METHYL-SUBSTITUTED PYRIDINE AND PYRIDAZINE COMPOUNDS, DERIVATIVES THEREOF, AND METHODS OF THEIR USE

Abstract

The invention provides methyl-substituted pyridine and pyridazine compounds, derivatives thereof, and methods of their use. The compounds are useful as pharmacological agents to treat a variety of conditions, including various pain states, itch, and cough.

Claims

1. A compound of Formula (II): ##STR02036## wherein: each of J.sub.1, J.sub.2, J.sub.4, and J.sub.5 is independently N, NO, or CR.sub.6; J.sub.3 is N, NO, or CR.sub.7; X is CH or N; Y is NR.sub.8 or O; Z is CH, N, or NO, R.sub.2 is alkyl, haloalkyl, alkoxy, or haloalkoxy; each instance of R.sub.6 is independently H, halogen, C.sub.1-3 alkyl, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, CD.sub.3 or CT.sub.3; and R.sub.7 is H, halogen, CD.sub.3, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, heterocyclyl in which each ring has 5 or 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl in which each ring has 5 or 6 members, O-heteroaryl in which each ring has 5 or 6 members, O-cycloalkyl, O-cycloheteroalkyl, each of which is optionally substituted where valency permits, R.sub.8 is H, C.sub.1-3 alkyl, or C.sub.3-5 cycloalkyl, acyl, with the provisos that: X and Z cannot both be CH; and not more than two of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Y is NR.sub.8.

3. The compound of claim 1, wherein Y is O.

4. The compound of claim 1, wherein R.sub.2 is alkyl.

5. The compound of claim 4, wherein R.sub.2 is CH.sub.3.

6. The compound of claim 1, wherein none of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO.

7. The compound of claim 1, wherein one of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 is N or NO.

8. The compound of claim 1, wherein two of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO.

9. The compound of claim 1, wherein Z is CH.

10. The compound of claim 1, wherein Z is N.

11. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of Formula (II). ##STR02037## wherein: each of J.sub.1, J.sub.2, J.sub.4, and J.sub.5 is independently N, NO, or CR.sub.6; J.sub.3 is N, NO, or CR.sub.7; X is CH or N; Y is NR.sub.8 or O; Z is CH, N, or NO, R.sub.2 is alkyl, haloalkyl, alkoxy, or haloalkoxy; each instance of R.sub.6 is independently H, halogen, C.sub.1-3 alkyl, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, CD.sub.3 or CT.sub.3; and R.sub.7 is H, halogen, CD.sub.3, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, heterocyclyl in which each ring has 5 or 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, O-aryl in which each ring has 5 or 6 members, O-heteroaryl in which each ring has 5 or 6 members, O-cycloalkyl, O-cycloheteroalkyl, each of which is optionally substituted where valency permits, R.sub.8 is H, C.sub.1-3 alkyl, or C.sub.3-5 cycloalkyl, with the provisos that: X and Z cannot both be CH; and not more than two of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein Y is NR.sub.8.

13. The method of claim 11, wherein Y is O.

14. The method of claim 11, wherein R.sub.2 is alkyl.

15. The method of claim 14, wherein R.sub.2 is CH.sub.3.

16. The method of claim 11, wherein none of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO.

17. The method of claim 11, wherein one of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 is N or NO.

18. The method of claim 11, wherein two of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO.

19. The method of claim 11, wherein Z is CH.

20. The method of claim 11, wherein Z is N.

21. A compound of Formula (III): ##STR02038## wherein: each of J.sub.1, J.sub.2, J.sub.4, and J.sub.5 is independently N, NO, or CR.sub.6; J.sub.3 is N, NO, or CR.sub.7; each of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 is independently N, CH, or CR.sub.9; X is CH or N; Z is CH, N, or NO, each instance of R.sub.6 is independently H, halogen, C.sub.1-3 alkyl, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, CD.sub.3 or CT.sub.3; and R.sub.7 is H, halogen, CD.sub.3, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, carbocyclyl in which each ring has 3-6 members, heterocyclyl in which each ring has 5 or 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl in which each ring has 3 to 6 members, or partially unsaturated heterocyclyl, O-aryl in which each ring has 5 or 6 members, O-heteroaryl in which each ring has 5 or 6 members, O-cycloalkyl, O-cycloheteroalkyl, each of which is optionally substituted where valency permits, each instance of R.sub.9 is independently C(O)NR.sub.10R.sub.11, S(O).sub.2C.sub.1-6 alkyl, S(O)(NH)C.sub.1-6 alkyl, C.sub.1-3 alkyl, or C.sub.3-5 cycloalkyl; and each of R.sub.10 and R.sub.11 is independently selected from H and C.sub.1-5 alkyl, or R.sub.10 and Rn together with the nitrogen atom to which they are attached form a heterocyclyl having 3-6 members, in which each of the C.sub.1-5 alkyl and heterocyclyl is optionally substituted where valency permits, with the provisos that: not more than two of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO; not more than two of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 are N; not more than three of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 are CR.sub.9; and X and Z cannot both be CH, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein W.sub.3 is CR.sub.9.

23. The compound of claim 22, wherein R.sub.9 is C(O)NH.sub.2.

24. The compound of claim 21, wherein W.sub.3 is N.

25. The compound of claim 21, wherein W.sub.2 is CH and W.sub.4 is CR.sub.9.

26. The compound claim 25, wherein R.sub.9 is C(O)NH.sub.2.

27. The compound of claim 21, wherein W.sub.2 and W.sub.4 are both CR.sub.9.

28. The compound of claim 27, wherein W.sub.2 is CC(O)NH.sub.2 and W.sub.4 is CS(O).sub.2CH.sub.3.

29. The compound of claim 21, wherein X and Z are both N.

30. The compound of claim 21, wherein the compound is selected from the group consisting of Formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), and (III-8): ##STR02039## ##STR02040##

31. An inhibitor of a Na.sub.V 1.8 sodium channel having a structure of Formula (III): ##STR02041## wherein: each of J.sub.1, J.sub.2, J.sub.4, and J.sub.5 is independently N, NO, or CR.sub.6; J.sub.3 is N, NO, or CR.sub.7; each of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 is independently N, CH, or CR.sub.9; X is CH or N; Z is CH, N, or NO, each instance of R.sub.6 is independently H, halogen, C.sub.1-3 alkyl, C.sub.3-5 cycloalkyl, C.sub.1-3 alkoxy, CD.sub.3 or CT.sub.3; and R.sub.7 is H, halogen, CD.sub.3, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, carbocyclyl in which each ring has 3-6 members, heterocyclyl in which each ring has 5 or 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl in which each ring has 3 to 6 members, or partially unsaturated heterocyclyl, O-aryl in which each ring has 5 or 6 members, O-heteroaryl in which each ring has 5 or 6 members, O-cycloalkyl, O-cycloheteroalkyl, each of which is optionally substituted where valency permits, each instance of R.sub.9 is independently C(O)NR.sub.10R.sub.11, S(O).sub.2C.sub.1-6 alkyl, S(O)(NH)C.sub.1-6 alkyl, C.sub.1-3 alkyl, or C.sub.3-5 cycloalkyl; and each of R.sub.10 and Rn is independently selected from H and C.sub.1-5 alkyl, or R.sub.10 and R.sub.11 together with the nitrogen atom to which they are attached form a heterocyclyl having 3-6 members, in which each of the C.sub.1-5 alkyl and heterocyclyl is optionally substituted where valency permits, with the provisos that: not more than two of J.sub.1, J.sub.2, J.sub.3, J.sub.4, and J.sub.5 are N or NO; not more than two of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 are N; not more than three of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 are CR.sub.9; and X and Z cannot both be CH, or a pharmaceutically acceptable salt thereof.

32. The inhibitor of claim 31, wherein W.sub.3 is CR.sub.9.

33. The inhibitor of claim 32, wherein R.sub.9 is C(O)NH.sub.2.

34. The inhibitor of claim 31, wherein W.sub.3 is N.

35. The inhibitor of claim 31, wherein W.sub.2 is CH and W.sub.4 is CR.sub.9.

36. The compound claim 35, wherein R.sub.9 is C(O)NH.sub.2.

37. The inhibitor of claim 31, wherein W.sub.2 and W.sub.4 are both CR.sub.9.

38. The inhibitor of claim 37, wherein W.sub.2 is CC(O)NH.sub.2 and W.sub.4 is CS(O).sub.2CH.sub.3.

39. The inhibitor of claim 31, wherein X and Z are both N.

40. The inhibitor of claim 31, wherein the inhibitor is represented by a structure selected from the group consisting of Formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), and (III-8): ##STR02042## ##STR02043##

41. A compound of Formula (I): ##STR02044## wherein: R.sub.1 is CN or CF.sub.3; R.sub.3 is halogen, alkyl, alkoxy, or CD.sub.3; R.sub.5 is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, a fused heterocyclyl in which each ring has 5 or 6 members, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted where valency permits; E is CH or CF; X is CH or N; Z is CH or N; and CD.sub.3 is fully deuterated methyl group, with the proviso that X and Z cannot both be CH, or a pharmaceutically acceptable salt thereof.

42. The compound of claim 41, wherein R.sub.1 is CN.

43. The compound of claim 42, wherein R.sub.1 is CF.sub.3.

44. The compound of claim 41, wherein R.sub.3 is halogen.

45. The compound of claim 41, wherein R.sub.3 is alkyl.

46. The compound of claim 41, wherein R.sub.3 is alkoxy.

47. The compound of claim 41, wherein E is CH.

48. The compound of claim 41, wherein E is CF.

49. The compound of claim 41, wherein Z is CH.

50. The compound of claim 41, wherein Z is N.

51. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of Formula (I). ##STR02045## wherein: R.sub.1 is CN or CF.sub.3; R.sub.3 is halogen, alkyl, alkoxy, or CD.sub.3; R.sub.5 is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, a fused heterocyclyl in which each ring has 5 or 6 members, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted where valency permits; E is CH or CF; X is CH or N; Z is CH or N; and CD.sub.3 is fully deuterated methyl group, with the proviso that X and Z cannot both be CH, or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein R.sub.1 is CN.

53. The method of claim 52, wherein R.sub.1 is CF.sub.3.

54. The method of claim 51, wherein R.sub.3 is halogen.

55. The method of claim 51, wherein R.sub.3 is alkyl.

56. The method of claim 51, wherein R.sub.3 is alkoxy.

57. The method of claim 51, wherein E is CH.

58. The method of claim 51, wherein E is CF.

59. The method of claim 51, wherein Z is CH.

60. The method of claim 51, wherein Z is N.

61. A compound of Formula (I): ##STR02046## wherein: R.sub.1 is halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; R.sub.2 is selected from the group consisting of aryl, heteroaryl, and unsaturated heterocyclyl, wherein: each of the aryl, heteroaryl, and unsaturated heterocyclyl is optionally fused to one selected from the group consisting of optionally saturated carbocyclyl containing 5-6 ring members and optionally saturated heterocyclyl containing 5-6 ring members and 1-3 hetereoatoms; each of the aryl, heteroaryl, and unsaturated heterocyclyl is optionally substituted with one or more groups selected from the group consisting of (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)NR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)OR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)R.sup.j, (CH.sub.2).sub.nNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mR.sup.j, alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl, alkylsulfoxide, alkylsulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, C(O)NH.sub.2, C(O)NR.sup.eR.sup.j, C(O)R.sup.j, C.sub.1-C.sub.4 alkoxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6cycloheteroalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.6cycloalkyl, CF.sub.3, CN, CO.sub.2H, CO.sub.2R.sup.j, cyano, H, halogen, heteroaryl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, or trihaloalkoxyl, morpholinyl, nitro, O-aryl, OC(O)N(R.sup.j).sub.2, OC(O)NR.sup.eR.sup.j, OC(O)R.sup.j, OC.sub.1-C.sub.6alkyl, OC.sub.2-C.sub.6alkenyl, OC.sub.2-C.sub.6cycloheteroalkyl, OC.sub.3-C.sub.6cycloalkyl, OH, O-heteroaryl, oxazolyl, oxo, S(O).sub.2R.sup.j, SO.sub.2aryl, SO.sub.2C.sub.1-C.sub.6alkenyl, SO.sub.2C.sub.1-C.sub.6alkyl, SO.sub.2C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2C.sub.3-C.sub.6cycloalkyl, SO.sub.2heteroaryl, SO.sub.2NH.sub.2, SO.sub.2NR.sup.e-aryl, SO.sub.2NR.sup.eC(O)C.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC(O)C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC(O)C.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.eC.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6alkenyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.e-heteroary 1, SO.sub.3H, SR.sup.j, sulfoximinyl S(O)(?NR.sup.a)R.sup.a, sulfonimidamide S(O)(?NR.sup.a)N(R.sup.a).sub.2, sulfonimidoyl fluoride S(O)(?NR.sup.a)F, and sulfondiimine S(?NR.sup.a).sub.2R.sup.a, wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH.sub.2, NH(C.sub.1-C.sub.6alkyl) and N(C.sub.1-C.sub.6alkyl).sub.2; the unsaturated heterocyclyl is optionally substituted with R.sup.kR.sup.l; and each heteroatom in the heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S or N(R.sup.h).sub.q, each of which may be in its oxidized or unoxidized state; R.sub.3 is selected from the group consisting of H, cyano, halogen, C.sub.1-C.sub.4 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, optionally substituted C.sub.1-C.sub.8 alkyl, and C.sub.3-C.sub.8 cycloalkyl optionally substituted with 1-4 fluorine atoms; each R.sup.a is independently halogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; each R.sup.e is independently H, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6 alkenyl; each R.sup.h is independently H, or C.sub.1-C.sub.6 alkyl; each R.sup.j is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 cycloheteroalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl in R.sup.j is optionally substituted with one or more substituents independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, OH, OC.sub.1-C.sub.6alkyl, OC.sub.3-C.sub.6cycloalkyl, halogen, cyano, and S(O).sub.2CH.sub.3; R.sup.k and R.sup.l, together with the atom to which they are attached, form a cycloalkyl or cycloheteroalkyl containing 3-7 ring members; E is CH, CF, or N; Q is CH, CF, or N; T is CH, CF or N; W is CH, CF, or N; X is halogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, Y is N or N.sup.+O.sup.?; Z is N, N.sup.+O.sup.?, or CH; each m is independently 0-2; each n is independently 0-4; and each q is independently 0 or 1, or a pharmaceutically acceptable salt thereof.

62. The compound of claim 61, wherein R.sub.2 is an optionally substituted aryl.

63. The compound of claim 61, wherein R.sub.2 is an optionally substituted heteroaryl.

64. The compound of claim 61, wherein R.sub.2 is an optionally substituted unsaturated heterocyclyl.

65. The compound of claim 61, wherein R.sub.1 is halogen.

66. The compound of claim 61, wherein R.sub.1 is C.sub.1-C.sub.3 alkyl.

67. The compound of claim 61, wherein R.sub.1 is C.sub.3-C.sub.4 cycloalkyl.

68. The compound of claim 61, wherein R.sub.1 is haloalkyl.

69. The compound of claim 61, wherein R.sub.1 is halocycloalkyl.

70. The compound of claim 61, wherein R.sub.1 is H.

71. The compound of claim 61, wherein R.sub.3 is a mono-, di-, or trihalo-C.sub.1-C.sub.4 alkyl.

72. The compound of claim 61, wherein R.sub.3 is CF.sub.3.

73. The compound of claim 61, wherein E is CH or CF.

74. The compound of claim 61, wherein E is N.

75. The compound of claim 61, wherein Q is CH or CF.

76. The compound of claim 61, wherein Q is N.

77. The compound of claim 61, wherein T is CH or CF.

78. The compound of claim 61, wherein T is N.

79. The compound of claim 61, wherein W is CH or CF.

80. The compound of claim 61, wherein W is N.

81. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of Formula (I): ##STR02047## wherein: R.sub.1 is halogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; R.sub.2 is selected from the group consisting of aryl, heteroaryl, and unsaturated heterocyclyl, wherein: each of the aryl, heteroaryl, and unsaturated heterocyclyl is optionally fused to one selected from the group consisting of optionally saturated carbocyclyl containing 5-6 ring members and optionally saturated heterocyclyl containing 5-6 ring members and 1-3 hetereoatoms; each of the aryl, heteroaryl, and unsaturated heterocyclyl is optionally substituted with one or more groups selected from the group consisting of (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)NR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)OR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)R.sup.j, (CH.sub.2).sub.nNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mR.sup.j, alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl, alkylsulfoxide, alkylsulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, C(O)NH.sub.2, C(O)NR.sup.eR.sup.j, C(O)R.sup.j, C.sub.1-C.sub.4 alkoxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6cycloheteroalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.6cycloalkyl, CF.sub.3, CN, CO.sub.2H, CO.sub.2R.sup.j, cyano, H, halogen, heteroaryl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, or trihaloalkoxyl, morpholinyl, nitro, O-aryl, OC(O)N(R.sup.j).sub.2, OC(O)NR.sup.eR.sup.j, OC(O)R.sup.j, OC.sub.1-C.sub.6alkyl, OC.sub.2-C.sub.6alkenyl, OC.sub.2-C.sub.6cycloheteroalkyl, OC.sub.3-C.sub.6cycloalkyl, OH, O-heteroaryl, oxazolyl, oxo, S(O).sub.2R.sup.j, SO.sub.2aryl, SO.sub.2C.sub.1-C.sub.6alkenyl, SO.sub.2C.sub.1-C.sub.6alkyl, SO.sub.2C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2C.sub.3-C.sub.6cycloalkyl, SO.sub.2heteroaryl, SO.sub.2NH.sub.2, SO.sub.2NR.sup.e-aryl, SO.sub.2NR.sup.eC(O)C.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC(O)C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC(O)C.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.eC.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6alkenyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.e-heteroary 1, SO.sub.3H, SR.sup.j, sulfoximinyl S(O)(?NR.sup.a)R.sup.a, sulfonimidamide S(O)(?NR.sup.a)N(R.sup.a).sub.2, sulfonimidoyl fluoride S(O)(?NR.sup.a)F, and sulfondiimine S(?NR.sup.a).sub.2R.sup.a, wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH.sub.2, NH(C.sub.1-C.sub.6alkyl) and N(C.sub.1-C.sub.6alkyl).sub.2; the unsaturated heterocyclyl is optionally substituted with R.sup.kR.sup.l; and each heteroatom in the heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S or N(R.sup.h).sub.q, each of which may be in its oxidized or unoxidized state; R.sub.3 is selected from the group consisting of H, cyano, halogen, C.sub.1-C.sub.4 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, optionally substituted C.sub.1-C.sub.8 alkyl, and C.sub.3-C.sub.8 cycloalkyl optionally substituted with 1-4 fluorine atoms; each R.sup.a is independently halogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; each R.sup.e is independently H, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6 alkenyl; each R.sup.h is independently H, or C.sub.1-C.sub.6 alkyl; each R.sup.j is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 cycloheteroalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl in R.sup.j is optionally substituted with one or more substituents independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, OH, OC.sub.1-C.sub.6alkyl, OC.sub.3-C.sub.6cycloalkyl, halogen, cyano, and S(O).sub.2CH.sub.3; R.sup.k and R.sup.l, together with the atom to which they are attached, form a cycloalkyl or cycloheteroalkyl containing 3-7 ring members; E is CH or CF; Q is CH, CF, or N; T is CH, CF or N; W is CH, CF, or N; X is halogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, Y is N or N.sup.+O.sup.?; Z is N or N.sup.+O.sup.?, each m is independently 0-2; each n is independently 0-4; and each q is independently 0 or 1, or a pharmaceutically acceptable salt thereof.

82. The method of claim 81, wherein R.sub.2 is an optionally substituted aryl.

83. The method of claim 81, wherein R.sub.2 is an optionally substituted heteroaryl.

84. The method of claim 81, wherein R.sub.2 is an optionally substituted unsaturated heterocyclyl.

85. The method of claim 81, wherein R.sub.1 is halogen.

86. The method of claim 81, wherein R.sub.1 is C.sub.1-C.sub.3 alkyl.

87. The method of claim 81, wherein R.sub.1 is C.sub.3-C.sub.4 cycloalkyl.

88. The method of claim 81, wherein R.sub.1 is haloalkyl.

89. The method of claim 81, wherein R.sub.1 is halocycloalkyl.

90. The method of claim 81, wherein R.sub.1 is H.

91. The method of claim 81, wherein R.sub.3 is a mono-, di-, or trihalo-C.sub.1-C.sub.4 alkyl.

92. The method of claim 81, wherein R.sub.3 is CF.sub.3.

93. The method of claim 81, wherein E is CH or CF.

94. The method of claim 81, wherein E is N.

95. The method of claim 81, wherein Q is CH or CF.

96. The method of claim 81, wherein Q is N.

97. The method of claim 81, wherein T is CH or CF.

98. The method of claim 81, wherein T is N.

99. The method of claim 81, wherein W is CH or CF.

100. The method of claim 81, wherein W is N.

101. The method of claim 81, wherein the condition is selected from the group consisting of abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma/injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcotneuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, and whiplash associated disorder.

102. The method of claim 101, wherein the condition is selected from the group consisting of abdominal cancer pain, acute idiopathic transverse myelitis, acute pain, acute pain in major trauma/injury, ankylosing spondylitis, Behcet disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, constant unilateral facial pain with additional attacks, dental pain, complex regional pain syndromes, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, erythromelalgia, Fabry disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, irritable bowel syndrome, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, myofascial orofacial pain, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, oral mucosal pain, orofacial pain, osteoarthritis, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, Parkinson disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud disease, renal colic, rheumatoid arthritis, salivary gland pain, sarcoidosis, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, temporomandibular joint disorders, tension-type headache, vascular leg ulcers, vulvodynia, and whiplash associated disorder.

103. The method of claim 101, wherein the condition is selected from the group consisting of acute itch, allergic dermatitis, chronic itch, contact dermatitis, itch, and pruritus.

104. The method of claim 101, wherein the condition is selected from the group consisting of acute cough, chronic cough, cough, and subacute cough.

105. A compound of Formula (I): ##STR02048## wherein: R.sub.1 is halogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; R.sub.2 is selected from the group consisting of cycloalkyl containing 4-6 ring members, cycloheteroalkyl containing 5-6 ring members, spirocycloalkyl containing 5-14 ring members, and spirocycloheteroalkyl containing 5-14 ring members, wherein: each of the cycloalkyl, cycloheteroalkyl, spirocycloalkyl, and spirocycloheteroalkyl is optionally fused to one selected from the group consisting of an optionally saturated carbocyclyl containing 5-6 ring members and an optionally saturated heterocyclyl containing 5-6 ring members and 1-3 hetereoatoms; each of the cycloalkyl, cycloheteroalkyl, spirocycloalkyl, and spirocycloheteroalkyl is optionally substituted with one or more groups selected from the group consisting of (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)NR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)OR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)R.sup.j, (CH.sub.2).sub.nNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mR.sup.j, alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl, alkylsulfoxide, alkylsulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, C(O)NH.sub.2, C(O)NR.sup.eR.sup.j, C(O)R.sup.j, C.sub.1-C.sub.4 alkoxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6cycloheteroalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.6cycloalkyl, CF.sub.3, CN, CO.sub.2H, CO.sub.2R.sup.j, cyano, H, halogen, heteroaryl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, or trihaloalkoxyl, morpholinyl, nitro, O-aryl, OC(O)N(R.sup.j).sub.2, OC(O)NR.sup.eR.sup.j, OC(O)R.sup.j, OC.sub.1-C.sub.6alkyl, OC.sub.2-C.sub.6alkenyl, OC.sub.2-C.sub.6cycloheteroalkyl, OC.sub.3-C.sub.6cycloalkyl, OH, O-heteroaryl, oxazolyl, oxo, S(O).sub.2R.sup.j, SO.sub.2aryl, SO.sub.2C.sub.1-C.sub.6alkenyl, SO.sub.2C.sub.1-C.sub.6alkyl, SO.sub.2C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2C.sub.3-C.sub.6cycloalkyl, SO.sub.2heteroaryl, SO.sub.2NH.sub.2, SO.sub.2NR.sup.e-aryl, SO.sub.2NR.sup.eC(O)C.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC(O)C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC(O)C.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.eC.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6alkenyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.e-heteroaryl, SO.sub.3H, SR.sup.j, sulfoximinyl S(O)(?NR.sup.a)R.sup.a, sulfonimidamide S(O)(?NR.sup.a)N(R.sup.a).sub.2, sulfonimidoyl fluoride S(O)(?NR.sup.a)F, sulfondiimine S(?NR.sup.a).sub.2R.sup.a, and R.sup.kR.sup.l, wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH.sub.2, NH(C.sub.1-C.sub.6alkyl) and N(C.sub.1-C.sub.6alkyl).sub.2; and each heteroatom in the cycloheteroalkyl, spirocycloheteroalkyl, and optionally saturated heterocyclyl is independently O, S or N(R.sup.h).sub.q, each of which may be in its oxidized or unoxidized state; R.sub.3 is selected from the group consisting of H, cyano, halogen, C.sub.1-C.sub.4 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, optionally substituted C.sub.1-C.sub.8 alkyl, and C.sub.3-C.sub.8 cycloalkyl optionally substituted with 1-4 fluorine atoms; each R.sup.a is independently halogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; each R.sup.e is independently H, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6 alkenyl; each R.sup.h is independently H, or C.sub.1-C.sub.6 alkyl; each R.sup.j is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 cycloheteroalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl in R.sup.j is optionally substituted with one or more substituents independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, OH, OC.sub.1-C.sub.6alkyl, OC.sub.3-C.sub.6cycloalkyl, halogen, cyano, and S(O).sub.2CH.sub.3; R.sup.k and R.sup.l, together with the atom to which they are attached, form a cycloalkyl or cycloheteroalkyl containing 3-7 ring members; E is CH or CF; Q is CH, CF, or N; T is CH, CF or N; W is CH, CF, or N; X is halogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, Y is N or N.sup.+O.sup.?; Z is N or N.sup.+O.sup.?, each m is independently 0-2; each n is independently 0-4; and each q is independently 0 or 1, or a pharmaceutically acceptable salt thereof.

106. The compound of claim 105, wherein R.sub.2 is an optionally substituted cycloalkyl.

107. The compound of claim 105, wherein R.sub.2 is an optionally substituted cycloheteroalkyl.

108. The compound of claim 105, wherein R.sub.2 is an optionally substituted spirocycloalkyl.

109. The compound of claim 105, wherein R.sub.2 is an optionally substituted spirocycloheteroalkyl.

110. The compound of claim 105, wherein R.sub.1 is halogen.

111. The compound of claim 105, wherein R.sub.1 is C.sub.1-C.sub.3 alkyl.

112. The compound of claim 105, wherein R.sub.1 is C.sub.3-C.sub.4 cycloalkyl.

113. The compound of claim 105, wherein R.sub.1 is haloalkyl.

114. The compound of claim 105, wherein R.sub.1 is halocycloalkyl.

115. The compound of claim 105, wherein R.sub.1 is H.

116. The compound of claim 105, wherein R.sub.3 is CF.sub.3.

117. The compound of claim 105, wherein E is CH or CF.

118. The compound of claim 105, wherein E is N.

119. The compound of claim 105, wherein Q is CH or CF.

120. The compound of claim 105, wherein Q is N.

121. The compound of claim 105, wherein T is CH or CF.

122. The compound of claim 105, wherein T is N.

123. The compound of claim 105, wherein W is CH or CF.

124. The compound of claim 105, wherein W is N.

125. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound of Formula (I): ##STR02049## wherein: R.sub.1 is halogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; R.sub.2 is selected from the group consisting of cycloalkyl containing 4-6 ring members, cycloheteroalkyl containing 5-6 ring members, spirocycloalkyl containing 5-14 ring members, and spirocycloheteroalkyl containing 5-14 ring members, wherein: each of the cycloalkyl, cycloheteroalkyl, spirocycloalkyl, and spirocycloheteroalkyl is optionally fused to one selected from the group consisting of an optionally saturated carbocyclyl containing 5-6 ring members and an optionally saturated heterocyclyl containing 5-6 ring members and 1-3 hetereoatoms; each of the cycloalkyl, cycloheteroalkyl, spirocycloalkyl, and spirocycloheteroalkyl is optionally substituted with one or more groups selected from the group consisting of (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)N(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eC(O)NR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)OR.sup.j, (CH.sub.2).sub.nNR.sup.eC(O)R.sup.j, (CH.sub.2).sub.nNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.e).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mN(R.sup.j).sub.2, (CH.sub.2).sub.nNR.sup.eS(O).sub.mNR.sup.eR.sup.j, (CH.sub.2).sub.nNR.sup.eS(O).sub.mR.sup.j, alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl, alkylsulfoxide, alkylsulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, C(O)NH.sub.2, C(O)NR.sup.eR.sup.j, C(O)R.sup.j, C.sub.1-C.sub.4 alkoxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6cycloheteroalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.6cycloalkyl, CF.sub.3, CN, CO.sub.2H, CO.sub.2R.sup.j, cyano, H, halogen, heteroaryl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, or trihaloalkoxyl, morpholinyl, nitro, O-aryl, OC(O)N(R.sup.j).sub.2, OC(O)NR.sup.eR.sup.j, OC(O)R.sup.j, OC.sub.1-C.sub.6alkyl, OC.sub.2-C.sub.6alkenyl, OC.sub.2-C.sub.6cycloheteroalkyl, OC.sub.3-C.sub.6cycloalkyl, OH, O-heteroaryl, oxazolyl, oxo, S(O).sub.2R.sup.j, SO.sub.2aryl, SO.sub.2C.sub.1-C.sub.6alkenyl, SO.sub.2C.sub.1-C.sub.6alkyl, SO.sub.2C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2C.sub.3-C.sub.6cycloalkyl, SO.sub.2heteroaryl, SO.sub.2NH.sub.2, SO.sub.2NR.sup.e-aryl, SO.sub.2NR.sup.eC(O)C.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC(O)C.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC(O)C.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.eC.sub.1-C.sub.6alkyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6alkenyl, SO.sub.2NR.sup.eC.sub.2-C.sub.6cycloheteroalkyl, SO.sub.2NR.sup.eC.sub.3-C.sub.6cycloalkyl, SO.sub.2NR.sup.e-heteroaryl, SO.sub.3H, SR.sup.j, sulfoximinyl S(O)(?NR.sup.a)R.sup.a, sulfonimidamide S(O)(?NR.sup.a)N(R.sup.a).sub.2, sulfonimidoyl fluoride S(O)(?NR.sup.a)F, sulfondiimine S(?NR.sup.a).sub.2R.sup.a, and R.sup.kR.sup.l, wherein each alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituent is itself optionally substituted with one or more substituents selected from the group consisting of halogen, OH, NH.sub.2, NH(C.sub.1-C.sub.6alkyl) and N(C.sub.1-C.sub.6alkyl).sub.2; and each heteroatom in the cycloheteroalkyl, spirocycloheteroalkyl, and optionally saturated heterocyclyl is independently O, S or N(R.sup.h).sub.q, each of which may be in its oxidized or unoxidized state; R.sub.3 is selected from the group consisting of H, cyano, halogen, C.sub.1-C.sub.4 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, optionally substituted C.sub.1-C.sub.8 alkyl, and C.sub.3-C.sub.8 cycloalkyl optionally substituted with 1-4 fluorine atoms; each R.sup.a is independently halogen, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.4 cycloalkyl, haloalkyl, halocycloalkyl, or H; each R.sup.e is independently H, C.sub.1-C.sub.6 alkyl, or C.sub.2-C.sub.6 alkenyl; each R.sup.h is independently H, or C.sub.1-C.sub.6 alkyl; each R.sup.j is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 cycloheteroalkyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl in R.sup.j is optionally substituted with one or more substituents independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, OH, OC.sub.1-C.sub.6alkyl, OC.sub.3-C.sub.6cycloalkyl, halogen, cyano, and S(O).sub.2CH.sub.3; R.sup.k and R.sup.l, together with the atom to which they are attached, form a cycloalkyl or cycloheteroalkyl containing 3-7 ring members; E is CH or CF; Q is CH, CF, or N; T is CH, CF or N; W is CH, CF, or N; X is halogen, alkyl, haloalkyl, cycloalkyl, or halocycloalkyl, Y is N or N.sup.+O.sup.?; Z is N or N.sup.+O.sup.?, each m is independently 0-2; each n is independently 0-4; and each q is independently 0 or 1, or a pharmaceutically acceptable salt thereof.

126. The method of claim 125, wherein R.sub.2 is an optionally substituted cycloalkyl.

127. The method of claim 125, wherein R.sub.2 is an optionally substituted cycloheteroalkyl.

128. The method of claim 125, wherein R.sub.2 is an optionally substituted spirocycloalkyl.

129. The method of claim 125, wherein R.sub.2 is an optionally substituted spirocycloheteroalkyl.

130. The method of claim 125, wherein R.sub.1 is halogen.

131. The method of claim 125, wherein R.sub.1 is C.sub.1-C.sub.3 alkyl.

132. The method of claim 125, wherein R.sub.1 is C.sub.3-C.sub.4 cycloalkyl.

133. The method of claim 125, wherein R.sub.1 is haloalkyl.

134. The method of claim 125, wherein R.sub.1 is halocycloalkyl.

135. The method of claim 125, wherein R.sub.1 is H.

136. The method of claim 125, wherein R.sub.3 is CF.sub.3.

137. The method of claim 125, wherein E is CH or CF.

138. The method of claim 125, wherein E is N.

139. The method of claim 125, wherein Q is CH or CF.

140. The method of claim 125, wherein Q is N.

141. The method of claim 125, wherein T is CH or CF.

142. The method of claim 125, wherein T is N.

143. The method of claim 125, wherein W is CH or CF.

144. The method of claim 125, wherein W is N.

145. The method of claim 125, wherein the condition is selected from the group consisting of abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major trauma/injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcotneuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, and whiplash associated disorder.

146. The method of claim 145, wherein the condition is selected from the group consisting of abdominal cancer pain, acute idiopathic transverse myelitis, acute pain, acute pain in major trauma/injury, ankylosing spondylitis, Behcet disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, constant unilateral facial pain with additional attacks, dental pain, complex regional pain syndromes, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, erythromelalgia, Fabry disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, irritable bowel syndrome, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, myofascial orofacial pain, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, oral mucosal pain, orofacial pain, osteoarthritis, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, Parkinson disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud disease, renal colic, rheumatoid arthritis, salivary gland pain, sarcoidosis, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, temporomandibular joint disorders, tension-type headache, vascular leg ulcers, vulvodynia, and whiplash associated disorder.

147. The method of claim 145, wherein the condition is selected from the group consisting of acute itch, allergic dermatitis, chronic itch, contact dermatitis, itch, and pruritus.

148. The method of claim 145, wherein the condition is selected from the group consisting of acute cough, chronic cough, cough, and subacute cough.

149. A compound of formula (I): ##STR02050## wherein: R.sub.1 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more groups selected from the group consisting of mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.10 cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C.sub.1-C.sub.8 alkoxyl, mono-, di-, or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl, and arylalkoxyl; R.sub.2 is selected from the group consisting of aryl, heteroaryl, and heterocycle, wherein the aryl, heteroaryl, and heterocycle unsubstituted or are substituted with one or more groups selected from the group consisting of mono-, di-, andtrihalo-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.10 cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C.sub.1-C.sub.8 alkoxyl, mono-, di-, or trihaloalkoxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl, and oxazolyl; R.sub.3 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-C.sub.8 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, NO.sub.2; R.sub.4 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-C.sub.8 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, and morpholinyl, provided that R.sub.3 and R.sub.4 are not hydrogen at the same time; or R.sub.3 and R.sub.4 together form a C.sub.3-C.sub.5 carbocyclic ring including carbon atoms to which R.sub.3 and R.sub.4 are attached; and pharmaceutically acceptable salts thereof.

150. The compound of claim 149, wherein: R.sub.1 is phenyl or pyridinyl, wherein the phenyl or pyridinyl is unsubstituted or substituted with one or more groups selected from the group consisting of substituted or unsubstituted C.sub.1-C.sub.8 alkyl, halogen, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, and SCF.sub.3; R.sub.2 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3-benzothiazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3-benzothiazolyl are unsubstituted or are substituted with one or more groups selected from the group consisting of unsubstituted or substituted C.sub.1-C.sub.8 alkyl, halogen, cyano, oxo, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, and CHF.sub.2, (CH.sub.2).sub.qOH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, morpholinyl, oxazolyl, C(?O)R.sub.8, wherein R.sub.8 is selected from the group consisting of NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkyl, S(?O)R.sub.9, S(?O).sub.2R.sub.9, S(?O)(?NR.sub.10)R.sub.11, and N?S(?O)(R.sub.1).sub.2, wherein each R.sub.9 is independently C.sub.1-C.sub.4 alkyl, CF.sub.3, or NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, R.sub.10 is H or C.sub.1-C.sub.4 alkyl, and R.sub.11 is C.sub.1-C.sub.4 alkyl, provided that when Y is nitrogen and R.sub.2 is phenyl or pyridyl, R.sub.8 cannot be NR.sub.6R.sub.7; R.sub.3 is selected from the group consisting of hydrogen, cyano, halogen, CF.sub.3, C.sub.1-C.sub.8 alkoxyl, OCH(F).sub.2, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, N.sup.+(?O)O.sup.?; R.sub.4 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-C.sub.8 alkoxyl, CF.sub.3, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, and morpholinyl, provided that R.sub.3 and R.sub.4 are not hydrogen at the same time; or R.sub.3 and R.sub.4 together form a C.sub.3-C.sub.5 carbocyclic ring including carbon atoms to which R.sub.3 and R.sub.4 are attached.

151. The compound of claim 149, wherein the compound is a compound of formula (II): ##STR02051## wherein: R.sub.2 is selected from the group consisting of aryl, heteroaryl, and heterocycle, wherein the aryl, heteroaryl, and heterocycle unsubstituted or are substituted with one or more groups selected from the group consisting of mono-, di-, andtrihalo-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.10 cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C.sub.1-C.sub.8 alkoxyl, mono-, di-, or trihaloalkoxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl, and oxazolyl; R.sub.3 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-C.sub.8 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, NO.sub.2; R.sub.4 is selected from the group consisting of hydrogen, cyano, halogen, C.sub.1-C.sub.8 alkoxyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, mono-, di-, and trihalo-C.sub.1-C.sub.4 alkoxyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, and morpholinyl, provided that R.sub.3 and R.sub.4 are not hydrogen at the same time; or R.sub.3 and R.sub.4 together form a C.sub.3-C.sub.5 carbocyclic ring including carbon atoms to which R.sub.3 and R.sub.4 are attached; n is an integer selected from 0, 1, 2, 3, 4, and 5; each R.sub.24 is independently selected from the group consisting of mono-, di-, and trihalo-C.sub.1-C.sub.4 alkyl, substituted or unsubstituted C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.10 cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C.sub.1-C.sub.8 alkoxyl, mono-, di-, or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl, and arylalkoxyl.

152. The compound of claim 151, wherein R.sub.2 is selected from the group consisting of: ##STR02052## wherein: m is an integer selected from the group consisting of 0, 1, 2, 3, and 4; R.sub.25 is selected from the group consisting of H, morpholinyl, oxazolyl, halogen, cyano, (CH.sub.2).sub.qOH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, C(?O)R.sub.8, wherein R.sub.8 is selected from the group consisting of NR.sub.6R.sub.7 and C.sub.1-C.sub.4 alkyl, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, S(?O)R.sub.9, S(?O).sub.2R.sub.9, S(?O)(?NR.sub.10)R.sub.11, and N?S(?O)(R.sub.11).sub.2, wherein each R.sub.9 is independently C.sub.1-C.sub.4 alkyl, CF.sub.3, or NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, R.sub.10 is H or C.sub.1-C.sub.4 alkyl, and Ru is C.sub.1-C.sub.4 alkyl, provided that when Y is nitrogen and R.sub.2 is phenyl or pyridyl, R.sub.8 cannot be NR.sub.6R.sub.7; R.sub.26 is halogen or cyano; each R.sub.27 is independently selected from the group consisting of H, halogen, C.sub.1-C.sub.8 alkoxyl, cyano, -and NR.sub.6R.sub.7; and each R.sub.28 is independently H or C.sub.1-C.sub.4 alkyl.

153. The compound of claim 151, wherein the compound is a compound of formula (II-a): ##STR02053## wherein: R.sub.2 is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted with a substituent group selected from the group consisting of unsubstituted or substituted C.sub.1-C.sub.8 alkyl, halogen, cyano, oxo, heterocycloalkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CH.sub.2F, and CHF.sub.2, (CH.sub.2).sub.qOH, wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, morpholinyl, oxazolyl, C(?O)R.sub.8, wherein R.sub.8 is selected from the group consisting of NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, and C.sub.1-C.sub.4 alkyl, S(?O)R.sub.9, S(?O).sub.2R.sub.9, S(?O)(?NR.sub.10)R.sub.11, and N?S(?O)(R.sub.1).sub.2, wherein each R.sub.9 is independently C.sub.1-C.sub.4 alkyl, CF.sub.3, or NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl, R.sub.10 is H or C.sub.1-C.sub.4 alkyl, and R.sub.11 is C.sub.1-C.sub.4 alkyl; R.sub.12 is selected from the group consisting of halogen, OR.sub.23, wherein R.sub.23 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CH.sub.2F, and CHF.sub.2; and R.sub.12 is selected from the group consisting of H, halogen, OR.sub.13, wherein R.sub.13 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CH.sub.2F, and CHF.sub.2.

154. The compound of claim 153, wherein the aryl and heteroaryl are selected from the group consisting of phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide, pyridazinyl, and pyrimidinyl.

155. The compound of claim 154, wherein R.sub.2 is selected from the group consisting of (trifluorosulfonyl)phenyl, 1,2,4-triazolyl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-6-yl, 2-fluoro-5-methylsulfonylphenyl, 2-methoxy-4-pyridyl, 2-methyl-4-pyridyl, 3-(dimethylsulfamoyl)phenyl, 3-(methylsulfonimidoyl)phenyl, 3-(N,S-dimethylsulfonimidoyl)phenyl, 3-carbamoylphenyl, 3-cyanophenyl, 3-dimethylsulfamoylphenyl, 3-methylsulfinylphenyl, 3-methylsulfonylphenyl, 3-morpholinophenyl, 3-oxazol-5-ylphenyl, 3-pyridyl, 4-cyanophenyl, 4-pyridyl, 6-cyano-3-pyridyl, 6-methyl-3-pyridyl, dimethyl(oxo)-?6-sulfanylidene]amino]phenyl, phenyl, pyrazolyl, pyridazine-4-yl, pyridazinyl, pyridizin-4-yl, pyridyl, pyrimidin-4-yl, pyrimidinyl, and thiadiazolyl.

156. The compound of claim 149, wherein the compound is a compound of formula (III): ##STR02054## wherein: R.sub.1 is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4yl, wherein the phenyl and pyridyl can be unsubstituted or substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, SCF.sub.3, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; R.sub.2 is selected from the group consisting of: ##STR02055## and R.sub.3 and R.sub.4 are H or CF.sub.3, provided that if R.sub.3 is H, then R.sub.4 is CF.sub.3 and if R.sub.4 is H, then R.sub.3 is CF.sub.3.

157. The compound of claim 156, wherein the compound is a compound of formula (III-a): ##STR02056## wherein: R.sub.1 is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4yl, wherein the phenyl and pyridyl can be unsubstituted or substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, SCF.sub.3, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; and R.sub.3 and R.sub.4 are H or CF.sub.3, provided that if R.sub.3 is H, then R.sub.4 is CF.sub.3 and if R.sub.4 is H, then R.sub.3 is CF.sub.3.

158. The compound of claim 157, wherein R.sub.1 is selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl, and 2-chloro-4-methoxyphenyl.

159. The compound of claim 156, wherein the compound is a compound of formula (III-b): ##STR02057## wherein: R.sub.1 is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4yl, wherein the phenyl and pyridyl can be unsubstituted or substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, SCF.sub.3, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; and R.sub.3 and R.sub.4 are H or CF.sub.3, provided that if R.sub.3 is H, then R.sub.4 is CF.sub.3 and if R.sub.4 is H, then R.sub.3 is CF.sub.3.

160. The compound of claim 156, wherein the compound is a compound of formula (III-c): ##STR02058## wherein: R.sub.1 is phenyl substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8.

161. The compound of claim 160, wherein R.sub.1 is selected from the group consisting of 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl, and 3,4-difluorophenyl.

162. The compound of claim 156, wherein the compound is a compound of formula (III-d): ##STR02059## wherein: R.sub.1 is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4yl, wherein the phenyl and pyridyl can be unsubstituted or substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, SCF.sub.3, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; and R.sub.3 and R.sub.4 are H or CF.sub.3, provided that if R.sub.3 is H, then R.sub.4 is CF.sub.3 and if R.sub.4 is H, then R.sub.3 is CF.sub.3.

163. The compound of claim 162, wherein the compound is a compound of formula (III-d): ##STR02060## wherein R.sub.1 is selected from the group consisting of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, and 2,4-difluorophenyl.

164. The compound of claim 156, wherein the compound is a compound of formula (III-e): ##STR02061## wherein: R.sub.1 is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4yl, wherein the phenyl and pyridyl can be unsubstituted or substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, SCF.sub.3, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; and R.sub.3 and R.sub.4 are H or CF.sub.3, provided that if R.sub.3 is H, then R.sub.4 is CF.sub.3 and if R.sub.4 is H, then R.sub.3 is CF.sub.3.

165. The compound of claim 164, wherein the compound is a compound of formula (III-e): ##STR02062## wherein R.sub.1 is selected from the group consisting of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, and 2,4-difluorophenyl.

166. The compound of claim 156, wherein the compound is a compound of formula (III-f): ##STR02063## wherein: R.sub.1 is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4yl, wherein the phenyl and pyridyl can be unsubstituted or substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, SCF.sub.3, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; and R.sub.3 and R.sub.4 are H or CF.sub.3, provided that if R.sub.3 is H, then R.sub.4 is CF.sub.3 and if R.sub.4 is H, then R.sub.3 is CF.sub.3.

167. The compound of claim 166, wherein the compound is a compound of formula (III-f): ##STR02064## wherein: R1 is selected from the group consisting of 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxylphenyl, 3,4-difluorphenyl, and 2-chloro-4-fluorophenyl.

168. The compound of claim 156, wherein the compound is a compound of formula (III-g): ##STR02065## wherein: R.sub.1 is ##STR02066## wherein R.sub.2c is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, halogen, and C.sub.1-C.sub.4 alkoxyl; and R.sub.4c is selected from the group consisting of OCF.sub.3, C.sub.1-C.sub.4 alkoxyl, and halogen; and R.sub.2 is selected from the group consisting of: ##STR02067##

169. The compound of claim 168, wherein R.sub.1 is selected from the group consisting of: ##STR02068##

170. The compound of claim 168, wherein the compound of formula (III-g) is selected from the group consisting of: 3-(3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide; 3-(3-(2,4-dimethoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide; 3-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide; 3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-fluoro-2-methoxyphenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(pyridazin-4-yl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-dimethoxyphenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 5-(3-(2,4-dimethoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide; 5-(3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide; 5-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide; and 5-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide.

171. The compound of claim 149, wherein the compound is a compound of formula (IV): ##STR02069## wherein: R.sub.2 is selected from the group consisting of: ##STR02070## wherein R.sub.2b is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, and halogen; and R.sub.14 is C.sub.1-C.sub.4 alkyl; ##STR02071## wherein R.sub.5b is selected from the group consisting of C(?O)R.sub.8, (CH.sub.2).sub.nOH, and cyano, wherein R.sub.8 is C.sub.1-C.sub.4 alkyl and n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8; ##STR02072## wherein R.sub.5b is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; ##STR02073## wherein R.sub.4b is H or halogen; ##STR02074## wherein R.sub.9 is H or C.sub.1-C.sub.4 alkyl; and ##STR02075##

172. The compound of claim 171, wherein the compound is a compound of formula (IV-a): ##STR02076##

173. The compound of claim 172, wherein R.sub.2 is selected from the group consisting of: ##STR02077##

174. The compound of claim 172, wherein the compound of formula (IV-a) is selected from the group consisting of: 3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-ethylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6-methyl-phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6-fluoro-phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-acetylphenyl)-3-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-[3-(hydroxymethyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-[3-cyanophenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(3-pyridyl-N-oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(4-pyridyl-N-oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(2-fluoro-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(2-methyl-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(6-fluoro-3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(6-chloro-3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(1-methyl-2-oxo-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoro-phenoxy)-N-(2-oxidopyridazin-2-ium-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and 3-(2-chloro-4-fluoro-phenoxy)-N-pyrimidin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide.

175. The compound of claim 171, wherein the compound is a compound of formula (IV-b): ##STR02078## wherein: R.sub.1 is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4yl, wherein the phenyl and pyridyl can be unsubstituted or substituted with one or more of halogen, C.sub.1-C.sub.8 alkyl, OR.sub.5, wherein R.sub.5 is selected from the group consisting of C.sub.1-C.sub.8 alkyl, CF.sub.3, CHF.sub.2, and (CH.sub.2).sub.pCF.sub.3, wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, SCF.sub.3, NR.sub.6R.sub.7, wherein R.sub.6 and R.sub.7 are selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; R.sub.3 and R.sub.4 are H or CF.sub.3, provided that if R.sub.3 is H, then R.sub.4 is CF.sub.3 and if R.sub.4 is H, then R.sub.3 is CF.sub.3; R.sub.2b is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, and halogen; and R.sub.14 is C.sub.1-C.sub.4 alkyl; R.sub.14 is C.sub.1-C.sub.4 alkyl; and R.sub.15 is O or NR.sub.10, wherein R.sub.10 is H or C.sub.1-C.sub.4 alkyl.

176. The compound of claim 175, wherein R.sub.1 is selected from the group consisting of phenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-trifluromethoxyphenyl, 4-trifluoromethoxyphenyl, difluoromethoxyphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluorophenyl, 2,5-difluorophenyl, 4-methylphenyl, 3-chloro-5-flurophenyl, 2-isopropylphenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(trifluoromethylsulfanyl)phenyl, 2-dimethylaminophenyl, 2-trifluromethylphenyl, 2,4-dimethoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl-3-pyridyl, 1,3-benzothiazol-4-yl, 4-difluoromethoxyphenyl, 2-chloro-4-methoxyphenyl, and 2-chlorophenyl.

177. The compound of claim 171, wherein the compound is a compound of formula (IV-c): ##STR02079## wherein: R.sub.1 is ##STR02080## wherein: R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, and R.sub.1e are each independently selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 alkoxyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, and NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are C.sub.1-C.sub.4 alkyl, provided that at least one of R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, and R.sub.1e are not H; and pharmaceutically acceptable salts thereof.

178. The compound of claim 177, wherein: (i) R.sub.4a is halogen; R.sub.2a is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, halogen, and C.sub.1-C.sub.4 alkoxyl; R.sub.3a is H or halogen; R.sub.5a is H or halogen; and R.sub.6a is H; (ii) R.sub.2a and R.sub.4a are each C.sub.1-C.sub.4 alkoxyl; (iii) R.sub.4a is OF.sub.3; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (iv) R.sub.4a is OCHF.sub.2; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (v) R.sub.4a is OCH.sub.2F; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (vi) R.sub.4a is OCH.sub.2F.sub.3; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a, R.sub.5a, and R.sub.6a are each H; (vii) R.sub.3a is halogen; R.sub.2a is H or halogen; R.sub.4a and R.sub.5a are H; and R.sub.6a is H or halogen; and (viii) R.sub.2 is NR.sub.5R.sub.6; and R.sub.3a, R.sub.4a, R.sub.5a, and R.sub.6a are each H.

179. The compound of claim 178, wherein R.sub.1 is selected from the group consisting of: ##STR02081##

180. The compound of claim 177, wherein the compound of formula (IV-c) is selected from the group consisting of: 3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-dichlorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-dimethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-methyl-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-methyl-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-methyl-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3,4-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3,4,5-trifluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3,6-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,3-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-3-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-chloro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and 3-(2-dimethylaminophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide.

181. The compound of claim 171, wherein the compound is a compound of formula (IV-d): ##STR02082## wherein: R.sub.1 is ##STR02083## wherein: R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, and R.sub.1e are each independently selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 alkoxyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, and NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are C.sub.1-C.sub.4 alkyl, provided that at least one of R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, and R.sub.1e are not H; and pharmaceutically acceptable salts thereof.

182. The compound of claim 181, wherein: (i) R.sub.4a is halogen; R.sub.2a is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, halogen, and C.sub.1-C.sub.4 alkoxyl; R.sub.3a is H or halogen; R.sub.5a is H or halogen; and R.sub.6a is H; (ii) R.sub.2a and R.sub.4a are each C.sub.1-C.sub.4 alkoxyl; (iii) R.sub.4a is OF.sub.3; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (iv) R.sub.4a is OCHF.sub.2; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (v) R.sub.4a is OCH.sub.2F; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (vi) R.sub.4a is OCH.sub.2F.sub.3; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a, R.sub.5a, and R.sub.6a are each H; (vii) R.sub.3a is halogen; R.sub.2a is H or halogen; R.sub.4a and R.sub.5a are H; and R.sub.6a is H or halogen; and (viii) R.sub.2 is NR.sub.5R.sub.6; and R.sub.3a, R.sub.4a, R.sub.5a, and R.sub.6a are each H.

183. The compound of claim 182, wherein R.sub.1 is selected from the group consisting of: ##STR02084##

184. The compound of claim 181, wherein the compound of formula (IV-d) is selected from the group consisting of: 3-(4-fluoro-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-dichlorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-dimethoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(difluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(methylsulfonyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(methylsulfonyl)phenyl)-3-(4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-fluoro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(fluoromethoxy)-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3,4-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)-3-(3,4,5-trifluorophenoxy)pyridazine-4-carboxamide; 3-(2,5-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,3-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-3-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3-fluoro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-chloro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and 3-(2-(dimethylamino)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide.

185. The compound of claim 171, wherein the compound is a compound of formula (IV-e): ##STR02085## wherein: R.sub.3 is selected from the group consisting of CF.sub.2H, CH.sub.2F, halogen, OCF.sub.3, OCHF.sub.2, OCFH.sub.2, cyclopropyl, branched or straightchain C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, cyano, nitro, SCF.sub.3, and SF.sub.5; and R.sub.4 is selected from the group consisting of H and branched or straightchain C.sub.1-C.sub.4 alkyl.

186. The compound of claim 185, wherein the compound of formula (IV-e) is selected from the group consisting of: 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(difluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(fluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-chloro-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethoxy)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(difluoromethoxy)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(fluoromethoxy)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-bromo-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-cyclopropyl-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-tert-butyl-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-isopropyl-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-methyl-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5,6-dimethyl-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-methoxy-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-methyl-6-methoxy-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-cyano-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-nitro-pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-((trifluoromethyl)thio)pyridazine-4-carboxamide; and 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(pentafluoro-?.sup.6-sulfaneyl)pyridazine-4-carboxamide.

187. The compound of claim 171, wherein the compound is a compound of formula (IV-f): ##STR02086## wherein: R.sub.1 is ##STR02087## wherein: R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, and R.sub.1e are each independently selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, halogen, C.sub.1-C.sub.4 alkoxyl, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, and NR.sub.5R.sub.6, wherein R.sub.5 and R.sub.6 are C.sub.1-C.sub.4 alkyl, provided that at least one of R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d, and R.sub.1e are not H.

188. The compound of claim 187, wherein: (i) R.sub.4a is halogen; R.sub.2a is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, halogen, and C.sub.1-C.sub.4 alkoxyl; R.sub.3a is H or halogen; R.sub.5a is H or halogen; and R.sub.6a is H; (ii) R.sub.2a is C.sub.1-C.sub.4 alkoxyl and R.sub.4a is selected from the group consisting of C.sub.1-C.sub.4 alkoxyl and halogen; (iii) R.sub.4a is OF.sub.3; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (iv) R.sub.4a is OCHF.sub.2; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (v) R.sub.4a is OCH.sub.2F; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a and R.sub.6a are each H; R.sub.5a is H or halogen; (vi) R.sub.4a is OCH.sub.2F.sub.3; R.sub.2a is selected from the group consisting of H, halogen, and C.sub.1-C.sub.4 alkyl; R.sub.3a, R.sub.5a, and R.sub.6a are each H; (vii) R.sub.3a is halogen; R.sub.2a is H or halogen; R.sub.4a and R.sub.5a are H; and R.sub.6a is H or halogen; and (viii) R.sub.2 is NR.sub.5R.sub.6; and R.sub.3a, R.sub.4a, R.sub.5a, and R.sub.6a are each H.

189. The compound of claim 187, wherein R.sub.1 is selected from the group consisting of: ##STR02088##

190. The compound of claim 187, wherein the compound of formula (IV-f) is selected from the group consisting of: N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-dichlorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,4-dimethoxyphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide hydrochloride; 3-(4-(difluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(fluoromethoxy)-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(3,4-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)-3-(3,4,5-trifluorophenoxy)pyridazine-4-carboxamide; 3-(2,5-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2,3-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-chloro-3-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3-fluoro-4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(4-chloro-2-methoxyphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; 3-(2-(dimethylamino)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide.

191. The compound of claim 171, wherein the compound is a compound of formula (IV-g): ##STR02089## wherein: R.sub.1 is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, and 2,4-difluorophenyl; R.sub.20 is C.sub.1-C.sub.4 alkyl; and R.sub.21 is H or C.sub.1-C.sub.4 alkyl.

192. A method for modulating a Na.sub.V1.8 sodium ion channel, the method comprising administering to a subject in need thereof, a modulating-effective amount of a compound of formula (I-VI) of any of claims 149-191 to the subject.

193. A method for inhibiting Na.sub.V1.8, the method comprising administering to a subject in need thereof, an inhibiting-effective amount of a compound of formula (I-VI) of any of claims 149-191 to the subject.

194. A method for treating and/or reducing symptoms of a condition, disease, or disorder associated with an increased Na.sub.V1.8 activity or expression, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a compound of formula (I-VI) of any of claims 149-191 to the subject to treat and/or reduce the symptoms of the condition, disease, or disorder.

195. The method of claim 194, wherein the condition, disease, or disorder associated with an increased Na.sub.V1.8 activity or expression is selected from the group consisting of pain, respiratory diseases, neurological disorders, and psychiatric diseases, and combinations thereof.

196. The method of claim 195, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, and combinations thereof.

197. The method of claim 194, wherein the disease or condition is selected from the group consisting of HIV-treatment induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxi related illnesses, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and general tonic seizures, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection under ischaemic conditions cause by stroke or neural trauma, tach-arrhythmias, atrial fibrillation, ventricular fibrillation, and Pitt Hopkins Syndrome (PTHS).

198. The method of claim 194, further comprising administering to the subject one or more additional therapeutic agents.

199. The method of claim 198, wherein the one or more additional therapeutic agents is selected from the group consisting of acetaminophen, one or more NSAIDs, opioid analgesics, and combinations thereof.

200. The use of a compound of formula (I-IV) from claims 149-191 in the manufacture of a medicament for treating a condition, disease, or disorder associated with an increased Na.sub.v1.8 activity or expression in a subject afflicted with such a disorder.

201. A compound of Formula (I): ##STR02090## or a pharmaceutically acceptable salt thereof wherein: R.sub.1 is CN, CF.sub.3, an optionally substituted 5 or 6 ring membered ring, including aryl or heteroaryl rings, wherein the 5 or 6 ring membered ring optionally includes one or more N or S in the ring, wherein the substitutions on the 5 or 6 ring membered ring are selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, a fused heterocyclyl in which each ring has 5 or 6 members, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted where valency permits R.sub.2 is alkyl, haloalkyl, alkoxy, or haloalkoxy; R.sub.3 is halogen, alkyl, or alkoxy; R.sub.4 is halogen, alkyl, or H; R.sub.5 is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, a fused heterocyclyl in which each ring has 5 or 6 members, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted where valency permits; X is CH or N; and Z is CH or N, wherein X and Z are not both CH; R.sub.2 is CH.sub.3, CD.sub.3, or CT.sub.3, wherein D is deuterium and T is tritium; R.sub.3 is CH.sub.3, CD.sub.3, or CT.sub.3, wherein D is deuterium and T is tritium.

202. A compound of Formula (IV), ##STR02091## or a pharmaceutically acceptable salt thereof wherein: Y is N or CR.sub.13; A and B are independently aryl, heteroaryl, or a 3-6 membered ring containing one or more heteroatoms independently selected from O, S, and N; wherein A is unsubstituted or substituted with one or more substituents selected from: H, halo, C.sub.1-C.sub.6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, SR, CH.sub.2-cycloalkyl, CF.sub.2-cycloalky, CH(CH.sub.3)-cycloalkyl, CH.sub.2 aryl, CF.sub.2-aryl, CH(CH.sub.3)-aryl, C(?O)-alkyl, C(?O)cycloalkyl, C(?O)NH-alkyl, C(?O)NH.sub.2, hydroxy, COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NRRNHSOR, NHC(?O)-alkyl-NH(C?O)NRR, SO.sub.2R, trifluoromethyl, bromo, chloro, fluoro, cyclopropylmethyl, sufonylmethyl, 3-6 membered cycloalkyl; 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; R.sub.12, R.sub.13, and R.sub.14 are individually selected from: H, CF.sub.3, halo, C.sub.1-C.sub.6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, CH.sub.2-cycloalkyl, CF.sub.2-cycloalky, CH(CH.sub.3)-cycloalkyl, CH.sub.2-aryl, CF.sub.2-aryl, CH(CH.sub.3)-aryl, C(?O)-alkyl, C(?O)cycloalkyl, C(?O)NH-alkyl, C(?O)NH.sub.2, hydroxy, COOH (and ester thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NRRNHSO.sub.2R.sub.1, NHC(?O)-alkyl-NH(C?O)NRR, spirocyclyl, morpholinyl, pyrrolidinyl, piperidinyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein the 5 or 6 ring membered ring optionally includes one or more N or S in the ring, wherein the substitutions on the 5 or 6 ring membered ring are selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, C(?O)NH-alkyl, C(?O)NH.sub.2 cyano, CF.sub.3, CHF.sub.2, OCH.sub.3, OCF.sub.3, a fused heterocyclyl in which each ring has 5 or 6 members, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted where valency permits; the substituents R and R may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted, unsubstituted heteroaryl, or CD.sub.3.

203. A compound of claim 202 wherein, A is CH.sub.2CF.sub.3

204. A compound of claim 202 wherein, A is or ##STR02092##

205. A compound of formula (V), ##STR02093## A, and B are as described in Formula (IV) R.sub.2 is as described in Formula (II) R.sub.13 and R.sub.14 are as described in Formula (IV) X is CH or N; Y is NR.sub.8 or O; Z is CH, N, or NO.

206. A compound of Formula (I): ##STR02094## wherein: R.sub.1 is CN, CF.sub.3, an optionally substituted 5 or 6 ring membered ring, including aryl or heteroaryl rings, wherein the 5 or 6 ring membered ring optionally includes one or more N or S in the ring, wherein the substitutions on the 5 or 6 ring membered ring are selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, a fused heterocyclyl in which each ring has 5 or 6 members, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted where valency permits R.sub.2 is alkyl, haloalkyl, alkoxy, or haloalkoxy; R.sub.3 is halogen, alkyl, or alkoxy; R.sub.4 is halogen, alkyl, or H; R.sub.5 is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulphonyl, alkyl sulfoximinyl, alkyl sulfonamide, cyano, CF.sub.3, OCF.sub.3, a fused heterocyclyl in which each ring has 5 or 6 members, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted where valency permits; X is CH or N; and Z is CH or N, with the proviso that X and Z cannot both be CH, or a pharmaceutically acceptable salt thereof.

207. A compound of claim 206, wherein R.sub.2 is selected from a group consisting of CH.sub.3, CD.sub.3, or CT.sub.3, and wherein D is deuterium and T is tritium.

208. A compound of claim 206, where in R.sub.3 is selected from a group consisting of CH.sub.3, CD.sub.3, or CT.sub.3, wherein D is deuterium and T is tritium.

209. A compound of claim 206, wherein R.sub.5 is optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, or halogen.

210. A compound selected from the compounds recited in Examples 7-101.

211. A compound selected from the compounds recited in Examples 103-105.

212. A compound selected from the compounds recited in Examples 110-114.

213. A compound selected from the compounds recited in Example 119.

214. A compound selected from the compounds recited in Example 121.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0753] FIG. 1: A depiction of Protocol 1 for conducting the Na.sub.V1.8 Inhibition Assay.

V. EXAMPLES

[0754] The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner to make compounds of the disclosure by other methods.

A. Examples for First Set of Compounds

Example 1

[0755] Methods of making the compounds of the present invention, and intermediates used in their synthesis, are provided in the General Synthetic Schemes and Specific Syntheses Procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. dry glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted.

[0756] All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized. The chemical names were generated using the ChemDraw Professional 19.1, available from PerkinElmer or ChemAxon.

[0757] Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD MILLIPORE?. Purification was performed with CombiFlash NextGen 300 Automated Flash Chromatography System or purified using one of the preparative HPLC methods mentioned below. Analytical data was collected using one of the analytical methods described below.

Example 2

Prep Method 1 (P1): Acidic Early Method

[0758] Purification (METCR/Prep004) (P1) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 2 (P2): Acidic Standard Method

[0759] Purification (METCR/Prep001) (P2) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 30% B (A=0.10% formic acid in water; B=0.1% formic acid in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 3 (P3): Basic Early Method

[0760] Purification (METCR/Prep002) (P3) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 10% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 4 (P4): Basic Standard Method

[0761] Purification (METCR/Prep003) (P4) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 30% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

[0762] Analytical LCMC were collected using one of following methods

[0763] Method 1 (M1): Acidic IPC Method (METCR1410MS17, MS18, MS19) Analytical (MET/CR/1410) (M1) HPLC-MS were performed using a Kinetex Core shell C18 column (2.1 mm?50 mm, 5 ?m; temperature: 40? C.), with an injection volume of 3 ?L at a flow rate of 1.2 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.10% formic acid in acetonitrile) over 1.2 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.01 min and held for 0.39 min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector, spectrum range: 210-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0764] Method 3 (M3): Basic IPC Method (MET-uPLC-AB-2005MS16, MSQ5) Analytical (MET/uPLC/AB2005) (M14) uHPLC-MS were performed using a Waters uPLC? BEHTM C18 column (2.1 mm?30 mm, 1.7 ?m; temperature 40? C.), with an injection volume of 1 ?L at a flow rate of 1.0 mL/min and a gradient of 1-100% B (A=2 mM ammonium bicarbonate in water, buffered to pH 10; B=acetonitrile) over 1.1 min, then 100% B for 0.25 min. A second gradient of 100-1% B was then applied over 0.05 min and held for 0.4 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0765] Method 4 (M4): Acidic Final Analysis Method (METCR-uPLC-AB101MSQ1, MSQ2, MSQ4)

[0766] Analytical (MET/uPLC/AB101) (M4) uHPLC-MS were performed using a Phenomenex Kinetex-XB C18 column (2.1 mm?100 mm, 1.7 ?m; temperature: 40? C.), with an injection volume of 1 ?L at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm, ELS data was collected on a Waters ACQUITY ELS detector when reported. Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDA. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0767] Method 5 (M5): Acidic Final Analysis Method (METCR1416MS18, MS19) Analytical (MET/CR/1416) (M5) HPLC-MS were performed using a Waters Atlantis dC18 column (2.1 mm?100 mm, 3 ?m; temperature: 40? C.), with an injection volume of 3 ?L at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 5 min, then 100% B for 0.4 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.58 min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector, spectrum range: 210-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0768] Method 6 (M6): Basic Final Analysis Method (MET-uPLC-AB105MS16, MSQ5) Analytical (MET/uHPLC/AB105) (M8) uHPLC-MS were performed using a Waters uPLC? BEHTM C18 column (2.1 mm?100 mm, 1.7 ?m column; temperature: 40? C.), with an injection volume of 1 ?L and at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=2 mM ammonium bicarbonate in water, buffered to pH 10; B=acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 7

[0769] Mass spectrometry data were collected using a Waters Acquity H-class ultra-high pressure liquid chromatograph coupled to a Waters Acquity TQD mass spectrometer. An Acquity UPLC BEH C18 column (2.1?50 mm) was used for separation and resolving samples. The compounds were eluted from the column using a 10 minutes linear solvent gradient: 0-0.5 min, 5% B; 0.5-6.5 min, 100% B, 6.5-7.5 min; 100% B, 7.5-8.1 min; 5% B, 8.1-10 min; 5% B. The solvent flow rate is 0.45 mL per minute. Solvent A was water and solvent B was acetonitrile. Mass spectra were collected in positive or negative ion mode, with following parameters: 2.5 kV capillary voltage; 25 V sampling cone voltage; 140 C source temperature; 400 C desolvation temperature; nitrogen desolvation at 800 L/hr.

[0770] Unless otherwise stated, .sup.1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker? 300 MHz, or 500 MHz, 400 MHz or 250 MHz on either a Bruker Avance III HD 500 MHz spectrometer Bruker Avance III HD 400 MHz spectrometer. Chemical shifts, 6, are quoted in parts per million (ppm) relative to TMS and calibrated using residual un-deuterated solvent as an internal reference. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

Example 3

[0771] Purification Methods are as follows:

Prep Method 1 (P1): Acidic Early Method

[0772] Purification (METCR/Prep004) (P1) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 2 (P2): Acidic Standard Method

[0773] Purification (METCR/Prep001) (P2) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 30% B (A=0.10% formic acid in water; B=0.10% formic acid in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 3 (P3): Basic Early Method

[0774] Purification (METCR/Prep002) (P3) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 10% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 4 (P4): Basic Standard Method

[0775] Purification (METCR/Prep003) (P4) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 30% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

Example 4

Abbreviations and Acronyms

[0776] When the following abbreviations are used herein, they have the following meaning:

TABLE-US-00001 Ac2O acetic anhydride anhy Anhydrous n-BuOH n-butanol t-BuOH t-butanol CD.sub.3OD methanol-d.sub.4 Celite? diatomaceous earth filter agent, ?Celite Corp. CH.sub.2Cl.sub.2 methylene chloride DCM dichloromethane CI-MS chemical ionization mass spectroscopy conc concentrated dec decomposition bs broad singlet br broad DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide DMSO-d.sub.6 dimethylsulfoxide-d.sub.6 ELSD evaporative light scattering device EtOAc ethyl acetate EtOH ethanol (100%) Et.sub.2O diethyl ether Et.sub.3N triethylamine HPLC ESI-MS high performance liquid chromatography- electrospray mass spectroscopy MPLC medium pressure liquid chromatography NMR nuclear magnetic resonance spectroscopy TOF-MS time-of-flight-mass spectroscopy NMM 4-methylmorpholine Ph.sub.3P triphenylphosphine Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene]dichloro- palladium(II) Pd(PPh.sub.3).sub.4 tetrakis(triphenylphosphine)palladium(0) Pd(OAc).sub.2 palladium(II) acetate P(O)Cl.sub.3 phosphorous oxychloride Rf TLC retention factor RT retention time (HPLC) rt room temperature MS Mass spectra THF tetrahydrofuran TFA trifluoroacetic acid TLC thin layer chromatography LC-MS (ESI) liquid chromatography-mass spectroscopy (electrospray ionization) DIEA diisopropylethylamine Et.sub.3N triethylamine MsCl Methanesulfonylchloride HATU N-[(dimethylamino)-1H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]- N-methylmethanaminium hexafluorophosphate N-oxide EDC N-(3-dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride AcOH acetic acid HCl hydrochloric acid H.sub.2SO.sub.4 sulfuric acid HNO.sub.3 nitric acid HBr hydrobromic acid CDCl.sub.3 chloroform-d CHCl.sub.3 chloroform H.sub.2O water NaOAc sodium acetate KOH potassium hydroxide NaOH sodium hydroxide NaCl sodium chloride NaHCO.sub.3 sodium bicarbonate Na.sub.2CO.sub.3 sodium carbonate K.sub.2CO.sub.3 potassium carbonate Na.sub.2SO.sub.4 sodium sulfate MgSO.sub.4 magnesium sulfate MeOH methanol SiO.sub.2 silica gel K.sub.3PO.sub.4 potassium phosphate NH.sub.4Cl ammonium chloride DMAP N,N-dimethylpyridin-4-amine LG leaving group TsCl p-toluenesulfonyl chloride PG protecting group AIBN 2,2-axo bisisobutyronitrile

Example 5

General Synthetic Schemes

[0777] Methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. The present invention further provides processes for the preparation of compounds of structural Formula (I) and Formula (II) as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following exemplary compounds are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention.

##STR00078##

[0778] Compounds of the Formula (I) may be synthesized in seven step linear synthesis starting from a heteroaromatic dichlorocarboxylic acid ester A-1 by nucleophilic displacement of Cl adjacent to the carboxylic acid using various substituted phenols in the presence of base, such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaOH, KOH or other organic bases to provide intermediates of type A-2. Intermediates of type A-2 may be further treated with nitromethane in DMSO using organic base to produce A-3. A-3 can be converted to corresponding iodo compound by treating with HI (50%), HI(57%) or HI (40%) to furnish intermediates of type A-4. Variously substituted R.sub.1 groups can be introduced either by Pd mediated or Cu mediated coupling with intermediates of type A-4 to produce intermediates of type A-5. The carboxylic acid of intermediates type A-6 can be prepared by hydrolyzing ester intermediates of type A-5 using a base, such as aqueous NaOH, KOH, or LiOH. Alternatively, intermediates of type A-6 can be prepared by treating intermediates A-5 using aqueous 1 to 6N HCl. The carboxylic acids (A-6) can be converted to the corresponding acid chlorides and followed by reacting with 3-(substitutedthio)aniline to afford A-7. Alternatively, A-7 can be prepared from carboxylic acids (A-6) and 3-(substitutedthio)aniline using standard amide coupling agents, not limited to HATU, TBTU, EDC or T.sub.3P in organic solvents and base, such as DIEA. The compounds of the Formula (I) may be prepared by reacting intermediates of type A-7 with ammonium carbonate and (diacetoxyiodo)benzene in organic solvents such as methanol.

##STR00079##

[0779] The intermediates of type B-3 can be prepared analogous to the steps described for A-4 in Scheme 1. Intermediates of type B-3 were further reacted with methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, TBAI, CuI using DMF or HMPA as a solvent and heating at 25? C.-120? C. for a period of 1-12 h to furnish B-4. The acid intermediates (B-5) can be prepared by similar hydrolysis procedures as described in scheme 1 from B-4. Intermediates of type B-6 may be prepared using standard coupling conditions described in scheme 1 from the corresponding acids. Compounds of Formula (II) may be prepared by treating B-6 with Oxone in organic solvents or mCPBA in DCM. Alternatively, the of compounds of the Formula (II) can be prepared from carboxylic acids (B-5) and appropriately 3-substituted aniline using standard coupling conditions as described in scheme 1. The compounds of the Formula (II) can also be prepared by reacting intermediates of type B-6 with ammonium carbonate and (diacetoxyiodo)benzene in organic solvents such as methanol.

##STR00080##

[0780] Compounds of Formula (III) may be prepared by treating B-5 with substituted aniline or heteroaryl aniline using standard amide coupling agents, not limited to HATU, TBTU, EDC or T3P in organic solvents and base, such as DIEA.

Example 6

Specific Synthesis

Scheme 4, Intermediates 1-5

3-(4-Fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic Acid

[0781] ##STR00081##

[0782] Reagents & conditions: a) 4-fluoro-2-methylphenol, K.sub.2CO.sub.3, CH.sub.3CN, 80? C., 3 h; b) nitromethane, Et.sub.3N, DMSO, rt, 48 h; c) HI (57%), 55? C., 16 h; d) methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, TBAI, CuI, DMF, 90? C., 2 h; e) LiOH, THF:H.sub.2O (5:1), rt.

Intermediate 1

[0783] Step 1: methyl 6-chloro-3-(4-fluoro-2-methylphenoxy)pyridazine-4-carboxylate: A mixture of 4-fluoro-2-methylphenol (3.01 g, 23.8 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (4.70 g, 22.7 mmol) and K.sub.2CO.sub.3 (4.71 g, 34.1 mmol) in CH.sub.3CN (47 mL) was stirred at 80? C. for 3 h. The reaction was cooled to room temperature, filtered, and washed with CH.sub.3CN (20 mL). Filtrate was concentrated in vacuo to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 15% EtOAc in heptane afforded the title compound methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (95.0%) (4.10 g, 58%) as a pale yellow oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.26 (s, 1H), 7.29-7.20 (m, 2H), 7.16-7.06 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H). LC-MS: m/z: 297/299 [M+H].sup.+, (ESI+), RT=4.26 LCMS Method 5.

Intermediate 2

[0784] Step 2: methyl 6-chloro-3-(4-fluoro-2-methylphenoxy)-5-methylpyridazine-4-carboxylate: To a mixture of methyl 6-chloro-3-(4-fluoro-2-methylphenoxy)pyridazine-4-carboxylate (1.20 g, 4.04 mmol) in DMSO (3.6 mL), nitromethane (1.1 mL, 20.2 mmol) was added and the mixture was stirred for 30 min at rt, triethylamine (0.85 mL, 6.07 mmol) was added to the reaction and stirred at rt for 48 h. The reaction was diluted with water (100 mL) and brine (25 mL) extracted with EtOAc (2?50 mL). Organic layers were dried (MgSO.sub.4), filtered, concentrated under reduced pressure to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane afforded the title compound (1.110 g, 85%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.26-7.19 (m, 2H), 7.15-7.08 (m, 1H), 3.99 (s, 3H), 2.38 (s, 3H), 2.08 (s, 3H). LC-MS: m/z 310.95, 312.9 [M+H].sup.+, (ESI+), RT=1.27 LCMS Method 5.

Intermediate 3

[0785] Step 3: methyl 3-(4-fluoro-2-methylphenoxy)-6-iodo-5-methylpyridazine-4-carboxylate: A mixture of methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylate (1.10 g, 3.54 mmol) in 55% aqueous hydrogen iodide (55%, 24 mL, 0.177 mol) was stirred at 40? C. for 16 h. The reaction was diluted with water (50 mL) and sat. sodium thiosulphate (100 mL), extracted with EtOAc (2?100 mL). Organic layer separated, dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound methyl 3-(4-fluoro-2-methylphenoxy)-6-iodo-5-methylpyridazine-4-carboxylate (42.0%) (1153 mg, 34%) as a brown oil. LC-MS: m/z 403.0 [M+H]+, (ESI+), RT=1.29 LCMS Method 1.

Intermediate 4

[0786] Step 4: methyl 3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: To a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methylpyridazine-4-carboxylate (42%, 1.153 g, 1.20 mmol), iodocopper (0.35 g, 1.81 mmol), and tetrabutylammonium iodide (0.18 g, 0.482 mmol) in DMF (6.4023 mL), methyl difluoro(fluorosulfonyl)acetate (1.16 g, 6.02 mmol) was added and stirred at 70? C. for 2 h. The reaction was cooled to rt, filtered and washed with EtOAc (2?20 mL). The filtrate was washed with brine (50 mL) and dried over MgSO.sub.4, filtered, concentrated under reduced pressure to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 20% EtOAc in heptane afforded the title compound (97.0%) (425 mg, 99%) as a pale yellow oil. LC-MS: m/z 345.0 [M+H]+, (ESI+), RT=1.33 LCMS Method 1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ?7.31-7.23 (m, 2H), 7.14 (td, J=8.6, 3.2 Hz, 1H), 4.02 (s, 3H), 2.48-2.44 (m, 3H), 2.09 (s, 3H).

Intermediate 5

[0787] Step 5: 3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (97%, 425 mg, 1.20 mmol) in THF (4.5806 mL):Water (0.9161 mL), lithium hydroxide (149 mg, 5.99 mmol) was added and the mixture was stirred at rt for 16 h. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The aqueous layer was extracted with EtOAc (20 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound (407 mg, 99%) as a pale-yellow solid.

[0788] The intermediates 6-15 listed in Table 1 were prepared by a similar procedure as described for step 1 of scheme 4 using appropriate starting materials.

TABLE-US-00002 TABLE 1 Intermediate Structure & Name Analytical data 6 [00082] .sup.1H NMR (500 MHZ, DMSO- d.sub.6) ? 8.32 (s, 1H), 7.81-7.77 (m, 1H), 7.68-7.64 (m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 2.22 (s, 3H). LC-MS: m/z 346.9 [M + H].sup.+, (ESI+), RT = 1.25 LCMS Method 1 Methyl 6-chloro-3-(2-methyl-4- (trifluoromethyl)phenoxy)pyridazine-4- carboxylate 7 [00083] .sup.1H NMR (400 MHZ, DMSO- d.sub.6) ? 8.37 (s, 1H), 7.65-7.55 (m, 1H), 7.52-7.44 (m, 1H), 3.99-3.89 (m, 3H). LC-MS: m/z 384.9 [M + H].sup.+, (ESI+), RT = 1.37 LCMS Method 1 Methyl 6-chloro-3-[2,3-difluoro-4- (trifluoromethoxy)phenoxy]pyridazine-4- carboxylate 8 [00084] .sup.1H NMR (500 MHZ, DMSO- d.sub.6) ? 8.29 (s, 1H), 7.44-7.41 (m, 1H), 7.35-7.29 (m, 2H), 3.94 (s, 3H), 2.15 (s, 3H). LC-MS: m/z 362.95/364.90 [M + H].sup.+, (ESI+), RT = 1.33 LCMS Method 1 Methyl 6-chloro-3-[2-methyl-4- (trifluoromethoxy)phenoxy] pyridazine-4-carboxylate 9 [00085] .sup.1H NMR (400 MHZ, DMSO- d.sub.6) ? 8.33 (s, 1H), 7.99-7.93 (m, 2H), 7.50-7.45 (m, 2H), 3.91 (s, 3H). LC-MS: m/z 289.9 [M + H].sup.+, (ESI+), RT = 1.07 LCMS Method 1 Methyl 6-chloro-3-(4-cyano- phenoxy)pyridazine-4-carboxylate 10 [00086] .sup.1H NMR (500 MHZ, DMSO- d.sub.6) ? 8.28 (s, 1H), 7.54-7.51 (m, 2H), 7.32-7.29 (m, 2H), 3.92 (s, 3H). LC-MS: m/z 298.8/300.9 [M + H].sup.+, (ESI+), RT = 1.16 LCMS Method 1 Methyl 6-chloro-3-(4- chlorophenoxy)pyridazine-4- carboxylate 11 [00087] .sup.1H NMR (300 MHZ, CDCl.sub.3) ? 7.96 (s, 1H), 7.40-7.18 (m, 5H), 4.02 (s, 3H), 3.76 (s, 3H). Methyl 6-chloro-3-(4-cyano-2- methoxyphenoxy)pyridazine-4-carboxylate 12 [00088] .sup.1H NMR (300 MHZ, CDCl.sub.3) ? 7.91 (s, 1H), 7.16-7.10 (m, 1H), 6.98 (dd, J = 6.9, 2.2 Hz, 2H), 4.01 (d, J = 1.2 Hz, 3H), 3.72 (s, 3H). Methyl 6-chloro-3-(4-chloro-2- methoxyphenoxy)pyridazine-4-carboxylate 13 [00089] .sup.1H NMR (300 MHZ, CDCl.sub.3) ? 7.95 (s, 1H), 7.27-7.24 (m, 1H), 7.21 (d, J = 1.2 Hz, 2H), 4.02 (s, 3H). Methyl 6-chloro-3-(4-chloro-2- fluorophenoxy)pyridazine-4-carboxylate 14 [00090] .sup.1H NMR (300 MHZ, CDCl.sub.3) ? 7.90 (s, 1H), 7.43 (td, J = 2.9, 2.4, 1.6 Hz, 1H), 7.36 (ddd, J = 8.5, 2.5, 0.7 Hz, 1H), 6.99 (dd, J = 8.5, 6.4 Hz, 1H), 4.02 (d, J = 1.5 Hz, 3H), 2.17 (s, 3H). Methyl 3-(4-bromo-2-methylphenoxy)-6- chloropyridazine-4-carboxylate 15 [00091] .sup.1H NMR (300 MHZ, CDCl.sub.3) ? 7.94 (s, 1H), 7.34-7.27 (m, 1H), 7.23-7.09 (m, 2H), 4.03 (d, J = 1.6 Hz, 3H), 2.23 (d, J = 4.8 Hz, 3H). Methyl 6-chloro-3-(2-chloro-6- methylphenoxy)pyridazine-4- carboxylate

[0789] The intermediates 16-24 listed in Table 2 were prepared by a similar procedure as described for step 2 of scheme 4 using appropriate starting materials.

TABLE-US-00003 TABLE 2 Intermediate Structure & Name Analytical data 16 [00092] .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ? 7.80-7.76 (m, 1H), 7.66 (dd, J = 8.5, 2.3 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 3.99 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H). LC-MS: m/z 360.9 [M + H].sup.+, (ESI+), RT = 1.27 LCMS Method 1 Methyl 6-chloro-5-methyl-3-(2-methyl-4- (trifluoromethyl)phenoxy)pyridazine-4- carboxylate 17 [00093] .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ? 7.43-7.39 (m, 1H), 7.36-7.27 (m, 2H), 3.99 (s, 3H), 2.39 (s, 3H), 2.12 (s, 3H). LC-MS: m/z 377.35/ 378.95 [M + H].sup.+, (ESI+), RT = 1.38 LCMS Method 1 Methyl 6-chloro-5-methyl-3-[2- methyl-4-(trifluoromethoxy) phenoxy]pyridazine-4- carboxylate 18 [00094] .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 7.96 (dd, J = 8.9, 2.2 Hz, 2H), 7.47 (dd, J = 8.9, 2.2 Hz, 2H), 3.96 (d, J = 2.3 Hz, 3H), 2.40 (d, J = 2.3 Hz, 3H). LC-MS: m/z 304.0/305.95 [M + H].sup.+, (ESI+), RT = 1.17 LCMS Method 1 Methyl 6-chloro-3-(4-cyanophen- oxy)-5-methyl-pyridazine-4- carboxylate 19 [00095] .sup.1H NMR (500 MHZ, DMSO-d.sub.6) ? 7.53-7.50 (m, 2H), 7.30-7.27 (m, 2H), 3.97 (s, 3H), 2.38 (s, 3H) LC-MS: m/z 312.9/314.85 [M + H].sup.+, (ESI+), RT = 1.28 LCMS Method 1 Methyl 6-chloro-3-(4-chlorophenoxy)-5- methyl-pyridazine-4-carboxylate 20 [00096] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.39-7.19 (m, 3H), 4.02 (s, 3H), 3.77 (s, 3H), 2.43 (s, 3H) Methyl 6-chloro-3-(4-cyano-2- methoxyphenoxy)-5-methylpyridazine-4- carboxylate 21 [00097] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.15-7.05 (m, 1H), 7.04-6.86 (m, 2H), 4.02 (s, 3H), 3.73 (s, 3H), 2.41 (s, 3H). Methyl 6-chloro-3-(4-chloro-2- methoxyphenoxy)-5-methylpyridazine-4- carboxylate 22 [00098] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.24-7.21 (m, 1H), 7.21-7.12 (m, 2H), 4.02 (d, J = 2.4 Hz, 3H), 2.40 (d, J = 6.7 Hz, 3H). Methyl 6-chloro-3-(4-chloro-2- fluorophenoxy)-5-methylpyridazine-4- carboxylate 23 [00099] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.42 (ddd, J = 5.4, 2.4, 0.9 Hz, 1H), 7.36 (dddd, J = 8.5, 4.6, 2.5, 0.7 Hz, 1H), 6.99 (dd, J = 12.6, 8.6 Hz, 1H), 4.02 (s, 3H), 2.42 (s, 3H), 2.14 (d, J = 2.5 Hz, 3H). Methyl 3-(4-bromo-2-methylphenoxy)-6- chloro-5-methylpyridazine-4-carboxylate 24 [00100] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.33-7.27 (m, 1H), 7.21-7.08 (m, 2H), 4.04 (d, J = 1.6 Hz, 3H), 2.44 (d, J = 5.1 Hz, 3H), 2.27-2.16 (m, 3H) Methyl 6-chloro-3-(2-chloro-6- methylphenoxy)-5-methylpyridazine-4- carboxylate

[0790] The intermediates 25-35 listed in Table 3 were prepared by a similar procedure as described for step 3 of scheme 4 using appropriate starting materials.

