Compounds useful for inhibiting RET kinase

Abstract

Provided herein are RET kinase inhibitors according to the formula: ##STR00001##
pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods for their use in the treatment of diseases that can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders. A, R.sub.1, n, X.sub.1, X.sub.2, X.sub.3, X.sub.4, and R.sub.2 have the meanings given in the specification.

Claims

1. A compound of the formula: ##STR00725## wherein A is a five- or six-member aryl or heteroaryl; Each R.sub.1 is independently hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, —(C.sub.0-C.sub.4 alkyl)(C.sub.5-C.sub.6 heteroalkyl), —(C.sub.0-C.sub.4 alkyl)(C.sub.3-C.sub.7 cycloalkyl), —(C.sub.0-C.sub.4 heteroalkyl)(C.sub.3-C.sub.7 cycloalkyl), —(C.sub.0-C.sub.4 alkyl)(C.sub.4-C.sub.7 cycloheteroalkyl), —(C.sub.0-C.sub.4 heteroalkyl)(C.sub.3-C.sub.7 cycloheteroalkyl), —(C.sub.0-C.sub.4 alkyl)(C.sub.4-C.sub.10 bicyclic), —(C.sub.0-C.sub.4 alkyl)(C.sub.5-C.sub.6 aryl), —(C.sub.0-C.sub.4 alkyl)(C.sub.5-C.sub.6 heteroaryl), —(C.sub.0-C.sub.4 alkyl)(C.sub.4-C.sub.10 heterobicyclic), C.sub.5-C.sub.12 spirane, C.sub.5-C.sub.12 heterospirane, adamantane, difluoromethylsulfane, or pentafluorosulfane, wherein each R.sub.1 is optionally substituted with one or more groups that are independently halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N-dimethylmethylamine, or mono-, di-, or tri-halomethyl, and wherein two R.sub.1 groups can fuse to form a ring structure that includes a portion of A and is optionally aromatic, and n is 1, 2, or 3; X.sub.1, X.sub.2, X.sub.3, and X.sub.4 are each independently N, CH, C—CH.sub.3, C—CH.sub.2—OH, C—OCH.sub.3, C—CH.sub.2—OCH.sub.3, or C-halogen; and R.sub.2 is C.sub.1-C.sub.4 alkyl, —(C.sub.0-C.sub.4 alkyl)(C.sub.3-C.sub.7 cycloalkyl), —(C.sub.0-C.sub.4 alkyl)(C.sub.4-C.sub.7 heterocycloalkyl), —(C.sub.0-C.sub.4 alkyl)(C.sub.4-C.sub.10 bicyclic) each optionally substituted with one or more groups that are independently deuterium, halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein each of X.sub.1, X.sub.2, X.sub.3, and X.sub.4 is CH, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein A-(R.sub.1).sub.n is ##STR00726## or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein A-(R.sub.1).sub.n is ##STR00727## or or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3, wherein R.sub.1 is 2,2-dimethylpropyl; 2-chloro-4-fluoro-phenyl; 2,4-dichlorophenyl; 1,1-dimethyl-2,2,2-trifluoroethyl; 1,1-dimethylethyl; 1,1-dimethylpropyl; trifluoromethyl; 1,1-dimethyl-2,2-difluoropropyl; 1,1-dimethyl-3,3,3-trifluoropropyl; 1-methylcyclopropyl; (1-methylcyclopropyl)methyl; 3-methylbicyclo[1.1.1]pentan-1-yl; 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl; (3,3-dimethylcyclobutyl)methyl or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 3, wherein R.sub.1 is 2,2-dimethylpropyl, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 4, wherein R.sub.1 is 2,2-dimethylpropyl, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 3, wherein at least one R.sub.1 is halogen, —CH.sub.2C(CH.sub.3).sub.3, ##STR00728## or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 4, wherein at least one R.sub.1 is halogen, —CH.sub.2C(CH.sub.3).sub.3, ##STR00729## or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 3, wherein R.sub.2 is ##STR00730## or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 5, wherein R.sub.2 is ##STR00731## or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 4, wherein R.sub.2 is —CH(CH.sub.3).sub.2, —CH(CF.sub.3)CH.sub.3, —CH(CH.sub.3)CHF.sub.2, or ##STR00732## or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 5, wherein R.sub.2 is —CH(CH.sub.3).sub.2, —CH(CF.sub.3)CH.sub.3, —CH(CH.sub.3)CHF.sub.2, or ##STR00733## or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 4, wherein R.sub.2 is ##STR00734## or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 5, wherein R.sub.2 is ##STR00735## or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, of the formula: ##STR00736## or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, of the formula: ##STR00737## or a pharmaceutically acceptable salt thereof.

18. A compound that is: ##STR00738## ##STR00739## ##STR00740## ##STR00741## ##STR00742## or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18, wherein the formulas have R-enantiomeric chirality at the ϕ position.

20. The compound according to claim 18, wherein the formulas have S-enantiomeric chirality at the ϕ position.

21. A method of treating cancer in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the cancer is a RET-associated cancer.

22. The method according to claim 21, wherein the cancer is selected from the group consisting of: lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.

23. The method of claim 21, wherein the cancer is medullary thyroid cancer.

24. The method of claim 22, wherein the lung cancer is small cell lung carcinoma, non-small cell lung cancer, bronchioles lung cell carcinoma, RET fusion lung cancer, or lung adenocarcinoma.

25. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 1 with one or more pharmaceutically acceptable carriers, diluents, or excipients.

Description

PREPARATIONS AND EXAMPLES

Preparation 1

Methyl 2-(5-bromo-2-pyridyl)propanoate

(1) ##STR00294##

(2) To methyl 2-(5-bromopyridin-2-yl)acetate (4.20 g, 17.5 mmol) in THF (84 mL) under N2 and at −20° C. is added 60% NaH (w/w) in mineral oil (771 mg, 19.3 mmol). The mixture is stirred at −20° C. until gas evolution has subsided. To the reaction mixture is then added iodomethane (4.4 mL, 70.1 mmol). The mixture is stirred for 5 min at −20° C. after which time it is allowed to warm to RT. After 1 hr the reaction mixture is concentrated under reduced pressure and dried under vacuum. To the residue is added DCM (15 mL), H.sub.2O (10 mL) and saturated aqueous NaHCO.sub.3 solution (10 mL). The organic layer is separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material is purified by silica gel flash chromatography eluting with a gradient of EtOAc in DCM from 0% to 20% to give the title compound as a colorless oil (3.16 g, 68.59%).

Preparation 2

Methyl 2-[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]propanoate

(3) ##STR00295##

(4) 60% NaH (w/w) in mineral oil (3.85 g, 96.091 mmol) is added to THF (180 mL) in portions at RT under N.sub.2. To this mixture is added malononitrile (3.17 g, 48.046 mmol) in THF (20 mL) dropwise at 0-10° C. and the mixture is stirred for 30 min at RT. To this mixture is added methyl 2-(4-chlorocarbonylphenyl)propanoate (13 g, crude) in THF (30 mL) dropwise at 0° C. and the mixture is stirred for 2 hrs at RT. The resulting mixture is used directly without further purification.

Preparation 2a

2-[(4-Bromo-2,3-difluoro-phenyl)-hydroxy-methylene]propanedinitrile

(5) ##STR00296##

(6) To a stirred mixture of NaH (1.68 g, 42.13 mmol, 60%) in THF (100 mL) is added malononitrile (1.53 g, 23.160 mmol) in THF (100 mL) dropwise at 0° C. under N.sub.2. The mixture is stirred for 30 min at RT under N.sub.2. To the above mixture is added 4-bromo-2,3-difluorobenzoyl chloride in THF (10 mL) dropwise at 0° C. The mixture is stirred for additional 2 hr at RT. The mixture is used without further purification.

Preparation 3

Methyl 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]propanoate

(7) ##STR00297##

(8) To crude methyl 2-[4-(2,2-dicyano-1-hydroxy-vinyl)phenyl]propanoate in THF solution is added dimethyl sulfate (7.67 g, 60.810 mmol) dropwise at RT under N.sub.2 and the mixture is stirred overnight at 80° C. under N.sub.2. The mixture is allowed to cool to RT and quenched with H.sub.2O (300 mL). The mixture is extracted with EtOAc (3×300 mL) and the combined organic extracts are washed with saturated aqueous NaCl solution (3×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with hexanes/EtOAc (6:1-1:1) to give the title compound (5 g, 36.49% over 3 steps) as a yellow oil. .sup.1H NMR (d.sub.6-DMSO) δ 7.71-7.62 (m, 2H), 7.59-7.50 (m, 2H), 4.00-3.93 (m, 1H), 3.90 (s, 3H), 3.63 (s, 3H), 1.44 (d, 3H).

Preparation 3a

2-[(4-Bromo-2,3-difluoro-phenyl)-methoxy-methylene]propanedinitrile

(9) ##STR00298##

(10) To crude 2-[(4-bromo-2,3-difluoro-phenyl)-hydroxy-methylene]propanedinitrile is added dimethyl sulfate (3.35 g, 26.56 mmol) dropwise at RT. The mixture is stirred overnight at 80° C. under N.sub.2. The mixture is cooled to RT. The reaction is quenched with H.sub.2O at RT. The mixture is extracted with EtOAc (3×100 mL). The combined organic extracts are washed with brine (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (3:1-2:1) to give the title compound (5.0 g, 75.5% over 3 steps) as a light grey solid. .sup.1H NMR (300 MHz, CDCl.sub.3) δ7.64-7.54 (m, 1H), 7.18-7.11 (m, 1H), 3.99 (d, 3H).

Preparation 3b

2-[(4-Bromo-2-fluorophenyl)(methoxy)methylidene]propanedinitrile

(11) ##STR00299##

(12) Into a solution of 2-(4-bromo-2-fluorobenzoyl)propanedinitrile (23.40 g, 87.62 mmol) in THF (300 mL), is added dimethyl sulfate (13.26 g, 105.13 mmol) and the mixture is stirred overnight at 80° C. under N.sub.2. The solution is cooled to RT and concentrated under reduced pressure. The crude product is dissolved in EtOAc (200 mL) and diluted with H.sub.2O (200 mL). The mixture is extracted with EtOAc (3×200 mL) and the organic extract is washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a gradient of 5:1 to 3:1 PE to EtOAc to give the title product (23.5 g, 95.4%) as brown semi-solid. ES/MS m/z (.sup.79Br/.sup.81Br) 265.0/267.0 [M+H].sup.+.

Preparation 4

5,5-Difluoro-4,4-dimethyl-3-oxohexanenitrile

(13) ##STR00300##

(14) To a stirred mixture of LDA (20.81 mL, 41.62 mmol) in THF (100 mL) is added ACN (1.82 g, 44.33 mmol) in THF dropwise at −70° C. The mixture is stirred for 30 min at −70° C. To the above mixture is added ethyl 3,3-difluoro-2,2-dimethylbutanoate (5 g, 27.75 mmol) in THF dropwise at −70° C. and the mixture is slowly warmed to RT. The reaction is quenched by the addition of sat. NH.sub.4Cl (aq.) (30 mL) at 0° C. and extracted with PE (200 mL). The aqueous phase is acidified to pH=3 with HCl (aq.) (1 N) and extracted with EtOAc (3×100 mL). The EtOAc extracts are washed with saturated aqueous NaCl solution (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (1.9 g, 39.09%) as a brown oil which is used without further purification. .sup.1H NMR (CDCl.sub.3) δ3.79 (s, 2H), 1.63 (t, 3H), 1.34 (s, 6H).

Preparation 5

4-(3-Bicyclo[1.1.1]pentanyl)-3-oxo-butanenitrile

(15) ##STR00301##

(16) 60% NaH (w/w) in mineral oil (140 mg, 3.5 mmol) in THF (1 mL) is added dropwise to a stirring solution of benzyl 2-(3-bicyclo[1.1.1]pentanyl)acetate (504 mg, 2.33 mmol) and ACN (134 μL, 2.56 mmol) in THF (8 mL, 0.3 M) at RT. The reaction mixture is heated and stirred at 60° C. for 25 min. The reaction mixture is quenched with ice H.sub.2O (10 mL), acidified to pH 5 with HCl (c) and extracted with EtOAc (3×10 mL). The combined organic extracts are washed with saturated aqueous NaCl solution (10 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure to give the title compound (350 mg).

Preparation 5a

3-[3-Methylbicyclo[1.1.1]pentan-1-yl]-3-oxopropanenitrile

(17) ##STR00302##

(18) To THF (5.00 mL) is added n-BuLi (1.71 mL, 4.28 mmol, 2.5 M in THF) at 0° C. under N.sub.2. To the mixture is added ACN (187.42 mg, 4.56 mmol) in THF (5 mL) dropwise over 5 min at −78° C. under N.sub.2. The mixture is stirred for 1 hr at −78° C. To the mixture is added methyl 3-methylbicyclo[1.1.1]pentane-1-carboxylate (400.00 mg, 2.85 mmol) in THF (5 mL) dropwise at −78° C. under N.sub.2. The mixture is stirred for 1 hr at RT. The reaction is quenched by the addition of saturated NH.sub.4Cl aq. (20 mL) at 0° C. The mixture is acidified to pH 4 with HCl (1 N) aq. and extracted with DCM (3×50 mL). The combined organic extracts are washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure, to give the title compound (360 mg, 84.5%) as a brown liquid.

Preparation 5b

3-Oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]propanenitrile

(19) ##STR00303##

(20) n-BuLi (0.83 mL, 2.087 mmol, 2.5 M in hexanes) is added to THF (10 mL) at 0° C. under N.sub.2. ACN (91.34 mg, 2.23 mmol) in THF (2 mL) is added dropwise over 2 min at −78° C. under N.sub.2 and the reaction is stirred for 1 hr at −78° C. Methyl 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (270.00 mg, 1.39 mmol) in THF (2 mL) is added dropwise to the reaction mixture at −78° C. and the reaction is stirred at RT for 12 hr. The reaction is quenched by the addition of sat. NH.sub.4Cl (aq., 20 mL), acidified to pH=4 with concentrated HCl, and extracted with DCM (3×50 mL). The combined organic extracts are washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product (290 mg) is used without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3) δ3.54 (s, 2H), 2.39 (s, 6H).

(21) The following compound in Table 1 is prepared essentially as described for 3-oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]propanenitrile, adjusting reaction time to determine completion of the reaction, and purification conditions as appropriate. The reaction can be allowed to warm to RT after the carboxylate is added. n-BuLi can be added in hexanes or THF.

(22) TABLE-US-00003 TABLE 1 Prep. No. Chemical name Structure 5c 3-Oxo-3-[4- (trifluoromethyl)bicyclo[2.2.1]heptan-1- yl]propanenitrile 04

Preparation 6

tert-Butyl N-(tert-butoxycarbonylamino)-N-(2-methoxy-1,1-dimethyl-ethyl)carbamate

(23) ##STR00305##

(24) To a stirred solution of Mn(dpm).sup.3 (60.31 mg, 0.100 mmol) in IPA (20.00 mL) is added 3-methoxy-2-methyl-prop-1-ene (860.00 mg, 9.984 mmol), PhSiH.sub.3 (1.08 g, 9.984 mmol), and (E)-N-[(tert-butoxycarbonyl)imino](tert-butoxy)formamide (3.45 g, 14.98 mmol) in portions at 0° C. under N.sub.2. The resulting mixture is stirred for 2 hrs at RT under N.sub.2 and concentrated under vacuum. H.sub.2O (15 mL) is added, and the resulting mixture is extracted with EtOAc (3×30 mL). The combined organic extracts are washed with saturated aqueous NaCl solution (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE/EtOAc (10:1 to 7:3) to give the title compound (1.8 g, 56.62%) as a colorless oil. .sup.1H NMR (CDCl.sub.3) δ3.38-3.32 (m, 5H), 1.49-1.46 (m, 24H).

Preparation 7

tert-Butyl N-(1-methylcyclopropyl)-N-nitroso-carbamate

(25) ##STR00306##

(26) To a stirred solution of tert-butyl N-(1-methylcyclopropyl)carbamate (2.00 g, 11.68 mmol) in DCM (20.00 mL) is added tert-butyl nitrite (2.40 g, 23.36 mmol) in portions at RT under N.sub.2 and the mixture is stirred for 2 hrs at RT under N.sub.2. The mixture is concentrated under reduced pressure and the residue is purified by silica gel column chromatography, eluting with PE/EtOAc (25/1 to 20/1) to give the title compound (1.3 g, 55.59%) as a brown liquid. .sup.1H NMR (d.sub.6-DMSO) δ1.59 (s, 9H), 1.10 (s, 3H), 0.86-0.84 (m, 2H), 0.70-0.65 (m, 2H).

Preparation 8

(1-Methylcyclopropyl)hydrazine hydrochloride

(27) ##STR00307##

(28) To a stirred solution of tert-butyl N-(1-methylcyclopropyl)-N-nitroso-carbamate (1.20 g, 5.99 mmol) in 4 N HCl (8.00 mL) is added Zn (783.98 mg, 11.99 mmol) in portions at 0° C. under N.sub.2 and the mixture is stirred for 12 hrs at RT under N.sub.2. The mixture is filtered, the filter cake is washed with H.sub.2O (3×10 mL), and the filtrate is concentrated under reduced pressure to give the title compound (2 g, crude) as an off-white solid which is used directly without further purification. .sup.1H NMR (d.sub.6-DMSO) δ1.30 (s, 3H), 0.77-0.73 (m, 2H), 0.54-0.50 (m, 2H).

Preparation 9

(1-Methoxy-2-methylpropan-2-yl)hydrazine hydrochloride

(29) ##STR00308##

(30) A solution of tert-butyl N-(tert-butoxycarbonylamino)-N-(2-methoxy-1,1-dimethyl-ethyl)carbamate (1.6 g, 5.00 mmol) in HCl (gas) in 1,4-dioxane (15.00 mL) is stirred for 6 hrs at RT under N.sub.2. The mixture is concentrated under vacuum and triturated with Et.sub.2O (3×10 mL) to give the title compound (400 mg, 52%) as a semi-solid. .sup.1H NMR (d.sub.6-DMSO) δ3.36 (s, 2H), 3.32 (s, 3H), 1.17 (s, 6H).

Preparation 10

(1,1,1-Trifluoro-2-methylpropan-2-yl)hydrazine dihydrochloride

(31) ##STR00309##

(32) To a stirred mixture of N′-(1,1,1-trifluoro-2-methylpropan-2-yl)benzohydrazide (7.50 g) in H.sub.2O (40.00 mL) is added HCl (c) (40.00 mL) in portions at RT under N.sub.2. The resulting mixture is stirred for 12 hrs at 80° C. under N.sub.2. The mixture is allowed to cool to RT and concentrated under reduced pressure. The resulting solid is triturated with Et.sub.2O (30 mL) and the precipitated solids are collected by filtration and washed with Et.sub.2O (3×30 mL) to give the title compound (4.0 g, 61%) as an off-white solid. .sup.1H NMR (d.sup.6-DMSO) δ9.55 (br, s, 2H), 5.60 (br, s, 3H), 1.34 (s, 6H).

Preparation 11

N-[(E)-(4-Bromophenyl)methyleneamino]propan-2-amine

(33) ##STR00310##

(34) A solution of 4-bromo-benzaldehyde (100.00 g, 540.48 mmol), isopropylhydrazine hydrochloride (65.75 g, 594.53 mmol), and DIPEA (76.84 g, 594.53 mmol) in DMF (500 mL) is stirred for 3 hrs at 80° C. under N.sub.2. The reaction is cooled to RT. The resulting mixture is used directly without workup or further purification. ES/MS m/z (.sup.79Br/.sup.81Br) 241.1/243.1 [M+H].sup.+.

(35) The following compounds in Table 1a are prepared essentially as described for N-[(E)-(4-bromophenyl)methyleneamino]propan-2-amine using the appropriate reagents and adjusting reaction times to determine completion of the reactions.

(36) TABLE-US-00004 TABLE 1a ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 12 5-Bromo-2-[(1E)-[2-(1- methylcyclopropyl)hydrazin- 1-ylidene]methyl]pyridine  254.0, 256.0 13 5-Bromo-2-[(1E)-[2-(1,1,1- trifluoropropan-2- yl)hydrazin-1- ylidene]methyl]pyridine  295.9, 297.9

Preparation 13a

N′-[(2Z/E)-1-bromo-1,1-difluoropropan-2-ylidene]benzohydrazide

(37) ##STR00313##

(38) To a crude solution of 1-bromo-1,1-difluoro-propan-2-one (200 mL of 3/1 Et.sub.2O/toluene) is added benzohydrazide (23.62 g) in sealed tube at RT under N.sub.2. The mixture is stirred 2 hrs at 50° C. under N.sub.2. The mixture is allowed to cool to RT. The precipitated solids are collected by filtration and washed with toluene (3×100 mL) to give the title compound (28 g, 34%, over 2 steps, purity 62% on .sup.1H-NMR) as a white solid.

