selective 5-HT₂c receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

In some embodiments, prior to administering the selective 5-HT_2C receptor agonist, the method further comprises the steps of:

providing a plurality of potential selective 5-HT_2C receptor agonists,

testing the plurality of potential selective 5-HT_2C receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

Also provided is a method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual comprising:

providing a plurality of potential selective 5-HT_2C receptor agonists;

testing the plurality of potential selective 5-HT_2C receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

providing a plurality of potential selective 5-HT_2C receptor agonists;

testing the plurality of potential selective 5-HT_2C receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT₂c receptor agonist exhibits at least about 10-fold selectivity for the 5-HT₂c receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the 5-HT₂c receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

testing a plurality of potential selective 5-HT_2C receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

testing a plurality of potential selective 5-HT_2C receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

obtaining an agonist previously determined to be a selective 5-HT_2C receptor agonist, wherein the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and

formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

obtaining an agonist previously determined to be a selective 5-HT_2C receptor agonist, wherein the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and

Also provided is a method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual, comprising: providing at least one potential selective 5-HT₂c receptor agonist;

testing the at least one potential selective 5-HT₂c receptor agonist in a functional inositol phosphate accumulation assay, to identify a selective 5-HT₂c receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

Also provided is a method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual, comprising:

testing at least one potential selective 5-HT_2C receptor agonist in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

Also provided is a method for manufacturing a smoking cessation product, comprising:

providing at least one potential selective 5-HT_2C receptor agonist;

testing the at least one potential selective 5-HT_2C receptor agonist in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

testing at least one potential selective 5-HT_2C receptor agonist in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual. Also provided is a method for manufacturing a smoking cessation product, comprising:

obtaining an agonist previously determined to be a selective 5-HT₂c receptor agonist, wherein the selective 5-HT₂c receptor agonist exhibits at least about 10-fold selectivity for the 5-HT₂c receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and

Also provided is a method for manufacturing a pharmaceutical product for

reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco,

aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product,

aiding in smoking cessation and preventing associated weight gain,

controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco,

reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco,

treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or

reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use, comprising:

providing at least one potential selective 5-HT_2C receptor agonist;

Also provided is a method for manufacturing a pharmaceutical product for

aiding in smoking cessation and preventing associated weight gain,

reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or

testing at least one potential selective 5-HT₂c receptor agonist in a functional inositol phosphate accumulation assay, to identify a selective 5-HT₂c receptor agonist, wherein the selective 5-HT₂c receptor agonist exhibits at least about 10-fold selectivity for the 5-HT₂c receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual.

Also provided is a method for manufacturing a pharmaceutical product for

aiding in smoking cessation and preventing associated weight gain,

In some of the embodiments directed to methods of formulating or manufacturing, the "at least one potential selective 5-HT_2C receptor agonist" is one potential selective 5-HT_2C receptor agonist. In some of the embodiments directed to methods of formulating or manufacturing, the "at least one potential selective 5-HT_2C receptor agonist" is a plurality of potential selective 5-HT_2C receptor agonists.

In some of the embodiments directed to methods of formulating or manufacturing, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5- HT_2A receptor and at least about 100-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor. Γη some of the embodiments directed to methods of formulating or manufacturing, selectivity levels can be any of the following:

In some embodiments, 5-HT₂c receptor selectivity is relative to the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5 -HT₂c receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5- HT_2C receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor. In some embodiments, 5-HT_2C receptor selectivity is relative to the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, 5-HT_2C receptor selectivity is relative to the 5-HT_2A and 5-HT_2B receptors. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5- HT_2C receptor over the 5-HT_2A receptor and at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT₂c receptor agonist exhibits at least about 10-fold selectivity for the 5-HT₂c receptor over the 5-HT_2A receptor and at least about 75-fold selectivity for the HT₂c receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5- HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 25 -fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15- fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 75- fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15 -fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 25 -fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20- fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 75- fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 25 -fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25- fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 75- fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25 -fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT₂c receptor over the 5-HT₂B receptor. In some embodiments, the selective 5-HT₂c receptor agonist exhibits at least about 5-fold, at least about 10-fold, at least about 15- fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, at least about 55-fold, at least about 60-fold, at least about 65-fold, at least about 70-fold, at least about 75-fold, at least about 80-fold, at least about 85-fold, at least about 90-fold, at least about 95-fold, at least about 100-fold, at least about 110-fold, at least about 120-fold, at least about 125-fold, at least about 130-fold, at least about 140-fold, at least about 150-fold, at least about 160-fold, at least about 170-fold, at least about 175- fold, at least about 180-fold, at least about 190-fold, at least about 200-fold, at least about 225-fold, at least about 250-fold, at least about 275-fold, at least about 300-fold, at least about 325-fold, at least about 350-fold, at least about 375-fold, at least about 400-fold, at least about 425-fold, at least about 450-fold, at least about 475-fold, at least about 500-fold, at least about 600-fold, at least about 700-fold, at least about 800- fold, at least about 900-fold, or at least about 1000-fold selectivity for the 5-HT₂c receptor over the 5-HT_2A and/or 5-HT_2B receptor, and every combination thereof for selectivity of the 5-HT_2C receptor over the 5-HT_2A and 5-HT_2B receptors. In some embodiments, the selectivity refers to relative in vitro potency of an agonist for the receptors. In some embodiments, the selectivity refers to relative binding affinity of an agonist for the receptors.

Optionally in the embodiments directed to methods of formulating or manufacturing is an additional step of testing for nicotine self-administration in an animal model. For example, some embodiments include an additional step of testing for nicotine self-administration in a rat. See Int. J. Neuropsychopharmacol. 2012 Oct; 15(9): 1265-74. doi: 10.1017/S 1461145711001398. Epub 2011 Sep 23. Optionally in the embodiments directed to methods of formulating or manufacturing is an additional element of having previously tested for nicotine self-administration in an animal model. For example, some embodiments include an additional element of having previously tested for nicotine self-administration in a rat.

Optionally in the embodiments directed to methods of formulating or manufacturing is an additional step of testing for smoking cessation or cessation of nicotine self-administration in a human. For example, some embodiments further comprise administering the selective 5-HT_2C receptor agonist to a human and determining the impact on self- administration of cigarettes. Optionally in the embodiments directed to methods of formulating or manufacturing is an additional element of having previously tested for smoking cessation or cessation of nicotine self-administration in a human. For example, some embodiments include having previously tested for self-administration of cigarettes in a human.

Methods related to nicotine addiction and smoking cessation Also provided is a method of reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco, aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product, aiding in smoking cessation and preventing associated weight gain, controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use, comprising:

selecting an individual with an initial BMI > 27 kg/m²; and

administering a selective 5-HT_2C receptor agonist to an individual;

monitoring the individual for BMI during said administration; and

monitoring the individual for body weight during said administration; and discontinuing said administration if the body weight of the individual decreases by more than about 1 % during said administration.

In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 2% during said administration. In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 3% during said administration. In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 4% during said administration. In some embodiments, administration is discontinued if the body weight of the individual decreases by more than about 5% during said administration.

administering a selective 5-HT₂c receptor agonist to an individual;

monitoring the individual for body weight during said administration; and

In some embodiments, the selective 5-HT₂c agonist is for use as an aid to smoking cessation treatment. In some embodiments, the selective 5-HT₂c agonist is for use as an aid for cessation of cigarette smoking. In some embodiments, the selective 5-HT₂c agonist is for use as an aid to smoking cessation treatment and the prevention of associated weight gain. In some embodiments, the selective 5-HT_2c agonist is for use as a weight-neutral intervention for smoking cessation. In some embodiments, the weight gain occurs during smoking cessation. In some embodiments, the weight gain occurs post- smoking cessation.

Any embodiment of the invention directed to smoking cessation or the cessation or lessening of use of a tobacco product can be adapted to the cessation or lessening of use of nicotine administration from any and all sources or any individual source, including tobacco products (or specific examples thereof), tobacco replacement therapy (or specific examples thereof), and/or any electronic nicotine delivery system (e.g., electronic cigarettes or personal vaporizers). The present invention specifically embraces all such embodiments.

"Selectivity" as disclosed herein refers to a relative comparison of the effects of an agonist on two or more receptors. In some embodiments, selectivity refers to the relative in vitro potency of an agonist for two receptors. In some embodiments, in vitro potency is quantified using a second messenger assay. In some embodiments, in vitro potency is quantified by EC₅₀. In some embodiments, selectivity refers to the relative binding affinity of an agonist for two receptors. In some embodiments, binding affinity is quantified by Ki. In some embodiments, selectivity is measured by comparing data generated from an IP accumulation assay. In some embodiments, selectivity is measured by comparing data generated from a calcium assay. In some embodiments, selectivity is measured by comparing data generated from a DOI assay. In some embodiments, selectivity values are determined using in vitro potency values generated in assays according to Example 2. For methodologies of ensuring the accuracy of in vitro potency values, see pages 155-157 of Cavero et al. (Cavero I and Guillon J-M. Safety Pharmacology assessment of drugs with biased 5-HT₂B receptor agonism mediating cardiac valvulopathy. J Pharmacological and Toxicological Methods 69 (2014 ); 150-161).

In some embodiments, 5-HT₂c receptor selectivity is relative to the 5-HT_2A receptor. In some embodiments, the selective 5-HT₂c receptor agonist exhibits at least about 5-fold selectivity for the 5- HT_2C receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5- HT_2C receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5- HT_2C receptor over the 5-HT_2A receptor. In some embodiments, 5-HT_2C receptor selectivity is relative to the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, 5-HT_2C receptor selectivity is relative to the 5-HT_2A and 5- HT_2B receptors. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5- fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT₂c receptor agonist exhibits at least about 10-fold selectivity for the 5-HT₂c receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT₂c receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 15-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 20-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 25-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 75-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 25-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor. In some embodiments, the selective 5-HT_2C receptor agonist exhibits at least about 5-fold, at least about 10-fold, at least about 15- fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, at least about 55-fold, at least about 60-fold, at least about 65-fold, at least about 70-fold, at least about 75-fold, at least about 80-fold, at least about 85-fold, at least about 90-fold, at least about 95-fold, at least about 100-fold, at least about 110-fold, at least about 120-fold, at least about 125-fold, at least about 130-fold, at least about 140-fold, at least about 150-fold, at least about 160-fold, at least about 170-fold, at least about 175-fold, at least about 180-fold, at least about 190-fold, at least about 200-fold, at least about 225 -fold, at least about 250-fold, at least about 275-fold, at least about 300-fold, at least about 325-fold, at least about 350-fold, at least about 375-fold, at least about 400-fold, at least about 425-fold, at least about 450-fold, at least about 475-fold, at least about 500-fold, at least about 600-fold, at least about 700-fold, at least about 800-fold, at least about 900-fold, or at least about 1000-fold selectivity for the 5-HT₂c receptor over the 5-HT_2A and/or 5-HT₂B receptor, and every combination thereof for selectivity of the 5 -HT₂c receptor over the 5- HT_2A and 5-HT_2B receptors. In some embodiments, the selectivity refers to relative in vitro potency of an agonist for the receptors. In some embodiments, the selectivity refers to relative binding affinity of an agonist for the receptors.

In some embodiments, the 5-HT_2C agonist is a compound selected from the compounds described in the following documents, and pharmaceutically acceptable salts, solvates, and hydrates thereof: WO2014/159067, WO2014/ 140631, WO2014/100815, WO2014/041131, WO2014/046544, WO2013/133325, WO2011/111817, WO2011/097336, WO2011/016459, WO2010/147226,

WO2010/124042. US2010/0298563, WO2010/129048, WO2010/103001, WO2010/060952, WO2009/102805. WO2009/079765, WO2009/063993, WO2009/063992, WO2009/063991, WWOO22000099//003377222200,. WWOO22000088//111177116699,, WO2008/108445, WO2008/052088, WO2008/052087, WO2008/052086. WO2008/052078, WO2008/052075, WO2008/007664, WO2008/007661, WO2008/156707. WO2008/154044, WO2008/010073, WO2008/009125, WO2007/140213, WO2007/132841. WO2007/084622, WO2007/030150, WO2007/028132, WO2007/028131, WO2007/028083. WO2007/028082, WO2007/025144, WO2006/116170, WO2006/116165, WO2006/116158. WO2006/116151, WO2006/116150, WO2006/103511, WO2006/086464, WO2006/077025. WO2006/065706, WO2006/065600, WO2006/052886, WO2006/050007, WO2006/000902. WO2006/117304, WO2006/079637, WO2006/047288, WO2006/044762, WO2005/105082. WO2005/082859, WO2005/044812, WO2005/042491, WO2005/042490, WO2005/040146. WO2005/035533, WO2005/019180, WO2005/016902, WO2005/000849, WWOO22000055//000033009966,. WWOO22000055//001122228822,, WO2004/056324, WO2004/000830, WO03/097636,

WO03/091257, WO03/091251, WO03/091250, WO03/086306, WO03/064423, WO03/000666, WO03/000663, WO2002/074746, WO02/072584, WO02/059129, WO02/059127, WO02/059124, WO02/40456, WO02/36596, US2002/0198190, US2002/0058689, US2002/0055504, US2002/0173503, US2001/0051622, WO02/48124, WO02/44152, WO02/42304, WO02/36596, WO02/30902, WO01/83487, WO01/66548, WO01/12603, WO01/09126, WO01/09123, WO01/09122, WO01/09111, WO00/77001, WO00/76984, WO00/44753, WO00/44737, WO00/35922, WO00/17170, WO00/12510, WO00/12502, WO00/12482, WO00/12481, WO00/12475, US2007/0293475, US6,667,303, EP1023898, W099/43647, W098/56768, WO98/30548, and US6,239,129. In some embodiments, the 5-HT₂c agonist is a combination of one or more compounds selected from the compounds described in the following documents, and pharmaceutically acceptable salts, solvates, and hydrates thereof: WO2014/159067, WO2014/140631, WO2014/100815, WO2014/041131, WO2014/046544, WO2013/133325, WO2011/111817, WO2011/097336, WO2011/016459, WO2010/147226, WO2010/124042, US2010/0298563, WO2010/129048, WO2010/103001, WO2010/060952, WO2009/102805, WO2009/079765, WO2009/063993, WO2009/063992, WO2009/063991, WO2009/037220, WO2008/117169, WO2008/108445, WO2008/052088, WO2008/052087, WO2008/052086, WO2008/052078, WO2008/052075, WO2008/007664, WO2008/007661, WO2008/156707, WO2008/154044, WO2008/010073, WO2008/009125, WO2007/140213, WO2007/132841, WO2007/084622, WO2007/030150, WO2007/028132, WO2007/028131, WO2007/028083, WO2007/028082, WO2007/025144, WO2006/116170, WO2006/116165, WO2006/116158, WO2006/116151, WO2006/116150, WO2006/103511, WO2006/086464, WO2006/077025, WO2006/065706, WO2006/065600, WO2006/052886, WO2006/050007, WO2006/000902, WO2006/117304, WO2006/079637, WO2006/047288, WO2006/044762, WO2005/105082, WO2005/082859, WO2005/044812, WO2005/042491, WO2005/042490, WO2005/040146, WO2005/035533, WO2005/019180, WO2005/016902, WO2005/000849, WO2005/003096, WO2005/012282, WO2004/056324, WO2004/000830,

WO03/097636, WO03/091257, WO03/091251, WO03/091250, WO03/086306, WO03/064423, WO03/000666, WO03/000663, WO2002/074746, WO02/072584, WO02/059129, WO02/059127, WO02/059124, WO02/40456, WO02/36596, US2002/0198190, US2002/0058689, US2002/0055504, US2002/0173503, US2001/0051622, WO02/48124, WO02/44152, WO02/42304, WO02/36596, WO02/30902, WOOl/83487, WOOl/66548, WOOl/12603, WOOl/09126, WOOl/09123, WOOl/09122, WOOl/09111, WOOO/77001, WOOO/76984, WOOO/44753, WOOO/44737, WOOO/35922, WOOO/17170, WO00/12510, WO00/12502, WO00/12482, WO00/12481, WO00/12475, US2007/0293475, US6,667,303, EP1023898, W099/43647, W098/56768, WO98/30548, and US6,239,129. In some embodiments, the 5-HT_2C agonist is a selective 5-HT_2C agonist.

In some embodiments, the selective 5-HT₂c agonist is selected from 8-chloro-l-methyl-2, 3,4,5- tetrahydro-l/f-3-benzazepine and pharmaceutically acceptable salts, solvates, and hydrates thereof.

In some embodiments, the selective 5-HT_2C agonist is selected from (S)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-l/f-3-benzazepine and pharmaceutically acceptable salts, solvates, and hydrates thereof.

In all embodiments, the selective 5-HT_2C agonist is optionally not (R)-8-chloro-l-methyl- 2,3,4,5-tetrahydro-l/f-3-benzazepine or pharmaceutically acceptable salts, solvates, and hydrates thereof.

In all embodiments, the selective 5-HT_2C agonist is optionally not a compound of Formula I or pharmaceutically acceptable salts, solvates, and hydrates thereof.

In all embodiments, the selective 5-HT_2C agonist is optionally not a compound of Formula XI or pharmaceutically acceptable salts, solvates, and hydrates thereof. In all embodiments, the selective 5-HT₂c agonist is optionally not a compound of Formula XXI or pharmaceutically acceptable salts, solvates, and hydrates thereof.

In some embodiments, prior to administration of the selective 5-HT₂c receptor agonist, the individual smokes > 10 cigarettes per day. In some embodiments, prior to administration of the selective 5-HT₂c receptor agonist, the individual smokes 11-20 cigarettes per day. In some embodiments, prior to administration of the selective 5-HT₂c receptor agonist, the individual smokes 21 -30 cigarettes per day. In some embodiments, prior to administration of the selective 5-HT_2C receptor agonist, the individual smokes > 31 cigarettes per day.

In some embodiments, the individual has an initial BMI selected from one of the following: > 24 kg/m², > 23 kg/m², > 22.5 kg/m², > 22 kg/m², > 21 kg/m², > 20 kg/m², > 19 kg/m², or > 18.5 kg/m². In some embodiments, prior to administration, the individual has an initial BMI > 23 kg/m². In some embodiments, prior to administration, the individual has an initial BMI > 22.5 kg/m². In some embodiments, prior to administration, the individual has an initial BMI > 22 kg/m². In some embodiments, prior to administration, the individual has an initial BMI > 18.5 kg/m². In some embodiments, prior to administration, the individual has an initial BMI > 18 kg/m². In some embodiments, prior to administration, the individual has an initial BMI > 17.5 kg/m². In some embodiments, prior to administration, the individual has an initial body mass index > 25 kg/m² and at least one weight-related comorbid condition.

In some embodiments, prior to administration, the individual has an initial body mass index > 27 kg/m². In some embodiments, prior to administration, the individual has an initial body mass index > 27 kg/m² and at least one weight-related comorbid condition.

In some embodiments, the weight-related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea. In some embodiments, the weight-related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

In some embodiments, prior to administration, the individual has an initial body mass index >

30 kg/m².

In some embodiments, the initial BMI of the individual prior to administration is 18.5 to 25 kg/m².

In some embodiments, the individual is suffering from depression prior to being administered the selective 5-HT_2C receptor agonist.

In some embodiments, the individual is suffering from a preexisting psychiatric disease prior to being administered the selective 5-HT_2C receptor agonist.

In some embodiments, the preexisting psychiatric disease is chosen from schizophrenia, bipolar disorder, or major depressive disorder.

In some embodiments, individuals are assessed for nicotine dependence based on the

Fagerstrom score. In some embodiments, the individual has a score of 0, 1, or 2. In some embodiments, the individual has a score of 3 or 4. In some embodiments, the individual has a score of 5. In some embodiments, the individual has a score of 6 or 7. In some embodiments, the individual has a score of 8, 9, or 10. In some embodiments, the individual has a score > 3. In some embodiments, the individual has a score > 5. In some embodiments, the individual has a score > 6. In some embodiments, the individual has a score > 8.

In some embodiments, the individual has a Fagerstrom score of 0, 1, or 2 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of 0, 1, or 2 and a BMI > 25 kg/m and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of 0, 1 , or 2 and a BMI > 30 kg/m².

In some embodiments, the individual has a Fagerstrom score of 3 or 4 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of 3 or 4 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of 3 or 4 and a BMI > 30 kg/m .

In some embodiments, the individual has a Fagerstrom score of 5 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of 5 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of 5 and a BMI > 30 kg/m².

In some embodiments, the individual has a Fagerstrom score of 6 or 7 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of 6 or 7 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of 6 or 7 and a BMI > 30 kg/m .

In some embodiments, the individual has a Fagerstrom score of 8, 9, or 10 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of 8, 9, or 10 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of 8, 9, or 10 and a BMI > 30 kg/m².

In some embodiments, the individual has a Fagerstrom score of > 3 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of > 3 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of > 3 and a BMI > 30 kg/m².

In some embodiments, the individual has a Fagerstrom score of > 5 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of > 5 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of > 5 and a BMI > 30 kg/m².

In some embodiments, the individual has a Fagerstrom score of > 6 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of > 6 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of > 6 and a BMI > 30 kg/m².

In some embodiments, the individual has a Fagerstrom score of > 8 and a BMI < 25 kg/m². In some embodiments, the individual has a Fagerstrom score of > 8 and a BMI > 25 kg/m² and < 30 kg/m². In some embodiments, the individual has a Fagerstrom score of > 8 and a BMI > 30 kg/m².

In some embodiments, a questionnaire is used to evaluate symptoms experienced during quit, such as the urge to smoke, withdrawal, or reinforcing effects. In some embodiments, the questionnaire is selected from: the Minnesota Nicotine Withdrawal Score (MNWS), Brief Questionnaire of Smoking Urges (QSU-Brief), McNett Coping Effectiveness Questionnaire (mCEQ), Three-Factor Eating Questionnaire (TFEQ), and Food Craving Inventory (FCI). In some embodiments, the nicotine dependency, addiction and/or withdrawal results from the use of tobacco products. In some embodiments, the nicotine dependency, addiction, and/or withdrawal results from cigarette smoking.

In some embodiments, the nicotine dependency, addiction and/or withdrawal results from the use of nicotine replacement therapies.

In some embodiments, the individual is first administered the selective 5-HT₂c agonist on the target quit day. In some embodiments, the individual is administered the selective 5-HT₂c agonist at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days prior to the target quit day. In some embodiments, the individual is administered the selective 5-HT₂c agonist at least 7 days prior to the target quit day. In some embodiments, the individual is administered the selective 5-HT₂c agonist about 7 to about 35 days prior to the target quit day. In some embodiments, the individual is administered the selective 5-HT_2C agonist at least 14 days prior to the target quit day. In some embodiments, the individual is administered the selective 5-HT_2C agonist about 14 to about 35 days prior to the target quit day.

In some embodiments, the individual quits smoking between days 8 and 35 of treatment. In some embodiments, the individual quits smoking between days 15 and 35 of treatment. In some embodiments, the individual quits smoking between days 22 and 35 of treatment. In some embodiments, the individual quits smoking on day 8 of treatment. In some embodiments, the individual quits smoking on day 15 of treatment. In some embodiments, the individual quits smoking on day 22 of treatment.

In some embodiments, prior to administering the selective 5-HT_2C receptor agonist, the method further comprises the step of: instructing the individual to set a date to cease smoking tobacco. In some embodiments, administration of the selective 5-HT_2C receptor agonist is initiated about 7 days prior to the date set to cease smoking tobacco.

In some embodiments, after administering the selective 5-HT_2C receptor agonist, the method further comprises the step of: instructing the individual to set a date to cease smoking tobacco. In some embodiments, the date set to cease smoking tobacco occurs after at least 7 days of administration of the selective 5-HT_2C receptor agonist. In some embodiments, the date set to cease smoking tobacco occurs prior to 35 days of administration of the selective 5-HT_2C receptor agonist.

In some embodiments, the individual previously attempted to cease smoking tobacco but did not succeed in ceasing smoking tobacco. In some embodiments, the individual previously attempted to cease smoking tobacco but subsequently relapsed and resumed smoking tobacco.

In some embodiments, the administration leads to a statistically significant improvement in the ability to tolerate the cessation of smoking as measured by analysis of data from the MPSS test.

In some embodiments, the individual has abstained from nicotine use for 12 weeks prior to prescribing and/or administering the selective 5-HT_2C receptor agonist.

In some embodiments, the individual has abstained from nicotine use for 24 weeks prior to prescribing and/or administering the selective 5-HT_2C receptor agonist. In some embodiments, the individual has abstained from nicotine use for 9 months prior to prescribing and/or administering the selective 5-HT₂c receptor agonist.

In some embodiments, the individual has abstained from nicotine use for 52 weeks prior to prescribing and/or administering the selective 5-HT_2C receptor agonist.

In some embodiments, abstinence is self-reported. In some embodiments, the self-reporting based on response to a questionnaire. In some embodiments, the questionnaire is a Nicotine Use Inventory. In some embodiments, an individual self -reports as not having smoking any cigarettes (even a puff). In some embodiments, the individual self -reports as not having used any other nicotine- containing products. In some embodiments, the individual self-reports as not having smoking any cigarettes (even a puff) and not having used any other nicotine-containing products.

In some embodiments, the duration of treatment is selected from: 12 weeks, 6 months, 9 months, 1 year, 18 months, 2 years, 3 years, 4 years, and 5 years.

In some embodiments, the selective 5-HT_2C receptor agonist is administered for at least about 2 weeks. In some embodiments, the selective 5-HT₂c receptor agonist is administered for at least about 4 weeks. In some embodiments, the selective 5-HT_2C receptor agonist is administered for at least about 8 weeks. In some embodiments, the selective 5-HT_2C receptor agonist is administered for at least about 12 weeks. In some embodiments, the selective 5-HT_2C receptor agonist is administered for at least about 6 months. In some embodiments, the selective 5-HT_2C receptor agonist is administered for at least about 1 year. In some embodiments, the selective 5-HT_2C receptor agonist is administered for at least about 2 years. In some embodiments, the selective 5-HT_2C receptor agonist is administered for between about 7 weeks to about 12 weeks. In some embodiments, the selective 5-HT_2C receptor agonist is administered for between about 12 weeks to about 52 weeks. In some embodiments, the selective 5- HT_2C receptor agonist is administered for between about 6 months to about 1 year.

In some embodiments, the individual receives treatment for a first treatment period. In some embodiments, the individual receives treatment for an additional treatment period, e.g., to increase the likelihood of long-term abstinence. In some embodiments, an individual who fails in a first treatment period is administered the selective 5-HT_2C agonist optionally in combination with a supplemental agent for a second treatment period. In some embodiments, an individual who relapses during a first treatment is administered the selective 5-HT_2C agonist optionally in combination with a supplemental agent for a second treatment period. In some embodiments, an individual who relapses following a first treatment is administered the selective 5-HT_2C agonist optionally in combination with a supplemental agent for a second treatment period. In some embodiments, the first treatment period is 12 weeks. In some embodiments, the second treatment period is 12 weeks or less. In some embodiments, the second treatment period is 12 weeks. In some embodiments, the second treatment period is more than 12 weeks. In some embodiments, the first treatment period is one year. In some embodiments, the second treatment period is one year or less. In some embodiments, the second treatment period is one year. In some embodiments, the first treatment period is longer than the second treatment period. In some embodiments, the first treatment period is shorter than the second treatment period. In some embodiments, the first treatment period and the second period are of the same length of time.

In some embodiments, the prevention or reduction of weight gain, or inducement of weight loss, is measured relative to the amount of weight gain or loss typically experienced when an individual attempts smoking cessation. In some embodiments, the prevention or reduction of weight gain, or inducement of weight loss, is measured relative the amount of weight gain or loss typically experienced when an individual attempts smoking cessation with another drug.

In some embodiments, controlling weight gain comprises preventing weight gain. In some embodiments, controlling weight gain comprises inducing weight loss. In some embodiments, controlling weight gain comprises inducing weight loss of at least about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%. In some embodiments, the weight loss is at least 1%. In some embodiments, the weight loss is at least 1.5%. In some embodiments, the weight loss is at least about 2%. In some embodiments, the weight loss is at least 3%. In some embodiments, the weight loss is at least 4%. In some embodiments, the weight loss is at least 5%. In some embodiments, controlling weight gain comprises decreasing BMI. In some embodiments, controlling weight gain comprises decreasing in percent body fat. In some embodiments, controlling weight gain comprises decreasing waist circumference. In some embodiments, controlling weight gain comprises decreasing BMI by at least about 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 kg/m². In some embodiments, BMI is decreased by at least 1 kg/m². In some embodiments, BMI is decreased by at least 1.5 kg/m². In some embodiments, BMI is decreased by at least 2 kg/m². In some embodiments, BMI is decreased by at least 2.5 kg/m². In some embodiments, BMI is decreased by at least 5 kg/m². In some embodiments, BMI is decreased by at least 10 kg/m². In some embodiments, controlling weight gain comprises decreasing percent body fat by at least about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%. In some embodiments, the decrease in percent body fat is at least 1%. In some embodiments, the decrease in percent body fat is at least 2.5%. In some embodiments, the decrease in percent body fat is at least 5%. In some embodiments, controlling weight gain comprises decreasing waist circumference by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 cm. In some embodiments, the decrease in waist circumference is at least 1 cm. In some embodiments, the decrease in waist circumference is at least 2.5 cm. In some embodiments, the decrease in waist circumference is at least 5 cm. In some embodiments, controlling weight gain comprises decreasing body weight by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 kg. In some embodiments, the decrease in body weight is at least 1 kg. In some embodiments, the decrease in body weight is at least 2.5 kg. In some embodiments, the decrease in body weight is at least 5 kg.

In some embodiments, the BMI of the individual becomes a BMI selected from one of the following: > 18 kg/m², > 17.5 kg/m², > 17 kg/m², > 16 kg/m², and > 15 kg/m². In some embodiments, the decrease in body weight is selected from one of the following: more than about 1.5%, more than about 2%, more than about 2.5%, more than about 3%, more than about 3.5%, more than about 4%, more than about 4.5%, and more than about 5%.

In some embodiments, the decrease in body weight is selected from one of the following: more than about 1.5 kg, more than about 2 kg, more than about 2.5 kg, more than about 3 kg, more than about 3.5 kg, more than about 4 kg, more than about 4.5 kg, and more than about 5 kg.

In some embodiments, the individual in need of treatment has a BMI selected from: > 25 kg/m², > 24 kg/m², > 23 kg/m², > 22 kg/m², > 21 kg/m², > 20 kg/m², > 19 kg/m², and > 18.5 kg/m². In some embodiments, BMI is not decreased by more than about 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,15, 16, 17, 18, 19, or 20 kg/m². In some embodiments, BMI is not decreased by more than 1 kg/m². In some embodiments, BMI is not decreased by more than 1.5 kg/m². In some embodiments, BMI is not decreased by more than 2 kg/m². In some embodiments, BMI is not decreased by more than 2.5 kg/m². In some embodiments, BMI is not decreased by more than 5 kg/m². In some embodiments, BMI is not decreased by more than 10 kg/m². In some embodiments, percent body fat is not decreased by more than about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%. In some embodiments, percent body fat is not decreased by more than 1 %. In some embodiments, percent body fat is not decreased by more than 2.5%. In some embodiments, percent body fat is not decreased by more than 5%. In some embodiments, waist circumference is not decreased by more than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 cm. In some embodiments, waist circumference is not decreased by more than 1 cm. In some embodiments, waist circumference is not decreased by more than 2.5 cm. In some embodiments, waist circumference is not decreased by more than 5 cm. In some embodiments, body weight is not decreased by more than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 kg. In some embodiments, the decrease in body weight is not more than 1 kg. In some embodiments, the decrease in body weight is not more than 2.5 kg. In some embodiments, the decrease in body weight is not more than 5 kg.

In some embodiments, controlling weight gain comprises maintaining at least some weight loss for at least about 12 weeks, at least about 6 months, at least about 9 months, at least about one year, at least about 18 months, or at least about two years. For example, in some embodiments, an individual loses 5 kg during a first treatment and maintains at least 1 kg of that weight loss during a second treatment. In some embodiments, an individual loses 3 kg during the first 12 weeks of a treatment, and loses a total of 5 kg after one year of the treatment.

In some embodiments, use of the selective 5-HT₂c agonist is discontinued. For example, in some embodiments, use of the selective 5-HT₂c agonist is discontinued if the BMI of an individual becomes < about 15 kg/m², < about 15.5 kg/m², < about 16 kg/m², < about 16.5 kg/m², < about 17 kg/m², < about 17.5 kg/m², < about 18 kg/m², < about 18.5 kg/m², < about 19 kg/m², < about 19.5 kg/m² < about 20 kg/m², < about 20.5 kg/m², < about 21 kg/m², < about 21.5 kg/m², < about 22 kg/m², < about 22.5 kg/m², or < about 23 kg/m². In some embodiments, the individual experiences one or more additional beneficial effects as a result of the administration of the selective 5-HT₂c agonist, optionally in combination with at least one supplemental agent, as described herein.

In some embodiments, the one or more additional beneficial effects are chosen from a decrease in an assessment of weight, an improvement in cardiovascular indications, and/or an improved glycemia. In some embodiments, the one or more additional beneficial effects are chosen from a decrease in an assessment of weight, an improvement in cardiovascular indications, and/or an improved lipidemia.

In some embodiments, the one or more additional beneficial effects comprise a decrease in an assessment of weight. In some embodiments, the decrease in an assessment of weight comprises weight loss. In some embodiments, the one or more beneficial effects comprises a decrease in hunger, a decrease in food cravings, or an increase in intermeal interval.

In some embodiments, the one or more additional beneficial effects comprise an improvement in one or more cardiovascular indications. In some embodiments, the improvement in one or more cardiovascular indications comprises one or more of a reduction in systolic and diastolic blood pressure (SBP and DBP, respectively), a decrease in heart rate, a decrease in total cholesterol, a decrease in LDL cholesterol, a decrease in HDL cholesterol, and/or a decrease in triglyceride levels.

In some embodiments, the one or more additional beneficial effects comprise a reduction in SBP. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is at least about 2 rnmHg. In some embodiments, the reduction in SBP in an individual without type 2 diabetes is between 2 and 5 rnmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is at least about 2 rnmHg. In some embodiments, the reduction in SBP in an individual with type 2 diabetes is between about 2 and 5 rnmHg. In some embodiments, the reduction in SBP in an individual with baseline impaired fasting glucose is at least about 1 mmHg. In some embodiments, the reduction in SBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg.

In some embodiments, the one or more additional beneficial effects comprise a reduction in DBP. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is at least about

1 mmHg. In some embodiments, the reduction in DBP in an individual without type 2 diabetes is at least between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with type 2 diabetes is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with type

2 diabetes is between about 1 and 5 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is at least about 1 mmHg. In some embodiments, the reduction in DBP in an individual with baseline impaired fasting glucose is between about 1 and 5 mmHg.

In some embodiments, the one or more additional beneficial effects comprise a reduction in heart rate. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual without type 2 diabetes is between about 2 and 5 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual with type 2 diabetes is between about 2 and 5 BPM. Γη some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is at least about 2 BPM. In some embodiments, the reduction in heart rate in an individual with baseline impaired fasting glucose is between about 2 and 5 BPM.

In some embodiments, the improvement in lipidemia comprises a decrease in total cholesterol level. In some embodiments, the decrease in total cholesterol level in individuals without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals without type 2 diabetes is between about 1.5 and 2 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with type 2 diabetes is at least about 0.5 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with type 2 diabetes is between about 0.5 and 1 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in total cholesterol level in individuals with baseline impaired fasting glucose is between about 2 and 3 mg/dL.

In some embodiments, the improvement in lipidemia comprises a decrease in LDL cholesterol level. In some embodiments, the decrease in LDL cholesterol level in individuals without type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals without type 2 diabetes is between about 1 and 2 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with type 2 diabetes is at least about 1 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with type 2 diabetes is between about 1 and 1.5 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in LDL cholesterol level in individuals with baseline impaired fasting glucose is between about 2 and 3 mg/dL.

In some embodiments, the improvement in lipidemia comprises a decrease in HDL cholesterol level. In some embodiments, the decrease in HDL cholesterol level in individuals without type 2 diabetes is at least about 4 mg/dL. In some embodiments, the decrease in HDL cholesterol level in individuals without type 2 diabetes is between about 3 and 6 mg/dL. In some embodiments, the decrease in HDL cholesterol level in individuals with type 2 diabetes is at least about 5 mg/dL. In some embodiments, the decrease in HDL cholesterol level in individuals with type 2 diabetes is between about 7 and 10 mg/dL. In some embodiments, the decrease in HDL cholesterol level in individuals with baseline impaired fasting glucose is at least about 2 mg/dL. In some embodiments, the decrease in HDL cholesterol level in individuals with baseline impaired fasting glucose is between about 2 and 3 mg/dL.

In some embodiments, the one or more additional beneficial effects comprise an improvement in glycemia. In some embodiments, the improvement in glycemia comprises a reduction in fasting plasma glucose and/or a reduction in glycated hemoglobin (AIC) levels. In some embodiments, the improvement in glycemia comprises a reduction in fasting plasma glucose. In some embodiments, the improvement in glycemia comprises a reduction in glycated hemoglobin (AIC) levels. In some embodiments, the improvement in glycemia comprises a decrease in triglyceride levels. The compounds provided herein can be administered in a wide variety of dosage forms. It will be obvious to those skilled in the art that the dosage forms may comprise, as the active component, either a compound provided herein or a pharmaceutically acceptable salt, solvate or hydrate of a compound provided herein.

In some embodiments, the selective 5-HT₂c receptor agonist is administered in a tablet suitable for oral administration.

In some embodiments, the active ingredient is formulated as an immediate-release dosage form using, e.g., techniques known in the art. In some embodiments, the active ingredient is formulated as a modified -re lease dosage form using, e.g., techniques known in the art. In some embodiments, the active ingredient is formulated as a sustained-release dosage form using, e.g., techniques known in the art. In some embodiments, the active ingredient is formulated as a delayed-release dosage form using, e.g., techniques known in the art.

In some embodiments, the method comprises a plurality of administrations of the modified- release dosage form, with a frequency wherein the average interval between any two sequential administrations is: at least about 24 hours; or about 24 hours.

In some embodiments, the method comprises a plurality of administrations of the modified- release dosage form, and the modified-release dosage form is administered once-a-day.

In some embodiments, the plurality of administrations is: at least about 30; at least about 180; at least about 365; or at least about 730.

COMBINATION THERAPY

A compound disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof can be administered as the sole active pharmaceutical agent (i.e., mono-therapy), or it can be used in combination with one or more weight loss drug either administered together or separately. Provided are methods for weight management, inducing satiety, decreasing food intake, aiding smoking cessation, and for preventing and treating obesity, an tip sycho tic-induced weight gain, type 2 diabetes, Prader- Willi syndrome, tobacco dependence, nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, sex addiction, obsessive-compulsive spectrum disorders, impulse control disorders, nail-biting, onychophagia, sleep disorders, insomnia, fragmented sleep architecture, disturbances of slow-wave sleep, urinary incontinence, psychiatric disorders, schizophrenia, anorexia nervosa, bulimia nervosa, Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorder, parkinsonism, antipsychotic-induced movement disorder, hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are methods for decreasing food intake in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein. Also provided are methods for inducing satiety in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are methods for the treatment of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are methods for the prevention of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are methods for weight management in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are methods for preventing type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

When a compound disclosed herein is administered as a combination therapy with a weight loss drug the compound and the weight loss drug can be formulated as separate pharmaceutical compositions given at the same time or at different times; or the compound disclosed herein and the pharmaceutical agent can be formulated together as a single unit dosage.

Provided are the compounds described herein for use in combination with a weight loss drug for use in a method of treatment of the human or animal body by therapy.

Also provided are the compounds described herein for use in combination with a weight loss drug for weight management, inducing satiety, decreasing food intake, aiding smoking cessation, and for preventing and treating obesity, an tip sycho tic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, addiction, tobacco dependence, nicotine dependence, drug addiction, alcohol addiction, pathological gambling, reward deficiency syndrome, sex addiction, obsessive-compulsive spectrum disorders, impulse control disorders, nail-biting, onychophagia, sleep disorders, insomnia, fragmented sleep architecture, disturbances of slow-wave sleep, urinary incontinence, psychiatric disorders, schizophrenia, anorexia nervosa, bulimia nervosa, Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorder, parkinsonism, antipsychotic-induced movement disorder, hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are the compounds described herein for use in combination with a weight loss drug for decreasing food intake in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein. Also provided are the compounds described herein for use in combination with a weight loss drug for inducing satiety in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are the compounds described herein for use in combination with a weight loss drug for the treatment of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are the compounds described herein for use in combination with a weight loss drug for the prevention of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are the compounds described herein for use in combination with a weight loss drug for weight management in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are the compounds described herein for use in combination with a weight loss drug for treating type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

Also provided are the compounds described herein for use in combination with a weight loss drug for preventing type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein.

In some embodiments, the compound described herein and the weight loss drug are administered simultaneously.

In some embodiments, the compound described herein and the weight loss drug are administered separately.

In some embodiments, the compound described herein and the weight loss drug are administered sequentially.

In some embodiments, the weight loss drug chosen from sodium/glucose cotransporter-2 (SGLT2) inhibitors, lipase inhibitors, monoamine reuptake inhibitors, anticonvulsants, glucose sensitizers, incretin mimetics, amylin analogs, GLP-1 analogs, Y receptor peptides, 5-HT₂c receptor agonists, opioid receptor antagonists, appetite suppressants, anorectics, and hormones and the like, either specifically disclosed herein or specifically disclosed in any reference recited herein just as if each and every combination was individually and explicitly recited. In some embodiments, the weight loss drug is chosen from dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin, empagliflozin, remogliflozin etabonate, orlistat, cetilistat, alaproclate, citalopram, dapoxetine, escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine, indalpine, omiloxetine, panuramine, paroxetine, pirandamine, sertraline, zimelidine, desmethylcitalopram, desmethylsertraline, didesmethylcitalopram, seproxetine, cianopramine, litoxetine, lubazodone, trazodone, vilazodone, vortioxetine,

methylenedioxypyrovalerone, methylphenidate, nomifensine, oxolinic acid, pipradrol, prolintane, pyrovalerone, tametraline, nefopam, amitifadine, tesofensine, tedatioxetine, bicifadine, brasofensine, diclofensine, taxil, naphyrone, hyperforin, topiramate, zonisamide, metformin, rosiglitazone, pioglitazone, troglitazone, exenatide, liraglutide, taspoglutide, obinepitide, pramlintide, peptide YY, vabicaserin, naltrexone, naloxone, phentermine, diethylpropion, oxymetazoline, benfluorex, butenolide cathine, phenmetrazine, phenylpropanolamine, pyroglutamyl-histidyl-glycine , amphetamine, benzphetamine, dexmethylphenidate, dextroamphetamine, methylenedioxypyrovalerone, glucagon, lisdexamfetamine, methamphetamine, methylphenidate, phendimetrazine, phenethylamine, caffeine, bromocriptine, ephedrine, pseudoephedrine, rimonabant, surinabant, mirtazapine, Dietex®, MG Plus Protein™, insulin, and leptin and pharmaceutically acceptable salts and combinations thereof. In some embodiments, the weight loss drug is phentermine.

In some embodiments, the weight management further comprises a reduced-calorie diet.

In some embodiments, the weight management further comprises a program of regular exercise.

In some embodiments, the individual has an initial body mass index > 25 kg/m².

In some embodiments, the individual has an initial body mass index > 27 kg/m².

In some embodiments, the individual has at least one weight related comorbid condition.

In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea.

In some embodiments, the weight related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

In some embodiments, the individual has an initial body mass index > 30 kg/m².

Also provided are methods for treating type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound described herein, in combination with one or more weight loss drugs as described herein. REPRESENTATIVE METHODS

Provided are methods for decreasing food intake in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

In some embodiments, the weight management comprises weight loss.

In some embodiments, the weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea.

Also provided are methods for the treatment of antipsychotic-induced weight gain in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein. Also provided are methods for the treatment of type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein combination with one or more type 2 diabetes medications.

In some embodiments, the need for the one or more type 2 diabetes treatments is reduced. In some embodiments, the need for the one or more type 2 diabetes treatments is eliminated.

Also provided are methods for the prevention of type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of Prader-Willi syndrome in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of addiction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of drug and alcohol addiction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of alcohol addiction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of drug addiction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

In some embodiments, the drug is nicotine.

In some embodiments, the drug is amphetamine.

In some embodiments, the drug is a substituted amphetamine.

In some embodiments, the drug is meth amphetamine.

In some embodiments, the drug is a benzodiazepine.

In some embodiments, the drug is an atypical benzodiazepine receptor ligand.

In some embodiments, the drug is marijuana.

In some embodiments, the drug is cocaine.

In some embodiments, the drug is dextromethorphan.

In some embodiments, the drug is eszopiclone.

In some embodiments, the drug is GHB. In some embodiments, the drug is LSD.

In some embodiments, the drug is ketamine.

In some embodiments, the drug is a monoamine reuptake inhibitor.

In some embodiments, the drug is an opiate.

In some embodiments, the drug is PCP.

In some embodiments, the drug is a substituted phenethylamine.

In some embodiments, the drug is psilocybin.

In some embodiments, the drug is an anabolic steroid.

In some embodiments, the drug is Zolpidem.

Also provided are methods for aiding smoking cessation in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of tobacco dependence in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of nicotine dependence in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of alcoholism in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of pathological gambling in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of reward deficiency syndrome in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of sex addiction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of an obsessive-compulsive spectrum disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of an impulse control disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein. Also provided are methods for the treatment of nail-biting in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of onychophagia in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of a sleep disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of insomnia in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of fragmented sleep architecture in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of disturbances of slow-wave sleep in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of urinary incontinence in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of a psychiatric disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of schizophrenia in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of anorexia nervosa in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of bulimia nervosa in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of Alzheimer disease in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein. Also provided are methods for the treatment of sexual dysfunction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of erectile dysfunction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of a seizure disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of epilepsy in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of Dravet syndrome in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of a movement disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of parkinsonism in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of antipsychotic-induced movement disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of hypertension in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of dyslipidemia in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of nonalcoholic fatty liver disease in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are methods for the treatment of obesity-related renal disease in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein. Also provided are methods for the treatment of sleep apnea in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound provided herein.

Also provided are uses of a compound provided herein for the manufacture of a medicament for decreasing food intake.

Also provided are uses of a compound provided herein for the manufacture of a medicament for inducing satiety of a compound provided herein.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of obesity.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the prevention of obesity.

Also provided are uses of a compound provided herein for the manufacture of a medicament for weight management.

In some embodiments, the weight management comprises weight loss.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of antipsychotic-induced weight gain.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of type 2 diabetes.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of type 2 diabetes in combination with one or more type 2 diabetes medications.

In some embodiments, the need for the one or more type 2 diabetes treatments is eliminated. Also provided are uses of a compound provided herein for the manufacture of a medicament for the prevention of type 2 diabetes.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of Prader-Willi syndrome.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of addiction.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of drug and alcohol addiction.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of alcohol addiction.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of drug addiction.

In some embodiments, the drug is nicotine.

In some embodiments, the drug is amphetamine.

In some embodiments, the drug is a substituted amphetamine.

In some embodiments, the drug is methamphetamine.

In some embodiments, the drug is a benzodiazepine.

In some embodiments, the drug is an atypical benzodiazepine receptor ligand.

In some embodiments, the drug is marijuana.

In some embodiments, the drug is cocaine.

In some embodiments, the drug is dextromethorphan.

In some embodiments, the drug is eszopiclone.

In some embodiments, the drug is GHB.

In some embodiments, the drug is LSD.

In some embodiments, the drug is ketamine.

In some embodiments, the drug is a monoamine reuptake inhibitor.

In some embodiments, the drug is an opiate.

In some embodiments, the drug is PCP.

In some embodiments, the drug is a substituted phenethylamine.

In some embodiments, the drug is psilocybin.

In some embodiments, the drug is an anabolic steroid.

In some embodiments, the drug is Zolpidem.

Also provided are uses of a compound provided herein for the manufacture of a medicament for aiding smoking cessation. Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of tobacco dependence.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of nicotine dependence.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of alcoholism.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of pathological gambling.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of reward deficiency syndrome.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of sex addiction.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of an obsessive-compulsive spectrum disorder.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of an impulse control disorder.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of nail-biting.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of onychophagia.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of a sleep disorder.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of insomnia.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of fragmented sleep architecture.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of disturbances of slow-wave sleep.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of urinary incontinence.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of a psychiatric disorder.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of schizophrenia.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of anorexia nervosa.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of bulimia nervosa. Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of Alzheimer disease.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of sexual dysfunction.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of erectile dysfunction.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of a seizure disorder.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of epilepsy.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of Dravet syndrome.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of a movement disorder.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of parkinsonism.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of antipsychotic-induced movement disorder.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of hypertension.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of dyslipidemia.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of nonalcoholic fatty liver disease.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of obesity-related renal disease.

Also provided are uses of a compound provided herein for the manufacture of a medicament for the treatment of sleep apnea.

In some embodiments, the individual is also being prescribed and/or administered a supplemental agent.

Also provided is a composition comprising a selective 5-HT_2C receptor agonist and at least one supplemental agent.

As used herein, "supplemental agent" refers to an additional therapeutic agent which complements the activity of the 5-HT₂c agonists described herein as it relates to methods for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use. In some embodiments, the "supplemental agent" is not phentermine.

Supplemental agents include nicotine replacement therapies, antidepressants and anxiolytics such as selective serotonin reuptake inhibitors, e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and the like. Serotonin and norepinephrine reuptake inhibitors, such as duloxetine, venlafaxine, and the like may also be used. Norepinephrine and dopamine reuptake inhibitors such as bupropion may also be used. Tetracyclic antidepressants such as mirtazapine; combined reuptake inhibitors and receptor blockers such as trazodone, nefazodone, maprotiline; tricyclic antidepressants, such as amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline and trimipramine; monoamine oxidase inhibitors, such as phenelzine, tranylcypromine, isocarboxazid, selegiline; benzodiazepines such as lorazepam, clonazepam, alprazolam, and diazepam; serotonin 1A receptor agonists such as buspirone, aripiprazole, quetiapine, tandospirone and bifeprunox; and a beta- adrenergic receptor blocker, such as propranolol may also be used. Other supplemental agents include other pharmacologic agents such as UTP, amiloride, antibiotics, bronchodilators, anti-inflammatory agents, and mucolytics (e.g., n-acetyl-cysteine).

In some embodiments, the supplemental agent is chosen from nicotine replacement therapies. In some embodiments, the nicotine replacement therapy is chosen from nicotine gum, nicotine transdermal systems, nicotine lozenges, nicotine microtabs, and nicotine sprays or inhalers. In some embodiments, the supplemental agent is an electronic cigarette.

In some embodiments, the supplemental agent is nicotine gum, and the composition is a composition comprising a selective 5-HT₂c receptor agonist and nicotine gum.

In some embodiments, the supplemental agent is a nicotine transdermal system, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and a nicotine transdermal system.

In some embodiments, the supplemental agent is nicotine lozenges, and the composition is a composition comprising a selective 5-HT₂c receptor agonist and nicotine lozenges.

In some embodiments, the supplemental agent is nicotine microtabs, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and nicotine microtabs.

In some embodiments, the supplemental agent is nicotine sprays or inhalers, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and nicotine sprays or inhalers.

In some embodiments, the supplemental agent is an electronic cigarette, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and an electronic cigarette. In some embodiments, the supplemental agent is chosen from antidepressants, and the composition is a composition comprising a selective 5-HT₂c receptor agonist and a supplemental agent chosen from antidepressants.

In some embodiments, the supplemental agent is an antidepressant, and the composition is a composition comprising a selective 5-HT₂c receptor agonist and an antidepressant.

In some embodiments, the selective 5-HT₂c receptor agonist and the antidepressant are formulated as a fixed dose combination product.

In some embodiments, the selective 5-HT_2C receptor agonist and the antidepressant are formulated as a co-packaged product.

In some embodiments, the selective 5-HT_2C receptor agonist and the antidepressant are formulated for adjunctive therapy.

In some embodiments, the supplemental agent is nortriptyline, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and nortriptyline.

In some embodiments, the selective 5-HT_2C receptor agonist and the nortriptyline are formulated as a fixed dose combination product.

In some embodiments, the selective 5-HT_2C receptor agonist and the nortriptyline are formulated as a co-packaged product.

In some embodiments, the selective 5-HT_2C receptor agonist and the nortriptyline are formulated for adjunctive therapy.

In some embodiments, the supplemental agent is nortriptyline, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and bupropion.

In some embodiments, the selective 5-HT_2C receptor agonist and the bupropion are formulated as a fixed dose combination product.

In some embodiments, the selective 5-HT_2C receptor agonist and the bupropion are formulated as a co-packaged product.

In some embodiments, the selective 5-HT_2C receptor agonist and the bupropion are formulated for adjunctive therapy.

In some embodiments, the supplemental agent is nortriptyline, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and clonidine.

In some embodiments, the selective 5-HT_2C receptor agonist and the clonidine are formulated as a fixed dose combination product.

In some embodiments, the selective 5-HT_2C receptor agonist and the clonidine are formulated as a co-packaged product.

In some embodiments, the selective 5-HT_2C receptor agonist and the clonidine are formulated for adjunctive therapy.

In some embodiments, the supplemental agent is nortriptyline, and the composition is a composition comprising a selective 5-HT_2C receptor agonist and varenicline. In some embodiments, the selective 5-HT₂c receptor agonist and the varenicline are formulated as a fixed dose combination product.

In some embodiments, the selective 5-HT₂c receptor agonist and the varenicline are formulated as a co-packaged product.

In some embodiments, the selective 5-HT₂c receptor agonist and the varenicline are formulated for adjunctive therapy.

In some embodiments, the individual has previously undergone treatment with a supplemental agent. In some embodiments, the individual was refractory to the previous treatment with the supplemental agent.

In some embodiments, the individual has previously undergone treatment with a nicotine replacement therapy. In some embodiments, the individual was refractory to the previous treatment with the nicotine replacement therapy.

Also provided is a composition comprising a selective 5-HT_2C receptor agonist and at least one supplemental agent for:

reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco;

aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product;

aiding in smoking cessation and preventing associated weight gain;

controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco;

reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco;

treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or

reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use.

Also provided is a composition comprising a selective 5-HT_2C receptor agonist and at least one supplemental agent for use as a medicament for:

aiding in smoking cessation and preventing associated weight gain;

reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or

Also provided is a composition comprising a selective 5-HT_2C receptor agonist and at least one supplemental agent in the manufacture of a medicament for: reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use.

Also provided is a unit dosage form of a composition comprising a selective 5-HT₂c receptor agonist and at least one supplemental agent.

A selective 5-HT₂c receptor agonist for use in combination with a supplemental agent, for: reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use.

Also provided is a supplemental agent chosen from nicotine replacement therapies, for use in combination with a selective 5-HT_2C receptor agonist.

Also provided is a supplemental agent for use in combination with a selective 5-HT_2C receptor agonist for: reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product; aiding in smoking cessation and preventing associated weight gain; controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco; treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal; or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use. In some embodiments, the 5-HT₂c agonist is formulated as an immediate-release dosage form and the supplemental agent is also formulated as an immediate -release dosage form. In some embodiments, the 5-HT_c agonist is formulated as an immediate -release dosage form and the supplemental agent is formulated as a modified-release dosage form. In some embodiments, the 5- HT₂c agonist is formulated as a modified-release dosage form and the supplemental agent is formulated as an immediate-release dosage form. In some embodiments, the 5-HT₂c agonist is formulated as a modified-release dosage form and the supplemental agent is also formulated as a modified-release dosage form.

