WO2011014520A2 - Compounds and compositions as modulators of gpr119 activity - Google Patents

Compounds and compositions as modulators of gpr119 activity Download PDF

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WO2011014520A2
WO2011014520A2 PCT/US2010/043433 US2010043433W WO2011014520A2 WO 2011014520 A2 WO2011014520 A2 WO 2011014520A2 US 2010043433 W US2010043433 W US 2010043433W WO 2011014520 A2 WO2011014520 A2 WO 2011014520A2
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phenyl
methyl
pyrazolo
pyrimidin
trifluoromethyl
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PCT/US2010/043433
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French (fr)
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WO2011014520A3 (en
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Phillip Alper
Mihai Azimioara
Christopher Cow
Robert Epple
Gerald Lelais
Daniel Mutnick
Victor Nikulin
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Irm Llc
Mecom, John
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Publication of WO2011014520A2 publication Critical patent/WO2011014520A2/en
Publication of WO2011014520A3 publication Critical patent/WO2011014520A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPRl 19.
  • GPRl 19 is a G-protein coupled receptor (GPCR) that is mainly expressed in the pancreas, small intestine, colon and adipose tissue.
  • GPCR G-protein coupled receptor
  • the expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of obesity and diabetes.
  • the novel compounds of this invention modulate the activity of GPRl 19 and are, therefore, expected to be useful in the treatment of GPRl 19-associated diseases or disorders such as, but not limited to, diabetes, obesity and associated metabolic disorders.
  • the present invention provides a compound of Formula I:
  • R 1 is selected from C 2 -ioalkenyl, C 6-1 oaryl, C 6 -ioaryl-C 2 - 3 alkynyl, C 1 .
  • Y 5 is N and Y 6 is CR 2 ; or Y 5 is CR 2 and Y 6 is N;
  • R 2 is selected from hydrogen, C 1-6 alkyl, Ci_ 6 alkoxy, halo-substituted-Ci_
  • R 3 is selected from cyano, -C(O)ORi u , -C(O)R 1 la , -X 2 OC(O)R 1 la , -
  • R 4 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkenyl, C 6 -ioarylCi_ 4 alkyl, -
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 6-1 oaryl, Ci ⁇ heteroaryl, C 3 - gheterocycloalkyl; wherein said alkyl, aryl, heteroaryl or heterocycloalkyl of R 5 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, - S(0)o- 2 Ri 3a , halo-substituted-Ci_ 4 alkyl, Ci_ 4 alkyl, halo-substituted-Ci_ 4 alkoxy, Ci_ 4 alkoxy, C 6-1 oaryl, -C(O)NR 13a R 13b and -C(O)OR 13a ; wherein R 13a and R 13b are independently selected from hydrogen and C 1-4 alkyl;
  • Y 2 is selected from a bond, CH 2 , C(O), NR 17 and O; wherein R 17 is selected from hydrogen, halo-substituted-Ci ⁇ alkyl and C 1-4 alkyl; or R 4 and Y 2 taken together form a double bond or a cyclopropyl ring;
  • Y 4 is selected from N and -CR 6 ; wherein Re is selected from hydrogen, halo, cyano, Ci_ 6 alkyl, X 4 NR 14a R 14b , X 4 OR 14a ; wherein X 4 is selected from a bond, C 1 .
  • R 14a and R 14b are independently selected from hydrogen and Ci_ 4 alkyl; with the proviso that when Y 4 is N, Y 1 is CH.
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal in which modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula
  • the present invention provides the use of a compound of
  • GPRl 19 activity contributes to the pathology and/or symptomology of the disease.
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Alkyl as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be straight-chained, branched, cyclic or spiro.
  • C 1- ⁇ alkoxy includes methoxy, ethoxy, and the like.
  • Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
  • Alkylene is a divalent alkyl radical that includes -C(CH 3 ) 2 -.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl can be phenyl or naphthyl, preferably phenyl.
  • Heteroaryl is as defined for aryl where one or more of the ring members are a heteroatom.
  • C ⁇ ioheteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl,
  • Heteroaryl also includes the N-oxide derivatives, for example, pyridine N-oxide derivatives with the following structure:
  • Ce-ioarylCi ⁇ alkyl means an aryl as described above connected via a alkylene grouping.
  • C 6 - 1 oarylC 1 _ 4 alkyl includes phenethyl, benzyl, etc.
  • 1 oaryl-C 2 - 3 alkynyl includes, for example, phenyl-ethynyl, etc.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3 _iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Enantiomers as used in this application for compounds of Formula I, describe each chiral center as labeled R or S according to a system by which its substituents are each assigned a priority, according to the Cahn Ingold Prelog priority rules (CIP), based on atomic number. If the center is oriented so that the lowest-priority of the four is pointed away from a viewer, the viewer will then see two possibilities: If the priority of the remaining three substituents decreases in clockwise direction, it is labeled R (for Rectus), if it decreases in counterclockwise direction, it is S (for Sinister).
  • CIP Cahn Ingold Prelog priority rules
  • the R enentiomer of a compound of Formula I is where R 3 has priority over the core (fused bicyclic) which has priority over Y 2 R 5 which in turn has priority over R 4 .
  • the R-enantiomer is preferred over the S-enantiomer (see examples N1-N5).
  • C 3 _ 8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo-pyrrolidin-l-yl, 2-oxo-piperidin-l-yl, etc.
  • Heterocycloalkenyl means heterocycloalkyl, as defined in this application, provided that at least one double bond exists in the ring.
  • GPRl 19 means G protein-coupled receptor 119 (GenBank ® Accession No.
  • GPRl 19 includes the human sequences found in GeneBank accession number AY288416, naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof.
  • Halogen (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
  • Treatment refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • the present invention provides compounds, compositions and methods for the treatment of diseases in which modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I.
  • compounds of Formula I are compounds of Formula Ia, Ib and Ic:
  • n is selected from 1, 2 and 3;
  • R 1 is selected from C 2 -ioalkenyl, C 6- ioaryl, C 6 -ioaryl-C 2 - 3 alkynyl, C ⁇ gheteroaryl, acetylenyl, C 3 .
  • alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R 1 is optionally substituted with 1 to 3 radicals
  • R 1 Oc and R 1 Od are selected from hydrogen, C 1-6 alkyl, C 3 - iocycloalkyl optionally substituted with C 1-6 alkyl or halo;
  • R 3 is selected from cyano, - C(O)OR 1 U, -C(O)R 1 U, -X 2 OC(O)R lla , -C(O)OX 2 R 1 U, -X 2 OS(O) 0 - 2 Rii a , -X 2 S(O) 0 .
  • R 4 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkenyl, C 6 -ioarylCi_ 4 alkyl, -X 3 ORi 2 , - X 3 NRi 2 Ri 2 and -X 3 C(O)ORi 2 ; wherein X 3 is selected from a bond and Ci_ 4 alkylene; and each Ri 2 is independently selected from hydrogen and C 1-4 alkyl; Re is selected from hydrogen, halo, cyano, C 1-6 alkyl, X 4 NRi 4a Ri 4b , X 4 ORi 4a ; wherein X 4 is selected from a bond, Ci_ 6 alkylene; and Ri 4a and Ri 4b are independently selected from hydrogen and C 1- 4 alkyl; Rig is selected halo, cyano, -S(0)o- 2 Ri 3a ,halo-substituted-Ci_
  • R 1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, benzimidazolyl, styryl, l,2,4-oxadiazol-5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl,
  • R 3 is selected from: cyano; ethoxy-methyl; (2- methoxyethyl)(methyl)carbamoyl; (tetrahydro-2H-pyran-4-yloxy)carbonyl;
  • thiazolyl-methyl pyrazinyl-methyl; pyridinyl-methyl; (2-(dimethylamino)-2- oxoethyl)(methyl)carbamoyl; (2-(2-oxopyrrolidin- l-yl)ethoxy)carbonyl; 3- hydroxypyrrolidine-1-carbonyl; (carboxymethyl)(methyl)carbamoyl; (2,3- dihydroxypropyl)(methyl)carbamoyl; tetrahydrofuran-3-ylcarbamoyl; ((1-methyl-lH- imidazol-4-yl)methoxy)carbonyl; (azetidin-3-ylmethoxy)carbonyl; (2-hydroxy-3- (methylamino)propoxy)carbonyl; dimethoxy-ethyl-carbamoyl,
  • n is selected from 1, 2 and 3;
  • R 1 is selected from C 2 -ioalkenyl, Ce- ioaryl, C ⁇ gheteroaryl, acetylenyl, C 3 _gheterocycloalkyl, Cs.gheterocycloalkenyl, C 3 .
  • R 7 is selected from hydrogen, Ci- ⁇ alkyl, C 3 -iocycloalkyl optionally substituted with Ci_ 6 alkyl or halo
  • Rg is selected from -X 1 Rg; wherein X 1 is selected from a bond and Ci- 4 alkylene optionally substituted with halo
  • R 9 is selected from phenyl and pyridinyl; wherein said phenyl or pyridinyl of R 9 is optionally substituted with 1 to 3 trifluoromethyl radicals
  • R 2 is selected from hydrogen, Ci_ 6 alkyl, Ci- ⁇ alkoxy, halo-substituted-Ci- ⁇ alkyl, halo-substituted-Ci- ⁇ alkoxy, -
  • R 4 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkenyl, C 6-1 oa ⁇ ylC 1-4 alkyl, - X 3 OR 12 and -X 3 C(O)OR 12 ; wherein X 3 is selected from a bond and C 1-4 alkylene; and R 12 is selected from hydrogen and C 1-4 alkyl; R 6
  • R 1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, l,2,4-oxadiazol-5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
  • R 3 is selected from cyano, ethoxy- methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl, methyl((tetrahydrofuran-2-yl)methyl)carbamoyl, (2-methoxy-2- oxoethyl)(methyl)carbamoyl, methoxy-ethyl-carbamoyl, methoxy-propoxy
  • [0043] in a further embodiment are compounds selected from: ethyl (2R)-2- methyl-3-phenyl-2- ⁇ 8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4- yljpropanoate; ethyl 2-methyl-3-phenyl-2- ⁇ 8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2- c][l,2,4]triazin-4-yl ⁇ propanoate; ethyl 2- ⁇ 3-fluoro-8-[4- (trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4-yl ⁇ -2-methyl-3- phenylpropanoate; ethyl 2-[8-(4-chlorophenyl)pyrazolo[3,2-c][l,2,4]triazin-4-yl]-2- methyl-3-pheny
  • R 1 is selected from C 2 -ioalkenyl, C 6-1O aTyI, C ⁇ heteroaryl, acetylenyl, Cs-sheterocycloalkyl, Cs-sheterocycloalkenyl, C3 -6 cycloalkyl, C 3 - 6 cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, C 1-4 alkyl, halo- substituted-C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkoxy, C 6-1 oaryl, Ci-gheteroaryl, Cs- ⁇ hetero
  • X 5 C(O)NR 1 OaRiOb, -X 5 NR 1 ObC(O)R 1 Oa and -X 5 C(O)OR 10a wherein said X 5 is selected from a bond and C ⁇ alkylene wherein any methylene of X 5 can have a hydrogen substituted with hydroxyl, C 6-1 oaryl, C 3 _iocycloalkyl, heteroaryl or heterocycloalkyl; and R 1 Oa and R 1 Ob are independently selected from hydrogen, Ci_ 4 alkyl and Ci_ 4 alkoxy; or R 1 Oa and R 1Ob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C 1-4 alkyl, halo-substituted
  • R 1 Oc and R 1 Od are selected from hydrogen, Ci_6alkyl, C 3 _iocycloalkyl optionally substituted with Ci_6alkyl or halo;
  • R 3 is selected from cyano, -C(O)OR lla , - C(O)R lla , -X 2 OC(O)R lla , -C(O)OX 2 R lla , -X 2 OS(0)o- 2 R lla , -X 2 S(O) 0-2 R 1 la , - C(0)0X 2 0R lla , -C(0)0X 2 NR lla R llb , -C(O)N R lla R llb , -X 2 NR lla R ⁇ b, -NR lla C(0)R llb , -NRiiaC(O)ORnb, -NRnaS(0)o- 2 Riib, -
  • R 1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, l,2,4-oxadiazol-5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
  • R 3 is selected from cyano, ethoxy-methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl,
  • [0049] in another embodiment are compounds selected from: ethyl 2-[8-(4- chlorophenyl)imidazo[l,5-a]pyrimidin-4-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[3,2-b][l,3]thiazol-6-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3- (4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2,3-dihydro-lH-indene-2-carboxylate; 3- (4-chlorophenyl)-N-phenyl-N-propylpyrazolo[ 1 ,5-a]pyrimidine-7-carboxamide; 3-(4- chlorophenyl)-N-methyl-N-phenylpyrazolo[l,5-a]pyrimidine-7-carbox
  • the present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof.
  • An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F, 36 Cl and 123 I.
  • Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies.
  • 3 H and 14 C isotopes may be used for their ease of preparation and detectability.
  • substitution with isotopes such as 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. For example, the following three examples can be deuterated as shown:
  • Compounds of the invention modulate the activity of GPRl 19 and, as such, are useful for treating diseases or disorders in which the activity of GPRl 19 contributes to the pathology and/or symptomology of the disease.
  • This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which GPRl 19 activity contributes to the pathology and/or symptomology of the disease.
  • Type II diabetes The resultant pathologies of Type II diabetes are impaired insulin signaling at its target tissues and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal.
  • Current therapies to treat the latter include inhibitors of the ⁇ -cell ATP- sensitive potassium channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these achieves accurate normalization of blood glucose levels and both carry the risk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function in a glucose-dependent action, i.e.
  • Physiological signaling systems which function in this manner are well-characterized and include the gut peptides GLP-I, GIP and PACAP. These hormones act via their cognate G-protein coupled receptor to stimulate the production of cAMP in pancreatic ⁇ -cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or pre-prandial state.
  • a series of biochemical targets of c AMP signaling including the ATP- sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, ⁇ -cell GPCRs, including GPRl 19, would also stimulate the release of endogenous insulin and
  • cAMP for example as a result of GLP-I stimulation, promotes ⁇ -cell proliferation, inhibits ⁇ -cell death and thus improves islet mass. This positive effect on ⁇ - cell mass is expected to be beneficial in both Type II diabetes, where insufficient insulin is produced, and Type I diabetes, where ⁇ -cells are destroyed by an inappropriate autoimmune response.
  • hypothalamus where they modulate hunger, satiety, decrease food intake, controlling or decreasing weight and energy expenditure.
  • agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.
  • an embodiment of the invention is a method for treatment of a metabolic disease and/or a metabolic-related disorder in an individual comprising administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.
  • the metabolic diseases and metabolic-related disorders are selected from, but not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g., hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease,
  • necrosis and apoptosis dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
  • GPRl 19 activity modulators derived from increasing levels of GIP and PPY. For example, neuroprotection, learning and memory, seizures and peripheral neuropathy.
  • GLP-I and GLP-I receptor agonists have been shown to be effective for treatment of neurodegenerative diseases and other neurological disorders.
  • GLP-I and exendin-4 have been shown to stimulate neurite outgrowth and enhance cell survival after growth factor withdrawal in PC 12 cells.
  • GLP-I and exendin-4 restore cholinergic marker activity in the basal forebrain.
  • Central infusion of GLP-I and exendin-4 also reduce the levels of amyloid- ⁇ peptide in mice and decrease amyloid precursor protein amount in cultured PC 12 cells.
  • GLP-I receptor agonists have been shown to enhance learning in rats and the GLP-I receptor knockout mice show deficiencies in learning behavior.
  • the knockout mice also exhibit increased susceptibility to kainate-induced seizures which can be prevented by administration of GLP-I receptor agonists.
  • GLP-I and exendin-4 has also been shown to be effective in treating pyridoxine- induced peripheral nerve degeneration, an experimental model of peripheral sensory neuropathy.
  • Glucose-dependent insulinotropic polypeptide has also been shown to have effects on proliferation of hippocampal progenitor cells and in enhancing sensorimotor coordination and memory recognition.
  • GLP-2 and short bowel syndrome are therapeutic benefits of GPRl 19 activity modulators.
  • GLP-2 and short bowel syndrome SBS.
  • SBS short bowel syndrome
  • GLP-2 is a trophic hormone that plays an important role in intestinal adaptation. Its role in regulation of cell proliferation, apoptosis, and nutrient absorption has been well documented.
  • Short bowel syndrome is characterized by malabsorption of nutrients, water and vitamins as a result of disease or surgical removal of parts of the small intestine (eg. Crohn's disease). Therapies that improve intestinal adaptation are thought to be beneficial in treatment of this disease.
  • phase II studies in SBS patients have shown that teduglutide, a GLP-2 analog, modestly increased fluid and nutrient absorption.
  • GLP-I GLP-I
  • GIP calcitonin related gene peptide
  • osteoporosis a disease that is caharacterized by reduced bone mineral density and thus GLP-I induced increase in calcitonin might be therapeutically beneficial.
  • GIP has been reported to be involved in upregulation of markers of new bone formation in osetoblasts including collagen type I mRNA and in increasing bone mineral density. Like GLP-I, GIP has also been shown to inhibit bone resorption.
  • GPRl 19 activity modulators derived from increasing levels of GIP and PPY.
  • GPRl 19 located on the pancreatic polypeptide (PP) cells of the islets has been implicated in the secretion of PPY.
  • PPY has been reported to have profound effects on various physiological processes including modulation of gastric emptying and gastrointestinal motility. These effects slow down the digestive process and nutrient uptake and thereby prevent the postprandial elevation of blood glucose.
  • PPY can suppress food intake by changing the expression of hypothalamic feeding-regulatory peptides.
  • PP-overexpressing mice exhibited the thin phenotype with decreased food intake and gastric emptying rate.
  • the present invention further provides a method for preventing or ameliorating the symptamology of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount See, "Administration and Pharmaceutical Compositions ", infra
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations can also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
  • synergistic effects can occur with other anti-obesity agents, anorectic agents, appetite suppressant and related agents. Diet and/or exercise can also have synergistic effects.
  • Anti-obesity agents include, but are not limited to,
  • apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors MCR-4 agonists, cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte- stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [for example, compounds described in WO2006/047516), melanin concentrating hormone antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolip statin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), Neuropeptide-Y antagonists,
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • a combined preparation or pharmaceutical composition can comprise a compound of the invention as defined above or a pharmaceutical acceptable salt thereof and at least one active ingredient selected from:
  • anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP- 112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB- 517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BA
  • hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A
  • HMG-CoA reductase inhibitors e.g., lovastatin and related compounds such as those disclosed in U.S. Pat. No. 4,231,938, pitavastatin, simvastatin and related compounds such as those disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such as those disclosed in U.S. Pat. No.4,346,227, cerivastatin, mevastatin and related compounds such as those disclosed in U.S. Pat. No. 3,983,140, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and related statin compounds disclosed in U.S. Pat. No.
  • phosphinic acid compounds useful in inhibiting ⁇ MG CoA reductase suitable for use herein are disclosed in GB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;
  • an anti-obesity agent or appetite regulating agent such as a CB 1 activity modulator, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MC ⁇ R) antagonists, growth hormone secretagogue receptor (G ⁇ SR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-I agonists, and other Pre-proglucagon-derived peptides; NPYl or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl- CoA carboxylase (ACC) inihibitors, 11- ⁇ -HSD-l inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such as AJ9677 (Taked
  • a thyroid receptor beta modulator such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CaI SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-I inhibitor as disclosed in WO2005011655, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT- 933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or
  • anti-hypertensive agents such as loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan,
  • NEP neutralendopeptidase
  • ECE inhibitors e.g. SLV306
  • ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril
  • angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan
  • renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168
  • beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol
  • inotropic agents such as digoxin, dobutamine and milrinone
  • calcium channel blockers such as amlodipine, bepridil,
  • thrombin inhibitors such as Ximelagatran
  • aldosterone inhibitors such as anastrazole, fadrazole, eplerenone
  • a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( ⁇ N- ⁇ 5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2- methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine ⁇ ) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamin
  • an agent interacting with a 5-HT 3 receptor and/or an agent interacting with 5-HT 4 receptor such as tegaserod described in the US patent No. 5510353 as example 13, tegaserod hydrogen maleate, cisapride, cilansetron;
  • n) an agent for treating tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban®) and nicotine replacement therapies;
  • an agent for treating tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban®) and nicotine replacement therapies;
  • an agent for treating erectile dysfunction e.g., dopaminergic agents, such as apomorphine
  • ADD/ ADHD agents e.g., Ritalin®, Strattera®, Concerta® and Adderall®
  • an agent for treating alcoholism such as opioid antagonists (e.g., naltrexone (also known under the tradename Re Via®) and nalmefene), disulfiram (also known under the tradename Antabuse®), and acamprosate (also known under the tradename Campral®)).
  • opioid antagonists e.g., naltrexone (also known under the tradename Re Via®) and nalmefene), disulfiram (also known under the tradename Antabuse®), and acamprosate (also known under the tradename Campral®)
  • agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin®);
  • COX-2 inhibitors COX-2 inhibitors
  • antidepressants e.g., fluoxetine hydrochloride (Prozac®)
  • cognitive improvement agents e.g., donepezil hydrochloride (Aircept®) and other
  • acetylcholinesterase inhibitors include neuroprotective agents (e.g., memantine) ; antipsychotic medications (e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®));
  • neuroprotective agents e.g., memantine
  • antipsychotic medications e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®)
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term "pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term "fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
  • a compound of Formula 1-1 and 1-2 can be prepared as in reaction scheme
  • a compound of the formula 4 (for example, Bioorg. Med. Chem. Lett. 2004, 14, 3669) can be coupled with a compound of the formula 3 in an appropriate solvent such as an alcohol (methanol, ethanol, and the like) or organic acid such as acetic acid and the like, in the presence of an acidic promoter such as HCl, trifluoroacetic acid or the like at an elevated temperature such as 6O 0 C to 15O 0 C to afford 1-1.
  • an appropriate solvent such as an alcohol (methanol, ethanol, and the like) or organic acid such as acetic acid and the like
  • an acidic promoter such as HCl, trifluoroacetic acid or the like
  • compound 1-1 may be further reacted with a compound of formula 5 (where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like) in a solvent such as DMF, NMP, THF and the like using a base such at KOz-Bu, Cs 2 CO 3 or the like to afford 1-2.
  • a compound of formula 5 where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like
  • a solvent such as DMF, NMP, THF and the like
  • a base such at KOz-Bu, Cs 2 CO 3 or the like
  • a compound of formula 4 can be prepared as in reaction scheme I by reacting a compound of formula 6 with a compound of the formula 2 (where R 49 and R 2 o are low molecular weight alkanes such as methyl, ethyl and the like) in a suitable solvent such as DMF and the like at an elevated temperature (80- 120 0 C) to generate an intermediate of the formula 7.
  • Intermediate 7 may be further reacted with hydrazine hydrochloride (8) or the like, in a suitable solvent such as a mixture of ethanol and water or the like at an elevated temperature (60- 100 0 C) to yield a compound of formula 4.
  • preparations such as described J. Het. Chem. 1977, 1(1), 65; J. Med. Chem. 1964, 7(3), 259) may be used.
  • R 4 , R 5 , Re and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-3 may be prepared as in reaction scheme II.
  • a compound of formula 9 can be reacted with a compound of formula 10 (or a similar diol used in the protection of ketones) using an acid catalyst such as /7-toluenesulfonic acid and the like in a suitable solvent consisting of diol 10 and a trialkylorthoformate to generate an intermediate of formula 11.
  • Intermediate 11 can then be reacted with a base such as lithium hydroxide and the like in a high boiling alcoholic solvent such as ethylene glycol or the like at elevated temperature (50-120 0 C) to generate compounds of formula 12, which can subsequently be reduced using lithium aluminum hydride or the like to afford an intermediate of formula 13.
  • Intermediate 13 may be deprotected using an aqueous acid such as HCl and the like in an appropriate solvent such as acetone or the like at elevated temperature (40-70 0 C) to afford an intermediate of formula 14.
  • This intermediate can be reacted with a compound of formula 15 (where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like) to afford a protected compound of the formula 16.
  • Compound 16 may be manipulated in an analogous manner as compound 1 in scheme I to afford intermediate 17. This intermedtiate can then be further deprotected and derivatized to afford various compounds of the formula 1-3 where R 23 refers to the definition of R 3 excluding one methylene group.
  • R 1 , R 2 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-4 can be prepared as in reaction scheme III by reacting a compound of formula 18 (where X refers to a group competent to be transmetallated such as chloride, bromide, triflate and the like) which can be prepared by any of the other methods mentioned in this patent with an appropriate coupling partner such as a boronic acid, organostannane, organozinc, olefin or terminal acetylene or the like using the organometallic coupling chemistry known in the art (for example, Hartwig, J. F. Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E., Ed., Wiley- Interscience: Weinheim, 2002).
  • R 1 , R 2 , R 3 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-5 can be prepared as in reaction scheme IV by reacting a compound of formula 19 with an appropriate activating agent such as
  • a compound of formula 1-6 can be prepared as in reaction scheme V by reacting a compound of formula 21 with a compound of formula 22 and a metal cyanide such as KCN or the like in an appropriate solvent such as a mixture of ethanol and water or the like at an elevated temperature such as 50 0 C to afford an intermediate of formula 23.
  • This material can then be treated with an intermediate of formula 3 as described in scheme I to afford 1-6.
  • the groups designated as R 1 , R 2 , R 3 , R 4 , R 5 , Re and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of Formula 1-7 can be prepared as in reaction scheme VI by reacting a compound of formula 1 with a halogenating agent such as bromine or chlorine (X 2 ) in an appropriate solvent such as acetic acid to generate an intermediate of formula 24.
  • This intermediate can be reacted with a trivalent phosphorous reagent such as a trialkyl-or triarylphosphine or a trialkyl phosphite either neat or in an appropriate solvent such as tetrahydrofuran, toluene or the like to generate and intermediate with the formula 25 where Z refers to either a phosphorous ylide or a phosphonate ester.
  • a compound of the formula 4 can be diazotized with a metal nitrite such as KNO 2 in an appropriate solvent such as acetic acid to generate an intermediate of the formula 26. Then, intermediates 25 and 26 can be reacted in a biphasic solvent mixture such as DCM and water containing an aqueous base such as sodium carbonate or the like to generate 1-7 (for an example, see J. Het. Chem. 1981, 18(4), 675).
  • a biphasic solvent mixture such as DCM and water containing an aqueous base such as sodium carbonate or the like to generate 1-7 (for an example, see J. Het. Chem. 1981, 18(4), 675).
  • the groups designated as R 1 , R 2 , R 3 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-8 can be prepared as in reaction scheme VII by reacting a compound of formula 26 with thiourea (27) in the solvent used to generate 26 to afford an intermediate with formula 28.
  • This intermediate can be reacted with a metal hydroxide such as NaOH or the like at elevated temperature (80- 100 0 C) in an appropriate solvent such as ethanol, methanol or the like, quenched with a stoichiometric amount of acid such as HCl or the like and then reacted with a compound of the formula 24 (from scheme VI) to generate 1-8.
  • R 1 , R 2 , R 3 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of Formula 1-9 can be prepared as in reaction scheme VIII by reacting a compound of formula 1-2 (wherein R is methyl) with a halogenating agent (R 22 X) such as N-bromosuccinimide (wherein R 22 is any group attached to a halogen as a delivery system for said halogen) in the presence of a radical initiator such as AIBN or the like in an appropriate solvent such as carbon tetrachloride or the like at an elevated temperature such as about 4O 0 C to about 100 0 C to afford an intermediate of formula 25.
  • a halogenating agent such as N-bromosuccinimide (wherein R 22 is any group attached to a halogen as a delivery system for said halogen)
  • a radical initiator such as AIBN or the like
  • an appropriate solvent such as carbon tetrachloride or the like
  • an elevated temperature such as about 4O 0 C to about 100 0 C to afford an intermediate of formula 25.
  • This intermediate can be reacted with a nucleophile of structure R 23 Z r- H, where Z represents a heteroatom such as N, O, S, or the like (and R 23 is any alkyl, aryl, heteroalkyl or heteroaryl sidechain attached to a nucleophilic atom like N, O or S) in the presence of a base like cesium carbonate in an appropriate solvent such as acetonitrile,
  • R 1 , R 3 , R 4 , R 5 , R 6 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from,
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • a suitable carbamylating agent e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the
  • diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by
  • the compounds of Formula I can be made by a process, which involves:
  • Step A A mixture of ethyl 2-benzyl-3-oxobutanoate Ala (510 mg, 2.3 mmol) and dimethylformamide diethyl acetal (341 mg, 2.3 mmol) is heated to 100 0 C overnight. The solvent is removed to afford ethyl 2-benzyl-5-(dimethylamino)-3- oxopent-4-enoate Alb; ESIMS calcd. for Ci 6 H 22 NO 3 ([M+H]+) 276.2, found 276.0. The compound is used without purification.
  • Step B A microwave vial charged with a solution of Intermediate Alb
  • Example Al A solution of Example Al (33.4 mg, 83 ⁇ mol) in tetrahydrofuran (1 niL) is added to a solution of potassium tert-butoxide (9.4 mg, 83 ⁇ mol) in tetrahydrofuran (1 mL) at 0 0 C.
  • the reaction is then treated with iodomethane (14 mg, 100 ⁇ mol) and allowed to come to room temperature and stir overnight.
  • the reaction is then evaporated to dryness and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered, evaporated and purified on a reversed phase HPLC
  • Step A A solution of Intermediate AlOa (6.58g, 28.08 mmol) in a mixture of ethylene glycol (25 ml) and triethyl orthoformate (20 mL) is treated with p- toluenesulfonic acid (200 mg, 1.3 mmol) and heated to 55 0 C overnight. The reaction is then cooled to room temperature and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered and evaporated to afford ethyl 2-methyl- 2-(2-methyl-l,3-dioxolan-2-yl)-3-phenylpropanoate AlOb; ESIMS calcd. for Ci 6 H 23 O 4 ([M+H] + ) 279.2, found 279.1. The product is used without purification.
  • Step B A solution of Intermediate AlOb in ethylene glycol (50 ml) is treated with lithiumhydroxide (3 g, 71 mmol) and heated to 200 0 C for 30 minutes using conventional heating. At this point, the reaction solidifies. After cooling to room temperature, the solid mass is repeatedly digested with hot IM NaOH until all of the material dissolves. The resulting aqueous solution is extracted once with ethyl acetate and the organics are discarded. The aqueous solution is adjusted to pH 4 with concentrated HCl and extracted twice with ethyl acetate. The combined organic extracts are dried over MgSO 4 , filtered and evaporated.
  • lithiumhydroxide 3 g, 71 mmol
  • Step C A solution of Intermediate AlOc (3.36 g, 13.44 mmol) in IN HCl is extracted with ethyl acetate five times. The combined organics are dried over Na 2 SO 4 , filtered and evaporated. The resulting acid is then dissolved in tetrahydrofuran (100 mL) and is slowly added to a pre-cooled (0 0 C) solution of lithiumaluminiumhydride (2.0 g, 53.76 mmol) in tetrahydrofuran (100 niL). After stirring for 10 minutes the ice-bath is removed and the contents heated to reflux for 2 hours.
  • Step D A solution of Intermediate AlOd (1.8 g, 7.62 mmol) in acetone
  • Step E A solution of intermediate AlOe (110 mg, 0.573 mmol) in dichloromethane (1 mL) is treated with triethylamine (120 ⁇ L, 0.860 mmol), benzoyl chloride (80 ⁇ L, 0.688 mmol), and DMAP (5 mg, 0.04 mmol). After stirring for 2 hours the reaction is quenched with water and the aqueous layer extracted with
  • Step F A solution of Intermediate AlOf (1.34 g, 4.53 mmol) and dimethylformamide diethyl acetal (3.9 mL, 22.63 mmol) is heated at 125 0 C for 16 hours. Excess dimethylformamide diethyl acetal is removed and the crude is purified by flash chromatography (80 g SiO 2 , hexanes/ethyl acetate gradient) to afford 2-benzyl-5- (dimethylamino)-2-methyl-3-oxopent-4-enyl benzoate AlOg as a yellow oil.
  • Step G In a Smith Process vial charged with Intermediate AlOg (1.34 g,
  • Step H To a solution of Intermediate AlOh (1.34 g, 2.79 mmol) in methanol (120 mL) is added sodium methoxide (2M solution in methanol, 6 mL, 12 mmol) and the mixture is stirred for 1.5 hours. Methanol is removed under vacuum and the residue partitioned between saturated aqueous NH 4 Cl and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x). The combined organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step I To a solution of Intermediate AlOi (20 mg, 0.053 mmol) in dichloromethane (1 rnL) is added diisopropylethylamine (13 ⁇ L, 0.080 mmol) followed by methanesulfonyl chloride (5 ⁇ L, 0.064 mmol). After 1 hour the reation is quenched with water and the aqueous layer is extracted with dichloromethane. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step A To a mixture of tetrabutyl ammonium bromide (247 mg, 0.768 mmol) in 50% aqueous NaOH (7 mL) is added a solution of dibromo-oxylene (4.05 g, 15.36 mmol) in toluene (20 mL) and stirred vigourosly. Next, a solution of
  • Step B A solution of Intermediate A13b (432 mg, 1.86 mmol) in dimethylformamide diethyl acetal (683 ⁇ L, 3.72 mmol) is heated at 120 0 C for 16 hours.
  • Step C In a Smith Process vial charged with Intermediate A13c (45 mg,
  • Step A A solution of Intermediate AlOa (2.1 g, 9 mmol) and
  • Step B A solution of Intermediate A14a (2.48 g, 8.6 mmol) in ethanol
  • Step A To a solution of intermediate A14a (720 mg, 2.49 mmol) in chloroform (20 mL) is added iV-chlorosuccinimide (366 mg, 2.75 mmL) and the mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (80 g SiO 2 , hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4-chloro-5-(dimethylamino)-2-methyl-3-oxopent-4-enoate A15a as a yellow solid.
  • Step B In a Smith Process vial charged with Intermediate A15a (458 mg,
  • Example A16 is obtained.
  • Step A A solution of Intermediate A14a (204 mg, 0.71 mmol) in dichloromethane (7 rnL) cooled to -15 0 C is treated with a solution of N-fluoro benzenesulfonamide (267 mg, 0.85 mmL) in acetonitrile (10 mL). The mixture is then allowed to stir at room temperature overnight. The solvent is removed in vacuo and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-5-(dimethylamino)-4-fluoro-2-methyl-3-oxopent-4-enoate A17a as a yellow oil.
  • Step B By following a similar procedure as the one used for preparing
  • Step A A solution of diisopropylamine (589 mg, 5.8 mmol) in tetrahydrofuran (10 niL) is cooled to -78 0 C (dry ice/acetone bath) and treated with butyllithium (2.46 M in hexane, 1.73 rnL, 4.3 mmol) dropwise and allowed to stir cold for 15 minutes. The reaction is then treated dropwise with a solution of Intermediate A18a (870 mg, 3.9 mmol) in tetrahydrofuran (2 mL) and stirred cold for 20 minutes.
  • Step B A solution of Intermediate A18b (489 mg, 0.19 mmol) and hydrazine hydrate (133 mg, 1.9 mmol) in ethanol (10 mL) and water (2 mL) is heated to 60 0 C for 2 hours. The reaction is then cooled to room temperature and the solvent is removed to afford tert-butyl 4-(5-amino-lH-pyrazol-4-yl)piperidine-l-carboxylate A18c; ESIMS calcd. for Ci 3 H 23 N 4 O 2 ([M+H] + ) 267.2, found 267.1. The product is used without purification.
  • Step C A solution of Intermediate A18c (94.3 mg, 0.35 mmol) and
  • Step A A solution of Intermediate A21a (1 g, 6.94 mmol) in
  • tetrahydrofuran (5 rnL) is added slowly to a pre-cooled (O 0 C) mixture of 60% NaH (333 mg, 8.33 mmol) in tetrahydrofuran (20 mL) and stirred for 1 hour. The mixture is then cooled to -78 0 C, NBS (1.35 g, 7.63 mmol) is added in one portion and the mixture is allowed to stir for an additional 1 hour. The reaction is quenched with water and allowed to warm to room temperature at which time tetrahydrofuran is removed under reduced pressure. The remaining residue is partitioned between water and ethyl acetate and the aqueous layer is extracted with ethyl acetate.
  • Step B To a solution of Intermediate A21b (100 mg, 0.45 mmol) in toluene (2 rnL) is added Cs 2 CO 3 (176 mg, 0.54 mmol) followed by phenol (42 mg, 0.45 mmol). The mixture is then heated to 120 0 C for 2 hours, the contents cooled, and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to afford ethyl 2-methyl-3-oxo-2-phenoxybutanoate A21c.
  • Step C A solution of Intermediate A21c (70 mg, 0.297) and
  • dimethylformamide diethyl acetal (3 mL) is heated at 100 0 C for 16 hours. Excess dimethylformamide diethyl acetal is removed in vacuo and the crude is purified by flash chromatography (12 g SiO 2 ) to afford ethyl 5-(dimethylamino)-2-methyl-3-oxo-2- phenoxypent-4-enoate A21d as an orange oil.
  • Step D In a Smith Process vial charged with Intermediate A21d (43 mg,
  • Step A A solution of Intermediate A22a (1 g, 4.58 mmol) and
  • dimethylformamide-DEA (1.6 rnL, 9.33 mmol) is heated at 120 0 C for 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzylidene-5-(dimethylamino)-3- oxopent-4-enoate A22b as a 1.5:1 mixture of isomers.
  • Step B In a Smith Process vial charged with Intermediate A22b (69 mg,
  • Step A A solution of Intermediate A23a (260 mg, 1.12 mmol; prepared following experimental procedure from Synthesis 1992, 884-887) and
  • dimethylformamide-DEA (1 mL, 5.83 mmol) is heated at 80 0 C for 16 hours and then at 120 0 C for another 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl l-(3- (dimethylamino)acryloyl)-2-phenylcyclopropanecarboxylate A23b as an orange oil.
  • ESIMS calcd. for Ci 7 H 22 NO 3 ([M+H] + ) 288.1, found 288.2.
  • Step B A solution of Intermediate A23b (233 mg, 0.81 mmol) and 4-(4-
  • Step C A solution of Intermediate A23c (33 mg, 0.07 mmol) in
  • Step A To a O 0 C solution of intermediate A14a (300 mg, 1.04 mmol) in ethanol (1 niL) is added dropwise a solution of hydroxylamine hydrochloride (72 mg, 1.04 mmol) and sodium acetate (128 mg, 1.56 mmol) in water (1 mL). The mixture is then stirred for 17 hours while allowed to warm to room temperature. The solvent is evaporated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-5-(hydroxyimino)-2-methyl-3-oxopentanoate A26a as a white oil.
  • ESIMS calcd. for Ci 5 H 20 NO 4 ([M+H] + ) 278.1, found 278.1.
  • Step B A solution of Intermediate A26a (153 mg, 0.55 mmol) and dimethylformamide-DEA (0.5 mL, 2.92 mmol) is stirred at room temperature for 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4-cyano-5- (dimethylamino)-2-methyl-3-oxopent-4-enoate A26b as a yellow oil.
  • Step C In a Smith Process vial charged with Intermediate A26b (58 mg,
  • Step A A solution of Intermediate A27a (486 mg, 2.55 mmol; prepared following experimental procedure from Synthesis 1989, 688-690) and
  • dimethylformamide-DEA (2 mL, 11.7 mmol) is heated at 120 0 C for 16 hours. Excess dimethylformamide-DEA is removed and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford 5-(dimethylamino)-2,2- dimethyl- l-phenylpent-4-ene-l,3-dione A27b as an orange oil.
  • ESIMS calcd. for
  • Step B In a Smith Process vial charged with Intermediate A27b (54 mg,
  • Step A To a solution of Intermediate A14a (80 mg, 0.27 mmol) in CHCl 3
  • N-bromo succinimide 60 mg, 0.37 mmL
  • N-bromo succinimide 60 mg, 0.37 mmL
  • the solvent is removed and the remaining contents partitioned between water and ethyl acetate.
  • the organic layer is washed with 10% aqueous NaHSO 3 , dried over Na 2 SO 4 , and volatiles are removed to afford 2-benzyl-4- bromo-5-(dimethylamino)-2-methyl-3-oxopent-4-enoate A28a.
  • the product is used without further purification.
  • Step B In a Smith Process vial charged with Intermediate A28a (1.90 g,
  • Step A By following a similar procedure as the one used for preparing
  • Step B By following a similar procedure as the one used for preparing
  • Step C By following a similar procedure as the one used for preparing
  • Step A Into a 50 ml round bottom flask is placed methyl 2-((l,3- dioxoisoindolin-2-yl)methyl)-3-oxobutanoate A31a (500 mg, 1.18 mmol), K 2 CO 3 (376 mg, 2.27 mmol), benzyl bromide (258 ⁇ L, 2.17 mmol), and acetonitrile (20 ml) and the mixture is stirred for 24 hours. The mixture is partitioned between water and ethyl acetate and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step B A 20 ml vial is charged with Intermediate A3 Ib (134 mg, 0.367 mmol) and dimethylformamide-dimethylacetal (1.5 ml) and the mixture is heated to 110 0 C for 24 hours. The solvent is removed and the crude material is purified by flash chromatography (12 g SiO 2 , hexanes/ethyl acetate gradient) to afford methyl 2-benzyl-5- (dimethylamino)-2-((l,3-dioxoisoindolin-2-yl)methyl)-3-oxopent-4-enoate A31c as a dark yellow oil.
  • Step C Into a 20 ml vial is placed 4-(4-trifluoromethylphenyl)- IH- pyrazol-5-amine (60 mg, 0.262 mmol), Intermediate A31c (110 mg, 0.262 mmol), acetic acid (200 ⁇ L), and methanol (2 ml).
  • Step D Into a 20 ml vial is placed Intermediate A3 Id (13 mg, 0.022 mmol), hydrazine monohydrate (5 ⁇ L, 0.089 mmol), methanol (200 ⁇ L), and
  • Step A A solution of 3-methyl-lH-pyrazol-5-amine A32a (1 g, O.Olmol) in acetic acid (10 niL) is treated with cyclohexanone (1.2 rnL, 0.012 mol) and stirred at 7O 0 C overnight. The reaction is cooled to room temperature, concentrated, and the crude material is purified by reversed-phase HPLC (acetonitrile/water gradient) to afford 4- cyclohexenyl-3-methyl-lH-pyrazol-5-amine A32b.
  • acetic acid 10 niL
  • cyclohexanone 1.2 rnL, 0.012 mol
  • Step B By following a similar procedure as the one used for preparing
  • Example A34 is obtained: ESIMS calcd. for C 20 H 19 F 3 N 3 O 4 ([M+H] + ) 422.1, found 422.1.
  • Example A35
  • Example A36 ESIMS calcd. for C 27 H 25 F 3 N 3 O 4 ([M+H] + ) 511.2, found 511.1.
  • Step A A mixture of methanesulfonyl acetone A37a (2.0 g, 14.7 mmol), potassium carbonate (2.0 g, 14.7 mmol) and methyl iodide (916 ⁇ L, 14.7 mmol) in acetone (50 mL) is stirred at room temperature for 2h. The mixture is then filtered, concentrated, and the crude material is purified by flash chromatography (SiO 2 , hexanes/ethyl acetate gradient) to provide 3-(methylsulfonyl)butan-2-one A37b.
  • ESIMS calcd. for C 5 H 11 O 3 S ([M+H] + ) 151.0, found 151.0.
  • Step B A mixture of Intermediate A37b (753 mg, 5.0 mmol), benzyl bromide (566 ⁇ L, 4.8 mmol) and potassium carbonate (1.38 g, 10.0 mmol) is stirred in acetone (25 mL) at room temperature for 3h.
  • Step C A solution of Intermediate A37c (300 mg, 1.25 mmol) and N,N- dimethylformamide dimethyl acetal (167 ⁇ L, 1.25 mmol) are heated to 100 0 C for 12h. The mixture is concentrated to provide (E)-l-(dimethylamino)-4-methyl-4- (methylsulfonyl)-5-phenylpent-l-en-3-one A37d, which is used directly in the next step without further purification.
  • ESIMS calcd. for C15H22NO3S ([M+H]+) 296.1, found 296.0.
  • Step D A mixture of 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine
  • Step A Ethyl 2-methyl-3-oxobutanoate A21a (1.25 g, 8.7 mmol) is dissolved in acetone (10 niL), then potassium carbonate (1.43 g, 10.4 mmol) and 3- fluorobenzyl chloride (2.1 mL, 17.3 mmol) are added and the mixture is heated for 12h at 60 0 C. The mixture is cooled, filtered, concentrated, and the crude material is purified by flash chromatography (SiO 2 , hexanes/ethyl acetate gradient) to provide ethyl 2-(3- fluorobenzyl)-2-methyl-3-oxobutanoate A38a: ESIMS calcd. for Ci 4 Hi 8 FO 3 ([M+H] + ) 253.1, found 253.1.
  • Step B A solution of Intermediate A38a (1.93 g, 7.65 mmol) and N,N- dimethylformamide diethyl acetal (1.31 mL, 7.65 mmol) are heated at 100 0 C for 12h. The mixture is concentrated to afford (E)-ethyl 5-(dimethylamino)-2-(3-fluorobenzyl)-2- methyl-3-oxopent-4-enoate A38b as a red-brown oil.
  • ESIMS calcd. for Ci 7 H 23 FNO 3 ([M+H] + ) 308.2, found 308.1. The product is used in the next step without purification.
  • Step C A solution of 4-trifluoromethylphenylacetonitrile (0.54 g, 2.9 mmol) and N,N-dimethylacetamide dimethyl acetal (0.42 niL, 2.9 mmol) is heated to 100 0 C for 2h. The mixture is concentrated to afford (Z)-3-(dimethylamino)-2-(4- (trifluoromethyl)phenyl)but-2-enenitrile A38c, which is used in the next step without further purification.
  • ESIMS calcd. for Ci 3 H 14 F 3 N 2 ([M+H] + ) 255.1, found 255.1.
  • Step D A solution of Intermediate A38c (2.9 mmol) and hydrazine-HCl
  • Step E A mixture of Interemediate A38b (209 mg, 0.68 mmol) and
  • Step A By following a similar procedure as the one used for preparing
  • Step B A mixture of Intermediate BIa (65 mg, 0.17 mmol),
  • Step A By following a similar procedure as the one used for preparing
  • Example Al from intermediate Alb except substituting 4-bromo-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine, Example B4a is obtained; ESIMS calcd. for Ci 8 Hi 9 BrN 3 O 2 ([M+H] + ) 388.1, found 388.1.
  • Step B By following a similar procedure as the one used for preparing
  • a Smith Process vial charged with Intermediate B4a (48 mg, 0.12 mmol), biphenylboronic acid (30 mg, 0.12 mmol) and cesium fluoride (57 mg, 3.7 mmol) in dioxane (1 mL) is treated with Pd 2 dba 3 (2.3 mg, 2.5 ⁇ mol) and tri-tert-butylphosphonium tetrafluoroborate (2.2 mg, 7.5 ⁇ mol).
  • the vial is then sealed and the mixture is subjected to microwave irradiation (120 0 C, 20 min).
  • the reaction mixture is cooled and partitioned between ethyl acetate and water.
  • Example A14 38 mg, 0.08 mmol
  • pyridin-3-yl boronic acid 30 mg, 0.2 mmol
  • powdered potassium carbonate 50 mg, 0.36 mmol
  • dimethoxyethane 2.5 mL
  • water 0.5 mL
  • Tetrakis(triphenylphosphino)-palladium(II) 30 mg, 0.03 mmol
  • Example B19 from Example A14 except substituting pyridin-4-yl boronic acid for pyridin-3-yl boronic acid, Example B20 is obtained; ESIMS calcd. for C 29 H 27 N 4 O 2 ([M+H] + ) 463.2, found 463.1.
  • Example B21 from Example A14 except substituting 1-phenylethanamine for (6- (trifluoromethyl)pyridin-3-yl)methanamine, Example B22 is obtained; ESIMS calcd. for C 32 H 33 N 4 O 2 ([M+H] + ) 505.2, found 505.1.
  • Step A By following a similar procedure as the one used for preparing
  • Step B By following a similar procedure as the one used for preparing
  • Step A A solution of Intermediate B23a (109 mg, 0.25 mmol) in tetrahydrofuran (250 ⁇ L) is cooled to 0 0 C (ice/water bath) and treated isopropyl magnesium chloride (2M in tetrahydrofuran, 163 ⁇ L, 0.33 mmol) over 2 minutes and allowed to stir cold for 1 hour. The reaction is then treated with a 1 M zinc chloride in diethyl ether (0.376 mL, 0.38 mmol), stirred cold for an additional hour and then warmed to room temperature. The reaction is then treated with a solution of 2-trifluoromethyl-5- bromopyridine (85 mg, 0.38 mmol) and Pd(PPh 3 ) 4 (5.8 mg, 5.0 ⁇ mol) in
  • Step A By following a similar procedure as the one used for preparing
  • Step B A solution of intermediate B27a (51 mg, 0.13 mol) in
  • dimethylformamide (1 mL) is treated with dimethylamine (2M in tetrahydrofuran, 0.13 mL), sealed and heated to 100 0 C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water.
  • Example B28 A solution of Example B28 (41.6 mg, 85 ⁇ mol) in dichloromethane (0.5 niL) and trifluoroacetic acid (0.5 niL) is aged for 1 hour and the solvent is removed. The reaction is then treated with dichloromethane (1 mL), 1-methylcyclopropyl 4-nitrophenyl carbonate (21 mg, 89 ⁇ mol) and triethylamine (30 ⁇ L, 0.21 mmol). The reaction mixture is stirred for 1.5 hours and partitioned between ethyl acetate and water.
  • Example B31 To a solution of Example B31 (41 mg, 0.1 mmol) in dichloromethane (0.3 mL) is added deoxo-fluor (31 ⁇ L, 0.17 mmol) and stirred at room temperature for 4 h. Another portion of deoxo-fluor (31 ⁇ L, 0.17 mmol) is added and the reaction mixture stirred at room temperature overnight. The excess of reagent is quenched with saturated aqueous NaHCO 3 (1 mL), extracted with dichloromethane (3 x 10 mL), dried (Na 2 SO 4 ) and concentrated.
  • Step A By following a similar procedure as the one used for preparing
  • Step B A cold (O 0 C) solution of Intermediate B41a (50.1 mg, 0.113 mmol) in tetrahydrofuran (1 rnL) is treated with methyl magnesium bromide (3M in diethyl ether, 0.79 mL) and stirred for 2.5 hours. The reaction mixture is then quenched with water and extracted with ethyl actetate.
  • Example B41 from Intermediate B41a except substituting pentamethylene (bis) magnesium bromide for methyl magnesium bromide, Example B42 is obtained; ESIMS calcd. for C 30 H 34 N 3 O 3 ([M+H] + ) 484.6, found 484.1.
  • Example B43
  • Step A By following a similar procedure as the one used for preparing
  • Step B A solution of Intermediate CIa (129 mg, 0.36 mol) in dimethylformamide (1.5 mL) is treated with N-hydroxysuccinimide (59 mg) and EDC (91 mg, 0.47 mmol) and stirred overnight at room temperature. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered, evaporated and the residue is purified by flash chromatography
  • Step C A solution of Intermediate CIb (137 mg, 0.30 mmol) and N'- hydroxyisobutyrimidamide in dioxane (2 mL) is sealed and heated to 110 0 C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered, evaporated and the residue is purified on a reversed phase HPLC (H 2 O/MeCN gradient) to provide the title compound
  • Step A Asolution of diisopropylamine (3.08 g, 30.5 mmol) in tetrahydrofuran (20 rnL) is cooled in a dry ice/acetone bath and treated with a solution of butyllithium (6.7 rnL of a 2.5 M solution, 16.8 mmol) and allowed to stir cold for 15 minutes. The reaction is then treated with Intermediate DIa (2.0 g, 15.3 mmol) and allowed to stir for 15 minutes cold. The reaction is then allowed to come to room temperature over 30 minutes and treated with ethyl acetate (669 mg, 7.6 mmol) and stirred for an additional 30 minutes.
  • dimethylformamide dimethyl acetal (3.5 ml, excess) is heated to 100 0 C for 1 hour and the solvent is removed in vacuo. The residue is coevaporated with ethanol twice and then dissolved in ethanol (5 mL) and treated with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (726 mg, 3.75 mmol) and 4M HCl in dioxane (1 mL, 4 mmol). The reaction is heated to 150 0 C for 30 minutes, cooled to room temperature, diluted with ethyl acetate and washed with water (3x).
  • Example Dl 75 mg, 0.36 mol
  • methanol 1 mL
  • a 50% aqueous solution of hydroxylamine N-hydroxysuccinimide 50 ⁇ L, 0.76 mmol
  • the reaction is then cooled to room temperature and the solvent was removed.
  • the residue is co evaporated with dioxane and treated with dioxane (1 mL) followed by acetic anhydride (42 mg, 0.42 mmol).
  • the reaction is heated to 120 0 C for 2 hours.
  • 50 ⁇ L of acetic acid is added and the reaction is heated to 120 0 C for 3 days.
  • the reaction is cooled to room temperature and the solvent is removed.
  • Step A A solution of Intermediate EIa (250 mg, 1.8 mmol), amidine hydrochloride (157 mg, 2.0 mmol) and potassium cyanide (122 mg, 1.9 mmol) in a mxture of ethanol (3 mL) and water (3 mL) is heated to 50 0 C overnight. The reaction is then diluted with ethyl acetate and the organics are extracted twice with 1 M NaOH. The aqueous phase is discarded and the organics are extracted twice with 1 M HCl and discarded. The combined aqueous layers are made basic with solid Na 2 CO 3 , extracted twice with ethyl acetate.
  • Step B By following a similar procedure as the one used for preparing
  • Step A A solution of Intermediate AlOa (600 mg, 2.6 mmol) in acetic acid (8 mL) is treated with bromine (409 mg, 2.6 mmol) and stirred at room temperature overnight. The reaction is then diluted with ethyl acetate and the organics are extracted with IM NaOH (Ix) and with saturated aqueous sodiumhydrogencarbonate (2x). The organics are isolated, dried over MgSO 4 , filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4- bromo-2-methyl-3-oxobutanoate FIa; ESIMS calcd. for Ci 4 Hi 8 BrO 3 ([M+H] + ) 313.0, found 313.0.
  • Step B A solution of Intermediate FIa (95 mg, 0.30 mmol) in tetrahydrofuran (3 rnL) is treated with triphenylphosphine (180 mg, 0.69 mmol) and heated to 50 0 C overnight. The reaction is then evaporated to dryness and the residue is treated with ether and the ether is decanted. This procedure is repeated a total of 6 times and the resulting residue is dissolved in dichloromethane. A separate flask is charged with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (194 mg, lmmol) followed by cone. HCl (0.5 mL) and water (2 mL).
  • the resulting suspension is then treated with sodium nitrite (69 mg, 1 mmol) in water (0.3 mL) and stirred for 30 minutes.
  • the reaction is quenched with a saturated aqueous solution of sodium carbonate and when the bubbling subsides, the ylide solution prepared above is added to the reaction and stirring is maintained for 1 hour.
  • the entire reaction is then poured onto a silica gel plug and eluted with
  • Step A Into a 100 ml round bottom flask containing methyl 3- oxopentanoate (3.0 g, 23.0 mmol) in acetonitrile (40 ml) is added K 2 CO 3 (4.76 g, 34.5 mmol) followed by benzyl bromide (2.6 ml, 21.9 mmol). After stirring for 72 hours the mixture is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x), the combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. Purification of the crude material by flash
  • Step B To a 100 ml round bottom flask containing Intermediate F2b (2.3 g, 10.45 mmol) in acetonitrile (30 ml) is added K 2 CO 3 (2.16 g, 15.67 mmol) followed by methyl iodide (1.62 ml, 26.12 mmol). The mixture is refluxed for 24 hours and acetonitrile is removed under vacuum. The contents are partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x), the combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step C To a 20 ml vial containing Intermediate F2c (500 mg, 2.13 mmol) in acetic acid (3 ml), bromine (109 ⁇ L, 2.13 mmol) is added dropwise at room temperature
  • Step D To a 20 ml vial containing Intermediate F2d (625 mg, 1.99 mmol) in toluene (5 ml) is added triethyl phosphite (1.74 ml, 9.98 mmol) and the mixture is heated at 130 0 C for 18 hours. The solvent is removed and the crude material is purified by flash chromatography (40 g SiO 2 , hexanes/ethyl acetate gradient) to yield methyl 2- benzyl-4-(diethoxyphosphoryl)-2-methyl-3-oxopentanoate F2e as a clear oil.
  • ESEVIS calcd. for Ci 8 H 28 O 6 P ([M+H] + ) 371.1, found 371.1.
  • Step E To a 20 ml vial containing 4-(4-trifluoromethylphenyl)- IH- pyrazol-5-amine (100 mg, 0.440 mmol) in acetic acid (1 ml) is added a solution Of NaNO 2 (30 mg, 0.440 mmol) in water (100 ⁇ L). After 10 minutes the reaction is diluted with dichloromethane (3 ml) and treated with saturated aqueous Na 2 CO 3 until p ⁇ > 8. A solution of Intermediate F2e (125 mg, 0.338 mmol) in dichloromethane (1 ml) is then added and the mixture is stirred for 6 hours. The mixture is then partitioned between brine and dichloromethane.
