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Last Updated: March 29, 2024

Claims for Patent: 8,846,681


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Summary for Patent: 8,846,681
Title:Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
Abstract: The present invention provides compounds of Formula I, including tautomers, resolved enantiomers, diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof. ##STR00001## Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.
Inventor(s): Mitchell; Ian S. (Lafayette, CO), Blake; James F. (Longmont, CO), Xu; Rui (Longmont, CO), Kallan; Nicholas C. (Boulder, CO), Xiao; Dengming (Longmont, CO), Spencer; Keith Lee (Lyons, CO), Bencsik; Josef R. (Longmont, CO), Wallace; Eli M. (Lyons, CO), Schlachter; Stephen T. (Boulder, CO), Banka; Anna L. (Longmont, CO), Liang; Jun (Palo Alto, CA), Safina; Brian (Redwood City, CA), Li; Jun (Foster City, CA), Chabot; Christine (San Mateo, CA)
Assignee: Array BioPharma, Inc. (Boulder, CO) Genentech, Inc. (South San Francisco, CA)
Application Number:13/160,351
Patent Claims:1. A method of inhibiting the activity of AKT in a mammal, said method comprising administering to said mammal an effective amount of a compound of the Formula: ##STR00246## and enantiomers and salts thereof, wherein: R.sup.1 and R.sup.1a are independently selected from H, Me, Et, CH.dbd.CH.sub.2, CH.sub.2OH, CF.sub.3, CHF.sub.2 or CH.sub.2F; R.sup.2 and R.sup.2a are independently selected from H or F; R.sup.5 is H, Me, Et, or CF.sub.3; A is ##STR00247## wherein G is phenyl optionally substituted with one to four R.sup.9 groups or a 5-6 membered monocyclic or 9 member bicyclic heteroaryl optionally substituted by a halogen; R.sup.6 and R.sup.7 are independently H, (C.sub.3-C.sub.6 cycloalkyl)-(CH.sub.2), (C.sub.3-C.sub.6 cycloalkyl)-(CH.sub.2CH.sub.2), V--(CH.sub.2).sub.0-1 wherein V is a 5-6 membered heteroaryl, W--(CH.sub.2).sub.1-2 wherein W is phenyl optionally substituted with F, Cl, Br, I, OMe, CF.sub.3or Me, C.sub.3-C.sub.6-cycloalkyl, hydroxy-(C.sub.3-C.sub.6-cycloalkyl), fluoro-(C.sub.3-C.sub.6-cycloalkyl), CH(CH.sub.3)CH(OH)phenyl, 4-6 membered heterocycle optionally substituted with F, OH, cyclopropylmethyl, C.sub.1-C.sub.3alkyl or C(.dbd.O)(C.sub.1-C.sub.3alkyl), or C.sub.1-C.sub.6-alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C.sub.1-C.sub.6-alkyl), CN, F, NH.sub.2, NH(C.sub.1-C.sub.6-alkyl), N(C.sub.1-C.sub.6-alkyl).sub.2, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, oxetanyl, piperidinyl, and pyrrolidinyl, or R.sup.6 and R.sup.7 together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2OH, C(.dbd.O)CH.sub.3, and (C.sub.1-C.sub.3)alkyl; R.sup.a and R.sup.b are H, or R.sup.a is H, and R.sup.b and R.sup.6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; R.sup.c and R.sup.d are H or Me, or R.sup.c and R.sup.d together with the atom to which they are attached form a cyclopropyl ring; R.sup.8 is H, Me, or OH, or R.sup.8 and R.sup.6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; each R.sup.9 is independently halogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, O--(C.sub.1-C.sub.6-alkyl), CF.sub.3, OCF.sub.3, S(C.sub.1-C.sub.6-alkyl), CN, OCH.sub.2-phenyl, CH.sub.2O-phenyl, NH.sub.2, NO.sub.2, NH--(C.sub.1-C.sub.6-alkyl), N--(C.sub.1-C.sub.6-alkyl).sub.2, piperidine, pyrrolidine, CH.sub.2F, CHF.sub.2, OCH.sub.2F, OCHF.sub.2, OH, SO.sub.2(C.sub.1-C.sub.6-alkyl), C(O)NH.sub.2, C(O)NH(C.sub.1 -C.sub.6-alkyl), and C(O)N(C.sub.1-C.sub.6-alkyl).sub.2; and m, n and p are independently 0 or 1.

