WO2007089335A2 - Multicyclic amino acid derivatives and methods of their use - Google Patents

Multicyclic amino acid derivatives and methods of their use Download PDF

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Publication number
WO2007089335A2
WO2007089335A2 PCT/US2006/047579 US2006047579W WO2007089335A2 WO 2007089335 A2 WO2007089335 A2 WO 2007089335A2 US 2006047579 W US2006047579 W US 2006047579W WO 2007089335 A2 WO2007089335 A2 WO 2007089335A2
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WO
WIPO (PCT)
Prior art keywords
amino
phenyl
optionally substituted
alkyl
propanoic acid
Prior art date
Application number
PCT/US2006/047579
Other languages
French (fr)
Other versions
WO2007089335A3 (en
Inventor
Arokiasamy Devasagayaraj
Haihong Jin
Qingyun Liu
Brent Marinelli
Lakshama Samala
Zhi-Cai Shi
Ashok Tunoori
Ying Wang
Wenxue Wu
Chengmin Zhang
Haiming Zhang
Original Assignee
Lexicon Pharmaceutical Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN2006800499070A priority Critical patent/CN101351451B/en
Priority to AU2006337137A priority patent/AU2006337137B2/en
Priority to DK06849951.6T priority patent/DK1984344T3/en
Priority to JP2008548561A priority patent/JP5483883B2/en
Priority to CA2635531A priority patent/CA2635531C/en
Priority to EP06849951A priority patent/EP1984344B1/en
Priority to PL06849951T priority patent/PL1984344T3/en
Priority to ES06849951T priority patent/ES2395392T3/en
Application filed by Lexicon Pharmaceutical Inc. filed Critical Lexicon Pharmaceutical Inc.
Priority to BRPI0620756-1A priority patent/BRPI0620756B1/en
Priority to EA200870127A priority patent/EA019879B1/en
Priority to NZ568946A priority patent/NZ568946A/en
Priority to KR1020087015697A priority patent/KR101360621B1/en
Publication of WO2007089335A2 publication Critical patent/WO2007089335A2/en
Publication of WO2007089335A3 publication Critical patent/WO2007089335A3/en
Priority to IL191998A priority patent/IL191998A/en
Priority to NO20083324A priority patent/NO344848B1/en
Priority to HK09102308.4A priority patent/HK1124841A1/en

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    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
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Definitions

  • the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior. In peripheral tissues, serotonin is reportedly implicated in the regulation of vascular tone, gut motility, primary hemostasis, and cell- mediated immune responses. Walther, D.J., et al., Science 299:76 (2003).
  • TPH tryptophan hydroxylase
  • mice genetically deficient for the tphl gene
  • the mice reportedly expressed normal amounts of serotonin in classical serotonergic brain regions, but largely lacked serotonin in the periphery. Id.
  • the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin. C ⁇ t ⁇ , F., et ah, PNAS 100(23): 13525-13530 (2003).
  • This invention is directed, in part, to compounds of formula I:
  • A is optionally substituted cycloalkyl, aryl, or heterocycle
  • A is optionally substituted cycloalkyl, aryl, or heterocycle
  • TPH ⁇ e.g., TPHl
  • This invention is also directed to pharmaceutical compositions and to methods of treating, preventing and managing a variety of diseases and disorders.
  • This invention is based, in part, on the discovery that knocking out the tphl gene in mice significantly reduces levels of GI serotonin, yet causes little, if any, measurable effect on the central nervous system (CNS).
  • This invention is also based on the discovery of compounds that inhibit TPH (e.g., TPHl).
  • TPH e.g., TPHl
  • preferred compounds of the invention reduce serotonin levels, and may be used in the treatment, prevention and management of a wide range of diseases and disorders.
  • alkenyl means a straight chain, branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond.
  • alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyi, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2- heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1- decenyl, 2-decenyl and 3-decenyl.
  • alkyl means a straight chain, branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as "lower alkyl.” Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
  • Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and/or cyclic portions (e.g., l-ethyl-4-methyl- cyclohexyl).
  • alkyl includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.
  • alkoxy means an — O— alkyl group. Examples of alkoxy groups include -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -0(CHz) 3 CH 3 , -O(CH 2 ) 4 CH 3 , and -O(CH 2 ) 5 CH 3 .
  • alkylaryl or “alkyl-aryl” means an alkyl moiety bound to an aryl moiety.
  • alkylheteroaryl or “alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.
  • alkylheterocycle or “alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.
  • alkynyl means a straight chain, branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond.
  • alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.
  • aryl means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms.
  • An aryl moiety may comprise multiple rings bound or fused together.
  • aryl moieties include anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and tolyl.
  • arylalkyl or "aryl-alkyl” means an aryl moiety bound to an alkyl moiety.
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureido, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable esters include lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable amides include lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkyl-carbonyl amides.
  • biohydrolyzable carbamates include lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • disease or disorder mediated by peripheral serotonin and “disease and disorder mediated by peripheral serotonin” mean a disease and/or disorder having one or more symptoms, the severity of which are affected by peripheral serotonin levels.
  • heteroalkyl refers to an alkyl moiety ⁇ e.g., linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S).
  • heteroaryl means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S).
  • heteroatom e.g., N, O or S.
  • examples include acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, and tri
  • heterocycle refers to an aromatic, partially aromatic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, O or S).
  • a heterocycle may comprise multiple (i.e., two or more) rings fused or bound together.
  • Heterocycles include heteroaryls.
  • Examples include benzo[l,3]dioxolyl, 2,3-dihydro-benzo[l,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl.
  • heterocyclealkyl or “heterocycle-alkyl” refers to a heterocycle moiety bound to an alkyl moiety.
  • heterocycloalkyl refers to a non-aromatic heterocycle.
  • heterocycloalkylalkyl or “heterocycloalkyl- alkyl” refers to a heterocycloalkyl moiety bound to an alkyl moiety.
  • the terms “manage,” “managing” and “management” encompass preventing the recurrence of the specified disease or disorder, or of one or more of its symptoms, in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission.
  • the terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • Suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Suitable non-toxic acids include inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, fiiroic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
  • inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,
  • Non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids.
  • Examples of specific salts thus include hydrochloride and mesylate salts.
  • Others are well-known in the art. See, e.g., Remington' s Pharmaceutical Sciences, 18 th ed. (Mack Publishing, Easton PA: 1990) and Remington: The Science and Practice of Pharmacy, 19 th ed. (Mack Publishing, Easton PA: 1995).
  • the term “potent TPHl inhibitor” is a compound that has a TPHl_IC 5 o of less than about 10 ⁇ M.
  • the terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder, or of one or more of its symptoms. The terms encompass prophylaxis.
  • prodrug encompasses pharmaceutically acceptable esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters of compounds disclosed herein.
  • prodrugs include compounds that comprise a biohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzable ester, biohydrolyzable phosphate, or biohydrolyzable ureide analog).
  • Prodrugs of compounds disclosed herein are readily envisioned and prepared by those of ordinary skill in the art. See, e.g., Design of Prodrugs. Bundgaard, A. Ed., Elseview, 1985; Bundgaard, H., “Design and Application of Prodrugs," A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • protecting group when used to refer to part of a molecule subjected to a chemical reaction, means a chemical moiety that is not reactive under the conditions of that chemical reaction, and which may be removed to provide a moiety that is reactive under those conditions.
  • Protecting groups are well known in the art. See, e.g., Greene, T. W. and Wuts, P.G.M., Protective Groups in Organic Synthesis (3 rd ed., John Wiley & Sons: 1999); Larock, R. C, Comprehensive Organic Transformations (2 nd ed., John Wiley & Sons: 1999). Some examples include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, and pthalimido.
  • pseudohalogen refers to a polyatomic anion that resembles a halide ion in its acid-base, substitution, and redox chemistry, generally has low basicity, and forms a free radical under atom transfer radical polymerization conditions.
  • pseudohalogens include azide ions, cyanide, cyanate, thiocyanate, thiosulfate, sulfonates, and sulfonyl halides.
  • selective TPHl inhibitor is a compound that has a TPH2_IC 5 o that is at least about 10 times greater than its TPHl_IC 5 o-
  • stereomerically enriched composition of a compound refers to a mixture of the named compound and its stereoisomer(s) that contains more of the named compound than its stereoisomers).
  • a stereoisomerically enriched composition of (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and (R)- butan-2-ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10, 95/5, and 98/2.
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one stereocenter will be substantially free of the opposite stereoisomer of the compound.
  • a stereomerically pure composition of a compound having two stereocenters will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • substituted when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as, but not limited to, alcohol, aldehylde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl ⁇ or -alkylNHC(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH 2 ), amine (primary, secondary and tertiary such as alkylamino, arylam ⁇ no, arylalkylamino), aroyl, ary
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition.
  • a therapeutically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • TPHl_ICso is the IC50 of a compound for
  • TPHl as determined using the in vitro inhibition assay described in the Examples, below.
  • TPH2_ICso is the IC50 of a compound for TPH2 as determined using the in vitro inhibition assay described in the Examples, below.
  • treat contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder, or one or more of its symptoms, or retards or slows the progression of the disease or disorder.
  • one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns.
  • the phrase "optionally substituted alky, aryl, or heteroaryl” has the same meaning as “optionally substituted alky, optionally substituted aryl, or optionally substituted heteroaryl.”
  • a chemical moiety that forms part of a larger compound may be described herein using a name commonly accorded it when it exists as a single molecule or a name commonly accorded its radical.
  • the terms “pyridine” and “pyridyl” are accorded the same meaning when used to describe a moiety attached to other chemical moieties.
  • the two phrases “XOH, wherein X is pyridyl” and “XOH, wherein X is pyridine” are accorded the same meaning, and encompass the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof.
  • any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences.
  • chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit.
  • A is optionally substituted cycloalkyl, aryl, or heterocycle
  • D is optionally substituted aryl or heterocycle
  • Rj is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle
  • R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or
  • A is optionally substituted cycloalkyl, aryl, or heterocycle
  • particular compounds include those wherein A is optionally substituted cycloalkyl (e.g., 6-membered and 5-membered).
  • A is optionally substituted aryl (e.g., phenyl or naphthyl).
  • A is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • A is aromatic. In others, A is not aromatic.
  • A is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
  • each of Ai and A 2 is independently a monocyclic optionally substituted cycloalkyl, aryl, or heterocycle.
  • Compounds encompassed by this formula include those wherein A 1 and/or A 2 is optionally substituted cycloalkyl (e.g., 6-membered and 5-membered).
  • Ai and/or A 2 is optionally substituted aryl (e.g., phenyl or naphthyl).
  • Ai and/or A 2 is optionally substituted heterocycle (e.g., 6-membered and 5-membered).
  • 6- membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • 5-membered heterocycles examples include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • a 1 and/or A 2 is aromatic. In others, Ai and/or A 2 is not aromatic.
  • D is optionally substituted aryl (e.g., phenyl or naphthyl).
  • D is optionally substituted heterocycle (e.g., 6-membered and 5-membered).
  • 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • 5- membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • D is aromatic. In others, D is not aromatic.
  • D is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
  • E is optionally substituted aryl (e.g., phenyl or naphthyl).
  • E is optionally substituted heterocycle (e.g., 6-membered and 5-membered).
  • 6- membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan.
  • E is aromatic.
  • E is not aromatic.
  • E is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
  • particular compounds include those wherein Ri is hydrogen or optionally substituted alkyl.
  • R 2 is hydrogen or optionally substituted alkyl.
  • n 1 or 2.
  • X is a bond or S.
  • X is -O-, -C(R 3 R 4 )O-, or -OC(RsR 4 )-, and, for example, R 3 is hydrogen or optionally substituted alkyl, and R 4 is hydrogen or optionally substituted alkyl. In some, R 3 is hydrogen and R 4 is trifluromethyl.
  • X is -S(Oz)-, -S(O 2 )N(R 5 )-, -N(R 5 )S(O 2 )-, -C(R 3 R 4 )S(O 2 )-, or -S(O 2 )C(R 3 R 4 )-, and, for example, R 3 is hydrogen or optionally substituted alkyl, R 4 is hydrogen or optionally substituted alkyl, and R 5 is hydrogen or optionally substituted alkyl.
  • X is -N(Rs)-, -N(R 5 )C(O)N(R 5 )-, -C(R 3 R 4 )N(R 5 )-, or -N(R 5 )C(R 3 R 4 )-, and, for example, R 3 is hydrogen or optionally substituted alkyl, R 4 is hydrogen or optionally substituted alkyl, and each R 5 is independently hydrogen or optionally substituted alkyl.
  • R 3 is trifluoromethyl. Others are encompassed by the formula:
  • R 3 is hydrogen
  • each of Zj, Z 2 , Z 3 , and Z 4 is independently N or CR 6 ; each R ⁇ is independently hydrogen, cyano, halogen, OR 7 , NRgRg, amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R 7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R 8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R 9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and m is 1-4. Certain such compounds are of the formula:
  • R3 is trifluoromethyl. Others are of the formula: wherein, for example, R 3 is hydrogen.
  • some compounds are such that all OfZ 1 , Z2, Z 3 , and Z 4 are N. In others, only three of Zi, Z 2 , Z 3 , and Z 4 are N. In others, only two of Zi, Z 2 , Z 3 , and Z4 are N. In others, only one of Z 1 , Z 2 , Z 3 , and Z4 is N. In others, none of Z 1 , Z2, Z 3 , and Z 4 are N.
  • each of Z'i, Z'2, and Z' 3 is independently N, NH, S, O or CR 6 ; each Rg is independently amino, cyano, halogen, hydrogen, OR 7 , SR 7 , NRgRg, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R 7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rs is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-3. Certain such compounds are of the formula:
  • R 3 is hydrogen
  • some compounds are such that all of Z' I , Z'2, and Z' 3 are N or NH. In others, only two of Z'i, Z' 2 , and Z' 3 are N or NH. In others, only one of Z'x, Z 2 , and Z' 3 is N or NH. In others, none of Z'i, Z' 2 , and Z' 3 are N or NH.
  • Certain such compounds are of the formula:
  • R 3 is trifluoromethyl. Others are of the formula:
  • R 3 is hydrogen
  • some compounds are such that all of Z"i, Z" 2 , Z" 3> and Z" 4 are N. In others, only three of Z' ⁇ , Z" 2 , Z" 3 , and Z" 4 are N. In others, only two of Z"i, Z" 2 , Z" 3 , and Z" 4 are N. In others, only one of Z"i, Z" 2> Z" 3 , and Z" 4 is N. In others, none of Z" 1 ⁇ Z" 2 , Z" 3 , and Z" 4 are N.
  • each of Z"i, Z" 2 , Z" 3 , and Z" 4 is independently N or CRJ O ; each R 1O is independently amino, cyano, halogen, hydrogen, ORn, SR 11 , NR12R 13 , or optionally substituted alkyl.
  • R 3 is trifluoromethyl. Others are of the formula:
  • R 3 is hydrogen
  • some compounds are such that all of Z"i, Z" 2 , Z" 3 ⁇ and Z" 4 are N. In others, only three of Z" u Z" 2 , Z" 3 , and Z" 4 are N. In others, only two of Z"i, Z" 2 , Z" 3 , and Z" 4 are N. In others, only one of Z" u Z" 2 , Z" 3 , and Z" 4 is N. In others, none of Z' ⁇ , Z" 2 , Z" 3 , and Z" 4 are N.
  • E and D are not both optionally substituted phenyl (i.e., E is not phenyl optionally substituted with at least one moiety in addition to D and the -[CH 2 In- moiety, and D is not phenyl optionally substituted with at least one moiety in addition to E and X).
  • E and D are not both optionally substituted phenyl when A is optionally substituted phenyl (i.e., A is phenyl optionally substituted with at least one moiety in addition to X).
  • E and D are not both phenyl. 4) E and D are not both phenyl when A is optionally substituted phenyl.
  • E is para-phenyl (i.e., D is attached at the position para to the — [CH.] n - moiety), and n is 1, D is not optionally substituted pyridazin-3(2H)-one.
  • n is 1
  • Ri is -C(O)(optionally substituted phenyl)
  • R 2 is H
  • D is not optionally substituted pyridazin-
  • A is not optionally substituted pyrrolidine.
  • D when E is para-phenyl, and n is 1, D is not optionally substituted 2,6- dimethoxyphenyl.
  • E when E is para-phenyl, n is 1, X is -CH 2 -, and A is pyrrolidine, D is not optionally substituted pyridazin-3(2H)-one.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 05/068415.
  • D is not optionally substituted quinazoline.
  • E is para-phenyl
  • n is 1, D is not optionally substituted quinazoline-2,4(lH,3H)-dione.
  • Ri is -C(O) (optionally substituted phenyl)
  • D is not optionally substituted quinazoline-2,4(lH,3H)-dione.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 05/061466.
  • E is optionally substituted phenyl (i.e., E is phenyl optionally substituted with moieties in addition to D and the -[CHj] n - moiety)
  • D is optionally substituted phenyl (i.e., D is phenyl optionally substituted with moieties in addition to X and E)
  • n is 1, and X is -OCH 2 -
  • A is not phenyl.
  • E is meta-(optionally substituted phenyl) (i.e., E is phenyl optionally substituted with moieties in addition to D and the
  • D is optionally substituted phenyl, n is 1, and X is -OCH 2 -, A is not phenyl.
  • E meta-(optionally substituted phenyl)
  • D is optionally substituted phenyl, n is 1, X is — OCH 2 -, and R 2 is optionally substituted alkyl or alkyl-aryl, A is not phenyl.
  • E meta-(substituted phenyl)
  • E is phenyl substituted with one or more moieties in addition to D and the — [CH 2 ] n — moiety, and D is attached at the position meta to the -[CH 2 ],,- moiety
  • D is substituted phenyl (i.e., D is phenyl optionally substituted with at least one moiety in addition to X and E)
  • n is 1
  • X is -OCH2-
  • A is not phenyl.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 05/058943, WO 05/033129, WO 04/012816, or WO 03/106480. 10)
  • E is para-phenyl
  • D is phenyl
  • n is 1
  • X is O or
  • A is not cycloalkyl or optionally substituted phenyl (i.e., phenyl optionally substituted with at least one moiety in addition to X).
  • E para-phenyl
  • D is para-phenyl (i.e., X is attached at the position para to E) or ortho-phenyl (i.e., X is attached at the position ortho to E)
  • n is 1, and X is O or -OCH 2 -
  • A is not cycloalkyl or optionally substituted phenyl.
  • E when E is para-phenyl, D is phenyl, n is 1, X is O or -OCH 2 -, and Rj is not H, A is not cycloalkyl or optionally substituted phenyl.
  • D when E is para-phenyl, D is phenyl, n is 1, X is O or -OCH 2 -, Ri is not H, and R 2 is methyl or H, A is not cycloalkyl or optionally substituted phenyl.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 05/014534, WO 05/014533, WO 05/014532, or WO 04/014844.
  • E is para-phenyl
  • D is optionally substituted purine
  • n is 1
  • X is -CH 2 -
  • A is not phenyl.
  • E is para-phenyl
  • D is optionally substituted purine
  • n is 1
  • X is -CH 2 -
  • at least one of Ri and R 2 is H
  • A is not phenyl.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 04/094426.
  • E is phenyl
  • D is optionally substituted phthalazine (i.e., phthalazine optionally substituted with at least one moiety other than E and X), and X is -CH 2 -
  • A is not optionally substituted pyridine (i.e., pyridine optionally substituted with a moiety other than X).
  • E is phenyl
  • D is optionally substituted phthalazine
  • X is -CH 2 -
  • A is not substituted pyridine.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 04/056798.
  • E is not isoxazole.
  • D is para- phenyl
  • n is 1
  • X is not -OCH2-.
  • E isoxazole.
  • D is para-phenyl
  • n is 1
  • X is — OCH 2 -
  • A is not optionally substituted quinoline (Le., quinoline optionally substituted with one or more moieties in addition to X).
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 04/043349.
  • D is not optionally substituted 1,4-piperazine (i.e., piperazine optionally substituted with at least one moiety in addition to E and X, which are bound to the nitrogen atoms at the 1 and 4 positions).
  • 1,4-piperazine i.e., piperazine optionally substituted with at least one moiety in addition to E and X, which are bound to the nitrogen atoms at the 1 and 4 positions.
  • X is not a bond or -CH 2 -.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 03/089410.
  • D is not optionally substituted l,l-dioxo-l,2,5-thiadiazolidine.
  • D when E is para-phenyl, D is not optionally substituted 1,1-dioxo- 1,2,5-thiadiazolidine.
  • n when E is para-phenyl, n is 1, and D is optionally substituted l,l-dioxo-l,2,5-thiadiazolidine, X is not -CH 2 -.
  • E when E is para-phenyl, n is 1, D is l,l-dioxo-l,2,5-thiadiazolidine-3-one, and X is -CH 2 -, A is not optionally substituted phenyl.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 03/082841.
  • D is not optionally substituted quinazoline or 1,2,3,4-tetrahydroquinazoline (e.g., 3,4-dihydroquinazolin-2(lH)-one, quinazoline-2,4( 1 H, 3H)-dione, 2-thioxo-2,3 -dihydroquinazolin-4( 1 H)-one, quinazolin-4(3H)-one, or lH-benzo[c][l,2,6]thiadiazin-4(3H)-one, any of which may be optionally substituted with moieties in addition to E and X).
  • quinazoline or 1,2,3,4-tetrahydroquinazoline e.g., 3,4-dihydroquinazolin-2(lH)-one, quinazoline-2,4( 1 H, 3H)-dione, 2-thioxo-2,3 -dihydroquinazolin-4( 1 H)-one, quin
  • D when E is para-phenyl, n is 1 , and R] is 2,6- dichlorobenzoyl, D is not optionally substituted optionally substituted quinazoline or 1,2,3,4-tetrahydroquinazoline.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 03/070709 or WO 02/016329.
  • D is not optionally substituted piperidine.
  • E is optionally substituted ⁇ yrimidin-2(lH)-one (i.e., pyrimidin-2(lH)-one optionally substituted with moieties in addition to D and the — [CH 2 ] n - moiety), and n is 1
  • D is not optionally substituted piperidine.
  • E is optionally substituted pyrimidin-2(lH)-one
  • n is 1, and D is optionally substituted piperidine
  • X is not -CH 2 - or -CH 2 NH-.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 03/066624.
  • E is meta-phenyl, substituted at the position para to the -[CH2] n - moiety with OH, n is 1, and D is optionally substituted ortho-phenyl, X is not — O- .
  • n is 1, D is optionally substituted ortho-phenyl, and X is -O-, A is not substituted tetrahydro-2H-pyran (i.e., tetrahydro-2H-pyran substituted with at least one moiety in addition to X).
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 6,951 ,840.
  • E is not optionally substituted quinazolin-4(3H)-one.
  • n when E is optionally substituted quinazolin-4(3H)-one, n is 1, and D is phenyl, X is not -NH-.
  • E when E is optionally substituted quinazolin-4(3H)-one, n is 1, D is phenyl, and X is-NH-, A is not 4,5-dihydro-lH-imidazole.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 02/081467.
  • D is not piperidine.
  • n is 1, and D is piperidine, X is not a bond.
  • E is purine, n is 1, D is piperidine, and X is a bond,
  • A is not l,2,3,4-tetrahydro-l,8- naphthyridine.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 02/018384.
  • E when E is para-phenyl, n is 1, and D is meta-phenyl, X is not -NH-, -CH2NH-, or -NHCH 2 -.
  • n when E is para-phenyl, n is 1, D is meta-phenyl, and R2 is H, X is not -NH-, -CH 2 NH-, or -NHCH 2 -.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 6,677,360 or international patent application WO 00/035864.
  • E is optionally substituted phenyl
  • n is 1
  • D is optionally substituted phenyl
  • X is -O—
  • A is not optionally substituted phenyl.
  • E is meta-(substituted phenyl)
  • n is 1
  • D is meta- (substituted phenyl)
  • X is -O-
  • A is not optionally substituted phenyl.
  • E meta-(substituted phenyl)
  • n is 1, D is meta-(substituted phenyl)
  • Rj is H
  • R 2 is H
  • X is -O-
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 01/054486. 28)
  • E is para-phenyl
  • n is 1
  • D is optionally substituted imidazolidin-4- one (i.e., imidazolidin-4-one optionally substituted with at least one moiety in addition to X and A)
  • X is not -CH 2 -.
  • E is para- phenyl
  • n is 1
  • D is optionally substituted imidazolidin-4-one (i.e., imidazolidin-4-one optionally substituted with at least one moiety in addition to X and A)
  • X is -CH 2 -
  • A is not pyridine.
  • a more specific embodiment does not encompass compounds disclosed in U.S.
  • E when E is para-phenyl, n is 1, and D is ortho-phenyl, X is not -CH 2 -. In another specific embodiment, when E is para-phenyl, n is 1, D is ortho-phenyl, and X is -CH 2 -, A is not optionally substituted piperidine. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,469,047. 32) When E is para-phenyl, and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is para-phenyl, n is 1, and D is optionally substituted phenyl, X is not -CH 2 -, -O- or -OCH 2 -.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 6,420,418. 33)
  • E is para-phenyl. and n is 1, D is not optionally substituted phenyl.
  • n is 1, and D is optionally substituted phenyl, X is not -CH 2 -, -OCH 2 -, -NH-, or -CH 2 ISfH-.
  • a more specific embodiment does not encompass compounds disclosed in Japanese patent 2001089368.
  • E is not optionally substituted pyrimidin-2(lH)-one (i.e., pyrimidin-2(lH)-one optionally substituted with at least one moiety in addition to D and the -[CH 2 ]n- moiety).
  • D is not piperidine or piperazine.
  • E is optionally substituted pyrimidin-2(lH)-one, and n is 1, X is not -CH 2 -, -NH-, or -CH 2 NH-.
  • a more specific embodiment does not encompass compounds disclosed in international patent application WO 00/061551.
  • D is not optionally substituted imidazolidin-4-one.
  • E when E is para-phenyl, and n is 1 , D is not optionally substituted imidazolidin- 4-one.
  • n when E is para-phenyl, n is 1, and D is optionally substituted imidazolidin-4-one, X is not -CH 2 - or a bond.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 6,423,728; 6,806,365 or 6,229,011. 36) D is not optionally substituted phenyl.
  • D is not phenyl or 2,6-dimethoxyphenyl (i.e., phenyl substituted at the 2 and 6 positions by methoxy in addition to its substitutions by E and X).
  • E is para-phenyl
  • n is 1
  • D is optionally substituted phenyl
  • X is not -CH 2 -, -OCH2-, or -CH 2 NH-.
  • E is not optionally substituted indole.
  • E is optionally substituted indole, and n is 1 , D is not substituted tetrahydro-2H- pyran.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 6,610,502.
  • E is not optionally substituted isoxazole (i.e., isoxazole optionally substituted with at least one moiety in addition to D and -[CHa] n -)-
  • isoxazole optionally substituted with at least one moiety in addition to D and -[CHa] n -
  • D is not phenyl.
  • X is not -OCH2- or -CH 2 -.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 6,114,328 or 5,849,736, or international patent application WO 95/14683.
  • E is phenyl, n is 1, and D is phenyl, X is not -OCH 2 -.
  • n is 1, D is phenyl, and X is -OCH 2 -, A is not phenyl.
  • a more specific embodiment does not encompass compounds disclosed in Japanese patent 09118662. 40) E is not optionally substituted imidazolidine-2,4-dione (i.e., imidazolidine-2,4- dione optionally substituted with at least one moiety in addition to D and
  • A is not optionally substituted benzoimidazole (i.e., benzoimidazole optionally substituted with at least one moiety in addition to X).
  • n is not 2.
  • D is not phenyl.
  • E is optionally substituted imidazolidine-2,4- dione, n is 2, and D is phenyl, A is not benzoimidazole.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 6,620,820.
  • E is not optionally substituted morpholine.
  • n is 1, D is not optionally substituted phenyl.
  • X is not -OCH2-.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent 3,658,806.
  • D is not piperidine or piperazine.
  • X is not -NH- or — NHCH2-.
  • D is piperazine, X is not -CH2-.
  • a more specific embodiment does not encompass compounds disclosed in U.S. patent application 2004/077638 or 2004/063934.
  • E when E is optionally substituted phenyl, and n is 1, D is not optionally substituted indoline. In another specific embodiment, when E is optionally substituted phenyl, n is 1 , and D is optionally substituted indoline, X is not a bond.
  • a more specific embodiment does not encompass compounds disclosed in Nicolaou, K.C., et al., JACS 126(40): 12897-12906 (2004) or Nicolaou, K.C., et al. Aneew. Chemie. Int. Ed. 42(151:1753-1758 (2003). 47) E is not optionally substituted triazole.
  • D is not optionally substituted tetrahydro-2H-pyran.
  • E is not triazole. Ih another specific embodiment, when E is optionally substituted triazole, D is not optionally substituted tetrahydro-2H- ⁇ yran. In another specific embodiment, when E is optionally substituted triazole, A is not phenyl. In another specific embodiment, when E is optionally substituted triazole, X is not -O- or -OCH 2 -. A more specific embodiment does not encompass compounds disclosed in Kuijpers, B.H.M., et al., Organic Let. 6(18):3123-3126 (2004).
  • E is not optionally substituted triazole or isoxazole.
  • D is not optionally substituted tetrahydro-2H-pyran.
  • n is 1
  • D is not optionally substituted tetrahydro-2H-pyran.
  • X is not -OCEb-.
  • a more specific embodiment does not encompass compounds disclosed in Dondoni, A., et al , Organic Let. 6(17):2929-2932.
  • E is optionally substituted phenyl
  • n is 1
  • D is optionally substituted phenyl
  • A is not phenyl.
  • E is optionally substituted phenyl
  • n is 1
  • D is optionally substituted phenyl
  • X is -OCH 2 -
  • A is not phenyl.
  • a more specific embodiment does not encompass compounds disclosed in Hutton, CA. and Skaff, O., Tetrahedron Let.
  • E is phenyl
  • n is 1
  • D is optionally substituted phenyl
  • X is -CH 2 -
  • A is not pyrrolidine.
  • E is not optionally substituted pyrimidin-2(lH)-one or 5,6,7,8- tetrahydroquinazolin-2(3H)-one.
  • D is not piperidine.
  • E is optionally substituted pyrimidin-2(lH)- one, and n is 1, D is not piperidine.
  • E is optionally substituted ⁇ yrimidin-2(lH)-one, n is 1, and D is piperidine, X is not -NH-, -CH2-, or CH 2 NH-.
  • a more specific embodiment does not encompass compounds disclosed in Zechel, C, et al, Bioorg. Med. Chem. Let. 13(2):165-169 (2003).
  • A is not optionally substituted piperazine.
  • E is phenyl
  • n is 1
  • D is phenyl
  • X is -CH 2 -
  • A is not optionally substituted piperazine.
  • a more specific embodiment does not encompass compounds disclosed in Castanedo, G.M., et al, Bioorg. Med. Chem. Let. 12(20):2913- 2917 (2002).
  • E is not optionally substituted indole.
  • n is 1, and D is optionally substituted tetrahydro- 2H-pyran, X is not -CH 2 O-.
  • n is 1, D is optionally substituted tetrahydro-2H- pyran, and X is -CH2O-, A is not phenyl.
  • a more specific embodiment does not encompass compounds disclosed in Nishikawa, T., et al, Bioscience, Biotech, and Biochem. 66(10): 2273 -2278 (2002) or Nishikawa, T., et al, Org. Biomol. Chem. 3(4):687-700 (2005).
  • E, D and A are not all phenyl. Ih a specific embodiment, when E, D and A are all phenyl, X is not -CH 2 -. A more specific embodiment does not encompass compounds disclosed in Sircar, I., et al, Bioorg. Med. Chem. 10(6):2051-2066 (2002). 55) A is not cyclopropyl. In a specific embodiment, when E is phenyl, n is 1, D is optionally substituted phenyl, and X is -O-, A is not cyclopropyl. In another embodiment, D is not 2H-imidazol-2-one.
  • E is not purine.
  • D is not piperidine.
  • n is 1
  • D is piperidine
  • X is -CH 2 NH-
  • A is not imidazole.
  • a more specific embodiment does not encompass compounds disclosed in Peyman, A., et al, Aneew. Chemie 39(16):2874-2877 (2000).
  • E is not 4,5-dihydroisoxazole (i.e., 4,5-dihydroisoxazole connected to D and the -[CH 2 J n - moiety), hi a specific embodiment, when E is 4,5- dihydroisoxazole, n is 1, and A is phenyl, X is not -OCH 2 -. In another specific embodiment, when E is 4,5-dihydroisoxazole, n is 1, A is phenyl, and X is -OCH 2 -, A is not optionally substituted piperidine. A more specific embodiment does not encompass compounds disclosed in Wityak, J., et al., J 1 Med. Chem. 40(1)50-60 (1997).
  • E is not optionally substituted 3,4-dihydro-2H-benzo[b][l,4]thiazine.
  • D is not optionally substituted 3,4-dihydro-2H- benzo[b][l,4]thiazine.
  • A is not optionally substituted 3,4-dihydro-2H-benzo[b][l,4]thiazine.
  • E, D and A are not all optionally substituted 3,4-dihydro-2H-benzo[b][l,4]thiazine.
  • a more specific embodiment does not encompass compounds disclosed in Napolitano, A., et al, JOC 61(2):S98-604 (1996).
  • E is not dihydropyrimidine-2,4(lH,3H)-dione.
  • E is dihydropyrimidme-2,4(lH,3H)-dione, and n is 2, D is not optionally substituted tetrahydrofuran.
  • a more specific embodiment does not encompass compounds disclosed in Nawrot, B., et al, Nucleosides & Nucleotides 14(1&2):143-165 (1995).
  • E is not indoline.
  • n is 1
  • D is optionally substituted phenyl
  • A is not optionally substituted phenyl.
  • E is indoline
  • n is 1
  • D is optionally substituted phenyl
  • A is optionally substituted phenyl
  • X is not -O-.
  • D does not comprise boron.
  • a more specific embodiment does not encompass compounds disclosed in Shull, B.K., et al, J. Pharm. Sci. 89(2):215-222
  • D is not optionally substituted tetrahydro-2H-pyran.
  • A is phenyl, and n is 1, D is not optionally substituted tetrahydro-2H-pyran.
  • a more specific embodiment does not encompass compounds disclosed in Manabe, S. and Ito, Y., Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 41:139-143 (1999).
  • E is not isoxazole.
  • n is 1, and D is phenyl, X is not -OCH 2 --
  • a more specific embodiment does not encompass compounds disclosed in Wityak, G, et al, JMC 40(8):1292 (1997).
  • E, D and A are not all optionally substituted indole.
  • a more specific embodiment does not encompass compounds disclosed in Humphries, K.A., et al, J. Electro. Chem. 346(l-2):377-403 (1993).
  • D is not lH-imidazol-2(3H)-one.
  • n is 1, and A is phenyl, D is not lH-imidazol-2(3H)-one.
  • A is not cyclopropyl.
  • E is phenyl, n is 1, and
  • X is — O— , A is not cyclopropyl.
  • D is not optionally substituted purine.
  • E is phenyl
  • n is 1, and A is phenyl
  • D is not purine.
  • A is not phenyl.
  • n is 1, and X is -CH 2 -, D is not optionally substituted imidazole (e.g.,
  • D is not optionally substituted phthalazine.
  • n is 1, and X is -CH 2 -, D is not optionally substituted phthalazine.
  • D is not optionally substituted 2-oxo-pyridine.
  • E is phenyl, n is 1, and X is — CH2-, D is not optionally substituted 2- oxo-pyridine.
  • A is not optionally substituted morpholine.
  • E is phenyl
  • n is 1
  • X is -CH 2 -
  • A is not optionally substituted morpholine.
  • Particular compounds of the invention are potent TPHl inhibitors.
