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TRPML MODULATORS

20230104936 · 2023-04-06

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

    Claims

    1. A compound of Formula I′: ##STR01953## or a pharmaceutically acceptable salt thereof, wherein A′ is phenyl, 5- to 10-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, or 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with R.sup.a; Cy is absent, or a bivalent moiety selected from C.sub.1-6 aliphatic, 4- to 14-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C.sub.6-12 aryl, or C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R.sup.1; L.sup.1 is absent, —S—, —C(O)—NR.sup.3—, —NR.sup.3—C(O)—, or an optionally substituted bivalent moiety selected from C.sub.1-6 alkylenyl, C.sub.2-6 alkenylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.0-6 alkylenyl, —O—C.sub.0-6 alkylenyl, —C(O)—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-C(O)—, —C(O)O—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-O—C(O)—, —C.sub.3-6 cycloalkyl, and —NR.sup.3—C(O)—C.sub.0-6 alkylenyl-O—; L.sup.2 is —(NR.sup.3).sub.s—S(O)—(NR.sup.3)—, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C(O)—(NR.sup.3).sub.s—, —NR.sup.3—C(O)—, or an optionally substituted bivalent moiety selected from —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O)—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.3-6 cycloalkyl, —NR.sup.3—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-S(O)—(NR.sup.3).sub.s—, —C.sub.1-6 alkylenyl-S(O).sub.2—(NR.sup.3).sub.s—, 2- to 6-membered heteroaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein V is substituted with (R.sup.6).sub.m; Z is selected from P(O)(R.sup.3).sub.2, C(O)N(R.sup.3).sub.2, C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 2- to 10-atom heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q; each R.sup.a is independently H, halo, —CN, oxo, or an optionally substituted group selected from C.sub.1-6 aliphatic. C.sub.3-6 cycloaliphatic, and O—C.sub.1-6 aliphatic; each R.sup.1 is independently selected from halo, oxo, —N(R.sup.3).sub.2, —OH, —CN, —C(O)N(R.sup.3).sub.2, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 aliphatic; each R.sup.2 is independently selected from halo, oxo, —CN, —OH, O—R.sup.2a, —C(O)—R.sup.2a, —C(O)O—R.sup.2a, and an optionally group selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.2a is independently H or an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.3-12 cycloaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic; each R.sup.5 is —N(R.sup.3).sub.2 or an optionally substituted group selected from C.sub.1-6 aliphatic, P(O)(C.sub.1-6 aliphatic).sub.2, C.sub.3-12 cycloaliphatic, and 5- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.6 is independently selected from halo, oxo, —SF.sub.5, —S(O)—R.sup.5, S(O).sub.2-R.sup.5, —S(O)(NH)—R.sup.5, —S(O).sub.2—(NH)—R.sup.5, —S(O)—N(R.sup.5).sub.2, —S(O).sub.2—N(R.sup.5).sub.2, —CN, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, —O—R.sup.5, or an optionally substituted group selected from C.sub.1-6 aliphatic, S—C.sub.1-6 aliphatic, 2- to 12-membered heteroaliphatic, —C.sub.0-6 alkylenyl-C(O)—R.sup.5, —C.sub.0-6 alkylenyl-C(O)O—R.sup.5, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, 4, 5, or 6; and each s is independently 0 or 1.

    2. The compound of claim 1, wherein A′ is phenyl.

    3. The compound of claim 1, wherein A′ is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    4. The compound of claim 1, wherein A′ is 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    5. The compound of claim 1, wherein A′ is 9-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    6. The compound of claim 1, wherein A′ is selected from Table A′:

    7. The compound of claim 6, wherein A′ is ##STR01954##

    8. The compound any one of claims 1-7, wherein Cy is absent or 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    9. The compound of any one of claims 1-8, wherein Cy is absent.

    10. The compound of any one of claims 1-8, wherein Cy is 4- to 7-membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, and S.

    11. The compound of claim 10, wherein Cy is 4- to 7-membered monocyclic heterocyclic comprising 1 heteroatom selected from N, O, and S.

    12. The compound of claim 11, wherein Cy is piperidinyl.

    13. The compound of claim 1, wherein Cy is selected from Table Cy.

    14. The compound of any one claims 1-13, wherein L.sup.1 is absent, or an optionally substituted group selected from C.sub.1-6 alkylenyl, —NR.sup.3—C.sub.0-6 alkylenyl, —C(O)C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-C(O)— and —C.sub.1-6 alkylenyl-OC(O)—.

    15. The compound of any one of claim 1-14, wherein L.sup.1 is absent.

    16. The compound of any one of claims 1-14, wherein L.sup.1 is optionally substituted C.sub.3-6 cycloalkyl.

    17. The compound of any one of claims 1-14, wherein L.sup.1 is —NR.sub.3—.

    18. The compound of any one of claims 1-17, wherein L.sup.2 is optionally substituted C.sub.1-6 alkylenyl.

    19. The compound of any one of claims 1-17, wherein L.sup.2 is optionally substituted —C.sub.1-6 alkylenyl-S(O).sub.2—(NR.sup.3).sub.s, —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl, or —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl.

    20. The compound of any one of claims 1-17, wherein L.sup.2 is absent, —C.sub.1-6 alkylenyl-S(O).sub.2, —(NR.sup.3).sub.s—S(O)—, or —(NR.sup.3).sub.s—S(O).sub.2—.

    21. The compound of claim 20, wherein L.sup.2 is absent, —C.sub.1-6 alkylenyl-S(O).sub.2, or —NR.sup.3—S(O).sub.2—.

    22. The compound of claim 21, wherein L.sup.2 is —NR.sub.3—S(O).sub.2—.

    23. The compound of claim 22, wherein L.sup.2 is —NH—S(O).sub.2—.

    24. The compound of claim 21, wherein L.sup.2 is —C.sub.1-6 alkylenyl-S(O).sub.2.

    25. The compound of claim 24, wherein L.sup.2 is —CH(CH.sub.3)—S(O).sub.2—.

    26. The compound of any one claims 1-25, wherein Z is C.sub.6-12 aryl, 2- to 10-atom heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q.

    27. The compound of any claims 1-26, wherein Z is C.sub.6-12 aryl or 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    28. The compound of claim 27, wherein Z is C.sub.6-12 aryl.

    29. The compound of claim 27, wherein Z is 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    30. The compound of claim 29, wherein Z is 10- to 16-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    31. The compound of any one of claims 1-30, wherein Z is substituted with 0, 1, 2, 3, or 4 R.sup.2, and each R.sup.2 is independently halo or O—R.sup.2a, where R.sup.2a is optionally substituted C.sub.1-6 aliphatic.

    32. The compound of claim 31, wherein Z is substituted with 0, 1, 2, 3, or 4 R.sup.2, and R.sup.2 is halo.

    33. The compound of claim 1, wherein Z is selected from Table Z.

    34. The compound of any one of claims 1-33, wherein V is C.sub.6-12 aryl or 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    35. The compound of any one of claims 1-34, wherein V is C.sub.6-12 aryl.

    36. The compound of claim 35 wherein V is substituted with 0, 1, 2, 3, or 4 R.sup.6, and each R.sup.6 is independently halo, S(O)—R.sup.5, S(O).sub.2-R.sup.5, S(O)(NH)—R.sup.5, or an optionally substituted O—C.sub.1-6 aliphatic.

    37. The compound of any one of claims 1-36, wherein R.sup.6 is S(O)—R.sup.5, S(O).sub.2-R.sup.5, or an optionally substituted C.sub.1-6 aliphatic.

    38. The compound of any one of claims 1-36, wherein R.sup.6 is halo.

    39. The compound of claim 38, wherein R.sup.6 is fluoro or chloro.

    40. The compound of claim 37, wherein R.sup.6 is S(O).sub.2-R.sup.5.

    41. The compound of claim 40, wherein R.sup.6 is —S(O).sub.2—C.sub.1-6 aliphatic.

    42. The compound of claim 41, wherein R.sup.6 is —S(O).sub.2—CH.sub.3 or —S(O).sub.2—CHF.sub.2.

    43. The compound of claim 37, wherein R.sup.6 is —S(O).sub.2—N(C.sub.1-6 aliphatic).sub.2.

    44. The compound of claim 43, wherein R.sup.6 is —S(O).sub.2—N(CH.sub.3).sub.2.

    45. The compound of claim 1, wherein V is selected from Table V.

    46. The compound of claim 1, wherein the compound is of formula IIa-1: ##STR01955## or a pharmaceutically acceptable salt thereof.

    47. The compound of claim 1, wherein the compound is of formula IIa-2: ##STR01956## or a pharmaceutically acceptable salt thereof.

    48. The compound of claim 1, wherein the compound is of formula IIa-3: ##STR01957##

    49. The compound of claim 1, wherein the compound is of formula IIb: ##STR01958## or a pharmaceutically acceptable salt thereof.

    50. The compound of claim 1, wherein the compound is of formula IIb-1: ##STR01959## or a pharmaceutically acceptable salt thereof.

    51. The compound of claim 1, wherein the compound is of formula IId: ##STR01960## or a pharmaceutically acceptable salt thereof.

    52. The compound of claim 1, wherein the compound is of formula IId-1: ##STR01961## or a pharmaceutically acceptable salt thereof.

    53. The compound of claim 1, wherein the compound is of formula IId-2: ##STR01962## or a pharmaceutically acceptable salt thereof.

    54. The compound of claim 1, wherein the compound is of formula IId-3: ##STR01963## or a pharmaceutically acceptable salt thereof.

    55. A compound of Formula II′: ##STR01964## or a pharmaceutically acceptable salt thereof, wherein X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are each independently selected from N, C, CR.sup.a, wherein X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are C or N when bound to Cy-L.sup.1-Z or L.sup.2-V, and are CR.sup.a when not bound to Cy-L.sup.1-Z or L.sup.2-V; Y.sup.1′ and Y.sup.2′ are selected from each C, N, and CR.sup.a, or one of Y.sup.1′ or Y.sup.2′ is absent and the other of Y.sup.1′ or Y.sup.2′ is selected from C, N, and CR.sup.a; Cy is absent, or a bivalent moiety selected from C.sub.1-6 aliphatic, 4- to 14-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C.sub.6-12 aryl, or C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R.sup.1; L.sup.1 is absent, S—, —C(O)—NR.sup.3—, —NR.sup.3—C(O)—, or an optionally substituted group selected from C.sub.1-6 alkylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.0-6 alkylenyl, —O—C.sub.0-6 alkylenyl, —C(O)—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-C(O)—, —C(O)O—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-O—C(O)—, —C.sub.3-6 cycloalkyl, and —NR.sup.3—C(O)—C.sub.0-6 alkylenyl-O—; L.sup.2 is —(NR.sup.3).sub.s—S(O)—(NR.sup.3)—, —(NR.sub.3).sub.s—S(O).sub.2—NR.sup.3—, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C(O)—(NR.sup.3).sub.s—, —NR.sup.3—C(O)—, or an optionally substituted bivalent moiety selected from —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O)—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.3-6 cycloalkyl, —NR.sup.3—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-S(O)—(NR.sup.3).sub.s—, —C.sub.1-6 alkylenyl-S(O).sub.2—(NR.sup.3).sub.s—, 2- to 6-membered heteroaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein V is substituted with (R.sup.6).sub.m; Z is selected from P(O)(R.sup.3).sub.2, C(O)N(R.sup.3).sub.2, C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 2- to 10-atom heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q; each R.sup.a is independently H, halo, —CN, oxo, or an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.3-6 cycloaliphatic, and O—C.sub.1-6 aliphatic, or two R.sup.a together when on adjacent atoms form a fused optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or a fused optionally substituted heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S; each R.sup.1 is independently selected from halo, oxo, —N(R.sup.3).sub.2, —OH, —CN, —C(O)N(R.sup.3).sub.2, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 aliphatic; each R.sup.2 is independently selected from halo, oxo, —CN, —OH, O—R.sup.2a, —C(O)—R.sup.2a, —C(O)O—R.sup.2a, and an optionally group selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.2a is independently H or an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.3-12 cycloaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic; each R.sup.5 is —N(R.sup.3).sub.2 or an optionally substituted group selected from C.sub.1-6 aliphatic, P(O)(C.sub.1-6 aliphatic).sub.2, C.sub.3-12 cycloaliphatic, and 5- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; each R.sup.6 is independently selected from halo, oxo, —SF.sub.5, —S(O)—R.sup.5, S(O).sub.2-R.sup.5, —S(O)(NH)—R.sup.5, —S(O).sub.2—(NH)—R.sup.5, —S(O)—N(R.sup.5).sub.2, —S(O).sub.2—N(R.sup.5).sub.2, —CN, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, —O—R.sup.5, or an optionally substituted group selected from C.sub.1-6 aliphatic, S—C.sub.1-6 aliphatic, 2- to 12-membered heteroaliphatic, —C.sub.0-6 alkylenyl-C(O)—R.sup.5, —C.sub.0-6 alkylenyl-C(O)O—R.sup.5, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; m is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, 4, 5, or 6; and each s is independently 0 or 1.

    56. The compound of claim 55, wherein X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are each independently selected from C and CR.sup.a, wherein X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V, and are CR.sup.a when not bound to Cy-L.sup.1-Z or L.sup.2-V;

    57. The compound of claims 55 or 56, wherein Y.sup.1′ and Y.sup.2′ are each CR.sup.a.

    58. A compound selected from Table A.

    59. A compound selected from Table B.

    60. A pharmaceutical composition comprising a compound of any one of claims 1-59 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

    61. A method of modulating TRPML1 comprising administering to a subject a compound of any one of claims 1-59, or a composition thereof.

    62. A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one of claims 1-59, or a composition thereof.

    63. The method of claim 62, wherein the disease, disorder, or condition is a lysosomal storage disorder.

    64. The method of claim 63, wherein the lysosomal storage disorder is selected from Niemann-Pick C disease, Gaucher disease, and Pompe disease.

    65. The method of claim 62, wherein the disease, disorder, or condition is age-related common neurodegenerative disease.

    66. The method of claim 62, wherein the disease, disorder, or condition is selected from Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.

    67. The method of claim 62, wherein the disease, disorder, or condition is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML1.

    68. The method of claim 62, wherein the disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, an oncological disease, or an infectious disease.

    69. The method of claim 68, wherein the disease, disorder, or condition is a muscular disease.

    70. The method of claim 69, wherein the muscular disease is a muscular dystrophy.

    71. The method of claim 70, wherein the muscular dystrophy is Duchenne muscular dystrophy.

    72. The method of claim 68, wherein the disease, disorder, or condition is an infectious disease.

    73. The method of claim 72, wherein the infectious disease is an infection of Helicobacter pylori or Mycobacterium tuberculosis.

    74. The method of claim 73, wherein the infectious disease is an infection of Mycobacterium tuberculosis.

    Description

    DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

    TRPML1 and Autophagy

    [0119] Autophagy is a mechanism of the cell that degrades cytoplasmic material and organelles. There are multiple types of autophagy: (1) macroautophagy (generally referred to as autophagy); (2) microautophagy; and (3) chaperone-mediateed autophagy. See Eskelinen & Saftig, Biochimica et Biophysica Acta-Mol. Cell Res., 1793(4):664-673 (2009). In macroautophagy, the autophagosome engulfs waste materials in the cytoplasm and fuses to the lysosome, where materials are delivered for degradation. The lysosome is as a subcellular organelle containing more than 50 soluble acid hydrolases useful for digesting cellular components. Fusion of the lysosome to the autophagosome is activated, in part, by release of ions through ion channels in the membrane of the lysome, including Ca.sup.2+. See Cao, et al., J. Bio. Chem., 292(20) 8424-8435 (2017).

    [0120] Transient Receptor Potential Mucolipin-1 (also known as TRPML1 or ML1) is a Ca.sup.2+ channel in the lysosome that regulates autophagy. See Wang, et al., PNAS, E1373-E1381 (Mar. 2, 2015). In particular, TRPML1 is an inwardly rectifying current channel that transports cations from the lumen of the lysosome to the cytosol. See Di Paolda, et al., Cell Calcium 69:112-121 (2018). Release of Ca.sup.2+ from the lysosome via TRPML1 modulates transcription factor EB activity via local calcineurin activation, which ultimately induces autophagy and lysosomal biogenesis. See Medina, et al., Nat. Cell. Biol., 17(3):288-299 (2015).

    [0121] It has recently been discovered that upregulation of autophagy is beneficial to patients suffering from a number of diseases and disorders. For example, it has been reported that inducing autophagy promotes clearance of hepatotoxic alpha-1-anti-trypsin (ATZ) in the liver. See Pastore, et al., EMBO Mol. Med. 5(3): 397-412 (March 2013). Moreover, autophagy was recently found to be useful in the treatment of neurodegenerative disorders, cancer, and heart disease. See Pierzynowska, et al., Metab. Brain Dis., 33(4); 989-1008 (2018) (discussing neurodegenerative disorders); Nelson & Shacka, Curr. Pathobiol. Rep., 1(4): 239-245 (2013) (discussing cancer); Sciaretta, et al., Annual Review of Physiology, 80:1-26 (2018) (discussing heart disease); Maiuri & Kroemer, Cell Death & Differentiation, 26: 680-689 (2019) (discussing therapeutic applications of autophagy, generally). It is, therefore, desirable to identify methods and modes of promoting autophagy. Given TRPML1's role in autophagy, described herein are TRPML1 modulators useful for promoting autophagy and/or treating certain diseases, disorders, or conditions.

    [0122] The present disclosure provides the insight that TRMPL1 may represent a particularly desirable target that, among other things, may permit modulation (e.g., enhancement) of autophagy in certain contexts.

    TRPML1 Modulators

    Structure

    [0123] In some embodiments, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula I:


    Z-L.sup.1-Cy-A-L.sup.2-V  I

    or a pharmaceutically acceptable salt thereof, wherein [0124] A is C.sub.6-12 aryl, 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein A is substituted with 0, 1, 2, 3 or 4 R.sup.a; [0125] Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, C.sub.1-6 aliphatic, C.sub.3-12 cycloalkyl, or —C.sub.0-6 alkylenyl-C(O)—NH—, wherein Cy is optionally substituted with one or more of R.sup.1; [0126] L.sup.1 is absent, —NR.sup.3—, —O—, —S—, —C(O)—NR.sup.3—, —NR.sup.3—C(O)—, —C(O)—C(O)—, or an optionally substituted group selected from C.sub.1-6 alkylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.1-6 alkylenyl,—O—C.sub.1-6 alkylenyl, —C(O)—C.sub.0-6 alkylenyl, —C.sub.0-6 alkylenyl-C(O)— and —C.sub.0-6 alkylenyl-OC(O)—; [0127] L.sup.2 is —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O)—(NR.sup.3)—, —S(O).sub.2—NR.sup.3—, —NR.sup.3—C.sub.1-6 alkylenyl, —NR.sup.3—C.sub.1-6 haloalkylenyl, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C.sub.1-6 alkylenyl-S(O)—, —C.sub.1-6 alkylenyl-S(O).sub.2—, —C(O)—(NR.sup.3).sub.s—, —(NR.sup.3).sub.s—C(O)—, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0128] V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic of bicyclic aryl, and C.sub.3-12 monocyclic or polycyclic cycloalkyl, wherein V is substituted with (R.sup.6).sub.m; [0129] Z is C.sub.1-6 aliphatic, 2- to 10-membered heteroaliphatic, P(O)(R.sup.3).sub.2, —C(O)C.sub.1-6 aliphatic, —C(O)N(R.sup.3).sub.2, C.sub.6-12 aryl, C.sub.3-12 monocyclic or polycyclic cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q; [0130] each R.sup.a is independently hydrogen, halo, oxo, CN, or optionally substituted C.sub.1-6 aliphatic or O—C.sub.1-6 aliphatic; [0131] each R.sup.1 is independently selected from halo, N(R.sup.3).sub.2, OH, CN, C(O)NHR.sup.3, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 alkyl; [0132] each R.sup.2 is independently selected from halo, oxo, CN, OH, C(O)OH, C(O)O—R.sup.2a, C.sub.6-12 aryl, and an optionally substituted group selected from C.sub.1-6 aliphatic, C(O)C.sub.1-6 aliphatic, and O—C.sub.1-6 aliphatic, where R.sup.2a is hydrogen or an optionally substitute group selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, C.sub.1-6 aliphatic, C.sub.3-12 cycloalkyl; [0133] each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic; [0134] each R.sup.5 is independently selected from C.sub.1-6 alkyl, —N(R.sup.3).sub.2, —O—C.sub.1-6 alkyl, C(O)—C.sub.1-6 alkyl, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R.sup.5 is optionally substituted with one or more substituents selected from halo, OH, and 2- to 12-membered heteroaliphatic; [0135] each R.sup.6 is halo, oxo, SF.sub.5, S(O)—R.sup.5, S(O).sub.2—R.sup.5, S(O)(NH)—R.sup.5, S(O).sub.2(NH)—R.sup.5, —CN, —C(O)—R.sup.5, —C.sub.0-6 alkylenyl-C(O)O—R.sup.5, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, —O—R.sup.5, or an optionally substituted group selected from O—C.sub.1-6 alkyl, S—C.sub.1-6 alkyl, C.sub.1-6 alkyl, C.sub.6-12 aryl, 2- to 12-membered heteroaliphatic, C.sub.3-12 cycloalkyl, —O—C.sub.0-6 alkylenyl-C.sub.3-12 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0136] m is 0, 1, 2, 3, or 4; [0137] q is 0, 1, 2, 3, or 4; and [0138] s is 0 or 1.

    [0139] In some embodiments, the present disclosure provides a compound of Formula I′:

    ##STR00018##

    or a pharmaceutically acceptable salt thereof, wherein [0140] A′ is phenyl, 5- to 10-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, or 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with R.sup.a; [0141] Cy is absent, or a bivalent moiety selected from C.sub.1-6 aliphatic, 4- to 14-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C.sub.6-12 aryl, and C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R.sup.1; [0142] L.sup.1 is absent, —S—, —C(O)—NR.sup.3—, —NR.sup.3—C(O)—, or an optionally substituted bivalent moiety selected from C.sub.1-6 alkylenyl, C.sub.2-6 alkenylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.0-6 alkylenyl, —O—C.sub.0-6 alkylenyl, —C(O)—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-C(O)—, —C(O)O—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-O—C(O)—, —C.sub.3-6 cycloalkyl, and —NR.sup.3—C(O)—C.sub.0-6 alkylenyl-O—; [0143] L.sup.2 is —(NR.sup.3).sub.s—S(O)—(NR.sup.3)—, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C(O)—(NR.sup.3).sub.s—, —NR.sup.3—C(O)—, or an optionally substituted bivalent moiety selected from —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O)—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.3-6 cycloalkyl, —NR.sup.3—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-S(O)—(NR.sup.3).sub.s—, —C.sub.1-6 alkylenyl-S(O).sub.2—(NR.sup.3).sub.s—, 2- to 6-membered heteroaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0144] V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein V is substituted with (R.sup.6).sub.m; [0145] Z is selected from P(O)(R.sup.3).sub.2, C(O)N(R.sup.3).sub.2, C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 2- to 10-atom heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q; [0146] each R.sup.a is independently H, halo, —CN, oxo, or an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.3-6 cycloaliphatic, and O—C.sub.1-6 aliphatic; [0147] each R.sup.1 is independently selected from halo, oxo, —N(R.sup.3).sub.2, —OH, —CN, —C(O)N(R.sup.3).sub.2, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 aliphatic; [0148] each R.sup.2 is independently selected from halo, oxo, —CN, —OH, O—R.sup.2a, —C(O)—R.sup.2a, —C(O)O—R.sup.2a, and an optionally group selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; [0149] each R.sup.2a is independently H or an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.3-12 cycloaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0150] each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic; [0151] each R.sup.5 is —N(R.sup.3).sub.2 or an optionally substituted group selected from C.sub.1-6 aliphatic, P(O)(C.sub.1-6 aliphatic).sub.2, C.sub.3-12 cycloaliphatic, and 5- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0152] each R.sup.6 is independently selected from halo, oxo, —SF.sub.5, —S(O)—R.sup.5, S(O).sub.2—R.sup.5, —S(O)(NH)—R.sup.5, —S(O).sub.2—(NH)—R.sup.5, —S(O)—N(R.sup.5).sub.2, —S(O).sub.2—N(R.sup.5).sub.2, —CN, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, —O—R.sup.5, or an optionally substituted group selected from C.sub.1-6 aliphatic, S—C.sub.1-6 aliphatic, 2- to 12-membered heteroaliphatic, —C.sub.0-6 alkylenyl-C(O)—R.sup.5, —C.sub.0-6 alkylenyl-C(O)O—R.sup.5, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0153] m is 0, 1, 2, 3, or 4; [0154] q is 0, 1, 2, 3, 4, 5, or 6; and [0155] each s is independently 0 or 1.

    [0156] In some embodiments, the present disclosure provides and/or utilizes TRMPL1 modulators that are small molecule compounds having a chemical structure as indicated below in Formula II:

    ##STR00019##

    or a pharmaceutically acceptable salt thereof, wherein [0157] X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are each independently selected from N, C, and CR.sup.a, wherein X.sup.1′, X.sup.2′, X.sup.3′, or X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V, and are N or CR.sup.a when not bound to Cy-L.sup.1-Z or L.sup.2-V; [0158] A1 is absent, an optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or an optionally substituted fused heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S; [0159] Cy is absent, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C.sub.1-6 aliphatic, or C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R.sup.1; [0160] L.sup.1 is absent, —NR.sup.3—, —O—, —S—, C.sub.1-6 alkylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.1-6 alkylenyl,—O—C.sub.1-6 alkylenyl, —C(O)C.sub.0-6 alkylenyl; —C(O)NR.sup.3—, or —C(O)—C(O)—; [0161] L.sup.2 is —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O)(NR.sup.3)—, —S(O).sub.2—NR.sup.3—, —NR.sup.3—C.sub.1-6 haloalkylenyl, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C.sub.1-6 alkylenyl-S(O)—, —C.sub.1-6 alkylenyl-S(O).sub.2—, —C(O)—(NR.sup.3).sub.s—, —(NR.sup.3).sub.s—C(O)—, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0162] V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic of bicyclic aryl, and C.sub.3-12 cycloalkyl, wherein V is substituted with (R.sup.6).sub.m; [0163] Z is C.sub.1-6 aliphatic, 2- to 10-membered heteroaliphatic, P(O)(R.sup.3).sub.2, —C(O)C.sub.1-6 aliphatic, C(O)N(R.sup.3).sub.2, C.sub.6-12 aryl, C.sub.3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q; [0164] each R.sup.a is independently hydrogen, halo, oxo, or optionally substituted C.sub.1-6 aliphatic; [0165] each R.sup.1 is independently selected from N(R.sup.3).sub.2, OH, CN, C(O)NHR.sup.3, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 alkyl; [0166] each R.sup.2 is independently selected from halo, —CN, C(O)OH, and an optionally substituted group selected from C.sub.1-6 alkyl, C(O)C.sub.1-6 aliphatic, and O—C.sub.1-6 aliphatic; [0167] each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic; [0168] each R.sup.5 is independently selected from C.sub.1-6 alkyl, —N(R.sup.3).sub.2, —O—C.sub.1-6 alkyl, C(O)—C.sub.1-6 alkyl, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R.sup.5 is optionally substituted with one or more substituents selected from halo and OH; [0169] each R.sup.6 is halo, S(O)—R.sup.5, S(O).sub.2—R.sup.5, S(O)(NH)—R.sup.5, —CN, —C(O)—R.sup.5, —C(O)O—R.sup.5, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, or an optionally substituted group selected from O—C.sub.1-6 alkyl, C.sub.1-6 alkyl, and C.sub.6-12 aryl; [0170] m is 0, 1, 2, 3, or 4; [0171] q is 0, 1, 2, 3, or 4; and [0172] each s is independently 0 or 1.

    [0173] In some embodiments the present disclosure provides a compound of Formula II′:

    ##STR00020##

    or a pharmaceutically acceptable salt thereof, wherein [0174] X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are each independently selected from N, C, CR.sup.a, wherein X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V, and are N or CR.sup.a when not bound to Cy-L.sup.1-Z or L.sup.2-V; [0175] Y.sup.1′ and Y.sup.2′ are selected from each C, N, and CR.sup.a, or one of Y.sup.1′ or Y.sup.2′ is absent and the other of Y.sup.1′ or Y.sup.2′ is selected from C, N, and CR.sup.a; [0176] Cy is absent, or a bivalent moiety selected from C.sub.1-6 aliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R.sup.1; [0177] L.sup.1 is absent, —S—, —C(O)—NR.sup.3—, —NR.sup.3—C(O)—, —C(O)—C(O)—, or an optionally substituted bivalent group selected from C.sub.1-6 alkylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.0-6 alkylenyl, —O—C.sub.0-6 alkylenyl, —C(O)—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-C(O)—, —C(O)O—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-O—C(O)—, —C.sub.3-6 cycloalkyl, and —NR.sup.3—C(O)—C.sub.0-6 alkylenyl-O—; [0178] L.sup.2 is —(NR.sup.3).sub.s—S(O)—(NR.sup.3)—, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C(O)—(NR.sup.3).sub.s—, —NR.sup.3—C(O)—, or an optionally substituted bivalent group selected from —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-,—(NR.sup.3).sub.s—S(O)—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.3-6 cycloalkyl, —NR.sup.3—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-S(O)—(NR.sup.3).sub.s—, —C.sub.1-6 alkylenyl-S(O).sub.2—(NR.sup.3).sub.s—, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0179] V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein V is substituted with (R.sup.6).sub.m; [0180] Z is selected from P(O)(R.sup.3).sub.2, C(O)N(R.sup.3).sub.2, C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 2- to 10-atom heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q; [0181] each R.sup.a is independently H, halo, —CN, oxo, or an optionally substituted group selected from C.sub.1-6 aliphatic and O—C.sub.1-6 aliphatic, or two R.sup.a together when on adjacent atoms form a fused optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or a fused optionally substituted heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S; [0182] each R.sup.1 is independently selected from halo, —N(R.sup.3).sub.2, —OH, —CN, —C(O)N(R.sup.3).sub.2, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 aliphatic; [0183] each R.sup.2 is independently selected from halo, oxo, —CN, —OH, O—R.sup.2a, —C(O)—R.sup.2a, —C(O)O—R.sup.2a, and an optionally group selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S; [0184] each R.sup.2a is independently H or an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.3-12 cycloaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0185] each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic; [0186] each R.sup.5 is —N(R.sup.3).sub.2 or an optionally substituted group selected from C.sub.1-6 aliphatic, P(O)(C.sub.1-6 aliphatic).sub.2, C.sub.3-12 cycloaliphatic, and 5- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0187] each R.sup.6 is independently selected from halo, oxo, —SF.sub.5, —S(O)—R.sup.5, S(O).sub.2—R.sup.5, —S(O)(NH)—R.sup.5, —S(O).sub.2—(NH)—R.sup.5, —S(O)—N(R.sup.5).sub.2, —S(O).sub.2—N(R.sup.5).sub.2, —CN, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, —O—R.sup.5, or an optionally substituted group selected from C.sub.1-6 aliphatic, S—C.sub.1-6 aliphatic, 2- to 12-membered heteroaliphatic, —C.sub.0-6 alkylenyl-C(O)—R.sup.5, —C.sub.0-6 alkylenyl-C(O)O—R.sup.5, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0188] m is 0, 1, 2, 3, or 4; [0189] q is 0, 1, 2, 3, 4, 5, or 6; and [0190] each s is independently 0 or 1.

    [0191] Compounds of formula I, I′, II, and/or II′ are described with respect to the exemplary embodiments herein.

    [0192] As defined generally above for compounds of formula I′, A′ is phenyl, 5- to 10-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, or 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with R.sup.a.

    [0193] In some embodiments, A′ is phenyl.

    [0194] In some embodiments, A′ is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A′ is indazolyl.

    [0195] In some embodiments, A′ is 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A′ is pyrazolyl, imidazolyl, triazolyl, thiadiazolyl, or isoxazolyl.

    [0196] In some embodiments, A′ is 9- or 10-membered bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, A′ is isoindolinyl, tetrahydroquinoxalinyl, tetrahydropyrazolopyridinyl, tetrahydroquinoxalinyl, or dihydrobenzoimidazolonyl.

    [0197] In some embodiments, A′ is selected from Table A′:

    TABLE-US-00001 TABLE A′ [00021]embedded image [00022]embedded image [00023]embedded image [00024]embedded image [00025]embedded image [00026]embedded image [00027]embedded image [00028]embedded image [00029]embedded image [00030]embedded image [00031]embedded image [00032]embedded image [00033]embedded image [00034]embedded image [00035]embedded image [00036]embedded image [00037]embedded image [00038]embedded image [00039]embedded image [00040]embedded image

    [0198] In some embodiments, A′ is

    ##STR00041##

    In some embodiments, A′ is

    ##STR00042##

    In some embodiments, A′ is

    ##STR00043##

    In some embodiments, A′ is

    ##STR00044##

    [0199] As defined generally above for compounds of formula II and/or II′, X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are each independently selected from N, C, and CR.sup.a, wherein X.sup.1′, X.sup.2′, X.sup.3′, or X.sup.4′ are C or N when bound to Cy-L.sup.1-Z or L.sup.2-V, as valency permits. That is, when any of X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are bound to Cy-L.sup.1-Z or L.sup.2-V, a value for variables X.sup.1′, X.sup.2′, X.sup.3′, or X.sup.4′ is C-Cy-L.sup.1-Z or C-L.sup.2-V, and the remaining values for variables of X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are independently selected from N and CR.sup.a. It is understood that only one instance of Cy-L.sup.1-Z and L.sup.2-V will appear on a compound of formula II or II′.

    [0200] In some embodiments, each of X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are C or CR.sup.a, where X.sup.1′, X.sup.2′, X.sup.3′, or X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V, and the remaining variables are CR.sup.a. In some embodiments, X.sup.1′ is C-Cy-L.sup.1-Z, X.sup.2′ is C-L.sup.2-V, and X.sup.3′ and X.sup.4′ are each CR.sup.a. In some embodiments, X.sup.2′ is C-Cy-L.sup.1-Z, X.sup.3′ is C-L.sup.2-V, and X.sup.1′ and X.sup.4′ are each CR.sup.a. In some embodiments, X.sup.3′ is C-Cy-L.sup.1-Z, X.sup.4′ is C-L.sup.2-V, and X.sup.1′ and X.sup.2′ are each CR.sup.a. In some embodiments, X.sup.4′ is C-Cy-L.sup.1-Z, X.sup.1′ is C-L.sup.2-V, and X.sup.2′ and X.sup.3′ are each CR.sup.a.

    [0201] As defined generally above with respect to formula II′, Y.sup.1′ and Y.sup.2′ are selected from each C, N, and CR.sup.a, or one of Y.sup.1′ or Y.sup.2′ is absent and the other of Y.sup.1′ or Y.sup.2′ is selected from C, N, and CR.sup.a. In some embodiments, each of Y.sup.1′ and Y.sup.2′ are CR.sup.a. In some embodiments, when each of Y.sup.1′ and Y.sup.2′ are CR.sup.a, two R.sup.a on can come together to form a ring, and formula II′ may be represented by:

    ##STR00045##

    where A1′ is a fused optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or an optionally substituted fused heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S.

    [0202] As defined generally above, with respect to formula II, A1 is absent or an optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or an optionally substituted fused heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, A1 is absent, a compound of formula II is represented by:

    ##STR00046##

    where Z, L.sup.1, Cy, X.sup.1′, X.sup.1′, X.sup.2′, X.sup.3′, X.sup.4′, L, and V are as defined in classes and subclasses herein.

    [0203] In some embodiments, A1 is absent, and each X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ is C or CR.sup.a, and wherein X.sup.1′, X.sup.2′, X.sup.3′, or X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V, a compound of formula II is represented by:

    ##STR00047##

    where Z, L.sup.1, Cy, R.sup.a, L, and V are as defined in classes and subclasses herein.

    [0204] In some embodiments of formula II′, each of Y.sup.1′ and Y.sup.2′ is CR.sup.a, each of X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ is C or CR.sup.a, wherein X.sup.1′, X.sup.2′, X.sup.3′, or X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V, and a compound of formula II′ is represented by:

    ##STR00048##

    where Z, L.sup.1, Cy, R.sup.a, L, and V are as defined in classes and subclasses herein.

    [0205] In some embodiments of formula II′, each of Y.sup.1′ and Y.sup.2′ is CR.sup.a, each of X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ is C or CR.sup.a, wherein X.sup.1′, X.sup.2′, X.sup.3′, or X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V, and a compound of formula II′ is represented by:

    ##STR00049##

    where Z, L.sup.1, Cy, R.sup.a, L, and V are as defined in classes and subclasses herein.

    [0206] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, each R.sup.a is independently H, halo, —CN, oxo, or an optionally substituted group selected from C.sub.1-6 aliphatic and O—C.sub.1-6 aliphatic, or two R.sup.a together when on adjacent atoms form a fused optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or a fused optionally substituted heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S.

    [0207] In some embodiments, R.sup.a is hydrogen.

    [0208] In some embodiments, R.sup.a is optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.a is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.a is optionally substituted C.sub.1-3 alkyl. In some embodiments, R.sup.a is methyl.

    [0209] In some embodiments, R.sup.a is optionally substituted O—C.sub.1-6 alkyl. In some embodiments, R.sup.a is optionally substituted O—C.sub.1-3 alkyl. In some embodiments, R.sup.a is OCH.sub.3.

    [0210] In some embodiments, R.sup.a is halo. In some embodiments, R.sup.a is bromo, chloro, fluoro, or iodo. In some embodiments, R.sup.a is bromo. In some embodiments, R.sup.a is chloro. In some embodiments, R.sup.a is fluoro. In some embodiments, R.sup.a is iodo.

    [0211] In some embodiments, R.sup.a is CN.

    [0212] In some embodiments, two R.sup.a together when on adjacent atoms form a fused optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or a fused optionally substituted heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S.

    [0213] In some embodiments, a compound of formula I, I′, II or II′ is represented by:

    ##STR00050##

    where Cy, L.sup.1, L.sup.2, Z, and V are described in classes and subclasses herein.

    [0214] As defined generally above for compounds of formula I, I′, II, II′, or any other formulae provided herein, Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, C.sub.1-6 aliphatic, or C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more R.sup.1.

    [0215] In some embodiments, Cy is absent, C.sub.1-6 aliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C.sub.3-12 cycloaliphatic, wherein Cy is optionally substituted with one or more of R.sup.1. It is understood that Cy is a bivalent moiety in any of formula I, I′, II, II′ or any other formulae provided herein. That is, reference to a particular Cy group is intended to refer to a bivalent variation of the referenced group.

    [0216] In some embodiments, Cy is optionally substituted with one or more R.sup.1, i.e., is substituted with 0, 1, 2, 3, or 4 R.sup.1. In some embodiments, Cy is unsubstituted (i.e., is substituted with 0 R.sup.1). In some embodiments, Cy is substituted with 1, 2, 3, or 4 R.sup.1. In some embodiments, Cy is substituted with 1 R.sup.1. In some embodiments, Cy is substituted with 2 R.sup.1. In some embodiments, Cy is substituted with 3 R.sup.1. In some embodiments, Cy is substituted with 4 R.sup.1.

    [0217] In some embodiments, Cy is absent.

    [0218] In some embodiments, Cy is 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 4- to 7-membered monocyclic heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 4- to 7-membered monocyclic heterocyclyl comprising 1 heteroatom selected from N, O, P, and S. In some embodiments, Cy is 4-membered monocyclic heterocyclic comprising 1 heteroatom selected from N, O, P, and S. In some embodiments, Cy is 5-membered monocyclic heterocyclic comprising 1 to 2 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 6-membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 7-membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, P, and S. In some embodiments, In some embodiments, Cy is azetidinyl, pyrrolidinyl, piperadinyl, piperazinyl, or azepanyl.

    [0219] In some embodiments, Cy is azetidinyl, optionally substituted with one or more R.sup.1.

    [0220] In some embodiments, Cy is piperadinyl optionally substituted with one or more R.sup.1. In some embodiments, Cy is unsubstituted piperadinyl. In some embodiments, Cy is piperadinyl substituted with one or more R.sup.1.

    [0221] In some embodiments, Cy is piperazinyl optionally substituted with one or more R.sup.1. In some embodiments, Cy is unsubstituted piperazinyl. In some embodiments, Cy is piperazinyl substituted with one or more R.sup.1.

    [0222] In some embodiments, Cy is azepanyl optionally substituted with one or more R.sup.1. In some embodiments, Cy is unsubstituted azepanyl. In some embodiments, Cy is azepanyl substituted with one or more R.sup.1.

    [0223] In some embodiments, Cy is

    ##STR00051##

    optionally substituted with one or more R.sup.1. In some embodiments, Cy is unsubstituted

    ##STR00052##

    In some embodiments, Cy is

    ##STR00053##

    substituted with one or more R.sup.1.

    [0224] In some embodiments, Cy is 7- to 12-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10- to 12-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 11-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 12-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S.

    [0225] In some embodiments, Cy is

    ##STR00054##

    In some embodiments, Cy is

    ##STR00055##

    In some embodiments, Cy is

    ##STR00056##

    In some embodiments, Cy is

    ##STR00057##

    [0226] In some embodiments, Cy is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 5- or 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 5-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Cy is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0227] In some embodiments, Cy is 7- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 9- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 11-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S. In some embodiments, Cy is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S.

    [0228] In some embodiments, Cy is C.sub.1-6 aliphatic. In some embodiments, Cy is C.sub.1-6 alkylenyl. In some embodiments, Cy is C.sub.1-3 alkylenyl.

    [0229] In some embodiments, Cy is C.sub.3-12 cycloaliphatic. In some embodiments, Cy is C.sub.3-12 cycloalkyl. In some embodiments, Cy is C.sub.3-6 cycloalkyl. In some embodiments, Cy is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, Cy is cyclobutyl. In some embodiments, Cy is cyclopentyl. In some embodiments, Cy is cyclohexyl.

    [0230] In some embodiments, Cy is absent or a bivalent moiety selected from 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, P, and S, C.sub.1-6 aliphatic, or C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more R.sup.1, and wherein Cy is not piperazinyl. In some embodiments, Cy is 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, wherein Cy is not piperazinyl.

    [0231] As defined generally above, each R.sup.1 is independently selected from N(R.sup.3).sub.2, OH, CN, C(O)NHR.sup.3, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 alkyl.

    [0232] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, each R.sup.1 is independently selected from halo, —N(R.sup.3).sub.2, —OH, —CN, —C(O)N(R.sup.3).sub.2, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 aliphatic.

    [0233] In some embodiments, R.sup.1 is halo. In some embodiments, R.sup.1 is bromo, chloro, fluoro, or iodo. In some embodiments, R.sup.1 is bromo. In some embodiments, R.sup.1 is chloro. In some embodiments, R.sup.1 is fluoro. In some embodiments, R.sup.1 is iodo.

    [0234] In some embodiments, R.sup.1 is —N(R.sup.3).sub.2. In some embodiments, R.sup.1 is NH.sub.2. In some embodiments, R.sup.1 is N(H)(C.sub.1-6 aliphatic). In some embodiments, R.sup.1 is N(H)(CH.sub.3). In some embodiments, R.sup.1 is N(CH.sub.3).sub.2.

    [0235] In some embodiments, R.sup.1 is —OH. In some embodiments, R.sup.1 is —CN.

    [0236] In some embodiments, R.sup.1 is —C(O)N(R.sup.3).sub.2. In some embodiments, R.sup.1 is —C(O)NHR.sup.3. In some embodiments, R.sup.1 is C(O)N.sub.12.

    [0237] In some embodiments, R.sup.1 is optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.1 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.1 is optionally substituted methyl, ethyl, propyl, or butyl. In some embodiments, R.sup.1 is methyl.

    [0238] In some embodiments, R.sup.1 is N(R.sup.3)—C(O)—C.sub.1-6 aliphatic. In some embodiments, R.sup.1 is N(R.sup.3)—C(O)—C.sub.1-6 alkyl.

    [0239] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R.sup.1 group is selected from: halo, OH, NH.sub.2, and oxo.

    [0240] In some embodiments, Cy is selected from Table Cy:

    TABLE-US-00002 TABLE Cy —CH.sub.2—, —CH.sub.2—C(O)—NH—, [00058]embedded image [00059]embedded image [00060]embedded image [00061]embedded image [00062]embedded image [00063]embedded image [00064]embedded image [00065]embedded image [00066]embedded image [00067]embedded image [00068]embedded image [00069]embedded image [00070]embedded image [00071]embedded image [00072]embedded image [00073]embedded image [00074]embedded image [00075]embedded image [00076]embedded image [00077]embedded image [00078]embedded image [00079]embedded image [00080]embedded image [00081]embedded image [00082]embedded image [00083]embedded image [00084]embedded image [00085]embedded image

    [0241] As defined generally above for compounds of formula I, I′, II, II′, or any other formulae provided herein, L.sup.1 is absent, —NR.sup.3—, —O—, —S—, C.sub.1-6 alkylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.1-6 alkylenyl, —O—C.sub.1-6 alkylenyl, —C(O)C.sub.0-6 alkylenyl, —C(O)NR.sup.3—, or —C(O)—C(O)—. It is understood that L.sup.1 is a bivalent moiety in any of formula I, I′, II, II′ or any other formulae provided herein. That is, reference to a particular L.sup.1 group is intended to refer to a bivalent variation of the referenced group.

    [0242] In some embodiments, L.sup.1 is absent, —S—, —C(O)—NR.sup.3—, —NR.sup.3—C(O)—, —C(O)—C(O)—, or an optionally substituted group selected from C.sub.1-6 alkylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.0-6 alkylenyl, —O—C.sub.0-6 alkylenyl, —C(O)—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-C(O)—, —C(O)O—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-O—C(O)—, —C.sub.3-6 cycloalkyl, and —NR.sup.3—C(O)—C.sub.0-6 alkylenyl-O—.

    [0243] In some embodiments, L.sup.1 is absent.

    [0244] In some embodiments, L.sup.1 is —NR.sup.3—. In some embodiments, L.sup.1 is —N(C.sub.1-6 aliphatic)-. In some embodiments, L.sup.1 is —N(CH.sub.3). In some embodiments, L.sup.1 is —NH—.

    [0245] In some embodiments, L.sup.1 is —O—. In some embodiments, L.sup.1 is —S—.

    [0246] In some embodiments, L.sup.1 is —C(O)—NR—. In some embodiments, L.sup.1 is —C(O)—NH—. In some embodiments, L.sup.1 is —C(O)—N(C.sub.1-6 aliphatic)-. In some embodiments, L.sup.1 is —C(O)—N(CH.sub.3)—.

    [0247] In some embodiments, L.sup.1 is —NR.sup.3—C(O)—. In some embodiments, L.sup.1 is —N(C.sub.1-6 aliphatic)-C(O)—. In some embodiments, L.sup.1 is —N(CH.sub.3)—C(O)—. In some embodiments, L.sup.1 is —NH—C(O)—.

    [0248] In some embodiments, L.sup.1 is —C(O)—C(O)—.

    [0249] In some embodiments, L.sup.1 is optionally substituted C.sub.1-6 alkylenyl. In some embodiments, L.sup.1 is optionally substituted C.sub.1-4 alkylenyl. In some embodiments, L.sup.1 is C.sub.1-6 alkylenyl. In some embodiments, L.sup.1 is C.sub.1-6 alkylenyl substituted with —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º; —O(CH.sub.2).sub.0-4R.sup.º. In some embodiments, L.sup.1 is C.sub.1-6 alkylenyl substituted with one or more R.sup.º, where R.sup.º is halo (e.g., fluoro, bromo, chloro, iodo). In some embodiments, L.sup.1 is —CH.sub.2—. In some embodiments, L.sup.1 is —(CH.sub.2).sub.2—. In some embodiments, L.sup.1 is —(CH.sub.2).sub.3—. In some embodiments, L.sup.1 is —CH(CF.sub.3)—. In some embodiments, L.sup.1 is —CH(CH.sub.3)—. In some embodiments, L.sup.1 is —CH.sub.2—CH(CH.sub.3)—. In some embodiments, L.sup.1 is —C(CH.sub.3).sub.2—.

    [0250] In some embodiments, L.sup.1 is optionally substituted C.sub.2-6 alkynylenyl. In some embodiments, L.sup.1 is

    ##STR00086##

    [0251] In some embodiments, L.sup.1 is optionally substituted —NR.sup.3—C.sub.1-6 alkylenyl. In some embodiments, L.sup.1 is —NR.sup.3—C.sub.1-6 alkylenyl substituted with —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º; —O(CH.sub.2).sub.0-4R.sup.º. In some embodiments, L.sup.1 is —NR.sup.3—C.sub.1-6 alkylenyl substituted with one or more R.sup.º, where R.sup.º is halo (e.g., fluoro, bromo, chloro, iodo). In some embodiments, L.sup.1 is optionally substituted —O—C.sub.1-6 alkylenyl. In some embodiments, L.sup.1 is —O—C.sub.1-6 alkylenyl substituted with —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º; —O(CH.sub.2).sub.0-4R.sup.º. In some embodiments, L.sup.1 is −)—C.sub.1-6 alkylenyl substituted with one or more R.sup.º, where R.sup.º is halo (e.g., fluoro, bromo, chloro, iodo). In some embodiments, L.sup.1 is optionally substituted —O—C.sub.1-3 alkylenyl. In some embodiments, L.sup.1 is —O—CH.sub.2—.

    [0252] In some embodiments, L.sup.1 is optionally substituted —C(O)C.sub.0-6 alkylenyl. In some embodiments, L.sup.1 is —C(O)—. In some embodiments, L.sup.1 is —C(O)—CH.sub.2—. In some embodiments, L.sup.1 is —C(O)—C(CH.sub.3).sub.2—. In some embodiments, L.sup.1 is optionally substituted —C.sub.0-6 alkylenyl-C(O)—. In some embodiments, L.sup.1 is optionally substituted —C.sub.1-3 alkylenyl-C(O)—. In some embodiments, L.sup.1 is —CH.sub.2—C(O)—. In some embodiments, L.sup.1 is —CH(CH.sub.3)—C(O)—. In some embodiments, L.sup.1 is —C(CH.sub.3).sub.2—C(O)—. In some embodiments, L.sup.1 is optionally substituted —C.sub.0-6 alkylenyl-OC(O)—. In some embodiments, L.sup.1 is optionally substituted —C.sub.1-3 alkylenyl-OC(O)—. In some embodiments, L.sup.1 is —OC(O)—. In some embodiments, L.sup.1 is —CH.sub.2—OC(O)—. In some embodiments, L.sup.1 is —C(CH.sub.3).sub.2—C(O)O—.

    [0253] In some embodiments, L.sup.1 is —C(O)NR—. In some embodiments, L.sup.1 is —C(O)NH—. In some embodiments, L.sup.1 is —C(O)N(C.sub.1-6 aliphatic)-. In some embodiments, L.sup.1 is —C(O)N(CH.sub.3)—

    [0254] In some embodiments, L.sup.1 is —C(O)—C(O)—.

    [0255] In some embodiments, L.sup.1 is C.sub.3-6 cycloalkyl. In some embodiment, L.sup.1 is

    ##STR00087##

    [0256] As defined generally above formulae I, I′, II, II′, or any other formulae provided herein, Z is C.sub.1-6 aliphatic, 2- to 10-membered heteroaliphatic, P(O)(R.sup.3).sub.2, —C(O)C.sub.1-6 aliphatic, C(O)N(R.sup.3).sub.2, C.sub.6-12 aryl, C.sub.3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q.

    [0257] In some embodiments, Z is selected from P(O)(R.sup.3).sub.2, C(O)N(R.sup.3).sub.2, C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 2- to 10-atom heteroaliphatic, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q.

    [0258] In some embodiments, Z is substituted with (R.sup.2).sub.q. As defined generally above, q is 0, 1, 2, 3, 4, 5, or 6. That is, in some embodiments, Z is substituted with 0, 1, 2, 3, 4, 5, or 6 R.sup.2. In some embodiments, Z is unsubstituted (i.e., q is 0). In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6.

    [0259] In some embodiments, Z is P(O)(R.sup.3).sub.2. In some embodiments, Z is P(O)(C.sub.1-6 aliphatic).sub.2. In some embodiments, Z is P(O)(CH.sub.3).sub.2.

    [0260] In some embodiments, Z is —C(O)N(R.sup.3).sub.2. In some embodiments, Z is —C(O)N(C.sub.1-6 aliphatic).sub.2. In some embodiments, Z is —C(O)NH(C.sub.1-6 aliphatic). In some embodiments, Z is —C(O)NHC(CH.sub.3).sub.3. In some embodiments, Z is —C(O)N(CH.sub.3)(C(CH.sub.3).sub.3). In some embodiments, Z is —C(O)N(CH.sub.3).sub.2.

    [0261] In some embodiments, Z is C.sub.1-6 aliphatic. In some embodiments, Z is C.sub.1-6 alkyl. In some embodiments, Z is C.sub.1-3 alkyl. In some embodiments, Z is methyl, ethyl, propyl (e.g., iso-propyl, n-propyl), butyl (e.g., n-butyl, iso-butyl, tert-butyl). In some embodiments, Z is methyl. In some embodiments, Z is ethyl. In some embodiments, Z is iso-propyl. In some embodiments, Z is tert-butyl. In some embodiments, Z is —CH.sub.2—C(CH.sub.3).sub.2—CH.sub.2—CH.sub.3. In some embodiments, Z is —C(CH.sub.3).sub.2—CH.sub.2—CH.sub.3. In some embodiments, Z is methyl substituted with 1, 2 or 3 R.sup.2. In some embodiments, Z is methyl substituted with 1, 2 or 3 halo. In some embodiments, Z is methyl substituted with 1, 2 or 3 fluoro. In some embodiments, Z is ethyl substituted with 1, 2, 3 or 4 R.sup.2. In some embodiments, Z is ethyl substituted with 1, 2, 3 or 4 halo. In some embodiments, Z is ethyl substituted with 1, 2, 3 or 4 fluoro. In some embodiments, Z is iso-propyl substituted with 1, 2, 3 or 4 R.sup.2.

    [0262] In some embodiments, Z is C.sub.6-12 aryl. In some embodiments, Z is phenyl. In some embodiments, Z is phenyl substituted with 0, 1, 2, 3, 4, 5, or 6 R.sup.2. In some embodiments, Z is unsubstituted phenyl (i.e., Z is phenyl substituted with 0 R.sup.2). In some embodiments, Z is phenyl substituted with 1, 2, 3, 4, or 5 R.sup.2. In some embodiments, Z is phenyl substituted with 1 or 2 R.sup.2. In some embodiments, Z is phenyl substituted with 1 R.sup.2. In some embodiments, Z is phenyl substituted with R.sup.2, and R.sup.2 is selected from halo, —C(O)—R.sup.2a, —C(O)O—R.sup.2a, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0263] In some embodiments, Z is 2- to 10-membered heteroaliphatic. In some embodiments, Z is 2- to 5-membered heteroaliphatic. In some embodiments, Z is 2- to 5-membered heteroaliphatic substituted with 1, 2 or 3 R.sup.2. In some embodiments, Z is —O—CH.sub.3, —O—CH.sub.2—CH.sub.3, —CH.sub.2—O—CH.sub.3, —O—CH.sub.2—CH.sub.2—O—CH.sub.3, —O—CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.2—O—CH.sub.3, —O—C(CH.sub.3).sub.3, —NH—C(CH.sub.3).sub.3, —N(CH.sub.2CH.sub.3).sub.2. In some embodiments, Z is —O—CH.sub.3. In some embodiments, Z is —CH.sub.2—O—CH.sub.3. In some embodiments, Z is —O—CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.2—O—CH.sub.3. In some embodiments, Z is —O—CH.sub.2—CH.sub.2—O—CH.sub.3. In some embodiments, Z is —O—C(CH.sub.3).sub.3. In some embodiments, Z is —O—CH.sub.2—CH.sub.3. In some embodiments, Z is —NH—C(CH.sub.3).sub.3. In some embodiments, Z is —N(CH.sub.2CH.sub.3).sub.2.

    [0264] In some embodiments, Z is C.sub.3-12 cycloalkyl (e.g., monocyclic or polycyclic cycloalkyl). In some embodiments, Z is C.sub.3-6 monocyclic cycloalkyl. In some embodiments, Z is cyclopropyl. In some embodiments, Z is cyclobutyl. In some embodiments, Z is cyclopentyl. In some embodiments, Z is cyclohexyl. In some embodiments, Z is cyclopropyl substituted with 1, 2, 3 or 4 R.sup.2. In some embodiments, Z is cyclobutyl substituted with 1, 2, 3, 4, 5, or 6 R.sup.2. In some embodiments, Z is cyclopentyl substituted with 1, 2, 3, 4, 5, or 6 R.sup.2. In some embodiments, Z is cyclohexyl substituted with 1, 2, 3, 4, 5, or 6 R.sup.2.

    [0265] In some embodiments, Z is C.sub.5-12 polycyclic cycloalkyl. In some embodiments, Z is C.sub.10-12 polycyclic cycloalkyl. In some embodiments, Z is adamantyl.

    [0266] In some embodiments, Z is 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 4- to 6-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 4-membered monocyclic heterocyclyl comprising 1 heteroatom selected from N, O, and S. In some embodiments, Z is 5-membered monocyclic heterocyclyl comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Z is 6-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 4- to 6-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S substituted with 0, 1, 2, 3, 4, 5, or 6 R.sup.2.

    [0267] In some embodiments, Z is 10- to 12-membered bicyclic heterocyclyl. In some embodiments, Z is 10- to 12-membered fused bicyclic heterocyclyl. In some embodiments, Z is 10- to 12-membered bridged bicyclic heterocyclyl. In some embodiments, Z is 10- to 12-membered bridged bicyclic heterocyclyl substituted with 0, 1, 2, 3, 4, 5, or 6 R.sup.2.

    [0268] In some embodiments, Z is 10- to 16-membered polycyclic heterocyclyl. In some embodiments, Z is 10-membered polycyclic heterocyclyl. In some embodiments, Z is 11-membered polycyclic heterocyclyl. In some embodiments, Z is 12-membered polycyclic heterocyclyl. In some embodiments, Z is 13-membered polycyclic heterocyclyl. In some embodiments, Z is 14-membered polycyclic heterocyclyl. In some embodiments, Z is 15-membered polycyclic heterocyclyl. In some embodiments, Z is 16-membered polycyclic heterocyclyl. In some embodiments, a polycyclic Z moiety is a spirocyclic and fused tricyclic moiety.

    [0269] In some embodiments, Z is 9- to 12-membered spirocyclic heterocyclyl. In some embodiments, Z is 9-membered spirocyclic heterocyclyl. In some embodiments, Z is 10-membered spirocyclic heterocyclyl. In some embodiments, Z is 11-membered spirocyclic heterocyclyl. In some embodiments, Z is 12-membered spirocyclic heterocyclyl. In some embodiments, Z is 9- to 12-membered spirocyclic heterocyclyl substituted with 0, 1, 2, 3, 4, 5, or 6 R.sup.2.

    [0270] In some embodiments, Z is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 5-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0271] In some embodiments, Z is 8- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 8-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 9-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 11-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0272] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, each R.sup.2 is independently selected from halo, CN, C(O)OH, and an optionally substituted group selected from C.sub.1-6 aliphatic, C(O)C.sub.1-6 aliphatic, and O—C.sub.1-6 aliphatic.

    [0273] In some embodiments, each R.sup.2 is independently selected from halo, oxo, —CN, —OH, 0-R.sup.2a, —C(O)—R.sup.2a, —C(O)O—R.sup.2a, and an optionally group selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0274] In some embodiments, R.sup.2 is halo. In some embodiments, R.sup.2 is selected from fluoro, chloro, bromo, and iodo.

    [0275] In some embodiments, R.sup.2 is oxo.

    [0276] In some embodiments, R.sup.2 is —CN.

    [0277] In some embodiments, R.sup.2 is —OH.

    [0278] In some embodiments, R.sup.2 is C(O)—R.sup.2a. In some embodiments, R.sup.2 is optionally substituted C(O)—C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is C(O)—C.sub.1-6 aliphatic substituted with halogen; —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º. In some embodiments, R.sup.2 is C(O)—C.sub.1-6 aliphatic substituted with halogen or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

    [0279] In some embodiments, R.sup.2 is C(O)O—R.sup.2a. In some embodiments, R.sup.2 is C(O)OH. In some embodiments, R.sup.2 is optionally substituted C(O)O—C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is C(O)O—C.sub.1-6 aliphatic substituted with halogen; —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º. In some embodiments, R.sup.2 is C(O)O—C.sub.1-6 aliphatic substituted with halogen or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

    [0280] In some embodiments, R.sup.2 is optionally substituted C.sub.6-12 aryl. In some embodiments, R.sup.2 is optionally substituted phenyl. In some embodiments, R.sup.2 is phenyl substituted with substituted with halogen; —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º.

    [0281] In some embodiments, R.sup.2 is an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-2 alkyl. In some embodiments, R.sup.2 is methyl. In some embodiments, R.sup.2 is ethyl. In some embodiments, R.sup.2 is propyl (e.g., n-propyl, iso-propyl) In some embodiments, R.sup.2 is butyl (e.g., n-butyl, isobutyl, tert-butyl, sec-butyl). In some embodiments, R.sup.2 is C.sub.1-6 aliphatic substituted with halogen; —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º. In some embodiments, R.sup.2 is C.sub.1-6 aliphatic substituted with halogen or 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

    [0282] In some embodiments, R.sup.2 is an optionally substituted O—R.sup.2a. In some embodiments, R.sup.2 is optionally substituted O—C.sub.1-6 aliphatic. In some embodiments, R.sup.2 is optionally substituted O—C.sub.1-6 alkyl. In some embodiments, R.sup.2 is optionally substituted O—C.sub.1-4 alkyl. In some embodiments, R.sup.2 is optionally substituted O—C.sub.1-2 alkyl. In some embodiments, R.sup.2 is O-methyl. In some embodiments, R.sup.2 is O-ethyl. In some embodiments, R.sup.2 is O-propyl (e.g., O-n-propyl, O-iso-propyl).

    [0283] In some embodiments, R.sup.2 is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is 5-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2 is 6-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0284] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R.sup.2 group, as defined herein and above, is halo (e.g., bromo, chloro, fluoro, iodo).

    [0285] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, in some embodiments, each R.sup.2a is independently H or an optionally substituted group selected from C.sub.1-6 aliphatic, C.sub.3-12 cycloaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R.sup.2a is H. In some embodiments, R.sup.2a is an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.2a is C.sub.3-12 cycloaliphatic. In some embodiments, R.sup.2a is 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0286] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.3 is H. In some embodiments, R.sup.3 is an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.3 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.3 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.3 is optionally substituted C.sub.1-2 alkyl. In some embodiments, R.sup.3 is methyl. In some embodiments, R.sup.3 is ethyl. In some embodiments, R.sup.3 is tert-butyl.

    [0287] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R.sup.3 group is halo (e.g., bromo, chloro, fluoro, iodo).

    [0288] In some embodiments, Z is selected from Table Z:

    TABLE-US-00003 TABLE Z halo (e.g., bromo, chloro, fluoro, iodo), —CH.sub.3, —CH.sub.2—CH.sub.3, —CH.sub.2—O—CH.sub.3, —CH(CH.sub.3)—CH.sub.2—O—CH.sub.3, —CH.sub.2—O—CH.sub.2—CH.sub.3, —CH.sub.2—CH.sub.2—O—CH.sub.3, —CH.sub.2—CH.sub.2—CH.sub.2—O—CH.sub.3, —CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.3, —CH.sub.2—O—CH.sub.2—CH.sub.2—O—CH.sub.3, —CH.sub.2—OH, —CH(OH)—CH.sub.3, —CH.sub.2—CH.sub.2—OH, —CH.sub.2F, —CHF.sub.2, —CF.sub.3, —CH.sub.2—CH.sub.2F, —CH.sub.2—O—C(CH.sub.3).sub.3, —CH.sub.2—O—CF.sub.2—CH.sub.2F, —C(CH.sub.3)F.sub.2, —CF.sub.2—CHF.sub.2, —CF.sub.2—CH.sub.3, —CF.sub.2—CH.sub.2—O—CH.sub.3, —CH.sub.2—O—CHF.sub.2, —CH.sub.2—O—CH.sub.2—CHF.sub.2, —CH.sub.2—O—CF.sub.3, —O—CH.sub.3, —O—CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.2—O—CH.sub.3, —O—CH.sub.2—CH.sub.2—O—CH.sub.3, —O—C(CH.sub.3).sub.3, —O—CH.sub.2—CH.sub.3, —O—CHF.sub.2, —O—CF.sub.3, —O—CH.sub.2—CHF.sub.2, —NH—C(CH.sub.3).sub.3, —N(CH.sub.2CH.sub.3).sub.2, [00088]embedded image [00089]embedded image [00090]embedded image [00091]embedded image [00092]embedded image [00093]embedded image [00094]embedded image [00095]embedded image [00096]embedded image [00097]embedded image [00098]embedded image [00099]embedded image [00100]embedded image [00101]embedded image [00102]embedded image [00103]embedded image [00104]embedded image [00105]embedded image [00106]embedded image [00107]embedded image [00108]embedded image [00109]embedded image [00110]embedded image [00111]embedded image [00112]embedded image [00113]embedded image [00114]embedded image [00115]embedded image [00116]embedded image [00117]embedded image [00118]embedded image [00119]embedded image [00120]embedded image [00121]embedded image [00122]embedded image [00123]embedded image [00124]embedded image [00125]embedded image [00126]embedded image [00127]embedded image [00128]embedded image [00129]embedded image [00130]embedded image [00131]embedded image [00132]embedded image [00133]embedded image [00134]embedded image [00135]embedded image [00136]embedded image [00137]embedded image [00138]embedded image [00139]embedded image [00140]embedded image [00141]embedded image [00142]embedded image [00143]embedded image [00144]embedded image [00145]embedded image [00146]embedded image [00147]embedded image [00148]embedded image [00149]embedded image [00150]embedded image [00151]embedded image [00152]embedded image [00153]embedded image [00154]embedded image [00155]embedded image [00156]embedded image [00157]embedded image [00158]embedded image [00159]embedded image [00160]embedded image [00161]embedded image [00162]embedded image [00163]embedded image [00164]embedded image [00165]embedded image [00166]embedded image [00167]embedded image [00168]embedded image [00169]embedded image [00170]embedded image [00171]embedded image [00172]embedded image [00173]embedded image [00174]embedded image [00175]embedded image [00176]embedded image [00177]embedded image [00178]embedded image [00179]embedded image [00180]embedded image [00181]embedded image [00182]embedded image [00183]embedded image [00184]embedded image [00185]embedded image [00186]embedded image [00187]embedded image

    [0289] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, L.sup.2 is absent, —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O)(NR.sup.3)—, —S(O).sub.2—NR.sup.3—, —NR.sup.3—C.sub.1-6 haloalkylenyl, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C.sub.1-6 alkylenyl-S(O)—, —C.sub.1-6 alkylenyl-S(O).sub.2—, —C(O)—(NR.sup.3).sub.s—, —(NR.sup.3).sub.s—C(O)—, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. It is understood that L.sup.2 is a bivalent moiety in any of formula I, II, II′ or any other formulae provided herein. That is, reference to a particular L.sup.2 group is intended to refer to a bivalent variation of the referenced group.

    [0290] In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—S(O)—(NR.sup.3)—, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C(O)—(NR.sup.3).sub.s—, —NR.sup.3—C(O)—, or an optionally substituted bivalent moiety selected from —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-,—(NR.sup.3).sub.s—S(O)—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—C.sub.0-6 alkylenyl, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.3-6 cycloalkyl, —NR.sup.3—C.sub.0-6 alkylenyl, —C.sub.1-6 alkylenyl-S(O)—(NR.sup.3).sub.s—, —C.sub.1-6 alkylenyl-S(O).sub.2—(NR.sup.3).sub.s—, 2- to 6-membered heteroaliphatic, and 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0291] In some embodiments, L.sup.2 is absent.

    [0292] In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—S(O)—(NR.sup.3)—. In some embodiments, L.sup.2 is S(O)—(NR.sup.3)—. In some embodiments, L.sup.2 is S(O)—(NH)—. In some embodiments, L.sup.2 is S(O)—N(C.sub.1-6 aliphatic)-. In some embodiments, L.sup.2 is S(O)—N(CH.sub.3)—In some embodiments, L.sup.2 is —(NR.sup.3)—S(O)—(NR.sup.3)—.

    [0293] In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—. In some embodiments, L.sup.2 is S(O).sub.2—(NR.sup.3)—. In some embodiments, L.sup.2 is S(O).sub.2—(NH)—. In some embodiments, L.sup.2 is S(O).sub.2—N(C.sub.1-6 aliphatic)-. In some embodiments, L.sup.2 is S(O).sub.2—N(CH.sub.3)—In some embodiments, L.sup.2 is —(NR.sup.3)—S(O).sub.2—(NR.sup.3)—.

    [0294] In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—P(O)(R.sup.3)—. In some embodiments, L.sup.2 is —P(O)(R.sup.3)—. In some embodiments, L.sup.2 is —(NR.sup.3)—P(O)(R.sup.3)—. In some embodiments, L.sup.2 is —P(O)(CH.sub.3)—. In some embodiments, L.sup.2 is —NH—P(O)(CH.sub.3)—.

    [0295] In some embodiments, L.sup.2 is —C(O)—(NR.sup.3).sub.s—. In some embodiments, L.sup.2 is —C(O)—NH—. In some embodiments, L.sup.2 is —C(O)—. In some embodiments, L.sup.2 is —N(R.sup.3)—C(O)—.

    [0296] In some embodiments, L.sup.2 is —NR.sup.3—C(O)—. In some embodiments, L.sup.2 is —NH—C(O)—.

    [0297] In some embodiments, L.sup.2 is optionally substituted —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted S(O)—C.sub.0-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —(NR.sup.3).sub.s—S(O)—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —S(O)—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—S(O)—. In some embodiments, L.sup.2 is —S(O)—. In some embodiments, L.sup.2 is —NR.sup.3—S(O)—. In some embodiments, L.sup.2 is —NH—S(O)—. In some embodiments, L.sup.2 is —N(CH.sub.3)—S(O)—.

    [0298] In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—S(O).sub.2— C.sub.0-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted S(O).sub.2—C.sub.0-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —(NR.sup.3).sub.s—S(O).sub.2—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —S(O).sub.2—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—S(O).sub.2—. In some embodiments, L.sup.2 is —S(O).sub.2—. In some embodiments, L.sup.2 is —NR.sup.3—S(O).sub.2—. In some embodiments, L.sup.2 is —NH—S(O).sub.2—. In some embodiments, L.sup.2 is —N(CH.sub.3)—S(O).sub.2—. In some embodiments, L.sup.2 is —NH—S(O).sub.2—CH.sub.2—. In some embodiments, L.sup.2 is —NH—S(O).sub.2—(CH.sub.2).sub.3—. In some embodiments, L.sup.2 is —NH—S(O).sub.2—. In some embodiments, L.sup.2 is —N(CH.sub.3)—S(O).sub.2—.

    [0299] In some embodiments, L.sup.2 is optionally substituted —(NR.sup.3).sub.s—S(O)—NR.sup.3—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted S(O)—NR.sup.3—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —NR.sup.3—S(O)—NR.sup.3—C.sub.1-6 alkylenyl.

    [0300] In some embodiments, L.sup.2 is optionally substituted —(NR.sup.3).sub.s—S(O).sub.2—NR.sup.3—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted S(O).sub.2—NR.sup.3—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —NR.sup.3—S(O).sub.2—NR.sup.3—C.sub.1-6 alkylenyl.

    [0301] In some embodiments, L.sup.2 is optionally substituted —NR.sup.3—C.sub.0-6 alkylenyl. In some embodiments, L.sup.2 is —NR—. In some embodiments, L.sup.2 is optionally substituted —NR.sup.3—C.sub.1-6 alkylenyl. In some embodiments, L.sup.2 is —NR.sup.3—C.sub.1-6 alkylenyl substituted with halogen; —(CH.sub.2).sub.0-4R.sup.º; and/or —(CH.sub.2).sub.0-4OR.sup.º. In some embodiments, L.sup.2 is optionally substituted —NR.sup.3—C.sub.1-3 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —NR.sup.3—C.sub.2 alkylenyl. In some embodiments, L.sup.2 is optionally substituted —NR.sup.3—C.sub.1 alkylenyl. In some embodiments, L.sup.2 is —NR.sup.3—CH.sub.2—. In some embodiments, L.sup.2 is —NH—CH.sub.2—. In some embodiments, L.sup.2 is —N(CH.sub.3)—CH.sub.2—. In some embodiments, L.sup.2 is —NR.sup.3—CH(CH.sub.3)—. In some embodiments, L.sup.2 is —NH—CH(CH.sub.3)—. In some embodiments, L.sup.2 is —N(CH.sub.3)—CH(CH.sub.3)—. In some embodiments, L.sup.2 is —NH—CH(CF.sub.3)—.

    [0302] In some embodiments, L.sup.2 is —NR.sup.3—C.sub.1-6 haloalkylenyl.

    [0303] In some embodiments, L.sup.2 is optionally substituted —C.sub.1-6 alkylenyl-S(O)—(NR.sup.3).sub.s—. In some embodiments, L.sup.2 is optionally substituted —C.sub.1-6 alkylenyl-S(O)—. In some embodiments, L.sup.2 is optionally substituted —C.sub.1-6 alkylenyl-S(O)—(NR.sup.3)—. In some embodiments, L.sup.2 is —CH.sub.2—S(O)—.

    [0304] In some embodiments, L.sup.2 is optionally substituted —C.sub.1-6 alkylenyl-S(O).sub.2—. In some embodiments, L.sup.2 is optionally substituted —C.sub.1-3 alkylenyl-S(O).sub.2—. In some embodiments, L.sup.2 is optionally substituted —C.sub.1 alkylenyl-S(O).sub.2—. In some embodiments, L.sup.2 is —CH.sub.2—S(O).sub.2. In some embodiments, L.sup.2 is —CH(CH.sub.3)—S(O).sub.2—. In some embodiments, L.sup.2 is —C(CH.sub.3).sub.2—S(O).sub.2—. In some embodiments, L.sup.2 is:

    ##STR00188##

    [0305] In some embodiments, L.sup.2 is:

    ##STR00189##

    [0306] In some embodiments, L.sup.2 is —C(O)—(NR 3).sub.s—. In some embodiments, L.sup.2 is —C(O)—NH—. In some embodiments, L.sup.2 is —C(O)—N(CH.sub.3)—.

    [0307] In some embodiments, L.sup.2 is —(NR.sup.3).sub.s—C(O)—. In some embodiments, L.sup.2 is —(NR.sup.3)—C(O)—. In some embodiments, L.sup.2 is —NH—C(O)—. In some embodiments, L.sup.2 is —N(C.sub.1-6 aliphatic)-C(O)—. In some embodiments, L.sup.2 is —N(CH.sub.3)—C(O)—. In some embodiments, L.sup.2 is —C(O)—.

    [0308] In some embodiments, L.sup.2 is optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 4- to 6-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 4-membered monocyclic heterocyclyl comprising 1 heteroatom selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 5-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 6-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0309] In some embodiments, L.sup.2 is optionally substituted 8- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 8-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 9-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 10-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 11-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L.sup.2 is optionally substituted 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0310] In some embodiments, L.sup.2 is 2- to 6-membered heteroliphatic. In some embodiments, L.sup.2 is —CH(CH.sub.3)—S—.

    [0311] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted L.sup.2 group is halogen; —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º. In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted L.sup.2 group is halogen or C.sub.1-6 aliphatic.

    [0312] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic aryl, and C.sub.3-12 cycloalkyl, wherein V is substituted with (R.sup.6).sub.m.

    [0313] In some embodiments, V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, and 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein V is substituted with (R.sup.6).sub.m.

    [0314] As defined generally above for each of formula I, II, and II′, V is substituted with (R.sup.6).sub.m. As defined generally above, m is 0, 1, 2, 3, or 4. That is, in some embodiments, V is substituted with 0, 1, 2, 3, or 4 R.sup.6. In some embodiments, V is unsubstituted (i.e., m is 0). In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

    [0315] In some embodiments, V is C.sub.1-6 aliphatic. In some embodiments, V is C.sub.1-6 alkyl. In some embodiments, V is selected from methyl, ethyl, propyl, butyl, propyl, and hexyl.

    [0316] In some embodiments, V is C.sub.6-12 aryl (e.g., monocyclic or bicyclic). In some embodiments, V is phenyl. In some embodiments, V is naphthalenyl.

    [0317] In some embodiments, V is C.sub.3-12 cycloaliphatic (e.g., monocyclic or polycyclic). In some embodiments, V is C.sub.3-12 cycloalkyl (e.g., monocyclic or polycyclic). In some embodiments, V is C.sub.3-6 monocyclic cycloalkyl. In some embodiments, V is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, V is cyclopropyl. In some embodiments, V is cyclobutyl. In some embodiments, V is cyclopentyl. In some embodiments, V is cyclohexyl. In some embodiments, V is C.sub.5-1.sub.2 polycyclic cycloalkyl. In some embodiments, V is adamantyl.

    [0318] In some embodiments, V is 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 4- to 6-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 4-membered heterocyclic comprising 1 heteroatom selected from N, O, and S. In some embodiments, V is 5-membered heterocyclic comprising 1 to 4 heteroatom selected from N, O, and S. In some embodiments, V is 6-membered heterocyclic comprising 1 to 4 heteroatom selected from N, O, and S. In some embodiments, V is morpholinyl. In some embodiments, V is piperazinyl. In some embodiments, V is piperidinyl.

    [0319] In some embodiments, V is 7- to 12-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 7-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 8-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 9-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 10-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 11-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 12-membered polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0320] In some embodiments, V is 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 5-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is thiophenyl. In some embodiments, V is pyrazolyl. In some embodiments, V is 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is pyridyl.

    [0321] In some embodiments, V is 7- to 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 7-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 8-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 9-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 11-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is 12-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, V is indolyl.

    [0322] As defined generally above for compounds of formulae I, I′, II, II′, or any other formulae provided herein, each R.sup.6 is independently selected from halo, S(O)—R.sup.5, S(O).sub.2—R.sup.5, S(O)(NH)—R.sup.5, —CN, —C(O)—R.sup.5, —C(O)O—R.sup.5, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, or an optionally substituted group selected from O—C.sub.1-6 alkyl, C.sub.1-6 alkyl, and C.sub.6-12 aryl.

    [0323] In some embodiments, each R.sup.6 is independently selected from halo, oxo, —SF.sub.5, —S(O)—R.sup.5, S(O).sub.2—R.sup.5, —S(O)(NH)—R.sup.5, —S(O).sub.2—(NH)—R.sup.5, —S(O)—N(R.sup.5).sub.2, —S(O).sub.2—N(R.sup.5).sub.2, —CN, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, —O—R.sup.5, or an optionally substituted group selected from C.sub.1-6 aliphatic, S—C.sub.1-6 aliphatic, 2- to 12-membered heteroaliphatic, —C.sub.0-6 alkylenyl-C(O)—R.sup.5, —C.sub.0-6 alkylenyl-C(O)O—R.sup.5, C.sub.6-12 aryl, C.sub.3-12 cycloaliphatic, and 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0324] In some embodiments, R.sup.6 is halo, S(O)—R.sup.5, S(O).sub.2—R.sup.5, or an optionally substituted C.sub.1-6 aliphatic.

    [0325] In some embodiments, R.sup.6 is halo. In some embodiments, R.sup.6 is chloro, fluoro, bromo, or iodo. In some embodiments, R.sup.6 is fluoro. In some embodiments, R.sup.6 is chloro. In some embodiments, R.sup.6 is bromo. In some embodiments, R.sup.6 is iodo.

    [0326] In some embodiments, R.sup.6 is oxo.

    [0327] In some embodiments, R.sup.6 is SF.sub.5.

    [0328] In some embodiments, R.sup.6 is —S(O)—R.sup.5. In some embodiments, R.sup.6 is optionally substituted —S(O)—C.sub.1-6 aliphatic. In some embodiments, R.sup.6 is —S(O)—CH.sub.3.

    [0329] In some embodiments, R.sup.6 is —S(O).sub.2—R.sup.5. In some embodiments, R.sup.6 is optionally substituted —S(O).sub.2—C.sub.1-6 aliphatic. In some embodiments, R.sup.6 is —S(O).sub.2—CH.sub.3. In some embodiments, R.sup.6 is —S(O).sub.2—CH.sub.2CH.sub.3. In some embodiments, R.sup.6 is —S(O).sub.2—CHF.sub.2. In some embodiments, R.sup.6 is —S(O).sub.2—CF.sub.3.

    [0330] In some embodiment, R.sup.6 is —S(O)—N(R.sup.5).sub.2. In some embodiments, R.sup.6 is optionally substituted —S(O)—N(C.sub.1-6 aliphatic).sub.2. In some embodiments, R.sup.6 is —S(O)—N(CH.sub.3).sub.2. In some embodiments, R.sup.6 is —S(O)—NH(C.sub.1-6 aliphatic). In some embodiments, R.sup.6 is —S(O)—NH—CH.sub.3.

    [0331] In some embodiment, R.sup.6 is —S(O).sub.2—N(R.sup.5).sub.2. In some embodiments, R.sup.6 is optionally substituted —S(O).sub.2—N(C.sub.1-6 aliphatic).sub.2. In some embodiments, R.sup.6 is —S(O).sub.2—N(CH.sub.3).sub.2. In some embodiments, R.sup.6 is —S(O).sub.2—NH(C.sub.1-6 aliphatic). In some embodiments, R.sup.6 is —S(O).sub.2—NH—CH.sub.3.

    [0332] In some embodiments, R.sup.6 is —CN.

    [0333] In some embodiments, R.sup.6 is optionally substituted —C.sub.0-6 alkylenyl-C(O)—R.sup.5. In some embodiments, R.sup.6 is optionally substituted —C.sub.1-6 alkylenyl-C(O)—R.sup.5. In some embodiments, R.sup.6 is —C(O)—R.sup.5. In some embodiments, R.sup.6 is —C(O)—CH.sub.3. In some embodiments, R.sup.6 is —C(O)—CH(CH.sub.3).sub.2. In some embodiments, R.sup.6 is —C(O)—CF.sub.3. In some embodiments, R.sup.6 is —C(O)-pyrolidinyl.

    [0334] In some embodiments, R.sup.6 is optionally substituted —C.sub.0-6 alkylenyl-C(O)O—R.sup.5. In some embodiments, R.sup.6 is optionally substituted —C(O)O—C.sub.1-6 aliphatic. In some embodiments, R.sup.6 is —C(O)O—CH.sub.3. In some embodiments, R.sup.6 is —C(O)O—CH.sub.2CH.sub.3. In some embodiments, R.sup.6 is —C(CH.sub.3).sub.2—C(O)O—CH.sub.3.

    [0335] In some embodiments, R.sup.6 is —C(O)—NH(R.sup.5). In some embodiments, R.sup.6 is —C(O)—NH(CH.sub.3). In some embodiments, R.sup.6 is —C(O)—NH-cyclopropyl.

    [0336] In some embodiments, R.sup.6 is —C(O)—N(R.sup.5).sub.2. In some embodiments, R.sup.6 is —C(O)—N(CH.sub.3).sub.2.

    [0337] In some embodiments, R.sup.6 is —P(O)(R.sup.5).sub.2. In some embodiments, R.sup.6 is —P(O)(CH.sub.3).sub.2.

    [0338] In some embodiments, R.sup.6 is —O—R.sup.5. In some embodiments, R.sup.6 is —O-cyclopentyl. In some embodiments, R.sup.6 is optionally substituted O—C.sub.1-6 aliphatic. In some embodiments, R.sup.6 is optionally substituted O—C.sub.1-6 alkyl. In some embodiments, R.sup.6 is O—CH.sub.3. In some embodiments, R.sup.6 is O—CH.sub.2CH.sub.3. In some embodiments, R.sup.6 is O—CH.sub.2—CH.sub.2—CH.sub.3. In some embodiments, R.sup.6 is O—CF.sub.3. In some embodiments, R.sup.6 is O—CH(CH.sub.3).sub.2. In some embodiments, R.sup.6 is —O—CH.sub.2—CF.sub.3. In some embodiments, R.sup.6 is —O—CHF.sub.2.

    [0339] In some embodiments, R.sup.6 is optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.6 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.6 is optionally substituted C.sub.1-4 alkyl. In some embodiments, R.sup.6 is methyl. In some embodiments, R.sup.6 is ethyl. In some embodiments, R.sup.6 is propyl. In some embodiments, R.sup.6 is iso-propyl. In some embodiments, R.sup.6 is butyl. In some embodiments, R.sup.6 is tert-butyl. In some embodiments, R.sup.6 is pentyl. In some embodiments, R.sup.6 is neo-pentyl. In some embodiments, R.sup.6 is —CH.sub.2F. In some embodiments, R.sup.6 is —CHF.sub.2. In some embodiments, R.sup.6 is CF.sub.3. In some embodiments, R.sup.6 is —CH.sub.2—CF.sub.3. In some embodiments, R.sup.6 is —CF.sub.2—CH.sub.3. In some embodiments, R.sup.6 is —CF.sub.2—CF.sub.3. In some embodiments, R.sup.6 is —C(CH.sub.3).sub.2—CF.sub.3. In some embodiments, R.sup.6 is —C(CH.sub.3).sub.2—CN.

    [0340] In some embodiments, R.sup.6 is optionally substituted S—C.sub.1-6 aliphatic. In some embodiments, R.sup.6 is S—CH.sub.3.