The selective 5-HT₂c agonists may be administered sequentially or concurrently with the one or more other supplemental agents identified herein. The amounts of formulation and pharmacologic agent depend, for example, on what type of pharmacologic agent(s) are used, and the scheduling and routes of administration

Supplemental agents may be delivered concomitantly with the selective 5-HT_2C agonists, or may be administered independently. Supplemental agent delivery may be via any suitable method known in the art including orally, inhalation, injection, etc.

In some embodiments, the methods described herein further comprise the step of: providing the individual with educational materials and/or counseling. In some embodiments, the counseling relates to smoking cessation. In some embodiments, the counseling relates to weight management, including without limitation counseling regarding diet and exercise. In some embodiments, the counseling relates to both smoking cessation and weight management, including without limitation counseling regarding diet and exercise.

In some embodiments, the methods described herein further comprise the step of: providing the individual with biochemical feedback; acupuncture; hypnosis; behavioral intervention; support services; and/or psychosocial treatment.

It will be apparent to those skilled in the art that the dosage forms described herein may comprise, as the active component, either a compound described herein, a pharmaceutically acceptable salt of a compound described herein, a solvate or hydrate of a compound described herein, or a solvate or hydrate of a pharmaceutically acceptable salt of a compound described herein. Moreover, various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K.J. Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect of the present disclosure pertains to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X- ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like. There are several commercial entities that provide quick and efficient services for identifying solvates and hydrates on a routine basis. Example companies offering these services include Wilmington

PharmaTech (Wilmington, DE), Avantium Technologies (Amsterdam) and Aptuit (Greenwich, CT).

PSUEDOPOLYMORPHISM

Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphs show the same properties in the liquid or gaseous state but they may behave differently in the solid state.

Besides single-component polymorphs, drugs can also exist as salts and other multicomponent crystalline phases. For example, solvates and hydrates may contain an API host and either solvent or water molecules, respectively, as guests. Analogously, when the guest compound is a solid at room temperature, the resulting form is often called a cocrystal. Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as pseudopolymorphs of one another.

Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.

Recently, polymorph screens of 245 compounds revealed that about 90% of them exhibited multiple solid forms. Overall, approximately half the compounds were polymorphic, often having one to three forms. About one-third of the compounds formed hydrates, and about one-third formed solvates. Data from cocrystal screens of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates. (G. P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026.)

ISOTOPES

The present disclosure includes all isotopes of atoms occurring in the present salts and crystalline forms thereof. Isotopes include those atoms having the same atomic number but different mass numbers. One aspect of the present invention includes every combination of one or more atoms in the present salts and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass number. One such example is the replacement of an atom that is the most naturally abundant isotope, such as ¾ or ¹²C, found in one the present salts and crystalline forms thereof, with a different atom that is not the most naturally abundant isotope, such as ²H or ³H

(replacing ¾), or ⁿC, ¹³C, or ¹⁴C (replacing ¹²C). A salt wherein such a replacement has taken place is commonly referred to as being isotopically-labeled. Isotopic-labeling of the present salts and crystalline forms thereof can be accomplished using any one of a variety of different synthetic methods know to those of ordinary skill in the art and they are readily credited with understanding the synthetic methods and available reagents needed to conduct such isotopic-labeling. By way of general example, and without limitation, isotopes of hydrogen include ²H (deuterium) and ³H (tritium). Isotopes of carbon include ⁿC, ¹³C, and ¹⁴C. Isotopes of nitrogen include ¹³N and ¹⁵N. Isotopes of oxygen include ¹⁵0, ¹⁷0, and C. An isotope of fluorine includes F. An isotope of sulfur includes S. An isotope of chlorine includes ³⁶C1. Isotopes of bromine include ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, and ⁸²Br. Isotopes of iodine include ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. Another aspect of the present invention includes compositions, such as, those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as, those prepared with the intent of using in a mammal for the treatment of one or more of the disorders described herein, comprising one or more of the present salts and crystalline forms thereof, wherein the naturally occurring distribution of the isotopes in the composition is perturbed. Another aspect of the present invention includes compositions and pharmaceutical compositions comprising salts and crystalline forms thereof as described herein wherein the salt is enriched at one or more positions with an isotope other than the most naturally abundant isotope. Methods are readily available to measure such isotope perturbations or enrichments, such as, mass spectrometry, and for isotopes that are radioisotopes additional methods are available, such as, radio-detectors used in connection with HPLC or GC.

Improving absorption, distribution, metabolism, excretion and toxicity (ADMET) properties while maintaining a desired pharmacological profile is a major challenge in drug development.

Structural changes to improve ADMET properties often alter the pharmacology of a lead compound. While the effects of deuterium substitution on ADMET properties are unpredictable, in select cases deuterium can improve a compound's ADMET properties with minimal perturbation of its pharmacology. Two examples where deuterium has enabled improvements in therapeutic entities are: CTP-347 and CTP-354. CTP-347 is a deuterated version of paroxetine with a reduced liability for mechanism-based inactivation of CYP2D6 that is observed clinically with paroxetine. CTP-354 is a deuterated version of a promising preclinical gamma-aminobutyric acid A receptor (GABAA) modulator (L-838417) that was not developed due to poor pharmacokinetic (PK) properties. In both cases, deuterium substitution resulted in improved ADMET profiles that provide the potential for improved safety, efficacy, and/or tolerability without significantly altering the biochemical potency and selectivity versus the all-hydrogen compounds. Provided are deuterium substituted compounds of the present invention with improved ADMET profiles and substantially similar biochemical potency and selectivity versus the corresponding all-hydrogen compounds. OTHER UTILITIES

Provided are radio-labeled compounds provided herein useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating 5-HT₂c receptors in tissue samples, including human, and for identifying 5-HT₂c receptor ligands by inhibition binding of a radiolabeled compound. Also provided are novel 5-HT₂c receptor assays of which comprise such radio- labeled compounds.

Certain isotopically-labeled compounds provided herein are useful in compound and/or substrate tissue distribution assays. In some embodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in these studies. Further, substitution with heavier isotopes such as deuterium {i.e. , ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Isotopically labeled compounds provided herein can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are useful are discussed infra.

Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds provided herein and are well known in the art. These synthetic methods, for example, incorporating activity levels of tritium into target molecules, include the following:

A. Catalytic Reduction with Tritium Gas: This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors.

B. Reduction with Sodium Borohydride [¾] : This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.

C. Reduction with Lithium Aluminum Hydride [³H] : This procedure offers products at almost theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like.

D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H] : This procedure is usually employed to prepare O- methyl or iV-methyl (3H) products by treating appropriate precursors with high specific activity methyl iodide (3H). This method in general allows for higher specific activity, such as for example, about 70- 90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into target molecules include:

A. Sandmeyer and like reactions: This procedure transforms an aryl amine or a heteroaryl amine into a diazonium salt, such as a diazonium tetrafluoroborate salt and subsequently to ¹²⁵I labeled compound using Na¹²⁵I. A represented procedure was reported by Zhu, G-D. and co-workers in J. Org. Chem. , 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols: This procedure allows for the incorporation of ¹²⁵I at the ortho position of a phenol as reported by Collier, T. L. and co-workers in J. Labelled Compd.

Radiopharm. , 1999, 42, S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I: This method is generally a two step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [e.g. Pd(Ph₃P)₄] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)3] . A representative procedure was reported by Le Bas, M.-D. and co-workers in J. Labelled Compd.

Radiopharm. 2001, 44, S280-S282. A radiolabeled 5-HT₂c receptor agonist of a compound disclosed herein can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of a radio-labeled compound to a 5-HT_2C receptor. The ability of a test compound to compete with a radio-labeled compound disclosed herein for the binding to a 5-HT₂c receptor directly correlates to its binding affinity.

Certain labeled compounds provided herein bind to certain 5-HT₂c receptors. In one embodiment the labeled compound has an IC₅₀ less than about 500 μΜ. In one embodiment the labeled compound has an IC₅₀ less than about 100 μΜ. In one embodiment the labeled compound has an IC₅₀ less than about 10 μΜ. In one embodiment the labeled compound has an IC₅₀ less than about 1 μΜ. In one embodiment the labeled compound has an IC₅₀ less than about 0.1 μΜ. In one embodiment the labeled compound has an IC₅₀ less than about 0.01 μΜ. In one embodiment the labeled compound has an IC₅₀ less than about 0.005 μΜ.

Other uses of the disclosed receptors and methods will become apparent to those skilled in the art based upon, inter alia, a review of this disclosure.

COMPOSITIONS AND FORMULATIONS

Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants and disintegrants can be used in tablets and capsules for oral administration. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral preparations can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants can be added to the liquid preparations. Parenteral dosage forms can be prepared by dissolving the compound provided herein in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.

A compound provided herein can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically-acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20* Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al).

While it is possible that, for use in the prophylaxis or treatment, a compound provided herein can, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier. Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the needs of the artisan.

The compounds provided herein, together with a conventional adjuvant, carrier, or diluent, can thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including

subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof can comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.

Compounds provided herein or a solvate, hydrate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as 5-HT₂c receptor modulators. The term "active ingredient", defined in the context of a "pharmaceutical composition"," refers to a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized as providing no pharmaceutical benefit.

The dose when using the compounds provided herein can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the individual, such as a patient, on the compound employed, on whether an acute or chronic disease state is treated, or prophylaxis conducted, or on whether further active compounds are administered in addition to the compounds provided herein. Representative doses include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the healthcare provider it may be necessary to deviate upward or downward from the doses described herein.

All dosage amounts disclosed herein are calculated with respect to the active moiety, i.e., the molecule or ion that gives the intended pharmacologic or physiologic action.

The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the individual and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.

Representative factors include the type, age, weight, sex, diet and medical condition of the individual, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, whether an acute or chronic disease state is being treated or prophylaxis conducted or whether further active compounds are administered in addition to the compounds provided herein such as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions provided herein is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods disclosed herein.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.

The compounds provided herein can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the dosage forms may comprise, as the active component, either a compound provided herein or a pharmaceutically acceptable salt, hydrate, or solvate of a compound provided herein. For preparing pharmaceutical compositions from the compounds provided herein, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.

The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "preparation" refers to the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water -propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds provided herein may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

For topical administration to the epidermis the compounds provided herein may be formulated as ointments, creams or lotions, or as a transdermal patch.

Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant. If the compounds provided herein or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds provided herein as an aerosol can be prepared by processes well known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds provided herein in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

The compounds provided herein may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfide, tartaric, oxalic, j-toluenesulfonic and the like. Certain compounds provided herein which contain a carboxylic acid functional group may optionally exist as pharmaceutically acceptable salts containing non-toxic, pharmaceutically acceptable metal cations and cations derived from organic bases. Representative metals include, but are not limited to, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. In some embodiments the pharmaceutically acceptable metal is sodium. Representative organic bases include, but are not limited to, benzathine (TV^A^-dibenzylethane- 1,2-diamine), chloroprocaine (2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline,

diethanolamine, ethylenediamine, meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane-l,2, 3,4,5- pentaol), procaine (2-(diethylamino)ethyl 4-aminobenzoate), and the like. Certain pharmaceutically acceptable salts are listed in Berge, et ah, Journal of Pharmaceutical Sciences, 66: 1 -19 (1977).

The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds provided herein may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

Compounds provided herein can be converted to "pro-drugs." The term "pro-drugs" refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds provided herein containing one or more specialized nontoxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drug" approach is utilized to facilitate oral absorption. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

Some embodiments include a method of producing a pharmaceutical composition for

"combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.

It is noted that when the 5-HT_2C receptor modulators are utilized as active ingredients in pharmaceutical compositions, these are not intended for use in humans only, but in non-human mammals as well. Recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as 5-HT₂c receptor modulators, for the treatment of a 5-HT₂c receptor-associated disease or disorder in companionship animals (e.g., cats, dogs, etc.) and in livestock animals (e.g., horses, cows, etc.) Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.

As will be recognized, the steps of the methods provided herein need not be performed any particular number of times or in any particular sequence. Additional objects, advantages and novel features of the invention(s) will become apparent to those skilled in the art upon examination of the following examples thereof, which are intended to be illustrative and not intended to be limiting.

EXAMPLES The compounds disclosed herein and their syntheses are further illustrated by the following examples. The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. The compounds described herein, supra and infra, are named according to the AutoNom version 2.2, CS ChemDraw Ultra Version 9.0.7, or ChemBioDraw Ultra 12.0.2.1076. In certain instances common names are used and it is understood that these common names would be recognized by those skilled in the art.

Chemistry: Proton nuclear magnetic resonance (¾ NMR) spectra were recorded on a Bruker Avance III-400 equipped with a 5 mm BBFO probe. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference. NMR abbreviations are used as follows: s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, bs = broad singlet, sxt = sextet. Microwave irradiations were carried out using a Smith Synthesizer™ or an Emrys Optimizer™ (Biotage). Thin-layer chromatography (TLC) was performed on silica gel 60 F₂5₄ (Merck), preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm (Merck). Evaporation was done under reduced pressure on a Biichi rotary evaporator. Celite^® 545 was used for filtration of palladium.

LCMS spec: HPLC- Agilent 1200; pumps: G1312A; DAD:G1315B; Autosampler: G1367B; Mass spectrometer- Agilent G1956A; ionization source: ESI; Drying Gas How: 10 L/min; Nebulizer Pressure: 40 psig; Drying Gas Temperature: 350 °C; Capillary Voltage: 2500 V) Software: Agilent Chemstation Rev.B.04.03.

Example 1A: Syntheses of Compounds of Formula I

Illustrated syntheses for compounds of Formula I are shown in Figure 1 wherein the variables (e.g., X, R¹) have the same definitions as used throughout this disclosure. Example 1.1: Preparation of 2-(ieri-Butoxycarbonyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /w]indole-8-carboxylic Acid (Intermediate 1).

Method A.

Step A: Preparation of Methyl l-(2-Aminoethyl)indoline-4-carboxylate.

A mixture of methyl indoline-4-carboxylate (2.1 g, 11.85 mmol) and 2-bromoethanamine hydrobromide (2.550 g, 12.44 mmol) was heated at 122 °C for 15 h. The mixture was dissolved in 2 M HC1 and purified by HPLC to give the title compound (2.3 g). LCMS mlz = 221.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.21 (t, J = 6.6 Hz, 2H), 3.28-3.34 (m, 2H), 3.35-3.45 (m, 4H), 3.85 (s, 3H), 6.78 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 7.29 (dd, J_} = 8.0 Hz, J₂ = 0.9 Hz, 1H).

Step B: Preparation of Methyl l,2,3,4,6,7-Hexahydro-[l,4]diazepino[6,7,l-/H-]indole-8- carboxylate.

To a solution of the TFA salt of methyl l-(2-aminoethyl)indoline-4-carboxylate (2.3 g, 6.880 mmol) and paraformaldehyde (0.248 g, 8.256 mmol) in MeOH (100 mL) was added TFA (0.632 mL, 8.256 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by HPLC to give the title compound (1.37 g). LCMS m/z = 233.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.26-3.30 (m, 2H), 3.34-3.40 (m, 2H), 3.50-3.56 (m, 4H), 3.88 (s, 3H), 4.32 (s, 2H), 7.12 (d, 7 = 8.1 Hz, 1H), 7.40 (d, 7 = 8.0 Hz, 1H).

Step C: Preparation of 2-tert-Butyl 8-Methyl 3,4,6,7-Tetrahydro-[l,4]diazepino[6,7,l-

/»]indole-2,8(l/7)-dicarboxylate.

To a solution of the TFA salt of methyl l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l - i;]indole-8- carboxylate (1.368 g, 3.950 mmol) and triethylamine (2.202 mL, 15.80 mmol) in CH₂C1₂ (20 mL) was added a solution of di-ieri-butyl dicarbonate (0.862 g, 3.950 mmol) in CH₂C1₂ (20 mL). The reaction was stirred at 23 °C for 2 h. The mixture was extracted with H₂0. The organic extract was concentrated. The residue was purified by column chromatography to give the title compound (1.26 g). LCMS m/z = 333.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.40 (s, 9H), 3.05 (s, 2H), 3.32-3.47 (m, 4H), 3.67-3.74 (m, 2H), 3.78 (s, 3H), 4.32-4.47 (m, 2H), 6.89-7.09 (m, 1H), 7.36 (d, 7 = 7.9 Hz, 1H).

Step D: Preparation of 2-(teri-Butoxycarbonyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole-8-carboxylic Acid (Intermediate 1).

To a solution of 2-feri-butyl 8-methyl 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole- 2,8(l//)-dicarboxylate (1.26 g, 3.791 mmol) in MeOH (6 mL) was added 5 M sodium hydroxide (1.516 mL, 7.581 mmol). The reaction was stirred at 65 °C for 3 h. The mixture was concentrated. To the residue was added 4 M hydrogen chloride (1.801 mL, 7.202 mmol). The reaction was stirred for 10 min. The mixture was concentrated to give the title compound (1.29 g). LCMS m/z = 319.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.38 (s, 3H), 1.43 (s, 6H), 3.02-3.07 (m, 2H), 3.24-3.42 (m, 4H), 3.66-3.76 (m, 2H), 4.40 (s, 2H), 6.89-7.00 (m, 1H), 7.27 (d, 7 = 7.9 Hz, 1H).

Method B.

Step A: Preparation of Methyl l-(Cyanomethyl)indoline-4-carboxylate.

To a mixture of methyl indoline-4-carboxylate (5.0 g, 28.22 mmol) in H₂0 (2.5 mL) was added 2-hydroxyacetonitrile (3.073 g, 29.63 mmol). The reaction was heated at 110 °C for 15 h. The mixture was filtered. The solid was collected and recrystallized from MeOH (12 mL) to give the title compound (5.6 g). LCMS m/z = 217.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 3.37-3.45 (m, 2H), 3.46-3.54 (m, 2H), 3.89 (s, 3H), 4.11 (s, 2H), 6.71 (d, 7 = 7.6 Hz, 1H), 7.22 (t, 7 = 7.9 Hz, 1H), 7.47 (dd, 7 1= 8.0 Hz, 7₂ = 0.9 Hz, 1H).

Step B: Preparation of Methyl l-(2-Aminoethyl)indoline-4-carboxylate.

To the reaction vessel was added Raney-Nickel 2800 (2.606 g, 44.40 mmol). The catalyst was washed with methanol multiple times before the addition of ammonia in methanol (7 M, 95.13 mL, 665.9 mmol). Methyl l-(cyanomethyl)indoline-4-carboxylate (4.8 g, 22.20 mmol) was added. The reaction was shaken under H₂ (50 atm) for 20 h at 23 °C. The mixture was filtered. The filtrate was concentrated to give the title compound (3.9 g). LCMS m/z = 221 A [M+H]⁺. Step C: Preparation of Methyl l,2,3,4,6,7-Hexahydro-[l,4]diazepino[6,7,l-/M-]indole-8- carboxylate.

To a solution of methyl l-(2-aminoethyl)indoline-4-carboxylate (3.8 g, 17.25 mmol) and paraformaldehyde (1.658 g, 55.21 mmol) in MeOH (250 mL) was added TFA (10.57 mL, 138.0 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by HPLC to give the title compound (3.93 g). LCMS m/z = 233.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.25-3.30 (m, 2H), 3.34-3.40 (m, 2H), 3.49-3.56 (m, 4H), 3.88 (s, 3H), 4.32 (s, 2H), 7.12 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H).

Step D: Preparation of 2-tert- Butyl 8-Methyl 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- ¾i]indole-2,8(l//)-dicarboxylate.

To a solution of the TFA salt of methyl l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole-8- carboxylate (3.95 g, 11.41 mmol) and triethylamine (6.359 mL, 45.62 mmol) in CH₂C1₂ (55 mL) was added a solution di-feri-butyl dicarbonate (2.489 g, 11.41 mmol) in CH₂C1₂ (55 mL). The reaction was stirred at 23 °C for 2 h. The mixture was extracted with H₂0. The organic extract was concentrated. The residue was purified by column chromatography to give the title compound (3.7 g). LCMS m/z = 333.6 [M+H]⁺.

Step E: Preparation of 2-(teri-Butoxycarbonyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole-8-carboxylic Acid (Intermediate 1).

To a solution of 2-feri-butyl 8-methyl 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole- 2,8(l//)-dicarboxylate (2.8165 g, 8.473 mmol) in MeOH (12.5 mL) was added 5 M sodium hydroxide (3.389 mL, 16.95 mmol). The reaction was stirred at 65 °C for 3 h. The mixture was concentrated. To the residue was added 4 M hydrogen chloride (4.025 mL, 16.10 mmol). The reaction was stirred for 10 min. The mixture was concentrated to give the title compound (2.89 g). LCMS m/z = 319.2 [M+H]⁺. Example 1.2: Preparation of N-(2-Methoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 1).

To a solution of Intermediate 1 (300 mg, 0.754 mmol), 2-methoxyethanamine (67.95 mg, 0.905 mmol), and triethylamine (0.315 mL, 2.262 mmol) in DMF (6 mL) was added HATU (0.430 g, 1.131 mmol). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give feri-butyl 8-((2-methoxyethyl)carbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;^']indole-2(l//)- carboxylate as a white solid. The above solid was then dissolved in HC1 (1.25 M in methanol). The reaction was stirred at room temperature for 24 h. The mixture was concentrated to give the title compound (107 mg). LCMS m/z = 276.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.20-3.29 (m, 4H), 3.38 (s, 3H), 3.47-3.58 (m, 8H), 4.31 (s, 2H), 7.03 (d, J = 8.1 Hz, 1H), 7.11 (d, 7 = 8.0 Hz, 1H).

Example 1.3: Preparation of N-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M-]indole-8- carboxamide (Compound 2). To a solution of Intermediate 1 (150 mg, 0.358 mmol), 33% methanamine in EtOH (0.374 mL, 3.581 mmol), and triethylamine (0.150 mL, 1.074 mmol) in DMF (3 mL) was added HATU (0.204 g, 0.537 mmol). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give feri-butyl 8-(methylcarbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-2(l//)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at 50 °C for 2 h. The mixture was concentrated to give the title compound (78 mg). LCMS m/z = 232.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.88 (s, 3H), 3.22-3.29 (m, 4H), 3.47-3.55 (m, 4H), 4.31 (s, 2H), 7.02 (d, 7 = 7.9 Hz, 1H), 7.1 1 (d, 7 = 7.9 Hz, 1H). Example 1.4: Preparation of N-(2-Ethoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /w]indole-8-carboxamide (Compound 8).

To a solution of Intermediate 1 (16 mg, 38.19 μιηοΐ), 2-ethoxyethanamine (3.745 mg, 42.01 μιηοΐ), and triethylamine (15.97 μΐ,, 0.115 mmol) in DMF (0.5 mL) was added HATU (21.78 mg, 57.29 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give feri-butyl 8-((2-ethoxyethyl)carbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;]indole-2(l//)- carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated to give the title compound (10.2 mg). LCMS m/z = 290.0 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ 1.20 (t, 7 = 7.1 Hz, 3H), 3.21-3.30 (m, 4H), 3.48-3.62 (m, 10H), 4.32 (s, 2H), 7.05 (d, 7 = 7.9 Hz, 1H), 7.1 1 (d, 7 = 8.0 Hz, 1H).

Example 1.5: Preparation of N-Propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole-8- carboxamide (Compound 5).

To a solution of Intermediate 1 (25 mg, 59.68 μιηοΐ), propan-1 -amine (3.528 mg, 59.68 μιηοΐ), and triethylamine (24.95 μΐ,, 0.179 mmol) in DMF (0.8 mL) was added HATU (34.04 mg, 89.52 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give ieri-butyl 8-(propylcarbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(l/f)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated to give the title compound (4.2 mg). LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.98 (t, 7 = 7.4 Hz, 3H), 1.57-1.69 (m, 2H), 3.20-3.33 (m, 6H), 3.47-3.56 (m, 4H), 4.31 (s, 2H), 7.02 (d, 7 = 7.9 Hz, 1H), 7.11 (d, 7 = 8.0 Hz, 1H).

Example 1.6: Preparation of N-(3-Methoxypropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /w]indole-8-carboxamide (Compound 4).

To a solution of Intermediate 1 (40 mg, 0.095 mmol), 3-methoxypropan-l-amine (10.21 mg, 0.1 15 mmol), and triethylamine (39.93 0.286 mmol) in DMF (0.8 mL) was added HATU (54.46 mg, 0.143 mmol). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give feri-butyl 8-((3-methoxypropyl)carbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;]indole- 2(l/f)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated. The residue was purified by HPLC to give the title compound (12.8 mg). LCMS m/z = 290.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.81-1.90 (m, 2H), 3.19-3.29 (m, 4H), 3.34 (s, 3H), 3.42 (t, 7 = 6.9 Hz, 2H), 3.46-3.55 (m, 6H), 4.30 (s, 2H), 7.00 (d, 7 = 7.9 Hz, 1H), 7.10 (d, 7 = 7.9 Hz, 1H).

Example 1.7: Preparation of N-(Pyridin-3-yl)-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 3).

From Intermediate 1 and pyridine-3-amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.6. LCMS m/z = 295.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.30-3.40 (m, 4H), 3.53-3.61 (m, 4H), 4.38 (s, 2H), 7.23 (d, 7 = 8.0 Hz, 1H), 7.28 (d, 7 = 8.0 Hz, 1H), 7.91-7.98 (m, 1H), 8.52-8.57 (m, 1H), 8.58-8.63 (m, 1H), 9.40 (d, 7 = 2.3 Hz, 1H). Example 1.8: Preparation of N-Isopropyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole-8- carboxamide (Compound 6).

From Intermediate 1 and pyridine-2-amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.4. LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.23 (d, 7 = 6.6 Hz, 6H), 3.23 (t, 7 = 8.4 Hz, 2H), 3.27-3.30 (m, 2H), 3.49-3.58 (m, 4H), 4.10-4.22 (m, 1H), 4.32 (s, 2H), 7.03 (d, 7 = 7.9 Hz, 1H), 7.13 (d, 7 = 7.9 Hz, 1H).

Example 1.9: Preparation of N-Cyclopropyl-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l-/H-]indole- 8-carboxamide (Compound 7).

From Intermediate 1 and cyclopropanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.4. LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.58-0.64 (m, 2H), 0.77-0.83 (m, 2H), 2.78-2.86 (m, 1H), 3.21 -3.28 (m, 2H), 3.28-3.32 (m, 2H), 3.49-3.58 (m, 4H), 4.32 (s, 2H), 7.03 (d, 7 = 7.9 Hz, 1H), 7.12 (d, 7 = 7.9 Hz, 1H).

Example 1.10: Preparation of N-(Pyridin-2-ylmethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 11).

To a solution of Intermediate 1 (15 mg, 37.69 μιηοΐ), pyridin-2-ylmethanamine (4.484 mg, 41.46 μιηοΐ), and triethylamine (15.76 0.113 mmol) in MeCN (0.5 mL) was added HATU (21.50 mg, 56.54 μιηοΐ). The reaction was stirred at 23 °C for 15 hr. The mixture was purified by HPLC to give feri-butyl 8-((pyridin-2-ylmethyl)carbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole- 2(l/f)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at 55 °C for 6 h. The mixture was concentrated to give the title compound (8.4 mg). LCMS m/z = 309.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.25-3.37 (m, 4H), 3.50-3.61 (m, 4H), 4.36 (s, 2H), 4.89 (s, 2H), 7.20 (d, 7 = 8.0 Hz, 1H), 7.27 (d, 7 = 8.0 Hz, 1H), 8.02 (t, 7 = 6.7 Hz, 1H), 8.10 (d, 7 = 8.1 Hz, 1H), 8.63 (t, 7 = 8.1 Hz, 1H), 8.80 (d, 7 = 5.5 Hz, 1H).

Example 1.11: Preparation of N-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 12).

From Intermediate 1 and (6-(trifluoromethyl)pyridin-3-yl)methanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 377.2 [M+H]⁺. Example 1.12: Preparation of N-Ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole-8- carboxamide (Compound 10).

From Intermediate 1 and ethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 246.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.21 (d, 7 = 7.2 Hz, 3H), 3.26 (t, 7 = 8.5 Hz, 2H), 3.29-3.34 (m, 2H), 3.38 ( q, 7 = 7.2 Hz, 2H), 3.50-3.59 (m, 4H), 4.33 (s, 2H), 7.06 (d, 7 = 7.9 Hz, 1H), 7.14 (d, 7 = 7.9 Hz, 1H).

Example 1.13: Preparation of Methyl 2-(l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l-/H-]indole-8- carboxamido)acetate (Compound 9).

To a solution of Intermediate 1 (16 mg, 38.19 μιηοΐ), 2-aminoacetonitrile hydrochloride (3.887 mg, 42.01 μιηοΐ), and triethylamine (15.97 0.115 mmol) in DMF (0.5 mL) was added

HATU (21.78 mg, 57.29 μιηοΐ). The reaction was stirred at 23 °C for 15 hr. The mixture was purified by HPLC to give ieri-butyl 8-((cyanomethyl)carbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l-i;]indole-2(l//)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at 55 °C for 6 h. The mixture was concentrated to give the title compound (9.8 mg). LCMS m/z = 290.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.25-3.33

(m, 4H), 3.50-3.58 (m, 4H), 3.76 (s, 3H), 4.09 (s, 2H), 4.34 (s, 2H), 7.13 (d, 7 = 7.9 Hz, 1H), 7.15 (d, 7 = 8.0 Hz, 1H).

Example 1.14: Preparation of N-(2-(Methylsulfonyl)ethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 14).

From Intermediate 1 and 2-(methylsulfonyl)ethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 324.2 [M+H]⁺.

Example 1.15: Preparation of N-(2-(Methylthio)ethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 13).

From Intermediate 1 and 2-(methylthio)ethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 292.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.14 (s, 3H), 2.72 (t, J = 6.9 Hz, 2H), 3.02 (s, 2H), 3.24-3.37 (m, 4H), 3.52-3.62 (m, 4H), 4.34 (s, 2H), 7.09 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H).

Example 1.16: Preparation of N-(2-(Ethylthio)ethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indole-8-carboxamide (Compound 18).

From Intermediate 1 and 2-(ethylthio)ethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mlz = 306.4 [M+H]⁺.

Example 1.17: Preparation of N-(Cyclopropylmethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indole-8-carboxamide (Compound 16)

From Intermediate 1 and cyclopropylmethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mlz = 272.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.21 -0.35 (m, 2H), 0.45-0.60 (m, 2H), 1.01-1.15 (m, 1H), 3.19-3.34 (m, 6H), 3.50-3.60 (m, 4H), 4.33 (s, 2H), 7.07 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H).

Example 1.18: Preparation of N-(2-Isopropoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indole-8-carboxamide (Compound 17).

From Intermediate 1 and 2-isopropoxyethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mlz = 304.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.16 (d, J = 6.2 Hz, 6H), 3.24-3.37 (m, 4H), 3.50 (t, J = 5.5 Hz, 2H), 3.53- 3.70 (m, 7H), 4.35 (s, 2H), 7.10 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H).

Example 1.19: Preparation of N-(2-Chloroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indole-8-carboxamide (Compound 15).

From Intermediate 1 and 2-chloroethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mlz = 280.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.23-3.33 (m, 4H), 3.49-3.57 (m, 4H), 3.63-3.75 (m, 4H), 4.33 (s, 2H), 7.07 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H). Example 1.20: Preparation of N-(l-Ethoxypropan-2-yl)-l,2,3,4,6,7-hexahydro-

[l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 20).

From Intermediate 1 and l-ethoxypropan-2-amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 304.4 [M+H]⁺. ¾

NMR (400 MHz, CD₃OD) δ 1.19 (t, J = 7.0 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 3.22-3.29 (m, 2H), 3.31 - 3.35 (m, 2H), 3.42-3.61 (m, 8H), 4.22-4.30 (m, 1H), 4.34 (s, 2H), 7.06 (d, J = 7.9 Hz, 1H), 7.15 (d, J =

7.9 Hz, 1H). Example 1.21: Preparation of N-(l-Methoxypropan-2-yl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 19).

From Intermediate 1 and l-methoxypropan-2-amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mJz = 290.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.22 (d, 7 = 6.8 Hz, 3H), 3.19-3.28 (m, 2H), 3.28-3.34 (m, 2H), 3.37 (s, 3H), 3.38-3.49 (m, 2H), 3.50-3.58 (m, 4H), 4.22-4.30 (m, 1H), 4.33 (s, 2H), 7.05 (d, 7 = 7.9 Hz, 1H), 7.14 (d, 7 = 7.9 Hz, 1H).

Example 1.22: Preparation of N-(2-Methoxypropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indole-8-carboxamide (Compound 21).

From Intermediate 1 and 2-methoxypropan-l -amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mJz = 290.4 [M+H]⁺;

¾ NMR (400 MHz, CD₃OD) δ 1.18 (d, 7 = 6.2 Hz, 3H), 3.26 (t, 7 = 8.4 Hz, 3H), 3.31-3.35 (m, 2H),

3.33-3.47 (m, 2H), 3.38 (s, 3H), 3.52-3.60 (m, 5H), 4.34 (s, 2H), 7.08 (d, 7 = 7.9 Hz, 1H), 7.15 (d, 7 = 7.9 Hz, 1H).

Example 1.23: Preparation of N-(2-Propoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indole-8-carboxamide (Compound 23).

From Intermediate 1 and 2-propoxyethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mJz = 304.4 [M+H]⁺; ¾

NMR (400 MHz, CD₃OD) δ 0.93 (t, 7 = 7.3 Hz, 3H), 1.54-1.64 (m, 2H), 3.25 (t, 7 = 8.5 Hz, 2H), 3.27- 3.31 (m, 2H), 3.45 (t, 7 = 6.5 Hz, 2H), 3.49-3.57 (m, 6H), 3.57-3.62 (m, 2H), 4.33 (s, 2H), 7.06 (d, 7 = 7.9 Hz, 1H), 7.13 (d, 7 = 7.9 Hz, 1H). Example 1.24: Preparation of N-(2-Fluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-

/»]indole-8-carboxamide (Compound 27).

From Intermediate 1 and 2-fluoroethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS mJz = 264.2 [M+H]⁺; ¾

NMR (400 MHz, CD₃OD) δ 3.28 (t, 7 = 8.5 Hz, 2H), 3.32-3.37 (m, 2H), 3.52-3.59 (m, 4H), 3.61 (t, 7 = 5.1 Hz, 1H), 3.68 (t, 7 = 5.1 Hz, 1H), 4.35 (s, 2H), 4.49 (t, 7 = 5.1 Hz, 1H), 4.61 (t, 7 = 5.1 Hz, 1H),

7.11 (d, 7 = 7.9 Hz, 1H), 7.17 (d, 7 = 7.9 Hz, 1H).

Example 1.25: Preparation of N-(3-Fluoropropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indole-8-carboxamide (Compound 28).

From Intermediate 1 and 3-fluoropropan-l -amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 278.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.91-2.06 (m, 2H), 3.26 (t, 7 = 8.5 Hz, 2H), 3.31-3.36 (m, 2H), 3.48 (t, 7 = 6.8 Hz, 2H), 3.51-3.60 (m, 4H), 4.34 (s, 2H), 4.47 (t, 7 = 5.8 Hz, 1H), 4.59 (t, 7 = 5.8 Hz, 1H), 7.08 (d, 7 = 7.9 Hz, 1H), 7.15 (d, 7 = 7.9 Hz, 1H).

Example 1.26: Preparation of N-Butyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole-8- carboxamide (Compound 29).

From Intermediate 1 and butan-1 -amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 2Ί4.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.97 (t, 7 = 7.3 Hz, 3H), 1.36-1.47 (m, 2H), 1.54-1.64 (m, 2H), 3.24 (t, 7 = 8.5 Hz, 2H), 3.27-3.32 (m, 2H), 3.34 (t, 7 = 7.1 Hz, 2H), 3.48-3.58 (m, 4H), 4.32 (s, 2H), 7.03 (d, 7 = 7.9 Hz, 1H), 7.12 (d, 7 = 7.9 Hz, 1H).

Example 1.27: Preparation of N-(2-Phenoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 24).

From Intermediate 1 and 2-phenoxyethanamine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 338.4 [M+H]⁺; ¾

NMR (400 MHz, CD₃OD) δ 3.23 (t, 7 = 8.5 Hz, 2H), 3.26-3.30 (m, 2H), 3.46-3.57 (m, 4H), 3.74 (t, 7 = 5.5 Hz, 2H), 4.15 (t, 7 = 5.6 Hz, 2H), 4.31 (s, 2H), 6.89-6.98 (m, 3H), 7.04 (d, 7 = 7.9 Hz, 1H), 7.12 (d, 7 = 7.9 Hz, 1H), 7.22-7.30 (m, 2H). Example 1.28: Preparation of N-(2-Ethoxypropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 22).

From Intermediate 1 and 2-ethoxypropan-l-amine, the title compound was obtained as a white solid using a similar method to the one described in Example 1.10. LCMS m/z = 304.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.15-1.20 (m, 6H), 3.26 (t, 7 = 8.5 Hz, 2H), 3.31-3.74 (m, 11H), 4.33 (s, 2H), 7.07 (d, 7 = 7.9 Hz, 1H), 7.15 (d, 7 = 7.9 Hz, 1H).

Example 1.29: Preparation of N-(2-Methoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /w]indole-8-carbothioamide (Compound 25).

To a solution of the hydrochloride salt of Compound 1 (16 mg, 45.94 μιηοΐ) in dioxane (0.4 ml) was added Lawesson's reagent (37.16 mg, 91.88 μιηοΐ). The reaction was heated at 100 °C for 50 min. The mixture was concentrated. The residue was dissolved in DCM and washed with 1 M NaOH. The organics were purified by HPLC to give the title compound. LCMS m/z = 292.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.12 (t, 7 = 8.5 Hz, 2H), 3.21-3.26 (m, 2H), 3.38 (s, 3H), 3.44-3.54 (m, 4H), 3.68 (t, 7 = 5.5 Hz, 2H), 3.90-3.96 (m, 2H), 4.27 (s, 2H), 6.85 (d, 7 = 7.9 Hz, 1H), 7.05 (d, 7 = 7.9 Hz, 1H).

Example 1.30: Preparation of N-Methyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole-8- carbothioamide (Compound 26). From the hydrochloride salt of Compound 2, the title compound was obtained as a white solid using a similar method to the one described in Example 1.29. LCMS m/z = 248.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 3.13 (t, 7 = 8.5 Hz, 2H), 3.19 (s, 3H), 3.22-3.27 (m, 2H), 3.35 (s, 2H), 3.43-3.54 (m, 4H), 4.28 (s, 2H), 6.83 (d, 7 = 7.9 Hz, 1H), 7.05 (d, 7 = 7.9 Hz, 1H).

Example IB: Syntheses of Compounds of Formula XI

Illustrated syntheses for compounds of Formula XI are shown in Figures 21a-d, 22 and 23 wherein the variables have the same definitions as used throughout this disclosure.

Example 1B.1: Preparation of N,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 104).

Step A: Preparation of 3,3-dimethyl-3H-indole-4-carboxylic acid.

3-Hydrazinylbenzoic acid (3 g, 19.72 mmol) was added to a solution of isobutyraldehyde (1.564 g, 21.69 mmol) in AcOH : H₂0 (100 mL, 1 : 1 ratio). The reaction mixture was heated at 60 °C for 3 hours. After the mixture was cooled down in an ice-water bath, the precipitate was collected, washed with ether, and dried to give the title compound (2.218 g) as a beige solid with about 90% purity. LCMS m/z = 190.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.57 (s, 6H), 7.48 (t, 7 = 7.8 Hz, 1H), 7.76 (dd, 7 = 7.7 and 1.0 Hz, 1H), 7.96 (dd, 7 = 7.9 and 0.9 Hz, 1H), 8.16 (s, 1H).

Step B: Preparation of methyl 3,3-dimethyl-3H-indole-4-carboxylate.

To a suspension of 3,3-dimethyl-3H-indole-4-carboxylic acid (1 g, 5.285 mmol) in 10 mL DCM:MeOH (7 :3) was added a 2M solution of (diazomethyl)trimethylsilane in ether (3.964 mL, 7.928 mmol) dropwise in an ice-water bath under nitrogen. The reaction mixture was stirred for 2 hours while slowly warmed to room temperature. The reaction was quenched with water and extracted with DCM. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (888 mg) as a colorless oil. LCMS m/z = 204.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.53 (s, 3H), 1.56 (s, 3H), 3.94 (s, 3H), 7.41 (t, 7 = 7.8 Hz, 1H), 7.80 (dd, 7 = 7.7 and 1.0 Hz, 1H), 7.90 (dd, 7 = 7.9 and 0.9 Hz, 1H), 8.00 (s, 1H).

Step C: Preparation of methyl 3,3-dimethylindoline-4-carboxylate.

To a solution of methyl 3,3-dimethyl-3H-indole-4-carboxylate (888 mg, 4.369 mmol) in DCM (15 mL) was added sodium triacetoxyborohydride (1.852 g, 8.739 mmol) under nitrogen in an ice -water bath, then acetic acid (1.251 mL, 21.85 mmol) was added. The reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NaHC0₃ solution and extracted with DCM. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (761 mg) as colorless oil. LCMS m/z = 206.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.43 (s, 6H), 3.29 (s, 2H), 3.89 (s, 3H), 6.76 (dd, 7 = 7.7 and 1.1 Hz, 1H), 7.06 (t, 7 = 7.7 Hz, 1H), 7.13 (dd, 7 = 7.8 and 1.1 Hz, 1H).

Step D: Preparation of methyl l-(2-aminoethyl)-3,3-dimethylindoline-4-carboxylate. Methyl 3,3-dimethylindoline-4-carboxylate (0.43 g, 2.095 mmol) and 2-bromoethanamine hydrobromide (0.451 g, 2.200 mmol) were heated neat (i.e., without solvent) at 120 °C for 15 hours. The solid mixture was dissolved in DMSO and purified by HPLC (10-70% CH₃CN H₂0 with 0.1 % TFA over 30 minutes). The combined fractions were adjusted to basic pH using saturated NaHC0₃, partially concentrated, extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (243 mg). LCMS m/z = 249.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.42 (s, 6H), 2.89 (t, 7 = 6.3 Hz, 2H), 3.13 (s, 2H), 3.17 (t, 7 = 6.4 Hz, 2H), 3.87 (s, 3H), 6.74 (dd, 7 = 7.9 and 0.9 Hz, 1H), 7.02 (dd, 7 = 7.8 and 1.0 Hz, 1H), 7.12 (t, 7 = 7.8 Hz, 1H).

Step E: Preparation of 2-teri-butyl 8-methyl 7,7-dimethyl-3,4,6,7-tetrahydro-

[l,4]diazepino[6,7,l-/»]indole-2,8(lH)-dicarboxylate.

To a solution of methyl l-(2-aminoethyl)-3,3-dimethylindoline-4-carboxylate (0.24 g, 0.966 mmol) and 37% formaldehyde in water (0.216 mL, 2.899 mmol) in methanol (6 mL) was added TFA (0.444 mL, 5.799 mmol). The reaction was stirred at 80 °C for 1 hour. The mixture was concentrated. The residue was dissolved in ethyl acetate. The organic phase was washed with aqueous saturated NaHC0₃, water and brine, dried with Na₂S0₄, filtered, then concentrated to give crude methyl 7,7- dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l - i;^']indole-8-carboxylate. The crude product obtained above was dissolved in DCM (6 mL), triethylamine (0.204 mL, 1.450 mmol) was added, followed by di-ieri-butyl dicarbonate (0.274 g, 1.256 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated. The residue was purified by silica gel column chromatography to give the title compound (233 mg) as a colorless oil. LCMS m/z = 361.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.39-1.42 (br, 15H), 3.02 (br, 2H), 3.13 (s, 2H), 3.72 (br, 2H), 3.88 (s, 3H), 4.36-4.44 (m, 2H), 6.91-7.05 (m, 1H), 7.10 (d, 7 = 7.8 Hz, 1H).

Step F: Preparation of 2-(ieri-butoxycarbonyl)-7,7-dimethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole-8-carboxylic acid.

To a solution of 2-ieri-butyl 8-methyl 7,7-dimethyl-3,4,6,7-tetrahydro-[l ,4]diazepino[6,7, l- /i;]indole-2,8(lH)-dicarboxylate (280 mg, 0.777 mmol) in THF (5 mL) was added 1M solution of lithium hydroxide in water (4.661 mL, 4.661 mmol). The reaction was stirred at 65 °C overnight. Three equivalents more LiOH solution and dioxane (3 mL) were added. The reaction was heated at 85 °C for 5 hours. After the pH of the mixture was adjusted to 3-4, the mixture was extracted with ethyl acetate. The combined organic fractions were concentrated. The residue was purified by HPLC. The fractions were partially concentrated and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered then concentrated to give the title compound (200 mg) as gum. LCMS m/z = 347.2 [M+H]⁺.

Step G: Preparation of N,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-

&i]indole-8-carboxamide.

To a stirred solution of 2-(feri-butoxycarbonyl)-7,7-dimethyl-l ,2,3,4,6,7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (50 mg, 0.144 mmol), and triethylamine (60.35 μΐ, 0.433 mmol) in CH₃CN (1.5 mL) was added HATU (82.32 mg, 0.216 mmol). After 10 minutes, 2M methanamine in THF (0.722 mL, 1.443 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was purified by HPLC to give feri-butyl 7,7-dimethyl-8-(methylcarbamoyl)- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-/i;]indole-2(lH)-carboxylate (33 mg). LCMS m/z = 360.4 [M+H]⁺.

To a solution of feri-butyl 7,7-dimethyl-8-(methylcarbamoyl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate (33 mg, 91.80 μιηοΐ) in dioxane (1 mL) was added 4M hydrogen chloride in dioxane (0.459 mL, 1.836 mmol). The reaction was stirred at room temperature for 5 hours. The mixture was concentrated. The residue was purified by HPLC to give the title compound. LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.40 (s, 6H), 2.89 (s,

3H), 3.22 (s, 2H), 3.24-3.28 (m, 2H), 3.52-3.56 (m, 2H), 4.32 (s, 2H), 6.78 (d, 7 = 7.8 Hz, 1H), 7.10 (d, 7 = 7.8 Hz, 1H).

Example 1B.2: Preparation of N-(2-methoxyethyl)-7,7-dimethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 101).

From 2-(feri-butoxycarbonyl)-7,7-dimethyl- 1,2,3,4, 6,7-hexahydro-[l,4]diazepino[6, 7,1-i;^']indole-8-carboxylic acid obtained in accordance with Example 1B.1, Step F, and 2- methoxyethanamine, the title compound was obtained using a similar method to the one described in Example 1B.1, Step G. LCMS m/z = 304.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.41 (s, 6H), 3.22 (s, 2H), 3.24-3.28 (m, 2H), 3.38 (s 3H), 3.52-3.60 (m, 6H), 4.32 (s, 2H), 6.80 (d, 7 = 7.8 Hz, 1H), 7.11 (d, 7 = 7.8 Hz, 1H).

Example 1B.3: Preparation of N,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole- 8-carboxamide (Compound 111).

Step A: Preparation of methyl 3-formyl-lH-indole-4-carboxylate.

A 2M solution of oxalyl dichloride in DCM (1.712 mL, 3.425 mmol) was added to DCM (15 mL) in an ice-water bath. /V,/V-dimethylformamide (0.250 g, 3.425 mmol) was added dropwise under nitrogen. The reaction was stirred for 30 minutes at 0 °C. Then methyl lH-indole-4-carboxylate (0.5 g, 2.854 mmol) in DCM (10 mL) was added. The reaction was warmed to room temperature and stirred for 1 hour. The solvent was removed. THF (15 mL) and 20% aqueous ammonium acetate were added. The reaction was stirred for 30 minutes under reflux (-70 °C). The mixture was then extracted with ethyl acetate. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (551 mg) as a white solid. LCMS m/z = 204.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 4.00 (s, 3H), 7.34 (t, 7 = 7.8 Hz, 1H), 7.63 (dd, 7 = 8.0 and 1.0 Hz, 1H), 7.87 (dd, 7 = 7.5 and 1.0 Hz, 1H), 8.10 (d, 7 = 3.2 Hz, 1H), 9.08 (bs, 1H), 10.53 (s, 1H).

Step B: Preparation of methyl 3-methyl-lH-indole-4-carboxylate.

To a stirred solution of methyl 3-formyl-lH-indole-4-carboxylate (551 mg, 2.712 mmol) in DMF (8 mL) was added 4-methylbenzenesulfonohydrazide (0.657 g, 3.525 mmol) followed by p- toluenesulfonic acid monohydrate (77.37 mg, 0.407 mmol) and tetramethylene sulfone (sulfolane, 8 mL). The reaction mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.682 g, 10.85 mmol) was added portionwise. Then the reaction was stirred at 100 °C for 2 hours. The mixture was cooled down, diluted with water, extracted with 50% ethyl acetate/ hexanes. The organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (355 mg) as an off-white solid. LCMS m/z = 190.4

[M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 2.41 (d, 7 = 1.0 Hz, 3H), 3.96 (s, 3H), 7.07-7.10 (m, 1H), 7.18 (t, 7 = 7.8 Hz, 1H), 7.50 (dd, 7 = 8.0 and 1.0 Hz, 1H), 7.64 (dd, 7 = 7.5 and 1.0 Hz, 1H), 8.12 (bs, 1H).

Step C: Preparation of methyl 3-methylindoline-4-carboxylate.

To a solution of methyl 3-methyl-lH-indole-4-carboxylate (884 mg, 4.672 mmol) in acetic acid

(20 mL) in an ice-water bath was added sodium cyanoborohydride (0.734 g, 11.68 mmol). The reaction was warmed to room temperature and stirred overnight. The mixture was concentrated. The residue was purified by HPLC. The combined organic fractions were neutralized with saturated NaHC0₃ and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (635 mg) as a yellow oil. LCMS m/z = 192.0 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.25 (d, 7 = 6.9 Hz, 3H), 3.25 (dd, 7 = 8.6 and 1.7 Hz, 1H), 3.68 (t, 7 = 8.5 Hz, 1H), 3.83-3.92 (m, 1H), 3.90 (s, 3H), 6.78 (dd, 7 = 7.8 and 1.0 Hz, 1H), 7.07 (t, 7 = 7.8 Hz, 1H), 7.34 (dd, 7 = 7.8 and 1.0 Hz, 1H).

Step D: Preparation of methyl l-(2-aminoethyl)-3-methylindoline-4-carboxylate.

Methyl 3-methylindoline-4-carboxylate (0.2 g, 1.046 mmol) and 2-bromoethanamine hydrobromide (0.257 g, 1.255 mmol) were heated neat (no solvent) at 115 °C for 15 hours. The solid mixture was dissolved in methanol and purified by HPLC. The combined fractions were neutralized with saturated NaHC0₃ solution, partially concentrated, and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (117 mg) as yellow oil. LCMS m/z = 235.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.24 (d, 7 = 7.0 Hz, 3H), 2.92-3.00 (m, 3H), 3.25 (dd, 7 = 8.5 and 1.7 Hz, 1H), 3.30-3.40 (m, 2H), 3.80-3.90 (m, 1H), 3.88 (s, 3H), 6.64 (d, 7 = 7.7 Hz, 1H), 7.11 (t, 7 = 7.8 Hz, 1H), 7.27 (dd, 7 = 7.9 and 0.8 Hz, 1H).

Step E: Preparation of 2-teri-butyl 8-methyl 7-methyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/»]indole-2,8(lH)-dicarboxylate.

To a solution of methyl l-(2-aminoethyl)-3-methylindoline-4-carboxylate (0.110 g, 0.469 mmol) and 37% formaldehyde in water (0.105 mL, 1.408 mmol) in methanol (3 mL) was added TFA (0.216 mL, 2.817 mmol). The reaction was stirred at 80 °C for 1 hour. The mixture was concentrated. The residue was dissolved in ethyl acetate. The organic phase was washed with saturated NaHC0₃ solution, water and brine, dried with Na₂S0₄, filtered, then concentrated to give crude methyl 7- methyl-1, 2, 3,4,6,7 -hexahydro-[l,4]diazepino[6,7,l- i;^']indole-8-carboxylate. The product obtained above was dissolved in DCM (3 mL). Triethylamine (98.94 μΐ, 0.704 mmol) was added, followed by di-feri-butyl dicarbonate (0.133 g, 0.610 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by HPLC. The combined fractions were neutralized with saturated NaHC0₃ solution, partially concentrated, and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (80 mg) as an oil. LCMS m/z = 347.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ rotamers 1.20 (d, J = 6.9 Hz, 3H), 1.35-1.45 (br, 9H), 2.80-2.95 (m, 1H), 3.08-3.18 (m, lH), 3.24-3.35 (m, 2H), 3.35-3.45 (m, 1H), 3.85-3.95 (m, 1H), 3.86 (s, 3H), 3.97-4.08 (m, 2H), 4.62-4.88 (m, 1H), 6.91 -7.06 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H).

Step F: Preparation of 2-(teri-butoxycarbonyl)-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole-8-carboxylic acid.

To a solution of 2-feri-butyl 8-methyl 7-methyl-3,4,6,7-tetrahydro-[l ,4]diazepino[6,7,l -i;]indole-2,8(lH)-dicarboxylate (80 mg, 0.231 mmol) in dioxane (3 mL) was added 1M solution of lithium hydroxide in water (1.386 mL, 1.386 mmol). The reaction was stirred at 90 °C overnight. Citric acid solution (5%) was added to the mixture to adjust pH to 4. The mixture was extracted with ethyl acetate. The combined organic fractions were concentrated to give the title compound (55 mg) as a gum. LCMS m/z = 333.4 [M+H]⁺.

Step G: Preparation of N,7-dimethyl-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l-/H-]indole-

8-carboxamide.

To a stirred solution of 2-(feri-butoxycarbonyl)-7-methyl- 1,2,3, 4,6,7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (22 mg, 66.19 μιηοΐ), and triethylamine (27.68 μΐ, 0.199 mmol) in DMF (2 mL) was added HATU (37.75 mg, 99.28 μιηοΐ). After 10 minutes, 2M methanamine in THF (0.331 mL, 0.662 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was purified by HPLC to give ieri-butyl 7-methyl-8-(methylcarbamoyl)- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;^']indole-2(lH)-carboxylate (18 mg, 78.7 ). Exact mass calculated for Ci₉H₂₇N₃0₃: 345.2, found LCMS m/z = 346.2 [M+H]⁺. To a solution of the compound obtained above in methanol (0.5 mL) was added 4M hydrogen chloride in dioxane (0.5 mL). The reaction was stirred at room temperature for 3 hours. The mixture was concentrated. The residue was lyophilized to give the title compound as HC1 salt (14 mg). LCMS m/z = 246.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.21 (d, 7 = 6.9 Hz, 3H), 2.91 (s, 3H), 3.14-3.22 (m, 1H), 3.30 (dd, J = 9.6 and 3.6 Hz, 1H), 3.34-3.41 (m, 1H), 3.44-3.88 (m, 4H), 4.24 (d, J = 4.9 Hz, 1H), 4.42 (d, J = 4.9 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H).

Example 1B.4: Preparation of N-(2-ethoxyethyl)-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 102).

To a stirred solution of 2-(ieri-butoxycarbonyl)-7-methyl- 1,2,3, 4,6,7-hexahydro- [l,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (22 mg, 66.19 μιηοΐ), obtained in accordance with Step F of example 1B.3, and triethylamine (27.68 μΐ,, 0.199 mmol) in DMF (2 mL) was added HATU (37.75 mg, 99.28 μιηοΐ). After 10 minutes, 2-ethoxyethanamine (11.80 mg, 0.132 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was purified by HPLC to give feri-butyl 8-((2-emoxyemyl)carbamoyl)-7-memyl-3,4,6,7 etrahydro-[l,4]diazepino[6,7, l- i;^']indole- 2(lH)-carboxylate (19 mg). LCMS m/z = 404.4 [M+H]⁺.