Preparation 13b

(Z/E)-N-[(2,2,2-Trideuterio-1-methyl-ethylidene)amino]benzamide

(39) ##STR00314##

(40) To a stirred mixture of 1,1,1-trideuteriopropan-2-one (0.24 g, 3.93 mmol) in THF (50 mL) is added benzohydrazide (2.14 g, 15.71 mmol, dissolved in THF (10 mL)) dropwise at −78° C. under N.sub.2. The mixture is stirred for 2 hrs at −78° C. The mixture is diluted with EtOAc (200 mL). The organic phase is washed with H.sub.2O (2×50 mL) and brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound which is used directly without further purification. ES/MS (m/z) 180.1 (M+H).

Preparation 13c

N-[[2,2,2-Trideuterio-1-(trideuteriomethyl)ethylidene]amino]benzamide

(41) ##STR00315##

(42) To a stirred solution of benzohydrazide (5.00 g, 36.723 mmol) in MeOH (100.00 mL) is added 1,1,1,3,3,3-hexadeuteriopropan-2-one (2.35 g, 36.723 mmol) dropwise at RT. The mixture is stirred overnight at RT and then concentrated under reduced pressure to give the title compound (5 g, 74.70%) as a white solid. ES/MS (m/z) 183.3 (M+H).

Preparation 13d

N′-(2,2,2-Trideuterio-1-methyl-ethyl)benzohydrazide

(43) ##STR00316##

(44) To a stirred mixture of (Z/E)-N-[(2,2,2-trideuterio-1-methyl-ethylidene)amino]benzamide (695 mg, 3.88 mmol) in MeOH (5 mL) is added NaBH.sub.4 (293.40 mg, 7.76 mmol) in portions at 0° C. The mixture is stirred at rt for 1 hr. The mixture is diluted with EtOAc (100 mL), washed with H.sub.2O (30 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (3:1˜1:3) to give the title compound (280 mg, 39.8%) as a white solid. ES/MS (m/z) 182.2 (M+H).

Preparation 13e

N′-[2,2,2-Trideuterio-1-(trideuteriomethyl)ethyl]benzohydrazide

(45) ##STR00317##

(46) To a stirred solution of N-[[2,2,2-Trideuterio-1-(trideuteriomethyl)ethylidene]amino]benzamide (2.00 g, 10.97 mmol) in MeOH (30.00 mL) is added NaBH.sub.4 (0.81 g, 21.95 mmol) in portions at RT. The mixture is stirred for 2 hrs. The reaction is quenched with H.sub.2O (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts are washed with H.sub.2O (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure to give the title compound (1.9 g, 93.96%) as a white solid. ES/MS (m/z) 185.3 (M+H).

Preparation 13f

N′-(1,2,2,2-Tetradeuterio-1-methyl-ethyl)benzohydrazide

(47) ##STR00318##

(48) To a stirred mixture of (Z/E)-N-[(2,2,2-trideuterio-1-methyl-ethylidene)amino]benzamide (695.00 mg, 3.88 mmol) in CD.sub.3OD (5 mL) is added NaBD.sub.4 (326.15 mg, 7.77 mmol) in portions at 0° C. The mixture is stirred at RT for 1 hr. The mixture is diluted with EtOAc (100 mL) and washed with H.sub.2O (30 mL) brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with PE:EtOAc (3:1˜1:3) to give the title compound (260 mg, 36.6%) as a white solid. ES/MS (m/z) 183.2 (M+H).

(49) The following compound in Table 1b is prepared essentially as described for N′-(1,2,2,2-tetradeuterio-1-methyl-ethyl)benzohydrazide using the appropriate reagents and adjusting reaction times to determine completion of the reactions. NaBD.sub.4 can be added at RT and can be used without further purification.

(50) TABLE-US-00005 TABLE 1b ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 13g N′-[1,2,2,2-Tetradeuterio-1- (trideuteriomethyl)ethyl]benzohydrazide 186.3

Preparation 13h

N′-(2-bromo-2,2-difluoro-1-methyl-ethyl)benzohydrazide

(51) ##STR00320##

(52) To a stirred solution of N′-[(2E)-1-bromo-1,1-difluoropropan-2-ylidene]benzohydrazide (12 g, 41.22 mmol) in THF (100 mL) is added BH.sub.3-THF (82.45 mL, 82.45 mmol, 1 M in THF) dropwise at 0° C. under N.sub.2. The mixture is stirred for 12 hrs at RT under N.sub.2. The reaction is quenched by the addition of MeOH (5 mL) at 0° C. The mixture is diluted with H.sub.2O (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts are washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (8/1 to 6/1) to give the title compound (7 g, 57%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78-7.73 (m, 2H), 7.60-7.53 (m, 1H), 7.52-7.45 (m, 2H), 3.57-3.49 (m, 1H), 1.45 (d, 3H).

Preparation 13i

[2,2,2-Trideuterio-1-(trideuteriomethyl)ethyl]hydrazine.HCl

(53) ##STR00321##

(54) A mixture of N′-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]benzohydrazide (500 mg, 2.71 mmol) in HCl (5.00 mL, cone) is stirred overnight at 80° C. The mixture is allowed to cool to RT and concentrated under reduced pressure. The crude product is triturated with Et.sub.2O (3 mL). The resulting precipitate is filtered, and the filter cake is washed with Et.sub.2O (3×2 mL) to give the title compound (180 mg, 56.88%) as a white solid.

(55) The following compounds in Table 1c are prepared essentially as described for [2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]hydrazine.HCl using the appropriate reagents and adjusting reaction times to determine completion of the reactions.

(56) TABLE-US-00006 TABLE 1c Prep. No. Chemical name Structure 13j (2,2,2-Trideuterio-1-methyl- ethyl)hydrazine•HCl 13k (1,2,2,2-Tetradeuterio-1-methyl- ethyl)hydrazine•HCl 13l [1,2,2,2-Tetradeuterio-1- (trideuteriomethyl)ethyl]hydrazine•HCl  13m (1-Bromo-1,1-difluoropropan-2- yl)hydrazine•HCl

Preparation 14

(1Z)-4-Bromo-N-isopropyl-benzohydrazonoyl bromide

(57) ##STR00326##

(58) To N-[(E)-(4-bromophenyl)methyleneamino]propan-2-amine is added NBS (106.04 g, 595.77 mmol) in DMF dropwise and the mixture is stirred for 3 hrs at 0° C. under N.sub.2. The resulting mixture is used directly without workup or further purification.

(59) The following compounds in Table 2 are prepared essentially as described for (1Z)-4-bromo-N-isopropyl-benzohydrazonoyl bromide using the appropriate reagents and adjusting reaction times to determine completion of the reactions.

(60) TABLE-US-00007 TABLE 2 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 15 (Z)-5 Bromo-N-(1- methylcyclopropyl)pyridine-2- carbohydrazonoyl bromide 333.9 16 (Z)-5-Bromo-N-(1,1,1- trifluoropropan-2-yl)pyridine- 2-carbohydrazonoyl bromide  373.9, 377.9

Preparation 17

5-Amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carbonitrile

(61) ##STR00329##

(62) A solution of sodium ethoxide (91.88 g, 1.351 mol) and propanedinitrile (39.24 g, 594.53 mmol) in EtOH (400 mL) is stirred for 1 hr at 0° C. under N.sub.2. The crude solution of (1Z)-4-bromo-N-isopropyl-benzohydrazonoyl bromide is added to the mixture. The mixture is stirred for 2 hrs at RT. The mixture is concentrated under reduced pressure, diluted with H.sub.2O (3 L), and the resulting precipitated solids are collected by filtration, washed with H.sub.2O (3×200 mL), and the solid is dried in an oven at 50° C. to give the title compound (127 g, 73.7% over 3 steps). ES/MS (m/z) (.sup.79Br/.sup.81Br 305/307 (M+H).

(63) The following compounds in Table 3 are prepared essentially as described for 5-amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carbonitrile using the appropriate reagents, adjusting reaction times to determine completion of the reactions and purification conditions if appropriate. The crude reaction can be diluted with H.sub.2O, extracted with EtOAc, and purified with chromatography using appropriate conditions.

(64) TABLE-US-00008 TABLE 3 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 18 5-Amino-3-(5-bromopyridin- 2-yl)-1-(1- methylcyclopropyl)pyrazole- 4-carbonitrile 0  318.0, 320.0 19 5-Amino-3-(5-bromopyridin- 2-yl)-1-(1,1,1- trifluoropropan-2-yl)pyrazole- 4-carbonitrile  360.0, 362.0

Preparation 20

5-Amino-3-(4-bromophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile

(65) ##STR00332##

(66) (1-Methylcyclopropyl)hydrazine hydrochloride (1.63 g, 13.30 mmol), THF (20 mL), Et.sub.3N (3.08 g, 30.41 mmol), and 2-[(4-bromophenyl)(methoxy)methylidene]propanedinitrile (1.00 g, 3.80 mmol) are added together and stirred for 6 hrs at 50° C. The resulting mixture is diluted with EtOAc (100 mL), washed with H.sub.2O (2×30 mL), and saturated aqueous NaCl solution (20 mL). The organic phase is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: C18; ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3), UV 254 nm eluting with a gradient of 70% to 100% in 15 mins to give the title compound (375 mg, 31%) as an off-white solid. ES/MS m/z (.sup.79Br/.sup.81Br) 317.0/319.0 [M+H].sup.+.

(67) The following compounds in Table 3a are prepared essentially as described for 5-amino-3-(4-bromophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile using the appropriate reagents, adjusting reaction times to determine completion of the reactions. The Et.sub.3N can be added dropwise. The crude reaction can be concentrated to dryness and purified as appropriate.

(68) TABLE-US-00009 TABLE 3a ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 20a 5-Amino-3-(4-bromo-2,3- difluorophenyl)-1- isopropylpyrazole-4- carbonitrile 528.0/526.0 20b 5-Amino-1-(1-bromo-1,1- difluoropropan-2-yl)-3-(4- bromophenyl)pyrazole-4- carbonitrile 418.9/420.9/422.9

Preparation 20c

5-Amino-3-(4-bromo-2-fluorophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile

(69) ##STR00335##

(70) A solution of 2-[(4-bromo-2-fluorophenyl)(methoxy)methylidene]propanedinitrile (1.50 g, 5.34 mmol), (1-methylcyclopropyl)hydrazine HCl (1.96 g, 15.99 mmol) and Et.sub.3N (2.70 g, 26.682 mmol) in EtOH (20.00 mL) is stirred for 1 hr at RT under N.sub.2. The mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography, eluting with a gradient of 3:1 to 2:1 PE:EtOAc to give the title compound (1.2 g, 67.09%) as a light yellow solid. ES/MS m/z (.sup.79Br/.sup.81Br) 335.1/337.1 [M+H].sup.+.

(71) The following compounds in Table 3b are prepared essentially as described for 5-amino-3-(4-bromo-2-fluorophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile using the appropriate reagents, adjusting reaction times to determine completion of the reactions and purification conditions if appropriate. The reaction can be stirred at 50° C. and the hydrazine can be the free amine if available.

(72) TABLE-US-00010 TABLE 3b ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 20d Methyl 2-[4-[5-amino-4-cyano-1- (2,2,2-trideuterio-1-methyl- ethyl)pyrazol-3- yl]phenyl]propanoate 316.3 20e Methyl 2-[4-[5-amino-4-cyano-1- (1,2,2,2-tetradeuterio-1-methyl- ethyl)pyrazol-3- yl]phenyl]propanoate 317.3 20f 5-Amino-3-(4-bromophenyl)-1- (1,1-difluoropropan-2- yl)pyrazole-4-carbonitrile 340.9/342.9 20g 5-Amino-3-(4-bromophenyl)-1- [2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazole- 4-carbonitrile 360.1/362.1

Preparation 20h

5-Amino-3-(4-bromophenyl)-1-(2-deuterio-2,2-difluoro-1-methyl-ethyl)pyrazole-4-carbonitrile

(73) ##STR00340##

(74) To a stirred solution of 5-amino-1-(1-bromo-1,1-difluoropropan-2-yl)-3-(4-bromophenyl)pyrazole-4-carbonitrile (300.00 mg, 0.71 mmol, co-evaporated with 2×CD.sub.3OD) in CD.sub.3COOD (3.00 mL) is added Zn (467.14 mg, 7.14 mmol, co-evaporated with 2×CD.sub.3OD) in portions at RT under N.sub.2. The mixture is stirred for 1 hr at 80° C. under N.sub.2. The mixture is allowed to cool to RT and quenched with EtOAc. The mixture is filtered, the filter cake is washed with EtOAc (3×10 mL) and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (2:1-1:1) to give the title compound (100 mg, 40.92%) as a yellow solid. .sup.1H NMR (300 MHz, d.sub.6-DMSO) δ7.79-7.65 (m, 4H), 7.00 (s, 2H), 4.93-4.68 (m, 1H), 1.48 (d, 3H).

Preparation 20i

Methyl 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propanoate

(75) ##STR00341##

(76) A solution of methyl 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]propanoate (500 mg, 1.85 mmol), [2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]hydrazine.HCl (648 mg, 5.56 mmol) and Et.sub.3N (936 mg, 9.25 mmol) in EtOH (20 mL) is stirred for 1 hr at RT. The solution is diluted with H.sub.2O (30 mL) and extracted with EtOAc (3×50 mL). The organic layer is dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (650 mg, crude) as a light yellow solid. The crude product is used without further purification. ES/MS (m/z) 319.40 (M+H).

Preparation 21

tert-Butyl N-tert-butoxycarbonyl-N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate

(77) ##STR00342##

(78) To a stirred solution of 5-amino-1-isopropyl-pyrazole-4-carbonitrile (13.58 g, 85.0 mmol) in THF (170 mL) are added successively N,N-dimethylpyridin-4-amine (1.05 g, 8.50 mmol), Et.sub.3N (36 mL, 0.255 mol), and tert-butoxycarbonyl tert-butyl carbonate (40.81 g, 0.187 mol). The reaction mixture is stirred at RT overnight. The reaction mixture is quenched with a saturated aqueous solution of NH.sub.4Cl (15 mL). The aqueous layer is extracted with EtOAc (3×20 mL) and the combined organic extracts are washed with saturated aqueous NaCl solution, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude is purified by silica gel flash chromatography eluting with a gradient of EtOAc in cyclohexane from 2% to 30% to give the title compound as a pale yellow solid (9.29 g, 31%) and a second batch as a pale yellow solid (4.86 g, 16%) which combined gives 14.15 g, 47% yield.

Preparation 22

Methyl 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propanoate

(79) ##STR00343##
and

Preparation 23

Methyl 2-[5-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propanoate

(80) ##STR00344##

(81) tert-Butyl N-tert-butoxycarbonyl-N-(4-cyano-2-isopropyl-pyrazol-3-yl)carbamate (4.02 g, 11.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.39 g, 9.42 mmol), di-μ-methoxybis(1,5-cyclooctadiene)diiridium (CAS #12148-71-9) (1:2) (136 mg, 0.21 mmol) and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (112 mg, 0.41 mmol) are added together under vacuum, THF (11.60 mL) is added, and the reaction is kept under N.sub.2. The mixture is stirred and heated at 80° C. for 6 hrs. The reaction mixture is cooled to RT and stirred overnight. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in a mixture of DCM/EtOAc 3:1 (10 mL) and this solution is passed through a pad of silica gel and washed with DCM/EtOAc 3:1 (2×10 mL). The filtrates are combined, concentrated under reduced pressure, and dried under vacuum to give a crude residue. To the crude material is added Cs.sub.2CO.sub.3 (8049 mg, 24.6 mmol), methyl 2-(5-bromo-2-pyridyl)propanoate (2.00 g, 8.19 mmol), Pd(dppf)Cl.sub.2) DCM (342 mg, 0.410 mmol) and 4 Å molecular sieves (5 g). The reaction mixture is then degassed by vacuum/N.sub.2 (3×) and heated to 100° C. for 2 hrs. The reaction is cooled to RT, filtered through a bed of Perlite and the bed of Perlite being washed with THF (3×60 mL). The organic solutions are combined, concentrated under reduced pressure, and dried under vacuum. To the residue is added DCM (60 mL), H.sub.2O (80 mL) and saturated aqueous NaHCO.sub.3 solution (60 mL). The organic layer is separated, dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure, and dried under vacuum. The crude material is purified by silica gel flash chromatography eluting with a gradient of EtOAc in DCM from 0% to 20% to give the Preparation 22 title compound (2.47 g, 68.53%) and Preparation 23 title compound. The material of Preparation 23 is further purified with silica gel chromatography eluting with a gradient of 10% to 80% EtOAc in cyclohexane to give the title compound of Preparation 23.

Preparation 24

5-Amino-1-isopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile

(82) ##STR00345##

(83) A mixture of 5-amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carbonitrile (100 g, 327.68 mmol), bis(pinacolato)diboron (91.53 g, 360.444 mmol), KOAc (48.24 g, 491.52 mmol), and Pd(dppf)Cl.sub.2 (11.99 g, 16.38 mmol) in 1,4-dioxane (1 L) is stirred for 6 hrs at 80° C. under N.sub.2. The mixture is allowed to cool to RT. The resulting mixture is filtered, washed with EtOAc (3×100 mL), and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (10:1-5:1) to give the title compound (100 g, 86.6%) as a brown solid. ES/MS (m/z) 353.2 (M+H).

(84) The following compounds in Table 4 are prepared essentially as described for 5-amino-1-isopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile using the appropriate reagents, adjusting reaction times to determine completion of the reactions, and adjusting purification conditions if appropriate. The material can also be filtered without work-up and used without further purification.

(85) TABLE-US-00011 TABLE 4 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 25 5-Amino-1-isopropyl-3-[5- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2- yl]pyrazole-4-carbonitrile 354.20 26 5-Amino-1-(1- methylcyclopropyl)-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pyrazole-4-carbonitrile 365.2   27c 5-Amino-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-1-(1,1,1- trifluoropropan-2-yl)pyrazole-4- carbonitrile 407.2  28 5-Amino-1-(1- methylcyclopropyl)-3-[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl]pyrazole-4- carbonitrile 284.2  29 5-Amino-3-[5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2-yl]-1-(1,1,1- trifluoropropan-2-yl)pyrazole-4- carbonitrile 0 326.2   29a 5-Amino-1-(1,1-difluoropropan- 2-yl)-3-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)phenyl]pyrazole-4-carbonitrile 389.1   29b 5-Amino-3-[2,3-difluoro-4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-1- isopropyl-pyrazole-4-carbonitrile  29c 5-Amino-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-1-[2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazole- 4-carbonitrile 410.3   29e 5-Amino-1-(2-deuterio-2,2- difluoro-1-methyl-ethyl)-3-[4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]pyrazole-4-carbonitrile 390.1 

Alternate Preparation 26

5-Amino-1-(1-methylcyclopropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile

(86) ##STR00355##

(87) 5-Amino-3-(4-bromophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile (350 mg, 1.10 mmol), bis(pinacolato)diboron (560.41 mg, 2.21 mmol), KOAc (325 mg, 3.31 mmol), and Pd(dppf)Cl.sub.2 (121 mg, 0.17 mmol) are added together in dioxane (5.00 mL). The solution is stirred for 2 hrs at 80° C. under N.sub.2. The mixture is filtered and used directly without purification. ES/MS (m/z) 365.2 (M+H).

Preparation 29f

5-Amino-3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile

(88) ##STR00356##

(89) A solution of 5-amino-3-(4-bromo-2-fluorophenyl)-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile (700 mg, 2.09 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (636.40 mg, 2.51 mmol), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (341.10 mg, 0.42 mmol) and KOAc (614.89 mg, 6.26 mmol) in dioxane (10.00 mL) is stirred for 1 hr at 80° C. under N.sub.2. The solution is cooled to RT, filtered, and the filter cake is washed with 1,4-dioxane (2×3 mL). The mixture is used directly without further purification. ES/MS (m/z) 383.3 (M+H).

Preparation 29 g

Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]prop-2-enoate

(90) ##STR00357##

(91) A solution of 5-amino-3-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carbonitrile (980 mg, 2.56 mmol), methyl 2-(trifluoromethanesulfonyloxy)prop-2-enoate (1200.61 mg, 5.13 mmol), Pd(dppf)Cl.sub.2.Math.CH.sub.2Cl.sub.2 (418.73 mg, 0.51 mmol) and K.sub.2CO.sub.3 (708.65 mg, 5.128 mmol) in dioxane/H.sub.2O (4:1, 10 mL) is stirred for 1 hr at 80° C. under N.sub.2. The solution is cooled to RT and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, eluting with a gradient of 3:1 to 2:1 PE:EtOAc to give the title compound (430 mg, 49.28%) as a yellow solid. ES/MS (m/z) 341.2 (M+H).

Preparation 30

Methyl 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]prop-2-enoate

(92) ##STR00358##

(93) A mixture of 5-amino-1-isopropyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile (100.00 g, 283.89 mmol), methyl 2-(trifluoromethanesulfonyloxy)prop-2-enoate (99.71 g, 425.83 mmol), K.sub.2CO.sub.3 (117.71 g, 851.67 mmol) and Pd(dppf)Cl.sub.2 (10.39 g, 14.19 mmol) in 1,4-dioxane (1 L) and H.sub.2O (250 mL) is stirred overnight at 90° C. under N.sub.2. The mixture is allowed to cool to RT. The resulting mixture is filtered, and the filter cake is washed with EtOAc (3×100 mL). The filtrate is concentrated under reduced pressure, diluted with H.sub.2O (500 mL), and extracted with EtOAc (3×500 mL). The combined organic extracts are washed with saturated aqueous NaCl solution (3×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (10:1-3:1) to give the title compound (43 g, 48.8%) as a yellow solid. ES/MS (m/z): 311.2 (M+H).

