Claims for Patent: 8,865,698

Summary for Patent: 8,865,698

Title:	Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
Abstract:	Provided herein are methods for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal, which comprises administering to said mammal in need thereof a therapeutically effective amount of a compound of Formula I: ##STR00001## in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, X, Y and n have the meanings given in the specification.
Inventor(s):	Haas; Julia (Boulder, CO), Andrews; Steven W. (Boulder, CO), Jiang; Yutong (Boulder, CO), Zhang; Gan (Niwot, CO)
Assignee:	Array BioPharma Inc. (Boulder, CO)
Application Number:	13/943,590
Patent Claims:	1. A method for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal, which comprises administering to said mammal in need thereof a therapeutically effective amount of a compound of Formula I ##STR00157## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is H or (1-6C alkyl); R.sup.2 is NR.sup.bR.sup.c, (1-4C)alkyl, (1-4C)fluoroalkyl, CF.sub.3, (1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr.sup.1, -(1-4C alkyl)NH.sub.2, -(1-4C alkyl)NH(1-4C alkyl), -(1-4C alkyl)N(1-4C alkyl).sub.2, hetAr.sup.2, hetCyc.sup.1, hetCyc.sup.2, phenyl which is optionally substituted with NHSO.sub.2(1-4C alkyl), or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, OMe, NH.sub.2, NHMe, N(CH.sub.3).sub.2, F, CF.sub.3, CO.sub.2(1-4C alkyl), CO.sub.2H, C(.dbd.O)NR.sup.eR.sup.f or C(.dbd.O)OR.sup.g; R.sup.b is H or (1-6C alkyl); R.sup.c is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr.sup.3, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF.sub.3 and --O(1-4C alkyl), or NR.sup.bR.sup.c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, --OC(.dbd.O)(1-4C alkyl), NH.sub.2, --NHC(.dbd.O)O(1-4C alkyl) and (1-4C)hydroxyalkyl, or NR.sup.bR.sup.c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO.sub.2, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF.sub.3, (1-4C)alkyl, CO.sub.2(1-4C alkyl), CO.sub.2H, NH.sub.2, NHC(.dbd.O)O(1-4C alkyl) and oxo, or NR.sup.bR.sup.c forms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with CO.sub.2(1-4C alkyl); hetAr.sup.1 is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms; hetAr.sup.2 is 5-6 membered heteroaryl ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, -(1-4 C)alkoxy and NH(1-4C alkyl); hetCyc.sup.1 is a carbon-linked 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-4C alkyl), and CO.sub.2(1-4C alkyl); hetCyc.sup.2 is a pyridinone or pyridazinone ring which is optionally substituted with a substituent selected from (1-4C)alkyl; hetAr.sup.3 is a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from (1-4C)alkyl; R.sup.e is H or (1-4C)alkyl; R.sup.f is H, (1-4C)alkyl, or (3-6C)cycloalkyl; or NR.sup.eR.sup.f forms a 4-6-membered azacyclic ring optionally having an additional ring heteroatom selected from N and O, wherein the azacyclic ring is optionally substituted with OH; R.sup.g is H or (1-6C)alkyl; Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF.sub.3 and CHF.sub.2, or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more halogen atoms; X is null, --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2O--, or --CH.sub.2NR.sup.d--; R.sup.d is H or (1-4C alkyl); R.sup.3 is H or (1-4C alkyl); each R.sup.4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4 C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, 2, 3, 4, 5 or 6. 2. The method of claim 1, wherein R.sup.2 is NR.sup.bR.sup.c, (1-4C)alkyl, (1-4C)fluoroalkyl, CF.sub.3, (1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr.sup.1, -(1-4C alkyl)NH.sub.2, -(1-4C alkyl)NH(1-4C alkyl), -(1-4C alkyl)N(1-4C alkyl).sub.2, hetAr.sup.2, hetCyc.sup.1, hetCyc.sup.2, phenyl which is optionally substituted with NHSO.sub.2(1-4C alkyl), or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, OMe, NH.sub.2, NHMe, N(CH.sub.3).sub.2, F, CF.sub.3, CO.sub.2(1-4C alkyl) or CO.sub.2H. 3. The method of claim 1, wherein R.sup.2 is NR.sup.bR.sup.c. 4. The method of claim 3, wherein: NR.sup.bR.sup.c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, --OC(.dbd.O)(1-4C alkyl), NH.sub.2, --NHC(.dbd.O)O(1-4C alkyl) and (1-4C)hydroxyalkyl, or NR.sup.bR.sup.c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO.sub.2, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF.sub.3, (1-4C)alkyl, CO.sub.2(1-4C alkyl), CO.sub.2H, NH.sub.2, NHC(.dbd.O)O(1-4C alkyl) and oxo, or NR.sup.bR.sup.c forms a 7-8 membered bridged heterocyclic ring having a ring nitrogen atom and optionally having a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with CO.sub.2(1-4C alkyl). 5. The method of claim 3, wherein: R.sup.c is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr.sup.3, or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF.sub.3 and --O(1-4C alkyl). 6. The method of claim 1, wherein R.sup.2 is (1-4C)alkyl, (1-4C)fluoroalkyl, CF.sub.3, -(1-4C alkyl)hetAr.sup.1 or -(1-4C alkyl)NH(1-4C alkyl). 7. The method of claim 1, wherein R.sup.2 is hetAr.sup.2, hetCyc.sup.1 or hetCyc.sup.2. 8. The method of claim 1, wherein R.sup.2 is phenyl optionally substituted with NHSO.sub.2(1-4C alkyl). 9. The method of claim 1, wherein R.sup.2 is (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, CF.sub.3, CO.sub.2(1-4C alkyl) or CO.sub.2H. 10. The method of claim 1, wherein R.sup.2 is C(.dbd.O)NR.sup.eR.sup.f or C(.dbd.O)OR.sup.g. 11. The method of claim 1, wherein X is null, --CH.sub.2-- or --CH.sub.2CH.sub.2--. 12. The method of claim 11, wherein X is --CH.sup.2--. 13. The method of claim 1, wherein X is --CH.sub.2O--. 14. The method of claim 1, wherein X is --CH.sub.2NR.sup.d--. 