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

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]

[0008] in which:

[0009] R₁ is selected from C₂-ioalkenyl, C_6-1oaryl, 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, C_6-10aryl, C_1-9heteroaryl, 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, C_1-4alkyl, halo-substituted Ci_₄alkyl and Ci_₄alkoxy; wherein R₇ is selected from hydrogen, C_1-6alkyl, C₃-iocycloalkyl optionally substituted with C_1-6alkyl 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, C_1-6alkyl, Ci_₆alkoxy, halo-substituted-Ci_

₆alkyl, halo-substituted-Ci-ealkoxy, -X₅S(O)O₂RiOa, -X₅OR_10a, -X₅NR_1Oa X₅RiOb, - X₅S(0)o-₂NRio_aRiob, -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, C_ό-ioaryl, C₃_₁₀cycloalkyl, heteroaryl or heterocycloalkyl; and R_1Oa and R_1Ob are independently selected from hydrogen, Ci_₄alkyl, Ci_₄alkoxy, C_6-1oaryl, 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, C_1-4alkyl, halo-substituted-Ci^alkyl, Ci_₄alkoxy, halo- substituted-Ci_₄alkoxy, C_6-1oaryl, Ci.gheteroaryl,

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, C_1-4alkyl, halo-substituted Ci_₄alkyl and C_1-4alkoxy; wherein R₁Oc and R₁Od are selected from hydrogen, C_1-6alkyl, C₃_iocycloalkyl optionally substituted with Ci_₆alkyl or halo;

[0012] R₃ is selected from cyano, -C(O)ORi_u, -C(O)R_{1 la}, -X₂OC(O)R_{1 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, -X₂NRn_aRiib, - NRiiaC(O)Rii_b, -NRiiaC(0)0Rnb, -NRii_aS(0)o-₂Riib, -C(O)NX₂Ri IaX₂RiIb, - C(O)NRiIaX₂ORHb, -C(O)NRi iaX₂C(0)0R_llb, -C(O)NRi i_aX₂C(O)NR_llaRiib, - 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; R_lla and R₁₁₁, are independently selected from hydrogen, cyano, C_1-4alkyl, C_1-4alkoxy, C_6-1OaTyI, Ci.gheteroaryl,

wherein said aryl, heteroaryl or heterocycloalkyl of R₃ is optionally substituted by 1 to 2 methyl radicals; or R_{1 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 R_{1 la} and Ru_b is optionally substituted with hydroxyl;

[0013] R₄ is selected from hydrogen, C_1-4alkyl, C_1-4alkenyl, C₆-ioarylCi_₄alkyl, -

X₃ORi₂, -X₃NRi₂Ri₂ and -X₃C(O)ORi₂; wherein X₃ is selected from a bond and C_1-4alkylene; and each Ri₂ is independently selected from hydrogen and C_1-4alkyl; or when - Y₂R₅ is benzyl, the ortho hydrogen of R₅ and R₄ can form a cyclopentyl;

[0014] R₅ is selected from hydrogen, C_1-4alkyl, C_6-1oaryl, 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-₂Ri_3a, halo-substituted-Ci_₄alkyl, Ci_₄alkyl, halo-substituted-Ci_₄alkoxy, Ci_₄alkoxy, C_6-1oaryl, -C(O)NR_13aR_13b and -C(O)OR_13a; wherein R_13a and R_13b are independently selected from hydrogen and C_1-4alkyl;

[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 C_1-4 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, X₄NR_14aR_14b, X₄OR_14a; wherein X₄ is selected from a bond, C₁.

₆alkylene; and R_14a and R_14b 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. C_1- 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:

[0025] "Ce-ioarylCi^alkyl" means an aryl as described above connected via a alkylene grouping. For example, C₆-₁oarylC₁_₄alkyl includes phenethyl, benzyl, etc. C_6-

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:

[0035] in which: n is selected from 1, 2 and 3; R₁ is selected from C₂-ioalkenyl, C_6- ioaryl, C₆-ioaryl-C₂-₃alkynyl, Cμgheteroaryl, acetylenyl,

