OPTIONALLY FUSED HETEROCYCLYL-SUBSTITUTED DERIVATIVES OF PYRIMIDINE USEFUL FOR THE TREATMENT OF INFLAMMATORY, METABOLIC, ONCOLOGIC AND AUTOIMMUNE DISEASES

Abstract

Disclosed are compounds active towards nuclear receptors, pharmaceutical compositions containing the compounds and use of the compounds in therapy.

Claims

1. A compound of Formula (I): ##STR01128## or a pharmaceutically acceptable salt thereof, wherein: Y is NR or O; R is hydrogen or substituted or unsubstituted C.sub.1-4 alkyl; R.sub.1 is selected from the group consisting of hydrogen, —OH, halogen, substituted or unsubstituted C.sub.1-4 alkyl, substituted or unsubstituted C.sub.1-4 alkoxy, and substituted or unsubstituted C.sub.2-4 alkenyl; R.sub.2 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-4 alkyl, substituted or unsubstituted C.sub.1-4 alkoxy, —CN, and —OH; or R and R.sub.2 are combined to form a substituted or unsubstituted fused ring; R.sub.3 is selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C.sub.1-4 alkyl, substituted or unsubstituted C.sub.1-4 alkoxy, oxo, and —C(═O)R.sub.10; R.sub.4a is selected from the group consisting of hydrogen, halogen, —OH, —CN, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-C.sub.6 alkoxy, substituted or unsubstituted C.sub.1-6 alkenyl, substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C.sub.1-6 alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C.sub.1-6 alkyl; R.sub.4b is selected from the group consisting of hydrogen, halogen, oxo, —OH, substituted or unsubstituted C.sub.1-4 alkyl, substituted or unsubstituted C.sub.1-4 alkoxy, and —C(═O)R.sub.10; R.sub.5 is selected from the group consisting of —(CR.sub.8R.sub.9)pOR.sub.12, —(CR.sub.8R.sub.9)p-CR.sub.13R.sub.14R.sub.15, —(CR.sub.8R.sub.9)p-C(═O)OR.sub.7, and —(CR.sub.8R.sub.9)p-C(═O)NR.sub.8R.sub.9; n, m, and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4; R.sub.6a and R.sub.6b are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted C.sub.1-6 alkoxy, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted C.sub.2-9 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or R.sub.6a and R.sub.6b taken together form an oxo group or R.sub.6a and R.sub.6b taken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-9 heteroalicyclyl, or R.sub.6a and R.sub.13 are taken together to form a ring system selected from substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-5 heteroalicyclyl; R.sub.7, R.sub.8, R.sub.9, and R.sub.12, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted C.sub.2-9 heteroalicyclyl; R.sub.10 is selected from the group consisting of substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkoxy, —OH, —NH.sub.2, —NH(C.sub.1-6 alkyl), —N(C.sub.1-6 alkyl).sub.2, and substituted or unsubstituted C.sub.3-7 cycloalkyl; R.sub.13 is absent, or selected from the group consisting of hydrogen, —OH, —CN, fluorine, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkenyl, substituted or unsubstituted C.sub.1-6 alkoxy, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, and —(CR.sub.8R.sub.9)p-C(═O)OR.sub.7, —(CR.sub.8R.sub.9)p-SO.sub.2R.sub.7 and —(CR.sub.8R.sub.9)p-C(═O)NR.sub.8R.sub.9; R.sub.14 and R.sub.15 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-9 heteroalicyclyl; or R.sub.14 and R.sub.15 taken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, substituted or unsubstituted C.sub.2-9 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; B is a ring system selected from the group consisting of aryl, heteroaryl, and bicyclic heteroalicyclyl, provided that B is not 5,6-dichloro-1H-benzo[d]imidazol-2-yl when R.sub.1 and R.sub.2 are both hydrogen; C is a C.sub.2-9 heteroalicyclyl ring system; and wherein B is attached to a carbon atom adjacent the N atom of ring system C; with the proviso the compound of Formula I is not: ##STR01129##

2. The compound of claim 1, wherein R and R.sub.2 together with the pyrimidine ring of formula (I) form a pyrrolo[2,3-d]pyrimidine or 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine.

3. The compound of claim 1, having the Formula (IIa): ##STR01130## wherein: R.sub.4e and R.sub.4d are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-4 alkyl, substituted or unsubstituted C.sub.1-4 alkoxy, and —OH.

4. The compound of claim 3, wherein R.sub.4e and R.sub.4d are independently selected from the group consisting of hydrogen, methyl, and fluorine.

5. The compound of claim 1, wherein R.sub.5 is —(CR.sub.8R.sub.9)p-C(═O)OR.sub.7, or —(CR.sub.8R.sub.9)p-C(═O)NR.sub.8R.sub.9.

6. The compound of claim 1, wherein R.sub.5 is —(CR.sub.8R.sub.9)pOR.sub.12.

7. The compound of claim 1, wherein R.sub.5 is —(CR.sub.8R.sub.9)p-CR.sub.13R.sub.14R.sub.15.

8. The compound of claim 7, wherein R.sub.14 and R.sub.15 taken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C.sub.3-7 cycloalkyl, substituted or unsubstituted C.sub.3-7 cycloalkenyl, substituted or unsubstituted C.sub.2-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

9. The compound of claim 7, wherein R.sub.14 and R.sub.15 taken together with the carbon to which they are attached form a ring system selected from the group consisting of substituted or unsubstituted C.sub.4-7 cycloalkyl, substituted or unsubstituted C.sub.6-12 aryl, substituted or unsubstituted 4-membered heteroalicyclyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 5-membered heteroalicyclyl, substituted or unsubstituted 6-membered heteroaryl, a substituted or unsubstituted 6membered heteroalicyclyl, substituted or unsubstituted 7-membered heteroaryl, and a substituted or unsubstituted 7-membered heteroalicyclyl.

10. The compound of claim 7, wherein R.sub.14 and R.sub.15 taken together with the carbon to which they are attached form a ring system selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazolyl imidazolyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathianyl thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl, dioxanyl, furyl, dihydrofuranyl, furazanyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dithianyl, thiopyranyl, thianyl, thienyl, oxetanyl, quinolyl, isoquinolyl, indolyl, iso-indolyl, and tetrahydrothienyl, any of which may be substituted or unsubstituted.

11. The compound of claim 10, wherein the ring system is selected from the group consisting of cycloheptyl, cyclohexyl, cyclopentyl, dioxanyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, phenyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, thiomorpholinyl, thiopyryl, and triazolyl, any of which may be substituted or unsubstituted.

12. The compound of claim 8, wherein the ring system is substituted with —(CH.sub.2)q(R.sub.5a) wherein R.sub.5a is independently selected from the group consisting of —CH.sub.2COOR.sub.20, —CH.sub.2CONR.sub.21R.sub.22, oxo, —CN, CH.sub.2CN, C.sub.1-6 alkyl, —CH.sub.2-imidazolyl, —CH.sub.2—SO.sub.2R.sub.20, CH.sub.2C(CH.sub.3).sub.2(OR.sub.20), —OR.sub.20, —CH.sub.2-triazolyl, —CF.sub.3, dimethyl substituted-imidazolyl-2,4-dione, —CH.sub.2—SO.sub.2NR.sub.21R.sub.22, morpholinyl, —C(═O)-morpholinyl, piperidyl-CH.sub.20R.sub.20, OCH.sub.2-tetrahydrofuryl, piperazinonyl, piperidinyl-CONR.sub.21R.sub.22, —OH, —CONR.sub.21R.sub.22, CH(OR.sub.20)CH.sub.3, —COOR.sub.20, —CH.sub.2-pyrrolidyl, C.sub.1-6 alkylene-OH, cyclopentyl, pyrrolidonyl, —NR.sub.21SO.sub.2R.sub.20, tetrazolyl, —CH.sub.2-tetrazolyl, —CH.sub.20R.sub.20, acyl, —SOR.sub.20, —SO.sub.3R.sub.20, —SO.sub.2R.sub.20, —SO.sub.2NR.sub.21R.sub.22, and halogen; R.sub.20, R.sub.21, and R.sub.22 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, —CN, substituted or unsubstituted C.sub.3-6 cycloalkyl, substituted or unsubstituted C.sub.2-6 heteroalicyclyl; and q is an integer selected from 0, 1 or 2.

13. The compound of claim 7, wherein R.sub.13 is absent or selected from the group consisting of hydrogen, —CN, —CH.sub.3, fluorine, —OH, —CH.sub.20H, —OCH.sub.3, —CH.sub.2CH.sub.2OH, —CO.sub.2H, —CO.sub.2—C.sub.1-4-alkyl, and —CONR.sub.8R.sub.9; wherein R.sub.8 and R.sub.9 are independently selected from the group consisting of hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 aminoalkyl, or R.sub.8 and R.sub.9 taken together with the nitrogen to which they are attached form a C.sub.2-C.sub.6 heteroalicyclyl.

14. The compound of claim 1, wherein Y is NR.

15. The compound of claim 14, wherein R is selected from the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4 hydroxyalkyl.

16. The compound of claim 15, wherein R is hydrogen.

17. The compound of claim 16, wherein R.sub.1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-4 alkyl, and substituted or unsubstituted C.sub.1-4 alkoxy.

18. The compound of claim 17, wherein R.sub.1 is selected from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4 hydroxyalkyl.

19. The compound of claim 18, wherein R.sub.1 is hydrogen or —CF.sub.3.

20. The compound of claim 19, wherein R.sub.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4 hydroxyalkyl.

21. The compound of claim 20, wherein R.sub.2 is halogen.

22. The compound of claim 21, wherein R.sub.2 is fluorine.

23. The compound of claim 1, wherein R.sub.3 is selected from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, oxo, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy.

24. The compound of claim 23, wherein R.sub.3 is selected from the group consisting of hydrogen, methyl, fluorine, chlorine, and oxo.

25. The compound of claim 1, wherein whenever m is an integer selected from 2, 3, or 4, at least two of the R.sub.3 groups present are bound to the same atom of ring system C.

26. The compound of claim 1, wherein R.sub.4a is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, —CN, C.sub.1-C.sub.6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.3-C.sub.5 cycloalkyl, heteroaryl and aryl.

27. The compound of claim 26, wherein R.sub.4a is selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-4 haloalkoxy, and heteroaryl.

28. The compound of claim 27, wherein R.sub.4a is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, fluorine, methoxy, ethoxy, C.sub.1-2 haloalkyl, C.sub.1-2 haloalkoxy, and triazolyl.

29. The compound of claim 28, wherein R.sub.4a is selected from the group consisting of —CF.sub.3, —CHF.sub.2, —OCF.sub.3, and —OCHF.sub.2.

30. The compound of claim 1, wherein R.sub.4b is selected from the group consisting of hydrogen, oxo, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.1-4 haloalkoxy.

31. The compound of claim 1, wherein R.sub.4b is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, fluorine, methoxy, ethoxy, —OH, C.sub.1-2 haloalkyl, and C.sub.1-2 haloalkoxy.

32. The compound of claim 1, wherein R.sub.4b is selected from the group consisting of —CF.sub.3, —CF.sub.2CF.sub.3, —CHF.sub.2, —OCF.sub.3, —OCF.sub.2CF.sub.3, and —OCHF.sub.2.

33. The compound of claim 1, wherein R.sub.4a is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkoxy, and substituted or unsubstituted aryl; or R.sub.6a and R.sub.13 are combined to form a ring system selected from substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-9 heteroalicyclyl, or R.sub.6a and R.sub.6b taken together with the carbon to which they are attached form a ring system selected from substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-9 heteroalicyclyl.

34. The compound of claim 33, wherein R.sub.6a is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, and aryl.

35. The compound of claim 34, wherein R.sub.6a is hydrogen.

36. The compound of claim 1, wherein R.sub.6b is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkoxy, substituted or unsubstituted aryl-C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-9 heteroalicyclyl-C.sub.1-6 alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl.

37. The compound of claim 1, wherein R.sub.6b is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.1-6-alkoxy-C.sub.1-6-alkyl; or R.sub.6b is selected from the group consisting of —(CH.sub.2).sub.q—C.sub.3-6 cycloalkyl, —(CH.sub.2).sub.q-aryl, —(CH.sub.2).sub.q—C.sub.2-9 heteroalicyclyl, and —(CH.sub.2).sub.q-heteroaryl, any of which can be unsubstituted or substituted by one or more substituent selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.3-5 cycloalkyl, —(CH.sub.2).sub.q—CONR.sub.23R.sub.24, —(CH.sub.2).sub.q—SO.sub.2R.sub.23, —(CH.sub.2).sub.q—NR.sub.23SO.sub.2R.sub.24 and —(CH.sub.2).sub.q—SO.sub.2NR.sub.23, wherein R.sub.23, and R.sub.24 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, —CN, substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-6 heteroalicyclyl; and q is an integer selected from 0, or 1.

38. The compound of claim 37, wherein R.sub.6b is selected from the group consisting of hydrogen, —(CH.sub.2)C(CH.sub.3).sub.3, —(CH.sub.2)CONH.sub.2, phenyl, phenyl substituted with 1 to 3 halogens, —CH(CH.sub.3)OC(CH.sub.3).sub.3, —CH.sub.2-phenyl-OCH.sub.3, phenyl-OCH.sub.3, —CH.sub.2-pyridyl, CH.sub.2-cyclohexyl-CH.sub.2CO.sub.2H, —CH.sub.2-cyclohexylCH.sub.2CONH.sub.2, CH.sub.2-cyclohexyl-CH.sub.2-tetrazolyl, —CH.sub.2-cyclohexyl-CH.sub.2OH, —CH.sub.2cyclohexyl-NHSO.sub.2CH.sub.3, CH.sub.2-cyclohexyl-NHSO.sub.2CH.sub.2CF.sub.3, CH.sub.2-cyclohexyl-CH.sub.2CN, —CH.sub.2-phenyl-CH.sub.2CO.sub.2H, —CH.sub.2-phenyl-CH.sub.2CONH.sub.2, —CH.sub.2-phenyl-CH.sub.2CONH.sub.2CH.sub.3, —CH.sub.2phenyl-CH.sub.2-tetrazolyl, —CH.sub.2-phenyl-CONH.sub.2, —CH.sub.2-phenyl-SO.sub.2NH-cyclopropyl, —CH.sub.2phenyl-SO.sub.2CH.sub.3, —CH.sub.2-phenyl-NHSO.sub.2CF.sub.3, —CH.sub.2-phenyl-NHSO.sub.2CH.sub.3, —CH.sub.2-phenyl-NHSO.sub.2CHF.sub.2, —CH.sub.2-pyridyl-CH.sub.3, —CH.sub.2-pyridyl-SO.sub.2CH.sub.3, —CH.sub.2-pyridyl-CH.sub.2CONH.sub.2, —CH.sub.2-pyrimidyl-NHSO.sub.2CH.sub.3, —CH.sub.2-piperidyl-COCH.sub.3, —CH.sub.2-piperidyl-SO.sub.2CH.sub.3, —CH.sub.2-piperidyl-SO.sub.2CF.sub.3, —CH.sub.2-thienyl-CH.sub.2CO.sub.2H, —CH.sub.2-cyclobutyl-CH.sub.2CO.sub.2H, —CH.sub.2cyclobutyl-CH.sub.2CONH.sub.2, —CH.sub.2-cyclobutyl-CO.sub.2H, —CH.sub.2-cyclobutyl-CONH.sub.2, —CH.sub.2-tetrahydrothiopyryl, —CH.sub.2-cyclopentyl, —CH.sub.2-cyclohexyl, —CH.sub.2-tetrahydrofuranyl, —CH.sub.2-tetrahydropyranyl, —CH.sub.2-oxetanyl, and —CH.sub.2-pyranyl.

39. The compound of claim 38, wherein R.sub.6b is hydrogen or —(CH.sub.2)C(CH.sub.3).sub.3.

40. The compound of claim 39, wherein R.sub.6b is hydrogen.

41. The compound of claim 1, wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.12 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted aryl-C.sub.1-6 alkyl, substituted or unsubstituted heteroaryl-C.sub.1-6 alkyl, and substituted or unsubstituted aryl.

42. The compound of claim 41, wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.12 are independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, and aryl.

43. The compound of claim 42, wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.12 are independently selected from the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4 hydroxyalkyl.

44. The compound of claim 43, wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.12 are independently selected from the group consisting of hydrogen, methyl, ethyl and tert-butyl.

45. The compound of claim 44, wherein ring system B is aryl or heteroaryl.

46. The compound of claim 1, wherein at least one of R.sub.4a and R.sub.4b is present and is not hydrogen.

47. The compound of claim 45, wherein ring system B is a 6-membered aryl ring with R.sub.4a in the para-position or meta-position relative to ring system C, a 6-membered heteroaryl ring with R.sub.4a in the para-position or meta-position relative to ring system C, or a 5-membered heteroaryl ring with R.sub.4a in the 2- or 3-position.

48. The compound of claim 47, wherein ring system B is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, naphthyl and furanyl.

49. The compound of claim 1, wherein ring system B is a C.sub.2-C.sub.9 bicyclic heteroalicyclyl ring.

50. The compound of claim 49, wherein the C.sub.2-C.sub.9 bicyclic heteroalicyclyl ring is selected from the group consisting of 2H-benzo[b][1,4]oxazin-3(4H)-one, 3, 4-dihydroquino lin-2(1H)-one, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-benzo [b][1,4]oxazine, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-benzo[d]imidazole, indoline, and 1,3-dihydro-2H-benzo[d]imidazol-2-one, and benzo[d]oxazol-2(3H)-one.

51. The compound of claim 1, wherein ring system C is a C.sub.2-9 heteroalicyclyl ring.

52. The compound of claim 1, wherein ring system C is a 4-7-membered heteroalicyclyl ring.

53. The compound of claim 52, wherein ring system C is a 5-membered heteroalicyclyl ring, or a 6-membered heteroalicyclyl ring.

54. The compound of claim 53, wherein ring system C is selected from the group consisting of pyrrolidinyl, piperidyl, azetidinyl and morpholinyl.

55. The compound of claim 1, wherein m is an integer selected from the group consisting of 1, 2, 3 and 4.

56. The compound of claim 55, wherein m is 1 or 2.

57. The compound of claim 1, wherein n is an integer selected from the group consisting of 1, 2, 3 and 4.

58. The compound of claim 1, wherein n is 0 and/or m is 0.

59. The compound of claim 1, wherein p is an integer selected from 0, 1 or 2.

60. The compound of claim 59, wherein p is 0.

61. The compound of claim 1, selected from the group consisting of: ##STR01131## ##STR01132## ##STR01133## ##STR01134## ##STR01135## ##STR01136## ##STR01137## ##STR01138## ##STR01139## ##STR01140## ##STR01141## ##STR01142## ##STR01143## ##STR01144## ##STR01145## ##STR01146## ##STR01147## ##STR01148## ##STR01149## ##STR01150## ##STR01151## ##STR01152## ##STR01153## ##STR01154## ##STR01155## ##STR01156## ##STR01157## ##STR01158## ##STR01159## ##STR01160## ##STR01161## ##STR01162## ##STR01163## ##STR01164## ##STR01165## ##STR01166## ##STR01167## ##STR01168## ##STR01169## ##STR01170## ##STR01171## ##STR01172## ##STR01173## ##STR01174## ##STR01175## ##STR01176## ##STR01177## ##STR01178## ##STR01179## ##STR01180## ##STR01181## ##STR01182## ##STR01183## ##STR01184## ##STR01185## ##STR01186## ##STR01187## ##STR01188## ##STR01189## ##STR01190## ##STR01191##

62. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutical acceptable excipient.

63. A method for modulating the activity of at least one retinoic acid receptor-related orphan receptor, the method comprising contacting at least one retinoic acid receptor-related orphan receptor with activity modulating amount of a compound of claim 1.

64. A method for treating or preventing inflammatory, metabolic or autoimmune diseases or disorders, the method comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

65. The method of claim 64, wherein the disease or disorder is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uvetis, sprue and food allergy, atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatisis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sj6gren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myastehnia Gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type II diabetes, and cancer.

66-69. (canceled)

70. The compound of claim 1, wherein the compound inhibits the activity of an RORγ receptor by at least 20% at a concentration of 0.1 μM.

71. The compound of claim 1, wherein R.sub.4a is selected from the group consisting of hydrogen, halogen, —OH, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-C.sub.6 alkoxy, substituted or unsubstituted C.sub.1-6 alkenyl, substituted or unsubstituted C.sub.3-C.sub.6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C.sub.1-6 alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl-C.sub.1-6 alkyl;

72. The compound of claim 1, wherein R.sub.13 is absent or is selected from the group consisting of hydrogen, —OH, —CN, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkenyl, substituted or unsubstituted C.sub.1-6 alkoxy, substituted or unsubstituted C.sub.3-8 cycloalkyl, substituted or unsubstituted C.sub.3-8 cycloalkenyl, and —(CR.sub.8R.sub.9)p-C(═O)OR.sub.7, —(CR.sub.8R.sub.9)p-SO.sub.2R.sub.7 and —(CR.sub.8R.sub.9)p-C(═O)NR.sub.8R.sub.9;

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0295] FIG. 1 illustrates the TAMRA-labelled probe.

[0296] FIG. 2 illustrates the characterisation of the Fluorescence Polarization (FP) assay with the TAMRA-labelled probe used in the FP assay.

[0297] FIG. 3 depicts the assay results of example no. 89 in (A) Fluorescence Polarization Assay, (B) RORγ Reporter Assay (Gal4), and (C) Th17 Assay. Specific examples of compounds are disclosed in Table 1 below.

[0298]