(94) The following compounds in Table 5 are prepared essentially as described for methyl 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]prop-2-enoate using the appropriate reagents and adjusting reaction times to determine completion of the reactions. Temperature is varied from 80-90° C. and dioxane and H.sub.2O can be used as solvents.

(95) TABLE-US-00012 TABLE 5 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 31  Methyl 2-[6-(5-amino-4-cyano- 1-isopropylpyrazol-3-yl)pyridin- 3-yl]prop-2-enoate 312.10  32* Methyl 2-[4-[5-amino-4-cyano- 1-(1-methylcyclopropyl)pyrazol- 3-yl]phenyl]prop-2-enoate 0 323.1 33  Methyl 2-[4-[5-amino-4-cyano- 1-(1,1,1-trifluoropropan-2- yl)pyrazol-3-yl]phenyl]prop-2- enoate 365.1 34  Methyl 2-[6-[5-amino-4-cyano- 1-(1-methylcyclopropyl)pyrazol- 3-yl]pyridin-3-yl]prop-2-enoate 324.1 35  Methyl 2-[6-[5-amino-4-cyano- 1-(1,1,1-trifluoropropan-2- yl)pyrazol-3-yl]pyridin-3- yl]prop-2-enoate 366.1 35a Methyl-2-[4-[5-amino-4-cyano- 1-(1,1-difluoropropan-2- yl)pyrazol-3-yl]phenyl]prop-2- enoate 347.0 35b Methyl 2-[4-(5-amino-4-cyano- 1-isopropylpyrazol-3-yl)-2,3- difluorophenyl]prop-2-enoate 347.2 35c Methyl 2-[4-[5-amino-4-cyano- 1-[2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]prop-2-enoate 368.2 35d Methyl 2-[4-[5-amino-4-cyano- 1-(2-deuterio-2,2-difluoro-1- methyl-ethyl)pyrazol-3- yl]phenyl]prop-2-enoate 348.0 *The title compound is purified by reverse combi-chromatography with the following conditions: C18; ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3) eluting with a gradient of 70% to 100% in 15 mins; UV 254 nm.

Alternate Preparation 32

Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]prop-2-enoate

(96) ##STR00368##

(97) 5-Amino-1-(1-methylcyclopropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrazole-4-carbonitrile (400 mg, 1.10 mmol), methyl 2-(trifluoromethanesulfonyloxy)prop-2-enoate (642.95 mg, 2.7 5 mmol), K.sub.2CO.sub.3 (455 mg, 3.30 mmol), and Pd(dppf)Cl.sub.2 (85 mg, 0.09 mmol) are added together in dioxane (6.00 mL) and H.sub.2O (1.50 mL). The solution is stirred for 2 hrs at 80° C. The mixture is diluted with EtOAc (100 mL), washed with H.sub.2O (2×30 mL), and brine (20 mL). The organic phase is separation and concentrated under reduced pressure. The residue is purified by reversed combi-chromatography with following conditions: C18; eluting with a gradient of ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3) to give the title compound (280 mg, 78.5) as a brown solid. ES/MS (m/z) 323.1 (M+H).

Preparation 36

Methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, Isomer 1

(98) and

Preparation 37

Methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, Isomer 2

(99) ##STR00369##

(100) Methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoropropan-2-yl)pyrazol-3-yl]phenyl]prop-2-enoate (2.00 g) is purified by Prep-HPLC with the following conditions: Column: N—(R,R)-Whelk-O1 4.6*50 mm, 3.5 μm; mobile phase A: mobile phase B: MeOH (0.1% DEA), with flow rate of 2 mL/min; eluting with 10% B, UV 254 nm; t.sub.(R) Isomer 1 is 6.7 min; t.sub.(R) Isomer 2 is 7.2; (700 mg, 35.0%, 100% ee) as a yellow solid and (700 mg, 35.0%, 100% ee) as a yellow solid.

(101) The following compounds in Table 6 are prepared essentially as described for methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, Isomer 1 and methyl 2-[4-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]phenyl]prop-2-enoate, Isomer 2 using the appropriate purification conditions.

(102) TABLE-US-00013 TABLE 6 Prep. t.sub.(R), No. Chemical name Structure min 38 Methyl 2-(6-[5-amino-4-cyano- 1-[1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)prop-2-enoate, Isomer 1 0 6.7 39 Methyl 2-(6-[5-amino-4-cyano- 1-[1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)prop-2-enoate, Isomer 2 7.2  39a.sup.1 Methyl-2-[4-[5-amino-4-cyano- 1-(1,1-difluoropropan-2- yl)pyrazol-3-yl]phenyl]prop-2- enoate, Isomer 1 5  39b.sup.1 Methyl-2-[4-[5-amino-4-cyano- 1-(1,1-difluoropropan-2- yl)pyrazol-3-yl]phenyl]prop-2- enoate, Isomer 2 7.4  39c.sup.3 Methyl 2-[4-[5-amino-4-cyano- 1-[2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]prop-2-enoate, Isomer 1 5.16  39d.sup.3 Methyl 2-[4-[5-amino-4-cyano- 1-[2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]prop-2-enoate, Isomer 2 7.65  39e.sup.2 Methyl 2-[4-[5-amino-4-cyano- 1-(2-deuterio-2,2-difluoro-1- methyl-ethyl)pyrazol-3- yl]phenyl]prop-2-enoate, Isomer 1 10.8  39f.sup.2 Methyl 2-[4-[5-amino-4-cyano- 1-(2-deuterio-2,2-difluoro-1- methyl-ethyl)pyrazol-3- yl]phenyl]prop-2-enoate, Isomer 2 13.6 .sup.1CHIRALPAK IG, 2*25 cm, 5 μm; eluting with 30% EtOH in hexanes (10 mM NH.sub.3—MeOH), flow rate: 20 mL/min, UV 234/274 nm .sup.2CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; eluting with 10% EtOH in hexanes (0.5% 2 M NH.sub.3—MeOH) flow rate 20 mL/min, 210/220 nm. .sup.3CHIRALPAK IH, 2.0*2.5 cm, 5 μm eluting with 40% EtOH in hexanes (10 mM NH.sub.3—MeOH), flow rate 20 mL/min, UV 235.275.

Preparation 40

Methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoate

(103) ##STR00378##

(104) A mixture of methyl 2-[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]prop-2-enoate (43.00 g, 138.55 mmol) and 50% Pd/C (43.00 g) in MeOH (1 L) is stirred for 4 hrs at RT under N.sub.2. The resulting mixture is filtered (through diatomaceous earth if needed) and the filter cake is washed with MeOH (300 ml). The filtrate is concentrated under reduced pressure to give the title compound (40 g, 92.4%) as a yellow solid. ES/MS (m/z) 313.2 (M+H).

(105) The following compounds in Table 7 are prepared essentially as described for methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoate using the appropriate reagents, using a balloon of hydrogen if appropriate, using 10-50% Pd/C, and adjusting reaction times to determine completion of the reactions. The products can also be purified by silica gel chromatography eluting with a solvent system such as PE:EtOAc of 2:1 to 1:1.

(106) TABLE-US-00014 TABLE 7 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 41 Methyl 2-[6-(5-amino-4-cyano- 1-isopropylpyrazol-3-yl)pyridin- 3-yl]propanoate 314.20 42 Methyl 2-[4-[5-amino-4-cyano- 1-(1-methylcyclopropyl)pyrazol- 3-yl]phenyl]propanoate 0 325.1 43 Methyl 2-(4-[5-amino-4-cyano- 1-[1,1,1-trifluoropropan-2- yl]pyrazol-3- yl]phenyl)propanoate, Isomer 1 367.2 44 Methyl 2-(4-[5-amino-4-cyano- 1-[1,1,1-trifluoropropan-2- yl]pyrazol-3- yl]phenyl)propanoate, Isomer 2 367.3 45 Methyl 2-[6-[5-amino-4-cyano- 1-(1-methylcyclopropyl)pyrazol- 3-yl]pyridin-3-yl]propanoate 326.1 46 Methyl 2-(6-[5-amino-4-cyano- 1-[1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)propanoate, Isomer 1e 368.2 47 Methyl 2-(6-[5-amino-4-cyano- 1-[1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)propanoate, Isomer 2 368.1 47a.sup.1 Methyl 2-(4-[5-amino-4-cyano- 1-[1,1-difluoropropan-2- yl]pyrazol-3- yl]phenyl)propanoate, Isomer 1 349.1 47b.sup.1 Methyl 2-(4-[5-amino-4-cyano- 1-[1,1-difluoropropan-2- yl]pyrazol-3- yl]phenyl)propanoate, Isomer 2 349.2 47c Methyl 2-[4-(5-amino-4-cyano- 1-isopropylpyrazol-3-yl)-2,3- difluorophenyl]propanoate 349.2 47d.sup.1 Methyl 2-[4-[5-amino-4-cyano- 1-[2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]propanoate, Isomer 1 370.2 47e.sup.1 Methyl 2-[4-[5-amino-4-cyano- 1-[2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]propanoate, Isomer 2 0 370.2 47f.sup.1 Methyl 2-[4-[5-amino-4-cyano- 1-(2-deuterio-2,2-difluoro-1- methyl-ethyl)pyrazol-3- yl]phenyl]propanoate, Isomer 1 350.1 47g Methyl 2-[4-[5-amino-4-cyano- 1-(2-deuterio-2,2-difluoro-1- methyl-ethyl)pyrazol-3- yl]phenyl]propanoate, Isomer 2 350.15 .sup.1PD(OH).sub.2/C is catalyst and DCM is solvent used

Alternate Preparation 42

Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoate

(107) ##STR00393##

(108) Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]prop-2-enoate (260 mg, 0.81 mmol), MeOH (15.00 mL) and 50% Pd/C (275 mg) are added together. The solution is stirred for 2 hrs at RT under H.sub.2. The mixture is filtered, and the solution is concentrated under vacuum to give the title compound (240 mg, 91%) as a light yellow solid. The crude product is used directly without further purification. ES/MS (m/z) 325.1 (M+H).

Alternate Preparation 42

Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoate

(109) To a stirred solution of methyl 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]propanoate (4.00 g, 14.80 mmol) and (1-methylcyclopropyl)hydrazine hydrochloride (1.81 g, 14.80 mmol) in THF (50.00 mL) is added Et.sub.3N (7.49 g, 73.99 mmol) dropwise at RT under N.sub.2. The mixture is stirred for 1 hr at 50° C. under N.sub.2. The mixture is diluted with H.sub.2O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts are washed with brine (3×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with hexanes/EtOAc (5:1-1:1) to give the title compound (3.8 g, 79.16%) as an off-white solid. ES/MS (m/z) 325.2 (M+H).

Preparation 47h

Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]propanoate

(110) ##STR00394##

(111) To a solution of methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]prop-2-enoate (410 mg, 1.21 mmol) in MeOH (10 mL) is added Pd/C (10%, 0.64 g). The mixture is hydrogenated at RT for 1 hr using a H.sub.2 balloon. The mixture is filtered, the filter cake is washed with MeOH (3×50 mL) and the filtrate is concentrated under reduced pressure to give the title compound (340 mg, 82.44%) as a dark yellow solid. ES/MS (m/z) 343.2 (M+H).

Preparation 48

Methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]propanoate

(112) ##STR00395##

(113) To a stirred mixture of methyl 2-[4-(2,2-dicyano-1-methoxyeth-1-en-1-yl)phenyl]propanoate (400.00 mg, 1.48 mmol) and (1,1,1-trifluoro-2-methylpropan-2-yl)hydrazine dihydrochloride (210.33 mg, 1.48 mmol) in EtOH (5.00 mL) is added Et.sub.3N (449.25 mg, 4.44 mmol) in portions at RT under N.sub.2. The resulting mixture is stirred for 2 hrs at 50° C. under N.sub.2. The mixture is allowed to cool to RT and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE/EtOAc (2/1 to 1/1) to give the title compound (270 mg, 47%) as an off-white solid. ES/MS (m/z) 381.2 (M+H).

(114) The following compound in Table 8 is prepared essentially as described for methyl 2-[4-[5-amino-4-cyano-1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]phenyl]propanoate using the appropriate reagents, adjusting reaction times to determine completion of the reactions, and adjusting purification conditions if needed. The reaction can be stirred from RT-50° C. and used without purification.

(115) TABLE-US-00015 TABLE 8 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 49 Methyl 2-[4-[5-amino-4-cyano- 1-(1-methoxy-2-methylpropan- 2-yl)pyrazol-3- yl]phenyl]propanoate 357.1 49a Methyl 2-[4-[5-amino-4-cyano- 1-(2,2,2-trideuterio-1-methyl- ethyl)pyrazol-3- yl]phenyl]propanoate 316.3 49b Methyl 2-[4-[5-amino-4-cyano- 1-(1,2,2,2-tetradeuterio-1- methyl-ethyl)pyrazol-3- yl]phenyl]propanoate 317.3 49c Methyl 2-[4-[5-amino-4-cyano- 1-[1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl] pyrazol-3- yl]phenyl]propanoate 320.1

Preparation 50

(116) Lithium; 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propanoate

(117) ##STR00400##

(118) Methyl 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propanoate (100 mg, 0.227 mmol), methyl 2-[5-[5-[bis(tert-butoxycarbonyl)amino]-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propanoate (958 mg, 1.87 mmol) are added together in MeOH (8.20 mL). LiOH (142 mg, 5.69 mmol) is solubilized in H.sub.2O (2.46 mL) and is added to the mixture. The reaction mixture is stirred at RT for 18 hrs and concentrated under reduced pressure to give the title compound (926 mg, 111.39%).

Preparation 51

2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid

(119) ##STR00401##

(120) A mixture of methyl 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoate (40.00 g, 128.05 mmol) and NaOH (25.61 g, 640.26 mmol) in MeOH (500 mL) and H.sub.2O (500 mL) is stirred for 5 hrs at 50° C. The mixture is allowed to cool to RT. The resulting mixture is concentrated under reduced pressure, diluted with H.sub.2O (500 mL), and the aqueous layer is extracted with EtOAc (2×300 mL). The aqueous layer is acidified to pH 3-4 with 6 N HCl and the resulting precipitated solids are collected by filtration, washed with H.sub.2O (3×50 mL), and dried under vacuum to give the title compound (34 g, 89.0%) as a light yellow solid. ES/MS (m/z) 299.2 (M+H).

(121) The following compounds in Table 9 are prepared essentially as described for 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid and stirring at RT until completion.

(122) TABLE-US-00016 TABLE 9 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 52 2-[6-(5-Amino-4- cyano-1- isopropylpyrazol-3- yl)pyridin-3- yl]propanoic acid 02 300.10 53.sup.1 2-[5-[5-(tert- Butoxycarbonylamino)- 4-cyano-1-isopropyl- pyrazol-3-yl]-2- pyridyl]propanoic acid 03 .sup.12 M NaOH used with no extra H.sub.2O, after acidification with potassium bisulfate, the mixture and is cooled at 0 °C. for 1 hr and the title compound is filtered, collected, dried, used directly without further purification.

Preparation 54

2-(6-[5-Amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoic acid, Isomer 1

(123) ##STR00404##

(124) To a stirred solution of methyl 2-(6-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoate, Isomer 2 (1.30 g, 3.53 mmol) in THF (16.00 mL) and H.sub.2O (4.00 mL) is added LiOH (253.56 mg, 10.59 mmol) in portions at RT under N.sub.2. The resulting mixture is stirred for 2 hrs at RT under N.sub.2. The mixture is concentrated under reduced pressure, diluted with H.sub.2O (20 mL), and acidified to pH 3 with HCl (c). The resulting mixture is extracted with EtOAc (3×50 mL). The combined organic extracts are washed with saturated aqueous NaCl solution (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the title compound (1.2 g, 96%) as a light yellow solid. ES/MS (m/z) 353.9 (M+H).

(125) The following compounds in Table 10 are prepared essentially as described for 2-(6-[5-amino-4-cyano-1-[−1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoic acid, Isomer 1 using the appropriate reagents at RT to 50° C. and adjusting reaction times to determine completion of the reactions. LiOH can be added portionwise or in a single amount depending on the scale of the reaction.

(126) TABLE-US-00017 TABLE 10 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 55 2-(4-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3- yl]phenyl)propanoic acid, Isomer 1 05 353.1 56 2-(4-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3- yl]phenyl)propanoic acid, Isomer 2 06 353.3 57 2-[4-[5-Amino-4-cyano-1- (1,1,1-trifluoro-2-methylpropan- 2-yl)pyrazol-3- yl]phenyl]propanoic acid 07 367.0 58 2-[4-[5-Amino-4-cyano-1-(1- methoxy-2-methylpropan-2- yl)pyrazol-3- yl]phenyl]propanoic acid 08 343.1 59 2-[6-[5-Amino-4-cyano-1-(1- methylcyclopropyl)pyrazol-3- yl]pyridin-3-yl]propanoic acid 09 312.1 60 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)propanoic acid, Isomer 2 0 354.0 60a 2-[4-[5-Amino-4-cyano-1- (2,2,2-trideuterio-1-methyl- ethyl)pyrazol-3- yl]phenyl]propanoic acid 302.2 60b 2-[4-[5-Amino-4-cyano-1- (1,2,2,2-tetradeuterio-1-methyl- ethyl)pyrazol-3- yl]phenyl]propanoic acid 303.3 60c 2-[4-[5-Amino-4-cyano-1- [1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]propanoic acid 306.2 60d 2-(4-[5-Amino-4-cyano-1-[1,1- difluoropropan-2-yl]pyrazol-3- yl]phenyl)propanic acid, Isomer 1 60e 2-(4-[5-Amino-4-cyano-1-[1,1- difluoropropan-2-yl]pyrazol-3- yl]phenyl)propanic acid, Isomer 2 335.1 60f 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)-2,3- difluorophenyl]propanoic acid 335.1 60g 2-[4-[5-Amino-4-cyano-1- [2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]propanoic acid, Isomer 1 356.2 60h 2-[4-[5-Amino-4-cyano-1- [2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]propanoic acid, Isomer 2 356.2 60i 2-[4-[5-Amino-4-cyano-1-(2- deuterio-2,2-difluoro-1-methyl- ethyl)pyrazol-3- yl]phenyl]propanoic acid, Isomer 1 336.2 60j 2-[4-[5-Amino-4-cyano-1-(2- deuterio-2,2-difluoro-1-methyl- ethyl)pyrazol-3- yl]phenyl]propanoic acid, Isomer 2 0 335.9

Preparation 60k

2-[4-[5-Amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propanoic acid

(127) ##STR00421##

(128) A solution of methyl 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propanoate (630 mg, 1.98 mmol) and LiOH (143 mg, 5.94 mmol) in MeOH/H.sub.2O (25 mL, 4:1) is stirred for 1 hr at RT. The solution is extracted with EtOAc (2×5 mL). The aqueous layer is acidified with HCl (2 M) and extracted with EtOAc (3×50 mL). The organic extract is dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give the title compound (460 mg, crude) as a light yellow solid. The product is washed with Et.sub.2O (10 mL) used directly without further purification. ES/MS (m/z) 305.20 (M+H).

Preparation 60I

2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid

(129) ##STR00422##

(130) Methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoate (220.00 mg, 0.68 mmol), MeOH (2.00 mL), H.sub.2O (2.00 mL), and NaOH (109 mg, 2.71 mmol) are added together. The solution is stirred for 2 hrs at 50° C. and then MeOH is removed under reduced pressure. The pH of the mixture is adjusted to with 4 N HCl and the mixture is extracted with EtOAc (2×50 mL). The combined organic extracts are washed with H.sub.2O (2×15 mL), washed with brine (10 mL) and concentrated to give the title compound (240 mg, 100% crude) as an off-white solid. The crude product is used directly without further purification. ES/MS (m/z) 311.2 (M+H).

Preparation 60m

2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]propanoic acid

(131) ##STR00423##

(132) A solution of methyl 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]propanoate (340 mg, 0.99 mmol) and LiOH (118.91 mg, 4.96 mmol) in THF/H.sub.2O (4:1, 5.00 mL) is stirred for 1 hr at 50° C. under N.sub.2. The solution is cooled to RT and the mixture is acidified to pH=3 with HCl (aq. 1 N). The mixture is extracted with EtOAc (3×100 mL). The combined organic extracts are washed with brine (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (280 mg, 85.87%) as a light yellow solid. ES/MS (m/z) 329.2 (M+H).

Preparation 61

2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, Isomer 1

(133) and

Preparation 62

2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, Isomer 2

(134) ##STR00424##

(135) 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (500 mg) is separated by prep-chiral with the following conditions: Column: (R,R)Whelk-O1, 21.1*250 mm, 5 μm; mobile phase A: hexanes (0.1% FA), mobile phase B:IPA; eluting with a gradient of 0-30% B in 17 min at 20 mL/min; UV 254 nm; t.sub.(R) isomer 1 9.2 min (209.6 mg, 41.2%, 100% ee) as a white solid, ES/MS (m/z) 299.1 (M+H), t.sub.(R) isomer 2 12 min (206.8 mg, 41.03%, 100% ee) as a white solid, ES/MS (m/z) 299.1 (M+H).