2. The method of claim 1, wherein R.sup.2 and R.sup.2a are H.

3. The method of claim 1, wherein R.sup.2 is H and R.sup.2a is F.

4. The method of claim 1, wherein R.sup.2 and R.sup.2a are F.

5. The method of claim 1, wherein R.sup.5 is H.

6. The method of claim 1, wherein R.sup.5 is methyl.

7. The method of claim 6, wherein R.sup.5 is in the (S) configuration.

8. The method of claim 1, wherein R.sup.5 is ethyl.

9. The method of claim 1, wherein R.sup.1 and R.sup.1a are independently selected from H, methyl, ethyl, CH.dbd.CH.sub.2 and CH.sub.2OH.

10. The method of claim 1, wherein R.sup.1 is methyl.

11. The method of claim 10, wherein R.sup.1 is in the (R) configuration.

12. The method of claim 1, wherein R.sup.1 is H.

13. The method of claim 1, wherein R.sup.1 is CH.sub.2OH.

14. The method of claim 13, wherein R.sup.1 is in the (R) configuration.

15. The method of claim 13, wherein R.sup.1 is in the (S) configuration.

16. The method of claim 1, wherein R.sup.1 is CH.dbd.CH.sub.2.

17. The method of claim 16, wherein R.sup.1 is in the (R) configuration.

18. The method of claim 16, wherein R.sup.1 is in the (S) configuration.

19. The method of claim 1, wherein R.sup.1 is ethyl.

20. The method of claim 19, wherein R.sup.1 is in the (S) configuration.

21. The method of claim 1, wherein R.sup.1a is H.

22. The method of claim 1, wherein R.sup.1a is methyl.

23. The method of claim 1, wherein G is phenyl optionally substituted with one to three R.sup.9 groups independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl, CN, OCH.sub.3, CF.sub.3, OCF.sub.3, SCH.sub.3, NO.sub.2, cyclopropyl and OCH.sub.2Ph.

24. The method of claim 23, wherein G is 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-bromophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl 4-bromophenyl, 4-chloro-2-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-iodophenyl, 4-nitrophenyl, or 4-tert-butylphenyl.

25. The method of claim 1, wherein G is a 5-6 membered monocyclic heteroaryl optionally substituted by one or more halogens.

26. The method of claim 25, wherein G is a thiophene or a pyridine, optionally substituted by halogens.

27. The method of claim 26, wherein G is selected from the structures: ##STR00248##

28. The method of claim 1, wherein G is a 9 member bicyclic heteroaryl optionally substituted by a halogen.

29. The method of claim 28, wherein G is an indole optionally substituted by a halogen.

30. The method of claim 29, wherein G is: ##STR00249##

31. The method of claim 1, wherein R.sup.6 or R.sup.7 may be H, (C.sub.3-C.sub.6-cycloalkyl) -CH.sub.2, heteroaryl-(CH.sub.2), C.sub.3-C.sub.6-cycloalkyl, hydroxy-(C.sub.3-C.sub.6-cycloalkyl), CH(CH.sub.3)CH(OH)phenyl, 5-6 membered heterocycle optionally substituted with C(.dbd.O)CH.sub.3, or (C.sub.1-6)-alkyl optionally substituted with one or more groups independently selected from OH, oxo, OMe, CN and F.

32. The method of claim 31, wherein R.sup.6 or R.sup.7 are selected from H, methyl, ethyl, isopropyl, --C(.dbd.O)H, CH.sub.2CH.sub.2OH, CH.sub.2-tBu (neopentyl) or CH.sub.2CF.sub.3, CH.sub.2-cyclopropyl, CH.sub.2-(pyrid-3-yl), cyclohexyl, or selected from the structures: ##STR00250##

33. The method of claim 1, wherein R.sup.6 and R.sup.7 together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF.sub.3, CH.sub.2CF.sub.3, CH.sub.2CH.sub.2OH, C(.dbd.O)CH.sub.3, and (C.sub.1-C.sub.3)alkyl.