    [0341] In some embodiments, R.sup.6 is optionally substituted 2- to 12-membered heteroaliphatic. In some embodiments, R.sup.6 is —C(CH.sub.3).sub.2—OCH.sub.3. In some embodiments, R.sup.6 is —O—CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.2—O—CH.sub.3. In some embodiments, R.sup.6 is —O—CH.sub.2—CH.sub.2—O—CH.sub.2—CH.sub.2—O—CH.sub.3. In some embodiments, R.sup.6 is —CF.sub.2—CF.sub.2—O—CH.sub.3.

    [0342] In some embodiments, R.sup.6 is optionally substituted C.sub.6-12 aryl. In some embodiments, R.sup.6 is phenyl.

    [0343] In some embodiments, R.sup.6 is optionally substituted C.sub.3-12 cycloaliphatic. In some embodiments, R.sup.6 is optionally substituted C.sub.3-12 cycloalkyl. In some embodiments, R.sup.6 is cyclopropyl. In some embodiments, R.sup.6 is cyclobutyl. In some embodiments, R.sup.6 is cyclopentyl. In some embodiments, R.sup.6 is cyclohexyl.

    [0344] In some embodiments, R.sup.6 is 4- to 7-membered monocyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R.sup.6 is dioxolanyl.

    [0345] In some embodiments, a substituent on an optionally substituted carbon atom of an optionally substituted R.sup.6 is halo (e.g., bromo, chloro, fluoro, iodo), —(CH.sub.2).sub.0-4R.sup.º; —(CH.sub.2).sub.0-4OR.sup.º; —O(CH.sub.2).sub.0-4R.sup.º, —O—(CH.sub.2).sub.0-4C(O)OR.sup.º, OH, CN, or oxo, wherein R.sup.º is C.sub.1-6 aliphatic.

    [0346] As defined generally above for each of formula I, II, and II′, each R.sup.5 is independently selected from C.sub.1-6 alkyl, —N(R.sup.3).sub.2, —O—C.sub.1-6 alkyl, C(O)—C.sub.1-6 alkyl, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R.sup.5 is optionally substituted with one or more substituents selected from halo, OH, and 2- to 12-membered heteroaliphatic.

    [0347] In some embodiments, each R.sup.5 is —N(R.sup.3).sub.2 or an optionally substituted group selected from C.sub.1-6 aliphatic, P(O)(C.sub.1-6 aliphatic).sub.2, C.sub.3-12 cycloaliphatic, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S.

    [0348] In some embodiments, R.sup.5 is —N(R.sup.3).sub.2. In some embodiments, R.sup.5 is optionally substituted —N(C.sub.1-6 aliphatic).sub.2. In some embodiments, R.sup.5 is optionally substituted —NH(C.sub.1-6 aliphatic). In some embodiments, R.sup.5 is —NH.sub.2. In some embodiments, R.sup.5 is —NH(CH.sub.3). In some embodiments, R.sup.5 is —N(CH.sub.3).sub.2.

    [0349] In some embodiments, R.sup.5 is optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.5 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.5 is C.sub.1-6 alkyl, wherein R.sup.5 is optionally substituted with one or more substituents selected from halo, OH, and 2- to 12-membered heteroaliphatic.

    [0350] In some embodiments, R.sup.5 is optionally substituted P(O)(C.sub.1-6 aliphatic).sub.2.

    [0351] In some embodiments, R.sup.5 is optionally substituted C.sub.3-12 cycloaliphatic. In some embodiments, R.sup.5 is cyclopentyl. In some embodiments, R.sup.5 is C.sub.3-12 cycloaliphatic, wherein R.sup.5 is optionally substituted with one or more substituents selected from halo, OH, and 2- to 12-membered heteroaliphatic.

    [0352] In some embodiments, R.sup.5 is 5- to 12-membered heterocyclyl (e.g., monocyclic or polycyclic) comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R.sup.5 is optionally substituted with one or more substituents selected from halo and OH.

    [0353] In some embodiments, V is selected from Table V:

    TABLE-US-00004 TABLE V [00190]embedded image [00191]embedded image [00192]embedded image [00193]embedded image [00194]embedded image [00195]embedded image [00196]embedded image [00197]embedded image [00198]embedded image [00199]embedded image [00200]embedded image [00201]embedded image [00202]embedded image [00203]embedded image [00204]embedded image [00205]embedded image [00206]embedded image [00207]embedded image [00208]embedded image [00209]embedded image [00210]embedded image [00211]embedded image [00212]embedded image [00213]embedded image [00214]embedded image [00215]embedded image [00216]embedded image [00217]embedded image [00218]embedded image [00219]embedded image [00220]embedded image [00221]embedded image [00222]embedded image [00223]embedded image [00224]embedded image [00225]embedded image [00226]embedded image [00227]embedded image [00228]embedded image [00229]embedded image [00230]embedded image [00231]embedded image [00232]embedded image [00233]embedded image [00234]embedded image [00235]embedded image [00236]embedded image [00237]embedded image [00238]embedded image [00239]embedded image [00240]embedded image [00241]embedded image [00242]embedded image [00243]embedded image [00244]embedded image [00245]embedded image [00246]embedded image [00247]embedded image [00248]embedded image [00249]embedded image [00250]embedded image [00251]embedded image [00252]embedded image [00253]embedded image [00254]embedded image [00255]embedded image [00256]embedded image [00257]embedded image [00258]embedded image [00259]embedded image [00260]embedded image [00261]embedded image [00262]embedded image [00263]embedded image [00264]embedded image [00265]embedded image [00266]embedded image [00267]embedded image [00268]embedded image [00269]embedded image [00270]embedded image [00271]embedded image [00272]embedded image [00273]embedded image [00274]embedded image [00275]embedded image [00276]embedded image [00277]embedded image [00278]embedded image [00279]embedded image [00280]embedded image [00281]embedded image [00282]embedded image [00283]embedded image [00284]embedded image [00285]embedded image [00286]embedded image [00287]embedded image [00288]embedded image [00289]embedded image [00290]embedded image [00291]embedded image [00292]embedded image [00293]embedded image [00294]embedded image [00295]embedded image [00296]embedded image [00297]embedded image [00298]embedded image [00299]embedded image [00300]embedded image

    [0354] In some embodiments, the present application provides a compound of formula IIa-1:

    ##STR00301##

    or a pharmaceutically acceptable salt thereof, wherein Z, L.sup.1, Cy, L.sup.2, V, and R.sup.a are defined in classes and subclasses provided herein.

    [0355] In some embodiments, the present application provides a compound of formula IIa-2:

    ##STR00302##

    or a pharmaceutically acceptable salt thereof, wherein Z, L.sup.2, V, and R.sup.a are defined in classes and subclasses provided herein.

    [0356] In some embodiments, the present application provides a compound of formula IIa-3:

    ##STR00303##

    or a pharmaceutically acceptable salt thereof, wherein Z, Cy, R.sup.a, and R.sup.6 are defined in classes and subclasses provided herein.

    [0357] In some embodiments, the present application provides a compound of formula IIa-4:

    ##STR00304##

    or a pharmaceutically acceptable salt thereof, wherein Z, L.sup.1, Cy, R.sup.a, and R.sup.6 are defined in classes and subclasses provided herein.

    [0358] In some embodiments, the present application provides a compound of formula IIb-1:

    ##STR00305##

    or a pharmaceutically acceptable salt thereof, wherein Z, R.sup.6, and m are defined in classes and subclasses provided herein.

    [0359] In some embodiments, the present application provides a compound of formula IIc:

    ##STR00306##

    or a pharmaceutically acceptable salt thereof, wherein R.sup.2, R.sup.6, and q are defined in classes and subclasses provided herein.

    [0360] In some embodiments, the present application provides a compound of formula IId:

    ##STR00307##

    or a pharmaceutically acceptable salt thereof, wherein R.sup.a, Z, L.sup.1, R.sup.6 and m are defined in classes and subclasses provided herein.

    [0361] In some embodiments, the present application provides a compound of formula IId-1:

    ##STR00308##

    or a pharmaceutically acceptable salt thereof, wherein R.sup.a, Z, L.sup.1, Cy, R.sup.6 and m are defined in classes and subclasses provided herein.

    [0362] In some embodiments, the present application provides a compound of formula IId-2:

    ##STR00309##

    or a pharmaceutically acceptable salt thereof, wherein R.sup.a, Z, L.sup.1, Cy, R.sup.6 and m are defined in classes and subclasses provided herein.

    [0363] In some embodiments, the present application provides a compound of formula IId-3:

    ##STR00310##

    [0364] or a pharmaceutically acceptable salt thereof, wherein R.sup.a, Z, L.sup.1, Cy, R.sup.6 and m are defined in classes and subclasses provided herein. It is to be understood that the above embodiments may be combined together, as if each and every combination were specifically and individually listed.

    [0365] In some embodiments, the present application provides a compound of formula IIe:

    ##STR00311##

    or a pharmaceutically acceptable salt thereof, wherein Z, L.sup.1, L.sup.2, V, and R.sup.a are defined in classes and subclasses provided herein.

    [0366] In some embodiments, a compound of the present disclosure is selected from Table A:

    TABLE-US-00005 TABLE A Structure Compound No. [00312]embedded image A-1 [00313]embedded image A-2 [00314]embedded image A-3 [00315]embedded image A-4 [00316]embedded image A-5 [00317]embedded image A-6 [00318]embedded image A-7 [00319]embedded image A-8 [00320]embedded image A-9 [00321]embedded image A-10 [00322]embedded image A-11 [00323]embedded image A-12 [00324]embedded image A-14 [00325]embedded image A-15 [00326]embedded image A-16 [00327]embedded image A-17 [00328]embedded image A-18 [00329]embedded image A-19 [00330]embedded image A-20 [00331]embedded image A-21 [00332]embedded image A-22 [00333]embedded image A-23 [00334]embedded image A-25 [00335]embedded image A-26 [00336]embedded image A-27 [00337]embedded image A-28 [00338]embedded image A-29 [00339]embedded image A-30 [00340]embedded image A-31 [00341]embedded image A-32 [00342]embedded image A-33 [00343]embedded image A-34 [00344]embedded image A-35 [00345]embedded image A-36 [00346]embedded image A-37 [00347]embedded image A-38 [00348]embedded image A-39 [00349]embedded image A-40 [00350]embedded image A-41 [00351]embedded image A-42 [00352]embedded image A-43 [00353]embedded image A-44 [00354]embedded image A-45 [00355]embedded image A-46 [00356]embedded image A-47 [00357]embedded image A-48 [00358]embedded image A-49 [00359]embedded image A-50 [00360]embedded image A-51 [00361]embedded image A-52 [00362]embedded image A-53 [00363]embedded image A-54 [00364]embedded image A-55 [00365]embedded image A-56 [00366]embedded image A-57 [00367]embedded image A-58 [00368]embedded image A-59 [00369]embedded image A-60 [00370]embedded image A-61 [00371]embedded image A-62 [00372]embedded image A-63 [00373]embedded image A-64 [00374]embedded image A-65 [00375]embedded image A-66 [00376]embedded image A-67 [00377]embedded image A-68 [00378]embedded image A-69 [00379]embedded image A-70 [00380]embedded image A-71 [00381]embedded image A-72 [00382]embedded image A-73 [00383]embedded image A-74 [00384]embedded image A-75 [00385]embedded image A-76 [00386]embedded image A-77 [00387]embedded image A-78 [00388]embedded image A-79 [00389]embedded image A-80 [00390]embedded image A-81 [00391]embedded image A-82 [00392]embedded image A-83 [00393]embedded image A-84 [00394]embedded image A-85 [00395]embedded image A-86 [00396]embedded image A-87 [00397]embedded image A-88 [00398]embedded image A-89 [00399]embedded image A-91 [00400]embedded image A-92 [00401]embedded image A-93 [00402]embedded image A-94 [00403]embedded image A-95 [00404]embedded image A-96 [00405]embedded image A-97 [00406]embedded image A-98 [00407]embedded image A-99 [00408]embedded image A-100 [00409]embedded image A-101 [00410]embedded image A-102 [00411]embedded image A-103 [00412]embedded image A-104 [00413]embedded image A-105 [00414]embedded image A-106 [00415]embedded image A-107 [00416]embedded image A-108 [00417]embedded image A-109 [00418]embedded image A-110 [00419]embedded image A-111 [00420]embedded image A-112 [00421]embedded image A-114 [00422]embedded image A-115 [00423]embedded image A-116 [00424]embedded image A-117 [00425]embedded image A-118 [00426]embedded image A-119 [00427]embedded image A-120 [00428]embedded image A-121 [00429]embedded image A-122 [00430]embedded image A-123 [00431]embedded image A-124 [00432]embedded image A-128 [00433]embedded image A-129 [00434]embedded image A-130 [00435]embedded image A-131 [00436]embedded image A-132 [00437]embedded image A-133 [00438]embedded image A-134 [00439]embedded image A-135 [00440]embedded image A-136 [00441]embedded image A-137 [00442]embedded image A-138 [00443]embedded image A-139 [00444]embedded image A-140 [00445]embedded image A-141 [00446]embedded image A-142 [00447]embedded image A-143 [00448]embedded image A-144 [00449]embedded image A-145 [00450]embedded image A-146 [00451]embedded image A-147 [00452]embedded image A-148 [00453]embedded image A-149 [00454]embedded image A-150 [00455]embedded image A-151 [00456]embedded image A-152 [00457]embedded image A-153 [00458]embedded image A-154 [00459]embedded image A-155 [00460]embedded image A-156 [00461]embedded image A-157 [00462]embedded image A-158 [00463]embedded image A-159 [00464]embedded image A-160 [00465]embedded image A-161 [00466]embedded image A-162 [00467]embedded image A-163 [00468]embedded image A-165 [00469]embedded image A-166 [00470]embedded image A-167 [00471]embedded image A-170 [00472]embedded image A-171 [00473]embedded image A-172 [00474]embedded image A-173 [00475]embedded image A-174 [00476]embedded image A-175 [00477]embedded image A-176 [00478]embedded image A-177 [00479]embedded image A-178 [00480]embedded image A-179 [00481]embedded image A-180 [00482]embedded image A-181 [00483]embedded image A-182 [00484]embedded image A-183 [00485]embedded image A-184 [00486]embedded image A-185 [00487]embedded image A-186 [00488]embedded image A-187 [00489]embedded image A-188 [00490]embedded image A-189 [00491]embedded 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    [0367] In some embodiments, a compound of the present disclosure is selected from Table B:

    TABLE-US-00006 TABLE B Compound No. Compound Name A-1 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}pyridine-3- sulfonamide A-2 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-1-methyl-1H- imidazole-4-sulfonamide A-3 N4-{2-[2-(4-chloro-2-fluorophenyl)ethynyl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-4 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-3- methoxybenzene-1-sulfonamide A-5 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-3-cyanobenzene- 1-sulfonamide A-6 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-1-methyl-1H- pyrazole-4-sulfonamide A-7 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-2,4-dimethyl-1,3- thiazole-5-sulfonamide A-8 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1- yl]phenyl}cyclohexanesulfonamide A-9 2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-N-[4- (dimethylsulfamoyl)phenyl]benzamide A-10 N4-{2-[4-(2-fluorophenyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-11 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-4- (dimethylsulfamoyl)benzamide A-12 N4-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-14 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}oxane-4- sulfonamide A-15 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-1-methyl-1H- pyrazole-5-sulfonamide A-16 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-1- methylpiperidine-4-sulfonamide A-17 1-acetyl-N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1- yl]phenyl}piperidine-4-sulfonamide A-18 N4-{5-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-1,3-dimethyl-1H- pyrazol-4-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-19 N4-{2-[1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-20 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}pyridine-2- sulfonamide A-21 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-1-methyl-1H- pyrazole-3-sulfonamide A-22 N4-{2-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-23 N4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-25 N4-{2-[(1R,5S)-3-(4-chloro-2-fluorophenyl)-3,8-diazabicyclo[3.2.1]octan-8- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-26 N4-{2-[5-(4-chloro-2-fluorophenyl)-2,5-diazabicyclo[2.2.2]octan-2- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-27 N4-{2-[3-(4-chloro-2-fluorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-28 N4-{2-[3-(4-chloro-2-fluorophenyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-29 N4-{5-[1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl]-1,3- dimethyl-1H-pyrazol-4-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-30 N4-{2-[6-(4-chloro-2-fluorophenyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-31 N4-{2-[5-(4-chloro-2-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-32 N4-{2-[4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-33 N4-{5-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-1,3-dimethyl-1H- pyrazol-4-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-34 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-2- methoxypyridine-4-sulfonamide A-35 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-3-methyl-1,2- oxazole-4-sulfonamide A-36 N4-{5-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-1,3,4-thiadiazol-2-yl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-37 4-({4-[1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl]-3- methyl-1H-pyrazol-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-38 4-({4-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-3-methyl-1H-pyrazol-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-39 4-({4-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-2-methyl-1H-imidazol-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-40 N4-{4-[1-(2-fluorophenyl)piperidin-4-yl]-1-methyl-1H-pyrazol-3-yl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-41 ethyl 4-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1- yl]phenyl}sulfamoyl)benzoate A-42 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1- yl]phenyl}benzenesulfonamide A-43 N-{2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}morpholine-4- sulfonamide A-44 4-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}sulfamoyl)-N,N- dimethylbenzamide A-45 4-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}sulfamoyl)-N- cyclopropylbenzamide A-46 N4-{3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-47 N4-{2-[4-(4-chlorophenyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-48 4-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}sulfamoyl)-N- methylbenzamide A-49 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-(pyrrolidine-1- carbonyl)benzene-1-sulfonamide A-50 4-({4-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]-3-methyl-1H-pyrazol-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-51 N4-{2-[4-(3-fluoropyridin-2-yl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-52 N4-[2-(4-cyclopropylpiperazin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-53 N4-[2-(4-cyclohexylpiperazin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-54 N1,N1-dimethyl-N4-[2-(4-methylpiperazin-1-yl)phenyl]benzene-1,4- disulfonamide A-55 N4-{4-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-1-methyl-1H-pyrazol-3- yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-56 N4-{2-[3-(4-chlorophenyl)azetidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-57 N4-{2-[4-(3-fluoropyridin-4-yl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-58 N1,N1-dimethyl-N4-(2-{5-methyl-octahydropyrrolo[3,4-c]pyrrol-2- yl}phenyl)benzene-1,4-disulfonamide A-59 N4-{5-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-1-methyl-1H-1,2,4- triazol-3-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-60 N1,N1-dimethyl-N4-{2-[4-(1-methyl-1H-pyrazol-4-yl)piperidin-1- yl]phenyl}benzene-1,4-disulfonamide A-61 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2-methyl-1-oxo- 2,3-dihydro-1H-isoindole-5-sulfonamide A-62 4-({3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]-1H-1,2,4-triazol-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-63 4-({3-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H- 1,3-benzodiazol-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-64 N4-{5-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-1,3,4-thiadiazol-2-yl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-65 N4-{4-[1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl]-3- methyl-1,2-oxazol-5-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-66 4-(4-chloro-2-fluorophenyl)-1-(2- {[methyl(phenyl)phosphoryl]amino}phenyl)piperidine A-67 4-({3-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H- imidazol-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-68 N4-{3-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-1-methyl-1H-1,2,4- triazol-5-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-69 N1,N1-dimethyl-N4-{2-[(1s,4s)-4-(4-chloro-2- fluorophenyl)cyclohexyl]phenyl}benzene-1,4-disulfonamide A-70 N1,N1-dimethyl-N4-{2-[(1r,4r)-4-(4-chloro-2- fluorophenyl)cyclohexyl]phenyl}benzene-1,4-disulfonamide A-71 4-({3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]-2-oxopyrrolidin-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-72 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-methylbenzene- 1-sulfonamide A-73 4-chloro-N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}benzene- 1-sulfonamide A-74 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-fluorobenzene- 1-sulfonamide A-75 N4-{4-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-1,3-dimethyl-1H- pyrazol-5-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-76 2-chloro-N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}benzene- 1-sulfonamide A-77 3-chloro-N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}benzene- 1-sulfonamide A-78 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-3-fluorobenzene- 1-sulfonamide A-79 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2-fluorobenzene- 1-sulfonamide A-80 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-3,4- difluorobenzene-1-sulfonamide A-81 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,6- difluorobenzene-1-sulfonamide A-82 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,5- difluorobenzene-1-sulfonamide A-83 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4- (trifluoromethyl)benzene-1-sulfonamide A-84 N4-{4-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-1-methyl-1H-imidazol-2- yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-85 2-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro-1λ.sup.6,2- benzothiazole-1,1,3-trione A-86 4-({3-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-2-oxoimidazolidin-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-87 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,4- difluorobenzene-1-sulfonamide A-88 N-(2-{5-chloro-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridin]-1′-yl}phenyl)-4- methylbenzene-1-sulfonamide A-89 4-({4-[4-(4-chloro-2-fluorophenyl)-2-oxopiperazin-1-yl]-2-methyl-1H- imidazol-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-91 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-3,5- difluorobenzene-1-sulfonamide A-92 4-methyl-N-{2-[4-(pyridin-2-yl)piperidin-1-yl]phenyl}benzene-1- sulfonamide A-93 N-{2-[3-(4-chloro-2-fluorophenyl)-1H-pyrrol-1-yl]phenyl}-4- methylbenzene-1-sulfonamide A-94 2-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro-1λ.sup.6,2- benzothiazole-1,1-dione A-95 N4-{3-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-1-methyl-1H-1,2,4- triazol-5-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-96 4-({3-[1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl]-1H-pyrazol-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-97 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3- difluorobenzene-1-sulfonamide A-98 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4- methanesulfonylbenzene-1-sulfonamide A-99 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4- methoxybenzene-1-sulfonamide A-100 N-{2-[4-(2,4-difluorophenyl)piperidin-1-yl]phenyl}-4- methanesulfonylbenzene-1-sulfonamide A-101 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-cyanobenzene- 1-sulfonamide A-102 N-{2-[3-(4-chloro-2-fluorophenyl)pyrrolidin-1-yl]phenyl}-4- methylbenzene-1-sulfonamide A-103 N-{2-[4-(5-chloropyridin-2-yl)piperidin-1-yl]phenyl}-4-methylbenzene-1- sulfonamide A-104 N1-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1,N4,N4- trimethylbenzene-1,4-disulfonamide A-105 N4-{4-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-3-methyl-1,2-oxazol-5- yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-106 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2- (hydroxymethyl)benzene-1-sulfonamide A-107 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N,4- dimethylbenzene-1-sulfonamide A-108 2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]-N-[4- (dimethylsulfamoyl)phenyl]benzene-1-sulfonamide A-109 N4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]pyridin-3-yl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-110 N-{2-[4-(5-chloro-3-fluoropyridin-2-yl)piperazin-1-yl]pyridin-3-yl}-4- methoxybenzene-1-sulfonamide A-111 2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]-N-(4-methylphenyl)benzene- 1-sulfonamide A-112 4-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}sulfamoyl)-N,N- dimethylbenzene-1-sulfonoimidamide A-114 N-{3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2-fluorobenzene- 1-sulfonamide A-115 N4-{2-[4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-116 N-{2-[4-(5-chloro-3-fluoropyridin-2-yl)piperazin-1-yl]pyridin-3-yl}-4- (trifluoromethoxy)benzene-1-sulfonamide A-117 N-{2-[4-(4-cyano-2-fluorophenyl)piperazin-1-yl]pyridin-3-yl}-4- methoxybenzene-1-sulfonamide A-118 N-{2-[4-(2,4-difluorophenyl)piperidin-1-yl]phenyl}-5-methoxypyridine-2- sulfonamide A-119 N-{2-[(1R,3S,5S)-3-(2-fluorophenyl)-8-azabicyclo[3.2.1]octan-8- yl]phenyl}-4-methylbenzene-1-sulfonamide A-120 N-{2-[(1R,3R,5S)-3-(2-fluorophenyl)-8-azabicyclo[3.2.1]octan-8- yl]phenyl}-4-methylbenzene-1-sulfonamide A-121 N4-{2-[(3R,5S)-4-(5-chloropyridin-2-yl)-3,5-dimethylpiperazin-1- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-122 N-{3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-3-fluorobenzene- 1-sulfonamide A-123 N-{2-[4-(2,4-difluorophenyl)piperidin-1-yl]phenyl}-6-methoxypyridine-3- sulfonamide A-124 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4- methanesulfonylbenzene-1-sulfonamide A-128 N-{3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-fluorobenzene- 1-sulfonamide A-129 N4-{6-chloro-3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]pyridazin-4-yl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-130 N-{3-[4-(5-chloro-3-fluoropyridin-2-yl)piperazin-1-yl]pyrazin-2-yl}-4- methoxybenzene-1-sulfonamide A-131 N-{2-[4-(3,5-difluoropyridin-2-yl)piperidin-1-yl]phenyl}-4- methanesulfonylbenzene-1-sulfonamide A-132 4-methanesulfonyl-N-{2-[4-(2,4,6-trifluorophenyl)piperidin-1- yl]phenyl}benzene-1-sulfonamide A-133 4-(4-chloro-2-fluorophenyl)-1-[2-(4- methylbenzenesulfonyl)phenyl]piperidine A-134 N4-{6-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]pyridin-2-yl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-135 N-{3-[4-(5-chloro-3-fluoropyridin-2-yl)piperazin-1-yl]pyridin-2-yl}-4- methoxybenzene-1-sulfonamide A-136 6-(difluoromethyl)-N-{2-[4-(2,4-difluorophenyl)piperidin-1- yl]phenyl}pyridine-3-sulfonamide A-137 5-(difluoromethyl)-N-{2-[4-(2,4-difluorophenyl)piperidin-1- yl]phenyl}pyridine-2-sulfonamide A-138 4-(4-chloro-2-fluorophenyl)-1-{2-[(4- methylbenzenesulfonyl)methyl]phenyl}piperidine A-139 N4-{3-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]pyridazin-4-yl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-140 N-{4-[4-(5-chloro-3-fluoropyridin-2-yl)piperazin-1-yl]-1-methyl-1H- indazol-5-yl}-4-methoxybenzene-1-sulfonamide A-141 N4-{2-[4-(2,4-difluorophenyl)-4-hydroxypiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-142 N-{2-[4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-1-yl]phenyl}-4- methanesulfonylbenzene-1-sulfonamide A-143 4-({2-[4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-1- yl]phenyl}sulfamoyl)-N,N-dimethylbenzene-1-sulfonoimidamide A-144 4-(4-chloro-2-fluorophenyl)-1-[2-(4- methylbenzenesulfinyl)phenyl]piperidine A-145 4-(4-chloro-2-fluorophenyl)-1-{2-[(4- methylbenzenesulfinyl)methyl]phenyl}piperidine A-146 4-{[3-(4-chloro-2-fluorophenyl)-4-methyl-1,2,3,4-tetrahydroquinoxalin-1- yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide A-147 N-{2-[4-(5-chloro-3-fluoropyridin-2-yl)piperidin-1-yl]phenyl}-4- methoxybenzene-1-sulfonamide A-148 N4-[2-(4-hydroxy-4-phenylpiperidin-1-yl)phenyl]-N1,N1-dimethylbenzene- 1,4-disulfonamide A-149 N4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-3-fluoro-N1,N1- dimethylbenzene-1,4-disulfonamide A-150 N4-{2-[4-amino-4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-151 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-methylbenzene- 1-sulfonoimidamide A-152 N-{2-[4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-1-yl]phenyl}-4- [iimino(methyl)oxo-λ.sup.6-sulfanyl]benzene-1-sulfonamide A-153 N-[4-(4-chloro-2-fluorophenyl)-1-{2-[4- (dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidin-4-yl]acetamide A-154 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]-5-fluorophenyl}-4- methanesulfonylbenzene-1-sulfonamide A-155 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]-4-fluorophenyl}-4- methanesulfonylbenzene-1-sulfonamide A-156 4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]benzenesulfonyl}-N,N- dimethylbenzene-1-sulfonamide A-157 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-(2,2,2-trifluoro- 1-hydroxyethyl)benzene-1-sulfonamide A-158 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-3-fluoro-4- (trifluoromethyl)benzene-1-sulfonamide A-159 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2-fluoro-4- (trifluoromethyl)benzene-1-sulfonamide A-160 N-{2-[4-(2,4-difluorophenyl)piperidin-1-yl]phenyl}-4- methanesulfinylbenzene-1-sulfonamide A-161 N4-{2-[4-(2,4-difluorophenyl)-4-(hydroxymethyl)piperidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-162 N4-{2-[3-(4-chloro-2-fluorophenyl)-3-hydroxyazetidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-163 4-(2,4-difluorophenyl)-1-{2-[4- (dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidine-4-carboxamide A-165 N-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]phenyl}-4- (dimethylphosphoryl)benzene-1-sulfonamide A-166 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4-[imino(methyl)oxo- λ.sup.6-sulfanyl]benzene-1-sulfonamide A-167 N-{2′,4′-difluoro-[1,1′-biphenyl]-2-yl}-4-methoxybenzene-1-sulfonamide A-170 4-[1-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}amino)-2,2,2- trifluoroethyl]-N,N-dimethylbenzene-1-sulfonamide A-171 4-{[3-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroquinoxalin-1- yl]sulfonyl}-N,N-dimethylbenzene-1-sulfonamide A-172 N-[4-(4-chloro-2-fluorophenyl)-1-{2-[4- (dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidin-4-yl]-N- methylacetamide A-173 N-{2-[4-(2,4-difluorophenyl)piperidin-1-yl]phenyl}-4- trifluoromethanesulfonylbenzene-1-sulfonamide A-174 N-{2-[4-(2,4-difluorophenyl)piperazin-1-yl]phenyl}-4- trifluoromethanesulfonylbenzene-1-sulfonamide A-175 N4-{2-[4-cyano-4-(2,4-difluorophenyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-176 N-{2-[4-(2,4-difluorophenyl)piperidin-1-yl]phenyl}-4- (dimethylphosphoryl)benzene-1-sulfonamide A-177 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4- (dimethylphosphoryl)benzene-1-sulfonamide A-178 N-{2-[4-(5-chloro-3-fluoropyridin-2-yl)piperazin-1-yl]phenyl}-4- trifluoromethanesulfonylbenzene-1-sulfonamide A-179 N4-[2-(4-{bicyclo[1.1.1]pentan-1-yl}piperazin-1-yl)phenyl]-N1,N1- dimethylbenzene-1,4-disulfonamide A-180 N-[2-(3,5-difluoropyridin-2-yl)phenyl]-4-methoxybenzene-1-sulfonamide A-181 4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]benzenesulfinyl}-N,N- dimethylbenzene-1-sulfonamide A-182 N2-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N5,N5- dimethylpyridine-2,5-disulfonamide A-183 N4-{2-[4-(2-chlorophenyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-184 N4-{2-[4-(4-chlorophenyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-185 4-difluoromethanesulfonyl-N-{2-[4-(2,4-difluorophenyl)piperidin-1- yl]phenyl}benzene-1-sulfonamide A-186 N-[2-(2,4-difluorophenoxy)phenyl]-4-methoxybenzene-1-sulfonamide A-187 N-{2-[(2,4-difluorophenyl)methoxy]phenyl}-4-methoxybenzene-1- sulfonamide A-188 N-(2-{3-[(2,4-difluorophenyl)(methyl)amino]azetidin-1-yl}phenyl)-4- methoxybenzene-1-sulfonamide A-189 N-(2-{4-[(2,4-difluorophenyl)(methyl)amino]piperidin-1-yl}phenyl)-4- methoxybenzene-1-sulfonamide A-190 4-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}methanesulfinyl)- N,N-dimethylbenzene-1-sulfonamide A-191 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-(2,2,2- trifluoroacetyl)benzene-1-sulfonamide A-192 N-{3-[4-(3,5-difluoropyridin-2-yl)piperidin-1-yl]pyridin-4-yl}-4- methoxybenzene-1-sulfonamide A-193 N-{4-[4-(3,5-difluoropyridin-2-yl)piperidin-1-yl]pyridin-3-yl}-4- methoxybenzene-1-sulfonamide A-194 N-(2-{4-[(2,4-difluorophenyl)methyl]piperazin-1-yl}phenyl)-4- methoxybenzene-1-sulfonamide A-195 N-(2-{4-[(2,4-difluorophenyl)methyl]piperidin-1-yl}phenyl)-4- methoxybenzene-1-sulfonamide A-196 N-{2-[4-(2,4-difluorophenoxy)piperidin-1-yl]phenyl}-4-methoxybenzene-1- sulfonamide A-197 N-(2-{3-[(2,4-difluorophenyl)methyl]pyrrolidin-1-yl}phenyl)-4- methoxybenzene-1-sulfonamide A-198 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4- (ethanesulfonyl)benzene-1-sulfonamide A-199 N-{2-[(2,4-difluorophenyl)(methyl)amino]phenyl}-4-methoxybenzene-1- sulfonamide A-200 N-{2-[3-(2,4-difluorophenoxy)azetidin-1-yl]phenyl}-4-methoxybenzene-1- sulfonamide A-201 N-(2-{3-[(2,4-difluorophenyl)(methyl)amino]pyrrolidin-1-yl}phenyl)-4- methoxybenzene-1-sulfonamide A-202 N-{2-[3-(2,4-difluorophenoxy)pyrrolidin-1-yl]phenyl}-4-methoxybenzene- 1-sulfonamide A-203 N-{2-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]phenyl}-4- methanesulfonylbenzene-1-sulfonamide A-204 N4-{2-[4-(4-chloro-2-fluorophenyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-205 N4-{2-[4-(2-chloro-4-fluorophenyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-206 N-{5-[4-(3,5-difluoropyridin-2-yl)piperidin-1-yl]pyridazin-4-yl}-4- methoxybenzene-1-sulfonamide A-207 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4- methoxymethanesulfonylbenzene-1-sulfonamide A-209 N4-{2-[4-(5-fluoropyridin-2-yl)-4-hydroxypiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-210 N4-{2-[4-(2-bromo-5-fluoropyridin-4-yl)-4-hydroxypiperidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-211 N4-{2-[4-(4-chloro-2-fluorophenyl)-4-(dimethylamino)piperidin-1- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-212 N4-{2-[4-(4-chloro-2-fluorophenyl)-4-(methylamino)piperidin-1- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-213 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4-(2-methylpropane-2- sulfonyl)benzene-1-sulfonamide A-214 4-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}methanesulfonyl)- N,N-dimethylbenzene-1-sulfonamide A-215 N4-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-216 4-(2,4-difluorophenyl)-1-{2-[4- (dimethylsulfamoyl)benzenesulfonamido]phenyl}-N-methylpiperidine-4- carboxamide A-217 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4-(morpholine-4- sulfonyl)benzene-1-sulfonamide A-218 N4-{2-[4-(2,4-difluorophenyl)-4-[(methylamino)methyl]piperidin-1- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-219 N-(2-{3-[(2,4-difluorophenyl)methyl]azetidin-1-yl}phenyl)-4- methoxybenzene-1-sulfonamide A-220 N-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-4-[(4-methylpiperazin- 1-yl)sulfonyl]benzene-1-sulfonamide A-221 N4-{2-[4-(2,4-difluorophenyl)-4-[(dimethylamino)methyl]piperidin-1- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-222 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-[1- (dimethylamino)-2,2,2-trifluoroethyl]benzene-1-sulfonamide A-223 N4-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-N1-(2-hydroxyethyl)- N1-methylbenzene-1,4-disulfonamide A-224 N4-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-N1-(2-hydroxy-2- methylpropyl)-N1-methylbenzene-1,4-disulfonamide A-225 N4-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-226 4-({2-[4-(2,6-difluorophenyl)piperidin-1-yl]-4-fluorophenyl}sulfamoyl)- N,N-dimethylbenzene-1-sulfonoimidamide A-227 N4-[2-(diethenylphosphoryl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-228 4-({2-[4-(2,6-difluorophenyl)piperidin-1-yl]-5-fluorophenyl}sulfamoyl)- N,N-dimethylbenzene-1-sulfonoimidamide A-229 4-({2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}methanesulfonyl)-N,N- dimethylbenzene-1-sulfonamide A-231 N4-(2-{4-[(dimethylamino)methyl]-4-(4-fluorophenyl)piperidin-1- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-232 N4-{2-[4-(4-fluorophenyl)-4-oxo-1,4λ.sup.5-azaphosphinan-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-241 4-[(1-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,2,2- trifluoroethyl)amino]-N,N-dimethylbenzene-1-sulfonamide A-243 N1-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-N1,N4,N4-trimethylbenzene-1,4-disulfonamide A-244 N1,N1-dimethyl-N4-(2-{2-methyl-1-oxo-2,8-diazaspiro[4.5]decan-8- yl}phenyl)benzene-1,4-disulfonamide A-245 N-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-4-methylbenzene-1-sulfonamide A-246 4-difluoromethanesulfonyl-N-(2-{6-fluoro-1-methyl-1,2- dihydrospiro[indole-3,4′-piperidin]-1′-yl}phenyl)benzene-1-sulfonamide A-247 N4-(4-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}-1- methyl-1H-indazol-5-yl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-251 N-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-4-methanesulfonylbenzene-1-sulfonamide A-252 N-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-4-methoxybenzene-1-sulfonamide A-253 N4-(2-{6-fluoro-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-254 4-(1-{2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}ethanesulfonyl)-N,N- dimethylbenzene-1-sulfonamide A-257 4-[(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)sulfamoyl]-N,N-dimethylbenzene-1-sulfonoimidamide A-258 N4-(2-{5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-259 2-(1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidin-4- yl)benzoic acid A-266 3-(1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidin-4- yl)benzoic acid A-267 4-(1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidin-4- yl)benzoic acid A-268 N4-(2-{6′-chloro-1′-methyl-1′,2′-dihydrospiro[piperidine-4,3′-pyrrolo[3,2- b]pyridin]-1-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-269 N1,N1-dimethyl-N4-(2-{1′-methyl-octahydrospiro[piperidine-4,3′- pyrrolo[3,2-b]pyridin]-1-yl}phenyl)benzene-1,4-disulfonamide A-271 N1,N1-dimethyl-N4-(2-{1′-methyl-1′,2′-dihydrospiro[piperidine-4,3′- pyrrolo(3,2-b]pyridin]-1-yl}phenyl)benzene-1,4-disulfonamide A-272 N1,N1-dimethyl-N4-(2-{4-[3-(2H-1,2,3,4-tetrazol-5-yl)phenyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-273 N1,N1-dimethyl-N4-(2-{4-[4-(1H-1,2,3,4-tetrazol-5-yl)phenyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-274 N-[3-chloro-2-(morpholin-4-yl)phenyl]-4-difluoromethanesulfonylbenzene- 1-sulfonamide A-275 N-[3-chloro-2-(morpholin-4-yl)phenyl]-4-methanesulfonylbenzene-1- sulfonamide A-276 N-[5-chloro-2-(morpholin-4-yl)phenyl]-4-(2-methylpropane-2- sulfonyl)benzene-1-sulfonamide A-277 N-[5-chloro-2-(morpholin-4-yl)phenyl]-4-difluoromethanesulfonylbenzene- 1-sulfonamide A-278 N-[3-chloro-2-(morpholin-4-yl)phenyl]-4-(2-methylpropane-2- sulfonyl)benzene-1-sulfonamide A-280 N1,N1-dimethyl-N4-(2-{4-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-281 N4-{2-[1-(dimethylamino)-8-azaspiro[4.5]decan-8-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-282 N1,N1-dimethyl-N4-(2-{1′-methyl-2′-oxo-1′,2′-dihydrospiro[piperidine-4,3′- pyrrolo[2,3-b]pyridin]-1-yl}phenyl)benzene-1,4-disulfonamide A-283 N4-{2-[4-(4-chloro-2-fluorophenyl)-2-oxopiperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-284 N-[5-chloro-2-(morpholin-4-yl)phenyl]-4-(dimethylphosphoryl)benzene-1- sulfonamide A-285 N1-[5-chloro-2-(morpholin-4-yl)phenyl]-N1,N4,N4-trimethylbenzene-1,4- disulfonamide A-286 N1-[3-chloro-2-(morpholin-4-yl)phenyl]-N1,N4,N4-trimethylbenzene-1,4- disulfonamide A-287 N-[3-chloro-2-(morpholin-4-yl)phenyl]-4-(dimethylphosphoryl)benzene-1- sulfonamide A-288 N-{3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-2,3- dihydro-1H-indene-5-sulfonamide A-289 N-[5-chloro-2-(4-ethylpiperazin-1-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide A-290 N4-[5-chloro-2-(morpholin-4-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-291 N-{5-chloro-2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]phenyl}-2,3- dihydro-1H-indene-5-sulfonamide A-292 N-{5-chloro-2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro- 1H-indene-5-sulfonamide A-293 N1,N1-dimethyl-N4-(2-{2-methyl-2,8-diazaspiro[4.5]decan-8- yl}phenyl)benzene-1,4-disulfonamide A-294 4-({3-[1-(4-chloro-2-fluorophenyl)piperidin-4-yl]-5,5-dimethyl-2,4- dioxoimidazolidin-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-295 N4-{2-[3-(dimethylamino)-2,3-dihydrospiro[indene-1,4′-piperidin]-1′- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-296 N4-{2-[6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-297 N-[3-chloro-2-(3-oxomorpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide A-298 N-{3-chloro-2-[4-(2,6-difluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro- 1H-indene-5-sulfonamide A-299 N-[5-chloro-2-(morpholin-4-yl)phenyl]-4-methanesulfonylbenzene-1- sulfonamide A-300 N-[3-chloro-2-(4-ethylpiperazin-1-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide hydrochloride A-301 N4-(2-{5-fluoro-2-methyl-3-oxo-2,3-dihydrospiro[isoindole-1,4′-piperidin]- 1′-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-302 N1,N1-dimethyl-N4-(2-{2-methyl-4-phenyl-2,8-diazaspiro[4.5]decan-8- yl}phenyl)benzene-1,4-disulfonamide A-303 N-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-4-(2-methylpropane-2-sulfonyl)benzene-1-sulfonamide A-304 N4-(2-{1-benzyl-6-fluoro-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-305 N4-(2-{6′-fluoro-1′-methyl-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-4- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-306 4-({4-[4-(4-chloro-2-fluorophenyl)-2-oxopiperazin-1-yl]-3-methyl-1H- pyrazol-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-307 N-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-4-methanesulfonyl-N-methylbenzene-1-sulfonamide A-308 ethyl 4-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}piperazine- 1-carboxylate A-309 methyl 4-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}piperazine- 1-carboxylate A-310 N4-(2-{5-fluoro-2-methyl-2,3-dihydrospiro[isoindole-1,4′-piperidin]-1′- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide; formic acid A-311 N4-[3-chloro-2-(morpholin-4-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-312 4-{[5-chloro-2-(morpholin-4-yl)phenyl]methanesulfonyl}-N,N- dimethylbenzene-1-sulfonamide A-313 N-{5-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3- dihydro-1H-indene-5-sulfonamide A-314 N-[5-chloro-2-(4-ethyl-2-oxopiperazin-1-yl)phenyl]-2,3-dihydro-1H-indene- 5-sulfonamide A-315 N-[3-chloro-2-(4-ethyl-2-oxopiperazin-1-yl)phenyl]-2,3-dihydro-1H-indene- 5-sulfonamide A-316 N-(5-chloro-2-{1-oxa-8-azaspiro[5.5]undecan-8-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-317 N-(5-chloro-2-{9,9-dioxo-1-oxa-9λ.sup.6-thia-4-azaspiro[5.5]undecan-4- yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide A-318 N1,N1-dimethyl-N4-(2-{2-methyl-1-oxo-4-phenyl-2,8- diazaspiro[4.5]decan-8-yl}phenyl)benzene-1,4-disulfonamide A-319 N-(2-{6-fluoro-2H-spiro[1-benzofuran-3,4′-piperidin]-1′-yl}phenyl)-4- methanesulfonylbenzene-1-sulfonamide A-320 4-methanesulfonyl-N-(2-{1′-methyl-1′,2′-dihydrospiro[piperidine-4,3′- pyrrolo[3,2-b]pyridin]-1-yl}phenyl)benzene-1-sulfonamide; formic acid A-321 4-({2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}sulfamoyl)-N,N- dimethylbenzene-1-sulfonoimidamide A-322 N1,N1-dimethyl-N4-{2-[4-(2-methylpropanoyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-323 N-tert-butyl-1-{2-[4- (dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidine-4-carboxamide A-324 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4- methanesulfonylbenzene-1-sulfonamide A-325 4-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-N,N- dimethylpiperazine-1-carboxamide A-326 N-[5-chloro-2-(3-oxomorpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide A-327 4-{[3-chloro-2-(morpholin-4-yl)phenyl]methanesulfonyl}-N,N- dimethylbenzene-1-sulfonamide A-328 N-(5-chloro-2-{1-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-329 N-[3-chloro-2-(morpholin-4-yl)phenyl]-1-methyl-1H-pyrazole-5- sulfonamide A-330 N2-[5-chloro-2-(morpholin-4-yl)phenyl]-N5,N5-dimethylpyridine-2,5- disulfonamide A-331 N1,N1-dimethyl-N4-(2-{1′-methyl-1′,2′-dihydrospiro[piperidine-4,3′- pyrrolo[2,3-b]pyridin]-1-yl}phenyl)benzene-1,4-disulfonamide A-332 N-(2-{5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl}phenyl)-4- methanesulfonylbenzene-1-sulfonamide A-333 4-methanesulfonyl-N-(2-{1-oxa-7-azaspiro[3.5]nonan-7-yl}phenyl)benzene- 1-sulfonamide A-334 4-methyl-N-{2-[4-(2-phenylpropanoyl)piperazin-1-yl]phenyl}benzene-1- sulfonamide A-335 N4-{2-[4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-336 propan-2-yl 4-{2-[4- (dimethylsulfamoyl)benzenesulfonamido]phenyl}piperazine-1-carboxylate A-337 N4-[2-(4-tert-butylpiperazin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-338 1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-N- phenylpiperidine-4-carboxamide A-339 1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-N-methyl-N- phenylpiperidine-4-carboxamide A-340 N2-[3-chloro-2-(morpholin-4-yl)phenyl]-N5,N5-dimethylpyridine-2,5- disulfonamide A-341 N-{3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3- dihydro-1H-indene-5-sulfonamide A-342 4-(1-{[3-chloro-2-(morpholin-4-yl)phenyl]amino}-2,2,2-trifluoroethyl)-N,N- dimethylbenzene-1-sulfonamide A-343 N-(5-chloro-2-{1,9-dioxa-4-azaspiro[5.5]undecan-4-yl}phenyl)-2,3-dihydro- 1H-indene-5-sulfonamide A-344 N-(5-chloro-2-{3-oxa-7-azatricyclo[3.3.2.0.sup.1,.sup.5]decan-7-yl}phenyl)-2,3- dihydro-1H-indene-5-sulfonamide A-345 N-(5-chloro-2-{2-oxa-6-azaspiro[3.5]nonan-6-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-346 N-(5-chloro-2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-347 N-(5-chloro-2-{2-oxa-8-azaspiro[5.5]undecan-8-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-348 4-methanesulfonyl-N-(2-{1′-methyl-1′,2′-dihydrospiro[piperidine-4,3′- pyrrolo[2,3-b]pyridin]-1-yl}phenyl)benzene-1-sulfonamide A-349 N-{2-[4-(2-hydroxy-2-phenylacetyl)piperazin-1-yl]phenyl}-4- methylbenzene-1-sulfonamide A-350 4-methyl-N-{2-[4-(2-oxo-2-phenylacetyl)piperazin-1-yl]phenyl}benzene-1- sulfonamide A-351 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4- (ethanesulfonyl)benzene-1-sulfonamide A-352 N4-{3-chloro-2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-353 N4-[2-(4-tert-butylpiperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-354 N4-{2-[3-(2,2-dimethylpropanoyl)-3,8-diazabicyclo[3.2.1]octan-8- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-355 N4-{2-[4-(3-fluoropyridin-2-yl)-4-hydroxypiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-356 4-(1-{[5-chloro-2-(morpholin-4-yl)phenyl]amino}-2,2,2-trifluoroethyl)-N,N- dimethylbenzene-1-sulfonamide A-357 N-(5-chloro-2-{3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl}phenyl)-2,3- dihydro-1H-indene-5-sulfonamide A-358 2-(1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}piperidin-4-yl)- 6-fluorobenzoic acid A-359 N-tert-butyl-1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-N- methylpiperidine-4-carboxamide A-360 N-tert-butyl-1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-N,4- dimethylpiperidine-4-carboxamide A-361 N-tert-butyl-1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-4- methylpiperidine-4-carboxamide A-362 N-(5-chloro-2-{1-oxa-7-azaspiro[4.5]decan-7-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-363 N-(5-chloro-2-{6-methyl-2-oxa-6,9-diazaspiro[4.5]decan-9-yl}phenyl)-2,3- dihydro-1H-indene-5-sulfonamide A-364 N-[3-chloro-2-(morpholin-4-yl)phenyl]-2-methoxyethane-1-sulfonamide A-365 N-[3-chloro-2-(morpholin-4-yl)phenyl]-1-(1,2-oxazol-3- yl)methanesulfonamide A-366 N-[3-chloro-2-(morpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5- carboxamide A-367 N-[3-chloro-2-(morpholin-4-yl)phenyl]-3-methoxybenzene-1-sulfonamide A-368 N-[3-chloro-2-(morpholin-4-yl)phenyl]-1-(3-chloro-4- fluorophenyl)methanesulfonamide A-369 N-[3-chloro-2-(morpholin-4-yl)phenyl]-4H,5H,6H,7H-pyrazolo[1,5- a]pyridine-3-sulfonamide A-370 N4-{2-[2-(dimethylamino)-2,3-dihydrospiro[indene-1,4′-piperidin]-1′- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-371 N-(2-{6-fluoro-1-[(pyridin-2-yl)methyl]-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}phenyl)-4-methanesulfonylbenzene-1-sulfonamide A-372 N-[2-(pyrrolidin-1-yl)phenyl]-3,4-dihydro-2H-1,5-benzodioxepine-7- sulfonamide A-390 N-[3-chloro-2-(morpholin-4-yl)phenyl]-3-cyclopropylbenzene-1- sulfonamide A-391 N-[3-chloro-2-(morpholin-4-yl)phenyl]-4-cyclopropylbenzene-1- sulfonamide A-392 N-[3-chloro-2-(morpholin-4-yl)phenyl]-2-cyclopropylbenzene-1- sulfonamide A-393 N-[3-chloro-2-(morpholin-4-yl)phenyl]-1-{1-oxaspiro[4.4]nonan-2- yl}methanesulfonamide A-394 1-(adamantan-1-yl)-N-[3-chloro-2-(morpholin-4- yl)phenyl]methanesulfonamide A-395 N-(5-chloro-2-{2-oxa-6-azaspiro[3.4]octan-6-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-396 N-(5-chloro-2-{5-oxa-11-azadispiro[3.1.3.sup.6.3.sup.4]dodecan-11-yl}phenyl)-2,3- dihydro-1H-indene-5-sulfonamide A-397 N-{5-chloro-2-[1-(oxolan-2-yl)-2-azaspiro[3.3]heptan-2-yl]phenyl}-2,3- dihydro-1H-indene-5-sulfonamide A-398 4-methanesulfonyl-N-(2-{2-methyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′- piperidin]-1′-yl}phenyl)benzene-1-sulfonamide; formic acid A-399 N4-{2-[4-(adamantane-1-carbonyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-400 N4-{5-chloro-2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-401 N4-{2-[4-(3-fluoropyridin-4-yl)-4-hydroxypiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-402 N-(2-{3,4-dihydrospiro[2-benzopyran-1,4′-piperidin]-1′-yl}phenyl)-4- methanesulfonylbenzene-1-sulfonamide A-403 N-(2-{6-fluoro-1-[(pyridin-4-yl)methyl]-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}phenyl)-4-methanesulfonylbenzene-1-sulfonamide A-404 2-{[1,1′-biphenyl]-2-yloxy}-N-{4-[methyl(1-methylpiperidin-4- yl)sulfamoyl]phenyl}acetamide A-405 N-(5-chloro-2-{7-oxa-1-azaspiro[4.5]decan-1-yl}phenyl)-2,3-dihydro-1H- indene-5-sulfonamide A-406 4-{[2-(4-benzylpiperazin-1-yl)phenyl]methanesulfonyl}-N,N- dimethylbenzene-1-sulfonamide A-407 N-(2-{6-fluoro-1-[(pyridin-3-yl)methyl]-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}phenyl)-4-methanesulfonylbenzene-1-sulfonamide A-408 N-{2-[4-(5-fluoropyridin-2-yl)-4-hydroxypiperidin-1-yl]phenyl}-4- methylbenzene-1-sulfonamide A-409 N-{2-[4-(5-fluoropyridin-2-yl)-4-hydroxypiperidin-1-yl]phenyl}-4- methoxybenzene-1-sulfonamide A-410 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-1- phenylmethanesulfonamide A-411 ethyl 1-[2-(2,3-dihydro-1H-indene-5-sulfonamido)phenyl]-4- methylpiperidine-4-carboxylate A-412 N1,N1-dimethyl-N4-(2-{1′-methyl-1′,2′-dihydrospiro[piperidine-4,3′- pyrrolo[2,3-c]pyridin]-1-yl}phenyl)benzene-1,4-disulfonamide A-413 N-{2-[4-(5-fluoropyridin-2-yl)-4-hydroxypiperidin-1-yl]phenyl(-4- (propane-2-sulfonyl)benzene-1-sulfonamide A-414 N4-{2-[4-(1-tert-butyl-1H-pyrazol-3-yl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-415 N4-(2-{4-[(tert-butylamino)methyl]piperidin-1-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-416 N1,N1-dimethyl-N4-{2-[(3S)-3-methyl-4-(1,3-thiazole-4- carbonyl)piperazin-1-yl]phenyl}benzene-1,4-disulfonamide A-417 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-3-(4- methylpiperazin-1-yl)propane-1-sulfonamide A-418 N4-{2-[4-(1-methoxypropan-2-yl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-419 N1,N1-dimethyl-N4-{2-[4-(oxolan-2-yl)piperidin-1-yl]phenyl}benzene-1,4- disulfonamide A-420 N4-[2-(4-cyclopropyl-4-hydroxypiperidin-1-yl)phenyl]-N1,N1- dimethylbenzene-1,4-disulfonamide A-421 rac-N4-(2-{4-[(1R,2S,4S)-bicyclo[2.2.1]heptan-2-yl]piperazin-1-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-422 N1,N1-dimethyl-N4-(2-{2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)benzene- 1,4-disulfonamide A-423 N-(2-{6-fluoro-1-[(oxolan-3-yl)methyl]-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}phenyl)-4-methanesulfonylbenzene-1-sulfonamide A-424 N1-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N4- methylbenzene-1,4-disulfonamide A-425 N1,N1-dimethyl-N4-{2-[4-(1-methylcyclobutanecarbonyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-426 N4-{2-[4-(3,3-dimethylpentanoyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-427 N4-{2-[4-(2,2-dimethylcyclopropanecarbonyl)piperazin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-428 N1,N1-dimethyl-N4-{2-[4-(2,3,3-trimethylbutanoyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-429 N4-{2-[4-(3,3-difluorocyclobutanecarbonyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-430 N4-(2-{4-[1-(fluoromethyl)cyclobutanecarbonyl]piperazin-1-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-431 N4-{2-[4-(2-methoxy-2-methylpropanoyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-432 N4-{2-[4-(2-fluoro-2-methylpropanoyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-433 N4-{2-[4-(1-hydroxycyclopropyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-434 N4-{2-[4-(methoxymethyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-435 N1,N1-dimethyl-N4-{2-[4-(oxan-2-yl)piperidin-1-yl]phenyl}benzene-1,4- disulfonamide A-436 N4-{2-[4-(hydroxymethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-437 N4-{2-[4-(1,4-dioxan-2-yl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-438 N4-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-439 N-(5-chloro-2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]- 1′-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide A-440 N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-441 4-methanesulfonyl-N-(2-{2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′- piperidin]-1′-yl}phenyl)benzene-1-sulfonamide A-442 oxolan-3-yl 1′-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-6- fluoro-1,2-dihydrospiro[indole-3,4′-piperidine]-1-carboxylate A-443 4-[1-({2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}amino)ethyl]- N,N-dimethylbenzene-1-sulfonamide A-444 N4-{2-[4-(1-methoxycyclopentanecarbonyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-445 N4-{2-[4-(1-methoxycyclohexanecarbonyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-446 N4-{2-[4-(2,2-difluoropropanoyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-447 N4-[2-(4-{2-azabicyclo[2.1.1]hexane-2-carbonyl(piperazin-1-yl)phenyl]- N1,N1-dimethylbenzene-1,4-disulfonamide A-448 N1,N1-dimethyl-N4-{2-[4-(2-methyloxane-2-carbonyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-449 rac-N1,N1-dimethyl-N4-(2-{4-[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptane-2- carbonyl]piperazin-1-yl}phenyl)benzene-1,4-disulfonamide A-450 N1,N1-dimethyl-N4-{2-[4-(oxan-3-yl)piperazin-1-yl]phenyl}benzene-1,4- disulfonamide A-451 N4-{2-[4-ethyl-4-(morpholin-4-yl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-452 N4-{2-[4-ethyl-4-(pyrrolidin-1-yl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-453 N4-[2-(4-cyclopentylpiperazin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-454 N4-[2-(4-methoxy-4-methylpiperidin-1-yl)phenyl]-N1,N1-dimethylbenzene- 1,4-disulfonamide A-455 N1,N1-dimethyl-N4-{2-[4-(2-methylbutan-2-yl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-456 N1,N1-dimethyl-N4-{2-[4-(1,1,1-trifluoropropan-2-yl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-457 N-[3-chloro-2-(morpholin-4-yl)phenyl]-4-(propan-2-yloxy)benzene-1- sulfonamide A-458 N4-{2-[4-(1-methoxycyclobutanecarbonyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-459 N4-{2-[4-(2,2-difluorocyclopentanecarbonyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-460 N4-[2-(4-{bicyclo[2.2.1]heptane-1-carbonyl}piperazin-1-yl)phenyl]-N1,N1- dimethylbenzene-1,4-disulfonamide A-461 N4-{2-[4-(1-fluorocyclopropanecarbonyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-462 N1,N1-dimethyl-N4-[2-(4-{spiro[2.2]pentane-1-carbonyl}piperazin-1- yl)phenyl]benzene-1,4-disulfonamide A-463 rac-N4-(2-{4-[(1R,2R)-2-(1,1- difluoroethyl)cyclopropanecarbonyl]piperazin-1-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-464 N4-{2-[4-(3-ethyloxetan-3-yl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-465 4-{1-[2-(4-benzylpiperazin-1-yl)phenyl]ethanesulfonyl}-N,N- dimethylbenzene-1-sulfonamide A-466 N-{2-[6-fluoro-1-(2-methoxyethyl)-1,2-dihydrospiro[indole-3,4′-piperidin]- 1′-yl]phenyl}-4-methanesulfonylbenzene-1-sulfonamide A-467 N-(2-{6-fluoro-1-[(oxolan-2-yl)methyl]-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}phenyl)-4-methanesulfonylbenzene-1-sulfonamide A-468 N-(2-{1-[(2,2-difluorocyclopropyl)methyl]-6-fluoro-1,2- dihydrospiro[indole-3,4′-piperidin]-1′-yl}phenyl)-4- methanesulfonylbenzene-1-sulfonamide A-469 oxolan-3-yl 6-fluoro-1′-[2-(4-methanesulfonylbenzenesulfonamido)phenyl]- 1,2-dihydrospiro[indole-3,4′-piperidine]-1-carboxylate A-470 N4-{2-[4-(2,2-dimethylpropanoyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-471 N4-[2-(4-tert-butyl-4-hydroxypiperidin-1-yl)phenyl]-N1,N1- dimethylbenzene-1,4-disulfonamide A-472 N4-(2-{6-fluoro-1-methyl-2′-oxo-1,2-dihydrospiro[indole-3,4′-piperidin]-1′- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-473 N4-(2-{3-fluoro-5-oxo-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-474 4-(1-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}ethanesulfonyl)- N,N-dimethylbenzene-1-sulfonamide A-475 N4-(2-{4′-ethyl-[1,4′-bipiperidin]-1′-yl}phenyl)-N1,N1-dimethylbenzene- 1,4-disulfonamide A-476 N1,N1-dimethyl-N4-{2-[4-(2-methyloxolane-2-carbonyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-477 rac-N4-(2-{4-[(1R,5R)-bicyclo[3.1.0]hexane-1-carbonyl]piperazin-1- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-478 N4-{2-[4-(3,3-difluoro-1-methylcyclobutanecarbonyl)piperazin-1- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-479 N4-{2-[4-(2,2-difluorocyclopropyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-480 N4-{2-[4-(2,2-dimethylpropanoyl)-1,4-diazepan-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-481 N-(2-{1,3-dihydrospiro[2-benzopyran-4,4′-piperidin]-1′-yl}phenyl)-4- methanesulfonylbenzene-1-sulfonamide A-482 N1-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}benzene-1,4- disulfonamide A-483 4-tert-butyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-484 N4-[2-(4-cyclopropyl-1,4-diazepan-1-yl)phenyl]-N1,N1-dimethylbenzene- 1,4-disulfonamide A-485 1-(3-bromophenyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}methanesulfonamide A-486 1-(3,4-dimethylphenyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}methanesulfonamide A-487 N4-[2-(4-{bicyclo[4.1.0]heptane-1-carbonyl}piperazin-1-yl)phenyl]-N1,N1- dimethylbenzene-1,4-disulfonamide A-488 1-(4-bromo-2-fluorophenyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}methanesulfonamide A-489 4-(2,2-dimethylpropyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-490 4-[1-({2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}amino)ethyl]- N,N-dimethylbenzene-1-sulfonamide A-491 4-(1-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}ethanesulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-492 4-methanesulfonyl-N-(2-{1′-methyl-2′,3′-dihydro-1′H-spiro[piperidine-4,4′- quinolin]-1-yl}phenyl)benzene-1-sulfonamide A-493 4-({2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-494 N4-(2-{4-[(tert-butoxy)methyl]piperidin-1-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-495 N1,N1-dimethyl-N4-(2-{4-[(oxolan-2-yl)methyl]piperazin-1- yl}phenyl)benzene-1,4-disulfonamide A-496 N4-{2-[4-(3-methoxypropyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-497 N1,N1-dimethyl-N4-(2-{1-oxa-7-azaspiro[4.5]decan-7-yl}phenyl)benzene- 1,4-disulfonamide A-498 N4-{2-[4-(2-ethoxyethyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-499 N1,N1-dimethyl-N4-(2-{7-oxa-1-azaspiro[4.5]decan-1-yl}phenyl)benzene- 1,4-disulfonamide A-500 1-(3,5-dimethylphenyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}methanesulfonamide A-501 1-(3,4-dihydro-1H-2-benzopyran-7-yl)-N-{2-[4-(2,2- dimethylpropanoyl)piperazin-1-yl]phenyl}methanesulfonamide A-502 N4-(2-{5-benzyl-octahydropyrrolo[3,4-c]pyrrol-2-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide; formic acid A-503 4-({3-[1-(2,6-difluorophenyl)piperidin-4-yl]-1H,4H,5H,6H,7H- pyrazolo[4,3-b]pyridin-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-504 4-({3-[1-(2,6-difluorophenyl)piperidin-4-yl]-4,5,6,7-tetrahydro-1H-indazol- 1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-505 N1,N1-dimethyl-N4-(2-{4-[1-(pyridin-3-yl)ethyl]piperazin-1- yl}phenyl)benzene-1,4-disulfonamide A-506 N4-{2-[4-(1,1-difluoroethyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-507 N1,N1-dimethyl-N4-(2-{2-oxa-6-azaspiro[3.5]nonan-6-yl}phenyl)benzene- 1,4-disulfonamide A-508 N1,N1-dimethyl-N4-(2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}phenyl)benzene- 1,4-disulfonamide A-509 N1,N1-dimethyl-N4-(2-{4-[(oxolan-3-yl)methyl]piperazin-1- yl}phenyl)benzene-1,4-disulfonamide A-510 N1,N1-dimethyl-N4-(2-{4-[(oxan-4-yl)methyl]piperazin-1- yl}phenyl)benzene-1,4-disulfonamide A-511 N1,N1-dimethyl-N4-(2-{2-oxa-8-azaspiro[5.5]undecan-8- yl}phenyl)benzene-1,4-disulfonamide A-512 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-(propan-2- yl)benzene-1-sulfonamide A-513 4-(butan-2-yl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-514 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-2,2-dimethyl-2,3- dihydro-1-benzofuran-5-sulfonamide A-515 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-1-methyl-1H- indole-5-sulfonamide A-516 4-tert-butyl-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-517 4-(tert-butylsulfanyl)-N-(2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′- piperidin]-1′-yl}phenyl)benzene-1-sulfonamide A-518 N4-(2-{4-[(2-methoxyethoxy)methyl]-4-methylpiperidin-1-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-519 N4-[2-(4-{[2-(2-methoxyethoxy)ethoxy]methyl}-4-methylpiperidin-1- yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-520 N-[5-methyl-2-(morpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide A-521 N-[5-methoxy-2-(morpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide A-522 N4-{2-[4-(2-hydroxypropan-2-yl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-523 N4-[2-(4-ethoxy-4-methylpiperidin-1-yl)phenyl]-N1,N1-dimethylbenzene- 1,4-disulfonamide A-524 N1,N1-dimethyl-N4-(2-{3-oxa-9-azaspiro[5.5]undecan-9- yl}phenyl)benzene-1,4-disulfonamide A-525 N4-{2-[4-(2,2-difluoropropyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-526 N1,N1-dimethyl-N4-{2-[4-(2-methylpropyl)-5-oxo-1,4-diazepan-1- yl]phenyl}benzene-1,4-disulfonamide A-527 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4- (trifluoromethyl)benzene-1-sulfonamide A-528 4-(2,2-difluorocyclopropyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-529 4-(difluoromethyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-530 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-2-methyl-2,3- dihydro-1-benzofuran-5-sulfonamide A-531 4-methoxy-N-{2-[4-(1,1,1-trifluoropropan-2-yl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-532 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1- phenylmethanesulfonamide A-533 4-({3-[1-(2,6-difluorophenyl)piperidin-4-yl]-1H,4H,5H,6H,7H- pyrazolo[4,3-c]pyridin-1-yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-534 2,2-dichloro-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-1-oxo- 2,3-dihydro-1H-indene-5-sulfonamide A-535 4-(1-cyano-1-methylethyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-536 4-(cyclopentyloxy)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-537 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-(1,1,2,2,2- pentafluoroethyl)benzene-1-sulfonamide A-538 4-methoxy-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-539 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4- methylbenzene-1-sulfonamide A-540 4-methanesulfonyl-N-{2-[4-(1,1,1-trifluoropropan-2-yl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-541 4-chloro-N-{2-[4-(1,1,1-trifluoropropan-2-yl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-542 1-phenyl-N-{2-[4-(1,1,1-trifluoropropan-2-yl)piperazin-1- yl]phenyl}methanesulfonamide A-543 N4-(2-{4-[(difluoromethoxy)methyl]piperidin-1-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-544 N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-545 N1,N1-dimethyl-N4-{2-[4-(2,2,2-trifluoro-1-phenylethyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-546 N4-[2-(4-ethyl-4-methoxypiperidin-1-yl)phenyl]-N1,N1-dimethylbenzene- 1,4-disulfonamide A-547 N1,N1-dimethyl-N4-(2-{4-[3-(morpholin-4-yl)propyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-548 N1,N1-dimethyl-N4-{2-[4-(oxan-4-yl)piperidin-1-yl]phenyl}benzene-1,4- disulfonamide A-549 N4-(2-{4-[(diethylamino)methyl]piperidin-1-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-550 N1,N1-dimethyl-N4-{2-[4-(trifluoromethyl)piperidin-1-yl]phenyl}benzene- 1,4-disulfonamide A-551 N1,N1-dimethyl-N4-{2-[4-(2,2,3,3-tetrafluoropropyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-552 N4-{2-[4-(2,2-difluoroethyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-553 N4-{2-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-554 N1,N1-dimethyl-N4-(2-{4-[(morpholin-4-yl)methyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-555 4-(cyclopropylmethoxy)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-556 benzyl 4-(2-{1-[4- (dimethylsulfamoyl)benzenesulfonyl]ethyl}phenyl)piperazine-1-carboxylate A-557 N4-{2-[4-(1-hydroxyethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-558 N4-{2-[4-(1-hydroxycyclopropyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-559 N4-{2-[4-(2-fluoroethyl)piperazin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-560 N1,N1-dimethyl-N4-{2-[4-(2,2,2-trifluoroethyl)piperazin-1- yl]phenyl}benzene-1,4-disulfonamide A-562 N1,N1-dimethyl-N4-(2-{1-oxa-9-azaspiro[5.5]undecan-9- yl}phenyl)benzene-1,4-disulfonamide A-563 1-(5-chloro-2-methoxyphenyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin- 1-yl]phenyl}methanesulfonamide A-564 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-1- phenylcyclopropane-1-sulfonamide A-565 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-1-(quinolin-8- yl)methanesulfonamide A-566 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-1-(naphthalen-2- yl)methanesulfonamide A-567 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-(2,2,2- trifluoroethyl)benzene-1-sulfonamide A-568 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4- (trifluoromethoxy)benzene-1-sulfonamide A-569 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-(1,1,2,2- tetrafluoro-2-methoxyethyl)benzene-1-sulfonamide A-570 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1- phenylmethanesulfonamide A-571 1-(3,4-dihydro-1H-2-benzopyran-7-yl)-N-{2-[4-(methoxymethyl)-4- methylpiperidin-1-yl]phenyl}methanesulfonamide A-572 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-(1,1,1-trifluoro- 2-methylpropan-2-yl)benzene-1-sulfonamide A-573 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-propoxybenzene- 1-sulfonamide A-574 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4- [(trifluoromethyl)sulfanyl]benzene-1-sulfonamide A-575 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-(pentafluoro-λ.sup.6- sulfanyl)benzene-1-sulfonamide A-576 4-cyclopropoxy-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-577 4-chloro-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}benzene- 1-sulfonamide A-578 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1-(4- methylphenyl)methanesulfonamide A-579 1-(2-fluorophenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-580 1-(4-fluorophenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-581 1-(3-cyanophenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-582 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1-(4- methoxyphenyl)methanesulfonamide A-583 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-1,2,3,4- tetrahydronaphthalene-2-sulfonamide A-584 N1,N1-dimethyl-N4-(2-{1-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)benzene- 1,4-disulfonamide A-585 N4-{2-[4-(difluoromethyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-586 l-(3-methanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin- 1-yl]phenyl}methanesulfonamide A-587 N4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1-{2-[2-(2- methoxyethoxy)ethoxylethyl}-N1-methylbenzene-1,4-disulfonamide A-588 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-{2-[2-(2- methoxyethoxy)ethoxy]ethoxy}benzene-1-sulfonamide A-589 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-[2-(2- methoxyethoxy)ethoxy]benzene-1-sulfonamide A-590 4-(1,1-difluoroethyl)-N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1- yl]phenyl}benzene-1-sulfonamide A-591 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-4-(2,2,2- trifluoroethoxy)benzene-1-sulfonamide A-592 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1-(2- methylphenyl)methanesulfonamide A-593 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1-(3- methylphenyl)methanesulfonamide A-594 1-(3-fluorophenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-595 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1-(2- methoxyphenyl)methanesulfonamide A-596 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1-(3- methoxyphenyl)methanesulfonamide A-597 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3-dihydro-1H- indene-1-sulfonamide A-598 benzyl 4-(2-{[4- (dimethylsulfamoyl)benzenesulfonyl]methyl}phenyl)piperazine-1- carboxylate A-599 N,N-dimethyl-4-({2-[4-(2-methylpropyl)piperazin-1- yl]phenyl}methanesulfonyl)benzene-1-sulfonamide A-600 N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-2-methyl-1,3- benzothiazole-6-sulfonamide A-601 1-(2-chlorophenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-602 1-(3-chlorophenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-603 N,N-dimethyl-4-(1-{2-[4-(oxetan-3-yl)piperazin-1- yl]phenyl}ethanesulfonyl)benzene-1-sulfonamide A-604 N,N-dimethyl-4-(1-{2-[4-(2-methylpropyl)piperazin-1- yl]phenyl}ethanesulfonyl)benzene-1-sulfonamide A-605 N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-5-fluorophenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-606 N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-4-fluorophenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-607 1-(1,3-dihydro-2-benzofuran-4-yl)-N-{2-[4-(methoxymethyl)-4- methylpiperidin-1-yl]phenyl}methanesulfonamide A-608 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3-dihydro-1H- indene-5-sulfonamide A-609 1-(3,4-dihydro-1H-2-benzopyran-7-yl)-N-[5-methoxy-2-(morpholin-4- yl)phenyl]methanesulfonamide A-610 1-(2-cyanophenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-611 N4-{2-[4-(2-methoxyethyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene- 1,4-disulfonamide A-612 1-(1,3-dihydro-2-benzofuran-5-yl)-N-{2-[4-(methoxymethyl)-4- methylpiperidin-1-yl]phenyl}methanesulfonamide A-613 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,2-dimethyl- 2,3-dihydro-1-benzofuran-5-sulfonamide A-614 N-{2-[4-(methoxymethyl)piperidin-1-yl]phenyl}-2,2-dimethyl-2,3-dihydro- 1-benzofuran-5-sulfonamide A-615 N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl(-3-fluorophenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-616 4-fluoro-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-3- methylbenzene-1-sulfonamide A-617 3-fluoro-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4- methylbenzene-1-sulfonamide A-618 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-3- methylbenzene-1-sulfonamide A-619 4-(1,3-dioxolan-2-yl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}thiophene-2-sulfonamide A-620 4-(difluoromethyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-621 4-cyclopropyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-622 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4- (trifluoromethoxy)benzene-1-sulfonamide A-623 4-bromo-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-624 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3-dihydro-1- benzoxepine-4-sulfonamide A-625 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-3,4-dihydro-1H- 2-benzopyran-7-sulfonamide A-626 N4-{2-[4-(2,2-difluorocyclohexyl)piperazin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-627 1-(3-tert-butylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-628 N-[5-methyl-2-(morpholin-4-yl)phenyl]-1-phenylmethanesulfonamide A-629 1-(3,4-dihydro-1H-2-benzopyran-7-yl)-N-[5-methyl-2-(morpholin-4- yl)phenyl]methanesulfonamide A-630 N-{5-methoxy-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3- dihydro-1H-indene-5-sulfonamide A-631 N-{2-[4-(2-ethoxyethyl)piperidin-1-yl]phenyl}-2,2-dimethyl-2,3-dihydro-1- benzofuran-5-sulfonamide A-632 2,2-dimethyl-N-(2-{2-oxa-8-azaspiro[5.5]undecan-8-yl}phenyl)-2,3- dihydro-1-benzofuran-5-sulfonamide A-633 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-3-(2- methoxypropan-2-yl)benzene-1-sulfonamide A-634 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3-(2- methoxypropan-2-yl)benzene-1-sulfonamide A-635 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2,2-dimethyl- 2,3-dihydro-1-benzofuran-5-sulfonamide A-636 N-{2-[4-(1,1-difluoroethyl)piperidin-1-yl]phenyl}-2,2-dimethyl-2,3- dihydro-1-benzofuran-5-sulfonamide A-637 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-(2- hydroxyethanesulfonyl)benzene-1-sulfonamide A-638 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2,2-dimethyl- 1-oxo-2,3-dihydro-1H-indene-5-sulfonamide A-639 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,2-dimethyl-1- oxo-2,3-dihydro-1H-indene-5-sulfonamide A-640 2,2-dimethyl-N-(2-{7-oxa-1-azaspiro[4.5]decan-1-yl}phenyl)-2,3-dihydro-1- benzofuran-5-sulfonamide A-641 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4-(2- methylpropanoyl)benzene-1-sulfonamide A-642 1-(3,4-dimethylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}methanesulfonamide A-643 3-cyclopropyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-644 2-(difluoromethyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}-3,4-dihydro-2H-1-benzopyran-6-sulfonamide A-645 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1,3-dihydro-2- benzofuran-5-sulfonamide A-646 1-(3-fluoro-4-methylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin- 1-yl]phenyl}methanesulfonamide A-647 1-[4-(difluoromethyl)phenyl]-N-{2-[4-(methoxymethyl)-4-methylpiperidin- 1-yl]phenyl}methanesulfonamide A-648 1-(2-fluoro-5-methylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin- 1-yl]phenyl}methanesulfonamide A-649 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1- phenylcyclopropane-1-sulfonamide A-650 4-(2,2-difluorocyclopropyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-651 3-(2,2-difluorocyclopropyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-652 N4-[3-chloro-2-(piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-653 N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3-fluoro- N1,N1-dimethylbenzene-1,4-disulfonamide A-654 2,2-dimethyl-N-(2-{3-oxa-9-azaspiro[5.5]undecan-9-yl}phenyl)-2,3- dihydro-1-benzofuran-5-sulfonamide A-655 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4-(2- methoxypropan-2-yl)benzene-1-sulfonamide A-656 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-4-(2- methoxypropan-2-yl)benzene-1-sulfonamide A-657 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-4-(2- methylpropanoyl)benzene-1-sulfonamide A-658 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-4-(propan-2- yl)benzene-1-sulfonamide A-659 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl]phenyl)-2-methoxy- 2,3-dihydro-1H-indene-5-sulfonamide A-660 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3-fluoro-4- methanesulfonylbenzene-1-sulfonamide A-661 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-4-fluoro-3- methylbenzene-1-sulfonamide A-662 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-4- methylbenzene-1-sulfonamide A-663 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1-(3,4- dimethylphenyl)methanesulfonamide A-664 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1-(3- methylphenyl)methanesulfonamide A-665 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3- methylbenzene-1-sulfonamide A-666 1-cyclobutyl-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)- 1H-pyrazole-4-sulfonamide A-667 4-(difluoromethoxy)-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)-3-fluorobenzene-1-sulfonamide A-668 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1-(3- fluorophenyl)methanesulfonamide A-669 3-cyclopropyl-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)benzene-1-sulfonamide A-670 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3-(1,3- dioxolan-2-yl)benzene-1-sulfonamide A-671 4-(difluoromethyl)-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)benzene-1-sulfonamide A-672 4-cyclopropyl-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)benzene-1-sulfonamide A-673 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-4- (trifluoromethoxy)benzene-1-sulfonamide A-674 5-cyclopropyl-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)thiophene-2-sulfonamide A-675 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2H-chromene- 3-sulfonamide A-676 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3,4- dihydronaphthalene-2-sulfonamide A-677 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1-(3-fluoro-4- methylphenyl)methanesulfonamide A-678 1-(3-chlorophenyl)-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)methanesulfonamide A-679 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1-(2-fluoro-5- methylphenyl)methanesulfonamide A-680 3-[({2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}sulfamoyl)methyl]-N,N-dimethylbenzene-1-sulfonamide A-681 N4-{3-fluoro-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-682 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-1,1-dimethyl- 1,3-dihydro-2-benzofuran-5-sulfonamide A-683 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-3,3-dimethyl- 1,3-dihydro-2-benzofuran-5-sulfonamide A-684 N,N-dimethyl-4-[2,2,2-trifluoro-1-({2-[4-(methoxymethyl)-4- methylpiperidin-1-yl]phenyl}amino)ethyl]benzene-1-sulfonamide A-685 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}spiro[1,3- benzodioxole-2,1′-cyclobutane]-6-sulfonamide A-686 N4-[2-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-687 3-(2,2-difluorocyclopropyl)-N-(2-{3,3-dimethyl-2-oxa-8- azaspiro[4.5]decan-8-yl}phenyl)benzene-1-sulfonamide A-688 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1-(2-fluoro-4- methylphenyl)methanesulfonamide A-689 1-(2,2-difluorocyclopropyl)-N-(2-{3,3-dimethyl-2-oxa-8- azaspiro[4.5]decan-8-yl}phenyl)-1H-pyrazole-3-sulfonamide A-690 2-(difluoromethyl)-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)-3,4-dihydro-2H-1-benzopyran-6-sulfonamide A-691 4-bromo-N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)benzene-1-sulfonamide A-692 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3-fluoro-4- methylbenzene-1-sulfonamide A-693 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-4- methanesulfonylbenzene-1-sulfonamide A-694 N4-{4-fluoro-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-695 N4-{5-fluoro-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-696 N1,N1-dimethyl-N4-(2-{4-[(trifluoromethoxy)methyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-697 4-methanesulfonyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-698 4-((1-(2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)ethyl)sulfonyl)- N,N-dimethylbenzenesulfonamide, enantiomer 1 A-699 4-((1-(2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)ethyl)sulfonyl)- N,N-dimethylbenzenesulfonamide, enantiomer 2 A-700 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1,1-dimethyl- 1,3-dihydro-2-benzofuran-5-sulfonamide A-701 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-(2- methoxyethanesulfonyl)benzene-1-sulfonamide A-702 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)-1- phenylmethanesulfonamide A-703 ethyl 2-(1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]phenyl}-4- fluoropiperidin-4-yl)acetate A-704 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2,2-dimethyl- 2H-1,3-benzodioxole-5-sulfonamide A-705 methyl 2-[4-({2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}sulfamoyl)phenyl]-2-methylpropanoate A-706 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4-(propan-2- yl)benzene-1-sulfonamide A-707 2-methoxy-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3- dihydro-1H-indene-5-sulfonamide A-708 5-cyclopropyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}thiophene-2-sulfonamide A-709 1-(2-fluoro-4-methylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin- 1-yl]phenyl}methanesulfonamide A-710 methyl 2-{4-[(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl)sulfamoyl]phenyl}-2-methylpropanoate A-711 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1-(4- methylphenyl)methanesulfonamide A-712 1-(3,4-dihydro-1H-2-benzopyran-7-yl)-N-(2-{3,3-dimethyl-2-oxa-8- azaspiro[4.5]decan-8-yl}phenyl)methanesulfonamide A-713 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2,3-dihydro- 1H-indene-5-sulfonamide A-714 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1,3-dihydro-2- benzofuran-5-sulfonamide A-715 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3,4-dihydro- 1H-2-benzopyran-7-sulfonamide A-716 1-[4-(difluoromethyl)phenyl]-N-(2-{3,3-dimethyl-2-oxa-8- azaspiro[4.5]decan-8-yl}phenyl)methanesulfonamide A-717 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-1- phenylcyclopropane-1-sulfonamide A-718 4-(2,2-difluorocyclopropyl)-N-(2-{3,3-dimethyl-2-oxa-8- azaspiro[4.5]decan-8-yl}phenyl)benzene-1-sulfonamide A-719 N4-{2-[4-(ethoxymethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-720 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2,2-dimethyl- 2,3-dihydro-1-benzofuran-6-sulfonamide A-721 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,2-dimethyl-2H- 1,3-benzodioxole-5-sulfonamide A-722 N4-{2-[4-fluoro-4-(2-hydroxyethyl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-723 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)spiro[1,3- benzodioxole-2,1′-cyclobutane]-6-sulfonamide A-724 N4-(3-cyano-2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-725 N4-{2-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-726 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3,4-dihydro- 1H-2-benzopyran-6-sulfonamide A-727 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-3,4-dihydro-1H- 2-benzopyran-6-sulfonamide A-728 N1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-5-fluorophenyl)- N1,N4,N4-trimethylbenzene-1,4-disulfonamide A-729 N1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-4-fluorophenyl)- N1,N4,N4-trimethylbenzene-1,4-disulfonamide A-730 N4-(2-{4-[(2,2-difluoroethoxy)methyl]piperidin-1-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-731 3-fluoro-4-methanesulfonyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-732 N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-[3- (trifluoromethyl)-3H-diazirin-3-yl]benzene-1-sulfonamide A-733 4-(2-{[2-(4-benzylpiperazin-1-yl)phenyl]amino}propan-2-yl)-N,N- dimethylbenzene-1-sulfonamide A-734 N4-{2-[3-(methoxymethyl)-3-methyl-8-azabicyclo[3.2.1]octan-8- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-735 N4-(2-{3,3-dimethyl-7-oxo-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-736 4-(azetidine-1-sulfonyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1- yl]phenyl}benzene-1-sulfonamide A-737 4-[1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-4- fluorophenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-738 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,2-dimethyl- 2,3-dihydro-1-benzofuran-6-sulfonamide A-739 N4-(2-{4-[(1,1-difluoroethoxy)methyl]piperidin-1-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-740 N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4-[3- (trifluoromethyl)-3H-diazirin-3-yl]benzene-1-sulfonamide A-741 N4-{2-[4-(1-methoxyethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-742 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-3,3-dimethyl- 2,3-dihydro-1-benzofuran-5-sulfonamide A-743 N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2- phenylethane-1-sulfonamide A-744 1-(3-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4- methylpiperidin-1-yl]phenyl}methanesulfonamide A-745 N4-{2-[4-(methoxymethyl)-2,4-dimethylpiperidin-1-yl]phenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-746 N4-{4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-1H-indazol-5- yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-747 1-(4-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4- methylpiperidin-1-yl]phenyl}methanesulfonamide A-748 N4-[2-(4-{1-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-749 N-[3-chloro-2-(piperidin-1-yl)phenyl]-4-[3-(trifluoromethyl)-3H-diazirin-3- yl]benzene-1-sulfonamide A-750 4-{1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]ethanesulfonyl}-N,N-dimethylbenzene-1-sulfonamide A-751 3,3-dimethyl-8-[2-(1-phenylmethanesulfonylethyl)phenyl]-2-oxa-8- azaspiro[4.5]decane A-752 4-[1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3- fluorophenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-753 N4-[3-(difluoromethyl)-2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8- yl}phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-754 N4-(2-{4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]piperidin-1- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-755 N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-756 N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)phenyl]-2,4-dimethyl-1,3-thiazole-5-sulfonamide A-757 N1,N1-dimethyl-N4-[5-methyl-2-(morpholin-4-yl)phenyl]benzene-1,4- disulfonamide A-758 4-difluoromethanesulfonyl-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide A-759 N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-2,3-dihydro-1H-indene-5-sulfonamide A-760 N-[2-(morpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5-sulfonamide A-761 N1,N1-dimethyl-N4-{2-[4-(morpholine-4-carbonyl)piperidin-1- yl]phenyl}benzene-1,4-disulfonamide A-762 N4-{3-fluoro-2-[4-({8-oxa-3-azabicyclo[3.2.1]octan-3-yl}methyl)piperidin- 1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-763 rac-N4-[2-(4-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-764 N4-(3-fluoro-2-{3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8- yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-765 4-(azetidine-1-sulfonyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide A-766 4-(difluoromethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide A-767 N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-1-phenylcyclopropane-1-sulfonamide A-768 2-cyclopropyl-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)phenyl]-4-methyl-1,3-thiazole-5-sulfonamide A-769 4-{[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]sulfamoyl}-N,N-dimethylbenzene-1-sulfonoimidamide A-770 N1,N1-dimethyl-N4-[2-(morpholin-4-yl)phenyl]benzene-1,4-disulfonamide A-771 N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-4-methylbenzene-1-sulfonamide A-772 1-(cyclopropylmethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)phenyl]-1H-pyrazole-4-sulfonamide A-773 N4-(2-{4-[(3,3-difluoropiperidin-1-yl)methyl]piperidin-1-yl}-3- fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-774 N4-(2-{4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidin-1-yl}-3- fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-775 4-[1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}pyridin-3- yl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-776 N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-4-methanesulfonylbenzene-1-sulfonamide A-777 N4-{2-[4-(methoxymethyl)-4-(trifluoromethyl)piperidin-1-yl]phenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-778 N4-{3-fluoro-2-[4-({3-oxa-6-azabicyclo[3.1.1]heptan-6- yl}methyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4- disulfonamide A-779 4-(1-cyclopropylethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)phenyl]benzene-1-sulfonamide A-780 N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide A-781 N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4- methylpiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-782 4-[(1R)-1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)-3-fluorophenyl]ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-783 4-[(1S)-1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)-3-fluorophenyl]ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-784 N1,N1-dimethyl-N4-(2-{4-methyl-4-[(trifluoromethoxy)methyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-785 N4-[3-fluoro-2-(4-{[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]methyl}piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-786 N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4- methoxypiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-787 N4-[3-fluoro-2-(4-{[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5- yl]methyl}piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-788 N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- (trifluoromethyl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-789 N4-(2-{4-[(4,4-difluoropiperidin-1-yl)methyl]piperidin-1-yl}-3- fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-790 N4-{3-fluoro-2-[4-({3-oxa-8-azabicyclo[3.2.1]octan-8-yl}methyl)piperidin- 1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-791 N4-{3-fluoro-2-[4-({6-oxa-3-azabicyclo[3.1.1]heptan-3- yl}methyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4- disulfonamide A-792 N4-(3-fluoro-2-{1-oxo-2,8-diazaspiro[4.5]decan-8-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-793 N1,N1-dimethyl-N4-[7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl]benzene- 1,4-disulfonamide A-794 N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidin- 1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-795 N-(1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]-6-fluorophenyl}-4- methylpiperidin-4-yl)acetamide A-796 N4-(3-fluoro-2-{2-oxo-1,8-diazaspiro[4.5]decan-8-yl}phenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-797 N1,N1-dimethyl-N4-(2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1- yl}phenyl)benzene-1,4-disulfonamide A-798 N4-(2-{4-fluoro-4-[(trifluoromethoxy)methyl]piperidin-1-yl}phenyl)- N1,N1-dimethylbenzene-1,4-disulfonamide A-799 N1,N1-dimethyl-N4-(2-((5R,7R)-3,3,7-trimethyl-2-oxa-8- azaspiro[4.5]decan-8-yl)phenyl)benzene-1,4-disulfonamide, cis, racemic A-800 (2R,6S)-4-[(1-{2-[1-(4-difluoromethanesulfonylbenzenesulfonyl)ethyl]-6- fluorophenyl}piperidin-4-yl)methyl]-2,6-dimethylmorpholine A-801 4-[1-(2-{4-[(4,4-difluoropiperidin-1-yl)methyl]piperidin-1-yl}-3- fluorophenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-802 4-[1-(2-{4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidin-1-yl}-3- fluorophenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-803 4-((1-(2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 1 A-804 4-((1-(2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 2 A-805 4-((1-(2-(4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 1 A-806 4-((1-(2-(4-((3,3-difluoropyrrolidin-1-yl)methyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 2 A-807 4-((1-(2-(1-((4-((difluoromethyl)sulfonyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)piperidin-4-yl)methyl)-2,6-dimethylmorpholine; enantiomer 1 A-808 4-((1-(2-(1-((4-((difluoromethyl)sulfonyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)piperidin-4-yl)methyl)-2,6-dimethylmorpholine; enantiomer 2 A-809 3-[4-(dimethylsulfamoyl)benzenesulfonamido]-N-methyl-2-(piperidin-1- yl)benzamide A-810 4-{[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]sulfamoyl}-N,N-dimethylbenzene-1-sulfonoimidamide; enantiomer 1 A-811 4-{[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]sulfamoyl}-N,N-dimethylbenzene-1-sulfonoimidamide; enantiomer 2 A-812 N4-[4-ethynyl-2-(piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-813 N4-{5-[4-(methoxymethyl)-4-methylpiperidin-1-yl]imidazo[1,2-a]pyridin-6- yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-814 4-(cyclopropyldifluoromethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide A-815 N4-[2-chloro-5-methyl-3-(morpholin-4-yl)phenyl]-N1,N1-dimethylbenzene- 1,4-disulfonamide A-816 N4-(2-{1,7-diazaspiro[3.5]nonan-7-yl}-3-fluorophenyl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-817 N4-[2-(4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-818 N4-[2-(4-{[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-819 2-(2,3-dihydro-1H-indene-5-sulfonyl)-4-(morpholin-4-yl)-2,3-dihydro-1H- isoindole A-820 2-(4-methylbenzenesulfonyl)-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindole A-821 N4-{2-[4-amino-4-(trifluoromethyl)piperidin-1-yl]-3-fluorophenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-822 N4-{7-[4-(methoxymethyl)-4-methylpiperidin-1-yl]pyrazolo[1,5-a]pyridin- 6-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-823 N-[2-chloro-5-methyl-3-(morpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide A-824 N4-[2-(4-{[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-825 methyl N-(1-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]-6- fluorophenyl}-4-methylpiperidin-4-yl)carbamate A-826 N4-[2-(4-{[(2S,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-827 N-{3-[4-(dimethylsulfamoyl)benzenesulfonamido]-2-(piperidin-1- yl)phenyl}acetamide A-828 (2S,6R)-4-((1-(2-(1-((2,3-dihydro-1H-inden-5-yl)sulfonyl)ethyl)-6- fluorophenyl)piperidin-4-yl)methyl)-2,6-dimethylmorpholine; enantiomer 1 A-829 N4-{2-[8-(methoxymethyl)-8-methyl-3-azabicyclo[3.2.1]octan-3- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-830 N4-{2-[4-(difluoromethyl)-4-methylpiperidin-1-yl]-3-fluorophenyl}-N1,N1- dimethylbenzene-1,4-disulfonamide A-831 N4-[3-(difluoromethyl)-2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-832 4-((1-(2-(4-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 1 A-833 N-(2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)- 4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 1 A-834 N-(2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)- 4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 2 A-835 N-(2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)- 4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 3 A-836 N-(2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)- 4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 4 A-837 4-{1-[3-fluoro-2-(4-{[(1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3- yl]methyl}piperidin-1-yl)phenyl]ethanesulfonyl}-N,N-dimethylbenzene-1- sulfonamide A-838 N-[2-(4-{[(3S,5S)-3,5-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-4-methanesulfonylbenzene-1-sulfonamide A-839 4-(1-{3-fluoro-2-[4-({3-oxa-8-azabicyclo[3.2.1]octan-8- yl}methyl)piperidin-1-yl]phenyl}ethanesulfonyl)-N,N-dimethylbenzene-1- sulfonamide A-840 4-{[2-(4-{[(3S,5S)-3,5-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]sulfamoyl}-N,N-dimethylbenzene-1-sulfonoimidamide A-841 N-(2-(4-(((2R,6S)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3- fluorophenyl)-4-(S-methylsulfonimidoyl)benzenesulfonamide; formic acid A-842 4-{1-[3-cyano-2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)phenyl]ethanesulfonyl}-N,N-dimethylbenzene-1- sulfonamide A-843 N1-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)- N4,N4-dimethylbenzene-1,4-disulfonamide, trans A-844 4-({3-fluoro-2-[4-({8-oxa-3-azabicyclo[3.2.1]octan-3-yl}methyl)piperidin- 1-yl]phenyl}sulfamoyl)-N,N-dimethylbenzene-1-sulfonoimidamide A-845 4-[1-[3-cyano-2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)phenyl]ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonamide; enantiomer 2 A-846 N-(2-(4-(((2R,6S)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3- fluorophenyl)-4-(S-methylsulfonimidoyl)benzenesulfonamide; enantiomer 1 A-847 N-(2-(4-(((2R,6S)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3- fluorophenyl)-4-(S-methylsulfonimidoyl)benzenesulfonamide; enantiomer 2 A-848 4-[1-[3-fluoro-2-(4-{[(1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3- yl]methyl}piperidin-1-yl)phenyl]ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonamide; enantiomer 1 A-849 4-[1-[3-fluoro-2-(4-{[(1R,5S)-6-oxa-3-azabicyclo[3.1.1]heptan-3- yl]methyl}piperidin-1-yl)phenyl]ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonamide; enantiomer 2 A-850 4-{1-[3-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)pyridin-4-yl]ethanesulfonyl}-N,N-dimethylbenzene-1-sulfonamide A-851 N4-{3-fluoro-2-[8-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-852 N-(2-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; enantiomer 1 A-853 N-(2-(4-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; enantiomer 2 A-854 4-((-1-(3-cyano-2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)piperidin-1- yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 1 A-855 4-((1-(2-(4-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 2 A-856 N4-[5-fluoro-4-(piperidin-1-yl)pyridin-3-yl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-857 4-[(3-fluoro-2-{4-[1-(morpholin-4-yl)propyl]piperidin-1- yl}phenyl)sulfamoyl]-N,N-dimethylbenzene-1-sulfonoimidamide A-858 4-[(3-fluoro-2-{4-[1-(morpholin-4-yl)cyclopropyl]piperidin-1- yl}phenyl)sulfamoyl]-N,N-dimethylbenzene-1-sulfonoimidamide A-859 4-{1-[2-(4-{[(2R,6R)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]ethanesulfonyl}-N,N-dimethylbenzene-1-sulfonamide A-860 4-(1-{3-fluoro-2-[4-({3-oxa-6-azabicyclo[3.1.1]heptan-6- yl}methyl)piperidin-1-yl]phenyl}ethanesulfonyl)-N,N-dimethylbenzene-1- sulfonamide A-861 N4-{2-[4-(1,1-difluoro-2-methoxyethyl)piperidin-1-yl]-3-fluorophenyl}- N1,N1-dimethylbenzene-1,4-disulfonamide A-862 N4-[2-(4-{[(2S,5S)-2,5-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-863 N4-[3-cyclopropyl-2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4- yl]methyl}piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-864 N4-[3-bromo-2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin- 1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-865 N4-[2-(4-{[(2R,5S)-2,5-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-866 4-difluoromethanesulfonyl-N-(2-{4-[(3,5-dimethylmorpholin-4- yl)methyl]piperidin-1-yl}-3-fluorophenyl)benzene-1-sulfonamide A-867 4-[(2-{4-[(3,3-dimethylmorpholin-4-yl)methyl]piperidin-1-yl}-3- fluorophenyl)sulfamoyl]-N,N-dimethylbenzene-1-sulfonoimidamide; formic acid A-868 N4-(2-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]piperidin-1-yl}-3- fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-869 rel-4-[(1R)-1-{3-fluoro-2-[4-({3-oxa-6-azabicyclo[3.1.1]heptan-6- yl}methyl)piperidin-1-yl]phenyl}ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonamide; formic acid A-870 4-((1-(2-(4-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamideformate; enantiomer 2 A-871 N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; isomer 1 A-871A N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 1 A-871B N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 2 A-872 N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; isomer 2 A-872A N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 3 A-872B N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3- fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide; diastereomer 4 A-873 N1-(2-(3-((3,5-dimethylmorpholino)methyl)azetidin-1-yl)-3-fluorophenyl)- N4,N4-dimethylbenzene-1,4-disulfonamide A-874 N4-[3-fluoro-2-(4-{2-oxa-7-azaspiro[4.4]nonan-7-yl}piperidin-1-yl)phenyl]- N1,N1-dimethylbenzene-1,4-disulfonamide A-875 N-{3-fluoro-2-[4-({3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}methyl)piperidin- 1-yl]phenyl}-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide A-876 N-{3-fluoro-2-[4-({3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}methyl)piperidin- 1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide A-877 N,N-dimethyl-4-[(2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1- yl}phenyl)sulfamoyl]benzene-1-sulfonoimidamide A-878 N4-[3-cyano-2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin- 1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-879 4-{1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)pyridin-3-yl]ethanesulfonyl}-N,N-dimethylbenzene-1-sulfonamide A-880 N-{3-fluoro-2-[4-({3-oxa-8-azabicyclo[3.2.1]octan-8-yl}methyl)piperidin-1- yl]phenyl}-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-sulfonamide A-881 N-{3-fluoro-2-[4-({3-oxa-8-azabicyclo[3.2.1]octan-8-yl}methyl)piperidin-1- yl]phenyl}-4-methylbenzene-1-sulfonamide A-882 N-{3-fluoro-2-[4-({3-oxa-8-azabicyclo[3.2.1]octan-8-yl}methyl)piperidin-1- yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide A-883 N4-{2-[4-({6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}methyl)piperidin-1- yl]-3-fluorophenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-884 4-(((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl)sulfonyl)- N,N-dimethylbenzenesulfonimidamide A-885 4-[1-[2-(4-{[2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide; diastereomer 4 A-886 8-{[1-(2-{1-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]ethyl}- 6-fluorophenyl)piperidin-4-yl]methyl}-3-oxa-8-azabicyclo[3.2.1]octane A-887 N-[3-chloro-5-methyl-2-(morpholin-4-yl)phenyl]-2,3-dihydro-1H-indene-5- sulfonamide A-888 N4-[3-chloro-5-methyl-2-(morpholin-4-yl)phenyl]-N1,N1-dimethylbenzene- 1,4-disulfonamide A-889 N-{3-fluoro-2-[4-({3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}methyl)piperidin- 1-yl]phenyl}-4-methylbenzene-1-sulfonamide A-890 4-[(1R)-1-[2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]ethanesulfonyl]- N,N-dimethylbenzene-1-sulfonoimidamide; diastereomer 1 A-891 4-[(1R)-1-[2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]ethanesulfonyl]- N,N-dimethylbenzene-1-sulfonoimidamide; diastereomer 2 A-892 4-[(1R)-1-(3-fluoro-2-{4-[1-(morpholin-4-yl)cyclopropyl]piperidin-1- yl}phenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonoimidamide; diastereomer 1 A-893 4-[(1R)-1-(3-fluoro-2-{4-[1-(morpholin-4-yl)cyclopropyl]piperidin-1- yl}phenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonoimidamide; diastereomer 2 A-894 4-[(1R)-1-[3-fluoro-2-(piperidin-1-yl)phenyl]ethanesulfonyl]-N,N- dimethylbenzene-1-sulfonoimidamide; diastereomer 1 A-895 4-[(1R)-1-[3-fluoro-2-(piperidin-1-yl)phenyl]ethanesulfonyl]-N,N- dimethylbenzene-1-sulfonoimidamide; diastereomer 2 A-896 N4-{2-[(3R)-3-{[3,5-dimethylmorpholin-4-yl]methyl}pyrrolidin-1-yl]-3- fluorophenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide; diastereomer 1 A-897 N4-{2-[(3R)-3-{[3,5-dimethylmorpholin-4-yl]methyl}pyrrolidin-1-yl]-3- fluorophenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide; diastereomer 2 A-898 4-(cyclopropyldifluoromethyl)-N-{3-fluoro-2-[4-({3-oxa-6- azabicyclo[3.1.1]heptan-6-yl}methyl)piperidin-1-yl]phenyl}benzene-1- sulfonamide A-899 N4-[2-(4-amino-4-methylpiperidin-1-yl)-3-fluorophenyl]-N1,N1- dimethylbenzene-1,4-disulfonamide A-900 N4-[2-(3-{[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl}azetidin-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-901 N4-[3-ethynyl-2-(piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4- disulfonamide A-902 4-[(1R)-1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)-3-fluorophenyl]ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonoimidamide; diastereomer 3 A-903 4-[(1R)-1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)-3-fluorophenyl]ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonoimidamide; diastereomer 4 A-904 8-[(1-{2-fluoro-6-[1-(4- methanesulfonylbenzenesulfonyl)ethyl]phenyl}piperidin-4-yl)methyl]-3- oxa-8-azabicyclo[3.2.1]octane; formic acid A-905 8-[(1-{2-fluoro-6-[1-(4-methylbenzenesulfonyl)ethyl]phenyl}piperidin-4- yl)methyl]-3-oxa-8-azabicyclo[3.2.1]octane; formic acid A-906 8-{[1-(2-{1-[4-(difluoromethyl)benzenesulfonyl]ethyl}-6- fluorophenyl)piperidin-4-yl]methyl}-3-oxa-8-azabicyclo[3.2.1]octane; formic acid A-907 8-{[1-(2-{1-[4-(cyclopropyldifluoromethyl)benzenesulfonyl]ethyl}-6- fluorophenyl)piperidin-4-yl]methyl}-3-oxa-8-azabicyclo[3.2.1]octane A-908 8-[(1-{2-[1-(2,3-dihydro-1H-indene-5-sulfonyl)ethyl]-6- fluorophenyl}piperidin-4-yl)methyl]-3-oxa-8-azabicyclo[3.2.1]octane A-909 N1-(2-(4-(2-oxa-7-azaspiro[4.4]nonan-7-yl)piperidin-1-yl)-3-fluorophenyl)- N4,N4-dimethylbenzene-1,4-disulfonamide; enantiomer 1 A-910 N1-(2-(4-(2-oxa-7-azaspiro[4.4]nonan-7-yl)piperidin-1-yl)-3-fluorophenyl)- N4,N4-dimethylbenzene-1,4-disulfonamide; enantiomer 2 A-911 4-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N- dimethylbenzenesulfonamide; enantiomer 1 A-912 4-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N- dimethylbenzenesulfonamide; enantiomer 2 A-913 8-((1-(2-fluoro-6-(1-((4- (methylsulfonyl)phenyl)sulfonyl)ethyl)phenyl)piperidin-4-yl)methyl)-3-oxa- 8-azabicyclo[3.2.1]octane; enantiomer 1 A-914 8-((1-(2-fluoro-6-(1-((4- (methylsulfonyl)phenyl)sulfonyl)ethyl)phenyl)piperidin-4-yl)methyl)-3-oxa- 8-azabicyclo[3.2.1]octane; enantiomer 2 A-915 rel-N4-[2-(3-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}azetidin-1-yl)- 3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide; diastereomer 1 A-916 rel-N4-[2-(3-{[(3R,5R)-3,5-dimethylmorpholin-4-yl]methyl}azetidin-1-yl)- 3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide; diastereomer 2 A-917 N4-[3-fluoro-2-(4-{6-oxa-1-azaspiro[3.5]nonan-1-yl}piperidin-1-yl)phenyl]- N1,N1-dimethylbenzene-1,4-disulfonamide A-918 N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}azepan-1-yl)-3- fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide A-919 4-(cyclopropyldifluoromethyl)-N-{3-fluoro-2-[4-({3-oxa-8- azabicyclo[3.2.1]octan-8-yl}methyl)piperidin-1-yl]phenyl}benzene-1- sulfonamide A-920 5-{1-[3-fluoro-2-(piperidin-1-yl)phenyl]ethanesulfonyl}-2,3-dihydro-1λ.sup.6- benzothiophene-1,1-dione A-921 N4-[3-(3,3-difluoroprop-1-yn-1-yl)-2-(piperidin-1-yl)phenyl]-N1,N1- dimethylbenzene-1,4-disulfonamide A-922 (4-(((R)-1-(3-fluoro-2-(piperidin-1- yl)phenyl)ethyl)sulfonyl)phenyl)(imino)(isopropyl)-λ.sup.6-sulfanone A-923 (4-(((R)-1-(3-fluoro-2-(piperidin-1- yl)phenyl)ethyl)sulfonyl)phenyl)(imino)(isopropyl)-λ.sup.6-sulfanone; diastereomer 3 A-924 8-((1-(2-fluoro-6-(1-tosylethyl)phenyl)piperidin-4-yl)methyl)-3-oxa-8- azabicyclo[3.2.1]octane; enantiomer 1 A-925 4-((1-(2-(4-(difluoromethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide, enantiomer 1 A-926 4-(((S)-1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N- dimethylbenzenesulfonimidamide; diastereomer 1 A-927 4-(((S)-1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N- dimethylbenzenesulfonimidamide; diastereomer 2 A-928 4-(((R)-1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N- dimethylbenzenesulfonimidamide; diastereomer 2 A-929 4-(((R)-1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N- dimethylbenzenesulfonimidamide; diastereomer 1 A-930 4-[(1S)-1-[3-fluoro-2-(piperidin-1-yl)phenyl]ethanesulfonyl]-N,N- dimethylbenzene-1-sulfonoimidamide; diastereomer 2 A-931 4-[(1S)-1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4yl]methyl}piperidin-1- yl)-3-fluorophenyl]ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonoimidamide; diastereomer 1 A-932 4-[(1S)-1-{3-fluoro-2-[4-(trifluoromethyl)piperidin-1- yl]phenyl}ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonoimidamide; diastereomer 1 A-933 4-((1-(2-(4-(difluoromethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 2 A-934 N4-(1-cyclohexyl-4-methyl-6-oxo-1,6-dihydropyridin-2-yl)-N1,N1- dimethylbenzene-1,4-disulfonamide A-935 4-(((S)-1-(3-fluoro-2-(4-(trifluoromethyl)piperidin-1- yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 2 A-936 4-[(1S)-1-[2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl]ethanesulfonyl]- N,N-dimethylbenzene-1-sulfonoimidamide; diastereomer 2 A-937 (difluoromethyl)(4-((1-(3-fluoro-2-(piperidin-1- yl)phenyl)ethyl)sulfonyl)phenyl)(imino)-l6-sulfanone; diastereomer 1 A-938 (difluoromethyl)(4-((1-(3-fluoro-2-(piperidin-1- yl)phenyl)ethyl)sulfonyl)phenyl)(imino)-l6-sulfanone; diastereomer 2 A-939 (difluoromethyl)(4-((1-(3-fluoro-2-(piperidin-1- yl)phenyl)ethyl)sulfonyl)phenyl)(imino)-l6-sulfanone; diastereomer 3 A-940 (difluoromethyl)(4-((1-(3-fluoro-2-(piperidin-1- yl)phenyl)ethyl)sulfonyl)phenyl)(imino)-l6-sulfanone; diastereomer 4 A-941 6-{1-[3-fluoro-2-(piperidin-1-yl)phenyl]ethanesulfonyl}-N,N- dimethylpyridazine-3-sulfonamide A-942 4-((1-(2-(4-(difluoromethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 1 A-943 4-((1-(2-(4-(difluoromethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 2 A-944 4-((1-(2-(4-(ethoxymethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 1 A-945 4-((1-(2-(4-(ethoxymethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 2 A-946 4-((1-(2-(4-(tert-butoxymethyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 1 A-947 5-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-1-imino-2,3- dihydro-1H-1l4-benzo[b]thiophene 1-oxide; diastereomer 1 A-948 5-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-1-imino-2,3- dihydro-1H-1l4-benzo[b]thiophene 1-oxide; diastereomer 2 A-949 4-((1-(2-(8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)ethyl)sulfonyl)- N,N-dimethylbenzenesulfonimidamide; diastereomer 1 A-950 4-((1-(2-(8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)ethyl)sulfonyl)- N,N-dimethylbenzenesulfonimidamide; diastereomer 2 A-951 4-{cyclopropyl[3-fluoro-2-(piperidin-1-yl)phenyl]methanesulfonyl}-N,N- dimethylbenzene-1-sulfonamide A-952 N4-(2-{4-[(4,4-difluoropiperidin-1-yl)methyl]piperidin-1-yl}-5- methylpyridin-3-yl)-N1,N1-dimethylbenzene-1,4-disulfonamide A-953 4-((1-(2-(4-(tert-butoxymethyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 2 A-954 4-((1-(2-(4-(ethoxymethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 3 A-955 4-((1-(2-(4-(ethoxymethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 4 A-956 4-{[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3- fluorophenyl]sulfamoyl}-N,N,N-trimethylbenzene-1-sulfonoimidamide; formic acid A-957 5-{1-[3-fluoro-2-(morpholin-4-yl)phenyl]ethanesulfonyl}-2,3-dihydro-1λ.sup.6- benzothiophene-1,1-dione A-958 4-[1-(5-chloro-2-{4-[(4,4-difluoropiperidin-1-yl)methyl]piperidin-1- yl}pyridin-3-yl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-959 5-(((S)-1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-1-imino-2,3- dihydro-1H-1λ.sup.4-benzo[b]thiophene 1-oxide; diastereomer 3 A-960 5-(((S)-1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)-1-imino-2,3- dihydro-1H-1λ.sup.4-benzo[b]thiophene 1-oxide; diastereomer 4 A-961 4-((1-(2-(4-(tert-butoxymethyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 4 A-962 4-((1-(2-(4-(tert-butoxymethyl)piperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 3 A-963 4-(difluoromethyl)-1-(2-(1-((4-(difluoromethyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)-4-methylpiperidine; enantiomer 1 A-964 4-(difluoromethyl)-1-(2-(1-((4-(difluoromethyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)-4-methylpiperidine; enantiomer 2 A-965 8-((1-(2-fluoro-6-(1-tosylethyl)phenyl)piperidin-4-yl)methyl)-3-oxa-8- azabicyclo[3.2.1]octane; enantiomer 2 A-966 5-((1-(3-fluoro-2-morpholinophenyl)ethyl)sulfonyl)-2,3- dihydrobenzo[b]thiophene 1,1-dioxide; enantiomer 1 A-967 5-((1-(3-fluoro-2-morpholinophenyl)ethyl)sulfonyl)-2,3- dihydrobenzo[b]thiophene 1,1-dioxide; enantiomer 2 A-968 4-({3-[(3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl]-1H-indazol-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-969 4-({3-[(3R,5S)-4-fluoro-3,5-dimethylpiperidin-1-yl]-1H-indazol-1- yl}sulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-970 4-{1-[2-(4-{[(3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1- yl]methyl}piperidin-1-yl)-3-fluorophenyl]ethanesulfonyl}-N,N- dimethylbenzene-1-sulfonamide A-971 1-(2-{1-[(4-difluoromethanesulfonylphenyl)sulfanyl]ethyl}-6- fluorophenyl)piperidine A-972 1-{2-[1-(4-difluoromethanesulfonylbenzenesulfinyl)ethyl]-6- fluorophenyl}piperidine A-973 1-{2-[1-(4-difluoromethanesulfonylbenzenesulfonyl)ethyl]-6- fluorophenyl}piperidine A-974 4-((1-(2-(4-(difluoromethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 3 A-975 4-((1-(2-(4-(difluoromethyl)-4-methylpiperidin-1-yl)-3- fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide; diastereomer 4 A-976 4-(tert-butoxymethyl)-1-(2-(1-((4-(difluoromethyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)piperidine; enantiomer 1 A-977 4-(tert-butoxymethyl)-1-(2-(1-((4-(difluoromethyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)piperidine; enantiomer 2 A-978 4-((1-(5-chloro-2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1- yl)pyridin-3-yl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 1 A-979 4-((1-(5-chloro-2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1- yl)pyridin-3-yl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 2 A-980 1-(4-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)phenyl)-4,5- dihydro-3H-isothiazole 1-oxide;; diastereomer 2 A-981 1-(4-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)phenyl)-4,5- dihydro-3H-isothiazole 1-oxide;; diastereomer 1 A-982 4-((cyclopropyl(3-fluoro-2-(piperidin-1-yl)phenyl)methyl)sulfonyl)-N,N- dimethylbenzenesulfonamide; enantiomer 1 A-983 4-((cyclopropyl(3-fluoro-2-(piperidin-1-yl)phenyl)methyl)sulfonyl)-N,N- dimethylbenzenesulfonamide; enantiomer 2 A-984 N4-{2-[(3R)-3-{[(3R,5S)-3,5-dimethylmorpholin-4-yl]methyl(pyrrolidin-1- yl]-3-fluorophenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide A-985 4-(1-{2-[4-({8,8-difluoro-3-azabicyclo[3.2.1]octan-3-yl}methyl)piperidin-1- yl]-3-fluorophenyl}ethanesulfonyl)-N,N-dimethylbenzene-1-sulfonamide A-986 4-{1-[4-(4,4-difluoropiperidin-1-yl)-5-fluoropyridin-3-yl]ethanesulfonyl}- N,N-dimethylbenzene-1-sulfonamide A-987 4-[1-(2-{4-[(4,4-difluoropiperidin-1-yl)methyl]piperidin-1-yl}pyridin-3- yl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-988 4-((1-(2-(8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)ethyl)sulfonyl)- N,N-dimethylbenzenesulfonimidamide; diastereomer 3 A-989 4-((1-(2-(8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)ethyl)sulfonyl)- N,N-dimethylbenzenesulfonimidamide; diastereomer 4 A-990 4-((1-(2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-5- methylpyridin-3-yl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide;; enantiomer 1 A-991 1-(4-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)phenyl)-4,5- dihydro-3H-isothiazole 1-oxide; diastereomer 3 A-992 1-(4-((1-(3-fluoro-2-(piperidin-1-yl)phenyl)ethyl)sulfonyl)phenyl)-4,5- dihydro-3H-isothiazole 1-oxide; diastereomer 4 A-993 5-chloro-2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3-(1-((2,3- dihydro-1H-inden-5-yl)sulfonyl)ethyl)pyridine; enantiomer 1 A-994 5-chloro-2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3-(1-((2,3- dihydro-1H-inden-5-yl)sulfonyl)ethyl)pyridine;; enantiomer 2 A-995 4-((1-(2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-5- methylpyridin-3-yl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide; enantiomer 2 A-996 4-[1-(4-{4-[(4,4-difluoropiperidin-1-yl)methyl]piperidin-1-yl}-5- fluoropyridin-3-yl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide A-997 1-((1-(2-(1-((4-(difluoromethyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)piperidin-4-yl)methyl)-4,4-difluoropiperidine; enantiomer 1 A-998 1-((1-(2-(1-((4-(difluoromethyl)phenyl)sulfonyl)ethyl)-6- fluorophenyl)piperidin-4-yl)methyl)-4,4-difluoropiperidine; enantiomer 2 A-999 2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3-(1-((2,3-dihydro- 1H-inden-5-yl)sulfonyl)ethyl)-5-methylpyridine; enantiomer 1 A-1000 2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3-(1-((2,3-dihydro- 1H-inden-5-yl)sulfonyl)ethyl)-5-methylpyridine; enantiomer 2 A-1001 4-[(1S)-1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1- yl)-3-fluorophenyl]ethanesulfonyl]-N,N-dimethylbenzene-1- sulfonoimidamide; diastereomer 2 A-1002 [(4-{1-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)- 3-fluorophenyl]ethanesulfonyl}phenyl)imino]dimethyl-λ.sup.6-sulfanone