TABLE-US-00004 TABLE 3 Intermediate Structure & Name Analytical data 25 [00101] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.80-7.74 (m, 1H), 7.70-7.61 (m, 1H), 7.47-7.38 (m, 1H), 3.97 (s, 3H), 2.39 (s, 3H), 2.17 (s, 3H) LC-MS: m/z 452.8 [M + H].sup.+, (ESI+), RT = 1.29 LCMS Method 1 Methyl 6-iodo-5-methyl-3-(2-methyl-4- (trifluoromethyl)phenoxy)pyridazine-4- carboxylate 26 [00102] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.63-7.55 (m, 1H), 7.53-7.44 (m, 1H), 3.98 (s, 3H), 2.43-2.39 (m, 3H). LC-MS: m/z 490.9 [M + H].sup.+, (ESI+), RT = 1.40 LCMS Method 1 Methyl 3-(2,3-difluoro-4- (trifluoromethoxy)phenoxy)-6-iodo-5- methylpyridazine-4-carboxylate 27 [00103] .sup.1H NMR (500 MHz, DMSO)-d.sub.6 ? 7.41-7.40 (m, 1H), 7.31-7.27 (m, 2H), 3.97 (s, 3H), 2.38 (s, 3H), 2.11 (s, 3H). LC-MS: m/z 468.95 [M + H].sup.+, (ESI+), RT = 1.40 LCMS Method 1 Methyl 6-iodo-5-methyl-3-[2-methyl-4- (trifluoromethoxy)phenoxy]pyridazine-4- carboxylate 28 [00104] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.32-7.25 (m, 1H), 7.25-7.21 (m, 1H), 4.01 (s, 3H), 3.81 (d, J = 1.4 Hz, 3H), 2.38 (s, 3H). LC-MS: m/z 437.3 [M + H].sup.+, (ESI+), RT = 1.28 LCMS Method 1 Methyl 3-(3,4-difluoro-2-methoxy- phenoxy)-6-iodo-5-methyl-pyridazine-4- carboxylate 29 [00105] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.99-7.90 (m, 2H), 7.49-7.40 (m, 2H), 3.94 (s, 3H), 2.39 (s, 3H). LC-MS: m/z 395.8 [M + H].sup.+, (ESI+), RT = 1.12 LCMS Method 1 Methyl 3-(4-cyanophenoxy)-6-iodo-5- methyl-pyridazine-4-carboxylate 30 [00106] 1H NMR (500 MHz, DMSO) ? 7.52-7.49 (m, 2H), 7.28-7.25 (m, 2H), 3.95 (s, 3H), 2.37 (s, 3H). LC-MS: m/z 404.8 [M + H].sup.+, (ESI+), RT = 1.19 LCMS Method 1 Methyl 3-(4-chlorophenoxy)-6-iodo-5- methyl-pyridazine-4-carboxylate 31 [00107] MS: m/z 426.1 [M + H].sup.+ Methyl 3-(4-cyano-2-methoxyphenoxy)- 6-iodo-5-methylpyridazine-4-carboxylate 32 [00108] MS: m/z 457.0 [M + Na].sup.+ Methyl 3-(4-chloro-2-methoxyphenoxy)- 6-iodo-5-methylpyridazine-4-carboxylate 33 [00109] MS: m/z 445.0 [M + Na].sup.+ Methyl 3-(4-chloro-2-fluorophenoxy)-6- iodo-5-methylpyridazine-4-carboxylate 34 [00110] MS: m/z 463.0, 465.0 [M + H].sup.+ Methyl 3-(4-bromo-2-methylphenoxy)-6- iodo-5-methylpyridazine-4-carboxylate 35 [00111] MS: m/z 463.0, 465.0 [M + H].sup.+ Methyl 3-(2-chloro-6-methylphenoxy)-6- iodo-5-methylpyridazine-4-carboxylate

[0791] The intermediates 36-46 listed in Table 4 were prepared by a similar procedure as described for step 4 of scheme 4 using appropriate starting materials.

TABLE-US-00005 TABLE 4 Intermediate Structure & Name Analytical data 36 [00112] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.81 (d, J = 1.9 Hz, 1H), 7.69 (dd, J = 8.5, 2.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H), 2.49-2.47 (m, 3H), 2.19 (s, 3H). LC-MS: m/z 394.9 [M + H].sup.+, (ESI+), RT = 1.31 LCMS Method 1 37 [00113] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.46- 7.42 (m, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.34-7.29 (m, 1H), 4.02 (s, 3H), 2.48- 2.45 (m, 3H), 2.14 (s, 3H). LC-MS: m/z 410.9 [M + H].sup.+, (ESI+), RT = 1.34 LCMS Method 1 38 [00114] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.67- 7.60 (m, 1H), 7.55 (ddd, J = 9.6, 7.8, 2.2 Hz, 1H), 4.02 (s, 3H), 2.51-2.48 (m, 3H). Me peak hidden under DMSO, identified in HSQC. LC-MS: m/z 432.95 [M + H].sup.+, (ESI+), RT = 1.43 LCMS Method 1 39 [00115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.34- 7.21 (m, 2H), 4.02 (s, 3H), 3.80 (d, J = 1.3 Hz, 3H), 2.49-2.47 (m, 3H). LC-MS: m/z 379.35 [M + H].sup.+, (ESI+), RT = 1.32 LCMS Method 1 40 [00116] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.02- 7.96 (m, 2H), 7.56-7.51 (m, 2H), 4.00 (s, 3H), 2.49-2.47 (m, 3H) LC-MS: m/z 338.5 [M + H].sup.+, (ESI+), RT = 1.16 LCMS Method 1 41 [00117] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.58- 7.51 (m, 2H), 7.38-7.31 (m, 2H), 4.00 (s, 3H), 2.48-2.43 (m, 3H) LC-MS: m/z 346.95/348.95 [M + H].sup.+, (ESI+), RT = 1.34 LCMS Method 1 42 [00118] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.27 (d, J = 1.7 Hz, 2H), 7.17 (d, J = 1.7 Hz, 1H), 3.98 (s, 3H), 3.71 (s, 3H), 2.44 (q, J = 1.4 Hz, 3H). 43 [00119] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.15- 7.09 (m, 1H), 7.00-6.93 (m, 2H), 4.04 (s, 3H), 3.73 (s, 3H), 2.49 (q, J = 1.5 Hz, 3H). 44 [00120] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.29- 7.24 (m, 1H), 7.23 (dd, J = 1.6, 0.8 Hz, 1H), 7.22-7.19 (m, 1H), 4.06 (s, 3H), 2.51 (q, J = 1.4 Hz, 3H) 45 [00121] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.48- 7.31 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 4.05 (s, 3H), 2.50 (q, J = 1.4 Hz, 3H), 2.15 (s, 3H). 46 [00122] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.36- 7.26 (m, 1H), 7.26-7.08 (m, 2H), 4.07 (s, 3H), 2.52 (q, J = 1.5 Hz, 3H), 2.21 (s, 3H).

[0792] The intermediates 47-56 listed in Table 5 were prepared by a similar procedure as described for step 5 of scheme 4 using appropriate starting materials.

TABLE-US-00006 TABLE 5 Intermediate Structure & name Analytical data 47 [00123] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.79 (d, J = 1.9 Hz, 1H), 7.67 (dd, J = 8.5, 2.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 2.48-2.45 (m, 3H), 2.18 (s, 3H) LC-MS: m/z 380.9 [M + H].sup.+, (ESI+), RT = 1.14 LCMS Method 1 48 [00124] LC-MS: m/z 365.0 [M + H].sup.+, (ESI+), RT = 1.02 LCMS Method 1 49 [00125] LC-MS: m/z 397.0 [M + H].sup.+, (ESI+), RT = 1.18 LCMS Method 1 50 [00126] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.03- 7.92 (m, 2H), 7.55-7.46 (m, 2H), 2.50 (s, 3H, from HSQC analysis).. LC-MS: m/z 323.9 [M + H].sup.+, (ESI+), RT = 0.88 LCMS Method 1 51 [00127] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.57- 7.49 (m, 2H), 7.35-7.27 (m, 2H), 2.45 (d, J = 1.5 Hz, 3H). LC-MS: m/z 332.95 [M + H].sup.+, (ESI+), RT = 1.02 LCMS Method 1 52 [00128] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 7.76 (d, J = 1.8 Hz, 1H), 7.62-7.46 (m, 2H), 3.78 (s, 3H), 2.54 (s, 3H). 53 [00129] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 7.42- 7.25 (m, 2H), 7.10 (dd, J = 8.5, 2.4 Hz, 1H), 3.74 (s, 3H), 2.49-2.41 (m, 3H). 54 [00130] .sup.1H NMR (300 MHz, CD.sub.3OD) ? 7.47- 7.35 (m, 2H), 7.31 (ddd, J = 8.7, 2.4, 1.2 Hz, 1H), 2.56 (q, J = 1.5 Hz, 3H). 55 [00131] .sup.1H NMR (300 MHz, CD.sub.3OD) ? 7.57- 7.32 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 2.54 (q, J = 1.5 Hz, 3H), 2.14 (s, 3H). 56 [00132] .sup.1H NMR (300 MHz, CD.sub.3OD) ? 7.42- 7.32 (m, 1H), 7.32-7.17 (m, 2H), 2.57 (q, J = 1.5 Hz, 3H), 2.20 (s, 3H)

Intermediate 57

4-(cyclobutoxy)-2,3-difluoro-phenol

[0793] ##STR00133##

[0794] Step 1: cyclobutyl 4-methylbenzenesulfonate: To a solution of cyclobutanol (0.22 mL, 2.77 mmol) in DCM (6 mL) under an atmosphere of nitrogen was added 4-methylbenzenesulfonyl chloride (635 mg, 3.33 mmol) followed by triethylamine (0.46 mL, 3.33 mmol). The mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2?5 mL). The organic phases were dried (MgSO.sub.4), filtered and concentrated to afford a clear oil. Purification by FCC (Biotage isolera, SiO.sub.2 gradient elution, 0 to 20% EtOAc in heptane) afforded cyclobutyl 4-methylbenzenesulfonate (97%) (362 mg, 1.599 mmol, 58%) as a clear oil. m/z: 227.1 [M+H].sup.+, (ESI+), RT=0.91 METCR1704 (2 minute uPLC gradient method for IPCs).

[0795] Step 2: 1-bromo-4-(cyclobutoxy)-2,3-difluoro-benzene: To a solution of 4-bromo-2,3-difluorophenol (1.40 g, 6.70 mmol) and cyclobutyl 4-methylbenzenesulfonate (1.82 g, 8.04 mmol) in DMF (10 mL) was added dipotassium; carbonate (1.39 g, 10.0 mmol). The mixture was heated at 90? C. for 4 h. The mixture was allowed to cool to room temperature, then diluted with ethyl acetate (60 mL) and washed with water (3?30 mL) and brine (30 mL). The organics were dried (MgSO.sub.4), filtered and concentrated to afford an orange oil. Purification by FCC (Biotage isolera, SiO.sub.2 gradient elution, 0 to 10% EtOAc in heptane) afforded 1-bromo-4-(cyclobutoxy)-2,3-difluoro-benzene (76%) (0.983 g, 3.737 mmol, 43%) as a clear oil. LC-MS: m/z 263.2 [M].sup.+, (ESI+), RT=1.10 METCR1704 (2 minute uPLC gradient method for IPCs).

[0796] Step 3: 4-(cyclobutoxy)-2,3-difluoro-phenol: A mixture of 1-bromo-4-(cyclobutoxy)-2,3-difluoro-benzene (980 mg, 3.73 mmol) and potassium hydroxide (418 mg, 7.45 mmol) in 1,4-Dioxane (5 mL) and Water (5 mL) was degassed by nitrogen bubbling for 10 min then, di-tert-butyl[3,4,5,6-tetramethyl-246-tri(propan-2-yl)biphenyl-2-yl]phosphane (143 mg, 0.298 mmol) and (1 {E},4{E})-1,5-diphenylpenta-1,4-dien-3-one; palladium (68 mg, 0.0745 mmol) were added and the reaction was stirred at 100 C for 18 h. The pH was adjusted to ?3 with 1M HCl, and the mixture extracted with ethyl acetate (3?8 mL). The combined organics were dried (MgSO4), filtered and concentrated to afford a brown oil. Purification by FCC (Biotage isolera, SiO2 gradient elution, 0 to 5% EtOAc) in heptane afforded 4-(cyclobutoxy)-2,3-difluoro-phenol (90%) (622 mg, 3.107 mmol, 75%) as a pale orange solid. LC-MS: m/z 199.1 [M?H].sup.?, (ESI?), RT=0.82 METCR1704 (2 minute uPLC gradient method for IPCs).

Intermediate 58 and Intermediate 59

tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-?.SUP.6.-sulfaneylidene) carbamate [Intermediate 58] and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-?.SUP.6.-sulfaneylidene) carbamate [Intermediate 59]

[0797] ##STR00134##

[0798] Step 1: imino(methyl)(3-nitrophenyl)-?.sup.6-sulfanone: To a mixture of methyl(3-nitrophenyl) sulfane (8.2 g, 48.5 mmol) and ammonium acetate (5.6 g, 72.7 mmol) in EtOH (120 mL) was added PhI(OAc).sub.2 (31.2 g, 97 mmol) in one portion. The reaction mixture was stirred at room temperature under atmosphere for 16 h. The mixture was concentrated directly to give a residue which was purified by silica gel chromatography column (PE:EA=5:1 to 1:3) to afford imino(methyl)(3-nitrophenyl)-?.sup.6-sulfanone as a white solid (7.0 g, 72%). MS (ESI+): m/z found 201.03 [M+H].sup.+.

[0799] Step 2: tert-butyl (methyl(3-nitrophenyl)(oxo)-?.sup.6-sulfaneylidene)carbamate: To a solution of imino(methyl)(3-nitrophenyl)-?.sup.6-sulfanone (3.5 g, 17.5 mmol) in t-BuOH (200 mL) cooled with ice water bath was added t-BuOK (3.9 g, 35.0 mmol) under N.sub.2 protection. Subsequently, (Boc).sub.2O (7.6 g, 35.0 mmol) was added slowly and the reaction mixture was then refluxed for 10 h. The reaction mixture was quenched with saturated NH.sub.4Cl solution (200 mL) and extracted with EA (200 mL?2). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give a residue which was purified with silica gel chromatography column (PE:EA=5:1 to 1:1) to afford tert-butyl (methyl(3-nitrophenyl)(oxo)-?.sup.6-sulfaneylidene)carbamate as yellow solid (1.8 g, 34%). LC-MS(ESI+): m/z 301.09 [M+H].sup.+.

[0800] Step 3: (3-aminophenyl)(imino)(methyl)-?.sup.6-sulfanone: To a solution of tert-butyl (methyl(3-nitrophenyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (1.8 g, 6 mmol) in MeOH (30 mL) was added Pd(OH).sub.2 (300 mg) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated to give a residue which was re-dissolved in EA (30 mL) and the resulting solution was filtered through celite again and washed with EA (100 mL). The filtrate was concentrated to give tert-butyl ((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate (1.4 g, 86%) as off-white solid. MS (ESI+): m/z found 271.10 [M+H].sup.+.

[0801] Step 4: SFC separation: The racemic product was separated by chiral HPLC with the Chiral separation condition: Column: Daicel CHIRALPAK IG, 250 mm?20 mm I.D., 5 ?m; Mobile Phase A: CO.sub.2/MeOH [0.2% NH.sub.3 (7M Solution in MeOH)]=70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35? C. The first eluting isomer tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate [Intermediate 58]. .sup.1H NMR (DMSO-d.sub.6) ?7.26 (t, 1H), 7.08 (s, 1H), 6.97 (d, 1H), 6.83 (d, 1H), 5.71 (s, 2H), 3.28 (s, 3H), 1.27 (s. 9H) and the second eluting isomer tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate [Intermediate 59]. .sup.1H NMR (DMSO-d.sub.6) ?7.26 (t, 1H), 7.08 (s, 1H), 6.97 (d, 1H), 6.83 (d, 1H), 5.71 (s, 2H), 3.28 (s, 3H), 1.27 (s. 9H).

Example 7

Compound 1: 3-(4-Fluoro-2-methylphenoxy)-5-methyl-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0802] ##STR00135##

[0803] A mixture of N,N-diisopropylethylamine(DIEA) (0.16 mL, 0.908 mmol), 3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100 g, 0.303 mmol) and 3-(methylsulfonyl)aniline (0.062 g, 0.363 mmol) were dissolved in DCM (4.8 mL) under nitrogen at rt. To the above mixture 50% Propylphosphonic anhydride solution in EtOAc (50%, 0.36 mL, 0.606 mmol) was added in one portion. The reaction mixture was stirred at rt for 4 h. The reaction was then stirred at 55? C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo to obtain the crude residue. Purification by Prep LC Method P1 to afford the title compound (0.025 g, 17%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.39 (s, 1H), 8.38 (t, J=1.8 Hz, 1H), 7.90 (ddd, J=7.9, 2.0, 1.2 Hz, 1H), 7.78-7.73 (m, 1H), 7.70 (t, J=7.9 Hz, 1H), 7.29 (dd, J=8.9, 5.0 Hz, 1H), 7.24 (dd, J=9.4, 3.1 Hz, 1H), 7.14 (td, J=8.5, 3.1 Hz, 1H), 3.24 (s, 3H), 2.54-2.51 (m, 3H), 2.12 (s, 3H). LC-MS: m/z 484.0 [M+H].sup.+, (ESI+), RT=4.24 LCMS Method 5.

Example 8

Compound 2: 5-Methyl-N-(3-methylsulfonylphenyl)-3-[2-methyl-4-(trifluoromethyl)phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0804] ##STR00136##

[0805] The title compound was prepared by a similar method as described for compound 1 using 5-methyl-3-(2-methyl-4-(trifluoromethyl)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 3-(methylsulfonyl)aniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.42 (s, 1H), 8.37 (t, J=1.8 Hz, 1H), 7.93-7.87 (m, 1H), 7.80-7.66 (m, 4H), 7.51 (d, J=8.4 Hz, 1H), 3.24 (s, 3H), 2.56-2.53 (m, 3H), 2.21 (s, 3H). m/z: 534.1 [M+H].sup.+, (ESI+), RT=3.81 LCMS Method 4

Example 9

Compound 3: 5-Methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0806] ##STR00137##

[0807] A mixture of 3-(methyl sulfonyl)aniline (41 mg, 0.242 mmol), using 5-methyl-3-(2-methyl-4-(methyl-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (85 mg, 0.202 mmol) were dissolved in DMF (0.5085 mL) under nitrogen at rt. Then N-ethyl-N-isopropyl-propan-2-amine (0.070 mL, 0.403 mmol) was added followed by N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (77 mg, 0.202 mmol). The reaction mixture was stirred at rt for 1 h. The reaction was diluted with brine (10 mL) extracted with EtOAc (2?10 mL). Organics washed with 1M HCl (10 mL), dried over MgSO.sub.4, filtered, concentrated under reduced pressure to obtain the crude residue, which was purified using preparative method Prep1 to afford the 5-methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (51 mg, 46%) as an off white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.41 (t, J=1.9 Hz, 1H), 7.97 (ddd, J=8.1, 2.1, 1.1 Hz, 1H), 7.79 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.29-7.25 (m, 1H), 7.21 (dd, J=8.8, 2.7 Hz, 1H), 3.15 (s, 3H), 2.62-2.57 (m, 3H), 2.21 (s, 3H). m/z: 550.5 [M+H].sup.+, (ESI+), RT=4.50 LCMS Method 5.

Example 10

Compound 4: 3-(4-Cyano-2-methoxyphenoxy)-5-methyl-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0808] ##STR00138##

[0809] To a mixture of 3-(4-cyano-2-methoxyphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.060, 0.170 mmol), 3-methanesulfonylaniline (0.029 g, 0.170 mmol), HATU (0.097 g, 0.255 mmol) in DMF (3 mL) was added DIEA (0.089 mL, 0.510 mmol) at 25? C. and stirring continue for further 16 h at 25? C. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2?30 mL). The combined EtOAc layer was washed with 1M LiCl (10 mL) followed by brine (20 mL). The EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated. The crude product was chromatographed over SiO.sub.2 with a gradient of 0 to 10% EtOAc in DCM to afford 3-(4-cyano-2-methoxyphenoxy)-N-(3-methanesulfonylphenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (0.028 g, 33%). .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.52 (s, 1H), 8.15-7.97 (m, 2H), 7.77 (dt, J=7.9, 1.3 Hz, 1H), 7.63 (t, J=8.0 Hz, H), 7.41 (d, J=1.5 Hz, 2H), 7.30 (s, 1H), 3.89 (s, 3H), 3.09 (s, 3H), 2.67 (q, J=1.5 Hz, 3H). LC-MS: m/z 505.3 [M?H].sup.+

[0810] The compounds 5-7 listed in Table 6 were prepared by a similar procedure as described for compound 4.

TABLE-US-00007 TABLE 6 Compound Structure & Name Analytical data 5 [00139] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.37 (s, 1H), 8.39 (t, J = 1.8 Hz, 1H), 7.91 (dt, J = 7.7, 1.8 Hz, 1H), 7.81-7.64 (m, 2H), 7.39- 7.29 (m, 2H), 7.11 (dd, J = 8.5, 2.3 Hz, 1H), 3.76 (s, 3H), 3.25 (s, 3H), 2.53(s, 3H). Methyl peak at 2.53 peak buried under residual DMSO solvent. LC-MS: m/z 516.3 [M + H].sup.+ 6 [00140] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.79 (s, 1H), 8.26 (ddd, J = 8.0, 2.3, 1.2 Hz, 1H), 8.00 (t, J = 1.9 Hz, 1H), 7.75-7.57 (m, 2H), 7.24 (dd, J = 2.6, 1.7 Hz, 1H), 7.21-7.15 (m, 2H), 3.02 (s, 3H), 2.59 (q, J = 1.5 Hz, 3H). LC- MS: m/z 504.2[M + H].sup.+ 7 [00141] LC-MS: m/z 500.3 [M + H].sup.+

Example 11

Compound 8: 3-(4-Fluoro-2-methylphenoxy)-5-methyl-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0811] ##STR00142##

[0812] To a mixture of 3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.303 mmol) in DCM (1.9151 mL) at RT, N-ethyl-N-isopropyl-propan-2-amine (0.12 mL, 0.666 mmol) and N,N-dimethylpyridin-4-amine (7.4 mg, 0.0606 mmol) were added followed by 5000 Propylphosphonic anhydride solution in EtOAc (500%, 0.36 mL, 0.606 mmol) the mixture was stirred at me for 15 min. 3-(methylsulfanyl)aniline (51 mg, 0.363 mmol) was added to the reaction. The reaction mixture was stirred at rt for 10 min and then at 55? C. for 16 h. The volatiles were removed in vacuo. Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane followed by 0-60% MeOH in EtOAC afforded 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (43.00) (110 mg, 350) as a yellow solid. LC-MS: m/z 452.6 [M+H].sup.+, (ESI+), RT=4.81 LCMS Method 5.

[0813] The compounds 9-13 listed in Table 7 were prepared by a similar procedure as described for compound 8.

TABLE-US-00008 TABLE 7 Compound Structure and name Analytical data 9 [00143] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.97 (s, 1H), 8.01-7.95 (m, 2H), 7.63-7.58 (m, 1H), 7.56-7.49 (m, 2H), 7.39 (ddd, J = 8.1, 1.9, 0.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.06 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H), 2.51-2.50 (m, 3H), 2.46 (s, 3H). LC-MS: m/z 445.05 [M + H].sup.+, (ESI+), RT = 1.33 LCMS Method 1 10 [00144] LC-MS: m/z 453.95 [M + H].sup.+, (ESI+), RT = 1.41 LCMS Method 1 11 [00145] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.00 (s, 1H), 7.43-7.39 (m, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 8.9, 5.0 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.5, 3.2 Hz, 1H), 7.09-7.06 (m, 1H), 2.89 (s, 3H), 2.73 (s, 3H), 2.48 (s, 3H). LC-MS: m/z 486.5 [M + H].sup.+, (ESI+), RT = 4.75 LCMS Method 5 12 [00146] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.02 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.5, 2.2 Hz, 1H), 7.65 (t, J = 1.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41 (ddd, J = 8.1, 1.9, 1.1 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.08 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 2.53- 2.51 (m, 3H), 2.48 (s, 3H), 2.21 (s, 3H). LC-MS: m/z 502.0 [M + H].sup.+, (ESI+), RT = 1.47 LCMS Method 1 13 [00147] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.00 (s, 1H), 7.65 (t, J = 1.8 Hz, 1H), 7.41 (d, J = 5.3 Hz, 2H), 7.37 (d, J = 9.5 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 7.8 Hz, 1H), 2.51 (s, 3H), 2.48 (s, 3H), 2.16 (s, 3H). LC-MS: m/z 517.9 [M + H].sup.+, (ESI+), RT = 1.14 LCMS Method 1

Example 12

Compound 14: 3-(4-Cyano-2-methylphenoxy)-5-methyl-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0814] ##STR00148##

[0815] Reagents & conditions: HATU, 3-(methyl sulfanyl)aniline, DIEA, DMVF, rt, 16 h.

[0816] To a mixture of 3-(4-cyano-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.300 g, 0.890 mmol), 3-(methylsulfanyl)aniline (0.124 g, 0.890 mmol) and HATU (0.676 g, 1.78 mmol) in DMF (10 mL) was added DIEA (0.0345 g, 2.67 mmol) at rt. The resulting mixture was stirred further for 16 h, at the end of this period water (10 mL) was added and extracted with EtOAc (2?40 mL). The combined EtOAc layer was washed with 1M LiCl (20 mL) followed by brine (30 mL). The EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated. The crude material was chromatographed over SiO.sub.2 with a gradient of 0-50% EtOAc in hexane to afford 3-(4-cyano-2-methylphenoxy)-5-methyl-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.165 g, 40.46%). .sup.1H NMR (300 MHz, CDCl3) ? 7.72-7.49 (m, 3H), 7.37-7.21 (m, 4H), 7.19-7.06 (m, 1H), 2.63 (q, J=1.5 Hz, 3H), 2.52 (s, 3H), 2.23 (s, 3H). LC-MS: m/z 457.3[M?H].sup.+.

[0817] The compounds 15-19 listed in Table 8 were prepared by a similar procedure as described for compound 14.

TABLE-US-00009 TABLE 8 Compound Structure and name Analytical data 15 [00149] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.07 (s, 1H), 7.62 (q, J = 1.5 Hz, 1H), 7.39 (d, J = 1.4 Hz, 2H), 7.32-7.24 (m, 4H), 7.09 (ddd, J = 6.4, 2.8, 1.8 Hz, 1H), 3.85 (s, 3H), 2.66 (q, J = 1.5 Hz, 3H), 2.51 (s, 3H). 16 [00150] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.20 (s, 1H), 7.63 (q, J = 1.5 Hz, 1H), 7.31- 7.27 (m, 2H), 7.26-7.21 (m, 1H), 7.12- 6.99 (m, 3H), 3.83 (s, 3H), 2.66(q, J = 1.5 Hz, 3H), 2.51 (s, 3H). 17 [00151] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.73- 7.57 (m, 2H), 7.39-7.18 (m, 6H), 7.11 (dt, J = 6.3, 1.9 Hz, 1H), 2.63 (q, J = 1.5 Hz, 3H), 2.52 (s, 3H). 18 [00152] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 10.90 (s, 1H), 8.66 (s, 1H), 7.65 (dt, J = 12.5, 2.0 Hz, 2H), 7.56-7.22 (m, 4H), 7.07 (dt, J = 7.9, 1.5 Hz, 1H), 2.49 (s, 3H), 2.13 (s, 3H) 19 [00153] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.99 (s, 1H), 7.67 (t, J = 2.0 Hz, 1H), 7.38- 7.28 (m, 3H), 7.23-7.13 (m, 2H), 7.10 (dt, J = 7.3, 1.7 Hz, 1H), 2.67 (q, J = 1.5 Hz, 3H), 2.52 (s, 3H), 2.24 (s, 3H).

Example 13

[0818] Compound 20: 3-(4-Fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

##STR00154##

[0819] To a solution of 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (43%) (0.090 g, 0.0857 mmol) was dissolved in Methanol (0.3518 mL) and treated with ammonium carbonate (0.012 g, 0.13 mmol) and (diacetoxyiodo)benzene (0.064 mg, 0.197 mmol), each added in one portion. The resulting mixture was stirred at rt for 24 h. The solvent was removed in vacuo. Purification by chromatography afforded the title compound (0.032 g, 75%) as a light brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.35 (s, 1H), 8.36 (t, J=1.9 Hz, 1H), 7.90-7.84 (m, 1H), 7.76-7.71 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.29 (dd, J=8.9, 5.0 Hz, 1H), 7.24 (dd, J=9.3, 3.0 Hz, 1H), 7.14 (td, J=8.5, 3.1 Hz, 1H), 4.25 (s, 1H), 3.07 (s, 3H), 2.52 (s, 3H), 2.12 (s, 3H). LC-MS: m/z 482.9 [M+H].sup.+, (ESI+), RT=3.83 LCMS Method 5.

[0820] The compounds 21-29 listed in Table 9 were prepared by a similar procedure as described for compound 20.

TABLE-US-00010 TABLE 9 Compound Structure & name Analytical data 21 [00155] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.32 (s, 1H), 8.33 (t, J = 1.9 Hz, 1H), 8.03-7.97 (m, 2H), 7.87 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.76-7.70 (m, 1H), 7.68-7.60 (m, 1H), 7.57-7.50 (m, 2H), 4.26 (s, 1H), 3.07 (d, J = 0.8 Hz, 3H), 2.54-2.53 (m, 3H). m/z: 475.9 [M + H].sup.+, (ESI+), RT = 3.58 LCMS Method 5 22 [00156] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.93-7.85 (m, 1H), 7.76-7.70 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.59-7.52 (m, 2H), 7.41- 7.30 (m, 2H), 4.26 (s, 1H), 3.07 (s, 3H), 2.52-2.51 (m, 3H). m/z: 484.9 [M + H].sup.+, (ESI+), RT = 3.89 LCMS Method 5 23 [00157] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.88 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.75-7.71 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.33-7.26 (m, 1H), 7.24 (ddd, J = 9.3, 5.2, 1.8 Hz, 1H), 4.27 (s, 1H), 3.81 (d, J = 1.1 Hz, 3H), 3.07 (d, J = 0.8 Hz, 3H), 2.54-2.51 (m, 3H). m/z: 516.9 [M + H].sup.+, (ESI+), RT = 3.85 LCMS Method 5 24 [00158] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.35 (t, J = 1.9 Hz, 1H), 7.97-7.79 (m, 3H), 7.75 (dt, J = 8.0, 1.3 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.28 (d, J = 1.3 Hz, 1H), 3.08 (d, J = 1.1 Hz, 3H), 2.54 (d, J = 1.7 Hz, 3H), 2.18 (s, 3H). LC-MS: m/z 488.2[M + H].sup.+ 25 [00159] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.32 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.88 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.74 (dd, J = 8.8, 1.7 Hz, 2H), 7.70-7.48(m, 3H), 4.28 (d, J = 1.4 Hz, 1H), 3.80 (s, 3H), 3.08 (d, J = 1.1 Hz, 3H), 2.51(s, 3H). LC-MS: m/z 504.2 [M ? H].sup.+ 26 [00160] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.30 (s, 1H), 8.37 (t, J = 1.9 Hz, 1H), 7.88 (dd, J = 8.2, 1.7 Hz, 1H), 7.78-7.58 (m, 2H), 7.32 (dd, J = 5.5, 3.1 Hz, 2H), 7.11 (dd, J = 8.5, 2.3 Hz, 1H), 4.32-4.19 (m, 1H), 3.76 (s, 3H), 3.08 (d, J = 1.1 Hz, 3H). A peak at 2.51 is buried under DMSO residual solvent peak. LC-MS: m/z 515.4[M + H].sup.+ 27 [00161] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.37 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.89 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.80-7.70 (m, 2H), 7.70-7.49 (m, 2H), 7.44 (ddd, J = 8.8, 2.5, 1.2 Hz, 1H), 4.29 (s, 1H), 3.08 (d, J = 1.1 Hz, 3H), 2.54 (d, J = 1.3 Hz, 3H). LC-MS: 503.3 [M + H].sup.+ 28 [00162] LC-MS: m/z 543.4, 545.3[M + H].sup.+ 29 [00163] LC-MS: m/z 499.4[M + H].sup.+

Example 14

[0821] Compounds 30 and 31: 3-(4-Fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide Chiral Separation

##STR00164##

[0822] The chiral purification of 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (compound 20) was performed using preparative chiral HPLC on a Chiralpak AD-H, (20?250 m) 5 ?m eluting with a mixture of Heptane:Ethanol (70:30), flow rate 18 mL/min. Fractions containing product were evaporated and isolated as sticky oils, these were re-dissolved in 1:1 MeCN:water (1 mL) and lyophilized to afford first eluting isomer (compound 30) (39 mg, 32%) as an off white solid. LC-MS: m/z: 483.2 [M+H].sup.+, (ESI+), RT=3.15 LCMS Method 6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.31 (s, 1H), 8.38-8.33 (m, 1H), 7.90-7.83 (m, 1H), 7.77-7.70 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.29 (dd, J=8.8, 5.0 Hz, 1H), 7.24 (dd, J=9.4, 3.0 Hz, 1H), 7.14 (td, J=8.7, 3.2 Hz, 1H), 4.25 (s, 1H), 3.07 (s, 3H), 2.52-2.52 (m, 3H), 2.12 (s, 3H). Analytical method: Mobile phase 70:30 Heptane:Ethanol, Column Chiralpak AD-H, 4.6?250 mm, 5 ?m Flow rate 1 mL/min. and the second eluting isomer (compound 31) (0.038 mg, 32%) as an off white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.45 (t, J=1.9 Hz, 1H), 7.96 (ddd, J=8.1, 2.1, 1.0 Hz, 1H), 7.84 (ddd, J=7.9, 1.8, 1.0 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.21 (dd, J=8.8, 4.9 Hz, 1H), 7.09 (dd, J=9.1, 3.1 Hz, 1H), 7.01 (td, J=8.5, 3.1 Hz, 1H), 3.17 (s, 3H), 2.62-2.55 (m, 3H), 2.17 (s, 3H). m/z: 483.5 [M+H].sup.+, (ESI+), RT=3.82 LCMS Method 5.

Example 15

Compounds 32 and 33: 5-Methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide Chiral Separation

[0823] ##STR00165##

[0824] 5-Methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was prepared by similar procedure described for compound 20 and was purified using preparative chiral HPLC on a Chiralpak AD-H, (20?250 m) 5 ?m eluting with a mixture of Heptane:Ethanol (70:30), flow rate 18 mL/min. Fractions containing product were evaporated to and isolated as sticky oils, these were re-dissolved in 1:1 MeCN:water (1 mL) and lyophilized to afford first eluting isomer (compound 32) (63 mg, 37%) as a beige solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.33 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.90-7.83 (m, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.44-7.38 (m, 2H), 7.35-7.30 (m, 1H), 4.25 (s, 1H), 3.07 (d, J=0.8 Hz, 3H), 2.54-2.52 (m, 3H), 2.16 (s, 3H). m/z: 549.2 [M+H].sup.+, (ESI+), RT=3.60 LCMS method 6 and the second eluting isomer (compound 33) (54 mg, 31%) as a beige solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.33 (s, 1H), 8.35 (t, J=1.9 Hz, 1H), 7.89-7.83 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.45-7.37 (m, 2H), 7.35-7.29 (m, 1H), 4.25 (s, 1H), 3.10-3.01 (m, 3H), 2.53-2.52 (m, 3H), 2.16 (s, 3H). m/z: 549.2 [M+H].sup.+, (ESI+), RT=3.60 LCMS method 6.

Example 16

Compounds 34 and 35: 5-Methyl-3-(2-methyl-4-(trifluoromethyl)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide Chiral Separation

[0825] ##STR00166##

[0826] 5-Methyl-3-(2-methyl-4-(trifluoromethyl)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was prepared by similar procedure described for compound 20 and was purified using preparative chiral HPLC on a Chiralpak AD-H, (20?250 m) 10 ?m eluting with a mixture of HPLC on a Chiralpak AD-H, (20?250 m) 5 ?m eluting with a mixture of Heptane:Ethanol (85:15), flow rate 18 mL/min. Fractions containing product were evaporated to afford first eluting isomer (compound 34) (99 mg, 29%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.33 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.91-7.84 (m, 1H), 7.81-7.77 (m, 1H), 7.76-7.68 (m, 2H), 7.64 (t, J=7.9 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.25 (s, 1H), 3.10-3.04 (m, 3H), 2.55-2.53 (m, 3H), 2.21 (s, 3H). LC-MS: m/z 533.6 [M+H].sup.+, (ESI+), RT=4.15 LCMS method 5 and second eluting isomer (compound 35) (92 mg, 27%) as white solids. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.33 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.90-7.85 (m, 1H), 7.81-7.77 (m, 1H), 7.76-7.67 (m, 2H), 7.64 (t, J=7.9 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 4.25 (s, 1H), 3.11-3.05 (m, 3H), 2.55-2.52 (m, 3H), 2.21 (s, 3H). LC-MS: m/z: 533.6 [M+H].sup.+, (ESI+), RT=4.14 LCMS method 5.

Example 17

[0827] The compounds 1401-1429 listed in Table 10 were prepared by a similar procedure as described for compound 14.

TABLE-US-00011 TABLE 10 Compound Structure & Name Analytical data 1401 [00167] LC-MS: m/z 465.4[M + H].sup.+ 1402 [00168] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.19 (s, 1H), 8.01-7.85 (m, 3H), 7.81-7.67 (m, 2H), 7.61 (dd, J = 2.5, 0.9 Hz, 1H), 7.51 (dd, J = 8.7, 2.5 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 2.51 (s, 3H; buried under DMSO residual solvent), 2.12 (s, 3H). LC-MS: m/z 509.3, 511.3 [M + H].sup.+ 1403 [00169] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.16 (s, 1H), 7.93 (d, J = 8.8 Hz, 3H), 7.81-7.67 (m, 2H), 7.40-7.23 (m, 3H), 7.11 (dd, J = 8.5, 2.4 Hz, 1H), 3.76 (s, 3H), 2.50 (s, 3H). 2.50 peak buried under residual DMSO solvent). LC-MS: m/z 481.4[M + H].sup.+ 1404 [00170] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.23 (s, 1H), 8.01-7.88 (m, 3H), 7.74 (dd, J = 9.5, 2.4 Hz, 3H), 7.55 (t, J = 8.5 Hz, 1H), 7.48-7.32 (m, 2H), 2.53(s, 3H). LC-MS: m/z 469.3 [M + H].sup.+ 1405 [00171] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.18 (s, 1H), 8.00-7.86 (m, 3H), 7.81-7.67 (m, 3H), 7.63-7.47 (m, 2H), 7.35 (s, 1H), 3.80 (s, 3H), 2.50(s, 3H). LC-MS: m/z 470.3 [M ? H].sup.+ 1406 [00172] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.08 (s, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.01 (s, 1H), 7.84-7.77 (m, 1H), 7.69-7.63 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.6, 3.1 Hz, 1H), 2.52 (s, 3H), 2.12 (s, 3H). LC-MS: m/z: 449.5 [M + H].sup.+, (ESI+), RT = 3.88 METCR1416 Hi res 7 min 1407 [00173] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.54 (s, 1H), 8.47 (t, J = 1.8 Hz, 1H), 8.39-8.35 (m, 1H), 8.30 (s, 1H), 8.21 (t, J = 1.4 Hz, 1H), 7.68 (s, 1H), 7.30 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.5, 3.1 Hz, 1H), 3.29 (s, 3H), 2.55- 2.52 (m, 3H), 2.12 (s, 3H). LC-MS: m/z: 527.5 [M + H].sup.+, (ESI+), RT = 3.82 METCR1416 Hi res 7 min 1408 [00174] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.54 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 5.4, 2.1 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.9, 5.0 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.6, 3.1 Hz, 1H), 2.53-2.51 (m, 3H), 2.11 (s, 3H). LC-MS: m/z: 449.9 [M + H].sup.+, (ESI+), RT = 3.94 METCR1416 Hi res 7 min 1409 [00175] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.12 (s, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.02 (br.s, 1H), 7.84-7.79 (m, 1H), 7.70-7.65 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.41 (br.s, 1H), 7.28-7.21 (m, 1H), 7.17-7.11 (m, 1H), 4.71 (hept, J = 6.0 Hz, 1H), 2.54- 2.51 (m, 3H), 1.32 (d, J = 6.0 Hz, 6H). LC- MS: m/z: 511.2 [M + H].sup.+, (ESI+), RT = 3.42 1410 [00176] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.59 (s, 1H), 8.59 (m, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.83 (m, 1H), 7.69 (s, 1H), 7.29 (m, 3H), 3.81 (s, 3H), 2.53 (s, 3H). LC-MS: m/z: 484.2 [M + H].sup.+, (ESI+), RT = 3.18 LCMS Method 7 1411 [00177] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.60 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 5.4, 2.1 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.29-7.22 (m, 1H), 7.17-7.11 (m, 1H), 4.70 (hept, J = 6.0 Hz, 1H), 2.53- 2.52 (m, 3H), 1.31 (d, J = 6.0 Hz, 6H). LC- MS: m/z: 512.2 [M + H].sup.+, (ESI+), RT = 3.54 LCMS Method 4 1412 [00178] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.71 (s, 1H), 9.36-9.32 (m, 1H), 9.17 (d, J = 5.8 Hz, 1H), 8.06 (dd, J = 5.9, 2.7 Hz, 1H), 7.28-7.23 (m, 1H), 7.17-7.11 (m, 1H), 4.71 (hept, J = 6.0 Hz, 1H), 2.54-2.51 (m, 3H), 1.32 (d, J = 6.0 Hz, 6H). LC-MS: m/z: 470.2 [M + H].sup.+, (ESI+), RT = 3.42 LCMS Method 4 1413 [00179] .sup.1H NMR (500 MHz, MeOH-d.sub.4) ? 9.35 (dd, J = 2.7, 1.0 Hz, 1H), 9.12 (dd, J = 5.9, 1.1 Hz, 1H), 8.22 (dd, J = 6.0, 2.7 Hz, 1H), 7.15-7.03 (m, 2H), 3.85 (d, J = 1.7 Hz, 3H), 2.58 (q, J = 1.5 Hz, 3H). LC-MS: m/z: 442.0 [M + H].sup.+, (ESI+), RT = 3.41 LCMS Method 4 1414 [00180] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.14 (br.s, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.02 (br.s, 1H), 7.83-7.78 (m, 1H), 7.69-7.65 (m, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.42 (br.s, 1H), 7.30 (dd, J = 9.1, 1.5 Hz, 1H), 2.55-2.52 (m, 3H), 2.14- 2.10 (m, 3H). LC-MS: m/z 550.3 [M + NH.sub.4].sup.+ RT 3.66 min, LCMS Method 6 1415 [00181] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.14 (s, 1H), 7.96-7.84 (m, 3H), 7.77-7.68 (m, 2H), 7.35-7.22 (m, 2H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 3.74 (s, 3H), 2.54-2.45 (m, 3H). m/z: 465.2 [M + H].sup.+, (ESI+), RT = 2.93 LCMS Method 4 1416 [00182] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.18 (s, 1H), 7.96-7.87 (m, 3H), 7.79-7.68 (m, 2H), 7.35-7.27 (m, 2H), 7.24 (dd, J = 9.3, 3.2 Hz, 1H), 7.14 (td, J = 8.5, 3.2 Hz, 1H), 2.55-2.44 (m, 3H), 2.12 (s, 3H). m/z: 449.3 [M + H]+, (ESI+), RT = 3.08 LCMS Method 6 1417 [00183] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.88 (s, 1H), 8.18 (t, J = 1.8 Hz, 1H), 7.99 (br.s, 1H), 7.82 (ddd, J = 8.1, 2.1, 0.8 Hz, 1H), 7.63 (dt, J = 7.7, 1.0 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.39 (br.s, 1H), 7.31-7.20 (m, 1H), 7.17 (ddd, J = 9.3, 5.3, 2.1 Hz, 1H), 3.82-3.77 (m, 3H), 3.12-3.02 (m, 4H), 2.22-2.12 (m, 2H). LC-MS: m/z 441.2 [M + H].sup.+, (ESI+), RT = 2.50 MET- uPLC-AB-101 (7 min, low pH) 1418 [00184] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.31 (s, 1H), 7.78 (dt, J = 7.0, 2.0 Hz, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.66-7.59 (m, 2H), 7.57 (dd, J = 8.3, 1.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.43 (s, 2H), 3.79 (s, 3H), 2.52 (s, 3H). LC-MS: m/z 508.1 [M + H].sup.+, (ESI+), RT = 2.93 LCMS Method 6 1419 [00185] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.35 (s, 1H), 8.36 (t, J = 1.8 Hz, 1H), 7.96-7.87 (m, 1H), 7.76 (dt, J = 7.9, 1.4 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.68-7.59 (m, 1H), 7.54 (ddd, J = 9.6, 7.7, 2.1 Hz, 1H), 3.24 (s, 3H), 2.59-2.53 (m, 3H). LC-MS: m/z 572.0 [M + H].sup.+, (ESI+), RT = 3.88 LCMS Method 4 1420 [00186] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.40 (s, 1H), 8.38 (t, J = 1.8 Hz, 1H), 7.92-7.85 (m, 1H), 7.78-7.66 (m, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 3.24 (s, 3H), 2.53-2.52 (m, 3H), 2.46 (s, 3H), 2.28 (s, 3H). LC-MS: m/z 481.2 [M + H].sup.+, (ESI+), RT = 3.05 LCMS Method 6 1421 [00187] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.41 (s, 1H), 8.38 (t, J = 1.8 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.57 (t, J = 8.6 Hz, 1H), 7.23 (dd, J = 8.9, 1.2 Hz, 1H), 3.25 (s, 3H), 2.57-2.52 (m, 3H), 2.11 (d, J = 1.7 Hz, 3H). LC-MS: m/z 516.2, 518.3 [M ? H].sup.?, (ESI?), RT = 3.94 LCMS Method 6 1422 [00188] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.45 (s, 1H), 8.37 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.80-7.65 (m, 2H), 7.54-7.18 (m, 3H), 3.25 (s, 3H), 2.57-2.53 (m, 3H). LC-MS: m/z 553.9 [M + H].sup.+, (ESI+), RT = 3.73 LCMS Method 4 1423 [00189] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.36 (s, 1H), 8.20-8.08 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 8.2 Hz, 2H), 3.05 (s, 3H), 2.69-2.56 (m, 3H). LC-MS: m/z 572 [M + H].sup.+, (ESI+), RT = 3.83 LCMS Method 4 1424 [00190] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.42 (s, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.91 (ddd, J = 7.9, 2.0, 1.3 Hz, 1H), 7.76 (dt, J = 7.8, 1.3 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.25 (td, J = 8.9, 8.2, 2.1 Hz, 1H), 7.18-7.10 (m, 1H), 4.71 (hept, J = 6.0 Hz, 1H), 3.25 (s, 3H), 2.54-2.52 (m, 3H), 1.32 (d, J = 6.0 Hz, 6H). LC-MS: m/z 546.1 [M + H].sup.+, (ESI+), RT = 3.80 LCMS Method 4 1425 [00191] .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.60 (s, 1H), 8.16 (t, J = 1.8 Hz, 1H), 8.07 (m, 1H), 7.81-7.73 (m, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.05 (ddd, J = 9.2, 4.9, 2.2 Hz, 1H), 7.02-6.91 (m, 1H), 3.90 (d, J = 2.4 Hz, 3H), 3.09 (s, 3H), 2.67 (m, 3H). LC-MS: m/z 518.1 [M + H].sup.+, (ESI+), RT = 3.47 ET-uPLC-AB-101 (7 min, low pH) LCMS Method 4 1426 [00192] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.43 (s, 1H), 8.37 (m, 1H), 7.91 (m, 1H), 7.76 (m, 1H), 7.71 (m, 1H), 7.24 (m, 1H), 6.97 (m, 1H), 4.88-4.77 (m, 1H), 3.25 (s, 3H), 2.44 (m, 2H), 2.19-2.05 (m, 2H), 1.82 (m, 1H), 1.73-1.57 (m, 1H). LC-MS: m/z: 558.2 [M + H].sup.+, (ESI+), RT = 3.92 MET- uPLC-AB-101 (7 min, low pH) LCMS Method 4 1427 [00193] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.28 (t, J = 2.0 Hz, 1H), 7.85 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.67 (ddd, J = 7.9, 1.8, 1.1 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 6.91-6.84 (m, 2H), 3.76 (s, 3H), 3.03 (s, 3H), 2.46 (q, J = 1.5 Hz, 3H), 1.96 (d, J = 2.3 Hz, 3H). LC- MS: m/z 514.0 [M + H].sup.+, (ESI+), RT = 3.55 MET-uPLC-AB-101 (7 min, low pH) 1428 [00194] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.41 (t, J = 1.9 Hz, 1H), 7.97 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.79 (ddd, J = 7.9, 1.8, 1.1 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 3.90 (s, 3H), 3.15 (s, 3H), 2.59 (q, J = 1.5 Hz, 3H), 2.28 (s, 3H). LC-MS: m/z 497.3 [M + H].sup.+, (ESI+), RT = 3.30 LCMS Method 6 1429 [00195] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.61 (s, 1H), 8.57 (t, J = 1.9 Hz, 1H), 8.53-8.48 (m, 1H), 8.21 (t, J = 1.6 Hz, 1H), 7.30 (dd, J = 9.0, 5.1 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.6, 3.2 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.32 (s, 3H), 2.55- 2.53 (m, 3H), 2.12 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). LC-MS: m/z 556.6 [M + H].sup.+, (ESI+), RT = 4.46 LCMS Method 5

Example 18

Compound 1430: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-pyridazin-4-yl-pyridazine-4-carboxamide

[0828] ##STR00196##

[0829] Step 1: methyl 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylate: (4R)-4-hydroxy-L-proline (16 mg, 0.124 mmol) was added to a N.sub.2 degassed mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (250 mg, 0.622 mmol), 3-fluoroazetidine hydrochloride (139 mg, 1.24 mmol), copper iodide (12 mg, 0.0622 mmol) and tripotassium phosphate (396 mg, 1.86 mmol) in anhydrous Acetonitrile (2.5 mL) and anhydrous DMSO (2 mL) and the reaction was stirred at 50? C. for 80 hr. Additional reagents (4R)-4-hydroxy-L-proline (16 mg, 0.124 mmol), methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (250 mg, 0.622 mmol), 3-fluoroazetidine hydrochloride (1:1) (139 mg, 1.24 mmol), copper(1+) iodide (12 mg, 0.0622 mmol) and tripotassium phosphate (396 mg, 1.86 mmol) were added and the reaction was stirred at 70? C. for a further 24 h. The reaction was diluted in EtOAc (?60 mL) and washed successively with 1M aq. HCl, water and brine, dried over sodium sulfate and concentrated to dryness in vacuum to give crude title compound methyl 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylate (699 mg, 100%) as a brown gum, assumed 100% molar yield, that was used as such in the next step without further analysis or purification. m/z: 350 [M+H].sup.+, (ESI+), RT=0.89 min METCR1704 (2 minute uPLC gradient method for IPCs).

[0830] Step 2: 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylic acid: Lithium hydroxide (93 mg, 3.73 mmol) was added to a mixture of methyl 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylate (217 mg 0.622 mmol) in THE (4.2 mL) and Water (0.6 mL) and the mixture was stirred at rt for 16 h. The reaction was stirred for a further 24 h, then heated at 40? C. for a further 8 h (56 h total). The reaction was diluted with water (20 mL) and the pH was adjusted to ?1-2 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?20 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuum to give the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylic acid (59.0%) (353 mg, 100%) as a brown solid, which was used in the next step without further analysis or purification. LC-MS: m/z 336 [M+H].sup.+, (ESI+), RT=0.46 min METCR1704 (2 minute uPLC gradient method for IPCs).

[0831] Step 3: 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-pyridazin-4-yl-pyridazine-4-carboxamide: HATU (130 mg, 0.342 mmol) was added to a mixture of 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylic acid (104 mg, 0.311 mmol) and N-ethyl-N-isopropyl-propan-2-amine (119 uL, 0.684 mmol) in DMF (2 mL) at rt and the reaction was stirred at rt for 5 min, then pyridazin-4-amine (44 mg, 0.466 mmol) was added and the reaction was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3?50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness to give crude product. Purification by high pH prep HPLC (early method) to give the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-pyridazin-4-yl-pyridazine-4-carboxamide (20 mg, 0.0478 mmol, 15%) as an off-white solid. .sup.1H NMR (400 MHz, MeOH-d.sub.4) ? 9.31 (d, J=1.9 Hz, 1H), 9.08 (d, J=5.9 Hz, 1H), 8.19 (dd, J=5.9, 2.7 Hz, 1H), 7.11 (dd, J=8.9, 4.9 Hz, 1H), 7.00 (dd, J=9.2, 3.0 Hz, 1H), 6.97-6.88 (m, 1H), 5.43 (dm, J=57.8, 9.4, 5.9, 3.5 Hz, 1H), 4.55-4.41 (m, 2H), 4.31-4.18 (m, 2H), 2.30 (s, 3H), 2.15 (s, 3H). m/z: 413.3 [M+H].sup.+, (ESI+), RT=2.45 LCMS Method 6

Example 19

Compound 1431: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[0832] ##STR00197##

[0833] Step 1: 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: HATU (130 mg, 0.342 mmol) was added to a mixture of 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylic acid (104 mg, 0.311 mmol) and N-ethyl-N-isopropyl-propan-2-amine (119 uL, 0.684 mmol) in DMF (2 mL) at rt and the reaction was stirred at rt for 5 min, then 3-(methylsulfanyl)aniline (57 uL, 0.466 mmol) was added and the reaction was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (?50 mL) and washed with water (3??50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give crude product. Purification by FCC (Biotage Isolera, SiO2, gradient elution 10-50% EtOAc:Heptanes) gave the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (90.0%) (30 mg, 0.0591 mmol, 19%) as a yellow gum. LC-MS: m/z: 457 [M+H].sup.+, (ESI+), RT=0.95 min METCR1704 (2 minute uPLC gradient method for IPCs)

[0834] Step 2: 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: Phenyl Iodonium Di-Acetate (PIDA) (49 mg, 0.151 mmol) and diammonium carbonate (10 mg, 0.105 mmol) were added to a solution of 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (30 mg, 0.0657 mmol) in Methanol (1 mL) at rt and the reaction was stirred at rt for 3 days. The reaction mixture was concentrated to dryness in vacuum to give crude product. The residue was purified by low pH prep HPLC (early method). The product containing fractions were combined and the solvent was removed in vacuum, to give the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (100.0%)) (12 mg, 0.0246 mmol, 37%) as an off white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.43 (t, J=1.9 Hz, 1H), 7.99-7.90 (m, 1H), 7.86-7.76 (m, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.11 (dd, J=8.9, 4.9 Hz, 1H), 7.01 (dd, J=9.1, 3.0 Hz, 1H), 6.99-6.93 (m, 1H), 5.52-5.34 (dm, J=57.8, Hz, 1H), 4.48 m, 2H), 4.24-4.19 (m, 2H), 3.17 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H). m/z: 488.3 [M+H].sup.+, (ESI+), RT=2.65 min LCMS Method 6.

Example 20

Compound 1432: 6-Cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[0835] ##STR00198##

[0836] Step 1: 3-(2-fluoro-4-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid:Lithium; hydroxide (126 mg, 5.05 mmol) was added to a mixture of methyl 3-(2-fluoro-4-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (677 mg, 1.68 mmol) in THF (11 mL) and Water (1.7 mL) and the mixture was stirred at rt for 40 h. The reaction was diluted with water (20 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuum to give the title compound 3-(2-fluoro-4-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid (617 mg, 1.59 mmol, 94%) as a pale yellow solid which was used as such in the next step. LC-MS: m/z: 389 [M+H].sup.+, (ESI+), RT=0.61 METCR1410 Generic 2 min

[0837] Step 2: 3-[2,6-difluoro-4-(trifluoromethoxy)phenoxy]-5-methyl-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: HATU (665 mg, 1.75 mmol) was added to a mixture of 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid (617 mg, 1.59 mmol) and N-ethyl-N-isopropyl-propan-2-amine (555 uL, 3.18 mmol) in DMF (11.5 mL) at rt and the reaction was stirred at rt for 5 min, then 3-(methylsulfanyl)aniline (235 uL, 1.91 mmol) was added and the reaction was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3?50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give crude product. Purification by FCC (Biotage Isolera, SiO.sub.2 gradient elution 10-30% EtOAc:Heptanes) gave the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (682 mg, 68%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.63 (s, 1H), 7.37-7.26 (m, 3H), 7.19-7.04 (m, 2H), 6.94 (dd, J=8.8, 3.0 Hz, 1H), 6.86 (td, J=8.3, 3.1 Hz, 1H), 2.69-2.52 (m, 3H), 2.50 (s, 3H), 2.15 (d, J=4.6 Hz, 3H). m/z: 510 [M+H].sup.+, (ESI+), RT=1.02 min METCR1410 Generic 2 min

[0838] Step 3: 6-cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: Palladium acetate (4.4 mg, 0.0196 mmol) was added to a stirred, N.sub.2 degassed solution of 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (50 mg, 0.0982 mmol), potassium hexacyanoferrate(II) trihydrate (36 mg, 0.0982 mmol), sodium carbonate (21 mg, 0.196 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (21 mg, 0.0393 mmol) in 1,4-Dioxane (0.28 mL) and Water (0.28 mL). The reaction mixture was heated at 70? C. for 1 h in a pressure vial. Reaction seemed inhomogeneous, therefore NMP (0.25 mL) was added and the reaction was stirred overnight (20 h) at 70? C. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3?20 mL) and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuum to give crude product (?130 mg). Purification by FCC (Biotage Isolera, SiO.sub.2, gradient elution 0-50% EtOAc:Heptanes) gave the title compound 6-cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (99.0%) (30 mg, 0.0727 mmol, 74%) as a yellow solid. LC-MS: m/z: 409 [M+H].sup.+, (ESI+), RT=0.99 min METCR1410 Generic 2 min

[0839] Step 4: 6-cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-[3(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: Phenyl Iodonium Di-Acetate (PIDA) (54 mg, 0.169 mmol) and diammonium carbonate (10 mg, 0.110 mmol) were added to a solution of 6-cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (30 mg, 0.0734 mmol) in Methanol (1 mL) at rt and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated to dryness in vacuum to give crude product. Purification by FCC (Biotage isolera, gradient elution 0-100% EtOAc:Heptanes,) gave the title compound below required % purity therefore the product was further purified by low pH prep HPLC (early method). The product containing fractions were combined and the solvent was removed in vacuo by freeze drying overnight, to give the title compound 6-cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (99.0%) (6.1 mg, 0.0137 mmol, 19%) as an off white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (t, J=1.9 Hz, 1H), 7.99-7.92 (m, 1H), 7.87-7.81 (m, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.21 (dd, J=8.9, 4.9 Hz, 1H), 7.09 (dd, J=9.0, 3.0 Hz, 1H), 7.06-6.97 (m, 1H), 3.17 (s, 3H), 2.62 (s, 3H), 2.16 (s, 3H). LC-MS: m/z 440 [M+H].sup.+, (ESI+), RT=2.83 min MET-uPLC-AB-101 (7 min, low pH).

Example 21

Compound 1433: 6-Cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[(methylsulfonimidoyl)phenyl] pyridazine-4-carboxamide

[0840] ##STR00199##

[0841] Step 1: 6-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: Palladium-triphenylphosphane (1:4) (18 mg, 0.0159 mmol) was added to a stirred, N.sub.2 degassed solution of 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (81 mg, 0.159 mmol) and tributyl(cyclopropyl)stannane in Toluene Anhydrous (0.5 mL) and the reaction mixture was stirred at 70? C. for 16 h in a pressure vial. The reaction mixture was concentrated to dryness in vacuum to give crude product. Purification by FCC (Biotage Isolera, SiO.sub.2, gradient elution 0-30% EtOAc:Heptanes) gave the title compound 6-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (66.0%) (98 mg, 0.153 mmol, 96%) as a pale yellow oil. LC-MS: m/z 424 [M+H].sup.+, (ESI+), RT=1.00 min METCR1410 Generic 2 min

[0842] Step 2: 6-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide:Phenyl Iodonium Di-Acetate (PIDA) (226 mg, 0.703 mmol) and diammonium carbonate (43 mg, 0.458 mmol) were added to a solution of 6-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (66%, 98 mg, 0.153 mmol) in methanol (2.2 mL) at rt and the reaction was stirred at rt for 4 days. The reaction mixture was concentrated under reduced pressure and purified by column chromatography Biotage Isolera SiO.sub.2, gradient elution (0-100% EtOAc:Heptanes). The product was below required purity, therefore the product was purified by low pH prep HPLC (early method). The product containing fractions were combined and the solvent was removed in vacuum by freeze drying overnight, to give the title compound 6-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (100.0%) (22 mg, 0.0477 mmol, 31%) as an off-white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.45 (t, J=1.9 Hz, 1H), 7.99-7.92 (m, 1H), 7.87-7.78 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.13 (dd, J=8.9, 4.9 Hz, 1H), 7.03 (dd, J=9.1, 3.0 Hz, 1H), 6.95 (td, J=8.5, 3.1 Hz, 1H), 3.17 (s, 3H), 2.54 (s, 3H), 2.24 (p, J=6.6 Hz, 1H), 2.15 (s, 3H), 1.09 (d, J=6.4 Hz, 4H). LC-MS: m/z 455 [M+H].sup.+, (ESI+), RT=2.63 min MET-uPLC-AB-101 (7 min, low pH).

Example 22

Compound 1434: 3-(4-Fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(prop-1-yn-1-yl)pyridazine-4-carboxamide

[0843] ##STR00200##

[0844] Step 1: 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: Phenyl Iodonium Di-Acetate (PIDA) (780 mg, 2.42 mmol) and diammonium carbonate (158 mg, 1.68 mmol) were added to a solution of 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (536 mg, 1.05 mmol) in Methanol (15 mL) at rt and the reaction was stirred at rt for 5 h. The reaction mixture was concentrated to dryness in vacuum to give crude product. Purification by FCC (Biotage Isolera, gradient elution 10-100% EtOAc:Heptanes) gave the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (89.0%) (520 mg, 0.856 mmol, 81%) as a pale yellow solid. LC-MS: m/z 541 [M+H].sup.+, (ESI+), RT=0.75 METCR1410 Generic 2 min

[0845] Step 2: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(prop-1-yn-1-yl)pyridazine-4-carboxamide: A solution of 1 M prop-1-yne (1 Min THF) (925 uL, 0.925 mmol) was added to a stirred, N2 degassed mixture of 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (50 mg, 0.0925 mmol), copper(1+) iodide (21 mg, 0.111 mmol) and 1,1bis(diphenylphosphanyl)ferrocene-dichloropalladium (1:1) (6.8 mg, 9.25 ?mol) in THF-Anhydrous (0.5 mL) and the reaction mixture was stirred at rt for 20 h in a pressure vial. The reaction mixture was concentrated to dryness in vacuum to give crude product. Purification by FCC (Biotage Isolera, SiO.sub.2, gradient elution 0-30% EtOAc:Heptanes) gave the title compound which was below required purity spec, therefore the product was purified by low pH prep HPLC (standard method). The product containing fractions were combined and the solvent was removed in vacuum, to give the title compound 3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-prop-1-ynyl-pyridazine-4-carboxamide (100.0%) (15 mg, 0.0340 mmol, 37%) as an off white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (t, J=1.9 Hz, 1H), 7.99-7.92 (m, 1H), 7.85-7.78 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.17 (dd, J=8.9, 4.9 Hz, 1H), 7.05 (dd, J=9.1, 3.0 Hz, 1H), 7.02-6.94 (m, 1H), 3.17 (s, 3H), 2.51 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H). LC-MS: m/z 453.3 [M+H].sup.+, (ESI+), RT=2.78 MET-uPLC-AB-107 (7 min, high pH).

Example 23

Compound 1435: 3-(3,4-difluoro-2-methoxyphenoxy)-5,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide

[0846] ##STR00201##

[0847] Step 1: 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carbonitrile A mixture of 3,4-difluoro-2-methoxy-phenol (1.00 g, 6.25 mmol), 3-chloro-5,6-dimethylpyridazine-4-carbonitrile (1.00 g, 5.97 mmol) and dipotassium; carbonate (1.25 g, 9.04 mmol) in Acetonitrile (8.5 mL) was stirred at 70? C. for 18 h. The reaction was filtered, washed with EtOAc (2?) and the filtrate was washed with brine, the organics separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was then purified using the Biotage Isolena 4 flash purification system (Sfar Duo 50 g, 0-45% EtOAc in heptanes). Fractions containing the product were combined and evaporated in vacuo to the desired product 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carbonitrile (97.0%) (1.70 g, 5.66 mmol, 95%) as an off-white powder.

[0848] Step 2: 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carboxamide: 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carbonitrile (97%, 200 mg, 0.666 mmol) was dissolved in Water (6 mL) and barium dihydroxide (560 mg, 3.27 mmol) was added. The resulting solution was stirred at 80? C. for 17 h. The solution was neutralised to pH 7 with 2M hydrochloric acid (aq) and the precipitate was filtered off and washed with water (?3) and EtOAc (?2). The solid was dried in a vacuum oven overnight to yield the desired product 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carboxamide (98.0%) (200 mg, 0.634 mmol, 95%) as a white powder.

[0849] Step 3: 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: To a degassed solution of 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carboxamide (180 mg, 0.582 mmol), 1-bromo-3-(methylsulfanyl)benzene (142 mg, 0.699 mmol) and dicaesium carbonate (567 mg, 1.74 mmol) in anhydrous 1,4-Dioxane (3 mL) was added (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (27 mg, 0.0295 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (34 mg, 0.0588 mmol) and the reaction was degassed for a further 5 minutes. The vial was then sealed, and reaction stirred at 100? C. for 4 hours. The reaction mixture was then diluted with DCM and filtered through a phase separator. The filtrate was then washed with aq sat sodium bicarbonate solution, followed by brine. The organic extract was then dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography (Sfar Duo 10 g, eluting in 0-100% EtOAc in Heptanes). Fractions containing the product (F41-54) were combined to give the desired product, 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (109 mg, 0.174 mmol, 30%) as a yellow solid.

[0850] Step 4: 3-(3,4-difluoro-2-methoxyphenoxy)-5,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: diammonium carbonate (26 mg, 0.276 mmol) and bis(acetyloxy)(phenyl)-lambda?3?-iodane (PIDA) (130 mg, 0.404 mmol) were added to a solution of 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (69%, 109 mg, 0.174 mmol) in Methanol (2 mL) at rt and the reaction was stirred at rt for 17 h. The reaction mixture was concentrated to dryness in vacuo to give crude product which was purified by prep-HPLC (Acidic Early Elute Method). Combination of fractions containing the product, evaporation in vacuo and freeze drying overnight gave the title compound, 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (41 mg, 51%) as an off-white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.18 (s, 1H), 8.42-8.36 (m, 1H), 7.90-7.83 (m, 1H), 7.74-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.30-7.20 (m, 1H), 7.17-7.10 (m, 1H), 4.24 (s, 1H), 3.81-3.76 (m, 3H), 3.08-3.04 (m, 3H), 2.58 (s, 3H), 2.33 (s, 3H). m/z: 463.2 [M+H].sup.+, (ESI+), RT=2.46 LCMS Method 6.

Example 24

Compound 1436: 3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide

[0851] ##STR00202## ##STR00203##

[0852] Step 1: methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylate: 1,1bis(diphenylphosphanyl)ferrocene-dichloropalladium (1:1) (17 mg, 0.0235 mmol) was added to a stirred, N2 degassed solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (100 mg, 0.235 mmol), phenylboronic acid (43 mg, 0.353 mmol) and, 2 M disodium carbonate (0.35 mL, 0.706 mmol) in 1,4-Dioxane (3.5 mL). The reaction mixture was stirred at 90? C. for 1 h in a pressure vial. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3?20 ml) and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give crude product. The residue was purified by FCC (Biotage Isolera, SiO2, gradient elution 10-100% EtOAc:Heptanes) gave the title compound methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylate (85 mg, 0.226 mmol, 96%) as an off white solid. LC-MS: m/z: 376 [M+H].sup.+, (ESI+), RT=0.92 METCR1704 (2 minute uPLC gradient method for IPCs).

[0853] Step 2: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylic acid: Lithium hydroxide (20 mg, 0.835 mmol) was added to a stirred solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylate (85 mg, 0.226 mmol) in THF (2 mL) and Water (0.25 mL) The reaction mixture was stirred at rt for 2 days. 1M HCl aq. was added to the reaction mixture to pH ?2 and the reaction was extracted with EtOAc (3?20 mL). The organic phase was dried with sodium sulfate, filtered and concentrated to dryness in vacuum to give crude product 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylic acid (83.0%) (64 mg, 0.147 mmol, 65%) as an off white solid, which was used as such in the next step. Assumed 100% molar yield. LC-MS: m/z 362 [M+H].sup.+, (ESI+), RT=0.65 METCR1704 (2 minute uPLC gradient method for IPCs).

[0854] Step 3: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)-6-phenyl-pyridazine-4-carboxamide: HATU (74 mg, 0.195 mmol) was added to a mixture of 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylic acid (64 mg, 0.177 mmol) and N-ethyl-N-isopropyl-propan-2-amine (68 uL, 0.390 mmol) in DMF (1.1 mL) at rt and the reaction was stirred at rt for 5 min then 3-(methylsulfanyl)aniline (33 uL, 0.266 mmol) was added and the reaction was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (?50 mL) and washed with water (3?50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give crude product. Purification by FCC (Biotage Isolera, SiO.sub.2 gradient elution 10-80% EtOAc:Heptanes) gave the title compound 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)-6-phenyl-pyridazine-4-carboxamide (76.0%)(79 mg, 0.124 mmol, 70%) as a yellow gum. LC-MS: m/z 483 [M+H].sup.+, (ESI+), RT=1.03 METCR1704 (2 minute uPLC gradient method for IPCs).

[0855] Step 4: 3-(4-cyano-2-methoxy phenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-phenyl-pyridazine-4-carboxamide, Phenyl Iodonium Di-Acetate (PIDA) (121 mg, 0.377 mmol) and diammonium carbonate (25 mg, 0.262 mmol) were added to a solution of 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)-6-phenyl-pyridazine-4-carboxamide (79 mg, 0.164 mmol) in methanol (2.5 mL) at rt and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated to dryness in vacuum to give crude product. The residue was purified by low pH prep HPLC (early method). The product containing fractions were combined and the solvent was removed in vacuum, to give the title compound 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-phenyl-pyridazine-4-carboxamide (17 mg, 0.0327 mmol, 20%) as an off white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.46 (t, J=1.9 Hz, 1H), 8.00-7.95 (m, 1H), 7.85-7.80 (m, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.59-7.49 (m, 6H), 7.48-7.39 (m, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.41 (s, 3H). LC-MS: m/z 514 [M+H].sup.+, (ESI+), RT=2.78 min MET-uPLC-AB-107 (7 min, high pH).

Example 25

Compound 1437: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamid

[0856] ##STR00204##

[0857] Step 1: tert-butyl N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]carbamate: To a mixture of 3-[(tert-butoxycarbonyl)amino]benzoic acid (200 mg, 0.843 mmol), HATU (385 mg, 1.01 mmol) and DIPEA (442 uL, 2.53 mmol) in DCM (3 mL) was added 3-hydroxyazetidine.Math.HCl (111 mg, 1.01 mmol). The reaction mixture was stirred at room temperature for 18 h then partitioned between DCM (10 mL) and water (10 mL). The layers were separated, and the aqueous phase extracted with DCM (2?10 mL). The combined organics were washed with brine (10 mL), dried using a phase separator and concentrated under reduced pressure. The resulting crude product was purified by FCC (Biotage Isolera 4, 25 g Sfar Duo, lambda-all collect) using a 0-100% EtOAc/heptane followed by a 0-20% MeOH/EtOAc gradient to afford tert-butyl N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]carbamate (68.0%) (312 mg, 0.726 mmol, 86%) as a colorless gum. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.49 (s, 1H), 7.75 (s, 1H), 7.58-7.53 (m, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.18 (dt, J=7.7, 1.2 Hz, 1H), 5.74 (d, J=6.3 Hz, 1H), 4.52-4.45 (m, 1H), 4.39 (t, J=7.7 Hz, 1H), 4.27-4.18 (m, 1H), 4.01-3.96 (m, 1H), 3.80-3.71 (m, 1H), 1.48 (s, 9H). m/z: 293.1 [M+H].sup.+, (ESI+), RT=0.66 LCMS Method M2.

[0858] Step 2: (3-aminophenyl)-(3-hydroxyazetidin-1-yl)methanone: To a solution of tert-butyl N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]carbamate (68%, 312 mg, 0.726 mmol) in DCM (3 mL) was added trifluoroacetic acid (1.1 mL, 14.5 mmol). The reaction mixture was stirred at room temperature for 66 h then concentrated under reduced pressure. The resulting residue was co-evaporated with DCM-heptane (1:1) three times. The crude product was dissolved in MeOH (?1 mL) and loaded to a pre-wet SCX-2 cartridge (5 g, 25 mL). After washing with MeOH the product was eluted with ?2.5M NH.sub.3 in MeOH. The product fractions were combined and concentrated under reduced pressure to afford (3-aminophenyl)-(3-hydroxyazetidin-1-yl)methanone (80.0%) (138 mg, 0.574 mmol, 79%) as a pale yellow opaque gum. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.05 (t, J=7.8 Hz, 1H), 6.83-6.79 (m, 1H), 6.69 (dt, J=7.6, 1.2 Hz, 1H), 6.65 (ddd, J=8.0, 2.3, 0.9 Hz, 1H), 5.71 (br.s, 1H), 5.23 (br.s, 2H), 4.51-4.42 (m, 1H), 4.41-4.32 (m, 1H), 4.24-4.14 (m, 1H), 4.00-3.91 (m, 1H), 3.78-3.67 (m, 1H). m/z: 193.1 [M+H].sup.+, (ESI+), RT=0.23 LCMS Method M2.

[0859] Step 3: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: To a mixture of 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (93%, 50 mg, 0.132 mmol), HATU (60 mg, 0.158 mmol) and DIPEA (46 uL, 0.263 mmol) in DMF (0.5 mL) was added (3-aminophenyl)-(3-hydroxyazetidin-1-yl)methanone (80%, 38 mg, 0.158 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DMSO-MeCN-water (3:2:1, 1 mL), filtered and purified by prep HPLC (Prep Method 4). Product fractions were combined and concentrated under reduced pressure. The resulting residue was freeze-dried from MeCN-water (1:1) to afford 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (99.0%) (32 mg, 0.0595 mmol, 45%) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.13 (s, 1H), 8.00 (t, J=1.9 Hz, 1H), 7.79-7.72 (m, 2H), 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.53-7.45 (m, 2H), 7.40 (dt, J=7.8, 1.3 Hz, 1H), 5.77 (s, 1H), 4.57-4.39 (m, 2H), 4.31-4.21 (m, 1H), 4.08-3.97 (m, 1H), 3.85-3.76 (m, 4H), 2.52-2.51 (m, 3H). m/z: 528.2 [M+H].sup.+, (ESI+), RT=2.71 LCMS Method M4.

Example 26

Compound 1438: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(piperazine-1-carbonyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0860] ##STR00205##

[0861] Step 1: 9H-fluoren-9-ylmethyl 4-[3-(tert-butoxycarbonylamino)benzoyl]piperazine-1-carboxylate: To a mixture of 3-[(tert-butoxycarbonyl)amino]benzoic acid (500 mg, 2.11 mmol), HATU (962 mg, 2.53 mmol) and DIPEA (1.1 mL, 6.32 mmol) in DCM (7.5 mL) was added Fmoc-piperazine hydrochloride (872 mg, 2.53 mmol). The reaction mixture was stirred at room temperature for 66 h then partitioned between DCM (20 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with DCM (2?10 mL). The combined organics were washed with brine (20 mL), dried using a phase separator and concentrated under reduced pressure. The resulting residue was purified by FCC (Biotage Isolera 4, 25 g Sfar Duo, lambda-all collect) using a 0-75% EtOAc/heptane gradient. Product fractions were combined and concentrated under reduced pressure to afford 9H-fluoren-9-ylmethyl 4-[3-(tert-butoxycarbonylamino)benzoyl]piperazine-1-carboxylate (90.0%) (1.19 g, 2.03 mmol, 96%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.50 (d, J=10.9 Hz, 1H), 7.92-7.86 (m, 2H), 7.86-7.82 (m, 1H), 7.63 (d, J=7.4 Hz, 1H), 7.56-7.45 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.27 (m, 3H), 7.01-6.91 (m, 1H), 4.40 (d, J=6.5 Hz, 1H), 4.32-4.22 (m, 1H), 3.63-3.45 (m, 3H), 3.30-3.14 (m, 3H), 2.77-2.55 (m, 2H), 1.66-1.55 (m, 1H), 1.51-1.45 (m, 9H). LC-MS: m/z 550.3 [M+Na].sup.+, (ESI+), RT=1.08 LCMS Method M2.

[0862] Step 2: 9H-fluoren-9-ylmethyl 4-(3-aminobenzoyl)piperazine-1-carboxylate: 9H-fluoren-9-ylmethyl 4-[3-(tert-butoxycarbonylamino)benzoyl]piperazine-1-carboxylate (1.19 g, 2.26 mmol) was dissolved in 4M HCl in dioxane (25 mL). The reaction mixture was allowed to stir at room temp for 4 h then concentrated under reduced pressure. The solvent was co-evaporated with DCM-heptane (1:1) to give 9H-fluoren-9-ylmethyl 4-(3-aminobenzoyl)piperazine-1-carboxylate hydrochloride (85.0%) (1.23 g, 2.25 mmol, 100%) as a pink solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.90 (d, J=7.4 Hz, 2H), 7.63 (d, J=7.4 Hz, 2H), 7.49 (t, J=8.0 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.34 (t, J=7.8 Hz, 3H), 7.30-7.24 (m, 2H), 4.39 (d, J=6.5 Hz, 2H), 4.32-4.24 (m, 1H), 3.73-3.64 (m, 2H), 3.55-3.43 (m, 4H), 3.35-3.11 (m, 4H). LC-MS: m/z 428.3 [M+H].sup.+, (ESI+), room temperature=0.88 LCMS Method M2.

[0863] Step 3: 9H-fluoren-9-ylmethyl 4-[3-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]benzoyl]piperazine-1-carboxylate: To a mixture of 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (93%, 100 mg, 0.263 mmol), HATU (120 mg, 0.316 mmol) and DIPEA (138 uL, 0.790 mmol) in DMF (1 mL) was added 9H-fluoren-9-ylmethyl 4-(3-aminobenzoyl)piperazine-1-carboxylate; hydrochloride (85%, 172 mg, 0.316 mmol). The reaction mixture was stirred at room temperature for 16 h then poured into water (10 mL) and extracted with EtOAc (15 mL). The organic phase was washed with water (2?10 mL) then 5% aq LiCl solution (2?10 mL), dried over MgSO.sub.4 and concentrated under reduced pressure. The crude pro duct was purified by FCC (Biotage Isolera 4, 10 g Sfar Duo, lambda-all collect) using a 0-100% EtOAc/heptane gradient. Product fractions were combined and concentrated under reduced pressure to afford 9H-fluoren-9-ylmethyl 4-[3-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]benzoyl]piperazine-1-carboxylate (88.0%) (184 mg, 0.212 mmol, 81%) as a yellow glass. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 8.89 (s, 1H), 7.83-7.79 (m, 1H), 7.79-7.74 (m, 2H), 7.68-7.66 (m, 1H), 7.58-7.52 (m, 2H), 7.44 (t, J=7.9 Hz, 1H), 7.42-7.38 (m, 2H), 7.38-7.36 (m, 2H), 7.34-7.29 (m, 2H), 7.27 (s, 1H), 7.11 (d, J=7.7 Hz, 1H), 4.54-4.50 (m, 2H), 4.26-4.20 (m, 1H), 3.82 (s, 3H), 3.57-3.27 (m, 8H), 2.60-2.55 (m, 3H). LC-MS: m/z 785.1 [M+Na].sup.+, (ESI+), RT=1.11 LCMS Method M2.

[0864] Step 4: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(piperazine-1-carbonyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide: A solution of 9H-fluoren-9-ylmethyl 4-[3-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]benzoyl]piperazine-1-carboxylate (184 mg, 0.241 mmol) in Acetonitrile (3 mL) was treated with piperidine (95 uL, 0.965 mmol) and the mixture stirred at room temp for 16 h. The reaction mixture was then concentrated under reduced pressure and purified by prep HPLC (Prep Method 3). Product fractions were combined and concentrated under reduced pressure. The resulting residue was freeze-dried from MeCN-water (1:1) to afford 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(piperazine-1-carbonyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (60 mg, 0.111 mmol, 46%) as an off-white powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.11 (s, 1H), 7.76 (t, J=1.7 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.67 (ddd, J=8.2, 2.0, 0.9 Hz, 1H), 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.20-7.14 (m, 1H), 3.79 (s, 3H), 3.58-3.47 (m, 2H), 3.29-3.21 (m, 2H), 2.80-2.57 (m, 4H), 2.53-2.51 (m, 3H). Piperazine NH not observed. LC-MS: m/z 541.2 [M+H].sup.+, (ESI+), RT=2.69 LCMS Method M6.

Example 27

Compound 1439: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(2-methoxyethylsulfamoyl)phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0865] ##STR00206##

[0866] Step 1: N-(2-methoxyethyl)-3-nitro-benzenesulfonamide: To a mixture of 2-methoxyethanamine (94 uL, 1.09 mmol) and triethylamine (0.25 mL, 1.79 mmol) in DCM (4.5 mL) was added 3-nitrobenzenesulfonyl chloride (200 mg, 0.902 mmol). The reaction was stirred at rt for 17 h. The reaction mixture was then poured into aq NaHCO.sub.3 and extracted with DCM (2?). The combined organic phases were filtered through a phase separator and concentrated under reduced pressure to give the desired product, N-(2-methoxyethyl)-3-nitro-benzenesulfonamide (99.0%) (216 mg, 0.822 mmol, 91%) as a brown oil.

[0867] Step 2: 3-amino-N-(2-methoxyethyl)benzenesulfonamide: To a solution of 3-amino-N-(2-methoxyethyl)benzenesulfonamide (92.0%) (166 mg, 0.663 mmol, 81%) in Ethanol (6 mL) were added iron (459 mg, 8.22 mmol) and Ammonium chloride (440 mg, 8.23 mmol) at room temperature. The resulting mixture was then stirred at 90? C. for 22 hours. The reaction was filtered through celite, washed with methanol (2?20 mL) and evaporated under reduced pressure gave the crude material. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3?20 mL), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 3-amino-N-(2-methoxyethyl)benzenesulfonamide (92.0%) (166 mg, 0.663 mmol, 81%) as an off-white powder.

[0868] Step 3: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(2-methoxyethylsulfamoyl)phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (93%, 50 mg, 0.132 mmol) and N-[3-(dimethylamino)propyl]-Nthylcarbodiimide hydrochloride (1:1) (51 mg, 0.266 mmol) in Pyridine (1 mL) was added 3-amino-N-(2-methoxyethyl)benzenesulfonamide (92%, 66 mg, 0.264 mmol). The mixture was stirred at room temperature for 4 h. The solvents were removed (co-evaporated with MeCN) and the residue purified by prep HPLC (Acidic Early Elute Method). Fractions containing the desired product were combined, evaporated and freeze dried overnight to afford the desired product, 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(2-methoxyethylsulfamoyl)phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (99.0%) (21 mg, 0.0368 mmol, 28%), as an off-white powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.31 (s, 1H), 8.29-8.25 (m, 1H), 7.88-7.82 (m, 1H), 7.82-7.79 (m, 1H), 7.76-7.73 (m, 1H), 7.64-7.58 (m, 2H), 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.52-7.49 (m, 1H), 3.79 (s, 3H), 3.32-3.28 (m, 2H, overlap with H.sub.2O peak), 3.15 (s, 3H), 2.96-2.91 (m, 2H), 2.53-2.51 (m, 3H, overlap with DMSO peak). m/z: 566.1 [M+H].sup.+, (ESI+), RT=3.25 LCMS Method 4.

[0869] The compounds 1440-1445 listed in Table 11 were prepared by a similar procedure as described for compound 1439, using appropriate acids and substituted anilines

TABLE-US-00012 TABLE 11 Compound Structure Analytical Data 1440 [00207] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.11 (s, 1H), 8.87 (t, J = 5.8 Hz, 1H), 8.19-8.15 (m, 1H), 7.86-7.81 (m, 1H), 7.77-7.73 (m, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 8.2, 1.8 Hz, 1H), 7.54-7.47 (m, 2H), 3.80 (s, 3H), 3.70 (dd, J = 21.0, 5.9 Hz, 2H), 2.54-2.50 (m, 3H, overlap with DMSO peak), 1.04-0.94 (m, 2H), 0.85- 0.77 (m, 2H). LC-MS: m/z 561.3 [M + NH4].sup.+, (ESI+), RT = 3.64 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)- N-[3-[(1- fluorocyclopropyl)methylcarbamoyl]phenyl]- 5-methyl-6- (trifluoromethyl)pyridazine-4- carboxamide 1441 [00208] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.36 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.75 (s, 1H), 6.71 (t, J = 7.9 Hz, 2H), 6.65 (s, 2H), 3.02 (s, 3H), 2.92 (t, J = 5.8 Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 1.80 (s, 3H). LC-MS: m/z: 516.2 [M + H].sup.+, (ESI+), RT = 3.03 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)- N-[3-(2- hydroxyethylcarbamoyl)phenyl]- 5-methyl-6- (trifluoromethyl)pyridazine-4- carboxamide 1442 [00209] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.16 (s, 1H), 8.02 (t, J = 1.8 Hz, 1H), 7.78 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.53- 7.47 (m, 2H), 7.42 (dt, J = 7.7, 1.2 Hz, 1H), 4.60-4.46 (m, 2H), 4.39-4.28 (m, 1H), 4.24-4.13 (m, 1H), 3.85 (p, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.52 (d, J = 1.4 Hz, 3H). LC-MS: m/z 537.1 [M + H].sup.+, (ESI+), RT = 3.06 MET-uPLC-AB-101 (7 min, low pH) N-[3-(3-cyanoazetidine-1- carbonyl)phenyl]-3-(4-cyano-2- methoxy-phenoxy)-5-methyl-6- (trifluoromethyl)pyridazine-4- carboxamide 1443 [00210] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.10 (s, 1H), 8.57 (t, J = 5.4 Hz, 1H), 8.14 (t, J = 1.9 Hz, 1H), 7.83-7.79 (m, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.65-7.62 (m, 1H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.53-7.45 (m, 2H), 3.79 (s, 3H), 3.47-3.40 (m, 4H), 3.26 (s, 3H), 2.52-2.51 (m, 3H). LC-MS: m/z 530.0 [M + H]+, (ESI+), RT = 3.12 MET-uPLC-AB-101 (7 min, low pH) 3-(4-cyano-2-methoxy-phenoxy)- N-[3-(2- methoxyethylcarbamoyl)phenyl]- 5-methyl-6- (trifluoromethyl)pyridazine-4- carboxamide 1444 [00211] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.09 (s, 1H), 8.19 (d, J = 7.4 Hz, 1H), 8.04 (t, J = 1.9 Hz, 1H), 7.86 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.58-7.53 (m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.37-7.30 (m, 1H), 6.88- 6.82 (m, 1H), 4.43 (p, J = 6.9 Hz, 1H), 3.79 (s, 3H), 2.86 (q, J = 7.9 Hz, 1H), 2.53- 2.51 (m, 3H), 1.95-1.75 (m, 5H), 1.57- 1.46 (m, 1H). LC-MS: m/z 583.5 [M + H].sup.+, (ESI+), RT = 3.06 MET-uPLC-AB-101 (7 min, low pH) N-[3-[(2- carbamoylcyclopentyl)carbamoyl]phenyl]- 3-(4-cyano-2-methoxy- phenoxy)-5-methyl-6- (trifluoromethyl)pyridazine-4- carboxamide 1445 [00212] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.11 (s, 1H), 8.70 (d, J = 7.8 Hz, 1H), 8.15 (t, J = 1.9 Hz, 1H), 7.85 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.66-7.62 (m, 1H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.54-7.49 (m, 2H), 4.49 (p, J = 7.9 Hz, 1H), 3.79 (s, 3H), 3.00 (q, J = 8.3 Hz, 1H), 2.52 (q, J = 1.5 Hz, 3H), 2.19-2.10 (m, 1H), 2.09-1.99 (m, 1H), 1.89-1.80 (m, 1H), 1.80-1.70 (m, 2H), 1.68-1.57 (m, 1H). LC-MS: m/z 565.5 [M + H].sup.+, (ESI+), RT = 3.44 MET-uPLC-AB-101 (7 min, low pH) N-[3-[(2- cyanocyclopentyl)carbamoyl]phenyl]- 3-(4-cyano-2-methoxy- phenoxy)-5-methyl-6- (trifluoromethyl)pyridazine-4- carboxamide

Example 28

Compound 1446: 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[0870] ##STR00213## ##STR00214##

[0871] Step 1: 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid: Lithium hydroxide (37 mg, 1.55 mmol) was added to a solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (200 mg, 0.470 mmol) in THF (4 mL) and Water (0.6 mL) at rt and the reaction was stirred at rt for 2 d. 1M HCl aq. was added to the reaction mixture to pH ?2 and the reaction was extracted with EtOAc (3?20 mL). The organic phase was dried with sodium sulfate, filtered and concentrated to dryness in vacuum to give crude product 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid (91.0%) (193 mg, 0.428 mmol, 91%) which was used as such in the next step. Assumed 100% molar yield. LC-MS: m/z 412 [M+H].sup.+, (ESI+), RT=0.55 min LCMS Method 1.

[0872] Step 2: 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (196 mg, 0.516 mmol) was added to a mixture of 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid (193 mg, 0.469 mmol) and N-ethyl-N-isopropyl-propan-2-amine (180 uL, 1.03 mmol) in DMF (3 mL) at rt and the reaction was stirred at rt for 5 min, then 3-(methylsulfanyl)aniline (87 uL, 0.704 mmol) was added and the reaction was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (?50 mL) and washed with water (3??50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give crude product. Purification by FCC (Biotage isolera, SiO.sub.2 gradient elution 10-50% EtOAc:Heptanes) gave 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (80.0%) (239 mg, 0.359 mmol, 77%) as a yellow gum. LC-MS: m/z 533 [M+H].sup.+, (ESI+), RT=1.01 min LCMS Method 1.