15. The method of claim 1, wherein Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF.sub.3 and CHF.sub.2. 16. The method of claim 15, wherein Y is phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl, 2-methoxy-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl or 3-chloro-5-fluorophenyl. 17. The method of claim 1, wherein Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said ring is optionally substituted with one or more halogen atoms. 18. The method of claim 1, wherein Y has the absolute configuration of Figure Ia: ##STR00158## 19. The method of claim 1, wherein R.sup.3 is H. 20. The method of claim 1, wherein: R.sup.1 is H or (1-6C alkyl); R.sup.2 is NR.sup.bR.sup.c; NR.sup.bR.sup.c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, --OC(.dbd.O)(1-4C alkyl), NH.sub.2, --NHC(.dbd.O)O(1-4C alkyl) and (1-4C)hydroxyalkyl, or NR.sup.bR.sup.c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO.sub.2, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF.sub.3, (1-4C)alkyl, CO.sub.2(1-4C alkyl), CO.sub.2H, NH.sub.2, NHC(.dbd.O)O(1-4C alkyl) and oxo; Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF.sub.3 and CHF.sub.2; X is null, --CH.sub.2--, or --CH.sub.2CH.sub.2--; R.sup.3 is H or (1-4C alkyl); each R.sup.4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4 C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2. 21. The method according to claim 20, wherein: R.sup.1 is H or (1-6C alkyl); R.sup.2 is NR.sup.bR.sup.c; NR.sup.bR.sup.c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO.sub.2, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF.sub.3, (1-4C)alkyl, CO.sub.2(1-4C alkyl), CO.sub.2H, NH.sub.2, NHC(.dbd.O)O(1-4C alkyl) and oxo; Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF.sub.3 and CHF.sub.2; X is --CH.sub.2--; R.sup.3 is H or (1-4C alkyl); each R.sup.4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4 C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2. 22. The method of claim 21, wherein the heterocyclic ring formed by NR.sup.bR.sup.c is optionally substituted with one or two substituents independently selected from OH, F, NH.sub.2, CO.sub.2H, CO.sub.2Et, NHCO.sub.2C(CH.sub.3).sub.3, CF.sub.3, methyl, ethyl, isopropyl, CO.sub.2C(CH.sub.2).sub.3 and oxo. 23. The method of claim 22, wherein Y is phenyl optionally substituted with one or more halogen atoms. 24. The method of claim 23, wherein Y is phenyl optionally substituted with one or two fluorine atoms. 25. The method of claim 20, wherein: R.sup.1 is H or (1-6C alkyl); R.sup.2 is NR.sup.bR.sup.c; NR.sup.bR.sup.c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, --OC(.dbd.O)(1-4C alkyl), NH.sub.2, --NHC(.dbd.O)O(1-4C alkyl) and (1-4C)hydroxyalkyl; Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF.sub.3 and CHF.sub.2; X is --CH.sub.2--; R.sup.3 is H or (1-4C alkyl); each R.sup.4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4 C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2. 26. The method of claim 25, wherein the heterocyclic ring formed by NR.sup.bR.sup.c is optionally substituted with one or two substituents independently selected from F, OH, methyl, OMe, OC(.dbd.O)C(CH.sub.3).sub.2, NH.sub.2, --NHC(.dbd.O)OC(CH.sub.3).sub.3 and CH.sub.2OH. 27. The method of claim 26, wherein Y is phenyl optionally substituted with one or more halogen atoms. 28. The method according to claim 27, wherein Y is phenyl optionally substituted with one or two fluorine atoms. 29. The method of claim 28, wherein n is zero or one. 30. The method of claim 29, wherein R.sup.3 is hydrogen. 31. The method of claim 30, wherein R.sup.1 is hydrogen. 32. The method of claim 1, which is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt. 33. The method of claim 1, wherein said compound of Formula I is selected from: (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyr- imidin-3-yl)-3-hydroxyazetidine-1-carboxamide; (R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-1,1-dimethylurea; (R)-1-tert-butyl-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5- -a]pyrimidin-3-yl)urea; (R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-3-phenylurea; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)isobutyramide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide; (R)--N-(5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-3-hydroxyazetidine-1-carboxamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)morpholine-4-carboxamide; N-(5-(2-(3-fluorophenyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-hydroxyazetidine-1-carboxamide; (R)--N-(5-(2-(3-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-3-hydroxyazetidine-1-carboxamide; (R)--N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[- 1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)morpholine-4-carboxamide; (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; 4R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-methoxyazetidine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide; (R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-3-(4-fluorophenyl)urea; (R)-1-(4-chlorophenyl)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazo- lo[1,5-a]pyrimidin-3-yl)urea; (R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-3-(4-methoxyphenyl)urea; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-3-methoxyazetidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)morpholine-4-carboxamide; (S)-tert-butyl 