Preparation 63

2-[6-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]propanoic acid, Isomer 1

(136) and

Preparation 64

2-[6-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]propanoic acid, Isomer 2

(137) ##STR00425##

(138) 2-[6-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]propanoic acid (290.00 mg) is separated by prep-chiral with the following conditions: Column: CHIRALPAK AD-H, 2.0*25 cm L; mobile phase A: hexanes (0.1% TFA), mobile phase B: IPA eluting with a gradient of 30%-0% B in 9.5 min; flow rate 20 mL/min; UV 230/254 nm, t.sub.(R) Isomer 1 6.2 min, (102.5 mg, 35.3%) as a white solid with 100% ee; ES/MS (m/z) 300.1 (M+H), t.sub.(R) Isomer 2 7.8 min (104.8 mg, 36.1%) as a white solid with 100% ee, ES/MS (m/z) 300.1 (M+H).

Preparation 64a

2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid

(139) ##STR00426##

(140) A mixture of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (1.00 g, 3.352 mmol), NaOH (671 mg, 16.759 mmol) and H.sub.2O.sub.2 (7.81 mL, 68.873 mmol, 30%) in EtOH (20.00 mL)/DMSO (2.00 mL) is stirred overnight at 50° C. The reaction is quenched with saturated Na.sub.2SO.sub.3 aqueous (20 mL) at 0° C. The resulting mixture is diluted with H.sub.2O (200 mL) and acidified to pH 3-4 with 6 N HCl. The precipitated solids are collected by filtration and washed with H.sub.2O (2×10 mL). The solid is purified by reverse Combi-flash chromatography with the following conditions: column, C18; mobile phase, ACN in H.sub.2O eluting with a gradient of 30% to 60% in 25 min; detector, UV 220 nm and then lyophilized to give the title compound (670 mg, 62.5%) as an off-white solid. ES/MS (m/z) 317.2 (M+H).

Preparation 64b

2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, Isomer 1

(141) and

Preparation 64c

2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, Isomer 2

(142) ##STR00427##

(143) 2-[4-(5-Amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (280 mg) is separated by prep-chiral HPLC with the following conditions: Column: CHIRALPAK AD-H, 2.0*25 cm; mobile phase A: hexanes (0.1% FA), mobile phase B: IPA; flow rate: 20 mL/min eluting with 15% B in 21 min; UV 210Y254 nm; t.sub.(R) Isomer 1 16 min, (106.2 mg, 37.6%, 100% ee) as a white solid, ES/MS (m/z) 317.1 (M+H); t.sub.(R) Isomer 2 19 min, (94.96 mg, 33.3%, 98.3% ee) as a white solid, ES/MS (m/z) 317.1 (M+H).

Preparation 65

(Z/E)-5,5-Difluoro-N′-hydroxy-4,4-dimethyl-3-oxohexanimidamide

(144) ##STR00428##

(145) A solution of 5,5-difluoro-4,4-dimethyl-3-oxohexanenitrile (1.50 g, 8.56 mmol), NaHCO.sub.3 (1.80 g, 21.427 mmol), and bis(hydroxylammonium); sulfate (1.69 g, 10.30 mmol) in H.sub.2O (27.00 mL) and MeOH (3.00 mL) is stirred overnight at 65° C. under N.sub.2. The mixture is used directly without further purification. ES/MS m/z 209.2 (M+H).

Preparation 66

3-(3,3-Dimethylcyclobutyl)-1,2-oxazol-5-amine

(146) ##STR00429##

(147) A solution of 3-(3,3-dimethylcyclobutyl)-3-oxopropanenitrile (1.50 g, 9.92 mmol), NH.sub.2OH.HCl (0.76 g, 10.94 mmol), and NaOH (0.79 g, 19.84 mmol) in H.sub.2O (15.00 mL) is stirred for 2 hrs at 100° C. under N.sub.2. The mixture is allowed to cool to RT. The precipitated solids are collected by filtration and washed with H.sub.2O (3×30 mL). The resulting mixture is concentrated under reduced pressure to give the title compound (1.5 g, 90.97%) as an off-white solid. ES/MS (m/z) 167.3 (M+H).

(148) The following compound in Table 11 is prepared essentially as described for 3-(3,3-dimethylcyclobutyl)-1,2-oxazol-5-amine using the appropriate reagents and adjusting the reaction time to determine completion of the reaction. The base can be added in portions and the reaction mixture can be extracted with DCM or filtered as appropriate.

(149) TABLE-US-00018 TABLE 11 NMR (300 MHz, CDCl.sub.3) δ or ES/MS Prep. (m/z) No. Chemical name Structure (M + H 67 3-(2- Methylbutan- 2-yl)- 1,2-oxazol-5- amine 0 5.01 (s, 1H), 4.35 (br, s, 2H), 1.60(q, 2H), 1.25 (s, 6H), 0.83 (t, 3H) 67a 3-(4- (Trifluoromethyl) bicyclo[2.2.1] heptan-1-yl) isoxazol-5-amine 247.1

Preparation 67b

3-(3-Methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-amine

(150) ##STR00432##

(151) To a stirred mixture of 3-[3-methylbicyclo[1.1.1]pentan-1-yl]-3-oxopropanenitrile (350.00 mg, 2.41 mmol) and hydroxylamine HCl (183.83 mg, 2.65 mmol) in H.sub.2O (8.00 mL) is added NaOH (192.38 mg, 4.81 mmol) in portions at RT under N.sub.2. The mixture is stirred for 1 hr at 100° C. under N.sub.2. The mixture is allowed to cool to RT. The precipitated solids are collected by filtration and washed with H.sub.2O (3×20 mL), to give the title compound (300 mg, 77.9%) as a light yellow solid. ES/MS m/z (M+H) 165.1.

Preparation 67c

3-(2,2-Dimethylpropyl)-4-fluoro-1,2-oxazol-5-amine

(152) ##STR00433##

(153) A solution of 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (5.00 g, 32.42 mmol) and Selectfluor™ (13.78 g, 38.90 mmol) in MeOH (100 mL, 780.04 mmol) is stirred for 30 mins at 50° C. under N.sub.2. The reaction is cooled to RT, diluted with H.sub.2O (100 mL) and extracted with EtOAc (3×100 mL). The organic extract is dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product is purified by silica gel chromatography (PE:EtOAc=10:1 to 5:1) to give the title compound (1.55 g, 27.7%) as a light yellow solid. LC-MS: (ES+H, m/z):[M+H]+=173.10

Preparation 67d

3-(3-(Trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine

(154) ##STR00434##

(155) A mixture of 3-oxo-3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]propanenitrile (280.00 mg, 1.38 mmol), hydroxylamine HCl (105.35 mg, 1.52 mmol) and H.sub.2O (10 mL) is added NaOH (110.25 mg, 2.76 mmol) in portions at RT under N.sub.2. The resulting mixture is heated to 100° C. for 1 hr. The mixture is allowed to cool to RT and is extracted with DCM (3×50 mL). The combined organic extracts are washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting solid is triturated with Et.sub.2O (10 mL). The resulting solids are collected by filtration and washed with Et.sub.2O to give the title compound (220 mg, 73%). ES/MS m/z (M+H) 219.2.

Preparation 68

5-(3,3-Difluoro-2-methylbutan-2-yl)-1,2-oxazol-3-amine

(156) ##STR00435##

(157) The crude solution of (Z)-5,5-difluoro-N′-hydroxy-4,4-dimethyl-3-oxohexanimidamide is acidified to pH=1 with HCl (c) and the resulting mixture is stirred for 1 hr at 100° C. under N.sub.2. The mixture is slowly cooled to RT and concentrated under reduced pressure. The residue is purified by reversed combi-flash chromatography with the following conditions: Column, C18; mobile phase, ACN in H.sub.2O eluting with a 30% to 50% gradient in 20 min; UV 220 nm to give the title compound (230 mg, 14%) as a yellow solid. ES/MS (m/z) 191.2 (M+H).

Preparation 69

3-(2-Chloro-4-fluorophenyl)-1,2-oxazol-5-amine

(158) ##STR00436##

(159) To a crude mixture of 3-(2-chloro-4-fluorophenyl)-3,2-oxopropanenitrile (2.8 g, 14 mmol) is added NH.sub.2OH.HCl (0.98 g, 14.17 mmol), KOAc (2.09 g, 21.30 mmol) and 1,4-dioxane (30.00 mL). The resulting mixture is stirred at 100° C. overnight. The mixture is allowed to cool to RT and diluted with H.sub.2O (30 mL) and EtOAc (30 mL). The mixture is extracted with EtOAc (3×30 mL). The combined organic extracts are dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with a gradient of PE/EtOAc (9:1-2:1) to give the title compound (1.2 g, 39.83%) as a yellow solid. ES/MS (m/z) (.sup.35Cl/.sup.37Cl) 213.0/215.0 (M+H).

(160) The following compound in Table 12 is prepared essentially as described for 3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-amine using the appropriate reagents, adjusting the reaction time to determine completion of the reaction, and purification conditions as appropriate. The reaction temperature can range from about 70° C. to 100° C. NaOAc can be substituted for KOAc and EtOH can be substituted for 1,4-dioxane.

(161) TABLE-US-00019 TABLE 12 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 70 3-(3- Bicyclo[1.1.1] pentanylmethyl) isoxazol- 5-amine 165.1

Preparation 71

5-(2-Methylbutan-2-yl)-1,2-oxazol-3-amine

(162) ##STR00438##

(163) To a stirred mixture of 4,4-dimethyl-3-oxohexanenitrile (3.00 g, 21.55 mmol) and hydroxylamine sulfate (3.89 g, 23.71 mmol) in MeOH (5.00 mL) and H.sub.2O (45 mL) is added NaHCO.sub.3 (4.53 g, 53.88 mmol) in portions at RT under N.sub.2. The resulting mixture is stirred for 5 hrs at 65° C. under N.sub.2. The mixture is allowed to cool to RT. The mixture is acidified to pH 1 with HCl (c) and stirred for 20 min at 130° C. under N.sub.2. The mixture is allowed to cool to RT and the pH adjusted to 8 with NaOH. The resulting mixture is extracted with DCM (3×200 mL). The combined organic extracts are washed with saturated aqueous NaCl solution (2×200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by reverse phase combi-flash chromatography with the following conditions: Column, C18; mobile phase, ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3), eluting with a 30% to 40% gradient in 10 min; UV 220 nm, to give the title compound (1.2 g, 36%) as a light yellow solid. .sup.1H NMR (CDCl.sub.3) δ5.53 (s, 1H), 1.66 (q, 2H), 1.27 (s, 6H), 0.82 (t, 3H).

Preparation 72

3-(2,4-Dichlorophenyl)-1,2-oxazol-5-amine

(164) ##STR00439##

(165) A solution of NH.sub.2OH.HCl (535.66 mg, 7.71 mmol) and KOAc (756.53 mg, 7.71 mmol) in MeOH (10.00 mL) is stirred for 1 hr at RT under N.sub.2. To the mixture is added 3-(2,4-dichlorophenyl)-3-oxopropanenitrile (550.00 mg, 2.57 mmol) and the reaction is stirred for an additional 1 hr at RT. The resulting mixture is filtered, the filter cake is washed with MeOH (3×20 mL), and the filtrate is concentrated under reduced pressure. The residue is diluted with H.sub.2O (30 mL) and the precipitated solids are collected by filtration, washed with H.sub.2O (3×20 mL), and dried under reduced pressure to give the title compound (200 mg, 35.0%) as a yellow solid. ES/MS m/z (.sup.35Cl/.sup.37Cl) 229.0/231.0 (M+H).

Preparation 72a

5-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole

(166) ##STR00440##

(167) A solution of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500.0 mg, 2.59 mmol), hexane-2,5-dione (886.3 mg, 7.77 mmol) and HOAc (15.5 mg, 0.26 mmol) in toluene (10.00 mL) is stirred for 2 hr at 100° C. under N.sub.2. The mixture is concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography eluting with the following conditions: Column, C18 gel eluting with a gradient of 30% to 50% ACN in H.sub.2O (0.1% FA) over 10 min; UV 254 nm to give the title compound (610 mg, 87%) as a yellow solid. ES/MS m/z (M+H) 272.1.

Preparation 72b

3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole

(168) ##STR00441##

(169) A solution of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole (500.0 mg, 1.84 mmol), Mel (1046.4 mg, 7.37 mmol) and K.sub.2CO.sub.3 (509.4 mg, 3.69 mmol) in ACN (10.00 mL) is stirred for 4 hr at 80° C. under N.sub.2. The mixture is concentrated under reduced pressure. The residue is purified by Prep-TLC eluting with 5:1 PE/EtOAc, 254 nm to give the title compound (95 mg, 18%) as a white solid. ES/MS m/z (M+H) 286.2.

Preparation 72c

1-Methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-amine

(170) ##STR00442##

(171) A solution of KOH (53.1 mg, 0.95 mmol) in EtOH (1.00 mL) and H.sub.2O (1.00 mL) is added to a solution of hydroxylamine HCl (131.5 mg, 1.89 mmol) in EtOH (2.00 mL). 3-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazole (90.0 mg, 0.32 mmol) is added and the mixture is stirred for 4 hr at 100° C. under N.sub.2. The mixture is concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Column, C18 gel eluting with a gradient of 10% to 30% ACN in H.sub.2O (0.1% FA) over 10 min; UV 254 nm to give the title compound (45 mg, 68%) as a white solid. ES/MS m/z (M+H) 208.1.

Preparation 73

Tert-Butyl N-[4-cyano-5-[6-[2-[[5-(1,1-dimethylpropyl)isoxazol-3-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]-2-isopropyl-pyrazol-3-yl]carbamate

(172) ##STR00443##

(173) To a suspension of lithium; 2-[5-[5-(tert-butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propanoate (300 mg, 0.740 mmol) in pyridine (1.85 mL) under N.sub.2 is added MeTHF (1.85 mL), 5-(1,1-dimethylpropyl)isoxazol-3-amine (171 mg, 1.11 mmol) then T3P® solution in MeTHF (50%, 1413 mg, 2.22 mmol). The reaction mixture is stirred at RT overnight and then poured into a saturated aqueous solution of NH.sub.4Cl. The aqueous layer is extracted with EtOAc (2×). The combined organic extracts are washed with saturated aqueous NaCl solution, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material is purified by silica gel flash chromatography eluting with a gradient of acetone in DCM from 1 to 10% to give the title compound (181.3 mg, 43%). .sup.1H NMR (d.sup.6-DMSO) δ11.17 (s, 1H), 9.91 (s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.2, 2.4 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 6.61 (s, 1H), 4.58 (p, J=6.5 Hz, 1H), 4.16 (q, J=6.9 Hz, 1H), 1.61 (q, J=7.5 Hz, 2H), 1.50 (d, J=8.4 Hz, 13H), 1.41 (d, J=6.6 Hz, 7H), 1.24 (s, 7H), 1.08 (s, 1H), 0.73 (t, J=7.5 Hz, 3H).

(174) The following compounds in Table 13 are prepared essentially as described for tert-butyl N-[4-cyano-5-[6-[2-[[5-(1,1-dimethylpropyl)isoxazol-3-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]-2-isopropyl-pyrazol-3-yl]carbamate adjusting the reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification.

(175) TABLE-US-00020 TABLE 13 ES/MS Prep. (m/z) No. Chemical name Structure (M + H) 74 tert-Butyl N-[4-cyano-2- isopropyl-5-[6-[1- methyl-2-oxo-2-[[5- (2,2,2-trifluoro-1,1- dimethyl-ethyl)isoxazol- 3-yl]amino]ethyl]-3- pyridyl]pyrazol-3- yl]carbamate 576 75 tert-Butyl N-[4-cyano-2- isopropyl-5-[6-[1- methyl-2-oxo-2-[[3- (2,2,2-trifluoro-1,1- dimethyl-ethyl)isoxazol- 5-yl]amino]ethyl]-3- pyridyl]pyrazol-3- yl]carbamate .sup.a 76 tert-Butyl N-[4-cyano-5- [6-[2-[[3-(2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-2- isopropyl-pyrazol-3- yl]carbamate .sup.b 77 tert-Butyl N-[4-cyano-5- [6-[2-[[5-(2,2- dimethylpropyl)isoxazol- 3-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-2- isopropyl-pyrazol-3- yl]carbamate 536 78 tert-Butyl N-[4-cyano-5- [6-[2-[[3-(2,4- dichlorophenyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-2- isopropyl-pyrazol-3- yl]carbamate .sup.c 79 tert-Butyl N-[4-cyano-5- [6-[2-[[3-(1,1- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-2- isopropyl-pyrazol-3- yl]carbamate .sup.a1H NMR (400 MHz, d.sup.6-DMSO) δ 8.95-8.90 (m, 1H), 8.58 (dd, J = 5.8, 1.6 Hz, 1H), 8.17 (dd, J = 8.2, 2.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.39 (ddd, J = 7.6, 4.3, 1.5 Hz, 1H), 6.38 (s, 1H), 4.58 (p, J = 6.5 Hz, 1H), 4.17 (q, J =7.0 Hz, 1H), 1.55-1.46 (m, 20H), 1.41 (d, J = 6.6 Hz, 8H). .sup.b1H NMR (400 MHz, d.sup.6-DMSO) δ 11.76 (s, 1H), 9.91 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 8.2, 2.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 6.12 (s, 1H), 4.58 (p, J = 6.6 Hz, 1H), 4.15 (q, J = 7.0 Hz, 1H), 2.45 (s, 2H), 1.52-1.49 (m, 12H), 1.41 (d, J = 6.6 Hz, 6H), 0.93 (s, 9H). .sup.c2-[5-[5-(tert-Butoxycarbonylamino)-4-cyano-1-isopropyl-pyrazol-3-yl]-2-pyridyl]propanoic acid used instead of the lithium salt

Preparation 80

2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide

(176) ##STR00450##

(177) To a mixture of 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (62 mg, 0.402 mmol), 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (120 mg, 0.402 mmol), and NMI (99 mg, 1.206 mmol) in ACN (5.00 mL) is added TCFH (338 mg, 1.206 mmol). The resulting mixture is stirred at 50° C. for 2 hrs under N.sub.2 and then concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; mobile phase, ACN in H.sub.2O (0.1% NH.sub.4CO.sub.3) and eluting with a gradient of 0% to 50% in 25 min; UV 254 nm to give the title compound (130 mg, 74.41%) as a white solid. ES/MS (m/z) 435.2 (M+H).

(178) The following compounds in Table 14 are prepared essentially as described for 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide using the appropriate reagents, adjusting reaction time to determine completion of the reaction, and purification conditions as appropriate. The reaction temperature can range from about 50° C. to 80° C.