[0873] Step 3: 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: Phenyl Iodonium Di-Acetate (PIDA) (1044 mg, 3.24 mmol) and diammonium carbonate (212 mg, 2.25 mmol) were added to a solution of 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (750 mg, 1.41 mmol) in Methanol (22 mL) at rt and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated to dryness in vacuum to give crude product. The residue was purified by FCC (Biotage Isolera SiO.sub.2, gradient elution 10-100% EtOAc:heptane) 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (83.0%) (773 mg, 1.14 mmol, 81%). LC-MS: m/z 564 [M+H].sup.+, (ESI+), RT=0.71 min LCMS Method 1.

[0874] Step 4: 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: 1,1 bis(diphenylphosphanyl)ferrocene-dichloropalladium (1:1) (5.8 mg, 7.99 V mol) was added to a stirred, N.sub.2 degassed solution of 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (45 mg, 0.0799 mmol), 4-cyanophenyl)boronic acid (23 mg, 0.160 mmol) and 2 M disodium carbonate (2M aq.) (120 uL, 0.240 mmol) in 1,4-Dioxane (1.8 mL). The reaction mixture was stirred at 80? C. for 2 h in a pressure vial. The reaction mixture was diluted with EtOAc (?3 mL) and washed with water (?2 ml). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness to give crude product. The residue was purified by high pH prep HPLC (early method). The product containing fractions were combined and the solvent was removed in vacuo by freeze drying, to give 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (99.0%) (12 mg, 0.0224 mmol, 28%) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.30 (s, 1H), 8.39 (s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.87 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.74-7.67 (m, 2H), 7.65-7.59 (m, 1H), 7.58-7.53 (m, 1H), 7.49 (d, J=8.2 Hz, 1H), 4.24 (s, 1H), 3.80 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). LC-MS: m/z 539.1 [M+H].sup.+, (ESI+), RT=2.60 LCMS Method 7.

[0875] The compounds 1447-1457 listed in Table 12 were prepared by a similar procedure described for step 4 of example 28, using 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide coupling with the appropriate boronate(s) or boronic acids.

TABLE-US-00013 TABLE 12 Compound Structure Analytical Data 1447 [00215] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.46 (t, J = 1.9 Hz, 1H), 8.00-7.94 (m, 1H), 7.90- 7.78 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.50-7.41 (m, 2H), 7.37 (s, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.18 (s, 3H), 2.50 (s, 3H) 2 exchangeable Hs not seen. LC-MS: m/z 518.1 [M + H].sup.+, (ESI+), RT = 2.01 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-6-(3-methylimidazol-4-yl)-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide 1448 [00216] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.24 (s, 1H), 8.40 (s, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 6.9 Hz, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.2, 1.8 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H), 4.24 (s, 1H), 3.95 (s, 3H), 3.79 (s, 3H), 3.07 (s, 3H), 2.63 (s, 3H). LC-MS: m/z 518.1 [M + H].sup.+, (ESI+), RT = 2.24 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-6-(1-methylpyrazol-3-yl)-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide 1449 [00217] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.20 (s, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.80-7.66 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.2, 1.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 4.25 (s, 1H), 3.79 (s, 3H), 3.07 (s, 3H), 2.71 (s, 3H), 2.59 (s, 3H). LC- MS: m/z 535.1 [M + H].sup.+, (ESI+), RT = 2.40 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-N-[3- (methylsulfonimidoyl)phenyl]-6-(2- methylthiazol-5-yl)pyridazine-4- carboxamide 1450 [00218] .sup.1H NMR (400 MHz, CD.sub.3OD) 8 8.46 (t, J = 1.9 Hz, 1H), 8.00-7.94 (m, 1H), 7.83 (dd, J = 6.9, 1.7 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 1.4 Hz, 1H), 7.45- 7.40 (m, 4H), 7.36 (d, J = 8.0 Hz, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H). 2 exchangeable Hs not seen. LC-MS: m/z: 528.1 [M + H].sup.+, (ESI+), RT = 2.93 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3- (methylsulfonimidoyl)phenyl]-6-(p- tolyl)pyridazine-4-carboxamide 1451 [00219] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.40 (s, 1H), 8.10 (s, 1H), 8.06- 7.98 (m, 1H), 7.97-7.92 (m, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.74-7.67 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.07 (s, 3H), 2.37 (s, 3H). LC-MS: m/z 539 [M + H].sup.+, (ESI+), RT = 2.58 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-6- (3-cyanophenyl)-5-methyl-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide 1452 [00220] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.35 (s, 1H), 8.40 (t, J = 1.8 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.81-7.68 (m, 2H), 7.67-7.58 (m, 2H), 7.58-7.47 (m, 3H), 7.47-7.36 (m, 2H), 4.25 (s, 1H), 3.81 (s, 3H), 3.07 (s, 3H), 2.23 (d, J = 1.2 Hz, 3H). LC-MS: m/z 532 [M + H].sup.+, (ESI+), RT = 2.73 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-6- (2-fluorophenyl)-5-methyl-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide 1453 [00221] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.46 (t, J = 2.0 Hz, 1H), 8.01-7.94 (m, 1H), 7.83 (m, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.71- 7.62 (m, 3H), 7.53 (m, 1H), 7.49-7.40 (m, 2H), 6.88 (t, J = 56.1 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 3H), 2.42 (s, 3H). LC- MS: m/z 564.2 [M + H].sup.+, (ESI+), RT = 2.84 LCMS Method 4 3-(4-cyano-2-methoxy-phenoxy)-6- [4-(difluoromethyl)phenyl]-5- methyl-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide 1454 [00222] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.46 (t, J = 2.0 Hz, 1H), 8.01-7.93 (m, 1H), 7.83 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.54- 7.38 (m, 5H), 7.12-7.06 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.17 (s, 3H), 2.43 (s, 3H). LC-MS: m/z 544.2 [M + H].sup.+, (ESI+), RT = 2.68 LCMS Method 4 3-(4-cyano-2-methoxy-phenoxy)-6- (4-methoxyphenyl)-5-methyl-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide 1455 [00223] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.62 (d, J = 2.0 Hz, 1H), 8.46 (t, J = 1.9 Hz, 1H), 8.02-7.94 (m, 2H), 7.86-7.80 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.56-7.48 (m, 2H), 7.47-7.37 (m, 2H), 3.83 (s, 3H), 3.18 (s, 3H), 2.64 (s, 3H), 2.44 (s, 3H). LC-MS: m/z 529.2 [M + H].sup.+, (ESI+), RT = 2.35 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-6-(6-methyl-3-pyridyl)-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide 1456 [00224] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 9.49 (dd, J = 2.3, 1.2 Hz, 1H), 9.39 (dd, J = 5.3, 1.2 Hz, 1H), 8.46 (t, J = 1.9 Hz, 1H), 8.02 (dd, J = 5.3, 2.4 Hz, 1H), 7.98 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 7.84 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 1.5 Hz, 1H), 7.48-7.43 (m, 2H), 3.83 (s, 3H), 3.18 (s, 3H), 2.51 (s, 3H). LC-MS: m/z 516.1 [M + H].sup.+, (ESI+), RT = 1.94 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-N-[3- (methylsulfonimidoyl)phenyl]-6- pyridazin-4-yl-pyridazine-4- carboxamide 1457 [00225] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.95 (s, 2H), 8.46 (t, J = 1.9 Hz, 1H), 8.01-7.95 (m, 1H), 7.86-7.81 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.48-7.41 (m, 2H), 3.82 (s, 3H), 3.18 (s, 3H), 2.80 (s, 3H), 2.49 (s, 3H). LC-MS: m/z 530.2 [M + H].sup.+, (ESI+), RT = 2.16 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-6-(2-methylpyrimidin-5-yl)- N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide

Example 29

Compound 1458: 3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(pyridin-2-yl)pyridazine-4-carboxamide

[0876] ##STR00226##

[0877] 2-(tributylstannanyl)pyridine (82 mg, 0.224 mmol) was added to a mixture of 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (63 mg, 0.112 mmol) and CuI (2.1 mg, 0.0112 mmol) in 1,4-Dioxane (2.5 mL) at rt and the reaction was stirred at rt for 5 min then palladium-triphenylphosphane (1:4) (13 mg, 0.0112 mmol) was added and the reaction was stirred at 110? C. for 16 h. The reaction mixture was diluted with EtOAc (?3 mL) and washed with 1M aq. KF, the mixture was stirred at rt for 15 min and filtered thru a pad of celite. The layers were separated and the organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuum to give crude product. The residue was purified by low pH prep HPLC (early method). The product containing fractions were combined and the solvent was removed in vacuum by freeze drying. The crude product was diluted in CH.sub.3CN (3 mL) and MP-TMT (200 mg, 0.132 mmol, 0.66 mmol/g) and stirred at rt for ?16 h. The product was diluted in 1:1 ACN:H.sub.2O (?3 ml) and concentrated to dryness by freeze drying overnight to give 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(2-pyridyl)pyridazine-4-carboxamide (98.0%) (21 mg, 0.0404 mmol, 36%) as an off white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.79-8.65 (m, 1H), 8.47 (t, J=1.9 Hz, 1H), 8.06-8.01 (m, 1H), 8.01-7.95 (m, 1H), 7.88-7.80 (m, 2H), 7.66 (t, J=8.0 Hz, 1H), 7.58-7.50 (m, 2H), 7.49-7.38 (m, 2H), 3.83 (s, 3H), 3.18 (s, 3H), 2.51 (s, 3H).

[0878] The compounds 1459-1464 listed in Table 13 were prepared by similar procedure described for example 29 using appropriate substituted R-SnBu3 and 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

TABLE-US-00014 TABLE 13 Compound Structure Analytical Data 1459 [00227] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.56-8.41 (m, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 2H), 4.58 (s, 1H), 3.81 (s, 3H), 3.18 (s, 3H), 2.70 (s, 3H). LC-MS: m/z 589.1 [M + H].sup.+, (ESI+), RT = 3.06 LCMS Method 4 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-N-[3- (methylsulfonimidoyl)phenyl]-6-[2- (trifluoromethyl)thiazol-5-yl]pyridazine- 4-carboxamide 1460 [00228] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 9.16 (s, 1H), 8.46 (t, J = 2.0 Hz, 1H), 8.39 (s, 1H), 8.01-7.94 (m, 1H), 7.83 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.44 (m, 2H), 3.82 (s, 3H), 3.18 (s, 3H), 2.67 (s, 3H). LC-MS: m/z 521.2 [M + H].sup.+, (ESI+), RT = 2.31 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-N-[3- (methylsulfonimidoyl)phenyl]-6-thiazol- 5-yl-pyridazine-4-carboxamide 1461 [00229] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.39 (s, 1H), 8.43 (s, 2H), 8.39 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.55-7.51 (m, 1H), 7.47 (d, J = 8.2 Hz, 1H), 4.25 (s, 1H), 4.09 (s, 3H), 3.78 (s, 3H), 3.07 (s, 3H), 2.59 (s, 3H). Bis formic acid salt. LC-MS: LC-MS: m/z 551.2 [M + H].sup.+, (ESI+), RT = 2.72 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-6-(2- methoxythiazol-5-yl)-5-methyl-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide; formic acid 1462 [00230] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.54 (s, 3H), 8.46 (s, 1H), 8.15 (s, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.50-7.41 (m, 3H), 3.81 (s, 3H), 3.18 (s, 3H), 2.79 (s, 3H). TRIS FORMATE SALT. LC-MS: m/z 505.1 [M + H].sup.+, (ESI+), RT = 2.23 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-N-[3- (methylsulfonimidoyl)phenyl]-6-oxazol- 2-yl-pyridazine-4-carboxamide; formic acid 1463 [00231] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.46 (t, J = 1.9 Hz, 1H), 8.04 (d, J = 3.3 Hz, 1H), 8.00-7.95 (m, 1H), 7.86-7.79 (m, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.48-7.41 (m, 2H), 3.82 (s, 3H), 3.18 (s, 3H), 2.89 (s, 3H). LC-MS: m/z 521.1 [M + H].sup.+, (ESI+), RT = 2.65 LCMS Method 6 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-N-[3- (methylsulfonimidoyl)phenyl]-6-thiazol- 2-yl-pyridazine-4-carboxamide 1464 [00232] .sup.1H NMR (400 MHz, MeOD) ? 8.57 (m, 1H), 8.47 (m, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (m, 1H), 7.49-7.39 (m, 2H), 3.82 (s, 3H), 3.18 (s, 3H), 2.50 (s, 3H), 2.46 (s, 3H). LC-MS: m/z 529.2 [M + H].sup.+, (ESI+), RT = 2.39 LCMS Method 4 3-(4-cyano-2-methoxy-phenoxy)-5- methyl-6-(5-methyl-2-pyridyl)-N-[3- (methylsulfonimidoyl)phenyl]pyridazine- 4-carboxamide

Example 30

Compound 1465: 3-(4-cyano-2-methylphenoxy)-N-(3-methanesulfonylphenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0879] ##STR00233##

[0880] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.42 (br.s, 1H), 8.39-8.33 (m, 1H), 7.93-7.85 (m, 2H), 7.81 (dd, J=8.4, 1.8 Hz, 1H), 7.77-7.66 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 3.24 (s, 3H), 2.56-2.53 (m, 3H), 2.17 (s, 3H). m/z: 491.0 [M+H].sup.+, (ESI+), RT=3.28 LCMS Method 4.

Example 31

Compound 1466: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0881] ##STR00234##

[0882] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.30 (s, 1H), 8.34-8.29 (m, 1H), 7.77 (dt, J=7.5, 1.8 Hz, 1H), 7.67-7.58 (m, 2H), 7.44 (s, 2H), 7.29 (dd, J=8.9, 5.1 Hz, 1H), 7.24 (dd, J=9.4, 3.0 Hz, 1H), 7.14 (td, J=8.6, 3.2 Hz, 1H), 2.53-2.51 (m, 3H), 2.12 (s, 3H). m/z: 485.0 [M+H].sup.+, (ESI+), RT=3.97 LCMS Method 5.

Example 32

Compound 1467: 3-[2-fluoro-4-(trifluoromethoxy)phenoxy]-N-(3-methanesulfonylphenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0883] ##STR00235##

[0884] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.41 (t, J=1.9 Hz, 1H), 7.98 (ddd, J=8.1, 2.1, 1.0 Hz, 1H), 7.79 (ddd, J=7.8, 1.6, 1.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.54 (t, J=8.8 Hz, 1H), 7.37 (dd, J=10.5, 2.4 Hz, 1H), 7.28-7.22 (m, 1H), 3.15 (s, 3H), 2.62-2.58 (m, 3H). 1 proton (NH) not observed. m/z: 554.0 [M+H].sup.+, (ESI+), RT=3.78 LCMS Method 4.

Example 33

Compound 1468: N-(3-methanesulfonylphenyl)-5-methyl-3-{[2-methyl-6-(trifluoromethyl)pyridin-3-yl]oxy}-6-(trifluoromethyl)pyridazine-4-carboxamide

[0885] ##STR00236##

[0886] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.41 (t, J=1.9 Hz, 1H), 7.97 (ddd, J=8.2, 2.2, 1.0 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.81-7.76 (m, 2H), 7.69 (t, J=8.0 Hz, 1H), 3.15 (s, 3H), 2.62 (q, J=1.5 Hz, 3H), 2.47 (s, 3H). m/z: 535.5 [M+H].sup.+, (ESI+), RT=3.62 LCMS Method 4.

Example 34

Compound 1469: 3-[(6-bromo-2-methylpyridin-3-yl)oxy]-N-(3-methanesulfonylphenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0887] ##STR00237##

[0888] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.40 (t, J=2.0 Hz, 1H), 7.96 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.79 (ddd, J=7.8, 1.7, 1.0 Hz, 1H), 7.71-7.62 (m, 2H), 7.56-7.51 (m, 1H), 3.15 (s, 3H), 2.60 (q, J=1.5 Hz, 3H), 2.37 (s, 3H). m/z: 545.3, 547.3 [M+H].sup.+, (ESI+), RT=3.44 LCMS Method 4.

Example 35

Compound 1470: 3-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0889] ##STR00238##

[0890] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.41 (t, J=2.0 Hz, 1H), 7.93 (ddd, J=8.1, 2.2, 1.0 Hz, 1H), 7.85 (ddd, J=7.9, 1.9, 1.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 4.88 (s, 2H), 3.18 (s, 3H), 2.52-2.49 (m, 3H), 2.02 (d, J=2.5 Hz, 7H). m/z: 473.4 [M+H].sup.+, (ESI+), RT=2.94 LCMS Method 4

Example 36

Compounds: 1471 and 1472

[0891] ##STR00239##

[0892] Racemic mixture of 3-(4-chloro-2-fluoro-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions. Mobile phase: 85% Heptane, 15% Ethanol. Column: Chiralpak AS, 20?250 mm, 10 ?m Flow rate: 18 mL/min. First eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.35 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.91-7.86 (m, 1H), 7.76-7.71 (m, 2H), 7.64 (t, J=7.9 Hz, 1H), 7.54 (t, J=8.6 Hz, 1H), 7.45-7.41 (m, 1H), 4.26 (s, 1H), 3.11-3.04 (m, 3H), 2.54-2.52 (m, 3H). m/z: 503.1, 505.1 [M+H].sup.+, (ESI+), RT=3.13 MET-uPLC-AB-101 (7 min, low pH) and the second eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.36 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.91-7.86 (m, 1H), 7.76-7.70 (m, 2H), 7.64 (t, J=7.9 Hz, 1H), 7.54 (t, J=8.6 Hz, 1H), 7.45-7.41 (m, 1H), 4.27 (s, 1H), 3.13-3.03 (m, 3H), 2.54-2.52 (m, 3H). m/z: 503.1, 505.1 [M+H].sup.+, (ESI+), RT=3.13 MET-uPLC-AB-101 (7 min, low pH).

Example 37

Compounds: 1473 and 1474

[0893] ##STR00240##

[0894] Racemic mixture of 3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Mobile phase 85:15 Heptane:Ethanol. Column Chiralpak AS, 20?250 mm, 10 ?m. Flow rate (mL/min) 18. First eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.33 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.33-7.26 (m, 1H), 7.24 (ddd, J=9.3, 5.3, 1.8 Hz, 1H), 4.26 (s, 1H), 3.87-3.76 (m, 3H), 3.11-2.99 (m, 3H), 2.54-2.52 (m, 3H). m/z: 516.9 [M+H].sup.+, (ESI+), RT=3.85 METCR1416 Hi res 7 min and the second eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.32 (s, 1H), 8.36 (t, J=1.9 Hz, 1H), 7.90-7.84 (m, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.34-7.26 (m, 1H), 7.24 (ddd, J=9.3, 5.3, 1.9 Hz, 1H), 4.26 (s, 1H), 3.85-3.76 (m, 3H), 3.10-3.02 (m, 3H), 2.54-2.52 (m, 3H). m/z: 516.9 [M+H].sup.+, (ESI+), RT=3.86 METCR1416 Hi res 7 min.

Example 38

Compounds: 1475 and 1476

Compound 1475: 3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-(3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0895] ##STR00241##

[0896] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.24 (br.s, 1H), 8.82 (d, J=2.3 Hz, 1H), 8.39 (dd, J=4.7, 1.4 Hz, 1H), 8.16 (ddd, J=8.3, 2.6, 1.5 Hz, 1H), 7.45 (dd, J=8.1, 4.5 Hz, 1H), 7.34-7.20 (m, 2H), 3.84-3.78 (m, 3H), 2.54-2.52 (m, 3H). m/z: 441.1 [M+H].sup.+, (ESI+), RT=3.00 MET-uPLC-AB-101 (7 min, low pH).

Compound 1476: 3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0897] ##STR00242##

[0898] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.48 (br.s, 1H), 8.72 (t, J=1.6 Hz, 1H), 8.11-8.05 (m, 1H), 7.54-7.48 (m, 1H), 7.44 (dd, J=8.4, 6.3 Hz, 1H), 7.36-7.20 (m, 2H), 3.85-3.78 (m, 3H), 2.54-2.52 (m, 3H). m/z: 457.1 [M+H].sup.+, (ESI+), RT=2.77 MET-uPLC-AB-101 (7 min, low pH).

Example 39

Compounds: 1477 and 1478

[0899] ##STR00243##

[0900] Racemic mixture of 3-[2,3-difluoro-4-(trifluoromethoxy)phenoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: 10% IPA, 90% CO.sub.2, Chiralpak IC, 10?250 mm, 5 ?m, 15 mL/min, sample in Methanol, IPA. First eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.38 (s, 1H), 8.34 (t, J=1.8 Hz, 1H), 7.92-7.84 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.70-7.59 (m, 2H), 7.58-7.49 (m, 1H), 4.26 (s, 1H), 3.12-3.03 (m, 3H), 2.56-2.53 (m, 3H). LC-MS: m/z 571.6 [M+H].sup.+, (ESI+), RT=4.24 LCMS Method 5 and the second eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.41 (s, 1H), 8.35 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.79-7.70 (m, 1H), 7.64 (t, J=8.0 Hz, 2H), 7.57-7.50 (m, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.57-2.53 (m, 3H). LC-MS: m/z 571.1 [M+H].sup.+, (ESI+), RT=3.48 LCMS LCMS Method M2.

Example 40

Compounds: 1479 and 1480

[0901] ##STR00244##

[0902] Racemic mixture of 3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Mobile phase 20% Methanol: 80% CO.sub.2 Column Chiralpak IC, 10?250 mm, 5 ?m Flow rate (mL/min) 15. First eluting isomer (S)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.33 (t, J=2.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.75-7.68 (m, 2H), 7.62 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.3, 1.8 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 4.24 (s, 1H), 3.77 (s, 3H), 3.05 (d, J=1.1 Hz, 3H), 2.51-2.50 (m, 3H). m/z: 506.3 [M+H].sup.+, (ESI+), RT=2.89 LCMS Method 6 and the second eluting isomer (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.33 (t, J=2.0 Hz, 1H), 7.89-7.82 (m, 1H), 7.75-7.68 (m, 2H), 7.62 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.2, 1.8 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 4.24 (s, 1H), 3.77 (s, 3H), 3.05 (d, J=1.1 Hz, 3H), 2.51-2.50 (m, 3H). m/z: 506.3 [M+H].sup.+, (ESI+), RT=2.89 LCMS Method 6.

Example 41

Compounds: 1481 and 1482

[0903] ##STR00245##

[0904] Racemic mixture of 3-(4-chloro-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Chiral Separation: 85% Heptane, 15% Ethanol, Chiralpak AS, 20?250 mm, 10 ?m, 18 mL/min, sample in Methanol, Ethanol. First eluting isomer 1H NMR (500 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.36 (t, J=1.8 Hz, 1H), 7.89-7.85 (m, 1H), 7.75-7.70 (m, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.33-7.29 (m, 2H), 7.10 (dd, J=8.6, 2.3 Hz, 1H), 4.26 (s, 1H), 3.75 (s, 3H), 3.09-3.05 (m, 3H). 3H (one Me) not observedhidden by DMSO signal. m/z: 503.1, 505.1 [M+H].sup.+, (ESI+), RT=3.06 LCMS Method 4 and the second eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.36 (t, J=1.8 Hz, 1H), 7.90-7.85 (m, 1H), 7.75-7.70 (m, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.33-7.28 (m, 2H), 7.10 (dd, J=8.6, 2.3 Hz, 1H), 4.26 (s, 1H), 3.75 (s, 3H), 3.10-3.04 (m, 3H). 3H (one CH.sub.3) not observedhidden by DMSO signal m/z: 503.1, 505.1 [M+H].sup.+, (ESI+), RT=3.13 LCMS Method 4.

Example 42

Compound 1483: 3-[(2,6-dimethylpyridin-3-yl)oxy]-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0905] ##STR00246##

[0906] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.37 (t, J=1.9 Hz, 1H), 8.13 (s, 1H), 7.89-7.84 (m, 1H), 7.77-7.71 (m, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 3.17 (s, 1H), 3.12 (s, 3H), 2.54-2.52 (m, 3H), 2.47 (s, 3H), 2.28 (s, 3H). m/z: 480.3 [M+H].sup.+, (ESI+), RT=2.74 LCMS Method 6.

Example 43

Compounds: 1484 and 1485

[0907] ##STR00247##

[0908] Racemic mixture of 3-[(2,6-dimethylpyridin-3-yl)oxy]-N-{3-[imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Mobile phase 70:30 Heptane: IPA+0.2% DEA Column Cellulose-4, 21.2?250 mm, 5 ?m Flow rate (mL/min) 9. First eluting isomer .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.33 (t, J=2.0 Hz, 1H), 7.84 (ddd, J=8.2, 2.2, 1.0 Hz, 1H), 7.72 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 3.05 (s, 3H), 2.47 (q, J=1.5 Hz, 3H), 2.41 (s, 3H), 2.24 (s, 3H). m/z: 480.3 [M+H].sup.+, (ESI+), RT=2.55 LCMS Method 6 and the second eluting isomer .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.33 (t, J=2.0 Hz, 1H), 7.84 (ddd, J=8.1, 2.2, 1.0 Hz, 1H), 7.72 (ddd, J=7.9, 1.9, 1.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 3.05 (s, 3H), 2.48 (q, J=1.5 Hz, 3H), 2.41 (s, 3H), 2.24 (s, 3H). m/z: 480.3 [M+H].sup.+, (ESI+), RT=2.54 LCMS Method 6.

Example 44

Compound 1486: 3-(4-chloro-3-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0909] ##STR00248##

[0910] .sup.1H NMR (400 MHz, DMSO) ? 11.35 (s, 1H), 8.36 (s, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.57 (t, J=8.6 Hz, 1H), 7.23 (d, J=8.9 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.56-2.51 (m, 3H), 2.11 (d, J=1.9 Hz, 3H). m/z: 517.1, 519.1 [M+H].sup.+, (ESI+), RT=3.30 LCMS Method 4

Example 45

Compound: 1487 and 1488

[0911] ##STR00249##

[0912] Racemic mixture of 3-(4-chloro-3-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Mobile phase 15% Methanol, 85% CO.sub.2 Column Chiralpak AS-H, 10?250 mm, 5 ?m Flow rate (mL/min) 15. First eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.35 (t, J=2.0 Hz, 1H), 7.90-7.81 (m, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.56 (t, J=8.6 Hz, 1H), 7.22 (dd, J=8.9, 1.6 Hz, 1H), 4.26 (s, 1H), 3.07 (d, J=1.1 Hz, 3H), 2.54-2.51 (m, 3H), 2.10 (d, J=2.2 Hz, 3H). m/z: 517.4, 519.4 [M+H].sup.+, (ESI+), RT=3.42 LCMS Method 4 and the second eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.35 (t, J=2.0 Hz, 1H), 7.89-7.80 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.56 (t, J=8.6 Hz, 1H), 7.22 (dd, J=8.9, 1.6 Hz, 1H), 4.26 (s, 1H), 3.07 (d, J=1.1 Hz, 3H), 2.54-2.52 (m, 3H), 2.12-2.08 (m, 3H). m/z: 517.4, 519.4 [M+H].sup.+, (ESI+), RT=3.42 LCMS Method 4.

Example 46

Compound 1489: 3-(4-chloro-3-fluoro-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0913] ##STR00250##

[0914] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.36 (t, J=1.9 Hz, 1H), 7.93-7.84 (m, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.45 (dd, J=9.0, 7.8 Hz, 1H), 7.28 (dd, J=9.0, 2.0 Hz, 1H), 4.27 (s, 1H), 3.80 (d, J=1.3 Hz, 3H), 3.08 (d, J=0.8 Hz, 3H), 2.56-2.51 (m, 3H). m/z: 533.1, 535.1 [M+H].sup.+, (ESI+), RT=3.21 LCMS Method 4.

Example 47

Compounds: 1490 and 1491

[0915] ##STR00251##

[0916] Racemic mixture of 3-(4-chloro-3-fluoro-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Mobile phase 15% Methanol, 85% CO.sub.2 Column Chiralpak AS-H, 10?250 mm, 5 ?m Flow rate (mL/min) 15. First eluting isomer .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.33 (s, 1H), 8.35 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.44 (dd, J=9.0, 7.7 Hz, 1H), 7.27 (dd, J=9.0, 1.9 Hz, 1H), 4.26 (s, 1H), 3.79 (d, J=1.3 Hz, 3H), 3.07 (d, J=1.1 Hz, 3H), 2.54-2.52 (m, 3H). m/z: 533.1, 535.1 [M+H].sup.+, (ESI+), RT=3.22 LCMS Method 4 and the second eluting isomer .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.34 (s, 1H), 8.35 (t, J=1.9 Hz, 1H), 7.92-7.83 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.44 (dd, J=9.0, 7.7 Hz, 1H), 7.27 (dd, J=9.0, 2.0 Hz, 1H), 4.27 (s, 1H), 3.79 (d, J=1.3 Hz, 3H), 3.07 (d, J=1.1 Hz, 3H), 2.55-2.52 (m, 3H). m/z: 533.1, 535.1 [M+H].sup.+, (ESI+), RT=3.22 LCMS Method 4.

Example 48

Compound 1492: 3-[4-(cyclobutoxy)-2,3-difluoro-phenoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0917] ##STR00252##

[0918] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.47 (t, J=1.9 Hz, 1H), 7.98 (m, 1H), 7.86 (m, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.11 (td, J=8.7, 2.4 Hz, 1H), 6.90-6.81 (m, 1H), 4.80 (p, J=6.9 Hz, 1H), 3.19 (s, 3H), 2.61 (d, J=1.4 Hz, 3H), 2.57-2.45 (m, 2H), 2.29-2.15 (m, 2H), 1.90 (m, 1H), 1.84-1.67 (m, 1H). m/z: 557.3 [M+H].sup.+, (ESI+), RT=3.63 LCMS Method 6.

Example 49

Compounds: 1493 and 1494

[0919] ##STR00253##

[0920] Racemic mixture of 3-(4-cyclobutoxy-2,3-difluorophenoxy)-N-{3-[imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Mobile phase 15% Methanol, 85% CO.sub.2 Column Chiralpak AS-H, 10?250 mm, 5 ?m Flow rate (mL/min) 15. First eluting isomer .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.47 (t, J=1.9 Hz, 2H), 8.02-7.94 (m, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.16-7.07 (m, 1H), 6.90-6.81 (m, 1H), 4.86-4.74 (m, 1H), 3.19 (s, 3H), 2.61 (d, J=1.4 Hz, 3H), 2.57-2.45 (m, 2H), 2.29-2.15 (m, 2H), 1.91 (m, 1H), 1.84-1.68 (m, 1H). m/z: 557.2 [M+H].sup.+, (ESI+), RT=2.16 and the second .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.47 (t, J=1.9 Hz, 1H), 7.98 (m, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.16-7.07 (m, 1H), 6.90-6.81 (m, 1H), 4.80 (p, J=7.1 Hz, 1H), 3.19 (s, 3H), 2.63-2.58 (m, 3H), 2.51 (m, 2H), 2.29-2.15 (m, 2H), 1.90 (m, 1H), 1.76 (m, 1H). m/z: 557.2 [M+H].sup.+, (ESI+), RT=3.81 Chiral LC.

Example 50

Compound 1495: 3-[2-fluoro-4-(trifluoromethoxy)phenoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[0921] ##STR00254##

[0922] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.37 (s, 1H), 8.35 (t, J=1.9 Hz, 1H), 7.89 (ddd, J=8.0, 2.0, 0.9 Hz, 1H), 7.77-7.69 (m, 2H), 7.69-7.61 (m, 2H), 7.44-7.37 (m, 1H), 4.26 (s, 1H), 3.10-3.06 (m, 3H), 2.55-2.52 (m, 3H). m/z: 553.1 [M+H].sup.+, (ESI+), RT=3.36 LCMS Method 4.

Example 51

Compounds: 1496 and 1497

[0923] ##STR00255##

[0924] Racemic mixture of 3-[2-fluoro-4-(trifluoromethoxy)phenoxy]-N-{3-[imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: Chiral Separation: 10% Methanol, 90% CO.sub.2, Chiralpak IC, 10?250 mm, 5 ?m, 15 mL/min, sample in Methanol. First eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.37 (s, 1H), 8.38-8.32 (m, 1H), 7.92-7.85 (m, 1H), 7.76-7.70 (m, 2H), 7.68-7.61 (m, 2H), 7.40 (d, J=9.0 Hz, 1H), 4.26 (s, 1H), 3.07 (s, 3H), 2.55-2.52 (m, 3H). m/z: 553.1 [M+H].sup.+, (ESI+), RT=3.36 LCMS Method 4 and the second eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.37 (s, 1H), 8.37-8.33 (m, 1H), 7.91-7.86 (m, 1H), 7.77-7.69 (m, 2H), 7.69-7.61 (m, 2H), 7.40 (d, J=9.1 Hz, 1H), 4.26 (s, 1H), 3.08 (s, 3H), 2.55-2.52 (m, 3H). m/z: 553.1 [M+H].sup.+, (ESI+), RT=3.36 LCMS Method 4.

Example 52

Compound 1498: 3-[(6-cyclobutoxy-2-methylpyridin-3-yl)oxy]-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0925] ##STR00256##

[0926] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.40 (s, 1H), 8.37 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.69-7.60 (m, 2H), 6.72 (d, J=8.7 Hz, 1H), 5.10 (p, J=7.2 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.45-2.36 (m, 2H), 2.22 (s, 3H), 2.05 (m, 2H), 1.78 (m, 1H), 1.64 (m, 1H). m/z: 536.2 [M+H].sup.+, (ESI+), RT=3.35 LCMS Method 4.

Example 53

Compounds: 1499 and 1500

[0927] ##STR00257##

[0928] Racemic mixture of 3-((6-cyclobutoxy-2-methylpyridin-3-yl)oxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following Chiral Separation conditions: 100% Ethanol, Chirapak AD-H, 20?250 mm, 5 ?m, 9 mL/min. First eluting isomer .sup.1H NMR (500 MHz, CD.sub.3OD) ? ? 8.47 (t, J=1.9 Hz, 1H), 7.98 (m, 1H), 7.89-7.83 (m, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.13 (p, J=7.3 Hz, 1H), 3.19 (s, 3H), 2.61 (d, J=1.3 Hz, 3H), 2.53-2.42 (m, 2H), 2.28 (s, 3H), 2.14 (m, 2H), 1.93-1.80 (m, 1H), 1.72 (m, 1H). m/z: 536.2 [M+H].sup.+, (ESI+), RT=3.35 MET-uPLC-AB-101 (7 min, low pH LCMS Method 4 and the second eluting isomer .sup.1H NMR (500 MHz, CD.sup.3OD) ? 8.47 (t, J=1.9 Hz, 1H), 7.98 (m, 1H), 7.86 (m, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.14 (p, J=7.2 Hz, 1H), 3.19 (s, 1H), 2.61 (d, J=1.3 Hz, 3H), 2.54-2.43 (m, 2H), 2.28 (s, 3H), 2.14 (m, 2H), 1.93-1.81 (m, 1H), 1.72 (m, 1H).

Example 54

Compound 1501: 3-[2,3-difluoro-4-(propan-2-yloxy)phenoxy]-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0929] ##STR00258##

[0930] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.37 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.92-7.85 (m, 1H), 7.78-7.70 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.29-7.20 (m, 1H), 7.18-7.11 (m, 1H), 4.71 (hept, J=6.0 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.54-2.51 (m, 3H), 1.32 (d, J=6.0 Hz, 6H). m/z: 545.3 [M+H].sup.+, (ESI+), RT=3.53 LCMS Method 6.

Example 55

Compounds: 1502 and 1503

[0931] ##STR00259##

[0932] Racemic mixture of 3-(2,3-difluoro-4-isopropoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following chiral conditions: 80% Heptane, 20% IPA, Chiralpak AS, 20?250 mm, 10 ?m, 18 mL/min, sample in Methanol, IPA. First eluting isomer .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.36 (br.s, 1H), 8.37-8.33 (m, 1H), 7.91-7.85 (m, 1H), 7.77-7.71 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.29-7.20 (m, 1H), 7.18-7.10 (m, 1H), 4.71 (hept, J=5.9 Hz, 1H), 4.27 (s, 1H), 3.10-3.05 (m, 3H), 2.55-2.51 (m, 3H), 1.32 (d, J=6.0 Hz, 6H). LC-MS: m/z 545.3 [M+H].sup.+, (ESI+), RT=3.50 LCMS Method 6 and the second eluting isomer .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.36 (br.s, 1H), 8.37-8.33 (m, 1H), 7.91-7.85 (m, 1H), 7.77-7.71 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.29-7.20 (m, 1H), 7.19-7.10 (m, 1H), 4.71 (hept, J=5.9 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.54-2.52 (m, 3H), 1.32 (d, J=6.0 Hz, 6H). LC-MS: m/z 545.3 [M+H].sup.+, (ESI+), RT=3.51 LCMS Method 6.

Example 56

Compound 1504: 3-(3-fluoro-4-methoxy-2-methylphenoxy)-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0933] ##STR00260##

[0934] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.45 (t, J=2.0 Hz, 1H), 7.96 (ddd, J=8.1, 2.1, 1.0 Hz, 1H), 7.84 (ddd, J=7.9, 1.9, 1.0 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.04-6.95 (m, 2H), 3.88 (s, 3H), 3.17 (s, 3H), 2.58 (q, J=1.5 Hz, 3H), 2.07 (d, J=2.2 Hz, 3H). m/z: 513.3 [M+H].sup.+, (ESI+), RT=3.12 LCMS Method 6.

Example 57

Compounds: 1505 and 1506

[0935] ##STR00261##

[0936] Racemic mixture of 3-(3-fluoro-4-methoxy-2-methylphenoxy)-N-{3-[imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following chiral conditions: Mobile phase: 10% Methanol: 90% CO.sub.2 Column: Chiralpak AS-H, 10?250 mm, 5 ?m Flow rate (mL/min) 15. First eluting isomer. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.31 (s, 1H), 8.34 (t, J=1.8 Hz, 1H), 7.90-7.80 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.13-7.01 (m, 2H), 4.25 (s, 1H), 3.83 (s, 3H), 3.06 (d, J=1.1 Hz, 3H), 2.51-2.50 (m, 3H), 2.01 (d, J=2.2 Hz, 3H). m/z: 513.3 [M+H].sup.+, (ESI+), RT=3.13 LCMS Method 6. and the second .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.31 (s, 1H), 8.34 (t, J=2.0 Hz, 1H), 7.88-7.81 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.13-7.02 (m, 2H), 4.25 (s, 1H), 3.83 (s, 3H), 3.06 (d, J=1.1 Hz, 3H), 2.51-2.50 (m, 3H), 2.01 (d, J=2.1 Hz, 3H). m/z: 513.3 [M+H].sup.+, (ESI+), RT=3.13 LCMS Method 6.

Example 58

Compound 1507: N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-3-[(6-methoxy-2-methylpyridin-3-yl)oxy]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0937] ##STR00262##

[0938] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.45 (t, J=2.0 Hz, 1H), 7.96 (ddd, J=8.2, 2.2, 1.0 Hz, 1H), 7.84 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 3.91 (s, 3H), 3.17 (s, 3H), 2.59 (q, J=1.6 Hz, 3H), 2.28 (s, 3H). m/z: 496.3 [M+H].sup.+, (ESI+), RT=2.96 LCMS Method 6.

Example 59

Compounds: 1508 and 1509

[0939] ##STR00263##

[0940] Racemic mixture of N-{3-[imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-3-[(6-methoxy-2-methylpyridin-3-yl)oxy]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following chiral conditions: Mobile phase: 85:15 heptane: ethanol Column: Chiralpak AS, 20?250 mm, 10 m Flow rate (mL/min) 18. First eluting isomer .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.30 (s, 1H), 8.34 (t, J=2.0 Hz, 1H), 7.89-7.83 (m, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.65-7.59 (m, 2H), 6.75 (d, J=8.5 Hz, 1H), 4.25 (s, 1H), 3.84 (s, 3H), 3.06 (d, J=1.1 Hz, 3H), 2.51-2.50 (m, 3H), 2.23 (s, 3H). m/z: 496.3 [M+H].sup.+, (ESI+), RT=2.95 LCMS Method 6 and the second eluting isomer .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.31 (s, 1H), 8.34 (t, J=2.0 Hz, 1H), 7.87-7.81 (m, 1H), 7.75-7.68 (m, 1H), 7.66-7.57 (m, 2H), 6.75 (d, J=8.8 Hz, 1H), 4.25 (s, 1H), 3.84 (s, 3H), 3.06 (d, J=1.2 Hz, 3H), 2.51-2.50 (m, 3H), 2.23 (s, 3H). m/z: 496.3 [M+H].sup.+, (ESI+), RT=2.95 LCMS Method 6.

Example 60

Compound 1510: 3-[4-(difluoromethoxy)-2,3-difluoro-phenoxy]-5-methyl-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0941] ##STR00264##

[0942] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.39 (s, 1H), 8.36 (t, J=1.8 Hz, 1H), 7.89 (dd, J=8.1, 1.1 Hz, 1H), 7.78-7.72 (m, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.53-7.17 (m, 3H), 4.28 (s, 1H), 3.09 (s, 3H), 2.57-2.53 (m, 3H). m/z: 553.1 [M+H].sup.+, (ESI+), RT=3.18 LCMS Method 4.

Example 61

Compounds: 1511 and 1512

[0943] ##STR00265##

[0944] Racemic mixture of 3-[4-(difluoromethoxy)-2,3-difluorophenoxy]-N-{3-[imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide was separated using following chiral conditions: Mobile phase: 85:15 Heptane:Ethanol Column: Chiralpak AD-H, 20?250 mm, 5 ?m Flow rate (mL/min):18 mL/min, sample in Ethanol, Methanol & Acetonitrile. First eluting isomer .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.37 (s, 1H), 8.34 (t, J=2.0 Hz, 1H), 7.88 (ddd, J=8.0, 2.2, 1.1 Hz, 1H), 7.78-7.70 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.55-7.14 (m, 3H), 4.27 (d, J=1.4 Hz, 1H), 3.08 (d, J=1.1 Hz, 3H), 2.56-2.53 (m, 3H). m/z: 553.1 [M+H].sup.+, (ESI+), RT=3.19 LCMS Method 4 and the second eluting isomer .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.39 (s, 1H), 8.34 (t, J=2.0 Hz, 1H), 7.88 (ddd, J=7.9, 2.2, 1.1 Hz, 1H), 7.76-7.70 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.54-7.14 (m, 3H), 4.27 (s, 1H), 3.08 (d, J=1.2 Hz, 3H), 2.56-2.53 (m, 3H). m/z: 553.1 [M+H].sup.+, (ESI+), RT=3.19 LCMS Method 4.

Example 62

Compound 1513: 3-(4-carbamoylphenoxy)-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0945] ##STR00266##

[0946] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.32 (s, 1H), 8.33 (t, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.99-7.94 (m, 2H), 7.87 (ddd, J=8.1, 2.1, 1.1 Hz, 1H), 7.71 (ddd, J=7.8, 1.8, 1.1 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.38-7.34 (m, 2H), 4.29-4.18 (m, 1H), 3.11-3.01 (m, 3H), 2.51-2.50 (m, 3H). m/z: 494.5 [M+H].sup.+, (ESI+), RT=2.19 LCMS Method 4.

Example 63

Compound 1514: 3-[2,6-difluoro-4-(trifluoromethoxy)phenoxy]-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0947] ##STR00267##

[0948] .sup.1H NMR (400 MHz, CD3OD) ? 8.46 (t, J=1.9 Hz, 1H), 7.96 (ddd, J=8.1, 2.1, 0.9 Hz, 1H), 7.85 (ddd, J=7.9, 1.7, 1.0 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 3.18 (s, 3H), 2.61 (d, J=1.4 Hz, 3H) 2 NH not seen. m/z: 571 [M+H].sup.+, (ESI+), RT=3.55 LCMS Method 4.

Example 64

Compound 1515: 3-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0949] ##STR00268##

[0950] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.38 (br.s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.77-7.70 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.56 (t, J=8.8 Hz, 1H), 7.30 (dd, J=9.1, 1.6 Hz, 1H), 4.26 (s, 1H), 3.07 (s, 3H), 2.55-2.52 (m, 3H), 2.14-2.10 (m, 3H). m/z: 567.3 [M+H].sup.+, (ESI+), RT=3.66 LCMS Method 6.

Example 65

Compound 1516: 3-(3,4-difluoro-2-methoxyphenoxy)-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5H,6H,7H-cyclopenta[c]pyridazine-4-carboxamide

[0951] ##STR00269##

[0952] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.12 (s, 1H), 8.38 (t, J=1.8 Hz, 1H), 7.88 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.70 (dt, J=7.8, 1.1 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.30-7.21 (m, 1H), 7.17 (ddd, J=9.3, 5.3, 2.0 Hz, 1H), 4.24 (s, 1H), 3.82-3.75 (m, 3H), 3.12-3.02 (m, 7H), 2.22-2.12 (m, 2H). m/z: 475.3 [M+H].sup.+, (ESI+), RT=2.54 LCMS Method 6.

Example 66

Compound 1517: (S)-3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0953] ##STR00270## ##STR00271##

[0954] Step 1: methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate A mixture of 4-fluoro-2-methoxyphenol (98%, 3.86 g, 26.6 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (5.25 g, 25.4 mmol) and K.sub.2CO.sub.3 (5.26 g, 38.0 mmol) in Acetonitrile (52 mL) was stirred at 70? C. for 3.5 h. The reaction mixture was cooled to room temperature, filtered through a phase separator, washed with DCM (3?50 mL) and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane over silica (on a Biotage Sfar 100 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate (71.0%) (6.26 g, 56%) as a pale yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.26 (s, 1H), 7.29 (dd, J=8.8, 5.8 Hz, 1H), 7.14 (dd, J=10.8, 2.9 Hz, 1H), 6.88-6.82 (m, 1H), 3.94 (s, 3H), 3.72 (s, 3H). LC-MA: m/z 313.0, 315.0 [M+H].sup.+, (ESI+), RT=0.88 LCMS Method M2.

[0955] Step 2: methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate To a stirring solution of methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate (84%, 6.19 g, 16.6 mmol) and sodium iodide (12.55 g, 83.1 mmol) in Acetonitrile (120 mL) was added acetyl chloride (1.3 mL, 18.3 mmol) dropwise at 0? C. The reaction was subsequently stirred at 0? C. for 1 h. The reaction was diluted with EtOAc (200 mL), washed with sat. aq Na.sub.2CO.sub.3 (200 mL) and sat. sodium sulfite aq (50 mL). The aqueous was re-extracted with EtOAc (2?200 mL), passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane over silica (using a Biotage Sfar 100 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (84.0%) (3.54 g, 44%) a as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.35 (s, 1H), 7.25 (dd, J=8.8, 5.8 Hz, 1H), 7.11 (dd, J=10.7, 2.9 Hz, 1H), 6.86-6.80 (m, 1H), 3.91 (s, 3H), 3.70 (s, 3H). LC-MS: m/z 405.1 [M+H].sup.+, (ESI+), RT=0.91 LCMS Method M2.

[0956] Step 3: methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: To a mixture of methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (84%, 3.54 g, 7.36 mmol), iodocopper (2.11 g, 11.0 mmol), and tetrabutylammonium; iodide (1.09 g, 2.94 mmol) in DMF (38 mL), methyl difluoro(fluorosulfonyl)acetate (4.7 mL, 36.8 mmol) was added and stirred at 70? C. for 4 h. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (3?200 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo (high vac for DMF removal). The compound was purified by FCC using 0-50% EtOAc in heptane over silica (on a Biotage Sfar 100 g column, compound wet-loaded using DCM), concentrated in vacuo to afford methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (93.0%) (2.52 g, 6.77 mmol, 92%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.53 (s, 1H), 7.33 (dd, J=8.9, 5.8 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.87 (ddd, J=8.9, 8.2, 2.9 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H). m/z: 347.0 [M+H].sup.+, (ESI+), RT=0.95 LCMS Method M2.

[0957] Step 4: methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate: To a stirring solution of 2,2,6,6-tetramethylpiperidine (0.68 mL, 4.03 mmol) in THF-Anhydrous (24 mL), butyllithium (2.5M in hexanes) (1.1 mL, 2.69 mmol) was added dropwise at 0? C. and stirred for 30 mins. The reaction was cooled to ?78? C. and treated with a dropwise addition of methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (93%, 500 mg, 1.34 mmol) in THF-Anhydrous (5 mL) at ?78? C. (over 40 minutes) and stirred for 30 mins at ?78? C. The reaction was cooled again to ?78? C. and 1-iodopyrrolidine-2,5-dione (332 mg, 1.48 mmol) in THF-Anhydrous (5 mL) was added dropwise (over 20 mins) at ?78? C. and stirred at this temperature for 30 mins. The reaction was quenched with sat. aq. NH4Cl (2 mL) at ?78? C. and allowed to warm to room temperature, stirring for 30 mins. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (3?100 mL), passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-50% EtOAc in heptane over silica (on a Biotage Sfar 10 g column, compound wet-loaded using DCM), concentrated in vacuo to afford methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (82.0%) (216 mg, 0.375 mmol, 28%) as an orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.32 (dd, J=8.8, 5.8 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.85 (td, J=8.5, 2.9 Hz, 1H), 4.02 (s, 3H), 3.73 (s, 3H). LC-MS: m/z 473.1 [M+H].sup.+, (ESI+), RT=1.03 LCMS Method M2.

[0958] Step 5: methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylate: To a stirring solution of methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (82%, 216 mg, 0.375 mmol) in Methanol-Anhydrous (3.3 mL), 5.4 MNaOMe in MeOH (0.069 mL, 0.375 mmol) was added at 0? C. dropwise. The reaction was subsequently allowed to stir at room temperature for 0.5 h. The reaction was re-treated with 5.4 MNaOMe in MeOH (0.035 mL, 0.188 mmol) at 0? C. and stirred for 0.5 h. The reaction was re-treated further time with 5.4 MNaOMe in MeOH (0.017 mL, 0.0938 mmol) and stirred at room temperature for 0.5 h. The reaction was quenched with sat. NH4Cl (aq) (1 mL) and acidified to pH 1 using 2M HCl (aq). The reaction mixture was concentrated in vacuo, poured into water (10 mL) and extracted with EtOAc (3?10 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc (on a Biotage Sfar 5 g column, compound wet-loaded using DCM), concentrated in vacuo to afford methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylate (68.0%) (148 mg, 0.267 mmol, 71%) as a pale yellow solid. LC-MS: m/z 377.1 [M+H].sup.+, (ESI+), RT=3.75 LCMS Method 4.

[0959] Step 6: 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a mixture of methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylate (68%, 143 mg, 0.258 mmol) in THF (0.8 mL):Water (0.2 mL), lithium hydroxide (12 mg, 0.517 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 2M HCl (aqueous) to pH 1, poured into water (10 mL) and extracted with EtOAc (3?10 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-60% MeOH in EtOAc over silica (on a Biotage Sfar 5 g column, compound wet-loaded using EtOAc) and concentrated in vacuo to afford 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid (82.0%) (71 mg, 0.161 mmol, 62%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.25 (dd, J=8.8, 5.8 Hz, 1H), 7.14 (dd, J=10.7, 2.9 Hz, 1H), 6.84 (ddd, J=8.9, 8.2, 2.9 Hz, 1H), 4.17 (s, 3H), 3.73 (s, 3H). LC-MS: m/z 363.1 [M+H].sup.+, (ESI+), RT=3.03 LCMS Method 4.

[0960] Step 7: tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate: To a stirring solution of 3-(4-fluoro-2-methyl-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid (82%, 95 mg, 0.225 mmol) in DMF-Anhydrous (1.0 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.079 mL, 0.450 mmol) and HATU (103 mg, 0.270 mmol) at room temperature followed by tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate (79 mg, 0.292 mmol) in DMF-Anhydrous (0.5 mL). The reaction was stirred at room temperature for 18 h. The reaction was poured into water (10 mL) and extracted with EtOAc (3?15 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC firstly using 0-100% EtOAc in heptane over silica (on a Biotage Sfar 5 g column, compound wet-loaded using DCM), concentrated in vacuo and then purified again using 0-100% DCM in heptane, then 0-100% EtOAc in DCM and flushed with 0-20% MeOH in EtOAc over silica (on a Biotage Sfar 10 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate. (88.0%) (74 mg, 0.106 mmol, 47%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.50 (s, 1H), 8.35 (s, 1H), 7.98-7.87 (m, 1H), 7.77-7.65 (m, 2H), 7.26 (dd, J=8.9, 5.8 Hz, 1H), 7.12 (dd, J=10.7, 2.9 Hz, 1H), 6.83 (td, J=8.5, 2.9 Hz, 1H), 4.18 (s, 3H), 3.74 (s, 3H), 3.39 (s, 3H), 1.21 (s, 9H). LC-MS: m/z 615.3 [M+H].sup.+, (ESI+), RT=0.84 LCMS Method M2.

[0961] Step 8: (S)-3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a stirring solution of tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (74 mg, 0.120 mmol) in 1,4-Dioxane (0.5 mL) was added 4 M HCl in dioxane (0.50 mL, 2.00 mmol) was added and the reaction was stirred at room temperature for 4 h. The reaction was quenched with sat, Na.sub.2CO.sub.3 (aq) (2 mL), poured into water (10 mL) and extracted with EtOAc (3?15 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc over silica (on a Biotage Sfar 5 g column, compound wet-loaded using DCM) and concentrated in vacuo. The compound was further purified by reverse-phase FCC using 10-100% MeCN+0.1% formic acid in water+0.1% formic acid (on a C18 Biotage Sfar 6 g column, compound loaded using a sample preloaded with a MeOH solution), concentrated in vacuo to afford 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (99.0%) (9.0 mg, 14%) as a white solid and (S)-3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (99.0%) (18 mg, 29%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.43 (s, 1H), 8.33 (t, J=2.0 Hz, 1H), 7.87 (ddd, J=8.0, 2.2, 1.1 Hz, 1H), 7.73 (dt, J=8.0, 1.3 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.28 (dd, J=8.8, 5.8 Hz, 1H), 7.13 (dd, J=10.7, 2.9 Hz, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 4.28-4.23 (m, 1H), 4.19 (s, 3H), 3.74 (s, 3H), 3.07 (d, J=1.0 Hz, 3H). LC-MS: m/z 515.1 [M+H].sup.+, (ESI+), RT=3.06, LC-MS Method 4.

Example 67

Compound 1518: (S)-5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0962] ##STR00272##

[0963] Step 1: 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid To a mixture of methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (500 mg, 1.44 mmol) in THF (4.5 mL):Water (1 mL), lithium hydroxide (173 mg, 7.22 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 2M HCl (aq) to pH1, poured into water (50 mL) and extracted with EtOAc (3?50 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo to afford 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (69.0%) (509 mg, 73%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.47 (s, 1H), 7.32 (dd, J=8.8, 5.8 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.87 (td, J=8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC_MS: m/z 333.0 [M+H].sup.+, (ESI+), RT=2.96 LCMS Method 4.

[0964] Step 2: tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo) ?.sup.6-sulfaneylidene)carbamate: A mixture of 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.301 mmol), tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate (98 mg, 0.361 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (69 mg, 0.361 mmol) were dissolved in Pyridine (2 mL) and stirred at room temperature for 2 h. The reaction was re-treated with tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate (20 mg, 0.072 mmol) and stirred at room temperature for 2 h. The reaction was re-treated with 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (14 mg, 0.072 mmol) and stirred at room temperature for 3 h. The reaction was poured into water (30 mL) and extracted with DCM (3?40 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo, purified by FCC using 0-100% EtOAc in heptane over silica (on a Biotage Sfar 10 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (95.0%) (175 mg, 0.284 mmol, 94%) as a pale yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.26 (s, 1H), 8.64 (s, 1H), 8.37-8.31 (m, 1H), 8.03-7.95 (m, 1H), 7.75-7.67 (m, 2H), 7.37 (dd, J=8.8, 5.9 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.72 (s, 3H), 3.40 (s, 3H), 1.25 (s, 9H). LC-MS: m/z 585.2 [M+H].sup.+, (ESI+), RT=1.00 LCMS Method M2.

[0965] Step 3: tert-butyl (S)-((3-(5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate: To a stirring solution of tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (72 mg, 0.123 mmol) in THF-Anhydrous (1.5 mL), bromo(ethyl)magnesium (3M in Et.sub.2O) (0.21 mL, 0.616 mmol) was added at ?78? C. and stirred for 2.5 h. The reaction was re-treated with bromo(ethyl)magnesium (3M in Et.sub.2O) (0.21 mL, 0.616 mmol) and stirred at ?78? C. for 1 h. The reaction was quenched with methanol (0.40 mL, 9.85 mmol). NBS (39 mg, 0.222 mmol) was subsequently added to the reaction, allowed to warm to room temperature and stirred for 26 h. The reaction was re-treated with NBS (13 mg, 0.073 mmol, 0.6 eq) and stirred at room temperature for 15.5 h. The reaction was re-treated with NBS (13 mg, 0.073 mmol, 0.6 eq) and stirred at room temperature for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3?20 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane over silica and flushed with 0-20% MeOH in EtOAc (on a Biotage Sfar 5 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford tert-butyl (S)-((3-(5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (60.0%) (66 mg, 52%) as a yellow oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.41 (s, 1H), 8.39 (t, J=2.0 Hz, 1H), 7.93 (dt, J=6.8, 2.2 Hz, 1H), 7.76-7.70 (m, 2H), 7.31 (dd, J=8.8, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.86 (td, J=8.5, 2.9 Hz, 1H), 3.75 (s, 3H), 3.40 (d, J=1.4 Hz, 3H), 2.85 (q, J=7.3 Hz, 2H), 1.29-1.24 (m, 3H), 1.23 (s, 9H). m/z: 613.3[M+H].sup.+, (ESI+), RT=0.91 LCMS Method M3.

[0966] Step 4: (S)-5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a stirring solution of tert-butyl (S)-((3-(5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (60%, 66 mg, 0.0646 mmol) in DCM (0.8 mL), TFA (0.048 mL, 0.646 mmol) was added dropwise and stirred at room temperature for 2 h. The reaction was basified with sat. NaHCO.sub.3 aq solution (2 mL), poured into water (10 mL) and extracted with DCM (3?20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified by reverse phase using 10-100% MeCN+01% formic acid in water+0.1% formic acid (on a Biotage Sfar C18 6 g column, compound loaded onto a sampler pre-loaded with the compound solution in MeOH and dried in a 40? C. oven), concentrated in vacuo and freeze-dried overnight to afford (S)-5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (90.0%) (14 mg, 38%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.31 (s, 1H), 8.36 (t, J=2.0 Hz, 1H), 7.89-7.83 (m, 1H), 7.77-7.69 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.32 (dd, J=8.9, 5.8 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.86 (td, J=8.5, 2.9 Hz, 1H), 4.26 (s, 1H), 3.74 (s, 3H), 3.08 (d, J=1.1 Hz, 3H), 2.84 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). LC-MS: m/z 513.2 1 [M+H].sup.+, (ESI+), RT=3.04 LCMS Method 4.

Example 68

Compound 1519: (S)-5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0967] ##STR00273## ##STR00274##

[0968] Step 1: methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate: A mixture of 4-fluoro-2-methyl-phenol (5.05 g, 40.1 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (7.90 g, 38.2 mmol) and dipotassium carbonate (7.91 g, 57.2 mmol) in Acetonitrile (79 mL) was stirred at 70? C. for 14.5 h. The reaction was cooled to room temperature, filtered and washed with DCM (2?100 mL) and concentrated in vacuo. The compound was purified by FCC using 0-50% EtOAc in heptane over silica (on a Biotage Sfar 350 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (9.12 g, 20.9 mmol, 55%) as a pale yellow solid. H NMR (400 MHz, DMSO-d.sub.6) ? 8.27 (s, 1H), 7.26-7.21 (m, 2H), 7.16-7.07 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H). LC-MS: m/z 297.0, 299.0 [M+H].sup.+, (ESI+), RT=0.93 LCMS Method M2.

[0969] Step 2: methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate: To a stirring solution of methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (3.00 g, 10.1 mmol) and sodium iodide (15.16 g, 0.101 mol) in Acetonitrile-Anhydrous (34 mL) was added a solution of acetyl chloride (0.79 mL, 11.1 mmol) in Acetonitrile-Anhydrous (34 mL) dropwise over 30 mins at 0 to 5? C. The reaction was subsequently stirred at 5? C. for 30 mins then at room temperature for 2 h. The reaction was re-treated with acetyl chloride (0.10 mL, 1.41 mmol) at 0? C. and stirred at room temperature for 2 h. The reaction mixture was diluted with sat. aq. NaHCO.sub.3 (20 mL) and stirred for 5 min. Water (100 mL) was added and the resulting solution extracted with EtOAc (3?100 mL). The combined organic phases were washed with sat. aq sodium thiosulfate (2?50 ml), passed through a phase separator, concentrated in vacuo and purified by FCC using 0-100% EtOAc in heotane over silica (on a Biotage Sfar 200 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (95.0%) (2.19 g, 5.36 mmol, 53%) as a pale yellow oil. LC-MS: m/z 389.0 [M+H].sup.+, (ESI+), RT=1.04 LCMS Method M2.

[0970] Step 3: methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: To a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (2.19 g, 5.64 mmol), iodocopper (1.62 g, 8.46 mmol), and tetrabutylammonium iodide (836 mg, 2.26 mmol) in DMF (29.14 mL), methyl difluoro(fluorosulfonyl)acetate (3.6 mL, 28.2 mmol) was added and stirred at 70? C. for 4 h. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (3?200 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo (high vac for DMF removal). The compound was purified by FCC using 0-50% EtOAc in heptane over silica (on a Biotage Sfar 200 g column, compound wet-loaded using DCM), concentrated in vacuo to afford methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (76.0%) (1.49 g, 3.43 mmol, 61%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.54 (s, 1H), 7.34-7.24 (m, 2H), 7.18-7.11 (m, 1H), 3.97 (s, 3H), 2.13 (s, 3H). LC-MS: m/z 331.1 [M+H].sup.+, (ESI+), RT=0.98 LCMS Method M2.

[0971] Step 4: methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate: To a stirring solution of 2,2,6,6-tetramethylpiperidine (0.58 mL, 3.45 mmol) in THF-Anhydrous (12 mL), butyllithium (2.5M in hexanes) (0.92 mL, 2.30 mmol) was added dropwise at 0? C. and stirred for 30 minutes. The reaction was cooled to ?78? C. and a pre-cooled mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (76%, 500 mg, 1.15 mmol) in THF-Anhydrous (12 mL) was transferred by cannula to the LiTMP mixture, both at ?78? C. A pre-cooled mixture of 1-iodopyrrolidine-2,5-dione (259 mg, 1.15 mmol) in THF-Anhydrous (6 mL) was immediately added afterwards at ?78? C. and stirred at this temperature for 30 mins. The reaction was quenched with sat. NH.sub.4Cl (aq) (1 mL) and allowed to warm to rt. The reaction was poured into water (30 mL), extracted with EtOAc (3?50 mL), combined organic phases passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane over silica and flushed with 0-60% MeOH in EtOAc (on a Biotage Sfar 25 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (85.0%) (342 mg, 0.637 mmol, 55%) as a orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.32 (dd, J=9.0, 5.0 Hz, 1H), 7.26 (dd, J=9.4, 3.1 Hz, 1H), 7.15 (td, J=8.5, 3.2 Hz, 1H), 4.04 (s, 3H), 2.10 (s, 3H). LC-MS: m/z 457.0 [M+H].sup.+, (ESI+), RT=1.06 LCMS Method M2.

[0972] Step 5: methyl 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: A mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (75%, 203 mg, 0.334 mmol), cyclopropylboronic acid (34 mg, 0.401 mmol), bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (14 mg, 0.0167 mmol) and dipotassium carbonate (92 mg, 0.668 mmol) in 1,4-Dioxane (1.8 mL):Water (0.2 mL) was degassed with nitrogen and heated to 100? C. for 3 h. The reaction was re-treated with and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (14 mg, 0.0167 mmol), degassed with nitrogen and stirred at 100? C. for 1 h. The reaction was re-treated with cyclopropylboronic acid (34 mg, 0.401 mmol), bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; dichloropalladium (14 mg, 0.0167 mmol) and dipotassium carbonate (51 mg, 0.334 mmol), degassed with nitrogen and stirred at 100? C. for 4 h. The reaction mixture was allowed to warm to room temperature, poured into water (20 mL) and extracted with DCM (3?20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified by FCC using 0-100% EtOAc in heptane over silica and flushed with 0-60% MeOH in EtOAc (on a Biotage Sfar 10 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford methyl 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (81.0%) (114 mg, 0.249 mmol, 75%) as a yellow sticky oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6-) ? 7.28-7.22 (m, 2H), 7.13 (td, J=8.5, 3.5 Hz, 1H), 4.00 (s, 3H), 2.18-2.12 (m, 1H), 2.08 (s, 3H), 1.12-1.06 (m, 2H), 0.82-0.75 (m, 2H). LC-MS: m/z 371.2 [M+H].sup.+, (ESI+), RT=1.04 LCMS Method M2.

[0973] Step 6: 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a mixture of methyl 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (113 mg, 0.305 mmol) in THF (1 mL):Water (0.25 mL), lithium hydroxide (15 mg, 0.610 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction was re-treated with LiOH (29 mg, 1.22 mmol) and stirred at room temperature for 1 h. The reaction was re-treated with LiOH (29 mg, 1.22 mmol) and stirred at room temperature for 16 h. The reaction was re-treated with LiOH (29 mg, 1.22 mmol) and stirred at 40? C. 20 h. The reaction was re-treated with LiOH (29 mg, 1.22 mmol) and stirred at 60? C. for 6.5 h. The reaction was re-treated with lithium hydroxide (29 mg, 1.22 mmol) and stirred at 40? C. for 3 h. The reaction mixture was acidified with 2M HCl (aqueous) to pH 1, poured into water (10 mL) and extracted with EtOAc (3?10 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc over silica (on a Biotage Sfar 5 g column, compound wet-loaded using EtOAc) and concentrated in vacuo to afford 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (62 mg, 0.174 mmol, 57%) as a as a orange solid. LC-MS: m/z 357.2 [M+H].sup.+, (ESI+), RT=0.74 LCMS Method M2.

[0974] Step 7: tert-butyl N[(S)-{3-[5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate: To a stirring solution of 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (92%, 52 mg, 0.134 mmol) in DCM (0.6 mL), N,N-dimethylformamide (2.1 uL, 0.0269 mmol) was added followed by oxalyl chloride (13 uL, 0.148 mmol) under nitrogen and at rt. The reaction was stirred for 1 h. Subsequently tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate (44 mg, 0.161 mmol) in DCM (0.2 mL) was added followed by DIEA (47 uL, 0.269 mmol) and the reaction was stirred at room temperature for 1.5 h. Water (2 mL) was added to the reaction and the reaction mixture passed through a phase separator and rinsed with DCM (3?3 mL). The combined organic phases were combined, concentrated in vacuo and purified by FCC using 0-100% EtOAc in Heptane over silica and flushed with 0-60% MeOH in EtOAc (on a Biotage Sfar 5 g column, compound wet-loaded using DCM) and concentrated in vacuo to tert-butyl N[(S)-{3-[5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (94.0%) (79 mg, 0.122 mmol, 91%) as a white sticky solid. m/z: 509.1 [M-Boc+H].sup.+, (ESI+), RT=0.99 LCMS Method M2.

[0975] Step 8: (S)-5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a stirring solution of tert-butyl N[(S)-{3-[5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (94%, 79 mg, 0.122 mmol) in DCM (1.5 mL), TFA (0.091 mL, 1.22 mmol) was added dropwise and stirred at room temperature for 3 h. The reaction was basified with sat. NaHCO.sub.3 aq solution (2 mL), poured into water (10 mL) and extracted with DCM (3?20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified using 0-100% EtOAc in heptane over silica (on a Biotage Sfar 5 g column, compound wet-loaded using DCM), concentrated in vacuo and freeze-dried overnight in 1:1 MeCN/Water to afford (S)-5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (95.0%) (28 mg, 42%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.21 (s, 1H), 8.29 (t, J=2.0 Hz, 1H), 7.93-7.84 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.29-7.21 (m, 2H), 7.13 (td, J=8.5, 3.2 Hz, 1H), 4.26 (s, 1H), 3.12-3.03 (m, 3H), 2.23-2.16 (m, 1H), 2.11 (s, 3H), 1.10-1.02 (m, 2H), 0.99-0.91 (m, 2H). LC-MS: m/z 509.1 [M+H].sup.+, (ESI+), RT=3.11 LCMS Method 4.

Example 69

Compound 1520: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0976] ##STR00275##

[0977] The title compound was prepared by a similar procedure described for compound 1519 using appropriate reagents. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.06 (s, 1H), 8.03 (t, J=2.0 Hz, 1H), 7.67-7.61 (m, 1H), 7.60-7.55 (m, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.51-7.44 (m, 5H), 7.34 (dd, J=8.9, 5.0 Hz, 1H), 7.28 (dd, J=9.4, 3.2 Hz, 1H), 7.18 (td, J=8.7, 3.3 Hz, 1H), 4.21 (s, 1H), 3.04-2.95 (m, 3H), 2.19 (s, 3H). m/z: 545.3 [M+H].sup.+, (ESI+), RT=3.37 LCMS Method 4.

Compound 1521: (S)-3-(4-fluoro-2-methylphenoxy)-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0978] ##STR00276##

[0979] The title compound was prepared by a similar procedure described for compound 1519 using appropriate reagents. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.20 (s, 1H), 8.17 (t, J=2.0 Hz, 1H), 8.06 (s, 1H), 7.74-7.67 (m, 2H), 7.65 (s, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.31 (dd, J=8.9, 5.0 Hz, 1H), 7.26 (dd, J=9.4, 3.2 Hz, 1H), 7.16 (td, J=8.6, 3.2 Hz, 1H), 4.24 (s, 1H), 3.89 (s, 3H), 3.05 (s, 3H), 2.15 (s, 3H). m/z: 549.3 [M+H].sup.+, (ESI+), RT=2.88 LCMS Method 4.

Example 70

Compound 1522: (S)-5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[0980] ##STR00277## ##STR00278##

[0981] Step 1: methyl 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: A mixture containing methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (75%, 203 mg, 0.334 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (87 uL, 0.501 mmol) and cyclopropanamine (35 uL, 0.501 mmol) in Acetonitrile-Anhydrous (2 mL) was stirred at 50? C. for 3.5 h. The reaction was combined with trial from concentrated in vacuo and purified by FCC using 0-100% EtOAc in heptane over silica and flushed with 0-60% MeOH in EtOAc (on a Biotage Sfar 5 g column, compound wet-loaded using DCM) and concentrated in vacuo to afford methyl 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (75.0%) (182 mg, 0.354 mmol, 106%) as a orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.31-7.25 (m, 1H), 7.22-7.15 (m, 2H), 7.08 (td, J=8.5, 3.2 Hz, 1H), 3.91 (s, 3H), 2.57-2.52 (m, 1H), 2.07 (s, 3H), 0.79-0.73 (m, 2H), 0.68-0.62 (m, 2H). LC-MS: m/z 386.2 [M+H]+, (ESI+), RT=1.00 LCMS Method M2.

[0982] Step 2: 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a mixture of methyl 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (75%, 182 mg, 0.354 mmol) in THF (1 mL):Water (0.3 mL), lithium hydroxide (17 mg, 0.709 mmol) was added and the mixture was stirred at room temperature for 65 h. The reaction mixture was quenched with 2M HCl (aqueous) to pH1, poured into water (10 mL) and extracted with EtOAc (3?20 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc over silica (on a Biotage Sfar 5 g column, compound wet-loaded using EtOAc) and concentrated in vacuo to afford 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (86.0%) (164 mg, 0.380 mmol, 107%) as a pale yellow sticky oil. LC-MS: m/z 372.2 [M+H]+, (ESI+), RT=0.78 LCMS Method M2.

[0983] Step 3: tert-butyl N[(S)-{3-[5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate: To a stirring solution of 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (78 mg, 0.210 mmol), tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate (74 mg, 0.273 mmol) and 1-methylimidazole (NMI) (59 uL, 0.735 mmol) in Acetonitrile-Anhydrous (0.5528 mL), N-[chloro(dimethylamino)methylidene]-N-methylmethanaminium hexafluorophosphate (TCFH) (71 mg, 0.252 mmol) was added in a single portion and the reaction was stirred at room temperature for 15.5 h. The reaction was re-treated with 1-methylimidazole (NMI) (59 uL, 0.735 mmol) and N-[chloro(dimethylamino)methylidene]-N-methylmethanaminium hexafluorophosphate (TCFH) (71 mg, 0.252 mmol) and stirred at room temperature for 24 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3?20 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in heptane and flushed with 0-60% MeOH in EtOAc (on a Biotage Sfar 5 g column, compound wet-loaded using DCM and a few drops of EtOAc) and concentrated in vacuo to afford tert-butyl N[(S)-{3-[5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (138 mg, 0.153 mmol, 73%) as a pale yellow. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.23 (s, 1H), 8.38-8.32 (m, 1H), 7.96-7.86 (m, 1H), 7.70-7.62 (m, 2H), 7.23-7.13 (m, 2H), 7.13-7.03 (m, 2H), 3.36 (s, 3H), 2.68-2.65 (m, 1H), 2.09 (s, 3H), 1.17 (s, 9H), 0.74-0.69 (m, 2H), 0.63-0.54 (m, 2H). m/z: 624.2 1 [M+H].sup.+, (ESI+), RT=0.93 LCMS Method M2.

[0984] Step 4: (S)-5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide: To a stirring solution of tert-butyl N[(S)-{3-[5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (69%, 138 mg, 0.153 mmol) in DCM (2.7 mL), TFA (0.11 mL, 1.53 mmol) was added dropwise and stirred at room temperature for 3 h. The reaction was basified with sat. NaHCO.sub.3 aq solution (2 mL), poured into water (10 mL) and extracted with DCM (3?20 mL). The combined organic phases were passed through a phase separator, concentrated in vacuo and purified using 0-100% EtOAc in heptane over silica (on a Biotage Sfar 5 g column, compound wet-loaded using DCM), concentrated in vacuo. The compound was further purified by reverse-phase FCC using 10-100% MeCN+0.1% formic acid in water+0.1% formic acid (on a C18 Biotage Sfar 6 g column, compound loaded on a sampler pre-loaded with a compound solution in MeOH), concentrated in vacuo and freeze-dried overnight to afford (S)-5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (100.0%) (44 mg, 0.0840 mmol, 55%) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.13 (s, 1H), 8.33 (t, J=1.9 Hz, 1H), 7.87 (ddd, J=8.0, 2.2, 1.1 Hz, 1H), 7.70-7.64 (m, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.23-7.14 (m, 2H), 7.13-7.03 (m, 2H), 4.22 (d, J=1.3 Hz, 1H), 3.05 (d, J=1.0 Hz, 3H), 2.73-2.66 (m, 1H), 2.10 (s, 3H), 0.75-0.68 (m, 2H), 0.66-0.58 (m, 2H). LC-MS: m/z 524.1 [M+H].sup.+, (ESI+), RT=2.79 LCMS Method 4.

[0985] The following compounds were synthesised in the same manner as described above.

[0986] Compound 1523: (S)-5-(azetidin-3-ylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

##STR00279##

[0987] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.21 (s, 1H), 8.35 (t, J=2.0 Hz, 1H), 7.94-7.85 (m, 1H), 7.75-7.67 (m, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.23-7.12 (m, 2H), 7.08 (td, J=8.5, 3.1 Hz, 1H), 4.56-4.44 (m, 1H), 4.27 (s, 1H), 3.68-3.58 (m, 2H), 3.49-3.41 (m, 2H), 3.07 (s, 3H), 2.08 (s, 3H). m/z: 539.2 [M+H].sup.+, (ESI+), RT=1.71 LCMS Method 4.

Compound 1524: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-morpholino-6-(trifluoromethyl)pyridazine-4-carboxamide

[0988] ##STR00280##

Example 71

Compound 1525:3-(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0989] ##STR00281##

[0990] Step 1: methyl 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: A mixture of 4-hydroxy-3-methylbenzonitrile (650 mg, 4.88 mmol), methyl 3-chloro-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (94%, 1.20 g, 4.43 mmol) and K.sub.2CO.sub.3 (920 mg, 6.66 mmol) in Acetonitrile (11.5 mL) was stirred at 70? C. for 17 h. The reaction was cooled to room temperature, filtered and washed with EtOAc (60 mL). Filtrate was washed with water (60 mL) and brine (60 mL), organic separated, passed through phase separator and concentrated in vacuo to obtain methyl 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (90.0%) (1.68 g, 4.30 mmol, 97%) as an off-white powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.94 (d, J=1.5 Hz, 1H), 7.82 (dd, J=8.4, 2.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 2.51-2.47 (m, 16H), 2.16 (s, 3H). m/z: 352.1 [M?BOC+H].sup.+, (ESI+), RT=0.94 LCMS Method 2.

[0991] Step 2: 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a solution of methyl 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (90%, 1.68 g, 4.30 mmol) in THE (15 mL):Water (3 mL), lithium hydroxide (236 mg, 9.46 mmol) was added, and the mixture stirred at rt for 18 h. The reaction was diluted with EtOAc and the product was extracted with water (?3). The pH of the aqueous phase was adjusted to 1 by dropwise addition of 1M HCl (aq). The aqueous layer was then extracted with EtOAc (3?), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (99.0%) (1.48 g, 100%) as an off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.95-7.91 (m, 1H), 7.81 (dd, J=8.4, 2.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 2.51-2.47 (m, 3H, overlap with DMSO peak), 2.16 (s, 3H). m/z: 338.1 [M+H].sup.+, (ESI+), RT=2.67 LCMS Method 4.

[0992] Step 3: tert-butyl N[(S)-{3-[3-(4-cyano-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (1000 mg, 2.63 mmol) was added to a solution of intermediate 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (740 mg, 2.19 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.77 mL, 4.41 mmol) in DMF-Anhydrous (15 mL). tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (98%, 787 mg, 2.85 mmol) was then added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (3?50 mL). The organics were dried (MgSO.sub.4), filtered and concentrated to afford tert-butyl N-[[33-[[3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]phenyl]-methyl-oxo-?.sup.6-sulfanylidene]carbamate (48.0%)(1.95 g, 72%) as a brown oil. The material was used in the next reaction without further purification. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.44 (s, 1H), 8.40-8.36 (m, 1H), 7.95-7.87 (m, 2H), 7.85-7.80 (m, 1H), 7.78-7.69 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 3.40 (s, 3H), 2.69 (s, 3H), 2.17 (s, 3H), 1.22 (s, 9H). m/z: 490.1 [M-BOC+H].sup.+, (ESI+), RT=0.91 LCMS Method 2.

[0993] Step 4: 3-(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide: To a solution of tert-butyl N[(S)-{3-[3-(4-cyano-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (48%, 1.95 g, 1.59 mmol) in DCM (12 mL) was added 2,2,2-trifluoroacetic acid (2.4 mL, 32.3 mmol). The mixture was stirred at RT for 4 h. The reaction was diluted with sat. NaHCO.sub.3, extracted with DCM (3?), dried (MgSO.sub.4), filtered and concentrated to afford a yellow oil. Purification by basic (0.1% NH.sub.3) reverse phase chromatography (Sfar C18 60 g D Duo 30, 10-40% MeCN in H.sub.2O, fractions 14 to 16 combined), evaporation and freeze drying over the weekend gave 3-(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (141 mg, 0.282 mmol, 18%) as an off-white powder. Impure fractions were evaporated to a yellow oil (471 mg) and purified further by Prep Method 1. Earlier obtained material and the material obtained from Prep Method 1 were combined and freeze dried overnight to give 3-(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (463 mg, 60%) as a white powder. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (t, J=1.9 Hz, 1H), 7.98-7.94 (m, 1H), 7.87-7.82 (m, 1H), 7.77-7.73 (m, 1H), 7.71-7.64 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 3.17 (s, 3H), 2.62-2.59 (m, 3H), 2.23 (s, 3H). m/z: 490.2 [M+H].sup.+, (ESI+), RT=2.80 LCMS Method 4.

Example 72

Compound 1526: 3-(4-cyano-2-methylphenoxy)-N-{3-[(R)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[0994] ##STR00282##

[0995] The title compound was prepared by a similar reaction sequence as described for compound xx using 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic and tert-butyl N[(R)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.44 (t, J=1.9 Hz, 1H), 7.98-7.93 (m, 1H), 7.86-7.82 (m, 1H), 7.77-7.73 (m, 1H), 7.71-7.64 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 3.17 (s, 3H, overlap with CD.sub.3OD satellite), 2.63-2.58 (m, 3H), 2.23 (s, 3H). m/z: 490.2 [M+H].sup.+, (ESI+), RT=2.80 LCMS Method 4.

Example 73

Compound 1527: 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)pyridazine-4-carboxamide

[0996] ##STR00283##

[0997] Step 1: 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)pyridazine-4-carboxamide: To a mixture of 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid (64 mg, 0.156 mmol), HATU (71 mg, 0.187 mmol) DIEA (0.082 mL, 0.467 mmol) in DMF (1.5 mL) was added 1-oxidopyridin-1-ium-3-amine; hydrochloride (25 mg, 0.171 mmol). The reaction mixture was stirred at 40? C. for 3 h, then at rt overnight. LCMS analysis indicated the reaction was complete. The mixture was diluted with ethyl acetate (10 mL) and washed with water (3?5 mL) and brine (5 mL). Dried (MgSO4), filtered and concentrated to afford an orange oil. The residue was purified by FCC (5 g, 0 to 100% MeOH in EA) to afford 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)pyridazine-4-carboxamide (80.0%) (32 mg, 33%) as an orange solid. m/z: 504.0 [M+H].sup.+, (ESI+), RT=0.62 min LCMS Method 2.

[0998] Step 2: 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)pyridazine-4-carboxamide: 2M Na.sub.2CO.sub.3 (2M aq.) (170 uL, 0.340 mmol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (29 mg, 0.115 mmol), 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (50 mg, 0.0888 mmol) and Pd(dppf)Cl.sub.2 (6.5 mg, 8.88 ?mol) in 1,4-Dioxane (2 mL). The mixture was degassed with nitrogen for 5 minutes, then heated at 90? C. for 6 h. LCMS analysis indicated the reaction was complete. The mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL) and brine (5 mL). The organics were dried (MgSO.sub.4), filtered and concentrated to afford a brown oil. Purification by prep. HPLC (standard method) afforded 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)pyridazine-4-carboxamide (99.0%) (10 mg, 18%) as a white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 9.06 (t, J=1.9 Hz, 1H), 8.18 (m, 1H), 7.95-7.89 (m, 2H), 7.81-7.73 (m, 3H), 7.57 (dd, J=8.6, 6.4 Hz, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.49-7.41 (m, 2H), 3.82 (s, 3H), 2.41 (s, 3H). m/z: 479.2 [M+H].sup.+, (ESI+), RT=2.36 LCMS Method 4.

Example 74

Compound 1528: 3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-N-{3-[(S)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

[0999] ##STR00284## ##STR00285##

[1000] Step 1: methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylate: methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (250 mg, 0.588 mmol), potassium; (2,2-difluorocyclopropyl)-trifluoro-boranuide (130 mg, 0.706 mmol) and, 2 M disodium carbonate (882 uL, 1.76 mmol) in 1,4-Dioxane (2 mL) was degassed with nitrogen. Pd Amphos (42 mg, 0.0588 mmol) was added and the solution heated at 100? C. overnight for 3 days. No additional boronate was available to retreat. The solution was cooled and the material purified using FCC (10 g silica, 0-100% EtOAc in heptane; directly loading reaction mixture). Clean fractions were evaporated in vacuo to afford methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylate (45 mg, 0.120 mmol, 20%) as an off white solid. m/z: 376.2 [M+H].sup.+, (ESI+), RT=0.87 min LCMS Method 2.

[1001] Step 2: 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylic acid: To a solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylate (35 mg, 0.0933 mmol) in THF-Anhydrous (3 mL) was added 1 M sodium trimethylsilanolate (140 uL, 0.140 mmol) and the solution stirred for 3 h at ambient. The solvent was removed in vacuo to afford 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylic acid (75.0%) (45 mg, 0.0934 mmol, 100%) as a tan solid. Material used in next step without further purification. m/z: 362.1 [M+H].sup.+, (ESI+), RT=0.61 min LCMS Method 2.

[1002] Step 3: tert-butyl N[(S)-{3-[3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-5-methylpyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate: A mixture of 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylic acid (45 mg, 0.125 mmol), (S)-tert-butyl N-[(3-aminophenyl)-methyl-oxo-?.sup.6-sulfanylidene]carbamate (22 mg, 0.0830 mmol), HATU (35 mg, 0.0913 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.032 mL, 0.183 mmol) was stirred at ambient in DMF-Anhydrous (3.3672 mL) for 4 h. IPC indicated formation of the desired product. The mixture was directly purified using FCC (0-100% EtOAc followed by 0-20% MeOH in DCM, 10 g silica). Clean fractions were evaporated in vacuo to afford tert-butyl N[(S)-{3-[3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-5-methylpyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (11 mg, 0.0142 mmol, 110%) as a white solid. m/z: 614.2 [M+H].sup.+, (ESI+), RT=0.87 min LCMS Method 2.

[1003] Step 4 3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide: To a solution of tert-butyl N-[[3-[[3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carbonyl]amino]phenyl]-methyl-oxo-?.sup.6-sulfanylidene]carbamate (11 mg, 0.0179 mmol) in DCM (0.2423 mL) was added TFA (0.2423 mL) and the solution stirred at ambient for 4 h. IPC indicated formation of the desired product. The solvent was removed under a stream of nitrogen. saturated sodium carbonate aq (1 mL) was added and the solution extracted with DCM (3?1 mL). The combined organics were washed again with saturated sodium carbonate passed through a phase separating frit and the solvent removed in vacuo to afford the crude solid. Purification was attempted with reverse phase standard acidic gradient. Compound eluted ?90% purity. Purification using standard FCC (10 g silica; 0-100% EtOAc in heptanes followed by 0-30% MeOH in DCM eluted the title compound and impurities ?10% MeOH). The solvent was removed in vacuo and the solid freeze dried to afford 3 3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide (90.0%) (8.3 mg, 0.0145 mmol, 81%) as an off white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.47-8.43 (m, 1H), 7.98-7.93 (m, 1H), 7.82 (ddd, J=7.9, 1.8, 1.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.43-7.39 (m, 2H), 3.79 (s, 3H), 3.26-3.21 (m, 1H), 3.17 (s, 3H), 2.52 (s, 3H), 2.48-2.39 (m, 1H), 2.04-1.97 (m, 1H). m/z: 514.2 [M+H].sup.+, (ESI+), RT=2.57 LCMS Method 4.

Example 75

Compound 1529: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-?6-sulfanyl]phenyl}-5-methyl-6-(4-methylphenyl)pyridazine-4-carboxamide

[1004] ##STR00286## ##STR00287##

[1005] Step 1: methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylate: 1,1is(diphenylphosphanyl)ferrocene-dichloropalladium (1:1) (0.17 g, 0.235 mmol) was added to a stirred, N2 degassed solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (1.00 g, 2.35 mmol), (4-methylphenyl)boronic acid (0.64 g, 4.70 mmol) and 2 M disodium carbonate (2M aq.) (3.5 mL, 7.06 mmol) in 1,4-Dioxane (12 mL). The reaction mixture was stirred at 80? C. for 2 h in a pressure vial. LCMS analysis indicated the reaction was complete. The mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL) and brine (15 mL). The organics were dried (MgSO4), filtered and concentrated to afford a brown solid. Purification by FCC (25 g, 0 to 40% EA in heptane) afforded methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylate (77.0%)(1.20 g, 100%) as a pale yellow solid. LCMS and .sup.1H-NMR analysis indicated this was the desired product, with excess tolyl boronic acid. Used directly in the next step.

[1006] Step 2: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylic acid: To a solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylate (0.92 g, 2.35 mmol) in THF (6 mL):Water (2 mL), lithium hydroxide (0.13 g, 5.17 mmol) was added, and the mixture was stirred at RT for 18 h. LCMS analysis indicated ca. 50% conversion. Additional lithium hydroxide (0.13 g, 5.17 mmol) in Water (2 mL) was added, and the mixture stirred at rt for 18 h. LCMS analysis indicated ca. 75% conversion with 18% carboxamide at 215 nm. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2?15 mL). The organics were concentrated to afford a yellow semi-solid, 565 mg. The the pH was then adjusted to 1 by dropwise addition of 2M HCl (aq), and the aqueous layer was extracted with EtOAc (2?15 mL) and the organics concentrated to afford 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylic acid (93.0%) (0.69 g, 73%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.72 (d, J=1.8 Hz, 1H), 7.53 (dd, J=8.2, 1.8 Hz, 1H), 7.49-7.40 (m, 3H), 7.32 (d, J=7.9 Hz, 2H), 3.79 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H). m/z: 376.2 [M+H].sup.+, (ESI+), RT=0.71 min LCMS Method 2.