  • Example F2 The aqueous layer is extracted with dichloromethane (Ix) and the combined organic layers are washed with brine, dried over MgSO 4 and evaporated in vacuo.
  • the crude material is dissolved in MeOH (2 ml) and is then subjected to microwave irradiation (150 0 C, 2 hours). The solvent is removed and the crude material is purified by flash chromatography (12 g SiO 2 , hexanes/ethyl acetate gradient) to afford the title compound (Example F2) as a yellow semi-solid.
  • Step A A sample of Intermediate F5a is prepared from Intermediate FIa in an analogous manner as the preparation of Intermediate F2e from Intermediate F2d.
  • a solution of potassium tert-butoxide (234 mg, 2.43 mmol) in tetrahydrofuran (3.5 mL) is treated with a solution of Intermediate F5a (850 mg, 2.43 mmol) in tetrahydrofuran (7 mL) and added to a cooled (ice/water) suspension of Selectfluor (1.72 g, 4.86 mmol) in acetonitrile (7 mL). The cooling bath is removed and the reaction is allowed to stir for 3 hours at room temperature.
  • Step B A solution of 4-(4-trifluoromethylphenyl)-lH-pyrazol-5-amine
  • Step A A solution of Intermediate GIa (100 mg, 0.51 mmol) in acetic acid (1 niL) is treated with a solution of sodium nitrite (37 mg, 0.51 mmol) in water (0.5 mL). After stirring for 15 minutes, the reaction is treated with thiourea (80 mg, 1.1 mmol) and stirred for 30 minutes. The reaction immediately evolves gas and becomes thick with solid. The solvent is removed and the residue is purified on a reversed phase HPLC (H 2 OZMeCN gradient) to provide 4-(4-chlorophenyl)-lH-pyrazol-3-yl
  • Step B In a microwave vial a solution of Intermediate GIb (50 mg, 0.14 mmol) in ethanol (2 mL) is treated with potassium hydroxide (38 mg, 0.68 mmol). The vial is sealed and the mixture is subjected to microwave irradiation (100 0 C, 5 min). The reaction is then treated with 4 M HCl in dioxane (187 ⁇ L, 0,75 mmol) followed by a solution of Intermediate FIa (100 mg, 0.32 mmol) in ethanol (1 niL) and the reaction is subjected to microwave irradiation (165 0 C, 20 min).
  • Step A In a Smith Process vial charged with Example N8 (29 mg, 0.06 mmol) in iV,./V-dimethylacetamide (1.5 ml) is added Pd 2 dba 3 (2 mg, 0.0023 mmol), dppf (2.6 mg, 0.0048 mmol), zinc (1 mg, 0.012 mmol), and zinc cyanide (9 mg, 0.072 mmol). The mixture is purged with nitrogen, the vial sealed, and then evacuated and re-purged with nitrogen. The mixture is then subjected to microwave irradiation (160 0 C, 1 hour). The solution is partitioned between water and ethyl acetate.
  • Step A In a Smith Process vial charged with Example N8 (30 mg, 0.062 mmol) in dioxane (1 ml) is added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (85 ⁇ L, 0.62 mmol), Pd(dppf)Cl 2 - dichloromethane complex (5 mg, 0.0062 mmol), and IM aqueous cesium carbonate (124 ⁇ L, 0.124 mmol). The mixture is purged with nitrogen, the vial sealed, and then evacuated and re-purged with nitrogen. The mixture is then subjected to microwave irradiation (160 0 C, 10 minutes).
  • Step A In a Smith Process vial charged with Example N8 (60 mg, 0.082 mmol) in dioxane (3 ml) and water (300 ⁇ L) is added potassium
  • Step A A cold (O 0 C) solution of Intermediate B23a (141 mg, 0.323 mmol) tetrahydrofuran (2 niL) is treated with the dropwise addition of isopropylmagnesium chloride (2.0M in tetrahydrofuran, 178 ⁇ L, 0.356 mmol) and stirred for 15 minutes. Dimethylformamide (100 ⁇ L) is then added. After 30 minutes, water is added and the reaction extracted with ethylacetate. The organics are dried (MgSO 4 ), filtered, concentrated, and the crude material is purified by flash chromatography
  • Step B A mixture of Intermediate Ha (77 mg, 0.23 mmol) and sodium metabisulfite (43 mg, 0.23 mmol) in dimethylformamide (1.5 mL) is heated to HO 0 C and maintained for 10 min. 4-(trifluoromethyl)benzene-l,2-diamine (35 mg, 0.20 mmol) is added and the reaction stirred at 11O 0 C for 3 hours. The reaction is cooled to room temperature, diluted with water and extracted with ethylacetate. The organics are dried (MgSO 4 ), filtered, concentrated, and the crude material is purified by flash
  • Step A A solution of Intermediate JIa (346 mg, 1 mmol) (prepared according to S.Pirc, D. Bevk, A. Golobic, B.Stanovnik, J.Svete, HeIv. Chim. Acta, 2006, 89, 30-44) and 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-3-amine (250 mg, 1.1 mmol) in ethanol (8 mL) and 37% aq HCl (100 ⁇ L, 1.2 mmol) is heated to 7O 0 C overnight. The reaction mixture is then cooled to -30 0 C. The resulting precipitate is filtered and washed with cold ethanol to afford tert-butyl 2-phenyl-l-(3-(4-
  • Step C To a solution of Intermediate JIc (46 mg, 0.12 mmol) in dichloromethane (2 rnL) is added diisopropylethylamine (128 ⁇ L, 0.72 mmol) followed by acetyl chloride (32 ⁇ L, 0.45 mmol) and the mixture is stirred overnight at room temperature. Dichloromethane is then added and the reaction mixture is washed with brine, 10% aqueous citric acid solution, brine, saturated aqueous NaHCO 3 solution, and brine.
  • the organic phase is dried (Na 2 SO 4 ), filtered, evaporated and the residue is purified by chiral chromatography using a Chiral Technologies 10x250mm ChiralPak IC column with a 7 minute isocratic elution using CO 2 /75:25 THF:MeOH (80:20) as mobile phase at 10 mL per minute.
  • the second eluting peak is collected and reanalyzed on a using a Chiral Technologies 4.6xl00mm ChiralPak IC column with 5 minute isocratic elution using CO 2 /75:25 THF:MeOH (80:20) as mobile phase at 2 mL per minute and 30 0 C.
  • Step A A solution of Intermediate J4a (0.91 g, 2.96 mmol) in anhydrous toluene is cooled to -78°C and treated dropwise with diisobutylaluminium hydride (IM in toluene, 7.4 rnL, 7.4 mmol). After stirring the reaction mixture at -78°C for 2 hours methanol (0.75 mL) is added followed by saturated NaHCO 3 (20 mL). The flask is warmed to RT, water (10 mL) and ether (10 mL) are added and stirred for another 1 hour. Organics are extracted with ether, dried with Na 2 SO 4 and concentrated.
  • IM in toluene 7.4 rnL, 7.4 mmol
  • the mixture consists mostly of tert-butyl l-hydroxy-2-methyl-3-phenylpropan-2-ylcarbamate J4c (ESIMS calcd. for Ci 5 H 23 NNaO 3 ([M+Na] + ) 288.2, found 288.2) with some tert-butyl 2- methyl-l-oxo-3-phenylpropan-2-ylcarbamate J4b (ESIMS calcd. for Ci 5 H 2I NNaO 3 ([M+Na] + ) 286.1, found 286.2) and is used without purification.
  • Step B To a solution of Dess-Martin periodinane (1.506 g, 3.55 mmol) in dichloromethane (10 mL) is added a solution of Intermediates J4b and J4c (0.793 g, 2.96 mmol) in dichloromethane (10 mL) and the mixture is stirred at ROOM
  • Step C A solution of Intermediate J4b (500 mg, 1.9 mmol) in anhydrous THF (4 mL) is cooled to -78°C and ethynylmagnesium bromide (0.5 M solution in THF, 15.2 mL, 7.6 mmol) is slowly added. The cooling bath is removed and the reaction mixture is stirred for 2 hours at room temperature. The excess of
  • ethynylmagnesium bromide is quenched by addition of saturated NH 4 Cl (10 mL). The mixture is extracted with ethylacetate, the organic phase is dried (Na 2 SO 4 ) and concentrated to yield tert-butyl 3-hydroxy-2-methyl-l-phenylpent-4-yn-2-ylcarbamate J4d as a mixture of diastereomers; ESIMS calcd. for Ci 7 H 23 NNaO 3 ([M+Na] + ) 312.2, found 312.1. The crude material is used without purification.
  • Step D To a solution of Intermediate J4d (1.9 mmol) in
  • dichloromethane (5 mL) is added Dess-Martin periodinane (967 mg, 2.28 mmol) in dichloromethane (15 mL) and the mixture is stirred at room temperature overnight. Aqueous solution of NaHCO 3 and Na 2 S 2 O 3 is added, the mixture is stirred for 20 min, extracted with dichloromethane (3x), dried (Na 2 SO 4 ), and concentrated to afford tert- butyl 2-methyl-3-oxo-l-phenylpent-4-yn-2-ylcarbamate J4e; ESIMS calcd. for
  • the crude material is used in without purification.
  • Step E Diethylamine (204 ⁇ L, 2 mmol) is added to a cold (0 0 C) solution of Intermediate J4e (1.9 mmol) in dichloromethane (20 mL). The reaction mixture is stirred at room temperature overnight, the solvent is evaporated and the crude material is purified by flash chromatography (hexane/ethylacetate gradient) to afford tert-butyl 5- (diethylamino)-2-methyl-3-oxo-l-phenylpent-4-en-2-ylcarbamate J4f; ESIMS calcd. for C 2I H 33 N 2 O 3 ([M+H] + ) 361.3, found 361.2.
  • Step G A solution of Intermediate J4g (160 mg, 0.32 mmol) in dichloromethane (4 mL) is treated with trifluoroacetic acid (2 mL) and stirred at room temperature overnight. The solvent is removed, the crude material is treated with saturated aqueous NaHCO 3 and extracted with dichloromethane (3x). the combined organic phase is dried (Na 2 SO 4 ) and concentrated to yield l-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propan-2-amine J4h; ESIMS calcd. for C 22 H 20 F 3 N 4 ([M+H] + ) 397.2, found 397.2. The crude material is used in without purification.
  • Step A A sample of Example K4a is subjected to chiral chromatography using a Chiral Technologies 21x250mm ChiralPak AD-H column with a 2.5 minute stacked injections, 5 minute isocratic elution using methanol/CO 2 (30:70) as mobile phase at 8Og/ min and 40 0 C.
  • the first eluting peak is collected and reanalyzed using a Chiral Technologies 4.6x100mm ChiralPak AD-H column with 10 minute isocratic elution using methanol/CO 2 (30:70) as mobile phase at 2 mL/min and 30 0 C.
  • Intermediate J5a comes off at 1.98 min.
  • the 1 H NMR and ESIMS data for Intermediate J5a are identical to Intermediate K4a.
  • Step B To a solution of Intermediate J5a (217 mg, 0.51 mmol) in toluene (3.5 rnL) is added diisopropylethylamine (106 ⁇ L, 0.61 mmol) followed by diphenyl phosphoryl azide (132 ⁇ L, 0.61 mmol) and the reaction mixture is stirred at room temperature for 2 hours. Tert-buthanol (488 ⁇ L, 5.1 mmol) is then added and the reaction mixture is stirred at 110 0 C overnight. Water is added and the mixture is extracted with dichloromethane. The organic phase is dried (Na2SO4), concentrated in vacuo and the crude material is purified by flash chromatography (hexane/ethylacetate gradient). The 1 H NMR and ESIMS data for Intermediate J5b are identical to
  • Step C By following a similar procedure as the one used for preparing
  • Step D By following a similar procedure as the one used for preparing
  • Step A To a solution of Intermediate AlOi (116 mg, 0.308 mmol) in dichloromethane (5 mL) are added pyridine (50 ⁇ L, 0.615 mmol) and Dess-Martin reagent (261 mg, 0.615 mmol). The mixture is then stirred at room temperature for 3 hours. The mixture is quenched with 10% aqueous Na 2 S 2 O 3 and saturated aqueous Na 2 CO 3 and the aqueous layer is extracted with dichloromethane. The combined organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step B To a solution of dimethylamine in tetrahydrofuran (2M, 0.4 mL,
  • Example K2 Kl from Intermediate KIa except substituting morpholine for dimethylamine, Example K2 is obtained.
  • Step A To a solution of Intermediate K3a (25 mg, 0.061 mmol; prepared by following a similar procedure as the one used for preparing Intermediate KIa from Intermediate AlOg except substituting 4-(4-trifluoromethylphenyl)-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine in step G) in methanol (1.5 mL) is added K 2 CO 3 (25 mg, 0.183 mmol) followed by p-toluenesulfonylmethyl isocyanide (13 mg, 0.067 mmol) and the mixture is heated to 80 0 C for 16 hours.
  • K 2 CO 3 25 mg, 0.183 mmol
  • p-toluenesulfonylmethyl isocyanide 13 mg, 0.067 mmol
  • Step A To a solution of Intermediate K3a (25 mg, 0.061 mmol) in a mixture of tetrahydrofuran (300 ⁇ L), /-BuOH (500 ⁇ L), and water (100 ⁇ L) is added 2- methyl-2-butene (28 ⁇ L, 0.268 mmol) followed by NaH 2 PO 4 (25 mg, 0.213 mmol). The mixture is cooled to 0 0 C and a solution of NaClO 2 (15 mg, 0.165 mmol) in water (200 ⁇ L) is added.
  • Step B To a solution of Intermediate K4a (12 mg, 0.028 mmol) in dichloromethane (200 ⁇ L) is added oxalyl chloride (8 ⁇ L, 0.084 mmol) followed by catalytic amounts of dimethylformamide (50 ⁇ L). Reaction progress is monitored by diluting an aliquot of the reaction mixture with methanol and analyzing the conversion of K4a to the corresponding methyl ester by ESIMS. After 30 minutes, the solvent is evaporated in vacuo to afford 2-methyl-3-phenyl-2-(3-(4-
  • Step C To a solution of Intermediate K4b (45 mg, 0.027 mmol) in tetrahydrofuran (200 ⁇ L) is added an excess of 28% ammonium hydroxide and stirred at room temperature. After 10 minutes, the contents is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step D To a Smith Process vial charged with Intermediate K4c (12 mg,
  • Step A To a solution of Intermediate K4b (50 mg, 0.113 mmol) in pyridine (1 rnL) is added N-hydroxysuccinimide (20 mg, 0.169 mmol) and the mixture is stirred for 1 hour. The solvent is removed in vacuo and the residue is purified by flash chromatography (12 g SiO 2 ) to yield 2,5-dioxopyrrolidin-l-yl 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5- ⁇ ]pyrimidin-7-yl)propanoate K6a as a yellow solid.
  • Step B To a solution of Intermediate K6a (34 mg, 0.065 mmol) in dioxane
  • Step A To a solution of Intermediate K6a (120 mg, 0.230 mmol) in dioxane (1 rnL) is added hyrdrazine (73 ⁇ L, 2.30 mmol) and the mixture is stirred for 30 min. The solvent is removed in vacuo and the residue is purified by flash chromatography (12 g SiO 2 , dichloromethane/methanol gradient) to yield 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanehydrazide K7a as a yellow glass.
  • Step B To a Smith Process vial charged with Intermediate K7a (15 mg,
  • Step A A mixture of Intermediate A21a (4mL, 20 mmol) and dimethylformamide diethyl acetal (3.35 rnL, 20 mmol) is heated to 100 0 C overnight. The solvent is removed and the resulting residue of Intermediate LIa is used without further purification; ESIMS calcd. for Ci 0 H 18 NO 3 ([M+H] + ) 200.1, found 200.1.
  • Step B A solution of Intermediate LIa (1.75 mL, 8.8 mmol) in ethanol
  • Step C A mixture of Intermediate Lib (23 mg, 0.07 mmol), 4- methylbenzylbromide (16.8 mg, 0.09 mmol) and Cs 2 CO 3 (68 mg, 0.21 mmol) in acetonitrile (3 mL) is heated at 60 0 C for 3h. The mixture is cooled, filtered, and concentrated.
  • Step A A microwave vial charged with Intermediate Lib (40 mg, 0.12 mmol), Boc-4-(bromomethyl)-piperidine (56 mg, 0.18 mmol) and Cs 2 CO 3 (118 mg, 0.36 mmol) in dimethylformamide (1 mL) is subjected to microwave irradiation (180 0 C, 5 min). The mixture is then cooled, extracted with ethyl acetate, washed with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • Step B A solution of Intermediate L15a (85 mg, 0.15 mmol) in a mixture of trifluoroacetic acid (1 mL) and dichloro methane (3 mL) is stirred at room temperature for 1 hour.
  • Step C A solution of Intermediate L15b (21 mg, 0.05 mmol) and diisopropylethylamine (26 ⁇ L, 0.15 mmol) in dichloromethane (3 mL) is treated with methanesulfonyl chloride (5 ⁇ L, 0.06 mmol) and stirred at room temperature for 1 hour. The mixture is concentrated and the residue is purified by flash chromatography
  • Step A A solution of Intermediate MIa (5.28 g, 33.4 mmol) in acetone
  • Step B A solution of Intermediate MIb (8.6 g, 50 mmol) in N,N- dimethylformamide-di-te/t-butyl acetal (11.97 g, 50 mmol) is heated to 100 0 C for 3 hours. The solvent is removed and the resulting residue of MIc is used without further purification;
  • Step C A solution of Intermediate MIc (0.60 g, 2.6 mmol) in tert- butanol (6 mL) is treated with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (0.51 g, 2.6 mmol) followed by trifluoroacetic acid (0.3 mL) and heated to 60 0 C for Ih.
  • Step D A mixture of Intermediate MId (280 mg, 0.78 mmol), benzyl bromide (280 ⁇ L, 2.35 mmol) and Cs 2 CO 3 (767 mg, 2.35 mmol) in acetonitrile (5 mL) is heated at 80 0 C for 3 hours. The mixture is cooled to room temperature, and

Abstract

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPR119.

Description

COMPOUNDS AND COMPOSITIONS AS
MODULATORS OF GPR119 ACTIVITY
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Patent
Application Number 61/229,434, filed 29 July 2009. The full disclosure of this application is incorporated herein by reference in its entirety and for all purposes.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPRl 19.
[0003]
Background
[0004] GPRl 19 is a G-protein coupled receptor (GPCR) that is mainly expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of obesity and diabetes. The novel compounds of this invention modulate the activity of GPRl 19 and are, therefore, expected to be useful in the treatment of GPRl 19-associated diseases or disorders such as, but not limited to, diabetes, obesity and associated metabolic disorders.
[0005]
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides a compound of Formula I:
[0007]
Figure imgf000003_0001
[0008] in which:
[0009] R1 is selected from C2-ioalkenyl, C6-1oaryl, C6-ioaryl-C2-3alkynyl, C1.
gheteroaryl, acetylenyl, C3_gheterocycloalkyl, C3_gheterocycloalkenyl, C3_6cycloalkyl, C3_ 6cycloalkyl-C2-3alkynyl, C3_6cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R1 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, C^alkyl, halo-substituted-C1_4alkyl, Ci_4alkoxy, halo-substituted-C^alkoxy, C6-10aryl, C1-9heteroaryl, C3-8heterocycloalkyl, C3-10cycloalkyl, -C(O)OR7, -C(O)R7, - NR7R8, -S(O)1-2R7; wherein said alkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R1 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted Ci_4alkyl and Ci_4alkoxy; wherein R7 is selected from hydrogen, C1-6alkyl, C3-iocycloalkyl optionally substituted with C1-6alkyl or halo; and Rg is -X1Rg; wherein X1 is selected from a bond and Ci_4alkylene optionally substituted with halo; and R9 is selected from hydrogen, phenyl and pyridinyl; wherein said phenyl or pyridinyl of R9 is optionally substituted with 1 to 3 trifluoromethyl radicals;
[0010] Y5 is N and Y6 is CR2; or Y5 is CR2 and Y6 is N;
[0011] R2 is selected from hydrogen, C1-6alkyl, Ci_6alkoxy, halo-substituted-Ci_
6alkyl, halo-substituted-Ci-ealkoxy, -X5S(O)O2RiOa, -X5OR10a, -X5NR1Oa X5RiOb, - X5S(0)o-2NRioaRiob, -X5NRiOaRiOb, -X5C(O)NRiOaRiOb, -X5NRiObC(O)RiOa and - X5C(O)ORiOa; wherein said X5 is selected from a bond and Ci_4alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, cyano, Cό-ioaryl, C3_ 10cycloalkyl, heteroaryl or heterocycloalkyl; and R1Oa and R1Ob are independently selected from hydrogen, Ci_4alkyl, Ci_4alkoxy, C6-1oaryl, Ci_9heteroaryl and C3_gheterocycloalkyl; or R1Qa and R1Qb together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C1-4alkyl, halo-substituted-Ci^alkyl, Ci_4alkoxy, halo- substituted-Ci_4alkoxy, C6-1oaryl, Ci.gheteroaryl,
Figure imgf000004_0001
C3_iocycloalkyl, - C(O)OR10C, -C(O)R10C, -NR1Oc Riod, -S(O)1-2R1Oc; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted Ci_4alkyl and C1- 4alkoxy; wherein R1Oc and R1Od are selected from hydrogen, C1-6alkyl, C3_iocycloalkyl optionally substituted with Ci_6alkyl or halo;
[0012] R3 is selected from cyano, -C(O)ORi u, -C(O)R1 la, -X2OC(O)R1 la, -
C(O)OX2RlIa, -X2OS(0)o-2Rlla, -X2S(O)0-2RlIa, -C(O)OX2ORlIa, "
C(O)OX2C(O)NRiIaRiIb, -C(O)OX2NRi uRiib, -C(O)NRi uRiib, -X2NRnaRiib, - NRiiaC(O)Riib, -NRiiaC(0)0Rnb, -NRiiaS(0)o-2Riib, -C(O)NX2Ri IaX2RiIb, - C(O)NRiIaX2ORHb, -C(O)NRi iaX2C(0)0Rllb, -C(O)NRi iaX2C(O)NRllaRiib, - C(O)NRiIaX2OX2ORiIb, -X2RiIb; wherein each X2 is independently selected from a bond and Ci_4alkylene; wherein any methylene of X2 can have a hydrogen substituted with hydroxy; Rlla and R111, are independently selected from hydrogen, cyano, C1-4alkyl, C1- 4alkoxy, C6-1OaTyI, Ci.gheteroaryl,
Figure imgf000004_0002
wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or R1 la and R111, together with the nitrogen atom to which they are both attached form a cyclic group selected from azetidine, pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said azetidine, pyrrolidine, pyrrolidin-2-one-l-yl or morpholinyl of the combination of R1 la and Rub is optionally substituted with hydroxyl;
[0013] R4 is selected from hydrogen, C1-4alkyl, C1-4alkenyl, C6-ioarylCi_4alkyl, -
X3ORi2, -X3NRi2Ri2 and -X3C(O)ORi2; wherein X3 is selected from a bond and C1- 4alkylene; and each Ri2 is independently selected from hydrogen and C1-4alkyl; or when - Y2R5 is benzyl, the ortho hydrogen of R5 and R4 can form a cyclopentyl;
[0014] R5 is selected from hydrogen, C1-4alkyl, C6-1oaryl, Ci^heteroaryl, C3- gheterocycloalkyl; wherein said alkyl, aryl, heteroaryl or heterocycloalkyl of R5 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, - S(0)o-2Ri3a, halo-substituted-Ci_4alkyl, Ci_4alkyl, halo-substituted-Ci_4alkoxy, Ci_4alkoxy, C6-1oaryl, -C(O)NR13aR13b and -C(O)OR13a; wherein R13a and R13b are independently selected from hydrogen and C1-4alkyl;
[0015] Y1 and Y3 are independently selected from CH and N; or -Y3=Y1- is replaced with S;
[0016] Y2 is selected from a bond, CH2, C(O), NR17 and O; wherein R17 is selected from hydrogen, halo-substituted-Ci^alkyl and C1-4 alkyl; or R4 and Y2 taken together form a double bond or a cyclopropyl ring;
[0017] Y4 is selected from N and -CR6; wherein Re is selected from hydrogen, halo, cyano, Ci_6alkyl, X4NR14aR14b, X4OR14a; wherein X4 is selected from a bond, C1.
6alkylene; and R14a and R14b are independently selected from hydrogen and Ci_4alkyl; with the proviso that when Y4 is N, Y1 is CH.
[0018] In a second aspect, the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
[0019] In a third aspect, the present invention provides a method of treating a disease in an animal in which modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula
I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
[0020] In a fourth aspect, the present invention provides the use of a compound of
Formula I in the manufacture of a medicament for treating a disease in an animal in which
GPRl 19 activity contributes to the pathology and/or symptomology of the disease.
[0021] In a fifth aspect, the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0022] "Alkyl" as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be straight-chained, branched, cyclic or spiro. C1- βalkoxy includes methoxy, ethoxy, and the like. Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like. Alkylene is a divalent alkyl radical that includes -C(CH3)2-.
[0023] "Aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, aryl can be phenyl or naphthyl, preferably phenyl.
[0024] "Heteroaryl" is as defined for aryl where one or more of the ring members are a heteroatom. For example, Cμioheteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl,
benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, lH-pyridin-2-onyl, 6-oxo-l,6-dihydro- pyridin-3-yl, etc. Heteroaryl also includes the N-oxide derivatives, for example, pyridine N-oxide derivatives with the following structure:
Figure imgf000006_0001
[0025] "Ce-ioarylCi^alkyl" means an aryl as described above connected via a alkylene grouping. For example, C6-1oarylC1_4alkyl includes phenethyl, benzyl, etc. C6-
1oaryl-C2-3alkynyl includes, for example, phenyl-ethynyl, etc.
[0026] "Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated. For example, C3_iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
[0027] "Enantiomers" as used in this application for compounds of Formula I, describe each chiral center as labeled R or S according to a system by which its substituents are each assigned a priority, according to the Cahn Ingold Prelog priority rules (CIP), based on atomic number. If the center is oriented so that the lowest-priority of the four is pointed away from a viewer, the viewer will then see two possibilities: If the priority of the remaining three substituents decreases in clockwise direction, it is labeled R (for Rectus), if it decreases in counterclockwise direction, it is S (for Sinister). For example, the R enentiomer of a compound of Formula I is where R3 has priority over the core (fused bicyclic) which has priority over Y2R5 which in turn has priority over R4. In such a case, the R-enantiomer is preferred over the S-enantiomer (see examples N1-N5).
[0028] "Heterocycloalkyl" means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected from -O-, -N=, -NR-, -C(O) -, -S-, -S(O) - or -S(O)2-; wherein R is hydrogen, C^alkyl or a nitrogen protecting group or any nitrogen substitution in the Summary of the Invention. For example, C3_8heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo-pyrrolidin-l-yl, 2-oxo-piperidin-l-yl, etc. "Heterocycloalkenyl" means heterocycloalkyl, as defined in this application, provided that at least one double bond exists in the ring.
[0029] GPRl 19 means G protein-coupled receptor 119 (GenBank® Accession No.
AAP72125) is also referred to in the literature as RUP3 and GPRl 16. The term GPRl 19 as used herein includes the human sequences found in GeneBank accession number AY288416, naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof.
[0030] "Halogen" (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
[0031] "Treat", "treating" and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms.
[0032]
Description of the Preferred Embodiments
[0033] The present invention provides compounds, compositions and methods for the treatment of diseases in which modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I. [0034] In one embodiment, with reference to compounds of Formula I, are compounds of Formula Ia, Ib and Ic:
Figure imgf000008_0001
[0035] in which: n is selected from 1, 2 and 3; R1 is selected from C2-ioalkenyl, C6- ioaryl, C6-ioaryl-C2-3alkynyl, Cμgheteroaryl, acetylenyl,
Figure imgf000008_0002
C3.
gheterocycloalkenyl, C3_6cycloalkyl, C3_6cycloalkyl-C2-3alkynyl, C3_6cycloalkenyl;
wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R1 is optionally substituted with 1 to 3 radicals
independently selected from halo, nitro, cyano, hydroxy, C^alkyl, halo-substituted-Cμ 4alkyl, Ci_4alkoxy, halo-substituted-Ci-4alkoxy, C6-1oaryl, Ci-gheteroaryl, C3- βheterocycloalkyl, C3-10cycloalkyl, -C(O)OR7, -C(O)R7, -NR7R8, -S(O)1-2R7; wherein said alkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R1 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, Ci_4alkyl, halo- substituted Ci_4alkyl and Ci_4alkoxy; wherein R7 is selected from hydrogen, Ci-βalkyl, C3- iocycloalkyl optionally substituted with Ci-βalkyl or halo; and Rg is -X1Rg; wherein X1 is selected from a bond and C^alkylene optionally substituted with halo; and R9 is selected from hydrogen, phenyl and pyridinyl; wherein said phenyl or pyridinyl of R9 is optionally substituted with 1 to 3 trifluoromethyl radicals; R2 is selected from hydrogen, Ci-βalkyl, Q-βalkoxy, halo-substituted-Ci-βalkyl, halo-substituted-Ci-βalkoxy, -XsS(O)O2RiOa, -
XsOR1Oa, -X5NR1Oa X5RlOb, -X5S(O)O-2NR1OaRlOb, -X5NR1OaRlOb, -X5C(O)NR1OaRlOb, ~
X5NR1ObC(O)R1Oa and -XsC(O)OR1Oa; wherein said X5 is selected from a bond and C1. 4alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, cyano, C6-1oaryl, C^iocycloalkyl, heteroaryl or heterocycloalkyl; and R1Oa and R1Ob are independently selected from hydrogen, Ci_4alkyl, cyano-substituted-C1_4alkyl, Ci_4alkoxy, phenyl, azetidinyl, imidazolyl and pyrazolyl; or R1Oa and R1Ob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system of R1Oa, Riob or the combination of R1Oa and R1Ob can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C1-4alkyl, halo-substituted-Ci_4alkyl, C1- 4alkoxy, halo-substituted-Ci_4alkoxy, C6-1oaryl, Ci^heteroaryl, C^heterocycloalkyl, C3- 10cycloalkyl, -C(O)OR10c, -C(O)R10c, -NR1Oc Riod, -S(O)1-2RiOc; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted C1. 4alkyl and C1-4alkoxy; wherein R1Oc and R1Od are selected from hydrogen, C1-6alkyl, C3- iocycloalkyl optionally substituted with C1-6alkyl or halo; R3 is selected from cyano, - C(O)OR1U, -C(O)R1U, -X2OC(O)Rlla, -C(O)OX2R1U, -X2OS(O)0-2Riia, -X2S(O)0. 2Rlla, -C(O)OX2ORiIa, -C(O)OX2NRiIaRiIb, -C(O)NR1 laRllb, -X2NR1 laRl lb, - NRiiaC(O)Rnb, -NRiiaC(0)0Rnb, -NRiiaS(O)0-2Riib, -C(O)NX2Ri IaX2RiIb, - C(O)NRiIaX2ORiIb, -C(O)OX2C(O)NRi uRiib, -C(O)NR1 UX2C(O)OR1 lb, - C(O)NRiiaX2C(O)NRiiaRiib, -C(O)NRi iaX2OX2ORiib, -X2RiH,; wherein each X2 is independently selected from a bond and Ci_4alkylene; wherein any methylene of X2 can have a hydrogen substituted with hydroxy; R1 la and R1 lb are independently selected from hydrogen, cyano, C1-4alkyl, Ci_4alkoxy, Cβ-ioaryl, Ci^heteroaryl, C3_8heterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or R1 la and R1 lb together with the nitrogen atom to which they are both attached form a cyclic group selected from azetidine, pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said azetidine, pyrrolidine, pyrrolidin-2-one-l-yl or
morpholinyl of the combination of R1 la and R1 lb is optionally substituted with hydroxyl; R4 is selected from hydrogen, C1-4alkyl, C1-4alkenyl, C6-ioarylCi_4alkyl, -X3ORi2, - X3NRi2Ri2 and -X3C(O)ORi2; wherein X3 is selected from a bond and Ci_4alkylene; and each Ri2 is independently selected from hydrogen and C1-4alkyl; Re is selected from hydrogen, halo, cyano, C1-6alkyl, X4NRi4aRi4b, X4ORi4a; wherein X4 is selected from a bond, Ci_6alkylene; and Ri4a and Ri4b are independently selected from hydrogen and C1- 4alkyl; Rig is selected halo, cyano, -S(0)o-2Ri3a,halo-substituted-Ci_4alkyl, C1-4alkyl, halo- substituted-Ci-4alkoxy, Ci-4alkoxy, Cβ-ioaryl, -C(O)NRi8aRi8b and -C(0)0Ri8a; wherein R18a and R18b are independently selected from hydrogen and Ci_4alkyl; and Y2 is selected from CH2, C(O) and NR17; wherein R17 is selected from hydrogen and methyl.
[0036] In another embodiment, R1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, benzimidazolyl, styryl, l,2,4-oxadiazol-5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy-carbonyl, methyl-sulfonyl, t-butoxy-carbonyl, dimethyl- amino, 2-hydroxypropan-2-yl, 2- fluoropropan-2-yl, 1-phenylethylamino, (l-methylcyclopropoxy)carbonyl, t-butyl, (6- (trifluoromethyl)pyridin-3-yl)methyl-amino, 6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl, phenyl, pyridinyl, cyclohexyl and cyclopropyl; wherein said cyclohexyl or cyclopropyl substituent of R1 is optionally substituted with a radical selected from hydroxy, halo, isopropyl, dimethylamine and methyl.
[0037] In another embodiment, R3 is selected from: cyano; ethoxy-methyl; (2- methoxyethyl)(methyl)carbamoyl; (tetrahydro-2H-pyran-4-yloxy)carbonyl;
(ethyl)(methyl)carbamoyl; (4-hydroxybutoxy)carbonyl; hydroxy-propyl-carbamoyl;
thiazolyl-methyl; pyrazinyl-methyl; pyridinyl-methyl; (2-(dimethylamino)-2- oxoethyl)(methyl)carbamoyl; (2-(2-oxopyrrolidin- l-yl)ethoxy)carbonyl; 3- hydroxypyrrolidine-1-carbonyl; (carboxymethyl)(methyl)carbamoyl; (2,3- dihydroxypropyl)(methyl)carbamoyl; tetrahydrofuran-3-ylcarbamoyl; ((1-methyl-lH- imidazol-4-yl)methoxy)carbonyl; (azetidin-3-ylmethoxy)carbonyl; (2-hydroxy-3- (methylamino)propoxy)carbonyl; dimethoxy-ethyl-carbamoyl,
(cyanomethyl)(methyl)carbamoyl; pyrazolyl-methyl optionally substituted with methyl; methoxy-carbonyl; methoxy-ethyl-carbamoyl; carbamoyl-methoxy-carbonyl; (methoxy- propoxy-ethyl)(methyl)carbamoyl; (methoxy-ethoxy-ethyl)(methyl)carbamoyl; 3- hydroxyazetidine- 1-carbonyl; (methoxy-propyl)(methyl)carbamoyl; ethoxy-carbonyl; (furan-2-ylmethyl)(methyl)carbamoyl; (morpholino-methyl)(methyl)carbamoyl; 5- methyloxazol-2-yl); (2-methoxyethoxy)carbonyl; butyl(methyl)carbamoyl; dimethyl- amino-carbonyl; isopropyl-carbamoyl; (propyl)(methyl)carbamoyl; (ethyl)methyl-amino- carbonyl; methyl((tetrahydrofuran-2-yl)methyl)carbamoyl; (2-methoxy-2- oxoethyl)(methyl)carbamoyl; methoxy-ethyl-carbamoyl; methoxy-propoxy-carbonyl; methoxy-butoxy-carbonyl; (cyanomethyl)(methyl)carbamoyl; hydroxy-ethoxy-carbonyl, hydroxy-ethoxy-ethyl-carbamoyl; (hydroxy-propyl)(methyl)carbamoyl;
(hydroxyethyl)(methyl)carbamoyl; acetamido, isobutyramido;
(hydroxypropyl)(methyl)carbamoyl; isopropoxy-carbonyl; ethyl-carbamoyl; dimethoxy- ethyl-carbamoyl; hydroxy-ethoxy-carbonyl; hydroxy-propoxy-carbonyl; (methoxy- ethoxy-ethyl)(methyl)carbamoyl; butyl-carbamoyl; carbamoyl-methoxy-carbonyl;
(methoxy-carbonyl-methyl)(methyl)carbamoyl; (methoxyethyl)(methyl)carbamoyl; pyrrolidine- 1-carbonyl; hydroxy-ethyl-carbamoyl; methoxy-carbonyl-ethyl-carbamoyl; morpholino-methyl; t-butoxy-carbonyl; (tetrahydro-2H-pyran-4-yloxy)carbonyl;
morpholino-ethoxy-carbonyl; morpholino-propoxy-carbonyl; 3-hydroxyazetidine- 1- carbonyl; methyl-sulfonyl; (2,3-dihydroxypropyl)(methyl)carbamoyl; ethyl-amino- carbonyl; carbamoyl; (methoxy-carbonyl-methyl)(methyl)carbamoyl; tetrahydrofuran- 3-yl-carbamoyl; 5-methyl-l,3,4-oxadiazol-2-yl; 1,2,4-oxadiazole optionally substituted with methyl; ((l-methyl-lH-imidazol-4-yl)methoxy)carbonyl; methoxy-propyl- carbamoyl; (methyl-sulfonyl-oxy)methyl; methyl-sulfonyl- amino; (azetidin-3- ylmethoxy)carbonyl; (2-hydroxy-3-(methyl-amino)propoxy)carbonyl; hydroxy-butyl- carbamoyl; dimethyl-amino-methyl; dimethyl-amino-carbonyl-methyl-carbamoyl;
benzoxy-carbonyl; methoxy-carbonyl-methyl-carbamoyl; oxazolyl optionally substituted with methyl; (2H-l,2,3-triazol-2-yl)methyl; (dimethyl-amino-carbonyl- methyl)carbamoyl; (lH-pyrazol-l-yl)methyl; (oxetan-3-yloxy)carbonyl; dimethyl- amino-propoxy-carbonyl; acetoxy- methyl; 3-hydroxy-pyrrolidine- 1-carbonyl; (carboxy- methyl)(methyl)carbamoyl; (2-(2-oxopyrrolidin- l-yl)ethoxy)carbonyl; (oxetan-3- yloxy)carbonyl; (carbamoyl-methyl)(methyl)carbamoyl; morpholino-carbonyl; (2H- tetrazol-2-yl)methyl; methyl((3-methyloxetan-3-yl)methyl)carbamoyl; and 5 -methyl- IH- l,2,4-triazol-3-yl.
[0038] In another embodiment are compounds selected from: (2R)-N-(2- methoxyethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; 4-hydroxybutyl (2R)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (2R)-2-{6- chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; (2R)-N-(2-methoxyethyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl (2R)-2- methyl-2- { 6-methyl-3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl } -3- phenylpropanoate; (2R)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2- methoxyethyl)-N,2-dimethyl-3-phenylpropanamide; (2R)-N-(furan-2-ylmethyl)-N,2- dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl Jpropanamide; ethyl (2R)-2- { 6-cyano-3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; methyl (2S)-2-methyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl (2R)-2- { 6- chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; ethyl 2- { 6-chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; N-(2-methoxyethyl)-N,2-dimethyl-3- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 2-{3-[4-(l-fluorocyclohexyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; ethyl 2-methyl-3-phenyl-2-{3-[4-
(trifluoromethoxy)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2-methoxyethyl 2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-methyl-3-phenyl-2-{3-[4-(propan-2-yl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; N-butyl-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl (2S ) -2- [3 - (4- bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-{6- cyano-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; ethyl 2-[6-chloro-3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methyl-3-phenylpropanoate; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2- methoxyethyl) -N,2-dimethyl- 3 -phenylpropanamide ; ethyl (2S ) -2- [3 - (4- bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 3-(3- fluorophenyl)-2-methyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; ethyl (2E)-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}prop-2-enoate; 4-hydroxybutyl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (2R)-2-methyl- 3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (2R)-2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin- 7-yl}propanoate; (2R)-N,N,2-trimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 3-(3- cyanophenyl)-2-methyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-2-{3-[4-(l-methylcyclopropyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-3-phenylpropanoate; ethyl 3-(3,5-difluorophenyl)-2-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; N,2-dimethyl-3- phenyl-N-propyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; ethyl (2S)-2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methyl-3-phenylpropanoate; methyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- phenyl-2-[3-(4-phenylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; N-(furan-2- ylmethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; N,2-dimethyl-N-(oxolan-2-ylmethyl)-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2-methyl-3 - phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate;
methyl 2-[(2R)-2-benzyl-N-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamido] acetate; ethyl 3-(3-chlorophenyl)-2-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- phenyl-2-{3-[6-(trifluoromethyl)pyridin-3-yl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3-(3-methylphenyl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-ethyl-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2- { 3 - [4- (difluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4-chlorophenyl)-6-fluoropyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- phenylpropanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3- phenylpropanoate; N,N,2-trimethyl-3-phenyl-2-{ 3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl (2S ) -2- [3 - (4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; 3- hydroxypropyl 2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4-chloro-2-methylphenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-3-phenylpropanoate; ethyl 2-[3-(4-chloro-2- methylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl (2S)- 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; methyl 2-(2-benzyl-N-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanamido)acetate; ethyl 3-(3-bromophenyl)-2-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-{3- [4-(2-fluoropropan-2-yl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; 3-methoxypropyl 2-methyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; ethyl (2Z) -3 -phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}prop-2-enoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(furan-2-ylmethyl)-N,2-dimethyl-3- phenylpropanamide; N-(2-methoxyethyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2- [3 - (4- cyclopropylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl (2S)-2-methyl-2-[3-(4-nitrophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; N-(3-methoxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl (lS,2S)-l-{3- [2-nitro-4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2- phenylcyclopropane-1-carboxylate; ethyl 3-(3-methoxyphenyl)-2-methyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- phenyl-2-(3-{ 1 -[4-(trifluoromethyl)phenyl]- 1 ,2,3,6-tetrahydropyridin-4-yl }pyrazolo[ 1 ,5- a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-2-[3-(4-methylphenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-3-phenylpropanoate; N-(cyanomethyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; N- (2- hydroxyethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; propan-2-yl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-ethyl-2-methyl-3-phenylpropanamide; N,N-bis(2-methoxyethyl)-2-methyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2-methyl-3 - phenyl-2-(3-{4-[(l-phenylethyl)amino]phenyl}pyrazolo[l,5-a]pyrimidin-7-yl)propanoate; 2-hydroxyethyl 2-methyl-3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propanoate; N-[2-(2-methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 2-[3-(4- tert-butylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; N-[2-(3- methoxypropoxy)ethyl]-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; N-butyl-2-methyl- 3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; (2R)-N-[2-(2-methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2- [3 - (4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(3-methylphenyl)propanoate; 2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N,N,2-trimethyl-3- phenylpropanamide; ethyl 2-methyl-3-phenyl-2- { 3- [6-(trifluoromethyl)- IH- 1,3- benzodiazol-2-yl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-{3-[(E)-2-(4- chlorophenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-3-phenylpropanoate;
carbamoylmethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3-phenyl-2-{3-[4-({ [6- (trifluoromethyl)pyridin-3-yl]methyl}amino)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-3-phenyl-2-[3-(l-phenyl-l,2,3,6-tetrahydropyridin-4- yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; ethyl (lS,2R)-2-phenyl-l-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl } cyclopropane- 1 -carboxylate; ethyl (2R)-2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- phenylpropanoate; methyl 2- { 2-benzyl-2- [3-(4-chlorophenyl)pyrazolo[ 1 ,5-a]pyrimidin-7- yl]-N-methylpropanamido} acetate; N-[2-(2-hydroxyethoxy)ethyl]-2-methyl-3-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 2-[3-(4- chlorophenyl)-2-methylpyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; ethyl 2-[3- (6-chloropyridin-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; 2-[3- (4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N,2-dimethyl-3-phenyl-N- propylpropanamide; ethyl 2-{3-[4-(l-hydroxycyclohexyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; 4-methoxybutyl 2-methyl-3-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (1S,2R)- 2-phenyl-l-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}cyclopropane- 1 -carboxylate; ethyl 2-methyl-3-[3-(trifluoromethyl)phenyl]-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (lR,2S)-2- phenyl- l-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}cyclopropane-l- carboxylate; (2S)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2- methoxyethyl)-N,2-dimethyl-3-phenylpropanamide; ethyl 2-methyl-3-phenyl-2-{ 3-[4- (pyridin-3-yl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 1-ethyl 4-methyl 2- benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]butanedioate; ethyl 2-[3-(4- methoxyphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; N-(3- hydroxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; N-[(2R)-l-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propan-2- yl] acetamide ; 2-methyl- 3-phenyl-N-(propan-2-yl)-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yl } prop an amide ; N- [ ( 1 R) -2-phenyl- 1 - { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}ethyl]acetamide; ethyl 2-benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]pent-4-enoate; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methyl-3-phenyl-l-(pyrrolidin-l-yl)propan-l-one; 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-N-(2-hydroxyethyl)-2-methyl-3-phenylpropanamide; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2-methoxyethyl)-2-methyl-3- phenylpropanamide; N-ethyl-2-methyl-3-phenyl-2-{ 3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2- [3 - (4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(2-methylphenyl)propanoate; methyl 3-(2-benzyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl}propanamido)propanoate; ethyl 3-(3,4-difluorophenyl)-2-methyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; tert-butyl 2-methyl- 3 - phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; (2S)- N-(2-methoxyethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; oxan-4-yl 2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-[3-(4-fluorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- phenylpropanoate; ethyl 3-(2-chloro-6-fluorophenyl)-2-[3-(4-chlorophenyl)-2- methylpyrazolo[l,5-a]pyrimidin-7-yl]propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(4-methylphenyl)propanoate; ethyl (lS,2R)-l-{3-[2-nitro-4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2- phenylcyclopropane- 1 -carboxylate; ethyl 3-(3,5-dimethylphenyl)-2-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3-[3- (trifluoromethoxy)phenyl] -2- { 3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; 2-(morpholin-4-yl)ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin- 7-yl]-2-methyl-3-phenylpropanoate; N-[(lR)-2-phenyl-l-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl } ethyl] acetamide; ethyl 2-methyl- 3-phenyl-2-[3-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; l-(3- hydroxyazetidin- 1 - yl) -2-methyl-3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propan- 1-one; methyl (2R)-2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 1,3-diethyl 2-benzyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanedioate; ethyl 2- methyl-3 -phenyl-2- {3-[(E)-2-[4- (trifluoromethyl)phenyl] ethenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propanoate; 1-methylcyclopropyl 4-[7-(2-benzyl-l-ethoxy-l- oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin-3-yl]-l,2,3,6-tetrahydropyridine-l-carboxylate; ethyl 2-{3-[(lE)-hex-l-en-l-yl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; N-(2,3-dihydroxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2- [3 - (2- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2- benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]pentanoate; ethyl 2-[3-(3- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2- methyl-2-[3-(5-methylpyrazin-2-yl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; methyl 3-(2-chloro-6-fluorophenyl)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7- yl]propanoate; ethyl 3-phenyl-2-{3-phenylpyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-ethyl-2-methyl-3- phenylpropanamide; ethyl 2- { 3-[4-(2-hydroxypropan-2-yl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4- formylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; tert-butyl 4- [7-(2-benzyl- l-ethoxy-l-oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin-3-yl]- 1,2,3,6- tetrahydropyridine- 1-carboxylate; ethyl 3-(2-chloro-6-fluorophenyl)-2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; methyl 2-[(2S)-2-benzyl-N- methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamido] acetate; 2-methyl-N-(oxolan-3-yl)-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 2-methyl-5-(l- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propan-2-yl)- 1,3,4-oxadiazole; (1 -methyl- lH-imidazol-4-yl)methyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-{3-[(E)-2-(4- chlorophenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; 7- (2-methanesulf onyl- 1 -phenylprop an-2-yl)-3-[4- (trifluoromethyl)phenyl] pyrazolo [1,5- a] pyrimidine ; methyl N- [ ( 1 S ) -2-phenyl- 1 - { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}ethyl]carbamate; ethyl 2-benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-3-methoxypropanoate; N-(3-methoxypropyl)-2-methyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl (2R)-2-[3- (4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropyl methanesulfonate; 5-methyl-2-(l-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl }propan-2-yl)- 1 ,3-oxazole; (2S)-N-(2-methoxyethyl)-N,2-dimethyl-3-phenyl-2- { 3- [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl (2S ) -2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; azetidin-3-ylmethyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; 2-hydroxy- 3 - (methylamino)propyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-(4-hydroxybutyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2-methyl-3 - phenyl-2-(3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; 3-methyl-5-( l-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl }propan-2-yl)- 1 ,2,4-oxadiazole; { 2- [3-(4-chlorophenyl)pyrazolo[ 1 ,5- a]pyrimidin-7-yl]-2-methyl-3-phenylpropyl}dimethylamine; benzyl 2-methyl-3-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl 2-(2- benzyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl }propanamido)acetate; 5-( l-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propan-2-yl)-l,3-oxazole; methyl 3-(3-ethoxy-2-methyl-3-oxo-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl }propyl)benzoate; 2- { 2-benzyl-2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propyl}-2H-l,2,3-triazole; N- [(dimethylcarbamoyl)methyl] -2-methyl-3-phenyl-2- { 3- [4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 2-{3-[6- (dimethylamino)pyridin-3-yl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; N-( l-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propan-2-yl)acetamide; 3-(morpholin-4-yl)propyl 2-methyl-3-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl- 3-phenyl-2-[3-(pyridin-4-yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; ethyl 2-{3-[(E)-2- (4-fluorophenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; methyl N-[(lR)-2-phenyl-l-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl}ethyl]carbamate; N-[(lS)-2-phenyl-l-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}ethyl]acetamide; ethyl 2-{3-[(E)-2-(4- methoxyphenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; 1- {2-benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propyl}-lH-pyrazole; oxetan-3-yl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; ethyl (2S)-2-{6-chloro-3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; 3- (dimethylamino)propyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3-phenyl-2-{ 3-[4-(pyridin-4- yl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 1-methylcyclopropyl 4-[7-(2- benzyl-l-ethoxy-l-oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin-3-yl]piperidine-l- carboxylate; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- phenylpropyl acetate; N- [( lR)-2-phenyl- 1- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}ethyl]methanesulfonamide; 3-{ l-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2-phenylethyl}-5-methyl-l,2,4-oxadiazole; 4-methyl-2-(l-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propan-2-yl)- 1 ,3-oxazole; ethyl (2S)-2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanoate; 4-hydroxybutyl (2S)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-2-{3- [(E)-2-(4-methylphenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-3-phenylpropanoate; ethyl 2-benzyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yljpropanoate; N-(3-hydroxypropyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; N- [(dimethylcarbamoyl)methyl]-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; 4- { 2-benzyl-2- [3 - (4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propyl}morpholine; ethyl 2-[3-(cyclohex- l-en-l-yl)-2-methylpyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; (2S)-N,N,2- trimethyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yljpropanamide; 2-(dimethylamino)ethyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanenitrile; tert-butyl 4-[7-(2- benzyl-l-ethoxy-l-oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin-3-yl]piperidine-l- carboxylate; ethyl (2R)-2-{6-[(dimethylamino)methyl]-3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; ethyl ( 1 S ,2S ) -2-phenyl- 1 - { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yljcyclopropane-l-carboxylate; ethyl 2-methyl-3-phenyl-2-{3-[3-(propan-2-yl)- 1,2,4- oxadiazol-5-yl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; l-(3-hydroxypyrrolidin-l-yl)- 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl}propan-l-one; 2-(2-benzyl-N-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamido)acetic acid; ethyl 2-methyl-3-phenyl-2-[3-(2- phenylethynyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; 2-(2-oxopyrrolidin-l-yl)ethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; methyl 4-[7-(2-benzyl-l-ethoxy-l-oxopropan-2- yl)pyrazolo[l,5-a]pyrimidin-3-yl]piperidine-l-carboxylate; 5-methyl-3-(l-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl }propan-2-yl)- IH-1 ,2,4-triazole; ethyl 3-(2-chloro-6-fluorophenyl)-2-[3-(4-methanesulfonylphenyl)pyrazolo[l,5- a]pyrimidin-7-yl]propanoate; 2-[(2-methyl-3-phenyl-2-{ 3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoyl)oxy]acetic acid; N- (carbamoylmethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl Jpropanamide; 2-methyl- 1 - (morpholin-4-yl)-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl}propan-l-one; ethyl 2-methyl-3-phenyl-2-[3-(pyridin-4-yl)pyrazolo[l,5-a]pyrimidin-7- yl]propanoate; 2-{2-benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propyl}- 2H-l,2,3,4-tetrazole; 3-(4-chlorophenyl)-7-(l-ethoxy-2-methyl-3-phenylpropan-2- yl)pyrazolo[l,5-a]pyrimidine; ethyl 2-methyl-3-phenyl-2-[3-(pyrimidin-5- yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; N,2-dimethyl-N-[(3-methyloxetan-3- yl)methyl] - 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl Jpropanamide; N-(2-hydroxyethyl)-2-methyl-3-phenyl-2- { 3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2-methyl-3 - phenyl-2-(3-{2-[3-(trifluoromethyl)phenyl]ethynyl}pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; Ethyl 3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin- 7-yl)acrylate; (Trans)-ethyl 2-phenyl-l-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- a]pyrimidin-7-yl)cyclopropanecarboxylate; (Cis)-ethyl l-(3-(2-nitro-4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)-2- phenylcyclopropanecarboxylate; (Trans)-ethyl l-(3-(2-nitro-4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)-2- phenylcyclopropanecarboxylate; Ethyl 2-(6-cyano-3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; 2- Methyl-l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)propan- 1-one; Ethyl 2-(6-bromo-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-2- methyl-3-phenylpropanoate; 2-(3-(4-Chlorophenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-2- methyl-3-phenylpropyl acetate; Ethyl 2-(methyl(phenyl)amino)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; Methyl 3-amino-2- benzyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; Ethyl 2-(3-cyclohexenyl-2-methylpyrazolo[ 1 ,5-α]pyrimidin-7-yl)-3-phenylpropanoate; Ethyl 2- benzyl- 3 -phenyl-2- (3 - (4- (trifluoromethyl)phenyl)pyrazolo [1,5 -a] pyrimidin-7 - yl)propanoate; diethyl 2-benzyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5- a]pyrimidin-7-yl)malonate; 7-(2-(methylsulfonyl)-l-phenylpropan-2-yl)-3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidine; Ethyl 3-(3-fluorophenyl)-2-methyl-2- (2-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; Ethyl 2-methyl-3-phenyl-2-(3-(phenylethynyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; Ethyl 2-methyl-3-phenyl-2-(3-(phenylethynyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; ethyl 2-methyl-2-(3-(4-(l-methylcyclopropyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-3- phenylpropanoate; ethyl 2-methyl-3-phenyl-2-(3-( l-(4-(trifluoromethyl)phenyl)- 1,2,3,6- tetrahydropyridin-4-yl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- phenyl-2-(3-(l-phenyl- 1,2,3, 6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-phenyl-2-(3-(pyridin-2-yl)pyrazolo[ 1 ,5-a]pyrimidin-7- yl)propanoate; Ethyl 2-(3-(4-(2-hydroxypropan-2-yl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7- yl)-2-methyl-3-phenylpropanoate; Ethyl 2-(3-(4-(l- hydroxycyclohexyl)phenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; Ethyl 2-(3-(4-(2-fluoropropan-2-yl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3- phenylpropanoate; Ethyl 2-(3-(4-(l-fluorocyclohexyl)phenyl)pyrazolo[l,5-α]pyrimidin-7- yl)-2-methyl-3-phenylpropanoate; 2-(3-(4-chlorophenyl)pyrazolo[l,5-α]pyrimidin-7-yl)- 3-phenylpropanenitrile; (R)-Ethyl 2-(6-cyano-3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5- α]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; (R)-Ethyl 2-methyl-2-(6-methyl-3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)-3-phenylpropanoate; (R)-Ethyl 2- (6-((dimethylamino)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7- yl)-2-methyl-3-phenylpropanoate; Ethyl 2-methyl-3-phenyl-2-(3-(6-(trifluoromethyl)- IH- benzo[d]imidazol-2-yl)pyrazolo[l,5-α]pyrimidin-7-yl)propanoate; N-(l-Phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)propan-2-yl)acetamide; (R)-N-(I- phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)propan-2- yl)acetamide; (R)-N-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- α]pyrimidin-7-yl)propan-2-yl)butyramide; 4-(2-(3-(4-Chlorophenyl)pyrazolo[l,5- α]pyrimidin-7-yl)-2-methyl-3-phenylpropyl)morpholine; 5-(l-Phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propan-2-yl)oxazole; 4-Methyl-2- (l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)propan-2- yl)oxazole; 5-Methyl-2-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- α]pyrimidin-7-yl)propan-2-yl)oxazole; 3-methyl-5-(l-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propan-2-yl)- 1 ,2,4-oxadiazole; 2- methyl-5-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7- yl)propan-2-yl)-l,3,4-oxadiazole; Ethyl 3-(3,5-difluorophenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-m- tolyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2- methyl-3-(thiazol-4-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(pyrazin-2-yl)-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(l- methyl- lΗ-pyrazol-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(pyridin-3-yl)-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 3-(3,4- difluorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3,5-dimethylphenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 3-(3,4- difluorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3,5-dimethylphenyl)-2-methyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(3- (trifluoromethyl)phenyl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3-fluorophenyl)-2-methyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(3- (trifluoromethoxy)phenyl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3-methoxyphenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 3-(3- chlorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3-bromophenyl)-2-methyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; methyl 3-(3-ethoxy-2- methyl-3-oxo-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propyl)benzoate; ethyl 3-(3-cyanophenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2-methoxyethyl)-N,2-dimethyl-3- phenylpropanamide; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(furan-2- ylmethyl)-N,2-dimethyl-3-phenylpropanamide; methyl 2-{2-benzyl-2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-methylpropanamido}acetate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N,2-dimethyl-3-phenyl-N- propylpropanamide; 2-(morpholin-4-yl)ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; N-(2-methoxyethyl)-N,2-dimethyl-3- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; N- butyl-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanamide; 4-hydroxybutyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; N,2-dimethyl-3- phenyl-N-propyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; methyl 2-methyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; N- (furan-2- ylmethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-
99 a]pyrimidin-7-yl}propanamide; N,2-dimethyl-N-(oxolan-2-ylmethyl)-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; N-ethyl-N,2- dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; N,N,2-trimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 3-hydroxypropyl 2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; methyl 2-(2-benzyl-N-methyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamido)acetate; 3- methoxypropyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-(2-methoxyethyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; N- (3 - methoxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; N-(cyanomethyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; N- (2- hydroxyethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; propan-2-yl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; N,N-bis(2- methoxyethyl) -2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propanamide; N-[2-(2-methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 2- hydroxyethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-butyl-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; N-[2-(3- methoxypropoxy)ethyl]-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; carbamoylmethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; N-[2-(2-hydroxyethoxy)ethyl]-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; 4-methoxybutyl 2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; N-(3-hydroxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 2-methyl-3-phenyl- N-(propan-2-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl Jpropanamide; methyl 3-(2-benzyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamido)propanoate; N-ethyl-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; tert-butyl 2-methyl- 3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; oxan-4-yl 2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin- 7-yl}propanoate; l-(3-hydroxyazetidin-l-yl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propan-l-one; N-(2,3- dihydroxypropyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl Jpropanamide; N-(4-hydroxybutyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; 2-methyl-N- (oxolan-3-yl)-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl Jpropanamide; (1 -methyl- lH-imidazol-4-yl)methyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; N- (3 - methoxypropyl)-2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl Jpropanamide; azetidin-3-ylmethyl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl J propano ate ; 2-hydroxy- 3 - (methylamino)propyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-ylJpropanoate; 3-(morpholin-4-yl)propyl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl 2-(2-benzyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-ylJpropanamido)acetate; benzyl 2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yljpropanoate; N-[(dimethylcarbamoyl)methyl]-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl J propanamide ; oxetan- 3 -yl 2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; 3-(dimethylamino)propyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl J propano ate ; N- (3 - hydroxypropyl)-2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl Jpropanamide; N-[(dimethylcarbamoyl)methyl]-N,2-dimethyl-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-ylJpropanamide; 2-(2- oxopyrrolidin- l-yl)ethyl 2-methyl-3 -phenyl-2- { 3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl J propano ate ; 1 - (3 - hydroxypyrrolidin-l-yl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } prop an- 1 - one ; 2- (dimethylamino)ethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; 2-(2-benzyl-N-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamido)acetic acid;
(IR,2S)-Ethy\ 2-phenyl-l-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-α]pyrimidin-7- yl)cyclopropanecarboxylate; (S)-Ethy\ 2-(6-chloro-3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; (R)-ethyl 2-(6-chloro-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2- methyl-3-phenylpropanoate; (S)-Ethyl 2-(6-bromo-3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; (R)-ethyl 2-(6-bromo-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-2- methyl-3-phenylpropanoate; (tf)-N-(l-Phenyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propan-2-yl)acetamide; ((R)-Ethyl 2-methyl-2-(3-(4-nitrophenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-3-phenylpropanoate;
methyl (2R)-2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; methyl (2S)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; (2R)-N,N,2- trimethyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yljpropanamide; (2S)-N,N,2-trimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; (2R)-N- (2- methoxyethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; (2S)-N-(2-methoxyethyl)-N,2-dimethyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; (2R)-N-(furan- 2-ylmethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; methyl 2-[(2R)-2-benzyl-N-methyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamido]acetate; methyl 2- [(2S)-2-benzyl-N-methyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanamido] acetate; (2R)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2- methoxyethyl)-N,2-dimethyl-3-phenylpropanamide; (2S)-2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2-methoxyethyl)-N,2-dimethyl-3- phenylpropanamide; (2R)-N-[2-(2-methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 4-hydroxybutyl (2R)-2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; 4-hydroxybutyl (2S)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-2-{6- chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyramidin-7-yl}-3-(3-fluorophenyl)- 2-methylpropanoate; methyl (2S)-2- { 6-chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}-3-(3-fluorophenyl)-2-methylpropanoate; (2R)-2-{6-chloro-3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-3-(3-fluorophenyl)-N-(2- methoxyethyl)-N,2-dimethylpropanamide; (2S)-2- { 6-chloro-3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-3-(3-fluorophenyl)-N-(2- methoxyethyl)-N,2-dimethylpropanamide; methyl (2R)-3-(3-fhiorophenyl)-2-methyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl (2S)-3- (3-fluorophenyl)-2-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-methyl-2-{2-methyl-3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-3-(3- fluorophenyl)-2-[2-(hydroxymethyl)-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl]-2-methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-methyl-2-[2- (morpholin-4-ylmethyl)-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl]propanoate; methyl (2R)-3-(3-fluorophenyl)-2-methyl-2-{2-[(methylamino)methyl]-3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2-{2-[(phenylamino)methyl]-3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2-[2-(phenoxymethyl)-3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl] propanoate ; methyl 1 - ( { 7 - [ (2R) -2- [(3-fluorophenyl)methyl] - 1 -methoxy- 1 -oxopropan-2-yl] -3- [4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-2-yl}methyl)azetidine-3-carboxylate; methyl (2R)-3-(3-fluorophenyl)-2-[2-(lH-imidazol-l-ylmethyl)-3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]-2-methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-methyl-2-[2-(lH-pyrazol-l-ylmethyl)-3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl]propanoate; methyl (2R)-2-[2- (cyanomethyl)-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]-3-(3- fluorophenyl)-2-methylpropanoate; methyl (2R)-2-[2-(aminomethyl)-3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl] - 3 - (3 -fluorophenyl) -2- methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-[2-(methanesulfonylmethyl)-3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]-2-methylpropanoate; 7-[(2R)-2-
[(3-fluorophenyl)methyl] - 1 -methoxy- 1 -oxopropan-2-yl] -3- [4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidine-2-carboxylic acid; 2- { 7-[(2R)-2-[(3- fluorophenyl)methyl] - 1 -methoxy- 1 -oxopropan-2-yl] -3 - [4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-2-yl}acetic acid; methyl (2R)-3-(3- fluorophenyl) -2-methyl-2- [2- (methylsulf anyl) - 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl]propanoate; methyl (2R)-3-(3-fluorophenyl)-2-{2-methanesurfinyl-3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } -2-methylpropano ate ; methyl
(2R)-3-(3-fluorophenyl)-2-{2-methanesulfonyl-3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } -2-methylpropano ate ; methyl
(2R)-3-(3-fluorophenyl)-2-methyl-2-[2-(trifluoromethyl)-3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl]propanoate; methyl (2R)-2- { 2- amino-3-phenylpyrazolo[l,5-a]pyrimidin-7-yl}-3-(3-fluorophenyl)-2-methylpropanoate; and methyl (2R)-2-[2-amino-3-(4-nitrophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-(3- fluorophenyl)-2-methylpropanoate.
