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Last Updated: October 30, 2020

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Claims for Patent: 8,513,263

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Summary for Patent: 8,513,263
Title:Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
Abstract: Compounds of Formula (I) 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, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor. ##STR00001##
Inventor(s): Haas; Julia (Boulder, CO), Andrews; Steven W. (Boulder, CO), Jiang; Yutong (Boulder, CO), Zhang; Gan (Boulder, CO)
Assignee: Array BioPharma Inc. (Boulder, CO)
Application Number:13/125,263
Patent Claims: 1. A compound having the general 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 allyl)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), (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], 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)hydroxyallyl, 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), (1-4C)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, -(1-4C)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 pyridinyl ring, wherein said pyridinyl ring is optionally substituted with one or more halogen atoms; 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, (1-4C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, 2, 3, 4, 5 or 6.

2. A compound of claim 1, wherein R.sup.2 is NR.sup.bR.sup.c, (1-4C)alkyl, (1-4C)fluoroalkyl, CF.sub.3, (1-4C)hydroxyallyl, -(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. A compound of claim 1, wherein R.sup.2 is NR.sup.bR.sup.c.

4. A compound according to claim 1, 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), (1-4C)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. A compound according to claim 1, 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. A compound 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. A compound of claim 1, wherein R.sup.2 is hetAr.sup.2, hetCyc.sup.1 or hetCyc.sup.2.

8. A compound of claim 1, wherein R.sup.2 is phenyl optionally substituted with NHSO.sub.2(1-4C alkyl).

9. A compound 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. A compound of claim 1, wherein R.sup.2 is C(.dbd.O)NR.sup.eR.sup.f or C(O)OR.sup.g.

11. A compound according to 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.

12. A compound according to claim 11, 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.

13. A compound according to claim 1, wherein Y is a pyridinyl ring, wherein said pyridinyl ring is optionally substituted with one or more halogen atoms.

14. A compound according to claim 1, wherein Y has the absolute configuration of FIG. Ia: ##STR00158##

15. A compound according to claim 1, wherein R.sup.3 is H.

16. A compound according to 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), (1-4C)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 --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, (1-4C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2.

17. A compound according to claim 16, 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, (1-4C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2.

18. A compound according to claim 17, 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.

19. A compound according to claim 18, wherein Y is phenyl optionally substituted with one or more halogen atoms.

20. A compound according to claim 19, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

21. A compound according claim 16, 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), (1-4C)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, (1-4C)alkoxy, NH.sub.2, NH(1-4C alkyl) and CH.sub.2OH; and n is 0, 1, or 2.

22. A compound according to claim 21, 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.

23. A compound according to claim 22, wherein Y is phenyl optionally substituted with one or more halogen atoms.

24. A compound according to claim 23, wherein Y is phenyl optionally substituted with one or two fluorine atoms.

25. A compound according to claim 16, wherein n is zero or one.

26. A compound according to claim 25, wherein R.sup.3 is hydrogen.

27. A compound according to claim 26, wherein R.sup.1 is hydrogen.

28. A compound according to claim 1, which is a trifluoroacetate salt, a sulfate salt or a hydrochloride salt.

29. A compound according to claim 1, selected from: (R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-- 3-yl)-3-hydroxyazetidine- l -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-difluorophenyppyrrolidin-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-yl- )-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]p- yrimidin-3-yl)-3-hydroxyazetidine- 1-carboxamide; (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxyazetidine-1-carboxamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )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]pyrim- idin-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]pyrimi- din-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (3R,4R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]py- rimidin-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]pyrim- idin-3-yl)-3-methoxyazetidine-1-carboxamide; (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide; (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-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]p- yrimidin-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]pyrimi- din-3-yl)-3-methylpiperazine-1-carboxamide hydrochloride; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-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]p- yrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazo- lo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (S)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyppyrrolidin-1-yl)pyrazol- o[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-y1)-4-hydroxypiperidine-1-carboxamide; (R)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazo- lo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)-N-(5-((R)-2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazo- lo[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]p- yrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-4-hydroxypiperidine-1-carboxamide; (R)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-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]pyrim- idin-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]pyrim- idin-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]pyrimi- din-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-yl- )picolinamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-3-methylpicolinamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-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-yl- )-1-methyl-1H-pyrazole-3-carboxamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-1H-pyrazole-3-carboxamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-6-methoxypicolinamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )nicotinamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )isonicotinamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-6-methylnicotinamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-2-methoxynicotinamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-3-methylisonicotinamide; (S)-N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]p- yrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-5-methylpyrazine-2-carboxamide; (R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl- )-1-methyl-1H-imidazole-2-carboxamide; (S)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyraz- olo[1,5-a]pyrimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (S)-N-(5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyraz- olo[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]pyri- midin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (R)-N-(5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-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-methoxypheny)pyrrolidin-1-yl)pyrazolo[1,5-a]py- rimidin-3-yl)-3-hydroxypiperidine-1-carboxamide; (1S,4S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]py- rimidin-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]pyrimi- din-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (1S,3R)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]py- rimidin-3-yl)-3-hydroxycyclopentanecarboxamide; (1S,3S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]py- rimidin-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]pyri- midin-3-yl)-N.sup.2,N.sup.2-dimethyloxalamide; (R)-N.sup.1-(5-(2-(2,5-difluorophenyOpyrrolidin-1-yl)pyrazolo[1,5-a]pyrim- idin-3-yl)-N.sup.2-methyloxalamide; (R)-N.sup.1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyri- midin-3-yl)oxalamide; (R)-N.sup.1-cyclopropyl-N2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyra- zolo[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.

30. A pharmaceutical composition, which comprises a compound of Formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

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