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-Cμ₄alkyl, Ci_₄alkoxy, halo-substituted-Ci-₄alkoxy, C_6-1oaryl, 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, C_6-1oaryl, 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 R_1Oa and R_1Ob can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C_1-4alkyl, halo-substituted-Ci_₄alkyl, C_1-4alkoxy, halo-substituted-Ci_₄alkoxy, C_6-1oaryl, Ci^heteroaryl, C^heterocycloalkyl, C₃-₁₀cycloalkyl, -C(O)OR_10c, -C(O)R_10c, -NR_1Oc 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, C_1-4alkyl, halo-substituted C₁.₄alkyl and C_1-4alkoxy; wherein R₁Oc and R₁Od are selected from hydrogen, C_1-6alkyl, C₃- iocycloalkyl optionally substituted with C_1-6alkyl or halo; R₃ is selected from cyano, - C(O)OR₁U, -C(O)R₁U, -X₂OC(O)R_lla, -C(O)OX₂R₁U, -X₂OS(O)₀-₂Rii_a, -X₂S(O)₀. 2R_lla, -C(O)OX₂ORiIa, -C(O)OX₂NRiIaRiIb, -C(O)NR_{1 la}R_llb, -X₂NR_{1 la}R_{l lb}, - NRiiaC(O)Rnb, -NRiiaC(0)0Rnb, -NRii_aS(O)₀-₂Riib, -C(O)NX₂Ri IaX₂RiIb, - C(O)NRiIaX₂ORiIb, -C(O)OX₂C(O)NRi uRiib, -C(O)NR₁ UX₂C(O)OR_{1 lb}, - C(O)NRiiaX₂C(O)NRiiaRiib, -C(O)NRi i_aX₂OX₂ORii_b, -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; R_{1 la} and R_{1 lb} are independently selected from hydrogen, cyano, C_1-4alkyl, 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 R_{1 la} and R_{1 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 R_{1 la} and R_{1 lb} is optionally substituted with hydroxyl; R₄ is selected from hydrogen, C_1-4alkyl, C_1-4alkenyl, 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 C_1-4alkyl; Re is selected from hydrogen, halo, cyano, C_1-6alkyl, X₄NRi_4aRi_4b, X₄ORi_4a; wherein X₄ is selected from a bond, Ci_₆alkylene; and Ri_4a and Ri_4b are independently selected from hydrogen and C_1-4alkyl; Rig is selected halo, cyano, -S(0)o-₂Ri_3a,halo-substituted-Ci_₄alkyl, C_1-4alkyl, halo- substituted-Ci-₄alkoxy, Ci-₄alkoxy, Cβ-ioaryl, -C(O)NRi8_aRi8b and -C(0)0Ri8_a; wherein R_18a and R_18b 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:

[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, C_6-1oaryl, 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)ORi_0a; wherein said X₅ is selected from a bond and Ci_₄alkylene wherein any methylene of X₅ can have a hydrogen substituted with hydroxyl, C_6-1oaryl, C₃_iocycloalkyl, heteroaryl or heterocycloalkyl; and RiOa and Riob are independently selected from hydrogen, Ci_₄alkyl and Ci_₄alkoxy; or Rio_a and Rio_b 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, C_6-1oaryl, Ci_₉heteroaryl, C₃_gheterocycloalkyl, C₃_iocycloalkyl, - C(O)ORiOc, -C(O)RiOc, -NRioc Riod, -S(O)i_₂Ri_0c; 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 C_1-4alkoxy; wherein Ri_Oc and Rio_d are selected from hydrogen, Ci_₆alkyl, C₃_iocycloalkyl optionally substituted with Ci_₆alkyl or halo; R₃ is selected from cyano, -C(0)0Rπ_a, - C(O)Rii_a, -X₂0C(0)Rii_a, -C(O)OX₂RiIa, -X₂OS(0)o-₂Riia, -X₂S(OV₂RiIa, - C(O)OX₂ORiIa, -C(O)OX₂NRiIaRiIb, -C(O)N RiuRiib, -X₂NRiIaRiIb, -NRii_aC(0)Rn_b, -NRiiaC(0)0Rii_b,

-C(O)N Rn_aX₂Riib, -C(O)N Rii_aX₂0Rn_b, - C(O)N RiiaX₂C(0)0Rii_b, -C(O)NRi i_aX₂C(O)NRii_aRiib, -C(O)N Rii_aX₂OX₂ORii_b, X₂Ri_Ib; wherein each X₂ is independently selected from a bond and Ci_₄alkylene; wherein any methylene of X₂ can have a hydrogen substituted with hydroxy; R_{1 la} and R₁₁₁, are independently selected from hydrogen, cyano, Ci_₄alkyl, Ci_₄alkoxy, C_6-1OaTyI, C₁.

gheteroaryl, C^sheterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R₃ is optionally substituted by 1 to 2 methyl radicals; or R_{1 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 R_lla and R₁₁₁, is optionally substituted with hydroxyl; R₄ is selected from hydrogen, C_1-4alkyl, C_1-4alkenyl, C_6-1oaτylC_1-4alkyl, - X₃OR₁₂ and -X₃C(O)OR₁₂; wherein X₃ is selected from a bond and C_1-4alkylene; and R₁₂ is selected from hydrogen and C_1-4alkyl; R₆ is selected from hydrogen, halo, cyano, C₁.₆alkyl, X₄NR_14aR_14b, X₄OR₁₄₁; wherein X₄ is selected from a bond, Ci-βalkylene; and R_14a and R_14b are independently selected from hydrogen and C_1-4alkyl; and R_1S is selected halo, cyano, -S(0)o-₂Ri_3a,halo-substituted-C₁-₄alkyl, C_1-4alkyl, halo-substituted-C_1-4alkoxy, C_1-4alkoxy, C_6-1OaTyI, -C(O)NR_18aRi8b and -C(O)OR_18a; wherein R_18a and R_18b are independently selected from hydrogen and C_1-4alkyl.