34. The method of claim 33, wherein NR.sup.6R.sup.7 is selected from the structures: ##STR00251##

35. The method claim 1, wherein R.sup.a is H, and R.sup.b and R.sup.6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms.

36. The method of claim 1, wherein R.sup.8 and R.sup.6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms.

37. The method of claim 1, wherein A is represented by the formula: ##STR00252##

38. The method of claim 37, wherein A has the configuration: ##STR00253##

39. The method of claim 37, wherein R.sup.c and R.sup.d are H.

40. The method of claim 39, wherein R.sup.8 is H or OH.

41. The method of claims 40, wherein R.sup.6 and R.sup.7 are independently H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2CH.sub.2OH, CH(CH.sub.2CH.sub.2OH).sub.2, CH.sub.2CH.sub.2OMe, CH(CH.sub.2CH.sub.2OMe).sub.2, CH.sub.2CH.sub.2CH.sub.2OMe, CH.sub.2CN, CH.sub.2-cyclopropyl, CH.sub.2-cyclobutyl, CH.sub.2-tBu, cyclopentyl, cyclohexyl, CH.sub.2-phenyl, CH.sub.2-(pyrid-2-yl), CH.sub.2-(pyrid-3-yl), CH.sub.2-(pyrid-4-yl), 4-hydroxycyclohex-1-yl, CH(CH.sub.3)CH(OH)phenyl, CH.sub.2CF.sub.3, --C(.dbd.O)H, or selected from the structures: ##STR00254## or R.sup.6 and R.sup.7 together with N form a pyrrolidinyl, piperidinyl, azetidinyl, morpholinyl or piperazinyl ring, wherein said pyrrolidinyl, piperidinyl azetidinyl, morpholinyl or piperazinyl rings are optionally substituted with one or more groups independently selected from Me, Et, OH, CH.sub.2CH.sub.2OH, C(.dbd.O)CH.sub.3, isopropyl and F.

42. The method of claim 1, wherein NR.sup.6R.sup.7 is selected from the structures: ##STR00255## ##STR00256##

43. The method of claim 37, wherein A is selected from: ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265##

44. The method of claim 37, wherein A is selected from: ##STR00266##

45. The method of claim 1, wherein m is 1, n is 1 and p is 0, such that A is represented by the formula: ##STR00267##

46. The method of claim 45, wherein A has the configuration: ##STR00268##

47. The method of claim 45, wherein R.sup.8 is H.

48. The method of claim 45, wherein R.sup.8 is methyl.

49. The method of claim 45, wherein R.sup.c and R.sup.d are H.

50. The method of claim 45, wherein R.sup.c and R.sup.d are methyl.

51. The method of claim 45, wherein R.sup.6 and R.sup.7 are independently H, methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, or cyclobutylmethyl, or R.sup.6 and R.sup.7 together with N form a pyrrolidinyl, piperidinyl, or azetidinyl ring, or R.sup.6 and R.sup.8 together with the atoms to which they are attached form a piperidinyl or pyrrolidinyl ring.

52. The method of claim 51, wherein NR.sup.6R.sup.7 is NH.sub.2, NHMe, NHEt, NHPr, NH(iPr), NH(cyclopropylmethyl), NH(cyclobutylmethyl), NMe.sub.2, NMeEt, NMePr, NMe(iPr), NEt.sub.2, NEtPr, or NEt(iPr).

53. The method of claim 51, wherein NR.sup.6R.sup.7 is selected from the structures: ##STR00269##

54. The method of claim 45, wherein R.sup.6 and R.sup.7 are independently H or Me.

55. The method of claim 45, wherein A is selected from: ##STR00270## ##STR00271##

56. The method of claim 1, wherein A is represented by the formula: ##STR00272##

57. The method of claim 56, wherein A has the configuration: ##STR00273##

58. The method of claim 56, wherein R.sup.8 is H.

59. The method of claim 58, wherein R.sup.6 and R.sup.7 are independently H, methyl, ethyl, propyl, isopropyl, t-butyl, CH.sub.2-cyclopropyl, or CH.sub.2-cyclobutyl.