[0039] In another embodiment are compounds selected from Formula Id, Ie and
If:
Figure imgf000028_0001
[0040] in which: n is selected from 1, 2 and 3; R1 is selected from C2-ioalkenyl, Ce- ioaryl, Cμgheteroaryl, acetylenyl, C3_gheterocycloalkyl, Cs.gheterocycloalkenyl, C3.
6cycloalkyl, C3_6cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R1 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, Ci_4alkyl, halo-substituted-Ci-4alkyl, Ci-4alkoxy, halo-substituted-Ci-4alkoxy, C6-1oaryl, Ci.gheteroaryl, Cs-sheterocycloalkyl, C3-i0cycloalkyl, -C(O)OR7, -C(O)R7, -NR7R8, - S(O)1-2R7; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent Of R1 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1. 4alkyl, halo-substituted Ci-4alkyl and Ci-4alkoxy; wherein R7 is selected from hydrogen, Ci-βalkyl, C3-iocycloalkyl optionally substituted with Ci_6alkyl or halo; and Rg is selected from -X1Rg; wherein X1 is selected from a bond and Ci-4alkylene optionally substituted with halo; and R9 is selected from phenyl and pyridinyl; wherein said phenyl or pyridinyl of R9 is optionally substituted with 1 to 3 trifluoromethyl radicals; R2 is selected from hydrogen, Ci_6alkyl, Ci-βalkoxy, halo-substituted-Ci-βalkyl, halo-substituted-Ci-βalkoxy, -
X5S(O)0-2Rl0a, "X5ORlOa, "X5NRlOa X5RlOb, -X5S(0)o-2NRlOaRlOb, -X5NRlOaRlOb, -
X5C(O)NRiOaRiOb, -X5NRiObC(O)RiOa and -X5C(O)ORi0a; wherein said X5 is selected from a bond and Ci_4alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, C6-1oaryl, C3_iocycloalkyl, heteroaryl or heterocycloalkyl; and RiOa and Riob are independently selected from hydrogen, Ci_4alkyl and Ci_4alkoxy; or Rioa and Riob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, Ci_4alkyl, halo-substituted-Ci_4alkyl, Ci_4alkoxy, halo- substituted-Ci_4alkoxy, C6-1oaryl, Ci_9heteroaryl, C3_gheterocycloalkyl, C3_iocycloalkyl, - C(O)ORiOc, -C(O)RiOc, -NRioc Riod, -S(O)i_2Ri0c; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, Ci_4alkyl, halo-substituted Ci_4alkyl and C1- 4alkoxy; wherein RiOc and Riod are selected from hydrogen, Ci_6alkyl, C3_iocycloalkyl optionally substituted with Ci_6alkyl or halo; R3 is selected from cyano, -C(0)0Rπa, - C(O)Riia, -X20C(0)Riia, -C(O)OX2RiIa, -X2OS(0)o-2Riia, -X2S(OV2RiIa, - C(O)OX2ORiIa, -C(O)OX2NRiIaRiIb, -C(O)N RiuRiib, -X2NRiIaRiIb, -NRiiaC(0)Rnb, -NRiiaC(0)0Riib,
Figure imgf000029_0001
-C(O)N RnaX2Riib, -C(O)N RiiaX20Rnb, - C(O)N RiiaX2C(0)0Riib, -C(O)NRi iaX2C(O)NRiiaRiib, -C(O)N RiiaX2OX2ORiib, X2RiIb; wherein each X2 is independently selected from a bond and Ci_4alkylene; wherein any methylene of X2 can have a hydrogen substituted with hydroxy; R1 la and R111, are independently selected from hydrogen, cyano, Ci_4alkyl, Ci_4alkoxy, C6-1OaTyI, C1.
gheteroaryl, C^sheterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or R1 la and R111, together with the nitrogen atom to which they are both attached form a cyclic group selected from pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said pyrrolidine, pyrrolidin- 2-one-l-yl or morpholinyl of the combination of Rlla and R111, is optionally substituted with hydroxyl; R4 is selected from hydrogen, C1-4alkyl, C1-4alkenyl, C6-1oaτylC1-4alkyl, - X3OR12 and -X3C(O)OR12; wherein X3 is selected from a bond and C1-4alkylene; and R12 is selected from hydrogen and C1-4alkyl; R6 is selected from hydrogen, halo, cyano, C1. 6alkyl, X4NR14aR14b, X4OR141; wherein X4 is selected from a bond, Ci-βalkylene; and R14a and R14b are independently selected from hydrogen and C1-4alkyl; and R1S is selected halo, cyano, -S(0)o-2Ri3a,halo-substituted-C1-4alkyl, C1-4alkyl, halo-substituted-C1-4alkoxy, C1- 4alkoxy, C6-1OaTyI, -C(O)NR18aRi8b and -C(O)OR18a; wherein R18a and R18b are independently selected from hydrogen and C1-4alkyl.
[0041] In another embodiment, R1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, l,2,4-oxadiazol-5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy-carbonyl, methyl-sulfonyl, t-butoxy-carbonyl, dimethyl- amino, 2-hydroxypropan-2-yl, 2- fluoropropan-2-yl, 1-phenylethylamino, (l-methylcyclopropoxy)carbonyl, t-butyl, (6- (trifluoromethyl)pyridin-3-yl)methyl-amino, 6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl, phenyl, pyridinyl, cyclohexyl and cyclopropyl; wherein said cyclohexyl or cyclopropyl substituent of R1 is optionally substituted with a radical selected from hydroxy, halo, isopropyl and methyl.
[0042] In another embodiment, R3 is selected from cyano, ethoxy- methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl, methyl((tetrahydrofuran-2-yl)methyl)carbamoyl, (2-methoxy-2- oxoethyl)(methyl)carbamoyl, methoxy-ethyl-carbamoyl, methoxy-propoxy-carbonyl, methoxy-butoxy-carbonyl, (cyanomethyl)(methyl)carbamoyl, hydroxy-ethoxy-ethyl- carbamoyl, (hydroxyethyl)(methyl)carbamoyl, acetamido, isobutyramido,
(hydroxypropyl)(methyl)carbamoyl, isopropoxy-carbonyl, ethyl-carbamoyl, dimethoxy- ethyl-carbamoyl, hydroxy-ethoxy-carbonyl, (methoxy-ethoxy-ethyl)(methyl)carbamoyl, butyl-carbamoyl, carbamoyl-methoxy-carbonyl, (methoxy-carbonyl- methyl)(methyl)carbamoyl, (methoxyethyl)(methyl)carbamoyl, pyrrolidine- 1-carbonyl, hydroxy-ethyl-carbamoyl, methoxy-carbonyl-ethyl-carbamoyl, t-butoxy-carbonyl, (tetrahydro-2H-pyran-4-yloxy)carbonyl, morpholino-ethoxy-carbonyl, 3- hydroxyazetidine- 1-carbonyl, methyl- sulfonyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, ethyl-amino-carbonyl, carbamoyl, (methoxy-carbonyl-methyl)(methyl)carbamoyl, tetrahydrofuran-3-yl-carbamoyl, 5-methyl-l,3,4-oxadiazol-2-yl, ((1-methyl-lH-imidazol- 4-yl)methoxy)carbonyl, methoxy-propyl-carbamoyl, (methyl-sulfonyl-oxy)methyl, methyl- sulfonyl- amino, (azetidin-3-ylmethoxy)carbonyl, (2-hydroxy-3-(methyl- amino)propoxy)carbonyl, hydroxy-butyl-carbamoyl, dimethyl-amino-methyl, benzoxy- carbonyl, methoxy-carbonyl-methyl-carbamoyl, oxazolyl, (2H-l,2,3-triazol-2-yl)methyl, (dimethyl-amino-carbonyl-methyl)carbamoyl, (lH-pyrazol-l-yl)methyl, (oxetan-3- yloxy)carbonyl, dimethyl-amino-propoxy-carbonyl, acetoxy-methyl, 3-hydroxy- pyrrolidine- 1-carbonyl, (carboxy-methyl)(methyl)carbamoyl, (2-(2-oxopyrrolidin-l- yl)ethoxy)carbonyl, (carbamoyl-methyl)(methyl)carbamoyl, morpholino-carbonyl, (2H- tetrazol-2-yl)methyl, methyl((3-methyloxetan-3-yl)methyl)carbamoyl and 5-methyl-lH- l,2,4-triazol-3-yl.
[0043] In a further embodiment are compounds selected from: ethyl (2R)-2- methyl-3-phenyl-2-{8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4- yljpropanoate; ethyl 2-methyl-3-phenyl-2-{ 8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2- c][l,2,4]triazin-4-yl}propanoate; ethyl 2-{3-fluoro-8-[4- (trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4-yl}-2-methyl-3- phenylpropanoate; ethyl 2-[8-(4-chlorophenyl)pyrazolo[3,2-c][l,2,4]triazin-4-yl]-2- methyl-3-phenylpropanoatel; methyl 2-methyl-2-(3-methyl-8-(4-
(trifluoromethyl)phenyl)pyrazolo[5, 1-c] [ 1 ,2,4]triazin-4-yl)-3-phenylpropanoate; Methyl 3- (3-fluorophenyl)-2-methyl-2- (3-methyl- 8- (4- (trifluoromethyl)phenyl)pyrazolo [5 , 1 - c][l,2,4]triazin-4-yl)propanoate; Ethyl 2-methyl-3-phenyl-2-(8-(4- (trifluoromethyl)phenyl)pyrazolo[5, l-c] [ 1 ,2,4]triazin-4-yl)propanoate; Ethyl 2-(3-fluoro- 8-(4-(trifluoromethyl)phenyl)pyrazolo[5,l-c][l,2,4]triazin-4-yl)-2-methyl-3- phenylpropanoate; and (R)-Ethyl 2-methyl-3-phenyl-2-(8-(4-(trifluoromethyl)phenyl)- pyrazolo[5,l-c][l,2,4]triazin-4-yl)propanoate.
[0044] hi another embodiment are compounds selected from Formula Ig, Ih and Ik:
Figure imgf000032_0001
Ig Ih Ik
[0045] in which: R1 is selected from C2-ioalkenyl, C6-1OaTyI, C^heteroaryl, acetylenyl, Cs-sheterocycloalkyl, Cs-sheterocycloalkenyl, C3-6cycloalkyl, C3- 6cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R1 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, C1-4alkyl, halo- substituted-C1-4alkyl, C1-4alkoxy, halo-substituted-C1-4alkoxy, C6-1oaryl, Ci-gheteroaryl, Cs-βheterocycloalkyl, C3-10cycloalkyl, -C(O)OR7, -C(O)R7, -NR7R8, -S(O)1-2R7; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R1 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo- substituted C1-4alkyl and C1-4alkoxy; wherein R7 is selected from hydrogen, C1-6alkyl, C3- iocycloalkyl optionally substituted with C1-6alkyl or halo; and Rg is selected from -X1Rg; wherein X1 is selected from a bond and C1_4alkylene optionally substituted with halo; and R9 is selected from phenyl and pyridinyl; wherein said phenyl or pyridinyl of R9 is optionally substituted with 1 to 3 trifluoromethyl radicals; R2 is selected from hydrogen, C1-6alkyl, Ci-βalkoxy, halo-substituted-C1-6alkyl, halo-substituted-Ci-βalkoxy, -XsS(0)o-
2Rl0a, -XsOR1Oa, -X5NR1Oa X5RlOb, -X5S(O)O-2NR1OaRlOb, -X5NR1OaRlOb, ~
X5C(O)NR1OaRiOb, -X5NR1ObC(O)R1Oa and -X5C(O)OR10a; wherein said X5 is selected from a bond and C^alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, C6-1oaryl, C3_iocycloalkyl, heteroaryl or heterocycloalkyl; and R1Oa and R1Ob are independently selected from hydrogen, Ci_4alkyl and Ci_4alkoxy; or R1Oa and R1Ob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C1-4alkyl, halo-substituted-Ci_4alkyl, Ci_4alkoxy, halo- substituted-Ci-4alkoxy, Cβ-ioaryl, Ci^heteroaryl, C^heterocycloalkyl, C3-iocycloalkyl, - C(O)OR10C, -C(O)R10C, -NR10C Riod, -S(O)1-2R1Oc; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, Ci_4alkyl, halo-substituted Ci_4alkyl and C1. 4alkoxy; wherein R1Oc and R1Od are selected from hydrogen, Ci_6alkyl, C3_iocycloalkyl optionally substituted with Ci_6alkyl or halo; R3 is selected from cyano, -C(O)ORlla, - C(O)Rlla, -X2OC(O)Rlla, -C(O)OX2Rlla, -X2OS(0)o-2Rlla, -X2S(O)0-2R1 la, - C(0)0X20Rlla, -C(0)0X2NRllaRllb, -C(O)N RllaRllb, -X2NRllaRπb, -NRllaC(0)Rllb, -NRiiaC(O)ORnb, -NRnaS(0)o-2Riib, -C(O)N RπaX2Riib, -C(O)N RiiaX20Riib, - C(O)N RiIaX2C(O)ORiIb, -C(O)NRi iaX2C(O)NRnaRiib, -C(O)N RiiaX2OX2ORiib, X2RiIb; wherein each X2 is independently selected from a bond and Ci_4alkylene; wherein any methylene of X2 can have a hydrogen substituted with hydroxy; R1 la and R1 lb are independently selected from hydrogen, cyano, Ci_4alkyl, Ci_4alkoxy, Cβ-ioaryl, C1- gheteroaryl, C3_8heterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or R1 la and R1 lb together with the nitrogen atom to which they are both attached form a cyclic group selected from pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said pyrrolidine, pyrrolidin- 2-one-l-yl or morpholinyl of the combination of Rlla and Rllb is optionally substituted with hydroxyl; R4 is selected from hydrogen, Ci_4alkyl, Ci_4alkenyl, C6-ioarylCi_4alkyl, - X3ORi2 and -X3C(O)ORi2; wherein X3 is selected from a bond and Ci_4alkylene; and Ri2 is selected from hydrogen and Ci_4alkyl; R5 is selected from hydrogen, Ci_4alkyl, naphthyl, Ci^heteroaryl, C^heterocycloalkyl; wherein said alkyl, naphthyl, heteroaryl or heterocycloalkyl of R5 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, -S(0)o-2Ri3a, halo-substituted-C1-4alkyl, Ci_4alkyl, halo-substituted-Ci_ 4alkoxy, Ci-4alkoxy, C6-1oaryl, -C(O)NRi3aRi3b and -C(0)0Ri3a; wherein Ri3a and Ri3b are independently selected from hydrogen and Ci_4alkyl; Y2 is selected from a bond, CH2, C(O), NRn and O; wherein R17 is selected from hydrogen, halo-substituted-C1_4alkyl and C1-4 alkyl; or R4 and Y2 taken together form a double bond or a cyclopropyl ring; and Re is selected from hydrogen, halo, cyano, Ci-βalkyl, X4NR14aR14b, X4OR14a; wherein X4 is selected from a bond, Ci_6alkylene; and R14a and R14b are independently selected from hydrogen and C1-4alkyl.
[0046] In a further embodiment, R1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, l,2,4-oxadiazol-5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy-carbonyl, methyl-sulfonyl, t-butoxy-carbonyl, dimethyl- amino, 2-hydroxypropan-2-yl, 2- fluoropropan-2-yl, 1-phenylethylamino, (l-methylcyclopropoxy)carbonyl, t-butyl, (6- (trifluoromethyl)pyridin-3-yl)methyl-amino, 6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl, phenyl, pyridinyl, cyclohexyl and cyclopropyl; wherein said cyclohexyl or cyclopropyl substituent of R1 is optionally substituted with a radical selected from hydroxy, halo, isopropyl and methyl.
[0047] In a further embodiment, R3 is selected from cyano, ethoxy-methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl,
methyl((tetrahydrofuran-2-yl)methyl)carbamoyl, (2-methoxy-2- oxoethyl)(methyl)carbamoyl, methoxy-ethyl-carbamoyl, methoxy-propoxy-carbonyl, methoxy-butoxy-carbonyl, (cyanomethyl)(methyl)carbamoyl, hydroxy-ethoxy-ethyl- carbamoyl, (hydroxyethyl)(methyl)carbamoyl, acetamido, isobutyramido,
(hydroxypropyl)(methyl)carbamoyl, isopropoxy-carbonyl, ethyl-carbamoyl, dimethoxy- ethyl-carbamoyl, hydroxy-ethoxy-carbonyl, (methoxy-ethoxy-ethyl)(methyl)carbamoyl, butyl-carbamoyl, carbamoyl-methoxy-carbonyl, (methoxy-carbonyl- methyl)(methyl)carbamoyl, (methoxyethyl)(methyl)carbamoyl, pyrrolidine- 1-carbonyl, hydroxy-ethyl-carbamoyl, methoxy-carbonyl-ethyl-carbamoyl, t-butoxy-carbonyl, (tetrahydro-2H-pyran-4-yloxy)carbonyl, morpholino-ethoxy-carbonyl, 3- hydroxyazetidine- 1-carbonyl, methyl- sulfonyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, ethyl-amino-carbonyl, carbamoyl, (methoxy-carbonyl-methyl)(methyl)carbamoyl, tetrahydrofuran-3-yl-carbamoyl, 5-methyl-l,3,4-oxadiazol-2-yl, ((1-methyl-lH-imidazol- 4-yl)methoxy)carbonyl, methoxy-propyl-carbamoyl, (methyl-sulfonyl-oxy)methyl, methyl- sulfonyl- amino, (azetidin-3-ylmethoxy)carbonyl, (2-hydroxy-3-(methyl- amino)propoxy)carbonyl, hydroxy-butyl-carbamoyl, dimethyl-amino-methyl, benzoxy- carbonyl, methoxy-carbonyl-methyl-carbamoyl, oxazolyl, (2H-l,2,3-triazol-2-yl)methyl, (dimethyl-amino-carbonyl-methyl)carbamoyl, (lH-pyrazol-l-yl)methyl, (oxetan-3- yloxy)carbonyl, dimethyl-amino-propoxy-carbonyl, acetoxy-methyl, 3-hydroxy- pyrrolidine- 1-carbonyl, (carboxy-methyl)(methyl)carbamoyl, (2-(2-oxopyrrolidin-l- yl)ethoxy)carbonyl, (carbamoyl-methyl)(methyl)carbamoyl, morpholino-carbonyl, (2H- tetrazol-2-yl)methyl, methyl((3-methyloxetan-3-yl)methyl)carbamoyl and 5-methyl-lH- l,2,4-triazol-3-yl.
[0048] In a further embodiment, are compounds selected from: ethyl 2-methyl-3-
(l-methyl-lH-imidazol-2-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-4- (morpholin-4-yl)butanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methyl-3-(oxolan-3-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin- 7-yl]-2-methyl-3-(l,3-thiazol-4-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2-methyl-3-(oxolan-2-yl)propanoate; ethyl 2-methyl-3-(oxan-4-yl)-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl- 3-(l,3-thiazol-4-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-3-(oxan-3-yl)-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(oxan-4-yl)propanoate; ethyl 2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(pyridin-3-yl)propanoate; ethyl 2-methyl-3-(l-methyl-lH-pyrazol-3-yl)-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- (pyridin-3-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-3-(oxolan-3-yl)-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 3-(5-chloro- l,2,4-thiadiazol-3-yl)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methylpropanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl- 3-(5-methyl-l,2-oxazol-3-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2,4-dimethylpentanoate; ethyl 2-methyl-3-(5-methyl-l,2-oxazol-3-yl)- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2- methyl-3-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]- 2-methyl-3-(pyridin-2-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2-methyl-3-(pyridin-4-yl)propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-phenylacetate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-(l-methanesulfonylpiperidin-4-yl)-2- methylpropanoate; ethyl 2-methyl-3-(2-phenyl-l,3-thiazol-4-yl)-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; 1,3 -diethyl 2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanedioate ; ethyl 2-methyl- 3 - (piperidin-3-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl Jpropanoate; ethyl 2-phenoxy-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; ethyl 2-[methyl(phenyl)amino]-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(pyridin-4-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-4-methoxy-2-methylbutanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; 3-(4- chlorophenyl)-N-ethyl-N-phenylpyrazolo[ 1 ,5-a]pyrimidine-7-carboxamide; diethyl 2-(3- (4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)malonate; ethyl 2-methyl-3- (thiazol-4-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(pyrazin-2-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5- a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(l -methyl- lH-pyrazol-3-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- (pyridin-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(pyrimidin-2-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5- a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(3-methyl-l,2,4-oxadiazol-5-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(5- methylisoxazol-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(lH-l,2,4-triazol-l-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- (pyrimidin-5-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(tetrahydro-2H-pyran-4-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(2- phenylthiazol-4-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(tetrahydrofuran-3-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- (tetrahydro-2H-pyran-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; and ethyl 2-methyl-3-(piperidin-3-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate.
[0049] In another embodiment are compounds selected from: ethyl 2-[8-(4- chlorophenyl)imidazo[l,5-a]pyrimidin-4-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[3,2-b][l,3]thiazol-6-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3- (4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2,3-dihydro-lH-indene-2-carboxylate; 3- (4-chlorophenyl)-N-phenyl-N-propylpyrazolo[ 1 ,5-a]pyrimidine-7-carboxamide; 3-(4- chlorophenyl)-N-methyl-N-phenylpyrazolo[l,5-a]pyrimidine-7-carboxamide; and ethyl 3- phenyl-2-{9-[4-(trifluoromethoxy)phenyl]-9H-purin-6-yl}propanoate.
[0050] Further compounds of the invention are detailed in the Examples and
Tables, infra.
[0051] The present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof. An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
Examples of isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as as 2H, 3H, 11C, 13C, 14C, 15N, 170, 180, 35S, 18F, 36Cl and 123I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples, 3H and 14C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as 2H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. For example, the following three examples can be deuterated as shown:
Deuterated derivatives of Example A5
Figure imgf000038_0001
Pharmacology and Utility
[0052] Compounds of the invention modulate the activity of GPRl 19 and, as such, are useful for treating diseases or disorders in which the activity of GPRl 19 contributes to the pathology and/or symptomology of the disease. This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which GPRl 19 activity contributes to the pathology and/or symptomology of the disease.
[0053] The resultant pathologies of Type II diabetes are impaired insulin signaling at its target tissues and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal. Current therapies to treat the latter include inhibitors of the β-cell ATP- sensitive potassium channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these achieves accurate normalization of blood glucose levels and both carry the risk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function in a glucose-dependent action, i.e.
potentiators of glucose signaling. Physiological signaling systems which function in this manner are well-characterized and include the gut peptides GLP-I, GIP and PACAP. These hormones act via their cognate G-protein coupled receptor to stimulate the production of cAMP in pancreatic β-cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or pre-prandial state. However, a series of biochemical targets of c AMP signaling, including the ATP- sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, β-cell GPCRs, including GPRl 19, would also stimulate the release of endogenous insulin and
consequently promote normoglycemia in Type II diabetes. It is also established that increased cAMP, for example as a result of GLP-I stimulation, promotes β-cell proliferation, inhibits β-cell death and thus improves islet mass. This positive effect on β- cell mass is expected to be beneficial in both Type II diabetes, where insufficient insulin is produced, and Type I diabetes, where β-cells are destroyed by an inappropriate autoimmune response.
[0054] Some β-cell GPCRs, including GPRl 19, are also present in the
hypothalamus where they modulate hunger, satiety, decrease food intake, controlling or decreasing weight and energy expenditure. Hence, given their function within the hypothalamic circuitry, agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.
[0055] It is also well-established that metabolic diseases exert a negative influence on other physiological systems. Thus, there is often the codevelopment of multiple disease states (e.g. type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, obesity or cardiovascular disease in "Syndrome X") or secondary diseases which clearly occur secondary to diabetes (e.g. kidney disease, peripheral neuropathy). Thus, it is expected that effective treatment of the diabetic condition will in turn be of benefit to such interconnected disease states.
[0056] In an embodiment of the invention is a method for treatment of a metabolic disease and/or a metabolic-related disorder in an individual comprising administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof. The metabolic diseases and metabolic-related disorders are selected from, but not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g. necrosis and apoptosis), dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
[0057] In an embodiment of the invention are therapeutic benefits of GPRl 19 activity modulators derived from increasing levels of GIP and PPY. For example, neuroprotection, learning and memory, seizures and peripheral neuropathy.
[0058] GLP-I and GLP-I receptor agonists have been shown to be effective for treatment of neurodegenerative diseases and other neurological disorders. GLP-I and exendin-4 have been shown to stimulate neurite outgrowth and enhance cell survival after growth factor withdrawal in PC 12 cells. In a rodent model of neurodegeneration, GLP-I and exendin-4 restore cholinergic marker activity in the basal forebrain. Central infusion of GLP-I and exendin-4 also reduce the levels of amyloid-β peptide in mice and decrease amyloid precursor protein amount in cultured PC 12 cells. GLP-I receptor agonists have been shown to enhance learning in rats and the GLP-I receptor knockout mice show deficiencies in learning behavior. The knockout mice also exhibit increased susceptibility to kainate-induced seizures which can be prevented by administration of GLP-I receptor agonists. GLP-I and exendin-4 has also been shown to be effective in treating pyridoxine- induced peripheral nerve degeneration, an experimental model of peripheral sensory neuropathy.
[0059] Glucose-dependent insulinotropic polypeptide (GIP) has also been shown to have effects on proliferation of hippocampal progenitor cells and in enhancing sensorimotor coordination and memory recognition.
[0060] In an embodiment of the invention are therapeutic benefits of GPRl 19 activity modulators. For example, GLP-2 and short bowel syndrome (SBS). Several studies in animals and from clinical trials have shown that GLP-2 is a trophic hormone that plays an important role in intestinal adaptation. Its role in regulation of cell proliferation, apoptosis, and nutrient absorption has been well documented. Short bowel syndrome is characterized by malabsorption of nutrients, water and vitamins as a result of disease or surgical removal of parts of the small intestine (eg. Crohn's disease). Therapies that improve intestinal adaptation are thought to be beneficial in treatment of this disease. In fact, phase II studies in SBS patients have shown that teduglutide, a GLP-2 analog, modestly increased fluid and nutrient absorption.
[0061] In an embodiment of the invention are therapeutic benefits of GPRl 19 activity modulators derived from increasing levels of GIP and PPY. For example, GLP-I, GIP and osteoporosis. GLP-I has been shown to increase calcitonin and calcitonin related gene peptide (CGRP) secretion and expression in a murine C-cell line (CA-77). Calcitonin inhibits bone resorption by osteoclasts and promotes mineralization of skeletal bone. Osteoporosis is a disease that is caharacterized by reduced bone mineral density and thus GLP-I induced increase in calcitonin might be therapeutically beneficial.
[0062] GIP has been reported to be involved in upregulation of markers of new bone formation in osetoblasts including collagen type I mRNA and in increasing bone mineral density. Like GLP-I, GIP has also been shown to inhibit bone resorption.
[0063] In an embodiment of the invention are therapeutic benefits of GPRl 19 activity modulators derived from increasing levels of GIP and PPY. For example, PPY and gastric emptying. GPRl 19 located on the pancreatic polypeptide (PP) cells of the islets has been implicated in the secretion of PPY. PPY has been reported to have profound effects on various physiological processes including modulation of gastric emptying and gastrointestinal motility. These effects slow down the digestive process and nutrient uptake and thereby prevent the postprandial elevation of blood glucose. PPY can suppress food intake by changing the expression of hypothalamic feeding-regulatory peptides. PP-overexpressing mice exhibited the thin phenotype with decreased food intake and gastric emptying rate.
[0064] In accordance with the foregoing, the present invention further provides a method for preventing or ameliorating the symptamology of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
Administration and Pharmaceutical Compositions
[0065] In general, compounds of the invention will be administered in
therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A
therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
[0066] Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations can also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[0067] Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
[0068] For example, synergistic effects can occur with other anti-obesity agents, anorectic agents, appetite suppressant and related agents. Diet and/or exercise can also have synergistic effects. Anti-obesity agents include, but are not limited to,
apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, MCR-4 agonists, cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic agents, β3 adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte- stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [for example, compounds described in WO2006/047516), melanin concentrating hormone antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolip statin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), Neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or an analogue thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon- like peptide- 1 receptor agonists, ciliary neutrotrophic factors (such as Axokine™), human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, noradrenergic anorectic agents (for example, phentermine, mazindol and the like) and appetite suppressants (for example, bupropion).
[0069] Where compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
[0070] A combined preparation or pharmaceutical composition can comprise a compound of the invention as defined above or a pharmaceutical acceptable salt thereof and at least one active ingredient selected from:
[0071] a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP- 112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB- 517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY R3401; biguanides such as metformin; alpha-glucosidase inhibitors such as acarbose; GLP-I (glucagon like peptide- 1), GLP-I analogs such as Exendin-4 and GLP-I mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors such as DPP728, LAF237 (vildagliptin - Example 1 of WO 00/34241), MK-0431, saxagliptin, GSK23A ; an AGE breaker; a thiazolidone derivative (glitazone) such as pioglitazone, rosiglitazone, or (R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-lH-indole-2-carboxylic acid described in the patent application WO 03/043985, as compound 19 of Example 4, a non- glitazone type PPAR gamma agonist e.g. GI-262570; Diacylglycerol acetyltransferase (DGAT) inhibitors such as those disclosed in WO 2005044250, WO 2005013907, WO 2004094618 and WO 2004047755;
[0072] b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A
(HMG-CoA) reductase inhibitors, e.g., lovastatin and related compounds such as those disclosed in U.S. Pat. No. 4,231,938, pitavastatin, simvastatin and related compounds such as those disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such as those disclosed in U.S. Pat. No.4,346,227, cerivastatin, mevastatin and related compounds such as those disclosed in U.S. Pat. No. 3,983,140, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and related statin compounds disclosed in U.S. Pat. No. 5,753,675, rivastatin, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6- [2- (substituted-pyrrol-l-yl)-alkyl)pyran-2- ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3- substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3- carboxy-2- hydroxy- propane-phosphonic acid derivatives as disclosed in French Patent No. 2,596,393, 2,3- disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4, 499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application
No.0,142,146 A2, and quinoline and pyridine derivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. In addition, phosphinic acid compounds useful in inhibiting ΗMG CoA reductase suitable for use herein are disclosed in GB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;
[0073] c) an anti-obesity agent or appetite regulating agent such as a CB 1 activity modulator, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCΗR) antagonists, growth hormone secretagogue receptor (GΗSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-I agonists, and other Pre-proglucagon-derived peptides; NPYl or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl- CoA carboxylase (ACC) inihibitors, 11-β-HSD-l inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5, 491,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator, such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CaI SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-I inhibitor as disclosed in WO2005011655, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT- 933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or mazindol, anorectic agents such as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophic factor)/Axokine® (Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion, benzphetamine, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine;
[0074] d) anti-hypertensive agents such as loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan,
SQ29072; ECE inhibitors e.g. SLV306; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168; beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; aldosterone synthase inhibitors; and dual ET/ All antagonist such as those disclosed in WO 00/01389.
[0075] e) a HDL increasing compound;
[0076] f) Cholesterol absorption modulator such as Zetia® and KT6-971;
[0077] g) Apo-Al analogues and mimetics;
[0078] h) thrombin inhibitors such as Ximelagatran;
[0079] i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone;
[0080] j) Inhibitors of platelet aggregation such as aspirin, clopidogrel bisulfate;
[0081] k) estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator;
[0082] 1) a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( { N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2- methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine }) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide described in the patent application WO 04/005281 as example 92; and
[0083] m) an agent interacting with a 5-HT3 receptor and/or an agent interacting with 5-HT4 receptor such as tegaserod described in the US patent No. 5510353 as example 13, tegaserod hydrogen maleate, cisapride, cilansetron;
[0084] n) an agent for treating tobacco abuse, e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban®) and nicotine replacement therapies;
[0085] o) an agent for treating erectile dysfunction, e.g., dopaminergic agents, such as apomorphine), ADD/ ADHD agents (e.g., Ritalin®, Strattera®, Concerta® and Adderall®); [0086] p) an agent for treating alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename Re Via®) and nalmefene), disulfiram (also known under the tradename Antabuse®), and acamprosate (also known under the tradename Campral®)). In addition, agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin®);
[0087] q) other agents that are useful including anti-inflammatory agents (e.g.,
COX-2 inhibitors) ; antidepressants (e.g., fluoxetine hydrochloride (Prozac®)); cognitive improvement agents (e.g., donepezil hydrochloride (Aircept®) and other
acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine) ; antipsychotic medications (e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®));
[0088] or, in each case a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.
[0089] The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.
[0090] The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
[0091] The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the
administration of 3 or more active ingredients.
Processes for Making Compounds of the Invention
[0092] The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
[0093] In the following schemes, several methods of preparing the compounds of the present invention are illustrative. One of skill in the art will appreciate that these methods are representative, and in no way inclusive of all methods for preparing the compounds of the present invention. The radicals in the schemes are as described in Formula I.
Reaction Scheme I
Figure imgf000050_0001
(7)
H2N-NH2 HCI heat
(8)
Figure imgf000050_0002
[0094] A compound of Formula 1-1 and 1-2 can be prepared as in reaction scheme
I by reacting a compound of formula 1 with a compound of the formula 2 (where R19 and R20 are low molecular weight alkanes such as methyl, ethyl, £-butyl and the like) either neat or in a suitable solvent such as DMF, THF and the like at an elevated temperature such as from about 3O0C to about 15O0C to generate an intermediate of the formula 3. One may also use any of the other preparations of compounds of the formula 3 reported in the literature (for example: HeIv. Chim. Acta 2006, 89(1), 30). If needed, one may oxidize intermediate 3 with a halogenating agent such as Selectfluor, NCS or the like to transform R6 from hydrogen to a halogen. Then, a compound of the formula 4 (for example, Bioorg. Med. Chem. Lett. 2004, 14, 3669) can be coupled with a compound of the formula 3 in an appropriate solvent such as an alcohol (methanol, ethanol, and the like) or organic acid such as acetic acid and the like, in the presence of an acidic promoter such as HCl, trifluoroacetic acid or the like at an elevated temperature such as 6O0C to 15O0C to afford 1-1. In the case where R21 = H, compound 1-1 may be further reacted with a compound of formula 5 (where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like) in a solvent such as DMF, NMP, THF and the like using a base such at KOz-Bu, Cs2CO3 or the like to afford 1-2.
[0095] A compound of formula 4 can be prepared as in reaction scheme I by reacting a compound of formula 6 with a compound of the formula 2 (where R49 and R2o are low molecular weight alkanes such as methyl, ethyl and the like) in a suitable solvent such as DMF and the like at an elevated temperature (80- 120 0C) to generate an intermediate of the formula 7. Intermediate 7 may be further reacted with hydrazine hydrochloride (8) or the like, in a suitable solvent such as a mixture of ethanol and water or the like at an elevated temperature (60- 100 0C) to yield a compound of formula 4. Alternatively, preparations such as described J. Het. Chem. 1977, 1(1), 65; J. Med. Chem. 1964, 7(3), 259) may be used.
[0096] In this scheme, it is understood that the groups designated as R1, R2, R3,
R4, R5, Re and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
Reaction Scheme II
Figure imgf000052_0001
[0097] A compound of formula 1-3 may be prepared as in reaction scheme II. A compound of formula 9 can be reacted with a compound of formula 10 (or a similar diol used in the protection of ketones) using an acid catalyst such as /7-toluenesulfonic acid and the like in a suitable solvent consisting of diol 10 and a trialkylorthoformate to generate an intermediate of formula 11. Intermediate 11 can then be reacted with a base such as lithium hydroxide and the like in a high boiling alcoholic solvent such as ethylene glycol or the like at elevated temperature (50-1200C) to generate compounds of formula 12, which can subsequently be reduced using lithium aluminum hydride or the like to afford an intermediate of formula 13. Intermediate 13 may be deprotected using an aqueous acid such as HCl and the like in an appropriate solvent such as acetone or the like at elevated temperature (40-700C) to afford an intermediate of formula 14. This intermediate can be reacted with a compound of formula 15 (where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like) to afford a protected compound of the formula 16. Compound 16 may be manipulated in an analogous manner as compound 1 in scheme I to afford intermediate 17. This intermedtiate can then be further deprotected and derivatized to afford various compounds of the formula 1-3 where R23 refers to the definition of R3 excluding one methylene group. In this scheme, it is understood that the groups designated as R1, R2, R4, R5 and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
Reaction Scheme III
Heck, StUIe,
Suzuki,
Sonogashira
or similar
chemistry
Figure imgf000053_0002
Figure imgf000053_0001
[0098] A compound of formula 1-4 can be prepared as in reaction scheme III by reacting a compound of formula 18 (where X refers to a group competent to be transmetallated such as chloride, bromide, triflate and the like) which can be prepared by any of the other methods mentioned in this patent with an appropriate coupling partner such as a boronic acid, organostannane, organozinc, olefin or terminal acetylene or the like using the organometallic coupling chemistry known in the art (for example, Hartwig, J. F. Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E., Ed., Wiley- Interscience: Weinheim, 2002). In this scheme, it is understood that the groups designated as R1, R2, R3, R4, R5 and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
Reaction Scheme IV
Figure imgf000053_0003
[0099] A compound of formula 1-5 can be prepared as in reaction scheme IV by reacting a compound of formula 19 with an appropriate activating agent such as
EDC/NHS, DCC or trialkylamine/alkyl chloroformate or the like followed by a compound of formula 20 (where R24 refers to the radicals in the definition of R1 that may be attached to an aromatic heterocycle) using any of the protocols known in the literature (such as Science of Synthesis 2004, 13, 127, Tetrahedron Lett. 2006, 47, 3629 and J. Med. Chem. 2004, 47, 5821). In this scheme, it is understood that the groups designated as R2, R3, R4, R5 and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
Reaction Scheme V
Figure imgf000054_0001
[00100] A compound of formula 1-6 can be prepared as in reaction scheme V by reacting a compound of formula 21 with a compound of formula 22 and a metal cyanide such as KCN or the like in an appropriate solvent such as a mixture of ethanol and water or the like at an elevated temperature such as 50 0C to afford an intermediate of formula 23. This material can then be treated with an intermediate of formula 3 as described in scheme I to afford 1-6. In this scheme, it is understood that the groups designated as R1, R2, R3, R4, R5, Re and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme. Reaction Scheme VI
Figure imgf000055_0001
[00101] A compound of Formula 1-7 can be prepared as in reaction scheme VI by reacting a compound of formula 1 with a halogenating agent such as bromine or chlorine (X2) in an appropriate solvent such as acetic acid to generate an intermediate of formula 24. This intermediate can be reacted with a trivalent phosphorous reagent such as a trialkyl-or triarylphosphine or a trialkyl phosphite either neat or in an appropriate solvent such as tetrahydrofuran, toluene or the like to generate and intermediate with the formula 25 where Z refers to either a phosphorous ylide or a phosphonate ester. A compound of the formula 4 can be diazotized with a metal nitrite such as KNO2 in an appropriate solvent such as acetic acid to generate an intermediate of the formula 26. Then, intermediates 25 and 26 can be reacted in a biphasic solvent mixture such as DCM and water containing an aqueous base such as sodium carbonate or the like to generate 1-7 (for an example, see J. Het. Chem. 1981, 18(4), 675). In this scheme, it is understood that the groups designated as R1, R2, R3, R4, R5 and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
Reaction Scheme VII
[00102] A compound of formula 1-8 can be prepared as in reaction scheme VII by reacting a compound of formula 26 with thiourea (27) in the solvent used to generate 26 to afford an intermediate with formula 28. This intermediate can be reacted with a metal hydroxide such as NaOH or the like at elevated temperature (80- 100 0C) in an appropriate solvent such as ethanol, methanol or the like, quenched with a stoichiometric amount of acid such as HCl or the like and then reacted with a compound of the formula 24 (from scheme VI) to generate 1-8. In this scheme, it is understood that the groups designated as R1, R2, R3, R4, R5 and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
Reaction Scheme VIII
Figure imgf000056_0002
[00103] A compound of Formula 1-9 can be prepared as in reaction scheme VIII by reacting a compound of formula 1-2 (wherein R is methyl) with a halogenating agent (R22X) such as N-bromosuccinimide (wherein R22 is any group attached to a halogen as a delivery system for said halogen) in the presence of a radical initiator such as AIBN or the like in an appropriate solvent such as carbon tetrachloride or the like at an elevated temperature such as about 4O0C to about 1000C to afford an intermediate of formula 25.
This intermediate can be reacted with a nucleophile of structure R 23 Z r- H, where Z represents a heteroatom such as N, O, S, or the like (and R23 is any alkyl, aryl, heteroalkyl or heteroaryl sidechain attached to a nucleophilic atom like N, O or S) in the presence of a base like cesium carbonate in an appropriate solvent such as acetonitrile,
dimethylformamide, dichloromethane or the like to generate 1-9. In this scheme, it is understood that the groups designated as R1, R3, R4, R5, R6 and Y2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
[00104] Detailed descriptions of the synthesis of compounds of the Invention are given in the Examples, infra.
Additional Processes for Making Compounds of the Invention
[00105] A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
[00106] The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from,
respectively. For example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
[00107] Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0C. [00108] Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
[00109] Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.
[00110] Compounds of the present invention can be prepared conveniently, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
[00111] Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the
diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by
chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981. [00112] In summary, the compounds of Formula I can be made by a process, which involves:
[00113] (a) that of reaction schemes I, II, III, IV, V, VI, VII & VIII; and
[00114] (b) optionally converting a compound of the invention into a
pharmaceutically acceptable salt;
[00115] (c) optionally converting a salt form of a compound of the invention to a non-salt form;
[00116] (d) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;
[00117] (e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;
[00118] (f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;
[00119] (g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and
[00120] (h) optionally converting a prodrug derivative of a compound of the invention to its non-derivatized form.
[00121] Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.
[00122] One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used.
Examples
[00123] The present invention is further exemplified, but not limited, by the following Examples that illustrate the preparation of compounds of the invention and their intermediates.
Example Al
Ethyl 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-3-phenylpropanoate
Figure imgf000060_0001
Figure imgf000060_0002
[00124] Step A: A mixture of ethyl 2-benzyl-3-oxobutanoate Ala (510 mg, 2.3 mmol) and dimethylformamide diethyl acetal (341 mg, 2.3 mmol) is heated to 100 0C overnight. The solvent is removed to afford ethyl 2-benzyl-5-(dimethylamino)-3- oxopent-4-enoate Alb; ESIMS calcd. for Ci6H22NO3 ([M+H]+) 276.2, found 276.0. The compound is used without purification.
[00125] Step B: A microwave vial charged with a solution of Intermediate Alb
(125 mg, 0.45 mmol) in ethanol (1.5 mL) is treated with 4-(4-chlorophenyl)-lH-pyrazol- 5-amine (88 mg, 0.45 mmol) and 4M HCl in dioxane (227 μL, 0.91 mmol). The vial is then sealed and the mixture is subjected to microwave irradiation (150 0C, 10 min). The mixture is cooled and the solvent is removed. Purification by flash chromatography (ethyl acetate/hexane gradient) affords the title compound (Example Al); 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 4.3 Hz, IH), 8.44 (s, IH), 8.00 (d, J = 8.6 Hz, 2H), 7.42 (d, J= 8.6 Hz, 2H), 7.21 (m, 5H), 6.78 (d, J= 4.3 Hz, IH), 4.81 (t, J= 7.6 Hz, IH), 4.14 (q, J= 7.1 Hz, 2H), 3.48 (m, 2H), 1.11 (t, J= 7.1 Hz, 3H); ESIMS calcd. for C23H2iClN3O2
([M+H]+) 406.1, found 406.1.
Example A2
Ethyl 2-(3-(4-chlorophenyl)-2-methylpyrazolor 1 ,5-αlpyrimidin-7-yl)-3-phenylpropanoate
Figure imgf000061_0001
[00126] By following a similar procedure as the one used for preparing Example
Al from Intermediate Alb except substituting 4-(4-chlorophenyl)-3-methyl-lH-pyrazol- 5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine, Example A2 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.39 (d, J = 4.3 Hz, IH), 7.67 (m, 2H), 7.44 (m, 2H), 7.22 (m, 5H), 6.73 (d, J = 4.3 Hz, IH), 4.84 (dd, J = 7.6, 7.6 Hz, IH), 4.13 (m, 2H), 3.45 (d, J = 7.6 Hz, 2H), 2.64 (s, 3H), 1.12 (dd, J = 7.1, 7.1 Hz, IH); ESIMS calcd. for C24H23ClN3O2 ([M+H]+) 420.1, found 420.1.
Example A3
Ethyl 3-(2-chloro-6-fluorophenyl)-2-(3-(4-chlorophenyl)-2-methylpyrazolori,5- αlpyrimidin-7-yl)propanoate
Figure imgf000061_0002
[00127] By following a similar procedure as the one used for preparing Example
Al from Intermediate Ala except substituting ethyl 2-(2-chloro-6-fluorobenzyl)-3- oxobutanoate for Intermediate Ala in step A and 4-(4-chlorophenyl)-3-methyl-lH- pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine in step B, Example A3 is obtained; 1U NMR (CDCl3, 400.13 MHz): δ 8.35 (d, J= 4.3 Hz, IH), 7.66 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.12 (m, 2H), 6.87 (m, IH), 6.63 (d, J = 4.3 Hz, IH), 4.68 (m, IH), 4.18 (m, 2H), 3.73 (m, 2H), 2.58 (s, 3H), 1.14 (t, J= 7.1 Hz, 3H); ESIMS calcd. for C24H2ICl2FN3O2 ([M+H]+) 472.1, found 472.1.
Example A4
Ethyl 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-phenvlacetate
Figure imgf000062_0001
[00128] By following a similar procedure as the one used for preparing Example
Al from Intermediate Ala except substituting ethyl 3-oxo-2-phenylbutanoate for Intermediate Ala in step A, Example A4 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.49 (d, J = 4.3 Hz, IH), 8.43 (s, IH), 7.99 (d, J = 8.6 Hz, 2H), 7.45 (m, 5H), 7.41 (d, J = 8.6 Hz, 2H), 6.55 (dd, J = 4.3, 0.8 Hz, IH), 5.76 (s, IH), 4.26 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C22H19ClN3O2 ([M+H]+) 391.1, found 392.1.
Example A5
Ethyl 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate.
Figure imgf000062_0002
[00129] A solution of Example Al (33.4 mg, 83 μmol) in tetrahydrofuran (1 niL) is added to a solution of potassium tert-butoxide (9.4 mg, 83 μmol) in tetrahydrofuran (1 mL) at 0 0C. The reaction is then treated with iodomethane (14 mg, 100 μmol) and allowed to come to room temperature and stir overnight. The reaction is then evaporated to dryness and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and purified on a reversed phase HPLC
(H2CVMeCN gradient) to provide the title compound Example A5; 1H NMR (CDCl3, 400.13 MHz): δ 8.48 (s, IH), 8.40 (d, J = 4.3 Hz, IH), 8.06 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.09 (m, 3H), 6.47 (m, 2H), 6.39 (d, J = 4.4 Hz, IH), 4.13 (q, J = 7.1 Hz, 2H), 4.10 (d, J = 13.6 Hz, IH), 3.34 (d, J = 13.6 Hz, IH), 1.65 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C24H23ClN3O2 ([M+H]+) 419.1, found 420.1.
Example A6
Ethyl 2-benzyl-2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)pentanoate
Figure imgf000063_0001
[00130] A solution of diisopropylamine (28 mg, 0.27 mmol) in tetrahydrofuran (1 mL) is cooled to -78 0C (dry ice/acetone bath) and treated with butyllithium (2.46 M in hexane, 111 μL, 0.27 mmol) and allowed to stir for 5 minutes. The reaction is then treated with a solution of Example Al (77 mg, 0.18 mmol) in tetrahydrofuran (0.5 mL) and stirred for 15 minutes. Then iodopropane (62 mg, 0.36 mmol) is added and the reaction is allowed to come to room temperature and stir overnight. The reaction is then evaporated to dryness and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and purified on a reversed phase HPLC
(H2OMeCN gradient) to provide the title compound Example A6; 1H NMR (CDCl3, 400.13 MHz): δ 8.46 (s, IH), 8.39 (d, J = 4.4 Hz, IH), 8.05 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.08 (m, 3H), 6.43 (m, 2H), 6.40 (d, J = 4.5 Hz, IH), 4.14 (m, 2H), 3.94 (d, J = 13.9 Hz, IH), 3.44 (d, J= 13.9 Hz, IH), 2.01 (m, IH), 1.88 (m, IH), 1.65 (m, IH), 1.41 (m, IH), 1.05 (m, 6H); ESIMS calcd. for C26H27ClN3O2 ([M+H]+) 448.2, found 448.0.