TABLE-US-00001 TABLE 1 Example Compounds by Structure and Name. Ex. No. Structure Name 4 [00014] 3-[[2-[4-[2-(4- phenylphenyl)pyrrolidin-1- yl]pyrrolo[2,3-d]pyrimidin-7- yl]butanoylamino]methyl]furan-2- carboxamide 5 [00015] (2R)-2-[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide or (2R)-2- [[5-fluoro-6-[(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 6 [00016] (2R)-4,4-dimethyl-2-[[6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]pentanamide 9 [00017] (2R)-2-[[6-[2-(1,3-benzothiazo1-2- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4-yl]amino]-3-(2,4,5- trifluorophenyl)propanamide 11 [00018] (2R)-2-[[6-[2-(2,4- dichlorophenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 13 [00019] (2R)-2-[[5-fluoro-2- (trifluoromethyl)-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 14 [00020] (2R)-4,4-dimethyl-2-[[5-methyl-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]pentanamide 15 [00021] (2R)-2-[[2,5-dimethyl-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 16 [00022] 5-fluoro-N-(3-methoxy-1,3- dimethyl-butyl)-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 17 [00023] (2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(4- methoxyphenyl)propanamide 18 [00024] (2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 19 [00025] (2R)-2-[[6-[2-(4-tert- butylphenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 20 [00026] (2R)-2-[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 21 [00027] N-(3,3-dimethylbutyl)-5-fluoro-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 23 [00028] (2R)-2-[[5-fluoro-6-[2-(6- quinolyl)pyrrolidin-1-yl]pyrimidin- 4-yl]amino]-4,4-dimethyl- pentanamide 24 [00029] (2R)-2-[[6-[2-(2,3-dihydro-1,4- benzodioxin-6-yl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 29 [00030] (2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(4- methoxyphenyl)propan-1-ol 30 [00031] (2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentan-1-ol 31 [00032] (2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]-methyl- amino]-N,4,4-trimethyl- pentanamide 32 [00033] 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 33 [00034] (2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4- methyl-pentanoic acid 34 [00035] (2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4- methyl-pentanamide 35 [00036] (2R)-2-[[6-[2-[2-chloro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]-4,4-dimethyl- pentanamide 36 [00037] (2R)-2-[[6-[2-[2-chloro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]-4,4-dimethyl-pentanoic acid 37 [00038] (2R)-2-[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(4- fluorophenyl)propanamide 38 [00039] (2R)-2-[[5-fluoro-6-[3-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 39 [00040] (2R)-2-[[3-fluoro-2-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-4-pyridyl]amino]-4,4- dimethyl-pentanamide 40 [00041] 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 41 [00042] 5-fluoro-N-(1-methyl-2- tetrahydropyran-4-yl-ethyl)-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 42 [00043] (2R)-2-[[5-fluoro-6-[2-[5- (trifluoromethyl)-2- pyridyl]pyrrolidin-1-yl]pyrimidin-4- yl]amino]-4,4-dimethyl- pentanamide 43 [00044] (2R)-2-[[6-[2-(4-tert- butoxyphenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 44 [00045] 4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzoic acid 45 [00046] 3-[[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methyl]- 5,5-dimethyl-imidazolidine-2,4- dione 46 [00047] [4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methane- sulfonamide 48 [00048] 5-fluoro-N-[[4- (trifluoromethyl)phenyl]methyl]-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 51 [00049] (2R)-3-tert-butoxy-2-[[5-fluoro-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]butanamide 52 [00050] (2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3- tetrahydropyran-4-yl-propanamide 53 [00051] N-[(3,4-dimethoxyphenyl)methyl]- 5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 54 [00052] N-[(2,3-dimethoxyphenyl)methyl]- 5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 55 [00053] N-[1-(3,4-dihydro-2H-1,5- benzodioxepin-7-yl)propyl]-5- fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 56 [00054] 5-fluoro-N-[(4- morpholinophenyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 57 [00055] [4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]- morpholino-methanone 58 [00056] [1-[5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 2-pyridyl]-4-piperidyl]methanol 59 [00057] 5-fluoro-N-[[4-(tetrahydrofuran-2- ylmethoxy)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 60 [00058] 4-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]piperazin- 2-one 61 [00059] 1-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]piperidine- 3-carboxamide 62 [00060] (2R)-2-[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide or (2R)-2- [[5-fluoro-6-[(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 63 [00061] (2R)-2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3-(2- oxopyrrolidin-3-yl)propanamide 64 [00062] N-[(1R)-3,3-dimethyl-1-morpholin- 2-yl-butyl]-5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 65 [00063] (2R)-2-[[5-fluoro-6-[2-[2-methoxy-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 66 [00064] 3-fluoro-N-[(6-methyl-3- pyridyl)methyl]-4-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyridin-2-amine 67 [00065] 1-[(3,4-dimethoxyphenyl)methyl]-4- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-b]pyridine 68 [00066] (2R)-2-[[5-fluoro-6-[3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 69 [00067] 7-[(3,4-dimethoxyphenyl)methyl]-4- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidine 70 [00068] methyl 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetate 71 [00069] 1-[2-[(1R)-1-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-3,3- dimethyl-butyl]morpholin-4- yl]ethanone 72 [00070] (2R)-2-[[5-fluoro-6-[2-[3-fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanamide 73 [00071] 5-fluoro-4-[2-[3-fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-6-[(6-methyl-3- pyridyl)methoxy]pyrimidine 74 [00072] 5-fluoro-4-[(6-methyl-3- pyridyl)methoxy]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidine 77 [00073] (2R)-2-[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide or (2R)-2-[5-fluoro-6- [(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide 78 [00074] (2R)-2-[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide or (2R)-2-[5-fluoro-6- [(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide 79 [00075] 2-[4-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]oxymethyl]phenyl]acetic acid 80 [00076] (2R)-2-[5-fluoro-6-[5-[4- (trifluoromethyl)phenyl]pyrazol-1- yl]pyrimidin-4-yl]oxy-4-methyl- pentanamide 81 [00077] 2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 83 [00078] 2-[4-[[5-fluoro-6-[[4- (trifluoromethyl)phenyl]methylamino] pyrimidin-4- yl]oxymethyl]phenyl]acetic acid 84 [00079] 2-[4-[[5-fluoro-6-[2-[6- (trifluoromethyl)-3- pyridyl]pyrrolidin-1-yl]pyrimidin-4- yl]oxymethyl]phenyl]acetamide 85 [00080] 2-[4-[[4-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetic acid 86 [00081] 2-[5-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]oxymethyl]pyrimidin-2- yl]acetamide 87 [00082] 2-[5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyrimidin-2- yl]acetamide 88 [00083] 4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzonitrile 89 [00084] 5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 90 [00085] 5-fluoro-6-[2-(4- methoxyphenyl)pyrrolidin-1-yl]-N- [(6-methyl-3- pyridyl)methyl]pyrimidin-4-amine 91 [00086] 2-[4-[[[5-fluoro-6-[3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 93 [00087] 5-fluoro-N-[(4- methylcyclohexyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 94 [00088] 5-fluoro-N-[[4-(imidazol-1- ylmethyl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 95 [00089] 5-fluoro-N-[[4- (methylsulfonylmethyl)phenyl] methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 96 [00090] 5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[5-[4- (trifluoromethyl)phenyl]triazol-1- yl]pyrimidin-4-amine 97 [00091] 5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[2-[4- (trifluoromethoxy)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 98 [00092] 1-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]-2-methyl- propan-2-ol 99 [00093] 5-fluoro-N-[(2-methoxy-6-methyl- 3-pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 100 [00094] 5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyridin-2-ol 104 [00095] 2-[1-[5-fluoro-6-[(6-methyl-3- pyridyl)methylamino]pyrimidin-4- yl]pyrrolidin-2-yl]-5- (trifluoromethyl)pheno1 105 [00096] 5-fluoro-N-[(1-methylpyrrol-3- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 106 [00097] 5-fluoro-N-[(1-methylpyrazo1-4- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 107 [00098] 5-fluoro-N-[(5-methyl-2- furyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 108 [00099] 5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyrrolidin-2-one 109 [00100] 4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 1-methyl-pyrrolidin-2-one 110 [00101] 5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- N,N-dimethyl-tetrahydrofuran-2- carboxamide 111 [00102] 5-fluoro-N-[(4- methoxytetrahydropyran-4- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 112 [00103] 1-[6-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 2-methyl-3-pyridyl]ethanol 113 [00104] 5-fluoro-N-[(2-methoxy-4- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 114 [00105] 5-fluoro-N-[(6-methoxy-3- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 115 [00106] 5-fluoro-N-[[4-(1,2,4-triazol-1- ylmethyl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 116 [00107] 5-fluoro-N-[(6-methoxy-3- pyridyl)methyl]-N-methyl-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 117 [00108] 2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 118 [00109] 2-[4-[[[5-fluoro-6-[(2S)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 119 [00110] 2-[4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 120 [00111] 4-[2-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]ethyl]benzoic acid 121 [00112] [3-[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]pyrrolidin-1-yl]-(4- pyridyl)methanone 122 [00113] 5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]indolin-2-one 123 [00114] 5-fluoro-N-[3-methyl-1-(1H- tetrazol-5-yl)butyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 124 [00115] 1-[[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methyl] pyrrolidin-2-one 126 [00116] 5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-N-[[6-(trifluoromethyl)-3- pyridyl]methyl]pyrimidin-4-amine 128 [00117] 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]ethanol 129 [00118] 4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran- 4-ol 130 [00119] 1-cyclopentyl-4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]pyrrolidin-2-one 131 [00120] 5-fluoro-N-[(4-methoxy-2- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 132 [00121] 5-fluoro-N-[(6-methyl-2- pyridyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 134 [00122] 9-[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]-3,9- diazaspiro[4.5]decan-2-one 135 [00123] 4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]-methyl- amino]methyl]-1-methyl-pyrrolidin- 2-one 136 [00124] N-[(5-ethyl-2-pyridyl)methyl]-5- fluoro-N-methyl-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 137 [00125] 1-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]pyrrolidin- 2-one 138 [00126] 5-fluoro-N-[[4-(1H-tetrazol-5- yl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 139 [00127] N-benzyl-5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 140 [00128] 5-fluoro-N-(4-pyridylmethyl)- 6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 141 [00129] 5-fluoro-N-(3-pyridylmethyl)- 6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 142 [00130] N-[(3,5-dimethoxyphenyl)methyl]- 5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 143 [00131] 1-[3-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]pyrrolidin- 2-one 144 [00132] 3-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- N-methyl-benzamide 145 [00133] 3-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- N,N-dimethyl-benzamide 146 [00134] 5-fluoro-N-[[3-(1,2,4-triazol-1- ylmethyl)phenyl]methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 147 [00135] 5-fluoro-N-[[3- (methoxymethyl)phenyl]methyl]-6- [2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 148 [00136] 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl]acetic acid 150 [00137] 5-fluoro-6-[2-(5-methyl-2- furyl)pyrrolidin-1-yl]-N-[(6-methyl- 3-pyridyl)methyl]pyrimidin-4- amine 151 [00138] N-(cyclobutylmethyl)-5-fluoro- 6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 152 [00139] 5-fluoro-N-[(1- methylcyclobutyl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 154 [00140] 5-fluoro-N-(tetrahydrofuran-3- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 155 [00141] 5-fluoro-N-(tetrahydropyran-2- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 159 [00142] 5-fluoro-N-(tetrahydrothiophen-2- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 161 [00143] 5-fluoro-N-[(4- methyltetrahydropyran-4- yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 164 [00144] 5-fluoro-N-(tetrahydrothiopyran-4- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 165 [00145] 3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydrothiophen- 3-ol 166 [00146] N-[(4,4- dimethylcyclohexyl)methyl]-5- fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 167 [00147] 1-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cycloheptanol 168 [00148] 5-fluoro-N-[(2- methoxycyclohexyl)methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 169 [00149] 4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydrothiopyran- 4-o1 170 [00150] N-[(1,1-dioxothiolan-2-yl)methyl]- 5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 175 [00151] N-[(2-tert-butyltetrahydropyran-3- yl)methyl]-5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 178 [00152] 5-fluoro-N-[(4- isopropylcyclohexyl)methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 181 [00153] 5-fluoro-N-(tetrahydrofuran-2- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 182 [00154] 4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzenesulfonamide 183 [00155] N-[(6-chloro-3-pyridyl)methyl]-5- fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 184 [00156] N-[(1,1-dioxothiolan-3-yl)methyl]- 5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 185 [00157] 5-fluoro-N-(3-thienylmethyl)-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 186 [00158] 5-fluoro-N-(tetrahydropyran-3- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 188 [00159] 5-fluoro-N-[[1- (methoxymethyl)cyclobutyl]methyl]- 6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 189 [00160] 2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]-N-methyl- acetamide 190 [00161] 5-fluoro-N-[[4-(1H-tetrazol-5- ylmethyl)cyclohexyl]methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 191 [00162] 1-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 1-piperidyl]ethanone 192 [00163] 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethoxy)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 193 [00164] 5-fluoro-N-[(1-oxidopyridin-1-ium- 3-yl)methyl]-6-[(2R)-2[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 194 [00165] 5-fluoro-N-[(1-oxidopyridin-1-ium- 4-yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 195 [00166] 2-[4-[[4-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetic acid 196 [00167] 2-[4-[[4-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetamide 197 [00168] 5-fluoro-N-[(1-methylsulfonyl-4- piperidyl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 198 [00169] 5-fluoro-N-[(3-methyloxetan-3- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 199 [00170] 5-fluoro-N-[(2- methyltetrahydrofuran-2- yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 200 [00171] 2-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cyclohexanol 201 [00172] 5-fluoro-N-[(2- methyltetrahydrothiophen-2- yl)methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 202 [00173] N-[(4,4-dioxo-1,4-oxathian-2- yl)methyl]-5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 203 [00174] 5-fluoro-N-(2-thienylmethyl)-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 204 [00175] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 205 [00176] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl]acetic acid 206 [00177] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] acetamide 207 [00178] 2-[5-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 2-thienyl]acetic acid 208 [00179] 5-fluoro-N-(tetrahydropyran-4- ylmethyl)-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 209 [00180] 5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[2-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 210 [00181] 5-fluoro-6-[(2R)-2-[2-fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-N-[(6-methyl-3- pyridyl)methyl]pyrimidin-4-amine 211 [00182] 5-fluoro-N-[(6-methyl-3- pyridyl)methyl]-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 212 [00183] 5-fluoro-6-[4-methoxy-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-N-[(6-methyl-3- pyridyl)methyl]pyrimidin-4-amine 213 [00184] 5-fluoro-N-[(5-methyloxazol-2- yl)methyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 214 [00185] 5-(((5-fluoro-6-(2-(4- (trifluoromethyl)phenyl)pyrrolidin- 1-yl)pyrimidin-4-yl)amino)methyl)- 1,3,4-oxadiazol-2-ol 215 [00186] 5-fluoro-N-[1-(5-methyl-1,2,4- oxadiazo1-3-yl)propyl]-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 216 [00187] 5-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]isoxazol-3-ol 217 [00188] [3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methanol 218 [00189] N-(cyclopentylmethyl)-5-fluoro-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 219 [00190] 5-fluoro-N-[(4- methylsulfonylphenyl)methyl]-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 220 [00191] 3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydrofuran- 3-ol 221 [00192] 2-[4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- yl]ethanol 222 [00193] N-[(1,1-dioxothian-4-yl)methyl]-5- fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-amine 223 [00194] 4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]methyl]- 1,1-dioxo-thian-4-ol 224 [00195] N-cyclopropyl-4-[[[5-fluoro-6- [(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzenesulfonamide 225 [00196] [4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] methanol 226 [00197] 4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzamide 227 [00198] [4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]methanol 228 [00199] [3-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]oxetan-3- yl]methano1 229 [00200] 2-[4-[[[5-fluoro-6-[2-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 230 [00201] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 231 [00202] 2-[4-[[[6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide 232 [00203] 2-[4-[[[5-fluoro-6-[(2R)-2-[2- fluoro-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 233 [00204] 1-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 1-piperidyl]ethanone 234 [00205] 4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 1,1-dioxo-thian-4-ol 235 [00206] 5-fluoro-N-[(3-methyloxetan-3- yl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 236 [00207] N-cyclopropyl-4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl] benzenesulfonamide 237 [00208] 5-fluoro-N-[(1-methylsulfonyl-4- piperidyl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 238 [00209] 3-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydrofuran- 3-ol 239 [00210] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran- 4-yl]ethanol 240 [00211] 5-fluoro-N-[[4- (methylsulfonylmethyl) tetrahydropyran-4-yl] methyl]-6-[(2R)-2-[4- (trifluoromethyl)phenyl] pyrrolidin- 1-yl]pyrimidin-4-amine 241 [00212]   [00213] 2-[4-[[[5-fluoro-6-[(2R,4R)-4- fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide AND 2-[4-[[[5-fluoro-6-[(2S,4S)- 4-fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 242 [00214]   [00215] 2-[4-[[[5-fluoro-6-[(2S,4R)-4- fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide AND 2-[4-[[[5-fluoro-6-[(2R,4S)-4- fluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 243 [00216] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl]acetic acid 244 [00217] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]-N-methyl- acetamide 245 [00218] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] acetamide 246 [00219] 5-fluoro-N-[[4-(1H-tetrazol-5- ylmethyl)phenyl]methyl]-6-[(3S)-3- [4-(trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4-amine 247 [00220] 5-fluoro-N-(tetrahydropyran-4- ylmethyl)-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 248 [00221] 2-[4-[[[5-fluoro-6-[4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 249 [00222] 1-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl] cyclopentanecarboxamide 250 [00223] 1-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- N,N-dimethyl- cyclopentanecarboxamide 251 [00224] N-[2-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclopentyl] methanesulfonamide 252 [00225] 2-[4-[[4-[(3S)-3-[4- (trifluoromethoxy)phenyl] morpholin-4-yl]pyrrolo[2,3-d] pyrimidin-7- yl]methyl]phenyl]acetamide 253 [00226] 5-fluoro-N-[[4- (methylsulfonylmethyl) tetrahydropyran-4-yl]methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 254 [00227] methyl 4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran- 4-carboxylate 255 [00228] 4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carboxamide 256 [00229] N-(2-aminoethyl)-4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carboxamide 257 [00230] 4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carbonitrile 258 [00231] 2-[4-[[[5-fluoro-6-[(3S)-3-[2-fluoro- 4-(trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 259 [00232] 6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-N-(tetrahydropyran- 4-ylmethyl)pyrimidin-4-amine 260 [00233] 6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-N-[[4- (methylsulfonylmethyl) tetrahydropyran-4-yl] methyl]pyrimidin-4-amine 261 [00234] [3-[[[6-[4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5-fluoro-pyrimidin-4- yl]amino]methyl]oxetan-3- yl]methanol 262 [00235] 1-[4-fluoro-4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 1-piperidyl]ethanone 263 [00236] 5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]-N-[[1- (trifluoromethylsulfonyl)-4- piperidyl]methyl]pyrimidin-4-amine 264 [00237] 5-fluoro-N-[(4- fluorotetrahydropyran-4-yl)methyl]- 6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 265 [00238] 2-[4-[[4-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]-5,6-dihydropyrrolo[2,3- d]pyrimidin-7- yl]methyl]phenyl]acetamide 266 [00239] 5-fluoro-N-[(4-fluoro-1- methylsulfonyl-4-piperidyl)methyl]- 6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 267 [00240] N-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethoxy)phenyl] morpholin-4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] methanesulfonamide 268 [00241] 4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]tetrahydropyran-4- carboxylic acid 273 [00242] N-cyclopropyl-4-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl] benzenesulfonamide 274 [00243] 5-fluoro-N-[(1-methylsulfonyl-4- piperidyl)methyl]-6-(3- phenylmorpholin-4-yl)pyrimidin-4- amine 276 [00244] 2-[4-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl]phenyl]acetic acid 279 [00245] 2-[4-[[[5-fluoro-6-(2- phenylpyrrolidin-1-yl)pyrimidin-4- yl]amino]methyl]phenyl]acetamide 280 [00246] 2-[4-[[[5-fluoro-6-[4-oxo-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 282 [00247] 2-[5-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl]-2-thienyl]acetic acid 283 [00248] 2-[5-[[[5-fluoro-6-(3- phenylmorpholin-4-yl)pyrimidin-4- yl]amino]methyl]-2- thienyl]acetamide 284 [00249] 2-[4-[[4-(3-phenylmorpholin-4- yl)pyrrolo[2,3-d]pyrimidin-7- yl]methyl]phenyl]acetamide 285 [00250] 2,2,2-trifluoro-N-[4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethoxy)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl] cyclohexyl]ethane sulfonamide 286 [00251] 4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- N-methyl-tetrahydropyran-4- carboxamide 287 [00252] 2-[4-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclohexyl] acetonitrile 288 [00253] 5-fluoro-N-[[4-(1H-tetrazol-5- ylmethyl)cyclohexyl]methyl]-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 290 [00254] (3S)-4-[7-[(1-methylsulfonyl-4- piperidyl)methyl]pyrrolo[2,3- d]pyrimidin-4-yl]-3-[4- (trifluoromethoxy)phenyl] morpholine 291 [00255] 1,1,1-trifluoro-N-[4-[[[5-fluoro-6- [(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl] methanesulfonamide 292 [00256] N-cyano-2-[4-[[[5-fluoro-6-[3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 293 [00257] 5-fluoro-N-[(6-methylsulfonyl-3- pyridyl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 294 [00258] N-(2,2-dimethyl-4-methylsulfonyl- butyl)-5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 295 [00259] 2-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]amino]methyl]- 2-methyl-cyclohexanol 296 [00260] [1-[[[5-fluoro-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4- yl]amino]methyl]cyclopropyl] methanol 297 [00261] N-[1-[5-fluoro-6-[(3 S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-yl]-4- piperidyl]methanesulfonamide 299 [00262] 2-[4-[[[6-[2-(1,3-benzodioxol-5- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide 300 [00263] 2-[4-[[[5-fluoro-6-[2-(4- hydroxyphenyl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 301 [00264] 2-[4-[[[6-[2-(4- ethoxyphenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide 302 [00265] 2-[4-[[[5-fluoro-6-[2-(p- tolyl)pyrrolidin-1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 303 [00266] 2-[4-[[[5-fluoro-6-[2-(4- isopropylphenyl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 304 [00267] 2-[4-[[[5-fluoro-6-[2-(3- methoxyphenyl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 305 [00268] 2-[4-[[[6-[2-(3- bromophenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide 306 [00269] 2-[4-[[[6-[2-(3- chlorophenyl)pyrrolidin-1-yl]-5- fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide 307 [00270] 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]azetidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 308 [00271] 2-[4-[[[5-fluoro-6-[2-[4- (trifluoromethyl)phenyl]-1- piperidyl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 309 [00272] 5-fluoro-N-[(4- methylsulfonylmorpholin-2- yl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 310 [00273] 2-[4-[[[6-[2-(1,3-benzothiazol-2- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide 311 [00274] 2-[4-[[[5-fluoro-6-[2-(1- naphthyl)pyrrolidin-1-yl]pyrimidin- 4- yl]amino]methyl]phenyl] acetamide 312 [00275] 2-[4-[[[5-fluoro-6-[2-(2- naphthyl)pyrrolidin-1-yl]pyrimidin- 4-yl]amino]methyl]phenyl] acetamide 313 [00276] 2-[4-[[[5-fluoro-6-[2-(5-methyl-2- furyl)pyrrolidin-1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 314 [00277] 2-[4-[[[5-fluoro-6-[2-(5-methyl- 1,2,4-oxadiazol-3-yl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 315 [00278] 2-[4-[[[5-fluoro-6-[2-(5-methyl- 1,3,4-oxadiazol-2-yl)pyrrolidin-1- yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 316 [00279] 2-[4-[[[6-[2-(5-ethyl-2- furyl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide 317 [00280] 2-[4-[[[6-[2-(1,3-dimethylpyrazol-4- yl)pyrrolidin-1-yl]-5-fluoro- pyrimidin-4- yl]amino]methyl]phenyl]acetamide 318 [00281] 2-[4-[[[6-[2-(2,4- dimethoxyphenyl)pyrrolidin-1-yl]- 5-fluoro-pyrimidin-4- yl]amino]methyl]phenyl]acetamide 319 [00282] 4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]benzenesulfonic acid 320 [00283] 4-[[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino] methyl]-N-(2- methoxyethyl)benzenesulfonamide 323 [00284] 2-[4-[[[5-fluoro-6-[2-[2-hydroxy-4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4- yl]amino]methyl]phenyl]acetamide 324 [00285] 2-[1-[5-fluoro-6-[(1-methylsulfonyl- 4-piperidyl)methylamino]pyrimidin- 4-yl]pyrrolidin-2-yl]-5- (trifluoromethyl)phenol 325 [00286] (2R)-2-[[5-fluoro-6-[(2R)-2-[4- (trifluoromethyl)phenyl]pyrrolidin- 1-yl]pyrimidin-4-yl]amino]-4,4- dimethyl-pentanoic acid 326 [00287] 2-[4-[[4-[(3S)-3-[6- (trifluoromethyl)-3- pyridyl]morpholin-4-yl]pyrrolo[2,3- d]pyrimidin-7- yl]methyl]phenyl]acetamide 327 [00288] 5-fluoro-N-[(1- methylsulfonylpyrrolidin-3- yl)methyl]-6-[(3S)-3-[4- (trifluoromethyl)phenyl]morpholin- 4-yl]pyrimidin-4-amine 328 [00289] 2-[4-[[4-[(3S)-3-[5- (trifluoromethyl)-2- pyridyl]morpholin-4-yl]pyrrolo[2,3- d]pyrimidin-7- yl]methyl]phenyl]acetamide 329 [00290] (3S)-4-[7-[(6-methylsulfonyl-3- pyridyl)methyl]pyrrolo[2,3- d]pyrimidin-4-yl]-3-[4- (trifluoromethoxy)phenyl] morpholine 330 [00291] (3S)-4-[7-[(5-methylsulfonyl-2- pyridyl)methyl]pyrrolo[2,3- d]pyrimidin-4-yl]-3-[4- (trifluoromethoxy)phenyl] morpholine

[0299] In a related aspect there is provided a prodrug of a compound of Formula (I) as described herein.

[0300] Pharmaceutical Compositions

[0301] In another aspect, the present disclosure relates to a pharmaceutical composition comprising physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein. The compounds of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), included in the pharmaceutical composition may also be any compound of the preferred embodiments described above. In another aspect, the present disclosure relates to a pharmaceutical composition comprising physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe). Acceptable carriers or diluents, as well as other additives to be combined with a compound of Formula (I), compounds of Formula (IIa), and compounds of any one of Formulae (IIb-IIe), as disclosed herein to provide a pharmaceutical composition, for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, taste masking agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate-methacrylate copolymer as a derivative of polyvinyl may be used as suspension agents; and plasticizers such as ester phthalates and the like may be used as suspension agents.

[0302] The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Similar, pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic bases, such as ammonia, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and the like.

[0303] The term “carrier” defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

[0304] The term “diluent” defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0305] The term “physiologically acceptable” defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0306] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990.

[0307] Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.

[0308] The pharmaceutical compositions may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0309] Pharmaceutical compositions for use as described herein may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.

[0310] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. Physiologically compatible buffers include, but are not limited to, Hanks's solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.

[0311] For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation.

[0312] Pharmaceutical formulations for parenteral administration, e.g., by bolus injection or continuous infusion, include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0313] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0314] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0315] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0316] For administration by inhalation, the compounds for use as described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0317] Further disclosed herein are various pharmaceutical compositions well known in the pharmaceutical art for uses that include intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Topical ophthalmic compositions may be formulated as a solution in water buffered at a pH of 5.0 to 8.0. Other ingredients that may be desirable to use in the ophthalmic preparations include preservatives (such as benzalkonium chloride, stabilized oxychloro complex, which is sold as Purite™, or stabilized chlorine dioxide), cosolvents (such as polysorbate 20, 60 and 80, Pluronic® F-68, F-84 and P-103, cyclodextrin, or Solutol) and viscosity-building agents (such as polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, or hydroxypropyl cellulose). The compounds disclosed herein may also be used in an intraocular implant as described in U.S. Pat. No. 7,931,909 which is hereby incorporated by reference. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, such as eyedrops, or in gellan gum (Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al., Ophthalmologica, 210(2):101-3 (1996)); ophthalmic ointments; ophthalmic suspensions, such as microparticulates, drug-containing small polymeric particles that are suspended in a liquid carrier medium (Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)), lipid-soluble formulations (Alm et al., Prog. Clin. Biol. Res., 312:447-58 (1989)), and microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); and ocular inserts. All of the above-mentioned references, are incorporated herein by reference in their entireties. Such suitable pharmaceutical formulations for intraocular delivery are most often and preferably formulated to be sterile, isotonic and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to simulate in many respects nasal secretions to ensure maintenance of normal ciliary action. As disclosed in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference in its entirety, and well-known to those skilled in the art, suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.

[0318] The compounds disclosed herein may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0319] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0320] For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.

[0321] Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[0322] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0323] Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external micro-environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. The liposome may be coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the desired organ. Alternatively, small hydrophobic organic molecules may be directly administered intracellularly.

[0324] Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical compositions. Alternatively or additionally, pharmaceutical compositions may be combined with other compositions that contain other therapeutic or diagnostic agents.

[0325] Uses

[0326] The compounds or pharmaceutical compositions disclosed herein as described above may be used to modulate the activity of a retinoic acid receptor-related orphan receptor (ROR), such as a RORα, RORβ and/or RORγ (RORc) receptor. Modulators of RORγ have been reviewed by B. Fauber and S. Magnuson in J. Med. Chem., Feb. 6, 2014, which hereby is incorporated by reference in its entirety. Examples of RORγ receptors are RORγ1 and RORγt receptors. The compounds or pharmaceutical compositions as described above may also display selective modulation of a particular ROR receptor relative to a different ROR receptor. For example, according to some embodiments disclosed herein some compounds or pharmaceutical compositions modulate the activity of an RORγ receptor to a larger extent than they modulate the activity of RORα and/or RORβ receptors.

[0327] The compounds or pharmaceutical compositions disclosed herein may also be used to modulate the activity of regulatory T cells (Tregs).

[0328] The compounds or pharmaceutical compositions disclosed herein may also be used to modulate the activity of cells producing IL17 in a RORγt dependent manner, for example, γδT cells, Th17 cells and ILC3 cells.

[0329] Publications providing useful background information are Arthritis & Rheumatism, 2014, 66, 579-588; Curr Top Microbial Immun, 2014, 378, 171-182; Drug Disc. Today, 2014, May; Nature Rev. Drug Disc. 2012, 11, 763-776, and Nature Rev. Drug Disc., 2014, 13, 197-216, all of which are hereby incorporated by reference in their entirety.

[0330] The compounds or pharmaceutical compositions as described herein and above may also be used in therapy or may be used to treat inflammatory, metabolic, oncologic and autoimmune diseases or disorders. Examples of such diseases or disorders are inflammatory, metabolic, oncologic and autoimmune diseases or disorders mediated or affected by IL17 and/or RORγ (RORc). The role of RORγ in the pathogenesis of autoimmune or inflammatory diseases has been disclosed in Immunity 2007, 26, 643-654; Nat. Rev. Immunol. 2006, 6, 205-217; J. Immunol. 2009, 183, 7169-7177; Brain Pathol. 2004, 14, 164-174; Brain 2007, 130, 1089-1104; and Nat Rev. Immunol. 2008, 8, 183-192 all of which are hereby incorporated by reference in their entirety.