(179) TABLE-US-00021 TABLE 14 ES/MS Prep. m/z No. Chemical name Structure (M + H) 81 2-[6-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)pyridin-3- yl]-N-[3-(2,2-dimethylpropyl)- 1,2-oxazol-5-yl]propanamide 436.4 82 2-[4-[5-Amino-4-cyano-1-(1- methylcyclopropyl)pyrazol-3- yl]phenyl]-N-[3-(2,2- dimethylpropyl)-1,2-oxazol-5- yl]propanamide 477.3 83 2-(4-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]phenyl)-N-[3- (2,2-dimethylpropyl)-1,2- oxazol-5-yl]propanamide, Isomer 2 489.1 84 2-[4-[5-Amino-4-cyano-1- (1,1,1-trifluoro-2-methylpropan- 2-yl)pyrazol-3-yl]phenyl]-N-[3- (2,2-dimethylpropyl)-1,2- oxazol-5-yl]propanamide 503.3 85 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)phenyl]- N-[5-(4,4,4-trifluoro-2- methylbutan-2-yl)-1,2-oxazol-3- yl]propenamide 489.2 86 2-[6-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)pyridin-3- yl]-N-[5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2-oxazol- 3-yl]propenamide 476.2 87 2-[6-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)pyridin-3- yl]-N-[5-(2-methylbutan-2-yl)- 1,2-oxazol-3-yl]propanamide 436.2 88* 2-[6-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)pyridin-3- yl]-N-[5-(4,4,4-trifluoro-2- methylbutan-2-yl)-1,2-oxazol-3- yl]propenamide 490.2 89* 2-(6-(5-Amino-4-cyano-1- isopropyl-1H-pyrazol-3- yl)pyridin-3-yl)-N-(3-(1,1,1- trifluoro-2-methylpropan-2- yl)isoxazol-5-yl)propenamide 476.2 90 2-[6-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)pyridin-3- yl]-N-[3-(2,4-dichlorophenyl)- 1,2-oxazol-5-yl]propenamide 0 510.3, 512.3 91 2-(6-(5-Amino-4-cyano-1- isopropyl-1H-pyrazol-3- yl)pyridin-3-yl)-N-(3-(2-chloro- 4-fluorophenyl)isoxazol-5- yl)propenamide 494.1. 496.1 92 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)phenyl]- N-[5-(2-methylbutan-2-yl)-1,2- oxazol-3-yl]propanamide 435.2 93 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)phenyl]- N-[3-(2,4-dichlorophenyl)-1,2- oxazol-5-yl]propenamide 509.2, 511.2 94 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)phenyl]- N-(5-tert-butyl-1,2-thiazol-3- yl)propenamide 437.3 95 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)phenyl]- N-[5-(1-methylcyclopropyl)-1,2- oxazol-3-yl]propanamide 419.2 96 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)phenyl]- N-[3-(1-methylcyclopropyl)-1,2- oxazol-5-yl]propanamide 419.2 96a 2-[4-[5-Amino-4-cyano-1- (2,2,2-trideuterio-1-methyl- ethyl)pyrazol-3-yl]phenyl]-N-[3- (2,2-dimethylpropyl)isoxazol-5- yl]propanamide 438.3 96b 2-[4-[5-Amino-4-cyano-1- [2,2,2-trideuterio-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]-N-[3-(2,2- dimethylpropyl)isoxazol-5- yl]propanamide 441.4 96c 2-[4-[5-Amino-4-cyano-1- (1,2,2,2-tetradeuterio-1-methyl- ethyl)pyrazol-3-yl]phenyl]-N-[3- (2,2-dimethylpropyl)isoxazol-5- yl]propanamide 439.3 96d 2-[4-[5-Amino-4-cyano-1- [1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]-N-[3-(2,2- dimethylpropyl)isoxazol-5- yl]propanamide 0 442.3 96e 2-(4-[5-Amino-4-cyano-1-[1,1- difluoropropan-2-yl]pyrazol-3- yl]phenyl)-N-[3-(2,2- dimethylpropyl)-1,2-oxazol-5- yl]propanamide, Isomer 1 471.3 96f 2-(4-[5-Amino-4-cyano-1-[1,1- difluoropropan-2-yl]pyrazol-3- yl]phenyl)-N-[3-(2,2- dimethylpropyl)-1,2-oxazol-5- yl]propanamide, Isomer 2 471.3 96g 2-[4-[5-Amino-4-cyano-1- [2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]-N-[3-(2,2- dimethylpropyl)isoxazol-5- yl]propanamide, Isomer 1 492.2 96h 2-[4-[5-Amino-4-cyano-1- [2,2,2-trifluoro-1- (trideuteriomethyl)ethyl]pyrazol- 3-yl]phenyl]-N-[3-(2,2- dimethylpropyl)isoxazol-5- yl]propanamide, Isomer 2 492.1 96i 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)phenyl]- N-[3-(2,2-dimethylpropyl)-4- fluoro-1,2-oxazol-5- yl]propanamide 453.3 96j 2-[4-[5-Amino-4-cyano-1-(2- deuterio-2,2-difluoro-1-methyl- ethyl)pyrazol-3-yl]phenyl]-N-[3- (2,2-dimethylpropyl)isoxazol-5- yl]propanamide, Isomer 1 472.1 96k 2-[4-[5-Amino-4-cyano-1-(2- deuterio-2,2-difluoro-1-methyl- ethyl)pyrazol-3-yl]phenyl]-N- [3-(2,2-dimethylpropyl) isoxazol-5-yl] propanamide, Isomer 2 472.3 *4Å molecular sieves added to reaction

Alternate Preparation 82

2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide

(180) ##STR00478##

(181) To a stirred mixture of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid (220 mg, 0.71 mmol) and 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (131 mg, 0.85 mmol) in ACN (3.00 mL) is added NMI (291 mg, 3.54 mmol) and TCFH (995 mg, 3.54 mmol). The mixture is stirred for 3 hr at 50° C. The mixture is purified by reversed Combi-flash chromatography with following conditions: C18; eluting with a gradient of 50% to 80% ACN in H.sub.2O (0.1% FA) to give the title compound (200 mg, 63.1%) as an off-white solid. ES/MS (m/z) 447.3 (M+H).

Preparation 96l

2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)propanamide

(182) ##STR00479##

(183) To a stirred mixture of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid (150 mg, 0.48 mmol) and 3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (79.36 mg, 0.48 mmol) in ACN (5.00 mL) is added NMI (119.05 mg, 1.45 mmol) and TCFH (271.22 mg, 0.97 mmol) in portions at RT under N.sub.2. The mixture is stirred for 2 hr at 50° C. under N.sub.2. The mixture is allowed to cool to RT and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (3/1 to 2/1) to give the title compound (130 mg, 58.9%) as an off-white solid. ES/MS (m/z) 457.2 (M+H).

Preparation 96m

2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)propanamide

(184) ##STR00480##

(185) To a solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]propanoic acid (150 mg, 0.46 mmol), 3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (90.02 mg, 0.55 mmol) and NMI (112.52 mg, 1.37 mmol) in ACN (5.00 mL) is added TCFH (192.27 mg, 0.68 mmol). The reaction is stirred for 1 hr at 50° C. The mixture is allowed to cool to RT and concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 20% to 40% ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3) to give the title compound (110 mg, 50.74%) as a white solid. ES/MS (m/z) 475.1 (M+H).

Preparation 96n

2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]propanamide

(186) ##STR00481##

(187) To a solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (300 mg, 1.01 mmol), 3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (264 mg, 1.21 mmol) and NMI (248 mg, 3.02 mmol) in ACN (20 mL), TCFH (1.41 g, 5.03 mmol) is added and the mixture is stirred for 1 hr at 50° C. under N.sub.2 in a sealed tube. The mixture is cooled to RT and concentrated under reduced pressure. The residue is purified by reserved phase Combi-flash chromatography with the following condition: Column, C18, eluting with a gradient of 10% to 50% ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3) to give the title compound (250 mg, 49.9%) as light brown solid. ES/MS (m/z) 499.10 (M+H).

Preparation 96o

2-[4-[5-Amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]propanamide

(188) ##STR00482##

(189) To a stirred solution of 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]propanoic acid (700 mg, 2.30 mmol) and 3-(2,2-dimethylpropyl)-4-fluoro-1,2-oxazol-5-amine (435.62 mg, 2.53 mmol) in ACN (5.00 mL) is added NMI (1.89 g, 22.99 mmol) and TCFH (6.45 g, 22.99 mmol) dropwise at RT under N.sub.2. The mixture is stirred for 3 hrs at 50° C. under N.sub.2. The mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (3:2-1:1) to give the title compound (400 mg, 39.93%) as an off-white solid. ES/MS (m/z) 459.2 (M+H).

Preparation 97

2-[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-bicyclo[1.1.1]pentanylmethyl)isoxazol-5-yl]propanamide, Isomer 1

(190) ##STR00483##

(191) T3P® (250 μL, 0.427 mmol, 50% solution in EtOAc) is added dropwise to a stirring solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, Isomer 1 (51 mg, 0.171 mmol), 3-(3-bicyclo[1.1.1]pentanylmethyl)isoxazol-5-amine (28.1 mg, 0.171 mmol) and pyridine (27.7 μL, 0.342 mmol) in EtOAc (2 mL, 0.1 M). The reaction is stirred at RT for 18 hrs. The reaction mixture is partitioned between EtOAc (5 mL) and saturated aqueous NaCl solution (5 mL). The organic layer is isolated and concentrated to dryness. The crude product is purified by C18 HPLC eluting with H.sub.2O:ACN (5-95%) with 0.1% TFA to give the title compound as a salt. The free base of the desired product is formed by eluting the desired product through a cartridge of carbonate resin to give the title compound (10 mg, 0.0225 mmol, 13%). ES/MS (m/z) 445.2 (M+H).

Preparation 98

2-(6-[5-Amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)-N-[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]propanamide, Isomer 2

(192) ##STR00484##

(193) To a solution of 2-(6-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)propanoic acid, Isomer 2 (200 mg, 0.57 mmol), 3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-amine (180 mg, 0.84 mmol), and DIPEA (273 mg, 2.11 mmol) in DCM (15 mL) is added T3P® (2.24 g, 3.52 mmol, 50% in EtOAc) and the mixture is stirred overnight at 50° C. The reaction is cooled to RT and concentrated under reduced pressure. The residue is purified by reversed phase Combi-flash with the following conditions: Column, C18; mobile phase, ACN in H.sub.2O (0.1% NH.sub.4CO.sub.3) eluting with a gradient of 10% to 50% in 10 min; UV 254 nm to give the title compound (100 mg, 32.2%) as an off-white solid. ES/MS (m/z) 548.10 (M+H).

(194) The following compounds in Table 15 are prepared essentially as described for 2-(6-[5-amino-4-cyano-1-[1,1,1-trifluoropropan-2-yl]pyrazol-3-yl]pyridin-3-yl)-N-[3-(2-chloro-4-fluorophenyl)-1,2-oxazol-5-yl]propanamide, Isomer 2 using the appropriate reagents, adjusting reaction time to determine completion of the reaction, and using appropriate chromatography conditions for purification. Temperature can range from RT to 80° C. and can be completed in a sealed tube if appropriate. Dimethylacetamide (DMA) can be substituted for DCM.

(195) TABLE-US-00022 TABLE 15 ES/MS Prep. m/z No. Chemical name Structure (M + H)  99 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)-N-[3-(2-chloro-4- fluorophenyl)-1,2-oxazol-5- yl]propanamide, Isomer 1 548.1, 550.1 100 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)-N-[3-(2,4- dichlorophenyl)-1,2-oxazol- 5-yl]propanamide, Isomer 1 564.3, 566.3 101 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)-N-[3-(2,2- dimethylpropyl)-1,2-oxazol- 5-yl]propanamide, Isomer 1 490.2 102 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)-N-[5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3-yl]propanamide, Isomer 2 530.3 103 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)-N-[3-(2,2- dimethylpropyl)-1,2-oxazol- 5-yl]propanamide, Isomer 2 490.3 104 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)-N-[3-(2,4- dichlorophenyl)-1,2-oxazol- 5-yl]propanamide, Isomer 2 0 564.3, 566.3 105 2-[4-[5-Amino-4-cyano-1- [2,2,2-trifluoro-1-methyl- ethyl]pyrazol-3-yl]phenyl]- N-[3-(2,2- dimethylpropyl)isoxazol-5- yl]propanamide, Isomer 1 489.3 106 2-[4-[5-Amino-4-cyano-1- (1- methylcyclopropyl)pyrazol- 3-yl]phenyl]-N-[3-(3,3- dimethylcyclobutyl)-1,2- oxazol-5-yl]propanamide 459.3 107 2-[4-[5-Amino-4-cyano-1- (1- methylcyclopropyl)pyrazol- 3-yl]phenyl]-N-[5-(2,2- dimethylpropyl)-1,2-oxazol- 3-yl]propanamide 447.2 108 2-[4-[5-Amino-4-cyano-1- (1-methoxy-2- methylpropan-2-yl)pyrazol- 3-yl]phenyl]-N-[3-(2,2- dimethylpropyl)-1,2-oxazol- 5-yl]propanamide 479.3 109 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)phenyl]-N-[3-(2- methylbutan-2-yl)-1,2- oxazol-5-yl]propanamide 434.6 110 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)phenyl]-N-[5-(3,3- difluoro-2-methylbutan-2- yl)-1,2-oxazol-3- yl]propanamide 493.1 111 2-[6-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)pyridin-3-yl]-N-[5-(3,3- difluoro-2-methylbutan-2- yl)-1,2-oxazol-3- yl]propanamide 472.5 112 2-[6-[5-Amino-4-cyano-1- (1- methylcyclopropyl)pyrazol- 3-yl]pyridin-3-yl]-N-[5- (1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3-yl]propanamide 488.2 113 2-[6-[5-Amino-4-cyano-1- methylcyclopropyl)pyrazol- 3-yl]pyridin-3-yl]-N-[3- (2,2-dimethylpropyl)-1,2- oxazol-5-yl]propanamide 448.3 114 2-[6-[5-Amino-4-cyano-1- (1- methylcyclopropyl)pyrazol- 3-yl]pyridin-3-yl]-N-[3- (2,4-dichlorophenyl)-1,2- oxazol-5-yl]propanamide 00 522.1, 524.1 115 2-[6-[5-Amino-4-cyano-1- (1- methylcyclopropyl)pyrazol- 3-yl]pyridin-3-yl]-N-[3-(2- chloro-4-fluorophenyl)-1,2- oxazol-5-yl]propanamide 01 506.1 116 2-(6-[5-Amino-4-cyano-1- [1,1,1-trifluoropropan-2- yl]pyrazol-3-yl]pyridin-3- yl)-N-[5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3-yl]propanamide, Isomer 1 02 530.3 117 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)phenyl]-N-[3- (trifluoromethyl)phenyl] propanamide 03 442.3 118 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)phenyl]-N-[3-(1,1,1- trifluoro-2-methylpropan-2- yl)-1,2-oxazol-5- yl]propanamide 04 475.2 119 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)phenyl]-N-[5-(1,1,1- trifluoro-2-methylpropan-2- yl)-1,2-oxazol-3- yl]propanamide 05 475.1 119a 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)phenyl]-N-[5-(1,1,1- trifluoro-2-methylpropan-2- yl)-1H-pyrazol-3- yl]propanamide 06 474.2 119b 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3- yl)phenyl]-N-[1-methyl-5- (1,1,1-trifluoro-2- methylpropan-2-yl)pyrazol- 3-yl]propanamide 07 488.4 119c 2-[4-(5-Amino-4-cyano-1- (1- methylcyclopropyl)pyrazol- 3-yl]-3-fluorophenyl]-N-[3- [3- (trifluoromethyl)bicyclo[1.1. 1]pentan-1-yl]-1,2-oxazol-5- yl]propanamide 08 529.3 119e 2-[4-[5-Amino-4-cyano-1- (1- methylcyclopropyl)pyrazol- 3-yl]-3 -fluorophenyl]-N-[3 - [4- (trifluoromethyl)bicyclo[2.2. 1]heptan-1-yl]-1,2-oxazol-5- yl]propanamide 09 557.4 119f 2-[4-(5-Amino-4-cyano-1- isopropylpyrazol-3-yl)-2,3 - difluorophenyl]-N-[3-(2,2- dimethylpropyl)-1,2-oxazol- 5-yl]propanamide 0 471.3

Preparation 119 g

2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]propanamide

(196) ##STR00511##

(197) To a stirred mixture of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]propanoic acid (400 mg, 1.29 mmol) and 3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-amine (281.20 mg, 1.29 mmol) in DCM (5.00 mL) is added DIPEA (499.72 mg, 3.87 mmol) and T3P® (4.10 g, 6.44 mmol, 50 wt % in EtOAc) dropwise in sealed tube at RT under N.sub.2. The mixture is stirred for 1 hr at 80° C. under N.sub.2. The mixture is concentrated under reduced pressure. The residue is purified by reverse combi-flash chromatography with the following conditions: C18; eluting with a gradient of 30% to 50% ACN in H.sub.2O to give the title compound (230 mg, 34%) as a light yellow solid. ES/MS (m/z) 511.2 (M+H).

Preparation 119h

2-[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]propanamide, Isomer 1

(198) ##STR00512##

(199) 2-[4-(5-Amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]propanoic acid, Isomer 1 (78 mg, 0.25 mmol), 3-(3-methylbicyclo[1.1.1]pentan-1-yl)isoxazol-5-amine (34 mg, 0.21 mmol) and 1-methylimidazole (39 mg, 0.038 mL, 0.48 mmol) are combined in EtOAc (3 mL). The orange solution is stirred for 2 mins at RT then T3P® (0.31 g, 0.29 mL, 50% Wt in EtOAc, 0.49 mmol) is added. The reaction is stirred for 16 hrs. The reaction is then diluted with 5 mL H.sub.2O and extracted with EtOAc (3×25 mL). The combined organic extracts are dried over Na.sub.2SO.sub.4, and the solvent is removed under reduced pressure. The residue is used without further purification. ES/MS (m/z) 511.2 (M+H). ES/MS (m/z) 445.2 (M+H).

Preparation 120

Tert-Butyl N-[4-carbamoyl-2-isopropyl-5-[6-[1-methyl-2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]-3-pyridyl]pyrazol-3-yl]carbamate

(200) ##STR00513##

(201) tert-Butyl N-[4-cyano-2-isopropyl-5-[6-[1-methyl-2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]-3-pyridyl]pyrazol-3-yl]carbamate (130 mg, 0.226 mmol) and platinate(2-), tris(dimethylphosphinito-P)hydro-, dihydrogen (Parkins catalyst, CAS #173416-05-2) (116 mg, 0.271 mmol) are added together in a mixture of tert-BuOH (2.6 mL) and H.sub.2O (1.3 mL). The reaction mixture is stirred at 60° C. overnight, filtered through a pad of talcum powder, and washed with EtOAc. The organic phase is washed with H.sub.2O and the aqueous phase is extracted with EtOAc. The organic extracts are combined, dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to give the title compound as a white solid (147.8 mg, 104.73%). The material is used directly without purification.

(202) The following compounds in Table 16 are prepared essentially as described for tert-butyl N-[4-carbamoyl-2-isopropyl-5-[6-[1-methyl-2-oxo-2-[[5-(2,2,2-trifluoro-1,1-dimethyl-ethyl)isoxazol-3-yl]amino]ethyl]-3-pyridyl]pyrazol-3-yl]carbamate using the appropriate reagents, adjusting reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification if needed. Temperature can vary from about 60 to 70° C.

(203) TABLE-US-00023 TABLE 16 ES/MS Prep. m/z No. Chemical name Structure (M + H) 121 tert-Butyl N-[4-carbamoyl-2- isopropyl-5-[6-[1-methyl-2- oxo-2-[[3-(2,2,2-trifluoro-1,1- dimethyl-ethyl)isoxazol-5- yl]amino]ethyl]-3- pyridyl]pyrazol-3- yl]carbamate 594 122 tert-Butyl N-[4-carbamoyl-5- [6-[2-[[3-(2,4- dichlorophenyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]-3-pyridyl]-2-isopropyl- pyrazol-3-yl]carbamate 123 tert-Butyl N-[4-carbamoyl-5- [6-[2-[[5-(1,1- dimethylpropyl)isoxazol-3- yl]amino]-1-methyl-2-oxo- ethyl]-3-pyridyl]-2-isopropyl- pyrazol-3-yl]carbamate 124 tert-Butyl N-[4-carbamoyl-5- [6-[2-[[5-(2,2- dimethylpropyl)isoxazol-3- yl]amino]-1-methyl-2-oxo- ethyl]-3-pyridyl]-2-isopropyl- pyrazol-3-yl]carbamate 125 tert-Butyl N-[4-carbamoyl-5- [6-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]-3-pyridyl]-2-isopropyl- pyrazol-3-yl]carbamate 554 126 tert-Butyl N-[4-carbamoyl-5- [5-[2-[[3-(1,1- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]-2-pyridyl]-2-isopropyl- pyrazol-3-yl]carbamate 127 5-Amino-1-cyclopropyl-3-[4- [2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]pyrazole-4- carboxamide 0 451.3 128.sup.1 5-Amino-1-isopropyl-3-[4-[1- methyl-2-[[3-[(1- methylcyclopropyl)methyl] isoxazol-5-yl]amino]-2-oxo- ethyl]phenyl]pyrazole-4- carboxamide 451.1 129 tert-Butyl N-[4-carbamoyl-5- [5-[2-[[3-(1,1- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]-2-pyridyl]-2-isopropyl- pyrazol-3-yl]carbamate 554.4 .sup.1EtOH can be substituted for tert-BuOH.

Preparation 129a

5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide

(204) ##STR00523##

(205) To a mixture of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide (120 mg, 0.276 mmol), NaOH (55 mg, 1.38 mmol), H.sub.2O (2.00 mL), and DMSO (1.00 mL) in EtOH (5.00 mL) is added H.sub.2O.sub.2 (187.86 mg, 5.523 mmol, 30% aq.). The resulting mixture is stirred at 40° C. for 4 hrs. The mixture is allowed to cool to RT and quenched by the addition of saturated Na.sub.2SO.sub.3 aqueous (10 mL). The mixture is extracted with EtOAc (3×50 mL). The combined organic extracts are washed with saturated aqueous NaCl solution (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; mobile phase ACN in H.sub.2O (0.1% NH.sub.4CO.sub.3) eluting with a gradient of 0% to 50% in 25 min; UV 254 nm to give the title compound (100 mg, 80.02%) as a white solid. ES/MS (m/z) 453.4 (M+H).

(206) The following compounds in Table 17 are prepared essentially as described for 5-amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide using the appropriate reagents, adjusting reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification. NaOH and H.sub.2O.sub.2 can be added in portions and the relative amounts of solvents H.sub.2O, EtOH, and DMSO may be varied. Temperature can vary from RT to 50° C.