60. The method of claim 59, wherein NR.sup.6R.sup.7 is NH.sub.2, NHMe, NHEt, NHPr, NH(iPr), NHtBu, NH(CH.sub.2-cyclopropyl), or NH(CH.sub.2-cyclobutyl).

61. The method of claim 56, wherein A is: ##STR00274##

62. The method of claim 56, wherein R.sup.a and R.sup.8 are H, and R.sup.b and R.sup.6 together with the atoms to which they are attached form a 5 to 6 membered heterocyclic ring.

63. The method of claim 62, wherein R.sup.b and R.sup.6 together with the atoms to which they are attached form a pyrrolidinyl ring.

64. The method of claim 56, wherein R.sup.7 is H.

65. The method of claim 56, wherein A is selected from: ##STR00275##

66. The method of claim 1, wherein m is 0, n is 0 and p is 1, such that A is represented by the formula: ##STR00276##

67. The method of claim 66, wherein A has the configuration: ##STR00277##

68. The method of claim 66, wherein R.sup.8 is H.

69. The method of claim 68, wherein R.sup.6 and R.sup.7 are independently H or Me.

70. The method of claim 69, wherein A is selected from: ##STR00278## ##STR00279## ##STR00280##

71. The method of claim 69, wherein A is selected from: ##STR00281##

72. The method of claim 1, wherein the compound has the formula: ##STR00282## wherein: R.sup.1 is H, Me, Et, CF.sub.3, CHF.sub.2 or CH.sub.2F; R.sup.2 and R.sup.2a are H or F; R.sup.5 is H, Me, Et, or CF.sub.3; A is ##STR00283## wherein G is phenyl optionally substituted with one to four R.sup.9 groups; R.sup.6 and R.sup.7 are independently H, (C.sub.3-C.sub.6 cycloalkyl)-(CH.sub.2), (C.sub.3-C.sub.6 cycloalkyl)-(CH.sub.2CH.sub.2), V--(CH.sub.2).sub.0-1 wherein V is a 5-6 membered heteroaryl, W--(CH.sub.2).sub.1-2 wherein W is phenyl optionally substituted with F, Cl or Me, C.sub.3-C.sub.6-cycloalkyl, hydroxy-(C.sub.3-C.sub.6-cycloalkyl), fluoro-(C.sub.3-C.sub.6-cycloalkyl), CH(CH.sub.3)CH(OH)phenyl, or C.sub.1-C.sub.6-alkyl optionally substituted with one or more groups independently selected from OH, O(C.sub.1-C.sub.6-alkyl), CN, F, NH.sub.2, NH(C.sub.1-C.sub.6-alkyl), N(C.sub.1-C .sub.6-alkyl).sub.2, piperidinyl, and pyrrolidinyl, or R.sup.6 and R.sup.7 together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF.sub.3, CH.sub.2CF.sub.3, and (C.sub.1-C.sub.3)alkyl; R.sup.a and R.sup.b are H, or R.sup.a is H, and R.sup.b and R.sup.6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; R.sup.c and R.sup.d are H or Me; R.sup.8 is H, Me, or OH, or R.sup.8 and R.sup.6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; each R.sup.9 is independently halogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.6-cycloalkyl, O--(C.sub.1-C.sub.6-alkyl), CF.sub.3, OCF.sub.3, S(C.sub.1-C.sub.6-alkyl), CN, CH.sub.2O-phenyl, NH.sub.2, NH--(C.sub.1-C.sub.6-alkyl), N--(C.sub.1-C.sub.6-alkyl).sub.2, piperidine, pyrrolidine, CH.sub.2F, CHF.sub.2, OCH.sub.2F, OCHF.sub.2, OH, SO.sub.2(C.sub.1-C.sub.6-alkyl), C(O)NH.sub.2, C(O)NH(C.sub.1-C.sub.6-alkyl), and C(O)N(C.sub.1-C.sub.6-alkyl).sub.2; and m, n and p are independently 0 or 1.