[0331] More specific examples of diseases or disorders include asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergy, atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myasthenia Gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance and type II diabetes and cancer.

[0332] More specifically, compounds or pharmaceutical compositions having an antagonistic or inverse agonistic effect on RORγ may be used to reduce levels of IL17 and/or other gene products, such as interleukins, and cytokines, regulated RORγ. This may for example be in subjects suffering from for example, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, helicobacter pylori infection, allergic diseases including allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergy, atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myasthenia Gravis, Guillain-Barre syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance and type II diabetes.

[0333] Conversely, compounds or pharmaceutical compositions having an agonistic effect on RORγ may be used to increase IL17 levels. Increasing IL17 levels may be particularly useful in immune compromised conditions or boosting the immune system response for example during infections and in cancer.

[0334] Methods of Administration

[0335] The compounds or pharmaceutical compositions may be administered to the patient by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area, e.g., by depot implantation, by intratumoral injection, or by intra-lymph node injection; (e) administration topically; as well as (f) administration to cells ex vivo followed by insertion of said cells into the patient; as deemed appropriate by those of skill in the art for bringing the compound disclosed herein into contact with living tissue.

[0336] Pharmaceutical compositions suitable for administration include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including mammal, e.g. human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0337] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.

[0338] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication.

[0339] Typically, dosages may be between about 10 microgram/kg and 100 mg/kg body weight, preferably between about 100 microgram/kg and 10 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.

[0340] The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in “The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED.sub.50 or ID.sub.50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0341] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps the dose frequency will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0342] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg, e.g. 5 to 200 mg. An ocular eye drop may range in concentration between 0.005 and 5 percent. In one embodiment, an eye drop may range between 0.01 and 1 percent, or between 0.01 and 0.3 percent in another embodiment. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of each active ingredient of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg is used. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each active ingredient up to 1000 mg per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range or frequency in order to effectively and aggressively treat particularly aggressive diseases or infections. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0343] Dosage amount and interval may be adjusted individually to provide plasma or tissue levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0344] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0345] In cases of local or ex vivo administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0346] The amount of composition administered may be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0347] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition, including but not limited to cancer, cardiovascular disease, and various immune dysfunction. Similarly, acceptable animal models may be used to establish efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0348] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0349] General Remarks

[0350] As described above with reference to specific illustrative embodiments, it is not intended to be limited to the specific form set forth herein. Any combination of the above mentioned embodiments should be appreciated as being within the scope of the invention. Rather, the invention is limited only by the accompanying claims and other embodiments than the specific above are equally possible within the scope of these appended claims.

[0351] In the claims, the term “comprises/comprising” does not exclude the presence of other species or steps. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms “a”, “an”, “first”, “second” etc. do not preclude a plurality. The phrases “at least one” or “one or more” refer to 1 or a number greater than 1, such as to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

EXPERIMENTAL

[0352] The following examples are mere examples and should by no mean be interpreted to limit the scope of the invention. Rather, the invention is limited only by the accompanying claims.

[0353] General Chemical Procedures

[0354] Unless otherwise stated, starting materials were obtained from commercial suppliers, such as (but not limited to); ABchem, ABCR, Alfa Aesar, Anaspec, Anichem, Apollo Scientific, ASDI-Inter, Asiba Pharmatech, Astatech, Bachem, Chem-Impex, ChemCollect, Chembridge, Combi-Blocks, Enamine, Fluka, Fluorochem, Frontier Scientific, HDH Pharma, InFarmatik, InterBioScreen, Life Chemicals, Manchester organics, Matrix, MercaChem, NetChem, Oakwood Chemical, PepTech, Pharmcore, PrincetonBio, Sigma-Aldrich, TRC, Tyger Scientific and Ukrorgsyn. N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and dichloromethane (DCM) were dried over molecular sieves. Analytical HPLC was performed on a Waters Acquity system using a C18 reverse phase column (Merck Chromolith Speedrod RP-18E) with a linear gradient of the binary solvent system water/acetonitrile/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 3.0 mL/min and UV detection at 254 nm at room temperature, combined with MS detection on a Waters Micromass QZ Quadrupole Mass Spectrometer instrument using electron spray ionization, or on a Shimadzu Nexera X2 system using a C18 reverse phase column (Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm), with a linear gradient of the binary solvent system water/methanol/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 0.78 mL/min and UV detection at 254 nm, combined with MS detecting on a Shimadzu LCMS-2020 Spectrometer instrument using electron spray ionization. Preparative HPLC was performed on a Waters Acquity system using a C18 reverse phase column (Supelco ASCENTIS C18 581358-U, 15 cm×21.2 mm), with a linear gradient of the binary solvent system water/acetonitrile/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 15 mL/min and UV detection at 254 nm, combined with MS detection on a Waters Micromass QZ Quadrupole Mass Spectrometer instrument using electron spray ionization. Chiral resolution was performed on a Lux Cellulose2 (250×21 mm) column using a mobile phase of 0.2% diethyamine in hexane/ethanol, with a flow of 20 mL/min and UV detection at 290 nm. .sup.1H NMR spectra were recorded on a Bruker Avance 300 spectrometer (at 300 MHz), using CD.sub.3OD, CDCl.sub.3, DMSO-d.sub.6 or C.sub.6D.sub.6 solvents. Chemical shifts are reported in ppm (δ) using residual solvent as an internal standard; CDCl.sub.3: 7.26 ppm; CD.sub.3OD: 3.31; DMSO-d6: 2.50 ppm. Coupling constants (J) are given in Hz.

[0355] Synthetic Methods

[0356] The compounds disclosed herein may be made by one of the following four general methods. Further, additional guidance for preparing building blocks to be used in providing compounds disclosed herein is present in the co-pending international application PCT/EP2015/067692 also claiming priority from SE 1450920-2 and SE 1451406-1.

##STR00292##

[0357] A fluorenylmethyloxycarbonyl (Fmoc) protected amino acid was coupled to a Rink resin to produce 1a using the coupling reagents 1-hydroxy-7-azabenzotriazol (HOAt) and N,N′-diisopropylcarbodiimide (DIC) in the presence of a suitable base, e.g. ethyldiisopropylamine (DIPEA), in DCM/DMF (e.g. in a 1:1 ratio). The mixture was agitated at a suitable temperature until complete conversion of the starting materials was observed, typically overnight at room temperature (i.e. 20-25° C.). The Fmoc group was removed from 1a by treatment with a base, e.g. 20% piperidine in DMF for 30 minutes at room temperature, to yield 1b. An aromatic fluorinated building block, e.g. 4,5,6-trifluoro-pyrimidine, was coupled to a compound containing a free amino group in a nucleophilic aromatic substitution reaction to produce 1c. The reaction may for example be done by addition of DIPEA in dimethyl sulfoxide (DMSO) followed by agitation overnight at room temperature. An aromatic nucleophilic substitution reaction was subsequently performed by addition of a compound containing a free amine to 1c, in the presence of a suitable base, to yield 1d. An example the addition of 4-methyl-2-[4-(trifluoromethyl)phenyl]pyrrolidine and DIPEA in DMSO, followed by agitation overnight at elevated temperature, e.g. 80-100° C. The desired compound 1e was obtained by cleavage from the resin upon treatment of 1d with an acid, e.g. 2,2,2-trifluoroethanoic acid (TFA) as an 80% solution in DCM upon stirring for 1 hour at room temperature. The obtained mixture was concentrated in vacuo and purification by e.g. flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc on silica gel.

Use of General Method 1 to Prepare Example No. 37:

[0358] ##STR00293##

[0359] A rink amide resin (0.88 g, 0.68 mmol/g, 0.6 mmol) was swelled in dry DMF (8 mL) for 15 minutes. The resin was drained and treated twice with 20% piperidine in DMF (2×8 mL) for 30 minutes each. The resin was drained and washed with DMF (3×8 mL), methanol (2×8 mL), DMF (2×8 mL) and DCM (3×8 mL). The resin was swelled in dry DCM (8 mL) for 15 minutes and drained. A solution of (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-fluorophenyl)propanoic acid (0.49 g, 1.2 mol) and 1-hydroxy-7-azabenzotriazol (0.16 mg, 1.2 mmol) dissolved in DMF/DCM (1:1, 8 mL) was added, followed by DIPEA (0.31 mL, 3.6 mmol) and DIC (0.19 mL, 1.2 mmol). The reaction was agitated at room temperature overnight, drained and washed with DMF (3×8 mL), MeOH (2×8 mL), DMF (2×8 mL) and DCM (3×8 mL). The resin was swelled in dry DCM (8 mL) for 15 minutes and drained. A solution of acetic anhydride (0.57 mL, 6 mmol) and pyridine (0.97 mL, 12 mmol) dissolved in DCM (8 mL) was added and the mixture was agitated at room temperature for 1 hour. The resin was drained and washed with DCM (3×8 mL), DMF (3×8 mL) and DCM (3×8 mL). The resin was swelled in dry DMSO (8 mL) for 15 minutes and drained. A solution of 4,5,6-trifluoro-pyrimidine (0.16 g, 1.2 mmol) in dry DMSO (6 mL) was added, followed by DIPEA (0.26 mL, 3.0 mmol). The mixture was agitated overnight at room temperature, drained and washed with DCM (3×8 mL), DMF (3×8 mL) and DCM (3×8 mL). The resin was swelled in dry DMSO (8 mL) for 15 minutes and drained. A solution of 4-methyl-2-[4-(trifluoromethyl)phenyl]pyrrolidine (0.28, 1.2 mmol) in dry DMSO (6 mL) was added, followed by DIPEA (0.26 mL, 3.0 mmol). The mixture was agitated overnight at 80° C., drained and washed with DCM (3×8 mL), DMF (3×8 mL) and DCM (3×8 mL). The resin was swelled in dry DCM (8 mL) for 15 minutes and drained. A solution of 80% TFA in dry DCM (8 mL) was added and the mixture was agitated for 1 hour. The filtrate was collected and the treatment repeated once. The resin was washed with acetonitrile (ACN, 8 mL) and the filtrated collected. The pooled filtrates were concentrated in vacuo and purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding (2R)-2-[[5-fluoro-6-[4-methyl-2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]amino]-3-(4-fluorophenyl)propanamide 37 (37 mg, 12% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.70-7.55 (m, 2H), 7.50-7.45 (s, 1H), 7.43-7.36 (m, 2H), 7.33-7.23 (m, 2H), 7.10-7.00 (m, 2H), 5.22-5.18 (m, 1H), 4.67-4.55 (m, 1H), 4.02-3.92 (m, 1H), 3.43-3.38 (m, 1H), 3.05-2.96 (m, 1H), 2.57-2.52 (m, 1H), 2.31-2.28 (m, 1H), 1.35-1.29 (m, 1H), 1.02 (d, J=6.1 Hz, 3H). m/z 506 (M+H).

[0360] General method 1 was used to prepare the following example numbers using the shown starting materials:

TABLE-US-00002 Ex. Aromatic fluorinated No. Fmoc protected amino acid building block Free amine 5 [00294]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00295]   4,5,6- trifluoropyrimidine [00296]   2-[4-(trifluorometh- yl)phenyl]pyrrolidine 6 [00297]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00298]   4,6-difluoropyrimidine [00299]   2-[4-(trifluorometh- yl)phenyl]pyrrolidine 9 [00300]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(2,4,5- trifluorophenyl)propanoic acid [00301]   4,5,6- trifluoropyrimidine [00302]   2-pyrrolidin-2-yl- 1,3-benzothiazole 11 [00303]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00304]   4,5,6- trifluoropyrimidine [00305]   2-(2,4- dichlorophenyl)pyr- rolidine 13 [00306]   9H-fluoren-9-ylmethyl N- [(1R)-1-carbamoyl-3,3- dimethyl-butyl]carbamate [00307]   4,5,6-trifluoro-2- (trifluoromethyl) pyrimidine [00308]   2-[4- (trifluoromethyl)phenyl]pyr- rolidine 14 [00309]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00310]   4,6-difluoro-5- methyl-pyrimidine [00311]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 15 [00312]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00313]   4,6-difluoro-2,5- dimethyl-pyrimidine [00314]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 17 [00315]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(4- methoxyphenyl)propanoic acid [00316]   4,5,6- trifluoropyrimidine [00317]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 18 [00318]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00319]   4,5,6- trifluoropyrimidine [00320]   4-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine 19 [00321]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00322]   4,5,6- trifluoropyrimidine [00323]   2-(4-tert- butylphen- yl)pyrrolidine 20 [00324]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00325]   4,5,6- trifluoropyrimidine [00326]   3-[4- (trifluorometh- yl)phenyl]morp- holine 23 [00327]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00328]   4,5,6- trifluoropyrimidine [00329]   6-pyrrolidin-2-ylquinoline 24 [00330]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00331]   4,5,6- trifluoropyrimidine [00332]   2-(2,3-dihydro-1,4- benzodioxin-6- yl)pyrrolidine 34 [00333]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4-methyl-pentanoic acid [00334]   4,5,6- trifluoropyrimidine [00335]   4-methyl-2-[4- (trifluorometh- yl)phenyl]pyr- rolidine 35 [00336]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00337]   4,5,6- trifluoropyrimidine [00338]   2-[2-chloro-4- (trifluorometh- yl)phenyl]pyrrolidine 37 [00339]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)-3-(4- fluorophenyl)propanoic acid [00340]   4,5,6- trifluoropyrimidine [00341]   4-methyl-2-[4- (trifluorometh- yl)phenyl]pyr- rolidine 38 [00342]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00343]   4,5,6- trifluoropyrimidine [00344]   3-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine 39 [00345]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00346]   2,3,4- trifluoropyridine [00347]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 42 [00348]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00349]   4,5,6- trifluoropyrimidine [00350]   2-pyrrolidin-2-yl-5- (trifluoromethyl)pyridine 43 [00351]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00352]   4,5,6- trifluoropyrimidine [00353]   2-pyrrolidin-2-yl-5- (trifluoromethyl)pyridine 51 [00354]   (2R)-3-tert-butoxy-2-(9H- fluoren-9-ylmethoxycarbonyl- amino)butanoic acid [00355]   4,5,6- trifluoropyrimidine [00356]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 52 [00357]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 3-tetrahydropyran-4-yl- propanoic acid [00358]   4,5,6- trifluoropyrimidine [00359]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 62 [00360]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00361]   4,5,6- trifluoropyrimidine [00362]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 63 [00363]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 3-(2-oxopyrrolidin-3- yl)propanoic acid [00364]   4,5,6- trifluoropyrimidine [00365]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine 65 [00366]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00367]   4,5,6- trifluoropyrimidine [00368]   2-[2-methoxy-4- (trifluoromethyl)phenyl]pyrrolidine 68 [00369]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00370]   4,5,6- trifluoropyrimidine [00371]   3-[4- (trifluoromethoxy)phenyl]morpholine 72 [00372]   (2R)-2-(9H-fluoren-9- ylmethoxycarbonylamino)- 4,4-dimethyl-pentanoic acid [00373]   4,5,6- trifluoropyrimidine [00374]   2-[3-fluoro-4- (trifluoromethyl)phenyl]pyrrolidine 77 [00375]   (2R)-2-hydroxy-4- methyl-pentanoic acid [00376]   4,5,6- trifluoropyrimidine [00377]   2-[4- (trifluoromethyl)phenyl]pyrrolidine 78 [00378]   (2R)-2-hydroxy-4- methyl-pentanoic acid [00379]   4,5,6- trifluoropyrimidine [00380]   2-[4- (trifluoromethyl)phenyl]pyrrolidine

##STR00381##

[0361] A halogenated pyrrolopyrimidine 2b, e.g. 6-chloro-7-deazapurine, was N-alkylated by addition of an alkyl halide 2a, e.g. 4-(bromomethyl)-1,2-dimethoxy-benzene, and an appropriate base in a suitable solvent, e.g. cesium carbonate in dry dioxane or sodium hydride in dry tetrahydrofuran. The mixture was stirred at room temperature until completion of reaction, typically overnight. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Nucleophilic aromatic substitution of the halogen on intermediate 2c was achieved upon addition of a building block containing a free amino group, e.g. 2-(4-trifluoromethyl-phenyl)-pyrrolidine, and a suitable base in an appropriate solvent, e.g. cesium carbonate in dry DMSO. The reaction was achieved by microwave irradiation at elevated temperatures for a period of time, e.g. at 100-150° C. for 1 hour. The reaction may for example be monitored by thin layer chromatography. The desired compound 2d was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.

[0362] Use of General Method 2 to Prepare Example No. 69:

##STR00382##

[0363] 6-Chloro-7-deazapurine (77 mg, 0.5 mmol) and 4-(bromomethyl)-1,2-dimethoxy-benzene (127 mg, 0.55 mmol) were dissolved in dry dioxane (5 mL) and cesium carbonate (325 mg, 1.0 mmol) was added. The mixture was stirred overnight at room temperature, concentrated in vacuo, redissolved in water, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding 4-chloro-7-(3,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg, 43% yield).

[0364] 4-Chloro-7-(3,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (63 mg, 0.21 mmol) and 2-(4-trifluoromethyl-phenyl)-pyrrolidine (45 mg, 0.21 mmol) were dissolved in dry DMSO (4 mL). Cesium carbonate (137 mg, 0.42 mmol) was added, and the mixture was heated at 150° C. for 30 minutes in a microwave reactor. The mixture was poured onto 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC yielding 7-[(3,4-dimethoxyphenyl)methyl]-4-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrrolo[2,3-d]pyrimidine 69 (9 mg, 9% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.07 (s, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.22 (s, 1H), 6.97 (s, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 5.62 (s, 1H), 5.22 (s, 2H), 4.30-3.81 (m, 3H), 3.68 (s, 6H), 2.22-1.71 (m, 4H). m/z 483 (M+H).

[0365] General method 2 was used to prepare the following example numbers using the shown starting materials:

TABLE-US-00003 Ex. Halogenated No. pyrrolopyrimidine Alkyl halide Free amine 4 [00383]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00384]   3-[(2-bromobutanoyl- amino)methyl]furan-2- carboxylic acid [00385]   2-(4-phenylphenyl)pyrrolidine 67 [00386]   4-chloro-1H- pyrrolo[2,3- d]pyrimidine [00387]   4-(bromomethyl)- 1,2-dimethoxy- benzene [00388]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine 69 [00389]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00390]   4-(bromomethyl)- 1,2-dimethoxy- benzene [00391]   2-[4- (trifluoromethyl)phenyl]pyrrolidine 85 [00392]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00393]   2-[4-(bromometh- yl)phenyl]acetic acid [00394]   2-[4- (trifluoromethyl)phenyl]pyr- rolidine 195 [00395]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00396]   2-[4-(bromometh- yl)phenyl]acetic acid [00397]   (2R)-2-[4- (trifluoromethyl)phenyl]pyr- rolidine 196 [00398]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00399]   2-[4-(chloromethyl)phen- yl]acetamide [00400]   (2R)-2-[4- (trifluoromethyl)phenyl]pyr- rolidine 252 [00401]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00402]   2-[4-(chloromethyl)phen- yl]acetamide [00403]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine 265 [00404]   4-chloro-6,7- dihydro-5H- pyrrolo[2,3- d]pyrimidine [00405]   2-[4-(chloromethyl)phen- yl]acetamide [00406]   (2R)-2-[4- (trifluoromethyl)phenyl]pyr- rolidine 284 [00407]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00408]   2-[4-(chloromethyl)phen- yl]acetamide [00409]   3-phenylmorpholine 290 [00410]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00411]   4-(bromomethyl)-1- methylsulfonyl- piperidine [00412]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine 326 [00413]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00414]   2-[4-(chloromethyl)phen- yl]acetamide [00415]   (3S)-3-[6-(trifluoromethyl)-3- pyridyl]morpholine 328 [00416]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00417]   2-[4-(chloromethyl)phen- yl]acetamide [00418]   (3S)-3-[5-(trifluoromethyl)-2- pyridyl]morpholine 329 [00419]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00420]   5-(chloromethyl)-2- methylsulfonyl- pyridine [00421]   (3S)-3-[4-(trifluoromethoxy)phen- yl]morpholine 330 [00422]   4-chloro-7H- pyrrolo[2,3- d]pyrimidine [00423]   2-(chloromethyl)-5- methylsulfonyl- pyridine [00424]   (3S)-3-[4-(trifluoromethoxy)phen- yl]morpholine

[0366] Synthesis of Selected Alkyl Halide

2-[4-(Chloromethyl)phenyl]acetamide

[0367] To a solution of 2-(4-(hydroxymethyl) phenyl) acetic acid (20 g, 120.48 mmol) in MeOH:toluene (1:1) (200 mL) at 0° C. was added trimethylsilyldiazomethane (TMSCHN.sub.2, 27.51 g, 240 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, the solvent was evaporated and the crude compound was purified by flash CC (Eluent: EtOAc/pet ether, on silica gel) to afford methyl 2-(4-(hydroxymethyl) phenyl) acetate (Compound-2) (18 g, 83%) as an off white solid.

[0368] To a solution of methyl 2-(4-(hydroxymethyl) phenyl) acetate (3.4 g, 1.87 mmol) in MeOH (10 vol) was added aqueous NH.sub.3 (34 ml), and the mixture was heated at 90° C. for 16 hours in a sealed tube. After completion, the reaction mixture was allowed to room temperature, filtered and concentrated in vacuo to afford 2-(4-(hydroxymethyl) phenyl) acetamide (1.1 g, 35%) as an off white solid.

[0369] To a solution of 2-(4-(hydroxymethyl) phenyl) acetamide (2 g, 12.12 mmol), Et.sub.3N (5.1 mL, 36.36 mmol) in DMF (20 mL) was added methane sulfonyl chloride (1.5 mL, 18.18 mmol), and the mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was poured into ice water and filtered the solid to afford 2-(4-(chloromethyl) phenyl) acetamide (1.2 g, 54%) as an off white solid.

##STR00425##

[0370] A compound containing a free amino or hydroxyl group 3a, e.g. 1-tetrahydropyran-4-ylpropan-2-amine, was coupled to a fluorinated aromatic compound 3b, e.g. 4,5,6-trifluoro-pyrimidine, upon treatment with a suitable base in an appropriate solvent, e.g. DIPEA or cesium carbonate in dry DMSO or dioxane. Conversion to 3c was typically achieved after stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Subsequent nucleophilic aromatic substitution of 3c with a building block containing a free amino or hydroxyl group can be achieved upon treatment with a suitable base in an appropriate solvent. An example of such treatment is cesium carbonate in dry DMSO, heated under microwave irradiation during a period of time, e.g. at 80-150° C. for 1 hour. The reaction may for example be monitored by thin layer chromatography. The desired compound 3d was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.

[0371] Use of General Method 3 to Prepare Example No. 41:

##STR00426##

[0372] 4,5,6-Trifluoro-pyrimidine (0.27 g, 2.0 mmol) and 2-(4-trifluoromethyl-phenyl)-pyrrolidine (0.43 g, 2.0 mmol) were dissolved in dry DMSO (4 mL) and DIPEA (0.7 mL, 4.0 mmol) was added. The reaction was stirred at room temperature overnight, poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding 4,5-difluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidine (0.58 g, 88% yield).

[0373] 4,5-difluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidine (0.33 g, 1.0 mmol) and 1-tetrahydropyran-4-ylpropan-2-amine hydrochloride (0.18 g, 1.0 mmol) were dissolved in dry DMSO (2 mL) and cesium carbonate (0.65 g, 2.0 mmol) was added. The reaction was heated in a microwave reactor for 1 hour at 100° C., poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel), yielding 5-fluoro-N-(1-methyl-2-tetrahydropyran-4-yl-ethyl)-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-amine 41 (205 mg, 45% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.90 (s, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.40 (d, J=7.8 Hz, 1H), 4.28-4.24 (m, 2H), 4.05-4.00 (m, 1H), 4.00-3.91 (m, 2H), 3.86-3.79 (m, 1H), 3.39-3.25 (m, 2H), 2.39-2.25 (m, 1H), 1.99-1.83 (m, 3H), 1.76-1.64 (m, 2H), 1.41-1.18 (m, 7H). m/z 453 (M+H).