[1007] Step 3: tert-butyl N[(R){3-[3-(4-cyano-2-methoxyphenoxy)-5-methyl-6-(4-methylphenyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.79 g, 2.08 mmol) was added to a solution of 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylic acid (0.65 g, 1.73 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.60 mL, 3.46 mmol) in DMF-Anhydrous (7 mL). The mixture was stirred at rt for 5 minutes, before the addition of tert-butyl N[(R)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate (0.51 g, 1.90 mmol) as a solution in DMF-Anhydrous (4 mL). The mixture was stirred at RT for 18 h. LCMS analysis indicated the reaction was mostly complete. The mixture was diluted with ethyl acetate (30 mL) and washed with water (3?15 mL) and brine (15 mL). Organics were dried (MgSO.sub.4), filtered and concentrated to afford a yellow foam. Purification by FCC (25 g, 0 to 100% EA in heptane) tert-butyl N[(R){3-[3-(4-cyano-2-methoxyphenoxy)-5-methyl-6-(4-methylphenyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (90.0%) (0.90 g, 74%) as a pale yellow foam. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.49 (t, J=2.0 Hz, 1H), 8.02-7.95 (m, 1H), 7.78 (m, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.51 (m, 1H), 7.47-7.39 (m, 4H), 7.36 (d, J=8.0 Hz, 2H), 3.83 (s, 3H), 3.35 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 1.27 (s, 9H). m/z: 628.2 [M+H].sup.+, (ESI+), RT=0.94 min LCMS Method 2.

[1008] Step 4: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-?6-sulfanyl]phenyl}-5-methyl-6-(4-methylphenyl)pyridazine-4-carboxamide: To a solution of tert-butyl N[(R){3-[3-(4-cyano-2-methoxyphenoxy)-5-methyl-6-(4-methylphenyl)pyridazine-4-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (898 mg, 1.43 mmol) in 1,4-Dioxane-Anhydrous (8 mL) was added 4 M hydrogen chloride 4m in dioxane (18 mL, 71.5 mmol). The mixture was stirred at rt for 2 h. LCMS analysis indicated the reaction was complete. The mixture was cooled to 0C, diluted with ethyl acetate (20 mL) and the pH adjusted to ?9 with sat. NaHCO.sub.3. Extracted with ethyl acetate (3?30 mL), and the organics dried (MgSO.sub.4), filtered and concentrated to afford an orange solid. Purification by acidic (0.10% Formic acid) reverse phase chromatography (Sfar C18 30 g D Duo, 10% MeCN in H.sub.2O 2 CV 10-25% MeCN in H.sub.2O 2 CV, 25-40% MeCN in H.sub.2O 12 CV, 40% MeCN in H.sub.2O 8 CV THEN 40-100%?6CV) afforded a white solid (?480 mg) which was taken up in MeCN (20 mL) and scavenged with Si TMT (TCI chemicals, 0.5 mmol/g, 1.41 g) for 30 min at rt. The mixture was filtered and concentrated, then freeze dried to afford 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(4-methylphenyl)pyridazine-4-carboxamide (100.0%)(435 mg, 58%) as a white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.46 (t, J=2.0 Hz, 1H), 7.97 (m, 1H), 7.83 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.51 (d, J=1.6 Hz, 1H), 7.47-7.39 (m, 4H), 7.36 (d, J=7.8 Hz, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H). m/z: 528.2 [M+H].sup.+, (ESI+), RT=2.88 LCMS Method 4.

Example 76

Compound 1530: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methyl-6-(4-methylphenyl)pyridazine-4-carboxamide

[1009] ##STR00288##

[1010] Title compound was made using a similar method to that above but using tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate. This route yields 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methyl-6-(4-methylphenyl)pyridazine-4-carboxamide (0.52 g, 0.984 mmol) as a white solid .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.46 (t, J=2.0 Hz, 1H), 8.01-7.93 (m, 1H), 7.83 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.51 (m, 1H), 7.47-7.40 (m, 4H), 7.36 (d, J=8.0 Hz, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H). m/z: 528.2 [M+H].sup.+, (ESI+), RT=2.88 LCMS Method 4.

Example 77

Compound 1531: (R)-3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide

[1011] ##STR00289## ##STR00290##

[1012] Step 1: methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine-4-carboxylate: Pd(dppf)Cl.sub.2.Math.DCM (1:1) (172 mg, 0.23 5 mmol) was added to a stirred, N.sub.2 degassed solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (1000 mg, 2.35 mmol), (4-cyanophenyl)boronic acid (691 mg, 4.70 mmol) and 2 M disodium carbonate (2M aq.) (3.5 mL, 7.06 mmol) in 1,4-Dioxane (40 mL). The reaction mixture was stirred at 80? C. for 4 h. The reaction mixture was diluted with EtOAc (?80 mL) and washed with water (?20 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give crude product. Purification by FCC (Biotage isolera, SiO.sub.2, gradient elution 10-100% EtOAc:Heptanes gave methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine-4-carboxylate (92.0%) (891 mg, 87%) as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.82 (dd, J=16.0, 8.2 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 7.39-7.31 (m, 2H), 7.26-7.19 (m, 1H), 4.05 (s, 3H), 3.80 (s, 3H), 2.37 (s, 3H). m/z: 401 [M+H].sup.+, (ESI+), RT=0.87 LCMS Method 2.

[1013] Step 2: 3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxylic acid: lithium hydroxide (117 mg, 4.90 mmol) was added to a solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine-4-carboxylate (891 mg, 2.23 mmol) in THF-Anhydrous (19 mL) and water (2.5 mL) at rt and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated to low volume (remove THF), diluted in water (?20 ml) and washed with TBME (?20 ml). The basic aqueous phase was cooled to OC and acidified to pH 2-3 by addition of 2M HCl aq. The organic phase was extracted with EtOAc (3?50 ml). The organic phase was dried with sodium sulfate, filtered and concentrated to dryness in vacuum. to give crude product 3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxylic acid (91.0%) (674 mg, 1.745 mmol) which was used as such in the next step. Assumed 100% molar yield.

[1014] Step 3: tert-butyl (R)-((3-(3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (730 mg, 1.92 mmol) was added to a mixture of 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine-4-carboxylic acid (674 mg, 1.74 mmol) and N-ethyl-N-isopropyl-propan-2-amine (670 uL, 3.84 mmol) in DMF (6 mL) at rt and the reaction was stirred at rt for 5 min then a solution of) tert-butyl N[(R)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate (472 mg, 1.74 mmol) in DMF (6 mL) was added and the reaction was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (?50 mL) and washed with water (3??50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give crude product. Purification by FCC (Biotage isolera, SiO.sub.2 gradient elution 10-50% EtOAc:Heptanes) to provide tert-butyl (R)-((3-(3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (887 mg, 80%) as a yellow gum. Material used in the next step without further purification.

[1015] Step 4: (R)-3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide: 4 M hydrogen chloride (4M in dioxane) (12 mL, 46.8 mmol) was added to a solution tert-butyl (R)-((3-(3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (598 mg, 0.936 mmol) in 1,4-Dioxane (5.5 mL) and 2-Propanol (5.5 mL). The mixture was stirred at rt for 4 h. The reaction wad cooled to ? C., diluted in EtOAc, ?50 ml. Basified to pH9 by the dropwise addition of satd aq NaHCO.sub.3. The aq. phase was extracted with EtOAc (3?50 mL). The org. phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuum to give crude desired product which was purified by low pH reverse phase Biotage 2?(Sfar C18 12 g D Duo, 10% MeCN in H2O 2 CV, 10-25% MeCN in H.sub.2O 2 CV, 25-40% MeCN in H.sub.2O 12 CV, 40% MeCN in H.sub.2O 8 CV, then 40-100% ACN 6CV) The product containing fractions were combined and the solvent was removed in vacuo, to give the desired product 381 mg as a white solid, which was diluted in ACN (30 ml) and scavenged with Si TMT, TCI chemicals, 0.5 mmol/g, 1.85 g) for 30 min at rt. The scavenger was filtered thru a douche tube and concentrated to dryness in vacuum. The residue was diluted in 3:2 water:ACN (10 ml) and freeze dried overnight to give (R)-3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (100.0%)(331 mg, 66%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.31 (s, 1H), 8.39 (s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.87 (d, J=8.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.75-7.68 (m, 2H), 7.62 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.2, 1.7 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 4.25 (s, 1H), 3.80 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). m/z: 539.2 [M+H].sup.+, (ESI+), RT=2.67 LCMS Method 6.

Example 78

Compound 1532: 3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-N-{3-[(S)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

[1016] ##STR00291##

[1017] The title compound was made with a similar method to that described for example 77, compound 1531 but using 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine-4-carboxylic acid and tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?6-sulfanylidene]carbamate to eventually yield 3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide (279 mg, 0.513 mmol). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.40 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.88 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.75-7.68 (m, 2H), 7.62 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.2, 1.7 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 4.26 (s, 1H), 3.80 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). 0.3WT % ACN. m/z: 539.0 [M+H].sup.+, (ESI+), RT=2.67 MET-uPLC-AB-101 (7 min, low pH).

[1018] Compounds 1533 to 1537 were prepared using a related route, but using appropriate commercially available boronic acids/esters/BF3 salts for the Suzuki step and the appropriate chiral intermediates tert-butyl N[(S)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate or tert-butyl N[(R)-(3-aminophenyl)(methyl)oxo-?.sup.6-sulfanylidene]carbamate for the relevant chiral sulfoximine products.

[1019] Compounds 1533: 3-(4-cyano-2-methoxyphenoxy)-6-[4-(difluoromethyl)phenyl]-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

##STR00292##

[1020] .sup.1H NMR (400 MHz, DMSO-d.sub.6)) ? 11.29 (s, 1H), 8.40 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.83-7.68 (m, 6H), 7.62 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.2, 1.6 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.14 (t, J=55.8 Hz, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). m/z: 564.0 [M+H].sup.+, (ESI+), RT=2.91 LCMS Method 4.

Compound 1534: 3-(4-cyano-2-methoxyphenoxy)-6-[4-(difluoromethyl)phenyl]-N-{3-[(R)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

[1021] ##STR00293##

[1022] .sup.1H NMR (400 MHz, DMSO-d.sub.6)) ? 11.29 (s, 1H), 8.40 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.81-7.67 (m, 6H), 7.62 (t, J=7.9 Hz, 1H), 7.55 (dd, J=8.2, 1.7 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.14 (t, J=55.8 Hz, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). m/z: 564.0 [M+H].sup.+, (ESI+), RT=2.91 LCMS Method 4.

Compound 1535: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxamide

[1023] ##STR00294##

[1024] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.46 (t, J=2.0 Hz, 1H), 7.97 (m, 1H), 7.83 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.54-7.46 (m, 3H), 7.46-7.38 (m, 2H), 7.12-7.06 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.17 (s, 3H), 2.42 (s, 3H). m/z: 544.1 [M+H].sup.+, (ESI+), RT=2.68 LCMS Method 4.

Compound 1536: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-6-(4-methoxyphenyl)-5-methylpyridazine-4-carboxamide

[1025] ##STR00295##

[1026] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.46 (t, J=2.0 Hz, 1H), 7.97 (m, 1H), 7.82 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.53-7.46 (m, 3H), 7.45-7.36 (m, 2H), 7.13-7.04 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 2.42 (s, 3H). m/z: 544.4 [M+H].sup.+, (ESI+), RT=2.77 LCMS Method 4.

Compound 1537: 3-(4-cyano-2-methoxyphenoxy)-6-(2-fluorophenyl)-N-{3-[(R)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

[1027] ##STR00296##

[1028] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.46 (t, J=2.0 Hz, 1H), 7.97 (m, 1H), 7.83 (m, J=7.8, 1.8, 1.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.59 (m, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.51-7.41 (m, 3H), 7.38 (td, J=7.5, 1.1 Hz, 1H), 7.31 (m, 1H), 3.84 (s, 3H), 3.17 (s, 3H), 2.33 (d, J=1.4 Hz, 3H). m/z: 532.1 [M+H].sup.+, (ESI+), RT=2.71 LCMS Method 4.

Example 79

Compound 1538: 5-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]thiazole-2-carboxamide

[1029] ##STR00297##

[1030] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 12.70 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.76-7.73 (m, 2H), 7.57 (dd, J=8.2, 1.8 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 3.78 (s, 3H), 2.48 (m, 3H). m/z: 479.1 [M+H].sup.+, (ESI+), RT=2.73 MET-uPLC-AB-101 (7 min, low pH).

Compound 1539: N-(6-carbamoyl-3-pyridyl)-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[1031] ##STR00298##

[1032] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.47 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.32 (dd, J=8.6, 2.5 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.08-8.01 (m, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.61 (s, 1H), 7.57 (dd, J=8.2, 1.8 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 3.80 (s, 3H), 2.54 (d, J=1.4 Hz, 3H). m/z: 473.1 [M+H].sup.+, (ESI+), RT=2.69 MET-uPLC-AB-107 (7 min, high pH)

Compound 1540: 3-(4-cyano-2-methoxy-phenoxy)-N-(5-cyano-3-pyridyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[1033] ##STR00299##

[1034] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.98 (d, J=2.5 Hz, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.68 (dd, J=2.5, 1.8 Hz, 1H), 7.54 (d, J=1.4 Hz, 1H), 7.45 (t, J=1.3 Hz, 2H), 3.81 (s, 3H), 2.59 (q, J=1.5 Hz, 3H). m/z: 455.0 [M+H].sup.+, (ESI+), RT=3.35 MET-uPLC-AB-101 (7 min, low pH)

Compound 1541: N-(3-carbamoyl-4-methoxy-phenyl)-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[1035] ##STR00300##

[1036] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.14 (d, J=2.8 Hz, 1H), 8.01 (dd, J=9.0, 2.8 Hz, 1H), 7.53 (d, J=1.6 Hz, 1H), 7.46-7.42 (m, 2H), 7.22 (d, J=9.0 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 2.61-2.55 (m, 3H). m/z: 502.0 [M+H].sup.+, (ESI+), RT=3.00 MET-uPLC-AB-101 (7 min, low pH)

Compound 1542: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonylcarbamoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[1037] ##STR00301##

[1038] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.12 (s, 1H), 7.88-7.83 (m, 1H), 7.66-7.61 (m, 1H), 7.46-7.41 (m, 2H), 7.38-7.32 (m, 2H), 3.72 (s, 3H), 3.23 (s, 3H), 2.50 (d, J=1.4 Hz, 3H). m/z: 550.0 [M+H].sup.+, (ESI+), RT=1.97 MET-uPLC-AB-107 (7 min, high pH)

Compound 1543: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-(3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1039] ##STR00302##

[1040] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.21 (br.s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.39 (dd, J=4.7, 1.3 Hz, 1H), 8.16 (ddd, J=8.3, 2.6, 1.5 Hz, 1H), 7.74 (d, J=1.7 Hz, 1H), 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.45 (dd, J=8.3, 4.7 Hz, 1H), 3.79 (s, 3H), 2.53-2.51 (m, 3H). m/z: 430.2 [M+H].sup.+, (ESI+), RT=2.99 MET-uPLC-AB-101 (7 min, low pH)

Compound 1544: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1041] ##STR00303##

[1042] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 9.04 (t, J=1.9 Hz, 1H), 8.21-8.15 (m, 1H), 7.76 (m, 1H), 7.60-7.52 (m, 2H), 7.45 (s, 2H), 3.81 (s, 3H), 2.58 (m, 3H). m/z: 446.2 [M+H].sup.+, (ESI+), RT=2.44 MET-uPLC-AB-101 (7 min, low pH).

Compound 1545: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-[(E)-N-methoxy-C-methyl-carbonimidoyl]phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[1043] ##STR00304##

[1044] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.06 (s, 1H), 8.03-7.98 (m, 1H), 7.78-7.71 (m, 2H), 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.47-7.42 (m, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 2.52-2.51 (m, 3H), 2.18 (s, 3H). m/z: 500.0 [M+H].sup.+, (ESI+), RT=4.09 MET-uPLC-AB-101 (7 min, low pH).

Compound 1546: methyl 3-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]benzoate

[1045] ##STR00305##

[1046] .sup.19F NMR (376 MHz, DMSO-d.sub.6) ? ?63.30. m/z: 487.1 [M+H].sup.+, (ESI+), RT=3.57 MET-uPLC-AB-107 (7 min, high pH)

Compound 1547: 3-(4-fluoro-2-methyl-phenoxy)-6-(1-hydroxyethyl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[1047] ##STR00306##

[1048] .sup.1H NMR (500 MHz, CD.sub.3OD) ?, 8.46 (t, J=1.9 Hz, 1H), 8.02-7.89 (m, 1H), 7.86-7.77 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.16 (dd, J=8.9, 4.9 Hz, 1H), 7.05 (dd, J=9.1, 2.9 Hz, 1H), 7.01-6.93 (m, 1H), 5.23 (q, J=6.5 Hz, 1H), 3.17 (s, 3H), 2.56 (s, 3H), 2.16 (s, 3H), 1.61 (d, J=6.6 Hz, 3H) 3 exchangeable Hs not seen. m/z: 459.1 [M+H].sup.+, (ESI+), RT=2.25 MET-uPLC-AB-107 (7 min, high pH)

Compound 1548: 3-(4-cyano-2-methoxy-phenoxy)-N-(3-cyanophenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[1049] ##STR00307##

[1050] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.35 (s, 1H), 8.18 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.65 (dt, J=15.6, 7.7 Hz, 3H), 7.57 (dd, J=8.2, 1.8 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 3.80 (s, 3H). m/z: 454.2 [M+H].sup.+, (ESI+), RT=3.52 MET-uPLC-AB-101 (7 min, low pH).

Compound 1549: N-(3-carbamoylphenyl)-3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

[1051] ##STR00308##

[1052] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.10 (s, 1H), 8.18 (t, J=1.8 Hz, 1H), 8.01 (br.s, 1H), 7.81 (ddd, J=8.1, 2.2, 0.9 Hz, 1H), 7.67 (dt, J=7.8, 1.0 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.41 (br.s, 1H), 7.33-7.26 (m, 1H), 7.24 (ddd, J=9.3, 5.2, 1.9 Hz, 1H), 3.83-3.79 (m, 3H), 2.54-2.52 (m, 3H). m/z: 483.1 [M+H].sup.+, (ESI+), RT=3.09 MET-uPLC-AB-101 (7 min, low pH).

Compound 1550: 3-[(6-cyclopropyl-2-methoxy-3-pyridyl)oxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide

[1053] ##STR00309##

[1054] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.46-8.43 (m, 1H), 7.98-7.94 (m, 1H), 7.85-7.81 (m, 1H), 7.68-7.63 (m, 1H), 7.46-7.44 (m, 1H), 6.93-6.90 (m, 1H), 3.81 (s, 3H), 3.17 (s, 3H), 2.59-2.55 (m, 3H), 2.07-2.01 (m, 1H), 1.04-0.99 (m, 2H), 0.96-0.91 (m, 2H). m/z: 522.3 [M+H].sup.+, (ESI+), RT=3.48 MET-uPLC-AB-107 (7 min, high pH).

Compound 1551: 3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1055] ##STR00310##

[1056] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 9.09 (d, J=7.5 Hz, 1H), 8.67 (s, 1H), 7.48-7.39 (m, 1H), 7.18-7.01 (m, 2H), 3.86 (s, 3H), 2.61 (s, 3H). m/z: 481.9 [M+H].sup.+, (ESI+), RT=3.98 MET-uPLC-AB-101 (7 min, low pH).

Compound 1552: 3-(4-chloro-3-fluoro-2-methoxy-phenoxy)-5-methyl-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1057] ##STR00311##

[1058] .sup.1H NMR (400 MHz, DMSO) ? 11.40 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.79-7.66 (m, 2H), 7.45 (dd, J=9.0, 7.8 Hz, 1H), 7.28 (dd, J=9.0, 1.9 Hz, 1H), 3.80 (d, J=1.2 Hz, 3H), 3.25 (s, 3H), 2.57-2.52 (m, 3H). m/z: 534.1, 536.0 [M+H].sup.+, (ESI+), RT=3.65 MET-uPLC-AB-101 (7 min, low pH).

Compound 1553: 3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[1059] ##STR00312##

[1060] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.19 (s, 1H), 9.06 (s, 1H), 8.38 (t, J=1.9 Hz, 1H), 7.92-7.84 (m, 1H), 7.74-7.68 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.28-7.16 (m, 2H), 7.10 (td, J=8.5, 3.1 Hz, 1H), 4.23 (s, 1H), 3.08-3.05 (m, 3H), 2.39 (s, 3H), 2.10 (s, 3H) m/z: 414.9 [M+H].sup.+, (ESI+), RT=3.19 MET-uPLC-AB-101 (7 min, low pH).

Example 80

[1061] The compounds 1554, 1555 and 1556 were prepared by a similar procedure described for example 77, using 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide coupling with the appropriate boronate(s) or boronic acids.

Compound 1554: 6-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[1062] ##STR00313##

[1063] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (t, J=1.9 Hz, 1H), 7.99-7.92 (m, 1H), 7.86-7.78 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 2H), 6.05-5.96 (m, 1H), 4.31-4.22 (m, 2H), 3.89-3.76 (m, 5H), 3.17 (s, 3H), 2.68-2.59 (m, 1H), 2.57-2.49 (m, 1H), 2.46 (s, 3H), 2.18 (2?s, amide rotamers, 3H).2 exchangeable Hs not seen. m/z: 561.1 [M+H].sup.+, (ESI+), RT=2.05 MET-uPLC-AB-107 (7 min, high pH)

Compound 1555: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[1064] ##STR00314##

[1065] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (t, J=1.9 Hz, 1H), 8.00-7.90 (m, 1H), 7.85-7.77 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 2H), 5.95 (dt, J=2.5, 1.1 Hz, 1H), 3.80 (s, 3H), 3.27-3.19 (m, 2H), 3.17 (s, 3H), 2.77 (t, J=5.7 Hz, 2H), 2.63-2.56 (m, 2H), 2.47 (s, 3H), 2.44 (s, 3H). 2 exchangeable Hs not seen. m/z: 533.1 [M+H].sup.+, (ESI+), RT=2.20 MET-uPLC-AB-107 (7 min, high pH).

Compound 1556: 3-(4-cyano-2-methoxy-phenoxy)-6-(2,5-dihydrofuran-3-yl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[1066] ##STR00315##

[1067] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.45 (t, J=1.9 Hz, 1H), 8.01-7.92 (m, 1H), 7.86-7.79 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 2H), 6.70-6.62 (m, 1H), 5.13 (td, J=4.7, 2.1 Hz, 2H), 4.94 (td, J=4.7, 1.9 Hz, 2H), 3.80 (s, 3H), 3.17 (s, 3H), 2.60 (s, 3H) 2 exchangeable Hs not seen. m/z: 506.1 [M+H].sup.+, (ESI+), RT=2.24 MET-uPLC-AB-107 (7 min, high pH).

Example 81

[1068] Exemplary compounds of the invention are provided below. The number of each compound is provided directly below its structural formula.

TABLE-US-00015 TABLE 14 [00316] 36 [00317] 37 [00318] 38 [00319] 39 [00320] 40 [00321] 41 [00322] 42 [00323] 43 [00324] 44 [00325] 46 [00326] 47 [00327] 48 [00328] 49 [00329] 50 [00330] 51 [00331] 52 [00332] 53 [00333] 54 [00334] 55 [00335] 56 [00336] 57 [00337] 58 [00338] 59 [00339] 60 [00340] 61 [00341] 62 [00342] 63 [00343] 64 [00344] 65 [00345] 66 [00346] 67 [00347] 68 [00348] 69 [00349] 70 [00350] 71 [00351] 72 [00352] 74 [00353] 77 [00354] 79 [00355] 80 [00356] 81 [00357] 82 [00358] 83 [00359] 84 [00360] 85 [00361] 86 [00362] 87 [00363] 88 [00364] 89 [00365] 90 [00366] 91 [00367] 92 [00368] 93 [00369] 94 [00370] 95 [00371] 96 [00372] 97 [00373] 98 [00374] 99 [00375] 100 [00376] 101 [00377] 102 [00378] 103 [00379] 104 [00380] 105 [00381] 106 [00382] 107 [00383] 108 [00384] 110 [00385] 111 [00386] 112 [00387] 113 [00388] 114 [00389] 115 [00390] 116 [00391] 117 [00392] 118 [00393] 119 [00394] 120 [00395] 121 [00396] 122 [00397] 131 [00398] 132 [00399] 133 [00400] 134 [00401] 144 [00402] 145 [00403] 146 [00404] 147 [00405] 148 [00406] 149 [00407] 150 [00408] 151 [00409] 152 [00410] 153 [00411] 154 [00412] 155 [00413] 156 [00414] 157 [00415] 164 [00416] 165 [00417] 166 [00418] 167 [00419] 168 [00420] 169 [00421] 170 [00422] 171 [00423] 172 [00424] 173 [00425] 174 [00426] 175 [00427] 176 [00428] 177 [00429] 178 [00430] 179 [00431] 180 [00432] 181 [00433] 182 [00434] 183 [00435] 184 [00436] 185 [00437] 186 [00438] 187 [00439] 188 [00440] 189 [00441] 190 [00442] 191 [00443] 192 [00444] 193 [00445] 194 [00446] 195 [00447] 199 [00448] 200 [00449] 201 [00450] 202 [00451] 203 [00452] 204 [00453] 205 [00454] 206 [00455] 207 [00456] 208 [00457] 209 [00458] 210 [00459] 211 [00460] 212 [00461] 213 [00462] 214 [00463] 215 [00464] 216 [00465] 220 [00466] 221 [00467] 222 [00468] 224 [00469] 225 [00470] 226 [00471] 227 [00472] 228 [00473] 229 [00474] 230 [00475] 231 [00476] 236 [00477] 237 [00478] 238 [00479] 239 [00480] 241 [00481] 242 [00482] 243 [00483] 244 [00484] 245 [00485] 246 [00486] 247 [00487] 248 [00488] 249 [00489] 250 [00490] 251 [00491] 252 [00492] 258 [00493] 259 [00494] 260 [00495] 261 [00496] 262 [00497] 263 [00498] 264 [00499] 265 [00500] 266 [00501] 267 [00502] 268 [00503] 269 [00504] 270 [00505] 271 [00506] 272 [00507] 273 [00508] 274 [00509] 275 [00510] 276 [00511] 277 [00512] 278 [00513] 279 [00514] 280 [00515] 281 [00516] 282 [00517] 283 [00518] 284 [00519] 285 [00520] 286 [00521] 287 [00522] 288 [00523] 289 [00524] 290 [00525] 291 [00526] 292 [00527] 293 [00528] 294 [00529] 295 [00530] 296 [00531] 297 [00532] 298 [00533] 299 [00534] 300 [00535] 301 [00536] 302 [00537] 304 [00538] 305 [00539] 306 [00540] 308 [00541] 309 [00542] 310 [00543] 311 [00544] 312 [00545] 313 [00546] 314 [00547] 315 [00548] 316 [00549] 317 [00550] 318 [00551] 319 [00552] 320 [00553] 321 [00554] 321 [00555] 322 [00556] 323 [00557] 324 [00558] 325 [00559] 326 [00560] 327 [00561] 328 [00562] 329 [00563] 330 [00564] 331 [00565] 332 [00566] 333 [00567] 334 [00568] 335 [00569] 336 [00570] 337 [00571] 338 [00572] 339 [00573] 340 [00574] 341 [00575] 342 [00576] 343 [00577] 344 [00578] 345 [00579] 346 [00580] 347 [00581] 348 [00582] 349 [00583] 350 [00584] 351 [00585] 352 [00586] 353 [00587] 354 [00588] 355 [00589] 356 [00590] 357 [00591] 358 [00592] 359 [00593] 360 [00594] 361 [00595] 362 [00596] 363 [00597] 364 [00598] 365 [00599] 368 [00600] 369 [00601] 371 [00602] 372 [00603] 373 [00604] 374 [00605] 375 [00606] 376 [00607] 377 [00608] 378 [00609] 379 [00610] 380 [00611] 381 [00612] 382 [00613] 383 [00614] 384 [00615] 385 [00616] 390 [00617] 391 [00618] 392 [00619] 393 [00620] 394 [00621] 395 [00622] 396 [00623] 402 [00624] 403 [00625] 404 [00626] 405 [00627] 406 [00628] 407 [00629] 408 [00630] 416 [00631] 428 [00632] 429 [00633] 430 [00634] 431 [00635] 432 [00636] 433 [00637] 434 [00638] 435 [00639] 436 [00640] 437 [00641] 438 [00642] 439 [00643] 440 [00644] 441 [00645] 443 [00646] 444 [00647] 445 [00648] 451 [00649] 452 [00650] 453 [00651] 454 [00652] 455 [00653] 456 [00654] 457 [00655] 458 [00656] 459 [00657] 460 [00658] 461 [00659] 462 [00660] 463 [00661] 471 [00662] 472 [00663] 473 [00664] 474 [00665] 475 [00666] 476 [00667] 477 [00668] 478 [00669] 479 [00670] 480 [00671] 481 [00672] 482 [00673] 483 [00674] 484 [00675] 485 [00676] 486 [00677] 487 [00678] 488 [00679] 489 [00680] 490 [00681] 491 [00682] 492 [00683] 493 [00684] 494 [00685] 495 [00686] 496 [00687] 497 [00688] 498 [00689] 499 [00690] 500 [00691] 501 [00692] 502 [00693] 503 [00694] 504 [00695] 505 [00696] 506 [00697] 507 [00698] 508 [00699] 509 [00700] 510 [00701] 511 [00702] 512 [00703] 513 [00704] 514 [00705] 515 [00706] 516 [00707] 517 [00708] 518 [00709] 519 [00710] 520 [00711] 521 [00712] 522 [00713] 523 [00714] 524 [00715] 525 [00716] 526 [00717] 527 [00718] 528 [00719] 529 [00720] 530 [00721] 531 [00722] 532 [00723] 533 [00724] 534 [00725] 535 [00726] 536 [00727] 537 [00728] 538 [00729] 539 [00730] 540 [00731] 541 [00732] 542 [00733] 543 [00734] 544 [00735] 545 [00736] 546 [00737] 547 [00738] 548 [00739] 549 [00740] 550 [00741] 551 [00742] 552 [00743] 553 [00744] 554 [00745] 555 [00746] 556 [00747] 557 [00748] 558 [00749] 559 [00750] 560 [00751] 561 [00752] 562 [00753] 563 [00754] 564 [00755] 565 [00756] 566 [00757] 567 [00758] 568 [00759] 569 [00760] 570 [00761] 571 [00762] 572 [00763] 573 [00764] 574 [00765] 575 [00766] 576 [00767] 577 [00768] 578 [00769] 579 [00770] 580 [00771] 581 [00772] 582 [00773] 583 [00774] 584 [00775] 585 [00776] 586 [00777] 587 [00778] 588 [00779] 589 [00780] 590 [00781] 591 [00782] 592 [00783] 593 [00784] 594 [00785] 595 [00786] 596 [00787] 597 [00788] 598 [00789] 599 [00790] 600 [00791] 601 [00792] 602 [00793] 603 [00794] 604 [00795] 605 [00796] 606 [00797] 607 [00798] 608 [00799] 609 [00800] 610 [00801] 611 [00802] 612 [00803] 613 [00804] 614 [00805] 615 [00806] 616 [00807] 617 [00808] 618 [00809] 619 [00810] 620 [00811] 621 [00812] 622 [00813] 623 [00814] 624 [00815] 625 [00816] 626 [00817] 627 [00818] 628 [00819] 630 [00820] 631 [00821] 632 [00822] 633 [00823] 634 [00824] 635 [00825] 636 [00826] 637 [00827] 638 [00828] 639 [00829] 640 [00830] 641 [00831] 642 [00832] 643 [00833] 644 [00834] 645 [00835] 646 [00836] 647 [00837] 648 [00838] 649 [00839] 650 [00840] 651 [00841] 652 [00842] 653 [00843] 654 [00844] 655 [00845] 656 [00846] 657 [00847] 658 [00848] 659 [00849] 660 [00850] 661 [00851] 662 [00852] 663 [00853] 664 [00854] 665 [00855] 666 [00856] 667 [00857] 668 [00858] 669 [00859] 670 [00860] 671 [00861] 672 [00862] 673 [00863] 674 [00864] 675 [00865] 676 [00866] 677 [00867] 678 [00868] 679 [00869] 680 [00870] 681 [00871] 682 [00872] 683 [00873] 684 [00874] 685 [00875] 686 [00876] 687 [00877] 687 [00878] 688 [00879] 689 [00880] 690 [00881] 691 [00882] 692 [00883] 693 [00884] 694 [00885] 695 [00886] 696 [00887] 697 [00888] 698 [00889] 699 [00890] 700 [00891] 701 [00892] 702 [00893] 703 [00894] 704 [00895] 705 [00896] 706 [00897] 707 [00898] 708 [00899] 709 [00900] 710 [00901] 711 [00902] 712 [00903] 713 [00904] 714 [00905] 715 [00906] 716 [00907] 717 [00908] 718 [00909] 719 [00910] 720 [00911] 721 [00912] 722 [00913] 723 [00914] 724 [00915] 725 [00916] 726 [00917] 727 [00918] 728 [00919] 729 [00920] 730 [00921] 731 [00922] 732 [00923] 733 [00924] 734 [00925] 735 [00926] 736 [00927] 737 [00928] 738 [00929] 739 [00930] 740 [00931] 741 [00932] 742 [00933] 743 [00934] 744 [00935] 745 [00936] 746 [00937] 747 [00938] 748 [00939] 749 [00940] 750 [00941] 751 [00942] 752 [00943] 753 [00944] 754 [00945] 755 [00946] 756 [00947] 757 [00948] 758 [00949] 759 [00950] 760 [00951] 761 [00952] 762 [00953] 763 [00954] 764 [00955] 765 [00956] 766 [00957] 767 [00958] 768 [00959] 769 [00960] 770 [00961] 771 [00962] 772 [00963] 773 [00964] 774 [00965] 775 [00966] 776 [00967] 777 [00968] 778 [00969] 779 [00970] 780 [00971] 781 [00972] 782 [00973] 783 [00974] 784 [00975] 785 [00976] 786 [00977] 787 [00978] 788 [00979] 789 [00980] 790 [00981] 791 [00982] 792 [00983] 793 [00984] 794 [00985] 795 [00986] 796 [00987] 797 [00988] 798 [00989] 799 [00990] 800 [00991] 801 [00992] 802 [00993] 803 [00994] 804 [00995] 805 [00996] 806 [00997] 807 [00998] 808 [00999] 809 [01000] 810 [01001] 811 [01002] 812 [01003] 813 [01004] 814 [01005] 815 [01006] 816 [01007] 817 [01008] 818 [01009] 819 [01010] 820 [01011] 821 [01012] 822 [01013] 823 [01014] 824 [01015] 825 [01016] 826 [01017] 827 [01018] 828 [01019] 829 [01020] 830 [01021] 831 [01022] 832 [01023] 833 [01024] 834 [01025] 835 [01026] 836 [01027] 837 [01028] 838 [01029] 839 [01030] 840 [01031] 841 [01032] 842 [01033] 843 [01034] 844 [01035] 845 [01036] 846 [01037] 847 [01038] 848 [01039] 849 [01040] 850 [01041] 851 [01042] 852 [01043] 853 [01044] 854 [01045] 855 [01046] 856 [01047] 857 [01048] 858 [01049] 859 [01050] 860 [01051] 861 [01052] 862 [01053] 863 [01054] 864 [01055] 865 [01056] 866 [01057] 867 [01058] 868 [01059] 869 [01060] 870 [01061] 871 [01062] 872 [01063] 873 [01064] 874 [01065] 875 [01066] 876 [01067] 877 [01068] 878 [01069] 879 [01070] 880 [01071] 881 [01072] 882 [01073] 883 [01074] 884 [01075] 885 [01076] 886 [01077] 887 [01078] 888 [01079] 889 [01080] 890 [01081] 891 [01082] 892 [01083] 893 [01084] 894 [01085] 895 [01086] 896 [01087] 897 [01088] 898 [01089] 899 [01090] 900 [01091] 901 [01092] 902 [01093] 903 [01094] 904 [01095] 905 [01096] 906 [01097] 907 [01098] 908 [01099] 909 [01100] 910 [01101] 911 [01102] 912 [01103] 913 [01104] 914 [01105] 915 [01106] 916 [01107] 917 [01108] 918 [01109] 919 [01110] 920 [01111] 921 [01112] 922 [01113] 923 [01114] 924 [01115] 925 [01116] 926 [01117] 927 [01118] 928 [01119] 929 [01120] 930 [01121] 931 [01122] 932 [01123] 933 [01124] 934 [01125] 935 [01126] 936 [01127] 937 [01128] 938 [01129] 939 [01130] 940 [01131] 941 [01132] 942 [01133] 943 [01134] 944 [01135] 945 [01136] 946 [01137] 947 [01138] 948 [01139] 949 [01140] 950 [01141] 951 [01142] 952 [01143] 953 [01144] 954 [01145] 955 [01146] 956 [01147] 957 [01148] 958 [01149] 959 [01150] 960 [01151] 961 [01152] 962 [01153] 964 [01154] 965 [01155] 966 [01156] 967 [01157] 968 [01158] 969 [01159] 970 [01160] 971 [01161] 972 [01162] 973 [01163] 974 [01164] 975 [01165] 976 [01166] 977 [01167] 978 [01168] 979 [01169] 980 [01170] 981 [01171] 982 [01172] 983 [01173] 984 [01174] 985 [01175] 986 [01176] 987 [01177] 988 [01178] 989 [01179] 990 [01180] 991 [01181] 992 [01182] 993 [01183] 994 [01184] 995 [01185] 996 [01186] 997 [01187] 998 [01188] 999 [01189] 1000 [01190] 1001 [01191] 1002 [01192] 1003 [01193] 1004 [01194] 1005 [01195] 1006 [01196] 1007 [01197] 1008 [01198] 1009 [01199] 1010 [01200] 1011 [01201] 1012 [01202] 1013 [01203] 1014 [01204] 1015 [01205] 1016 [01206] 1017 [01207] 1018 [01208] 1019 [01209] 1020 [01210] 1021 [01211] 1022 [01212] 1023 [01213] 1024 [01214] 1025 [01215] 1026 [01216] 1027 [01217] 1028 [01218] 1029 [01219] 1030 [01220] 1031 [01221] 1032 [01222] 1033 [01223] 1034 [01224] 1035 [01225] 1036 [01226] 1037 [01227] 1038 [01228] 1039 [01229] 1040 [01230] 1041 [01231] 1042 [01232] 1043 [01233] 1044 [01234] 1045 [01235] 1046 [01236] 1047 [01237] 1048 [01238] 1049 [01239] 1050 [01240] 1051 [01241] 1052 [01242] 1053 [01243] 1054 [01244] 1055 [01245] 1056 [01246] 1057 [01247] 1058 [01248] 1059 [01249] 1060 [01250] 1061 [01251] 1062 [01252] 1063 [01253] 1064 [01254] 1065 [01255] 1066 [01256] 1067 [01257] 1068 [01258] 1069 [01259] 1070 [01260] 1071 [01261] 1072 [01262] 1073 [01263] 1074 [01264] 1075 [01265] 1076 [01266] 1077 [01267] 1078 [01268] 1079 [01269] 1080 [01270] 1081 [01271] 1082 [01272] 1083 [01273] 1084 [01274] 1085 [01275] 1086 [01276] 1087 [01277] 1088 [01278] 1089 [01279] 1090 [01280] 1091 [01281] 1092 [01282] 1093 [01283] 1094 [01284] 1095 [01285] 1096 [01286] 1097 [01287] 1098 [01288] 1099 [01289] 1100 [01290] 1101 [01291] 1102 [01292] 1103 [01293] 1004 [01294] 1105 [01295] 1106 [01296] 1107 [01297] 1108 [01298] 1109 [01299] 1110 [01300] 1111 [01301] 1112 [01302] 1113 [01303] 1114 [01304] 1115 [01305] 1116 [01306] 1117 [01307] 1118 [01308] 1119 [01309] 1120 [01310] 1121 [01311] 1122 [01312] 1123 [01313] 1124 [01314] 1125 [01315] 1126 [01316] 1127 [01317] 1128 [01318] 1129 [01319] 1130 [01320] 1131 [01321] 1132 [01322] 1133 [01323] 1134 [01324] 1135 [01325] 1136 [01326] 1137 [01327] 1138 [01328] 1139 [01329] 1140 [01330] 1141 [01331] 1142 [01332] 1143 [01333] 1144 [01334] 1145 [01335] 1146 [01336] 1147 [01337] 1148 [01338] 1149 [01339] 1150 [01340] 1151 [01341] 1152 [01342] 1153 [01343] 1154 [01344] 1155 [01345] 1156 [01346] 1157 [01347] 1158 [01348] 1159 [01349] 1161 [01350] 1162 [01351] 1163 [01352] 1193 [01353] 1194 [01354] 1195 [01355] 1196 [01356] 1197 [01357] 1198 [01358] 1199 [01359] 1200 [01360] 1201 [01361] 1202 [01362] 1203 [01363] 1204 [01364] 1205 [01365] 1206 [01366] 1207 [01367] 1208 [01368] 1209 [01369] 1210 [01370] 1211 [01371] 1212 [01372] 1213 [01373] 1214 [01374] 1215 [01375] 1216 [01376] 1217 [01377] 1218 [01378] 1219 [01379] 1220 [01380] 1221 [01381] 1222 [01382] 1223 [01383] 1224 [01384] 1225 [01385] 1226 [01386] 1227 [01387] 1228 [01388] 1229 [01389] 1230 [01390] 1231 [01391] 1232 [01392] 1233 [01393] 1234 [01394] 1235 [01395] 1236 [01396] 1237 [01397] 1238 [01398] 1239 [01399] 1240 [01400] 1241 [01401] 1242 [01402] 1243 [01403] 1244 [01404] 1245 [01405] 1246 [01406] 1247 [01407] 1248 [01408] 1249 [01409] 1250 [01410] 1251 [01411] 1252 [01412] 1253 [01413] 1254 [01414] 1255 [01415] 1256 [01416] 1257 [01417] 1258 [01418] 1259 [01419] 1260 [01420] 1261 [01421] 1262 [01422] 1263 [01423] 1264 [01424] 1265 [01425] 1266 [01426] 1267 [01427] 1268 [01428] 1269 [01429] 1270 [01430] 1271 [01431] 1272 [01432] 1273 [01433] 1274 [01434] 1275 [01435] 1276 [01436] 1277 [01437] 1278 [01438] 1279 [01439] 1280 [01440] 1281 [01441] 1282 [01442] 1283 [01443] 1284 [01444] 1285 [01445] 1286 [01446] 1287 [01447] 1288 [01448] 1289 [01449] 1290 [01450] 1291 [01451] 1292 [01452] 1293 [01453] 1294 [01454] 1295 [01455] 1296 [01456] 1297 [01457] 1298 [01458] 1299 [01459] 1300 [01460] 1301 [01461] 1302 [01462] 1303 [01463] 1304 [01464] 1305 [01465] 1306 [01466] 1307 [01467] 1308 [01468] 1309 [01469] 1310 [01470] 1311 [01471] 1312 [01472] 1313

Example 82

General Synthetic Routes for the Synthesis of Substituted Analogs

Compound 1557

Route 1: 2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide

[1069] ##STR01473##

[1070] Step 1: methyl 5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate: To a solution of 4-fluoro-2-methylphenol (1.08 g, 8.5 mmol) in DMF (7 mL) was added sodium hydride (60%, 0.21 g, 8.5 mmol). The mixture was stirred at room temperature for 0.5 h. Then the mixture was added to a solution of methyl 5-bromo-2-chloro-4-methylpyridine-3-carboxylate (1.5 g, 5.7 mmol) in DMF (8 mL). The mixture was heated at 70? C. for 4 h. LCMS showed the reaction was completed. The resulting solution was quenched with water (80 mL) and extracted with EtOAc (50 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give methyl 5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate (1.1 g, 49.2% yield). LC-MS: (ESI) calcd. for C.sub.15H.sub.14BrFNO.sub.3 [M+H].sup.+ m/z 356.02, found 355.90.

[1071] Step 2: methyl 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl) nicotinate: To a stirred solution of methyl 5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridine-3-carboxylate (500 mg, 1.41 mmol), HMPA (506 mg, 2.82 mmol) and copper(I) iodide (538 mg, 2.82 mmol) in NMP (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (1.36 g, 7.06 mmol) dropwise at 150? C. under an atmosphere of N.sub.2. The mixture was heated at 150? C. for 2 h. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with DCM (30 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give methyl 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinate (260 mg, 37.6% yield). LC-MS: (ESI) calcd. for C.sub.16H.sub.14F.sub.4NO.sub.3 [M+H].sup.+ m/z 344.09, found 344.00.

[1072] Step 3: 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: To a solution of methyl 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinate (250 mg, 0.73 mmol) in MeOH/H.sub.2O (1/1, 4 mL) was added KOH (384 mg, 5.83 mmol) at room temperature. The mixture was heated at 70? C. for 4 hours. After the reaction was completed, the mixture was concentrated to remove most MeOH. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL?3). The combined organic phases were washed with brine, dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (210 mg, 78.8% yield) as a white solid. LC-MS: (ESI) calcd. for C.sub.15H.sub.12F.sub.4NO.sub.3 [M+H].sup.+ m/z 330.08, found 329.95.

[1073] Step 4: tert-butyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl) nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate: A mixture of 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (240 mg, 0.73 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (295 mg, 1.09 mmol) in pyridine (5 mL) was added POCl.sub.3 (200 ?L) dropwise at 0? C. The reaction solution was stirred at 0? C. for 1 hour. After the reaction was completed, the resulting solution was quenched with water (30 mL) and extracted with EtOAc (30 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give tert-butyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (70 mg, 14.9% yield) as a white solid. LC-MS: (ESI) calcd. for C.sub.27H.sub.28F.sub.4N.sub.3O.sub.5S [M+H].sup.+ m/z 582.17, found 582.15.

[1074] Step 5: 2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl) nicotinamido)phenyl)(methyl)(oxo)-?6-sulfaneylidene)carbamate (70 mg, 0.12 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was dissolved in THF (2 mL) then adjusted to pH=8-9 with saturated aqueous NaHCO.sub.3. The resulting solution was extracted with DCM (10 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C.sub.18 column, 150*21.2 mm, eluting with 40% to 85% MeCN/H.sub.2O containing 0.1% FA) to provide 2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (32.1 mg, 52%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm) ? 11.17 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.8 Hz, 1 H), 7.61 (t, J=7.9 Hz, 1H), 7.19 (dd, J=8.6, 5.2 Hz, 2H), 7.09 (td, J=8.5, 2.9 Hz, 1H), 4.24 (s, 1H), 3.07 (s, 3H), 2.48 (s, 3H), 2.08 (s, 3H). LC-MS: (ESI) calcd. for C.sub.22H.sub.20F.sub.4N.sub.3O.sub.3S [M+H].sup.+ m/z 482.12, found 482.00.

Route 2: 2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide

[1075] ##STR01474##

[1076] Step 1: 2-(4-fluoro-2-methyl-phenoxy)-5-iodo-4-methyl-pyridine-3-carbonitrile: A mixture of 4-fluoro-2-methyl-phenol (533 mg, 4.22 mmol), 2-chloro-5-iodo-4-methyl-pyridine-3-carbonitrile (980 mg, 3.52 mmol) and K.sub.2CO.sub.3 (584 mg, 4.22 mmol) in acetonitrile (5 mL) was stirred at 60? C. for 16 h. The reaction mixture was retreated with 4-fluoro-2-methyl-phenol (533 mg, 4.22 mmol) and stirred at 60? C. for a further 6 h. The reaction was cooled to room temperature, filtered and washed with MeCN (20 mL). Filtrate was concentrated in vacuo to obtain the crude residue. Purification by chromatography on silica (Biotage Isolera, 50 g Sfar Duo column) eluting with a gradient of 0 to 13% EtOAc in heptane afforded 2-(4-fluoro-2-methyl-phenoxy)-5-iodo-4-methyl-pyridine-3-carbonitrile (94.0%) (930 mg, 2.37 mmol, 67%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.60 (s, 1H), 7.25-7.18 (m, 2H), 7.14-7.05 (m, 1H), 2.62 (s, 3H), 2.08 (s, 3H). m/z: 369.1 [M+H].sup.+, (ESI+), RT=1.04 LCMS Method 2

[1077] Step 2: 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carbonitrile: To a mixture of 2-(4-fluoro-2-methyl-phenoxy)-5-iodo-4-methyl-pyridine-3-carbonitrile (94%, 930 mg, 2.37 mmol), iodocopper (682 mg, 3.56 mmol), and tetrabutylammonium; iodide (352 mg, 0.950 mmol) in DMF (10 mL), methyl difluoro(fluorosulfonyl)acetate (2281 mg, 11.9 mmol) was added and stirred at 70? C. for 16 h. The reaction was cooled to rt, filtered and washed with EtOAc (2?10 mL). The filtrate was washed with brine (20 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure to obtain the crude residue. Purification by chromatography on silica (Biotage Isolera, 50 g Sfar Duo column) eluting with a gradient of 0 to 5% EtOAc in heptane afforded 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carbonitrile (533 mg, 1.39 mmol, 59% Yield) as a yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.66 (s, 1H), 7.29-7.22 (m, 2H), 7.13 (td, J=8.5, 3.2 Hz, 1H), 2.70-2.66 (m, 3H), 2.10 (s, 3H). m/z: 311.3 [M+H].sup.+, (ESI+), RT=1.02 LCMS Method 2

[1078] Step 3: 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carboxamide: 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carbonitrile (533 mg, 1.39 mmol) was suspended in water (4 mL) and barium hydroxide (1.19 g, 6.96 mmol) was added. The resulting mixture was stirred at 90? C. for 16 h. The reaction mixture was diluted with water (4 mL) and retreated with barium hydroxide (1.19 g, 6.96 mmol). Stirring at 90? C. resumed for a total of 70 h. The cooled reaction mixture was diluted with water (50 mL) and acidified to pH 1 using 5M HCl. The aqueous was extracted with EtOAc (3?15 mL) and the combined organics were dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product was purified by FCC (Biotage Isolera 4, 10 g Sfar Duo, lambda-all collect) using a 0-50-100% EtOAc/heptane followed by a 0-20% MeOH/EtOAc gradient. Product fractions were combined and concentrated under reduced pressure to afford 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carboxamide (98.0%) (220 mg, 47%) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.39 (s, 1H), 8.16 (br.s, 1H), 7.90 (br.s, 1H), 7.21-7.04 (m, 3H), 2.42 (s, 3H), 2.07 (s, 3H). m/z: 329.1 [M+H].sup.+, (ESI+), RT=0.81 LCMS Method 2.

[1079] Step 4: 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: To a degassed solution of 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carboxamide (98%, 200 mg, 0.597 mmol), 1-bromo-3-(methylsulfanyl)benzene (97 uL, 0.719 mmol) and caesium carbonate (584 mg, 1.79 mmol) in 1,4-Dioxane-Anhydrous (3 mL) was added (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) Pd.sub.2(dba).sub.3 (27 mg, 0.0295 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane [XantPhos] (35 mg, 0.0605 mmol). The reaction was degassed for a further 5 minutes then the vial sealed and stirred at 100? C. for 4 hours. The cooled reaction mixture was diluted with EtOAc (5 mL) and filtered through a pad of Celite. The Celite was washed with EtOAc (2?3 mL) and the combined filtrate washed with sat. aq. sodium bicarbonate solution (10 mL), followed by brine (10 mL). The organic phase was dried using a phase separation cartridge and concentrated under vacuum to give 352 mg as a yellow solid. The crude product was purified by column chromatography (Sfar Duo 10 g, eluting in 0-100% EtOAc in heptanes, lambda-all collection). Product fractions were combined and concentrated under reduced pressure to give the desired product, 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (72.0%) (240 mg, 0.384 mmol, 64%) as a pale yellow powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.83 (s, 1H), 8.50 (s, 1H), 7.70 (t, J=1.9 Hz, 1H), 7.47-7.43 (m, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.21-7.16 (m, 2H), 7.09 (td, J=8.5, 2.9 Hz, 1H), 7.04 (ddd, J=7.9, 1.8, 0.9 Hz, 1H), 2.48-2.44 (m, 6H), 2.08 (s, 3H). m/z: 451.1 [M+H].sup.+, (ESI+), RT=1.09 LCMS Method 2.

[1080] Step 5: 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide: To a solution of 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (72%, 240 mg, 0.384 mmol) in Methanol (7.5 mL), bis(acetoxy)iodobenzene (395 mg, 1.23 mmol) and ammonium carbonate (75 mg, 0.797 mmol) were added and the reaction was stirred at rt for 15 h. The reaction mixture was retreated with bis(acetoxy)iodobenzene (132 mg, 0.410 mmol) and ammonium carbonate (25 mg, 0.266 mmol) and stirred for 2 h then left to stand over the weekend at ambient temperature. Stirring was resumed for 1 h before work-up. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by column chromatography using 0-100% EtOAc in heptane followed by 0-20% MeOH in EtOAc (on a Biotage Sfar Duo 10 g column, lambda-all collection). The resulting residue was dried in a vacuum oven at 40? C. for 2 h to afford 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (95.0%) (98 mg, 0.193 mmol, 50%) as an off-white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.17 (s, 1H), 8.51 (s, 1H), 8.44-8.37 (m, 1H), 7.92-7.84 (m, 1H), 7.72-7.67 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.22-7.15 (m, 2H), 7.09 (td, J=8.5, 3.0 Hz, 1H), 4.23 (s, 1H), 3.07 (s, 3H), 2.49-2.47 (m, 3H), 2.08 (s, 3H). m/z: 482.2 [M+H].sup.+, (ESI+), RT=3.12 LCMS Method 4.

Example 83

Compound 1558: 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide

[1081] ##STR01475## ##STR01476##

[1082] Step 1: methyl 5-chloro-2-hydroxy-4-methylnicotinate: To a solution of methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (5.0 g, 30 mmol) in DCM (50 mL) was added NCS (4.0 g, 30 mmol) at 0? C. The mixture was stirred at the same temperature for 60 minutes. The mixture was quenched with water (50 mL) and extracted with DCM (50 mL?2). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by triturate with (PE/EtOAc=3/1) to provide methyl 5-chloro-2-hydroxy-4-methylnicotinate (4 g, 66% yield) as a light brown solid. LC-MS: (ESI) calcd. for C.sub.8H.sub.9ClNO.sub.3 [M+H].sup.+ m/z 202.02, found 202.0.

[1083] Step 2: methyl 2,5-dichloro-4-methylnicotinate: A solution of methyl 5-chloro-2-hydroxy-4-methylnicotinate (2.0 g, 10 mmol) in phenyl dichlorophosphate (10 mL) was heated to 170? C. for 2 h. The resulting solution was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (30 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=10/1) to provide methyl 2,5-dichloro-4-methylnicotinate (1 g, 45% yield) as a light-yellow oil. LC-MS: (ESI) calcd. for C.sub.8H.sub.8Cl.sub.2NO.sub.2 [M+H].sup.+ m/z 219.99, found 220.0.

[1084] Step 3: methyl 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate: To a solution of 4-fluoro-2-methylphenol (286 mg, 2.27 mmol) in DMF (5 mL) was added NaH (60%, 110 mg, 2.72 mmol) at 0? C. The mixture was stirred at the same temperature for 60 minutes, then 2,5-dichloro-4-methylnicotinate (500 mg, 2.27 mmol) was added. The mixture was heated at 70? C. for 16 hours. The resulting mixture was quenched with water (20 mL) and extracted with DCM (50 mL?2). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified column chromatography on silica gel (PE/EtOAc=3/1) to provide methyl 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate (250 mg, 35% yield) as a light-yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3, ppm) ? 8.05 (s, 1H), 7.06-6.76 (m, 3H), 3.98 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H).

[1085] Step 4: 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinic acid: To a solution of methyl 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate (250 mg, 0.81 mmol) in MeOH (5 mL) was added a solution of KOH (453 mg, 8.1 mmol) in water (2 mL). The solution was heated at 60? C. for 16 h. The resulting mixture was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (30 mL?2). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinic acid (150 mg, 63% yield) as a white solid. LC-MS: (ESI) calcd. for C.sub.14H.sub.12ClFNO.sub.3 [M+H].sup.+ m/z 296.04, found 296.0.

[1086] Step 5: tert-butyl ((3-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinamido) phenyl)(methyl)(oxo)-?6-sulfaneylidene)carbamate: A solution of 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinic acid (100 mg, 0.34 mmol) in SOC.sub.2 (1 mL) was heated to 50? C. and stirred for 0.5 hour. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate was added to a stirred solution of tert-butyl ((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate (92 mg, 0.34 mmol) and DIPEA (88 mg, 0.68 mmol) in DCM (2 mL) at 0? C. The resulting mixture was stirred at 25? C. for 1 h. Then the mixture was quenched with water (10 mL) and extracted with DCM (10 mL?2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl ((3-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (80 mg, 43% yield) as a white oil. LC-MS: (ESI) calcd. for C.sub.26H.sub.28ClFN.sub.3O.sub.5S [M+H].sup.+ m/z 548.13, found 548.0.

[1087] Step 6: Preparation of 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: To a solution of tert-butyl ((3-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinamido)phenyl)(methyl)(oxo)-sulfaneylidene) carbamate (80 mg, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL) at 0? C. The mixture was stirred at 25? C. for 1 hour. The resulting mixture was adjusted to pH=8-9 with saturated aqueous NaHCO.sub.3 and extracted with DCM (10 mL?2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum and the residue was purified by prep-HPLC (Gemini 5 um C.sub.18 column, 150*21.2 mm, eluting with 30% to 90% MeCN/H.sub.2O containing 0.1% FA) to afford 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide (25 mg, 38%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm) ? 11.09 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.16 (dd, J=8.8, 4.6 Hz, 2H), 7.10-7.03 (m, 1H), 4.23 (s, 1H), 3.06 (s, 3H), 2.39 (s, 3H), 2.08 (s, 3H). LC-MS: (ESI) calcd. for C.sub.21H.sub.20ClFN.sub.3O.sub.3S [M+H].sup.+ m/z 448.08, found 448.05.

Example 84

Compound 1559: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide

[1088] ##STR01477## ##STR01478##

[1089] Step 1: 6-fluoro-2-methylpyridin-3-ol: To a solution of (6-fluoro-2-methylpyridin-3-yl)boronic acid (2.5 g, 16.12 mmol) in THF (20 mL) was added NaOH (516 mg, 12.89 mmol), H.sub.2O (5 mL) and H.sub.2O.sub.2 (1 mL, 30%) at 0? C. The mixture was stirred at room temperature for 1 h. Then the mixture was adjusted to pH=3-4 with 1N HCl and extracted with EtOAc (20 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=3/1) to give 6-fluoro-2-methylpyridin-3-ol (1.8 g, 70.59% yield) as a yellow solid. L-CMS: (ESI) calcd. for C.sub.6H.sub.6FNO [M+H].sup.+ m/z 128.05, found 128.15.

[1090] Step 2: methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: To a solution of 6-fluoro-2-methylpyridin-3-ol (1.50 g, 11.81 mmol) in DMF (8 mL) was added sodium hydride (60%, 977 mg, 23.62 mmol) at 0? C. The mixture was stirred at room temperature for 0.5 h. Then the mixture was added to a stirred solution of methyl 5-bromo-2-chloro-4-methylnicotinate (2.08 g, 7.91 mmol) in DMF (8 mL). The mixture was heated at 70? C. for 4 h. LCMS showed the reaction was completed. The resulting solution was quenched with water (80 mL) and extracted with EtOAc (50 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to give methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (0.71 g, 16.9% yield). LC-MS: (ESI) calcd. for C.sub.14H.sub.13BrFN.sub.2O.sub.3[M+H].sup.+ m/z 355.01, found 354.95.

[1091] Step 3: methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinate: To a stirred solution of methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (650 mg, 1.84 mmol), HMPA (658 mg, 3.68 mmol) and copper (I) iodide (703 mg, 3.68 mmol) in NMP (10 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (3.53 g, 18.4 mmol) dropwise at 150? C. under an atmosphere of N.sub.2. The mixture was heated at 150? C. for 2 h. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with DCM (30 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=2/1) to afford methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinate (330 mg, 51.9% yield). LC-MS: (ESI) calcd. for C.sub.15H.sub.13F.sub.4N.sub.2O.sub.3[M+H].sup.+ m/z 345.09, found 345.05.

[1092] Step 4: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: To a solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinate (300 mg, 0.87 mmol) in THF/H.sub.2O (1/1, 4 mL) was added KOH (487 mg, 8.69 mmol) at room temperature. The mixture was heated at 70? C. for 4 hours. After the reaction was completed, the mixture was concentrated to remove most THF. The aqueous phase was adjusted to pH=3-4 with 1N HCl then extracted with EtOAc (20 mL?3). The combined organic phases were washed with brine, dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (280 mg, 97.2%) as a white solid. LC-MS: (ESI) calcd. for C.sub.14H.sub.11F.sub.4N.sub.2O.sub.3[M+H].sup.+ m/z 331.07, found 331.00.

[1093] Step 5: tert-butyl (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl) nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate: A solution of 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.36 mmol) in SOCl.sub.2 (1 mL) was heated to 50? C. and stirred for 0.5 h. The solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate was added to a stirred solution of tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (117 mg, 0.43 mmol) and DIEA (88 mg, 0.68 mmol) in DCM (2 mL) at 0? C. The resulting mixture was stirred at 25? C. for 1 h. Then the mixture was quenched with water (10 mL) and extracted with DCM (10 mL?2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to provide tert-butyl (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?6-sulfaneylidene)carbamate (100 mg, 47.6%) as a white oil. LC-MS: (ESI) calcd. for C.sub.26H.sub.27F.sub.4N.sub.4O.sub.5S [M+H].sup.+ m/z 583.17, found 583.10.

[1094] Step 6: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?6-sulfaneylidene)carbamate (100 mg, 0.17 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was dissolved in THE (2 mL) then adjusted to pH=8-9 with saturated aqueous NaHCO.sub.3. The resulting solution was extracted with DCM (10 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C.sub.18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H.sub.2O containing 0.05% NH.sub.4OH) to provide (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (57.2 mg, 69.6%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm) ? 11.20 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.96-7.78 (m, 2H), 7.74-7.56 (m, 2H), 7.11 (dd, J=8.7, 3.4 Hz, 1H), 4.24 (s, 1H), 3.32 (s, 3H), 3.07 (s, 3H), 2.25 (s, 3H). LC-MS: (ESI) calcd. for C.sub.21H.sub.19F.sub.4N.sub.4O.sub.3S [M+H].sup.+ m/z 483.11, found 483.00.

Example 85

Compound 1560: (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide

[1095] ##STR01479##

[1096] Step 1: tert-butyl (S)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl) nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate: A solution of 22-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.36 mmol) in SOCl.sub.2 (1 mL) was heated to 50? C. and stirred for 0.5 h. Then the solution was concentrated under vacuum to provide the chloride intermediate. Then the chloride intermediate was added to a stirred solution of tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (117 mg, 0.43 mmol) and DIEA (88 mg, 0.68 mmol) in DCM (2 mL) at 0? C. The resulting mixture was stirred at 25? C. for 1 h. Then the mixture was quenched with water (10 mL) and extracted with DCM (10 mL?2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to tert-butyl (S)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (100 mg, 47.6% yield) as a white oil. LC-MS: (ESI) calcd. for C.sub.26H.sub.27F.sub.4N.sub.4O.sub.5S [M+H].sup.+ m/z 583.17, found 583.15.

[1097] Step 2: (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: A solution of tert-butyl (S)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (100 mg, 0.17 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was dissolved in THF (2 mL) then adjusted to pH=8-9 with saturated aqueous NaHCO.sub.3. The resulting solution was extracted with DCM (10 mL?3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C.sub.18 column, 150*21.2 mm, eluting with 40% to 95% MeCN/H.sub.2O containing 0.05% NH.sub.4OH) to give (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (61.3 mg, 74.6% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6, ppm) ? 11.20 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.99-7.76 (m, 2H), 7.76-7.52 (m, 2H), 7.11 (dd, J=8.6, 3.4 Hz, 1H), 4.24 (s, 1H), 3.32 (s, 3H), 3.07 (s, 3H), 2.25 (s, 3H). LC-MS: (ESI) calcd. for C.sub.21H.sub.19F.sub.4N.sub.4O.sub.3S [M+H].sup.+ m/z 483.11, found 482.95.

Example 86

[1098] Exemplary compounds of the invention are provided below.

Compound 1561: General route 1: 2-(4-cyano-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[1099] ##STR01480##

[1100] Step 1: methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate: A mixture of 2-chloro-5-trifluoromethyl-nicotinic acid methyl ester (100 mg, 0.417 mmol), 4-hydroxy-3-methoxybenzonitrile (93 mg, 0.624 mmol) and potassium carbonate (87 mg, 0.629 mmol) in acetonitrile-anhydrous (2.5 mL) was stirred at 70? C. in a pressure relief vial for 18 h. The reaction mixture was allowed to cool to rt, diluted with MeCN, filtered through a phase separator and the solids washed with MeCN (2?). The combined filtrate was concentrated under reduced pressure to give the crude material. This crude compound was purified by FCC (Biotage Isolera 4 flash purification system, Sfar Duo 10 g, 0-40% EtOAc in heptanes) to give the desired product, methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (94.0%) (142 mg, 0.379 mmol, 91%), as a white powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.73-8.70 (m, 1H), 8.60-8.58 (m, 1H), 7.69-7.66 (m, 1H), 7.54-7.50 (m, 1H), 7.44-7.41 (m, 1H), 3.90 (s, 3H), 3.74 (s, 3H). LC-MS Method 2. m/z 353.1 [M+H].sup.+, (ESI+), RT=0.96.

[1101] Step 2. 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid: To a mixture of methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (142 mg, 0.403 mmol) in THF (2 mL) and water (0.5 mL), lithium hydroxide monohydrate (35 mg, 0.834 mmol) was added and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with water and was adjusted to pH 2 by dropwise addition of 2M HCl. Extraction with EtOAc (3?), drying over MgSO.sub.4 and concentration in vacuo afforded the desired product, 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (94.0%) (127 mg, 0.353 mmol, 88% Yield), as a white powder. The product was carried onto the next step crude.

[1102] Step 3. 2-(4-cyano-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: To a solution of 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (94%, 63 mg, 0.175 mmol) and N-[3-(dimethylamino)propyl]-Nthylcarbodiimide hydrochloride (1:1) (67 mg, 0.350 mmol) in pyridine (1.2 mL) was added 3-aminobenzenesulfonamide (60 mg, 0.348 mmol). The mixture was stirred at room temperature for 2 h. The solvents were removed (co-evaporated with MeCN) and the residue purified by prep HPLC (Prep method 3). Fractions containing the desired product were combined and evaporated to a white powder that was freeze dried overnight to afford the desired product, 2-(4-cyano-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (98.0%) (53 mg, 0.105 mmol, 60% Yield), as an off-white powder. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.91 (s, 1H), 8.68-8.64 (m, 1H), 8.57-8.54 (m, 1H), 8.32-8.29 (m, 1H), 7.87-7.83 (m, 1H), 7.70-7.68 (m, 1H), 7.61-7.49 (m, 4H), 7.44-7.38 (m, 2H), 3.76 (s, 3H). LC-MS Method 4: m/z 493.1 [M+H].sup.+, (ESI+), RT=3.24.

Compound 1562: 2-(4-cyano-2-methoxyphenoxy)-N-{3-[imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide

[1103] ##STR01481##

[1104] Step 1: 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: To a mixture of 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (71 mg, 0.210 mmol), DIPEA (0.11 mL, 0.630 mmol) and HATU (96 mg, 0.252 mmol) in DMF (1.2 mL) was added 3-(methylthio)aniline (31 uL, 0.252 mmol). The reaction was stirred at rt for 4 h. The reaction mixture was then poured into water and extracted with EtOAc (2?). The combined organic phases were washed with aq brine (2?), dried over MgSO.sub.4, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by FCC (Biotage Isolera 4, 10 g Sfar Duo, lambda-all collection) using a 0-50% EtOAc/heptane gradient to afford 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (80.0%) (68 mg, 0.118 mmol, 56% Yield) as a brown oil. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.62 (s, 1H), 8.66-8.64 (m, 1H), 8.54-8.51 (m, 1H), 7.72-7.66 (m, 2H), 7.57-7.49 (m, 2H), 7.48-7.43 (m, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.05-7.01 (m, 1H), 3.76 (s, 3H), 2.48-2.47 (m, 3H). LC-MS Method 2: m/z 460.1 [M+H].sup.+, (ESI+), RT=1.06.

[1105] Step 2: 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide: Diammonium carbonate (20 mg, 0.213 mmol) and bis(acetyloxy)(phenyl)-lambda-3-iodane (PIDA) (107 mg, 0.332 mmol) were added to a solution of 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (96%, 68 mg, 0.142 mmol) in methanol (0.8 mL) at rt and the reaction was stirred at rt for 17 h. The reaction mixture was concentrated to dryness in vacuo to give crude product which was then purified using FCC (0-100% EtOAc, Sfar Duo 10 g, dry loading onto silica with DCM). Fractions 9-12 were combined, evaporated and freeze dried overnight to the desired product, 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (99.0%) (49 mg, 0.0989 mmol, 70% Yield), as an off-white powder. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.94 (s, 1H), 8.68-8.65 (m, 1H), 8.56 (d, 1H), 8.39-8.35 (m, 1H), 7.97-7.92 (m, 1H), 7.72-7.67 (m, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.56-7.48 (m, 2H), 4.23 (s, 1H), 3.76 (s, 3H), 3.06 (s, 3H). LC-MS Method 4: m/z 491.1 [M+H].sup.+, (ESI+), RT=2.94.

Compound 1563: General Route 2: 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[1106] ##STR01482##

[1107] Step 1. 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (2.00 g, 8.87 mmol), 50% propylphosphonic anhydride solution in EtOAc (50%, 6.3 mL, 10.6 mmol), N-ethyl-N-isopropyl-propan-2-amine (3.1 mL, 17.7 mmol) and N,N-dimethylpyridin-4-amine (0.22 g, 1.77 mmol) and were dissolved in DCM (44.336 mL) under nitrogen at rt. After 10 mins 3-(methylsulfonyl)aniline (1.82 g, 10.6 mmol) was added in one portion. The reaction mixture was stirred at rt for 4 h. IPC shows desired product. The reaction mixture was poured into water (20 mL) and brine (10 mL) and extracted with DCM (3?50 mL), dried with sodium sulfate and concentrated. Purification by chromatography on silica eluting with a gradient of 0 to 388% EtOAc in heptane to afford 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (99.0%) (1.90 g, 4.97 mmol, 56% Yield) as a yellow solid. .sup.1H NMR (500 MHz, DMSO-d6) ? 11.15 (s, 1H), 9.05-9.00 (m, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.34 (t, J=1.8 Hz, 1H), 7.97-7.92 (m, 1H), 7.76-7.66 (m, 2H), 3.24 (s, 3H). LC-MS Method 1: m/z 378.95 [M+H].sup.+, (ESI+), RT=1.09.

[1108] Step 2: 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: A mixture of 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (99%, 100 mg, 0.261 mmol), 4-(difluoromethoxy)phenol (63 mg, 0.392 mmol) and dipotassium carbonate (54 mg, 0.392 mmol) in acetonitrile (0.5411 mL) was stirred at 60? C. for 1 h. IPC1 showed desired product. The reaction was cooled to room temperature, filtered and washed with MeCN (15 mL). The filtrate was concentrated in vacuo to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 70% EtOAc in heptane afforded 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (99.0%) (102 mg, 0.200 mmol, 77% Yield) as an off-white solid. .sup.1H NMR (500 MHz, DMSO-d6) ? 11.02 (s, 1H), 8.71-8.66 (m, 1H), 8.55 (d, J=2.3 Hz, 1H), 8.38 (t, J=1.8 Hz, 1H), 7.97 (dt, J=7.6, 1.7 Hz, 1H), 7.73-7.63 (m, 2H), 7.41-7.08 (m, 5H), 3.22 (s, 3H). LC-MS Method 5: m/z 502.9 [M+H].sup.+, (ESI+), RT=4.44.

Compound 1564: General Route 3: N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxamide

[1109] ##STR01483##

[1110] Step 1: 2-chloro-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (4.00 g, 17.7 mmol), dissolved in DCM (80 mL) under air at RT, was treated with 50% propylphosphonic anhydride solution in EtOAc (50%, 13 mL, 21.3 mmol), and N-ethyl-N-isopropyl-propan-2-amine (6.2 mL, 35.5 mmol). Then stirred at RT for 30 minutes. Then added N,N-dimethylpyridin-4-amine (0.43 g, 3.55 mmol) and 3-(methylsulfanyl)aniline (2.2 mL, 17.7 mmol) together in one portion. The reaction mixture was stirred at RT for 2 h. The mixture was poured into water (60 mL) and brine (60 mL) and extracted with DCM (3?40 mL), dried (MgSO.sub.4) and concentrated. Purification by column chromatography (50 g, 0 to 10% EA in heptane) afforded 2-chloro-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (6.12 g, 17.6 mmol, 100% Yield) as a yellow solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.79 (s, 1H), 9.04-8.98 (m, 1H), 8.66 (d, J=2.1 Hz, 1H), 7.66 (s, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 2.49 (s, 3H). LC-MS Method 1: m/z 347.1 [M+H].sup.+, (ESI+), RT=0.93.

[1111] Step 2: 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide: [acetoxy(phenyl)-$l{circumflex over ()}{3}-iodanyl] acetate (348 mg, 1.08 mmol) was dissolved in methanol (7.2096 mL) and treated with 2-chloro-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (250 mg, 0.721 mmol) and diammonium carbonate (104 mg, 1.08 mmol), each added in one portion. The reaction was stirred at RT for 18 h. The mixture was concentrated in vacuo to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 30% EtOAc in heptane afforded 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (98.0%) (171 mg, 0.444 mmol, 62% Yield) as a beige solid. .sup.1H NMR (500 MHz, DMSO-d6) ? 11.08 (s, 1H), 9.02 (dd, J=2.4, 0.8 Hz, 1H), 8.74-8.63 (m, 1H), 8.32 (t, J=1.9 Hz, 1H), 7.92 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 7.71 (ddd, J=7.8, 1.7, 1.1 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.07 (d, J=0.9 Hz, 3H). LC-MS Method 1: m/z 378.95 [M+H].sup.+, (ESI+), RT=1.00.

[1112] Step 3: N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxamide: A suspension of 4-(trifluoromethyl)phenol (63 mg, 0.389 mmol), 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (98%, 150 mg, 0.389 mmol) and dipotassium carbonate (81 mg, 0.584 mmol) in acetonitrile (0.8055 mL) under nitrogen was heated to 60? C. for 2 h. The reaction mixture was cooled to rt, filtered and concentrated in vacuo. The filtrate was purified by preparative HPLC (Prep Method 1) afforded N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxamide (97.0%) (97 mg, 0.187 mmol, 48% Yield) as a white solid. .sup.1H NMR (500 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.75-8.68 (m, 1H), 8.61-8.56 (m, 1H), 8.37 (t, J=1.8 Hz, 1H), 7.99-7.94 (m, 1H), 7.89-7.81 (m, 2H), 7.75-7.66 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 4.24 (s, 1H), 3.06 (s, 3H). LC-MS Method 5: m/z 503.9 [M+H].sup.+, (ESI+), RT=4.20.

Compound 1565: General Route 4: N-(3-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3-carboxamide

[1113] ##STR01484##

[1114] Step 1: N-(3-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide: To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (4.00 g, 17.7 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (4.08 g, 21.3 mmol) in pyridine (60 mL) was added 3-aminobenzamide (2.66 g, 19.5 mmol). The mixture was stirred at room temperature for one hour, then concentrated in vacuo. The residue was absorbed onto SiO2 and purified by column chromatography (SiO2, 0 to 100% EA in heptane) to afford N-(3-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (99%) (EV-TXY001-053-001) (4.51 g, 13.1 mmol, 74% Yield) as a an off-white solid. LC-MS and .sup.1H NMR analysis indicated this was the desired product. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.87 (s, 1H), 9.01 (d, J=1.6 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.16 (t, J=1.8 Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J=8.0, 1.3 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.40 (s, 1H). LC-MS Method 2: m/z 344.1 [M+H].sup.+, (ESI+), RT=0.65.

[1115] Step 2: N-(3-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3-carboxamide: To a mixture of N-(3-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (50 mg, 0.145 mmol) and 6-(cyclobutoxy)-2-methyl-pyridin-3-ol (34 mg, 0.189 mmol) in acetonitrile-anhydrous (0.5 mL) was added dipotassium carbonate (30 mg, 0.218 mmol). The mixture was heated at 65? C. in a pressure vial for 2 hours. The mixture was filtered and concentrated to afford a pale yellow oil. Purification by prep. HPLC (prep. Method 2). Product containing fractions were combined to afford N-(3-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3-carboxamide (99%) (57 mg, 0.117 mmol, 81% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired compound. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.55 (s, 2H), 8.19 (s, 1H), 7.96 (m, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.13 (m, 1H), 2.54-2.45 (m, 2H), 2.27 (s, 3H), 2.21-2.09 (m, 2H), 1.93-1.82 (m, 1H), 1.80-1.67 (m, 1H). LC-MS Method 4: m/z 487.2 [M+H].sup.+, (ESI+), RT=3.70 LC-MS Method 4.

Compound 1566: General Route 5: N-(4-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3-carboxamide

[1116] ##STR01485##

[1117] Step 1: N-(4-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide: To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (4.00 g, 17.7 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (4.08 g, 21.3 mmol) in pyridine (60 mL) was added 4-aminobenzamide (2.66 g, 19.5 mmol). The mixture was stirred at room temperature for one hour, then concentrated in vacuo. The residue was absorbed onto SiO2 and purified by column chromatography (SiO.sub.2, 0 to 100% EA in heptane) to afford (100%) N-(4-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (3.33 g, 9.67 mmol, 55% Yield) as an off-white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.76 (d, J=1.7 Hz, 2H), 8.32 (d, J=2.3 Hz, 1H), 7.85-7.79 (m, 2H), 7.73-7.67 (m, 2H), 7.57-7.50 (m, 1H), 6.59-6.52 (m, 1H). LC-MS Method 2: m/z 344.0 [M+H].sup.+, (ESI+), RT=0.65.

[1118] Step 2: N-(4-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3-carboxamide: To a mixture of N-(4-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (50 mg, 0.145 mmol) and 6-(cyclobutoxy)-2-methyl-pyridin-3-ol (34 mg, 0.189 mmol) in acetonitrile-anhydrous (0.5 mL) was added dipotassium carbonate (30 mg, 0.218 mmol). The mixture was heated at 65? C. in a pressure vial for 2 h. The mixture was filtered and concentrated to afford an orange oil. Purification by prep. HPLC (prep. Method 2). Product containing fractions were combined to afford (100%) N-(4-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3-carboxamide (49 mg, 0.101 mmol, 69%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired compound. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.58-8.51 (m, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.7 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 5.13 (p, J=7.1 Hz, 1H), 2.54-2.44 (m, 2H), 2.27 (s, 3H), 2.21-2.09 (m, 2H), 1.93-1.82 (m, 1H), 1.80-1.67 (m, 1H). LC-MS Method 4: m/z 487.2 [M+H].sup.+, (ESI+), RT=3.68.

Compound 1567: General Route 6: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide

[1119] ##STR01486##

[1120] Step 1: methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: To a mixture of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol) in DMF-anhydrous (10 mL) was added cesium carbonate (1.95 g, 5.99 mmol). The mixture was heated at 80? C. in a pressure vial for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4?15 mL) and brine (15 mL). The organics were dried (MgSO4), filtered and concentrated to afford an orange oil. Purification by FCC (25 g 20 ?m, 0 to 15% EA in heptane) afforded methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (95.0%) (EV-TXY001-100-002) (1.15 g, 2.92 mmol, 73% Yield) as a white solid. LC-MS and .sup.1H NMR analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.08-6.91 (m, 2H), 3.95 (s, 3H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 374.1 [M+H].sup.+, (ESI+), RT=1.00.

[1121] Step 2:5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: To a solution of methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol) in THF (8 mL):Water (2 mL), lithium hydroxide (0.17 g, 6.76 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (97.0%) (1.04 g, 2.79 mmol, 91%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 360.1 [M]+, (ESI+), RT=0.86.

[1122] Step 3: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide: To a solution of 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (300 mg, 0.833 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (192 mg, 1.00 mmol) in pyridine-anhydrous (3 mL) was added 3-(methylsulfanyl)aniline (139 mg, 1.00 mmol). The mixture was stirred at RT for 0.5 h. LC-MS analysis indicated the reaction was complete. The solvents were removed in vacuo and the residue purified by FCC (10 g, 0 to 30% EA in heptane) to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (92.0%) (402 mg, 0.768 mmol, 92% Yield) as a clear oil. .sup.1H NMR and LC-MS analysis indicated this was the desired compound. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.38 (d, J=2.5 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 7.72 (t, J=2.0 Hz, 1H), 7.39 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.17-7.00 (m, 3H), 3.84 (d, J=1.7 Hz, 3H), 2.49 (s, 3H). LC-MS Method 2: m/z 481.1 [M]+, (ESI+), RT=1.12.

[1123] Step 4: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide: Phenyl Iodonium diacetate (PIDA) (803 mg, 2.49 mmol) and diammonium carbonate (235 mg, 2.49 mmol) were added to a solution of 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (400 mg, 0.831 mmol) in methanol (12 mL) at rt and the reaction was stirred at room temperature for 1 hour. The solvents were removed in vacuo, and the residue purified by FCC (10 g, 0 to 100% EA in heptane) to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (88.0%) (328 mg, 0.563 mmol, 68% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired compound. 30 mg was purified by prep. HPLC (Prep. Method 2). Product fractions were combined, concentrated under reduced pressure and the resulting residue was freeze-dried from MeCN-water (1:1) to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (100.0%) (17 mg, 0.0332 mmol, 4.0%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired compound. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (t, J=2.0 Hz, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.98 (m, 1H), 7.80 (m, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.17-7.00 (m, 2H), 3.84 (d, J=1.7 Hz, 3H), 3.17 (s, 3H). LC-MS Method 7: m/z 512.2 [M]+, (ESI+), RT=3.33.

Compound 1568: General Route 7: 5-bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide

[1124] ##STR01487##

[1125] Step 1: methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: To a mixture of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol) in DMF-anhydrous (10 mL) was added cesium carbonate (1.95 g, 5.99 mmol). The mixture was heated at 80? C. in a pressure vial for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4?15 mL) and brine (15 mL). The organics were dried (MgSO.sub.4), filtered and concentrated to afford an orange oil. Purification by FCC (25 g 20 ?m, 0 to 15% EA in heptane) afforded methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (95.0%) (1.15 g, 2.92 mmol, 73%) as a white solid. LC-MS and .sup.1H NMR analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.08-6.91 (m, 2H), 3.95 (s, 3H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 374.1 [M+H].sup.+, (ESI+), RT=1.00.

[1126] Step 2: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: To a solution of methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol) in THF (8 mL):Water (2 mL), lithium hydroxide (0.17 g, 6.76 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (97.0%)(1.04 g, 2.79 mmol, 91%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 360.1 [M].sup.+, (ESI+), RT=0.86.

[1127] Step 3: 5-bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide: To a solution of 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (300 mg, 0.833 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (192 mg, 1.00 mmol) in pyridine-anhydrous (3 mL) was added 3-aminobenzamide (139 mg, 1.00 mmol). The mixture was stirred at rt for 0.5 hours. The solvents were removed and the residue purified by FCC (10 g, 0 to 100% EA in heptane) to afford 5-bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (92.0%) (385 mg, 0.741 mmol, 89%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. 30 mg was further purified by purified by prep. HPLC (Prep. Method 2). Product fractions were combined, concentrated under reduced pressure and the resulting residue was freeze-dried from MeCN-water (1:1) to afford 5-bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (100.0%) (23 mg, 0.0481 mmol, 5.8%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.42 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 8.16 (t, J=2.0 Hz, 1H), 7.92 (m, 1H), 7.70-7.63 (m, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.13 (m, 1H), 7.10-7.02 (m, 1H), 3.84 (d, J=1.7 Hz, 3H). LC-MS Method 4: m/z 478.1 [M]+, (ESI+), RT=3.36.

Compound 1569: General Route 8: 5-bromo-N-(4-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide

[1128] ##STR01488##

[1129] Step 1: methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: To a mixture of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol) in DMF-anhydrous (10 mL) was added cesium carbonate (1.95 g, 5.99 mmol). The mixture was heated at 80? C. in a pressure vial for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4?15 mL) and brine (15 mL). The organics were dried (MgSO.sub.4), filtered and concentrated to afford an orange oil. Purification by FCC (25 g 20 ?m, 0 to 15% EA in heptane) afforded methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (95.0%) (1.15 g, 2.92 mmol, 73% Yield) as a white solid. LC-MS and .sup.1H NMR analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.08-6.91 (m, 2H), 3.95 (s, 3H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 374.1 [M+H].sup.+, (ESI+), RT=1.00.

[1130] Step 2: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: To a solution of methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol) in THF (8 mL):water (2 mL), lithium hydroxide (0.17 g, 6.76 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (97.0%) (1.04 g, 2.79 mmol, 91%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 360.1 [M]+, (ESI+), RT=0.86.

[1131] Step 3: 5-bromo-N-(4-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide: To a solution of 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (300 mg, 0.833 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (192 mg, 1.00 mmol) in pyridine-anhydrous (3 mL) was added 4-aminobenzamide (139 mg, 1.00 mmol). The mixture was stirred at RT for 0.5 h. LC-MS analysis indicated the reaction was complete. The solvents were removed and the residue purified by FCC (10 g, 0 to 100% EA in heptane, then 0 to 5% MeOH in EA) to afford 5-bromo-N-(4-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (95.0%) (298 mg, 0.592 mmol, 71%) as a white solid. 1H-19F-NMR and LC-MS analysis indicated this was the desired product. 30 mg was further purified by prep. HPLC (Prep. Method 2) to afford 5-bromo-N-(4-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (100.0%) (21 mg, 0.0439 mmol, 5.3%) as a white solid after freeze drying. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.39 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.95-7.87 (m, 2H), 7.85-7.78 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 3.84 (d, J=1.7 Hz, 3H). LC-MS Method 3: m/z 478.2 [M]+, (ESI+), RT=3.36

Compound 1570: General Route 9: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-pyridine-3-carboxamide

[1132] ##STR01489##

[1133] Step 1: methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: To a mixture of methyl 5-bromo-2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol) in DMF-anhydrous (10 mL) was added cesium carbonate (1.95 g, 5.99 mmol). The mixture was heated at 80? C. in a pressure vial for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4?15 mL) and brine (15 mL). The organics were dried (MgSO.sub.4), filtered and concentrated to afford an orange oil. Purification by FCC (25 g 20 ?m, 0 to 15% EA in heptane) afforded methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (95.0%) (1.15 g, 2.92 mmol, 73% Yield) as a white solid. LC-MS and .sup.1H NMR analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.08-6.91 (m, 2H), 3.95 (s, 3H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 374.1 [M+H].sup.+, (ESI+), RT=1.00.

[1134] Step 2: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: To a solution of methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol) in THF (8 mL):water (2 mL), lithium hydroxide (0.17 g, 6.76 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?10 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (97.0%) (1.04 g 2.79 mmol, 91%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.44 (d, J=2.6 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 7.07-6.93 (m, 2H), 3.82 (d, J=1.4 Hz, 3H). LC-MS Method 2: m/z 360.1 [M]+, (ESI+), RT=0.86.

[1135] Step 3: 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-pyridine-3-carboxamid To a solution of 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (165 mg, 0.458 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (105 mg, 0.550 mmol) in pyridine-anhydrous (1.65 mL) was added pyridazin-4-amine (52 mg, 0.550 mmol). The mixture was stirred at RT for 1 h. LC-MS analysis (EV-TXY001-107-IPC1) indicated the reaction was complete. The solvents were removed and the residue purified by FCC (10 g, 0 to 100% EA in heptane) to afford 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-pyridine-3-carboxamide (146 mg, 0.334 mmol, 73% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired compound. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 9.41 (dd, J=2.7, 1.0 Hz, 1H), 9.07 (dd, J=6.0, 1.0 Hz, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.34 (d, J=2.5 Hz, 1H), 8.23 (dd, J=6.0, 2.7 Hz, 1H), 7.16-7.00 (m, 2H), 3.83 (d, J=1.7 Hz, 3H). LC-MS Method 3: m/z 437.1 [M].sup.+, (ESI+), RT=3.24.

Compound 1571: General Route 10: methyl 3-[[2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate

[1136] ##STR01490##

[1137] Step 1: methyl 3-[2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl]bicyclo[1.1.1]pentane-1-carboxylate: To a solution of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (100 mg, 0.443 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (102 mg, 0.532 mmol) in pyridine (1.5 mL) was added methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (79 mg, 0.443 mmol) The mixture was stirred at room temperature for 1 h. LC-MS analysis indicated the reaction was mostly complete. The solvents were removed and the residue purified by FCC (10 g, 0 to 40% EA in heptane) to afford methyl 3-[[2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (100%) (126 mg, 0.361 mmol, 82%) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.82 (d, J=1.6 Hz, 1H), 8.25 (d, J=2.3 Hz, 1H), 3.72 (s, 3H), 2.46 (s, 6H). LC-MS Method 2: m/z 349.0 [M+H].sup.+, (ESI+), RT=0.76.