    Characteristics

    [0368] Among other things, in some embodiments, the present disclosure describes one or more characteristics of certain TRPML1 modulators provided by and/or useful in the practice of the present disclosure.

    [0369] In some embodiments, the present disclosure provides technologies for assessing one or more relevant characteristics and/or for identifying, selecting, prioritizing, and/or characterizing one or more useful TRPML1 modulators.

    [0370] In some embodiments, the present disclosure provides certain biological and/or chemical assays (e.g., that facilitate and/or permit assessment of one or more feature(s) of TRMPL1 expression and/or activity, and/or of impact of TRPML1 modulator(s) on such expression and/or activity. Alternatively or additionally, the present disclosure provides technologies for identifying and/or characterizing one or more aspects of biological pathway(s) (e.g., autophagy pathway(s)) involving TRMPL1, and thus permits identification and/or characterization of additional useful targets within such pathway(s) and/or of modulator(s) that impact such pathway(s) (whether or not targeting TRPML1 itself).

    Compositions

    [0371] In some embodiments, the present disclosure provides and/or utilizes a composition that comprises and/or delivers a compound as described herein (e.g., together with one or more other components).

    [0372] In some embodiments, the present disclosure provides compositions that comprise and/or deliver compounds reported herein (e.g., compounds of Formula I-IIc), or an intermediate, degradant, or an active metabolite thereof, e.g., when contacted with or otherwise administered to a system or environment e.g., which system or environment may include TRPML1 activity; in some embodiments, administration of such a composition to the system or environment achieves the regulation of autophagy and lysosomal biogenesis as described herein.

    [0373] In some embodiments, a provided composition as described herein may be a pharmaceutical composition in that it comprises an active agent (e.g., a compound of Formula I-IIc or an active metabolite thereof) and one or more pharmaceutically acceptable excipients (e.g., one or more pharmaceutically acceptable adjuvants, carriers, excipients, and/or vehicles); in some such embodiments, a provided pharmaceutical composition comprises and/or delivers a compound described herein (e.g., a compound of Formula I-IIc), or an active metabolite thereof to a relevant system or environment (e.g., to a subject in need thereof) as described herein.

    [0374] In some embodiments, a provided composition (e.g., a pharmaceutical composition) includes a compound (e.g., as described herein) in a salt form such as a pharmaceutically acceptable salt form.

    [0375] Is some embodiments, a provided composition (e.g., a pharmaceutical composition) may be formulated for administration to a subject (e.g., a human) according to a particular route (e.g., orally, parenterally, by inhalation or nasal spray, topically (e.g., as by powders, ointments, or drops), rectally, buccally, intravaginally, intraperitoneally, intracisternally or via an implanted reservoir, etc).

    [0376] In some embodiments, a provided composition (e.g., a pharmaceutical composition) comprises or delivers an amount of a compound as described herein (or an active metabolite thereof) that is effective to measurably modulate TRPML1 activity, and/or to induce autophagy and/or lysosomal biogenesis in a biological sample or in a subject, when administered in accordance with a therapeutic regimen.

    [0377] In certain embodiments, a provided compound or composition is formulated for administration to a patient in need of such composition. In some embodiments, a compound or composition as described herein may be administered in a dose amount and/or by a route of administration effective for treating or lessening the severity of a disease or disorder described herein.

    [0378] In some embodiments, a composition (e.g., a pharmaceutical composition) as described herein may be formulated in unit form (e.g., which may offer ease of administration and/or uniformity of dosage).

    [0379] Those skilled in the art will appreciate that effective dose amounts may vary from subject to subject, for example depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed and its route of administration; the species, age, body weight, sex and diet of the patient; the general condition of the subject; the time of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and the like.

    [0380] In some embodiments, an appropriate dosage level may be within a range of about 0.01 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

    Applications and Uses

    [0381] The present application provides a variety of uses and applications for compounds and/or compositions as described herein, for example in light of their activities and/or characteristics as described herein. In some embodiments, such uses may include therapeutic and/or diagnostic uses. Alternatively, in some embodiments such uses may include research, production, and/or other technological uses.

    [0382] Among other things, in some embodiments, the present disclosure provides technologies for modulating TRPML1 activity. In some embodiments, the present application relates to a method of modulating TRPML1 activity in a subject comprising administering to the subject a provided compound, or a composition as described herein.

    Diseases, Disorders, and Conditions

    [0383] The present disclosure demonstrates that compounds and/or compositions as described herein may be useful in medicine (e.g., in the treatment of one or more diseases, disorders, or conditions).

    [0384] Among other things, as described herein, the present disclosure provides an insight that targeting (e.g., agonizing) TRPML1 may be a particularly effective strategy for modulating (e.g., enhancing) autophagy and/or lysosomal biogenesis.

    [0385] In some embodiments, a disease, disorder or condition that may be treated as described herein may be or comprise a disease, disorder or condition associated with TRPML1 deficiency. Furthermore, in some embodiments, the present disclosure identifies that TRMPL1 deficiency is associated with particular diseases, disorders or conditions, some or all of which may be treated in accordance with the present disclosure.

    [0386] In some embodiments, treatment provided herein involves administration of a TRMPL1 modulator as described herein in an amount effective to modulate TRMPL1 activity in a lysosome and/or increase autophagy.

    [0387] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is or comprises a liver disease, a neurodegenerative disorder, cancer, or a heart disease.

    [0388] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is or comprises a lysosomal storage disease, such as Niemann-Pick C (NPC) disease, Gaucher disease, and Pompe disease.

    [0389] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is an age-related common neurodegenerative disease, such as Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.

    [0390] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML1.

    [0391] In some embodiments, a disease, disorder, or condition amenable to treatment as described herein is related to reactive oxygen species or oxidative stress.

    [0392] In some embodiments, a disease, disorder, or condition is a muscular disease, a liver disease, a metabolic disease, an atherosclerotic disease, an inflammatory bowel disease, an atherosclerotic disease, a neurodegenerative disease, an oncological disease, or an infectious disease.

    [0393] In some embodiments, a disease, disorder, or condition is a muscular disease. In some embodiments, a muscular disease is a muscular dystrophy. In some embodiments, a muscular dystrophy is Duchenne muscular dystrophy.

    [0394] In some embodiments, a disease, disorder, or condition is a liver disease. In some embodiments, a disease, disorder, or condition is a metabolic disease. In some embodiments, a disease, disorder, or condition is an atherosclerotic disease. In some embodiments, a disease, disorder, or condition is an inflammatory bowel disease. In some embodiments, a disease, disorder, or condition is an atherosclerotic disease. In some embodiments, a disease, disorder, or condition is a neurodegenerative disease. In some embodiments, a disease, disorder, or condition is an oncological disease. In some embodiments, a disease, disorder, or condition is an infectious disease.

    [0395] In some embodiments, an infectious disease is an infection of Helicobacter pylori or Mycobacterium tuberculosis. In some embodiments, an infectious disease is an infection of Helicobacter pylori. In some embodiments, an infectious disease is an infection of Mycobacterium tuberculosis. In some embodiments, the infectious disease is tuberculosis.

    [0396] In some embodiments, the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament e.g., for modulation of TRPML1 activity.

    [0397] In some embodiments, the present application relates to use of a compound and/or composition described herein for use in the manufacture of a medicament for treating a disease, disorder or condition, e.g., through modulation of TRPML1 activity; in some embodiments, the disease, disorder, or condition is a liver disease, a neurodegenerative disorder, cancer, or a heart disease.

    Exemplary Embodiments

    [0398] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the disclosure: [0399] 1. A compound of Formula II:

    ##STR01264##

    or a pharmaceutically acceptable salt thereof, wherein [0400] X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are each independently selected from N, C, and CR.sup.a′, wherein X.sup.1′, X.sup.2′, X.sup.3′, and X.sup.4′ are C when bound to Cy-L.sup.1-Z or L.sup.2-V; A1 is absent, an optionally substituted fused heterocyclyl ring comprising 1 or 2 heteroatoms selected from N, O, and S, or an optionally substituted fused heteroaryl group comprising 1 or 2 heteroatoms selected from N, O, and S [0401] Cy is absent, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, P, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C.sub.1-6 aliphatic, or C.sub.3-12 cycloalkyl, wherein Cy is optionally substituted with one or more of R.sup.1; [0402] L.sup.1 is absent, —NR.sup.3—, —O—, —S—, C.sub.1-6 alkylenyl, C.sub.2-6 alkynylenyl, —NR.sup.3—C.sub.1-6 alkylenyl,—O—C.sub.1-6 alkylenyl, —C(O)C.sub.0-6 alkylenyl; —C(O)NR.sup.3—, —C(O)—C(O)—; [0403] L.sup.2 is —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl-, —(NR.sup.3).sub.s—S(O)(NR.sup.3)—, —S(O).sub.2—NR.sup.3—, —NR.sup.3—C.sub.1-6 haloalkylenyl, —(NR.sup.3).sub.s—P(O)(R.sup.3)—, —C.sub.1-6 alkylenyl-S(O)—, —C.sub.1-6 alkylenyl-S(O).sub.2—, —C(O)—(NR.sup.3).sub.s—, —(NR.sup.3).sub.s—C(O)—, or an optionally substituted 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S; [0404] V is selected from C.sub.1-6 aliphatic, C.sub.6-12 aryl, 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 12-membered monocyclic of bicyclic aryl, and C.sub.3-12 cycloalkyl, wherein V is substituted with (R.sup.6).sub.m; [0405] Z is C.sub.1-6 aliphatic, 2- to 10-atom heteroaliphatic, P(O)(R.sup.3).sub.2, —C(O)C.sub.1-6 aliphatic, C(O)N(R.sup.3).sub.2, C.sub.6-12 aryl, C.sub.3-12 cycloalkyl, 4- to 16-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q; [0406] each R.sup.a is independently halo, oxo, or optionally substituted C.sub.1-6 aliphatic; [0407] each R.sup.1 is independently selected from N(R.sup.3).sub.2, OH, CN, C(O)NHR.sup.3, and an optionally substituted group selected from C.sub.1-6 aliphatic and N(R.sup.3)—C(O)—C.sub.1-6 alkyl; [0408] each R.sup.2 is independently selected from halo, —CN, C(O)OH, and an optionally substituted group selected from C.sub.1-6 alkyl, C(O)C.sub.1-6 aliphatic, and O—C.sub.1-6 aliphatic; [0409] each R.sup.3 is independently selected from H and optionally substituted C.sub.1-6 aliphatic; [0410] each R.sup.5 is independently selected from C.sub.1-6 alkyl, —N(C.sub.1-6 alkyl).sub.2, —O—C.sub.1-6 alkyl, C(O)—C.sub.1-6 alkyl, P(O)(C.sub.1-6 alkyl).sub.2, C.sub.3-12 cycloalkyl, and 5- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R.sup.5 is optionally substituted with one or more substituents selected from halo and OH; [0411] each R.sup.6 is halo, S(O)—R.sup.5, S(O).sub.2—R.sup.5, S(O)(NH)—R.sup.5, —CN, —C(O)—R.sup.5, —C(O)O—R.sup.5, —C(O)—NH(R.sup.5), —C(O)—N(R.sup.5).sub.2, —P(O)(R.sup.5).sub.2, or an optionally substituted group selected from O—C.sub.1-6 alkyl, C.sub.1-6 alkyl, and C.sub.6-12 aryl; [0412] m is 0, 1, 2, 3, or 4; [0413] q is 0, 1, 2, 3, or 4; and [0414] s is 0 or 1. [0415] 2. The compound embodiment 1, wherein Cy is absent or 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. [0416] 3. The compound of any one of the preceding embodiments, wherein Cy is absent. [0417] 4. The compound of any one of the preceding embodiments, wherein Cy is 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. [0418] 5. The compound of any one of the preceding embodiments, wherein Cy is 4- to 6-membered monocyclic heterocyclic comprising 1 to 3 heteroatoms selected from N, O, and S. [0419] 6. The compound of any one of the preceding embodiments, wherein Cy is piperadinyl or piperazinyl. [0420] 7. The compound of any one of the preceding embodiments, wherein Cy is selected from Table Cy. [0421] 8. The compound of any one of the preceding embodiments, wherein L.sup.1 is absent, —NR.sup.3—, or C.sub.1-6 alkylenyl. [0422] 9. The compound of any one of the preceding embodiments, wherein L.sup.1 is absent. [0423] 10. The compound of any one of the preceding embodiments, wherein L.sup.1 is-NR—. [0424] 11. The compound of any one of the preceding embodiments, wherein L.sup.2 is absent, —(NR.sup.3).sub.s—S(O)—C.sub.0-6 alkylenyl, or —(NR.sup.3).sub.s—S(O).sub.2—C.sub.0-6 alkylenyl. [0425] 12. The compound of any one of the preceding embodiments, wherein L.sup.2 is absent, —(NR.sup.3).sub.s—S(O)—, or —(NR.sup.3).sub.s—S(O).sub.2—. [0426] 13. The compound of any one of the preceding embodiments, wherein L.sup.2 is absent or —(NR.sup.3).sub.s—S(O).sub.2—. [0427] 14. The compound of any one of the preceding embodiments, wherein L.sup.2 is —NR.sup.3—S(O).sub.2—. [0428] 15. The compound of any one of the preceding embodiments, wherein L.sup.2 is —NH—S(O).sub.2—. [0429] 16. The compound of any one of the preceding embodiments, wherein Z is C.sub.6-12 aryl, 2- to 10-atom heteroaliphatic, 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, or 5- to 12-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein Z is substituted with (R.sup.2).sub.q. [0430] 17. The compound of any one of the preceding embodiments, wherein Z is C.sub.6-12 aryl or 4- to 12-membered monocyclic or polycyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. [0431] 18. The compound of any one of the preceding embodiments, wherein Z is C.sub.6-12 aryl. [0432] 19. The compound of any one of the preceding embodiments, wherein Z is C.sub.6-12 aryl substituted with 1, 2, 3, or 4 R.sup.2. [0433] 20. The compound of any one of the preceding embodiments, wherein R.sup.2 is halo. [0434] 21. The compound of any one of the preceding embodiments, wherein Z is selected from Table Z. [0435] 22. The compound of any one of the preceding embodiments, wherein V is C.sub.6-12 aryl or 4- to 12-membered monocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. [0436] 23. The compound of any one of the preceding embodiments, wherein V is C.sub.6-12 aryl. [0437] 24. The compound of any one of the preceding embodiments, wherein V is C.sub.6-12 aryl substituted with 1, 2, 3, or 4 R.sup.6. [0438] 25. The compound of any one of the preceding embodiments, wherein R.sup.6 is halo, S(O)—R.sup.5, S(O).sub.2—R.sup.5, S(O)(NH)—R.sup.5, or an optionally substituted O—C.sub.1-6 alkyl. [0439] 26. The compound of any one of the preceding embodiments, wherein R.sup.6 is S(O)—R.sup.5, S(O).sub.2—R.sup.5, or an optionally substituted C.sub.1-6 alkyl. [0440] 27. The compound of any one of the preceding embodiments, wherein R.sup.6 is halo. [0441] 28. The compound of any one of the preceding embodiments, wherein R.sup.6 is fluoro or chloro. [0442] 29. The compound of any one of the preceding embodiments, wherein R.sup.6 is S(O).sub.2—R.sup.5. [0443] 30. The compound of any one of the preceding embodiments, wherein R.sup.6 is —S(O).sub.2—C.sub.1-6 alkyl. [0444] 31. The compound of any one of the preceding embodiments, wherein R.sup.6 is —S(O).sub.2—CH.sub.3. [0445] 32. The compound of any one of the preceding embodiments, wherein R.sup.6 is —S(O).sub.2—N(C.sub.1-6 alkyl).sub.2. [0446] 33. The compound of any one of the preceding embodiments, wherein R.sup.6 is —S(O).sub.2—N(CH.sub.3).sub.2. [0447] 34. The compound of any one of the preceding embodiments, wherein V is selected from Table V. [0448] 36. The compound of any one of the preceding embodiments, wherein the compound is of formula IIa-1:

    ##STR01265##

    or a pharmaceutically acceptable salt thereof. [0449] 37. The compound of any one of the preceding embodiments, wherein the compound is of formula IIa-2:

    ##STR01266##

    or a pharmaceutically acceptable salt thereof. [0450] 38. The compound of any one of the preceding embodiments, wherein the compound is of formula IIb-1:

    ##STR01267##

    or a pharmaceutically acceptable salt thereof. [0451] 39. The compound of any one of the preceding embodiments, wherein the compound is of formula IIc:

    ##STR01268##

    or a pharmaceutically acceptable salt thereof. [0452] 40. A compound selected from Table A. [0453] 41. A compound selected from Table B. [0454] 42. A pharmaceutical composition comprising a compound of any one of the preceding embodiments and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [0455] 43. A method of modulating TRPML1 comprising administering to a subject a compound of any one of the preceding embodiments. [0456] 44. A method of treating a disease, disorder, or condition in a subject comprising administering a compound of any one of the preceding embodiments. [0457] 45. The method of embodiment 44, wherein the disease, disorder, or condition is a lysosomal storage disorder. [0458] 46. The method of embodiment 45, wherein the lysosomal storage disorder is selected from Niemann-Pick C disease, Gaucher disease, and Pompe disease. [0459] 47. The method of embodiment 45, wherein the disease, disorder, or condition is age-related common neurodegenerative disease. [0460] 48. The method of embodiment 47, wherein the disease, disorder, or condition is selected from Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. [0461] 49. The method of embodiment 45, wherein the disease, disorder, or condition is a type IV Mucolipidosis (ML4) neurodegenerative lysosomal storage disease caused by mutations in TRPML1.

    EXEMPLIFICATION

    [0462] The present teachings include descriptions provided in the Examples that are not intended to limit the scope of any claim. Unless specifically presented in the past tense, inclusion in the Examples is not intended to imply that the experiments were actually performed. The following non-limiting examples are provided to further illustrate the present teachings. Those of skill in the art, in light of the present application, will appreciate that many changes can be made in the specific embodiments that are provided herein and still obtain a like or similar result without departing from the spirit and scope of the present teachings

    TABLE-US-00007 Table of Abbreviatons ACN Acetonitrile B.sub.2pin.sub.2 Bis(pinacolato)diboron BH.sub.3•DMS Borane dimethylsulfide BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) Boc tert-Butyloxycarbonyl CMBP Cyanomethyltributylphosphorane Davephos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethane DCM Dichloromethane DEAD Diethyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMA Dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide eq Equivalent EtOAc Ethyl acetate h Hour or hours HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HPLC High pressure liquid chromatography IPA Isopropyl alcohol Jones Chromium trioxide in diluted sulfuric acid reagent LAH Lithium aluminum hydride Lawesson's 2,4-Bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4- Reagent disulfide LCMS Liquid chromatography mass spectrometry LDA Lithium diisopropylamine LiHMDS Lithium bis(trimethylsilyl)amide mCPBA m-chloroperbenzoic acid MHz Megahertz MS Mass spectrometry MsCl Mesylchlroide MW Microwave NaHMDS Sodium bis(trimethylsilyl)amide NaOtBu Sodium tert-butoxide NBS N-bromosuccinimide n-BuLi n-butyl lithium NMR Nuclear Magnetic Resonance ON Overnight Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone)dipalladium(0) PdCl.sub.2(dppf) [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloride PTSA p-Toluenesulfonic acid Py Pyridine PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate RT Room temperature RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl STAB Sodium triacetoxyborohydride TBA•HSO.sub.4 Tetrabutylammonium hydrogensulfate TBAI Tetrabutylammonium iodide TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl TsCl Tosylchloride Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene X-phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

    Synthetic Examples

    [0463] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

    A. Certain Synthetic Intermediates

    [0464] ##STR01269##

    Step-1: Synthesis of 1-(2,3-dimethoxyphenyl)ethan-1-ol

    [0465] To a stirred solution of 2,3-dimethoxybenzaldehyde (1 g, 6.01 mmol, 1 eq) in THF (20 mL) was added dropwise a 3 M solution of methyl magnesium bromide in diethyl ether (3 ml, 9.03 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the titled compound 1-(2,3-dimethoxyphenyl)ethan-1-ol (0.7 g, 64%). LCMS: 183.09 [M+H].sup.+.

    Step-2: Synthesis of 1-(2,3-dimethoxyphenyl)ethan-1-one

    [0466] To a stirred mixture of 1-(2,3-dimethoxyphenyl)ethan-1-ol (0.8 g, 4.39 mmol, 1 eq) in acetone (20 ml), was added 2 M Jones reagent in aq. H.sub.2SO.sub.4 (6.6 ml, 13.18 mmol, 3 eq) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with isopropanol and concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 1-(2,3-dimethoxyphenyl)ethan-1-one (0.6 g, 76%). LCMS: 181.08 [M+1].sup.+.

    Procedure for synthesis of 1-methyl-1H-indole-4-carbaldehyde

    [0467] ##STR01270##

    Step-1: Synthesis of 1-methyl-1H-indole-4-carbaldehyde

    [0468] To a stirred solution of 1H-indole-4-carbaldehyde (1 g, 6.8 mmol, 1 eq) in DMF (10 mL) was added NaH (0.130 g, 7.4 mmol, 1.1 eq) at 0° C. under the nitrogen atmosphere followed by addition of methyl iodide (1.06 g, 7.5 mmol, 1.1 eq). The reaction mixture was stirred at 0° C. for 1 hour. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the titled compound 1-methyl-1H-indole-4-carbaldehyde (0.90 g, 82.56%). LCMS: 160.07 [M+H].sup.+.

    ##STR01271##

    Step-1: General procedure for synthesis of 1-Boc-4-aryl-3,6-dihydropyridine Derivatives

    [0469] Method A (Ar=a/c/f): A pyrex tube was charged with respective aryl halides (1.1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 eq), 2 M Na.sub.2CO.sub.3 solution (3 eq) in a mixture of 1.4 dioxane:H.sub.2O (4:1, 10 vol) and the reaction mixture was purged with argon for 15 min. Tetrakis(triphenylphosphine)palladium(0) (0.1 eq) was added to then reaction under an argon atmosphere and purged the reaction mixture with argon for 15 min. The tube was then fitted with a screw cap and the reaction was stirred at 90° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted ethyl acetate. The combine organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford respective 1-Boc-4-aryl-3,6-dihydropyridine derivative.

    [0470] Method B (Ar=b/e/g): A pyrex tube was charged with respective aryl halide (1.1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 eq), potassium carbonate (2 eq) in a mixture of DMF:H.sub.2O (5:1, 10 vol) and the reaction mixture was purged with argon for 10 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 eq) was then added to the reaction under an argon atmosphere and purged the reaction mixture with argon for 5 min. The tube was then fitted with a screw cap and the reaction was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted ethyl acetate. The combine organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford respective 1-Boc-4-aryl-3,6-dihydropyridine derivative.

    [0471] Method C (Ar=d): A pyrex tube was charged with respective aryl halide (1.1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 eq), cesium carbonate (2 eq) in a mixture of 1.4 dioxane:H.sub.2O (4:1, 10 vol) and the reaction mixture was purged with argon for 10 min. Dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) was then added to the reaction under an argon atmosphere and purged the reaction mixture with argon for 15 min. The tube was then fitted with a screw cap and the reaction was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted ethyl acetate. The combine organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford respective 1-Boc-4-aryl-3,6-dihydropyridine derivative.

    Step-2: General Procedure for Synthesis of 1-Boc-4-arylpiperidine Derivatives

    [0472] Method A (Ar=a/b): A solution of respective 1-Boc-4-aryl-3,6-dihydropyridine (1 eq) in ethyl acetate was purged with nitrogen for 10 min. Platinum (IV) oxide (10% w/w) was added to the reaction under a nitrogen atmosphere at room temperature. The reaction mixture was purged with hydrogen for 2-3 minutes and stirred at room temperature for 3 h under an atmosphere of hydrogen (100 Psi pressure). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to afford respective 1-Boc-4-arylpiperidine derivative. The crude product was used in the next step without further purification.

    [0473] Method B (Ar=c/d/e/f/g): A solution of respective 1-Boc-4-aryl-3,6-dihydropyridine (1 eq) in methanol was purged with nitrogen for 10 min. 10-20% Palladium on carbon (10% w/w) was added to the reaction under nitrogen atmosphere at room temperature. The reaction mixture was purged with hydrogen for 2-3 minutes and stirred at room temperature for 12 h under an atmosphere of hydrogen under balloon pressure. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to dryness to afford respective 1-Boc-4-arylpiperidine derivative. The crude product was used in the next step without further purification.

    Step-3: General Procedure for Synthesis of 4-arylpiperidine Derivatives

    [0474] Method A (Ar=a/c/e/f/g): To stirred solution of respective 1-Boc-4-arylpiperidine (1 eq) in DCM (5 vol), a 50% solution of trifluoroacetic acid solution in DCM (5 vol) was added dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 to 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the respective 4-arylpiperidine derivative. The crude product was used in the next step without further purification.

    [0475] Method B (Ar=b/d): To a stirred solution of respective 1-Boc-4-arylpiperidine (1 eq) in 1,4-dioxane (10 vol), a 4 M solution of HCl in 1,4-dioxane (5 vol) was added at 5 to 10° C. The reaction mixture was warmed to room temperature and stirred for 4 to 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was dissolve in saturated aqueous NaHCO.sub.3 solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the respective 4-arylpiperidine derivative. The crude product was used in the next step without further purification.

    TABLE-US-00008 Ar = Structure MS a [01272]embedded image 214.07 [M + H].sup.+ b [01273]embedded image 196.08 [M + H].sup.+ c [01274]embedded image 180.10 [M + H].sup.+ d [01275]embedded image 166.13 [M + H].sup.+ e [01276]embedded image NA f [01277]embedded image 163.12 [M + H].sup.+ g [01278]embedded image 166.13 [M + H].sup.+

    Synthesis of 3-(piperidin-4-yl)isoxazole

    [0476] ##STR01279##

    Step-1: Synthesis of tert-butyl (E)-4-((hydroxyimino)methyl)piperidine-1-carboxylate

    [0477] To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (1 g, 4.6 mmol, 1 eq) in water (10 mL) in methanol (10 mL), hydroxyl amine hydrochloride (390 mg, 5.6 mmol, 1.2 eq) followed by Na.sub.2CO.sub.3 (248 mg, 2.3 mmol, 0.5 eq) were added. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound tert-butyl (E)-4-((hydroxyimino)methyl)piperidine-1-carboxylate (The reaction was repeated on 1 g scale) (1.9 g, crude, combined yields from 1 g×2 batches). This compound was used in the next step without further purification. LCMS: 229.15 [M+H].sup.+.

    Step-2: Synthesis of tert-butyl (Z)-4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate

    [0478] To a stirred solution of tert-butyl (E)-4-((hydroxyimino)methyl)piperidine-1-carboxylate (1 g, 4.4 mmol, 1 eq) in DMF (3 mL), N-chlorosuccinimide (0.59 g, 4.4 mmol, 1 eq) was added. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water, the resulting solid was filtered out and dried under reduced pressure to afford the titled compound tert-butyl (Z)-4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (1 g, Crude). This compound was used in the next step without further purification. LCMS: 263.11 [M+H].sup.+.

    Step-3: Synthesis of tert-butyl 4-(5-(trimethylsilyl)isoxazol-3-yl)piperidine-1-carboxylate

    [0479] To a stirred solution of tert-butyl (Z)-4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (1.7 g, 6.4 mmol, 1 eq) in ethyl acetate (100 mL), ethynyltrimethylsilane (3.14 g, 32 mmol, 5 eq) followed by triethyl amine (1.24 g, 9.6 mmol, 1.5 eq) were added at 0° C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound tert-butyl 4-(5-(trimethylsilyl)isoxazol-3-yl)piperidine-1-carboxylate (2 g, 96%). LCMS: 325.19 [M+H].sup.+.

    Step-4: Synthesis of tert-butyl 4-(isoxazol-3-yl)piperidine-1-carboxylate

    [0480] To a stirred solution of tert-butyl 4-(5-(trimethylsilyl)isoxazol-3-yl)piperidine-1-carboxylate (1.4 g, 4.3 mmol, 1 eq) in a mixture of water (1 mL) and methanol (10 mL), potassium bifluoride (33 mg, 0.43 mmol, 0.1 eq) was added. The reaction mixture was stirred at room temperature for 6 days. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the titled compound tert-butyl 4-(isoxazol-3-yl)piperidine-1-carboxylate (1 g, crude). This compound was used in the next step without further purification. LCMS: 253.15 [M+H].sup.+.

    Step-5: Synthesis of 3-(piperidin-4-yl)isoxazole

    [0481] To a stirred solution of tert-butyl 4-(isoxazol-3-yl)piperidine-1-carboxylate (1 g, 4 mmol, 1 eq) in DCM (20 mL), trifluoroacetic acid (10 mL) was added dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness to afford the titled compound 3-(piperidin-4-yl)isoxazole (1 g. crude). This compound was used in the next step without further purification. LCMS: 153.09 [M+H].sup.+.

    Synthesis of 3-formyl-2-methoxybenzonitrile

    [0482] ##STR01280##

    Step 1: Synthesis of 3-formyl-2-hydroxybenzonitrile

    [0483] To a stirred solution of 2-hydroxybenzonitrile (1 g, 8.39 mmol, 1 eq) in acetic acid (10 mL), hexamethylenetetramine (1.8 g, 12.59 mmol, 1.5 eq) was added. The reaction was stirred at 120° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 3-formyl-2-hydroxybenzonitrile (105 mg, 8.5%) and 5-formyl-2-hydroxybenzonitrile (330 mg, 27%). LCMS: No ionization.

    Step 2: Synthesis of 3-formyl-2-methoxybenzonitrile

    [0484] To a stirred solution of 3-formyl-2-hydroxybenzonitrile (100 mg, 0.68 mmol, 1 eq) in DMF (2 mL), potassium carbonate (188 mg, 1.36 mmol, 2 eq) followed by iodomethane (145 mg, 1.02 mmol, 1.5 eq) were added. The reaction was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 3-formyl-2-methoxybenzonitrile (100 mg, crude). This compound was used in the next step without further purification. LCMS: No ionization.

    Synthesis of (pyridin-2-ylmethoxy)benzaldehyde Derivatives

    [0485] ##STR01281##

    General Procedure for Synthesis of (pyridin-2-ylmethoxy)benzaldehyde Derivatives

    [0486] To a stirred solution of respective hydroxybenzaldehyde (1 eq) in DMF (10 vol), potassium carbonate (3 eq) followed by 2-(chloromethyl)pyridine hydrochloride (1.1 eq) were added. The reaction was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature; ice-cold water was added and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the respective (pyridin-2-ylmethoxy)benzaldehyde derivative.

    TABLE-US-00009 Aldehyde Structure MS a [01282]embedded image 214.10 [M + H].sup.+ b [01283]embedded image 214.10 [M + H].sup.+ c [01284]embedded image 214.10 [M + H].sup.+

    Synthesis of [1,1′-biphenyl]-4-carbaldehyde

    [0487] ##STR01285##

    [0488] A pyrex tube was charged with a solution of 4-bromobenzaldehyde (1.86 g, 10.06 mmol, 1.2 eq), phenylboronic acid (1 g, 8.38 mmol, 1 eq) and K.sub.3PO.sub.4 (4.44 g, 20.9 mmol, 2.5 eq) in water (3 mL) and 1,4-dioxane (6 mL). The tube was sealed with a septum and the reaction mixture was purged with argon via an argon balloon for 15 min. PdCl.sub.2(dppf) (183 mg, 0.25 mmol, 0.03 eq) was then added to the reaction under an argon atmosphere and the purging with argon was continued for 5 min. The tube was then sealed with a screw cap and the reaction was heated at 100° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature and the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound [1,1′-biphenyl]-4-carbaldehyde (500 mg, crude). This compound was used in the next without further purification. LCMS: No ionization.

    Synthesis of 3,4-dimethoxypicolinaldehyde

    [0489] ##STR01286##

    [0490] To a stirred solution of 3,4-dimethoxypyridine (250 mg, 1.79 mmol, 1 eq) in THE (5 mL), 1.6 M solution of n-BuLi in hexane (1.2 mL, 1.97 mmol, 1.1 eq) was added dropwise at −78° C. under an argon atmosphere. The reaction was stirred at the same temperature for 30 min. DMF (0.31 mL, 3.95 mmol, 2.2 eq) was then added to the reaction at −78° C. under an argon atmosphere. The reaction was stirred at the same temperature for 30 min under an argon atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 3,4-dimethoxypicolinaldehyde (62 mg, 20.6%). LCMS: 168.10 [M+H].sup.+.

    Synthesis of 4,5-dimethoxynicotinaldehyde

    [0491] ##STR01287##

    Step-1: Synthesis of 4-chloro-3-methoxypyridine

    [0492] To a stirred solution of 4-chloropyridin-3-ol (1 g, 7.71 mmol, 1 eq) in toluene (10 mL), a solution of cyanomethyltributylphosphorane (CMBP) 1 M in toluene (23.1 mL, 23.1 mmol, 3 eq) followed by methanol (0.93 mL, 23.1 mmol, 3 eq) were added at 0° C. The reaction was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-chloro-3-methoxypyridine (280 mg, 25.45%). LCMS: 144.00 [M+H].sup.+.

    Step-2: Synthesis of 4-chloro-5-methoxynicotinaldehyde

    [0493] A stirred solution of 4-chloro-3-methoxypyridine (180 mg, 1.25 mmol, 1 eq) in THE (5 mL) was cooled to −78° C. and to which a 2 M solution of LDA in THE (1.25 mL, 2.51 mmol, 2 eq) was added. The reaction was stirred at the same temperature for 30 min. N,N-Dimethylformamide (0.19 mL, 2.51 mmol, 2 eq) was then added to the reaction at −78° C. The reaction was gradually warmed to room temperature and stirred for 2.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0° C., quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 4-chloro-5-methoxynicotinaldehyde (210 mg, crude). This compound was used in the next step without further purification. LCMS: 172.00 [M+H].sup.+.

    Step-3: Synthesis of 4,5-dimethoxynicotinaldehyde

    [0494] To a stirred solution 4-chloro-5-methoxynicotinaldehyde (200 mg, 1.16 mmol, 1 eq) in methanol (5 mL), sodium methoxide (126 mg, 2.33 mmol, 2 eq) was added and the reaction was stirred at 60° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 4,5-dimethoxynicotinaldehyde (83 mg, 43%). LCMS: 168.10 [M+H].sup.+.

    Synthesis of 2,3-dimethoxyisonicotinaldehyde

    [0495] ##STR01288##

    [0496] To a stirred solution of 2,3-dimethoxypyridine (1 g, 7.18 mmol, 1 eq) in THF, 2.5 M solution of n-BuLi in hexane (6.33 mL, 15.7 mmol, 2.2 eq) was added dropwise at −78° C. under an argon atmosphere. The reaction was warmed to 0° C. and stirred for 1 h. DMF (2.4 mL, 31.4 mmol, 4.38 eq) was then added dropwise to the reaction at −78° C. under an argon atmosphere. The reaction was warmed to 0° C. and stirred for 30 min under an argon atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 2,3-dimethoxyisonicotinaldehyde (250 mg, 20.83%). LCMS: 168.00 [M+H].sup.+.

    Synthesis of 4-(4-chlorophenyl)piperidine

    [0497] ##STR01289##

    Step-1: Synthesis of tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

    [0498] A pyrex tube was charged with a solution of 1-bromo-4-chlorobenzene (2 g, 10.44 mmol, 1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.87 g, 12.53 mmol, 1.2 eq) and potassium carbonate (2.8 g, 20.6 mmol, 2.5 eq) in a mixture of water (4 mL) and DMF (20 mL). The tube was sealed with a septum and the reaction mixture was purged with argon via an argon balloon for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (752 mg, 1.04 mmol, 0.1 eq) was then added to the reaction under an argon atmosphere and the purging with argon was continued for 5 min. The tube was then sealed with a screw cap and the reaction was heated at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to room temperature and the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 49%). LCMS: 294.10 [M+H].sup.+.

    Step-2: Synthesis of tert-butyl 4-(4-chlorophenyl)piperidine-1-carboxylate

    [0499] To a stirred solution of tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.4 mmol, 1 eq) in ethyl acetate (20 mL), the reaction mixture was purged with nitrogen for 5 min and platinum (IV) oxide (150 mg, 15% w/w) was added under an atmosphere of nitrogen. The reaction mixture was then purged with hydrogen for 2 min and stirred at room temperature for 3 h under an atmosphere of hydrogen via hydrogen balloon. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to afford the titled compound tert-butyl 4-(4-chlorophenyl)piperidine-1-carboxylate (900 mg, crude). This compound was used in the next step without further purification. LCMS: 296.10 [M+H].sup.+.

    Step-3: Synthesis of 4-(4-chlorophenyl)piperidine

    [0500] To a stirred solution of tert-butyl 4-(4-chlorophenyl)piperidine-1-carboxylate (990 mg, 3.35 mmol, 1 eq) in DCM (5 mL), trifluoroacetic acid (5 mL) was added dropwise at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCO.sub.3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-(4-chlorophenyl)piperidine (600 g, 91.6%). LCMS: 196.10 [M+H].sup.+.

    Synthesis of tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

    [0501] ##STR01290##

    Step-1: Procedure for Synthesis of 1-(tert-butyl) 3-methyl pyrrolidine-1,3-dicarboxylate

    [0502] To a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (5 g, 23.23 mmol, 1 eq) in acetone (20 mL), cesium carbonate (15.14 g, 46.46 mmol, 2 eq) followed by iodomethane (4.9 g, 34.85 mmol, 1.5 eq) were added. The reaction was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolve in water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 1-(tert-butyl) 3-methyl pyrrolidine-1,3-dicarboxylate (3 g, crude). This compound was used in the next step without further purification. LCMS: 230.15 [M+H].sup.+.

    Step-2: Procedure for Synthesis of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate

    [0503] To a stirred solution of 1-(tert-butyl) 3-methyl pyrrolidine-1,3-dicarboxylate (3 g, 13.33 mmol, 1 eq) in methanol (10 mL), sodium borohydride (1.5 g, 39.99 mmol, 3 eq) was added in portions at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 50%). LCMS: 202.15 [M+H].sup.+.

    Step-3: Procedure for Synthesis of tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

    [0504] To a stirred solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg, 2.53 mmol, 1 eq), triethyl amine (0.71 mL, 5.07 mmol, 2 eq) and DMAP (31 mg, 0.025 mmol, 0.01 eq) in DCM (5 mL), methanesulfonyl chloride (0.24 mL, 3.04 mmol, 1.2 eq) was added dropwise at 0° C. The reaction was warmed to room temperature and stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (600 mg, crude). This compound was used in the next step without further purification.

    B. SYNTHETIC EXAMPLES

    Example 1: Preparation of Compounds

    [0505] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Schemes 1, 2, 3, and 4, which comprise different sequences of assembling intermediates III, IV, V, VI VII, and VIII. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.

    ##STR01291##

    wherein Cy, L.sup.1, R.sup.a, R.sup.6 and Z are as defined herein.

    ##STR01292##

    wherein Cy, L.sup.1, R.sup.a, R.sup.6 and Z are as defined herein.

    ##STR01293##

    wherein Cy, Lt, R.sup.a, R.sup.6 and Z are as defined herein.

    ##STR01294##

    wherein Cy, L.sup.1, R.sup.a, R.sup.6 and Z are as defined herein.

    [0506] The general way of preparing target molecules IIa and IIc by using intermediates III, IV, V, VI, VII and VIII is outlined in General Scheme 1-4. Displacement of aryl halides (IV) with intermediates amine (III) under standard nucleophilic substitution conditions using base such as N,N-diisopropylethylamine, and/or potassium carbonate, cesium carbonate in solvent DMSO or DMF gives intermediate Va or Vc. Buchwald N—C coupling or Suzuki C—C coupling of aryl halides (IV) with 2° amine or boronic acid (III), in presence of palladium catalyst under elevated temperature also yield intermediate (Vb). Following multiple step chemical transformation from intermediate V to VII leads the formation of the final compounds of Formulae I, I′, II, and/or II′, as provided herein. A mixture of enantiomers, diastereomers, cis/trans isomers resulted from the process can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation.

    [0507] It should be understood that in the description and formulae shown above, the various groups Cy, L.sup.1, R.sup.a, R.sup.6 and Z and other variables are as defined above, except where otherwise indicated. Furthermore, for synthetic purposes, the compounds of General Schemes 1-4 are mere representative with elected radicals to illustrate the general synthetic methodology of the compound of Formulae I, I′, II, and/or II′, as provided herein.

    Example A1: Synthesis of N1-(2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-305)

    [0508] ##STR01295##

    Step-1: Procedure for Synthesis of 6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-3-en-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A1.3)

    [0509] To a stirred solution of 6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-4-one (A1.1) (720 mg 3 mmol, 1 eq) in THF (dry) (10 mL) was added DBU (1.17 mL, 7.7 mmol, 2.5 eq) at 0° C. and the reaction mixture was stirred at the same temperature for 10 min. 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (A1.2) (1.39 g, 4.6 mmol, 1.5 eq) was then added to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-3-en-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate A1.3 (800 mg, 50.3%). LCMS: 516.10 [M+H].sup.+.

    Step-2: Procedure for Synthesis of 2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-3-en-4-yl)nitrobenzene (A1.5)

    [0510] A pyres tube was charged with a solution of 6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-3-en-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A1.3) (800 mg, 1.5 mmol, 1 eq), (2-Nitrophenyl)boronic acid (A1.4) (280 mg, 1.7 mmol, 1.1 eq) and cesium carbonate (1 g, 3.1 mmol, 2 eq) in a mixture of water (4 mL) and 1,4-dioxane (16 mL). The tube was sealed with a septum and the reaction mixture was purged with argon for 10 min. Bis(triphenylphosphine)palladium(II) dichloride (54 mg, 0.07 mmol, 0.05 eq) was then added to the reaction mixture under an argon atmosphere. The tube was then fitted with a screw cap and the reaction mixture was heated at 100° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-3-en-4-yl)nitrobenzene (A1.5) (450 mg, 86.5%). LCMS: 339.15 [M+H].sup.+.

    Step-3: Procedure for Synthesis of 2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-4-yl)aniline (A1.6)

    [0511] An autoclave was charged with a solution of 2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-3-en-4-yl)nitrobenzene (A1.5) (450 mg, 1.3 mmol, 1 eq) in methanol (10 mL) was purged with nitrogen for 5 min. 10% Palladium on carbon (135 mg, 30% w/w) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was purged with hydrogen and stirred at room temperature for 2 h under hydrogen atmosphere (60 psi pressure). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-4-yl)aniline (A1.6) (200 mg, 47.8). LCMS: 313.20 [M+H].sup.+.

    Step-4: Procedure for Synthesis of N-(2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-305)

    [0512] To a stirred solution of 2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-4-yl)aniline (A1.6) (200 mg, 0.6 mmol, 1 eq) in acetonitrile (4 mL) was added pyridine (0.1 mL, 1.2 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at the same temperature for 10 min. Compound A1.7 (200 mg, 0.7 mmol, 1.1 eq) was then added to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound N1-(2-(6′-fluoro-1′-methylspiro[cyclohexane-1,3′-indolin]-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-305). Yield: 60 mg, 17.14%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.42-7.14 (m, 2H), 7.27 (t, J=8.0 Hz, 1H), 7.16 (t, J=6.8 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.38-6.31 (m, 2H), 3.04 (s, 2H), 2.74-2.65 (m, 1H), 2.68 (s, 3H), 2.62 (s, 6H), 1.73-1.55 (m, 4H), 1.44-1.33 (m, 2H), 1.12 (d, J=12.0 Hz, 2H); HPLC purity: 99.52%; LCMS Calculated for C.sub.28H.sub.32FN.sub.3O.sub.4S.sub.2: 557.18; Observed: 558.40 [M+H].sup.+.

    Example A2: Synthesis of 4-((4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-39)

    [0513] ##STR01296## ##STR01297## ##STR01298##

    Step-1: Procedure for Synthesis of 8-(4-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A2.3)

    [0514] To a stirred mixture of 1,4-dioxa-8-azaspiro[4.5]decane (A2.1) (26 g, 124 mmol, 1 eq) and 1-bromo-4-chloro-2-fluorobenzene 2.2 (18 g, 130 mmol, 1.05 eq) in 1,4-dioxane (250 mL) was added NaOtBu (23 g, 248 mmol, 2 eq) (0.1 eq), purged reaction mixture with argon for 20 min followed by the addition of Tris(dibenzylideneacetone)dipalladium(0) (3.4 g, 3.7 mmol, 0.03 eq) and BINAP (4.62 g, 7.4 mmol, 0.06 eq). The reaction mixture was stirred at 80° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite, the Celite pad was washed with ethyl acetate and the filtrate was evaporated to dryness under reduced pressure. The crude was purified by column chromatography on silica gel to afford 8-(4-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A2.3) (20 g, 60%). LCMS: 272.08 [M+H].sup.+.

    Step-2: Procedure for Synthesis of 1-(4-chloro-2-fluorophenyl)piperidin-4-one (A2.4)

    [0515] To a stirred solution of 8-(4-chloro-2-fluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A2.3) (20 g) in THE (70 mL), 10% H.sub.2SO.sub.4 (300 mL) was added at 0° C. The resulting reaction mixture was stirred at 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 1-(4-chloro-2-fluorophenyl)piperidin-4-one (A2.4) (15 g, 89%). LCMS: 228.05 [M+H].sup.+.

    Step-3: Procedure for Synthesis of 1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A2.6)

    [0516] To a stirred mixture of 1-(4-chloro-2-fluorophenyl)piperidin-4-one (A2.4) (5 g, 22.05 mmol, 1 eq) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (A2.5) (4.5 mL, 26.46 mmol, 1.2 eq) in THE (50 mL) DBU (3.9 mL, 26.46 mmol, 1.2 eq) was added and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A2.6) (9 g, 80%). LCMS: 509.99 [M+H].sup.+.

    Step-4: Procedure for Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A2.8)

    [0517] To a mixture of 1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A2.6) (9 g, 17.68 mmol, 1 eq) and bispinacolato diboron (A2.7) (4.47 g, 17.68 mmol, 1 eq) in 1,4-dioxane (70 mL), purged the reaction mixture with argon for 10 min followed by the addition of dppf (0.29 g, 0.053 mmol, 3 eq) and [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.39 g, 0.53 mmol, 0.03 eq) and stirred at 100° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A2.8). Yield: 4.5 g, 76%; Appearance: Pale yellow solid; .sup.1H NMR (400 MHz, CdCl.sub.3) δ 7.09-6.93 (m, 2H), 6.88 (t, J=9.1 Hz, 1H), 6.59 (dq, J=4.5, 2.2 Hz, 1H), 3.68 (q, J=2.9 Hz, 2H), 3.18 (q, J=6.4, 6.0 Hz, 2H), 2.40 (m, J=6.8, 3.5, 2.9 Hz, 2H), 1.28 (d, J=5.1 Hz, 12H); LCMS Calculated for C.sub.17H.sub.22BClFNO.sub.2: 337.14; Observed: 338.14 [M+H].sup.+.

    Step-5: General Procedure for Synthesis of 4-((4-bromo-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.11)

    [0518] To a stirred solution of 4-bromo-2-methyl-1H-imidazole (A2.9) (0.5 g, 3.11 mmol, 1 eq) in acetonitrile (20 mL) was added pyridine (0.5 g, 6.21 mmol, 2 eq) at 0° C. followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A2.10) (0.97 g, 3.42 mmol, 1.1 eq) at 0° C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the precipitated solid was filtered, washed with acetonitrile. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography followed by prep HPLC to afford 4-((4-bromo-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.11) (1 g, 79.3%). LCMS: 407.96 [M+H].sup.+.

    Step-6: General Procedure for Synthesis of 4-((4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.12)

    [0519] To a stirred solution of 4-((4-bromo-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.11) (0.25 g, 0.61 mmol, 1 eq) and 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A2.8) (0.27 g, 0.80 mmol, 1.3 eq) in 1,4-dioxane and water (10:2 mL) was added Cs.sub.2CO.sub.3 (0.4 g, 1.23 mmol, 2 eq) and PdCl.sub.2(PPh.sub.3).sub.2 (0.043 g, 0.061 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred at 65° C. for 7 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by column chromatography on silica gel to afford compound 4-((4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.12) (0.24 g, 71.1%). LCMS: 539.09 [M+H].sup.+.

    Step-7: General Procedure for Synthesis of 4-((4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.13)

    [0520] To a stirred solution of 4-((4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A2.12) (0.23 g, 0.43 mmol, 1 eq) in ethyl acetate (25 mL) was added PtO.sub.2 (0.12 g) at room temperature. The reaction mixture was stirred under hydrogen gas pressure (75 psi) at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite, the Celite pad was washed with ethyl acetate and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 4-((4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-39). Yield: 10 mg, 4.33%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.28 (d, J=8.2 Hz, 2H), 8.04 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.31 (dd, J=12.4, 2.5 Hz, 1H), 7.17 (dd, J=8.7, 2.5 Hz, 1H), 7.06 (t, J=9.1 Hz, 1H), 3.39-3.33 (m, 2H), 2.78-2.68 (m, 8H), 2.61 (m, 1H), 2.47 (m, 3H), 2.00-1.92 (m, 2H), 1.68 (tt, J=12.0, 6.1 Hz, 2H); HPLC purity: >99%; LCMS Calculated for C.sub.23H.sub.26ClFN.sub.4O.sub.4S.sub.2: 540.11; Observed: 541.30 [M+H].sup.+.

    [0521] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00010 Compound No. Structure Analytical data A-37 [01299]embedded image Yield: 0.46 mg, 58.97%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.46 (s, 1H), 8.19 (d, J = 7.6 Hz, 2H), 8.02 − 8.0 (m, 2H), 7.35 − 7.32 (m, 1H), 7.17 (m, 1H), 7.08 (t, J = 9.6 Hz, 1H), 6.08 (m, 1H), 3.69 (m, 2H), 3.25 (m, 4H), 2.65 (s, 6H), 2.29 (s, 3H); HPLC purity: 97.41%; LCMS Calculated for C.sub.23H.sub.24ClFN.sub.4O.sub.4S.sub.2: 538.09; Observed: 539.1 [M + H].sup.+. A-38 [01300]embedded image Yield: 0.04 g, 25%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.28 (s, IH), 8.24 − 8.14 (m, 2H), 8.05 − 7.97 (m, 2H), 7.32 (dd, J = 12.4, 2.4 Hz, 1H), 7.17 (ddd, J = 8.7, 2.4, 1.0 Hz, 1H), 7.07 (t, J = 9.1 Hz, 1H), 3.37 (d, J = 12.3 Hz, 2H), 2.74 (t, J = 11.6 Hz, 2H), 2.66 (s, 6H), 2.60 − 2.47 (m, 1H), 2.19 (s, 3H), 1.87 (d, J = 12.3 Hz, 2H), 1.74 − 1.64 (m, 2H); HPLC purity: 98.86%; LCMS Calculated for C.sub.23H.sub.26ClFN.sub.4O.sub.4S.sub.2: 540.11; Observed: 541.30 [M + H].sup.+. A-84 [01301]embedded image Yield: 0.01 g, 6.66%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.39 (s, 1H), 8.07 − 8.05 (m, 2H), 7.86 − 7.84 (m, 2H), 7.33 (m, 1H), 7.17 (d, J = 8 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H), 6.71 (s, 1H), 3.38 − 3.35 (m, 2H), 3.25 (s, 3H), 2.73 − 2.68 (m, 3H), 2.64 (s, 6H), 1.99 − 1.96 (m, 2H), 1.62 − 1.53 (m, 2H); HPLC purity: >99%; LCMS Calculated for C.sub.23H.sub.27ClFN.sub.5O.sub.4S.sub.2: 555.12; Observed: 556.10 [M + H].sup.+.

    Example A3: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-33) and N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-29)

    [0522] ##STR01302## ##STR01303##

    Step-1: Synthesis of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (A3.2)

    [0523] To a stirred solution of 5-chloro-1,3-dimethyl-1H-pyrazole (A3.1) (3.85 g, 29.6 mmol, 1 eq) in H.sub.2SO.sub.4 (15 mL) was added portion wise KNO.sub.3 (3.59 g, 35.5 mmol, 1.2 eq) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture poured into ice water. The obtained solid separated, dissolved in DCM and washed with water. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the desired product 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (A3.2) (3.8 g, 73%). LCMS: 176.01 [M+H].sup.+.

    Step-2: Synthesis of tert-butyl 4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A3.4)

    [0524] To a stirred solution of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (A3.2) (2 g, 11 mmol, 1 eq) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A3.3) (3.88 g, 12.5 mmol, 1.1 eq) in 1,4-dioxane (50 mL) was added 2 M Na.sub.2CO.sub.3 (3.29 g, 34.2 mmol, 3 eq) purged reaction mixture with argon for 15 min followed by the addition of Tetrakis(triphenylphosphine)palladium(0) (1.32 g, 1.14 mmol, 0.1 eq) and stirred at 100° C. for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product tert-butyl 4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A3.4) (3.5 g, 94%). LCMS: 323.16 [M+H].sup.+.

    Step-3: Synthesis of 4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine, TFA Salt (A3.5)

    [0525] To a stirred solution of tert-butyl 4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A3.4) (3.5 g, 10.8 mmol, 1 eq) in DCM (40 mL) was added dropwise TFA (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude was triturated with diethyl ether, obtained precipitate was filtered and concentrated to provide the desired compound 4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine, TFA salt (A3.5) (2 g, 82%).

    Step-4: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine (A3.7)

    [0526] To a stirred mixture of 4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine, TFA salt. (A3.5) (2 g, 5.9 mmol, 1 eq), 1-bromo-4-chloro-2-fluorobenzene (A3.6) (1.37 g, 6.5 mmol, 1.1 eq) in 1.4 dioxane (100 mL) was added followed by Cs.sub.2CO.sub.3 (3.88 g, 11.9 mmol, 2 eq) purged the reaction mixture with argon followed by addition of Davephos (0.47 gm 11.9 mmol, 0.2 eq) and Pd.sub.2(dba).sub.3 (0.54 g, 0.59 mmol, 0.1 eq). The reaction mixture was stirred at 90° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine (A3.7) (1.5 g, 63.5%). LCMS: m/z 351.09 [M+H].sup.+.