[0374] General method 3 was used to prepare the following example numbers using the shown starting materials:

TABLE-US-00004 Ex. Fluorinated No. Free amine or alcohol (1) Free amine or alcohol (2) aromatic compound 16 [00427]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00428]   4-methoxy-4-methyl- pentan-2-amine [00429]   4,5,6- trifluoropyrimidine 21 [00430]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00431]   3,3-dimethylbutan-1- amine [00432]   4,5,6- trifluoropyrimidine 29 [00433]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00434]   (2R)-2-amino- 3-(4- methoxyphen- yl)propan-1-ol [00435]   4,5,6- trifluoropyrimidine 30 [00436]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00437]   (2R)-2-amino-4,4- dimethyl-pentan-1-ol [00438]   4,5,6- trifluoropyrimidine 31 [00439]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00440]   (2R)-N,4,4-trimethyl-2- (methylamino)pentan- amide [00441]   4,5,6- trifluoropyrimidine 33 [00442]   4-methyl-2-[4- (trifluorometh- yl)phenyl]pyr- rolidine [00443]   (2R)-2-amino-4- methyl-pentanoic acid [00444]   4,5,6- trifluoropyrimidine 36 [00445]   2-[2-chloro-4- (trifluoromethyl)phen- yl]pyrrolidine [00446]   (2R)-2-amino-4,4- dimethyl-pentanoic acid [00447]   4,5,6- trifluoropyrimidine 41 [00448]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00449]   1-tetrahydropyran-4-ylpropan- 2-amine [00450]   4,5,6- trifluoropyrimidine 44 [00451]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00452]   4-(aminomethyl)benzoic acid [00453]   4,5,6- trifluoropyrimidine 45 [00454]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00455]   3-[[4- (aminomethyl)phenyl]methyl]-5,5- dimethyl-imidazolidine-2,4-dione [00456]   4,5,6- trifluoropyrimidine 46 [00457]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00458]   [4-(aminomethyl)phenyl]methanesulfon- amide [00459]   4,5,6- trifluoropyrimidine 48 [00460]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00461]   [4-(trifluoromethyl)phenyl]methan- amine [00462]   4,5,6- trifluoropyrimidine 53 [00463]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00464]   (3,4- dimethoxyphenyl)methan- amine [00465]   4,5,6- trifluoropyrimidine 54 [00466]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00467]   (2,3- dimethoxyphenyl)methan- amine [00468]   4,5,6- trifluoropyrimidine 55 [00469]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00470]   1-(3,4-dihydro-2H-1,5- benzodioxepin-7-yl)propan-1- amine [00471]   4,5,6- trifluoropyrimidine 56 [00472]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00473]   (4-morpholinophenyl)methanamine [00474]   4,5,6- trifluoropyrimidine 57 [00475]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00476]   [4-(aminomethyl)phenyl]-morpholino- methanone [00477]   4,5,6- trifluoropyrimidine 58 [00478]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00479]   [1-[5- (aminomethyl)-2- pyridyl]-4- piperidyl]methanol [00480]   4,5,6- trifluoropyrimidine 59 [00481]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00482]   [4-(tetrahydrofuran-2-ylmethoxy)phen- yl]methanamine [00483]   4,5,6- trifluoropyrimidine 60 [00484]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00485]   4-[4-(aminomethyl)phenyl]piperazin- 2-one [00486]   4,5,6- trifluoropyrimidine 61 [00487]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00488]   1-[4- (aminomethyl)phenyl]piperidine-3-carboxamide [00489]   4,5,6- trifluoropyrimidine 64 [00490]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00491]   (1R)-3,3-dimethyl-1- morpholin-2-yl-butan-1-amine [00492]   4,5,6- trifluoropyrimidine 66 [00493]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00494]   (6-methyl-3- pyridyl)methanamine [00495]   2,3,4- trifluoropyridine 70 [00496]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00497]   methyl 2-[4- (aminomethyl)phen- yl]acetate [00498]   4,5,6- trifluoropyrimidine 71 [00499]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00500]   1-[2-[(1R)-1-amino-3,3- dimethyl-butyl]morpholin- 4-yl]ethanone [00501]   4,5,6- trifluoropyrimidine 73 [00502]   2-[3-fluoro-4- (trifluoromethyl)phen- yl]pyrrolidine [00503]   (6-methyl-3- pyridyl)methanol [00504]   4,5,6- trifluoropyrimidine 74 [00505]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00506]   (6-methyl-3- pyridyl)methanol [00507]   4,5,6- trifluoropyrimidine 80 [00508]   5-[4- (trifluoromethyl)phenyl]-1H-pyrazole [00509]   (2R)-2-hydroxy-4- methyl-pentanamide [00510]   4,5,6- trifluoropyrimidine 88 [00511]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00512]   4-(aminometh- yl)benzonitrile [00513]   4,5,6- trifluoropyrimidine 89 [00514]   2-[4-(trifluorometh- yl)phenyl]pyrrolidine [00515]   (6-methyl-3- pyridyl)methan- amine [00516]   4,5,6- trifluoropyrimidine 90 [00517]   2-(4- methoxyphenyl)pyr- rolidine [00518]   (6-methyl-3- pyridyl)methan- amine [00519]   4,5,6- trifluoropyrimidine 93 [00520]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00521]   (4-methylcyclo- hexyl)methan- amine [00522]   4,5,6- trifluoropyrimidine 94 [00523]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00524]   [4-(imidazol-1- ylmethyl)phenyl]methan- amine [00525]   4,5,6- trifluoropyrimidine 95 [00526]   2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00527]   [4- (methylsulfonylmeth- yl)phenyl]methan- amine [00528]   4,5,6- trifluoropyrimidine 96 [00529]   5-[4- (trifluoromethyl)phen- yl]-1H-triazole [00530]   (6-methyl-3- pyridyl)methan- amine [00531]   4,5,6- trifluoropyrimidine 97 [00532]   2-[4- (trifluoromethoxy)phen- yl]pyrrolidine [00533]   (6-methyl-3- pyridyl)methan- amine [00534]   4,5,6- trifluoropyrimidine 98 [00535]   2-[4- (trifluoromethyl)phenyl] pyrrolidine [00536]   1-[4- (aminomethyl)phenyl]-2- methyl-propan-2-ol [00537]   4,5,6- trifluoropyrimidine 99 [00538]   2-[4- (trifluoromethyl)phenyl] pyrrolidine [00539]   (2-methoxy-6-methyl-3- pyridyl)methanamine [00540]   4,5,6- trifluoropyrimidine 100 [00541]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00542]   5-(aminomethyl)pyridin-2-ol [00543]   4,5,6- trifluoropyrimidine 104 [00544]   2-pyrrolidin-2-yl-5- (trifluoromethyl)phenol [00545]   (6-methyl-3- pyridyl)methan- amine [00546]   4,5,6- trifluoropyrimidine 105 [00547]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00548]   (1-methylpyrrol-3- yl)methanamine [00549]   4,5,6- trifluoropyrimidine 106 [00550]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00551]   (1-methylpyrazol-4- yl)methanamine [00552]   4,5,6- trifluoropyrimidine 107 [00553]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00554]   (5-methyl-2-furyl)methan- amine [00555]   4,5,6- trifluoropyrimidine 108 [00556]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00557]   5-(aminomethyl)pyrrolidin- 2-one [00558]   4,5,6- trifluoropyrimidine 109 [00559]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00560]   4-(aminomethyl)-1-methyl- pyrrolidin-2-one [00561]   4,5,6- trifluoropyrimidine 110 [00562]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00563]   5-(aminomethyl)-N,N-dimethyl- tetrahydrofuran-2-carboxamide [00564]   4,5,6- trifluoropyrimidine 111 [00565]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00566]   (4- methoxytetrahydropyran- 4-yl)methanamine [00567]   4,5,6- trifluoropyrimidine 112 [00568]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00569]   1-[6-(aminomethyl)-2-methyl-3- pyridyl]ethanol [00570]   4,5,6- trifluoropyrimidine 113 [00571]   2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00572]   (2-methoxy-4- pyridyl)methanamine [00573]   4,5,6- trifluoropyrimidine 114 [00574]   2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00575]   (6-methoxy-3- pyridyl)methanamine [00576]   4,5,6- trifluoropyrimidine 115 [00577]   2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00578]   [4-(1,2,4-triazol-1- ylmethyl)phenyl]methan- amine [00579]   4,5,6- trifluoropyrimidine 116 [00580]   2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00581]   1-(6-methoxy- 3-pyridyl)-N- methyl- methanamine [00582]   4,5,6- trifluoropyrimidine 120 [00583]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00584]   4-(2-aminoethyl)benzoic acid [00585]   4,5,6- trifluoropyrimidine 121 [00586]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00587]   (3-aminopyrrolidin-1-yl)-(4- pyridyl)methanone [00588]   4,5,6- trifluoropyrimidine 122 [00589]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00590]   5-(aminomethyl)indolin-2-one [00591]   4,5,6- trifluoropyrimidine 123 [00592]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00593]   3-methyl-1-(1H-tetrazol- 5-yl)butan-1-amine [00594]   4,5,6- trifluoropyrimidine 124 [00595]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00596]   1-[[4- (aminomethyl)phenyl]methyl]pyrrolidin- 2-one [00597]   4,5,6- trifluoropyrimidine 126 [00598]   2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00599]   [6-(trifluoromethyl)-3- pyridyl]methanamine [00600]   4,5,6- trifluoropyrimidine 128 [00601]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00602]   2-[4-(aminomethyl)phenyl]ethanol [00603]   4,5,6- trifluoropyrimidine 129 [00604]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00605]   4- (aminomethyl)tetrahy- dropyran-4-ol [00606]   4,5,6- trifluoropyrimidine 130 [00607]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00608]   4-(aminomethyl)-1-cyclopentyl- pyrrolidin-2-one [00609]   4,5,6- trifluoropyrimidine 131 [00610]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00611]   (4-methoxy-2- pyridyl)methanamine [00612]   4,5,6- trifluoropyrimidine 132 [00613]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00614]   (6-methyl-2- pyridyl)methanamine [00615]   4,5,6- trifluoropyrimidine 134 [00616]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00617]   3,9- diazaspiro[4.5]decan- 2-one [00618]   4,5,6- trifluoropyrimidine 135 [00619]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00620]   1-methyl-4- (methylaminomethyl)pyr- rolidin-2-one [00621]   4,5,6- trifluoropyrimidine 136 [00622]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00623]   1-(5-ethyl-2-pyridyl)-N-methyl- methanamine [00624]   4,5,6- trifluoropyrimidine 137 [00625]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00626]   1-[4- (aminomethyl)phenyl]pyrrolidin-2-one [00627]   4,5,6- trifluoropyrimidine 138 [00628]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00629]   [4-(1H-tetrazol-5-yl)phenyl]methanamine [00630]   4,5,6- trifluoropyrimidine 139 [00631]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00632]   phenylmethanamine [00633]   4,5,6- trifluoropyrimidine 140 [00634]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00635]   4-pyridylmethanamine [00636]   4,5,6- trifluoropyrimidine 141 [00637]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00638]   3-pyridylmethanamine [00639]   4,5,6- trifluoropyrimidine 142 [00640]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00641]   (3,5-dimethoxyphen- yl)methanamine [00642]   4,5,6- trifluoropyrimidine 143 [00643]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00644]   1-[3-(aminomethyl)phenyl]pyrrolidin- 2-one [00645]   4,5,6- trifluoropyrimidine 144 [00646]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00647]   3-(aminomethyl)-N-methyl- benzamide [00648]   4,5,6- trifluoropyrimidine 145 [00649]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00650]   3-(aminomethyl)-N,N-dimethyl- benzamide [00651]   4,5,6- trifluoropyrimidine 146 [00652]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00653]   [3-(1,2,4-triazol-1-ylmethyl)phen- yl]methanamine [00654]   4,5,6- trifluoropyrimidine 147 [00655]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00656]   [3-(methoxymethyl)phenyl]methan- amine [00657]   4,5,6- trifluoropyrimidine 148 [00658]   2-[4-(trifluorometh- yl)phenyl]pyrrolidine [00659]   2-[4-(aminometh- yl)cyclohexyl]acetic acid [00660]   4,5,6- trifluoropyrimidine 150 [00661]   (6-methyl-3-pyridyl)methanamine [00662]   2-(5-methyl-2- furyl)pyrrolidine [00663]   4,5,6- trifluoropyrimidine 151 [00664]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00665]   cyclobutyl- methanamine [00666]   4,5,6- trifluoropyrimidine 152 [00667]   2-[4- (trifluoromethyl)phenyl]pyrrolidine [00668]   (1-methylcyclo- butyl)methanamine [00669]   4,5,6- trifluoropyrimidine 154 [00670]   (2R)-2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00671]   tetrahydrofuran-3- ylmethanamine [00672]   4,5,6- trifluoropyrimidine 155 [00673]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00674]   tetrahydropyran-2- ylmethanamine [00675]   4,5,6- trifluoropyrimidine 159 [00676]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00677]   tetrahydrothiophen-2- ylmethanamine [00678]   4,5,6- trifluoropyrimidine 161 [00679]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00680]   (4- methyltetrahydropyran- 4-yl)methanamine [00681]   4,5,6- trifluoropyrimidine 164 [00682]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00683]   tetrahydrothiopyran-4- ylmethanamine [00684]   4,5,6- trifluoropyrimidine 165 [00685]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00686]   3-(aminomethyl)tetra- hydrothiophen-3-ol [00687]   4,5,6- trifluoropyrimidine 166 [00688]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00689]   (4,4- dimethylcyclohexyl)methan- amine [00690]   4,5,6- trifluoropyrimidine 167 [00691]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00692]   1-(aminomethyl)cyclo- heptanol [00693]   4,5,6- trifluoropyrimidine 168 [00694]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00695]   (2-methoxycyclohex- yl)methanamine [00696]   4,5,6- trifluoropyrimidine 169 [00697]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00698]   4-(aminomethyl)tetra- hydrothiopyran-4-ol [00699]   4,5,6- trifluoropyrimidine 170 [00700]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00701]   (1,1-dioxothiolan-2- yl)methanamine [00702]   4,5,6- trifluoropyrimidine 175 [00703]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00704]   (2-tert- butyltetrahydropyran-3- yl)methanamine [00705]   4,5,6- trifluoropyrimidine 178 [00706]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00707]   (4- isopropylcyclohexyl)methanamine [00708]   4,5,6- trifluoropyrimidine 181 [00709]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00710]   tetrahydrofuran-2- ylmethanamine [00711]   4,5,6- trifluoropyrimidine 182 [00712]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00713]   4-(aminomethyl)benzenesulfonamide [00714]   4,5,6- trifluoropyrimidine 183 [00715]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00716]   (6-chloro-3-pyridyl)methanamine [00717]   4,5,6- trifluoropyrimidine 184 [00718]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00719]   (1,1-dioxothiolan-3- yl)methanamine [00720]   4,5,6- trifluoropyrimidine 185 [00721]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00722]   3-thienylmethanamine [00723]   4,5,6- trifluoropyrimidine 186 [00724]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00725]   tetrahydropyran-3- ylmethanamine [00726]   4,5,6- trifluoropyrimidine 188 [00727]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00728]   [1-(methoxymeth- yl)cyclobutyl]methan- amine [00729]   4,5,6- trifluoropyrimidine 189 [00730]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00731]   2-[4-(aminomethyl)phenyl]- N-methyl-acetamide [00732]   4,5,6- trifluoropyrimidine 190 [00733]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00734]   [4-(1H-tetrazol-5- ylmethyl)cyclohex- yl]methanamine [00735]   4,5,6- trifluoropyrimidine 191 [00736]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyrrolidine [00737]   1-[4- (aminomethyl)- 1-piperidyl]ethanone [00738]   4,5,6- trifluoropyrimidine 193 [00739]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00740]   (1-oxidopyridin-1-ium-3- yl)methanamine [00741]   4,5,6- trifluoropyrimidine 194 [00742]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00743]   (1-oxidopyridin-1-ium- 4-yl)methanamine [00744]   4,5,6- trifluoropyrimidine 197 [00745]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00746]   (1-methylsulfonyl-4- piperidyl)methanamine [00747]   4,5,6- trifluoropyrimidine 198 [00748]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00749]   (3-methyloxetan- 3-yl)methanamine [00750]   4,5,6- trifluoropyrimidine 199 [00751]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00752]   (2- methyltetra- hydrofuran-2- yl)methanamine [00753]   4,5,6- trifluoropyrimidine 200 [00754]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00755]   2-(aminomethyl)cyclo- hexanol [00756]   4,5,6- trifluoropyrimidine 201 [00757]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00758]   (2- methyltetrahy- drothiophen-2- yl)methanamine [00759]   4,5,6- trifluoropyrimidine 202 [00760]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00761]   (4,4-dioxo-1,4- oxathian-2- yl)methanamine [00762]   4,5,6- trifluoropyrimidine 203 [00763]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00764]   2-thienyl- methanamine [00765]   4,5,6- trifluoropyrimidine 208 [00766]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00767]   tetrahydropyran- 4-ylmethanamine [00768]   4,5,6- trifluoropyrimidine 209 [00769]   2-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00770]   (6-methyl-3- pyridyl)methan- amine [00771]   4,5,6- trifluoropyrimidine 210 [00772]   (2R)-2-[2-fluoro-4- (trifluoromethyl)phen- yl]pyrrolidine [00773]   (6-methyl-3- pyridyl)methanamine [00774]   4,5,6- trifluoropyrimidine 211 [00775]   4-methyl-2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00776]   (6-methyl-3- pyridyl)methanamine [00777]   4,5,6- trifluoropyrimidine 212 [00778]   4-methoxy-2-[4- (trifluoromethyl)phen- yl]pyrrolidine [00779]   (6-methyl-3- pyridyl)methanamine [00780]   4,5,6- trifluoropyrimidine 213 [00781]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00782]   (5-methyloxazol-2- yl)methanamine [00783]   4,5,6- trifluoropyrimidine 214 [00784]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00785]   5-(aminomethyl)-1,3,4- oxadiazol-2-ol [00786]   4,5,6- trifluoropyrimidine 215 [00787]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00788]   1-(5-methyl-1,2,4-oxadiazol- 3-yl)propan-1-amine [00789]   4,5,6- trifluoropyrimidine 216 [00790]   2-[4-(trifluoromethyl)phenyl]pyr- rolidine [00791]   5- (aminomethyl)isoxazol-3-ol [00792]   4,5,6- trifluoropyrimidine 217 [00793]   (2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine [00794]   [3- (aminomethyl)phenyl]methanol [00795]   4,5,6- trifluoropyrimidine 218 [00796]   (2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine [00797]   cyclopentylmethanamine [00798]   4,5,6- trifluoropyrimidine 219 [00799]   (2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine [00800]   (4- methylsulfonylphenyl)methanamine [00801]   4,5,6- trifluoropyrimidine 220 [00802]   (2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine [00803]   3-(aminometh- yl)tetrahydrofuran- 3-ol [00804]   4,5,6- trifluoropyrimidine 221 [00805]   (2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine [00806]   2-[4- (aminomethyl)tetrahydro- pyran-4-yl]ethanol [00807]   4,5,6- trifluoropyrimidine 222 [00808]   (2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine [00809]   (1,1-dioxothian-4- yl)methanamine [00810]   4,5,6- trifluoropyrimidine 223 [00811]   (2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine [00812]   4-(aminomethyl)-1,1- dioxo-thian-4-ol [00813]   4,5,6- trifluoropyrimidine 224 [00814]   (2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine [00815]   4-(aminomethyl)-N- cyclopropyl- benzenesulfonamide [00816]   4,5,6- trifluoropyrimidine 225 [00817]   (2R)-2-[4- (trifluorometh- yl)phenyl]pyrrolidine [00818]   [4- (aminomethyl)cy- clohexyl]methanol [00819]   4,5,6- trifluoropyrimidine 226 [00820]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00821]   4-(aminometh- yl)benzamide [00822]   4,5,6- trifluoropyrimidine 227 [00823]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00824]   [4-(aminometh- yl)phenyl]methan- ol [00825]   4,5,6- trifluoropyrimidine 228 [00826]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00827]   [3- (aminomethyl)oxetan- 3-yl]methanol [00828]   4,5,6- trifluoropyrimidine 229 [00829]   2-methyl-2-[4- (trifluorometh- yl)phenyl]pyrrolidine [00830]   2-[4-(aminometh- yl)phenyl]acetamide [00831]   4,5,6- trifluoropyrimidine 230 [00832]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00833]   2-[4-(aminometh- yl)phenyl]acetamide [00834]   4,5,6- trifluoropyrimidine 231 [00835]   4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine [00836]   2-[4-(aminometh- yl)phenyl]acetamide [00837]   4,5,6- trifluoropyrimidine 232 [00838]   (2R)-2-[2-fluoro-4- (trifluoromethyl)phenyl]pyrrolidine [00839]   2-[4-(aminometh- yl)phenyl]acetamide [00840]   4,5,6- trifluoropyrimidine 233 [00841]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00842]   1-[4- (aminomethyl)- 1-piperid- yl]ethanone [00843]   4,5,6- trifluoropyrimidine 234 [00844]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00845]   4-(aminomethyl)- 1,1-dioxo-thian-4- ol [00846]   4,5,6- trifluoropyrimidine 235 [00847]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00848]   (3- methyloxetan-3- yl)methanamine [00849]   4,5,6- trifluoropyrimidine 236 [00850]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00851]   4-(aminomethyl)-N- cyclopropyl- benzenesulfonamide [00852]   4,5,6- trifluoropyrimidine 237 [00853]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00854]   (1- methylsulfonyl- 4- piperidyl)methan- amine [00855]   4,5,6- trifluoropyrimidine 238 [00856]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00857]   3- (aminomethyl)tetra- hydrofuran-3-ol [00858]   4,5,6- trifluoropyrimidine 239 [00859]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00860]   2-[4- (aminomethyl)tetrahydro- pyran-4-yl]ethanol [00861]   4,5,6- trifluoropyrimidine 240 [00862]   (2R)-2-[4-(trifluoro- methyl)phenyl]pyr- rolidine [00863]   [4- (methylsulfonylmethyl)tetra- hydropyran-4-yl]methanamine [00864]   4,5,6- trifluoropyrimidine 241 [00865]   4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidine [00866]   2-[4- (aminomethyl)phen- yl]acetamide [00867]   4,5,6- trifluoropyrimidine 242 [00868]   4-methyl-2-[4- (trifluoromethyl)phenyl]pyrrolidine [00869]   2-[4- (aminomethyl)phen- yl]acetamide [00870]   4,5,6- trifluoropyrimidine 243 [00871]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00872]   2-[4- (aminomethyl)cyclohexyl]acetic acid [00873]   4,5,6- trifluoropyrimidine 244 [00874]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00875]   2-[4- (aminomethyl)phen- yl]acetamide [00876]   4,5,6- trifluoropyrimidine 245 [00877]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00878]   2-[4-(aminomethyl)cyclohexyl]acet- amide [00879]   4,5,6- trifluoropyrimidine 246 [00880]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00881]   [4-(1H-tetrazol-5-ylmeth- yl)phenyl]methanamine [00882]   4,5,6- trifluoropyrimidine 247 [00883]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00884]   tetrahydropyran- 4- ylmethanamine [00885]   4,5,6- trifluoropyrimidine 248 [00886]   4-methyl-2-[4-(trifluoromethyl)phen- yl]pyrrolidine [00887]   2-[4-(aminomethyl)phenyl]acetamide [00888]   4,5,6- trifluoropyrimidine 249 [00889]   (3S)-3-[4-(trifluoromethyl)phen- yl]morpholine [00890]   1-(aminomethyl)cyclo- pentanecarboxamide [00891]   4,5,6- trifluoropyrimidine 250 [00892]   (3S)-3-[4-(trifluoromethyl)phen- yl]morpholine [00893]   1-(aminomethyl)- N,N-dimethyl- cyclopentanecarbox- amide [00894]   4,5,6- trifluoropyrimidine 251 [00895]   (3S)-3-[4-(trifluoromethyl)phen- yl]morpholine [00896]   N-[2- (aminomethyl)cyclo- pentyl]methanesulfon- amide [00897]   4,5,6- trifluoropyrimidine 253 [00898]   (3S)-3-[4-(trifluoromethyl)phen- yl]morpholine [00899]   [4-(methylsulfonyl- methyl)tetrahydro- pyran-4- yl]methanamine [00900]   4,5,6- trifluoropyrimidine 254 [00901]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00902]   methyl 4- (aminomethyl)tetra- hydropyran-4- carboxylate [00903]   4,5,6- trifluoropyrimidine 255 [00904]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00905]   4- (aminomethyl)tetra- hydropyran-4- carboxamide [00906]   4,5,6- trifluoropyrimidine 256 [00907]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00908]   N-(2-aminoethyl)-4- (aminomethyl)tetrahydropyran- 4-carboxamide [00909]   4,5,6- trifluoropyrimidine 257 [00910]   (3S)-3-[4-(trifluoromethyl)phen- yl]morpholine [00911]   4- (aminomethyl)tetra- hydropyran-4- carbonitrile [00912]   4,5,6- trifluoropyrimidine 258 [00913]   (3S)-3-[2-fluoro-4- (trifluoromethoxy)phenyl]morpholine [00914]   2-[4- (aminomethyl)phen- yl]acetamide [00915]   4,5,6- trifluoropyrimidine 259 [00916]   4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine [00917]   tetrahydropyran- 4-ylmethanamine [00918]   4,5,6- trifluoropyrimidine 260 [00919]   4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine [00920]   [4- (methylsulfonylmeth- yl)tetrahydropyran-4- yl]methanamine [00921]   4,5,6- trifluoropyrimidine 261 [00922]   4,4-difluoro-2-[4- (trifluoromethyl)phenyl]pyrrolidine [00923]   [3- (aminomethyl)oxetan- 3-yl]methanol [00924]   4,5,6- trifluoropyrimidine 262 [00925]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00926]   1-[4- (aminomethyl)-4- fluoro-1- piperidyl]ethanone [00927]   4,5,6- trifluoropyrimidine 263 [00928]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00929]   [1-(trifluoromethyl- sulfonyl)-4- piperidyl]methanamine [00930]   4,5,6- trifluoropyrimidine 264 [00931]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00932]   (4- fluorotetrahy- dropyran-4- yl]methanamine [00933]   4,5,6- trifluoropyrimidine 266 [00934]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00935]   (4-fluoro-1- methylsulfonyl-4- piperidyl)methanamine [00936]   4,5,6- trifluoropyrimidine 267 [00937]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine [00938]   N-[4- (aminomethyl)cyclo- hexyl]methanesul- fonamide [00939]   4,5,6- trifluoropyrimidine 268 [00940]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00941]   4- (aminomethyl)tetra- hydropyran-4- carboxylic acid [00942]   4,5,6- trifluoropyrimidine 273 [00943]   3- phenylmorpholine [00944]   4-(aminomethyl)-N- cyclopropyl- benzenesulfonamide [00945]   4,5,6- trifluoropyrimidine 274 [00946]   3- phenylmorpholine [00947]   (1- methylsulfonyl-4- piperidyl)methan- amine [00948]   4,5,6- trifluoropyrimidine 276 [00949]   3- phenylmorpholine [00950]   2-[4- (aminomethyl)phen- yl]acetic acid [00951]   4,5,6- trifluoropyrimidine 279 [00952]   2- phenylpyrrolidine [00953]   2-[4- (aminomethyl)phen- yl]acetamide [00954]   4,5,6- trifluoropyrimidine 280 [00955]   5-[4- (trifluoromethyl)phenyl]pyrrolidin- 3-one [00956]   2-[4- (aminomethyl)phen- yl]acetamide [00957]   4,5,6- trifluoropyrimidine 282 [00958]   3- phenylmorpholine [00959]   2-[5-(aminomethyl)-2- thienyl]acetic acid [00960]   4,5,6- trifluoropyrimidine 283 [00961]   3- phenylmorpholine [00962]   2-[5-(aminomethyl)-2- thienyl]acetamide [00963]   4,5,6- trifluoropyrimidine 285 [00964]   (3S)-3-[4- (trifluoromethoxy)phenyl]morpholine AND Enantiomer   [00965]   N-[4- (aminomethyl)cyclohexyl]- 2,2,2-trifluoro- ethanesulfonamide [00966]   4,5,6- trifluoropyrimidine 286 [00967]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00968]   4-(aminomethyl)-N- methyl-tetrahydropyran- 4-carboxamide [00969]   4,5,6- trifluoropyrimidine 287 [00970]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00971]   2-[4- (aminomethyl)cyclo- hexyl]acetonitrile [00972]   4,5,6- trifluoropyrimidine 288 [00973]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00974]   [4-(1H-tetrazol-5- ylmethyl)cyclohex- yl]methanamine [00975]   4,5,6- trifluoropyrimidine 291 [00976]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00977]   N-[4- (aminomethyl)phenyl]- 1,1,1-trifluoro- methanesulfonamide [00978]   4,5,6- trifluoropyrimidine 292 [00979]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00980]   2-[4- (aminomethyl)phen- yl]-N-cyano- acetamide [00981]   4,5,6- trifluoropyrimidine 293 [00982]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00983]   (6- methylsulfonyl- 3-pyridyl)meth- anamine [00984]   4,5,6- trifluoropyrimidine 294 [00985]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00986]   2,2-dimethyl-4-methylsulfonyl- butan-1-amine [00987]   4,5,6- trifluoropyrimidine 295 [00988]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00989]   2-(aminomethyl)-2- methyl-cyclohexanol [00990]   4,5,6- trifluoropyrimidine 296 [00991]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00992]   [1- (aminomethyl)cy- clopropyl]methanol [00993]   4,5,6- trifluoropyrimidine 297 [00994]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [00995]   N-(4- piperidyl)methanesulfonamide [00996]   4,5,6- trifluoropyrimidine 299 [00997]   2-(1,3-benzodioxol-5- yl)pyrrolidine [00998]   2-[4-(aminomethyl)phenyl]acetamide [00999]   4,5,6- trifluoropyrimidine 300 [01000]   4-pyrrolidin-2-ylphenol [01001]   2-[4-(aminomethyl)phenyl]acetamide [01002]   4,5,6- trifluoropyrimidine 301 [01003]   2-(4- ethoxyphenyl)pyrrolidine [01004]   2-[4-(aminomethyl)phenyl]acetamide [01005]   4,5,6- trifluoropyrimidine 302 [01006]   2-(p-tolyl)pyrrolidine [01007]   2-[4-(aminomethyl)phenyl]acetamide [01008]   4,5,6- trifluoropyrimidine 303 [01009]   2-(4- isopropylphenyl)pyrrolidine [01010]   2-[4-(aminomethyl)phenyl]acetamide [01011]   4,5,6- trifluoropyrimidine 304 [01012]   2-(3- methoxyphenyl)pyr- rolidine [01013]   2-[4-(aminomethyl)phenyl]acetamide [01014]   4,5,6- trifluoropyrimidine 305 [01015]   2-(3-bromophenyl)pyr- rolidine [01016]   2-[4-(aminomethyl)phenyl]acetamide [01017]   4,5,6- trifluoropyrimidine 306 [01018]   2-(3-chlorophenyl)pyr- rolidine [01019]   2-[4-(aminomethyl)phenyl]acetamide [01020]   4,5,6- trifluoropyrimidine 307 [01021]   2-[4- (trifluoromethyl)phen- yl]azetidine [01022]   2-[4-(aminomethyl)phenyl]acetamide [01023]   4,5,6- trifluoropyrimidine 308 [01024]   2-[4-(trifluoromethyl)phen- yl]piperidine [01025]   2-[4-(aminomethyl)phenyl]acetamide [01026]   4,5,6- trifluoropyrimidine 309 [01027]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [01028]   (4-methylsulfonylmorph- olin-2-yl)methanamine [01029]   4,5,6- trifluoropyrimidine 310 [01030]   2-pyrrolidin-2-yl-1,3- benzothiazole [01031]   2-[4-(aminomethyl)phenyl]acetamide [01032]   4,5,6- trifluoropyrimidine 311 [01033]   2-(1-naphthyl)pyrrolidine [01034]   2-[4-(aminomethyl)phenyl]acetamide [01035]   4,5,6- trifluoropyrimidine 312 [01036]   2-(2- naphthyl)pyrrolidine [01037]   2-[4-(aminomethyl)phenyl]acetamide [01038]   4,5,6- trifluoropyrimidine 313 [01039]   2-(5-methyl-2- furyl)pyrrolidine [01040]   2-[4-(aminomethyl)phenyl]acetamide [01041]   4,5,6- trifluoropyrimidine 314 [01042]   5-methyl-3-pyrrolidin- 2-yl-1,2,4-oxadiazole [01043]   2-[4-(aminomethyl)phenyl]acetamide [01044]   4,5,6- trifluoropyrimidine 315 [01045]   2-methyl-5- pyrrolidin-2-yl- 1,3,4-oxadiazole [01046]   2-[4-(aminomethyl)phenyl]acetamide [01047]   4,5,6- trifluoropyrimidine 316 [01048]   2-(5-ethyl-2- furyl)pyrrolidine [01049]   2-[4-(aminomethyl)phenyl]acetamide [01050]   4,5,6- trifluoropyrimidine 317 [01051]   1,3-dimethyl-4- pyrrolidin-2-yl- pyrazole [01052]   2-[4-(aminomethyl)phenyl]acetamide [01053]   4,5,6- trifluoropyrimidine 318 [01054]   2-(2,4- dimethoxyphenyl)pyr- rolidine [01055]   2-[4-(aminomethyl)phenyl]acetamide [01056]   4,5,6- trifluoropyrimidine 319 [01057]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [01058]   4-(aminomethyl)benzenesulfonic acid [01059]   4,5,6- trifluoropyrimidine 320 [01060]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [01061]   4-(aminomethyl)-N-(2- methoxyethyl)benzenesulfonamide [01062]   4,5,6- trifluoropyrimidine 321 [01063]   2- benzylpyrrolidine [01064]   2-[4-(aminomethyl)phenyl]acetamide [01065]   4,5,6- trifluoropyrimidine 324 [01066]   2-pyrrolidin-2-yl-5- (trifluoromethyl)phenol [01067]   (1-methylsulfonyl-4- piperidyl)methanamine [01068]   4,5,6- trifluoropyrimidine 325 [01069]   (2R)-2-[4-(trifluorometh- yl)phenyl]pyrrolidine [01070]   (2R)-2-amino-4,4- dimethyl-pentanoic acid [01071]   4,5,6- trifluoropyrimidine 327 [01072]   (3S)-3-[4- (trifluoromethyl)phenyl]morpholine [01073]   (1- methylsulfonyl- pyrrolidin-3- yl)methanamine [01074]   4,5,6- trifluoropyrimidine