[1138] Step 2: methyl 3-[[2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate: To a mixture of methyl 3-[[2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (50 mg, 0.143 mmol) and 3,4-difluoro-2-methoxy-phenol (30 mg, 0.186 mmol) in acetonitrile-anhydrous (0.5 mL) was added dipotassium carbonate (30 mg, 0.215 mmol). The mixture was heated at 65? C. in a pressure vial for 3 h. LC-MS analysis indicated the reaction was complete. The mixture was filtered and concentrated to afford a clear oil. Purification by FCC (10 g, 0 to 20% EA in Heptane) afforded methyl 3-[[2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (99.0%) (55 mg, 0.115 mmol, 80% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.51 (dd, J=2.4, 0.9 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 7.14-7.03 (m, 2H), 3.85 (d, J=1.8 Hz, 3H), 3.71 (s, 3H), 2.47 (s, 6H). LC-MS Method 6: m/z 473.3 [M+H].sup.+, (ESI+), RT=3.98.

Compound 1572: General Route 11: 2-(4-cyano-2-methoxy-phenoxy)-N-(1-oxidopyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide

[1139] ##STR01491##

[1140] Step 1: methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate: A mixture of 2-chloro-5-trifluoromethyl-nicotinic acid methyl ester (100 mg, 0.417 mmol), 4-hydroxy-3-methoxybenzonitrile (93 mg, 0.624 mmol) and potassium carbonate (87 mg, 0.629 mmol) in acetonitrile-anhydrous (2.5 mL) was stirred at 80? C. in a pressure relief vial for 1 h. LC-MS analysis indicated the reaction was mostly complete. The mixture was filtered and concentrated to afford a clear oil. Purification by FCC (5 g, 0 to 40% EA in heptane) afforded methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (100.0%) (142 mg, 0.403 mmol, 97%) as a white semi-solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, DMSO-d6) ? 8.73 (m, 1H), 8.60 (d, J=2.5 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.53 (dd, J=8.2, 1.8 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H). LC-MS Method 2: m/z 353.1 [M+H].sup.+, (ESI+), RT=0.94.

[1141] Step 2: 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid: To a solution of methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (142 mg, 0.403 mmol) in THF (1.8 mL):water (0.4 mL), lithium hydroxide (10 mg, 0.403 mmol) was added, and the mixture was stirred at rt for 1 h. LC-MS analysis indicated the reaction was complete. The mixture was diluted with water (5 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?5 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (100.0%)(134 mg, 0.396 mmol, 98% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, DMSO-d6) ? 8.68 (m, 1H), 8.55 (d, J=2.5 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.53 (dd, J=8.2, 1.8 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 3.75 (s, 3H). LC-MS Method 2: m/z 339.1 [M+H].sup.+, (ESI+), RT=0.79.

[1142] Step 3: 2-(4-cyano-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide: To a solution of 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (70 mg, 0.207 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (48 mg, 0.248 mmol) in pyridine (0.8 mL) was added pyridin-3-amine (21 mg, 0.228 mmol). The mixture was stirred at room temperature for 1 h. LC-MS analysis indicated the reaction was complete. The solvents were removed and the residue purified by FCC (5 g, 0 to 70% EA in heptane) to afford 2-(4-cyano-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (98.0%) (75 mg, 0.177 mmol, 86% Yield) as a white solid. 1H-19F-NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.83 (s, 1H), 8.86 (d, J=2.5 Hz, 1H), 8.67 (m, 1H), 8.58 (d, J=2.5 Hz, 1H), 8.35 (dd, J=4.7, 1.5 Hz, 1H), 8.17 (dt, J=8.5, 1.8 Hz, 1H), 7.69 (m, 1H), 7.58-7.48 (m, 2H), 7.43 (dd, J=8.3, 4.7 Hz, 1H), 3.76 (s, 3H). LC-MS Method 2: m/z 415.2 [M+H].sup.+, (ESI+), RT=0.78.

[1143] Step 4: 2-(4-cyano-2-methoxy-phenoxy)-N-(1-oxidopyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide: A solution of 2-(4-cyano-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (75 mg, 0.181 mmol) in DCM (3 mL) at 0? C. was treated with 3-chloroperoxybenzoic acid (73%, 45 mg, 0.190 mmol) then allowed to warm to room temperature and stirred for 0.5 h. LC-MS analysis indicated the reaction was mostly complete. The mixture was concentrated under reduced pressure and the residue purified by prep. HPLC (Prep. Method 2) to afforded a white solid (about 80 mg, containing mCBA). Further purification (Prep. Method 1) afforded 2-(4-cyano-2-methoxy-phenoxy)-N-(1-oxidopyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (100.0%) (13 mg, 0.0302 mmol, 17% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 9.10 (m, 1H), 8.58 (m, 1H), 8.54 (m, 1H), 8.19-8.13 (1H), 7.81 (n, NH), 7.58-7.41 (m, 4H), 3.80 (s, 3H). LC-MS Method 4: m/z 431.2 [M+H].sup.+, (ESI+), RT=2.63.

Example 87

[1144] Exemplary compounds of the invention are listed in Table 15 were prepared using one of the general routes described above.

TABLE-US-00016 TABLE 15 Compound Route Structure and name Analytical data 1573 2 [01492] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.04 (s, 1H), 8.69 (dd, J = 2.3, 0.9 Hz, 1H), 8.62 ? 8.53 (m, 1H), 8.40 (t, J = 1.9 Hz, 1H), 7.97 (dt, J = 7.6, 1.6 Hz, 1H), 7.73 7.65 (m, 2H), 7.40 ? 7.36 (m, 2H), 7.32 ? 7.27 (m, 1H), 3.22 (s, 3H), 2.13 (s, 3H). m/z 534.9 [M + H].sup.+, (ESI+), RT = 4.82 LC-MS Method 5 N-(3-methylsulfonylpheny1)- 2-[2-methyl-4- (trifluoromethoxy)phenoxy]- 5-(trifluoromethyl)pyridine- 3-carboxamide 1574 2 [01493] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.03 (s, 1H), 8.71 ? 8.65 (m, 1H), 8.62 ? 8.52 (m, 1H), 8.43 ? 8.35 (m, 1H), 7.97 (dt, J = 7.6, 1.7 Hz, 1H), 7.72 ? 7.63 (m, 2H), 7.27 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 (dd, J = 9.4, 3.0 Hz, 1H), 7.11 (td, J = 8.5, 3.1 Hz, 1H), 3.22 (s, 3H), 2.09 (s, 3H). m/z 468.9 [M + H].sup.+, (ESI+), RT = 4.49 LC-MS Method 5 2-(4-fluoro-2-methyl- phenoxy)-N-(3- methylsulfonylphenyl)-5- (trifluoromethyl)pyridine-3- carboxamide 1575 2 [01494] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.98 (s, 1H), 8.69 ? 8.62 (m, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.46 ? 8.35 (m, 1H), 7.98 (dt, J = 7.5, 1.7 Hz, 1H), 7.72 ? 7.65 (m, 2H), 7.32 (dd, J = 8.8, 5.9 Hz, 1H), 7.10 (dd, J = 10.7, 2.9 Hz, 1H), 6.84 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H), 3.22 (s, 3H). m/z 484.9 [M + H].sup.+, (ESI+), RT = 4.43 LC-MS Method 8 1576 [01495] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.66 (s, 1H), 8.74 (d, J = 5.3 Hz, 1H), 8.69 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 7.82 (ddd, J = 8.4, 4.4, 2.4 Hz, 1H), 7.67 ? 7.59 (m, 1H), 7.35 (dd, J = 8.6, 6.0 Hz, 1H), 7.12 (dd, J = 10.7, 2.8 Hz, 1H), 6.86 (td, J = 8.5, 2.8 Hz, 1H), 3.72 (s, 3H), 3.26 (s, 3H). m/z 503.0 [M + H].sup.+, (ESI+), RT = 4.57 LC-MS Method 5 1577 [01496] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.57 (s, 1H), 8.34 (q, J = 2.5 Hz, 2H), 7.71 (t, J = 1.8 Hz, 1H), 7.48 ? 7.43 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.8, 5.1 Hz, 1H), 7.16 (dd, J = 9.4, 3.0 Hz, 1H), 7.08 (td, J = 8.5, 3.1 Hz, 1H), 7.02 (ddd, J =7.8, 1.8, 0.9 Hz, 1H), 2.47 (s, 3H), 2.08 (s, 3H). m/z 446.95,448.95 [M + H].sup.+, (ESI+), RT = 1.47 LC-MS Method 1 1578 [01497] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.99 (s, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.38 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.27 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 (dd, J = 9.4, 2.9 Hz, 1H), 7.10 (dt, J = 8.5, 4.2 Hz, 1H), 4.23 (s, 1H), 3.06 (s, 3H), 2.08 (s, 3H). m/z 424.9 [M + H].sup.+, (ESI+), RT = 3.65 LC-MS Method 5 1579 [01498] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.65 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H), 7.70 (t, J = 1.8 Hz, 1H), 7.48 ? 7.41 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.26 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 (dd, J = 9.4, 3.0 Hz, 1H), 7.11 (td, J = 8.5, 3.1 Hz, 1H), 7.07 ? 6.98 (m, 1H), 2.47 (s, 3H), 2.07 (s, 3H). m/z 393.9 [M + H].sup.+, (ESI+), RT = 4.76 LC-MS Method 5 1581 2 [01499] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.20 (s, 1H), 9.31 (s, 1H), 8.68 ? 8.65 (m, 1H), 8.63 ? 8.59 (m, 1H), 8.55 (s, 1H), 8.47 ? 8.42 (m, 1H), 8.29 ? 8.22 (m, 1H), 8.02 (dt, J = 7.1, 2.0 Hz, 1H), 7.99 ? 7.94 (m, 1H), 7.85 ? 7.74 (m, 2H), 7.73 ? 7.66 (m, 2H), 3.22 (s, 3H). m/z 488.5 [M + H].sup.+, (ESI+), RT = 3.96 LC- MS Method 5 1582 2 [01500] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.21 (s, 1H), 8.72 ? 8.66 (m, 1H), 8.66 ? 8.60 (m, 1H), 8.47 ? 8.41 (m, 2H), 8.40 ? 8.33 (m, 1H), 8.10 ? 8.05 (m, 1H), 8.02 (dt, J = 7.5, 1.8 Hz, 1H), 7.98 ? 7.87 (m, 2H), 7.74 ? 7.66 (m, 2H), 3.23 (s, 3H). m/z 522.5 [M + H].sup.+, (ESI+), RT = 4.49 LC-MS Method 5 1583 2 [01501] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.20 (s, 1H), 9.45 (s, 1H), 8.70 (d, J = 5.9 Hz, 1H), 8.68 ? 8.65 (m, 1H), 8.65 ? 8.62 (m, 1H), 8.44 ? 8.42 (m, 1H), 8.01 (dt, J = 7.3, 1.8 Hz, 1H), 7.99 (dd, J = 5.9, 0.9 Hz, 1H), 7.76 ? 7.66 (m, 3H), 7.63 (dd, J = 8.5, 4.2 Hz, 1H), 3.22 (s, 3H). m/z 506.5 [M + H].sup.+, (ESI+), RT = 4.04 LC-MS Method 5 1584 2 [01502] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.95 (s, 1H), 8.73 ? 8.67 (m, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.98 ? 7.92 (m, 1H), 7.72 ? 7.66 (m, 1H), 7.64 ? 7.57 (m, 1H), 7.45 ? 7.36 (m, 2H), 7.35 ? 7.25 (m, 2H), 7.20 ? 7.12 (m, 1H), 7.12 ? 6.98 (m, 4H), 4.22 (s, 1H), 3.06 (s, 3H). m/z 528.0 [M + H].sup.+, (ESI+), RT = 4.45 LC-MS Method 5 1585 2 [01503] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.97 (s, 1H), 8.74 ? 8.68 (m, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.38 (t, J = 1.9 Hz, 1H), 7.99 ? 7.93 (m, 1H), 7.77 ? 7.72 (m, 2H), 7.71 ? 7.66 (m, 3H), 7.65 ? 7.59 (m, 1H), 7.51 ? 7.45 (m, 2H), 7.40 ? 7.34 (m, 3H), 4.23 (s, 1H), 3.06 (s, 3H). m/z 512.0 [M + H].sup.+, (ESI+), RT = 4.47 LC-MS Method 1 1586 2 [01504] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.96 (s, 1H), 8.74 ? 8.68 (m, 1H), 8.58 ? 8.53 (m, 1H), 8.37 (t, J = 1.8 Hz, 1H), 8.27 ? 8.21 (m, 1H), 8.13 (s, 1H), 8.01 ? 7.91 (m, 1H), 7.77 ? 7.68 (m, 3H), 7.67 ? 7.58 (m, 1H), 7.47 ? 7.39 (m, 2H), 7.17 ? 7.08 (m, 1H), 4.23 (s, 1H), 3.06 (s, 3H). m/z 501.9 [M + H].sup.+, (ESI+), RT = 2.86 LC-MS Method 5 1587 2 [01505] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.92 (s, 1H), 8.69 ? 8.63 (m, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.99 ? 7.91 (m, 1H), 7.73 ? 7.66 (m, 1H), 7.66 ? 7.55 (m, 1H), 7.49 ? 7.44 (m, 2H), 7.43 ? 7.37 (m, 2H), 7.36 ? 7.31 (m, 1H), 7.21 ? 7.16 (m, 2H), 7.10 ? 7.04 (m, 2H), 5.12 (s, 2H), 4.22 (s, 1H), 3.08 ? 3.03 (m, 3H). m/z 541.9 [M + H].sup.+, (ESI+), RT = 4. 6 LC-MS Method 5 1588 2 [01506] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.93 (s, 1H), 8.70 ? 8.63 (m, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.41 ? 8.33 (m, 1H), 7.99 ? 7.91 (m, 1H), 7.72 ? 7.66 (m, 1H), 7.66 ? 7.57 (m, 1H), 7.26 ? 7.15 (m, 2H), 7.15 ? 7.08 (m, 2H), 4.22 (s, 1H), 3.89 ? 3.80 (m, 1H), 3.06 (s, 3H), 0.82 ? 0.75 (m, 2H), 0.71 ? 0.61 (m, 2H). m/z 492.5 [M + H].sup.+, (ESI+), RT = 4.16 LC-MS Method 5 1589 3 [01507] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.55 (s, 2H), 8.46 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.86 ? 7.78 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.17 (s, 3H), 2.32 (s, 3H). 2 NH not seen. m/z 469.0 [M + H].sup.+, (ESI+), RT = 3.01 LC- MS Method 4 1590 3 [01508] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.69 ? 8.61 (m, 1H), 8.55 ? 8.37 (m, 2H), 8.05 ? 7.98 (m, 1H), 7.89 ? 7.75 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 3H), 2.12 (s, 3H) 2NH not seen. m/z 454.2 [M + H].sup.+, (ESI+), RT = 2.39 LC-MS Method 4 1591 3 [01509] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.60 ? 8.54 (m, 1H), 8.54 ? 8.48 (m, 1H), 8.47 ? 8.40 (m, 1H), 8.04 ? 7.97 (m, 1H), 7.86 ? 7.77 (m, 1H), 7.73 ? 7.58 (m, 2H), 7.55 (dd, J = 9.1, 2.9 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 3.99 (s, 3H), 3.17 (s, 3H). 2 NH not seen. m/z 491.2 [M + H].sup.+, (ESI+), RT = 2.99 LC-MS Method 4 1592 3 [01510] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.59 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.43 (t, J = 1.8 Hz, 1H), 8.03 ? 7.97 (m, 1H), 7.84 ? 7.78 (m, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.30 ? 7.18 (m, 3H), 3.86 (s, 3H), 3.17 (s, 3H). 2NH not seen. m/z 491.2 [M + H].sup.+, (ESI+), RT = 3.17 LC-MS Method 6 1593 3 [01511] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.76 ? 8.51 (m, 2H), 8.46 (t, J = 1.8 Hz, 1H), 8.08 ? 7.96 (m, 1H), 7.93 ? 7.73 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.7, 3.2 Hz, 1H), 3.17 (s, 3H), 2.32 (s, 3H). 2 exchangeable Hs not seen. m/z 469.7 [M + H].sup.+, (ESI+), RT = 2.88 LC- MS Method 6. Chiral Analysis Conditions Chiralpak IG (4.6 mm ? 250 mm, 5um) Column Temperature 40? C. Flow Rate 4 mL/min Injection Volume 1.0 uL BPR 125 BarG Isocratic Conditions 50:50 MeOH:CO2 (0.1%% v/v NH3). Chiral LC m/z 469.2 [M + H].sup.+, (ESI+), RT = 2.06 1594 3 [01512] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.63 ? 8.51 (m, 2H), 8.46 (t, J = 1.9 Hz, 1H), 8.05 ? 7.97 (m, 1H), 7.86 ? 7.76 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.7, 3.1 Hz, 1H), 3.17 (s, 3H), 2.32 (s, 3H). 2 exchangeable Hs not seen. m/z 469.7 [M + H].sup.+, (ESI+), RT = 2.88 LC- MS Method 6. Chiralpak IG (4.6mm x 250mm, 5um) Column Temperature 40?? C. Flow Rate 4 mL/min Injection Volume 1.0 uL BPR 125 BarG Isocratic Conditions 50:50 MeOH:CO2 (0.1%% v/v NH3). Chiral LC m/z 469.2 [M + H].sup.+, (ESI+), RT = 3.23 1595 2 [01513] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.05 (s, 1H), 8.72 ? 8.63 (m, 1H), 8.59 (d, J = 2.2 Hz, 1H), 8.41 ? 8.32 (m, 1H), 7.99 ? 7.91 (m, 1H), 7.76 ? 7.72 (m, 1H), 7.72 ? 7.61 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H), 3.21 (s, 3H), 2.17 (s, 3H). m/z 519.1 [M + H].sup.+, (ESI+), RT = 4.04 LC-MS Method 4 1596 2 [01514] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.83 (s, 1H), 8.77 (dd, J = 2.4, 1.0 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H), 7.87 (dt, J = 7.5, 1.8 Hz, 1H), 7.69 ? 7.60 (m, 2H), 7.48 (dd, J = 8.4, 6.1 Hz, 1H), 7.06 (dd, J = 10.0, 2.6 Hz, 1H), 6.97 (td, J = 8.6, 2.7 Hz, 1H), 5.50 (s, 2H), 3.19 (s, 3H), 2.33 (s, 3H). m/z 483.1 [M + H].sup.+, (ESI+), RT = 4.08 LC-MS Method 4 1597 2 [01515] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.03 (s, 1H), 8.74 ? 8.71 (m, 1H), 8.62 (d, J = 7.3 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.40 (t, J = 1.9 Hz, 1H), 8.17 (s, 1H), 7.99 (dt, J = 7.6, 1.8 Hz, 1H), 7.96 (s, 1H), 7.74 ? 7.64 (m, 2H), 7.57 (d, J = 1.0 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 7.4, 2.3 Hz, 1H), 3.23 (s, 3H). m/z 477.2 [M + H].sup.+, (ESI+), RT = 1.67 LC-MS Method 4 1598 2 [01516] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.98 (s, 1H), 10.41 (s, 1H), 8.69 ? 8.63 (m, 1H), 8.50 (d, J = 2.5 Hz, 1H), 8.42 ? 8.35 (m, 1H), 7.97 (dt, J = 7.2, 1.9 Hz, 1H), 7.74 ? 7.61 (m, 2H), 7.15 (s, 1H), 7.06 (dd, J = 8.3, 2.3 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.52 (s, 2H), 3.22 (s, 3H). m/z 492.5 [M + H].sup.+, (ESI+), RT = 3.66 LC-MS Method 5 1599 2 [01517] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.39 (s, 1H), 8.66 (d, J = 1.4 Hz, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.53 (dd, J =6.8, 0.9 Hz, 1H), 8.44 (t, J = 1.8 Hz, 1H), 8.05 (d, J = 1.2 Hz, 1H), 8.01 (dt, J = 7.4, 1.8 Hz, 1H), 7.73 ? 7.63 (m, 2H), 7.54 (d, J = 1.1 Hz, 1H), 7.36 ? 7.31 (m, 1H), 6.99 (t, J = 7.1 Hz, 1H), 3.32 (s, 3H). m/z 476.8 [M + H].sup.+, (ESI+), RT = 3.13 LC- MS Method 5 1600 2 [01518] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.72 (s, 1H), 8.75 (dd, J = 2.4, 1.0 Hz, 1H), 8.40 ? 8.34 (m, 2H), 7.94 (dt, J = 7.3, 1.8 Hz, 1H), 7.73 ? 7.62 (m, 2H), 4.52 (q, J = 7.0 Hz, 2H), 3.22 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H). m/z 388.9 [M + H].sup.+, (ESI+), RT = 4.24 LC-MS Method 5 1601 2 [01519] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.01 (s, 1H), 10.50 (s, 1H), 8.69 (dd, J = 2.4, 0.9 Hz, 1H), 8.55 ? 8.50 (m, 1H), 8.38 (t, J = 1.8 Hz, 1H), 7.97 (dt, J = 7.3, 1.9 Hz, 1H), 7.74 ? 7.58 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.0, 2.2 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 3.49 (s, 2H), 3.22 (s, 3H). m/z 491.9 [M + H].sup.+, (ESI+), RT = 3.72 LC-MS Method 5 1602 2 [01520] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.72 (s, 1H), 8.74 (dd, J = 2.4, 0.9 Hz, 1H), 8.38 (d, J = 2.1 Hz, 2H), 7.95 (dt, J = 7.0, 2.0 Hz, 1H), 7.73 ? 7.63 (m, 2H), 4.33 (d, J = 7.1 Hz, 2H), 3.23 (s, 3H), 1.37 ? 1.24 (m, 1H), 0.62 ? 0.51 (m, 2H), 0.45 ? 0.36 (m, 2H). m/z 415.5 [M + H].sup.+, (ESI+), RT = 4.51 LC-MS Method 5 1603 2 [01521] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.00 (s, 1H), 8.69 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.78 ? 7.60 (m, 3H), 7.34 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 3.22 (s, 3H). m/z 546.5, 548.4 [M + H].sup.+, (ESI+), RT = 4.56 LC-MS Method 5 1604 2 [01522] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.66 (s, 1H), 8.79 (dd, J = 2.4, 1.0 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.39 ? 8.35 (m, 1H), 7.91 (dt, J = 7.2, 1.9 Hz, 1H), 7.73 ? 7.61 (m, 2H), 4.69 (t, J = 6.0 Hz, 2H), 3.22 (s, 3H), 2.87 (m, 2H). m/z 457.5 [M + H].sup.+, (ESI+), RT = 4.32 LC-MS Method 5 1605 [01523] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.66 (s, 1H), 8.78 (dd, J =2.4, 1.0 Hz, 1H), 8.43 ? 8.38 (m, 1H), 8.38 ? 8.33 (m, 1H), 7.91 (dt, J = 7.2, 1.9 Hz, 1H), 7.72 ? 7.63 (m, 2H), 4.62 ? 4.55 (m, 2H), 3.34 (m, 1H), 3.21 (s, 3H), 2.48 ? 2.41 (m, 2H), 1.98 ? 1.83 (m, 1H), 1.73 ? 1.59 (m, 1H). m/z 465.5 [M + H].sup.+, (ESI+), RT = 4.44 LC-MS Method 5 1606 [01524] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.63 (s, 1H), 8.78 (dd, J = 2.5, 1.0 Hz, 1H), 8.44 ? 8.38 (m, 1H), 8.37 ? 8.32 (m, 1H), 7.88 (dt, J = 7.7, 1.8 Hz, 1H), 7.71 ? 7.62 (m, 2H), 7.46 ? 7.40 (m, 1H), 5.61 ? 5.52 (m, 1H), 3.62 ? 3.51 (m, 1H), 3.45 ? 3.37 (m, 1H), 3.23 (s, 3H), 2.35 ? 2.24 (m, 1H), 2.23 ? 2.05 (m, 3H). m/z 458.5 [M + H].sup.+, (ESI+), RT = 3.53 LC-MS Method 5 1607 3 [01525] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.93 (s, 1H), 8.73 ? 8.70 (m, 1H), 8.62 ? 8.58 (m, 1H), 8.33 (t, J = 1.9 Hz, 1H), 7.96 ? 7.91 (m, 1H), 7.76 (dd, J = 8.5, 3.0 Hz, 1H), 7.73 ? 7.58 (m, 4H), 4.23 (s, 1H), 3.10 ? 3.02 (m, 3H). m/z 521.8 [M + H].sup.+, (ESI+), RT = 4.16 LC-MS Method 5 1608 2 [01526] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.99 (s, 1H), 8.67 (dd, J = 2.4, 1.0 Hz, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.44 ? 8.35 (m, 1H), 7.98 (dt, J = 7.3, 1.9 Hz, 1H), 7.74 ? 7.63 (m, 2H), 7.58 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H), 3.22 (s, 3H), 2.42 (s, 3H). m/z 482.5 [M + H].sup.+, (ESI+), RT = 4.41 LC-MS Method 5 1609 3 [01527] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.92 (s, 1H), 8.69 ? 8.63 (m, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.39 ? 8.34 (m, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.72 ? 7.65 (m, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.21 ? 7.10 (m, 2H), 7.03 ? 6.91 (m, 2H), 4.21 (s, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.06 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). m/z 480.5 [M + H].sup.+, (ESI+), RT = 4.09 LC-MS Method 5 1610 2 [01528] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.00 (s, 1H), 8.74 (dd, J = 2.4, 0.9 Hz, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.40 ? 8.35 (m, 1H), 7.97 (dt, J = 7.3, 1.9 Hz, 1H), 7.89 (s, 1H), 7.73 ? 7.62 (m, 2H), 7.48 (s, 1H), 3.83 (s, 3H), 3.22 (s, 3H). m/z 441.5 [M + H].sup.+, (ESI+), RT = 3.72 LC- MS Method 5 1611 2 [01529] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.68 (dd, J = 2.4, 1.0 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.43 ? 8.35 (m, 1H), 7.95 (dt, J = 7.3, 1.9 Hz, 1H), 7.73 ? 7.62 (m, 2H), 3.65 (s, 3H), 3.22 (s, 3H), 2.07 (s, 3H), 1.94 (s, 3H). m/z 469.5 [M + H].sup.+, (ESI+), RT = 3.84 LC- MS Method 5 1612 2 [01530] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.73 ? 8.67 (m, 1H), 8.58 ? 8.52 (m, 1H), 8.39 ? 8.31 (m, 1H), 7.97 (dt, J = 7.4, 1.9 Hz, 1H), 7.74 ? 7.61 (m, 2H), 7.58 ? 7.50 (m, 2H), 7.35 ? 7.24 (m, 2H), 3.22 (s, 3H), 1.38 ? 1.31 (m, 2H), 1.20 ? 1.11 (m, 2H). m/z 544.9 [M + H].sup.+, (ESI+), RT = 4.74 LC-MS Method 5 1613 2 [01531] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.05 (s, 1H), 8.72 (d, J = 1.4 Hz, 1H), 8.62 ? 8.58 (m, 1H), 8.41 ? 8.37 (m, 1H), 7.99 (dt, J = 7.4, 1.9 Hz, 1H), 7.75 ? 7.63 (m, 2H), 7.45 (t, J = 9.0 Hz, 1H), 7.10 (dd, J = 9.4, 1.8 Hz, 1H), 3.92 (s, 3H), 3.22 (s, 3H). m/z 518.8 [M + H].sup.+, (ESI+), RT = 4.49 LC-MS Method 5 1614 2 [01532] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.02 (s, 1H), 8.75 ? 8.68 (m, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.43 ? 8.35 (m, 1H), 7.98 (dt, J = 7.4, 1.9 Hz, 1H), 7.74 ? 7.62 (m, 2H), 7.49 (dd, J = 11.3, 7.4 Hz, 1H), 7.37 (dd, J = 11.9, 8.0 Hz, 1H), 3.88 (s, 3H), 3.22 (s, 3H). m/z 502.9 [M + H].sup.+, (ESI+), RT = 4.33 LC-MS Method 5 1615 2 [01533] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.96 (s, 1H), 8.71 ? 8.66 (m, 1H), 8.55 (d, J = 2.4 Hz, 1H), 8.40 (t, J = 2.0 Hz, 1H), 7.97 (dt, J = 7.8, 1.9 Hz, 1H), 7.73 ? 7.64 (m, 2H), 7.55 (dd, J = 10.7, 8.3 Hz, 1H), 7.38 (dd, J = 12.5, 7.7 Hz, 1H), 3.70 (s, 3H), 3.22 (s, 3H). m/z 503.0 [M + H].sup.+, (ESI+), RT = 3.86 LC-MS Method 4 1616 2 [01534] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.05 (s, 1H), 8.69 (dd, J = 2.4, 1.1 Hz, 1H), 8.60 (d, J = 2.5 Hz, 1H), 8.40 (t, J = 1.9 Hz, 1H), 7.97 (dt, J = 7.5, 1.9 Hz, 1H), 7.75 ? 7.61 (m, 3H), 7.32 (s, 1H), 3.22 (s, 3H), 2.41 (s, 3H), 2.13 (s, 3H). m/z 533.1 [M + H].sup.+, (ESI+), RT = 4.21 LC- MS Method 4 1617 3 [01535] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.88 (s, 1H), 8.68 (dd, J =2.4, 1.1 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H), 8.38 (t, J = 2.0 Hz, 1H), 7.94 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H), 7.69 (dt, J = 7.9, 1.4 Hz, 1H), 7.65 ? 7.48 (m, 2H), 7.38 (dd, J = 12.6, 7.7 Hz, 1H), 4.23 (s, 1H), 3.70 (s, 3H), 3.06 (s, 3H). m/z 502.1 [M + H].sup.+, (ESI+), RT = 3.24 LC-MS Method 4 1618 3 [01536] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.02 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.41 (dd, J = 9.1, 5.7 Hz, 1H), 7.31 (t, J = 9.0 Hz, 1H), 4.24 (s, 1H), 3.75 (s, 3H), 3.06 (s, 3H). m/z 518.1, 520.1 [M + H].sup.+, (ESI+), RT = 3.36 LC-MS Method 4 1619 5 [01537] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.76 (s, 1H), 8.70 ? 8.65 (m, 1H), 8.55 (d, J = 2.5 Hz, 1H), 8.19 (t, J = 1.9 Hz, 1H), 7.98 (s, 1H), 7.92 ? 7.83 (m, 1H), 7.65 ? 7.59 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.31 ? 7.18 (m, 2H), 3.80 (d, J = 1.2 Hz, 3H). m/z 468.2 [M + H].sup.+, (ESI+), RT = 3.32 LC-MS Method 4 1620 3 [01538] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.90 (s, 1H), 8.70 ? 8.63 (m, 1H), 8.55 (d, J = 2.5 Hz, 1H), 8.39 (t, J = 2.0 Hz, 1H), 7.99 ? 7.90 (m, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.81 (dd, J = 8.6, 2.1 Hz, 1H), 7.72 ? 7.66 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 4.26 ? 4.20 (m, 1H), 3.80 (s, 3H), 3.09 ? 3.03 (m, 3H). m/z 491.2 [M + H].sup.+, (ESI+), RT = 2.96 LC-MS Method 4 1621 3 [01539] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.93 (s, 1H), 8.67 (dd, J = 2.4, 1.1 Hz, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.39 (t, J = 2.0 Hz, 1H), 7.97 ? 7.88 (m, 1H), 7.75 ? 7.66 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.25 (s, 1H), 4.27 ? 4.21 (m, 1H), 3.93 (s, 3H), 3.11 ? 3.02 (m, 3H), 2.18 (s, 3H). m/z 505.0 [M + H].sup.+, (ESI+), RT = 3.20 LC-MS Method 4 1622 3 [01540] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.64 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.57 ? 8.54 (m, 1H), 8.44 (t, J = 2.0 Hz, 1H), 8.17 (d, J = 2.2 Hz, 1H), 8.04 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.82 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.17 (s, 3H). m/z 510.5 [M + H].sup.+, (ESI+), RT = 2.33 LC-MS Method 4 1623 3 [01541] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.60 ? 8.55 (m, 2H), 8.51 (d, J = 2.0 Hz, 1H), 8.43 (t, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.03 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H), 7.82 (ddd, J = 7.9, 1.9, 1.1 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.17 (s, 3H). m/z 492.4 [M + H].sup.+, (ESI+), RT = 3.00 LC-MS Method 4 1624 2 [01542] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.10 (s, 1H), 8.62 ? 8.58 (m, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.44 ? 8.40 (m, 1H), 7.99 (dt, J = 7.3, 1.9 Hz, 1H), 7.72 ? 7.65 (m, 2H), 7.39 ? 7.34 (m, 1H), 7.29 (d, J = 3.1 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.23 ? 6.17 (m, 1H), 3.81 (s, 3H), 3.21 (s, 3H). m/z 489.9 [M + H].sup.+, (ESI+), RT = 4.35 LC- MS Method 5 1625 2 [01543] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.18 (s, 1H), 8.64 (d, J = 2.3 Hz, 1H), 8.62 ? 8.56 (m, 1H), 8.43 (t, J = 1.8 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.00 (dt, J = 7.6, 1.8 Hz, 1H), 7.91 ? 7.84 (m, 1H), 7.81 ? 7.74 (m, 1H), 7.74 ? 7.65 (m, 2H), 7.50 ? 7.45 (m, 1H), 7.44 (d, J = 8.5 Hz, 1H), 3.22 (s, 3H), 2.66 (s, 3H). m/z 501.9 [M + H].sup.+, (ESI+), RT = 3.45 LC-MS Method 5 1626 2 [01544] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.96 (s, 1H), 8.68 ? 8.64 (m, 1H), 8.50 (d, J = 2.4 Hz, 1H), 8.40 (t, J = 1.7 Hz, 1H), 7.99 (dt, J = 7.5, 1.7 Hz, 1H), 7.72 ? 7.65 (m, 2H), 7.08 (dd, J = 7.9, 1.3 Hz, 1H), 7.01 ? 6.95 (m, 1H), 6.87 (t, J = 7.8 Hz, 1H), 4.07 ? 3.98 (m, 2H), 3.22 (s, 3H), 2.78 (t, J = 6.4 Hz, 2H), 1.88 (p, J = 6.3 Hz, 2H). m/z 492.9 [M + H].sup.+, (ESI+), RT = 4.55 LC-MS Method 5 1627 2 [01545] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.03 (s, 1H), 8.72 ? 8.66 (m, 1H), 8.58 ? 8.52 (m, 1H), 8.41 ? 8.37 (m, 1H), 7.97 (dt, J = 7.4, 1.8 Hz, 1H), 7.73 ? 7.65 (m, 2H), 7.25 (dd, J = 8.9, 5.2 Hz, 1H), 7.06 (td, J = 8.5, 3.1 Hz, 1H), 6.83 (dd, J = 10.1, 3.0 Hz, 1H), 3.22 (s, 3H), 1.94 ? 1.82 (m, 1H), 0.86 ? 0.74 (m, 2H), 0.70 ? 0.57 (m, 2H). m/z 495.5 [M + H].sup.+, (ESI+), RT = 4.57 LC-MS Method 5 1628 2 [01546] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.00 (s, 1H), 8.69 ? 8.60 (m, 1H), 8.57 ? 8.49 (m, 1H), 8.41 ? 8.36 (m, 1H), 7.98 (dt, J = 7.4, 1.9 Hz, 1H), 7.73 ? 7.64 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.4, 2.3 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.22 (s, 3H), 2.09 (s, 3H), 1.29 (s, 9H). m/z 507.6 [M + H].sup.+, (ESI+), RT = 5.01 LC-MS Method 5 1629 [01547] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.75 (s, 1H), 8.76 ? 8.72 (m, 1H), 8.40 ? 8.35 (m, 2H), 7.94 (dt, J = 6.7, 2.2 Hz, 1H), 7.72 ? 7.65 (m, 2H), 4.73 (s, 2H), 3.22 (s, 3H), 2.02 (d, J = 2.7 Hz, 6H). m/z 458.9 [M + H].sup.+, (ESI+), RT = 4.46 LC- MS Method 5 1630 3 [01548] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.99 (s, 1H), 8.72 ? 8.67 (m, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.38 (t, J = 1.9 Hz, 1H), 7.98 ? 7.92 (m, 1H), 7.72 ? 7.68 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.31 ? 7.19 (m, 2H), 4.23 (s, 1H), 3.80 (d, J = 0.9 Hz, 3H), 3.06 (s, 3H). m/z 501.9 [M + H].sup.+, (ESI+), RT = 4.06 LC-MS Method 5 1631 3 [01549] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.66 (s, 1H), 8.73 ? 8.67 (m, 1H), 8.39 ? 8.31 (m, 2H), 7.93 ? 7.87 (m, 1H), 7.71 ? 7.65 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 4.47 (s, 2H), 4.23 (s, 1H), 3.05 (s, 3H), 2.20 (s, 6H). m/z 465.0 [M + H].sup.+, (ESI+), RT = 3.16 LC-MS Method 4 1632 3 [01550] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.65 (s, 1H), 8.73 ? 8.66 (m, 1H), 8.39 ? 8.31 (m, 2H), 7.91 ? 7.82 (m, 1H), 7.70 ? 7.63 (m, 1H), 7.59 (t, J = 7.9 Hz, 1H), 5.27 (p, J = 7.1 Hz, 1H), 4.22 (s, 1H), 3.05 (s, 3H), 2.73 ? 2.57 (m, 6H), 2.37 ? 2.26 (m, 2H). m/z 490.3 [M + H].sup.+, (ESI+), RT = 3.67 LC-MS Method 6 1633 3 [01551] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.79 (s, 1H), 8.78 ? 8.71 (m, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.33 (t, J = 1.9 Hz, 1H), 7.91 ? 7.84 (m, 1H), 7.70 ? 7.64 (m, 1H), 7.58 (t, J = 7.9 Hz, 1H), 4.22 (s, 1H), 3.04 (s, 3H), 2.58 (s, 6H). m/z 494.2 [M + H].sup.+, (ESI+), RT = 3.86 LC- MS Method 6 1634 5 [01552] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.57 (s, 1H), 8.80 ? 8.72 (m, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.14 (t, J = 1.9 Hz, 1H), 7.96 (s, 1H), 7.86 ? 7.76 (m, 1H), 7.65 ? 7.56 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 2.58 (s, 6H). m/z 458.2 [M ? H]? , (ESI?), RT = 3.93 LC-MS Method 6 1635 5 [01553] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.74 (s, 1H), 8.70 ? 8.64 (m, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.17 (t, J = 1.9 Hz, 1H), 7.99 (s, 1H), 7.93 ? 7.86 (m, 1H), 7.66 ? 7.59 (m, 1H), 7.48 ? 7.03 (m, 7H). m/z 468.0 [M + H].sup.+, (ESI+), RT = 3.38 LC- MS Method 4 1636 3 [01554] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.02 (s, 1H), 8.75 ? 8.69 (m, 1H), 8.66 ? 8.60 (m, 1H), 8.39 ? 8.34 (m, 1H), 8.30 (dd, 1H), 8.09 (dd, 1H), 7.99 ? 7.92 (m, 1H), 7.74 ? 7.66 (m, 1H), 7.66 ? 7.55 (m, 2H), 4.24 (s, 1H), 3.06 (s, 3H). m/z 521.1 [M + H].sup.+, (ESI+), RT = 3.13 LC- MS Method 4 1637 3 [01555] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.97 (s, 1H), 8.73 ? 8.68 (m, 1H), 8.60 ? 8.55 (m, 1H), 8.40 ? 8.36 (m, 1H), 7.97 ? 7.92 (m, 1H), 7.72 ? 7.67 (m, 1H), 7.64 ? 7.58 (m, 1H), 7.53 ? 7.45 (m, 1H), 7.40 ? 7.33 (m, 1H), 4.23 (s, 1H), 3.88 (s, 3H), 3.08 ? 3.04 (m, 3H). m/z 502.1 [M + H].sup.+, (ESI+), RT = 3.19 LC-MS Method 4 1638 5 [01556] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.74 (s, 1H), 8.73 ? 8.68 (m, 1H), 8.57 ? 8.53 (m, 1H), 8.21 ? 8.16 (m, 1H), 8.03 ? 7.94 (m, 1H), 7.92 ? 7.86 (m, 1H), 7.66 ? 7.60 (m, 1H), 7.53 ? 7.48 (m, 1H), 7.48 ? 7.43 (m, 1H), 7.40 ? 7.34 (m, 2H), 3.88 (s, 3H). m/z 485.3 [M + NH4].sup.+, (ESI+), RT = 3.33 LC-MS Method 6 1639 3 [01557] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.97 (s, 1H), 8.71 ? 8.68 (m, 1H), 8.59 ? 8.56 (m, 1H), 8.40 ? 8.37 (m, 1H), 7.96 ? 7.91 (m, 1H), 7.80 (d, J = 10.4 Hz, 1H), 7.72 ? 7.67 (m, 1H), 7.62 (t, J = 7.9 Hz, 1H), 4.24 (s, 1H), 3.95 (s, 3H), 3.06 (s, 3H), 2.22 (s, 3H). m/z 499.3 [M + H].sup.+, (ESI+), RT = 3.44 LC-MS Method 6 1640 3 [01558] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.93 (s, 1H), 8.71 ? 8.67 (m, 1H), 8.54 ? 8.50 (m, 1H), 8.38 ? 8.35 (m, 1H), 7.97 ? 7.91 (m, 1H), 7.72 ? 7.66 (m, 1H), 7.64 ? 7.58 (m, 1H), 7.30 ? 7.20 (m, 2H), 7.11 ? 7.06 (m, 1H), 4.23 (s, 1H), 3.86 (s, 3H), 3.06 (s, 3H). m/z 484.3 [M + H]*, (ESI+), RT = 3.20 LC-MS Method 6 1642 3 [01559] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.74 ? 8.71 (m, 1H), 8.65 ? 8.62 (m, 1H), 8.39 ? 8.36 (m, 1H), 8.30 (dd, J = 4.8, 1.6 Hz, 1H), 8.09 (dd, J = 8.0, 1.6 Hz, 1H), 7.98 ? 7.94 (m, 1H), 7.72 ? 7.68 (m, 1H), 7.64 ? 7.57 (m, 2H), 4.24 (s, 1H), 3.07 ? 3.05 (m, 3H). m/z 521.2 [M + H].sup.+, (ESI+), RT = 3.26 1643 3 [01560] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.74 ? 8.71 (m, 1H), 8.65 ? 8.62 (m, 1H), 8.39 ? 8.36 (m, 1H), 8.30 (dd, J = 4.8, 1.6 Hz, 1H), 8.09 (dd, J = 8.0, 1.6 Hz, 1H), 7.98 ? 7.94 (m, 1H), 7.72 ? 7.68 (m, 1H), 7.64 ? 7.58 (m, 2H), 4.24 (s, 1H), 3.07 ? 3.05 (m, 3H). m/z 521.2 [M + H].sup.+, (ESI+), RT = 4.03 1644 3 [01561] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.94 (s, 1H), 8.73 ? 8.71 (m, 1H), 8.57 ? 8.55 (m, 1H), 8.37 ? 8.35 (m, 1H), 7.96 ? 7.92 (m, 1H), 7.71 ? 7.67 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.51 ? 7.45 (m, 2H), 7.42 ? 7.10 (m, 2H), 4.23 (s, 1H), 3.07 ? 3.05 (m, 3H). m/z 520.1 [M + H].sup.+, (ESI+), RT = 3.28 LC-MS Method 4 1645 1 [01562] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.97 (s, 1H), 8.77 ? 8.71 (m, 1H), 8.61 ? 8.57 (m, 1H), 8.38 ? 8.34 (m, 1H), 7.95 ? 7.91 (m, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.71 ? 7.67 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.24 ? 7.21 (m, 1H), 7.02 (dd, J = 8.5, 2.1 Hz, 1H), 4.24 (s, 1H), 3.89 (s, 3H), 3.06 (s, 3H). m/z 491.1 [M + H].sup.+, (ESI+), RT = 2.89 LC-MS Method 4 1646 [01563] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.99 (s, 1H), 8.73 ? 8.69 (m, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.40 ? 8.35 (m, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.00 ? 7.92 (m, 2H), 7.71 (t, J = 72.8 Hz, 1H), 7.72 ? 7.69 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 4.24 (s, 1H), 3.07 (s, 3H). m/z 501.3 [M ? H]?, (ESI+), RT = 3.12 LC-MS Method 4 1647 [01564] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.92 (s, 1H), 8.71 (d, J = 1.5 Hz, 1H), 8.55 ? 8.50 (m, 1H), 8.40 ? 8.34 (m, 1H), 7.98 ? 7.91 (m, 1H), 7.73 ? 7.66 (m, 1H), 7.66 ? 7.58 (m, 1H), 7.31 ? 7.20 (m, 2H), 7.10 ? 7.02 (m, 1H), 4.61 (hept, J = 6.0 Hz, 1H), 4.27 ? 4.22 (m, 1H), 3.07 (s, 3H), 1.30 (d, J = 6.0 Hz, 6H). m/z 512.2 [M + H].sup.+, (ESI+), RT = 3.59 LC- MS Method 6 1648 [01565] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.97 (s, 1H), 8.71 ? 8.66 (m, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.43 (dd, J = 8.6, 2.4 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 4.24 (s, 1H), 3.07 (s, 3H), 1.93 ? 1.82 (m, 1H), 0.82 ? 0.74 (m, 2H), 0.71 ? 0.62 (m, 2H). m/z 554.8, 556.7 [M + H].sup.+, (ESI+), RT = 3.82 LC-MS Method 6 1649 [01566] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.79 (s, 1H), 8.75 ? 8.69 (m, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.30 ? 7.20 (m, 1H), 7.17 ? 7.07 (m, 3H), 4.70 (hept, J = 6.1 Hz, 1H), 1.33 (d, J = 6.0 Hz, 6H). m/z 519.1 [M + H].sup.+, (ESI+), RT = 3.81 LC-MS Method 6 1650 [01567] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.23 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.34 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.74 ? 7.67 (m, 1H), 7.64 ? 7.58 (m, 2H), 7.20 (dt, J = 9.9, 5.1 Hz, 2H), 7.10 (td, J = 8.5, 3.3 Hz, 1H), 4.25 (s, 1H), 3.07 (s, 3H), 2.10 (s, 3H). m/z 468.1 [M + H].sup.+, (ESI+), RT = 2.87 LC-MS Method 6 1651 [01568] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.24 (s, 1H), 8.52 ? 8.47 (m, 1H), 8.34 (t, J = 1.9 Hz, 1H), 7.88 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.71 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.26 (q, J = 9.6 Hz, 1H), 7.14 (ddd, J = 9.3, 5.2, 2.2 Hz, 1H), 4.26 (s, 1H), 3.81 (d, J = 0.9 Hz, 3H), 3.10 ? 3.06 (m, 3H). m/z 502.1 [M + H].sup.+, (ESI+), RT = 2.88 LC-MS Method 6 1652 [01569] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.00 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.16 (t, J = 1.8 Hz, 1H), 8.00 (s, 1H), 7.82 ? 7.77 (m, 1H), 7.64 (dd, J = 8.9, 6.7 Hz, 2H), 7.45 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.25 (q, J = 9.5 Hz, 1H), 7.14 (ddd, J = 9.2, 5.1, 2.1 Hz, 1H), 3.83 ? 3.79 (m, 3H). m/z 485.1 [M + NH4].sup.+, (ESI+), RT = 2.89 LC-MS Method 6 1653 [01570] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.21 (s, 1H), 8.46 (d, J = 5.1 Hz, 1H), 8.33 (t, J = 1.8 Hz, 1H), 7.89 ? 7.83 (m, 1H), 7.74 ? 7.67 (m, 2H), 7.66 ? 7.57 (m, 2H), 7.52 (dd, J = 8.2, 1.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 4.25 (s, 1H), 3.78 (s, 3H), 3.11 ? 3.00 (m, 3H). m/z 491 [M + H].sup.+, (ESI+), RT = 2.56 LC-MS Method 6 1655 [01571] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.99 (s, 1H), 8.77 ? 8.69 (m, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.37 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 4.24 (s, 1H), 3.86 (s, 3H), 3.07 (s, 3H). m/z 492.2 [M + H].sup.+, (ESI+), RT = 3.01 LC-MS Method 4 1656 2 [01572] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.98 (s, 1H), 8.73 ? 8.67 (m, 1H), 8.56 ? 8.51 (m, 1H), 8.41 ? 8.36 (m, 1H), 7.97 (dt, J = 7.2, 1.8 Hz, 1H), 7.72 ? 7.64 (m, 2H), 7.43 ? 7.34 (m, 1H), 7.19 ? 7.15 (m, 2H), 7.07 ? 7.00 (m, 1H), 4.05 (d, J = 7.2 Hz, OH), 3.22 (s, 3H), 2.48 (s, 3H). m/z 483.0 [M + H].sup.+, (ESI+), RT = 4.52 LC-MS Method 5 1657 2 [01573] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.00 (s, 1H), 8.75 ? 8.71 (m, 1H)), 8.60 ? 8.55 (m, 1H), 8.41 ? 8.36 (m, 1H), 7.98 ? 7.94 (m, 1H), 7.73 ? 7.64 (m, 2H), 7.61 (t, J = 8.3 Hz, 1H), 7.40 (s, 1H), 7.38 ? 7.33 (m, 1H), 7.33 ? 7.29 (m, 1H), 3.22 (s, 3H). m/z 521.0 [M + H].sup.+, (ESI+), RT = 4.67 LC-MS Method 5 1658 2 [01574] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.04 (s, 1H), 8.76 ? 8.74 (m, 1H), 8.65 ? 8.61 (m, 1H), 8.41 ? 8.38 (m, 1H), 7.98 (dt, J = 7.3, 1.8 Hz, 1H), 7.73 ? 7.64 (m, 3H), 7.59 (t, J = 9.5 Hz, 1H), 7.46 ? 7.38 (m, 1H), 3.22 (s, 3H). m/z 539.0 [M + H].sup.+, (ESI+), RT = 4.68 LC-MS Method 5 1659 2 [01575] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.73 (s, 1H), 8.77 (dd, J = 2.3, 0.9 Hz, 1H), 8.43 ? 8.40 (m, 1H), 8.38 ? 8.36 (m, 1H), 7.93 (dt, J = 7.2, 1.9 Hz, 1H), 7.72 ? 7.69 (m, 1H), 7.69 ? 7.64 (m, 1H), 4.64 ? 4.57 (m, 1H), 4.53 ? 4.46 (m, 1H), 3.22 (s, 3H), 2.36 ? 2.25 (m, 1H), 1.79 ? 1.65 (m, 1H), 1.67 ? 1.53 (m, 1H). m/z 449.3 [M ? H]?, (ESI?), RT = 3.79 LC-MS Method 7 1660 2 [01576] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.75 (s, 1H), 8.75 (dd, J = 2.4, 1.0 Hz, 1H), 8.42 ? 8.37 (m, 1H), 8.38 ? 8.33 (m, 1H), 7.90 (dt, J = 7.1, 1.9 Hz, 1H), 7.73 ? 7.62 (m, 2H), 5.45 ? 5.37 (m, 1H), 3.21 (s, 3H), 2.06 ? 1.91 (m, 8H). m/z 477.3 [M ? H]?, (ESI?), RT = 3.92 LC- MS Method 7 1661 2 [01577] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.07 (s, 1H), 8.76 ? 8.70 (m, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.03 ? 7.96 (m, 1H), 7.74 ? 7.59 (m, 4H), 7.41 ? 7.32 (m, 1H), 3.22 (s, 3H). m/z 537.2 [M]?, (ESI?), RT = 4.12 LC-MS Method 7 1662 2 [01578] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.68 (s, 1H), 8.78 ? 8.73 (m, 1H), 8.41 ? 8.36 (m, 2H), 7.95 ? 7.87 (m, 1H), 7.73 ? 7.61 (m, 2H), 5.72 ? 5.66 (m, 1H), 3.95 (dd, J = 10.5, 4.6 Hz, 1H), 3.90 ? 3.84 (m, 1H), 3.84 ? 3.78 (m, 1H), 3.78 ? 3.73 (m, 1H), 3.22 (s, 3H), 2.31 ? 2.20 (m, 1H), 2.13 ? 2.03 (m, 1H). m/z 429.2 1663 2 [01579] [M]?, (ESI?), RT = 3.30 LC-MS Method 7 .sup.1H NMR (500 MHz, DMSO-d6) ? 10.77 (s, 1H), 8.82 ? 8.78 (m, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.38 ? 8.35 (m, 1H), 7.94 ? 7.89 (m, 1H), 7.72 ? 7.69 (m, 1H), 7.69 ? 7.65 (m, 1H), 6.57 ? 6.32 (m, 1H), 4.77 (td, J = 14.8, 3.5 Hz, 2H), 3.22 (s, 3H). m/z 423.2 [M] ?, (ESI ?), RT = 3.40 LC-MS Method 7 1664 2 [01580] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.05 (s, 1H), 8.71 ? 8.68 (m, 1H), 8.61 ? 8.54 (m, 1H), 8.41 ? 8.34 (m, 1H), 8.00 ? 7.95 (m, 1H), 7.73 ? 7.61 (m, 2H), 7.45 ? 7.38 (m, 1H), 7.39 ? 7.29 (m, 2H), 5.18 (s, 1H), 3.21 (s, 3H), 1.43 (s, 6H). m/z 535.1 [M + Na].sup.+, (ESI+), RT = 3.32 LC-MS Method 4 1665 3 [01581] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.68 (d, J = 10.5 Hz, 2H), 8.48 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 5.47 ? 5.39 (m, 1H), 3.59 (s, 3H), 3.16 ? 3.04 (m, 3H), 2.65 (m, 2H). m/z 439.2 [M + H].sup.+, (ESI+), RT = 2.74 LC-MS Method 4 1666 4 [01582] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.66 (s, 1H), 8.52 ? 8.43 (m, 2H), 7.98 (dd, J = 19.1, 7.9 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 5.50 ? 5.38 (m, 1H), 3.20 (s, 3H), 3.01 ? 2.76 (m, 3H), 2.45 ? 2.35 (m, 2H). m/z 482.2 [M + H].sup.+, (ESI+), RT = 3.38 and 3.50 LC-MS Method 4. Data supports product obtained as a mixture of diastereomers. 1667 [01583] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.65 (d, J = 1.5 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.22 (t, J = 1.8 Hz, 1H), 7.88 (dd, J = 8.1, 1.2 Hz, 1H), 7.69 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 5.44 (p, J = 7.1 Hz, 1H), 2.99 ? 2.75 (m, 3H), 2.43 (m, 2H). m/z 465.3 [M + NH4].sup.+, (ESI+), RT = 3.54 and 3.69 LC-MS Method 6 Data supports product obtained as a mixture of diastereomers. 1668 4 [01584] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.65 (m, 1H), 8.48 (m, 1H), 8.21 (t, 1H), 7.93 (m, 1H), 7.69 (dd, J = 8.0, 1.4 Hz, 1H), 7.51 (m, 1H), 5.47 ? 5.36 (m, 1H), 3.15 ? 3.01 (m, 3H), 2.67 (m, 1H). m/z 405.2 [M + H].sup.+, (ESI+), RT = 2.83 and 2.87 LC-MS Method 4. Data supports product obtained as a mixture of diastereomers. 1669 3 [01585] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.58 ? 8.52 (m, 2H), 8.46 (t, J = 1.8 Hz, 1H), 8.05 ? 7.99 (m, 1H), 7.86 ? 7.80 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.7 Hz, 1H), 5.13 (p, J = 7.3 Hz, 1H), 3.19 (s, 3H), 2.54 ? 2.44 (m, 2H), 2.26 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H). m/z 521.2 [M + H].sup.+, (ESI+), RT = 3.62 LC-MS Method 4 1670 5 [01586] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.65 (s, 1H), 8.47 (m, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 5.45 (p, J = 7.2 Hz, 1H), 3.00 ? 2.75 (m, 3H), 2.42 (m, 2H). m/z 448.2 [M + H].sup.+, (ESI+), RT = 3.46 and 3.60 LC-MS Method 4. Data supports product obtained as a mixture of diastereomers. 1671 5 [01587] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.64 (m, 1H), 8.48 (m, 1H), 7.98 ? 7.91 (m, 2H), 7.88 ? 7.81 (m, 2H), 5.46 ? 5.38 (m, 1H), 3.14 ? 3.09 (m, 3H), 2.72 ? 2.62 (m, 2H). m/z 405.2 [M + H].sup.+, (ESI+), RT = 2.84 and 2.88 LC-MS Method 4 Data supports product obtained as a mixture of diastereomers. 1672 1 [01588] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.69 ? 8.63 (m, 1H), 8.55 (m, 1H), 8.49 (t, J = 2.0 Hz, 1H), 7.96 ? 7.88 (m, 1H), 7.82 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 5.97 (m, 1H), 3.18 (s, 3H), 2.89 ? 2.81 (m, 2H), 2.23 ? 2.14 (m, 4H). m/z 476.3 [M + H].sup.+, (ESI+), RT = 3.44 LC-MS Method 6 1673 5 [01589] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.67 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H), 7.99 ? 7.91 (m, 2H), 7.83 (d, J = 8.7 Hz, 2H), 5.98 (m, 1H), 2.92 ? 2.84 (m, 2H), 2.21 (m, 4H). m/z 442.2 [M + H].sup.+, (ESI+), RT = 3.38 LC-MS Method 4 1674 3 [01590] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.68 ? 8.55 (m, 3H), 8.47 (m, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.96 (dd, J = 8.6, 2.6 Hz, 1H), 7.84 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 6.79 (t, J = 55.2 Hz, 1H), 3.19 (s, 3H). m/z 487.1 [M + H].sup.+, (ESI+), RT = 2.83 LC-MS Method 4 1675 4 [01591] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.67 (d, J = 2.5 Hz, 1H), 8.63 ? 8.55 (m, 2H), 8.20 (t, J = 1.8 Hz, 1H), 7.96 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.69 (dt, J = 7.8, 1.1 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 6.79 (t, J = 55.2 Hz, 1H). m/z 453.3 [M + H].sup.+, (ESI+), RT = 3.11 LC- MS Method 6 1676 5 [01592] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.69 ? 8.54 (m, 3H), 7.95 (m, 3H), 7.85 (m, 3H), 6.79 (t, J = 55.2 Hz, 1H). m/z 453.3 [M + H].sup.+, (ESI+), RT = 3.08 LC- MS Method 6 1677 4 [01593] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.67 (m, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.27 (m, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.69 (m, 1H), 7.52 (t, J = 7.9 Hz, 1H), 5.98 (m, 1H), 2.87 (m, 2H), 2.21 (m, 4H). m/z 459.3 [M + NH4].sup.+, (ESI+), RT = 3.52 LC-MS Method 6 1678 10 [01594] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.47 (s, 2H), 7.53 (s, 1H), 7.46 (m, 2H), 3.80 (s, 3H), 3.71 (s, 3H), 2.47 (s, 6H). m/z 462.3 [M + H].sup.+, (ESI+), RT = 3.69 LC- MS Method 6 1679 10 [01595] .sup.1H NMR (400 MHz, CD.sub.3OD) 88.51 (dd, J = 2.4, 0.9 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.14 ? 7.03 (m, 2H), 3.85 (d, J = 1.8 Hz, 3H), 3.71 (s, 3H), 2.47 (s, 6H). m/z 473.3 [M + H].sup.+, (ESI+), RT = 3.98 LC-MS Method 6 1680 9 [01596] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.42 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.16 (t, J = 2.0 Hz, 1H), 7.92 (m, 1H), 7.70 ? 7.63 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.13 (m, 1H), 7.10 ? 7.02 (m, 1H), 3.84 (d, J = 1.7 Hz, 3H). m/z 478.1 [M].sup.+, (ESI+), RT = 3.36 LC-MS Method 4 1681 8 [01597] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.39 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 7.95 ? 7.87 (m, 2H), 7.85 ? 7.78 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 3.84 (d, J = 1.7 Hz, 3H). m/z 478.2 [M].sup.+, (ESI+), RT = 3.36 LC-MS Method 6 1683 9 [01598] .sup.1H NMR (400 MHz, CD.sub.3OD) 89.41 (dd, J = 2.7, 1.0 Hz, 1H), 9.07 (dd, J = 6.0, 1.0 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.23 (dd, J = 6.0, 2.7 Hz, 1H), 7.16 ? 7.00 (m, 2H), 3.83 (d, J = 1.7 Hz, 3H). m/z 437.1 [M].sup.+, (ESI+), RT = 3.24 LC-MS Method 6 1684 3 [01599] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.60 ? 8.52 (m, 2H), 8.45 (t, J = 2.0 Hz, 1H), 8.00 (m, 1H), 7.82 (m, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 3.17 (s, 3H), 2.36 (s, 3H). m/z 529.2 [M].sup.+, (ESI+), RT = 3.24 LC-MS Method 6 1685 3 [01600] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.56 (s, 2H), 8.43 (t, J = 2.0 Hz, 1H), 8.06 ? 7.99 (m, 1H), 7.82 (m, 1H), 7.69 ? 7.59 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.17 (s, 3H). m/z 545.1 [M].sup.+, (ESI+), RT = 3.57 LC-MS Method 6 1686 6 [01601] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.85 (s, 1H), 8.41 ? 8.34 (m, 3H), 7.96 ? 7.89 (m, 1H), 7.70 ? 7.66 (m, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 4.22 (s, 1H), 3.75 (s, 3H), 3.05 (d, J = 1.1 Hz, 3H). m/z 501.1, 503.1 [M].sup.+, (ESI+), RT = 3.13 LC-MS Method 4 1687 4 [01602] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.75 (s, 1H), 8.74 (m, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.18 (t, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.89 (m, 1H), 7.69 ? 7.60 (m, 3H), 7.46 (t, J = 7.9 Hz, 1H), 7.38 (s, 1H), 5.54 (q, J = 6.7 Hz, 1H), 1.74 (d, J = 6.6 Hz, 3H). m/z 507.1 [M + H].sup.+, (ESI+), RT = 3.32 LC-MS Method 4 1688 5 [01603] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.85 (s, 1H), 8.74 (dd, J = 2.4, 1.1 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 7.94 ? 7.86 (m, 3H), 7.79 (d, J = 8.6 Hz, 2H), 7.64 (m, 2H), 7.29 (s, 1H), 5.54 (q, J = 6.6 Hz, 1H), 1.74 (d, J = 6.7 Hz, 3H). m/z 507.1 [M + H].sup.+, (ESI+), RT = 3.36 LC-MS Method 4 1689 3 [01604] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.97 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.38 (m, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.73 ? 7.58 (m, 4H), 5.54 (q, J = 6.7 Hz, 1H), 4.24 (s, 1H), 3.06 (d, J = 1.1 Hz, 3H), 1.74 (d, J = 6.7 Hz, 3H). m/z 541.1 [M + H].sup.+, (ESI+), RT = 3.31 LC-MS Method 4 1690 3 [01605] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.99 (s, 1H), 8.68 (m, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.39 (t, J = 1.9 Hz, 1H), 7.84 ? 7.39 (m, 4H), 7.24 (d, J = 8.1 Hz, 1H), 4.23 (s, 1H), 3.06 (d, J = 1.0 Hz, 3H), 2.46 (s, 3H). m/z 517.2 [M + H].sup.+, (ESI+), RT = 3.26 LC-MS Method 4 1691 4 [01606] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.77 (s, 1H), 8.68 (m, 1H), 8.57 (d, J = 2.7 Hz, 1H), 8.20 (t, J = 1.9 Hz, 1H), 7.98 (s, 1H), 7.90 (m, 1H), 7.86 ? 7.42 (m, 4H), 7.38 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 2.47 (s, 3H). m/z 483.2 [M + H].sup.+, (ESI+), RT = 3.33 LC-MS Method 4 1692 1 [01607] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.79 (s, 1H), 8.74 (m, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.19 (t, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.1, 3.1 Hz, 1H), 7.98 (s, 1H), 7.92 ? 7.85 (m, 1H), 7.75 (m, 1H), 7.70 ? 7.60 (m, 2H), 7.46 (t, J = 7.9 Hz, 1H), 7.38 (s, 1H). m/z 445.2 [M + H].sup.+, (ESI+), RT = 3.00 LC-MS Method 4 1693 1 [01608] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.07 (s, 1H), 8.73 (m, 1H), 8.69 ? 8.64 (m, 1H), 8.39 (t, J = 1.9 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.97 (dt, J = 7.6, 1.9 Hz, 1H), 7.75 ? 7.64 (m, 2H), 3.23 (s, 3H), 2.39 (s, 3H). m/z 477.2 [M + H].sup.+, (ESI+), RT = 3.26 LC-MS Method 4 1694 1 [01609] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.07 (s, 1H), 8.71 (m, 2H), 8.66 (d, J = 2.4 Hz, 1H), 8.39 (m, 1H), 8.15 (s, 1H), 7.97 (m, 1H), 7.75 ? 7.64 (m, 2H), 3.23 (s, 3H), 2.22 (s, 3H). m/z 477.1 [M + H].sup.+, (ESI+), RT = 3.26 LC-MS Method 4 1695 1 [01610] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.80 (s, 1H), 9.20 (s, 2H), 8.76 (m, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.17 (t, J = 1.9 Hz, 1H), 7.98 (s, 1H), 7.95 ? 7.90 (m, 1H), 7.64 (m, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.39 (s, 1H). m/z 472.1 [M + H].sup.+, (ESI+), RT =3.13 LC-MS Method 4 1696 1 [01611] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.03 (s, 1H), 9.19 (s, 2H), 8.77 (m, 1H), 8.67 (d, J = 2.5 Hz, 1H), 8.37 (t, J = 2.0 Hz, 1H), 8.03 ? 7.93 (m, 1H), 7.71 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 4.25 (s, 1H), 3.07 (s, 3H). m/z 506.1 [M + H].sup.+, (ESI+), RT = 3.05 LC-MS Method 4 1697 1 [01612] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.80 (s, 1H), 8.72 (m, 1H), 8.62 (m, 1H), 8.17 (t, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.92 ? 7.85 (m, 1H), 7.79 (m, 1H), 7.63 (m, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.38 (s, 1H), 2.44 (d, J = 2.1 Hz, 3H). m/z 459.2 [M + H].sup.+, (ESI+), RT = 3.19 LC-MS Method 4 1698 4 [01613] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.71 (s, 1H), 8.70 (m, 1H), 8.54 (d, J = 2.5 Hz, 1H), 8.17 (t, J = 1.9 Hz, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.98 (s, 1H), 7.94 ? 7.85 (m, 2H), 7.63 (m, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.39 (s, 1H), 3.97 (s, 3H). m/z 451.1 [M + H].sup.+, (ESI+), RT = 3.09 LC-MS Method 4 1699 3 [01614] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.94 (s, 1H), 8.72 (m, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.37 (t, J = 2.0 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.95 (m, 1H), 7.88 (dd, J = 10.8, 2.4 Hz, 1H), 7.70 (m, 1H), 7.62 (t, J = 7.9 Hz, 1H), 4.24 (s, 1H), 3.97 (s, 3H), 3.06 (s, 3H). m/z 485.2 [M + H].sup.+, (ESI+), RT = 3.00 LC-MS Method 4 1700 1 [01615] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.57 (m, 1H), 8.18 (m, 1H), 7.95 ? 7.88 (m, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.67 (m, 1H), 7.49 (t, J = 7.9 Hz, 1H), 2.46 (s, 3H). m/z 442.2 [M + H].sup.+, (ESI+), RT = 2.84 LC-MS Method 4 1701 1 [01616] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.62 ? 8.55 (m, 2H), 8.45 (m, 1H), 8.00 (m, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.87 ? 7.78 (m, 2H), 7.64 (t, J = 8.0 Hz, 1H), 3.17 (s, 3H), 2.45 (s, 3H). m/z 476.2 [M + H].sup.+, (ESI+), RT = 2.76 LC-MS Method 4 1702 11 [01617] .sup.1H NMR (400 MHz, CD.sub.3OD) 89.10 (m, 1H), 8.58 (m, 1H), 8.54 (m, 1H), 8.19 ? 8.13 (m, 1H), 7.81 (m, 1H), 7.58 ? 7.41 (m, 4H), 3.80 (s, 3H). m/z 431.2 [M + H].sup.+, (ESI+), RT = 2.63 LC-MS Method 4 1703 [01618] .sup.1H NMR (500 MHz, DMSO-d6) ? 12.60 (br.s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.17 ? 7.83 (m, 6H), 7.72 ? 7.65 (m, 2H), 3.18 (s, 3H). m/z 463.1 [M + H].sup.+, (ESI+), RT = 2.33 LC-MS Method 4 1704 [01619] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.69 (s, 1H), 8.78 (dd, J = 2.4, 0.9 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.38 ? 8.32 (m, 1H), 7.97 ? 7.89 (m, 1H), 7.72 ? 7.63 (m, 2H), 4.77 (dd, J = 11.0, 5.4 Hz, 1H), 4.44 (dd, J = 10.9, 7.3 Hz, 1H), 4.08 (br.s, 1H), 3.89 (d, J = 12.3 Hz, 1H), 3.29 ? 3.08 (m, 4H), 2.91 (br.s, 1H), 2.76 ? 2.58 (m, 1H), 1.89 (dt, J = 13.9, 3.6 Hz, 1H), 1.57 ? 1.42 (m, 1H), 1.37 (s, 9H). m/z 616.0 [M + Na].sup.+, (ESI+), RT = 4.17 LC-MS Method 4 1705 [01620] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.82 (s, 1H), 9.69 (br.s, 2H), 8.78 (dd, J = 2.3, 0.9 Hz, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.39 ? 8.36 (m, 1H), 7.95 (dt, J = 7.4, 1.7 Hz, 1H), 7.72 ? 7.64 (m, 2H), 4.80 (dd, J = 11.1, 5.5 Hz, 1H), 4.49 (dd, J = 11.1, 7.3 Hz, 1H), 3.73 ? 3.64 (m, 1H), 3.52 ? 3.38 (m, 2H), 3.28 ? 3.20 (m, 4H), 3.00 (td, J = 12.5, 2.8 Hz, 1H), 2.93 ? 2.77 (m, 1H), 2.18 ? 2.08 (m, 1H), 1.82 ? 1.69 (m, 1H). m/z 494.0 [M + H].sup.+, (ESI+), RT = 1.93 LC-MS Method 4 1706 [01621] .sup.1H NMR (400 MHz, DMSO-d6) ? 10.91 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.24 (q, J ? 7.6 Hz, 1H), 7.05 ? 6.92 (m, 2H), 4.55 (hept, J = 5.9 Hz, 1H), 4.23 (s, 1H), 3.06 (s, 3H), 1.07 (d, J = 5.9 Hz, 6H). m/z 512.2 [M + H].sup.+, (ESI+), RT = 3.44 LC-MS Method 4 1707 [01622] .sup.1H NMR (400 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.23 (t, J = 8.8 Hz, 1H), 7.11 (t, J = 8.9 Hz, 1H), 4.69 (hept, J = 5.9 Hz, 1H), 4.24 (s, 1H), 3.06 (s, 3H), 1.32 (d, J = 6.0 Hz, 6H). m/z 530.1 [M + H].sup.+, (ESI+), RT = 3.59 LC-MS Method 4 1708 [01623] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.67 (s, 1H), 8.69 ? 8.64 (m, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.20 (t, J = 1.7 Hz, 1H), 7.98 (s, 1H), 7.92 ? 7.86 (m, 1H), 7.66 ? 7.61 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H), 7.24 (td, J = 8.5, 6.5 Hz, 1H), 7.04 ? 6.94 (m, 2H), 4.55 (hept, J = 6.1 Hz, 1H), 1.07 (d, J = 6.0 Hz, 6H). m/z 495.3 [M + NH4].sup.+, (ESI+), RT = 3.61 LC-MS Method 6 1709 [01624] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.79 (s, 1H), 8.73 ? 8.69 (m, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.19 (t, J = 1.7 Hz, 1H), 7.98 (s, 1H), 7.92 ? 7.87 (m, 1H), 7.66 ? 7.61 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.38 (s, 1H), 7.27 ? 7.21 (m, 1H), 7.15 ? 7.08 (m, 1H), 4.69 (hept, J = 6.0 Hz, 1H), 1.32 (d, J = 6.0 Hz, 6H). m/z 513.3 [M + NH4].sup.+, (ESI+), RT = 3.75 LC-MS Method 6 1710 [01625] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.78 (s, 1H), 8.70 ? 8.65 (m, 1H), 8.57 (d, J = 2.3 Hz, 1H), 7.96 ? 7.85 (m, 3H), 7.83 ? 7.75 (m, 2H), 7.29 (br.s, 1H), 7.24 (td, J = 8.5, 6.5 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 7.01 ? 6.93 (m, 1H), 4.55 (hept, J = 6.0 Hz, 1H), 1.07 (d, J = 6.0 Hz, 6H). m/z 478.3 [M + H].sup.+, (ESI+), RT = 3.61 LC-MS Method 6 1711 [01626] .sup.1H NMR (500 MHz, DMSO-d6) ? 10.89 (s, 1H), 8.75 ? 8.70 (m, 1H), 8.58 (d, J = 2.4 Hz, 1H), 7.98 ? 7.85 (m, 3H), 7.82 ? 7.76 (m, 2H), 7.30 (br.s, 1H), 7.27 ? 7.21 (m, 1H), 7.15 ? 7.07 (m, 1H), 4.69 (hept, J = 6.0 Hz, 1H), 1.32 (d, J = 6.0 Hz, 6H). m/z 496.3 [M + H].sup.+, (ESI+), RT = 3.75 LC-MS Method 6 1712 [01627] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.02 (s, 1H), 8.73 ? 8.68 (m, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.38 (t, J = 1.8 Hz, 1H), 7.98 ? 7.91 (m, 1H), 7.70 (dt, J = 7.8, 1.1 Hz, 1H), 7.62 (t, J ? 7.9 Hz, 1H), 7.53 (t, J = 8.8 Hz, 1H), 7.31 ? 7.24 (m, 1H), 4.24 (s, 1H), 3.06 (s, 3H), 2.13 ? 2.07 (m, 3H). m/z 552.1 [M + H].sup.+, (ESI+), RT = 3.73 LC-MS Method 4 1714 [01628] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.72 ? 8.68 (m, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.97 ? 7.91 (m, 1H), 7.70 (ddd, J = 7.8, 1.6, 1.1 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.53 (t, J = 8.8 Hz, 1H), 7.27 (dd, J = 9.1, 1.4 Hz, 1H), 4.23 (s, 1H), 3.06 (s, 3H), 2.12 ? 2.07 (m, 3H). m/z 552.2 [M + H].sup.+, (ESI+), RT = 6.98 Chiral LC 1715 [01629] .sup.1H NMR (500 MHz, DMSO-d6) ? 11.01 (s, 1H), 8.72 ? 8.68 (m, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.37 (t, J = 1.7 Hz, 1H), 7.97 ? 7.91 (m, 1H), 7.73 ? 7.67 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.53 (t, J = 8.8 Hz, 1H), 7.27 (dd, J = 9.1, 1.2 Hz, 1H), 4.24 (s, 1H), 3.06 (s, 3H), 2.13 ? 2.06 (m, 3H). m/z 552.2 [M + H].sup.+, (ESI+), RT = 5.61 Chiral LC

Example 88

Compound 1716: N-[3-(N-acetyl-S-methyl-sulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide

[1145] ##STR01630##

[1146] To a solution of (R)-2-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (50 mg, 0.107 mmol) in DCM (1.0697 mL) at rt was added pyridine (0.017 mL, 0.214 mmol) and acetic anhydride (0.012 mL, 0.128 mmol). The mixture was stirred at rt overnight under an atmosphere of nitrogen. Reaction was concentrated under a stream of nitrogen. Loaded on to 10 g Sfar Duo cartridge in DCM (3?0.5 mL), then eluted with 0-50% EtOAc/Hept. Relevant fractions concentrated to yield N-[3-(N-acetyl-S-methyl-sulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (98.0%) (45 mg, 0.0873 mmol, 82%). .sup.1H NMR (400 MHz, DMSO-d6) ? 11.05 (s, 1H), 8.67-8.63 (m, 1H), 8.57-8.53 (m, 1H), 8.41-8.36 (m, 1H), 8.00-7.94 (m, 1H), 7.70-7.63 (m, 2H), 7.28-7.22 (m, 1H), 7.22-7.15 (m, 1H), 7.13-7.05 (m, 1H), 3.40 (s, 3H), 2.08 (s, 3H), 1.96 (s, 3H). LC-MS Method 4: m/z 510.1 [M+H].sup.+, (ESI+), RT=3.51.

Example 89

Compound 1717: N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide

[1147] ##STR01631##

[1148] (R)-2-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (50 mg, 0.107 mmol), copper(2+) diacetate (29 mg, 0.160 mmol) and methylboronic acid (13 mg, 0.214 mmol), were suspended in 1,4-Dioxane-Anhydrous (0.8557 mL) was stirred at RT under air for 5 minutes. Then pyridine (0.017 mL, 0.214 mmol) was added, the vessel sealed and heated to 100? C. for 40 minutes. Reaction mixture diluted with water (?1.5 mL) and DCM (3 mL), shaken vigorously then the mixture filtered through a PTFE phase separator. Aqueous re-extracted with DCM (2 mL) and layers separated. Combined organics were concentrated under a gentle stream of nitrogen. Crude material was purified by preparatory HPLC (Prep Method 2) to yield N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide, as a white powder (43 mg, 51%). .sup.1H NMR (500 MHz, DMSO-d6) ? 10.97 (s, 1H), 8.66 (dd, J=2.5, 1.1 Hz, 1H), 8.57-8.53 (m, 1H), 8.30 (t, J=1.9 Hz, 1H), 7.95 (ddd, J=8.0, 2.2, 1.2 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.60-7.56 (m, 1H), 7.26 (dd, J=8.9, 5.1 Hz, 1H), 7.20 (dd, J=9.7, 3.2 Hz, 1H), 7.11 (td, J=8.5, 3.2 Hz, 1H), 3.11 (s, 3H), 2.49 (s, 3H), 2.09 (s, 3H). LC-MS Method 6: m/z 482.3 [M+H].sup.+, (ESI+), RT=3.62.

Example 90

Compound 1718: 2-(3-methylsulfonylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

[1149] ##STR01632##

[1150] 2-(3-methylsulfanylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (48 mg, 0.0997 mmol) was dissolved in Methanol (1.0 mL) and treated with potassium; oxido hydrogen sulfate (33 mg, 0.219 mmol) and the resultant mixture stirred at RT. After 24 hrs more potassium; oxido hydrogen sulfate (40 mg, 0.267 mmol) was added and the reaction stirred at RT for a further 24 hrs. Diluted reaction with DCM (25 mL) and NaHCO.sub.3 (sat. aq. soln, 25 mL). Stirred vigorously for 5 minutes and filtered through a phase separator. Aqueous re-extracted with DCM (?1) and filtered. Combined organics concentrated in vacuo to a white solid. Columned in 0-100% EtOAc/Hep on 10 g Sfar Duo cartridge yielding 2-(3-methylsulfonylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (98.0%) (33 mg, 0.0629 mmol, 63%). .sup.1H NMR (400 MHz, DMSO-d6) ? 11.04 (s, 1H), 8.74-8.71 (m, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.41-8.38 (m, 1H), 7.97 (dt, J=7.3, 1.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.76 (t, J=7.9 Hz, 1H), 7.73-7.64 (m, 3H), 3.27 (s, 3H), 3.22 (s, 3H). LC-MS Method 4: m/z 515.1 [M+H].sup.+, (ESI+), RT=3.06.

Example 91

Compound 1719: tert-butyl (R)-(2-(((3-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.SUP.6.-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate

[1151] ##STR01633##

[1152] To N-(tert-butoxycarbonyl)-N-methylglycine (18 mg, 0.0941 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (18 mg, 0.0941 mmol) was added DCM (0.4279 mL) at rt and then N-ethyl-N-(propan-2-yl)propan-2-amine (0.036 mL, 0.205 mmol). The suspension was stirred at rt for 5-10 minutes, then added (R)-2-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (100%, 40 mg, 0.0856 mmol) in one portion. The resulting suspension was stirred at rt. Reaction was concentrated under a stream of nitrogen. Loaded onto 10 g Sfar Duo cartridge in DCM (3?0.5 mL), then eluted with 0-50% EtOAc/Hept. Relevant fractions concentrated to yield colorless glass (54 mg, 99%). .sup.1H NMR (400 MHz, DMSO-d6) ? 11.07 (s, 1H), 8.68-8.64 (m, 1H), 8.57-8.51 (m, 1H), 8.50-8.43 (m, 1H), 8.01-7.92 (m, 1H), 7.71-7.63 (m, 2H), 7.26 (dd, J=8.9, 5.0 Hz, 1H), 7.20 (dd, J=9.3, 3.1 Hz, 1H), 7.11 (td, J=8.5, 3.1 Hz, 1H), 3.97-3.77 (m, 2H), 3.47 (s, 3H), 2.80-2.72 (m, 3H), 2.09 (s, 3H), 1.36 (s, 4H), 1.28 (s, 5H). LC-MS Method 6: m/z 639.3 [M+H].sup.+, (ESI+), RT=4.15.

Example 92

Compound 1720: (R)-2-(4-fluoro-2-methylphenoxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide

[1153] ##STR01634##

[1154] To a solution of tert-butyl (R)-(2-(((3-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)amino)-2-oxoethyl)(methyl)carbamate (61 mg, 0.0955 mmol) in DCM (1.0 mL) was added phosphoric acid (85% wt) in water (85%, 0.044 mL, 0.382 mmol) (added 12 ?L) at rt. The mixture was stirred vigorously for 2-3 hrs at rt. Reaction mixture diluted with NaOH (2N, 5 mL) and extracted twice with DCM (2?5 mL). Each extraction filtered through a phase separator cartridge and concentrated to a brown gum. Crude material loaded on to 10 g Sfar Duo cartridge and eluted with 0-100% EtOAc/Hep then 0-50% MeOH/EtOAc to yield (R)-2-(4-fluoro-2-methylphenoxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (93.5%) (36 mg, 0.0625 mmol, 65% Yield) as a pale brown powder. .sup.1H NMR (400 MHz, DMSO-d6) ? 11.07 (s, 1H), 8.70-8.65 (m, 1H), 8.58-8.54 (m, 1H), 8.47-8.41 (m, 1H), 8.02-7.96 (m, 1H), 7.74-7.65 (m, 2H), 7.27 (dd, J=8.9, 5.0 Hz, 1H), 7.21 (dd, J=9.3, 3.1 Hz, 1H), 7.12 (td, J=8.5, 3.3 Hz, 1H), 3.46 (s, 3H), 3.20 (s, 2H), 2.24 (s, 3H), 2.10 (s, 3H). LC-MS Method 6: m/z 539.2 [M+H].sup.+, (ESI+), RT=3.42.

Example 93

Compound 1721: N-(3-carbamoyl-1-bicyclo[1.1.1]pentanyl)-2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide

[1155] ##STR01635##

[1156] Methyl 3-[[2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (34 mg, 0.0737 mmol) was dissolved in IPA (0.257 mL) and diluted with 14.5 M ammonium hydroxide (1.0 mL, 14.5 mmol). The solution was stirred at 40? C. in a pressure vial for 2 h. LC-MS analysis indicated the reaction was mostly complete. The solvents were removed and the residue purified by prep. HPLC (Prep. Method 2) to afford N-(3-carbamoyl-1-bicyclo[1.1.1]pentanyl)-2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (100.0%) (13 mg, 0.0291 mmol, 40% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.47 (s, 2H), 7.54 (d, J=1.3 Hz, 1H), 7.51-7.41 (m, 2H), 3.81 (s, 3H), 2.45 (s, 6H). LC-MS Method 6: m/z 447.3 [M+H].sup.+, (ESI+), RT=2.96.

Example 94

Compound 1722: N-(3-carbamoyl-1-bicyclo[1.1.1]pentanyl)-2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide

[1157] ##STR01636##

[1158] methyl 3-[[2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (35 mg, 0.0741 mmol) was dissolved in IPA (0.2584 mL) and diluted with 14.5 M ammonium hydroxide (0.50 mL, 7.3 mmol). The solution was stirred at 40? C. in a pressure vial for 1 h. LC-MS analysis indicated the reaction was mostly complete. Purification by prep. HPLC (Prep. Method 2) afforded N-(3-carbamoyl-1-bicyclo[1.1.1]pentanyl)-2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (100.0%) (16 mg, 0.0350 mmol, 47% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired compound. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.51 (m, 1H), 8.44 (m, 1H), 7.19-7.03 (m, 2H), 3.85 (d, J=1.8 Hz, 3H), 2.45 (s, 6H). LC-MS Method 6: m/z 458.2 [M+H].sup.+, (ESI+), RT=3.23.

Example 95

Compound 1723: 5-cyano-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3 (methylsulfonimidoyl)phenyl]pyridine-3-carboxamide

[1159] ##STR01637##

[1160] Palladium acetate (8.8 mg, 0.0390 mmol) was added to a stirred, degassed solution of (LTGO 0001070) 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (200 mg, 0.390 mmol), potassium hexakis(cyano-kappaC)ferrate(4-) hydrate (4:1:3) (82 mg, 0.195 mmol), sodium carbonate (41 mg, 0.390 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (42 mg, 0.0781 mmol) in DMF (2 mL) and Water (2 mL). The reaction mixture was heated at 70? C. for 3 h. LC-MS analysis indicated the reaction was complete. Diluted with water (10 mL) and extracted with ethyl acetate (3?8 mL). Organics were dried (MgSO4), filtered and concentrated to afford an orange oil. Purification by prep. HPLC (Prep. Method 2) afforded 5-cyano-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (100.0%) (59 mg, 0.129 mmol, 33% Yield) as a white solid. .sup.1H and .sup.19F NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.60 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.45 (t, J=2.0 Hz, 1H), 8.03-7.95 (m, 1H), 7.81 (m, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.17-7.10 (m, 1H), 7.10-7.03 (m, 1H), 3.85 (d, J=1.8 Hz, 3H), 3.17 (s, 3H). LC-MS Method 7: m/z 459.2 [M+H].sup.+, (ESI+), RT=2.87.

Example 96

Compound 1724: N-(3-carbamoylphenyl)-5-cyano-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide

[1161] ##STR01638##

[1162] Palladium acetate (4.7 mg, 0.0209 mmol) was added to a stirred, degassed solution of 5-bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (100 mg, 0.209 mmol), potassium hexakis(cyano-kappaC)ferrate(4-) hydrate (4:1:3) (44 mg, 0.105 mmol), sodium carbonate (22 mg, 0.209 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (23 mg, 0.0418 mmol) in DMF (1.5 mL) and Water (1.5 mL). The reaction mixture was heated at 75? C. for 4 h. LC-MS analysis indicated starting material remaining, but reaction profile becoming more messy, so reaction stopped. Diluted with water (10 mL) and extracted with ethyl acetate (3?8 mL). Organics were dried (MgSO.sub.4), filtered and concentrated to afford an orange oil. Purification by prep. HPLC (Prep. Method 2) afforded 15 mg as a white solid. LC-MS analysis indicated this was the desired compound, but not clean (84% at 215 nm). Further purification by prep. HPLC (Prep. Method 1) afforded 10.2 mg as a white solid. LC-MS analysis indicated only 82% at 215 nm. Further purification by prep. HPLC (Waters Sunfire C18 column (19 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 20 mL/min at 5% B (A=0.10% formic acid in water; B=0.10% formic acid in acetonitrile for 1.9. min then a gradient of 35-95% B over 16 min then held for 2 min. UV spectra were recorded at 215 nm using a Gilson detector) afforded N-(3-carbamoylphenyl)-5-cyano-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (100.0%) (6.8 mg, 0.016 mmol, 7.7% Yield) as a white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.62 (s, 1H), 8.92 (d, J=2.3 Hz, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.08 (t, J=1.9 Hz, 1H), 8.02-7.96 (m, 1H), 7.60 (m, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.10-6.94 (m, 2H), 6.14 (s, 1H), 5.58 (s, 1H), 3.93 (d, J=2.8 Hz, 3H). LC-MS Method 4: m/z 425.5 [M+H].sup.+, (ESI+), RT=2.93.

Example 97

Compound 1725: 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(3-oxabicyclo[4.1.0]heptan-6-yl)pyridine-3-carboxamide

[1163] ##STR01639##

[1164] A mixture of 5-bromo-2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (40 mg, 0.0798 mmol), potassium; trifluoro(3-oxabicyclo[4.1.0]heptan-6-yl)boranuide (20 mg, 0.0957 mmol), cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (5.9 mg, 7.98 ?mol) and cesium carbonate (52 mg, 0.160 mmol) was suspended in Toluene (0.8 mL) and Water (0.2 mL) then degassed for 5 minutes. The mixture was heated to 80? C. for 2 h. LC-MS analysis indicated the starting material had been consumed. The mixture was diluted with ethyl acetate (5 mL), filtered and concentrated to afford a brown oil. Purification by prep. HPLC (standard method) afforded 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(3-oxabicyclo[4.1.0]heptan-6-yl)pyridine-3-carboxamide (100.0%) (20 mg, 0.0386 mmol, 48% Yield) as an off-white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.39 (m, 1H), 8.23 (d, J=2.5 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.01 (m, 1H), 7.83-7.76 (m, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.53-7.39 (m, 3H), 4.10 (dd, J=11.4, 4.5 Hz, 1H), 3.92 (m, 1H), 3.81 (s, 3H), 3.58 (m, 1H), 3.54-3.41 (m, 1H), 3.17 (s, 3H), 2.18 (m, 1H), 2.01 (m, 1H), 1.42 (m, 1H), 1.12 (m, 1H), 1.00 (t, J=5.4 Hz, 1H). LC-MS Method 4: m/z 519.2 [M+H].sup.+, (ESI+), RT=2.69.