  • Specific compounds have a TPHl_IC 5 o of less than about 10, 5, 2.5, 1, 0.75, 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 ⁇ M.
  • Particular compounds are selective TPHl inhibitors.
  • Specific compounds have a TPHl-IC 50 that is about 10, 25, 50, 100, 250, 500, or 1000 times less than their TPH2_IC 50 .
  • Particular compounds do not significantly inhibit human tyrosine hydroxylase (TH).
  • specific compounds have an IC 50 for TH of greater than about 100, 250, 500 or 1000 ⁇ M.
  • Particular compounds do not significantly inhibit human phenylalanine hydroxylase (PAH).
  • PAH human phenylalanine hydroxylase
  • specific compounds have an IC50 for PAH of greater than about 100, 250, 500 or 1000 ⁇ M.
  • Particular compounds of the invention do not significantly bind (e.g., inhibit with an IC 50 of greater than about 10, 25, 50, 100, 250, 500, 750, or 1000 ⁇ M) to one or more of the following: angiotensin converting enzyme, erythropoietin (EPO) receptor, factor IX, factor
  • XI integrin
  • integrin e.g., ⁇ 4
  • isoxazoline or isoxazole fibrinogen receptor metalloprotease, neutral endopeptidase (NEP), phosphatase (e.g., tyrosine phosphatase), phosphodiesterase (e.g., PDE-4), polymerase, PPAR ⁇ , TNF- ⁇ , vascular cell adhesion molecule-1 (VCAM-I), or the vitronectin receptor.
  • NEP neutral endopeptidase
  • phosphatase e.g., tyrosine phosphatase
  • phosphodiesterase e.g., PDE-4
  • polymerase e.g., PDE-4
  • certain compounds of the invention do not readily cross the blood/brain barrier (e.g., less than about 5, 2.5, 2, 1.5, 1, 0.5, or 0.01 percent of compound in the blood passes into the brain).
  • the ability or inability of a compound to cross the blood/brain barrier can be determined by methods known in the art. See, e.g., Riant, P. et ah, Journal of Neurochemistry 51:421-425 (1988); Kastin, A. J., Akerstrom, V., J. Pharmacol. Exp. Therapeutics 294:633-636 (2000); W. A. Banks, W.A., et al, J. Pharmacol. Exp. Therapeutics 302:1062-1069 (2002).
  • A is optionally substituted phenyl, biphenyl or napthyl.
  • Pj is R 1 or a protecting group
  • P 2 is a protecting group
  • P3 is OR 2 or a protecting group
  • X' is, for example, O or N
  • Y 1 and Y3 are halogen (e.g., Br, Cl) or an appropriate pseudohalide (e.g., triflate)
  • each R' is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl. or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane (e.g., 4,4,5,5-tet ⁇ amethyl-
  • Z" l5 Z" 2 , Z" 3 , and Z" 4 are also defined herein, although it is to be understood that with regard to the scheme shown above, one of them is attached to the phenyl ring.
  • Z"i and ⁇ may be independently CRi o (which is defined herein), while Z' ( 2 is N and Z" 3 is a carbon atom bound to the adjacent phenyl ring.
  • the A moiety can be bicyclic (e.g., optionally substituted biphenyl).
  • the starting material containing A can be prepared as shown below:
  • Y 2 is halogen or pseudohalogen, and each R is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane (e.g., 4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolane).
  • a cyclic dioxaborolane e.g., 4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolane.
  • X is N, O or S
  • cyclic moiety D can be any of a variety of structures, which are readily incorporated into compounds of the invention.
  • D is oxazole
  • Scheme 7 compounds wherein D is oxazole can be prepared as shown below in Scheme 7:
  • This invention encompasses a method of inhibiting TPH, which comprises contacting TPH with a compound of the invention (i.e., a compound disclosed herein).
  • a compound of the invention i.e., a compound disclosed herein.
  • the TPH is TPHl.
  • the TPH is TPH2.
  • the inhibition is in vitro. Ih another, the inhibition is in vivo.
  • One embodiment encompasses a method of inhibiting TPHl in a mammal, which comprises administering to the mammal a compound of the invention.
  • TPH2 is not significantly inhibited.
  • the compound does not readily cross the blood/brain barrier.
  • the compound is a selective inhibitor of TPHl.
  • This invention encompasses methods of treating, preventing and managing various diseases and disorders mediated by peripheral serotonin, which comprise inhibiting TPHl activity in a patient in need of such treatment, prevention or management.
  • the inhibition is accomplished by administering to the patient a therapeutically or prophylactically effective amount of a potent TPHl inhibitor. Examples of potent TPHl inhibitors are disclosed herein.
  • diseases and disorders include carcinoid syndrome and gastrointestinal diseases and disorders.
  • specific diseases and disorders include abdominal pain (e.g., associated with medullary carcinoma of the thyroid), anxiety, carcinoid syndrome, celiac disease, constipation (e.g., constipation having an iatrogenic cause, and idiopathic constipation), Crohn's disease, depression, diabetes, diarrhea (e.g., bile acid diarrhea, enterotoxin-induced secretory diarrhea, diarrhea having an iatrogenic cause, idiopathic diarrhea (e.g., idiopathic secretory diarrhea), and traveler's diarrhea), emesis, functional abdominal pain, functional dyspepsia, irritable bowel syndrome (IBS), lactose intolerance, MEN types I and II, Ogilvie's syndrome, Pancreatic Cholera Syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, and Zollinger
  • the treatment, management and/or prevention of a disease or disorder is achieved while avoiding adverse effects associated with alteration of central nervous system (CNS) serotonin levels.
  • CNS central nervous system
  • adverse effects include agitation, anxiety disorders, depression, and sleep disorders (e.g., insomnia and sleep disturbance).
  • compositions comprising one or more compounds of the invention.
  • Certain pharmaceutical compositions are single unit dosage forms suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous
  • the formulation should suit the mode of administration.
  • the oral administration of a compound susceptible to degradation in the stomach may be achieved using an enteric coating.
  • a formulation may contain ingredients that facilitate delivery of the active ingredient(s) to the site of action.
  • compounds may be administered in liposomal formulations in order to protect them from degradative enzymes, facilitate transport in circulatory system, and effect their delivery across cell membranes.
  • poorly soluble compounds may be incorporated into liquid dosage forms (and dosage forms suitable for reconstitution) with the aid of solubilizing agents, emulsifiers and surfactants such as, but not limited to, cyclodextrins (e.g., ⁇ -cyclodextrin, ⁇ -cyclodextrin, Captisol ® , and EncapsinTM (see, e.g., Davis and Brewster, Nat. Rev. Drug Disc.
  • solubilizing agents e.g., ⁇ -cyclodextrin, ⁇ -cyclodextrin, Captisol ®
  • EncapsinTM see, e.g., Davis and Brewster, Nat. Rev. Drug Disc.
  • Labrasol ® Labrafil ® , Labrafac ® , cremafor, and non-aqueous solvents, such as, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, dimethyl sulfoxide (DMSO), biocompatible oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof (e.g., DMSOxornoil).
  • DMSO dimethyl formamide
  • biocompatible oils e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils
  • glycerol tetrahydr
  • Nanoparticles of a compound may be suspended in a liquid to provide a nanosuspension (see, e.g., Rabinow, Nature Rev. Drug Disc. 3:785-796 (2004)).
  • Nanoparticle forms of compounds described herein may be prepared by the methods described in U.S. Patent Publication Nos. 2004-0164194, 2004-0195413, 2004-0251332,
  • the nanoparticle form comprises particles having an average particle size of less than about 2000 am, less than about 1000 nm, or less than about 500 nm.
  • the composition, shape, and type of a dosage form will typically vary depending with use.
  • a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. How to account for such differences will be apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g. , flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • tablets and capsules represent the most advantageous oral dosage unit forms.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • Such dosage forms can be prepared by conventional methods of pharmacy.
  • pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • Disintegrants may be incorporated in solid dosage forms to facility rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (e.g., tablets).
  • Parenteral dosage forms can be administered to patients by various routes including subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are specifically sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include: Water for Injection USP; aqueous vehicles such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles such as ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • mice homozygous (-/-) for the disruption of tphl were studied in conjunction with mice heterozygous (+/-) for the disruption of the gene, along with wild-type (+/+) litter mates.
  • the mice were subject to a medical work-up using an integrated suite of medical diagnostic procedures designed to assess the function of the major organ systems in a mammalian subject.
  • TPHl GI tract isoform of TPH
  • TPH2 brain isoform of TPH
  • TPH2 brain isoform of TPH
  • Disruption of the gene caused no measurable adverse effects on the central nervous system. This was confirmed by serotonin imrnun ⁇ chemistry, which showed that serotonin was greatly reduced or absent in the stomach, duodenum, jejunum, ileum, cecum and colon, while serotonin levels were unaffected in raphe neurons. Mice homozygous (-/-) for the disruption of the tphl gene had a decrease in thrombosis without a significant increase in bleeding or other adverse indications. ' 6.3. HPLC Characterization
  • HPLC high performance liquid chromatography
  • the organic layer was separated and washed with H 2 O (2x100ml), dried over Na 2 SO 4 , and concentrated in vacuo to give crude intermediate.
  • the crude compound was dissolved in 5ml of MeCN and 5ml OfH 2 O in a 20ml microwave reaction vial. To this solution were added L-/>-borono-phenylalanine (253mg, 1.21mmol), sodium carbonate (256mg, 2.42mmol) and catalytic amount of dichlorobis(triphenylphosphine)- ⁇ alladium(II) (42.1mg, O.O ⁇ mmol). The mixture was sealed and stirred in the microwave reactor at 150 0 C for 5 minutes, followed by the filtration through celite.
  • Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-trifluoromethyl-benzaldehyde (1.74g, lOmmol) and trifluoromethyltrimethylsilane (TMSCF 3 ) (1.8ml, 12 mmol) in 10 ml THF at 0 0 C.
  • TMSCF 3 trifluoromethyltrimethylsilane
  • the formed mixture was warmed up to room temperature and stirred for 4 hours.
  • the reaction mixture was then treated with 12 ml of IN HCl and stirred overnight.
  • the product was extracted with ethyl acetate (3x20ml).
  • the organic layer was separated and dried over sodium sulfate.
  • the organic solvent was evaporated to give 2.2g of l-(2- trifluoromethylphenyl)-2,2,2-tri£luoro-ethanol, yield 90%.
  • Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 4-methyl-benzaldehyde (1.2g, lOmmol) and TMSCF 3 (1.8ml, 12 mmol) in 10 ml THF at 0 0 C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of IN HCl and stirred overnight. The product was extracted with ethyl acetate (3x20ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 1.6g of l-(4- methylphenyl)-2,2,2-trifluoro-ethanol, yield 86%.
  • a microwave vial was charged with 4 ⁇ chloro-2-ammo-6-[l-(4-methylphenyl)-2,2,2- trifluoro-ethoxy]-pyrimidine (33mg, O.lmmol), 4-borono-L-phenylalanine (31mg, 0.15mmol) and 1 ml of acetonitrile, 0.7ml of water.
  • Aqueous sodium carbonate (0.3 ml, IN) was added to above solution followed by 5 mol percent of dichlorobis ⁇ riphenylphosphine)- palladi Um(II).
  • the reaction vessel was sealed and heated to 150 0 C for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness.
  • Cyclohexanecarbaldehyde (0.9 g, 5mmol) was dissolved in 10ml aqueous 1,4- dioxane, to which 200mg (10 mmol) sodium borohydride was added. The reaction was run overnight at room temperature. After completion of the reaction, 5ml 10% HCl solution was added and the product was extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.8g of 1-cyclohexyl- 2,2,2-trifluoro-ethanol, yield 88%.
  • 3-(4-Chlorophenyl)piperidine (232mg, lmmol) was added to a solution of 2,4- dichlorotriazine (149.97mg, lmmol), and 300mg diisopropylethyl amine in 10ml THF at 0°C. The formed mixture was warmed up to room temperature and stirred for 1 hour. The product was extracted with ethyl acetate (3x20ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 328mg of 2-chloro-4-[3-(4- chlorophenyl)-piperidin-l-yl]-[l, 3, 5] triazine.
  • a microwave vial was charged with 2-chloro-4-[3-(4-chlorophenyl)-piperidin-l-yl]- [1, 3, 5]triazine (62mg, 0.2mmol), 4-borono-L-phenylalanine(60mg, 0.3mmol), 1 ml of acetonitrile, and 0.7ml of water.
  • Aqueous sodium carbonate (0.6 ml; IM) was added to the solution, followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II).
  • the reaction vessel was sealed and heated to 150 0 C for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness.
  • Aqueous sodium carbonate (0.3 ml, IM) was added to above solution followed by 5 mol percent dichlorobis(tri ⁇ henylphosphine)-palladium(II).
  • the reaction vessel was sealed and heated to 150 0 C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified with Prep-LC to give 3.2mg 2-amino-3- ⁇ 4-[4-amino-6-(l- phenyl-2,2,2-trifluoro-ethoxy]-[l,3,5]triazin-2yl]-phenyl)-propionic acid.
  • a microwave vial was charged with 6-chloro-N-[l-naphthalen-2yl-ethyl]- [l,3,5]triazine-2,4-diamine (30mg, O.lmmol), 2-boc protected-amino-3- ⁇ 5-[4,4,5,5,- tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin2-yl-3-propionic acid (50mg, 0.15mmol) 1 ml of acetonitrile, and 0.7ml of water.
  • Aqueous sodium carbonate (0.3 ml; IN) was added to the solution, followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II).
  • the reaction vessel was sealed and heated to 150 0 C for 5 mintues by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and was then purified by Prep-LC to give 7 mg of boc protected 2-amino-3- ⁇ 5-[4- amino-6-( 1 -naphthalen-2-yl-ethylamino)-[ 1 ,3 ,5]triazin-2-yl]-pyridin-2-yl ⁇ proionic acid.
  • 6-Chloro-N-[l-naphthalen-2yl-ethyl]-[l,3,5]triazine-2,4-diatnine (30mg, O.lmmol)
  • 2- boc-protected amino-3- ⁇ 3-[4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyrazol-l-yl]- propionic acid 50mg, 0.15mmol
  • 1 ml of acetonitrile 1 ml of acetonitrile
  • 0.7ml of water Aqueous sodium carbonate (0.3 ml and IN) was added to a microwave vial, followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium( ⁇ ).
  • reaction vessel was sealed and heated to 150 0 C for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol, and then was purified with Prep- LC to give 6.8 mg of boc protected 2-amino-3- ⁇ 3-[4-amino-6-(l-naphthalen-2-yl- ethylamino)[l,3,5]triazin-2-yl]-pvrazol-l-yl ⁇ proionic acid.
  • Emrys process vial (2 ⁇ 5ml) for microwave was charged with (6-chloro-pyrazin-2- 5 yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50mg, 0.15mmol), 4-borono-L- phenylalanine (31mg, 0.15mmol) and 2 ml of acetonitrile.
  • Aqueous sodium carbonate (2 ml, IM) was added to the solution followed by 5 mol percent of dichlorobis(triphenylphosphine)- palladium(II).
  • the reaction vessel was sealed and heated to 150 0 C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness.
  • An Emrys process vial (2-5ml) for microwave was charged with (5-bromo-pyrazin-2- yl)-(4'-methyl-biphenyl-2-ylmethyl)-amine (25mg, 0.071mmol), 4-borono-L-phenylalanine (22mg, O.l lmmol) and 1 ml of acetonitrile.
  • Aqueous sodium carbonate (1 ml, IM) was added to the solution followed by 5 mol percent dichlorobis(triphenylphosphine)- palladium(II).
  • the reaction vessel was sealed and heated to 150 0 C for 5 mintues by microwave. After cooling, the reaction mixture was evaporated to dryness.
  • Tetrabutylammonium fluoride (TBAF: 0.1 ml, IM) in THF was added to a solution of 3,4-difluro-benzaldehyde (1.42g, lOmmol) and (trifluroraethyl)trimethylsilane (1.7Og, 12mmol) in 10 ml THF at 0 0 C.
  • the mixture was warmed up to room temperature and stirred for 4 hours.
  • the reaction mixture was treated with 12 ml of IM HCl and stirred overnight.
  • the product was extracted with dicloromethane (3x20ml), the organic layer was combined and passed through a pad of silica gel. The organic solvent was evaporated to give 1.9g of 1- (3,4-difluoro-phenyl)-2,2,2-trifluoro-ethanol, yield 90%.
  • Aqueous sodium carbonate (0.3 ml, IM) was added to above solution followed by 5 mol % of dichlorobis(triphenylphosphine)-palladium( ⁇ ).
  • the reaction vessel was sealed and heated to 150 0 C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, then purified with Prep-LC to give 10 mg of 2-amino-3 -(4- ⁇ 6-[ 1 -(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyridin-4-yl ⁇ - phenyl)-propionic acid, yield 21%.
  • reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparative-HPLC using YMC-Pack ODS 100x30 mm ID column (MeOH/H 2 O/TFA solvent system). The pure fractions were concentrated in vacuum. The product was then suspended in 5 ml of water, frozen and lyophilized to give the title compound as a trifluoro salt (12 mg, 20 %).
  • the reaction mixture was stirred at about -40 0 C for 0.5 hours, then the cold bath was removed and the temperature was allowed to rise slowly to room temperature.
  • the solvent was evaporated and the residue was extracted with hexane (4x20 ml). The collected extractions were washed with cold 10% aqueous NaHCO 3 and dried over Na 2 SO 4 .
  • the solvent was evaporated at reduced pressure to afford 3,5-difluorophenyl-l- trimethylsilyloxyalkene (2.03 g, 7.929 mmol, 57% crude yield), which was used in the successive reaction without further purification.
  • ammonium acetate (2.841g, 36.896 mmol), sodium cyanoborohydride (232 mg, 3.389mmol) and molecular sieves (3A, 7.6 g) were added.
  • the mixture was stirred at room temperature for two days.
  • the solid was filtered and the filtrate was concentrated.
  • the residue was dissolved in water and concentrated aqueous HCl was added dropwise until the pH » 2.
  • the mixture was then extracted with ethyl acetate to remove the unfinished ketone and other byproducts.
  • the water layer was basified to pH « 10 with aqueous sodium hydroxide (IM), and was extracted with dichloromethane and the organic layers were combined, dried over magnesium sulfate and concentrated to afford 290 mg of l-(5,7-difluoro-naphthalen-2-yl)- ethylamine (38% yield).
  • the fresh made amine (290mg, 1.401mmol) was added directly to a suspension of 2- amino-4,6-dichloro triazine (277mg, 1.678 rnmol) in anhydrous 1,4-dioxane (60 ml), and followed by addition of N,N-diisopropylethylamine (1 ml, 5.732 mmol).
  • the above-made alcohol (660 mg, 2.481 mmol) was dissolved in anhydrous 1,4- dioxane (10 ml).
  • Sodium hydride (119 mg, 60% in mineral oil, 2.975 mmol) was added all at once and the mixture was stirred at room temperature for 30 minutes.
  • the solution was transferred into a flask containing a suspension of 2-amino-4,6-dichloro-triazine (491 mg, 2.976 mmol) in 1,4-dioxane (70 ml). The mixture was stirred at room temperature for 6 hours.
  • 5-Chloro-pyrazine-2 carboxylic acid (3,4-dimethoxy-phenyl)-amide (0.18 g, 0.61 mmol), L-p-borono phenylalanine (0.146 g, 0.70 mmol), CH 3 CN (2.5 ml), H 2 O (2.5 ml), Na 2 CO 3 (0.129 g, 1.22 mmol) were combined in a microwave vial. The mixture was sealed and kept at 150 0 C for 5 minutes. The mixture was filtered and concentrated.
  • N-(biphenyl-4-ylmethyl)-5-bromopyrazm-2-amine 60 mg, 0.176 mmol
  • L-p- boronophenylalanine 37 mg, 0.176 mmol
  • palladiumtriphenylphosphine dichloride 3.6 mg, 0.0052 mmol
  • Na 2 CO 3 37 mg, 0.353 mmol
  • acetonitrile 1.25 mis
  • water (1.25 mis
  • Benzylmercaptan (0.14g, 1.11 mmol) was treated with NaH (60% in mineral oil, 67 mg, 1.66 mmol) in dry THF (15 ml) for 30 minutes.
  • 2-Amino-4,6-dichloropyrimidine (0.2 g, 1.22 mmol) was added and the mixture was stiired overnight.
  • the mixture was diluted with methylenechloride, washed with water, then brine, dried over MgS O4, and concentrated to give 0.11 g of 4-(benzylthio)-6-chloropyrimidin-2 -amine.
  • 2-Mercaptonapthalene (0.2 g, 1.148) was treated with NaH (60% in Mineral oil, 92 mg, 2.30 mmol) in dry THF (10 ml) for 30 minutes.
  • 2-Amino-4,6-dichloropyrimidine (0.21 g, 1.26 mmol) was added and the mixture was stirred overnight.
  • the mixture was diluted with methylenechloride, washed with water, then brine, dried over MgSO4, and concentratred to give 0.18 g 4-chloro-6-(naphthalen-2-ylmethylthio)pyrimidin-2-amine.
  • 3,5-Difluorophenyl-trifluoromethyl ketone was treated with NaBH 4 (0.18 g, 4.76 mmol) in THF (5 ml) for 2 hours. The mixture was quenched with water, extracted with methylene chloride (2x). The organics were combined, filtered through silica gel and concentrated to give 0.46g of l-(3,4-difluorophenyl)-2,2,2-trifluoroethanol. l-(3,4-Difluoro ⁇ henyl)-2,2,2-trifluoroethanol (0.1 g, 0.471 mmol) was treated with NaH (60% in mineral oil, 38 mg, 0.943 mmol) in dry THF (3 ml) for 30 minutes.
  • tetrabutylammoniumfluoride (TBAF 1.0 N in THF 13 uL, 3.3 mg, 0.013 mmol) was added to a mixture of 3-methyl-biphenyl-2-carboxaldehyde (0.25g, 1.27 mmol) and trifluoromethytrimethyl silane (0.25 g, 1.53 mmol), in THF (1.5 ml) at 0 0 C.
  • the reaction was warmed to room temperature and stirred for 4 hours.
  • HCl (3.0 N, 2.0 ml) was added, and the mixture was stirred for 3 hours.
  • the mixture was concentrated, dissolved in methylene chloride, filtered through silica gel, and concentrated to give 0.15 g of 2,2,2- trifluoro-l-(3'-methylbiphenyl-2-yl)ethanol.
  • reaction vessel was sealed and heated to 190 0 C for 10 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 10 ml of THF, to which was added 5N.HC1 (5ml). The mixture was refluxed for 2 hours in order to deprotect the benzophone and tert-butyl groups. The resulting reaction mixture was concentrated and dissolved in methanol (8ml) and purified with Prep-LC to afford 15mg of2-amino-3-(4(4-amino-6-((R)-l-(naphthalene-2-yl)ethylamino)-l,3,5-trizin-2- yl)phenyl)pro ⁇ anoic acid.
  • Aqueous sodium carbonate (2 ml, IM) was added to above solution followed by 10 mol percent dichlorobis(triphenylphosphine)-palladium(II).
  • the reaction vessel was sealed and heated to 190 0 C for 10 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 10 ml of THF, to which 5N.HC1 (2ml) was then added. The mixture was refluxed for 2 hours (deprotection of benzophone and tert-butyl groups).
  • Adamantyl0ethylamino (adamantyl0ethylamino)-l,3,5-triazin-2-yl)phenyl)propanoic acid
  • Adamantane (2-yl) ethyl cyanoguanidine was prepared by forming a solution of cyanoguanidine (1 equivalent), (S)-2-amino-3-(4-cyanophenylpropanoic acid (1 equivalent) and potassium tertiary butaoxide (3.5 equivalent, Aldrich) in dry n-BuOH, which was vigorously refluxed at 160 0 C in a sealed tube for 2 days. After completion of the reaction, the mixture was allowed to cool to room temperature, and the reaction was quenched with water. Solvent was removed under reduced pressure.
  • the crude intermediate (250mg, 0.83mmol) was then dissolved in 6.0ml of MeCN and 6ml OfH 2 O in a 20ml microwave vial. To this solution were added L-p-borono- phenylalanine (173.6mg, 0.83mmol), sodium carbonate (173.6mg, 1.66mmol) and catalytic amount of dichlorobis(triphenylphosphine)-palladium(II) (11.6mg, 0.0166mmol). The reaction vial was then sealed and stirred in the microwave reactor at 150 0 C for 7 minutes.
  • the crude intermediate (150mg, 0.497mmol) was then dissolved in 3.0ml of MeCN and 3ml OfH 2 O in a 10 ml microwave vial.
  • L-p-borono- phenylalanine (104mg, 0.497mmol)
  • sodium carbonate 150mg, 0.994mmol
  • catalytic amount of dichlorobis(triphenylphosphine)-palladium( ⁇ ) (6.9mg, 0.00994mmol).
  • the reaction vial was then sealed and stirred in the microwave reactor at 150 0 C for 5 minutes.
  • Reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparative-HPLC using YMC-Pack ODS 100x30 mm ID column (MeOH/H 2 O/TFA solvent system). The pure fractions were concentrated in vacuum. The product was then suspended in 5 ml of water, frozen and lyophilized to give 5 mg of pure product, 2-amino-3-[5-(5-phenyl-thiophen-2-yl)- lH-indol-3-yl]-propionic acid.
  • IH-NMR 300 MHz, CD 3 OD: 3.21-3.26 (m, 2H), 4.25 (q, IH), 7.15-7.35 (m, 8H), 7.58 (d, 2H), 7.82 (d, IH).
  • Residue was purified by preparative HPLC using MeOH/H 2 O/TFA as solvent system to obtain (S)-2-amino-3-[4-(2- amino-6-phenylethynyl-pyrimidin-4-yl(-phenyl]-propionic acid as a TFA salt.
  • 1 H-NMR 400 MHz, CD 3 OD: ⁇ (ppm) 3.20-3.42 (m, 2H), 4.31 (m, IH), 7.40-7.51 (m, 6H), 7.62 (d, 2H), 8.18 (d, 2H).
  • TPHl Human TPHl, TPH2, tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PH) were all generated using genes having the following accession numbers, respectively: X52836, AY098914, X05290, and U49897.
  • the full-length coding sequence of human TPHl was cloned into the bacterial expression vector pET24 (Novagen, Madison, WI, USA). A single colony of BL21(DE3) cells harboring the expression vector was inoculated into 50 ml of L broth (LB)- kanamycin media and grown up at 37°C overnight with shaking.
  • Expression of TPHl was induced with 15% D-lactose over a period of 10 hours at 25°C. The cells were spun down and washed once with phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • TPHl was purified by affinity chromatography based on its binding to pterin.
  • the cell pellet was resuspended in a lysis buffer (100 ml/20 g) containing 50 mM Tris-Cl, pH 7.6, 0.5 M NaCl, 0.1% Tween-20, 2 mM EDTA, 5 mM DTT, protease inhibitor mixture (Roche Applied Science, Indianapolis, IN, USA) and 1 mM phenylmethanesulfonyl fluoride (PMSF), and the cells were lyzed with a microfluidizer.
  • a lysis buffer 100 ml/20 g
  • PMSF phenylmethanesulfonyl fluoride
  • the lysate was centrifuged and the supernatant was loaded onto a pterin-coupled sepharose 4B column that was equilibrated with a buffer containing 50 mM Tris, pH 8.0, 2 M NaCl, 0.1% Tween-20, 0.5 mM EDTA, and 2 mM DTT.
  • the column was washed with 50 ml of this buffer and TPHl was eluded with a buffer containing 30 mM NaHCO 3 , pH 10.5, 0.5 M NaCl, 0.1% Tween-20, 0.5 mM EDTA, 2 mM DTT, and 10% glycerol.
  • Eluted enzyme was immediately neutralized with 200 mM KH 2 PO 4 , pH 7.0, 0.5 M NaCl, 20 mM DTT, 0.5mM EDTA, and 10% glycerol, and stored at -80 0 C.
  • TPH2 Human tryptophan hydroxylase type II
  • TH tyrosine hydroxylase
  • PAH phenylalanine hydroxylase
  • TPHl and TPH2 activities were measured in a reaction mixture containing 50 mM 4- morpholinepropanesulfonic acid (MOPS), pH 7.0, 60 ⁇ M tryptophan, 100 mM ammonium sulfate, 100 ⁇ M ferrous ammonium sulfate, 0.5 mM tris(2-carboxyethyl)phosphine (TCEP), 0.3 mM 6-methyl tetrahydropterin, 0.05 mg/ml catalase, and 0.9 mM DTT.
  • Human TH and PAH activities were determined by measuring the amount Of 3 H 2 O generated using L-[3,4- 3 H]-tyrosine and L-[4- 3 H]-phenylalanine, respectively.
  • the enzyme (100 nM) was first incubated with its substrate at 0.1 mM for about 10 minutes, and added to a reaction mixture containing 50 mM MOPS 5 pH 7.2, 100 mM ammonium sulfate, 0.05% Tween-20, 1.5 mM TCEP, 100 ⁇ M ferrous ammonium sulfate, 0.1 mM tyrosine or phenylalanine, 0.2 mM 6-methyl tetrahydropterin, 0.05 mg/ml of catalase, and 2 mM DTT. The reactions were allowed to proceed for 10-15 minutes and stopped by the addition of 2 M HCl. The mixtures were then filtered through activated charcoal and the radioactivity in the filtrate was determined by scintillation counting. Activities of of compounds on TH and PAH were determined using this assay and calculated in the same way as on TPHl and TPH2.
  • RBL2H3 is a rat mastocytoma cell line, which contains TPHl and makes 5-hydroxytrypotamine (5HT) spontaneously
  • BON is a human carcinoid cell line, which contains TPHl and makes 5-hydroxytryptophan (5HTP).
  • the CBAs were performed in 96-well plate format.
  • the mobile phase used in HPLC contained 97% of 100 mM sodium acetate, pH 3.5 and 3% acetonitrile.
  • a Waters C18 column (4.6 x 50 mm) was used with Waters HPLC (model 2795).
  • a multi-channel fluorometer (model 2475) was used to monitor the flow through by setting at 280 nm as the excitation wavelength and 360 nm as the emission wavelength.
  • RBL CBA Cells were grown in complete media (containing 5 % bovine serum) for
  • the average of 5HT level in cells without compound treated was used as the maximum value in the IC 50 derivation according to the equation provided above.
  • the minimum value of 5HT is either set at 0 or from cells that treated with the highest concentration of compound if a compound is not cytotoxic at that concentration.
  • BON CBA Cells were grown in equal volume of DMEM and F12K with 5 % bovine serum for 3-4 hours (2OK cell/well) and compound was added at a concentration range of 0.07 ⁇ M to 50 ⁇ M. The cells were incubated at 37°C overnight. Fifty ⁇ M of the culture supernatant was then taken for 5HTP measurement. The supernatant was mixed with equal volume of IM TCA, then filtered through glass fiber.
  • the filtrate was loaded on reverse phase HPLC for 5HTP concentration measurement.
  • the cell viability was measured by treating the remaining cells with Promega Celltiter-Glo Luminescent Cell Viability Assay.
  • the compound potency was then calculated in the same way as in the RBL CBA.
  • the compound was formulated in different vehicles to provide either a suspension or solution.
  • 14-week-old male C57 albino mice were dosed once daily by oral gavage at 5 ml/kg for four consecutive days. Five hours after the last dose, the animals were quickly sacrificed. Various regions of the intestinal tract and whole brain were taken and frozen immediately. 5-HT was extracted from the tissues and measured by HPLC. Blood samples were taken for exposure analysis.
  • the potent TPHl inhibitor was found to reduce 5-HT levels in both the small and large intestine, but not in the brain.
  • the compound was formulated in H 2 O and administered to mice at four different dose levels: 15, 50, 150, and 500 mg/kg, once daily by oral gavage.
  • the compound caused significant reduction of 5-HT in the jejunum and ileum in a dose-dependent fashion.
  • the colon statistically significant reduction of 5-HT was seen at the 50, 150, and 500 mg/kg/day dose levels. No significant change of 5-HT levels was observed in the brain at any of the dose levels.

Abstract

Compounds of formulae I and II are disclosed, as well as compositions comprising them and methods of their use to treat, prevent and manage serotonin-mediated diseases and disorders.

Description

MULTICYCLIC AMINO ACID DERIVATIVES AND METHODS OF THEIR USE
This application claims priority to U.S. patent application no. 60/754,955, filed December 29, 2005.
1. FIELD OF THE INVENTION This invention relates to multicyclic compounds, compositions comprising them, and their use in the treatment, prevention and management of diseases and disorders.
1. BACKGROUND
The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior. In peripheral tissues, serotonin is reportedly implicated in the regulation of vascular tone, gut motility, primary hemostasis, and cell- mediated immune responses. Walther, D.J., et al., Science 299:76 (2003).
The enzyme tryptophan hydroxylase (TPH) catalyzes the rate limiting step of the biosynthesis of serotonin. Two isoforms of TPH have been reported: TPHl, which is expressed in the periphery, primarily in the gastrointestinal (GI) tract; and TPH2, which is expressed in the brain. Id. The isoform TPHl is encoded by the tphl gene; TPH2 is encoded by the tph.2 gene. Id.
Mice genetically deficient for the tphl gene ("knockout mice") have been reported. In one case, the mice reportedly expressed normal amounts of serotonin in classical serotonergic brain regions, but largely lacked serotonin in the periphery. Id. In another, the knockout mice exhibited abnormal cardiac activity, which was attributed to a lack of peripheral serotonin. Cδtέ, F., et ah, PNAS 100(23): 13525-13530 (2003).
Because serotonin is involved in so many biochemical processes, drugs that affect serotonin levels are often attended by adverse effects. Thus, a need exists for new ways of treating diseases and disorders that are affected by serotonin. 3. SUMMARY OF THE INVENTION
This invention is directed, in part, to compounds of formula I:
Figure imgf000003_0001
I and pharmaceutically acceptable salts and solvates thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond (i.e., A is directly bound to D), -O-, -S-, -C(O)-, -C(R4)=, ^C(R4)-, -C(R3R4)-, -C(I^)=C(R4)-, -C≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-; D is optionally substituted aryl or heterocycle; Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
The invention also encompassed compounds of formula II:
Figure imgf000003_0002
II and pharmaceutically acceptable salts and solvates thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond (i.e., A is directly bound to D), -0-, -S-, -C(O)-, -C(R4)=, ^C(R4)-, -C(R3R4)-, -C(R-O=C(R4)-, -C≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-; D is optionally substituted aryl or heterocycle; E is optionally substituted aryl or heterocycle; Rj is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
Particular compounds inhibit TPH {e.g., TPHl) activity.
This invention is also directed to pharmaceutical compositions and to methods of treating, preventing and managing a variety of diseases and disorders.
4. BRIEF DESCRIPTION OF THE FIGURE
Aspects of the invention may be understood with reference to the attached figure. Figure 1 shows the effects of a potent TPHl inhibitor of the invention in the mouse gastrointestinal tract and brain after oral administration. All data are presented as percentage of the mean of the control (vehicle-dosed) group. Error bars are S. E.M. N = 5 per group. The symbols are *, p < 0.05 vs control group. For the brain data, p = 0.5, one-way ANOVA.
5. DETAILED DESCRIPTION
This invention is based, in part, on the discovery that knocking out the tphl gene in mice significantly reduces levels of GI serotonin, yet causes little, if any, measurable effect on the central nervous system (CNS).
This invention is also based on the discovery of compounds that inhibit TPH (e.g., TPHl). When administered to mammals, preferred compounds of the invention reduce serotonin levels, and may be used in the treatment, prevention and management of a wide range of diseases and disorders.
5.1. Definitions
Unless otherwise indicated, the term "alkenyl" means a straight chain, branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond. Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyi, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2- heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1- decenyl, 2-decenyl and 3-decenyl.