[0375] Synthesis of Selected Amines

[4-(1H-Tetrazol-5-ylmethyl)cyclohexyl]methanamine

[0376] To 4-[(tert-butoxycarbonylamino)methyl]cyclohexanecarboxylic acid (0.84 g, 3.2 mmol) was added slowly solution of a BH.sub.3-THF solution in THF (16 mL, 1M). The reaction was allowed to stir for 2.5 hours, concentrated in vacuo, and the residue was redissolved and stirred with an aq. sodium hydroxide solution (1M, 30 mL) for 20 min. Ethyl acetate was added, and the mixture was allowed to stir for another 10 min. The phases were separated and the EtOAc phase was concentrated in vacuo and the crude product thereof was purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4 (hydroxymethyl)cyclohexyl]methyl]carbamate (0.76 g, quant yield).

[0377] Tert-butyl N-[[4-(hydroxymethyl)cyclohexyl]methyl]carbamate (0.60 g, 2.5 mmol) was dissolved in DCM (20 mL) and Et3N (1 mL) and then methanesulfonyl chloride was the added to the solution. The reaction was stirred over night at room temperature whereafter concentration under reduced pressure yielded a solid that was mixed with water and EtOAc. The EtOAc phase was separated and washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo of the EtOAC phase gave a solid that was dissolved dry DMSO (10 mL). Potassium cyanide (0.36 g, 5.5 mmol) was added and the reaction was heated to 90° C. for 4 hours. The crude reaction was poured into water and the resulting mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4-(cyanomethyl)cyclohexyl]methyl]carbamate (0.57 g, 88% yield).

[0378] To a solution of tert-butyl N-[[4-(cyanomethyl)cyclohexyl]methyl]carbamate (160 mg, 0.60 mmol) in nitrobenzene was added triethylammonium chloride (160 mg, 1.2 mmol) and sodium azide (91 mg, 1.4 mmol). The resulting mixture was heated to 105° C. for 11 hours using microwave irradiation. Some more sodium azide (40 mg, 0.7 mmol) was added and the reaction was heated for another 45 min at 105° C. with microwave irradiation. The reaction was extracted with water and the water phase was washed with ether, made acidic with IM HCl and extracted with EtOAc. The EtOAc phase was dried using sodium sulfate, filtered and concentrated in vacuo and finally purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methyl]carbamate (33 mg, 18% yield).

[0379] Tert-butyl N-[[4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methyl]carbamate (33 mg, 0.11 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added, and the reaction was stirred for 2 hours. Concentration of the reaction mixture yielded [4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methylammonium 2,2,2-trifluoroacetate that was used without further purification. Using an extra equivalent of the base in the General Method 3 gave [4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methanamine in situ during the reaction.

1-Oxidopyridin-1-ium-3-yl)methanamine

[0380] Tert-butyl N-(3-pyridylmethyl)carbamate (1.7 g, 8.4 mmol) was dissolved in DCM, meta-chloroperbenzoic acid (6.1 g, 25 mmol, 70%) was added, and the reaction was stirred at room temperature for 3 hours. After concentration in vacuo, the crude product was purified by flash CC (eluent: EtOAc/heptane followed by EtOAc/MeOH/ammonium hydroxide, on silica gel) to yield tert-butyl N-[(1-oxidopyridin-1-ium-3-yl)methyl]carbamate (1.9 g, 97% yield).

[0381] Tert-butyl N-[(1-oxidopyridin-1-ium-3-yl)methyl]carbamate (1.9 g, 8.2 mmol) was dissolved in DCM (2 mL) followed by the addition of TFA. The reaction was heated to reflux overnight. After concentration in vacuo the residue was dissolved in a mixture of MEOH and DCM and the solution was then stirred together with Amberlite IRA-67 free base (7 g, washed and dried) for 30 min. The mixture was filtered with DCM and MeOH. Concentration of the filtrate gave 1-oxidopyridin-1-ium-3-yl)methanamine (0.91 g, 91% yield).

1-Oxidopyridin-1-ium-4-yl)methanamine

[0382] Tert-butyl N-(4-pyridylmethyl)carbamate (100 mg, 0.48 mmol) was dissolved in DCM, meta-chloroperbenzoic acid (350 mg, 2.2 mmol, 70%) was added, and the reaction was stirred at room temperature for 4 hours. After concentration in vacuo the crude product was purified by flash CC (eluent: EtOAc/heptane followed by ethyl acetate/MeOH/ammonium hydroxide, on silica gel) to yield tert-butyl N-[(1-oxidopyridin-1-ium-4-yl)methyl]carbamate.

[0383] Tert-butyl N-[(1-oxidopyridin-1-ium-4-yl)methyl]carbamate (80 mg, 0.64 mmol) was dissolved in DCM followed by the addition of TFA (0.19 mL). The reaction was heated to 60° C. by microwave irradiation for 30 min. After cooling, the solution was then stirred together with Amberlite IRA-67 free base (0.5 g, washed and dried) for 30 min. The mixture was filtered with DCM and MeOH. Concentration of the filtrate yielded 1-oxidopyridin-1-ium-4-yl)methanamine (48 mg, 61% yield).

1-[4-(Aminomethyl)-4-fluoro-1-piperidyl]ethanone

[0384] Tert-butyl N-[(4-fluoro-4-piperidyl)methyl]carbamate (232 mg, 1 mmol) was dissolved in 4 mL DCM and trimethylamine (TEA, 160 μL, 1.1 mmol) was added. The mixture was cooled to 0° C. and acetyl chloride (80 μL, 1.1 mmol) was added. The mixture was stirred for 1 hour while returning to room temperature. The mixture was poured into H.sub.2O, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash CC (eluent: Heptane/EtOAc, on silica gel) yielding tert-butyl N-[(1-acetyl-4-fluoro-4-piperidyl)methyl]carbamate. The product was dissolved in 2 mL DCM and a solution of 4M HCl in dioxane (2 mL) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated, and the crude 1-[4-(aminomethyl)-4-fluoro-1-piperidyl]ethanone hydrochloride was used in the next step without further purification (180 mg, 86%).

(4-Fluoro-1-methylsulfonyl-4-piperidyl)methanamine

[0385] Tert-butyl N-[(4-fluoro-4-piperidyl)methyl]carbamate (232 mg, 1 mmol) was dissolved in 4 mL DCM and TEA (160 μL, 1.1 mmol) was added. The mixture was cooled to 0° C. and methanesulfonyl chloride (90 μL, 1.1 mmol) was added. The mixture was stirred for 1 hour while returning to room temperature. The mixture was poured into H.sub.2O, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash CC (eluent: Heptane/EtOAc) yielding tert-butyl N-[(4-fluoro-1-methylsulfonyl-4-piperidyl)methyl]carbamate. The product was dissolved in 2 mL DCM and a solution of 4M HCl in dioxane (2 mL) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated, and the crude (4-fluoro-1-methylsulfonyl-4-piperidyl)methanamine hydrochloride was used in the next step without further purification (162 mg, 61%).

N-[4-(aminomethyl)cyclohexyl]methanesulfonamide

[0386] To a solution of tert-butyl (((trans)-4-aminocyclohexyl)methyl)carbamate (2 g, 8.77 mmol) in CH.sub.2Cl.sub.2 (20 mL) at −78° C. was added DIPEA (2.26 g, 17.54 mmol), methane sulfonyl chloride (1 g, 8.77 mmol), and the mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was poured into ice water and extracted with CH.sub.2Cl.sub.2 (3×30 mL). The combined extracts were washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by flash CC (eluent: DCM/MeOH, on silica gel) to afford tert-butyl (((trans)-4-(methylsulfonamido)cyclohexyl)methyl)carbamate (230 mg) as yellow liquid.

[0387] To a solution of tert-butyl (((trans)-4-(methylsulfonamido) cyclohexyl)methyl) carbamate (0.23 g, 0.751 mmol) in dioxane (1 mL) was added 4 N HCl in dioxane (2.3 mL), and the mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was evaporated to afford N-((trans)-4-(aminomethyl)cyclohexyl)methanesulfonamide (140 mg, 91%) as an off white solid.

N-[4-(aminomethyl)phenyl]-1,1,1-trifluoro-methanesulfonamide

[0388] To a solution of tert-butyl 4-aminobenzylcarbamate (2 g, 9.0 mmol) in CH.sub.2Cl.sub.2 (20 mL) at −78° C. was added Et.sub.3N (1.8 g, 18.01 mmol), trifluoromethanesulfonic anhydride (2.54 g, 9.0 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with CH.sub.2Cl.sub.2 (75 mL) and washed with saturated aq. NaHCO.sub.3 (40 mL), water (40 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by flash CC (Eluent: EtOAc/Pet ether, on silica gel) to afford tert-butyl 4-(trifluoromethylsulfonamido) benzylcarbamate (1.3 g, 41%) as pale yellow solid. N-[4-(aminomethyl)phenyl]-1,1,1-trifluoro-methanesulfonamide was isolated after BOC deprotection, as described for tert-butyl (((trans)-4-(methylsulfonamido) cyclohexyl)methyl) carbamate.

2-[4-(aminomethyl)phenyl]-N-cyano-acetamide

[0389] 2-[4-[(tert-butoxycarbonylamino)methyl]phenyl]acetic acid (265 mg, 1.0 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (HATU, 380 mg, 1.0 mmol) and cyanamide (42 mg, 1.0 mmol) were dissolved in 5 mL dry DMF, and DIPEA (0.35 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 4 hours, poured into H.sub.2O, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding tert-butyl tert-butyl N-[[4-[2-(cyanoamino)-2-oxo-ethyl]phenyl]methyl]carbamate. The product was dissolved in 2 mL DCM and a solution of 4M HCl in dioxane (2 mL) was added. The mixture was stirred overnight at room temperature, concentrated, and the crude 2-[4-(aminomethyl)phenyl]-N-cyano-acetamide hydrochloride was used in the next step without further purification (120 mg, 53%).

##STR01075##

[0390] The initial two steps of general method 4 may be performed in accordance with general method 3. The methyl ester 4a was subsequently hydrolyzed to yield 4b, e.g. by treatment with 1M lithium hydroxide in an appropriate solvent combination, e.g. water/tetrahydrofuran/methanol (e.g. in a ratio of 1:1:1). Hydrolysis was typically achieved after stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Amide analogues 4c were prepared by treatment of 4b with ammonium chloride, HOAt, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and DIPEA in an appropriate solvent, e.g. DMF, followed by stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography. The desired compound 4c was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatrography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.

[0391] Use of General Method 4 to Prepare Example No. 86:

##STR01076##

[0392] Methyl 2-[5-(hydroxymethyl)pyrimidin-2-yl]acetate (0.36 g, 2.0 mmol) and 4,5,6-trifluoro-pyrimidine (0.27 g, 2.0 mmol) were dissolved in dry DMSO (4 mL) and DIPEA (0.7 mL, 4.0 mmol) was added. The reaction was stirred at room temperature overnight, poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding methyl 2-[5-[(5,6-difluoropyrimidin-4-yl)oxymethyl]pyrimidin-2-yl]acetate (0.39 g, 66% yield).

[0393] Methyl 2-[5-[(5,6-difluoropyrimidin-4-yl)oxymethyl]pyrimidin-2-yl]acetate (0.30 g, 1.0 mmol) and 2-(4-trifluoromethyl-phenyl)-pyrrolidine (0.22 g, 1.0 mmol) were dissolved in dry DMSO (2 mL) and cesium carbonate (0.65 g, 2.0 mmol) was added. The reaction was heated in a microwave reactor for 1 hour at 100° C., poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding methyl 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetate (0.24 g, 49% yield).

[0394] Methyl 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetate (0.20 g, 0.41 mmol) was dissolved in 2M aq. lithium hydroxide/tetrahydrofuran/methanol (1:1:1, 10 mL) and stirred at room temperature overnight. The solvents were removed in vacuo and the residue purified by preparative HPLC yielding 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetic acid (0.15 g, 76% yield).

[0395] 2-[5-[[5-Fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetic acid (0.12 g, 0.25 mmol), ammonium chloride (14 mg, 0.25 mmol), HOAt (31 mg, 0.25 mmol), EDC (39 mg, 0.25 mmol) and DIPEA (45 μL, 0.25 mmol) were dissolved in dry DMF (2 mL), and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo, redissolved in EtOAc, washed with sat. aq. potassium carbonate, aq. potassium bisulfate (10%) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash CC (eluent: eluent: DCM/MeOH, on silica gel) yielding 2-[5-[[5-fluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidin-4-yl]oxymethyl]pyrimidin-2-yl]acetamide 86 (68 mg, 56% yield). .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.02 (s, 1H), 7.94-7.83 (m, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 5.32 (d, J=7.7 Hz, 1H), 4.02-3.96 (m, 1H), 3.81-3.52 (m, 4H), 2.38-2.19 (m, 1H), 1.97-1.71 (m, 3H). m/z 477 (M+H).

[0396] General method 4 was used to prepare the following example numbers using the shown starting materials:

TABLE-US-00005 Fluorinated Ex Free amine or aromatic No. alcohol (1) Methyl ester compound 32 [01077] [01078] [01079] 40 [01080] [01081] [01082] 79 [01083] [01084] [01085] 81 [01086] [01087] [01088] 83 [01089] [01090] [01091] 84 [01092] [01093] [01094] 86 [01095] [01096] [01097] 87 [01098] [01099] [01100] 91 [01101] [01102] [01103] 117 [01104] [01105] [01106] 118 [01107] [01108] [01109] 119 [01110] [01111] [01112] 192 [01113] [01114] [01115] 204 [01116] [01117] [01118] 205 [01119] [01120] [01121] 206 [01122] [01123] [01124] 207 [01125] [01126] [01127]
Table of .sup.1H NMR and MS Data for example compounds.