Example 98

Compound 1726: 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide

[1165] ##STR01640##

[1166] Step 1: 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide: A mixture of 5-bromo-2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (50 mg, 0.106 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (5.1 mg, 0.0106 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (25 mg, 0.117 mmol) and tripotassium phosphate (68 mg, 0.319 mmol) in 1,4-dioxane (0.8 mL) and Water (0.2 mL) was degassed with nitrogen for 5 minutes, before the addition of palladium(2+) diacetate (2.4 mg, 0.0106 mmol). The mixture was heated to 80? C. for 8 h in a pressure vial. LC-MS analysis indicated the reaction was complete. Diluted with ethyl acetate (8 mL) and washed with water (5 mL) and brine (5 mL). Organics dried (MgSO.sub.4), filtered and concentrated to afford a brown oil. Purification by FCC (5 g, 0 to 30% EA in Heptane) afforded 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (37.0%) (34 mg, 0.0266 mmol, 25% Yield) an off-white solid, 34 mg. LC-MS analysis indicated this was a ca. 5:4 mixture of hydrodehalogenated by-product (1.06 min) and desired product (1.11 min). Used without further purification in oxidation. LC-MS Method 2: m/z 474.2 [M+H].sup.+, (ESI+), RT=1.11.

[1167] Step 2: 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide: Phenyl iodonium diacetate (PIDA) (29 mg, 0.0912 mmol) and diammonium carbonate (8.6 mg, 0.0912 mmol) were added to a solution of 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (40%, 36 mg, 0.0304 mmol) in methanol (0.4 mL) and the reaction was stirred at room temperature for 1 h. LC-MS analysis indicated the reaction was complete. The solvents were removed, and the residue purified by prep. HPLC (Prep. Method 1) to afford 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (100.0%) (8.0 mg, 0.0159 mmol, 52% Yield) as a white solid after freeze drying. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (500 MHz, DMSO-d6) ? 10.78 (s, 1H), 8.39 (m, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 7.94 (m, 1H), 7.69-7.66 (m, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.51 (dd, J=8.2, 1.9 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 6.38 (s, 1H), 4.23 (d, J=2.8 Hz, 2H), 4.21 (s, 1H), 3.82 (t, J=5.4 Hz, 2H), 3.75 (s, 3H), 3.05 (d, J=1.0 Hz, 3H). LC-MS Method 6: m/z 505.3 [M+H].sup.+, (ESI+), RT=1.11.

Example 99

Compound 1727: 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-tetrahydropyran-4-yl-pyridine-3-carboxamide

[1168] ##STR01641## ##STR01642##

[1169] Step 1: methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate: A mixture of methyl 5-bromo-2-(4-cyano-2-methoxy-phenoxy)pyridine-3-carboxylate (250 mg, 0.688 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (33 mg, 0.0688 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (217 mg, 1.03 mmol) and tripotassium phosphate (438 mg, 2.07 mmol) in 1,4-dioxane (5 mL) and water (1.5 mL) was degassed with nitrogen for 5 minutes, before the addition of palladium(2+) diacetate (15 mg, 0.0688 mmol). The mixture was heated to 80? C. for 2 h in a pressure vial. LC-MS analysis indicated the reaction was complete. Diluted with ethyl acetate (20 mL) and washed with water (8 mL) and brine (8 mL). Organics dried (MgSO4), filtered and concentrated. Purification by FCC (5 g, 0 to 30% EA in Heptane) afforded methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate (99.0%) (249 mg, 0.673 mmol, 98% Yield) as a beige foam. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.30 (d, J=2.3 Hz, 1H), 8.22 (d, J=2.6 Hz, 1H), 7.34 (dd, J=8.2, 1.8 Hz, 1H), 7.25-7.21 (m, 2H), 6.17 (m, 1H), 4.32 (q, J=2.8 Hz, 2H), 3.96 (s, 3H), 3.94 (t, J=5.5 Hz, 2H), 3.76 (s, 3H), 2.52-2.45 (m, 2H). LC-MS Method 2: m/z 367.2 [M+H].sup.+, (ESI+), RT=0.86.

[1170] Step 2: methyl 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylate: Three vacuum/nitrogen cycles were applied to a solution of methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate (100 mg, 0.273 mmol) in ethanol (2 mL). Palladium (10%, 29 mg, 0.0273 mmol) was added, and three vacuum/hydrogen cycles were applied. The mixture was stirred at rt for 4 h. LC-MS analysis indicated the starting material had been consumed. Filtered through celite and concentrated to afford a clear oil. Purification by FCC (10 g, 0 to 100% EA in heptane) afforded methyl 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylate (87.0%) (28 mg, 0.0661 mmol, 24% Yield) as a white semi-solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.17 (d, J=2.5 Hz, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.33 (dd, J=8.2, 1.9 Hz, 1H), 7.25-7.18 (m, 2H), 4.15-4.04 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.52 (m, 2H), 2.79 (m, 1H), 1.81-1.73 (m, 4H). LC-MS Method 2: m/z 369.2 [M+H].sup.+, (ESI+), RT=0.83.

[1171] Step 3: 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid: To a solution of methyl 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylate (28 mg, 0.0760 mmol) in THF (0.2 mL):water (0.1 mL), lithium hydroxide (4.2 mg, 0.167 mmol) was added, and the mixture was stirred at RT for 2 h. LC-MS analysis indicated the reaction was complete. The mixture was diluted with water (5 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3?5 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid (90.0%) (25 mg, 0.0635 mmol, 84% Yield) as a clear oil. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.37 (d, J=2.2 Hz, 1H), 8.13 (d, J=2.5 Hz, 1H), 7.46-7.32 (m, 2H), 4.10 (m, 2H), 3.81 (s, 3H), 3.53 (m, 2H), 2.83 (m, 1H), 1.89-1.75 (m, 4H). LC-MS Method 2: m/z 355.2 [M+H].sup.+, (ESI+), RT=0.69.

[1172] Step 4: 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-tetrahydropyran-4-yl-pyridine-3-carboxamide: To a solution of 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid (25 mg, 0.0705 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (16 mg, 0.0847 mmol) in pyridine-anhydrous (0.4 mL) was added 3-(methylsulfanyl)aniline (12 mg, 0.0847 mmol). The mixture was stirred at RT for 1 h. LC-MS analysis indicated the reaction was complete. The solvents were removed and the residue purified by FCC (5 g, 0 to 60% EA in heptane) to afford 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-tetrahydropyran-4-yl-pyridine-3-carboxamide (87.0%) (17 mg, 0.0311 mmol, 44%) as an off-white solid. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 9.92 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.08 (d, J=2.6 Hz, 1H), 7.98-7.92 (m, 2H), 7.53 (m, 2H), 7.41 (dd, J=8.3, 1.8 Hz, 1H), 7.39-7.36 (m, 1H), 7.31 (d, J=1.8 Hz, 1H), 4.10 (m, 2H), 3.89 (s, 3H), 3.60-3.49 (m, 2H), 2.91-2.81 (m, 1H), 2.76 (s, 3H), 1.89-1.79 (m, 4H). m/z 476.2 [M+H].sup.+, (ESI+), RT=1.01.

[1173] Step 5: 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-tetrahydropyran-4-yl-pyridine-3-carboxamide: Phenyl iodonium diacetate (PIDA) (35 mg, 0.107 mmol) and diammonium carbonate (10 mg, 0.107 mmol) were added to a solution of 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-tetrahy dropyran-4-yl-pyridine-3-carboxamide (17 mg, 0.0357 mmol) in methanol (0.5 mL) and the reaction was stirred at room temperature for 2 h. LC-MS analysis indicated the reaction was complete. The solvents were removed, and the residue purified by prep. HPLC (standard method) to afford 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-tetrahydropyran-4-yl-pyridine-3-carboxamide (98.0%) (10 mg, 0.0193 mmol, 54% Yield) as a white solid after freeze drying. .sup.1H NMR and LC-MS analysis indicated this was the desired product. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.73 (s, 1H), 8.39 (m, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.94 (m, 1H), 7.70-7.66 (m, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.51 (dd, J=8.2, 1.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 4.22 (s, 1H), 3.96 (m, 2H), 3.76 (s, 3H), 3.49-3.38 (m, 2H), 3.06 (s, 3H), 2.87 (m, 1H), 1.76-1.67 (m, 4H). LC-MS Method 4: m/z 507.2 [M+H].sup.+, (ESI+), RT=2.53.

Example 100

Compound 1728: 5-bromo-2-(4-fluoro-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-4-methylpyridine-3-carboxamide

[1174] ##STR01643## ##STR01644##

[1175] Step 1: 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carbonitrile 5-bromo-2-chloro-4-methyl-pyridine-3-carbonitrile was made as described in WO2016021742A. A mixture of 4-fluoro-2-methyl-phenol (1.61 g, 12.8 mmol), 5-bromo-2-chloro-4-methyl-pyridine-3-carbonitrile (1.98 g, 8.53 mmol) and K.sub.2CO.sub.3 (2.36 g, 17.1 mmol) in DMF-Anhydrous (20 mL) was stirred at 100? C. for 16 hours. The reaction was cooled to room temperature, poured into ice cold water, and the mixture extracted with EtOAc (25?3 mL). The combined layers were dried to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 20% EtOAc in heptane afforded 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carbonitrile (100.0%) (1.00 g, 36%) as a white solid. 1H NMR (500 MHz, DMSO-d.sub.6) ? 8.47 (s, 1H), 7.29-7.18 (m, 2H), 7.16-7.05 (m, 1H), 2.60 (s, 3H), 2.09 (s, 3H). m/z: 321.0 (Br isotope pattern) [M+H].sup.+, (ESI+), RT=4.21 LCMS Method 4.

[1176] Step 2: 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxamide 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carbonitrile (1.00 g, 3.11 mmol) was dissolved in DMSO (17.2 mL), then potassiooxycarbonyloxypotassium (1.90 g, 13.7 mmol) was added. The reaction mixture was cooled slightly in a water bath. To the reaction mixture was added hydrogen peroxide 50% wt aq (50%, 1.9 mL, 34.2 mmol) dropwise over 5 min (slight exotherm), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (80 mL) and dilute HCl (1N) (25 mL). Organic phase was separated, washed with sat. NaHCO.sub.3 (2?25 mL) and brine (1?25 mL), dried and filtered. Solvent was removed under reduced pressure delivering 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxamide (99.0%) (950 mg, 2.77 mmol, 89%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.19 (s, 1H), 8.08-8.07 (m, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.15 (dd, J=9.4, 3.0 Hz, 1H), 7.12-7.02 (m, 2H), 2.36 (s, 3H), 2.08 (s, 3H). m/z: 339.4 (Br isotope pattern) [M+H].sup.+, (ESI+), RT=2.85 LCMS Method 4.

[1177] Step 3: 5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridine-3-carboxylic acid: To a stirred solution of 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxamide (170 mg, 0.501 mmol) in Acetic acid (1.5 mL), tert-butyl nitrite (0.18 mL, 1.51 mmol) was added slowly under N.sub.2 atmosphere. Then the reaction mixture was allowed to stir for 2 hours min at 70? C. After completion, the reaction mixture was evaporated to dryness and NaOH (2 M) added. The aqueous phase was washed with EtOAc (3?10 mL) and then the pH adjusted to 1. The aqueous layer has then been extracted with EtOAc (3?15 mL), the organic layers collected and dried to obtain 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxylic acid (89.0%) (154 mg, 0.403 mmol, 80%) as an orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.25 (s, 1H), 7.17 (dd, J=9.5, 3.0 Hz, 1H), 7.10 (dd, J=8.9, 5.2 Hz, 1H), 7.05 (td, J=8.5, 3.1 Hz, 1H), 2.38 (s, 3H), 2.05 (s, 3H). m/z: 340.0 (Br isotope pattern) [M+H].sup.+, (ESI+), RT=3.25 LCMS Method 4.

[1178] Step 4: tert-butyl N[(S)-{3-[5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridine-3-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate; A mixture of N-ethyl-N-(propan-2-yl)propan-2-amine (195 ?L, 1.12 mmol), (S)-tert-butyl N-[(3-aminophenyl)-methyl-oxo-?.sup.6-sulfanylidene]carbamate (83 mg, 0.307 mmol), 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxylic acid (89%, 107 mg, 0.280 mmol) in DMF-Anhydrous (0.56 mL) was stirred for 10 minutes. Next HATU (160 mg, 0.421 mmol) was added. The reaction mixture was stirred at 55? C. for 26 hours. The reaction mixture was concentrated in vacuo then purified via flash chromatography. Fractions containing desired compound were combined and concentrated to afford tert-butyl N[(S)-{3-[5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridine-3-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (139 mg, 0.235 mmol, 84% Yield) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.18 (s, 1H), 8.46-8.37 (m, 1H), 8.32 (s, 1H), 7.98-7.90 (m, 1H), 7.70-7.65 (m, 2H), 7.19-7.11 (m, 2H), 7.06 (td, J=8.6, 3.1 Hz, 1H), 3.38 (s, 3H), 2.40 (s, 3H), 2.07 (s, 3H), 1.22 (s, 9H). m/z: 492.0 (Br isotope pattern) [M-BOC+H].sup.+, (ESI+), RT=0.98 LCMS Method 2.

[1179] Step 5: 5-bromo-2-(4-fluoro-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-?.sup.6-sulfanyl]phenyl}-4-methylpyridine-3-carboxamide. To a solution of tert-butyl N[(S)-{3-[5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridine-3-amido]phenyl}(methyl)oxo-?.sup.6-sulfanylidene]carbamate (115 mg, 0.194 mmol) in 1,4-Dioxane-Anhydrous (1 mL) and 2-Propanol (1 mL) was added 4 M hydrogen chloride 4m in dioxane (2.4 mL, 9.72 mmol). The mixture was stirred at rt overnight. The mixture was then cooled to 0? C., diluted with ethyl acetate (20 mL) and the pH adjusted to ?9 with sat. NaHCO.sub.3. Extracted with ethyl acetate (3?30 mL), and the organics dried (MgSO.sub.4), filtered and concentrated. Purification by flash chromatography afforded (100.0%) ((31 mg, 33%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.09 (s, 1H), 8.41-8.39 (m, 1H), 8.31 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.16 (d, J=4.4 Hz, 1H), 7.14 (d, J=4.5 Hz, 1H), 7.06 (td, J=8.6, 3.0 Hz, 1H), 4.22 (s, 1H), 3.06 (s, 3H), 2.41 (s, 3H), 2.08 (s, 3H). m/z: 492.0 (Br isotope pattern) [M+H].sup.+, (ESI+), RT=2.98 LCMS Method 4.

Example 101

Compound 1729: 2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide

[1180] ##STR01645##

[1181] Step 1: 2-chloro-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide To a mixture of 2-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid (300 mg, 1.33 mmol), HATU (607 mg, 1.60 mmol) and DIPEA (465 uL, 2.66 mmol) in DMF (3.6 mL) was added 3-(methylthio)aniline (197 uL, 1.60 mmol). The reaction mixture was stirred at rt for 17 h then poured into water (20 mL) and extracted with EtOAc (3?15 mL). The combined organic phases were washed with 5% aq LiCl (2?10 mL), dried over MgSO4 and concentrated under reduced pressure to give 737 mg, as a brown gum. The crude product was purified by FCC (Biotage Isolera 4, 25 g Sfar Duo, lambda-all collection) using a 0-100% EtOAc/heptane gradient to afford 2-chloro-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (97.0%) (277 mg, 58%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.79 (br.s, 1H), 8.42 (d, J=7.5 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.66 (t, J=1.9 Hz, 1H), 7.42 (ddd, J=8.1, 1.9, 0.9 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.05 (ddd, J=7.8, 1.7, 0.9 Hz, 1H), 2.48 (s, 3H). m/z: 347.0, 349.0 [M+H].sup.+, (ESI+), RT=0.93 LCMS Method 2.

[1182] Step 2: 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide: To a solution of 2-chloro-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (97%, 277 mg, 0.775 mmol) in Methanol (11 mL), bis(acetoxy)iodobenzene (574 mg, 1.78 mmol) and ammonium carbonate (109 mg, 1.16 mmol) were added and the reaction was stirred at rt for 16 h. The reaction mixture was then diluted with DCM, dry-loaded onto silica and purified by column chromatography using 0-100% EtOAc in heptane followed by 0-20% MeOH in EtOAc (on a Biotage Sfar Duo 10 g column, lambda-all collection) to afford 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (95.0%) (272 mg, 88%) as a beige powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.11 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 8.34 (t, J=1.9 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.89 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.72 (dt, J=7.8, 1.1 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 4.25 (s, 1H), 3.07 (s, 3H). m/z: 378.1, 380.0 [M+H].sup.+(ESI+), RT=0.68 LCMS Method 2.

[1183] Step 3: 2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide: A mixture of 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (120 mg, 0.318 mmol), 3,4-difluoro-2-methoxy-phenol (56 mg, 0.349 mmol) and potassium carbonate (66 mg, 0.476 mmol) in Acetonitrile-Anhydrous (2.4 mL) was stirred at 60? C. for 17 h. The reaction mixture was allowed to cool, diluted with MeCN (2 mL), filtered through a phase separator and the solids washed with MeCN (2?2 mL). The combined filtrate was concentrated under reduced pressure to give 183 mg as a yellow gum. The crude compound was purified by prep. HPLC (Prep. Method 1). Product fractions were combined and concentrated under reduced pressure. The resulting residue was freeze-dried from MeCN-water (1:1) to afford 2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (99.0%) (129 mg, 80%) as a white powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.01 (s, 1H), 8.45-8.36 (m, 2H), 7.96-7.89 (m, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.69 (dt, J=7.9, 1.2 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.32-7.18 (m, 2H), 4.24 (s, 1H), 3.81-3.73 (m, 3H), 3.06 (s, 3H). m/z: 502.0 [M+H].sup.+, (ESI+), RT=3.40 LCMS Method 4.

Compound 1730: (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide

[1184] ##STR01646## ##STR01647##

[1185] Step 1: ethyl 4-methyl-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylate: To a solution of ethyl malonate monoamide (1.56 g, 11.9 mmol) and (E)-1,1,1-trifluoro-4-methoxy-pent-3-en-2-one (2.00 g, 11.9 mmol) in Ethanol (20 mL) was added sodium ethoxide in ethanol (21%, 23 mL, 61.8 mmol) and the mixture was heated at 85? C. for 17 h. Aqueous 2M HCl was added to the reaction mixture at room temp until pH 5 and the volatiles removed under reduced pressure. The remaining aqueous was extracted with EtOAc (3?30 mL) and the combined organics washed with brine (30 mL), dried over MgSO.sub.4 and concentrated under reduced pressure to afford ethyl 4-methyl-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylate (86.0%) (1.49 g, 5.14 mmol, 430%) as a brown free-flowing oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 12.36 (br.s, 1H), 7.31 (s, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.30 (s, 3H), 1.28 (t, J=7.1 Hz, 3H). m/z: 250.1 [M+H].sup.+, (ESI+), RT=0.75 LCMS Method 2

[1186] Step 2: ethyl 2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate: A mixture of ethyl 4-methyl-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylate (86%, 750 mg, 2.59 mmol), trimethylamine hydrochloride (1:1) (371 mg, 3.88 mmol) and phosphorus oxychloride (6.0 mL, 64.2 mmol) was stirred at 105? C. in a pressure-relief vial for 17 h. The reaction mixture was allowed to cool then retreated with phosphorus oxychloride (2.0 mL, 21.4 mmol) and trimethylamine hydrochloride (1:1) (124 mg, 1.29 mmol). Heating at 105? C. was resumed for 18 h. The reaction mixture was retreated again with phosphorus oxychloride (2.0 mL, 21.4 mmol) and trimethylamine hydrochloride (1:1) (124 mg, 1.29 mmol) at room temp. Heating at 105? C. was resumed for 18 h. The cooled reaction mixture was added dropwise to a stirring solution of water and sat. aq. Na.sub.2CO.sub.3 (1:1, 50 mL). The mixture was neutralised by the cautious addition of solid Na.sub.2CO.sub.3 before the product was extracted with DCM (3?50 mL). The combined organics were dried using a phase separation cartridge and concentrated under reduced pressure to give ethyl 2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (87.0%) (425 mg, 1.38 mmol, 53%) as a dark brown free-flowing oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.04 (s, 1H), 4.45 (q, J=7.1 Hz, 2H), 2.44 (s, 3H), 1.34 (t, J=7.1 Hz, 3H). m/z: 268.0, 270.0 [M+H].sup.+, (ESI+), RT=0.97 LCMS Method 2.

[1187] Step 3: ethyl 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate: A mixture of ethyl 2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (79%, 208 mg, 0.614 mmol), 4-hydroxy-3-methoxybenzonitrile (137 mg, 0.921 mmol) and potassium carbonate (255 mg, 1.84 mmol) in NMP-Anhydrous (2.5 mL) was stirred at 100? C. for 22 h in an Ace pressure tube. The reaction mixture was allowed to cool to RT then diluted with DCM (15 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with DCM (2?15 mL). The combined organics were dried using a phase separator and concentrated under reduced pressure to give a brown free-flowing oil. The crude product was purified by FCC (Biotage Isolera, 10 g Sfar Duo cartridge, lambda-all collection) using a 0-25% EtOAc/heptane gradient. Product fractions were combined and concentrated under reduced pressure to give ethyl 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (35.0%) (571 mg, 0.525 mmol, 86%) as a yellow free-flowing oil. 65% NMP w/w .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 7.71-7.67 (m, 2H), 7.50 (dd, J=8.2, 1.8 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 3.73 (s, 3H), 2.45 (s, 3H), 1.30 (t, J=7.1 Hz, 3H). m/z: 381.1 [M+H].sup.+, (ESI+), RT=1.01 LCMS Method 2

[1188] Step 4: 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid: To a mixture of ethyl 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (42%, 571 mg, 0.631 mmol) in THF (3 mL)-Water (1.5 mL), lithium hydroxide (45 mg, 1.89 mmol) was added and the mixture stirred at rt for 16 h. The reaction mixture was retreated with lithium hydroxide (45 mg, 1.89 mmol) and stirring at rt continued for 5 h. Methanol (0.2 mL) was added to the reaction mixture and stirring at rt continued for 17 h. The reaction mixture was retreated with lithium hydroxide (45 mg, 1.89 mmol) and stirred for a further 22 h. The reaction mixture was diluted with water (15 mL) and the pH adjusted to 1 by dropwise addition of 2M HCl then extracted with EtOAc (3?10 mL), dried using a phase separator and concentrated in vacuo to give 256 mg, as a pale yellow gum. The crude product was purified by FCC (Biotage Isolera 4, 10 g Sfar Duo, lambda-all collect) using a 0-100% EtOAc/heptane gradient and flushed with 0-60% MeOH/EtOAC. Product fractions were combined and concentrated under reduced pressure to afford 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (99.0%) (108 mg, 0.304 mmol, 48%) as a white powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 7.68 (d, J=1.8 Hz, 1H), 7.64 (s, 1H), 7.50 (dd, J=8.2, 1.9 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 3.73 (s, 3H), 2.45 (s, 3H). Acid proton not observed m/z: 353.1 [M+H].sup.+, (ESI+), RT=0.81 LCMS Method 2.

[1189] Step 5: tert-butyl (R)-((3-(2-(4-cyano-2-methoxyphenoxy)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate To a stirring solution of 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (99%, 105 mg, 0.295 mmol) in DCM-Anhydrous (1.3 mL), anhydrous DMF (4.6 uL, 0.0590 mmol) was added followed by oxalyl chloride (28 uL, 0.325 mmol) under nitrogen and at rt. The reaction was stirred for 50 mins. Subsequently tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (86%, 111 mg, 0.354 mmol) in DCM-Anhydrous (0.5 mL) was added followed by DIPEA (103 uL, 0.590 mmol) and the reaction was stirred at rt for 1 h. Water (2 mL) was added to the reaction and the mixture passed through a phase separator and rinsed with DCM (3?3 mL). The combined organic phases were concentrated in vacuo to give 227 mg as a light yellow foam. The crude product was purified by FCC using 0-100% EtOAc in Heptane over silica and flushed with 0-20% MeOH in EtOAc (on a Biotage Sfar Duo 10 g column) and concentrated in vacuo to afford tert-butyl (R)-((3-(2-(4-cyano-2-methoxyphenoxy)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (89.0%)(171 mg, 0.252 mmol, 85%) as an off-white solid. m/z: 505.1 [M-BOC+H].sup.+, (ESI+), RT=0.94 LCMS Method 2

[1190] Step 6: (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide: To a solution of tert-butyl (R)-((3-(2-(4-cyano-2-methoxyphenoxy)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (89%, 168 mg 0.247 mmol) in 1,4-Dioxane-Anhydrous (1.4 mL) and 2-Propanol (1.4 mL) was added 4 M HCl in dioxane (3.1 mL, 12.4 mmol) and the mixture stirred at rt for 1 h 15 mins. The reaction mixture was then cooled to 0? C., diluted with EtOAc (20 mL) and basified to pH 9 with sat. aq. NaHCO.sub.3. The layers were separated and the aqueous phase extracted with EtOAc (2?15 mL). The combined organics were dried over MgSO.sub.4 and concentrated to dryness under vacuum to give 206 mg crude as a pale yellow residue. The crude was purified by acidic (0.1% Formic acid) reverse phase chromatography (Sfar C18 6 g D Duo, 10-100% MeCN in water). Pure product fractions were concentrated under reduced pressure and the resulting residue freeze-dried from MeCN-water (1:1) to afford (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (97.0%) (88 mg, 0.169 mmol, 68%) as a white powder. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.09 (s, 1H), 8.40 (t, J=1.9 Hz, 1H), 7.88 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 7.72 (s, 1H), 7.71-7.67 (m, 2H), 7.60 (t, J=7.9 Hz, 1H), 7.51 (dd, J=8.2, 1.9 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 4.22 (s, 1H), 3.75 (s, 3H), 3.09-3.04 (m, 3H), 2.48 (s, 3H). m/z: 505.1 [M+H].sup.+, (ESI+), RT=2.89 LCMS Method 4.

Compound 1731: (R)-5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide

[1191] ##STR01648##

[1192] The title compound was prepared by a similar procedure described for compound 1728 using appropriate starting materials. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.10 (s, 1H), 8.41 (t, J=1.9 Hz, 1H), 8.31 (s, 1H), 7.91-7.84 (m, 1H), 7.75-7.66 (m, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.19-7.12 (m, 2H), 7.06 (td, J=8.4, 3.1 Hz, 1H), 4.23 (s, 1H), 3.07-3.04 (m, 3H), 2.41 (s, 3H), 2.08 (s, 3H). m/z: 492.0-494.0 [M+H].sup.+, (ESI+), RT=2.98 LCMS Method 4.

Compound 1732: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(piperidin-1-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1193] ##STR01649##

[1194] The title compound was prepared by a similar procedure described for compound 1522 using appropriate starting materials. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.24 (s, 1H), 8.31 (t, J=1.9 Hz, 1H), 7.87 (ddd, J=8.1, 2.2, 1.1 Hz, 1H), 7.72 (dt, J=8.0, 1.3 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.29-7.16 (m, 2H), 7.11 (td, J=8.7, 3.3 Hz, 1H), 4.27 (d, J=1.3 Hz, 1H), 3.25-3.17 (m, 4H), 3.07 (d, J=1.1 Hz, 3H), 2.12 (s, 3H), 1.64-1.43 (m, 6H). m/z: 552.1 [M+H].sup.+, (ESI+), RT=3.48 LCMS Method 4.

Compound 1733: (R)-3-(4-cyano-2-methoxyphenoxy)-6-(6-methoxypyridin-3-yl)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide

[1195] ##STR01650##

[1196] The title compound was prepared by a similar procedure described for compound 1531 using appropriate starting materials. .sup.1H NMR (400 MHz, MeOD) ? 6.92 (t, J=2.0 Hz, 1H), 6.81 (m, 1H), 6.43 (m, 1H), 6.36 (dd, J=8.6, 2.5 Hz, 1H), 6.29 (m, 1H), 6.11 (t, J=8.0 Hz, 1H), 5.98 (d, J=1.5 Hz, 1H), 5.93-5.85 (m, 2H), 5.42 (m, 1H), 2.45 (s, 3H), 2.28 (s, 3H), 1.63 (s, 3H), 0.91 (s, 3H). m/z: 545.1 [M+H].sup.+, (ESI+), RT=2.46 LCMS Method 4.

Compound 1734: (R)N-[3-(N-acetyl-S-methyl-sulfonimidoyl)phenyl]-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxamide

[1197] ##STR01651##

[1198] The title compound was prepared (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(p-tolyl)pyridazine-4-carboxamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.38 (s, 1H), 8.43-8.39 (m, 1H), 7.95 (dt, J=6.8, 2.1 Hz, 1H), 7.73-7.66 (m, 3H), 7.55 (dd, J=8.2, 1.8 Hz, 1H), 7.52-7.43 (m, 3H), 7.36 (d, J=7.9 Hz, 2H), 3.81 (s, 3H), 3.43 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H), 1.98 (s, 3H). m/z: 570.1 [M+H].sup.+, (ESI+), RT=3.14 LCMS Method 4.

Compound 1735: (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(o-tolyl)pyridazine-4-carboxamide

[1199] ##STR01652##

[1200] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.46 (t, J=2.0 Hz, 1H), 7.98 (m, 1H), 7.83 (m, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.49-7.31 (m, 5H), 7.24 (m, 1H), 3.83 (s, 3H), 3.17 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H). m/z: 528.2 [M+H].sup.+, (ESI+), RT=2.79 LCMS Method 4

Compound 1736: (R)-3-((6-cyano-2-methoxypyridin-3-yl)oxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1201] ##STR01653##

[1202] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.32 (s, 1H), 8.34 (t, J=1.9 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.90-7.86 (m, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.76-7.71 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 4.27 (d, J=1.2 Hz, 1H), 3.88 (s, 3H), 3.08 (d, J=1.1 Hz, 3H), 2.54-2.52 (m, 3H). m/z: 507.3 [M+H].sup.+, (ESI+), RT=2.95 LCMS Method 4.

Compound 1737: (R)-3-((6-cyano-2-methylpyridin-3-yl)oxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1203] ##STR01654##

[1204] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.39 (s, 1H), 8.35 (t, J=1.9 Hz, 1H), 8.10-8.03 (m, 2H), 7.87 (ddd, J=8.0, 2.2, 1.1 Hz, 1H), 7.77-7.71 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 4.27 (s, 1H), 3.11-3.02 (m, 3H), 2.57-2.54 (m, 3H), 2.41 (s, 3H). m/z: 491.4 [M+H].sup.+, (ESI+), RT=2.73 LCMS Method 4.

Compound 1738: (R)-3-(4-cyano-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1205] ##STR01655##

[1206] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.21 (s, 1H), 8.69 (s, 1H), 8.34 (t, J=1.9 Hz, 1H), 7.93 (ddd, J=8.0, 2.2, 1.1 Hz, 1H), 7.78-7.69 (m, 2H), 7.64 (t, J=7.9 Hz, 1H), 7.58 (d, J=1.0 Hz, 2H), 4.26 (s, 1H), 3.78 (s, 3H), 3.07 (s, 3H). m/z: 492.4 [M+H].sup.+, (ESI+), RT=2.84 LCMS Method 4.

Compound 1739: (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-6-(p-tolyl)pyridazine-4-carboxamide

[1207] ##STR01656##

[1208] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.42 (s, 1H), 8.44 (s, 1H), 7.93 (d, J=7.4 Hz, 1H), 7.80-7.60 (m, 3H), 7.54 (dd, J=8.2, 1.7 Hz, 1H), 7.51-7.40 (m, 3H), 7.35 (d, J=8.0 Hz, 2H), 3.80 (s, 3H), 3.71-3.66 (m, 1H), 3.45 (s, 3H), 3.18 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H). m/z: 599.1 [M+H].sup.+, (ESI+), RT=2.16 LCMS Method 2.

Compound 1740: (R)-5-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide

[1209] ##STR01657##

[1210] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.13 (s, 1H), 8.46 (t, J=2.0 Hz, 1H), 8.05 (s, 1H), 8.01-7.94 (m, 2H), 7.91-7.86 (m, 1H), 7.71-7.65 (m, 1H), 7.64-7.56 (m, 3H), 7.27-7.14 (m, 2H), 7.08 (td, J=8.5, 3.1 Hz, 1H), 4.23-4.21 (m, 1H), 3.09-2.98 (m, 3H), 2.28 (s, 3H), 2.13 (s, 3H). m/z: 515.2 [M+H].sup.+, (ESI+), RT=3.06 LCMS Method 4.

Compound 1741: (S)-5-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide

[1211] ##STR01658##

[1212] 1H NMR (400 MHz, DMSO-d.sub.6) ? 11.13 (s, 1H), 8.45 (t, J=1.9 Hz, 1H), 8.05 (s, 1H), 7.99-7.94 (m, 2H), 7.91-7.87 (m, 1H), 7.70-7.66 (m, 1H), 7.64-7.57 (m, 3H), 7.22-7.14 (m, 2H), 7.07 (td, J=8.6, 3.2 Hz, 1H), 4.23-4.21 (m, 1H), 3.12-3.02 (m, 3H), 2.28 (s, 3H), 2.12 (s, 3H). m/z: 515.2 [M+H].sup.+, (ESI+), RT=3.06 LCMS Method 4.

Compound 1742: N-(3-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide

[1213] ##STR01659## ##STR01660##

[1214] Step 1: ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-5,6-dihydro-1H-pyrimidine-5-carboxylate: 2,2,2-trifluoroethanimidamide (0.40 mL, 4.46 mmol) and diethyl ethylidenepropanedioate (0.90 mL, 4.91 mmol) were dissolved in Ethanol (5 mL) and heated at 90? C. in a pressure tube for 2 h. The mixture was concentrated, and the residue dissolved in water (10 mL). The pH was adjusted to pH 4 with 1M HCl, then extracted with ethyl acetate (3?10 mL). The organics were dried, filtered and concentrated to afford a yellow oil. Purification by FCC (EtOAc in DCM) afforded ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-5,6-dihydro-1H-pyrimidine-5-carboxylate (90.0%) (285 mg, 1.02 mmol, 21% Yield) as a yellow oil. 1H-19F-NMR and LCMS analysis indicated this was the desired product as a ca. 8:1 mixture of isomers. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 8.57 (s, 1H), 4.36-4.14 (m, 3H), 3.28 (d, J=8.8 Hz, 1H), 1.39 (d, J=6.9 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H). m/z: 253.1 [M+H].sup.+, (ESI+), RT=0.63 LCMS Method 2.

[1215] Step 2: ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-1H-pyrimidine-5-carboxylate: A mixture of ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-5,6-dihydro-1H-pyrimidine-5-carboxylate (1.33 g, 5.29 mmol), 2,2(E)-diazene-1,2-diylbis(2-methylpropanenitrile) (0.043 g, 0.264 mmol), 1-bromopyrrolidine-2,5-dione (1.32 g, 7.41 mmol) and K.sub.2CO.sub.3 (7.31 g, 52.9 mmol) in ?,?,?-Trifluorotoluene (40 mL) in a pressure vial was heated at 70? C. for 1 h. LCMS analysis indicated the reaction was complete. The mixture was filtered through cotton wool, eluted further with MeCN, and concentrated to afford an orange oil. Purification by FCC (25 g, 0 to 100% EA in DCM, then 0 to 15% MeOH in EA) afforded ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-1H-pyrimidine-5-carboxylate (91.0%) (0.60 g, 2.19 mmol, 41% Yield) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 4.49 (m, 2H), 2.78 (s, 3H), 1.45 (t, J=7.2 Hz, 3H). m/z: 251.1 [M+H].sup.+, (ESI+), RT=0.68 LCMS Method 2.

[1216] Step 3: ethyl 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate: To solution of ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-1H-pyrimidine-5-carboxylate (412 mg, 1.65 mmol) and triphenylphosphine (1296 mg, 4.94 mmol) in Toluene Anhydrous (10 mL) was added 2,2,2-trichloroacetonitrile (0.25 mL, 2.47 mmol). The mixture was heated at 100? C. for 0.5 h. Filtered and concentrated to afford ethyl 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (11.0%)(2402 mg, 0.984 mmol, 60% Yield) as a brown oil. Used directly in the next step. m/z: 538.3 [2M+H].sup.+, (ESI+), RT=1.00 LCMS Method 2.

[1217] Step 4: ethyl 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate: To a solution of ethyl 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (442 mg, 1.65 mmol) and 4-hydroxy-3-methoxybenzonitrile (295 mg, 1.97 mmol) in Acetonitrile (10 mL) was added K.sub.2CO.sub.3 (455 mg, 3.29 mmol). the mixture was stirred at 60? C. for 3 h. The mixture was diluted with water (20 mL) extracted with ethyl acetate (3?20 mL). The combined organics were dried (MgSO.sub.4), filtered and concentrated to afford a brown oil. Purification by FCC (25 g, 0 to 100% EA in Heptane) afforded ethyl 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (84.0%) (323 mg, 0.712 mmol, 43% Yield) as a pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.34 (dd, J=8.2, 1.8 Hz, 1H), 7.24 (d, J=1.9 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 2.67 (s, 3H), 1.42 (t, J=7.1 Hz, 3H). m/z: 382.2 [M+H].sup.+, (ESI+), RT=1.04 LCMS Method 2.

[1218] Step 5: 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid: To a solution of ethyl 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (323 mg, 0.847 mmol) in THF (2.5 mL):Water (0.5 mL), lithium hydroxide (47 mg, 1.86 mmol) was added, and the mixture stirred at 40? C. for 2 h then overnight at rt. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl (aq). The aqueous layer was extracted with EtOAc (3?8 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford a yellow oil. Purification by FCC (10 g, 0 to 20% MeOH in EA) afforded 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid (323 mg, 0.847 mmol) as a pale yellow foam. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 7.36 (dd, J=8.2, 1.8 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.25 (m, 1H), 3.78 (s, 3H), 2.79 (s, 3H). m/z: 354.2 [M+H].sup.+, (ESI+), RT=0.76 LCMS Method 2

[1219] Step 6: N-(3-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (77 mg, 0.204 mmol) was added to a solution of 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid (60 mg, 0.170 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.059 mL, 0.340 mmol) in DMF-Anhydrous (1.2 mL). The mixture was stirred at rt for 5 minutes, before the addition of 3-aminobenzamide (98%, 31 mg, 0.221 mmol). The mixture was stirred at rt for 1 h. LCMS analysis indicated the reaction was complete. The mixture was diluted with ethyl acetate (8 mL) and washed with water (3?4 mL) and brine (4 mL). Organics were dried (MgSO.sub.4), filtered and concentrated to afford an orange oil. Purification by Prep Method 2 afforded N-(3-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide (100.0%) (44 mg, 0.0933 mmol, 55% Yield) as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.18 (t, J=1.9 Hz, 1H), 7.91 (m, 1H), 7.68 (m, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.46-7.39 (m, 2H), 3.81 (s, 3H), 2.69 (s, 3H). m/z: 472.5 [M+H].sup.+, (ESI+), RT=2.94 LCMS Method 4.

Compound 1743: 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-N-[3-(methylsulfonimidoyl)phenyl]-2-(trifluoromethyl)pyrimidine-5-carboxamide

[1220] ##STR01661##

[1221] The title compound was prepared using 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid an appropriate substituted aniline. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.45 (t, J=2.0 Hz, 1H), 7.98 (m, 1H), 7.83 (m, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.47-7.37 (m, 2H), 3.81 (s, 3H), 3.17 (s, 3H), 2.69 (s, 3H). m/z: 506.5 [M+H].sup.+, (ESI+), RT=2.93 LCMS Method 4.

Compound 1744: N-(4-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide

[1222] ##STR01662##

[1223] The title compound was prepared using 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid and 4-aminobenzamide using coupling conditions described above. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.05 (s, 1H), 7.95-7.87 (m, 3H), 7.78-7.71 (m, 3H), 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.31 (s, 1H), 3.78 (s, 3H), 2.63 (s, 3H). m/z: 472.2 [M+H].sup.+, (ESI+), RT=2.86 MET-uPLC-AB-101 (7 min, low pH).

Example 102

Compound Profiling on Na.SUB.V.1.8Human Na.SUB.V.1.8 Cell LineSyncroPatch384PE Assay

[1224] Compounds were tested on recombinant human Na.sub.V1.8 stably transfected HEK cells using the SyncroPatch384PE system, an automated patch clamp device. Cells were cultured at 37? C./5% CO.sub.2 in DMEM medium supplemented with GlutaMAX I, NEAA 1%, FBS 10% and seeded in T175 flasks. Cells were cultured at 30? C. one day prior to recording sodium currents. On the day of the recordings, cells were detached with 0.05% Trypsin-EDTA, resuspended in serum free DMEM medium and placed into the SyncroPatch384PE 6? C. pre-cooled cell hotel and shaken at 200 rpm. Intracellular solution (IC) contained, in mM: 10, CsCl; 110, CsF; 20, EGTA; 10, HEPES. Extracellular solution (EC) contained, in mM: 140, NaCl; 4, KCl; 5, Glucose; 10, HEPES; 2, CaCl.sub.2; 1, MgCl.sub.2. Washing solution contained, in mM: 40, NMDG; 100, NaCl; 4, KCl; 10, Glucose; 10, HEPES; 5, CaCl.sub.2; 1, MgCl.sub.2.

[1225] Compounds were tested in triplicate in 0.1% DMSO and 0.030% Pluronic Acid. Compounds were diluted 1:3 in EC solution to create a 10-point concentration response curve, spanning a final concentration range from 20-0.001 ?M in the assay plate. Each plate contained tetracaine and another tool compound as positive controls. Up to 8 compounds were tested on one plate. 250 ?M tetracaine and 0.1% DMSO were used as high and low controls, respectively. Whole cell patch clamp recordings were conducted according to Nanion's standard procedure for SyncroPatch384PE?. Cells were held at a holding potential of ?120 mV. A depolarization step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarization step to ?100 mV for 100 ms. An inactivation step at ?40 mV for 10 sec was applied before stepping to ?100 mV for 20 ms, followed by a step to 10 mV for 30 ms (P2 measurement) and then back to ?100 mV for 30 ms. Sweep interval was 15 sec with a sampling rate of 10 kHz. Following establishment of the whole-cell configuration in EC, two washing steps with reference buffer were performed to stabilize the baseline. Compounds were then applied by the SynchroPatch into each well and the current was recorded for five minutes in EC, followed by application of tetracaine to achieve full block at the end of the experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls. The IC50 values are listed in Table 16 as follows: A represents an IC50 less than or equal to 20 nM, B represents an IC50 greater than 20 nM to less than or equal to 40 nM, C represents an IC50 greater than 40 nM to less than or equal to 200 nM, D represents an IC50 greater than 200 nM to less than or equal to 500 nM.

TABLE-US-00017 TABLE 16 Compound P1IC50 P2IC50 Compound P1IC50 P2IC50 1 A A 2 A A 4 A A 14 D D 20 A B 21 B C 22 B C 23 A B 24 B C 25 A A 30 C C 31 C B 1401 D D 1402 B B 1403 B B 1404 C C 1405 A A 1406 C C 1407 D D 1408 C C 1409 A A 1412 A A 1415 A A 1416 C C 1417 D D 1418 A A 1419 A A 1420 D D 1421 A A 1422 A A 1423 D D 1424 A A 1425 A A 1426 A A 1427 A A 1428 C C 1429 D D 1431 D D 1432 D D 1433 C C 1434 D D 1435 D D 1436 B C 1437 C C 1438 C C 1439 C C 1440 D D 1441 D D 1442 D D 1443 D D 1444 D D 1445 D D 1446 B B 1447 B B 1448 D D 1449 D D 1450 A A 1451 D D 1452 C C 1453 A A 1454 A A 1455 D D 1456 D D 1457 D D 1458 D D 1459 A A 1460 D D 1461 D C 1462 D D 1463 A A 1464 D D 1465 A A 1466 A A 1467 A A 1468 A A 1469 A A 1470 D D 1471 A A 1472 A A 1473 A A 1474 A A 1475 A A 1476 A A 1477 A A 1478 A A 1479 A A 1480 A A 1481 A A 1482 A A 1484 D D 1485 D D 1486 A A 1487 A A 1488 A A 1489 A A 1490 A A 1491 A A 1492 A A 1493 A A 1494 A B 1495 A A 1496 A A 1497 A A 1498 C C 1499 C C 1500 C C 1501 A A 1502 A A 1503 A A 1504 A A 1505 A A 1506 A A 1507 C C 1508 C C 1509 C C 1510 A A 1511 A A 1512 A A 1513 D D 1514 C C 1515 A A 1516 D D 1517 A B 1518 A A 1519 B B 1520 D D 1521 D D 1522 D D 1523 D D 1524 D D 1525 A A 1526 A A 1527 B B 1528 C C 1529 A A 1530 C C 1531 C C 1532 C C 1533 B B 1534 B B 1535 B B 1536 C C 1537 B B 1538 C C 1539 C B 1540 C C 1541 D D 1542 D D 1543 C C 1544 C B 1545 D D 1546 C C 1547 D D 1548 B B 1549 A A 1550 A A 1551 A A 1552 A A 1553 D D 1554 D D 1555 D D 1556 C C 1557 A A 1558 A A 1559 A A 1560 A A 1561 A A 1562 A A 1563 B B 1564 B C 1565 D D 1566 D D 1567 A A 1568 B B 1569 A A 1570 B A 1571 D D 1572 C C 1573 A A 1574 A A 1575 A A 1576 C C 1577 D D 1578 D D 1579 D D 1581 D D 1582 D D 1583 B B 1584 ND ND 1585 D D 1586 D D 1587 C C 1588 C C 1589 C C 1590 D D 1591 D D 1592 D D 1593 A A 1594 C C 1595 B A 1596 D D 1597 D D 1598 D D 1599 D D 1600 D D 1601 D D 1602 D D 1603 A A 1604 C D 1605 D D 1606 D D 1607 nd nd 1608 A A 1609 C C 1610 D D 1611 D D 1612 ND ND 1613 ND ND 1614 ND ND 1615 A A 1616 D D 1617 B B 1618 A A 1619 A A 1620 D D 1621 D D 1622 D D 1623 D D 1624 D D 1625 D D 1626 D D 1627 ND ND 1628 ND ND 1629 C C 1630 A A 1631 D D 1632 D D 1633 C D 1634 D D 1635 C C 1636 A A 1637 D D 1638 D D 1639 D D 1640 D D 1642 A A 1643 A A 1644 A A 1645 D D 1646 C C 1647 A A 1648 A A 1649 D D 1650 C C 1651 A A 1652 B B 1653 C C 1655 A A 1656 C C 1657 D D 1658 D C 1659 C C 1660 C C 1661 A A 1662 D D 1663 D D 1664 D D 1665 D D 1666 C C 1667 D D 1668 D D 1669 C C 1670 D D 1671 D D 1672 D D 1673 D D 1674 D D 1675 D D 1676 D D 1677 D D 1678 D D 1679 D D 1680 B B 1681 A A 1683 B A 1684 A A 1685 A A 1686 A A 1687 D D 1688 D D 1689 C C 1690 A A 1691 C C 1692 C C 1693 A A 1694 D D 1695 D D 1696 D D 1697 B B 1698 D D 1699 D D 1700 D D 1701 B B 1702 C C 1703 D D 1704 ND ND 1705 ND ND 1706 D D 1707 A A 1708 D D 1709 A B 1710 D D 1711 B B 1712 A A 1714 A A 1715 A A 1716 A A 1717 A A 1718 D D 1719 A A 1720 A A 1721 D D 1722 D D 1723 B B 1724 C C 1725 D D 1726 D D 1727 D D 1728 A A 1729 A A 1730 A A 1731 A A 1732 D D 1733 D C 1742 C B 1743 A A 1744 C C NDNot Determined

B. Examples for Second Set of Compounds

Example 103

[1226] Compound 1: 2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.sup.2H.sub.3)methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide

##STR01663##

[1227] Step 1: 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid: To a solution of methyl 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (8.80 g, 26.1 mmol) in THF: water (33.4 mL; 5:1 v/v) was added LiOH.Math.H.sub.2O (5.61 g, 134 mmol) at rt. The resulting mixture was stirred at rt for further 3 h. AT the end of the tis period solvent was evaporated, to the residue water (20 mL) was added and acidified with 1N HCl. The solid separated was filtered and washed with water (2?20 mL) to provide 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (7.6 g, 90%). .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.63 (dd, J=2.6, 0.7 Hz, 1H), 8.47 (dq, J=2.7, 0.9 Hz, 1H), 7.03-6.84 (m, 3H), 2.09 (s, 3H).

[1228] Step 2: 2-(4-fluoro-2-methylphenoxy)-N-{3-[(.sup.2H.sub.3)methylsulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide: To a mixture of 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (6.0 g, 19.0 mmol), 3-[(.sup.2H.sub.3)methylsulfanyl]aniline (2.98 g, 20.9 mmol) in DMF (30 mL) was added HATU (10.9 g, 28.6 mmol) followed by DIEA (7.38 g, 57.1 mmol) at rt. The resulting mixture was stirred at rt for 16 h. At the end of this period water (30 mL) was added and extracted with EtOAc (2?40 mL). The EtOAc layer was washed with water (30 mL) and brine (30 mL), the organic layer was dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated. The crude was chromatographed over SiO.sub.2 with a gradient of 0-30 EtOAc % in hexane to provide 2-(4-fluoro-2-methylphenoxy)-N-{3-[(.sup.2H.sub.3)methylsulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide (7.80 g, 93%). .sup.1H NMR (300 MHz, CDCl.sub.3) ? 9.63 (s, 1H), 8.92-8.87 (m, 1H), 8.41 (dq, J=1.8, 0.9 Hz, 1H), 7.65 (t, J=1.9 Hz, 1H), 7.29-7.16 (m, 2H), 7.09-6.92 (m, 4H), 2.13 (s, 3H).

[1229] Step 3: 2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.sup.2H.sub.3)methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide: To a solution of 2-(4-fluoro-2-methylphenoxy)-N-{3-[(.sup.2H.sub.3)methylsulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide (7.80 g, 17.7 mmol) in MeOH (150 mL) was added ammonium carbobane (2.56 g, 26.6 mmol) and PIDA (13.1 g, 40.8 mmol) at rt. The mixture was stirred for 16 h at rt. At the end of this period solvent was evaporated, crude was dissolved in EtOAc (150 mL) and washed with saturated NaHCO3 solution, The EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated. The crude mixture was chromatographed over SiO.sub.2 with a gradient of 0-10% MeOH in DCM to provide 2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.sup.2H.sub.3)methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide (6.02 g, 72%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 10.98 (s, 1H), 8.67 (dt, J=2.5, 1.1 Hz, 1H), 8.61-8.52 (m, 1H), 8.39 (t, J=1.9 Hz, 1H), 7.95 (dt, J=8.2, 1.4 Hz, 1H), 7.75-7.56 (m, 2H), 7.34-7.06 (m, 3H), 4.25 (s, 1H), 2.10 (s, 3H).

Example 104

Compounds 2 and 3: (S)-2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.SUP.2.H.SUB.3.)methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide and (R)-2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.SUP.2.H.SUB.3.)methyl)oxo-?.SUP.6.-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide

[1230] ##STR01664##

[1231] Racemic mixture of 2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((2H.sub.3)methyl)oxo-6-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide was separated using following Chiral Purification Method: Mobile phase: 20% Methanol: 80% CO.sub.2; Column: Chiralpak AD-H, 10?250 mm, 5 ?m. Flow rate: 15 ml/min. First eluting isomer (S)-2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.sup.2H.sub.3)methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide (S)-2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.sup.2H.sub.3)methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.96 (s, 1H), 8.66 (dd, J=2.4, 1.0 Hz, 1H), 8.57-8.51 (m, 1H), 8.38 (t, J=1.8 Hz, 1H), 7.96-7.90 (m, 1H), 7.71-7.65 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.27 (dd, J=8.9, 5.1 Hz, 1H), 7.20 (dd, J=9.5, 3.0 Hz, 1H), 7.11 (td, J=8.5, 3.1 Hz, 1H), 4.21 (s, 1H), 2.09 (s, 3H). m/z 471.5 [M+H].sup.+, (ESI+), RT=4.04 LC-MS Method 5 and the second eluting isomer(R)-2-(4-fluoro-2-methylphenoxy)-N-{3-[imino((.sup.2H.sub.3)methyl)oxo-?.sup.6-sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide. .sup.1H NMR (400 MHz, DMSO-d6) ? 10.96 (s, 1H), 8.66 (dd, J=2.4, 1.0 Hz, 1H), 8.57-8.51 (m, 1H), 8.38 (t, J=1.9 Hz, 1H), 7.98-7.90 (m, 1H), 7.72-7.67 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.27 (dd, J=8.8, 5.1 Hz, 1H), 7.20 (dd, J=9.5, 3.0 Hz, 1H), 7.11 (td, J=8.5, 3.0 Hz, 1H), 4.22 (s, 1H), 2.09 (s, 3H). m/z 471.5 [M+H].sup.+, (ESI+), RT=4.05 LC-MS Method 5.

Example 105

Compound Profiling on Na.SUB.V.1.8Human Na.SUB.V.1.8 Cell LineSyncroPatch384PE Assay

[1232] Compounds were tested on recombinant human Na.sub.V1.8 stably transfected HEK cells using the SyncroPatch384PE system, an automated patch clamp device. Cells were cultured at 37? C./5% CO.sub.2 in DMEM medium supplemented with GlutaMAX I, NEAA 1%, FBS 10% and seeded in T175 flasks. Cells were cultured at 30? C. one day prior to recording sodium currents. On the day of the recordings, cells were detached with 0.05% Trypsin-EDTA, resuspended in serum free DMEM medium and placed into the SyncroPatch384PE 6? C. pre-cooled cell hotel and shaken at 200 rpm. Intracellular solution (IC) contained, in mM: 10, CsCl; 110, CsF; 20, EGTA; 10, HEPES. Extracellular solution (EC) contained, in mM: 140, NaCl; 4, KCl; 5, Glucose; 10, HEPES; 2, CaCl.sub.2; 1, MgCl.sub.2. Washing solution contained, in mM: 40, NMDG; 100, NaCl; 4, KCl; 10, Glucose; 10, HEPES; 5, CaCl.sub.2; 1, MgCl.sub.2.

[1233] Compounds were tested in triplicate in 0.1% DMSO and 0.030% Pluronic Acid. Compounds were diluted 1:3 in EC solution to create a 10-point concentration response curve, spanning a final concentration range from 20-0.001 ?M in the assay plate. Each plate contained tetracaine and another tool compound as positive controls. Up to 8 compounds were tested on one plate. 250 ?M tetracaine and 0.1% DMSO were used as high and low controls, respectively. Whole cell patch clamp recordings were conducted according to Nanion's standard procedure for SyncroPatch384PE?. Cells were held at a holding potential of ?120 mV. A depolarization step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarization step to ?100 mV for 100 ms. An inactivation step at ?40 mV for 10 sec was applied before stepping to ?100 mV for 20 ms, followed by a step to 10 mV for 30 ms (P2 measurement) and then back to ?100 mV for 30 ms. Sweep interval was 15 sec with a sampling rate of 10 kHz. Following establishment of the whole-cell configuration in EC, two washing steps with reference buffer were performed to stabilize the baseline. Compounds were then applied by the SynchroPatch into each well and the current was recorded for five minutes in EC, followed by application of tetracaine to achieve full block at the end of the experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls. The IC50 values are listed in Table 17 as follows: A represents an IC50 less than or equal to 20 nM, B represents an IC50 greater than 20 nM to less than or equal to 40 nM, C represents an IC50 greater than 40 nM to less than or equal to 200 nM, D represents an IC50 greater than 200 nM to less than or equal to 500 nM.

TABLE-US-00018 TABLE 17 Compound P1IC50 P2IC50 1 B B 2 A A 3 A A

C. Examples for Third Set of Compounds

Example 106

[1234] Methods of making the compounds of the present invention, and intermediates used in their synthesis, are provided in the General Synthetic Schemes and Specific Syntheses Procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. Dry glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted.

[1235] All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized. The chemical names were generated using the ChemDraw Professional 19.1, available from PerkinElmer or chem Axon.

[1236] Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD MILLIPORE?. Purification was performed with CombiFlash NextGen 300 Automated Flash Chromatography System or purified using one of the preparative HPLC methods mentioned below.

Prep Method 1 (P1): Acidic Early Method

[1237] Purification (METCR/Prep004) (P1) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 2 (P2): Acidic Standard Method

[1238] Purification (METCR/Prep001) (P2) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 30% B (A=0.10% formic acid in water; B=0.1% formic acid in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 3 (P3): Basic Early Method

[1239] Purification (METCR/Prep002) (P3) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 10% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 4 (P4): Basic Standard Method

[1240] Purification (METCR/Prep003) (P4) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 300% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

[1241] Analytical LCMC were collected using one of following methods.

Method 1 (M1): Acidic IPC Method (METCR1410MS17, MS18, MS19)

[1242] Analytical (MET/CR/1410) (M1) HPLC-MS were performed using a Kinetex Core shell C18 column (2.1 mm?50 mm, 5 ?m; temperature: 40? C.), with an injection volume of 3 ?L at a flow rate of 1.2 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.10% formic acid in acetonitrile) over 1.2 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.01 min and held for 0.39 min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector, spectrum range: 210-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 2(M2):

[1243] Mass spectrometry data were collected using a Waters Acquity H-class ultra-high pressure liquid chromatograph coupled to a Waters Acquity TQD mass spectrometer. An Acquity UPLC BEH C18 column (2.1?50 mm) was used for separation and resolving samples. The compounds were eluted from the column using a 10-minute linear solvent gradient: 0-0.5 min, 5% B; 0.5-6.5 min, 100% B, 6.5-7.5 min; 100% B, 7.5-8.1 min; 5% B, 8.1-10 min; 5% B. The solvent flow rate is 0.45 mL per minute. Solvent A was water and solvent B was acetonitrile. Mass spectra were collected in positive or negative ion mode, with following parameters: 2.5 kV capillary voltage; 25 V sampling cone voltage; 140 C source temperature; 400 C desolvation temperature; nitrogen desolvation at 800 L/hr.

Method 3 (M3): Basic IPC Method (MET-uPLC-AB-2005MS16, MSQ5)

[1244] Analytical (MET/uPLC/AB2005) (M14) uHPLC-MS were performed using a Waters uPLC? BEHTM C18 column (2.1 mm?30 mm, 1.7 ?m; temperature 40? C.), with an injection volume of 1 ?L at a flow rate of 1.0 mL/min and a gradient of 1-100% B (A=2 mM ammonium bicarbonate in water, buffered to pH 10; B=acetonitrile) over 1.1 min, then 100% B for 0.25 min. A second gradient of 100-1% B was then applied over 0.05 min and held for 0.4 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 4 (M4): Acidic Final Analysis Method (METCR-uPLC-AB101MSQ1, MSQ2, MSQ4)

[1245] Analytical (MET/uPLC/AB101) (M4) uHPLC-MS were performed using a Phenomenex Kinetex-XB C18 column (2.1 mm?100 mm, 1.7 ?m; temperature: 40? C.), with an injection volume of 1 ?L at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm, ELS data was collected on a Waters ACQUITY ELS detector when reported. Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDA. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 5 (M5): Acidic Final Analysis Method (METCR1416MS18, MS19)

[1246] Analytical (MET/CR/1416) (M5) HPLC-MS were performed using a Waters Atlantis dC18 column (2.1 mm?100 mm, 3 ?m; temperature: 40? C.), with an injection volume of 3 ?L at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 5 min, then 100% B for 0.4 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.58 min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector, spectrum range: 210-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 6 (M6): Basic Final Analysis Method (MET-uPLC-ABI05MS16, MSQ5)

[1247] Analytical (MET/uHPLC/AB105) (M8) uHPLC-MS were performed using a Waters uPLC? BEHTM C18 column (2.1 mm?100 mm, 1.7 ?m column; temperature: 40? C.), with an injection volume of 1 ?L and at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=2 mM ammonium bicarbonate in water, buffered to pH 10; B=acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[1248] SFC chiral resolution was performed using following method: Column: Daicel CHIRALPAK IG, 250 mm?20 mm I.D., 5 ?m; Mobile Phase A: CO.sub.2/MeOH [0.2% NH.sub.3 (7M Solution in MeOH)]=70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35? C.

[1249] Unless otherwise stated, .sup.1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker? 300 MHz, or 500 MHz, 400 MHz or 250 MHz on either a Bruker Avance III HD 500 MHz spectrometer Bruker Avance III HD 400 MHz spectrometer. Chemical shifts, 6, are quoted in parts per million (ppm) relative to TMS and calibrated using residual un-deuterated solvent as an internal reference. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

Example 107

General Synthetic Schemes

[1250] Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. The present invention further provides processes for the preparation of compounds of structural Formula I as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention.

##STR01665##

[1251] Scheme 1 represents a general method for the preparation of carboxamide derivatives of the present invention by treating carboxylic acid A-1 with R.sub.2NH.sub.2 using amide coupling agent HATU and DIEA as the base to provide intermediates of type A-2. The compounds of type A-3 can be obtained by reacting intermediates of type A-2 in organic solvents with various phenols in the presence of base, such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, DIEA or Et.sub.3N.

##STR01666## ##STR01667##

[1252] Alternatively, compounds of the formula A-3 may be synthesized in five step linear synthesis starting from dichlorocarboxylic acid ester B-1 by nucleophilic displacement of Cl adjacent to the carboxylic acid ester using various substituted phenols in the presence of base, such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaH, KH or other organic bases to provide intermediates of type B-2. Intermediates of type B-2 was further treated with HI (50%), HI (57%) or HI (40%) to furnish intermediates of type B-3. Variously substituted R.sub.3 groups can be introduced either by Pd mediated or Cu mediated coupling with intermediates of type B-3 to furnish B4. The carboxylic acid of intermediates type B-5 can be prepared by hydrolyzing ester intermediates of type B-4 using a base, such as aqueous NaOH, KOH, or LiOH. Alternatively, intermediates of type B-5 can be prepared by treating intermediates B-4 using aqueous 1 to 6N HCl. The carboxylic acids (B-5) can be activated to the acid chloride and coupled with R.sub.2NH.sub.2 or carboxylic acids (B-5) can be coupled with R.sub.2NH.sub.2 using standard amide coupling agents, not limited to HATU, TBTU, EDC or T.sub.3P in organic solvents and base, such as DIEA, Et.sub.3N, DMAP or pyridine to furnish A-3.

##STR01668##

[1253] Alternatively, compounds of the formula A-3 can be prepared nucleophilic displacement of C1 intermediates of type C-1 using various substituted phenols in the presence of base, such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaH, KH or other organic bases to provide intermediates of type C-2. The carboxylic acid of intermediates type C-3 can be prepared by hydrolyzing ester intermediates of type C-2 using a base, such as aqueous NaOH, KOH, or LiOH. Alternatively, intermediates of type C-3 can also be prepared by treating intermediates C-2 using aqueous 1 to 6N HCl. The carboxylic acids (C-3) can be activated to the acid chloride and coupled with R.sub.2NH.sub.2 or carboxylic acids (C-3) can coupled with R.sub.2NH.sub.2 using standard amide coupling agents, not limited to HATU, TBTU, EDC or T.sub.3P in organic solvents and base, such as DIEA, Et.sub.3N, DMAP or pyridine to furnish A-3.

##STR01669##

[1254] Alternatively, compounds of type A-3 can also be prepared by activating carboxylic acids (A-1) to the acid chloride and coupled with R.sub.2NH.sub.2 or carboxylic acids (A-1) can be coupled with R.sub.2NH.sub.2 using standard amide coupling agents, not limited to TBTU, EDC or T.sub.3P in organic solvents and base, such as DIEA, Et.sub.3N, DMAP or pyridine to furnish D-1. The compounds of type A-3 can be obtained by treating intermediates of type D-1 with various phenols in the presence of base, such as NaH (60%), K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, DIEA or Et.sub.3N in organic solvents.

Example 108

Specific Synthesis

Intermediate 1: 3-(4-Fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic Acid

[1255] ##STR01670##

Step 1: methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate

[1256] A mixture of 4-fluoro-2-methyl-phenol (3.01 g, 23.8 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (4.70 g, 22.7 mmol) and potassium carbonate (4.71 g, 34.1 mmol) in acetonitrile (47 mL) was stirred at 80? C. for 3 h. The reaction was cooled to room temperature, filtered, and washed with MeCN (20 mL). Filtrate was concentrated in vacuo to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 15% EtOAc in heptane afforded methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (95.0%) (4.10 g, 58%) as a pale yellow oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.26 (s, 1H), 7.29-7.20 (m, 2H), 7.16-7.06 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H). LC-MS (Method 5): m/z: 297/299 [M+H].sup.+, (ESI+), RT=4.26.

[1257] Step 2: methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate: A mixture of methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (4.10 g, 13.1 mmol) in hydroiodic acid (55%) (50 mL, 0.197 mol) was stirred at 40? C. for 3 h. The mixture was left overnight at rt. The reaction mixture was filtered. The filter cake was washed with water. The solid was re-dissolved in 55% aqueous hydrogen iodide (50 mL, 0.197 mol) and stirred at 40? C. for 24 h. The mixture was cooled to RT and filtered, the solid was washed with water and dried in high vacuum oven at 40? C. overnight to afford methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (79.0%) (2.70 g, 5.50 mmol, 42% Yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.37 (s, 1H), 7.26-7.17 (m, 2H), 7.15-7.05 (m, 1H), 3.91 (s, 3H), 2.09 (s, 3H). LC-MS (Method 1): m/z: 388.9 [M+H].sup.+, (ESI+), RT=1.24.

[1258] Step 3: methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: To a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (80%, 2.70 g, 5.57 mmol), copperiodide (1.598 g, 8.35 mmol), tetrabutylammonium iodide (0.824 g, 2.23 mmol) in DMF (10 mL). The mixture was degassed with nitrogen for 5 minutes and methyl difluoro(fluorosulfonyl)acetate (5.346 g, 27.8 mmol) was added and stirred at 90? C. for 2 h. The reaction was cooled to rt, filtered and the cake was washed with EtOAc (2?10 mL). The filtrate was washed with brine (50 mL) and dried over MgSO.sub.4, filtered, concentrated under reduced pressure to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 50% EtOAc in heptane afforded the title compound methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (0.770 g, 41%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.54 (s, 1H), 7.32-7.20 (m, 2H), 7.14 (td, J=8.5, 3.2 Hz, 1H), 3.97 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z: 316.95 [M+H].sup.+, (ESI+), RT=1.06 and unreacted starting material methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (0.220 g, 13%) as a pale yellow oil.

[1259] Step 4: 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: To a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (0.770 g, 2.31 mmol) in THF: H.sub.2O (10 mL, 4:1; v/v), lithium hydroxide (0.288 g, 11.5 mmol) was added and the mixture was stirred at rt overnight. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The solids were filtered, washed with water (2?10 mL), dissolved in EtOAc (20 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.640 g, 87%) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.49 (s, 1H), 7.31-7.22 (m, 2H), 7.18-7.09 (m, 1H), 2.12 (s, 3H). LC-MS (Method 1): m/z: 316.95 [M+H].sup.+, (ESI+), RT=1.06.

[1260] The intermediates listed in Table 18 were synthesized by a similar method as described for step 1 of Intermediate 1 synthesis using appropriate starting materials.

TABLE-US-00019 TABLE 18 Intermediate Structure and name Analytical data 2 [01671] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.24 (s, 1H), 7.28 (dd, J = 8.8, 5.8 Hz, 1H), 7.12 (dd, J = 10.7, 2.9 Hz, 1H), 6.88-6.79 (m, 1H), 3.93 (s, 3H), 3.71 (s, 3H). LC-MS (Method 1) m/z: 313.3/315.3 [M + H].sup.+, (ESI+), RT = 1.20 3 [01672] LC-MS: m (Method 2): m/z 301.0, 302.9 [M + H].sup.+ 4 [01673] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.96 (s, 1H), 7.65-7.49 (m, 3H), 7.23 (dd, J = 8.3, 2.7 Hz, 1H), 4.04 (s, 1H), 4.03 (s, 3H), 2.24 (d, J = 1.6 Hz, 3H) 5 [01674] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.90 (s, 1H), 7.43 (td, J = 2.9, 2.4, 1.6 Hz, 1H), 7.36 (ddd, J = 8.5, 2.5, 0.7 Hz, 1H), 6.99 (dd, J = 8.5, 6.4 Hz, 1H), 4.02(d, J = 1.5 Hz, 3H), 2.17 (s, 3H). 6 [01675] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.87 (s, 1H), 7.04-6.88 (m, 3H), 4.00 (s, 3H), 2.14 (s, 3H), 1.88 (tt, J = 8.4, 5.0 Hz, 1H), 1.02- 0.86 (m, 2H), 0.76-0.62 (m, 2H). 7 [01676] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.29 (s, 1H), 7.38-7.07 (m, 3H), 3.94 (s, 3H), 3.68 (s, 3H). 8 [01677] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.97 (s, 1H), 7.45 (ddd, J = 9.0, 5.6, 3.7 Hz, 1H), 7.08 (dt, J = 8.5, 3.2 Hz, 1H), 7.04-6.94 (m, 1H), 4.03 (d, J = 1.1 Hz,3H). 9 [01678] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.92 (s, 1H), 7.25-7.19 (m, 1H), 6.98-6.77 (m, 2H), 4.02 (d, J = 1.8 Hz, 3H), 2.14 (d, J = 1.0 Hz, 3H). 10 [01679] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 7.96 (s, 1H), 7.42-7.17 (m, 3H), 4.03 (d, J = 3.2 Hz, 3H), 3.77 (d, J = 6.0 Hz, 3H) 11 [01680] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.01 (s, 1H), 7.60-7.31 (m, 3H), 4.03 (d, J = 2.0 Hz, 3H) 12 [01681] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.27 (s, 1H), 7.46-7.05 (m, 5H), 3.92 (s, 3H). LC-MS (Method 1): m/z 330.95 [M + H].sup.+, (ESI+), RT = 1.20 13 [01682] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.29 (s, 1H), 7.44-7.40 (m, 1H), 7.39-7.26 (m, 2H), 3.94 (s, 3H), 2.16 (s, 3H). LC-MS (Method 1): m/z 363.0 [M + H].sup.+, (ESI+), RT = 1.32 14 [01683] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.29 (s, 1H), 7.78-7.74 (m, 1H), 7.67-7.61 (m, 1H), 7.47-7.38 (m, 1H), 3.92 (s, 3H), 2.20 (s, 3H). LC-MS(Method 1): m/z 347.1 [M + H].sup.+, (ESI+), RT = 0.98 15 [01684] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.35 (s, 1H), 7.68-7.57 (m, 2H), 7.48-7.40 (m, 1H), 3.94 (s, 3H). LC-MS (Method 1): m/z 367.3 [M + H].sup.+, (ESI+), RT = 1.30 16 [01685] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.30 (s, 1H), 7.64-7.58 (m, 1H), 7.41-7.28 (m, 3H), 3.92 (s, 3H). LC-MS (Method1): m/z 348.95 [M + H].sup.+, (ESI+), RT = 1.29 17 [01686] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.21 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.90-6.88 (m, 1H), 6.84-6.77 (m, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 2.05 (s, 3H) LC-MS (Method 1): m/z 309.0 [M + H].sup.+, (ESI+), RT = 1.22 18 [01687] LC-MS (ESI): m/z 301.0, 302.9[M + H].sup.+

[1261] The intermediates listed in Table 19 were synthesized by a similar method as described for step 2 of Intermediate 1 synthesis using appropriate starting material.

TABLE-US-00020 TABLE 19 Intermediate Structure and name Analytical data 19 [01688] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.35 (s, 1H), 7.25 (m, 1H), 7.13- 7.09 (m, 1H), 6.84-6.79 (m, 1H), 3.90 (s, 3H), 3.70 (s, 3H). LC-MS (Method 1): m/z: 404.9 [M + H].sup.+, (ESI+), RT = 1.19 20 [01689] MS (ESI+): m/z 392.9 [M + H].sup.+. 21 [01690] MS (ESI+): m/z 396.1 [M + H].sup.+ 22 [01691] MS (ESI+): m/z 449.0, 451.0[M + H].sup.+ 23 [01692] MS(ESI+): m/z 411.1,413.1[M + H].sup.+ 24 [01693] MS(ESI+): m/z 405.1[M + H].sup.+ 25 [01694] 26 [01695] MS(ESI+): m/z 389.0[M + H].sup.+ 27 [01696] MS(ESI+): m/z 412.1 [M + H].sup.+ 28 [01697] MS(ESI+): m/z 400.0 [M + H].sup.+ 29 [01698] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.38 (s, 1H), 7.41-7.10 (m, 5H), 3.90 (s, 3H). LC-MS (Method 1): m/z 422.95 [M + H].sup.+, (ESI+), RT = 1.23 30 [01699] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.40 (s, 1H), 7.43-7.39 (m, 1H), 7.34-7.24 (m, 2H), 3.91 (s, 3H), 2.14 (s, 3H). LC-MS (Method 1): m/z 454.95 [M + H].sup.+, (ESI+), RT = 1.35 31 [01700] LC-MS (Method 1): m/z 438.9 [M + H].sup.+, (ESI+), RT = 1.35 32 [01701] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.35 (s, 1H), 7.68-7.57 (m, 2H), 7.47-7.41 (m, 1H), 3.94 (s, 3H). LC-MS (Method 1): m/z 458.9 [M + H].sup.+, (ESI+), RT = 1.31 33 [01702] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.41 (s, 1H), 7.65-7.57 (m, 1H), 7.37-7.25 (m, 3H), 3.90 (s, 3H). LC-MS (Method 3): m/z 441.1 [M + H].sup.+, (ESI+), RT = 0.87 34 [01703] LC-MS (Method 1): m/z 401.0 [M + H]+, (ESI+), RT = 1.24 35 [01704] LC-MS (ESI): m/z 392.9 [M + H].sup.+

[1262] The intermediates listed in Table 20 were synthesized by a similar method as described for step 3 of Intermediate 1 synthesis using appropriate starting material.

TABLE-US-00021 TABLE 20 Intermediate Structure and name Analytical data 36 [01705] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.53 (s, 1H), 7.32 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 (td, J = 8.5, 2.9 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H). LC-MS(Method 3): m/z: 347.3 [M + H].sup.+, (ESI+), RT = 3.57 Methyl 3-(4-fluoro-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 37 [01706] MS(ESI+): m/z 335.0 [M + H].sup.+. Methyl 3-(2,4-difluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 38 [01707] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.28 (s, 1H), 7.68-7.55 (m, 2H), 7.27 (d, J = 8.5 Hz, 2H), 4.06 (s, 3H), 2.25 (s, 3H). Methyl 3-(4-cyano-2- methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 39 [01708] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.62 (s, 1H), 7.70 (dd, J = 2.5, 0.8 Hz, 1H), 7.57 (ddd, J = 8.6, 2.5, 0.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 4.03 (s, 3H), 2.19 (s, 3H) Methyl 3-(4-bromo-2- methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 40 [01709] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.20 (d, J = 3.1 Hz, 1H), 7.11-6.85 (m, 3H), 4.08-3.99 (m, 5H), 2.21 (dd, J = 9.1, 3.7 Hz, 1H), 2.16 (d, J = 7.0 Hz,4H), 1.06-0.84 (m, 2H), 0.78-0.52 (m, 2H). Methyl 3-(4-cyclopropyl-2- methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 41 [01710] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.25 (s, 1H), 7.07-6.88 (m, 3H), 4.05 (s, 3H), 3.70 (s, 3H). Methyl 3-(5-fluoro-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 42 [01711] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.29 (s, 1H), 7.47 (dd, J = 8.9, 5.6 Hz, 1H), 7.17- 6.97 (m, 2H), 4.07 (s, 3H). Methyl 3-(2-chloro-5- fluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 43 [01712] MS(ESI+): m/z 331.1[M + H].sup.+ Methyl 3-(5-fluoro-2- methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 44 [01713] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.28 (s, 1H), 7.43-7.30 (m, 2H), 7.30-7.23 (m, 2H), 4.06 (s, 3H), 3.76 (s, 3H). Methyl 3-(4-cyano-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 45 [01714] .sup.1H NMR (300 MHz, CDCl.sub.3) ? 8.32 (s, 1H), 7.62-7.53 (m, 2H), 7.51-7.44 (m, 1H), 4.07 (s, 3H). Methyl 3-(4-cyano-2- fluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 46 [01715] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.54 (s, 1H), 7.44-7.12 (m, 5H), 3.96 (s, 3H). LC-MS (Method 1): m/z 365.0 [M + H].sup.+, (ESI+), RT = 1.26 Methyl 3-(4- (difluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 47 [01716] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.56 (s, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.33 (dd, J = 8.9, 2.7 Hz, 1H), 3.97 (s, 3H), 2.17 (s, 3H). LC-MS (Method 1): m/z 397.0 [M + H].sup.+, (ESI+), RT = 1.38 Methyl 3-(2-methyl-4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 48 [01717] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.57 (s, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.68 (dd, J = 8.5, 2.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 2.22 (s, 3H). LC-MS (Method 1): m/z 381.0 [M + H].sup.+, (ESI+), RT = 1.36 Methyl 3-(2-methyl-4- (trifluoromethyl)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 49 [01718] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.62 (s, 1H), 7.72 (dd, J = 6.1, 2.7 Hz, 1H), 7.65 (t, J = 9.5 Hz, 1H), 7.51-7.46 (m, 1H), 3.97 (s, 3H). LC-MS (Method 1): m/z 400.95 [M + H]+, (ESI+), RT = 1.36 Methyl 3-(2-fluoro-5- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 50 [01719] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.57 (s, 1H), 7.68-7.60 (m, 1H), 7.49- 7.44 (m, 1H), 7.43-7.33 (m, 2H), 3.96 (s, 3H). LC-MS (Method 1): m/z 382.95 [M + H].sup.+, (ESI+), RT = 1.38 Methyl 3-(3- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 51 [01720] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.50 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 8.8, 3.1 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 2.07 (s, 3H).LC-MS (Method 4): m/z 343.0 [M + H].sup.+, (ESI+), RT = 1.29 methyl 3-(4-methoxy-2- methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate 52 [01721] LC-MS (ESI): m/z 335.0 [M + H].sup.+ Methyl 3-(2,4-difluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylate

[1263] The intermediates listed in Table 21 were synthesized by a similar method as described for step 4 of Intermediate 1 synthesis using appropriate starting materials.

TABLE-US-00022 TABLE 21 Intermediate Structure and name Analytical data 53 [01722] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.11 (s, 1H), 7.24 (dd, J = 8.8, 5.9 Hz, 1H), 7.12 (dd, J = 10.7, 2.8 Hz, 1H), 6.84 (dt, J = 8.5, 4.2 Hz, 1H), 3.71 (s, 4H). LC- MS(Method 1): m/z: 332.95 [M + H].sup.+, (ESI+), RT = 1.03 3-(4-Fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 54 [01723] LC-MS (Method 2): m/z 321.0 [M + H].sup.+. 3-(2,4-Difluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 55 [01724] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.55 (s, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.4, 2.1 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 2.20 (s, 3H). 3-(4-Cyano-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 56 [01725] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.56 (s, 1H), 7.69 (dd, J = 2.4, 0.9 Hz, 1H), 7.56 (dd, J = 8.6, 2.5 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 2.18 (s, 3H). 3-(4-Bromo-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 57 [01726] MS(ESI+): m/z 337.0 [M ? H].sup.+ 3-(4-Cyclopropyl-2- methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 58 [01727] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.51 (s, 1H), 7.38-7.29 (m, 1H), 7.29-7.12 (m, 2H), 3.69 (s, 3H) 3-(5-Fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 59 [01728] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.62 (s, 1H), 7.79 (dd, J = 9.0, 5.7 Hz, 1H), 7.62 (dd, J = 9.1, 3.0 Hz, 1H), 7.47- 7.26 (m, 1H). 3-(2-Chloro-5-fluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 60 [01729] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.27 (s, 1H), 7.40 (dd, J = 8.5, 6.6 Hz, 1H), 7.21-7.03 (m, 2H), 2.07 (d, J = 2.9 Hz, 3H). 3-(5-Fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 61 [01730] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.53 (s, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.63- 7.49 (m, 2H), 3.77 (s, 3H) 3-(4-Cyano-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 62 [01731] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 8.56 (s, 1H), 8.26-8.10 (m, 1H), 7.96-7.80 (m, 1H), 7.83-7.71 (m, 1H). 3-(4-Cyano-2-fluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 63 [01732] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.48 (s, 1H), 7.47-7.06 (m, 5H).LC-MS (Method 1): m/z 350.95 [M + H].sup.+, (ESI+), RT = 1.07 3-(4-(Difluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 64 [01733] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.50 (s, 1H), 7.46-7.29 (m, 3H), 2.16 (s, 3H). LC-MS (Method 1): m/z 382.95 [M + H].sup.+, (ESI+), RT = 1.19 3-(2-Methyl-4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 65 [01734] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.16 (s, 1H), 8.51 (s, 1H), 7.82-7.78 (m, 1H), 7.67 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 2.21 (s, 3H). LC-MS (Method 1): m/z 367.0 [M + H].sup.+, (ESI+), RT = 1.18 3-(2-Methyl-4- (trifluoromethyl)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 66 [01735] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.53 (s, 1H), 7.71 (dd, J = 6.3, 2.7 Hz, 1H), 7.67-7.59 (m, 1H), 7.46 (d, J = 9.2 Hz, 1H). LC-MS (Method 1): m/z 386.85 [M + H].sup.+, (ESI+), RT = 1.15 3-(2-Fluoro-5- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 67 [01736] LC-MS (Method 1): m/z 368.9 [M + H].sup.+, (ESI+), RT = 1.14 3-(3-(Trifluoromethoxy)phenoxy)- 6-(trifluoromethyl)pyridazine-4- carboxylic acid 68 [01737] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.43 (s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 8.8, 3.0 Hz, 1H), 3.76 (s, 3H), 2.06 (s, 3H). LC- MS (Method 1): m/z 328.95 [M + H].sup.+, (ESI+), RT = 1.06 3-(4-Methoxy-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid 69 [01738] LC-MS (ESI): m/z found 321.0 [M + H].sup.+ 3-(2,4-Difluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxylic acid

Example 109

Intermediate 70: 2-ethoxy-4-fluoro-phenol

[1264] ##STR01739##

[1265] (2-Ethoxy-4-fluoro-phenyl)boronic acid (0.725 g, 3.94 mmol) was dissolved in THE (15.7 mL) and cooled to 0? C. Then 14.7 M hydrogen peroxide (50% aqueous solution) (50%, 1.2 mL, 17.3 mmol) and 2 M sodium hydroxide (3.9 mL, 7.88 mmol) were added. The reaction mixture was slowly warmed to rt. Stirred at rt for 90 minutes. The reaction was diluted with HCl (2N, 20 mL) and water (10 mL) and extracted with EtOAc (?2). Combined organics dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to a dark brown gum. Purified by column chromatography in a gradient of (0-50%) ethyl acetate and heptane to yield the title compound 2-ethoxy-4-fluoro-phenol (0.503 g, 690%) as a pale brown oil. .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.83 (dd, J=8.7, 5.5 Hz, 1H), 6.60 (dd, J=9.8, 2.8 Hz, 1H), 6.55 (td, J=8.6, 2.8 Hz, 1H), 5.38 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H). LC-MS (Method 3): m/z: 155.1 [M?H].sup.?, (ESI?), RT=0.61.

Intermediate 71 and 72

Synthesis of tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-?.SUP.6.-sulfaneylidene) carbamate [Intermediate 71] and tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-?.SUP.6.-sulfaneylidene) carbamate [Intermediate 72]

[1266] ##STR01740##

Step 1: imino(methyl)(3-nitrophenyl)-?.SUP.6.-sulfanone

[1267] To a mixture of methyl(3-nitrophenyl) sulfane (8.2 g, 48.5 mmol) and ammonium acetate (5.6 g, 72.7 mmol) in EtOH (120 mL) was added PhI(OAc).sub.2 (31.2 g, 97 mmol) in one portion. The reaction mixture was stirred at room temperature under atmosphere for 16 h. The mixture was concentrated directly to give a residue which was purified by silica gel chromatography column (PE:EA=5:1 to 1:3) to afford imino(methyl)(3-nitrophenyl)-?.sup.6-sulfanone as a white solid (7.0 g, 72%). MS (ESI+): m/z found 201.03 [M+H].sup.+.

Step 2: tert-butyl (methyl(3-nitrophenyl)(oxo)-?.SUP.6.-sulfaneylidene)carbamate

[1268] To a solution of imino(methyl)(3-nitrophenyl)-16-sulfanone (3.5 g, 17.5 mmol) in t-BuOH (200 mL) cooled with ice water bath was added t-BuOK (3.9 g, 35.0 mmol) under N.sub.2 protection. Subsequently, (Boc).sub.2O (7.6 g, 35.0 mmol) was added slowly and the reaction mixture was then refluxed for 10 h. The reaction mixture was quenched with saturated NH.sub.4Cl solution (200 mL) and extracted with EA (200 mL?2). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give a residue which was purified with silica gel chromatography column (PE:EA=5:1 to 1:1) to afford tert-butyl (methyl(3-nitrophenyl)(oxo)-?.sup.6-sulfaneylidene)carbamate as yellow solid (1.8 g, 34%). LC-MS(ESI+): m/z 301.09 [M+H].sup.+.

Step 3: (3-aminophenyl)(imino)(methyl)-?.SUP.6.-sulfanone

[1269] To a solution of tert-butyl (methyl(3-nitrophenyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (1.8 g, 6 mmol) in MeOH (30 mL) was added Pd(OH).sub.2 (300 mg) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through celite and washed with MeOH (100 mL). The filtrate was concentrated to give a residue which was re-dissolved in EA (30 mL) and the resulting solution was filtered through celite again and washed with EA (100 mL). The filtrate was concentrated to give tert-butyl ((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate (1.4 g, 86%) as off-white solid. MS (ESI+): m/z found 271.10 [M+H].sup.+.

Step 4: SFC Separation

[1270] The racemic product was separated by chiral HPLC with the Chiral separation condition: Column: Daicel CHIRALPAK IG, 250 mm?20 mm I.D., 5 ?m; Mobile Phase A: CO.sub.2/MeOH [0.2% NH.sub.3 (7M Solution in MeOH)]=70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35? C. The first eluting isomer tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate [Intermediate 71]. .sup.1H NMR (DMSO-d.sub.6) ?7.26 (t, 1H), 7.08 (s, 1H), 6.97 (d, 1H), 6.83 (d, 1H), 5.71 (s, 2H), 3.28 (s, 3H), 1.27 (s. 9H) and the second eluting isomer tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate [Intermediate 72]. .sup.1H NMR (DMSO-d.sub.6) ?7.26 (t, 1H), 7.08 (s, 1H), 6.97 (d, 1H), 6.83 (d, 1H), 5.71 (s, 2H), 3.28 (s, 3H), 1.27 (s. 9H).

Example 110

Compound 1: 3-(4-fluoro-2-methoxyphenoxy)-N-(2-(methylsulfonyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1271] ##STR01741##

[1272] A mixture of 50% propylphosphonic anhydride solution in EtOAc (0.098 g, 0.309 mmol) 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.090 g, 0.257 mmol), N,N-dimethylpyridin-4-amine (6.3 mg, 0.0515 mmol) and N-ethyl-N-isopropyl-propan-2-amine (DIEA) (0.090 mL, 0.515 mmol) were dissolved in DCM (1.28 mL) under nitrogen at rt. After 15 min 2-methylsulfonylpyridin-4-amine (0.053 g, 0.309 mmol) was added in one portion. The reaction mixture was stirred at rt for 3 h. The reaction mixture was poured into water (10 mL) and brine (5 mL) and extracted with DCM (3?10 mL), dried over Na.sub.2SO.sub.4 and concentrated. Purification by Method 2 afforded the title compound 3-(4-fluoro-2-methoxy-phenoxy)-N-(2-methylsulfonyl-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.087 g, 69%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.67 (s, 1H), 8.74 (d, J=5.4 Hz, 1H), 8.68 (s, 1H), 8.40 (d, J=1.9 Hz, 1H), 7.91 (dd, J=5.4, 2.0 Hz, 1H), 7.39 (dd, J=8.8, 5.8 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 3.29 (s, 3H). LC-MS (Method 1): m/z: 487.3 [M+H].sup.+, (ESI+), RT=3.15.

[1273] The compounds listed in Table 22 were synthesized by a similar method as described for Compound 1 using appropriate acids and substituted anilines.