[00131] By following a similar procedure as the one used for preparing Example
A6 from Example Al except substituting the appropriate alkyl halide for iodopropane, the following examples are obtained:
Figure imgf000064_0001
Example AlO
2-(3-(4-Chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenylpropyl
methanesulfonate
Figure imgf000065_0001
[00132] Step A: A solution of Intermediate AlOa (6.58g, 28.08 mmol) in a mixture of ethylene glycol (25 ml) and triethyl orthoformate (20 mL) is treated with p- toluenesulfonic acid (200 mg, 1.3 mmol) and heated to 55 0C overnight. The reaction is then cooled to room temperature and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered and evaporated to afford ethyl 2-methyl- 2-(2-methyl-l,3-dioxolan-2-yl)-3-phenylpropanoate AlOb; ESIMS calcd. for Ci6H23O4 ([M+H]+) 279.2, found 279.1. The product is used without purification.
[00133] Step B: A solution of Intermediate AlOb in ethylene glycol (50 ml) is treated with lithiumhydroxide (3 g, 71 mmol) and heated to 200 0C for 30 minutes using conventional heating. At this point, the reaction solidifies. After cooling to room temperature, the solid mass is repeatedly digested with hot IM NaOH until all of the material dissolves. The resulting aqueous solution is extracted once with ethyl acetate and the organics are discarded. The aqueous solution is adjusted to pH 4 with concentrated HCl and extracted twice with ethyl acetate. The combined organic extracts are dried over MgSO4, filtered and evaporated. The resulting oil is dissolved in diethyl ether and treated with dicyclohexylamine (5.07 g, 28 mmol) and stirred for 1 hour. The resulting solid is collected and dried to afford 2-methyl-2-(2-methyl-l,3-dioxolan-2-yl)-3-phenylpropanoic acid AlOc as a DCHA salt; ESIMS calcd. for Ci4Hi9O4 ([M+H]+) 251.1, found 251.1.
[00134] Step C: A solution of Intermediate AlOc (3.36 g, 13.44 mmol) in IN HCl is extracted with ethyl acetate five times. The combined organics are dried over Na2SO4, filtered and evaporated. The resulting acid is then dissolved in tetrahydrofuran (100 mL) and is slowly added to a pre-cooled (0 0C) solution of lithiumaluminiumhydride (2.0 g, 53.76 mmol) in tetrahydrofuran (100 niL). After stirring for 10 minutes the ice-bath is removed and the contents heated to reflux for 2 hours. The flask is then cooled to 0 0C and a solution of saturated aqueous Na2SO4 is added until reaction is quenched. The resulting solids are then filtered through Celite and the solids washed extensively with tetrahydrofuran. Evaporation of the solvent yields 2-methyl-2-(2-methyl-l,3-dioxolan-2- yl)-3-phenylpropan-l-ol AlOd as a pure clear liquid. 1H NMR (400 MHz, CDCl3) δ = 7.30-7.28 (m, 5H), 4.11-4.05 (m, 4H), 3.31-3.22 (m, 2H), 3.06 (d, J = 12.8 Hz, IH), 2.61 (d, J = 12.8 Hz, IH), 1.40 (s, 3H), 0.80 (s, 3H); ESIMS calcd. for Ci4H2iO3 ([M+H]+) 237.1, found 237.2. The product is used without purification.
[00135] Step D: A solution of Intermediate AlOd (1.8 g, 7.62 mmol) in acetone
(20 mL) is treated with IN HCl (5 mL) and stirred for 1 hour. Acetone is then removed and the contents partitioned between ethyl acetate and water. The aqueous layer is extracted with ethyl acetate (2x). The combined organic phase is washed with saturated aqueous NaHCO3, brine, and dried over Na2SO4. Evaporation of the solvent yields 3- benzyl-4-hydroxy-3-methylbutan-2-one AlOe as a clear oil. 1H NMR (400 MHz, CDCl3) δ = 7.30-7.16 (m, 5H), 3.58-3.50 (m, 2H), 2.93 (d, J = 13.2 Hz, IH), 2.83 (d, J = 13.2 Hz, IH), 2.38-2.34 (m, IH), 2.15 (s, 3H), 1.10 (s, 3H); ESIMS calcd. for Ci2H17O2 ([M+H]+) 193.1, found 193.1. The product is used without purification.
[00136] Step E: A solution of intermediate AlOe (110 mg, 0.573 mmol) in dichloromethane (1 mL) is treated with triethylamine (120 μL, 0.860 mmol), benzoyl chloride (80 μL, 0.688 mmol), and DMAP (5 mg, 0.04 mmol). After stirring for 2 hours the reaction is quenched with water and the aqueous layer extracted with
dichloromethane. The organic layer is dried over Na2SO4 and concentrated. Purification of the crude material by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) yields 2-benzyl-2-methyl-3-oxobutyl benzoate AlOf as a clear oil. 1H NMR (400 MHz, CDCl3) δ = 8.00 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 7.6, IH), 7.47 (d, J = 7.6 Hz, 2H), 7.29- 7.24 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 4.40-4.33 (m, 2H), 3.02-2.95 (m, 2H), 2.19 (s, 3H), 1.24 (s, 3H); ESIMS calcd. for Ci9H2iO3 ([M+H]+) 297.1, found 297.2.
[00137] Step F: A solution of Intermediate AlOf (1.34 g, 4.53 mmol) and dimethylformamide diethyl acetal (3.9 mL, 22.63 mmol) is heated at 125 0C for 16 hours. Excess dimethylformamide diethyl acetal is removed and the crude is purified by flash chromatography (80 g SiO2, hexanes/ethyl acetate gradient) to afford 2-benzyl-5- (dimethylamino)-2-methyl-3-oxopent-4-enyl benzoate AlOg as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.03 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 12.4, IH), 7.55 (t, J = 7.2 Hz, IH), 7.43 (t, J = 8.0 Hz, 2H), 7.23-7.15 (m, 4H), 5.19 (d, J = 12 Hz, IH), 4.35 (q, J = 11.2 Hz, 2H), 3.48 (d, J = 5.6 Hz, IH), 3.07-2.97 (m, 4H), 2.88-2.77 (br s, 3H), 1.22 (s, 3H); ESIMS calcd. for C22H26NO3 ([M+H]+) 352.1, found 352.1.
[00138] Step G: In a Smith Process vial charged with Intermediate AlOg (1.34 g,
3.83 mmol) in ethanol (15 mL) is added 4-(4-chlorophenyl)-lH-pyrazol-5-amine (0.745 mg, 3.83 mmol) and 4M HCl in dioxane (1.92 mL, 7.7 mmol). The mixture is then subjected to microwave irradiation (150 0C, 15 min). The mixture is treated with saturated aqueous NH4Cl and extracted with ethyl acetate (2x). The combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (120 g SiO2, hexanes/ethyl acetate gradient) yields 2-(3-(4-chlorophenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-2-methyl-3-phenylpropyl benzoate AlOh as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.53 (s, IH), 8.40 (d, J = 4.4, IH), 8.06 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7,2Hz, IH), 7.44 (d, J = 6.8 Hz, 2H), 7.35 (t, J = 8.0 Hz, 2H), 7.12-7.06 (m, 3H), 6.62 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 4.8 Hz, IH), 5.49 (d, J = 11.2 Hz, IH), 4.77 (d, J = 10.8 Hz, IH), 4.12 (d, J = 5.6 Hz, IH), 3.28 (d, J = 13.6, IH), 1.66 (s, 3H); ESIMS calcd. for C29H25ClN3O2 ([M+H]+) 482.2, found 482.2.
[00139] Step H: To a solution of Intermediate AlOh (1.34 g, 2.79 mmol) in methanol (120 mL) is added sodium methoxide (2M solution in methanol, 6 mL, 12 mmol) and the mixture is stirred for 1.5 hours. Methanol is removed under vacuum and the residue partitioned between saturated aqueous NH4Cl and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x). The combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (80 g SiO2, hexanes/ethyl acetate gradient) yields 2-(3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-2-methyl-3-phenylpropan-l-ol AlOi as a yellow glass. 1H NMR (400 MHz, CDC13) δ = 8.50 (s, IH), 8.37 (d, J = 4.4, IH), 8.05 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.11-7.05 (m, 3H), 6.60 (d, J = 7.6 Hz, 2H), 6.48 (d, J = 4.4 Hz, IH), 4.44-4.39 (m, IH), 3.99-3.96 (m, 3H), 3.06 (d, J = 13.2, IH), 1.47 (s, 3H); ESIMS calcd. for C22H2iClN3O ([M+H]+) 378.1, found 378.2. [00140] Step I: To a solution of Intermediate AlOi (20 mg, 0.053 mmol) in dichloromethane (1 rnL) is added diisopropylethylamine (13 μL, 0.080 mmol) followed by methanesulfonyl chloride (5 μL, 0.064 mmol). After 1 hour the reation is quenched with water and the aqueous layer is extracted with dichloromethane. The organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) yields the title compound (Example AlO) as a yellow oil. 1H NMR (400 MHz, CDCl3) d = 8.52 (s, IH), 8.41 (d, J = 4.4 Hz, IH), 8.07 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.13-7.07 (m, 3H), 6.60 (d, J = 6.4 Hz, 2H), 6.50 (d, J = 4.4 Hz, IH), 5.70 (d, J = 9.2 Hz, IH), 4.55 (d, J = 9.2 Hz, IH), 4.04 (d, J = 13.2 Hz, IH), 3.04 (d, J = 13.2 Hz, IH), 2.70 (s, 3H), 1.61 (s, 3H); ESIMS calcd. for C23H23ClN3O3S ([M+H]+) 456.1, found 456.3.
Example All
3-(4-Chlorophenyl)-7-(2-methyl-l-phenyl-3-(lH-pyrazol-l-yl)propan-2-yl)pyrazolori,5- αlpvrimidine
Figure imgf000068_0001
[00141] To a solution of Example AlO (25 mg, 0.055 mmol) in dimethylsulfoxide
(1 mL) is added pyrazole sodium salt (50 mg, 0.550 mmol) and the mixture is heated to 110 0C for 1.5 hours. The reaction is then partitioned between ethyl acetate and water. The organics are washed with brine, dried over Na2SO4, and concentrated in vacuo.
Purification of the crude material by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) yields the title compound (Example All) as a yellow oil; 1H NMR (CDCl3, 400.13 MHz): δ = 8.63 (s, IH), 8.25 (d, J = 4.4 Hz, IH), 8.11 (d, J = 8.8Hz, 2H), 7.46 (d, J = 2 Hz, 8.8 Hz, 2H), 7.31 (s, IH), 7.09-7.07 (m, 3H), 6.58 (d, J = 6.4 Hz, 2H), 6.50 (d, J = 2 Hz, IH), 6.23 (d, J = 4.8 Hz, IH), 5.96 (d, J = 14 Hz, IH), 5.92 (t, J = 2 Hz, IH), 4.49 (d, J = 14 Hz, IH), 4.41 (d, J = 13.2 Hz, IH), 2.93 (d, J = 13.2Hz, IH), 1.51 (s, 3H); ESIMS calcd. for C25H23ClN5 ([M+H]+) 428.2, found 428.1.
Example A12
3-(4-Chlorophenyl)-7-(2-methyl-l-phenyl-3-(2g-l,2,3-triazol-2-yl)propan-2- vPpyrazolor 1 ,5-αlpyrimidine
Figure imgf000069_0001
[00142] By following a similar procedure as the one used for preparing Example
Al l from Example AlO except substituting 1,2,3-triazole sodium salt for pyrazole sodium salt, Example A12 is obtained; 1H NMR (CDCl3, 400.13 MHz): d = 8.62 (s, IH), 8.25 (d, J = 4.4 Hz, IH), 8.11 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.37 (s, 2H), 7.11-7.06 (m, 3H), 6.60 (d, J = 7.6 Hz, 2H), 6.32 (d, J = 13.6 Hz, IH), 6.18 (d, J = 4.4 Hz, IH), 4.83 (d, J = 13.6 Hz, IH), 4.45 (d, J = 13.2 Hz, IH), 3.00 (d, J = 13.2 Hz, IH), 1.38 (s, 3H); ESIMS calcd. for C24H22ClN6 ([M+H]+) 429.1, found 429.1.
Example A13
Ethyl 2-(3-(4-chlorophenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-2,3-dihvdro- lH-indene-2- carboxylate
Figure imgf000070_0001
Figure imgf000070_0002
Example A13
[00143] Step A: To a mixture of tetrabutyl ammonium bromide (247 mg, 0.768 mmol) in 50% aqueous NaOH (7 mL) is added a solution of dibromo-oxylene (4.05 g, 15.36 mmol) in toluene (20 mL) and stirred vigourosly. Next, a solution of
ethylacetoacetate A13a (1.96 mL, 15.36 mmol) in toluene (2 mL) is added and the mixture is stirred for 2 hours. Water is added and the aqueous layer is extracted with toluene. The combined organic phase is then washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (40 g SiO2) yields ethyl 2-acetyl-2,3-dihydro-lH-indene-2-carboxylate A13b as a pale yellow oil. 1H NMR (CDCl3, 400.13 MHz); δ = 7.20-7.14 (m, 4H), 4.21 (q, J = 8.8 Hz, 2H), 3.58-3.48 (m, 4H), 2.23 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); ESIMS calcd. for Ci4H17O3 ([M+H]+) 233.1, found 233.1. [00144] Step B: A solution of Intermediate A13b (432 mg, 1.86 mmol) in dimethylformamide diethyl acetal (683 μL, 3.72 mmol) is heated at 120 0C for 16 hours. Excess dimethylformamide diethyl acetal is removed and the crude is purified by flash chromatography (12 g SiO2) to afford ethyl 2-(3-(dimethylamino)acryloyl)-2,3-dihydro- lH-indene-2-carboxylate A13c as a yellow oil. 1H NMR (CDCl3, 400.13 MHz); δ = 7.70- 7.67 (m, IH), 7.18-7.16 (m, 2H), 7.13-7.10 (m, 2H), 5.07-5.04 (m, IH), 4.15 (q, J = 7.2 Hz, 2H) 3.58 (s, 4H), 3.15-2.70 (m, 6H), 1.84 (br s, IH), 1.22 (t, J = 7.2 Hz, 3H); ESIMS calcd. for Ci7H22NO3 ([M+H]+) 288.1, found 288.2.
[00145] Step C: In a Smith Process vial charged with Intermediate A13c (45 mg,
0.027 mmol) in ethanol (1 mL) are added 4-(4-chlorophenyl)-lH-pyrazol-5-amine (50 mg, 0.259 mmol) and 4M HCl in dioxane (130 μL, 0.518 mmol). The mixture is then subjected to microwave irradiation (100 0C, 10 min). The solution is partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) yields the title compound (Example A13) as a yellow oil. 1H NMR (CDCl3, 400.13 MHz): δ = 8.45 (d, J = 4.4 Hz, IH), 8.41 (s, IH), 7.98 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.21 (m, 4H), 6.71 (d, J = 4.4 Hz, IH), 4.12 (q, J = 7.2 Hz, 2H), 3.98 (d, J = 16.4 Hz, 2H), 3.51 (d, J = 16.8 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C24H2iClN3O2 ([M+H]+) 418.1, found 418.2.
Example A14
Ethyl 2-(3-(4-bromophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenylpropanoate
Figure imgf000071_0001
Figure imgf000072_0001
Example A14 B
[00146] Step A: A solution of Intermediate AlOa (2.1 g, 9 mmol) and
dimethylformamide diethyl acetal (3 rnL, 17.5 mmol) in DMF (2 mL) is heated to 90 0C overnight. The solvent is removed to afford ethyl 2-benzyl-5-(dimethylamino)-2-methyl- 3-oxopent-4-enoate A14a; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 12.3 Hz, IH), 7.2 (m, 5H), 5.04 (d, J = 12.3 Hz, IH), 4.16 (m, 2H), 3.34 (d, J = 13.7 Hz, IH), 3.10 (d, J = 13.7 Hz, IH), 3.09 (s, br, 3H), 2.79 (s, br, 3H), 2.17 (s, 3H), 1.26 (s, 3H), 1.25 (t, J= 7.1 Hz, 3H); ESIMS calcd. for Ci7H24NO3 ([M+H]+) 290.2, found 290.1. The product is used without purification.
[00147] Step B: A solution of Intermediate A14a (2.48 g, 8.6 mmol) in ethanol
(15 mL) is treated with 4-(4-bromophenyl)-lH-pyrazol-5-amine (1.81 g, 7.6 mmol) followed by 4 M HCl in dioxane (4 mL, 16 mmol) and heated to 80 0C for 8h. The resulting mixture is cooled and the solvent is removed. Purification of the crude material by flash chromatography (hexanes/ethyl acetate gradient) affords the title compound
(Example A14); 1U NMR (400 MHz, CDCl3) δ 8.48 (s, IH), 8.40 (d, J = 4.4 Hz, IH), 8.00 (d, J = 8.6 Hz, 2H), 7.58 (d, J= 8.6 Hz, 2H), 7.10 (m, 3H), 6.47 (m, 2H), 6.39 (d, J = 4.4 Hz, IH), 4.13 (m, 2H), 4.10 (d, J = 13.6 Hz, IH), 3.34 (d, J = 13.6 Hz, IH), 1.65 (s, 3H), 1.04 (t, J= 7.1 Hz, 3H); ESIMS calcd. for C24H23BrN3O2 ([M+H]+) 464.2, found
464.1.
Example A15
Ethyl 2-(6-chloro-3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-2-methyl-
3 -phen vlpropano ate
Figure imgf000073_0001
Figure imgf000073_0002
A14a A15a
Figure imgf000073_0003
Example A15
[00148] Step A: To a solution of intermediate A14a (720 mg, 2.49 mmol) in chloroform (20 mL) is added iV-chlorosuccinimide (366 mg, 2.75 mmL) and the mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (80 g SiO2, hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4-chloro-5-(dimethylamino)-2-methyl-3-oxopent-4-enoate A15a as a yellow solid. 1H NMR (CDCl3, 400.13 MHz); δ = 7.66 (s, IH), 7.23-7.18 (m, 3H), 7.10- 7.08 (m, 2H), 4.18-4.06 (m, 3H), 3.31 (d, J = 14.0 Hz, IH) 3.24-3.21 (m, 7H), 1.34 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); ESIMS calcd. for Ci7H23ClNO3 ([M+H]+) 324.1, found 324.1.
[00149] Step B: In a Smith Process vial charged with Intermediate A15a (458 mg,
1.41 mmol) in ethanol (4 mL) are added 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5- amine (321 mg, 1.41 mmol) and 4M HCl in dioxane (705 μL, 2.82 mmol). The mixture is then subjected to microwave irradiation (160 0C, 20 min). The solution is partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash
chromatography (40 g SiO2, hexanes/ethyl acetate gradient) yields the title compound (Example A15) as a yellow glass. 1H NMR (CDCl3, 400.13 MHz): δ = 8.47 (s, IH), 8.28 (s, IH), 8.18 (d, J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 2H), 7.16 (d, J = 7.2 Hz, IH), 7.10 (t, J = 7.6 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 4.18-4.05 (m, 3H), 3.31 (d, J = 14 Hz, IH), 2.03 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C25H22ClF3N3O2 ([M+H]+) 488.1, found 488.2.
Example A16
Ethyl 2-(6-chloro-3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000074_0001
[00150] By following a similar procedure as the one used for preparing Example
A15 from Intermediate A15a except substituting 4-(4-chlorophenyl)-lH-pyrazol-5-amine for 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine, Example A16 is obtained. 1H NMR (CDCl3, 400.13 MHz): δ = 8.40 (s, IH), 8.24 (s, IH), 8.00 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8 Hz, 2H), 7.19-7.15 (m, IH), 7.12-7.08 (m, 2H), 6.57 (d, J = 7.2 Hz, 2H), 4.19- 4.06 (m, 2H), 4.07 (d, J = 14 Hz, IH), 3.31 (d, J = 14 Hz, IH), 2.02 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C24H22Cl2N3O2 ([M+H]+) 454.1, found 454.2.
Example A17
Ethyl 2-(3-(4-chlorophenyl)-6-fruoropyrazolor 1 ,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000075_0001
Figure imgf000075_0002
Example Al 7
[00151] Step A: A solution of Intermediate A14a (204 mg, 0.71 mmol) in dichloromethane (7 rnL) cooled to -15 0C is treated with a solution of N-fluoro benzenesulfonamide (267 mg, 0.85 mmL) in acetonitrile (10 mL). The mixture is then allowed to stir at room temperature overnight. The solvent is removed in vacuo and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-5-(dimethylamino)-4-fluoro-2-methyl-3-oxopent-4-enoate A17a as a yellow oil. 19F-NMR spectra shows multiple fluorine peaks suggesting the presence of several fluoro compounds. ESIMS calcd. for Ci7H23FNO3 ([M+H]+) 308.2, found 308.2. The product is used without further purification.
[00152] Step B: By following a similar procedure as the one used for preparing
Example A15 from Intermediate A15a except substituting Intermediate A17a for Intermediate A15a, Example A17 is obtained. 1H NMR (CD3OD, 400.13 MHz): δ = 8.62 (s, IH), 8.44 (d, J = 2.8 Hz, IH), 8.13 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.29- 7.19 (m, IH), 7.16-7.06 (m, 4H), 6.57 (d, J = 6.8 Hz, 2H), 4.16-4.09 (m, 3H), 3.26 (d, J = 13.6 Hz, IH), 1.89 (d, J = 6.4 Hz, 3H), 1.05 (t, J = 7.2 Hz, 3H); 19F-NMR (376.5 MHz, CDCl3) δ = -162.65; ESIMS calcd. for C24H22ClFN3O2 ([M+H]+) 438.1, found 438.2. Example A18
tert-Butyl 4-(7-(l-ethoxy-2-methyl-l-oxo-3-phenyrpropan-2-yl)pyrazolori,5- αlpyrimidin-3-yl)piperidine-l-carboxvlate.
Figure imgf000076_0001
Figure imgf000076_0002
A18c Example A18
[00153] Step A: A solution of diisopropylamine (589 mg, 5.8 mmol) in tetrahydrofuran (10 niL) is cooled to -78 0C (dry ice/acetone bath) and treated with butyllithium (2.46 M in hexane, 1.73 rnL, 4.3 mmol) dropwise and allowed to stir cold for 15 minutes. The reaction is then treated dropwise with a solution of Intermediate A18a (870 mg, 3.9 mmol) in tetrahydrofuran (2 mL) and stirred cold for 20 minutes. The reaction is then treated with ethyl formate (144 mg, 1.9 mmol) and allowed to warm to ice/water bath temperature and stirred for 30 minutes at which point it is quenched with a 10% aqueous solution of NaH2PO4 and extracted twice with ethyl acetate. The organics are isolated, dried over MgSO4, filtered and evaporated. Purification of the crude material by flash chromatography (hexanes/ethyl acetate gradient) affords tert-butyl 4-(l-cyano-2- hydroxyvinyl)piperidine-l-carboxylate A18b; ESIMS calcd. for C13H21N2O3 ([M+H]+) 253.2, found 253.1. [00154] Step B: A solution of Intermediate A18b (489 mg, 0.19 mmol) and hydrazine hydrate (133 mg, 1.9 mmol) in ethanol (10 mL) and water (2 mL) is heated to 60 0C for 2 hours. The reaction is then cooled to room temperature and the solvent is removed to afford tert-butyl 4-(5-amino-lH-pyrazol-4-yl)piperidine-l-carboxylate A18c; ESIMS calcd. for Ci3H23N4O2 ([M+H]+) 267.2, found 267.1. The product is used without purification.
[00155] Step C: A solution of Intermediate A18c (94.3 mg, 0.35 mmol) and
Intermediate A14a (102.5 mg, 0.35 mmol) in ethanol (2 mL) is treated with
trifluoroacetic acid (40.4 mg, 0.35 mmol) and heated to 60 0C for 1 hour. The solvent is removed and the residue is purified on a reversed phase HPLC (H2CVMeCN gradient) to provide the title compound (Example A18); 1H NMR (CDCl3, 400.13 MHz): δ = 8.25 (d, J = 4.3 Hz, IH), 8.00 (s, IH), 7.09 (m, 3H), 6.44 (m, 2H), 6.30 (d, J = 4.4 Hz, IH), 4.24 (m, 2H), 4.11 (m, 2H), 4.04 (d, J = 13.6 Hz, IH), 3.31 (d, J = 13.6 Hz, IH), 3.19 (m, IH), 2.92 (m, 2H), 2.07 (m, 2H), 1.85-1.69 (m, 2H), 1.60 (s, 3H), 1.49 (s, 9H), 1.01 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C28H37N4O4 ([M+H]+) 493.3, found 493.2.
Example A19
Methyl 4-(7-(l-ethoxy-2-methyl-l-oxo-3-phenylpropan-2-yl)pyrazolori,5-αlpyrimidin-3- vPpiperidine- 1 -carboxylate
Figure imgf000077_0001
[00156] A solution of Intermediate A18 (100 mg, 0.20 mmol) in dichloromethane
(1 mL) is treated with trifluoroacetic acid (1 mL) and stirred for 1 hour. The solvent is then removed and the residue is taken on without further purification. Half of the material from the deprotection is dissolved in dichloromethane (1 mL) and treated with
triethylamine (72 mg, 0.71 mmol) followed by methyl chloroformate (15 mg, 0.16 mmol). After stirring for 1 hour, the reaction is diluted with ethyl acetate and extracted with water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified on a reversed phase HPLC (H2OZMeCN gradient) to provide the title compound (Example A19); 1H NMR (CDCl3, 400.13 MHz): δ = 8.25 (d, J = 4.3 Hz, IH), 7.99 (s, 3H), 7.07 (m, 3H), 6.45 (m, 2H), 6.31 (d, J = 4.4 Hz, IH), 4.30 (m, 2H), 4.11 (m, 2H), 4.04 (d, J = 13.6 Hz, IH), 3.73 (s, 3H), 3.31 (d, J = 13.6 Hz, IH), 3.22 (m, IH), 2.98 (m, 2H), 2.09 (m, 2H), 1.86-1.72 (m, 2H), 1.61 (s, 3H), 1.01 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C25H3IN4O4 ([M+H]+) 451.2, found 451.1.
Example A20
1-Methylcyclopropyl 4-(7-(l-ethoxy-2-methyl-l-oxo-3-phenyrpropan-2-yl)pyrazolori,5- αlpyrimidin-3-yl)piperidine-l-carboxylate.
Figure imgf000078_0001
[00157] By following a similar procedure as the one used for preparing Example
A19 from Example A18 except substituting 1-methylcyclopropyl chloroformate for methyl chloroformate, Example A20 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ = 8.25 (d, J = 4.3 Hz, IH), 7.99 (s, IH), 7.08 (m, 3H), 6.44 (m, 2H), 6.31 (d, J = 4.4 Hz, IH), 4.31 (m, 2H), 4.11 (m, 2H), 4.04 (d, J = 13.6 Hz, IH), 3.31 (d, J = 13.6 Hz, IH), 3.19 (m, IH), 2.93 (m, 2H), 2.08 (m, 2H), 1.77 (m, 2H), 1.60 (s, 3H), 1.58 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H), 0.90 (m, 2H), 0.64 (m, 2H); ESIMS calcd. for C28H35N4O4 ([M+H]+) 491.3, found 491.1. Example A21
Ethyl 2-phenoxy-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7- vDpropanoate
Figure imgf000079_0001
Figure imgf000079_0002
A21a A21b A21c
Figure imgf000079_0003
[00158] Step A: A solution of Intermediate A21a (1 g, 6.94 mmol) in
tetrahydrofuran (5 rnL) is added slowly to a pre-cooled (O 0C) mixture of 60% NaH (333 mg, 8.33 mmol) in tetrahydrofuran (20 mL) and stirred for 1 hour. The mixture is then cooled to -78 0C, NBS (1.35 g, 7.63 mmol) is added in one portion and the mixture is allowed to stir for an additional 1 hour. The reaction is quenched with water and allowed to warm to room temperature at which time tetrahydrofuran is removed under reduced pressure. The remaining residue is partitioned between water and ethyl acetate and the aqueous layer is extracted with ethyl acetate. The combined organic phase is washed with 10% aqueous Na2S2O3, water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude by flash chromatography (40 g SiO2) yields ethyl 2-bromo-2- methyl-3-oxobutanoate A21b as a pale yellow liquid. 1H NMR (CDCl3, 400.13 MHz): δ = 4.31-4.25 (m, 2H), 2.44 (s, 3H), 1.97 (s, 3H), 1.30 (t, J = 7.2, 3H); ESIMS calcd. for C7Hi2BrO3 ([M+H]+) 223.0, found 223.2.
[00159] Step B: To a solution of Intermediate A21b (100 mg, 0.45 mmol) in toluene (2 rnL) is added Cs2CO3 (176 mg, 0.54 mmol) followed by phenol (42 mg, 0.45 mmol). The mixture is then heated to 120 0C for 2 hours, the contents cooled, and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-methyl-3-oxo-2-phenoxybutanoate A21c. 1H NMR (CDCl3, 400.13 MHz): δ = 7.28-7.24 (m, 2H), 7.04 (t, J = 7.6 Hz, IH), 6.90-6.87 (m, 2H), 4.24 (q, J = 7.2, 2H), 2.43 (s, 3H), 1.64 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); ESIMS calcd. for Ci3Hi7O4 ([M+H]+) 237.1, found 237.2. The product is used without purification.
[00160] Step C: A solution of Intermediate A21c (70 mg, 0.297) and
dimethylformamide diethyl acetal (3 mL) is heated at 100 0C for 16 hours. Excess dimethylformamide diethyl acetal is removed in vacuo and the crude is purified by flash chromatography (12 g SiO2) to afford ethyl 5-(dimethylamino)-2-methyl-3-oxo-2- phenoxypent-4-enoate A21d as an orange oil. 1H NMR (CDCl3, 400.13 MHz): δ = 7.75 (d, J = 12.8, IH), 7.25-7.21 (m, 2H), 7.00-6.93 (m, 3H), 5.66 (d, J = 12.4, IH), 4.27-4.20 (m, 2H), 3.12 (br s, 3H), 2.87 (br s, 3H) 1.68 (s, 3H), (t, 1.23, J = 7.2 Hz, 3H); ESIMS calcd. for Ci6H22NO4 ([M+H]+) 292.1, found 292.2.
[00161] Step D: In a Smith Process vial charged with Intermediate A21d (43 mg,
0.148 mmol) in ethanol (1 mL) is treated with 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol- 5-amine (30 mg, 0.134 mmol) and 4M HCl in dioxane (67 μL, 0.268 mmol). The mixture is then subjected to microwave irradiation (120 0C, 10 min). The solution is partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash
chromatography (40 g SiO2, hexanes/ethyl acetate gradient) yields the title compound (Example A21) as a yellow glass. 1H NMR (CDCl3, 400.13 MHz): δ = 8.73 (d, J = 4.4Hz, IH), 8.46 (s, IH), 8.20 (d, J = 8 Hz, 2H), 7.70 (d, J = 8 Hz, 2H), 7.47 (d, J = 4.4 Hz, IH), 7.31 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.2 Hz, IH), 6.97 (d, J = 7.6 Hz, 2H), 4.22-4.16 (m, 2H), 1.98 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C24H2IF3N3O3 ([M+H]+) 456.1, found 456.2. Example A22
Ethyl 3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)acrylate
Figure imgf000081_0001
Figure imgf000081_0002
[00162] Step A: A solution of Intermediate A22a (1 g, 4.58 mmol) and
dimethylformamide-DEA (1.6 rnL, 9.33 mmol) is heated at 120 0C for 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzylidene-5-(dimethylamino)-3- oxopent-4-enoate A22b as a 1.5:1 mixture of isomers. 1H NMR (400 MHz, CDC13) δ = 7.83 (d, J = 12.0 Hz, 0.4H), 7.70 (br s, 0.6H), 7.64 (s, 0.4H), 7.60-7.57 (m, 1.2H), 7.46- 7.43 (m, 0.8H), 7.38-7.32 (m, 3H), 5.30 (d, J = 12.0 Hz, 0.4H), 5.28-5.15 (br d, 0.6H), 4.36-4.28 (m, 2H), 3.17 (br s, 1.2H), 3.03 (br s, 1.8H), 2.90 (br s, 1.2H), 2.79 (br s, 1.8H), 1.34 (t, J = 7.2 Hz, 1.8H), 1.27 (t, J = 7.2, 1.2H); ESIMS calcd. for Ci6H20NO3 ([M+H]+) 274.1, found 274.1.
[00163] Step B: In a Smith Process vial charged with Intermediate A22b (69 mg,
0.25 mmol) in ethanol (1 mL) are added 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5- amine (57 mg, 0.25 mmol) and 4M HCl in dioxane (0.13 mL, 0.5 mmol). The mixture is then subjected to microwave irradiation (100 0C, 15 min). The solvent is evaporated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example A22) as a mixture of 2 isomers. Isomer A: 1H NMR (CDCl3, 400.13 MHz): δ = 8.65 (d, J = 4.4 Hz, IH), 8.47 (s, IH), 8.19 (d, J = 8.0 Hz, 2H), 7.77 (s, IH), 7.70 (d, J = 8.0 Hz, 2H), 7.53-7.51 (m, 2H), 7.44-7.42 (m, 3H), 7.03 (d, J= 4.4 Hz, IH), 4.26 (q, J= 8.8 Hz, 2H), 1.15 (t, J= 7.2 Hz, 3H); 19F NMR (376.5 MHz, CDCl3) δ = -62.35; ESIMS calcd. for C24H19F3N3O2 ([M+H]+) 438.1, found 438.0; Isomer B: 1H NMR (CDCl3, 400.13 MHz): δ = 8.56 (d, J = 4.4 Hz, IH), 8.51 (s, IH), 8.26-8.24 (m, 3H), 7.72 (d, J = 8.0 Hz, 2H), 7.33-7.29 (m, IH), 7.24-7.20 (m, 2H), 7.07-7.05 (m, 2H), 6.77 (d, J = 4.4 Hz, IH), 4.29 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H); 19F NMR (376.5 MHz, CDCl3) δ = -62.33; ESIMS calcd. for C24H19F3N3O2 ([M+H]+) 438.1, found 438.0.
Example A23
(Trans)-ethyl 2-phenyl-l-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7- yPcyclopropanecarboxylate
Example A24
(Cis)-ethyl l-(3-(2-nitro-4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-2- phenylcyclopropanecarboxylate
Example A25
(Trans)-ethyl l-(3-(2-nitro-4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-2- phenylcyclopropanecarboxylate
Figure imgf000082_0001
3
Figure imgf000083_0001
[00164] Step A: A solution of Intermediate A23a (260 mg, 1.12 mmol; prepared following experimental procedure from Synthesis 1992, 884-887) and
dimethylformamide-DEA (1 mL, 5.83 mmol) is heated at 80 0C for 16 hours and then at 120 0C for another 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl l-(3- (dimethylamino)acryloyl)-2-phenylcyclopropanecarboxylate A23b as an orange oil. ESIMS calcd. for Ci7H22NO3 ([M+H]+) 288.1, found 288.2.
[00165] Step B: A solution of Intermediate A23b (233 mg, 0.81 mmol) and 4-(4-
(trifluoromethyl)phenyl)-lH-pyrazol-5-amine (184 mg, 0.81 mmol) in ethanol (3 mL) and acetic acid (0.5 mL) is heated to 85 0C for 16 hours. The solvent is then evaporated and the crude material is purified by reversed-phase HPLC (acetonitrile/water gradient) to afford (cis)-ethyl 2 -phenyl- l-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl) cyclopropanecarboxylate A23c and Example A23. A23c: 1H NMR (CDCl3, 400.13 MHz): δ = 8.68 (d, J = 4.4 Hz, IH), 8.58 (s, IH), 8.23 (d, J = 8.0 Hz, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.58-7.56 (m, 2H), 7.42-7.37 (m, 2H), 7.34-7.30 (m, IH), 7.06 (d, J= 4.0 Hz, IH), 3.92-3.77 (m, 2H), 3.23 (t, J = 8.8, IH), 2.67 (dd, J = 8.0, 5.6, IH), 1.75 (dd, J = 9.6, 5.6, IH), 1.31-1.26 (m, IH), 0.79 (t, J= 7.2 Hz, 3H); 19F NMR (376.5 MHz, CDCl3) δ = - 62.33; ESIMS calcd. for C25H2IF3N3O2 ([M+H]+) 452.1, found 452.1. [00166] Example A23: 1H NMR (CDCl3, 400.13 MHz): δ = 8.39 (s, IH), 8.37 (d, J
= 4.0 Hz, IH), 8.12 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.00-6.95 (m, 5H), 6.60 (d, J= 4.0 Hz, IH), 4.25-4.06 (m, 2H), 3.65 (t, J = 8.0, IH), 2.20-2.14 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H); 19F NMR (376.5 MHz, CDCl3) δ = -62.34; ESIMS calcd. for
C25H2IF3N3O2 ([M+H]+) 452.1, found 452.0.
[00167] Step C: A solution of Intermediate A23c (33 mg, 0.07 mmol) in
trifluoroacetic acid (0.5 mL) is cooled to 0 0C and treated with sodium nitrite (5.1 mg, 0.07 mmol). The mixture is then stirred at 0 0C for 1 hour, poured in saturated aqueous NaHCO3, and extracted with ethyl acetate (3x). The organic phase is dried over Na2SO4, concentrated in vacuo and the crude material is purified by reversed-phase HPLC
(acetonitrile/water gradient) to afford the title compounds Example A24 and Example A25. Example A24: 1H NMR (CDCl3, 400.13 MHz): δ = 8.59 (d, J = 4.4 Hz, IH), 8.39 (s, IH), 8.20 (d, J = 0.8 Hz, IH), 8.01-7.99 (m, IH), 7.91-7.88 (m, IH), 7.56-7.54 (m, 2H), 7.39-7.35 (m, 2H), 7.32-7.28 (m, IH), 7.07 (d, J = 4.4 Hz, IH), 3.89-3.75 (m, 2H), 3.21 (t, J= 8.8, IH), 2.65 (dd, J= 8.4, 5.6, IH), 1.77 (dd, J = 9.6, 5.2, IH), 0.77 (t, J= 7.2 Hz, 3H); 19F NMR (376.5 MHz, CDCl3) δ = -62.74; ESIMS calcd. for C25H20F3N4O4
([M+H]+) 497.1, found 497.1. Example A25: 1H NMR (CDCl3, 400.13 MHz): δ = 8.31 (d, J = 4.4 Hz, IH), 8.18 (s, IH), 8.12 (d, J = 0.8 Hz, IH), 7.89-7.87 (m, IH), 7.84-7.81 (m, IH), 7.00-6.96 (m, 5H), 6.63 (d, J = 4.4 Hz, IH), 4.27-4.08 (m, 2H), 3.64 (t, J= 8.4, IH), 2.19 (s, IH), 2.17 (s, IH), 1.09 (t, J = 7.2 Hz, 3H); 19F NMR (376.5 MHz, CDCl3) δ = -62.77; ESIMS calcd. for C25H20F3N4O4 ([M+H]+) 497.1, found 497.0.
Example A26
Ethyl 2-(6-cyano-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000084_0001
A14a A26a
Figure imgf000085_0002
[00168] Step A: To a O 0C solution of intermediate A14a (300 mg, 1.04 mmol) in ethanol (1 niL) is added dropwise a solution of hydroxylamine hydrochloride (72 mg, 1.04 mmol) and sodium acetate (128 mg, 1.56 mmol) in water (1 mL). The mixture is then stirred for 17 hours while allowed to warm to room temperature. The solvent is evaporated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-5-(hydroxyimino)-2-methyl-3-oxopentanoate A26a as a white oil. ESIMS calcd. for Ci5H20NO4 ([M+H]+) 278.1, found 278.1.
[00169] Step B: A solution of Intermediate A26a (153 mg, 0.55 mmol) and dimethylformamide-DEA (0.5 mL, 2.92 mmol) is stirred at room temperature for 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4-cyano-5- (dimethylamino)-2-methyl-3-oxopent-4-enoate A26b as a yellow oil. 1H NMR (CDCl3, 400.13 MHz): δ = 7.94 (s, IH), 7.28-7.21 (m, 3H), 7.15-7.13 (m, 2H), 4.24-4.15 (m, 2H), 3.44 (s, 3H), 3.32 (d, J = 7.2 Hz, 2H), 3.29 (s, 3H), 1.43 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H); ESIMS calcd. for Ci8H23N2O3 ([M+H]+) 315.2, found 315.1.
[00170] Step C: In a Smith Process vial charged with Intermediate A26b (58 mg,
0.18 mmol) in ethanol (1 mL) are added 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5- amine (42 mg, 0.18 mmol) and 4M HCl in dioxane (0.1 mL, 0.4 mmol). The mixture is then subjected twice to microwave irradiation (100 and 120 0C, 15 min each). The mixture is then treated with additional 4M HCl (50 μL, 0.2 mmol) and heated to 120 0C for 16 hours. The solvent is evaporated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example A26). 1H NMR (CDCl3, 400.13 MHz): δ = 8.67 (s, IH), 8.41 (s, IH), 8.20 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.22-7.18 (m, IH), 7.14-7.10 (m, 2H), 6.51 (d, J= 7.2 Hz, 2H), 4.23-4.08 (m, 3H), 3.37 (d, J = 14.0 Hz, IH), 2.10 (s, 3H), 1.08 (t, J= 7.2 Hz, 3H); 19F NMR (376.5 MHz, CDCl3) δ = -62.52; ESIMS calcd. for C26H22F3N4O2 ([M+H]+) 479.2, found 479.2.
Example A27
2-Methyl-l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7- yl)propan-l-one
Figure imgf000086_0001
Figure imgf000086_0002
[00171] Step A: A solution of Intermediate A27a (486 mg, 2.55 mmol; prepared following experimental procedure from Synthesis 1989, 688-690) and
dimethylformamide-DEA (2 mL, 11.7 mmol) is heated at 120 0C for 16 hours. Excess dimethylformamide-DEA is removed and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford 5-(dimethylamino)-2,2- dimethyl- l-phenylpent-4-ene-l,3-dione A27b as an orange oil. ESIMS calcd. for
Ci4Hi8NO2 ([M+H]+) 232.1, found 232.2.
[00172] Step B: In a Smith Process vial charged with Intermediate A27b (54 mg,
0.22 mmol) in ethanol (1 rnL) are added 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5- amine (50 mg, 0.22 mmol) and 4M HCl in dioxane (0.11 mL, 0.44 mmol). The mixture is then subjected to microwave irradiation (100 0C, 15 min). The solvent is evaporated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example A27). 1H NMR (CDCl3, 400.13 MHz): δ = 8.69 (d, J = 4.4 Hz, IH), 8.25 (s, IH), 8.09 (d, J = 8.0 Hz, 2H), 7.67-7.62 (m, 4H), 7.34- 7.29 (m, IH), 7.19-7.13 (m, 3H), 1.89 (s, 6H); 19F NMR (376.5 MHz, CDCl3) δ = -62.38; ESIMS calcd. for C23Hi9F3N4O ([M+H]+) 410.1, found 410.0.
Example A28
Ethyl 2-(6-bromo-3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-fllpyrimidin-7-yl)-2-methyl-
3 -phen ylpropano ate
Figure imgf000087_0001
Figure imgf000087_0002
[00173] Step A: To a solution of Intermediate A14a (80 mg, 0.27 mmol) in CHCl3
(3 mL) is added N-bromo succinimide (60 mg, 0.37 mmL) and the mixture is stirred at room temperature for 30 minutes. The solvent is removed and the remaining contents partitioned between water and ethyl acetate. The organic layer is washed with 10% aqueous NaHSO3, dried over Na2SO4, and volatiles are removed to afford 2-benzyl-4- bromo-5-(dimethylamino)-2-methyl-3-oxopent-4-enoate A28a. The product is used without further purification.
[00174] Step B: In a Smith Process vial charged with Intermediate A28a (1.90 g,
5.15 mmol) in ethanol (15 mL) are added 4-(4-trifluoromethylphenyl)-lH-pyrazol-5- amine (1.17 g, 5.15 mmol) and 48% HBr in water (2.0 ml, 12.36 mmol). The mixture is then subjected to microwave irradiation (140 0C, 20 min). The solution is partitioned between saturated aqueous NaHCO3 and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash
chromatography (80 g SiO2, hexanes/ethyl acetate gradient) affords the title compound (Example 28) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.42 (d, J = 10.4 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.20-7.17 (m, IH), 7.12-7.08 (m, 2H), 6.58-6.56 (m, 2H), 4.18-4.08 (m, 2H), 4.06 (d, J = 13.6 Hz, IH), 3.32 (d, J= 13.6 Hz, IH), 1.05 (t, J= 7.2 Hz, 3H); 19F NMR (376.46 MHz, CDCl3) δ = -62.40; ESIMS calcd. for C25H22BrF3N3O2 ([M+H]+) 532.1, found 532.1.
Example A29
2-(3-(4-Chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenyrpropyl acetate
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000089_0002
Example A29 a
[00175] To a solution of Intermediate AlOi (20 mg, 0.053 mmol) in
dichloromethane (1 rnL) is added triethylamine (11 μL, 0.080 mmol) followed by acetyl chloride (4.5 μL, 0.064 mmol). After 1 hour the mixture is concentrated in vacuo and the residue is purified by flash chromatography (12 g SiO2) to afford the title compound (Example A29) as a yellow oil; 1H NMR (CDCl3, 400.13 MHz): δ = 8.51 (s, IH), 8.37 (d, J = 4.4 Hz, IH), 8.07 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.09-7.06 (m, 3H), 6.56 (d, J = 8.0 Hz, 2H), 6.44 (d, J = 4.4 Hz, IH), 5.29 (d, J = 10.8 Hz, IH), 4.51 (d, J = 10.8 Hz, IH), 4.05 (d, J = 13.2 Hz, IH), 3.13 (d, J= 13.2 Hz, IH), 1.93 (s, 3H), 1.54 (s, 3H); ESIMS calcd. for C24H23ClN3O2 ([M+H]+) 420.1, found 420.2.
Example A30
Ethyl 2-(methyl(phenyl)amino)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5- αlpyrimidin-7-yl)propanoate
Figure imgf000089_0003
Figure imgf000090_0001
[00176] Step A: By following a similar procedure as the one used for preparing
Intermediate A21c from Intermediate A21b except substituting N-methylaniline for phenol, Intermediate A30a is obtained. 1H NMR (CDCl3, 400.13 MHz): δ = 7.25-7.21 (m, 2H), 6.98-6.94 (m, 3H), 4.25 (q, J = 7.2 Hz, 2H), 3.00 (s, 3H), 2.25 (s, 3H), 1.57 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); ESIMS calcd. for Ci4H20NO3 ([M+H]+) 250.1, found 250.1.
[00177] Step B: By following a similar procedure as the one used for preparing
Intermediate A21d from Intermediate A21c except substituting Intermediate A30a for Intermediate A21b, Intermediate A30b is obtained. 1H NMR (CDCl3, 400.13 MHz): δ = 7.66 (d, J = 12.8 Hz, IH), 7.20 (t, J = 7.2 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.90 (t, J = 7.2 Hz, IH), 6.50 (d, J = 12.8 Hz, IH), 4.26-4.20 (m, 2H), 3.07 (br s, 3H), 3.02 (s, 3H), 2.81 (br s, 3H), 1.59 (s, 3H), 1.25 (t, J= 6.8 Hz, 3H); ESIMS calcd. for Ci7H25N2O3 ([M+H]+) 305.2, found 305.2.
[00178] Step C: By following a similar procedure as the one used for preparing
Example A21 from Intermediate A21d except substituting Intermediate A30b for Intermediate A21d, Example A30 is obtained. 1H NMR (CDCl3, 400.13 MHz): δ = 8.72 (d, J = 4.4 Hz, IH), 8.43 (s, IH), 8.20 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 4.4 Hz, IH), 7.35 (t, J = 8.0 Hz, 2H), 7.30-7.23 (m, 3H), 4.31-4.21 (m, 2H), 2.94 (s, 3H), 1.65 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C25H24F3N4O2 ([M+H]+) 469.2, found 469.2.
Example A31
Methyl 3-amino-2-benzyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7- vPpropanoate
Figure imgf000091_0001
Figure imgf000091_0002
A31a A31 b A31c
Figure imgf000091_0003
[00179] Step A: Into a 50 ml round bottom flask is placed methyl 2-((l,3- dioxoisoindolin-2-yl)methyl)-3-oxobutanoate A31a (500 mg, 1.18 mmol), K2CO3 (376 mg, 2.27 mmol), benzyl bromide (258 μL, 2.17 mmol), and acetonitrile (20 ml) and the mixture is stirred for 24 hours. The mixture is partitioned between water and ethyl acetate and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (40 g SiO2, hexanes/ethyl acetate gradient) affords methyl 2- benzyl-2-((l,3-dioxoisoindolin-2-yl)methyl)-3-oxobutanoate A3 Ib as a clear oil. 1H NMR (400 MHz, CDCl3) δ = 7.86-7.84 (m, 2H), 7.74-7.72 (m, 2H), 7.31-7.20 (m, 5H), 4.38 (d, J = 14.4 Hz, IH), 4.27 (d, J = 14.4 Hz, IH), 3.69 (s, 3H), 3.27-3.18 (m, 2H), 2.04 (s, 3H); ESIMS calcd. for C2IH20NO5 ([M+H]+) 366.1, found 366.1. [00180] Step B: A 20 ml vial is charged with Intermediate A3 Ib (134 mg, 0.367 mmol) and dimethylformamide-dimethylacetal (1.5 ml) and the mixture is heated to 110 0C for 24 hours. The solvent is removed and the crude material is purified by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) to afford methyl 2-benzyl-5- (dimethylamino)-2-((l,3-dioxoisoindolin-2-yl)methyl)-3-oxopent-4-enoate A31c as a dark yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.82-7.80 (m, 2H), 7.70-7.68 (m, 2H),
7.51 (d, J = 12.4Hz, IH), 7.32-7.30 (m, 2H), 7.20-7.12 (m, 3H), 4.72 (d, J = 12.0 Hz, IH), 4.55 (d, J = 14.8 Hz, IH), 4.18 (d, J = 14.4 Hz, IH), 3.74 (s, 3H), 3.44 (d, J = 14.4 Hz, IH), 3.23 (d, J= 14.4 Hz, IH), 3.02 (br s, 3H), 2.62 (br s, 3H); ESIMS calcd. for
C24H25N2O5 ([M+H]+) 421.1, found 421.1.
[00181] Step C: Into a 20 ml vial is placed 4-(4-trifluoromethylphenyl)- IH- pyrazol-5-amine (60 mg, 0.262 mmol), Intermediate A31c (110 mg, 0.262 mmol), acetic acid (200 μL), and methanol (2 ml). After heating at 90 0C for 24 hours volatiles are removed and the crude material is purified by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) to afford methyl 2-benzyl-3-(l,3-dioxoisoindolin-2-yl)-2- (3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-α]pyrimidin-7-yl)propanoate A3 Id as a dark yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.51 (s, IH), 8.41 (d, J = 4.4 Hz, IH), 8.22 (d, J= 8.4 Hz, 2H), 7.80-7.78 (m, 2H), 7.73-7.68 (m, 4H), 7.19 (br s, 4H), 6.83 (d, J= 4.4 Hz, IH), 4.72 (d, J= 14.4 Hz, IH), 4.53 (d, J= 14.0 Hz, IH), 3.86 (d, J= 13.6 Hz, IH),
3.52 (s, 3H), 3.47 (d, J = 13.6 Hz, IH); 19F NMR (376.46 MHz, CDCl3) δ = -62.31;
ESIMS calcd. for C32H24F3N4O4 ([M+H]+) 585.2, found 585.2.
[00182] Step D: Into a 20 ml vial is placed Intermediate A3 Id (13 mg, 0.022 mmol), hydrazine monohydrate (5 μL, 0.089 mmol), methanol (200 μL), and
tetrahydrofuran (200 μL). After heating at 50 0C for 24 hours the volatiles are removed and the crude material is purified by flash chromatography (4 g SiO2, hexanes/ethyl acetate gradient) to afford the title compound (Example A31) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.50 (s, IH), 8.46 (d, J = 4.4 Hz, IH), 8.21 (d, J = 8.0 Hz, 2H), 7.70 (d, J= 8.4 Hz, 2H), 7.18-7.10 (m, 3H), 6.63 (d, / = 6.4 Hz, 2H), 6.51 (d, / = 4.4 Hz, IH), 3.94 (d, J = 13.2 Hz, IH), 3.66 (s, 3H), 3.48 (d, J= 13.2 Hz, IH), 1.78-1.36 (m, 4H); 19F NMR (376.46 MHz, CDCl3) δ = -62.34; ESIMS calcd. for C24H22F3N4O2 ([M+H]+) 455.1, found 455.1. Example A32
Ethyl 2-(3-cvclohexenyl-2-methylpyrazolor 1 ,5-αlpyrimidin-7-yl)-3-phenylpropanoate
Figure imgf000093_0001
Figure imgf000093_0002
[00183] Step A: A solution of 3-methyl-lH-pyrazol-5-amine A32a (1 g, O.Olmol) in acetic acid (10 niL) is treated with cyclohexanone (1.2 rnL, 0.012 mol) and stirred at 7O0C overnight. The reaction is cooled to room temperature, concentrated, and the crude material is purified by reversed-phase HPLC (acetonitrile/water gradient) to afford 4- cyclohexenyl-3-methyl-lH-pyrazol-5-amine A32b.
[00184] Step B: By following a similar procedure as the one used for preparing
Example Al from Intermediate Alb except substituting Intermediate A32b for
Intermediate Alb, Example A32 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.30 (d, J = 4.3 Hz, IH), 7.21 (m, 5H), 6.61 (d, J = 4.3 Hz, IH), 5.93 (m, IH), 4.80 (t, J = 7.6 Hz, IH), 4.11 (m, 2H), 3.40 (d, J = 7.6 Hz, 2H), 2.52 (s, 3H), 2.27 (m, 2H), 1.82 (m, 2H), 1.73 (m, 2H), 1.16 (m, 2H), 1.16 (m, 2H), 1.10 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C24H28N3O2 ([M+H]+) 390.5, found 390.2.
Example A33
Ethyl 2-methyl-2-(3-(4-nitrophenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-3-phenyrpropanoate
Figure imgf000094_0001
[00185] By following a similar procedure as the one used for preparing Example
A5, the title compound (Example A33) is obtained: 1H NMR (CDCl3, 400.13 MHz): δ 8.59 (s, IH), 8.48 (d, J = 4.4 Hz, IH), 8.33 (m, 4H), 7.09 (m, 3H), 6.48 (m, 3H), 4.15 (q, J = 7.1 Hz, 2H), 4.09 (d, J = 13.7 Hz, IH), 3.36 (d, J = 13.7 Hz, IH), 1.67 (s, 3H), 1.06 (t, J = 7.1Hz, 3H); ESIMS calcd. for C24H23N4O4 ([M+H]+) 431.2, found 431.0.
Example A34
Diethyl 2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-alpyrimidin-7-yl)malonate
Figure imgf000094_0002
[00186] By following a similar procedure as the one used for preparing Example
Al from Intermediate Ala except substituting diethyl 2-acetylmalonate for Intermediate Ala in step A, and using 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine instead of 4- (4-chlorophenyl)-lH-pyrazol-5-amine in Step B, Example A34 is obtained: ESIMS calcd. for C20H19F3N3O4 ([M+H]+) 422.1, found 422.1. Example A35
Ethyl 2-benzyl-3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7- yl)propanoate
Figure imgf000095_0001
[00187] By following a similar procedure as the one used for preparing Example
A5, except substituting ethyl 3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- a]pyrimidin-7-yl)propanoate for Example Al, and using benzyl bromide instead of iodomethane, the title compound (Example A34) is obtained: 1H NMR (CDCl3, 400.13 MHz): δ 8.52 (s, IH), 8.40 (d, J = 4.5 Hz, IH), 8.24 (d, J = 8.2 Hz, 2H), 7.71 (d, J= 8.2 Hz, 2H), 7.2 (m, 10H), 6.57 (d, J = 4.5 Hz, IH), 4.03 (q, J = 7.1 Hz, 2H), 3.74 (d, J = 13.6 Hz, 2H), 3.39 (d, J= 13.6 Hz, 2H), 0.97 (t, J= 7.1Hz, 3H); 19F NMR (CDCl3, 376.46 MHz): δ -62.32; ESIMS calcd. for C3IH27F3N3O4 ([M+H]+) 530.2, found 530.1.
Example A36
diethyl 2-benzyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-alpyrimidin-7-yl)malonate
Figure imgf000095_0002
[00188] By following a similar procedure as the one used for preparing Example
A5, except substituting ethyl Example A34 for Example Al, and using benzyl bromide instead of iodomethane, the title compound (Example A36) is obtained: ESIMS calcd. for C27H25F3N3O4 ([M+H]+) 511.2, found 511.1.