(207) TABLE-US-00024 TABLE 17 ES/MS Prep. m/z No. Chemical name Structure (M + H) 130 5-Amino-3-[5-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-isopropylpyrazole- 4-carboxamide 454.2 131 5-Amino-3-[5-(1-[[3-(2- chloro-4-fluorophenyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2 566.20 132 5-Amino-3-[5-(1-[[3-(2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1 582.1, 584.1 133 5-Amino-3-[5-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1 508.3 134 5-Amino-3-[5-(1-[[5- (1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2 548.2 135 5-Amino-3-[5-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2 508.2 136 5-Amino-3-[5-(1-[[3-(2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2 0 582.3, 584.3 137 5-Amino-3-[5-(1-[[3-(2- chloro-4-fluorophenyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1 566.1, 568.1 138 5-Amino-3-[4-[1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl]phenyl]- 1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 465.3 139 5-Amino-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]-1-[3,3,3- trifluoro-1-methyl- propyl]pyrazole-4- carboxamide, Isomer 1 507.3 140 5-Amino-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-[1,1,1-trifluoropropan- 2-yl]pyrazole-4- carboxamide, Isomer 2 529.4 (M + Na) 141 5-Amino-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-(1,1,1-trifluoro-2- methylpropan-2- yl)pyrazole-4-carboxamide 521.3 142 5-Amino-3-[4-(1-[[3-(3,3- dimethylcyclobutyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 477.4 143 5-Amino-3-[4-(1-[[5-(2,2- dimethylpropyl)-1,2- oxazol-3 - yl]carbamoyl]ethyl)phenyl]- 1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 465.4 144 5-Amino-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-(1-methoxy-2- methylpropan-2- yl)pyrazole-4-carboxamide 497.3 145 5-Amino-1-isopropyl-3-[4- (1-[[3-(2-methylbutan-2- yl)-1,2-oxazol-5- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 453.4 146 5-Amino-3-[4-(1-[[5-(3,3- difluoro-2-methylbutan-2- yl)-1,2-oxazol-3- yl]carbamoyl]ethyl)phenyl]- 1-isopropylpyrazole-4- carboxamide 0 489.2 147* 5-Amino-1-isopropyl-3-[4- (1[[5-(4,4,4-trifluoro-2- methylbutan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 507.1 148* 5-Amino-1-isopropyl-3-[5- (1-[[5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl)pyridin- 2-yl]pyrazole-4- carboxamide 494.1 149* 5-Amino-1-isopropyl-3-[5- (1-[[5-(2-methylbutan-2- yl)-1,2-oxazol-3- yl]carbamoyl]ethyl)pyridin- 2-yl]pyrazole-4- carboxamide 454.3 150 5-Amino-1-isopropyl-3-[5- (1-[[5-(4,4,4-trifluoro-2- methylbutan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl)pyridin- 2-yl]pyrazole-4-carboxamide 508.2 151* 5-Amino-3-[5-(1-[[5-(3,3- difluoro-2-methylbutan-2- yl)-1,2-oxazol-3- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-isopropylpyrazole- 4-carboxamide 490.4 152 5-Amino-1-isopropyl-3-[5- (1-[[3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]pyrazole-4- carboxamide 494.2 153 5-Amino-3-(5-(1-((3-(2,4- dichlorophenyl)isoxazol-5- yl)amino)-1-oxopropan-2- yl)pyridin-2-yl)-1- isopropyl-1H-pyrazole-4- carboxamide 528.2, 530.2 154 5-Amino-3-(5-(1-((3-(2- chloro-4- fluorophenyl)isoxazol-5- yl)amino)-1-oxopropan-2- yl)pyridin-2-yl)-1- isopropyl-1H-pyrazole-4- carboxamide 155 5-Amino-1-(1- methylcyclopropyl)-3-[5- (1-[[5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl)pyridin- 2-yl]pyrazole-4- carboxamide 506.2 156 5-Amino-3-[5-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 0 466.2 157 5-Amino-3-[5-(1-[[3-(2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 540.1, 542.1 158 5-Amino-3-[5-(1-[[3-(2- chloro-4-fluorophenyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 524.3 159 5-Amino-3-[5-(1-[[5- (1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl)pyridin- 2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1 548.2 160* 5-Amino-1-isopropyl-3-[4- (1-[[5-(2-methylbutan-2- yl)-1,2-oxazol-3- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 453.3 161 5-Amino-1-isopropyl-3-[4- (1-[[3- (trifluoromethyl)phenyl] carbamoyl]ethyl) phenyl]pyrazole- 4-carboxamide 460.3 162 5-Amino-3-[4-(1-[[3-(2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-isopropylpyrazole-4- carboxamide 527.1, 529.1 163 5-Amino-3-(4-[1-[(5-tert- butyl-1,2-thiazol-3- yl)carbamoyl]ethyl]phenyl)- 1-isopropylpyrazole-4- carboxamide 455.2 164 5-Amino-1-isopropyl-3-[4- (1-[[5-(1- methylcyclopropyl)-1,2- oxazol-3- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 437.2 165 5-Amino-1-isopropyl-3-[4- (1-[[3-(1- methylcyclopropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 437.2 166 5-Amino-1-isopropyl-3-[4- (1-[[3-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 0 493.2 167 5-Amino-1-isopropyl-3-[4- (1-[[5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 493.2 167a 5-Amino-1-isopropyl-3-[4- (1-[[5-(1,1,1-trifluoro-2- methylpropan-2-yl)-1H- pyrazol-3- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide 492.2 167b 5-Amino-3-[2-fluoro-4-[1- ([3-[3- (trifluoromethyl)bicyclo[1. 1.1]pentan-1-yl]-1,2- oxazol-5- yl]carbamoyl)ethyl]phenyl]- 1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 547.30 167c 5-Amino-3-[2-fluoro-4-[1- ([3-[4- (trifluoromethyl)bicyclo[2. 2.1]heptan-1-yl]-1,2- oxazol-5- yl]carbamoyl)ethyl]phenyl]- 1-(1- methylcyclopropyl)pyrazole- 4-carboxamide 575.4 167d 5-Amino-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]-1-(2,2,2- trideuterio-1-methyl- ethyl)pyrazole-4- carboxamide 456.4 167e 5-Amino-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]-1-[2,2,2- trideuterio-1- (trideuteriomethyl)ethyl] pyrazole-4-carboxamide 459.5 167f 5-Amino-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]-1-(1,2,2,2- tetradeuterio-1-methyl- ethyl)pyrazole-4- carboxamide 457.3 167g 5-Amino-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]-1-[1,2,2,2- tetradeuterio-1- (trideuteriomethyl)ethyl] pyrazole-4-carboxamide 460.3 167h 5-Amino-1-[1,1- difluoropropan-2-yl]-3-[4- (1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide, Isomer 1 489.3 167i 5-Amino-1-[1,1- difluoropropan-2-yl]-3-[4- (1-[[3-[2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)phenyl] pyrazole-4-carboxamide, Isomer 2 0 489.3 167j 5-Amino-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl)-2,3- difluorophenyl]-1- isopropylpyrazole-4- carboxamide 489.3 167k 5-Amino-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]-1-[2,2,2- trifluoro-1- (trideuteriomethyl) ethyl]pyrazole-4- carboxamide, Isomer 1 510.2 167l 5-Amino-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]-1-[2,2,2- trifluoro-1- (trideuteriomethyl)ethyl] pyrazole-4-carboxamide, Isomer 2 510.2 167m 5-Amino-3-[4-(1-[[3-(2,2- dimethylpropyl)-4-fluoro- 1,2-oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-isopropylpyrazole-4- carboxamide 471.1 167n 5-Amino-1-(2-deuterio- 2,2-difluoro-1-methyl- ethyl)-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]pyrazole-4- carboxamide, Isomer 1 490 167o 5-Amino-1-(2-deuterio- 2,2-difluoro-1-methyl- ethyl)-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol-5- yl]amino]-1-methyl-2-oxo- ethyl]phenyl]pyrazole-4- carboxamide, Isomer 2 490 *The mixture is acidified to pH = 3-6 with HCl (aq.) after quenching.

Alternate Preparation 129

5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide

(208) A mixture of 2-[4-(5-amino-4-carbamoyl-1-isopropylpyrazol-3-yl)phenyl]propanoic acid (1.30 g, 4.109 mmol), 3-(2,2-dimethylpropyl)-1,2-oxazol-5-amine (0.70 g, 4.520 mmol), NMI (2.12 g, 16.437 mmol) and TCFH (2.31 g, 8.218 mmol) in DMF (50 mL) is stirred for 4 hrs at RT under N.sub.2. The mixture is diluted with H.sub.2O (200 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts are washed with saturated aqueous NaCl solution (3×100 mL) and concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: column, C18; mobile phase, ACN in H.sub.2O (0.1% FA) eluting with a gradient of 55% to 65% in 10 min; UV 220 nm to give the title compound (500 mg, 26.9%) as a light yellow solid. ES/MS (m/z) 453.4 (M+H).

Alternate Preparation 130

5-Amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide

(209) ##STR00577##

(210) To a mixture of 2-[6-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)pyridin-3-yl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide (120 mg, 0.28 mmol), NaOH (55 mg, 1.38 mmol), DMSO (0.40 mL), H.sub.2O (0.80 mL) in EtOH (2.00 mL) is added H.sub.2O.sub.2 (937 mg, 8.27 mmol 30%). The mixture is stirred at 40° C. for 4 hrs. The mixture is allowed to cool to RT, quenched by the addition of saturated Na.sub.2SO.sub.3 (aq 30 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Column, C18, eluting with a gradient of 0 to 50% ACN in H.sub.2O (0.1% NH.sub.4CO.sub.3) to give the title compound (100 mg, 80%) as a white solid. ES/MS (m/z) 454.2 (M+H).

Alternate Preparation 138

5-Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

(211) 2-[4-[5-Amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]propanamide (190 mg, 0.43 mmol), EtOH (5.00 mL), H.sub.2O (2.00 mL), DMSO (1.00 mL), NaOH (170.00 mg, 4.26 mmol) and H.sub.2O.sub.2 (2.43 g, 21.30 mmol, 30%) are added together. The solution is stirred for 5 hrs at 40° C. The reaction is quenched by saturated Na.sub.2SO.sub.3 (10 mL). The solution is diluted with EtOAc (100 mL), washed with H.sub.2O (2×30 mL), and brine (20 mL). The organic phase is concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with following conditions: C18; eluting with a gradient of 50% to 80% ACN in H.sub.2O (0.1% NH.sub.4CO.sub.3) to give the title compound (190 mg, 95.9%) as a white solid. ES/MS (m/z) 465.3 (M+H).

Preparation 167p

5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide

(212) ##STR00578##

(213) To a stirred solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]propanamide (225.00 mg, 0.44 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL) is added NaOH (176.28 mg, 4.41 mmol) and H.sub.2O.sub.2 (30%, 999.40 mg, 8.82 mmol, 30 wt %) in portions at RT under N.sub.2. The mixture is stirred for 2 hr at 50° C. in sealed tube under N.sub.2. The mixture is cooled down to RT. The reaction is quenched by the addition of saturated Na.sub.2SO.sub.3 (20 mL) at RT. The mixture is extracted with EtOAc (3×50 mL). The combined organic extracts are washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure. The residue is purified by reverse combi-flash chromatography with the following conditions: column, C18; eluting with a gradient of 40% to 50% ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3) to give the title compound (70 mg, 30%) as a white solid. ES/MS (m/z) 529.2 (M+H)

Preparation 167q

5-Amino-3-(4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

(214) ##STR00579##

(215) To a stirred solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]phenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)propanamide (130 mg, 0.29 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL) is added NaOH (113.89 mg, 2.85 mmol) and H.sub.2O.sub.2 (30%, 645.70 mg, 5.70 mmol, 30 wt %) in portions at RT under N.sub.2. The mixture is stirred for 4 hr at 50° C. under N.sub.2. The mixture is allowed to cool to RT and quenched by the addition of saturated Na.sub.2SO.sub.3 (30 mL) at RT. The mixture is extracted with DCM (3×50 mL) and the combined organic extracts are washed with brine (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 50% ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3) to give the title compound (95 mg, 70%) as a pink solid. ES/MS (m/z) 497.2 (M+Na).

Preparation 167r

5-Amino-1-isopropyl-3-[4-(1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide

(216) ##STR00580##

(217) A solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]propanamide (130 mg, 0.27 mmol), NaOH (53.33 mg, 1.33 mmol) in EtOH/DMSO (6 mL, 5:1), H.sub.2O.sub.2 (907 mg, 7.99 mmol, 30%) is added together and stirred for 2 hrs at 50° C. The solution is cooled to RT, quenched with saturated Na.sub.2SO.sub.3 solution (10 mL) and extracted with EtOAc (3×20 mL), the organic extracts are dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product is purified by reversed phase Combi-flash with the following condition: Column, C18; eluting with a gradient of 40% to 60% ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3), to give the title compound (100 mg, 74.18%). ES/MS (m/z) 506.4 (M+H).

Preparation 167s

5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide

(218) ##STR00581##

(219) To a solution of 2-[4-[5-amino-4-cyano-1-(1-methylcyclopropyl)pyrazol-3-yl]-3-fluorophenyl]-N-(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)propanamide (100 mg, 0.21 mmol) and NaOH (42.14 mg, 1.05 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL) is added H.sub.2O.sub.2 (358.39 mg, 3.161 mmol, 30%). The reaction is stirred for 2 hrs at 50° C. The reaction is quenched with saturated Na.sub.2SO.sub.3 (aq. 10 mL) at 0° C. The aqueous layer is extracted with EtOAc (3×30 mL). The combined organic layers are washed with brine (2×20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 20% to 40% ACN in H.sub.2O (0.1% NH.sub.4HCO.sub.3) to give the title compound (70 mg, 67.44%) as a white solid. ES/MS (m/z) 493.2 (M+H).

Preparation 167t

5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide

(220) ##STR00582##

(221) A solution of 2-[4-(5-amino-4-cyano-1-isopropylpyrazol-3-yl)phenyl]-N-[3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]propanamid (230 mg, 0.46 mmol), H.sub.2O.sub.2 (1.05 g, 9.23 mmol, 30%) and NaOH (93 mg, 2.31 mmol) in EtOH/DMSO (20 mL, 4:1) is stirred for 2 hr at 40° C. The solution is cooled to RT, saturated Na.sub.2SO.sub.3 solution (10 mL) is added and the mixture is stirred for 10 mins at RT. The mixture is concentrated under reduced pressure and purified by reversed phase Combi-flash with the following condition: Column, C18; eluting with a gradient of 20% to 50% MeOH in H.sub.2O (0.1% NH.sub.4HCO.sub.3) to give the title compound (166 mg, 69.7%) as white solid. ES/MS (m/z) 517.10 (M+H).

Preparation 167u

5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide

(222) ##STR00583##

(223) To a stirred solution of 2-[4-[5-amino-4-cyano-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazol-3-yl]phenyl]-N-[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]propanamide (400 mg, 0.87 mmol) in EtOH (5.00 mL) and DMSO (1.00 mL) is added NaOH (174.44 mg, 4.36 mmol) and H.sub.2O.sub.2 (1.98 g, 17.45 mmol 30 wt %) dropwise at RT under N.sub.2. The mixture is stirred for 1 hr at 50° C. under N.sub.2 and then is quenched with saturated Na.sub.2SO.sub.3. The mixture is extracted with EtOAc (3×100 mL). The combined organic extracts are washed with brine (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue is purified by reverse combi-flash chromatography with the following conditions: Column C18; eluting with 30% to 50% ACN in H.sub.2O to give the title compound (120.00 mg, 28.87%) as a yellow solid. ES/MS (m/z) 477.3 (M+H).

Preparation 168

5-Amino-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide

(224) ##STR00584##

(225) To tert-butyl N-[4-carbamoyl-5-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]-2-isopropyl-pyrazol-3-yl]carbamate (134 mg, 0.242 mmol) in DCM (1.45 mL) is added TFA (0.72 mL, 9.68 mmol). The reaction mixture is stirred at RT for 3 hrs. The reaction mixture is quenched with cold saturated aqueous solution of NaHCO.sub.3 and the aqueous layer is extracted with EtOAc. The combined organic extract is washed with saturated aqueous NaCl solution, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude material is purified by silica gel flash chromatography eluting with a gradient of MeOH in DCM from 0% to 5% to give the title compound (68 mg, 61.95%).

(226) The following compounds in Table 18 are prepared essentially as described for 5-amino-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide adjusting reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification. The product can also be triturated in isopropyl ether, filtered, and dried under vacuum.

(227) TABLE-US-00025 TABLE 18 ES/MS Prep. m/z No. Chemical name Structure (M + H) t.sub.(R) 169 5-Amino-3-[6-[2-[[5-(2,2- dimethylpropyl)isoxazol- 3-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-1- isopropyl-pyrazole-4- carboxamide 454.4 18.4 170 5-Amino-1-isopropyl-3- [6-[1-methyl-2-oxo-2-[[5- (2,2,2-trifluoro-1,1- dimethyl-ethyl)isoxazol-3- yl]amino]ethyl]-3- pyridyl]pyrazole-4- carboxamide 494.4  5.2 171 5-Amino-1-isopropyl-3- [6-[1-methyl-2-oxo-2-[[3- (2,2,2-trifluoro-1,1- dimethyl-ethyl)isoxazol-5- yl]amino]ethyl]-3- pyridyl]pyrazole-4- carboxamide 494  3.5 172 5-Amino-3-[6-[2-[[3-(2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-1- isopropyl-pyrazole-4- carboxamide 454 28.5 173 5-Amino-3-[6-[2-[[3-(2,4- dichlorophenyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-1- isopropyl-pyrazole-4- carboxamide 13.7 174 5-Amino-3-[6-[2-[[5-(1,1- dimethylpropyl)isoxazol- 3-yl]amino]-1-methyl-2- oxo-ethyl]-3-pyridyl]-1- isopropyl-pyrazole-4- carboxamide 0  7.8

Example 1

5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, Isomer 1

(228) and

Example 2

5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, Isomer 2

(229) ##STR00591##

(230) 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide (100.00 mg, 0.22 mmol) is separated by prep-chiral chromatography with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexanes (10 mM NH.sub.3), mobile phase B:IPA; flow rate 20 mL/min; eluting 30% B in 15 min; 254 nm; t.sub.(R) Isomer 1 is 8.2 min (33.3 mg, 33.3%), [α]D.sup.20=0.22696° (C=0.1, MeOH) as a white solid with 100% ee. t.sub.(R) Isomer 2 is 11.0 min (33.1 mg, 33.1%), [α]D.sup.20=−0.2113° (C=0.1, MeOH) as a white solid with 100% ee. ES/MS (m/z) 453.4 (M+H).

(231) The following compounds in Table 19 are prepared essentially as described for 5-amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, Isomer 1 and Isomer 2 and adjusting the purification system as appropriate.