[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:

Ig Ih Ik

[0045] in which: R₁ is selected from C₂-ioalkenyl, C_6-1OaTyI, 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, C_1-4alkyl, halo- substituted-C_1-4alkyl, C_1-4alkoxy, halo-substituted-C_1-4alkoxy, C_6-1oaryl, 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, C_1-4alkyl, halo- substituted C_1-4alkyl and C_1-4alkoxy; wherein R₇ is selected from hydrogen, C_1-6alkyl, C₃- iocycloalkyl optionally substituted with C_1-6alkyl 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, C_1-6alkyl, Ci-βalkoxy, halo-substituted-C_1-6alkyl, 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)OR_10a; wherein said X₅ is selected from a bond and C^alkylene wherein any methylene of X₅ can have a hydrogen substituted with hydroxyl, C_6-1oaryl, C₃_iocycloalkyl, heteroaryl or heterocycloalkyl; and R₁Oa and R₁Ob are independently selected from hydrogen, Ci_₄alkyl and Ci_₄alkoxy; or R₁Oa 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_1-4alkyl, 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)OR_lla, - C(O)R_lla, -X₂OC(O)R_lla, -C(O)OX₂R_lla, -X₂OS(0)o-₂R_lla, -X₂S(O)_0-2R_{1 la}, - C(0)0X₂0R_lla, -C(0)0X₂NR_llaR_llb, -C(O)N R_llaR_llb, -X₂NR_llaRπb, -NR_llaC(0)R_llb, -NRiiaC(O)ORnb, -NRnaS(0)o-₂Riib, -C(O)N Rπ_aX₂Riib, -C(O)N Rii_aX₂0Rii_b, - C(O)N RiIaX₂C(O)ORiIb, -C(O)NRi iaX₂C(O)NRn_aRiib, -C(O)N Rii_aX₂OX₂ORii_b, X₂Ri_Ib; wherein each X₂ is independently selected from a bond and Ci_₄alkylene; wherein any methylene of X₂ can have a hydrogen substituted with hydroxy; R_{1 la} and R_{1 lb} are independently selected from hydrogen, cyano, Ci_₄alkyl, Ci_₄alkoxy, Cβ-ioaryl, C_1- gheteroaryl, C₃_₈heterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R₃ is optionally substituted by 1 to 2 methyl radicals; or R_{1 la} and R_{1 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 R_lla and R_llb 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-₂Ri_3a, halo-substituted-C_1-4alkyl, Ci_₄alkyl, halo-substituted-Ci_₄alkoxy, Ci-₄alkoxy, C_6-1oaryl, -C(O)NRi_3aRi₃b and -C(0)0Ri_3a; wherein Ri_3a 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 C_1-4 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, X₄NR_14aR₁₄b, X₄OR_14a; wherein X₄ is selected from a bond, Ci_₆alkylene; and R_14a and R_14b are independently selected from hydrogen and C_1-4alkyl.

[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 as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷0,¹⁸0,³⁵S,¹⁸F,³⁶Cl and¹²³I. Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as³H or¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. In particular examples,³H and¹⁴C isotopes may be used for their ease of preparation and detectability. In other examples, substitution with isotopes such as²H 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

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

(7)

H₂N-NH₂ HCI heat

(8)

[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- 120⁰C) 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- 100⁰C) 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

[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

[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

[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

[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 50⁰C 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

[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- 100⁰C) 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

[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 80⁰C. [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", 3^rd 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

[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 100⁰C 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 (150⁰C, 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

[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

[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

[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.

[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 0⁰C. 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

[00130] A solution of diisopropylamine (28 mg, 0.27 mmol) in tetrahydrofuran (1 mL) is cooled to -78⁰C (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:

Example AlO

2-(3-(4-Chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenylpropyl

methanesulfonate

[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 55⁰C 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 200⁰C 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 (0⁰C) 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 0⁰C 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 125⁰C 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 (150⁰C, 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

[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 110⁰C 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

[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

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 120⁰C 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 (100⁰C, 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

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 90⁰C 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 80⁰C 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

A14a A15a

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 (160⁰C, 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

[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

Example Al 7

[00151] Step A: A solution of Intermediate A14a (204 mg, 0.71 mmol) in dichloromethane (7 rnL) cooled to -15⁰C 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.

A18c Example A18

[00153] Step A: A solution of diisopropylamine (589 mg, 5.8 mmol) in tetrahydrofuran (10 niL) is cooled to -78⁰C (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 60⁰C 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 60⁰C 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

[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.