    Step-5: Synthesis of 5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-4-amine (A3.8)

    [0527] To a stirred solution of 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine (A3.7) (0.6 g, 1.7 mmol, 1 eq) in mixture of ethanol (20 mL) and water (6 mL) was added ammonium chloride (0.45 g, 8.5 mmol, 5 eq) followed by addition of Fe powder (0.47 g, 8.57 mmol, 5 eq) at room temperature. The resulting reaction mixture was refluxed at 90° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The crude was diluted with water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-4-amine A3.8 (500 mg, 90%). 321.12: [M+H].sup.+.

    Step-6: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-29)

    [0528] To a stirred solution of 5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-4-amine (A3.8) (100 mg, 0.31 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A3.9) (0.11 gm 0.37 mmol, 1.2 eq) in acetonitrile (3 mL) was added pyridine (0.075 mL, 0.93 mmol, 3 eq) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude was purified by prep HPLC to afford the titled compound N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-29). Yield: 35 mg, 19%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (bs, 1H), 7.93-7.83 (m, 4H), 7.31 (dd, J=12.6, 2.5 Hz, 1H), 7.15 (ddd, J=8.6, 2.6, 1.2 Hz, 1H), 7.02 (t, J=9.1 Hz, 1H), 5.65 (m, 1H), 3.53 (d, J=14.3 Hz, 5H), 2.98 (t, J=5.5 Hz, 2H), 2.58 (s, 6H), 2.17 (d, J=4.0 Hz, 2H), 1.71 (s, 3H); HPLC purity: 98.3%; LCMS Calculated for C.sub.24H.sub.27ClFN.sub.5O.sub.4S.sub.2: 567.12; Observed: 568.35 [M+H].sup.+.

    Step-7: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-33)

    [0529] To a stirred solution of N1-(5-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-29) (0.20 g, 0.35 mmol, 1 eq) in ethyl acetate (10 mL) was added PtO.sub.2 (0.10 g) under nitrogen atmosphere. The reaction mixture was stirred at 100 psi hydrogen gas pressure at room temperature for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was evaporated under reduced pressure. The crude was purified by column chromatography followed by prep HPLC to afford the titled compound N1-(5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-33). Yield: 50 mg, 25%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 7.96 (m, 4H), 7.38-7.29 (m, 1H), 7.23-7.15 (m, 1H), 7.06 (t, J=9.0 Hz, 1H), 3.71 (s, 3H), 3.33 (m, 2H), 2.64-2.50 (m, 9H), 2.11-1.96 (m, 2H), 1.48 (d, J=32.2 Hz, 5H); HPLC purity: 96.85%; LCMS Calculated for C.sub.24H.sub.29ClFN.sub.5O.sub.4S.sub.2:569.13; Observed: 570.1 [M+H].sup.+.

    Example A4: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-75)

    [0530] ##STR01304## ##STR01305##

    Step-1: Synthesis of N-(1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.2)

    [0531] To a stirred solution of 1,3-dimethyl-1H-pyrazol-5-amine (A4.1) (3 g, 27 mmol, 1 eq) in ethyl acetate (30 mL) was added potassium acetate (2.91 g, 29.70 mmol, 1.1 eq) and acetic anhydride (3.03 g, 29.7 mmol, 1.1 eq) at 0° C. The reaction mixture was stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product N-(1,3-dimethyl-1H-pyrazol-5-yl)acetamide A4.2 (4 g, 96.8%). LCMS: 154.09 [M+H].sup.+.

    Step-2: Synthesis of N-(4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.3)

    [0532] To a stirred solution of N-(1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.2) (4 g, 26.14 mmol, 1 eq) in DCM (40 mL) was added NBS (5.58 g, 31.37 mmol, 1.2 eq) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM and washed with sodium thiosulphate solution. The organic layer was separated, washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to provide titled compound N-(4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.3) (5.5 g, crude). The crude was used as such for next step without purification. LCMS: 232 [M+H].sup.+.

    Step-3: Synthesis of N-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.5)

    [0533] To a stirred solution of N-(4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.3) (1.5 g, 6.46 mmol, 1 eq) and 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A4.4) (4.3 g, 12.93 mmol, 2 eq) in 1.4 dioxane:H.sub.2O (4:1, 30 mL) was added K.sub.2CO.sub.3 (1.78 g, 10.29 mmol, 2 eq) at room temperature. reaction mixture was purged with argon for 10 min followed by addition of X-phos (0.061 g, 0.12 mmol, 0.02 eq) and Pd(OAC).sub.2 (0.1 g, 0.45 mmol, 0.07 eq) The reaction mixture was stirred at 100° C. for 12 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was partitioned between water and ethyl acetate. The organic layers were separated, washed with water dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by column chromatography to provide the desired compound N-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.5) (1 g, 42.7%). LCMS: 363.13 [M+H].sup.+.

    Step-4: Synthesis of N-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.6)

    [0534] To a stirred solution of N-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.5) (1 g, 2.75 mmol, 1 eq) in MeOH:ethyl acetate (1:1, 20 mL) was added and PtO.sub.2 (0.2 g) at room temperature. the reaction mixture was stirred at 50 Psi hydrogen gas pressure at room temperature for 1.5 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite, the filtrate was evaporated under reduced pressure. The crude was purified by column chromatography followed by prep HPLC to afford titled compound N-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.6) (0.7 g, 71%). LCMS: 365.15 [M+H].sup.+.

    Step-5: Synthesis of 4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-amine (A4.7)

    [0535] A solution of N-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)acetamide (A4.6) (0.71 g, 1.94 mmol, 1 eq) in a mixture of ethanol and a solution of sodium hydroxide (50% aq) (1:1, 14 mL) was stirred at 90° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure. The crude was diluted with water and extracted with DCM. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to afford titled compound 4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-amine (A4.7) (0.45 g, 72.5%). LCMS: 323.14 [M+H].sup.+.

    Step-6: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-75)

    [0536] To a stirred solution of 4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-amine (A4.7) (0.45 g, 1.39 mmol, 1 eq) in ACN (10 mL) was added pyridine (0.22 mL, 2.78 mmol, 2 eq) at 0° C., stirred the reaction mixture for 10 min at same temperature followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A4.8) (0.44 g, 1.53 mmol, 1.1 eq) at 0° C. The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by prep HPLC to afford titled compound N1-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-75). Yield: 20 mg, 2.5%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.48 (s, 1H), 8.02 (d, J=1.3 Hz, 4H), 7.29 (dd, J=12.3, 2.5 Hz, 1H), 7.19-7.11 (m, 1H), 6.98 (t, J=9.1 Hz, 1H), 3.52 (s, 3H), 3.18 (d, J=11.4 Hz, 2H), 2.66 (s, 6H), 2.22 (t, J=12.0 Hz, 2H), 2.10 (s, 3H), 1.81 (ddd, J=15.4, 7.8, 3.3 Hz, 1H), 1.72-1.64 (m, 2H), 1.08 (s, 2H); HPLC purity: 98.14%; LCMS Calculated for C.sub.24H.sub.29ClFN.sub.5O.sub.4S.sub.2: 569.13; Observed: 570.20 [M+H].sup.+.

    Example A5: Synthetic Scheme for Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-55)

    [0537] ##STR01306## ##STR01307##

    Step-1: Synthesis of tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A5.3)

    [0538] To a mixture of 4-bromo-1-methyl-1H-pyrazol-3-amine (A5.1) (1.5 g, 8.5 mmol, 1 eq) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A5.2) (3.42 g, 11 mmol, 1.3 eq) in 1,4-dioxane:H.sub.2O mixture (4:1, 20 mL), Cs.sub.2CO.sub.3 (5.55 g, 17.03 mmol, 2 eq) was added at room temperature, purged reaction mixture with argon for 10 min followed by the addition of dichlorobis(triphenylphosphine)palladium(II) PdCl.sub.2(PPh.sub.3).sub.2 (0.41 g, 0.59 mmol, 0.07 eq) and stirred at 100° C. for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A5.3) (1.8 g, 75.9%). LCMS: 279.17 [M+H].sup.+.

    Step-2: Synthesis of tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (A5.4)

    [0539] To a stirred solution of 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A5.3) (1.8 g, 6.4 mmol, 1 eq) in a mixture of methanol and ethyl acetate (1:1, 36 mL) was added triethylsilane (16 mL, 97.12 mmol, 15 eq) and Pd/C (0.36 g) at 0° C. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite, the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired compound tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (A5.4) (1.3 g, 71.8%). LCMS: 281.19 [M+H].sup.+.

    Step-3: Synthesis of tert-butyl 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (A5.6)

    [0540] To a stirred solution of tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (A5.4) (1.3 g, 4.63 mmol, 1 eq) in acetonitrile (25 mL) was added pyridine (0.73 mL, 9.27 mmol, 2 eq) at 0° C., stirred the reaction mixture for 5 min at same temperature followed by portion wise addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride A5.5 (1.44 g, 5.10 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired compound tert-butyl 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (A5.6) (1.5 g, 61.4%). LCMS: 528.19 [M+H].sup.+.

    Step-4: Synthesis of N1,N1-dimethyl-N4-(1-methyl-4-(piperidin-4-yl)-1H-pyrazol-3-yl)benzene-1,4-disulfonamide (A5.7)

    [0541] To a stirred solution of tert-butyl 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (A5.6) (1.5 g, 2.8 mmol, 1 eq) in DCM (7.5 mL, 5 Vol) was added TFA (7.5 mL, 5 Vol) at 0° C. The reaction mixture was stirred at room temperature for 2 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated to dryness and crude salt was neutralized by using saturated solution of sodium bicarbonate to attain a pH of about 7 and extracted with DCM. The organic layers were separated, washed with water dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to provide the desired compound N1,N1-dimethyl-N4-(1-methyl-4-(piperidin-4-yl)-1H-pyrazol-3-yl)benzene-1,4-disulfonamide (A5.7) (0.5 g, crude). The crude was used as such next step without purification. LCMS: 428.13 [M+H].sup.+.

    Step-5: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-55)

    [0542] To a stirred solution of N1,N1-dimethyl-N4-(1-methyl-4-(piperidin-4-yl)-1H-pyrazol-3-yl)benzene-1,4-disulfonamide (A5.7) (0.12 g, 0.57 mmol, 1 eq) and 1-bromo-4-chloro-2-fluorobenzene (A5.8) (0.27 g, 0.63 mmol, 1.1 eq) in 1,4-dioxane (5 mL) was added NaOtBu (0.11 g, 1.14 mmol, 2 eq) at room temperature, reaction mixture was purged with argon for 10 min followed by addition of Davephos (13.45 mg, 0.03 mmol, 0.06 eq) and Pd.sub.2(dba).sub.3 (15.66 mg, 0.02 mmol, 0.03 eq). The reaction mixture was stirred at 90° C. for 12 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were separated, washed with water dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by silica gel column chromatography to provide the desired compound N1-(4-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-55). Yield: 0.018 mg, 5.1%; Appearance: Off-white solid; 1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H), 8.06-7.92 (m, 4H), 7.52 (s, 1H), 7.31 (dd, J=12.5, 2.5 Hz, 1H), 7.22-7.14 (m, 1H), 7.06 (t, J=9.1 Hz, 1H), 3.62 (s, 3H), 3.30 (m, 2H), 2.65-2.57 (m, 8H), 2.38 (m, 1H), 1.73 (d, J=10.8 Hz, 2H), 1.55 (qd, J=12.2, 3.7 Hz, 2H); HPLC purity: >99%; LCMS Calculated for C.sub.23H.sub.27ClFN.sub.5O.sub.4S.sub.2: 555.12; Observed: 556.1 [M+H].sup.+.

    Example A6: Synthesis of N1-(2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-296)

    [0543] ##STR01308## ##STR01309##

    Step-1: Synthesis of tert-butyl 6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (A6.3)

    [0544] A pyrex tube was charged with a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride (A6.1) (850 mg, 3.62 mmol, 1 eq), 1-bromo-4-chloro-2-fluorobenzene (A6.2) (833 mg, 3.98 mmol, 1.1 eq) and cesium carbonate (2.36 g, 7.23 mmol, 2 eq) in toluene (15 mL). The tube was sealed with a septum and the reaction mixture was purged with argon for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (99 mg, 0.108 mmol, 0.3 eq) and BINAP (157 gm 0.253 mmol, 0.07 eq) were added to the reaction mixture under an argon atmosphere. The tube was then fitted with a screw cap and the reaction mixture was heated at 100° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound tert-butyl 6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (A6.3) (1 g, 84.74%). LCMS: 327.10 [M+H].sup.+.

    Step-2: Synthesis of 2-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane TFA Salt (A6.4)

    [0545] To a stirred solution of tert-butyl 6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (A6.3) (1 g, 3.07 mmol, 1 eq) in DCM (20 mL) was added trifluoroacetic acid (1.75 mL, 12.27 mmol, 4 eq) at room temperature and the reaction mixture was stirred at the same temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was further co-evaporated with DCM to dryness under reduced pressure to afford the titled compound 2-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane (A6.4) (1.1 g, crude) as TFA salt. This compound was used in the next step without further purification. LCMS: 227.10 [M+H].sup.+.

    Step-3: Synthesis of 2-(4-chloro-2-fluorophenyl)-6-(2-nitrophenyl)-2,6-diazaspiro[3.3]heptane (A6.6)

    [0546] To a stirred solution of 2-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptane TFA salt (A6.4) (1.1 g, 3.41 mmol, 1 eq) in DMF (20 mL) was added potassium carbonate and 1-fluoro-2-nitrobenzene (A6.5) (0.528 g, 3.75 mmol, 1.1 eq). The reaction mixture was heated at 85° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated reduced pressure to dryness to afford the titled compound 2-(4-chloro-2-fluorophenyl)-6-(2-nitrophenyl)-2,6-diazaspiro[3.3]heptane (A6.6) (0.71 g, crude). This compound was used in the next step without further purification. LCMS: 348.10 [M+H].sup.+.

    Step-4: Synthesis of 2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)aniline (A6.7)

    [0547] To a stirred solution of 2-(4-chloro-2-fluorophenyl)-6-(2-nitrophenyl)-2,6-diazaspiro[3.3]heptane (A6.6) (600 mg, 1.73 mmol, 1 eq) in a mixture of water (2 mL) and ethanol (10 mL) was added iron powder (386 mg, 6.92 mmol, 4 eq) and ammonium chloride (370 mg, 6.92 mmol, 4 eq). The reaction mixture was heated at 80° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)aniline (A6.7) (310 mg, 56.56%). LCMS: 318.10 [M+H].sup.+.

    Step-5: Synthesis of N-(2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A6.9)

    [0548] To a stirred solution of 2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)aniline (A6.7) (200 mg, 0.631 mmol, 1 eq) in acetonitrile (5 mL) was added pyridine (0.1 mL, 1.26 mmol, 2 eq) and followed by 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride A6.8 (196 mg, 0.694 mmol, 1.1 eq) at room temperature and the reaction mixture was stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with 1N aqueous HCl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel. The compound was further triturated with diethyl ether, the solids were filtered out and dried under reduced pressure to afford the titled compound N1-(2-(6-(4-chloro-2-fluorophenyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-296). Yield: 30 mg, 8.42%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.58 (s, 1H), 7.95 (s, 4H), 7.24 (d, J=12.4 Hz, 1H), 7.12-7.03 (m, 2H), 6.58 (t, J=9.2 Hz, 1H), 6.52 (t, J=7.6 Hz, 1H), 6.48-6.38 (m, 2H), 4.03 (d, J=6.8 Hz, 8H), 2.65 (s, 6H); HPLC purity: 99.53%; LCMS calculated for C.sub.25H.sub.26ClFN.sub.4O.sub.4S.sub.2: 564.11; Observed: 565.15 [M+H].sup.+.

    Example A7: Synthesis of N1-(4-(1-(2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-40)

    [0549] ##STR01310## ##STR01311##

    Step-1: Synthesis of tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A7.3)

    [0550] To a mixture of 4-bromo-1-methyl-1H-pyrazol-3-amine (A7.1) (1.5 g, 8.5 mmol, 1 eq) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A7.2) (3.42 g, 11 mmol, 1.3 eq) in 1,4-dioxane:H.sub.2O mixture (4:1, 20 mL), Cs.sub.2CO.sub.3 (5.55 g, 17.03 mmol, 2 eq) was added at room temperature, purged reaction mixture with argon for 10 min followed by the addition of Dichlorobis(triphenylphosphine)palladium(II) PdCl.sub.2(PPh.sub.3).sub.2 (0.41 g, 0.59 mmol, 0.07 eq) and stirred at 100° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A7.3) (1.5 g, 63.5%). LCMS: 279.17 [M+H].sup.+.

    Step-2: Synthesis of tert-butyl 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A7.5)

    [0551] To a stirred solution of tert-butyl 4-(3-amino-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A7.3) (1.5 g, 5.39 mmol, 1 eq) in acetonitrile (20 mL) was added pyridine (0.9 mL, 10.79 2 eq) at 0° C., stirred the reaction mixture for 5 min at same temperature followed by portion wise addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A7.4) (1.68 g, 5.93 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure. The crude was purified by column chromatography to afford titled compound tert-butyl 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A7.5) (1.85 g, 65.3%). LCMS: 526.17 [M+H].sup.+.

    Step-3: Synthesis of N1,N1-dimethyl-N4-(1-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-3-yl)benzene-1,4-disulfonamide (A7.6)

    [0552] To a stirred solution of tert-butyl 4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A7.5) (1.85 g, 3.5 mmol, 1 eq) in DCM (9.25 mL, 5 Vol) was added TFA (9.25 mL, 5 Vol) at 0° C. The reaction mixture was stirred at room temperature for 2 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was evaporated to dryness and saturated solution of sodium bicarbonate was added to reaction mixture up to pH of about 8, obtained solid was filtered and concentrated under reduced pressure provide the desired N1,N1-dimethyl-N4-(1-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-3-yl)benzene-1,4-disulfonamide (A7.6) (0.8 g, crude). The crude was used as such next step without purification. LCMS: 426.12 [M+H].sup.+.

    Step-4: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.8)

    [0553] To a stirred solution of N1,N1-dimethyl-N4-(1-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-3-yl)benzene-1,4-disulfonamide A7.6 (0.32 g, 1.5 mmol, 1 eq) and 1-bromo-4-chloro-2-fluorobenzene (A7.7) (0.71 g, 1.68 mmol, 1.1 eq) in 1,4-dioxane (20 mL) was added NaOtBu (0.29 g, 3 mmol, 2 eq) at room temperature, reaction mixture was purged with argon for 15 min followed by addition of Davephos (3 mg, 0.09 mmol, 0.06 eq) and Pd.sub.2(dba).sub.3 (42 mg, 0.46 mmol, 0.03 eq). The reaction mixture was stirred at 90° C. for 12 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were separated, washed with water dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by silica gel column chromatography to provide the desired compound N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.8) (0.33 g, 35.8%). LCMS: 554.10 [M+H].sup.+.

    Step-5: Synthesis of N-(4-(1-(2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.9)

    [0554] To a stirred solution of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A7.8) (0.3 g, 0.54 mmol, 1 eq) in methanol:ethyl acetate (1:1, 9 mL) was added triethylsilane (0.94 mL, 8.12 mmol, 15 eq) and Pd/C (0.06 g) at 0° C. The reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite, the filtrate was evaporated under reduced pressure. The crude was diluted with water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired N1-(4-(1-(2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-pyrazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-40). Yield: 0.015 g, 5.3%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.04 (s, 1H), 8.06-7.93 (m, 4H), 7.53 (s, 1H), 7.17-7.01 (m, 3H), 7.01-6.91 (m, 1H), 3.64 (s, 3H), 3.35 (s, 2H), 2.65 (s, 6H), 2.62-2.56 (m, 2H), 2.39-2.33 (m, 1H), 1.77-1.68 (m, 2H), 1.61-1.52 (m, 2H); HPLC purity: 97.08%; LCMS Calculated for C.sub.23H.sub.28FN.sub.5O.sub.4S.sub.2: 521.16; Observed: 522.40 [M+H].sup.+.

    Example A8: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylisoxazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-65)

    [0555] ##STR01312##

    Step-1: Synthesis of tert-butyl 4-(5-amino-3-methylisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A8.3)

    [0556] To a stirred solution of 3-methylisoxazol-5-amine A8.1 (1 g, 10 mmol, 1 eq) in acetic acid (15 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (A8.2) (3.04 g, 15 mmol, 1.5 eq). The reaction mixture was stirred at 70° C. for 12 h. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated; crude was basified with 10% NaOH solution and extracted with ethyl acetate. The combined organic extracted were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product tert-butyl 4-(5-amino-3-methylisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A8.3) (2 g, 70%). LCMS: 280.16 [M+H].sup.+.

    Step-2: Synthesis of tert-butyl 4-(5-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-3-methylisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A8.5)

    [0557] To a mixture of tert-butyl 4-(5-amino-3-methylisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A8.3) (2 g, 7.16 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A8.4) (2.44 g, 8.6 mmol, 1.2 eq) in dry THE (15 mL) was added LiHMDS (11 mL, 10.7 mmol, 1.5 eq) at −78° C., stirred reaction mixture for 15 min at same temperature then again stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 1N HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was triturated with diethyl ether and concentrated under reduced pressure to afford the desired product tert-butyl 4-(5-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-3-methylisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A8.5) (3 g, 79%). LCMS: 527.16 [M+H].sup.+.

    Step-3: Synthesis of N,N-dimethyl-N4-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)isoxazol-5-yl)benzene-1,4-disulfonamide, TFA Salt (A8.6)

    [0558] To a stirred solution of tert-butyl 4-(5-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-3-methylisoxazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A8.5) (2 g, 3.8 mmol, 1 eq) in DCM (50 mL) was added dropwise TFA (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated, crude was triturated with diethyl ether dried under reduced pressure to provide the desired compound N1,N1-dimethyl-N4-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)isoxazol-5-yl)benzene-1,4-disulfonamide, TFA salt (A8.6) (2 g, crude). The crude was used as such next step without purification. LCMS: 427.10 [M+H].sup.+.

    Step-4: Synthesis of N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylisoxazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A8.8)

    [0559] To a mixture of N1,N1-dimethyl-N4-(3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)isoxazol-5-yl)benzene-1,4-disulfonamide, TFA salt (A8.6) (2 g, 3.6 mmol, 1 eq) and 2-bromo-4-chloro-1-fluorobenzene (A8.7) (0.92 g, 4.4 mmol, 1.2 eq) in 1,4-dioxane (50 mL) was added NaOtBu (1.41 g, 14.7 mmol, 4 eq) purged reaction mixture with nitrogen followed by addition of Davephos (84 mg, 2.16 mmol, 0.06 eq) and Pd.sub.2(dba).sub.3 (98 mg, 0.11 mmol, 0.03 eq). The reaction mixture was stirred at 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was triturated with hexane and concentrated under reduced pressure. The crude product was purified by prep HPLC to afford the desired product N1-(4-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylisoxazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-65). Yield: 30 mg, 2%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08-7.92 (m, 4H), 7.33 (dt, J=11.4, 3.2 Hz, 1H), 7.17 (dd, J=8.8, 2.5 Hz, 1H), 7.05 (t, J=9.1 Hz, 1H), 5.83-5.69 (m, 1H), 3.59 (q, J=3.6 Hz, 2H), 3.11 (t, J=5.5 Hz, 2H), 2.63 (s, 6H), 2.89 (m, 2H), 2.16 (s, 3H), 1 exchangeable proton not observed due to moisture in the solvent; HPLC purity: 95.85%; LCMS Calculated for C.sub.23H.sub.24ClFN.sub.4O.sub.5S.sub.2: 554.09; Observed: 555.0 [M+H].sup.+.

    Example A9: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-64)

    [0560] ##STR01313## ##STR01314##

    Step-1: Synthesis of ethyl 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate (A9.3)

    [0561] To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (A9.1) (1 g, 4.7 mmol, 1 eq) and ethyl piperidine-4-carboxylate (A9.2) (1.1 g, 7.1 mmol, 1.5 eq) in DMF (20 mL) was added Cs.sub.2CO.sub.3 (3 g, 9.4 mmol, 2 eq) reaction mixture was purged with argon for 15 min followed by addition of Davephos (110 mg, 0.28 mmol, 0.06 eq) and Pd.sub.2(dba).sub.3 (430 mg, 0.47 mmol, 0.1 eq). The reaction mixture was stirred at 100° C. for 4 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were separated, washed with water dried over Na.sub.2SO.sub.4 and concentrated. The crude residue was purified by silica gel column chromatography to provide the desired ethyl 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate (A9.3) (500 mg, 38%). LCMS: 286.09 [M+H].sup.+.

    Step-2: Synthesis of 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic Acid (A9.4)

    [0562] To stirred solution of ethyl 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate (A9.3) (0.5 g, 2.78 mmol, 1 eq) in ethanol:Water (5:1, 12 mL) was added LiOH (83 mg, 3.5 mmol, 2 eq) at room temperature. The mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated and the residue was acidified with dil. HCl and extracted with DCM. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford titled compound 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic acid (A9.4) (400 mg, crude). The crude was used as such next step without purification. LCMS: 258.06 [M+H].sup.+.

    Step-3: Synthesis of 2-(1-(4-chloro-2-fluorophenyl)piperidine-4-carbonyl)hydrazine-1-carbothioamide (A9.6)

    [0563] To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperidine-4-carboxylic acid (A9.4) (400 mg, 1.5 mmol, 1 eq) in DMF (10 mL) was added HATU (855 mg, 2.2 mmol, 1.5 eq) and NMM (454 mg, 4.5 mmol, 3 eq) at room temperature, stirred the reaction mixture for 10 min followed by addition of hydrazinecarbothioamide (A9.5) (170 mg, 1.86 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 16 h. The reaction progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water then methanol was added, filtered the solid formed and filtrate was concentrated under reduced pressure to afford the titled 2-(1-(4-chloro-2-fluorophenyl)piperidine-4-carbonyl)hydrazine-1-carbothioamide (A9.6) (450 mg, 87%). LCMS: 331.07 [M+H].sup.+.

    Step-4: Synthesis of 5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3,4-thiadiazol-2-amine (A9.7)

    [0564] Stirred the solution of 2-(1-(4-chloro-2-fluorophenyl)piperidine-4-carbonyl)hydrazine-1-carbothioamide (A9.6) (450 mg, 1.3 mmol, 1 eq) in H.sub.2SO.sub.4 (15 mL) at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water then ammonia solution and methanol were added, filtered the reaction mixture, filtrated was concentrated under reduced pressure to afford the desired product 5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3,4-thiadiazol-2-amine (A9.7) (400 mg, crude). The crude was used as such next step without purification. LCMS: 313.06 [M+H].sup.+.

    Step-5: Synthesis of N1-(5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-64)

    [0565] To a stirred solution of 5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3,4-thiadiazol-2-amine (A9.7) (400 mg, 1.2 mmol, 1 eq) in acetonitrile (20 mL) was added pyridine (0.21 mL, 2.4 mmol, 2 eq) at 0° C., stirred the reaction mixture for 15 min followed addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A9.8) (407 g, 1.4 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to afford titled compound N1-(5-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-64). Yield: 60 mg, 8%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.27 (s, 1H), 8.08-8.00 (m, 2H), 7.96-7.88 (m, 2H), 7.32 (dd, J=12.4, 2.5 Hz, 1H), 7.17 (ddd, J=8.8, 2.4, 1.0 Hz, 1H), 7.07 (t, J=9.1 Hz, 1H), 3.39-3.32 (m, 2H), 3.13-3.06 (m, 1H), 2.83-2.6 (m, 2H), 2.64 (s, 6H), 2.13-2.04 (m, 2H), 1.88-1.73 (m, 2H); HPLC purity: 96.07%; LCMS Calculated for C.sub.21H.sub.23ClFN.sub.5O.sub.4S.sub.3: 559.06; Observed: 559.9 [M+H].sup.+.

    Example A10: Synthesis of N1-(3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-95)

    [0566] ##STR01315## ##STR01316##

    Step-1: Synthesis of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (A10.2)

    [0567] To a stirred solution of compound (A10.1) (5 g, 22 mmol, 1 eq) in DMF (25 mL) was added K.sub.2CO.sub.3 (4.56 g, 33 mmol, 1.5 eq) at 0° C. followed by addition of methyl iodide (1.64 g, 26.4 mmol, 1.2 eq) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by column chromatography to provide the desired compound 3,5-dibromo-1-methyl-1H-1,2,4-triazole (A10.2). The reaction was repeated on 5 g scale & combined yield details are (9 g, 85.87%). LCMS: 239.87 [M+H].sup.+.

    Step-2: Synthesis of 3-bromo-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.4)

    [0568] To a stirred solution of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (A10.2) (4 g, 16.8 mmol, 1 eq) in 1,4-dioxane (30 mL) were added DIPEA (5.8 g, 33.6 mmol, 2 eq) and DMA (15 mL) at room temperature followed by addition of (4-methoxyphenyl)methanamine A10.3 (9.2 g, 67.2 mmol, 4 eq). The reaction mixture was stirred at 120° C. for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by silica gel column chromatography to provide the desired compound 3-bromo-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.4) (2.6 g, 53%). LCMS: 297.03 [M+H].sup.+.

    Step-3: Synthesis of 3-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.6)

    [0569] To a mixture of 3-bromo-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.4) (1 g, 3.37 mmol, 1 eq), 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A10.5) (1.25 g, 3.71 mmol, 1.1 eq) and Na.sub.2CO.sub.3 (0.71 g, 6.75 mmol, 2 eq) in a mixture of 1,4-dioxane and water (4:1, 10 mL) was purged with argon for 15 min followed by the addition of Tetrakis(triphenylphosphine)palladium(0) (0.27 g, 2.36 mmol, 0.07 eq). The reaction mixture was stirred at 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 3-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.6) (1 g, 69.4%). LCMS: 428.16 [M+H].sup.+.

    Step-4: Synthesis of 3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.7)

    [0570] To a stirred solution of 3-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.6) (1 g, 2.34 mmol, 1 eq) in methanol (20 mL), Pd/C (0.2 g) was added. The reaction mixture was stirred at room temperature for 12 h under hydrogen balloon pressure. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through Celite, filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.7) (0.5 g, 50%). LCMS: 430.17 [M+H].sup.+.

    Step-5: Synthesis of 3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.8)

    [0571] 3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.7) (0.5 g, 1.16 mmol, 1 eq) was taken in TFA (2.5 mL) at 0° C. then stirred it room temperature for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with ice cold NaHCO.sub.3 solution and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The crude was washed with water and pentane to provide the desired compound 3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.8) (0.3 g, 82.87%). LCMS: 310.12 [M+H].sup.+.

    Step-6: Synthesis of N1-(3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-95)

    [0572] To a stirred solution of 3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-1,2,4-triazol-5-amine (A10.8) (0.3 g, 0.97 mmol, 1 eq) in DMF (15 mL) was added NaH (0.14 g, 5.8 mmol, 6 eq) at 0° C., stirred the reaction mixture at room temperature for 15 min followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A10.9) (0.41 g, 1.45 mmol, 1.5 eq). The reaction mixture was stirred at 80° C. for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by column chromatography followed by prep HPLC to provide the desired compound N1-(3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-95). Yield: 0.07 g, 13.2%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.78 (s, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.88 (d, J=8.1 Hz, 2H), 7.32 (dd, J=12.2, 2.4 Hz, 1H), 7.21-7.13 (m, 1H), 7.08 (t, J=9.1 Hz, 1H), 3.45 (s, 3H), 3.38 (d, J=12.2 Hz, 2H), 2.91-2.89 (m, 1H), 2.80-2.69 (m, 2H), 2.64 (s, 6H), 2.10-1.97 (m, 2H), 1.81-1.73 (m, 2H); HPLC purity: >99%; LCMS Calculated for C.sub.22H.sub.26ClFN.sub.6O.sub.4S.sub.2:556.11; Observed: 557.10 [M+H].sup.+.

    Example A11: Synthesis of 4-((3-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-1H-pyrazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-96)

    [0573] ##STR01317## ##STR01318##

    Step-1: Synthesis of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate A11.2

    [0574] To a stirred solution of ethyl piperidine-4-carboxylate (A11.1) (10 g, 63.61 mmol, 1 eq) and boc anhydride (13.4 mL, 95.41 mmol, 1.5 eq) in DCM (300 mL) was added drop wise TEA (13.4 mL, 95.41 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate A11.2 (8 g, 48.89%). LCMS: 358.16 [M+H].sup.+.

    Step-2: Synthesis of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (A11.4)

    [0575] To a stirred solution of 1-(tert-butyl) 4-ethyl piperidine-1,4-dicarboxylate (A11.2) (3 g, 11.66 mmol, 1 eq) and N,O-dimethylhydroxylamine (A11.3) (1.3 g, 13.99 mmol, 1.2 eq) in THE (100 mL) was added drop wise isopropyl magnesium chloride (11.66 mL, 23.32 mmol, 2 eq) at −20° C. The reaction mixture was stirred at −5° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (A11.4) (2.1 g, 66.12%). LCMS: 273.17 [M+H].sup.+.

    Step-3: Synthesis of tert-butyl 4-acetylpiperidine-1-carboxylate (A11.5)

    [0576] To a stirred solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (A11.4) (2 g, 10.64 mmol, 1 eq) in THE (40 mL) was added methyl magnesium chloride (10.29 mL, 30.87 mmol, 2.9 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with NH.sub.4Cl and extracted with ethyl acetate. The organic layer was separated washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product tert-butyl 4-acetylpiperidine-1-carboxylate (A11.5) (1.3 g, 89.82%). LCMS: 228.15 [M+H].sup.+.

    Step-4: Synthesis of tert-butyl (Z)-4-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate (A11.6)

    [0577] A solution of tert-butyl 4-acetylpiperidine-1-carboxylate (A11.5) (2 g, 8.80 mmol, 1 eq) in DMF.DMA (6.3 g, 53.79 mmol, 6 eq) was stirred at 110° C. for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with water and 1% HCl, dried over Na.sub.2SO.sub.4 and concentrated to provide the desired tert-butyl (Z)-4-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate (A11.6) (2 g Crude). The crude was used as such next step without further purification LCMS: 283.19 [M+H].sup.+.

    Step-5: Synthesis of tert-butyl 4-(1H-pyrazol-3-yl)piperidine-1-carboxylate (A11.7)

    [0578] To a stirred solution of tert-butyl (Z)-4-(3-(dimethylamino)acryloyl)piperidine-1-carboxylate (A11.6) (2 g, 7.80 mmol, 1 eq) in hydrazine hydrate (30 mL). The reaction mixture was stirred at 110° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired tert-butyl 4-(1H-pyrazol-3-yl)piperidine-1-carboxylate (A11.7). LCMS: 252.16 [M+H].sup.+.

    Step-6: Synthesis of tert-butyl 4-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (A11.9)

    [0579] To a stirred solution of tert-butyl 4-(1H-pyrazol-3-yl)piperidine-1-carboxylate A11.7 (0.45 g, 1.77 mmol, 1 eq) & 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A11.8) (0.61 g, 2.15 mmol, 1.2 eq) in ACN (8 mL) was added pyridine (0.42 mL, 5.31 mmol, 3 eq) at 0° C. followed by addition of compound 11.8 (0.21 g, 0.75 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product tert-butyl 4-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (A11.9). LCMS: 499.16 [M+H].sup.+.

    Step-7: Synthesis of N,N-dimethyl-4-((3-(piperidin-4-yl)-1H-pyrazol-1-yl)sulfonyl)benzenesulfonamide (A11.10)

    [0580] To a stirred solution of tert-butyl 4-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (A11.9) (0.3 g, 0.60 mmol, 1 eq) in DCM (5 mL), 50% TFA (2 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with ether & concentrated to afford the titled compound N,N-dimethyl-4-((3-(piperidin-4-yl)-1H-pyrazol-1-yl)sulfonyl)benzenesulfonamide (A11.10) (0.26 g, Crude). The crude was used as such next step without purification. LCMS: 399.11 [M+H].sup.+.

    Step-8: Synthesis of 4-((3-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-1H-pyrazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-96)

    [0581] To a stirred solution of N,N-dimethyl-4-((3-(piperidin-4-yl)-1H-pyrazol-1-yl)sulfonyl)benzenesulfonamide (A11.10) (0.07 g, 0.18 mmol, 1 eq) and 5-chloro-2,3-difluoropyridine (A11.11) (39 mg, 0.26 mmol, 1.5 eq) in DMF (3 mL) was added DIPEA (0.15 mL, 0.88 mmol, 5 eq) at room temperature. The reaction mixture was stirred at 100° C. for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with water and 1% HCl, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by silica gel column chromatography followed by prep HPLC to provide the desired compound 4-((3-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-1H-pyrazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-96). Yield: 2 mg, 9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.44 (d, J=2.9 Hz, 1H), 8.18 (d, J=8.2 Hz, 2H), 8.13-7.98 (m, 3H), 7.80 (d, J=13.0 Hz, 1H), 6.65 (d, J=2.7 Hz, 1H), 3.92 (d, J=13.4 Hz, 2H), 2.64 (s, 6H), 2.94 (dt, J=32.4, 12.3 Hz, 3H), 1.93-1.84 (m, 2H), 1.72-1.60 (m, 2H); HPLC purity: 98.54%; LCMS Calculated for C.sub.21H.sub.23ClFN.sub.5O.sub.4S.sub.2: 527.09; Observed: 528.0 [M+H].sup.+.

    Example A12: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-oxoimidazolidin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide)(A-86)

    [0582] ##STR01319## ##STR01320##

    Step-1: Synthesis of tert-butyl (2-((1-(4-chloro-2-fluorophenyl)piperidin-4-yl)amino)ethyl)carbamate (A12.3)

    [0583] To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperidin-4-one (A12.1) (3.5 g, 11.32 mmol, 1 eq) and tert-butyl (2-aminoethyl)carbamate (A12.2) (1.81 g, 11.32 mmol, 1 eq) in methanol (50 mL) was added acetic acid (3.23 mL, 56.61 mmol, 5 eq) at room temperature, reaction mixture was stirred at room temperature for 3.5 h followed by addition of sodium cyanoborohydride (2.13 g, 33.96 mmol, 3 eq). The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduce pressure, crude was diluted with saturated solution of sodium bicarbonate and DCM. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the titled compound tert-butyl (2-((1-(4-chloro-2-fluorophenyl)piperidin-4-yl)amino)ethyl)carbamate (A12.3) (3.5 g, 83.3%). LCMS: 372.18 [M+H].sup.+.

    Step-2: Synthesis of N1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)ethane-1,2-diamine (A12.4)

    [0584] To a stirred solution of tert-butyl (2-((1-(4-chloro-2-fluorophenyl)piperidin-4-yl)amino)ethyl)carbamate (A12.3) (3.5 g, 9.41 mmol, 1 eq) in DCM (35 mL) was added HCl in 1,4-dioxane (35 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was concentrated, and the resulting residue was washed with ether and dried under vacuum to give desired compound N1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)ethane-1,2-diamine (A12.4) (2.4 g, 94.11%). LCMS: 272.13 [M+H].sup.+.

    Step-3: Synthesis of 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)imidazolidin-2-one (A12.5)

    [0585] To a stirred solution of N1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)ethane-1,2-diamine (A12.4) (2.4 g, 8.83 mmol, 1 eq) in ACN (25 mL) was added CDI (1.57 g, 9.71 mmol, 1.1 eq) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with saturated solution of sodium bicarbonate and DCM. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the titled compound 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)imidazolidin-2-one (A12.5) (1.3 g, 49.42%). LCMS: 298.10 [M+H].sup.+.

    Step-4: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-oxoimidazolidin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-86)

    [0586] To a stirred solution of 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)imidazolidin-2-one (A12.5) (0.4 g, 1.34 mmol, 1 eq) in THE (8 mL) was added NaH (0.06 g, 2.68 mmol, 2 eq) at 0° C., stirred the reaction mixture for 5 min at same temperature followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A12.6) (0.41 g, 1.47 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by prep HPLC to afford the titled compound 4-((3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-oxoimidazolidin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-86). Yield: 30 mg, 8%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19 (d, J=8.1 Hz, 2H), 8.01 (d, J=8.1 Hz, 2H), 7.30 (d, J=12.4 Hz, 1H), 7.16-7.14 (m, 1H), 7.06-7.03 (m, 1H), 3.86 (t, J=7.6 Hz, 2H), 3.62 (m, 1H), 3.50-3.41 (m, 2H), 2.67 (s, 9H), 1.74 (q, J=11.7 Hz, 2H), 1.62 (t, J=7.8 Hz, 3H); HPLC purity: 98.25%; LCMS Calculated for C.sub.22H.sub.26ClFN.sub.4O.sub.5S.sub.2: 544.10; Observed: 545.10 [M+H].sup.+.

    Example A13: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-67)

    [0587] ##STR01321## ##STR01322##

    Step-1: Synthesis of 1-(4-chloro-2-fluorophenyl)piperidin-4-one Oxime (A13.2)

    [0588] To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperidin-4-one (A13.1) (3.5 g, 15.42 mmol, 1 eq) in ethanol (35 mL) and water (35 mL) was added hydroxyl amine hydrochloride (1.6 g, 23.12 mmol, 1.5 eq). The reaction mixture was refluxed for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured in ice water; obtained solid was filtered & concentrated under reduced pressure to afford the desired product 1-(4-chloro-2-fluorophenyl)piperidin-4-one oxime (A13.2) (3.6 g, Crude). LCMS: 243.06 [M+H].sup.+.

    Step-2: Synthesis of 1-(4-chloro-2-fluorophenyl)piperidin-4-amine (A13.3)

    [0589] To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperidin-4-one oxime (A13.2) (3.5 g, 14.52 mmol, 1 eq) in methanol (40 mL) was added Raney Nickel (1.8 g, 50%) at room temperature, stirred the reaction mixture at room temperature for 12 h under hydrogen gas balloon pressure. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the titled compound 1-(4-chloro-2-fluorophenyl)piperidin-4-amine (A13.3) (2.1 g, 63.44%). LCMS: 229.08 [M+H].sup.+.

    Step-3: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-isocyanatopiperidine (A13.4)

    [0590] To a stirred solution of triphosgene (1.56 g, 5.26 mmol, 1 eq) in DCM (20 mL) was added 1-(4-chloro-2-fluorophenyl)piperidin-4-amine (A13.3) (1.2 g, 5.26 mmol, 1 eq) and DIPEA (3.6 mL, 21.05 mmol, 4 eq) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and DCM. The organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the desired product 1-(4-chloro-2-fluorophenyl)-4-isocyanatopiperidine (A13.4) (1.3 g, 97.77%). LCMS: 255.06 [M+H].sup.+.

    Step-4: Synthesis of 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-3-(2,2-dimethoxyethyl)urea (A13.6)

    [0591] To a stirred solution of 1-(4-chloro-2-fluorophenyl)-4-isocyanatopiperidine (A13.4) (1.3 g, 5.12 mmol, 1 eq) in acetonitrile (10 mL) was added 2,2-dimethoxyethan-1-amine (A13.5) (0.81 g, 7.67 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the resultant precipitate was filtered out and dried under reduced pressure to afford the desired product 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-3-(2,2-dimethoxyethyl)urea (A13.6) (1.5 g, 88.96%). LCMS: 360.14 [M+H].sup.+.

    Step-5: Synthesis of 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (A13.7)

    [0592] To a stirred solution of 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-3-(2,2-dimethoxyethyl)urea (A13.6) (1.5 g, 4.18 mmol, 1 eq) in methanol (15 mL) and water (15 mL) was added 1 M HCl (15 mL). The reaction mixture was stirred at room temperature for 72 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the titled compound 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (A13.7) (1.1 g, 89%). LCMS: 296.09 [M+H].sup.+.

    Step-6: Synthesis of 4-((3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-67)

    [0593] To a stirred solution of 1-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (A13.7) (0.3 g, 1.02 mmol, 1 eq) in THE (6 mL) was added NaH (41 mg 31.02 mmol, 1 eq) at 0° C., stirred reaction mixture at same temperature for 5 min followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A13.8) (0.29 g, 1.02 mmol, 1 eq). The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured in ice cold water; obtained precipitate was filtered and dried under reduced pressure. The crude product was purified by column chromatography followed by prep HPLC to afford the desired product 4-((3-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-67). Yield: 30 mg, 5.44%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.28-8.21 (m, 2H), 8.09-8.02 (m, 2H), 7.31 (dd, J=12.8 Hz, 12.4 Hz, 1H), 7-7.15 (m, 1H), 7.21-6.98 (m, 3H), 3.90-3.84 (m, 1H), 3.38-3.35 (m, 2H), 2.75 (t, J=12 Hz, 2H), 2.67 (s, 6H), 1.93-1.85 (m, 2H), 1.76-1.74 (m, 2H); HPLC purity: 98.23%; LCMS Calculated for C.sub.22H.sub.24ClFN.sub.4O.sub.5S.sub.2: 542.09; Observed: 543.10 [M+H].sup.+.

    Example A14: Synthesis of N1-(2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-19) and N1-(2-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-22)

    [0594] ##STR01323## ##STR01324##

    Step-1: Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(2-nitrophenyl)-1,2,3,6-tetrahydropyridine (A14.3)

    [0595] To a stirred solution of 1-chloro-2-nitrobenzene (A14.1) (0.2 g, 1.2 mmol, 1 eq) and 1-(4-chloro-2-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A14.2) (0.47 g, 1.4 mmol, 1.1 eq) in a mixture of 1,4-dioxane and water (4:1), K.sub.3PO.sub.4 (0.81 g, 3.7 mmol, 3 eq) was added and purged with argon for 30 min followed by the addition of Tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.1 mmol, 0.1 eq) and stirred at 100° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 1-(4-chloro-2-fluorophenyl)-4-(2-nitrophenyl)-1,2,3,6-tetrahydropyridine (A14.3) (0.3 g, 71%). LCMS: 333.07 [M+H].sup.+.

    Step-2: Synthesis of 2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)aniline (A14.4)

    [0596] To a stirred solution of 1-(4-chloro-2-fluorophenyl)-4-(2-nitrophenyl)-1,2,3,6-tetrahydropyridine (A14.3) (0.3 g, 1.5 mmol, 1 eq) in mixture of ethanol (3 mL) and water (1.2 mL) were added iron powder (0.24 g, 7.5 mmol, 5 eq) and ammonium chloride (0.24 g, 7.5 mmol, 5 eq) at room temperature. The resulting reaction mixture was heated at 80° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the filtrate was evaporated. The crude reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the titled compound 2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)aniline (A14.4) (0.2 g, 44%). LCMS: 303.10 [M+H].sup.+.

    Step-3: Synthesis of Synthesis of N1-(2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-19)

    [0597] To a stirred solution of 2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)aniline (A14.4) (0.1 g, 0.33 mmol, 1 eq) in acetonitrile (1 mL) was added pyridine (0.08 mL, 0.99 mmol, 3 eq) at 0° C. followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A14.5) (0.11 g, 0.397 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for overnight; the reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography to afford the desired product N1-(2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-19). Yield: 15 mg, 8%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.83 (s, 1H), 7.92 (s, 4H), 7.36 (dd, J=12.8 Hz, 2.8 Hz, 1H), 7.23-7.17 (m, 4H), 7.10 (t, J=9.2 Hz, 1H), 7.05-7.02 (m, 1H), 5.47 (m, 1H), 3.59 (m, 2H), 3.16 (t, J=5.6 Hz, 2H), 2.62 (s, 6H), 2.23 (m, 2H): HPLC purity: >99%; LCMS Calculated for C.sub.25H.sub.25ClFN.sub.3O.sub.4S.sub.2: 549.10; Observed: 550.15 [M+H].sup.+.

    Step-4: Synthesis of N1-(2-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-22)

    [0598] To the stirred solution of N1-(2-(1-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-19) (0.12 g, 2.1 mmol, 1 eq) in methanol (6 mL) was added PtO.sub.2 (24 mg). The reaction mixture was hydrogenated at 45 psi for 1 h at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, the Celite pad was washed with methanol and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to afford the titled compound N1-(2-(1-(4-chloro-2-fluorophenyl)piperidin-4-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-22). Yield: 43 mg, 35.83%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.11 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.88 (d, J=7.6 Hz, 2H), 7.34-7.30 (m, 2H), 7.26-7.15 (m, 3H), 7.06 (t, J=9.2 Hz, 2H), 3.29-3.26 (m, 2H), 2.64 (m, 8H), 1.65-1.57 (m, 2H), 1.23-1.20 (m, 2H), (1 is proton merged with solvent peak): HPLC purity: 99.31%; LCMS Calculated for C.sub.25H.sub.27ClFN.sub.3O.sub.4S.sub.2: 551.11; Observed: 552.1 [M+H].sup.+.

    Example A15: Synthesis of N1-(2-(4-(4-chloro-2-fluorophenyl)cyclohexyl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-69/Isomer-I) and (A-70/Isomer-II)

    [0599] ##STR01325## ##STR01326## ##STR01327##

    Step-1: Synthesis of 8-(4-chloro-2-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene A15.3

    [0600] To a mixture of 1-bromo-4-chloro-2-fluorobenzene A15.1 (3 g, 14.3 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (A15.2) (4.48 g, 15.7 mmol, 1.1 eq) in a mixture of 1,4-dioxane and water (4:1, 50 mL), Na.sub.2CO.sub.3 (3 g, 28.7 mmol, 2 eq) was added and purged with argon for 30 min followed by the addition of Tetrakis(triphenylphosphine)palladium(0) (1 g, 1.43 mmol, 0.1 eq) and stirred at 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 8-(4-chloro-2-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (A15.3) (3.3 g, 85.93%). LCMS: 269.07 [M+H].sup.+.

    Step-2: Synthesis of 8-(4-chloro-2-fluorophenyl)-1,4-dioxaspiro[4.5]decane (A15.4)

    [0601] The solution of 8-(4-chloro-2-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene A15.3 (3.3 g, 12.3 mmol, 1 eq) in ethyl acetate (50 mL) was added PtO.sub.2 (1.65 g), the reaction mixture was hydrogenated at 100 psi for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 8-(4-chloro-2-fluorophenyl)-1,4-dioxaspiro[4.5]decane (A15.4) (1.1 g, 33.13%). LCMS: 271.08 [M+H].sup.+.

    Step-3: Synthesis of 4-(4-chloro-2-fluorophenyl)cyclohexan-1-one (A15.5)

    [0602] To a stirred solution of 8-(4-chloro-2-fluorophenyl)-1,4-dioxaspiro[4.5]decane A15.4 (1.1 g, 4.07 mmol, 1 eq) in THE (20 mL) was added 10% aqueous H.sub.2SO.sub.4 (16.5 ml). The reaction mixture was stirred at 70° C. for 12 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 at 0° C. and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 4-(4-chloro-2-fluorophenyl)cyclohexan-1-one (A15.5) (0.8 g, 86.95%). LCMS: 227.06 [M+H].sup.+.

    Step-4: Synthesis of 4′-chloro-2′-fluoro-1,2,3,6-tetrahydro-[,1′-biphenyl]-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A15.7)

    [0603] To a stirred solution of 4-(4-chloro-2-fluorophenyl)cyclohexan-1-one (A15.5) (0.8 g, 3.53 mmol, 1 eq) in THE (10 mL) were added DBU (0.64 g, 4.24 mmol, 1.2 eq) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (A15.6) (1.28 g, 4.24 mmol, 1.2 eq) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and ethyl acetate. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 4′-chloro-2′-fluoro-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A15.7) (1.4 g, 78.21%). LCMS: 509.00 [M+H].sup.+.

    Step-5: Synthesis of 2-(4′-chloro-2′-fluoro-1,2,3,6-tetrahydro-[,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A15.8)

    [0604] To a stirred solution of 4′-chloro-2′-fluoro-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (A15.7) (0.7 g, 1.37 mmol, 1 eq) in 1,4-dioxane (20 mL) were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.35 g, 1.37 mmol, 1 eq), KOAc (0.4 g, 4.11 mmol, 3 eq) reaction mixture was purged with argon for 30 min followed by addition of PdCl.sub.2(dppf) (0.03 g, 0.04 mmol, 0.03 eq). The reaction mixture was stirred at 100° C. for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Same reaction was repeated on 0.7 g. The crude product was combined and purified by column chromatography to afford the desired product 2-(4′-chloro-2′-fluoro-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A15.8) (0.6 g, 63%). LCMS: 337.15 [M+H].sup.+.

    Step-6: Synthesis of 4″-chloro-2″-fluoro-2′,3′,4′,5′-tetrahydro-[,1′:4′,1″-terphenyl]-2-amine (A15.10)

    [0605] To a mixture of 2-(4′-chloro-2′-fluoro-1,2,3,6-tetrahydro-[1,1′-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A15.8) (0.3 g, 1.36 mmol, 1 eq) and 2-iodoaniline (A15.9) (0.5 g, 1.50 mmol, 1.1 eq) in a mixture of 1,4-dioxane and water (4:1, 20 mL), Na.sub.2CO.sub.3 (0.29 g, 2.7 mmol, 2 eq) was added and purged with argon for 30 min followed by the addition of Tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.09 mmol, 0.07 eq) and stirred at 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and ethyl acetate. The organic layer was separated, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 4″-chloro-2″-fluoro-2′,3′,4′,5′-tetrahydro-[1,1′:4′,1″-terphenyl]-2-amine (A15.10) (0.35 g, 85%). LCMS: 302.10 [M+H].sup.+.

    Step-7: Synthesis of 2-(4-(4-chloro-2-fluorophenyl)cyclohexyl)aniline (A15.11)

    [0606] To a stirred solution of 4″-chloro-2″-fluoro-2′,3′,4′,5′-tetrahydro-[1,1′:4′,1″-terphenyl]-2-amine (A15.10) (0.3 g, 0.99 mmol, 1 eq) in methanol (30 mL) was added Pd/C (0.15 g). The reaction mixture was stirred under hydrogen at 100 psi pressure at room temperature for 8 h. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to obtained crude residue. The crude product was purified by column chromatography to afford the titled compound 2-(4-(4-chloro-2-fluorophenyl)cyclohexyl)aniline (A15.11) (0.14 mg, 46.51%).

    Step-8: Synthesis of N1-(2-(4-(4-chloro-2-fluorophenyl)cyclohexyl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-69 Isomer-I) and (A-70 Isomer-II)

    [0607] To a stirred solution of 2-(4-(4-chloro-2-fluorophenyl)cyclohexyl)aniline (A15.11) (0.14 g, 0.46 mmol, 1 eq) in MeCN (10 mL) was added pyridine (0.1 g, 0.92 mmol, 2 eq) at 0° C., and stirred for 10 min followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A15.12) (0.16 g, 0.55 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 12 h; the reaction progress was monitored by TLC. After completion, reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified preparative HPLC to afford N1-(2-(4-(4-chloro-2-fluorophenyl)cyclohexyl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-70/Isomer-I) and (A-70/Isomer-II), which were confirmed by NOE.

    [0608] A-69 (Isomer-I): Yield: 25 mg, 5.56%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.06 (s, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.55-7.51 (m, 1H), 7.34 (dd, J=11.2 Hz, 10.8 Hz, 1H), 7.25 (dd, J=8.4 Hz, 8.4 Hz, 1H), 7.22-7.11 (m, 3H), 7.03-7.01 (m, 1H), 3.18 (m, 1H), 2.82-2.73 (m, 1H), 2.64 (m, 6H), 1.91-1.88 (m, 2H), 1.71-1.65 (m, 2H), 1.43-1.36 (m, 2H), 1.17-1.14 (m, 2H); HPLC purity: >99%; LCMS Calculated for C.sub.26H.sub.28ClFN.sub.2O.sub.4S.sub.2: 550.12; Observed: 551.15 [M+H].sup.+.

    [0609] A-70 (Isomer-II): Yield: 25 mg, 5.56%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.06 (s, 1H), 7.95 (d, J=8 Hz, 2H), 7.89 (d, J=8 Hz, 2H), 7.39-7.34 (m, 2H), 7.31-7.21 (m, 3H), 7.16-7.12 (m, 1H), 7.06-7.04 (m, 1H), 2.84-2.79 (s, 1H), 2.67-2.64 (m, 1H), 2.62 (s, 6H), 1.71-1.68 (m, 2H), 1.47-1.34 (m, 4H), 1.29-1.24 (m, 2H); HPLC purity: 98.15%; LCMS Calculated for C.sub.26H.sub.28ClFN.sub.2O.sub.4S.sub.2: 550.12; Observed: 551.15 [M+H].sup.+.

    Example A16: Synthesis of N1-(2-((4-chloro-2-fluorophenyl)ethynyl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-3)

    [0610] ##STR01328##

    Step-1: Synthesis of 2-((4-chloro-2-fluorophenyl)ethynyl)aniline (A16.3)

    [0611] To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene A16.1 (0.1 g, 0.48 mmol, 1 eq) and 2-ethynylaniline (A16.2) (0.056 g, 0.48 mmol, 1 eq) in DMF (4 mL) was added DIPEA (0.17 mL, 0.96 mmol, 2 eq). The reaction mixture was purged with argon for 15 min followed by the addition of copper iodide (0.036 g, 0.19 mmol, 0.4 eq) and Bis(triphenylphosphine)palladium chloride (0.07 g, 0.095 mmol, 0.2 eq) stirred at 80° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, the Celite pad was washed with ethyl acetate. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the desired product 2-((4-chloro-2-fluorophenyl)ethynyl)aniline (A16.3) (50 mg, 42%). LCMS: 246.04 [M+H].sup.+.

    Step-2: Synthesis of N1-(2-((4-chloro-2-fluorophenyl)ethynyl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-3)

    [0612] To a stirred solution of 2-((4-chloro-2-fluorophenyl)ethynyl)aniline (A16.3) (500 mg, 0.2 mmol, 1 eq) in DMF (6 mL) was added a 60% suspension of sodium hydride in mineral oil (122 mg, 3.06 mmol, 1.5 eq) at 0° C. and reaction mixture was stirred for 10 min followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A16.4) (579 mg, 2 mmol, 1 eq). The reaction mixture was stirred at room temperature for 2 h; the reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture diluted with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na.sub.2SO.sub.4 and evaporated to provide crude residue which was purified by column chromatography followed by prep HPLC to afford the desired product N1-(2-((4-chloro-2-fluorophenyl)ethynyl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-3). Yield: 25 mg, 3%; Appearance: Off-white solid; 1H NMR (400 MHz, DMSO-d.sub.6) δ 7.92-7.91 (m, 2H), 7.78-7.71 (m, 3H), 7.44-7.37 (m, 3H), 7.24-7.11 (m, 4H), 2.67 (s, 6H); HPLC purity: >99%; LCMS Calculated for C.sub.22H.sub.18ClFN.sub.2O.sub.4S.sub.2:492.04; Observed: 494.75 [M+2].sup.+.

    Example A17: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-62)

    [0613] ##STR01329##

    Step-1: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(1H-1,2,4-triazol-3-yl)piperidine (A17.3)

    [0614] A solution of 3-bromo-1H-1,2,4-triazole (A17.1) (400 mg, 2.7 mmol, 1 eq) and 4-(4-chloro-2-fluorophenyl)piperidine (A17.2) (1.15 g, 5.4 mmol, 2 eq) was stirred at 140° C. in microwave for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with ether & pentane to afford the desired product 4-(4-chloro-2-fluorophenyl)-1-(1H-1,2,4-triazol-3-yl)piperidine (A17.3) (400 mg, Crude). The crude was used as such next step without purification. LCMS: 281.09 [M+H].sup.+.

    Step-2: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-62)

    [0615] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(1H-1,2,4-triazol-3-yl)piperidine (A17.3) (400 mg, 0.4 mmol, 1 eq) in ACN (8 mL) was added pyridine (0.023 mL, 0.29 mmol, 2 eq) at 0° C. followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A17.4) (445 mg, 0.16 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude was diluted with water and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 4-((3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-1H-1,2,4-triazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-62). Yield: 30 mg, 4%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.11 (s, 1H), 8.30-8.22 (m, 2H), 8.09-7.97 (m, 2H), 7.40-7.26 (m, 2H), 7.22 (dd, J=8.4, 2.2 Hz, 1H), 4.08-4.00 (m, 2H), 2.96 (ddd, J=15.3, 10.0, 2.9 Hz, 3H), 2.67 (s, 6H), 1.73 (dd, J=12.8, 3.4 Hz, 2H), 1.60 (qd, J=12.5, 4.1 Hz, 2H); HPLC purity: 95.33%; LCMS Calculated for C.sub.21H.sub.23ClFN.sub.5O.sub.4S.sub.2: 527.09; Observed: 528.05 [M+H].sup.+.

    Example A18: Synthesis of 4-((4-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-50)

    [0616] ##STR01330##

    Step-1: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(3-methyl-1H-pyrazol-4-yl)piperidine (A18.3)

    [0617] A solution of 4-(4-chloro-2-fluorophenyl)piperidine (A18.1) (0.1 g, 6.2 mmol, 1 eq) and 4-bromo-3-methyl-1H-pyrazole (A18.2) (0.15 g, 0.68 mmol, 1.1 eq) in THF (10 mL) was purged with argon for 10 min followed by the addition Tris(dibenzylideneacetone)dipalladium(0) (0.06 g, 0.06 mmol, 0.1 eq), Davephos (0.06 g, 0.15 mmol, 0.25 eq) at room temperature, cooled the reaction mixture at 0° C. then dropwise 1 M in THE LiHMDS (1.5 mL, 1.49 mmol, 2.4 eq) was added. The reaction mixture was stirred at 70° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 4-(4-chloro-2-fluorophenyl)-1-(3-methyl-1H-pyrazol-4-yl)piperidine (A18.3). Four more batches were repeated on same scale and the combined yield details are (0.4 g, 44.44%), LCMS: 294.11 [M+1].sup.+.

    Step-2: Synthesis of 4-((4-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-50)

    [0618] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(3-methyl-1H-pyrazol-4-yl)piperidine (A18.3) (0.2 g, 6.8 mmol, 1 eq) in ACN (10 mL) was added pyridine (0.1 g, 1.36 mmol, 2 eq) at 0° C. followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A18.4) (0.21 g, 0.75 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography followed by prep HPLC to afford the desired product 4-((4-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-3-methyl-1H-pyrazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-50). Yield: 0.05 g, 13.58%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15-8.07 (m, 2H), 7.99-7.89 (m, 3H), 7.41-7.30 (m, 2H), 7.22 (dd, J=8.3, 2.1 Hz, 1H), 3.25 (dd, J=12.5, 3.3 Hz, 2H), 2.85 (tt, J=10.9, 4.8 Hz, 1H), 2.62 (s, 8H), 2.12 (s, 3H), 1.75 (ddt, J=12.5, 8.9, 4.5 Hz, 4H); HPLC purity: 97.52%; LCMS Calculated for C.sub.23H.sub.26ClFN.sub.4O.sub.4S.sub.2: 540.11; Observed: 541.05 [M+H].sup.+.

    Example A19: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-71)

    [0619] ##STR01331##

    Step-1: Synthesis of 2-oxopyrrolidin-3-yl Methanesulfonate A19.2

    [0620] To a stirred solution of 3-hydroxypyrrolidin-2-one (A19.1) (4.66 g, 46.09 mmol, 1 eq) in DCM (80 mL) was added triethyl amine (13 mL, 92.18 mmol, 2 eq) and dropwise methane sulphonyl chloride (1.5 mL, 14.84 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the desired product 2-oxopyrrolidin-3-yl methanesulfonate (A19.2) (6.5 g, 79.2%). LCMS: 180.03 [M+H]+.

    Step-2: Synthesis of 3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)pyrrolidin-2-one (A19.4)

    [0621] To a stirred solution of 4-(4-chloro-2-fluorophenyl)piperidine (A19.3) (0.2 g, 0.61 mmol, 1 eq) in ACN (10 mL) was added DIPEA (0.7 mL, 3.67 mmol, 6 eq) and 2-oxopyrrolidin-3-yl methanesulfonate (A19.2) (0.12 g, 0.67 mmol, 1.1 eq) at room temperature. The reaction mixture was stirred at 80° C. for 4 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated, washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by silica gel column chromatography to provide the desired compound 3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)pyrrolidin-2-one (A19.4) (15 mg, 8.2%). LCMS: 297.11 [M+H].sup.+.

    Step-3: Synthesis of 4-((3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-71)

    [0622] To a stirred solution of 3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)pyrrolidin-2-one (A19.4) (1 g, 3.38 mmol, 1 eq) in dry THE (20 mL) was added dropwise 2 M solution of n-BuLi (0.3 mL, 0.74 mmol, 1.1 eq) in hexane at −78° C., stirred the reaction mixture. at same temperature for 1 h followed by drop wise addition of solution of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A19.5) (0.29 g, 1.01 mmol, 1.5 eq) in THF. The reaction mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched at −78° C. with saturated solution of ammonium chloride; reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography followed by prep HPLC to afford the desired product 4-((3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-71). Yield: 100 mg, 27.32%; Appearance: Off-white solid; 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.22 (d, J=8 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 7.34-7.31 (m, 2H), 7.22-7.20 (m, 1H), 4.00-3.92 (m, 1H), 3.77-3.65 (m, 2H), 2.99-2.83 (m, 1H), 2.72-2.62 (m, 9H), 2.29-2.01′ (m, 3H), 1.60-1.54 (m, 4H); HPLC purity: 97.62%; LCMS Calculated for C.sub.23H.sub.27ClFN.sub.3O.sub.5S.sub.2: 543.11; Observed: 544.05 [M+H].sup.+.

    Example A20: Synthesis of 2-(4-chloro-2-fluorophenyl)-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (A-371)

    [0623] ##STR01332##

    Step-1: Synthesis of 2-(4-chloro-2-fluorophenyl)-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (A-371)

    [0624] To a stirred solution of 2-((4-methoxybenzyl)amino)phenol (A20.1) (0.3 g, 1.31 mmol, 1 eq) and methyl 2-bromo-2-(4-chloro-2-fluorophenyl)acetate (A20.2) (0.43 g, 1.57 mmol, 1.2 eq) in ACN (10 mL) was added K.sub.2CO.sub.3 (542 mg, 3.93 mmol, 3 eq) at room temperature. The reaction mixture was stirred at 80° C. for 12 h. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was concentrated; crude was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to afford titled compound 2-(4-chloro-2-fluorophenyl)-4-(4-methoxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (A-371). Yield: 100 mg, 19%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.63-7.49 (m, 2H), 7.37 (dd, J=8.3, 2.0 Hz, 1H), 7.29-7.21 (m, 2H), 7.22-7.12 (m, 1H), 7.01 (ddt, J=9.9, 6.8, 3.9 Hz, 3H), 6.94-6.85 (m, 2H), 6.09 (d, J=1.5 Hz, 1H), 5.23-5.09 (m, 2H), 3.71 (d, J=1.6 Hz, 3H); HPLC purity: 95.41%; LCMS Calculated for C.sub.22H.sub.17ClFNO.sub.3: 397.09; Observed: 398.00 [M+H].sup.+.

    Example A21: Synthesis of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-N-(p-tolyl)benzenesulfonamide (A-111)

    [0625] ##STR01333##

    Step-1: Synthesis of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-N-(p-tolyl)benzenesulfonamide (A-111)

    [0626] To a stirred solution of 2-fluoro-N-(p-tolyl)benzenesulfonamide (A21.1) (400 mg, 1.51 mmol, 1 eq) and 4-(4-chloro-2-fluorophenyl)piperidine A21.2 (385 mg, 1.81 mmol, 1.2 eq) in THF (5 mL) and acetonitrile (5 mL), triethyl amine (0.630 mL, 4.52 mmol, 3 eq) was added in a microwave tube. The tube was sealed with a septum and the reaction was heated at 180° C. for 2 h in a microwave reactor. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-N-(p-tolyl)benzenesulfonamide (A-111). Yield: 92 mg, 13%; Appearance: white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.60-7.53 (m, 1H), 7.51-7.45 (m, 1H), 7.40-7.30 (m, 2H), 7.26 (t, J=7.6 Hz, 1H), 7.00-6.90 (m, 4H), 3.11-3.01 (m, 2H), 3.00-2.90 (m, 1H), 2.84 (t, J=10.8 Hz, 2H), 2.25-2.10 (m, 2H), 2.12 (s, 3H), 1.72 (d, J=11.6 Hz, 2H); HPLC purity: 99.53%; LCMS Calculated for C.sub.24H.sub.24ClFN.sub.2O.sub.2S: 458.12; Observed: 459.05 [M+H].sup.+.

    Example A22: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfonamido)-N,N-dimethylbenzenesulfonamide (A-108)

    [0627] ##STR01334##

    Step-1: Synthesis of 4-((2-fluorophenyl)sulfonamido)-N,N-dimethylbenzenesulfonamide (A22.3)

    [0628] To a stirred solution of 4-amino-N,N-dimethylbenzenesulfonamide (A22.1) (500 mg, 2.57 mmol, 1 eq) and 2-fluorobenzenesulfonyl chloride (A22.2) (514 mg, 2.57 mmol) in acetonitrile (5 mL), pyridine (609 mg, 7.71 mmol, 3 eq) was added at 0° C. The reaction was warmed to room temperature and stirred for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-((2-fluorophenyl)sulfonamido)-N,N-dimethylbenzenesulfonamide (A22.3) (600 mg, 65.2%). LCMS: 359.10 [M+H].sup.+.

    Step-2: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfonamido)-N,N-dimethylbenzenesulfonamide)(A-108)

    [0629] To a stirred solution of 4-((2-fluorophenyl)sulfonamido)-N,N-dimethylbenzenesulfonamide (A22.3) (300 mg, 0.837 mmol, 1 eq) and 4-(4-chloro-2-fluorophenyl)piperidine (A22.4) (215 mg, 1 mmol, 1.2 eq) in THF (5 mL) and acetonitrile (5 mL), triethyl amine (0.350 mL, 2.51 mmol, 3 eq) was added in a microwave tube. The tube was sealed with a septum and the reaction was heated at 170° C. for 2 h in a microwave reactor. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfonamido)-N,N-dimethylbenzenesulfonamide (A-108). Yield: 96 mg, 20.8%; Appearance: white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.39 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.68-7.60 (m, 2H), 7.58-7.49 (m, 3H), 7.41-7.32 (m, 3H), 7.23 (d, J=8.4 Hz, 2H), 3.00-2.90 (m, 3H), 2.88-2.80 (m, 2H), 2.48 (s, 6H), 2.20-2.06 (m, 2H), 1.71 (d, J=11.2 Hz, 2H); HPLC purity: 97.01%; LCMS Calculated for C.sub.25H.sub.27ClFN.sub.3O.sub.4S.sub.2: 551.11; Observed: 552.10 [M+H].sup.+.

    Example A23: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-214)

    [0630] ##STR01335## ##STR01336##

    Step-1: Synthesis of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzaldehyde A23.3

    [0631] To a stirred solution of 4-(4-chloro-2-fluorophenyl)piperidine TFA salt A23.1 (2 g, 6.1 mmol, 1 eq) and 2-fluorobenzaldehyde (A23.2) (910 mg, 7.32 mmol, 1.2 eq) in DMF (15 mL), potassium carbonate (2.53 g, 18.3 mmol, 3 eq) was added in one lot. The reaction was heated at 80° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with cold water (50 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the titled compound 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzaldehyde (A23.3) (1.6 g, 82.5%). LCMS: 318.10 [M+H].sup.+.

    Step-2: Synthesis of (2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)methanol (A23.4)

    [0632] A stirred solution of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzaldehyde (A23.3) (1.6 g, 5.03 mmol, 1 eq) in ethanol (30 mL) and THE (20 mL) at 0° C. was added sodium borohydride (290 mg, 7.55 mmol, 1.5 eq). The reaction was stirred at the same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution (25 mL). The product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by trituration with n-hexane and the solids were filtered out, and dried under reduced pressure to afford the titled compound (2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)methanol (A23.4) (1.5 g, 93.2%) as a white solid. This compound was used in the next step without further purification. LCMS: 320.11 [M+H].sup.+.

    Step-3: Synthesis of 1-(2-(bromomethyl)phenyl)-4-(4-chloro-2-fluorophenyl)piperidine (A23.5)

    [0633] To a stirred solution of (2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)methanol (A23.4) (500 mg, 1.56 mmol, 1 eq) in DCM (10 mL), pyridine (0.24 mL, 3.13 mmol, 2 eq) was added at 0° C. and the reaction was stirred for 10 min. PBr.sub.3 (0.22 mL, 2.34 mmol, 1.5 eq) was then added dropwise to the reaction at 0° C. The reaction was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched slowly with saturated aqueous NaHCO.sub.3 solution and the product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 1-(2-(bromomethyl)phenyl)-4-(4-chloro-2-fluorophenyl)piperidine (A23.5) (400 mg, crude). This compound was used in the next step without further purification. LCMS: 382.10 [M+H].sup.+.

    Step-4: Synthesis of Sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A23.6)

    [0634] To a stirred solution of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A23.7) (1.5 g, 5.2 mmol, 1 eq) in water (15 mL), Na.sub.2SO.sub.3 (1.33 g, 10.57 mmol, 2 eq) followed by NaHCO.sub.3 (0.82 g, 10.57 mmol, 2 eq) were added at room temperature. The reaction was heated at 100-110° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethanol, filtered and the filtrate was concentrated to dryness under reduced pressure to afford the titled compound sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A23.6) (0.8 g, crude). This compound was used in the next step without further purification. LCMS: 250.00 [M+H].sup.+ (Observed mass for corresponding acid).

    Step-5: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-214)

    [0635] To a stirred solution of 1-(2-(bromomethyl)phenyl)-4-(4-chloro-2-fluorophenyl)piperidine (A23.5) (400 mg, 1.04 mmol, 1 eq) in DMF (10 mL), sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate A23.6 (390 mg, 1.36 mmol, 1.3 eq) followed by tetra-n-butylammonium bromide (38 mg, 0.10 mmol, 0.1 eq) were added at room temperature. The reaction was heated at 105° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with ice-cold water. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography followed by reverse phase preparative HPLC to afford the titled compound 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-214). Yield: 30 mg, 5.2%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ; 7.80-7.10 (m, 4H), 7.57 (d, J=7.2 Hz, 1H), 2.37-7.31 (m, 1H), 7.21-7.14 (m, 3H), 7.08 (d, J=10.4 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 4.66 (s, 2H), 2.88-2.74 (m, 1H), 2.71 (s, 6H), 2.70-2.60 (m, 2H), 2.50-2.42 (m, 2H), 1.83-1.75 (m, 2H), 1.69-1.55 (m, 2H); HPLC purity: 97.95%; LCMS calculated for C.sub.26H.sub.28ClFN.sub.2O.sub.4S.sub.2: 550.12; Observed: 551.15 [M+H].sup.+.

    Example A24: Synthesis of 4-((2-(4-(2,6-difluorophenyl)piperidin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-229)

    [0636] ##STR01337## ##STR01338##

    Step-1: Synthesis of Sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A24.2)

    [0637] To a stirred solution of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A24.1) (1.5 g, 5.28 mmol, 1 eq) in water (15 mL), sodium sulfite (1.33 g, 10.57 mmol, 2 eq) and sodium bicarbonate (0.88 g, 10.57 mmol, 2 eq) were added at room temperature. The reaction mixture was stirred at 110° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethanol and filtered. The filtrate was concentrated under reduced pressure to dryness to afford the titled compound sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A24.2) (0.8 g, crude). LCMS: No ionization.

    Step-2: Synthesis of 2-(4-(2,6-difluorophenyl)piperidin-1-yl)benzaldehyde (A24.5)

    [0638] To a stirred solution of 4-(2,6-difluorophenyl)piperidine (A24.3) (2 g, 10.14 mmol, 1 eq) in DMF (20 mL), potassium carbonate (3.51 g, 25.38 mmol, 2.5 eq) and 2-fluorobenzaldehyde (A24.4) (1.5 g, 12.17 mmol, 1.2 eq) were added at room temperature. The reaction mixture was stirred at 100° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with ice-cold water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 2-(4-(2,6-difluorophenyl)piperidin-1-yl)benzaldehyde (A24.5) (2.9 g, crude). LCMS: 302.15 [M+H].sup.+.

    Step-3: Synthesis of (2-(4-(2,6-difluorophenyl)piperidin-1-yl)phenyl)methanol (A24.6)

    [0639] To a stirred solution of 2-(4-(2,6-difluorophenyl)piperidin-1-yl)benzaldehyde (A24.5) (2.9 g, 9.6 mmol, 1 eq) in methanol (3 mL), sodium borohydride (1.06 g, 28 mmol, 2.9 eq) was added in portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound (2-(4-(2,6-difluorophenyl)piperidin-1-yl)phenyl)methanol (A24.6 (0.7 g, 24%). LCMS: 304.15 [M+H].sup.+.

    Step-4: Synthesis of 1-(2-(bromomethyl)phenyl)-4-(2,6-difluorophenyl)piperidine (A24.7)

    [0640] To a stirred solution of (2-(4-(2,6-difluorophenyl)piperidin-1-yl)phenyl)methanol (A24.6) (700 mg, 2.3 mmol, 1 eq) in DCM (15 mL), pyridine (0.36 mL, 4.6 mmol, 2 eq) was added at 0° C. and the reaction mixture was stirred at the same temperature for 10 min. Phosphorus tribromide (0.32 mL, 3.4 mmol, 1.5 eq) was then added dropwise to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dilute with DCM and washed with saturated aqueous NaHCO.sub.3 solution. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 1-(2-(bromomethyl)phenyl)-4-(2,6-difluorophenyl)piperidine (A24.7) (410 mg, crude). This compound was used in the next step without further purification. LCMS: 366.10 [M+H].sup.+.

    Step-5: Synthesis of 4-((2-(4-(2,6-difluorophenyl)piperidin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-229)

    [0641] To a stirred solution of 1-(2-(bromomethyl)phenyl)-4-(2,6-difluorophenyl)piperidine (A24.7) (300 mg, 0.82 mmol, 1 eq) and sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A24.2) (300 mg, 1.05 mmol, 1.3 eq) in DMF (6 mL), tetra-butylammonium bromide (30 mg, 0.08 mmol, 0.1 eq) was added at room temperature. The reaction mixture was stirred at 110° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with ice-cold water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 4-((2-(4-(2,6-difluorophenyl)piperidin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-229). Yield: 50 mg, 11.6%; Appearance: White solid; 1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 7.46 (d, J=7.6 Hz, 1H), 7.38-7.29 (m, 2H), 7.20-7.14 (m, 1H), 7.13-7.05 (m, 3H), 4.79 (s, 2H), 3.00-2.90 (m, 1H), 2.61 (s, 6H), 1.98-1.85 (m, 2H), 1.61 (d, J=11.2 Hz, 2H), (4H merged with the solvent peak); HPLC purity: 99.71%; LCMS calculated for C.sub.26H.sub.28F2N.sub.2O.sub.4S.sub.2: 534.15; Observed: 535.15 [M+H].sup.+.

    Example A25: Synthesis of 4-((1-(2-(4-(2,6-difluorophenyl)piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-254)

    [0642] ##STR01339##

    Step-1: Synthesis of 4-((1-(2-(4-(2,6-difluorophenyl)piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-254)

    [0643] To a stirred solution of 4-((2-(4-(2,6-difluorophenyl)piperidin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-229) (300 mg, 0.561 mmol, 1 eq) in THE (6 mL), a 2.5 M solution of n-butyl lithium in hexanes (0.26 mL, 0.673 mmol, 1.2 eq) was added dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 15 min and slowly allowed to attain 0° C. and methyl iodide (0.04 mL, 0.673 mmol, 1.2 eq) was added and stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0° C., quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 4-((1-(2-(4-(2,6-difluorophenyl)piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-254). Yield: 70 mg, 23.3%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.81 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.59 (dd, J=1.2, 8.0 Hz, 1H), 7.38-7.29 (m, 2H), 7.23 (t, J=6.8 Hz, 1H), 7.14-7.06 (m, 2H), 7.00 (d, J=8.0 Hz, 1H), 5.14 (q, J=7.2 Hz, 1H), 3.01-2.92 (m, 1H), 2.81-2.70 (m, 2H), 2.59 (s, 6H), 2.50-2.40 (m, 1H), 2.20-2.07 (m, 1H), 1.91-1.79 (m, 2H), 1.76 (d, J=6.8 Hz, 3H), 1.69 (d, J=12.8 Hz, 1H), 1.59 (d, J=11.6 Hz, 1H); HPLC purity: 99.89%; LCMS calculated for C.sub.27H.sub.30F2N.sub.2O.sub.4S.sub.2: 548.16; Observed: 549.25 [M+H].sup.+.

    Example A26: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-(tosylmethyl)phenyl)piperidine (A-138); 4-(4-chloro-2-fluorophenyl)-1-(2-((p-tolylsulfinyl)methyl)phenyl)piperidine (A-145)

    [0644] ##STR01340##

    Step-1: Synthesis of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl Methanesulfonate (A26.2)

    [0645] A solution of (2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)methanol A26.1 (0.5 g, 1.56 mmol, 1 eq), triethyl amine (0.44 mL, 3.13 mmol, 2 eq) and DMAP (25 mg, catalytic) in DCM (20 mL) were cooled to 0° C. and treated with methanesulfonyl chloride (0.182 mL, 2.35 mmol, 1.5 eq) dropwise. The reaction was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water (25 mL) and the product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled compound 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl methanesulfonate (A26.2) (600 mg, crude). This compound was used in the next step without further purification. LCMS: No ionization.

    Step-2: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-((p-tolylthio)methyl)phenyl)piperidine (A26.4)

    [0646] To a stirred solution of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl methanesulfonate (A26.2) (600 mg, 1.51 mmol, 1 eq) and 4-methylbenzenethiol A26.3 (206 mg, 1.66 mmol, 1.1 eq) in DMF (5 mL), potassium carbonate (625 mg, 4.52 mmol, 3 eq) was added. The reaction was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water (25 mL) and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography on silica gel to afford the titled compound 4-(4-chloro-2-fluorophenyl)-1-(2-((p-tolylthio)methyl)phenyl)piperidine (A26.4) (400 mg, 62.3%) as a white solid. LCMS: 426.14 [M+H].sup.+.

    Step-3: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-((p-tolylsulfinyl)methyl)phenyl)piperidine (A-145)

    [0647] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(2-((p-tolylthio)methyl)phenyl)piperidine (A26.4) (300 mg, 0.704 mmol, 1 eq) in DCM (10 mL), m-chloroperoxybenzoic acid (65%) (190 mg, 0.704, 1 eq) was added at 0° C. The reaction was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO.sub.3 solution (10 mL) and stirred for 15 min. the product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography on silica gel to afford the titled compound 4-(4-chloro-2-fluorophenyl)-1-(2-((p-tolylsulfinyl)methyl)phenyl)piperidine (A-145). Yield: 200 mg, 64.3%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.47-7.24 (m, 9H), 7.17-7.12 (m, 1H), 7.10-7.04 (m, 1H), 4.19 (s, 2H), 2.90-2.80 (m, 2H), 2.80-2.64 (m, 3H), 2.33 (s, 3H), 1.80-1.68 (m, 4H); HPLC purity: 99.16%; LCMS calculated for C.sub.25H25ClFNOS: 441.13; Observed: 442.05 [M+H].sup.+.

    Step-4: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-(tosylmethyl)phenyl)piperidine (A-138)

    [0648] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(2-((p-tolylsulfinyl)methyl)phenyl)piperidine (A-145) (175 mg, 0.396 mmol, 1 eq) in DCM (5 mL), m-chloroperoxybenzoic acid (65%) (105 mg, 0.396, 1 eq) was added at 0° C. The reaction was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO.sub.3 solution (10 mL) and stirred for 15 min and extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 4-(4-chloro-2-fluorophenyl)-1-(2-(tosylmethyl)phenyl)piperidine (A-138). Yield: 22 mg, 12%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.49-7.42 (m, 4H), 7.38 (d, J=10.8 Hz, 1H), 7.34-7.28 (m, 4H), 7.17-7.08 (m, 2H), 4.66 (s, 2H), 2.84-2.73 (m, 1H), 2.62-2.55 (m, 2H), 2.50-2.40 (m, 2H), 2.33 (s, 3H), 1.69-1.55 (m, 4H); HPLC purity: 99.34%; LCMS calculated for C.sub.25H.sub.25ClFNO.sub.2S: 457.13; Observed: 458.05 [M+H].sup.+.

    Example A27: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)sulfinyl)-N,N-dimethylbenzenesulfonamide (A-190)

    [0649] ##STR01341##

    Step-1: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)thio)-N,N-dimethylbenzenesulfonamide (A27.3)

    [0650] To a stirred solution of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl methanesulfonate (A27.1) (720 mg, 1.81 mmol, 1 eq) and 4-mercapto-N,N-dimethylbenzenesulfonamide (A27.2) (432 mg, 1.99 mmol, 1.1 eq) in DMF (10 mL), potassium carbonate (750 mg, 5.43 mmol, 3 eq) was added. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)thio)-N,N-dimethylbenzenesulfonamide (A27.3) (300 mg, 32%). LCMS: 519.13 [M+H].sup.+.