(232) TABLE-US-00026 TABLE 19 ES/MS Prep. m/z No. Chemical name Structure (M + H) t.sub.(R)  3.sup.1 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer A 508.2 13.1  4.sup.1 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer B 508.2 15.8  5.sup.1 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer A 529.3 (M + Na)  6.2  6.sup.1 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer B 529.3 (M + Na) 12.6  7 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-(1,1,1- trifluoro-2-methylpropan-2- yl]pyrazole-4- carboxamide, Isomer 1 521.4 12.2  8 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-(1,1,1- trifluoro-2-methylpropan-2- yl]pyrazole-4- carboxamide, Isomer 2 521.4 14.3  9 5-Amino-3-[4-[1-[[3- (3,3- dimethylcyclobutyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl]phenyl]-1-(1- methylcyclopropyl)pyrazole- 4-carboxamide, Isomer 1 477.4  8.6 10 5-Amino-3-[4-[1-[[3- (3,3- dimethylcyclobutyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4-carboxamide, Isomer 2 477.4 11.1 11 5-Amino-3-[4-[1-[[5- (2,2- dimethylpropyl)- 1,2-oxazol-3- yl]carbamoyl]ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4-carboxamide, Isomer 1 00 465.2 11.9 12 5-Amino-3-[4-[1-[[5- (2,2-dimethylpropyl)- 1,2-oxazol-3- yl]carbamoyl]ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4-carboxamide, Isomer 2 01 465.2 14.4 13 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-(1- methoxy-2- methylpropan-2- yl)pyrazole-4- carboxamide, Isomer 1 02 497.2 14.2 14 5-Amino-3-[4-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-(1- methoxy-2- methylpropan-2- yl)pyrazole-4- carboxamide, Isomer 2 03 497.2 17.6 15 5-Amino-1-isopropyl-3- [4-(1-[[3-(2- methylbutan-2-yl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1 04 453.2  9.3 16 5-Amino-1-isopropyl-3- [4-(1-[[3-(2- methylbutan-2-yl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 05 453.2 11.4 17 5-Amino-1-isopropyl-3- [4-(1-[[3-(1,1,1- trifluoro-2- methylpropan-2-yl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1 06 493.2  6.9 18 5-Amino-1-isopropyl-3- [4-(1-[[3-(1,1,1- trifluoro-2- methylpropan-2-yl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 07 493.2  8.0 19.sup.2 5-Amino-3-[5-[1-[[3-(2- chloro-4-fluorophenyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer A 08 566.1, 568.1 13.7 20.sup.2 5-Amino-3-[5-[1-[[3-(2- chloro-4-fluorophenyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer B 09 566.1, 568.1 21.2 21.sup.3 5-Amino-1-isopropyl-3- [4-(1-[[3- (trifluoromethyl)phenyl] carbamoyl]ethyl)phenyl] pyrazole-4- carboxamide, Isomer 1 0 460.3  9.0 22.sup.3 5-Amino-1-isopropyl-3- [4-(1-[[3- (trifluoromethyl)phenyl] carbamoyl]ethyl)phenyl] pyrazole-4- carboxamide, Isomer 2 460.3 12.8 23.sup.4 5-Amino-3-[5-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer A 508.15  4.0 24.sup.4 5-Amino-3-[5-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer B 508.15 11 25.sup.5 5-Amino-3-[5-[1-[[5- (1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1 548.2  7.5 26.sup.5 5-Amino-3-[5-[1-[[5- (1,1,1-trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2 548.2 11 27.sup.5 5-Amino-1-isopropyl-3- [4-(1-[[5-(4,4,4- trifluoro-2-methylbutan- 2-yl)-1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1 507.15  8 28.sup.5 5-Amino-1-isopropyl-3- [4-(1-[[5-(4,4,4- trifluoro-2-methylbutan- 2-yl)-1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 507.15 10.8 29.sup.6 5-Amino-3-[5-[1-[[3- (2,4-dichlorophenyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer A 582.0, 584.0 11.7 30.sup.6 5-Amino-3-[5-[1-[[3- (2,4-dichlorophenyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer B 582.1, 584.1 15.8 31.sup.7 5-Amino-1-(1- methylcyclopropyl)-3- [5-[(1-[[5-[1,1,1- trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl] pyridin-2-yl]pyrazole-4- carboxamide, Isomer 1 0 506.3  8.6 32.sup.7 5-Amino-1-(1- methylcyclopropyl)-3- [5-[(1-[[5-[1,1,1- trifluoro-2- methylpropan-2-yl)-1,2- oxazol-3- yl]carbamoyl]ethyl] pyridin-2-yl]pyrazole-4- carboxamide, Isomer 2 506.3 10.0 33.sup.8 5-Amino-3-[5-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-(1- methylcyclopropyl)pyrazole- 4-carboxamide, Isomer 1 466.35  8.8 34.sup.8 5-Amino-3-[5-[1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-(1- methylcyclopropyl)pyrazole- 4-carboxamide, Isomer 2 466.35 13.6 35 5-Amino-1-isopropyl-3- [4-(1-[[3-(1- methylcyclopropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1 437.2  8.2 36 5-Amino-1-isopropyl-3- [4-(1-[[3-(1- methylcyclopropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 437.2 11 36a.sup.9 5-Amino-3-[4-(1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl)-2,3- difluorophenyl]-1- isopropylpyrazole-4- carboxamide, Isomer 1 489.2 10 36b.sup.9 5-Amino-3-[4-(1-[[3- (2,2-dimethylpropyl)- 1,2-oxazol-5- yl]carbamoyl]ethyl)-2,3- difluorophenyl]-1- isopropylpyrazole-4- carboxamide, Isomer 2 489.2 12.8 .sup.1Column Chiralpak AD-H, 2*25 cm, 5 μm. .sup.2Column: (R,R)Whelk-O 1, 21.1*250 mm, 5 μm. .sup.3Column: (R,R)Whelk-O 1, Kromasil(02), 5*25 cm, 5 μm. .sup.4CHIRALPAK IF, 2*25 cm, 5 μm. .sup.5CHIRALPAK IA, 2*25 cm, 5 μm. .sup.6CHIRALPAK IA, 2*25 cm, 5 μm. .sup.7Mobile phase B, EtOH. .sup.8(R,R)-Whelk-01, 2.12*25, 5 μm, mobile phase B, EtOH. .sup.9Eluting with 25% IPA, 246/210 nm

Alternate Example 1

5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide, Isomer 1

(233) 5-Amino-3-[4-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)phenyl]-1-isopropylpyrazole-4-carboxamide (17 g) is isolated by prep-chiral with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A hexanes (10 mM NH.sub.3-MeOH), mobile phase B IPA; flow rate 20 mL/min; eluting with 30% B in 12 min; UV 254/220 nm; t.sub.(R) Isomer 1 is 7.0. The resulting solution is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: column, C18; mobile phase, ACN in H.sub.2O (0.1% FA) eluting with a gradient of 55% to 65% in 10 min; UV 220 nm, (6.1315 g, 35.7%) as white solid with 99.8% ee, MP 128° C., ES/MS (m/z) 453.2 (M+H).

Example 36c

5-Amino-3-[4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 1

(234) and

Example 36d

5-Amino-3-[4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 2

(235) ##STR00628##

(236) 5-Amino-3-(4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide (93 mg) is purified by Prep-HPLC with the following conditions: Column CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; eluting with 20% IPA in hexanes (10 mM NH.sub.3-MeOH), flow rate 20 mL/min; 254/210 nm to give Isomer 1, t.sub.(R) 12.22, (30.8 mg, 33% yield, 100% ee) as a white solid, ES/MS (m/z) 475.3 (M+H) and Isomer 2, t.sub.(R) 16.56, (30.5 mg, 33% yield 100% ee) as a white solid, ES/MS (m/z) 475.3 (M+H).

Example 36e

5-Amino-1-isopropyl-3-[4-[1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl]phenyl]pyrazole-4-carboxamide, Isomer 1

(237) and

Example 36f

5-Amino-1-isopropyl-3-[4-[1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl]phenyl]pyrazole-4-carboxamide, Isomer 2

(238) ##STR00629##

(239) 5-Amino-1-isopropyl-3-[4-(1-[[1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide (90 mg) is purified by Prep-CHIRAL-HPLC with the following conditions: Column CHIRALPAK IC, 2*25 cm, 5 μm; eluting with 30% IPA in hexanes (10 mM NH.sub.3-MeOH), flow rate 20 mL/min; 240/210 nm to give the title compound of Isomer 1, t.sub.(R) 15.48, (35.2 mg, 39.22% yield, 100% ee), ES/MS (m/z) 506.3 (M+H) as a white solid and the title compound of Isomer 2, t.sub.(R) 20.74, (32.3 mg, 35.89% yield 97.7% ee), ES/MS (m/z) 506.3 (M+H) as a white solid.

Example 36 g

5-Amino-1-isopropyl-3-(4-(1-((3-(3-methylbicyclo[1.1.1]pentan-1-yl)isoxazol-5-yl)amino)-1-oxopropan-2-yl)phenyl)-1H-pyrazole-4-carboxamide, Isomer 1

(240) ##STR00630##

(241) 2-[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-methyl-1-bicyclo[1.1.1]pentanyl)isoxazol-5-yl]propanamide, Isomer 1 (110 mg, 247 μmol) and Parkins catalyst (106 mg, 247 μmol) are combined in EtOH (4 mL) and H.sub.2O (1 mL). The mixture is heated to 60° C. for 24 hrs. The mixture is passed through a 0.45 μM filter and the solvent is removed under reduced pressure. The residue is purified via silica gel flash chromatography eluting with a gradient of 0-100% heptane:EtOAc to give the title compound (26 mg, 23%) as a yellow solid. ES/MS (m/z) 463.2 (M+H).

Example 36h

5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, Isomer 1

(242) and

Example 36i

5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, Isomer 2

(243) ##STR00631##

(244) 5-Amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide (68 mg) is purified by Prep-CHIRAL-HPLC with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; eluting with 15% EtOH in hexanes (10 mM NH.sub.3-MeOH), flow rate 20 mL/min in 18 min, 254/210 nm to give the title compound of Isomer 1, t.sub.(R) 11.72, (15.3 mg, 22% yield with 100% ee) as a white solid, ES/MS (m/z) 529.2 (M+H) and the title compound of Isomer 2, t.sub.(R) 14.41, (16.8 mg, 24% yield with 100% ee) as a white solid, ES/MS (m/z) 529.2 (M+H).

(245) The following compounds in Table 19a are prepared essentially as described for 5-amino-1-(1-methylcyclopropyl)-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, Isomer 1 and Isomer 2 and adjusting chromatography conditions as appropriate.

(246) TABLE-US-00027 TABLE 19a ES/MS Ex. m/z t.sub.(R) No. Chemical name Structure (M + H) min 36j 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]-1-(2,2,2- trideuterio-1-methyl- ethyl)pyrazole-4- carboxamide, Isomer 1 456.2 11.62 36k 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]-1-(2,2,2- trideuterio-1-methyl- ethyl)pyrazole-4- carboxamide, Isomer 2 456.2 14.55 36l.sup.1 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]-1-[2,2,2- trifluoro-1- (trideuteriomethyl)ethyl] pyrazole-4- carboxamide, Isomer 1, Diastereomer A 510.2 7.4 36m.sup.1 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]-1-[2,2,2- trifluoro-1- (trideuteriomethyl)ethyl] pyrazole-4- carboxamide, Isomer 1. Diastereomer B 510.2 11.6 36n.sup.3 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]-1-[2,2,2- trifluoro-1- (trideuteriomethyl)ethyl] pyrazole-4- carboxamide, Isomer 2, Diastereomer A 510.05 6.05 36o.sup.3 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]-1-[2,2,2- trifluoro-1- (trideuteriomethyl)ethyl] pyrazole-4- carboxamide, Isomer 2, Diastereomer B 510.05 7.59 36p.sup.2 5-Amino-1-(2-deuterio- 2,2-difluoro-1-methyl- ethyl)-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 1, Diastereomer A 490.2 26.3 36q.sup.2 5-Amino-1-(2-deuterio- 2,2-difluoro-1-methyl- ethyl)-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 1, Diastereomer B 490.2 29.45 36r.sup.4 5-Amino-1-(2-deuterio- 2,2-difluoro-1-methyl- ethyl)-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide carboxamide, Isomer 2, Diastereomer A 0 490.15 11.8 36s.sup.4 5-Amino-1-(2-deuterio- 2,2-difluoro-1-methyl- ethyl)-3-[4-[2-[[3-(2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 2, Diastereomer B 490.15 14.5 .sup.1Eluting with 10% EtOH in 1:1 hexanes:MTBE (0.5% 2M NH.sub.3—MeOH). .sup.2Eluting with 10% EtOH in hexanes (10 mM NH.sub.3—MeOH), 245/210 nm. .sup.3Column: CHIRALPAK ID 2*25 cm, 5 μm; eluting with 8% IPA in 1:1 hexanes:MTBE (0.5% 2M NH.sub.3—MeOH), 245/210 nm. .sup.4UV 245/210 nm.

Example 36t

5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 1

(247) and

Example 36u

5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 2

(248) ##STR00642##

(249) 5-Amino-3-(2-fluoro-4-[1-[(3-[3-methylbicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl)carbamoyl]ethyl]phenyl)-1-(1-methylcyclopropyl)pyrazole-4-carboxamide (70 mg) is purified by Prep-Chiral-HPLC by following conditions: Column CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm eluting with 30% IPA in hexanes (10 mM NH.sub.3-MeOH), 250/210 nm to give the title compound of Isomer 1 t.sub.(R) 7.04, (20.3 mg, 29.0%, 99.76% ee) as a white solid, ES/MS (m/z) 454.2 (M+H) and the title compound of Isomer 2 trio 9.48, (18.9 mg, 27.0%, 99.26% ee) as a white solid, ES/MS (m/z) 454.2 (M+H).

Example 36v

5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, Isomer 1

(250) and

Example 36w

5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, Isomer 2

(251) ##STR00643##

(252) 5-Amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide (162 mg) is purified by Prep-Chiral-HPLC by following conditions: Column CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm eluting with 20% EtOH in hexanes (10 mM NH.sub.3-MeOH), 254/210 nm to give the title compound of Isomer 1 t.sub.(R) 10.66, (48.1 mg, 29.6%, 100% ee) as a white solid, ES/MS (m/z) 517.05 (M+H) and the title compound of Isomer 2 t.sub.(R) 13.23, (50.4 mg, 30.6%, 99.74% ee) as a white solid, ES/MS (m/z) 517.05 (M+H).

(253) The following compounds in Table 19b are prepared essentially as described for 5-amino-1-isopropyl-3-[4-[1-([3-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-1,2-oxazol-5-yl]carbamoyl)ethyl]phenyl]pyrazole-4-carboxamide, Isomer 1 and Isomer 2 and adjusting chromatography conditions as appropriate.

(254) TABLE-US-00028 TABLE 19b ES/MS Ex. m/z t.sub.(R) No. Chemical name Structure (M + H) min 36x 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]phenyl]-1- [2,2,2-trideuterio-1- (trideuteriomethyl)ethyl] pyrazole-4-carboxamide, Isomer 1 459.1 7.55 36y 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]phenyl]-1- [2,2,2-trideuterio-1- (trideuteriomethyl)ethyl] pyrazole-4-carboxamide, Isomer 2 459.1 9.18 36z 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]phenyl]-1- (1,2,2,2-tetradeuterio-1- methyl-ethyl)pyrazole-4- carboxamide, Isomer 1 457.1 7.9 36za 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]phenyl]-1- (1,2,2,2-tetradeuterio-1- methyl-ethyl)pyrazole-4- carboxamide, Isomer 2 457.1 9.65 36zb 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]phenyl]-1- [1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl] pyrazole-4-carboxamide, Isomer 1 460.3 7.42 36zc 5-Amino-3-[4-[2-[[3- (2,2- dimethylpropyl)isoxazol- 5-yl]amino]-1-methyl-2- oxo-ethyl]phenyl]-1- [1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl] pyrazole-4-carboxamide, Isomer 2 460.3 9.04 36zd.sup.1 5-Amino-3-[4-(1-[[3- (2,2-dimethylpropyl)-4- fluoro-1,2-oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-isopropylpyrazole- 4-carboxamide, Isomer 1 0 471.1 8 36ze.sup.1 5-Amino-3-[4-(1-[[3- (2,2-dimethylpropyl)-4- fluoro-1,2-oxazol-5- yl]carbamoyl]ethyl)phenyl]- 1-isopropylpyrazole- 4-carboxamide. Isomer 2 471.1 9.7 .sup.1UV is 210/237 nm

Example 36zf

5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide, Isomer 1

(255) and

Example 36zg

5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide, Isomer 2

(256) ##STR00652##

(257) 5-Amino-3-[4-[2-[[3-(2,2-dimethylpropyl)-4-fluoro-isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]pyrazole-4-carboxamide (120 mg) is purified by Prep-Chiral-HPLC by following conditions: Column CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm eluting with 20% EtOH in hexanes (10 mM NH.sub.3-MeOH), 213/237 nm to give the title compound of Isomer 1 t.sub.(R) 7.78, (22.2 mg, 18.5%, 100% ee) as a beige solid, ES/MS (m/z) 477.25 (M+H) and the title compound of Isomer 2 t.sub.(R) 9.43, (27.1 mg, 22.6%, 98.14% ee) as a beige solid, ES/MS (m/z) 477.25 (M+H).

Example 37

5-Amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide, Isomer 1

(258) and

Example 38

5-Amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide, Isomer 2

(259) ##STR00653##

(260) 5-Amino-3-[5-(1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide (97.00 mg, 0.21 mmol) is separated by prep-chiral chromatography with the following conditions: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexanes (10 mM NH.sub.3), mobile phase B: EtOH; flow rate 20 mL/min; eluting with 40% B in 11 min; 254/220 nm; t.sub.(R) Isomer 1 is 5.2 min (35.8 mg, 36.9%) as a white solid with 100% ee. ES/MS (m/z) 454.2 (M+H). t.sub.(R) Isomer 2 is 7.5 min (42.1 mg, 43.4%) as a white solid with 100% ee. ES/MS (m/z) 454.2 (M+H).

(261) The following compounds in Table 20 are prepared essentially as described for 5-amino-3-[5-(1-[[3-(2,2-dim ethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl)pyridin-2-yl]-1-isopropylpyrazole-4-carboxamide, Isomer 1 and Isomer 2 and adjusting the purification system as appropriate.