To a solution of feri-butyl 8-((2-ethoxyethyl)carbamoyl)-7-methyl-3,4,6,7-tetrahydro- [l ,4]diazepino[6,7, l- i;]indole-2(lH)-carboxylate (20 mg, 49.56 μιηοΐ) in methanol (0.5 mL) was added 4M hydrogen chloride in dioxane (0.5 mL). The reaction was stirred at room temperature for 3 hours. The mixture was concentrated. The residue was lyophilized to give the title compound as HC1 salt (16 mg). LCMS m/z = 304.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.21 (d, J = 6.9 Hz, 3H), 1.21 (t, 7 = 7.0 Hz, 3H), 3.14-3.22 (m, 1H), 3.30 (dd, 7 = 9.6 and 3.6 Hz, 1H), 3.34-3.41 (m, 1H), 3.44-3.88 (m, 10H), 4.23 (d, 7 = 4.9 Hz, 1H), 4.41 (d, 7 = 4.9 Hz, 1H), 6.99 (d, 7 = 7.8 Hz, 1H), 7.14 (d, 7 = 7.8 Hz, 1H).

Example 1B.5: Preparation of 7-ethyl-N-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 107) and of the corresponding (R) and (S) enantiomers.

Step A: Preparation of methyl 3-acetyl-lH-indole-4-carboxylate.

To a solution of methyl lH-indole-4-carboxylate (1 g, 5.708 mmol) in DCM (20 mL) was added 1M solution of diethylaluminum chloride (8.562 mL, 8.562 mmol) in an ice-water bath under nitrogen. After 30 minutes, acetyl chloride (0.812 mL, 11.42 mmol) was added dropwise. The reaction was stirred for 2 hours in an ice-water bath. The reaction was quenched with water, then added saturated NaHC0₃ solution to adjust pH to 7. The mixture was extracted with ethyl acetate. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.18 g) as an off-white solid. LCMS m/z = 218.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 2.46 (s, 3H), 3.99 (s, 3H), 7.28 (dd, 7 = 8.2 and 7.4 Hz, 1H), 7.43 (dd, 7 = 7.4 and 1.0 Hz, 1H), 7.46 (dd, 7 = 8.2 and 1.0 Hz, 1H), 7.77 (d, 7 = 3.1 Hz, 1H), 9.14 (bs, 1H).

Step B: Preparation of methyl 3-ethyl-lH-indole-4-carboxylate.

To a solution of methyl 3-acetyl-lH-indole-4-carboxylate (400 mg, 1.841 mmol) in anhydrous

THF (10 mL) was added sodium borohydride (0.139 g, 3.683 mmol) under nitrogen in an ice-water bath. Boron trifluoride diethyl etherate (0.700 mL, 5.524 mmol) was then added dropwise. The reaction was stirred for 2 hours while warmed to room temperature. The reaction was poured into a mixture of ice-water and 5% aqueous NaHC0₃ and extracted with ethyl acetate. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (320 mg) as an oil. LCMS m/z = 204.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.25 (t, 7 = 7.4 Hz, 3H), 2.87-2.94 (m, 2H), 3.97 (s, 3H), 7.11-7.14 (m, 1H), 7.19 (t, 7 = 7.8 Hz, 1H), 7.51 (dd, 7 = 8.1 and 1.0 Hz, 1H), 7.60 (dd, 7 = 7.4 and 1.0 Hz, 1H), 8.16 (bs, 1H).

Step C: Preparation of methyl 3-ethylindoline-4-carboxylate.

To a solution of methyl 3-ethyl-lH-indole-4-carboxylate (320 mg, 1.575 mmol) in TFA (10 mL) in an ice-water bath was added 1M solution of borane THF complex (2.677 mL, 2.677 mmol) dropwise under nitrogen. The reaction was stirred for 30 minutes. A 20% NaOH solution was added to neutralize the mixture. The mixture was then extracted with ethyl acetate. The combined organic fractions were concentrated. The residue was purified by HPLC. The combined fractions were neutralized with saturated NaHC0₃, partially concentrated, and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (270 mg) as a yellow oil. LCMS m/z = 206.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 0.96 (t, 7 = 7.4 Hz, 3H), 1.50-1.70 (m, 2H), 3.42 (dd, 7 = 8.7 and 1.7 Hz, 1H), 3.60 (t, 7 = 8.6 Hz, 1H), 3.68-3.75 (m, 1H), 3.88 (s, 3H), 6.77 (dd, J = 7.8 and 1.0 Hz, 1H), 7.07 (t, 7 = 7.8 Hz, 1H), 7.33 (dd, 7 = 7.8 and 1.0 Hz, 1H).

Step D: Preparation of methyl l-(2-aminoethyl)-3-ethylindoline-4-carboxylate.

Methyl 3-ethylindoline-4-carboxylate (205 mg, 0.999 mmol) and 2-bromoethanamine hydrobromide (0.246 g, 1.199 mmol) were heated at 120 °C for 15 hours. The mixture was dissolved in methanol and purified by HPLC to give the title compound as a TFA salt (148 mg). LCMS m/z = 249.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.00 (t, J = 7.4 Hz, 3H), 1.53-1.68 (m, 2H), 3.14-3.29 (m, 4H), 3.52 (dd, 7 = 8.8 and 1.8 Hz, 1H), 3.57-3.65 (m, 1H), 3.65-3.73 (m, 1H), 3.88 (s, 3H), 6.81 (d, 7 = 7.5 Hz, 1H), 7.17 (t, 7 = 7.8 Hz, 1H), 7.31 (dd, 7 = 7.9 and 0.9 Hz, 1H).

Step E: Preparation of 2-teri-butyl 8-methyl 7-ethyl-3,4,6,7-tetrahydro-

[l,4]diazepino[6,7,l-/H]indole-2,8(lH)-dicarboxylate.

To a solution of methyl l-(2-aminoethyl)-3-ethylindoline-4-carboxylate 2,2,2-trifluoroacetate (140 mg, 0.386 mmol) and 37% formaldehyde in water (86.30 μΐ, 1.159 mmol) in methanol (5 mL) was added TFA (0.148 mL, 1.932 mmol). The reaction was stirred at 80 °C for 2 hours. The mixture was concentrated, The residue was dissolved in ethyl acetate. The organic solution was washed with saturated NaHC0₃, water and brine, dried with Na₂S0₄, filtered, then concentrated to give crude methyl 7-ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole-8-carboxylate. The crude product obtained above was dissolved in DCM (5 mL). Triethylamine (81.43 μΐ, 0.580 mmol) was added, followed by di-ieri-butyl dicarbonate (0.110 g, 0.502 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (92 mg) as an oil. LCMS m/z = 361.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 0.95 (t, 7 = 7.4 Hz, 3H), 1.35-1.45 (br, 9H), 1.40-1.50 (m, 1H), 1.54-1.64 (m, 1H), 2.80-2.98 (m, 1H), 3.10-3.18 (m,lH), 3.24 (t, 7 = 8.9 Hz, 1H), 3.34-3.45 (m, 2H), 3.68-3.76 (m, 1H), 3.87 (s, 3H), 3.97-4.08 (m, 2H), 4.62-4.88 (m, 1H), 6.91-7.06 (m, 1H), 7.36 (d, 7 = 8.0 Hz, 1H).

Step F: Preparation of 2-(tert-butoxycarbonyl)-7-ethyl-l,2,3,4,6,7-hexahydro-

[l,4]diazepino[6,7,l-/»]indole-8-carboxylic acid.

To a solution of 2-feri-butyl 8-methyl 7-ethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;^']indole-2,8(lH)-dicarboxylate (92 mg, 0.255 mmol) in dioxane (5 mL) was added 1M solution of lithium hydroxide in water (1.531 mL, 1.531 mmol). The reaction was stirred at 90 °C overnight. A 5% citric acid solution was added to adjust the pH of the mixture to 3-4. The mixture was then extracted with ethyl acetate. The combined organic fractions were concentrated to give the title compound (90 mg) as gum. LCMS m/z = 347.2 [M+H]⁺. Step G: Preparation of 7-ethyl-N-methyl-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l- /M]indole-8-carboxamide.

To a stirred solution of 2-(feri-butoxycarbonyl)-7-ethyl- 1,2, 3,4,6, 7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (25 mg, 72.17 μιηοΐ) and triethylamine (30.18 μΐ, 0.216 mmol) in DMF (2 mL) was added HATU (41.16 mg, 0.108 mmol). After 10 minutes, 2M methanamine in THF (0.361 mL, 0.722 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was purified by HPLC to give feri-butyl 7-ethyl-8-(methylcarbamoyl)-3, 4,6,7- tetrahydro-[l ,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate , which was then dissolved in methanol (1 mL), then 1 mL 4M HC1 in dioxane was added. The reaction was stirred at room temperature for 2 hours. The mixture was concentrated. The residue was purified by HPLC to give the title compound as a TFA salt (15 mg). LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.89 (t, J = 7.4 Hz, 3H), 1.40-1.52 (m, IH), 1.54-1.65 (m, IH), 2.88 (s, 3H), 3.08-3.16 (m, IH), 3.32-3.48 (m, 4H), 3.56- 3.64 (m, IH), 3.64-3.74 (m, IH), 4.18 (d, J = 4.8 Hz, IH), 4.39 (d, J = 4.8 Hz, IH), 6.95 (d, J = 7.8 Hz, IH), 7.10 (d, 7 = 7.8 Hz, IH).

Racemic 7-ethyl-/Y-methyl- l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole-8- carboxamide was resolved to give two enantiomers by normal phase preparative chiral HPLC under the following conditions: Column: normal phase semi preparative CHIRALPAK^® IC column 250 x 20 mm (L x I.D.)

Eluent: 15 % ethanol/hexanes with 0.05 % Et₃N

Gradient: Isocratic.

How: 12 mL/min.

Detector: UV 254 nm.

Retention Times: 1^st eluting enantiomer: 24.5 minutes; 2^nd eluting enantiomer: 29.1 minutes.

1^st eluting enantiomer: LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ free base 0.92 (t, 7 = 7.4 Hz, 3H), 1.42-1.52 (m, IH), 1.54-1.65 (m, IH), 2.81-2.88 (m, IH), 2.88 (s, 3H), 2.94-3.02 (m, IH), 3.14-3.22 (m, 2H), 3.36-3.40 (m, 2H), 3.65-3.72 (m, IH), 3.75 (d, 7 = 5.2 Hz, IH), 3.96 (d, 7 = 5.2 Hz, IH), 6.86 (d, 7 = 7.8 Hz, IH), 6.96 (d, 7 = 7.8 Hz, IH).

2^nd eluting enantiomer: LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ free base 0.92 (t, 7 = 7.4 Hz, 3H), 1.42-1.52 (m, IH), 1.54-1.65 (m, IH), 2.81-2.88 (m, IH), 2.88 (s, 3H), 2.94-3.02 (m, IH), 3.14-3.22 (m, 2H), 3.36-3.40 (m, 2H), 3.65-3.72 (m, IH), 3.75 (d, 7 = 5.2 Hz, IH), 3.96 (d, 7 = 5.2 Hz, IH), 6.86 (d, 7 = 7.8 Hz, IH), 6.96 (d, 7 = 7.8 Hz, IH).

Example 1B.6: Preparation of N-(2-ethoxyethyl)-7-ethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 103). To a stirred solution of 2-(feri-butoxycarbonyl)-7-ethyl- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7,l- i;]indole-8-carboxylic acid (25 mg, 72.17 μιηοΐ), obtained in accordance with Step F of example 1B.5, and triethylamine (30.18 μΐ, 0.216 mmol) in DMF (2 mL) was added HATU (41.16 mg, 0.108 mmol). After 10 minutes, 2-ethoxyethanamine (12.87 mg, 0.144 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was purified by HPLC to give feri-butyl 8-((2-ethoxyethyl)carbamoyl)-7-ethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole- 2(lH)-carboxylate. The above material was then dissolved in methanol (1 mL) and added 4M HC1 in dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was purified by HPLC to give the title compound as TFA salt (18 mg). LCMS m/z = 318.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.90 (t, 7 = 7.4 Hz, 3H), 1.19 (t, 7 = 7.0 Hz, 3H), 1.42- 1.55 (m, 1H), 1.56-1.68 (m, 1H), 3.08-3.18 (m, 1H), 3.32-3.62 (m, 11H), 3.66-3.75 (m, 1H), 4.18 (d, 7 = 4.8 Hz, 1H), 4.39 (d, 7 = 4.8 Hz, 1H), 6.96 (d, 7 = 7.8 Hz, 1H), 7.11 (d, 7 = 7.8 Hz, 1H).

Example 1B.7: Preparation of N-methyl-7-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 105) and of the corresponding (R) and (S) enantiomers.

Step A: Preparation of methyl 3-propionyl-lH-indole-4-carboxylate.

To a solution of methyl lH-indole-4-carboxylate (1.02 g, 5.822 mmol) in DCM (20 mL) was added 1M solution of diethylaluminum chloride in hexane (8.734 mL, 8.734 mmol) in an ice-water bath under nitrogen. After 30 minutes, propionyl chloride (1.017 mL, 11.64 mmol) was added dropwise. The reaction was quenched with water, then added saturated NaHC0₃ solution to adjust pH to 7. The mixture was extracted with DCM. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.23 g) as an off-white solid. LCMS m/z = 232.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.21 (t, 7 = 7.4 Hz, 3H), 2.78 (q, 7 = 7.4 Hz, 2H), 3.96 (s, 3H), 7.28 (dd, 7 = 8.3 and 7.3 Hz, 1H), 7.42 (dd, 7 = 3.0 and 1.0 Hz, 1H), 7.44 (dd, 7 = 2.9 and 1.0 Hz, 1H), 7.72 (d, 7 = 3.1 Hz, 1H), 9.37 (bs, 1H).

Step B: Preparation of methyl 3-propyl-lH-indole-4-carboxylate.

To a solution of methyl 3-propionyl-lH-indole-4-carboxylate (0.5 g, 2.162 mmol) in anhydrous THF (10 mL) was added sodium borohydride (0.164 g, 4.324 mmol) under nitrogen in an ice-water bath. Boron triflouride diether etherate (0.822 mL, 6.487 mmol) was then added dropwise. The reaction was stirred for 2 hours while warmed to room temperature. The reaction was poured into a mixture of ice-water and 5% aqueous NaHC0₃ and extracted with ethyl acetate. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (420 mg) as an oil. LCMS m/z = 218.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 0.97 (t, 7 = 7.3 Hz, 3H), 1.55-1.65 (m, 2H), 2.82-2.87 (m, 2H), 3.97 (s, 3H), 7.09-7.12 (m, 1H), 7.18 (t, 7 = 7.8 Hz, 1H), 7.50 (dd, 7 = 8.1 and 1.0 Hz, 1H), 7.58 (dd, 7 = 7.4 and 1.0 Hz, 1H), 8.14 (bs, 1H).

Step C: Preparation of methyl 3-propylindoline-4-carboxylate.

To a solution of methyl 3-propyl-lH-indole-4-carboxylate (420 mg, 1.933 mmol) in TFA (5 mL) in an ice-water bath was added triethylsilane (1.235 mL, 7.733 mmol) dropwise under nitrogen. The reaction was stirred for 3 hours at room temperature. The mixture was concentrated, diluted with ethyl acetate, and washed with saturated NaHC0₃. The organic extract was dried over anhydrous Na₂S0₄, filtered, then concentrated. The residue was purified by silica gel column chromatography to give the title compound (415 mg) as an orange oil. LCMS m/z = 220.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 0.93 (t, 7 = 7.3 Hz, 3H), 1.38-1.48 (m, 2H), 1.50-1.68 (m, 2H), 3.42 (dd, 7 = 8.9 and 1.6 Hz, 1H), 3.59 (t, 7 = 8.5 Hz, 1H), 3.75-3.82 (m, 1H), 3.89 (s, 3H), 6.77 (dd, 7 = 7.7 and 1.0 Hz, 1H), 7.07 (t, 7 = 7.8 Hz, 1H), 7.34 (dd, 7 = 7.8 and 1.0 Hz, 1H).

Step D: Preparation of methyl l-(2-aminoethyl)-3-propylindoline-4-carboxylate.

Methyl 3-propylindoline-4-carboxylate (0.313 g, 1.427 mmol) and 2-bromoethanamine hydrobromide (0.351 g, 1.713 mmol) were heated at 110 °C for 15 hours. The solid mixture was dissolved in methanol and purified by HPLC to give the title compound as a TFA salt (300 mg). LCMS m/z = 263.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.95 (t, 7 = 7.4 Hz, 3H), 1.40-1.60 (m, 4H), 3.14- 3.29 (m, 4H), 3.52 (dd, 7 = 8.8 and 1.8 Hz, 1H), 3.57-3.65 (m, 1H), 3.65-3.73 (m, 1H), 3.88 (s, 3H), 6.81 (d, 7 = 7.5 Hz, 1H), 7.17 (t, 7 = 7.8 Hz, 1H), 7.31 (dd, 7 = 7.9 and 0.9 Hz, 1H).

Step E: Preparation of 2-teri-butyl 8-methyl 7-propyl-3,4,6,7-tetrahydro-

[l,4]diazepino[6,7,l-/»]indole-2,8(lH)-dicarboxylate .

From methyl l-(2-aminoethyl)-3-propylindoline-4-carboxylate, the title compound was obtained using a similar method to the one described in Example 1B.5, Step E. LCMS m/z = 375.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ rotamers 0.92 (t, 7 = 7.0 Hz, 3H), 1.35-1.55 (br, 13H), 2.80- 2.95 (m, 1H), 3.08-3.18 (m,lH), 3.22 (t, 7 = 8.9 Hz, 1H), 3.33-3.45 (m, 2H), 3.76-3.84 (m, 1H), 3.87 (s, 3H), 3.97-4.08 (m, 2H), 4.55-4.80 (m, 1H), 6.81-6.94 (m, 1H), 7.25 (d, 7 = 8.0 Hz, 1H).

Step F: Preparation of 2-(ieri-butoxycarbonyl)-7-propyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole-8-carboxylic acid.

From 2-ieri-butyl 8-methyl 7-propyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2,8(lH)- dicarboxylate, the title compound was obtained using a similar method to the one described in Example 1B.5, Step F. LCMS m/z = 361.2 [M+H]⁺.

Step G: Preparation of N-methyl-7-propyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 105).

To a stirred solution of 2-(feri-butoxycarbonyl)-7-propyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l- i;]indole-8-carboxylic acid (30 mg, 83.23 μιηοΐ) and triethylamine (34.80 μΐ, 0.250 mmol) in DMF (2 mL) was added HATU (47.47 mg, 0.125 mmol). After 10 minutes, 2M methanamine in THF (0.416 mL, 0.832 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was purified by HPLC to give ieri-butyl 8-(methylcarbamoyl)-7-propyl-3,4,6,7- tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate (25 mg, 80.4 ). The above material was dissolved in methanol (1 mL) and added 4M HCl in dioxane (1 mL). The reaction was stirred at room temperature for 2 h and concentrated. The residue was purified by HPLC to give the title compound as a TFA salt (19 mg). LCMS m/z = 274.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.90 (t, 7 = 7.2 Hz, 3H), 1.30-1.55 (m, 4H), 2.88 (s, 3H), 3.08-3.15 (m, 1H), 3.30-3.50 (m, 4H), 3.55-3.63 (m, 1H), 3.72- 3.80 (m, 1H), 4.18 (d, 7 = 4.9 Hz, 1H), 4.40 (d, 7 = 4.9 Hz, 1H), 6.95 (d, 7 = 7.9 Hz, 1H), 7.10 (d, 7 = 7.9 Hz, 1H).

Racemic A^?-methyl-7-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole-8- carboxamide was resolved to give two enantiomers by normal phase preparative chiral HPLC under the following conditions:

Column: normal phase semi preparative CHIRALPAK^® IC column 250 x 20 mm (L x I.D.) Eluent: 15 % ethanol/hexanes with 0.05 % Et₃N

Gradient: Isocratic.

How: 12 mL/min.

Detector: UV 254 nm.

Retention Times: 1^st eluting enantiomer: 23.0 minutes; 2^nd eluting enantiomer: 30.0 minutes.

After separation by normal phase Chiral HPLC, the enantiomers were then purified separately by reverse phase HPLC to give TFA salts.

1^st eluting enantiomer: LCMS m/z = 274.4 [M+H]⁺. ¾ NMR (400 MHz, CD₃OD) δ 0.90 (t, 7 = 7.2 Hz, 3H), 1.30-1.55 (m, 4H), 2.90 (s, 3H), 3.10-3.18 (m, 1H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, 1H), 3.72- 3.80 (m, 1H), 4.20 (d, 7 = 4.9 Hz, 1H), 4.41 (d, 7 = 4.9 Hz, 1H), 6.97 (d, 7 = 7.9 Hz, 1H), 7.12 (d, 7 = 7.9 Hz, 1H).

2^nd eluting enantiomer: LCMS m/z = 274.4 [M+H]⁺. ¾ NMR (400 MHz, CD₃OD) δ 0.90 (t, 7 = 7.2 Hz, 3H), 1.30-1.55 (m, 4H), 2.90 (s, 3H), 3.10-3.18 (m, 1H), 3.30-3.50 (m, 4H), 3.55-3.65 (m, 1H), 3.72- 3.80 (m, 1H), 4.20 (d, 7 = 4.9 Hz, 1H), 4.41 (d, 7 = 4.9 Hz, 1H), 6.97 (d, 7 = 7.9 Hz, 1H), 7.12 (d, 7 = 7.9 Hz, 1H).

Example 1B.8: Preparation of 6-ethyl-N-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 112).

Step A: Preparation of methyl 2-ethyl-lH-indole-4-carboxylate

A mixture of methyl lH-indole-4-carboxylate (1 g, 5.708 mmol) , potassium hydrogen phosphate (2.983 g, 17.12 mmol) , (lR,4S)-bicyclo[2.2.1]hept-2-ene (norbornene) (1.075 g, 11.42 mmol) and PdCl₂(MeCN)₂ (0.222 g, 0.856 mmol) in DMA (20 mL, 0.5 M H₂0) was degassed and filled back with argon. Bromoethane (1.244 g, 11.42 mmol) in DMA (8 mL, 0.5 M H₂0) was added. The reaction was heated at 70 °C overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography followed by HPLC. The combined fractions were neutralized with saturated NaHC0₃, partially concentrated, and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered then concentrated to give the title compound (858 mg) as white solid. LCMS m/z = 204.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.38 (t, J = 7.6 Hz, 3H), 2.82-2.87 (m, 2H), 3.98 (s, 3H), 6.88-6.92 (m, 1H), 7.15 (t, 7 = 7.8 Hz, 1H), 7.48 (dt, 7 = 8.0 and 0.9 Hz, 1H), 7.86 (dd, 7 = 7.6 and 1.0 Hz, 1H), 8.08 (bs, 1H).

Step B: Preparation of methyl 2-ethylindoline-4-carbox late

To a solution of methyl 2-ethyl-lH-indole-4-carboxylate (890 mg, 4.379 mmol) in TFA (3 mL) in an ice-water bath was added triethylsilane (3 mL, 18.78 mmol) dropwise under nitrogen. The reaction was warmed to room temperature, stirred overnight, then heated at 55 °C for 4 hours. The mixture was concentrated. The residue was added water. The pH was adjusted to 8 with saturated NaHC0₃ solution and extracted with ethyl acetate. The combined organic fractions were concentrated. The residue was purified by silica gel column chromatography to give the title compound (900 mg) as an oil. LCMS m/z = 206.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 0.98 (t, 7 = 7.4 Hz, 3H), 1.59-1.66 (m, 2H), 3.00 (dd, 7 = 17.4 and 8.0 Hz, 1H), 3.54 (dd, 7 = 17.5 and 8.9 Hz, 1H), 3.77-3.85 (m, 1H), 3.88 (s, 3H), 6.72 (dd, 7 = 7.7 and 0.8 Hz, 1H), 7.05 (t, 7 = 7.8 Hz, 1H), 7.31 (dd, 7 = 7.8 and 0.9 Hz, 1H).

Step C: Preparation of methyl l-(2-aminoethyl)-2-ethylindoline-4-carboxylate

Methyl 2-ethylindoline-4-carboxylate (0.714 g, 3.479 mmol) and 2-bromoethanamine hydrobromide (0.855 g, 4.174 mmol) were heated neat at 115 °C overnight. The mixture was dissolved in methanol and purified by preparative HPLC. The combined fractions were neutralized with saturated NaHC0₃, partially concentrated, and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (456 mg). LCMS m/z = 249.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.95 (t, 7 = 7.4 Hz, 3H), 1.48-1.60 (m, 1H), 1.83- 1.92 (m, 1H), 2.87-2.94 (m, 3H), 3.27 (t, 7 = 6.9 Hz, 2H), 3.48-3.62 (m, 2H), 3.86 (s, 3H), 6.65 (dd, 7 = 7.8 and 0.5 Hz, 1H), 7.09 (t, 7 = 7.8 Hz, 1H), 7.20 (dd, 7 = 7.9 and 0.9 Hz, 1H).

Step D: Preparation of methyl 6-ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /w]indole-8-carboxylate

To a solution of methyl l-(2-aminoethyl)-2-ethylindoline-4-carboxylate (456 mg, 1.836 mmol) and 37% formaldehyde in water (0.410 mL, 5.509 mmol) in methanol (5 mL) was added TFA (0.703 mL, 9.182 mmol). The reaction was stirred at 80 °C for 1 hour. The mixture was concentrated. The residue was purified by HPLC. The combined fractions were adjusted to basic with saturated NaHC0₃, partially concentrated, and extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (420 mg). LCMS m/z = 261.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.02 (t, 7 = 7.4 Hz, 3H), 1.58-1.68 (m, 1H), 1.83-1.92 (m, 1H), 2.88 (dd, 7 = 17.9 and 9.3 Hz, 1H), 3.07-3.15 (m, 1H), 3.33-3.39 (m, 1H), 3.42-3.50 (m, 2H), 3.62- 3.68 (m, 1H), 3.73 (dd, 7 = 17.9 and 9.3 Hz, 1H), 3.87 (s, 3H), 4.10 (d, 7 = 4.9 Hz, 1H), 4.50 (d, 7 = 4.8 Hz, 1H), 7.12 (d, 7 = 8.0 Hz, 1H), 7.40 (d, 7 = 8.0 Hz, 1H).

Step E: Preparation of 2-tert-butyl 8-methyl 6-ethyl-3,4,6,7-tetrahydro-

[l,4]diazepino[6,7,l-/H]indole-2,8(lH)-dicarboxylate.

To a solution of methyl 6-ethyl-l, 2,3,4, 6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole-8- carboxylate (420 mg, 1.613 mmol) in DCM (2 mL) was added di-ieri-butyl dicarbonate (0.528 g, 2.420 mmol) and triethylamine (0.675 mL, 4.840 mmol). The reaction was stirred at room temperature for 5 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (516 mg). LCMS m/z = 361.2 [M+H]⁺.

Step F: Preparation of 2-(tert-butoxycarbonyl)-6-ethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole-8-carboxylic acid.

To a solution of 2-tert-butyl 8-methyl 6-ethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;^']indole- 2,8(lH)-dicarboxylate (516 mg, 1.432 mmol) in dioxane (8 mL) was added 1M solution of lithium hydroxide in water (8.589 mL, 8.589 mmol). The reaction was stirred at 90 °C overnight. The mixture was added 5% citric acid solution to adjust pH to 3-4. The solid precipitate was collected, washed with water, and dried to give the title compound (440 mg) as an off-white solid. LCMS m/z = 347.2 (M+H⁺).

Step G: Preparation of 6-ethyl-N-methyl-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l- /w]indole-8-carboxamide.

To a stirred solution of 2-(tert-butoxycarbonyl)-6-ethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (50 mg, 0.144 mmol), and triethylamine (60.35 μΐ, 0.433 mmol) in DMF (3 mL) was added HATU (82.32 mg, 0.216 mmol). After 10 minutes, 2M methanamine in THF (0.722 mL, 1.443 mmol) was added. The reaction was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by silica gel column

chromatography to give tert-butyl 6-ethyl-8-(methylcarbamoyl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7, l-/i;]indole-2(lH)-carboxylate. LCMS m/z = 360.4 [M+H]⁺.

The compound obtained above was dissolved in MeOH (0.5 mL) and added 4M HC1 in dioxane (0.5 mL). The reaction was stirred at room temperature for 4 hours. The mixture was concentrated. The residue was purified by HPLC. The combined fractions were lyophilized to give the title compound as a TFA salt (45 mg). LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.02 (t, J = 7.4 Hz, 3H), 1.58-1.68 (m, 1H), 1.83-1.92 (m, 1H), 2.84 (dd, 7 = 16.8 and 9.3 Hz, 1H), 2.88 (s, 3H), 3.05-3.12 (m, 1H), 3.32-3.49 (m, 3H), 3.55 (dd, J = 16.7 and 9.2 Hz, 1H), 3.62-3.68 (m, 1H), 4.09 (d, J = 4.9 Hz, 1H), 4.48 (d, 7 = 4.8 Hz, 1H), 7.01 (d, 7 = 7.9 Hz, 1H), 7.09 (d, 7 = 7.9 Hz, 1H).

Example 1B.9: Preparation of N-methyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 113).

Step A: Preparation of methyl 3-(2,2,2-trifluoroacetyl)indoline-4-carboxylate.

To a solution of methyl lH-indole-4-carboxylate (0.40 g, 2.283 mmol) in DMF (15 mL) was added TFAA (0.317 mL, 2.283 mmol) at room temperature. The reaction was stirred at 40 °C for 2 h. The mixture was poured into sodium bicarbonate solution (100 mL). The precipitate was filtered. The filtrate was extracted with EtOAc. The organic extract was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography to give the title compound (220 mg). LCMS m/z = 272.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃C1₃) δ 3.99 (s, 3H), 7.37 (t, 7 = 7.9 Hz, 1H), 7.51-7.57 (m, 2H), 8.00-8.05 (m, 1H), 9.50 (bs, 1H). Step B: Preparation of methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate.

To a solution of methyl 3-(2,2,2-trifluoroacetyl)-lH-indole-4-carboxylate (0.10 g, 0.369 mmol) in TFA (1.412 mL, 18.44 mmol) in an ice-bath was added Triethylsilane (0.589 mL, 3.687 mmol) dropwise under N2. The reaction was stirred at 23 °C for 15 h. The mixture was poured into saturated NaHC0₃ solution and extracted with ethyl acetate. The combined organics was concentrated. The residue was purified by silica gel column chromatography to give the title compound (40 mg). LCMS m/z = 260.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃C1₃) δ 2.31-2.44 (m, IH), 3.56-3.65 (m, 2H), 3.91 (s, 3H), 4.03-4.12 (m, IH), 6.82 (d, J = 7.8 Hz, IH), 7.14 (t, J = 7.8 Hz, IH), 7.37-7.44 (m, IH).

Step C: Preparation of methyl l-(2-aminoethyl)-3-(2,2,2-trifluoroethyl)indoline-4- carbox late.

A mixture of methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate (0.040 g, 0.154 mmol) and 2-bromoethanamine.HBr (34.78 mg, 0.170 mmol) was heated at 122 °C for 15 h. The mixture was dissolved in 2M HC1 and purified by HPLC to give the title compound (20 mg). LCMS m/z = 303.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.34-2.64 (m, 2H), 3.10-3.30 (m, 4H), 3.58-3.72 (m, 2H), 3.89 (s, 3H), 4.03-4.12 (m, IH), 6.88 (d, J = 7.9 Hz, IH), 7.25 (t, J = 7.9 Hz, IH), 7.40 (d, J = 7.9 Hz, IH).

Step D: Preparation of methyl 7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole-8-carboxylate.

To a solution of methyl l-(2-aminoethyl)-3-(2,2,2-trifluoroethyl)indoline-4- carboxylate trifluoroacetic acid (60 mg, 0.144 mmol) and Formaldehyde (4.327 mg, 0.144 mmol) in MeOH (4 mL) was added TFA (11.04 μΐ, 0.144 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by HPLC to give the title compound (60 mg). LCMS m/z = 315.2 [M+H]⁺.

Step E: Preparation of 2-tert-butyl 8-methyl 7-(2,2,2-trifluoroethyl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/H]indole-2,8(lH)-dicarboxylate.

To a solution of methyl 7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /i;]indole-8-carboxylate trifluoroacetic acid (60 mg, 0.140 mmol), Triethylamine (78.10 μΐ, 0.560 mmol) in CH₂C1₂ (1.2 mL) was added a solution di-ieri-butyl dicarbonate (30.57 mg, 0.140 mmol) in CH₂C1₂ (1.2 mL). The reaction was stirred at 23 °C for 2 h. The mixture was extracted with 1M NaOH. The organic extract was concentrated. The residue was purified by column chromatography to give the title compound (44 mg). LCMS m/z = 415.6 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 1.32-1.47 (m, 9H), 2.24-2.40 (m, 2H), 2.81-3.00 (m, IH), 3.12-3.27 (m, 2H), 3.35-3.48 (m, IH), 3.58-3.65 (m, IH), 3.90 (s, 3H), 3.97-4.13 (m, 3H), 4.63-4.93 (m, IH), 6.95-7.16 (m, IH), 7.42 (d, J = 7.9 Hz, IH).

Step F: Preparation of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7- hexahydro-[l_>4]diazepino[6,7,l-/H]indole-8-carboxylic acid.

To a solution of 2-tert-butyl 8-methyl 7-(2,2,2-trifiuoroethyl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/i;]indole-2,8(lH)-dicarboxylate (0.044 g, 0.106 mmol) in MeOH (0.2 mL) was added 5M sodium hydroxide (40.35 μL, 0.202 mmol). The reaction was stirred at 65 °C for 3 h. The mixture was concentrated. The residue was added 4M hydrogen chloride (49.90 μΐ_^, 0.200 mmol). The reaction was stirred for 10 min. The mixture was concentrated to give the title compound. LCMS m/z = 401.4 [M+H]⁺.

Step G: Preparation of N-methyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/H]indole-8-carboxamide.

To a solution of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6,7-hexahydro- [l ,4]diazepino[6,7, l-/i;]indole-8-carboxylic acid (0.030 g, 59.94 μιηοΐ), HATU (34.19 mg, 89.91 μιηοΐ), and triethylamine (25.06 μΐ_^, 0.180 mmol) in MeCN (0.6 mL) was added 33% methanamine in EtOH (62.68 μΐ, 0.599 mmol). The reaction was stirred at 23 °C for 3 h. The mixture was concentrated. The residue was purified by HPLC to give ieri-butyl 8-(methylcarbamoyl)-7-(2,2,2-trifluoroethyl)- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;^']indole-2(lH)-carboxylate as a white solid. LCMS m/z = 414.4 [M+H]⁺. The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at 55 °C for 5 h. The mixture was concentrated to give the title compound (18.5 mg). LCMS m/z = 314.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.25-2.43 (m, IH), 2.47-2.63 (m, IH), 2.89 (s, 3H), 3.12-3.22 (m, IH), 3.38-3.52 (m, 3H), 3.58-3.68 (m, 2H), 4.01-4.10 (m, IH), 4.22 (d, 7 = 15 Hz, IH), 4.47 (d, 7 = 15 Hz, IH), 7.05 (d, 7 = 7.9 Hz, IH), 7.19 (d, 7 = 7.9 Hz, IH).

Racemic /V-methyl-7-(2,2,2-trifluoroethyl)- 1,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6, 7,1-i;^']indole-8-carboxamide was resolved to give two enantiomers by normal phase preparative chiral HPLC under the following conditions:

Column: normal phase semi preparative CHIRALPAK® IC column 250 x 20 mm (L x I.D.)

Eluent: 9 % ethanol/hexanes with 0.1 % Et3N

Gradient: Isocratic.

Flow: 10 mL/min.

Detector: UV 254 nm.

Retention Times: 1st eluting enantiomer: 26.0 min.; 2nd eluting enantiomer: 30.0 min.

1^st eluting enantiomer: LCMS m/z = 314.2 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ 2.25-2.42 (m, IH), 2.47-2.63 (m, IH), 2.89 (s, 3H), 3.11-3.21 (m, IH), 3.36-3.52 (m, 3H), 3.58-3.68 (m, 2H), 4.01-4.10 (m, IH), 4.22 (d, 7 = 15 Hz, IH), 4.46 (d, 7 = 15 Hz, IH), 7.05 (d, 7 = 7.9 Hz, IH), 7.18 (d, 7 = 7.9 Hz, IH).

2^nd eluting enantiomer: LCMS m/z = 314.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.25-2.43 (m, IH), 2.47-2.63 (m, IH), 2.89 (s, 3H), 3.11-3.20 (m, IH), 3.38-3.51 (m, 3H), 3.58-3.67 (m, 2H), 4.01-4.11 (m, IH), 4.22 (d, 7 = 15 Hz, IH), 4.46 (d, 7 = 15 Hz, IH), 7.05 (d, 7 = 7.9 Hz, IH), 7.18 (d, 7 = 7.9 Hz, IH). Example 1B.10: Preparation of N-(2-ethoxyethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 127).

To a solution of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6,7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (7 mg, 10.89 μιηοΐ), 2-ethoxyethanamine (1.067 mg, 11.97 μιηοΐ), and triethylamine (4.552 μL, 32.66 μmol) in MeCN (0.2 mL) was added HATU (6.209 mg, 16.33 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give tert-butyl 8-((2-ethoxyethyl)carbamoyl)-7-(2,2,2-trifluoroethyl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7, l-/i;]indole-2(lH)-carboxylate as a white solid. LCMS m/z = 472.6 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.19 (t, J = 7.0 Hz, 3H), 1.32-1.49 (m, 9H), 2.19-2.38 (m, 1H), 2.42- 2.60 (m, 1H), 2.88-3.05 (m, 1H), 3.12-3.24 (m, 1H), 3.32-3.38 (m, 1H), 3.43-3.64 (m, 8H), 3.78-4.02 (m, 2H), 4.15-4.29 (m, 1H), 4.56-4.71 (m, 1H), 6.90-6.99 (m, 1H), 7.00-7.11 (m, 1H).

The above solid was then dissolved in 1.25 M methanol solution of HC1 (12 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated to give the title compound (3.5 mg). LCMS m/z = 372.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.19 (t, J = 7.0 Hz, 3H),2.25-2.43 (m, 1H), 2.48-2.65 (m, 1H), 3.11-3.22 (m, 1H), 3.38-3.67 (m, 11H), 4.00-4.11 (m, 1H), 4.23 (d, J = 15.0 Hz, 1H), 4.46 (d, J = 15.0 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H).

Example 1B.11: Preparation of N-butyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 128).

To a solution of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6,7-hexahydro-

[l,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (7 mg, 10.89 μιηοΐ), butan-l-amine (1.291 μL, 13.06 μιηοΐ), and triethylamine (4.552 μ^ 32.66 μιηοΐ) in MeCN (0.2 mL) was added HATU (6.209 mg, 16.33 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give tert- butyl 8-(butylcarbamoyl)-7-(2,2,2-trifluoroethyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole- 2(lH)-carboxylate as a white solid. LCMS m/z = 456.4 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.97 (t, J = 7.3 Hz, 3H), 1.33-1.47 (m, 11H), 1.53-1.64 (m, 2H), 2.21 -2.38 (m, 1H), 2.40-2.58 (m, 1H), 2.89-3.05 (m, 1H), 3.11-3.23 (m, 1H), 3.30-3.40 (m, 3H), 3.48-3.65 (m, 2H), 3.77-4.01 (m, 2H), 4.15- 4.30 (m, 1H), 4.55-4.72 (m, 1H), 6.88-6.97 (m, 1H), 6.98-7.10 (m, 1H).

The above solid was then dissolved in 1.25 M methanol solution of HC1 (12 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated to give the title compound (2.8 mg). LCMS m/z = 356.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.97 (t, J = 7.3 Hz, 3H), 1.34-1.47 (m, 2H), 1.54-1.64 (m, 2H), 2.26-2.43 (m, 1H), 2.45-2.62 (m, 1H), 3.12-3.22 (m, 1H), 3.33-3.52 (m, 5H), 3.58- 3.67 (m, 2H), 4.00-4.10 (m, 1H), 4.23 (d, J = 15.0 Hz, 1H), 4.45 (d, J = 15.0 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H).

Example 1B.12: Preparation of N-propyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 129). To a solution of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6,7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (7 mg, 10.89 μιηοΐ), propan-l-amine (1.074 13.06 μιηοΐ), and triethylamine (4.552 μL, 32.66 μιηοΐ) in MeCN (0.2 mL) was added HATU (6.209 mg, 16.33 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give tert- butyl 8-(propylcarbamoyl)-7-(2,2,2-trifluoroethyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate as a white solid. LCMS m/z = 442.6 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.97 (t, J = 7.4 Hz, 3H), 1.33-1.47 (m, 9H), 1.56-1.68 (m, 2H), 2.21-2.38 (m, 1H), 2.41-2.58 (m, 1H), 2.89-3.05 (m, 1H), 3.12-3.22 (m, 1H), 3.22-3.39 (m, 3H), 3.49-3.66 (m, 2H), 3.78-4.01 (m, 2H), 4.15- 4.30 (m, 1H), 4.55-4.71 (m, 1H), 6.90-6.97 (m, 1H), 6.99-7.11 (m, 1H).

The above solid was then dissolved in 1.25 M methanol solution of HC1 (12 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated to give the title compound (3.3 mg). LCMS m/z = 342.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.97 (t, J = 7.5 Hz, 3H), 1.56-1.68 (m, 2H), 2.26-2.43 (m, 1H), 2.45-2.62 (m, 1H), 3.11 -3.22 (m, 1H), 3.23-3.37 (m, 2H), 3.37-3.52 (m, 3H), 3.57- 3.67 (m, 2H), 4.00-4.09 (m, 1H), 4.23 (d, J = 15.0 Hz, 1H), 4.46 (d, J = 15.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H).

Example 1B.13: Preparation of N-(2-methoxyethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 130).

From 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7, l- i;]indole-8-carboxylic acid and 2-methoxyethanamine, the title compound was obtained using a similar method to the one described in Example IB.10. LCMS m/z = 358.4 [M+l]⁺.

Example 1B.14: Preparation of N-(2-isopropoxyethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7- hexahydro-[l>4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 131).

From 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2, 3,4,6, 7-hexahydro-

[l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid and 2-isopropoxyethanamine, the title compound was obtained using a similar method to the one described in Example IB.10. LCMS m/z = 386.6 [M+l]⁺.

Example 1B.15: Preparation of N-ethyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 132).

To a solution of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6,7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (9.5 mg, 14.77 μιηοΐ), 2M ethanamine in methanol (73.87 μ^ 0.148 mmol), and triethylamine (6.178 μL, 44.32 μιηοΐ) in MeCN (0.25 mL) was added HATU (8.426 mg, 22.16 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give tert-butyl 8-(ethylcarbamoyl)-7-(2,2,2-trifluoroethyl)-3,4,6,7-tetrahydro-

[l ,4]diazepino[6,7, l-/i;]indole-2(lH)-carboxylate as a white solid. LCMS m/z = 428.0 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm ¾ NMR (400 MHz, CD₃OD) δ ppm 1.20 (t, J = 7.3 Hz, 3H), 1.33- 1.48 (m, 9H), 2.21-2.38 (m, 1H), 2.41-2.58 (m, 1H), 2.87-3.05 (m, 1H), 3.12-3.24 (m, 1H), 3.32-3.41 (m, 3H), 3.49-3.66 (m, 2H), 3.77-4.02 (m, 2H), 4.15-4.28 (m, 1H), 4.55-4.71 (m, 1H), 6.89-6.98 (m, 1H), 6.99-7.10 (m, 1H).

The above solid was then dissolved in 1.25 M methanol solution of HC1 (12 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated to give the title compound (3.1 mg). LCMS m/z = 328.4 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.21 (t, J = 7.3 Hz, 3H), 2.27- 2.44 (m, 1H), 2.46-2.62 (m, 1H), 3.12-3.23 (m, 1H), 3.34-3.52 (m, 5H), 3.58-3.67 (m, 2H), 4.00-4.10 (m, 1H), 4.22 (d, J = 15.0 Hz, 1H), 4.46 (d, J = 15.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H). Example 1B.16: Preparation of N-(2-fluoroethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 133).

To a solution of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6,7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (10 mg, 19.98 μιηοΐ), 2-fluoroethanamine (2.103 μΐ_^, 23.98 μιηοΐ), and triethylamine (8.355 μ^ 59.94 μιηοΐ) in MeCN (0.2 mL) was added HATU (11.40 mg, 29.97 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give tert-butyl 8-((2-fluoroethyl)carbamoyl)-7-(2,2,2-trifluoroethyl)-3, 4,6, 7-tetrahydro-[l,4]diazepino [6,7,1-i;]indole-2(lH)-carboxylate as a white solid. LCMS m/z = 446.4 [M+l]⁺.

The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated to give the title

compound. LCMS m/z = 346.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.25-2.43 (m, 1H), 2.47- 2.63 (m, 1H), 3.12-3.22 (m, 1H), 3.38-3.52 (m, 3H), 3.55-3.76 (m, 4H), 4.01-4.11 (m, 1H), 4.23 (d, J = 15.0 Hz, 1H), 4.42-4.52 (m, 2H), 4.58-4.64 (m, 1H), 7.08 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H).

Example 1B.17: Preparation of N-(2,2-difluoroethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7- hexahydro-[l>4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 134).

To a solution of 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2,3, 4,6,7-hexahydro- [l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (10 mg, 19.98 μιηοΐ), 2,2-difluoroethanamine (2.703 μ^ 23.98 μιηοΐ), and triethylamine (8.355 μ^ 59.94 μιηοΐ) in MeCN (0.2 mL) was added HATU (11.40 mg, 29.97 μιηοΐ). The reaction was stirred at 23 °C for 15 h. The mixture was purified by HPLC to give tert-butyl 8-((2,2-difluoroethyl)carbamoyl)-7-(2,2,2-trifluoroethyl)-3,4,6,7-tetrahydro- [l ,4]diazepino[6,7, l- i;]indole-2(lH)-carboxylate as a white solid. LCMS m/z = 464.2 [M+l]⁺.

The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated to give the title compound. LCMS m/z = 364.4 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.25-2.43 (m, 1H), 2.47-2.62 (m, 1H), 3.12-3.22 (m, 1H), 3.38-3.52 (m, 3H), 3.58-3.79 (m, 4H), 4.01-4.11 (m, 1H), 4.23 (d, J = 15.0 Hz, 1H), 4.48 (d, J = 15.0 Hz, 2H), 5.83-6.16 (m, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H). Example 1B.18: Preparation of N,7-bis(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 137).

From2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7, l- i;]indole-8-carboxylic acid and 2,2,2-trifluoroethanamine (3.303 pL, 23.98 μιηοΐ), the title compound was obtained using a similar method to the one described in Example

1B.10. LCMS m/z = 381.8 [M+l]⁺.

Example 1B.19: Preparation of N-(2,2,3,3,3-pentafluoropropyl)-7-(2,2,2-trifluoroethyl)- l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H]indole-8-carboxamide (Compound 138).

From 2-(tert-butoxycarbonyl)-7-(2,2,2-trifluoroethyl)- 1,2, 3,4,6, 7-hexahydro-

[l ,4]diazepino[6,7, l- i;]indole-8-carboxylic acid and 2,2,3,3,3-pentafluoropropan-l -amine (4.971 pL, 23.98 pmol), the title compound was obtained using a similar method to the one described in Example 1B.10. LCMS m/z = 432.4 [M+l]⁺. Example 1B.20: Preparation of 7-ethyl-N-(2-fluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 139).

To the solution of 2-(tert-butoxycarbonyl)-7-ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l-i;]indole-8-carboxylic acid (45 mg, 0.130 mmol), HATU (74.04 mg, 0.195 mmol) and triethylamine (36.21 μΐ, 0.260 mmol) in DMF (2 mL) was added 2-fluoroethanamine (12.29 mg, 0.195 mmol). The reaction mixture was stirred at room temperature overnight. The crude was purified by semi preparative HPLC (15-85% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give tert-butyl 7-ethyl-8-((2-fluoroethyl)carbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole- 2(lH)-carboxylate, which was dissolved in dioxane (0.5 mL), 4M HC1 in dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 5 hr, concentrated. The residue was purified by semi preparative HPLC (5-60% CH₃CN H₂0 with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give the title compound as the TFA salt (35 mg). LCMS m/z = 292.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 0.89 (t, 7 = 7.4 Hz, 3H), 1.40-1.52 (m, 1H), 1.54-1.65 (m, 1H), 3.09-3.18 (m, 1H), 3.32-3.50 (m, 4H), 3.52-3.74 (m, 4H), 4.18 (d, 7 = 4.9 Hz, 1H), 4.39 (d, 7 = 4.9 Hz, 1H), 4.48 (t, 7 = 5.0 Hz, 1H), 4.61 (t, 7 = 5.0 Hz, 1H), 6.98 (d, 7 = 7.8 Hz, 1H), 7.12 (d, 7 = 7.9 Hz, 1H).

Example 1B.21: Preparation of N-(2,2-difluoroethyl)-7-ethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxamide (Compound 140).

To the solution of 2-(tert-butoxycarbonyl)-7-ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l-i;]indole-8-carboxylic acid (50 mg, 0.144 mmol), HATU (82.27 mg, 0.216 mmol) and triethylamine (40.23 μΐ, 0.289 mmol) in DMF (2 mL) was added 2,2-difluoroethanamine (17.55 mg, 0.216 mmol). The reaction mixture was stirred at room temperature overnight. The crude was purified by semi preparative HPLC (15-85% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give tert-butyl 8-((2,2-difluoroethyl)carbamoyl)-7-ethyl-3,4,6,7-tetrahydro- [l ,4]diazepino[6,7, l- i;]indole-2(lH)-carboxylate which was dissolved in dioxane (0.5 mL), 4M HCl in dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 4 hr, concentrated. The residue was purified by semi preparative HPLC (5-60% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give the title compound as the TFA salt (40 mg). LCMS m/z = 310.6 [M+H]⁺. ¾ NMR (400 MHz, CD₃OD) δ 0.89 (t, 7 = 7.4 Hz, 3H), 1.40-1.52 (m, 1H), 1.54-1.65 (m, 1H), 3.09-3.18 (m, 1H), 3.32-3.50 (m, 4H), 3.54-3.72 (m, 4H), 4.18 (d, 7 = 4.9 Hz, 1H), 4.40 (d, J = 4.9 Hz, 1H), 6.00 (tt, J = 56.0 and 3.9 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 7.12 (d, 7 = 7.9 Hz, 1H). Example 1B.23: Preparation of N-methyl-6-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide (Compound 125).

Step A: Preparation of methyl 2-propyl-lH-indole-4-carboxylate

The flask containing methyl lH-indole-4-carboxylate (1 g, 5.708 mmol) , potassium hydrogen phosphate (2.983 g, 17.12 mmol) , (lR,4S)-bicyclo[2.2.1]hept-2-ene (norbornene) (1.075 g, 11.42 mmol) and PdCl₂(MeCN)₂ (0.222 g, 0.856 mmol) in 20 mL DMA (0.5 M H₂0) was degassed and charged with argon. 1-Bromopropane (1.404 g, 11.42 mmol) in 8 mL DMA (0.5 M H₂0) was added. The whole reaction mixture was heated at 70 °C overnight. Concentrated, the residue was purified by silica gel column chromatography with 15% ethyl acetate/hexanes then preparative HPLC (15-85% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined organics were neutralized with saturated NaHC0₃, partially concentrated, extracted with ethyl acetate. The combined organics were dried over anhydrous Na₂S0₄, filtered then concentrated to give the title compound (915 mg) as white solid. LCMS m/z = 218.4 [M+H]⁺. ¾ NMR (400 MHz, CDC1₃) δ 1.02 (t, 7 = 7.6 Hz, 3H), 1.76-1.82 (m, 2H), 2.76-2.81 (m, 2H), 3.97 (s, 3H), 6.88-6.92 (m, 1H), 7.14 (t, 7 = 7.8 Hz, 1H), 7.48 (dt, 7 = 8.0 and 0.9 Hz, 1H), 7.85 (dd, J = 7.6 and 0.9 Hz, 1H), 8.06 (br s, 1H).

Step B: Preparation of methyl 2-propyllindoline-4-carboxylate

To a solution of methyl 2-propyl-lH-indole-4-carboxylate (915 mg, 4.211 mmol) in TFA (3 mL) at ice-water bath was added triethylsilane (3 ml, 18.78 mmol) dropwise under nitrogen. The reaction mixture was warmed to room temperature and stirred overnight then heated at 55 °C for 4 hr. Concentrated, water was added, adjusted pH to 8 with aqueous saturated NaHC0₃ solution, extracted with ethyl acetate. The combined organics were concentrated. The residue was purified by silica gel column chromatography with 15% ethyl acetate/hexanes to give the title compound (768 mg) as oil. Exact mass calculated for Ci₃H₁₇N0₂: 219.1, found LCMS m/z = 220.2 [M+H]⁺. ¾ NMR (400 MHz, CD₃OD) δ 0.98 (t, 7 = 7.2 Hz, 3H), 1.38-1.66 (m, 4H), 2.88 (dd, 7 = 17.4 and 8.3 Hz, 1H), 3.47 (dd, 7 = 17.4 and 8.8 Hz, 1H), 3.77-3.85 (m, 1H), 3.87 (s, 3H), 6.75 (dd, 7 = 7.7 and 0.8 Hz, 1H), 7.03 (t, 7 = 7.8 Hz, 1H), 7.23 (dd, 7 = 7.8 and 1.0 Hz, 1H).

Step C: Preparation of methyl l-(2-aminoethyl)-2-propylindoline-4-carboxylate

The mixture of methyl 2-propylindoline-4-carboxylate (0.532 g, 2.426 mmol) and 2- bromoethanamine hydrobromide (0.597 g, 2.911 mmol) were heated neat at 115 °C overnight. The mixture was dissolved in methanol and purified by preparative HPLC (10-70% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined fractions were neutralized with aqueous saturated NaHC0₃, partially concentrated, extracted with ethyl acetate. The combined organics were dried over anhydrous Na₂S0₄, filtered, then concentrated to give the title compound (300 mg). LCMS m/z = 263.2 [M+H]⁺. ¾ NMR (400 MHz, CD₃OD) δ 1.00 (t, J = 7.4 Hz, 3H), 1.30- 1.52 (m, 3H), 1.70-1.78 (m, 1H), 2.70-2.90 (m,

3H), 3.22 (t, J = 6.9 Hz, 2H), 3.48-3.62 (m, 2H), 3.86 (s, 3H), 6.64 (dd, J = 7.7 and 0.4 Hz, 1H), 7.08 (t, 7 = 7.8 Hz, 1H), 7.18 (dd, J = 7.9 and 0.9 Hz, 1H).

Step D: Preparation of 2-tert-butyl 8-methyl 6-propyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/»]indole-2,8(lH)-dicarboxylate

To a solution of methyl l-(2-aminoethyl)-2-propylindoline-4-carboxylate (300 mg, 1.144 mmol) and 37% formaldehyde in water (0.255 ml, 3.431 mmol) in methanol (8 mL) was added TFA (0.438 ml, 5.718 mmol). The reaction was stirred at 80 °C for lhr. The mixture was concentrated, ethyl acetate was added, washed with saturated aqueous NaHC0₃, dried over anhydrous Na₂S0₄, filtered then concentrated to give crude methyl 6-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l- i;^']indole-8- carboxylate, which was then dissolved in DCM (8 mL), triethylamine (0.319 ml, 2.287 mmol) was added followed by di-tert-butyl dicarbonate (0.374 g, 1.715 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, the residue was purified by silica gel column

chromatography with 20% ethyl acetate/hexanes to the title compound (338 mg). LCMS m/z = 375.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 0.98 (t, J = 7.2 Hz, 3H), 1.40 (s, 9H), 1.30-1.55 (m, 3H), 1.70- 1.78 (m, 1H), 2.80-2.90 (m, 2H), 3.10-3.40 (m, 3H), 3.70 (dd, J = 17.7 and 9.4 Hz, 1H), 3.86 (s, 3H),

3.95 (d, J = 15.4 Hz, 1H), 4.00-4.20 (m, 1H), 4.65-4.90 (m, 1H), 6.88-7.05 (m, 1H), 7.34 (d, J = 7.9 Hz, 1H).