Example A37
7-(2-(methylsulfonyl)-l-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolori,5- alpyrimidine
Figure imgf000096_0001
Figure imgf000096_0002
A37a A37b A37c
Figure imgf000096_0003
[00189] Step A: A mixture of methanesulfonyl acetone A37a (2.0 g, 14.7 mmol), potassium carbonate (2.0 g, 14.7 mmol) and methyl iodide (916 μL, 14.7 mmol) in acetone (50 mL) is stirred at room temperature for 2h. The mixture is then filtered, concentrated, and the crude material is purified by flash chromatography (SiO2, hexanes/ethyl acetate gradient) to provide 3-(methylsulfonyl)butan-2-one A37b. ESIMS calcd. for C5H11O3S ([M+H]+) 151.0, found 151.0. [00190] Step B: A mixture of Intermediate A37b (753 mg, 5.0 mmol), benzyl bromide (566 μL, 4.8 mmol) and potassium carbonate (1.38 g, 10.0 mmol) is stirred in acetone (25 mL) at room temperature for 3h. The mixture is filtered, concentrated, and the crude material is purified by flash chromatography (SiO2, hexanes/ethyl acetate gradient) to provide 3-methyl-3-(methylsulfonyl)-4-phenylbutan-2-one A37c; IH NMR (CDC13, 400 MHz): 7.30 (m, 3H), 7.09 (m, 2H), 3.81 (d, J = 12.8 Hz, IH), 3.01 (s, 3H), 2.99 (d, J = 12.8 Hz, IH), 2.26 (s, 3H), 1.61 (s, 3H); ESIMS calcd. for C12H17O3S ([M+H]+) 241.1, found 241.0.
[00191] Step C: A solution of Intermediate A37c (300 mg, 1.25 mmol) and N,N- dimethylformamide dimethyl acetal (167 μL, 1.25 mmol) are heated to 100 0C for 12h. The mixture is concentrated to provide (E)-l-(dimethylamino)-4-methyl-4- (methylsulfonyl)-5-phenylpent-l-en-3-one A37d, which is used directly in the next step without further purification. ESIMS calcd. for C15H22NO3S ([M+H]+) 296.1, found 296.0.
[00192] Step D: A mixture of 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine
(284 mg, 1.25 mmol) and Intermediate A37d (1.25 mmol) in methanol (5 mL) and TFA (0.2 mL) is heated at 60 0C for 12h. The mixture is concentrated and purified by flash chromatography (SiO2, hexanes/ethyl acetate gradient) to provide the title compound (Example A37) as a pale yellow solid; IH NMR (CDC13, 400 MHz): 8.65 (s, IH), 8.56 (d, J = 4.4 Hz, IH), 8.27 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.12 (m, 3H), 6.89 (d, J = 4.4 Hz, IH), 6.60 (d, J = 7.6 Hz, IH), 5.49 (d, J = 12.8 Hz, IH), 3.41 (s, 3H), 3.29 (d, J = 12.8 Hz, IH), 1.90 (s, 3H); ESIMS calcd. for C23H21F3N3O2S ([M+H]+) 460.1, found 460.1.
Example A38
Ethyl 3-(3-fluorophenyl)-2-methyl-2-(2-methyl-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000097_0001
Figure imgf000098_0001
A38c A38d
Figure imgf000098_0002
Example A38
[00193] Step A: Ethyl 2-methyl-3-oxobutanoate A21a (1.25 g, 8.7 mmol) is dissolved in acetone (10 niL), then potassium carbonate (1.43 g, 10.4 mmol) and 3- fluorobenzyl chloride (2.1 mL, 17.3 mmol) are added and the mixture is heated for 12h at 60 0C. The mixture is cooled, filtered, concentrated, and the crude material is purified by flash chromatography (SiO2, hexanes/ethyl acetate gradient) to provide ethyl 2-(3- fluorobenzyl)-2-methyl-3-oxobutanoate A38a: ESIMS calcd. for Ci4Hi8FO3 ([M+H]+) 253.1, found 253.1.
[00194] Step B: A solution of Intermediate A38a (1.93 g, 7.65 mmol) and N,N- dimethylformamide diethyl acetal (1.31 mL, 7.65 mmol) are heated at 100 0C for 12h. The mixture is concentrated to afford (E)-ethyl 5-(dimethylamino)-2-(3-fluorobenzyl)-2- methyl-3-oxopent-4-enoate A38b as a red-brown oil. ESIMS calcd. for Ci7H23FNO3 ([M+H]+) 308.2, found 308.1. The product is used in the next step without purification. [00195] Step C: A solution of 4-trifluoromethylphenylacetonitrile (0.54 g, 2.9 mmol) and N,N-dimethylacetamide dimethyl acetal (0.42 niL, 2.9 mmol) is heated to 100 0C for 2h. The mixture is concentrated to afford (Z)-3-(dimethylamino)-2-(4- (trifluoromethyl)phenyl)but-2-enenitrile A38c, which is used in the next step without further purification. ESIMS calcd. for Ci3H14F3N2 ([M+H]+) 255.1, found 255.1.
[00196] Step D: A solution of Intermediate A38c (2.9 mmol) and hydrazine-HCl
(199 mg, 2.9 mmol) in ethanol (4 mL) and water (1 mL) is heated to 80 0C for 12h. The mixture is cooled, basified with saturated aq. NaHCO3, and extracted with ethyl acetate (2x). The organic layers are combined, washed with brine, dried (MgSO4), and concentrated to provide 3-methyl-4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine A38d; 1H NMR (CDCl3, 400 MHz): δ 7.69 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H),
2.33 (s, 3H); ESIMS calcd. for C11H11F3N3 ([M+H]+) 242.1, found 242.1.
[00197] Step E: A mixture of Interemediate A38b (209 mg, 0.68 mmol) and
Intermediate A38d (137 mg, 0.57 mmol) in ethanol (10 mL) and TFA (0.5 mL) is heated to 80 0C for 12h. The mixture is concentrated and purified by flash chromatography (SiO2, hexanes/ethyl acetate gradient) to provide the title compound (Example A38) as a yellow powder; 1H NMR (CDCl3, 400 MHz): δ 8.40 (d, J = 4.8 Hz, IH), 7.91 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.04 (m, IH), 6.86 (m, IH), 6.41 (d, J = 4.8 Hz, IH),
6.34 (m, IH), 6.22 (d, J = 7.6 Hz, IH), 4.18 (m, 3H), 3.35 (d, J = 13.6 Hz, IH), 2.69 (s, 3H), 1.67 (s, 3H), 1.12 (t, J= 7.2 Hz, 3H); ESIMS calcd. for C26H24F4N3O2 ([M+H]+) 486.2, found 486.2.
Example Bl
Ethyl 3-phenyl-2-(3-phenylpyrazolor 1 ,5-αlpyrimidin-7-yl)propanoate
Figure imgf000099_0001
Figure imgf000100_0001
[00198] Step A: By following a similar procedure as the one used for preparing
Example Al from Intermediate Alb except substituting 4-bromo-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine, Intermediate BIa is obtained; ESIMS calcd. for Ci7H17BrN3O2 ([M+H]+) 374.0, found 374.0.
[00199] Step B: A mixture of Intermediate BIa (65 mg, 0.17 mmol),
phenylboronic acid (35 mg, 0.26 mmol) and sodium carbonate (129 mg, 1.2 mmol) in tetrahydrofuran (1.1 mL) and water (0.28 mL) is treated with PdCl2(PPh3)2 (6.1 mg, 8.7 μmol) and heated to 80 0C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example Bl); ESEVIS calcd. for C23H22N3O2 ([M+H]+) 372.4, found 372.2.
[00200] By following a similar procedure as the one used for preparing Example
Bl from Intermediate BIa except substituting the appropriate boronic acid for phenylboronic acid, the following examples are obtained:
Figure imgf000100_0002
Example B4
(EVEthyl 2-(3-(4-chlorostyryl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000101_0001
Figure imgf000101_0002
A14a B4a
Figure imgf000101_0003
[00201] Step A: By following a similar procedure as the one used for preparing
Example Al from intermediate Alb except substituting 4-bromo-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine, Example B4a is obtained; ESIMS calcd. for Ci8Hi9BrN3O2 ([M+H]+) 388.1, found 388.1.
[00202] Step B: By following a similar procedure as the one used for preparing
Example Bl from Intermediate BIa except substituting (£)-4-chlorostyrylboronic acid for phenylboronic acid and Intermediate B4a for Intermediate BIa, Example B4 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.39 (s, 2H), 7.50 (d, J = 7.7 Hz, 2H), 7.34 (m, 4H), 7.09 (m, 3H), 6.47 (d, J = 1.3 Hz, 2H), 6.39 (d, J = 3.8 Hz, IH), 4.13 (q, J = 7.1 Hz, 2H), 4.08 (d, J = 13.7 Hz, IH), 3.33 (d, J = 13.7 Hz, IH), 1.65 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C26H25ClN3O2 ([M+H]+) 446.2, found 446.0. [00203] By following a similar procedure as the one used for preparing Example
B4 from Intermediate B4a except substituting the appropriate boronic acid for (E)-4- chlorostyrylboronic acid the following examples are obtained:
Figure imgf000102_0001
Figure imgf000103_0001
Example B 13
Ethyl 2-(3-(biphenyl-4-yl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenylpropanoate
Figure imgf000104_0001
[00204] A Smith Process vial charged with Intermediate B4a (48 mg, 0.12 mmol), biphenylboronic acid (30 mg, 0.12 mmol) and cesium fluoride (57 mg, 3.7 mmol) in dioxane (1 mL) is treated with Pd2dba3 (2.3 mg, 2.5 μmol) and tri-tert-butylphosphonium tetrafluoroborate (2.2 mg, 7.5 μmol). The vial is then sealed and the mixture is subjected to microwave irradiation (120 0C, 20 min). The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified on a reversed phase HPLC (H2CVMeCN gradient) to provide the title compound (Example B13); 1H NMR (CDCl3, 400.13 MHz): δ 8.54 (s, IH), 8.42 (d, J = 4.3 Hz, IH), 8.19 (m, 2H), 7.73 (m, 2H), 7.67 (m, 2H), 7.47 (m, 2H), 7.37 (m, IH), 7.08 (m, 3H), 6.49 (m, 2H), 6.39 (d, J = 4.4 Hz, IH), 4.15 (m, 3H), 3.35 (d, J= 13.6 Hz, IH), 1.66 (s, 3H), 1.05 (t, J= 7.1 Hz, 3H); ESIMS calcd. for C30H28N3O2 ([M+H]+) 462.2, found 462.1.
Example B 14
Ethyl 2-methyl-3-phenyl-2-(3-p-tolylpyrazolori,5-αlpyrimidin-7-yl)propanoate
Figure imgf000105_0001
[00205] A mixture of Intermediate B4a (47 mg, 0.12 mmol), 4- methylphenylboronic acid (24 mg, 0.12 mmol) and sodium carbonate (39 mg, 3.6 mmol) in dimethoxyethane (1 mL) and water (0.1 mL) is treated with Pd(PPh3)4 (7 mg, 6 μmol) is heated to 110 0C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified on a reversed phase HPLC (H2CVMeCN gradient) to provide the title compound (Example B14); 1H NMR (CDCl3, 400.13 MHz): δ 8.46 (s, IH), 8.39 (d, J = 4.4 Hz, IH), 7.92 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.08 (m, 3H), 6.49 (m, 2H), 6.37 (d, J = 4.4 Hz, IH), 4.13 (m, 3H), 3.34 (d, J= 13.6 Hz, IH), 2.41 (s, 3H), 1.65 (s, 3H), 104 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C25H26N3O2 ([M+H]+) 400.2, found 400.1.
[00206] By following a similar procedure as the one used for preparing Example
B14 from Intermediate B4a except substituting the appropriate boronic acid for 4- methylphenylboronic acid the following examples are obtained:
Figure imgf000105_0002
1H NMR (CDCl3, 400.13 MHz):
δ 8.47 (s, IH), 8.40 (d, 7 = 4.3 Hz, IH), 8.12 (d, J = 8.8 Hz, 2H), 7.32 (d, 7 = 8.1 Hz, 2H), 7.07 (m, 3H), 6.47 (m, 2H), 6.40
B16 (d, 7 = 4.4 Hz, IH), 4.13 (q, J =
7.1 Hz, 2H), 4.10 (d, 7 = 13.7 Hz, IH), 3.34 (d, 7 = 13.6 Hz,
Figure imgf000106_0001
IH), 1.65 (s, 3H), 1.04 (t, 7 = 7.1
Hz, 3H); ESIMS calcd. for C25H23F3N3O3 ([MH-H]+) 470.2, found 470.2.
1H NMR (CDCl3, 400.13 MHz): δ 8.43 (s, IH), 8.37 (d, J = 4.4 Hz, IH), 8.00 (d, 7 = 8.9 Hz, 2H), 7.07 (m, 5H), 6.48 (m, 2H),
B17 6.35 (d, 7 = 4.4 Hz, 1 H), 4.12 (m,
3H), 3.87 (s, 3H), 3.34 (d, J = 13.6 Hz, IH), 1.64 (s, 3H), 1.04
Figure imgf000106_0002
(t, 7 = 7.1 Hz, 3H); ESIMS calcd.
for C25H26N3O3 ([MH-H]+) 416.2, found 416.1.
1H NMR (CDCl3, 400.13 MHz): δ 8.39 (d, 7 = 4.5 Hz, IH), 8.25 (s, IH), 7.42 (d, J = 8.2 Hz, IH), 7.34 (d, 7 = 1.9 Hz, IH), 7.28 (m, IH), 7.11 (m, 3H), 6.49 (m, 2H),
B18 6.47 (d, 7 = 4.6 Hz, IH), 4.15 (m,
3H), 3.36 (d, J = 13.6 Hz, IH), 2.30 (s, 3H), 1.70 (s, 3H), 1.06 (t,
Figure imgf000106_0003
7 = 7.1 Hz, 3H); ESIMS calcd.
for C25H25ClN3O2 ([MH-H]+) 434.2, found 434.1.
Example B19
Ethyl 2-methyl-3-phenyl-2-(3-(4-(pyridin-3-yl)phenyl) pyrazolori,5-αlpyrimidin-7- vDpropanoate
Figure imgf000106_0004
[00207] In a microwave vial a solution of Example A14 (38 mg, 0.08 mmol), pyridin-3-yl boronic acid (30 mg, 0.2 mmol), and powdered potassium carbonate (50 mg, 0.36 mmol) in dimethoxyethane (2.5 mL) and water (0.5 mL) is degassed using argon. Tetrakis(triphenylphosphino)-palladium(II) (30 mg, 0.03 mmol) is added, the solution is degassed again, the vial is sealed and the mixture is subjected to microwave irradiation (180 0C, 10 min). The reaction mixture is cooled, filtered and the residue is purified on a reversed phase HPLC (H2OZMeCN gradient) to provide the title compound (Example B19); ESIMS calcd. for C29H27N4O2 ([M+H]+) 463.2, found 463.1.
Example B20
Ethyl 2-methyl-3-phenyl-2-(3-(4-(pyridin-4-yl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7- vPpropanoate
Figure imgf000107_0001
[00208] By following a similar procedure as the one used for preparing Example
B19 from Example A14 except substituting pyridin-4-yl boronic acid for pyridin-3-yl boronic acid, Example B20 is obtained; ESIMS calcd. for C29H27N4O2 ([M+H]+) 463.2, found 463.1.
Example B21
Ethyl 2-methyl-3-phenyl-2-(3-(4-((6-(trifluoromethyl) pyridin-3- yl)methylamino)phenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)propanoate
Figure imgf000108_0001
[00209] A mixture of Example A14 (28 mg, 0.06 mmol), (6-
(trifluoromethyl)pyridin-3-yl)methanamine (30 mg, 0.17 mmol), palladium dichloride dppf dichloromethane complex (30 mg, 0.04 mmol), l,l'bis(diphenylphosphino)ferrocene (30 mg, 0.05 mmol), and powdered cesium carbonate (50 mg, 0.36 mmol) in 1,4-dioxane (5 mL) is degassed using argon and stirred at 120 0C for 18 h. The reaction mixture is cooled, filtered and the residue is purified on a reversed phase HPLC (H2CVMeCN gradient) to provide the title compound (Example B21); ESEVIS calcd. for C31H29F3N5O2 ([M+H]+) 560.2, found 560.1.
Example B22
Ethyl 2-methyl-3-phenyl-2-(3-(4-(l-phenylethylamino) phenyl)pyrazolori,5-αlpyrimidin-
7-yl)propanoate
Figure imgf000108_0002
[00210] By following a similar procedure as the one used for preparing Example
B21 from Example A14 except substituting 1-phenylethanamine for (6- (trifluoromethyl)pyridin-3-yl)methanamine, Example B22 is obtained; ESIMS calcd. for C32H33N4O2 ([M+H]+) 505.2, found 505.1.
Example B23
Ethyl 2-(3-(4-isopropylphenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000109_0001
Figure imgf000109_0002
A14a B23a
Figure imgf000109_0003
[00211] Step A: By following a similar procedure as the one used for preparing
Example Al from Intermediate Alb except substituting 4-iodo-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine and Intermediate A14a for Intermediate Alb, Intermediate B23a is obtained.
[00212] Step B: By following a similar procedure as the one used for preparing
Example B14 from Intermediate B4a except substituting Intermediate B23a for intermediate B4a and 4-isopropylphenylboronic acid for 4-methylphenylboronic acid, Example B23 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.47 (s, IH), 8.38 (d, J = 4.4 Hz, IH), 7.99 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.07 (m, 3H), 6.47 (m, 2H), 6.35 (d, J = 4.4 Hz, IH), 4.13 (m, 3H), 3.32 (d, J = 13.6 Hz, IH), 2.96 (sept, J = 6.9 Hz, IH), 1.65 (s, 3H), 1.30 (d, J= 6.9 Hz, 6H), 1.03 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C27H30N3O2 ([M+H]+) 428.5, found 428.3.
[00213] By following a similar procedure as the one used for preparing Example
B23 from Intermediate B23a except substituting the appropriate boronic acid for A- isopropylphenylboronic acid the following examples are obtained:
Figure imgf000110_0001
Example B26
Ethyl 2-methyl-3-phenyl-2-(3-(6-(trifluoromethyl)pyridin-3-yl)pyrazolor 1 ,5-αlpyrimidin-
7-vl)propanoate
Figure imgf000111_0001
[00214] Step A: A solution of Intermediate B23a (109 mg, 0.25 mmol) in tetrahydrofuran (250 μL) is cooled to 0 0C (ice/water bath) and treated isopropyl magnesium chloride (2M in tetrahydrofuran, 163 μL, 0.33 mmol) over 2 minutes and allowed to stir cold for 1 hour. The reaction is then treated with a 1 M zinc chloride in diethyl ether (0.376 mL, 0.38 mmol), stirred cold for an additional hour and then warmed to room temperature. The reaction is then treated with a solution of 2-trifluoromethyl-5- bromopyridine (85 mg, 0.38 mmol) and Pd(PPh3)4 (5.8 mg, 5.0 μmol) in
dimethylformamide (0.63 mL) and heated to 80 0C for 1 hour. The reaction mixture is cooled, quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example B26); 1H NMR (CDCl3, 400.13 MHz): δ 9.50 (d, J = 1.8 Hz, IH), 8.77 (dd, J = 8.2, 2.0 Hz, IH), 8.61 (s, IH), 8.49 (d, J = 4.4 Hz, IH), 7.82 (d, J= 8.3 Hz, IH), 7.09 (m, 3H), 6.49 (m, 3H), 4.16 (q, J= 7.1 Hz, 2H), 4.08 (d, J= 13.7 Hz, IH), 3.36 (d, J = 13.7 Hz, IH), 1.68 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C24H22F3N4O2 ([M+H]+) 455.2, found 455.2.
Example B27
Ethyl 2-(3-(6-(dimethylamino)pyridin-3-yl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenvlpropanoate
Figure imgf000112_0001
Figure imgf000112_0002
[00215] Step A: By following a similar procedure as the one used for preparing
Example B23 from Intermediate B23a except substituting 6-fluoropyridin-3-ylboronic acid for 4-isopropylphenylboronic acid, intermediate B27a is obtained; ESIMS calcd. for C23H22FN4O2 ([M+H]+) 405.2, found 405.1.
[00216] Step B: A solution of intermediate B27a (51 mg, 0.13 mol) in
dimethylformamide (1 mL) is treated with dimethylamine (2M in tetrahydrofuran, 0.13 mL), sealed and heated to 100 0C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified on a reversed phase HPLC (H2O/MeCN gradient) to provide the title compound (Example B27); 1H NMR (CDCl3, 400.13 MHz): δ 8.82 (m, IH), 8.63 (d, J = 9.5 Hz, IH), 8.45 (s, IH), 8.42 (m, IH), 7.09 (m, 3H), 6.99 (d, J = 9.5 Hz, IH), 6.46 (m, 3H), 4.14 (m, 2H), 4.06 (d, J= 13.7 Hz, IH), 3.37 (s, 6H), 3.35 (d, J = 13.7 Hz, IH), 1.65 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C25H28N5O2 ([M+H]+) 430.2, found 430.1.
I l l Example B28
tert-Butyl 4-(7-(l-ethoxy-2-methyl-l-oxo-3-phenyrpropan-2-yl)pyrazolori,5- αlpyrimidin-3-yl)-5,6-dihvdropyridine- 1 (2H)-carboxylate
Figure imgf000113_0001
[00217] A microwave vial charged with Intermediate B23a (173 mg, 0.40 mmol), tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)- carboxylate (148 mg, 0.48 mmol) and cesium carbonate (389 mg, 1.2 mmol) is treated with dioxane (4 mL) and water (1.2 mL) followed by Pd(dppf)Cl2 (29 mg, 40 μmol). The vial is sealed and the mixture is subjected to microwave irradiation (120 0C, 30 min). The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example B28); 1H NMR (CDCl3, 400.13 MHz): δ 8.32 (d, J = 4.4 Hz, IH), 8.16 (s, IH), 7.07 (m, 3H), 6.76 (m, IH), 6.44 (m, 2H), 6.33 (d, J = 4.4 Hz, IH), 4.18 (m, 2H), 4.10 (m, 3H), 3.72 (m, 2H), 3.31 (d, J = 13.6 Hz, IH), 2.72 (m, 2H), 1.62 (s, 3H), 1.50 (s, 9H), 1.02 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C28H35N4O4 ([M+H]+) 491.3, found 491.3.
[00218] By following a similar procedure as the one used for preparing Example
B28 from Intermediate B23a except substituting the appropriate boronic acid for tert- butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)- carboxylate the following examples are obtained:
Figure imgf000113_0002
IH),
Hz, IH), Hz, 2H), Hz, IH), Hz, 3H); 402.2,
2H), (m, 2H), (q, 7 (d, J = Hz, 3H); 387.2,
(s, (d, 7 (m, 4.04 (q, 3.28 (d, 7 7.1 Hz, 414.2,
Figure imgf000114_0001
Example B32
1-Methylcvclopropyl 4-(7-(l-ethoxy-2-methyl-l-oxo-3-phenylpropan-2-yl)pyrazolori,5- αlpyrimidin-3-yl)-5,6-dihvdropyridine- 1 (2H)-carboxylate
Figure imgf000114_0002
[00219] A solution of Example B28 (41.6 mg, 85 μmol) in dichloromethane (0.5 niL) and trifluoroacetic acid (0.5 niL) is aged for 1 hour and the solvent is removed. The reaction is then treated with dichloromethane (1 mL), 1-methylcyclopropyl 4-nitrophenyl carbonate (21 mg, 89 μmol) and triethylamine (30 μL, 0.21 mmol). The reaction mixture is stirred for 1.5 hours and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example B32); 1H NMR (CDCl3, 400.13 MHz): δ 8.32 (d, J = 4.4 Hz, IH), 8.15 (s, IH), 7.07 (m, 3H), 6.76 (m, IH), 6.43 (m, 2H), 6.33 (d, J = 4.4 Hz, IH), 4.21 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.07 (d, J = 13.9 Hz, IH), 3.70 (m, 2H), 3.31 (d, J = 13.6 Hz, IH), 2.72 (m, 2H), 1.62 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H), 0.94 (m, 2H), 0.65 (m, 2H); ESIMS calcd. for C28H33N4O4 ([M+H]+) 489.2, found 489.3.
Example B33
Ethyl 2-(3-(4-(difluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000115_0001
[00220] To a solution of Example B31 (41 mg, 0.1 mmol) in dichloromethane (0.3 mL) is added deoxo-fluor (31 μL, 0.17 mmol) and stirred at room temperature for 4 h. Another portion of deoxo-fluor (31 μL, 0.17 mmol) is added and the reaction mixture stirred at room temperature overnight. The excess of reagent is quenched with saturated aqueous NaHCO3 (1 mL), extracted with dichloromethane (3 x 10 mL), dried (Na2SO4) and concentrated. The residue is purified on a reversed phase HPLC (H2O/MeCN gradient) to provide the title compound (Example B33); 1H NMR (CDCl3, 400.13 MHz): δ 8.54 (s, IH), 8.42 (d, J = 4.4 Hz, IH), 8.22 (d, J = 7.9 Hz, 2H), 7.61 (d, J= 7.9 Hz, 2H), 7.08 (m, 3H), 6.70 (t, J = 56.6 Hz, IH), 6.49 (m, 2H), 6.41 (d, J = 4.4 Hz, IH), 4.14 (q, J = 7.1 Hz, 2H), 4.10 (d, J = 13.7 Hz, IH), 3.35 (d, J = 13.7 Hz, IH), 1.66 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C25H24F2N3O2 ([M+H]+) 436.2, found 436.2. Example B34
Ethyl 2-methyl-3-phenyl-2-(3-((4-(trifluoromethyl)phenyl)ethynyl)pyrazolor 1 ,5- αlpvrimidin-7-vl)propanoate
Figure imgf000116_0001
[00221] A flask filled with Intermediate B23a (51.4 mg, 0.12 mmol),
copper(I)iodide (2.2 mg, 0.01 mmol) and potassium carbonate (40.8 mg, 0.30 mmol) is treated with dimethoxyethane (0.2 mL) and water (0.2 mL) followed by Pd(dppf)Cl2 (4.3 mg, 5.9 μmol) and l-ethynyl-4-(trifluoromethyl)benzene (50 mg, 0.30 mmol). The reaction is sealed and heated to 80 0C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example B34); 1H NMR (CDCl3, 400.13 MHz): δ 8.42 (d, J = 4.4 Hz, IH), 8.37 (s, IH), 7.69 (d, J = 8.0 Hz, 2H), 7.59 (d, J= 8.2 Hz, 2H), 7.07 (m, 3H), 6.42 (m, 3H), 4.11 (m, 2H), 4.05 (d, J = 13.8 Hz, IH), 3.32 (d, J = 13.7 Hz, IH), 1.63 (s, 3H), 1.02 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C27H23F3N3O2 ([M+H]+) 478.5, found 478.2.
Example B35
Ethyl 2-methyl-3-phenyl-2-(3-(phenylethvnyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)propanoate
Figure imgf000117_0001
[00222] By following a similar procedure as the one used for preparing Example
B34 from Intermediate B23a, except substituting ethynylbenzene for l-ethynyl-4- (trifluoromethyl)benzene, Example B35 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.41 (d, J = 4.4 Hz, IH), 8.37 (s, IH), 7.62 (m, 2H), 7.35 (m, 3H), 7.09 (m, 3H), 6.45 (m, 2H), 6.40 (d, J = 4.4 Hz, IH), 4.12 (m, 2H), 4.08 (d, J= 13.7 Hz, IH), 3.33 (d, J= 13.7 Hz, IH), 1.56 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C26H24N3O2 ([M+H]+) 410.5, found 410.2.
Example B36
Ethyl 2-methyl-3-phenyl-2-(3-(phenylethvnyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)propanoate
Figure imgf000117_0002
[00223] By following a similar procedure as the one used for preparing Example
B27 from Intermediate B23a, except substituting 4-cyclopropylphenylboronic acid for phenylboronic acid, Example B36 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.46 (s, IH), 8.37 (d, J = 4.3 Hz, IH), 7.98 (d, J = S3 Hz, IH), 7.19 (d, J = 8.3 Hz, 2H), 7.07 (m, 3H), 6.48 (m, 2H), 6.34 (d, J = 4.3 Hz, IH), 4.13 (m, 3H), 3.33 (d, J = 13.6 Hz, IH), 1.95 (m, IH), 1.64 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H), 0.98 (m, 2H), 0.74 (m, 2H); ESIMS calcd. for C27H28N3O2 ([M+H]+) 426.5, found 426.1.
[00224] By following a similar procedure as the one used for preparing Example
B36 from Intermediate B23a except substituting the appropriate boronic acid for phenylboronic acid, the following examples are obtained:
Figure imgf000118_0001
Figure imgf000119_0003
Example B41
Ethyl 2-(3-(4-(2-hvdroxypropan-2-yl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000119_0001
Figure imgf000119_0002
Example B41
[00225] Step A: By following a similar procedure as the one used for preparing
Example B23 from Intermediate B23a except substituting A-
(methoxycarbonyl)phenylboronic acid for 4-isopropylphenylboronic acid, Intermediate B41a is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.56 (s, IH), 8.43 (d, J = AA Hz, IH), 8.22 (d, J = 8.7 Hz, 2H), 8.13 (d, J = 8.6 Hz, 2H), 7.08 (m, 3H), 6.47 (m, 2H), 6.41 (d, J = A.A Hz, IH), 4.13 (q, J = 7.1 Hz), 4.10 (d, J = 13.7 Hz, IH), 3.94 (s, 3H), 3.34 (d, J = 13.7 Hz, IH), 1.65 (s, J = 3H), 1.04 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C26H26N3O4 ([M+H]+) 444.5, found 444.1.
[00226] Step B: A cold (O0C) solution of Intermediate B41a (50.1 mg, 0.113 mmol) in tetrahydrofuran (1 rnL) is treated with methyl magnesium bromide (3M in diethyl ether, 0.79 mL) and stirred for 2.5 hours. The reaction mixture is then quenched with water and extracted with ethyl actetate. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example B41); 1H NMR (CDCl3, 400.13 MHz): δ 8.50 (s, IH), 8.38 (d, J= 4.4 Hz, IH), 8.07 (d, J= 8.6 Hz, 2H), 7.61 (d, J= 8.6 Hz, 2H), 7.06 (m, 3H), 6.48 (d, J= 6.9 Hz, 2H), 6.36 (d, J= 4.4 Hz, IH), 4.14 (m, 4H), 3.34 (d, J = 13.6 Hz, IH), 1.65 (s, 3H), 1.64 (s, 6H), 1.03 (t, J= 7.1 Hz, 3H); ESIMS calcd. for C27H30N3O3 ([M+H]+) 444.5, found 444.1.
Example B42
Ethyl 2-(3-(4-(l-hvdroxycvclohexyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenvlpropanoate
Figure imgf000120_0001
[00227] By following a similar procedure as the one used for preparing Example
B41 from Intermediate B41a except substituting pentamethylene (bis) magnesium bromide for methyl magnesium bromide, Example B42 is obtained; ESIMS calcd. for C30H34N3O3 ([M+H]+) 484.6, found 484.1. Example B43
Ethyl 2-(3-(4-(2-fluoropropan-2-yl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000121_0001
[00228] A cold (0 0C) solution of diethylamino sulfur trifluoride (0.066 niL, 0.050 mmol) in dichloromethane (0.25 rnL) is treated with the dropwise addition of Example B41 (20.0 mg, 0.0451 mmol). The reaction is warmed to room temperature and stirred overnight. The reaction is then treated with ice, diluted with dichloromethane and washed with water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue purified on a reversed phase HPLC (H2CVMeCN gradient) to provide the title compound (Example B43); 1H NMR (CDCl3, 400.13 MHz): δ 8.50 (s, IH), 8.39 (bs, IH), 8.07 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.07 (m, 3H), 6.48 (m, 2H), 6.37 (d, J = 4.1 Hz, IH), 4.13 (m, 3H), 3.34 (d, J = 13.6 Hz, IH), 2.20 (s, 3H), 1.65 (s, 6H), 1.04 (t, J= 7.1 Hz, 3H); ESIMS calcd. for C27H28FN3O2 ([M]+) 444.5, found 444.1.
Example B44
Ethyl 2-(3-(4-(l-fluorocvclohexyl)phenyl)pyrazolo[l,5-α1pyrimidin-7-yl)-2-methyl-3- phenvlpropanoate
Figure imgf000122_0001
[00229] By following a similar procedure as the one used for preparing Example
B43 from Example B41 except substituting Example B42 for Example B41, Example
B44 is obtained; ESIMS calcd. for C30H32FN3O2 ([M]+) 486.6, found 486.1.
Example Cl
Ethyl 2-(3-(3-isopropyl-l,2,4-oxadiazol-5-yl)pyrazolo[l,5-α]pyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000122_0002
Figure imgf000123_0001
A14a CIa
Figure imgf000123_0002
[00230] Step A: By following a similar procedure as the one used for preparing
Example Al from Intermediate Alb except substituting Intermediate A14a for
Intermediate Alb and 5-amino-lH-pyrazole-4-carboxylic acid for 4-(4-chlorophenyl)- lH-pyrazol-5-amine, Intermediate CIa is obtained; ESIMS calcd. for Ci9H20N3O4
([M+H]+) 354.1, found 354.1.
[00231] Step B: A solution of Intermediate CIa (129 mg, 0.36 mol) in dimethylformamide (1.5 mL) is treated with N-hydroxysuccinimide (59 mg) and EDC (91 mg, 0.47 mmol) and stirred overnight at room temperature. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified by flash chromatography
(hexanes/ethyl acetate gradient) to afford 2,5-dioxopyrrolidin-l-yl 7-(l-ethoxy-2-methyl- l-oxo-3-phenylpropan-2-yl)pyrazolo[l,5-α]pyrimidine-3-carboxylate CIb.
[00232] Step C: A solution of Intermediate CIb (137 mg, 0.30 mmol) and N'- hydroxyisobutyrimidamide in dioxane (2 mL) is sealed and heated to 110 0C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified on a reversed phase HPLC (H2O/MeCN gradient) to provide the title compound
(Example Cl); 1H NMR (CDCl3, 400.13 MHz): δ 8.80 (s, IH), 8.66 (d, J = 4.6 Hz, IH), 7.07 (m, 3H), 6.59 (d, J = 4.6 Hz, IH), 6.44 (m, 2H), 4.13 (m, 2H), 4.06 (d, J = 13.7 Hz, IH), 3.36 (d, J = 13.7 Hz, IH), 3.25 (sept, J = 7.0 Hz, IH), 1.69 (s, 3H), 1.44 (d, /= 7.0 Hz, 6H), 1.03 (t, J = 7.1 Hz, 3H); ESIMS calcd. for C23H26N5O3 ([M+H]+) 420.2, found 420.1.
Example Dl
2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-3-phenylpropanenitrile
Figure imgf000124_0001
Figure imgf000124_0002
[00233] Step A: Asolution of diisopropylamine (3.08 g, 30.5 mmol) in tetrahydrofuran (20 rnL) is cooled in a dry ice/acetone bath and treated with a solution of butyllithium (6.7 rnL of a 2.5 M solution, 16.8 mmol) and allowed to stir cold for 15 minutes. The reaction is then treated with Intermediate DIa (2.0 g, 15.3 mmol) and allowed to stir for 15 minutes cold. The reaction is then allowed to come to room temperature over 30 minutes and treated with ethyl acetate (669 mg, 7.6 mmol) and stirred for an additional 30 minutes. The reaction is then quenched with a solution of NaH2PO4 (1Og) in water (100 mL) and diluted with ethyl acetate. The organics are isolated, washed with saturated aqueous NaHCO3 (2x), dried over MgSO4, filtered, evaporated and purified on silica gel to afford 2-benzyl-3-oxobutanenitrile DIb; 1H NMR (CDCl3, 400.13 MHz): 57.40-7.25 (m, 5H), 3.66 (dd, J = 5.5, 8.6 Hz, IH), 3.26 (dd, J = 5.5, 13.9 Hz, IH), 3.12 (dd, J= 8.6, 13.9 Hz, IH), 2.37 (s, 3H); ESIMS calcd. for Cl1H11NO ([M+H]+) 174.1, found 174.1. [00234] Step B: Asolution of Intermediate DIb (1.30 g, 7.5 mmol) in
dimethylformamide dimethyl acetal (3.5 ml, excess) is heated to 100 0C for 1 hour and the solvent is removed in vacuo. The residue is coevaporated with ethanol twice and then dissolved in ethanol (5 mL) and treated with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (726 mg, 3.75 mmol) and 4M HCl in dioxane (1 mL, 4 mmol). The reaction is heated to 150 0C for 30 minutes, cooled to room temperature, diluted with ethyl acetate and washed with water (3x). The organics are dried over MgSO4, filtered, evaporated and the crude material is purified on silica gel to afford the title compound (Example Dl); ESIMS calcd. for C2iH15ClN4 ([M+H]+) 359.1, found 359.1.
Example D2
3-( 1 -(3-(4-Chlorophenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-2-phenylethyl)-5-methyl- 1 ,2,4- oxadiazole
Figure imgf000125_0001
[00235] A solution of Example Dl (75 mg, 0.36 mol) in methanol (1 mL) is treated with a 50% aqueous solution of hydroxylamine N-hydroxysuccinimide (50 μL, 0.76 mmol), sealed, and heated to 80 0C overnight. The reaction is then cooled to room temperature and the solvent was removed. The residue is co evaporated with dioxane and treated with dioxane (1 mL) followed by acetic anhydride (42 mg, 0.42 mmol). The reaction is heated to 120 0C for 2 hours. Then, 50 μL of acetic acid is added and the reaction is heated to 120 0C for 3 days. The reaction is cooled to room temperature and the solvent is removed. The residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example D2); 1H NMR (CDCl3, 400.13 MHz): δ 8.50 (d, J= 4.3 Hz, IH), 8.45 (s, IH), 7.99 (m, 2H), 7.41 (m, 2H), 7.22 (m, 5H), 6.92 (d, J = 4.3 Hz, IH), 5.60 (dd, J = 6.4, 8.8 Hz, IH), 3.65 (dd, J = 6.4, 13.8 Hz, IH), 3.54 (dd, J= 8.8, 13.8 Hz, IH), 2.59 (s, 3H); ESIMS calcd. for C23H19ClN5O ([M+H]+) 416.1, found 416.1.
Example El
Ethyl 2-(8-(4-chlorophenyl)imidazori,5-αlpyrimidin-4-yl)-2-methyl-3-phenylpropanoate.
Figure imgf000126_0001
Figure imgf000126_0002
[00236] Step A: A solution of Intermediate EIa (250 mg, 1.8 mmol), amidine hydrochloride (157 mg, 2.0 mmol) and potassium cyanide (122 mg, 1.9 mmol) in a mxture of ethanol (3 mL) and water (3 mL) is heated to 50 0C overnight. The reaction is then diluted with ethyl acetate and the organics are extracted twice with 1 M NaOH. The aqueous phase is discarded and the organics are extracted twice with 1 M HCl and discarded. The combined aqueous layers are made basic with solid Na2CO3, extracted twice with ethyl acetate. The combined organics are then dried over MgSO4, filtered and evaporated to afford Intermediate EIb; ESIMS calcd. for C9H9ClN3 ([M+H]+) 194.0, found 194.1. The product is used without purification. [00237] Step B: By following a similar procedure as the one used for preparing
Example Al from Intermediate Alb except substituting Intermediate EIb for 4 (4- chlorophenyl)-lH-pyrazol-5-amine and Intermediate A14a for Intermediate Alb,
Example El is obtained; 1H NMR (CDCl3, 400.13 MHz): δ 8.49 (m, IH), 8.23 (m, 3H), 7.43 (m, 2H), 7.09 (m, 5H), 6.59 (m, 2H), 6.42 (d, J = 3.9 Hz, IH), 4.18 (m, 2H), 3.44 (dd, J = 13.7, 74.0 Hz, IH), 1.60 (s, 3H), 1.11 (dd, J = 7.0, 7.0 Hz, IH); ESIMS calcd. for C24H23ClN3O2 ([M+H]+) 420.1, found 420.1.
Example Fl
Ethyl 2-(8-(4-chlorophenyl)pyrazolor5,l-ciri,2,41triazin-4-yl)-2-methyl-3- phenylpropanoate
Figure imgf000127_0001
Figure imgf000127_0002
AlOa FIa
Figure imgf000127_0003
[00238] Step A: A solution of Intermediate AlOa (600 mg, 2.6 mmol) in acetic acid (8 mL) is treated with bromine (409 mg, 2.6 mmol) and stirred at room temperature overnight. The reaction is then diluted with ethyl acetate and the organics are extracted with IM NaOH (Ix) and with saturated aqueous sodiumhydrogencarbonate (2x). The organics are isolated, dried over MgSO4, filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4- bromo-2-methyl-3-oxobutanoate FIa; ESIMS calcd. for Ci4Hi8BrO3 ([M+H]+) 313.0, found 313.0.
[00239] Step B: A solution of Intermediate FIa (95 mg, 0.30 mmol) in tetrahydrofuran (3 rnL) is treated with triphenylphosphine (180 mg, 0.69 mmol) and heated to 50 0C overnight. The reaction is then evaporated to dryness and the residue is treated with ether and the ether is decanted. This procedure is repeated a total of 6 times and the resulting residue is dissolved in dichloromethane. A separate flask is charged with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (194 mg, lmmol) followed by cone. HCl (0.5 mL) and water (2 mL). The resulting suspension is then treated with sodium nitrite (69 mg, 1 mmol) in water (0.3 mL) and stirred for 30 minutes. The reaction is quenched with a saturated aqueous solution of sodium carbonate and when the bubbling subsides, the ylide solution prepared above is added to the reaction and stirring is maintained for 1 hour. The entire reaction is then poured onto a silica gel plug and eluted with
dichloromethane. The solvent is removed and the residue is purified on a reversed phase HPLC (H2OMeCN gradient) to provide the title compound (Example El); 1H NMR (CDCl3, 400.13 MHz): δ 8.62 (s, IH), 8.42 (m, IH), 8.23 (m, 2H), 7.50 (m, 2H), 7.12 (m, IH), 7.08 (m, 2H), 6.47 (m, 2H), 4.14 (dd, J = 7.1, 14.2 Hz, 2H), 4.04 (d, J = 13.7 Hz, IH), 3.40 (d, J = 17.3 Hz, IH), 1.74 (s, 3H), 1.04 (dd, J = 7.1, 7.1 Hz, 3H); ESIMS calcd. for C23H22ClN4O2 ([M+H]+) 421.1, found 421.0.
Example F2
Methyl 2-methyl-2-(3-methyl-8-(4-(trifluoromethyl)phenyl)pyrazolor5,l-ciri,2,41triazin-
4-vl)-3-phenvrpropanoate
Figure imgf000129_0001
Figure imgf000129_0002
[00240] Step A: Into a 100 ml round bottom flask containing methyl 3- oxopentanoate (3.0 g, 23.0 mmol) in acetonitrile (40 ml) is added K2CO3 (4.76 g, 34.5 mmol) followed by benzyl bromide (2.6 ml, 21.9 mmol). After stirring for 72 hours the mixture is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x), the combined organic layers are washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash
chromatography (80 g SiO2, hexanes/ethyl acetate gradient) affords methyl 2-benzyl-3- oxopentanoate F2b as a clear oil. 1H NMR (400 MHz, CDCl3) δ = 7.31-7.27 (m, 2H), 7.24-7.21 (m, 3H), 3.82 (t, J = 7.6 Hz, IH), 3.70 (s, 3H), 3.18 (d, J = 7.6 Hz, 2H), 2.63- 2.53 (m, IH), 2.38-2.28 (m, IH), 1.01 (t, / =7.2 Hz, 3H); ESIMS calcd. for Ci3Hi6O3 ([M+H]+) 221.1, found 221.1.
[00241] Step B: To a 100 ml round bottom flask containing Intermediate F2b (2.3 g, 10.45 mmol) in acetonitrile (30 ml) is added K2CO3 (2.16 g, 15.67 mmol) followed by methyl iodide (1.62 ml, 26.12 mmol). The mixture is refluxed for 24 hours and acetonitrile is removed under vacuum. The contents are partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x), the combined organic layers are washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (120 g SiO2, hexanes/ethyl acetate gradient) yields methyl 2-benzyl-2-methyl-3-oxopentanoate F2c as a clear oil. 1H NMR (400 MHz, CDCl3) δ = 7.29-7.23 (m, 3H), 7.10-7.08 (m, 2H), 3.73 (s, 3H), 3.28 (d, J = 14.0 Hz, IH), 3.09 (d, J = 14.0 Hz, IH), 2.50-2.44 (m, 2H), 1.31 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H); ESIMS calcd. for Ci4H19O3 ([M+H]+) 235.1, found 235.1.
[00242] Step C: To a 20 ml vial containing Intermediate F2c (500 mg, 2.13 mmol) in acetic acid (3 ml), bromine (109 μL, 2.13 mmol) is added dropwise at room
temperature and the mixture is stirred for 2 hours. The reaction is quenched with 10% aqueous NaHSO3 and the aqueous layer is extracted with ethyl acetate (2x). The organic layer is washed with saturated aqueous NaHCO3, brine, and dried over Na2SO4.
Evaporation of solvent affords methyl 2-benzyl-4-bromo-2-methyl-3-oxopentanoate F2d. The compound is used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ = 7.29-7.21 (m, 2H), 7.11-7.06 (m, 3H), 3.75 (s, 3H), 3.40 (d, J = 13.6 Hz, IH), 3.14 (d, J = 13.6 Hz, IH), 1.71 (d, J = 6.8 Hz, 3H), 1.37 (s, 3H); ESIMS calcd. for Ci4H17BrO3 ([M+H]+) 313.1, found 313.1.
[00243] Step D: To a 20 ml vial containing Intermediate F2d (625 mg, 1.99 mmol) in toluene (5 ml) is added triethyl phosphite (1.74 ml, 9.98 mmol) and the mixture is heated at 1300C for 18 hours. The solvent is removed and the crude material is purified by flash chromatography (40 g SiO2, hexanes/ethyl acetate gradient) to yield methyl 2- benzyl-4-(diethoxyphosphoryl)-2-methyl-3-oxopentanoate F2e as a clear oil. ESEVIS calcd. for Ci8H28O6P ([M+H]+) 371.1, found 371.1.
[00244] Step E: To a 20 ml vial containing 4-(4-trifluoromethylphenyl)- IH- pyrazol-5-amine (100 mg, 0.440 mmol) in acetic acid (1 ml) is added a solution Of NaNO2 (30 mg, 0.440 mmol) in water (100 μL). After 10 minutes the reaction is diluted with dichloromethane (3 ml) and treated with saturated aqueous Na2CO3 until pΗ > 8. A solution of Intermediate F2e (125 mg, 0.338 mmol) in dichloromethane (1 ml) is then added and the mixture is stirred for 6 hours. The mixture is then partitioned between brine and dichloromethane. The aqueous layer is extracted with dichloromethane (Ix) and the combined organic layers are washed with brine, dried over MgSO4 and evaporated in vacuo. The crude material is dissolved in MeOH (2 ml) and is then subjected to microwave irradiation (150 0C, 2 hours). The solvent is removed and the crude material is purified by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) to afford the title compound (Example F2) as a yellow semi-solid. 1H NMR (400 MHz, CDCl3) δ = 8.55 (s, IH), 8.39 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.19-7.17 (m, IH), 7.10 (t, J= 6.8 Hz, 2H), 3.98 (d, J= 14.0 Hz, IH), 3.61 (s, 3H), 3.34 (d, J = 14.0 Hz, IH), 2.34 (s, 3H), 1.90 (s, 3H); 19F NMR (376.46 MHz, CDCl3) δ = -62.47; ESIMS calcd. for
C24H22F3N4O2 ([M+H]+) 455.1, found 455.1.
Example F3
Methyl 3-(3-fluorophenyl)-2-methyl-2-(3-methyl-8-(4- (trifluoromethyl)phenyl)pyrazolor5 J-cl [ 1 ,2,41triazin-4-yl)propanoate
Figure imgf000131_0001
[00245] By following a similar procedure as the one used for preparing Example
F2 from Intermediate F2a except substituting 3-fluorobenzyl bromide for benzyl bromide in Step A, Example F3 is obtained; 1H NMR (400 MHz, CDCl3) δ = 8.55 (s, IH), 8.38 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.07-7.00 (m, IH), 6.92-6.87 (m, IH), 6.41- 6.38 (m, IH), 6.12 (d, J = 7.6 Hz, IH), 3.98 (d, J = 13.6 Hz, IH), 3.61 (s, 3H), 3.34 (d, J = 14.0 Hz, IH), 2.45 (s, 3H), 1.91 (s, 3H); 19F NMR (376.46 MHz, CDCl3) δ = -112.64, - 62.48; ESIMS calcd. for C24H2IF4N4O2 ([M+H]+) 473.1, found 473.1.
Example F4
Ethyl 2-methyl-3-phenyl-2-(8-(4-(trifluoromethyl)phenyl)pyrazolor5,l-ciri,2,41triazin-4- vPpropanoate
Figure imgf000132_0001
[00246] By following a similar procedure as the one used for preparing Example
F2 from Intermediate F2d except substituting Intermediate FIa for Intermediate F2d, Example F3 is obtained; 1H NMR (400 MHz, CDCl3) δ = 8.66 (s, IH), 8.44-8.8.40 (m, 2H), 8.42 (s, IH), 7.80-7.76 (m, 2H), 7.17-7.04 (m, 3H), 6.48-6.44 (m, 2H), 4.14 (dd, J = 7.1, 14.2 Hz, 2H), 4.05 (d, J = 13.8 Hz, IH), 3.41 (d, J = 13.8 Hz, IH), 1.74 (s, 3H), 1.05 (dd, J= 7.1, 7.1 Hz, IH); ESIMS calcd. for C24H2IF3N4O2 ([M+H]+) 455.2, found 455.2.
Example F5
Ethyl 2-(3-fluoro-8-(4-(trifluoromethyl)phenyl)pyrazolor5,l-ciri,2,41triazin-4-yl)-2- methyl-3-phenylpropanoate
Figure imgf000132_0002
Figure imgf000133_0001
[00247] Step A: A sample of Intermediate F5a is prepared from Intermediate FIa in an analogous manner as the preparation of Intermediate F2e from Intermediate F2d. A solution of potassium tert-butoxide (234 mg, 2.43 mmol) in tetrahydrofuran (3.5 mL) is treated with a solution of Intermediate F5a (850 mg, 2.43 mmol) in tetrahydrofuran (7 mL) and added to a cooled (ice/water) suspension of Selectfluor (1.72 g, 4.86 mmol) in acetonitrile (7 mL). The cooling bath is removed and the reaction is allowed to stir for 3 hours at room temperature. The reaction is diluted with ethyl acetate, extracted with water twice, dried over MgSO4, filtered, evaporated and the crude material is purified by flash chromatography (25 g SiO2, hexanes/ethyl acetate gradient) to afford ethyl 2- benzyl-4-(diethoxyphosphoryl)-4-fluoro-2-methyl-3-oxobutanoate F5b; ESIMS calcd. for C18H26FO6P ([M+H]+) 389.2, found 389.2.
[00248] Step B: A solution of 4-(4-trifluoromethylphenyl)-lH-pyrazol-5-amine
(334 mg, 1.47 mmol) in acetic acid (3 mL) is treated with a solution Of NaNO2 (101 mg, 1.47 mmol) in water (0.3 mL). After stirring for 5 minutes, the reaction is diluted with dichloromethane (10 mL) and treated with excess saturated aqueous Na2CO3 solution until gas evolution ceases and then 3 more mL of the solution are added. The reaction is then treated with a solution of Intermediate F5b (408 mg, 1.05 mmol) in dichloromethane (3 mL) and stirred overnight. The organic phase is separated and the aqueous phase is extracted with dichloromethane and discarded. The combined organics are dried over MgSO4, filtered, evaporated and the crude material is purified by flash chromatography (25 g SiO2, hexanes/ethyl acetate gradient) to afford the title compound (Example F5); 1H NMR (400 MHz, CDCl3) δ = 8.65 (s, IH), 8.38-8.34 (m, 2H), 7.80-7.76 (m, 2H), 7.18- 7.07 (m, 3H), 6.55-6.50 (m, 2H), 4.23-4.08 (m, 2H), 4.04 (d, J = 13.9 Hz, IH), 3.36 (d, J = 13.9 Hz, IH), 1.92 (d, J = 6.2 Hz, 3H), 1.07 (dd, J = 7.1, 7.1 Hz, IH); ESIMS calcd. for C24H20F4N4O2 ([M+H]+) 473.2, found 473.2. Example Gl
Ethyl 2-(7-(4-chlorophenyl)pyrazolor5J-blthiazol-3-yl)-2-methyl-3-phenylpropanoate
Figure imgf000134_0001
Figure imgf000134_0002
GIa GIb
Figure imgf000134_0003
[00249] Step A: A solution of Intermediate GIa (100 mg, 0.51 mmol) in acetic acid (1 niL) is treated with a solution of sodium nitrite (37 mg, 0.51 mmol) in water (0.5 mL). After stirring for 15 minutes, the reaction is treated with thiourea (80 mg, 1.1 mmol) and stirred for 30 minutes. The reaction immediately evolves gas and becomes thick with solid. The solvent is removed and the residue is purified on a reversed phase HPLC (H2OZMeCN gradient) to provide 4-(4-chlorophenyl)-lH-pyrazol-3-yl
carbamimidothioate GIb as a TFA salt; ESIMS calcd. for Ci0H10ClN4S ([M+H]+) 253.0, found 253.0.
[00250] Step B: In a microwave vial a solution of Intermediate GIb (50 mg, 0.14 mmol) in ethanol (2 mL) is treated with potassium hydroxide (38 mg, 0.68 mmol). The vial is sealed and the mixture is subjected to microwave irradiation (100 0C, 5 min). The reaction is then treated with 4 M HCl in dioxane (187 μL, 0,75 mmol) followed by a solution of Intermediate FIa (100 mg, 0.32 mmol) in ethanol (1 niL) and the reaction is subjected to microwave irradiation (165 0C, 20 min). The solvent is then evaporated and the residue is purified on a reversed phase HPLC (H2OZMeCN gradient) to afford the title compound (Example Gl); 1H NMR (CDCl3, 400.13 MHz): δ 8.16 (d, J = 1.4 Hz, IH), 7.48 (m, 2H), 7.41 (m, 2H), 7.13 (m, 3H), 6.62 (m, 2H), 6.36 (d, J = 1.4 Hz, IH), 4.19 (m, 2H), 3.92 (d, J = 13.5 Hz, IH), 3.33 (d, J = 13.5 Hz, IH), 1.59 (s, 3H), 1.13 (dd, J = 7.1, 7.1 Hz, 3H); ESIMS calcd. for C23H22ClN2O2S ([M+H]+) 425.1, found 425.0.
Example Hl
(R)-Ethyl 2-(6-cvano-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2- methvl-3-phenvlpropanoate
Figure imgf000135_0001
Figure imgf000135_0002
[00251] Step A: In a Smith Process vial charged with Example N8 (29 mg, 0.06 mmol) in iV,./V-dimethylacetamide (1.5 ml) is added Pd2dba3 (2 mg, 0.0023 mmol), dppf (2.6 mg, 0.0048 mmol), zinc (1 mg, 0.012 mmol), and zinc cyanide (9 mg, 0.072 mmol). The mixture is purged with nitrogen, the vial sealed, and then evacuated and re-purged with nitrogen. The mixture is then subjected to microwave irradiation (160 0C, 1 hour). The solution is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (25 g SiO2, hexanes/ethyl acetate gradient) affords the title compound (Example Hl) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 8.65 (s, IH), 8.40 (s, IH), 8.18 (d, J = 16.0 Hz, 2H), 7.73 (d, J = 16.0 Hz, 2H), 7.18-7.16 (m, IH), 7.10 (t, J = 7.2 Hz, 2H), 7.14 (quartet, J = 7.2 Hz, 2H), 4.08 (d, J = 14.0 Hz, IH), 3.35 (d, J = 14.0 Hz, IH), 2.08 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); 19F NMR (376.46 MHz, CDCl3) δ = - 62.52; ESIMS calcd. for C26H22F3N4O2 ([M+H]+) 479.1, found 479.1.
Example H2
(R)-Ethyl 2-methyl-2-(6-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-
7-vl)-3-phenvrpropanoate
Figure imgf000136_0001
Figure imgf000136_0002
[00252] Step A: In a Smith Process vial charged with Example N8 (30 mg, 0.062 mmol) in dioxane (1 ml) is added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (85 μL, 0.62 mmol), Pd(dppf)Cl2 - dichloromethane complex (5 mg, 0.0062 mmol), and IM aqueous cesium carbonate (124 μL, 0.124 mmol). The mixture is purged with nitrogen, the vial sealed, and then evacuated and re-purged with nitrogen. The mixture is then subjected to microwave irradiation (160 0C, 10 minutes). The solution is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (12 g SiO2,
hexanes/ethyl acetate gradient) affords the title compound (Example H2) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 8.44 (s, IH), 8.21 (d, J = 8.0 Hz, 2H), 8.17 (s, IH), 7.70 (d, J = 16.0 Hz, 2H), 7.18-7.16 (m, IH), 7.10 (t, J= 7.2 Hz, 2H), 7.14 (quartet, J= 7.2 Hz, 2H), 4.08 (d, J= 14.0 Hz, IH), 3.35 (d, J= 14.0 Hz, IH), 2.08 (s, 3H), 1.07 (t, J= 7.2 Hz, 3H); 19F NMR (376.46 MHz, CDCl3) δ = -62.52; ESIMS calcd. for
C26H22F3N4O2 ([M+H]+) 479.1, found 479.1.