Unless otherwise indicated, the term "alkyl" means a straight chain, branched and/or cyclic ("cycloalkyl") hydrocarbon having from 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as "lower alkyl." Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl. Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and/or cyclic portions (e.g., l-ethyl-4-methyl- cyclohexyl). The term "alkyl" includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.
Unless otherwise indicated, the term "alkoxy" means an — O— alkyl group. Examples of alkoxy groups include -OCH3, -OCH2CH3, -O(CH2)2CH3, -0(CHz)3CH3, -O(CH2)4CH3, and -O(CH2)5CH3. Unless otherwise indicated, the term "alkylaryl" or "alkyl-aryl" means an alkyl moiety bound to an aryl moiety.
Unless otherwise indicated, the term "alkylheteroaryl" or "alkyl-heteroaryl" means an alkyl moiety bound to a heteroaryl moiety.
Unless otherwise indicated, the term "alkylheterocycle" or "alkyl-heterocycle" means an alkyl moiety bound to a heterocycle moiety.
Unless otherwise indicated, the term "alkynyl" means a straight chain, branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond. Representative alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-l-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.
Unless otherwise indicated, the term "aryl" means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms. An aryl moiety may comprise multiple rings bound or fused together. Examples of aryl moieties include anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and tolyl.
Unless otherwise indicated, the term "arylalkyl" or "aryl-alkyl" means an aryl moiety bound to an alkyl moiety.
Unless otherwise indicated, the terms "biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureido" and "biohydrolyzable phosphate" mean an amide, ester, carbamate, carbonate, ureido, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable amides include lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkyl-carbonyl amides. Examples of biohydrolyzable carbamates include lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
Unless otherwise indicated, the phrases "disease or disorder mediated by peripheral serotonin" and "disease and disorder mediated by peripheral serotonin" mean a disease and/or disorder having one or more symptoms, the severity of which are affected by peripheral serotonin levels.
Unless otherwise indicated, the terms "halogen" and "halo" encompass fluorine, chlorine, bromine, and iodine. Unless otherwise indicated, the term "heteroalkyl" refers to an alkyl moiety {e.g., linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S).
Unless otherwise indicated, the term "heteroaryl" means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S). Examples include acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, and triazinyl. Unless otherwise indicated, the term "heteroarylalkyl" or "heteroaryl-alkyl" means a heteroaryl moiety bound to an alkyl moiety.
Unless otherwise indicated, the term "heterocycle" refers to an aromatic, partially aromatic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, O or S). A heterocycle may comprise multiple (i.e., two or more) rings fused or bound together. Heterocycles include heteroaryls.
Examples include benzo[l,3]dioxolyl, 2,3-dihydro-benzo[l,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl.
Unless otherwise indicated, the term "heterocyclealkyl" or "heterocycle-alkyl" refers to a heterocycle moiety bound to an alkyl moiety. Unless otherwise indicated, the term "heterocycloalkyl" refers to a non-aromatic heterocycle.
Unless otherwise indicated, the term "heterocycloalkylalkyl" or "heterocycloalkyl- alkyl" refers to a heterocycloalkyl moiety bound to an alkyl moiety.
Unless otherwise indicated, the terms "manage," "managing" and "management" encompass preventing the recurrence of the specified disease or disorder, or of one or more of its symptoms, in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder. Unless otherwise indicated, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, fiiroic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art. See, e.g., Remington' s Pharmaceutical Sciences, 18th ed. (Mack Publishing, Easton PA: 1990) and Remington: The Science and Practice of Pharmacy, 19th ed. (Mack Publishing, Easton PA: 1995).
Unless otherwise indicated, the term "potent TPHl inhibitor" is a compound that has a TPHl_IC5o of less than about 10 μM. Unless otherwise indicated, the terms "prevent," "preventing" and "prevention" contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder, or of one or more of its symptoms. The terms encompass prophylaxis. Unless otherwise indicated, the term "prodrug" encompasses pharmaceutically acceptable esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters of compounds disclosed herein. Examples of prodrugs include compounds that comprise a biohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzable ester, biohydrolyzable phosphate, or biohydrolyzable ureide analog). Prodrugs of compounds disclosed herein are readily envisioned and prepared by those of ordinary skill in the art. See, e.g., Design of Prodrugs. Bundgaard, A. Ed., Elseview, 1985; Bundgaard, H., "Design and Application of Prodrugs," A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38.
Unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence. A prophylactically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
Unless otherwise indicated, the term "protecting group" or "protective group," when used to refer to part of a molecule subjected to a chemical reaction, means a chemical moiety that is not reactive under the conditions of that chemical reaction, and which may be removed to provide a moiety that is reactive under those conditions. Protecting groups are well known in the art. See, e.g., Greene, T. W. and Wuts, P.G.M., Protective Groups in Organic Synthesis (3rd ed., John Wiley & Sons: 1999); Larock, R. C, Comprehensive Organic Transformations (2nd ed., John Wiley & Sons: 1999). Some examples include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, and pthalimido.
Unless otherwise indicated, the term "pseudohalogen" refers to a polyatomic anion that resembles a halide ion in its acid-base, substitution, and redox chemistry, generally has low basicity, and forms a free radical under atom transfer radical polymerization conditions. Examples of pseudohalogens include azide ions, cyanide, cyanate, thiocyanate, thiosulfate, sulfonates, and sulfonyl halides.
Unless otherwise indicated, the term "selective TPHl inhibitor" is a compound that has a TPH2_IC5o that is at least about 10 times greater than its TPHl_IC5o-
Unless otherwise indicated, the term "stereomerically enriched composition of a compound refers to a mixture of the named compound and its stereoisomer(s) that contains more of the named compound than its stereoisomers). For example, a stereoisomerically enriched composition of (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and (R)- butan-2-ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10, 95/5, and 98/2.
Unless otherwise indicated, the term "stereoisomeric mixture" encompasses racemic mixtures as well as stereomerically enriched mixtures (e.g., R/S = 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and 70/30).
Unless otherwise indicated, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one stereocenter will be substantially free of the opposite stereoisomer of the compound. A stereomerically pure composition of a compound having two stereocenters will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
Unless otherwise indicated, the term "substituted," when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as, but not limited to, alcohol, aldehylde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl~ or -alkylNHC(O)alkyl), amidinyl (-C(NH)NH-alkyl or -C(NR)NH2), amine (primary, secondary and tertiary such as alkylamino, arylamϊno, arylalkylamino), aroyl, aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamyl (e.g., CONH2, as well as CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carbonyl, carboxyl, carboxylic acid, carboxylic acid anhydride, carboxylic acid chloride, cyano, ester, epoxide, ether (e.g., methoxy, ethoxy), guanidino, halo, haloalkyl (e.g., -CCI3, -CF3, -C(CF3)3), heteroalkyl, hemiacetal, imine (primary and secondary), isocyanate, isothiocyanate, ketone, nitrile, nitro, oxygen, (i.e., to provide an oxo group), phosphodiester, sulfide, sulfonamido (e.g., SO2NH2), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g. , sulfhydryl, thioether) and urea (-NHCONH-alkyl-).
Unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A therapeutically effective amount of a compound is an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. Unless otherwise indicated, the term "TPHl_ICso" is the IC50 of a compound for
TPHl as determined using the in vitro inhibition assay described in the Examples, below.
Unless otherwise indicated, the term "TPH2_ICso" is the IC50 of a compound for TPH2 as determined using the in vitro inhibition assay described in the Examples, below.
Unless otherwise indicated, the terms "treat," "treating" and "treatment" contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder, or one or more of its symptoms, or retards or slows the progression of the disease or disorder.
Unless otherwise indicated, the term "include" has the same meaning as "include" and the term "includes" has the same meaning as "includes, but is not limited to." Similarly, the term "such as" has the same meaning as the term "such as, but not limited to."
Unless otherwise indicated, one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns. For example, the phrase "optionally substituted alky, aryl, or heteroaryl" has the same meaning as "optionally substituted alky, optionally substituted aryl, or optionally substituted heteroaryl."
It should be noted that a chemical moiety that forms part of a larger compound may be described herein using a name commonly accorded it when it exists as a single molecule or a name commonly accorded its radical. For example, the terms "pyridine" and "pyridyl" are accorded the same meaning when used to describe a moiety attached to other chemical moieties. Thus, the two phrases "XOH, wherein X is pyridyl" and "XOH, wherein X is pyridine" are accorded the same meaning, and encompass the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol. It should also be noted that if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it. Similarly, names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof. Moreover, any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences. In addition, chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit.
5.2. Compounds This invention encompasses, inter alia, compounds of formula I:
Figure imgf000011_0001
I and pharmaceutically acceptable salts and solvates thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond, -O-, -S-, -C(O)-, -C(R4)=, ^=C(Rt)-, -C(R3R4)-, -C(R4)=C(R4)-, -G≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-,
-N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-; D is optionally substituted aryl or heterocycle; Rj is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
Particular compounds are of formula 1(A):
Figure imgf000012_0001
KA)
Also encompassed by the invention are compounds of formula II:
Figure imgf000012_0002
II and pharmaceutically acceptable salts and solvates thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond, -O-, -S-, -C(O)-, -C(R4)=, ^(R4)-, -C(R3R4)-, -C(RO=C(R4)-, -C≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-; D is optionally substituted aryl or heterocycle; E is optionally substituted aryl or heterocycle; R1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3. Particular compounds are of formula H(A):
Figure imgf000012_0003
H(A)
With regard to the formulae disclosed herein (e.g., 1, 1(A), II and H(A)), particular compounds include those wherein A is optionally substituted cycloalkyl (e.g., 6-membered and 5-membered). In some, A is optionally substituted aryl (e.g., phenyl or naphthyl). In others, A is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, A is aromatic. In others, A is not aromatic. In some, A is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
Particular compounds are of the formula:
Figure imgf000013_0001
wherein: each of Ai and A2 is independently a monocyclic optionally substituted cycloalkyl, aryl, or heterocycle. Compounds encompassed by this formula include those wherein A1 and/or A2 is optionally substituted cycloalkyl (e.g., 6-membered and 5-membered). In some, Ai and/or A2 is optionally substituted aryl (e.g., phenyl or naphthyl). In others, Ai and/or A2 is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6- membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, A1 and/or A2 is aromatic. In others, Ai and/or A2 is not aromatic.
With regard to the formulae disclosed herein, particular compounds include those wherein D is optionally substituted aryl (e.g., phenyl or naphthyl). In others, D is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6-membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5- membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, D is aromatic. In others, D is not aromatic. In some, D is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
With regard to the various formulae disclosed herein, particular compounds include those wherein E is optionally substituted aryl (e.g., phenyl or naphthyl). In others, E is optionally substituted heterocycle (e.g., 6-membered and 5-membered). Examples of 6- membered heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of 5-membered heterocycles include pyrrole, imidazole, triazole, thiazole, thiophene, and furan. In some compounds, E is aromatic. In others, E is not aromatic. In some, E is an optionally substituted bicyclic moiety (e.g., indole, iso-indole, pyrrolo-pyridine, or napthylene).
With regard to the various formulae disclosed herein, particular compounds include those wherein Ri is hydrogen or optionally substituted alkyl.
In some, R2 is hydrogen or optionally substituted alkyl.
In some, n is 1 or 2.
In some, X is a bond or S. In others, X is -C(R4)=, =C(R4)-) -C(R3R4)-, -C(R4)=C(R4)-, or -C=C-, and, for example, R4 is independently hydrogen or optionally substituted alkyl. In others, X is -O-, -C(R3R4)O-, or -OC(RsR4)-, and, for example, R3 is hydrogen or optionally substituted alkyl, and R4 is hydrogen or optionally substituted alkyl. In some, R3 is hydrogen and R4 is trifluromethyl. In some compounds, X is -S(Oz)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-, and, for example, R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl, and R5 is hydrogen or optionally substituted alkyl. In others, X is -N(Rs)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, or -N(R5)C(R3R4)-, and, for example, R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl, and each R5 is independently hydrogen or optionally substituted alkyl.
Some compounds of the invention are encompassed by the formula:
Figure imgf000014_0001
wherein, for example, R3 is trifluoromethyl. Others are encompassed by the formula:
Figure imgf000014_0002
wherein, for example, R3 is hydrogen.
Some compounds are encompassed by the formula:
Figure imgf000015_0001
wherein: each of Zj, Z2, Z3, and Z4 is independently N or CR6; each R^ is independently hydrogen, cyano, halogen, OR7, NRgRg, amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and m is 1-4. Certain such compounds are of the formula:
Figure imgf000015_0002
Others are of the formula:
Figure imgf000015_0003
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000016_0001
wherein, for example, R3 is hydrogen.
Referring to the various formulae above, some compounds are such that all OfZ1, Z2, Z3, and Z4 are N. In others, only three of Zi, Z2, Z3, and Z4 are N. In others, only two of Zi, Z2, Z3, and Z4 are N. In others, only one of Z1, Z2, Z3, and Z4 is N. In others, none of Z1, Z2, Z3, and Z4 are N.
Some compounds are of the formula:
wherein: each of Z'i, Z'2, and Z'3 is independently N, NH, S, O or CR6; each Rg is independently amino, cyano, halogen, hydrogen, OR7, SR7, NRgRg, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rs is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and p is 1-3. Certain such compounds are of the formula:
Figure imgf000016_0003
Others are of the formula:
Figure imgf000017_0001
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000017_0002
wherein, for example, R3 is hydrogen.
Referring to the various formulae above, some compounds are such that all of Z'I, Z'2, and Z'3 are N or NH. In others, only two of Z'i, Z'2, and Z'3 are N or NH. In others, only one of Z'x, Z 2, and Z'3 is N or NH. In others, none of Z'i, Z'2, and Z'3 are N or NH.
Some compounds are encompassed by the formula:
Figure imgf000017_0003
wherein: each of Z"i, ZM 2, Z"3, and Z" 4 is independently N or CR10; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRu, NRi2Rn, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rj 1 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R^ is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and each Ri 3 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain such compounds are of the formula:
Figure imgf000018_0001
Others are of the formula:
Figure imgf000018_0002
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000018_0003
wherein, for example, R3 is hydrogen.
Referring to the various formulae above, some compounds are such that all of Z"i, Z"2, Z"3> and Z"4 are N. In others, only three of Z'\, Z"2, Z"3, and Z"4 are N. In others, only two of Z"i, Z"2, Z"3, and Z"4 are N. In others, only one of Z"i, Z"2> Z"3, and Z"4 is N. In others, none of Z"1 } Z"2, Z"3, and Z"4 are N.
Some compounds are of the formula:
Figure imgf000019_0001
wherein: each of Z"i, Z"2, Z"3, and Z"4 is independently N or CRJO; each R1O is independently amino, cyano, halogen, hydrogen, ORn, SR11, NR12R13, or optionally substituted alkyl. alkyl-aryl or alkyl-heterocycle; each Ri 1 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri2 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle. Certain such compounds are of the formula:
Figure imgf000019_0002
Others are of the formula:
Figure imgf000019_0003
wherein, for example, R3 is trifluoromethyl. Others are of the formula:
Figure imgf000020_0001
wherein, for example, R3 is hydrogen.
Referring to the various formulae above, some compounds are such that all of Z"i, Z"2, Z"3} and Z"4 are N. In others, only three of Z"u Z"2, Z"3, and Z"4 are N. In others, only two of Z"i, Z"2, Z"3, and Z"4 are N. In others, only one of Z"u Z"2, Z"3, and Z"4 is N. In others, none of Z'\, Z"2, Z"3, and Z"4 are N.
Some are of the formula:
Figure imgf000020_0002
the substituents of which are defined herein. Others are of the formula:
Figure imgf000020_0003
the substituents of which are defined herein. Others are of the formula:
Figure imgf000020_0004
the substituents of which are defined herein. Others are of the formula:
Figure imgf000020_0005
the substituents of which are defined herein. Referring to the various formulae disclosed herein, particular compounds include those wherein both A and E are optionally substituted phenyl and, for example, X is -O-, -C(RsR4)O-, or -OC(RsR4)- and, for example, Rj is hydrogen and R4 is trifluoromethyl and, for example, n is 1. With reference to the various generic chemical structures described herein, certain embodiments of the invention are such that one or more of the following conditions apply:
1) E and D are not both optionally substituted phenyl (i.e., E is not phenyl optionally substituted with at least one moiety in addition to D and the -[CH2In- moiety, and D is not phenyl optionally substituted with at least one moiety in addition to E and X).
2) E and D are not both optionally substituted phenyl when A is optionally substituted phenyl (i.e., A is phenyl optionally substituted with at least one moiety in addition to X).
3) E and D are not both phenyl. 4) E and D are not both phenyl when A is optionally substituted phenyl.
5) E, D and A are not all phenyl.
6) When E is para-phenyl (i.e., D is attached at the position para to the — [CH.]n- moiety), and n is 1, D is not optionally substituted pyridazin-3(2H)-one. In a specific embodiment, when E is para-phenyl, n is 1 , Ri is -C(O)(optionally substituted phenyl), and R2 is H, D is not optionally substituted pyridazin-
3(2H)-one. A more specific embodiment does not encompass compounds disclosed in international patent application WO 05/077915.
7) A is not optionally substituted pyrrolidine. In a specific embodiment, when E is para-phenyl, and n is 1, D is not optionally substituted 2,6- dimethoxyphenyl. In another specific embodiment, when E is para-phenyl, n is 1, X is -CH2-, and A is pyrrolidine, D is not optionally substituted pyridazin-3(2H)-one. A more specific embodiment does not encompass compounds disclosed in international patent application WO 05/068415.
8) When E is para-phenyl, and n is 1, D is not optionally substituted quinazoline. In a specific embodiment, when E is para-phenyl, n is 1, and X is -NH- or
-CH2-, D is not optionally substituted quinazoline. In another specific embodiment, when E is para-phenyl, and n is 1, D is not optionally substituted quinazoline-2,4(lH,3H)-dione. In another specific embodiment, when E is para-phenyl, n is 1, and Ri is -C(O) (optionally substituted phenyl), D is not optionally substituted quinazoline-2,4(lH,3H)-dione. A more specific embodiment does not encompass compounds disclosed in international patent application WO 05/061466. 9) When E is optionally substituted phenyl (i.e., E is phenyl optionally substituted with moieties in addition to D and the -[CHj]n- moiety), D is optionally substituted phenyl (i.e., D is phenyl optionally substituted with moieties in addition to X and E), n is 1, and X is -OCH2-, A is not phenyl. In a specific embodiment, when E is meta-(optionally substituted phenyl) (i.e., E is phenyl optionally substituted with moieties in addition to D and the
-[CRyn- moieties, and D is attached at the position meta to the -[CH2],,- moiety), D is optionally substituted phenyl, n is 1, and X is -OCH2-, A is not phenyl. In another specific embodiment, when E is meta-(optionally substituted phenyl), D is optionally substituted phenyl, n is 1, X is — OCH2-, and R2 is optionally substituted alkyl or alkyl-aryl, A is not phenyl. In another specific embodiment, when E is meta-(substituted phenyl) (i.e., E is phenyl substituted with one or more moieties in addition to D and the — [CH2]n— moiety, and D is attached at the position meta to the -[CH2],,- moiety), D is substituted phenyl (i.e., D is phenyl optionally substituted with at least one moiety in addition to X and E), n is 1 , and X is -OCH2-, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in international patent application WO 05/058943, WO 05/033129, WO 04/012816, or WO 03/106480. 10) When E is para-phenyl, D is phenyl, n is 1, X is not O or -OCH2-. In a specific embodiment, when E is para-phenyl, D is phenyl, n is 1 , and X is O or
-OCH2-, A is not cycloalkyl or optionally substituted phenyl (i.e., phenyl optionally substituted with at least one moiety in addition to X). In another specific embodiment, when E is para-phenyl, D is para-phenyl (i.e., X is attached at the position para to E) or ortho-phenyl (i.e., X is attached at the position ortho to E), n is 1, and X is O or -OCH2-, A is not cycloalkyl or optionally substituted phenyl. In another specific embodiment, when E is para-phenyl, D is phenyl, n is 1, X is O or -OCH2-, and Rj is not H, A is not cycloalkyl or optionally substituted phenyl. In another specific embodiment, when E is para-phenyl, D is phenyl, n is 1, X is O or -OCH2-, Ri is not H, and R2 is methyl or H, A is not cycloalkyl or optionally substituted phenyl. A more specific embodiment does not encompass compounds disclosed in international patent application WO 05/014534, WO 05/014533, WO 05/014532, or WO 04/014844.
11) When E is para-phenyl, D is ortho-phenyl, n is 1 , and X is -CH2-, A is not piperidine. A more specific embodiment does not encompass compounds disclosed in international patent application WO 04/014844.
12) When E is para-phenyl, D is optionally substituted purine, n is 1, and X is -CH2-, A is not phenyl. In a specific embodiment, when E is para-phenyl, D is optionally substituted purine, n is 1, X is -CH2-, and at least one of Ri and R2 is H, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in international patent application WO 04/094426.
13) When E is para-phenyl, D is optionally substituted purine, n is 1, and X is a bond, A is not optionally substituted tetrahydrofuran. In a specific embodiment, when E is para-phenyl, D is optionally substituted purine, n is 1, X is -CH2-, and neither of Ri and R2 is H, A is not optionally substituted tetrahydrofuran. A more specific embodiment does not encompass compounds disclosed in international patent application WO 04/094426. 14) When E is phenyl, D is optionally substituted phthalazine (i.e., phthalazine optionally substituted with at least one moiety other than E and X), and X is -CH2-, A is not optionally substituted pyridine (i.e., pyridine optionally substituted with a moiety other than X). In a specific embodiment, when E is phenyl, D is optionally substituted phthalazine, and X is -CH2-, A is not substituted pyridine. A more specific embodiment does not encompass compounds disclosed in international patent application WO 04/056798.
15) When E is para-(optionally substituted phenyl), D is meta-(optionally substituted phenyl), and n is 1, X is not a bond, -CH2-, -CH2O-, -NR5-, or -CH2NRs-. A more specific embodiment does not encompass compounds disclosed in international patent application WO 04/046091.
16) E is not isoxazole. In a specific embodiment, when E is isoxazole, D is para- phenyl, and n is 1, X is not -OCH2-. In another specific embodiment, when E is isoxazole. D is para-phenyl, n is 1, and X is — OCH2- , A is not optionally substituted quinoline (Le., quinoline optionally substituted with one or more moieties in addition to X). A more specific embodiment does not encompass compounds disclosed in international patent application WO 04/043349.
17) When E is para-(optionally substituted phenyl), and n is 1, D is not optionally substituted 1,4-piperazine (i.e., piperazine optionally substituted with at least one moiety in addition to E and X, which are bound to the nitrogen atoms at the 1 and 4 positions). Ih a specific embodiment, when E is para-(optionally substituted phenyl), n is 1, D is optionally substituted 1,4-piperazine, X is not a bond or -CH2-. A more specific embodiment does not encompass compounds disclosed in international patent application WO 03/089410.
18) D is not optionally substituted l,l-dioxo-l,2,5-thiadiazolidine. In a specific embodiment, when E is para-phenyl, D is not optionally substituted 1,1-dioxo- 1,2,5-thiadiazolidine. In another specific embodiment, when E is para-phenyl, n is 1, and D is optionally substituted l,l-dioxo-l,2,5-thiadiazolidine, X is not -CH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is l,l-dioxo-l,2,5-thiadiazolidine-3-one, and X is -CH2-, A is not optionally substituted phenyl. A more specific embodiment does not encompass compounds disclosed in international patent application WO 03/082841.
19) When E is para-phenyl, and n is 1, D is not optionally substituted quinazoline or 1,2,3,4-tetrahydroquinazoline (e.g., 3,4-dihydroquinazolin-2(lH)-one, quinazoline-2,4( 1 H, 3H)-dione, 2-thioxo-2,3 -dihydroquinazolin-4( 1 H)-one, quinazolin-4(3H)-one, or lH-benzo[c][l,2,6]thiadiazin-4(3H)-one, any of which may be optionally substituted with moieties in addition to E and X). In a specific embodiment, when E is para-phenyl, n is 1 , and R] is 2,6- dichlorobenzoyl, D is not optionally substituted optionally substituted quinazoline or 1,2,3,4-tetrahydroquinazoline. A more specific embodiment does not encompass compounds disclosed in international patent application WO 03/070709 or WO 02/016329.
20) D is not optionally substituted piperidine. In a specific embodiment, when E is optionally substituted ρyrimidin-2(lH)-one (i.e., pyrimidin-2(lH)-one optionally substituted with moieties in addition to D and the — [CH2]n- moiety), and n is 1 , D is not optionally substituted piperidine. In another specific embodiment, when E is optionally substituted pyrimidin-2(lH)-one, n is 1, and D is optionally substituted piperidine, X is not -CH2- or -CH2NH-. A more specific embodiment does not encompass compounds disclosed in international patent application WO 03/066624.
21) When E is meta-phenyl, substituted at the position para to the -[CH2]n- moiety with OH, n is 1, and D is optionally substituted ortho-phenyl, X is not — O- . In a specific embodiment, when E is meta-(oρtionally substituted phenyl), n is 1, D is optionally substituted ortho-phenyl, and X is -O-, A is not substituted tetrahydro-2H-pyran (i.e., tetrahydro-2H-pyran substituted with at least one moiety in addition to X). A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,951 ,840.
22) E is not optionally substituted quinazolin-4(3H)-one. In a specific embodiment, when E is optionally substituted quinazolin-4(3H)-one, n is 1, and D is phenyl, X is not -NH-. In another embodiment, when E is optionally substituted quinazolin-4(3H)-one, n is 1, D is phenyl, and X is-NH-, A is not 4,5-dihydro-lH-imidazole. A more specific embodiment does not encompass compounds disclosed in international patent application WO 02/081467.
23) When E is para-phenyl, and n is 1, D is not optionally substituted isoindoline- 1,3-dione. In a specific embodiment, when E is para-phenyl, n is 1, and D is optionally substituted isoindoline-1 ,3-dione, X is not -OCH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is isoindo line- 1,3- dione, X is-OCH2— , and R2 is H, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in international patent application WO 02/028830.
24) D is not piperidine. In a specific embodiment, when E is purine, n is 1, and D is piperidine, X is not a bond. In another specific embodiment, when E is purine, n is 1, D is piperidine, and X is a bond, A is not l,2,3,4-tetrahydro-l,8- naphthyridine. A more specific embodiment does not encompass compounds disclosed in international patent application WO 02/018384.
25) When E is meta-(optionally substituted phenyl), n is 1, D is optionally substituted phenyl, and X is O, A is not substituted phenyl. In a specific embodiment, when E is meta-(optionally substituted phenyl), n is 1, D is optionally substituted phenyl, Ri is acetyl, R2 is ethyl, and X is O, A is not substituted phenyl. A more specific embodiment does not encompass compounds disclosed in international patent application WO 02/000245. 26) When E is para-phenyl, n is 1, and D is phenyl, X is not -NH-, -CH2NH-, or -NHCH2-. In a specific embodiment, when E is para-phenyl, n is 1, and D is meta-phenyl, X is not -NH-, -CH2NH-, or -NHCH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is meta-phenyl, and R2 is H, X is not -NH-, -CH2NH-, or -NHCH2-. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,677,360 or international patent application WO 00/035864. 27) When E is optionally substituted phenyl, n is 1 , D is optionally substituted phenyl, and X is -O— , A is not optionally substituted phenyl. In a specific embodiment, when E is meta-(substituted phenyl), n is 1, D is meta- (substituted phenyl), and X is -O-, A is not optionally substituted phenyl. In another specific embodiment, when E is meta-(substituted phenyl), n is 1, D is meta-(substituted phenyl), Rj is H, R2 is H, and X is -O-, A is not optionally substituted phenyl. A more specific embodiment does not encompass compounds disclosed in international patent application WO 01/054486. 28) When E is para-phenyl, n is 1, and D is optionally substituted imidazolidin-4- one (i.e., imidazolidin-4-one optionally substituted with at least one moiety in addition to X and A), X is not -CH2-. In a specific embodiment, E is para- phenyl, n is 1, D is optionally substituted imidazolidin-4-one (i.e., imidazolidin-4-one optionally substituted with at least one moiety in addition to X and A), and X is -CH2-, A is not pyridine. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,903,128. 29) When E is para-(optionally substituted phenyl), n is 1 , and D is optionally substituted pyridin-2(lH)-one, X is not -CH2-. In a specific embodiment, when E is para-(optionally substituted phenyl), n is I3 D is optionally substituted pyridin-2(lH)-one, and X is -CH2-, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,916,933.
30) When E is para-phenyl, and n is 1, D is not qumazoline-2,4(lH,3H)-dione or 2,4-dimethyleneimidazolidine. In a specific embodiment, when E is para- phenyl, n is 1, and X is -CH2-, D is not quinazoline-2,4(lH,3H)-dione or 2,4- dimethyleneimidazolidine. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,855,706. 31) A is not optionally substituted piperidine. In another embodiment, when E is para-phenyl, and n is 1, D is not ortho-phenyl. In a specific embodiment, when E is para-phenyl, n is 1, and D is ortho-phenyl, X is not -CH2-. In another specific embodiment, when E is para-phenyl, n is 1, D is ortho-phenyl, and X is -CH2-, A is not optionally substituted piperidine. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,469,047. 32) When E is para-phenyl, and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is para-phenyl, n is 1, and D is optionally substituted phenyl, X is not -CH2-, -O- or -OCH2-. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,420,418. 33) When E is para-phenyl. and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is para-phenyl, n is 1, and D is optionally substituted phenyl, X is not -CH2-, -OCH2-, -NH-, or -CH2ISfH-. A more specific embodiment does not encompass compounds disclosed in Japanese patent 2001089368. 34) E is not optionally substituted pyrimidin-2(lH)-one (i.e., pyrimidin-2(lH)-one optionally substituted with at least one moiety in addition to D and the -[CH2]n- moiety). In a specific embodiment, when E is optionally substituted pyrimidin-2(lH)-one, and n is 1, D is not piperidine or piperazine. In another specific embodiment, when E is optionally substituted pyrimidin-2(lH)-one, and n is 1, X is not -CH2-, -NH-, or -CH2NH-. A more specific embodiment does not encompass compounds disclosed in international patent application WO 00/061551.
35) D is not optionally substituted imidazolidin-4-one. In a specific embodiment, when E is para-phenyl, and n is 1 , D is not optionally substituted imidazolidin- 4-one. In another specific embodiment, when E is para-phenyl, n is 1, and D is optionally substituted imidazolidin-4-one, X is not -CH2- or a bond. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,423,728; 6,806,365 or 6,229,011. 36) D is not optionally substituted phenyl. In a specific embodiment, D is not phenyl or 2,6-dimethoxyphenyl (i.e., phenyl substituted at the 2 and 6 positions by methoxy in addition to its substitutions by E and X). In another specific embodiment, when E is para-phenyl, and n is 1, D is not optionally substituted phenyl. In another specific embodiment, when E is para-phenyl, n is 1 , and D is optionally substituted phenyl, X is not -CH2-, -OCH2-, or -CH2NH-. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,855,843.
37) E is not optionally substituted indole. In a specific embodiment, when E is optionally substituted indole, and n is 1 , D is not substituted tetrahydro-2H- pyran. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,610,502.
38) E is not optionally substituted isoxazole (i.e., isoxazole optionally substituted with at least one moiety in addition to D and -[CHa]n-)- In a specific embodiment, when E is isoxazole, and n is 1, D is not phenyl. In another specific embodiment, when E is isoxazole, n is 1, and D is phenyl, X is not -OCH2- or -CH2-. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,114,328 or 5,849,736, or international patent application WO 95/14683. 39) When E is phenyl, n is 1, and D is phenyl, X is not -OCH2-. In a specific embodiment, when E is phenyl, n is 1, D is phenyl, and X is -OCH2-, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Japanese patent 09118662. 40) E is not optionally substituted imidazolidine-2,4-dione (i.e., imidazolidine-2,4- dione optionally substituted with at least one moiety in addition to D and
-[CH2],,-). A is not optionally substituted benzoimidazole (i.e., benzoimidazole optionally substituted with at least one moiety in addition to X). In a specific embodiment, when E is optionally substituted imidazolidine- 2,4-dione, n is not 2. In another specific embodiment, when E is optionally substituted imidazolidine-2,4-dione, and n is 2, D is not phenyl. In another specific embodiment, when E is optionally substituted imidazolidine-2,4- dione, n is 2, and D is phenyl, A is not benzoimidazole. A more specific embodiment does not encompass compounds disclosed in U.S. patent 6,620,820.
41) E is not optionally substituted morpholine. In a specific embodiment, when E is optionally substituted morpholine, and n is 1, D is not optionally substituted phenyl. In another specific embodiment, when E is optionally substituted morpholine, n is 1, and D is optionally substituted phenyl, X is not -OCH2-. A more specific embodiment does not encompass compounds disclosed in U.S. patent 3,658,806.
42) When E is optionally substituted phenyl, and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is optionally substituted phenyl, n is 1, and D is optionally substituted phenyl, A is not optionally substituted phenyl. In another specific embodiment, when E is optionally substituted phenyl, n is 1, D is optionally substituted phenyl, and X is — O-, A is not optionally substituted phenyl. A specific embodiment does not encompass diisodityrosine. A more specific embodiment does not encompass compounds disclosed in U.S. patent application 2005/233964 or 2005/074838, or in international patent application WO 05/076972, WO 05/069845, or WO 04/094590.
43) When E is phenyl, and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is phenyl, n is 1, and D is optionally substituted phenyl, X is not -O-. In another embodiment, when E is phenyl, A is not optionally substituted phenyl. A more specific embodiment does not encompass compounds disclosed in U.S. patent application 2005/059705.
44) When E is optionally substituted pyrimidin-2(lH)-one, and n is 1 , D is not piperidine or piperazine. In another embodiment, when D is piperidine, and n is 1 , X is not -NH- or — NHCH2-. In another embodiment, when D is piperazine, X is not -CH2-. A more specific embodiment does not encompass compounds disclosed in U.S. patent application 2004/077638 or 2004/063934.
45) When E is optionally substituted phenyl, and n is 1, D is not optionally substituted phenyl. In a specific embodiment, when E is optionally substituted phenyl, n is 1, and D is optionally substituted phenyl, A is not phenyl. In another specific embodiment, when E is optionally substituted phenyl, n is 1, and D is optionally substituted phenyl, X is not -OCH2-. A more specific embodiment does not encompass compounds disclosed in Skaff, O., et ah, JOC 70(18):7353-7363 (2005). 46) D is not optionally substituted indoline. In a specific embodiment, when E is optionally substituted phenyl, and n is 1, D is not optionally substituted indoline. In another specific embodiment, when E is optionally substituted phenyl, n is 1 , and D is optionally substituted indoline, X is not a bond. A more specific embodiment does not encompass compounds disclosed in Nicolaou, K.C., et al., JACS 126(40): 12897-12906 (2004) or Nicolaou, K.C., et al. Aneew. Chemie. Int. Ed. 42(151:1753-1758 (2003). 47) E is not optionally substituted triazole. In another embodiment, D is not optionally substituted tetrahydro-2H-pyran. In a specific embodiment, E is not triazole. Ih another specific embodiment, when E is optionally substituted triazole, D is not optionally substituted tetrahydro-2H-ρyran. In another specific embodiment, when E is optionally substituted triazole, A is not phenyl. In another specific embodiment, when E is optionally substituted triazole, X is not -O- or -OCH2-. A more specific embodiment does not encompass compounds disclosed in Kuijpers, B.H.M., et al., Organic Let. 6(18):3123-3126 (2004).