TABLE-US-00006 Ex. No. .sup.1H NMR or MS Data 4 m/z 589 (M + H) 5 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 6.46 (s, 1H), 5.41 (d, J = 7.9 Hz, 1H), 5.24 (s, 1H), 4.69 (s, 1H), 4.58 (s, 1H), 4.08-3.99 (m, 1H), 3.83-3.72 (m, 1H), 2.36 (dt, J = 15.4, 5.7 Hz, 1H), 2.05 (dd, J = 14.6, 3.6 Hz, 1H), 2.01-1.86 (m, 3H), 1.50 (dd, J = 14.7, 8.7 Hz, 1H), 0.96 (s, 9H). 6 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.23 (s, 1H), 8.06-7.92 (m, 1H), 7.75-7.55 (m, 2H), 7.48-7.29 (m, 2H), 5.44-4.98 (m, 2H), 4.50-4.21 (m, 1H), 3.95-3.48 (m, 3H), 2.62-2.42 (m, 1H), 2.11-1.90 (m, 3H), 0.94 (s, 9H). 9 m/z 517 (M + H) 11 m/z 454 (M + H) 13 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.57 (dd, J = 8.2, 3.3 Hz, 2H), 7.31 (dd, J = 8.0, 3.3 Hz, 2H), 5.46-5.30 (m, 1H), 4.69-4.51 (m, 1H), 4.17-4.00 (m, 1H), 3.91-3.77 (m, 1H), 2.54-2.25 (m, 1H), 2.12-1.87 (m, 4H), 1.64-1.46 (m, 1H), 1.04-0.77 (m, 9H). 14 m/z 450 (M + H) 15 m/z 464 (M + H) 16 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.94 (d, J = 1.8 Hz, 1H), 7.65-7.50 (m, 2H), 7.35-7.28 (m, 2H), 5.62-5.47 (m, 1H), 5.42 (t, J = 8.8 Hz, 1H), 4.22-3.94 (m, 2H), 3.89-3.66 (m, 1H), 2.49-2.28 (m, 1H), 2.05-1.82 (m, 3H), 1.81-1.55 (m, 4H), 1.26 (dd, J = 6.3, 0.8 Hz, 3H), 1.23-1.15 (m, 4H), 1.11 (s, 2H). 17 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.90 (dd, J = 3.2, 1.8 Hz, 1H), 7.63-7.52 (m, 2H), 7.35-7.25 (m, 2H), 7.23-7.11 (m, 2H), 6.90-6.76 (m, 2H), 5.41 (d, J = 8.0 Hz, 1H), 5.12-4.96 (m, 1H), 4.83-4.66 (m, 1H), 4.12-3.98 (m, 1H), 3.79 (s, 3H), 3.20-2.98 (m, J = 6.7 Hz, 2H), 2.46-2.27 (m, 1H), 2.04-1.83 (m, 3H). 18 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.71-7.55 (m, 3H), 7.42 (t, J = 9.0 Hz, 2H), 7.15 (s, 1H), 6.89 (d, J = 6.9 Hz, 1H), 6.63-6.49 (m, 1H), 5.29-5.17 (m, 1H), 4.53-4.39 (m, 1H), 4.17-3.90 (m, 1H), 3.42 (t, J = 10.0 Hz, 2H), 2.66-2.53 (m, 1H), 2.41-2.18 (m, 1H), 1.75-1.54 (m, 2H), 1.42-1.28 (m, 1H), 1.10-0.99 (m, 3H), 0.85 (dd, J = 8.4, 3.7 Hz, 9H). 19 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.75 (dd, J = 6.4, 1.9 Hz, 1H), 7.30 (dd, J = 8.1, 6.1 Hz, 2H), 7.18-7.01 (m, 3H), 6.87 (d, J = 14.0 Hz, 1H), 6.55-6.44 (m, 1H), 5.30 (d, J = 7.2 Hz, 1H), 4.46 (qd, J = 9.1, 3.4 Hz, 1H), 3.99-3.89 (m, 1H), 3.73-3.60 (m, 1H), 2.34-2.19 (m, 1H), 1.91-1.50 (m, 5H), 1.31-1.17 (m, 9H). 20 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.93-7.83 (m, 1H), 7.71 (dd, J = 8.4, 2.5 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.22 (s, 1H), 6.93 (d, J = 6.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.46 (d, J = 3.3 Hz, 1H), 4.58-4.45 (m, 1H), 4.35-4.26 (m, 1H), 4.07-3.81 (m, 3H), 3.73-3.60 (m, 1H), 3.50-3.38 (m, 1H), 1.81-1.55 (m, 2H), 0.88 (d, J = 3.6 Hz, 9H). 21 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.95 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 5.41 (d, J = 8.2 Hz, 1H), 4.44 (s, 1H), 4.12-3.96 (m, 1H), 3.88-3.69 (m, 1H), 3.53-3.31 (m, 2H), 2.48-2.28 (m, 1H), 2.06-1.81 (m, 3H), 1.56-1.40 (m, 2H), 0.95 (s, 9H). 23 m/z 437 (M + H) 24 m/z 444 (M + H) 29 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.74-7.59 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 8.0 Hz, 2H), 6.78 (dd, J = 8.4, 6.2 Hz, 2H), 6.46-6.31 (m, 1H), 5.34 (d, J = 7.7 Hz, 1H), 4.72 (t, J = 5.3 Hz, 1H), 4.21-4.07 (m, 1H), 4.02-3.86 (m, 1H), 3.68 (s, 3H), 2.88-2.58 (m, 2H), 2.41-2.21 (m, 1H), 1.98-1.68 (m, 3H), 1.05 (t, J = 7.0 Hz, 1H). 30 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.77-7.58 (m, 3H), 7.46-7.32 (m, 2H), 6.29 (d, J = 8.6 Hz, 1H), 5.41-5.29 (m, 1H), 4.70-4.53 (m, 1H), 4.24-4.08 (m, 1H), 4.02-3.88 (m, 1H), 3.76-3.60 (m, 1H), 2.44-2.23 (m, 1H), 2.01-1.70 (m, 3H), 1.55-1.33 (m, 2H), 0.90-0.78 (m, 9H). 31 m/z 482 (M + H) 32 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.72 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.32-7.17 (m, 4H), 5.49-5.37 (m, 1H), 4.61-4.45 (m, 2H), 4.13-3.96 (m, 1H), 3.90-3.72 (m, 1H), 3.57 (s, 2H), 2.54-2.35 (m, 1H), 2.08-1.85 (m, 3H). 33 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.94-7.75 (m, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.32 (dd, J = 8.4, 2.8 Hz, 2H), 5.27 (t, J = 8.4 Hz, 1H), 4.93-4.79 (m, 1H), 4.66-4.48 (m, 1H), 4.21-4.04 (m, 1H), 3.53-3.38 (m, 1H), 2.68-2.51 (m, 1H), 2.48-2.27 (m, 1H), 1.90-1.57 (m, 3H), 1.12 (d, J = 6.4 Hz, 3H), 1.01-0.84 (m, 6H). 34 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.89-7.77 (m, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 5.27 (t, J = 8.7 Hz, 1H), 4.91-4.73 (m, 1H), 4.64-4.47 (m, 1H), 4.24-4.02 (m, 1H), 3.46 (t, J = 10.4 Hz, 1H), 2.71-2.50 (m, 1H), 2.46-2.29 (m, 1H), 1.89-1.58 (m, 3H), 1.17-1.04 (m, 3H), 1.01-0.90 (m, 6H). 35 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.93 (dd, J = 5.7, 1.9 Hz, 1H), 7.70-7.64 (m, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.21 (dd, J = 8.1, 5.4 Hz, 1H), 5.59-5.44 (m, 1H), 4.76-4.68 (m, 1H), 4.64-4.50 (m, 1H), 3.89-3.74 (m, 1H), 2.52-2.36 (m, 1H), 2.13-1.80 (m, 4H), 1.58-1.43 (m, 1H), 1.02-0.89 (m, 9H). 36 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.93 (d, J = 4.1 Hz, 1H), 7.67 (s, 1H), 7.45 (t, J = 6.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.72-5.60 (m, 1H), 4.83-4.70 (m, 1H), 4.61-4.46 (m, 1H), 4.16-4.02 (m, 1H), 3.92-3.74 (m, 1H), 2.53-2.36 (m, 1H), 2.12-1.81 (m, 4H), 1.62-1.47 (m, 1H), 1.03-0.93 (m, 9H). 37 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.70-7.55 (m, 3H), 7.52-7.45 (m, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.35-7.20 (m, 2H), 7.08-6.99 (m, 2H), 5.29-5.10 (m, 1H), 3.48-3.37 (m, 1H), 2.98 (t, J = 11.9 Hz, 2H), 2.34-2.20 (m, 1H), 1.41-1.21 (m, 1H), 1.10-0.94 (m, 3H). 38 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.95-7.85 (m, 1H), 7.62-7.50 (m, 2H), 7.35-7.29 (m, 1H), 7.26-7.17 (m, 1H), 5.33-5.23 (m, 1H), 4.15 (t, J = 9.9 Hz, 1H), 4.03-3.88 (m, 1H), 3.83-3.70 (m, 1H), 1.77-1.62 (m, 3H), 1.19 (d, J = 6.6 Hz, 2H), 1.01-0.87 (m, 12H). 39 m/z 453 (M + H) 40 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.70 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.23-7.08 (m, 4H), 6.92-6.75 (m, 1H), 5.37 (d, J = 7.9 Hz, 1H), 4.56-4.37 (m, 2H), 4.05-3.86 (m, 1H), 3.78-3.61 (m, 1H), 3.31-3.27 (m, 2H), 2.46-2.22 (m, 2H), 1.97-1.70 (m, 3H). 41 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (S, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 5.40 (d, J = 7.9 Hz, 1H), 4.25 (s, 2H), 4.07-3.97 (m, 1H), 3.91 (dd, J = 11.1, 4.3 Hz, 2H), 3.83-3.71 (m, 1H), 3.39-3.26 (m, 2H), 2.42-2.30 (m, 1H), 2.03-1.85 (m, 3H), 1.69 (d, J = 13.0 Hz, 2H), 1.49-1.20 (m, 4H), 1.19-1.13 (m, 3H). 42 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.83-8.77 (m, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 6.2 Hz, 1H), 7.62-7.55 (m, 1H), 5.59 (s, 1H), 4.67-4.58 (m, 1H), 4.07 (t, J = 9.7 Hz, 1H), 3.92-3.81 (m, 1H), 2.56 (s, 1H), 2.21-1.95 (m, 4H), 1.89-1.73 (m, 2H), 0.97-0.87 (m, 9H). 43 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (dd, J = 6.4, 2.0 Hz, 1H), 7.03 (dd, J = 8.6, 4.2 Hz, 2H), 6.93-6.86 (m, 2H), 6.52 (s, 1H), 5.35 (s, 1H), 5.22 (s, 1H), 4.61 (s, 1H), 4.58-4.48 (m, 1H), 3.98 (s, 1H), 3.73 (t, J = 7.3 Hz, 1H), 2.38-2.22 (m, 1H), 2.06 (dt, J = 14.5, 3.0 Hz, 1H), 1.98-1.88 (m, 3H), 1.53-1.42 (m, 1H), 1.32 (dd, J = 5.6, 1.2 Hz, 9H), 0.93 (dd, J = 17.0, 3.0 Hz, 9H). 44 m/z 461 (M + H) 45 m/z 557 (M + H) 46 m/z 510 (M + H) 48 m/z 485 (M + H) 51 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92 (dd, J = 5.3, 2.0 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.26 (s, 2H), 6.23 (s, 1H), 5.45-5.31 (m, 2H), 5.18 (dd, J = 7.6, 2.3 Hz, 1H), 4.54-4.45 (m, 1H), 4.14-3.99 (m, 2H), 3.84-3.73 (m, 1H), 2.45-2.31 (m, 1H), 2.04-1.85 (m, 3H), 1.21 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 22.8 Hz, 9H). 52 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.75 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.5, 2.7 Hz, 2H), 7.46-7.39 (m, 2H), 7.34-7.29 (m, 1H), 6.95 (d, J = 11.9 Hz, 1H), 6.77 (d, J = 20.9 Hz, 1H), 5.38 (s, 1H), 4.52-4.37 (m, 1H), 3.97 (d, J = 8.1 Hz, 1H), 3.83-3.67 (m, 3H), 3.29-3.09 (m, 2H), 2.40-2.30 (m, 1H), 1.98-1.74 (m, 3H), 1.73-1.46 (m, 5H), 1.25-1.05 (m, 2H). 53 m/z 477 (M + H) 54 m/z 477 (M + H) 55 m/z 517 (M + H) 56 m/z 502 (M + H) 57 m/z 530 (M + H) 58 m/z 531 (M + H) 59 m/z 517 (M + H) 60 m/z 515 (M + H) 61 m/z 543 (M + H) 62 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 6.46 (s, 1H), 5.41 (d, J = 7.9 Hz, 1H), 5.24 (s, 1H), 4.69 (s, 1H), 4.58 (s, 1H), 4.08-3.99 (m, 1H), 3.83-3.72 (m, 1H), 2.36 (dt, J = 15.4, 5.7 Hz, 1H), 2.05 (dd, J = 14.6, 3.6 Hz, 1H), 2.01-1.86 (m, 3H), 1.50 (dd, J = 14.7, 8.7 Hz, 1H), 0.96 (s, 9H). 63 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (dd, J = 5.1, 2.0 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 22.7 Hz, 1H), 6.71 (d, J = 3.7 Hz, 1H), 6.41 (s, 0H), 5.61 (d, J = 8.8 Hz, 1H), 5.47-5.29 (m, 2H), 4.81-4.56 (m, 1H), 4.09-3.98 (m, 1H), 3.84-3.71 (m, 1H), 3.44-3.28 (m, 2H), 2.59-2.47 (m, 1H), 2.46-2.29 (m, 2H), 2.25-2.10 (m, 1H), 2.09-1.81 (m, 6H). 64 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.73 (dd, J = 7.1, 2.0 Hz, 1H), 7.64 (t, J = 7.3 Hz, 2H), 7.41 (dd, J = 7.8, 3.7 Hz, 2H), 6.51-6.22 (m, 1H), 5.35 (d, J = 7.5 Hz, 1H), 4.21 (s, 1H), 3.96 (s, 1H), 3.69 (d, J = 10.0 Hz, 2H), 3.35 (s, 1H), 3.27-3.05 (m, 1H), 2.69 (d, J = 11.7 Hz, 1H), 2.64-2.52 (m, 2H), 2.42-2.14 (m, 3H), 1.99-1.71 (m, 3H), 1.51 (d, J = 11.3 Hz, 1H), 1.47-1.32 (m, 1H), 0.79 (dd, J = 9.0, 4.2 Hz, 9H). 65 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.93 (dd, J = 6.8, 1.7 Hz, 1H), 7.15-6.99 (m, 3H), 6.44 (s, 1H), 5.60 (d, J = 8.1 Hz, 1H), 5.20 (s, 1H), 4.66-4.51 (m, 2H), 4.02 (s, 1H), 3.93 (d, J = 2.4 Hz, 3H), 3.75 (t, J = 8.8 Hz, 1H), 2.30 (t, J = 7.3 Hz, 1H), 2.09-2.02 (m, 1H), 1.90 (dt, J = 27.6, 9.5 Hz, 3H), 1.47 (M, 1H), 0.93 (d, J = 17.1 Hz, 9H). 66 m/z 431 (M + H) 67 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.15 (s, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.7 Hz, 2H), 7.17 (d, J = 3.4 Hz, 1H), 6.96 (s, 1H), 6.82 (dd, J = 8.0, 1.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 5.90 (d, J = 5.6 Hz, 1H), 5.31 (d, J = 8.3 Hz, 1H), 5.26-5.14 (m, 2H), 4.19-4.02 (m, 1H), 3.92-3.76 (m, 1H), 3.70-3.63 (m, 6H), 2.47-2.37 (m, 1H), 2.09-1.79 (m, 3H). 68 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.99 (d, J = 1.7 Hz, 1H), 7.58-7.47 (m, 2H), 7.22-7.13 (m, 2H), 6.36 (s, 1H), 5.57 (s, 1H), 5.29 (s, 1H), 4.89 (d, J = 7.5 Hz, 1H), 4.68-4.58 (m, 1H), 4.42-4.31 (m, 1H), 4.08-3.90 (m, 3H), 3.84-3.69 (m, 1H), 3.50-3.35 (m, 1H), 2.15-2.02 (m, 1H), 1.64-1.56 (m, 1H), 0.99 (s, 9H). 69 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.71 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.21-7.10 (m, 5H), 5.37 (d, J = 7.9 Hz, 1H), 4.55-4.38 (m, 2H), 4.05-3.87 (m, 1H), 3.81-3.65 (m, 1H), 3.64-3.53 (m, 5H), 2.39-2.21 (m, 1H), 1.99-1.67 (m, 3H). 70 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.71 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.21-7.10 (m, 5H), 5.37 (d, J = 7.9 Hz, 1H), 4.55-4.38 (m, 2H), 4.05-3.87 (m, 1H), 3.81-3.65 (m, 1H), 3.64-3.53 (m, 5H), 2.39-2.21 (m, 1H), 1.99-1.67 (m, 3H). 71 m/z 538 (M + H) 72 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.90 (d, J = 5.4 Hz, 1H), 7.52 (q, J = 7.2 Hz, 1H), 7.10-6.97 (m, 2H), 6.41 (s, 1H), 5.36 (s, 1H), 5.22 (s, 1H), 4.70 (s, 1H), 4.58 (s, 1H), 4.03 (s, 1H), 3.78 (d, J = 10.8 Hz, 1H), 2.37 (s, 1H), 2.10-1.86 (m, 4H), 1.52-1.46 (m, 1H), 1.26 (s, 1H), 0.95 (d, J = 11.6 Hz, 8H). 73 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.57 (d, J = 2.4 Hz, 1H), 7.96 (s, 1H), 7.66 (dd, J = 7.8, 2.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 11.0 Hz, 1H), 5.44-5.32 (m, 3H), 4.06 (dt, J = 6.8, 3.9 Hz, 1H), 3.86-3.76 (m, 1H), 2.55 (s, 3H), 2.45-2.32 (m, 1H), 2.07-1.87 (m, 3H). 74 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.56 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.65 (dd, J = 7.9, 2.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.28 (s, 2H), 7.14 (d, J = 7.8 Hz, 1H), 5.46-5.31 (m, 3H), 4.12-4.02 (m, 1H), 3.86-3.77 (m, 1H), 2.55 (s, 3H), 2.43-2.32 (m, 1H), 2.03-1.87 (m, 3H). 77 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.95 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 9.8 Hz, 4H), 6.10 (s, 1H), 5.46 (dt, J = 8.1, 3.4 Hz, 2H), 5.30 (s, 1H), 4.15-4.01 (m, 1H), 3.92-3.75 (m, 1H), 2.47-2.31 (m, 1H), 2.07-1.72 (m, 7H), 1.02-0.86 (m, 6H). 78 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.93 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.26 (d, 4H), 6.17 (s, 1H), 5.53-5.32 (m, 3H), 4.09 (s, 1H), 3.91-3.78 (m, 1H), 2.48-2.31 (m, 1H), 2.08-1.48 (m, 7H), 0.92 (dd, J = 7.8, 6.1 Hz, 6H). 79 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.96 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 4H), 5.47-5.30 (m, 3H), 4.13-4.01 (m, 1H), 3.88-3.75 (m, 1H), 3.65 (s, 2H), 2.44-2.31 (m, 1H), 2.04-1.85 (m, 3H). 80 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.46 (s, 0.3H), 8.77-8.73 (m, 0.64H), 8.69 (d, J = 2.9 Hz, 0.63H), 8.53 (s, 0.57H), 8.19 (dd, J = 8.1, 2.5 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.61 (s, 0.68H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 7.22 (s, 0.67H), 5.81 (d, J = 6.0 Hz, 0.36H), 5.31 (dd, J = 9.6, 3.7 Hz, 0.71H), 4.27-4.20 (m, 0.42H), 1.95-1.79 (m, 2H), 1.79-1.66 (m, 1H), 1.59-1.51 (m, 1H), 1.01-0.89 (m, 6H). Note: Due to the presence of isomers the protons were integrated in decimals 81 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.95 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.31-7.21 (m, 6H), 5.41 (d, J = 7.9 Hz, 1H), 4.93 (s, 1H), 4.66-4.50 (m, 2H), 4.10-3.98 (m, 1H), 3.86-3.72 (m, 1H), 3.63 (s, 2H), 2.49-2.29 (m, 1H), 2.03-1.84 (m, 3H). 83 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.10 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.46 (dd, J = 8.3, 2.2 Hz, 4H), 7.37-7.29 (m, 2H), 5.46 (s, 2H), 4.79 (d, J = 6.1 Hz, 2H), 3.68 (s, 2H). 84 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.74-8.60 (m, 1H), 8.01-7.84 (m, 2H), 7.80 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.95-6.73 (m, 1H), 5.44 (d, J = 7.7 Hz, 1H), 5.40-5.24 (m, 2H), 4.17-3.95 (m, 1H), 3.86-3.67 (m, 1H), 3.36 (s, 2H), 2.46-2.29 (m, 1H), 2.04-1.76 (m, 3H). 85 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.19 (s, 1H), 8.07 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.16 (s, 5H), 6.80-6.55 (m, 1H), 5.61 (d, J = 7.8 Hz, 1H), 5.44-5.19 (m, 2H), 4.32-4.05 (m, 1H), 4.05-3.78 (m, 1H), 3.50 (s, 2H), 2.44-2.27 (m, 1H), 2.12-1.70 (m, 3H). 86 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.02 (dd, J = 2.3, 1.2 Hz, 1H), 7.93-7.85 (m, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.32 (d, J = 7.7 Hz, 1H), 4.81 (d, J = 4.9 Hz, 2H), 4.04-3.92 (m, 1H), 3.72-3.55 (m, 3H), 2.40-2.19 (m, 1H), 1.95-1.70 (m, 3H). 87 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.92 (s, 1H), 7.84-7.79 (m, 1H), 7.65 (t, J = 1.6 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 5.34-5.26 (m, 1H), 4.39-4.25 (m, 2H), 4.00-3.87 (m, 1H), 3.77-3.60 (m, 3H), 2.40-2.23 (m, 1H), 1.96-1.73 (m, 3H). 88 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.70 (t, J = 1.7 Hz, 1H), 7.67-7.56 (m, 4H), 7.45 (dd, J = 8.2, 1.6 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 5.47-5.39 (m, 1H), 4.63 (s, 2H), 4.13-4.00 (m, 1H), 3.86-3.73 (m, 1H), 2.51-2.35 (m, 1H), 2.06-1.84 (m, 3H). 89 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.35 (d, J = 2.2 Hz, 1H), 7.78-7.70 (m, 1H), 7.65 (dd, J = 8.0, 2.3 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 1H), 5.48-5.36 (m, 1H), 4.55 (d, J = 3.5 Hz, 2H), 4.13-3.95 (m, 1H), 3.89-3.70 (m, 1H), 2.47 (s, 3H), 2.46-2.31 (m, 1H), 2.04-1.81 (m, 3H). 90 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.39-8.30 (m, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.0, 2.3 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.07-7.01 (m, 2H), 6.84-6.77 (m, 2H), 5.36-5.24 (m, 1H), 4.53 (d, J = 3.8 Hz, 2H), 4.05-3.92 (m, 1H), 3.75-3.64 (m, 5H), 2.47 (s, 3H), 2.36-2.23 (m, 1H), 1.95-1.82 (m, 3H). 91 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.20 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.63 (q, J = 4.5 Hz, 1H), 7.53-7.47 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7.25-7.14 (m, 4H), 5.42 (s, 1H), 4.58-4.44 (m, 2H), 4.28 (dd, J = 12.1, 2.3 Hz, 1H), 4.01-3.81 (m, 3H), 3.65 (td, J = 11.2, 2.9 Hz, 2H), 3.51 (s, 2H), 3.30-3.24 (m, 1H). 93 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.72 (t, J = 2.0 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 5.44-5.37 (m, 1H), 4.10-3.99 (m, 1H), 3.84-3.72 (m, 1H), 3.31-3.25 (m, 1H), 3.16 (dd, J = 7.0, 5.2 Hz, 1H), 2.51-2.34 (m, 1H), 2.04-1.84 (m, 3H), 1.81-1.65 (m, 3H), 1.48-1.38 (m, 2H), 1.38-1.21 (m, 2H), 1.00-0.82 (m, 6H). 94 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.70 (s, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.06 (s, 1H), 6.96 (s, 1H), 5.44-5.38 (m, 1H), 4.55 (d, J = 4.7 Hz, 2H), 4.10-3.98 (m, 1H), 3.85-3.69 (m, 1H), 2.49-2.32 (m, 1H), 2.03-1.82 (m, 3H). 95 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.72 (dd, J = 1.7, 0.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.43-7.29 (m, 6H), 5.46-5.39 (m, 1H), 4.65-4.52 (m, 2H), 4.37 (s, 2H), 4.11-4.00 (m, 1H), 3.80 (dtd, J = 10.4, 7.5, 2.8 Hz, 1H), 2.83 (s, 3H), 2.52-2.35 (m, 1H), 2.07-1.85 (m, 3H). 96 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.46 (s, 1H), 8.90 (t, J = 5.9 Hz, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.27 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.6 Hz, 2H), 7.66 (dd, J = 8.0, 2.3 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.67 (d, J = 5.9 Hz, 2H), 2.44 (s, 3H). 97 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.34 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.0, 2.3 Hz, 1H), 7.44-7.34 (m, 1H), 7.33-7.22 (m, 4H), 7.14 (d, J = 7.9 Hz, 1H), 5.38-5.28 (m, 1H), 4.52-4.36 (m, 2H), 4.00-3.86 (m, 1H), 3.71-3.62 (m, 1H), 2.40 (s, 3H), 2.36-2.25 (m, 1H), 2.01-1.66 (m, 3H). 98 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.72 (d, J = 1.7 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.25-7.09 (m, 4H), 5.51-5.37 (m, 1H), 4.63-4.46 (m, 2H), 4.12-4.00 (m, 1H), 3.86-3.73 (m, 1H), 2.72 (s, 2H), 2.54-2.38 (m, 1H), 2.04-1.86 (m, 3H), 1.15 (s, 6H). 99 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.69 (t, J = 1.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.39-7.31 (m, 3H), 6.66 (d, J = 7.3 Hz, 1H), 5.40 (d, J = 7.7 Hz, 1H), 4.45 (s, 2H), 4.09-3.98 (m, 1H), 3.92 (d, J = 1.2 Hz, 3H), 3.85-3.69 (m, 1H), 2.50-2.33 (m, 4H), 2.05-1.81 (m, 3H). 100 m/z 434 (M + H) 104 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 10.29 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 7.9, 2.3 Hz, 1H), 7.44-7.29 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.11-6.96 (m, 3H), 5.46 (d, J = 7.9 Hz, 1H), 4.51-4.33 (m, 2H), 4.04-3.86 (m, 1H), 3.76-3.56 (m, 1H), 2.40 (s, 3H), 2.31-2.10 (m, 1H), 2.01-1.83 (m, 1H), 1.83-1.60 (m, 2H). 105 m/z 420 (M + H) 106 m/z 421 (M + H) 107 m/z 421 (M + H) 108 m/z 424 (M + H) 109 m/z 438 (M + H) 110 m/z 482 (M + H) 111 m/z 455 (M + H) 112 m/z 476 (M + H) 113 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.99 (dd, J = 5.3, 1.0 Hz, 1H), 7.71 (t, J = 1.3 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 6.86 (dt, J = 5.4, 1.2 Hz, 1H), 6.67 (s, 1H), 5.43 (d, J = 7.8 Hz, 1H), 4.63-4.46 (m, 2H), 4.13-3.98 (m, 1H), 3.90-3.75 (m, 4H), 2.52-2.35 (m, 1H), 2.06-1.84 (m, 3H). 114 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.05 (dd, J = 2.4, 0.8 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.67-7.60 (m, 2H), 7.59 (d, J = 2.5 Hz, 0H), 7.39 (d, J = 8.2 Hz, 3H), 6.73 (dd, J = 8.5, 0.8 Hz, 1H), 5.36 (d, J = 7.8 Hz, 1H), 4.48-4.32 (m, 2H), 3.98-3.90 (m, 1H), 3.79 (s, 3H), 3.76-3.62 (m, 1H), 2.38-2.26 (m, 1H), 1.97-1.71 (m, 3H). 115 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.62 (s, 1H), 7.94 (s, 1H), 7.71-7.61 (m, 3H), 7.46-7.35 (m, 3H), 7.30-7.13 (m, 4H), 5.35 (s, 3H), 4.54-4.33 (m, 2H), 3.98-3.89 (m, 1H), 3.77-3.61 (m, 1H), 2.42-2.27 (m, 1H), 1.95-1.70 (m, 3H). 116 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.97 (s, 1H), 7.77 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 8.8, 1.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.6 Hz, 1H), 5.46-5.34 (m, 1H), 4.55 (q, J = 15.5 Hz, 2H), 4.11-3.97 (m, 1H), 3.86 (s, 3H), 3.85-3.68 (m, 1H), 2.95 (d, J = 3.7 Hz, 3H), 2.50-2.34 (m, 1H), 2.02-1.80 (m, 3H). 117 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.95 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.31-7.21 (m, 6H), 5.41 (d, J = 7.9 Hz, 1H), 4.93 (s, 1H), 4.66-4.50 (m, 2H), 4.10-3.98 (m, 1H), 3.86-3.72 (m, 1H), 3.63 (s, 2H), 2.49-2.29 (m, 1H), 2.03-1.84 (m, 3H). 118 m/z 475 (M + H) 119 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.25 (s, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.75-7.56 (m, 5H), 7.27-7.11 (m, 4H), 5.46 (s, 1H), 4.51 (d, J = 6.1 Hz, 2H), 4.30 (dd, J = 12.1, 2.3 Hz, 1H), 4.08-3.81 (m, 4H), 3.66 (td, J = 11.0, 2.9 Hz, 1H), 3.51 (s, 2H). 120 m/z 475 (M + H) 121 m/z 501 (M + H) 122 m/z 472 (M + H) 123 m/z 465 (M + H) 124 m/z 514 (M + H) 126 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.67 (s, 1H), 7.95-7.89 (m, 1H), 7.82 (dd, J = 7.8, 0.7 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 6.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 5.37 (d, J = 8.0 Hz, 1H), 4.69-4.49 (m, 2H), 4.06-3.91 (m, 1H), 3.80-3.63 (m, 1H), 2.39-2.26 (m, 1H), 2.02-1.70 (m, 3H). 128 m/z 461 (M + H) 129 m/z 441 (M + H) 130 m/z 492 (M + H) 131 m/z 448 (M + H) 132 m/z 432 (M + H) 134 m/z 464 (M + H) 135 m/z 452 (M + H) 136 m/z 460 (M + H) 137 m/z 500 (M + H) 138 m/z 485 (M + H) 139 m/z 417 (M + H) 140 m/z 418 (M + H) 141 m/z 418 (M + H) 142 m/z 477 (M + H) 143 m/z 500 (M + H) 144 m/z 474 (M + H) 145 m/z 488 (M + H) 146 m/z 498 (M + H) 147 m/z 461 (M + H) 148 m/z 481 (M + H) 150 m/z 368 (M + H) 151 m/z 495 (M + H) 152 m/z 409 (M + H) 154 m/z 411 (M + H) 155 m/z 425 (M + H) 159 m/z 427 (M + H) 161 m/z 439 (M + H) 164 m/z 441 (M + H) 165 m/z 443 (M + H) 166 m/z 451 (M + H) 167 m/z 453 (M + H) 168 m/z 453 (M + H) 169 m/z 457 (M + H) 170 m/z 459 (M + H) 175 m/z 481 (M + H) 178 m/z 465 (M + H) 181 m/z 411 (M + H) 182 m/z 496 (M + H) 183 m/z 452 (M + H) 184 m/z 459 (M + H) 185 m/z 423 (M + H) 186 m/z 425 (M + H) 188 m/z 439 (M + H) 189 m/z 488 (M + H) 190 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.71 (s (br), 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 5.41 (d, J = 7.9 Hz, 1H), 4.14-3.96 (m, 1H), 3.87-3.72 (m, 1H), 3.28-3.06 (m, 2H), 2.82 (d, J = 6.8 Hz, 2H), 2.57-2.33 (m, 1H), 2.07-1.85 (m, 3H), 1.85-1.63 (m, 5H), 1.63-1.42 (m, 1H), 1.17-0.81 (m, 4H). 