    Step-2: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)sulfinyl)-N,N-dimethylbenzenesulfonamide (A-190)

    [0651] To a stirred solution of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)thio)-N,N-dimethylbenzenesulfonamide (A27.3) (300 mg, 0.578 mmol, 1 eq) in DCM (15 mL), m-chloroperbenzoic acid (65%) (153 mg, 0.578 mmol, 1 eq) was added at −50° C. The reaction was stirred at the same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO.sub.3 solution and stirred for 15 min and the product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford the titled compound 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)benzyl)sulfinyl)-N,N-dimethylbenzenesulfonamide (A-190). Yield: 20 mg, 6%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.79 (d, J=7.2 Hz, 2H), 7.62 (d, J=7.2 Hz, 2H), 7.51-7.46 (m, 1H), 7.41-7.36 (m, 1H), 7.32-7.24 (m, 3H), 7.10-7.04 (m, 2H), 4.42 (d, J=12.4 Hz, 1H), 4.27 (d, J=12.4 Hz, 1H), 2.90-2.80 (m, 1H), 2.75-2.65 (m, 4H), 2.59 (s, 6H), 1.81-1.66 (m, 4H); HPLC purity: 98.10%; LCMS Calculated for C.sub.26H.sub.28ClFN.sub.2O.sub.3S.sub.2: 534.12; Observed: 535.10 [M+H].sup.+.

    Example A28: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-tolylphenyl)piperidine (A-133) and 4-(4-chloro-2-fluorophenyl)-1-(2-(p-tolylsulfinyl)phenyl)piperidine (A-144)

    [0652] ##STR01342## ##STR01343##

    Step-1: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-iodophenyl)piperidine (A28.2)

    [0653] To a stirred solution of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)aniline (A28.1) (1.4 g, 4.59 mmol, 1 eq) in THE (20 mL), copper iodide (875 mg, 4.59 mmol, 1 eq), diiodomethane (1.85 mL, 23 mmol, 5 eq) and isoamyl nitrite (1.6 g, 13.8 mmol, 3 eq) were added at room temperature. The reaction was heated at 70° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-(4-chloro-2-fluorophenyl)-1-(2-iodophenyl)piperidine (A28.2) (900 mg, 47.1%). LCMS: 416.00 [M+H].sup.+.

    Step-2: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-(p-tolylthio)phenyl)piperidine (A28.4)

    [0654] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(2-iodophenyl)piperidine (A28.2) (900 mg, 2.17 mmol, 1 eq) and 4-methylbenzenethiol (A28.3) (283 mg, 2.27 mmol, 1.05 eq) in DMF (20 mL), potassium carbonate (598 mg, 4.33 mmol, 2 eq) and copper iodide (21 mg, 0.108 mmol, 0.05 eq) were added and heated at 140° C. for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-(4-chloro-2-fluorophenyl)-1-(2-(p-tolylthio)phenyl)piperidine (A28.4) (400 mg, 44.8%). LCMS: 412.10 [M+H].sup.+.

    Step-3: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-tolylphenyl)piperidine (A-133)

    [0655] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(2-(p-tolylthio)phenyl)piperidine (A28.4) (380 mg, 0.922 mmol, 1 eq) in DCM (8 mL), m-chloroperbenzoic acid (65%) (490 mg, 1.84 mmol, 2 eq) was added at 0° C. The reaction was warmed to room temperature and stirred for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO.sub.3 solution (10 mL) and stirred for 15 min. the product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford the titled compound 4-(4-chloro-2-fluorophenyl)-1-(2-tolylphenyl)piperidine (A-133). Yield: 13 mg, 3.17%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (d, J=7.2 Hz, 1H), 7.76-7.70 (m, 3H), 7.53-7.44 (m, 2H), 7.42-7.32 (m, 5H), 2.88-2.71 (m, 5H), 2.36 (s, 3H), 1.62-1.52 (m, 4H); HPLC purity: 96.85%; LCMS Calculated for C.sub.24H.sub.23ClFNO.sub.2S: 443.11; Observed: 444.05 [M+H].sup.+.

    Step-4: Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-(p-tolylsulfinyl)phenyl)piperidine (A-144)

    [0656] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(2-(p-tolylthio)phenyl)piperidine (A28.4) (500 mg, 1.21 mmol, 1 eq) in DCM (10 mL), m-chloroperbenzoic acid (65%) (322 mg, 1.84 mmol, 1 eq) was added at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO.sub.3 solution (10 mL) and stirred for 15 min. the product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-(4-chloro-2-fluorophenyl)-1-(2-(p-tolylsulfinyl)phenyl)piperidine (A-144). Yield: 180 mg, 34.7%; Appearance: white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.85 (d, J=7.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.52-7.42 (m, 2H), 7.41-7.35 (m, 2H), 7.34-7.25 (m, 4H), 3.42 (d, J=11.2 Hz, 1H), 3.00-2.83 (m, 2H), 2.74 (t, J=11.2 Hz, 1H), 2.43 (d, J=11.2 Hz, 1H), 2.30 (s, 3H), 2.02-1.90 (m, 1H), 1.85-1.78 (m, 1H), 1.70-1.51 (m, 2H); HPLC purity: 95.11%; LCMS Calculated for C.sub.24H.sub.23ClFNOS: 427.12; Observed: 428.05 [M+H].sup.+.

    Example A29: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-156)

    [0657] ##STR01344##

    Step-1: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)thio)-N,N-dimethylbenzenesulfonamide (A29.3)

    [0658] To a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(2-iodophenyl)piperidine (A29.1) (400 mg, 0.962 mmol, 1 eq) and compound (A29.2) (219 mg, 1.01 mmol, 1.05 eq) in DMF (10 mL), potassium carbonate (264 mg, 1.92 mmol, 2 eq) and copper iodide (9 mg, 0.05 mmol, 0.05 eq) were added and heated at 130° C. for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)thio)-N,N-dimethylbenzenesulfonamide (A29.3) (480 mg, 98.8%). LCMS: 505.10 [M+H].sup.+.

    Step-2: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-156)

    [0659] To a stirred solution of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)thio)-N,N-dimethylbenzenesulfonamide (A29.3) (200 mg, 0.396 mmol, 1 eq) in DCM (15 mL), m-chloroperbenzoic acid (65%) (105 mg, 0.396 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated aqueous NaHCO.sub.3 solution (10 mL) and stirred for 15 min, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound, 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-156). Yield: 20 mg; 9.4%: Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (d, J=8.0 Hz, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 7.40-7.79 (m, 1H), 7.62-7.53 (m, 2H), 7.39-7.32 (m, 2H), 7.31-27 (m, 1H), 2.84-2.65 (m, 5H), 2.52 (s, 6H), 1.52 (d, J=11.6 Hz, 2H), 1.34-1.22 (m, 2H); HPLC purity: 97.55%; LCMS calculated for C.sub.25H.sub.26ClFN.sub.2O.sub.4S.sub.2: 536.10; Observed: 537.05 [M+H].sup.+.

    Example A30: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfinyl)-N,N-dimethylbenzenesulfonamide (A-181)

    [0660] ##STR01345##

    Step-1: Synthesis of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfinyl)-N,N-dimethylbenzenesulfonamide (A-181)

    [0661] To a stirred solution of 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)thio)-N,N-dimethylbenzenesulfonamide (A30.1) (200 mg, 0.39 mmol, 1 eq) in DCM (10 mL), m-chloroperbenzoic acid (65%) (105 mg, 0.39 mmol, 1 eq) was added at 0° C. and the reaction was stirred at the same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution and stirred for 15 min, and the product was extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by reverse phase preparative HPLC to afford the titled compound 4-((2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)sulfinyl)-N,N-dimethylbenzenesulfonamide (A-181). Yield: 21 mg, 8%; Appearance: off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.58-7.34 (m, 5H), 7.30 (d, J=8.4 Hz, 1H), 3.42 (d, J=11.6 Hz, 1H), 3.04-2.96 (m, 1H), 2.95-2.85 (m, 1H), 2.79-2.71 (m, 1H), 2.57 (s, 6H), 2.46 (m, 1H), 1.99-1.86 (m, 1H), 1.85-1.78 (m, 1H), 1.71-1.64 (m, 1H), 1.62-1.50 (m, 1H); HPLC purity: 99.17%; LCMS Calculated for C.sub.25H.sub.26ClFN.sub.2O.sub.3S.sub.2: 520.11; Observed: 521.05 [M+H].sup.+.

    Example A31: Synthesis of 4-((1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethyl)amino)-N,N-dimethylbenzenesulfonamide (A-241)

    [0662] ##STR01346##

    Step-1: Synthesis of 1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethan-1-one (A31.3)

    [0663] To a stirred solution of 4-(4-chloro-2-fluorophenyl)piperidine (A31.1) (500 mg, 2.35 mmol, 1 eq) and 2,2,2-trifluoro-1-(2-fluorophenyl)ethan-1-one (A31.2) (540 mg, 2.81 mmol, 1.2 eq) in acetonitrile (5 mL), DIPEA (1.02 mL, 5.86 mmol, 2.5 eq) was added at room temperature. The reaction mixture was stirred at 80° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethan-1-one (A31.3) (105 mg, 11.6%). LCMS: 403.90 [M+H.sub.3O].sup.+.

    Step-2: Synthesis of (Z)-4-((1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethylidene)amino)-N,N-dimethylbenzenesulfonamide (A31.5)

    [0664] To a stirred solution of 1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethan-1-one (A31.3) (100 mg, 0.259 mmol, 1 eq) and 4-amino-N,N-dimethylbenzenesulfonamide (A31.4) (52 mg, 0.259 mmol, 1 eq) in toluene (3 mL), a 2 M solution of trimethyl aluminium in toluene (0.65 mL, 1.3 mmol, 5 eq) was added dropwise at 0° C. The reaction mixture was warmed to room temperature over a period of 10 min and heated at 110° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled (Z)-4-((1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethylidene)amino)-N,N-dimethylbenzenesulfonamide (A31.5) (55 mg, 37.36%). LCMS: 568.15 [M+H].sup.+.

    Step-3: Synthesis of 4-((1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethyl)amino)-N,N-dimethylbenzenesulfonamide (A-241)

    [0665] To a stirred solution of (Z)-4-((1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethylidene)amino)-N,N-dimethylbenzenesulfonamide (A31.5) (55 mg, 0.095 mmol, 1 eq) in methanol (5 mL), sodium borohydride (18 mg, 0.48 mmol, 5 eq) was added at 0° C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel followed by reverse phase preparative HPLC to afford the titled compound 4-((1-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-2,2,2-trifluoroethyl)amino)-N,N-dimethylbenzenesulfonamide (A-241). Yield: 20 mg, 36.36%; Appearance: Off white solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.59 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.46-7.37 (m, 2H), 7.26-7.21 (m, 1H), 7.20-7.16 (m, 1H), 7.10 (dd, J=2.0, 10.0 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 6.00-5.92 (m, 1H), 5.20 (bs, 1H), 3.16-3.10 (m, 1H), 3.03-2.90 (m, 4H), 2.65 (s, 6H), 2.02-1.80 (m, 4H), (1H merged with the solvent peak); HPLC purity: 99.77%; LCMS calculated for C27H28ClF.sub.4N.sub.3O.sub.2S: 569.15; Observed: 570.25 [M+H].sup.+.

    Example A32: Synthesis of 4-((4-(4-(4-chloro-2-fluorophenyl)-2-oxopiperazin-1-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-89)

    [0666] ##STR01347##

    Step-1: Procedure for Synthesis of 4-(4-chloro-2-fluorophenyl)piperazin-2-one (A32.3)

    [0667] To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (A32.1) (2 g, 9.67 mmol, 1 eq) and piperazin-2-one (A32.2) (1.06 g, 10.63 mmol, 1.1 eq) in 1,4-dioxane (30 mL) was added Cs.sub.2CO.sub.3 (9.45 g, 29.01 mmol, 3 eq), reaction mixture was purged with argon for 15 min followed by addition of Pd.sub.2(dba).sub.3 (531 mg, 0.58 mmol, 0.03 eq) and xantphos (335 mg, 0.58 mmol, 0.06 eq). The reaction mixture was stirred at 120° C. for 12 h; the reaction progress was monitored by TLC. After completion, the reaction mixture was partitioned between water and ethyl acetate. The organic layers were separated, washed with water dried over Na.sub.2SO.sub.4 and concentrated to provide 4-(4-chloro-2-fluorophenyl)piperazin-2-one (A32.3) (0.54 g, crude). The crude was used as such next step without purification. LCMS: 229.05 [M+H].sup.+.

    Step-2: Procedure for Synthesis of 4-((4-(4-(4-chloro-2-fluorophenyl)-2-oxopiperazin-1-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-89)

    [0668] To a stirred solution of 4-(4-chloro-2-fluorophenyl)piperazin-2-one (A32.3) (0.2 g, 0.88 mmol, 1 eq) and 4-((4-bromo-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A32.4) (0.43 g, 1.06 mmol, 1.2 eq) in toluene (5 mL) was added K.sub.2CO.sub.3 (0.33 g, 1.76 mmol, 2 eq), purged reaction mixture with argon for 15 min followed by addition of (1R,2R)-(−)-N,N-Dimethylcyclohexane-1,2-diamine (0.05 g, 0.35 mmol, 0.4 eq) and Copper iodide (0.033 g, 1.76 mol, 0.2 eq) at room temperature. The reaction mixture was stirred at 120° C. for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by prep HPLC to provide 4-((4-(4-(4-chloro-2-fluorophenyl)-2-oxopiperazin-1-yl)-2-methyl-1H-imidazol-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-89). Yield: 0.140 g, 29%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31-8.29 (m, 2H), 8.05-8.03 (m, 2H), 7.90 (s, 1H), 7.41-7.38 (m, 1H), 7.22-7.2 (m, 1H), 7.09 (t, J=9.2 Hz, 1H), 3.90 (m, 4H), 3.46 (m, 2H), 2.67 (s, 6H), 2.52 (m, 3H); HPLC purity: 97.11%; LCMS Calculated for C.sub.22H.sub.23ClFN.sub.5O.sub.5S.sub.2: 555.08; Observed: 556 [M+H].sup.+.

    Example A33: Synthesis of N1-(3-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-68) and N1-(5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-59)

    [0669] ##STR01348##

    Step-1: Procedure for Synthesis of Phenyl (E)-4-(4-chloro-2-fluorophenyl)-N-cyanopiperazine-1-carbimidate (A33.3)

    [0670] To a stirred solution of 1-(4-chloro-2-fluorophenyl)piperazine (A33.1) (1 g, 4.6 mmol, 1 eq) in DCM (20 mL) was added diphenyl cyanocarbonimidate (A33.2) (1.1 g, 4.6 mmol, 1 eq). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure. The crude was purified by column chromatography to afford phenyl (E)-4-(4-chloro-2-fluorophenyl)-N-cyanopiperazine-1-carbimidate (A33.3) (0.7 g, 41.91%). LCMS: 359.10 [M+H].sup.+.

    Step-2: Procedure for Synthesis of 3-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-5-amine (A33.4) and 5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-3-amine (A33.5)

    [0671] To a stirred solution of (E)-4-(4-chloro-2-fluorophenyl)-N-cyanopiperazine-1-carbimidate (A33.3) (0.5 g, 1.39 mmol, 1 eq) in IPA (30 mL) was added methyl hydrazine (0.13 g, 2.79 mmol, 2 eq) at room temperature. The reaction mixture was stirred at 90° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure. The crude was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford mixture of regioisomers 3-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-5-amine (A33.4) and 5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-3-amine (A33.5) (0.3 g, crude). The crude was used as such next step without purification. LCMS: 311.11 [M+H].sup.+.

    Step-3: Procedure for Synthesis of N-(3-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-68) and NJ-(5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-59)

    [0672] To a stirred solution of mixture of regioisomers 3-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-5-amine (A33.4) and 5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-3-amine (A33.5) (0.25 g, 0.8 mmol, 1 eq) in DMF (5 mL) was added NaH (0.12 g, 4.8 mmol, 6 eq) at 0° C., stirred the reaction mixture at room temperature for 10 min followed by addition of 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A33.6) (0.34 g, 1.2 mmol, 1.5 eq). The reaction mixture was stirred at 90° C. for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The crude was purified by column chromatography followed by prep HPLC to provide the N1-(3-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-68) and N1-(5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-59) as separate product. A-68: Yield: 0.03 g, 6.68%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.23 (s, 1H), 8.05 (d, J=8.1 Hz, 2H), 7.87 (d, J=8.2 Hz, 2H), 7.35 (dd, J=12.5, 2.4 Hz, 1H), 7.18 (dd, J=8.7, 2.3 Hz, 1H), 7.08 (t, J=9.0 Hz, 1H), 3.37 (d, J=7.8 Hz, 7H), 3.09-3.02 (m, 4H), 2.62 (s, 6H); HPLC purity: 98.75%; LCMS Calculated for C.sub.21H.sub.25ClFN.sub.7O.sub.4S.sub.2: 557.11; Observed: 558.0 [M+H].sup.+. A-59: Yield: 0.035 g, 6.5%; Appearance: white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.16 (s, 1H), 8.19-8.11 (m, 2H), 8.00-7.92 (m, 2H), 7.36 (dd, J=12.5, 2.4 Hz, 1H), 7.20 (ddd, J=8.5, 2.4, 1.1 Hz, 1H), 7.07 (t, J=9.1 Hz, 1H), 3.54 (s, 3H), 3.20 (dd, J=6.6, 3.2 Hz, 4H), 3.12-3.04 (m, 4H), 2.63 (s, 6H); HPLC purity: 98.04%; LCMS Calculated for C.sub.21H.sub.25ClFN.sub.7O.sub.4S.sub.2: 557.11; Observed: 558.0 [M+H].sup.+.

    Example A34: Synthesis of N1-(5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-18)

    [0673] ##STR01349##

    Step-1: Procedure for Synthesis of 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)piperazine (A34.3)

    [0674] To a stirred solution of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (A34.1) (1 g, 5.7 mmol, 1 eq) and 1-(4-chloro-2-fluorophenyl)piperazine (A34.2) (1.3 g, 6.2 mmol, 1.1 eq) in DMSO (10 mL) was added TEA (3 mL, 22.8 mmol, 4 eq) at room temperature. The reaction mixture was stirred at 80° C. for 16 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)piperazine (A34.3) (0.9 g, crude). The crude was used as such next step without purification. LCMS: 354.11 [M+H].sup.+.

    Step-2: Procedure for Synthesis of 5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1,3-dimethyl-1H-pyrazol-4-amine (A34.4)

    [0675] To a stirred solution of 1-(4-chloro-2-fluorophenyl)-4-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)piperazine (A34.3) (0.9 g, 2.5 mmol, 1 eq) in mixture of ethanol (12 mL) and water (4 mL) was added Fe powder (0.71 g, 12.7 mmol, 5 eq) and ammonium chloride (0.67 g, 12.7 mmol, 5 eq) at room temperature. The resulting reaction mixture was stirred at 80° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness to afford 5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1,3-dimethyl-1H-pyrazol-4-amine (A34.4) (0.7 g, crude). The crude was used as such next step without purification. LCMS: 324.13 [M+H].sup.+.

    Step-3: Procedure for Synthesis of N1-(5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-18)

    [0676] To a stirred solution of 5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1,3-dimethyl-1H-pyrazol-4-amine (A34.4) (0.1 g, 0.31 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A34.5) (96 mg, 0.34 mmol, 1.1 eq) in ACN (5 mL) was added pyridine (0.08 mL, 0.93 mmol, 3 eq) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude was purified by prep HPLC to afford N1-(5-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-1,3-dimethyl-1H-pyrazol-4-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-18). Yield: 60 mg, 34%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.44 (s, 1H), 7.95 (q, J=8.5 Hz, 4H), 7.37 (dd, J=12.5, 2.4 Hz, 1H), 7.23-7.2 (m, 1H), 7.09 (t, J=9.1 Hz, 1H), 3.53 (s, 3H), 3.23 (m, 4H), H), 3.08 (m, 4H), 2.61 (s, 6H), 1.24 (s, 3H); HPLC purity: >99%; LCMS Calculated for C.sub.23H.sub.28ClFN.sub.6O.sub.4S.sub.2: 570.13; Observed: 571.30 [M+H].sup.+.

    Example A35: Synthesis of 2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-N-(4-(N,N-dimethylsulfamoyl)phenyl)benzamide (A-9)

    [0677] ##STR01350##

    Step-1: Procedure for synthesis of 2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)benzoic Acid (A35.3)

    [0678] To a stirred solution of methyl 2-(piperazin-1-yl)benzoate (A35.1) (3.1 g, 14.09 mmol, 1 eq) and 1-bromo-4-chloro-2-fluorobenzene (A35.2) (4.4 g, 21.14 mmol, 1.5 eq) in 1,4-dioxane (40 mL) was added sodium tert-butoxide (4.7 g. 49.32 mmol, 3.5 eq). The reaction mixture was purged with argon for 20 min followed by addition of and BINAP (1.75 g, 2.81 mmol, 0.2 eq) and Pd.sub.2(dba).sub.3 (1.28 g, 1.41 mmol, 0.1 eq). The reaction mixture was stirred at 100° C. for 12 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was poured in water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford the pure compound 2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)benzoic acid (A35.3) (2.2 g, 44.89%). LCMS: 335.09 [M+H].sup.+.

    Step-2: Procedure for Synthesis of 2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-N-(4-(N,N-dimethylsulfamoyl)phenyl)benzamide (A-9)

    [0679] To a stirred solution of 2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)benzoic acid (A35.3) (0.4 g, 1.19 mmol, 1 eq) and 4-amino-N,N-dimethylbenzenesulfonamide (A35.4) (0.29 g, 1.44 mmol, 1.2 eq) in THF (3 mL) was added T.sub.3P (1.13 g, 3.57 mmol, 3 eq) and DIPEA (0.6 mL, 3.57 mmol, 3 eq) at room temperature. The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured in water and extracted with ethyl acetate. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by prep HPLC to afford the titled compound 2-(4-(4-chloro-2-fluorophenyl)piperazin-1-yl)-N-(4-(N,N-dimethylsulfamoyl)phenyl)benzamide (A-9). Yield: 0.03 g, 4.55%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.46 (s, 1H), 8.01 (d, J=8.8 Hz, 2H), 7.73 (m, 3H), 7.57-7.53 (m, 1H), 7.38-7.32 (m, 2H), 7.24 (t, J=7.2 Hz, 1H), 7.17 (dd, J=8.4 Hz, 8.8 Hz, 1H), 7.01 (t, J=8.8 Hz, 1H)), 3.15-3.13 (m, 8H), 2.58 (s, 6H); HPLC purity: >99%; LCMS Calculated for C.sub.25H.sub.26ClFN.sub.4O.sub.3S: 516.14; Observed: 517.30 [M+H].sup.+.

    Example A36: Synthesis of N-(2-(3,5-difluoropyridin-2-yl)phenyl)-4-methoxybenzenesulfonamide (A-180)

    [0680] ##STR01351##

    Step-1: Synthesis of 3,5-difluoro-2-(2-nitrophenyl)pyridine (A36.3)

    [0681] A pyrex tube was charged with 2-bromo-3,5-difluoropyridine A41.1 (1 g, 5.1 mmol, 1 eq), (2-nitrophenyl)boronic acid (A36.2) (1.03 g, 6.1 mmol, 1.2 eq) and potassium carbonate (1.62 g, 11.7 mmol, 2.3 eq) in a mixture of 1,4-dioxane (40 mL) and water (10 mL). The tube was sealed with a septum and the reaction mixture was purged with argon for 30 min. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.26 g, 0.35 mmol, 0.07 eq) was then added to the reaction mixture under an argon atmosphere and the reaction mixture was purged with argon for 5 min. The tube was then fitted with a screw cap and the reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 3,5-difluoro-2-(2-nitrophenyl)pyridine (A36.3) (0.36 g, 20%). LCMS: 237.04 [M+H].sup.+.

    Step-2: Synthesis of 2-(3,5-difluoropyridin-2-yl)aniline (A36.4)

    [0682] A stirred solution of 3,5-difluoro-2-(2-nitrophenyl)pyridine (A36.3) (0.36 g, 4.9 mmol, 1 eq) in ethyl acetate (3 mL) was purged with nitrogen for 5 min. 10% Palladium on carbon (0.036 g, 10% w/w) was added to the reaction mixture under a nitrogen atmosphere. The reaction mixture was stirred under a hydrogen atmosphere via a hydrogen balloon at room temperature for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 2-(3,5-difluoropyridin-2-yl)aniline (A36.4) (0.22 g, 88%). LCMS: 207.07 [M+H].sup.+.

    Step-3: Synthesis of N-(2-(3,5-difluoropyridin-2-yl)phenyl)-4-methoxybenzenesulfonamide (A-180)

    [0683] To a stirred solution of 2-(3,5-difluoropyridin-2-yl)aniline (A36.4) (220 mg, 1.06 mmol, 1 eq) in acetonitrile (3 mL), pyridine (0.213 mL, 2.66 mmol, 2.5 eq) was added at room temperature and stirred for 5 min. 4-methoxybenzenesulfonyl chloride (A36.5) (262 mg, 1.28 mmol, 1.2 eq) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound N-(2-(3,5-difluoropyridin-2-yl)phenyl)-4-methoxybenzenesulfonamide (A-180). Yield: 48 mg, 13%; Appearance: White sticky solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.58 (s, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.02-7.91 (m, 1H), 7.46-7.23 (m, 6H), 6.96-6.87 (m, 2H), 3.79 (s, 3H); HPLC purity: >99%; LCMS Calculated for C.sub.18H.sub.14F.sub.2N.sub.2O.sub.3S: 376.07; Observed: 377.00 [M+H].sup.+.

    Example A37: Synthesis of N1-(2-(divinylphosphoryl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-227)

    [0684] ##STR01352##

    Step-1: Synthesis of Diethyl (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonate (A37.3)

    [0685] To a stirred solution of diethyl (2-aminophenyl)phosphonate (A37.1) (4 g, 17.4 mmol, 1 eq) in acetonitrile (40 mL), pyridine (2.75 mL, 34.9 mmol, 2 eq) was added at 0° C. and stirred the reaction mixture for 10 min. 4-(N,N-Dimethylsulfamoyl)benzenesulfonyl chloride A37.2 (5.44 g, 19.1 mmol, 1.1 eq) was then added to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound diethyl (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonate (A37.3) (7 g, 84%). LCMS: 477.08 [M+H].sup.+.

    Step-2: Synthesis of (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonic Acid (A37.4)

    [0686] To a stirred solution of diethyl (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonate A37.3 (2 g, 4.19 mmol, 1 eq) in acetonitrile (20 mL), trimethylsilyl bromide (4 mL) was added at room temperature. The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was triturated with n-pentane, the solids were filtered out and dried under reduced pressure to afford the titled compound (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonic acid (A37.4) (1.5 g, crude). This compound was used in the next step without further purification. LCMS: 421.02 [M+H].sup.+.

    Step-3: Synthesis of (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonic dichloride (A37.5)

    [0687] To a stirred solution of (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonic acid (A37.4) (1.5 g, 3.57 mmol, 1 eq) in DCM (15 mL), DMF (2-3 drop) followed by oxalyl chloride (1.15 g, 8.92 mmol, 2.5 eq) were added at 0° C. under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness to afford the titled compound (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonic dichloride (A37.5) (1.6 g, crude). This compound was used in the next step without further purification. LCMS: No ionization.

    Step-4: Synthesis of N1-(2-(divinylphosphoryl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-227)

    [0688] To a stirred solution of (2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)phosphonic dichloride (A37.5) (1.6 g, 3.51 mmol, 1 eq) in THE (20 mL), a 2 M solution of vinyl magnesium bromide in THE A37.6 (5.26 mL, 10.52 mmol, 3 eq) was added dropwise at 0° C. The resulting reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound N1-(2-(divinylphosphoryl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-227). Yield: 240 mg, 19%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.50 (s, 1H), 8.03-7.94 (m, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.57-7.43 (m, 3H), 7.22 (t, J=6.8 Hz, 1H), 6.63 (ddd, J=26.6, 18.5, 12.7 Hz, 2H), 6.25 (dd, J=12.4, 1.8 Hz, 1H), 6.18-5.98 (m, 3H), 2.60 (s, 6H); HPLC purity: 96.77%; LCMS Calculated for C.sub.18H.sub.21N.sub.2O.sub.5PS.sub.2: 440.06; Observed: 441.00 [M+H].sup.+.

    Example A38: Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-2-yl)-4-methoxybenzenesulfonamide (A-167)

    [0689] ##STR01353##

    Step-1: Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-2-yl)-4-methoxybenzenesulfonamide, (A-167)

    [0690] A pyrex tube was charged with N-(2-bromophenyl)-4-methoxybenzenesulfonamide (A38.1) (0.4 g, 1.17 mmol, 1 eq), (2,4-difluorophenyl)boronic acid A38.2 (0.22 g, 1.41 mmol, 1.2 eq) and cesium carbonate (0.76 g, 2.34 mmol, 2 eq) in a mixture of 1,4-dioxane (16 mL) and water (4 mL). The tube was sealed with a septum and the reaction mixture was purged with nitrogen for 30 min. Bis(triphenylphosphine)palladium(II) dichloride (0.06 g, 0.08 mmol, 0.07 eq) was then added to the reaction mixture under the atmosphere of nitrogen at room temperature. The tube was then sealed with screw cap and the reaction mixture was stirred at 100° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was diluted with brine and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford title compound N-(2′,4′-difluoro-[1,1′-biphenyl]-2-yl)-4-methoxybenzenesulfonamide (A-167). Yield: 0.025 g, 11%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H), 7.56-7.45 (m, 2H), 7.36-6.95 (m, 9H), 3.85-3.80 (m, 3H); HPLC purity: 97.13%; LCMS Calculated for C.sub.19H.sub.15F.sub.2NO.sub.3S: 375.07; Observed: 375.95 [M+H].sup.+.

    Example A39: Synthesis of N-(2-(2,4-difluorophenoxy)phenyl)-4-methoxybenzenesulfonamide (A-186)

    [0691] ##STR01354##

    Step-1: Synthesis of N-(2-(2,4-difluorophenoxy)phenyl)-4-methoxybenzenesulfonamide (A-186)

    [0692] To a stirred solution of 2-(2,4-difluorophenoxy)aniline (A39.1) (0.2 g, 0.9 mmol, 1 eq) in acetonitrile (5 mL), pyridine (0.18 mL, 2.2 mmol, 2.5 eq) was added at room temperature and the reaction mixture was stirred at the same temperature for 5 min. 4-Methoxybenzenesulfonyl chloride A39.2 (0.22 g, 1.08 mmol, 1.2 eq) was then added to the reaction mixture. The reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound N-(2-(2,4-difluorophenoxy)phenyl)-4-methoxybenzenesulfonamide (A-186). Yield: 0.12 g, 34%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.87 (s, 1H), 7.72-7.63 (m, 2H), 7.47-7.30 (m, 2H), 7.12-6.94 (m, 5H), 6.75-6.59 (m, 2H), 3.79 (d, J=1.0 Hz, 3H); HPLC purity: 98.28%; LCMS Calculated for C.sub.19H.sub.15F.sub.2NO.sub.4S: 391.07; Observed: 391.95 [M+H].sup.+.

    Example A40: Synthesis of N-(2-((2,4-difluorobenzyl)oxy)phenyl)-4-methoxybenzenesulfonamide (A-187)

    [0693] ##STR01355##

    Step-1: Synthesis of 2,4-difluoro-1-((2-nitrophenoxy)methyl)benzene (A40.3)

    [0694] To a stirred solution of 1-(bromomethyl)-2,4-difluorobenzene (A40.1) (1 g, 4.83 mmol, 1 eq) in acetonitrile (20 mL), potassium carbonate (1.3 g, 9.66 mmol, 2 eq), 2-nitrophenol (A40.2) (739 mg, 5.31 mmol, 1.1 eq) and potassium iodide (80 mg, 0.48 mmol, 0.1 eq) were added at room temperature. The reaction mixture was stirred at 75° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound 2,4-difluoro-1-((2-nitrophenoxy)methyl)benzene A40.3 (1 g, 78.12%). LCMS: 266.06 [M+H].sup.+.

    Step-2: Synthesis of 2-((2,4-difluorobenzyl)oxy)aniline (A40.4)

    [0695] To a stirred solution of 2,4-difluoro-1-((2-nitrophenoxy)methyl)benzene (A40.3) (1 g, 3.77 mmol, 1 eq) in a mixture of ethanol (14 mL) and water (3 mL), iron powder (1.05 g, 18.87 mmol, 5 eq) and ammonium chloride (1 g, 18.87 mmol, 5 eq) were added at room temperature. The resulting reaction mixture was stirred at 90° C. for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with ethanol. The filtrated was concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford the titled compound 2-((2,4-difluorobenzyl)oxy)aniline (A40.4) (680 mg, 76.74%). LCMS: 236.08 [M+H].sup.+.

    Step-3: Synthesis of N-(2-((2,4-difluorobenzyl)oxy)phenyl)-4-methoxybenzenesulfonamide (A40.6)

    [0696] To a stirred solution of 2-((2,4-difluorobenzyl)oxy)aniline (A40.4) (200 mg, 0.85 mmol, 1 eq) in acetonitrile (10 mL), pyridine (171 mL, 2.13 mmol, 2.5 eq) and 4-methoxybenzenesulfonyl chloride (A40.5) (211 mg, 1.02 mmol, 1.2 eq) were added at room temperature and the reaction mixture was stirred at the same temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of the reaction, 1N aqueous HCl solution was added and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the titled compound N-(2-((2,4-difluorobenzyl)oxy)phenyl)-4-methoxybenzenesulfonamide (A-187). Yield: 180 mg, 52.32%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.34 (s, 1H), 7.58-7.44 (m, 3H), 7.33-7.22 (m, 2H), 7.16-7.05 (m, 2H), 7.01 (dd, J=8.3, 1.5 Hz, 1H), 6.95-6.84 (m, 3H), 4.87 (s, 2H), 3.75 (d, J=1.4 Hz, 3H); HPLC purity: >99%; LCMS Calculated for C.sub.20H.sub.17F.sub.2NO.sub.4S: 405.08; Observed: 405.90 [M+H].sup.+.

    Example A41

    [0697] ##STR01356##

    General Procedure for Synthesis of Aminobenzyl Series Compounds—Method A

    [0698] Sulfonyl chloride (1.1 eq) was added to the vial containing aniline (1 eq) in dry pyridine (1 mL). The reaction mixture was heated at 100° C. with stirring for 16 h. After cooling to the room temperature the mixture was evaporated. The residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities if there were any. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade methanol (acetonitrile)).

    [0699] The following examples were prepared using method A:

    TABLE-US-00011 Compound No. Structure Analytical data A-390 [01357]embedded image Yield: 106.4 mg, 50.7%; Appearance: Light-brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.00 (s, 1H), 7.47-7.29 (m, 5H), 7.24-7.15 (m, 2H), 3.69-3.55 (m, 4H), 3.31-3.20 (m, 2H), 2.13-1.89 (m, 3H), 1.06- 0.91 (m, 2H), 0.65-0.50 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21ClN.sub.2O.sub.3S: 392.90; Observed: 392.12 [M − H].sup.−. A-392 [01358]embedded image Yield: 80.4 mg, 38.3%; Appearance: Brown solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.17 (s, 1H), 7.88 (dd, J = 8.0, 1.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.19-7.06 (m, 3H), 7.03 (d, J = 7.9 Hz, 1H), 3.67 (s, 4H), 3.48-3.35 (m, 2H), 3.32-3.19 (m, 2H), 2.73-2.59 (m, 1H), 0.97 (dt, J = 8.5, 3.2 Hz, 2H), 0.82-0.70 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21ClN.sub.2O.sub.3S: 392.90; Observed: 392.12 [M − H].sup.−. A-393 [01359]embedded image Yield: 70.3 mg, 33.6%; Appearance: Light-brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.62 (s, 1H), 7.40 (dd, J = 8.0, 1.6 Hz, 1H), 7.21 (t, J = 8.1 Hz, 1H), 7.15 (dd, J = 8.1, 1.6 Hz, 1H), 4.26 (p, J = 6.2 Hz, 1H), 3.87-3.74 (m, 2H), 3.74-3.61 (m, 2H), 3.56-3.42 (m, 4H), 2.84-2.61 (m, 2H), 2.18-2.05 (m, 1H), 1.81- 1.67 (m, 3H), 1.56-1.39 (m, 8H); HPLC purity: 98.05%; LCMS Calculated for C.sub.19H.sub.27ClN.sub.2O.sub.4S: 414.95; Observed: 414.17 [M − H].sup.−. A-394 [01360]embedded image Yield: 9.9 mg, 4.72%; Appearance: Beige solid; .sup.1H NMR (500 MHz, Chloroform-d.sub.6) δ 8.40 (s, 1H), 7.45 (dd, J = 8.2, 1.4 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.02 (dd, J = 8.1, 1.4 Hz, 1H), 3.98 (dd, J = 11.2, 2.9 Hz, 2H), 3.89-3.79 (m, 2H), 3.71 (td, J = 11.4, 2.4 Hz, 2H), 2.94 (s, 2H), 2.57 (d, J = 11.7 Hz, 2H), 2.01 (s, 3H), 1.85- 1.79 (m, 5H), 1.77-1.61 (m, 8H); HPLC purity: 98.96%; LCMS Calculated for C.sub.21H.sub.29ClN.sub.2O.sub.3S: 424.98; Observed: 424.2 [M − H].sup.−. A-410 [01361]embedded image Yield: 62.8 mg, 40.0%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 7.40-7.32 (m, 3H), 7.34-7.27 (m, 3H), 7.30-7.20 (m, 2H), 7.13- 7.05 (m, 2H), 4.62 (s, 2H), 3.65 (t, J = 4.7 Hz, 4H), 2.72 (t, J = 4.5 Hz, 4H), 1.21 (s, 9H); HPLC purity: 95.72%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.3S: 415.55; Observed: 415.23 [M − H].sup.−. A-563 [01362]embedded image Yield: 11.9 mg, 32.8%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.44 (s, 1H), 7.36 (dd, J = 8.8, 2.5 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.29 (dd, J = 7.6, 1.9 Hz, 1H), 7.20 (dd, J = 7.6, 2.0 Hz, 1H), 7.12- 7.03 (m, 2H), 7.00 (d, J = 8.9 Hz, 1H), 4.60 (s, 2H), 3.64 (t, J = 4.8 Hz, 4H), 3.57 (s, 3H), 2.70 (t, J = 4.8 Hz, 4H), 1.19 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30ClN.sub.3O.sub.4S: 480.02; Observed: 479.2 [M − H].sup.−. A-485 [01363]embedded image Yield: 59.5 mg, 20.9%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.45 (s, 1H), 7.58-7.53 (m, 1H), 7.50 (s, 1H), 7.32 (d, J = 3.9 Hz, 2H), 7.30-7.19 (m, 2H), 7.12-7.04 (m, 2H), 4.65 (s, 2H), 3.65 (s, 4H), 2.72 (t, J = 4.7 Hz, 4H), 1.19 (s, 9H); HPLC purity: 99.64%; LCMS Calculated for C.sub.22H.sub.28BrN.sub.3O.sub.3S: 494.45; Observed: 493.45 [M − H].sup.−. A-500 [01364]embedded image Yield: 36.2 mg, 32.8%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 7.32 (d, J = 5.9 Hz, 1H), 7.23 (d, J = 5.3 Hz, 1H), 7.13-7.06 (m, 2H), 6.98 (s, 1H), 6.90 (s, 2H), 4.53 (s, 2H), 3.65 (t, J = 5.2 Hz, 4H), 2.69 (t, J = 4.9 Hz, 4H), 2.22 (s, 6H), 1.21 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.3S: 443.61; Observed: 443.27 [M − H].sup.−. A-564 [01365]embedded image Yield: 16.5 mg, 10.6%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.99 (s, 1H), 7.38-7.28 (m, 5H), 7.17 (dd, J = 7.6, 1.9 Hz, 1H), 7.06-6.95 (m, 3H), 3.51 (s, 4H), 2.60 (t, J = 4.9 Hz, 4H), 1.73-1.67 (m, 2H), 1.31 (q, J = 5.0 Hz, 2H), 1.17 (s, 9H); HPLC purity: 99.37%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.3S: 441.59; Observed: 441.25 [M − H].sup.−. A-501 [01366]embedded image Yield: 41.3 mg, 26.3%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 7.31 (d, J = 5.9 Hz, 1H), 7.23 (d, J = 5.9 Hz, 1H), 7.14-7.06 (m, 4H), 6.95 (s, 1H), 4.58 (d, J = 13.9 Hz, 4H), 3.89-3.81 (m, 2H), 3.63 (t, J = 5.1 Hz, 4H), 2.76 (s, 2H), 2.69 (t, J = 3.8 Hz, 4H), 1.21 (s, 9H); HPLC purity: 95.53%; LCMS Calculated for C.sub.25H.sub.33N.sub.3O.sub.4S: 471.62; Observed: 471.26 [M − H].sup.−. A-486 [01367]embedded image Yield: 48.5 mg, 30.8%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.19-7.00 (m, 4H), 6.99 (s, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.39 (s, 2H), 3.62 (s, 4H), 2.69 (t, J = 4.9 Hz, 4H), 2.25 (s, 3H), 2.21 (s, 3H), 1.24 (s, 9H); HPLC purity: 96.53%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.3S: 443.61; Observed: 443.27 [M − H].sup.−. A-488 [01368]embedded image Yield: 34.3 mg, 20.9%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.62 (s, 1H), 7.59 (dd, J = 9.3, 2.2 Hz, 1H), 7.50-7.42 (m, 1H), 7.42- 7.30 (m, 1H), 7.30-7.19 (m, 2H), 7.13-7.03 (m, 2H), 4.66-4.61 (m, 2H), 3.66 (s, 4H), 2.75 (d, J = 5.1 Hz, 4H), 1.20 (s, 9H); HPLC purity: 96.83%; LCMS Calculated for C.sub.22H.sub.27BrFN.sub.3O.sub.3S: 512.44; Observed: 512.13 [M − H].sup.−. A-512 [01369]embedded image Yield: 69.6 mg, 44.3%; Appearance: Light-brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.71 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.12-7.00 (m, 3H), 3.56 (t, J = 4.9 Hz, 4H), 2.95 (p, J = 6.9 Hz, 1H), 2.35 (t, J = 4.8 Hz, 4H), 1.23 (d, J = 6.8 Hz, 6H), 1.21 (s, 9H); HPLC purity: 96.81%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.3S: 443.61; Observed: 444.1 [M+H].sup.−. A-513 [01370]embedded image Yield: 73.9 mg, 47.1%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.70 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.11-7.00 (m, 3H), 3.56 (s, 4H), 2.65 (q, J = 7.2 Hz, 1H), 2.33 (t, J = 4.4 Hz, 4H), 1.62-1.52 (m, 2H), 1.21 (d, J = 2.7 Hz, 12H), 0.77 (t, J = 7.4 Hz, 3H); HPLC purity: 96.93%; LCMS Calculated for C.sub.25H.sub.35N.sub.3O.sub.3S: 457.63; Observed: 457.29 [M − H].sup.−. A-514 [01371]embedded image Yield: 16.2 mg, 11.5%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.79 (s, 1H), 7.64 (s, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (dd, J = 7.7, 1.8 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.13-7.03 (m, 3H), 6.79 (d, J = 8.4 Hz, 1H), 3.61 (t, J = 4.8 Hz, 4H), 3.01 (s, 2H), 2.43 (t, J = 4.9 Hz, 4H), 1.40 (s, 6H), 1.20 (s, 9H); HPLC purity: 99.13%; LCMS Calculated for C.sub.25H.sub.33N.sub.3O.sub.4S: 471.62; Observed: 471.26 [M − H].sup.−. A-527 [01372]embedded image Yield: 28.0 mg, 17.8%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.21 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 6.6 Hz, 1H), 7.06 (s, 3H), 3.57 (t, J = 4.5 Hz, 4H), 2.47 (t, J = 4.7 Hz, 4H), 1.22 (s, 9H); HPLC purity: 97.38%; LCMS Calculated for C.sub.22H.sub.26F.sub.3N.sub.3O.sub.3S: 469.52; Observed: 469.2 [M − H].sup.−. A-515 [01373]embedded image Yield: 34.9 mg, 22.2%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 8.07 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 3.3 Hz, 1H), 7.09-6.91 (m, 3H), 6.53 (d, J = 3.3 Hz, 1H), 3.84 (s, 3H), 3.59 (s, 4H), 2.37 (t, J = 4.9 Hz, 4H), 1.20 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30N.sub.4O.sub.3S: 454.59; Observed: 454.24 [M − H].sup.−. A-528 [01374]embedded image Yield: 31.6 mg, 20.1%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.04 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.34 (dd, J = 7.4, 2.1 Hz, 1H), 7.14-7.03 (m, 3H), 3.51 (t, J = 4.7 Hz, 4H), 3.08 (q, J = 10.1 Hz, 1H), 2.31 (t, J = 5.2 Hz, 4H), 2.01 (q, J = 9.9 Hz, 2H), 1.16 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.29F.sub.2N.sub.3O.sub.3S: 477.57; Observed: 477.23 [M − H].sup.−. A-516 [01375]embedded image Yield: 48.5 mg, 30.8%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.72 (s, 1H), 7.68- 7.56 (m, 2H), 7.48-7.41 (m, 3H), 7.11-7.01 (m, 3H), 3.55 (s, 4H), 2.32 (t, J = 4.8 Hz, 4H), 1.30 (s, 9H), 1.20 (s, 9H); HPLC purity: 98.57%; LCMS Calculated for C.sub.25H.sub.35N.sub.3O.sub.3S: 457.63; Observed: 457.29 [M − H].sup.−. A-529 [01376]embedded image Yield: 50.1 mg, 31.8%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 8.04-7.97 (m, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.48-7.41 (m, 1H), 7.11-6.71 (m, 4H), 3.55 (s, 4H), 2.32 (t, J = 4.8 Hz, 4H), 1.24 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27F.sub.2N.sub.3O.sub.3S: 451.53; Observed: 451.21 [M − H].sup.−. A-534 [01377]embedded image Yield: 15.1 mg, 9.59%; Appearance: Violet solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.99 (s, 1H), 7.87 (dd, J = 8.1, 1.6 Hz, 1H), 7.31-7.26 (m, 1H), 7.15-7.10 (m, 2H), 7.11- 7.05 (m, 1H), 4.16 (s, 2H), 3.47 (t, J = 4.9 Hz, 4H), 2.44 (t, J = 4.7 Hz, 4H), 1.14 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.27Cl.sub.2N.sub.3O.sub.4S: 524.46; Observed: 524.14 [M − H].sup.−. A-535 [01378]embedded image Yield: 26.3 mg, 16.7%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.15 (s, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.37-7.31 (m, 1H), 7.14-7.05 (m, 3H), 3.50 (t, J = 4.6 Hz, 4H), 2.33 (t, J = 4.8 Hz, 4H), 1.65 (s, 6H), 1.16 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.4O.sub.3S: 468.62; Observed: 468.26 [M − H].sup.−. A-572 [01379]embedded image Yield: 16.3 mg, 10.3%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.10 (s, 1H), 7.70 (s, 4H), 7.40 (d, J = 6.8 Hz, 1H), 7.15-7.06 (m, 3H), 3.49- 3.44 (m, 4H), 2.23 (t, J = 4.8 Hz, 4H), 1.51 (s, 6H), 1.14 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32F.sub.3N.sub.3O.sub.3S: 511.6; Observed: 511.26 [M − H].sup.-. A-536 [01380]embedded image Yield: 19.5 mg, 12.4%; Appearance: Yellow Solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.84 (s, 1H), 7.66-7.60 (m, 2H), 7.35 (dd, J = 7.8, 1.8 Hz, 1H), 7.12 (dd, J = 7.4, 2.0 Hz, 1H), 7.10-7.02 (m, 2H), 7.02-6.95 (m, 2H), 4.87-4.81 (m, 1H), 3.56 (t, J = 4.7 Hz, 4H), 2.38 (t, J = 4.9 Hz, 4H), 1.92-1.85 (m, 2H), 1.66-1.59 (m, 4H), 1.59-1.52 (m, 2H), 1.16 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.35N.sub.6O.sub.4S: 485.64; Observed: 485.28 [M − H].sup.−. A-530 [01381]embedded image Yield: 65.9 mg, 42.0%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.55 (s, 1H), 7.62 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.10-6.98 (m, 3H), 6.71 (d, J = 8.4 Hz, 1H), 5.00 (dd, J = 14.2, 6.6 Hz, 1H), 3.66 (s, 4H), 3.42-3.31 (m, 1H), 2.81 (dd, J = 16.2, 7.4 Hz, lH), 2.50(s, 7H), 1.43 (d, J = 6.1 Hz, 3H), 1.23 (s, 9H); HPLC purity: 97.23%; LCMS Calculated for C.sub.24H.sub.31N.sub.3O.sub.4S: 457.59; Observed: 457.24 [M − H].sup.−. A-590 [01382]embedded image Yield: 32.0 mg, 20.4%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.26 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.34-7.28 (m, 1H), 7.12-7.06 (m, 3H), 3.49 (t, J = 4.8 Hz, 4H), 2.36 (t, J = 4.8 Hz, 4H), 1.93 (t, J = 19.0 Hz, 4H), 1.15 (s, 9H).; HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.29F.sub.2N.sub.3O.sub.3S: 465.56; Observed: 465.23 [M − H].sup.−. A-591 [01383]embedded image Yield: 4.3 mg, 2.73%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.98 (s, 2H), 7.76- 7.70 (m, 2H), 7.30 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 7.3 Hz, 1H), 7.06-7.01 (m, 2H), 4.83 (q, J = 8.8 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 2.45- 2.41 (m, 4H), 1.17 (s, 9H); HPLC purity: 95.24%; LCMS Calculated for C.sub.23H.sub.28F.sub.3N.sub.3O.sub.4S: 499.55; Observed: 499.21 [M − H].sup.−. A-573 [01384]embedded image Yield: 14.5 mg, 9.19%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.89 (s, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.35 (dd, J = 7.0, 2.4 Hz, 1H), 7.18-7.11 (m, 1H), 7.14-7.02 (m, 4H), 3.97 (t, J = 6.4 Hz, 2H), 3.62 (s, 4H), 2.44 (t, J = 4.8 Hz, 4H), 1.76-1.66 (m, 2H), 1.20 (s, 9H), 1.01-0.90 (m, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.4S: 459.61; Observed: 459.26 [M − H].sup.−. A-574 [01385]embedded image Yield: 21.4 mg, 13.6%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.38 (s, 1H), 7.94-7.81 (m, 4H), 7.41-7.34 (m, 1H), 7.19-7.09 (m, 3H), 3.53 (s, 4H), 2.35 (s, 4H), 1.18 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.26F.sub.3N.sub.3O.sub.3S.sub.2: 501.58; Observed: 501.17 [M − H].sup.−. A-567 [01386]embedded image Yield: 37.6 mg, 23.9%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.5 Hz, 1H), 7.14-7.04 (m, 3H), 3.73 (q, J = 11.4 Hz, 2H), 3.50 (s, 4H), 2.28 (s, 4H), 1.15 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.28F.sub.3N.sub.3O.sub.3S: 483.55; Observed: 483.22 [M − H].sup.−. A-568 [01387]embedded image Yield: 38.4 mg, 24.4%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 7.93-7.84 (m, 2H), 7.40 (d, J = 8.4 Hz, 3H), 7.07 (d, J = 3.0 Hz, 3H), 3.59 (s, 4H), 2.44 (t, J = 4.9 Hz, 4H), 1.22 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.26F.sub.3N.sub.3O.sub.4S: 485.52; Observed: 485.19 [M − H].sup.−. A-575 [01388]embedded image Yield: 21.4 mg, 13.6%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (s, 1H), 8.02-7.92 (m, 4H), 7.35 (d, J = 8.7 Hz, 1H), 7.13-7.03 (m, 3H), 3.54 (t, J = 5.3 Hz, 4H), 2.44 (t, J = 4.8 Hz, 4H), 1.21 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26F.sub.5N.sub.3O.sub.3S.sub.2: 527.57; Observed: 527.17 [M − H].sup.−. A-537 [01389]embedded image Yield: 39.8 mg, 25.3%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 8.00-7.90 (m, 4H), 7.41-7.33 (m, 1H), 7.18-7.09 (m, 3H), 3.47 (d, J = 6.1 Hz, 4H), 2.34 (t, J = 4.7 Hz, 4H), 1.17 (s, 9H); HPLC purity: 96.14%; LCMS Calculated for C.sub.23H.sub.26F.sub.5N.sub.3O.sub.3S: 519.53; Observed: 519.2 [M − H].sup.−. A-569 [01390]embedded image Yield: 16.0 mg, 10.2%; Appearamce: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.38- 7.33 (m, 1H), 7.15-7.08 (m, 3H), 3.61 (s, 3H), 3.48- 3.41 (m, 4H), 2.28 (t, J = 4.9 Hz, 4H), 1.15 (s, 9H); HPLC purity: 96%; LCMS Calculated for C.sub.24H.sub.29F.sub.4N.sub.3O.sub.4S: 531.57; Observed: 531.22 [M − H].sup.−. A-576 [01391]embedded image Yield: 39.2 mg, 24.9%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.91 (s, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.36 (dd, J = 12, 2.4 Hz, 1H), 7.26-7.03 (m, 5H), 4.00-3.87 (m, 1H), 3.71-3.57 (m, 4H), 2.47-2.39 (m, 4H), 1.20 (s, 9H), 0.85-0.76 (m, 2H), 0.69-0.62 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31N.sub.3O.sub.4S: 457.59; Observed: 457.24 [M − H].sup.−. A-538 [01392]embedded image Yield: 23.9 mg, 15.7%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.32-7.26 (m, 1H), 7.21-7.15 (m, 1H), 7.05-6.98 (m, 4H), 3.76 (s, 3H), 3.26 (s, 3H), 3.12 (s, 2H), 2.51-2.47 (m, 21H), 2.44-2.37 (m, 2H), 1.60- 1.53 (m, 2H), 1.33-1.26 (m, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28N.sub.2O.sub.4S: 404.53; Observed: 404.21 [M − H].sup.−. A-539 [01393]embedded image Yield: 47.8 mg, 32.6%; Appearance: Blue solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.56 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.33-7.24 (m, 3H), 7.21-7.15 (m, 1H), 7.04-6.97 (m, 2H), 3.26 (s, 3H), 3.11 (s, 2H), 2.52- 2.48 (m, 3H), 2.43-2.36 (m, 2H), 2.30 (s, 3H), 1.60- 1.52 (m, 2H), 1.29 (dt, J = 13.4, 3.9 Hz, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28N.sub.2O.sub.3S: 388.53; Observed: 388.22 [M − H].sup.−. A-577 [01394]embedded image Yield: 10.2 mg, 6.97%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.86 (s, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.04-6.97 (m, 1H), 3.26 (s, 3H), 3.10 (s, 2H), 2.56- 2.50 (m, 2H), 2.44 (d, J = 6.3 Hz, 2H), 1.55-1.47 (m, 2H), 1.29-1.22 (m, 2H), 0.91 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.25ClN.sub.2O.sub.3S: 408.94; Observed: 408.16 [M − H].sup.−. A-532 [01395]embedded image Yield: 26.7 mg, 16.0%; Appearance: Yellow oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.96 (s, 1H), 7.36- 7.29 (m, 3H), 7.29-7.25 (m, 1H), 7.25-7.18 (m, 3H), 7.08-7.01 (m, 2H), 4.60 (s, 2H), 3.24 (s, 3H), 3.09 (s, 2H), 2.72-2.61 (m, 4H), 1.56-1.48 (m, 2H), 1.32- 1.25 (m, 2H), 0.93 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28N.sub.2O.sub.3S: 388.53; Observed: 388.53 [M − H].sup.−. A-540 [01396]embedded image Yield: 21.7 mg, 16.0%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.32 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.19-7.09 (m, 2H), 7.10-7.01 (m, 1H), 3.52- 3.42 (m, 1H), 3.27 (s, 3H), 2.70-2.61 (m, 4H), 2.62- 2.53 (m, 6H), 1.19 (d, J = 7.0 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.24F.sub.3N.sub.3O.sub.4S.sub.2: 491.54; Observed: 491.14 [M − H].sup.−. A-531 [01397]embedded image Yield: 13.8 mg, 9.56%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.64 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.29-7.22 (m, 1H), 7.17-7.10 (m, 1H), 7.07-6.97 (m, 4H), 3.77 (s, 3H), 3.53-3.42 (m, 1H), 2.78-2.64 (m, 4H), 2.52 (d, J = 4.6 Hz, 4H), 1.18 (d, J = 7.1 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.24F.sub.3N.sub.3O.sub.3S: 443.49; Observed: 443.18 [M − H].sup.−. A-541 [01398]embedded image Yield: 69.7 mg, 47.2%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.03 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.19 (dd, J = 8.0, 1.5 Hz, 1H), 7.12 (dd, J = 8.0, 1.6 Hz, 1H), 7.08 (td, J = 7.6, 1.6 Hz, 1H), 7.02 (td, J = 7.6, 1.6 Hz, 1H), 3.51- 3.39 (m, 1H), 2.71-2.59 (m, 4H), 2.58-2.52 (m, 4H), 1.17 (d, J = 7.0 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21ClF.sub.3N.sub.3O.sub.2S: 447.9; Observed: 447.13 [M − H].sup.−. A-542 [01399]embedded image Yield: 24.9 mg, 15.8%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (s, 1H), 7.35- 7.21 (m, 6H), 7.17 (d, J = 7.6 Hz, 1H), 7.11-6.99 (m, 2H), 4.49 (s, 2H), 3.38-3.25 (m, 1H), 2.83-2.69 (m, 8H), 1.24 (d, J = 7.0 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.24F.sub.3N.sub.3O.sub.2S: 427.49; Observed: 427.19 [M − H].sup.−. A-592 [01400]embedded image Yield: 67.8 mg, 43.8%; Appearance: Green oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.09 (s, 1H), 7.28 (dd, J = 7.4, 2.1 Hz, 1H), 7.25-7.10 (m, 5H), 7.09-7.00 (m, 2H), 4.60 (s, 2H), 3.24 (s, 3H), 3.10 (s, 2H), 2.76-2.65 (m, 4H), 2.26 (s, 3H), 1.60-1.53 (m, 2H), 1.35-1.28 (m, 2H), 0.94 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.30N.sub.2O.sub.3S: 402.55; Observed: 402.24 [M − H].sup.−. A-593 [01401]embedded image Yield: 40.6 mg, 25.8%; Appearance: Olive solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.96 (s, 1H), 7.31- 7.22 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.09-7.03 (m, 2H), 7.03-6.98 (m, 2H), 4.56 (s, 2H), 3.24 (s, 3H), 3.09 (s, 2H), 2.73-2.59 (m, 4H), 2.22 (s, 3H), 1.55-1.48 (m, 2H), 1.32-1.25 (m, 2H), 0.93 (s, 3H).; HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.30N.sub.2O.sub.3S: 402.55; Observed: 402.24 [M − H].sup.−. A-578 [01402]embedded image Yield: 65.9 mg, 43.4%; Appearance: Beige solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.73 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.11-6.99 (m, 6H), 4.40 (s, 2H), 3.30 (s, 3H), 3.11 (s, 2H), 2.81-2.60 (m, 4H), 2.33 (s, 3H), 1.57-1.48 (m, 2H), 1.37-1.28 (m, 2H), 0.97 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.30N.sub.2O.sub.3S: 402.55; Observed: 402.24 [M − H].sup.−. A-579 [01403]embedded image Yield: 47.6 mg, 30.3%; Appearance: Beige solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.41- 7.33 (m, 2H), 7.32-7.26 (m, 1H), 7.24 (s, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 9.3 Hz, 1H), 7.06-7.00 (m, 2H), 4.55 (s, 2H), 3.31 (s, 3H), 3.14 (s, 2H), 2.77 (s, 4H), 1.63 (s, 2H), 1.40 (d, J = 13.1 Hz, 2H), 1.00 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27FN.sub.2O.sub.3S: 406.52; Observed: 406.21 [M − H].sup.−. A-594 [01404]embedded image Yield: 56.6 mg, 36.0%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 7.37 (td, J = 8.0, 6.1 Hz, 1H), 7.32-7.25 (m, 1H), 7.23- 7.20 (m, 1H), 7.18 (td, J = 8.7, 2.7 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.09-7.01 (m, 3H), 4.66 (s, 2H), 3.24 (s, 3H), 3.10 (s, 2H), 2.73-2.62 (m, 4H), 1.58-1.50 (m, 2H), 1.33-1.26 (m, 2H), 0.93 (s, 3H); HPLC purity: 95.73%; LCMS Calculated for C.sub.21H.sub.27FN.sub.2O.sub.3S: 406.52; Observed: 406.21 [M − H].sup.−. A-580 [01405]embedded image Yield: 62.6 mg, 39.8%; Appearance: Brown oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.82 (s, 1H), 7.33- 7.17 (m, 4H), 7.10-6.99 (m, 4H), 4.49 (s, 2H), 3.31 (s, 3H), 2.79-2.65 (m, 4H), 1.64-1.53 (m, 2H), 1.36 (d, J = 13.6 Hz, 2H), 0.99 (s, 3H); HPLC purity: 95.73%; LCMS Calculated for C.sub.21H.sub.27FN.sub.2O.sub.3S: 406.52; Observed: 406.21 [M − H].sup.−. A-601 [01406]embedded image Yield: 4.8 mg, 2.78%; Appearance: Yellow oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.26 (s, 1H), 7.48- 7.41 (m, 2H), 7.40-7.31 (m, 2H), 7.29 (dd, J = 7.7, 1.8 Hz, 1H),7.22 (dd, J = 7.8, 1.9 Hz, 1H), 7.10-7.01 (m, 2H), 4.75 (s, 2H), 3.24 (s, 3H), 3.11 (s, 2H), 2.77-2.67 (m, 4H), 1.62-1.54 (m, 2H), 1.36-1.29 (m, 2H), 0.94 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27ClN.sub.2O.sub.3S: 422.97; Observed: 422.18 [M − H].sup.−. A-602 [01407]embedded image Yield: 33.0 mg, 19.0%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (s, 1H), 7.37-7.26 (m, 4H), 7.24-7.16 (m, 3H), 7.05 (t, J = 5.8 Hz, 2H), 4.52 (s, 2H), 3.30 (s, 3H), 3.12 (s, 2H), 2.76-2.69 (m, 4H), 1.65-1.53 (m, 2H), 1.36 (d, J = 13.0 Hz, 2H), 0.99 (s, 3H); HPLC purity: 95.33%; LCMS Calculated for C.sub.21H.sub.27ClN.sub.2O.sub.3S: 422.97; Observed: 422.18 [M − H].sup.−. A-610 [01408]embedded image Yield: 14.9 mg, 9.46%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.46 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.59-7.52 (m, 2H), 7.28 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 4.78 (s, 2H), 3.25 (s, 3H), 3.12 (s, 2H), 2.76 (t, J = 5.6 Hz, 4H), 1.66-1.58 (m, 2H), 1.39-1.32 (m, 2H), 0.95 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27N.sub.3O.sub.3S: 413.54; Observed: 413.21 [M − H].sup.−. A-581 [01409]embedded image Yield: 37.3 mg, 23.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.35-7.26 (m, 1H), 7.23 (dd, J = 6.0, 3.5 Hz, 1H), 7.10-7.01 (m, 2H), 4.62 (s, 2H), 3.31 (s, 3H), 3.14(s, 2H), 2.82-2.69 (m, 4H), 1.69-1.57 (m, 2H), 1.39 (d, J = 12.8 Hz, 2H), 1.00 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27N.sub.3O.sub.3S: 413.54; Observed: 413.21 [M − H].sup.−. A-596 [01410]embedded image Yield: 38.4 mg, 24.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.95 (s, 1H), 7.31-7.20 (m, 3H), 7.09-7.01 (m, 2H), 6.90 (dd, J = 8.3, 2.7 Hz, 1H), 6.80 (dt, J = 7.6, 1.2 Hz, 1H), 6.74 (dd, J = 2.6, 1.5 Hz, 1H), 4.58 (s, 2H), 3.65 (s, 3H), 3.24 (s, 3H), 3.09 (s, 2H), 2.71-2.58 (m, 4H), 1.54-1.46 (m, 2H), 1.31- 1.24 (m, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.30N.sub.2O.sub.4S: 418.55; Observed: 418.23 [M − H].sup.−. A-705 [01411]embedded image Yield: 8.3 mg, 5.08%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.62 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.34-7.30 (m, 1H), 7.20-7.15 (m, 1H), 7.07-7.02 (m, 2H), 3.53 (s, 3H), 3.25 (s, 3H), 3.09 (s, 2H), 2.41 (t, J = 9.8 Hz, 3H), 2.32-2.27 (m, 2H), 1.53-1.45 (m, 3H), 1.44 (s, 6H), 1.26-1.20 (m, 2H), 0.90 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.34N.sub.2O.sub.5S: 474.62; Observed: 474.26 [M − H].sup.−. A-641 [01412]embedded image Yield: 49.1 mg, 30.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.96 (s, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.9 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.7 Hz, 1H), 3.60 (p, J = 6.9 Hz, 1H), 3.24 (s, 3H), 3.07 (s, 2H), 2.53-2.49 (m, 2H), 2.45-2.38 (m, 2H), 1.52-1.44 (m, 2H), 1.22 (d, J = 13.0 Hz, 2H), 1.05 (d, J = 6.8 Hz, 6H), 0.89 (s, 3H); HPLC purity: 98.66%; LCMS Calculated for C.sub.24Hz.sub.32NO.sub.4S: 444.59; Observed: 444.25 [M − H].sup.−. A-706 [01413]embedded image Yield: 15.4 mg, 9.29%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.54 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.35-7.28 (m, 1H), 7.20-7.15 (m, 1H), 7.07-7.00 (m, 2H), 3.25 (s, 4H), 3.10 (s, 2H), 2.94-2.86 (m, 1H), 2.45-2.40 (m, 2H), 2.36-2.29 (m, 2H), 1.55-1.47 (m, 2H), 1.28- 1.21 (m, 2H), 1.13 (d, J = 6.9 Hz, 6H), 0.90 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.2O.sub.3S: 416.58; Observed: 416.26 [M − H].sup.−. A-707 [01414]embedded image Yield: 19.2 mg, 11.3%; Appearance: Colorless oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.55 (s, 1H), 7.64 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.33-7.25 (m, 2H), 7.18 (dd, J = 5.9, 3.6 Hz, 1H), 7.04-6.99 (m, 2H), 4.19- 4.12 (m, 1H), 3.26 (s, 3H), 3.18 (s, 3H), 3.11 (s, 2H), 3.11-3.02 (m, 3H), 2.91-2.83 (m, 2H), 2.53-2.49 (m, 2H), 2.43-2.35 (m, 3H), 1.59-1.52 (m, 2H), 1.32- 1.25 (m, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444.59; Observed: 444.25 [M − H].sup.−. A-616 [01415]embedded image Yield: 66.9 mg, 41.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.38 (s, 1H), 7.72 (d, J = 6.6 Hz, 1H), 7.66-7.57 (m, 1H), 7.40-7.32 (m, 1H), 7.18-7.08 (m, 2H), 7.07-6.96 (m, 2H), 3.32 (s, 3H), 3.14 (s, 2H), 2.61-2.50 (m, 3H), 2.49-2.39 (m, 2H), 2.28 (s, 3H), 1.70-1.58 (m, 2H), 1.42-1.31 (m, 2H), 0.98 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27FN.sub.2O.sub.3S: 406.52; Observed: 406.21 [M − H].sup.−. A-642 [01416]embedded image Yield: 47.1 mg, 28.1%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.74 (s, 1H), 7.38 (dd, J = 7.9, 1.7 Hz, 1H), 7.20 (dd, J = 7.7, 1.8 Hz, 1H), 7.12-6.99 (m, 3H), 6.92 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.37 (s, 2H), 3.30 (s, 3H), 3.11 (s, 2H), 2.74- 2.57 (m, 4H), 2.21 (d, J = 15.0 Hz, 6H), 1.58-1.46 (m, 2H), 1.37-1.26 (m, 2H), 0.98 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.2O.sub.3S: 416.58; Observed: 416.26 [M − H].sup.−. A-617 [01417]embedded image Yield: 62.0 mg, 39.7%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (s, 1H), 7.53-7.43 (m, 2H), 7.40-7.30 (m, 2H), 7.13 (dd, J = 6.1, 3.4 Hz, 1H), 7.06-6.97 (m, 2H), 3.32 (s, 3H), 3.14 (s, 2H), 2.63-2.51 (m, 2H), 2.51-2.42 (m, 2H), 2.30 (s, 3H), 1.69-1.58 (m, 2H), 1.42-1.31 (m, 2H), 0.98 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27FN.sub.2O.sub.3S: 406.52; Observed: 406.21 [M − H].sup.−. A-618 [01418]embedded image Yield: 73.8 mg, 45.8%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.28 (s, 1H), 7.59 (s, 1H), 7.56-7.49 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.39- 7.28 (m, 2H), 7.12 (d, J = 7.3 Hz, 1H), 7.07-6.95 (m, 2H), 3.32 (s, 3H), 3.14 (s, 2H), 2.54 (s, 2H), 2.40 (s, 2H), 2.37 (s, 3H), 1.62 (t, J = 11.4 Hz, 2H), 1.35 (d, J = 13.0 Hz, 2H), 0.98 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28N.sub.2O.sub.3S: 388.53; Observed: 388.22 [M − H].sup.−. A-619 [01419]embedded image Yield: 59.0 mg, 37.0%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (s, 1H), 7.74 (s, 1H), 7.50-7.41 (m, 2H), 7.21-7.14 (m, 1H), 7.12-7.01 (m, 2H), 5.71 (s, 1H), 4.00-3.88 (m, 4H), 3.32 (s, 3H), 3.14 (s, 2H), 2.62-2.52 (m, 3H), 2.49- 2.42 (m, 3H), 1.63 (t, J = 10.7 Hz, 2H), 1.37 (d, J = 13.1 Hz, 2H), 0.98 (s, 3H); HPLC purity: 97.62%; LCMS Calculated for C.sub.21H.sub.28N.sub.2O.sub.5S.sub.2: 452.58; Observed: 452.17 [M − H].sup.−. A-643 [01420]embedded image Yield: 65.4 mg, 40.8%; Appearance: Light brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.57 (s, 1H), 7.49- 7.43 (m, 1H), 7.40-7.33 (m, 2H), 7.33-7.26 (m, 2H), 7.22-7.15 (m, 1H), 7.10-7.00 (m, 2H), 3.25 (s, 3H), 3.10 (s, 2H), 2.46-2.40 (m, 2H), 2.36-2.29 (m, 2H), 1.94 (tt, J = 8.3, 5.1 Hz, 1H), 1.56-1.49 (m, 2H), 1.29- 1.22 (m, 2H), 0.98-0.90 (m, 2H), 0.91 (s, 3H), 0.61- 0.54 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 414.24 [M − H].sup.−. A-620 [01421]embedded image Yield: 60.1 mg, 36.5%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.58 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.39-7.31 (m, 1H), 7.12-6.78 (m, 4H), 3.32 (s, 3H), 3.13 (s, 2H), 2.54 (t, J = 9.3 Hz, 2H), 2.49-2.38 (m, 2H), 1.61 (tt, J = 9.6, 3.9 Hz, 2H), 1.34 (d, J = 12.4 Hz, 2H), 0.97 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26F.sub.2N.sub.2O.sub.3S: 424.51; Observed: 424.2 [M − H].sup.−. A-621 [01422]embedded image Yield: 95.2 mg, 58.7%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.22 (s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.38 (dd, J = 7.2, 2.1 Hz, 1H), 7.11 (d, J = 7.8 Hz, 3H), 7.06-6.94 (m, 2H), 3.32 (s, 3H), 3.14 (s, 2H), 2.54 (d, J = 10.6 Hz, 2H), 2.45-2.35 (m, 2H), 1.93 (tt, J = 8.7, 4.9 Hz, 1H), 1.67-1.56 (m, 2H), 1.35 (d, J = 13.2 Hz, 2H), 1.08-0.99 (m, 2H), 0.98 (s, 3H), 0.77- 0.68 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 414.24 [M − H].sup.−. A-622 [01423]embedded image Yield: 80.4 mg, 51.5%; Appearance: yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 9.1 Hz, 3H), 7.16-7.08 (m, 1H), 7.08-6.98 (m, 2H), 3.32 (s, 3H), 3.12 (s, 2H), 2.54 (d, J = 8.8 Hz, 2H), 2.47-2.36 (m, 2H), 1.66-1.54 (m, 2H), 1.38-1.27 (m, 2H), 0.96 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.25F.sub.3N.sub.2O.sub.4S: 458.5; Observed: 458.18 [M − H].sup.−. A-623 [01424]embedded image Yield: 53.2 mg, 33.8%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.55 (s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.37-7.28 (m, 1H), 7.16-7.08 (m, 1H), 7.07-6.96 (m, 2H), 3.32 (s, 3H), 3.14 (s, 2H), 2.63-2.51 (m, 2H), 2.51-2.39 (m, 2H), 1.68-1.57 (m, 2H), 1.36 (t, J = 9.0 Hz, 2H), 0.98 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.25BrN.sub.2O.sub.3S: 453.4; Observed: 453.11 [M − H].sup.−. A-708 [01425]embedded image Yield: 20.5 mg, 12.5%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.65 (s, 1H), 7.37-7.32 (m, 1H), 7.30 (d, J = 3.9 Hz, 1H), 7.26-7.21 (m, 1H), 7.11-7.03 (m, 2H), 6.77 (d, J = 3.9 Hz, 1H), 3.26 (s, 3H), 3.11 (s, 2H), 2.58-2.52 (m, 2H), 2.46-2.39 (m, 4H), 2.13 (tt, J = 8.6, 5.0 Hz, 1H), 1.60-1.53 (m, 2H), 1.33-1.26 (m, 2H), 1.08-0.99 (m, 2H), 0.93 (s, 3H), 0.69-0.61 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28N.sub.2O.sub.3S.sub.2: 420.59; Observed: 420.19 [M − H].sup.−. A-644 [01426]embedded image Yield: 43.3 mg, 27.0%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.48 (s, 1H), 7.58 (s, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.32-7.26 (m, 1H), 7.23- 7.16 (m, 1H), 7.05-6.99 (m, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.21 (t, J = 52.8 Hz, 1H), 4.43 (q, J = 11.0 Hz, 1H), 3.26 (s, 3H), 3.12 (s, 2H), 2.86-2.74 (m, 2H), 2.56- 2.46 (m, 2H), 2.42 (td, J = 12.2, 11.6, 5.7 Hz, 2H), 2.10- 2.03 (m, 1H), 1.77-1.67 (m, 1H), 1.60-1.53 (m, 2H), 1.33-1.27 (m, 2H), 0.93 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30F.sub.2N.sub.2O.sub.4S: 480.57; Observed: 480.23 [M − H].sup.−. A-645 [01427]embedded image Yield: 40.7 mg, 25.3%; Appearance: Brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.68 (s, 1H), 7.76 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 7.5, 2.0 Hz, 1H), 7.18 (dd, J = 7.3, 2.0 Hz, 1H), 7.06-6.98 (m, 2H), 4.97 (d, J = 5.0 Hz, 4H), 3.26 (s, 3H), 3.11 (s, 2H), 2.50 (d, J = 8.2 Hz, 2H), 2.45-2.38 (m, 2H), 1.58-1.50 (m, 2H), 1.31-1.24 (m, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.28N.sub.2O.sub.4S: 416.54; Observed: 416.21 [M − H].sup.−. A-625 [01428]embedded image Yield: 11.4 mg, 6.83%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 7.50 (s, 2H), 7.28-7.22 (m, 2H), 7.21-7.15 (m, 1H), 7.06- 6.98 (m, 2H), 4.65 (s, 2H), 3.85-3.78 (m, 2H), 3.26 (s, 3H), 3.11 (s, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.50 (s, 2H), 2.41 (dd, J = 11.2, 5.3 Hz, 2H), 1.59-1.49 (m, 2H), 1.32- 1.25 (m, 2H), 0.92 (d, J = 1.8 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.4S: 430.56; Observed: 430.23 [M − H].sup.−. A-624 [01429]embedded image Yield: 51.7 mg, 30.6%; Appearance: Violet solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (s, 1H), 7.43-7.14 (m, 6H), 7.07-6.96 (m, 3H), 6.91 (d, J = 8.1 Hz, 1H), 4.18 (s, 2H), 3.32 (s, 3H), 3.16 (s, 2H), 2.91 (d, J = 5.2 Hz, 2H), 2.76 (d, J = 6.5 Hz, 4H), 1.78-1.64 (m, 2H), 1.45 (d, J = 12.9 Hz, 2H), 1.01 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30N.sub.2O.sub.4S: 442.57; Observed: 442.23 [M − H].sup.−. A-646 [01430]embedded image Yield: 38.8 mg, 23.8%; Appearance: Brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.19 (s, 1H), 7.54-7.42 (m, 3H), 7.32-7.24 (m, 2H), 7.19 (d, J = 9.0 Hz, 2H), 4.83 (s, 2H), 3.47 (s, 3H), 3.32 (s, 2H), 2.95-2.82 (m, 4H), 2.41 (s, 3H), 1.79-1.69 (m, 2H), 1.55-1.47 (m, 2H), 1.15 (s, 3H); HPLC purity: 98.79%; LCMS Calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S: 420.54; Observed: 420.23 [M − H].sup.−. A-709 [01431]embedded image Yield: 17.5 mg, 11.2%; Appearance: Beige oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.13 (s, 1H), 7.27 (dd, J = 6.9, 2.3 Hz, 1H), 7.25-7.19 (m, 2H), 7.09-6.97 (m, 4H), 4.57 (s, 2H), 3.24 (s, 3H), 3.10 (s, 2H), 2.76-2.65 (m, 4H), 2.28 (s, 3H), 1.59-1.52 (m, 2H), 1.34-1.27 (m, 2H), 0.94 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S: 420.54; Observed: 420.23 [M − H].sup.−. A-647 [01432]embedded image Yield: 6.2 mg, 3.97%; Appearance: Orange oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.27 (dd, J = 6.8, 2.4 Hz, 1H), 7.25-7.19 (m, 1H), 7.10-6.90 (m, 3H), 4.70 (s, 2H), 3.24 (s, 3H), 3.09 (s, 2H), 2.72-2.60 (m, 4H), 1.55-1.48 (m, 2H), 1.31-1.24 (m, 2H), 0.92 (s, 3H); HPLC purity: 98.99%; LCMS Calculated for C.sub.22H.sub.28F.sub.2N.sub.2O.sub.3S: 438.53; Observed: 438.22 [M − H].sup.−. A-648 [01433]embedded image Yield: 71.1 mg, 44.4%; Appearance: Yellow oil; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.45 (s, 1H), 7.52 (dd, J = 6.9, 2.3 Hz, 1H), 7.47 (dd, J = 7.0, 2.6 Hz, 1H), 7.45- 7.35 (m, 2H), 7.34-7.24 (m, 3H), 4.83 (s, 2H), 3.48 (s, 3H), 3.35 (s, 2H), 3.01-2.89 (m, 4H), 2.45 (s, 3H), 1.86- 1.77 (m, 2H), 1.60-1.52 (m, 2H), 1.18 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S: 420.54; Observed: 420.23 [M − H].sup.−. A-649 [01434]embedded image Yield: 14.0 mg, 8.47%; Appearance: Brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.72 (s, 1H), 7.33-7.24 (m, 6H), 7.12-7.06 (m, 1H), 7.00 (tt, J = 7.4, 5.5 Hz, 2H), 3.23 (s, 3H), 3.06 (s, 2H), 2.65-2.57 (m, 2H), 2.57- 2.51 (m, 2H), 1.72-1.64 (m, 2H), 1.42-1.35 (m, 2H), 1.32-1.25 (m, 2H), 1.24-1.17 (m, 2H), 0.90 (d, J = 1.4 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 414.24 [M − H].sup.−. A-650 [01435]embedded image Yield: 79.8 mg, 50.8%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 7.72 (dd, J = 8.4, 2.0 Hz, 2H), 7.42-7.32 (m, 3H), 7.15-7.08 (m, 1H), 7.07-6.96 (m, 2H), 3.32 (s, 3H), 3.13 (s, 2H), 2.98- 2.87 (m, 1H), 2.49 (d, J = 1.5 Hz, 2H), 2.38 (q, J = 9.4 Hz, 2H), 2.02-1.79 (m, 2H), 1.66-1.55 (m, 2H), 1.34 (d, J = 13.1 Hz, 2H), 0.97 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.28F.sub.2N.sub.2O.sub.3S: 450,54; Observed: 450.22 [M − H].sup.−. A-651 [01436]embedded image Yield: 13.9 mg, 8.85%; Appearance: Light brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.67 (s, 1H), 7.67- 7.61 (m, 2H), 7.48 (d, J = 7.0 Hz, 2H), 7.28 (dd, J = 7.4, 2.2 Hz, 1H), 7.18 (dd, J = 7.4, 2.1 Hz, 1H), 7.07-6.98 (m, 2H), 3.25 (s, 3H), 3.10 (s, 2H), 3.09-3.04 (m, 1H), 2.46-2.40 (m, 2H), 2.39-2.30 (m, 2H), 2.04-1.95 (m, 1H), 1.92-1.83 (m, 1H), 1.57-1.49 (m, 2H), 1.29- 1.23 (m, 2H), 0.91 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.28F.sub.2N.sub.2O.sub.3S: 450.54; Observed: 450.22 [M − H].sup.−. A-710 [01437]embedded image Yield: 56.0 mg, 35.7%; Appearance: Grey solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.69 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.33 (dt, J = 7.6, 3.8 Hz, 1H), 7.12 (dt, J = 7.6, 3.8 Hz, 1H), 7.05 (dd, J = 6.0, 3.5 Hz, 2H), 3.54 (s, 3H), 3.52 (s, 2H), 2.29 (d, J = 5.7 Hz, 4H), 1.57 (s, 2H), 1.52 (tq, J = 13.1, 7.6, 6.4 Hz, 4H), 1.44 (s, 6H), 1.16 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.36N.sub.2O.sub.5S: 500.23; Observed: 499.2 [M − H].sup.−. A-657 [01438]embedded image Yield: 29.0 mg, 16.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.68 (s, 1H), 8.06-7.98 (m, 2H), 7.94-7.83 (m, 2H), 7.41-7.31 (m, 1H), 7.07 (dd, J = 6.0, 3.5 Hz, 1H), 7.02 (dp, J = 7.3, 3.5 Hz, 2H), 3.66-3.50 (m, 3H), 2.45 (t, J = 5.6 Hz, 4H), 1.63 (d, J = 5.4 Hz, 6H), 1.21 (d, J = 2.5 Hz, 6H), 1.14 (dd, J = 6.8, 2.5 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.34N.sub.2O.sub.4S: 470.63; Observed: 469.4 [M − H].sup.−. A-658 [01439]embedded image Yield: 71.7 mg, 41.5%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.28 (s, 1H), 7.71-7.60 (m, 2H), 7.42 (dt, J = 7.7, 1.8 Hz, 1H), 7.35-7.25 (m, 2H), 7.14-6.92 (m, 3H), 3.57 (d, J = 1.6 Hz, 2H), 2.94 (p, J = 6.8 Hz, 1H), 2.38 (d, J = 5.6 Hz, 4H), 1.62 (q, J = 4.1 Hz, 6H), 1.23 (d, J = 1.6 Hz, 3H), 1.21 (d, J = 1.6 Hz, 9H). HPLC purity: 97.02%; LCMS Calculated for C.sub.25H.sub.34N.sub.2O.sub.3S: 442.62; Observed: 441.2 [M − H].sup.−. A-659 [01440]embedded image Yield: 19.2 mg, 11.3%; Appearance: Colorless oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.27 (s, 1H), 7.64 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.41 (dt, J = 7.8, 1.5 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.12-7.04 (m, 1H), 7.04- 6.95 (m, 2H), 4.20 (dt, J = 6.6, 3.2 Hz, 1H), 3.58 (s, 2H), 3.20 (s, 3H), 3.11 (dd, J = 16.9, 6.2 Hz, 2H), 2.93 (d, J = 16.6 Hz, 2H), 2.43 (d, J = 7.8 Hz, 4H), 1.65 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 1.3 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.34N.sub.2O.sub.4S: 470.63; Observed: 469.2 [M − H].sup.−. A-693 [01441]embedded image Yield: 75.9 mg, 43.9%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.19 (s, 1H), 8.14-8.03 (m, 2H), 8.04-7.90 (m, 2H), 7.22 (dd, J = 8.0, 1.5 Hz, 1H),7.11 (dd, J = 8.0, 1.7 Hz, 1H), 7.08 (td, J = 7.6, 1.5 Hz, 1H), 7.01 (td, J = 7.6, 1.7 Hz, 1H), 3.52 (s, 2H), 3.24 (s, 3H), 2.46-2.42 (m, 4H), 1.57 (s, 2H), 1.50 (h, J = 7.9 Hz, 4H), 1.16 (s, 6H). HPLC purity: 95.40%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.5S.sub.2: 478.62; Observed: 477.1 [M − H].sup.−. A-660 [01442]embedded image Yield: 26.9 mg, 15.5%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.14 (s, 1H), 8.02 (t, J = 7.4 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.16-7.06 (m, 2H), 7.06- 6.93 (m, 1H), 3.57 (s, 2H), 3.28 (s, 3H), 2.55 (t, J = 5.5 Hz, 4H), 1.63 (d, J = 6.1 Hz, 6H), 1.22 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.29FN.sub.2O.sub.5S.sub.2: 496.61; Observed: 495.2 [M − H].sup.−. A-661 [01443]embedded image Yield: 70.8 mg, 40.9% ; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.43 (s, 1H), 7.73 (dd, J = 7.0, 2.4 Hz, 1H), 7.62 (ddd, J = 7.5, 4.7, 2.3 Hz, 1H), 7.42-7.35 (m, 1H), 7.19-7.10 (m, 1H), 7.08 (dt, J = 7.7, 1.8 Hz, 1H), 7.05-6.95 (m, 2H), 3.59 (s, 2H), 2.47 (t, J = 5.5 Hz, 4H), 2.29 (d, J = 2.0 Hz, 3H), 1.69 (dd, J = 13.3, 7.5 Hz, 3H), 1.64 (d, J = 1.6 Hz, 3H), 1.22 (d, J = 1.6 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.29FN.sub.2O.sub.3S: 432.55; Observed: 431.2 [M − H].sup.−. A-711 [01444]embedded image Yield: 44.2 mg, 28.1%; Appearance: Grey solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.94 (s, 1H), 7.26 (dd, J = 7.5, 2.0 Hz, 1H), 7.24-7.17 (m, 1H), 7.12 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.07-6.99 (m, 2H), 4.54 (s, 2H), 3.54 (s, 2H), 2.61 (t, J = 5.5 Hz, 4H), 2.26 (s, 3H), 1.60 (s, 2H), 1.54 (q, J = 5.9 Hz, 4H), 1.17 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.2O.sub.3S: 428.59; Observed: 427.2 [M − H].sup.−. A-662 [01445]embedded image Yield: 38.1 mg, 22.0%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.30 (s, 1H), 7.75-7.57 (m, 2H), 7.39 (dt, J = 7.6, 1.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.16-7.04 (m, 1H), 7.00 (tt, J = 92, 6.3 Hz, 2H), 3.58 (d, J = 1.7 Hz, 2H), 2.44 (t, J = 5.0 Hz, 4H), 2.38 (s, 3H), 1.82-1.50 (m, 6H), 1.22 (d, J = 1.7 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 413.2 [M − H].sup.−. A-663 [01446]embedded image Yield: 36.9 mg, 21.3%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.77 (s, 1H), 7.38 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 (dd, J = 7.7, 1.7 Hz, 1H), 7.08 (td, J = 7.7, 1.7 Hz, 1H), 7.05-6.99 (m, 2H), 6.91 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 7.7, 1.8 Hz, 1H), 4.37 (s, 2H), 3.57 (s, 2H), 2.63 (t, J = 5.5 Hz, 4H), 2.21 (d, J = 15.9 Hz, 6H), 1.63 (s, 3H), 1.59 (q, J = 5.5 Hz, 3H), 1.22 (d, J = 2.0 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.34N.sub.2O.sub.3S: 442.62; Observed: 441.1 [M − H].sup.−. A-692 [01447]embedded image Yield: 52.5 mg, 30.3%; Appearance: Grey solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.86 (s, 1H), 7.54 (dd, J = 9.3, 1.8 Hz, 1H), 7.48 (dd, J = 8.0, 1.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.24 (dd, J = 7.8, 1.8 Hz, 1H), 7.12 (dd, J = 7.7, 1.7 Hz, 1H), 7.03 (dtd, J = 19.2, 7.5, 1.7 Hz, 2H), 3.54 (s, 2H), 2.44 (t, J = 5.5 Hz, 4H), 2.23 (d, J = 1.9 Hz, 3H), 1.59 (s, 3H), 1.58-1.51 (m, 3H), 1.17 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.29FN.sub.2O.sub.3S: 432.55; Observed: 431.0 [M − H].sup.−. A-664 [01448]embedded image Yield: 63.0 mg, 36.2%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.83 (s, 1H), 7.39-7.32 (m, 1H), 7.17 (ddd, J = 7.4, 4.3, 2.8 Hz, 2H), 7.14-7.09 (m, 1H), 7.05 (ddd, J = 12.4, 7.6, 1.6 Hz, 2H), 7.00 (s, 1H), 6.97 (d, J = 7.4 Hz, 1H), 4.42 (s, 2H), 3.58 (s, 2H), 2.65 (t, J = 5.5 Hz, 4H), 2.30 (s, 3H), 1.61 (dd, J = 11.3, 5.8 Hz, 6H), 1.21 (d, J = 1.2 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.2O.sub.3S: 428.59; Observed: 427.2 [M − H].sup.−. A-665 [01449]embedded image Yield: 52.1 mg, 30.1%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 7.59 (s, 1H), 7.52 (dt, J = 6.7, 2.0 Hz, 1H), 7.41 (dd, J = 7.8, 1.9 Hz, 1H), 7.38-7.28 (m, 2H), 7.07 (dd, J = 7.5, 2.1 Hz, 1H), 7.01 (tdd, J = 11.1, 5.8, 2.1 Hz, 2H), 3.58 (d, J = 2.4 Hz, 2H), 2.41 (t, J = 5.3 Hz, 4H), 2.38 (d, J = 2.4 Hz, 3H), 1.80-1.52 (m, 6H), 1.22 (d, J = 2.4 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 413.3 [M − H].sup.−. A-666 [01450]embedded image Yield: 40.8 mg, 23.5%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.24 (s, 1H), 8.14 (s, 1H), 7.55 (s, 1H), 7.47-7.36 (m, 1H), 7.11 (t, J = 6.5 Hz, 1H), 7.06 (dd, J = 7.6, 1.8 Hz, 1H), 7.04-6.95 (m, 1H), 4.80 (p, J = 8.4 Hz, 1H), 3.61 (d, J = 21.2 Hz, 2H), 2.54 (d, J = 1.7 Hz, 1H), 2.52-2.43 (m, 5H), 2.43-2.26 (m, 2H), 1.82 (dt, J = 18.2, 9.2 Hz, 2H), 1.71 (p, J = 6.5, 5.4 Hz, 3H), 1.66 (s, 3H), 1.22 (d, J = 1.6 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.3S: 444.59; Observed: 443.2 [M − H].sup.−. A-667 [01451]embedded image Yield: 78.9 mg, 4.56%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.74 (s, 1H), 7.72 (dd, J = 9.8, 2.1 Hz, 1H), 7.68-7.56 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.39-7.33 (m, 1H), 7.33-7.10 (m, 1H), 7.07 (d, J = 8.9 Hz, 1H), 7.05-6.96 (m, 2H), 3.58 (s, 2H), 2.49 (t, J = 3.2 Hz, 4H), 1.65 (d, J = 11.9 Hz, 6H), 1.22 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.27F.sub.3N.sub.2O.sub.4S: 484.53; Observed: 483.1 [M − H].sup.−. A-668 [01452]embedded image Yield: 46.0 mg, 26.6%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.92 (s, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.19 (dd, J = 7.4, 1.9 Hz, 1H), 7.06 (qd, J = 8.9, 4.6 Hz, 4H), 6.98 (d, J = 9.7 Hz, 1H), 4.53 (s, 2H), 3.59 (s, 2H), 2.69 (t, J = 5.5 Hz, 4H), 1.64 (d, J = 4.6 Hz, 6H), 1.22 (s, 6H). HPLC purity: 97.37%; LCMS Calculated for C.sub.23H.sub.29FN.sub.2O.sub.3S: 432.55; Observed: 431.1 [M − H].sup.−. A-669 [01453]embedded image Yield: 76.5 mg, 44.2%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.30 (s, 1H), 7.52-7.46 (m, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.40-7.35 (m, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 6.2 Hz, 2H), 7.03-6.98 (m, 1H), 3.80-3.47 (m, 2H), 2.38 (t, J = 5.5 Hz, 4H), 1.93 (tt, J = 92, 5.4 Hz, 1H), 1.63 (d, J = 5.4 Hz, 6H), 1.34-1.11 (m, 6H), 1.07- 0.90 (m, 2H), 0.62 (d, J = 5.2 Hz, 2H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.2O.sub.3S 440.60; Observed: 439.2 [M − H].sup.−. A-670 [01454]embedded image Yield: 61.3 mg, 35.4%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.44 (s, 1H), 7.86-7.76 (m, 1H), 7.73 (dd, J = 7.9, 1.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.48 (td, J = 7.8, 1.4 Hz, 1H), 7.44- 7.34 (m, 1H), 7.13-6.93 (m, 3H), 5.74 (s, 1H), 3.99 (h, J = 2.5 Hz, 4H), 3.56 (s, 2H), 2.41 (t, J = 5.6 Hz, 4H), 1.64 (h, J = 7.0, 6.4 Hz, 6H), 1.21 (d, J = 1.4 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.2O.sub.5S 472.60; Observed: 471.2 [M − H].sup.−. A-671 [01455]embedded image Yield: 64.1 mg, 37.0%; Appearance: Light Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.64 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.36 (dd, J = 5.9, 3.7 Hz, 1H), 7.06 (q, J = 7.1, 6.1 Hz, 1H), 7.05-7.01 (m, 2H), 7.01-6.77 (m, 1H), 3.57 (s, 2H), 2.44 (d, J = 11.2 Hz, 4H), 1.72-1.47 (m, 6H), 1.21 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.28F.sub.2N.sub.2O.sub.3S 450.54; Observed: 449.1 [M − H].sup.−. A-672 [01456]embedded image Yield: 53.6 mg, 31.0%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.27 (s, 1H), 7.68-7.56 (m, 2H), 7.39 (dt, J = 7.7, 1.8 Hz, 1H), 7.19-7.10 (m, 2H), 7.10-7.03 (m, 1H), 7.00 (ddt, J = 8.8, 7.1, 3.6 Hz, 2H), 3.58 (d, J = 1.6 Hz, 2H), 2.43 (d, J = 5.7 Hz, 4H), 1.94 (tt, J = 8.9, 5.5 Hz, 1H), 1.65 (d, J = 7.1 Hz, 6H), 1.22 (d, J = 1.6 Hz, 6H), 1.04 (dtd, J = 8.2, 4.6, 1.4 Hz, 2H), 0.73 (qd, J = 4.8, 2.3 Hz, 2H). HPLC purity: 97.82%; LCMS Calculated for C.sub.25H.sub.32N.sub.2O.sub.3S 440.60; Observed: 439.2 [M − H].sup.−. A-673 [01457]embedded image Yield: 64.1 mg, 37.0%; Appearance: Grey oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.63 (s, 1H), 7.89 (dd, J = 8.6, 1.6 Hz, 2H), 7.45-7.28 (m, 3H), 7.05 (dddt, J = 10.1, 5.7, 4.1, 2.5 Hz, 3H), 3.56 (s, 2H), 2.43 (t, J = 5.6 Hz, 4H), 1.63 (hept, J = 6.8, 6.0 Hz, 6H), 1.21 (d, J = 1.5 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.27F.sub.3N.sub.2O.sub.4S 484.53; Observed: 483.2 [M − H].sup.−. A-691 [01458]embedded image Yield: 53.7 mg, 31.0%; Appearance: Violet solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.93 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.32-7.22 (m, 1H), 7.12 (dd, J = 7.9, 1.6 Hz, 1H), 7.06 (td, J = 7.6, 1.6 Hz, 1H), 7.01 (td, J = 7.6, 1.5 Hz, 1H), 3.53 (s, 2H), 2.43 (d, J = 6.4 Hz, 4H), 1.58 (s, 2H), 1.53 (tq, J = 12.6, 6.5, 4.9 Hz, 4H), 1.17 (s, 6H). HPLC purity: 95.16%; LCMS Calculated for C.sub.22H.sub.27BrN.sub.2O.sub.3S 479.43; Observed: 479.0 [M − H].sup.−. A-674 [01459]embedded image Yield: 58.2 mg, 33.6%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.36 (s, 1H), 7.44 (dt, J = 7.6, 2.0 Hz, 1H), 7.27 (dd, J = 3.9, 1.8 Hz, 1H), 7.17- 7.11 (m, 1H), 7.06 (tt, J = 9.4, 6.4 Hz, 2H), 6.70 (dd, J = 4.0, 1.6 Hz, 1H), 3.59 (d, J = 1.8 Hz, 2H), 2.48 (s, 4H), 2.10 (ddt, J = 13.4, 8.8, 5.0 Hz, 1H), 1.78-1.53 (m, 6H), 1.22 (d, J = 1.7 Hz, 6H), 1.14-1.02 (m, 2H), 0.70 (qd, J = 5.5, 4.7, 3.1 Hz, 2H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S.sub.2 446.62; Observed: 445.2 [M − H].sup.−. A-712 [01460]embedded image Yield: 11.9 mg, 7.58%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.99 (s, 1H), 7.27 (dd, J = 6.9, 2.4 Hz, 1H), 7.21 (dd, J = 6.8, 2.4 Hz, 1H), 7.13-7.04 (m, 3H), 7.03-6.94 (m, 1H), 6.83 (s, 1H), 4.54 (d, J = 4.6 Hz, 4H), 3.82 (t, J = 5.7 Hz, 2H), 3.55 (s, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.60 (t, J = 5.5 Hz, 4H), 1.60 (s, 2H), 1.56 (h, J = 7.6 Hz, 4H), 1.17 (s, 6H). HPLC purity: 100%; LCMS Calculated C.sub.26H.sub.34N.sub.2O.sub.4S for 470.63; Observed: 469.0 [M − H].sup.−. A-690 [01461]embedded image Yield: 86.1 mg, 49.8%; Appearance: Grey solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.55 (s, 1H), 7.59 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 7.1 Hz, 1H), 7.22-7.09 (m, 1H), 7.10-6.96 (m, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.22 (t, J = 54.5 Hz, 1H), 4.52-4.39 (m, 1H), 3.57 (s, 2H), 2.82 (d, J = 17.9 Hz, 2H), 2.43 (d, J = 7.0 Hz, 4H), 2.08 (d, J = 13.5 Hz, 1H), 1.73 (dq, J = 11.4, 5.9 Hz, 1H), 1.61 (d, J = 8.0 Hz, 6H), 1.18 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.32F.sub.2N.sub.2O.sub.4S 506.61; Observed: 505.2 [M − H].sup.−. A-713 [01462]embedded image Yield: 45.6 mg, 29.0%; Appearance: Violet solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 7.64 (s, 1H), 7.47 (dd, J = 7.9, 1.8 Hz, 1H), 7.35-7.25 (m, 2H), 7.17-7.08 (m, 1H), 7.02 (qd, J = 7.4, 3.8 Hz, 2H), 3.55 (s, 2H), 2.84 (t, J = 7.5 Hz, 4H), 2.40 (t, J = 5.5 Hz, 4H), 2.07-1.91 (m, 2H), 1.69-1.38 (m, 6H), 1.17 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.2O.sub.3S 440.60; Observed: 439.2 [M − H].sup.−. A-714 [01463]embedded image Yield: 26.8 mg, 17.0%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.73 (s, 1H), 7.76 (s, 1H), 7.64 (dd, J = 7.9, 1.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.32-7.23 (m, 1H), 7.18-7.09 (m, 1H), 7.02 (qd, J = 7.4, 3.6 Hz, 2H), 4.97 (dd, J = 6.4, 2.0 Hz, 4H), 3.54 (s, 2H), 2.42 (t, J = 5.5 Hz, 4H), 1.59 (s, 2H), 1.57 (q, J = 5.5 Hz, 4H), 1.17 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30N.sub.2O.sub.4S 442.57; Observed: 441.2 [M − H].sup.−. A-715 [01464]embedded image Yield: 18.2 mg, 11.5%; Appearance: Brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.64 (s, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.34-7.20 (m, 2H), 7.17-7.10 (m, 1H), 7.05-6.96 (m, 2H), 4.65 (s, 2H), 3.82 (t, J = 5.7 Hz, 2H), 3.55 (s, 2H), 2.78 (t, J = 5.8 Hz, 2H), 2.42 (t, J = 5.5 Hz, 4H), 1.59 (d, J = 7.0 Hz, 2H), 1.59-1.30 (m, 4H), 1.17 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.2O.sub.4S 456.60; Observed: 455.2 [M − H].sup.−. A-675 [01465]embedded image Yield: 32.6 mg, 18.8%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.63 (s, 1H), 7.43-7.31 (m, 1H), 7.28 (s, 1H), 7.28-7.18 (m, 2H), 7.20-7.10 (m, 1H), 7.09-6.99 (m, 2H), 6.93 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 4.90 (s, 2H), 3.60 (d, J = 1.5 Hz, 2H), 2.75 (t, J = 5.3 Hz, 4H), 1.77 (hept, J = 7.2, 6.2 Hz, 4H), 1.67 (s, 2H), 1.22 (d, J = 1.5 Hz, 6H). HPLC purity: 96.54%; LCMS Calculated for C.sub.25H.sub.30N.sub.2O.sub.4S 454.59; Observed: 453.0 [M − H].sup.−. A-676 [01466]embedded image Yield: 60.4 mg, 34.9%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (s, 1H), 7.44-7.32 (m, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.25-7.19 (m, 2H), 7.14 (dd, J = 13.2, 7.9 Hz, 2H), 7.08-6.93 (m, 2H), 3.62 (s, 2H), 2.81 (t, J = 8.3 Hz, 2H), 2.74 (t, J = 5.6 Hz, 4H), 2.60-2.51 (m, 2H), 1.77 (q, J = 6.0 Hz, 4H), 1.68 (s, 2H), 1.23 (s, 6H). HPLC purity: 98.76%; LCMS Calculated for C.sub.26H.sub.32N.sub.2O.sub.3S 452.61; Observed: 451.2 [M − H].sup.−. A-689 [01467]embedded image Yield: 81.0 mg, 46.8%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.82-8.65 (m, 1H), 8.05 (d, J =2.5 Hz, 1H), 7.33 (dd, J = 7.3, 2.1 Hz, 1H), 7.15 (dd, J = 7.3, 2.0 Hz, 1H), 7.01 (tt, J = 7.4, 5.6 Hz, 2H), 6.71 (d, J = 2.4 Hz, 1H), 4.77-4.57 (m, 1H), 3.57 (s, 2H), 2.56 (t, J = 5.4 Hz, 4H), 2.35 (q, J = 11.7, 11.2 Hz, 2H), 1.82-1.49 (m, 6H), 1.18 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.28F.sub.2N.sub.4O.sub.3S 466.55; Observed: 465.2 [M − H].sup.−. A-677 [01468]embedded image Yield: 52.1 mg, 30.1%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.85 (s, 1H), 7.38 (dt, J = 7.7, 1.6 Hz, 1H), 7.23-7.13 (m, 2H), 7.13- 6.99 (m, 2H), 6.90 (dd, J = 13.8, 9.0 Hz, 2H), 4.46 (s, 2H), 3.58 (d, J = 1.4 Hz, 2H), 2.68 (t, J = 5.5 Hz, 4H), 2.26 (s, 3H), 1.63 (dd, J = 11.0, 4.9 Hz, 6H), 1.22 (d, J = 1.4 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31FN.sub.2O.sub.3S 446.58; Observed: 445.0 [M − H].sup.−. A-688 [01469]embedded image Yield: 54.9 mg, 31.7%; Appearance: Grey solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.19 (s, 1H), 7.23 (q, J = 5.5, 4.7 Hz, 3H), 7.15-6.79 (m, 4H), 4.58 (d, J = 3.5 Hz, 2H), 3.57 (d, J = 3.5 Hz, 2H), 2.68 (q, J = 4.8 Hz, 4H), 2.29 (d, J = 3.4 Hz, 3H), 1.81-1.31 (m, 6H), 1.18 (d, J = 3.5 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31FN.sub.2O.sub.3S 446.58; Observed: 445.2 [M − H].sup.−. A-716 [01470]embedded image Yield: 24.1 mg, 15.3%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.06 (s, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.30- 7.24 (m, 1H), 7.21 (dd, J = 5.9, 3.6 Hz, 1H), 7.05 (dd, J = 6.0, 3.6 Hz, 2H), 7.00 (t, J = 55.9 Hz, 1H), 4.69 (s, 2H), 3.54 (s, 2H), 2.62 (t, J = 5.4 Hz, 4H), 1.59 (s, 2H), 1.54 (dq, J = 13.2, 7.2, 6.4 Hz, 4H), 1.17 (d, J = 1.3 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30F.sub.2N.sub.2O.sub.3S 464.57; Observed: 463.2 [M − H].sup.−. A-678 [01471]embedded image Yield: 49.3 mg, 28.5%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.93 (s, 1H), 7.42-7.27 (m, 3H), 7.25-7.13 (m, 3H), 7.06 (tt, J = 9.1, 6.6 Hz, 2H), 4.52 (s, 2H), 3.72-3.37 (m, 2H), 2.70 (t, J = 5.5 Hz, 4H), 1.65 (d, J = 4.0 Hz, 6H), 1.22 (d, J = 1.4 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.29ClN.sub.2O.sub.3S 449.01; Observed: 447.2 [M − H].sup.−. A-679 [01472]embedded image Yield: 67.9 mg, 39.3%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06 (s, 1H), 7.37-7.27 (m, 1H), 7.23-7.10 (m, 3H), 7.03 (dt, J = 6.1, 2.8 Hz, 2H), 6.96 (t, J = 9.1 Hz, 1H), 4.48 (d, J = 2.9 Hz, 2H), 3.60 (d, J = 3.1 Hz, 2H), 2.72 (t, J = 5.4 Hz, 4H), 2.31 (d, J = 3.0 Hz, 3H), 1.92-1.48 (m, 6H), 1.22 (d, J = 3.1 Hz, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31FN.sub.2O.sub.3S 446.58; Observed: 445.2 [M − H].sup.−. A-717 [01473]embedded image Yield: 23.2 mg, 14.7%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.77 (s, 1H), 7.39-7.30 (m, 1H), 7.29 (d, J = 4.0 Hz, 4H), 7.22-7.16 (m, 1H), 7.12-7.06 (m, 1H), 6.99 (hept, J = 5.2 Hz, 2H), 3.51 (s, 2H), 2.55 (t, J = 5.4 Hz, 4H), 1.73-1.65 (m, 2H), 1.57 (s, 2H), 1.45 (q, J = 4.7 Hz, 4H), 1.36-1.27 (m, 2H), 1.16 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.2O.sub.3S 440.60; Observed: 439.2 [M − H].sup.−. A-718 [01474]embedded image Yield: 33.2 mg, 21.1%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.71 (s, 1H), 7.77-7.62 (m, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.36-7.21 (m, 1H), 7.22-7.09 (m, 1H), 7.09-6.95 (m, 2H), 3.53 (s, 2H), 3.07 (dt, J = 12.9, 9.6 Hz, 1H), 2.36 (q, J = 6.4, 5.7 Hz, 4H), 2.15-1.94 (m, 2H), 1.58 (s, 2H), 1.57-1.28 (m, 4H), 1.16 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.30F.sub.2N.sub.2O.sub.3S 476.58; Observed: 475.2 [M − H].sup.−. A-687 [01475]embedded image Yield: 54.7 mg, 31.6%; Appearance: Violet solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.72 (s, 1H), 7.66 (s, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.37-7.25 (m, 1H), 7.17-7.07 (m, 1H), 7.07-6.92 (m, 2H), 3.53 (s, 2H), 3.09 (td, J = 12.5, 8.5 Hz, 1H), 2.42- 2.30 (m, 4H), 2.08-1.94 (m, 1H), 1.94-1.80 (m, 1H), 1.57 (d, J = 9.9 Hz, 2H), 1.54 (dd, J = 12.8, 6.9 Hz, 4H), 1.16 (s, 6H). HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.30F.sub.2N.sub.2O.sub.3S 476.58; Observed: 475.2 [M − H].sup.−. A-372 [01476]embedded image Yield: 21.7 mg, 13.8% ; Appearance: Violet solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.79 (s, 1H), 7.25-7.19 (m, 2H), 7.00 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.80-6.71 (m, 2H), 6.60 (t, J = 7.4 Hz, 1H), 4.24 (dt, J = 20.7, 5.6 Hz, 4H), 3.19 (t, J = 6.3 Hz, 4H), 2.21 (p, J = 5.7 Hz, 2H), 1.92-1.85 (m, 4H); HPLC purity: 95.13%%; LCMS Calculated for C.sub.19H.sub.22N.sub.2O.sub.4S: 374,46; Observed: 374.15 [M − H].sup.−. A-457 [01477]embedded image Yield: 59.3 mg, 29.4%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.68 (s, 1H), 7.65- 7.59 (m, 2H), 7.41 (dd, J = 8.1, 1.5 Hz, 1H), 7.12 (t, J = 8.1 Hz, 1H), 7.02 (dd, J = 8.1, 1.5 Hz, 1H), 6.93-6.88 (m, 2H), 4.65 (p, J = 6.0 Hz, 1H), 3.72-3.56 (m, 4H), 3.53-3.36 (m, 2H), 2.12 (d, J = 11.3 Hz, 2H), 1.30 (s, 3H), 1.29 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.23ClN.sub.2O.sub.4S: 410.92; Observed: 410.13 [M − H].sup.−. A-608 [01478]embedded image Yield: 16.2 mg, 9.93%; Appearance: Brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.54 (s, 1H), 7.63 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 6.0, 3.6 Hz, 1H), 7.18 (dd, J = 5.9, 3.5 Hz, 1H), 7.01 (dd, J = 6.0, 3.5 Hz, 2H), 3.26 (s, 3H), 3.11 (s, 2H), 2.87-2.78 (m, 4H), 2.50-2.48 (m, 2H), 2.42- 2.36 (m, 2H), 1.98 (p, J = 7.4 Hz, 2H), 1.59-1.51 (m, 2H), 1.32-1.25 (m, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 414.24 [M − H].sup.−.