Step E: Preparation of 2-(tert-butoxycarbonyl)-6-propyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole-8-carboxylic acid

To a solution of 2-tert-butyl 8-methyl 6-propyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l-

/i;]indole-2,8(lH)-dicarboxylate (338 mg, 0.903 mmol) in dioxane (8 mL) was added 1M solution of lithium hydroxide in water (5.416 ml, 5.416 mmol). The reaction was stirred at 80 °C for 5 hr. Adjusted pH to 3-4 with aqueous 5% citric acid, the off-white solid was collected and washed with water and dried to give the title compound (302 mg). LCMS m/z = 361.6 [M+H]⁺.

Step F: Preparation of 6-propyl-N-methyl-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l-

&i]indole-8-carboxamide

To a stirred solution of 2-(tert-butoxycarbonyl)-6-propyl- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7, l- i;]indole-8-carboxylic acid (50 mg, 0.139 mmol), and triethylamine (38.67 μΐ, 0.277 mmol) in DMF (1.5 mL) was added HATU (79.07 mg, 0.208 mmol). After 10 min, a solution of 2M methanamine in THF (0.104 ml, 0.208 mmol) was added. The reaction mixture was stirred at room temperature overnight, concentrated. The crude was purified by semi preparative HPLC (15-85% CH₃CN/H₂O with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give tert-butyl 8-(memylcarbamoyl)-6-propyl-3,4,6,7-tetrahydro-[l,4]diazepm^ (38 mg, 73.3 %). LCMS m/z = 374.4 [M+H]⁺.

To a solution of tert-butyl 8-(methylcarbamoyl)-6-propyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l-i;]indole-2(lH)-carboxylate (38 mg, 0.102 mmol) in ether (1 mL) was added a solution of 4 M hydrogen chloride in dioxane (25.44 μΐ, 0.102 mmol). The reaction mixture was stirred at room temperature for 4 hr, the white precipitate was collected and washed with ether and dried to give the title compound as HCl salt (32 mg). LCMS m/z = 274.4 [M+H]⁺. ¾ NMR (400 MHz, CD₃OD) δ 1.02 (t, 7 = 7.3 Hz, 3H), 1.40-1.63 (m, 3H), 1.80-1.90 (m, 1H), 2.82 (dd, 7 = 16.4 and 9.1 Hz, 1H), 2.88 (s, 3H), 3.05-3.12 (m, 1H), 3.30-3.40 (m, 1H), 3.42-3.52 (m, 2H), 3.55 (dd, 7 = 16.4 and 9.1 Hz, 1H), 3.62- 3.68 (m, 1H), 4.10 (d, 7 = 4.9 Hz, 1H), 4.48 (d, 7 = 4.8 Hz, 1H), 7.01 (d, 7 = 7.9 Hz, 1H), 7.10 (d, 7 = 7.9 Hz, 1H).

Example 1B.24: Preparation of N,4-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- hi]indole-8-carboxamide (Compound 118).

Step A: Preparation of methyl l-(l-cyanoethyl)indoline-4-carboxylate

A mixture of methyl indoline-4-carboxylate (114 mg, 0.643 mmol), potassium carbonate (270 mg, 1.954 mmol), and 2-bromopropanenitrile (277 μΐ, 3.267 mmol) in 2 ml CH₃CN was stirred at 80°C (oil bath) overnight. Mixture was purified by HPLC (CH₃CN/H₂0 gradient + 0.1 % TFA). Fractions containing product were partly concentrated and residue was extracted with 1 M NaHC0₃ and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated to give methyl 1-(1- cyanoethyl)indoline-4-carboxylate (106 mg, 72 %). LCMS m/z = 331.4 [M+l]⁺. ¾ NMR (400 MHz, CDC1₃) δ 1.65 (d, 7 = 7.2 Hz, 3H), 3.19-3.31 (m, 2H), 3.52-3.67 (m, 2H), 3.88 (s, 3H), 4.57 (q, 7 = 7.2 Hz, 1H), 6.72 (d, 7 = 7.8 Hz, 1H), 7.19-7.23 (m, 1H), 7.36 (dd, J_} = 7.8 Hz, 7₂ = 0.8 Hz, 1H).

Step B: Preparation of l-(l-cyanoethyl)-N-methylindoline-4-carboxamide

To a solution of methyl l-(l-cyanoethyl)indoline-4-carboxylate (103 mg, 0.447 mmol) in 2 ml CH₃CN/H₂0 (50: 1), Lithium bromide (828 mg, 9.534 mmol) and triethylamine (380 μΐ, 2.730 mmol) were added. After stirring at 75°C overnight, mixture was extracted with 2 M HCl and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated. Residue was dissolved in 4 ml DMF and triethylamine (0.09 ml, 1.22 mmol) and HATU (200 mg, 0.526 mmol) were added. After stirring at RT for 10 min, 1 M methanamine in THF (1.8 ml, 1.800 mmol) was added. After stirring at RT overnight, solution was extracted with water and AcOEt. Organic phases were dried over MgS0₄, filtered, and concentrated. Residue was purified by biotage CC (Si0₂, hexane/AcOEt gradient) to give 1 -(1- cyanoethyl)-N-methylindoline-4-carboxamide (137 mg, 99 %). LCMS m/z = 330.2 [M+l]⁺. ¾ NMR (400 MHz, CDC1₃) δ 1.65 (d, 7 = 7.3 Hz, 3H), 2.99 (d, 7 = 4.9, 3H), 3.20-3.30 (m, 2H), 3.39-3.46 (m, 1H), 3.59-3.66 (m, 1H), 4.56 (q, 7 = 7.3 Hz, 1H), 6.66 (d, 7 = 7.8 Hz, 1H), 6.95 (dd, 7, = 7.4 Hz, 7₂ = 0.6 Hz, 1H), 7.15-7.19 (m, 1H), 8.02 (s, 1H).

Step C: Preparation of tert-butyl (2-(4-(methylcarbamoyl)indolin-l-yl)propyl)carbamate To a solution of l-(l-cyanoethyl)-N-methylindoline-4-carboxamide (135 mg, 0.436 mmol) in 15 ml MeOH, cobalt(II) chloride hexahydrate (315 mg, 1.324 mmol) was added. After stirring at RT for 5 min, sodium tetrahydroborate (137 mg, 3.621 mmol) was added in small portions (over ca. 15 min) whereupon vigorous bubbling and slight exotherm was observed. After stirring at RT for 1 h, di-tert- butyl dicarbonate (192 mg, 0.880 mmol) was added. After stirring at RT for 15 min, mixture was extracted with water and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated. Residue was purified by biotage CC (Si0₂, hexane/AcOEt gradient) to give tert-butyl (2-(4-

(methylcarbamoyl)indolin-l-yl)propyl)carbamate (95.8 mg, 66 %). LCMS m/z = 334.0 [M+l]⁺. ¾ NMR (400 MHz, CDC1₃) δ 1.08 (d, 7 = 6.7 Hz, 3H), 1.26 (s, 9H), 2.98 (d, 7 = 4.8 Hz, 3H), 3.14-3.43 (m, 6H), 3.76-3.85 (m, 1H), 5.94 (s br, 1H), 5.94 (s br, 1H), 6.50 (d, 7 = 7.9 Hz, 1H), 6.74 (dd, J₁ = 7.4 Hz, J₂ = 0.5 Hz, 1H), 7.05-7.09 (m, 1H).

Step D: Preparation of N,4-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M-]indole-

8-carboxamide.

To a solution of tert-butyl (2-(4-(methylcarbamoyl)indolin-l-yl)propyl)carbamate (92.2 mg, 0.277 mmol) in 2 ml CH₂C1₂, TFA (635 μΐ, 8.292 mmol) was added. After stirring at RT for 1 h, solution was concentrated and dried under high vacuum. Residue was dissolved in 3 ml MeOH, and 2,2,2-trifluoroacetic acid (64 μΐ, 0.836 mmol) and 37% formaldehyde (62 μΐ, 0.833 mmol) were added. After stirring at 70°C for 45 min, mixture was purified by HPLC (CH₃CN/H₂0 gradient + 0.1 % TFA). Fractions containing product were partly concentrated, 1.25 M HC1 in MeOH was added (ca. 1 ml), concentrated, and dried under high vacuum to give 7Y,4-dimethyl- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7, l-hi]indole-8-carboxamide dihydrochloride (71.9 mg, 82 %) as a tanned solid. LCMS m/z = 246.2 [M+l]⁺. ¾ NMR (400 MHz, MeOD) δ 1.27 (d, 7 = 6.7 Hz, 3H), 2.88 (s, 3H), 3.12- 3.59 m (m, 6H), 3.67-3.73 (m, 1H), 4.20 (d, 7 = 14.9 Hz, 1H), 4.40 (d, 7 = 14.9 Hz, 1H), 7.01 (d, 7 = 7.9 Hz, 1H), 7.08 (d, 7 = 7.4 Hz, 1H).

Example 1B.25: Preparation of an enantiomer of N-propyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7- hexahydro-[l,4]diazepino[6,7,l-¾i]indole-8-carboxamide. An enantiomer of the compound 129 (see Example IB.12) was prepared as follows.

Step A: Preparation of methyl 3-(2,2,2-trifluoroacetyl)-lH-indole-4-carboxylate

A 3-neck RB flask equipped with a mechanical stirrer was charged with a solution of methyl l/f-indole-4-carboxylate (250 g, 1.43 mol) in DMF (1.0 L). The flask was immersed in an ice bath and placed under positive nitrogen pressure. TFAA (267.8 ml, 1.927 mol) was added via addition funnel over lh. The reaction mixture was slowly warmed to room temperature and stirred for 18h at which time additional TFAA (0.5 equiv.) was added and the mixture stirred for an additional 3.5h. The mixture, which contained a white precipitate, was slowly and carefully poured into a cold 7.5% aqueous sodium carbonate solution (4.5L). 10% aq. NaOH (approx. 150 mL) was added to ensure the mixture was basic. The precipitate was filtered (coarse frit) and washed several times with water to give 488g of a white solid. The solid was dried in a vacuum oven (35 °C) to give methyl 3-(2,2,2-trifluoroacetyl)- l/f-indole-4-carboxylate (341 g, 1.20 mol, 84% yield) as a white solid in good purity (-95% by ¾ NMR, >98% by LC MS). ¾ NMR (400 MHz, CDC1₃): δ 9.90 (bs, 1H), 7.98 (m, 1H), 7.54-7.49 (m, 2H), 7.34 (dd, J = 7.7, 7.6 Hz, 1H). 3.99 (s, 3H), . ¹³C APT NMR (100 MHz, CDC1₃): δ up ( H, C¾): 135.0 (q, 7 = 4.9 Hz), 124.5, 123.6, 114.9, 52.7; down (C, H₂): 175.0 (q, 7 = 34.9 Hz), 170.5, 137.0, 127.6, 121.7, 117.0 (q, 7 = 289.0 Hz), 111.0. LCMS (ESI⁺): m/z 272.4 [M + H]⁺.

Step B: Preparation of methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate

To an ice-cooled (1 °C internal temp.) mixture of TFA (63.5 ml, 830 mmol) and Triethylsilane

(30.9 ml, 194 mmol) under N₂ was added methyl 3-(2,2,2-trifluoroacetyl)-l/f-indole-4-carboxylate (15.0 g, 55.3 mmol) in 3 equal portions over 20 min. Upon completion of the addition, the flask was heated to 50 °C for 18h. Cooled the mixture to room temperature and concentrated in vacuo to remove all volatiles. Diluted with EtOAc and washed w/sat. aq. NaHC0₃ (3X), and brine. Dried organics over MgS0₄, filtered, and concentrated. Purification by silica gel chromatography (2% EtOAc in hexanes gradient to 25% EtOAc in hexanes) gave methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate (5.83 g, 21.8 mmol, 39% yield) as a white solid. ¾ NMR (400 MHz, CDC1₃): δ 7.40 (dd, 7 = 7.8, 1.0 Hz, 1H), 7.14 (t, 7 = 7.8 Hz, 1H), 6.82 (dd, 7 = 7.8, 0.6 Hz, 1H), 4.07 (m, 1H), 3.91 (s, 3H), 3.86 (bs, 1H), 3.64- 3.55 (m, 2H), 2.43-2.31 (m, 2H). LCMS (ESI⁺): m/z 260.2 [M + H]⁺.

Step C: Preparation of an enantiomer of methyl 3-(2,2,2-trifluoroethyl)indoline-4- carboxylate and of an enantiomer of 3-(2,2,2-trifluoroethyl)indoline-4-carboxylic acid.

To a solution of rac-methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate (5.81 g, 21.7 mmol) in DME (15 mL) and 135 mL of a 0.5M phosphate buffer (pH = 7.5) was added CLEA102-OM (Clea from C. Antarctica lipase B), which is commercially available, e.g., from CLEA Technologies. The mixture was heated in a sealed tube with stirring (stir bar) at 53 °C (oil bath temp) for 60h. The mixture was diluted w/EtOAc (making sure to dissolve any precipitated ester) and filtered through a medium frit. The filtrate was washed with w/10% aq. NaOH (2X), and brine. Dried organics over MgS0₄, filtered, and concentrated to give 3.43 g of recovered ester.

To the isolated ester (3.43g, from above) in DME (30 mL) and 250 mL of a 0.5M phosphate buffer (pH = 7.5) was added CAL-B CLEA-OM (6.2g). The mixture was heated in a sealed tube with stirring (stir bar) at 53 °C (oil bath temp) for 42h. The mixture was filtered and work up was as described above to give the title enantiomer of methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate (2.86 g, 10.5 mmol, 48%, 79% ee) as an off-white solid. The enantiopurity of the product was performed by ester hydrolysis and subsequent amide coupling with optically pure (S)-phenylglycine methyl ester. The ratio of the diastereomeric products were integrated by ¾ NMR.

Step D: Preparation of an enantiomer of N-propyl-3-(2,2,2-trifluoroethyl)indoline-4- carboxamide

A mixture of the enantiomer of methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate (2.86 g, 10.5 mmol, 48%, 79% ee) prepared in Step C of this Example IB.25, w-propylamine (1.22 g, 20.7 mmol), and 2,3,4,6,7,8-hexahydro-l/f-pyrimido[l,2-a]pyrimidine (144 mg, 1.03 mmol) in THF (10 mL) was stirred in a sealed reaction vessel at 40 °C for 90h. The mixture was concentrated in vacuo and re-dissolved in THF (5 mL). w-propylamine (2.44 g, 41.4 mmol) and additional 2,3,4,6,7,8- hexahydro-l/f-pyrimido[l,2-a]pyrimidine (144 mg, 1.03 mmol) were added. The reaction mixture was heated in the microwave at 60 °C for 18h. The mixture was concentrated in vacuo and partitioned between EtOAc and sat. aq. NH₄C1. The layers were separated and the organics were washed successively with sat. aq. NH₄C1 (2X), sat. aq. NaHC0₃, and brine. Dried organics over MgS0₄, filtered, and concentrated. The concentrated material was suspended in hexanes/EtOH (10 : 1, approx. 5 mL). Heated gently and agitated the solid with a spatula. Filtered and washed the filter cake with hexanes to leave behind the title enantiomeric amide product (1.99g) as an off white solid in good purity. The first two aqueous washes from above (sat. aq. NH₄C1), which contained some desired amide, were combined with the filtrates from the recrystallization and partitioned between EtOAc and 10% aq. NaOH. The phases were separated and the organics were washed with brine. Dried organics over MgS0 , were filtered and concentrated. The concentrated material was treated with

hexanes EtOH as described above and filtered to give an additional 100 mg of amide product. The title enantiomer (in total 2.09 g, 6.35 mmol, 62 %) was obtained as an off-white solid. ¾ NMR (400 MHz, CDC1₃): δ 7.09 (t, 7 = 7.8 Hz, 1H), 6.82 (dd, 7 = 7.8, 0.5 Hz, 1H), 6.72 (d, 7 = 7.8 Hz, 1H), 6.01 (bs, 1H), 4.02 (m, 1H), 3.66-3.55 (m, 2H), 3.47-3.32 (m, 2H), 2.65 (m, 1H), 2.31 (m, 1H), 1.62 (sextet, 7 = 7.4 Hz), 0.98 (t, 7 = 7.4 Hz). LCMS (ESI⁺): m/z 287.4 [M + H]⁺.

Step E: Preparation of an enantiomer of tert-butyl (2-(4-(propylcarbamoyl)-3-(2,2,2- trifluoroethyl)indolin-l-yl)ethyl)carbamate

A mixture of the enantiomer of N-propyl-3-(2,2,2-trifluoroethyl)indoline-4-carboxamide (2.07 g, 6.29 mmol), prepared in Step D of this Example lB.25,and 2-bromoethanamine hydrobromide (2.58 g, 12.6 mmol) was heated (neat) in a sealed tube flushed with N₂ at 125 °C for 18h. The mixture was cooled to room temperature and MeOH (35 mL) was added. Stirring and gentle heating was necessary to dissolve all solids. The reaction flask was cooled in an ice bath and triethylamine (3.51 ml, 25.2 mmol) was added followed by (BOC)₂0 (4.46 g, 20.4 mmol) ("BOC" or "Boc" = t-butoxycarbonyl). It was allowed to slowly warm to room temperature and stirred for 4h at which time additional (BOC)₂0 (800 mg, 3.67 mmol) was added. The mixture was stirred overnight at room temperature and concentrated to remove volatiles. Partitioned between EtOAc and sat. aq. NH₄C1. Separated and washed the organics with sat. aq. NH₄C1 (2X), sat. aq. NaHC0₃, and brine. The organics were dried over MgS0 , filtered, and concentrated. The desired product was recrystallized from the concentrate with hot MTBE. Cooled and filtered. Filter cake was washed with hexanes to leave behind 1.30g of an off-white solid. This material was further purified by silica gel chromatography (15% EtOAc in hexanes gradient to 50% EtOAc in hexanes) to give the title enantiomer (cropl, 895 mg) in good purity. The filtrates from the above recrystallization were concentrated and purified by silica gel chromatography (15% EtOAc in hexanes gradient to 50% EtOAc in hexanes) to give 850 mg of white solid that contained the title enantiomer (70 wt. %) along with the starting indoline (30 wt.%). In total, 1.41 g (3.27 mmol, 52 yield %) of the title enantiomer of tert-butyl (2-(4-(propylcarbamoyl)-3 -(2,2,2- trifluoroethyl)indolin-l-yl)ethyl)carbamate was obtained. ¾ NMR (400 MHz, CDC1₃): δ 7.13 (t, 7 = 7.6 Hz, 1H), ), 6.76 (dd, 7 = 7.6, 0.5 Hz, 1H), 6.59 (d, 7 = 7.6 Hz, 1H), 6.00 (bs, 1H), 4.73 (bs, 1H), 3.98 (m, 1H), 3.53 (dd, J = 9.3, 1.6 Hz, 1H), 3.46-3.30 (m, 6H), 3.09 (m, 1H), 2.69 (m, 1H), 2.27 (m, 1H), 1.63 (sextet, 7 = 7.4 Hz), 1.44 (s, 9H), 0.98 (t, J = 7.4 Hz). LCMS (ESI⁺): m/z 430.6 [M + H]⁺.

Step F: Preparation of an enantiomer of N-propyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7- hexahydro-[l>4]diazepino[6,7,l-hi]indole-8-carboxamide

A mixture of the enantiomer of tert-butyl (2-(4-(propylcarbamoyl)-3-(2,2,2- trifluoroethyl)indolin-l-yl)ethyl)carbamate (crop 1 prepared in Step E of this Example 1B.25, 850 mg, 1.19 mmol) and TFA (1.36 ml, 17.8 mmol) was stirred at room temperature for lh. The mixture was diluted with MeOH (10 mL) and Formaldehyde (37 wt. % in water) (0.311 ml, 4.16 mmol) was added. The mixture was heated to 60 °C in a microwave for 5h and subsequently concentrated in vacuo. The concentrated material was stirred in AN HCl/dioxane (3 mL) at room temperature for 45 min and concentrated in vacuo to give the crude tricycle as the bis-HCl salt. Attempted recrystallizations using MeOH/MTBE were unsuccessful. LC/MS and ¾ NMR revealed considerable impurities present. The material was purified by rev. phase HPLC. The product-containing fractions were concentrated in vacuo and treated with AN HCl/dioxane to convert the product to the bis-HCl salt. The title enantiomer of iV-propyl-7-(2,2,2-trifluoroethyl)- 1,2, 3,4,6,7 -hexahydro-[l,4]diazepino[6,7, l-hi]indole-8- carboxamide (121 mg, 0.213 mmol, 17.9 %) in approx. 60% purity (LC/MS, ¾ NMR).

Recrystallization attempts to further purify this material were unsuccessful. A second batch of the title enantiomer (121 mg of 60 wt.% purity material, mmol, % yield) was prepared from the filtrate batch of the enantiomer of tert-butyl (2-(4-(propylcarbamoyl)-3-(2,2,2-trifluoroethyl)indolin-l - yl)ethyl)carbamate prepared as described in Step E. Both batches were combined and further purified as follows:

To a combined solution of the enantiomer of N-propyl-7-(2,2,2-trifluoroethyl)- 1,2,3,4,6,7- hexahydro-[l,4]diazepino[6,7, l-hi]indole-8-carboxamide.2HCl (410 mg, 0.693 mmol) in MeOH (4 mL) was added triethylamine (0.459 ml, 3.29 mmol) followed by (BOC)₂0 (0.325 g, 1.49 mmol). The mixture was stirred at room temperature for 2h and concentrated in vacuo. The mixture was partitioned between water and EtOAc. The phases were separated and the organics were washed w/brine. The organics were dried over MgS0₄, filtered, and concentrated. Purification by silica gel chromatography (15% EtOAc in hexanes gradient to 55% EtOAc in hexanes) gave the Boc-protected tricycle (246 mg, 80% yield). LCMS (ESI⁺): m/z 342.4 [M + H]⁺.

The purified compound was stirred in 4N HC1 dioxane (5 mL) at room temperature for 1.5h and concentrated to give trycyclic product as the bis-HCl salt. The product was converted to the free amine by passage through an SCX strong cation exchange column (MeOH eluant, 2N NH₃ in MeOH to release product from resin). Recrystallization of the free amine was successful using an MTBE/hexanes (~1 : 1) mixture to give:

Crop 1 : White solid 90 mg, >95% ee)

Filtrate: White solid 23 mg, 65% ee)

Analytical chiral HPLC conditions: Chiralpak IC column (4.6 mm X 250 mm). Conditions: Isocratic 8% EtOH in hexanes (containing 0.1 % Et3N) @ lmL/min monitored at 254 nm. ent-1 retention time ~ 15.4 min, ent-2 retention time ~ 17.9 min. The desired enantiomer is the slower eluting second isomer (ent-2). ¾ NMR (400 MHz, *-DMSO): δ 8.27 (t, 7 = 5.5 Hz, 1H), 6.94 (d, 7 = 7.8 Hz, 1H), 6.88 (d, 7 = 7.8 Hz, 1H), 3.91 (m, 1H), 3.86 (d, 7 = 15.2 Hz, 1H), 3.62 (d, 7 = 15.2 Hz, 1H), 3.38 (dd, 7 = 10.1, 1.8 Hz, 1H), 3.30-3.02 (m, 5H), 2.81 (m, 1H), 2.71 (m, 1H), 2.55 (m, 1H), 2.31 (m, 1H), 1.49 (sextet, 7 = 7.3 Hz), 0.88 (t, 7 = 7.3 Hz). LCMS (ESI⁺): m/z 342.4 [M + H]⁺.

Example 1B.26: Preparation of an enantiomer of N-methyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7- hexahydro-[l,4]diazepino[6,7,l-&i]indole-8-carboxamide. An enantiomer of the compound 113 (see Example 1B.0) was prepared as follows.

Step A: Preparation of an enantiomer of N-methyl-3-(2,2,2-trifluoroethyl)indoline-4- carboxamide

A mixture of the enantiomer of methyl 3-(2,2,2-trifluoroethyl)indoline-4-carboxylate (3.14 g, 12.1 mmol, 57% ee, prepared from the previously described enzymatic resolution procedure), methylamine (9.1 mL of a 2.0M solution in THF, 18.2 mmol), and 2, 3,4,6,7, 8-hexahydro-l/f- pyrimido[l,2-a]pyrimidine (168 mg, 1.21 mmol) in THF (10 mL) was stirred in a sealed reaction vessel at 40 °C for 88h. Additional methylamine (6.05 mL of a 2.0 M solution in THF, 12.1 mmol) was added and stirring was continued at 40 °C for an additonal 24h. Additional catalyst (84.0 mg, 0.605 mmol) was added and the continued stirring at for 40 °C 24h at which time additional methylamine (6.05 mL of a 2.0 M solution in THF, 12.1 mmol) was added and the mixture and 40 °C for an additonal

24h. The mixture was concentrated in vacuo and partitioned between d in EtOAc and sat. aq. NH₄C1. The layers were separated and the organics were washed sequentially with sat. aq. NH₄C1, and brine. Dried the organics over MgS0₄, filtered, and concentrated. The concentrated material was suspended in hexanes EtOH (10 : 1, approx. 15 mL). Heated gently and agitated solid with a spatula. Filtered and washed the filter cake with hexanes to leave behind 2.66 g of the desired amide as a white solid with mild green tint (crop 1, approx. 80% purity by ¾ NMR and LC MS). A small amount of solids crashed out in the filtrate. This material was filtered and washed with hexanes to give an additional 117 mg of the desired amide as a white solid (crop 2, approx. 80% purity).

In total, 2.78 g of the title enantiomer (8.61 mmol, 71 % yield) were obtained. ¾ NMR (400 MHz, CDC1₃): δ 7.08 (t, 7 = 7.8 Hz, 1H), 6.81 (dd, 7 = 7.8, 0.7 Hz, 1H), 6.72 (d, 7 = 7.8 Hz, 1H), 6.04 (bs,

1H), 4.02 (m, 1H), 3.64-3.55 (m, 2H), 2.98 (d, 7 = 4.9 Hz, 3H), 2.65 (m, 1H), 2.30 (m, 1H). LCMS

(ESI⁺): m/z 259.4 [M + H]⁺.

Step B: Preparation of an enantiomer of tert-butyl (2-(4-(methylcarbamoyl)-3-(2,2,2- trifluoroethyl)indolin-l-yl)ethyl)carbamate

A mixture of the previously obtained enantiomer of N-methyl-3-(2,2,2-trifluoroethyl)indoline-

4-carboxamide (cropl from above, 2.63 g, 8.66 mmol) and 2-bromoethanamine hydrobromide (2.66 g,

13.0 mmol) were heated (neat) at 125 °C for 18h. The mixture was cooled to rt and the material was dissolved in IPA (25 mL). In order to dissolve all solids the mixture was heated and agitated with a spatula several times. Upon full dissolution the IPA was removed in vacuo. Additional

bromoethylamine hydrobromide (444 mg ,2.17 mmol) was added and the mixture was heated (neat) at 125 °C for 4h, then cooled to room temperature and dissolved the mixture in MeOH (25 mL). The flask was cooled in an ice bath and Triethylamine (4.22 ml, 30.3 mmol) was added followed by (BOC)₂0 (3.78 g, 17.3 mmol). The reaction was stirred at rt for 3h and concentrated to remove volatiles. Partitioned between EtOAc and sat. aq. NH₄C1. Separated and washed organics with sat. NH₄C1 (2X), sat. NaHC0₃, and brine. Dried organics over MgS0₄, filtered, and concentrated. The concentrated material was suspended in MTBE/Hexanes (~5 : 1) and gently heated. Cooled and filtered. The filter cake was washed with hexanes to leave behind the desired product (1.21g, crop 1) as an off- white solid. The filtrate was concentrated and purified by silica gel chromatography (25% EtOAc in hexanes gradient to 70% EtOAc in hexanes) to give an additional 808 mg of the desired product as a white solid. In total 2.018 g of the enantiomer of tert-butyl (2-(4-(methylcarbamoyl)-3-(2,2,2- trifluoroethyl)indolin-l-yl)ethyl)carbamate (5.027 mmol, 58.1 %) was obtained as a white solid.

¾ NMR (400 MHz, CDC1₃): δ 7.14 (t, 7 = 7.6 Hz, 1H), ), 6.77 (dd, J = 7.6, 0.5 Hz, 1H), 6.60 (d, J = 7.6 Hz, lH), 6.00 (bs, 1H), 4.73 (bs, 1H), 3.98 (m, 1H), 3.55 (dd, J = 9.3, 1.6 Hz, 1H), 3.41-3.29 (m, 4H), 3.09 (m, 1H), 2.98 (d, J = 4.9 Hz, 3H), 2.70 (m, 1H), 2.27 (m, 1H), 1.44 (s, 9H). LCMS (ESI⁺): m/z 402.4 [M + H]⁺.

Step C: Preparation of an enantiomer of N-methyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7- hexahydro-[l>4]diazepino[6,7,l-/H]indole-8-carboxamide

To the previously obtained enantiomer of tert-butyl (2-(4-(methylcarbamoyl)-3-(2,2,2- trifluoroethyl)indolin-l-yl)ethyl)carbamate (crop 1 from above, 1.15 g, 2.87 mmol) was added TFA (1.76 ml, 22.9 mmol) dropwise over 1 min. The mixture was stirred for 2h at which time the mixture was diluted with MeOH (15 mL) and formaldehyde (37% in water, 0.644 ml, 8.59 mmol) was added. The mixture was heated to 65 °C in a sealed tube overnight at which time the reaction was cooled to rt and concentrated in vacuo. The material was stirred in AN HCl/dioxane (5 mL) at rt for 45 min and concentrated in vacuo. The material was dissolved in a small amount of MeOH (-2.5 mL) and MTBE (approx.. 10 mL) was added. A solid slowly precipitated out. After standing for 15 min the mixture was filtered and the filter cake was washed w/MTBE to give the desired product (crop 1, 343 mg) as a white solid. The filtrates were concentrated and the procedure above was repeated to give additional desired product (crop 2, 131 mg) as a white solid. The filtrates were concentrated to 473 mg of a brown solid. This material is approx. 70 wt. % desired product by ¾ NMR and LC/MS analysis. In total, the title enantiomer of iV-methyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- hi]indole-8-carboxamide.2HCl (804 mg, 2.082 mmol, 73% yield) was obtained. The following batches/materials were analyzed by analytical chiral HPLC:

Initial reaction mixture concentrate (pre-crystallization): >92% ee

Cropl : >98% ee

Crop2: >98% ee

Filtrates: >91 % ee HPLC conditions: Chiralpak IC column (4.6 mm X 250 mm). Conditions: Isocratic 8% EtOH in hexanes (containing 0.1 % Et3N) @ lmL/min monitored at 254 nm. Enantiomer 1 had a retention time (rt) of ~ 17.6 min, Enantiomer 2 had a retention time ~ 20.4 min. The desired product is the slower eluting second isomer (Enantiomer 2).

¾ NMR (400 MHz, *-DMSO): δ 9.75 (bs, 1H), 9.38 (bs, 1H), 8.39 (q, J = 4.6 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.35 (d, J = 14.4 Hz, 1H), 4.10 (dd, J = 14.4, 6.8 Hz, 1H), 3.96 (m, 1H), 3.53-3.44 (m, 2H), 3.34-3.21 (m, 2H), 3.08 (m, 1H), 2.75 (d, J = 4.6 Hz, 3H), 2.61 (m, 1H), 2.32 (m, 1H). LCMS (ESI⁺): m/z 314.4 [M + H]⁺. Optical rotation: [a]22D: -30° (c 2.0, MeOH).

Example 1C: Syntheses of Compounds of Formula XXI

Illustrated syntheses for compounds of Formula XXI are shown in Figure 26 wherein the variables (e.g., R¹, R², etc.) have the same definitions as used throughout this disclosure.

Example 1C.1: Preparation of 8-bromo-l,2,3,4,6,7-hexahydro-[l>4]diazepino[6,7,l-/H-]indole (Compound 202).

Step A: Preparation of 2-(4-bromoindolin-l-yl)ethanamine.

A mixture of 4-bromoindoline (0.8 g, 4.039 mmol) and 2-bromoethanamine hydrobromide (0.869 g, 4.241 mmol) was heated at 122 °C for 24 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (0.81 g). LCMS m/z = 241.0 [M+H]⁺.

Step B: Preparation of 8-bromo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M-]indole.

To a solution of a TFA salt of 2-(4-bromoindolin-l-yl)ethanamine (0.400 g, 0.853 mmol) and paraformaldehyde (38.40 mg, 1.279 mmol) in MeOH (18 mL) was added TFA (78.34 yL, 1.023 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC and treated with 2M HC1 to give the HC1 salt of the title compound (0.295 g). LCMS m/z = 253.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.05 (t, J = 1.4 Hz, 2H), 3.26- 3.30 (m, 2H), 3.49-3.58 (m, 4H), 4.25 (s, 2H), 6.95(s, 2H).

Example 1C.2: Preparation of 8-chloro-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 203).

Step A: Preparation of 2-(4-chloroindolin-l-yl)acetonitrile.

To a mixture of 4-chloroindoline (3 g, 19.53 mmol) in H₂0 (3 mL) was added 2- hydroxyacetonitrile (1.988 mL, 20.51 mmol). The reaction was heated at 105 °C for 15 h. The mixture was diluted with EtOAc. The organics were washed with H₂0, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (3.3 g). LCMS m/z = 192.8 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.02 (t, J = 8.2 Hz, 2H), 3.46 (t, J = 8.2 Hz, 2H), 4.28 (s, 2H), 6.60 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.0Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H).

Step B: Preparation of 2-(4-chloroindolin-l-yl)ethanamine. To a stirring solution of cobalt chloride (hexahydrate) (0.124 g, 0.519 mmol) in EtOH (1 mL) was added a solution of sodium borohydride (39.28 mg, 1.038 mmol) in EtOH (1 mL) over 2 minutes under N₂. After 15 min, a solution of 2-(4-chloroindolin-l-yl)acetonitrile (0.5 g, 2.595 mmol) in EtOH (18 mL) was added through a syringe. The reaction was stirred at 23 °C for 15 min and added (BOC)₂0 (0.595 g, 2.725 mmol) followed by sodium borohydride (0.295 g, 7.786 mmol). The reaction was stirred at 23 °C for 1.5 h before it was worked up with 1M Sodium Hydroxide (2.855 mL, 2.855 mmol). The mixture was filtered. The filtrate was concentrated. The residue was extracted with

DCM/H₂0. The organic extract was dried over Na₂S0₄, filtered and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl (2-(4-chloroindolin-l- yl)ethyl)carbamate as an oil. LCMS m/z = 297.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.44 (s, 9H), 3.03 (t, J = 8.4 Hz, 2H), 3.19 (t, J = 6.1 Hz, 2H), 3.29-3.39 (m, 2H), 3.44 (t, J = 8.5 Hz, 2H), 6.34 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H).

The above oil was treated with 4M HC1 in dioxane (5 mL) at 23 °C for 1 h. The mixture was concentrated to give the title compound (0.406 g). LCMS m/z = 197.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.09 (t, J = 8.3 Hz, 2H), 3.32 (t, J = 6.1 Hz, 2H), 3.45 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 8.3 Hz, 2H), 6.63 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H).

Step C: Preparation of 8-chloro-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/M-]indole.

To a solution of 2-(4-chloroindolin-l-yl)ethanamine.2trifluoroacetic acid (0.337 g, 0.793 mmol) and paraformaldehyde (71.47 mg, 2.380 mmol) in MeOH (8 mL) was added TFA (0.182 mL, 2.380 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (0.258 g). LCMS m/z = 209.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.07 (t, J = 8.6 Hz, 2H), 3.22-3.29 (m, 2H), 3.47-3.58 (m, 4H), 4.25 (s, 2H), 6.78 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H). Example 1C.3: Preparation of 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole (Compound 215).

Step A: Preparation of 2-(3,3-dimethylindolin-l-yl)ethanamine.

A mixture of 3,3-dimethylindoline (2.1 g, 14.26 mmol) and 2-bromoethanamine hydrobromide (3.215 g, 15.69 mmol) was heated at 122 °C for 15 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (1.9 g). LCMS m/z = 191.4 [M+H]⁺; H NMR (400 MHz, CD₃OD) δ ppm 1.31 (s, 6H), 3.14 (s, 2H), 3.19 (t, J = 6.1Hz, 2H), 3.33 (t, J = 6.1 Hz, 2H), 6.60 (d, J = 7.9 Hz, 1H), 6.70-6.76 (m, 1H), 7.01-7.09 (m, 2H).

Step B: Preparation of 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole.

To a solution of a TFA salt of 2-(3,3-dimethylindolin-l-yl)ethanamine (1.90 g, 6.244 mmol) and paraformaldehyde (0.562 g, 18.73 mmol) in MeOH (150 mL) was added TFA (1.434 mL, 18.73 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC and treated with 1.25 M HC1 in methanol to give the HC1 salt of the title compound (1.15 g). LCMS m/z = 203.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.30 (s, 6H), 3.19-3.26 (m, 4H), 3.48-3.55 (m, 2H), 4.26 (s, 2H), 6.84 (d, J = 7.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 7.4 Hz, 1H).

Example 1C.4: Preparation of 8-(trifluoromethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- fa^'jindole (Compound 204).

Step A: Preparation of 2-(4-(trifluoromethyl)indolin-l-yl)ethanamine.

The HC1 salt of 4-(trifluoromethyl)indoline (0.3 g, 1.342 mmol) was extracted with DCM and NaOH solution. The obtained free base of 4-(trifluoromethyl)indoline and 2-bromoethanamine hydrobromide (0.289 g, 1.409 mmol) was heated at 122 °C for 15 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (0.534 g). LCMS m/z = 231.2

[M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.15 (t, J = 8.3 Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H), 3.40 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 8.4 Hz, 2H), 6.80 (d, J = 8.0 Hz, 1H), 6.91(d, J = 7.9 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H).

Step B: Preparation of 8-(trifluoromethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

To a solution of the TFA salt of 2-(4-(trifluoromethyl)indolin-l-yl)ethanamine (0.534 g, 1.551 mmol) and paraformaldehyde (0.139 mL, 1.861 mmol) in MeOH (24 mL) was added TFA (0.131 mL, 1.706 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC and treated with HC1 (1.25M in MeOH) to give the HC1 salt of the title compound (0.252 g). LCMS m/z = 243.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.29 (t, J = 8.4 Hz, 2H), 3.34-3.39 (m, 2H), 3.58-3.67 (m, 4H), 4.41 (s, 2H), 7.24-7.31 (m, 2H).

Example 1C.5: Preparation of 8-bromo-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 212).

Step A: Preparation of 2-(4-bromo-3,3-dimethylindolin-l-yl)ethanamine.

From 4-bromo-3,3-dimethylindoline and 2-bromoethanamine hydrobromide, the title compound was obtained using a similar method to the one described in Example 1C.3, Step A. LCMS m/z = 269.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.46 (s, 6H), 3.15-3.21 (m, 4H), 3.36 (t, J = 6.2 Hz, 2H), 6.56 (d, J = 7.9 Hz, 1H), 6.83 (d, J = 7.9Hz, 1H), 6.95 (t, J = 7.9 Hz, 1H).

Step B: Preparation of 8-bromo-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-

&i] indole.

From 2-(4-bromo-3,3-dimethylindolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 281.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.45 (s, 6H), 3.25-3.36 (m, 4H), 3.47-3.52 (m, 2H), 4.25 (s, 2H), 6.90-6.97 (m, 2H).

Example 1C.6: Preparation of 8-fluoro-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H]indole (Compound 219). Step A: Preparation of 4-fluoroindoline.

To a solution of 4-fluoro-lH-indole (1.0 g, 7.400 mmol) and TFA (5.667 mL, 74.00 mmol) in CH₂C1₂ (25 mL) was added triethylsilane (3.546 mL, 22.20 mmol). The reaction was stirred at 23 °C for 15 h before quenched with saturated NaHC0₃. The mixture was extracted with DCM. The organic extract was concentrated. The residue was purified by preparative HPLC to give the title compound (0.15 g). LCMS m/z = 137.8 [M+H]⁺.

Step B: Preparation of 2-(4-fluoroindolin-l-yl)ethanamine.

From the TFA salt of 4-fluoroindoline, the title compound was obtained using a similar method to the one described in Example 1C.4, Step A. LCMS m/z = 181.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.01 (t, J = 8.3 Hz, 2H), 3.19 (t, J = 6.0 Hz, 2H), 3.36 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 8.3 Hz, 2H), 6.37-6.44 (m, 2H), 7.00-7.09 (m, 1H).

Step C: Preparation of 8-fluoro-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H]indole. From the TFA salt of 2-(4-fluoroindolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.4, Step B. LCMS m/z = 193.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.04 (t, J = 8.5 Hz, 2H), 3.22-3.29 (m, 2H), 3.47-3.58 (m, 4H), 4.24 (s, 2H), 6.52 (t, J = 8.4 Hz, 1H), 6.99-7.06 (m, 1H).

Example 1C.7: Preparation of 2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-/M-]indole-7,l'- cyclobutane] (Compound 250).

Step A: Preparation of 2-(spiro[cyclobutane-l,3'-indolin]-l'-yl)ethanamine.

A mixture of spiro[cyclobutane-l,3'-indoline] (0.20 g, 1.256 mmol) and 2-bromoethanamine hydrobromide (0.283 g, 1.382 mmol) was heated at 122 °C for 4 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (0.325 g). LCMS m/z = 203.4

[M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.97-2.09 (m, 2H), 2.20-2.38 (m, 4H), 3.20 (t, J = 6.0 Hz, 2H), 3.28-3.34 (m, 2H), 3.44 (s, 2H), 6.58 (d, J = 7.9 Hz, 1H), 6.78 (dt, J₁ = 0.9 Hz, J₂ = 7.4 Hz, 1H), 7.06 (dt, Jj = 1.2 Hz, J₂ = 7.7 Hz, 1H), 7.30 (dt, J_{1 =} 0.9 Hz, J₂ = 7.4 Hz, 1H).

Step B: Preparation of 2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-/H-]indole-7,l'- cyclobutane].

To a solution of a TFA salt of 2-(spiro[cyclobutane-l,3'-indolin]-r-yl)ethanamine (210 mg, 0.664 mmol) and paraformaldehyde (59.80 mg, 1.992 mmol) in MeOH (14 mL) was added TFA (0.153 mL, 1.992 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (0.105 g). LCMS m/z = 215.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.97-2.10 (m, 2H), 2.19-2.38 (m, 4H), 3.15-3.23 (m, 2H), 3.46- 3.52 (m, 2H), 3.53 (s, 2H), 4.25 (s, 2H), 6.90 (t, J = 7.5 Hz, 1H), 7.04 (dd, J_: = 1.1 Hz, J₂ = 7.6 Hz, 1H), 7.38 (dd, J_{1 =} 1.1 Hz, J₂ = 7.4 Hz, 1H).

Example 1C.8: Preparation of 8-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 207). In a microwave reaction vial was placed a TFA salt of 8-bromo- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7,l- i;^']indole (10.0 mg, 27.24 μιηοΐ), methylboronic acid (1.793 mg, 29.96 μιηοΐ), bis(di-t-butyl-p-dimethylaminophenylphosphino)palladium chloride (386.8 μg, 0.545 μιηοΐ), and sodium carbonate (10.10 mg, 95.33 μιηοΐ) in dioxane (0.20 mL) and H₂0 (0.04 mL). The reaction was heated at 130 °C for 3 h under microwave irradiation. The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (3.3 mg). LCMS m/z = 189.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.22 (s, 3H), 2.97 (t, J = 8.5 Hz, 2H), 3.18-3.23 (m, 2H), 3.44-3.51 (m, 4H), 4.21 (s, 2H), 6.64 (d, J = 7.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H). Example 1C.9: Preparation of 8-chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- &i]indole (Compound 217).

Step A: Preparation of 2-(4-chloro-3,3-dimethylindolin-l-yl)ethanamine.

From 4-chloro-3,3-dimethylindoline and 2-bromoethanamine hydrobromide, the title compound was obtained using a similar method to the one described in Example 1C.3, Step A. LCMS m/z = 225.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.46 (s, 6H), 3.15-3.22 (m, 4H), 3.36 (t, J = 6.2 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H).

Step B: Preparation of 8-chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i] indole.

From a TFA salt of 2-(4-chloro-3,3-dimethylindolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step

B. LCMS m/z = 237.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.45 (s, 6H), 3.25-3.30 (m, 4H), 3.47-3.53 (m, 2H), 4.26 (s, 2H), 6.76 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H).

Example 1C.10: Preparation of 8-phenyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 205).

In a microwave reaction vial was placed a TFA salt of 8-chloro-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l- i;^']indole (20.0 mg, 61.98 μιηοΐ), phenylboronic acid (8.312 mg, 68.17 μιηοΐ), bis(di-t-butyl-p-dimethylaminophenylphosphino)palladium chloride (880.2 μg, 1.2 μιηοΐ), and sodium carbonate (19.71 mg, 0.186 mmol) in dioxane (0.40 mL) and H₂0 (0.08 mL). The reaction was heated at 130 °C for 2 h under microwave irradiation. The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (12.5 mg). LCMS m/z = 251.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.08 (t, J = 8.4 Hz, 2H), 3.23-3.28 (m, 2H), 3.45 (t, J = 8.4 Hz, 2H), 3.51-3.56 (m, 2H), 4.31 (s, 2H), 6.86 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.30-7.38 (m, 1H), 7.38-7.46 (m, 4H).

Example 1C.11: Preparation of 8-ethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole (Compound 206). From a TFA salt of 8-bromo-l,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;]indole and ethylboronic acid, the title compound was obtained using a similar method to the one described in Example 1C.8. LCMS m/z = 203.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.17 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.00 (t, J = 8.5 Hz, 2H), 3.17-3.24 (m, 2H), 3.42 -3.53 (m, 4H), 4.22 (s, 2H), 6.67 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H).

Example 1C.12: Preparation of 8-benzyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 209).

To a TFA salt of 8-bromo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole (25 mg, 51.96 μιηοΐ) and dihydrogen di-μ-chlorodichlorobis(di-tert-butylphosphinito-κP)dipalladate (2-) (POPd2) (1.420 mg, 2.1 μιηοΐ) was added 0.5 M benzylzinc(II) chloride (0.416 mL, 0.208 mmol) in THF. The reaction was heated at 85 °C for 15 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (12.5 mg). LCMS m/z = 265.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.90 (t, J = 8.5 Hz, 2H), 3.17-3.23 (m, 2H), 3.43 (t, J = 8.5 Hz, 2H), 3.46 -3.51 (m, 2H), 3.90 (s, 2H), 4.23 (s, 2H), 6.66 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.10-7.19 (m, 3H), 7.20-7.27 (m, 2H).

Example 1C.13: Preparation of 8-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 211).

From a TFA salt of 8-bromo-l,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;]indole and propylzinc(II) bromide, the title compound was obtained using a similar method to the one described in Example 1C.12. LCMS m/z = 217.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.94 (t, J = 7.4 Hz, 3H), 1.53-1.66 (m, 2H), 2.53 (t, J = 7.6 Hz, 2H), 2.99 (t, J = 8.4 Hz, 2H), 3.17-3.24 (m, 2H), 3.42 -3.53 (m, 4H), 4.22 (s, 2H), 6.65 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H).

Example 1C.14: Preparation of 8-phenethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 210).

From a TFA salt of 8-bromo-l,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole and phenethylzinc(II) bromide, the title compound was obtained using a similar method to the one described in Example 1C.12. LCMS m/z = 279.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.78 (t, J = 8.4 Hz, 2H), 2.81-2.90 (m, 4H), 3.15-3.20 (m, 2H), 3.36 (t, J = 8.5 Hz, 2H), 3.44 -3.51 (m, 2H), 4.22 (s, 2H), 6.66 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 7.06-7.13 (m, 2H), 7.13-7.17 (m, 1H), 7.17-7.24 (m, 2H).

Example 1C.15: Preparation of 8-isobutyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 213).

From a TFA salt of 8-bromo-l,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;]indole and isobutylzinc(II) bromide, the title compound was obtained using a similar method to the one described in Example 1C.12. LCMS m/z = 231.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.90 (d, J = 6.6 Hz, 6H), 1.80-1.95 (m, 1H), 2.43 (d, J = 7.2 Hz, 2H), 2.99 (t, J = 8.4 Hz, 2H), 3.18-3.24 (m, 2H), 3.41 - 3.53 (m, 4H), 4.23 (s, 2H), 6.63 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H). Example 1C.16: Preparation of 7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 218) and of the corresponding (R) and (S) enantiomers.

Step A: Preparation of N,N-dimethyl-l-(4-methyl-lH-indol-3-yl)methanamine.

To a solution of 2 M dimethylamine in MeOH (3.812 mL, 7.623 mmol) in methanol were added acetic acid (4 mL) followed by adding 37% aqueous formaldehyde (0.571 mL, 7.623 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 45 min. The mixture was added THF (2.5 mL) and a solution of 4-methyl-lH-indole (1.0 g, 7.623 mmol) in MeOH (4 mL) dropwise. The reaction was allowed to warm to room temperature while stirring overnight, the reaction was diluted with EtOAc and made basic with IN NaOH. The organic layer was separated and concentrated. The residue was purified by preparative HPLC to give the title compound (0.52 g). LCMS m/z = 189.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.67 (s, 3H), 2.85 (s, 6H), 4.56 (s, 2H), 6.85-6.89 (m, 1H), 7.06 (t, J = 8.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.50 (s, 1H).

Step B: Preparation of 3,4-dimethylindoline.

A solution of A^?,/V-dimethyl-l-(4-methyl- lH-indol-3-yl)methanamine (0.235 g, 1.248 mmol) in MeOH (5 mL) was added 10% palladium on carbon (0.133 g, 0.125 mmol) followed by 4 drops of hydrogen chloride (12.30 μΐ_^, 0.125 mmol). The reaction was stirred under 70 psi of H2 at 23 °C for 24 h. The mixture was filtered. The filtrate was concentrated. The residue was purified by preparative HPLC to give the title compound (0.210 g). LCMS m/z = 148.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.36 (d, J = 7.0 Hz, 3H), 2.40 (s, 3H), 3.52 (dd, Jl=2.7 Hz, J2=11.4Hz, 1H), 3.66-3.77 (m, 1H), 3.88(dd, Jl=8.0 Hz, J2=l 1.4 Hz, 1H), 7.21-7.36 (m, 3H).

Step C: Preparation of 2-(3,4-dimethylindolin-l-yl)ethanamine.

A mixture of a TFA salt of 3,4-dimethylindoline (0.120 g, 0.459 mmol) in DCM (5 mL) was washed with 1 M NaOH (3 mL). The organic layer was washed with H₂0, dried and concentrated. The oil residue was mixed with 2-bromoethanamine hydrobromide (0.104 g, 0.505 mmol) and heated at 122 °C for 2.5 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (0.071 g). LCMS m/z = 191.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.25 (d, J = 6.7 Hz, 3H), 2.24 (s, 3H), 3.07-3.23 (m, 4H), 3.26-3.39 (m, 2H), 3.43 -3.53 (m, 1H), 6.43 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H).

Step D: Preparation of 7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole. To a solution of a TFA salt of 2-(3,4-dimethylindolin-l-yl)ethanamine.2trifluoroacetic acid (0.070 g, 0.167 mmol) and paraformaldehyde (6.029 mg, 0.201 mmol) in MeOH (7 mL) was added

TFA (15.38 μΐ_^, 0.201 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (0.026 g). LCMS m/z = 203.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.20 (d, J = 7.0 Hz, 3H), 2.27 (s, 3H), 2.98-3.08 (m, 1H), 3.28-3.45 (m, 5H), 3.55 -3.64 (m, 1H), 4.10 (d, J = 14.6 Hz, 1H), 4.33 (d, J = 14.6 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H).

Racemic 7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole was resolved to give two enantiomers by normal phase preparative chiral HPLC under the following conditions:

Column: normal phase semi preparative CHIRALPAK® IC column 250 x 20 mm (L x I.D.) Eluent: 2 % ethanol/hexanes with 0.1 % Et3N

Gradient: Isocratic.

How: 2 mL/min.

Detector: UV 254 nm.

Retention Times: 1st eluting enantiomer: 200 min.; 2nd eluting enantiomer: 220 min.

Example 1C.17: Preparation of 7,7,8-trimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- &i]indole (Compound 222).

From a TFA salt of 8-chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole and methylboronic acid, the title compound was obtained using a similar method to the one described in Example 1C.8. LCMS m/z = 217.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.38 (s, 6H), 2.34 (s, 3H), 3.17-3.22 (m, 4H), 3.45 -3.51 (m, 2H), 4.21 (s, 2H), 6.61 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H).

Example 1C.18: Preparation of 8-ethyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 223).

In a microwave reaction vial was placed tert-butyl 8-bromo-7,7-dimethyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate (25 mg, 50.47 μιηοΐ), ethylboronic acid (7.458 mg, 0.101 mmol), bis(di-t-butyl-p-dimethylaminophenylphosphino)palladium chloride (1.792 mg, 2.5 μιηοΐ), and cesium carbonate (41.11 mg, 0.126 mmol) in dioxane (0.50 mL) and H₂0 (0.10 mL). The reaction was heated at 130 °C for 3 h under microwave irradiation. The mixture was filtered. The filtrate was added 2M HC1 and purified by preparative HPLC to give tert-butyl 8-ethyl-7,7-dimethyl- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. LCMS m/z = 331.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.24 (t, J = 7.5 Hz, 3H), 1.33-1.47 (m, 15H), 2.70 (q, J = 7.5 Hz, 2H), 3.10-3.17 (m, 2H), 3.23 (s, 2H), 3.75 (s, 2H), 4.39 (s, 2H), 6.75 (d, J = 7.4 Hz, 1H), 6.90-7.02 (m, 1H).

The above solid was added 1.25M HC1 (2 mL). The reaction was heated at 60 °C for 2 h. The mixture was concentrated to give the title compound (2.6 mg). LCMS m/z = 231.2 [M+H]⁺.

Example 1C.19: Preparation of 8-cyclopropyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole (Compound 235). To a mixture of tert-butyl 8-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;]indole-2(lH)-carboxylate (20 mg, 52.45 μιηοΐ), cyclopropylboronic acid (6.758 mg, 78.68 μιηοΐ), potassium phosphate (27.83 mg, 0.131 mmol), and palladium (II) acetate (706.5 μg, 3.1 μιηοΐ) in dioxane (0.4 mL) was added S-phos (2.153 mg, 5.2 μιηοΐ). The reaction was stirred at 80 °C for 15 h. The mixture was filtered by a syringe filter. The filtrate was purified by preparative HPLC to give tert- butyl 8-cyclopropyl-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate. LCMS m/z = 343.4 [M+H]⁺;

The above material was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at 55 °C for 6 h. The mixture was concentrated to give the title compound (8.5 mg). LCMS m/z = 243.4 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ ppm 0.73-0.83 (m, 2H), 0.95-1.09 (m, 2H), 1.56 (s, 6H), 2.09-2.19 (m, 1H), 3.50 (s, 2H), 3.51-3.58 (m, 2H), 3.68-3.75 (m, 2H), 4.38 (s, 2H), 6.72 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H).

Example 1C.20: Preparation of 8-cyclopropyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 236).

From tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate and cyclopropylboronic acid, the title compound was obtained using a similar method to the one described in Example 1C.19. LCMS m/z = 215.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.64- 0.77 (m, 2H), 0.94-1.08 (m, 2H), 1.84-1.95 (m, 1H), 3.29 (t, J = 8.3 Hz, 2H), 3.52-3.59 (m, 2H), 3.68- 3.75 (m, 2H), 3.81 (t, J = 8.3 Hz, 2H), 4.39 (s, 2H), 6.68 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H).