191 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.73 (s (br), Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 5.41(d, J = 7.9 Hz, 2H), 4.56-4.42 (m, 1H), 4.19-3.99 (m, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.85-3.3.73 (m, 1H), 3.30-3.15 (m, 2H), 3.13-3.0 (m, 1H), 2.66-2.52 (m, 1H), 2.52-2.36 (m, 1H), 2.08 (s (br), 3H), 2.05-1.68 (m, 6H), 1.33-0.98 (m, 2H). 192 .sup.1H NMR (300 MHz, cdcl.sub.3) δ 7.96 (d, J = 1.8 Hz, 2H), 7.25 (d, J = 4.5 Hz, 11H), 7.20-7.09 (m, 4H), 5.38 (d, J = 7.9 Hz, 1H), 4.94 (s, 1H), 4.58 (t, J = 6.0 Hz, 2H), 4.02 (s, 1H), 3.82-3.70 (m, 1H), 3.63 (s, 2H), 2.40-2.29 (m, 1H), 2.00-1.84 (m, 3H). 193 .sup.1H NMR (300 MHz, C.sub.6D.sub.6) δ 8.11 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.64 (d, J = 6.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 7.8 Hz, 1H), 6.11 (dd, J = 7.9, 6.4 Hz, 1H), 5.84-5.74 (m, 1H), 5.18 (d, J = 7.9 Hz, 1H), 4.20-3.99 (m, 2H), 3.92-3.75 (m, 1H), 3.64-3.46 (m, 1H), 1.89-1.68 (m, 1H), 1.48-1.28 (m, 3H). 194 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.13-8.07 (m, 2H), 7.72 (d, J = 2.0 Hz, 1H), 7.69-7.62 (m, 2H), 7.51-7.44 (m, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.27-7.20 (m, 2H), 5.38 (d, J = 7.8 Hz, 2H), 4.43 (t, J = 5.5 Hz, 2H), 4.04-3.91 (m, 2H), 3.77-3.65 (m, 2H), 2.40-2.30 (m, 1H), 1.94-1.75 (m, 4H). 195 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 12.19 (s, 1H), 8.07 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.16 (s, 5H), 6.80-6.55 (m, 1H), 5.61 (d, J = 7.8 Hz, 1H), 5.44-5.19 (m, 2H), 4.32-4.05 (m, 1H), 4.05-3.78 (m, 1H), 3.50 (s, 2H), 2.44-2.27 (m, 1H), 2.12-1.70 (m, 3H). 196 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.20 (s, 1H), 6.71 (d, J = 8.1 Hz, 2H), 6.53 (d, J = 8.1 Hz, 2H), 6.35 (d, J = 8.0 Hz, 2H), 6.24 (d, J = 7.9 Hz, 2H), 6.13 (s, 1H), 5.60 (s, 1H), 4.78 (d, J = 7.9 Hz, 1H), 4.55-4.35 (m, 2H), 3.43-3.27 (m, 1H), 3.21-3.03 (m, 1H), 1.74-1.52 (m, 1H), 1.26-1.02 (m, 3H). 197 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.73 (s, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.43-7.34 (m, 2H), 6.89 (s, 1H), 5.47-5.23 (m, 1H), 4.07-3.88 (m, 1H), 3.76-3.63 (m, 1H), 3.57-3.46 (m, 2H), 3.27-3.06 (m, 2H), 2.81 (s, 3H), 2.67-2.54 (m, 2H), 2.42-2.27 (m, 1H), 2.01-1.56 (m, 5H), 1.27-1.01 (m, 3H). 198 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 5.41 (d, J = 7.9 Hz, 1H), 4.80 (s, 1H), 4.52 (dd, J = 6.1, 2.1 Hz, 2H), 4.38 (d, J = 6.0 Hz, 2H), 4.08-3.97 (m, 1H), 3.79-3.70 (m, 1H), 3.68 (dd, J = 13.7, 6.3 Hz, 1H), 3.58 (dd, J = 13.7, 5.9 Hz, 1H), 2.39-2.36 (m, 1H), 1.97-1.89 (m, 3H), 1.32 (s, 3H). 199 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.89 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 9.3 Hz, 2H), 5.40 (d, J = 7.7 Hz, 1H), 4.92 (s, 1H), 4.03-4.01 (m, 1H), 3.89-3.72 (m, 3H), 3.52-.3.44 (m, 2H), 2.39-2.35 (m, 1H), 2.00-1.73 (m, 6H), 1.73-1.58 (m, 1H), 1.20 (d, J = 3.0 Hz, 3H). 200 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.84 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 5.38 (t, J = 7.5 Hz, 1H), 4.99 (s, 1H), 4.76 (s, 1H), 4.00 (s, 1H), 3.84-3.59 (m, 3H), 3.00-2.90 (m, 1H), 2.3-2.32 (m, 1H), 2.01-1.81 (m, 4H), 1.77-1.51 (m, 3H), 1.50-1.33 (m, 3H), 1.32-1.21 (m, 2H). 201 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.89 (d, J = 1.8 Hz, 1H), 7.55 (dd, J = 8.4, 2.2 Hz, 2H), 7.30 (dd, J = 8.5, 2.2 Hz, 2H), 5.41 (d, J = 7.2 Hz, 1H), 5.06 (s, 1H), 4.04 (s, 1H), 3.77 (td, J = 7.5, 3.2 Hz, 1H), 3.57 (dd, J = 6.1, 3.9 Hz, 1H), 3.01-2.80 (m, 2H), 2.37 (td, J = 9.6, 8.8, 4.5 Hz, 1H), 2.13-2.00 (m, 2H), 2.00-1.79 (m, 4H), 1.73-1.68 (m, 1H), 1.42 (s, 3H). 202 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.91 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 5.40 (d, J = 7.8 Hz, 1H), 4.77 (s, 1H), 4.57-4.42 (m, 1H), 4.21-4.09 (m, 2H), 4.02-4.01 (m, 1H), 3.85-3.50 (m, 3H), 3.26-3.13 (m, 2H), 2.38-2.35 (m, 1H), 2.20-2.05 (m, 2H), 1.97-1.89 (m, 3H). 203 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.96 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.29-7.26 (m, 2H), 7.20 (dd, J = 5.0, 1.3 Hz, 1H), 6.98 (d, J = 3.3 Hz, 1H), 6.94-6.92 (m, 1H), 5.40 (d, J = 8.0 Hz, 1H), 4.90-4.66 (m, 2H), 4.03-4.01 (m, 1H), 3.80-3.75 (m, 1H), 2.37-2.35 (m, 1H), 2.00-1.82 (m, 3H). 204 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.84 (d, J = 1.7 Hz, 1H), 7.75-7.55 (m, 5H), 7.41 (s, 1H), 7.25-7.13 (m, 4H), 6.83 (s, 1H), 5.45 (s, 1H), 4.50 (d, J = 6.1 Hz, 2H), 4.29 (dd, J = 12.2, 2.3 Hz, 1H), 4.04-3.78 (m, 3H), 3.75-3.59 (m, 1H). 205 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.98 (s, 1H), 7.59 (d, J = 1.4 Hz, 4H), 5.53 (s, 1H), 4.81 (s, 1H), 4.34 (d, J = 12.0 Hz, 1H), 4.07-3.88 (m, 3H), 3.83-3.71 (m, 1H), 3.54-3.15 (m, 3H), 2.25 (d, J = 6.5 Hz, 2H), 1.91-1.80 (m, 5H), 1.09-0.99 (m, 4H). 206 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.98 (d, J = 1.7 Hz, 1H), 7.62-7.55 (m, 4H), 5.52 (s, 1H), 5.40-5.21 (m, 2H), 4.80 (s, 1H), 4.33 (dd, J = 11.9, 2.4 Hz, 1H), 4.06-3.89 (m, 3H), 3.83-3.72 (m, 1H), 3.48-3.35 (m, 1H), 3.32 (t, J = 6.4 Hz, 2H), 2.10 (d, J = 6.8 Hz, 2H), 1.90-1.78 (m, 5H), 1.52-1.41 (m, 1H), 1.02 (q, J = 10.5, 10.1 Hz, 4H). 207 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.98 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 6.80 (dd, J = 20.3, 3.4 Hz, 2H), 5.42 (d, J = 7.8 Hz, 1H), 5.06 (s, 1H), 4.83-4.50 (m, 2H), 4.05 (m, 1H), 3.80 (s, 3H), 2.38 (q, J = 7.5 Hz, 1H), 2.01-1.87 (m, 3H). 208 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.92 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.34-7.21 (m, 2H), 5.40 (d, J = 7.8 Hz, 1H), 4.61 (s, 1H), 4.07-3.90 (m, 3H), 3.85-3.69 (m, 1H), 3.43-3.22 (m, 4H), 2.46-2.30 (m, 1H), 2.03-1.71 (m, 4H), 1.71-1.47 (m, 2H), 1.41-1.17 (m, 3H). 209 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.35 (s, 1H), 7.72-7.60 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 4.55 (s, 2H), 4.10-3.95 (m, 2H), 2.50 (s, 3H), 2.28-2.13 (m, 1H), 2.12-1.83 (m, 6H). 210 m/z 450 (M + H) 211 m/z 446 (M + H) 212 m/z 462 (M + H) 213 m/z 422 (M + H) 214 m/z 425 (M + H) 215 m/z 451 (M + H) 216 m/z 424 (M + H) 217 m/z 447 (M + H) 218 m/z 409 (M + H) 219 m/z 495 (M + H) 220 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.85 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 5.61 (s, 1H), 5.41 (d, J = 7.9 Hz, 1H), 5.05 (s, 1H), 4.09-3.70 (m, 5H), 3.64-3.54 (m, 3H), 2.46-2.30 (m, 1H), 2.05-1.86 (m, 5H). 221 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 5.40 (d, J = 7.9 Hz, 1H), 5.07 (s, 1H), 4.03-4.00 (m, 1H), 3.82-3.72 (m, 6H), 3.65-3.57 (m, 3H), 3.50 (dd, J = 14.1, 6.8 Hz, 1H), 2.43-2.31 (m, 1H), 1.98-1.90 (m, 3H), 1.64 (t, J = 5.8 Hz, 2H), 1.59-1.42 (m, 4H). 222 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.89 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.6 Hz, 3H), 5.39 (d, J = 8.1 Hz, 1H), 4.68 (s, 1H), 4.04-4.01 (m, 1H), 3.81-3.72 (m, 1H), 3.43-3.33 (m, 2H), 3.09-3.05 (m, 2H), 2.94 (t, J = 12.5 Hz, 2H), 2.39-2.34 (m, 1H), 2.15 (d, J = 10.4 Hz, 2H), 1.97-1.85 (m, 6H). 223 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.28 (s, 2H), 6.57 (s, 1H), 5.41 (d, J = 7.8 Hz, 1H), 4.95 (s, 1H), 4.05 (s, 1H), 3.79 (d, J = 7.9 Hz, 1H), 3.59-3.26 (m, 4H), 2.86 (d, J = 13.5 Hz, 2H), 2.39 (t, J = 7.2 Hz, 1H), 2.21-1.74 (m, 6H). 224 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.92 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 5.46-5.33 (m, 1H), 4.94 (s, 1H), 4.80-4.62 (m, 3H), 4.05-4.01 (m, 1H), 3.80-3.78 (m, 1H), 2.41-2.36 (m, 1H), 2.23-2.21 (m, 1H), 1.99-1.91 (m, 3H), 0.70-0.54 (m, 4H). 225 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.96 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 5.47 (d, J = 7.9 Hz, 1H), 4.16-4.05 (m, 1H), 3.92-3.79 (m, 1H), 3.49-3.23 (m, 3H), 2.49-2.34 (m, 1H), 2.12-1.58 (m, 9H), 1.25 (s, 1H), 1.14-0.79 (m, 4H). 226 m/z 460 (M + H) 227 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.87 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.33-7.19 (m, 6H), 5.37 (d, J = 7.8 Hz, 1H), 4.59 (s, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.07-3.94 (m, 1H), 3.83-3.68 (m, 1H), 2.46-2.25 (m, 1H), 2.03-1.80 (m, 3H). 228 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.84 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 5.44-5.24 (m, 2H), 4.89 (s, 1H), 4.46-4.31 (m, 4H), 4.10-3.96 (m, 1H), 3.86-3.66 (m, 5H), 2.46-2.28 (m, 1H), 2.04-1.85 (m, 3H). 229 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.61 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 4.53 (s, 2H), 4.10-3.96 (m, 2H), 3.48 (s, 2H), 2.26-2.10 (m, 1H), 2.09-1.82 (m, 6H). 230 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 7.30-7.24 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 5.53 (s, 1H), 5.32 (s, 2H), 5.03 (s, 1H), 4.67 (d, J = 5.7 Hz, 2H), 4.38-4.29 (m, 1H), 4.05-3.90 (m, 3H), 3.77 (td, J = 11.2, 2.8 Hz, 1H), 3.58 (s, 2H), 3.48-3.39 (m, 1H). 231 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.4 Hz, 2H), 5.88-5.49 (m, 1H), 5.31 (s, 2H), 4.94 (s, 1H), 4.72-4.50 (m, 2H), 4.31 (q, J = 13.0 Hz, 1H), 4.19 (q, J = 12.6 Hz, 1H), 3.57 (s, 2H), 3.16-2.77 (m, 1H), 2.58-1.97 (m, 1H). 232 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (d, J = 1.9 Hz, 1H), 7.34-7.28 (m, 4H), 7.25-7.17 (m, 3H), 5.60 (d, J = 8.2 Hz, 1H), 5.30 (s, 2H), 4.85 (s, 1H), 4.72-4.39 (m, 2H), 4.20-3.95 (m, 1H), 3.90-3.73 (m, 1H), 3.57 (s, 2H), 2.55-2.22 (m, 1H), 2.11-1.75 (m, 3H). 233 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.86 (s, 1H), 7.65-7.56 (m, 4H), 5.45 (s, 1H), 4.60-4.46 (m, 1H), 4.30 (dd, J = 12.0, 2.8 Hz, 1H), 4.04-3.84 (m, 4H), 3.84-3.69 (m, 1H), 3.50-3.36 (m, 2H), 2.83 (s, 2H), 2.36 (t, J = 8.1 Hz, 1H), 2.13-2.06 (m, 3H), 1.96-1.69 (m, 3H), 1.33-0.98 (m, 2H). 234 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.88 (s, 1H), 7.63 (d, J = 1.1 Hz, 4H), 5.53-5.47 (m, 1H), 4.34 (dd, J = 12.1, 2.5 Hz, 1H), 4.11 (q, J = 7.2 Hz, 1H), 4.06-3.88 (m, 3H), 3.85-3.70 (m, 1H), 3.52 (s, 2H), 3.50-3.36 (m, 2H), 2.97-2.86 (m, 2H), 2.15-2.02 (m, 4H). 235 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.86 (s, 1H), 7.67-7.58 (m, 4H), 5.49-5.44 (m, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.36-4.26 (m, 3H), 4.05-3.87 (m, 3H), 3.84-3.71 (m, 1H), 3.61 (s, 2H), 3.50-3.38 (m, 1H), 1.33 (s, 3H). 236 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.67-7.58 (m, 3H), 7.41 (s, 4H), 7.31 (d, J = 8.1 Hz, 2H), 5.34-5.23 (m, 1H), 4.51 (s, 2H), 4.12 (dd, J = 12.0, 2.6 Hz, 1H), 3.83-3.65 (m, 3H), 3.56 (td, J = 10.8, 2.8 Hz, 1H), 3.29-3.16 (m, 1H), 1.96-1.88 (m, 1H), 0.34-0.22 (m, 4H). 237 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.86 (s, 1H), 7.66-7.59 (m, 4H), 5.47-5.42 (m, 1H), 4.30 (dd, J = 12.0, 2.9 Hz, 1H), 4.04-3.86 (m, 3H), 3.84-3.68 (m, 3H), 3.50-3.38 (m, 1H), 2.81 (s, 3H), 2.76-2.63 (m, 2H), 2.02 (d, J = 0.9 Hz, 1H), 1.92-1.67 (m, 3H), 1.38-1.19 (m, 3H). 238 m/z 443 (M + H) 239 m/z 485 (M + H) 240 m/z 517 (M + H) 241 m/z 492 (M + H) 242 m/z 492 (M + H) 243 m/z 513 (M + H) 244 m/z 504 (M + H) 245 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.99 (d, J = 1.6 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.50 (s, 1H), 5.41-5.18 (m, 2H), 4.81 (s, 1H), 4.33 (d, J = 11.8 Hz, 1H), 4.06-3.88 (m, 3H), 3.82-3.71 (m, 1H), 3.47-3.26 (m, 3H), 2.11 (d, J = 6.8 Hz, 2H), 1.91-1.73 (m, 5H), 1.03 (q, J = 10.3, 9.7 Hz, 4H). 246 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.93 (d, J = 1.6 Hz, 1H), 7.58-7.46 (m, 2H), 7.27-7.10 (m, 6H), 5.56 (s, 1H), 5.36 (m, 1H), 4.59 (d, J = 5.7 Hz, 2H), 4.35 (dd, J = 12.0, 2.0 Hz, 1H), 4.24 (s, 2H), 4.08-3.89 (m, 3H), 3.77 (td, J = 11.2, 2.7 Hz, 1H), 3.49 (s, 1H), 3.43 (m, 1H). 247 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (s, 1H), 7.61 (s, 4H), 5.44 (t, J = 3.1 Hz, 1H), 4.29 (dd, J = 12.1, 2.9 Hz, 2H), 4.00-3.86 (m, 4H), 3.84-3.72 (m, 1H), 3.50-3.26 (m, 5H), 1.96-1.79 (m, 1H), 1.71-1.62 (m, 2H), 1.37-1.20 (m, 2H). 248 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.36-7.27 (m, 4H), 7.23 (d, J = 8.1 Hz, 2H), 5.28-5.24 (m, 3H), 4.82 (m, 2H), 4.60 (dd, J = 10.3, 5.7 Hz, 2H), 4.08 (m, 1H), 3.57 (s, 2H), 3.45 (t, J = 10.3 Hz, 1H), 2.64-2.51 (m, 1H), 2.36 (m, 1H), 1.52-1.40 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H). 249 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.95 (d, J = 1.6 Hz, 1H), 7.58 (s, 4H), 5.94 (s, 1H), 5.51 (d, J = 17.3 Hz, 2H), 5.39-5.17 (m, 1H), 4.39-4.28 (m, 1H), 4.07-3.85 (m, 4H), 3.85-3.69 (m, 1H), 3.66 (d, J = 6.0 Hz, 2H), 3.51-3.30 (m, 1H), 1.98-1.94 (m, 2H), 1.88-1.66 (m, 6H). 250 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.93 (d, J = 1.6 Hz, 1H), 7.58 (s, 4H), 5.50 (s, 2H), 4.32 (dd, J = 12.1, 2.3 Hz, 1H), 4.09-3.86 (m, 3H), 3.82-3.68 (m, 1H), 3.63 (d, J = 5.8 Hz, 2H), 3.48-3.30 (m, 1H), 3.00 (s, 6H), 2.28-1.92 (m, 2H), 1.94-1.75 (m, 6H). 251 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.97 (s, 1H), 7.58 (s, 4H), 5.65-5.39 (m, 2H), 4.63 (d, J = 8.1 Hz, 1H), 4.39-4.28 (m, 1H), 4.08-3.69 (m, 5H), 3.61-3.24 (m, 4H), 2.98 (d, J = 2.2 Hz, 3H), 2.33-1.80 (m, 3H), 1.83-1.58 (m, 3H). 252 .sup.1H NMR (300 MHz, CDCl3): δ 8.46 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.28-7.18 (m, 6H), 6.97 (d, J = 3.7 Hz, 1H), 6.44 (d, J = 3.7 Hz, 1H), 6.05 (s, 1H), 5.44-5.35 (m, 3H), 4.55-451 (m, 2H), 4.13-08 (m, 2H), 3.86-3.72 (m, 1H), 3.60-155 (m, 3H). 253 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.94 (d, J = 1.7 Hz, 1H), 7.59 (s, 4H), 5.78 (m, 1H), 5.55 (s, 1H), 4.35 (dd, J = 12.0, 2.2 Hz, 1H), 4.09-3.83 (m, 7H), 3.82-3.65 (m, 3H), 3.48-3.35 (m, 1H), 3.13 (s, 2H), 3.00 (s, 3H), 1.87-1.60 (m, 4H). 254 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.96 (d, J = 1.7 Hz, 1H), 7.59 (s, 4H), 5.54 (s, 1H), 5.02 (m, 1H), 4.37-4.32 (m, 1H), 4.04-3.76 (m, 6H), 3.73-3.55 (m, 5H), 3.55-3.41 (m, 3H), 2.14-2.09 (m, 2H), 1.65-1.55 (m, 2H). 255 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.95 (d, J = 1.8 Hz, 1H), 7.59 (s, 4H), 5.88 (s, 1H), 5.55 (s, 1H), 5.43 (s, 1H), 5.22 (q, J = 5.5 Hz, 1H), 4.37-4.33 (m, 1H), 4.04-4.63 (m, 10H), 3.46-3.37 (m, 1H), 2.06 (m, 2H), 1.75-1.66 (m, 2H). 256 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.96-7.84 (m, 2H), 7.84-7.75 (m, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 6.87 (s, 1H), 5.44 (s, 1H), 4.37-4.04 (m, 3H), 4.04-3.81 (m, 4H), 3.61 (dd, J = 42.7, 13.3 Hz, 5H), 3.40-3.21 (m, 4H), 2.82 (d, J = 6.2 Hz, 2H), 1.95 (d, J = 13.7 Hz, 2H), 1.48 (t, J = 11.0 Hz, 2H). 257 .sup.1H NMR (300 MHz, CDCl.sub.3): 7.97 (d, J = 1.7 Hz, 1H), 7.60 (s, 4H), 5.59 (s, 1H), 5.07 (s, 1H), 4.39-4.35 (m, 1H), 4.04-3.93 (m, 5H), 3.80-3.64 (m, 5H), 3.48-3.38 (m, 1H), 1.89-1.54 (m, 4H). 258 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.00 (d, J = 1.6 Hz, 1H), 7.58 (t, J = 8.4 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.26 (s, 2H), 7.00-6.93 (m, 2H), 5.61 (s, 1H), 5.33 (s, 2H), 5.02 (s, 1H), 4.70-4.61 (m, 2H), 4.20-4.16 (m, 1H), 4.06-3.96 (m, 3H), 3.81-3.75 (m, 1H), 3.62-3.55 (m, 3H). 259 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.89 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 5.60 (m, 1H), 4.73 (s, 1H), 4.32-4.16 (m, 2H), 3.99-3.94 (m, 2H), 3.40-3.30 (m, 4H), 2.94-2.87 (m, 1H), 2.41-2.35 (m, 1H), 1.82 (m, 1H), 1.66-1.62 (m, 2H), 1.40-1.26 (m, 2H). 260 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.84 (d, J = 1.8 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 5.66-5.58 (m, 2H), 4.31-4.15 (m, 2H), 4.06-3.86 (m, 4H), 3.70-3.66 (m, 2H), 3.09 (s, 2H), 2.98-2.86 (m, 4H), 2.40-2.34 (m, 1H), 1.80-1.54 (m, 4H), 1.11-0.95 (m, 1H). 261 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.84 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.60 (m, 1H), 5.01 (m, 1H), 4.93 (t, J = 7.3 Hz, 1H), 4.44-4.32 (m, 4H), 4.29-4.15 (m, 2H), 3.86-3.80 (m, 2H), 3.71 (d, J = 7.1 Hz, 2H), 2.94-2.86 (m, 1H), 2.45-2.34 (m, 1H). 262 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.86 (s, 1H), 7.70-7.55 (s, 4H), 5.47 (s, 1H), 4.38-4.25 (m, 2H), 4.05-3.86 (m, 3H), 3.86-3.55 (m, 4H), 3.53-3.30 (m, 3H), 2.10 (s, 3H), 1.96-1.48 (m, 4H). 263 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.86 (s, 1H), 7.67-7.61 (m, 4H), 5.45 (s, 1H), 4.31 (dd, J = 12.0, 2.8 Hz, 2H), 4.05-3.88 (m, 5H), 3.85-3.72 (m, 1H), 3.51-3.35 (m, 2H), 3.16-3.01 (m, 2H), 1.95-1.81 (m, 3H), 1.38-1.20 (m, 2H). 264 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.87 (t, J = 1.3 Hz, 1H), 7.67-7.61 (m, 4H), 5.47 (s, 1H), 4.06-3.89 (m, 3H), 3.86-3.63 (m, 7H), 3.49-3.38 (m, 1H), 1.92-1.69 (m, 4H). 265 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.11 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 5.39 (d, J = 8.0 Hz, 1H), 5.31 (s, 2H), 4.56-4.44 (m, 2H), 4.01 (t, J = 9.8 Hz, 1H), 3.79-3.77 (m, 1H), 3.56 (s, 2H), 3.28-3.10 (m, 3H), 2.91-2.63 (m, 1H), 2.35 (m, 1H), 1.96-1.90 (m, 3H). 266 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.87 (s, 1H), 7.71-7.56 (m, 4H), 5.48 (s, 1H), 4.33 (d, J = 11.9 Hz, 2H), 4.06-3.85 (m, 3H), 3.85-3.53 (m, 5H), 3.52-3.30 (m, 2H), 2.85 (s, 3H), 2.05-1.63 (m, 4H). 267 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.98 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 5.51 (s, 1H), 4.79 (d, J = 2.9 Hz, 1H), 4.33 (dd, J = 1.7, 12.0 Hz, 1H), 4.18 (br d, J = 7.8 Hz, 1H), 4.05-3.90 (m, 3H), 3.76 (dt, J = 3.2, 11.4 Hz, 1H), 3.48-3.23 (m, 4H), 2.98 (s, 3H), 2.11 (d, J = 10.3 Hz, 2H), 1.89 (br d, J = 12.7 Hz, 2H), 1.59-1.49 (m, 1H), 1.33-1.19 (m, 3H), 1.12 (m, 2H). 268 m/z 485 (M + H) 273 m/z 484 (M + H) 274 m/z 450 (M + H) 276 m/z 423 (M + H) 279 m/z 406 (M + H) 280 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.97 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.8 Hz, 4H), 7.26-7.21 (m, 2H), 5.99 (d, J = 9.3 Hz, 1H), 5.33 (br s, 2H), 4.99 (m, 1H), 4.69-4.56 (m, 2H), 4.38-4.20 (m, 2H), 3.57 (s, 2H), 3.22 (dd, J = 9.5, 18.3 Hz, 1H), 2.62-2.57 (m, 1H). 282 m/z 429 (M + H) 283 m/z 428 (M + H) 284 m/z 428 (M + H) 285 .sup.1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 1.7 Hz, 1H), 7.55-7.47 (m, 2H), 7.17 (dq, J = 8.9, 1.0 Hz, 2H), 5.51 (d, J = 2.8 Hz, 1H), 4.87 (s, 1H), 4.54 (d, J = 8.0 Hz, 1H), 4.33 (dd, J = 12.1, 2.1 Hz, 1H), 4.04-3.91 (m, 3H), 3.89-3.64 (m, 3H), 3.49-3.26 (m, 4H), 2.19-2.06 (m, 2H), 1.97-1.84 (m, 2H), 1.65-1.45 (m, 1H), 1.38-1.20 (m, 2H), 1.20-1.01 (m, 2H). 286 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.86 (d, J = 1.6 Hz, 1H), 7.66-7.60 (m, 4H), 5.44 (t, J = 3.1 Hz, 1H), 4.31 (dd, J = 12.1, 2.9 Hz, 1H), 4.06-3.74 (m, 7H), 3.61 (d, J = 2.0 Hz, 2H), 3.53-3.39 (m, 3H), 2.67 (s, 3H), 2.14-1.99 (m, 2H), 1.72-1.54 (m, 2H). 287 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.84 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.12 (s, 1H), 5.44-5.39 (m, 1H), 4.27 (dd, J = 12.1, 2.5 Hz, 1H), 3.89 (m, 3H), 3.72-3.60 (m, 1H), 3.41-3.25 (m, 2H), 3.20-3.12 (m, 2H), 2.41 (d, J = 6.5 Hz, 2H), 1.80-1.67 (m, 4H), 1.60-1.43 (m, 2H), 1.07-0.80 (m, 4H). 288 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.83 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.15-7.06 (m, 1H), 5.41 (s, 1H), 4.27 (dd, J = 12.1, 2.5 Hz, 1H), 3.99-3.80 (m, 3H), 3.71-3.60 (m, 1H), 3.39-3.25 (m, 2H), 3.18-3.11 (m, 2H), 2.75 (d, J = 6.7 Hz, 2H), 1.75-1.57 (m, 5H), 1.57-1.41 (m, 1H), 1.03-0.79 (m, 4H). 290 .sup.1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 3.9 Hz, 1H), 6.54 (d, J = 2.9 Hz, 1H), 5.93 (s, 1H), 4.53 (d, J = 13.2 Hz, 1H), 4.42 (d, J = 11.7 Hz, 1H), 4.14-4.05 (m, 2H), 4.00-3.91 (m, 2H), 3.66 (dt, J = 2.7, 11.6 Hz, 1H), 3.57-3.43 (m, 3H), 2.81 (s, 3H), 2.69-2.55 (m, 2H), 1.97 (m, 1H), 1.54 (br d, J = 11.2 Hz, 2H), 1.32-1.19 (m, 2H). 291 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.95 (s, 1H), 7.56 (s, 4H), 7.19 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 5.53 (s, 1H), 5.15-5.06 (m, 1H), 4.58 (d, J = 5.4 Hz, 2H), 4.32 (d, J = 12.2 Hz, 1H), 4.03-3.86 (m, 3H), 3.80-3.70 (m, 1H), 3.40 (t, J = 10.5 Hz, 1H), 2.60 (s, 1H). 292 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (d, J = 1.6 Hz, 1H), 7.67-7.62 (m, 4H), 7.32 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 5.51-5.44 (m, 1H), 4.62 (s, 2H), 4.33 (dd, J = 12.1, 2.8 Hz, 1H), 4.07-3.89 (m, 3H), 3.85-3.75 (m, 1H), 3.66 (s, 2H), 3.53-3.37 (m, 1H). 293 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.72 (s, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00-7.92 (m, 2H), 7.60 (s, 4H), 5.60 (s, 1H), 5.22 (s, 1H), 4.81 (d, J = 5.9 Hz, 2H), 4.38 (dd, J = 2.0, 12.2 Hz, 1H), 4.09-3.99 (m, 2H), 3.95 (d, J = 11.2 Hz, 1H), 3.78 (dt, J = 2.7, 11.4 Hz, 1H), 3.44 (ddd, J = 3.4, 11.0, 13.9 Hz, 1H), 3.22 (s, 3H). 294 m/z 505 (M + H) 295 m/z 469 (M + H) 296 m/z 427 (M + H) 297 m/z 504 (M + H) 299 m/z 450 (M + H) 300 m/z 422 (M + H) 301 m/z 450 (M + H) 302 m/z 420 (M + H) 303 m/z 448 (M + H) 304 m/z 436 (M + H) 305 m/z 485 (M + H) 306 m/z 440 (M + H) 307 m/z 460 (M + H) 308 m/z 488 (M + H) 309 m/z 520 (M + H) 310 m/z 463 (M + H) 311 m/z 456 (M + H) 312 m/z 456 (M + H) 313 m/z 410 (M + H) 314 m/z 412 (M + H) 315 m/z 412 (M + H) 316 m/z 424 (M + H) 317 m/z 424 (M + H) 318 m/z 466 (M + H) 319 m/z 497 (M + H) 320 m/z 554 (M + H) 323 m/z 490 (M + H) 324 m/z 518 (M + H) 325 m/z 455 (M + H) 326 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.92 (s, 1H), 8.40 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.69-7.60 (m, 1H), 7.25-7.17 (m, 4H), 6.95 (d, J = 3.7 Hz, 1H), 6.42 (d, J = 3.7 Hz, 1H), 6.21 (s, 1H), 5.40 (s, 2H), 5.33 (br s, 2H), 4.49 (d, J = 12.5 Hz, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.18-4.05 (m, 2H), 3.90-3.76 (m, 1H), 3.68-3.58 (m, 1H), 3.56 (s, 2H). 327 m/z 504 (M + H) 328 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.91 (s, 1H), 8.38 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25-7.16 (m, 4H), 6.91 (d, J = 3.7 Hz, 1H), 6.35 (d, J = 3.7 Hz, 1H), 5.96 (s, 1H), 5.47-5.29 (m, 4H), 4.93 (d, J = 11.3 Hz, 1H), 4.70 (d, J = 12.4 Hz, 1H), 4.04 (dd, J = 3.7, 11.3 Hz, 2H), 3.88-3.62 (m, 2H), 3.55 (s, 2H). 329 m/z 534 (M + H) 330 m/z 534 (M + H)