73. The method of claim 1 wherein the compound is: 2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-c- yclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6- ,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(aminomethyl)-3-(4-chloro-3-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-meth- yl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(2,4-dichlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-di- hydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((R)-5-methyl-6,- 7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-- 5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(3,4-difluorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-di- hydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-fluorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]p- yrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]p- yrimidin-4-yl)piperazin-1-yl)-3-(pyrrolidin-1-yl)propan-1-one; (R,S)-3-amino-2-(4-chloro-1-fluorobenzyl)-1-(4-((R)-5-methyl-6,7-dihydro-- 5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-2-hydroxy-3-(isopropylamino)-1-(4-((R)-5-methyl-- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; ((3S,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-dihyd- ro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; ((3R,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-dihyd- ro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; ((3S,4R)-4-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; ((3R,4S)-4-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; (R,S)-4-amino-2-(4-chloro-3-fluorophenyl)-4-methyl-1-(4-(R)-5-methyl-6,7-- dihydro-5H-cyclop enta[d]pyrimidin-4-yl)piperazin-1-yl)pentan-1-one; (R,S) 4-amino-2-(4-fluorophenyl)-4-methyl-1-(4-(R)-5-methyl-6,7-dihydro-5H-cycl- openta [d]pyrimidin-4-yl)piperazin-1-yl)pentan-1-one; (R,S)-4-amino-2-(4-bromophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclope- nta [d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (R,S)-4-amino-2-(4-chlorophenyl)-2-methyl-1-(4-((R)-5-methyl-6,7-dihydro-- 5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)butan-1-one; (R,S)-(3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-dihydro-5H-- cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone; (R,S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-((R)-3-methyl-4-((R)-5-meth- yl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S) 2-(4-chlorophenyl)-3-(4-hydroxypiperidin-1-yl)-1-(4-((R)-5-methyl-6- ,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)2-(4-chlorophenyl)-3-((S)-3-hydroxypyrrolidin-1-yl)-1-(4-((R)-5-meth- yl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S) 2-(4-chlorophenyl)-3-((R)-3-hydroxypyrrolidin-1-yl)-1-(4-((R)-5-met- hyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one- ; (R,S)-2-(4-fluorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]- pyrimidin-4-yl)piperazin-1-yl)-3-(methylamino)propan-1-one; (R,S)-3-(isopropylamino)-2-(4-methoxyphenyl)-1-(4-((R)-5-methyl-6,7-dihyd- ro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-3-amino-2-(3,4-dichlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cy- clopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-3-(ethylamino)-2-(4-fluorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H- -cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-3-(ethylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H- -cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-4-amino-2-(4-chlorophenyl)-4-methyl-1-(4-((R)-5-methyl-6,7-dihydro-- 5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)pentan-1-one; (R,S)-2-(4-chlorophenyl)-3-(2-hydroxyethylamino)-1-(4-((R)-5-methyl-6,7-d- ihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]p- yrimidin-4-yl)piperazin-1-yl)-3-(neopentylamino)propan-1-one; (R,S)-2-(4-bromophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro- -5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopen- ta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-3-(isopropyl(methyl)amino)-1-(4-((R)-5-methyl-6,- 7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R,S)-2-(4-chlorophenyl)-3-((S)-3-fluoropyrrolidin-1-yl)-1-(4-((R)-5-meth- yl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((R)-7,7-difluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihy- dro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-- 4-ylamino)propan-1-one; 2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimid- in-4-yl)piperazin-1-yl)-3-(2,2,2-trifluoroethylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7-fluoro-- 5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-- 1-one; (S)-2-(4-chlorophenyl)-1-(4-(5,5-dimethyl-6,7-dihydro-5H-cyclopenta- [d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((S)-5-vinyl-6,7-dihydro-5- H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((R)-5-(hydroxymethyl)-6,7-dihydro-5H-cyclope- nta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; 2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimid- in-4-yl) piperazin-1-yl)-3-(2-methylaziridin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(3-hydroxyazetidin-1-yl)-1-(4-((R)-5-methyl-6,7-dihy- dro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimid- in-4-yl)piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one; 4-(3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyri- midin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)benzonitrile; 2-(4-chlorophenyl)-3-(3,3-difluoroazetidin-1-yl)-1-(4-((R)-5-methyl-6,7-d- ihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(4,4-difluoropiperidin-1-yl)-1-(4-((R)-5-methyl-6,7-- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(3,3-difluoropyrrolidin-1-yl)-1-(4-((R)-5-methyl-6,7- -dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimid- in-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; 3-(azetidin-1-yl)-2-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cy- clopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(dimethylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cy- clopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-(ethyl(methyl)amino)-1-(4-((R)-5-methyl-6,7-dihydro-- 