48) E is not optionally substituted triazole or isoxazole. In another embodiment, D is not optionally substituted tetrahydro-2H-pyran. In a specific embodiment, when E is triazole or isoxazole, and n is 1 , D is not optionally substituted tetrahydro-2H-pyran. In another specific embodiment, when E is triazole or isoxazole, n is 1, and D is optionally substituted tetrahydro-2H-pyran, X is not -OCEb-. A more specific embodiment does not encompass compounds disclosed in Dondoni, A., et al , Organic Let. 6(17):2929-2932.
49) When E is optionally substituted phenyl, n is 1 , and D is optionally substituted phenyl, A is not phenyl. In a specific embodiment, when E is optionally substituted phenyl, n is 1, D is optionally substituted phenyl, and X is -OCH2-, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Hutton, CA. and Skaff, O., Tetrahedron Let.
44(26):4895-4898 (2003), and Yoburn, LC. or Van Vranken, D.L., Organic Let. 5(16):2817-2820 (2003). 50) When E is phenyl, n is 1, D is optionally substituted phenyl, and X is -CH2-, A is not pyrrolidine. A more specific embodiment does not encompass compounds disclosed in Doherty, G. A., et al, Bioorg. Med. Chem. Let. 13(11):1891-1895 (2003). 51) E is not optionally substituted pyrimidin-2(lH)-one or 5,6,7,8- tetrahydroquinazolin-2(3H)-one. In another embodiment, D is not piperidine. In a specific embodiment, when E is optionally substituted pyrimidin-2(lH)- one, and n is 1, D is not piperidine. In another specific embodiment, when E is optionally substituted ρyrimidin-2(lH)-one, n is 1, and D is piperidine, X is not -NH-, -CH2-, or CH2NH-. A more specific embodiment does not encompass compounds disclosed in Zechel, C, et al, Bioorg. Med. Chem. Let. 13(2):165-169 (2003).
52) A is not optionally substituted piperazine. In a specific embodiment, when E is phenyl, n is 1, D is phenyl, and X is -CH2-, A is not optionally substituted piperazine. A more specific embodiment does not encompass compounds disclosed in Castanedo, G.M., et al, Bioorg. Med. Chem. Let. 12(20):2913- 2917 (2002).
53) E is not optionally substituted indole. In a specific embodiment, when E is optionally substituted indole, n is 1, and D is optionally substituted tetrahydro- 2H-pyran, X is not -CH2O-. In another specific embodiment, when E is optionally substituted indole, n is 1, D is optionally substituted tetrahydro-2H- pyran, and X is -CH2O-, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Nishikawa, T., et al, Bioscience, Biotech, and Biochem. 66(10): 2273 -2278 (2002) or Nishikawa, T., et al, Org. Biomol. Chem. 3(4):687-700 (2005).
54) E, D and A are not all phenyl. Ih a specific embodiment, when E, D and A are all phenyl, X is not -CH2-. A more specific embodiment does not encompass compounds disclosed in Sircar, I., et al, Bioorg. Med. Chem. 10(6):2051-2066 (2002). 55) A is not cyclopropyl. In a specific embodiment, when E is phenyl, n is 1, D is optionally substituted phenyl, and X is -O-, A is not cyclopropyl. In another embodiment, D is not 2H-imidazol-2-one. In a specific embodiment, when E is phenyl, n is 1, D is 2H~imidazol-2-one, and X is -CH2-, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Yang, G.X., et al, Bioore. Med. Chem. Let. 12(ll):1497-1500 (2002).
56) E is not purine. In another embodiment, D is not piperidine. In a specific embodiment, when E is purine, n is 1 , D is piperidine, and X is -CH2NH-, A is not imidazole. A more specific embodiment does not encompass compounds disclosed in Peyman, A., et al, Aneew. Chemie 39(16):2874-2877 (2000).
57) When E is optionally substituted phenyl, n is 1, and D is optionally substituted phenyl, X is not — O-. In a specific embodiment, when E is optionally substituted phenyl, n is 1, D is optionally substituted phenyl, and X is— O— , A is not optionally substituted phenyl. A more specific embodiment does not encompass compounds disclosed in Wu, W., et al, J. Biol. Chem. 274(36):25933-25944 (1999) or Jacob, J.S., et al, J. Biol. Chem. 271(33): 19950-19956 (1996).
58) E is not 4,5-dihydroisoxazole (i.e., 4,5-dihydroisoxazole connected to D and the -[CH2Jn- moiety), hi a specific embodiment, when E is 4,5- dihydroisoxazole, n is 1, and A is phenyl, X is not -OCH2-. In another specific embodiment, when E is 4,5-dihydroisoxazole, n is 1, A is phenyl, and X is -OCH2-, A is not optionally substituted piperidine. A more specific embodiment does not encompass compounds disclosed in Wityak, J., et al., J1 Med. Chem. 40(1)50-60 (1997).
59) When E is imidazole, n is 1, and D is optionally substituted phenyl, X is not -OCH2-. In a specific embodiment, when E is imidazole, n is 1, D is optionally substituted phenyl, and X is -OCH2-, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Feldman, K.S., et al, JOC 61(19):6656-6665 (1996).
60) E is not optionally substituted 3,4-dihydro-2H-benzo[b][l,4]thiazine. In another embodiment, D is not optionally substituted 3,4-dihydro-2H- benzo[b][l,4]thiazine. In another embodiment, A is not optionally substituted 3,4-dihydro-2H-benzo[b][l,4]thiazine. In a specific embodiment, E, D and A are not all optionally substituted 3,4-dihydro-2H-benzo[b][l,4]thiazine. A more specific embodiment does not encompass compounds disclosed in Napolitano, A., et al, JOC 61(2):S98-604 (1996). 61) E is not dihydropyrimidine-2,4(lH,3H)-dione. In a specific embodiment, when E is dihydropyrimidme-2,4(lH,3H)-dione, and n is 2, D is not optionally substituted tetrahydrofuran. A more specific embodiment does not encompass compounds disclosed in Nawrot, B., et al, Nucleosides & Nucleotides 14(1&2):143-165 (1995).
62) E is not indoline. In a specific embodiment, when E is indoline, n is 1 , and D is optionally substituted phenyl, A is not optionally substituted phenyl. In another specific embodiment, when E is indoline, n is 1, D is optionally substituted phenyl, and A is optionally substituted phenyl, X is not -O-. A more specific embodiment does not encompass compounds disclosed in
Naruse. N.. et oL. J. Antibiotics 46fl2'):1812-1818 (19931.
63) When E, A and D are all optionally substituted phenyl, X is not -O-. A more specific embodiment does not encompass compounds disclosed in Fetterer, R.H., et al, J. Parasit. 79(2):160-166 (1993). 64) When E, A and D are all optionally substituted phenyl, X is not -OCH2-. A more specific embodiment does not encompass compounds disclosed in Schmidt, U., et al, Synthesis 12:1248-54 (1992), Schmidt, U., et al, JACS. Chem. Comm, 13:951-953 (1992) or Schmidt, U., et al, JACS. Chem. Comm. 5:275-277 (1991). 65) When E is quinazoline, and n is 1, D is not phenyl. In a more specific embodiment, when E is quinazoline, n is 1, and D is phenyl, X is not -NH-. A more specific embodiment does not encompass compounds disclosed in Lawson, E.C., et al, Letters Drug Design & Disc. 1(1):14-18 (2004).
66) When E is phenyl, n is 1 , and D is optionally substituted phenyl, X is not -CH2-. In a more specific embodiment, when E is phenyl, n is 1, D is optionally substituted phenyl, and X is -CH2-, A is not pyrrolidine. A more specific embodiment does not encompass compounds disclosed in Doherty, G.A., et al, Bioorg. Med. Chem. Let. 13(17):2937-2938 (2003).
67) D does not comprise boron. A more specific embodiment does not encompass compounds disclosed in Shull, B.K., et al, J. Pharm. Sci. 89(2):215-222
(2000).
68) When E is phenyl, and n is 1, D is not 2,5-dioxo-pyrrolidine. In a specific embodiment, when E is phenyl, n is 1, and D is 2,5-dioxo-pyrrolidine, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Tilley, J. W., et al, Bioorg. Med. Chem. Let. 11(1): 1-4 (2001).
69) D is not optionally substituted tetrahydro-2H-pyran. In a specific embodiment, when A is phenyl, and n is 1, D is not optionally substituted tetrahydro-2H-pyran. A more specific embodiment does not encompass compounds disclosed in Manabe, S. and Ito, Y., Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 41:139-143 (1999).
70) E is not isoxazole. In a specific embodiment, when E is isoxazole, n is 1, and D is phenyl, X is not -OCH2-- A more specific embodiment does not encompass compounds disclosed in Wityak, G, et al, JMC 40(8):1292 (1997).
71) E, D and A are not all optionally substituted indole. A more specific embodiment does not encompass compounds disclosed in Humphries, K.A., et al, J. Electro. Chem. 346(l-2):377-403 (1993).
72) When E is substituted phenyl, n is 1, and D is substituted phenyl, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Schmidt, U., et al, Synthesis 10:1025-1030 (1992); Schmidt, U., etal, JACS Chem. Comm. 10:744 (1991); or Schmidt, U., et al, Angewandte Chemie 101(7):946-948 (1989).
73) When E is oxadiazole, and n is 1, D is not phenyl. In a specific embodiment, when E is oxadiazole, n is 1, and D is phenyl, A is not phenyl. A more specific embodiment does not encompass compounds disclosed in Moussebois, C, et al, HeIv. Chimica Acta 60(l):237-242 (1977).
74) D is not lH-imidazol-2(3H)-one. In a more specific embodiment, when E is phenyl, n is 1, and A is phenyl, D is not lH-imidazol-2(3H)-one. 75) A is not cyclopropyl. In a specific embodiment, when E is phenyl, n is 1, and
X is — O— , A is not cyclopropyl.
76) D is not optionally substituted purine. In a specific embodiment, when E is phenyl, n is 1, and A is phenyl, D is not purine.
77) When X is -CH2-, A is not phenyl. In a specific embodiment, when E is phenyl, n is 1, and X is -CH2-, D is not optionally substituted imidazole (e.g.,
1 H-imidazol-2(3H)-one).
78) D is not optionally substituted phthalazine. In a specific embodiment, when E is phenyl, n is 1, and X is -CH2-, D is not optionally substituted phthalazine. 79) D is not optionally substituted 2-oxo-pyridine. In a specific embodiment, when E is phenyl, n is 1, and X is — CH2-, D is not optionally substituted 2- oxo-pyridine.
80) A is not optionally substituted morpholine. In a specific embodiment, when E is phenyl, n is 1 , and X is -CH2-, A is not optionally substituted morpholine.
81) None of E, A or D is optionally substituted piperidine or piperazine.
82) When E is imidazole, n is 1, and D is optionally substituted triazole, X is not -NH-. In a specific embodiment, when E is imidazole, n is 1 , D is optionally substituted triazole, and X is -NH-, A is not optionally substituted phenyl. This invention encompasses stereomerically pure compounds and stereomerically enriched compositions of them. Stereoisomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns, chiral resolving agents, or enzymatic resolution. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
Particular compounds of the invention are potent TPHl inhibitors. Specific compounds have a TPHl_IC5o of less than about 10, 5, 2.5, 1, 0.75, 0.5, 0.4, 0.3, 0.2, 0.1, or 0.05 μM.
Particular compounds are selective TPHl inhibitors. Specific compounds have a TPHl-IC50 that is about 10, 25, 50, 100, 250, 500, or 1000 times less than their TPH2_IC50. Particular compounds do not significantly inhibit human tyrosine hydroxylase (TH). For example, specific compounds have an IC50 for TH of greater than about 100, 250, 500 or 1000 μM.
Particular compounds do not significantly inhibit human phenylalanine hydroxylase (PAH). For example, specific compounds have an IC50 for PAH of greater than about 100, 250, 500 or 1000 μM.
Particular compounds of the invention do not significantly bind (e.g., inhibit with an IC50 of greater than about 10, 25, 50, 100, 250, 500, 750, or 1000 μM) to one or more of the following: angiotensin converting enzyme, erythropoietin (EPO) receptor, factor IX, factor
XI, integrin (e.g., α4), isoxazoline or isoxazole fibrinogen receptor, metalloprotease, neutral endopeptidase (NEP), phosphatase (e.g., tyrosine phosphatase), phosphodiesterase (e.g., PDE-4), polymerase, PPARγ, TNF-α, vascular cell adhesion molecule-1 (VCAM-I), or the vitronectin receptor. The ability of a compound to bind to (e.g., inhibit) any of these targets can be readily determined using methods known in the art, as described in references cited above. Specific compounds of the invention do not inhibit cell adhesion.
When administered to mammals {e.g., mice, rats, dogs, monkeys or humans), certain compounds of the invention do not readily cross the blood/brain barrier (e.g., less than about 5, 2.5, 2, 1.5, 1, 0.5, or 0.01 percent of compound in the blood passes into the brain). The ability or inability of a compound to cross the blood/brain barrier can be determined by methods known in the art. See, e.g., Riant, P. et ah, Journal of Neurochemistry 51:421-425 (1988); Kastin, A. J., Akerstrom, V., J. Pharmacol. Exp. Therapeutics 294:633-636 (2000); W. A. Banks, W.A., et al, J. Pharmacol. Exp. Therapeutics 302:1062-1069 (2002).
5.3. Synthesis of Compounds
Compounds of the invention can be prepared by methods known in the art, and by methods described herein.
For example, with reference to formula I, compounds in which E is phenyl and D is optionally substituted pyrazine, pyridiazine, pyridine or phenyl can generally be prepared by the method shown in Scheme 1 :
Figure imgf000036_0001
Figure imgf000036_0002
SOCI2, Ethanol
Figure imgf000036_0003
Figure imgf000036_0004
Scheme 1
wherein, for example:
Figure imgf000037_0001
Compounds wherein X is — OCR3- can generally be prepared using the method shown in Scheme 2, wherein R3 is CF3 and D is pyrimidine:
Figure imgf000037_0002
Scheme 2
wherein, for example, A is optionally substituted phenyl, biphenyl or napthyl.
Compounds of the invention can also be prepared using the approach shown below in Scheme 3:
Figure imgf000038_0001
Scheme 3
wherein Pj is R1 or a protecting group; P2 is a protecting group; P3 is OR2 or a protecting group; X' is, for example, O or N; Y1 and Y3 are halogen (e.g., Br, Cl) or an appropriate pseudohalide (e.g., triflate); and each R' is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl. or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane (e.g., 4,4,5,5-tetτamethyl-
1,3,2-dioxaborolane). The groups A, Ri, R2, R3, Re and m are defined elsewhere herein. The moieties Z"l5 Z"2, Z"3, and Z"4 are also defined herein, although it is to be understood that with regard to the scheme shown above, one of them is attached to the phenyl ring. For example, Z"i and Ε\ may be independently CRi o (which is defined herein), while Z'(2 is N and Z"3 is a carbon atom bound to the adjacent phenyl ring.
The individual reactions shown above can be performed using conditions known in the art. For example, palladium catalysts and conditions suitable for the Suzuki coupling of the boron and halogen-containing moieties are well known, and examples are provided below. In addition, types and appropriate uses of protecting groups are well known, as are methods of their removal and replacement with moieties such as, but not limited to, hydrogen (e.g., hydrolysis under acidic or basic conditions).
The A moiety can be bicyclic (e.g., optionally substituted biphenyl). In such cases, the starting material containing A can be prepared as shown below:
Figure imgf000039_0001
wherein Y2 is halogen or pseudohalogen, and each R is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane (e.g., 4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolane).
Another approach to the preparation of compounds wherein D is optionally substituted pyrimidine or triazine is shown below in Scheme 4:
Figure imgf000040_0001
Scheme 4
wherein, for example, X is N, O or S, and FG is defined below: FG = B(OH)2 when E is optionally substituted Phenyl
Figure imgf000040_0002
Ester derivatives of these and other compounds of the invention can be readily prepared using methods such as that shown below in Scheme 5, wherein E is optionally substituted phenyl:
Figure imgf000041_0001
Scheme 5
An alternate approach to the preparation of triazine-based compounds is shown below in Scheme 6:
Figure imgf000041_0002
dry n-BuOH/ tBuOK 3.5 eq. 1600C, sealed tube, 2 days
Figure imgf000041_0003
Figure imgf000041_0004
Scheme 6 The cyclic moiety D can be any of a variety of structures, which are readily incorporated into compounds of the invention. For example, compounds wherein D is oxazole can be prepared as shown below in Scheme 7:
Figure imgf000042_0001
Scheme 7
Using methods known in the art, the synthetic approaches shown above are readily modified to obtain a wide range of compounds. For example, chiral chromatography and other techniques known in the art may be used to separate stereoisomers of the final product. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S . H., et al., Tetrahedron 33:2125 (1977); Eliel, E. L.,
Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H.. Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). In addition, as shown in some of the schemes above, syntheses may utilize chiral starting materials to yield stereomerically enriched or pure products.
5.4. Methods of Use
This invention encompasses a method of inhibiting TPH, which comprises contacting TPH with a compound of the invention (i.e., a compound disclosed herein). In a particular method, the TPH is TPHl. In another, the TPH is TPH2. In a particular method, the inhibition is in vitro. Ih another, the inhibition is in vivo.
One embodiment encompasses a method of inhibiting TPHl in a mammal, which comprises administering to the mammal a compound of the invention. In a particular method, TPH2 is not significantly inhibited. In one method, the compound does not readily cross the blood/brain barrier. In another, the compound is a selective inhibitor of TPHl. This invention encompasses methods of treating, preventing and managing various diseases and disorders mediated by peripheral serotonin, which comprise inhibiting TPHl activity in a patient in need of such treatment, prevention or management. In a particular embodiment, the inhibition is accomplished by administering to the patient a therapeutically or prophylactically effective amount of a potent TPHl inhibitor. Examples of potent TPHl inhibitors are disclosed herein.
Particular diseases and disorders include carcinoid syndrome and gastrointestinal diseases and disorders. Examples of specific diseases and disorders include abdominal pain (e.g., associated with medullary carcinoma of the thyroid), anxiety, carcinoid syndrome, celiac disease, constipation (e.g., constipation having an iatrogenic cause, and idiopathic constipation), Crohn's disease, depression, diabetes, diarrhea (e.g., bile acid diarrhea, enterotoxin-induced secretory diarrhea, diarrhea having an iatrogenic cause, idiopathic diarrhea (e.g., idiopathic secretory diarrhea), and traveler's diarrhea), emesis, functional abdominal pain, functional dyspepsia, irritable bowel syndrome (IBS), lactose intolerance, MEN types I and II, Ogilvie's syndrome, Pancreatic Cholera Syndrome, pancreatic insufficiency, pheochromacytoma, scleroderma, somatization disorder, and Zollinger-Ellison Syndrome.
In particular methods of the invention, the treatment, management and/or prevention of a disease or disorder is achieved while avoiding adverse effects associated with alteration of central nervous system (CNS) serotonin levels. Examples of such adverse effects include agitation, anxiety disorders, depression, and sleep disorders (e.g., insomnia and sleep disturbance).
5.5. Pharmaceutical Compositions
This invention encompasses pharmaceutical compositions comprising one or more compounds of the invention. Certain pharmaceutical compositions are single unit dosage forms suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. The formulation should suit the mode of administration. For example, the oral administration of a compound susceptible to degradation in the stomach may be achieved using an enteric coating. Similarly, a formulation may contain ingredients that facilitate delivery of the active ingredient(s) to the site of action. For example, compounds may be administered in liposomal formulations in order to protect them from degradative enzymes, facilitate transport in circulatory system, and effect their delivery across cell membranes.
Similarly, poorly soluble compounds may be incorporated into liquid dosage forms (and dosage forms suitable for reconstitution) with the aid of solubilizing agents, emulsifiers and surfactants such as, but not limited to, cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, Captisol®, and Encapsin™ (see, e.g., Davis and Brewster, Nat. Rev. Drug Disc. 3:1023-1034 (2004)), Labrasol®, Labrafil®, Labrafac®, cremafor, and non-aqueous solvents, such as, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, dimethyl sulfoxide (DMSO), biocompatible oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, and mixtures thereof (e.g., DMSOxornoil).
Poorly soluble compounds may also be incorporated into suspensions using other techniques known in the art. For example, nanoparticles of a compound may be suspended in a liquid to provide a nanosuspension (see, e.g., Rabinow, Nature Rev. Drug Disc. 3:785-796 (2004)). Nanoparticle forms of compounds described herein may be prepared by the methods described in U.S. Patent Publication Nos. 2004-0164194, 2004-0195413, 2004-0251332,
2005-0042177 Al, 2005-0031691 Al, and U.S. Patent Nos. 5,145,684, 5,510,118, 5,518,187, 5,534,270, 5,543,133, 5,662,883, 5,665,331, 5,718,388, 5,718,919, 5,834,025, 5,862,999, 6,431,478, 6,742,734, 6,745,962, the entireties of each of which are incorporated herein by reference. In one embodiment, the nanoparticle form comprises particles having an average particle size of less than about 2000 am, less than about 1000 nm, or less than about 500 nm. The composition, shape, and type of a dosage form will typically vary depending with use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. How to account for such differences will be apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
5.5.1. Oral Dosage Forms
Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g. , flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).
Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by conventional methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. Disintegrants may be incorporated in solid dosage forms to facility rapid dissolution. Lubricants may also be incorporated to facilitate the manufacture of dosage forms (e.g., tablets).
5.5.2. Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various routes including subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are specifically sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include: Water for Injection USP; aqueous vehicles such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as ethyl alcohol, polyethylene glycol, and polypropylene glycol; and nonaqueous vehicles such as corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
6. EXAMPLES
6.1. Production of tphl Gene Disrupted Mice
Exon 3 of the murine TPHl gene was removed by gene targeting essentially as described by Wattler et al, Biotechniαues 26(6): 1150-6 (1999). The resulting knockout animals displayed normal TPH activity in the brain but drastically reduced TPH expression in the gut.
6.2. Physiological Effects of tphl Gene Disruption
Mice homozygous (-/-) for the disruption of tphl were studied in conjunction with mice heterozygous (+/-) for the disruption of the gene, along with wild-type (+/+) litter mates. During this analysis, the mice were subject to a medical work-up using an integrated suite of medical diagnostic procedures designed to assess the function of the major organ systems in a mammalian subject. By studying the homozygous (-/-) knockout mice in the described numbers and in conjunction with heterozygous(+/-) and wild-type (+/+) litter mates, more reliable and repeatable data was obtained.
Disruption of tphl gene primarily affected the GI tract isoform of TPH (TPHl), and had little or no effect on the brain isoform of TPH (TPH2). Disruption of the gene caused no measurable adverse effects on the central nervous system. This was confirmed by serotonin imrnunσchemistry, which showed that serotonin was greatly reduced or absent in the stomach, duodenum, jejunum, ileum, cecum and colon, while serotonin levels were unaffected in raphe neurons. Mice homozygous (-/-) for the disruption of the tphl gene had a decrease in thrombosis without a significant increase in bleeding or other adverse indications. ' 6.3. HPLC Characterization
In some of the following synthetic examples, high performance liquid chromatography (HPLC) retention times are provided. Unless otherwise noted, the various conditions used to obtain those retention times are described below: Method A: YMC-PACK ODS-A 3.0x50mm; Solvent A = 90% water, 10% MeOH,
0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 4 min.; flow rate = 2 ml/min; observation wavelength = 220 nm.
Method B: YMC-PACK ODS-A 3.0x50mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH5 10% water, 0.1% TFA; %B from 10 to 100% over 4 min.; flow rate = 3 ml/min; observation wavelength = 220 nm.
Method C: YMC-PACK ODS-A 3.0x50mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 5 min.; flow rate = 2 ml/min. ; observation wavelength = 220 nm.
Method D: Shim VP ODS 4.6x50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 4 min.; flow rate = 3 ml/min.; observation wavelength = 220 nm.
Method E: Shim VP ODS 4.6x50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 4 min.; flow rate = 3 ml/min; observation wavelength = 254 nm. Method F: YMC-PACK ODS-A 4.6x33mm; Solvent A = 90% water, 10% MeOH,
0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 4 min.; flow rate = 3 ml/min.; observation wavelength = 220 nm.
Method G: YMC-PACK ODS-A 4.6x50mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 2 min.; flow rate = 2.5 ml/min.; observation wavelength = 220 nm.
Method H: C184.6x20mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 2 min. flow rate = 2ml/min.; observation wavelength = 220 nm.
Method I: YMC PACK ODS-A 3.0 x 50 mm; Solvent A = 90% water, 10% MeOH, 0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 10 to 100% over 4 min.; flow rate = 2ml/min.; observation wavelength = 220 nm. Method J: YMC Pack ODS-A 3.0x50mm; Solvent A = H2O, 0.1% TFA; Solvent B = MeOH, 0.1% TFA; %B from about 10 to about 90% over 4 min.; flow rate = 2ml/min.; observation wavelength = 220 ran.
Method K: Sunfire Cl 8 50 mm x 4.6 mm x 3.5 μm; Solvent A = IO mM NH4OAc in water; Solvent B = MeCN; B% from 10 to 95% over 2 min.; flow rate = 4.5 ml/min.; observation wavelength = 220 run.
Method L: Sunfire C18 50 mm x 4.6 mm x 3.5 μm; Solvent A = IO mM NH4OAc; Solvent B = MeCN; B% from 2 to 20% over 0.8 min, then to 95% B over 2 min; flow rate = 4.5 ml/min.; observation wavelength = 220 nm. Method M: YMC-PACK ODS-A 4.6x33mm; Solvent A = 90% water, 10% MeOH,
0.1% TFA; Solvent B = 90% MeOH, 10% water, 0.1% TFA; B% from 0 to 100% over 5 min.; flow rate = 2.5 ml/min.; observation wavelength = 254 nm.
Method N: YMC-PACK ODS-A 3.0x50mm; Solvent A = H2O, 0.1% TFA; Solvent B = MeOH, 0.1% TFA; B% from 10 to 90% over 4 min.; flow rate = 2 ml/min.; observation wavelength = 220 and 254 nm.
Method 0: YMC-PACK ODS-A 3.0x50mm; Solvent A = 90% water, 10% MeOH with 0.1% TFA; Solvent B = 90% MeOH, 10% water with 0.1% TFA; B% from 0 to 100% over 4 min.; flow , rate = 2 ml/min.; observation wavelength = 220 and 254 nm.
Method P: ShimPack VP ODS 4.6x50mm; Solvent A = 90% H2O, 10% MeOH, 1%TFA; Solvent B = 10% H2O, 90% MeOH, 1%TFA; B% from 0 to 100% over 2 min.; flow rate = 3.5 ml/min.; observation wavelength = 220 and 254 nm.
Method Q: Shim VP ODS 4.6x50 mm; Solvent A = H2O with 0.1 % TFA; Solvent B = MeOH with 0.1 % TFA; B% from 0 to 100% over 4 min.; flow rate = 3 ml/min.; observation wavelength = 254 nm. Method R: YMC Pack ODS-A 4.6 x 33 mm; Solvent A = H2O, 0.1 % TFA; Solvent B
= MeOH with 0.1% TFA; B% from 10 to 90% over 3 min.; flow rate 2 ml/min.; observation wavelength 220 and 254 nm.
Method S: YMC-Pack ODS-A 3.0x50 mm; Solvent A = 90% H20, 10% MeOH, 1% TFA; Solvent B = 10% H2O, 90% MeOH, 1%TFA; B% from 10 to 90% over 4 min.; flow rate = 2 ml/min. observation wavelength == 220 and 254 nm. 6.4. Synthesis of (S)-2-Amino-3-(4-(4-amino-6-((RM-fnaphthalen-2- vI)ethvlamino)-l,3,5-triazin-2-vϊ)phenvr)propanoie acid
Figure imgf000049_0001
A mixture of 2-amino-4,6-dichloro-[l,3,5]triazine (200mg, 1.21mmol), (R)-(+)-l-(2- naphthyl)ethylamine (207mg, 1.21mmol) and diisopropyl-ethylamine (3.63mmol) was dissolved in 150 ml of 1,4-dioxane. The solution was refluxed at 900C for 3 hours. After the completion of reaction (monitored by LCMS), solvent was removed and the reaction mixture was extracted with CH2Cl2 (100ml) and H2O (100ml). The organic layer was separated and washed with H2O (2x100ml), dried over Na2SO4, and concentrated in vacuo to give crude intermediate. The crude compound was dissolved in 5ml of MeCN and 5ml OfH2O in a 20ml microwave reaction vial. To this solution were added L-/>-borono-phenylalanine (253mg, 1.21mmol), sodium carbonate (256mg, 2.42mmol) and catalytic amount of dichlorobis(triphenylphosphine)-ρalladium(II) (42.1mg, O.Oβmmol). The mixture was sealed and stirred in the microwave reactor at 1500C for 5 minutes, followed by the filtration through celite. The filtrate was concentrated and dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA solvent system. The combined pure fractions were evaporated in vacuo and further dried on a lyophilizer to give 238mg of 2- amino-3-{4-[4-amino-6-(l-naphthalen-2-yl)-ethylamino)-[l,3,5]triazin-2-yl]-phenyl}- propionic acid (yield: 46%, LC: Column: YMC Pack ODS-A 3.0x50mm, %B=0~100%, Gradient time = 4min, Flow Rate = 2ml/min, wavelength=220, Solvent A= 90: 10 wateπMeOH w/ 0.1%TFA, Solvent B=90: 10 MeOH:water w/0.1%TFA , RT = 2.785 min, MS: M+l = 429). NMR: 1H-NMR (400 MHz5 CD3OD): δ 1.65 (d, 3H), 3.22-3.42 (m, 2H), 4.3 (m, IH), 5.45 (m, IH), 7.4(m, IH), 7.6(m 4H), 7.8(m, 4H), 8.2(m, 2H).
6.5. Alternative Synthesis of (SV2-Amino-3-(4-(4-amino-6-((RVl-(naphthaIen- 2-vI)ethylaminoVl,3,5-triazin-2-yl)phenylmropanoic acid
(R)-I -(I -(Napthalen-2-yl) ethyl) cyanoguanidine was prepared by forming a mixture of naphthalene amine (1 equivalent), sodium dicyanide (0.95 eq.) and followed by 5N HCl (1 eq.) in n-BuOH: H2O (1:1). The mixture was refluxed for 1 day in a sealed tube at 160°C, and progress of reaction was monitored by LCMS. After completion of reaction, solvent (n- BuOH) was removed under reduced pressure and IN HCl was added to adjust pH to 3-5 range. The aqueous solution was extracted with EtOAc (2x100) and combined organic phase was dried over Na2SO4. Solvent was removed in vacuo to give crude product. The compound was purified by ISCO column chromatography using as the solvent system EtOAc:hexane (7:3 and 1:1), to obtain white solid 48-71% yield for Ig to 22.5 gram scale. NMR: 1H-NMR (400 MHz, CD3OD): δ 1.5(d, 3H), 5.1(m, IH), 7.5 (m, 4H), 7.8(s, IH), 7.9 (m, 2H); LCMS: RT 1.69, M+l: 239, Yield: 71%. The title compound was prepared from (R)-I-(I -(napthalen-2-yl) ethyl) cyanoguanidine according to the method shown in Scheme 6.
6.6. Synthesis of (S)-2-Amino-3-(4-(4-amino-6-ff4t-methylbiphenyI-4- vDmethylaminoVl ,3..5-triaziii-2-vDphenyDpropanoic acid
Figure imgf000050_0001
A mixture of 2-amino-4,6-dichloro-[l,3,5]τriazine (lOOmg, 0.606mmol), 4'-methyl- biphenyl-4-yl-methylamine (142mg, 0.606mmol), and cesium carbonate (394mg, 1.21mmol) was dissolved in 1 ,4-dioxane (1.5ml) and H2O (1.5ml) in a 5ml microwave vial. The mixture was stirred in microwave reactor at 1000C for 15 minutes. Solvent was removed and the residue was dissolved in CH2Cl2 (20ml) and washed with H2O (2x20ml), dried over Na2SO4 and then removed in vacuo. The crude intermediate was then dissolved in 1.5ml of MeCN and 1.5ml of H2O in a 5ml microwave vial. To this solution were added L-/?-borono- phenylalanine (126mg, 0.606mmol), sodium carbonate (128mg, 1.21mmol) and catalytic amount of dichlorobis(triphenylphosphine)-palladium(IT) (21.1mg, 0.03mmol). The mixture was sealed and stirred in the microwave reactor at 1500C for 5 minutes followed by the filtration through celite. The filtrate was concentrated and dissolved in MeOH and H2O (1 : 1) and purified by preparative HPLC using MeOH/H2O/TFA solvent system. The combined pure fractions were evaporated in vacuo and further dried on a lyophilizer to give 21.6 mg of 2-amino-3-(4- {4-amino-6-[(4'-methyl-biphenyl-4-yhnethyl)-amino]-[l ,3,5]triazin-2-yl} - phenyl)-propionic acid (LC: Column: YMC Pack ODS-A 3.0x50mm, %B=0~100%, Gradient time = 4min, Flow Rate = 2ml/min, wavelength=220, Solvent A= 90:10 water:MeOH w/ 0.1%TFA, Solvent B=90:10 MeOH:water w/0.1%TFA , RT = 3.096 min, MS: M+l = 455). 1H NMR(400 MHz, CD3OD) δ 2.33 (s, 3H), 3.24-3.44 (m, 2H), 4.38 (m, IH), 7.02 (d, 2H), 7.42 (m, 2H), 7.50-7.60 (m, 6H), 8.22 (m, 2H).
6.7. Synthesis of (SV2-Amino-3-(4-(4-morpholino-6-(naphthalen-2- ylmethvIaminoVl,3,5-triazin-2-yl)phenvl)propanoic acid
Figure imgf000051_0001
A mixture of 2,4-dichloro-6-morpholin-4-yl-[l,3,5]triazine (121mg, 0.516mmol), C- naphthalen-2-yl-methylamine hydrochloride (1 OOmg, 0.516mmol), cesium carbonate (336mg, 1.03mxnol) was dissolved in 1,4-Dioxane (1.5ml) and H2O (1.5ml) in a 5ml microwave vial. The mixture was stirred in microwave reactor at 1800C for 600 seconds. Solvent was removed, and the residue was dissolved in CH2Cl2 (10ml) and washed with H2O (2xl0ml), dried over Na2SO4 and then in vacuo. The residue was purified by preparative HPLC to give 20mg intermediate (yield 11%, M+l=356). The intermediate was then dissolved in 0.5ml of MeCN and 0.5ml OfH2O in a 2ml microwave vial. To this solution were added L-j?-borono- phenylalanine (11.7mg, 0.0562mmol), sodium carbonate (11.9mg, 0.112mmol) and a catalytic amount of dichlorobis(triphenylphosphine)-palladium(II) (2.0mg, 5%). The mixture was sealed and stirred in the microwave reactor at 1500C for 5 minutes followed by the filtration through celite. The filtrate was concentrated and dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA solvent system. The combined pure fractions were evaporated in vacuo and further dried on lyophilizer to give 17mg of 2- amino-3-(4- {4-morpholin-4-yl-6-[(naphthalene-2-yhnethyl)-amino]-[l ,3,5]triazin-2-yl} - phenyl)-propionic acid (yield: 63%, LC: Method B5 RT = 3.108 min, MS: M+l = 486). 6.8. Synthesis of f2S)-2-Amino-3-(4-f2-ainino-6-(2.2.2-trifluoro-l-(2-
(trifluoromethyl)phenyr)ethoxy)pyrimidin-4-vDphenyl^propanoic acid
Figure imgf000052_0001
Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-trifluoromethyl-benzaldehyde (1.74g, lOmmol) and trifluoromethyltrimethylsilane (TMSCF3) (1.8ml, 12 mmol) in 10 ml THF at 00C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of IN HCl and stirred overnight. The product was extracted with ethyl acetate (3x20ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 2.2g of l-(2- trifluoromethylphenyl)-2,2,2-tri£luoro-ethanol, yield 90%.