Example 1C.21: Preparation of 9-fluoro-8-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 226).

Step A: Preparation of 2-(5-fluoro-4-methylindolin-l-yl)ethanamine.

From 5-fluoro-4-methylindoline and 2-bromoethanamine hydrobromide, the title compound was obtained using a similar method to the one described in Example 1C.3, Step A. LCMS m/z = 195.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.11 (d, J = 1.5 Hz, 3H), 2.92 (t, J = 8.2 Hz, 2H), 3.15-3.22 (m, 2H), 3.23-3.29 (m, 2H), 3.36 (t, J = 8.2 Hz, 2H), 6.37 (dd, J₁₌3.8 Hz, J₂=8.4 Hz, 1H), 6.72 (t, J = 9.3 Hz, 1H).

Step B: Preparation of 9-fluoro-8-methyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-

/wjindole.

From 2-(5-fluoro-4-methylindolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 207.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.14 (d, J = 1.2 Hz, 3H), 2.99 (t, J = 8.5 Hz, 2H), 3.15-3.20 (m, 2H), 3.45-3.53 (m, 4H), 4.20 (s, 2H), 6.77 (d, J = 10.2 Hz, 1H).

Example 1C.22: Preparation of 7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 216). Step A: Preparation of 2-(3-methylindolin-l-yl)ethanamine.

A mixture of hydrochloride salt of 3-methylindoline (0.272 g, 1.603 mmol) in DCM (5 mL) was washed with 1 M NaOH (3 mL). The organic layer was washed with H₂0, dried and concentrated. The oil residue was mixed with 2-bromoethanamine hydrobromide (0.361 g, 1.764 mmol) and heated at 122 °C for 15 h. The mixture was dissolved in 2M HCl and purified by preparative HPLC to give the title compound (130 mg). LCMS m/z = 177.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.77 (t, J = 8.6 Hz, 1H), 3.09-3.24 (m, 3H), 3.24-3.36 (m, 1H), 3.42-3.53 (m, 1H), 3.65 (t, J = 8.4 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.72 (dt, J₁₌0.8 Hz, J₂=7.4 Hz, 1H), 7.02-7.09 (m, 2H).

Step B: Preparation of 7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H]indole. To a solution of a TFA salt of 2-(3-methylindolin-l-yl)ethanamine (0.130 g, 0.322 mmol) and paraformaldehyde (10.70 0.386 mmol) in MeOH (15 mL) was added TFA (29.55 0.386 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (82 mg). LCMS m/z = 189.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (t, J = 6.9 Hz, 3H), 2.94-3.02 (m, 1H), 3.10-3.19 (m, 1H), 3.21-3.38 (m, 2H), 3.42-3.59 (m, 2H), 3.67 (t, J = 9.1 Hz, 1H), 4.20 (d, J = 14.8 Hz, 1H), 4.31 (d, J = 14.8 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H).

Example 1C.23: Preparation of 9-bromo-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 224).

Step A: Preparation of 2,2,2-trifluoro-l-(7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-

¾i]indol-2(lH)-yl)ethanone.

To a solution of a TFA salt of 7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole (52.5 mg, 0.174 mmol) and 2,2,2-trifluoroacetic anhydride (40.12 mg, 0.191 mmol) in CH₂C1₂ (1 mL) was added triethylamine (77.46 μL, 0.556 mmol). The reaction was stirred at 23 °C for 24 h. The reaction was diluted with DCM (50 mL). The mixture was washed with H₂0. The organics were concentrated. The residue was purified by silica gel column chromatography to give the title compound (28 mg). LCMS m/z = 285.2 [M+H]⁺.

Step B: Preparation of l-(9-bromo-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- &i]indol-2(lH)-yl)-2,2,2-trifluoroethanone.

To a solution of 2,2,2-trifluoro-l-(7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indol-

2(lH)-yl)ethanone (10 mg, 35.18 μιηοΐ) in MeCN (0.5 mL) was added NBS (6.574 mg, 36.94 μιηοΐ). The reaction was stirred at 65 °C for 15 h. The mixture was concentrated. The residue was dissolved in DCM and washed with 1 M HCl and NaHC03. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (10 mg). LCMS m/z = 363.0 [M+H]⁺.

Step C: Preparation of 9-bromo-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole. To a solution of l-(9-bromo-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indol-2(lH)- yl)-2,2,2-trifluoroethanone (10 mg, 27.54 μιηοΐ) in H₂0 (0.02 mL) was added 7M ammonia (0.393 mL, 2.754 mmol) in MeOH. The reaction was stirred at 23 °C for 18 h. The mixture was concentrated. The residue was purified HPLC to give the title compound (3.3 mg). LCMS m/z = 267.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (t, J = 6.8 Hz, 3H), 2.98-3.05 (m, 1H), 3.11-3.20 (m, 1H), 3.22-3.40 (m, 2H), 3.42-3.58 (m, 2H), 3.69 (t, J = 9.1 Hz, 1H), 4.20 (d, J = 15.0 Hz, 1H), 4.30 (d, J = 15.0 Hz, 1H), 7.19-7.22 (m 1H), 7.24-7.27 (m, 1H).

Example 1C.24: Preparation of 9-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 225).

Step A: Preparation of l-(9-chloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- &i]indol-2(lH)-yl)-2,2,2-trifluoroethanone.

To a solution of 2,2,2-trifluoro-l-(7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indol- 2(lH)-yl)ethanone (18 mg, 63.32 μιηοΐ) in MeCN (1 mL) was added NCS (8.878 mg, 66.48 μιηοΐ). The reaction was stirred at 65 °C for 15 h. The mixture was concentrated. The residue was dissolved in

DCM and washed with 1 M HC1 and NaHC0₃. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (12 mg). LCMS m/z = 319.2 [M+H]⁺.

Step B: Preparation of 9-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

To a solution of l-(9-chloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indol-2(lH)- yl)-2,2,2-trifluoroethanone (12 mg, 37.65 μιηοΐ) in H20 (0.02 mL) was added 7M ammonia (0.538 mL, 3.765 mmol) in MeOH. The reaction was stirred at 23 °C for 18 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (3.1 mg). LCMS m/z = 223.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (t, J = 6.8 Hz, 3H), 2.99-3.05 (m, 1H), 3.11-3.20 (m, 1H), 3.22-3.39 (m, 2H), 3.43-3.58 (m, 2H), 3.70 (t, J = 9.1 Hz, 1H), 4.20 (d, J = 15.0 Hz, 1H), 4.30 (d, J = 15.0 Hz, 1H), 7.05-7.09 (m, 1H), 7.11-7.15 (m, 1H).

Example 1C.25: Preparation of 9-bromo-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 227).

Step A: Preparation of l-(7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-/H-]indol- 2(lH)-yl)-2,2,2-trifluoroethanone.

To a solution of a TFA salt of 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-i;^']indole (19.3 mg, 61.01 μιηοΐ) and 2,2,2-trifluoroacetic anhydride (15.38 mg, 73.22 μιηοΐ) in CH₂C1₂ (0.3 mL) was added triethylamine (27.21 μL, 0.195 mmol). The reaction was stirred at 23 °C for 24 h. The reaction was diluted with DCM (50 mL). The mixture was washed with H₂0. The organics were concentrated. The residue was purified by silica gel column chromatography to give the title compound (14.5 mg). LCMS m/z = 299.4 [M+H]⁺. Step B: Preparation of l-(9-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l_>4]diazepino[6,7,l- &i]indol-2(lH)-yl)-2,2,2-trifluoroethanone.

To a solution of l-(7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-/iz]indol-2(lH)-yl)- 2,2,2-trifluoroethanone (6.2 mg, 20.78 μιηοΐ) in MeCN (0.5 mL) was added NBS (3.884 mg, 21.82 μιηοΐ). The reaction was stirred at 65 °C for 15 h. The mixture was concentrated. The residue was dissolved in DCM and washed with 1 M HC1 and NaHC0₃. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (5.1 mg). LCMS m/z = 377.2 [M+H]⁺.

Step C: Preparation of 9-bromo-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

To a solution of l-(9-bromo-7,7-dimethyl-3, 4,6,7 -tetrahydro-[l,4]diazepino[6,7,l- i;^']indol- 2(lH)-yl)-2,2,2-trifluoroethanone (5 mg, 13.26 μιηοΐ) in H₂0 (0.01 mL) was added 7M ammonia (0.189 mL, 1.326 mmol) in MeOH. The reaction was stirred at 23 °C for 18 h. The mixture was concentrated. The residue was purified HPLC to give the title compound (4.3 mg). LCMS m/z = 281.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (s, 6H), 3.20-3.25 (m, 2H), 3.27 (s, 2H), 3.49-3.54 (m, 2H), 4.26 (s, 2H), 7.20-7.23 (m, 2H).

Example 1C.26: Preparation of 9-chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 228).

Step A: Preparation of l-(9-chloro-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-

¾i]indol-2(lH)-yl)-2,2,2-trifluoroethanone.

To a solution of l-(7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indol-2(lH)-yl)- 2,2,2-trifluoroethanone (8.3 mg, 27.82 μιηοΐ) in MeCN (0.5 mL) was added NCS. The reaction was stirred at 65 °C for 15 h. The mixture was concentrated. The residue was dissolved in DCM and washed with 1 M HC1 and NaHC0₃. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (5.0 mg). LCMS m/z = 333.6 [M+H]⁺.

Step B: Preparation of 9-chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- &i]indole.

To a solution of l-(9-chloro-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indol- 2(lH)-yl)-2,2,2-trifluoroethanone (5 mg, 15.03 μιηοΐ) in H₂0 (0.01 mL) was added 7M ammonia (0.215 mL, 1.503 mmol) in MeOH. The reaction was stirred at 23 °C for 18 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (3.8 mg). LCMS m/z = 237.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (s, 6H), 3.20-3.25 (m, 2H), 3.27 (s, 2H), 3.49-3.54 (m, 2H), 4.26 (s, 2H), 7.06-7.11 (m, 2H).

Example 1C.27: Preparation of 8-fluoro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 237).

Step A: Preparation of 2-(4-fluoro-3,3-dimethylindolin-l-yl)ethanamine. From 4-fluoro-3,3-dimethylindoline and 2-bromoethanamine hydrobromide, the title compound was obtained using a similar method to the one described in Example 1C.3, Step A. LCMS m/z = 209.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.42 (s, 6H), 3.14-3.22 (m, 4H), 3.37 (t, J = 6.2 Hz, 2H), 6.35-6.43 (m, 2H), 7.01-7.09 (m, 1H).

Step B: Preparation of 8-fluoro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-

&i] indole.

From 2-(4-fluoro-3,3-dimethylindolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 221.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.42 (s, 6H), 3.23-3.28 (m, 2H), 3.29 (s, 2H), 3.48-3.53 (m, 2H), 4.25 (s, 2H), 6.48-6.55 (m, 1H), 7.01-7.07 (m, 1H).

Example 1C.28: Preparation of 7,7,9-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 254).

Step A: Preparation of tert-butyl 7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- &i]indole-2(lH)-carboxylate.

To a solution of 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-i;]indole.trifluoroacetic acid (1.02 g, 3.225 mmol), Triethylamine (1.798 mL, 12.90 mmol) in CH₂C1₂ (15 mL) was added a solution di-tert-butyl dicarbonate (0.739 g, 3.386 mmol) in CH₂C1₂ (15 mL). The reaction was stirred at 23 °C for 2 h. The mixture was extracted with H₂0. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (736 mg). LCMS m/z = 303.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.29 (s, 6H), 1.41 (s, 9H), 3.00 (bs, 2H), 4.37 (s, 1H), 4.44 (bs, 2H), 6.74 (t, J = 7.4 Hz, 1H), 6.84-7.04 (m, 2H).

Step B: Preparation of tert-butyl 9-bromo-7,7-dimethyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/»]indole-2(lH)-carboxylate.

To a solution of tert-butyl 7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-

2(lH)-carboxylate (200 mg, 0.661 mmol) in MeCN (10 ml) was added NBS (0.124 g, 0.694 mmol). The reaction was stirred at 65 °C for 15 h. The mixture was concentrated. The residue was dissolved in DCM and washed with 1 M HC1 and NaHC0₃. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compounds (209 mg). LCMS m/z = 381.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.27 (s, 6H), 1.35-1.48 (m, 9H), 2.97-3.04 (m, 2H), 3.16 (s, 2H), 3.65-3.75 (m, 2H), 4.34 (s, 2H), 6.97-7.09 (m, 2H).

Step C: Preparation of 7,7,9-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i] indole.

To a mixture of tert-butyl 9-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;^']indole-2(lH)-carboxylate (20 mg, 52.45 μιηοΐ), methylboronic acid (4.710 mg, 78.68 μιηοΐ), potassium phosphate (27.83 mg, 0.131 mmol), and palladium (II) acetate (706.5 μg, 3.1 μιηοΐ) in dioxane (0.5 mL) was added S-phos (2.153 mg, 5.2 μιηοΐ). The reaction was stirred at 80 °C for 15 h. The mixture was filtered through a syringe filter. The filtrate was purified by preparative HPLC to give tert-butyl 7 ,9-trimethyl-3,4,6 -tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate. The above material was treated with 1.25 M HCl in methanol (2 mL) at 50 °C for 1 h. The mixture was concentrated to give the title compound (6.4 mg). LCMS m/z = 217.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.37 (s, 6H), 2.34 (s, 3H), 3.46-3.54 (m, 4H), 3.69-3.75 (m, 2H), 4.39 (s, 2H), 7.06 (s, 1H), 7.12 (s, 1H).

Example 1C.29: Preparation of 9-cyclopropyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole (Compound 255).

To a mixture of tert-butyl 9-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;^']indole-2(lH)-carboxylate (20 mg, 52.45 μιηοΐ), cyclopropylboronic acid (6.758 mg, 78.68 μιηοΐ), potassium phosphate (27.83 mg, 0.131 mmol), and palladium (II) acetate (706.5 μg, 3.1 μιηοΐ) in dioxane (0.5 mL) was added S-phos (2.153 mg, 5.2 μιηοΐ). The reaction was stirred at 80 °C for 15 h. The mixture was filtered through a syringe filter. The filtrate was purified by preparative HPLC to give tert-butyl 9-cyclopropyl-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-2(lH)- carboxylate. The above material was treated with 1.25 M HCl in methanol (2 mL) at 50 °C for 1 h. The mixture was concentrated to give the title compound (9.0 mg). LCMS m/z = 243.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.62-0.76 (m, 2H), 0.91-1.05 (m, 2H), 1.38 (s, 6H), 1.90-2.00 (m, 1H), 3.49-3.57 (m, 4H), 3.70-3.78 (m, 2H), 4.41 (s, 2H), 6.98 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H). Example 1C.30: Preparation of 2,2',3,3',4,5',6,6'-octahydro-lH-spiro[[l,4]diazepino[6,7,l- /w]indole-7,4'-pyran] (Compound 230).

Step A: Preparation of 2-(2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-l- yl)ethanamine.

From 2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]and 2-bromoethanamine hydrobromide, the title compound was obtained using a similar method to the one described in Example 1C.3, Step A. LCMS m/z = 233.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.62-1.71 (m, 2H), 1.90-2.02 (m, 2H), 3.22 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 6.1 Hz, 2H), 3.41 (s, 2H), 3.58-3.68 (m, 2H), 3.90-3.98 (m, 2H), 6.59-6.65 (m, 1H), 6.72-6.80 (m, 1H), 7.05-7.13 (m, 2H).

Step B: Preparation of 2,2',3,3',4,5',6,6'-octahydro-lH-spiro[[l,4]diazepino[6,7,l- /w]indole-7,4'-pyran].

From 2-(2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 245.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.57-1.67 (m, 2H), 1.90-2.02 (m, 2H), 3.24-3.29 (m, 2H), 3.48-3.55 (m, 4H), 3.57-3.67 (m, 2H), 3.89-3.97 (m, 2H), 4.27 (s, 2H), 6.87 (t, J = 7.5 Hz, 1H), 7.03-7.09 (m, 1H), 7.14-7.20 (m, 1H). Example 1C.31: Preparation of (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)methanamine (Compound 233).

Step A: Preparation of methyl l-(2-aminoethyl)indoline-4-carboxylate.

A mixture of Methyl indoline-4-carboxylate (2.1 g, 11.85 mmol) and the HBr salt of 2- bromoethanamine (2.550 g, 12.44 mmol) was heated at 122 °C for 15 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (2.3 g). LCMS m/z = 221.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.21 (t, J = 6.6 Hz, 2H), 3.28-3.34 (m, 2H), 3.35-3.45 (m, 4H), 3.85 (s, 3H), 6.78 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 7.29 (dd, Jj = 8.0 Hz, J₂ = 0.9 Hz, 1H).

Step B: Preparation of methyl l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/M-]indole-8- carboxylate.

To a solution of the TFA salt of methyl l-(2-aminoethyl)indoline-4-carboxylate (2.3 g, 6.880 mmol) and paraformaldehyde (0.248 g, 8.256 mmol) in MeOH (100 mL) was added TFA (0.632 mL, 8.256 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (1.37 g). LCMS m/z = 233.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.26-3.30 (m, 2H), 3.34-3.40 (m, 2H), 3.50-3.56 (m, 4H), 3.88 (s, 3H), 4.32 (s, 2H), 7.12 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H).

Step C: Preparation of 2-tert-butyl 8-methyl 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- /»]indole-2,8(lH)-dicarboxylate.

To a solution of the TFA salt of methyl l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole-

8-carboxylate (1.368 g, 3.950 mmol), triethylamine (2.202 mL, 15.80 mmol) in CH₂C1₂ (20 mL) was added a solution of di-tert-butyl dicarbonate (0.862 g, 3.950 mmol) in CH2C12 (20 mL). The reaction was stirred at 23 °C for 2 h. The mixture was extracted with H20. The organic extract was

concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.26 g). LCMS m/z = 333.4 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.40 (s, 9H), 3.05 (s, 2H), 3.32-3.47 (m, 4H), 3.67-3.74 (m, 2H), 3.78 (s, 3H), 4.32-4.47 (m, 2H), 6.89-7.09 (m, 1H), 7.36 (d, J = 7.9 Hz, 1H).

Step D: Preparation of 2-(tert-butoxycarbonyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-¾i]indole-8-carboxylic acid.

To a solution of 2-tert-butyl 8-methyl 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-

2,8(lH)-dicarboxylate (1.26 g, 3.791 mmol) in MeOH (6 mL) was added 5M sodium hydroxide (1.516 mL, 7.581 mmol). The reaction was stirred at 65 °C for 3 h. The mixture was concentrated. The residue was added 4M hydrogen chloride (1.801 mL, 7.202 mmol). The reaction was stirred for 10 min. The mixture was concentrated to give the title compound (1.29 g). LCMS m/z = 319.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.38 (s, 3H), 1.43 (s, 6H), 3.02-3.07 (m, 2H), 3.24-3.42 (m, 4H), 3.66-3.76 (m, 2H), 4.40 (s, 2H), 6.89-7.00 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H).

Step E: Preparation of l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole-8- carboxamide To a solution of 2-(tert-butoxycarbonyl)-l,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;]indole- 8-carboxylic acid (40 mg, 0.095 mmol), ammonia (0.136 ml, 0.955 mmol), and Triethylamine (53.24 μΐ, 0.382 mmol) in DMF (0.8 ml) was added HATU (54.46 mg, 0.143 mmol). The reaction was stirred at 23 °C for 15 hr. The mixture was purified by preparative HPLC to give tert-butyl 8-carbamoyl- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. LCMS m/z = 318.0 [M+H]⁺.

The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (11 mg). LCMS m/z = 218.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.24-3.31 (m, 4H), 3.48-3.56 (m, 4H), 4.32 (s, 2H), 7.12 (s, 2H).

Step F: Preparation of (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)methanamine

To a solution of a TFA salt of 1,2, 3,4,6,7 -hexahydro-[l,4]diazepino[6,7,l- i;]indole-8- carboxamide (20 mg, 44.91 μιηοΐ) in THF (2.5 mL) was added Borane-THF (0.225 mL, 0.449 mmol). The reaction was refluxed at 100 °C for 1 h. The mixture was cooled to room temperature and added methanol (0.273 mL, 6.737 mmol) dropwise. The reaction was refluxed for another 30 min. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (1.1 mg). LCMS m/z = 204.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.13 (t, J = 8.5 Hz, 2H), 3.25-3.30 (m, 2H), 3.50-3.59 (m, 4H), 4.07 (s, 2H), 4.29 (s, 2H), 6.89 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H).

Example 1C.32: Preparation of 8-(piperidin-l-ylmethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole (Compound 234).

From of (1,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;^']indol-8-yl)(piperidin-l-yl)methanone and Borane-THF, the title compound was obtained using a similar method to the one described in Example 1C.31. LCMS m/z = 272.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.46-1.63 (m, 1H), 1.66-2.01 (m, 5H), 2.96-3.09 (m, 2H), 3.11-3.21 (m, 2H), 3.27-3.30 (m, 2H), 3.46-3.60 (m, 6H), 4.24 (s, 2H), 4.30 (s, 2H), 6.98 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H). Example 1C.33: Preparation of 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol- 8-amine (242).

A mixture of acetamide (3.904 mg, 66.09 μιηοΐ), palladium (II) acetate (618.2 μg, 2.8 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.549 mg, 4.4 μιηοΐ) and cesium carbonate (26.92 mg, 82.61 μιηοΐ) was degassed and purged with nitrogen twice. Dry dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;]indole-2(lH)-carboxylate (21 mg, 55.07 μιηοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8-acetamido-7,7-dimemyl-3,4,6,7-tetrahydro-[l,4]diazepm^ as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at 55 °C for 6 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (1.8 mg). LCMS m/z = 218.2 [M+H]⁺.

Example 1C.34: Preparation of ethyl (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)carbamate (Compound 243).

Step A: Preparation of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- /w]indole-2(lH)-carboxylate.

To a solution of a TFA salt of 8-bromo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole

(772 mg, 1.604 mmol), triethylamine (0.894 ml, 6.417 mmol) in CH₂C1₂ (10 ml) was added a solution di-tert-butyl dicarbonate (0.525 g, 2.407 mmol) in CH₂C1₂ (10 mL). The reaction was stirred at 23 °C for 2 h. The mixture was extracted with H₂0. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (515 mg). LCMS m/z = 353.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.41 (bs, 9H), 2.96-3.07 (m, 4H), 3.42 (t, J = 8.6 Hz, 2H), 3.64-3.71 (m, 4H), 4.25-4.40 (m, 2H), 6.68-6.88 (m, 2H).

Step B: Preparation of ethyl (l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indol-8- yl)carbamate.

A mixture of ethyl carbamate (5.044 mg, 56.62 μιηοΐ), palladium (II) acetate (635.5 μg, 2.8 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.621 mg, 4.5 μιηοΐ) and cesium carbonate (27.67 mg, 84.92 μιηοΐ) was degassed and purged with nitrogen twice. Dry dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (20 mg, 56.62 μιηοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8-

((ethoxycarbonyl)amino)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate as a white solid. LCMS m/z = 362.4 [M+H]⁺.

The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (3.3 mg). LCMS m/z = 262.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.30 (t, J = 7.1 Hz, 3H), 2.98 (t, J = 8.5 Hz, 2H), 3.18-3.25 (m, 2H), 3.43-3.53 (m, 4H), 4.19 (q, J = 7.1 Hz, 2H), 4.22 (s, 2H), 6.99 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H).

Example 1C.35: Preparation of N-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)butyramide (Compound 244).

A mixture of butyramide (4.932 mg, 56.62 μιηοΐ), palladium (II) acetate (635.5 μg, 2.8 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.621 mg, 4.5 μιηοΐ) and cesium carbonate (27.67 mg, 84.92 μιηοΐ) was degassed and purged with nitrogen twice. Dry dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (20 mg, 56.62 μιηοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8-butyramido- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (2.0 mg). LCMS m/z = 260.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.01 (t, J = 7.4 Hz, 3H), 1.66-1.80 (m, 2H), 2.37 (t, J = 7.4 Hz, 2H), 2.97 (t, J = 8.4 Hz, 2H), 3.19-3.26 (m, 2H), 3.42- 3.54 (m, 4H), 4.25 (s, 2H), 6.92-7.04 (m, 2H).

Example 1C.36: Preparation of 7,7-diethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole (Compound 251).

Step A: Preparation of 2-(3,3-diethylindolin-l-yl)ethanamine.

A mixture of 3,3-diethylindoline (0.10 g, 0.571 mmol) and 2-bromoethanamine hydrobromide

(0.129 g, 0.628 mmol) was heated at 122 °C for 5 h. The mixture was dissolved in 2M HCl and purified by preparative HPLC to give the title compound (65 mg). LCMS m/z = 219.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.82 (t, J = 7.5 Hz, 6H), 1.57-1.80 (m, 4H), 3.14-3.23 (m, 2H), 3.34 (t, J = 6.5 Hz, 2H), 6.58 (d, J = 7.9 Hz, 1H), 6.71 (dt, J₁₌ 1.0 Hz, J₂=7.4 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 7.05 (dt, J₁₌1.3 Hz, J₂=7.6 Hz, 1H).

Step B: Preparation of 7,7-diethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole. From 2-(3,3-diethylindolin-l-yl)ethanamine.trifluoroacetic acid and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 231.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.80 (t, J = 7.5 Hz, 6H), 1.57-1.77 (m, 4H), 3.17-3.24 (m, 2H), 3.31-3.33 (m, 2H), 3.46-3.52 (m, 2H), 4.25 (s, 2H), 6.84 (t, J = 7.5 Hz, 1H), 7.00- 7.08 (m, 2H).

Example 1C.37: Preparation of methyl 3-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)propanoate (Compound 252).

To a mixture of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (20 mg, 56.62 μιηοΐ), potassium (3-ethoxy-3-oxopropyl)trifluoroborate (17.67 mg, 84.92 μιηοΐ), potassium phosphate (30.04 mg, 0.142 mmol), and palladium (II) acetate (762.7 μg, 3.4 μιηοΐ) in dioxane (0.4 mL) was added S-phos (2.324 mg, 5.7 μιηοΐ). The reaction was stirred at 80 °C for 15 h. The mixture was filtered through a syringe filter. The filtrate was purified by preparative HPLC to give tert-butyl 8-(3-ethoxy-3-oxopropyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-2(lH)- carboxylate. LCMS m/z = 375.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.20 (t, J = 7.2 Hz, 3H), 1.33-1.49 (m, 9H), 2.58 (t, J = 7.6 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 3.01 (t, J = 8.4 Hz, 2H), 3.05-3.12 (m, 2H), 3.45 (t, J = 8.2 Hz, 2H), 3.72 (bs, 2H), 4.08 (q, J = 7.1 Hz, 2H), 4.37 (s, 2H), 6.61-6.72 (m, 1H), 6.84-6.97 (m, 1H).

The above material was treated with 1.25 M HC1 in methanol (2 mL) at 50 °C for 15 h. The mixture was concentrated to give the title compound (2.3 mg). LCMS m/z = 261.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.61 (t, J = 7.5 Hz, 2H), 2.87 (t, J = 7.5 Hz, 2H), 3.07 (t, J = 8.2 Hz, 2H), 3.22-3.29 (m, 1H), 3.50-3.60 (m, 4H), 3.62 (s, 3H), 4.27 (s, 2H), 6.75 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H).

Example 1C.38: Preparation of 8-(2-ethoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 253).

To a mixture of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (20 mg, 56.62 μιηοΐ), potassium (2-ethoxyethyl)trifluoroborate (15.29 mg, 84.92 μιηοΐ), potassium phosphate (30.04 mg, 0.142 mmol), and palladium (II) acetate (762.7 μg, 3.4 μιηοΐ) in Dioxane (0.4 mL) was added S-phos (2.324 mg, 5.7 μιηοΐ). The reaction was stirred at 80 °C for 15 h. The mixture was filtered by syringe filter. The filtrate was purified by preparative HPLC to give tert- butyl 8-(2-ethoxyethyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-/i;]indole-2(lH)-carboxylate. LCMS m/z = 347.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.16 (t, J = 7.0 Hz, 3H), 1.33-1.48 (m, 9H), 2.78 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 8.3 Hz, 2H), 3.03-3.08 (m, 2H), 3.41 (t, J = 8.3 Hz, 2H), 3.49 (q, J = 7.0 Hz, 2H), 3.60 (t, J = 7.0 Hz, 2H), 3.71 (bs, 2H), 4.37 (s, 2H), 6.62-6.71 (m, 1H), 6.82-6.94 (m, 1H).

The above material was treated with 1.25 M HC1 in methanol (2 mL) at 50 °C for 1 h. The mixture was concentrated to give the title compound (4.3 mg). LCMS m/z = 247.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.14 (t, J = 7.0 Hz, 3H), 2.82 (t, J = 6.8 Hz, 2H), 3.09 (t, J = 8.4 Hz, 2H), 3.47 (q, J = 7.0 Hz, 2H), 3.52-3.59 (m, 4H), 3.62 (t, J = 6.8 Hz, 2H), 4.27 (s, 2H), 6.80 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H).

Example 1C.39: Preparation of 6,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 258 and Compound 259).

Step A: Preparation of 2-(2,3-dimethylindolin-l-yl)ethanamine.

A mixture of 2,3-dimethylindoline (0.10 g, 0.679 mmol) and 2-bromoethanamine

hydrobromide (0.153 g, 0.747 mmol) was heated at 122 °C for 15 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (128 mg). LCMS m/z = 191.2

[M+H]⁺.

Step B: Preparation of 6,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M-]indole

To a solution of 2-(2,3-dimethylindolin-l-yl)ethanamine.2trifluoroacetic acid (128 mg, 0.306 mmol) and paraformaldehyde (27.56 mg, 0.918 mmol) in MeOH (6 mL) was added TFA (70.29 μL,

0.918 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give two stereoisomers (258 (cis) and 259 (trans) of the title compound. (Isomer 1, 10 mg) LCMS m/z = 203.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.09 (d, J = 7.2 Hz, 3H), 1.30 (d, J = 6.5 Hz, 3H), 2.86-2.96 (m, 1H), 3.32-3.39 (m, 2H), 3.44-3.55 (m, 2H), 3.63- 3.71 (m, 1H), 4.11 (d, J = 4.8 Hz, 1H), 4.41 (d, J = 4.5 Hz, 1H), 3.62 (t, J = 6.8 Hz, 2H), 6.82 (t, J = 7.6 Hz, 1H), 6.98-7.03 (m, 1H), 7.12-7.16 (m, 1H).

(Isomer 2, 9.8 mg) LCMS m/z = 203.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.35 (d, J

= 6.7 Hz, 3H), 1.30 (d, J = 6.1 Hz, 3H), 2.71-2.82 (m, 1H), 2.87-3.01 (m, 1H), 3.32-3.39 (m, 1H), 3.41- 3.48 (m, 1H), 3.63-3.71 (m, 1H), 4.08 (d, J = 4.7 Hz, 1H), 4.45 (d, J = 4.5 Hz, 1H), 6.83 (t, J = 7.5 Hz, 1H), 6.99-7.05 (m, 1H), 7.07-7.13 (m, 1H). Example 1C.40: Preparation of 7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 263).

Step A: Preparation of 2,2,2-trifluoro-l-(lH-indol-3-yl)ethanone

To a solution of lH-indole (0.38 g, 3.244 mmol) in DMF (15 ml) was added TFAA (0.451 ml, 3.244 mmol) at room temperature. The reaction was stirred at 40 °C for 2 hr. The mixture was poured into sodium bicarbonate solution (400 mL). The precipitate was filtered and washed with H20. The solid was dissolved in EtOAc and purified by silica gel column chromatography to give the title compound (650 mg). LCMS m/z = 214.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 7.28-7.37 (m, 2H), 7.49-7.56 (m, 1H), 8.20-8.24 (m, 1H), 8.25-8.29 (m, 1H).

Step B: Preparation of 3-(2,2,2-trifluoroethyl)-lH-indole.

To a solution of 2,2,2-trifluoro-l-(lH-indol-3-yl)ethanone (0.20 g, 0.938 mmol) in THF (1 mL) in an ice-bath was added sodium borohydride (71.00 mg, 1.877 mmol) under N2. Then boron trifluoride diethyl ether (0.357 mL, 2.815 mmol) was added dropwise. The reaction was let stirred for 2 h while warmed to room temperature. The mixture was poured into a mixture of ice-water and 5% aqueous NaHC0₃ and extracted with ethyl acetate. The combined organics were concentrated. The residue was purified by silica gel column chromatography to give the title compound (90 mg). LCMS m/z = 200.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.57 (q, J = 11.1 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.20 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H).

Step C: Preparation of 3-(2,2,2-trifluoroethyl)indoline.

To a solution of 3-(2,2,2-trifluoroethyl)-lH-indole (0.088 g, 0.442 mmol) in TFA (1.015 mL, 13.25 mmol) in an ice -bath was added triethylsilane (0.212 mL, 1.325 mmol) dropwise under N₂. The reaction was stirred at 23 °C for 15 h. The mixture was concentrated. The residue was added water. The pH was adjusted to 8 with 1M aqueous NaOH solution, extracted with ethyl acetate. The combined organics was concentrated. The residue was purified by silica gel column chromatography to give the title compound (40 mg). LCMS m/z = 202.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.27-2.46 (m, 1H), 2.66-2.83 (m, 1H), 3.24 (t, J = 8.6 Hz, 1H), 3.47-3.57 (m, 1H), 3.67 (t, J = 8.6 Hz, 1H), 6.66- 6.75 (m, 2H), 6.99-7.06 (m, 1H), 7.12 (d, J = 7.5 Hz, 1H).

Step D: Preparation of 2-(3-(2,2,2-trifluoroethyl)indolin-l-yl)ethanamine. The HC1 salt of 3-(2,2,2-trifluoroethyl)indoline (0.040 g, 0.199 mmol) was extracted with DCM and NaOH solution. The free base of 4-(trifluoromethyl)indoline and 2-bromoethanamine

hydrobromide (42.77 mg, 0.209 mmol) was heated at 122 °C for 3 h. The mixture was dissolved in 2M HC1 and purified by preparative HPLC to give the title compound (41mg). LCMS m/z = 245.2

[M+H]⁺.

Step E: Preparation of 7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

From 2-(3-(2,2,2-trifluoroethyl)indolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 257.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.33-2.51 (m, 1H), 2.79-2.87 (m, 1H), 3.15- 3.30 (m, 3H), 3.44-3.63 (m, 1H), 3.73 (t, J = 9.3 Hz, 1H), 4.24 (d, J = 14.9 Hz, 1H), 4.35 (d, J = 14.9 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H).

Example 1C.41: Preparation of 8-iodo-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole (Compound 214).

Step A: Preparation of tert-butyl 8-iodo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-/H-]indole- 2(lH)-carboxylate.

To a mixture of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (20 mg, 56.62 μιηοΐ) and sodium 2,2,3,3,3-pentafluoropropanoate (31.59 mg, 0.170 mmol) in DMF (0.25 mL) was added copper (I) iodide (32.35 mg, 0.170 mmol). The reaction was heated under microwave irradiation at 150 °C for 4 h. The mixture was filtered. The filtrate was purified by preparative HPLC to give the title compound. LCMS m/z = 401.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.33-1.50 (m, 9H), 2.92 (t, J = 8.5 Hz, 2H), 3.01-3.08 (m, 2H), 3.40 (t, J = 8.6 Hz, 2H), 3.68 (bs, 2H), 4.33 (s, 2H), 6.59-6.71 (m, 1H), 7.01-7.11 (m, 1H).

Step B: Preparation of 8-iodo-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole

To tert-butyl 8-iodo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate.trifluoroacetic acid (9.1 mg, 17.69 μιηοΐ) was added 4M hydrogen chloride in dioxane (0.442 mL, 1.769 mmol). The reaction was stirred at 23 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound. LCMS m/z = 301.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.99 (t, J = 8.6 Hz, 2H), 3.21-3.26 (m, 2H), 3.46-3.54 (m, 4H), 4.22 (s, 2H), 6.77 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H).

Example 1C.42: Preparation of (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8-yl)methanol (Compound 232).

Step A: Preparation of methyl l-(2-aminoethyl)indoline-4-carboxylate.

From the HC1 salt of methyl indoline-4-carboxylate and 2-bromoethanamine hydrobromide, the title compound was obtained using a similar method to the one described in Example 1C.4, Step A. LCMS m/z = 221.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.22 (t, J = 5.9 Hz, 2H), 3.22-3.47 (m, 6H), 3.86 (s, 3H), 6.79 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.30 (dd, J₁₌0.8 Hz, J₂=7.9 Hz, 1H).

Step B: Preparation of methyl l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole-8- carboxylate

From methyl 1 -(2-aminoethyl)indoline-4-carboxylate and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.4, Step B. LCMS m/z = 233.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.25-3.30 (m, 2H), 3.34 (t, J = 8.3 Hz, 2H), 3.47-3.55 (m, 4H), 3.86 (s, 3H), 4.31 (s, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H).

Step C: Preparation of (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M-]indol-8-yl)methanol To methyl 1,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole-8-carboxylate.2trifluoroacetic acid (178 mg, 0.387 mmol) in THF (1 mL) was added 2M THF solution of lithium aluminum hydride (1.933 mL, 3.867 mmol) under N₂. The reaction was stirred at 23 °C for 2 h. The reaction was worked with 2M HCl solution. The mixture was filtered. The filtrate was purified by preparative HPLC to give the title compound (25 mg). LCMS m/z = 205.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.13 (t, J = 8.4 Hz, 2H), 3.36-3.42 (m, 2H), 3.59-3.68 (m, 4H), 4.34 (s, 2H), 4.58 (s, 2H), 7.02 (d, J = 7.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H).

A736-10

Example 1C.43: Preparation of 8-methoxy-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (1)

Step A: Preparation of 2-(4-methoxyindolin-l-yl)ethanamine.

From 4-methoxyindoline and 2-bromoethanamine hydrobromide, the title compound was obtained using a similar method to the one described in Example 1C.3, Step A. LCMS m/z = 193.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.79 (t, J = 8.3 Hz, 2H), 3.06 (t, J = 6.0 Hz, 2H), 3.16- 3.28 (m, 4H), 3.66 (s, 3H), 6.17 (d, J = 7.9 Hz, 1H), 6.25 (d, J = 8.2 Hz, 1H), 6.92 (t, J = 8.1 Hz, 1H). A711-36

Step B: Preparation of 8-methoxy-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole.

From 2-(4-methoxyindolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 205.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.94 (t, J = 8.5 Hz, 2H), 3.16-3.22 (m, 2H), 3.43-3.50 (m, 4H), 3.80 (s, 3H), 4.19 (s, 2H), 6.46 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 8.4 Hz, 1H).

Example 1C.44: Preparation of l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole-8- carbonitrile (Compound 274).

To a mixture of 8-bromo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole.2trifluoroacetic acid (20 mg, 41.56 μιηοΐ) and dicyanozinc (19.52 mg, 0.166 mmol) in DMF (0.2 mL) was added dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (590.3 μg, 0.831 μιηοΐ). The reaction was heated under microwave at 180 °C for 12 min. The mixture was purified by preparative HPLC to give the title compound (8.8 mg). LCMS m/z = 200.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.32 (t, J = 8.6 Hz, 2H), 3.51-3.56 (m, 2H), 3.60 (t, J = 8.6 Hz, 2H), 4.34 (s, 2H), 7.07 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H). Example 1C.45: Preparation of N-(2-methoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indol-8-amine (Compound 275).

Bis(tri-t-butylphosphine)palladium (2.893 mg, 5.7 μιηοΐ) was added to a suspension of 2- methoxyethanamine (4.465 mg, 59.45 μιηοΐ), tert-butyl 8-bromo-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate (20 mg, 56.62 μιηοΐ), and sodium tert-butoxide (9.250 mg, 96.25 μιηοΐ) in Toluene (0.5 mL). The reaction was warmed to 100 °C and stirred for 16 h. The reaction mixture was purified by silica gel column chromatography to give tert-butyl 8-((2- methoxyethyl)amino)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate. The purified intermediate was added 1.25 M HCl in methanol. The reaction was stirred at 50 °C for 1 h and concentrate. The residue was purified by preparative HPLC to give the title compound (2.8 mg). LCMS m/z = 248.4 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ ppm 3.21 (t, J = 8.5 Hz, 2H), 3.33- 3.38 (m, 2H), 3.43 (s, 3H), 3.53-3.66 (m, 8H), 4.35 (s, 2H), 6.86 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H).

Example 1C.46: Preparation of l-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H]indol-8-yl)-N,N- dimethylmethanamine (Compound 276).

Step A: Preparation of N,N-dimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indole- 8-carboxamide.

To a solution of 2-(tert-butoxycarbonyl)-l,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole- 8-carboxylic acid (40 mg, 0.095 mmol), dimethylamine (0.477 ml, 0.955 mmol), and triethylamine (39.93 μΐ, 0.286 mmol) in DMF (0.8 ml) was added HATU (54.46 mg, 0.143 mmol). The reaction was stirred at 23 °C for 15 h. The mixture was purified by preparative HPLC to give tert-butyl 8- (dimethylcarbamoyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. LCMS m/z = 346.2 [M+H]⁺.

The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (15.2 mg). LCMS m/z = 246.2 [M+H]⁺.

Step B: Preparation of l-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M]indol-8-yl)-N,N- dimethylmethanamine.

To a solution of a TFA salt of N,N-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-i;^']indole-8-carboxamide (18.7 mg, 52.04 μιηοΐ) in THF (2.5 mL) was added Borane-THF (0.260 mL, 0.520 mmol). The reaction was refluxed at 100 °C for 1 h. The mixture was cooled to room temperature and added methanol (0.316 mL, 7.806 mmol) dropwise. The reaction was refluxed for 30 min. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (10.2 mg). LCMS m/z = 232.4 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ ppm 2.88 (s, 6H), 3.19 (t, J = 8.5 Hz, 2H), 3.51-3.61 (m, 4H), 4.30 (d, J = 9.76 Hz, 4H), 6.98 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H). Example 1C.47: Preparation of 8-(pyrrolidin-l-ylmethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole (Compound 277).

Step A: Preparation of (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M-]indol-8- yl)(pyrrolidin-l-yl)methanone.

To a solution of 2-(tert-butoxycarbonyl)-l,2, 3,4,6, 7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole- 8-carboxylic acid (40 mg, 0.095 mmol), pyrrolidine (8.149 mg, 0.115 mmol), and triethylamine (39.93 μΐ, 0.286 mmol) in DMF (0.8 ml) was added HATU (54.46 mg, 0.143 mmol). The reaction was stirred at 23 °C for 15 h. The mixture was purified by preparative HPLC to give tert-butyl 8-(pyrrolidine-l- carbonyl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. LCMS m/z = 372.4 [M+H]⁺.

The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at room temperature for 24 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound. LCMS m/z = 272.4 [M+H]⁺.

Step B: Preparation of 8-(pyrrolidin-l-ylmethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole.

To a solution of a TFA salt of (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indol-8- yl)(pyrrolidin-l-yl)methanone (23.3 mg, 60.46 μιηοΐ) in THF (2.5 mL) was added Borane-THF (0.302 mL, 0.605 mmol). The reaction was refluxed at 100 °C for 1 h. The mixture was cooled to room temperature and added methanol (0.367 mL, 9.069 mmol) dropwise. The reaction was refluxed for 30 min. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (26.8 mg). LCMS m/z = 258.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.96-2.12 (m, 2H), 2.12-2.27 (m, 2H), 3.14-3.22 (m, 4H), 3.25-3.29 (m, 2H), 4.31 (s, 2H), 4.34 (s, 2H), 6.97 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H).

Example 1C.48: Preparation of N-((l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)methyl)-3-methoxypropan-l-amine (Compound 278).

Step A: Preparation of N-(3-methoxypropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /w]indole-8-carboxamide.

From 2-(tert-butoxycarbonyl)- 1,2, 3,4,6,7 -hexahydro-[l,4]diazepino[6,7,l- i;^']indole-8- carboxylic acid and 3-methoxypropan-l -amine, the title compound was obtained using a similar method to the one described in Example 1C.47, Step A. LCMS m/z = 290.0 [M+H]⁺.

Step B: Preparation of N-((l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indol-8- yl) methyl) -3-methoxypropan- 1 -amine. From /V-(3-methoxypropyl)- 1,2,3,4, 6,7-hexahydro-[l,4]diazepino[6,7, l- i;]indole-8- carboxamide and Borane-THF, the title compound was obtained using a similar method to the one described in Example 1C.47, Step B. LCMS m/z = 276.2 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ ppm 1.94-2.05 (m, 2H), 3.10-3.22 (m, 4H), 3.25-3.30 (m, 4H), 3.35 (s, 1H), 3.36 (s, 3H), 3.50-3.60 (m, 6H), 4.17 (s, 2H), 4.30 (s, 2H), 6.91 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H).

Example 1C.49: Preparation of l-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H]indol-8-yl)-N- methylmethanamine (Compound 279).

Step A: Preparation of N-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole-8- carboxamide.

From 2-(tert-butoxycarbonyl)- 1,2, 3,4,6,7 -hexahydro-[l, 4]diazepino[6,7, l- i;^']indole-8- carboxylic acid and 33% methanamine in EtOH, the title compound was obtained using a similar method to the one described in Example 1C.47, Step A. LCMS m/z = 232.2 [M+H]⁺.

Step B: Preparation of l-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8-yl)-N- methylmethanamine.

From A^?-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l- i;]indole-8-carboxarnide and Borane-THF, the title compound was obtained using a similar method to the one described in Example 1C.47, Step B. LCMS m/z = 218.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.75 (s, 3H), 3.17 (t, J = 8.6 Hz, 2H), 3.26-3.30 (m, 1H), 3.50-3.61 (m, 4H), 4.14 (s, 2H), 4.30 (s, 2H), 6.94 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H).

Example 1C.50: Preparation of 8-((4-methoxypiperidin-l-yl)methyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole (Compound 280).

Step A: Preparation of (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8-yl)(4- methoxypiperidin- 1 -yl)methanone.

From 2-(tert-butoxycarbonyl)- 1,2, 3,4,6,7 -hexahydro-[l,4]diazepino[6,7, l- i;^']indole-8- carboxylic acid and 4-methoxypiperidine, the title compound was obtained using a similar method to the one described in Example 1C.47, Step A. LCMS m/z = 316.4 [M+H]⁺.

Step B: Preparation of 8-((4-methoxypiperidin-l-yl)methyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole.

From (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7, l- i;^']indol-8-yl)(4-methoxypiperidin- l- yl)methanone and Borane-THF, the title compound was obtained using a similar method to the one described in Example 1C.47, Step B. LCMS m/z = 302.4 [M+H]⁺. Example 1C.51: Preparation of N-((l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)methyl)pyridin-4-amine (Compound 281).

Step A: Preparation of N-(pyridin-4-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole-8-carboxamide. From 2-(tert-butoxycarbonyl)- 1,2, 3,4,6,7 -hexahydro-[l,4]diazepino[6,7,l- i;]indole-8- carboxylic acid and pyridin-4-amine, the title compound was obtained using a similar method to the one described in Example 1C.47, Step A. LCMS m/z = 295.2 [M+H]⁺.

Step B: Preparation of N-((l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indol-8- yl)methyl)pyridin-4-amine.

From A^?-(pyridin-4-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole-8-carboxarnide and Borane-THF, the title compound was obtained using a similar method to the one described in

Example 1C.47, Step B. LCMS m/z = 281.4 [M+H]⁺. Example 1C.52: Preparation of N-(7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /»]indol-8-yl)acetamide (Compound 282).

A mixture of acetamide (3.904 mg, 66.09 μιηοΐ), palladium (II) acetate (618.2 μg, 2.8 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.549 mg, 4.4 μιηοΐ) and cesium carbonate (26.92 mg, 82.61 μιηοΐ) was degassed and purged with nitrogen twice. Dry Dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-

/i;]indole-2(lH)-carboxylate (21 mg, 55.07 μιηοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8-acetarrddo-7,7-dimemyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at 55 °C for 6 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compounds (1.0 mg). LCMS m/z = 260.0 [M+H]⁺.

Example 1C.53: Preparation of N-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)acetamide (Compound 283).

A mixture of acetamide (6.020 mg, 0.102 mmol), palladium (II) acetate (953.3 μg, 4.2 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.931 mg, 6.8 μιηοΐ) and cesium carbonate (41.51 mg, 0.127 mmol) was degassed and purged with nitrogen twice. Dry Dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (30 mg, 84.92 μιηοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8- acetamido-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (2.0 mg). LCMS m/z = 232.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.14 (s, 3H), 3.03 (t, J = 8.4 Hz, 2H), 3.31-3.35 (m, 2H), 3.53-3.60 (m, 4H), 4.29 (s, 2H), 7.04-7.14 (m, 2H). Example 1C.54: Preparation of l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/M]indol-8-amine (Compound 284).

A mixture of acetamide (6.020 mg, 0.102 mmol), palladium (II) acetate (953.3 μg, 4.2 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.931 mg, 6.8 μιηοΐ) and cesium carbonate (41.51 mg, 0.127 mmol) was degassed and purged with nitrogen twice. Dry dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (30 mg, 84.92 μιηοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8-acetamido-7,7- dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (8.0 mg). LCMS m/z = 190.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 3.17 (t, J = 8.5 Hz, 2H), 3.31-3.38 (m, 2H), 3.52-3.58 (m, 2H), 3.62 (t, J = 8.5 Hz, 2H), 4.33 (s, 2H), 6.83 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H).

Example 1C.55: Preparation of N-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol-8- yl)propionamide (Compound 285).

A mixture of propionamide (4.138 mg, 56.62 μιηοΐ), palladium (II) acetate (635.5 μg, 2.8 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.621 mg, 4.5 μιηοΐ) and cesium carbonate (27.67 mg, 84.92 μιηοΐ) was degassed and purged with nitrogen twice. Dry dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (20 mg, 56.62 μιηοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8-propionamido- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HC1 (2 mL). The reaction was stirred at 55 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC to give the title compound (3.1 mg). LCMS m/z = 246.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.20 (t, J = 7.6 Hz, 3H), 2.41 (q, J = 7.6 Hz, 2H), 2.97 (t, J = 8.5 Hz, 2H), 3.21-3.26 (m, 2H), 3.45-3.53 (m, 4H), 4.25 (s, 2H), 6.96-7.03 (m, 2H).

Example 1C.56: Preparation of ethyl (7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- /w]indol-8-yl)carbamate (Compound 286).

A mixture of ethyl carbamate (4.673 mg, 52.45 μιηοΐ), palladium (II) acetate (588.8 μg, 2.6 μιηοΐ), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.428 mg, 4.2 μιηοΐ) and cesium carbonate (25.63 mg, 78.68 μιηοΐ) was degassed and purged with nitrogen twice. Dry dioxane (0.5 mL) was added followed by tert-butyl 8-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;]indole-2(lH)-carboxylate (20 mg, 52.45 μηιοΐ). The reaction was heated to 105 °C overnight and then allowed to cool to room temperature. The mixture was filtered and the filter cake was washed with ACN. The filtrate was concentrated. The residue was purified by preparative HPLC to give tert-butyl 8-acetarrddo-7 -dimemyl-3,4,6 -tetrahydro-[l,4]diazepino[6 J- i;]indole-2(lH)-carboxylate as a white solid. The above solid was then dissolved in 1.25 M methanol solution of HCl (2 mL). The reaction was stirred at 55 °C for 40 min. The mixture was concentrated to give the title compound (2.8 mg). LCMS m/z = 246.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.29 (t, J = 7.1 Hz, 3H), 1.38 (s, 6H), 3.21 (s, 3H), 3.22-3.27 (m, 2H), 3.47-3.54 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.26 (s, 2H), 6.82 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H).

Example 1C.57: Preparation of 9-fluoro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 287).

Step A: Preparation of 2-(5-fluoro-3,3-dimethylindolin-l-yl)ethanamine.

A mixture of 5-fluoro-3,3-dimethylindoline (0.20 g, 1.211 mmol) and 2-bromoethanamine.HBr

(0.273 g, 1.332 mmol) was heated at 122 °C for 4 h. The mixture was dissolved in 2M HCl and purified by preparative HPLC to give the title compound (253 mg). LCMS m/z = 209.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.38 (s, 6H), 3.15 (m, 2H), 3.18 (t, J = 6.1 Hz, 2H), 3.26-3.30 (m, 1H), 6.52-6.58 (m, 1H), 6.73-6.82 (m, 2H).

Step B: Preparation of 9-fluoro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-

&i] indole.

From 2-(5-fluoro-3,3-dimethylindolin-l-yl)ethanamine and paraformaldehyde, the title compound was obtained using a similar method to the one described in Example 1C.3, Step B. LCMS m/z = 221.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (s, 6H), 3.17-3.22 (m, 2H), 3.26 (s, 2H), 3.49-3.54 (m, 2H), 4.25 (s, 2H), 6.82 (dd, J₁₌2.5 Hz, J₂=9.4 Hz, 1H), 6.89 (dd, J₁₌2.5 Hz, J₂=8.2 Hz, 1H).

Example 1C.58: Preparation of 7,7-dimethyl-9-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 288).

Step A: Preparation of tert-butyl 7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- hi] indole-2( 1H) -carboxylate.

To a solution of 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-i;]indole.trifluoroacetic acid (1.02 g, 3.225 mmol), Triethylamine (1.798 mL, 12.90 mmol) in CH₂C1₂ (15 mL) was added a solution di-tert-butyl dicarbonate (0.739 g, 3.386 mmol) in CH₂C1₂ (15 mL). The reaction was stirred at 23 °C for 2 h. The mixture was extracted with H₂0. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (736 mg). LCMS m/z = 303.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.29 (s, 6H), 1.41 (s, 9H), 3.00 (bs, 2H), 4.37 (s, 1H), 4.44 (bs, 2H), 6.74 (t, J = 7.4 Hz, 1H), 6.84-7.04 (m, 2H). Step B: Preparation of tert-butyl 9-bromo-7,7-dimethyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/»]indole-2(lH)-carboxylate.

To a solution of tert-butyl 7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (200 mg, 0.661 mmol) in MeCN (10 mL) was added NBS (0.124 g, 0.694 mmol). The reaction was stirred at 65 °C for 15 h. The mixture was concentrated. The residue was dissolved in DCM and washed with 1 M HC1 and NaHC0₃. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give the title compound (209 mg). LCMS m/z = 381.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.27 (s, 6H), 1.35-1.48 (m, 9H), 2.97-3.04 (m, 2H), 3.16 (s, 2H), 3.65-3.75 (m, 2H), 4.34 (s, 2H), 6.97-7.09 (m, 2H).

Step C: Preparation of 7,7-dimethyl-9-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-

/wjindole.

To a mixture of tert-butyl 9-bromo-7,7-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;^']indole-2(lH)-carboxylate (20 mg, 52.45 μιηοΐ), propylboronic acid (6.917 mg, 78.68 μιηοΐ), potassium phosphate (27.83 mg, 0.131 mmol), and palladium (II) acetate (706.5 μg, 3.1 μιηοΐ) in dioxane (0.5 mL) was added S-phos (2.153 mg, 5.2 μιηοΐ). The reaction was stirred at 80 °C for 15 h. The mixture was filtered through a syringe filter. The filtrate was purified by preparative HPLC to give tert-butyl 7,7-dimethyl-9-propyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate. The above material was treated with 1.25 M HC1 in methanol (2 mL) at 50 °C for 1 h. The mixture was concentrated to give the title compound (1.8 mg). LCMS m/z = 245.4 [M+H]⁺.

Example 1C.59: Preparation of 2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-/H-]indole-7,l'- cyclopentane] (Compound 289).

Step A: Preparation of spiro[cyclopentane-l,3'-indolin]-2'-one.