TABLE-US-00023 TABLE 22 Compound Structure & name Analytical data 2 [01742] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.68 (s, 1H), 8.75 (d, J = 5.3 Hz, 1H), 8.70 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 7.92-7.85 (m, 1H), 7.35 (dd, J = 9.0, 5.0 Hz, 1H), 7.26 (dd, J = 9.5, 2.9 Hz, 1H), 7.19-7.12 (m, 1H), 3.29 (s, 3H), 2.13 (s, 3H). LC- MS(Method 6): m/z: 470.9 [M + H].sup.+, (ESI+), RT = 4.22 3-(4-Fluoro-2-methylphenoxy)-N-(2- (methylsulfonyl)pyridin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 3 [01743] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.36 (s, 1H), 10.94 (s, 1H), 8.63 (s, 1H), 7.40-7.30 (m, 2H), 7.25 (dd, J = 9.4, 3.1 Hz, 1H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 6.38 (dd, J = 7.2, 2.0 Hz, 1H), 2.12 (s, 3H). LC-MS(Method 4): m/z 408.9 [M + H].sup.+, (ESI+), RT = 3.72 3-(4-Fluoro-2-methylphenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 4 [01744] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.90 (s, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 8.24 (t, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.32 (s, 1H), 7.24 (dd, J = 9.3, 2.9 Hz, 1H), 7.14 (td, J = 8.6, 3.0 Hz, 1H), 3.25 (s, 3H), 2.11 (s, 3H). LC-MS (method 4): m/z 470.9 [M + H].sup.+, (ESI+), RT = 4.3 3-(4-Fluoro-2-methylphenoxy)-N-(6- (methylsulfonyl)pyridin-2-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 5 [01745] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 12.96 (s, 1H), 11.34 (s, 1H), 8.67 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 9.0, 5.0 Hz, 1H), 7.29-7.23 (m, 2H), 7.16 (td, J = 8.5, 3.1 Hz, 1H), 2.13 (s, 3H). LC-MS (Method 4): m/z 409.9 [M + H].sup.+, (ESI+), RT = 3.75 3-(4-Fluoro-2-methylphenoxy)-N-(6- oxo-1,6-dihydropyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 6 [01746] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.53 (s, 1H), 9.05 (d, J = 2.4 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.73 (t, J = 2.2 Hz, 1H), 8.69 (s, 1H), 7.35 (dd, J = 8.9, 5.0 Hz, 1H), 7.26 (dd, J = 9.4, 3.0 Hz, 1H), 7.16 (td, J = 8.5, 3.1 Hz, 1H), 3.37 (s, 3H), 2.14 (s, 3H). LC-MS (Method 4): m/z 470.9 [M + H].sup.+, (ESI+), RT = 4.09 3-(4-Fluoro-2-methylphenoxy)-N-(5- (methylsulfonyl)pyridin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 7 [01747] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.27 (s, 1H), 8.68 (s, 1H), 8.30 (t, J = 1.8 Hz, 1H), 8.00-7.93 (m, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.68-7.64 (m, 1H), 7.34 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 3.42 (hept, J = 6.7 Hz, 1H), 2.13 (s, 3H), 1.18 (d, J = 6.7 Hz, 6H). LC-MS (Method 5): m/z 498.0 [M + H].sup.+, RT = 4.53 3-(4-Fluoro-2-methylphenoxy)-N-(3- (isopropylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 8 [01748] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.91 (s, 1H), 9.86 (s, 1H), 8.63 (s, 1H), 7.64 (t, J = 2.0 Hz, 1H), 7.50- 7.43 (m, 1H), 7.38-7.30 (m, 2H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 7.04-6.97 (m, 1H), 3.00 (s, 3H), 2.13 (s, 3H). LC-MS (Method 5): m/z 484.9 [M + H].sup.+, RT = 4.24 3-(4-Fluoro-2-methylphenoxy)-N-(3- (methylsulfonamido)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 9 [01749] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.87 (s, 1H), 9.17 (s, 1H), 8.55 (s, 1H), 8.25 (t, J = 2.0 Hz, 1H), 8.19 (s, 1H), 7.72-7.68 (m, 1H), 7.66 (ddd, J = 8.2, 2.1, 1.1 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 (dd, J = 9.3, 3.1 Hz, 1H), 7.11 (td, J = 8.5, 3.1 Hz, 1H), 2.17 (s, 3H). LC-MS (Method 5): m/z 458.9 [M + H].sup.+, (ESI+), RT = 4.33 N-(3-(1H-1,2,4-Triazol-1-yl)phenyl)-3- (4-fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 10 [01750] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.97 (s, 1H), 8.65 (s, 1H), 7.77 (t, J = 1.9 Hz, 1H), 7.74-7.70 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.34 (dd, J = 9.0, 5.0 Hz, 1H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.23-7.19 (m, 1H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 4.53 (s, 2H), 2.94 (s, 3H), 2.13 (s, 3H). LC- MS (Method 5): m/z 483.9 [M + H].sup.+, (ESI+), RT = 4.21 3-(4-Fluoro-2-methylphenoxy)-N-(3- ((methylsulfonyl)methyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 11 [01751] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.35 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H), 8.57 (d, J = 7.3 Hz, 1H), 8.25 (s, 1H), 7.36 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.3, 3.1 Hz, 1H), 7.16 (td, J = 8.5, 3.1 Hz, 1H), 7.06 (dd, J = 7.4, 1.8 Hz, 1H), 2.14 (s, 3H). LC- MS(Method 5): m/z: 433.0 [M + H]+, (ESI+), RT = 3.68 N-([1,2,4]Triazolo[4,3-a]pyridin-7-yl)-3- (4-fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 12 [01752] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.15 (s, 1H), 9.07 (s, 2H), 8.64 (s, 1H), 8.01-7.94 (m, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.52-7.45 (m, 1H), 7.34 (dd, J = 8.8, 5.1 Hz, 1H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 2.14 (s, 3H). LC-MS (Method 5): m/z: 458.9 [M + H]+, (ESI+), RT = 4.01 N-(3-(4H-1,2,4-Triazol-4-yl)phenyl)-3- (4-fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 13 [01753] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.54 (s, 1H), 9.39 (m, 1H), 9.18 (m, 1H), 8.69 (s, 1H), 8.06 (dd, J = 5.9, 2.7 Hz, 1H), 7.39 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.89 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H). LC-MS (Method 6): m/z: 486.3 [M + H].sup.+, (ESI+), RT = 3.48 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 14 [01754] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.54 (s, 1H), 9.39 (m, 1H), 9.18 (m, 1H), 8.69 (s, 1H), 8.06 (dd, J = 5.9, 2.7 Hz, 1H), 7.39 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.89 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H). LC-MS (Method 6): m/z: 410.4 [M + H]+, (ESI+), RT = 2.52 3-(4-Fluoro-2-methoxyphenoxy)-N- (pyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 15 [01755] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.86 (s, 1H), 8.62 (s, 1H), 8.48 (m, 1H), 8.25 (t, J = 8.0 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.36 (m, 1H), 7.14 (dd, J = 10.6, 2.6 Hz, 1H), 6.86 (m, 1H), 3.72 (s, 3H), 3.30-3.18 (m, 3H). LC-MS (Method 6): m/z 487.3 [M + H].sup.+, (ESI+), RT = 3.4 3-(4-Fluoro-2-methoxyphenoxy)-N-(6- (methylsulfonyl)pyridin-2-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 16 [01756] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.50 (s, 1H), 9.07 (d, J = 2.4 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.73 (t, J = 2.2 Hz, 1H), 8.67 (s, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 3.37 (s, 3H). LC-MS (Method 6): m/z 487.3 [M + H]+, RT = 3.07 3-(4-Fluoro-2-methoxyphenoxy)-N-(5- (methylsulfonyl)pyridin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 17 [01757] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.27 (s, 1H), 8.66 (s, 1H), 8.32 (t, J = 1.8 Hz, 1H), 7.97 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.65 (dt, J = 7.8, 1.2 Hz, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 3.42 (hept, J = 6.8 Hz, 1H), 1.18 (d, J = 6.8 Hz, 6H). LC-MS (Method 5): m/z 514.0 [M + H].sup.+, RT = 4.47 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (isopropylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 18 [01758] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.91 (s, 1H), 9.87 (s, 1H), 8.59 (s, 1H), 7.66 (t, J = 2.0 Hz, 1H), 7.49- 7.43 (m, 1H), 7.41-7.29 (m, 2H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 7.00 (ddd, J = 8.1, 2.0, 0.8 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 3.00 (s, 3H). LC-MS (Method 5): m/z 500.9 [M + H].sup.+, RT = 4.18 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (methylsulfonamido)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 19 [01759] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.96 (s, 1H), 8.61 (s, 1H), 7.83- 7.76 (m, 1H), 7.76-7.69 (m, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.25-7.18 (m, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 4.53 (s, 2H), 3.73 (s, 3H), 2.94 (s, 3H). LC-MS (Method 5): m/z 499.9 [M + H].sup.+, RT = 4.14 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- ((methylsulfonyl)methyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 20 [01760] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.13 (s, 1H), 9.30 (s, 1H), 8.63 (s, 1H), 8.31 (t, J = 2.0 Hz, 1H), 8.26 (s, 1H), 7.71-7.68 (m, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.58 (dd, J = 8.7, 7.4 Hz, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H). LC-MS (Method 6): m/z: 475.5 [M + H].sup.+, RT = 3.43 N-(3-(1H-1,2,4-Triazol-1-yl)phenyl)-3- (4-fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 21 [01761] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 9.20-9.20 (m, 1H), 8.68 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H), 8.25 (s, 1H), 7.40 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.8 Hz, 1H), 7.06 (dd, J = 7.4, 1.7 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H). LC-MS (Method 5): m/z: 449.0 [M + H].sup.+, RT = 3.58 N-([1,2,4]Triazolo[4,3-a]pyridin-7-yl)-3- (4-fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 22 [01762] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.15 (s, 1H), 9.08 (s, 2H), 8.62 (s, 1H), 8.00 (t, J = 2.0 Hz, 1H), 7.71 (ddd, J = 8.3, 2.0, 1.0 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 7.49 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H). LC-MS (Method 5): m/z 474.9 [M + H].sup.+,RT = 3.93 N-(3-(4H-1,2,4-Triazol-4-yl)phenyl)-3- (4-fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 23 [01763] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.01 (s, 1H), 8.73 (dd, J = 7.1, 2.3 Hz, 1H), 8.61 (s, 1H), 7.85 (ddd, J = 8.6, 4.5, 2.4 Hz, 1H), 7.66 (dd, J = 10.4, 8.7 Hz, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.74 (s, 3H), 3.26 (s, 3H). LC_MS (Method 5): m/z 503.9 [M + H].sup.+, RT = 4.30 3-(4-Fluoro-2-methoxyphenoxy)-N-(2- fluoro-5-(methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 24 [01764] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 12.94 (s, 1H), 11.32 (s, 1H), 8.65 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.9, 5.8 Hz, 1H), 7.27 (s, 1H), 7.16 (dd, J = 10.8, 2.8 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.72 (s, 3H). LC-MS (Method 5): m/z 425.9 [M + H].sup.+, RT = 3.64 3-(4-Fluoro-2-methoxyphenoxy)-N-(6- oxo-1,6-dihydropyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 25 [01765] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.25 (s, 1H), 8.66 (s, 1H), 8.37- 8.31 (m, 1H), 7.99-7.92 (m, 1H), 7.73-7.66 (m, 2H), 7.38 (dd, J = 8.9, 5.9 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 2.91-2.84 (m, 1H), 1.15-1.10 (m, 2H), 1.10-1.04 (m, 2H). LC-MS (Method 5): m/z 511.9 [M + H].sup.+, RT = 4.39 N-(3-(Cyclopropylsulfonyl)phenyl)-3-(4- fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 26 [01766] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.95 (s, 1H), 8.61 (s, 1H), 8.17 (t, J = 1.8 Hz, 1H), 8.00 (s, 1H), 7.89- 7.82 (m, 1H), 7.69-7.62 (m, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.42-7.34 (m, 2H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H). LC_MS (Method 5): m/z 450.9 [M + H].sup.+, RT = 3.88 N-(3-Carbamoylphenyl)-3-(4-fluoro-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 27 [01767] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.05 (s, 1H), 8.63 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.38 (dd, J = 8.8, 5.9 Hz, 1H), 7.31 (s, 2H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.8 Hz, 1H), 3.73 (s, 3H). LC-MS (Method 5): m/z 450.9 [M + H].sup.+, RT = 3.88 N-(4-Carbamoylphenyl)-3-(4-fluoro-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 28 [01768] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.32 (s, 1H), 8.63 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.35 (dd, J = 8.9, 5.0 Hz, 1H), 7.27 (dd, J = 9.4, 3.1 Hz, 1H), 7.17 (td, J = 8.7, 3.3 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 2.39 (s, 3H), 2.15 (s, 3H). LC-MS (Method 6): m/z 437.4 [M + H].sup.+, RT = 3.92 3-(4-Fluoro-2-methylphenoxy)-N-(6- methoxy-2-methylpyridin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 29 [01769] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.24 (s, 1H), 8.65 (s, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 7.37 (dd, J = 8.8, 5.1 Hz, 1H), 7.27 (dd, J = 9.3, 3.0 Hz, 1H), 7.17 (td, J = 8.6, 3.1 Hz, 1H), 3.83 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H). LC-MS (Method 6): m/z 437.4 [M + H].sup.+, RT = 4.0 3-(4-Fluoro-2-methylphenoxy)-N-(2- methoxy-5-methylpyridin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 30 [01770] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.55 (s, 1H), 8.64 (s, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 5.5 Hz, 1H), 7.39 (dd, J = 9.0, 5.1 Hz, 1H), 7.27 (dd, J = 9.3, 2.9 Hz, 1H), 7.17 (td, J = 8.5, 3.2 Hz, 1H), 3.94 (s, 3H), 2.18 (s, 3H). LC-MS (Method 5): m/z 500.9, 502.9 [M + H].sup.+, RT = 5.09 3-(4-Fluoro-2-methylphenoxy)-N-(2- methoxy-3-methylpyridin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 31 [01771] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.55 (s, 1H), 8.64 (s, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 5.5 Hz, 1H), 7.39 (dd, J = 9.0, 5.1 Hz, 1H), 7.27 (dd, J = 9.3, 2.9 Hz, 1H), 7.17 (td, J = 8.5, 3.2 Hz, 1H), 3.94 (s, 3H), 2.18 (s, 3H). LC-MS (Method 5) m/z 500.9, 502.9 [M + H].sup.+, RT = 5.09 N-(3-Bromo-2-methoxypyridin-4-yl)-3- (4-fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 32 [01772] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.84 (s, 1H), 8.63 (s, 1H), 7.70- 7.63 (m, 2H), 7.37-7.29 (m, 3H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.6, 3.2 Hz, 1H), 2.47 (s, 3H), 2.13 (s, 3H). 3-(4-Fluoro-2-methylphenoxy)-N-(4- (methylthio)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 33 [01773] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.17 (s, 1H), 8.64 (s, 1H), 8.16- 8.10 (m, 1H), 7.37 (dd, J = 8.8, 5.9 Hz, 1H), 7.22-7.11 (m, 3H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 3H). LC_MS (Method 5): m/z 439.1 [M + H].sup.+, RT = 4.35 3-(4-Fluoro-2-methoxyphenoxy)-N-(2- methoxypyridin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 34 [01774] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.24 (s, 1H), 8.64 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.98-7.93 (m, 1H), 7.74 (dt, J = 7.9, 1.5 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.45-7.11 (m, 5H), 3.23 (s, 3H). LCMS (Method 5): m/z 504.0 [M + H].sup.+, RT = 4.23 3-(4-(Difluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 35 [01775] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.26 (s, 1H), 8.69 (s, 1H), 8.36 (t, J = 1.8 Hz, 1H), 7.97-7.92 (m, 1H), 7.75 (dt, J = 7.8, 1.4 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.48-7.41 (m, 2H), 7.34 (dd, J = 8.8, 2.8 Hz, 1H), 3.23 (s, 3H), 2.18 (s, 3H). LCMS (Method 5): m/z 536.0 [M + H].sup.+, RT = 4.59 3-(2-Methyl-4- (trifluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 36 [01776] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.13 (s, 1H), 8.64 (s, 1H), 8.05 (s, 1H), 8.02 (t, J = 2.0 Hz, 1H), 7.78- 7.71 (m, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.42 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 7.38 (dd, J = 8.8, 5.9 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.6, 2.9 Hz, 1H), 3.73 (s, 3H), 2.51 (s, 3H). LC-MS (Method 6): m/z 489.3 [M + H].sup.+, RT = 3.39 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (5-methyl-1H-1,2,4-triazol-1-yl)phenyl)- 6-(trifluoromethyl)pyridazine-4- carboxamide 37 [01777] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.06 (s, 1H), 8.67 (s, 1H), 7.91 (d, J = 8.7 Hz, 3H), 7.74 (d, J = 8.7 Hz, 2H), 7.48-7.39 (m, 2H), 7.36-7.28 (m, 2H), 2.16 (s, 3H). LC-MS (Method 4): m/z 501.1 [M + H].sup.+, RT = 3.47 N-(4-Carbamoylphenyl)-3-(2-methyl-4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 38 [01778] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.07 (s, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.88- 7.83 (m, 1H), 7.61-7.53 (m, 2H), 7.39 (dd, J = 8.9, 6.0 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.77 (s, 3H), 3.73 (s, 3H). LC-MS (Method 5): m/z 489.0 [M + H].sup.+, RT = 3.9 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (4-methyl-4H-1,2,4-triazol-3-yl)phenyl)- 6-(trifluoromethyl)pyridazine-4- carboxamide 39 [01779] .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.55 (s, 1H), 8.44 (s, 1H), 8.33 (t, J = 1.9 Hz, 1H), 7.91 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 7.73 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.8, 5.6 Hz, 1H), 6.99 (dd, J = 10.3, 2.8 Hz, 1H), 6.83- 6.76 (m, 1H), 3.77 (s, 3H). LC- MS(Method 5): m/z 486.9 [M + H].sup.+, RT = 4.01 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 40 [01780] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.68 (s, 1H), 8.02- 7.89 (m, 4H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.6, 3.2 Hz, 1H), 3.19 (s, 3H), 2.13 (s, 3H). LCMS (Method 5): m/z 470.1 [M + H].sup.+, RT = 4.16 3-(4-Fluoro-2-methylphenoxy)-N-(4- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 41 [01781] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.48 (bs, 1H), 10.62 (s, 1H), 8.59 (s, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 9.7, 2.8 Hz, 1H), 7.33 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.5, 2.9 Hz, 1H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 6.43 (d, J = 9.7 Hz, 1H), 2.13 (s, 3H). LCMS (Method 5): m/z 409.1 [M + H].sup.+, RT = 3.6 3-(4-Fluoro-2-methylphenoxy)-N-(6- oxo-1,6-dihydropyridin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 42 [01782] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.30 (s, 1H), 8.71 (s, 1H), 8.36 (t, J = 1.8 Hz, 1H), 7.97-7.91 (m, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.76-7.67 (m, 3H), 7.55 (d, J = 8.5 Hz, 1H), 3.23 (s, 3H), 2.23 (s, 3H). LCMS (Method 4): m/z 520.1 [M + H].sup.+, RT = 3.79 3-(2-Methyl-4- (trifluoromethyl)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 43 [01783] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.55 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.98 (s, 2H), 7.37 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC-MS (Method 4): m/z: 513.0 [M + H].sup.+, RT = 3.64 N-(1,1-Dioxido-3-oxo-2,3- dihydrobenzo[d]isothiazol-6-yl)-3-(4- fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 44 [01784] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.27 (s, 1H), 8.75 (s, 1H), 8.36 (t, J = 1.8 Hz, 1H), 7.96 (dt, J = 7.8, 1.6 Hz, 1H), 7.80-7.69 (m, 3H), 7.65 (t, J = 9.5 Hz, 1H), 7.52-7.45 (m, 1H), 3.24 (s, 3H). LC-MS (Method 5): m/z 539.9 [M + H].sup.+, RT = 4.50 3-(2-Fluoro-5- (trifluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 45 [01785] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.19 (s, 1H), 8.64 (s, 1H), 8.32- 8.27 (m, 1H), 8.00-7.94 (m, 1H), 7.70-7.61 (m, 2H), 7.38 (dd, J = 8.9, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.88-3.79 (m, 1H), 3.73 (s, 3H), 3.71-3.61 (m, 1H), 3.44-3.37 (m, 2H), 2.31-2.13 (m, 2H). LC-MS (Method 5): m/z 510.9 [M + H]+, (ESI+), RT = 3.48 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (1-oxido-4,5-dihydro-3H-1l6-isothiazol- 1-yl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 46 [01786] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 12.14 (s, 1H), 9.64 (s, 1H), 9.03 (s, 1H), 8.68-8.57 (m, 1H), 7.47-7.28 (m, 1H), 7.15 (dd, J = 10.7, 2.7 Hz, 1H), 6.87 (td, J = 8.5, 2.8 Hz, 1H), 3.91 (s, 3H), 3.72 (s, 2H). LC-MS (Method 5): m/z 467.9 [M + H]+, (ESI+), RT = 4.28 Methyl 6-(3-(4-fluoro-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamido)pyrazine-2-carboxylate 47 [01787] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.15 (s, 1H), 8.67 (s, 1H), 8.30- 8.24 (m, 1H), 7.80 (dt, J = 7.2, 1.9 Hz, 1H), 7.64-7.55 (m, 2H), 7.51- 7.36 (m, 4H), 7.32 (dd, J = 8.8, 2.6 Hz, 1H), 2.16 (s, 3H). LC-MS (Method 4): m/z 537.1 [M + H].sup.+, (ESI+), RT = 3.64 3-(2-Methyl-4- (trifluoromethoxy)phenoxy)-N-(3- sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 48 [01788] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.19 (s, 1H), 8.67 (s, 1H), 7.91- 7.82 (m, 4H), 7.40-7.30 (m, 3H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 2.13 (s, 3H). LC-MS (Method 5): m/z 471.0 [M + H].sup.+, (ESI+), RT = 3.96 3-(4-Fluoro-2-methylphenoxy)-N-(4- sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 49 [01789] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.43 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.76 (d, J = 2.1 Hz, 1H), 8.69 (t, J = 2.2 Hz, 1H), 8.67 (s, 1H), 7.71 (s, 2H), 7.38 (dd, J = 8.8, 5.9 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H). LC-MS (Method 5): m/z 488.1 [M + H].sup.+, (ESI+), RT = 3.71 3-(4-Fluoro-2-methoxyphenoxy)-N-(5- sulfamoylpyridin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 50 [01790] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.59 (s, 1H), 8.71-8.61 (m, 2H), 8.28 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 5.4, 2.0 Hz, 1H), 7.49 (s, 2H), 7.38 (dd, J = 8.8, 5.9 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.4, 3.0 Hz, 1H), 3.72 (s, 3H). LC-MS (Method 5): m/z 488.1 [M + H].sup.+, (ESI+), RT = 3.71 3-(4-Fluoro-2-methoxyphenoxy)-N-(2- sulfamoylpyridin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide 51 [01791] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.17 (s, 1H), 8.67 (s, 1H), 8.32- 8.26 (m, 1H), 7.82 (dt, J = 7.2, 2.1 Hz, 1H), 7.66-7.57 (m, 2H), 7.45 (s, 2H), 7.35 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.3, 3.1 Hz, 1H), 7.16 (td, J = 8.5, 3.1 Hz, 1H), 2.13 (s, 3H). LC-MS (Method5): m/z 470.9 [M + H].sup.+, (ESI+), RT = 4.07 3-(4-Fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 52 [01792] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.22 (s, 1H), 8.66 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.95 (dt, J = 7.8, 1.7 Hz, 1H), 7.76-7.62 (m, 3H), 7.51- 7.48 (m, 1H), 7.46-7.41 (m, 1H), 7.40-7.33 (m, 1H), 3.23 (s, 3H). LC-MS (Method 5): m/z 522.0 [M + H].sup.+, (ESI+), RT = 4.38 N-(3-(Methylsulfonyl)phenyl)-3-(3- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 53 [01793] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.23 (s, 1H), 8.62 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.95-7.91 (m, 1H), 7.74-7.65 (m, 2H), 7.18 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 2.9 Hz, 1H), 6.84 (dd, J = 8.8, 3.0 Hz, 1H), 3.75 (s, 3H), 3.22 (s, 3H), 2.08 (s, 3H). LC-MS (Method 5): m/z 481.9 [M + H].sup.+, (ESI+), RT = 4.17 3-(4-Methoxy-2-methylphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 54 [01794] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.15 (s, 1H), 8.69 (s, 1H), 8.60 (s, 1H), 7.85 (t, J = 1.9 Hz, 1H), 7.78- 7.73 (m, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.36 (dd, J = 8.8, 5.8 Hz, 1H), 7.32 (ddd, J = 8.0, 2.1, 0.9 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H), 2.34 (s, 3H). LC-MS (Method 4): m/z 489.2 [M + H].sup.+, (ESI+), RT = 2.98 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (3-methyl-4H-1,2,4-triazol-4-yl)phenyl)- 6-(trifluoromethyl)pyridazine-4- carboxamide 55 [01795] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.90 (s, 1H), 9.55 (d, J = 2.5 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J = 2.6 Hz, 1H), 7.36 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC-MS (Method 5): m/z 434.9 [M + H].sup.+, (ESI+), RT = 4.06 N-(6-Cyanopyridazin-4-yl)-3-(4-fluoro- 2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 56 [01796] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 12.37 (s, 1H), 9.46 (d, J = 1.7 Hz, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 7.36 (dd, J = 8.7, 6.0 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC-MS (Method 5): m/z 434.9 [M + H].sup.+, (ESI+), RT = 4.18 N-(5-Cyanopyridazin-3-yl)-3-(4-fluoro- 2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide 57 [01797] .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.95 (s, 1H), 8.60 (s, 1H), 8.04 (t, J = 2.1 Hz, 1H), 7.58-7.53 (m, 1H), 7.44-7.35 (m, 2H), 7.30-7.26 (m, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 4.49- 4.38 (m, 2H), 4.10-4.00 (m, 2H), 3.73 (s, 3H). LC-MS (Method 5): m/z 493.1 [M + H].sup.+, (ESI+), RT = 4.27 3-(4-Fluoro-2-methoxyphenoxy)-N-(3- (2-oxooxazolidin-3-yl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide 58 [01798] .sup.1H NMR (400 MHz, DMSO-d.sub.6)) ? 11.26 (s, 1H), 8.67 (s, 1H), 8.39- 8.32 (m, 1H), 7.98-7.91 (m, 1H), 7.77-7.66 (m, 2H), 7.34 (dd, J = 8.9, 5.0 Hz, 1H), 7.26 (dd, J = 9.3, 3.1 Hz, 1H), 7.16 (td, J = 8.5, 3.1 Hz, 1H), 3.23 (s, 3H), 2.13 (s, 3H). LC- MS (Method 5): m/z 469.9 [M + H].sup.+, (ESI+), RT = 4.31 3-(4-Fluoro-2-methylphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide

Example 111

Compound 59: 3-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide

[1274] ##STR01799##

[1275] A mixture of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.216 g, 0.569 mmol) and 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.150 g, 0.474 mmol) were dissolved in DMF (1.9 mL) under nitrogen at rt. Then pyridazin-4-amine (0.054 g, 0.569 mmol) was added in one portion followed by N-ethyl-N-isopropyl-propan-2-amine (0.17 mL, 0.949 mmol). The reaction mixture was stirred at rt for 1 h. The reaction was diluted with brine (20 mL) and extracted using EtOAc (2?10 mL), organic layer separated, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to obtain the crude residue. Purification by preparative HPLC using Method A afforded the title compound 3-(4-fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide (0.139 g, 75%) as an off white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.53 (s, 1H), 9.42-9.32 (m, 1H), 9.22-9.12 (m, 1H), 8.70 (s, 1H), 8.05 (dd, J=6.0, 2.7 Hz, 1H), 7.35 (dd, J=9.0, 5.0 Hz, 1H), 7.26 (dd, J=9.4, 3.0 Hz, 1H), 7.16 (td, J=8.6, 3.2 Hz, 1H), 2.13 (s, 3H). LC-MS (Method 4): m/z 394.2 [M+H].sup.+, (ESI+), RT=2.93

Compound 60: 3-(3-(2,4-Difluorophenoxy)-6-(trifluoromethyl) pyridazine-4-carboxamido) pyridine 1-oxide

[1276] ##STR01800##

[1277] To a solution of 3-(2,4-difluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.110 g, 0.34 mmol, 1.0 eq), 3-aminopyridine 1-oxide (0.075 g, 0.68 mmol, 2.0 eq) and DIEA (0.222 g, 1.72 mmol, 5.0 eq) in DMF (10 mL) was added HATU (0.196 g, 0.52 mmol, 1.5 eq). The reaction mixture was stirred at 25? C. for 16 h. After reaction, the mixture was quenched with H.sub.2O (40 mL) and extracted with EtOAc (3?50 mL) and the organic layer was concentrated and the residue was purified by preparative HPLC to give 3-(3-(2,4-difluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine-1-oxide (0.0405 g, 28%) as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.30 (s, 1H), 8.73 (d, J=4.2 Hz, 2H), 8.09 (d, J=6.2 Hz, 1H), 7.70-7.40 (m, 4H), 7.25 (t, J=8.5 Hz, 1H). MS(ESI+): m/z 413.1 [M+H].sup.+.

[1278] Compounds 61 to 88 listed in Table 23 were synthesized using the similar method as described for Compound 60 using appropriate carboxylic acids and substituted aryl or heteroaryl aniline.

TABLE-US-00024 TABLE 23 Compound Structure & Name Analytical data 61 [01801] 3-(3-(4-Fluoro-2-methylphenoxy)-6- (trifluoromethyl) pyridazine-4- carboxamido) pyridine 1-oxide .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ? 11.28 (s, 1H), 8.82-8.58 (m, 2H), 8.17-8.00 (m, 1H), 7.62-7.42 (m, 2H), 7.40-7.11 (m, 3H), 2.13 (s, 3H). MS: m/z 409.1 [M + H].sup.+ 62 [01802] 3-(3-(2-chloro-4-fluorophenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamido)pyridine 1-oxide .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ? 11.33 (s, 1H), 8.79-8.65 (m, 2H), 8.16-8.02 (m, 1H), 7.72 (dd, J = 8.4, 3.0 Hz, 1H), 7.64 (dd, J = 9.1, 5.2 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.50- 7.35 (m, 2H). LC-MS (ESI): m/z found 429.0 [M + H].sup.+ 63 [01803] 3-(2-Chloro-4-fluorophenoxy)-N- (pyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, CDCl.sub.3) ? 9.69 (s, 1H), 9.30 (d, J = 2.7 Hz, 1H), 9.19 (d, J = 5.9 Hz, 1H), 8.66 (s, 1H), 8.20 (dd, J = 5.8, 2.8 Hz, 1H), 7.50 (dd, J = 9.1, 4.9 Hz, 1H), 7.37 (dd, J = 7.7, 3.0 Hz, 1H), 7.21 (ddd, J = 9.1, 7.5, 3.0 Hz, 2H), 1.54-1.40 (m, 1H). 64 [01804] 3-(2-Chloro-4-fluorophenoxy)-N-(3- (methylsulfony1)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.28 (s, 1H), 8.74 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.96 (dt, J = 7.6, 1.9 Hz, 1H), 7.80-7.69 (m, 3H), 7.69-7.58 (m, 1H), 7.41 (ddd, J =9.1, 8.1, 3.0 Hz, 1H), 3.24 (s, 3H). LC-MS (Method 2): m/z 488.4[M ? H].sup.+ 65 [01805] 3-(2-Chloro-4-fluorophenoxy)-N-(2- (methylsulfonyl)pyridin-4-yl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.70 (s, 1H), 8.83-8.73 (m, 2H), 8.40 (d, J = 2.0 Hz, 1H), 7.92 (dd, J= 5.5, 2.1 Hz, 1H), 7.79-7.56 (m, 2H), 7.41 (ddd, J =9.1, 8.1, 3.0 Hz, 1H), 3.30 (s, 3H). LC-MS (method 2): m/z 491.6[M + H].sup.+ 66 [01806] 3-(2-Chloro-4-fluorophenoxy)-N-(5- (methylsulfony1)580yridine-3-y1)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, CDCl.sub.3) ? 9.76 (s, 1H), 9.13 (d, J = 2.5 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.78 (t, J = 2.2 Hz, 1H), 8.72 (s, 1H), 7.52 (dd, J = 9.1,4.9 Hz, 1H), 7.39 (dd, J = 7.7, 2.9 Hz, 1H), 7.23 (ddd, J = 9.1, 7.5, 3.0 Hz, 2H), 3.19 (s, 3H). LC-MS (Method 2): m/z 489.4[M ? H].sup.+ 67 [01807] 3-(2-Chloro-4-fluorophenoxy)-N-(2- methoxypyridin-4-y1)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, CDCl.sub.3) ? 9.52 (s, 1H), 8.67 (s, 1H), 8.16 (d, J = 5.7 Hz, 1H), 7.46 (dd, J =9.1, 4.9 Hz, 1H), 7.35 (dd, J = 7.7, 2.9 Hz, 1H), 7.25- 7.10 (m, 3H), 3.96 (s, 3H). LC-MS (Method 2): m/z 443.3 [M + H].sup.+. 68 [01808] 3-(2-Chloro-4-fluorophenoxy)-N-(6- (methylsulfony1)580yridine-2-yl)-6- (trifluoromethyl)pyridazine-4-carboxamide 1H NMR (300 MHz, CDCl.sub.3) ? 10.10 (s, 1H), 8.67 (d, J = 6.7 Hz, 2H), 8.11 (t, J = 8.0 Hz, 1H), 7.95 (dd, J = 7.6, 0.9 Hz, 1H), 7.48 (dd, J = 9.0, 4.9 Hz, 1H), 7.34 (dd, J = 7.8, 2.9 Hz, 1H), 7.19 (ddd, J = 9.0, 7.5, 3.0 Hz, 1H), 3.19 (s, 3H). LC-MS (Method 2): m/z 513.4[M + Na].sup.+ 69 [01809] 3-(2-Chloro-4-fluorophenoxy)-N-(3- oxo-2,3-dihydro-1H-isoindol-5-y1)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, CDCl.sub.3) ? 9.69 (s, 1H), 8.72 (s, 1H), 8.25 (dd, J = 8.3, 2.1 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 9.0, 4.9 Hz, 1H), 7.35 (dd, J = 7.8, 2.9 Hz, 1H), 7.19(ddd, J = 9.0, 7.5, 3.0 Hz, 2H), 6.31 (s, 1H), 4.49 (s, 2H). LC-MS (Method 2): m/z 465.0, 367.0[M ? H].sup.+ 70 [01810] 3-(5-Fluoro-2-methylphenoxy)-N-(3- methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.26 (s, 1H), 8.70 (s, 1H), 8.37 (t, J = 1.9 Hz, 1H), 7.95 (dt, J = 7.5, 1.9 Hz, 1H), 7.82-7.62 (m, 2H), 7.50-7.35 (m, 1H), 7.29 (dd, J = 9.5, 2.7 Hz, 1H), 7.14 (td, J = 8.5, 2.7 Hz, 1H), 3.24 (s, 3H), 2.11 (s, 3H). LC-MS (Method 2): m/z 468.4 [M ? H].sup.+ 71 [01811] 3-(5-Fluoro-2-methylphenoxy)-N-(2- fluoro-5-methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide 1HNMR (300 MHz, DMSO-d.sub.6) ? 11.04 (s, 1H), 8.80-8.61 (m, 2H), 7.86 (ddd, J = 8.6, 4.5, 2.4 Hz, 1H), 7.67 (dd, J = 10.5, 8.7 Hz, 1H), 7.49-7.37 (m, 1H), 7.29 (dd, J = 9.5, 2.7 Hz, 1H), 7.14 (td, J = 8.5, 2.7 Hz, 1H), 3.27 (s, 3H), 2.13 (s, 3H). LC-MS (Method 2): m/z 486.4 [M ? H].sup.+ 72 [01812] 3-(2-Chloro-4-fluorophenoxy)-N-(2- fluoro-5-methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.09 (s, 1H), 8.73 (d, J =9.4 Hz, 2H), 7.86 (ddd, J = 8.7, 4.6, 2.4 Hz, 1H), 7.76-7.55 (m, 3H), 7.41 (ddd, J = 9.1, 8.1, 3.0 Hz, 1H), 3.27 (s, 3H). LC-MS (Method 2): m/z 506.2[M ? H].sup.+ 73 [01813] 3-(2-Chloro-5-fluorophenoxy)-N-(3- methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.28 (s, 1H), 8.77 (s, 1H), 8.37 (t, J = 1.9 Hz, 1H), 7.96 (dt, J = 7.6, 1.8 Hz, 1H), 7.81-7.59 (m, 4H), 7.33 (ddd, J = 9.0, 8.1, 3.0 Hz, 1H), 3.24 (s, 3H). LC-MS (Method 2): m/z 488.3 [M ? H].sup.+ 74 [01814] 3-(2-Chloro-5-fluorophenoxy)-N-(2- fluoro-5-methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.08 (s, 1H), 8.72 (d, J = 8.6 Hz, 2H), 7.87 (ddd, J = 8.6, 4.5, 2.4 Hz, 1H), 7.80-7.51 (m, 3H), 7.34 (ddd, J = 9.0, 8.1,3.0 Hz, 1H), 3.27 (s, 3H). LC-MS (method 2): m/z 506.2 [M ? H].sup.+ 75 [01815] 3-(4-Cyano-2-methoxyphenoxy)-N-(3- methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.29 (s, 1H), 8.72 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.96 (dt, J = 7.5, 1.9 Hz, 1H), 7.81-7.66 (m, 3H), 7.59 (d, J = 1.1 Hz, 2H), 3.79 (s, 3H), 3.24 (s, 3H). LC-MS (Method 2): m/z 491.3 [M ? H].sup.+ 76 [01816] N-(3-Carbamoylphenyl)-3-(4-cyano-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.00 (s, 1H), 8.69 (s, 1H), 8.18 (t, J = 1.9 Hz, 1H), 7.99 (d, J = 20.7 Hz, 1H), 7.87 (ddd, J = 8.0, 2.3, 1.0 Hz, 1H), 7.76 (t, J = 1.1 Hz, 1H), 7.67 (dt, J = 7.8, 1.2 Hz, 1H), 7.59 (d, J = 1.1 Hz, 2H), 7.47 (dd, J = 15.6, 7.7 Hz, 2H), 3.79 (s, 3H), 2.70 (s, 2H). LC-MS (Method 2): m/z 456.3 [M ? H].sup.+ 77 [01817] 3-(4-Cyano-2-methoxyphenoxy)-N-(2- fluoro-5-methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, CDCl.sub.3) ? 9.93 (d, J = 3.3 Hz, 1H), 9.15 (dd, J = 7.0, 2.3 Hz, 1H), 8.65 (s, 1H), 7.82 (ddd, J = 8.6, 4.8, 2.3 Hz, 1H), 7.56-7.41 (m,2H), 7.40-7.31 (m, 2H), 3.83 (s, 3H), 3.13 (s, 3H). LCMS (Method 2): m/z 509.3 [M ? H].sup.+ 78 [01818] 3-(4-Cyano-2-methylphenoxy)-N-(3- methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.28 (s, 1H), 8.74 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 8.00-7.90 (m, 2H), 7.89- 7.76 (m, 1H), 7.76-7.64 (m, 2H), 7.56(d, J = 8.4 Hz, 1H), 3.25 (s, 3H), 2.20 (s, 3H). LC-MS (Method 2): m/z 475.3 [M ? H].sup.+ 79 [01819] N-(3-Carbamoylphenyl)-3-(4-cyano-2- methylphenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.00 (s, 1H), 8.72 (s, 1H), 8.18 (t, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.97-7.92 (m, 1H), 7.90-7.80 (m, 2H), 7.68 (dt, J = 7.9, 1.3 Hz, 1H), 7.62-7.39 (m, 3H), 2.20 (s, 3H). LC-MS (Method 2): m/z 440.3 [M ? H].sup.+ 80 [01820] N-(3-Carbamoylphenyl)-3-(5-fluoro-2- methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 10.96 (s, 1H), 8.65 (s, 1H), 8.18 (t, J = 1.9 Hz, 1H), 8.02 (s, 1H), 7.91-7.83 (m, 1H), 7.71-7.63 (m, 1H), 7.55- 7.30(m, 3H), 7.29-7.15 (m, 2H), 3.70 (s, 3H). LC-MS (Method 2): m/z 449.3 [M ? H].sup.+ 81 [01821] 3-(5-Fluoro-2-methoxyphenoxy)-N-(3- methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.25 (s, 1H), 8.68 (s, 1H), 8.38 (t, J = 1.9 Hz, 1H), 7.97 (dt, J = 7.5, 1.9 Hz, 1H), 7.81-7.66 (m, 2H), 7.36 (dd, J = 8.7,2.7 Hz, 1H), 7.30-7.14 (m, 2H), 3.70 (s, 3H), 3.25 (s, 3H). LC-MS (Method 2): 484.3 [M ? H].sup.+ 82 [01822] 3-(4-Bromo-2-methylphenoxy)-N-(3- methanesulfonylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6 ) 8 11.27 (s, 1H), 8.70 (s, 1H), 8.37 (t, J = 1.9 Hz, 1H), 7.95 (dt, J = 7.6, 1.8 Hz, 1H), 7.81-7.67 (m, 2H), 7.66-7.60 (m,1H), 7.58-7.47 (m, 1H), 7.29 (d, J = 8.6 Hz, 1H), 3.25 (s, 3H), 2.14 (s, 3H). LC-MS (Method 2): m/z 528.2, 530.2 [M ? H].sup.+ 83 [01823] 3-(4-Bromo-2-methylphenoxy)-N-(4- carbamoylphenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.08 (s, 1H), 8.69 (s, 1H), 7.93 (d, J = 8.7 Hz, 3H), 7.81-7.70 (m, 2H), 7.62 (dd, J = 2.6, 0.8 Hz, 1H), 7.52 (dd, J = 8.9, 2.4 Hz, 1H), 7.31 (t, J = 9.0 Hz, 2H), 2.13 (s, 3H). HPLC purity 100%. LC-MS (Method 2): 495.3, 497.3 [M + H].sup.+ 84 [01824] N-(5-Carbamoylpyridin-3-y1)-3-(2- chloro-5-fluorophenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (300 MHZ, DMSO-d.sub.6) ? 11.26 (s, 1H), 8.96 (d, J = 2.5 Hz, 1H), 8.86 (d, J = 1.9 Hz, 1H), 8.78 (s, 1H), 8.58 (t, J = 2.2 Hz, 1H), 8.26 (s, 1H), 7.79-7.57 (m, 3H), 7.34 (ddd, J = 9.0, 8.1, 3.0 Hz, 1H). LC-MS (Method 2): m/z 454.3 [M + H].sup.+ 85 [01825] N-(3-(1H-Pyrazol-3-yl)phenyl)-3-(4- fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.44 (s, 1H), 8.10 (t, J = 1.8 Hz, 1H), 7.74- 7.58 (m, 3H), 7.45 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 8.9, 4.9 Hz, 1H), 7.11 (dd, J = 9.1, 3.0 Hz, 1H), 7.04 (td, J = 8.4, 3.0 Hz, 1H), 6.68 (d, J = 2.2 Hz, 1H), 2.21 (s, 3H). LC-MS (Method 4): m/z 458.2 [M + H].sup.+, (ESI+), RT = 3.55 86 [01826] 3-(4-Fluoro-2-methylphenoxy)-N-(2- methoxypyridin-4-y1)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (400 MHZ, DMSO-d.sub.6) ? 11.22 (s, 1H), 8.66 (s, 1H), 8.19-8.09 (m, 1H), 7.34 (dd, J = 8.9, 5.1 Hz, 1H), 7.25 (dd, J = 9.5, 3.0 Hz, 1H), 7.21- 7.11 (m, 3H), 3.85 (s, 3H), 2.12 (s, 3H). LC-MS (Method 4): m/z 423.2 [M + H].sup.+, (ESI+), RT = 3.63 87 [01827] 3-(4-Cyclopropyl-2-methylphenoxy)- N-(3-(methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (400 MHZ, CD.sub.3OD) ? 8.43 (s, 1H), 8.41 (t, J = 1.9 Hz, 1H), 8.00- 7.95 (m, 1H), 7.78 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 7.07-7.03 (m, 1H), 7.00 (dd, J = 8.4, 2.2 Hz, 1H), 3.15 (s, 3H), 2.15 (s, 3H), 1.97-1.88 (m, 1H), 1.01-0.93 (m, 2H), 0.72- 0.64 (m, 2H). m/z 492.2 [M + H].sup.+ 88 [01828] 3-(2-Methyl-4-(prop-1-en-2-yl)phenoxy)-N-(3- (methylsulfony1)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (400 MHZ, CD.sub.3OD) ? 8.44 (s, 1H), 8.41 (t, J = 1.9 Hz, 1H), 7.99 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.78 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.34-7.24 (m, 2H), 7.16 (d, J = 8.3 Hz, 1H), 6.42 (dd, J = 15.7, 1.4 Hz, 1H), 6.35-6.20 (m, 2H), 3.15 (s, 3H), 2.17 (s, 3H), 1.88 (dd, J = 6.5, 1.5 Hz, 3H). m/z 492.2 [M + H].sup.+

Example 112

Compound 89: 3-(2-Chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1279] ##STR01829##

[1280] To a solution of 3-(2-chloro-4-fluorophenoxy)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.117 g, 0.264 mmol) in anhydrous acetonitrile (10 mL) was added iodotrimethylsilane (0.062 mL) at room temperature. After complete addition of iodotrimethylsilane the mixture was stirred at 60? C. for 24 h. At the end of this period mixture was cooled to rt and solvent evaporated to dryness, water was added (15 mL) and extracted with EtOAc (3?20 mL). The EtOAc layers were combined and washed with water (20 ml) and brine (20 mL), the organic layer was dried (Na.sub.2SO.sub.4), filtered and the solvent evaporated. The mixture was chromatographed over SiO.sub.2 with a gradient of 0-15% EtOAC in DCM to afford 3-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.0416 g, 37%). 1H NMR (300 MHz, DMSO-d.sub.6) ? 11.40 (s, 1H), 10.95 (s, 1H), 8.72 (s, 1H), 7.71 (dd, J=8.4, 3.0 Hz, 1H), 7.63 (dd, J=9.1, 5.2 Hz, 1H), 7.47-7.34 (m, 2H), 6.78 (d, J=2.0 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H). LC-MS (Method 2): m/z 427.0 [M?H].sup.+.

Compound 90: 3-(4-Fluoro-2-methylphenoxy)-N-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1281] ##STR01830##

[1282] The title compound was prepared by a similar procedure described for Compound 89 using 3-(4-fluoro-2-methylphenoxy)-N-(2-methoxy-5-methylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide. .sup.1H NMR (400 MHz, DMSO-dr) ? 11.31 (s, 1H), 9.95 (s, 1H), 8.63 (s, 1H), 7.36 (dd, J=8.9, 4.9 Hz, 1H), 7.27 (dd, J=9.5, 3.1 Hz, 1H), 7.24 (s, 1H), 7.17 (td, J=8.6, 3.2 Hz, 1H), 7.11 (s, 1H), 2.15 (s, 3H), 2.00 (s, 3H). LC-MS (Method 5): m/z 422.9 [M+H].sup.+, (ESI+), RT=3.83.

Compound 91: 3-(4-Fluoro-2-methylphenoxy)-N-(3-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1283] ##STR01831##

[1284] The title compound was prepared by a similar procedure described for Compound 89 using 3-(4-fluoro-2-methylphenoxy)-N-(2-methoxy-3-methylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.47 (s, 1H), 10.26 (s, 1H), 8.63 (s, 1H), 7.35 (dd, J=8.6, 5.3 Hz, 1H), 7.30-7.23 (m, 2H), 7.16 (td, J=8.6, 3.1 Hz, 1H), 6.76 (d, J=7.1 Hz, 1H), 2.14 (s, 3H), 1.95 (s, 3H). LC-MS (Method 6): m/z 423.2 [M+H].sup.+, (ESI+), RT=3.05.

Compound 92: 3-(4-Fluoro-2-methylphenoxy)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1285] ##STR01832##

[1286] The title compound was prepared by a similar procedure described for Compound 89 using 3-(4-fluoro-2-methylphenoxy)-N-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.73 (s, 1H), 10.10 (s, 1H), 8.61 (s, 1H), 7.43 (d, J=9.5 Hz, 1H), 7.33 (dd, J=9.0, 5.1 Hz, 1H), 7.26 (dd, J=9.5, 3.0 Hz, 1H), 7.16 (td, J=8.5, 3.2 Hz, 1H), 6.22 (d, J=8.9 Hz, 1H), 2.16 (s, 3H), 2.14 (s, 3H). LC-MS (Method 6): m/z 423.2 [M+H].sup.+, (ESI+), RT=2.85.

Compound 93: 3-(4-Fluoro-2-methyl-phenoxy)-6-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

[1287] ##STR01833##

[1288] Step 1: 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide. A mixture of 3-(methylsulfanyl)aniline (1.2 mL, 6.95 mmol), 3-chloro-6-methylpyridazine-4-carboxylic acid (1.00 g, 5.79 mmol) were dissolved in DCM (23.179 mL) under an atmosphere of nitrogen at RT ? C. Then N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (2.42 g, 6.37 mmol) was added in one portion. To the above mixture N-ethyl-N-isopropyl-propan-2-amine (2.0 mL, 11.6 mmol) was added dropwise over 2-3 minutes. The reaction mixture was stirred at rt for 18 h. The reaction was diluted with sat. NaHCO.sub.3 solution (30 mL) and stirred vigorously for 45 minutes and then extracted with DCM (30 mL?2). The combined organic extracts were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to obtain the dark brown crude residue. Purification by chromatography eluting with a gradient of 0 to 50% EtOAc in heptane yields the title compound 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide (68.0%) (1.29 g, 2.23 mmol, 39% Yield) isolated impure as a beige solid. .sup.1H NMR (500 MHz, CDCl.sub.3) ? 9.51 (s, 1H), 8.72 (dd, J=4.5, 1.4 Hz, 1H), 8.53 (dd, J=8.4, 1.4 Hz, 1H), 8.10 (s, 1H), 7.71 (t, J=1.9 Hz, 1H), 7.51 (dd, J=8.4, 4.5 Hz, 1H), 7.46 (ddd, J=8.1, 2.0, 0.8 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.10 (ddd, J=7.9, 1.8, 0.9 Hz, 1H), 2.76 (s, 3H), 2.51 (s, 3H). LC-MS (Method 3): m/z 394.4 [M+H].sup.+, (ESI+), RT=0.76.

[1289] Step 2: 3-(4-fluoro-2-methyl-phenoxy)-6-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide. 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide (68%, 0.25 g, 0.432 mmol) and 4-fluoro-2-methyl-phenol (65 mg, 0.519 mmol) were suspended in anhydrous acetonitrile (4.3211 mL) under an atmosphere of nitrogen and treated with cesium carbonate (0.282 g, 0.864 mmol). The resulting mixture was stirred at rt overnight. Reaction diluted with sat. NH.sub.4Cl solution (10 mL) and EtOAc (10 mL) then stirred at rt for 10 minutes. Layers shaken and separated, then aqueous re-extracted with EtOAc (?1). Combined organics dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo to yield a brown gum. The material was purified by column chromatography with a gradient of EtOAc and Heptane (0-100%) to obtain the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (0.122 g, 71%) as a yellow/brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): ? 9.75 (s, 1H), 8.21 (s, 1H), 7.71 (t, J=1.8 Hz, 1H), 7.36 (m, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.17 (dd, J=8.8, 4.8 Hz, 1H), 7.09 (dt, J=7.7, 1.1 Hz, 2H), 7.05 (dd, J=8.9, 2.9 Hz, 1H), 7.00 (td, J=8.3, 3.1 Hz, 1H), 2.75 (s, 3H), 2.52 (s, 3H), 2.22 (s, 3H). LC-MS (Method 3): m/z 384 [M+H].sup.+, (ESI+), RT=0.89.

[1290] Step 3: 3-(4-fluoro-2-methyl-phenoxy)-6-methyl-N-[3 (methylsulfonimidoyl) phenyl]pyridazine-4-carboxamide. 3-(4-fluoro-2-methyl-phenoxy)-6-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (0.122 g, 0.318 mmol) was dissolved in Methanol (3.2 mL) and treated with ammonium carbonate (0.046 g, 0.477 mmol) and diacetoxyiodo-benzene (0.236 g, 0.732 mmol), each added in one portion. After 60 minutes added more ammonium carbonate (0.046 g, 0.477 mmol) and diacetoxyiodo-benzene (0.236 g, 0.732 mmol). After a further 2 hours at rt the mixture was concentrated in vacuo to yield a brown gum. Purified using column chromatography with a gradient of methanol in ethyl acetate yielding the impure title compound. This was purified further using a preparative HPLC (Gilson 6) to yield the title compound (0.064 mg, 47%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.06 (s, 1H), 8.36 (t, J=1.9 Hz, 1H), 7.90 (ddd, J=8.0, 2.0, 0.9 Hz, 1H), 7.90 (s, 1H), 7.70 (ddd, J=7.8, 1.6, 1.1 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.25 (dd, J=8.9, 5.1 Hz, 1H), 7.20 (dd, J=9.4, 3.0 Hz, 1H), 7.11 (td, J=8.5, 3.2 Hz, 1H), 4.24 (s, 1H), 3.07-3.05 (m, 3H), 2.61 (s, 3H), 2.10 (s, 3H). LC-MS (Method 6): m/z 415.3 [M+H]+, (ESI+), RT=2.55.

Compound 94: 3-(4-Fluoro-2-methoxyphenoxy)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide

[1291] ##STR01834##

[1292] Step 13-(4-fluoro-2-methoxyphenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide. 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide (68%, 0.500 g, 0.864 mmol) and 4-fluoro-2-methoxyphenol (0.150 g, 1.04 mmol) and cesium carbonate (0.563 g, 1.73 mmol) were suspended in anhydrous acetonitrile (8.6 mL) and the resulting mixture was stirred at rt for 16 h. Reaction diluted with Sat. NH.sub.4Cl solution (20 mL) and DCM (10 mL) then stirred at rt for 10 minutes. Layers separated and the aqueous re-extracted with DCM (10 mL). Combined organics concentrated in vacuo to yield a brown solid that was purified with column chromatography with a gradient of (0-100%) ethyl acetate and heptane to yield the title compound (0.320 g 88%) as a pink crystalline solid .sup.1H NMR (500 MHz, CDCl.sub.3): ? 9.84 (s, 1H), 8.18 (s, 1H), 7.71 (t, J=1.9 Hz, 1H), 7.42 (dd, J=8.6, 5.4 Hz, 1H), 7.38 (ddd, J=8.1, 2.0, 0.9 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.08 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 6.79 (dt, J=4.6, 2.2 Hz, 1H), 6.78-6.74 (m, 1H), 3.79 (s, 3H), 2.78 (s, 3H), 2.52 (s, 3H). LC-MS (Method 6): m/z 400.5 [M+H].sup.+, (ESI+), RT=4.01.

[1293] Step 23-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. Title compound was prepared by similar procedure as described for step 3 of Compound 93 using 3-(4-fluoro-2-methoxyphenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.00 (s, 1H), 8.37 (t, J=1.8 Hz, 1H), 7.94-7.89 (m, 1H), 7.86 (s, 1H), 7.73-7.67 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.31 (dd, J=8.8, 5.9 Hz, 1H), 7.10 (dd, J=10.7, 2.9 Hz, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 4.24 (s, 1H), 3.70 (s, 3H), 3.06 (s, 3H), 2.61 (s, 3H). LC-MS (Method 6): m/z 431.3 [M+H]+, (ESI+), RT=2.43.

Compound 95: 3-(2-Ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide

[1294] ##STR01835##

[1295] Step 13-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide. The title compound (0.388 g, 99%) was prepared as an off-white crystalline solid by a similar method as described for step 2 of Compound 93, but using 2-ethoxy-4-fluoro-phenol and 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide. .sup.1H NMR (500 MHz, CDCl.sub.3): ? 9.83 (s, 1H), 8.16 (s, 1H), 7.72 (t, J=1.9 Hz, 1H), 7.39 (dd, J=9.4, 5.7 Hz, 1H), 7.37-7.34 (m, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.08 (ddd, J=7.8, 1.8, 1.0 Hz, 1H), 6.79-6.76 (m, 1H), 6.75 (d, J=2.3 Hz, 1H), 4.00 (q, J=7.0 Hz, 2H), 2.77 (s, 3H), 2.51 (s, 3H), 1.15 (t, J=7.0 Hz, 3H). LC-MS (Method 1): m/z 414.3 [M+H].sup.+, (ESI+), RT=0.90.

[1296] Step 23-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl) pyridazine-4-carboxamide. Title compound was prepared by similar procedure as described for step 3 of Compound 93 using 3-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.97 (s, 1H), 8.37 (t, J=1.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.87 (s, 1H), 7.71-7.68 (m, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.32 (dd, J=8.8, 5.9 Hz, 1H), 7.06 (dd, J=10.7, 2.9 Hz, 1H), 6.82 (td, J=8.5, 2.9 Hz, 1H), 4.24 (s, 1H), 3.97 (q, J=7.0 Hz, 2H), 3.06 (s, 3H), 2.61 (s, 3H), 1.05 (t, J=7.0 Hz, 3H). LC-MS (Method 6): m/z 445.3 [M+H].sup.+, (ESI+), RT=2.62.

Compound 96: 3-(2-Chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1297] ##STR01836##

[1298] Step 1: 3-(2-chloro-4-fluorophenoxy)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide. To a mixture of 3-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100 g, 0.297 mmol), 3-(methylsulfanyl)aniline (0.041 g, 0.356 mmol), HATU (0.226 g, 0.594 mmol) in DMF (3 mL) was added DIEA (0.129 mL, 0.743 mmol) at 25? C. and stirring continue for further 2 h at 25? C. At the end of this period water (5 mL) was added and extracted with EtOAc (3?25 mL). The organic layers combined and washed with 1M LiCl solution (20 mL) followed by brine (20 mL). The EtOAc layer was dried (Na.sub.2SO.sub.4), filtered and the solvent evaporated. The crude mixture was chromatographed over SiO.sub.2 with a gradient of 0-60% EtOAc in hexane to provide 3-(2-chloro-4-fluorophenoxy)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.086 g, 63.23%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 10.90 (s, 1H), 8.70 (s, 1H), 7.79-7.54 (m, 3H), 7.49-7.22 (m, 3H), 7.07 (ddd, J=7.8, 1.9, 1.1 Hz, 1H), 2.48 (s, 3H). LC-MS (Method 2): m/z 456.3 [M?H].sup.+.

[1299] Step 2: 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. 3-(2-chloro-4-fluorophenoxy)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide 0.133 g, 0.291 mmol) was dissolved in Methanol (5.0 mL) and treated with ammonium carbonate (0.42 g, 0.436 mmol) and diacetoxyiodo-benzene (0.215 mg, 0.668 mmol), each added in one portion. The reaction mixture was stirred for 3 h at rt. At the end of this period the reaction mixture was concentrated in vacuo and the crude mixture was chromatographed over SiO.sub.2 eluting with a gradient of 0-100% EtOAc in DCM to provide 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.098 g, 69%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.21 (s, 1H), 8.73 (s, 1H), 8.35 (t, J=1.9 Hz, 1H), 7.99-7.87 (m, 1H), 7.79-7.58 (m, 4H), 7.41 (ddd, J=9.1, 8.1, 3.0 Hz, 1H), 4.27 (s, 1H), 3.07 (d, J=1.1 Hz, 3H). LC-MS (Method 2): m/z 489.5 [M+H].sup.+.

Compound 97: 3-(2-Chloro-4-fluorophenoxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1300] ##STR01837##

[1301] Step 1: 3-(2-chloro-4-fluorophenoxy)-N-(2-(methylthio)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide. The title compound (0.0913 g, 45%) was prepared by a similar procedure described for step 1 of Compound 96 using 3-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 2-(methylthio)pyridin-4-amine. H NMR (300 MHz, CDCl.sub.3) ? 9.49 (s, 1H) 8.66 (s, 1H), 8.42 (dd, J=5.6, 0.7 Hz, 1H), 7.63 (dd, J=2.1, 0.7 Hz, 1H), 7.47 (dd, J=9.1, 4.9 Hz, 1H), 7.36 (dd, J=7.7, 2.9 Hz, 1H), 7.31-7.15 (m, 3H), 2.59 (s, 3H).

[1302] Step 2: 3-(2-chloro-4-fluorophenoxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide. Title compound (0.0366 g, 42%) was prepared by a similar procedure described for step 2 of Compound 96. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.62 (s, 1H), 8.77 (s, 1H), 8.69 (d, J=5.4 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.86 (dd, J=5.4, 2.1 Hz, 1H), 7.76-7.58 (m, 2H), 7.41 (ddd, J=9.1, 8.1, 3.0 Hz, 1H), 4.44 (s, 1H), 3.16 (d, J=1.1 Hz, 3H). LC-MS (Method 2): m/z 490.4 [M+H].sup.+.

Compound 98: 3-(4-Fluoro-2-methylphenoxy)-N-(4-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1303] ##STR01838##

[1304] The title compound 3-(4-fluoro-2-methylphenoxy)-N-(4-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was prepared by a similar procedure described for step 2 of Compound 96 using 3-(4-fluoro-2-methylphenoxy)-N-(4-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.21 (s, 1H), 8.67 (s, 1H), 7.99-7.85 (m, 4H), 7.35 (dd, J=8.9, 5.1 Hz, 1H), 7.25 (dd, J=9.4, 2.9 Hz, 1H), 7.15 (td, J=8.6, 3.2 Hz, 1H), 4.17 (s, 1H), 3.08-3.00 (m, 3H), 2.13 (s, 3H). LC-MS (Method 5): m/z 469.1 [M+H]+, (ESI+), RT=3.80.

Compound 99: 3-(4-Fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1305] ##STR01839##

[1306] Step 1: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. Title compound was prepared by a similar procedure described for Compound 1 using 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 3-(methylthio)aniline. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 10.85 (s, 1H), 8.60 (s, 1H), 7.67 (t, J=1.9 Hz, 1H), 7.49-7.40 (m, 1H), 7.40-7.28 (m, 2H), 7.15 (dd, J=10.7, 2.8 Hz, 1H), 7.10-6.99 (m, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 2.48 (s, 3H). LC-MS (Method 1) m/z 453.9 [M+H]+, (ESI+), RT=4.87.

[1307] Step 2: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. Title compound was prepared by similar procedure described for step 2 of Compound 93 using 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide, (NH.sub.4).sub.2CO.sub.3 and diacetoxyiodo-benze to provide 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide as a racemic mixture. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.20 (s, 1H), 8.63 (s, 1H), 8.38-8.32 (m, 1H), 7.96-7.88 (m, 1H), 7.77-7.69 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.38 (dd, J=8.8, 5.8 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 4.27 (s, 1H), 3.73 (s, 3H), 3.07 (s, 3H). LC-MS (Method 1): m/z 485.0 [M+H]+, (ESI+), RT=3.84.

Compounds 100 & 101: First Eluting Isomer and Second Eluting Isomer

[1308] ##STR01840##

[1309] The racemic mixture from Compound 99 was purified by SFC to give the title compounds: first eluting isomer (Compound 100).sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.18 (s, 1H), 8.63 (s, 1H), 8.35 (t, J=1.8 Hz, 1H), 7.95-7.90 (m, 1H), 7.72 (dt, J=7.8, 1.1 Hz, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.38 (dd, J=8.8, 5.8 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 4.26 (s, 1H), 3.73 (s, 3H), 3.07 (s, 3H). LC-MS (Method 6): m/z 485.3 [M+H].sup.+, (ESI+), RT=3.09 and the second eluting isomer (Compound 101).sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.20 (s, 1H), 8.61 (s, 1H), 8.34 (t, J=1.9 Hz, 1H), 7.94-7.89 (m, 1H), 7.74-7.69 (m, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.37 (dd, J=8.8, 5.8 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 4.25 (s, 1H), 3.73 (s, 3H), 3.06 (s, 3H). LC-MS (Method 1): m/z 484.9 [M+H].sup.+, (ESI+), RT=3.83.

Compound 102: (R)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) pyridazine-4-carboxamide

[1310] ##STR01841##

[1311] Step 1: tert-butyl (R)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl) pyridazine-4-carboxamido) phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate: To a mixture of 3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (300 mg, 0.95 mmol), tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate[Intermediate 72](255 mg, 0.94 mmol) and N,N-Diisopropylethylamine (366 mg, 2.8 mmol) in DMF (5 mL) was added N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uranium (719 mg, 1.8 mmol) at 25? C. under nitrogen gas. The reaction mixture was stirred at 25? C. for 1 h. The reaction mixture was quenched with ice water and extracted with EA. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the crude product. The residue was chromatographed over SiO.sub.2 with a gradient of 0-60% EtOAc in petroleum ether to afford tert-butyl (R)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl) pyridazine-4-carboxamido) phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate (510 mg, 94%) as a yellow oil. LC-MS: m/z 591.0 [M+23].sup.+.

[1312] Step 2: (R)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) pyridazine-4-carboxamide. To a mixture of tert-butyl (R)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl) pyridazine-4-carboxamido) phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate (0.510 g, 0.89 mmol) in DCM (3 mL) was added HCl/1,4-Dioxane (4M, 3 mL) at 25? C. The reaction mixture was stirred at 25? C. for 2 h. The reaction mixture was concentrated to give the crude product. The residue was purified with reversed phase flash chromatography (eluting with ACN/H.sub.2O (0.1% NH.sub.3) 0?45%) to afford (R)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) pyridazine-4-carboxamide (0.300 g, 71%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.20 (s, 1H), 8.67 (s, 1H), 8.35 (t, J=4 Hz, 1H), 7.98-7.87 (m, 1H), 7.73 (dt, J=8 Hz, 1.2 Hz, 1H), 7. 65 (t, J=8 Hz), 7.35 (dd, J=8 Hz, 4 Hz, 1H), 7.26 (dd, J=8 Hz, 3.2 Hz, 1H), 7.16 (td, J=8.4 Hz, 3.2 Hz, 1H), 4.27 (s, 1H), 3.11-3.02 (s, 3H), 2.13 (s, 3H). LC-MS (ESI): m/z 469.1 [M+1].sup.+.

Compound 103: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) pyridazine-4-carboxamide

[1313] ##STR01842##

[1314] Step 1: tert-butyl (S)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl) pyridazine-4-carboxamido) phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate. To a mixture of 3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.350 g, 1.1 mmol), tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene)carbamate (0.298 g, 1.1 mmol) and N,N-Diisopropylethylamine (0.428 g, 3.3 mmol) in DMF (5 mL) was added HATU (0.839 g 2.2 mmol) at 25? C. under nitrogen atmosphere. The reaction mixture was stirred at 25? C. for 1 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the crude product which was purified with flash chromatography (eluting with EA/PE 0?60%) to afford tert-butyl (S)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl) pyridazine-4-carboxamido) phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate (0.550 g, 87%) as a yellow oil. LC-MS: m/z found 591.0 [M+23].sup.+.

[1315] Step 2: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) pyridazine-4-carboxamide. To a mixture of tert-butyl (S)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl) pyridazine-4-carboxamido) phenyl)(methyl)(oxo)-?.sup.6-sulfaneylidene) carbamate (0.550 g, 0.96 mmol) in DCM (3 mL) was added HCl/1,4-Dioxane (4M, 3 mL) at 25? C. The reaction mixture was stirred at 25? C. for 2 h. The reaction mixture was concentrated to give the crude product. The residue was purified with reversed phase flash chromatography (eluting with ACN/H.sub.2O (0.1% NH.sub.3) 0-45%) to afford (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) pyridazine-4-carboxamide (0.305 g, 67%) as an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.20 (s, 1H), 8.67 (s, 1H), 8.35 (t, J=4 Hz, 1H), 7.98-7.87 (m, 1H), 7.73 (dt, J=8 Hz, 1.2 Hz, 1H), 7. 65 (t, J=8 Hz), 7.35 (dd, J=8 Hz, 4 Hz, 1H), 7.26 (dd, J=8 Hz, 3.2 Hz, 1H), 7.16 (td, J=8.4 Hz, 3.2 Hz, 1H), 4.27 (s, 1H), 3.11-3.02 (s, 3H), 2.13 (s, 3H). LC-MS: m/z found 469.1[M+1].sup.+.

Compounds 104 and 105: 3-(4-Fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridazine-4-carboxamide and 3-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfinylphenyl)pyridazine-4-carboxamide

[1316] ##STR01843##

[1317] A solution of 3-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (0.130 g, 0.325 mmol) in Methanol (3.25 mL) was treated with Oxone (0.109 g, 0.716 mmol). The resultant mixture stirred at rt overnight. Then more oxone (0.109 g, 0.716 mmol) was added and the mixture stirred at rt for a further 6 h at rt. Diluted the reaction mixture with DCM (25 mL) and sat. NaHCO.sub.3 solution (25 mL). Layers were separated and the aqueous re-extracted with DCM (25 mL). Combined organics were concentrated in vacuo to a pale yellow solid. The material was purified using preparative HPLC Method 1 to afford 3-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridazine-4-carboxamide (0.087 g, 61%) as a white solid, .sup.1H NMR (500 MHz, CDCl.sub.3) ? 10.10 (s, 1H), 8.18-8.12 (m, 3H), 7.76 (dt, J=7.7, 1.3 Hz, 1H), 7.66-7.57 (m, 1H), 7.47 (dd, J=8.7, 5.6 Hz, 1H), 6.84-6.74 (m, 2H), 3.82 (s, 3H), 3.09 (s, 3H), 2.76 (s, 3H). LC-MS (Method 6): m/z 432.3 [M+H].sup.+, (ESI+), RT=2.78 and the second title compound 3-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfinylphenyl)pyridazine-4-carboxamide (0.015 g, 10%) as an off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.96 (s, 1H), 8.13 (t, J=1.7 Hz, 1H), 7.86 (s, 1H), 7.81-7.76 (m, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.42 (m, 1H), 7.31 (dd, J=8.8, 5.9 Hz, 1H), 7.09 (dd, J=10.7, 2.9 Hz, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 3.70 (s, 3H), 2.75 (s, 3H), 2.60 (s, 3H). LC-MS (Method 1): m/z 416.0 [M+H]+, (ESI+), RT=3.45.

Compound 106: 3-(4-Fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1318] ##STR01844##

[1319] Step 1: 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. The title compound was prepared by a similar procedure described for Compound 1 using 3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 4-methyl-3-(methylthio)aniline. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.83 (s, 1H), 8.63 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.40 (dd, J=8.1, 2.0 Hz, 1H), 7.34 (dd, J=8.9, 5.0 Hz, 1H), 7.25 (dd, J=9.5, 3.0 Hz, 1H), 7.22-7.18 (m, 1H), 7.15 (td, J=8.5, 3.2 Hz, 1H), 2.46 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z 451.9 [M+H]+, (ESI+), RT=5.05.

[1320] Step 2: 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. The title compound was prepared by a similar procedure described for Compounds 104 and 105 using 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide and excess Oxone. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.19 (s, 1H), 8.65 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.2, 2.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.34 (dd, J=9.0, 5.0 Hz, 1H), 7.25 (dd, J=9.4, 3.0 Hz, 1H), 7.15 (td, J=8.5, 3.1 Hz, 1H), 3.23 (s, 3H), 2.62 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z 451.9 [M+H].sup.+, (ESI+), RT=5.05.

Compound 107: 3-(4-Fluoro-2-methoxyphenoxy)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1321] ##STR01845##

[1322] 3-(4-fluoro-2-methoxyphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was prepared by similar procedure described for Compound 1 using 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 4-methyl-3-(methylthio)aniline and was used for the next step. The title compound was prepared by a similar procedure described for Compounds 104 and 105 using 3-(4-fluoro-2-methoxyphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.14 (s, 1H), 8.62 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 7.91 (dd, J=8.3, 2.3 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.37 (dd, J=8.8, 5.8 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 3.23 (s, 3H), 2.62 (s, 3H). LC-MS (Method 1): m/z 500.1 [M+H]+, (ESI+), RT=4.33.

Compound 108: 3-(2-Ethoxy-4-fluorophenoxy)-6-methyl-N-(3-methylsulfonyl)phenyl)pyridazine-4-carboxamide

[1323] ##STR01846##

[1324] The title compound was prepared by a similar procedure described for Compounds 104 and 105 using 3-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide and excess Oxone. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.04 (s, 1H), 8.38 (t, J=1.7 Hz, 1H), 7.95 (dt, J=7.7, 1.5 Hz, 1H), 7.88 (s, 1H), 7.71 (dt, J=7.8, 1.4 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.32 (dd, J=8.8, 5.9 Hz, 1H), 7.06 (dd, J=10.7, 2.9 Hz, 1H), 6.82 (td, J=8.5, 2.9 Hz, 1H), 3.97 (q, J=7.0 Hz, 2H), 3.22 (s, 3H), 2.61 (s, 3H), 1.04 (t, J=7.0 Hz, 3H). LC-MS (Method 6): m/z 446.3 [M+H].sup.+, (ESI+), RT=2.97.

Compound 109: 3-(4-Fluoro-2-methylphenoxy)-N-(4-methyl-3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1325] ##STR01847##

[1326] The title compound was prepared by a similar procedure described for step 3 of Compound 93 using 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.11 (s, 1H), 8.64 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 7.89 (dd, J=8.2, 2.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.9, 5.0 Hz, 1H), 7.25 (dd, J=9.5, 2.9 Hz, 1H), 7.15 (td, J=8.5, 3.2 Hz, 1H), 4.29 (s, 1H), 3.08 (s, 3H), 2.66 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z: 482.9 [M+H]+, (ESI+), RT=4.01.

[1327] Compounds 110 to 113 listed in Table 24 were synthesized using the similar method as described for step 1 of compound 59 using carboxylic acids with appropriate substituted aryl or heteroaryl aniline.

TABLE-US-00025 TABLE 24 Compound Structure and name Analytical data 110 [01848] 3-(4-Cyano-2-methylphenoxy)-N-(3- (methylthio)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 10.91 (s, 1H), 8.70 (s, 1H), 7.93 (dd, J = 2.2, 0.9 Hz, 1H), 7.84 (dd, J = 8.3, 2.1 Hz, 1H), 7.66 (t, J = 1.9 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48-7.29 (m, 2H), 7.08 (ddd, J = 7.7, 1.9, 1.1 Hz, 1H), 2.49 (s, 3H), 2.20 (s, 3H). 111 [01849] 3-(2-Chloro-5-fluorophenoxy)-N-(3- (methylthio)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, CDCl3) ? 9.42 (s, 1H), 8.71 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.56 (dd, J = 9.0, 5.5 Hz, 1H), 7.45- 7.27 (m, 3H), 7.17-7.06 (m, 2H), 2.52 (s, 3H). LC-MS (Method 2): m/z 456.2 [M ? H].sup.+ 112 [01850] 3-(5-Fluoro-2-methoxyphenoxy)-N-(3- (methylthio)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, CDCl3) ? 9.69 (s, 1H), 8.64 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.43-7.28 (m, 3H), 7.13-6.94 (m, 3H), 3.80 (s, 3H), 2.52 (s, 3H). 113 [01851] 3-(4-Bromo-2-methylphenoxy)-N-(3- (methylthio)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO) ? 10.90 (s, 1H), 8.66 (s, 1H), 7.65 (dt, J = 12.5, 2.0 Hz, 2H), 7.56-7.22 (m, 4H), 7.07 (dt, J = 7.9, 1.5 Hz, 1H), 2.49 (s, 3H), 2.13 (s, 3H).

[1328] Compounds 114 to 117 listed in Table 25 were synthesized using the similar method as described for step 3 of Compound 93 using appropriate substituted compounds listed in Table 24.

TABLE-US-00026 TABLE 25 Compound Structure and name Analytical data 114 [01852] 3-(4-Cyano-2-methylphenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.22 (s, 1H), 8.73 (s, 1H), 8.34 (t, J = 1.9 Hz, 1H), 7.92 (ddd, J = 9.3, 2.2, 1.1 Hz, 2H), 7.84 (dd, J = 8.5, 2.4 Hz, 1H), 7.74 (dt, J = 7.9, 1.4 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 4.29 (s, 1H), 3.08 (d, J = 0.9 Hz, 3H), 2.20 (s, 3H). LC-MS (Method 2): 474.5 [M ? H].sup.+ 115 [01853] 3-(2-Chloro-5-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO) ? 11.23 (s, 1H), 8.76 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.94 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.79-7.70 (m, 2H), 7.69-7.58 (m, 2H), 7.34 (ddd, J = 9.0, 8.1, 3.0 Hz, 1H), 4.29 (d, J = 23.2 Hz, 1H), 3.11 (s, 3H). LC- MS (Method 2): m/z 487.3 [M ? H].sup.+ 116 [01854] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.18 (s, 1H), 8.67 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.94 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.77-7.57 (m, 2H), 7.36 (dd, J = 8.7, 2.7 Hz, 1H), 7.30-7.16 (m, 2H), 4.28 (d, J = 1.3 Hz, 1H), 3.70 (s, 3H), 3.08 (d, J = 1.1 Hz, 3H). LC-MS (Method 2): m/z 483.3 [M ? H].sup.+ 117 [01855] 3-(4-Bromo-2-methylphenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.21 (s, 1H), 8.69 (s, 1H), 8.35 (t, J = 1.9 Hz, 1H), 7.92 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.74 (dt, J = 7.9, 1.3 Hz, 1H), 7.70-7.60 (m, 2H), 7.52 (ddd, J = 8.6, 2.5, 0.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 4.29 (d, J = 1.3 Hz, 1H), 3.07 (d, J = 1.1 Hz, 3H), 2.14 (s, 3H). LC-MS (Method 2): 529.2, 531.3 [M ? H].sup.+

Example 113

Compound 118: 3-(2-Chloro-5-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1329] ##STR01856##

[1330] A mixture of 3-(2-chloro-5-fluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100 g, 0.316 mmol), 3-aminobenzene-1-sulfonamide (0.082 g, 0.481 mmol) and EDC (0.0667 g, 0.348 mmol) in pyridine (4 mL) was stirred at rt for 16 h. The solvent was evaporated and the crude was chromatographed over SiO2 with a gradient of 0-100% EtOAc in hexane to provide 3-(2-chloro-5-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.086 g, 55.41%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.18 (s, 1H), 8.76 (s, 1H), 8.30 (t, J=1.5 Hz, 1H), 7.83 (dt, J=6.4, 2.4 Hz, 1H), 7.74 (dd, J=9.0, 5.7 Hz, 1H), 7.67-7.55 (m, 3H), 7.46 (s, 2H), 7.33 (ddd, J=9.0, 8.1, 3.0 Hz, 1H). LC-MS (Method 1): m/z 489.4 [M?H].sup.+.

[1331] Compounds 119 to 129 listed in Table 26 were synthesized using the similar method as described for Compound 118 using appropriate carboxylic acids with substituted aryl or heteroaryl aniline.

TABLE-US-00027 TABLE 26 Compound Structure & name Analytical data 119 [01857] 3-(5-Fluoro-2-methylphenoxy)-N-(3- sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.22 (s, 1H), 8.76 (s, 1H), 8.36 (q, J = 1.4 Hz, 1H), 7.93-7.82 (m, 1H), 7.74-7.61 (m, 2H), 7.51 (d, J = 6.7 Hz, 2H), 7.50- 7.42 (m, 1H), 7.35 (dd, J = 9.5, 2.7 Hz, 1H), 7.20 (td, J = 8.5, 2.7 Hz, 1H), 2.17 (s, 3H). LC-MS (Method 1): m/z 469.1 [M ? H].sup.+ 120 [01858] 3-(2-Chloro-5-fluorophenoxy)-N-(6- sulfamoylpyridin-2-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.83 (s, 1H), 8.73 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.19 (t, J = 8.0 Hz, 1H), 7.85- 7.65 (m, 2H), 7.56 (d, J = 28.7 Hz, 3H), 7.39-7.25 (m, 1H) 121 [01859] 3-(4-Cyano-2-methoxyphenoxy)-N- (3-sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.19 (s, 1H), 8.71 (s, 1H), 8.29 (q, J = 1.4 Hz, 1H), 7.84 (dt, J = 6.1, 2.4 Hz, 1H), 7.77 (t, J = 1.1 Hz, 1H), 7.67-7.56 (m, 4H), 7.46 (s, 2H), 3.78 (s, 3H). LC-MS (Method 2): m/z 492.4 [M ? H].sup.+ 122 [01860] 3-(5-Fluoro-2-methoxyphenoxy)-N- (3-sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.15 (s, 1H), 8.68 (s, 1H), 8.30 (q, J = 1.4 Hz, 1H), 7.90-7.78 (m, 1H), 7.68-7.56 (m, 2H), 7.46 (s, 2H), 7.36 (dd, J = 8.7, 2.7 Hz, 1H), 7.30-7.13 (m, 2H), 3.70 (s, 3H). LC-MS (Method 2): 485.3 [M ? H].sup.+ 123 [01861] 3-(4-Cyano-2-methylphenoxy)-N-(3- sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.24 (s, 1H), 8.79 (s, 1H), 8.38-8.33 (m, 1H), 7.99 (dd, J = 2.0, 0.9 Hz, 1H), 7.94- 7.84 (m, 2H), 7.74-7.58 (m, 3H), 7.52 (s, 2H), 2.25 (s, 3H). LC-MS (Method 2): m/z 476.3 [M ? H].sup.+ 124 [01862] 3-(4-Cyano-2-fluorophenoxy)-N-(3- sulfamoylphenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide. .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.23 (s, 1H), 8.79 (s, 1H), 8.32-8.26 (m, 1H), 8.19 (dd, J = 10.4, 1.9 Hz, 1H), 7.95-7.87 (m, 1H), 7.87-7.75 (m, 2H), 7.68-7.57 (m, 2H), 7.47 (s, 2H). 125 [01863] N-(6-Carbamoylpyridin-3-yl)-3-(4- fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.35 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.65 (s, 1H), 8.29 (dd, J = 8.6, 2.4 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.62-7.52 (m, 1H), 7.37 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC-MS (Method 4): m/z 452.1 [M + H].sup.+, (ESI+), RT = 2.96 126 [01864] N-(2-Carbamoylpyridin-4-yl)-3-(4- fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.39 (s, 1H), 8.65 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 5.4, 2.0 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.37 (dd, J = 8.8, 5.9 Hz, 1H), 7.14 (dd, J = 10.7, 2.8 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC-MS (Method 4): m/z: 452.1 [M + H].sup.+, (ESI+), RT = 3.03 127 [01865] 3-(4-Fluoro-2-methoxyphenoxy)-N- (4-(methylcarbamoyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.07 (s, 1H), 8.62 (s, 1H), 8.44-8.35 (m, 1H), 7.94-7.83 (m, 2H), 7.83-7.72 (m, 2H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 2.78 (d, J = 4.5 Hz, 3H). LC-MS (Method 5): m/z 464.9 [M + H].sup.+, (ESI+), RT = 3.95 128 [01866] N-(6-Carbamoylpyrazin-2-yl)-3-(4- fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 9.54 (s, 1H), 8.96, (s, 1H), 8.62, (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.36 (s, 1H), 7.15 (dd, J = 10.7, 2.8 Hz, 1H), 6.87 (td, J = 8.5, 2.9 Hz, 1H), 3.72 (s, 3H). LC-MS (method 5): m/z 452.9 [M + H].sup.+ RT = 3.80 129 [01867] 3-(4-Fluoro-2-methoxyphenoxy)-N- (3-(methylcarbamoyl)phenyl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 10.98 (s, 1H), 8.61 (s, 1H), 8.54- 8.43 (m, 1H), 8.20-8.13 (m, 1H), 7.90-7.81 (m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.8 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H), 2.78 (d, J = 4.5 Hz, 3H). LCMS (Method 5): m/z: 464.9 [M + H].sup.+, (ESI+), RT = 3.98

Example 114

Compound 130: 3-(4-Fluoro-2-hydroxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1332] ##STR01868##

[1333] Trichloroborane (1.0M in DCM, 1.0 mL, 1.03 mmol), tetrabutylammonium iodide (42 mg, 0.113 mmol) and 3-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (50 mg, 0.103 mmol) were stirred in dry DCM-Anhydrous (0.515 mL) at 0? C. for 1 h, cooled with ice-water bath. The reaction mixture was then concentrated under vacuum to obtain a crude residue. Purification by chromatography on silica eluting with a gradient of EtOAc in heptane. Fractions with product were combined and concentrated. Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane afforded the title compound (0.014 mg, 28%) as a white solid, and was re-purified by Prep LC. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.42 (bs, 1H), 10.42 (bs, 1H), 8.58 (s, 1H), 8.41-8.36 (m, 1H), 7.96 (dt, J=7.6, 1.7 Hz, 1H), 7.77-7.66 (m, 2H), 7.30 (dd, J=8.8, 6.0 Hz, 1H), 6.78-6.71 (m, 1H), 6.71-6.63 (m, 1H), 3.23 (s, 3H). (LC-MS (Method 5): m/z 472.0 [M+H].sup.+, (ESI+), RT=3.94.

Compound 131: 3-(4-Fluoro-2-hydroxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1334] ##STR01869##

[1335] The title compound 3-(4-fluoro-2-hydroxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.020 g, 66%) was prepared as a white solid by a similar method described for Compound 130, but starting from 3-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.15 (bs, 1H), 10.32 (bs, 1H), 8.59 (s, 1H), 8.31-8.28 (m, 1H), 7.84 (dt, J=6.6, 2.2 Hz, 1H), 7.64-7.57 (m, 2H), 7.43 (s, 2H), 7.30 (dd, J=8.8, 5.9 Hz, 1H), 6.77 (dd, J=10.2, 2.8 Hz, 1H), 6.74-6.65 (m, 1H). LC-MS (Method 6): m/z: 473.1[M+H].sup.+.

Compound 132: N-(3-Methanesulfonylphenyl)-3-[2-methyl-4-(1,2-oxazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxamide

[1336] ##STR01870##

[1337] A solution of KF (0.0164 g, 0.283 mmol) in H.sub.2O (0.200 mL) was added to a solution of 3-(4-bromo-2-methylphenoxy)-N-(3-methanesulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.050 g, 0.094 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (0.022 g, 0.113 mmol) in DMF (3 mL) at rt. The mixture was degassed by bubbling nitrogen for 10 min, to the above mixture pd(dppf)Cl.sub.2.Math.DCM (0.008 g, 10 mol %) was added and the resulting mixture was heated at 60? C. for 3 h. At the end of this period, it was cooled to rt and water (5 mL) was added and extracted with EtOAc (2?20 mL). The combined organics were washed with water (20 mL) and 1M LiCl (20 mL). The EtOAc layer was dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated under reduced pressure. The crude mixture was chromatographed over SiO.sub.2 with a gradient of 0-20% EtOAc in DCM to afford N-(3-methanesulfonylphenyl)-3-[2-methyl-4-(1,2-oxazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.021 g, 44%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) ? 11.29 (s, 1H), 9.48 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.01-7.89 (m, 1H), 7.81-7.61 (m, 4H), 7.38 (d, J=8.4 Hz, 1H), 3.25 (s, 3H), 2.18 (s, 3H). LC-MS (Method 2): m/z 517.3 [M?H].sup.+.

Compound 133: 3-[2-Methyl-4-(1H-pyrazol-4-yl)phenoxy]-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1338] ##STR01871##

Step 1: methyl 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate

[1339] A suspension of methyl 3-(4-bromo-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (100 mg, 0.256 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (75 mg, 0.256 mmol), Pd.sub.2(dba).sub.3 (12 mg, 0.0128 mmol) and Xphos (6.1 mg, 0.0128 mmol) in 1,4-Dioxane (2 mL) and Water (0.2 mL) was degassed with nitrogen and stirred at 40? C. for 18.5 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3?20 mL). The organic phases were combined, passed through a phase separator and concentrated in vacuo. The compound was purified by column chromatography over silica USING 0-100% EtOAc in heptane and flushed using 0-60% MeOH in DCM (on a Biotage Sfar 10 g column, compound dry-loaded onto silica using DCM) to afford methyl 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate (75.0%) (46 mg, 28%) as a pale yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.75 (s, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.69 (dd, J=8.3, 2.1 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.97 (s, 3H), 2.17 (s, 3H), 1.64-1.56 (m, 9H). LC-MS (Method 3): m/z 379.2 [M+H]+, (ESI+), RT=1.03.

Step 2: 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate, Lithium Salt

[1340] To a mixture of methyl 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate (75%, 46 mg, 0.0721 mmol) in THE (0.6 mL):Water (0.1 mL), lithium hydroxide (4.5 mg, 0.180 mmol) was added and the mixture was stirred at rt for 3 h. The reaction was concentrated in vacuo to afford 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate, lithium salt (85.0%) (40 mg, 0.0723 mmol, 100% Yield) as a pale yellow solid. LC-MS (Method 1): m/z 365.05 [M+H]+, (ESI+), RT=0.97. This material was used for the next step without any further purification.