5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-chlorophenyl)-3-((R)-3-fluoropyrrolidin-1-yl)-1-(4-((R)-5-methyl-6,7- -dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-(4-((R)-7,7-difluoro-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- -1-yl)-3-(isopropylamino)propan-1-one; (R)-2-amino-3-(4-iodophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta- [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 4-((R)-2-amino-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1 -yl)-3-oxopropyl)benzonitrile; (R)-2-amino-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl- )piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one; (R)-2-amino-3-(3,4-dichlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cycl- openta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-chlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyr- imidin-4-yl)piperazin-1-yl)-2-(methylamino)propan-1-one; (R)-2-amino-3-(4-iodophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-- 5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 4-((R)-2-amino-3-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)benzonitrile; (R)-2-amino-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]p- yrimidin-4-yl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)propan-1-one; (R)-2-amino-3-(3,4-dichlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-di- hydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyc- lopenta [d]pyrimidin-4-yl)piperazin-1-yl)-2-(methylamino)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5,5-dimethyl-6,7-dihydro-5H-cyclopen- ta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(2,4-dichlorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cycl- openta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(2,4-dichlorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-di- hydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; 2-(4-bromo-3-fluorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihy- dro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl- )piperazin-1-yl)-3-(4-nitrophenyl)propan-1-one; (R)-2-amino-3-(3,4-difluorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cycl- openta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(3,4-difluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-di- hydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-bromophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopent- a [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(4-bromophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro- -5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(2-fluorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopen- ta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-3-(2-fluorophenyl)-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]p- yrimidin-4-yl)piperazin-1-yl)-3-(4-nitrophenyl)propan-1-one; (R)-2-amino-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl- )piperazin-1-yl)-3-p-tolylpropan-1-one; (R)-2-amino-3-(4-tert-butylphenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cycl- openta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl- )piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-1-one; (R)-2-amino-3-(4-fluorophenyl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopen- ta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((S)-5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyri- midin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-3-(1-acetylpiperidin-4-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fl- uoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)pr- opan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(piperidin-4-ylamino)propan-1-o- ne; (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-fluo- ro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(1-acetylpiperidin-4-ylamino)-2-(4-chlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclop enta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(piperidin-4-ylamino)propan-1-one; (R)-2-amino-3-(4-chlorophenyl)-1-((S)-3-ethyl-4-((R)-5-methyl-6,7-dihydro- -5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-vinyl-6,7-dihydro-5- H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((S)-5-(hydroxymethyl)-6,7-dihydro-5H-cyclope- nta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)- propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)- propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclohexylamino)-1-(4-((5R,7R)-7-fluoro-5-methy- l-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-4-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one; (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-tetrahydrofuran-3-ylamino)- propan-1-one; (S)-2-(4-chlorophenyl)-3-(cyclohexylamino)-1-(4-((5R,7S)-7-fluoro-5-methy- l-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-((R)-tetrahydrofuran-3-ylamino)- propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1-- yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1-- yl)propan-1-one; (R)-3-(4-acetylpiperazin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-- 5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-- 1-one; (R)-3-(4-acetylpiperazin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-f- luoro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1- -yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-(2-hydroxyethyl)piperazin-1-yl)pro- pan-1-one; (S)-3-(4-acetylpiperazin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)- -7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(4-acetylpiperazin-1-yl)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-- 5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-4-amino-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-4-methylpentan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propa- n-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydr- o-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-o- ne; (R)-2-(4-chlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-- cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; 2-(4-chlorophenyl)-3-(4-ethylpiperazin-1-yl)-1-(4-((5R,7R)-7-fluoro-5-met-

hyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; (S)-2-(4-chlorophenyl)-3-(4-ethylpiperazin-1-yl)-1-(4-((5R,7R)-7-fluoro-5- -methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyc- lopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-morpholinopropan-1-one; (S)-3-amino-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-di- hydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(3,4-dichlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-di- hydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-bromophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro- -5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-amino-2-(4-bromophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro- -5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H- -cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylam- ino)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- -1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- -1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cycl- openta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)p- ropan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cycl- openta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)p- ropan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H- -cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-on- e; (S)-3-(cyclopropylmethylamino)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-f- luoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)p- ropan-1-one; (S)-3-amino-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6- ,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-3-(cyclopropylmethylamino)-2-(3,4-dichlorophenyl)-1-(4-((5R,7S)-7-flu- oro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)pro- pan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl- -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylam- ino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihyd- ro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4- -ylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-- 7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-y- l)propan-1-one; (R)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H- -cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one- ; (R)-2-(3,4-dichlorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5- H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one- ; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5- H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one- ; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-hydroxypiperidin-1-yl)propan-1-one- ; (R)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5- H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl- )propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H- -cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(4-isopropylpiperazin-1-yl)- propan-1-one; (S)-2-(3,4-dichlorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- -1-yl)-3-(4-isopropylpiperazin-1-yl)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7- -fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl- )propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- -1-yl)-3-(isopropylamino)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- -1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((5R,7R)-7- -fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl- )propan-1-one; (S)-2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydr- o-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-- 1-one; 2-(4-bromo-3-fluorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihy- dro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-- 4-ylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihyd- ro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4- -ylamino)propan-1-one; (S)-2-(4-chloro-3-fluorophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihyd- ro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan- -1-one; (S)-2-(4-chloro-3-fluorophenyl)-3-(cyclopropylmethylamino)-1-(4-((- 5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pipera- zin-1-yl)propan-1-one; N-((S)-2-(4-bromophenyl)-3-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-c- yclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)formamide; N-((S)-2-(4-bromophenyl)-3-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-c- yclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)formamide; (S)-3-(bis(cyclopropylmethyl)amino)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-flu- oro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)pro- pan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihyd- ro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan- -1-one; (S)-3-(bis(cyclopropylmethyl)amino)-2-(4-bromophenyl)-1-(4-((5R,7 S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin- -1-yl)propan-1-one; (S)-2-(4-bromophenyl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cycl- openta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one; (R)-2-amino-3-(1H-indol-3-yl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopent- a[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (R)-2-amino-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1 -yl)-3-(thiophen-2-yl)propan-1-one; (R)-2-amino-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazin-1 -yl)-3-(pyridin-2-yl)propan-1-one; (R)-2-amino-1-((S)-3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]p- yrimidin-4-yl)piperazin-1-yl)-3-(pyridin-2-yl)propan-1-one; (R)-2-amino-3-(5-bromothiophen-2-yl)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cy- clopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-- 5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl- amino)propan-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-- 5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-- one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihy- dro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propa- n-1-one; (S)-2-(5-bromothiophen-2-yl)-1-(4-((5R,7R)-7-fluoro-5-methyl-6,7-- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(tetrahydro-2H-py- ran-4-ylamino)propan-1-one; or (S)-2-(5-bromothiophen-2-yl)-3-(cyclopropylmethylamino)-1-(4-((5R,7S)-7-f- luoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)p- ropan-1-one; or a pharmaceutically acceptable salt thereof.