Example H3
(R)-Ethyl 2-(6-((dimethylamino)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5- a\ p yrimidin-7 - yl) -2-meth vl- 3 -phen vlpropano ate
Figure imgf000137_0001
Figure imgf000137_0002
[00253] Step A: In a Smith Process vial charged with Example N8 (60 mg, 0.082 mmol) in dioxane (3 ml) and water (300 μL) is added potassium
dimethylaminomethyltrifluoroborate (110 mg, 0.82 mmol), palladium acetate (2 mg, 0.0082 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (8mg, 0.016 mmol) and cesium carbonate (110 mg, 0.246 mmol). The mixture is purged with nitrogen, the vial sealed, and then evacuated and re-purged with nitrogen. The mixture is then subjected to microwave irradiation (160 0C, 4 hours). The solution is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material is purified by reversed-phase HPLC (acetonitrile/water gradient) to afford the title compound (Example H3) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.44 (d, J = 2.8 Hz, 2H), 8.22 (d, J = 8.0 Hz, 2H), 7.70 (d, J= 8.0 Hz, 2H), 7.19-7.04 (m, 3H), 6.59-6.57 (m, 2H), 4.20 (d, J = 13.6 Hz, IH), 4.12-4.06 (m, 2H), 3.32 (d, J = 13.2 Hz, IH), 3.21 (d, J = 14.0 Hz, IH), 2.92 (d, J = 13.6 Hz, IH), 1.98 (s, 6H); 19F NMR (376.46 MHz, CDCl3) δ = -62.30; ESIMS calcd. for C28H30F3N4O2 ([M+H]+) 511.2, found 511.2.
Example Il
Ethyl 2-methyl-3-phenyl-2-(3-(6-(trifluoromethyl)-lH-benzoMimidazol-2- vDpyrazolori, 5-αlpyrimidin-7-yl)propanoate
Figure imgf000138_0001
Figure imgf000139_0001
[00254] Step A: A cold (O0C) solution of Intermediate B23a (141 mg, 0.323 mmol) tetrahydrofuran (2 niL) is treated with the dropwise addition of isopropylmagnesium chloride (2.0M in tetrahydrofuran, 178 μL, 0.356 mmol) and stirred for 15 minutes. Dimethylformamide (100 μL) is then added. After 30 minutes, water is added and the reaction extracted with ethylacetate. The organics are dried (MgSO4), filtered, concentrated, and the crude material is purified by flash chromatography
(hexanes/ethylacetate gradient) to afford ethyl 2-(3-formylpyrazolo[l,5-a]pyrimidin-7- yl)-2-methyl-3-phenylpropanoate Ha; 1H NMR (CDCl3, 400 MHz): δ 10.35 (s, IH), 8.66 (s, IH), 8.57 (d, J = 4.5 Hz, IH), 7.08 (m, 3H), 6.58 (d, J = 4.6 Hz, IH), 6.44 (m, 2H), 4.13 (m, 2H), 4.02 (d, J = 13.7 Hz, IH), 3.35 (d, J= 13.7 Hz, IH), 1.68 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H); ESIMS calcd. for Ci9H20N3O3 ([M+H]+) 338.4, found 338.1.
[00255] Step B: A mixture of Intermediate Ha (77 mg, 0.23 mmol) and sodium metabisulfite (43 mg, 0.23 mmol) in dimethylformamide (1.5 mL) is heated to HO0C and maintained for 10 min. 4-(trifluoromethyl)benzene-l,2-diamine (35 mg, 0.20 mmol) is added and the reaction stirred at 11O0C for 3 hours. The reaction is cooled to room temperature, diluted with water and extracted with ethylacetate. The organics are dried (MgSO4), filtered, concentrated, and the crude material is purified by flash
chromatography (hexanes/ethylacetate gradient) to afford the title compound (Example II). ESIMS calcd. for C26H23F3N5O2 ([M+H]+) 494.5, found 494.0.
Example Jl
(R)-A^-(2-Phenyl-l-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7- vPethyPacetamide
Figure imgf000140_0001
Figure imgf000140_0002
JIc Example Jl
[00256] Step A: A solution of Intermediate JIa (346 mg, 1 mmol) (prepared according to S.Pirc, D. Bevk, A. Golobic, B.Stanovnik, J.Svete, HeIv. Chim. Acta, 2006, 89, 30-44) and 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-3-amine (250 mg, 1.1 mmol) in ethanol (8 mL) and 37% aq HCl (100 μL, 1.2 mmol) is heated to 7O0C overnight. The reaction mixture is then cooled to -30 0C. The resulting precipitate is filtered and washed with cold ethanol to afford tert-butyl 2-phenyl-l-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)ethylcarbamate JIb; 1H NMR (CDCl3, 400.13 MHz): δ 8.56 (s, IH), 8.43 (d, J = 3.6 Hz, IH), 8.20 (d, J = 8.1 Hz, 2H), 7.71 (d, J= 8.3 Hz, 2H), 7.21 (m, 3H), 6.99 (m, 2H), 6.54 (d, J = 3.3 Hz, IH), 6.10 (d, / = 8.4 Hz, IH), 5.48 (m, IH), 3.54 (dd, J = 13.3, 7.8 Hz, IH), 3.34 (dd, J= 13.3, 7.3 Hz, IH), 1.40 (s, 9H); ESIMS calcd. for C26H26F3N4O2 ([M+H]+) 483.2, found 483.2.
[00257] Step B: A solution of Intermediate JIb (150 mg, 0.31 mmol) in dichloromethane (4 mL) is treated with trifluoroacetic acid (2 mL) and stirred at room temperature for 2 hours. The reaction mixture is concentrated and treated with a saturated aqueous solution Of NaHCO3, extracted with dichloromethane, and dried (Na2SO4) to yield 2-phenyl-l-(3-(4-(trifluoromethyl) phenyl)pyrazolo[l,5-α]pyrimidin-7- yl)ethanamine JIc; 1H NMR (CDCl3, 400.13 MHz): δ 8.57 (d, J = 4.3 Hz, IH), 8.55 (s, IH), 8.21 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.28 (m, 5H), 6.95 (d, J= 4.3 Hz, IH), 4.97 (dd, J = 8.6, 4.6 Hz, IH), 3.56 (dd, J = 13.4, 4.6 Hz, IH), 2.97 (dd, J= 13.4, 8.6 Hz, IH); ESIMS calcd. for C2IHi8F3N4 ([M+H]+) 383.1, found 383.2. The product is used without purification.
[00258] Step C: To a solution of Intermediate JIc (46 mg, 0.12 mmol) in dichloromethane (2 rnL) is added diisopropylethylamine (128 μL, 0.72 mmol) followed by acetyl chloride (32 μL, 0.45 mmol) and the mixture is stirred overnight at room temperature. Dichloromethane is then added and the reaction mixture is washed with brine, 10% aqueous citric acid solution, brine, saturated aqueous NaHCO3 solution, and brine. The organic phase is dried (Na2SO4), filtered, evaporated and the residue is purified by chiral chromatography using a Chiral Technologies 10x250mm ChiralPak IC column with a 7 minute isocratic elution using CO2/75:25 THF:MeOH (80:20) as mobile phase at 10 mL per minute. The second eluting peak is collected and reanalyzed on a using a Chiral Technologies 4.6xl00mm ChiralPak IC column with 5 minute isocratic elution using CO2/75:25 THF:MeOH (80:20) as mobile phase at 2 mL per minute and 30 0C. Example Jl comes off at 3.01 minutes; 1H NMR (CDCl3, 400.13 MHz): δ 8.55 (s, IH), 8.41 (d, J = 4.2 Hz, IH), 8.20 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.37 (d, / = 9.5 Hz, IH), 7.20 (m, 3H), 6.96 (m, 2H), 6.51 (d, J = 4.2 Hz, IH), 5.72 (m, IH), 3.55 (dd, J= 13.5, 8.7 Hz, IH), 3.37 (dd, J = 13.5, 7.1 Hz, IH), 2.00 (s, 3H); ESIMS calcd. for C23H20F3N4 O ([M+H]+) 425.2, found 425.2.
[00259] By following a similar procedure as the one used for preparing Example
Jl from Intermediate JIc except substituting mesyl chloride or methyl chloroformate for acetyl chloride the following examples are obtained:
Figure imgf000141_0001
Figure imgf000142_0004
Example J4
A^-(l-Phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propan-2- vPacetamide
Figure imgf000142_0001
Boc
Figure imgf000142_0002
Figure imgf000142_0003
[00260] Step A. A solution of Intermediate J4a (0.91 g, 2.96 mmol) in anhydrous toluene is cooled to -78°C and treated dropwise with diisobutylaluminium hydride (IM in toluene, 7.4 rnL, 7.4 mmol). After stirring the reaction mixture at -78°C for 2 hours methanol (0.75 mL) is added followed by saturated NaHCO3 (20 mL). The flask is warmed to RT, water (10 mL) and ether (10 mL) are added and stirred for another 1 hour. Organics are extracted with ether, dried with Na2SO4 and concentrated. The mixture consists mostly of tert-butyl l-hydroxy-2-methyl-3-phenylpropan-2-ylcarbamate J4c (ESIMS calcd. for Ci5H23NNaO3 ([M+Na]+) 288.2, found 288.2) with some tert-butyl 2- methyl-l-oxo-3-phenylpropan-2-ylcarbamate J4b (ESIMS calcd. for Ci5H2INNaO3 ([M+Na]+) 286.1, found 286.2) and is used without purification.
[00261] Step B. To a solution of Dess-Martin periodinane (1.506 g, 3.55 mmol) in dichloromethane (10 mL) is added a solution of Intermediates J4b and J4c (0.793 g, 2.96 mmol) in dichloromethane (10 mL) and the mixture is stirred at ROOM
TEMPERATURE overnight. Saturated solutions of NaHCO3 and Na2S2O3 are then added and the mixture is stirred for 15 min. The aqueus phase is extracted with ethylacetate, the combined organic phase is dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (hexanes/ethyl acetate gradient) yields tert- butyl 2-methyl-l-oxo-3-phenylpropan-2-ylcarbamate J4b; 1H NMR (400 MHz, CDCl3) δ 9.53 (s, IH), 7.28 (m, 3H), 7.09 (m, 2H), 4.84 (bs, IH), 3.13 (m, 2H), 1.47 (s, 9H), 1.27 (s, 3H); ESIMS calcd. for Ci5H2iNNa03 ([M+Na]+) 286.1, found 286.2.
[00262] Step C. A solution of Intermediate J4b (500 mg, 1.9 mmol) in anhydrous THF (4 mL) is cooled to -78°C and ethynylmagnesium bromide (0.5 M solution in THF, 15.2 mL, 7.6 mmol) is slowly added. The cooling bath is removed and the reaction mixture is stirred for 2 hours at room temperature. The excess of
ethynylmagnesium bromide is quenched by addition of saturated NH4Cl (10 mL). The mixture is extracted with ethylacetate, the organic phase is dried (Na2SO4) and concentrated to yield tert-butyl 3-hydroxy-2-methyl-l-phenylpent-4-yn-2-ylcarbamate J4d as a mixture of diastereomers; ESIMS calcd. for Ci7H23NNaO3 ([M+Na]+) 312.2, found 312.1. The crude material is used without purification.
[00263] Step D. To a solution of Intermediate J4d (1.9 mmol) in
dichloromethane (5 mL) is added Dess-Martin periodinane (967 mg, 2.28 mmol) in dichloromethane (15 mL) and the mixture is stirred at room temperature overnight. Aqueous solution of NaHCO3 and Na2S2O3 is added, the mixture is stirred for 20 min, extracted with dichloromethane (3x), dried (Na2SO4), and concentrated to afford tert- butyl 2-methyl-3-oxo-l-phenylpent-4-yn-2-ylcarbamate J4e; ESIMS calcd. for
Ci7H2INNaO3 ([M+Na]+) 310.1, found 310.1. The crude material is used in without purification.
[00264] Step E. Diethylamine (204 μL, 2 mmol) is added to a cold (00C) solution of Intermediate J4e (1.9 mmol) in dichloromethane (20 mL). The reaction mixture is stirred at room temperature overnight, the solvent is evaporated and the crude material is purified by flash chromatography (hexane/ethylacetate gradient) to afford tert-butyl 5- (diethylamino)-2-methyl-3-oxo-l-phenylpent-4-en-2-ylcarbamate J4f; ESIMS calcd. for C2IH33N2O3 ([M+H]+) 361.3, found 361.2.
[00265] Step F. A solution of Intermediate J4f (413 mg, 1.15 mmol) and 4- (4-
(trifluoromethyl)phenyl)-lH-pyrazol-3-amine (286 mg, 1.26 mmol) in ethanol (8 mL) is treated with 37% aq HCl (125 μL, 1.5 mmol) and heated to 7O0C overnight. The reaction mixture is then cooled to -30 0C. The resulting precipitate is filtered and washed with cold ethanol to afford tert-butyl l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- a]pyrimidin-7-yl)propan-2-ylcarbamate J4g. Recristallization of the crude material from hexanes gives pure J4g; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, IH), 8.48 (d, J = 4.4 Hz, IH), 8.24 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.17 (m, 3H), 6.75 (m, 2H), 6.67 (d, J = 4.4 Hz, IH), 5.60 (s, IH), 3.77 (d, J = 12.9 Hz, IH), 3.56 (d, J = 12.9 Hz, IH), 1.92 (s, 3H), 1.27 (s, 9H); ESIMS calcd. for C27H28F3N4O2 ([M+H]+) 497.2, found 497.1.
[00266] Step G. A solution of Intermediate J4g (160 mg, 0.32 mmol) in dichloromethane (4 mL) is treated with trifluoroacetic acid (2 mL) and stirred at room temperature overnight. The solvent is removed, the crude material is treated with saturated aqueous NaHCO3 and extracted with dichloromethane (3x). the combined organic phase is dried (Na2SO4) and concentrated to yield l-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propan-2-amine J4h; ESIMS calcd. for C22H20F3N4 ([M+H]+) 397.2, found 397.2. The crude material is used in without purification.
[00267] Step H. A solution of Intermediate J4h (40 mg, 0.1 mmol) in
dichloromethane (2 mL) is treated with acetylchloride (32 μL, 0.45 mmol) and
diisopropylethylamine (128 μL, 0.72 mmol) and stirred at room temperature overnight. Water and saturated aqueous NaHCO3 are added; the mixture is extracted with dichloromethane (3x), the organic phase is dried over Na2SO4 and concentrated in vacuo. The crude material is purified by flash chromatography (hexane/ethylacetate gradient) to afford the title compound (Example J4); 1H NMR (400 MHz, CDCl3) δ 8.50 (s, IH), 8.49 (d, J = 4.4 Hz, IH), 8.21 (m, 2H), 7.71 (m, 2H), 7.19 (m, 3H), 6.77 (m, 2H), 6.73 (d, J = 4.4 Hz, IH), 6.37 (s, IH), 3.76 (d, J = 12.7 Hz, IH), 3.58 (d, J = 12.7 Hz, IH), 1.93 (s, 6H); ESIMS calcd. for C24H22F3N4O ([M+H]+) 439.2, found 439.2
Example J5
(R)-A^-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propan-
2-vl)acetamide
Figure imgf000145_0001
[00268] Step A. A sample of Example K4a is subjected to chiral chromatography using a Chiral Technologies 21x250mm ChiralPak AD-H column with a 2.5 minute stacked injections, 5 minute isocratic elution using methanol/CO2 (30:70) as mobile phase at 8Og/ min and 400C. The first eluting peak is collected and reanalyzed using a Chiral Technologies 4.6x100mm ChiralPak AD-H column with 10 minute isocratic elution using methanol/CO2 (30:70) as mobile phase at 2 mL/min and 30 0C. Intermediate J5a comes off at 1.98 min. The 1H NMR and ESIMS data for Intermediate J5a are identical to Intermediate K4a.
[00269] Step B. To a solution of Intermediate J5a (217 mg, 0.51 mmol) in toluene (3.5 rnL) is added diisopropylethylamine (106 μL, 0.61 mmol) followed by diphenyl phosphoryl azide (132 μL, 0.61 mmol) and the reaction mixture is stirred at room temperature for 2 hours. Tert-buthanol (488 μL, 5.1 mmol) is then added and the reaction mixture is stirred at 1100C overnight. Water is added and the mixture is extracted with dichloromethane. The organic phase is dried (Na2SO4), concentrated in vacuo and the crude material is purified by flash chromatography (hexane/ethylacetate gradient). The 1H NMR and ESIMS data for Intermediate J5b are identical to
Intermediate J4g.
[00270] Step C. By following a similar procedure as the one used for preparing
Intermediate J4h from Intermediate J4g, except substituting Intermediate J5b for Intermediate J4g, Intermediate J5c is obtained. The 1H NMR and ESIMS data for Intermediate J5c are identical to Intermediate J4h.
[00271] Step D. By following a similar procedure as the one used for preparing
Example J4 from Intermediate J4h except substituting propionyl chloride for acetyl chloride, Example J5 is obtained. 1H NMR (400 MHz, CDCl3) δ 8.49 (m, 2H), 8.21 (m, 2H), 7.70 (m, 2H), 7.19 (m, 3H), 6.78 (m, 2H), 6.74 (d, J = 4.5 Hz, IH), 6.36 (s, IH), 3.74 (d, J = 12.7 Hz, IH), 3.61 (d, J= 12.7 Hz, IH), 2.18 (m, 2H), 1.93 (s, 3H), 1.03 (t, J = 7.5 Hz, 3H); ESIMS calcd. for C25H24F3N4O ([M+H]+) 453.2, found 453.2.
Example J6
(R)-N-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propan-
2-vl)butvramide
Figure imgf000146_0001
[00272] By following a similar procedure as the one used for preparing Example
J5 from Intermediate J5c except substituting butyryl chloride for propionyl chloride, Example J6 is obtained; IH NMR (400 MHz, CDCl3) δ 8.49 (m, 2H), 8.21 (m, 2H), 7.70 (m, 2H), 7.19 (m, 3H), 6.77 (m, 2H), 6.74 (d, J = 4.5 Hz, IH), 6.34 (s, IH), 3.75 (d, J = 12.7 Hz, IH), 3.60 (d, J = 12.7 Hz, IH), 2.12 (m, 2H), 1.93 (s, 3H), 1.52 (sextet, J = 7.4 Hz, 2H), 0.82 (t, J= 7.4 Hz, 3H); ESIMS calcd. for C26H26F3N4O ([M+H]+) 467.2, found 467.2.
Example Kl
2-(3-(4-Chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-N,N,2-trimethyl-3-phenylpropan-l- amine
Figure imgf000147_0001
[00273] Step A: To a solution of Intermediate AlOi (116 mg, 0.308 mmol) in dichloromethane (5 mL) are added pyridine (50 μL, 0.615 mmol) and Dess-Martin reagent (261 mg, 0.615 mmol). The mixture is then stirred at room temperature for 3 hours. The mixture is quenched with 10% aqueous Na2S2O3 and saturated aqueous Na2CO3 and the aqueous layer is extracted with dichloromethane. The combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) yields 2-(3-(4-chlorophenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)-2-methyl-3-phenylpropanal KIa as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 9.94 (s, IH), 8.45 (s, IHz, IH), 8.42 (d, J = 4.4 Hz, IH), 8.02 (d, J = 8.4 Hz, 2H), 7.44 (d, J= 8.4 Hz, 2H), 7.17-7.08 (m, 3H), 6.57 (d, J= 7.6 Hz, 2H), 6.42 (d, J= 4.4 Hz, IH), 4.03 (d, J= 13.6 Hz, IH), 3.35 (d, J = 13.6, IH), 1.49 (s, 3H); ESIMS calcd. for C22H19ClN3O ([M+H]+) 376.1, found 376.2.
[00274] Step B: To a solution of dimethylamine in tetrahydrofuran (2M, 0.4 mL,
0.8 mmol) is added Intermediate KIa (20 mg, 0.053 mmol) followed by sodium triacetoxyborohydride (17 mg, 0.08 mmol) and acetic acid (25 μL). After 3 hours the mixture is quenched with IN NaOH and extracted with ethyl acetate. The combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo.
Purification of the crude material by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient) yields the title compound (Example Kl) as a yellow oil. 1H NMR (CDCl3, 400.13 MHz): δ = 8.52 (s, IH), 8.33 (d, J = 4.8 Hz, IH), 8.08 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.05-7.00 (m, 3H), 6.50-6.47 (m, 3H), 4.32 (d, J = 13.2 Hz, IH), 4.07 (d, J = 13.2 Hz, IH), 2.70 (d, J = 12.8 Hz, IH), 2.62 (d, J= 13.6, IH), 2.00 (s, 6H), 1.50 (s, 3H); ESIMS calcd. for C24H26ClN4 ([M+H]+) 405.2, found 405.2.
Example K2
4-(2-(3-(4-Chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenvlpropvPmorpholine
Figure imgf000148_0001
Figure imgf000149_0001
[00275] By following a similar procedure as the one used for preparing Example
Kl from Intermediate KIa except substituting morpholine for dimethylamine, Example K2 is obtained. 1H NMR (400 MHz, CDCl3) δ = 8.52 (s, IH), 8.34 (d, J = 4.4 Hz, IH), 8.08 (d, J = 8.4 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.02 (m, 3H), 6.52-6.49 (m, 2H), 6.47 (d, J= 4.4 Hz, IH), 4.34 (d, J= 13.2 Hz, IH), 4.04 (d, J= 13.2 Hz, IH), 3.38 (m, 4H), 2.67 (t, J= 13.2 Hz, 2H), 2.37 (m, 2H), 2.04 (m, 2H), 2.03 (s, 3H); ESIMS calcd. for C26H28ClN4O ([M+H]+) 447.2, found 447.1.
Example K3
5-(l-Phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propan-2- vPoxazole
Figure imgf000149_0002
Figure imgf000150_0001
3
[00276] Step A: To a solution of Intermediate K3a (25 mg, 0.061 mmol; prepared by following a similar procedure as the one used for preparing Intermediate KIa from Intermediate AlOg except substituting 4-(4-trifluoromethylphenyl)-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine in step G) in methanol (1.5 mL) is added K2CO3 (25 mg, 0.183 mmol) followed by p-toluenesulfonylmethyl isocyanide (13 mg, 0.067 mmol) and the mixture is heated to 80 0C for 16 hours. The solvent is removed and the crude is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate, the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (12 g SiO2) affords the title compound (Example K3) as a yellow oil (6 mg, 21%).1H NMR (CDCl3, 400.13 MHz): δ = 8.47 (d, J = 4.4 Hz, IH), 8.45 (s, IH), 8.20 (d, J = 8.0 Hz, 2H), 7.79 (s, IH), 7.70 (d, J = 8.4 Hz, 2H), 7.14-7.11 (m, 3H), 7.01 (s, IH), 6.61 (d, J= 6.8 Hz, 2H), 6.53 (d, J = 4.4 Hz, IH), 4.56 (d, J= 13.2 Hz, IH), 3.38 (d, J = 12.8 Hz, IH), 1.83 (s, 3H); ESIMS calcd. for C25H20F3N4O ([M+H]+) 449.1, found 449.2.
Example K4
4-Methyl-2-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7- vl)propan-2-vl)oxazole
Figure imgf000151_0001
Figure imgf000151_0002
Figure imgf000151_0003
[00277] Step A: To a solution of Intermediate K3a (25 mg, 0.061 mmol) in a mixture of tetrahydrofuran (300 μL), /-BuOH (500 μL), and water (100 μL) is added 2- methyl-2-butene (28 μL, 0.268 mmol) followed by NaH2PO4 (25 mg, 0.213 mmol). The mixture is cooled to 0 0C and a solution of NaClO2 (15 mg, 0.165 mmol) in water (200 μL) is added. After 1 hour, the mixture is quenched with IN HCl, the aqueous layer is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoic acid K4a as a yellow solid; 1H NMR (CD3OD, 400.13 MHz): δ = 8.72 (s, IH), 8.42 (d, J = 4.4 Hz, IH), 8.38 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.07-7.00 (m, 3H), 6.62 (d, J = 4.4 Hz, IH), 6.48 (d, J= 7.2 Hz, 2H), 4.28 (d, J= 13.2 Hz, IH), 3.23 (d, J= 13.2 Hz, IH), 1.70 (s, 3H); ESIMS calcd. for C23Hi9F3N3O2 ([M+H]+) 426.1, found 426.1. The product is used without further purification.
[00278] Step B: To a solution of Intermediate K4a (12 mg, 0.028 mmol) in dichloromethane (200 μL) is added oxalyl chloride (8 μL, 0.084 mmol) followed by catalytic amounts of dimethylformamide (50 μL). Reaction progress is monitored by diluting an aliquot of the reaction mixture with methanol and analyzing the conversion of K4a to the corresponding methyl ester by ESIMS. After 30 minutes, the solvent is evaporated in vacuo to afford 2-methyl-3-phenyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoyl chloride K4b. The product is used without further purification.
[00279] Step C: To a solution of Intermediate K4b (45 mg, 0.027 mmol) in tetrahydrofuran (200 μL) is added an excess of 28% ammonium hydroxide and stirred at room temperature. After 10 minutes, the contents is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic phase is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (12 g SiO2) yields 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanamide K4c as a yellow solid; 1H NMR (CDCl3, 400.13 MHz): δ = 8.58 (s, IH), 8.44 (d, J = 4.4 Hz, IH), 8.21 (d, J= 8.0 Hz, 2H), 7.70 (d, J= 8.0 Hz, 2H), 7.13-7.07 (m, 3H), 6.57-6.53 (m, 3H), 5.48 (br s, 2H), 4.19 (d, J = 12.8 Hz, IH), 3.31 (d, J = 13.2 Hz, IH), 1.73 (s, 3H); ESIMS calcd. for C23H20F3N4O ([M+H]+) 425.1, found 425.2.
[00280] Step D: To a Smith Process vial charged with Intermediate K4c (12 mg,
0.028 mmol) in ethanol (200 μL) is added chloroacetone (100 μL, 0.930 mmol). The mixture is then subjected to microwave irradiation (170 0C, 1 hour). The solvent is concentrated in vacuo and the residue is purified by flash chromatography (12 g SiO2) to afford the title compound (Example K4) as a yellow oil; 1H NMR (CDCl3, 400.13 MHz): δ = 8.48 (d, J = 4.4 Hz, IH), 8.40 (s, IH), 8.19 (d, J = 8Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.23 (s, IH), 7.09 (m, 3H), 6.60 (d, J = 4.4 Hz, IH), 6.54 (d, J = 8.4 Hz, 2H), 4.40 (d, J = 13.2 Hz, IH), 3.63 (d, J = 13.2 Hz, IH), 2.18 (s, 3H), 1.79 (s, 3H); ESIMS calcd. for C26H22F3N4O ([M+H]+) 463.2, found 463.2. Example K5
5-Methyl-2-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7- yl)propan-2-yl)oxazole
Figure imgf000153_0001
[00281] By following a similar procedure as the one used for preparing Example
K4 from Intermediate K4c except substituting 2-chloropropionaldehyde dimethyl acetal for chloroacetone in Step D, Example K5 is obtained; 1H NMR (CDCl3, 400.13 MHz): δ = 8.48 (d, J = 4.4 Hz, IH), 8.42 (s, IH), 8.20 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.14-7.06 (m, 3H), 6.71 (s, IH), 6.60 (d, J = 4.4 Hz, IH), 6.53 (d, J= 8.4 Hz, 2H), 4.41 (d, J = 13.2 Hz, IH), 3.61 (d, J = 13.2 Hz, IH), 2.22 (s, 3H), 1.79 (s, 3H); ESIMS calcd. for C26H22F3N4O ([M+H]+) 463.2, found 463.2.
ExampleKό
3-methyl-5-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7- yl)propan-2-vl)- 1 ,2,4-oxadiazole
Figure imgf000153_0002
Figure imgf000154_0001
[00282] Step A: To a solution of Intermediate K4b (50 mg, 0.113 mmol) in pyridine (1 rnL) is added N-hydroxysuccinimide (20 mg, 0.169 mmol) and the mixture is stirred for 1 hour. The solvent is removed in vacuo and the residue is purified by flash chromatography (12 g SiO2) to yield 2,5-dioxopyrrolidin-l-yl 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-α]pyrimidin-7-yl)propanoate K6a as a yellow solid. 1H NMR (CDCl3, 400.13 MHz): δ = 8.69 (s, IH), 8.45 (d, J = 4.8 Hz, IH), 8.27 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 7.2 Hz, IH), 7.11-7.07 (t, J = 1.2 Hz, 2H), 6.51 (d, J = 7.2 Hz, 2H), 6.46 (d, J = 4.0 Hz, IH), 4.36 (d, J = 13.6 Hz, IH), 3.41 (d, J = 14.0 Hz, IH), 2.84-2.79 (m, 4H), 1.91 (s, 3H); ESIMS calcd. for C27H22F3N4O4 ([M+H]+) 523.1, found 523.2.
[00283] Step B: To a solution of Intermediate K6a (34 mg, 0.065 mmol) in dioxane
(2 mL) is added N-hydroxyacetamidine (6 mg, 0.078 mmol) and the mixture is heated to 140 0C for 16 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (12 g SiO2) to afford the title compound (Example K6) as a yellow OiL1H NMR (CDCl3, 400.13 MHz): δ = 8.43 (d, J = 4.0 Hz, IH), 8.31 (s, IH), 8.12 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 7.2 Hz, IH), 7.03 (t, J = 6.0 Hz, 2H), 6.54 (d, J = 4.4 Hz, IH), 6.44 (d, J = 8.4 Hz, 2H), 4.36 (d, J = 13.2 Hz, IH), 3.54 (d, J = 13.2 Hz, IH), 2.34 (s, 3H), 1.76 (s, 3H); ESIMS calcd. for C25H2I F3N5O ([M+H]+) 464.2, found 464.2.
ExampleK7
2-methyl-5-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7- yl)propan-2-vl)-l,3,4-oxadiazole
Figure imgf000155_0001
Figure imgf000155_0002
3
[00284] Step A: To a solution of Intermediate K6a (120 mg, 0.230 mmol) in dioxane (1 rnL) is added hyrdrazine (73 μL, 2.30 mmol) and the mixture is stirred for 30 min. The solvent is removed in vacuo and the residue is purified by flash chromatography (12 g SiO2, dichloromethane/methanol gradient) to yield 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanehydrazide K7a as a yellow glass. 1H NMR (CDCl3, 400.13 MHz): δ = 8.53 (s, IH), 8.46 (d, J = 4.4 Hz, IH), 8.20 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.15-7.07 (m, 3H), 6.83 (br s, IH), 6.60- 6.55 (m, 3H), 4.08 (d, J = 12.8 Hz, IH), 3.88 (br s, 2H), 3.37 (d, J = 12.8 Hz, IH), 1.69 (s, 3H); ESIMS calcd. for C23H2IF3N5O ([M+H]+) 440.2, found 440.1.
[00285] Step B: To a Smith Process vial charged with Intermediate K7a (15 mg,
0.034 mmol) in ethanol (1 mL) is added acetamidine hydrochloride (13 mg, 0.137 mmol) followed by sodium methoxide (8 mg, 0.137). The mixture is then subjected to
microwave irradiation (170 0C, 30 minutes). The solvent is then concentrated in vacuo and the residue is purified by flash chromatography (12 g SiO2, hexanes/ethyl acetate gradient followed by ethyl acetate/methanol gradient) to afford 7-(2-(5-methyl-4H-l,2,4- triazol-3-yl)-l-phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- a]pyrimidine K7b and the title compound (Example K7) as yellow oils. K7b: 1H NMR (CDCl3, 400.13 MHz): δ = 8.40 (d, J = 4.4 Hz, IH), 8.36 (s, IH), 8.13 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.00-6.98 (m, 3H), 6.62 (d, J = 4.4 Hz, IH), 6.44 (d, J= 8.4 Hz, 2H), 4.51 (d, J= 13.2 Hz, IH), 3.52 (d, J= 13.2 Hz, IH), 2.36 (s, 3H), 1.75 (s, 3H); ESIMS calcd. for C25H22F3N6 ([M+H]+) 463.2, found 463.1. Example K7: 1H NMR (CDCl3, 400.13 MHz); δ = 8.43 (d, J = 4.4 Hz, IH), 8.32 (s, IH), 8.12 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.05-7.03 (m, 3H), 6.54 (d, J = 4.4 Hz, IH), 6.47 (d, J= SA Hz, 2H), 4.33 (d, J = 13.2 Hz, IH), 3.58 (d, J = 13.2 Hz, IH), 2.38 (s, 3H), 1.77 (s, 3H);
ESIMS calcd. for C25H2IF3N5O ([M+H]+) 464.2, found 464.1.
Example Ll
Ethyl 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-p-tolylpropanoate.
Figure imgf000156_0001
Figure imgf000156_0002
A21a LIa
Figure imgf000156_0003
[00286] Step A: A mixture of Intermediate A21a (4mL, 20 mmol) and dimethylformamide diethyl acetal (3.35 rnL, 20 mmol) is heated to 100 0C overnight. The solvent is removed and the resulting residue of Intermediate LIa is used without further purification; ESIMS calcd. for Ci0H18NO3 ([M+H]+) 200.1, found 200.1.
[00287] Step B: A solution of Intermediate LIa (1.75 mL, 8.8 mmol) in ethanol
(10 mL) is treated with Intermediate GIa (1 g, 4.8 mmol) followed by trifluoroacetic acid (0.5 mL) and heated to 60 0C for Ih. The resulting mixture crystallizes upon cooling, it is filtered and washed with ethanol (5 mL) to afford ethyl 2-(3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate Lib; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 4.0 Hz, IH), 8.34 (s, IH), 7.93 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.79 (d, J= 4.0 Hz, IH), 4.52 (q, J= 7.2 Hz, IH), 4.12 (q, J= 7.2 Hz, 2H), 1.67 (d, J= 7.2 Hz, 3H), 1.14 (t, J= 7.2 Hz, 3H); ESIMS calcd. for Ci7Hi6ClN3O2 ([M+H]+) 330.1, found 330.1.
[00288] Step C: A mixture of Intermediate Lib (23 mg, 0.07 mmol), 4- methylbenzylbromide (16.8 mg, 0.09 mmol) and Cs2CO3 (68 mg, 0.21 mmol) in acetonitrile (3 mL) is heated at 60 0C for 3h. The mixture is cooled, filtered, and concentrated. The residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound (Example Ll); 1H NMR (400 MHz, CDCl3) δ 8.39 (s, IH), 8.33 (d, J = 4.4 Hz, IH), 7.99 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.78 (d, J= 8.0 Hz, 2H), 6.33 (d, J= 4.0 Hz, IH), 6.29 (d, J= 8.0 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.97 (d, J= 13.6 Hz, IH), 3.23 (d, J = 13.6 Hz, IH), 2.15 (s, 3H), 1.56 (s, 3H), 0.97 (t, J= 7.2 Hz, 3H); ESIMS calcd. for C25H25ClN3O2 ([M+H]+) 434.2, found 434.2.
[00289] By following a similar procedure as the one used for preparing Example
Ll except substituting the appropriate alkyl halide for 4-methylbenzylbromide, the following examples are obtained:
Figure imgf000157_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Example L13
Ethyl 2-(3-(4-chlorophenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-2-methyl-3-(pyridin-3- vPpropanoate
Figure imgf000161_0002
[00290] By following a similar procedure as the one used for preparing Example
Ll except substituting 3-(bromomethyl)pyridine-HBr for 4-methylbenzylbromide, and using NaH/tetrahydrofuran/room temperature in place of the Cs2CO3/acetonitrile/60°C conditions in Step C, Example L13 is obtained: 1H NMR (CDCl3, 400 MHz): δ 8.40 (s, IH), 8.35 (d, J = 4.4 Hz, IH), 8.31 (m, IH), 7.97 (d, J = 8.4 Hz, 2H), 7.91 (m, IH), 7.37 (d, J= 8.4 Hz, 2H), 6.91 (m, IH), 6.57 (m, IH), 6.33 (d, J = 4.4 Hz, IH), 4.07 (m, 3H), 3.30 (d, J= 14.0 Hz, IH), 1.58 (s, 3H), 0.98 (t, / = 7.2 Hz, 3H); ESIMS calcd. for C23H22ClN4O2 ([M+H]+) 421.1, found 421.2. [00291] By following a similar procedure as the one used for preparing Example
L13 except substituting the appropriate alkyl halide for 3-(bromomethyl)pyridine-HBr, the following examples are obtained:
Figure imgf000162_0002
Example L15
Ethyl 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-(l- (methylsulfonyl)piperidin-4-yl)propanoate
Figure imgf000162_0001
Figure imgf000163_0001
L15b Example L15
[00292] Step A: A microwave vial charged with Intermediate Lib (40 mg, 0.12 mmol), Boc-4-(bromomethyl)-piperidine (56 mg, 0.18 mmol) and Cs2CO3 (118 mg, 0.36 mmol) in dimethylformamide (1 mL) is subjected to microwave irradiation (180 0C, 5 min). The mixture is then cooled, extracted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford tert-butyl 4-(2-(3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-3-ethoxy-2-methyl-3-oxopropyl)piperidine- 1-carboxylate L15a; ESIMS calcd. for C3iH34ClN4O4 ([M+H]+) 561.2, found 561.2.
[00293] Step B: A solution of Intermediate L15a (85 mg, 0.15 mmol) in a mixture of trifluoroacetic acid (1 mL) and dichloro methane (3 mL) is stirred at room temperature for 1 hour. The mixture is concentrated and the residue is purified by flash chromatography (dichloromethane/methanol gradient) to afford ethyl 2-(3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-2-methyl-3-(piperidin-4-yl)propanoate L15b; 1H NMR (CDCl3, 400 MHz): δ 8.51 (d, J = 4.0 Hz, IH), 8.30 (s, IH), 7.93 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 4.4 Hz, IH), 4.00 (m, 2H), 3.18 (d, J = 8.8 Hz, IH), 3.05 (d, J = 8.8 Hz, IH), 2.69 (m, IH), 2.50 (m, 2H), 2.05 (m, IH), 1.67 (s, 3H), 1.50 (m, 2H), 1.18 (m, 4H), 0.95 (t, J = 7.2 Hz, 3H); ESIMS calcd. for
C23H28ClN4O2 ([M+H]+) 427.2, found 427.2.
[00294] Step C: A solution of Intermediate L15b (21 mg, 0.05 mmol) and diisopropylethylamine (26 μL, 0.15 mmol) in dichloromethane (3 mL) is treated with methanesulfonyl chloride (5 μL, 0.06 mmol) and stirred at room temperature for 1 hour. The mixture is concentrated and the residue is purified by flash chromatography
(hexanes/ethyl acetate gradient) to afford the title compound (Example L15); 1H NMR (CDCl3, 400 MHz): 5 8.51 (d, J = 4.4 Hz, IH), 8.31 (s, IH), 7.94 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.78 (d, J= 4.4 Hz, IH), 3.98 (q, J= 7.6 Hz, 2H), 3.60 (m, IH), 3.45 (m, IH), 2.63 (s, 3H), 2.50 (m, 3H), 2.04 (dd, J = 4.8, 14.4 Hz, IH), 1.70 (s, 3H), 1.67 (m, IH), 1.39 (m, 2H), 1.08 (m, 2H), 0.93 (t, J= 7.2 Hz, 3H); ESIMS calcd. for C24H30ClN4O4S ([M+H]+) 505.2, found 505.2.
Example L16
Ethyl 3-(3,5-difluorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5- alpyrimidin-7-yl)propanoate
Figure imgf000164_0001
[00295] By following a similar procedure as the one used for preparing Example
Ll except substituting 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine instead of 4-(4- chlorophenyl)-lH-pyrazol-5-amine in Step B, and using l-(bromomethyl)-3,5- difluorobenzene instead of 4-methylbenzylbromide in Step C, Example L16 is obtained: 1H NMR (CDCl3, 400 MHz): δ 8.55 (s, IH), 8.53 (d, J= 4.4 Hz, IH), 8.23 (d, J= 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 6.62 (m, IH), 6.55 (d, J = 4.4 Hz, IH), 6.08 (dd, J = 2.4, 8.0 Hz, 2H), 4.16 (m, 3H), 3.38 (d, J = 13.6 Hz, IH), 1.70 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C25H2IF5N3O2 ([M+H]+) 490.2, found 490.2.
[00296] By following a similar procedure as the one used for preparing Example
L16 except substituting the appropriate alkyl halide for l-(bromomethyl)-3,5- difluorobenzene, the following examples are obtained:
Figure imgf000164_0002
(s,
(d, 7 2H), IH), 7 = IH), 3H), 3H); (d, (d, 7 2H), 7 = 7 = IH), 3H); (s, (m, (d, 7 IH), J = IH), 3H); (s, (d, 7 2H), 7 = IH), 7 = J = J = found (s, (d, 7 2H), IH), 3H), 3H), calcd.
Figure imgf000165_0001
(s,
(d, 7 2H), IH), 7 Hz, (s, (s, (d, 7 2H), IH), 2H), J = 3H), calcd. (d, (d, Hz, (t, 7 IH), J = IH), 3H); (d, (d, 7 2H), 7 = 2H), 3H), 3H); (d, (d, 7 2H), IH), 7 = IH), 7 = found 7.63 4.4 4.80 7.2 7.2
Figure imgf000166_0001
found (s,
Hz, (s, (d, J (d, J (t, J found
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Example Ml
2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-N-ethyl-2-methyl-3- phenylpropanamide
Figure imgf000170_0001
Figure imgf000170_0002
Example Ml
[00297] Step A: A solution of Intermediate MIa (5.28 g, 33.4 mmol) in acetone
(30 niL) is cooled to 0 0C and treated with K2CO3 (4.61 g, 33.4 mmol) followed by dropwise addition of a solution of methyl iodide (2.08 mL, 33.4 mmol) in acetone (20 mL) and the resulting mixture is stirred at room temperature for 12 hours. The mixture is filtered and concentrated, and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford tert-butyl 2-methyl-3-oxobutanoate MIb; 1H NMR (CDCl3, 400 MHz): δ 4.13 (q, J = 7.2 Hz, IH), 2.94 (s, 3H), 1.48 (s, 9H), 1.30 (d, J = 7.2 Hz, 3H); ESIMS calcd. for C9H17O3 ([M+H]+) 173.1, found 173.1.
[00298] Step B: A solution of Intermediate MIb (8.6 g, 50 mmol) in N,N- dimethylformamide-di-te/t-butyl acetal (11.97 g, 50 mmol) is heated to 100 0C for 3 hours. The solvent is removed and the resulting residue of MIc is used without further purification; 1H NMR (CDCl3, 400 MHz): δ 7.62 (d, J = 12.4 Hz, IH), 5.09 (d, J= 12.4 Hz, IH), 3.35 (q, J = 7.2 Hz, IH), 3.09 (br. s, 3H), 2.81 (br. s, 3H), 1.46 (s, 9H), 1.30 (d, J = 7.2 Hz, 3H); ESIMS calcd. for C12H22NO3 ([M+H]+) 228.1, found 228.1.
[00299] Step C: A solution of Intermediate MIc (0.60 g, 2.6 mmol) in tert- butanol (6 mL) is treated with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (0.51 g, 2.6 mmol) followed by trifluoroacetic acid (0.3 mL) and heated to 60 0C for Ih. The resulting mixture is concentrated and purified by flash chromatography (hexanes/ethyl acetate gradient) to afford tert-butyl 2-(3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate MId; 1H NMR (CDCl3, 400 MHz): δ 8.58 (d, J = 4.4 Hz, IH), 8.43 (s, IH), 8.03 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 4.4 Hz, IH), 4.51 (q, J = 12 Hz, IH), 1.72 (d, J = 12 Hz, 3H), 1.42 (s, 9H); ESIMS calcd. for Ci9H21ClN3O2 ([M+H]+) 358.1, found 358.1.
[00300] Step D: A mixture of Intermediate MId (280 mg, 0.78 mmol), benzyl bromide (280 μL, 2.35 mmol) and Cs2CO3 (767 mg, 2.35 mmol) in acetonitrile (5 mL) is heated at 80 0C for 3 hours. The mixture is cooled to room temperature, and
trifluoroacetic acid (3 mL) is added and stirred for 12 hours at room temperature, then is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO4), filtered, concentrated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford 2-(3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-2-methyl-3-phenylpropanoic acid MIe; 1H NMR (CDCl3, 400 MHz): δ 8.49 (s, IH), 8.44 (d, J= 4.4 Hz, IH), 8.02 (d, J= 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.10 (m, 3H), 6.51 (d, J= 8.4 Hz, 2H), 6.44 (d, J= 4.4 Hz, IH), 4.16 (d, J = 13.6 Hz, IH), 3.32 (d, J = 13.6 Hz, IH), 1.74 (s, 3H); ESIMS calcd. for C22Hi9ClN3O2 ([M+H]+) 392.1, found 392.1.
[00301] Step E: Intermediate MIe (236 mg, 0.60 mmol) is dissolved in dichloromethane (5 mL) and treated with oxalyl chloride (158 μL, 1.80 mmol) and DMF (20 μL) and stirred at room temperature for 1 hour. The mixture is concentrated; the residue is dissolved in dichloromethane and evaporated in vacuo. The crude 2-(3-(4- chlorophenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)-2-methyl-3-phenylpropanoyl chloride MIf is used without purification.
[00302] Step F: A solution of Intermediate MIf (25 mg, 0.06 mmol) in dichloromethane (2 mL) is treated with ethylamine (2M solution in tetrahydrofuran, 9 μL, 0.18 mmol) at room temperature for 1 hour. The mixture is concentrated and purified by flash chromatography (hexanes/ethyl acetate gradient) to afford the title compound
(Example Ml); 1H NMR (CDCl3, 400 MHz): δ 8.48 (s, IH), 8.37 (d, J = 4.4 Hz, IH), 8.02 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.13 (m, 3H), 6.58 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 4.4 Hz, IH), 5.69 (m, IH), 4.09 (d, J = 12.8 Hz, IH), 3.38 (d, J = 12.8 Hz, IH), 3.31 (m, 2H), 1.67 (s, 3H), 1.09 (t, J= 7.2 Hz, 3H); ESIMS calcd. for C24H24ClN4O ([M+H]+) 419.2, found 419.1.
[00303] By following a similar procedure as the one used for preparing Example
Ml except substituting the appropriate amine or alcohol for ethylamine in Step F, the following examples are obtained:
Figure imgf000172_0001
(s,
(d, J = (m, IH), IH), 3H); (s, (d, J = 2H), = 14.0 14.0 1.57 for found (s, (d, J = 2H), 2H), 3H), calcd. found (s, (d, J = (br s, (m, (m, (s, (m, (d, J = 2H), (s, Hz, (s,
Figure imgf000173_0001
1H NMR (CDCl3, 400 MHz): δ 8.55 (s,
IH) 8.36 (d, J = 4.4 Hz, IH), 8.07 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.13 (m, IH), 7.06 (m, 2H), 6.38 (m, 2H),
M9 6.30 (m, IH), 4.65 (d, J = 17.2 Hz, IH),
3.97 (d, J = 13.6 Hz, IH), 3.77 (s, 3H), 3.56 (m, 4H), 2.50 (s, 3H), 1.76 (s, 3H);
Figure imgf000174_0001
ESIMS calcd. for C26H26ClN4O3
([MH-H]+) 477.2, found 477.2.
1H NMR (CDCl3, 400 MHz): δ 8.43 (s, IH) 8.24 (d, J = 4.4 Hz, IH), 7.96 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.00 (m, IH), 6.94 (m, 2H), 6.27 (m, 2H), 6.17 (br s, IH), 4.42 (m, 2H), 3.82 (d, J =
MlO 13.6 Hz, IH), 3.42 (m, 2H), 3.14 (m, IH),
2.85 (m, 2H), 2.26 (s, 3H), 1.60 (s, 3H), 0.80 (m, 2H); ESIMS calcd. for
Figure imgf000174_0002
C26H28ClN4O ([MH-H]+) 447.2, found 447.2.
1H NMR (CDCI3^OO MHZ): δ 8.40 (s, IH) 8.37 (d, J = 4.4 Hz, IH), 7.95 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.07 (m, IH), 7.01 (m, 2H), 6.43 (m, 2H), 6.40 (d, J = 4.4 Hz, IH), 4.38 (m, 2H),
Mil 3.93 (d, J = 13.6 Hz, IH), 3.57 (m, 4H),
3.26 (d, J = 13.6 Hz, IH), 3.05 (m, 2H),
Figure imgf000174_0003
1.59 (s, 3H); ESIMS calcd. for
C28H30ClN4O3 ([MH-H]+) 505.2, found 505.2.
Example M12
N-(2-Methoxyethyl)-N,2-dimethyl-3-phenyl-2-(3-(4- (triiluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanamide
Figure imgf000174_0004
[00304] By following a similar procedure as the one used for preparing Example
Ml except substituting 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine for 4- (4- chlorophenyl)-lH-pyrazol-5-amine in Step C, and using 2-methoxy-N-methylethanamine instead of ethylamine in Step F, Example M12 is obtained: 1H NMR (CDCl3, 400 MHz): δ 8.62 (s, IH), 8.38 (d, J = 4.4 Hz, IH), 8.27 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.13 (m, IH), 7.06 (m, 2H), 6.39 (m, 2H), 6.32 (br s, IH), 3.94 (d, J = 13.6 Hz, IH), 3.73 (m, IH), 3.64 (s, 2H), 3.54 (d, J = 13.6 Hz, IH), 3.46 (m, IH), 3.30 (s, 3H), 2.93 (m, IH), 2.45 (s, 3H), 1.72 (s, 3H); ESIMS calcd. for C27H28F3N4O2 ([M+H]+) 497.2, found 497.2.
[00305] By following a similar procedure as the one used for preparing Example
M12 except substituting the appropriate amine or alcohol for ethylamine the following examples are obtained: (s, 7 = 7.22 6.41 3.63 2.46 1.44 (s, (d, 7 = 7.15 6.47 6.4 Hz, (s, (m, (s, 7 = 7.01 6.22 3.42 2.26 0.81
for found
(s, 7 = 7.15 6.45 (s, (s,
Figure imgf000175_0001
(s,
7 = 7.13 6.31 3.96 1.73 (s, (s, 7 = 7.01 6.21 13.6 1.78 ([MH-H]+) (s, 7 = 7.13 6.30 2.39 (s, (br s, (s, 7 = 7.11 7.2 Hz, (d, 7 = IH), (s, (s, 7 = 7.14 7.2 Hz, (t, 7 = IH), = 13.6 found (s, 7 = 7.11 7.2 Hz, (d, 7 = IH), IH),
Figure imgf000176_0001
found
(s, 7 = 7.13 7.2 Hz, (m, (s, (s, (s, 7 = 7.06 5.78 1.61 (s, 7 = 7.11 7.2 Hz, Hz, Hz, (m, (s,
(s, 7 = 7.11 3.91 13.6 1.75 (s, 7 = 6.99 7.2 Hz, (m, (d, J 7 = ([MH-H]+)
Figure imgf000177_0001
1H NMR (CDCl3, 400 MHz): δ 8.61 (s,
IH), 8.39 (d, 7 = 4.4 Hz, IH), 8.28 (d, 7 = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.12 (m, IH), 7.05 (m, 2H), 6.36 (m, 3H), 4.03
M29 (m, IH), 3.69 (m, IH), 3.57 (m, 4H), 3.34
(s, 3H), 3.20 (m, 2H), 2.87 (s, 3H), 2.12 (m, IH), 1.73 (s, 3H); ESIMS calcd. for C29H32F3N4O3 ([MH-H]+) 541.2, found 541.2.
1H NMR (CDCl3, 400 MHz): δ 8.61 (s, IH), 8.39 (d, 7 = 4.4 Hz, IH), 8.26 (d, 7 = 8.0 Hz, 2H), 7.74 (d, 7 = 8.0 Hz, 2H), 7.11 (m, IH), 7.08 (m, 2H), 6.39 (m, 2H) 6.30
M30 (br s, IH), 3.93 (d, 7 = 13.6 Hz, IH), 3.73
(s, 2H), 3.55 (m, 3H), 3.45 (s, 2H), 3.29 (s, 3H), 2.47 (s, 2H), 1.72 (s, 3H); ESIMS calcd. for C29H32F3N4O3 ([MH-H]+) 541.2, found 541.2.
1H NMR (CDCI3^OO MHZ): δ 8.59 (s, IH), 8.49 (d, 7 = 4.4 Hz, IH), 8.24 (d, 7 = 8.0 Hz, 2H), 7.73 (d, 7 = 8.0 Hz, 2H), 7.15 (m, IH), 7.10 (m, 2H), 6.52 (m, 3H), 4.46
M31 (m, IH), 4.20 (m, IH), 4.05 (d, 7 = 13.6
Hz, IH), 3.76 (m, IH), 3.70 (m, IH), 3.39 (d, J = 13.6 Hz, IH), 3.06 (s, 2H), 1.74 (s,
Figure imgf000178_0001
3H); ESIMS calcd. for C25H23F3N3O3
([MH-H]+) 470.2, found 470.2.
1H NMR (CDCl3, 400 MHz): δ 8.55 (s, IH), 8.47 (d, 7 = 4.4 Hz, IH), 8.23 (d, 7 = 8.0 Hz, 2H), 7.73 (d, 7 = 8.0 Hz, 2H), 7.15 (m, IH), 7.10 (m, 2H), 6.60 (m, 3H), 5.59
M32 (m, IH), 4.12 (d, 7 = 13.6 Hz, IH), 3.39
(d, J = 13.6 Hz, IH), 3.26 (m, 2H), 2.73 (br s, IH), 1.71 (s, 3H), 1.44 (m, 2H), 1.25
Figure imgf000178_0002
(m, 2H), 0.89 (t, 7 = 7.2 Hz, 3H); ESIMS calcd. for C27H28F3N4O ([MH-H]+) 481.2, found 481.2.
1H NMR (CDCI3^OO MHZ): δ 8.62 (s, IH), 8.38 (d, 7 = 4.4 Hz, IH), 8.28 (d, 7 = 8.0 Hz, 2H), 7.74 (d, 7 = 8.0 Hz, 2H), 7.12 (m, IH), 7.06 (m, 2H), 6.39 (m, 2H) 6.32
M33 (br s, IH), 3.96 (d, 7 = 13.6 Hz, IH), 3.71
(m, 2H), 3.55 (d, 7 = 13.6 Hz, IH), 3.46 (m, 2H), 3.30 (m, IH), 3.23 (s, 3H), 2.45
Figure imgf000178_0003
(s, 3H), 1.72 (s, 3H); ESIMS calcd. for
C30H34F3N4O3 ([MH-H]+) 555.3, found 555.3.
1H NMR (CDCI3^OO MHZ): δ 8.54 (d, 7 = 4.4 Hz, IH), 8.52 (s, IH), 8.24 (d, 7 = 8.4 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.17 (m, IH), 7.12 (m, 2H), 6.95 (s, IH), 6.59
M34 (d, 7 = 4.4 Hz, IH), 6.52 (d, 7 = 7.2 Hz,
2H), 5.79 (s, IH), 4.77 (d, 7 = 15.6 Hz, IH), 4.53 (d, 7 = 15.6 Hz, IH), 4.06 (d, 7
Figure imgf000178_0004
= 13.6 Hz, IH), 3.43 (d, J = 13.6 Hz, IH),
1.77 (s, 3H); ESIMS calcd. for
C25H22F3N4O3 ([MH-H]+) 483.2, found (s,
7 = 7.10 4.14 2.55 for found (s, 7 = 7.10 (d, (t, 7 = 2H), found (s, 7 = 7.03 7.2 Hz, (d, 7 = IH), IH), 5H); ([MH-H]+) (s, 7 = 7.14 8.0 Hz, Hz, (s, 467.2, (s, 7 = 7.12 (m, Hz, (d, 7 511.2, (s, 7 = 7.13 4.10 Hz, (t, 7 found
Figure imgf000179_0001
1H NMR (CDCI3^OO MHZ): δ 8.60 (s,
IH), 8.44 (d, 7 = 4.4 Hz, IH), 8.29 (d, 7 = 8.0 Hz, 2H), 7.74 (d, 7 = 8.0 Hz, 2H), 7.11 (m, IH), 7.70 (m, 2H), 6.49 (d, 7 = 7.2 Hz,
M41 2H), 6.41 (d, 7 = 4.4 Hz, IH), 4.18 (d, 7 =
13.6 Hz, IH), 3.31 (d, J = 13.6 Hz, IH), 1.66 (s, 3H), 1.33 (s, 9H); ESIMS calcd.
Figure imgf000180_0001
for C27H27F3N3O2 ([MH-H]+) 482.2, found
482.2.
1H NMR (CDCl3, 400 MHz): δ 8.53 (s, IH), 8.48 (d, 7 = 4.4 Hz, IH), 8.25 (d, 7 = 8.0 Hz, 2H), 7.74 (d, 7 = 8.4 Hz, 2H), 7.14 (m, IH), 7.10 (m, 2H), 6.54 (d, 7 = 7.2 Hz, 2H), 6.49 (d, 7 = 4.4 Hz, IH), 5.08 (m,
M42 IH), 4.13 (d, 7 = 13.6 Hz, IH), 3.65 (m,
IH), 3.54 (m, IH), 3.42 (m, 2H), 3.38 (d, 7 = 13.6 Hz, IH), 1.87 (m, 2H), 1.74 (m,
Figure imgf000180_0002
IH), 1.71 (s, 3H), 1.55 (m, IH), 1.39 (m, IH); ESIMS calcd. for C28H27F3N3O3 ([MH-H]+) 510.2, found 510.2.