    Example A42

    [0700] ##STR01479##

    General Procedure for Synthesis of Aminobenzyl Series Compounds Method B

    [0701] Sulfonyl chloride (1.1 eq) was added to the vial containing DIPEA (2.2 eq), aniline (1 eq) and acetonitrile (1 mL). The reaction mixture was heated at 50° C. with stirring for 16 h. After cooling to the room temperature the mixture was evaporated. The residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities if there were any. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade methanol (acetonitrile)).

    [0702] The following examples were prepared using method B:

    TABLE-US-00012 Compound No. Structure Analytical data A-417 [01480]embedded image Yield: 48.1 mg, 30.6%; Appearance: Orange oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 7.39 (dd, J = 7.6, 1.8 Hz, 1H), 7.18 (dd, J = 7.4, 2.0 Hz, 1H), 7.09 (tt, J = 8.0, 6.4 Hz, 2H), 3.77 (t, J = 4.8 Hz, 4H), 3.23 (t, J = 7.7 Hz, 2H), 3.02-2.38 (m, 17H, and signals of solvent and water), 1.93 (s, 2H), 1.26 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.39N.sub.5O.sub.3S: 465.66; Observed: 465.33 [M − H].sup.−. A-565 [01481]embedded image Yield: 32.8 mg, 20.8%; Appearance: Violet solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.72 (dd, J = 4.1, 1.8 Hz, 1H), 8.28 (dd, J = 8.4, 1.8 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.0 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.51-7.41 (m, 2H), 7.13-6.95 (m, 3H), 5.32 (s, 2H), 3.59 (s, 4H), 2.58 (t, J = 4.8 Hz, 4H), 1.23 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.30N.sub.4O.sub.3S: 466.6; Observed: 466.24 [M − H].sup.−. A-566 [01482]embedded image Yield: 5.8 mg, 3.69% yield; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.30 (s, 1H), 7.92- 7.86 (m, 2H), 7.86-7.81 (m, 1H), 7.79 (d, J = 1.9 Hz, 1H), 7.55-7.47 (m, 3H), 7.43 (dd, J = 8.4, 1.7 Hz, 1H), 131 (d, J = 2.2 Hz, 1H), 7.19 (dd, J = 13, 2.1 Hz, 1H), 7.11-7.03 (m, 3H), 4.78 (s, 2H), 3.45 (t, J = 4.7 Hz, 4H), 2.58 (t, J = 4.8 Hz, 4H), 1.13 (s, 9H); HPLC purity: 96.69%; LCMS Calculated for C.sub.26H.sub.31N.sub.3O.sub.3S: 465.61; Observed: 465.25 [M − H].sup.−. A-595 [01483]embedded image Yield: 23.6 mg, 15.0%; Appearance: Brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.92 (s, 1H), 7.34- 7.25 (m, 3H), 7.23 (dd, J = 7.6, 1.7 Hz, 1H), 7.10- 7.01 (m, 2H), 6.97-6.88 (m, 2H), 4.59-4.56 (m, 2H), 3.52 (s, 3H), 3.09 (s, 2H), 2.72-2.59 (m, 4H), 1.55- 1.48 (m, 2H), 1.32-1.25 (m, 2H), 0.93 (s, 3H); HPLC purity: 98.85%; LCMS Calculated for C.sub.22H.sub.30N.sub.2O.sub.4S: 418.55; Observed: 418.23 [M − H].sup.−. A-582 [01484]embedded image Yield: 35.5 mg, 22.6%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (s, 1H), 7.34 (dd, J = 7.8, 1.7 Hz, 1H), 7.20 (dd, J = 7.7, 1.8 Hz, 1H), 7.12-6.98 (m, 4H), 6.81 (d, J = 8.6 Hz, 2H), 4.39 (s, 2H), 3.77 (s, 3H), 3.31 (s, 3H), 3.12 (s, 2H), 2.77- 2.63 (m, 4H), 1.61-1.49 (m, 2H), 1.34 (d, J = 13.1 Hz, 2H), 0.98 (s, 3H); HPLC purity: 96.7%; LCMS Calculated for C.sub.22H.sub.30N.sub.2O.sub.4S: 418.55; Observed: 418.23 [M − H].sup.−. A-597 [01485]embedded image Yield: 15.6 mg, 9.93%; Appearance: Brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.14 (s, 1H), 7.34- 7.25 (m, 5H), 7.23-7.16 (m, 1H), 7.10-7.02 (m, 2H), 4.94 (dd, J = 9.0, 2.6 Hz, 1H), 3.25 (s, 3H), 3.12 (s, 2H), 3.01-2.92 (m, 1H), 2.89-2.81 (m, 1H), 2.78- 2.69 (m, 3H), 2.71-2.64 (m, 1H), 2.55-2.49 (m, 1H), 2.45-2.38 (m, 1H), 1.64-1.52 (m, 2H), 1.37-1.30 (m, 2H), 0.95 (s, 3H); HPLC purity: 98.9%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 414.24 [M − H].sup.−.

    Example A43

    [0703] ##STR01486##

    General Procedure for Synthesis of Aminobenzyl Series Compounds—Method C

    [0704] Sulfonyl chloride (1 eq) was added to the vial containing aniline (1 eq) and sodium acetate (1.1 eq) in acetic acid (0.5 mL). The reaction mixture was heated at 50° C. with stirring for 24 h. After cooling to the room temperature the mixture was evaporated. The residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities if there were any. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade methanol (acetonitrile)).

    [0705] The following example was prepared using method C:

    TABLE-US-00013 Compound No. Structure Analytical data A-391 [01487]embedded image Yield: 32.8 mg, 15.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.99 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.31 (dd, J = 6.6, 3.1 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.19-7.14 (m, 2H), 3.61 (t, J = 4.5 Hz, 4H), 3.31-3.22 (m, 2H), 2.13 (s, 2H), 1.96 (tt, J = 8.6, 5.0 Hz, 1H), 1.07-0.97 (m, 2H), 0.75-0.67 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.21ClN.sub.2O.sub.3S: 392.90; Observed: 392.12 [M − H].sup.−.

    Example A44

    [0706] ##STR01488##

    General Procedure for Synthesis of Aminobenzyl Series Compounds Method D

    [0707] The vial was charged with amine (1 eq), acid (1.2-1.3 eq), and DIPEA (6.5 eq). Then HATU (1.16 eq) was added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities if there were any. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade methanol (acetonitrile)).

    [0708] The following examples were prepared using method D:

    TABLE-US-00014 Compound No. Structure Analytical data A-425 [01489]embedded image Yield: 49.3 mg, 14.3%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.47 (s, 1H), 7.96 (q, J = 8.4 Hz, 5H), 7.32 (d, J = 6.7 Hz, 1H), 7.18-7.07 (m, 3H), 3.41 (s, 2H), 3.24 (s, 2H), 2.63 (s, 6H), 2.46-2.33 (m, 6H), 1.98-1.84 (m, 1H), 1.77 (t, J = 10.9 Hz, 2H), 1.62 (d, J = 10.6 Hz, 1H), 1.34 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.4O.sub.5S.sub.2: 520.66; Observed: 520.21 [M − H].sup.−. A-426 [01490]embedded image Yield: 71.4 mg, 45.5%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.25 (s, 1H), 8.03- 7.83 (m, 4H), 7.39-7.32 (m, 1H), 7.10-7.03 (m, 3H), 3.53 (s, 4H), 2.68 (s, 6H), 2.58-2.52 (m, 2H, in the solvent signal), 2.44-2.37 (m, 2H), 2.16 (s, 2H), 1.37 (q, J = 7.5 Hz, 2H), 0.96 (s, 6H), 0.85 (t, J = 7.5 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.36N.sub.4O.sub.5S.sub.2: 536.71; Observed: 536.2 5 [M − H].sup.−. A-427 [01491]embedded image Yield: 72.8 mg, 46.6%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.48 (s, 1H), 8.03- 7.91 (m, 4H), 7.31 (d, J = 7.5 Hz, 1H), 7.16-7.08 (m, 3H), 3.65-3.55 (m, 1H), 3.54-3.41 (m, 3H), 2.66-2.60 (m, 6H), 2.49-2.37 (m, 3H), 2.37-2.26 (m, 1H), 1.69 (t, J = 6.7 Hz, 1H), 1.15 (s, 3H), 0.95 (s, 3H), 0.94- 0.87 (m, 1H), 0.67-0.59 (m, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.4O.sub.5S.sub.2: 520.66; Observed: 520.21 [M − H].sup.−. A-428 [01492]embedded image Yield: 57.7 mg, 36.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.26 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.35 (dd, J = 6.9, 2.4 Hz, 1H), 7.11-7.02 (m, 3H), 3.65-3.58 (m, 2H), 3.59-3.43 (m, 3H), 2.76-2.64 (m, 7H, ), 2.60-2.51 (m, 3H), 2.44-2.31 (m, 2H), 1.17-0.85 (m, 12H); HPLC purity: 97.77%; LCMS Calculated for C.sub.25H.sub.36N.sub.4O.sub.5S.sub.2: 536.71; Observed: 536.25 [M − H].sup.−. A-429 [01493]embedded image Yield: 33.9 mg, 21.4%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 8.03- 7.90 (m, 4H), 7.29 (d, J = 7.5 Hz, 1H), 7.17-7.06 (m, 3H), 3.48-3.43 (m, 2H), 3.43-3.36 (m, 2H), 3.29-3.20 (m, 1H), 2.78 (dt, J = 15.9, 9.5 Hz, 4H), 2.63 (s, 6H), 2.54 (s, 2H), 2.39 (t, J = 4.7 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.28F.sub.2N.sub.4O.sub.5S.sub.2: 542.62; Observed: 542.17 [M − H].sup.−. A-430 [01494]embedded image Yield: 42.3 mg, 26.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.25 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 6.8 Hz, 1H), 7.07 (dd, J = 6.3, 3.9 Hz, 3H), 4.62 (s, 1H), 4.50 (s, 1H), 3.51 (s, 2H), 3.31 (s, 2H), 2.68 (s, 6H), 2.46-2.36 (m, 6H), 2.06-1.98 (m, 2H), 2.00-1.87 (m, 1H), 1.79-1.72 (m, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31FN.sub.4O.sub.5S.sub.2: 538.65; Observed: 538.2 [M − H].sup.−. A-431 [01495]embedded image Yield: 61.8 mg, 39.6%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.25 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.41-7.33 (m, 1H), 7.12-7.04 (m, 3H), 3.95 (s, 2H), 3.55 (s, 2H), 3.18 (s, 3H), 3.02 (s, 3H), 2.68 (s, 6H), 2.55 (d, J = 10.4 Hz, 2H, in the solvent signal), 2.44 (d, J = 13.9 Hz, 2H, in the solvent signal), 1.35 (s, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.6S.sub.2: 524.65; Observed: 524.2 [M − H].sup.−. A-432 [01496]embedded image Yield: 38.4 mg, 24.2%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 7.96 (q, J = 8.3 Hz, 5H), 7.37-7.30 (m, 1H), 7.18-7.08 (m, 3H), 3.67 (s, 2H), 3.49 (s, 2H), 2.62 (s, 6H), 1.54 (d, J = 21.9 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29FN.sub.4O.sub.5S.sub.2: 512.62; Observed: 512.18 [M − H].sup.−. A-487 [01497]embedded image Yield: 4.5 mg, 2.86%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.45 (s, 1H), 7.99- 7.88 (m, 4H), 7.30 (dd, J = 7.7, 1.6 Hz, 1H), 7.16- 7.06 (m, 3H), 3.44 (s, 4H), 2.60 (s, 6H), 2.37 (d, J = 20.2 Hz, 4H), 1.82-1.76 (m, 2H), 1.75-1.67 (m, 1H), 1.65-1.58 (m, 1H), 1.30-1.24 (m, 2H), 1.23-1.15 (m, 2H), 1.13-1.04 (m, 1H), 0.84 (dd, J = 9.4, 4.5 Hz, 1H), 0.47 (dd, J = 62, 4.5 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.34N.sub.4O.sub.5S.sub.2: 546.7; Observed: 546.23 [M − H].sup.−. A-476 [01498]embedded image Yield: 62.5 mg, 39.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 7.96 (q, J = 8.3, 7.8 Hz, 4H), 7.34 (d, J = 7.3 Hz, 1H), 7.18- 7.09 (m, 3H), 3.97-3.80 (m, 2H), 3.69 (q, J = 7.5 Hz, 2H), 3.51 (s, 1H), 3.46-3.36 (m, 1H), 2.63 (s, 6H), 2.41 (s, 4H), 1.90-1.45 (m, 4H), 1.36 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.4O.sub.6S.sub.2: 536.66; Observed: 536.2 [M − H].sup.−. A-478 [01499]embedded image Yield: 18.5 mg, 11.7%; Appearance: Orange solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 8.02- 7.92 (m, 4H), 7.30 (dd, J = 7.7, 1.8 Hz, 1H), 7.14 (dddd, J = 19.8, 9.8, 7.6, 1.9 Hz, 3H), 3.45 (s, 2H), 3.29 (s, 2H, in the solvent signal), 3.02 (q, J = 14.3 Hz, 3H), 2.63 (s, 6H), 2.59-2.52 (m, 4H, in the solvent signal), 2.39 (s, 2H), 1.40 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30F.sub.2N.sub.4O.sub.5S.sub.2: 556.64; Observed: 556., 19 [M − H].sup.−. A-459 [01500]embedded image Yield: 38.4 mg, 24.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 8.04- 7.90 (m, 4H), 7.32 (d, J = 6.3 Hz, 1H), 7.17-7.07 (m, 3H), 3.65 (d, J = 14.2 Hz, 2H), 3.55 (s, 2H), 3.46 (s, 1H), 2.62 (s, 6H), 2.58-2.54 (m, 2H), 2.47-2.29 (m, 2H), 2.29-1.96 (m, 3H), 1.83 (s, 2H), 1.74-1.61 (m, 1H); HPLC purity: 95.3%; LCMS Calculated for C.sub.24H.sub.30F.sub.2N.sub.4O.sub.5S.sub.2: 556.64; Observed: 556.19 [M − H].sup.−. A-460 [01501]embedded image Yield: 37.2 mg, 23.6%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 8.03- 7.91 (m, 4H), 7.32 (d, J = 7.1 Hz, 1H), 7.17-7.07 (m, 3H), 3.50 (s, 4H), 2.64 (d, J = 3.8 Hz, 6H), 2.40 (s, 4H), 2.10 (s, 1H), 1.66 (s, 6H), 1.57 (s, 2H), 1.34 (s, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.34N.sub.4O.sub.5S.sub.2: 546.7; Observed: 546.23 [M − H].sup.−. A-448 [01502]embedded image Yield: 16.5 mg, 8.04%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.48 (s, 1H), 7.96 (q, J = 8.3 Hz, 4H), 7.33 (d, J = 6.7 Hz, 1H), 7.18-7.08 (m, 3H), 3.99 (s, 1H), 3.83-3.72 (m, 2H), 3.59-3.34 (m, 3H), 2.63 (s, 6H), 2.44 (s, 4H), 2.25 (d, J = 13.0 Hz, 1H), 1.62-1.35 (m, 4H), 1.27 (s, 3H), 1.19-1.09 (m, 1H); HPLC purity: 96.,97%; LCMS Calculated for C.sub.25H.sub.34N.sub.4O.sub.6S.sub.2: 550.69; Observed: 550.22 [M − H].sup.−. A-461 [01503]embedded image Yield: 34.2 mg, 21.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 7.97 (q, J = 8.3 Hz, 4H), 7.35 (d, J = 6.6 Hz, 1H), 7.19-7.10 (m, 3H), 3.58 (s, 4H), 2.62 (s, 6H), 2.49-2.41 (m, 4H, in the solvent signal), 1.34-1.09 (m, 4H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27FN.sub.4O.sub.5S.sub.2: 510.6; Observed: 510.16 [M − H].sup.−. A-462 [01504]embedded image Yield: 19.6 mg, 12.4%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.48 (s, 1H), 8.03- 7.90 (m, 4H), 7.30 (d, J = 7.6 Hz, 1H), 7.20-7.04 (m, 3H), 3.49 (d, J = 45.0 Hz, 4H), 2.63 (s, 7H), 2.44- 2.31 (m, 3H), 2.32-2.17 (m, 1H), 1.38 (t, J = 3.8 Hz, 1H), 1.21-1.14 (m, 1H), 0.93-0.86 (m, 1H), 0.85- 0.73 (m, 2H), 0.70-0.63 (m, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30N.sub.4O.sub.5S.sub.2: 518.65; Observed: 518.19 [M − H].sup.−. A-463 [01505]embedded image Yield: 42.2 mg, 26.8%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.47 (s, 1H), 7.99- 7.87 (m, 4H), 7.28 (d, J = 7.5 Hz, 1H), 7.14-7.04 (m, 3H), 3.66 (s, 2H), 3.41 (s, 2H), 2.59 (s, 6H), 2.53 (s, 2H), 2.34 (s, 2H), 2.23-2.13 (m, 1H), 1.78 (s, 1H), 1.62 (t, J = 18.6 Hz, 3H), 1.05-0.98 (m, 1H), 0.99- 0.91 (m, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.30F.sub.2N.sub.4O.sub.5S.sub.2: 556.64; Observed: 556.19 [M − H].sup.−. A-477 [01506]embedded image Yield: 57.7 mg, 36.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.26 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 7.1, 2.4 Hz, 1H), 7.12-7.02 (m, 3H), 3.54 (s, 4H), 2.68 (s, 6H), 2.45 (d, J = 5.0 Hz, 4H), 1.95-1.66 (m, 5H), 1.59-1.52 (m, 1H), 1.32-1.22 (m, 1H), 0.74-0.62 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.4O.sub.5S.sub.2: 532.67; Observed: 532.21 [M − H].sup.−. A-449 [01507]embedded image Yield: 43.4 mg, 27.6%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 8.04- 7.91 (m, 4H), 7.30 (d, J = 7.5Hz, 1H), 7.16-7.06 (m, 3H), 4.65 (s, 1H), 4.52 (t, J = 5.1 Hz, 1H), 3.69-3.38 (m, 5H), 3.22-3.14 (m, 1H), 2.63 (s, 7H), 2.48-2.26 (m, 3H), 1.98 (dd, J = 11.5, 4.2 Hz, 1H), 1.71-1.66 (m, 1H), 1.58-1.53 (m, 1H), 1.48-1.40 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32N.sub.4O.sub.6S.sub.2: 548.67; Observed: 548.2 [M − H].sup.−.

    Example A45

    [0709] ##STR01508##

    General Procedure for Synthesis of Aminobenzyl Series Compounds Method E

    [0710] Amine (1.0 eq) was placed in a vial, dry acetonitrile (0.7 mL) and DIPEA (4.5 eq) were added followed by acid chloride (1.1 eq) addition. The reaction mixture was stirred for 12 h and then heated for 1 h at 80° C. After cooling to the room temperature the mixture was evaporated. The residue was dissolved in DMSO (2 mL), filtered from non-soluble impurities if there were any. The resulting filtrate was subjected to HPLC purification (deionized water/HPLC-grade methanol (acetonitrile)).

    [0711] The following examples were prepared using method E:

    TABLE-US-00015 Compound No. Structure Analytical data A-444 [01509]embedded image Yield: 59.7 mg, 34.5 Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.48 (s, 1H), 8.02- 7.90 (m, 4H), 7.36-7.29 (m, 1H), 7.19-7.07 (m, 3H), 3.75 (s, 2H), 3.49 (s, 2H), 3.09 (s, 3H), 2.62 (s, 6H), 2.42 (s, 4H, in the solvent signal), 2.11-2.03 (m, 2H), 1.83-1.74 (m, 2H), 1.63-1.46 (m, 4H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.34N.sub.4O.sub.6S.sub.2: 550.69; Observed: 550.22 [M − H].sup.−. A-445 [01510]embedded image Yield: 19.6 mg, 11.3%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 7.96 (q, J = 8.4 Hz, 4H), 7.33 (dd, J = 6.8, 1.9 Hz, 1H), 7.18- 7.08 (m, 3H), 3.89 (s, 2H), 3.48 (s, 2H), 3.11 (s, 3H), 2.63 (s, 6H), 2.42 (s, 4H), 1.86 (d, J = 13.7 Hz, 2H), 1.69-1.39 (m, 7H), 1.21 (s, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27BrFN.sub.3O.sub.3S: 564.72; Observed: 564.24 [M − H].sup.−. A-446 [01511]embedded image Yield: 29.9 mg, 17.3%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.43 (s, 1H), 8.01- 7.91 (m, 4H), 7.34 (dd, J = 6.4, 3.1 Hz, 1H), 7.19- 7.08 (m, 3H), 3.62 (s, 2H), 3.53 (s, 1H), 2.62 (s, 6H), 2.48-2.42 (m, 4H, in the solvent signal), 1.80 (t, J = 20.1 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26F.sub.2N.sub.4O.sub.5S.sub.2: 516.58; Observed: 516.15 [M − H].sup.−. A-458 [01512]embedded image Yield: 27.9 mg, 17.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.46 (s, 1H), 8.02- 7.90 (m, 4H), 7.33 (d, J = 7.2 Hz, 1H), 7.17-7.07 (m, 3H), 3.48 (s, 4H), 3.03 (s, 3H), 2.63 (s, 7H), 2.47- 2.38 (m, 5H), 2.06 (q, J = 10.4 Hz, 2H), 1.78-1.68 (m, 1H), 1.52 (q, J = 9.1 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.4O.sub.6S.sub.2: 536.66; Observed: 536.2 [M − H].sup.−. A-447 [01513]embedded image Yield: 81.8 mg, 47.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.03- 7.91 (m, 4H), 7.30 (d, J = 7.6 Hz, 1H), 7.17-7.05 (m, 3H), 4.04 (d, J = 6.8 Hz, 1H), 3.34-3.27 (m, 4H, in the solvent signal), 3.22 (s, 2H), 2.79-2.72 (m, 1H), 2.63 (s, 6H), 2.45 (d, J = 4.9 Hz, 4H, in the solvent signal), 1.80 (s, 2H), 1.24-1.15 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31N.sub.5O.sub.5S.sub.2: 533.66; Observed: 533.2 [M − H].sup.−.

    Example A46: Synthesis of 4-(1-{[3-chloro-2-(morpholin-4-yl)phenyl]amino}-2,2,2-trifluoroethyl)-N,N-dimethylbenzene-1-sulfonamide (A-374)

    [0712] ##STR01514##

    Step-1: Synthesis of N,N-dimethyl-4-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzenesulfonamide (A46.2)

    [0713] Dimethylamine hydrochloride (0.298 g, 3.66 mmol) and pyridine (0.579 g, 7.32 mmol) were added at room temperature to a stirred solution of 4-(2,2,2-trifluoroacetyl)benzene-1-sulfonyl chloride (A46.1) (0.5 g, 1.83 mmol) in dry acetonitrile (5 mL). The resulting mixture was stirred at room temperature for 36 h. After completion of the reaction (TLC control), the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (10 mL) and chloroform (10 mL). The water layer was separated and extracted with chloroform (10 mL). The combined organic layers were washed with 1 M hydrogen chloride solution (10 mL×2), water (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N,N-dimethyl-4-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzenesulfonamide (A46.2) (0.52 g, 1.73 mmol, 97% purity, 92.1% yield). This procedure was repeated to obtain enough material for next stages.

    Step-2. Synthesis of (E)-4-(1-((3-chloro-2-morpholinophenyl)imino)-2,2,2-trifluoroethyl)-N,N-dimethylbenzenesulfonamide (A46.4)

    [0714] Dry toluene (10 mL), 3-chloro-2-(morpholin-4-yl)aniline (A46.3) (0.808 g, 3.80 mmol), N,N-dimethyl-4-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzenesulfonamide (A46.2) (0.95 g, 3.17 mmol), and 4-methylbenzenesulfonic acid hydrate (0.602 g, 3.17 mmol) were placed in a round-bottom flask equipped with Dean-Stark apparatus. The resulting mixture was stirred under reflux overnight. After cooling to room temperature the mixture was evaporated. The residue was dissolved with chloroform (10 mL), washed with saturated sodium hydrogencarbonate solution (10 mL×2), water (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated to afford a crude (E)-4-(1-((3-chloro-2-morpholinophenyl)imino)-2,2,2-trifluoroethyl)-N,N-dimethylbenzenesulfonamide (A46.4) (0.7 g, 1.47 mmol, 95% purity, 44.3% yield).

    Step-3. Synthesis of 4-(1-{[3-chloro-2-(morpholin-4-yl)phenyl]amino}-2,2,2-trifluoroethyl)-N,N-dimethylbenzene-1-sulfonamide (A-374)

    [0715] Borane dimethylsulfide (0.334 g, 4.4 mmol) was added dropwise under Ar atmosphere to a stirred solution of (E)-4-(1-((3-chloro-2-morpholinophenyl)imino)-2,2,2-trifluoroethyl)-N,N-dimethylbenzene-sulfonamide (A46.4) (0.3 g, 0.630 mmol) in dry THF (5 mL). The resulting mixture was stirred under reflux for 4 h. After completion of the reaction (TLC control), the reaction mixture was cooled to room temperature and methanol (15 mL) was added dropwise. The resulting mixture was stirred for 15 min and then evaporated. The residue was diluted in 30% K.sub.2CO.sub.3 (20 mL) and ethyl acetate (15 mL). The water layer was separated and extracted with ethyl acetate (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4-(1-{[3-chloro-2-(morpholin-4-yl)phenyl]amino}-2,2,2-trifluoroethyl)-N,N-dimethylbenzene-1-sulfonamide (A-374). Yield: 300.0 mg, 94.6%; Appearance: Yellow oil; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 6.89 (t, J=8.1 Hz, 1H), 6.69 (dd, J=8.2, 1.4 Hz, 1H), 6.29 (d, J=8.0 Hz, 1H), 4.89 (q, J=7.0 Hz, 1H), 3.98 (d, J=11.0 Hz, 2H), 3.89-3.73 (m, 2H), 3.73-3.58 (m, 2H), 2.72 (s, 6H), 2.63 (d, J=11.2 Hz, 1H), 2.54 (d, J=11.8 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.23ClF.sub.3N.sub.3O.sub.3S: 477.93; Observed: 477.14 [M−H].sup.−.

    Example A47: Synthesis of N-{3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide (A-373)

    [0716] ##STR01515## ##STR01516##

    Step-1. Synthesis of {1-[(tert-butoxy)carbonyl]piperidin-4-yl}(iodo)zinc (A47.2)

    [0717] Zinc powder (6.50 g, 99.5 mmol) and silica gel (1.2 g) were suspended in anhydrous DMA (32 mL) under Ar atmosphere, and then the 2 mL of 7:5 v/v mixture of TMSCl (0.998 g, 9.18 mmol)/1,2-dibromoethane was added at a rate to maintain the temperature below 60° C. The resulting slurry was stirred for additional 15 min before the solution of tert-butyl 4-iodopiperidine-1-carboxylate (A47.1) (25 g, 80.3 mmol) in dry DMA (40 mL) was added dropwise at a rate to maintain a temperature below 60° C. The mixture was stirred at 55° C. for 2.5 h and then allowed to sedimentate for 72 h. The organic layer was cannulated under Ar atmosphere and the concentration of {1-[(tert-butoxy)carbonyl]piperidin-4-yl}(iodo)zinc (A47.2) was determined by titration (0.69 M, 86 mL, 59.3 mmol, 74% yield).

    Step-2. Synthesis of crude tert-butyl 4-(4-chloro-2-fluorophenyl)piperidine-1-carboxylate (A47.4)

    [0718] 4-chloro-2-fluoro-1-iodobenzene (A47.3) (10 g, 38.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II)-dichloromethane complex (1.27 g, 1.56 mmol) and copper(I) iodide (0.6 g, 3.15 mmol) were added under Ar atmosphere to a stirred solution of {1-[(tert-butoxy)carbonyl]piperidin-4-yl}(iodo)zinc (0.69 M, 72 mL, 49.68 mmol) in dry DMA (72 mL). The resulting mixture was stirred at 80° C. for 14 h and cooled to room temperature. After the reaction was quenched with 25% K.sub.2CO.sub.3 solution (250 mL) and diluted with MTBE (180 mL). The organic layer was separated and the aqueous layer was extracted with MTBE (150 mL). The combined organic layers were washed with 5% NH.sub.4OH (150 mL), water (150 mL), dried over anhydrous K.sub.2CO.sub.3, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give crude tert-butyl 4-(4-chloro-2-fluorophenyl)piperidine-1-carboxylate (A47.4) (11.2 g, 26.7 mmol, 75% purity, 70% yield) that was used in next step without further purification.

    Step-3. Synthesis of 4-(4-chloro-2-fluorophenyl)piperidine Hydrochloride (A47.5)

    [0719] 12 M HCl solution (130 mL) was added at room temperature to a stirred solution of crude tert-butyl 4-(4-chloro-2-fluorophenyl)piperidine-1-carboxylate (A47.4) (11.2 g, 74% purity by LCMS) in methanol (130 mL). The resulting mixture was stirred for 2 h at 55° C. After completion (TLC control) of the reaction, the reaction mixture was extracted with chloroform (130 mL×2), water layer was separated and concentrated under reduced pressure. The residue was washed with acetonitrile (50 mL) to afford the crude 4-(4-chloro-2-fluorophenyl)piperidine hydrochloride (A47.5) (7.2 g, 0.959 mmol, 75% purity, 95.2% yield) which was used in the next step without further purification.

    Step-4. Synthesis of 4-(4-chloro-2-fluorophenyl)-1-(2-chloro-6-nitrophenyl)piperidine (A47.7)

    [0720] 1-chloro-2-fluoro-3-nitrobenzene (A47.6) (0.921 g, 3.94 mmol) and potassium carbonate (1.23 g, 8.97 mmol) were added to a stirred solution of 4-(4-chloro-2-fluorophenyl)piperidine hydrochloride (0.9 g, 2.69 mmol, 75% purity) in dry DMF (10 mL). The reaction mixture was heated at 80° C. for 48 h. After completion of the reaction (TLC control), the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (20 mL) and ethyl acetate (15 mL). The water layer was separated and extracted with ethyl acetate (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform) to afford 4-(4-chloro-2-fluorophenyl)-1-(2-chloro-6-nitrophenyl)piperidine (A47.7) (0.45 g, 1.21 mmol, 95% purity, 43% yield).

    Step-5. Synthesis of 3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]aniline (A47.8)

    [0721] Iron powder (0.337 g, 6.05 mmol) and ammonium chloride (0.323 g, 6.05 mmol) were added to a stirred solution of 4-(4-chloro-2-fluorophenyl)-1-(2-chloro-6-nitrophenyl)piperidine (A47.7) (0.45 g, 1.21 mmol) in mixture of ethanol (15 mL) and water (4.5 mL) at room temperature. The resulting reaction mixture was heated at 80° C. for 5 h. After completion of the reaction (TLC control), the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was dissolved with water (10 mL) and chloroform (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform) to afford 3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]aniline (A47.8) (0.29 g, 0.854 mmol, 95% purity, 67% yield).

    Step-6. Synthesis of N-{3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamid (A-373)

    [0722] Pyridine (0.168 g, 2.131 mmol) was added to a stirred solution of 3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]aniline (A47.8) (0.29 g, 0.854 mmol) and 2,3-dihydro-1H-indene-5-sulfonyl chloride (A47.9) (0.203 g, 0.939 mmol) in dry acetonitrile (5 mL), at room temperature. The reaction was stirred at room temperature overnight. After completion of the reaction (TLC control), the reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by prep HPLC (deionized water/HPLC-grade methanol) to afford N-{3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide (A-373). Yield: 116.0 mg, 24.8%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.77 (s, 1H), 7.69 (s, 1H), 7.62-7.26 (m, 6H), 7.26-7.16 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 2.96-2.73 (m, 5H), 2.66 (s, 1H), 2.32-2.18 (m, 2H), 2.11-1.74 (m, 5H), 1.63 (d, J=11.9 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.25Cl.sub.2FN.sub.2O.sub.2S: 519.46; Observed: 518.14 [M−H].sup.−.

    Example A48: Synthesis of N-{3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide (A-375)

    [0723] ##STR01517##

    Step-1. Synthesis of 4-(4-chloro-2-nitrophenyl)-1,9-dioxa-4-azaspiro[5.5]undecane (A48.3)

    [0724] 4-chloro-1-fluoro-2-nitrobenzene (A48.1) (1 g, 5.69 mmol) was added to a stirred solution of 1,9-dioxa-4-azaspiro[5.5]undecane (A48.2) (0.9 g, 5.72 mmol) and triethylamine (0.863 g, 8.52 mmol) in dry THF (20 mL). The mixture was refluxed until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification (hexane/ethyl acetate) of crude product afforded 4-(4-chloro-2-nitrophenyl)-1,9-dioxa-4-azaspiro[5.5]undecane (A48.3) as an oil (1.15 g, 3.67 mmol, 95% purity, 61.5% yield).

    Step-2. Synthesis of 5-chloro-2-{1,9-dioxa-4-azaspiro[5.5]undecan-4-yl}aniline (A48.4)

    [0725] Iron powder (1.03 g, 18.4 mmol) and ammonium chloride (0.98 g, 18.3 mmol) were added to a stirred solution of 4-(4-chloro-2-nitrophenyl)-1,9-dioxa-4-azaspiro[5.5]undecane (A48.3) (1.15 g, 3.67 mmol) in mixture of ethanol (25 mL) and water (25 mL) at room temperature. The resulting reaction mixture was heated at 80° C. for 6 h. After completion of the reaction (TLC control), the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was dissolved with water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford crude 5-chloro-2-{1,9-dioxa-4-azaspiro[5.5]undecan-4-yl}aniline (A48.4) (0.55 g, 1.94 mmol, 93.93% purity, 50.0% yield) that was used in next step without further purification.

    Step-3. Synthesis of N-(5-chloro-2-{1,9-dioxa-4-azaspiro[5.5]undecan-4-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-375)

    [0726] 2,3-dihydro-1H-indene-5-sulfonyl chloride (A48.5) (0.42 g, 1.93 mmol) was added to the mixture of 5-chloro-2-{1,9-dioxa-4-azaspiro[5.5]undecan-4-yl}aniline (A48.4) (0.55 g, 1.94 mmol) and pyridine (0.23 g, 2.9 mmol) in dry THF (20 mL). The reaction mixture was refluxed for 4 h and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) that afforded N-(5-chloro-2-{1,9-dioxa-4-azaspiro[5.5]undecan-4-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-375). Yield: 54.0 mg, 5.71%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.60, J=4.4 Hz, 2H), 7.29 (d, J=8.1 Hz, 1H), 7.00 (s, 2H), 3.85-3.64 (m, 6H), 2.94 (t, J=7.4 Hz, 4H), 2.68-2.55 (m, 2H), 2.40 (s, 2H), 2.12 (p, J=7.4 Hz, 2H), 2.06-1.85 (m, 3H), 1.65-1.45 (m, 2H); HPLC purity: 98.13%; LCMS Calculated for C.sub.23H.sub.27ClN.sub.2O.sub.4S: 462.99; Observed: 462.17 [M−H].sup.−.

    [0727] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00016 Compound No. Structure Analytical data A-376 [01518]embedded image Yield: 106.0 mg, 18.7%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.91 (s, 1H), 7.68 (s, 1H), 7.62-7.56 (m, 1H), 7.56-7.52 (m, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7.08 (dd, J = 8.5, 3.2 Hz, 1H), 6.96 (dt, J = 8.5, 2.7 Hz, 1H), 3.94-3.82 (m, 2H), 3.64-3.48 (m, 2H), 2.98-2.86 (m, 4H), 2.86-2.73 (m, 2H), 2.68-2.59 (m, 2H), 2.16-1.98 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.25ClN.sub.2O.sub.3S: 444.97; Observed: 444.16 [M − H].sup.−. A-377 [01519]embedded image Yield: 30.0 mg, 3.27%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.80 (s, 1H), 7.69 (s, 1H), 7.55 (dd, J = 7.8, 1.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.21- 7.09 (m, 2H), 4.33-4.21 (m, 4H), 2.89 (t, J = 7.5 Hz, 4H), 2.70 (s, 2H), 2.41 (t, J = 5.3 Hz, 2H), 2.03 (p, J = 7.5 Hz, 2H), 1.73-1.66 (m, 2H), 1.58-1.48 (m, 2H); HPLC purity: 97.79%; LCMS Calculated for C.sub.22H.sub.25ClN.sub.2O.sub.3S: 432.96; Observed: 432.16 [M − H].sup.−. A-395 [01520]embedded image Yield: 30.0 mg, 3.27%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.30 (s, 1H), 7.51 (s, 1H), 7.43 (q, J = 7.9 Hz, 2H), 7.08 (dd, J = 8.9, 2.6 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 4.44 (q, J = 5.9 Hz, 4H), 3.34 (s, 2H, on the solvent signal), 3.15 (t, J = 6.8 Hz, 2H), 2.91 (q, J = 7.7 Hz, 4H), 2.13- 1.99 (m, 4H); HPLC purity: 98.56%; LCMS Calculated for C.sub.21H.sub.23ClN.sub.2O.sub.3S: 418.94; Observed: 418.14 [M − H].sup.−. A-396 [01521]embedded image Yield: 144.1 mg, 18.9%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.73 (s, 1H), 7.66 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 2.91 (q, J = 7.3 Hz, 4H), 2.72 (s, 4H), 2.16- 2.00 (m, 6H), 1.96 (t, J = 9.7 Hz, 4H), 1.70 (q, J = 11.4, 10.8 Hz, 2H), 1.59-1.41 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.29ClN.sub.2O.sub.3S: 473.02; Observed: 472.2 [M − H].sup.−. A-405 [01522]embedded image Yield: 104.0 mg, 11.1%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.71 (s, 1H), 7.66-7.58 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H), 6.99-6.91 (m, 2H), 3.72 (dt, J = 11.1, 2.9 Hz, 1H), 3.57 (d, J = 10.6 Hz, 1H), 2.99 (td, J = 11.4, 2.7 Hz, 2H), 2.92 (t, J = 7.4 Hz, 5H), 2.31 (dt, J = 12.9, 6.5 Hz, 1H), 2.10 (p, J = 7.5 Hz, 2H), 2.00- 1.87 (m, 2H), 1.71 (q, J = 9.9 Hz, 1H), 1.52 (d, J = 12.5 Hz, 1H), 1.41 (d, J = 13.8 Hz, 1H), 1.17-1.00 (m, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.27ClN.sub.2O.sub.3S: 446 99; Observed: 446.18 [M − H].sup.−. A-436 [01523]embedded image Yield: 389.4 mg, 15.8%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.09 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.14- 7.00 (m, 2H), 4.51 (s, 1H), 3.19 (s, 2H), 2.61 (s, 6H), 2.48-2.39 (m, 4H), 1.57- 1.46 (m, 2H), 1.21 (d, J = 13.0 Hz, 2H), 0.88 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.29N.sub.3O.sub.5S.sub.2: 467.6; Observed: 467.18 [M − H].sup.−. A-411 [01524]embedded image Yield: 900.0 mg, 46.7%; Appearance: Beige solid; .sup.1H NMR (500 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.18-6.99 (m, 3H), 4.19 (q, J = 7.1 Hz, 2H), 2.71 (s, 6H), 2.52 (t, J = 12.9 Hz, 2H), 2.40 (d, J = 13.4 Hz, 2H), 2.18 (d, J = 13.3 Hz, 2H), 1.53 (d, J = 14.1 Hz, 3H), 1.32-1.24 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.31N.sub.3O.sub.6S.sub.2: 509.64; Observed: 509.2 [M − H].sup.−. A-416 [01525]embedded image Yield: 53.2 mg, 5.16%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J = 2.2 Hz, 1H), 8.14 (s, 1H), 8.05-7.96 (m, 3H), 7.83 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.18-7.02 (m, 3H), 4.92 (s, 1H), 4.57 (d, J = 13.9 Hz, 1H), 3.46 (s, 4H), 2.95-2.82 (m, 2H), 2.70 (s, 6H), 2.63-2.46 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H); HPLC purity: 98.02%; LCMS Calculated for C.sub.23H.sub.27N.sub.5O.sub.5S.sub.3: 549.68; Observed: 549.13 [M − H].sup.−. A-418 [01526]embedded image Yield: 62.4 mg, 2.7%; Appearance: Orange solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.18-6.98 (m, 3H), 3.46 (s, 1H), 3.36 (s, 4H), 2.88-2.72 (m, 1H), 2.68 (s, 10H), 2.56 (s, 4H), 1.07 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.32N.sub.4O.sub.5S.sub.2: 496 64; Observed: 496.21 [M − H].sup.−.

    Example A49: Synthesis of N-(5-chloro-2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-439)

    [0728] ##STR01527##

    Step-1. Synthesis of 1′-(4-chloro-2-nitrophenyl)-6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidine] (A49.3)

    [0729] 4-chloro-1-fluoro-2-nitrobenzene (A49.2) (0.39 g, 2.22 mmol) was added to a stirred solution of 6-fluoro-1-methylspiro[indoline-3,4′-piperidine]dihydrochloride (A49.1) (0.65 g, 2.22 mmol) and potassium carbonate (0.613, 4.43 mmol) in dry THF (20 mL). The mixture was refluxed until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water, (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The HPLC purification (deionized water/HPLC-grade methanole) of crude product afforded 1′-(4-chloro-2-nitrophenyl)-6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidine](A49.3) as a powder (0.23 g, 0.611 mmol, 95% purity, 26.1% yield).

    Step-2. Synthesis of 5-chloro-2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}aniline (A49.4)

    [0730] Iron powder (0.17 g, 3.04 mmol) and ammonium chloride (0.16 g, 2.99 mmol) were added to a stirred solution of 1′-(4-chloro-2-nitrophenyl)-6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidine] (A49.3) (0.23 g, 0.611 mmol) in mixture of ethanol (25 mL) and water (25 mL) at room temperature. The resulting reaction mixture was heated at 80° C. for 6 h. After completion of the reaction (TLC control), the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was dissolved with water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford 5-chloro-2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}aniline (A49.4) (0.05 g, 0.144 mmol, 92.69% purity, 21.9% yield) that was used in next step without further purification.

    Step-3. Synthesis of N-(5-chloro-2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-439)

    [0731] 2,3-dihydro-1H-indene-5-sulfonyl chloride (A49.5) (0.03 g, 0.138 mmol) was added to the mixture of 5-chloro-2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}aniline (0.05 g, 0.144 mmol) and pyridine (0.017 g, 0.214 mmol) in dry THF (20 mL). The reaction mixture was refluxed for 4 h and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded N-(5-chloro-2-{6-fluoro-1-methyl-1,2-dihydrospiro[indole-3,4′-piperidin]-1′-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-439). Yield: 11.9 mg, 14.9%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.68 (s, 1H), 7.62 (d, J=2.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.07-6.90 (m, 3H), 6.45-6.33 (m, 1H), 6.16 (dd, J=10.2, 2.4 Hz, 1H), 3.26 (s, 2H), 2.94-2.80 (m, 3H), 2.74 (s, 3H), 2.57 (t, J=11.6 Hz, 2H), 2.52-2.38 (m, 2H), 2.04 (p, J=7.1 Hz, 2H), 1.96-1.82 (m, 2H), 1.72 (d, J=13.4 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.29ClFN.sub.3O.sub.2S: 526.07; Observed: 525.21 [M−H].sup.−.

    Example A50: Synthesis of N-(5-chloro-2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-378)

    [0732] ##STR01528##

    Step-1. Synthesis of 1-(4-chloro-2-nitrophenyl)-7-oxa-1-azaspiro[4.4]nonane (A50.3)

    [0733] 7-oxa-1-azaspiro[4.4]nonane (A50.2) (1 g, 7.86 mmol) and potassium carbon are (2.16 g, 15.7 mmol) were added to a stirred solution of 4-chloro-1-fluoro-2-nitrobenzene (A50.1) (1.51 g, 8.64 mmol) in dry DMF (10 mL). The reaction mixture was heated at 80° C. for 20 h. After completion of the reaction (TLC control), the reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (20 mL) and chloroform (15 mL). The water layer was separated and extracted with chloroform (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (chloroform) to afford 1-(4-chloro-2-nitrophenyl)-7-oxa-1-azaspiro[4.4]nonane (A50.3) (0.8 g, 2.68 mmol, 95% purity, 34.2% yield).

    Step-2. Synthesis of 5-chloro-2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}aniline (A50.4)

    [0734] Iron powder (0.787 g, 14.1 mmol) and ammonium chloride (0.754 g, 14.1 mmol) were added to a stirred solution of 1-(4-chloro-2-nitrophenyl)-7-oxa-1-azaspiro[4.4]nonane (A50.3) (0.8 g, 2.82 mmol) in mixture of ethanol (10 mL) and water (3 mL) at room temperature. The resulting reaction mixture was heated at 80° C. for 5 h. After completion of the reaction (TLC control), the reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was dissolved with water (10 mL) and chloroform (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (chloroform) to afford 5-chloro-2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}aniline (A50.4) (0.76 g, 3.00 mmol, 84% purity, 89.6% yield).

    Step-3. Synthesis of N-(5-chloro-2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-378)

    [0735] Pyridine (0.196 g, 2.49 mmol) was added to a stirred solution of 5-chloro-2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}aniline (A50.4) (0.3 g, 0.997 mmol) and 2,3-dihydro-1H-indene-5-sulfonyl chloride (A50.5) (0.236 g, 1.09 mmol) in dry acetonitrile (5 mL) at room temperature. The reaction was stirred at room temperature overnight. After completion of the reaction (TLC control), the reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by prep HPLC (deionized water/HPLC-grade methanol, ammonia) to afford N-(5-chloro-2-{7-oxa-1-azaspiro[4.4]nonan-1-yl}phenyl)-2,3-dihydro-1H-indene-5-sulfonamide (A-378). Yield: 220.0 mg, 48.4%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 7.69 (s, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 3.57 (q, J=8.1 Hz, 1H), 3.54-3.44 (m, 1H), 3.38 (d, J=8.7 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H), 2.88 (t, J 7.5 Hz, 4H), 2.02 (p, J=7.4 Hz, 2H), 1.96-1.81 (m, 4H), 1.71-1.51 (m, 2H); HPLC purity: 6.9; LCMS Calculated for C.sub.22H.sub.25ClN.sub.2O.sub.3S: 432.96; Observed: 432.16 [M−H].sup.−.

    [0736] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00017 Compound No. Structure Analytical data A-397 [01529]embedded image Yield: 65.9 mg, 15.9%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.20 (s, 1H), 7.55 (s, 1H), 7.45 (dd, J = 8.1, 1.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.04 (dd, J = 8.8, 2.5 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 4.16 (d, J = 7.9 Hz, 1H), 4.04-3.96 (m, 1H), 3.88 (d, J = 2.7 Hz, 1H), 3.62-3.47 (m, 2H), 3.39 (d, J = 7.9 Hz, 1H), 2.96-2.86 (m, 4H), 2.21 (q, J = 8.9, 7.9 Hz, 1H), 2.05 (dt, J = 12.9, 6.1 Hz, 3H), 1.84-1.50 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.29ClN.sub.2O.sub.3S: 473.03; Observed: 472.2 [M − H].sup.−. A-379 [01530]embedded image Yield: 207.4 mg, 48.7%; Appearance: Brown solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.88 (s, 1H), 7.69 (s, 1H), 7.60 (dd, J = 8.1, 1.7 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.22 (s, 1H), 7.00-6.85 (m, 2H), 3.78-3.61 (m, 2H), 3.60-3.50 (m, 1H), 3.41 (d, J = 11.2 Hz, 1H), 2.89 (t, J = 7.5 Hz, 4H), 2.59 (d, J = 11.2 Hz, 1H), 2.46 (t, J = 5.5 Hz, 2H), 2.44-2.31 (m, 1H), 2.07 (p, J = 7.6 Hz, 2H), 1.67-1.49 (m, 7H), 1.31 (s, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.29ClN.sub.2O.sub.3S: 461.02; Observed: 460.2 [M − H].sup.−. A-385 [01531]embedded image Yield: 36.4 mg, 7.2%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.26 (s, 1H), 7.46 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.39-7.30 (m, 4H), 7.31-7.24 (m, 1H), 7.12 (dd, J = 8.9, 2.7 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 5.08-4.85 (m, 2H), 3.62 (d, J = 10.9 Hz, 1H), 3.53 (q, J = 8.8 Hz, 1H), 3.44-3.33 (m, 2H), 3.13 (d, J = 10.9 Hz, 1H), 2.95- 2.69 (m, 4H), 2.15-2.04 (m, 2H), 2.01 (t, J = 7.5 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.25ClN.sub.2O.sub.3S: 481.01; Observed: 480.16 [M − H].sup.−. A-433 [01532]embedded image Yield: 609.7 mg, 68.6%; Appearance: Violet solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.11 (s, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 7.7 Hz, 1H), 7.17-6.91 (m, 3H), 4.99 (s, 1H), 2.61 (s, 8H), 2.42 (t, J = 11.3 Hz, 3H), 1.56 (q, J = 11.4 Hz, 4H), 1.00 (q, J = 8.9, 8.4 Hz, 1H), 0.56-0.47 (m, 2H), 0.41-0.31 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.5S.sub.2: 479.61; Observed: 479.18 [M − H].sup.−. A-420 [01533]embedded image Yield: 399.5 mg, 44.9%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.14 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 7.3 Hz, 1H), 7.16-7.01 (m, 3H), 3.75 (s, 1H), 2.71 (t, J = 11.1 Hz, 2H), 2.61 (s, 6H), 2.30 (d, J = 11.1 Hz, 2H), 1.59 (t, J = 12.4 Hz, 2H), 1.37 (d, J = 12.8 Hz, 2H), 0.88-0.77 (m, 1H), 0.37-0.29 (m, 2H), 0.25-0.16 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.5S.sub.2: 479.61; Observed: 479.18 [M − H].sup.−. A-421 [01534]embedded image Yield: 272.3 mg, 28.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.21 (s, 1H), 8.02-7.89 (m, 4H), 7.24 (d, J = 7.2 Hz, 1H), 7.19-7.01 (m, 3H), 2.62 (s, 6H), 2.58-2.54 (m, 4H), 2.37-2.19 (m, 5H), 2.13 (s, 1H), 2.07 (s, 1H), 1.66 (d, J = 11.5 Hz, 2H), 1.46-1.39 (m, 1H), 1.34 (d, J = 9.7 Hz, 1H), 1.28-1.20 (m, 2H), 1.19- 1.11 (m, 1H), 0.80 (d, J = 12.1 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.34N.sub.4O.sub.4S.sub.2: 518.69; Observed: 518.24 [M − H].sup.−. A-455 [01535]embedded image Yield: 330.0 mg, 38.3%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.21 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 4.2 Hz, 2H), 7.04 (dd, J = 8.1, 4.4 Hz, 1H), 2.61 (s, 6H), 2.57-2.50 (m, 4H), 2.47-2.42 (m, 4H), 1.39 (q, J = 7.4 Hz, 2H), 0.95 (s, 6H), 0.78 (t, J = 7.3 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.34N.sub.4O.sub.4S.sub.2: 494.67; Observed: 494.24 [M − H].sup.−. A-464 [01536]embedded image Yield: 351.2 mg, 36.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.25 (s, 1H), 8.10-7.88 (m, 4H), 7.25 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 4.0 Hz, 2H), 7.06 (dt, J = 8.6, 4.5 Hz, 1H), 4.44 (d, J = 6.3 Hz, 2H), 4.23 (d, J = 5.8 Hz, 2H), 2.61 (s, 6H), 2.59-2.51 (m, 7H), 2.41 (s, 4H), 1.70 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.5S.sub.2: 508.65; Observed: 508.21 [M − H].sup.−. A-475 [01537]embedded image Yield: 29.1 mg, 1.35%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.23 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.16-7.07 (m, 2H), 7.07-7.00 (m, 1H), 2.77-2.67 (m, 2H), 2.60 (s, 6H), 2.48- 2.44 (m, 4H), 2.31-2.23 (m, 2H), 1.65 (d, J = 13.8 Hz, 2H), 1.55-1.36 (m, 10H), 0.82 (t, J = 7.4 Hz, 3H); HPLC purity: 97.02%; LCMS Calculated for C.sub.26H.sub.38N.sub.4O.sub.4S.sub.2: 534.73; Observed: 534.28 [M − H].sup.−. A-454 [01538]embedded image Yield: 123.6 mg, 11.1%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.21 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.16-7.00 (m, 3H), 3.07 (s, 3H), 2.61 (s, 6H), 2.59 (d, J = 10.0 Hz, 2H), 2.29 (d, J = 11.2 Hz, 2H), 1.62 (d, J = 13.3 Hz, 2H), 1.58-1.46 (m, 2H), 1.10 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.29N.sub.3O.sub.5S.sub.2: 467.6; Observed: 467.18 [M − H].sup.−. A-422 [01539]embedded image Yield: 270.8 mg, 30.4%; Appearance: Grey solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.19 (s, 1H), 8.04-7.97 (m, 2H), 7.96- 7.89 (m, 2H), 7.28 (dd, J = 7.8, 1.6 Hz, 1H), 7.19-7.08 (m, 3H), 7.08-7.01 (m, 1H), 3.72 (t, J = 7.1 Hz, 2H), 3.44 (s, 2H), 2.62 (s, 6H), 2.46 (dd, J = 12.8, 5.9 Hz, 4H), 1.69 (t, J = 7.1 Hz, 2H), 1.58-1.45 (m, 4H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.5S.sub.2: 479.61; Observed: 479.18 [M − H].sup.−. A-419 [01540]embedded image Yield: 40.6 mg, 4.48%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.16 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.14-7.01 (m, 3H), 3.72 (dt, J = 8.0, 6.6 Hz, 1H), 3.66-3.55 (m, 1H), 3.52-3.44 (m, 1H), 2.62 (s, 6H), 2.57-2.50 (m, 2H), 2.41 (d, J = 10.9 Hz, 2H), 1.95-1.74 (m, 3H), 1.74-1.66 (m, 1H), 1.53-1.40 (m, 2H), 1.30 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2: 493.64; Observed: 493.2 [M − H].sup.−. A-434 [01541]embedded image Yield: 401.6 mg, 46.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.14 (s, 1H), 8.00 (d, J = 10.3 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.15-7.01 (m, 3H), 3.24 (s, 3H), 3.19 (d, J = 5.9 Hz, 2H), 2.62 (s, 6H), 2.54 (d, J = 3.6 Hz, 2H), 2.46-2.38 (m, 2H), 1.55 (d, J = 11.8 Hz, 3H), 1.25 (q, J = 11.9 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.29N.sub.3O.sub.5S.sub.2: 467.6; Observed: 467.18 [M − H].sup.−. A-435 [01542]embedded image Yield: 483.3 mg, 51.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.15 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.14-7.00 (m, 3H), 3.89 (d, J = 11.2 Hz, 1H), 3.00 (d, J = 10.8 Hz, 1H), 2.62 (s, 8H), 2.46-2.35 (m, 2H), 1.91-1.00 (m, 11H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.5S.sub.2: 507.66; Observed: 507.22 [M − H].sup.−. A-549 [01543]embedded image Yield: 52.6 mg, 5.13%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.70 (s, 1H), 9.17 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.31- 7.24 (m, 1H), 7.19-7.10 (m, 2H), 7.12- 7.02 (m, 1H), 3.13 (dt, J = 12.7, 6.8 Hz, 4H), 2.93 (t, J = 5.7 Hz, 2H), 2.63 (d, J = 2.2 Hz, 6H), 2.46 (d, J = 10.9 Hz, 2H), 1.76 (d, J = 12.1 Hz, 3H), 1.32 (d, J = 12.1 Hz, 2H), 1.28- 1.16 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.36N.sub.4O.sub.4S.sub.2: 508.7; Observed: 508.26 [M − H].sup.−. A-550 [01544]embedded image Yield: 96.8 mg, 9.19%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.42 (s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.18-7.03 (m, 3H), 2.62 (s, 8H), 2.54 (d, J = 1.9 Hz, 2H), 2.30 (s, 1H), 1.71-1.59 (m, 4H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.24F.sub.3N.sub.3O.sub.4S.sub.2: 491.54; Observed: 491.14 [M − H].sup.−. A-551 [01545]embedded image Yield: 58.9 mg, 6.07%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.29 (s, 1H), 8.03-7.89 (m, 4H), 7.25 (d, J = 7.9 Hz, 1H), 7.20-7.02 (m, 3H), 6.49 (t, J = 52.4 Hz, 1H), 3.00 (t, J = 15.2 Hz, 2H), 2.73-2.50 (m, 15H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26F.sub.4N.sub.4O.sub.4S.sub.2: 538.58; Observed: 538.16 [M − H].sup.−. A-450 [01546]embedded image Yield: 226.6 mg, 28.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.25 (s, 1H), 8.07-7.83 (m, 4H), 7.23 (d, J = 7.7 Hz, 1H), 7.16-7.08 (m, 2H), 7.05 (td, J = 8.2, 7.1, 2.9 Hz, 1H), 3.88 (d, J = 11.0 Hz, 1H), 3.73 (d, J = 11.1 Hz, 1H), 3.33-3.31 (m, 3H), 3.25-3.09 (m, 2H), 2.62 (s, 6H), 2.49-2.44 (m, 3H), 2.37-2.25 (m, 1H), 1.91 (d, J = 12.0 Hz, 1H), 1.66 (d, J = 12.7 Hz, 1H), 1.55-1.45 (m, 1H), 1.44- 1.32 (m, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.5S.sub.2: 508.65; Observed: 508.21 [M − H].sup.−. A-456 [01547]embedded image Yield: 303.0 mg, 36.0%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.30 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.17-7.10 (m, 2H), 7.10-7.01 (m, 1H), 3.51-3.42 (m, 1H), 2.70-2.59 (m, 10H), 2.58-2.51 (m, 5H), 1.18 (d, J = 7.0 Hz, 3H); HPLC purity: 96.33%; LCMS Calculated for C.sub.21H.sub.27F.sub.3N.sub.4O.sub.4S.sub.2: 520.59; Observed: 520.17 [M − H].sup.−. A-452 [01548]embedded image Yield: 85.0 mg, 5.93%; Appearance: Pink solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 13.9 Hz, 2H), 2.64 (d, J = 29.1 Hz, 13H), 2.23 (s, 2H), 1.73-1.46 (m, 10H), 0.89 (d, J = 8.0 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.36N.sub.4O.sub.4S.sub.2: 520.71; Observed: 520.26 [M − H].sup.−. A-451 [01549]embedded image Yield: 49.5 mg, 8.51%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.98-7.91 (m, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.56 (dd, J = 7.9, 1.8 Hz, 1H), 7.21-7.14 (m, 1H), 7.14- 7.01 (m, 2H), 3.66 (d, J = 4.5 Hz, 4H), 2.83 (d, J = 14.7 Hz, 2H), 2.68 (s, 6H), 2.56 (t, J = 4.5 Hz, 4H), 2.18 (s, 2H), 1.72 (d, J = 13.9 Hz, 2H), 1.57-1.38 (m, 4H), 0.89 (t, J = 7.6 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.36N.sub.4O.sub.5S.sub.2: 536.71; Observed: 536.25 [M − H].sup.−.

    Example A51: Synthesis of N4-[2-(4-cyclopentylpiperazin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-453)

    [0737] ##STR01550##

    Step-1. Synthesis of 1-cyclopentyl-4-(2-nitrophenyl)piperazine (A51.3)

    [0738] 1-fluoro-2-nitrobenzene (A51.1) (1.83 g, 12.9 mmol) was added to a stirred solution of 1-cyclopentylpiperazine (A51.2) (2 g, 12.9 mmol) and potassium carbonate (2.69 g, 19.4 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-cyclopentyl-4-(2-nitrophenyl)piperazine (1.12 g, 84.06 mmol, 85% purity, 26.8% yield) that was used in next step without further purification.

    Step-2. Synthesis of 2-(4-cyclopentylpiperazin-1-yl)aniline (A51.4)

    [0739] 1-cyclopentyl-4-(2-nitrophenyl)piperazine (A51.3) (1.12 g, 4.06 mmol) was dissolved in methanol (100 mL) and treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control, overnight). The catalyst was filtered off and the filtrate was evaporated to afford 2-(4-cyclopentylpiperazin-1-yl)aniline (A51.4) (0.696 g, 2.83 mmol, 95% purity, 66.3% yield).

    Step-3. Synthesis of N4-[2-(4-cyclopentylpiperazin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-453)

    [0740] 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A51.5) (0.8 g, 3.69 mmol) was added to the mixture of 2-(4-cyclopentylpiperazin-1-yl)aniline (A51.4) (0.69 g, 2.48 mmol) and pyridine (0.33 g, 4.17 mmol) in dry THF (20 mL). The reaction mixture was refluxed for 4 h and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded the product as beige solid. The analytical data provided for this compound provisionally supports the proposed structure for N4-[2-(4-cyclopentylpiperazin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-453). Yield: 312.7 mg, 24.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 7.16-7.06 (m, 2H), 7.06-7.00 (m, 1H), 2.68 (m, 15H), 1.88 (t, J=12.3 Hz, 2H), 1.70 (t, J=7.9 Hz, 2H), 1.61-1.50 (m, 2H), 1.41 (s, 2H); HPLC purity: 98.02%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.4S.sub.2: 492.65; Observed: 492.22 [M−H].sup.−.