A solution of indolin-2-one (1.0 g, 7.510 mmol) in THF (30 mL) was cooled to -77 °C and 1M LiHMDS (16.52mL, 16.52 mmol) was added. After stirring for 30 minutes 1,4-dibromobutane (1.784 g, 8.262 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for an additional 3hours. The reaction was quenched with sat. NH₄C1 (50mL) and extracted with EtOAc (2 x 30mL). The organics were dried over MgS0₄ and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (0-60% EtOAc in hexane) to give the title compound (0.20 g). LCMS m/z = 188.2

[M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.83-1.91 (m, 2H), 1.92-2.02 (m, 2H), 2.03-2.12 (m, 2H), 2.14-2.23 (m, 2H), 6.85 (m, 1H), 7.02 (ddd, J = 7.9, 7.4, 1.0 Hz, 1H), 7.15-7.20 (m, 2H), 7.43 (bs, 1H).

Step B: Preparation of 2-(spiro[cyclopentane-l,3'-indolin]-l'-yl)ethanamine.

To a solution of spiro[cyclopentane-l,3'-indolin]-2'-one (35 mg, 0.187 mmol) in THF (lmL) was added lithium aluminum hydride (0.5 ml, 0.500 mmol). After stirring at room temperature for 2 h, the reaction was quenched with IN NaOH (2mL) and stirred for 10 min. The mixture was filtered off solids and extracted with EtOAc (3 x 2mL). The combined organics were washed with brine and dried over MgS0₄. The mixture was filtered by vacuum filtration and solvent was removed under reduced pressure to give 30 mg of crude indoline. To the crude intermediate was added 2-bromoethanamine hydrobromide (42.13 mg, 0.206 mmol). The neat mixture was heated to 120°C for 3 h. the mixture was purified by preparative HPLC to give the title compound (3 mg) as a TFA salt. LCMS m/z = 217.0 [M+H]⁺.

Step C: Preparation of 2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-/H-]indole-7,l'- cyclopentane].

To a solution of 2-(spiro[cyclopentane-l,3'-indolin]-r-yl)ethanamine (3 mg, 13.87 μιηοΐ) in MeOH (0.2mL) was added TFA (4.248 55.47 μιηοΐ) followed by paraformaldehyde (1 mg, 33.30 μιηοΐ). The mixture was heated to 80°C under microwave irradiation for 1 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (1.9 mg) as a solid TFA salt. LCMS m/z = 229.0 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.69-1.87 (m, 8H), 3.17-3.21 (m, 2H), 3.27 (s, 2H), 3.44-3.49 (m, 2H), 4.19 (s, 2H), 6.81 (t, J = 7.8 Hz, 1H), 6.91 (m, 1H), 7.06 (dd, J = 7.4, 1.0 Hz, 1H), 9.58 (bs, 2H). Example 1C.60: Preparation of 8-fluoro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 229).

Step A: Preparation of 4-fluoro-lH-indole-3-carbaldehyde .

A 2M solution of oxalyl dichloride in DCM (4.440 mL, 8.880 mmol) was added to an ice-water bath cooled flask containing DCM (20 mL), N,N-dimethylformamide (0.688 mL, 8.880 mmol) was added dropwise under nitrogen. After stirred for 30 min at 0 °C, 4-fluoro-lH-indole (1 g, 7.400 mmol) in DCM (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1.5 h. Solvent was removed, 20 mL THF and 30 mL 20% aqueous ammonium acetate solution were added. The mixture was then heated at 65 °C for 30 min, cooled down, and extracted with ethyl acetate. The combined organics were washed with saturated NaHC0₃, water and brine, dried over anhydrous Na₂S0₄. The mixture was filtered and the filtrate was concentrated to give the title compound (1.22 g) as light yellow solid, which was used for the next step without further purification. LCMS m/z = 164.2 [M+H]⁺; ¾ NMR (400 MHz, DMSO) δ ppm 7.00 (ddd, J = 10.9, 7.8 and 0.7 Hz, 1H), 7.24 (td, J = 8.0 and 5.0 Hz, 1H), 7.34-7.36 (m, 1H), 8.29 (s, 1H), 10.0 (d, J = 3.1 Hz, 1H), 12.4 (bs, 1H).

Step B: Preparation of 4-fluoro-3-methyl-lH-indole.

To a solution of 4-fluoro-lH-indole-3-carbaldehyde (600 mg, 3.678 mmol) in THF (15 mL) in an ice- water bath was added a 2M solution of lithium aluminum hydride in THF (4 mL, 7.999 mmol) slowly under nitrogen. After 10 min, the reaction was heated at 65 °C for 1 h. The mixture was cooled down in an ice-water bath, and carefully added H₂0 (303 μL), 15% aqueous NaOH solution (303 μL), then H₂0 (910 μL) and anhydrous Na₂S0₄. After 15 min stirring, the mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (523 mg) as a colorless oil. LCMS m/z = 150.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 2.46 (t, J = 1.0 Hz, 3H), 6.72 (ddd, J = 10.2, 7.4 and 1.0 Hz, 1H), 6.87-6.90 (m, 1H), 7.02-7.12 (m, 2H), 7.92 (bs, 1H). Step C: Preparation of 4-fluoro-3-methyl-lH-indoline.

To a solution of 4-fluoro-3-methyl-lH-indole (523 mg, 3.506 mmol) in acetic acid (10 mL) in an ice-water bath was added sodium cyanoborohydride (0.881 g, 14.02 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was concentrated then dissolved in DCM. The organic layer was washed with saturated NaHC0₃, then concentrated, the residue was purified by preparative HPLC. The combined fractions were neutralized with saturated NaHC0₃, partially concentrated, extracted with ethyl acetate. The combined organics were dried over anhydrous Na₂S0₄, filtered then concentrated to give the title compound (80 mg) as a colorless oil. LCMS m/z = 152.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.36 (d, J = 6.8 Hz, 3H), 3.18 (dd, J = 6.8 and 6.4 Hz, 1H), 3.50-3.60 (m, 1H), 3.73 (t, J = 8.8 Hz, 1H), 6.35-6.40 (m, 2H), 6.93-6.99 (m, 1H).

Step D: Preparation of 2-(4-fluoro-3-methylindolin-l-yl)ethanamine.

4-Fluoro-3-methylindoline (0.07 g, 0.463 mmol) and 2-bromoethanamine hydrobromide (99.61 mg, 0.486 mmol) was heated neat at 120 °C for 15 h. The solid mixture was dissolved in DMSO and purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as the TFA salt (45 mg). LCMS m/z = 195.2 [M+H]⁺;

Step F: Preparation of 8-fluoro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

To a solution of 2-(4-fluoro-3-methylindolin-l-yl)ethanamine 2,2,2-trifluoroacetate (45 mg, 0.146 mmol) and 37% formaldehyde in water (32.60 μΐ, 0.438 mmol) in methanol (2 mL) was added TFA (44.71 μΐ, 0.584 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated, the residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as the TFA salt (29 mg) as yellow solid. LCMS m/z = 207.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.36 (d, J = 6.8 Hz, 3H), 3.18-3.30 (m, 3H), 3.46-3.60 (m, 3H), 3.67 (t, J = 9.2 Hz, 1H), 4.24 (d, J = 14.8 Hz, 1H), 4.28 (d, J = 14.8 Hz, 1H), 6.55 (t, J = 8.6 Hz, 1H), 7.04-7.08 (m, 1H).

Example 1C.61: Preparation of 8-bromo-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 231).

Step A: Preparation of 4-bromo-3-methyl-lH-indole.

To a solution of 4-bromo-lH-indole-3-carbaldehyde (896 mg, 3.999 mmol) in THF (15 mL) in an ice-water bath was added a 2M solution of lithium aluminum hydride in THF (4 mL, 7.998 mmol) slowly under nitrogen. After 10 min, the reaction was heated at 65 °C for 1 h. The mixture was cooled down in an ice-water bath, and carefully added H₂0 (303 μL), 15% aqueous NaOH solution (303 μL), then H₂0 (910 μL) and anhydrous Na₂S0₄. After 15 min stirring, the mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (730 mg) as a colorless oil. LCMS m/z = 210.0 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 2.56 (t, J = 1.1 Hz, 3H), 6.95-7.00 (m, 2H), 7.23-7.28 (m, 2H), 7.95 (bs, 1H).

Step B: Preparation of 4-bromo-3-methyl-indoline. To a solution of 4-bromo-3-methyl-lH-indole (2.224 g, 10.59 mmol) in TFA (20 mL) was added triethylsilane (6.764 mL, 42.35 mmol) dropwise under nitrogen. The reaction mixture was stirred at room temperature for 1 h, then 50 °C for 30 min. The mixture was concentrated, dissolved in ethyl acetate, and washed with saturated aqueous NaHC0₃. The organics were dried over anhydrous Na₂S0₄ and filtered. The filtrate was concentrated. The residue was purified by silica gel column

chromatography to give the title compound (2.02 g) as a dark red oil. LCMS m/z = 212.0 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.31 (d, J = 6.8 Hz, 3H), 3.22 (dd, J = 8.7 and 2.7 Hz, 1H), 3.33-3.43 (m, 1H), 3.72 (t, J = 8.7 Hz, 1H), 3.80 (bs, 1H), 6.50-6.54 (m, 1H), 6.80 (dd, J = 8.0 and 1.0 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H).

Step C: Preparation of 2-(4-bromo-3-methylindolin-l-yl)ethanamine.

4-Bromo-3-methylindoline (1 g, 4.715 mmol) and 2-bromoethanamine hydrobromide (1.014 g, 4.951 mmol) were heated at 115 °C overnight. The mixture was dissolved in methanol and purified by preparative HPLC. The combined fractions were made basic with saturated aqueous NaHC0₃, partially concentrate, extracted with ethyl acetate. The combined organics were dried over anhydrous Na₂S0₄, filtered then concentrated to give the title compound (805 mg) as a yellow oil. LCMS m/z = 255.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.29 (d, J = 6.7 Hz, 3H), 2.95-3.00 (m, 2H), 3.00-3.07 (m, 1H), 3.23-3.27 (m, 1H), 3.28-3.42 (m, 3H), 6.50 (d, J = 7.8 Hz, 1H), 6.75 (dd, J = 8.0 and 0.6 Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H).

Step D: Preparation of 8-bromo-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole.

To a solution of 2-(4-bromo-3-methylindolin-l-yl)ethanamine (805 mg, 3.155 mmol) in methanol (15 mL) was added 37% formaldehyde in water (0.705 mL, 9.465 mmol), followed by 2,2,2- trifluoroacetic acid (1.450 mL, 18.93 mmol). The reaction mixture was stirred at 80 °C for 1 h and concentrated. The residue was purified by preparative HPLC. The combined fractions were made basic with saturated NaHC0₃, partially concentrated, extracted with ethyl acetate. The combined organics were dried over anhydrous Na₂S0₄, filtered then concentrated to give the title compound (520 mg) as a light yellow oil. LCMS m/z = 267.0 [M+H]⁺; ^:H NMR (400 MHz, CD₃C1) δ ppm 1.28 (d, J = 7.0 Hz, 3H), 2.74-2.81 (m, 1H), 2.95-3.03 (m, 1H), 3.11-3.17 (m, 1H), 3.19-3.25 (m, 2H), 3.33-3.42 (m, 2H), 3.74 (d, J = 15.4 Hz, 1H), 3.95 (d, J = 15.4 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H).

Example 1C.62: Preparation of 8-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- /wjindole (Compound 238).

Step A: Preparation of 4-chloro-3-methylindoline.

To a solution of 4-chloro-3 -methyl- lH-indole (205 mg, 1.238 mmol) in TFA (3 mL) at room temperature was added triethylsilane (0.791 mL, 4.951 mmol) dropwise under nitrogen. The reaction mixture was stirred for 3 h at room temperature. The mixture was concentrated, diluted with ethyl acetate, washed with saturated aqueous NaHC0₃, dried over anhydrous Na₂S0₄, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (183 mg) as an orange oil. LCMS m/z = 168.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.33 (d, J = 6.8 Hz, 3H), 3.22 (dd, J = 8.8 and 3.4 Hz, 1H), 3.42-3.50 (m, 1H), 3.72 (t, J = 8.8 Hz, 1H), 3.78 (bs, 1H), 6.48 (d, J = 7.8 Hz, 1H), 6.64 (dd, J = 8.0 and 0.8 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H).

Step B: Preparation of 2-(4-chloro-3-methylindolin-l-yl)ethanamine.

4-Chloro-3-methylindoline (215 mg, 1.283 mmol) and 2-bromoethanamine hydrobromide

(0.289 g, 1.411 mmol) were heated at 115 °C overnight. The mixture was dissolved in methanol and purified by preparative HPLC. The combined fractions were made basic with saturated aqueous NaHC0₃, partially concentrated, extracted with ethyl acetate. The combined organics were dried over anhydrous Na₂S0₄, filtered then concentrated to give the title compound (170 mg) as yellow oil. LCMS m/z = 211.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J = 6.7 Hz, 3H), 2.88- 2.95 (m, 2H), 3.01-3.08 (m, 1H), 3.19-3.24 (m, 1H), 3.30-3.45 (m, 3H), 6.45 (d, J = 7.8 Hz, 1H), 6.58 (dd, J = 8.0 and 0.6 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H).

Step C: Preparation of 8-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

To a solution of 2-(4-chloro-3-methylindolin-l-yl)ethanamine (0.17 g, 0.807 mmol) and 37% formaldehyde in water (0.240 mL, 3.227 mmol) in methanol (2 mL) was added TFA (0.371 mL, 4.841 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as TFA salt (140 mg). LCMS m/z = 223.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.28 (d, J = 7.0 Hz, 3H), 3.08-3.15 (m, 1H), 3.30-3.35 (m, 1H), 3.35-3.45 (m, 2H), 3.45-3.55 (m, 2H), 3.57-3.64 (m, 1H), 4.14 (d, J = 14.8 Hz, 1H), 4.38 (d, J = 14.8 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H).

Example 1C.63: Preparation of 8-ethyl-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /u^'jindole (Compound 239).

Step A: Preparation of tert-butyl 8-bromo-7-methyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/»]indole-2(lH)-carboxylate.

To a solution of 8-bromo-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole (0.52 g, 1.946 mmol) in DCM (10 mL) was added triethylamine (0.543 mL, 3.893 mmol) followed by di-tert- butyl dicarbonate (0.637 g, 2.920 mmol) in an ice-water bath. The reaction was warmed to room temperature and stirred overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (654 mg) as colorless oil. LCMS m/z = 367.2 [M+H]⁺;

Step B: Preparation of 8-ethyl-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

To a mixture of tert-butyl 8-bromo-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (50 mg, 0.136 mmol), ethylboronic acid (20.12 mg, 0.272 mmol), potassium phosphate (86.69 mg, 0.408 mmol), and Pd(OAc)₂ (4.585 mg, 20.42 μιηοΐ) in dioxane (1.5 mL) was added 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (16.77 mg, 40.84 μιηοΐ). The reaction was stirred at 80 °C overnight. The mixture was filtered by a syringe filter. The filtrate was concentrated then purified by silica gel column chromatography to give tert-butyl 8-ethyl-7-methyl-3, 4,6,7- tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate, which was then dissolved in methanol (1 mL), a 4M solution of HC1 in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as the TFA salt (15 mg). LCMS m/z = 217.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.20 (d, J = 6.8 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H), 2.53-2.70 (m, 2H), 2.98-3.05 (m, 1H), 3.28-3.46 (m, 5H), 3.56-3.64 (m, 1H), 4.10 (d, J = 14.6 Hz, 1H), 4.35 (d, J = 14.6 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H).

Example 1C.64: Preparation of 8-cyclopropyl-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole (Compound 240).

To a mixture of tert-butyl 8-bromo-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (50 mg, 0.136 mmol), cyclopropylboronic acid (23.39 mg, 0.272 mmol), potassium phosphate (86.69 mg, 0.408 mmol), and Pd(OAc)₂ (4.585 mg, 20.42 μιηοΐ) in dioxane (1.5 mL) was added 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (16.77 mg, 40.84 μιηοΐ). The reaction was stirred at 80 °C overnight. The mixture was filtered by a syringe filter. The filtrate was concentrated then purified by silica gel column chromatography to give tert-butyl 8-cyclopropyl-7-methyl-3, 4,6,7- tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate, which was then dissolved in methanol (1 mL), a 4M solution of HC1 in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as the TFA salt (13 mg). LCMS m/z = 229.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.58-0.65 (m, 1H), 0.70-0.78 (m, 1H), 0.90-1.02 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H), 1.88-1.95 (m, 1H), 2.98-3.05 (m, 1H), 3.28-3.45 (m, 4H), 3.54-3.64 (m, 2H), 4.09 (d, J = 14.6 Hz, 1H), 4.32 (d, J = 14.6 Hz, 1H), 6.33 (d, J = 7.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H).

Example 1C.65: Preparation of (7-methyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H-]indol-8- yl)methanol (Compound 241).

To a solution of methyl 7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole-8- carboxylate (53 mg, 0.215 mmol) in THF (3 mL) was added a 2M solution of lithium aluminum hydride in THF (0.395 mL, 0.790 mmol) in an ice-water bath under nitrogen. The reaction mixture was then heated at reflux for 5 h. After cooled down in an ice-water bath, the mixture was added carefully water (30 μL), aqueous 15% NaOH (30 μL) then water (90 μL). The mixture was stirred for 10 min, filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated. The residue was purified by preparative HPLC (5-50% CH₃CN/H₂0 with 0.1% TFA over 30 min). The combined fractions were lyophilized to give the title compound with some impurities (52 mg). It was then dissolved in DCM (2 mL) and added Et₃N (47 μΐ., 0.34 mmol) and Boc₂0 (40 mg, 0.187 mmol). After stirring for 2 h at room temperature, it was concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 8-(hydroxymethyl)-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;]indole-2(lH)-carboxylate (30 mg, 94.22 μιηοΐ), which was then dissolved in ether (1 mL). A solution of 4M HC1 in dioxane (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The white precipitate was collected, washed with ether then dried to give the title compound as HC1 salt (24 mg). LCMS m/z = 219.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.24 (d, J = 6.8 Hz, 3H), 3.08-3.17 (m, 1H), 3.35-3.60 (m, 5H), 3.60-3.68 (m, 1H), 4.18 (d, J = 14.7 Hz, 1H), 4.40 (d, J = 14.7 Hz, 1H), 4.58 (d, J = 13.1 Hz, 1H), 4.67 (d, J = 13.1 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H).

Example 1C.66: Preparation of 8,9-dichloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 246).

To a solution of tert-butyl 8-chloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (40 mg, 0.124 mmol) in acetonitrile (2 mL) was added NCS (16.55 mg, 0.124 mmol). The reaction mixture was stirred at room temperature for overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 8,9- dichloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate, which was dissolved in methanol (1 mL), a solution of 4M HC1 in dioxane (1 mL) was added. The reaction was stirred at room temperature overnight, then purified by preparative HPLC. The fractions were lyophilized to give the title compound as a TFA salt (15 mg). LCMS m/z = 257.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.29 (d, J = 6.8 Hz, 3H), 3.08-3.16 (m, 1H), 3.35-3.55 (m, 5H), 3.56-3.64 (m, 1H), 4.13 (d, J = 14.6 Hz, 1H), 4.38 (d, J = 14.6 Hz, 1H), 7.24 (s, 1H). Example 1C.67: Preparation of 9-bromo-8-chloro-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole (Compound 245).

To a solution of tert-butyl 8-chloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (40 mg, 0.124 mmol) in acetonitrile (2 mL) was added NBS (24.26 mg, 0.136 mmol). The reaction mixture was stirred at room temperature for overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 9-bromo- 8-chloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate (40 mg).

The compound obtained above (15 mg, 37.3 μιηοΐ) was dissolved in dioxane (1 mL), a solution of 4M HC1 in dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature overnight. The white precipitate was collected and washed with ether and dried to give the title compound as a hydrochloride salt (9 mg). LCMS m/z = 301.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.28 (d, J = 7.0 Hz, 3H), 3.08-3.16 (m, 1H), 3.35-3.55 (m, 5H), 3.56-3.64 (m, 1H), 4.13 (d, J = 15.0 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 7.39 (s, 1H). Example 1C.68: Preparation of 8-bromo-9-chloro-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole (Compound 247).

To a solution of tert-butyl 8-bromo-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (100 mg, 0.272 mmol) in acetonitrile (3 mL) was added NCS (40 mg, 0.3 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 8-bromo-9-chloro-7- methyl-3, 4,6,7 -tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate (70 mg).

The product obtained above (20 mg) in methanol (0.8 mL) was added a solution of 4M HC1 in dioxane (0.8 mL). The mixture was stirred at room temperature overnight and purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as a TFA salt. LCMS m/z = 301.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.28 (d, J = 6.7 Hz, 3H), 3.08-3.16 (m, 1H), 3.30- 3.50 (m, 5H), 3.56-3.64 (m, 1H), 4.10 (d, J = 14.9 Hz, 1H), 4.38 (d, J = 14.9 Hz, 1H), 7.24 (s, 1H).

Example 1C.69: Preparation of 8-chloro-7,9-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 248).

To a mixture of tert-butyl 9-bromo-8-chloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- /i;]indole-2(lH)-carboxylate (25 mg, 62.23 μιηοΐ), tetrakis(triphenyl)phosphine palladium (9.789 mg, 12.45 μιηοΐ), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (8.593 mg, 68.45 μιηοΐ), and potassium carbonate (62.23 μΐ, 0.124 mmol) in dioxane (1.5 mL) was stirred at 90 °C overnight under nitrogen. The mixture was filtered by a syringe filter. The filtrate was concentrated then purified by preparative HPLC. The combined fractions were lyophilized to give tert-butyl 8-chloro-7,9-dimethyl- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate.

The compound obtained above in methanol (0.5 mL) was treated with a solution of 4M HC1 in dioxane (0.5 mL), stirred at room temperature for 4 h, then purified by preparative HPLC to give the title compound as TFA salt (8 mg). LCMS m/z = 237.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.20 (d, J = 6.7 Hz, 3H), 2.28 (s, 3H), 2.98-3.07 (m, 1H), 3.30-3.45 (m, 5H), 3.56-3.64 (m, 1H), 4.08 (d, J = 14.8 Hz, 1H), 4.35 (d, J = 14.8 Hz, 1H), 7.09 (s, 1H).

Example 1C.70: Preparation of 9-chloro-7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 249).

To a mixture of tert-butyl 8-bromo-9-chloro-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- /i;]indole-2(lH)-carboxylate (30 mg, 74.68 μιηοΐ), tetrakis(triphenylphosphine)palladium (11.75 mg, 14.94 μιηοΐ), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (10.31 mg, 82.15 μιηοΐ), and potassium carbonate (62.23 μΐ, 0.149 mmol) in dioxane (1.5 mL) was stirred at 90 °C overnight under nitrogen. The mixture was filtered by a syringe filter. The filtrate was concentrated then purified by preparative HPLC. The combined fractions were lyophilized to tert-butyl 9-chloro-7,8-dimethyl- 3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate. The compound obtained above in methanol (0.5 mL) was then treated with a solution of 4M HC1 in dioxane (0.5 mL), stirred at room temperature overnight, then purified by preparative HPLC to give the title compound as a TFA salt (8 mg). LCMS m/z = 237.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.27 (d, J = 6.7 Hz, 3H), 2.27 (s, 3H), 3.00-3.08 (m, 1H), 3.30-3.48 (m, 5H), 3.56-3.64 (m, 1H), 4.10 (d, J = 14.8 Hz, 1H), 4.33 (d, J = 14.8 Hz, 1H), 6.97 (s, 1H).

Example 1C.71: Preparation of 6-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 256).

Step A: Preparation of 2-(2-methylindolin-l-yl)ethanamine.

2-Methylindoline (0.150 g, 1.126 mmol) and 2-bromoethanamine hydrobromide (0.277 g,

1.351 mmol) was heated neat (no solvent) at 110 °C for 15 h. The solid mixture was dissolved in methanol and purified by preparative HPLC. The combined fractions lyophilized to give the title compound as a TFA salt (212 mg). LCMS m/z = 177.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J = 6.1 Hz, 3H), 2.61 (dd, J = 15.3 and 8.6 Hz, 1H), 3.10-3.19 (m, 3H), 3.30-3.40 (m, 2H), 3.62-3.72 (m 1H), 6.52 (d, J = 8.1 Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H), 7.00-7.06 (m, 2H).

Step B: Preparation of 6-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole. To a solution of 2-(2-methylindolin-l-yl)ethanamine 2,2,2-trifluoroacetate (212 mg, 0.524 mmol) and 37% formaldehyde in water (0.117 mL, 1.573 mmol) in methanol (5 mL) was added TFA (0.201 mL, 2.622 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as a TFA salt (148 mg). LCMS m/z = 189.0 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.38 (d, J = 6.1 Hz, 3H), 2.61 (dd, J = 15.8 and 10.5 Hz, 1H), 2.95-3.05 (m, 1H), 3.25-3.37 (m, 2H), 3.40-3.55 (m, 2H), 3.62-3.68 (m, 1H), 4.08 (d, J = 14.7 Hz, 1H), 4.42 (d, J = 14.7 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H).

Example 1C.72: Preparation of 7,9-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 257).

Step A: Preparation of tert-butyl 7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- /»]indole-2(lH)-carboxylate.

To a solution of 7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole bis(2,2,2- trifluoroacetate) (80 mg, 0.192 mmol) in DCM (5 mL) was added di-tert-butyl dicarbonate (62.91 mg, 0.288 mmol) and triethylamine (0.107 mL, 0.769 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (53 mg). LCMS m/z = 289.2 [M+H]⁺;

Step B: Preparation of tert-butyl 9-bromo-7-methyl-3,4,6,7-tetrahydro-

[l,4]diazepino[6,7,l-/»]indole-2(lH)-carboxylate.

To a solution of tert-butyl 7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (53 mg, 0.184 mmol) in acetonitrile (3 mL) was added N-bromosuccinimide (35.98 mg, 0.202 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (60 mg). LCMS m/z = 367.0 [M+H]⁺;

Step C: Preparation of 7,9-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole. To a mixture of tert-butyl 9-bromo-7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-

2(lH)-carboxylate (60 mg, 0.163 mmol), tetrakis(triphenylphosphine)palladium (37.76 mg, 32.67 μιηοΐ), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (22.56 mg, 0.180 mmol), and potassium carbonate (45.16 mg, 0.327 mmol) in dioxane (2.5 mL) was stirred at 90 °C overnight under nitrogen. The mixture was filtered by a syringe filter. The filtrate was concentrated then purified by preparative HPLC. The combined fractions were lyophilized to give tert-butyl 7,9-dimethyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate, which was dissolved in methanol (0.5 mL), a solution of 4M HC1 in dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 4 h, then purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as the TFA salt (4 mg). LCMS m/z = 203.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (d, J = 6.8 Hz, 3H), 2.28 (s, 3H), 2.95 (dd, J = 9.3 and 8.0 Hz, 1H), 3.07-3.15 (m, 1H), 3.20-3.35 (m, 2H), 3.42-3.58 (m, 2H), 3.67 (t, J = 9.0 Hz, 1H), 4.18 (d, J = 14.8 Hz, 1H), 4.29 (d, J = 14.8 Hz, 1H), 6.86 (s, 1H), 6.99 (s, 1H).

Example 1C.73: Preparation of 8-bromo-6-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 260).

Step A: Preparation of 4-bromo-2-methylindoline.

To a solution of 4-bromo-2-methyl-lH-indole (368 mg, 1.752 mmol) in TFA (8 mL) at room temperature was added triethylsilane (1.119 mL, 7.007 mmol) dropwise under nitrogen. The reaction mixture was stirred at room temperature for 6 h and heated at 40 °C for 3 h. The mixture was concentrated, diluted with ethyl acetate, washed with sat. NaHC0₃, dried over anhydrous Na₂S0₄, filtered then concentrated. The residue was purified by silica gel column chromatography to give the title compound (270 mg) as brown oil. LCMS m/z = 212.0 [M+H]⁺; ^:H NMR (400 MHz, CDC1₃) δ ppm 1.52 (d, J = 6.6 Hz, 3H), 2.88 (dd, J = 16.4 and 7.1 Hz, 1H), 3.37 (dd, J = 16.4 and 8.2 Hz, 1H), 4.22- 4.32 (m, 1H), 6.5 (bs, 1H), 7.05-7.03 (m, 2H), 7.30 (dd, J = 7.1 and 1.7 Hz, 1H).

Step B: Preparation of 2-(4-bromo-2-methylindolin-l-yl)ethanamine.

4-Bromo-2-methylindoline (0.27 g, 1.273 mmol) and 2-bromoethanamine hydrobromide (0.313 g, 1.528 mmol) was heated neat at 110 °C overnight. The mixture was dissolved in methanol and purified by preparative HPLC and silica gel column chromatography to give the title compound (60 mg). LCMS m/z = 255.4 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J = 6.1 Hz, 3H), 2.50- 2.60 (m, 1H), 2.83 (t, J = 6.7 Hz, 2H), 3.10-3.22 (m, 3H), 3.70-3.80 (m, 1H), 6.40 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 7.9 Hz, 1H).

Step C: Preparation of 8-bromo-6-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i] indole. To a solution of 2-(4-bromo-2-methylindolin-l-yl)ethanamine (60 mg, 0.235 mmol) and 37% formaldehyde in water (52.52 μΐ, 0.705 mmol) in methanol (3 mL) was added TFA (90.04 μΐ, 1.176 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as a TFA salt (77 mg). LCMS m/z = 267.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.39 (d, J = 6.2 Hz, 3H), 2.57 (dd, J = 16.4 and 10.0 Hz, 1H), 3.05-3.13 (m, 1H), 3.30-3.38 (m, 2H), 3.40-3.48 (m, 1H), 3.55-3.68 (m, 2H), 4.05 (d, J = 14.9 Hz, 1H), 4.41 (d, J = 14.9 Hz, 1H), 6.92 (s, 2 x 1H).

Example 1C.74: Preparation of 6,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole (Compound 262)

Step A: Preparation of tert-butyl 8-bromo-6-methyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-/»]indole-2(lH)-carboxylate.

To a solution of 8-bromo-6-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole 2,2,2- trifluoroacetate (55 mg, 0.144 mmol) in DCM (2 mL) was added di-tert-butyl dicarbonate (47.23 mg, 0.216 mmol) and triethylamine (60.33 μL, 0.433 mmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was concentrated. The residue was purified by silica gel column chromatography to give the title compound (54 mg).

Step B: Preparation of 6,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indole. To a mixture of tert-butyl 8-bromo-6-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate (25 mg, 68.07 μιηοΐ), tetrakistriphenylphosphine palladium (15.73 mg, 13.61 μιηοΐ), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (17.09 mg, 0.136 mmol), and potassium carbonate (28.22 mg, 0.204 mmol) in dioxane (1.5 mL) was stirred at 90 °C overnight under nitrogen. The mixture was filtered by a syringe filter. The filtrate was concentrated then purified by silica gel column

chromatography to give tert-butyl 6,8-dimethyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate.

To the compound obtained above in methanol (0.5 mL) was added a solution of 4M HC1 in dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 2 h, then purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as the TFA salt (7 mg). LCMS m/z = 203.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J = 6.1 Hz, 3H), 2.09 (s, 3H), 2.48 (dd, J = 15.8 and 10.2 Hz, 1H), 2.83-2.92 (m, 1H), 3.12-3.25 (m, 2H), 3.28-3.46 (m, 2H), 3.52-3.58 (m, 1H), 3.94 (d, J = 14.6 Hz, 1H), 4.26 (d, J = 14.3 Hz, 1H), 6.53 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H).

Example 1C.75: Preparation of 2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-/H-]indole-7,l'- cyclopropane] (Compound 261).

Step A: Preparation of spiro[cyclopropane-l,3'-indoline].

A solution of 3-(2-bromoethyl)-lH-indole (380 mg, 1.696 mmol) in anhydrous CH₃CN (10 mL) was added potassium carbonate (1.640 g, 11.87 mmol) at room temperature. The reaction mixture was stirred at reflux overnight. Filtered, washed with ethanol. To the filtrate was added sodium borohydride (64.15 mg, 1.696 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was diluted with aqueous saturated NaHC0₃ solution, extracted with ethyl acetate. The combined organics were concentrated. The residue was purified by silica gel column chromatography to give the title compound as colorless oil, which turned to brown upon standing. LCMS m/z = 146.4 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 0.94-1.05 (m, 4H), 3.61 (s, 2H), 3.82 (bs, 1H), 6.60-6.74 (m, 3H), 7.30 (td, J = 7.6 and 1.3 Hz, 1H).

Step B: Preparation of 2-(spiro[cyclopropane-l,3'-indolin]-l'-yl)acetonitrile.

To spiro[cyclopropane-l,3'-indoline] (81 mg, 0.558 mmol) in H₂0 (2 mL) was added 55% 2- hydroxyacetonitrile in water (60.76 mg, 0.586 mmol). The reaction mixture was heated at 110 °C overnight. The mixture was then purified by preparative HPLC. The combined fractions were neutralized with saturated NaHC0₃, partially concentrated, then extracted with ethyl acetate. The combined organics were concentrated to give the title compound (80 mg). LCMS m/z = 185.2 [M+H]⁺.

Step C: Preparation of 2-(spiro[cyclopropane-l,3'-indolin]-l'-yl)ethanamine.

To a stirring solution of cobalt chloride (hexahydrate) (20.66 mg, 86.84 μιηοΐ) in EtOH (1 mL) was added a solution of sodium borohydride (6.571 mg, 0.174 mmol) in EtOH (1 mL) dropwise under nitrogen. After 15 min, a solution of 2-(spiro[cyclopropane-l,3'-indolin]-l'-yl)acetonitrile (80 mg, 0.434 mmol) in EtOH (4 mL) was added through a syringe. The reaction was stirred room temperature for 15 min and added (BOC)₂0 (99.51 mg, 0.456 mmol) followed by sodium borohydride (49.28 mg, 1.303 mmol). The reaction was stirred at room temperature for 1.5 h before it was worked up with aqueous 1M sodium hydroxide solution (0.478 mL, 0.478 mmol). The mixture was filtered. The filtrate was concentrated. The residue was extracted with ethyl acetate. The organic extract was concentrated. The residue was purified by silica gel column chromatography to give tert-butyl (2- (spiro[cyclopropane-l,3'-indolin]-l'-yl)ethyl)carbamate (83 mg, 0.288 mmol, 66.3 %). It was then dissolved in DCM (2 mL), a solution of 4M HC1 in dioxane (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by preparative HPLC. The combined organics were lyophilized to give the title compound as TFA salt (82 mg). LCMS m/z = 189.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.97-1.00 (m, 4H), 3.18 (t, J = 5.9 Hz, 2H), 3.38 (t, J = 6.0 Hz, 2H), 3.41 (s, 2H), 6.58-6.63 (m, 2H), 6.67 (td, J = 7.3 and 0.9 Hz, 1H), 7.02 (td, J = 7.8 and 1.4 Hz, 1H).

Step D: Preparation of 2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-/H-]indole-7,l'- cyclopropane].

To a solution of 2-(spiro[cyclopropane-l,3'-indolin]-l'-yl)ethanamine 2,2,2-trifluoroacetate (40 mg, 0.132 mmol) and 37% formaldehyde in water (29.55 μΕ, 0.397 mmol) in methanol (3 mL) was added TFA (50.66 μΕ, 0.662 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated, the residue was purified by preparative HPLC. The combined fractions were lyophilized to give impure product (~ 9 mg), which was then dissolved in DCM (1 mL) and added Boc₂0 (8.6 mg, 39.7 μιηοΐ) and Et₃N (13.8 μΕ, 99.3 μιηοΐ). The reaction mixture was stirred at room temperature for 3 h, then purified by preparative HPLC, lyophilized to give Boc-protected compound, which was then dissolved in methanol (0.5 mL) and added a solution of 4M HCl in dioxane (0.5 mL). The mixture was stirred at room temperature for 1 h and concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as TFA salt (2.6 mg). LCMS m/z = 201.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.97-1.01 (m, 4H), 3.22-3.27 (m, 2H), 3.49-3.53 (m, 2H), 3.52 (s, 2H), 4.27 (s, 2H), 6.68 (dd, J = 7.4 and 1.0 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H).

Example 1C.76: Preparation of 9-methoxy-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 272).

Step A: Preparation of 5-methoxy-3-methyl-lH- indole.

To a solution of 5-methoxy-lH-indole-3-carbaldehyde (500 mg, 2.854 mmol) in THF (10 mL) at room temperature was added a 2M solution of LiAlH₄ in THF (2.846 mL, 5.691 mmol) drop wise under nitrogen. The reaction mixture was stirred for 3 h at reflux. After cooled down in an ice-water bath, the reaction was quenched carefully with water (216 μL), aqueous 15% NaOH solution (216 μL) and water (3 x 216 μL). The mixture was filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (400 mg) as an oil. LCMS m/z = 162.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 2.31 (d, J = 1.1 Hz, 3H), 3.88 (s, 3H), 6.86 (dd, J = 8.7 and 2.4 Hz, 1H), 6.94-6.97 (m, 1H), 7.02 (d, J = 2.4 Hz, 1H), 7.24 (dd, J = 8.8 and 0.4 Hz, 1H), 7.76 (bs, 1H).

Step B: Preparation of 5-methoxy-3-methylindoline.

To a solution of 5-methoxy-3-methyl-lH-indole (400 mg, 2.481 mmol) in TFA (5 mL) at room temperature was added triethylsilane (1.585 mL, 9.926 mmol) dropwise under nitrogen. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with ethyl acetate, washed with saturated aqueous NaHC0₃ solution, dried over anhydrous Na₂S0₄, filtered then concentrated. The residue was purified by silica gel column chromatography to give the title compound (200 mg) as orange oil. LCMS m/z = 164.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.31 (d, J = 6.8 Hz, 3H), 3.10 (t, J = 8.7 Hz, 1H), 3.27-3.38 (m, 1H), 3.50 (br, 1H), 3.68 (t, J = 8.6 Hz, 1H), 3.76 (s, 3H), 6.57-6.62 (m, 2H), 6.72-6.75 (m, 1H).

Step C: Preparation of 2-(5-methoxy-3-methylindolin-l-yl)ethanamine.

5-Methoxy-3-methylindoline (0.200 g, 1.225 mmol) and 2-bromoethanamine hydrobromide (0.301 g, 1.470 mmol) was heated neat at 110 °C for 15 h. The solid mixture was dissolved in methanol and purified by preparative HPLC. The combined fractions lyophilized to give the title compound as the TFA salt (300 mg). LCMS m/z = 207.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.31 (d, J = 6.8 Hz, 3H), 2.71 (t, J = 8.7 Hz, 1H), 3.00-3.08 (m, 1H), 3.17 (t, J = 5.9 Hz, 2H), 3.25-3.30 (m, 1H), 3.35-3.45 (m, 1H), 3.61 (t, J = 8.3 Hz, 1H), 3.72 (s, 3H), 6.53 (d, J = 8.5 Hz, 1H), 6.62-6.67 (m, 1H), 6.72-6.74 (m, 1H). Step D: Preparation of 9-methoxy-7-methyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- &i]indole.

To a solution of 2-(5-methoxy-3-methylindolin-l-yl)ethanamine 2,2,2-trifluoroacetate (0.3 g, 0.937 mmol) and 37% formaldehyde in water (0.209 mL, 2.810 mmol) in methanol (3 mL) was added TFA (0.359 mL, 4.683 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated, the residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound as the TFA salt (286 mg). LCMS m/z = 219.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.30 (d, J = 6.8 Hz, 3H), 2.93 (dd, J = 9.3 and 8.0 Hz, 1H), 3.03-3.08 (m, 1H), 3.15-3.25 (m, 1H), 3.28-3.3.35 (m, 1H, buried in solvent peak), 3.42-3.55 (m, 2H), 3.64 (dd, J = 9.3 and 8.6 Hz, 1H), 3.74 (s, 3H), 4.17 (d, J = 14.8 Hz, 1H), 4.27 (d, J = 14.8 Hz, 1H), 6.62-6.64 (m, 1H), 6.76-6.79 (m, 1H).

Example 1C.77: Preparation of 7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/M-]indol-9-ol (Compound 208).

9-Methoxy-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole bis(2,2,2- trifluoroacetate) (180 mg, 0.403 mmol) was dissolved in 48% HBr/AcOH (6 mL, 1 : 1 ratio). The reaction mixture was heated at 120 °C overnight. The mixture was concentrated. The residue was purified by preparative HPLC. The combined fractions were lyophilized to give the title compound (10 mg). LCMS m/z = 205.2 [M+H]⁺; ^:H NMR (400 MHz, CD₃OD) δ ppm 1.28 (d, J = 6.8 Hz, 3H), 2.91 (dd, J = 9.4 and 8.2 Hz, 1H), 3.00-3.08 (m, 1H), 3.15-3.25 (m, 1H), 3.22-3.30 (m, 1H), 3.40-3.55 (m, 2H), 3.63 (dd, J = 9.3 and 8.8 Hz, 1H), 4.12 (d, J = 14.7 Hz, 1H), 4.21 (d, J = 14.7 Hz, 1H), 6.49-6.50 (m, 1H), 6.63-6.65 (m, 1H).

Example 1C.78: Preparation of (7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/H-]indol- 8-yl)methanol (Compound 265).

Step A: Preparation of tert-butyl 8-(hydroxymethyl)-7,7-dimethyl-3,4,6,7-tetrahydro-

[l,4]diazepino[6,7,l-/»]indole-2(lH)-carboxylate.

To a solution of methyl 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole-8- carboxylate (90 mg, 0.346 mmol) in THF (3 mL) was added a 2M solution of lithium aluminum hydride (0.672 mL, 1.344 mmol) in an ice-water bath under nitrogen. The reaction mixture was then heated at reflux for 5 h. After cooled down in an ice-water bath, the mixture was added carefully water (51 μL), aqueous 15% NaOH solution (51 μL) and water (3 X 51 μL). The mixture was stirred for 10 min, filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in DCM (3 mL) and added triethylamine (93.64 μΐ, 0.672 mmol) and di-tert-butyl dicarbonate (95.31 mg, 0.437 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated. The residue was purified by silica gel column chromatography to give the title compound (42 mg) as oil. LCMS m/z = 333.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm rotamers 1.39(br, 9H), 1.40 (s, 6H), 1.69 (br, 1H), 2.99 (br, 2H), 3.10 (s, 2H), 3.70 (br, 2H), 4.34-4.40 (br, 2H), 4.74 (br, 2H), 6.78-6.80 (m, 1H), 6.90-7.00 (br, 1H). Step B: Preparation of (7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l-/H]indol- 8-yl)methanol.

To a solution of tert-butyl 8-(hydroxymethyl)-7,7-dimethyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate (42 mg, 0.126 mmol) in ether (1 mL) was added a solution of 4M hydrogen chloride in dioxane (1.263 mL, 5.054 mmol). The reaction mixture was stirred at room temperature overnight. The off-white solid was collected, washed with ether and dried to give the title compound as the HC1 salt (33 mg). LCMS m/z = 233.4 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.41 (s, 6H), 3.25 (s, 2H), 3.27-3.33 (m, 2H), 3.52-3.56 (m, 2H), 4.29 (s, 2H), 4.72 (s, 2H), 7.03 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H).

Example 1C.79 Preparation of 4-methyl-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- /M]indole-7,l'-cyclobutane] (Compound 270) (as the 2,2,2-trifluoroacetate salt).

Step A: Preparation of 2-(spiro[cyclobutane-l,3'-indolin]-l'-yl)propanenitrile.

A mixture of spiro[cyclobutane-l,3'-indoline] (0.1 g, 0.628 mmol) and 2-hydroxypropanenitrile (0.141 ml, 3.140 mmol) in 2 ml H20 was heated at 105°C for 15 h. The mixture was purified by preparative HPLC to give the title compound (0.122 g). LCMS m/z = 213.0 [M+l]⁺; ¾ NMR (400 MHz, CD₃C1) δ ppm 1.64 (d, J = 7.20 Hz, 3H), 1.98-2.11 (m, 2H), 2.14-2.24 (m, 2H), 2.26-2.33 (m, 1H), 2.51-2.58 (m, 1H), 3.25 (d, J = 8.60 Hz, 1H), 3.65 (d, J = 8.60 Hz, 1H), 4.55 (q, J = 7.27 Hz, 1H), 6.57 (d, J = 7.88 Hz, 1H), 6.88-6.92 (m, 1H), 7.13-7.17 (m, 1H), 7.34 (dd, J = 7.41, 0.82 Hz, 1H).

Step B: Preparation of 2-(spiro[cyclobutane-l,3'-indolin]-l'-yl)propan-l-amine 2,2,2- trifluoroacetate.

To a solution of 2-(spiro[cyclobutane-l,3'-indolin]-l'-yl)propanenitrile (0.12 g, 0.565 mmol) in MeOH (1.884 ml), was added cobalt(II) chloride hexahydrate (0.403 g, 1.696 mmol). After stirring at room temperature for 5 min, sodium tetrahydroborate (0.107 g, 2.826 mmol) was added in small portions. After stirring at room temperature for 1 h, mixture was extracted with water and DCM. The organic extract was concentrated. The residue was purified by preparative HPLC to give the title compound (57.3 mg). LCMS m/z = 217.4 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J = 6.68 Hz, 3H), 1.98-2.06 (m, 2H), 2.12-2.19 (m, 2H), 2.26-2.33 (m, 1H), 2.46-2.53 (m, 1H), 3.00-3.12 (m, 2H), 3.25 (d, J = 8.48 Hz, 1H), 3.46 (d, J = 8.44 Hz, 1H), 3.99 (brs, 1H), 6.60 (d, J = 7.64 Hz, 1H), 6.86-6.88 (m, 1H), 7.11 (t, J = 7.52 Hz, 1H), 7.32 (d, J = 6.92 Hz, 1H).

Step C: Preparation of 4-methyl-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- /M]indole-7,l'-cyclobutane] 2,2,2-trifluoroacetate.

A mixture of 2-(spiro[cyclobutane-l,3'-indolin]-r-yl)propan-l-amine 2,2,2-trifluoroacetate (55 mg, 0.166 mmol), 2,2,2-trifluoroacetic acid (38.25 μΐ, 0.499 mmol), and 37% formaldehyde in water (37.19 μΐ, 0.499 mmol) in MeOH (3 ml) was heated at 70°C for 1 h. The mixture was purified by preparative HPLC to give the title compound (0.0347 g). LCMS m/z = 229.6 [M+l]⁺; ¾ NMR (400 MHz, CD₃CI) δ ppm 1.26 (d, J = 6.56 Hz, 3H), 1.98-2.10 (m, 2H), 2.15-2.24 (m, 2H), 2.25-2.32 (m, IH), 2.45-2.52 (m, IH), 3.29-3.35 (m, IH), 3.40-3.43 (m, 2H), 3.54-3.57 (m, IH), 3.71-3.74 (m, IH), 4.17-4.31 (m, 2H), 6.91-6.96 (m, 2H), 7.35-7.37 (m, IH).

Example 1C.80: Preparation of 8-fluoro-4,7,7-trimethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole (Compound 273) (as the 2,2,2-trifluoroacetate salt).

Step A: Preparation of 2-(4-fluoro-3,3-dimethylindolin-l-yl)propanenitrile.

A mixture of 4-fluoro-3,3-dimethylindoline (0.1 g, 0.605 mmol) and 2-hydroxypropanenitrile (87.80 μΐ, 3.026 mmol) in 2 ml H₂0 was heated at 105°C for 15 h. The mixture was purified by preparative HPLC to give the title compound (0.0856 g). LCMS m/z = 219.4 [M+l]⁺; ¾-NMR (CDC1₃) 1.37 (s, 3H), 1.52 (s, 3H), 1.62 (d, J = 7.28 Hz, 3H), 3.10 (d, J = 8.32 Hz, IH), 3.25 (d, J =

8.28 Hz, IH), 4.54 (q, J = 7.27 Hz, IH), 6.34 (d, J = 7.88 Hz, IH), 6.48-6.52 (m, IH), 7.09 (dt, J = 5.70, 8.11 Hz, IH).

Step B: Preparation of 2-(4-fluoro-3,3-dimethylindolin-l-yl)propan-l-amine 2,2,2- trifluoroacetate.

To a solution of in 2-(4-fluoro-3,3-dimethylindolin-l-yl)propanenitrile (85.6 mg, 0.392 mmol) in MeOH (2 ml), cobalt(II) chloride hexahydrate (0.280 g, 1.177 mmol) was added. After stirring at room temperature for 5 min, sodium tetrahydroborate (74.18 mg, 1.961 mmol) was added in small portions (over ca. 15 min) whereupon vigorous bubbling and slight exotherm was observed. After stirring at room temperature for 1 h, mixture was extracted with water and CH₂C1₂. The organic extract was concentrated. The residue was purified by preparative HPLC to give the title compound (80.0 mg). LCMS m/z = 223.2 [M+l]⁺; ¾-NMR (CD₃OD) 1.15 (d, J = 6.72 Hz, 3H), 1.39 (s, 3H), 1.45 (s, 3H), 3.04-3.15 (m, 2H), 3.17 (s, 2H), 3.95-4.00 (m, IH), 6.34-6.39 (m, 2H), 7.04 (dt, J = 5.70, 8.11 Hz, IH).

Step C: Preparation of 8-fluoro-4,7,7-trimethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole 2,2,2-trifluoroacetate.

A mixture of 2-(4-fluoro-3,3-dimethylindolin-l-yl)propan-l -amine 2,2,2-trifluoroacetate (80 mg, 0.238 mmol), 2,2,2-ttifluoroacetic acid (72.86 μΐ, 0.951 mmol), and 37% formaldehyde in water (70.84 μΐ, 0.951 mmol) in AcOH (0.5 ml) and toluene (0.5 ml) was heated at 120°C for 3 h. Solvent was removed. The residue was purified by preparative HPLC to give the title compound (0.0167 g). LCMS m/z = 235.2 [M+l] ⁺. ¾-NMR (400 MHz, D₂0) 1.27 (d, J = 6.36 Hz, 3H), 1.36 (s, 3H), 1.44 (s, 3H), 3.26-3.37 (m, 3H), 3.42-3.55 (m, 3H), 4.15-4.31 (m, 2H), 6.56 -6.60 (m, IH), 7.04-7.07 (m, IH).

Example 1C.81: Preparation of (S)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 266).

Step A: Preparation of (S)-tert-butyl (l-(3,3-dimethylindolin-l-yl)-l-oxopropan-2- yl)carbamate.

To a solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (133 mg, 0.703 mmol) in 7 mL DMF, triethylamine (127 μ^ 0.912 mmol) and HATU (319 mg, 0.839 mmol) were added. After stirring at room temperature for 5 min, 3,3-dimethylindoline (97.2 mg, 0.660 mmol) was added. After stirring at room temperature for 4 h, the mixture was extracted with AcOEt and brine. The organic phase was dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give (S)-tert-butyl (l-(3,3-dimethylindolin-l-yl)-l-oxopropan-2-yl)carbamate (204 mg) as a white solid. LCMS m/z = 319.4 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.358 (s, 3H), 1.364 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H), 3.78 (d, J = 10.0 Hz, 1H), 4.00 (d, J = 10.0 Hz, 1H), 4.54-4.61 (m, 1H), 5.46 (d, J = 8.5 Hz, 1H), 7.07-7.10 (m, 1H), 7.15-7.16 (m, 1H), 7.20-7.24 (m, 1H), 8.17 (d, J = 8.1 Hz, 1H).

Step B: Preparation of (S)-tert-butyl (l-(3,3-dimethylindolin-l-yl)propan-2-yl)carbamate. To a solution of (S)-tert-butyl (l-(3,3-dimethylindolin-l-yl)-l-oxopropan-2-yl)carbamate (197 mg, 0.619 mmol) in 3 mL THF, 3 M lithium aluminum hydride in THF (0.412 mL, 1.236 mmol) was added slowly (over ca. 5 min). After stirring at room temperature for 1 h, the reaction was quenched by the dropwise addition of water. The residue was extracted with water and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography. Fractions containing product were concentrated and the residue was re -purified by preparative HPLC. Fractions containing product were partly concentrated and the residue was extracted with 1 M NaOH and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated to give (S)-tert-butyl (l-(3,3-dimethylindolin-l-yl)propan-2-yl)carbamate (21.6 mg). LCMS m/z = 305.2

[M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.21 (d, J = 6.6 Hz, 3H), 1.287 (s, 3H), 1.292 (s, 3H), 1.44 (s, 9H), 2.98-3.11 (m, 2H), 3.14 (d, J = 8.4 Hz, 1H), 3.21 (d, J = 8.4 Hz, 1H), 3.87-3.94 (m, 1H), 4.49

(bs, 1H), 6.47 (d, J = 7.8 Hz, 1H), 6.66-6.70 (m, 1H), 7.00 (dd, J₁ = 7.0 Hz, J₂ = 0.96 Hz, 1H), 7.04-7.08 (m, 1H).

Step C: Preparation of (S)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole.

To a solution of (S)-tert-butyl (l-(3,3-dimethylindolin-l-yl)propan-2-yl)carbamate (20.2 mg,

66.35 μιηοΐ) in 0.6 mL CH₂C1₂, TFA (142 μΐ_^, 1.854 mmol) was added. After stirring at room temperature for 1.5 h, the solution was concentrated and dried under high vacuum. The residue was dissolved in 1 mL MeOH, TFA (156 μΐ, 204 μιηοΐ) and 37% formaldehyde in water (152 μΐ,, 204 μιηοΐ) were added, and stirred at 80°C (oil bath). After 1 h, the solution was concentrated and the residue was purified by preparative HPLC. Fractions containing product were partly concentrated. The residue was treated with 1.25 M HC1 in MeOH (ca. 1 mL), concentrated and dried under high vacuum to give (S)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;]indole dihydrochloride (16.5 mg) as a tanned solid. LCMS m/z = 216.8 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.27 (s, 3H), 1.37 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 2.92-2.98 (m, 1H), 3.12 (d, J = 9.4, 1H), 3.40-3.47 (m, 2H), 3.74- 3.79 (m, 1H), 4.25 (d, J = 15.1 Hz, 1H), 4.37 (d, J = 15.1 Hz, 1H),6.87-6.91 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H). Example 1C.82: Preparation of (R)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- fa^'jindole (Compound 264).

Step A: Preparation of (R)-tert-butyl (l-(3,3-dimethylindolin-l-yl)-l-oxopropan-2- yl)carbamate.

To a solution of (R)-2-((tert-butoxycarbonyl)amino)propanoic acid (141 mg, 0.745 mmol) in 7 mL DMF, triethylamine (125 μΐ,, 0.897 mmol) and HATU (322 mg, 0.847 mmol) were added. After stirring at room temperature for 5 min, 3,3-dimethylindoline (101 mg, 0.686 mmol) was added. After stirring at room temperature for overnight, the mixture was extracted with AcOEt and brine. The organic phase was dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give (R)-tert-butyl (l-(3,3-dimethylindolin-l-yl)-l-oxopropan-2- yl)carbamate (205 mg) as a white solid. LCMS m/z = 319.4 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.358 (s, 3H), 1.364 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H), 3.78 (d, J = 10.0 Hz, 1H), 4.00 (d, J = 10.0 Hz, 1H), 4.54-4.61 (m, 1H), 5.46 (d, J = 8.5, 1H), 7.07-7.10 (m, 1H), 7.15-7.16 (m, 1H), 7.20-7.24 (m, 1H), 8.17 (d, J = 8.1 Hz, 1H).

Step B: Preparation of (R)-tert-butyl (l-(3,3-dimethylindolin-l-yl)propan-2- yl)carbamate.