NaH (80mg, 60%, 3.0mmol) was added to a solution of l-(2-trifluoromethylphenyl)- 2,2,2-trifiuoro-ethanol (244mg, lrnmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4, 6-dichloro-pyrimidine (164mg, lmmol) was added and then the reaction mixture was heated at 7O0C for 1 hour. After cooling, 5ml water was added and ethyl acetate (20ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 267 mg of 4-chloro-6-[2, 2, 2- trifiuoro-1 -(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-2-ylamine, yield 71%.
In a microwave vial, 4-chloro-2-amino-6-[l-(2-trifluoromethylphenyl)-2, 2, 2- trifluoro-ethoxy]-pyrimidine (33mg, O.lmmol), 4-borono-L-phenylalanine(31mg, O.lSmmol) and 1 ml of acetonitrile, 0.7ml of water. 0.3 ml of IN aqueous sodium carbonate was added to above solution followed by 5 mole percent of dichlorobis(triphenylphosphine)- palladium(H). The reaction vessel was sealed and heated at 1500C for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep- LC to give 5.6 mg of2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-l-(2-triifluoromethylphenyl)- ethoxy]- pyrimidin-4-yl}-ρhenyl)-ρropionic acid. 1H NMR (400MHz, CD3OD) δ 7.96 (m, 3H), 7.80 (d, J=8.06 Hz, IH), 7.74 (t, J=7.91 Hz IH), 7.63(t, J=8.06 Hz, IH), 7.41 (d, J=8.3Hz, 2 H)5 7.21 (m, IH), 6.69 (s, IH), 3.87 (m, 1 H), 3.34 (m, 1 H), 3.08 (m, IH). 6.9. Synthesis of f2S>2-Amino-3-(4-(2-amino-6-f2,2,2-trifluoro-l-p- tolylethoxy)pyrimidin-4-vftphenvDpropanoic acid
Figure imgf000053_0001
Tetrabutylammonium fluoride (0.1 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 4-methyl-benzaldehyde (1.2g, lOmmol) and TMSCF3 (1.8ml, 12 mmol) in 10 ml THF at 00C. The formed mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was then treated with 12 ml of IN HCl and stirred overnight. The product was extracted with ethyl acetate (3x20ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 1.6g of l-(4- methylphenyl)-2,2,2-trifluoro-ethanol, yield 86%.
NaH (80mg, 60%, 3.0mmol) was added to a solution of l-(4-methylphenyl)-2,2,2- trifluoro-ethanol (190mg, lmmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164mg, lmmol) was added and then the reaction mixture was heated at 700C for 1 hour. After cooling, 5ml water was added and ethyl acetate (20ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 209 mg of 4-chloro-6-[l-(4- methylphenyl)-2J2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine, yield 66%.
A microwave vial was charged with 4^chloro-2-ammo-6-[l-(4-methylphenyl)-2,2,2- trifluoro-ethoxy]-pyrimidine (33mg, O.lmmol), 4-borono-L-phenylalanine (31mg, 0.15mmol) and 1 ml of acetonitrile, 0.7ml of water. Aqueous sodium carbonate (0.3 ml, IN) was added to above solution followed by 5 mol percent of dichlorobisøriphenylphosphine)- palladi Um(II). The reaction vessel was sealed and heated to 1500C for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 14.6mg of 2-amino-3- (4-{2-amino-6-[2,2,2-trifluoro-l -(4-methylphenyl)- ethoxy]-pyrimidin-4-yl} -phenyl- propionic acid. 1H NMR (300MHz, CD3OD) δ 7.94 (d, J=8.20 Hz, 2H), 7.47 (d, J=7.24 Hz, 4 H), 7.27 (d, J=8.01 Hz, 2H) 6.80 (s, IH), 6.75 (m, IH), 4.30 (t, 1 H), 3.21-3.44 (m, 2 H), 2.37 (ss 3H). 6.10. Synthesis of (2S)-2-Amino-3-(4-f2-amino-6-(l-cvc.ohexyI-2,2,2- trifluoroethoxv)pyrimidin-4-vθDhen\i)propanoic acid
Figure imgf000054_0001
Cyclohexanecarbaldehyde (0.9 g, 5mmol) was dissolved in 10ml aqueous 1,4- dioxane, to which 200mg (10 mmol) sodium borohydride was added. The reaction was run overnight at room temperature. After completion of the reaction, 5ml 10% HCl solution was added and the product was extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 0.8g of 1-cyclohexyl- 2,2,2-trifluoro-ethanol, yield 88%. NaH (80mg, 60%, 3.0mmol) was added to the solution of l-cyclohexyl-2,2,2- trifluoro-ethanol (182mg, lmmol) in 10 ml of anhydrous THF, the mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164mg, lmmol) was added and then the reaction mixture was heated at 700C for 1 hour. After cooling, 5ml water was added and ethyl acetate (20ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 202 mg of 4-chIoro-6-[l-cyclohexyl-2,2,2- trifluoro-ethoxy]-pyrimidin-2-ylamine, yield 65%.
In a microwave vial, 4-chloro-2-amino-6-[l-cyclohexane-2,2,2-trifluoro-ethoxy]- pyrimidine (33mg, 0. lmmol), 4-borono-L-phenylalanine (31mg, 0.15mmol) and 1 ml of acetonitrile, 0.7ml of water, 0.3 ml of aqueous sodium carbonate (IM) was added to above solution followed by 5 mol percent of dichlorobis(triρhenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 1500C for 5 minutes with a microwave. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol, and the product was purified by Prep-LC to give 4.9 mg 2-amino-3-{4-[2- amino-6-(l-cyclohexyl-2, 2, 2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (300MHz, CD3Cl) δ 7.95 (d, J=8.39Hz, 2 H), 7.49 (d, J=8.39Hz, 2 H), 6.72 (s, IH), 5.90(m, IH), 4.33 (t, 1 H), 3.21-3.44 (m, 2 H), 1.73-2.00 (m, 6H), 1.23-1.39 (m, 5H). 6.11. Synthesis of (SV2-Am.no-3-(4-(6-f2-fluorophenoxy^pyrimidin-4- vDphenvUpropanoic acid
Figure imgf000055_0001
NaH (80mg, 60%, 3.0mmol) was added to a solution of 2-fluorophenol (112 mg, lmmol) in 10 ml of anhydrous THF, the mixture was stirred for 20 minutes, 4,6-dichloro- pyrimidine (149mg, lmmol) was added and then the reaction mixture was heated at 700C for 1 hour. After cooling, 5ml water was added and ethyl acetate (20ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 146 mg of 4-chlσro-6-(2-fluorophenoxy)-pyrirnidine, yield 65%. A microwave vial (2ml) was charged with 4-chloro-6-[2-fluorophenoxy]-pyrimidine,
(33mg, 0. lmmol), 4-borono-L-phenylalanine(31mg, 0.15mmol) and 1 ml of actonitrile, 0.7ml of water, 0.3 ml of aqueous sodium carbonate (IM) was added to above solution followed by 5 mol % of dichlorobis(triphenylphosphine)-palladium(π). The reaction vessel was sealed and heated to 1500C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 4.9 mg 2-amino-3-{4-[2-amino-6-(l-2-fluorophenyl-2,2,2- trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400MHz, CD3OD) δ 8.74 (S5 IH), 8.17 (d, ./=8.06 Hz, 2H), 7.63 (s, IH), 7.50(d, J=8.06 Hz, 2H), 7.30 (m, 5H), 4.33 (m, 1 H), 3.34 (m, 1 H).
6.12. Synthesis of (2S)-2-Amino-3-(4-(4-r3-(4-chlorophenvnpiperidin-l-vn- l,3,5-triazin-2-yl)phenvl)propanoic acid
Figure imgf000055_0002
3-(4-Chlorophenyl)piperidine (232mg, lmmol) was added to a solution of 2,4- dichlorotriazine (149.97mg, lmmol), and 300mg diisopropylethyl amine in 10ml THF at 0°C. The formed mixture was warmed up to room temperature and stirred for 1 hour. The product was extracted with ethyl acetate (3x20ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 328mg of 2-chloro-4-[3-(4- chlorophenyl)-piperidin-l-yl]-[l, 3, 5] triazine.
A microwave vial was charged with 2-chloro-4-[3-(4-chlorophenyl)-piperidin-l-yl]- [1, 3, 5]triazine (62mg, 0.2mmol), 4-borono-L-phenylalanine(60mg, 0.3mmol), 1 ml of acetonitrile, and 0.7ml of water. Aqueous sodium carbonate (0.6 ml; IM) was added to the solution, followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 1500C for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 5.1mg of 2-amino-3-(4-{4-[3-(4- chlorophenyl)-piperidin-l-yl]-[l,3,5]triazin-2-yl}-phenyl)-propionic acid. 1H NMR (400MHz, CD3Cl) δ 8.58 (d, 2H), 8.05 (d, 2H), 7.47 (m, 5 H), 4.96 (m, 1 H), 4.23(m, 2H), 3.21-3.44 (m, 4 H), 2.37 (m, 5H).
6.13. Synthesis of (2SV2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-l- phenylethoxy)-! ,3-5-triazin-2-yI)phenyl)propanoic acid
Figure imgf000056_0001
NaH (80mg, 60%, 3.0mmol) was added to a solution of 2,2,2-trifluoro-l-phenyl- ethanol (176mg, lmmol) in 10 ml of anhydrous 1,4- dioxane. The mixture was stirred for 20 minutes, then added to a solution of 2-amino-4,6-dichloro-triazine (164mg, lmmol) in 30ml of 1,4-dioxane at 00C for 1 hour. The reaction mixture was then warmed to room temperature. After completion of the reaction, 5ml of water was added and ethyl acetate (20ml) was used to extract the product. The organic layer was dried over sodium sulfate.
The solvent was removed by rotovap to give 198 mg of 4-chloro-6-[2,2,2-trifluoro-l-phenyl- ethoxy]-[l33,5]triazine-2-ylamine, yield 65%. A microwave vial was charged with 4-chloro-6-[2,2)2-trifluoro-l-phenyl-ethoxy]- [l,3,5]triazine-2-ylamine (33mg, O.lmmol), 4-borono-L-phenylalanine(31mg, 0.15mmol), 1ml of actonitrile, and 0.7ml of water. Aqueous sodium carbonate (0.3 ml, IM) was added to above solution followed by 5 mol percent dichlorobis(triρhenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 1500C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified with Prep-LC to give 3.2mg 2-amino-3-{4-[4-amino-6-(l- phenyl-2,2,2-trifluoro-ethoxy]-[l,3,5]triazin-2yl]-phenyl)-propionic acid. 1H NMR (300MHz, CD3OD) δ 8.22 (d, J=8.20 Hz, 2H), 7.52 (m, 2 H), 7.33 (m, 5H) 6.62 (m, IH), 4.19 (t, 1 H), 3.1-3.33 (m, 2 H).
6.14. Synthesis of (SV2-Amino-3-(5-f4-amino-6-((RM-fnaphthalen-2- vDethylaminoM ,3,5-triazin-2-vDpyridin-2-yl)propanoic acid
Figure imgf000057_0001
A microwave vial was charged with 6-chloro-N-[l-naphthalen-2yl-ethyl]- [l,3,5]triazine-2,4-diamine (30mg, O.lmmol), 2-boc protected-amino-3-{5-[4,4,5,5,- tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin2-yl-3-propionic acid (50mg, 0.15mmol) 1 ml of acetonitrile, and 0.7ml of water. Aqueous sodium carbonate (0.3 ml; IN) was added to the solution, followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 1500C for 5 mintues by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and was then purified by Prep-LC to give 7 mg of boc protected 2-amino-3-{5-[4- amino-6-( 1 -naphthalen-2-yl-ethylamino)-[ 1 ,3 ,5]triazin-2-yl]-pyridin-2-yl} proionic acid.
The above product (7.0 mg) was dissolved in 0.1ml of 10%TFA/DCM solution for 2 hours to provide 1.1 mg of 2-amino-3-{3-[4-amino-6-(l-naphthalen-2-yl-ethylamino)- [l,3,5]triazin-2-yl]-pyridin-2-yl}proionic acid. 1H NMR (300MHz, CD3Cl) δ 9.35 (d, 1 H), 8.57 (m, 1 H), 7.85 (m, 4H), 7.45 (m, 4 H), 6.94 (s, IH). S.58(m, IH), 4.72 (m, 2H), 4.44 (m, 1 H), 1.42 (d, 3H). 6.15. Synthesis of (SV2-Amino-3-(3-(4-ainino-6-(TRM-fnaphthalen-2- vπethylaminoVl,3.5-triazin-2-vI')-lH-PyrazoI-l-yl')prQpanoic acid
Figure imgf000058_0001
6-Chloro-N-[l-naphthalen-2yl-ethyl]-[l,3,5]triazine-2,4-diatnine (30mg, O.lmmol), 2- boc-protected amino-3-{3-[4,4,5,5,-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyrazol-l-yl]- propionic acid (50mg, 0.15mmol), 1 ml of acetonitrile, and 0.7ml of water. Aqueous sodium carbonate (0.3 ml and IN) was added to a microwave vial, followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(π). The reaction vessel was sealed and heated to 1500C for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol, and then was purified with Prep- LC to give 6.8 mg of boc protected 2-amino-3-{3-[4-amino-6-(l-naphthalen-2-yl- ethylamino)[l,3,5]triazin-2-yl]-pvrazol-l-yl}proionic acid.
The above product (6.8mg) was stirred in 0.1ml 10%TFA/DCM solution for 2 hours to provide 3mg of 2-amino-3-{3-[4-amino-6-(l-naphthalen-2-yl-ethylamino)-[l,3,5]triazin-2- yl]-pyrazol-l-yl}proionic acid. 1H NMR (300MHz, CD3Cl) δ 8.52 (s, 1 H), 8.21 (s, 1 H), 7.74 (m, 4 H), 7.36 (m, 3H), 5.35(m, IH), 4.72 (m, 2H), 4.44 (m, 1 H), 1.55 (d, 3H).
6.16. Synthesis of (SV2-Amino-3-(4'-(3-(cvcIopenty.oxyV4- methoxybenzylamino')piphenyl-4-vr)propanoic acid
Figure imgf000058_0002
Sodium triacetoxyl-borohydride (470m g, 2.21mmol) was added to a solution of 4- bromo-phenylamine (252mg, 1.47mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (324mg, 1.47mmol) in 10 ml of 1 ,2-dicloroethtane (DCE), 0.5 ml of HOAc was added. The mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water and dried over sodium sulfate. The solvent was removed by rotovap to give 656 mg of crude (4-bromo-phenyl)-(3-cyclopentyloxy-4- methoxy-benzyl)-arnine. It was used for next step without further purification.
An Emrys process vial (2-5ml) for microwave was charged with (4-bromo-phenyl)- (3-cyclopentyloxy-4-methoxy-benzyl)-amine (84mg, 0.22mmol), 4-borono-L- phenylalanine(46mg, 0.22mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, IM) was added to above solution, followed by 5 mol percent of dichlorobis- (triphenylphosphine)-palladium(H). The reaction vessel was sealed and heated to 1500C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified with Prep-LC to give 5 mg of 2- amino-3-[4'-(3-cyclophentyloxy-4-methoxy-benzylamino)-biphenyl-4-yl]-propionic acid, yield 5%. 1H-NMR (400 MHz, DMSOd6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01(m, 2H), 3.64 (s, 3H), 4.14 (s, 3H), 4.66(m, IH), 6.61(d, 2H), 6.81(s, 2H), 6.88(s, IH), 7.18(d, 2H), 7.31(d, 2H), 7.44(d, 2H), 7.60(m, IH), 8.19(s, 3H).
6.17. Synthesis of (SV2-Amino-3-f4-(6-(3-(cvcIopentyloxyV4- methoxybenzylamino)pyrimidin-4-vI)phenyl)propanoic acid
Figure imgf000059_0001
Sodium tiracetoxyl-borohydride (985mg, 4.65mmol) was added to a solution of 6- chloro-pyrimidin-4-ylamine (200mg, 1.55mmol) and 3-cyclopentyloxy-4-methoxy- benzaldehyde (682mg, 3.1mmol) in 25 ml of DCE. 1 ml of HOAc was added, and the mixture was stirred overnight at 500C, followed by addition of 25 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexanerEtOAc 5:1) to give 64 mg of (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4- methoxy-benzyl)-amine, yield 12%.
An Emrys process vial (2-5ml) for microwave was charged with (6-chloro-pyrirnidin- 4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (64mg, 0.19mmol), 4-borono-L- 5. phenylalanine (40mg, 0.19mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, IM) was added to above solution followed by 5 mol percent of dichlorobis- (triphenylphosphine)-palladium(π). The reaction vessel was sealed and heated to 1500C for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified with Prep-LC to give 5.3 mg of 0 2-amino-3- {4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}- propionic acid, yield 6%. 1H-NMR (400 MHz, DMSOd6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01(m, 2H), 3.08(m, 2H), 3.65(s, 3H), 4.20(m, IH), 4.46(d, 2H), 4.68(m, IH), 6.82(t, 2H), 6.87(d, 2H), 7.40(d, 2H), 7.90(s, 2H), 8.25(s, 2H), 8.6(s, IH).
6.18. Synthesis of (SV2-Aimno-3-(4-(6-(3-fcvcIopentvIoxy)-4- 5 methoxybenzylamino)pyrazin-2-yl)phenyl)propanoic aeid
Figure imgf000060_0001
Sodium triacetoxyl-borohydride (1315mg, 6.2mmol) was added to a solution of 6- chloro-pyrazin-2-yl- amine (400mg, 3.10mmol) and 3-cyclopentyloxy-4-methoxy- benzaldehyde (818mg, 3.7mmol) in 50 ml of DCE, 1 ml of HOAc was added and the mixture 0 was stirred overnight at 500C, followed by addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 6:1) to give 50 mg of (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy- benzyl)-amine, yield 10%.
An Emrys process vial (2~5ml) for microwave was charged with (6-chloro-pyrazin-2- 5 yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (50mg, 0.15mmol), 4-borono-L- phenylalanine (31mg, 0.15mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, IM) was added to the solution followed by 5 mol percent of dichlorobis(triphenylphosphine)- palladium(II). The reaction vessel was sealed and heated to 1500C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep- LC to give 5.5 mg of2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}- propionic acid, yield 6%. 1H-NMR (400 MHz5 DMSOd6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01(m, 2H), 3.08(m, 2H), 3.65(s, 3H), 4.0(m, IH), 4.45(d, 2H), 4.65(m, IH), 6.90(s, 2H), 6.95(s, IH), 7.32(d, 2H), 7.60(t, IH), 7.90(s, IH)5 7.95(d, 2H), 8.25(s, IH).
6.19. Synthesis of (SV2-Amino-3-(4-(S-f(4t-methylbiDhenyl-2- yI)methylamino)pyrazin-2-y0pheny0propano.c acid
Figure imgf000061_0001
Sodium tiracetoxyl borohydride (215mg, 1.02mmol) was added to the solution of 4'- methyl-biphenyl-2-carbaldehyde and 5-bromo-pyrazin-2-ylamine in 5 ml of DCE, 0.1 ml of HOAc was added and the mixture was stirred overnight at room temperature, followed by addition of 5 ml of DCE. The organic phase was washed with water, and purified with column (silica gel, hexane:EtOAc 6:1) to give 100 mg of (5-brorno-pyrazin-2-yl)-(4'-methyl- biphenyl-2-ylmethyl)-arnine5 yield 55%.
An Emrys process vial (2-5ml) for microwave was charged with (5-bromo-pyrazin-2- yl)-(4'-methyl-biphenyl-2-ylmethyl)-amine (25mg, 0.071mmol), 4-borono-L-phenylalanine (22mg, O.l lmmol) and 1 ml of acetonitrile. Aqueous sodium carbonate (1 ml, IM) was added to the solution followed by 5 mol percent dichlorobis(triphenylphosphine)- palladium(II). The reaction vessel was sealed and heated to 1500C for 5 mintues by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 19 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrazin-2-yl]-phenyl}- propionic acid, yield 63%. 1H-NMR (400 MHz, CD3OD): δ 2.22(s, 3H)5 3.09(m, IH),
3.25(m, IH), 4.18(t, IH), 4.40(s, 2H), 7.07(d, 2H), 7.14(m, 3H), 7.24(m, 4H), 7.36(m,lH), 7.72(d, 2H), 7.84(s, IH), 8.20(d, IH). 6.20. Synthesis of (2.SV2-Amino-3-(4-(6-f2.2,2-trifluoro-l-phenylethoxy)- pyrimidin-4-yr)phenvϊ)proρanoic acid
Figure imgf000062_0001
NaH (60%, 120mg, 3.0mmol) was added to a solution of 2,2,2-trifluoro-l-ρhenyl- ethanol (350mg, 2.03mmol) in 5 ml of THF. The mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (300mg, 2.03mmol) was added and then the reaction mixture was heated at 700C for 1 hour. After cooling, the THF was evaporated to provide a residue, which was dissolved in 15 ml of EtOAc, and then washed with water, and dried over sodium sulfate. The solvent was removed by rotovap to give 550 mg of 4-chloro-6-(2,2,2- trifluoro-l-phenyl-ethoxy)-pyrirnidine, yield 95%.
An Emrys process vial (2-5ml) for microwave was charged with 4-chloro-6-(2,2,2- trifluoro-l-phenyl-ethoxy)-pyrimidine (30mg, O.l lmmol), 4-borono-L-phenylalanine (32mg, O.lδmmol), 1 ml of acetonitrile and 0.6 ml of water. Aqueous sodium carbonate (0.42 ml, IM) was added to above solution followed by 10 mol percent of POPd2 (dihydrogen di-μ- chlorodichlorobis(di-tert-butylphosphinito-κP) dipalladate. The reaction vessel was sealed and heated to 1200C for 30 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and the product was purified with Prep-LC to give 4.8mg of 2-amino-3-{4-[6-(2,2,2-trifluoro-lphenyl-ethoxy)- pyrimidin-4-yl]-phenyl> -propionic acid, yield 11%. 1H-NMR (400 MHz, CD3OD): δ 3.20(m, IH), 3.40(m, IH)5 4.25(t, IH), 6.82(dd, IH), 7.43(m, 5H), 7.57(s5 IH), 7.60(m, 2H),8.10(d, 2H),8.75(s, IH).
6.21. Synthesis of (2SV2-Amino-3-(4-(6-fl-(3,4-difluorophenvn-2.2,2- trifluoroethoxy)pyriinidin-4-vDphenvDpropanoic acid
Figure imgf000062_0002
Tetrabutylammonium fluoride (TBAF: 0.1 ml, IM) in THF was added to a solution of 3,4-difluro-benzaldehyde (1.42g, lOmmol) and (trifluroraethyl)trimethylsilane (1.7Og, 12mmol) in 10 ml THF at 00C. The mixture was warmed up to room temperature and stirred for 4 hours. The reaction mixture was treated with 12 ml of IM HCl and stirred overnight. The product was extracted with dicloromethane (3x20ml), the organic layer was combined and passed through a pad of silica gel. The organic solvent was evaporated to give 1.9g of 1- (3,4-difluoro-phenyl)-2,2,2-trifluoro-ethanol, yield 90%.
NaH (80mg, 60%, 3.0mmol) was added to a solution of l-(3,4-Difluoro-phenyl)- 2,2,2-trifluoro-ethanol (212mg, lmmol) in 5 ml of THF, the mixture was stirred for 20 minutes at room temperature. 4,6-Dichloro-pyrimidine (149mg, lmmol) was added and then the reaction mixture was heated at 700C for 1 hour. After cooling, THF was evaporated. The residue was dissolved in 15 ml of EtOAc, and then washed with water, dried over sodium sulfate. The solvent was removed by rotovap to give 230 mg of 4-chloro-6-[l-(3,4-difluoro- phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine, yield 70%. An Emrys process vial (2-5ml) for microwave was charged with 4-chloro-6-[l-(3,4- difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33mg, 0. lmmol), 4-borono-L- phenylalanine (31mg, 0.15mmol), 1 ml of acetonitrile and 0.7ml of water. Aqueous sodium carbonate (0.3 ml, IM) was added to above solution followed by 5 mol % of dichlorobis(triphenylphosphine)-palladium(π). The reaction vessel was sealed and heated to 1500C for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, then purified with Prep-LC to give 10 mg of 2-amino-3 -(4- {6-[ 1 -(3,4-difluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyridin-4-yl} - phenyl)-propionic acid, yield 21%. 1H-NMR (400 MHz, CD3OD): δ 3.1 l(m, IH), 3.27(m, IH), 4.19(dd, IH), 6.78(q, IH), 7.26(m, 2H), 7.35(d, 3H),7.49(m, 2H), 8.02(d, 2H),8.66(s, IH). 6.22. Synthesis of (SV2-Amino-3-(4-(5-(3-(cvclopentvIoxy)-4- methoxvbenzvIaminol-Pvrazin-Σ-vDphenvltDroDanoic acid
Figure imgf000064_0001
A mixture of 3-cyclopentyloxy-4-methoxy-benzaldehyde (417 mg, 1.895 mmol), 2- amino-5-bromopyrazine (300 mg, 1.724 mmol), sodium triacetoxyborohydride (1.5 eq) and glacial acetic acid (3 eq) in dichloromethane (10 ml) was stirred at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate, and washed with water. The oraganic layer was dried over MgS O4 and filtered. The filtrate was concentrated to give the crude product, which was purified by ISCO (SiO2 flash column chromatography) (Hexane/ethyl acetate = 100/0 to 3/2) to give about 400 mg of 6-bromo-pyrazin-2-yl)-(3- cyclopentyloxy-4-methoxy-benzyl)-amine. Yield: 61%.
To a 5 ml microwave vial, the above 6-bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4- methoxy-benzyl)-amine (50 mg, 0.132 mmol), 4-borono-L-phenylalanine (30 mg , 0.144 mmol), Na2COa (31 mg, 0.288 mmol), acetonitrile (2 ml) and water (2 ml). Dichlorobis (triphenylphosphine)-palladium (5 mg, 0.007 mmol) was added. The vial was capped and stirred at 1500C for 5 minutes under microwave radiation. The reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparative-HPLC using YMC-Pack ODS 100x30 mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were concentrated in vacuum. The product was then suspended in 5 ml of water, frozen and lyophilized to give the title compound as a trifluoro salt (12 mg, 20 %). 1H NMR (CD3OD) δ 8.41 (s, IH), 7.99 (s, IH), 7.83 (d, J = 9.0 Hz, 2H), 7.37 (d, J - 6.0 Hz, 2H), 6.90- 6.95 (m, 3H), 4.78 (m, IH), 4.50 (s, 2H), 4.22-4.26 (m, IH). 3.79 (s, 3H), 3.12-3.39 (m, 2H), 1.80-1.81 (m, 6H), 1.60 (m, 2H). M+l = 463. 6.23. Synthesis of (S)-2-Amino-3-(4-(5-((3-(cyclopentyloxyV4-methoxybenzvIV (methvI)amino)pvrazin-2-vDphenvl)propanoic acid
Figure imgf000065_0001
To a solution of (6-bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (70 mg, 0.185 mmol) in acetonitrile (10 ml) was added formaldehyde (18.5 mmol) and sodium cyanoborohydride (17 mg, 0.278 mmol). Then, concentrated aqueous HCl was added dropwise until the pH « 2. The mixture was stirred for about 6 hours at room temperature. It was then diluted with ethyl acetate, washed with water (3 X 5 ml), dried over MgSO4. The solvent was removed by vacuum to give 70 mg of crude product 5-(bromo-pyrazin-2-yl)-(3- cyclopentyloxy-4-methoxy-benzyl)-methyl-amine (95 % crude yield), which was used in the next step without further purification.
The 5-(bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-methyl-amine (37 mg, 0.094 mmol) was subjected to a Suzuki coupling reaction as described above to afford 6 mg of the title compound. Yield: 13%. 1H NMR (CD3OD) δ 8.59 (s, IH), 8.12 (s, IH), 7.85 (d, 2H), 7.39 (d, 2H), 6.81-6.91 (m, 3H), 4.72 (m, IH), 4.30 (m, IH), 3.79 (s, 3H), 3.20-3.40 (m, 2H), 3.18 (s, 3H), 3.79 (s, 3H), 1.80 (m, 6H), 1.58 (m, 2H). M+l = 477.
6.24. Synthesis of fSV-2-Amino-3-(4-r5-(( 1.3-dimethyl-lH-pyrazol-4- yl)methyIaiiiino)pyrazin-2-yl)phenvl)propanoic acid
Figure imgf000065_0002
A mixture of l,3-dimethyl-lH-pyrazole-4-carbaldehyde (142 mg, 1.145 mmol), 2- amino-5-bromoρyτazine (200 mg, 1.149mmol), borane trimethylarnine complex (126 mg, 1.73mmol) and glacial acetic acid (137 mg, 2.29 mmol) in anhydrous methonol (3 ml) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over MgSO4 and filtered. The filtrate was concentrated to give 300 mg of (5-bromo-pyrazin-2-yl)-(l,3-dimethyl-lH-pyrazol-4-ylmethyl)amine as crude product, which was used for next step reaction without further purification. Crude yield: 93%.
The (5-bromo-pyrazin-2-yl)-(l,3-dimethyl-lH-pyrazol-4-yhnethyl)amine (40 mg, 0.142 mmol) was used in the Suzuki coupling reaction described above to afford 19 mg of of the title compound. Yield: 36.5%. 1HNMR (CD3OD) δ 8.48 (s, IH), 8.05 (s, IH), 7.87 (d, 2H), 7.39 (d, 2H), 6.10 (s, IH), 4.81 (s, 2H), 4.30 (m, IH), 3.83 (s, 3H), 3.11-3.38 (m, 2H), 2.10 (s, 3H). M+l = 367.
6.25. Synthesis of (SV2-Amino-3-f4-f4-amino-6-f(S>l-fnaphthalen-2- yl)ethylaminoVl,3-5-triaziii-2-yloxy^phenyl)propanoic acid
Figure imgf000066_0001
To a 250 ml flask, R-(+)-l-(2-naphthyl)ethylamine (400 mg, 2.424 mmol), 2-amino- 4,6-dichloro triazine (373mg, 2.181 mmol), anhydrous 1 ,4-dioxane (40 ml), and N,N- diisopropylethylamine (1 ml, 5.732 mmol) were added and heated to mild reflux for about 4 hours. The reaction was monitored carefully in order to avoid the formation of the disubstituted product. (It was observed that the longer the reaction, the more disubstituted product is formed). After 4 hours, the reaction mixture was cooled and the solvent was removed under reduced pressure. Water was added to the residue, and the solution was sonicated for 2-3 minutes. The solvent was then filtered, washed with water and dried to give 540 mg (83 % crude yield) of the mono-chloride, 6-chloro-N-(l-naphthalen-2yl-ethyl)- [l,3,5]triazine-2,2-diamine, which was used for the next step reaction without further purification.
A mixture of 6-chloro-N-(l-naphthalen-2yl-ethyl)-[l,3,5]triazine-2,2-diamine (90 mg, 0.300 mmol), 2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester (102 mg, 0.303 mmol) and potassium carbonate (82 mg, 0.594 mmol) in isopropanol (8 ml) was refluxed over night. The solvent was removed under reduced pressure and the residue was suspended in ethyl acetate. The solid was filtered and washed with ethyl acetate. The filtrate was concentrated and then redissolved in a mixture of methanol/water(90:10) and purified by a preparative-LC using a Sunfire Cl 8 OBD 100x30mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were combined and concentrated to give 50 mg of pure product, 3-{4-[4-amino-6-(l-naphthalen-2-yl-ethylamino)-[l,3,5]triazin- 2yloxy]-phenyl}2-ter*-butoxycarbonvlamino-propionic acid tert-butyl ester, (28% yield).
The above product (50 mg, O.083mmol) was dissolved in trifluoro acetic acid/dichloromethane (8ml/2ml) and stirred at room temperature over night. The solvent was removed under reduced pressure. The residue was then redissolved in a mixture of methanol/water(90:10) and purified by a preparative-LC using a Sunfire Cl 8 OBD 100x30mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were combined and concentrated under reduced pressure to afford about 4 ml, which was frozen and lyophilized to give 4 mg of the title compound as a TFA salt (11 % yield). 1H NMR (CD3OD) δ 7.37-7.81 (m, 8H), 7.19 (m, 2H), 6.98 (m, IH), 5.37 (m, IH)54.19 (m, IH), 3.17-3.38 (m, 2H), 1.56 (m, 3H). M+l = 445.
6.26. Synthesis of fSV2-Amino-3-f4-(4-amino-6-((RVl-(biphenyl-2-vn-2.2.2- trifluoroethoxy)-l,3,5-triazin-2-vπphenvl)propanoic acid
Figure imgf000067_0001
A mixture of l-biphenyl-2-yl-2,2,2-trifluoro-ethanone (300 mg, 1.2 mmol), borane tetrahydrofuran complexes (1.2 ml, IM in THF, 1.2 mmol) and S-2-methyl-CBS- oxazaborolidine (0.24 ml, IM in toluene, 0.24 mmol) in THF (8ml) was stirred at room temperature over night. Several drops of concentrated HCl were added and the mixture was stirred for 30 minutes. The product was purified by SiO2 chromatography (hexane/ethyl acetate = 100/0 to 3/1) to give 290 mg of l-biphenyl-2-yl-2,2,2-trifluoro-ethanol (96% yield).
The above alcohol (290 mg, 1.151 mmol) was dissolved in anhydrous THF (10 ml). Sodium hydride (55 mg, 1.375 mmol) was added all at once, and the mixture was stirred at room temperature for 30 minutes. The solution was then transferred into a flask that contained a suspension of 2-amino-4,6-dichloro-triazine (190 mg, 1.152 mmol) in THP (20 ml). The mixture was stirred at room temperature overnight. Water was added and the mixture was then diluted with ethyl acetate. The organic layer was washed with water, dried over MgSO4 and then concentrated to give 400 mg of crude product 2-amino-4-(l-biphenyl- 2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine.
The 2-amino-4-(l-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine (40 mg, 0.105 mmol) was subjected to the same Suzuki coupling reaction as described above to afford 5 mg of the title compound. Yield: 9.4%. 1H NMR (CD3OD) δ 8.18 (d, 2H), 7.86 (m, IH), 7.40-7.52 (m, 9H), 7.32 (m, IH), 7.07 (m, IH), 4.32 (m, IH), 3.22-3.41 (m, 2H). M+l = 510.
6.27. Synthesis of (2S)-2-Amino-3-(4-(4-amino-6-(l-(6.8-difluoronaphthaleri-2- vDethvIam.il oVl ,3,5-triazin-2-yr)phenvDpropanoic acid
Figure imgf000068_0001
In a three-neck flask, copper iodine (CuI) (299 mg, 1.515 mmol) and lithium chloride (LiCl) (145 mg, 3.452 mmol) were added under nitrogen to anhydrous THF (60 ml). The mixture was stirred at room temperature until a pale yellow solution was obtained. After cooling to 00C, methyl vinyl ketone and chlorotrimethylsilane were added, and the mixture was stirred until an orange color was observed (~20 min). After cooling to about -400C, a solution of 3,5-difluorophenylmagnesium bromide (27.65 ml, 13.8mmol) in THF (0.5M) was slowly added. The reaction mixture was stirred at about -400C for 0.5 hours, then the cold bath was removed and the temperature was allowed to rise slowly to room temperature. The solvent was evaporated and the residue was extracted with hexane (4x20 ml). The collected extractions were washed with cold 10% aqueous NaHCO3 and dried over Na2SO4. The solvent was evaporated at reduced pressure to afford 3,5-difluorophenyl-l- trimethylsilyloxyalkene (2.03 g, 7.929 mmol, 57% crude yield), which was used in the successive reaction without further purification.