[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

A21a A21b A21c

[00158] Step A: A solution of Intermediate A21a (1 g, 6.94 mmol) in

tetrahydrofuran (5 rnL) is added slowly to a pre-cooled (O⁰C) mixture of 60% NaH (333 mg, 8.33 mmol) in tetrahydrofuran (20 mL) and stirred for 1 hour. The mixture is then cooled to -78⁰C, 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 120⁰C 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 100⁰C 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 (120⁰C, 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 C₂₄H_2IF₃N₃O₃ ([M+H]⁺) 456.1, found 456.2. Example A22

Ethyl 3-phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)acrylate

[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 120⁰C 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 (100⁰C, 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

₃

[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 80⁰C for 16 hours and then at 120⁰C 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 85⁰C 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 C₂₅H_2IF₃N₃O₂ ([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

C₂₅H_2IF₃N₃O₂ ([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 0⁰C and treated with sodium nitrite (5.1 mg, 0.07 mmol). The mixture is then stirred at 0⁰C 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

A14a A26a

[00168] Step A: To a O⁰C 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 120⁰C, 15 min each). The mixture is then treated with additional 4M HCl (50 μL, 0.2 mmol) and heated to 120⁰C 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

[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 120⁰C 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 (100⁰C, 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

[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 (140⁰C, 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

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

[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

A31a A31 b A31c

[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 C_2IH₂₀NO₅ ([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 110⁰C 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 90⁰C 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 50⁰C 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

[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

[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

[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

[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 C_3IH₂₇F₃N₃O₄ ([M+H]⁺) 530.2, found 530.1.

Example A36

diethyl 2-benzyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolor 1 ,5-alpyrimidin-7-yl)malonate

[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

A37a A37b A37c

[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 100⁰C 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 60⁰C 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

A38c A38d

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 60⁰C. 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 100⁰C 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 100⁰C 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 80⁰C 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 80⁰C 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

[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 80⁰C 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:

Example B4

(EVEthyl 2-(3-(4-chlorostyryl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate

A14a B4a

[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:

Example B 13

Ethyl 2-(3-(biphenyl-4-yl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-phenylpropanoate

[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 (120⁰C, 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

[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 110⁰C 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:

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,

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

(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,

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

[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 (180⁰C, 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

[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

[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 120⁰C 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

[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

A14a B23a

[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:

Example B26

Ethyl 2-methyl-3-phenyl-2-(3-(6-(trifluoromethyl)pyridin-3-yl)pyrazolor 1 ,5-αlpyrimidin-

7-vl)propanoate

[00214] Step A: A solution of Intermediate B23a (109 mg, 0.25 mmol) in tetrahydrofuran (250 μL) is cooled to 0⁰C (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 80⁰C 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

[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 100⁰C 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

[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 (120⁰C, 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:

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,

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

[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

[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

[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 80⁰C 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

[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

[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:

Example B41

Ethyl 2-(3-(4-(2-hvdroxypropan-2-yl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3- phenylpropanoate

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

[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

[00228] A cold (0⁰C) 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

[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

A14a CIa

[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 110⁰C 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

[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 100⁰C 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 150⁰C 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

[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 80⁰C 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 120⁰C for 2 hours. Then, 50 μL of acetic acid is added and the reaction is heated to 120⁰C 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.

[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 50⁰C 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

AlOa FIa

[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 50⁰C 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

[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 (150⁰C, 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

[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

[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

[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

GIa GIb

[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 (100⁰C, 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 (165⁰C, 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

[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 (160⁰C, 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

[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 (160⁰C, 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

[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 (160⁰C, 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

[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

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 -30⁰C. 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 30⁰C. 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:

Example J4

A^-(l-Phenyl-2-(3-(4-(trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propan-2- vPacetamide

Boc

[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 Ci₅H_2INNaO₃ ([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

Ci₇H_2INNaO₃ ([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 C_2IH₃₃N₂O₃ ([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 -30⁰C. 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

[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 30⁰C. Intermediate J5a comes off at 1.98 min. The¹H 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). The¹H 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. The¹H 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

[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

[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

[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

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 80⁰C 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

[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 0⁰C 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 (170⁰C, 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

[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

[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 140⁰C 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 C₂₅H_2I 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

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 C₂₃H_2IF₃N₅O ([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 (170⁰C, 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 C₂₅H_2IF₃N₅O ([M+H]⁺) 464.2, found 464.1.

Example Ll

Ethyl 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-p-tolylpropanoate.

A21a LIa

[00286] Step A: A mixture of Intermediate A21a (4mL, 20 mmol) and dimethylformamide diethyl acetal (3.35 rnL, 20 mmol) is heated to 100⁰C 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 60⁰C 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 60⁰C 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:

Example L13

Ethyl 2-(3-(4-chlorophenyl)pyrazolor 1 ,5-αlpyrimidin-7-yl)-2-methyl-3-(pyridin-3- vPpropanoate

[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:

Example L15

Ethyl 2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-2-methyl-3-(l- (methylsulfonyl)piperidin-4-yl)propanoate

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 (180⁰C, 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

[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:

(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.