To a solution of (R)-tert-butyl (l-(3,3-dimethylindolin-l-yl)-l-oxopropan-2-yl)carbamate (202 mg, 0.634 mmol) in 5 mL THF, 1 M aluminum(III) lithium hydride in THF (1.3 mL, 1.300 mmol) was added slowly (over ca. 10 min). After stirring at room temperature for 1.5 h, the mixture was quenched by the slow addition of water and extracted with 2 M NH₄C1 and CH₂C1₂. Organic phases were concentrated and the residue was purified by preparative HPLC. Fractions containing product were partly concentrated and the residue was extracted with 1 M NaOH and CH₂C1₂. Organic phases were dried over MgS04, filtered, and concentrated to give (R)-tert- butyl (l-(3,3-dimethylindolin-l- yl)propan-2-yl)carbamate (25 mg) as a white solid. LCMS m/z = 305.2 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.21 (d, J = 6.6 Hz, 3H), 1.287 (s, 3H), 1.292 (s, 3H), 1.44 (s, 9H), 2.98-3.11 (m, 2H), 3.14 (d, J = 8.4 Hz, 1H), 3.21 (d, J = 8.4 Hz, 1H), 3.87-3.94 (m, 1H), 4.49 (bs, 1H), 6.47 (d, J = 7.8 Hz, 1H), 6.66-6.70 (m, 1H), 7.00 (dd, J_: = 7.0 Hz, J₂ = 0.96 Hz, 1H), 7.04-7.08 (m, 1H).

Step C: Preparation of (R)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole.

To a solution of (R)-tert-butyl (l-(3,3-dimethylindolin-l-yl)propan-2-yl)carbamate (23.7 mg,

77.85 μιηοΐ) in 0.8 mL CH₂C1₂, 2,2,2-trifluoroacetic acid (179 μΐ,, 2.338 mmol) was added. After stirring at room temperature for 2 h, the solution was concentrated and dried under high vacuum. The residue was dissolved in 1 mL MeOH, TFA (15.9 μΐ_^, 0.208 mmol), and 37% formaldehyde in water (15.5 μΐ_^, 0.208 mmol) were added and stirred at 80°C. After 1 h, the solution was concentrated and the residue was purified by preparative HPLC. Fractions containing product were partly concentrated. The residue was treated with 1.25 M HC1 in MeOH (ca. 1 mL), concentrated and dried under high vacuum to give (R)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- i;^']indole dihydrochloride (15.1 mg) as a tanned solid. LCMS m/z = 216.8 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.27 (s, 3H), 1.37 (s, 3H), 1.45 (d, J = 6.7 Hz, 3H), 2.92-2.98 (m, 1H), 3.12 (d, J = 9.4, 1H), 3.40-3.47 (m, 2H), 3.74- 3.79 (m, 1H), 4.25 (d, J = 15.1 Hz, 1H), 4.37 (d, J = 15.1 Hz, 1H),6.87-6.91 (m, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H). Example 1C.83: Preparation of 4,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 268).

Step A: Preparation of 2-(3,3-dimethylindolin-l-yl)propanenitrile.

A mixture of 3,3-dimethylindoline (103 mg, 0.700 mmol), potassium carbonate (288 mg, 2.084 mmol), and 2-bromopropanenitrile (303 μΐ_^, 3.506 mmol) in 2 mL CH₃CN was stirred at 80°C (oil bath) over night. The mixture was purified by preparative HPLC. Fractions containing product were partly concentrated and residue was extracted with 1 M NaHC0₃ and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated to give 2-(3,3-dimethylindolin-l-yl)propanenitrile (105 mg). LCMS m/z = 201.2 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.26 (s, 3H), 1.40 (s, 3H), 1.63 (d, J = 7.3 Hz, 3H), 3.05 (d, J = 8.2 Hz, 1H), 3.25 (d, J = 8.2 Hz, 1H), 4.57 (q, J = 7.3 Hz, 1 H), 6.57 (d, J = 7.9 Hz, 1H), 6.83-6.87 (m, 1H), 7.06 (dd, J₁ =7.4 Hz, J₂ = 0.8 Hz, 1H), 7.12-7.16 (m, 1H).

Step B: Preparation of tert-butyl (2-(3,3-dimethylindolin-l-yl)propyl)carbamate.

To a solution of 2-(3,3-dimethylindolin-l-yl)propanenitrile (101 mg, 0.504 mmol) in 17 mL MeOH, cobalt(II) chloride hexahydrate (360 mg, 1.513 mmol) was added. After stirring at room temperature for 5 min, sodium borohydride (97 mg, 2.564 mmol) was added in small portions (over ca. 15 min) whereupon vigorous bubbling and slight exotherm was observed. After stirring at room temperature for 1 h, (Boc)₂0 (221 mg, 1.013 mmol) was added. After stirring at room temperature for 15 min, the mixture was extracted with water and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give tert- butyl (2-(3,3-dimethylindolin-l-yl)propyl)carbamate (117 mg) as a viscous oil. LCMS m/z = 305.2 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.07 (d, J = 6.7 Hz, 3H), 1.08 (s, 3H), 1.33 (s, 3H), 1.40 (s, 9H), 3.05-3.18 (m, 3H), 3.31-3.40 (m, 1H), 3.73-3.81 (m, 1H), 5.30 (bs, 1H), 6.44 (d, J = 7.9 Hz, 1H), 6.65-6.69 (m, 1H), 7.00 (dd, J_: = 7.2 Hz, J₂ = 0.96 Hz, 1H), 7.04-7.08 (m, 1H).

Step C: Preparation of 4,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole.

To a solution of tert-butyl (2-(3,3-dimethylindolin-l-yl)propyl)carbamate (113 mg, 0.371 mmol) in 4 mL CH₂C1₂, TFA (868 μL, 11.33 mmol) was added. After stirring at room temperature for 1 h, the solution was concentrated and dried under high vacuum. The residue was dissolved in 5 mL MeOH and 2,2,2-trifluoroacetic acid (85.2 μL, 1.113 mmol) and formaldehyde (82.8 μL, 1.112 mmol) were added. After stirring at 70°C for 15 min, the mixture was purified by preparative HPLC. Fractions containing product were partly concentrated, 1.25 M HC1 in MeOH was added (ca. 1 mL), concentrated, and dried under high vacuum to give 4,7, 7-trimethyl- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7,l- i;^']indole dihydrochloride (66.2 mg) as a tanned solid. LCMS m/z = 217.0 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.25 (s, 3H), 1.31 (d, J = 6.6 Hz, 3H), 1.37 (s, 3H), 3.18 (d, J = 9.5 Hz, 1H), 3.30-3.59 (m, 4H), 4.19 (d, J = 15 Hz, 1H), 4.39 (d, J = 15 Hz, 1H), 6.87-6.91 (m, 1H), 7.03- 7.05 (m, 1H), 7.13-7.15 (m, 1H).

Example 1C.84: Preparation of 4-ethyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- fa^'jindole (Compound 269).

Step A: Preparation of ethyl 2-(3,3-dimethylindolin-l-yl)butanoate.

A mixture of 3,3-dimethylindoline (204 mg, 1.386 mmol), ethyl 2-bromobutanoate (1.023 mL, 6.928 mmol), and potassium carbonate (603 mg, 4.363 mmol) in 4 mL CH₃CN was stirred at 100°C (oil bath) for 23 h. The mixture was extracted with 2 M HCl and CH₂C1₂. Organic phases were concentrated and the residue was purified by preparative HPLC. Fractions containing product were partly concentrated and the residue was extracted with 1 M NaHC0₃ and CH₂C1₂. Organic phases were dried over MgS04, filtered, and concentrate to give ethyl 2-(3,3-dimethylindolin-l-yl)butanoate (254 mg) as an oil. LCMS m/z = 261.8 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.03 (t, J = 7.4 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H), 1.25 (s, 3H), 1.34 (s, 3H), 1.79-2.00 (m, 2H), 3.23 (d, J = 8.4 Hz, 1H), 3.41 (d, J = 8.4 Hz, 1H), 4.00-4.13 (m, 3 H), 6.41 (d, J = 7.8 Hz, 1H), 6.63-6.67 (m, 1H), 6.98-7.05 (m, 2H).

Step B: Preparation of 2-(3,3-dimethylindolin-l-yl)butan-l-ol.

To a solution of ethyl 2-(3,3-dimethylindolin-l-yl)butanoate (175 mg, 0.670 mmol) in 2 mL EtOH, sodium borohydride (102 mg, 2.696 mmol) was added. The mixture was stirred at 60°C (oil bath) overnight. More sodium borohydride was added (102 mg) and mixture was continued to be stirred at 75°C. After stirring overnight, the mixture was diluted with water, acidified by the addition of 2 M HCl, and extracted with CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 2-(3,3-dimethylindolin-l- yl)butan-l-ol (75 mg) as an oil. LCMS m/z = 220.2 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 0.92 (t, J = 7.4 Hz, 3H), 1.27 (s, 3H), 1.33 (s, 3H), 1.44-1.60 (m, 2H), 1.99 (m, 1H), 3.10-3.15 (m, 2H), 3.60- 3.73 (m, 3H), 6.50 (d, J = 7.9 Hz, 1H), 6.64-6.68 (m, 1H), 6.99-7.07 (m, 1H).

Step C: Preparation of 2-(2-(3,3-dimethylindolin-l-yl)butyl)isoindoline-l,3-dione.

To a solution of 2-(3,3-dimethylindolin-l-yl)butan-l-ol (71.3 mg, 0.325 mmol), isoindoline- 1,3-dione (58.6 mg, 0.398 mmol), and triphenylphosphine (134 mg, 0.511 mmol) in 3 mL THF, DIAD (77 μΐ_^, 0.391 mmol) was added. After stirring at room temperature overnight, the mixture was extracted with AcOEt and water. The organic phase was dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 2-(2-(3,3-dimethylindolin-l- yl)butyl)isoindoline-l,3-dione (53.9 mg). LCMS m/z = 349.4 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 0.95 (t, J = 7.4 Hz, 3H), 1.22-1.28 (m, 7H), 1.60-1.64 (m, 2H), 3.08 (d, J = 8.3 Hz, 1H), 3.39 (d, J = 8.3 Hz, 1H), 3.63-3.67 (m, 1H), 3.98-4.05 (m, 1H), 6.39-6.46 (m, 2H), 6.80-6.87 (m, 2H), 7.63-7.65 (m, 2H), 7.74-7.76 (m, 2H).

Step D: Preparation of 4-ethyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole. To a solution of 2-(2-(3,3-dimethylindolin-l-yl)butyl)isoindoline-l,3-dione (50.9 mg, 0.146 mmol) in 1 mL toluene, hydrazine (0.1 mL, 3.186 mmol) was added and stirred at 80°C (oil bath). After 1 h, the mixture was concentrated and dried under high vacuum. The residue was dissolved in 1 mL MeOH and TFA (67 μL, 0.875 mmol) and 37% formaldehyde in water (80 μL, 1.07 mmol) were added. The mixture was stirred at 70°C for 0.5 h, concentrated and purified by preparative HPLC. Fractions containing pure product were concentrated, 1.2 M HC1 in MeOH (ca 1 mL) was added, concentrated and dried under high vacuum to give 4-ethyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- WJindole dihydrochloride (10.1 mg). LCMS m/z = 231.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 1.05 (t, J = 7.4 Hz, 3H), 1.28 (s, 3H), 1.37 (s, 3H), 1.66-1.90 (m, 2H), 3.49-3.54 (m, 2H), 3.63-3.67 (m, 1H), 4.26 (d, J = 14.8, 1H), 4.38 (d, J = 14.8 Hz, 1H), 6.91-6.95 (m, 1H), 7.06-7.08 (dd, J_x = 7.4 Hz, J₂ = 0.3 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H).

Example 1C.85: Preparation of 4-cyclopropyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole (Compound 271).

Step A: Preparation of 2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)acetate.

A mixture of 3,3-dimethylindoline (105 mg, 0.713 mmol), ethyl 2-bromo-2-cyclopropylacetate (297 μL, 2.143 mmol), and potassium carbonate (300 mg, 2.171 mmol) in 2 mL CH₃CN was stirred at 100°C (oil bath) for 16 h. The mixture was extracted with 2 M HC1 and CH₂C1₂. Organic phases were concentrated and residue was purified by preparative HPLC. Fractions containing product were partly concentrated and the residue was extracted with 1 M NaHC0₃ and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrate to give ethyl 2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)acetate (162 mg) as a brownish oil. LCMS m/z = 274.4 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 0.37-0.43 (m, 1H), 0.52-0.58 (m, 1H), 0.61-0.73 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H), 1.26-1.34 (m, 7H), 3.33 (d, J = 9.4 Hz, 1H), 3.49 (d, J = 8.4 Hz, 1H), 3.61 (d, J = 8.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 6.30 (dd, J₁ = 7.5 Hz, J₂ = 0.8 Hz, 1H), 6.63-6.67 (m, 1H), 6.98-7.02 (m, 2H).

Step B: Preparation of 2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)ethanol.

To an ice-cooled solution of ethyl 2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)acetate (158 mg, 0.578 mmol) in 5 mL THF, 1 M lithium aluminum hydride in THF (1 mL, 1.000 mmol) was added slowly. After stirring at 0°C for 40 min, the reaction was quenched by the slow addition of water. The residue was extracted with water and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 2-cyclopropyl-2- (3,3-dimethylindolin-l-yl)ethanol (122 mg) as an oil. LCMS m/z = 231 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 0.27-0.35 (m, 2H), 0.43-0.58 (m, 2H), 0.84-0.93 (m, 1H), 1.26 (s, 3H), 1.37 (s, 3H), 2.97-3.03 (m, 1H), 3.24 (d, J = 8.5 Hz, 1H), 3.37 (d, J = 8.5 Hz, 1H), 3.68-3.80 (m, 2H), 6.45 (d, J = 7.8 Hz, 1H), 6.65-6.69 (m, 1H), 7.01-7.05 (m, 2H).

Step C: Preparation of 2-(2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)ethyl)isoindoline-l,3- dione. To a solution of 2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)ethanol (120 mg, 0.519 mmol), isoindoline-l,3-dione (94 mg, 0.639 mmol), and triphenylphosphine (0.184 g, 0.702 mmol) in 5 mL THF, (E)-diisopropyl diazene-l,2-dicarboxylate (0.133 mL, 0.675 mmol) was added. After stirring at room temperature for 4 h, the mixture was extracted with AcOEt and water. The organic phase was dried over MgS04, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 2-(2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)ethyl)isoindoline-l,3-dione (144 mg) as an oil. LCMS m/z = 361.4 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 0.26-0.35 (m, 2H), 0.43-0.49 (m, IH), 0.52-0.59 (m, IH), 0.94-1.03 (m, IH), 1.20 (s, 3H), 1.31 (s, 3H), 3.29-3.35 (m, IH), 3.37 (d, J = 8.2 Hz, IH), 3.45 (d, J = 8.2 Hz, IH), 3.83-3.88 (m, IH), 3.98-4.04 (m, IH), 6.36 (d, J = 7.9 Hz, IH), 6.48-6.52 (m, IH), 6.86-6.91 (m, 2H), 7.65-7.68 (m, 2H), 7.76-7.79 (m, 2H).

Step D: Preparation of 2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)ethanamine 2,2,2- trifluoroacetate.

A mixture of 2-(2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)ethyl)isoindoline-l,3-dione (142 mg, 0.394 mmol) and hydrazine (200 μΕ, 6.372 mmol) in 4 mL toluene was stirred at 80°C. After 4 h, the mixture was concentrated and the residue was purified by preparative HPLC to give 2-cyclopropyl- 2-(3,3-dimethylindolin-l-yl)ethanamine 2,2,2-trifluoroacetate (129 mg). LCMS m/z = 231.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.30-0.36 (m, 2H), 0.47-0.53 (m, IH), 0.57-0.65 (m, IH), 0.86- 0.95 (m, IH), 1.29 (s, 3H), 1.36 (s, 3H), 3.07-3.14 (m, IH), 3.20-3.22 (m, 2H), 3.27 (d, J = 8.5 Hz, IH), 3.39 (d, J = 8.5 Hz, IH), 6.49 (d, J = 8.0 Hz, IH), 6.64-6.68 (m, IH), 6.98-7.03 (m, 2H).

Step E: Preparation 4-cyclopropyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-

[l,4]diazepino[6,7,l-/»]indole (Compound 271).

A mixture of 2-cyclopropyl-2-(3,3-dimethylindolin-l-yl)ethanamine 2,2,2-trifluoroacetate (153 mg, 0.444 mmol), 2,2,2-trifluoroacetic acid (153 μΕ, 1.998 mmol), and 37% formaldehyde in water (148 μΕ, 1.988 mmol) in 6 mL MeOH was stirred at 80°C for 0.5 h. The mixture was purified by preparative HPLC. Fractions containing pure product were concentrated, 1.25 M HC1 in MeOH was added (ca. 1 mL), concentrated and dried under high vacuum to give 4-cyclopropyl-7,7-dimethyl- l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/i;]indole dihydrochloride (87.5 mg). LCMS m/z = 243.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 0.30-0.35 (m, IH), 0.61-0.71 (m, 2H), 0.84-0.99 (m, 2H), 1.28 (s, 3H), 1.37 (s, 3H), 2.62-2.67 (m, IH), 3.37 (d, J = 9.7 Hz, IH), 3.49-3.55 (m, IH), 3.67-3.71 (m, IH), 3.73 (d, J = 9.7 Hz, IH), 4.21 (d, J = 14.9 Hz, IH), 4.43 (d, J = 14.9 Hz, IH), 6.85-6.89 (m, IH), 7.01 (d, J = 7.4 Hz, IH), 7.13 (d, J = 7.4 Hz, IH).

Example 1C.86: Preparation of 7,7-dimethyl-2,4,6,7-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- /»]indole-3,l'-cyclopropane] (Compound 267).

Step A: Preparation of tert-butyl (l-(3,3-dimethylindoline-l- carbonyl)cyclopropyl)carbamate.

To a solution of l-((tert-butoxycarbonyl)amino)cyclopropanecarboxylic acid (155 mg, 0.770 mmol) in 7 mL DMF, triethylamine (130 μΐ,, 0.933 mmol) and HATU (325 mg, 0.855 mmol) were added. After stirring at room temperature for 5 min, 3,3-dimethylindoline (105 mg, 0.713 mmol) was added. After stirring at room temperature for overnight, the mixture was extracted with AcOEt and brine. Organic phase was dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl (l-(3,3-dimethylindoline-l- carbonyl)cyclopropyl)carbamate (215 mg) as a white solid. LCMS m/z = 331.2 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.02-1.15 (m, 2H), 1.33 (s, 6H), 1.40 (s, 9H), 1.54-1.57 (m, 2H), 4.03 (s, 2H), 7.03-7.05 (m, 1H), 7.13-7.15 (m, 1H), 7.18-7.22 (m, 1H), 7.92-7.93 (m, 1H).

Step B: Preparation of tert-butyl (l-((3,3-dimethylindolin-l- yl)methyl)cyclopropyl)carbamate.

To a solution of tert-butyl (1 -(3,3-dimethylindoline- l-carbonyl)cyclopropyl)carbamate (210 mg, 0.636 mmol) in 5 mL THF, 1 M aluminum(III) lithium hydride in THF (1.3 mL, 1.300 mmol) was added slowly (over ca. 10 min). After stirring at room temperature for 1 h, the mixture was quenched by the slow addition of water and extracted with 2 M NH₄C1 and CH₂C1₂. Organic phases were concentrated and residue was purified by preparative HPLC. Fractions containing product were partly concentrated and residue was extracted with 1 M NaOH and CH₂C1₂. Organic phases were dried over MgS0₄, filtered, and concentrated to give tert-butyl (l-((3,3-dimethylindolin-l- yl)methyl)cyclopropyl)carbamate (62.6 mg) as a white solid. LCMS m/z = 316.8 [M+l]⁺; ¾ NMR (400 MHz, CDCI₃) δ ppm 0.72-0.75 (m, 2H), 0.82-0.85 (m, 2H), 1.30 (s, 6H), 1.43 (s, 9H), 3.21 (s, 2H), 3.23 (s, 2H), 5.30 (s, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.63-6.67 (m, 1H), 6.98-7.06 (m, 2H).

Step C: Preparation of 7,7-dimethyl-2,4,6,7-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-

&i]indole-3,l '-cyclopropane] .

To a solution of tert-butyl (l-((3,3-dimethylindolin-l-yl)methyl)cyclopropyl)carbamate (60.7 mg, 0.192 mmol) in 2 mL CH₂C1₂, 2,2,2-trifluoroacetic acid (441 μΐ_^, 5.759 mmol) was added. After stirring at room temperature for 2 h, the solution was concentrated and dried under high vacuum. The residue was dissolved in 3 mL MeOH, TFA (38.8 μΐ_^, 0.507 mmol), and 37% formaldehyde in water (37.7 μΐ_^, 0.506 mmol) were added, and stirred at 80°C. After 0.5 h, the solution was purified by preparative HPLC. Fractions containing product were partly concentrated. The residue was treated with 2 M HCl in MeOH, concentrated, and dried under high vacuum to give 7,7-dimethyl-2,4,6,7-tetrahydro- lH-spiro[[l,4]diazepino[6,7,l- i;^']indole-3,l'-cyclopropane] dihydrochloride (45.0 mg) as a tanned solid. LCMS m/z = 229.2 [M+l]⁺; ¾ NMR (400 MHz, CDC1₃) δ ppm 1.20-1.23 (m, 2H), 1.30-1.35 (m, 8H), 3.28 (s, 2H), 3.33 (s, 2H), 4.37 (s, 2H), 7.00-7.04 (m, 1H), 7.15-7.17 (m, 1H), 7.23 (dd, Jj = 7.6 Hz, J₂ = 1.1 Hz, 1H).

Example 1C.87: Preparation of 8-bromo-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole (Compound 297).

Step A: Preparation of l-(4-bromo-lH-indol-3-yl)-2,2,2-trifluoroethanone

To a solution of 4-bromo-lH-indole (1 g, 5.101 mmol) in DMF (30 mL) was added TFAA (0.709 mL, 5.101 mmol) at room temperature. The reaction was stirred at 40 °C for 2 h. The mixture was poured into sodium bicarbonate solution (100 mL). The precipitate was filtered. The filtrate was extracted with EtOAc. The organic extract was dried over Na₂S0₄ and concentrated. The residue was purified by column chromatography to give the title compound. LCMS m/z = 292.2 [M+l]⁺.

Step B: Preparation of 4-bromo-3-(2,2,2-trifluoroethyl)indoline

To a solution of l-(4-bromo-lH-indol-3-yl)-2,2,2-trifluoroethanone (0.74 g, 2.534 mmol) in

TFA (9.702 mL, 126.7 mmol) in an ice-bath was added Triethylsilane (1.619 mL, 10.14 mmol) dropwise under N₂. The reaction was stirred at 23 °C for 15 h. The mixture was poured into 2M Na₂C0₃ solution and extracted with ethyl acetate. The combined organics were concentrated. The residue was purified by silica gel column chromatography to give the title compound. LCMS m/z = 280.2 [M+l]⁺.

Step C: Preparation of 2-(4-bromo-3-(2,2,2-trifluoroethyl)indolin-l-yl)ethanamine

A mixture of 4-bromo-3-(2,2,2-trifluoroethyl)indoline (0.229 g, 0.818 mmol) and 2- bromoethanamine hydrobromide (0.184 g, 0.899 mmol) was heated at 122 °C for 15 h. The mixture was dissolved in 2M HC1 and purified by HPLC to give the title compound. LCMS m/z = 323.2

[M+l]⁺.

Step D: Preparation of 8-bromo-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole

To a solution of 2-(4-bromo-3-(2,2,2-trifluoroethyl)indolin-l-yl)ethanamine.trifluoroacetic acid (0.042 g, 96.07 μιηοΐ) and formaldehyde (7.991

0.288 mmol) in MeOH (2.5 mL) was added TFA (22.07 0.288 mmol). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated. The residue was purified by HPLC to give the title compound (25 mg). LCMS m/z = 335.2 [M+l]⁺; ¾ NMR (400 MHz, CD₃OD) δ ppm 2.33-2.63 (m, 2H), 3.10-3.20 (m, 1H), 3.37-3.51 (m, 3H), 3.59-3.74 (m, 3H), 4.13 (d, J = 15.0 Hz, 1H), 4.42 (d, J = 15.0 Hz, 1H), 6.98-7.06 (m, 2H). Example 1C.88: Preparation of 8-(methoxymethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 301).

To a mixture of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (25.8 mg, 73.04 μιηοΐ), potassium trifluoro(methoxymethyl)borate (22.20 mg, 0.146 mmol), Cesium carbonate (59.86 mg, 0.183 mmol), and Palladium (II) Acetate (1.640 mg, 7.3 μιηοΐ) in Dioxane (0.5 mL) and H₂0 (0.05 mL) was added di((3S,5S,7S)-adamantan-l-yl)(butyl)phosphine (3.928 mg, 10.96 μιηοΐ). The reaction was stirred at 80 °C for 15 h. The mixture was filtered by syringe filter. The filtrate was purified by HPLC to give tert-butyl 8-(methoxymethyl)-3,4,6,7- tetrahydro-[l,4]diazepino[6,7,l-/i;]indole-2(lH)-carboxylate. LCMS m/z = 319.4 [M+l]⁺.

The above material was treated with 1.25 M HC1 in methanol (2 mL) at 50 °C for 1 h. The mixture was concentrated to give the title compound. LCMS m/z = 219 A [M+l]⁺.

Example 1C.89: Preparation of 8-(isopropoxymethyl)-l,2,3,4,6,7-hexahydro-[l_>4]diazepino[6,7,l- /wjindole (Compound 302). From tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;^']indole-2(lH)-carboxylate and trifluoro(isopropoxymethyl)borate, the title compound was obtained using a similar method to the one described in Example 1C.88. LCMS m/z = 247.4 [M+l]⁺. Example 1C.90: Preparation of 8-(3,3,3-trifluoropropyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-&i]indole (Compound 303).

From tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7, l- i;^']indole-2(lH)-carboxylate and potassium trifluoro(3,3,3-trifluoropropyl)borate, the title compound was obtained using a similar method to the one described in Example 1C.88. LCMS m/z = 271.0 [M+l]⁺.

Example 1C.91: Preparation of 8-bromo-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- ¾i]indole-7,l'-cyclobutane] (Compound 290).

Step A: Preparation of 4'-bromospiro[cyclobutane-l,3'-indolin]-2'-one

To a solution of 4-bromoindolin-2-one (500 mg, 2.358 mmol) in THF (8 mL) was added slowly a 1M solution of LiHMDS in THF (5.188 ml, 5.188 mmol) via syringe at -78 °C under nitrogen. The reaction mixture was stirred at that temperature for 30 min, then 1,3-diiodopropane (0.354 ml, 3.065 mmol) was added. The reaction mixture was warmed slowly to room temperature and stirred overnight. It was quenched with saturated aqueous NH₄C1, then extracted with ethyl acetate. The combined organics were concentrated, the residue was purified by silica gel column chromatography with 25% ethyl acetate hexanes. The combined solvent was concentrated to give the title compound (265 mg) with 85 % purity. LCMS m/z = 252.2 [M+H]⁺.

Step B: Preparation of 4'-bromospiro[cyclobutane-l,3'-indoline]

To a solution of 4'-bromospiro[cyclobutane-l,3'-indolin]-2'-one (265 mg, 1.051 mmol) in THF (8 mL) at ice-water bath was added a 1M solution of lithium aluminum hydride in THF (2.838 ml, 2.838 mmol) slowly under N₂. The reaction was warmed to room temperature and stirred overnight. It was carefully quenched with 110 μL water, 110 μL 15% NaOH solution and 330 μL water. Filtered and washed with ethyl acetate. The combined organics were concentrated, the residue was purified by silica gel column chromatography with 15% ethyl acetate/hexanes then preparative HPLC (5-70%

CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined organics were made basic, then partially concentrated, extracted with ethyl acetate. The combined organics were concentrated to give the title compound (100 mg). LCMS m/z = 238.2 [M+H]⁺; ¾ NMR (400 MHz, CDC1₃) δ 1.97-2.17 (m, 4H), 3.00-3.14 (m, 2H), 3.72 (s, 2H), 6.50-6.55 (m, 1H), 6.82-6.86 (m, 2H).

Step C: Preparation of 2-(4'-bromospiro[cyclobutane-l,3'-indolin]-l'-yl)ethanamine 2,2,2- trifluoroacetate.

The mixture of 4'-bromospiro[cyclobutane-l,3'-indoline] (100 mg, 0.420 mmol) and 2- bromoethanamine hydrobromide (94.65 mg, 0.462 mmol) were heated neat at 115 °C overnight. The mixture was dissolved in methanol and purified by preparative HPLC (5-60% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give the title compound (90 mg) as white solid. LCMS m/z = 281.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.03-2.15 (m, 4H), 3.04-3.14 (m, 2H), 3.20 (t, J = 6.0 Hz, 2H), 3.35 (t, J = 6.0 Hz, 2H), 3.59 (s, 2H), 6.56 (dd, J = 1.9 and 0.8 Hz, 1H), 6.85 (dd, 7 = 8.0 and 0.8 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H).

Step D: Preparation of 8-bromo-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- /»]indole-7,l'-cyclobutane].

To a solution of 2-(4'-bromospiro[cyclobutane-l,3'-indolin]-r-yl)ethanamine 2,2,2- trifluoroacetate (90 mg, 0.228 mmol) in methanol (5 mL) was added 37% formaldehyde in water (50.86 μΐ, 0.683 mmol) and TFA (52.32 μΐ, 0.683 mmol). The reaction mixture was stirred at 80 °C oil bath for 1 h (1 hr). The mixture was concentrated, the residue was purified by semi preparative HPLC (5-70% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give the title compound as the TFA salt (53 mg) as yellow solid. LCMS m/z = 293.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.01-2.14 (m, 4H), 3.02-3.08 (m, 2H), 3.24-3.28 (m, 2H), 3.47-3.51 (m, 2H), 3.68 (s, 2H), 4.22 (s, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H). Example 1C.92: Preparation of 8-chloro-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- /»]indole-7,l'-cyclobutane] (Compound 292).

Step A: Preparation of 4'-chlorospiro[cyclobutane-l,3'-indolin]-2'-one

To a solution of 4-chloroindolin-2-one (500 mg, 2.983 mmol) in THF (8 mL) was added slowly a 1M solution of LiHMDS in THF (6.564 ml, 6.564 mmol) via syringe at -78 °C under nitrogen. The reaction mixture was stirred at that temperature for 30 min, then 1,3-diiodopropane (0.448 ml, 3.878 mmol) was added. The reaction mixture was warmed slowly to room temperature and stirred overnight. It was quenched with saturated aqueous NH₄C1, extracted with ethyl acetate. The combined organics were concentrated, the residue was purified by silica gel column chromatography with 25% ethyl acetate/hexanes. The combined solvent was concentrated to give the title compound (247 mg) with 83% purity. LCMS m/z = 208.2 [M+H]⁺.

Step B: Preparation of 4'-chlorospiro[cyclobutane-l,3'-indoline]

To a solution of 4'-chlorospiro[cyclobutane-l,3'-indolin]-2'-one (247 mg, 1.189 mmol) in THF (10 mL) at ice-water bath was added a 1M solution of lithium aluminum hydride in THF (3.212 ml, 3.212 mmol) slowly under N₂. The reaction was warmed to room temperature and stirred overnight. Quenched with 125 μL water, 125 μL 15% NaOH solution and 3 x 125 μL water. Filtered and washed with ethyl acetate. The combined organics were concentrated, the residue was purified by silica gel column chromatography with 15% ethyl acetate/hexanes then preparative HPLC (5-70% CH₃CN/H₂0 with 0.1 % TFA over 30 min). The combined organics were made basic with saturated aqueous NaHC0₃, then partially concentrated, extracted with ethyl acetate. The combined organics were dried then concentrated to give the title compound (180 mg) as oil. LCMS m/z = 194.2 [M+H]⁺. ¾ NMR (400 MHz, CDCI₃) δ 1.92-2.15 (m, 4H), 2.95-3.05 (m, 2H), 3.71 (s, 2H), 6.48 (dd, J = 7.8 and 0.8 Hz, 1H), 6.66 (dd, J = 8.0 and 0.8 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H).

Step C: Preparation of 2-(4'-chlorospiro[cyclobutane-l,3'-indolin]-l'-yl)ethanamine 2,2,2- trifluoroacetate The mixture of 4'-chlorospiro[cyclobutane-l,3'-indoline] (180 mg, 0.929 mmol) and 2- bromoethanamine hydrobromide (0.209 g, 1.022 mmol) were heated neat at 115 °C overnight. The mixture was dissolved in methanol and purified by preparative HPLC (5-60% CH₃CN H₂0 with 0.1% TFA over 30 min). The combined fractions were lyophilized to give the title compound (168 mg). LCMS m/z = 237.2 [M+H]⁺.

Step D: Preparation of 8-chloro-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- /M]indole-7,l'-cyclobutane]

To a solution of 2-(4'-chlorospiro[cyclobutane-l,3'-indolin]-r-yl)ethanarnine 2,2,2- trifluoroacetate (168 mg, 0.479 mmol) in methanol (6 mL) was added 37% formaldehyde in water (0.107 ml, 1.437 mmol) and TFA (0.110 ml, 1.437 mmol). The reaction mixture was stirred at 80 °C oil bath for 1 hr. The mixture was concentrated, the residue was purified by semi preparative HPLC (5- 70% CH₃CN/H₂0 with 0.1% TFA over 30 min). The combined fractions were lyophilized to give the title compound (123 mg) as the TFA salt. LCMS m/z = 249.2 [M+H]⁺; ¾ NMR (400 MHz, CD₃OD) δ 2.04-2.14 (m, 4H), 2.93-3.05 (m, 2H), 3.23-3.27 (m, 2H), 3.47-3.51 (m, 2H), 3.67 (s, 2H), 4.24 (s, 2H), 6.80 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H).

Example 1C.93: Preparation of 8-methyl-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- ¾i]indole-7,l'-cyclobutane] (Compound 293).

Step A: Preparation of tert-butyl 8-bromo-3,4-dihydro-lH-spiro[[l,4]diazepino[6,7,l- ¾i]indole-7,l'-cyclobutane]-2(6H)-carboxylate

To a solution of 8-bromo-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- i;]indole-7,r- cyclobutane] (28 mg, 95.50 μιηοΐ) in DCM (3 mL) was added triethylamine (39.93 μΐ, 0.286 mmol) and di-tert-butyl dicarbonate (31.26 mg, 0.143 mmol). The reaction mixture was stirred at room temperature for 3 hr, concentrated, the residue was purified by silica gel column chromatography with 15% ethyl acetate/hexanes to the title compound (33 mg). LCMS m/z = 393.6 [M+H]⁺.

Step B: Preparation of tert-butyl 8-methyl-3,4-dihydro-lH-spiro[[l,4]diazepino[6,7,l- ¾i]indole-7,l'-cyclobutane]-2(6H)-carboxylate.

To a mixture of tert-butyl 8-bromo-3,4-dihydro-lH-spiro[[l,4]diazepino[6,7,l- i;]indole-7,l'- cyclobutane]-2(6H)-carboxylate (33 mg, 83.90 μιηοΐ), tetrakistriphenylphosphine palladium (19.39 mg, 16.78 μιηοΐ), 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (31.60 mg, 0.252 mmol), and potassium carbonate (34.79 mg, 0.252 mmol) in a mixed solvent dioxane (2 mL) and H₂0 (120 μL) was stirred at 90 °C overnight under N₂. The mixture was filtered by a syringe filter. The filtrate was concentrated then purified by silica gel column chromatography with 15% ethyl acetate/hexanes to give a mixture of tert-butyl 8-methyl-3,4-dihydro-lH-spiro[[l,4]diazepino[6,7,l- i;^']indole-7,l'-cyclobutane]-2(6H)- carboxylate and reduction byproduct.

To the mixture obtained above in methanol (0.5 mL) was treated with a solution of 4M HC1 in dioxane (0.5 mL), stirred at room temperature for 2 hr, then purified by semi preparative HPLC (5-60% CH₃CN/H₂O with 0.1 % TFA over 30 min). The combined fractions were lyophilized to give the title compound as the TFA salt (18 mg). LCMS m/z = 229.4 [M+H]⁺. ¾ NMR (400 MHz, CD₃OD) δ 2.04- 2.18 (m, 4H), 2.55 (s, 3H), 2.69-2.78 (m, 2H), 3.17-3.20 (m, 2H), 3.45-3.49 (m, 2H), 3.57 (s, 2H), 4.19 (s, 2H), 6.65 (d, 7 = 7.7 and 0.4 Hz, 1H), 6.93 (d, 7 = 0.7 Hz, 1H). Example 1C.94: Preparation of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- &i]indole-2(lH)-carboxylate (Intermediate 1).

Step A: Preparation of tert-butyl (2-(4-bromoindolin-l-yl)ethyl)carbamate.

A mixture of 4-bromoindoline (5.0 g, 25.24 mmol) and the HBr salt of 2-bromoethanamine (6.207 g, 30.29 mmol) was heated at 120 °C for 16 h. The mixture was dissolved in MeOH with (BOC)20 (11.02 g, 50.49 mmol) and Triethylamine (7.037 ml, 50.49 mmol) added. Mixture was stirred under room temperature for 16h. Solvent was removed. Crude was purified by biotage CC (Si02, hexane/AcOEt gradient) to give title compound (8.62g@80.25 pure). LCMS m/z = 341.2 [M+l]⁺.

Step B: Preparation of l,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- fa^'jindole bis(2,2,2-trifluoroacetate).

To tert-butyl (2-(4-bromoindolin-l-yl)ethyl)carbamate (8.62 g @80.25 pure, 20.26 mmol) was directly charged 2,2,2-trifluoroacetic acid (13.03 ml, 170.2 mmol). The mixture was stirred under room temperature for 1 h and dissolved in MeOH (123 ml) with formaldehyde (3.017 ml, 40.52 mmol) added and was stirred at 80°C for lh. Solvent was removed with crude dissolved in THF (123 ml) with 90 ml of saturated NaHC03 solution and (BOC)20 (6.632 g, 30.39 mmol) added. Reaction mixture was stirred under room temperature for lh. Mixture was extracted with DCM/H20. Organic layer was concentrated. Residue was purified by biotage CC (Si02, hexane/AcOEt gradient) to give title compound (4.18 g). LCMS m/z = 355.4 [M+l]⁺; ¾ NMR (400 MHz, CDC13) δ 1.40 (s, 9H), 2.99- 3.04(m, 4H), 3.44 (t, J = 8.6 Hz, 2H), 3.69 (s, 2H), 4.29-4.36 (m, 2H), 6.72-6.85 (m, 2H). Example 1C.95: Preparation of 8-(lH-pyrazol-5-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 300), as the dihydrochloride salt.

To a solution of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (50 mg, 0.142 mmol) in Dioxane (1 ml) was added (lH-pyrazol-5-yl)boronic acid (23.76 mg, 0.212 mmol), potassium phosphate (90.13 mg, 0.425 mmol), and Pd(dppf)2, DCM (11.64 mg, 14.15 μιηοΐ). Mixture was heated to 90 °C for 18h. Solid was filtered and washed with CH3CN.

Residue was purified by HPLC to give tert-butyl 8-(lH-pyrazol-5-yl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate. Tert-butyl 8-(lH-pyrazol-5-yl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate was dissolved in DCM with 4M HC1 in dioxane (0.708 ml, 2.831 mmol) added. Reaction was stirred under room temperature for 2h. Solid was filtered and washed with MTBE to give the title compound (9.85 mg). LCMS m/z = 241.0 [M+H]⁺; ¾ NMR (400 MHz, D20) δ 3.29 (t, J = 8.4 Hz, 2H), 3.35-3.38 (m, 2H), 3.60 (t, J = 8.4 Hz, 2H), 3.62-3.65 (m, 2H), 4.38 (s, 2H), 6.78 (d, J = 2.3 Hz, 1H), 7.25-7.31 (m, 2H), 7.96 (d, J = 2.3 Hz, 1H). Example 1C.96: Preparation of 8-(lH-pyrazol-l-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- &i]indole (Compound 294), as the dihydrochloride salt.

To a mixture of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (350 mg, 0.991 mmol), Nl,N2-dimethylethane-l,2-diamine (17.47 mg, 0.198 mmol), copper(I) iodide (18.87 mg, 99.08 μιηοΐ), and potassium phosphate (0.421 g, 1.982 mmol) in a sealed tube was added DMSO (5 ml). N2 was bubbled through the reaction mixture for 2 min and to this was added IH-pyrazole (0.101 g, 1.486 mmol). Reaction was stirred under 125 °C for 12 days. Mixture was purified by HPLC to give tert-butyl 8-(lH-pyrazol-l-yl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l-i;^']indole-2(lH)-carboxylate. Tert-butyl 8-(lH-pyrazol-l-yl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- /i;]indole-2(lH)-carboxylate was dissolved in DCM with 4M HC1 (2.972 ml, 11.89 mmol) added and stirred under room temperature for lh. Solvent was removed with MTBE added and sonicated. Solid was filtered and washed with MTBE to give title compound (180 mg). LCMS m/z = 241.2 [M+H]⁺; ¾ NMR (400 MHz, D20) δ 3.19 (t, J = 8.4 Hz, 2H), 3.36-3.38 (m, 2H), 3.59 (t, J = 8.4 Hz, 2H), 3.63-3.65 (m, 2H), 4.40 (s, 2H), 6.65 (t, J = 2.2 Hz, 1H), 7.09-7.12 (m, 1H), 7.27-7.29 (m, 1H), 7.87 (d, J = 1.76 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H).

Example 1C.97: Preparation of 8-(lH-imidazol-l-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 295), as the dihydrochloride.

From Intermediate 1 and lH-imidazole, the title compound was obtained using a similar method to the one described in Example 1C.96. LCMS m/z = 241.2 [M+H]⁺.

Example 1C.98: Preparation of 8-(lH-l,2,4-triazol-l-yl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-/»]indole (Compound 291), as the dihydrochloride.

From Intermediate 1 and lH-l,2,4-triazole, the title compound was obtained using a similar method to the one described in Example 1C.96. LCMS m/z = 242.4 [M+H]⁺.

Example 1C.99: Preparation of 8-(lH-pyrrol-2-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 296), as the dihydrochloride.

To a solution of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (80 mg, 0.226 mmol) in Dioxane (1 ml) was added Pd(dppf)2, DCM (18.63 mg, 22.65 μιηοΐ), 2M Sodium Carbonate (0.249 ml, 0.498 mmol), and (l-(tert-butoxycarbonyl)-lH-pyrrol-2- yl)boronic acid (57.35 mg, 0.272 mmol). Mixture was heated to 90 °C for 12 days. Solid was filtered and washed with CH3CN. Residue was purified by HPLC to give tert-butyl 8-(l-(tert-butoxycarbonyl)- lH-pyrrol-2-yl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)-carboxylate. Tert-butyl 8-(l- (tert-butoxycarbonyl)-lH-pyrrol-2-yl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate was dissolved in DCM with 4M HC1 in dioxane (0.623 ml, 2.491 mmol) added. Reaction was stirred under room temperature for 2h. Solid was filtered and washed with MTBE to give the title compound (51mg). LCMS m/z = 240.2 [M+H]⁺. Example 1C.100: Preparation of 8-(thiophen-3-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- fa^'jindole (Compound 298), as the dihydrochloride.

To a solution of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (50 mg, 0.142 mmol) in dioxane (0.621 ml)/H20 (0.310 ml) was added Potassium carbonate (43.04 mg, 0.311 mmol), Pd(dppf)C12 (10.36 mg, 14.15 μιηοΐ) and thiophen-3-ylboronic acid (21.73 mg, 0.170 mmol). Mixture was heated to 100 °C for 16h. Diluted with DMSO, residue was purified by HPLC to give tert-butyl 8-(thiophen-3-yl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate. Tert-butyl 8-(thiophen-3-yl)-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole- 2(lH)-carboxylate was dissolved in DCM with 4M HCl in dioxane (0.708 ml, 2.831 mmol) added. Reaction was stirred under room temperature for 2h. Solvent was removed with MTBE added and sonicated. Solid was filtered and washed with MTBE to give title compound (20 mg). LCMS m/z = 257.4 [M+H]⁺.

Example 1C.101: Preparation of 8-(lH-pyrazol-3-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (compound 299), as the dihydrochloride.

From Intermediate 1 and (lH-pyrazol-3-yl)boronic acid, the title compound was obtained using a similar method to the one described in Example 1C.100. LCMS m/z = 241.4 [M+H]⁺.

Example 1C.102: Preparation of 8-(furan-2-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- /wjindole (Compound 304), as the dihydrochloride.

To a solution of tert-butyl 8-bromo-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- i;^']indole-2(lH)- carboxylate (40 mg, 0.113 mmol) in dioxane (1.5 ml)was added Palladium (II) Acetate (762.7 μg, 3.4 μιηοΐ), 2M potassium phosphate (0.125 ml, 0.249 mmol), S-phos (2.789 mg, 6.8 μιηοΐ), and (3- bromofuran-2-yl)boronic acid (25.92 mg, 0.136 mmol). Mixture was heated to 90 °C for 16h in a sealed microwave tube under an inert atmosphere. Solid was filtered and washed with CH3CN. Solvent was removed with residue purified by HPLC to give tert-butyl 8-(furan-2-yl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate. Tert-butyl 8-(furan-2-yl)-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l- i;]indole-2(lH)-carboxylate was dissolved in DCM with 4 HCl in dioxane (0.283 ml, 1.132 mmol) added. Reaction was stirred under room temperature for 2h. Solid was filtered and washed with MTBE to give the title compound (11.3 mg). LCMS m/z = 241.2 [M+H]⁺; ¾ NMR (400 MHz, D20) δ 3.35 (t, J = 8.4 Hz, 2H), 3.40-3.46 (m, 2H), 3.65-3.69 (m, 4H), 4.38 (s, 2H), 6.68-6.69 (m, 1H), 6.82 (d, J = 3.4 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H).

Example 2 - Generation of Stable Cell Lines

Plasmid DNA coding for a receptor of interest is produced using standard molecular biology tools. The plasmid typically contains a multi-cloning site where the coding sequence for the receptor of interest is inserted, a promoter to drive expression of the receptor when introduced into a host cell, and a resistance gene sequence that causes the host cell to produce a protein that confers antibiotic resistance. A commonly used promoter is the cytomegalovirus promoter (CMV), and a commonly used resistance gene is the neo gene that confers resistance to neomycin. The plasmid DNA is introduced into parental cells (commonly used cell lines include CHO-K1 and HEK293) using methods such as lipofection or electroporation. Cells are then allowed to recover in culture for 1-2 days. At this point, a selection agent {e.g., neomycin if the expression plasmid contained the neo gene) is added to the cell culture media at a concentration sufficient to kill any cells that did not uptake the plasmid DNA and therefore have not become neomycin resistant.

Since transient transfection is an efficient method to introduce plasmid DNA into cells, many cells in the culture will initially display neomycin resistance. Over the course of a few cell divisions, expression of proteins encoded by the plasmid is typically lost and most cells will eventually be killed by the antibiotic. However, in a small number of cells, the plasmid DNA may become randomly integrated into the chromosomal DNA. If the plasmid DNA becomes integrated in a way that allows continued expression of the neo gene, these cells become permanently resistant to neomycin. Typically, after culturing the transfected cells for two weeks, most of the remaining cells are those that have integrated the plasmid in this manner.

The resulting stable pool of cells is highly heterogeneous, and may express vastly different levels of receptor (or no receptor at all). While these types of cell populations may provide functional responses when stimulated with appropriate agonists to the receptor of interest, they are typically not suitable for careful pharmacological studies in view of receptor reserve effects caused by high expression levels.

Clonal cell lines are therefore derived from this cell population. The cells are plated in multi- well plates at a density of one cell per well. After cell plating, the plates are inspected and wells containing more than one cell are rejected. The cells are then cultured for a period of time and those that continue to divide in the presence of neomycin are eventually expanded into larger culture vessels until there are sufficient cells for evaluation.

Evaluation of Cells

Numerous methods can be used to evaluate the cells. Characterization in functional assays may reveal that some cells exaggerate the potencies and efficacies of agonists, likely indicating the presence of a receptor reserve. The preparation of cell membranes for evaluation in radioligand binding assays allows for quantitative determination of membrane receptor densities. Evaluation of cell surface receptor density may also be performed by flow cytometry using antibodies to the receptor or an epitope tag that can be engineered into the receptor, typically at the N-terminus for GPCRs. The flow cytometry method allows one to determine if the clonal cell population expresses the receptor in a homogenous manner (which would be expected) and quantitate relative expression levels between each clonal cell population. However, it does not provide absolute receptor expression levels.

If the cell line is intended to be free of receptor reserve effects, receptor expression should be low (relative to other clones evaluated) and homogeneous (if flow cytometry evaluation is possible). In functional assays, a suitable clone will produce agonist potencies that are lower than other clones {i.e., higher EC5₀ values). If partial agonists are available, the absence of receptor reserve will be reflected in low efficacies relative to full agonists, whereas cells with higher receptor expression levels will exaggerate partial agonist efficacies. In cells expressing high receptor levels, partial agonists may no longer display efficacies lower than full agonists.

If agents that irreversibly bind to or covalently interact with the receptor of interest are available, treatment of cell lines that contain no receptor reserve should reduce the available receptor density measured by radioligand binding and may reduce the magnitude of functional responses to agonists. However, the reduction of receptor density should occur without producing reductions in agonist potencies or partial agonist efficacies.

Example 3 - Potency and Efficacy of Lorcaserin on 5-HT₂ Receptors

Lorcaserin potency and efficacy were evaluated for rat, monkey, and human 5-HT_2A, 5-HT₂B, and 5-HT_2C receptors. Lorcaserin-mediated signaling was observed in stable clonal cell lines expressing low receptor densities. Phenoxybenzamine (PBZ) was used as an irreversible 5-HT₂ receptor antagonist to allow for progressive reductions of receptor binding sites in each cell line in order to observe potency and efficacy in the absence of receptor reserve effects (which may have generated inconsistent results in previous studies).

Cell Lines

HEK293 cell lines were generated to stably express human, rat, and monkey 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors using standard procedures.

IP Accumulation Assay

HEK293 cells expressing recombinant 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors were added to sterile poly-D-lysine-coated 96-well microtiter plates (35,000 cells/well) and labeled with 0.6 μΟΛνεΙΙ of [³H]inositol in myo-inositol-free DMEM for 18 hours. PBZ prepared in myo-inositol-free DMEM was then added to a final specified concentration and incubation was conducted for 1 hour at room temperature. Unincorporated [³H]inositol and PBZ were removed by aspiration and replaced with fresh myo-inositol free DMEM supplemented with LiCl (10 mM final) and pargyline (10 μΜ final). Serially diluted test compounds were then added and incubation was conducted for 2 hours at 37°C. Incubations were then terminated by lysing cells with the addition of ice-cold 0.1 M formic acid followed by freezing at -80°C. After thawing, total [³H]inositol phosphates were resolved from [³H]inositol using AG1-X8 ion exchange resin (Biorad) and [³H]inositol phosphates were measured by scintillation counting using a Perkin Elmer TopCount scintillation counter. EC5₀ determinations were performed at a minimum total of 8 or 10 different concentrations, and triplicate determinations were made at each test concentration.

Raw counts from the scintillation counter were exported to GraphPad Prism for further analysis. Data were fit to a three parameter sigmoid dose response function using a nonlinear regression to obtain EC5₀ values and curve height. Compound efficacies were calculated as a percentage of the serotonin efficacy, which was defined as 100% in each experiment. Since IP accumulation experiments typically involved multiple assay plates with serotonin dose-responsed on only 1 plate, the magnitude of the serotonin response on each plate was determined from the positive and negative control wells, which contained serotonin (typically at 1 or 10 μΜ) and assay buffer, respectively. Each compound efficacy was calculated as a percentage of the serotonin positive control response on its assay plate.

Stable, clonal cell lines expressing recombinant human, rat, and monkey 5-HT_2A, 5-HT_2B, and

5-HT₂c receptors were established and used to profile lorcaserin and a panel of reference compounds in IP accumulation and calcium assays. Cell surface receptor densities, as assessed by radioligand binding, were very high in the human and monkey cell lines and were lower in the rat cell line. Receptor densities in all three cell lines were modulated by PBZ.

Calcium Assay

Cells were harvested, counted, resuspended in assay buffer [IX HBSS (with calcium and magnesium) containing 20 mM HEPES at pH 7.4], and plated at 20,000 cells per well (25 μΕ per well) into standard tissue culture grade black plates with clear bottoms. One vial of Molecular Devices Calcium 4 dye was diluted with 10 mL of assay buffer. A 1 mL aliquot was then diluted 10-fold with assay buffer supplemented with 2.5 mM probenecid. This dye stock was added to the assay plates at 25 μΕ per well and incubated for 1 hour at 37 °C. Test compounds were serially diluted in DMSO before being further diluted in assay buffer. Controls and test compounds (in 25 μΕ assay buffer) were then added to assay plates using a Molecular Devices FLIPR instrument. Plates were read every two seconds for 1.5 minutes and the peak height was determined for each well. Dose response curves included ten compound concentrations in which triplicate determinations were made at each test concentration.

Raw counts were exported to GraphPad Prism (v.5) for further analysis. Data were fit to a three parameter sigmoid dose response function using a nonlinear regression to obtain EC₅₀ values and curve height. Compound efficacies were calculated as a percentage of the serotonin efficacy, which was defined as 100% in each experiment.

Radioligand Binding Assay

HEK293 cells expressing the recombinant 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors were harvested, suspended in ice-cold phosphate buffered saline, pH 7.4 (PBS), and then centrifuged at 48,000 g for 20 min at 4°C. The resulting cell pellet was then re-suspended in wash buffer containing 20 mM HEPES, pH 7.4 and 0.1 mM EDTA, homogenized on ice using a Brinkman Polytron, and centrifuged (48,000 g for 20 min at 4°C). The pellet was then resuspended in 20 mM HEPES, pH 7.4, homogenized on ice, and centrifuged (48,000 g for 20 min at 4°C). Crude membrane pellets were stored at -80°C until used for radioligand binding assays.

Radioligand binding assays were performed using the commercially available 5-HT₂ receptor agonist [¹²⁵I]DOI as the radioligand and nonspecific binding was determined in the presence of unlabeled DOI at a saturating concentration of 10 μΜ. Competition experiments consisted of addition of 95 μΕ of Assay Buffer (20 mM HEPES, pH 7.4, 10 mM MgC12), 50 μΕ of membranes, 50 μΕ of radioligand stock, and 5 μΕ of test compound diluted in assay buffer to 96-well microtiter plates, which were then incubated for one hour at room temperature. Assay incubations were terminated by rapid filtration through Perkin Elmer F/C filtration plates under vacuum pressure using a 96-well Packard filtration apparatus, followed by washing filter plates several times with ice-cold Assay Buffer. Plates were then dried at 45 °C for a minimum of two hours. Finally, 25 μΐ_^ of BetaScint scintillation cocktail was added to each well and the plates were counted in a Packard TopCount scintillation counter. In each competition study, test compounds were dosed at eight to ten concentrations with triplicate determinations at each test concentration. A reference compound, typically DOI, was included in every runset for quality control purposes.

Raw data sets from scintillation counters were uploaded for processing. Competition curves were fit to a nonlinear least squares curve fitting program to obtain IC₅₀ values. Ki values were determined from IC₅₀ values using the Cheng-Prusoff equation and the Kd value for each radioligand- receptor pair. Mean Ki values were calculated from the mean of the logKi values.