Powered calcium carbonate (3.806g, 38.06 mmol) and ethyl vinyl ether (2.184g, 30.329 mmol) were added to a solution of eerie ammonium nitrate (10.43Og, 19.033 mmol) in methanol (40 ml) under nitrogen atmosphere. To the resulting suspension was added a solution of above made 3, 5-difluorophenyl-l -trimethylsilyloxyalkene (2.03g, 7.929 mmol) in ethyl vinyl (6 ml, 4.518g, 62.75 mmol) dropwise under vigorous stirring, and the mixture was stirred at room temperature overnight. The solid was filtered through a celite layer, and the filtrate was concentrated to one-fourth of its initial volume. The resulting thick mixture was slowly poured, under vigorous stirring, into l:lv/v diethyl ether-10% aqueous NaHCOa- The precipitate was filtered off, the ethereal solution was separated, and the solvent was evaporated at reduced pressure to give clear liquid. The solution of resulting liquid (a mixture of acyclic and cyclic acetates) in methanol (4ml) was added dropwise to a suspension of dichlorodicyanobenzoquinone (1.77g, 7.797mmol) in 80% aqueous sulfuric acid at 00C. After the addition was complete, the ice bath was removed and stirring was continued for 30 minutes. The mixture was poured into ice water; and the resulting brown precipitate was filtered and dissolved in acetone. Silica gel was added to make a plug, and the crude product was purified by chromatography (hexane/ethyl acetate = 100/0 to 3/1) to give 760 mg of 1- (5,7-difluoro-naphthalen-2-yl)-ethanone (48% in two-step yield) as a light yellow solid. The above ketone (760mg, 3.689mmol) was dissolved in methanol (40 ml). Then, ammonium acetate (2.841g, 36.896 mmol), sodium cyanoborohydride (232 mg, 3.389mmol) and molecular sieves (3A, 7.6 g) were added. The mixture was stirred at room temperature for two days. The solid was filtered and the filtrate was concentrated. The residue was dissolved in water and concentrated aqueous HCl was added dropwise until the pH » 2. The mixture was then extracted with ethyl acetate to remove the unfinished ketone and other byproducts. The water layer was basified to pH « 10 with aqueous sodium hydroxide (IM), and was extracted with dichloromethane and the organic layers were combined, dried over magnesium sulfate and concentrated to afford 290 mg of l-(5,7-difluoro-naphthalen-2-yl)- ethylamine (38% yield). The fresh made amine (290mg, 1.401mmol) was added directly to a suspension of 2- amino-4,6-dichloro triazine (277mg, 1.678 rnmol) in anhydrous 1,4-dioxane (60 ml), and followed by addition of N,N-diisopropylethylamine (1 ml, 5.732 mmol). The mixture was heated to mild reflux for about 3 hours. The reaction mixture was then cooled, and the solvent was removed under reduced pressure. To the residue was added water and the mixture was sonicated for 2-3 minutes. The resulting solid was filtered and washed with water and dried to give 395 mg (60 % crude yield) of 6-chloro-JV-[l-(6,8-difluoro- naphthalen-2-yl-ethyl]-[l,3,5]triazine-2,4-diamine, which was used for the next step reaction directly without further purification.
The above made mono-chloride (48 mg, 0.144 mmol) was subjected to the same Suzuki coupling reaction as described above to afford 12 mg of the title product. Yield: 17.9%. 1H NMR (CD3OD) δ 8.14-8.22 (m, 2H), 8.05 (m, IH)3 7.92 (m, IH), 7.63 (m, IH), 7.32-7.51 (m, 3H), 7.11 (m, IH), 5.48 (m, IH), 4.13 (m, IH), 3.13-3.41 (m, 2H), 1.66 (d, 3H). M+l = 465.
6.28. Synthesis of (2SV2- Ammo-3-(4-(4-amino-6-(2,2.2-triflttoro-l-f3t- methvIbiphenyl^-vDethoxyVl^^-triazin-Z-vπphenvDpropanoic acid
Figure imgf000070_0001
To a mixture of 3'-methyl-l-biphenyl-2-carbaldehyde (500mg, 2.551mrnol) and trifluoromethyl trimethylsilane (435mg, 3.061mmol) in THF (3ml) was added tetrabutyl ammonium fluoride (13mg, 0.05 mmol) at 00C. The temperature was allowed to warm to room temperature. The mixture was stirred for 5 hours at room temperature, then diluted with ethyl acetate, washed with water and brine and dried by MgSO4. The solvent was removed under reduced pressure to give 660 mg (97% crude yield) of 2,2,2-trifluoro-l-(3'- methyl-biphenyl-2-yl)-ethanol as crude product, which was used for next step without further purification.
The above-made alcohol (660 mg, 2.481 mmol) was dissolved in anhydrous 1,4- dioxane (10 ml). Sodium hydride (119 mg, 60% in mineral oil, 2.975 mmol) was added all at once and the mixture was stirred at room temperature for 30 minutes. The solution was transferred into a flask containing a suspension of 2-amino-4,6-dichloro-triazine (491 mg, 2.976 mmol) in 1,4-dioxane (70 ml). The mixture was stirred at room temperature for 6 hours. The solvent was removed, and the residue was suspended in ethyl acetate, which was washed with water, dried over MgSO4 and then concentrated to give 790 mg of crude product, which contained about 57% of the desired product 2-amino-4-( l-(3'-methyl- biρhenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine and about 43% byproduct (the bisubstituted product). The crude product was used without further purification.
The 2-amino-4-(l-(3'-methyl-biphenyl-2-yl-2,2,2-trifluoro-ethoxy-6-chloro-triazine (98 mg, 57% purity, 0.142 mmol) was used to run the same Suzuki coupling reaction as described above to afford 9 mg of the title compound. Yield: 12.0%. 1H NMR (CD3OD) δ 8.09 (m, 2H), 7.85 (m, IH), 7.50 (m, 2H), 7.28-7.43 (m, 5H)5 7.17-7.26 (m, 2H), 7.18 (m, IH), 3.85 (m, IH), 3.08-3.44 (m, 2H), 2.33 (s, 3H). M+l = 524.
6.29. Synthesis of (SV2-Amino-3-f 4-(5-(3,4-dimethoxyphenyIcarbamoyl>- Pyrazin-2-vDphenyl>propanoic acid
Figure imgf000071_0001
To a mixture of 3,4-dimethoxy phenylamine (0.306 g, 2 mmol) and triethylamine (0.557 ml, 4 mmol) in dichloromethane (20 ml) was added 5-chloro-pyrazine-2-carbonyl chloride (0.354 g, 2 mmol) at 0-50C. The mixture was allowed to stir at room temperature for 3 hours. The mixture was diluted with methylene chloride (20 ml), washed with saturated NaHCO3 (20 ml), brine (20 ml), dried (anhyd. Na2SO4) and concentrated to get 0.42 g of crude 5-chloro-ρyrazine-2 carboxylic acid (3,4-dimethoxy-phenyl)-amide, which was directly used in the next reaction.
5-Chloro-pyrazine-2 carboxylic acid (3,4-dimethoxy-phenyl)-amide (0.18 g, 0.61 mmol), L-p-borono phenylalanine (0.146 g, 0.70 mmol), CH3CN (2.5 ml), H2O (2.5 ml), Na2CO3 (0.129 g, 1.22 mmol) were combined in a microwave vial. The mixture was sealed and kept at 1500C for 5 minutes. The mixture was filtered and concentrated. The residue was dissolved in methanol/water (1:1) and purified by preparative HPLC, using MeOH/H2O/TFA as solvent system to afford 2-amino-3- {4-[5-(3,4-dimethoxy- phenylcarbomyl)-pyrazin-2yl]-phenyl} -propionic acid as a TFA salt (HPLC: Method A, Retention time = 2.846 min, LCMS M+l 423). 1H NMR (400 MHz, DMSOd6) δ 3.10-3.30 (m, 2H), 3.72 (d, 6H), 4.05 (m, IH), 7.42-7.62 (m, 4H), 8.22 (m, 3H), 9.30 (m, 2H) .
6.30. Synthesis of (S)-2-Amino-3-f4-f2-amino-6-f4-(2-(trifluoromethvnDhenyl)- pipericiin-l-vOpyrimidin-4-vOphenvDpropanoic acid
Figure imgf000072_0001
2- Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2- trifluoromethyl-phenyl)- piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H-O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210°C for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5 % methanol in CH2CI2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)- piperidin-l-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step.
The crude intermediate (0.42 g), L-p-borono-phenylalanine (0.209 g, 1 mmol), sodium carbonate (0.210 g, 2 mmol), and dichlorobis (triphenylphosphine)-palladium(II) (35 mg, 0.05 mmol) were dissolved in a mixture of MeCN (2.5 ml) and H2O (2.5 ml) in a 10 ml microwave vial. The vial was sealed and stirred in a microwave reactor at 1500C for 6 minutes. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOHZH2OZTFA as the solvent system to afford 2-amino-3-(4-{4-(2-trifluoromethyl-phenyl)-piperidine-l-yl]- pyrimidin-4yl}-phenyl)-propionic acid as a TFA salt. HPLC: Method A, Retention time = 3.203 min. LCMS M+l 486. 1H NMR (400 MHz, CD3OD) δ 1.80-2.20 (m, 5H), 3.0-3.16 (m,2H), 3.22-3.42 (m, 2H), 4.22(t, IH), 4.42-4.54 (m, IH), 5.22-5.34 (m. IH), 6.80(s, IH), 7.40(t, IH), 7.50-7.60(m, 4H), 7.68(d, IH), 7.82(d, 2H). 6.31. Synthesis of fSV2-Amino-3-(4-(2-amino-6-ffR)-l-fnaDhthalen-2- Λi>ethvIamino)pyrimidin-4-vI)phenyl)propanoic acid
Figure imgf000073_0001
2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), (R)-(+)-l-(2-naphthyl)- ethylamine (0.171 g, 1 mmol), and cesium carbonate (0.358 g, 1.1 mmol) were dissolved in a mixture of 1,4-dioxane (4 ml) and H2O (4 ml) in a 20 ml microwave vial. The vial was sealed and stirred at 21O0C for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml), dried (Na2SO4) and concentrated to afford the crude intermediate, 6-chloro-N-4-(naphthalene-2yl- ethyl)-pyrimidine-2,4-diamine (0.270 g) which was directly used in the following step. The crude intermediate (0.27 g), L-p-borono-phenylalanine (0.210 g, 1 mmol), sodium carbonate (0.210 g, 2 mmol), and dichlorobis(triρhenylphosphine)-palladium(II) (25 rag, 0.036 mmol) were dissolved in a mixture of MeCN (2.5 ml) and H2O (2.5 ml) in a microwave vial. The vial was sealed and stirred in the microwave reactor at 1500C for 6 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as the solvent system to afford 2 amino-3-{4-[2-amino-6-(l-naphthalen-2yl-ethylamino)- ρyrimidin-4-yl]-phenyl} -propionic acid as a TFA salt. HPLC: Method A, Retention time = 3.276 min. LCMS M+l 428. 1H NMR (400 MHz, CD3OD) δ 1.68 (d, 3H), 3.22-3.40 (m, 2H), 4.30(t, IH), 5.60 (q, IH), 6.42(s, IH), 7.42-7.54(m, 5H), 7.72(m, 2H), 7.82-7.84(m, 4H). 6.32. Synthesis of (SV2-Amino-3-(4-(2-amϊno-6-fmethyl(rRVl-fnaphthalen-2- yl)ethyl)amino)pyrimidin-4-vDphenvDpropanoic acid
Figure imgf000074_0001
2-Amino 4,6-dichloro pyrimidine (0.327 g, 2 mmol), methyl-(l-naphthalen-2yl- ethyl)-amine (0.360 g, 2 mmol), and cesium carbonate (0.717 g, 2.2 mmol) were dissolved in a mixture of 1,4-dioxane (7.5 ml) and H2O (7.5 ml) in a 20 ml microwave vial. The vial was sealed and stirred at 2100C for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO4) and concentrated to get the crude intermediate, 6-chloro-N-4-methyl-N-4-(l- napthalen-2-yl-ethyl)-pyrimidine-2,4-diamine (0.600 g), which was directly used in the following step.
The crude intermediate (0.30 g), L-p-borono-phenylalanine (0.210 g, 1 mmol), sodium carbonate (0.210 g, 2 mmol), and dichlorobis(triphenylphosphine)-palladium(II) (25 mg, 0.036 mmol) were dissolved in a mixture of MeCN (2.5 ml) and H2O (2.5 ml) in a microwave vial. The vial was sealed and stirred in the microwave reactor at 1500C for 6 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as the solvent system to afford 2-amino-3-(4-{2-amino-6-[methyl-(l-naphthalen-2yl- ethyl)amino]-pyrimidin-4yl}-phenyl)-propionic acid as a TFA salt (HPLC: Method C, Retention time = 2.945 min, LCMS M+l 442) 1H NMR (400 MHz, CD3OD) δ 1.70 (m, 3H), 2.92(s, 3H), 3.22-3.42(m, 2H), 4.28(m, IH), 6.60(s, IH), 6.72(m, IH), 7.40-7.92 (m, HH). 6.33. Synthesis of (S)-2-Amino-3-(4-(2-amino-6-((SV2.2.2-triπuoro-l-( 6- methoxynaphthaIen-2-y0ethoxy)pyrimidin-4-yl)phenyr)propanoic acid
Figure imgf000075_0001
2-Amino 4,6-dichloro pyrimidine (0.096 g, 0.6 mmol), 2,2,2-trifluoro-l-(6-methoxy- naphthalen-2-yl)-ethanol (0.140 g, 0.55 mmol), and NaH (96 mg, 0.60 mmol) were added to anhydrous dioxane (20 ml) under a nitrogen atmosphere. The reaction was stirred at 800C for 12 hours, cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated, and the residue dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO-O and concentrated to afford the crude intermediate, 4- chloro-6-[2,2,2-trifluoro-l-(6-methoxy-naphthalene-2-yl)-ethoxy]-pyrimidin-2-ylamine (0.22g) which was directly used in the following step.
The crude intermediate (0.22 g), L-p-borono-phenylalanine (0.126 g, 0.6 mmol), sodium carbonate (0.126 g, 1.2 mmol), and dichlorobis(triphenylphosphine)-palladium(II) (15 mg, 0.021 mmol) were dissolved in a mixture of MeCN (2.0 ml) and H2O (2.0 ml) in a microwave vial. The vial was sealed and stirred in the microwave reactor at 1500C for 6 minutes. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as the solvent system to afford 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-l-(6-methoxy- naphthalen-2-yl)-ethoxy]-pyrimidin-4-yl]-phenyl)-propionic acid as a TFA salt (HPLC: Method C, Retention time = 3.190 min. LCMS M+l 513. 1H NMR (400 MHz5 CD3OD) δ 3.22-3.42(m, 2H), 3.86(s, 3H), 4.32(1H), 6.88 (m, IH), 6.92(1H), 7.20(dd, IH), 7.26(s, IH), 7.50(d, 2H), 7.63(d, IH), 7.80-7.90(m, 4H), 8.05(s, IH). 6.34. Synthesis of (S>2-Amino-3-(4-(5-(biphenvI-4-ylmethylamino)pyrazin-2- vDphenvQpropanoie acid
Figure imgf000076_0001
4-Phenylbenzaldehyde (0.3 g, 1.65 mmol) and 2-amino-5-bromopyrazine (0.24 g, 1.37 mmol) were treated with Na(OAc)3BH (0.44 g, 2.06 mmol) in dichloroethane (7.0 mis) and acetic acid (0.25 mis) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N NaOH, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, EtOAc : Hex, 1:1) gave 0.18 g of N-(biphenyl-4- ylmethyl)-5-bromopyrazin-2-amine.
N-(biphenyl-4-ylmethyl)-5-bromopyrazm-2-amine (60 mg, 0.176 mmol), L-p- boronophenylalanine (37 mg, 0.176 mmol), palladiumtriphenylphosphine dichloride (3.6 mg, 0.0052 mmol), Na2CO3 (37 mg, 0.353 mmol), acetonitrile (1.25 mis) and water (1.25 mis) were heated in a microwave reactor at 1500C for 5 minutes. The mixture was concentrated, dissolved in 1.0 N HCl, washed twice with ether, concentrated and purified by preprative HPLC to give 41 mgs of the title compound. M+l = 425; 1H NMR (CD3OD) δ 8.42 (s, IH), 8.05 (s, IH), 7.92 (d, 2H), 7.58 (d, 4H), 7.40 (m, 7H), 4.60 (s, 2H)3 4.25 (m, IH), 3.40 (m, IH), 3.20 (m ,1H).
6.35. Synthesis of fS)-2-Amino-3-(4-(5-(naphthalen-2-ylmethyIamino)pyrazin-2- vDphenvDpropanoic acid
Figure imgf000076_0002
2-Napthaldehyde (0.6 g, 3.84 mmol) and 2-amino-5-bromopyrazine (0.56 g, 3.201 mmol) were treated with Na(OAc)3BH (1.02 g, 4.802 mmol) in dichloroethane (15.0 mis) and acetic acid (0.5 mis) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N NaOH, washed with brine, dried over MgSθ4, and concentrated. Chromatography (SiO2, EtOAc : Hex, 1 :1) gave 0.49 g 5-bromo-N- (naphthalen-2-ylmethyl)pyraziπ-2-amine.
5-Bromo-N-(naphthalen-2-ylmethyl)ρyrazin-2-amine (0.2 g, 0.637 mmol), L-p- boronophenylalanine (0.13 g, 0.637 mmol), palladiumtriphenylphosphine dichloride (13 mg, 0.019 mmol), Na2CO3 (0.13 g, 1.27 mmol), acetonitrile (5 mis) and water (5 mis) were heated in a microwave reactor at 1500C for 5 minutes. The mixture was concentrated, dissolved in 1.0 N HCl, washed twice with ether, concentrated, dissolved in methanol, filtered and concentrated to yield 0.12 g of the captioned compound. M+l = 399; 1H NMR (CD3OD) δ 8.51 (s, IH), 8.37 (s, IH), 7.90 (m, 6H), 7.50 (m, 5H), 4.85 (s, 2H), 4.30 (t, IH), 3.38 (m, IH), 3.22 (m5 IH).
6.36. Synthesis of fS)-2-(Tert-butoγvcarbonylaminoV3-f4-(5-fnaphthalen-2- ylmethylamino^pyrazin-2-vHphenyr)propanoic acid
Figure imgf000077_0001
(S)-2-Amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid (0.15 g, 0.345 mmol) was treated with triethylamine (87 mg, 0.S62 mmol), and boc- anhydride (84 mg, 0.379) in dioxane (3 ml) and H2O (3 ml) at 0°C. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and partitioned between EtOAc and H2O. The aqueous phase was acidified to pH = 1 with 1.0 N HCl and extracted with EtOAc. The organics were combined, washed with brine, dried over MgSO4, and concentrated to yield 48 mg of the captioned compound.
6.37. Synthesis of (S)-2-Morpholinoethyl 2-amino-3-(4-(S-(naphthaIen-2- vImethvIamino>pyrazin-2-yl)phenyr)propanoate
Figure imgf000077_0002
(S)-2-(Tert-butoxycarbonylamino)-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2- yl)phenyl)ρropanoic acid (48 mg, 0.090 mmol), 4-(2-hydroxyethyl)moφholine (12 mg, 0.090 mmol), triethylamine (18 mg, 0.180 ramol), and benzotriazole-l-yloxytris(dimethylamino)- phosphonium hexaflurophosphate (BOP, 18 mg, 0.090 πimol), in dichloromethane (3.0 ml) were stirred at room temperature for 5 hours. Additional triethylamine (18 mg, 0.180 mmol) and BOP (18 mg, 0.090 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated and purified via prep HPLC to give 2 mg of the captioned compound.
6-38. Synthesis of (2SV2-Amino-3-(4-(2-amino-6-f2,2.2-trifhioro-l-(3'- fluorobiphenvI-4-vilethoxy)pyrimidin-4-yl)phenvDpropanoic acid
Figure imgf000078_0001
To 4'-bromo-2,2,2-trifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50 mis) at 00C was added NaBH4 (1.5 g, 39.52 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was complete by TLC (CH2CI2). The mixture was quenched with H2O, rotary evaporated to remove most of the THF, and extracted 2 times with CH2CI2. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica was washed with CH2Cl2 to elute the product, and the resulting solution was concentrated to give 4.65 g of l-(4-bromophenyl)-2,2,2- trifluoroethanol. Yield 92 %.
To Pd(PPh3)4 (2.1 g, 1.823 mmol) was added 3-fluorophenylmagnesium bromide (55 mis, 1.0 M in THF, 55 mmol) at 00C over 15 minutes. The ice bath was removed and the mixture was stirred for 30 minutes. l-(4-Bromophenyl)-2,2,2-trifluoroethanol (4.65 g, 18.23 mmol) in THF (50 mis) was added over 10 minutes. The mixture was heated to reflux for 3 hours and was shown complete by LC (Sunure column, TFA). The mixture was cooled, quenched with H2O5 rotary evaporated to remove most of the THF, and extracted 3 times with CH2Cl2. The organics were combined washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2Cl2) gave 4.64 g of 2,2,2-trifluoro-l-(3'- fluorobiphenyl-4-yl)ethanol. Yield 94 %.
To 2,2,2-trifluoro-l-(3'-fluorobiphenyl-4-yl)ethanol (1.4 g, 5.18 mmol) in THF (50 mis) at 00C was added NaH (60 % in mineral oil, 0.31 g, 7.77 mmol). The ice bath was removed and the mixture was stirred for 30 minutes. 2-Amino-4,6-dichloropyrimidine (1.0 g, 6.22 mmol) in THF (25 mis) was added at once. The mixture was heated to 500C for 5 hours. The reaction was complete by LCMS (Sunfire, TFA). The mixture was cooled, quenched with brine, and extracted 3 times with CH2Cl2. The organics were combined, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2CI2) afforded 1.48 g of4-chloro-6-(2,2,2-trifluoro-l-(3'-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine. Yield 73%.
4-Chloro-6-(2,2,2-trifluoro- 1 -(3 l-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (0.75 g, 1.89 mmol), L-p-boronophenylalanine (0.47 g, 2.26 mmol), Pd(PPh3)2Cl2 (79 mgs, 0.113 mmol), Na2Cθ3 (0.44 g, 4.15 mmol), acetonitrile (10 mis), and H2O (10 mis) were combined in a 20 ml microwave reactor and heated in the microwave at 1500C for 7 minutes. The reaction was complete by LCMS (Sunfire, neutral). The mixture was concentrated, dissolved in NaOH (20 mis 0.5 N), filtered, extracted with ether three times, and cooled to 00C. At 0 0C, 1.0 N HCl was added slowly until a pH of 6.5 was attained. The mixture was stirred at 00C for 30 minutes and the product was filtered, dried in air, treated with excess 2.0 N HCl in ether, concentrated, then triturated with CH2Cl2 to give 1.12 g, 99% (95.5 % purity). 385 mgs were purified via prep HPLC (Sunfire, TFA), concentrated, treated with excess 1.0 N HCl (aq.), concentrated to a small volume and lyophilized to afford 240 mgs of the captioned compound. M+l = 527; 1H NMR δ (CD3OD) 7.86 (d, 2H), 7.64 (s, 4H), 7.49 (d, 2H)5 7.36 (m, 2H), 7.28 (m ,1H), 7.02 (m, IH), 6.95 (s, IH), 6.75 (q, IH), 4.26 (t, IH), 3.32 (m, IH), 3.21 (m, IH).
6.39. Synthesis of (SV2-Am-no-3-(4-(2-amino-6-(benzylth.o)pyrimidin-4- vDphenvDpropanoic acid
Figure imgf000079_0001
Benzylmercaptan (0.14g, 1.11 mmol) was treated with NaH (60% in mineral oil, 67 mg, 1.66 mmol) in dry THF (15 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (0.2 g, 1.22 mmol) was added and the mixture was stiired overnight. The mixture was diluted with methylenechloride, washed with water, then brine, dried over MgS O4, and concentrated to give 0.11 g of 4-(benzylthio)-6-chloropyrimidin-2 -amine.
4-(Benzylthio)-6-chloropyrimidin-2-amine (0.1 g, 0.397 mmol), L-p- boronophenylalanine (0.1 g, 0.477 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), Na2CO3 (93 mg, 0.874 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 1500C for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 0.42 g of the title compound. M+l = 381; 1H NMR (CD3OD) δ 7.8 (d, 2H), 7.37 (t, 4H), 7.23 (m, 2H), 7.16 (m, IH), 6.98 (s, IH), 4.43 (s, 2H), 4.20 (t, IH), 3.29 (m, IH), 3.13 (M, IH).
6.40. Synthesis of (S)-2-Amino-3-(4-(2-amino~6-(naphthalen-2- ylmethylthio^pyrimidin-4-yr)phenvT)propaiioie acid
Figure imgf000080_0001
2-Mercaptonapthalene (0.2 g, 1.148) was treated with NaH (60% in Mineral oil, 92 mg, 2.30 mmol) in dry THF (10 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (0.21 g, 1.26 mmol) was added and the mixture was stirred overnight. The mixture was diluted with methylenechloride, washed with water, then brine, dried over MgSO4, and concentratred to give 0.18 g 4-chloro-6-(naphthalen-2-ylmethylthio)pyrimidin-2-amine. 4-Chloro-6-(naphthalen-2-yhnethylthio)pyrimidin-2-amine (0.1 g, 0.331 mmol), L-p- boronophenylalanine (83 mg, 0.397 mmol), Pd(PPh3)2Cl2 (14 mg, 0.020 mmol), Na2CO3 (77 mg, 0.729 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 1500C for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 57 mg of the title compound. M+l = 431; 1H NMR (CD3OD) δ 7.85 (s, IH), 7.79 (d, 2H), 7.72 (d, 3H), 7.46 (dd, IH), 7.35 (m, 4H), 6.95 (s, IH), 4.58 (s, 2H), 4.17 (m, IH), 3.26 (m, IH), 3.11 (m, IH). 6.41. Synthesis of (2SV2- Amino-3-(4-(2-ammo-6-fl-(3,4-difluorophenyl)-2,2.2- trifluoroethoxv^pvriinidiii-4-vr)pb.envr)propanoic acid
Figure imgf000081_0001
3,5-Difluorophenyl-trifluoromethyl ketone was treated with NaBH4 (0.18 g, 4.76 mmol) in THF (5 ml) for 2 hours. The mixture was quenched with water, extracted with methylene chloride (2x). The organics were combined, filtered through silica gel and concentrated to give 0.46g of l-(3,4-difluorophenyl)-2,2,2-trifluoroethanol. l-(3,4-Difluoroρhenyl)-2,2,2-trifluoroethanol (0.1 g, 0.471 mmol) was treated with NaH (60% in mineral oil, 38 mg, 0.943 mmol) in dry THF (3 ml) for 30 minutes. 2-Amino- 4,6-dichloropyrimidine (77 mg, 0.471 mmol) was added and the mixture was stirred at 500C for 6 hours. The mixture was quenched with water and extracted with methylenechloride (2x). The organics were combined, washed with water, then brine, dried over MgS O4, and concentrated to give 0.14 g of 4-chloro-6-(l-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)- pyrimidin-2-amine. 4-Chloro-6-(l-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-2-amine (0.14 g,
0.421 mmol), L-p-boronophenylalanine (110 mg, 0.505 mmol), Pd(PPh3)2Cl2 (18 mg, 0.025 mmol), Na2CO3 (98 mg, 0.926 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 1500C for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 74 mg of the title compound. M+l = 469; 1H NMR (CD3OD) δ 7.83 (d, 2H), 7.47 (m, IH), 7.38 (m, 4H), 7.28 (m, IH), 4.21 (t, IH), 3.29 (m, IH), 3.15 (m, IH).
6.42. Synthesis of (2SV2-Amino-3-f4-(2-amino-6-f2.2.2-trifluoro-l-(3<- methvIbiphenvI-2-vDethoxy)Dyrimidin-4-yr)phenvI)propanoic acid
Figure imgf000081_0002
To 4'-bromo-2,2,2-txifluoroacetophenone (5.0 g, 19.76 mmol) in THF (50 mis) at 00C was added NaBH4 (1.5 g, 39.52 mmol). The mixture was warmed to room temperature and stirred for 1 hour. The reaction was complete by TLC (CH2Cl2). The mixture was quenched with H2O3 rotary evaporated to remove most of the THF, and extracted 2 times with CHaCl2. The organics were combined, washed with brine, concentrated to a small volume and filtered through a plug of silica gel. The silica was washed with CH2CI2 to elute the product, and the resulting solution was concentrated to give 4.65 g of l-(4-bromophenyl)-2,2,2- trifluoroethanoL Yield: 92 %. l-(4-Bromophenyl)-2,2,2-trifluoroethanol (0.13 g, 0.525 mmol), rø-tolylboronic acid (0.1 g, 0.736 mmol), Fibercat (4.28 % Pd, 47 mgs, 0.0157 mmol Pd), K2CO3 (0.22 g, 1.576 mmol), EtOH (3 mis), and H2O (0.5 mis) were combined and heated at 8O0C for 4 hours. The reaction was shown complete by TLC (CH2Cl2). The mixture was cooled, filtered, concentrated, slurried in CHaCl2, and chromatographed over silica gel (CH2Cl2) to give 0.1 g of2,2,2-trifluoro-l-(3'-methylbiphenyl-2-yl)ethanol. Yield: 72 %. Alternatively, l-(4-bromophenyl)-2,2,2-trifluoroethanol (0.98 g, 3.86 mmol), m- tolylboronic acid (0.63 g, 4.63 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.232 mmol Pd), Na2CO3 (0.90 g, 8.49 mmol), AcCN (10 mis), and H2O (10 mis) were combined and heated in the microwave at 1500C for 10 minutes. The reaction was shown complete by TLC (CH2CI2). The mixture was cooled, concentrated, slurried in CH2CI2, filtered, and chromatographed over silica gel (CH2Cl2) to give 0.80 g of 2,2,2-trifluoro-l-(3'-methylbiphenyl-2-yl)ethanol. Yield: 79 %.
Alternatively, tetrabutylammoniumfluoride (TBAF 1.0 N in THF 13 uL, 3.3 mg, 0.013 mmol) was added to a mixture of 3-methyl-biphenyl-2-carboxaldehyde (0.25g, 1.27 mmol) and trifluoromethytrimethyl silane (0.25 g, 1.53 mmol), in THF (1.5 ml) at 00C. The reaction was warmed to room temperature and stirred for 4 hours. HCl (3.0 N, 2.0 ml) was added, and the mixture was stirred for 3 hours. The mixture was concentrated, dissolved in methylene chloride, filtered through silica gel, and concentrated to give 0.15 g of 2,2,2- trifluoro-l-(3'-methylbiphenyl-2-yl)ethanol.
2,2,2-Trifluoro-l-(3'-methylbiphenyl-2-yl)ethanol (0.15 g, 0.563 mmol) was treated with NaH (60% in mineral oil, 45 mg, 1.12 mmol) in dry THF (5 ml) for 30 minutes. 2-
Amino-4,6-dichloropyrimidine (92 mg, 0.5633 mmol) was added and the mixture was stirred at 500C for 6 hours. The mixture was quenched with water and extracted wth methylenechloride (2x). The organics were combined, washed with water, then brine, dried over MgSO4, and concentrated to give 0.16 g of 4-chloro-6-(2,2,2-txifluoro-l-(3'- methylbiphenyl-2-yl)ethoxy)pyrimidin-2-amine.
4-Chloro-6-(2,2,2-trifluoro-l-(31-methylbiphenyl-2-yl)ethoxy)ρyrimidin-2-amine (0.16 g, 0.406 παmol), L-p-boronophenylalanine (10 mg, 0.487 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), Na2CO3 (95 mg, 0.894 mmol), MeCN (2.5 ml) and water (2.5 ml) were heated at 1500C for 5 minutes in a microwave. The mixture was concentrated and purified via prep HPLC to give 105 mg of the title compound. M+l = 523; 1H NMR (CD3OD) δ 7.85 (d, 2H)5 7.70 (d, IH), 7.44 (m, 4H), 7.31 (t, IH), 7.21 (m, 2H), 7.10 (m, 2H), 6.87 (q, IH), 6.84 (s, IH), 4.25 (t, IH), 3.30 (m, IH), 3.18 (m, IH).
6.43. Synthesis of fSV2-Amino-3-(4-(5-(3-(cvc.opentyloxyV4- methoxybenzyIamino)pyridin-3-v0phenvI)propanoic acid
Figure imgf000083_0001
Sodium triacetoxyl-borohydride (245mg, l.lδmmol) was added to the solution of 5- bromo-pyridine-3-amme(100mg, 0.57mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (127mg, 0.57mmol) in 10ml of 1 ,2-dicloroethtane (DCE), of HOAc (66μL, 2eq. 1.16mmol) was added, the mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water, and dried over sodium sulfate. The solvent was removed by under reduced pressure to give 200 mg of crude 5-bromo-N-(3- (cyclopentyloxy)-4-methoxybenzyl) pyridin-3-amine, which was used for the next step without further purification.
An Emrys process vial (2-5ml) for microwave was charged with 5-bromo-N-(3- (cyclopentyloxy)-4-methoxybenzyl)pyridin-3 -amine (40mg, 0.106mmol), 4-borono-L- phenylalanine (22mg, O.lOδmmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, IM) was added to above solution followed by 10 mol percent of dichlorobis (triphenylphosphine)-palladium QI). The reaction vessel was sealed and heated to 1800C for 10 minutes with a microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified with Prep-LC to give 20 mg of (S)-2-amino-3-(4-(5-3-(cyclophentyloxy-4-methoxy-benzylamino)pyridine-3-yl)ρhenyl)- propanoic acid. NMR: 1H-NMR (400 MHz, CD3OD): δ 1.59(m, 2H), 1.7 (m, 6H), 3.17(m, IH), 3.3 (m, IH), 3.75 (s, 3H), 4.2 (dd, IH) 4.39 (s, 2H), 4.7 (m, IH), 6.9(m, 3H)5 7.4(d, 2H), 7.6(d, 2H), 7.7(s, IH), 7.9 (s, IH), 8.15(s, IH); Analytical HPLC: RT 2.69; M+l: 462(RT: 1.285).
6.44. Synthesis of 2-Amino-3-(3-(4-amino-6-((RM-(naphthaIen-2- vI)ethylaminoVl.,3..5-triazin-2-yl')phenyr)propanoic acid
Figure imgf000084_0001
To a solution of tert-butyl 2-(diphenylmethylene-amino) acetate (400 mg, 1.35mmol) in THF (25ml) was added a solution of LDA (1.8M in THF, 2eq, 2.7mmol, fresh bottle from Aldrich) over 5 minutes at -78°C, and the resulting mixture was stirred for 20 minutes. A solution of 2-(3-(bromomethyl) phenyl)-5,5-dimethyl-l, 3, 2-dioxaborinane (460mg, 1.2eq. 1.62mmol) in THF (10ml) was added drop-wise to the reaction mixture over 5 minutes. The reaction was continued at same (-780C) temperature for 30 minutes, and left for 3 hours at room temperature. The reaction was quenched with saturated NH4Cl, followed by the addition of water (30ml), and was extracted with EtOAc (2x40ml). The organic fractions were combined and dried over Na2SO4. The solvent was then concentrated at reduced pressure and crude tert-Butyl-3-(3-(5, 5-dimethyl-l, 3, 2-dioxaborinan-2-yl)phenyl) 2(diphenylmethylene amino) propionate was purified by column chromatography to provide the product as a semi-solid. An Emrys process vial (20ml) for microwave was charged with (R)-6-chloro-N2-(l -
(naphthalene-2-yl)ethyl)-l,3,5-triazine-2,4-diamine (lOOmg, 0.33mmol), tert-butyl-3-(3-(5,5~ dimethyl- 1, 3, 2-dioxaborinan-2-yl)phenyl)-2-(diphenyl methyleneamino) propanoate (248mg, 0.5mmol, 1.5eq.) and 6ml of acetonitrile plus 6ml of aqueous sodium carbonate (IM) was added to above solution followed by 10 mol percent of dichlorobis(triphenylphosphine)- palladium(ϋ). The reaction vessel was sealed and heated to 1900C for 10 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 10 ml of THF, to which was added 5N.HC1 (5ml). The mixture was refluxed for 2 hours in order to deprotect the benzophone and tert-butyl groups. The resulting reaction mixture was concentrated and dissolved in methanol (8ml) and purified with Prep-LC to afford 15mg of2-amino-3-(4(4-amino-6-((R)-l-(naphthalene-2-yl)ethylamino)-l,3,5-trizin-2- yl)phenyl)proρanoic acid. NMR: 1H-NMR (400 MHz, CD3OD): δ 1.85(d, 3H), 3.2-3.45 (m, 2H), 4.37(m, IH), 5.5 (in, IH), 7.4(m, IH), 7.6(m 4H), 7.9(m, 4H), 8.18(m, 2H), Analytical HPLC: RT 2.79 M+l: 429 (RT: 1.35).