1H NMR (CDCI3^OO MHZ): δ 8.54 (s, IH), 8.33 (d, 7 = 4.4 Hz, IH), 8.16 (d, 7 = 8.0 Hz, 2H), 7.63 (d, 7 = 8.4 Hz, 2H), 7.04 (m, IH), 7.00 (m, 2H), 6.38 (d, 7 = 7.2 Hz,
M43 2H), 6.34 (d, 7 = 4.4 Hz, IH), 4.26 (m,
2H), 3.88 (d, 7 = 13.6 Hz, IH), 3.79 (m, IH), 3.35 (d, 7 = 13.6 Hz, IH), 3.00 (m,
Figure imgf000180_0003
2H), 1.56 (s, 3H); ESIMS calcd. for
C26H24F3N4O2 ([MH-H]+) 481.2, found 481.2.
1H NMR (CDCl3, 400 MHz): δ 8.63 (d, 7 = 7.6 Hz, IH), 8.40 (m, IH), 8.26 (d, 7 = 8.0 Hz, 2H), 7.74 (d, 7 = 8.4 Hz, 2H), 7.14
M44 (m, IH), 7.07 (m, 2H), 6.37 (m, 3H), 3.88
(m, 7H), 3.53 (d, 7 = 13.6 Hz, IH), 3.45 (m, IH), 2.51 (s, 3H), 1.75 (s, 3H); ESIMS
Figure imgf000180_0004
calcd. for C27H28F3N4O3 ([MH-H]+) 513.2, found 513.2.
1H NMR (CDCI3^OO MHZ): δ 8.56 (s, IH), 8.45 (d, 7 = 4.4 Hz, IH), 8.23 (d, 7 = 8.0 Hz, 2H), 7.72 (d, 7 = 8.4 Hz, 2H), 7.11 (m, 3H), 6.58 (m, 3H), 5.94 (m, IH), 4.13
M45 (d, 7 = 13.6 Hz, IH), 3.57 (m, 2H), 3.39
(d, 7 = 13.6 Hz, IH), 3.33 (m, 2H), 1.70
Figure imgf000180_0005
(s, 3H), 1.51 (m, 4H); ESIMS calcd. for
C27H28F3N4O2 ([MH-H]+) 497.2, found 497.2.
1H NMR (CDCI3^OO MHZ): δ 8.53 (d, 7 = 2.4 Hz, IH), 8.49 (d, 7 = 4.4 Hz, IH), 8.22 (d, 7 = 7.6 Hz, 2H), 7.73 (d, 7 = 8.0 Hz, 2H), 7.13 (m, 3H), 6.62 (m, 3H), 5.87
M46 (m, IH), 4.59 (m, IH), 4.01 (m, IH), 3.77
(m, 5H), 3.40 (m, IH), 2.23 (m, IH), 1.80 (m, IH), 1.71 (d, 7 = 3.2 Hz, 3H); ESIMS
Figure imgf000180_0006
calcd. for C27H26F3N4O2 ([MH-H]+) 495.2, found 495.2. (s,
(d, J = 7.31 6.89 (d, (d, J (d, J = calcd. found (s, (d, J = 7.12 4.4 Hz, (m, (m, 497.2, (s, J = 7.11 7.2 Hz, (m, Hz, (m, Hz, (m,
([MH-H]+) (s, (d, J = 7.13 7.2 Hz, (m, Hz, (s, found (s, J = 7.13 4.4 Hz, (m, (dd, J 18.4 for
Figure imgf000181_0001
found (d, 7
J = 7.17 (d, (d, 7 = IH), found (s, 7 = 7.02 6.48 Hz, (dd, 7 IH), 3H); ([MH-H]+) ([MH-H]+) (s, 7 = 7.13 7.2 Hz, (m, (s, (m, (s, 7 = 7.15 6.09 13.6 ([MH-H]+) (s, 7 = 7.12 4.94 Hz, (d, 7 3H), calcd. found
Figure imgf000182_0001
([MH-H]+) ([MH-H]+) (s, J = 7.13 7.2 Hz, (m, (d, J (s, found
([MH-H]+)
Figure imgf000183_0001
Example M63
Methyl 2-(6-chloro-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3- fluorophenvl)-2-methylpropanoate
Figure imgf000183_0002
[00306] By following a similar procedure as the one used for preparing Example
Ml except substituting (Z)-tert-butyl 4-chloro-5-(dimethylamino)-2-methyl-3-oxopent-4- enoate for MIc (prepared as in A15a) in Step C, 3-fluorobenzyl bromide for benzyl bromide in Step D, and using methanol instead of ethylamine in Step F, Example M63 is obtained: 1U NMR (CDCl3, 400 MHz): δ 8.39 (s, IH), 8.25 (s, IH), 8.10 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 6.98 (m, IH), 6.81 (m, IH), 6.34 (d, J = 9.6 Hz, IH), 6.21 (d, J = 7.6 Hz, IH), 3.97 (d, J = 14.0 Hz, IH), 3.56 (s, 3H), 3.26 (d, J = 14.0 Hz, IH), 1.97 (s, 3H); ESIMS calcd. for C24Hi9ClF4N3O2 ([M+H]+) 492.1, found 492.1.
Example M64
2-(6-Chloro-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3- fluorophenyl)-N-(2-methoxyethyl)-N,2-dimethylpropanamide
Figure imgf000184_0001
[00307] By following a similar procedure as the one used for preparing Example
M63 except substituting 2-methoxy-N-methylethanamine for methanol in Step F, Example M64 is obtained: 1U NMR (CDCl3, 400 MHz): δ 8.47 (s, IH), 8.18 (s, IH), 8.11 (d, J = 8.0 Hz, 2H), 7.64 (d, J= 8.0 Hz, 2H), 6.94 (m, IH), 6.79 (m, IH), 6.25 (d, J = 7.6 Hz, IH), 6.08 (d, J = 4.0 Hz, IH), 3.90 (d, J = 14.0 Hz, IH), 3.53 (m, 3H), 3.40 (m, 2H), 3.19 (s, 3H), 2.86 (m, IH), 2.40 (s, 3H), 2.00 (s, 3H), 1.56 (m, IH); ESIMS calcd. for C27H26ClF4N4O2 ([M+H]+) 549.2, found 549.2.
Example Nl
Ethyl 3-(3-fluorophenyl)-2-(2-Qivdroxymethyl)-3-(4^ (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-2-methylpropanoate
Figure imgf000184_0002
Figure imgf000185_0001
Figure imgf000185_0002
NIb Example Nl
[00308] Step A: Example A38 (102 mg, 0.21 mmol) and N-bromosuccinimide
(55 mg, 0.31 mmol) are dissolved in tetrachloromethane (10 mL). Azobisisobutyronitrile (3 mg, 0.021 mmol) is added and the mixture is heated to 60 0C for 12h. The mixture is diluted with IN HCl and extracted with dichloromethane (2 x 10 mL). The organic layers are combined, dried (MgSO4), concentrated and the crude material is purified by flash chromatography to provide ethyl 2-(2-(bromomethyl)-3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-3-(3-fluorophenyl)-2- methylpropanoate NIa as a yellow solid; 1H NMR (CDCl3, 400 MHz): δ 8.34 (d, J = 4.4 Hz, IH), 7.95 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 6.95 (m, IH), 6.76 (m, IH), 6.41 (d, J = 4.4 Hz, IH), 6.25 (m, IH), 6.16 (d, J = 7.6 Hz, IH), 4.70 (q, J = 10.4 Hz, 2H), 4.11 (q, J= 7.2 Hz, 2H), 4.02 (d, J = 14.0 Hz, IH), 3.28 (d, J = 13.6 Hz, IH), 1.60 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C26H23BrF4N3O2 ([M+H]+) 564.1, found 564.2.
[00309] Step B: Intermediate NIa (35 mg, 0.06 mmol), sodium formate (13 mg,
0.18 mmol) and sodium iodide (28 mg, 0.18 mmol) are dissolved in DMF (3 mL) and heated for Ih to 80 0C. The mixture is cooled, diluted with water, and extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO4), concentrated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide ethyl 3-(3-fluorophenyl)-2-(2-(formyloxymethyl)-3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-2-methylpropanoate NIb as a pale yellow solid. ESIMS calcd. for C27H24F4N3O4 ([M+H]+) 530.2, found 530.2.
[00310] Step C: Intermediate NIb (23 mg, 0.045 mmol) and NaHCO3 (19 mg,
0.22 mmol) are dissolved in a mixture of methanol (5 mL), water (5 mL) and THF (2 mL) and stirred at room temperature for Ih. The mixture is acidified with IN HCl and extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO4), concentrated, and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to yield the title compound (Example Nl) as a white solid; 1H NMR (CDCl3, 400 MHz): δ 8.37 (d, J = 4.4 Hz, IH), 7.92 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 6.95 (m, IH), 6.77 (m, IH), 6.42 (d, J = 4.4 Hz, IH), 6.27 (m, IH), 6.15 (d, J = 7.6 Hz, IH), 4.98 (s, 2H), 4.09 (q, J= 7.2 Hz, 2H), 3.99 (d, J = 13.6 Hz, IH), 3.28 (d, J = 13.6 Hz, IH), 2.44 (br s, IH), 1.60 (s, 3H), 1.02 (t, J= 7.2 Hz, 3H); ESIMS calcd. for C26H24F4N3O3 ([M+H]+) 502.2, found 502.2.
Example N2
Ethyl 2-(2-((dimethylamino)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5- alpyrimidin-7-yl)-3-(3-fluorophenyl)-2-methvrpropanoate
Figure imgf000186_0001
[00311] By following a similar procedure as the one used for preparing Example
Nl except substituting N,N-dimethylamine (2.0 M in MeOH) in MeOH for sodium formate and sodium iodide in DMF in Step B, and omitting Step C, the title compound is prepared; 1H NMR (CDCl3, 400 MHz): δ 8.33 (d, J = 4.4 Hz, IH), 8.12 (d, J= 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 6.93 (m, IH), 6.77 (m, IH), 6.37 (d, J = 4.4 Hz, IH), 6.25 (m, IH), 6.09 (d, J = 7.6 Hz, IH), 4.08 (m, 3H), 3.70 (br s, 2H), 3.27 (d, J = 13.6 Hz, IH), 2.32 (s, 6H), 1.59 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C28H29F4N4O2 ([M+H]+) 529.2, found 529.2.
Example N3
Ethyl 2-(3-(4-chlorophenyl)-2-(methoxymethyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3- fluorophenvl)-2-methylpropanoate
Figure imgf000187_0001
[00312] By following a similar procedure as the one used for preparing Example
Nl, except substituting sodium methoxide for sodium formate and sodium iodide in DMF in Step B, and omitting Step C,the title compound is prepared; 1H NMR (CDCl3, 400 MHz): δ 8.45 (d, J = 4.4 Hz, IH), 7.82 (d, J = 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 7.03 (m, IH), 6.86 (m, IH), 6.50 (d, J= 4.4 Hz, IH), 6.35 (m, IH), 6.21 (d, J = 7.6 Hz, IH), 4.75 (s, 2H), 4.15 (m, 3H), 3.48 (s, 3H), 3.37 (d, J = 13.6 Hz, IH), 1.69 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C26H26ClFN3O3 ([M+H]+) 482.2, found 482.2.
Example N4
Ethyl 3-(3-fluorophenyl)-2-methyl-2-(2-(methylthio)-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000187_0002
Figure imgf000188_0001
Example N4
[00313] Step A: A solution of 4-(trifTuoromethyl)phenylacetonitrile (2.0 g, 10.8 mmol) and carbon disulfide (714 μL, 11.8 mmol) in tetrahydrofuran (30 rnL) is added dropwise to a solution of sodium hydride (950 mg, 24 mmol) in tetrahydrofuran (20 mL) at 0 0C and stirred at room temperature for 3h. The mixture is cooled to 0 0C, and methyl iodide (1.5 mL, 24 mmol) is added slowly and stirred at room temperature for 12h. The mixture is poured into water and extracted with dichloromethane (2 x 60 mL). The organic layers are combined, washed with brine, dried (MgSO4), concentrated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide 3,3-bis(methylthio)-2-(4-(trifluoromethyl)phenyl)acrylonitrile N4a. ESIMS calcd. for CI2HHF3NS2 ([M+H]+) 290.0, found 290.1.
[00314] Step B: Intermediate N4a (764 mg, 2.64 mmol) and hydrazine-hydrate
(329 μL, 10.6 mmol) are dissolved in 2-methoxyethanol (3 mL) and heated at 200 0C for 40 min in a closed vessel. The reaction is diluted with water, and extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO4), concentrated, and the crude material is purified by flash chromatography (dichloromethane/methanol gradient) to provide 3-(methylthio)-4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine N4b as a white powder. ESIMS calcd. for C11H10F3N3S ([M+H]+) 274.0, found 274.1.
[00315] Step C: A mixture of Intermediate A38b (101 mg, 0.33 mmol) and
Intermediate N4b (90 mg, 0.33 mmol) in methanol (8 mL) and TFA (2 mL) is heated to 80 0C for 6h. The mixture is concentrated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide the title compound (Example N4) as a yellow powder; 1U NMR (CDCl3, 400 MHz): δ 8.30 (d, J = 4.8 Hz, IH), 8.05 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 6.95 (m, IH), 6.77 (m, IH), 6.30 (m, 2H), 6.16 (d, J = 7.6 Hz, IH), 4.05 (m, 3H), 3.25 (d, J = 13.6 Hz, IH), 2.63 (s, 3H), 1.58 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H); ESIMS calcd. for C26H24F4N3O2S ([M+H]+) 518.1, found 518.1.
Example Ol
(R)-Ethy\ 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate
Figure imgf000189_0001
[00316] A sample of Example A5 is subjected to chiral chromatography using a
Chiral Technologies 20x250mm ChiralPak AD-H column with an 11 minute isocratic elution using hexanes/isopropanol (7:3) as mobile phase at 20 mL per minute. The first eluting peak is collected and reanalyzed using a Chiral Technologies 4.6x250mm
ChiralPak AD-H column with an 11 minute isocratic elution with hexane/isopropanol (7:3) at 1 mL per minute. Example Ol comes off at 5.50 minutes. The 1H NMR and HRMS data for Example Ol are identical to Example A5.
Examples O2 and O3
ffl-Ethyl 2-(3-(4-bromophenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate and (R)-ethy\ 2-(3-(4-bromophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2- methyl- 3 -phen ylpropano ate .
Figure imgf000190_0001
[00317] A sample of Example A14 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm ChiralCel OJ-H column with a 5.5 minute isocratic elution using methanol/CO2 (40:60) as mobile phase at 80 mL per minute. Both eluting peaks are collected and reanalyzed using a Chiral Technologies 4.6x250mm ChiralPak OJ-H column with a 5 minute isocratic elution with methanol/CO2 (40:60) at 2 mL per minute. Example O2 comes off at 3.11 minutes; Example O3 comes off at 4.01 minutes. The 1H NMR and HRMS data for Example O2 and Example O3 are identical to
Example A14.
[00318] A sample of Example 03 is crystallized from hot methanol. Upon cooling and standing at room temperature for 36 h it yields light-yellow prismatic crystals.
Analysis by single-crystal diffraction revealed the absolute stereochemistry as (R).
Examples O4 and O5
ffl-Ethyl 2-methyl-3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7- vPpropanoate and (R)-ethγ\ 2-methyl-3-phenyl-2-(3-(4- (trifruoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)propanoate
Figure imgf000190_0002
[00319] A sample of Example B15 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm ChiralCel OJ-H column with a 5 minute isocratic elution using methanol/CO2 (15:85) as mobile phase at 70 mL per minute. Both eluting peaks are collected and reanalyzed using a Chiral Technologies 4.6x100mm ChiralCel OJ-H column with 5 minute isocratic elution using methanol/CO2 (20:80) as mobile phase at 2 mL per minute and 30 0C. Example O4 comes off at 2.42 minutes; Example O5 comes off at 3.01 minutes. The 1H NMR and HRMS data for Example O4 and Example O5 are identical to Example B 15.
Example O6
Figure imgf000191_0001
yPcyclopropanecarboxylate
Ph
Figure imgf000191_0002
[00320] A sample of Example A23 is subjected to chiral chromatography using a
Chiral Technologies 20x250mm ChiralPak AD-H column with an 15 minute isocratic elution using hexanes/isopropanol (9:1) as mobile phase at 20 mL per minute. The second eluting peak is collected and reanalyzed using a Chiral Technologies 4.6x250mm
ChiralPak AD-H column with an 11 minute isocratic elution with hexane/isopropanol (9:1) at 1 mL per minute. Example O6 comes off at 9.54 minutes. The 1H NMR and HRMS data for Example O6 are identical to Example A23. Examples O7 and O8
ffl-Ethyl 2-(6-chloro-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2- methyl-3-phenylpropanoate; (7?)-ethyl 2-(6-chloro-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenylpropanoate
Figure imgf000192_0001
[00321] A sample of Example A15 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm Chiralcel OJ-H column with a 3.5 minute isocratic elution using methanol/CO2 (10:90) as mobile phase at 80 g per minute. Both eluting peaks are collected and reanalyzed using a Chiral Technologies 4.6xl00mm ChiralCel OJ-H column with 5 minute isocratic elution using methanol/CO2 (10:90) as mobile phase at 2 g per minute. Example 07 comes off at 2.62 minutes; Example 08 comes off at 3.44 minutes. The 1H NMR and HRMS data for Example 07 and Example 08 are identical to Example A15.
Examples O9 and OIO
(S)-Ethyl 2-(6-bromo-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2- methyl-3-phenylpropanoate; (R)-ethyl 2-(6-bromo-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenylpropanoate
Figure imgf000192_0002
[00322] A sample of Example A28 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm ChiralPak AD column with a 12 minute isocratic elution using hexane/ethanol/methanol (90:5:5) as mobile phase at 20 mL per minute. Both eluting peaks are collected and reanalyzed using a Chiral Technologies 4.6x250mm ChiralPak AD column with 10 minute isocratic elution using hexane/ethanol/methanol (90:5:5) as mobile phase at 1 mL per minute. Example O9 comes off at 4.32 minutes; Example OIO comes off at 7.49 minutes. The 1H NMR and HRMS data for Example O9 and Example OIO are identical to Example A28.
Example Oil
(R)-Ethyl 2-methyl-3-phenyl-2-(8-(4-(trifluoromethyl)phenyl)pyrazolor5,l- cl r 1 ,2,41triazin-4-yl)propanoate
Figure imgf000193_0001
[00323] A sample of Example F4 is subjected to chiral chromatography using a
Chiral Technologies 20x250mm ChiralPak IA column with a 3 minute isocratic elution using CO2:methanol (60:40) as mobile phase at 20 mL per minute. Both eluting peaks are collected and reanalyzed using a Chiral Technologie ChiralPak IA column with 3 minute isocratic elution using CO2:methanol (60:40) as mobile phase at 2 mL per minute phase at 1 mL per minute. Example Ol 1 comes off at 2.01 minutes. The IH NMR and HRMS data for Example Oi l are identical to Example F4.
Example O12
(R)-A^-(l-Phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propan-
2-yl)acetamide
Figure imgf000194_0001
[00324] A sample of Example J4 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm ChiralPak IA column with a 3.75 minute isocratic elution using CO2/MeOH/THF (60:20:20) as mobile phase at 80 g/min. The first eluting peak is collected and reanalyzed using a Chiral Technologies 4.6xl00mm ChiralPak IA column with 5 minute isocratic elution using CO2/MeOH/THF (60:20:20) as mobile phase at 2 niL/min and 3O0C. Example O12 comes off at 1.35 minutes. The 1H NMR and ESIMS data for Example O12 are identical to Example J4.
Example O13
((R)-Ethγ\ 2-methyl-2-(3-(4-nitrophenyl)pyrazolori,5-αlpyrimidin-7-yl)-3- phenylpropanoate
Figure imgf000194_0002
[00325] A sample of Example A33 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm ChiralPak IA column with a 14 minute isocratic elution using Hexane/Ethanol/Methanol (70:15:15) as mobile phase at lml/min at ambient temperature. Example O13 comes off at 6.85 minutes. The 1H NMR and ESIMS data for Example O13 are identical to Example A33. Examples O14 and O15
(R)-Methyl 2-methyl-3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-alpyrimidin-
7-yl)propanoate and (S)-methyl 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000195_0001
[00326] A sample of Example M16 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm ChiralPak IA column with a 10 minute isocratic elution using CCVMethanol (90:10) as mobile phase at 2ml/min at 30 0C. Example O14 comes off at 3.89 minutes, and Example O15 comes off at 5.14 minutes. The 1H NMR and ESIMS data for Example O14 and O15 are identical to Example M16.
Examples O16 and O17
(R)-N,N,2-Trimethyl-3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-
7-yl)propanamide and (S)-N,N,2-trimethyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanamide
Figure imgf000195_0002
[00327] A sample of Example M20 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm ChiralPak IA column with a 10 minute isocratic elution using CCVMethanol (80:20) as mobile phase at 2ml/min at 30 0C. Example O16 comes off at 3.80 minutes, and Example O17 comes off at 5.92 minutes. The 1H NMR and ESIMS data for Example O16 and O17 are identical to Example M20.
Examples O18 and O19
(R)-N-(2-Methoxyethyl)-N,2-dimethyl-3-phenyl-2-(3-(4-
(trifluoromethvDphenvDpyrazolor 1 ,5-alpyrimidin-7-yl)propanamide and (S)-N-(2- methoxyethyl)-N,2-dimethyl-3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5- alpyrimidin-7-yl)propanamide
Figure imgf000196_0001
[00328] A sample of Example M 12 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm ChiralPak IA column with a 10 minute isocratic elution using COi/Methanol (80:20) as mobile phase at 2ml/min at 30 0C. Example 018 comes off at 3.39 minutes, and Example 019 comes off at 4.45 minutes. The 1H NMR and ESIMS data for Example 018 and 019 are identical to Example M12.
Example O20
(R)-N-(Furan-2-ylmethyl)-N,2-dimethyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanamide
Figure imgf000197_0001
[00329] A sample of Example M 17 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm ChiralPak IC column with a 10 minute isocratic elution using CCVMethanol (80:20) as mobile phase at 2ml/min at 30 0C. Example O20 comes off at 3.25 minutes. The 1H NMR and ESIMS data for Example O20 are identical to Example M 17.
Examples O21 and O22
(R)-Methyl 2-(N,2-dimethyl-3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5- alpyrimidin-7-yl)propanamido)acetate and (S)-methyl 2-(N,2-dimethyl-3-phenyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanamido)acetate
Figure imgf000197_0002
[00330] A sample of Example M22 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm ChiralPak IC column with a 5 minute isocratic elution using COi/Methanol (80:20) as mobile phase at 2ml/min at 30 0C. Example 021 comes off at 2.92 minutes, and Example 022 comes off at 3.58 minutes. The 1H NMR and ESIMS data for Example 021 and 022 are identical to Example M22.
Examples O23 and O24
(R)-2-(3-(4-chlorophenyl)pyrazolori,5-alpyrimidin-7-yl)-N-(2-methoxyethyl)-N,2- dimethyl-3-phenylpropanamide and (S)-2-(3-(4-chlorophenyl)pyrazolor 1 ,5-alpyrimidin-
7-yl)-N-(2-methoxyethyl)-N,2-dimethyl-3-phenylpropanamide
Figure imgf000198_0001
[00331] A sample of Example M4 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm ChiralPak IA column with a 16 minute isocratic elution using COi/Methanol (80:20) as mobile phase at 2ml/min at 30 0C. Example 023 comes off at 3.06 minutes, and Example 024 comes off at 4.00 minutes. The 1H NMR and ESIMS data for Example 023 and 024 are identical to Example M4.
Examples O25
(R)-N-(2-(2-Methoxyethoxy)ethyl)-N,2-dimethyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanamide
Figure imgf000199_0001
[00332] A sample of Example M30 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm ChiralPak IC column with a 10 minute isocratic elution using CCVMethanol (80:20) as mobile phase at 2ml/min at 30 0C. Example 025 comes off at 3.83 minutes. The 1H NMR and ESIMS data for Example 025 are identical to Example M30.
Examples O26 and O27
(R)-4-Hydroxybutyl 2-methyl-3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5- alpyrimidin-7-yl)propanoate and (S)-4-hydroxybutyl 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000199_0002
[00333] A sample of Example M 14 is subjected to chiral chromatography using a
Chiral Technologies 21x250mm ChiralPak IA column with a 5 minute isocratic elution using COi/Methanol (80:20) as mobile phase at 2ml/min at 30 0C. Example 026 comes off at 1.76 minutes, and Example 027 comes off at 2.78 minutes. The 1H NMR and ESIMS data for Example 026 and 027 are identical to Example M14.
Examples O28 and O29
(R)-Methyl 2-(6-chloro-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-3-
(3-fluorophenyl)-2-methylpropanoate and S)-methyl 2-(6-chloro-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3-fluorophenyl)-2- methylpropanoate
Figure imgf000200_0001
[00334] A sample of Example M63 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm ChiralPak IA column with a 5 minute isocratic elution using COi/Methanol (80:20) as mobile phase at 2ml/min at 30 0C. Example 028 comes off at 1.97 minutes, and Example 029 comes off at 3.48 minutes. The 1H NMR and ESIMS data for Example 028 and 029 are identical to Example M63.
Examples O30 and O31
(R)-2-(6-Chloro-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3- fluorophenyl)-N-(2-methoxyethyl)-N,2-dimethylpropanamide and (S)-2-(6-chloro-3-(4-
(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3-fluorophenyl)-N-(2- methoxyethyl)-N,2-dimethylpropanamide
Figure imgf000201_0001
[00335] A sample of Example M64 is subjected to chiral chromatography using a
Chiral Technologies 10x250mm Whelk Ol column with a 10 minute isocratic elution using CCVMethanol (80:20) as mobile phase at 2ml/min at 30 0C. Example O30 comes off at 6.25 minutes, and Example 031 comes off at 8.00 minutes. The 1H NMR and ESIMS data for Example O30 and 031 are identical to Example M64.
Examples Pl and P2
(R)-Methyl 3-(3-fluorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5- alpyrimidin-7-yl)propanoate and (S)-methyl 3-(3-fluorophenyl)-2-methyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000201_0002
Figure imgf000202_0001
Figure imgf000202_0002
Figure imgf000202_0003
Example P2
[00336] Step A: Methyl acetoacetate (10 g, 86.1 mmol) and potassium carbonate
(11.9 g, 86 mmol) are dissolved in acetone (50 mL) and cooled to 0 0C, then methyl iodide (5.3 mL, 86 mmol) in acetone (30 mL) is added dropwise over 30 min. The mixture is stirred for 12h at room temperature, then is filtered and concentrated to provide methyl 2-methyl-3-oxobutanoate PIa, which was used directly in Step B without further purification.
[00337] Step B: Intermediate PIa (86 mmol) is dissolved in acetone (100 mL), then potassium carbonate (14 g, 103 mmol) and 3-fluorobenzyl chloride (13.7 mL, 112 mmol) is added and the mixture is heated for 12h at 60 0C. The mixture is cooled, filtered, concentrated, and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide methyl 2-(3-fluorobenzyl)-2-methyl-3- oxobutanoate PIb. ESIMS calcd. for Ci3Hi6FO3 ([M+H]+) 239.1, found 239.1.
[00338] Step C: Intermediate PIb (13.21 g, 55.5 mmol) and N,N- dimethylformamide dimethyl acetal (6.62 g, 55.5 mmol) are heated at 80 0C for 72h. The mixture is concentrated and the crude material is purified by flash chromatography (dichloromethane/methanol gradient) to provide (E)-methyl 5-(dimethylamino)-2-(3- fluorobenzyl)-2-methyl-3-oxopent-4-enoate PIc as a pale oil. ESIMS calcd. for
Ci6H2IFNO3 ([M+H]+) 294.1, found 294.1.
[00339] Step D: A sample of Intermediate PIc is subjected to chiral
chromatography using a 21 x 250 mm ChiralPak IC column with a 10 minute isocratic elution using CO2/Isopropanol (80:20) as mobile phase at 2ml/min at 30 0C. PId comes off at 4.21 minutes, and PIe comes off at 5.41 minutes.
[00340] Step E: 4-(4-(Trifluoromethyl)phenyl)- lH-pyrazol-5-amine (25 mg, 0.11 mmol) and PId or PIe (33 mg, 0.11 mmol) are dissolved in methanol (5 mL) and TFA (0.2 mL) and heated at 60 0C for 12h. The mixtures are concentrated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide the title compounds respectively (Examples Pl and P2): 1H NMR (CDCl3, 400 MHz): δ 8.47 (s, IH), 8.39 (d, J = 4.4 Hz, IH), 8.16 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 6.95 (m, IH), 6.76 (td, J = 2.8, 8.4 Hz, IH), 6.40 (d, J = 4.4 Hz, IH), 6.25 (dt, J = 2.0, 9.6 Hz, IH), 6.10 (d, J = 7.6 Hz, IH), 4.01 (d, / = 14.0 Hz, IH), 3.57 (s, 3H), 3.30 (d, J = 14.0 Hz, IH), 1.60 (s, 3H); ESIMS calcd. for C24H20F4N3O2 ([M+H]+) 458.1, found 458.1.
Example P3
(R)-methyl 3-(3-fluorophenyl)-2-methyl-2-(2-methyl-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000203_0001
[00341] By following a similar procedure to Example A38, except substituting intermediate PId for intermediate A38b in Step E, the title compound is prepared; 1H NMR (CDCl3, 400 MHz): δ 8.29 (d, J = 4.4 Hz, IH), 7.84 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 6.94 (m, IH), 6.76 (m, IH), 6.31 (d, J = 4.4 Hz, IH), 6.24 (m, IH), 6.14 (d, J = 7.6 Hz, IH), 4.02 (s, IH), 3.59 (s, 3H), 3.27 (d, J = 13.6 Hz, IH), 2.60 (s, 3H), 1.57 (s, 3H); ESIMS calcd. for C25H22F4N3O2 ([M+H]+) 472.2, found 472.2.
Examples P4
(R)-Methyl 3-(3-fluorophenyl)-2-('2-('hvdroxymethyl)-3-('4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-2-methylpropanoate
Figure imgf000204_0001
Figure imgf000204_0002
Figure imgf000204_0003
P4b Example P4
[00342] By following a similar procedure to Example Nl, except substituting
Example P3 for Example A38 in Step A, the title compound is prepared; 1H NMR (CDCl3, 400 MHz): δ 8.37 (d, J = 4.4 Hz, IH), 7.91 (d, J= 8.0 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 6.95 (m, IH), 6.77 (m, IH), 6.41 (d, J = 4.4 Hz, IH), 6.25 (m, IH), 6.14 (d, J = 7.6 Hz, IH), 4.97 (d, J = 2.8 Hz, 2H), 3.95 (d, J = 13.6 Hz, IH), 3.58 (s, 3H), 3.29 (d, J = 13.6 Hz, IH), 1.59 (s, 3H); ESIMS calcd. for C25H22F4N3O3 ([M+H]+) 488.1, found 488.1.
[00343] By following a similar procedure as the one used for preparing Example
P4 except substituting the appropriate amine or alcohol for sodium formate in Step B and omitting Step C, the following examples are obtained:
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0002
Example P14
((R)-Methyl 3-(3-fluorophenyl)-2-methyl-2-(2-(methylsulfonylmethyl)-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propanoate
Figure imgf000207_0001
[00344] A sample of Intermediate P4a (15.2 mg, 0.02 mmol) in dimethylacetamide
(1.5 mL) is treated with sodium methanethiolate (10 mg, 0.14 mmol) and the mixture is heated to 45 0C for 3h. The mixture is cooled to room temperature and treated with meta- chloroperbenzoic acid (25 mg, 0.1 mmol) and the mixture is stirred at room tempreature for 4h. Purification of the mixture by reversed-phase HPLC yields the title compound (Example P14): ESIMS calcd. for C28H24F4N3O4S ([M+H]+) 550.2, found 550.2. Example P15
((R)-7-(3-(3-fluorophenyl)-l-methoxy-2-methyl-l-oxopropan-2-yl)-3-(4-
Figure imgf000208_0001
Figure imgf000208_0002
Figure imgf000208_0003
Example P15
[00345] Step A: Example P3 (300 mg, 0.64 mmol) and N-bromosuccinimide (229 mg, 1.28 mmol) are dissolved in tetrachloromethane (10 mL). Azobisisobutyronitrile (15 mg, 0.09 mmol) is added and the mixture is heated to 60 0C for 12h. The mixture is diluted with IN HCl and extracted with dichloromethane (2 x 10 mL). The organic layers are combined, dried (MgSO4), concentrated and the crude material is purified by flash chromatography to provide (R)-methyl 2-(2-(dibromomethyl)-3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-3-(3-fluorophenyl)-2- methylpropanoate P15a; ESIMS calcd. for C2SH20Br2F4N3O2 ([M+H]+) 628.0, found 628.0.
[00346] Step B: A sample of Intermediate P15a (70 mg, 0.11 mmol) in acetonitrile
(2 mL) is treated with silver nitrate (90 mg, 0.53 mmol) and water (2 mL) and the mixture is stirred at 50 0C overnight. The mixture is cooled to room temperature, extracted with ethyl acetate, dryed over Na2SO4 and concentrated to yield (R)-methyl 3-(3- fluorophenyl)-2-(2-formyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)- 2-methylpropanoate P15b as an oil; ESIMS calcd. for C25H20F4N3O3 ([M+H]+) 486.2, found 486.2. The product is used without purification.
[00347] Step C: The Intermediate PlOb is dissolved in a mixture of THF (0.5 mL) and tert-butanol (0.5 mL). The mixture is treated with 2-methyl-2-butene (IM solution in THF; 0.15 mL, 0.15 mmon), sodium dihydrogenphosphate (30 mg, 0.25 mmol), sodium chlorite (20 mg, 0.22 mmol), and water (0.5 mL) and vigorously stirred at room temperature for 4h. Purificaton crude material by reversed-phase HPLC yields the title compound (Example P15): ESIMS calcd. for C25H20F4N3O4 ([M+H]+) 502.2, found 502.2.
Example P16
(R)-2-(7-(3-(3-Fluorophenyl)-l-methoxy-2-methyl-l-oxopropan-2-yl)-3-(4- (trifluoromethyl)phenyl)pyrazolor 1 ,5-alpyrimidin-2-vl)acetic acid
Figure imgf000209_0001
Figure imgf000209_0002
[00348] Step A: A sample of Example P12 (13 mg, 0.027 mmol) in water (1 mL) is treated with acetic acid (1 mL) and sulfuric acid (1 mL) and heated to reflux for 2h. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO4), concentrated, and the crude material is purified by reversed-phase HPLC to provide the title compound (Example P16); 1H NMR (CDCl3, 400 MHz): δ 8.32 (d, J = 4.4 Hz, IH), 7.65 (m, 4H), 6.94 (m, IH), 6.75 (td, J = 2.4, 8.4 Hz, IH), 6.39 (d, J = 4.4 Hz, IH), 6.23 (d, J = 9.6 Hz, IH), 6.14 (d, J = 7.6 Hz, IH), 3.98 (m, 4H), 3.53 (s, 3H), 3.24 (d, J = 13.6 Hz, IH), 1.58 (s, 3H); ESIMS calcd. for
C26H22F4N3O4 ([M+H]+) 516.2, found 516.2.
Example P17
(R)-Methyl 3-(3-fluorophenyl)-2-methyl-2-(2-(methylthio)-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000210_0001
[00349] By following a similar procedure to Example N4, except substituting intermediate PId for intermediate A38b in Step C, the title compound is prepared; 1H NMR (CDCl3, 400 MHz): δ 8.39 (d, J = 4.4 Hz, IH), 8.13 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.05 (m, IH), 6.87 (m, IH), 6.38 (m, 2H), 6.24 (d, J = 7.6 Hz, IH), 4.06 (d, J = 13.6 Hz, IH), 3.67 (s, 3H), 3.35 (d, J = 13.6 Hz, IH), 2.71 (s, 3H), 1.67 (s, 3H), 1.57 (s, 3H); ESIMS calcd. for C25H22F4N3O2S ([M+H]+) 504.1, found 504.1.
Examples P18 and P19
(R)-methyl 3-(3-fluorophenyl)-2-methyl-2-(2-(methylsulfinyl)-3-(4-
(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate and (R)-methyl 3-(3- fluorophenyl)-2-methyl-2-(2-(methylsulfonyl)-3-(4-(trifluoromethyl)phenyl)pyrazolori,5- alpvrimidin-7-vl)propanoate
Figure imgf000211_0001
Figure imgf000211_0002
Example P19
Figure imgf000211_0003
[00350] Example P17 (50 mg, 0.1 mmol) is dissolved in acetic acid (3 niL).
Hydrogen peroxide (20 μL of 35% in H2O, 0.2 mmol) is added and the mixture is heated to 50 0C for 12h. A 50% aliquot of the solution is removed, concentrated and purified by flash chromatography (hexanes/ethyl acetate gradient) to provide the title compound (Example P18); 1H NMR (CDCl3, 400 MHz): δ 8.47 (m, IH), 8.06 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 6.98 (m, IH), 6.79 (m, IH), 6.58 (m, IH), 6.29 (m, IH), 6.16 (m, IH), 3.98 (d, J = 13.6 Hz, 0.5H), 3.78 (d, J = 13.6 Hz, 0.5H), 3.60 (d, 3H), 3.33 (dd, J = 3.6, 13.6 Hz, IH), 3.09 (s, 3H), 1.98 (d, IH), 1.63 (d, 3H); ESIMS calcd. for
C25H22F4N3O3S ([M+H]+) 520.1, found 520.1. The remaining 50% of the solution is heated to 80 0C for 12h, then concentrated and purified by flash chromatography
(hexanes/ethyl acetate gradient) to provide the title compound (Example P19); 1H NMR (CDCl3, 400 MHz): δ 8.60 (d, J = 4.4 Hz, IH), 8.13 (d, J= 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.07 (m, IH), 6.90 (m, IH), 6.72 (d, J = 4.4 Hz, IH), 6.41 (m, IH), 6.25 (d, J = 7.6 Hz, IH), 3.90 (d, J = 13.6 Hz, IH), 3.69 (s, 3H), 3.41 (s, 3H), 3.42 (d, J = 13.6 Hz, IH), 1.72 (s, 3H); ESIMS calcd. for C25H22F4N3O4S ([M+H]+) 535.1, found 535.1.
Example P20
(R)-methyl 3-(3-fluorophenyl)-2-methyl-2-(2-(trifluoromethyl)-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)propanoate
Figure imgf000212_0001
Figure imgf000212_0002
[00351] Step A: 5-Trifluoromethyl-2H-pyrazol-3-ylamine (236 mg, 1.56 mmol) and iodine (198 mg, 0.78 mmol) is dissolved in water, then 35% hydrogen peroxide (151 μL, 1.56 mmol) is added and stirred at room temperature for 12h. The mixture is poured into aqueous Na2SO3 and extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO4), and concentrated to provide 4-iodo-3-(trifluoromethyl)-lH- pyrazol-5-amine P20a, which was used directly in the next step without further purification. ESIMS calcd. for C4H4F3IN3 ([M+H]+) 277.9, found 278.0.
[00352] Step B: Intermediate PId (136 mg, 0.46 mmol) and 4-iodo-3-
(trifluoromethyl)-lH-pyrazol-5-amine P20a (128 mg, 0.46 mmol) are dissolved in methanol (5 mL) and TFA (0.1 mL) and heated at 80 0C for 12h. The mixture is concentrated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide (R)-methyl 3-(3-fluorophenyl)-2-(3-iodo-2- (trifluoromethyl)pyrazolo[l,5-a]pyrimidin-7-yl)-2-methylpropanoate P20b. ESEVIS calcd. for Ci8Hi5F4IN3O2 ([M+H]+) 508.0, found 508.0.
[00353] Step C: A mixture of Intermediate P20b (55 mg, 0.11 mmol), 4- trifluoromethylphenyl boronic acid (23 mg, 0.12 mmol), Pd(dppf)-Cl2 (8 mg, 0.01 mmol) and Cs2CO3 (0.3 mL of IM aqueous solution, 0.3 mmol) in dioxane (1 mL) is heated at 120 0C for 30 min. The mixture is diluted with water, and extracted with ethyl acetate. The organic layer is washed with brine, dried (MgSO4), concentrated, and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to provide the title compound (Example P20) as a pale yellow solid; 1H NMR (CDCl3, 400 MHz): δ 8.44 (d, J = 4.4 Hz, IH), 7.76 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 6.97 (m, IH), 6.79 (m, IH), 6.56 (d, J = 4.4 Hz, IH), 6.27 (m, IH), 6.17 (d, J = 7.6 Hz, IH), 3.91 (d, J = 14.0 Hz, IH), 3.62 (s, 3H), 3.32 (d, J = 14.0 Hz, IH), 1.63 (s, 3H); ESIMS calcd. for C25Hi9F7N3O2 ([M+H]+) 526.1, found 526.1.
Example P21
(R)-methyl 2-(2-amino-3-phenylpyrazolori,5-alpyrimidin-7-yl)-3-(3-fluorophenyl)-2- methylpropanoate
Figure imgf000213_0001
Figure imgf000213_0002
[00354] Step A: 2-Phenyl malonitrile (122 mg, 0.86 mmol) is dissolved in ethanol
(4 rnL) and water (1 rnL) and treated with hydrazine-HCl (59 mg, 0.86 mmol) at 80 0C for 12h. The mixture is concentrated to provide 4-phenyl-lH-pyrazole-3,5-diamine P21a, which is used directly in the next step without further purification. ESIMS calcd. for C9HnN4 ([M+H]+) 175.1, found 175.1.
[00355] Step B: Intermediate P21a (0.86 mmol) and intermediate PId (252 mg,
0.86 mmol) are heated to 80 0C in a mixture of methanol (10 mL) and TFA (1 mL) for 12h. The mixture is concentrated and purified by reversed-phase HPLC to provide the title compound (Example P21); 1U NMR (CDCl3, 400 MHz): δ 8.14 (d, J = 4.4 Hz, IH), 7.75 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.22 (m, IH), 6.95 (m, IH), 6.76 (m, IH), 6.30 (m, IH), 6.19 (d, J= 7.6 Hz, IH), 6.12 (d, J= 4.4 Hz, IH), 4.38 (s, 2H), 4.02 (d, J = 13.6 Hz, IH), 3.59 (s, 3H), 3.21 (d, J = 13.6 Hz, IH), 1.52 (s, 3H); ESIMS calcd. for C23H22FN4O2 ([M+H]+) 405.2, found 405.2.
Example P22
(R)-methyl 2-(2-amino-3-(4-nitrophenyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3- fluorophenvl)-2-methylpropanoate
Figure imgf000214_0001
[00356] By following a similar procedure to Example P21, except substituting 2-
(4-nitrophenyl)malononitrile for 2-phenyl malonitrile in Step A, Example P22 is prepared; 1U NMR (CDCl3, 400 MHz): δ 8.27 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 4.4 Hz, IH), 8.04 (d, J = 8.4 Hz, 2H), 6.97 (m, IH), 6.78 (m, IH), 6.29 (m, IH), 6.26 (d, J= 4.4 Hz, IH), 6.20 (d, J = 7.6 Hz, IH), 3.99 (d, J = 13.6 Hz, IH), 3.59 (s, 3H), 3.23 (d, J = 13.6 Hz, IH), 1.55 (s, 3H); ESIMS calcd. for C23H2iFN5O4 ([M+H]+) 450.2, found 450.2.
Biological Assays
[00357] Generation of Stable Cell Line
[00358] FIp-In-CHO cells (Invitrogen, Cat.# R758-07) are maintained in Ham' s
F12 medium supplemented with 10% fetal bovine serum, 1% antibiotic mixture and 2mM L-glutamine. The cells are transfected with a DNA mixture containing human GPRl 19 in pcDNA5/FRT vector and the pOG44 vector (1:9) using Fugeneό (Roche), according to the manufacturer's instruction. After 48 hours, the medium is changed to medium supplemented with 400μg/ml hygromycin B to initiate the selection of stably transfected cells.
[00359] Cyclic AMP Assay in Stable Cell Line
[00360] To test the activity of compounds of the invention, Flp-In-CHO-hGPRl 19 cells are harvested and resuspended in DMEM plus 3% lipid-depleted fetal bovine serum.
Forth μl of cells are plated in 384 well plates at a density of 15,000 cells/well. IBMX (3- isobutyl-1-methyl-xanthine) is added to the cells to a final concentration of ImM, followed by the addition of 500nl of the compound to be tested. The cells are incubated at
37°C for 30 minutes. Equal volume (20μl) of the HTRF reagents, anti-cAMP-Cryptate and cAMP-XL665, are added to the cells. The plates are incubated at room temperature for 1 hour and read on a HTRF reader according to the manufacturer's instruction.
[00361] Compounds of Formula I, in free form or in pharmaceutically acceptable salt form, produced a concentration-dependent increase in intracellular cAMP level. Compound of the invention show an EC50 of between IxIO"5 and Ix 10"10M, preferably less than 50OnM, more preferably less than 10OnM.
[00362] For example, compounds of the invention show EC50 values according to the following table:
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
[00363] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.
999

Claims

WE CLAIM:
1. A compound selected from Formula I:
Figure imgf000224_0001
in which:
Ri is selected from d ioalkenyl, C6-1OaTyI, C6-ioaryl-C2-3alkynyl, C1- gheteroaryl, acetylenyl, C^sheterocycloalkyl, C^heterocycloalkenyl, C3-6cycloalkyl, C3- 6cycloalkyl-C2-3alkynyl, C3-6cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of Ri is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, C1-4alkyl, halo-substituted-C1-4alkyl, Ci-4alkoxy, halo-substituted-Ci-4alkoxy, C6-10aryl, C1-9heteroaryl, C3_8heterocycloalkyl, C3-10cycloalkyl, -C(O)OR7, -C(O)R7, - NR7Rg, -S(O)1-2R7; wherein said alkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of Ri is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted C1-4alkyl and C1-4alkoxy; wherein R7 is selected from hydrogen, C1-6alkyl, C3_iocycloalkyl optionally substituted with C1-6alkyl or halo; and R8 is -XiR9; wherein Xi is selected from a bond and Ci_4alkylene optionally substituted with halo; and R9 is selected from hydrogen, phenyl and pyridinyl; wherein said phenyl or pyridinyl of R9 is optionally substituted with 1 to 3 trifluoromethyl radicals;
Y5 is N and Y6 is CR2; or Y5 is CR2 and Y6 is N;
R2 is selected from hydrogen, C1-6alkyl, Ci-βalkoxy, halo-substituted-Ci- ealkyl, halo-substituted-Ci-6alkoxy, -X5S(O)0-2Ri0a, -XsORiOa, -XsNRiOa XsRiob, - X5S(0)o-2NRioaRiob, -X5NRiOaRiOb, -X5C(O)NRiOaRiOb, -X5NRiObC(O)RiOa and - X5C(0)ORioa; wherein said X5 is selected from a bond and Ci_4alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, cyano, C6-1OaTyI, C3- locycloalkyl, heteroaryl or heterocycloalkyl; and Rioa and Riob are independently selected from hydrogen, C1-4alkyl, Ci_4alkoxy, C6-1oaryl, Ci-gheteroaryl and C3.
gheterocycloalkyl; or Rioa and Riob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C1-4alkyl, halo-substituted-Cμ 4alkyl, Cμ4alkoxy, halo-substituted-Ci-4alkoxy, C6-1oaryl,
Figure imgf000225_0001
C3- sheterocycloalkyl, C3-10cycloalkyl, -C(O)OR10c, -C(O)R10c, -NRioc R1Od,
Figure imgf000225_0002
wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1- 4alkyl, halo-substituted C1-4alkyl and C1-4alkoxy; wherein Rioc and Riod are selected from hydrogen, C1-6alkyl, C3-iocycloalkyl optionally substituted with C1-6alkyl or halo;
R3 is selected from cyano, -C(O)ORi la, -C(O)R1 la, -X2OC(O)R1 la, -
C(0)0X2Rlla, -X2OS(0)o-2Rna, -X2S(O)0-2R1U, -C(O)OX2OR1 la, -C(O)OX2NR1 laRllb, -C(O)NRiiaRiib, -X2NRiiaRiib, -C(O)OX2C(O)NRi laRllb, -NRl laC(0)Rl lb, - NRiiaC(0)0Rnb, -NRiiaS(0)o-2Riib, -C(O)NX2Ri iaX2Riib, -C(0)NRllaX20Rl lb, - C(O)N RiiaX2C(0)0Riib, -C(O)NRi iaX2C(O)NRiiaRiib, -C(O)N RiiaX2OX2ORiib, - X2RiIb; wherein each X2 is independently selected from a bond and Ci_4alkylene;
wherein any methylene of X2 can have a hydrogen substituted with hydroxy; R1 la and Rub are independently selected from hydrogen, cyano, C1-4alkyl, C1-4alkoxy, C6-1oaryl, Ci-gheteroaryl, Q.gheterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or Rl la and Rub together with the nitrogen atom to which they are both attached form a cyclic group selected from azetidine, pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said azetidine, pyrrolidine, pyrrolidin-2-one-l-yl or morpholinyl of the combination of R1 la and R1 ^ is optionally substituted with hydroxyl;
R4 is selected from hydrogen, C1-4alkyl, C1-4alkenyl, C6-ioarylCi_4alkyl, -
X3ORi2, -X3NRi2Ri2 and -X3C(O)ORi2; wherein X3 is selected from a bond and C1- 4alkylene; and each Ri2 is independently selected from hydrogen and C1-4alkyl; or when -Y2R5 is benzyl, the ortho hydrogen of R5 and R4 can form a cyclopentyl;
R5 is selected from hydrogen, C1-4alkyl, C6-1OaTyI, Ci-gheteroaryl, C3.
gheterocycloalkyl; wherein said alkyl, aryl, heteroaryl or heterocycloalkyl of R5 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, - S(0)o-2Ri3a, halo-substituted-C1-4alkyl, C1-4alkyl, halo-substituted-Ci-4alkoxy, Ci_4alkoxy,
Cό-ioaryl, -C(O)NRi3aRi3b and -C(O)ORi3a; wherein Ri3a and R13b are independently selected from hydrogen and Ci-4alkyl;
Yi and Y3 are independently selected from CH and N; or -Y3=Yi- is replaced with S;
Y2 is selected from a bond, CH2, C(O), NRn and O; wherein Rn is selected from hydrogen, halo-substituted-Ci-4alkyl and C1-4 alkyl; or R4 and Y2 taken together form a double bond or a cyclopropyl ring;
Y4 is selected from N and -CR6; wherein R6 is selected from hydrogen, halo, cyano, C1-
6alkyl, X4NRi4aRi4b, X4OR1^; wherein X4 is selected from a bond, Ci-6alkylene; and Ri4a and Ri4b are independently selected from hydrogen and C1-4alkyl; with the proviso that when Y4 is N, Yi is CH; and the pharmaceutically acceptable salts thereof.
2. The compound of claim 1 selected from Formula Ia, Ib and Ic:
Figure imgf000226_0001
Ia Ib Ic in which:
n is selected from 1, 2 and 3;
Ri is selected from C2-1oalkenyl, C6-1OaTyI, C6-ioaryl-C2-3alkynyl, C1- gheteroaryl, acetylenyl, C3-8heterocycloalkyl, C3-8heterocycloalkenyl, C3-6cycloalkyl, C3-
6cycloalkyl-C2-3alkynyl, C3-6cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of Ri is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, C1-4alkyl, halo-substituted-Ci-4alkyl, C^alkoxy, halo-substituted-Ci-4alkoxy, C6-10aryl, C1-9heteroaryl, C3-8heterocycloalkyl, C3-10cycloalkyl, -C(O)OR7, -C(O)R7, - NR7R8, -S(O)1-2R7; wherein said alkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of Ri is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted C1-4alkyl and C1-4alkoxy; wherein R7 is selected from hydrogen, C1-6alkyl, C3-iocycloalkyl optionally substituted with C1-6alkyl or halo; and R8 is selected from -X1R9; wherein Xi is selected from a bond and Ci-4alkylene optionally substituted with halo; and R9 is selected from phenyl and pyridinyl; wherein said phenyl or pyridinyl of R9 is optionally substituted with 1 to 3 trifluoromethyl radicals;
R2 is selected from hydrogen, C1-6alkyl, Ci-βalkoxy, halo-substituted-Ci-
6alkyl, halo-substituted-Ci_6alkoxy, -X5S(O)O2RiOa, -X5ORiOa, -X5NRiOa X5RiOb, - X5S(0)0-2NRioaRiob, -X5NRiOaRiOb, -X5C(O)NRiOaRiOb, -X5NRiObC(O)RiOa and - X5C(O)ORiOa; wherein said X5 is selected from a bond and Ci-4alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, cyano, Cό-ioaryl, C3- locycloalkyl, heteroaryl or heterocycloalkyl; and RiOa and RiOb are independently selected from hydrogen, C1-4alkyl, cyano-substituted-C1-4alkyl, C1-4alkoxy, phenyl, azetidinyl, imidazolyl and pyrazolyl; or Rioa and Riob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system of R1Oa, Riob or the combination of RiOa and Riob can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C1-4alkyl, halo-substituted-C^alkyl, C1-4alkoxy, halo- substituted-Ci-4alkoxy, C6-1oaryl, C1-9heteroaryl, C3-8heterocycloalkyl, C3-1ocycloalkyl, - C(O)ORiOc, -C(O)RiOc, -NRioc R1Od, -S(O)1-2R1Oc; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted C1-4alkyl and Ci-4alkoxy; wherein Rioc and Riod are selected from hydrogen, C1-6alkyl, C3- iocycloalkyl optionally substituted with C1-6alkyl or halo;
R3 is selected from cyano, -C(O)OR1 la, -C(O)R1 la, -X2OC(O)R1 la, -
C(0)0X2Riia, -X2OS(0)o-2Rlla, -X2S(O)0-2RlIa, "C(O)OX2ORiIa, -C(O)OX2NRiIaRlIb,
-C(O)NRiiaRiib, -X2NRiIaRiIb, -NRiiaC(O)Riib, -NRiiaC(0)0Riib, -NR1 US(O)0-2R1 lb, -C(O)NX2RiIaX2RiIb, -C(O)OX2C(O)NRiIaRiIb, -C(0)NRllaX20Rllb, - C(O)NRiiaX2C(O)ORnb, -C(O)NRi iaX2C(O)NRnaRnb, -C(O)NRi iaX2OX2ORnb, - X2RiIb; wherein each X2 is independently selected from a bond and Ci-4alkylene;
wherein any methylene of X2 can have a hydrogen substituted with hydroxy; Ri ia and Rub are independently selected from hydrogen, cyano, Ci_4alkyl, Ci_4alkoxy, Cό-ioaryl, Ci-gheteroaryl, Q.gheterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or Rna and Rub together with the nitrogen atom to which they are both attached form a cyclic group selected from azetidine, pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said azetidine, pyrrolidine, pyrrolidin-2-one-l-yl or morpholinyl of the combination of Ri ia and Ri ib is optionally substituted with hydroxyl;
R4 is selected from hydrogen, Ci-4alkyl, Ci-4alkenyl,
Figure imgf000228_0001
-
X3ORi2, -X3NRi2Ri2 and -X3C(O)ORi2; wherein X3 is selected from a bond and Ci_ 4alkylene; and each Ri2 is idependently selected from hydrogen and Ci_4alkyl;
Re is selected from hydrogen, halo, cyano, Ci-6alkyl, X4NRi4aRi4b, X4ORi4a; wherein X4 is selected from a bond, Ci-βalkylene; and Ri4a and Ri4b are independently selected from hydrogen and Ci_4alkyl;
Ri8 is selected halo, cyano, -S(0)o-2Ri3a,halo-substituted-Ci_4alkyl, Ci_4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, C6-ioaryl, -C(O)NRi8aRi8b and -C(0)0Ri8a; wherein Riga and Rigb are independently selected from hydrogen and Ci-4alkyl; and Y2 is selected from CH2, C(O) and NR17; wherein Ri7 is selected from hydrogen and methyl.
3. The compound of claim 2 in which Ri is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, benzimidazolyl, styryl, l,2,4-oxadiazol-5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, or l,2,3,6-tetrahydropyridin-4-yl of Ri is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy-carbonyl, methyl-sulfonyl, t-butoxy-carbonyl, dimethyl- amino, 2-hydroxypropan-2-yl, 2- fluoropropan-2-yl, 1-phenylethylamino, (l-methylcyclopropoxy)carbonyl, t-butyl, (6- (trifluoromethyl)pyridin-3-yl)methyl-amino, 6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl, phenyl, pyridinyl, cyclohexyl and cyclopropyl; wherein said cyclohexyl or cyclopropyl substituent of Ri is optionally substituted with a radical selected from hydroxy, halo, isopropyl and methyl.