(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

found (s,

Hz, (s, (d, J (d, J (t, J found

Example Ml

2-(3-(4-chlorophenyl)pyrazolori,5-αlpyrimidin-7-yl)-N-ethyl-2-methyl-3- phenylpropanamide

Example Ml

[00297] Step A: A solution of Intermediate MIa (5.28 g, 33.4 mmol) in acetone

(30 niL) is cooled to 0⁰C 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 100⁰C 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 60⁰C 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 80⁰C 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:

(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,

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);

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

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),

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

[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,

(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),

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]⁺)

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,

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

(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

(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

= 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

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.

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,

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,

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

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

(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

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

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

([MH-H]⁺) ([MH-H]⁺) (s, J = 7.13 7.2 Hz, (m, (d, J (s, found

([MH-H]⁺)

Example M63

Methyl 2-(6-chloro-3-(4-(trifluoromethyl)phenyl)pyrazolori,5-alpyrimidin-7-yl)-3-(3- fluorophenvl)-2-methylpropanoate

[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

[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

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 60⁰C 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 80⁰C. 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

[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

[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

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 0⁰C and stirred at room temperature for 3h. The mixture is cooled to 0⁰C, 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 C_I2H_HF₃NS₂ ([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 200⁰C 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 80⁰C 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

[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. The¹H 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 .

[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. The¹H 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

[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 30⁰C. Example O4 comes off at 2.42 minutes; Example O5 comes off at 3.01 minutes. The¹H NMR and HRMS data for Example O4 and Example O5 are identical to Example B 15.

Example O6

yPcyclopropanecarboxylate

Ph

[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. The¹H 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

[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. The¹H 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

[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. The¹H 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

[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

[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. The¹H 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

[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. The¹H 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

[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 30⁰C. Example O14 comes off at 3.89 minutes, and Example O15 comes off at 5.14 minutes. The¹H 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

[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 30⁰C. Example O16 comes off at 3.80 minutes, and Example O17 comes off at 5.92 minutes. The¹H 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

[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 30⁰C. Example 018 comes off at 3.39 minutes, and Example 019 comes off at 4.45 minutes. The¹H 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

[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 30⁰C. Example O20 comes off at 3.25 minutes. The¹H 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

[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 30⁰C. Example 021 comes off at 2.92 minutes, and Example 022 comes off at 3.58 minutes. The¹H 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

[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 30⁰C. Example 023 comes off at 3.06 minutes, and Example 024 comes off at 4.00 minutes. The¹H 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

[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 30⁰C. Example 025 comes off at 3.83 minutes. The¹H 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

[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 30⁰C. Example 026 comes off at 1.76 minutes, and Example 027 comes off at 2.78 minutes. The¹H 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

[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 30⁰C. Example 028 comes off at 1.97 minutes, and Example 029 comes off at 3.48 minutes. The¹H 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

[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 30⁰C. Example O30 comes off at 6.25 minutes, and Example 031 comes off at 8.00 minutes. The¹H 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

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 0⁰C, 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 60⁰C. 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 80⁰C 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 30⁰C. 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 60⁰C 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

[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

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:

Example P14

((R)-Methyl 3-(3-fluorophenyl)-2-methyl-2-(2-(methylsulfonylmethyl)-3-(4- (trifluoromethyl)phenyl)pyrazolori,5-αlpyrimidin-7-yl)propanoate

[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 45⁰C 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-

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 60⁰C 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 50⁰C 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

[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

[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

Example P19

[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 50⁰C 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 80⁰C 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

[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 80⁰C 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 120⁰C 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

[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 80⁰C 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 80⁰C 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

[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:

[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:

in which:

Ri is selected from d ioalkenyl, C_6-1OaTyI, C₆-ioaryl-C₂-₃alkynyl, C_1- gheteroaryl, acetylenyl, C^sheterocycloalkyl, C^heterocycloalkenyl, C_3-6cycloalkyl, C₃- 6cycloalkyl-C_2-3alkynyl, C_3-6cycloalkenyl; 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, C_1-4alkyl, halo-substituted-C_1-4alkyl, Ci-₄alkoxy, halo-substituted-Ci-₄alkoxy, C_6-10aryl, C_1-9heteroaryl, C₃_₈heterocycloalkyl, C_3-10cycloalkyl, -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, C_1-4alkyl, halo-substituted C_1-4alkyl and C_1-4alkoxy; wherein R₇ is selected from hydrogen, C_1-6alkyl, C₃_iocycloalkyl optionally substituted with C_1-6alkyl 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, C_1-6alkyl, 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)ORio_a; wherein said X₅ is selected from a bond and Ci_₄alkylene wherein any methylene of X₅ can have a hydrogen substituted with hydroxyl, cyano, C_6-1OaTyI, C₃- locycloalkyl, heteroaryl or heterocycloalkyl; and Rio_a and Riob are independently selected from hydrogen, C_1-4alkyl, Ci_₄alkoxy, C_6-1oaryl, Ci-gheteroaryl and C₃.