6.45. Synthesis of 2-Amino-3-(4-(4-amino-6-((R)-l-(naphthaIen-2- yl)ethylamino)-l,3,5-triazin-2-yl)-2-fluorophenvπpropanoic acid
Figure imgf000085_0001
To a solution of tert-butyl 2-(diphenylmethylene-amino) acetate (l.lg, 3.73mmol) in THF (30ml) was added a solution of LDA (1.8M in THF, leq, 3.73mmol, fresh bottle from Aldrich) over 5 minutes at -78°C, and the resulting mixture was stirred for 20 minutes. A solution of 4-bromo-l-(bromomethyl)-2-fluorobenezene (Ig, 3.74mmol) in THF (10ml) was added drop-wise to the reaction mixture over 5 minutes. The reaction was continued at -78°C for 30 minutes, after which it was left at room temperature for 3 hours. The reaction was quenched with saturated NH4Cl, after which water (30ml) was added. Product was extracted with EtOAc (2x40ml), and the organic fractions were combined and dried over Na2SO4. The solvent was concentrated at reduced pressure and crude tert-Butyl 3-(4-bromo-2- fluorophenyl)-2-(diphenylmethyleneamino)-propanoate was purified by column chromatography. The product was obtained as a solid.
An Emrys process vial (20ml) for microwave was charged with tert-bυty\ 3-(4- bromo-2-fiuorophenyl)-2-(diphenyhnethyiene-amino)propanoate (600mg, 1.24mmol),
Pd(dba)2 (71mg, 0.124mmol), PCy3 (35mg, 0.124mmol), 4,4,4l,4l,5,5,5l,5'-octamethyl-2,21- bi(l,3,2-dioxaborolane (346mg, l.leq. 1.36mmol) and KOAc (182mg, 1.5eq., 1.86mmol) 20ml of DMF. The reaction vessel was sealed and heated to 1600C for 20 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in H2O (30ml), extracted with EtOAc (2x40ml), and purified with Prep-LC to give 220mg of tert-butyl 2-(diphenylmethyleneamino)-3-(2-fluoro- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propanoate. An Emrys process vial (5ml) for microwave was charged with (R)-6-chloro-N2-(l- (naphthalene-2-yl)ethyl)-l,3,5-triazine-2,4-diamine (67mg, 0.22mmol), ter^-butyl-2- (diphenylmethyleneamino)-3-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ρropanoate (120mg, 0.22mmol) and 2ml of acetonitrile. Aqueous sodium carbonate (2 ml, IM) was added to above solution followed by 10 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 1900C for 10 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 10 ml of THF, to which 5N.HC1 (2ml) was then added. The mixture was refluxed for 2 hours (deprotection of benzophone and tert-butyl groups). After deprotection of two groups, the mixture was concentrated, dissolved in methanol (5ml), and purified with Prep-LC to afford lOmg of 2-amino-3-(4-(4-amino-6-((R)- 1 -(naρhthalene-2-yl)ethylamino)- 1 ,3,5-trizin-2-yl)-2-fluorophenyl)propanoic acid. NMR: 1H-NMR (400 MHz, CD3OD): δ 1.6 (d, 3H), 3.07 (m, IH), 3.45(m, IH), 3.8 (m, IH), 5.45 (m, IH), 7.4(m, 4H), 7.6(m IH), 7.8(m, 4H), 8.08(m, IH), Analytical HPLC: RT 2.88, M+l: 447 (RT: 1.44).
6.46. Synthesis of (2SV2-Amino-3-(4-(4-amino-6-(l-fadamantvIl)ethylamino)- 1.3,5-triazin-2-vI)phenyl)propanoic acid
Figure imgf000086_0001
A solution of adamantine amine (1 equivalent), 2-amino-4,6-dichloro-[ 1,3,5] triazine (1 equivalent) and diisopropyl ethyl amine (5 equivalents, Aldrich) in anhydrous 1,4-dioxane was refluxed at 130°C for 3 hours. After completion of the reaction, the dioxane was removed under reduced pressure. The reaction was then cooled to room temperature, water was added, and product was extracted with dichloromethane (2x40ml). The combined organic solution was dried over Na2SO4 and concentrated to afford product, which was used in the next step without purification.
An Emrys process vial (20ml) for microwave was charged with adamantine trizine chloride (200mg, 0.65mmol), 4-borono-L-phenylalanine(135mg, 0.65mmol) and 5ml of acetonitrile. Aqueous sodium carbonate (5 ml, IM) was added to above solution followed by 5 mol percent dichlorobis(triphenylphosphine)-palladiurn(II). The reaction vessel was sealed and heated to 1900C for 20 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 4 ml of methanol and purified with Prep-LC to give 60 mg (yield 21%) of coupled product. NMR: 1H-NMR (400 MHz, CD3OD): δ 1.22 (m, 3H), 1.6-1-8 (m, 12H), 2.01(d, 3H), 3.25-3.42 (m, 2H), 4.0 (m, IH), 4.40(m, IH), 7.6(d, 2H), 8.2(d, 2H), Analytical HPLC: RT 3.11, M+l: 437 (RT: 1.76).
6.47. Alternative Synthesis of (2SV2-Amino-3-(4-(4-amino-6-(l-
(adamantyl0ethylamino)-l,3,5-triazin-2-yl)phenyl)propanoic acid Adamantane (2-yl) ethyl cyanoguanidine was prepared by forming a solution of cyanoguanidine (1 equivalent), (S)-2-amino-3-(4-cyanophenylpropanoic acid (1 equivalent) and potassium tertiary butaoxide (3.5 equivalent, Aldrich) in dry n-BuOH, which was vigorously refluxed at 1600C in a sealed tube for 2 days. After completion of the reaction, the mixture was allowed to cool to room temperature, and the reaction was quenched with water. Solvent was removed under reduced pressure. Again, after allowing to cool to room temperature, the reaction mixture was brought to pH 12-14 by adding IN NaOH. Then, impurities were removed while extracting with EtheπEtOAc (9:1, 2x100 ml). The aqueous solution was cooled to 00C, IN HCl was then added to adjust pH to 7. The pale yellow product was slowly crashed out in H2O, the mixture was kept in a refrigerator for 30 minutes, and the solid was obtained by filtration with 92% purity. Compound was crystallized from MeOH to afford a white solid (>98% pure, 48-78% yield). 1H-NMR (400 MHz, CD3OD): δ 1.0(d, 3H), 1.45-L6(m, 6H), 4.62-4.8(m, 4H) 2.0 (m, 2H), 3.3(m, IH), 3.5 (m, IH); Analytical HPLC: RT 2.69; M+l : 462(RT: 1.285).
The title compound was prepared from adamantane (2-yl) ethyl cyanoguanidine using the method shown in Scheme 6. 6.48. Synthesis of (S)-2-Amino-3-(4-(5-fluoro-4-((R)-l-(naphthalen-2- yr)ethylamino)pyrimidin-2-vQphenyl)propanoic acid
Figure imgf000088_0001
A mixture of (R)-(+)-l-(2-napthyl)ethylamine (102.6mg, 0.599mmol), 2,4-dichloro-5- fluroro pyrimidine (lOOmg, 0.599mmol) and cesium carbonate (390mg, 1.2mmol) was dissolved in 1,4-dioxane (3ml) and H2O (3ml) in a 10 ml microwave vial. The mixture was stirred in the microwave reactor at 8O0C for 10 minutes. The residue was dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO4) and concentrated to get the crude intermediate 2-chloro-5-fluoro-pyrimidin-4-yl)-(l-naphthalen-2-yl-ethyl)- amine.
The crude intermediate (250mg, 0.83mmol) was then dissolved in 6.0ml of MeCN and 6ml OfH2O in a 20ml microwave vial. To this solution were added L-p-borono- phenylalanine (173.6mg, 0.83mmol), sodium carbonate (173.6mg, 1.66mmol) and catalytic amount of dichlorobis(triphenylphosphine)-palladium(II) (11.6mg, 0.0166mmol). The reaction vial was then sealed and stirred in the microwave reactor at 1500C for 7 minutes.
The contents were then filtered, and the filtrate was concentrated and dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using MeOH/H2O/TFA as the solvent system. The combined pure fraction were evaporated in vacuo and further dried on a lyophilizer to give 154mg of 2-amino-3- {4-[5-fluoro-4-(l -naphthalen-2-yl-ethylamino)-pryrimidin-2-yl]- phenyl}-propionic acid. NMR: 1H-NMR (400 MHz, CD3OD) δ 1.8(d, 3H) 3.2-3.4(m, 2H), 4.35(m, IH), 5.7(q, IH), 7.5(m, 4H), 7.6(d, IH), 7.8-7.9(m, 4H), 8.1(d, 2H), 8.3(d, IH). LCMS: M+l= 431. 6.49. Synthesis of (St-2-Ammo-3-(4-(2-ammo-6-f4-ftrifluoromethylV benzvIammo^pvrimidin-4-vDphenvπpropanoic acid
Figure imgf000089_0001
A mixture of trifluoromethyl benzylamine (106.8mg, O.βlOmmol), 2-amino-4,6- dichloropyrimidine (lOOmg, O.όlOmmol) and cesium carbonate (217mg, 1.2mmol) was dissolved in 1,4-dioxane (6ml) and H2O (6ml) in a 20 ml microwave vial. The mixture was stirred in the microwave reactor at 2100C for 25 minutes. The solvent was then removed. The residue was dissolved in CH2CI2 (50 ml), washed with water (20 ml), brine (20 ml), dried (Na2SO^ and concentrated to get the crude intermediate 6-chloro-N-4'-(trifluoromethyl- benzyl)-pryrimidine-2-4-diamine.
The crude intermediate (150mg, 0.497mmol) was then dissolved in 3.0ml of MeCN and 3ml OfH2O in a 10 ml microwave vial. To this solution were added L-p-borono- phenylalanine (104mg, 0.497mmol), sodium carbonate (150mg, 0.994mmol) and catalytic amount of dichlorobis(triphenylphosphine)-palladium(π) (6.9mg, 0.00994mmol). The reaction vial was then sealed and stirred in the microwave reactor at 1500C for 5 minutes.
The contents were filtered, and the filtrate was concentrated and dissolved in MeOH and H2O (1:1) and purified by preparative HPLC using a MeOH/H2O/TFA solvent system. The combined pure fractions were evaporated in vacuo and further dried on a lyophilizer to afford 2-amino-3-{4-[2-amino-6-(4-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-phenyl}- propionic acid. NMR: 1H-NMR (300MHz, CD3OD) δ 3. l-3.3(m, 2H), 4.2(t, IH), 4.7(s, 2H), 6.3(s, IH), 7.4-7.5(m, 4H), 7.6(d, 2H), 7.7(d, 2H). LCMS: M+l=432.
6.50. Synthesis of 2-Ammo-3-(5-(5-phenylth.ophen-2-yl)-lH-indol-3- vDpropanoic acid
Figure imgf000089_0002
SS 2-Amino-3-(5-bromo-lH-indol-3-yl)-propionic acid (0.020 g, 0.071 mmol) was added to a 5 ml microwave vial, which contained 5-phenyl-thiophen-2-boronic acid (0.016 g, 0.078mmol), Na2CO3 (0.015 g, 0.142 πrmol). acetonitrile (1.5 ml) / water (1.5 ml) and dichlorobis(triphenylphosphine)-palladium (3 mg, 0.003 mmol). Microwave vial was capped and stirred at 150°C for 5 min under microwave radiation. Reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparative-HPLC using YMC-Pack ODS 100x30 mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were concentrated in vacuum. The product was then suspended in 5 ml of water, frozen and lyophilized to give 5 mg of pure product, 2-amino-3-[5-(5-phenyl-thiophen-2-yl)- lH-indol-3-yl]-propionic acid. IH-NMR (300 MHz, CD3OD): 3.21-3.26 (m, 2H), 4.25 (q, IH), 7.15-7.35 (m, 8H), 7.58 (d, 2H), 7.82 (d, IH).
6.51. Synthesis of (S)-2-Amino-3-(4-(4-f4-phenoxyphenyl)-lH-l.,2.3-triazol-l- vDphenvDpropanoic acid
Figure imgf000090_0001
A mixture of l-ethynyl-4-phenoxy-benzene (126mg, O.65mmol) and (S)-3-(4-azido- phenyl)-2-tert-butoxycarbonylamino-propionic acid (200mg, 0.65mg) in H2θ:dioxane (5:1) was heated at 1000C in a sealed tube for overnight. After completion of reaction, 3N HCl (5 ml) was added and the mixture was stirred for 2hr at 500C. Removal of solvent gave crude product which was dissolved in MeOH and purified by preparative HPLC to give 45 mg of desired product (yield: 29%). 1H-NMR (400 MHz, CD3OD): δ (ppm) 3.2 (m, IH), 3.4 (m, IH), 4.3(m, IH), 6.9(d, 2H), 7.0(d, 2H), 7.2(m, IH), 7.3(d, 2H), 7.4-7.55 (m, 6H), 8.0(s, IH).
6.52. Synthesis of (S)-2-Amino-3-(4-(4-(4-(thiophene-2-carboxamido)phenyl)- lH-1.2.3-triazoI-l-yl)phenvπpropanoic acid and (SV2-Amino-3-(4-(5-f4- (thiophene-2-carboxamido')phenylMH-l,2,3-triazol-l- yQphenvDpropanoie acid
Figure imgf000091_0001
A mixture of thiophene-2-carboxylic acid (4-ethyl-phenyl) amide (117mg, 0.49mmol) and (S)-3-(4-azido-phenyl)-2-tert-butoxycarbonylamino-propionic acid (150mg, 0.49mg) in 5 ml of E^Oidioxane (5:1) was heated at 1000C in a sealed tube overnight. After completion of reaction, 3N HCl (5 ml) was added and the mixture was stirred for 2hr at 500C. Removal of solvent gave crude product which was dissolved in MeOH and purified by preparative HPLC. According to LCMS (retention time) and NMR, two regio-isomers were obtained (total yield: 70mg, 66%). The major product is (S)-2-amino-3-(4-(4-(4-(thiophene-2- carboxamido)phenyl)-lH-l,2,3-triazol-l-yl)phenyl)propanoic acid. NMR: 1H-NMR (400 MHz, CD3OD): δ 3.2 (m, IH), 3.4 (m, IH), 4.3(m, IH), 7.15(m, IH), 7.3(d, 2H), 7.6(m, 4H), 7.0(m, 3H), 7.95 (d, IH), 8.0(s, IH). The minor product is (S)-2-amino-3-(4-(5-(4- (thiophene-2-carboxamido)phenyl)-lH-l,2,3-triazol-l-yl)phenyl)propanoic acid. 1H-NMR (400 MHz, CD3OD): δ 3.2 (m, IH), 3.4 (m, IH), 4.35(m, IH), 7.2(m, IH)9 7.3(d, 2H), 7.5- 7.6(m, 4H), 7.75(m, 3H), 7.95 (d, IH), 8.05(s, IH).
6.53. Synthesis of (SV2-Amino-3-f4-(2-amino-6-(phenylethvnyr>pyrimidin-4- vDphenvDpropanoic acid
Figure imgf000091_0002
2- Amino 4,6-dichloro pyrimidine (0.180 g, 1.1 mmol), trimethyl-phenylethynyl- stannane (0.264 g, 1 mmol), were dissolved in THF (20 ml) and the mixture was stirred at 65°C for 12h. LCMS indicated the completion of reaction. Solvent was removed and the residue was directly used in the following step.
The crude intermediate (0.42 g), L-p-borono-phenylalanine (0.210 g, 1 mmol), sodium carbonate (0.210 g, 2 mmol), and dichlorobis (triphenylphosphine)-palladium(II) (25 mg, 0.036 mmol) were dissolved in a mixture of MeCN (3 ml) and H2O (3 ml) in a 10 ml microwave vial. The vial was sealed and stirred in the microwave reactor at 1500C for 6 min. The mixture was filtered and the filtrate was concentrated. Residue was purified by preparative HPLC using MeOH/H2O/TFA as solvent system to obtain (S)-2-amino-3-[4-(2- amino-6-phenylethynyl-pyrimidin-4-yl(-phenyl]-propionic acid as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ (ppm) 3.20-3.42 (m, 2H), 4.31 (m, IH), 7.40-7.51 (m, 6H), 7.62 (d, 2H), 8.18 (d, 2H).
6.54. Additional Compounds
Additional compounds prepared using methods known in the art and/or described herein are listed below:
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
6.55. In Vitro Inhibition Assays
Human TPHl, TPH2, tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PH) were all generated using genes having the following accession numbers, respectively: X52836, AY098914, X05290, and U49897.
The full-length coding sequence of human TPHl was cloned into the bacterial expression vector pET24 (Novagen, Madison, WI, USA). A single colony of BL21(DE3) cells harboring the expression vector was inoculated into 50 ml of L broth (LB)- kanamycin media and grown up at 37°C overnight with shaking. Half of the culture (25 ml) was then transferred into 3 L of media containing 1.5% yeast extract, 2% Bacto Peptone, 0.1 mM tryptophan, 0.1 mM ferrous ammonium sulfate, and 50 mM phosphate buffer (pH 7.0), and grown to ODfioo = 6 at 37°C with oxygen supplemented at 40%, pH maintained at 7.0, and glucose added. Expression of TPHl was induced with 15% D-lactose over a period of 10 hours at 25°C. The cells were spun down and washed once with phosphate buffered saline (PBS).
TPHl was purified by affinity chromatography based on its binding to pterin. The cell pellet was resuspended in a lysis buffer (100 ml/20 g) containing 50 mM Tris-Cl, pH 7.6, 0.5 M NaCl, 0.1% Tween-20, 2 mM EDTA, 5 mM DTT, protease inhibitor mixture (Roche Applied Science, Indianapolis, IN, USA) and 1 mM phenylmethanesulfonyl fluoride (PMSF), and the cells were lyzed with a microfluidizer. The lysate was centrifuged and the supernatant was loaded onto a pterin-coupled sepharose 4B column that was equilibrated with a buffer containing 50 mM Tris, pH 8.0, 2 M NaCl, 0.1% Tween-20, 0.5 mM EDTA, and 2 mM DTT. The column was washed with 50 ml of this buffer and TPHl was eluded with a buffer containing 30 mM NaHCO3, pH 10.5, 0.5 M NaCl, 0.1% Tween-20, 0.5 mM EDTA, 2 mM DTT, and 10% glycerol. Eluted enzyme was immediately neutralized with 200 mM KH2PO4, pH 7.0, 0.5 M NaCl, 20 mM DTT, 0.5mM EDTA, and 10% glycerol, and stored at -800C.
Human tryptophan hydroxylase type II (TPH2), tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PAH) were expressed and purified essentially in the same way, except the cells were supplemented with tyrosine for TH and phenylalanine for PAH during growth.
TPHl and TPH2 activities were measured in a reaction mixture containing 50 mM 4- morpholinepropanesulfonic acid (MOPS), pH 7.0, 60 μM tryptophan, 100 mM ammonium sulfate, 100 μM ferrous ammonium sulfate, 0.5 mM tris(2-carboxyethyl)phosphine (TCEP), 0.3 mM 6-methyl tetrahydropterin, 0.05 mg/ml catalase, and 0.9 mM DTT. The reactions were initiated by adding TPHl to a final concentration of 7.5 nM. Initial velocity of the reactions was determined by following the change of fluorescence at 360 run (excitation wavelength = 300 nm). TPHl and TPH2 inhibition was determined by measuring their activities at various compound concentrations, and the potency of a given compound was calculated using the equation:
Figure imgf000105_0001
where v is the initial velocity at a given compound concentration C, v o is the v when C = 0, b is the background signal, D is the Hill slope which is approximately equal to 1, and Icso is the concentration of the compound that inhibits half of the maximum enzyme activity. Human TH and PAH activities were determined by measuring the amount Of3H2O generated using L-[3,4-3H]-tyrosine and L-[4-3H]-phenylalanine, respectively. The enzyme (100 nM) was first incubated with its substrate at 0.1 mM for about 10 minutes, and added to a reaction mixture containing 50 mM MOPS5 pH 7.2, 100 mM ammonium sulfate, 0.05% Tween-20, 1.5 mM TCEP, 100 μM ferrous ammonium sulfate, 0.1 mM tyrosine or phenylalanine, 0.2 mM 6-methyl tetrahydropterin, 0.05 mg/ml of catalase, and 2 mM DTT. The reactions were allowed to proceed for 10-15 minutes and stopped by the addition of 2 M HCl. The mixtures were then filtered through activated charcoal and the radioactivity in the filtrate was determined by scintillation counting. Activities of of compounds on TH and PAH were determined using this assay and calculated in the same way as on TPHl and TPH2.
6.56. Cell-Based Inhibition Assays
Two types of cell lines were used for screening: RBL2H3 is a rat mastocytoma cell line, which contains TPHl and makes 5-hydroxytrypotamine (5HT) spontaneously; BON is a human carcinoid cell line, which contains TPHl and makes 5-hydroxytryptophan (5HTP). The CBAs were performed in 96-well plate format. The mobile phase used in HPLC contained 97% of 100 mM sodium acetate, pH 3.5 and 3% acetonitrile. A Waters C18 column (4.6 x 50 mm) was used with Waters HPLC (model 2795). A multi-channel fluorometer (model 2475) was used to monitor the flow through by setting at 280 nm as the excitation wavelength and 360 nm as the emission wavelength. RBL CBA: Cells were grown in complete media (containing 5 % bovine serum) for
3-4 hours to allow cells to attach to plate wells (7K cell/well). Compounds were then added to each well in the concentration range of 0.016 μM to 11.36 μM. The controls were cells in complete media without any compound present. Cells were harvested after 3 days of incubation at 37°C. Cells were >95% confluent without compound present. Media were removed from plate and cells were lysed with equal volume of 0.1 N NaOH. A large portion of the cell lysate was treated by mixing with equal volume of IM TCA and then filtered through glass fiber. The filtrates were loaded on reverse phase HPLC for analyzing 5HT concentrations. A small portion of the cell lysate was also taken to measure protein concentration of the cells that reflects the cytotoxicity of the compounds at the concentration used. The protein concentration was measured by using BCA method.
The average of 5HT level in cells without compound treated was used as the maximum value in the IC50 derivation according to the equation provided above. The minimum value of 5HT is either set at 0 or from cells that treated with the highest concentration of compound if a compound is not cytotoxic at that concentration. BON CBA: Cells were grown in equal volume of DMEM and F12K with 5 % bovine serum for 3-4 hours (2OK cell/well) and compound was added at a concentration range of 0.07 μM to 50 μM. The cells were incubated at 37°C overnight. Fifty μM of the culture supernatant was then taken for 5HTP measurement. The supernatant was mixed with equal volume of IM TCA, then filtered through glass fiber. The filtrate was loaded on reverse phase HPLC for 5HTP concentration measurement. The cell viability was measured by treating the remaining cells with Promega Celltiter-Glo Luminescent Cell Viability Assay. The compound potency was then calculated in the same way as in the RBL CBA.
6.57. In Vivo Effects
The in vivo effects of a potent TPHl inhibitor of the invention were evaluated in several studies by determining the change of 5-HT levels in the intestines and brains of mice following oral administration of the compound.
The compound was formulated in different vehicles to provide either a suspension or solution. Generally, 14-week-old male C57 albino mice were dosed once daily by oral gavage at 5 ml/kg for four consecutive days. Five hours after the last dose, the animals were quickly sacrificed. Various regions of the intestinal tract and whole brain were taken and frozen immediately. 5-HT was extracted from the tissues and measured by HPLC. Blood samples were taken for exposure analysis.
The potent TPHl inhibitor was found to reduce 5-HT levels in both the small and large intestine, but not in the brain. In one study, the compound was formulated in H2O and administered to mice at four different dose levels: 15, 50, 150, and 500 mg/kg, once daily by oral gavage. As shown in Fig. 1, the compound caused significant reduction of 5-HT in the jejunum and ileum in a dose-dependent fashion. In the colon, statistically significant reduction of 5-HT was seen at the 50, 150, and 500 mg/kg/day dose levels. No significant change of 5-HT levels was observed in the brain at any of the dose levels.

Claims

CLAIMSWhat is claimed is:
1. A potent TPH 1 inhibitor of formula I :
Figure imgf000108_0001
I or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -O-, -S-, -C(O)-, -C(R4)=, =C(R4)-, -C(R3R4)-, -C(R4)==C(R4)-, -C≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-;
D is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
2. The potent TPHl inhibitor of claim 1, which is of formula 1(A):
Figure imgf000108_0002
1(A)
3. A potent TPHl inhibitor of formula II:
Figure imgf000109_0001
II or a pharmaceutically acceptable salt or solvate thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -O-, -S-, -C(O)-, -C(R4)=, ^=C(R4)-, -C(R3R4)-, -C(R4)^C(R4)-, -C≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(Q2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-; D is optionally substituted aryl or heterocycle;
E is optionally substituted aryl or heterocycle;
R1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;
R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; R5 is hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
4. The potent TPHl inhibitor of claim 3, which is of formula H(A):
Figure imgf000109_0002
H(A) 5. The potent TPHl inhibitor of claim 1 or 3, wherein A is optionally substituted cycloalkyl.
6. The potent TPHl inhibitor of claim 5, wherein the cycloalkyl is 6-membered.
1OS
7. The potent TPHl inhibitor of claim 5, wherein the cycloalkyl is 5-membered.
8. The potent TPHl inhibitor of claim 1 or 3, wherein A is optionally substituted aryl.
9. The potent TPHl inhibitor of claim 8, wherein the aryl is phenyl or napthyl.
10. The potent TPHl inhibitor of claim 1 or 3, wherein A is optionally substituted heterocycle.
11. The potent TPH 1 inhibitor of claim 105 wherein the heterocycle is 6- membered.
12. The potent TPHl inhibitor of claim 11, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
13. The potent TPHl inhibitor of claim 10, wherein the heterocycle is 5- membered.
14. The potent TPHl inhibitor of claim 13, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene, or furan.
15. The potent TPHl inhibitor of claim 1 or 3, wherein A is aromatic.
16. The potent TPHl inhibitor of claim 1 or 3, wherein A is not aromatic.
17. The potent TPHl inhibitor of claim 1 or 3, wherein A is an optionally substituted bicyclic moiety.
18. The potent TPHl inhibitor of claim 17, wherein the bicyclic moiety is indole, iso-indole, pyrrolo-pyridine, or napthylene.
19. The potent TPHl inhibitor of claim 3, which is of the formula:
Figure imgf000110_0001
wherein: each OfA1 and A2 is independently a monocyclic optionally substituted cycloalkyl, aryl, or heterocycle.
20. The potent TPHl inhibitor of claim 19, wherein Ai is optionally substituted cycloalkyl.
21. The potent TPHl inhibitor of claim 20, wherein the cycloalkyl is 6-membered.
22. The potent TPHl inhibitor of claim 20, wherein the cycloalkyl is 5-membered.
23. The potent TPHl inhibitor of claim 19, wherein Ai is optionally substituted aryl.
24. The potent TPHl inhibitor of claim 23, wherein the aryl is phenyl.
25. The potent TPHl inhibitor of claim 19, wherein Ai is optionally substituted heterocycle.
26. The potent TPHl inhibitor of claim 25, wherein the heterocycle is 6- membered.
27. The potent TPHl inhibitor of claim 26, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
28. The potent TPHl inhibitor of claim 25, wherein the heterocycle is 5- membered.
29. The potent TPHl inhibitor of claim 28, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene, or furan.
30. The potent TPHl inhibitor of claim 19, wherein A] is aromatic.
31. The potent TPHl inhibitor of claim 19, wherein A] is not aromatic.
32. The potent TPHl inhibitor of claim 19, wherein A2 is optionally substituted cycloalkyl.
33. The potent TPHl inhibitor of claim 32, wherein the cycloalkyl is 6-membered.
34. The potent TPHl inhibitor of claim 32, wherein the cycloalkyl is 5-membered.
35. The potent TPHl inhibitor of claim 19, wherein A2 is optionally substituted aryl.
36. The potent TPHl inhibitor of claim 35, wherein the aryl is phenyl.
37. The potent TPHl inhibitor of claim 19, wherein A2 is optionally substituted heterocycle.
38. The potent TPHl inhibitor of claim 37, wherein the heterocycle is 6- membered.
39. The potent TPHl inhibitor of claim 38, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
40. The potent TPHl inhibitor of claim 37, wherein the heterocycle is 5- membered.
41. The potent TPHl inhibitor of claim 40, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene, or furan.
42. The potent TPHl inhibitor of claim 19, wherein A2 is aromatic.
43. The potent TPHl inhibitor of claim 19, wherein A2 is not aromatic.
44. The potent TPHl inhibitor of claim 1 or 3, wherein D is optionally substituted aryl.
45. The potent TPHl inhibitor of claim 44, wherein the aryl is phenyl or napthyl.
46. The potent TPHl inhibitor of claim 1 or 3, wherein D is optionally substituted heterocycle.
47. The potent TPHl inhibitor of claim 46, wherein the heterocycle is 6- membered.
48. The potent TPHl inhibitor of claim 47, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
49. The potent TPHl inhibitor of claim 46, wherein the heterocycle is 5- rnembered.
50. The potent TPHl inhibitor of claim 49, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene, or furan.
51. The potent TPHl inhibitor of claim 1 or 3, wherein D is aromatic.
52. The potent TPHl inhibitor of claim 1 or 3, wherein D is not aromatic.
53. The potent TPHl inhibitor of claim 1 or 3, wherein D is an optionally substituted bicyclic moiety.
54. The potent TPHl inhibitor of claim 53, wherein the bicyclic moiety is indole, iso-indole, pyrrolo-pyridine, or napthylene.
55. The potent TPHl inhibitor of claim 3, wherein E is optionally substituted aryl.
I l l
56. The potent TPHl inhibitor of claim 55, wherein the aryl is phenyl or napthyl.
57. The potent TPHl inhibitor of claim 3, wherein E is optionally substituted heterocycle.
58. The potent TPHl inhibitor of claim 57, wherein the heterocycle is 6- membered.
59. The potent TPHl inhibitor of claim 58, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
60. The potent TPHl inhibitor of claim 57, wherein the heterocycle is 5- membered.
61. The potent TPHl inhibitor of claim 60, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene, or furan.
62. The potent TPHl inhibitor of claim 3, wherein E is aromatic.
63. The potent TPHl inhibitor of claim 3, wherein E is not aromatic.
64. The potent TPHl inhibitor of claim 3, wherein E is an optionally substituted bicyclic moiety.
65. The potent TPHl inhibitor of claim 64, wherein the bicyclic moiety is indole, iso-indole, pyrrolo-pyridine, or napthylene.
66. The potent TPHl inhibitor of claim 1 or 3, wherein Ri is hydrogen or optionally substituted alkyl.
67. The potent TPHl inhibitor of claim 1 or 3, wherein R2 is hydrogen or optionally substituted alkyl.
68. The potent TPHl inhibitor of claim 1 or 3, wherein n is 1 or 2.
69. The potent TPHl inhibitor of claim 68, wherein n is 1.
70. The potent TPHl inhibitor of claim 1 or 3, wherein X is a bond or S.
71. The potent TPHl inhibitor of claim 1 or 3, wherein X is -C(R4)=, =C(R4)-,
-C(R3R4)-, -C(Rt)=C(R4)-, or -C=C-.
72. The potent TPHl inhibitor of claim 71, wherein each R4 is independently hydrogen or optionally substituted alkyl.
73. The potent TPHl inhibitor of claim 1 or 3, wherein X is -O-, -C(R3IU)CK or -OC(R3R4)-.
74. The potent TPHl inhibitor of claim 73, wherein R3 is hydrogen or optionally substituted alkyl, and R4 is hydrogen or optionally substituted alkyl.
75. The potent TPHl inhibitor of claim 74, wherein R3 is hydrogen and R4 is trifluromethyl.
76. The potent TPHl inhibitor of claim 1 or 3, wherein X is -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-.
77. The potent TPHl inhibitor of claim 76, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl, and R5 is hydrogen or optionally substituted alkyl.
78. The potent TPHl inhibitor of claim 1 or 3, wherein X is -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, Or -N(R5)C(R3R4)-.
79. The potent TPHl inhibitor of claim 78, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl, and each R5 is independently hydrogen or optionally substituted alkyl.
80. The potent TPHl inhibitor of claim 3, which is stereomerically pure and of the formula:
Figure imgf000114_0001
81. The potent TPHl inhibitor of claim 80, wherein R3 is trifluoromethyl.
82. The potent TPHl inhibitor of claim 3, which is stereomerically pure and of the formula:
Figure imgf000115_0001
83. The potent TPHl inhibitor of claim 82, wherein R3 is hydrogen.
84. The potent TPHl inhibitor of claim 3, which is of the formula:
Figure imgf000115_0002
wherein: each of Z], Z2, Z3, and Z4 is independently N or CRe; each R6 is independently hydrogen, cyano, halogen, OR7, NRgR9, amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; and m is 1-4.
85. The potent TPHl inhibitor of claim 84, which is of the formula:
Figure imgf000115_0003
86. The potent TPHl inhibitor of claim 84, which is stereomerically pure and of the formula:
Figure imgf000116_0001
87. The potent TPHl inhibitor of claim 86, wherein R3 is trifluoromethyl.
88. The potent TPHl inhibitor of claim 84, which is stereomerically pure and of the formula:
Figure imgf000116_0002
89. The potent TPHl inhibitor of claim 88, wherein R3 is hydrogen.
90. The potent TPHl inhibitor of claim 84, wherein all of Zi, Z2, Z3, and Z4 are N.
91. The potent TPHl inhibitor of claim 84, wherein only three of Z1, Z2, Z3, and
Z4 are N.
92. The potent TPHl inhibitor of claim 84, wherein only two of Zi, Z2, Z3, and Z4 are N.
93. The potent TPHl inhibitor of claim 84, wherein only one of Zj, Z2, Z3, and Z4 is N.
94. The potent TPHl inhibitor of claim 84, wherein none of Zi, Z2, Z3, and Z4 are
N.
95. The potent TPHl inhibitor of claim 3, which is of the formula:
Figure imgf000117_0001
wherein: each of Z\, Z'2, and Z'3 is independently N, NH, S, O or CR6; each Re is independently amino, cyano, halogen, hydrogen, OR7, SR7, NRsRci, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Rβ is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Rg is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; and p is 1-3.