4. The compound of claim 3 in which R3 is selected from: cyano; ethoxy-methyl; (2- methoxyethyl)(methyl)carbamoyl; (tetrahydro-2H-pyran-4-yloxy)carbonyl;
(ethyl)(methyl)carbamoyl; (4-hydroxybutoxy)carbonyl; hydroxy-propyl-carbamoyl; thiazolyl-methyl; pyrazinyl-methyl; pyridinyl-methyl; (2-(dimethylamino)-2- oxoethyl)(methyl)carbamoyl; (2-(2-oxopyrrolidin- l-yl)ethoxy)carbonyl; 3- hydroxypyrrolidine-1-carbonyl; (carboxymethyl)(methyl)carbamoyl; (2,3- dihydroxypropyl)(methyl)carbamoyl; tetrahydrofuran-3-ylcarbamoyl; ((1-methyl-lH- imidazol-4-yl)methoxy)carbonyl; (azetidin-3-ylmethoxy)carbonyl; (2-hydroxy-3- (methylamino)propoxy)carbonyl; dimethoxy-ethyl-carbamoyl,
(cyanomethyl)(methyl)carbamoyl; pyrazolyl-methyl optionally substituted with methyl; methoxy-carbonyl; methoxy-ethyl-carbamoyl; carbamoyl-methoxy-carbonyl; (methoxy- propoxy-ethyl)(methyl)carbamoyl; (methoxy-ethoxy-ethyl)(methyl)carbamoyl; 3- hydroxyazetidine- 1-carbonyl; (methoxy-propyl)(methyl)carbamoyl; ethoxy-carbonyl; (furan-2-ylmethyl)(methyl)carbamoyl; (morpholino-methyl)(methyl)carbamoyl; 5- methyloxazol-2-yl); (2-methoxyethoxy)carbonyl; butyl(methyl)carbamoyl; dimethyl- amino-carbonyl; isopropyl-carbamoyl; (propyl)(methyl)carbamoyl; (ethyl)methyl-amino- carbonyl; methyl((tetrahydrofuran-2-yl)methyl)carbamoyl; (2-methoxy-2- oxoethyl)(methyl)carbamoyl; methoxy-ethyl-carbamoyl; methoxy-propoxy-carbonyl; methoxy-butoxy-carbonyl; (cyanomethyl)(methyl)carbamoyl; hydroxy-ethoxy-carbonyl, hydroxy-ethoxy-ethyl-carbamoyl; (hydroxy-propyl)(methyl)carbamoyl;
(hydroxyethyl)(methyl)carbamoyl; acetamido, isobutyramido;
(hydroxypropyl)(methyl)carbamoyl; isopropoxy-carbonyl; ethyl-carbamoyl; dimethoxy- ethyl-carbamoyl; hydroxy-ethoxy-carbonyl; hydroxy-propoxy-carbonyl; (methoxy- ethoxy-ethyl)(methyl)carbamoyl; butyl-carbamoyl; carbamoyl-methoxy-carbonyl; (methoxy-carbonyl-methyl)(methyl)carbamoyl; (methoxyethyl)(methyl)carbamoyl; pyrrolidine- 1-carbonyl; hydroxy-ethyl-carbamoyl; methoxy-carbonyl-ethyl-carbamoyl; morpholino-methyl; t-butoxy-carbonyl; (tetrahydro-2H-pyran-4-yloxy)carbonyl;
morpholino-ethoxy-carbonyl; morpholino-propoxy-carbonyl; 3-hydroxyazetidine- 1- carbonyl; methyl-sulfonyl; (2,3-dihydroxypropyl)(methyl)carbamoyl; ethyl-amino- carbonyl; carbamoyl; (methoxy-carbonyl-methyl)(methyl)carbamoyl; tetrahydrofuran- 3-yl-carbamoyl; 5-methyl-l,3,4-oxadiazol-2-yl; 1,2,4-oxadiazole optionally substituted with methyl; ((l-methyl-lH-imidazol-4-yl)methoxy)carbonyl; methoxy-propyl- carbamoyl; (methyl-sulfonyl-oxy)methyl; methyl-sulfonyl- amino; (azetidin-3- ylmethoxy)carbonyl; (2-hydroxy-3-(methyl-amino)propoxy)carbonyl; hydroxy-butyl- carbamoyl; dimethyl-amino-methyl; dimethyl-amino-carbonyl-methyl-carbamoyl; benzoxy-carbonyl; methoxy-carbonyl-methyl-carbamoyl; oxazolyl optionally substituted with methyl; (2H-l,2,3-triazol-2-yl)methyl; (dimethyl-amino-carbonyl- methyl)carbamoyl; (lH-pyrazol-l-yl)methyl; (oxetan-3-yloxy)carbonyl; dimethyl- amino-propoxy-carbonyl; acetoxy- methyl; 3-hydroxy-pyrrolidine- 1 -carbonyl;
(carboxy-methyl)(methyl)carbamoyl; (2-(2-oxopyrrolidin-l-yl)ethoxy)carbonyl;
(oxetan-3-yloxy)carbonyl; (carbamoyl-methyl)(methyl)carbamoyl; morpholino- carbonyl; (2H-tetrazol-2-yl)methyl; methyl((3-methyloxetan-3-yl)methyl)carbamoyl; and 5-methyl-lH-l,2,4-triazol-3-yl.
5. The compound of claim 4 selected from: (2R)-N-(2-methoxyethyl)-N,2-dimethyl-3- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; A- hydroxybutyl (2R)-2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; ethyl (2R)-2-{6-chloro-3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl} -2-methyl-3-phenylpropanoate; (2R)-N-(2-methoxyethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl (2R)-2- methyl-2-{6-methyl-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-3- phenylpropanoate; (2R)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2- methoxyethyl)-N,2-dimethyl-3-phenylpropanamide; (2R)-N-(furan-2-ylmethyl)-N,2- dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; ethyl (2R)-2-{6-cyano-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; methyl (2S)-2-methyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl (2R)-2- { 6- chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; ethyl 2- { 6-chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; N-(2-methoxyethyl)-N,2-dimethyl-3- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 2-{3-[4-(l-fluorocyclohexyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; ethyl 2-methyl-3-phenyl-2-{3-[4-
(trifluoromethoxy)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2-methoxyethyl 2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-methyl- 3 -phenyl-2- { 3 - [4- (propan-2- yl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yljpropanoate; N-butyl-N,2-dimethyl-3-phenyl-2-{ 3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl (2S ) -2- [3 - (4- bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-{6- cyano-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; ethyl 2-[6-chloro-3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]- 2-methyl-3-phenylpropanoate; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N- (2-methoxyethyl)-N,2-dimethyl-3-phenylpropanamide; ethyl (2S)-2-[3-(4- bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 3-(3- fluorophenyl)-2-methyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; ethyl (2E)-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}prop-2-enoate; 4-hydroxybutyl 2-methyl-3 -phenyl-2- { 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl (2R)-2-methyl- 3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (2R)-2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin- 7-yl}propanoate; (2R)-N,N,2-trimethyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 3-(3- cyanophenyl)-2-methyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-2-{3-[4-(l-methylcyclopropyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-3-phenylpropanoate; ethyl 3-(3,5-difluorophenyl)-2-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; N,2-dimethyl-3- phenyl-N-propyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; ethyl (2S)-2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methyl-3-phenylpropanoate; methyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- phenyl-2-[3-(4-phenylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; N-(furan-2- ylmethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; N,2-dimethyl-N-(oxolan-2-ylmethyl)-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-methyl-3- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl 2-[(2R)-2-benzyl-N-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamido] acetate; ethyl 3-(3-chlorophenyl)-2-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- phenyl-2-{3-[6-(trifluoromethyl)pyridin-3-yl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3-(3-methylphenyl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-ethyl-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl 2- { 3 - [4- (difluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- phenylpropanoate; ethyl 2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl- 3-phenylpropanoate; ethyl 2-[3-(4-chlorophenyl)-6-fluoropyrazolo[l,5-a]pyrimidin-7- yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin- 7-yl]-3-phenylpropanoate; N,N,2-trimethyl-3-phenyl-2-{ 3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ethyl (2S ) -2- [3 - (4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; 3- hydroxypropyl 2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4-chloro-2-methylphenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-3-phenylpropanoate; ethyl 2-[3-(4-chloro-2- methylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl (2S)- 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; methyl 2-(2-benzyl-N-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanamido)acetate; ethyl 3-(3-bromophenyl)-2-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2-{3- [4-(2-fluoropropan-2-yl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; 3-methoxypropyl 2-methyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl (2Z)-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}prop-2-enoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(furan-2-ylmethyl)-N,2-dimethyl-3- phenylpropanamide; N-(2-methoxyethyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-[3-(4- cyclopropylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl (2S)-2-methyl-2-[3-(4-nitrophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; N-(3-methoxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl (lS,2S)-l-{3- [2-nitro-4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2- phenylcyclopropane-1-carboxylate; ethyl 3-(3-methoxyphenyl)-2-methyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- phenyl-2-(3-{ 1 -[4-(trifluoromethyl)phenyl]- 1 ,2,3,6-tetrahydropyridin-4-yl }pyrazolo[ 1 ,5- a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-2-[3-(4-methylphenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-3-phenylpropanoate; N-(cyanomethyl)-N,2-dimethyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; N-(2- hydroxyethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; propan-2-yl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-ethyl-2-methyl-3-phenylpropanamide; N,N-bis(2-methoxyethyl)-2-methyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-methyl-3- phenyl-2-(3-{4-[(l-phenylethyl)amino]phenyl}pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; 2-hydroxyethyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; N- [2- (2- methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-[3-(4-tert- butylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; N-[2-(3- methoxypropoxy)ethyl] -N,2-dimethyl-3-phenyl-2- { 3- [4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; N-butyl-2-methyl- 3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; (2R)-N-[2-(2-methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(3-methylphenyl)propanoate; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N,N,2-trimethyl-3- phenylpropanamide; ethyl 2-methyl-3-phenyl-2- { 3-[6-(trifluoromethyl)- IH- 1 ,3- benzodiazol-2-yl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-{3-[(E)-2-(4- chlorophenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-3-phenylpropanoate;
carbamoylmethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3-phenyl-2-{3-[4-({ [6- (trifluoromethyl)pyridin-3-yl]methyl}amino)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-3-phenyl-2-[3-(l-phenyl-l,2,3,6-tetrahydropyridin-4- yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; ethyl (lS,2R)-2-phenyl-l-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}cyclopropane- 1 -carboxylate; ethyl (2R)-2-[3-(4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- phenylpropanoate; methyl 2- { 2-benzyl-2- [3-(4-chlorophenyl)pyrazolo[ 1 ,5-a]pyrimidin- 7-yl]-N-methylpropanamido} acetate; N-[2-(2-hydroxyethoxy)ethyl]-2-methyl-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 2-[3- (4-chlorophenyl)-2-methylpyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; ethyl 2- [3-(6-chloropyridin-3-yl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N,2-dimethyl-3-phenyl-N- propylpropanamide; ethyl 2-{3-[4-(l-hydroxycyclohexyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; 4-methoxybutyl 2-methyl-3-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (1S,2R)- 2-phenyl-l-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}cyclopropane- 1 -carboxylate; ethyl 2-methyl-3-[3-(trifluoromethyl)phenyl]-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (lR,2S)-2- phenyl-l-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}cyclopropane-l- carboxylate; (2S)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2- methoxyethyl)-N,2-dimethyl-3-phenylpropanamide; ethyl 2-methyl-3-phenyl-2-{ 3-[4- (pyridin-3-yl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 1-ethyl 4-methyl 2- benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]butanedioate; ethyl 2-[3-(4- methoxyphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; N-(3- hydroxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; N-[(2R)-l-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propan-2- yl] acetamide ; 2- methyl-3-phenyl-N-(propan-2-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; N-[(lR)-2-phenyl-l-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } ethyl] acetamide ; ethyl 2-benzyl- 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]pent-4-enoate; 2-[3-(4- chlorophenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl] -2-methyl-3-phenyl- 1 -(pyrrolidin- 1 - yl)propan-l-one; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2- hydroxyethyl)-2-methyl-3-phenylpropanamide; 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-N-(2-methoxyethyl)-2-methyl-3-phenylpropanamide; N-ethyl-2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- (2-methylphenyl)propanoate; methyl 3-(2-benzyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamido)propanoate; ethyl 3-(3,4-difluorophenyl)-2-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; tert-butyl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; (2S)-N-(2- methoxyethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; oxan-4-yl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4- fluorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 3-(2- chloro-6-fluorophenyl)-2-[3-(4-chlorophenyl)-2-methylpyrazolo[l,5-a]pyrimidin-7- yl]propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(4- methylphenyl)propanoate; ethyl (lS,2R)-l-{3-[2-nitro-4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-phenylcyclopropane-l- carboxylate; ethyl 3-(3,5-dimethylphenyl)-2-methyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3-[3- (trifluoromethoxy)phenyl] -2- { 3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; 2-(morpholin-4-yl)ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin- 7-yl]-2-methyl-3-phenylpropanoate; N-[(lR)-2-phenyl-l-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } ethyl] acetamide ; ethyl 2-methyl- 3-phenyl-2-[3-(pyridin-2-yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; l-(3- hydroxyazetidin- 1 - yl) -2-methyl-3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propan- 1-one; methyl (2R)-2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; 1 ,3-diethyl 2-benzyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanedioate; ethyl 2- methyl-3 -phenyl-2- {3-[(E)-2-[4- (trifluoromethyl)phenyl] ethenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propanoate; 1-methylcyclopropyl 4-[7-(2-benzyl-l-ethoxy-l- oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin-3-yl]-l,2,3,6-tetrahydropyridine-l- carboxylate; ethyl 2-{3-[(lE)-hex-l-en-l-yl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; N-(2,3-dihydroxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-[3-(2- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2- benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]pentanoate; ethyl 2-[3-(3- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; ethyl 2- methyl-2-[3-(5-methylpyrazin-2-yl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; methyl 3-(2-chloro-6-fluorophenyl)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7- yl]propanoate; ethyl 3-phenyl-2-{3-phenylpyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-ethyl-2-methyl-3- phenylpropanamide; ethyl 2- { 3-[4-(2-hydroxypropan-2-yl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4- foraiylphenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; tert-butyl 4- [7-(2-benzyl- l-ethoxy-l-oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin-3-yl]- 1,2,3,6- tetrahydropyridine- 1-carboxylate; ethyl 3-(2-chloro-6-fluorophenyl)-2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; methyl 2-[(2S)-2-benzyl-N- methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamido] acetate; 2-methyl-N-(oxolan-3-yl)-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 2-methyl-5-(l- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propan-2-yl)- 1 ,3,4-oxadiazole; ( 1 -methyl- lH-imidazol-4-yl)methyl 2-methyl-3-phenyl-2- { 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-{3-[(E)-2-(4- chlorophenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3-phenylpropanoate; 7- (2-methanesulf onyl- 1 -phenylprop an-2-yl)-3-[4- (trifluoromethyl)phenyl] pyrazolo [1,5- a] pyrimidine ; methyl N- [ ( 1 S ) -2-phenyl- 1 - { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}ethyl]carbamate; ethyl 2-benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-3-methoxypropanoate; N-(3-methoxypropyl)-2-methyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl (2R)-2-[3- (4-bromophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-phenylpropyl
methanesulfonate; 5-methyl-2-(l-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propan-2-yl)-l,3-oxazole; (2S)-N-(2-methoxyethyl)-N,2-dimethyl-3- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl (2S)-2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanoate; azetidin-3-ylmethyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; 2-hydroxy-3- (methylamino)propyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-(4-hydroxybutyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-methyl-3- phenyl-2-(3-{2-[4-(trifluoromethyl)phenyl]ethynyl}pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; 3-methyl-5-( l-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl }propan-2-yl)- 1 ,2,4-oxadiazole; { 2- [3-(4-chlorophenyl)pyrazolo[ 1 ,5- a]pyrimidin-7-yl]-2-methyl-3-phenylpropyl}dimethylamine; benzyl 2-methyl-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl 2-(2- benzyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl}propanamido)acetate; 5-( l-phenyl-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l, 5- a]pyrimidin-7-yl}propan-2-yl)-l,3-oxazole; methyl 3-(3-ethoxy-2-methyl-3-oxo-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propyl)benzoate; 2- { 2-benzyl-2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propyl}-2H-l,2,3-triazole; N- [(dimethylcarbamoyl)methyl] -2-methyl-3-phenyl-2- { 3- [4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; ethyl 2-{3-[6- (dimethylamino)pyridin-3-yl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; N-( l-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propan-2-yl)acetamide; 3-(morpholin-4-yl)propyl 2-methyl-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2- methyl-3-phenyl-2-[3-(pyridin-4-yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; ethyl 2- {3-[(E)-2-(4-fluorophenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; methyl N-[(lR)-2-phenyl-l-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}ethyl]carbamate; N-[(lS)-2- phenyl- l-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}ethyl]acetamide; ethyl 2-{3-[(E)-2-(4-methoxyphenyl)ethenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; l-{2-benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7- yl]propyl}-lH-pyrazole; oxetan-3-yl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl (2S)-2-{6- chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2-methyl-3- phenylpropanoate; 3-(dimethylamino)propyl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- phenyl-2-{3-[4-(pyridin-4-yl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 1- methylcyclopropyl 4-[7-(2-benzyl-l-ethoxy-l-oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin- 3-yl]piperidine-l-carboxylate; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methyl-3-phenylpropyl acetate; N-[(lR)-2-phenyl-l-{3-[4-
(trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } ethyl] methanesulf onamide ; 3 - { 1 - [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-phenylethyl}-5-methyl- 1,2,4- oxadiazole ; 4-methyl-2- ( 1 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propan-2-yl)-l,3-oxazole; ethyl (2S)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; 4-hydroxybutyl (2S)- 2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yljpropanoate; ethyl 2-methyl-2-{3-[(E)-2-(4-methylphenyl)ethenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-3-phenylpropanoate; ethyl 2-benzyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; N- (3 - hydroxypropyl)-2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; N-[(dimethylcarbamoyl)methyl]-N,2-dimethyl-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 4-{2- benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propyl}morpholine; ethyl 2- [3-(cyclohex-l-en-l-yl)-2-methylpyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanoate; (2S)-N,N,2-trimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; 2-(dimethylamino)ethyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-phenylpropanenitrile; tert-butyl 4-[7-(2- benzyl-l-ethoxy-l-oxopropan-2-yl)pyrazolo[l,5-a]pyrimidin-3-yl]piperidine-l- carboxylate; ethyl (2R)-2-{6-[(dimethylamino)methyl]-3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl} -2-methyl-3-phenylpropanoate; ethyl ( 1 S ,2S ) -2-phenyl- 1 - { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yljcyclopropane-l-carboxylate; ethyl 2-methyl-3-phenyl-2-{3-[3-(propan-2-yl)- 1,2,4- oxadiazol-5-yl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; l-(3-hydroxypyrrolidin-l-yl)- 2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yl}propan-l-one; 2-(2-benzyl-N-methyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamido)acetic acid; ethyl 2-methyl-3-phenyl-2-[3-(2- phenylethynyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; 2-(2-oxopyrrolidin-l-yl)ethyl 2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yljpropanoate; 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; methyl 4-[7-(2-benzyl-l-ethoxy-l-oxopropan-2- yl)pyrazolo[l,5-a]pyrimidin-3-yl]piperidine-l-carboxylate; 5-methyl-3-(l-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl }propan-2-yl)- IH-1 ,2,4- triazole; ethyl 3-(2-chloro-6-fluorophenyl)-2-[3-(4-methanesulfonylphenyl)pyrazolo[l,5- a]pyrimidin-7-yl]propanoate; 2-[(2-methyl-3-phenyl-2-{ 3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoyl)oxy]acetic acid; N- (carbamoylmethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl Jpropanamide; 2-methyl- 1 - (morpholin-4-yl)-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yl}propan-l-one; ethyl 2-methyl-3-phenyl-2-[3-(pyridin-4-yl)pyrazolo[l,5-a]pyrimidin- 7-yl]propanoate; 2-{2-benzyl-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7- yl]propyl}-2H-l,2,3,4-tetrazole; 3-(4-chlorophenyl)-7-(l-ethoxy-2-methyl-3- phenylpropan-2-yl)pyrazolo[l,5-a]pyrimidine; ethyl 2-methyl-3-phenyl-2-[3-(pyrimidin- 5-yl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; N,2-dimethyl-N-[(3-methyloxetan-3- yl)methyl] - 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl Jpropanamide; N-(2-hydroxyethyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; ethyl 2-methyl-3- phenyl-2-(3-{2-[3-(trifluoromethyl)phenyl]ethynyl}pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; Ethyl 3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5- α]pyrimidin-7-yl)acrylate; (Trans)-ethyl 2-phenyl- 1-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)cyclopropanecarboxylate; (Cis)- ethyl l-(3-(2-nitro-4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-2- phenylcyclopropanecarboxylate; (Trans)-ethyl l-(3-(2-nitro-4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)-2- phenylcyclopropanecarboxylate; Ethyl 2-(6-cyano-3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; 2- Methyl- l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7- yl)propan-l-one; Ethyl 2-(6-bromo-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- α]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; 2-(3-(4-Chlorophenyl)pyrazolo[l,5- α]pyrimidin-7-yl)-2-methyl-3-phenylpropyl acetate; Ethyl 2-(methyl(phenyl)amino)-2- (3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; Methyl 3- amino-2-benzyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7- yl)propanoate; Ethyl 2-(3-cyclohexenyl-2-methylpyrazolo[l,5-α]pyrimidin-7-yl)-3- phenylpropanoate; Ethyl 2-benzyl-3-phenyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; diethyl 2-benzyl-2- (3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)malonate; 7-(2- (methylsulfonyl)- 1 -phenylpropan-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5- a]pyrimidine; Ethyl 3-(3-fluorophenyl)-2-methyl-2-(2-methyl-3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; Ethyl 2-methyl-3- phenyl-2-(3-(phenylethynyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; Ethyl 2-methyl- 3-phenyl-2-(3-(phenylethynyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propanoate; ethyl 2- methyl-2-(3-(4-(l-methylcyclopropyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)-3- phenylpropanoate; ethyl 2-methyl-3-phenyl-2-(3-( l-(4-(trifluoromethyl)phenyl)- 1,2,3,6- tetrahydropyridin-4-yl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- phenyl-2-(3-(l-phenyl- 1,2,3, 6-tetrahydropyridin-4-yl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-phenyl-2-(3-(pyridin-2-yl)pyrazolo[ 1 ,5-a]pyrimidin-7- yl)propanoate; Ethyl 2-(3-(4-(2-hydroxypropan-2-yl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7- yl)-2-methyl-3-phenylpropanoate; Ethyl 2-(3-(4-(l- hydroxycyclohexyl)phenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-2-methyl-3- phenylpropanoate; Ethyl 2-(3-(4-(2-fluoropropan-2-yl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin- 7-yl)-2-methyl-3-phenylpropanoate; Ethyl 2-(3-(4-(l- fluorocyclohexyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; 2-(3-(4-chlorophenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)-3-phenylpropanenitrile; (R)-Ethyl 2-(6-cyano-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3- phenylpropanoate; (R)-Ethyl 2-methyl-2-(6-methyl-3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)-3-phenylpropanoate; (R)-Ethyl 2-(6-((dimethylamino)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7- yl)-2-methyl-3-phenylpropanoate; Ethyl 2-methyl-3-phenyl-2-(3-(6-(trifluoromethyl)- lH-benzo[d]imidazol-2-yl)pyrazolo[l,5-α]pyrimidin-7-yl)propanoate; iV-(l-Phenyl-2-(3- (4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propan-2-yl)acetamide; (R)-N- (l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)propan-2- yl)acetamide; (R)-N-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- α]pyrimidin-7-yl)propan-2-yl)butyramide; 4-(2-(3-(4-Chlorophenyl)pyrazolo[l,5- α]pyrimidin-7-yl)-2-methyl-3-phenylpropyl)morpholine; 5-(l-Phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propan-2-yl)oxazole; 4-Methyl-2- (l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)propan-2- yl)oxazole; 5-Methyl-2-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5- α]pyrimidin-7-yl)propan-2-yl)oxazole; 3-methyl-5-(l-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propan-2-yl)- 1 ,2,4-oxadiazole; 2- methyl-5-(l-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7- yl)propan-2-yl)-l,3,4-oxadiazole; Ethyl 3-(3,5-difluorophenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-m- tolyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2- methyl-3-(thiazol-4-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(pyrazin-2-yl)-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(l- methyl- lΗ-pyrazol-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(pyridin-3-yl)-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 3-(3,4- difluorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3,5-dimethylphenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 3-(3,4- difluorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3,5-dimethylphenyl)-2-methyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(3- (trifluoromethyl)phenyl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3-fluorophenyl)-2-methyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(3- (trifluoromethoxy)phenyl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3-methoxyphenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 3-(3- chlorophenyl)-2-methyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 3-(3-bromophenyl)-2-methyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; methyl 3-(3-ethoxy- 2-methyl-3-oxo-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propyl)benzoate; ethyl 3-(3-cyanophenyl)-2-methyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2-methoxyethyl)-N,2-dimethyl-3- phenylpropanamide; 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(furan-2- ylmethyl)-N,2-dimethyl-3-phenylpropanamide; methyl 2-{2-benzyl-2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-methylpropanamido}acetate; 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N,2-dimethyl-3-phenyl-N- propylpropanamide; 2-(morpholin-4-yl)ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2-methyl-3-phenylpropanoate; N-(2-methoxyethyl)-N,2-dimethyl-3- phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; N- butyl-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanamide; 4-hydroxybutyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; N,2-dimethyl-3- phenyl-N-propyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; methyl 2-methyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; N-(furan-2- ylmethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; N,2-dimethyl-N-(oxolan-2-ylmethyl)-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; N-ethyl-N,2- dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; N,N,2-trimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; 3-hydroxypropyl 2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yljpropanoate; methyl 2-(2-benzyl-N-methyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamido)acetate; 3- methoxypropyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-(2-methoxyethyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; N- (3 - methoxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; N-(cyanomethyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; N-(2- hydroxyethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; propan-2-yl 2-methyl-3-phenyl-2-{ 3- [4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; N,N-bis(2- methoxyethyl) -2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propanamide; N-[2-(2-methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 2- hydroxyethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-butyl-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; N-[2-(3- methoxypropoxy)ethyl] -N,2-dimethyl-3-phenyl-2- { 3- [4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; carbamoylmethyl 2-methyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 , 5 -a] pyrimidin-7 - yljpropanoate; N-[2-(2-hydroxyethoxy)ethyl]-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; 4-methoxybutyl 2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; N-(3-hydroxypropyl)-N,2-dimethyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; 2-methyl-3- phenyl-N-(propan-2-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanamide; methyl 3-(2-benzyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamido)propanoate; N-ethyl-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; tert-butyl 2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; oxan-4-yl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; 1 - (3 - hydroxyazetidin- 1 - yl) -2-methyl-3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [1,5- a]pyrimidin-7-yl}propan- 1-one; N-(2,3-dihydroxypropyl)-N,2-dimethyl-3-phenyl-2-{ 3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; N-(4- hydroxybutyl)-2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; 2-methyl-N-(oxolan-3-yl)-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propanamide ; ( 1 -methyl- IH- imidazol-4-yl)methyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; N-(3-methoxypropyl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; azetidin-3- ylmethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanoate; 2-hydroxy-3-(methylamino)propyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; 3-(morpholin-4- yl)propyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin- 7-yl}propanoate; methyl 2-(2-benzyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamido)acetate; benzyl 2-methyl-3-phenyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; N- [(dimethylcarbamoyl)methyl] -2-methyl-3-phenyl-2- { 3- [4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; oxetan-3-yl 2- methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; 3-(dimethylamino)propyl 2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; N- (3 - hydroxypropyl)-2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; N-[(dimethylcarbamoyl)methyl]-N,2-dimethyl-3-phenyl- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 2-(2- oxopyrrolidin- l-yl)ethyl 2-methyl-3 -phenyl-2- { 3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; 1 - (3 - hydroxypyrrolidin-l-yl)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } prop an- 1 - one ; 2- (dimethylamino)ethyl 2-methyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; 2-(2-benzyl-N-methyl-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamido)acetic acid;
(lR^^-Ethyl 2-phenyl-l-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7- y^cyclopropanecarboxylate; (S)-Ethy\ 2-(6-chloro-3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; (R)-ethyl 2-(6-chloro-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2- methyl-3-phenylpropanoate; (S)-Ethyl 2-(6-bromo-3-(4-
(trifluoromethyl)phenyl)pyrazolo[l,5-fl]pyrimidin-7-yl)-2-methyl-3-phenylpropanoate; (R)-ethyl 2-(6-bromo-3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-α]pyrimidin-7-yl)-2- methyl-3-phenylpropanoate; (tf)-N-(l-Phenyl-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)propan-2-yl)acetamide; ((R)- Ethyl 2-methyl-2-(3-(4-nitrophenyl)pyrazolo[ 1 ,5-α]pyrimidin-7-yl)-3-phenylpropanoate; methyl (2R)-2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; methyl (2S)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; (2R)-N,N,2- trimethyl- 3 -phenyl-2- { 3 - [4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yljpropanamide; (2S)-N,N,2-trimethyl-3-phenyl-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanamide; (2R)-N-(2- methoxyethyl)-N,2-dimethyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanamide; (2S)-N-(2-methoxyethyl)-N,2-dimethyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; (2R)-N-(furan- 2-ylmethyl)-N,2-dimethyl-3-phenyl-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanamide; methyl 2-[(2R)-2-benzyl-N-methyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamido]acetate; methyl 2- [(2S)-2-benzyl-N-methyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanamido] acetate; (2R)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N- (2-methoxyethyl)-N,2-dimethyl-3-phenylpropanamide; (2S)-2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-N-(2-methoxyethyl)-N,2-dimethyl-3- phenylpropanamide; (2R)-N-[2-(2-methoxyethoxy)ethyl]-N,2-dimethyl-3-phenyl-2-{3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanamide; 4-hydroxybutyl (2R)-2-methyl-3-phenyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; 4-hydroxybutyl (2S)-2-methyl-3-phenyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-2-{6- chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyramidin-7-yl}-3-(3-fluorophenyl)- 2-methylpropanoate; methyl (2S)-2-{6-chloro-3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl} -3-(3-fhiorophenyl)-2- methylpropanoate; (2R)-2-{6-chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-3-(3-fluorophenyl)-N-(2-methoxyethyl)-N,2-dimethylpropanamide; (2S)-2-{6-chloro-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-3-(3- fluorophenyl)-N-(2-methoxyethyl)-N,2-dimethylpropanamide; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7- yljpropanoate; methyl (2S)-3-(3-fhiorophenyl)-2-methyl-2-{3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2- { 2-methyl-3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; methyl (2R)-3-(3-fluorophenyl)-2-[2-(hydroxymethyl)-3- [4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]-2-methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-methyl-2-[2-(morpholin-4-ylmethyl)-3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl]propanoate; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2-{2-[(methylamino)methyl]-3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2-{2-[(phenylamino)methyl]-3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2-[2-(phenoxymethyl)-3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; methyl l-({7-[(2R)- 2-[(3-fluorophenyl)methyl]-l-methoxy-l-oxopropan-2-yl]-3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-2-yl}methyl)azetidine-3-carboxylate; methyl (2R)-3-(3-fluorophenyl)-2-[2-(lH-imidazol-l-ylmethyl)-3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]-2-methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-methyl-2-[2-(lH-pyrazol-l-ylmethyl)-3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl]propanoate; methyl (2R)-2-[2- (cyanomethyl)-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]-3-(3- fluorophenyl)-2-methylpropanoate; methyl (2R)-2-[2-(aminomethyl)-3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl] - 3 - (3 -fluorophenyl) -2- methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-[2-(methanesulfonylmethyl)-3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl]-2-methylpropanoate; 7-[(2R)-2- [(3-fluorophenyl)methyl] - 1 -methoxy- 1 -oxopropan-2-yl] -3- [4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidine-2-carboxylic acid; 2- { 7-[(2R)-2-[(3- fluorophenyl)methyl] - 1 -methoxy- 1 -oxopropan-2-yl] -3 - [4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-2-yl} acetic acid; methyl (2R)-3-(3- fluorophenyl)-2-methyl-2-[2-(methylsulfanyl)-3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl]propanoate; methyl (2R)-3-(3- fluorophenyl)-2-{2-methanesulfinyl-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}-2-methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-{2- methanesulfonyl-3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}-2- methylpropanoate; methyl (2R)-3-(3-fluorophenyl)-2-methyl-2-[2-(trifluoromethyl)-3-[4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl]propanoate; methyl (2R)-2- { 2- amino-3-phenylpyrazolo[l,5-a]pyrimidin-7-yl}-3-(3-fluorophenyl)-2-methylpropanoate; and methyl (2R)-2-[2-amino-3-(4-nitrophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-(3- fluorophenyl)-2-methylpropanoate.
6. The compound of claim 1 selected from Formula Id, Ie and If:
Figure imgf000247_0001
in which:
n is selected from 1, 2 and 3;
Ri is selected from C2-1oalkenyl, C6-1OaTyI,
Figure imgf000247_0002
acetylenyl, C3- gheterocycloalkyl, C3-8heterocycloalkenyl, C3-6cycloalkyl, C3-6cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of Ri is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, Ci-4alkyl, halo-substituted-Ci-4alkyl, Ci-4alkoxy, halo- substituted-Ci-4alkoxy, C6-1oaryl, Cμgheteroaryl, Ca-gheterocycloalkyl, C3_iocycloalkyl, - C(O)OR7, -C(O)R7, -NR7R8, -^S(O)1-2R7; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of Ri is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted C^alkyl and C1-4alkoxy;
wherein R7 is selected from hydrogen, Ci_6alkyl, C3_iocycloalkyl optionally substituted with Ci-βalkyl or halo; and Rg is selected from -X1Rg; wherein Xi is selected from a bond and Ci-4alkylene optionally substituted with halo; and Rg is selected from phenyl and pyridinyl; wherein said phenyl or pyridinyl of R9 is optionally substituted with 1 to 3 trifluoromethyl radicals;
R2 is selected from hydrogen, C1-6alkyl, Ci-βalkoxy, halo-substituted-Ci- ealkyl, halo-substituted-Ci-6alkoxy, -X5S(O)0-IRiOa, -X5ORi0a, -X5NRiOa X5RiOb, - X5S(O)0-INRiOaRiOb, -X5NRiOaRiOb, -X5C(O)NRiOaRiOb, -X5NRiObC(O)RiOa and - X5C(0)ORioa; wherein said X5 is selected from a bond and C1-4alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, C6-1oaryl, C3- locycloalkyl, heteroaryl or heterocycloalkyl; and Rioa and Riob are independently selected from hydrogen, C1-4alkyl and C1-4alkoxy; or RiOa and Riob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C1-4alkyl, halo-substituted-C1-4alkyl, C1-4alkoxy, halo-substituted-Ci-4alkoxy, C6-1oaryl, Cμgheteroaryl, C3-8heterocycloalkyl, C3-10cycloalkyl, -C(O)OR10c, -C(O)R10c, -NRiOc Riod, -S(O)1-2R1Oc; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted C1-4alkyl and Ci-4alkoxy; wherein Rioc and Riod are selected from hydrogen, C1-6alkyl, C3_iocycloalkyl optionally substituted with C1- 6alkyl or halo;
R3 is selected from cyano, -C(O)ORi u, -C(O)R1 la, -X2OC(O)R1 la, -
C(O)OX2RlIa, -X2OS(0)o-2Rlla, -X2S(O)0-2RlIa, "C(O)OX2ORlIa, -C(O)OX2NRlIaRlIb,
-C(O)N RllaRllb, "X2NRiIaRlIb, "NRiIaC(O)RiIb, -NRiIaC(O)ORiIb, -NRiiaS(0)o-2Rllb,
-C(O)N RiIaX2RiIb, -C(O)N Rl laX20Rllb, -C(O)N RiiaX2C(0)0Riib, -
C(O)NRiIaX2C(O)NRiIaRiIb, -C(O)N RiIaX2OX2ORiIb, X2RiIb; wherein each X2 is independently selected from a bond and Ci-4alkylene; wherein any methylene of X2 can have a hydrogen substituted with hydroxy; R1 la and R1 ^ are independently selected from hydrogen, cyano, Ci-4alkyl, Ci-4alkoxy, Cβ-ioaryl,
Figure imgf000249_0001
C3-8heterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or R1 la and R1 ^ together with the nitrogen atom to which they are both attached form a cyclic group selected from pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said pyrrolidine, pyrrolidin-2-one-l-yl or morpholinyl of the combination of R1 la and R1 ^ is optionally substituted with hydroxyl;
R4 is selected from hydrogen, C1-4alkyl, C1-4alkenyl, C6-ioarylCi_4alkyl, -
X3ORi2 and -X3C(O)ORi2; wherein X3 is selected from a bond and Ci_4alkylene; and Ri2 is selected from hydrogen and C1-4alkyl;
Re is selected from hydrogen, halo, cyano, C1-6alkyl, X4NRi4aRi4b, X4ORi4a; wherein X4 is selected from a bond, Ci-6alkylene; and Ri4a and R14b are independently selected from hydrogen and C1-4alkyl; and
Rig is selected halo, cyano, -S(0)o-2R13a,halo-substituted-C1-4alkyl, C1-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, Cό-ioaryl, -C(O)NRi8aRi8b and -C(O)ORi8a; wherein Ri8a and Ri8b are independently selected from hydrogen and C1-4alkyl
7. The compound of claim 6 in which Ri is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, l,2,4-oxadiazol-5-yl, or l,2,3,6-tetrahydropyridin-4-yl of Ri is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy-carbonyl, methyl-sulfonyl, t-butoxy-carbonyl, dimethyl- amino, 2-hydroxypropan-2-yl, 2- fluoropropan-2-yl, 1-phenylethylamino, (l-methylcyclopropoxy)carbonyl, t-butyl, (6- (trifluoromethyl)pyridin-3-yl)methyl-amino, 6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl, phenyl, pyridinyl, cyclohexyl and cyclopropyl; wherein said cyclohexyl or cyclopropyl substituent of Ri is optionally substituted with a radical selected from hydroxy, halo, isopropyl and methyl.
8. The compound of claim 7 in which R3 is selected from cyano, ethoxy- methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl,
methyl((tetrahydrofuran-2-yl)methyl)carbamoyl, (2-methoxy-2- oxoethyl)(methyl)carbamoyl, methoxy-ethyl-carbamoyl, methoxy-propoxy-carbonyl, methoxy-butoxy-carbonyl, (cyanomethyl)(methyl)carbamoyl, hydroxy-ethoxy-ethyl- carbamoyl, (hydroxyethyl)(methyl)carbamoyl, acetamido, isobutyramido,
(hydroxypropyl)(methyl)carbamoyl, isopropoxy-carbonyl, ethyl-carbamoyl, dimethoxy- ethyl-carbamoyl, hydroxy-ethoxy-carbonyl, (methoxy-ethoxy-ethyl)(methyl)carbamoyl, butyl-carbamoyl, carbamoyl-methoxy-carbonyl, (methoxy-carbonyl- methyl)(methyl)carbamoyl, (methoxyethyl)(methyl)carbamoyl, pyrrolidine- 1-carbonyl, hydroxy-ethyl-carbamoyl, methoxy-carbonyl-ethyl-carbamoyl, t-butoxy-carbonyl, (tetrahydro-2H-pyran-4-yloxy)carbonyl, morpholino-ethoxy-carbonyl, 3- hydroxyazetidine- 1-carbonyl, methyl- sulfonyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, ethyl-amino-carbonyl, carbamoyl, (methoxy-carbonyl-methyl)(methyl)carbamoyl, tetrahydrofuran-3-yl-carbamoyl, 5-methyl-l,3,4-oxadiazol-2-yl, ((1-methyl-lH-imidazol- 4-yl)methoxy)carbonyl, methoxy-propyl-carbamoyl, (methyl-sulfonyl-oxy)methyl, methyl- sulfonyl- amino, (azetidin-3-ylmethoxy)carbonyl, (2-hydroxy-3-(methyl- amino)propoxy)carbonyl, hydroxy-butyl-carbamoyl, dimethyl-amino-methyl, benzoxy- carbonyl, methoxy-carbonyl-methyl-carbamoyl, oxazolyl, (2H-l,2,3-triazol-2-yl)methyl, (dimethyl-amino-carbonyl-methyl)carbamoyl, (lH-pyrazol-l-yl)methyl, (oxetan-3- yloxy)carbonyl, dimethyl-amino-propoxy-carbonyl, acetoxy-methyl, 3-hydroxy- pyrrolidine- 1-carbonyl, (carboxy-methyl)(methyl)carbamoyl, (2-(2-oxopyrrolidin-l- yl)ethoxy)carbonyl, (carbamoyl-methyl)(methyl)carbamoyl, morpholino-carbonyl, (2H- tetrazol-2-yl)methyl, methyl((3-methyloxetan-3-yl)methyl)carbamoyl and 5-methyl-lH- l,2,4-triazol-3-yl.
9. The compound of claim 8 selected from: ethyl (2R)-2-methyl-3-phenyl-2-{8-[4- (trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4-yl}propanoate; ethyl 2-methyl-3- phenyl-2-{8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4-yl}propanoate; ethyl 2-{3-fluoro-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4-yl}-2- methyl-3-phenylpropanoate; ethyl 2-[8-(4-chlorophenyl)pyrazolo[3,2-c][l,2,4]triazin-4- yl]-2-methyl-3-phenylpropanoatel; methyl 2-methyl-2-(3-methyl-8-(4- (trifluoromethyl)phenyl)pyrazolo[5, 1-c] [ 1 ,2,4]triazin-4-yl)-3-phenylpropanoate; Methyl 3-(3-fluorophenyl)-2-methyl-2-(3-methyl-8-(4-(trifluoromethyl)phenyl)pyrazolo[5,l- c][l,2,4]triazin-4-yl)propanoate; Ethyl 2-methyl-3-phenyl-2-(8-(4- (trifluoromethyl)phenyl)pyrazolo[5, 1-c] [ 1 ,2,4]triazin-4-yl)propanoate; Ethyl 2-(3-fluoro- 8-(4-(trifluoromethyl)phenyl)pyrazolo[5,l-c][l,2,4]triazin-4-yl)-2-methyl-3- phenylpropanoate; and (R)-Ethyl 2-methyl-3-phenyl-2-(8-(4-(trifluoromethyl)phenyl)- pyrazolo[5,l-c][l,2,4]triazin-4-yl)propanoate.
10. The compound of claim 1 selected from Formula Ig, Ih and Ik:
Figure imgf000251_0001
in which:
Ri is selected from C2-1oalkenyl, C6-1OaTyI, Q.gheteroaryl, acetylenyl, C3. gheterocycloalkyl, C3-8heterocycloalkenyl, C3-6cycloalkyl, C3-6cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of Ri is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, C1-4alkyl, halo-substituted-C^alkyl, C1-4alkoxy, halo- substituted-Ci_4alkoxy, C6-1oaryl, Q.gheteroaryl, C3-8heterocycloalkyl, C3-1ocycloalkyl, - C(O)OR7, -C(O)R7, -NR7R8, -S(O)i-2R7; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of Ri is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C1-4alkyl, halo-substituted C1-4alkyl and C1-4alkoxy;
wherein R7 is selected from hydrogen, C1-6alkyl, C3_iocycloalkyl optionally substituted with C1-6alkyl or halo; and Rg is selected from -X1Rg; wherein Xi is selected from a bond and Ci_4alkylene optionally substituted with halo; and R9 is selected from phenyl and pyridinyl; wherein said phenyl or pyridinyl of Rg is optionally substituted with 1 to 3 trifluoromethyl radicals;
R2 is selected from hydrogen, Ci_6alkyl, Ci_6alkoxy, halo-substituted-Ci_
6alkyl, halo-substituted-Ci_6alkoxy, -X5S(O)O2RiOa, -X5ORiOa, -X5NRiOa X5RiOb, - X5S(0)0-2NRioaRiob, -X5NRiOaRiOb, -X5C(O)NRiOaRiOb, -X5NRiObC(O)RiOa and - X5C(O)ORiOa; wherein said X5 is selected from a bond and Ci-4alkylene wherein any methylene of X5 can have a hydrogen substituted with hydroxyl, C6-1oaryl, C3.
locycloalkyl, heteroaryl or heterocycloalkyl; and RiOa and RiOb are independently selected from hydrogen, Ci-4alkyl and Ci-4alkoxy; or Rioa and Riob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, Ci-4alkyl, halo-substituted-Ci-4alkyl, Ci-4alkoxy, halo-substituted-Ci-4alkoxy, C6-1oaryl, Ci-gheteroaryl, C3-8heterocycloalkyl, C3-iocycloalkyl, -C(O)ORiOc, -C(O)RiOc, -NRioc Riod, -S(O)1-2R1Oc; wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R2 is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, Ci-4alkyl, halo-substituted Ci-4alkyl and Ci-4alkoxy; wherein Rioc and Riod are selected from hydrogen, Ci-6alkyl, C3-iocycloalkyl optionally substituted with C1- 6alkyl or halo;
R3 is selected from cyano, -C(O)OR1 la, -C(O)R1 la, -X2OC(O)R1 la, -
C(0)0X2Riia, -X2OS(0)o-2Rlla, -X2S(O)0-2RlIa, -C(0)0X20Riia, -C(O)OX2NRiIaRlIb,
-C(O)N RiiaRiib, -X2NRiIaRiIb, -NRiiaC(O)Riib, -NRiiaC(0)0Riib, -NRllaS(0)o-2Rllb, -C(O)N RiIaX2RiIb, -C(O)N RiiaX20Riib, -C(O)N RiiaX2C(0)0Riib, - C(O)NRiiaX2C(O)NRiiaRiib, -C(O)N RiiaX2OX2ORiib, X2Ri lb; wherein each X2 is independently selected from a bond and C1-4alkylene; wherein any methylene of X2 can have a hydrogen substituted with hydroxy; R1 la and R1 ^ are independently selected from hydrogen, cyano, C1-4alkyl, Ci-4alkoxy, Cβ ioaryl,
Figure imgf000252_0001
C3-8heterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R3 is optionally substituted by 1 to 2 methyl radicals; or R1 la and R1 ^ together with the nitrogen atom to which they are both attached form a cyclic group selected from pyrrolidine, pyrrolidin-2-one-l-yl and morpholinyl; wherein said pyrrolidine, pyrrolidin-2-one-l-yl or morpholinyl of the combination of R1 la and R1 ^ is optionally substituted with hydroxyl;
R4 is selected from hydrogen, Ci-4alkyl, Ci-4alkenyl, C6-ioarylCi-4alkyl, -
X3OR12 and -X3C(O)ORi2; wherein X3 is selected from a bond and Ci_4alkylene; and Ri2 is selected from hydrogen and Ci_4alkyl;
R5 is selected from hydrogen, Ci-4alkyl, naphthyl,
Figure imgf000253_0001
C3- gheterocycloalkyl; wherein said alkyl, naphthyl, heteroaryl or heterocycloalkyl of R5 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, -
S(0)o-2Ri3a, halo-substituted-C1-4alkyl, Ci_4alkyl, halo-substituted-Ci_4alkoxy, Ci_4alkoxy,
Cό-ioaryl, -C(O)NRi3aRi3b and -C(O)ORi3a; wherein Ri3a and Ri3b are independently selected from hydrogen and Ci-4alkyl;
Y2 is selected from a bond, CH2, C(O), NR17 and O; wherein Ri7 is selected from hydrogen, halo-substituted-Ci_4alkyl and C1-4 alkyl; or R4 and Y2 taken together form a double bond or a cyclopropyl ring; and
Re is selected from hydrogen, halo, cyano, C1-6alkyl, X4NRi4aRi4b, X4ORi4a; wherein X4 is selected from a bond, Ci_6alkylene; and Ri4a and R14b are independently selected from hydrogen and C1-4alkyl.
11. The compound of claim 10 in which Ri is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4- oxadiazol-5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, or l,2,3,6-tetrahydropyridin-4-yl of Ri is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
fluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, methoxy-carbonyl, methyl-sulfonyl, t-butoxy-carbonyl, dimethyl- amino, 2-hydroxypropan-2-yl, 2- fluoropropan-2-yl, 1-phenylethylamino, (l-methylcyclopropoxy)carbonyl, t-butyl, (6- (trifluoromethyl)pyridin-3-yl)methyl-amino, 6-(trifluoromethyl)-lH-benzo[d]imidazol-2- yl, phenyl, pyridinyl, cyclohexyl and cyclopropyl; wherein said cyclohexyl or
cyclopropyl substituent of Ri is optionally substituted with a radical selected from hydroxy, halo, isopropyl and methyl.
12. The compound of claim 11 in which R3 is selected from cyano, ethoxy-methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl,
methyl((tetrahydrofuran-2-yl)methyl)carbamoyl, (2-methoxy-2- oxoethyl)(methyl)carbamoyl, methoxy-ethyl-carbamoyl, methoxy-propoxy-carbonyl, methoxy-butoxy-carbonyl, (cyanomethyl)(methyl)carbamoyl, hydroxy-ethoxy-ethyl- carbamoyl, (hydroxyethyl)(methyl)carbamoyl, acetamido, isobutyramido,
(hydroxypropyl)(methyl)carbamoyl, isopropoxy-carbonyl, ethyl-carbamoyl, dimethoxy- ethyl-carbamoyl, hydroxy-ethoxy-carbonyl, (methoxy-ethoxy-ethyl)(methyl)carbamoyl, butyl-carbamoyl, carbamoyl-methoxy-carbonyl, (methoxy-carbonyl- methyl)(methyl)carbamoyl, (methoxyethyl)(methyl)carbamoyl, pyrrolidine- 1-carbonyl, hydroxy-ethyl-carbamoyl, methoxy-carbonyl-ethyl-carbamoyl, t-butoxy-carbonyl, (tetrahydro-2H-pyran-4-yloxy)carbonyl, morpholino-ethoxy-carbonyl, 3- hydroxyazetidine- 1-carbonyl, methyl- sulfonyl, (2,3-dihydroxypropyl)(methyl)carbamoyl, ethyl-amino-carbonyl, carbamoyl, (methoxy-carbonyl-methyl)(methyl)carbamoyl, tetrahydrofuran-3-yl-carbamoyl, 5-methyl-l,3,4-oxadiazol-2-yl, ((1-methyl-lH-imidazol- 4-yl)methoxy)carbonyl, methoxy-propyl-carbamoyl, (methyl-sulfonyl-oxy)methyl, methyl- sulfonyl- amino, (azetidin-3-ylmethoxy)carbonyl, (2-hydroxy-3-(methyl- amino)propoxy)carbonyl, hydroxy-butyl-carbamoyl, dimethyl-amino-methyl, benzoxy- carbonyl, methoxy-carbonyl-methyl-carbamoyl, oxazolyl, (2H-l,2,3-triazol-2-yl)methyl, (dimethyl-amino-carbonyl-methyl)carbamoyl, (lH-pyrazol-l-yl)methyl, (oxetan-3- yloxy)carbonyl, dimethyl-amino-propoxy-carbonyl, acetoxy-methyl, 3-hydroxy- pyrrolidine- 1-carbonyl, (carboxy-methyl)(methyl)carbamoyl, (2-(2-oxopyrrolidin-l- yl)ethoxy)carbonyl, (carbamoyl-methyl)(methyl)carbamoyl, morpholino-carbonyl, (2H- tetrazol-2-yl)methyl, methyl((3-methyloxetan-3-yl)methyl)carbamoyl and 5-methyl-lH- l,2,4-triazol-3-yl.
13. The compound of claim 12 selected from: ethyl 2-methyl-3-(l-methyl-lH-imidazol- 2-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-4-(morpholin-4- yl)butanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3- (oxolan-3-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methyl-3-(l,3-thiazol-4-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2-methyl-3-(oxolan-2-yl)propanoate; ethyl 2-methyl-3-(oxan-4-yl)-2- {3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2- methyl-3-(l,3-thiazol-4-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-3-(oxan-3-yl)-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(oxan-4-yl)propanoate; ethyl 2- [3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(pyridin-3-yl)propanoate; ethyl 2-methyl-3-(l-methyl-lH-pyrazol-3-yl)-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl 2-methyl-3- (pyridin-3-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-methyl-3-(oxolan-3-yl)-2-{3-[4-
(trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanoate; ethyl 3-(5-chloro- l,2,4-thiadiazol-3-yl)-2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2- methylpropanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl- 3-(5-methyl-l,2-oxazol-3-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2,4-dimethylpentanoate; ethyl 2-methyl-3-(5-methyl-l,2-oxazol-3-yl)- 2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2- methyl-3-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-2- { 3-[4-(trifluoromethyl)phenyl]pyrazolo[ 1 ,5- a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]- 2-methyl-3-(pyridin-2-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5- a]pyrimidin-7-yl]-2-methyl-3-(pyridin-4-yl)propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-phenylacetate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-3-(l-methanesulfonylpiperidin-4-yl)-2- methylpropanoate; ethyl 2-methyl-3-(2-phenyl-l,3-thiazol-4-yl)-2-{3-[4- (trifluoromethyl)phenyl] pyrazolo [ 1 ,5 - a] pyrimidin-7 - yl } propano ate ; 1,3 -diethyl 2- { 3 - [4- (trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]pyrimidin-7-yl}propanedioate; ethyl 2-methyl-3- (piperidin-3-yl)-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7- yljpropanoate; ethyl 2-phenoxy-2-{3-[4-(trifluoromethyl)phenyl]pyrazolo[l,5- a]pyrimidin-7-yl}propanoate; ethyl 2-[methyl(phenyl)amino]-2-{ 3-[4- (trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-7-yl}propanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2-methyl-3-(pyridin-4-yl)propanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl] -4-methoxy-2-methylbutanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]propanoate; 3-(4- chlorophenyl)-N-ethyl-N-phenylpyrazolo[ 1 ,5-a]pyrimidine-7-carboxamide; diethyl 2-(3- (4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)malonate; ethyl 2-methyl-3- (thiazol-4-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(pyrazin-2-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5- a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(l -methyl- lH-pyrazol-3-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- (pyridin-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(pyrimidin-2-yl)-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3-(3- methyl- 1 ,2,4-oxadiazol-5-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin- 7-yl)propanoate; ethyl 2-methyl-3-(5-methylisoxazol-3-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- (IH- 1 ,2,4-triazol- l-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(pyrimidin-5-yl)-2-(3-(4-
(trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- (tetrahydro-2H-pyran-4-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(2-phenylthiazol-4-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propanoate; ethyl 2-methyl-3- (tetrahydrofuran-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate; ethyl 2-methyl-3-(tetrahydro-2H-pyran-3-yl)-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanoate; and ethyl 2-methyl- 3-(piperidin-3-yl)-2-(3-(4-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7- yl)propanoate.
14. A compound selected from: ethyl 2-[8-(4-chlorophenyl)imidazo[l,5-a]pyrimidin-4- yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4-chlorophenyl)pyrazolo[3,2- b][l,3]thiazol-6-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2,3-dihydro-lH-indene-2-carboxylate; 3- (4-chlorophenyl)-N-phenyl-N-propylpyrazolo[ 1 ,5-a]pyrimidine-7-carboxamide; 3-(4- chlorophenyl)-N-methyl-N-phenylpyrazolo[ 1 ,5-a]pyrimidine-7-carboxamide; and ethyl 3-phenyl-2-{9-[4-(trifluoromethoxy)phenyl]-9H-purin-6-yl}propanoate.
15. A pharaiaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable excipient.
16. A method for modulating GPRl 19 activity, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby modulating said GPRl 19 activity.
17. The method of claim 16, wherein the compound of claim 1 directly contacts GPR 119.
18. The method of claim 16, wherein the contacting occurs in vitro or in vivo.
19. A method for treating a disease or condition wherein modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease or condition, comprising administering to a subject a therapeutically effective amount of the compound of claim 1 or pharmaceutically acceptable salts or pharmaceutical compositions thereof.
20. The method of claim 19, wherein said disease or condition is selected from obesity, type 1 diabetes, type 2 diabetes mellitus, hyperlipidemia, idiopathic type 1 diabetes, latent autoimmune diabetes in adults, early-onset type 2 diabetes, youth-onset atypical diabetes, maturity onset diabetes of the young, malnutrition-related diabetes and gestational diabetes.
21. The method of claim 19, wherein said disease or condition is selected from coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
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JP2014532058A (en) * 2011-10-04 2014-12-04 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Process for producing 5- [2- [7- (trifluoromethyl) -5- [4- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidin-3-yl] ethynyl] -2-pyridinamine
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US9546176B2 (en) 2012-11-20 2017-01-17 Discoverybiomed, Inc. Small molecule bicyclic and tricyclic CFTR correctors
CN114315899A (en) * 2020-09-30 2022-04-12 上海美迪西生物医药股份有限公司 3- (aromatic benzimidazolyl) pyrazolopyrimidine derivative and application thereof

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CN114315899A (en) * 2020-09-30 2022-04-12 上海美迪西生物医药股份有限公司 3- (aromatic benzimidazolyl) pyrazolopyrimidine derivative and application thereof

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