4-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-methylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-isopropylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-ethylpiperazine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-4-methylpiperazine-1-carboxamide; N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-3,5-dimethylpiperazine-1-carboxamide; (S)-tert-butyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate; (S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-methylpiperazine-1-carboxamide hydrochloride; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-3-hydroxyazetidine-1-carboxamide; (R)-methyl 1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- carbamoyl)cyclopropanecarboxylate; (R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-ylcarbamoyl)cyclopropanecarboxylic acid; (S)--N-(5-((R)-2-(3-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[- 1,5-a]pyrimidin-3-yl)-4-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-4-hydroxypiperidine-1-carboxamide; (R)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)pivalamide; (R)-tert-butyl 3-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-ylcarbamoyl)azetidine-1-carboxylate; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)azetidine-3-carboxamide; (R)-tert-butyl 4-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-ylcarbamoyl)-4-methylpiperidine-1-carboxylate; (R)--N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)-4-methylpiperidine-4-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-2-hydroxy-2-methylpropanamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide; (R)-1-cyano-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]py- rimidin-3-yl)cyclopropanecarboxamide; (R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-2-methylpyrrolidine-2-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-2-fluoro-2-methylpropanamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-2-(isopropylamino)thiazole-4-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-2-methyl-2-(1H-1,2,4-triazol-1-yl)propanamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)pyrazine-2-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-5-methylpyrazine-2-carboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)picolinamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-6-methylpicolinamide; (R)-5-chloro-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)picolinamide; (R)-4-chloro-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)picolinamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-methylpicolinamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-hydroxy-2,2-dimethylpropanamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-1-hydroxycyclopropanecarboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-2-methyl-2-(methylamino)propanamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)pyrimidine-2-carboxamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)picolinamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-3-methylpicolinamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide; (R)-6-chloro-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)picolinamide; (R)-4-(ethylsulfonamido)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo- [1,5-a]pyrimidin-3-yl)benzamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-1-methyl-1H-pyrazole-3-carboxamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-1H-pyrazole-3-carboxamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-6-methoxypicolinamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)nicotinamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)isonicotinamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-6-methylnicotinamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-2-methoxynicotinamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-3-methylisonicotinamide; (S)--N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]- pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-5-methylpyrazine-2-carboxamide; (R)--N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y- l)-1-methyl-1H-imidazole-2-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyra- zolo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyr- imidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)--N-(5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyr- imidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a- ]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)--N-(5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a- ]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; 4S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxamide; (R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (1S,3R)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3-hydroxycyclopentanecarboxamide; (1S,3S)--N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3-hydroxycyclopentanecarboxamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-3-hydroxycyclobutanecarboxamide; (R)--N.sup.1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyr- imidin-3-yl)-N.sup.2,N.sup.2-dimethyloxalamide; (R)--N.sup.1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyr- imidin-3-yl)-N.sup.2-methyloxalamide; (R)--N.sup.1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyr- imidin-3-yl)oxalamide; (R)--N.sup.1-cyclopropyl-N2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyr- azolo[1,5-a]pyrimidin-3-yl)oxalamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-2-(3-hydroxyazetidin-1-yl)-2-oxoacetamide; N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoacetamide; (R)--N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin- -3-yl)-2-morpholino-2-oxoacetamide; (R)-methyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- amino)-2-oxoacetate; (R)-2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-ylamino)-2-oxoacetic acid; or a pharmaceutically acceptable salt thereof.