gheterocycloalkyl; or Rio_a 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, C_1-4alkyl, halo-substituted-Cμ₄alkyl, Cμ₄alkoxy, halo-substituted-Ci-₄alkoxy, C_6-1oaryl,

C₃- sheterocycloalkyl, C_3-10cycloalkyl, -C(O)OR_10c, -C(O)R_10c, -NRioc R₁Od,

wherein said aryl, heteroaryl, heterocycloalkyl or cycloalkyl substituent of R₂ is optionally substituted by 1 to 2 radicals independently selected from halo, hydroxy, C_1-4alkyl, halo-substituted C_1-4alkyl and C_1-4alkoxy; wherein Rioc and Riod are selected from hydrogen, C_1-6alkyl, C₃-iocycloalkyl optionally substituted with C_1-6alkyl or halo;

R₃ is selected from cyano, -C(O)ORi_la, -C(O)R_{1 la}, -X₂OC(O)R_{1 la}, -

C(0)0X₂R_lla, -X₂OS(0)o-₂Rna, -X₂S(O)_0-2R₁U, -C(O)OX₂OR_{1 la}, -C(O)OX₂NR_{1 la}R_llb, -C(O)NRii_aRii_b, -X₂NRii_aRii_b, -C(O)OX₂C(O)NRi_laR_llb, -NR_{l la}C(0)R_{l lb}, - NRiiaC(0)0Rnb, -NRiiaS(0)o-₂Riib, -C(O)NX₂Ri i_aX₂Rii_b, -C(0)NR_llaX₂0R_{l lb}, - C(O)N RiiaX₂C(0)0Riib, -C(O)NRi iaX₂C(O)NRii_aRii_b, -C(O)N Rii_aX₂OX₂ORii_b, - X₂Ri_Ib; wherein each X₂ is independently selected from a bond and Ci_₄alkylene;

wherein any methylene of X₂ can have a hydrogen substituted with hydroxy; R_{1 la} and Rub are independently selected from hydrogen, cyano, C_1-4alkyl, C_1-4alkoxy, C_6-1oaryl, Ci-gheteroaryl, Q.gheterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R₃ is optionally substituted by 1 to 2 methyl radicals; or R_{l la} and Ru_b 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 R_{1 la} and R₁ ^ is optionally substituted with hydroxyl;

R₄ is selected from hydrogen, C_1-4alkyl, C_1-4alkenyl, C₆-ioarylCi_₄alkyl, -

X₃ORi₂, -X₃NRi₂Ri₂ and -X₃C(O)ORi₂; wherein X₃ is selected from a bond and C_1-4alkylene; and each Ri₂ is independently selected from hydrogen and C_1-4alkyl; or when -Y₂R₅ is benzyl, the ortho hydrogen of R₅ and R₄ can form a cyclopentyl;

R₅ is selected from hydrogen, C_1-4alkyl, C_6-1OaTyI, 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-₂Ri_3a, halo-substituted-C_1-4alkyl, C_1-4alkyl, halo-substituted-Ci-₄alkoxy, Ci_₄alkoxy,

Cό-ioaryl, -C(O)NRi3_aRi3b and -C(O)ORi3_a; wherein Ri3_a 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 C_1-4 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, C_1-

₆alkyl, X₄NRi_4aRi₄b, X₄OR₁^; wherein X₄ is selected from a bond, Ci-6alkylene; and Ri_4a and Ri_4b are independently selected from hydrogen and C_1-4alkyl; 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:

Ia Ib Ic in which:

n is selected from 1, 2 and 3;

Ri is selected from C_2-1oalkenyl, C_6-1OaTyI, C₆-ioaryl-C₂-₃alkynyl, C_1- gheteroaryl, acetylenyl, C_3-8heterocycloalkyl, C_3-8heterocycloalkenyl, C_3-6cycloalkyl, C₃-

₆cycloalkyl-C_2-3alkynyl, C_3-6cycloalkenyl; 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, C_1-4alkyl, halo-substituted-Ci-₄alkyl, C^alkoxy, halo-substituted-Ci-₄alkoxy, C_6-10aryl, C_1-9heteroaryl, C₃-₈heterocycloalkyl, C_3-10cycloalkyl, -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, C_1-4alkyl, halo-substituted C_1-4alkyl and C_1-4alkoxy; wherein R₇ is selected from hydrogen, C_1-6alkyl, C₃-iocycloalkyl optionally substituted with C_1-6alkyl 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, C_1-6alkyl, Ci-βalkoxy, halo-substituted-Ci-