74. The method of claim 1, wherein said mammal is suffering an inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, or dermatological disease or disorder.

75. The method of claim 74, wherein said disease or disorder is rheumatoid arthritis, osteoarthritis, Crohn's disease, angiofibroma, retinal vascularisation, diabetic retinopathy, age-related macular degeneration, macular degeneration, multiple sclerosis, obesity, Alzheimer's disease, restenosis, allergy, asthma, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prothetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, neurological damage due to tissue repair, scar tissue formation, inflammatory bowel disease, infection, pulmonary disease, neoplasm, Parkinson's disease, transplant rejection or septic shock.

76. The method of claim 74, wherein said disease or disorder is a hyperproliferative disease.

77. The method of claim 76, wherein said disease or disorder is a cancer.

78. The method of claim 77, wherein said disease or disorder is a cancer selected from cardiac, lung, gastrointestinal, genitourinary tract, liver, bone, nervous system, gynecological, hematologic, skin, adrenal, breast, colon, oral cavity, hairy cell leukemia, head and neck, refractory metastatic disease, Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

79. The method of claim 1 further comprising administering to said mammal an effective amount of an additional pharmaceutically active drug.

80. The method of claim 79 wherein the additional pharmaceutically active drug is a chemotherapeutic agent.

81. The method of claim 79 wherein the compound or the salt thereof and the additional pharmaceutically active drug are administered together in a unitary pharmaceutical composition.

82. The method of claim 79 wherein the compound or the salt thereof and the additional pharmaceutically active drug are administered separately and are administered simultaneously or sequentially.

83. The method of claim 79 wherein the additional pharmaceutically active drug is an alkylating agent, an alkyl sulfonate, an aziridine, an ethylenimine, a methylamelamine, a camptothecin, a cryptophycins, a sarcodictyin, a nitrogen mustard, a nitrosurea, an antibiotic, a bisphosphonate, an aclacinomysin, a mitomycin, an anti-metabolite, a folic acid analog, a purine analog, a pyrimidine analog, an androgen, an anti-adrenal, a folic acid replenisher, an epothilone, a maytansinoid, a trichothecene, a taxoid, a platinum analog, or a retinoid, or a pharmaceutically acceptable salt thereof.

84. The method of claim 79 wherein the additional pharmaceutically active drug is selected from erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK222584, oxaliplatin,5-fluorouracil, Leucovorin, Rapamycin, Lapatinib, Lonafarnib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophycin1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammal 1I, calicheamicin omegaI1, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfornithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2''-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, and retinoic acid, and pharmaceutically acceptable salts thereof.

85. The method of claim 79 wherein the additional pharmaceutically active drug is (i) an anti-hormonal agent, (ii) an aromatase inhibitor, (iii) an anti-androgen, (iv) a protein kinase inhibitor, (v) a lipid kinase inhibitor, (vi) an antisense oligonucleotide, (vii) a ribozyme, (viii) a vaccine, (ix) an anti-angiogenic agent, or (x) a pharmaceutically acceptable salt thereof.

86. The method of claim 79 wherein the additional pharmaceutically active drug is selected from tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifine citrate, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestanie, fadrozole, vorozole, letrozole, anastrozole, flutamide, nilutamide, bicalutamide, leuprolide, goserelin, troxacitabine, PKC-alpha, Ralf, H-Ras, and bevacizumab, and pharmaceutically acceptable salts thereof.

87. The method of claim 79 wherein the additional pharmaceutically active drug is a therapeutic antibody.

88. The method of claim 79 wherein the additional pharmaceutically active drug is selected from alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, pertuzumab, trastuzumab, tositumomab, and gemtuzumab ozogamicin.

89. The method of claim 79 wherein the additional pharmaceutically active drug is selected from alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

90. The method of claim 1, wherein said compound is administered orally.

91. The method of claim 90, wherein said compound is administered orally as pill, capsule or tablet.

Details for Patent 8,846,681

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Genentech, Inc. RITUXAN rituximab Injection 103705 11/26/1997 ⤷  Try a Trial 2027-07-05
Idec Pharmaceuticals Corp. RITUXAN rituximab Injection 103737 02/19/2002 ⤷  Try a Trial 2027-07-05
Hoffmann-la Roche Inc. ZENAPAX daclizumab Injection 103749 12/10/1997 ⤷  Try a Trial 2027-07-05
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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