Results

Figure 18 shows potency and efficacy data generated using the IP accumulation assay for each combination of the human, rat, and monkey 5-HT_2A, 5-HT_2B, and 5-HT₂c receptors. Lorcaserin demonstrated high selectivity for the human 5-HT₂c receptor, with an EC5₀ (39.2 nM) approximately 14 times lower than the EC5₀ for the 5-HT_2A receptor (553 nM) and approximately 60 times lower than the EC₅₀ for the 5-HT_2B receptor (2380 nM). Lorcaserin also demonstrated high efficacy (81 %) at the human 5-HT_2C receptor relative to serotonin. In contrast, lorcaserin demonstrated mixed potency for the rat 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors, with greatest selectivity for the 5-HT_2B receptor (195 nM, compared to 545 nM and 1110 nM for the 5-HT_2C and 5-HT_2A receptors, respectively). Lorcaserin also demonstrated high efficacy (94%) at the rat 5 -HT_2B receptor relative to serotonin.

Figure 19 (left side) shows a comparison of drug concentration in humans to the 5-HT_2A, 5- HT_2B, and 5-HT_2C receptor activation data. EC5₀ values (as measured by the IP accumulation assay) are shown as horizontal lines plotted against observed lorcaserin concentrations (expressed as plasma free fractions) for subjects treated with lorcaserin 10 mg BID in a previous study. Figure 19 (right side) shows a comparison of drug concentration in rats to the 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor activation data. EC5₀ values for receptor activation (as measured by the IP accumulation assay) are shown as horizontal lines plotted against the observed lorcaserin concentrations (expressed as plasma free fractions) for rats treated with 10 mg kg/day, 30 mg/kg/day, and 100 mg/kg/day of lorcaserin. In humans, the plasma drug concentration following the administration of lorcaserin was approximately equal to the EC₅₀ value from the IP accumulation assay for the 5-HT_2C receptor, and did not approach the EC₅₀ value for the 5-HT_2A or 5-HT_2B receptors. However, in rats, the plasma drug concentration for the lowest dose of lorcaserin administered (i.e., 10 mg kg/day) was greater than or equal to the EC₅₀ values from the IP accumulation assays for each of the 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. Providing higher doses of lorcaserin to rats increased the plasma drug concentration, but would be unlikely to improve efficacy given that full receptor activation is expected to be achieved at a low dose. A low dose of lorcaserin is therefore likely to be sufficient for efficacy observed in rats. Example 4 - Phase 2 Study

A 12-week, randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of lorcaserin as a potential aid to smoking cessation. In the trial, 603 active smokers were randomized to receive lorcaserin 10 mg BID, 10 mg QD, or placebo in a 1 : 1 : 1 ratio (BELVIQ (lorcaserin HCl) (package insert), revised August 2012). Patients at baseline were dependent on nicotine and averaged 18 cigarettes per day. Patients were dosed for two weeks before attempting to quit around day 15 of the trial, and received smoking cessation counseling during the trial. The primary objective of the study was to assess smoking cessation efficacy, as measured by the carbon monoxide-confirmed continuous abstinence rate (CAR) during the last four weeks of the trial (Weeks 9 to 12). The carbon monoxide - confirmed CAR is defined as no reported smoking or other nicotine use and an end-expiratory exhaled carbon monoxide measurement of less than or equal to ten parts per million. Secondary objectives for the study included assessment of body weight change, safety, and tolerability. Additional outcome measures included CAR for Weeks 5 to 8 of treatment, CAR for Weeks 5 to 12 of treatment, CAR for Weeks 3 to 12 of treatment, 7-day point prevalence (PP) smoking abstinence, and questionnaires regarding the urge to smoke, withdrawal, reinforcing effects, and eating behavior. Endpoints of interest also included the number of cigarettes smoked per day, abstinence with occasional slips (< 5 cigarettes per day), time to abstinence (in weeks), and time to relapse (if abstinent).

A schematic of the study design is provided in Figure 1. Baseline characteristics for the study subjects are provided in Figures 2 and 3. A summary of the disposition of subjects from the study is provided in Figure 4. Data for end-expiratory carbon monoxide (CO) -confirmed CARs for Weeks 5-8, 5-12, and 3-12 is provided in Figures 5-8.

Subjects treated with lorcaserin 10 mg BID had statistically significantly greater end-expiratory CO-confirmed CARs for Weeks 9 to 12 than subjects treated with lorcaserin 10 mg QD or placebo. The primary endpoint was achieved by 5.64%, 8.72%, and 15.31 % of subjects in the placebo, lorcaserin 10 mg QD, and lorcaserin 10 mg BID groups, respectively (p-value = 0.0027 and odds ratio = 3.02 for lorcaserin 10 mg BID versus placebo). End-expiratory CO-confirmed CARs for Weeks 9 to 12 were not significantly different for subjects treated with lorcaserin 10 mg QD versus subjects treated with placebo (Figure 5).

A statistically significantly greater percentage of subjects treated with lorcaserin 10 mg BID exhibited continuous abstinence during the 7-day period preceding a clinical visit (as verified by end- expiratory CO levels <10 ppm) for time points past 6 weeks of treatment compared to subjects treated with placebo (Figure 9). Further, subjects treated with lorcaserin 10 mg BID had a numerically greater reduction in the number of cigarettes smoked at Week 12 (as measured by the Nicotine Use Inventory) compared to subjects treated with placebo (Figure 10).

Subjects treated with lorcaserin 10 mg BID had significantly greater weight loss at Week 12 than subjects treated with lorcaserin 10 mg QD or placebo (p values = 0.0217 and 0.0004, respectively). Weight loss was not significantly different for subjects treated with lorcaserin 10 mg QD versus subjects treated with placebo (Figures 11 and 13). Comparable weight loss was observed at Week 12 for subjects treated with lorcaserin 10 mg BID across the entire BMI range studied, and for subjects treated with lorcaserin 10 mg QD across the entire BMI range studied (Figures 14 and 15).

Responders (defined as subjects with 4 weeks of continuous CO-confirmed abstinence from Weeks 9 to 12) who were treated with lorcaserin 10 mg BID lost 0.41 kg (SE 0.58 kg) at Week 12 relative to baseline, while those treated with lorcaserin 10 mg QD or placebo gained 0.76 kg (SE 0.47 kg) and 0.73 kg (SE 1.14 kg), respectively, at Week 12 relative to baseline (Figures 12 and 13).

Subjects treated with lorcaserin 10 mg BID, lorcaserin 10 mg QD, or placebo who did not quit smoking (i.e., non-responders) had greater weight loss than responders for each respective treatment at Week 12 (Figure 13). Non-responders who were treated with lorcaserin 10 mg BID lost 1.02 kg (SE 0.21 kg) at Week 12 relative to baseline, while those treated with lorcaserin 10 mg QD or placebo lost 0.50 kg (SE 0.21 kg) and 0.01 kg (SE 0.23 kg), respectively, at Week 12 relative to baseline (Figure 13).

A summary of treatment-emergent adverse events is shown in Figure 17. Overall, treatment with lorcaserin was well-tolerated. Adverse events were similar to those most frequently associated with lorcaserin in previous clinical trials (e.g., headache, nausea, constipation, dizziness, and dry mouth). Serious Adverse Events (SAEs) were infrequent and none were considered related to study treatment.

Example 5: Membrane Preparations for Radioligand Binding Assays.

For the compounds of formula I, XI, and XXI, the following procedure was used. HEK293 cells stably expressing recombinant 5-HT₂ receptors were harvested, suspended in ice-cold phosphate buffered saline, pH 7.4 (PBS), and then centrifuged at 48,000 g for 20 min at 4 °C. The resulting cell pellet was then re-suspended in wash buffer containing 20 mM HEPES, pH 7.4 and 0.1 mM EDTA, homogenized on ice using a Brinkman Polytron, and centrifuged (48,000 g for 20 min at 4 °C). The pellet was then resuspended in 20 mM HEPES, pH 7.4, homogenized on ice, and centrifuged (48,000 g for 20 min at 4 °C). Crude membrane pellets were stored at -80 °C until used for radioligand binding assays.

Example 6: Radioligand Binding Assay.

For the compounds of formula I, XI, and XXI, the following procedure was used. Radioligand binding assays were performed using the commercially available 5-HT₂ receptor agonist [¹²⁵IJDOI as the radioligand and nonspecific binding was determined in the presence of unlabeled DOI at a saturating concentration of 10 μΜ. Competition experiments utilized 5-HT₂ receptor expressing HEK293 cell membranes obtained as described in Example 5 (15-25 μg membrane protein/well) and radioligand at final assay concentrations of 0.4 to 0.6 nM. Experiments comprised addition of 95 μΕ of assay buffer (20 mM HEPES, pH 7.4, 10 mM MgCl₂), 50 μΕ of membranes, 50 μΕ of radioligand stock, and 5 μΕ of test compound diluted in assay buffer to 96-well microliter plates, which were then incubated for 1 h at room temperature. Assay incubations were terminated by rapid filtration through PerkinElmer F/C filtration plates under reduced pressure using a 96-well Packard filtration apparatus, followed by washing three times with ice cold assay buffer. Plates were then dried at 45 °C for a minimum of 2 h. Finally, 25 μΐ_^ of BetaScint™ scintillation cocktail was added to each well and the plates were counted in a Packard TopCount® scintillation counter. In each competition study, test compounds were dosed at ten concentrations with triplicate determinations at each test concentration.

The observed DOI Binding Ki values for several compounds of Formula I at 5-HT₂c, 5-HT_2B, and 5-HT_2A receptors are listed in Table B.

Table B

The observed DOI Binding Ki values for several compounds of Formula XI at 5-HT_2C, 5-HT_2B, and 5-HT_2A receptors are listed in Table BB.

Table BB

DOI Binding Ki

Compound Number

2C 2A 2Β

1^st eluting enantiomer

in example IB.5 3.83μΜ 65.6μΜ 94.2μΜ

2^nd eluting

enantiomer in

example IB.5 31.7nM 12.6μΜ 95.3μΜ

1^st eluting enantiomer

in example IB.7 ΙΟΟμΜ 62.6μΜ 93.8μΜ

2^nd eluting

enantiomer in

example IB.7 27.1nM 60.7μΜ 93.3μΜ

1^st eluting enantiomer

in example IB.9 10 μΜ 70.4 μΜ 95.5 μΜ

2^nd eluting

enantiomer in

example IB.9 18.6 nM 2.01 μΜ 95.6 μΜ

The observed DOI Binding Ki values for several compounds of Formula XXI at 5-HT₂c, 5- HT₂B, and 5-HT_2A receptors are listed in Table BBB.

Table BBB

Example 7: IP Accumulation Assays.

HEK293 cells expressing recombinant 5-HT₂ receptors were added to sterile poly-D-lysine- coated 96-well microtiter plates (35,000 cells/well) and labeled with 0.6 μΟΛνεΙΙ of [³H]inositol in myoinositol-free DMEM for 18 h. Unincorporated [³H]inositol was removed by aspiration and replaced with fresh myoinositol-free DMEM supplemented with LiCl (10 mM final) and pargyline (10 μΜ final). Serially diluted test compounds were then added and incubation was conducted for 2 h at 37 °C. Incubations were then terminated by lysing cells with the addition of ice-cold 0.1 M formic acid followed by freezing at -80 °C. After thawing, total [³H]inositol phosphates were resolved from

[³H]inositol using AG1-X8 ion exchange resin (Bio-Rad) and [³H]inositol phosphates were measured by scintillation counting using a Perkin Elmer TopCount® scintillation counter. All EC5₀

determinations were performed using 10 different concentrations and triplicate determinations were made at each test concentration. The observed IP Accumulation EC5₀ values for several compounds of Formula I at 5-HT₂ receptors are listed in Table C.

Table C

The observed IP Accumulation EC5₀ values for several compounds of Formula XI at 5-HT₂ receptors are listed in Table CC.

Table CC

IP Accumulation EC₅₀ (nM)

Compound Number

2C 2A 2Β

102 198nM ΙΟΟμΜ ΙΟΟμΜ

107 107nM ΙΟΟμΜ ΙΟΟμΜ

103 106nM ΙΟΟμΜ ΙΟΟμΜ

105 87.2nM ΙΟΟμΜ ΙΟΟμΜ

113 32.5 nM 100 μΜ 100 μΜ

1^st eluting enantiomer

in example IB.5 11.5μΜ ΙΟΟμΜ ΙΟΟμΜ

2^nd eluting

enantiomer in

example IB.5 37.1nM ΙΟΟμΜ ΙΟΟμΜ

1^st eluting enantiomer

in example IB.7 100 μΜ ΙΟΟμΜ ΙΟΟμΜ

2^nd eluting

enantiomer in

example IB.7 41.3nM ΙΟΟμΜ ΙΟΟμΜ

1^st eluting enantiomer

in example IB.9 28.4 μΜ 100 μΜ 100 μΜ

2^nd eluting

enantiomer in

example IB.9 16.4 nM 100 μΜ 100 μΜ

The observed IP Accumulation EC5₀ values for examples of compounds of Formula XXI, at 5-HT₂c, 5- HT_2B, and 5-HT_2A receptors, are listed in Table CCC.

Table CCC

Example 5: Effect of Compounds on Food Intake in the Male Sprague Dawley Rat.

Male Sprague Dawley rats (225-300 g) were housed three per cage in a temperature and humidity controlled environment (12 h: 12 h light:dark cycle, lights on at 0600 h). At 1600 h on the day before the test, rats were placed in fresh cages and food was removed. On test day, rats were placed into individual cages with grid floors at 1000 h with no access to food. At 1130 h, rats (n = 8) were administered either vehicle (20% hydroxypropyl-P-cyclodextrin) or test compound via oral gavage (PO, 1 mL kg) 30 min prior to food presentation. Food intake was measured at 60 min after drug administration (30 min after food presentation).

For test compounds of Formula I, data is expressed as % inhibition of food intake in treated rats relative to vehicle only rats (see Table D).

Table D

For test compounds of Formula XI, Figure 24 shows an example of food intake 1 hour after dosing the 2^nd eluting enantiomer in example 1B.5 at 2.5, 5, 7.5, and 10 mg kg compared to the vehicle ("VEH")- Figure 25 shows an example of food intake 1 hour after dosing the 2^nd eluting enantiomer in example 1B.9 at 10 mg kg compared to the vehicle.

For test compounds of Formula XXI, Figure 27 shows plots of (a) food intake vs. dose, and (b) % inhibition of food intake vs. dose, for compound 215 at 2.5, 5, 7.5, and 10 mg/kg compared to the vehicle ("VEH")- Figure 28 shows plots of (a) food intake vs. dose, and (b) % inhibition of food intake vs. dose, for compound 250 at 2.5, 5, 7.5, and 10 mg/kg compared to the vehicle ("VEH").

Other uses of the disclosed methods will become apparent to those in the art based upon, inter alia, a review of this patent document.

Claims

What is claimed is:

1. A compound selected from compounds of Formula I, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula I

wherein:

X is selected from O and S; and

R¹ is selected from: Ci-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-Ci-C₆ alkylene, heteroaryl, and heteroaryl-Ci-C₆ alkylene; each optionally substituted with one or more substituents selected from: Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylthio, Ci-C₆ alkylsulfonyl, aryloxy, halogen, and Ci-C₆ haloalkyl.

2. A compound of claim 1 , wherein X is O.

3. A compound of claim 1 , wherein X is S.

4. A compound of any one of claims 1 to 3, wherein R¹ is selected from: C₁-C6 alkyl, C3-C7

cycloalkyl, C3-C7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulionyl, propoxy, phenoxy, and trifluoromethyl.

5. A compound of any one of claims 1 to 3, wherein R¹ is selected from: butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, w-propyl, pyridinyl, and pyridinylmethyl; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulionyl, propoxy, phenoxy, and trifluoromethyl.

6. A compound of any one of claims 1 to 3, wherein R¹ is selected from: (6- (trifluoromethyl)pyridin-3-yl)methyl, l-ethoxypropan-2yl, 1 -methoxypropan-2-yl, 2- (ethylthio)ethyl, 2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2-chloroethyl, 2-ethoxyethyl, 2- ethoxypropyl, 2-iluoroethyl, 2-fluoropropyl, 2-isopropoxyethyl, 2-methoxy-2-oxoethyl, 2- methoxyethyl, 2-methoxypropyl, 2-phenoxyethyl, 2-propoxyethyl, 3-methoxypropyl, butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, propyl, pyridin-2-ylmethyl, and pyridin-3-yl.

7. A compound of claim 1 selected from compounds of Formula II, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula II

wherein R¹ is selected from: Ci-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-Ci-C₆ alkylene, heteroaryl, and heteroaryl-Ci-C₆ alkylene; each optionally substituted with one or more substituents selected from: Ci-C₆ alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkylthio, Ci-C₆ alkylsulfonyl, aryloxy, halogen, and Ci-C₆ haloalkyl.

8. A compound of claim 1 selected from compounds of Formula II, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula II

wherein R¹ is selected from: C₁-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl-Ci-C6 alkylene, heteroaryl, and heteroaryl-Ci-C6 alkylene; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy,

methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.

9. A compound of claim 1 selected from compounds of Formula II, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula II wherein R¹ is selected from: butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, n- propyl, pyridinyl, and pyridinylmethyl; each optionally substituted with one or more substituents selected from: chloro, ethoxy, ethylthio, fluoro, isopropoxy, methoxy, methoxycarbonyl, methylthio, methylsulfonyl, propoxy, phenoxy, and trifluoromethyl.

10. A compound of claim 1 selected from compounds of Formula II, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula II

wherein R¹ is selected from: (6-(trifluoromethyl)pyridin-3-yl)methyl, 1 -ethoxypropan-2yl, 1- methoxypropan-2-yl, 2-(ethylthio)ethyl, 2-(methylsulfonyl)ethyl, 2-(methylthio)ethyl, 2- chloroethyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-fluoroethyl, 2-fluoropropyl, 2-isopropoxyethyl, 2- methoxy-2-oxoethyl, 2-methoxy ethyl, 2-methoxypropyl, 2-phenoxyethyl, 2-propoxyethyl, 3- methoxypropyl, butyl, cyclopropyl, cyclopropylmethyl, ethyl, isopropyl, methyl, propyl, pyridin- 2-ylmethyl, and pyridin-3-yl.

11. A compound of claim 1 , selected from the following compounds, and pharmaceutically

acceptable salts, hydrates, and solvates thereof:

N-(2-methoxyethyl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide;

N- methyl- 1,2,3,4,6,7 -hexahydro- [1 ,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide ; N-(pyridin-3-yl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamide; N-(3-methoxypropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide;

N-propyl-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamide; N-isopropyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamide;

N-cyclopropyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamide; N-(2-ethoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamide; methyl 2-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamido)acetate; N-ethyl-l ,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole-8-carboxamide; N-(pyridin-2-ylmethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide; N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-l, 2,3,4,6 ,7-hexahydro-[l,4]diazepino[6,7,l- n^']indole-8 -carboxamide ;

N-(2-(methylthio)ethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(2-(methylsulfonyl)ethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(2-chloroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8-carboxamide; N-(cyclopropylmethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(2-isopropoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(2-(ethylthio)ethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-/z]indole-8- carboxamide;

N-(l-methoxypropan-2-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(l-ethoxypropan-2-yl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(2-methoxypropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(2-ethoxypropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8-carboxamide; N-(2-propoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8-carboxamide; N-(2-phenoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide;

N-(2-methoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carbothioamide;

N-methyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carbothioamide ;

N-(2-fluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8-carboxamide;

N-(3-fluoropropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8-carboxamide; and

N-butyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8-carboxamide.

12. A method for aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT₂c receptor agonist.

13. A method for aiding in the cessation of use of a tobacco product and the prevention of associated weight gain comprising the step of:

prescribing and/or administering an effective amount of a selective 5-HT_2C receptor agonist to an individual attempting to cease use of the tobacco product.

14. The method of claim 12 or 13, wherein aiding in the cessation of use of a tobacco product is aiding smoking cessation, and wherein the individual attempting to cease use of the tobacco product is an individual attempting to cease smoking.

15. A method for reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco comprising the step of:

16. A method for controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of:

17. The method of claim 16, wherein controlling weight gain comprises preventing weight gain. 18. The method of claim 17, wherein controlling weight gain comprises inducing weight loss.

19. The method of claim 18, wherein controlling weight gain comprises inducing weight loss of at least about 1 % after 12 weeks of administration. 20. The method of claim 18, wherein controlling weight gain comprises inducing weight loss of at least about 1.5% after 12 weeks of administration.

21. The method of claim 18, wherein controlling weight gain comprises inducing weight loss of at least about 2% after 12 weeks of administration.

22. The method of claim 18, wherein controlling weight gain comprises decreasing BMI.

23. The method of claim 18, wherein controlling weight gain comprises decreasing in percent body fat.

24. The method of claim 18, wherein controlling weight gain comprises decreasing waist circumference. 25. A method for reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco comprising the step of:

prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist. 26. The method of any one of claims 12 to 25, wherein prior to administering the selective 5-HT₂c receptor agonist, the method further comprises the step of:

instructing the individual to set a date to cease smoking tobacco.

27. The method of claim 26, wherein administration of the selective 5-HT₂c receptor agonist is initiated about 7 days prior to the date set to cease smoking tobacco.

28. The method of any one of claims 12 to 25, wherein after administering the selective 5-HT₂c receptor agonist, the method further comprises the step of:

instructing the individual to set a date to cease smoking tobacco.

29. The method of claim 28, wherein the date set to cease smoking tobacco occurs after at least 8 days of administration of the selective 5-HT_2C receptor agonist.

30. The method of claim 28 or 29, wherein the date set to cease smoking tobacco occurs prior to 35 days of administration of the selective 5-HT_2C receptor agonist.

31. The method of any one of claims 12 to 30, wherein the individual previously attempted to cease smoking tobacco but did not succeed in ceasing smoking tobacco.

32. The method of any one of claims 12 to 30, wherein the individual previously attempted to cease smoking tobacco but subsequently relapsed and resumed smoking tobacco.

33. The method of any one of claims 12 to 32, wherein the administration leads to a statistically significant improvement in the ability to tolerate the cessation of smoking as measured by analysis of data of the MPSS test.

34. A method of treatment for nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal comprising the step of: prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist.

35. A method of reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use comprising the step of:

36. The method of claim 34 or 35, wherein the individual has abstained from nicotine use for 12 weeks prior to prescribing and/or administering the selective 5-HT₂c receptor agonist.

37. The method of claim 34 or 35, wherein the individual has abstained from nicotine use for 24 weeks prior to prescribing and/or administering the selective 5-HT₂c receptor agonist.

38. The method of claim 34 or 35, wherein the individual has abstained from nicotine use for 9 months prior to prescribing and/or administering the selective 5-HT_2C receptor agonist.

39. The method of claim 34 or 35, wherein the individual has abstained from nicotine use for 52 weeks prior to prescribing and/or administering the selective 5-HT_2C receptor agonist.

40. The method of any one of claims 12 to 39, wherein, prior to administration, the individual has an initial body mass index < 25 kg/m².

41. The method of any one of claims 12 to 39, wherein, prior to administration, the individual has an initial body mass index > 25 kg/m².

42. The method of any one of claims 12 to 39, wherein, prior to administration, the individual has an initial body mass index > 27 kg/m². 43. The method of claim 41 or 42, wherein, prior to administration, the individual has at least one weight-related comorbid condition.

44. The method of claim 43, wherein the weight-related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea.

45. The method of claim 43, wherein the weight-related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

46. The method of any one of claims 12 to 39, wherein, prior to administration, the individual has an initial body mass index > 30 kg/m².

47. A method of reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco, aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product, aiding in smoking cessation and preventing associated weight gain, controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use, comprising:

selecting an individual with an initial BMI > 27 kg/m²; and

prescribing and/or administering to the individual an effective amount of a selective 5-HT_2C receptor agonist for at least one year. 48. The method of claim 47, wherein the individual is prescribed and/or administered the effective amount of the selective 5-HT_2C receptor agonist for one year.

49. The method of claim 47 or 48, wherein, prior to administration, the individual has at least one weight-related comorbid condition.

50. The method of claim 49, wherein the weight-related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea.

51. The method of claim 49, wherein the weight-related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

52. The method of any one of claims 47 to 51 , wherein, prior to administration, the individual has an initial body mass index > 30 kg/m².

53. A method of reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco, aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product, aiding in smoking cessation and preventing associated weight gain, controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use, comprising:

administering a selective 5-HT₂c receptor agonist to an individual;

monitoring the individual for BMI during said administration; and

54. The method of claim 53, wherein the initial BMI of the individual prior to administration is about 18.5 to about 25 kg/m².

55. The method of claim 54, wherein the individual has an initial BMI selected from one of the following: > 24 kg/m², > 23 kg/m², > 22.5 kg/m², > 22 kg/m², > 21 kg/m², > 20 kg/m², > 19 kg/m², and > 18.5 kg/m².

56. The method of claim 54 or 55 wherein the BMI of the individual becomes a BMI selected from one of the following: < 18 kg/m², < 17.5 kg/m², < 17 kg/m², < 16 kg/m², and < 15 kg/m².

57. A method of reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco, aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product, aiding in smoking cessation and preventing associated weight gain, controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use, comprising:

administering a selective 5-HT₂c receptor agonist to an individual with an initial BMI < 25 kg/m²; monitoring the individual for body weight during said administration; and

58. The method of claim 57, wherein the initial BMI of the individual prior to administration is about 18.5 to about 25 kg/m².

59. The method of claim 58, wherein the individual has an initial BMI selected from one of the following: > 24 kg/m², > 23 kg/m², > 22.5 kg/m², > 22 kg/m², > 21 kg/m², > 20 kg/m², > 19 kg/m², and > 18.5 kg/m².

60. The method of any one of claims 57 to 59, wherein the decrease in body weight is selected from one of the following: more than about 1.5%, more than about 2%, more than about 2.5%, more than about 3%, more than about 3.5%, more than about 4%, more than about 4.5%, and more than about 5%.

61. A method of reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco, aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product, aiding in smoking cessation and preventing associated weight gain, controlling weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, reducing weight gain associated with smoking cessation by an individual attempting to cease smoking tobacco, treating nicotine dependency, addiction and/or withdrawal in an individual attempting to treat nicotine dependency, addiction and/or withdrawal, or reducing the likelihood of relapse use of nicotine by an individual attempting to cease nicotine use, comprising:

administering a selective 5-HT₂c receptor agonist to an individual;

monitoring the individual for body weight during said administration; and

62. The method of claim 61, wherein the initial BMI of the individual prior to administration is 18.5 to 25 kg/m².

63. The method of claim 62, wherein the individual has an initial BMI selected from one of the following: > 24 kg/m², > 23 kg/m², > 22.5 kg/m², > 22 kg/m², > 21 kg/m², > 20 kg/m², > 19 kg/m², and > 18.5 kg/m². 64. The method of claim 62 or 63, wherein the decrease in body weight is selected from one of the following: more than about 1.5 kg, more than about 2 kg, more than about 2.5 kg, more than about 3 kg, more than about 3.5 kg, more than about 4 kg, more than about 4.5 kg, and more than about 5 kg. 65. The method of any one of claims 12 to 64, wherein prior to administering the selective 5-HT₂c receptor agonist, the method further comprises the steps of:

providing a plurality of potential selective 5-HT₂c receptor agonists,

testing the plurality of potential selective 5-HT₂c receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and

formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual. 66. The method of any one of claims 12 to 64, wherein prior to administering the selective 5-HT_2C receptor agonist, the method further comprises the steps of:

providing a plurality of potential selective 5-HT_2C receptor agonists,

67. A method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual, comprising:

providing a plurality of potential selective 5-HT_2C receptor agonists;

testing the plurality of potential selective 5-HT_2C receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and

68. A method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual, comprising:

providing a plurality of potential selective 5-HT_2C receptor agonists;

69. A method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual, comprising:

testing a plurality of potential selective 5-HT_2C receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT_2C receptor agonist, wherein the selective 5- HT_2C receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 50-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and

70. A method for formulating a selective 5-HT₂c receptor agonist in a manner suitable for administration to an individual, comprising:

testing a plurality of potential selective 5-HT₂c receptor agonists in a functional inositol phosphate accumulation assay, to identify a selective 5-HT₂c receptor agonist, wherein the selective 5- HT₂c receptor agonist exhibits at least about 10-fold selectivity for the 5-HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the 5-HT_2C receptor over the 5-HT_2B receptor; and formulating the selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual. 71. A method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual, comprising:

72. A method for formulating a selective 5-HT_2C receptor agonist in a manner suitable for administration to an individual comprising:

73. The method of any one of claims 67 to 72, wherein, prior to administration, the individual has an initial body mass index < 25 kg/m².

74. The method of any one of claims 67 to 72, wherein, prior to administration, the individual has an initial body mass index > 25 kg/m².

75. The method of any one of claims 67 to 72, wherein, prior to administration, the individual has an initial body mass index > 27 kg/m².

76. The method of claim 74 or 75, wherein, prior to administration, the individual has at least one weight-related comorbid condition.

77. The method of claim 76, wherein the weight-related comorbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea.

78. The method of claim 76, wherein the weight-related comorbid condition is selected from: hypertension, dyslipidemia, and type 2 diabetes.

79. The method of any one of claims 67 to 72, wherein, prior to administration, the individual has an initial body mass index > 30 kg/m².

80. The method of any one of claims 67 to 79, wherein controlling weight gain comprises preventing weight gain.

81. The method of any one of claims 67 to 79, wherein controlling weight gain comprises inducing weight loss.

82. The method of claim 81, wherein controlling weight gain comprises inducing weight loss of at least about 1 % after 12 weeks of administration.

83. The method of claim 81, wherein controlling weight gain comprises inducing weight loss of at least about 1.5% after 12 weeks of administration.

84. The method of claim 81, wherein controlling weight gain comprises inducing weight loss of at least about 2% after 12 weeks of administration.

85. The method of claim 81 , wherein controlling weight gain comprises decreasing BMI.

86. The method of claim 81 , wherein controlling weight gain comprises decreasing percent body fat.

87. The method of claim 81 , wherein controlling weight gain comprises decreasing waist circumference.

88. The method of any one of claims 67 to 79, wherein prior to administering the selective 5-HT₂c receptor agonist, the method further comprises the step of:

instructing the individual to set a date to cease smoking tobacco.

89. The method of claim 88, wherein administration of the selective 5-HT_2C receptor agonist is initiated about 7 days prior to the date set to cease smoking tobacco.

90. The method of any one of claims 67 to 79, wherein after administering the selective 5-HT_2C receptor agonist, the method further comprises the step of:

instructing the individual to set a date to cease smoking tobacco.

91. The method of claim 90, wherein the date set to cease smoking tobacco occurs after at least 7 days of administration of the selective 5-HT₂c receptor agonist.

92. The method of claim 90 or 91, wherein the date set to cease smoking tobacco occurs prior to 36 days of administration of the selective 5-HT_2C receptor agonist.

93. The method of any one of claims 47 to 92, wherein the individual previously attempted to cease smoking tobacco but did not succeed in ceasing smoking tobacco.

94. The method of any one of claims 47 to 92, wherein the individual previously attempted to cease smoking tobacco but subsequently relapsed and resumed smoking tobacco.

95. The method of any one of claims 12 to 94, wherein the administration leads to a statistically significant improvement in the ability to tolerate the cessation of smoking as measured by analysis of data from the MPSS test.

96. The method of any one of claims 12 to 95, wherein the individual is suffering from depression prior to being administered the selective 5-HT_2C receptor agonist.

97. The method of any one of claims 12 to 96, wherein the individual is suffering from a preexisting psychiatric disease prior to being administered the selective 5-HT₂c receptor agonist.

98. The method of claim 97, wherein the preexisting psychiatric disease is chosen from schizophrenia, bipolar disorder, and major depressive disorder.

99. The method of any one of claims 12 to 98, wherein the individual is also being prescribed and/or administered a supplemental agent. 100. The method of claim 99, wherein the supplemental agent is varenicline or a pharmaceutically acceptable salt thereof.

101. The method of claim 99, wherein the supplemental agent is clonidine. 102. The method of claim 99, wherein the supplemental agent is nicotine replacement therapy.

103. The method of claim 102, wherein the nicotine replacement therapy is chosen from nicotine gum, nicotine transdermal systems, nicotine lozenges, nicotine microtabs, and nicotine sprays or inhalers.

104. The method of claim 99, wherein the supplemental agent is an antidepressant.

105. The method of claim 104, wherein the antidepressant is chosen from nortriptyline and bupropion.

106. The method of any one of claims 12 to 105, wherein the individual has previously undergone treatment with a supplemental agent.

107. The method of claim 106, wherein the individual was refractory to said treatment with said supplemental agent.

108. The method of any one of claims 12 to 105, wherein the individual has previously undergone treatment with a nicotine replacement therapy.

109. The method of claim 108, wherein the individual was refractory to said treatment with said nicotine replacement therapy.

110. The method of any one of claims 12 to 109, wherein, prior to administration of the selective 5-HT₂c receptor agonist, the individual smokes >10 cigarettes per day.

111. The method of any one of claims 12 to 110, wherein, prior to administration of the selective 5-HT_2C receptor agonist, the individual has a moderate nicotine addiction as measured by the Fagerstrom Test for nicotine dependence.

112. The method of any one of claims 12 to 110, wherein, prior to administration of the selective 5-HT_2C receptor agonist, the individual has a high nicotine addiction as measured by the Fagerstrom Test for nicotine dependence score.

113. The method of any one of claims 12 to 110, wherein, prior to administration of the selective 5-HT₂c receptor agonist, the individual has a very high nicotine addiction as measured by the Fagerstrom Test for nicotine dependence score.

114. The method of any one of claims 12 to 113, wherein the selective 5-HT_2C receptor agonist is administered for at least about 2 weeks.

115. The method of any one of claims 12 to 113, wherein the selective 5-HT_2C receptor agonist is administered for at least about 4 weeks.

116. The method of any one of claims 12 to 113, wherein the selective 5-HT_2C receptor agonist is administered for at least about 8 weeks.

117. The method of any one of claims 12 to 113, wherein the selective 5-HT_2C receptor agonist is administered for at least about 12 weeks.

118. The method of any one of claims 12 to 113, wherein the selective 5-HT_2C receptor agonist is administered for at least about 6 months.

119. The method of any one of claims 12 to 113, wherein the selective 5-HT₂c receptor agonist is administered for at least about 1 year.

120. The method of any one of claims 12 to 113, wherein the selective 5-HT₂c receptor agonist is administered for at least about 2 years.

121. The method of any one of claims 12 to 113, wherein the selective 5-HT_2C receptor agonist is administered for between about 12 weeks to about 52 weeks.

122. The method of any one of claims 12 to 121 , further comprising the step of:

providing the individual with educational materials and/or counseling.

123. The method of any one of claims 12 to 122, further comprising the step of:

providing the individual with biochemical feedback; acupuncture; hypnosis; behavioral intervention; support services; and/or psychosocial treatment.

124. The method of any one of claims 12 to 123, wherein the selective 5-HT₂c receptor agonist exhibits at least about 15-fold selectivity for the 5 -HT_2C receptor over the 5-HT_2A receptor and at least about 100-fold selectivity for the HT_2C receptor over the 5-HT_2B receptor.

125. A composition comprising a selective 5-HT_2C receptor agonist and at least one supplemental agent.

126. The composition of claim 125, wherein the supplemental agent is chosen from nicotine replacement therapies.

127. The composition of claim 125, wherein the supplemental agent is chosen from antidepressants. 128. The composition of claim 125, wherein the supplemental agent is chosen from clonidine or a pharmaceutically acceptable salt thereof.

129. The composition of claim 125, wherein the supplemental agent is chosen from varenicline or a pharmaceutically acceptable salt thereof.

130. A composition as claimed in any one of claims 120 to 129 for use in a method of:

aiding in smoking cessation and preventing associated weight gain;

131. A composition according to any one of claims 120 to 129 for use as a medicament for: reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco;

aiding in smoking cessation and preventing associated weight gain;

132. The composition according to any one of claims 120 to 129 in the manufacture of a medicament for: reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco;

aiding in smoking cessation and preventing associated weight gain;

133. A unit dosage form of a composition according to any one of claims 120 to 129.

134. A selective 5-HT₂c receptor agonist for use in a method of:

aiding in smoking cessation and preventing associated weight gain;

135. A selective 5-HT_2C receptor agonist for use as a medicament for:

reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product;

aiding in smoking cessation and preventing associated weight gain;

136. A selective 5-HT_2C receptor agonist in the manufacture of a medicament for:

aiding in smoking cessation and preventing associated weight gain;

137. A selective 5-HT_2C receptor agonist having at least one of the attributes described herein for use in combination with a supplemental agent.

138. A selective 5-HT_2C receptor agonist according to claim 137, for use in a method of: reducing the frequency of smoking tobacco in an individual attempting to reduce frequency of smoking tobacco; aiding in the cessation or lessening of use of a tobacco product in an individual attempting to cease or lessen use of a tobacco product;

aiding in smoking cessation and preventing associated weight gain;

139. A supplemental agent chosen from nicotine replacement therapies, for use in combination with a selective 5-HT_2C receptor agonist having at least one of the attributes described herein.

140. A supplemental agent according to claim 139 for use in a method of:

aiding in smoking cessation and preventing associated weight gain;

141. A compound selected from compounds of Formula XI, and pharmaceutically acceptable salts, hydrates, and solvates thereof

Formula XI

wherein:

X¹ is selected from O and S;

R^12a and R^12b are each independently H, C3-C7 cycloalkyl or C₁-C6 alkyl, wherein the C3-C7 cycloalkyl and C₁-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C₁-C6 alkyl and C₁-C6 alkoxy;

R^13a and R^13b are each independently H, C3-C7 cycloalkyl or C₁-C6 alkyl, wherein the C3-C7 cycloalkyl and C₁-C6 alkyl are each optionally independently substituted with one or more substituents independently selected from halogen, C₁-C6 alkyl and C₁-C6 alkoxy;

or R^13a and R^13b taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring;

n is 0, 1, or 2;

wherein if n is 1, R¹⁴ is Ci-C₆ alkyl,

and wherein if n is 2, each R¹⁴ is Ci-C₆ alkyl bonded to the same carbon, or two R¹⁴ taken together with the carbon they are bonded to form a 3- to 5-membered spirocyclic ring;

provided that if R^12a, R^12b, R^13a and R^13b are each H then n is 1 or 2.

142. The compound of claim 141 , wherein , R¹¹ is ethyl.

143. The compound of claim 141 , wherein , R¹¹ is methyl.

144. The compound of any one of claims 141 to 143, wherein X¹ is O.

145. The compound of any one of claims 141 to 144, wherein each of R^12a and R^12b is H.

146. The compound of claim 141 to 144, wherein one of R ^a and R is H and the other is methyl.

147. The compound of claim 141 to 144, wherein one of R^12a and R^12b is H and the other is ethyl.

148. The compound of any one of claims 141 to 144, wherein one of R^12a and R^12b is H and the other is Ci-C₆ alkyl substituted with one or more halogen.

149. The compound of claim 148, wherein one of R^12a and R^12b is H and the other is 2,2,2- trifluoroethyl.

150. The compound of claim 141 , wherein the compound is selected from compounds of

Formula Ila-i, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula Xlla-i

wherein:

one of R^12a and R^12b is H and the other is C₁-C6 alkyl optionally substituted with one or more substituents independently selected from halogen and C₁-C6 alkoxy,

wherein X¹ is O.

151. The compound of claim 150, wherein one of R^12a and R^12b is H and the other is ethyl.

152. The compound of claim 150, wherein one of R^12a and R^12b is H and the other is 2,2,2- trifluoroethyl.

153. The compound of any one of claims 150 to 152, wherein the carbon bearing R ^a and R has (R) stereochemistry.

154. The compound of any one of claims 150 to 152, wherein the carbon bearing R^12a and R has (S) stereochemistry.

155. The compound of claim 141 , wherein the compound is selected from compounds of Formula XIIc, and pharmaceutically acceptable salts, hydrates, and solvates thereof

Formula XIIc

wherein:

each of R^12a and R^12b is H; or one of R^12a and R^12b is H and the other is C C₆ alkyl optionally substituted with one or more substituents independently selected from halogen and Ci-C₆ alkoxy.

156. The compound of claim 141 , wherein the compound is selected from the following

compounds, and salts, hydrates, and solvates thereof:

N-(2-methoxyethyl)-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole- 8-carboxamide;

N-(2-ethoxyethyl)-7-methyl-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide;

N-(2-ethoxyethyl)-7-ethyl-l ,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole-8- carboxamide;

N,7,7-trimethyl-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamide; N-methyl-7-propyl-l ,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole-8-carboxamide; (R)-N-methyl-7-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide;

7-ethyl-N-methyl-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole-8-carboxamide; (5)-7 -ethyl-N-methyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 - carboxamide;

(R)-7-ethyl-N-methyl-l,2,3,4,6,7-hexahydro 1,4]diazepino[6,7,l-/z ]indole-8- carboxamide;

f5)-N-methyl-7-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide;

N,7-dimethyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide ; 6 -ethyl-N-methyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide ; N-methyl-7-(2,2,2-trifluoroethyl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide;

f5)-N-methyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- hi] indole-8 -carboxamide.

fR N-methyl-7-(2,2,2-trifluoroethyl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- hi] indole-8 -carboxamide.

N-methyl-7-(trifluoromethyl)-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole-8- carboxamide;

N,6 -dimethyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide ; N,6,6-trimethyl-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8-carboxamide; 7-(methoxymethyl)-N-methyl-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole-8- carboxamide;

N,4-dimethyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide ; N,4,4-trimethyl- 1 ,2,3 ,4,6 ,7-hexahydro- [ 1 ,4] diazepino [6 ,7,1 -hi] indole-8 -carboxamide ; N,3 -dimethyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide ; and N, 1 -dimethyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide.

157. The compound of claim 141 , wherein the compound is selected from the following

compounds, and salts, hydrates, and solvates thereof:

N,4-dimethyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole- 8 -carboxamide (compound 124);

N-methyl-6-propyl-l ,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole-8-carboxamide (compound 125);

4-ethyl-N-methyl-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole-8-carboxamide (compound 126); N-(2-ethoxyethyl)-7-(2,2,2-trifluoroethyl)-l, 2,3,4,6 ,7-hexahydro-[l,4]diazepino[6,7,l- n^']mdole-8-carboxamide (compound 127);

N-butyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide (compound 128);

N-propyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8 carboxamide (compound 129);

N-(2-methoxyethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z]indole-8-carboxamide (compound 130);

N-(2-isopropoxyethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-z]indole-8-carboxamide (compound 131);

N-ethyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide (compound 132);

N-(2-fluoroethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- n^']mdole-8-carboxamide (compound 133);

N-(2,2-difluoroethyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l n^']mdole-8-carboxamide (compound 134);

(R)-N-propyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- n^']mdole-8-carboxamide (compound 135);

(S)-N-propyl-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- n^']mdole-8-carboxamide (compound 136);

N,7-bis(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide (compound 137);

N-(2,2,3,3,3-pentafluoropropyl)-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro- [l,4]diazepmo[6,7,l-n^']mdole-8-carboxamide (compound 138);

7-ethyl-N-(2-fluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide (compound 139); and

N-(2,2-difluoroethyl)-7-ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8- carboxamide (compound 140). A compound selected from compounds of Formula XXI, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula XXI

wherein:

each of R²⁵ and R²⁶ is independently hydrogen or C₁-C6 alkyl;

R²⁷ is hydrogen, C₁-C6 alkyl or C3-C7 cycloalkyl;

R²⁸ is hydrogen or C₁-C6 alkyl;

or R²² and R²³ taken together with the carbon they are bonded to form a three-, four-, five-, six- or seven-membered carbocyclic ring or heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, Ci-C₆ alkyl, and Ci-C₆ alkoxy;

R²⁴ is hydrogen, halogen, hydroxy, C₃-C₇ cycloalkyl, Ci-C₆ alkoxy or Ci-C₆ alkyl optionally substituted with Ci-C₆ alkoxy; and

R²¹ is selected from the group consisting of:

hydrogen;

halogen;

C₁-C6 alkyl optionally substituted with one or more substituents each of which is independently halogen, hydroxy, C₁-C6 alkoxy, amino, heteroarylamino, arylamino, d- (, dialkylamino, aryl, C₁-C6 alkoxycarbonyl, C₁-C6 alkylamino optionally substituted with C₁-C6 alkoxy, 3- to 7-membered heterocycloalkyl optionally substituted with C₁-C6 alkoxy, or C3-C7 cycloalkyl optionally substituted with C₁-C₆ alkoxy;

aryl;

heteroaryl;

C3-C7 cycloalkyl optionally substituted with C₁-C6 alkoxy;

amino;

Ci-C₆ alkylamino optionally substituted with Ci-C₆ alkoxy or with hydroxy; Ci-C₆ dialkylamino optionally substituted with Ci-C₆ alkoxy or with hydroxy; arylamino;

Ci-C₆ alkoxy optionally substituted with one or more halogens; hydroxy; -NHCO-Ci-Cs alkyl;

-NHCO(0)Ci-C₆ alkyl;

-OCO(NH)Ci-C₆ alkyl;

and

CN;

The compound of claim 158, wherein R is hydrogen. The compound of claim 158, wherein R²¹ is Ci-C₆ alkyl.

161. The compound of any one of claims 158 to 160, wherein each of R and R is methyl.

162. The compound of any one of claims 158 to 160, wherein R²² and R²³ taken together with the carbon they are bonded to form a four-membered carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from the group consisting of halogen, C₁-C6 alkyl, and C₁-C6 alkoxy.

163. A compound of claim 158, wherein the compound is selected from compounds of

Formula II, and pharmaceutically acceptable salts, hydrates, and solvates thereof:

Formula XXII

wherein:

R²¹ is selected from the group consisting of

hydrogen;

halogen;

and C3-C7 cycloalkyl;

R²² and R²³ are the same and each is hydrogen or C1-C6 alkyl optionally substituted with halogen; or R²² and R²³ taken together with the carbon they are bonded to form a three-membered carbocyclic ring, a four-membered carbocyclic ring, a five-membered carbocyclic ring or a six-membered carbocyclic ring;

and

R²⁴ is hydrogen;

provided that at least one of R 21 , R 22 and R 23 is other than hydrogen.

164. The compound of claim 158, wherein the compound is selected from the following

compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof:

8-methoxy-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-bromo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8 -chloro- 1 ,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8-(trifluoromethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8-phenyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-ethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-n^'] indole;

8-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7- methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-9-ol;

8- benzyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-n^'] indole;

8-phenethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-bromo-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8 -isobutyl- 1 ,2 ,3 ,4,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8-iodo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-n^'] indole;

7.7- dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7- methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8- chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7.8- dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8 -fluoro- 1 ,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

(S)-7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

(R)-7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

7,7,8 -trimethyl- 1 ,2 ,3 ,4 ,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8-ethyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole; 9-bromo-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

9-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

9-fluoro-8-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

9-bromo-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole; 9-chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-fluoro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

2,2',3,3',4,5',6,6'-octahydro-lH-spiro[[l, 4] diazepino [6, 7, 1-Λ] indole -7 ,4'-pyran];

8 -bromo-7-methyl- 1 ,2,3 ,4,6 ,7-hexahydro- [ 1 ,4] diazepino [6, 7 , 1 -hi] indole ;

( 1 ,2 ,3 ,4 ,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indol- 8 -yl)methanol;

(1 ,2 ,3 ,4 ,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indol- 8 -yl)methan amine ;

8-(piperidin-l-ylmethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8 -cyclopropyl-7 ,7 -dimethyl- 1 ,2 ,3 ,4 ,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8 -cyclopropyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8-fluoro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole; 8-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-ethyl-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8- cyclopropyl-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole; (7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)methanol; 7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-amine;

ethyl (l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)carbamate;

N-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)butyr amide;

9- bromo-8-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole; 8,9-dichloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8- bromo-9-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole; 8-chloro-7,9-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

9- chloro-7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole; 2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-z]indole-7,l '-cyclobutane]; 7,7-diethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

methyl 3-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)propanoate; 8-(2-ethoxyethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7,7 ,9-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

9-cyclopropyl-7 ,7 -dimethyl- 1 ,2 ,3 ,4 ,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ; 6-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7,9-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole; (6R,7R)-6 ,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

(6S,7R)-6,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8 -bromo-6-methyl- 1 ,2,3 ,4,6 ,7-hexahydro- [ 1 ,4]diazepino[6,7 , 1 -hi] indole ;

2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-z]indole-7,l '-cyclopropane];

6,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7- (2,2,2-trilluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

(R)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

(7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)methanol;

(S)-3,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7,7-dimethyl-2,4,6,7-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-z]indole-3,l'-cyclopropane]; 4 ,7 ,7-trimethyl- 1 ,2 ,3 ,4 ,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

4-ethyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

4-methyl-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-z]indole-7,l'-cyclobutane];

4-cyclopropyl-7 ,7 -dimethyl- 1 ,2 ,3 ,4 ,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

9 -methoxy-7 -methyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8- fluoro-4,7,7-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole-8-carbonitrile;

N-((l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)methyl)-2-methoxyethanamine; l-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)-N,N-dimethylmethanamine;

8-(pyrrolidin-l-ylmethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

N-((l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)methyl)-3-methoxypropan-l-amine l-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)-N-methylmeth an amine;

8- ((4-methoxypiperidin-l-yl)methyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole; N-((l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)methyl)pyridin-4-amine;

N-(7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)acetamide;

N-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)acetamide;

l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-amine;

N-(l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]mdol-8-yl)propionamide;

ethyl (7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indol-8-yl)carbamate;

9- fluoro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7,7-dimethyl-9-propyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole; and

2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-z]indole-7,l'-cyclopentane]

165. The compound of claim 158, wherein the compound is selected from the following compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof:

843romo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8 -chloro- 1 ,2,3,4,6,74iexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8-(trifluoromethyl)-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z] indole;

8-ethyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z]indole;

8-methyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z]indole;

7- methyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z]indol-9-ol;

8- propyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z]indole;

843romo-7,7-dimethyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z] indole;

8 -isobutyl- 1 ,2 ,3 ,4,6 ,7-hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8-iodo-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-n^'] indole;

7.7- dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7- methyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z]indole;

8- chloro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

7.8- dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

f5J-7,8-dimethyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-M]indole;

fRJ-7,8-dimethyl-l,2,3,4,6,74iexahydro-[l,4]diazepino[6,7,l-z]indole;

7,7,8-trimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-ethyl-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-fluoro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8 -cyclopropyl-7 ,7 -dimethyl- 1 ,2 ,3 ,4 ,6 ,7-hexahydro- [ 1 ,4]diazepino [6 ,7 , 1 -hi] indole ;

8 -cyclopropyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 ,1-hi] indole ;

8-fluoro-7,7-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8 -ethyl-7 -methyl- 1,2,3,4,6,7 -hexahydro- [1,4] diazepino [6 ,7 , 1 -hi] indole ;

8- cyclopropyl-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

9- bromo-8-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8.9- dichloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

8-bromo-9-chloro-7-methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z] indole;

8- chloro-7,9-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

9- chloro-7,8-dimethyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-z]indole;

2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l-z]indole-7,l '-cyclobutane]; 7,7-diethyl-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole;

2,3,4,6-tetrahydro-lH-spiro[[l ,4]diazepino[6,7,l- z ]indole-7,l '-cyclopropane];

7- (2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole; and

2,3,4,6-tetrahydro-lH-spiro[[l ,4]diazepino[6,7,l- z ]indole-7,l'-cyclopentane].

166. The compound of claim 158, wherein the compound is selected from the following compounds and pharmaceutically acceptable salts, hydrates, and solvates thereof:

8- bromo-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- z ]indole-7,l'-cyclobutane]

(compound 290);

8-(lH-l ,2,4-triazol-l-yl)-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole (compound 291); 8-chloro-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- z ]indole-7,l'-cyclobutane]

(compound 292);

8-methyl-2,3,4,6-tetrahydro-lH-spiro[[l,4]diazepino[6,7,l- z ]indole-7,l'-cyclobutane]

(compound 293);

8-(lH-pyrazol-l-yl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole (compound 294); 8-(lH-imidazol-l-yl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole (compound 295); 8-(lH-pyrrol-2-yl)-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole (compound 296); 8-bromo-7-(2,2,2-trifluoroethyl)-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ] indole

(compound 297);

8-(thiophen-3-yl)-l,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole (compound 298);

8-( 1 H-pyrazol-3 -yl)- 1 ,2,3 ,4,6 ,7-hexahydro- [ 1 ,4]diazepino [6,7, 1 -hi] indole (compound 299) ; 8-(lH-pyrazol-5-yl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole (compound 300); 8-(methoxymethyl)-l ,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- z ]indole (compound 301); 8-(isopropoxymethyl)-l ,2,3,4,6,7-hexahydro-[l ,4]diazepino[6,7,l- n^']indole (compound 302); 8-(3,3,3-trifluoropropyl)-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole (compound 303); 8-(furan-2-yl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole (compound 304); and 8-(lH-pyrazol-4-yl)-l ,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l- z ]indole (compound 305)

167. A pharmaceutical composition comprising a compound of any one of claims 1 to 11 or 141 to 166 and a pharmaceutically acceptable carrier.

168. A pharmaceutical composition comprising a compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

169. A pharmaceutical composition comprising a compound of any one of claims 141 to 157 and a pharmaceutically acceptable carrier.

170. A pharmaceutical composition comprising a compound of any one of claims 158 to 166 and a pharmaceutically acceptable carrier.

171. A process for preparing a pharmaceutical composition, comprising admixing a

compound of any one of claims 1 to 11 or 141 to 166 and a pharmaceutically acceptable carrier.

172. A method for decreasing food intake in an individual in need thereof, comprising

administering to said individual a therapeutically effective amount of a compound of any one of claims 1 to 11 or 141 to 166.

173. A method for inducing satiety in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of any one of claims 1 to 11 or 141 to 166.

174. A method for the treatment of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of any one of claims 1 to 11 or 141 to 166.

175. A method for the prevention of obesity in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of any one of claims 1 to 11 or 141 to 166.

176. A method for weight management in an individual in need thereof, comprising

177. The method of any one of claims 172 to 176, wherein said individual in need of weight management is an obese patient with an initial body mass index > 30 kg/m².

178. The method of any one of claims 172 to 176, wherein said individual in need of weight management is an overweight patient with an initial body mass index > 27 kg/m² in the presence of at least one weight related comorbid condition.

179. The method of claim 178, wherein said weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance and sleep apnea.

180. A method for the treatment of type 2 diabetes in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of any one of claims 1 to 11 or 141 to 166.

181. A method for the prevention of type 2 diabetes in an individual in need thereof,

comprising administering to said individual a therapeutically effective amount of a compound of any one of claims 1 to 11 or 141 to 166.

182. A method for the treatment of drug and alcohol addiction in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of any one of claims 1 to 11 or 141 to 166.

183. The method of claim 182 for the treatment of alcohol addiction.

184. The method of claim 182 for the treatment of drug addiction.

185. The method of claim 184 wherein said drug is nicotine.

186. The method of claim 184 for the treatment of tobacco dependence.

187. The method of claim 184 for aiding smoking cessation.

188. A method for the treatment of a seizure disorder in an individual in need thereof,

189. The method of claim 188, wherein said seizure disorder is epilepsy.

190. The method of claim 188, wherein said seizure disorder is Dravet syndrome.

191. A compound of any one of claims 1 to 11 or 141 to 166 for use in a method for treatment of the human or animal body by therapy.

192. A method of any one of claims 12 to 140, wherein the selective 5-HT_2C receptor agonist is a compound of any one of claims 1 to 11.

193. A method of any one of claims 12 to 140, wherein the selective 5-HT_2C receptor agonist is a compound of any one of claims 141 to 157.

194. A method of any one of claims 12 to 140, wherein the selective 5-HT₂c receptor agonist is a compound of any one of claims 158 to 166.

195. The compound of any one of claims 1 to 11 for use in a method according to any one of claims 12 to 140.

196. The compound of any one of claims 141 to 157 for use in a method according to any one of claims 12 to 140.

197. The compound of any one of claims 158 to 166 for use in a method according to any one of claims 12 to 140.