₆alkyl, halo-substituted-Ci_₆alkoxy, -X₅S(O)O₂RiOa, -X₅ORiOa, -X₅NRi_Oa 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, C_ό-ioaryl, C₃-_locycloalkyl, heteroaryl or heterocycloalkyl; and Ri_Oa and Ri_Ob are independently selected from hydrogen, C_1-4alkyl, cyano-substituted-C_1-4alkyl, C_1-4alkoxy, phenyl, azetidinyl, imidazolyl and pyrazolyl; or Rio_a 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 R_1Oa, Rio_b or the combination of Ri_Oa and Rio_b can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C_1-4alkyl, halo-substituted-C^alkyl, C_1-4alkoxy, halo- substituted-Ci-₄alkoxy, C_6-1oaryl, C_1-9heteroaryl, C₃-₈heterocycloalkyl, C_3-1ocycloalkyl, - 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, C_1-4alkyl, halo-substituted C_1-4alkyl and Ci-₄alkoxy; wherein Rioc and Riod are selected from hydrogen, C_1-6alkyl, C₃- iocycloalkyl optionally substituted with C_1-6alkyl or halo;

R₃ is selected from cyano, -C(O)OR_{1 la}, -C(O)R_{1 la}, -X₂OC(O)R_{1 la}, -

C(0)0X₂Rii_a, -X₂OS(0)o-₂Rlla, -X₂S(O)_0-2RlIa, "C(O)OX₂ORiIa, -C(O)OX₂NRiIaRlIb,

-C(O)NRiiaRiib, -X₂NRiIaRiIb, -NRiiaC(O)Rii_b, -NRiiaC(0)0Rii_b, -NR₁ US(O)_0-2R_{1 lb}, -C(O)NX₂RiIaX₂RiIb, -C(O)OX₂C(O)NRiIaRiIb, -C(0)NR_llaX₂0R_llb, - C(O)NRii_aX₂C(O)ORn_b, -C(O)NRi i_aX₂C(O)NRn_aRn_b, -C(O)NRi i_aX₂OX₂ORn_b, - X₂Ri_Ib; 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 i_a and Ru_b are independently selected from hydrogen, cyano, Ci_₄alkyl, Ci_₄alkoxy, C_ό-ioaryl, Ci-gheteroaryl, Q.gheterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R₃ is optionally substituted by 1 to 2 methyl radicals; or Rn_a and Ru_b 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 i_a and Ri i_b is optionally substituted with hydroxyl;

R₄ is selected from hydrogen, Ci-₄alkyl, Ci-₄alkenyl,

-

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, X₄NRi_4aRi₄b, X₄ORi_4a; wherein X₄ is selected from a bond, Ci-βalkylene; and Ri_4a and Ri_4b are independently selected from hydrogen and Ci_₄alkyl;

Ri₈ is selected halo, cyano, -S(0)o-₂Ri_3a,halo-substituted-Ci_₄alkyl, Ci_₄alkyl, halo-substituted-Ci-₄alkoxy, Ci-₄alkoxy, C₆-ioaryl, -C(O)NRi_8aRi8b and -C(0)0Ri_8a; wherein Rig_a and Rig_b 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:

in which:

n is selected from 1, 2 and 3;

Ri is selected from C_2-1oalkenyl, C_6-1OaTyI,

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, C_6-1oaryl, 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, C_1-4alkyl, halo-substituted C^alkyl and C_1-4alkoxy;

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, C_1-6alkyl, Ci-βalkoxy, halo-substituted-Ci- ealkyl, halo-substituted-Ci-₆alkoxy, -X₅S(O)₀-IRiOa, -X₅ORi_0a, -X₅NRi_Oa X₅RiOb, - X₅S(O)₀-INRiOaRiOb, -X₅NRiOaRiOb, -X₅C(O)NRiOaRiOb, -X₅NRiObC(O)RiOa and - X₅C(0)ORio_a; wherein said X₅ is selected from a bond and C_1-4alkylene wherein any methylene of X₅ can have a hydrogen substituted with hydroxyl, C_6-1oaryl, C_3-locycloalkyl, heteroaryl or heterocycloalkyl; and Rio_a and Riob are independently selected from hydrogen, C_1-4alkyl and C_1-4alkoxy; or Ri_Oa and Rio_b 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_1-4alkyl, halo-substituted-C_1-4alkyl, C_1-4alkoxy, halo-substituted-Ci-₄alkoxy, C_6-1oaryl, Cμgheteroaryl, C_3-8heterocycloalkyl, C_3-10cycloalkyl, -C(O)OR_10c, -C(O)R_10c, -NRi_Oc 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, C_1-4alkyl, halo-substituted C_1-4alkyl and Ci-₄alkoxy; wherein Rioc and Riod are selected from hydrogen, C_1-6alkyl, C₃_iocycloalkyl optionally substituted with C_1-6alkyl or halo;