    [0741] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00018 Compound No. Structure Analytical data A-505 [01551]embedded image Yield: 401.0 mg, 25.5%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.25 (s, 1H), 8.55-8.44 (m, 2H), 7.99-7.86 (m, 4H), 7.72 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 7.8, 4.7 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 4.3 Hz, 2H), 7.04 (dq, J = 8.6, 4.3 Hz, 1H), 3.53 (d, J = 7.0 Hz, 1H), 2.59 (s, 6H), 2.54 (s, 4H), 2.41 (s, 2H), 2.31 (s, 2H), 1.33 (d, J = 6.7 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.31N.sub.5O.sub.4S.sub.2: 529.67; Observed: 529.21 [M − H].sup.−. A-506 [01552]embedded image Yield: 112.8 mg, 8.84%; Appearance: Pink solid; .sup.1H NMR (500 MHz, DMSO- d.sub.6) δ 9.30 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 4.3 Hz, 2H), 7.10- 7.01 (m, 1H), 2.62 (s, 8H), 2.48-2.35 (m, 3H), 1.81 (t, J = 13.0 Hz, 1H), 1.66- 1.44 (m, 7H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27F.sub.2N.sub.3O.sub.4S.sub.2: 487.58; Observed: 487.17 [M − H].sup.−. A-494 [01553]embedded image Yield: 37.0 mg, 2.27%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.11 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 6.2 Hz, 1H), 7.12-6.99 (m, 3H), 3.16 (s, 2H), 2.62 (d, J = 3.0 Hz, 8H), 2.41 (t, J = 11.6 Hz, 2H), 1.59 (d, J = 12.5 Hz, 2H), 1.40 (s, 1H), 1.22 (d, J = 12.9 Hz, 2H), 1.14 (d, J = 2.9 Hz, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.35N.sub.3O.sub.5S.sub.2: 509.68; Observed: 509.24 [M − H].sup.−. A-495 [01554]embedded image Yield: 145.5 mg, 7.53%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02-7.90 (m, 4H), 7.22 (d, J = 7.5Hz, 1H), 7.12 (d, J = 4.3 Hz, 2H), 7.04 (s, 1H), 3.90 (s, 1H), 3.73 (s, 1H), 3.59 (d, J = 7.6 Hz, 1H), 2.62 (q, J = 4.9, 3.5 Hz, 7H), 2.54 (s, 5H), 2.39 (s, 5H), 1.91 (s, 1H), 1.77 (s, 2H), 1.46 (s, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.5S.sub.2: 508.65; Observed: 508.21 [M − H].sup.−. A-496 [01555]embedded image Yield: 215.2 mg, 10.2%; Appearance: Violet solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.11 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 4.5 Hz, 2H), 7.03 (dt, J = 8.8, 4.5 Hz, 1H), 3.30-3.26 (m, 2H), 3.20 (s, 3H), 2.59 (s, 6H), 2.51 (s, 4H), 2.39 (t, J = 10.5 Hz, 2H), 1.56- 1.44 (m, 4H), 1.29-1.09 (m, 5H); HPLC purity: 96.51%; LCMS Calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.65; Observed: 495.22 [M − H].sup.−. A-611 [01556]embedded image Yield: 176.4 mg, 7.42%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.09 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.0 Hz, IH), 7.11-7.06 (m, 2H), 7.06- 6.99 (m, 1H), 3.33 (d, J = 6.5 Hz, 2H), 3.19 (s, 3H), 2.59 (s, 6H), 2.52-2.49 (m, 2H), 2.43-2.35 (m, 2H), 1.52 (d, J = 12.5 Hz, 2H), 1.43 (q, J = 6.6 Hz, 2H), 1.37- 1.31 (m, 1H), 1.25-1.15 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.31N.sub.3O.sub.5S.sub.2: 481.63; Observed: 481.2 [M − H].sup.−. A-562 [01557]embedded image Yield: 137.1 mg, 16.2%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.21 (s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.16-7.00 (m, 3H), 3.53 (t, J = 5.3 Hz, 2H), 2.62 (s, 8H), 2.35-2.26 (m, 2H), 1.75 (d, J = 13.2 Hz, 2H), 1.63- 1.36 (m, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2: 493.64; Observed: 493.2 [M − H].sup.−. A-584 [01558]embedded image Yield: 291.9 mg, 22.5%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.19 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 8.0, 1.4 Hz, 1H), 7.12-7.05 (m, 2H), 7.05-6.99 (m, 1H), 3.67 (t, J = 6.7 Hz, 2H), 2.59 (s, 8H), 2.36 (dt, J = 10.9, 4.9 Hz, 2H), 1.86-1.78 (m, 2H), 1.66- 1.60 (m, 2H), 1.59-1.48 (m, 4H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.5S.sub.2: 479.61; Observed: 479.18 [M − H].sup.−. A-695 [01559]embedded image Yield: 718.6 mg, 28.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.28 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.26 (dd, J = 8.9, 5.9 Hz, 1H), 7.10 (dd, J = 10.3, 3.0 Hz, 1H), 6.93 (td, J = 8.5, 3.0 Hz, 1H), 3.24 (s, 3H), 3.08 (s, 2H), 2.58 (s, 6H), 2.42 (t, J = 10.1 Hz, 2H), 2.35- 2.28 (m, 2H), 1.53-1.45 (m, 2H), 1.26- 1.19 (m, 2H), 0.89 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.30FN.sub.3O.sub.5S.sub.2: 499 62; Observed: 499.19 [M − H].sup.−. A-694 [01560]embedded image Yield: 210.5 mg, 7.74%; Appearance: Violet solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (s, 1H), 7.93 (s, 5H), 7.19 (dd, J = 8.9, 6.3 Hz, 1H), 6.98 (dd, J = 10.8, 2.9 Hz, 1H), 6.86 (td, J= 8.4, 2.8 Hz, 1H), 3.26 (s, 3H), 3.07 (s, 2H), 2.63 (s, 6H), 2.53 (t, J = 4.5 Hz, 4H), 1.45- 1.33 (m, 2H), 1.23-1.12 (m, 2H), 0.89 (s, 3H); HPLC purity: 96.60%; LCMS Calculated for C.sub.22H.sub.30FN.sub.3O.sub.5S.sub.2: 499 62; Observed: 499.19 [M − H].sup.−.

    Example A52: Synthesis of N4-{2-[4-(1,4-dioxan-2-yl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-437)

    [0742] ##STR01561##

    Step-1. Synthesis of 4-(1,4-dioxan-2-yl)-1-(2-nitrophenyl)piperidine (A52.3)

    [0743] 1-fluoro-2-nitrobenzene (A52.1) (1.65 g, 11.6 mmol) was added to a stirred solution of 4-(1,4-dioxan-2-yl)piperidine (A52.2) (2 g, 11.6 mmol) and potassium carbonate (2.42 g, 17.5 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification (chloroform/ethyl acetate) of crude product afforded 4-(1,4-dioxan-2-yl)-1-(2-nitrophenyl)piperidine as a powder (A52.3) (1.7 g, 5.81 mmol, 95% purity, 47.4% yield).

    Step-2. Synthesis of 2-[4-(1,4-dioxan-2-yl)piperidin-1-yl]aniline (A52.4)

    [0744] Iron powder (1.63 g, 29.1 mmol) and ammonium chloride (1.56 g, 29.1 mmol) were added at rt to a stirred solution of 4-(1,4-dioxan-2-yl)-1-(2-nitrophenyl)piperidine (A52.3) (1.7 g, 5.81 mmol) in a mixture of ethanol (25 mL) and water (25 mL) and the resulting reaction mixture was refluxed for 6 h. After the reaction completion (TLC control) the mixture was filtered through silica gel and the filtrate was evaporated. The residue was dissolved in water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure that afforded the crude 2-[4-(1,4-dioxan-2-yl)piperidin-1-yl]aniline (A52.4) (0.6 g, 2.28 mmol, 95% purity, 37.5% yield).

    Step-3. Synthesis of N4-{2-[4-(1,4-dioxan-2-yl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-437)

    [0745] 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A52.5) (0.65 g, 2.99 mmol) was added to the mixture of 2-[4-(1,4-dioxan-2-yl)piperidin-1-yl]aniline (A52.4) (0.6 g, 2.28 mmol) and pyridine (0.27 g, 3.41 mmol) in dry THF (20 mL). The reaction mixture was refluxed for 4 h and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N4-{2-[4-(1,4-dioxan-2-yl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-437). Yield: 524.0 mg, 42.8%; Appearance: Beige solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.12-7.00 (m, 3H), 3.86-3.49 (m, 6H), 3.36 (d, J=6.1 Hz, 2H), 2.68 (s, 6H), 2.46 (d, J=12.4 Hz, 4H), 1.88 (s, 1H), 1.42 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.31N.sub.3O.sub.6S.sub.2: 509.64; Observed: 509.19 [M−H].sup.−.

    Example A53: Synthesis of N1,N1-dimethyl-N4-(2-{4-[(oxolan-3-yl)methyl]piperazin-1-yl}phenyl)benzene-1,4-disulfonamide (A-509)

    [0746] ##STR01562##

    Step-1. Synthesis of 1-(2-nitrophenyl)-4-[(oxolan-3-yl)methyl]piperazine (A53.3)

    [0747] 1-fluoro-2-nitrobenzene (A53.1) (1.66 g, 11.7 mmol) was added to a stirred solution of 1-((tetrahydrofuran-3-yl)methyl)piperazine (A53.2) (2 g, 11.7 mmol) and potassium carbonate (2.44 g, 17.6 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(2-nitrophenyl)-4-[(oxolan-3-yl)methyl]piperazine (A53.3) (1.5 g, 5.14 mmol, 85% purity, 37.3% yield) that was used in next step without further purification.

    Step-2. Synthesis of 2-{4-[(oxolan-3-yl)methyl]piperazin-1-1}aniline (A53.4)

    [0748] 1-(2-nitrophenyl)-4-[(oxolan-3-yl)methyl]piperazine (A53.3) (1.5 g, 5.14 mmol) was dissolved in methanol (100 mL) and treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control, overnight). The catalyst was filtered off and the filtrate was evaporated to afford 2-{4-[(oxolan-3-yl)methyl]piperazin-1-1}aniline (A53.4) (1.15 g, 4.39 mmol, 90% purity, 76.8% yield) that was used in next step without further purification.

    Step-3. Synthesis of N1,N1-dimethyl-N4-(2-{4-[(oxolan-3-yl)methyl]piperazin-1-yl}phenyl)benzene-1,4-disulfonamide (A-509)

    [0749] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A53.5) (1.25 g, 4.4 mmol) was added to the mixture of 2-{4-[(oxolan-3-yl)methyl]piperazin-1-yl}aniline (A53.4) (1.15 g, 4.4 mmol) and pyridine (0.52 g, 6.57 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) that afforded N1,N1-dimethyl-N4-(2-{4-[(oxolan-3-yl)methyl]piperazin-1-yl}phenyl)benzene-1,4-disulfonamide (A-509). Yield: 156.0 mg, 6.63%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.22 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.92 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.15-7.08 (m, 2H), 7.08-7.01 (m, 1H), 3.70 (td, J=8.7, 4.2 Hz, 2H), 3.60 (q, J=7.5 Hz, 1H), 3.36 (d, J=7.2 Hz, 2H), 2.62 (d, J=1.7 Hz, 6H), 2.55 (t, J=5.1 Hz, 5H), 2.44-2.31 (m, 6H), 2.33-2.21 (m, 3H), 1.97-1.87 (m, 1H), 1.56-1.43 (in, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.5S.sub.2: 508.65; Observed: 508.21 [M−H].sup.−.

    [0750] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00019 Compound No. Structure Analytical data A-510 [01563]embedded image Yield: 114.8 mg, 4.78%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.21 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 4.4 Hz, 2H), 7.08-7.00 (m, 1H), 3.81 (dd, J = 11.2, 4.3 Hz, 2H), 3.26 (d, J = 11.5 Hz, 2H), 2.62 (s, 6H), 2.55 (t, J = 4.8 Hz, 4H), 2.34 (s, 4H), 2.14 (d, J = 7.2 Hz, 2H), 1.72 (d, J = 14.3 Hz, 1H), 1.58 (d, J = 13.1 Hz, 2H), 1.10 (qd, J = 12.2, 4.4 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.34N.sub.4O.sub.5S.sub.2: 522.68; Observed: 522.23 [M − H].sup.−. A-523 [01564]embedded image Yield: 393.3 mg, 44.5%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 8.04-7.97 (m, 2H), 7.96-7.88 (m, 2H), 7.27 (d, J = 7.9 Hz, 1H), 7.14-7.00 (m, 3H), 3.30 (t, J = 7.0 Hz, 2H), 2.61 (d, J = 2.0 Hz, 8H), 2.31 (d, J = 10.9 Hz, 2H), 1.63 (d, J = 13.1 Hz, 2H), 1.52 (t, J = 10.8 Hz, 2H), 1.14- 1.03 (m, 6H); HPLC purity: 97.15%; LCMS Calculated for C.sub.22H.sub.31N.sub.3O.sub.5S.sub.2: 481.63; Observed: 481.2 [M − H].sup.−. A-545 [01565]embedded image Yield: 575.9 mg, 53.6%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (s, 1H), 7.96-7.82 (m, 4H), 7.47 (dt, J = 12.0, 8.2 Hz, 5H), 7.19-6.98 (m, 4H), 4.58 (q, J = 9.6 Hz, 1H), 2.66-2.49 (m, 14H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.29F.sub.3N.sub.4O.sub.4S.sub.2: 582.66; Observed: 582.19 [M − H].sup.−. A-544 [01566]embedded image Yield: 218.2 mg, 28.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.12 (s, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.9 Hz, 1H), 7.15-7.00 (m, 3H), 3.53 (t, J = 7.9 Hz, 2H), 2.69 (d, J = 11.0 Hz, 2H), 2.62 (s, 6H), 2.55 (d, J = 10.0 Hz, 2H), 2.42 (t, J = 11.2 Hz, 2H), 2.10 (d, J = 6.9 Hz, 2H), 1.57 (q, J = 11.7, 10.7 Hz, 5H), 1.14 (q, J = 10.5, 9.2 Hz, 2H), 1.04 (d, J = 6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.38N.sub.4O.sub.5S.sub.2: 550.73; Observed: 550.27 [M − H].sup.−. A-543 [01567]embedded image Yield: 199.2 mg, 24.0%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.17 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.13-6.98 (m, 3H), 6.66 (t, J = 76.3 Hz, 1H), 3.69 (d, J = 6.2 Hz, 2H), 2.59 (s, 6H), 2.52 (d, J = 11.0 Hz, 2H), 2.41 (d, J = 11.3 Hz, 2H), 1.56 (d, J = 13.1 Hz, 3H), 1.37-1.26 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27F.sub.2N.sub.3O.sub.5S.sub.2: 503.58; Observed: 503.16 [M − H].sup.−. A-546 [01568]embedded image Yield: 145.7 mg, 6.07%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.22 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.15- 7.02 (m, 3H), 3.02 (s, 3H), 2.62 (s, 7H), 2.57 (s, 1H), 2.30 (d, J = 11.2 Hz, 2H), 1.61 (d, J = 13.3 Hz, 2H), 1.45 (q, J = 8.2 Hz, 4H), 0.78 (t, J = 7.4 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.31N.sub.3O.sub.5S.sub.2: 481.63; Observed: 481.2 [M − H].sup.−. A-524 [01569]embedded image Yield: 64.4 mg, 2.53%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.17 (s, 2H), 8.00 (d, J = 7.8 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.14-7.00 (m, 2H), 3.53 (t, J = 5.5 Hz, 4H), 2.62 (d, J = 2.2 Hz, 6H), 2.47- 2.44 (m, 4H), 1.45 (dd, J = 24.0, 6.3 Hz, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2: 493.64; Observed: 493.2 [M − H].sup.−. A-547 [01570]embedded image Yield: 184.4 mg, 10.7%; Appearance: Red solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.14 (s, 1H), 8.04-7.96 (m, 2H), 7.96-7.88 (m, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.14-7.00 (m, 3H), 3.57 (t, J = 4.6 Hz, 4H), 2.62 (s, 7H), 2.42 (t, J = 10.5 Hz, 2H), 2.33 (s, 4H), 2.24 (t, J = 7.4 Hz, 2H), 1.55 (d, J = 10.2 Hz, 2H), 1.43 (s, 2H), 1.22 (t, J = 6.9 Hz, 5H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.38N.sub.4O.sub.5S.sub.2: 550.73; Observed: 550.27 [M − H].sup.−. A-548 [01571]embedded image Yield: 98.4 mg, 3.99%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.17 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.15- 7.08 (m, 2H), 7.08-7.01 (m, 1H), 3.87 (d, J = 11.1 Hz, 2H), 3.26 (d, J = 11.0 Hz, 2H), 2.61 (d, J = 5.4 Hz, 8H), 2.39 (t, J = 11.0 Hz, 2H), 1.56 (s, 4H), 1.37-0.95 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.5S.sub.2: 507.66; Observed: 507.22 [M − H].sup.−. A-498 [01572]embedded image Yield: 163.2 mg, 7.04%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (s, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 4.3 Hz, 2H), 7.09-7.02 (m, 1H), 3.39 (t, J = 6.6 Hz, 4H), 2.61 (s, 6H), 2.42 (t, J = 11.1 Hz, 2H), 1.55 (d, J = 12.4 Hz, 2H), 1.44 (t, J = 6.6 Hz, 2H), 1.37 (s, 1H), 1.27-1.18 (m, 2H), 1.10 (t, J = 7.0 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.65; Observed: 495.22 [M − H].sup.−. A-525 [01573]embedded image Yield: 87.5 mg, 4.72%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.27 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 4.5 Hz, 2H), 7.10-7.03 (m, 1H), 2.72 (t, J = 13.9 Hz, 2H), 2.61 (s, 6H), 2.53 (s, 8H), 1.61 (t, J = 18.9 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.28F.sub.2N.sub.4O.sub.4S.sub.2: 502.6; Observed: 502.18 [M − H].sup.−. A-497 [01574]embedded image Yield: 384.6 mg, 44.2%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.19 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 6.6 Hz, 2H), 7.37-7.30 (m, 1H), 7.08- 7.00 (m, 3H), 3.97-3.90 (m, 1H), 3.80 (q, J = 7.7, 7.1 Hz, 1H), 2.78 (t, J = 8.9 Hz, 1H), 2.60 (s, 7H), 2.41 (d, J = 11.6 Hz, 1H), 1.94- 1.84 (m, 2H), 1.82-1.38 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.5S.sub.2: 479.61; Observed: 479.18 [M − H].sup.−. A-507 [01575]embedded image Yield: 350.0 mg, 40.9%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.17 (s, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.18-7.08 (m, 3H), 7.08- 6.98 (m, 1H), 4.34-4.22 (m, 4H), 2.81 (s, 2H), 2.62 (s, 6H), 2.45 (d, J = 5.1 Hz, 2H), 1.70 (s, 2H), 1.49 (s, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27N.sub.3O.sub.5S.sub.2: 465.58; Observed: 465.16 [M − H].sup.−. A-508 [01576]embedded image Yield: 414.9 mg, 48.6%; Appearance: White solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.21 (s, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.31 (dd, J = 6.6, 3.0 Hz, 1H), 7.24-7.18 (m, 1H), 7.08 (dd, J = 6.7, 3.1 Hz, 2H), 3.61-3.49 (m, 2H), 2.93 (q, J = 7.7 Hz, 1H), 2.89-2.81 (m, 1H), 2.61 (s, 6H), 1.93- 1.80 (m, 4H), 1.67-1.56 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27N.sub.3O.sub.5S.sub.2: 465.58; Observed: 465.16 [M − H].sup.−. A-499 [01577]embedded image Yield: 43.4 mg, 2.35%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 7.1 Hz, 2H), 7.40 (d, J = 7.3 Hz, 1H), 7.25-7.20 (m, 1H), 7.19-7.11 (m, 1H), 7.10- 7.01 (m, 1H), 3.62-3.48 (m, 2H), 2.97- 2.79 (m, 4H), 2.61 (s, 6H), 2.06 (d, J = 11.6 Hz, 1H), 1.87-1.76 (m, 2H), 1.69-1.64 (m, 1H), 1.57-1.50 (m, 1H), 1.45-1.35 (m, 1H), 1.31-1.26 (m, 1H), 1.02-0.94 (m, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29N.sub.3O.sub.5S.sub.2: 479.61; Observed: 479.18 [M − H].sup.−. A-511 [01578]embedded image Yield: 91.0 mg, 3.45%; Appearance: Yellow solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.73 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.9 Hz, 1H), 7.17- 7.08 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 3.66- 3.56 (m, 2H), 3.52-3.39 (m, 2H), 2.61 (s, 8H), 2.37 (d, J = 11.6 Hz, 2H), 1.59-1.37 (m, 7H), 1.18 (d, J = 9.3 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2: 493.64; Observed: 493.2 [M − H].sup.−. A-479 [01579]embedded image Yield: 480.6 mg, 57.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.18 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.15- 7.02 (m, 3H), 2.62 (s, 6H), 2.57-2.52 (m, 2H), 2.41 (t, J = 11.2 Hz, 2H), 1.65-1.34 (m, 6H), 1.20-1.04 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27F.sub.2N.sub.3O.sub.4S.sub.2: 499.59; Observed: 499.17 [M − H].sup.−. A-484 [01580]embedded image Yield: 186.0 mg, 21.3%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.58 (s, 1H), 7.95 (q, J = 8.0 Hz, 4H), 7.11- 7.02 (m, 3H), 6.96-6.86 (m, 1H), 2.87 (d, J = 6.7 Hz, 4H), 2.82-2.71 (m, 4H), 2.63 (s, 6H), 1.90 (s, 1H), 1.74-1.64 (m, 2H), 0.42 (d, J = 6.7 Hz, 2H), 0.30 (s, 2H); HPLC purity: 96.15%; LCMS Calculated for C.sub.22H.sub.30N.sub.4O.sub.4S.sub.2: 478.63; Observed: 478.2 [M − H].sup.−. A-480 [01581]embedded image Yield: 191.6 mg, 19.2%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.30 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.16-7.04 (m, 3H), 7.00- 6.91 (m, 1H), 3.61 (s, 2H), 3.55 (s, 2H), 2.81 (t, J = 12.2 Hz, 4H), 2.62 (s, 7H), 1.81 (s, 2H), 1.17 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.34N.sub.4O.sub.5S.sub.2: 522.68; Observed: 522.23 [M − H].sup.−. A-628 [01582]embedded image Yield: 163.3 mg, 43.0%; Appearance: Green solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.13 (s, 1H), 7.35-7.30 (m, 3H), 7.30-7.25 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.86 (dd, J = 8.0, 2.0 Hz, 1H), 4.60 (s, 2H), 3.65-3.60 (m, 4H), 2.69-2.65 (m, 4H), 2.18 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.18H.sub.22N.sub.2O.sub.3S: 346.45; Observed: 346.16 [M − H].sup.−. A-681 [01583]embedded image Yield: 101.3 mg, 4.88%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.26 (s, 1H), 8.01-7.89 (m, 4H), 7.26-7.13 (m, 2H), 7.04-6.94 (m, 1H), 3.27 (s, 3H), 3.11 (s, 2H), 2.71-2.63 (m, 2H), 2.60 (s, 6H), 2.43- 2.31 (m, 2H), 1.50 (t, J = 11.4 Hz, 2H), 1.24 (d, J = 12.7 Hz, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.30FN.sub.3O.sub.5S.sub.2: 499.62; Observed: 499.19 [M − H].sup.−.

    Example A54: Synthesis of N4-{2-[4-(2-fluoroethyl)piperazin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-559)

    [0751] ##STR01584##

    Step-1. Synthesis of 1-(2-fluoroethyl)-4-(2-nitrophenyl)piperazine (A54.3)

    [0752] 1-fluoro-2-nitrobenzene (A54.1) (0.5 g, 3.54 mmol) was added to a stirred solution of 1-(2-fluoroethyl)piperazine dihydrochloride (A54.2) (0.8 g, 3.89 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in dry DMF (20 ml). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(2-fluoroethyl)-4-(2-nitrophenyl)piperazine (A54.3) (0.75 g, 2.96 mmol, 83% purity, 69.4% yield) that was used in next step without further purification.

    Step-2. Synthesis of 2-[4-(2-fluoroethyl)piperazin-1-yl]aniline (A54.4)

    [0753] 1-(2-fluoroethyl)-4-(2-nitrophenyl)piperazine (A54.3) (0.75 g, 2.96 mmol) was dissolved in methanol (10 mL) and treated with 5% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 2-[4-(2-fluoroethyl)piperazin-1-yl]aniline (A54.4) (0.61 g, 2.73 mmol, 100% purity, 92.4% yield).

    Step-3. Synthesis of N4-{2-[4-(2-fluoroethyl)piperazin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-559)

    [0754] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A54.5) (0.397 g, 1.4 mmol) was added to an ice-cooled solution of 2-[4-(2-fluoroethyl)piperazin-1-yl]aniline (A54.4) (0.3 g, 1.34 mmol) and triethylamine (0.271 g, 2.68 mmol) in DCM (10 mL). After, DMAP (0.082 g, 0.670 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred until completion (overnight, NMR control). After the reaction mixture was diluted with water (10 mL), the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N4-{2-[4-(2-fluoroethyl)piperazin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-559). Yield: 36.6 mg, 5.5%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.28 (s, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.0 Hz, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.17-7.11 (m, 2H), 7.11-7.04 (m, 1H), 4.63-4.56 (m, 1H), 4.51-4.41 (m, 1H), 2.67 (s, 1H), 2.62 (s, 7H), 2.56 (d, J=4.2 Hz, 4H), 2.48-2.43 (m, 4H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.27FN.sub.4O.sub.4S.sub.2: 470.58; Observed: 470.17 [M−H].sup.−.

    [0755] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00020 Compound No. Structure Analytical data A-552 [01585]embedded image Yield: 76.1 mg, 11.9%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.22 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 7.9 Hz, 1H), 7.14- 7.07 (m, 2H), 7.08-6.98 (m, 1H), 6.09 (tt, J = 55.8, 4.4 Hz, 1H), 2.71 (td, J = 15.7, 4.3 Hz, 2H), 2.58 (s, 6H), 2.49-2.42 (m, 8H); HPLC purity: 98.24%; LCMS Calculated for C.sub.20H.sub.26F.sub.2N.sub.4O.sub.4S.sub.2: 488.57; Observed: 488.16 [M − H].sup.−.

    Example A55: Synthesis of N1,N1-dimethyl-N4-(2-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}phenyl)benzene-1,4-disulfonamide (A-554)

    [0756] ##STR01586##

    Step-1. Synthesis of 4-{[1-(2-nitrophenyl)piperidin-4-yl]methyl}morpholine (A55.3)

    [0757] 1-fluoro-2-nitrobenzene (A55.1) (0.39 g, 2.76 mmol) was added to a stirred solution of 4-[(piperidin-4-yl)methyl]morpholine (A55.2) (0.5 g, 2.71 mmol) and potassium carbonate (0.565 g, 4.08 mmol) in dry DMF (5 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in EtOAc (15 mL), the organic layer was washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-{[1-(2-nitrophenyl)piperidin-4-yl]methyl}morpholine (A55.3) as oil (0.72 g, 2.35 mmol, 95% purity, 81.2% yield) which was used in the next step without further purification.

    Step-2. Synthesis of 2-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}aniline (A55.4)

    [0758] 4-{[1-(2-nitrophenyl)piperidin-4-yl]methyl}morpholine (A55.3) (0.72 g, 2.35 mmol) was dissolved in methanol (10 mL) and treated with 10% Pd/C (0.05 g). The resulting mixture was hydrogenated at 6 atm and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 2-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}aniline (A55.4) (0.53 g, 1.92 mmol, 95.9% purity, 77.7% yield).

    Step-3. Synthesis of N1,N1-dimethyl-N4-(2-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}phenyl)benzene-1,4-disulfonamide (A-554)

    [0759] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A55.5) (0.27 g, 0.951 mmol) was added to the mixture of 2-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}aniline (A55.4) (0.25 g, 0.907 mmol) and DIPEA (0.234 g, 1.81 mmol) in dry DCM (5 mL). The reaction mixture was stirred overnight, poured into water and extracted with DCM (10 mL×2). Combined organic layers were washed with sat aq NaHCO.sub.3 solution (20 mL) and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded N1,N1-dimethyl-N4-(2-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}phenyl)benzene-1,4-disulfonamide (A-554). Yield: 182.2 mg, 36.4%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.12 (s, 1H), 8.00 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.27 (d, J=7.8 Hz, 1H), 7.15-7.09 (m, 2H), 7.09-7.01 (m, 1H), 3.56 (t, J=4.5 Hz, 4H), 2.62 (s, 6H), 2.57-2.53 (m, 2H), 2.42 (t, J=11.3 Hz, 2H), 2.32 (s, 4H), 2.13 (d, J=7.1 Hz, 2H), 2.07 (s, 2H), 1.64-1.55 (m, 2H), 1.52 (s, 1H), 1.22-1.11 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.34N.sub.4O.sub.5S.sub.2: 522.68; Observed: 522.23 [M−H].sup.−.

    [0760] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00021 Compound No. Structure Analytical data A-553 [01587]embedded image Yield: 171.3 mg, 31.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.22 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.17-7.10 (m, 2H), 7.10-7.01 (m, 1H), 3.43 (d, J = 5.7 Hz, 2H), 3.24 (d, J = 1.6 Hz, 3H), 2.62 (s, 6H), 2.58-2.52 (m, 5H), 2.43 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.30N.sub.4O.sub.5S.sub.2: 482.61; Observed: 482.19 [M − H].sup.−. A-560 [01588]embedded image Yield: 209.3 mg, 40.5%; Appearance: Pink solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.30 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.20-7.09 (m, 2H), 7.07 (td, J = 7.2, 6.5, 2.3 Hz, 1H), 3.19 (q, J = 10.2 Hz, 2H), 2.63 (d, J = 5.6 Hz, 8H), 2.61-2.52 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.25F.sub.3N.sub.4O.sub.4S.sub.2: 506.56; Observed: 506.15 [M − H].sup.−. A-585 [01589]embedded image Yield: 75.3 mg, 13.7%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.24 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 4.4 Hz, 2H), 7.08-7.01 (m, 1H), 5.99-5.78 (m, 1H), 2.59 (s, 6H), 2.54 (d, J = 11.3 Hz, 2H), 2.43 (d, J = 11.2 Hz, 2H), 1.82-1.75 (m, 1H), 1.55 (d, J = 12.5 Hz, 2H), 1.52-1.42 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.25F.sub.2N.sub.3O.sub.4S.sub.2: 473.55; Observed: 473.15 [M − H].sup.−. A-697 [01590]embedded image Yield: 40.0 mg, 9.84%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.23 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 7.25-7.14 (m, 2H), 7.09 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 3.27 (d, J = 6.2 Hz, 6H), 3.10 (d, J = 3.5 Hz, 2H), 2.61-2.51 (m, 4H), 1.55-1.45 (m, 2H), 1.25 (d, J = 12.6 Hz, 2H), 0.92 (d, J = 3.4 Hz, 3H); HPLC purity: 97%; LCMS Calculated for C.sub.21H.sub.28N.sub.2O.sub.5S.sub.2: 452.59; Observed: 452.17 [M − H].sup.−. A-696 [01591]embedded image Yield: 193.1 mg, 38.5%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 8.04-7.97 (m, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.17-7.10 (m, 2H), 7.11-7.02 (m, 1H), 3.97 (d, J = 6.3 Hz, 2H), 2.62 (s, 6H), 2.56 (d, J = 11.7 Hz, 2H), 2.45 (d, J = 9.4 Hz, 2H), 1.74-1.67 (m, 1H), 1.59 (d, J = 11.5 Hz, 2H), 1.43-1.28 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26F.sub.3N.sub.3O.sub.5S.sub.2: 521.57; Observed: 521.15 [M − H].sup.−.

    Example A56: Synthesis of N1,N1-dimethyl-N4-{2-[4-(2-methylpropyl)-5-oxo-1,4-diazepan-1-yl]phenyl}benzene-1,4-disulfonamide (A-526)

    [0761] ##STR01592## ##STR01593##

    Step-1. Synthesis of tert-butyl 4-(2-methylpropyl)-5-oxo-1,4-diazepane-1-carboxylate (A56.3)

    [0762] tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (A56.1) (4 g, 18.6 mmol) solution in dry DMF (5 mL) was added dropwise to a suspension of NaH (60 w %, 0.9 g, 22.5 mmol) in dry DMF (10 mL) at −15° C. The mixture was stirred at this temperature for 20 minutes and 1-iodo-2-methylpropane (A56.2) (5 g, 27.1 mmol) was added. After the reaction mixture was allowed to warm up and stir for 8 h until the reaction completion. Than the mixture was quenched with water (15 mL) and the product was extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford tert-butyl 4-(2-methylpropyl)-5-oxo-1,4-diazepane-1-carboxylate (A56.3) (1.5 g, 5.54 mmol, 85% purity, 25.2% yield) that was used in next step without further purification.

    Step-2. Synthesis of 4-(2-methylpropyl)-1,4-diazepan-5-one hydrochloride (A56.4)

    [0763] Tert-butyl 4-(2-methylpropyl)-5-oxo-1,4-diazepane-1-carboxylate (A56.3) (1.5 g, 5.54 mmol) was dissolved in saturated HCl solution in dry dioxane (10 mL) at room temperature. The mixture was stirred overnight, evaporated to dryness, the residue was treated with ether (20 mL×2), formed precipitated was filtered, dried on air to afford 4-(2-methylpropyl)-1,4-diazepan-5-one hydrochloride (A564) (0.8 g, 3.87 mmol, 80% purity, 56.1% yield) that was used in next step without further purification.

    Step-3. Synthesis of 4-(2-methylpropyl)-1-(2-nitrophenyl)-1,4-diazepan-5-one (A56.6)

    [0764] 1-fluoro-2-nitrobenzene (A56.5) (0.55 g, 3.89 mmol) was added to a stirred solution of 4-(2-methylpropyl)-1,4-diazepan-5-one hydrochloride (A56.4) (0.8 g, 3.87 mmol) and potassium carbonate (1.6 g, 11.5 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification of residue (hexane/ethyl acetate) afforded 4-(2-methylpropyl)-1-(2-nitrophenyl)-1,4-diazepan-5-one (A56.6) (0.38 g, 1.3 mmol, 95% purity, 31.9% yield).

    Step-4. Synthesis of 1-(2-aminophenyl)-4-(2-methylpropyl)-1,4-diazepan-5-one (A56.7)

    [0765] 4-(2-methylpropyl)-1-(2-nitrophenyl)-1,4-diazepan-5-one (A56.6) (0.38 g, 1.3 mmol) was dissolved in methanol (100 mL) and treated with 5% Pd/C (0.05 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 1-(2-aminophenyl)-4-(2-methylpropyl)-1,4-diazepan-5-one (A56.7) (0.25 g, 0.956 mmol, 70% purity, 51.6% yield) that was used in next step without further purification.

    Step-5. Synthesis of N1,N1-dimethyl-N4-{2-[4-(2-methylpropyl)-5-oxo-1,4-diazepan-1-yl]phenyl}benzene-1,4-disulfonamide (A-526)

    [0766] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A56.8) (0.27 g, 0.951 mmol) was added to the mixture of 1-(2-aminophenyl)-4-(2-methylpropyl)-1,4-diazepan-5-one (A56.7) (0.25 g, 0.956 mmol) and pyridine (0.11 g, 1.39 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N1,N1-dimethyl-N4-{2-[4-(2-methylpropyl)-5-oxo-1,4-diazepan-1-yl]phenyl}benzene-1,4-disulfonamide (A-526). Yield: 42.2 mg, 8.23%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.47 (s, 1H), 8.02-7.90 (m, 4H), 7.41-7.34 (m, 1H), 7.16-7.07 (m, 3H), 3.43 (s, 2H), 3.09 (d, J=7.3 Hz, 2H), 2.62 (s, 6H), 2.55 (d, J=13.7 Hz, 4H), 2.47-2.41 (m, 3H), 1.85-1.71 (m, 1H), 0.82 (dd, J=6.9, 2.5 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.4O.sub.5S.sub.2: 508.65; Observed: 508.21 [M−H].sup.−.

    Example A57: Synthesis of N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-2-methyl-1,3-benzothiazole-6-sulfonamide (A-600)

    [0767] ##STR01594##

    [0768] 2-methyl-1,3-benzothiazole-6-sulfonyl chloride (A57.1) (0.5 g, 2.01 mmol) was added to the mixture of 1-[4-(2-aminophenyl)piperazin-1-yl]-2,2-dimethylpropan-1-one (A57.2) (0.53 g, 2.02 mmol) and pyridine (0.24 g, 3.03 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) that afforded N-{2-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl}-2-methyl-1,3-benzothiazole-6-sulfonamide (A-600). Yield: 137.2 mg, 13.6%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.13 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.79 (dd, J=8.6, 1.9 Hz, 1H), 7.36-7.31 (m, 1H), 7.10-7.01 (m, 3H), 3.49 (t, J=4.7 Hz, 4H), 2.80 (s, 3H), 2.36 (t, J=4.8 Hz, 4H), 1.14 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.28N.sub.4O.sub.3S.sub.2: 472.62; Observed: 472.19 [M−H].sup.−.

    [0769] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00022 Compound No. Structure Analytical data A-583 [01595]embedded image Yield: 15.4 mg, 1.47%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.23-7.11 (m, 5H), 7.13-7.05 (m, 3H), 3.87 (s, 4H), 3.49 (d, J = 11.0 Hz, 1H), 3.30-3.12 (m, 2H), 3.06-2.96 (m, 1H), 2.88 (t, J = 5.1 Hz, 5H), 2.46 (d, J = 13.0 Hz, 1H), 2.05 (qd, J = 12.2, 5.6 Hz, 1H), 1.34 (s, 9H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.33N.sub.3O.sub.3S: 455.62; Observed: 455.27 [M − H].sup.−. A-571 [01596]embedded image Yield: 205.0 mg, 32.3%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO- d.sub.6) δ 7.93 (s, 1H), 7.30-7.24 (m, 2H), 7.09- 7.01 (m, 3H), 6.99 (d, J = 7.0 Hz, 1H), 6.84 (s, 1H), 4.54 (d, J = 4.7 Hz, 4H), 3.82 (t, J = 5.7 Hz, 2H), 3.24 (s, 3H), 3.09 (s, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.70-2.63 (m, 3H), 2.64- 2.57 (m, 2H), 1.55-1.47 (m, 2H), 1.31- 1.24 (m, 2H), 0.93 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444.59; Observed: 444.25 [M − H].sup.−. A-609 [01597]embedded image Yield: 150.4 mg, 35.4%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 8.20 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.06 (q, J = 7.8 Hz, 2H), 6.90 (s, 1H), 6.73 (d, J = 2.9 Hz, 1H), 6.61 (dd, J = 8.7, 2.8 Hz, 1H), 4.55 (d, J = 9.6 Hz, 4H), 3.81 (t, J = 5.7 Hz, 2H), 3.70-3.59 (m, 7H), 2.72 (t, J = 5.8 Hz, 2H), 2.61 (d, J = 4.6 Hz, 4H); HPLC purity: 100%; LCMS Calculated for C21H26N2O5S: 418.51; Observed: 418.18 [M − H].sup.−. A-629 [01598]embedded image Yield: 144.3 mg, 32.7%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO- d.sub.6) δ 8.12 (s, 1H), 7.11-7.03 (m, 3H), 6.90 (s, 1H), 6.87 (s, 1H), 6.85 (dd, J = 8.1, 1.9 Hz, 1H), 4.54 (s, 4H), 3.81 (t, J = 5.7 Hz, 2H), 3.66-3.61 (m, 4H), 2.72 (t, J = 5.7 Hz, 2H), 2.68-2.63 (m, 4H), 2.17 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.26N.sub.2O.sub.4S: 402.51; Observed: 402.19 [M − H].sup.−.

    Example A58: Synthesis of N4-{2-[4-(2,2-difluorocyclohexyl)piperazin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-626)

    [0770] ##STR01599## ##STR01600##

    Step-1. Synthesis of 1-benzyl-4-(2,2-difluorocyclohexyl)piperazine (A58.3)

    [0771] Benzylbis(2-chloroethyl)amine hydrochloride (A58.2) (7.9 g, 29.4 mmol) was added to a stirred solution of 2,2-difluorocyclohexan-1-amine hydrochloride (A58.1) (5 g, 29.1 mmol) and potassium carbonate (20 g, 145 mmol) in dry acetonitrile (250 mL). The mixture was stirred at 60° C. for 16 h and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with water (250 mL), brine (250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (chloroform/methyl tert-butyl ether) to afford 1-benzyl-4-(2,2-difluorocyclohexyl)piperazine (A58.3) (0.9 g, 3.05 mmol, 95% purity, 9.98% yield).

    Step-2. Synthesis of 1-(2,2-difluorocyclohexyl)piperazine Hydrochloride (A58.4)

    [0772] 1-benzyl-4-(2,2-difluorocyclohexyl)piperazine (A58.3) (0.9 g, 3.05 mmol) was dissolved in methanol (10 mL) and conc. aqueous HCl (10 mL) and treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed. The catalyst was filtered off and the filtrate was evaporated to afford 1-(2,2-difluorocyclohexyl)piperazine hydrochloride (A58.4) (0.65 g, 2.7 mmol, 95% purity, 84% yield).

    Step-3. Synthesis of 1-(2,2-difluorocyclohexyl)-4-(2-nitrophenyl)piperazine (A58.6)

    [0773] 1-fluoro-2-nitrobenzene (A58.5) (0.4 g, 2.83 mmol) was added to a stirred solution of 1-(2,2-difluorocyclohexyl)piperazine hydrochloride (A58.4) (0.65 g, 2.7 mmol) and potassium carbonate (0.932 g, 6.75 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. for 5 h and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(2,2-difluorocyclohexyl)-4-(2-nitrophenyl)piperazine (A58.6) (0.85 g, 2.61 mmol, 67.85% purity, 65.6% yield) that was used in next step without further purification.

    Step-4. Synthesis of 2-[4-(2,2-difluorocyclohexyl)piperazin-1-yl]aniline (A58.7)

    [0774] 1-(2,2-difluorocyclohexyl)-4-(2-nitrophenyl)piperazine (A58.6) (0.85 g, 2.61 mmol) was dissolved in methanol (25 mL) and treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed. The catalyst was filtered off and the filtrate was evaporated to afford 2-[4-(2,2-difluorocyclohexyl)piperazin-1-yl]aniline (A58.7) (0.6 g, 2.03 mmol, 90% purity, 70.1% yield) that was used in next step without further purification.

    Step-5. Synthesis of 2-[4-(2,2-difluorocyclohexyl)piperazin-1-yl]aniline (A-626)

    [0775] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A58.8) (0.6 g, 2.11 mmol) was added to the mixture of 2-[4-(2,2-difluorocyclohexyl)piperazin-1-yl]aniline (A58.7) (0.6 g, 2.03 mmol) and pyridine (0.5 g, 6.32 mmol) in dry THF (20 mL). The reaction mixture was refluxed for 4 h and evaporated. The residue was diluted by saturated NaHCO.sub.3 solution (20 mL) and ethyl acetate (20 mL). Organic layer was separated, washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give N4-{2-[4-(2,2-difluorocyclohexyl)piperazin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-626). Yield: 335.4 mg, 28.9%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.21 (s, 1H), 7.97 (dd, J=8.5, 1.7 Hz, 2H), 7.89 (dd, J=8.5, 1.7 Hz, 2H), 7.19 (d, J=8.0 Hz, 1H), 7.14-7.07 (m, 2H), 7.02 (t, J=7.3 Hz, 1H), 2.81-2.73 (m, 1H), 2.73-2.65 (m, 4H), 2.59 (d, J=1.7 Hz, 6H), 2.56-2.48 (m, 6H), 1.95 (q, J=8.4 Hz, 1H), 1.77-1.68 (m, 2H), 1.64 (s, 2H), 1.54 (q, J=12.0 Hz, 1H), 1.31 (t, J=12.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32F.sub.2N.sub.4O.sub.4S.sub.2: 542.66; Observed: 542.22 [M−H].sup.−.

    Example A59: Synthesis of N4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-N1-methylbenzene-1,4-disulfonamide (A-587)

    [0776] ##STR01601## ##STR01602##

    Step-1. Synthesis of 4-bromo-N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-N-methylbenzene-1-sulfonamide (A59.3)

    [0777] Pyridine (5.56 g, 70.4 mmol) and 4-bromobenzene-1-sulfonyl chloride (A59.2) (12.0 g, 47.0 mmol) were added to a solution of 2,5,8-trioxa-11-azadodecane (A59.1) (10 g, 56.4 mmol) in acetonitrile (250 mL). The reaction mixture was stirred at room temperature for 18 h and the reaction mixture has been evaporated. The residue was subjected to silica gel chromatography purification (hexane/methyl tert-butyl ether) that afforded 4-bromo-N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-N-methylbenzene-1-sulfonamide as colorless oil (A59.3) (14 g, 35.3 mmol, 95% purity, 71.5% yield).

    Step-2. Synthesis of lithio 4-({2-[2-(2-methoxyethoxy)ethoxy]ethyl}(methyl)sulfamoyl)benzene-1-sulfinate (A59.4)

    [0778] n-butyllithium (16.9 mL, 2.5 M in hexane, 42.3 mmol) was added dropwise at −78° C. to a stirred solution of 4-bromo-N-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-N-methylbenzene-1-sulfonamide (A59.3) (14 g, 35.3 mmol) in dry THF (250 mL) at Ar atmosphere and the reaction mixture was stirred at −78° C. for 2 h. Solution of SO.sub.2 (6.72 g, 105 mmol) in dry THF (100 mL) was added at −78° C., after the reaction mixture was allowed to warm up and stir overnight at room temperature. The suspension was concentrated under reduced pressure to give lithio 4-({2-[2-(2-methoxyethoxy)ethoxy]ethyl}(methyl)sulfamoyl)benzene-1-sulfinate as white solid (A59.4) (16 g, 41.3 mmol, 77% purity, 90.4% yield) that was used in the next step without further purification.

    Step-3. Synthesis of 4-({2-[2-(2-methoxyethoxy)ethoxy]ethyl}(methyl)sulfamoyl)benzene-1-sulfonyl Chloride (A59.5)

    [0779] Sulfuroyl dichloride (6.68 g, 49.5 mmol) was added dropwise at −10° C. to a stirred solution of lithio 4-({2-[2-(2-methoxyethoxy)ethoxy]ethyl}(methyl)sulfamoyl)benzene-1-sulfinate (A59.4) (16 g, 41.3 mmol) in dry dichloromethane (250 mL), the reaction mixture was allowed to warm up and stir for 2 h at room temperature. The organic layer was washed with water with ice (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography purification (hexane/methyl tert-butyl ether) that afforded 4-({2-[2-(2-methoxyethoxy)ethoxy]ethyl}(methyl)sulfamoyl)benzene-1-sulfonyl chloride as colorless oil (A59.5) (8.49 g, 20.4 mmol, 90% purity, 44.6% yield) that was used in next step without further purification.

    Step-4. Synthesis of N4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1-{2-[2-(2-methoxy-ethoxy)ethoxy]ethyl}-N1-methylbenzene-1,4-disulfonamide (A-587)

    [0780] Pyridine (0.0972 g, 0.0989 mmol) and 4-({2-[2-(2-methoxyethoxy)ethoxy]ethyl}(methyl)sulfamoyl)benzene-1-sulfonyl chloride (A59.5) (0.375 g, 0.902 mmol) were added to a solution of 2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]aniline (A59.6) (0.25 g, 820 μmol) in acetonitrile (25 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford N4-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-N1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-N1-methylbenzene-1,4-disulfonamide (A-587). Yield: 223.9 mg, 37.7%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 7.98-7.90 (m, 4H), 7.40 (t, J=8.2 Hz, 1H), 7.38-7.26 (m, 3H), 7.17-7.04 (m, 3H), 3.47-3.41 (m, 4H), 3.42-3.35 (m, 6H), 3.19 (d, J=1.1 Hz, 3H), 3.10 (t, J=5.5 Hz, 2H), 2.83-2.75 (m, 1H), 2.68 (s, 3H), 2.59 (t, J=11.3 Hz, 3H), 2.52 (d, J=11.5 Hz, 3H), 1.81-1.71 (m, 2H), 1.57 (d, J=12.4 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.31H.sub.39ClFN.sub.3O.sub.7S.sub.2: 684.24; Observed: 683.23 [M−H].sup.−.

    Example A60: Synthesis of N-{2-[4-(4-chloro-2-fluorophenyl)piperidin-1-yl]phenyl}-4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}benzene-1-sulfonamide (A-588)

    [0781] ##STR01603##

    Step-1. Synthesis of {2-[2-(2-methoxyethoxy)ethoxy]ethoxy}benzene (A60.3)

    [0782] 1-bromo-2-(2-(2-methoxyethoxy)ethoxy)ethane (A60.1) (15 g, 66.0 mmol), potassium carbonate (25.0 g, 180 mmol), and potassium iodide (1 g, 6.02 mmol) were added to a stirred solution of the phenol (A60.2) (5.6 g, 59.5 mmol) in DMF (200 mL) and the mixture was stirred at 60° C. for 24 h. After water (400 mL) was added to the reaction mixture and the product was extracted with ethyl acetate (400 mL×3). The organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford {2-[2-(2-methoxyethoxy)ethoxy]ethoxy}benzene (A60.3) (14 g, 59.5 mmol, 95% purity, 93.6% yield).

    Step-2. Synthesis of 4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzene-1-sulfonyl chloride (A60.5)

    [0783] Sulfurochloridic acid (A60.4) (13.5 g, 116 mmol, 7.71 mL) was added dropwise under ice-cooling bath to the solution of (2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzene (A60.3) (14 g, 58.2 mmol) in DCM (200 mL). After the addition was completed, the mixture was warmed to room temperature and stirred for 1 h. The resulting mixture was poured into ice-water (30 mL) and then extracted with DCM (250 mL×3) for 3 times. Combined organic layers were washed with water (500 mL), brine (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzene-1-sulfonyl chloride as an yellow oil (A60.5) (17 g, 50.1 mmol, 100% purity, 86.2% yield).

    Step-3. Synthesis of N-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzenesulfonamide (A-588)

    [0784] 4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzene-1-sulfonyl chloride (A60.5) (0.28 g, 0.826 mmol) was added to the mixture of 2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)aniline (A60.6) (0.276 g, 0.908 mmol) and pyridine (0.653 g, 8.26 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford N-(2-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)phenyl)-4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzenesulfonamide (A-588). Yield: 218.8 mg, 41.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.67 (s, 1H), 7.71 (d, J=8.6 Hz, 2H), 7.50 (t, J=8.3 Hz, 1H), 7.39 (dd, J=8.6, 3.0 Hz, 2H), 7.33 (dd, J=8.4, 2.1 Hz, 1H), 7.19 (dd, J=6.2, 3.3 Hz, 1H), 7.07 (t, J=7.3 Hz, 4H), 4.11 (t, J=4.4 Hz, 2H), 3.70 (t, J=4.5 Hz, 2H), 3.53 (dd, J=6.1, 3.6 Hz, 2H), 3.50-3.44 (m, 4H), 3.39 (dd, J=5.9, 3.6 Hz, 2H), 3.20 (s, 3H), 2.85 (t, J=12.3 Hz, 1H), 2.64 (t, J=11.2 Hz, 2H), 1.90 (tt, J=12.5, 7.0 Hz, 2H), 1.65 (dd, J=12.8, 3.6 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.30H.sub.36ClFN.sub.2O.sub.6S: 607.13; Observed: 606.24 [M−H].sup.−.

    [0785] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00023 Compound No. Structure Analytical data A-589 [01604]embedded image Yield: 478.0 mg, 47.7%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO- d.sub.6) δ 7.96 (s, 1H), 7.31-7.22 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 1.1 Hz, 1H), 7.09-7.03 (m, 2H), 7.03-6.98 (m, 2H), 4.56 (s, 2H), 3.24 (s, 3H), 3.09 (s, 2H), 2.73-2.59 (m, 4H), 2.22 (s, 3H), 1.55-1.48 (m, 2H), 1.32-1.25 (m, 2H), 0.93 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.30N.sub.2O.sub.3S: 402.55; Observed: 402.24 [M − H].sup.−.

    Example A61: Synthesis of 3-[({2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}sulfamoyl)methyl]-N,N-dimethylbenzene-1-sulfonamide (A-680)

    [0786] ##STR01605##

    Step-1. Synthesis of sodium [3-(dimethylsulfamoyl)phenyl]methanesulfonate (A61.2)

    [0787] 3-(chloromethyl)-N,N-dimethylbenzene-1-sulfonamide (A61.1) (5.5 g, 23.5 mmol) and disodium sulfite (14.7 g, 117 mmol) in water/isopropanol mixture (50 mL/50 mL) were heated at 80° C. for 24 h. Then the reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was refluxed in methanol (100 mL) for 15 min and filtered. Organics were evaporated, suspended with acetonitrile (30 mL), formed precipitate was filtered and dried under vacuum to give sodium [3-(dimethylsulfamoyl)phenyl]methanesulfonate as a white solid (A61.2) (5.5 g, 18.2 mmol, 90% purity, 69.9% yield) that was used in next step without further purification.

    Step-2. Synthesis of [3-(dimethylsulfamoyl)phenyl]methanesulfonyl chloride (A61.3)

    [0788] Oxalic dichloride (0.313 g, 2.47 mmol) was added at −10° C. to a suspension of sodium [3-(dimethylsulfamoyl)phenyl]methanesulfonate (A61.2) (0.5 g, 1.65 mmol) in THE (50 mL) and DMF (1 mL) was added. The bath temperature was maintained below 0° C. for 1 h, at which point the reaction was filtrated through SiO2, the precipitate was washed with THE (50 mL). The combined filtrate was evaporated under reduced pressure to afford [3-(dimethylsulfamoyl)phenyl]methanesulfonyl chloride as an yellow oil (A61.3) (0.4 g, 1.34 mmol, 93% purity, 75.7% yield) that was used in the next step without further purification.

    Step-3. Synthesis of 3-[({2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}sulfamoyl)methyl]-N,N-dimethylbenzene-1-sulfonamide (A-680)

    [0789] Pyridine (0.132 g, 1.67 mmol) and [3-(dimethylsulfamoyl)phenyl]methanesulfonyl chloride (A61.3) (0.4 g, 1.34 mmol) were added to a 2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (A61.4) (0.260 g, 1.11 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 3-[({2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}sulfamoyl)methyl]-N,N-dimethylbenzene-1-sulfonamide (A-680). Yield: 325.9 mg, 56.1%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.12 (s, 1H), 7.81-7.75 (m, 1H), 7.77-7.69 (m, 1H), 7.69-7.59 (m, 2H), 7.27 (d, J=6.5 Hz, 1H), 7.10-6.95 (m, 3H), 4.85 (s, 2H), 3.27 (s, 3H), 3.13 (s, 2H), 2.83-2.62 (m, 4H), 2.50 (s, 6H), 1.70-1.54 (m, 2H), 1.34 (d, J=13.0 Hz, 2H), 0.96 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.65; Observed: 495.22 [M−H].sup.−.

    [0790] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00024 Compound No. Structure Analytical data A-627 [01606]embedded image Yield: 49.7 mg, 11.1%; Appearance: Brown oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.91 (s, 1H), 7.36- 7.31 (m, 1H), 7.28-7.20 (m, 3H), 7.13-7.07 (m, 1H), 7.06-6.96 (m, 3H), 4.62 (s, 2H), 3.24 (s, 3H), 3.09 (s, 2H), 2.67-2.60 (m, 2H), 2.60-2.54 (m, 2H), 1.55-1.48 (m, 2H), 1.31-1.22 (m, 2H), 1.16 (s, 9H), 0.92 (s, 3H); HPLC purity:; LCMS Calculated for C.sub.25H.sub.36N.sub.2O.sub.3S: 444.63; Observed: 444.3 [M − H].sup.−.

    Example A62: Synthesis of 1-(1,3-dihydro-2-benzofuran-4-yl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-607)

    [0791] ##STR01607## ##STR01608##

    Step-1. Synthesis of (1,3-dihydro-2-benzofuran-4-yl)methanol (A62.2)

    [0792] NaBH.sub.4 (1.21 g, 31.9 mmol) was added portionwise at 0° C. to a solution of 1,3-dihydroisobenzofuran-4-carbaldehyde (A62.1) (4.75 g, 32 mmol) in methanol (50 mL). Then, the reaction was warmed to r.t. and stirred for 12 h. After, the mixture was evaporated to dryness under reduced pressure. The residue was treated with ethyl acetate (100 mL) and the organic layer was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated to give (1,3-dihydro-2-benzofuran-4-yl)methanol (A62.2) (4 g, 26.6 mmol, 90% purity, 75% yield) which was used in the next step without further purification.

    Step-2. Synthesis of 4-(chloromethyl)-1,3-dihydro-2-benzofuran (A62.3)

    [0793] Thionyl chloride (4.92 g, 41.3 mmol, 3 mL) was added dropwise over 1 h at 0° C. to a solution of (1,3-dihydroisobenzofuran-4-yl)methanol (4 g, 26.6 mmol) in CH.sub.2Cl.sub.2 (40 mL) and pyridine (2.31 g, 29.2 mmol, 2.36 mL). Then, the reaction mixture was refluxed for 2 h, cooled to r.t. and poured in cold water (40 mL). The organic layer was separated, washed with brine (40 mL), dried over sodium sulfate, filtered and evaporated to afford 4-(chloromethyl)-1,3-dihydro-2-benzofuran as an yellow oil (A62.3) (4.4 g, 26 mmol, 90% purity, 88.3% yield) that was used in the next step without further purification.

    Step-3. Synthesis of sodium (1,3-dihydro-2-benzofuran-4-yl)methanesulfonate (A62.4)

    [0794] The mixture of 4-(chloromethyl)-1,3-dihydroisobenzofuran (A62.3) (4.4 g, 26 mmol) and disodium sulfite (10.5 g, 83.3 mmol) in water/methanol (50 mL/50 mL) were heated at 80° C. for 24 h. Then the reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was refluxed in methanol (100 mL) for 15 min and filtered. The filtrate was evaporated under reduced pressure, the residue was suspended in acetonitrile (20 mL), filtered, and formed precipitate was dried in vacuum to obtain sodium (1,3-dihydro-2-benzofuran-4-yl)methanesulfonate as a white solid (A62.4) (6.2 g, 26.2 mmol, 93.54% purity, 94.2% yield) that was used in the next step without further purification.

    Step-4. Synthesis of (1,3-dihydro-2-benzofuran-4-yl)methanesulfonyl chloride (A62.5)

    [0795] Oxalyl chloride (7.4 g, 58.3 mmol, 5 mL) was added dropwise over 1 h at −20° C. to a suspension of sodium (1,3-dihydroisobenzofuran-4-yl)methanesulfonate (A62.4) (1.18 g, 4.99 mmol) in THE (15 mL) and DMF (1 mL). The bath temperature was maintained below 0° C. for 1 h, at which point the reaction was diluted with ethyl acetate (25 mL). The organic layer was separated, washed with brine (25 mL), dried over sodium sulfate, filtered and evaporated to give (1,3-dihydro-2-benzofuran-4-yl)methanesulfonyl chloride (A62.5) as an yellow oil (0.7 g, 3 mmol, 100% purity, 60.2% yield).

    Step-5. Synthesis of 1-(1,3-dihydro-2-benzofuran-4-yl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-607)

    [0796] (1,3-dihydro-2-benzofuran-4-yl)methanesulfonyl chloride (A62.5) (0.32 g, 1.37 mmol) was added to the mixture of 2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (A62.6) (0.23 g, 0.981 mmol) and pyridine (0.982 g, 12.4 mmol) in dry acetonitrile (10 mL). The reaction mixture was stirred for 12 h and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 1-(1,3-dihydro-2-benzofuran-4-yl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-607). Yield: 208.8 mg, 47.0%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.09 (s, 1H), 7.30-7.22 (m, 3H), 7.18 (dd, J=7.4, 2.1 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H), 7.09-7.00 (m, 2H), 4.95 (s, 2H), 4.92 (s, 2H), 4.57 (s, 2H), 3.24 (s, 3H), 3.10 (s, 2H), 2.73-2.62 (m, 4H), 1.58-1.50 (m, 2H), 1.33-1.26 (m, 2H), 0.93 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.56; Observed: 414.23 [M−H].sup.−.

    Example A63: Synthesis of 1-(1,3-dihydro-2-benzofuran-5-yl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-612)

    [0797] ##STR01609## ##STR01610##

    Step-1. Synthesis of 5-(chloromethyl)-1,3-dihydro-2-benzofuran (A63.2)

    [0798] (1,3-dihydroisobenzofuran-5-yl)methanol (A63.1) (2 g, 13.3 mmol) was dissolved in anhydrous DCM (20 mL) and thionylchloride (1.75 g, 14.7 mmol) was added to this solution. The reaction mixture was stirred overnight at room temperature, then it was poured on water (20 mL), the organic layer was separated, washed with water (20 mL), dried over sodium sulfate, filtered and evaporated to afford crude 5-(chloromethyl)-1,3-dihydro-2-benzofuran (A63.2) (1.7 g, 10.0 mmol, 95% purity, 71.8% yield).

    [0799] Step-2. Synthesis of {[(1,3-dihydro-2-benzofuran-5-yl)methyl]sulfanyl}methanimidamide hydrochloride (A63.3)

    [0800] 5-(chloromethyl)-1,3-dihydroisobenzofuran (A63.2) (1.7 g, 10 mmol) was added to a stirred solution of thiourea (0.76 g, 9.98 mmol) in dry methanol (20 mL). The mixture was refluxed until the reaction completion (TLC control, 6 h) and concentrated under the reduced pressure. The residue was washed with MTBE (20 mL×2) and dried on air to afford {[(1,3-dihydro-2-benzofuran-5-yl)methyl]sulfanyl}methanimidamide hydrochloride (A63.3) (1.3 g, 5.31 mmol, 90% purity, 47.9% yield) that was used in the next step without additional purification.

    Step-3. Synthesis of (1,3-dihydro-2-benzofuran-5-yl)methanesulfonyl chloride (A63.4)

    [0801] Gaseous chlorine was bubbled at room temperature through a stirred solution of (1,3-dihydroisobenzofuran-5-yl)methyl carbamimidothioate hydrochloride (A63.3) (1.3 g, 5.31 mmol) in acetic acid (20 mL) for 10 min. The water (50 mL) was added after and the precipitate was filtered, dried to afford (1,3-dihydro-2-benzofuran-5-yl)methanesulfonyl chloride (A63.4) (0.8 g, 3.43 mmol, 88% purity, 57.2% yield) that was used in the next step without further purification.

    Step-4. Synthesis of 1-(1,3-dihydro-2-benzofuran-5-yl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-612)

    [0802] (1,3-dihydro-2-benzofuran-5-yl)methanesulfonyl chloride (A63.4) (0.2 g, 0.859 mmol) was added to the mixture of 2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (A63.5) (0.2 g, 0.853 mmol) and pyridine (0.1 g, 1.26 mmol) in dry THF (20 mL). The reaction mixture was stirred overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded 1-(1,3-dihydro-2-benzofuran-5-yl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-612). Yield: 87.6 mg, 22.5%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.97 (s, 1H), 7.29-7.22 (m, 3H), 7.17-7.10 (m, 2H), 7.08-7.02 (m, 2H), 4.94 (s, 2H), 4.91 (s, 2H), 4.62 (s, 2H), 3.24 (s, 3H), 3.09 (s, 2H), 2.71-2.59 (m, 4H), 1.55-1.48 (m, 2H), 1.31-1.24 (m, 2H), 0.93 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.30N.sub.2O.sub.4S: 430.56; Observed: 430.23 [M−H].sup.−.

    Example A64: Synthesis of N-{5-methoxy-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide (A-630)

    [0803] ##STR01611## ##STR01612##

    Step-1. Synthesis of 1-fluoro-4-methoxy-2-nitrobenzene (A64.2)

    [0804] 4-Fluoro-3-nitrophenol (A64.1) (5 g, 31.8 mmol) was dissolved in acetone (50 mL) and methyl iodide (6.77 g, 47.7 mmol) and potassium carbonate (6.59 g, 47.7 mmol) were added to this solution. The reaction mixture was stirred at room temperature for 24 hours and diluted with ethyl acetate (100 mL). The organic layer was separated, washed with 1N sodium hydroxide aqueous solution (100 mL), water (100 mL) and brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 1-fluoro-4-methoxy-2-nitrobenzene as yellow oil (A64.2) (5.3 g, 30.9 mmol, 95% purity, 92.4% yield).

    Step-2. Synthesis of 1-(4-methoxy-2-nitrophenyl)-4-(methoxymethyl)-4-methylpiperidine (A64.4)

    [0805] 1-fluoro-4-methoxy-2-nitrobenzene (A64.2) (1 g, 5.84 mmol) was added to a stirred solution of 4-(methoxymethyl)-4-methylpiperidine (A64.3) (0.836 g, 5.84 mmol) and K.sub.2CO.sub.3 (0.807 g, 5.83 mmol) in dry NMP (10 mL). The mixture was stirred until the reaction completion at 80° C. (TLC control, overnight). Then, it was cooled to room temperature, poured in water (20 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(4-methoxy-2-nitrophenyl)-4-(methoxymethyl)-4-methylpiperidine as orange oil (A64.4) (1.7 g, 5.77 mmol, 90% purity, 89.4% yield) that was used in the next step without further purification.

    Step-3. Synthesis of 5-methoxy-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (A64.5)

    [0806] 1-(4-methoxy-2-nitrophenyl)-4-(methoxymethyl)-4-methylpiperidine (A64.4) (1.7 g, 5.77 mmol) was dissolved in methanol (50 mL) and treated with 10% Pd/C (0.2 g). The resulting mixture was hydrogenated at ambient pressure and room temperature for 1 h. The catalyst was filtered off and the filtrate was evaporated to afford 5-methoxy-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline as a caramel oil (A64.5) (1.5 g, 5.67 mmol, 95% purity, 93.4% yield).

    Step-4. Synthesis of N-{5-methoxy-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide (A-630)

    [0807] 2,3-dihydro-1H-indene-5-sulfonyl chloride (A64.6) (0.41 g, 1.88 mmol) was added to the mixture of 5-methoxy-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (A64.5) (0.5 g, 1.89 mmol) and pyridine (0.982 g, 12.4 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded N-{5-methoxy-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-2,3-dihydro-1H-indene-5-sulfonamide (A-630). Yield: 645.0 mg, 72.8%; Appearance: Pink solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 7.64 (s, 1H), 7.47 (dd, J=7.9, 1.8 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 6.89 (d, J=2.9 Hz, 1H), 6.58 (dd, J=8.8, 2.9 Hz, 1H), 3.65 (s, 3H), 3.26 (s, 3H), 3.11 (s, 2H), 2.83 (t, J=7.3 Hz, 4H), 2.43 (t, J=9.2 Hz, 2H), 2.30-2.23 (m, 2H), 1.98 (p, J=7.5 Hz, 2H), 1.59-1.51 (m, 2H), 1.31-1.24 (m, 2H), 0.92 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444.59; Observed: 444.25 [M−H].sup.−.

    Example A65: Synthesis of N4-{2-[4-(ethoxymethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-719)

    [0808] ##STR01613## ##STR01614##

    Step-1. Synthesis of tert-butyl 4-(ethoxymethyl)-4-methylpiperidine-1-carboxylate (A65.3)

    [0809] Tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (A65.1) (1.6 g, 6.97 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 0.305 g, 7.66 mmol) in DMF (15 mL) and the mixture was stirred for 0.5 h at 50° C. Iodoethane (A65.2) (1.62 g, 10.4 mmol) was added dropwise after and the mixture was stirred at 50° C. overnight until completion. After the reaction mixture was diluted with water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), brine (25 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford tert-butyl 4-(ethoxymethyl)-4-methylpiperidine-1-carboxylate (A65.3) (1.8 g, 6.99 mmol, 80% purity, 80.4% yield) that was used in next step without further purification.

    Step-2. Synthesis of 4-(ethoxymethyl)-4-methylpiperidine hydrochloride (A65.5)

    [0810] Acetyl chloride (A65.4) (5 g, 63.6 mmol) was added to methanol (25 g, 780 mmol) at 0° C. and the mixture was stirred for 1 h. After tert-butyl 4-(ethoxymethyl)-4-methylpiperidine-1-carboxylate (A65.3) (1.8 g, 6.99 mmol) was added and the reaction mixture was allowed to warm and stir at room temperature overnight. After the solvent was evaporated under reduced pressure, the residue was treated with mixture ether/hexane (20 mL, 1/5). The formed precipitate was filtered off, dried on air to afford 4-(ethoxymethyl)-4-methylpiperidine hydrochloride (A65.5) (1.5 g, 7.74 mmol, 85% purity, 94% yield) that was used in next step without further purification.

    Step-3. Synthesis of 4-(ethoxymethyl)-4-methyl-1-(2-nitrophenyl)piperidine (A65.7)

    [0811] 1-fluoro-2-nitrobenzene (A65.6) (0.55 g, 3.89 mmol) was added to a stirred solution of 4-(ethoxymethyl)-4-methylpiperidine hydrochloride (A65.5) (0.75 g, 3.87 mmol) and potassium carbonate (1.33 g, 9.67 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. for 5 h and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4-(ethoxymethyl)-4-methyl-1-(2-nitrophenyl)piperidine (A65.7) (0.8 g, 2.87 mmol, 62% purity, 46.3% yield) that was used in next step without further purification.

    Step-4. Synthesis of 2-[4-(ethoxymethyl)-4-methylpiperidin-1-yl]aniline (A65.8)

    [0812] 4-(ethoxymethyl)-4-methyl-1-(2-nitrophenyl)piperidine (A65.7) (0.8 g, 2.87 mmol) was dissolved in methanol (25 mL) and treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed. The catalyst was filtered off and the filtrate was evaporated to afford 2-[4-(ethoxymethyl)-4-methylpiperidin-1-yl]aniline (A65.8) (0.7 g, 2.81 mmol, 65.61% purity, 64.4% yield) that was used in next step without further purification.

    Step-5. Synthesis of N4-{2-[4-(ethoxymethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-719)

    [0813] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A65.9) (0.84 g, 2.96 mmol) was added to the mixture of 2-[4-(ethoxymethyl)-4-methylpiperidin-1-yl]aniline (A65.8) (0.7 g, 2.81 mmol) and pyridine (0.5 g, 6.32 mmol) in dry THF (20 mL). The reaction mixture was refluxed for 4 h and evaporated. The residue was diluted with water (20 mL) and ethyl acetate (20 mL). Organic layer was separated, washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give N4-{2-[4-(ethoxymethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-719). Yield: 226.6 mg, 72.8%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.10 (s, 1H), 7.99-7.87 (m, 4H), 7.24 (d, J=6.5 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.09 (t, J=7.0 Hz, 1H), 7.02 (t, J=8.1 Hz, 1H), 3.41 (q, J=7.0 Hz, 2H), 3.12 (s, 2H), 2.59 (s, 6H), 2.52-2.46 (m, 14H), 2.46-2.39 (m, 3H), 1.50-1.43 (m, 2H), 1.27-1.18 (m, 2H), 1.10 (t, J=7.0 Hz, 3H), 0.89 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.65; Observed: 495.22 [M−H].sup.−.

    Example A66: Synthesis of N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-440)

    [0814] ##STR01615##

    Step-1. Synthesis of 3,3-dimethyl-8-(2-nitrophenyl)-2-oxa-8-azaspiro[4.5]decane (A66.3)

    [0815] 1-fluoro-2-nitrobenzene (A66.1) (1.38 g, 9.78 mmol) was added to a stirred solution of 3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane hydrochloride (A66.2) (2 g, 9.78 mmol) and potassium carbonate (2.8 g, 20.2 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (chloroform/acetonitrile) to give 3,3-dimethyl-8-(2-nitrophenyl)-2-oxa-8-azaspiro[4.5]decane (A66.3) (1.45 g, 4.99 mmol, 95% purity, 48.4% yield).

    Step-2. Synthesis of 2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}aniline (A66.4)

    [0816] Iron powder (1.4 g, 25 mmol) and ammonium chloride (1.34 g, 25 mmol) were added at room temperature to a stirred solution of 3,3-dimethyl-8-(2-nitrophenyl)-2-oxa-8-azaspiro[4.5]decane (A66.3) (1.45 g, 4.99 mmol) in a mixture of ethanol (25 mL)/water (25 mL) and the resulting reaction mixture was refluxed for 6 h. After the reaction completion (TLC control) the mixture was filtered through silica gel and the filtrate was evaporated under reduced pressure. The residue was dissolved in water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure that afforded the 2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}aniline (A66.4) (0.55 g, 2.11 mmol, 95% purity, 40.4% yield).

    Step-3. Synthesis of N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-440)

    [0817] 2,3-dihydro-1H-indene-5-sulfonyl chloride (A66.5) (0.6 g, 2.76 mmol) was added to the mixture of 2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}aniline (A66.4) (0.718 g, 2.76 mmol) and pyridine (0.218 g, 2.76 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture was refluxed for 4 h and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded the N4-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-440). Yield: 129.3 mg, 8.71%; Appearance: Brown solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.12 (s, 1H), 7.95 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.55 (d, J=7.9 Hz, 1H), 7.07 (q, J=11.3, 9.4 Hz, 3H), 3.67 (s, 2H), 2.68 (s, 6H), 2.44 (s, 4H), 1.66 (s, 6H), 1.26 (s, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.5S.sub.2: 507.67; Observed: 508.2[M+H].sup.+.

    Example A67: Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-544)

    [0818] ##STR01616##

    Step-1. Synthesis of (2R,6S)-2,6-dimethyl-4-{[1-(2-nitrophenyl)piperidin-4-yl]methyl}morpholine (A67.3)

    [0819] 1-fluoro-2-nitrobenzene (A67.1) (0.942 g, 6.66 mmol) was added to a stirred solution of (2R,6S)-2,6-dimethyl-4-[(piperidin-4-yl)methyl]morpholine (A67.2) (1.4 g, 6.6 mmol) and dipotassium carbonate (1.1 g, 8.03 mmol) in dry DMF (30 mL). The mixture was stirred until the reaction completion (TLC control) at 60° C. Then, it was cooled to room temperature, poured in water (30 mL) and extracted with ethyl acetate (25 mL×3). The organic layer was separated, washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (2R,6S)-2,6-dimethyl-4-{[1-(2-nitrophenyl)piperidin-4-yl]methyl}morpholine as an orange solid (A67.3) (1.9 g, 5.69 mmol, 95% purity, 81% yield).

    Step-2. Synthesis of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)aniline (A67.4)

    [0820] (2R,6S)-2,6-dimethyl-4-{[1-(2-nitrophenyl)piperidin-4-yl]methyl}morpholine (A67.3) (1.9 g, 5.69 mmol) was dissolved in methanol (100 mL). Pd/C (10 percent, 0.19 g) was added to the solution and then the black suspension was degassed three times and filled with H.sub.2 (g). The suspension was shaken at room temperature for 3 h, filtered, the solids were washed with MeOH (50 mL) and combined filtrates were concentrated under reduced pressure to afford 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)aniline (A67.4) as beige oil (1.65 g, 5.43 mmol, 95% purity, 90.6% yield).

    Step-3. Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-544)

    [0821] Pyridine (0.155 g, 1.96 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A67.5) (0.408 g, 1.44 mmol) were added to a solution of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)aniline (A67.4) (0.4 g, 1.31 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture has been filtered through SiO.sub.2, the filtrate was evaporated and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-544). Yield: 218.2 mg, 28.7%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (s, 1H), 8.00 (dd, J=8.4, 2.6 Hz, 2H), 7.95-7.88 (m, 2H), 7.27 (d, J=8.3 Hz, 1H), 7.11 (s, 2H), 7.06 (s, 1H), 3.52 (d, J=8.9 Hz, 2H), 2.69 (d, J=11.0 Hz, 2H), 2.62 (d, J=2.6 Hz, 6H), 2.54 (d, J=2.5 Hz, 2H), 2.42 (t, J=11.3 Hz, 2H), 2.14-2.06 (m, 2H), 1.57 (q, J=11.6, 10.1 Hz, 5H), 1.14 (d, J=12.0 Hz, 2H), 1.04 (dd, J=6.3, 2.5 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.38N.sub.4O.sub.5S.sub.2: 550.73; Observed: 551.2[M+H].sup.+.

    [0822] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00025 Compound No Structure Analytical Data A-756 [01617]embedded image Yield: 352 mg, 71%; Appearance: Brown oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8 7.30 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 4.1 Hz, 2H), 7.08 (s, 1H), 4.10 (d, J = 5.3 Hz, 1H), 3.54 (d, J = 8.2 Hz, 2H), 3.16 (d, J = 5.0 Hz, 2H), 2.68 (t, J = 13.9 Hz, 5H), 2.58 (s, 3H), 2.31 (s, 3H), 2.12 (d, J = 6.9 Hz, 2H), 1.67 (d, J = 12.0 Hz, 2H), 1.56 (t, J = 10.5 Hz, 3H), 1.25- 1.13 (m, 2H), 1.04 (d, J = 6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.34N.sub.4O.sub.3S.sub.2: 478.67; Observed: 479.1 [M + H].sup.+. A-757 [01618]embedded image Yield: 432.7 mg, 57.4%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.35 (s, 1H), 8.00-7.90 (m, 4H), 7.12 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 3.52 (t, J = 4.5 Hz, 4H), 2.62 (s, 6H), 2.41 (s, 4H), 2.23 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.25N.sub.3O.sub.5S.sub.2: 439.55; Observed: 440.2 [M + H].sup.+. A-788 [01619]embedded image Yield: 28.2 mg, 12.4%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03-7.96 (m, 2H), 7.91-7.80 (m, 3H), 7.37-7.32 (m, 1H), 7.24 (s, 1H), 3.70 (t, J = 8.5 Hz, 2H), 3.50 (s, 1H), 3.03 (t, J = 12.0 Hz, 2H), 2.72 (s, 8H), 2.63 (s, 2H), 2.47 (d, J = 12.1 Hz, 2H), 2.24 (d, J = 7.3 Hz, 2H), 1.87 (d, J = 12.9 Hz, 2H), 1.73 (t, J = 10.7 Hz, 3H), 1.24 (d, J = 12.1 Hz, 2H), 1.19 (d, J = 6.2 Hz, 6H); HPLC purity: 96.07; LCMS Calculated for C.sub.27H.sub.37F.sub.3N.sub.4O.sub.5S.sub.2: 618.73; Observed: 619.4 [M + H].sup.+. A-792 [01620]embedded image Yield: 87.8 mg, 12.6%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 8.00 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.55 (s, 1H), 7.18 (s, 2H), 6.96 (s, 1H), 3.15 (t, J = 6.9 Hz, 2H), 2.84 (t, J = 11.7 Hz, 2H), 2.37 (s, 2H), 1.97- 1.80 (m, 4H), 1.24 (d, J = 12.0 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27FN.sub.4O.sub.5S.sub.2: 510.6; Observed: 511.0 [M + H].sup.+. A-796 [01621]embedded image Yield: 78.2 mg, 7.27%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 9.35 (s, 1H), 7.95 (q, J = 8.3 Hz, 5H), 7.25-7.14 (m, 2H), 7.04-6.93 (m, 1H), 2.69 (s, 2H), 2.61 (s, 6H), 2.54 (s, 2H), 2.18 (t, J = 7.9 Hz, 2H), 1.83 (t, J = 7.9 Hz, 2H), 1.66 (s, 2H), 1.55 (s, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.27FN.sub.4O.sub.5S.sub.2: 510.6; Observed: 511.0 [M + H].sup.+. A-795 [01622]embedded image Yield: 46.2 mg, 8.67%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.30 (s, 1H), 8.00-7.87 (m, 4H), 7.34-7.24 (m, 2H), 7.23-7.14 (m, 1H), 6.98 (dd, J = 12.3, 8.2 Hz, 1H), 2.82 (s, 2H), 2.60 (t, J = 2.1 Hz, 6H), 2.11 (s, 2H), 1.96 (d, J = 13.0 Hz, 2H), 1.79 (t, J = 2.4 Hz, 3H), 1.56 (d, J = 11.8 Hz, 2H), 1.33-1.19 (m, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.29FN.sub.4O.sub.5S.sub.2: 512.62; Observed: 513.0 [M + H].sup.+.

    Example A68: Synthesis of 4-(2-{[2-(4-benzylpiperazin-1-yl)phenyl]amino}propan-2-yl)-N,N-dimethylbenzene-1-sulfonamide (A-733)

    [0823] ##STR01623## ##STR01624##

    Step-1. Synthesis of 4-(2-aminopropan-2-yl)-N,N-dimethylbenzenesulfonamide (A68.2)

    [0824] 3 M methylmagnesium bromide (0.417 g, 3.49 mmol) solution in ether (139 mL) in ether was added dropwise to a solution of the 4-cyano-N,N-dimethylbenzenesulfonamide (A68.1) (25 g, 118 mmol) in THE (500 mL), the reaction mixture was stirred for 30 minutes, and tetrakis(propan-2-yloxy)titanium (36.6 g, 129 mmol) was added. The mixture was heated for 12 h keeping temperature at 60° C., cooled to room temperature and a 10% NaOH aqueous solution (400 mL) was then added slowly at 0° C. The reaction mixture was stirred for 30 minutes at room temperature and diluted with 5% Na.sub.2CO.sub.3 aqueous solution (400 mL). The product was extracted with ethyl acetate (100 mL×3). The combined ethyl acetate layers were concentrated under reduced pressure. The residue was subjected to flash chromatography (MTBE/methanol) to give 4-(2-aminopropan-2-yl)-N,N-dimethylbenzenesulfonamide (A68.1) as a white solid (6.42 g, 26.4 mmol, 95% purity, 21.3% yield).

    Step-2. Synthesis of give N,N-dimethyl-4-(2-((2-nitrophenyl)amino)propan-2-yl)benzenesulfonamide (A68.4)

    [0825] 1-fluoro-2-nitrobenzene (A68.3) (3.72 g, 26.4 mmol) was added to a stirred solution of 4-(2-aminopropan-2-yl)-N,N-dimethylbenzenesulfonamide (A68.2) (6.42 g, 26.4 mmol) and potassium carbonate in dry NMP (20 mL). The mixture was stirred at 80° C. for 12 h. Then, it was cooled to room temperature, poured in water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (hexane/MTBE) to give N,N-dimethyl-4-(2-((2-nitrophenyl)amino)propan-2-yl)benzenesulfonamide as an orange oil (A68.4) (0.754 g, 2.07 mmol, 95% purity, 7.46% yield).

    Step-3. Synthesis of 4-{2-[(2-aminophenyl)amino]propan-2-yl}-N,N-dimethylbenzene-1-sulfonamide (A68.5)

    [0826] Iron powder (0.5 g, 8.95 mmol) was added at room temperature to a stirred solution of N,N-dimethyl-4-(2-((2-nitrophenyl)amino)propan-2-yl)benzenesulfonamide (A68.4) (0.754 g, 2.07 mmol) in acetic acid (5 mL) and the resulting reaction mixture was stirred for 12 h at room temperature. After the reaction completion (TLC control) the mixture was filtered through silica gel and the filtrate was evaporated. The residue was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure that afforded 4-{2-[(2-aminophenyl)amino]propan-2-yl}-N,N-dimethylbenzene-1-sulfonamide (A68.5) (0.6 g, 1.79 mmol, 90.84% purity, 78.9% yield) that was used in the next step without further purification.

    Step-4. Synthesis of 4-(2-{[2-(4-benzylpiperazin-1-yl)phenyl]amino}propan-2-yl)-N,N-dimethylbenzene-1-sulfonamide (A-733)

    [0827] A mixture of 4-(2-((2-aminophenyl)amino)propan-2-yl)-N,N-dimethylbenzenesulfonamide (A68.5) (0.5 g, 1.49 mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (A68.6) (0.48 g, 1.78 mmol) and triethylamine (0.527 g, 5.21 mmol) in acetonitrile (5 mL) was refluxed for 12 h. Then, it was cooled to room temperature and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 4-(2-{[2-(4-benzylpiperazin-1-yl)phenyl]amino}propan-2-yl)-N,N-dimethylbenzene-1-sulfonamide (A-733). Yield: 96.5 mg, 12.4%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.67 (s, 4H), 7.36-7.27 (m, 4H), 7.24 (tt, J=5.7, 2.6 Hz, 1H), 6.98 (dd, J=7.7, 1.4 Hz, 1H), 6.60 (td, J=7.7, 1.4 Hz, 1H), 6.47 (td, J=7.5, 1.3 Hz, 1H), 5.75 (dd, J=8.1, 1.3 Hz, 1H), 5.31 (s, 1H), 3.53 (s, 2H), 2.83 (s, 4H), 2.56 (s, 6H), 1.60 (s, 6H); HPLC purity: 96.62%; LCMS Calculated for C.sub.28H.sub.36N.sub.4O.sub.2S: 492.68; Observed: 493.2[M+H].sup.+.