96. The potent TPH 1 inhibitor of claim 95, which is of the formula:
Figure imgf000117_0002
97. The potent TPHl inhibitor of claim 95, which is stereomerically pure and of the formula:
Figure imgf000117_0003
98. The potent TPHl inhibitor of claim 97, wherein R3 is trifluoromethyl.
99. The potent TPHl inhibitor of claim 95, which is stereomerically pure and of the formula:
Figure imgf000118_0001
100. The potent TPHl inhibitor of claim 99, wherein R3 is hydrogen.
101. The potent TPHl inhibitor of claim 95, wherein all three of Z'I, Z'2, and Z'3 are N or NH.
102. The potent TPHl inhibitor of claim 95, wherein only two of Z'I, Z'2, and Z'3 are N or NH.
103. The potent TPHl inhibitor of claim 95, wherein only one of Z'i, Z'2> and Z'3 is
N or NH.
104. The potent TPHl inhibitor of claim 95, wherein none of Z'i, Z'2, and Z'3 are N or NH.
105. The potent TPHl inhibitor of claim 3, which is of the formula:
Figure imgf000118_0002
wherein: each of Z"i, Z"2, Z"3, and Zπ 4 is independently N or CRi0; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR12R13, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri _ is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; and each Ri 3 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle.
106. The potent TPHl inhibitor of claim 105, which is of the formula:
Figure imgf000119_0001
107. The potent TPHl inhibitor of claim 105, which is stereomerically pure and of the formula:
Figure imgf000119_0002
108. The potent TPHl inhibitor of claim 107, wherein R3 is trifluoromethyl.
109. The potent TPHl inhibitor of claim 105, which is stereomerically pure and of the formula:
Figure imgf000120_0001
110. The potent TPHl inhibitor of claim 109, wherein R3 is hydrogen.
111. The potent TPHl inhibitor of claim 105, wherein all of Z"i, Z"2, Z"3, and Z"4 are N.
112. The potent TPHl inhibitor of claim 105, wherein only three of Z"u Z"2, Z"3, and Z"4 are N.
113. The potent TPHl inhibitor of claim 105, wherein only two of Z"u Z"2, Z"3, and Z"4 are N.
114. The potent TPHl inhibitor of claim 105, wherein only one of Z"u Z"2, Z"3, and Z"4 is N.
115. The potent TPHl inhibitor of claim 105, wherein none of Z"u Z"2, Z"3, and Z"4 are N.
116. The potent TPHl inhibitor of claim 3, which is of the formula:
Figure imgf000120_0002
wherein: each of Z"l5 Z"2, Z"3, and Z"4 is independently N or CR1Q; each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NR12Rn, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R11 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Ri 2 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; and each Ri 3 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle.
117. The potent TPHl inhibitor of claim 116, which is of the formula:
Figure imgf000121_0001
118. The potent TPHl inhibitor of claim 116, which is stereomerically pure and of the formula:
Figure imgf000121_0002
119. The potent TPHl inhibitor of claim 118, wherein R3 is trifluoromethyl.
120. The potent TPHl inhibitor of claim 116, which is stexeomerically pure and of the formula:
Figure imgf000122_0001
121. The potent TPHl inhibitor of claim 120, wherein R3 is hydrogen.
122. The potent TPHl inhibitor of claim 116, wherein all of Z"u Z"2, Z"3> and Z"4 are N.
123. The potent TPHl inhibitor of claim 116, wherein only three of Z"i, Z"2, Z"3, and Z"4 are N.
124. The potent TPHl inhibitor of claim 116, wherein only two of Z"u Z"2, Z"3, and Z"4 are N.
125. The potent TPHl inhibitor of claim 116, wherein only one of Z"i, Z"2, Z"3, and Z"4 is N.
126. The potent TPHl inhibitor of claim 116, wherein none of Z"u Z"2, Z"3, and Z"4 are N.
127. A compound of the formula:
Figure imgf000122_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -O-, -S-, -C(O)-, -C(R4)=, K^(R4)-, -C(R3R4)-, -C(RO=C(R4)-, -OC-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or
-S(O2)C(R3R4)-; E is optionally substituted aryl or heterocycle;
R1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;
R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and each Rio is independently amino, cyano, halogen, hydrogen, OR11, SRj1, NR12Rn, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri 1 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Ri 3 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; n is 0-3; and q is 1-2.
128. A compound of the formula:
Figure imgf000123_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond, -O-, -S-, -C(O)-, -C(R4)=, =C(R4)-, -C(R3R4)-, -C(RO=C(R4)-, -C≡C-,
-N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-;
E is optionally substituted aryl or heterocycle; Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;
R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each Rs is independently hydrogen or optionally substituted alkyl or aryl; and each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRi 1, NR12R13, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Ri 2 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; n is 0-3; and q is 1-2.
129. A compound of the formula:
Figure imgf000124_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond, -O-, -S-, -C(O)-, -C(R4)=, ^=C(R4)-, -C(R3R4)-, -COfU)=C(R4)-, -O≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-;
E is optionally substituted aryl or heterocycle;
R1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and each Rio is independently amino, cyano, halogen, hydrogen, ORn, SRn, NRi2Ru, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri 1 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; n is 0-3; and r is 1-3.
130. A compound of the formula:
Figure imgf000125_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -O-, -S-, -C(O)-, -C(R4)=, ^C(R4)-. -C(R3R4)-, -C(Rt)=C(R4)-, -C=C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-;
E is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;
R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and each R1O is independently amino, cyano, halogen, hydrogen, ORn, SR11, NR12R13, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each Ri 1 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Ri 2 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; and n is 0-3.
131. The compound of one of claims 127- 130, wherein A is optionally substituted cycloalkyl.
132. The compound of claim 131, wherein the cycloalkyl is 6-membered.
133. The compound of claim 131, wherein the cycloalkyl is 5-membered.
134. The compound of one of claims 127-130, wherein A is optionally substituted aryl.
135. The compound of claim 134, wherein the aryl is phenyl or napthyl.
136. The compound of one of claims 127-130, wherein A is optionally substituted heterocycle.
137. The compound of claim 136, wherein the heterocycle is 6-membered.
138. The compound of claim 137, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
139. The compound of claim 136, wherein the heterocycle is 5-membered.
140. The compound of claim 139, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene, or furan.
141. The compound of one of claims 127-130, wherein A is aromatic.
142. The compound of one of claims 127-130, wherein A is not aromatic.
143. The compound of one of claims 127-130, wherein A is an optionally substituted bicyclic moiety.
144. The compound of claim 143, wherein the bicyclic moiety is indole;, iso-indole, pyrrolo-pyridine, or napthylene.
145. The compound of one of claims 127-130, wherein E is optionally substituted heterocycle.
146. The compound of claim 145, wherein the heterocycle is 6-membered.
147. The compound of claim 146, wherein the heterocycle is pyridine, pyridazine, pyrimidine, pyrazine, or triazine.
148. The compound of claim 145, wherein the heterocycle is 5-membered.
149. The compound of claim 148, wherein the heterocycle is pyrrole, imidazole, triazole, thiazole, thiophene, or furan.
150. The compound of one of claims 127-130, wherein E is aromatic.
151. The compound of one of claims 127-130, wherein E is not aromatic.
152. The compound of one of claims 127-130, wherein E is an optionally substituted bicyclic moiety.
153. The compound of claim 152, wherein the bicyclic moiety is indole, iso-indole, pyrrolo-pyridine, or napthylene.
154. The compound of one of claims 127-130, wherein R1 is hydrogen or optionally substituted alkyl.
155. The compound of one of claims 127-130, wherein R2 is hydrogen or optionally substituted alkyl.
156. The compound of one of claims 127-130, wherein n is 1 or 2.
157. The compound of claim 156, wherein n is 1.
158. The compound of one of claims 127-130, wherein X is a bond or S.
159. The compound of one of claims 127-130, wherein X is -C(R4)=, =C(R4)-, -C(R3R4)-, -C(R^=C(R4)-, or -C≡C-.
160. The compound of claim 159, wherein each R4 is independently hydrogen or optionally substituted alkyl.
161. The compound of one of claims 127- 130, wherein X is -O~, -C(R3R4)O-, or -OC(R3R4)-.
162. The compound of claim 161, wherein R3 is hydrogen or optionally substituted alkyl, and R4 is hydrogen or optionally substituted alkyl.
163. The compound of claim 162, wherein R3 is hydrogen and R4 is trifluromethyl.
164. The compound of one of claims 127-130, wherein X is -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)--
165. The compound of claim 168, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl, and each R5 is independently hydrogen or optionally substituted alkyl.
166. The compound of one of claims 127-130, wherein X is -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, or -N(R5)C(R3R4)-.
167. The compound of claim 166, wherein R3 is hydrogen or optionally substituted alkyl, R4 is hydrogen or optionally substituted alkyl, and R5 is hydrogen or optionally substituted alkyl.
168. The compound of one of claims 127-130, wherein both A and E are optionally substituted phenyl.
169. The compound of claim 168, wherein X is -O-, -C(R3R4)O-, or -OC(R3R4)-.
170. The compound of claim 169, wherein R3 is hydrogen and R4 is trifluromethyl.
171. The compound of claim 170, wherein n is 1.
172. The compound of claim 171, which is stereomerically pure.
173. The compound of one of claims 127- 130, which has a TPH 1 _IC5o of less than about 1 μM.
174. The compound of claim 173, which inhibits TPHl with an IC5O of less than about 500 nM.
175. The compound of claim 174, which has a TPHl-IC50 of less than about 250 nM.
176. A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:
(S)-2- Amino-3-(4-(4-arnmo-6-((R)- 1 -(naphthalen-2-yl)ethylamino)- 1 ,3 ,5-triazin-2- yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(4-amino-6-((4'-methylbiphenyl-4-yl)methylamino)-l,3,5-triazin-2- yl)phenyl)propanoic acid;
(S)-2- Amino-3 -(4-(4-morpholino-6-(naphthalen-2-ylmethylamino)- 1 ,3 , 5 -triazin-2- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2- (trifluoromethyl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2- Amino-3 -(4-(2-amino-6-(2,2,2-trifluoro- 1 -p-tolylethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2- Amino-3 -(4-(2-amino-6-( 1 -cyclohexyl-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(6-(2-fluorophenoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(4-(3-(4-chlorophenyl)piperidin-l-yl)-l,3,5-triazin-2- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-l-phenylethoxy)-l,3,5-triazin-2- yl)phenyl)propanoic acid; (S)-2-Amino-3-(5-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)-l,3,5-triazin-2- yl)ρyridin-2-yl)propanoic acid;
(S)-2-Amino-3-(3-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)-l,3,5-triazin-2- yl)-lH-pyrazol-l-yl)propanoic acid;
(S)-2-Amino-3-(4'-(3-(cyclopentyloxy)-4-methoxybenzylamino)biphenyl-4- yl)propanoic acid;
(S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyrazin-2- yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(5-((4'-methylbiphenyl-2-yl)methylamino)pyrazin-2- yl)phenyl)propanoic acid;
(2-S)-2-Amino-3 -(4-(6-(2,2,2-trifluoro- 1 -phenylethoxy)-pyrimidin-4- yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(6-(l-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-(3-(cyclopentyloxy)-4-methoxybenzylamino)-pyrazin-2- yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(5-((3-(cyclopentyloxy)-4-methoxybenzyl)-(methyl)amino)pyrazin-
2-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-((13-diiwethyl-lH-pyrazol-4-yl)methylainino)pyrazin-2- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(4-amino-6-((S)-l-(naphthalen-2-yl)ethylamino)-l,3,5-triazin-2- yloxy)phenyl)propanoic acid;
(S)-2-Ammo-3-(4-(4-amino-6-((R)-l-(biphenyl-2-yl)-2,2,2-trifluoroethoxy)-l,3,5- triazin-2-yl)phenyl)propanoic acid;
(2S)-2-Atnino-3-(4-(4-ammo-6-(l-(6,8-difluoronaphthalen-2-yl)ethylamino)-l,3,5- ' triazin-2-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro- 1 -(3 -methylbiphenyl-2-yl)ethoxy)-
1 ,3,5-triazin-2-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-(3,4-diniethoxyphenylcarbamoyl)-pyrazin-2- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-ainino-6-(4-(2-(trifluoroinethyl)phenyl)-piperidin-l- yl)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Ainino-3-(4-(2-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-Aπiino-3-(4-(2-amino-6-(methyl((R)-l-(naphthalen-2- yl)ethyl)amino)pyrimidin-4-yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(2-amino-6-((S)-2,2,2-trifluoro-l-(6-methoxyπaphthalen-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-(biphenyl-4-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid; (S)-2-(Tert-butoxycarbonylaniino)-3-(4-(5-(naphthalen-2-ylinethylamino)pyrazin-2- yl)phenyl)propanoic acid;
(S)-2-Mθφholinoethyl 2-amino-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2- yl)phenyl)propanoate; (2S)-2-Amino-3-(4-(2-ammo-6-(2,2,2-trifluoro-l-(3l-fluorobiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Ainino-3-(4-(2-ainino-6-(benzylthio)pyriini<iin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-(naphthalen-2-ylmethylthio)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(3,4-difluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-methylbiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(5-(3-(cyclopentyloxy)-4-methoxybenzylamino)pyridin-3- yl)phenyl)propanoic acid;
2-Amino-3-(3-(4-arnino-6-((R)-l-(naphthalen-2-yl)ethylarnino)-l,3,5-triazin-2- yl)phenyl)propanoic acid;
2-Amino-3-(4-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylainino)-l,3,5-triazin-2-yl)-2- fluorophenyl)propaπoic acid;
(2S)-2-Amino-3-(4-(4-amino-6-(l-(adamantyll)ethylam.ino)-l,3,5-triazin-2- yl)phenyl)proρanoic acid;
(S)-2-Amino-3-(4-(5-fluoro-4-((R)-l-(naphthalen-2-yl)ethylamino)pyrimidin-2- yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(2-amino-6-(4-(trifluoromethyl)-benzylamino)pyrimidin-4- yl)ρhenyl)proρanoic acid;
2-amino-3-(5-(5-phenylthiophen-2-yl)-lH-indol-3-yl)propanoic acid;
(S)-2-amino-3-(4-(4-(4-phenoxyphenyl)-lH-l,2,3-triazol-l-yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(4-(4-(thiophene-2-carboxamido)phenyl)-lH-l,2,3-triazol-l- yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(5-(4-(thiophene-2-carboxamido)phenyl)- IH- 1 ,2,3-triazol- 1 - yl)phenyl)propanoic acid;
(S)-2-amino-3-(4-(2-amino-6-(phenylethynyl)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-(2-fluoro-4,5-dimethoxybenzylamino)pyrazin-2- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-(4-(2-methoxyphenyl)piperidin-l-yl)pyrimidin-4- yl)phenyl)propaπoic acid; (S)-2-Amino-3-(4-(6-(3-(cyclopentyloxy)-4-methoxybenzylamino)-2- (dimethylamino)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-(3,4-dimethylbenzylamino)pyrazin-2-yl)phenyl)propanoic acid;
(S)-2-Ammo-3-(4-(5-(biphenyl-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid; (S)-Ethyl 2-amino-3-(4-(2-amino-6-(4-(tri£luoromethyl)benzylamino)pyrimidin-4- yl)phenyl)propanoate;
(S)-2-Atnino-3-(4-(5-(cyclopentylmethylaniino)pyrazin-2-yl)phenyl)propanoic acid;
(2S)-2-Ainino-3-(4-(2-amino-6-(3-(2-(trifluororaethyl)phenyl)pyrrolidin-l- yl)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(l,2,3,4-tetrahydronaphthalen-l-ylamino)pyriniidin-
4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-((R)-l-(naphthalen-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-Amino-3 -(4-(2-amino-6-( 1 ,2-diphenylethylamino)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-((R)-l-(4-(benzo[b]thiophen-3- yl)phenyl)ethylamino)pyrimidin-4-yl)phenyl)propaπoic acid;
(S)-2-Amino-3-(4-(4-amino-6-((R)-l-(4'-methoxybiphenyl-4-yl)ethylamino)-l,3,5- triazin-2-yl)phenyl)propanoic acid; 2-Amino-3-(l-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)-l,3,5-triazin-2- yl)piperidin-4-yl)propanoic acid;
(2S)-2-Amino-3 -(4-(4-amino-6-( 1 -(4-fluoronaphthalen- 1 -yl)ethylamino)- 1 ,3,5- triazin-2-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(4-amino-6-((3l-fluorobiphenyl-4-yl)methylamino)-l,3,5-triazm-2- yl)phenyl)propanoic acid;
2-Amino-3-(4-(4-amino-6-((R)- 1 -(naphthalen-2-yl)ethylamino)- 1 ,3>5-triazin-2-yl)-2- fluorophenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-((R)-2,252-trifluoro-l-(3l-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-l-(3'-fluorobiphenyl-2-yl)ethoxy)-
1 ,3,5-triazin-2-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(4-amino-6-(l-(4-tert-butylphenyl)ethylamino)-l,3,5-triazin-2- yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3l-fluorobiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(4-amino-6-(6,7-dihydroxy- 1 -methyl-3 ,4-dihydroisoquinolin- 2(lH)-yl)- 1 ,3,5-triazin-2-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(4-amino-6-(2,2,2-trifluoro-l-(3'-methylbiphenyl-4-yl)ethoxy)-
1 ,3,5-triazin-2-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(4-amino-6-((R)-l-(naphthalen-2-yl)ethylamino)pyrimidin-2- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-(benzylthio)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4l-fluorobiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Aπiino-3-(4-(6-(3-(4-chlorophenoxy)piperidin-l-yl)pyrimidin-4- yl)phenyl)propaπoic acid;
(S)-3-(4<4-Amino-6-((R)-l-(naphthalen-2-yl)ethylaτnino)-l5335-triazin-2-yl)phenyl)- 2-(2-aminoacetamido)propanoic acid;
(S)-2-Amino-3-(4-(6-((R)- 1 -(naphthalen-2-yl)ethylamino)-2- (trifluoromethyl)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-(4-(3-chlorophenyl)piperazin-l-yl)pyrimidin-4- yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-phenylethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l,4-diphenylbutylamino)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(l-(3f-chlorobiphenyl-2-yl)-2,2,2-trifluoroethoxy)pyriinidin-4- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(4-amino-6-(l-(biρhenyl-4-yl)-2,2,2-trifluoroethoxy)-l,3,5- triazin-2-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,3.3,3-pentafluoro-l-(3-fluoro-4- methylphenyl)propoxy)ρyrimidin-4-yl)phenyl)propanoic acid; (S)-Ethyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro- 1 -(3 '-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate;
(S)-2- Amino-3-(4-(2-amino-6-((S)-2,2,2-trifluoro- 1 -(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)ρropanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3-fluoro-3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(31-(dimethylamino)biphenyl-2-yl)-2,2,2- trifluoroethoxy)ρyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro- 1 -(3'-methoxy-5-methylbiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Araino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4'-methoxy-5-methylbiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3I-methoxy-3- (methylsulfonyl)biphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-(cyclopropylmethoxy)-4-fluorophenyl)-2,2>2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(l-(2-(cyclopropylmethoxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Aτnino-3-(4-(2-amino-6-(252,2-trifluoro- 1 -(2-
(isopentyloxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(5-(232,2-trifluoro-l-(3I-fluorobiphenyl-4-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-2-Amino-3 -(4-(2-amino-6-(2,2,2-triflύoro- 1 -(4'-methoxybiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(3'-carbamoylbiphenyl-2-yl)-2,252- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(4l-carbamoylbiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2>2-trifluoro-l-(4-(2- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-l-(4-(2- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3 -(4-(6-(2,2,2-trifluoro- 1 -(2-(isopentyloxy)phenyl)ethoxy)pyrimidin-4- yl)phenyl)proρanoic acid;
(2S)-3-(4-(6-(l-(3l-Acetamidobiphenyl-2-yl)-2,2,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)phenyl)-2-aminopropanoic acid; (2S)-3-(4-(6-(l-(4'-Acetamidobiphenyl-2-yl)-232,2-trifluoroethoxy)-2- aminopyrimidin-4-yl)phenyl)-2-aminopropanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(4-cyanophenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)phenyl)propanoic acid; (S)-Ethyl 2-arnino-3-(4-(2-amino-6^(R)-2,2,2-trifluoro-l-ρ-tolylethoxy)pyriinidin-4- yl)phenyl)propano ate;
(2S)-2-Amino-3-(4-(2-amino-6-(2J2,2-trifluoro-l-(l-methoxybicyclo[2.2.2]oct-5-en- 2-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(4-(cyclopentyloxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3 -(4-(6-( 1 -(4-(cyclopentyloxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Ammo-3-(4-(2~amino-6-(252,2-trifluoro- 1 -(4-(3- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)ρhenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(l -(4,5-dimethoxybiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(4,5-dimethoxy-3'-methylbiphenyl-2-yl)-252,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3<4-(5-(2,2,2-trifluoro-l-(2'-methylbiphenyl-2-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-l-(4-(3- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)ρhenyl)ρropanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-(3,5-difluorophenoxy)phenyl)-2,2,2- tri fluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro- 1 -(4-(4- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(4'-((S)-2-amino-2-carboxyethyl)biphenyl-2-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin- 4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(5-(2.2,2-trifluoro- 1 -(3 '-methylbiphenyl-2-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,252-trifluoro-l-(4-methoxybiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(5-(2-2,2-trifluoro-l-(2-(4-methylthiophen-3- yl)phenyl)ethoxy)pyrazin-2-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-methoxy-3l-raethylbiρhenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amiπo-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-(hydroxymethyl)biphenyl-2- yl) ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-aτnino-6-(l-(3'-cyanobiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(l-(2-(3,5-difluorophenoxy)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro- 1 -(4-(4- methoxyphenoxy)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3 -(4-(2-amino-6-(2,2,2-trifluoro- 1 -(2-(4-methylthiazol-2-yl)thiophen-
3-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(232J2-trifluoro-l-(5-(4-methoxyphenyl)isoxazol-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-phenyl-5-(trifluoromethyl)-lH- pyrazol-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-(cyclohexyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-araino-6-(l-(2-(cyclopentyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(l-(benzo[d]thiazol-6-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2- Amino-3-(4-(2-amino-6-(2,2,2-trifluoro- 1 -( 1 -methyl-1 H-imidazol-5- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(l-(2-(cyclopentyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidiπ-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(l-(2-(cyclohexyloxy)-4-methylphenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(pyridin-3-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-Aτnino-3-(4-(2-amino-6-(l-(l,3-dimethyl-lH-pyrazol-5-yl)-2,2,2- trifluoroetlioxy)pyriinidin-4-yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(2-amino-6-(3-hydroxypheπyl)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-hydroxybiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-(3,5-difluorophenyl)pyrimidin-4-yl)phenyl)propanoic acid;
{2S)-2-Amino-3-(4-(2-amino-6-(l-(3',5l-difluorobiphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-l-(3'-fluorobiphenyl-3-yl)ethoxy)ρyrazin-2- yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(l -(5-ethoxy-2-methyl-2,3-dihydrobenzofuran-6-yl)-
2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
{2S)-2-Amino-3-(4-(2-amino-6-(l-(benzofuran-5-yl)-2,2,2-trifluoroethoxy)pyrimidiπ- 4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-m-tolylfuran-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-Ethyl 3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)-2-(2-aminoacetamido)propanoate;
(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro- 1 -(2-(4-methylthioρhen-3- yl)phenyl)ethoxy)p yrazin-2-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro- 1 -(5-methyl-3-phenylisoxazol-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-(3-(methylthio)phenyl)pyrimidin-4- yl)phenyl)proρanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(3'-(methylthio)biphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(3l-((dimethylamino)methyl)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(2-amino-6-(3-(trifluoτomethoxy)phenyl)pyriinidin-4- yl)phenyl)propaπoic acid;
(2S)-2-Amino-3-(4-(2-amiαo-6-(252,2-trifluoro-l-(3'-(trifluoromethoxy)biphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (S)-3-(4-(2-Amiπo-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)-2-(2-aminoacetamido)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-methyl-5-phenyl-lH-pyrazol-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4- (methylsulfonyl)phenyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-((R)-l-(3'-(dimethylamino)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-chloro-4-(methylsulfonyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-arnmo-6-(2,2,2-trifluoro-l-(3-(furan-2-yl)thioρhen-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-(cyclopentyloxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propaπoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-1xifluoro-l-(2-(3-methoxyphenyl)cyclohex-l- enyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-ainino-6-(2}2,2-trifluoro-l-(pyrimidin-5-yl)ethoxy)pyriinidin- 4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(5-(2,2,2-trifluoro-l-(3l-methoxybiphenyl-3-yl)ethoxy)pyrazin-2- yl)phenyl)propanoic acid; (S)-2-Amino-3-(4-(2-amino-6-((S)-l-(3l-(dimethylamino)biphenyl-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(2-(furan-2- carboxamido)pheπyl)ethoxy)pyrirnidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-araino-6-(l-(4-chloro-2-(methylsulfonyl)phenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-Isopropyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate; (2S)-2-Amino-3-(4-(6-(l-(2-(cyclopentyloxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(l-(2-(cyclohexyloxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-.<2,2,2-trifluoro- 1 -(I -(thioρhen-2- yl) cyclohexyl) ethoxy)pyrimidin-4-yl)phenyl)proρanoic acid;
(2S)-2-Amino-3-(4-(2-(2,2,2-trifluoro- 1 -(3 '-methoxybiphenyl-4-yl)ethoxy)thiazol-5 - yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-(cyclohexyloxy)-4-fluorophenyl)-2,2,2- trifluoroethoxy)pyriinidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(l-(4- methoxyphenyl)cyclohexyl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-l-(4-jEluoro-2-methylphenyl)ethoxy)pyrimidin- 4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(4-fluoro-2- methylphenyl)ethoxy)pyrimidin-4-yl)phenyl)ρropanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(oxazol-2-yl(phenyl)methoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-(l-cyclohexyl-2,2,2- trifluoroethylideneaininooxy)pyriniidin-4-yl)ρhenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(2-(3-(diraethylamino)phenyl)furan-3-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,292-trifluoro-l-(5-phenylthiophen-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (S)-Phenyl 2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate;
(S)-2-Amino-3-(4-(2-ammo-6-((R)-l-(3'-((dimethylamino)methyl)biphenyl-4-yl)- 2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Aπiino-3-(4-(l-(3-methoxyben2oyl)-lH-pyrazol-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(6-(2,2,2-trifluoro-l-(5-phenylfuran-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(4-chloro-2-fluorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)proρanoic acid; (S3)-2-Amino-3-(4-(2-amino-6-(4-(trifluoromethyl)styryl)pyrimidin-4- yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-(3,4-dichlorophenyl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(l-(4-chloro-3-fluorophenyl)-2:>2,2- trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-((R)-l-(3'-(dimethylamino)biρhenyl-4-yl)-2,2,2- tri fluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l-chloro-2>2,2-trifluoro-l-(4-methoxybiphenyl-2- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3 -(4-(6-(2,2,2-trifluoro- 1 -(5-phenylthiophen-2-yl)ethoxy)pyrimidin-4- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(5-(4-phenoxyphenyl)-lH-l,2,3-triazol-l-yl)phenyl)propanoic acid; (S,E)-2-Amino-3-(4-(2-amino-6-(2-(biphenyl-4-yl)vinyl)pyrimidiπ-4- yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(4-amino-6-((R)-2,2,2-trifluoro-l-(3'-methoxybiphenyl-4- yl)ethoxy)pyrimidin-2-yl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(4'-methoxybiphenyl-4-ylsulfonamido)phenyl)propanoic acid; (2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(6-(3-methoxyphenyl)pyridin-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(6-(2-fluoro-3- methoxyphenyl)pyridin-3-yl)ethoxy)pyrimidin-4-yl)pheπyl)propanoic acid;
2-Amino-3-(5-(4'-methylbiphenyl-4-yl)-lH-indol-3-yl)propanoic acid; 2-Amino-3-(5-m-tolyl-lH-indol-3-yl)propanoic acid;
(2S)-2-Amino-3-(4-(2-(2-methoxyphenyl)furan-3-carboxamido)phenyl)propanoic acid;
2-Amino-3-(5-(l-benzyl-lH-pyrazol-4-yl)-lH-indol-3-yl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(2,2,2-trifluoro-l-(6-(thiophen-2-yl)pyridin-3- yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid;
2-Amino-3-(6-(l-benzyl-lH-pyrazol-4-yl)-lH-indol-3-yl)propanoic acid;
(S)-2-Amino-3-(4-((2-(4-(trifluoromethyl)phenyl)thiazol-4- yl)methylamino)phenyl)propanoic acid; (S)-2-Amino-3-(4-((4'-methoxybiphenyl-4-ylsulfonamido)methyl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(3-(2-methoxydibenzo[b,d]furan-3-yl)ureido)phenyl)propanoic acid; (S)-2-Amino-3-(4-(3-(2,2-diphenylethyl)ureido)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(phenylethynyl)phenyl)propanoic acid;
(S)-2-Amino-3-(4-(2-amino-6-((5-(l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl)thiophen-2-yl)methoxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(l,l,l-trifluoro-3-((R)-2,2,3-trimethylcyclopent-3- enyl)propan-2-yloxy)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(3-(2-hydroxyethylcarbamoyl)piperidin-l- yl)pyrimidin-4-yl)phenyl)propanoic acid;
(2S)-2-Amino-3-(4-(2-amino-6-(3-(pyridiii-2-yloxy)piperidin-l-yl)pyrimidin-4- yl)phenyl)propanoic acid; or (S)-2-Amino-3-(4-(2-amino-6-(4-chloro-3-(piperidine- 1 -carbonyl)phenyl)pyrimidin-
4-yl)phenyl)propanoic acid.
177. The compound of claim 176, which is stereomerically pure.
178. A stereomerically enriched composition of the potent TPHl inhibitor of claim 1 or 3.
179. A pharmaceutical formulation, which comprises a potent TPHl inhibitor of claim 1 or 3.
180. A single unit dosage form, which comprises the pharmaceutical formulation of claim 179.
181. A method of inhibiting TPH 1 activity, which comprises contacting TPHl with a compound of formula I:
Figure imgf000141_0001
I or a pharmaceutically acceptable salt or solvate thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond, -O-, -S-, -C(O)-, -C(R4)=, ^C(R4)-, -C(R3R4)-, -C(R4)^C(R4)-, -C=C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-; D is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;
R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
182. The method of claim 181, wherein the compound i s of formul a I(A) :
Figure imgf000142_0001
I(A)
183. A method of inhibiting TPHl activity, which comprises contacting TPHl with a compound of formula II:
Figure imgf000142_0002
II or a pharmaceutically acceptable salt or solvate thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X is a bond, -O-, -S-, -C(O)-, -C(R4)=, ^(R4)-, -C(R3R4)-, -C(R4)=C(R4)-, -C≡C-,
-N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-; D is optionally substituted aryl or heterocycle;
E is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;
R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl;
Rs is hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
184. The method of claim 183, wherein the compound is of formula H(A):
Figure imgf000143_0001
H(A)
185. A method of treating, preventing or managing a disease or disorder mediated by peripheral serotonin in a patient, which comprises inhibiting TPHl activity in the patient.
186. The method of claim 185, wherein the inhibition is caused by administering to the patient a therapeutically or prophylactically effective amount of a potent TPHl inhibitor.
187. The method of claim 185, wherein the inhibition is caused by administering to the patient a therapeutically or prophylactically effective amount of a compound of formula I:
Figure imgf000143_0002
I or a pharmaceutically acceptable salt or solvate thereof, wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -O-, -S-, -C(O)-, -C(R4)=, =C(R4)-, -CCR3R4)-, -C(RO=C(R4)-, -C≡C-,
-N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-;
D is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl; R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; each R5 is independently hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
188. The method of claim 187, wherein the compound is of formula 1(A):
Figure imgf000144_0001
1(A)
189. The method of claim 185, wherein the inhibition is caused by administering to the patient a therapeutically or prophylactically effective amount of a compound of formula II:
Figure imgf000144_0002
II or a pharmaceutically acceptable salt or solvate thereof, wherein:
A is optionally substituted cycloalkyl, aryl, or heterocycle;
X is a bond, -O-, -S-, -C(O)-, -C(R4)=, =C(R4)-, -C(R3R4)-, -C(R4)=C(R4)-, -C≡C-, -N(R5)-, -N(R5)C(O)N(R5)-, -C(R3R4)N(R5)-, -N(R5)C(R3R4)-, -ONC(R3)-, -C(R3)NO-, -C(R3R4)O-, -OC(R3R4)-, -S(O2)-, -S(O2)N(R5)-, -N(R5)S(O2)-, -C(R3R4)S(O2)-, or -S(O2)C(R3R4)-;
D is optionally substituted aryl or heterocycle; E is optionally substituted aryl or heterocycle;
Ri is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;
R4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl; Rs is hydrogen or optionally substituted alkyl or aryl; and n is 0-3.
190. The method of claim 189, wherein the compound is of formula H(A):
Figure imgf000145_0001
H(A) 191. The method of claim 185, wherein the disease or disorder is carcinoid syndrome.
192. The method of claim 185, wherein the disease or disorder is a gastrointestinal disease or disorder.
193. The method of claim 185, wherein the disease or disorder is emesis.
194. A method of treating, preventing or managing a gastrointestinal disease or disorder, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a potent TPHl inhibitor of claim 1 or 3.
195. The method of claim 194, wherein the disease or disorder is diarrhea, constipation, or irritable bowel syndrome.
196. A method of treating, preventing or managing emesis, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a compound of a potent TPHl inhibitor of claim 1 or 3.
197. A method of preparing a compound of formula 1 (a) :
Figure imgf000146_0001
l(a) which comprises contacting a compound of formula 2:
Figure imgf000146_0002
with a compound of formula 3:
Figure imgf000146_0003
3 under conditions sufficient for the formation of the compound of formula l(a), wherein: A is optionally substituted cycloalkyl, aryl, or heterocycle; X' is O, S, orNR5; Y] is halogen or pseudohalogen; one of Z"i, Zl! 2, ZM 3, and Z'\ is a carbon atom attached to the adjacent optionally substituted phenyl moiety, and the others are each independently CRi o or N; Pi is Ri or a protecting group; P2 is a protecting group; R1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;
R3 is hydrogen, cyano, or optionally substituted alkyl; each R6 is independently hydrogen, cyano, halogen, OR7, NR.8R9, amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R1O is independently hydrogen, cyano, halogen, ORn, NRi 2R13, amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; each R1 \ is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each R12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; each Rn is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl- heterocycle; and m is 1-4.
198. The method of claim 197, wherein the compound of formula 2 is prepared by contacting a compound of formula 4:
Figure imgf000147_0001
with a compound of formula 5:
Figure imgf000147_0002
5 under conditions sufficient for the formation of the compound of formula 2, wherein:
Ai is optionally substituted cycloalkyl, aryl, or heterocycle; A2 is optionally substituted cycloalkyl, aryl, or heterocycle;
Y2 is halogen or pseudohalogen; and each R is independently hydrogen, optionally substituted alkyl, alkyl-aryl, alkyl- heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane.
199. The method of claim 191, wherein the compound of formula 3 is prepared by contacting a compound of formula 6:
Figure imgf000148_0001
with a compound of formula 7:
Figure imgf000148_0002
7 under conditions sufficient for the formation of the compound of formula 3(a):
Figure imgf000148_0003
3(a) and deprotecting P3 to provide the compound of formula 3, wherein:
Y3 is halogen or pseudohalogen;
P3 is OR2 or a protecting group;
R2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle; and each R' is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl- heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane.
200. The method of claim 197, wherein the conditions sufficient for the formation of the compound of formula 2 comprise a transition metal catalyst, a base, and a solvent or solvent mixture with water.
201. The method of claim 199, wherein the conditions sufficient for the formation of the compound of formula 3(a) comprise a transition metal catalyst, a base, and a solvent or solvent mixture with water.
202. The method of claim 197, which further comprises deprotecting the compound of formula l(a) to provide a compound of formula l(b):
Figure imgf000149_0001
l(b)
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