R₃ is selected from cyano, -C(O)ORi u, -C(O)R_{1 la}, -X₂OC(O)R_{1 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 R_{l la}X₂0R_llb, -C(O)N Rii_aX₂C(0)0Rii_b, -

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; R_{1 la} and R₁ ^ are independently selected from hydrogen, cyano, Ci-₄alkyl, Ci-₄alkoxy, Cβ-ioaryl,

C₃-₈heterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R₃ is optionally substituted by 1 to 2 methyl radicals; or R_{1 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 R_{1 la} and R₁ ^ is optionally substituted with hydroxyl;

R₄ is selected from hydrogen, C_1-4alkyl, C_1-4alkenyl, 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 C_1-4alkyl;

Re is selected from hydrogen, halo, cyano, C_1-6alkyl, X₄NRi_4aRi₄b, X₄ORi_4a; wherein X₄ is selected from a bond, Ci-₆alkylene; and Ri_4a and R_14b are independently selected from hydrogen and C_1-4alkyl; and

Rig is selected halo, cyano, -S(0)o-₂R₁₃a,halo-substituted-C_1-4alkyl, C_1-4alkyl, halo-substituted-Ci-₄alkoxy, Ci-₄alkoxy, Cό-ioaryl, -C(O)NRi8_aRi8b and -C(O)ORi8_a; wherein Ri_8a and Ri_8b are independently selected from hydrogen and C_1-4alkyl

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:

in which:

Ri is selected from C_2-1oalkenyl, C_6-1OaTyI, Q.gheteroaryl, acetylenyl, C₃. gheterocycloalkyl, C_3-8heterocycloalkenyl, C_3-6cycloalkyl, C_3-6cycloalkenyl; 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, C_1-4alkyl, halo-substituted-C^alkyl, C_1-4alkoxy, halo- substituted-Ci_₄alkoxy, C_6-1oaryl, Q.gheteroaryl, C_3-8heterocycloalkyl, C_3-1ocycloalkyl, - 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, C_1-4alkyl, halo-substituted C_1-4alkyl and C_1-4alkoxy;

wherein R₇ is selected from hydrogen, C_1-6alkyl, C₃_iocycloalkyl optionally substituted with C_1-6alkyl 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, -X₅NRi_Oa 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, C_6-1oaryl, C₃.

locycloalkyl, heteroaryl or heterocycloalkyl; and Ri_Oa and Ri_Ob are independently selected from hydrogen, Ci-₄alkyl and Ci-₄alkoxy; or Rio_a 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, C_6-1oaryl, 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 C_1-6alkyl or halo;

R₃ is selected from cyano, -C(O)OR_{1 la}, -C(O)R_{1 la}, -X₂OC(O)R_{1 la}, -

C(0)0X₂Rii_a, -X₂OS(0)o-₂Rlla, -X₂S(O)_0-2RlIa, -C(0)0X₂0Rii_a, -C(O)OX₂NRiIaRlIb,

-C(O)N RiiaRiib, -X₂NRiIaRiIb, -NRiiaC(O)Rii_b, -NRiiaC(0)0Rii_b, -NR_llaS(0)o-₂R_llb, -C(O)N RiIaX₂RiIb, -C(O)N Rii_aX₂0Rii_b, -C(O)N Rii_aX₂C(0)0Rii_b, - C(O)NRiiaX₂C(O)NRiiaRiib, -C(O)N Rii_aX₂OX₂ORii_b, X₂Ri_lb; wherein each X₂ is independently selected from a bond and C_1-4alkylene; wherein any methylene of X₂ can have a hydrogen substituted with hydroxy; R_{1 la} and R₁ ^ are independently selected from hydrogen, cyano, C_1-4alkyl, Ci-₄alkoxy, Cβ ioaryl,

C₃-₈heterocycloalkyl; wherein said aryl, heteroaryl or heterocycloalkyl of R₃ is optionally substituted by 1 to 2 methyl radicals; or R_{1 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 R_{1 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,

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-₂Ri_3a, halo-substituted-C_1-4alkyl, Ci_₄alkyl, halo-substituted-Ci_₄alkoxy, Ci_₄alkoxy,

Cό-ioaryl, -C(O)NRi_3aRi₃b and -C(O)ORi_3a; wherein Ri_3a 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 C_1-4 alkyl; or R₄ and Y₂ taken together form a double bond or a cyclopropyl ring; and

Re is selected from hydrogen, halo, cyano, C_1-6alkyl, X₄NRi_4aRi₄b, X₄ORi_4a; wherein X₄ is selected from a bond, Ci_₆alkylene; and Ri_4a and R_14b are independently selected from hydrogen and C_1-4alkyl.

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.