[1341] Step 3. To a stirring solution of 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate lithium salt (40 mg, 0.0850 mmol), N-ethyl-N-isopropyl-propan-2-amine (0.030 mL, 0.170 mmol) and N,N-dimethylpyridin-4-amine (2.1 mg, 0.0170 mmol) in DCM (0.6 mL), 50% Propylphosphonic anhydride solution in EtOAc (50%, 0.061 mL, 0.102 mmol) was added dropwise at RT and stirred for 10 minutes. 3-(methylsulfonyl)aniline (17 mg, 0.102 mmol) was subsequently added in one portion and stirred for 1 h at RT. The reaction was re-treated with 50% Propylphosphonic anhydride solution in EtOAc (50%, 0.061 mL, 0.102 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.030 mL, 0.170 mmol) followed by DMF (0.1 mL) to facilitate dissolution. The reaction was stirred at RT for 16 h. The reaction was re-treated with 50% Propylphosphonic anhydride solution in EtOAc (50%, 0.061 mL, 0.102 mmol) and stirred for 2 hr at rt. The reaction was re-treated with N-ethyl-N-isopropyl-propan-2-amine (0.030 mL, 0.170 mmol), N,N-dimethylpyridin-4-amine (2.1 mg, 0.0170 mmol) and 50% Propylphosphonic anhydride solution in EtOAc (50%, 0.061 mL, 0.102 mmol) and stirred at 45? C. for 1 h. The reaction was concentrated in vacuo and 4 M HCl in dioxane (1.0 mL, 4.00 mmol) was added, the reaction was stirred at rt for 18 h. The reaction mixture was poured into water (10 mL) and extracted with DCM (3?20 mL), the combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by Prep Method 1, concentrated in vacuo and freeze-dried overnight to afford the title compound 3-[2-methyl-4-(1H-pyrazol-4-yl)phenoxy]-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (6.0 mg, 14%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 12.92 (s, 1H), 11.27 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.06 (s, 2H), 7.93 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.7 Hz, 2H), 7.61 (d, J=1.7 Hz, 1H), 7.53 (dd, J=8.3, 2.0 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 3.22 (s, 3H), 2.15 (s, 3H). LC-MS (Method 6): m/z 518.3 [M+H].sup.+, (ESI+), RT=2.94.

Compound 134: 3-(4-Fluoro-2-methyl-phenoxy)-N-([1,2,4]triazolo[4,3-a]pyridin-5-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1342] ##STR01872##

[1343] Step 1. 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide A suspension of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (300 mg, 0.908 mmol) in ammonium hydroxide (25%, 1.9 mL, 45.4 mmol) was stirred at 65? C. for 10 min. The mixture was cooled to room temperature and the suspension was filtered and washed with water (5 mL?2), dried under high vacuum at 40? C. for 2 h to obtain the crude product. Purification using Prep method P3 to afford the title compound (175 mg, 61%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.42 (s, 1H), 8.21 (d, J=5.3 Hz, 2H), 7.31 (dd, J=8.9, 5.1 Hz, 1H), 7.25 (dd, J=9.4, 3.0 Hz, 1H), 7.15 (td, J=8.6, 3.1 Hz, 1H), 2.12 (s, 3H). LC-MS (Method 6): m/z 316.1[M+H].sup.+, (ESI+), RT=2.95.

[1344] Step 2. 3-(4-fluoro-2-methyl-phenoxy)-N-([1,2,4]triazolo[4,3-a]pyridin-5-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide: A mixture of BrettPhos Pd G3 (29 mg, 0.0317 mmol), 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide (100 mg, 0.317 mmol) and 5-bromo[1,2,4]triazolo[4,3-a]pyridine (94 mg, 0.476 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL) under nitrogen at RT. The mixture was degassed with nitrogen for 5 minutes, then cesium carbonate (207 mg, 0.634 mmol) was added in one portion. The reaction mixture was stirred at 90? C. for 16 h. The solvent was removed in vacuo and the crude residue purified using Prep LC Method P1 to afford the title compound (95.0%) (13 mg, 9.3%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 11.66 (s, 1H), 9.33 (s, 1H), 8.79 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.49 (dd, J=9.1, 7.3 Hz, 1H), 7.38 (s, 1H), 7.27 (dd, J=9.2, 2.8 Hz, 2H), 7.17 (td, J=8.5, 3.0 Hz, 1H), 2.16 (s, 3H). LC-MS (Method 4): m/z 433.2 [M+H].sup.+, (ESI+), RT=2.89.

Compound 135: 3-(4-Fluoro-2-methylphenoxy)-N-(tetrazolo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1345] ##STR01873##

[1346] A mixture of BrettPhos Pd G3 (29 mg, 0.0317 mmol), (100 mg, 0.317 mmol) and 7-bromotetrazolo[1,5-a]pyridine (95 mg, 0.476 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL) under nitrogen at RT. Then cesium carbonate (207 mg, 0.634 mmol) was added in one portion, the suspension was degassed for 5 min. The reaction mixture was stirred at 70? C. for 2 h. The mixture was filtered through celite plug, washed with MeOH (5 mL) and the solvent was removed in vacuo. Purification by Prep LC (Method P1) to afford the desired product (63 mg) with impurities. The material was subsequently re-purified with prep method P3 to afford the title compound (26 mg, 19%) as a pale yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 11.67 (s, 1H), 9.30 (d, J=6.9 Hz, 1H), 8.73 (s, 1H), 8.61-8.53 (m, 1H), 7.45 (dd, J=7.4, 2.1 Hz, 1H), 7.36 (dd, J=9.0, 5.0 Hz, 1H), 7.26 (dd, J=9.3, 2.9 Hz, 1H), 7.16 (td, J=8.5, 3.2 Hz, 1H), 2.14 (s, 3H). LCMS (Method 5) m/z 434.1 [M+H]+, (ESI+), RT=4.08.

Compound 136: 3-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyrazine-2-carboxamide

[1347] ##STR01874## ##STR01875##

[1348] Step 1: methyl 3-chloro-6-iodo-pyrazine-2-carboxylate: To a solution of methyl 3-amino-6-iodopyrazine-2-carboxylate (100 mg, 0.358 mmol) in DCM-Anhydrous (1.5 mL) at 0? C. was added titanium tetrachloride (38 uL, 0.358 mmol) and the red solution stirred for 5 minutes before addition of tert-butyl nitrite (90%, 95 uL, 0.717 mmol) the solution was allowed to warm to ambient. After 30 minutes titanium tetrachloride (38 uL, 0.358 mmol) was added and the mixture stirred at ambient for 1 h before analysis by LCMS. Water (?5 mL) was added causiously and the solution extracted with DCM (?3?5 mL). The organics were passed through a phase separator and the solvent removed in vacuo to afford methyl 3-chloro-6-iodo-pyrazine-2-carboxylate (90.0%) (103 mg, 0.311 mmol, 87% Yield) as a pale yellow oil. Material used crude in subsequent step.

[1349] Step 2: methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-iodo-pyrazine-2-carboxylate: A mixture of 3,4-difluoro-2-methoxy-phenol (62 mg, 0.387 mmol), methyl 3-chloro-6-iodo-pyrazine-2-carboxylate (110 mg, 0.369 mmol) and K.sub.2CO.sub.3 (76 mg, 0.553 mmol) in Acetonitrile-Anhydrous (1.5 mL) was stirred at 60? C. overnight. The reaction was filtered through a phase separator and washed with DCM (3?10 mL), concentrated in vacuo and purified by FCC (10 g silica; 0-100% MTBE in Heptanes). Product fractions (single peak on trace) were evaporated in vacuo to afford methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-iodo-pyrazine-2-carboxylate (82.0%) (55 mg, 0.107 mmol, 29% Yield) as a colourless oil.

[1350] .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.53 (s, 1H), 7.10-6.97 (m, 2H), 4.00 (s, 3H), 3.85-3.83 (m, 3H) m/z: 423.0 [M+H].sup.+, (ESI+), RT=0.95 LCMS Method 2.

[1351] Step 3: methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylate: To a mixture of methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-iodo-pyrazine-2-carboxylate (55 mg, 0.130 mmol), copper iodide (37 mg, 0.195 mmol) and N,N,N-tributylbutan-1-aminium iodide (TBAI) (19 mg, 0.0521 mmol) in DMF-Anhydrous (0.5 mL) under N2 was added methyl difluoro(fluorosulfonyl)acetate (0.083 mL, 0.651 mmol). The reaction mixture was heated to 70? C. and stirred at this temperature for 3.5 h. The reaction mixture was cooled to rt, filtered, poured into water and extracted with EtOAc (3?). The combined organic phases were washed with brine (5?), dried with MgSO4, filtered and concentrated in vacuo to methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylate (90.0%) (36 mg, 0.0890 mmol, 68% Yield) as a dark brown oily solid. .sup.1H NMR (500 MHz, CD.sub.3OD) ? 8.59 (s, 1H), 6.99-6.95 (m, 3H), 3.94 (s, 3H), 3.78-3.74 (m, 3H). .sup.19F NMR (471 MHz, CD.sub.3OD) ? ?68.23, ?140.04-?141.07 (m), ?154.06-?155.17 (m).

[1352] Step 4: 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylic acid: To a mixture of methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylate (39 mg, 0.106 mmol) in THF (0.3 mL):Water (0.1 mL), LiOH (21 mg, 0.848 mmol) was added and the mixture was stirred at rt for 38 h. The reaction was diluted with water (40 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The aqueous layer was extracted with EtOAc (3?40 mL), passed through a phase separator and concentrated in vacuo. Product was used for the next step without any further purifications.

[1353] Step 5: 3-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyrazine-2-carboxamide: A mixture of 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylic acid (28 mg, 0.0800 mmol), N-ethyl-N-isopropyl-propan-2-amine (DIEA) (0.028 mL, 0.160 mmol), HATU (36 mg, 0.0959 mmol) and 3-(methylsulfanyl)aniline (13 mg, 0.0959 mmol) in DMF (0.1969 mL) was stirred at rt for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3?30 mL). The combined organic phases were passed through a phase separator and concentrated in vacuo. The compound was purified by FCC using 0-100% EtOAc in Heptane over silica (on a Biotage Sfar 10 g column, compound wet-loaded using DCM) to afford 3-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyrazine-2-carboxamide (55.0%)(68 mg, 0.0793 mmol, 99%) as a pale yellow solid. m/z: 472.1 [M+H].sup.+, (ESI+), RT=1.07 LCMS Method 2

[1354] Step 6: 3-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyrazine-2-carboxamide: To a suspension of 3-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyrazine-2-carboxamide (60%, 68 mg, 0.0866 mmol) in Methanol (1 mL), (Diacetoxyiodo)benzene (64 mg, 0.199 mmol) and (NH.sub.4).sub.2CO.sub.3 (12 mg, 0.130 mmol) were added and the reaction was stirred at rt for 4 h. The reaction was concentrated in vacuo and purified by Prep Method 1. Fractions evaporated in vacuo to afford 3-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyrazine-2-carboxamide (99.0%) (10 mg, 0.0203 mmol, 23% Yield) as an off white solid. .sup.1H NMR (400 MHz, CD.sub.3OD) ? 8.75 (s, 1H), 8.54 (t, J=1.9 Hz, 1H), 8.09 (dd, J=8.1, 1.2 Hz, 1H), 7.89-7.82 (m, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.18-7.05 (m, 2H), 3.90 (d, J=1.7 Hz, 3H), 3.20 (s, 3H). m/z: 501.3 [M?H].sup.?, (ESI?), RT=3.07 LCMS Method 4.

Example 115

Compound Profiling on NaV1.8 Human NaV1.8 Cell Line SyncroPatch384PE Assay

[1355] Compounds were tested on recombinant human Na.sub.V1.8 stably transfected HEK cells using the SyncroPatch384PE system, an automated patch clamp device. Cells were cultured at 37? C./5% CO2 in DMEM medium supplemented with GlutaMAX I, NEAA 1%, FBS 10% and seeded in T175 flasks. Cells were cultured at 30? C. one day prior to recording sodium currents. On the day of the recordings, cells were detached with 0.05% Trypsin-EDTA, resuspended in serum free DMEM medium and placed into the SyncroPatch384PE 6? C. pre-cooled cell hotel and shaken at 200 rpm. Intracellular solution (IC) contained, in mM: 10, CsCl; 110, CsF; 20, EGTA; 10, HEPES. Extracellular solution (EC) contained, in mM: 140, NaCl; 4, KCl; 5, Glucose; 10, HEPES; 2, CaCl.sub.2; 1, MgCl.sub.2. Washing solution contained, in mM: 40, NMDG; 100, NaCl; 4, KCl; 10, Glucose; 10, HEPES; 5, CaCl.sub.2; 1, MgCl.sub.2.

[1356] Compounds were tested in quadruplicates in 0.1% DMSO and 0.030% Pluronic Acid. Compounds were diluted 1:3.33 in EC solution to create a 10-point concentration response curve, spanning a final concentration range from 10-0.0002 ?M in the assay plate. Compounds with low nM potency were retested using a lower concentration range (1-0.00002 ?M). Each plate contained tetracaine and another tool compound as positive controls. Up to 7 compounds were tested on one plate. 150 ?M tetracaine and 0.1% DMSO were used as high and low controls, respectively.

[1357] Whole cell patch clamp recordings were conducted according to Nanion's standard procedure for SyncroPatch384PE?. Cells were held at a holding potential of ?120 mV. A depolarization step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarization step to ?100 mV for 100 ms. An inactivation step at ?40 mV for 10 sec was applied before stepping to ?100 mV for 20 ms, followed by a step to 10 mV for 30 ms (P2 measurement) and then back to ?100 mV for 30 ms. Sweep interval was 15 sec with a sampling rate of 10 kHz. Following establishment of the whole-cell configuration in EC, two washing steps with reference buffer were performed to stabilize the baseline. Compounds were then applied by the SynchroPatch into each well and the current was recorded for five minutes in EC, followed by application of tetracaine to achieve full block at the end of the experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls.

[1358] Table 27 shows the potency of compounds against human NaV1.8, where A represents an IC50 less than or equal to 200 nM, B represents an IC50 greater than 201 nM to less than or equal to 500 nM, C represents an IC50 greater than 501 nM to less than or equal to 1000 nM, D represents an IC50 greater than 1001 nM to less than or equal to 5000 nM, E represents an IC50 greater than 5001 nM.

TABLE-US-00028 TABLE 27 Compound P1 IC50 P2 IC50 1 A A 2 B A 3 B D 4 E E 5 C D 6 D B 7 D C 8 D D 9 E D 10 E E 11 D D 12 D D 13 A A 14 B B 15 E D 16 D D 17 C B 18 D C 19 D D 20 C C 21 C C 22 D D 23 B B 24 A A 25 A A 26 A A 27 A A 28 D D 29 E E 30 E E 31 E E 32 E E 33 A A 34 A A 35 A A 36 B C 37 A A 38 D D 39 A A 40 D E 41 D E 42 A A 43 C D 44 B C 45 B B 46 E E 47 A A 48 C D 49 A A 50 A A 51 A A 52 E E 53 A A 54 D D 55 D D 56 E E 57 E E 58 B B 59 C B 60 D D 61 E E 62 E E 63 B C 64 A A 65 C C 66 E D 67 E E 68 E E 69 E E 70 C C 71 E E 72 A A 73 B B 74 A C 75 A A 76 A A 77 B B 78 E E 79 B B 80 C C 81 B D 82 A A 83 A A 84 E E 85 E E 86 C C 87 A A 88 A A 89 D D 90 E E 91 E E 92 E E 93 D E 94 D E 95 E E 96 B C 97 D D 98 E E 99 A A 100 A A 101 A A 102 C B 103 E B 104 E E 105 E E 106 B B 107 A A 108 E E 109 B B 110 E E 111 E E 114 A A 116 B B 117 A A 118 A A 119 C C 121 A A 122 C B 123 A A 125 A B 126 A A 127 C C 128 E E 129 B B 130 E D 131 B C 132 B A 133 E E 134 E E 135 A C 136 A A

D. Examples for Fourth Set of Compounds

Example 116

[1359] Methods of making the compounds of the present invention, and intermediates used in their synthesis, are provided in the General Synthetic Schemes and Specific Syntheses Procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. Dry glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted.

[1360] All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized. The chemical names were generated using the ChemDraw Professional 19.1, available from PerkinElmer or chemAxon.

[1361] Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD MILLIPORE?. Purification was performed with CombiFlash NextGen 300 Automated Flash Chromatography System or purified using one of the preparative HPLC methods mentioned below.

Prep Method 1 (P1): Acidic Early Method

[1362] Purification (METCR/Prep004) (P1) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 2 (P2): Acidic Standard Method

[1363] Purification (METCR/Prep001) (P2) LC were performed using a Waters Sunfire C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 30% B (A=0.10% formic acid in water; B=0.10% formic acid in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 3 (P3): Basic Early Method

[1364] Purification (METCR/Prep002) (P3) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 10% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 10-95% B over 13.89 min and held for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Prep Method 4 (P4): Basic Standard Method

[1365] Purification (METCR/Prep003) (P4) LC were performed using a Waters X-Bridge C18 column (30 mm?100 mm, 5 ?m; temperature: room temperature), with an injection volume of 1500 ?L at flow rate of 40 mL/min at 300% B (A=0.2% ammonium hydroxide in water; B=0.2% ammonium hydroxide in acetonitrile) for 0.55 min then a gradient of 30-95% B over 10.45 min and held for 2.10 min. A second gradient of 95-30% B was then applied over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

[1366] Analytical LCMC were collected using one of following methods.

Method 1 (M1): Acidic IPC Method (METCRI410MS17, MS18, MS19)

[1367] Analytical (MET/CR/1410) (M1) HPLC-MS were performed using a Kinetex Core shell C18 column (2.1 mm?50 mm, 5 ?m; temperature: 40? C.), with an injection volume of 3 ?L at a flow rate of 1.2 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.10% formic acid in acetonitrile) over 1.2 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.01 min and held for 0.39 min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector, spectrum range: 210-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 2(M2):

[1368] Mass spectrometry data were collected using a Waters Acquity H-class ultra-high pressure liquid chromatograph coupled to a Waters Acquity TQD mass spectrometer. An Acquity UPLC BEH C18 column (2.1?50 mm) was used for separation and resolving samples. The compounds were eluted from the column using a 10-minute linear solvent gradient: 0-0.5 min, 5% B; 0.5-6.5 min, 100% B, 6.5-7.5 min; 100% B, 7.5-8.1 min; 5% B, 8.1-10 min; 5% B. The solvent flow rate is 0.45 mL per minute. Solvent A was water and solvent B was acetonitrile. Mass spectra were collected in positive or negative ion mode, with following parameters: 2.5 kV capillary voltage; 25 V sampling cone voltage; 140 C source temperature; 400 C desolvation temperature; nitrogen desolvation at 800 L/hr.

Method 3 (M3): Basic IPC Method (MET-uPLC-AB-2005MS16, MSQ5)

[1369] Analytical (MET/uPLC/AB2005) (M14) uHPLC-MS were performed using a Waters uPLC? BEHTM C18 column (2.1 mm?30 mm, 1.7 ?m; temperature 40? C.), with an injection volume of 1 ?L at a flow rate of 1.0 mL/min and a gradient of 1-100% B (A=2 mM ammonium bicarbonate in water, buffered to pH 10; B=acetonitrile) over 1.1 min, then 100% B for 0.25 min. A second gradient of 100-1% B was then applied over 0.05 min and held for 0.4 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 4 (M4): Acidic Final Analysis Method (METCR-uPLC-AB101MSQ1, MSQ2, MSQ4)

[1370] Analytical (MET/uPLC/AB101) (M4) uHPLC-MS were performed using a Phenomenex Kinetex-XB C18 column (2.1 mm?100 mm, 1.7 ?m; temperature: 40? C.), with an injection volume of 1 ?L at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm, ELS data was collected on a Waters ACQUITY ELS detector when reported. Mass spectra were obtained using a Waters SQD or Waters ACQUITY QDA. Data were integrated and reported using Waters MassLynx and OpenLynx software.

Method 5 (M5): Acidic Final Analysis Method (METCR1416MS18, MS19)

[1371] Analytical (MET/CR/1416) (M5) HPLC-MS were performed using a Waters Atlantis dC18 column (2.1 mm?100 mm, 3 ?m; temperature: 40? C.), with an injection volume of 3 ?L at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=0.1% formic acid in water; B=0.1% formic acid in acetonitrile) over 5 min, then 100% B for 0.4 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.58 min. UV spectra were recorded at 215 nm using a SPD-M20A PDA detector, spectrum range: 210-400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 6 (M6): Basic Final Analysis Method (MET-uPLC-AB]05MS16, MSQ5)

[1372] Analytical (MET/uHPLC/AB105) (M8) uHPLC-MS were performed using a Waters uPLC? BEHTM C18 column (2.1 mm?100 mm, 1.7 ?m column; temperature: 40? C.), with an injection volume of 1 ?L and at flow rate of 0.6 mL/min and a gradient of 5-100% B (A=2 mM ammonium bicarbonate in water, buffered to pH 10; B=acetonitrile) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min. UV spectra were recorded at 215 nm using a Waters ACQUITY PDA detector, spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[1373] SFC chiral resolution was performed using following method: Column: Daicel CHIRALPAK IG, 250 mm?20 mm I.D., 5 ?m; Mobile Phase A: CO.sub.2/MeOH [0.2% NH.sub.3 (7M Solution in MeOH)]=70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35? C.

[1374] Unless otherwise stated, .sup.1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker? 300 MHz, or 500 MHz, 400 MHz or 250 MHz on either a Bruker Avance III HD 500 MHz spectrometer Bruker Avance III HD 400 MHz spectrometer. Chemical shifts, 6, are quoted in parts per million (ppm) relative to TMS and calibrated using residual un-deuterated solvent as an internal reference. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.

Example 117

General Synthetic Schemes

[1375] Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. The present invention further provides processes for the preparation of compounds of structural Formula I as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention.

##STR01876## ##STR01877##

[1376] The compounds of the formula A-6 may be synthesized in five step linear synthesis starting from dichlorocarboxylic acid ester A-1 by nucleophilic displacement of Cl adjacent to the carboxylic acid using various substituted phenols in the presence of base, such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaH, KH or other organic bases to provide intermediates of type A-2. Intermediates of type A-2 was further treated with HI (50%), HI (57%) or HI (40%) to furnish intermediates of type A-3. Variously substituted R.sub.3 groups can be introduced either by Pd mediated or Cu mediated coupling with intermediates of type A-3. The carboxylic acid of intermediates type A-5 can be prepared by hydrolyzing ester intermediates of type A-4 using a base, such as aqueous NaOH, KOH, or LiOH. Alternatively, intermediates of type A-5 can be prepared by treating intermediates A-4 using aqueous 1 to 6N HCl. The carboxylic acids (A-5) can be activated to the acid chloride and coupled with R.sub.2NH.sub.2 or carboxylic acids (A-5) can be coupled with R.sub.2NH.sub.2 using standard amide coupling agents, not limited to HATU, TBTU, EDC or T.sub.3P in organic solvents and base, such as DIEA, Et.sub.3N, DMAP or pyridine to furnish A-6.

##STR01878##

[1377] Alternatively, compounds of the formula A-6 can be prepared nucleophilic displacement of Cl intermediates of type B-1 using various substituted phenols in the presence of base, such as K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NaH, KH or other organic bases to provide intermediates of type B-2. The carboxylic acid of intermediates type B-3 can be prepared by hydrolyzing ester intermediates of type B-2 using a base, such as aqueous NaOH, KOH, or LiOH. Alternatively, intermediates of type B-3 can also be prepared by treating intermediates B-2 using aqueous 1 to 6N HCl. The carboxylic acids (B-3) can be activated to the acid chloride and coupled with R.sub.2NH.sub.2 or carboxylic acids (B-3) can couple with R.sub.2NH.sub.2 using standard amide coupling agents, not limited to HATU, TBTU, EDC or T.sub.3P in organic solvents and base, such as DIEA, Et.sub.3N, DMAP or pyridine to furnish A-6.

##STR01879##

[1378] Alternatively, compounds of type A-6 can also be prepared by activating carboxylic acids (C-1) to the acid chloride and coupled with R.sub.2NH.sub.2 or carboxylic acids (C-1) can be coupled with R.sub.2NH.sub.2 using standard amide coupling agents, not limited to HATU, TBTU, EDC or T.sub.3P in organic solvents and base, such as DIEA, Et.sub.3N, DMAP or pyridine to furnish C-2. The compounds of type A-6 can be obtained by treating intermediates of type C-2 with various phenols in the presence of base, such as NaH, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, DIEA or Et.sub.3N using organic solvents.

Example 118

Specific Synthesis

Intermediate 1: 3-(4-Fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic Acid

[1379] ##STR01880##

Step 1: methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate

[1380] A mixture of 4-fluoro-2-methyl-phenol (3.01 g, 23.8 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (4.70 g, 22.7 mmol) and potassium carbonate (4.71 g, 34.1 mmol) in acetonitrile (47 mL) was stirred at 80? C. for 3 h.

[1381] The reaction was cooled to room temperature, filtered and washed with MeCN (20 mL). Filtrate was concentrated in vacuo to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 15% EtOAc in heptane afforded the title compound methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (95.0%) (4.10 g, 58%) as a pale yellow oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.26 (s, 1H), 7.29-7.20 (m, 2H), 7.16-7.06 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H). LC-MS: m/z: 297/299 [M+H].sup.+.

Step 2: methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate

[1382] A mixture of 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (95%, 4.10 g, 13.1 mmol) in 55% aqueous hydrogen iodide (50 mL, 0.197 mol) was stirred at 40? C. for 3 h. The mixture was left overnight at RT. The reaction mixture was filtered. The filter cake was washed with water. The solid was re-dissolved in 55% aqueous hydrogen iodide (50 mL, 0.197 mol) and stirred at 40? C. for 24 h. The mixture was cooled to RT and filtered, the solid was washed with water and dried in high vacuum oven at 40? C. overnight to afford methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (79.0%) (2.70 g, 42%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.37 (s, 1H), 7.26-7.17 (m, 2H), 7.15-7.05 (m, 1H), 3.91 (s, 3H), 2.09 (s, 3H). MS: m/z: 388.9 [M+H].sup.+.

Step 3: methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate

[1383] To a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (80%, 2.70 g, 5.57 mmol), CuI (1.6 g, 8.35 mmol), tetrabutylammonium; iodide (0.824 g, 2.23 mmol) in DMF (10 mL) (degassed with nitrogen for 5 minutes) methyl difluoro(fluorosulfonyl)acetate (5.34 g, 27.8 mmol) was added and stirred at 90? C. for 2 h. The reaction was cooled to RT, filtered and washed with EtOAc (2?10 mL). The filtrate was washed with brine (50 mL) and dried over MgSO.sub.4, filtered, concentrated under reduced pressure to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 50% EtOAc in heptane afforded the title compound methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (99.0%) (0.770 mg, 41%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.54 (s, 1H), 7.32-7.20 (m, 2H), 7.14 (td, J=8.5, 3.2 Hz, 1H), 3.97 (s, 3H), 2.13 (s, 3H). MS: m/z: 316.95 [M+H].sup.+, (ESI+). Unreacted starting material methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (220 mg, 13%) was recovered as a pale yellow oil.

Step 4: 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic Acid

[1384] To a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (99%, 770 mg, 2.31 mmol) in THF (7.92 mL):Water (1.98 mL), lithium hydroxide (288 mg, 11.5 mmol) was added and the mixture was stirred at rt overnight. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The solids were filtered, washed with water (2?10 mL), dissolved in EtOAc (20 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (99.0%) (640 mg, 87%) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.49 (s, 1H), 7.31-7.22 (m, 2H), 7.18-7.09 (m, 1H), 2.12 (s, 3H). LC-MS: m/z 316.95 [M+H].sup.+, (ESI+), RT=1.06 Method METCR1410 Generic 2 min.

Intermediate 2: 3-(4-Fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic Acid

[1385] ##STR01881##

Step 1: 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylic Acid

[1386] To solution of 4-fluoro-2-methoxyphenol (1.2 mL, 10.4 mmol) in DMF (20.7 mL) was added sodium hydride (60%) (0.622 g, 15.5 mmol) under nitrogen and the solution was stirred at rt for 30 min. To the resulting mixture 3,6-dichloropyridazine-4-carboxylic acid (1.00 g, 5.18 mmol) was added and stirring continued further at rt for 66 hours. At the end of this period, water (200 mL) was added and adjusted to pH1 with HCl (6N). The mixture was extracted with EtOAc (4?40 mL). The combined extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude mixture was purified by column chromatography over SiO.sub.2 with a 0-80% gradient of EtOAc in heptane to afford the title compound 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylic acid (1.211 g, 74%) as a pale red solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.32 (s, 1H), 7.27 (dd, J=8.8, 5.8 Hz, 1H), 7.12 (dd, J=10.7, 2.9 Hz, 1H), 6.84 (td, J=8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC-MS: m/z 299.0/301.0 [M+H].sup.+, (ESI+).

Step 2: methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate

[1387] 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylic acid (500 mg, 1.77 mmol) was dissolved in DCM (12.2 mL), Thionyl chloride (5.1 mL, 70.8 mmol) was added in one portion at rt and the resulting mixture was stirred at 50? C. for 8 h. Additional thionyl chloride (2.5 mL, 35 mmol) was added and the reaction was stirred at 50? C. for a further 1 h. The mixture was allowed to cool to 0? C., and anhydrous methanol (5.48 mL) was added dropwise. The resulting mixture was stirred at rt for 30 min. The reaction mixture was diluted with water (20 mL) followed by saturated aqueous Na.sub.2CO.sub.3 (20 mL) and the layers were separated and the organic layer dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica eluting with a gradient of EtOAc in heptane afforded methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (335 mg, 64%) as an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.25 (s, 1H), 7.25-7.18 (m, 2H), 7.10 (td, J=8.6, 3.1 Hz, 1H), 3.92 (s, 3H), 2.09 (s, 3H). LC-MS: m/z 297.3 [M+H].sup.+, (ESI+), RT=1.21 METCR1410 Generic 2 min.

Step 3: methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate

[1388] A mixture of methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate (8.10 g, 23.3 mmol) in 55% aqueous hydrogen iodide (18 mL, 0.350 mol) was stirred at 40? C. for 24 h. The mixture was cooled to rt and filtered. The solid was washed with water and dried in high vacuum oven at 40? C. overnight to afford the title compound methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (12.58 g, 88%) as an orange solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.35 (s, 1H), 7.25 (m, 1H), 7.13-7.09 (m, 1H), 6.84-6.79 (m, 1H), 3.90 (s, 3H), 3.70 (s, 3H). LC-MS: m/z: 404.9 [M+H].sup.+, (ESI+), RT=1.19, METCR1410 Generic 2 min.

Step 4: methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate

[1389] To a mixture of methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (13.34 g, 21.8 mmol), copper iodide (6.26 g, 32.7 mmol), tetrabutylammonium iodide (3.23 g, 8.71 mmol) in DMF (72 mL) (degassed with nitrogen for 5 minutes), methyl difluoro(fluorosulfonyl)acetate (20.92 g, 0.109 mol) was added and stirred at 90? C. for 2 h. The reaction was cooled to rt, poured into water (200 mL) and extracted with EtOAc (4?100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated under reduced pressure to obtain the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 50% EtOAc in heptane afforded the title compound (95.0%) (2.85 g, 36%) as a pale orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.53 (s, 1H), 7.32 (dd, J=8.8, 5.8 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.87 (td, J=8.5, 2.9 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H). LC-MS: m/z 347.3 [M+H].sup.+, (ESI+), RT=3.57 MET-uPLC-AB-105 (7 min, high pH).

Step 5: 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic Acid

[1390] To a mixture of methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (2.85 g, 7.82 mmol) in THF:H.sub.2O (4:1; v/v) (40 mL), lithium hydroxide (0.98 g, 39.1 mmol) was added and the mixture was stirred at rt for 24 h. The reaction was diluted with water (40 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The product was extracted with EtOAc (3?60 mL), dried (MgSO.sub.4), filtered and the solvent evaporated under reduced pressure to obtain the title compound 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (90.0%) (2.35 g, 82%) as an orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.11 (s, 1H), 7.24 (dd, J=8.8, 5.9 Hz, 1H), 7.12 (dd, J=10.7, 2.8 Hz, 1H), 6.84 (dt, J=8.5, 4.2 Hz, 1H), 3.71 (s, 4H). LC-MS: m/z 332.95 [M+H].sup.+, (ESI+), RT=1.03 Method XX METCR1410 Generic 2 min.

Example 119

Compound 1: tert-Butyl (R)-3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine-1-carboxylate

[1391] ##STR01882##

[1392] A mixture of N-ethyl-N-isopropyl-propan-2-amine (0.12 mL, 0.696 mmol), 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.316 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (76 mg, 0.379 mmol) were dissolved in DCM (5 mL) under nitrogen at rt. N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (144 mg, 0.379 mmol) was added in one portion. The reaction mixture was stirred at rt for 2 h. The solvent was reduced to 2 mL in vacuo. Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane afforded tert-butyl (3R)-3-[[3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]piperidine-1-carboxylate (95.0%) (140 mg, 0.267 mmol, 84% Yield) as an off white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.76 (d, J=7.5 Hz, 1H), 8.37 (s, 1H), 7.30 (dd, J=9.0, 5.0 Hz, 1H), 7.25 (dd, J=9.3, 3.1 Hz, 1H), 7.15 (dt, J=8.5, 4.3 Hz, 1H), 3.89-3.77 (m, 2H), 3.60-3.51 (m, 1H), 3.09-2.92 (m, 2H), 2.12 (s, 3H), 1.93-1.84 (m, 1H), 1.73-1.65 (m, 1H), 1.59-1.30 (m, 11H). LC-MS: m/z 496.95 [M?H].sup.+, (ESI?), RT=1.36 METCR1410 Generic 2 min.

Compound 2: (R)-3-(4-Fluoro-2-methylphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1393] ##STR01883##

[1394] tert-butyl (R)-3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine-1-carboxylate (0.130 g, 0.248 mmol) and 2,2,2-trifluoroacetic acid (0.37 mL, 4.96 mmol) was stirred in DCM (3.92 mL) under nitrogen at rt. The reaction mixture was stirred at rt for 3 h. The solvent was removed in vacuo and the residue was dissolved in DCM (10 mL), washed with sat. NaHCO.sub.3 (10 mL) and brine (10 mL). Organic layer separated, dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound (R)-3-(4-fluoro-2-methylphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.075 g, 72%) as an off white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.67 (d, J=7.9 Hz, 1H), 8.41 (s, 1H), 7.31 (dd, J=8.9, 5.0 Hz, 1H), 7.25 (dd, J=9.3, 3.1 Hz, 1H), 7.14 (td, J=8.5, 3.1 Hz, 1H), 3.89-3.79 (m, 1H), 2.96 (dd, J=11.8, 3.4 Hz, 1H), 2.71 (dt, J=12.1, 4.3 Hz, 1H), 2.48-2.42 (m, 2H), 2.31-2.18 (m, 1H), 2.13 (s, 3H), 1.89-1.79 (m, 1H), 1.67-1.56 (m, 1H), 1.52-1.34 (m, 2H). LC-MS: m/z 399.0 [M+H].sup.+, (ESI+), RT=2.95 MET-uPLC-AB-101 (7 min, low pH).

Compound 3: (R)-3-(4-Fluoro-2-methylphenoxy)-N-(1-(methylsulfonyl)piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1395] ##STR01884##

[1396] A mixture of triethylamine (0.015 mL, 0.107 mmol), (R)-3-(4-fluoro-2-methylphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.030 g, 0.0715 mmol) and methanesulfonyl chloride (0.0083 mL, 0.107 mmol) were dissolved in DCM (2 mL) under nitrogen at rt. To the above mixture N,N-dimethylpyridin-4-amine (8.7 mg, 0.0715 mmol) was added and stirring continued for further 1 h at rt. The solvent was removed in vacuo. Purification by preparative LC afforded the title compound (R)-3-(4-fluoro-2-methylphenoxy)-N-(1-(methylsulfonyl)piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.019 g, 57%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.87 (d, J=7.7 Hz, 1H), 8.41 (s, 1H), 7.30 (dd, J=8.9, 5.1 Hz, 1H), 7.24 (dd, J=9.4, 3.0 Hz, 1H), 7.14 (td, J=8.6, 3.1 Hz, 1H), 4.09-3.96 (m, 1H), 3.56 (dd, J=11.4, 3.7 Hz, 1H), 3.32-3.22 (m, 1H), 2.97-2.89 (m, 1H), 2.87 (s, 3H), 2.82 (dd, J=11.4, 8.3 Hz, 1H), 2.12 (s, 3H), 1.90-1.78 (m, 2H), 1.66-1.46 (m, 2H). LC-MS: m/z 477.0 [M+H]+, (ESI+), RT=4.1 MET-uPLC-AB-101 (7 min, low pH). [Early Elute Method:Column: Sunfire? Prep. C18 10 um OBDTM, 30?100 mm; Mobile Phase: 5-95% Acetonitrile (0.1% formic acid) in Water (0.1% formic acid) over 14 minutes, Flow Rate: 40 mL/min UV: 215 and 254 nm)

Compound 4: (R)N-(1-Acetylpiperidin-3-yl)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1397] ##STR01885##

[1398] A mixture of acetic anhydride (0.0099 mL, 0.107 mmol), (R)-3-(4-fluoro-2-methylphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.030 g, 0.0715 mmol) and triethylamine (0.015 mL, 0.107 mmol) were dissolved in DCM (2 mL) under nitrogen at rt, DMAP (0.0087 g, 7.15 ?mol) was added. The reaction mixture was stirred at rt for 1 h. The solvent was removed in vacuo. Purification by Preparative LC Method A afforded the title compound (R)N-(1-acetylpiperidin-3-yl)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.015 g, 49%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.52 (bs, 1H), 8.30 (s, 1H), 7.28 (dd, J=8.9, 5.0 Hz, 1H), 7.20 (dd, J=9.4, 3.1 Hz, 1H), 7.10 (td, J=8.5, 3.1 Hz, 1H), 4.04-3.74 (m, 2H), 3.59-3.49 (m, 1H), 3.40-3.19 (m, 2H), 2.15 (s, 3H), 2.02-1.91 (m, 4H), 1.78-1.61 (m, 2H), 1.59-1.44 (m, 1H). LC-MS: m/z 441.0 [M+H]+, (ESI+), RT=3.94 MET-uPLC-AB-101 (7 min, low pH).

Compound 5: tert-Butyl (S)-3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine-1-carboxylate

[1399] ##STR01886##

[1400] A mixture of, 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (140 mg, 0.421 mmol), tert-butyl (3S)-3-aminopiperidine-1-carboxylate (101 mg, 0.506 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.16 mL, 0.927 mmol) were dissolved in DCM (2.1071 mL) under nitrogen at rt. N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (192 mg, 0.506 mmol) was added in one portion. The reaction mixture was stirred at rt for 2 h. IPC1 LCMS showed formation of desired product. The reaction mixture was purified directly by chromatography on silica (Sfar Duo 10 g) eluting with a gradient of 0 to 50% of EtOAc in heptane to afford tert-butyl (3S)-3-[[3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]piperidine-1-carboxylate (95.0%) (182 mg, 80%) as a colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.71 (d, J=7.6 Hz, 1H), 8.34 (s, 1H), 7.34 (dd, J=8.8, 5.9 Hz, 1H), 7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.90-3.76 (m, 2H), 3.73 (s, 3H), 3.58-3.51 (m, 1H), 3.09-2.96 (m, 2H), 1.97-1.84 (m, 1H), 1.77-1.65 (m, 1H), 1.61-1.41 (m, 2H), 1.37 (s, 9H). m/z 513.6 [M+H].sup.+, (ESI+), RT=4.06 MET-uPLC-AB-105 (7 min, high pH).

Compound 6: (S)-3-(4-Fluoro-2-methoxyphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1401] ##STR01887##

[1402] The title compound was prepared by a similar procedure described for Compound 2 using tert-butyl (S)-3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine-1-carboxylate. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.64 (d, J=7.8 Hz, 1H), 8.37 (s, 1H), 7.35 (dd, J=8.8, 5.9 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 3.96-3.76 (m, 2H), 3.73 (s, 3H), 2.99 (m, 2H), 2.75 (m, 1H), 2.46 (m, 1H), 1.84 (m, 1H), 1.63 (s, 1H), 1.56-1.33 (m, 2H). m/z 415.3 [M+H].sup.+, (ESI+), RT=3.09 MET-uPLC-AB-105 (7 min, high pH).

Compound 7: (S)-3-(4-Fluoro-2-methoxyphenoxy)-N-(1-(methylsulfonyl)piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1403] ##STR01888##

[1404] The title product was prepared by a similar procedure described for Compound 3 using (S)-3-(4-fluoro-2-methoxyphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide and methanesulfonyl chloride. .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.83 (d, J=7.7 Hz, 1H), 8.38 (s, 1H), 7.34 (dd, J=8.8, 5.8 Hz, 1H), 7.15 (dd, J=10.7, 2.9 Hz, 1H), 6.87 (td, J=8.5, 2.9 Hz, 1H), 4.00 (m, 1H), 3.72 (s, 3H), 3.57 (dd, J=11.2, 3.9 Hz, 2H), 2.94-2.88 (m, 1H), 2.87 (s, 3H), 2.80 (dd, J=11.3, 8.4 Hz, 1H), 1.91-1.76 (m, 2H), 1.65-1.45 (m, 2H). m/z 492.9 [M+H]+, (ESI+), RT=4.06 METCR1416 Hi res 7 min.

Compound 8: (S)N-(1-Acetylpiperidin-3-yl)-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1405] ##STR01889##

[1406] The title product was prepared by a similar procedure described for Compound 4 using (S)-3-(4-fluoro-2-methoxyphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide and acetic anhydride. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.45 (s, 1H), 8.28 (s, 1H), 7.33 (dd, J=8.8, 5.8 Hz, 1H), 7.10 (dd, J=10.6, 2.9 Hz, 1H), 6.86 (td, J=8.5, 2.9 Hz, 1H), 4.03-3.85 (m, 2H), 3.74 (s, 3H), 3.60-3.45 (m, 1H), 3.25 (d, J=34.9 Hz, 2H), 1.97 (s, 3H), 1.95-1.87 (m, 1H), 1.68 (dd, J=11.5, 7.7 Hz, 2H), 1.51 (s, 1H). m/z 457.0 [M+H]+, (ESI+), RT=3.85 METCR1416 Hi res 7 min.

[1407] The compounds listed in Table 28 were prepared by a similar procedure described for Compound 1 using appropriate starting materials.

TABLE-US-00029 TABLE 28 Compound Structure and Name Analytical data 9 [01890] 3-(4-Fluoro-2-methoxyphenoxy)- N-(2-oxopiperidin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.98 (d, J = 7.4 Hz, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 7.36 (dd, J = 8.8, 5.9 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 (td, J = 8.5, 2.9 Hz, 1H), 4.37 (m, 6.5 Hz, 1H), 3.71 (s, 3H), 3.19-3.12 (m, 2H), 2.22-2.14 (m, 1H), 1.85-1.66 (m, 3H). m/z 429.0 [M + H]+, (ESI+), RT = 3.68 METCR1416 Hi res 7 min 10 [01891] 3-(4-Fluoro-2-methylphenoxy)-N- (2-oxopiperidin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.04 (d, J = 7.5 Hz, 1H), 8.36 (s, 1H), 7.73 (s, 1H), 7.32 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.4, 3.1 Hz, 1H), 7.15 (td, J = 8.6, 3.1 Hz, 1H), 4.47-4.31 (m, 1H), 3.21-3.12 (m, 2H), 2.26-2.16 (m, 1H), 2.14 (s, 3H), 1.89-1.66 (m, 3H). m/z 413.0 [M + H]+, (ESI+), RT = 3.80 METCR1416 Hi res 7 min 11 [01892] 3-(4-Fluoro-2-methylphenoxy)-N- (6-oxopiperidin-3-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide .sup.1H NMR (500 MHz, DMSO-d.sub.6) ? 8.99 (d, J = 7.3 Hz, 1H), 8.44 (s, 1H), 7.51-7.43 (m, 1H), 7.29 (dd, J = 8.9, 5.1 Hz, 1H), 7.25 (dd, J = 9.5, 3.1 Hz, 1H), 7.14 (td, J = 8.6, 3.2 Hz, 1H), 4.27-4.17 (m, 1H), 3.43- 3.40 (m, 1H), 3.11 (dd, J = 10.2, 6.3 Hz, 1H), 2.36-2.20 (m, 2H), 2.11 (s, 3H), 2.01-1.92 (m, 1H), 1.92-1.83 (m, 1H). m/z 412.9 [M + H]+, (ESI+), RT = 3.58 METCR1416 Hi res 7 min 12 [01893] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 8.95 (d, J = 7.3 Hz, 1H), 8.39 (s, 1H), 7.47-7.44 (m, 1H), 7.32 (dd, J = 8.8, 5.9 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 (td, J = 8.5, 2.9 Hz, 1H), 4.25-4.15 (m, 1H), 3.72 (s, 3H), 3.45-3.40 (m, 1H), 3.15- 3.05 (m, 1H), 2.37-2.19 (m, 2H), 2.00- 1.80 (m , 2H). m/z 429.0 [M + H]+, (ESI+), RT = 3.49 METCR1416 Hi res 7 min

Example 120

Compound Profiling on NaV1.8Human NaV1.8 Cell LineSyncroPatch384PE Assay

[1408] Compounds were tested on recombinant human Na.sub.V1.8 stably transfected HELK cells using the SyncroPatch384PE system, an automated patch clamp device. Cells were cultured at 37? C./5% CO2 in DMEM medium supplemented with GlutaMAX I, NEAA 1%, FBS 10% and seeded in T175 flasks. Cells were cultured at 30? C. one day prior to recording sodium currents. On the day of the recordings, cells were detached with 0.05% Trypsin-EDTA, resuspended in serum free DMEM medium and placed into the SyncroPatch384PE 6? C. pre-cooled cell hotel and shaken at 200 rpm. Intracellular solution (IC) contained, in mM: 10, CsCl; 110, CsF; 20, EGTA; 10, HEPES. Extracellular solution (EC) contained, in mM: 140, NaCl; 4, KCl; 5, Glucose; 10, HEPES; 2, CaCl.sub.2; 1, MgCl.sub.2. Washing solution contained, in mM: 40, NMDG; 100, NaCl; 4, KCl; 10, Glucose; 10, HEPES; 5, CaCl.sub.2; 1, MgCl.sub.2.

[1409] Compounds were tested in quadruplicates in 0.1% DMSO and 0.030% Pluronic Acid. Compounds were diluted 1:3.33 in EC solution to create a 10-point concentration response curve, spanning a final concentration range from 10-0.0002 ?M in the assay plate. Compounds with low nM potency were retested using a lower concentration range (1-0.00002 ?M). Each plate contained tetracaine and another tool compound as positive controls. Up to 7 compounds were tested on one plate. 150 ?M tetracaine and 0.1% DMSO were used as high and low controls, respectively.

[1410] Whole cell patch clamp recordings were conducted according to Nanion's standard procedure for SyncroPatch384PE?. Cells were held at a holding potential of ?120 mV. A depolarization step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarization step to ?100 mV for 100 ms. An inactivation step at ?40 mV for 10 sec was applied before stepping to ?100 mV for 20 ms, followed by a step to 10 mV for 30 ms (P2 measurement) and then back to ?100 mV for 30 ms. Sweep interval was 15 sec with a sampling rate of 10 kHz. Following establishment of the whole-cell configuration in EC, two washing steps with reference buffer were performed to stabilize the baseline. Compounds were then applied by the SynchroPatch into each well and the current was recorded for five minutes in EC, followed by application of tetracaine to achieve full block at the end of the experiment. The potency of the compounds was assessed on two read-outs, resting state block (P1 measurement) or inactivated state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls. Table 28 shows the potency of compounds against human NaV1.8.

[1411] Table 29 shows the potency of compounds against human NaV1.8, where A represents an IC50 less than or equal to 200 nM, B represents an IC50 greater than 201 nM to less than or equal to 500 nM, C represents an IC50 greater than 501 nM to less than or equal to 1000 nM, D represents an IC50 greater than 1001 nM to less than or equal to 5000 nM, E represents an IC50 greater than 5001 nM.

TABLE-US-00030 TABLE 29 Compound P1 IC50 P2 IC50 1 E E 3 E E 4 E E 5 E E 6 E E 7 E E 8 E E 9 E E 10 E E 11 E E 12 E E

E. Examples of Fifth Set of Compounds

Example 121

Synthetic Procedures

[1412] Exemplary compounds were prepared via several general synthetic routes set forth in the Examples below. Any of the disclosed compounds of the present invention can be prepared according to one or more of these synthetic routes or specific examples, or via modifications thereof accessible to the person of ordinary skill in the art.

##STR01894## ##STR01895##

Method A

Step 1: 4-bromo-6-(trifluoromethyl)pyridazin-3(2H)-one

[1413] 6-(trifluoromethyl)pyridazin-3(2H)-one (9.00 g, 54.8 mmol, 1.00 eq), 4 Angstrom molecular sieves (18.0 g) and dibromohydantoin (20.3 g, 71.3 mmol, 1.30 eq) were added into acetic acid (37.0 mL) and acetonitrile (863 mL), and the mixture was stirred at 60? C. for 48 hrs. The reaction mixture was diluted with water (1.00 L) and extracted with ethyl acetate (500 mL?3). The combined organic layers were washed with brine (1.50 L), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 15/1) to afford the desired product (7.00 g, 28.8 mmol, 52.5% yield) as a yellow solid.

[1414] .sup.1H NMR: 400 MHz CDCl.sub.3??12.22 (s, 1H), 7.86 (s, 3H).

[1415] MS, ES.sup.+ m/z 243 (M+H).sup.+

Step 2: methyl 3-oxo-6-(trifluoromethyl)-2,3-dihydropyridazine-4-carboxylate

[1416] To a solution of 4-bromo-6-(trifluoromethyl)pyridazin-3(2H)-one (5.00 g, 20.5 mmol, 1.00 eq) in methanol (100 mL) was added Xantphos (500 mg, 864 ?mol, 0.042 eq), Pd(OAc).sub.2 (115 mg, 514 umol, 0.0250 eq) and triethylamine (4.16 g, 41.1 mmol, 5.73 mL, 2.00 eq) to an autoclave, and the mixture was stirred under CO (50 psi) at 80? C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent, and the residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=30/1 to 0/1) to afford the desired compound (2.50 g, 11.2 mmol, 54.7% yield) as a yellow solid.

[1417] .sup.1H NMR: 400 MHz CDCl.sub.3? 12.54 (s, 1H), 8.11 (s, 1H), 3.99 (s, 3H).

[1418] MS, ES.sup.+ m/z 223 (M+H).sup.+

Step 3: methyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate

[1419] To a solution of methyl 3-oxo-6-(trifluoromethyl)-2,3-dihydropyridazine-4-carboxylate (1.50 g, 6.75 mmol, 1.00 eq) in 1, 4-dioxane (15.0 mL) was added phosphorus oxychloride (10.3 g, 67.5 mmol, 6.28 mL, 10.0 eq) at 0? C., and the mixture was stirred at 100? C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (20 mL?3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 8/1) to give the desired product (1.00 g, 4.16 mmol, 61.6% yield) as a yellow oil.

[1420] .sup.1H NMR: 400 MHz CDCl.sub.3??8.17 (s, 1H), 4.06 (s, 3H).

[1421] MS, ES.sup.+ m/z 241 (M+H).sup.+

Step 4: methyl 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate

[1422] To a solution of methyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate (500 mg, 2.1 mmol) in acetonitrile (10 mL) was added 4-fluoro-2-methoxy-phenol (325 mg, 2.3 mmol, 1.1 eq) and cesium carbonate (680 mg, 2.1 mmol, 1.0 eq). The resulting mixture was heated to 50? C. for 2 hours. After cooling to room temperature, the mixture was diluted with water (75 mL) and extracted with ethyl acetate (25 mL?3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the desired product. Used without further purification, and assumed quantitative yield.

[1423] MS, ES.sup.+ m/z 347 (M+H).sup.+

Step 5: 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic Acid

[1424] The crude product from step 4 (719 mg, 2.1 mmol) was dissolved in methanol (15 mL) and water (5 mL) and excess solid sodium hydroxide was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water (75 mL) and the pH was adjusted to ?2 by careful addition of 6N hydrochloric acid, causing a precipitate to form. This was collected by filtration, rinsed with water and dried under reduced pressure to afford the desired product (350 mg, 1.1 mmol, 51% yield) as a white solid.

[1425] MS, ES.sup.+ m/z 333 (M+H).sup.+

Step 6: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1426] 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (350 mg, 1.1 mmol) was taken up in dichloromethane (5 mL). Oxalyl chloride (0.1 mL, 1.2 mmol) and N,N-dimethylformamide (1 drop) were added, and the mixture was allowed to stir at room temperature for 1 hour. The mixture was cooled in an ice bath, and 3-methylsulfanylaniline (161 mg, 1.2 mmol) and N,N-diisopropylethylamine (272 mg, 2.1 mmol) were added dropwise as a solution in dichloromethane (5 mL). The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (SiO.sub.2, dichloromethane/methanol, 0-5%) to afford the desired product (355 mg, 0.8 mmol, 74% yield) as a solid.

[1427] MS, ES.sup.+ m/z 454 (M+H).sup.+

Step 7: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

[1428] To a solution of 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (355 mg, 0.8 mmol) in methanol (10 mL) was added ammonium carbonate (113 mg, 1.2 mmol, 1.5 eq) and iodobenzene diacetate (580 mg, 1.8 mmol, 2.3 eq). The mixture was allowed to stir at room temperature for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO.sub.2, dichloromethane/methanol, 0-12%) to afford the desired product (189 mg, 0.4 mmol, 50% yield) as a solid.

[1429] .sup.1H NMR (400 MHz, DMSO-d6) ? ppm 3.07 (d, J=0.76 Hz, 3H) 3.74 (s, 3H) 4.29 (s, 1H) 6.83-6.94 (m, 1H) 7.17 (dd, J=10.74, 2.91 Hz, 1H) 7.39 (dd, J=8.84, 5.81 Hz, 1H) 7.65 (t, J=7.96 Hz, 1H) 7.69-7.77 (m, 1H) 7.93 (ddd, J=8.02, 2.08, 1.01 Hz, 1H) 8.36 (t, J=1.89 Hz, 1H) 8.65 (s, 1H) 11.21 (s, 1H).

[1430] MS, ES.sup.+ m/z 485 (M+H).sup.+

##STR01896##

Method B

Step 1: methyl 6-chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylate

[1431] To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (1.5 g, 7.2 mmol) in acetonitrile (15 mL) was added 4-(trifluoromethoxy)phenol (1.4 g, 8.0 mmol) and cesium carbonate (2.4 g, 7.2 mmol). The resulting mixture was stirred at 40? C. for 1 hour, and then diluted with water (100 mL). The mixture was extracted with ethyl acetate (25 mL?3), and the combined organic layers were dried over anhydrous magnesium sulfate, concentrated, and purified by column chromatography (SiO.sub.2, heptane/ethyl acetate, 0-50% gradient) to afford the desired product (1.2 g, 3.4 mmol, 47% yield) as an oil which solidified on standing. MS, ES.sup.+ m/z 349 (M+H).sup.+

Step 2: 6-chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylic Acid

[1432] To a solution of methyl 6-chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylate (1.2 g, 3.4 mmol) in methanol (15 mL) was added water (5 mL) and excess solid sodium hydroxide. The resulting mixture was allowed to stir at room temperature for 1.5 hours, and then diluted with water (75 mL). The pH was adjusted to ?1 by careful addition of 6N hydrochloric acid, causing a precipitate to form. Precipitate was collected by filtration, rinsed with water, and sucked to dryness to afford the desired product (365 mg, 1.1 mmol, 32% yield) as a colorless solid.

[1433] MS, ES.sup.+ m/z 335 (M+H).sup.+

Step 3: 6-chloro-N-(3-(methylsulfonyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxamide

[1434] 6-chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylic acid (365 mg, 1.1 mmol) was taken up in dichloromethane (5 mL), and oxalyl chloride (0.14 mL, 1.6 mmol) was added, followed by a single drop of N,N-dimethylformamide. The resulting mixture was allowed to stir at room temperature for 1 hour, and then cooled in an ice bath. 3-(methylsulfonyl)aniline (225 mg, 1.3 mmol) and triethylamine (0.15 mL, 1.1 mmol) were added dropwise as a solution in dichloromethane (5 mL), and the mixture was allowed to warm to room temperature. Volatiles were removed under reduced pressure, and the resulting residue was purified by preparative RP-HPLC (water/acetonitrile, 5-95% gradient) to afford the desired product (239 mg, 0.49 mmol, 45% yield) as a colorless solid.

[1435] .sup.1H NMR (400 MHz, DMSO-d.sub.6): ? ppm 3.24 (s, 3H) 7.41-7.55 (m, 4H) 7.65-7.78 (m, 2H) 7.94 (dt, J=7.83, 1.64 Hz, 1H) 8.31-8.39 (m, 2H) 11.24 (s, 1H)

[1436] MS, ES.sup.+ m/z 488 (M+H).sup.+

[1437] The following compounds of formula (I-IV) could be prepared by the methodology:

TABLE-US-00031 TABLE 30 Compounds of Formula (IV-c) [01897] Example Name R.sub.1 4 3-(4-fluoro-2-methylphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01898] 5 3-(2,4-difluorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01899] 6 3-(2-chloro-4-fluorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01900] 7 3-(2,4-dichlorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01901] 8 3-(2,4-dimethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01902] 9 3-(2-chloro-4-trifluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01903] 10 3-(2-chloro-4-difluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01904] 11 3-(2-chloro-4-fluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01905] 12 3-(4-fluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01906] 13 3-(4-difluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01907] 14 3-(4-trifluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01908] 15 3-(4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01909] 16 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01910] 17 3-(2-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01911] 18 3-(2-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01912] 19 3-(2-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01913] 20 3-(2-methyl-4-trifluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01914] 21 3-(2-methyl-4-difluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01915] 22 3-(2-methyl-4-fluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01916] 23 3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01917] 24 3-(3,4-difluorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01918] 25 3-(3,4,5-trifluorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01919] 26 3-(3,6-difluorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01920] 27 3-(2,3-difluorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01921] 28 3-(2-chloro-3-fluorophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01922] 29 3-(3-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01923] 30 3-(3-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01924] 31 3-(3-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01925] 32 3-(4-chloro-2-methoxyphenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01926] 33 3-(2-dimethylaminophenoxy)-N-(3-(S- methylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01927]

TABLE-US-00032 TABLE 31 Compounds of Formula (IV-d) [01928] Example Name R.sub.1 34 3-(4-fluoro-2-methylphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01929] 35 3-(2,4-difluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01930] 36 3-(2-chloro-4-fluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01931] 37 3-(2,4-dichlorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01932] 38 3-(2,4-dimethoxyphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01933] 39 3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01934] 40 3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01935] 41 3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01936] 42 3-(4-(fluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01937] 43 3-(4-(difluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01938] 44 N-(3-(methylsulfonyl)phenyl)-3-(4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [01939] 45 N-(3-(methylsulfonyl)phenyl)-3-(4-(2,2,2- trifluoroethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [01940] 46 3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01941] 47 3-(2-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01942] 48 3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01943] 49 3-(2-fluoro-4-(fluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01944] 50 3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01945] 51 3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01946] 52 3-(4-(fluoromethoxy)-2-methylphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01947] 53 3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01948] 54 3-(3,4-difluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01949] 55 N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)-3- (3,4,5-trifluorophenoxy)pyridazine-4-carboxamide [01950] 56 3-(2,5-difluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01951] 57 3-(2,3-difluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01952] 58 3-(2-chloro-3-fluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01953] 59 3-(3-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01954] 60 3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01955] 61 3-(3-fluoro-4-(fluoromethoxy)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01956] 62 3-(4-chloro-2-methoxyphenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01957] 63 3-(2-(dimethylamino)phenoxy)-N-(3- (methylsulfonyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01958]

TABLE-US-00033 TABLE 32 Compounds of Formula (IV-a) [01959] Example Name R.sub.2 64 3-(2-chloro-4-fluorophenoxy)-N-(3- methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide [01960] 65 3-(2-chloro-4-fluorophenoxy)-N-(3- ethylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide [01961] 66 3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6- methyl-phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide [01962] 67 3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6- fluoro-phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide [01963] 68 N-(3-acetylphenyl)-3-(2-chloro-4-fluoro-phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [01964] 69 3-(2-chloro-4-fluoro-phenoxy)-N-[3- (hydroxymethyl)phenyl]-6- (trifluoromethyl)pyridazine-4-carboxamide [01965] 70 3-(2-chloro-4-fluoro-phenoxy)-N-[3-cyanophenyl]-6- (trifluoromethyl)pyridazine-4-carboxamide [01966] 71 3-(2-chloro-4-fluoro-phenoxy)-N-(4-pyridyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01967] 72 3-(2-chloro-4-fluoro-phenoxy)-N-(3-pyridyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [01968] 73 3-(2-chloro-4-fluoro-phenoxy)-N-(3-pyridyl-N- oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide [01969] 74 3-(2-chloro-4-fluoro-phenoxy)-N-(4-pyridyl-N- oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide [01970] 75 3-(2-chloro-4-fluoro-phenoxy)-N-(2-oxo-1H-pyridin- 4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide [01971] 76 3-(2-chloro-4-fluoro-phenoxy)-N-(2-fluoro-4- pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide [01972] 77 3-(2-chloro-4-fluoro-phenoxy)-N-(2-methyl-4- pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide [01973] 78 3-(2-chloro-4-fluoro-phenoxy)-N-(6-fluoro-3- pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide [01974] 79 3-(2-chloro-4-fluoro-phenoxy)-N-(6-chloro-3- pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide [01975] 80 3-(2-chloro-4-fluoro-phenoxy)-N-(1-methyl-2-oxo-4- pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide [01976] 81 3-(2-chloro-4-fluoro-phenoxy)-N-pyridazin-4-yl-6- (trifluoromethyl)pyridazine-4-carboxamide [01977] 82 3-(2-chloro-4-fluoro-phenoxy)-N-(2-oxidopyridazin- 2-ium-4-yl)-6-(trifluoromethyl)pyridazine-4- carboxamide [01978] 83 3-(2-chloro-4-fluoro-phenoxy)-N-pyrimidin-4-yl-6- (trifluoromethyl)pyridazine-4-carboxamide [01979]

TABLE-US-00034 TABLE 33 Compounds of Formula (IV-e) [01980] Example Name R.sub.3 R.sub.4 84 3-(2-chloro-4-fluorophenoxy)-N-(3- CF.sub.2H H (S-methylsulfonimidoyl)phenyl)-6- (difluoromethyl)pyridazine-4- carboxamide 85 3-(2-chloro-4-fluorophenoxy)-N-(3- CH.sub.2F H (S-methylsulfonimidoyl)phenyl)-6- (fluoromethyl)pyridazine-4- carboxamide 86 3-(2-chloro-4-fluorophenoxy)-N-(3- Cl H (S-methylsulfonimidoyl)phenyl)-6- chloro-pyridazine-4-carboxamide 87 3-(2-chloro-4-fluorophenoxy)-N-(3- OCF.sub.3 H (S-methylsulfonimidoyl)phenyl)-6- (trifluoromethoxy)pyridazine-4- carboxamide 88 3-(2-chloro-4-fluorophenoxy)-N-(3- OCHF.sub.2 H (S-methylsulfonimidoyl)phenyl)-6- (difluoromethoxy)pyridazine-4- carboxamide 89 3-(2-chloro-4-fluorophenoxy)-N-(3- OCFH.sub.2 H (S-methylsulfonimidoyl)phenyl)-6- (fluoromethoxy)pyridazine-4- carboxamide 90 3-(2-chloro-4-fluorophenoxy)-N-(3- Cl H (S-methylsulfonimidoyl)phenyl)-6- bromo-pyridazine-4-carboxamide 91 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- cyclopropyl-pyridazine-4- carboxamide [01981] H 92 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- tert-butyl-pyridazine-4-carboxamide [01982] H 93 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- isopropyl-pyridazine-4-carboxamide [01983] H 94 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- methyl-pyridazine-4-carboxamide [01984] H 95 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)- 5,6-dimethyl-pyridazine-4- carboxamide [01985] [01986] 96 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- methoxy-pyridazine-4-carboxamide [01987] H 97 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-5- methyl-6-methoxy-pyridazine-4- carboxamide [01988] [01989] 98 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- cyano-pyridazine-4-carboxamide [01990] H 99 3-(2-chloro-4-fluorophenoxy)-N-(3- (S-methylsulfonimidoyl)phenyl)-6- nitro-pyridazine-4-carboxamide [01991] H 100 3-(2-chloro-4-fluorophenoxy)-N-(3- SCF.sub.3 H (S-methylsulfonimidoyl)phenyl)-6- ((trifluoromethyl)thio)pyridazine-4- carboxamide 101 3-(2-chloro-4-fluorophenoxy)-N-(3- SF.sub.5 H (S-methylsulfonimidoyl)phenyl)-6- (pentafluoro-l6- sulfaneyl)pyridazine-4-carboxamide

TABLE-US-00035 TABLE 34 Compounds of Formula (III-g) [01992] Example Name Structure 102 3-(3-(4-(trifluoromethoxy)phenoxy)- 6-(trifluoromethyl)pyridazine-4- carboxamido)pyridine 1 -oxide [01993] 103 3-(3-(2,4-dimethoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamido)pyridine 1-oxide [01994] 104 3-(3-(2-chloro-4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamido)pyridine 1-oxide [01995] 105 3-(2-chloro-4- (trifluoromethoxy)phenoxy)-N- (pyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide [01996] 106 3-(4-fluoro-2-methoxyphenoxy)-N- (pyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide [01997] 107 N-(pyridazin-4-yl)-3-(4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamide [01998] 108 3-(2,4-dimethoxyphenoxy)-N- (pyridazin-4-yl)-6- (trifluoromethyl)pyridazine-4- carboxamide [01999] 109 5-(3-(2,4-dimethoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamido)pyridazine 1-oxide [02000] 110 5-(3-(4-(trifluoromethoxy)phenoxy)- 6-(trifluoromethyl)pyridazine-4- carboxamido)pyridazine 1-oxide [02001] 111 5-(3-(4-fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamido)pyridazine 1-oxide [02002] 112 5-(3-(2-chloro-4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4- carboxamido)pyridazine 1-oxide [02003]

TABLE-US-00036 TABLE 35 Compounds of Formula (VI-f) [02004] Example Name R.sub.1 N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4- fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02005] 3-(2,4-difluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02006] 3-(2-chloro-4-fluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02007] 3-(2,4-dichlorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02008] 3-(2,4-dimethoxyphenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02009] 3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02010] 3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02011] 3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02012] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4- (fluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide hydrochloride [02013] 3-(4-(difluoromethoxy)phenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02014] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4- (trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02015] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(2,2,2- trifluoroethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02016] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2- fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02017] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2- fluoro-4-(trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02018] 3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02019] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2- fluoro-4-(fluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02020] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2- methyl-4-(trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02021] 3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02022] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4- (fluoromethoxy)-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02023] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2- methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02024] 3-(3,4-difluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02025] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)-3-(3,4,5- trifluorophenoxy)pyridazine-4-carboxamide [02026] 3-(2,5-difluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02027] 3-(2,3-difluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02028] 3-(2-chloro-3-fluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02029] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3- fluoro-4-(trifluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02030] 3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02031] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3- fluoro-4-(fluoromethoxy)phenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02032] 3-(4-chloro-2-methoxyphenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02033] 3-(2-(dimethylamino)phenoxy)-N-(3-(N,S- dimethylsulfonimidoyl)phenyl)-6- (trifluoromethyl)pyridazine-4-carboxamide [02034] N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4- fluoro-2-methoxyphenoxy)-6- (trifluoromethyl)pyridazine-4-carboxamide [02035]

Example 122

Assay Methods

[1438] The ability of pyridazine carboxamide derivatives exemplified above to inhibit the Na.sub.V1.8 channel was determined using one or more of the methods described below.

HEK Na.SUB.V.1.8 ?1/?2 Stably Expressing Cell Line

[1439] A HEK293 cell line stably expressing the human Na.sub.V1.8 (hNa.sub.V1.8) ion channel with ?1/?2 subunits was constructed. The cell line is suitable for IC.sub.50 determination in fluorescence and electrophysiological based assays. It is also suitable to form mechanism of action pharmacology studies in electrophysiological assays. HEK293 Na.sub.V1.8 cells are grown as adherent monolayers in DMEM/high glucose media, 10% fetal bovine serum, Na pyruvate (2 mM), Hepes (10 mM) with selection agents G418 (400 mg/L) and puromycin (0.5 mg/L) at 37 degrees C., 10% CO.sub.2.

Na.SUB.v.1.8 Fluorescence Inhibition Assay

[1440] Compounds were made up to or supplied as a 10 mM stock solution using DMSO as the vehicle. Concentration-response curves were generated using a Matrix multichannel pipettor. Compound source plates were made by diluting 10 mM compound stocks to create 500 ?M (100?) solutions in DMSO in 96 well v-bottom plates. Compounds were then serially diluted in 100% DMSO to generate a 5 point, 4-fold dilution scheme dose response curve. 2 ?l of the 100? dose response curves was then added to preincubation and stimulation assay plates. 100 ?l of pre-incubation buffer and 200 ?l of stimulation buffer were then added to the plates resulting in a final assay test concentration range of 5 ?M to 0.02 ?M with a final DMSO concentration of 1%.

[1441] On the day of assay, plates were washed to remove cell culture media using 2K EBSS buffer (135 mM NaCl, 2 mM KCl, 5 mM Glucose, 2 mM CaCl.sub.2), 1 mM MgCl2, 10 mM HEPES, pH 7.4). The Na-sensitive fluorescent dye, Asante Natrium Green-2 (ANG-2) is incubated for 60 min to allow equilibration and then washed with 2K EBSS. Plates are the transferred to a fluorescence plate reader (FLIPR?, Molecular Devices) for fluorescence measurement using an excitation wavelength of 490 nm and an emission wavelength of 565 nm. Compounds are pre-incubated at for 5 min at final test concentration in the presence of ouabain (30 ?M) to inhibit Na+ efflux through Na+/K+ exchanger. Following the pre-incubation phase, hNa.sub.V1.8 channels are stimulated with 10 ?M of the pyrethroid deltamethrin to prevent channel inactivation. The assay was run for 15 min with vehicle and 30 ?M tetracaine serving as negative and positive controls, respectively. The peak change in fluorescence relative to negative and positive control wells was calculated and fit with a logistic equation to determine IC.sub.50.

PatchXpress Na.SUB.v.1.8 Inhibition Assay

[1442] HEK-Na.sub.V1.8 ?1/?2 cells were recorded in whole cell patch-clamp using the PatchXpress automated patch clamp platforms (Molecular Devices). Cells suspensions were obtained by trypsinization of adherent monolayers, followed by gentle rocking for minimally 30 min. Compounds were prepared from 10 mM DMSO stocks.

[1443] Na.sub.V1.8 channel variants were evaluated using Protocol 1, depicted in FIG. 1, in which cells were initially voltage clamped at a holding potential of ?100 mV to maintain Na.sub.V1.8 in a closed resting state. After current amplitude becomes stable, the mid-point voltage of steady state inactivation was determined for each cell using a series of 5 sec conditioning steps to increasingly depolarized voltages (?100 to 0 mV) The holding potential was then reset to a voltage that produces ?50% inactivation (V.sub.half-set automatically via PatchXpress scripts) so that closed and inactivated channel inhibition can be assessed. Protocol 1 was run at a frequency of 0.1 Hz until current amplitude is steady (automatically determined by PatchXpress scripts). The effect of test reagent on Nav current amplitude was monitored using custom PatchXpress stability scripts which determines the timing of compound addition and washout.

[1444] Data were processed and analyzed using DataXpress 2.0 (Molecular Devices). Percent inhibition is calculated using Microsoft Excel such that compound block is normalized to the average of control and washout currents according to the formula, % Inhibition=(((Ctrl+Wash)/2)?Drug)/((Ctrl+Wash)/2)*100. Normalized concentration-response relationships were fit using XLfit software (IDBS) 4 Parameter Logistic Model or Sigmoidal Dose-Response Model.

hNa.sub.V1.8 Automated Patch Clamp-IonFlux.sup.HT Assay

[1445] The IonFlux HT automated whole-cell patch-clamp instrument (Fluxion Biosciences, Inc., Almeda, CA USA) was used to record the inward sodium currents.

[1446] Cells: HEK-293 cells were stably transfected with human Na.sub.V1.8 cDNA (type X voltage-gated sodium channel alpha subunit, accession #NM_006514) and the human beta subunit 1 (accession #NM_001037). The cells were harvested with trypsin and maintained in serum free medium at room temperature before recording. The cells were washed and re-suspended in the Extracellular Solution before being applied to the instrument.

[1447] Test concentrations: Stock solution was prepared in DMSO at 300? the final assay concentrations, and stored at ?80? C. until the day of assay. On the day of the assay, an aliquot of the stock solution was thawed and diluted into external solution to make final test concentrations. A final concentration of 0.330% DMSO was maintained for each concentration of the assay compounds and controls.

[1448] Recording conditions: Intracellular Solution (mM): 100 CsF, 45 CsCl, 5 NaCl, 10 HEPES, 5 EGTA (pH 7.3, titrated with 1M CsOH).

[1449] Extracellular Solution (mM): 150 NaCl, 4 BaCl, 1 MgCl.sub.2, 1.8 CaCl.sub.2, 10 HEPES, 5 Glucose, (pH 7.4, titrated with 10M NaOH).

[1450] When sodium channels are held at a depolarized membrane potential, the channels open and inactivate and remain inactivated until the membrane potential is stepped back to a hyperpolarized membrane potential, when the inactivated channels recover into the closed state. Compounds that show more inhibition at pulse 2 compared to pulse 1 are state-dependent inhibitors. An example is Tetracaine, which is a much more potent inhibitor in the inactivated state than in the tonic or open state.

[1451] Cells were held at ?120 mV for 50 ms before stepping to ?10 mV for 2 s to completely inactivate the sodium channels (pulse 1), and stepped back to ?120 mV for 10 ms (to completely recover from inactivation, however, channels that have inhibitors bound to them may not recover from inactivation) before stepping to ?10 mV for 50 ms (pulse 2). The sweep interval is 20 s (0.05 Hz). Each concentration of compound was applied for two minutes. The assay was performed at room temperature.

[1452] Reference compounds: Tetracaine was used as the positive control and was tested concurrently with the test compound.

[1453] Data analysis: Only current amplitudes in excess of 3 nA at the control stage were analyzed. The amplitude of the sodium current was calculated by measuring the difference between the peak inward current on stepping to ?10 mV (i.e., peak of the current) and remaining current at the end of the step. The sodium current was assessed in vehicle control conditions and then at the end of each two (2) minute compound application. Individual cell trap results were normalized to the vehicle control amplitude and the mean?SEM calculated for each compound concentration. These values were then plotted and estimated IC.sub.50 curve fits calculated.

Activity of Representative Na.SUB.V.1.8 Inhibitors

[1454] The ability of representative pyridazine carboxamide derivatives exemplified above to inhibit the Nav1.8 channel was determined using one or more of the methods described immediately hereinabove.

TABLE-US-00037 Example Name Activity 1 3-(4-fluoro-2-methoxy-phenoxy)-N-[3- +++ (methylsulfonimidoyl)phenyl]-6- (trifluoromethyl)pyridazine-4-carboxamide 2 3-(4-fluoro-2-methyl-phenoxy)-N-[3- +++ (methylsulfonimidoyl)phenyl]-6- (trifluoromethyl)pyridazine-4-carboxamide 3 6-chloro-N-(3-methylsulfonylphenyl)-3-[4- +++ (trifluoromethoxy)phenoxy]pyridazine-4- carboxamide + IC.sub.50 >1 ?M ++ IC.sub.50 500 nM-1 ?M +++ IC.sub.50 <500 nM

REFERENCES

[1455] All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art. [1456] Pain Medicine: An Essential Review, Young, R J, Nguyen, M, Nelson, E, Urman, Eds. Springer, Cham, Switzerland. 2017, ISBN 978-3-319-43131-4. [1457] Yekkirala, A. S.; Roberson, D. P.; Bean, B. P.; Woolf, C. J., Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov 2017, 16 (8), 544-563. [1458] Skolnick, P., The Opioid Epidemic: Crisis and Solutions. Annual Review of Pharmacology and Toxicology, Vol 58 2018, 58, 143-159. [1459] Catterall, W. A., Voltage-gated sodium channels at 60: structure, function and pathophysiology. J Physiol-London 2012, 590 (11), 2577-2589. [1460] Ruiz, M. D.; Kraus, R. L., Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. J Med Chem 2015, 58 (18), 7093-7118. [1461] Yu, F. H.; Catterall, W. A., Overview of the voltage-gated sodium channel family. Genome Biol 2003, 4 (3). [1462] Eijkelkamp, N.; Linley, J. E.; Baker, M. D.; Minett, M. S.; Cregg, R.; Werdehausen, R.; Rugiero, F.; Wood, J. N., Neurological perspectives on voltage-gated sodium channels. Brain 2012, 135, 2585-2612. [1463] Bagal, S. K.; Chapman, M. L.; Marron, B. E.; Prime, R.; Storer, R. I.; Swain, N. A., Recent progress in sodium channel modulators for pain. Bioorganic & medicinal chemistry letters 2014, 24 (16), 3690-3699. [1464] Jukic, M.; Kikelj, D.; Anderluh, M., Isoform Selective Voltage-Gated Sodium Channel Modulators and the Therapy of Pain. Curr Med Chem 2014, 21 (2), 164-186. [1465] Deuis, J. R.; Mueller, A.; Israel, M. R.; Vetter, I., The pharmacology of voltage-gated sodium channel activators. Neuropharmacology 2017, 127, 87-108. [1466] Vetter, I.; Deuis, J. R.; Mueller, A.; Israel, M. R.; Starobova, H.; Zhang, A.; Rash, L. D.; Mobli, M., Na(V)1.7 as a pain targetFrom gene to pharmacology. Pharmacology & Therapeutics 2017, 172, 73-100. [1467] Bennett, D. L. H.; Woods, C. G., Painful and painless channelopathies. Lancet Neurol 2014, 13 (6), 587-599. [1468] McCormack, K.; Santos, S.; Chapman, M. L.; Krafte, D. S.; Marron, B. E.; West, C. W.; Krambis, M. J.; Antonio, B. M.; Zellmer, S. G.; Printzenhoff, D.; Padilla, K. M.; Lin, Z. X.; Wagoner, P. K.; Swain, N. A.; Stupple, P. A.; de Groot, M.; Butt, R. P.; Castle, N. A., Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels. P Natl Acad Sci USA 2013, 110 (29), E2724-E2732. [1469] Donnell, A.; Collins, S.; Ali, Z.; Iavarone, L.; Surujbally, R.; Kirby, S.; Butt, R. P., Efficacy of the Na.sub.V1.7 Blocker Pf-05089771 in A Randomised, Placebo-Controlled, Double-Blind Clinical Study in Subjects with Painful Diabetic Peripheral Neuropathy. Pain 2018. [1470] Zakrzewska, J. M.; Palmer, J.; Morisset, V.; Giblin, G. M. P.; Obermann, M.; Ettlin, D. A.; Cruccu, G.; Bendtsen, L.; Estacion, M.; Derjean, D.; Waxman, S. G.; Layton, G.; Gunn, K.; Tate, S., Safety and efficacy of a Na.sub.V1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. The Lancet Neurology 2017, 16(4), 291-300. [1471] Han, C. Y.; Huang, J. Y.; Waxman, S. G., Sodium channel Na(v)1.8 Emerging links to human disease. Neurology 2016, 86 (5), 473-483. [1472] Akopian, A. N.; Sivilotti, L.; Wood, J. N., A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 1996, 379 (6562), 257. [1473] Shields, S. D.; Ahn, H.-S.; Yang, Y.; Han, C.; Seal, R. P.; Wood, J. N.; Waxman, S. G.; Dib-Hajj, S. D., Na.sub.V1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. PAIN? 2012, 153 (10), 2017-2030. [1474] Akopian, A. N.; Souslova, V.; England, S.; Okuse, K.; Ogata, N.; Ure, J.; Smith, A.; Kerr, B. J.; McMahon, S. B.; Boyce, S.; Hill, R.; Stanfa, L. C.; Dickenson, A. H.; Wood, J. N., The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 1999, 2, 541. [1475] Dong, X.-W.; Goregoaker, S.; Engler, H.; Zhou, X.; Mark, L.; Crona, J.; Terry, R.; Hunter, J.; Priestley, T., Small interfering RNA-mediated selective knockdown of NaV1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience 2007, 146(2), 812-821. [1476] Faber, C. G.; Lauria, G.; Merkies, I. S. J.; Cheng, X.; Han, C.; Ahn, H.-S.; Persson, A.-K.; Hoeijmakers, J. G. J.; Gerrits, M. M.; Pierro, T.; Lombardi, R.; Kapetis, D.; Dib-Hajj, S. D.; Waxman, S. G., Gain-of-function Na_v1.8 mutations in painful neuropathy. Proceedings of the National Academy of Sciences 2012, 109 (47), 19444-19449. [1477] Lu, V. B.; Ikeda, S. R.; Puhl, H. L., A 3.7 kb Fragment of the Mouse Scn10a Gene Promoter Directs Neural Crest But Not Placodal Lineage EGFP Expression in a Transgenic Animal. J Neurosci 2015, 35 (20), 8021-8034. [1478] Black, J. A.; Dib-Hajj, S.; Baker, D.; Newcombe, J.; Cuzner, M. L.; Waxman, S. G., Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. P Natl Acad Sci USA 2000, 97 (21), 11598-11602. [1479] Damarjian, T. G.; Craner, M. J.; Black, J. A.; Waxman, S. G., Upregulation and colocalization of p75 and Na(v)1.8 in Purkinje neurons in experimental autoimmune encephalomyelitis. Neurosci Lett 2004, 369 (3), 186-190. [1480] Shields, S. D.; Cheng, X. Y.; Gasser, A.; Saab, C. Y.; Tyrrell, L.; Eastman, E. M.; Iwata, M.; Zwinger, P. J.; Black, J. A.; Dib-Hajj, S. D.; Waxman, S. G., A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis. Ann Neurol 2012, 71(2), 186-194. [1481] Shields, S. D.; Butt, R. P.; Dib-Hajj, S. D.; Waxman, S. G., Oral Administration of PF-01247324, a Subtype-Selective Na.sub.V1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis. Plos One 2015, 10 (3). [1482] Sweatt, J. D., Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp Mol Med 2013, 45. [1483] Rannals, M. D.; Hamersky, G. R.; Page, S. C.; Campbell, M. N.; Briley, A.; Gallo, R. A.; Phan, B. N.; Hyde, T. M.; Kleinman, J. E.; Shin, J. H.; Jaffe, A. E.; Weinberger, D. R.; Maher, B. J., Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1. Neuron 2016, 90 (1), 43-55. [1484] Bucknill, A. T.; Coward, K.; Plumpton, C.; Tate, S.; Bountra, C.; Birch, R.; Sandison, A.; Hughes, S. P.; Anand, P., Nerve fibers in lumbar spine structures and injured spinal roots express the sensory neuron-specific sodium channels SNS/PN3 and NaN/SNS2. Spine 2002, 27(2), 135-140. [1485] Renton, T.; Yiangou, Y.; Plumpton, C.; Tate, S.; Bountra, C.; Anand, P., Sodium channel Na v 1.8 immunoreactivity in painful human dental pulp. BMC oral health 2005, 5 (1), 5. [1486] Shembalkar, P. K.; Till, S.; Boettger, M. K.; Terenghi, G.; Tate, S.; Bountra, C.; Anand, P., Increased sodium channel SNS/PN3 immunoreactivity in a causalgic finger. Eur J Pain 2001, 5 (3), 319-323. [1487] Beyak, M.; Vanner, S., Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels. Neurogastroenterology & Motility 2005, 17 (2), 175-186. [1488] Cestele, S.; Catterall, W. A., Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 2000, 82 (9-10), 883-892. [1489] Bagal, S. K.; Bungay, P. J.; Denton, S. M.; Gibson, K. R.; Glossop, M. S.; Hay, T. L.; Kemp, M. I.; Lane, C. A. L.; Lewis, M. L.; Maw, G. N.; Million, W. A.; Payne, C. E.; Poinsard, C.; Rawson, D. J.; Stammen, B. L.; Stevens, E. B.; Thompson, L. R., Discovery and Optimization of Selective Na(v)1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain. Acs Med Chem Lett 2015, 6 (6), 650-654. [1490] Kort, M. E.; Drizin, I.; Gregg, R. J.; Scanio, M. J. C.; Shi, L.; Gross, M. F.; Atkinson, R. N.; Johnson, M. S.; Pacofsky, G. J.; Thomas, J. B.; Carroll, W. A.; Krambis, M. J.; Liu, D.; Shieh, C. C.; Zhang, X. F.; Hernandez, G.; Mikusa, J. P.; Zhong, C. M.; Joshi, S.; Honore, P.; Roeloffs, R.; Marsh, K. C.; Murray, B. P.; Liu, J. R.; Werness, S.; Faltynek, C. R.; Krafte, D. S.; Jarvis, M. F.; Chapman, M. L.; Marron, B. E., Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Na(v)1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain. J Med Chem 2008, 51 (3), 407-416. [1491] Zhang, X. F.; Shieh, C. C.; Chapman, M. L.; Matulenko, M. A.; Hakeem, A. H.; Atkinson, R. N.; Kort, M. E.; Marron, B. E.; Joshi, S.; Honore, P.; Faltynek, C. R.; Krafte, D. S.; Jarvis, M. F., A-887826 is a structurally novel, potent and voltage-dependent Na(v)1.8 sodium channel blocker that attenuates neuropathic tactile allodynia in rats. Neuropharmacology 2010, 59 (3), 201-207. [1492] Jarvis, M. F.; Honore, P.; Shieh, C. C.; Chapman, M.; Joshi, S.; Zhang, X. F.; Kort, M.; Carroll, W.; Marron, B.; Atkinson, R.; Thomas, J.; Liu, D.; Krambis, M.; Liu, Y.; McGaraughty, S.; Chu, K.; Roeloffs, R.; Zhong, C. M.; Mikusa, J. P.; Hernandez, G.; Gauvin, D.; Wade, C.; Zhu, C.; Pai, M.; Scanio, M.; Shi, L.; Drizin, I.; Gregg, R.; Matulenko, M.; Hakeem, A.; Grosst, M.; Johnson, M.; Marsh, K.; Wagoner, P. K.; Sullivan, J. P.; Faltynek, C. R.; Krafte, D. S., A-803467, a potent and selective Na(v)1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. P Natl Acad Sci USA 2007, 104 (20), 8520-8525. [1493] Payne, C. E.; Brown, A. R.; Theile, J. W.; Loucif, A. J. C.; Alexandrou, A. J.; Fuller, M. D.; Mahoney, J. H.; Antonio, B. M.; Gerlach, A. C.; Printzenhoff, D. M.; Prime, R. L.; Stockbridge, G.; Kirkup, A. J.; Bannon, A. W.; England, S.; Chapman, M. L.; Bagal, S.; Roeloffs, R.; Anand, U.; Anand, P.; Bungay, P. J.; Kemp, M.; Butt, R. P.; Stevens, E. B., A novel selective and orally bioavailable Na(v)1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Brit J Pharmacol 2015, 172 (10), 2654-2670. [1494] U.S. Pat. No. 10,005,768 to Yao et al., for Carboxamide Derivatives and Use Thereof, issued Jun. 26, 2018; [1495] U.S. Pat. No. 10,005,724 to Andrez et al., for Therapeutic Compounds and Methods of Use Thereof, issued Jun. 26, 2018; [1496] U.S. Pat. No. 10,000,475 to Tadesse et al., for Triazine Carboxamides as Sodium Channel Blockers, issued Jun. 19, 2018; [1497] U.S. Pat. No. 9,969,693 to Bogdan et al., for 6-heteroaryloxy- or 6-aryloxy-quinoline-2-Carboxamides and Method of Use, issued May 15, 2018; [1498] U.S. Pat. No. 9,828,397 to Anderson et al., for Prodrugs of Pyridone Amides Useful as Modulators of Sodium Channels, issued Nov. 28, 2017; [1499] U.S. Pat. No. 9,783,501 to Hadida-Ruah et al., for Substituted Quinolines as Modulators of Sodium Channels, issued Oct. 10, 2017; [1500] U.S. Pat. No. 8,536,195 to Termin et al., for Bicylic Derivatives as Modulators of Voltage Gated Ion Channels, issued Sep. 17, 2013; [1501] U.S. Pat. No. 8,492,403 to Kawatkar et al., for Bicylic Derivatives as Modulators of Voltage Gated Ion Channels, issued Jul. 23, 2013; [1502] U.S. Pat. No. 8,314,125 to Termin et al., for Bicyclic Derivatives as Modulators of Ion Channels, issued Nov. 20, 2012; [1503] U.S. Pat. No. 8,309,543 to Gonzalez et al., for Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels, issued Nov. 13, 2012; [1504] U.S. Pat. No. 8,236,833 to Martinborough et al., for Biphenyl Derivatives as Modulators of Voltage Gated Ion Channels, issued Aug. 7, 2012; [1505] U.S. Pat. No. 8,236,829 to Neubert et al., for Bicyclic Derivatives as Modulators of Voltage Gated ION Channels, issued Aug. 7, 2012; [1506] U.S. Pat. No. 7,989,481 to Neubert et al., for Indane Derivatives as Modulators of Sodium Channels, issued Aug. 2, 2011; [1507] U.S. Pat. No. 7,705,031 to Wilson et al., for Benzimidazoles Useful as Modulators of Ion Channels, issued Apr. 28, 2010.

VI. INCORPORATION BY REFERENCE

[1508] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

VII. EQUIVALENTS

[1509] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.