(262) TABLE-US-00029 TABLE 20 ES/MS Ex. m/z t.sub.(R) No. Chemical name Structure (M + H) min 39.sup.1 5-Amino-3-[5-(1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) pyridin-2-yl]-1- isopropylpyrazole-4- carboxamide, Isomer 1  528.3, 530.3 6 40.sup.1 5-Amino-3-[5-(1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) pyridin-2-yl]-1- isopropylpyrazole-4- carboxamide, Isomer 2  528.3, 530.3 8.5 41.sup.2 5-Amino-3-(5-(1-((3- (2-chloro-4- fluorophenyl)isoxazol- 5-yl)amino)-1- oxopropan-2- yl)pyridin-2-yl)-1- isopropyl-1H- pyrazole-4- carboxamide, Isomer 1   512.05,  514.05 5.8 42.sup.2 5-Amino-3-(5-(1-((3- (2-chloro-4- fluorophenyl)isoxazol- 5-yl)amino)-1- oxopropan-2- yl)pyridin-2-yl)-1- isopropyl-1H- pyrazole-4- carboxamide, Isomer 2   512.05,  514.05 7.5 43.sup.3 5-Amino-3-[5-[1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 1  540.4, 542.4 7.9 44.sup.3 5-Amino-3-[5-[1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 2  540.4, 542.4 17.6 45 5-Amino-3-[4-(1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]-1- isopropylpyrazole-4- carboxamide, Isomer 1 0   527.05,  529.05 7.5 46 5-Amino-3-[4-(1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]-1- isopropylpyrazole-4- carboxamide, Isomer 2   527.05,  529.05 9.5 47.sup.4 5-Amino-1- cyclopropyl-3-[4-[2- [[3-(2,2- dimethylpropyl) isoxazol-5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 1 451.3 1.89 48.sup.4 5-Amino-1- cyclopropyl-3-[4-[2- [[3-(2,2- dimethylpropyl) isoxazol-5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 2 451.3 2.77 49.sup.4 5-Amino-1- isopropyl-3-[4-[1- methyl-2-[[3-[(1- methylcyclopropyl) methyl]isoxazol-5- yl]amino]-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 1 451.3 1.65 50.sup.4 5-Amino-1- isopropyl-3-[4-[1- methyl-2-[[3-[(1- methylcyclopropyl) methyl]isoxazol-5- yl]amino]-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 2 451.3 2.32 51 5-Amino-1- isopropyl-3-[4-(1- [[5-(2-methylbutan- 2-yl)-1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1 453.4 10 52 5-Amino-1- isopropyl-3-[4-(1- [[5-(2-methylbutan- 2-yl)-1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 453.4 13.5 53 5-Amino-3-[5-[1-[[3- (2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer A 508.2 4.5 54 5-amino-3-[5-[1-[[3- (2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1, Diastereomer B 508.2 5.7 55.sup.5 5-Amino-3-[5-[1-[[3- (2-chloro-4- fluorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 1 0 524.1 6.4 56.sup.5 5-Amino-3-[5-[1-[[3- (2-chloro-4- fluorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 2 524.1 8.9 57.sup.6 5-Amino-3-[5-[1-[[3- (2-chloro-4- fluorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer A  566.10 8.6 58.sup.6 5-Amino-3-[5-[1-[[3- (2-chloro-4- fluorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer B  566.10 13.5 59.sup.6 5-Amino-3-[5-[1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer A   582.25,  584.25 9.2 60.sup.6 5-Amino-3-[5-[1-[[3- (2,4- dichlorophenyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2, Diastereomer B   582.25,  584.25 13.5 61.sup.7 5-Amino-3-[4-[1-[[3- (2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 1 465.3 11.5 62.sup.7 5-Amino-3-[4-[1-[[3- (2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 2 465.3 20 63.sup.6 5-Amino-1- isopropyl-3-[5-(1- [[5-(1,1,1-trifluoro- 2-methylpropan-2- yl)-1,2-oxazol-3- yl]carbamoyl]ethyl) pyridin-2-yl]pyrazole- 4-carboxamide, Isomer 1  494.15 8.5 64.sup.6 5-Amino-1- isopropyl-3-[5-(1- [[5-(1,1,1-trifluoro- yl)-1,2-oxazol-3- 2-methylpropan-2- yl]carbamoyl]ethyl) pyridin-2-yl]pyrazole- 4-carboxamide, Isomer 2 494.2 12.5 65.sup.6,8 5-Amino-1- isopropyl-3-[5-(1- [[5-(2-methylbutan- 2-yl)-1,2-oxazol-3- yl]carbamoyl]ethyl) pyridin-2-yl]pyrazole- 4-carboxamide, Isomer 1 0 454.4 5 66.sup.6,8 5-Amino-1- isopropyl-3-[5-(1- [[5-(2-methylbutan- 2-yl)-1,2-oxazol-3- yl]carbamoyl]ethyl) pyridin-2-yl]pyrazole- 4-carboxamide, Isomer 2 454.4 6.7 67.sup.7 5-Amino-1- isopropyl-3-(5-(1- oxo-1-((5-(4,4,4- trifluoro-2- methylbutan-2- yl)isoxazol-3- yl)amino)propan-2- yl)pyridin-2-yl)-1H- pyrazole-4- carboxamide, Isomer 1 508.4 8.5 68.sup.7 5-Amino-1- isopropyl-3-(5-(1- oxo-1-((5-(4,4,4- trifluoro-2- methylbutan-2- yl)isoxazol-3- yl)amino)propan-2- yl)pyridin-2-yl)-1H- pyrazole-4- carboxamide, Isomer 2 508.4 13 69.sup.6 5-Amino-3-[5-(1-[[5- (3,3-difluoro-2- methylbutan-2-yl)- 1,2-oxazol-3- yl]carbamoyl]ethyl) pyridin-2-yl]-1- isopropylpyrazole-4- carboxamide, Isomer 1  490.10 6 70.sup.6 5-Amino-3-[5-(1-[[5- (3,3-difluoro-2- methylbutan-2-yl)- 1,2-oxazol-3- yl]carbamoyl]ethyl) pyridin-2-yl]-1- isopropylpyrazole-4- carboxamide, Isomer 2  490.15 8.5 71.sup.10 5-Amino-1- isopropyl-3-[5-(1- [[3-(1,1,1-trifluoro- 2-methylpropan-2- yl)-1,2-oxazol-5- yl]carbamoyl]ethyl) pyridin-2-yl]pyrazole- 4-carboxamide, Isomer 1 494.2 7.2 72.sup.10 5-Amino-1- isopropyl-3-[5-(1- [[3-(1,1,1-trifluoro- 2-methylpropan-2- yl)-1,2-oxazol-5- yl]carbamoyl]ethyl) pyridin-2-yl]pyrazole- 4-carboxamide, Isomer 2 494.2 11 73.sup.9 5-Amino-3-[5-[1-[[5- (1,1,1-trifluoro-2- methylpropan-2-yl)- 1,2-oxazol-3- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 1 548.2 3.2 74.sup.9 5-Amino-3-[5-[1-[[5- (1,1,1-trifluoro-2- methylpropan-2-yl)- 1,2-oxazol-3- yl]carbamoyl]ethyl] pyridin-2-yl]-1-[1,1,1- trifluoropropan-2- yl]pyrazole-4- carboxamide, Isomer 2 548.2 6.2 75.sup.11 5-Amino-3-[4-(1-[[5- (3,3-difluoro-2- methylbutan-2-yl)- 1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]-1- isopropylpyrazole-4- carboxamide, Isomer 1 0  511.10 5.2 76.sup.11 5-Amino-3-[4-(1-[[5- (3,3-difluoro-2- methylbutan-2-yl)- 1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]-1- isopropylpyrazole-4- carboxamide, Isomer 2  511.10 7.5 77.sup.12 5-Amino-1- isopropyl-3-[4-(1- [[5-(1- methylcyclopropyl)- 1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1  437.25 7.5 78.sup.12 5-Amino-1- isopropyl-3-[4-(1- [[5-(1- methylcyclopropyl)- 1,2-oxazol-3- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 437.2 16 78a.sup.13 5-Amino-1- isopropyl-3-[4-[1- [[5-(1,1,1-trifluoro- 2-methylpropan-2- yl)-1H-pyrazol-3- yl]carbamoyl]ethyl] phenyl]pyrazole-4- carboxamide, Isomer 1 492.2 5.97 78b.sup.13 5-Amino-1- isopropyl-3-[4-[1- [[5-(1,1,1-trifluoro- 2-methylpropan-2- yl)-1H-pyrazol-3- yl]carbamoyl]ethyl] phenyl]pyrazole-4- carboxamide, Isomer 2 492.2 10.34 78c.sup.14 5-Amino-1- isopropyl-3-[4-[1- [[1-methyl-5-(1,1,1- trifluoro-2- methylpropan-2- yl)pyrazol-3- yl]carbamoyl]ethyl] phenyl]pyrazole-4- carboxamide, Isomer 1 506.3 15.48 78d.sup.14 5-Amino-1- isopropyl-3-[4-[1- [[1-methyl-5-(1,1,1- trifluoro-2- methylpropan-2- yl)pyrazol-3- yl]carbamoyl]ethyl] phenyl]pyrazole-4- carboxamide, Isomer 2 506.3 20.74 78e.sup.14 5-Amino-3-[2- fluoro-4-[1-([3-[3- (trifluoromethyl)bicyclo [1.1.1]pentan-1- yl]-1,2-oxazol-5- yl]carbamoyl)ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 1 547.3 5.30 78f.sup.14 5-Amino-3-[2- fluoro-4-[1-([3-[3- (trifluoromethyl)bicyclo [1.1.1]pentan-1- yl]-1,2-oxazol-5- yl]carbamoyl)ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 2 547.3 6.44 78g 5-Amino-3-[2- fluoro-4-[1-([3-[4- (trifluoromethyl)bicyclo [2.2.1]heptan-1- yl]-1,2-oxazol-5- yl]carbamoyl)ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 1 00 575.2 5.79 78h 5-Amino-3-[2- fluoro-4-[1-([3-[4- (trifluoromethyl)bicyclo [2.2.1]heptan-1- yl]-1,2-oxazol-5- yl]carbamoyl)ethyl] phenyl]-1-(1- methylcyclopropyl) pyrazole-4- carboxamide, Isomer 2 01 575.2 7.62 78i.sup.15 5-Amino-1-[1,1- difluoropropan-2- yl]-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1 02 489.2 5 78j.sup.15 5-Amino-1-[1,1- difluoropropan-2- yl]-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 03 489.2 7.4 78k.sup.16 5-Amino-1-[1,1- difluoropropan-2- yl]-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 1 04 489.2 6.1 78l.sup.16 5-Amino-1-[1,1- difluoropropan-2- yl]-3-[4-(1-[[3-(2,2- dimethylpropyl)-1,2- oxazol-5- yl]carbamoyl]ethyl) phenyl]pyrazole-4- carboxamide, Isomer 2 05 489.2 12.1 .sup.1Column CHIRAL ART Cellulose-SB, S-5 μm, 50*250 mm, 5 μm. .sup.2Column CHIRAL ART Cellulose-SB S-5 μm, 2*25 cm. .sup.3Column CHIRALCEL OD-H, 2*25 mm. .sup.4Column CHIRALCEL OD-H, 4.6X150 mm, 5 μm, 25% EtOH/CO.sub.2, 5 mL/min, 225 nm. .sup.5Column CHIRAL ART Cellulose-SC. .sup.6Column: (R,R)Whelk-O 1, 21.1*250 mm, 5 μm. .sup.7Column: (R,R)Whelk-O1, 2.12*25 cm, 5 μm. .sup.8EtOH used for mobile phase A and B, 50% isocratic. .sup.9Column: CHIRALPAK IH, 25*2 cm, 5 μm, mobile phase A CO.sub.2, mobile phase B IPA, isocratic 45% B. .sup.10(R,R)-Whelk-01, 2*25 mm, 5 μm. .sup.11Column: Chiralpak AD-H, 2*25 cm, 5 μm. .sup.12Column: Chiralpak AD-H, 2*25 cm, 5 μm, eluting with a gradient of 50% B to 0 B. .sup.13Column: Chiralpak ADH, 2*25 cm, 5 μm, eluting with hexanes (10 mM NH.sub.3MeOH and 30% IPA. .sup.14Solvent system is 30% EtOH in hexanes (10 mM NH.sub.3—MeOH). .sup.15Column: CHIRALPAK IG, 2*25 cm, 5 μm; eluting with 30% EtOH in hexanes (10 mM NH.sub.3—MeOH), flow rate 20 mL/min, 234/274 nm. .sup.16Column: CHIRAL ART Amylose-C NEO, 2.0*2 cm, 5 μm; eluting with 40% EtOH in hexanes (10 mM NH.sub.3—MeOH), flow rate 20 mL/min, 245/254 nm.

Alternate Example 61

5-Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 1

(263) and

Alternate Example 62

5-Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide, Isomer 2

(264) ##STR00706##

(265) 5-Amino-3-[4-[1-[[3-(2,2-dimethylpropyl)-1,2-oxazol-5-yl]carbamoyl]ethyl]phenyl]-1-(1-methylcyclopropyl)pyrazole-4-carboxamide (95 mg) is separated with the following conditions: Column: (R,R)-Whelk-O1, 2.12*25 cm, 5 μm; eluting with 30% EtOH in hexanes (10 mM-MeOH), flow rate 20 mL/min, UV 254 nm to give the title compound of Isomer 1 t.sub.(R) 11.5 min, (38.6 mg, 40.6%, 100% ee) as a white solid, ES/MS (m/z) 465.3 (M+H) and the title compound of Isomer 2 trio 20 min (30.7 mg, 32.3%, 99.6% ee) as a white solid, ES/MS (m/z) 465.3 (M+H).

Example 79

5-Amino-3-(4-[1-[(5-tert-butyl-1,2-thiazol-3-yl)carbamoyl]ethyl]phenyl)-1-isopropylpyrazole-4-carboxamide, Isomer 1

(266) and

Example 80

5-Amino-3-(4-[1-[(5-tert-butyl-1,2-thiazol-3-yl)carbamoyl]ethyl]phenyl)-1-isopropylpyrazole-4-carboxamide, isomer 2

(267) ##STR00707##

(268) 5-Amino-3-(4-[1-[(5-tert-butyl-1,2-thiazol-3-yl)carbamoyl]ethyl]phenyl)-1-isopropylpyrazole-4-carboxamide (90 mg, 0.20 mmol) is separated by prep-chiral chromatography with the following conditions: Column: CHIRALPAK IG-3, 4.6*50 mm, 3.0 μm, mobile phase A: hexanes (0.1% DEA); mobile phase B: EtOH eluting with a gradient of 70% to 30% B; flow rate 1 mL/min, UV 254 nm, t.sub.(R) Isomer 1 is 2.1 min (25 mg, 21.8%) as a white solid, t.sub.(R) Isomer 2 is 3.3 min (25 mg, 21.8%) as a white solid. ES/MS (m/z) 455.25 (M+H).

Example 81

5-Amino-1-isopropyl-3-[4-(1-[[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide, Isomer 1

(269) and

Example 82

5-Amino-1-isopropyl-3-[4-(1-[[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide, Isomer 2

(270) ##STR00708##

(271) 5-Amino-1-isopropyl-3-[4-(1-[[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]carbamoyl]ethyl)phenyl]pyrazole-4-carboxamide (90 mg, 0.18 mmol) is separated by prep-chiral chromatography with the following conditions: Column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: ACN; mobile phase B: MtBE eluting with 25% B; 210 nm, 254 nm; t.sub.(R) Isomer 1 is 5 min (39.3 mg, 43.6%, 100% ee) as a white solid. t.sub.(R) Isomer 2 is 6 min (36.1 mg, 40.1%, 100% ee) as a white solid. ES/MS (m/z) 493.3 (M+H).

Example 83

5-Amino-1-isopropyl-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]pyrazole-4-carboxamide, Isomer 1

(272) and

Example 84

5-Amino-1-isopropyl-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]pyrazole-4-carboxamide, Isomer 2

(273) ##STR00709##

(274) 5-Amino-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]-1-isopropyl-pyrazole-4-carboxamide (68 mg, 0.18 mmol) is chirally separated with the following conditions: Column: Acquity UPLC CSH C18 (2.1×50 mm) 1.7 μm; mobile phase A: H.sub.2O+0.02% FA; mobile phase B: ACN+0.02% FA eluting with a gradient of 2% B to 98% B over 4 min; flow rate of 1 ml/min, temperature of 55° C. t.sub.(R) isomer 1 is 3.3 min (22 mg, 20%). t.sub.(R) isomer 2 is 4.7 min (23 mg, 21%). ES/MS (m/z) 454 (M+H).

(275) The following compounds in Table 21 are chirally separated essentially as described for 5-amino-1-isopropyl-3-[6-[2-[[3-(1,1-dimethylpropyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]-3-pyridyl]pyrazole-4-carboxamide, Isomer 1 and Isomer 2 adjusting the conditions as appropriate. The title compounds can be triturated with isopropyl ether and dried under vacuum at about 45° C. for 14 hrs to give white solids.

(276) TABLE-US-00030 TABLE 21 ES/MS Ex. m/z No. Chemical name Structure (M + H) t.sub.(R) 85 5-Amino-1- isopropyl-3-[6-[2- [[5-(2,2- dimethylpropyl) isoxazol-3-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 2 0 454.4 17.2 86 5-Amino-1- isopropyl-3-[6-[2- [[5-(2,2- dimethylpropyl) isoxazol-3-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 1 454.3 16.1 87 5-Amino-1- isopropyl-3-[6-[1- methyl-2-oxo-2- [[5-(2,2,2-trifluoro- 1,1-dimethyl- ethyl)isoxazol-3- yl]amino]ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 1 494 3.2 88 5-Amino-1- isopropyl-3-[6-[1- methyl-2-oxo-2- [[5-(2,2,2-trifluoro- 1,1-dimethyl- ethyl)isoxazol-3- yl]amino]ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 2 494 5.2 89 5-Amino-1- isopropyl-3-[6-[1- methyl-2-oxo-2- [[3-(2,2,2-trifluoro- 1,1-dimethyl- ethyl)isoxazol-5- yl]amino]ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 1 494.4 2.5 90 5-Amino-1- isopropyl-3-[6-[1- methyl-2-oxo-2- [[3-(2,2,2-trifluoro- 1,1-dimethyl- ethyl)isoxazol-5- yl]amino]ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 2 494.4 3.5 91 5-Amino-1- isopropyl-3-[6-[2- [[3-(2,2- dimethylpropyl) isoxazol-5-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 2 454.4 20.2 92 5-Amino-1- isopropyl-3-[6-[2- [[3-(2,2- dimethylpropyl) isoxazol-5-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 1 454.4 20.1 93 5-Amino-1- isopropyl-3-[6-[2- [[3-(2,4- dichlorophenyl) isoxazol-5-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 1 528.3 14.6 94 5-Amino-1- isopropyl-3-[6-[2- [[3-(2,4- dichlorophenyl) isoxazol-5-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 2 528.3 16.8 95 5-Amino-1- isopropyl-3-[6-[2- [[5-(1,1- dimethylpropyl) isoxazol-3-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 2 0 454 8.8 96 5-Amino-1- isopropyl-3-[6-[2- [[5-(1,1- dimethylpropyl) isoxazol-3-yl]amino]- 1-methyl-2-oxo- ethyl]-3- pyridyl]pyrazole-4- carboxamide, Isomer 1 454 8.7

Example 97

5-Amino-3-[4-[2-[[3-(3-bicyclo[1.1.1]pentanylmethyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-Ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide, Isomer 1

(277) ##STR00722##

(278) 2-[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]-N-[3-(3-bicyclo[1.1.1]pentanylmethyl)isoxazol-5-yl]propanamide, Isomer 1 (10 mg, 0.023 mmol) and platinate(2-), tris(dimethylphosphinito-P)hydro-, dihydrogen (Parkins catalyst, CAS #173416-05-2) (10 mg, 0.023 mmol) are stirred in EtOH (0.2 ml) and H.sub.2O (0.2 ml) at 70° C. for 90 min. The reaction mixture is filtered through diatomaceous earth and concentrated. The residue is purified by C18 HPLC eluting with H.sub.2O:ACN (5-95%) with 0.1% TFA. The free base of the desired product is formed by eluting the material through a cartridge of carbonate resin to give the title compound (4.3 mg, 39%). ES/MS (m/z) 463.2 (M+H) 99% ee, chiral purity determination: YMA Chiral Cellulose-SB column, 4.6×100 mm, 3 μm eluting with 70/30 hexanes (0.1% ethylenediamine)/IPA 1 ml/min, t.sub.(R) 3.78.

(279) The following compounds in Table 22 are prepared essentially as described for 5-amino-3-[4-[2-[[3-(3-bicyclo[1.1.1]pentanylmethyl)isoxazol-5-yl]amino]-1-methyl-2-oxo-ethyl]phenyl]-1-isopropyl-pyrazole-4-carboxamide, Isomer 1 using the appropriate reagents, adjusting reaction time to determine completion of the reaction and using appropriate chromatography conditions for purification if needed. Temperature can vary from about 60 to 80° C. Further Parkin's catalyst can be used to push the reaction to completion if needed.

(280) TABLE-US-00031 TABLE 22 ES/MS Ex. m/z No. Chemical name Structure (M + H) t.sub.(R) .sup. 98.sup.1 5-Amino-3-[4-[2-[[3- (3,3- dimethylcyclobutyl) isoxazol-5-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]-1- isopropyl-pyrazole-4- carboxamide, Isomer 1 465.26 3.25 99 5-Amino-1-isopropyl- 3-[4-[2-[[5-(2,2- dimethylpropyl)isoxazol- 3-yl]amino]-1- methyl-2-oxo- ethyl]phenyl]pyrazole- 4-carboxamide, Isomer 1 453.3 4.96

(281) While only certain representative compounds, materials, and method steps disclosed herein are specifically described, other combinations of the compounds, materials, and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising”, and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed.

Biological Assays

(282) The following assays demonstrate that the compounds described herein are RET kinase inhibitors.

(283) Assay A: RET Enzyme Assay

(284) Compounds of formulas I, II, or III are screened for their ability to inhibit wildtype, V804M, and G810S mutant RET kinase using CisBio's HTRF® KinEASE™TK assay technology. N-terminal GST tagged recombinant human RET cytoplasmic domain (aa 658-end) from Eurofins (T25 nM RET; Catalog No. 14-570M) or N-terminal GST tagged recombinant human V804M mutant RET cytoplasmic domain (aa 658-end) from Millipore (1.25 nM enzyme; Catalog No. 14-760) or N-Terminal GST-tagged recombinant human G810S (aa-658-end) (1.25 nM Enzyme; produced in insect cells) is incubated with 62.5 nM TK-substrate biotin (CisBio, part of Catalog No. 62TK0PEC) and 1 mM ATP along with test compound (0.4% final DMSO in the assay) in a 1× Cisbio enzymatic buffer consisting of 1 nM DTT, 5 mM MgCl.sub.2, 0.04% BSA and 0.05% Tween20 in a volume of 10 μL. Compounds are typically prepared in a threefold serial dilution in DMSO and added to the assay to give the appropriate final concentration. After a 40-60 min (40 min for V804M, 60 min for WT and G810S) incubation at 22° C., the reaction is quenched by adding quench solution (10 μL) containing 7.8 nM Streptavidine-XL665 and 0.5×TK-ab-Cryptate in HTRF detection buffer (all from CisBio, part of Cat. No. 62TK0PEC). After a 60-80 min incubation (60 minutes for WT, 80 minutes for V804M and G810S) at 22° C., the extent of reaction is determined using a PHERastar plate reader via HTRF detection at excitation/emission 337/665 nm. Percent of inhibition is calculated with 0% inhibition referring to control conditions containing no compound (0.4% DMSO only) and 100% inhibition represented by conditions containing no enzyme. The % inhibition values are fit to a 4 parameter logistic curve, and the determined IC.sub.50 value is defined as the estimated concentration of inhibitor at the inflexion point of the fitted curve. The compounds of Examples 1, 15, 17, 35, 45, 52, 64, 66, 68, 70, 76, 80, 81, 84, 90, 94, and 98 all exhibited IC.sub.50 values of less than 100 nM for each of wildtype, V804M, and G810S mutant RET kinase in these assays. All of the compounds in Table A have IC.sub.50 values of less than 700 nm in the wildtype, V804M, and G810S mutant RET kinase assays.

Assay B: RET Cell Assay

(285) Compounds of formulas (I), (II), and (III) are screened for their ability to inhibit the intracellular autophosphorylation of RET at tyrosine 1062 as detected by In-Cell Western. HEK293 cells containing a doxycycline-inducible plasmid for inducible expression of KIF5B-RET WT and RET mutant forms V804M and G810S are seeded at 25,000 cells/well into black poly-D-lysine pre-coated 384-well plates (Corning, Catalog No. 356697). Expression of KIF5B-RET is induced with doxycycline at 1 μg/mL and cells are incubated at 37° C. overnight. Compounds are prepared in a threefold serial dilution in DMSO before further diluting 1:100 in media prior to the addition to the cells (0.1% final DMSO concentration). Compound treatment is performed for 1 hr at 37° C. followed by fixation of cells with 4% formaldehyde for 20 min at RT and cell permeabilisation with ice-cold MeOH for 10 min at RT. Cells are incubated with Intercept® blocking buffer (Li—COR, Catalogue No. 927-70010) for 1 hr at RT. Incubation with primary antibodies against human phospho-RET (Y1062) (R&D, Catalogue No. AF5009, 1/250 dilution) and human glyceraldehyde-3-phosphate dehydrogenase (clone 6C.sub.5, Merck, Catalog No. MAB374, 1/1000 dilution) are performed overnight at 4° C. Incubation with secondary antibodies IRDye® 800CW goat anti-rabbit IgG (Li—COR, Catalogue No. 926-32211, 1/1000 dilution) and IRDye® 680CW goat anti-mouse IgG (Li—COR, Catalogue No. 926-68070, 1/1000 dilution) are performed for 1 hr at RT. All antibody dilutions are done in Intercept® blocking buffer containing 0.05% Tween20. After washing cells with PBS-T (Cell Signaling technology, Catalogue No. 9809), the images are acquired on a Li—COR Odyssey LCx at 700 and 800 nm. Percent of DMSO control is calculated with 100% signal referring to control conditions containing no compound (0.4% DMSO only) and 0% signal represented by conditions containing control compound. The % of DMSO control values are fit to a 4 parameter logistic curve, and the determined EC.sub.50 value is defined as the estimated concentration of inhibitor at the inflexion point of the fitted curve. The compounds of Examples 1, 15, 17, 31, 33, 35, 45, 52, 64, 66, 68, 70, 76, 80, 81, 84, 90, 94, and 98 all inhibited the intracellular autophosphorylation of RET at tyrosine 1062 with EC.sub.50 values of less than 100 nM in each of wildtype, V804M, and G810S RET mutant cells in these assays. All of the compounds in Table B have IC.sub.50 values of less than 700 nm in the wildtype, V804M, and G810S mutant RET kinase assays.