[0397] Biological Evaluation

[0398] The activity of the compounds was evaluated using a Fluorescence Polarization (FP) Assay and, in most cases, a Th17 Assay and/or RORγ Reporter assay (also referred to as Gal4 assay). The FP assay is an in vitro assay monitoring binding within the ligand binding pocket. The RORγ and the Th17 assays are both cell-based assays monitoring functional activity of the compound assayed.

[0399] Fluorescence Polarization (FP) Assay

[0400] A buffer containing 10 mM Hepes, 150 mM NaCl, 1 mM DTT, 0.05% Pluronic F-127 detergent (all from Sigma), and 100 nM human RORγt (Ligand Binding Domain obtained from Crelux (Planegg, Germany), batch no PC5032-1) was complemented with 1 μl test compounds diluted in 100% DMSO. The total volume was 25 μl, in a black Perkin Elmer OptiPlate. As negative control, 1 μl DMSO was used. Samples were incubated at room temperature for 30 min, followed by addition 5 μl of probe diluted in assay buffer to a concentration of 125 nM (final concentration of probe is 25 nM). The probe is a fluorescently labeled (TAMRA) RORγt ligand identified by Nuevolution with a total molecular weight of 910 g/mole as shown in Graph A in FIG. 1. Graph (B) in FIG. 2 shows the polarization signal rises with increasing concentration of human RORγt (LBD), using 50 nM TAMRA-labelled probe concentration. Graph (C) of FIG. 2 shows the RORγt inhibitor SR2211 (1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4′-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; see Kumar et al, ACS Chem. Biol., 2012, 7 (4), pp 672-677) inhibits the probe from binding RORγt with an IC50 of 0.36 μM, which is close to the value reported in the literature. The plate was incubated for 10 min at room temperature and fluorescence polarization was read using an Envision 2102 plate reader (Perkin Elmer) with the TAMRA FP optical module installed.

[0401] Th17 Assay

[0402] Human peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats of healthy human volunteers using the Ficoll paque PLUS kit (GE Healthcare, cat no 17-1440-02), as instructed by the manufacturer. Naive CD4+ T cells were isolated with Naive CD4+ T cell kit, human (Milteny Biotec, cat no 130-094-131). The following modifications were made to the manufacturer's protocol: 1) Incubation with Biotin-Antibody Cocktail and Anti-Biotin MicroBeads was prolonged to 30 minutes, and 2) Cells were washed with 40 mL of Miltenyi buffer. Differentiation of Th17 cells in anti-CD3 (BD Pharmingen, 5 μg/ml) coated 96-well plates (400,000 cells/well, 160 μl RPMI 1640+10% Fetal Bovine Serum) containing 5 μg/ml anti-CD28 (BD Pharmingen), 10 ng/ml IL-2 (R&D Systems), 2.5 ng/ml TGFβ-1 (R&D Systems), 20 ng/ml IL-1β (R&D Systems), 20 ng/ml IL-6 (R&D Systems), 30 ng/ml IL-23 (R&D Systems), 2.5 μg/ml anti-IL-4 (R&D Systems) and 1 μg/ml anti-IFNγ (R&D Systems) and with test compound during the entire differentiation (or vehicle, 0.1% DMSO for control). Test compounds were tested in triplicates, diluted 1000-fold in medium (final DMSO concentration is 0.1%). Incubated for seven days at 37° C., 5% CO.sub.2, 95% humidity, and 2-fluoro-4′-[[4-(4-pyridinylmethyl)-1-piperazinyl]methyl]-α,α-bis(trifluoromethyl)-[1,1′-biphenyl]-4-methanol (SR2211 Calbiochem, Cat. No. 557353) was used as positive control. As negative control, cells were differentiated into Th0 using 5 μg/ml anti-CD28 (BD Pharmingen), 10 ng/ml IL-2 (R&D Systems), 2 μg/ml anti-IL4 (R&D Systems) and 2 μg/ml anti-IFNγ (R&D Systems) are negative control. IL-17 levels in supernatants were measured with ELISA (R&D Systems).

[0403] RORγ Reporter Assay (Gal4)

[0404] Cell-based RORγ functional assays were performed using a commercially available assay product (INDIGO Biosciences, State College, Pa., USA; product #IB04001). The RORγ reporter cells are HEK293t cells transfected with one vector that provides high level constitutive expression of a hybrid protein comprised of the yeast Gal4-DNA binding domain fused to the ligand binding domain of human RORγ, and a second vector comprising the firefly luciferase cDNA functionally linked to the upstream activation sequence (UAS) of yeast Gal4. A suspension of RORγ Reporter Cells was prepared using the protocol and culture medium provided in the kit product, and 100 μl of the Reporter Cell suspension was then dispensed into wells of a white, collagen-treated, 96-well assay plate. Concentrated stocks of test compounds were prepared in DMSO, then further diluted using media provided in the kit to generate ‘2×-concentration’ treatment media. 100 μl of medium for each respective treatment concentration dispensed into triplicate assay wells, thereby combining with the reporter cells. All media formulations contained 10% charcoal stripped Fetal Bovine Serum, but are otherwise proprietary to INDIGO Biosciences. Final treatment concentrations for each test compound were 1,000 nM and 100 nM, each with 0.1% residual DMSO. Separate control treatments were media supplemented with vehicle only (0.1% DMSO) to determine the constitutive level of RORγ activity in the reporter cells, and the reference inverse-agonist ursolic acid (f.c. 6,000 nM to 8.2 nM in 3-fold decrements) to establish a positive control inverse-agonist dose response. Assay plates were placed in a 37° C., 5% CO.sub.2, 85% humidity incubator for 24 hour. Treatment media were then discarded, 100 μl of luciferase detection reagent was added to each well, and relative light units (RLUs) were quantified from each assay well using a plate reading luminometer. Values of average RLU+/−standard deviation were computed for all treatment sets, followed by the calculations of fold-reduction: [Average RLU.sub.Vehicle/Average RLU.sub.Test Cmpd]. Percent-reduction of RORγ activity in response to respective test compound treatments was calculated: [100*(1−[Ave RLU.sub.Test Cmpd/Ave RLU.sub.Vehicle)] where the theoretical minimum reduction (0% reduction) derives from Vehicle treatment only, no treatment compound.

[0405] In some aspects it may be of interest to provide compounds with selective modulation of RORγ for example compounds that are selective to RORγ over RORα, compounds that are selective for RORγ versus RORβ, and compounds that are selective for RORγ versus BOTH RORα and RORβ. It may also be of interest to provide compounds that are selective for RORγ versus further nuclear hormone receptors such as CAR1, FXR, GR, LXRα, LXRβ, PPARα, PXR, RARα, RXRα, TRα, VDR. It is apparent to those skilled in the art that these nuclear hormone receptors are merely examples, and that selectivity against other nuclear receptors may also be of interest. It may for example be of interest to provide compounds that modulate RORγ and one or more further nuclear hormone receptors, as well as compounds that modulate both RORγ and RORα, or RORγ and RORP. It may also be of interest to provide compounds that modulate RORγ and BOTH RORα and RORβ, as well as compounds that modulate both RORγ and one or more further nuclear hormone receptors such as CAR1, FXR, GR, LXRα, LXRβ, PPARα, PXR, RARα, RXRα, TRα, VDR. It is apparent to those skilled in the art that these nuclear hormone receptors are merely examples, and that modulation of even other nuclear receptors may also be of interest. By substituting the ligand binding domain of another nuclear hormone receptor for the ligand binding domain of RORγ, the reporter assay (Gal4) may be modified to provide activity data for compounds against said other nuclear hormone receptor. Those skilled in the art know how to accomplish such modification. By comparing activity against RORγ to activity against another nuclear hormone receptor in this assay, the selectivity of a compound towards RORγ versus said other nuclear hormone receptor can be established. A compound may be said to be selective for RORγ versus another nuclear hormone receptor if the activity of the compound against RORγ is greater than 5, 10, 20, or 100 fold higher for RORγ than for said other nuclear receptor. The compound(s) or pharmaceutical composition(s) described herein may modulate the activity of an RORγ receptor to a larger extent than it modulates the activity of RORα and/or RORβ receptors.

[0406] The results of the Fluorescence Polarization (FP) Assay, Th17 Assay, and RORγ Reporter (Gal4) Assay are shown in Tables 2-5 below.

TABLE-US-00007 TABLE 2 Activity Data of Example Compounds obtained from the Fluorescence Polarization (FP) Assay. Example. FP activity range No. (nM) 4 <500 5 <500 6 <10000 9 <500 11 <500 13 <10000 14 <10000 15 <10000 17 <500 18 <500 19 <500 20 <2000 21 <10000 23 <500 24 <500 26 <500 29 <1000 30 <500 31 <10000 32 <500 33 <10000 34 <1000 35 <500 36 <2000 37 <1000 38 <2000 39 <10000 40 <1000 41 <2000 42 <2000 43 <1000 44 <10000 45 <10000 46 <1000 48 <2000 51 <1000 52 <2000 53 <1000 54 <1000 55 <10000 56 <2000 57 <10000 58 <10000 59 <10000 60 <2000 61 <10000 62 <500 63 <2000 64 <2000 65 <500 66 <2000 67 <2000 68 <2000 69 <1000 70 <2000 71 <10000 72 <1000 73 <2000 74 <2000 79 <500 81 <500 85 <500 88 <500 89 <500 90 <1000 91 <500 93 <500 94 <500 95 <1000 97 <1000 98 <1000 100 <2000 105 <10000 106 <10000 107 <10000 108 <10000 109 <2000 110 <10000 111 <500 113 <500 114 <1000 115 <500 116 <1000 117 <500 118 <10000 119 <1000 120 <10000 122 <10000 123 <10000 126 <2000 128 <500 129 <500 130 <10000 131 <2000 132 <10000 134 <10000 135 <10000 136 <2000 137 <10000 138 <500 139 <2000 140 <500 141 <2000 142 <2000 143 <2000 144 <10000 145 <10000 146 <2000 147 <2000 148 <1000 150 <10000 151 <10000 152 <500 154 <500 155 <10000 159 <2000 161 <500 164 <500 165 <500 166 <500 167 <500 168 <500 169 <500 170 <10000 175 <10000 178 <500 181 <10000 182 <500 183 <500 184 <500 185 <1000 186 <500 188 <500 189 <500 190 <500 191 <500 192 <500 193 <10000 194 <2000 195 <500 196 <500 197 <500 198 <500 199 <1000 200 <1000 201 <500 202 <10000 203 <2000 204 <500 205 <500 206 <1000 207 <500 208 <500 209 <1000 210 <1000 211 <1000 212 <10000 213 <10000 214 <10000 215 <10000 216 <10000 217 <10000 218 <10000 219 <10000 220 <500 221 <500 222 <2000 223 <500 224 <500 225 <500 226 <10000 227 <500 228 <500 229 <500 230 <500 231 <500 232 <500 233 <500 234 <1000 235 <2000 236 <500 237 <500 238 <10000 239 <500 240 <500 241 <1000 242 <2000 243 <500 244 <2000 245 <1000 246 <500 247 <10000 248 <1000 249 <10000 250 <10000 251 <10000 252 <500 253 <1000 254 <500 255 <2000 256 <10000 257 <500 258 <500 259 <500 260 <500 261 <1000 262 <1000 263 <500 264 <500 265 <500 266 <500 267 <500 268 <10000 273 <500 274 <2000 276 <2000 278 <500 280 <500 282 <10000 283 <1000 284 <500 285 <500 286 <2000 287 <500 288 <500 290 <500 291 <1000 292 <500 293 <1000 294 <10000 295 <500 296 <10000 297 <10000 299 <1000 300 <10000 301 <500 302 <500 303 <500 304 <500 305 <500 306 <500 307 <2000 308 <10000 309 <2000 310 <500 311 <500 312 <500 313 <500 314 <10000 315 <10000 316 <500 317 <10000 318 <500 319 <500 320 <500 323 <500 324 <500 325 <1000 326 <500 327 <1000 328 <500 329 <2000 330 <2000

TABLE-US-00008 TABLE 3 Activity Data of Example Compounds obtained from the Th17 Assay. Example. Th17 activity range @ 1 μM No. (% inhibition) 6 >20 13 >20 16 >0 18 >80 19 >80 29 >50 30 >50 33 >20 35 >50 36 >50 38 >50 40 >80 62 >80 67 >80 77 >50 78 >50 79 >50 80 >50 81 >80 83 >20 85 >80 88 >80 89 >20 91 >80 94 >80

TABLE-US-00009 TABLE 4 Activity Data of Example Compounds obtained from the RORγ Reporter Assay (Gal4) at 1 μM. Example. Gal4 activity range @ 1 μM No. (% inhibition) 14 >0 17 >80 20 >50 30 >80 31 >0 39 >20 42 >20 43 >80 51 >80 52 >80 53 >20 54 >50 56 >20 60 >20 62 >80 63 >20 64 >20 65 >20 66 >50 67 >80 68 >80 69 >50 72 >80 73 >20 74 >80 79 >50 81 >80 84 >20 85 >80 86 >20 87 >20 89 >80 90 >20 91 >80 93 >50 94 >80 95 >80 96 >20 97 >80 98 >80 99 >50 100 >20 104 >20 106 >20 107 >0 109 >20 110 >0 111 >80 112 >20 113 >80 114 >80 115 >80 116 >50 117 >80 118 >20 119 >80 121 >50 123 >20 124 >20 126 >50 190 >80 191 >80 197 >80 198 >80 199 >80 200 >80 201 >80 202 >50 203 >50 204 >80 205 >80 206 >80 207 >80 208 >80 209 >50 210 >80 211 >50 220 >80 221 >80 222 >80 223 >80 224 >80 225 >80 226 >50 227 >80 228 >80 229 >80 230 >80 231 >80 232 >80 233 >80 234 >50 235 >50 236 >80 237 >80 238 >50 239 >80 240 >80 245 >80 246 >80 247 >80 248 >80 252 >80 253 >80 254 >80 255 >50 257 >80 258 >80 259 >80 260 >80 261 >80 262 >50 263 >80 264 >80 265 >80 266 >80 267 >80 273 >80 274 >50 276 >20 279 >50 280 >20 282 >0 283 >20 284 >50 285 >20 286 >20 287 >80 288 >80 290 >80 291 >50 292 >20 295 >80 299 >80 300 >20 301 >80 302 >50 303 >80 304 >80 305 >80 306 >80 307 >50 308 >50 313 >80 316 >80 318 >20 319 >0 320 >80 323 >80 324 >80 326 >80 327 >80 328 >80

TABLE-US-00010 TABLE 5 Activity Data of Example Compounds obtained from the RORγ Reporter Assay (Gal4) at 0.1 μM. Example. Gal4 activity range @ 0.1 μM No. (% inhibition) 73 >0 89 >20 90 >0 91 >20 93 >0 94 >80 95 >20 96 >0 97 >20 98 >20 99 >20 104 >0 111 >50 112 >0 113 >50 114 >20 115 >50 116 >20 117 >50 118 >0 119 >20 121 >20 123 >0 126 >20 128 >50 129 >50 131 >20 140 >20 148 >50 152 >0 161 >20 164 >20 165 >50 167 >0 168 >50 169 >0 182 >50 183 >50 185 >50 186 >0 188 >0 189 >20 190 >80 191 >50 192 >50 195 >80 196 >80 197 >80 198 >20 199 >20 200 >20 201 >0 202 >0 203 >0 204 >50 205 >50 206 >20 207 >20 208 >50 209 >20 210 >50 211 >0 220 >20 221 >50 222 >20 223 >50 224 >80 225 >80 227 >80 228 >20 229 >50 230 >50 231 >50 232 >50 233 >20 234 >0 235 >0 236 >80 237 >80 238 >0 239 >20 240 >80 245 >20 246 >20 247 >20 248 >20 252 >80 253 >50 254 >50 255 >20 257 >50 258 >80 259 >50 260 >50 261 >20 262 >20 263 >50 264 >20 265 >80 266 >80 267 >80 273 >20 274 >20 276 >0 279 >20 280 >0 282 >0 283 >0 284 >20 285 >0 286 >20 287 >50 288 >80 290 >50 291 >0 292 >0 295 >20 299 >0 300 >20 301 >50 302 >20 303 >80 304 >20 305 >50 306 >50 307 >20 308 >20 313 >20 316 >20 318 >20 320 >80 323 >80 324 >50 326 >50 327 >20 328 >80

[0407] As can be seen from the tables above, the compounds were found to show beneficial activity across the assays. FIG. 3 graphically illustrates the assay results of example no. 89.

[0408] According to an embodiment, compounds having inhibition values of greater than 80% in both an RORγ Reporter Assay (Gal4) and a Th17 Assay are disclosed herein. According to an embodiment the compounds have inhibition values of greater than 80% in both a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 1000 nM, such as less than 500 nM.

[0409] According to an embodiment the compounds are having inhibition values of greater than 80% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 80% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 1000 nM, such as less than 500 nM.

[0410] According to an embodiment the compounds are having inhibition values of greater than 50% in both an RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 50% in both a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 1000 nM, such as less than 500 nM.

[0411] According to an embodiment the compounds are having inhibition values of greater than 50% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 50% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.

[0412] According to an embodiment the compounds are having inhibition values of greater than 20% in both an RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 20% in both a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.

[0413] According to an embodiment the compounds are having inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4) at 1 μM and inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4) at 0.1 μM. According to an embodiment the compounds are having inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4) at 1 μM and inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4) at 0.1 μM, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.

[0414] According to an embodiment the compounds are having inhibition values of greater than 20% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay. According to an embodiment the compounds have inhibition values of greater than 20% in at least one of a RORγ Reporter Assay (Gal4) and a Th17 Assay, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.

[0415] Experimental Autoimmune Encephalomyelitis (EAE) Study

[0416] EAE is an animal model for multiple sclerosis used to evaluate the efficacy of test compounds. EAE was induced at WuXi AppTec (Shanghai) in female C57BL/6 mice obtained from SLAC Laboratories, Shanghai by injection of 100 μl (100 μg MOG.sub.35-55 peptide in complete Freund's adjuvant containing 200 μg M. tuberculosis/mouse) emulsion (with a 25-G needle) subcutaneously in the shaved back of the mouse. Each mouse was also given 200 ng PTX in 200 μl of PBS by intraperitoneal injection at 0 and 48 hours after immunization. For treatment, compound or vehicle (2% DMSO, 10% HP-β-CD in MilliQ water) was given orally twice daily at various doses selected from 3, 10, and 30 mg/kg, beginning at the day of EAE induction. Treatment lasted for 25 days, and the animals were scored daily for EAE symptoms using the following scoring system: 0, Normal mouse; no overt signs of disease; 1, Limp tail or hind limb weakness but not both; 2 Limp tail and hind limb weakness; 3 Partial hind limb paralysis; 4 Complete hind limb paralysis; 5 Moribund state; death by EAE: sacrifice for humane reasons. The clinical score can be expressed as the mean score for each treatment group+/−S.E.M.

[0417] Results: Example 204 was tested in the EAE study at 10 and 30 mg/kg. Example 204 was shown to delay onset and lower clinical score at both doses.

[0418] Collagen-Induced Arthritis (CIA) Study

[0419] Collagen-induced arthritis is an animal model of rheumatoid arthritis used to evaluate the efficacy of test compounds. CIA was induced at Washington Biotechnology Inc. (Baltimore) in male DBA/1J mice (Jackson Laboratories) by subcutaneous injection at the base of the tail with 50 μl of a bovine collagen/complete Freund's adjuvant emulsion. After 21 days, the mice were further boosted by a further subcutaneous injection of 50 μl of a collagen/incomplete Freund's adjuvant emulsion. For treatment, compound or vehicle (2% DMSO, 10% HP-β-CD in MilliQ water) was given orally twice daily at various doses selected from 3, 10, 30 mg/kg, beginning at the day of CIA induction (Prophylactic setting), or after disease initiation (at day 27, therapeutic setting). Treatment lasted until day 41, and the animals were scored three times weekly. Each paw was scored and the sum of all four scores was recorded as the Arthritic Index (AI). The maximum possible AI was 16. 0=no visible effects of arthritis; 1=edema and/or erythema of one digit; 2=edema and/or erythema of 2 joints; 3=edema and/or erythema of more than 2 joints; 4=severe arthritis of the entire paw and digits including limb deformation and ankylosis of the joint. The Arthritis Index for each treatment can be expressed as the mean score for each treatment group+/−S.E.M.

[0420] Results: Example 204 was tested in the CIA study at 10 and 30 mg/kg in prophylactic setting and at 30 mg/kg in therapeutic setting. Example 204 was shown to significantly reduce disease severity at both prophylactic doses. Example 204 was shown to arrest disease development in the therapeutic setting.

[0421] In summary, compounds disclosed herein have been found to at least modulate the activity of RORγ. Additionally it has been found that compounds disclosed herein have in vivo usefulness, and could consequently be useful in treating inflammatory, metabolic and autoimmune diseases.