    Example A69: Synthesis of N4-2-[4-(methoxymethyl)-4-(trifluoromethyl)piperidin-1-yl]phenyl-N1,N1-dimethylbenzene-1,4-disulfonamide (A-777)

    [0828] ##STR01625## ##STR01626##

    Step-1. Synthesis of tert-butyl 4-(hydroxymethyl)-4-(trifluoromethyl)piperidine-1-carboxylate (A69.2)

    [0829] Triethylamine (3.46 g, 34.1 mmol, 4.77 mL) was added to a suspension of [4-(trifluoromethyl)piperidin-4-yl]methanol hydrochloride (A69.1) (3.0 g, 13.6 mmol) in dichloromethane (50 mL). Then di-tert-butyl dicarbonate (3.28 g, 15.00 mmol, 3.46 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 48 hours, after washed with 1 M HCl aq. solution (30 mL), aq. potassium carbonate solution (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give tert-butyl 4-(hydroxymethyl)-4-(trifluoromethyl)piperidine-1-carboxylate (A69.2) (3.3 g, 11.6 mmol, 95% yield, 81.2% yield).

    Step-2. Synthesis of tert-butyl 4-(methoxymethyl)-4-(trifluoromethyl)piperidine-1-carboxylate (A69.3)

    [0830] tert-butyl 4-(methoxymethyl)-4-(trifluoromethyl)piperidine-1-carboxylate (A69.2) (1.0 g, 3.52 mmol) was added at 0° C. to a suspension of sodium hydride (0.168 g, 4.16 mmol) in THE (30 mL). After stirring for 30 min iodomethane (1.25 g, 8.80 mmol) was added at the same temperature. The reaction mixture was stirred at room temperature overnight, diluted with NH.sub.4Cl sat. aq. solution (25 mL). The product was extracted with ethyl acetate (20 mL×3), combined ethyl acetate layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to give tert-butyl 4-(methoxymethyl)-4-(trifluoromethyl)piperidine-1-carboxylate (A69.3) (1.06 g, 3.51 mmol, 97.8% purity, 99% yield).

    Step-3. Synthesis of 4-(methoxymethyl)-4-(trifluoromethyl)piperidine hydrochloride (A69.4)

    [0831] 2 M HCl solution in dioxane (10 mL) was added to tert-butyl 4-(methoxymethyl)-4-(trifluoromethyl)piperidine-1-carboxylate (A69.3) (1.07 g, 3.6 mmol) solution in dioxane (30 mL). The reaction mixture was stirred at room temperature overnight and then evaporated under reduced pressure to dryness. Crude material was crystalized from MTBE to give 4-(methoxymethyl)-4-(trifluoromethyl)piperidine hydrochloride (A69.4) (0.560 g, 2.39 mmol, 99.75% purity, 66.5% yield).

    Step-4. Synthesis of 4-(methoxymethyl)-1-(2-nitrophenyl)-4-(trifluoromethyl)piperidine (A69.6)

    [0832] 4-(methoxymethyl)-4-(trifluoromethyl)piperidine hydrochloride (A69.4) (0.56 g, 2.39 mmol), 1-fluoro-2-nitrobenzene (A69.5) (0.337 g, 2.39 mmol) and potassium carbonate (0.825 g, 5.97 mmol) were mixed in DMF (30 mL) and heated at 80° C. overnight. After reaction completion (TLC control), the reaction mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (20 mL×3). Combined ethyl acetate layers were washed with water (10 mL×7), dried over sodium sulfate and evaporated to give 4-(methoxymethyl)-1-(2-nitrophenyl)-4-(trifluoromethyl)piperidine (A69.6) (0.67 g, 2.1 mmol, 82.5% purity, 72.6% yield) that was used in next step without further purification.

    Step-5. Synthesis of 2-[4-(methoxymethyl)-4-(trifluoromethyl)piperidin-1-yl]aniline (A69.7)

    [0833] 4-(Methoxymethyl)-1-(2-nitrophenyl)-4-(trifluoromethyl)piperidine (A69.6) (0.67 g, 2.1 mmol) was dissolved in methanol (20 mL) and treated with 10% Pd/C (0.07 g). The resulting mixture was hydrogenated at room temperature until the reaction was completed (LCMS control). The catalyst was filtered off and the filtrate was evaporated to afford 2-[4-(methoxymethyl)-4-(trifluoromethyl)piperidin-1-yl]aniline (A69.7) (0.6 g, 2.08 mmol, 100% purity, 99.1% yield).

    Step-6. Synthesis of N4-2-[4-(methoxymethyl)-4-(trifluoromethyl)piperidin-1-yl]phenyl-N1,N1-dimethylbenzene-1,4-disulfonamide (A-777)

    [0834] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A69.8) (0.283 g, 0.998 mmol) was added to a solution of 2-[4-(methoxymethyl)-4-(trifluoromethyl)piperidin-1-yl]aniline (A69.7) (0.262 g, 0.908 mmol) and pyridine (0.107 g, 1.36 mmol) in acetonitrile (10 mL) in one portion at 0° C. The reaction mixture was stirred at room temperature overnight, after evaporated under reduce pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) to give N4-2-[4-(methoxymethyl)-4-(trifluoromethyl)piperidin-1-yl]phenyl-N1,N1-dimethylbenzene-1,4-disulfonamide (A-777). Yield: 94.3 mg, 18.4%; Appearance: Violet solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H), 7.97-7.88 (m, 4H), 7.26 (dd, J=8.0, 1.6 Hz, 1H), 7.23-7.18 (m, 1H), 7.15-7.10 (m, 1H), 7.06 (t, J=7.6 Hz, 1H), 3.54 (s, 2H), 3.27 (s, 3H), 2.64 (d, J=12.6 Hz, 2H), 2.60 (s, 6H), 2.40 (d, J=12.1 Hz, 2H), 1.80 (td, J=12.6, 4.3 Hz, 2H), 1.55 (d, J=13.2 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.28F.sub.3N.sub.3O.sub.5S.sub.2: 535.6; Observed: 536.2[M+H].sup.+.

    Example A70: Synthesis of N4-(2-{4-fluoro-4-[(trifluoromethoxy)methyl]piperidin-1-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-798)

    [0835] ##STR01627## ##STR01628##

    Step-1. Synthesis of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (A70.2)

    [0836] Di-tert-butyl dicarbonate (4.23 g, 19.4 mmol) was added to a stirred solution of (4-fluoropiperidin-4-yl)methanol hydrochloride (A70.1) (3.15 g, 18.5 mmol) and triethylamine (3.74 g, 37.0 mmol) in methanol (50 mL). The mixture was stirred at room temperature until the reaction completion (TLC control, overnight) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (50 mL), this solution was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (A70.2) (4 g, 17.1 mmol, 95% purity, 88.1% yield).

    Step-2. Synthesis of tert-butyl 4-fluoro-4-[(trifluoromethoxy)methyl]piperidine-1-carboxylate (A70.3)

    [0837] Tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (A70.2) (0.4 g, 1.71 mmol), AgOTf (0.878 g, 3.42 mmol), selectfluor (0.906 g, 2.56 mmol) and KF (0.298 g, 5.13 mmol) were dissolved in ethyl acetate (10 mL) under nitrogen atmosphere, then 2-fluoropyridine (0.332 g, 3.42 mmol) was added, followed by trimethyl(trifluoromethyl)silane (0.486 g, 3.42 mmol) addition in a dropwise manner for 30 min. After, the mixture was stirred at room temperature for 30 h. Then NaHCO.sub.3 sat. aq. solution (40 mL) was added dropwise to reaction mixture and it was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl 4-fluoro-4-[(trifluoromethoxy)methyl]piperidine-1-carboxylate (A70.3) (0.4 g, 1.32 mmol, 85% purity, 66.0% yield) that was used in next step without further purification.

    Step-3. Synthesis of 4-fluoro-4-[(trifluoromethoxy)methyl]piperidine Hydrochloride (A70.4)

    [0838] Tert-butyl 4-fluoro-4-[(trifluoromethoxy)methyl]piperidine-1-carboxylate (A70.3) (0.4 g, 1.32 mmol) was dissolved in 1 M HCl solution in methanol (10 mL). The reaction mixture was stirred for 1 h at room temperature and evaporated under reduced pressure. The product was treated with MTBE (10 mL), formed precipitate was filtered off, dried on air to give 4-fluoro-4-[(trifluoromethoxy)methyl]piperidine hydrochloride (A70.4) (0.317 g, 1.33 mmol, 90% purity, 99.7% yield).

    Step-4. Synthesis of 4-fluoro-1-(2-nitrophenyl)-4-[(trifluoromethoxy)methyl]piperidine (A70.6)

    [0839] 1-fluoro-2-nitrobenzene (0.206 g, 1.46 mmol) was added to a stirred solution of 4-fluoro-4-[(trifluoromethoxy)methyl]piperidine hydrochloride (0.317 g, 1.33 mmol) and potassium carbonate (0.458 g, 3.32 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 4-fluoro-1-(2-nitrophenyl)-4-[(trifluoromethoxy)methyl]piperidine (0.15 g, 0.465 mmol, 100% purity, 35% yield).

    Step-5. Synthesis of 2-{4-fluoro-4-[(trifluoromethoxy)methyl]piperidin-1-yl}aniline (A70.7)

    [0840] 4-fluoro-1-(2-nitrophenyl)-4-[(trifluoromethoxy)methyl]piperidine (A70.6) (0.15 g, 0.465 mmol) was dissolved in methanol (10 mL) and treated with 5% Pd/C (0.05 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated under reduced pressure to afford 2-{4-fluoro-4-[(trifluoromethoxy)methyl]piperidin-1-yl}aniline (A70.7) (0.12 g, 0.410 mmol, 98% purity, 86.6% yield).

    Step-6. Synthesis of N4-(2-{4-fluoro-4-[(trifluoromethoxy)methyl]piperidin-1-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-798)

    [0841] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A70.8) (0.122 g, 0.430 mmol) was added to an ice-cooled solution of 2-{4-fluoro-4-[(trifluoromethoxy)methyl]piperidin-1-yl}aniline (A70.7) (0.12 g, 0.410 mmol) and pyridine (0.0972 g, 1.232 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and stir until completion (overnight, NMR control). After the reaction mixture was diluted with water (10 mL), the organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile, ammonia) to give N4-(2-{4-fluoro-4-[(trifluoromethoxy)methyl]piperidin-1-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-798). Yield: 58.3 mg, 25%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.28 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.30 (dd, J=7.8, 1.6 Hz, 1H), 7.16 (dd, J=7.8, 1.6 Hz, 1H), 7.08 (dtd, J=15.2, 7.6, 1.6 Hz, 2H), 4.20 (d, J=21.4 Hz, 2H), 2.65-2.60 (m, 2H), 2.59 (s, 6H), 2.39 (dd, J=10.8, 5.0 Hz, 2H), 1.86-1.81 (m, 1H), 1.79-1.70 (m, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.37F.sub.4N.sub.3O.sub.5S.sub.2: 539.56; Observed: 540.2[M+H].sup.+.

    [0842] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00026 Compound No. Structure Analytical Data A-784 [01629]embedded image Yield: 10.4 mg, 10.6%; Appearance: Beige solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.99 (dt, J = 8.5, 2.0 Hz, 2H), 7.84 (dt, J = 8.5, 2.0 Hz, 2H), 7.59 (dd, J = 7.9, 1.7 Hz, 1H), 7.19 − 7.02 (m, 3H), 3.77 (d, J = 1.7 Hz, 2H), 2.72 (q, J = 1.3 Hz, 6H), 2.66 − 2.58 (m, 2H), 2.43 (d, J = 12.0 Hz, 2H), 1.65 (t, J = 11.9 Hz, 2H), 1.49 (d, J = 13.8 Hz, 2H), 1.10 (d, J = 1.6 Hz, 3H). HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.28F.sub.3N.sub.3O.sub.5S.sub.2: 535.6; Observed: 536.2[M + H].sup.+.

    Example A71: Synthesis of N1,N1-dimethyl-N4-(2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1-yl}phenyl)benzene-1,4-disulfonamide (A797)

    [0843] ##STR01630##

    Step-1. Synthesis of 1-(2-nitrophenyl)-4-[(1,1,2-trifluoroethoxy)methyl]piperidine (A71.3)

    [0844] 1-fluoro-2-nitrobenzene (0.602 g, 4.27 mmol) was added to a stirred solution of 4-[(1,1,2-trifluoroethoxy)methyl]piperidine hydrochloride (1 g, 4.27 mmol) and potassium carbonate (1.46 g, 10.6 mmol) in dry DMF (20 mL). The reaction mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was separated, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude 1-(2-nitrophenyl)-4-[(1,1,2-trifluoroethoxy)methyl]piperidine (0.8 g, 2.51 mmol, 90% purity, 53.3% yield) that was used in the next step without further purification.

    Step-2. Synthesis of 2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1-yl}aniline (A71.4)

    [0845] 10% Pd/C (0.05 g) was added to a stirred solution of 1-(2-nitrophenyl)-4-[(1,1,2-trifluoroethoxy)methyl]piperidine (A71.3) (0.8 g, 2.51 mmol) in methanol (20 mL). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated under reduced pressure to afford 2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1-yl}aniline (A71.4) (0.5 g, 1.73 mmol, 90% purity, 62.2% yield) which was used in the next step without further purification.

    Step-3. Synthesis of N1,N1-dimethyl-N4-(2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1-yl}phenyl)benzene-1,4-disulfonamide (A-797)

    [0846] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A71.5) (0.49 g, 1.73 mmol) was added to the mixture of 2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1-yl}aniline (A71.4) (0.5 g, 1.73 mmol) and pyridine (0.204 g, 2.59 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture was stirred overnight and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N1,N1-dimethyl-N4-(2-{4-[(1,1,2-trifluoroethoxy)methyl]piperidin-1-yl}phenyl)benzene-1,4-disulfonamide (A-797). Yield: 152.3 mg, 15.5%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.99-7.93 (m, 2H), 7.91-7.83 (m, 2H), 7.27-7.23 (m, 1H), 7.10 (qd, J=8.0, 1.9 Hz, 2H), 7.04 (ddd, J=8.5, 6.6, 2.3 Hz, 1H), 4.74 (t, J=8.9 Hz, 1H), 4.66 (t, J=8.9 Hz, 1H), 3.78 (d, J=6.5 Hz, 2H), 2.59 (s, 6H), 2.52 (d, J=11.2 Hz, 2H), 2.45-2.40 (m, 2H), 1.59 (dd, J=27.1, 13.0 Hz, 3H), 1.30 (tt, J=12.1, 6.0 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.22H.sub.28F.sub.3N.sub.3O.sub.5S.sub.2: 535.6; Observed: 536.0[M+H].sup.+.

    Example A72: Synthesis of 3-fluoro-4-methanesulfonyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}benzene-1-sulfonamide (A-731)

    [0847] ##STR01631##

    [0848] 3-fluoro-4-methanesulfonylbenzene-1-sulfonyl chloride (A72.2) (0.5 g, 1.83 mmol) was added to the mixture of 2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (A72.1) (0.428 g, 1.83 mmol) and pyridine (A72.3) (0.216 g, 2.74 mmol) in dry THF (20 ml). The reaction mixture was stirred overnight and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded the 3-fluoro-4-methanesulfonyl-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}benzene-1-sulfonamide (A-731). Yield: 98.6 mg, 10.8%; Appearance: White solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 8.03 (dd, J=8.1, 6.8 Hz, 1H), 7.90 (dd, J=9.4, 1.6 Hz, 1H), 7.81 (dd, J=8.2, 1.6 Hz, 1H), 7.17 (ddd, J=7.9, 6.3, 1.5 Hz, 2H), 7.11 (td, J=7.6, 1.5 Hz, 1H), 7.01 (td, J=7.6, 1.4 Hz, 1H), 3.34 (s, 3H), 3.25 (s, 3H), 3.08 (s, 2H), 2.54 (dtd, J=15.6, 11.0, 10.2, 6.2 Hz, 4H), 1.47 (ddd, J=13.2, 9.0, 4.2 Hz, 2H), 1.23 (dt, J=13.1, 4.3 Hz, 2H), 0.90 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.21H.sub.27FN.sub.2O.sub.5S.sub.2: 470.58; Observed: 471.2[M+H].sup.+.

    [0849] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00027 Compound No. Structure Analytical Data A-742 [01632]embedded image Yield: 101.6 mg, 12.5%; Appearance: Blue solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.41 (s, 1H), 7.54 − 7.48 (m, 2H), 7.38 (dd, J = 7.9, 1.6 Hz, 1H), 7.14 (dd, J = 7.7, 1.6 Hz, 1H), 7.07 − 6.98 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 4.26 (s, 2H), 3.54 (s, 2H), 2.38 (t, J = 5.5 Hz, 4H), 1.63 − 1.50 (m, 6H), 1.18 (d, J = 17.6 Hz, 12H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.34N.sub.2O.sub.4S: 470.62; Observed: 471.2[M + H].sup.+. A-732 [01633]embedded image Yield: 221.6 mg, 46.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.14 (s, 1H), 7.92 − 7.82 (m, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.45 − 7.36 (m, 2H), 7.36 − 7.30 (m, 2H), 7.20 − 7.06 (m, 3H), 2.81 (td, J = 11.8, 10.2, 5.8 Hz, 1H), 2.64 − 2.56 (m, 2H), 2.53 (s, 2H), 1.80 − 1.69 (m, 2H), 1.63 − 1.53 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.21ClF.sub.4N.sub.4O.sub.2S: 552.97; Observed: 553.2 [M + H].sup.+. A-759 [01634]embedded image Yield: 235.7 mg, 45.9%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.67 (s, 1H), 7.66 (s, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.16 (q, J = 7.6 Hz, 1H), 6.94 − 6.85 (m, 1H), 3.53 (t, J = 8.0 Hz, 2H), 2.90 − 2.67 (m, 8H), 2.32 (d, J = 10.8 Hz, 2H), 2.14 (d, J = 6.9 Hz, 2H), 2.01 (q, J = 7.5 Hz, 2H), 1.66 − 1.45 (m, 5H), 1.24 (d, J = 12.1 Hz, 2H), 1.04 (d, J = 6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.36FN.sub.3O.sub.3S: 501.66; Observed: 502.2[M + H].sup.+. A-758 [01635]embedded image Yield: 313 mg, 57.3%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.39 (s, 1H), 8.21 − 8.15 (m, 2H), 8.14 − 8.06 (m, 2H), 7.53 − 7.35 (m, 1H), 7.27 − 7.17 (m, 2H), 7.04 − 6.93 (m, 1H), 3.59 − 3.49 (m, 2H), 2.81 − 2.67 (m, 4H), 2.29 (s, 2H), 2.09 (d, J = 6.5 Hz, 2H), 1.62 − 1.44 (m, 5H), 1.14 (d, J = 12.1 Hz, 2H), 1.04 (dd, J = 6.3, 4.1 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32F.sub.3N.sub.3O.sub.5S.sub.2: 575,.6; Observed: 576.2[M + H].sup.+. A-771 [01636]embedded image Yield: 131.9 mg, 28.2%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.67 (s, 1H), 7.64 − 7.59 (m, 2H), 7.35 − 7.29 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H), 7.13 (td, J = 8.3, 5.8 Hz, 1H), 6.86 (ddd, J = 12.1, 8.4, 1.3 Hz, 1H), 3.51 (dqd, J = 12.4, 6.1, 1.8 Hz, 2H), 2.79 (t, J = 11.4 Hz, 2H), 2.68 (d, J = 10.8 Hz, 2H), 2.34 (d, J = 11.1 Hz, 2H), 2.30 (s, 3H), 2.11 (d, J = 7.2 Hz, 2H), 1.61 (d, J = 12.5 Hz, 2H), 1.52 (t, J = 10.6 Hz, 3H), 1.22 (q, J = 10.6 Hz, 2H), 1.01 (d, J = 6.3 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.34FN.sub.3O.sub.3S: 475.62; Observed: 476.2[M + H].sup.+. A-767 [01637]embedded image Yield: 45.4 mg, 9.26%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.00 (s, 1H), 7.40 − 7.26 (m, 5H), 7.10 − 7.05 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.83 (dd, J = 11.8, 8.3 Hz, 1H), 3.52 − 3.47 (m, 2H), 2.86 (t, J = 11.5 Hz, 2H), 2.65 (d, J = 10.9 Hz, 2H), 2.61 (d, J = 11.2 Hz, 2H), 2.02 (d, J = 7.1 Hz, 2H), 1.72 (q, J = 5.0 Hz, 2H), 1.61 (d, J = 13.0 Hz, 2H), 1.55 (s, 1H), 1.50 (t, J = 10.6 Hz, 2H), 1.33 (q, J = 5.0 Hz, 2H), 1.00 (d, J = 6.3 Hz, 6H), 0.85 (d, J = 11.8 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.3FN.sub.3O.sub.3S: 501.66; Observed: 502.2[M + H].sup.+. A-766 [01638]embedded image Yield: 302.5 mg, 57.8%; Appearance: White solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.98 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.25 − 7.07 (m, 3H), 6.92 (ddd, J = 12.0, 8.3, 1.5 Hz, 1H), 3.51 (dtd, J = 12.2, 6.2, 2.1 Hz, 2H), 2.78 (t, J = 11.4 Hz, 2H), 2.69 (d, J = 10.9 Hz, 2H), 2.31 (d, J = 11.0 Hz, 2H), 2.10 (d, J = 6.8 Hz, 2H), 1.54 (q, J = 11.9, 10.4 Hz, 5H), 1.22 (t, J = 11.7 Hz, 2H), 1.02 (d, J = 6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.32F.sub.3N.sub.3O.sub.3S: 511.6; Observed: 512.2[M + H].sup.+.

    Example A73: Synthesis of N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2-phenylethane-1-sulfonamide (A-743)

    [0850] ##STR01639##

    Step-1. Synthesis of (1Z)—N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2-fluoro-2-phenylethene-1-sulfonamide (A73.3)

    [0851] 2-fluoro-2-phenylethene-1-sulfonyl chloride (A73.2) (0.5 g, 2.26 mmol) was added to the mixture of 2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}aniline (A73.1) (0.588 g, 2.26 mmol) and pyridine (0.267 g, 3.38 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture was stirred overnight and evaporated under reduced pressure. The residue was subjected to HPLC purification (chloroform/ethylacetate) that afforded N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2-fluoro-2-phenylethene-1-sulfonamide (A73.3) (0.3 g, 0.674 mmol, 95% purity, 28.5% yield).

    Step-2. Synthesis of N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2-phenylethane-1-sulfonamide (A-743)

    [0852] 10% Pd/C (0.007 g) was added at to a stirred solution of (1Z)—N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2-fluoro-2-phenylethene-1-sulfonamide (A73.3) (0.3 g, 0.674 mmol) in methanol (5 mL) and the reaction mixture was hydrogenated at 30 atm and room temperature. The reaction mixture was stirred overnight, filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}phenyl)-2-phenylethane-1-sulfonamide (A-743). Yield: 13.3 mg, 4.37%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.89 (s, 1H), 7.55 (dd, J=8.1, 1.5 Hz, 1H), 7.34-7.12 (m, 6H), 7.10 (dt, J=7.6, 1.7 Hz, 3H), 3.75 (s, 2H), 3.44-3.36 (m, 2H), 3.18-3.07 (m, 2H), 2.78 (d, J=6.1 Hz, 4H), 1.87-1.75 (m, 4H), 1.31 (s, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.2O.sub.3S: 428.6; Observed: 429.2[M+H].sup.+.

    Example A74: Synthesis of N4-{2-[4-(1-methoxyethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-741)

    [0853] ##STR01640## ##STR01641## ##STR01642##

    Step-1. Synthesis of tert-butyl 4-[methoxy(methyl)carbamoyl]-4-methylpiperidine-1-carboxylate (A74.3)

    [0854] A solution of 1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid (A74.1) (10 g, 41.1 mmol), methoxy(methyl)amine hydrochloride (A74.2) (4 g, 41.1 mmol), (3-{[(ethylimino)methylidene]amino}-propyl)dimethylamine hydrochloride (7.9 g, 41.2 mmol), 1H-1,2,3-benzotriazol-1-ol (5.55 g, 41.1 mmol) and ethylbis(propan-2-yl)amine (5.35 g, 41.3 mmol) in dry DMF (100 mL) was stirred at room temperature for 16 h and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-[methoxy(methyl)carbamoyl]-4-methylpiperidine-1-carboxylate (A74.3) (10.8 g, 37.7 mmol, 74.65% purity, 68.8% yield) that was used in next step without further purification.

    Step-2. Synthesis of tert-butyl 4-acetyl-4-methylpiperidine-1-carboxylate (A74.4)

    [0855] 3.2 M bromo(methyl)magnesium (4.86 g, 40.8 mmol) solution in 2-methyltetrahydrofuran (12.7 mL) was added to a stirred solution of tert-butyl 4-[methoxy(methyl)carbamoyl]-4-methylpiperidine-1-carboxylate (A74.3) (3.9 g, 13.6 mmol) in dry tetrahydrofuran (100 mL). The mixture was stirred at 50° C. for 16 h and quenched with NH.sub.4Cl sat. aq. solution (100 mL). The product was extracted with ethyl acetate (100 mL×2), combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl 4-acetyl-4-methylpiperidine-1-carboxylate (A74.4) (2.2 g, 9.11 mmol, 77% purity, 51.5% yield) that was used in next step without further purification.

    Step-3. Synthesis of tert-butyl 4-(1-hydroxyethyl)-4-methylpiperidine-1-carboxylate (A74.5)

    [0856] NaBH.sub.4 (0.25 g, 6.6 mmol) was added to a stirred solution of tert-butyl 4-acetyl-4-methylpiperidine-1-carboxylate (A74.4) (1 g, 4.14 mmol) in mixture of tetrahydrofuran/methanol=1/1 (20 mL). The mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), this solution was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl 4-(1-hydroxyethyl)-4-methylpiperidine-1-carboxylate (A74.5) (1 g, 4.1 mmol, 86.5% purity, 86.5% yield) that was used in the next step without further purification.

    Step-4. Synthesis of tert-butyl 4-(1-methoxyethyl)-4-methylpiperidine-1-carboxylate (A74.6)

    [0857] Sodium hydride (0.17 g, 60 w % in mineral oil, 4.25 mmol) was added to a solution of tert-butyl 4-(1-hydroxyethyl)-4-methylpiperidine-1-carboxylate (A74.5) (1 g, 4.1 mmol) in dry DMF (10 mL) and mixture was stirred for 0.5 h at 50° C. Then iodomethane (2.89 g, 20.4 mmol) was added dropwise and the mixture was stirred at 100° C. overnight. After, it was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give tert-butyl 4-(1-methoxyethyl)-4-methylpiperidine-1-carboxylate (A74.6) (1 g, 3.88 mmol, 50% purity, 47.6% yield) that was used in next step without further purification.

    Step-5. Synthesis of 4-(1-methoxyethyl)-4-methylpiperidine Hydrochloride (A74.7)

    [0858] Tert-butyl 4-(1-methoxyethyl)-4-methylpiperidine-1-carboxylate (A74.6) (1 g, 3.88 mmol) was added to HCl sat. solution in dioxane (30 mL) and the mixture was stirred at room temperature overnight. Then the solvent was evaporated under reduced pressure and the residue treated with ether (20 mL). Formed precipitate was filtered off, dried on air to give 4-(1-methoxyethyl)-4-methylpiperidine hydrochloride (A74.7) (0.75 g, 3.87 mmol, 38.6% purity, 38.4% yield) that was used in next step without further purification.

    Step-6. Synthesis of 4-(1-methoxyethyl)-4-methyl-1-(2-nitrophenyl)piperidine (A74.9)

    [0859] 1-fluoro-2-nitrobenzene (A74.8) (0.55 g, 3.89 mmol) was added to a stirred solution of crude 4-(1-methoxyethyl)-4-methylpiperidine hydrochloride (A74.7) (0.55 g, 3.89 mmol) and potassium carbonate (1.33 g, 9.67 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. for 5 h and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give 4-(1-methoxyethyl)-4-methyl-1-(2-nitrophenyl)piperidine (A74.9) (0.286 g, 1.02 mmol, 86% purity, 22.8% yield).

    Step-7. Synthesis of 2-[4-(1-methoxyethyl)-4-methylpiperidin-1-yl]aniline (A74.10)

    [0860] 4-(1-methoxyethyl)-4-methyl-1-(2-nitrophenyl)piperidine (A74.9) (0.286 g, 1.02 mmol) was dissolved in methanol (10 mL) and treated with 10% Pd/C (0.01 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give 2-[4-(1-methoxyethyl)-4-methylpiperidin-1-yl]aniline (A74.10) (0.25 g, 1 mmol, 88% purity, 86.9% yield) that was used in next step without further purification.

    Step-8. Synthesis of N4-{2-[4-(1-methoxyethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-741)

    [0861] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A74.11) (0.3 g, 1.05 mmol) was added to the mixture of 2-[4-(1-methoxyethyl)-4-methylpiperidin-1-yl]aniline (A74.10) (0.25 g, 1 mmol) and pyridine (0.237 g, 3 mmol) in dry tetrahydrofuran (5 mL). The reaction mixture was refluxed for 4 h, cooled to room temperature and evaporated under reduced pressure. The residue was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give N4-{2-[4-(1-methoxyethyl)-4-methylpiperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-741). Yield: 135.3 mg, 25.8%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.11 (s, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.2 Hz, 2H), 7.25 (d, J=7.8 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.12 (t, J=7.5 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 3.01-2.93 (m, 1H), 2.62 (s, 9H), 2.41 (d, J=13.0 Hz, 2H), 1.50 (d, J=10.5 Hz, 2H), 1.38 (d, J=13.3 Hz, 1H), 1.13 (d, J=13.2 Hz, 1H), 1.00 (d, J=6.2 Hz, 3H), 0.83 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.66; Observed: 496.2[M+H].sup.+.

    Example A75: Synthesis of 1-(3-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-744)

    [0862] ##STR01643## ##STR01644##

    Step-1. Synthesis of {3-[(methoxymethyl)sulfanyl]phenyl}methanol (A75.3)

    [0863] Bromo(methoxy)methane (A75.2) (9.79 g, 78.4 mmol) was added to a solution of (3-sulfanylphenyl)methanol (A75.1) (10 g, 71.3 mmol) and triethylamine (10.7 g, 106 mmol) in dichloromethane (150 mL) at −20° C. and the reaction mixture was stirred for 12 hours. After the solution was washed with 1 M hydrochloric acid aq. solution (150 mL), water (150 mL) and brine (150 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford {3-[(methoxymethyl)sulfanyl]phenyl}methanol (A75.3) (3 g, 16.2 mmol, 90% purity, 20.6% yield) that was used in next step without further purification.

    Step-2. Synthesis of 1-(chloromethyl)-3-[(methoxymethyl)sulfanyl]benzene (A75.4)

    [0864] Thionyl chloride (2.11 g, 17.8 mmol) was added dropwise to a solution of (3-((methoxymethyl)thio)phenyl)methanol (A75.3) (3 g, 16.2 mmol) and triethylamine (2.44 g, 24.2 mmol) in dichloromethane (50 mL) at −10° C. The mixture was stirred for 12 hours at room temperature, washed with 1 M hydrochloric acid aq. solution (50 mL), water (50 mL), sodium bicarbonate sat. aq. solution (50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 1-(chloromethyl)-3-[(methoxymethyl)sulfanyl]benzene (A75.4) (2 g, 9.86 mmol, 90% purity. 54.8% yield).

    Step-3. Synthesis of 1-(chloromethyl)-3-methoxymethanesulfonylbenzene (A75.5)

    [0865] Hexaammonium tris(dioxomolybdenumbis(olate))tetrakis(trioxomolybdenum) tetrahydrate (0.608 g, 0.492 mmol) and hydrogen peroxide (2.29 g, 23.6 mmol) were added to a solution of 1-(chloromethyl)-3-[(methoxymethyl)sulfanyl]benzene (A75.4) (2 g, 9.86 mmol) in methanol (50 mL) at 0° C. The solution was stirred overnight at room temperature and poured into brine (100 mL), the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 1-(chloromethyl)-3-methoxymethanesulfonylbenzene (A75.5) (0.9 g, 3.83 mmol, 95% purity, 37% yield).

    Step-4. Synthesis of sodium (3-methoxymethanesulfonylphenyl)methanesulfonate (A75.6)

    [0866] Sodium sulfite (2.88 g, 22.9 mmol) was added to a solution of 1-(chloromethyl)-3-((methoxymethyl)sulfonyl)benzene (A75.5) (0.9 g, 3.83 mmol) in 2-propanol (25 mL) and water (100 mL). The mixture was stirred at 100° C. until the reaction completion (TLC control) and concentrated after under the reduced pressure. The residue was extracted with hot methanol (100 mL), filtered and the filtrate was concentrated under the reduced pressure to give sodium (3-methoxymethanesulfonylphenyl)methanesulfonate (A75.6) (1 g, 3.3 mmol, 60% purity, 52.1% yield) that was used in next step without purification.

    Step-5. Synthesis of (3-methoxymethanesulfonylphenyl)methanesulfonyl chloride (A75.7)

    [0867] Oxalyl chloride (0.209 g, 1.65 mmol) was added dropwise to a suspension of sodium (3-methoxymethanesulfonylphenyl)methanesulfonate (A75.6) (0.25 g, 0.827 mmol) and DMF (1 drop) in tetrahydrofuran (50 mL) at −20° C. Mixture stirring was continued for an hour, the solution was filtered and the filtrate was evaporated under reduced pressure to afford (3-methoxymethanesulfonylphenyl)methanesulfonyl chloride (A75.7) (0.25 g, 0.836 mmol, 85% purity, 85.8% yield) that was used in next step without further purification.

    Step-6. Synthesis of 1-(3-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-744)

    [0868] (3-methoxymethanesulfonylphenyl)methanesulfonyl chloride (A75.7) (0.25 g, 0.836 mmol) was added to the mixture of 2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (A75.8) (0.195 g, 0.836 mmol) and pyridine (0.09 g, 1.13 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded the product 1-(3-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-744). Yield: 26 mg, 5.95%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.17 (s, 1H), 7.94-7.87 (m, 2H), 7.71-7.63 (m, 2H), 7.29 (dd, J=7.6, 1.7 Hz, 1H), 7.18 (dd, J=7.6, 1.9 Hz, 1H), 7.11-6.99 (m, 2H), 4.84 (s, 2H), 4.75 (s, 2H), 3.46 (d, J=1.2 Hz, 3H), 3.13 (s, 2H), 2.81-2.68 (m, 4H), 1.60 (dt, J=13.5, 6.5 Hz, 2H), 1.34 (d, J=12.8 Hz, 2H), 0.96 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.2O.sub.6S.sub.2: 496.64; Observed: 497.0[M+H].sup.+.

    Example A76: Synthesis of 1-(4-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-747)

    [0869] ##STR01645## ##STR01646## ##STR01647##

    Step-1. Synthesis of methyl 4-[(methoxymethyl)-sulfanyl]benzoate (A76.3)

    [0870] Bromo(methoxy)methane (A76.2) (8.16 g, 65.3 mmol) was added to a solution of methyl 4-mercaptobenzoate (A76.1) (10 g, 59.4 mmol) and triethylamine (9.01 g, 89.1 mmol) in dichloromethane (150 mL) at −20° C. and the reaction mixture was stirred for 12 hours. After the solution was washed with 1 M hydrochloric acid aq. solution (150 mL), water (150 mL) and brine (150 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure to afford methyl 4-[(methoxymethyl)-sulfanyl]benzoate (A76.3) (3 g, 14.1 mmol, 85% purity, 20.2% yield) that was used in next step without further purification.

    Step-2. Synthesis of {4-[(methoxymethyl)sulfanyl]phenyl}methanol (A76.4)

    [0871] A solution of methyl 4-((methoxymethyl)thio)benzoate (A76.3) (3 g, 14.1 mmol) in tetrahydrofuran (50 mL) was added dropwise at −5° C. to a suspension of lithium aluminum hydride (0.588 g, 15.5 mmol) in tetrahydrofuran (50 mL). After addition, the solution was warmed to room temperature and stirred for 12 hours. The solution was quenched with a mixture of water/tetrahydrofuran=1/1 (10 mL). The resulting mixture was filtered and filtrate evaporated under reduce pressure to give {4-[(methoxymethyl)sulfanyl]phenyl}methanol (A76.4) (2 g, 10.8 mmol, 85% purity, 65.6% yield) that was used in next step without further purification.

    Step-3. Synthesis of 1-(bromomethyl)-4-[(methoxymethyl)sulfanyl]benzene (A76.5)

    [0872] Triphenyl phosphine (2.83 g, 10.8 mmol) was added to a solution of tetrabromomethane (3.58 g, 10.8 mmol) in dichloromethane (50 mL) at −20° C. and the mixture was stirred for 20 minutes. (4-((methoxymethyl)sulfonyl)phenyl)methanol (A76.4) (2 g, 10.8 mmol) was added to the resulting solution and the reaction mixture was stirred for 12 h, diluted with hexane (150 mL), filtered and filtrate was evaporated under reduced pressure to give 1-(bromomethyl)-4-[(methoxymethyl)sulfanyl]benzene (A76.5) (2 g, 8.09 mmol, 85% purity, 63.9% yield) that was used in next step without further purification.

    Step-4. Synthesis of 1-(bromomethyl)-4-methoxymethanesulfonylbenzene (A76.6)

    [0873] Hexaammonium tris(dioxomolybdenumbis(olate))tetrakis(trioxomolybdenum) tetrahydrate (0.5 g, 0.404 mmol) and hydrogen peroxide (1.71 g, 17.7 mmol) were added to a solution of 1-(bromomethyl)-4-[(methoxymethyl)sulfanyl]benzene (A76.5) (2 g, 8.09 mmol) in methanol (50 mL). The solution was stirred overnight at room temperature and poured into brine (100 mL), the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 1-(bromomethyl)-4-methoxymethanesulfonylbenzene (A76.6) (1.1 g, 3.94 mmol, 80% purity, 39.1% yield) that was used in next step without further purification.

    Step-5. Synthesis of sodium (4-methoxymethanesulfonylphenyl)methanesulfonate (A76.7)

    [0874] Sodium sulfite (3 g, 23.8 mmol) was added to a solution of 1-(bromomethyl)-4-methoxymethanesulfonylbenzene (A76.6) (1 g, 3.58 mmol) in 2-propanol (25 mL) and water (100 mL). The mixture was stirred at 100° C. until the reaction completion (TLC control) and concentrated after under the reduced pressure. The residue was extracted with hot methanol (100 mL), filtered and the filtrate was concentrated under the reduced pressure to give sodium (4-methoxymethanesulfonylphenyl)methanesulfonate (A76.7) (1.2 g, 3.96 mmol, 60% purity, 66.6% yield) that was used in next step without further purification.

    Step-6. Synthesis of (4-methoxymethanesulfonylphenyl)methanesulfonyl chloride (A76.8)

    [0875] Oxalyl chloride (0.507 g, 4 mmol) was added dropwise to a suspension of sodium (4-methoxymethanesulfonylphenyl)methanesulfonate (A76.7) (1.2 g, 4 mmol) and DMF (1 drop) in tetrahydrofuran (10 mL) at −20° C. Mixture stirring was continued for an hour, the solution was filtered, formed precipitate was washed with tetrahydrofuran. Combined filtrates were evaporated under reduced pressure to give (4-methoxymethanesulfonylphenyl)methanesulfonyl chloride (A76.8) (0.3 g, 1 mmol, 90% purity, 22.6% yield).

    Step-7. Synthesis of 1-(4-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-747)

    [0876] (4-methoxymethanesulfonylphenyl)methanesulfonyl chloride (A76.8) (0.3 g, 1 mmol) was added to the mixture of 2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]aniline (0.234 g, 1 mmol) and pyridine (0.09 g, 1.13 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded the product 1-(4-methoxymethanesulfonylphenyl)-N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}methanesulfonamide (A-747). Yield: 19.4 mg, 3.7%; Appearance: Yellow oil; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.17 (s, 1H), 7.87-7.84 (m, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.27 (dd, J=7.8, 1.5 Hz, 1H), 7.17 (dd, J=7.9, 1.6 Hz, 1H), 7.05 (dtd, J=24.3, 7.6, 1.6 Hz, 2H), 4.79 (s, 4H), 3.48 (s, 3H), 3.24 (s, 3H), 3.10 (s, 2H), 2.70 (dt, J=9.0, 4.1 Hz, 4H), 1.56 (ddd, J=13.2, 8.7, 4.6 Hz, 2H), 1.31 (dt, J=13.4, 4.2 Hz, 2H), 0.93 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.32N.sub.2O.sub.6S.sub.2: 496.64; Observed: 497.2[M+H].sup.+.

    Example A77: Synthesis of N1,N1-dimethyl-N4-(2-((5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)benzene-1,4-disulfonamide (A-799)

    [0877] ##STR01648## ##STR01649## ##STR01650##

    Step-1. Synthesis of 1-tert-butyl 4-methyl (2R,4R)-2-methylpiperidine-1,4-dicarboxylate (A77.2)

    [0878] Di-tert-butyl dicarbonate (12.3 g, 56.7 mmol) was added to a stirred solution of methyl (2R,4R)-2-methylpiperidine-4-carboxylate hydrochloride (A77.1) (10 g, 51.6 mmol) and triethylamine (13.0 g, 129 mmol, 17.9 mL) in dry dichloromethane (250 mL). The mixture was stirred at 0° C. until the reaction completion (TLC control). Organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-tert-butyl 4-methyl (2R,4R)-2-methylpiperidine-1,4-dicarboxylate (A77.2) (13 g, 50.5 mmol, 95% purity, 93.1% yield).

    Step-2. Synthesis of 1-tert-butyl 4-methyl (2R)-2-methyl-4-(2-methylprop-2-en-1-yl)piperidine-1,4-dicarboxylate (A77.3)

    [0879] 2.5 M butyllithium (3.39 g, 53.0 mmol) solution in hexane (21.2 mL) was added to a diisopropylamine solution (5.61 g, 55.5 mmol) in THE (250 mL) at −78° C. and the mixture was stirred at this temperature for 1 h, followed by addition of 1-tert-butyl 4-methyl (2R,4R)-2-methylpiperidine-1,4-dicarboxylate (A77.2) (13 g, 50.5 mmol) in THE (50 mL). The reaction mixture was stirred at −78° C. for 1 h and then gradually warmed to −20° C. over 2 h. 3-bromo-2-methylprop-1-ene (7.49 g, 55.5 mmol) was added to the mixture at −20° C. and the mixture was allowed to warm to room temperature over 2 h. The reaction was quenched with NH.sub.4Cl sat. aq. solution (250 mL) and the product was extracted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL), brine (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/MTBE) to afford 1-tert-butyl 4-methyl (2R)-2-methyl-4-(2-methylprop-2-en-1-yl)piperidine-1,4-dicarboxylate as a colorless oil (A77.3) (10 g, 32.1 mmol, 95% purity, 60.5% yield).

    Step-3. Synthesis of tert-butyl (2R,4R)-4-(hydroxymethyl)-2-methyl-4-(2-methylprop-2-en-1-yl)piperidine-1-carboxylate (A77.4)

    [0880] 1 M DIBAL-H (13 g, 92.1 mmol) solution in toluene (92.1 mL) was added dropwise at −78° C. to a 1-tert-butyl 4-methyl (2R,4R)-2-methyl-4-(2-methylprop-2-en-1-yl)piperidine-1,4-dicarboxylate (A77.3) (9 g, 28.8 mmol) solution in dry tetrahydrofuran (150 mL) followed by stirring for 5 h. The mixture was warmed to room temperature, quenched with NH.sub.4Cl sat. aq. solution (250 mL) and the product was extracted with ethyl acetate (200 mL×3). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (2R,4R)-4-(hydroxymethyl)-2-methyl-4-(2-methylprop-2-en-1-yl)piperidine-1-carboxylate as pale yellow oil (A77.4) (4 g, 14.1 mmol, 95% purity, 46.5% yield).

    Step-4. Synthesis of tert-butyl (5R,7R)-3-(iodomethyl)-3,7-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (A77.5)

    [0881] 1-iodopyrrolidine-2,5-dione (4.11 g, 18.3 mmol) was added to a solution of tert-butyl (2R,4R)-4-(hydroxymethyl)-2-methyl-4-(2-methylprop-2-en-1-yl)piperidine-1-carboxylate (A77.4) (4 g, 14.1 mmol) in ethyl acetate (150 mL) at room temperature. The resulting mixture was stirred at room temperature overnight, quenched with Na.sub.2SO.sub.3 sat. aq. solution (50 mL), and diluted with water (100 mL). The product was extracted with ethyl acetate (200 mL×3), combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford tert-butyl (5R,7R)-3-(iodomethyl)-3,7-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (A77.5) (3.7 g, 9.03 mmol, 90% purity, 57.7% yield).

    Step-5. Synthesis of tert-butyl (5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (A77.6)

    [0882] Tert-butyl (5R,7R)-3-(iodomethyl)-3,7-dimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (A77.5) (3.7 g, 9.03 mmol) was dissolved in methanol (100 mL), triethylamine (1 g, 9.93 mmol, 1.37 mL) was added to this solution and the reaction mixture was treated with 10% Pd/C (0.37 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off, the filtrate was evaporated under reduced pressure. The residue was dissolved in MTBE (150 mL), the solution was washed with water (150 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford tert-butyl (5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (A77.6) (1.8 g, 6.35 mmol, 95% purity, 67% yield).

    Step-6. Synthesis of (5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-ium Chloride (A77.7)

    [0883] A solution of tert-butyl (5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (A77.6) (1.8 g, 6.35 mmol) in dioxane (10 mL) was added with sat. hydrochloric acid solution in dioxane (50 ml) at room temperature, the reaction mixture was stirred for 12 h at room temperature and evaporated to dryness. The residue was treated with MTBE (100 mL), formed precipitate was filtered off, dried on air to afford (5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-ium chloride (A77.7) (1.38 g, 6.27 mmol, 95% purity, 94.2% yield).

    Step-7. Synthesis of (5R,7R)-3,3,7-trimethyl-8-(2-nitrophenyl)-2-oxa-8-azaspiro[4.5]decane (A77.9)

    [0884] (5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-ium chloride (A77.7) (1.38 g, 6.27 mmol) was added to a stirred solution of 1-fluoro-2-nitrobenzene (A77.8) (884 mg, 6.27 mmol) and potassium carbonate (2.15 g mg, 15.6 mmol) in dry DMF (50 mL). The mixture was stirred at 90° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (150 mL), the organic layer was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (5R,7R)-3,3,7-trimethyl-8-(2-nitrophenyl)-2-oxa-8-azaspiro[4.5]decane (A77.9) (1.15 g, 3.77 mmol, 64% purity, 38.7% yield) that was used in next step without further purification.

    Step-8. Synthesis of 2-[(5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl]aniline (A77.10)

    [0885] (5R,7R)-3,3,7-trimethyl-8-(2-nitrophenyl)-2-oxa-8-azaspiro[4.5]decane (A77.9) (1.15 g, 2.41 mmol) was dissolved in methanol (50 mL) and the solution was treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 2-[(5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl]aniline (A77.10) (0.65 g, 2.36 mmol, 95% purity, 93.3% yield).

    Step-9. Synthesis of rac-N1,N1-dimethyl-N4-(2-((5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)benzene-1,4-disulfonamide (A-799)

    [0886] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (0.397 g, 1.40 mmol) was added to the mixture of 3-fluoro-2-[(5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl]aniline (0.375 g, 1.28 mmol) and pyridine (0.5 g, 6.32 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) to afford the product as white solid (0.0295 g, 0.0546 mmol, 95% purity, 4.05% yield). The analytical data provided for this compound provisionally supports the proposed structure for N1,N1-dimethyl-N4-(2-((5R,7R)-3,3,7-trimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)benzene-1,4-disulfonamide (A-799). Yield: 29.5 mg, 4.05%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 3.52-3.45 (m, 2H), 2.83 (s, 1H), 2.58 (s, 6H), 2.39 (d, J=12.0 Hz, 1H), 1.82 (d, J=11.4 Hz, 1H), 1.65 (dd, J=16.6, 4.1 Hz, 3H), 1.53 (d, J=12.6 Hz, 1H), 1.44 (d, J=11.6 Hz, 1H), 1.34 (d, J=12.5 Hz, 1H), 1.18 (d, J=8.7 Hz, 6H), 0.43 (d, J=5.9 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.35N.sub.3O.sub.5S.sub.2: 521.69; Observed: 522.2[M+H].sup.+.

    Example A78: Synthesis of N4-(2-{4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]piperidin-1-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-754)

    [0887] ##STR01651##

    Step-1. Synthesis of (2R,6S)-2,6-dimethyl-4-[1-(2-nitrophenyl)piperidine-4-carbonyl]morpholine (A78.6)

    [0888] 1-(2-Nitrophenyl)piperidine-4-carboxylic acid (A78.1) (1.0 g, 3.99 mmol), (2R,6S)-2,6-dimethylmorpholine (A78.2) (0.46 g, 3.99 mmol, 1.0 eq) and 1-methyl-1H-imidazole (A78.5) (1.6 g, 19.9 mmol, 5.0 eq) were dissolved in acetonitrile (20 mL) and [chloro(dimethylamino)methylidene]dimethylazanium (A78.3); hexafluoro-λ.sup.5-phosphanide (A78.4) (1.68 g, 5.98 mmol) was added in a single portion. The reaction was stirred overnight. After completion, the reaction mixture was concentrated. Dichloromethane (20 mL) was added to the residue and the obtained solution was washed with brine (2×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2R,6S)-2,6-dimethyl-4-[1-(2-nitrophenyl)piperidine-4-carbonyl]morpholine as oil (A78.6) (2.7 g, 3.49 mmol, 50.0% purity, 97.8% yield).

    Step-2. Synthesis of 2-{4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]piperidin-1-yl}aniline (A78.7)

    [0889] (2R,6S)-2,6-dimethyl-4-[1-(2-nitrophenyl)piperidine-4-carbonyl]morpholine (A78.6) (1.35 g, 3.88 mmol) was dissolved in THE (100 mL) and treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (LCMS control). The catalyst was filtered off and the filtrate was evaporated to afford product 2-{4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]piperidin-1-yl}aniline (A78.7) (1.0 g, 1.41 mmol, 64.8% purity, 52.6% yield).

    Step-3. Synthesis of N4-(2-{4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]piperidin-1-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-754)

    [0890] 4-(Dimethylsulfamoyl)benzene-1-sulfonyl chloride (A78.8) (0.282 g, 0.99 mmol) was added to the mixture of 2-4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]piperidin-1-ylaniline (A78.7) (0.5 g, 1.57 mmol) and ethylbis(propan-2-yl)amine (0.183 g, 1.41 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred overnight. After completion, it was diluted with water (20 mL) and extracted with dichloromethane (20 mL×2). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford N4-(2-{4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]piperidin-1-yl}phenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-754). Yield: 105.7 mg, 11.2%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.30 (s, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), 7.21 (d, J=7.9 Hz, 1H), 7.06 (s, 2H), 7.00 (s, 1H), 4.26 (d, J=13.0 Hz, 1H), 3.82 (d, J=13.3 Hz, 1H), 3.50-3.30 (m, 4H), 2.66 (dt, J=15.1, 11.3 Hz, 3H), 2.59 (s, 6H), 2.53 (s, 3H), 2.19 (t, J=11.9 Hz, 1H), 1.81-1.69 (m, 2H), 1.50 (d, J=12.8 Hz, 2H), 1.07 (t, J=6.8 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.36N.sub.4O.sub.6S.sub.2: 564.72; Observed: 565.0[M+H].sup.+.

    Example A79: Synthesis of N1,N1-dimethyl-N4-{2-[4-(morpholine-4-carbonyl)piperidin-1-yl]phenyl}benzene-1,4-disulfonamide (A-761)

    [0891] ##STR01652##

    Step-1. Synthesis of 4-[1-(2-nitrophenyl)piperidine-4-carbonyl]morpholine (A79.3)

    [0892] 1-fluoro-2-nitrobenzene (A79.2) (0.3 g, 2.12 mmol) was added to a stirred solution of 4-(piperidine-4-carbonyl)morpholine hydrochloride (A79.1) (0.5242 g, 2.23 mmol) and potassium carbonate (0.735 g, 5.31 mmol) in dry DMF (5 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control, overnight) and concentrated under the reduced pressure. The residue was dissolved in EtOAc (15 mL), the organic layer was washed twice with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-[1-(2-nitrophenyl)piperidine-4-carbonyl]morpholine (A79.3) (0.67 g, 2.09 mmol, 95% purity, 89.3% yield).

    Step-2. Synthesis of 2-[4-(morpholine-4-carbonyl)piperidin-1-yl]aniline (A79.4)

    [0893] 4-[1-(2-nitrophenyl)piperidine-4-carbonyl]morpholine (A79.3) (0.67 g, 2.09 mmol) was dissolved in methanol (10 mL) and treated with 10% Pd/C (0.075 g). The resulting mixture was hydrogenated at 6 atm and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 2-[4-(morpholine-4-carbonyl)piperidin-1-yl]aniline (A79.4) (0.6 g, 2.07 mmol, 95% purity, 94.3% yield).

    Step-3. Synthesis of N1,N1-dimethyl-N4-{2-[4-(morpholine-4-carbonyl)piperidin-1-yl]phenyl}benzene-1,4-disulfonamide (A-761)

    [0894] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A79.5) (0.196 g, 0.69 mmol) was added to the mixture of 2-[4-(morpholine-4-carbonyl)piperidin-1-yl]aniline (A79.4) (0.2 g, 0.69 mmol) and DIPEA (0.135 g, 1.04 mmol) in dry DCM (5 mL). The reaction mixture was stirred overnight and poured into sat. aq. NaHCO.sub.3 solution (10 mL). The organic layer was separated, the product was extracted from water layer with DCM (15 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) to give product as yellow solid (0.081 g, 0.150 mmol, 95% purity, 20.7% yield). The analytical data provided for this compound provisionally supports the proposed structure for N1,N1-dimethyl-N4-{2-[4-(morpholine-4-carbonyl)piperidin-1-yl]phenyl}benzene-1,4-disulfonamide (A-761). Yield: 81 mg, 20.7%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.29 (s, 1H), 8.04-7.97 (m, 2H), 7.93-7.85 (m, 2H), 7.24-7.18 (m, 1H), 7.07 (q, J=5.3, 4.6 Hz, 2H), 7.02 (ddd, J=8.6, 6.0, 2.9 Hz, 1H), 3.52 (q, J=5.3, 4.8 Hz, 4H), 3.50-3.39 (m, 4H), 2.59 (s, 6H), 2.58-2.48 (m, 6H), 1.76 (qd, J=12.1, 4.1 Hz, 2H), 1.57-1.46 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.32N.sub.4O.sub.6S.sub.2: 536.66; Observed: 537.0[M+H].sup.+.

    [0895] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00028 Compound No. Structure Analytical Data A-755 [01653]embedded image Yield: 78 mg, 14.4%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.16 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 6.7 Hz, 1H), 6.95 (t, J = 10.0 Hz, 1H), 3.49 (dtd, J = 12.6, 6.3, 2.0 Hz, 2H), 2.76 (t, J = 11.5 Hz, 2H), 2.67 (d, J = 10.9 Hz, 2H), 2.58 (s, 6H), 2.28 (d, J = 10.7 Hz, 2H), 2.08 (d, J = 6.7 Hz, 2H), 1.52 (d, J = 11.2 Hz, 5H), 1.22 − 1.14 (m, 2H), 1.01 (d, J = 6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.37FN.sub.4O.sub.5S.sub.2: 568.72; Observed: 569.2[M + H].sup.+.

    Example A80: Synthesis of N4-{4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-1H-indazol-5-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-746)

    [0896] ##STR01654## ##STR01655##

    Step-1. Synthesis of 4-chloro-1-methyl-5-nitro-1H-indazole (A80.2)

    [0897] Lithium hexamethyldisilazane (2.3 g, 13.8 mmol) was added to a solution of 4-chloro-5-nitro-1H-indazole (A80.1) (2.5 g, 12.6 mmol) in tetrahydrofuran (100 mL) at −78° C., the mixture was stirred for 20 minutes and iodomethane (1.78 g, 12.6 mmol) was added. The solution was allowed to warm to room temperature, stir for 12 hours and evaporated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (chloroform/MTBE) to give 4-chloro-1-methyl-5-nitro-1H-indazole (A80.2) (0.9 g, 4.25 mmol, 95% purity, 32.1% yield).

    Step-2. Synthesis of 4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-5-nitro-1H-indazole (A80.4)

    [0898] 4-chloro-1-methyl-5-nitro-1H-indazole (A80.2) (0.8 g, 3.78 mmol) was added to a stirred solution of 4-(methoxymethyl)-4-methylpiperidine hydrochloride (A80.3) (0.745 g, 4.15 mmol) and potassium carbonate (1.58 g, 11.3 mmol) in dry DMF (25 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (150 mL), the organic layer was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification (chloroform/acetonitrile) of crude product afforded 4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-5-nitro-1H-indazole (A80.4) (1 g, 3.14 mmol, 95% purity, 79.1% yield).

    Step-3. Synthesis of 4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-1H-indazol-5-amine (A80.5)

    [0899] 4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-5-nitro-1H-indazole (A80.4) (1 g, 3.14 mmol) was dissolved in methanol (100 mL) and treated with 5% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-1H-indazol-5-amine (A80.5) (0.9 g, 3.12 mmol, 95% purity, 94.4% yield).

    Step-4. Synthesis of N1-(4-(4-(methoxymethyl)-4-methylpiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-746)

    [0900] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A80.6) (0.391 g, 1.38 mmol) was added to the mixture of 4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-1H-indazol-5-amine (A80.5) (0.4 g, 1.38 mmol) and pyridine (0.150 g, 1.89 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 18 h, filtered through silica, the filtrate was evaporated under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N4-{4-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-1-methyl-1H-indazol-5-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-746). Yield: 109.8 mg, 14%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.92 (s, 1H), 7.94-7.78 (m, 5H), 7.16 (s, 2H), 3.99 (d, J=2.0 Hz, 3H), 3.17 (s, 2H), 2.95 (d, J=10.9 Hz, 2H), 2.76 (d, J=8.1 Hz, 2H), 2.64 (d, J=1.9 Hz, 6H), 1.57 (d, J=11.5 Hz, 2H), 1.35 (s, 2H), 1.03 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.33N.sub.5O.sub.5S.sub.2: 535.68; Observed: 536.2[M+H].sup.+.

    Example A81: Synthesis of N4-{5-[4-(methoxymethyl)-4-methylpiperidin-1-yl]imidazo[1,2-a]pyridin-6-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-813)

    [0901] ##STR01656## ##STR01657##

    Step-1. Synthesis of 6-chloro-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-3-nitropyridine (A81.3)

    [0902] 2,6-dichloro-3-nitropyridine (A81.1) (2.6 g, 13.4 mmol) was added to the mixture of 4-(methoxymethyl)-4-methylpiperidine (A81.2) (2 g, 13.9 mmol) and triethylamine (2 g, 19.7 mmol) in dry dichloromethane (50 mL). The reaction mixture was refluxed for 6 h, cooled to room temperature, washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 6-chloro-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-3-nitropyridine (A81.3) (3.7 g, 12.3 mmol, 90.5% purity, 83.2% yield) that was used in next step without further purification.

    Step-2. Synthesis of N-[(2,4-dimethoxyphenyl)methyl]-6-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-5-nitropyridin-2-amine (A81.5)

    [0903] 6-chloro-2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-3-nitropyridine (A81.3) (3.7 g, 12.3 mmol), 1-(2,4-dimethoxyphenyl)methanamine (A81.4) (2.25 g, 13.5 mmol) and triethylamine (1.86 g, 18.4 mmol) were mixed in dry DMF (50 mL). The reaction mixture was stirred at 100° C. for 16 h, cooled to room temperature and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (50 mL), the solution was washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give N-[(2,4-dimethoxyphenyl)methyl]-6-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-5-nitropyridin-2-amine (A81.5) (5.8 g, 13.4 mmol, 90.3% purity, 98.8% yield) that was used in next step without further purification.

    Step-3. Synthesis of 6-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-5-nitropyridin-2-amine (A81.6)

    [0904] N-[(2,4-dimethoxyphenyl)methyl]-6-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-5-nitropyridin-2-amine (A81.5) (5.8 g, 13.4 mmol) was dissolved in dichloromethane (40 mL). Trifluoroacetic acid (15 g, 131 mmol) was added to the mixture, it was stirred at room temperature overnight and concentrated under the reduced pressure. The residue was dissolved in NaHCO.sub.3 sat. aq. solution (50 mL) and extracted with ethyl acetate (40 mL×2). Combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-5-nitropyridin-2-amine (A81.6) (4 g, 14.2 mmol, 86.6% purity, 92.2% yield) that was used in next step without further purification.

    Step-4. Synthesis of 4-(methoxymethyl)-4-methyl-1-{6-nitroimidazo[1,2-a]pyridin-5-yl}piperidine (A81.8)

    [0905] 6-[4-(methoxymethyl)-4-methylpiperidin-1-yl]-5-nitropyridin-2-amine (A81.6) (2 g, 7.13 mmol), 2-chloroacetaldehyde (A81.7) (40% aqueous solution, 5 g, 25.4 mmol) and sodium hydrogen carbonate (1.2 g, 14.2 mmol) were mixed in n-butanol (50 mL). The mixture was stirred at 100° C. overnight and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), this solution was washed with water (50 mL), brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Crude material was purified by flash chromatography (chloroform/ethyl acetate) to give 4-(methoxymethyl)-4-methyl-1-{6-nitroimidazo[1,2-a]pyridin-5-yl}piperidine (A81.8) (0.5 g, 1.64 mmol, 85% purity, 19.5% yield) that was used in next step without further purification.

    Step-5. Synthesis of 5-[4-(methoxymethyl)-4-methylpiperidin-1-yl]imidazo[1,2-a]pyridin-6-amine (A81.9)

    [0906] 4-(methoxymethyl)-4-methyl-1-{6-nitroimidazo[1,2-a]pyridin-5-yl}piperidine (A81.8) (0.5 g, 1.39 mmol) was dissolved in methanol (15 mL) and treated with 10% Pd/C (0.05 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed. The catalyst was filtered off and the filtrate was evaporated to give 5-[4-(methoxymethyl)-4-methylpiperidin-1-yl]imidazo[1,2-a]pyridin-6-amine (A81.9) (0.3 g, 1.09 mmol, 100% purity, 78.7% yield).

    Step-6. Synthesis of N4-{5-[4-(methoxymethyl)-4-methylpiperidin-1-yl]imidazo[1,2-a]pyridin-6-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-813)

    [0907] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A81.10) (0.3 g, 1.09 mmol) was added to the solution of 5-[4-(methoxymethyl)-4-methylpiperidin-1-yl]imidazo[1,2-a]pyridin-6-amine (A81.9) (0.3 g, 1.05 mmol) in dry THF (15 mL). The reaction mixture was stirred at room temperature for 16 h and evaporated under reduced pressure. The crude material was purified by HPLC (deionized water/HPLC-grade methanol, ammonia) to give N4-{5-[4-(methoxymethyl)-4-methylpiperidin-1-yl]imidazo[1,2-a]pyridin-6-yl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-813). Yield: 7.8 mg, 1.3%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.97 (d, J=3.4 Hz, 4H), 7.70 (s, 1H), 7.60 (s, 1H), 7.04 (d, J=9.3 Hz, 1H), 6.47 (dd, J=22.9, 9.1 Hz, 1H), 3.71-3.48 (m, 3H), 3.41 (d, J=14.8 Hz, 3H), 3.21-3.12 (m, 3H), 2.74 (d, J=3.8 Hz, 6H), 2.67 (d, J=3.3 Hz, 2H), 1.82 (s, 2H), 1.61 (s, 1H), 1.50 (d, J=13.1 Hz, 1H), 1.15 (s, 2H), 1.09 (s, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.23H.sub.31N.sub.5O.sub.5S.sub.2: 521.65; Observed: 522.2[M+H].sup.+.

    Example A82: Synthesis of N1,N1-dimethyl-N4-[7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl]benzene-1,4-disulfonamide (A-793)

    [0908] ##STR01658## ##STR01659##

    Step-1. Synthesis of 7-chloropyrazolo[1,5-a]pyridine-6-carboxylic Acid (A82.2)

    [0909] 2.5 M n-butyllithium (7.36 g, 115 mmol) solution in hexane (46 mL) was added dropwise at −78° C. to a stirred solution of pyrazolo[1,5-a]pyridine-6-carboxylic acid (A82.1) (7.5 g, 46.2 mmol) in dry tetrahydrofuran (250 mL) under argon atmosphere and the reaction mixture was stirred at −70° C. for 4 h. Then 1,1,2-trichloro-1,2,2-trifluoroethane (25.8 g, 138 mmol) was added at −78° C., the reaction mixture was allowed to warm up and stir overnight at room temperature until completion. After the reaction mixture was poured in water (250 mL), acidified with NaHSO.sub.4 sat. aq. solution to pH=4 and extracted with ethyl acetate (250 mL×3). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (acetonitrile/chloroform) that afforded 7-chloropyrazolo[1,5-a]pyridine-6-carboxylic acid as white solid (A82.2) (2.45 g, 12.4 mmol, 91% purity, 24.4% yield).

    Step-2. Synthesis of 7-(piperidin-1-yl)pyrazolo[1,5-a]pyridine-6-carboxylic Acid (A82.4)

    [0910] 7-chloropyrazolo[1,5-a]pyridine-6-carboxylic acid (A82.2) (1.25 g, 6.35 mmol) was added to a stirred solution of piperidine (A82.3) (0.702 g, 8.25 mmol) and dipotassium carbonate (2.18 g, 15.8 mmol) in dry NMP (150 mL). The mixture was stirred at 120° C. for 18 h. Then, it was cooled to room temperature, poured in water (250 mL), acidified with NaHSO.sub.4 sat. aq. solution to pH=5 and extracted with ethyl acetate (250 mL×3). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-(piperidin-1-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid as white solid (A82.4) (1.1 g, 4.48 mmol, 95% purity, 67% yield).

    Step-3. Synthesis of Benzyl N-{7-[4-(methoxymethyl)-4-methylpiperidin-1-yl]pyrazolo[1,5-a]pyridin-6-yl}carbamate (A82.6)

    [0911] {[azido(phenoxy)phosphoryl]oxy}benzene (1.49 g, 5.43 mmol was added to a stirred solution of 7-[4-(methoxymethyl)-4-methylpiperidin-1-yl]pyrazolo[1,5-a]pyridine-6-carboxylic acid (A82.4) (1.1 g, 3.62 mmol), phenylmethanol (A82.5) (1.16 g, 10.8 mmol) and triethylamine (0.549 g, 5.43 mmol) in dry toluene (100 mL). The mixture was stirred at 100° C. for 18 h. Then it was cooled to room temperature, poured in water (200 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded benzyl N-{7-[4-(methoxymethyl)-4-methylpiperidin-1-yl]pyrazolo[1,5-a]pyridin-6-yl}carbamate (A82.6) as white solid (0.309 g, 0.756 mmol, 95% purity, 19.9% yield).

    Step-4. Synthesis of 7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-amine (A82.7)

    [0912] Benzyl N-[7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl]carbamate (A82.6) (0.1 g, 0.285 mmol) was dissolved in methanol/tetrahydrofuran=1/1 mixture (50 mL). 5% Pd/C (0.1 g) was added to the resulting orange solution wand the mixture was hydrogenated at ambient pressure and room temperature for 0.5 h, filtered. The filtrate was concentrated under reduced pressure to give 7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-amine as grey solid (A82.7) (0.055 g, 0.254 mmol, 86% purity, 76.7% yield) that was used in next step without further purification.

    Step-5. Synthesis of N1,N1-dimethyl-N4-[7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl]benzene-1,4-disulfonamide (A-793)

    [0913] Pyridine (0.0301 g, 381 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A82.8) (0.0791 g, 0.279 mmol) were added to 7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-amine (A82.7) (0.055 g, 0.254 mmol) solution in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 18 h and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded the product N1,N1-dimethyl-N4-[7-(piperidin-1-yl)pyrazolo[1,5-a]pyridin-6-yl]benzene-1,4-disulfonamide (A-793). Yield: 37.8 mg, 30.6%; Appearance: Brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71 (s, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.96-7.81 (m, 4H), 7.26 (dd, J=9.3, 1.9 Hz, 1H), 6.65 (d, J=9.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 2.62 (s, 6H), 1.71-1.38 (m, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.20H.sub.25N.sub.5O.sub.4S.sub.2: 463.57; Observed: 464.2[M+H].sup.+.

    Example A83: Synthesis of 4-[1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide (A-752)

    [0914] ##STR01660##

    Step-1. Synthesis of 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethan-1-one (A83.3)

    [0915] 1-(2,3-difluorophenyl)ethan-1-one (A83.1) (1.88 g, 12.1 mmol) was added to a stirred solution of 3,3-dimethyl-2-oxa-8-azaspiro[4.5]decane hydrochloride (A83.2) (2.5 g, 12.1 mmol) and dipotassium carbonate (4.17 g, 30.2 mmol) in dry NMP (100 mL). The mixture was stirred at 100° C. for 18 h. The reaction mixture cooled to room temperature, diluted with water (150 mL) and extracted with ethyl acetate (150 mL×3). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethan-1-one as yellow oil (A83.3) (2.6 g, 8.51 mmol, 90% purity, 63.4% yield) that was used in the next step without further purification.

    Step-2. Synthesis of give 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethan-1-ol (A83.4)

    [0916] Sodium boranuide (0.321 g, 8.51 mmol) was added to a stirred solution of 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethan-1-one (A83.3) (2.6 g, 8.51 mmol) in dry methanol (150 mL) at 10° C. The mixture was stirred at room temperature for 3 h, diluted with water (150 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethan-1-ol as beige oil (A83.4) (2.3 g, 7.48 mmol, 95% purity, 83.5% yield).

    Step-3. Synthesis of 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethyl methanesulfonate (A83.5)

    [0917] Methanesulfonyl chloride (0.222 g, 1.94 mmol) was added dropwise at 0° C. to a solution of 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethan-1-ol (A83.4) (0.5 g, 1.62 mmol) and triethylamine (0.245 g, 2.43 mmol) in dichloromethane (10 mL). The solution was stirred for 6 h at room temperature, washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethyl methanesulfonate (A83.5) (0.7 g, 1.81 mmol, 80% purity, 89.5% yield) that was used in next step without further purification.

    Step-4. Synthesis of 4-[1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide (A-752)

    [0918] 1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethyl methanesulfonate (A83.5) (0.624 g, 1.62 mmol) was added to a stirred solution of sodium 4-(dimethylsulfamoyl)benzene-1-sulfinate (A83.6) (0.526 g, 1.94 mmol) and dipotassium carbonate (0.335 g, 2.43 mmol) in dry DMF (50 mL). The mixture was stirred at 50° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×150 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded 4-[1-(2-{3,3-dimethyl-2-oxa-8-azaspiro[4.5]decan-8-yl}-3-fluorophenyl)ethanesulfonyl]-N,N-dimethylbenzene-1-sulfonamide (A-752). Yield: 152 mg, 16.5%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94-7.87 (m, 2H), 7.82-7.76 (m, 2H), 7.40 (t, J=7.4 Hz, 1H), 7.32 (td, J=8.2, 4.6 Hz, 1H), 7.18 (ddd, J=12.1, 8.2, 3.1 Hz, 1H), 5.40-5.33 (m, 1H), 3.64-3.57 (m, 1H), 3.56-3.50 (m, 1H), 2.89-2.78 (m, 2H), 2.62 (s, 6H), 2.57 (d, J=12.6 Hz, 1H), 1.65 (d, J=7.2 Hz, 4H), 1.60 (d, J=9.6 Hz, 3H), 1.50 (d, J=10.8 Hz, 2H), 1.36 (d, J=12.9 Hz, 1H), 1.19 (s, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.35FN.sub.2O.sub.5S.sub.2: 538.7; Observed: 539.2[M+H].sup.+.

    [0919] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example as indicated in the table below.

    TABLE-US-00029 Compound No. Structure Analytical Data A-750 [01661]embedded image Yield: 82.2 mg, 11.7%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.87 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.8 Hz, 1H), 7.28 (td, J = 8.0, 5.2 Hz, 1H), 7.15 (dd, J = 12.5, 8.2 Hz, 1H), 5.32 (t, J = 7.3 Hz, 1H), 3.50 (t, J = 8.1 Hz, 2H), 2.83 (t, J = 11.5 Hz, 1H), 2.76 (t, J = 11.8 Hz, 1H), 2.67 (td, J = 14.4, 12.7, 7.7 Hz, 3H), 2.59 (s, 6H), 2.14 − 2.07 (m, 2H), 1.66 (d, J = 10.6 Hz, 2H), 1.63 (d, J = 7.3 Hz, 3H), 1.52 (q, J = 9.6, 9.1 Hz, 4H), 1.16 (td, J = 12.2, 4.1 Hz, 1H), 1.01 (d, J = 6.2 Hz, 6H), 0.98 (d, J = 12.1 Hz, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.28H.sub.40FN.sub.3O.sub.5S.sub.2: 581.76; Observed: 582.4[M + H].sup.+.

    Example A84: Synthesis of N-[3-chloro-2-(piperidin-1-yl)phenyl]-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzene-1-sulfonamide (A-749)

    [0920] ##STR01662##

    Step-1. Synthesis of 1-(2-chloro-6-nitrophenyl)piperidine (A84.3)

    [0921] 1-chloro-2-fluoro-3-nitrobenzene (A84.1) (0.300 g, 1.7 mmol) was added to a stirred solution of piperidine (A84.2) (0.286 g, 3.4 mmol) and potassium carbonate (0.352 g, 2.55 mmol) in dry DMF (5 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (15 mL), the organic layer was washed with water (15 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 1-(2-chloro-6-nitrophenyl)piperidine as orange oil (A84.3) (0.37 g, 1.53 mmol, 95% purity, 85.8% yield).

    Step-2. Synthesis of 3-chloro-2-(piperidin-1-yl)aniline (A84.4)

    [0922] Iron powder (0.340 g, 6.112 mmol) and ammonium chloride (0.035 g) were added to a stirred solution of 1-(2-chloro-6-nitrophenyl)piperidine (A84.3) (0.37 g, 1.53 mmol) in a mixture of isopropanol (3.5 mL), water (0.35 mL) and conc. HCl (0.35 μL) and the resulting reaction mixture was refluxed for 1 h. After the reaction completion (TLC control) the mixture was filtered through silica, silica was washed with ethyl acetate (40 mL). The filtrate was partitioned between water (40 mL) and ethyl acetate (40 mL). The organic layer was washed with water (40 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure that afforded 3-chloro-2-(piperidin-1-yl)aniline (A84.4) (0.27 g, 1.28 mmol, 95% purity, 79.5% yield).

    Step-3. Synthesis of N-(3-chloro-2-(piperidin-1-yl)phenyl)-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonamide (A-749)

    [0923] 4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonyl chloride (A84.5) (0.398 g, 1.4 mmol) was added to the mixture of 3-chloro-2-(piperidin-1-yl)aniline (A84.4) (0.270 g, 1.28 mmol) and ethylbis(propan-2-yl)amine (0.248 g, 1.92 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred overnight and poured into NaHCO.sub.3 sat. aq. solution (15 mL). The product was and extracted with dichloromethane (20 mL×2). Combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Resulting solid was purified by HPLC (deionized water/HPLC-grade acetonitrile) to afford N-[3-chloro-2-(piperidin-1-yl)phenyl]-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzene-1-sulfonamide (A-749). Yield: 239.6 mg, 38.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.07 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.21 (dd, J=7.8, 1.7 Hz, 1H), 7.16-7.05 (m, 2H), 3.10 (s, 2H), 2.26 (s, 2H), 1.59 (s, 1H), 1.51-1.44 (m, 3H), 1.26 (s, 1H); HPLC purity: 98.57%; LCMS Calculated for C.sub.19H.sub.18ClF.sub.3N.sub.4O.sub.2S: 458.88; Observed: 459.2[M+H].sup.+.

    Example A85: Synthesis of N-{2-[4-(methoxymethyl)-4-methylpiperidin-1-yl]phenyl}-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzene-1-sulfonamide (A-740)

    [0924] ##STR01663##

    [0925] 4-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzenesulfonyl chloride (A85.2) (0.242 g, 0.853 mmol) was added to the mixture of 2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A85.1) (0.2 g, 0.853 mmol) and ethylbis(propan-2-yl)amine (A85.3) (0.164 g, 1.27 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred overnight and poured into NaHCO.sub.3 sat. aq. solution (15 mL). The product was extracted with dichloromethane (20 mL). Combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Resulting solid was purified by HPLC (deionized water/HPLC-grade acetonitrile) to afford N-{2-[4-(methoxymethyl)-4-methylpiperidin-1l-yl]phenyl}-4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzene-Y-sulfonamide (A-740). Yield: 170.2 mg, 39.1%; Appearance: Yellow oil; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.01 (s, 1H), 7.87-7.80 (m, 2H), 7.45 (dd, J=8.7, 2.9 Hz, 2H), 7.21 (dt, J=7.9, 2.1 Hz, 1H), 7.17 (dd, J=8.0, 1.8 Hz, 1H), 7.09 (ddd, J 10.3, 5.8, 2.2 Hz, 1H), 7.02 (tt, J 7.9, 2.2 Hz, 1H), 3.27 (s, 3H), 3.08 (d, J 3.1 Hz, 2H), 2.40 (dd, J=12.5, 4.9 Hz, 2H), 1.43 (tt, J=9.4, 3.8 Hz, 2H), 1.24-1.14 (m, 2H), 0.89 (d, J=3.1 Hz, 3H); HPLC purity: 98.45; LCMS Calculated for C.sub.22H.sub.25F.sub.3N.sub.4O.sub.3S: 482.52; Observed: 483.2[M+H].sup.+.

    [0926] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00030 Compound No. Structure Analytical Data A-776 [01664]embedded image Yield: 89 mg, 33.6%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 8.11 − 8.06 (m, 2H), 8.01 − 7.96 (m, 2H), 7.21 − 7.12 (m, 2H), 6.96 − 6.91 (m, 1H), 3.54 − 3.47 (m, 2H), 3.24 (s, 3H), 2.78 (t, J = 11.5 Hz, 2H), 2.68 (d, J = 10.7 Hz, 2H), 2.36 − 2.31 (m, 2H), 2.08 (d, J = 6.8 Hz, 2H), 1.52 (h, J = 8.0, 7.3 Hz, 5H), 1.19 − 1.12 (m, 2H), 1.01 (d, J = 6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.34FN.sub.3O.sub.5S.sub.2: 539.68; Observed: 540.0 [M + H].sup.+. A-760 [01665]embedded image Yield: 221.7 mg, 58.9%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO- δ 8.86 (s, 1H), 7.65 (s, 1H), 7.49 (dd, J = 7.8, 1.8 Hz, 1H), 7.35 − 7.29 (m, 2H), 7.16 (dt, J = 8.1, 3.0 Hz, 1H), 7.11 − 7.04 (m, 2H), 3.63 (t, J = 4.6 Hz, 4H), 2.86 (t, J = 7.3 Hz, 4H), 2.46 (d, J = 4.6 Hz, 4H), 2.01 (p, J = 7.4 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.22N.sub.2O.sub.3S: 358.46; Observed: 359.0[M + H].sup.+.

    Example A86: Synthesis of N4-(2-{4-[(3,5-dimethylmorpholin-4-yl)methyl]piperidin-1-yl}-3-fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-763)

    [0927] ##STR01666## ##STR01667##

    Step-1. Synthesis of tert-butyl 4-((3,5-dimethylmorpholino)methyl)piperidine-1-carboxylate (A86.3)

    [0928] 3,5-dimethylmorpholine (A86.2) (2.15 g, 18.7 mmol) and acetic acid (0.4 mL) were added to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (A86.1) (2 g, 9.37 mmol) in DCE/THF (40 mL/4 mL). After the mixture was stirred for several minutes, and NaBH(OAc).sub.3 (3.96 g, 18.7 mmol) was added. The mixture was stirred at room temperature for 2 days and poured after into sat aq NaHCO.sub.3 solution (50 mL). The product was extracted with EtOAc (50 mL×2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Flash column chromatography of residue (hexane/MTBE) afforded tert-butyl 4-((3,5-dimethylmorpholino)methyl)piperidine-1-carboxylate (A86.3) (1.2 g, 3.84 mmol, 100% purity, 41.0% yield).

    Step-2. Synthesis of 3,5-dimethyl-4-[(piperidin-4-yl)methyl]morpholine (A86.4)

    [0929] TFA (3 mL) was added in one portion to a stirred solution of tert-butyl 4-((3,5-dimethylmorpholino)methyl)piperidine-1-carboxylate (A86.3) (1.2 g, 3.84 mmol) in dichloromethane (5 mL). The resulting mixture was stirred overnight and evaporated. Crude residue was treated with 2 M NaOH aq. solution to pH=12 and the product was extracted with DCM (20 mL×3). Combined organic layers were dried over sodium sulfate, filtered and evaporated to afford 3,5-dimethyl-4-[(piperidin-4-yl)methyl]morpholine (A86.4) (0.55 g, 2.59 mmol, 95% purity, 64% yield).

    Step-3. Synthesis of 4-{[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-3,5-dimethylmorpholine (A86.6)

    [0930] 1,2-difluoro-3-nitrobenzene (A86.5) (0.186 g, 1.17 mmol) was added to a stirred solution of 3,5-dimethyl-4-(piperidin-4-ylmethyl)morpholine (0.250 g, 1.17 mmol) and potassium carbonate (0.241 g, 1.75 mmol) in dry DMF (5 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (15 mL), the organic layer was washed twice with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-{[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-3,5-dimethylmorpholine as orange oil (A86.6) (0.31 g, 0.882 mmol, 100% purity, 75.4% yield).

    Step-4. Synthesis of 2-{4-[(3,5-dimethylmorpholin-4-yl)methyl]piperidin-1-yl}-3-fluoroaniline (A86.7)

    [0931] 4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-3,5-dimethylmorpholine (A86.6) (0.31 g, 0.882 mmol) was dissolved in methanol (10 mL) and treated with 10% Pd/C (0.05 g). The resulting mixture was hydrogenated at 6 atm and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 2-{4-[(3,5-dimethylmorpholin-4-yl)methyl]piperidin-1-yl}-3-fluoroaniline (A86.7) (0.28 g, 0.871 mmol, 95% purity, 93.9% yield).

    Step-5. Synthesis of N4-(2-{4-[(3,5-dimethylmorpholin-4-yl)methyl]piperidin-1-yl}-3-fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-763)

    [0932] 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (0.271 g, 0.958 mmol) was added to the mixture of 2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (0.28 g, 0.871 mmol) and DIPEA (0.168 g, 1.30 mmol) in dry DCM (5 mL). The reaction mixture was stirred overnight and poured into sat. aq. NaHCO.sub.3 solution (15 mL). The product was extracted with dichloromethane (20 mL×2). Combined organic layers was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Resulting solid was purified by HPLC (deionized water/HPLC-grade acetonitrile) to afford N4-(2-{4-[(3,5-dimethylmorpholin-4-yl)methyl]piperidin-1-yl}-3-fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide as beige solid (0.0715 g, 0.125 mmol, 95% purity, 13.7% yield). The analytical data provided for this compound provisionally supports the proposed structure for N4-(2-{4-[(3,5-dimethylmorpholin-4-yl)methyl]piperidin-1-yl}-3-fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-763). Yield: 71.5 mg, 13.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 8.01-7.91 (m, 4H), 7.26-7.16 (m, 2H), 6.97 (t, J=10.2 Hz, 1H), 3.54 (dd, J=10.8, 3.1 Hz, 2H), 3.23 (s, 2H), 2.91-2.64 (m, 6H), 2.61 (d, J=2.6 Hz, 6H), 2.46-2.05 (m, 4H), 1.57 (dd, J=32.6, 12.3 Hz, 2H), 1.20 (dd, J=23.4, 11.6 Hz, 2H), 0.91 (dd, J=6.3, 2.7 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.37FN.sub.4O.sub.5S.sub.2: 568.72; Observed: 569.0[M+H].sup.+.

    [0933] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00031 Compound No. Structure Analytical Data A-748 [01668]embedded image Yield: 157.3 mg, 32.2%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.19 (s, 1H), 8.00 − 7.91 (m, 4H), 7.25 − 7.14 (m, 2H), 7.02 − 6.92 (m, 1H), 3.54 (t, J = 8.0 Hz, 1H), 3.48 − 3.40 (m, 1H), 2.83 − 2.72 (m, 2H), 2.61 (s, 6H), 2.45 (d, J = 10.4 Hz, 2H), 2.36 − 2.29 (m, 2H), 2.25 − 2.17 (m, 1H), 2.10 (t, J = 10.4 Hz, 1H), 1.82 (d, J = 12.8 Hz, 1H), 1.72 (t, J = 10.5 Hz, 1H), 1.49 (d, J = 12.2 Hz, 1H), 1.32 (d, J = 10.2 Hz, 1H), 1.18 (d, J = 12.8 Hz, 2H), 1.03 (t, J = 6.4 Hz, 6H), 0.86 (d, J = 6.5 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.39FN.sub.4O.sub.5S.sub.2: 585.75; Observed: 583.2[M + H].sup.+. A-762 [01669]embedded image Yield: 46.9 mg, 16.7%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.24 − 7.11 (m, 2H), 6.98 − 6.90 (m, 1H), 4.14 (s, 2H), 2.74 (t, J = 11.4 Hz, 2H), 2.57 (s, 6H), 2.25 (d, J = 11.1 Hz, 2H), 2.07 (t, J = 8.4 Hz, 4H), 1.77 (d, J = 6.6 Hz, 2H), 1.66 (d, J = 6.7 Hz, 2H), 1.50 (d, J = 13.0 Hz, 2H), 1.42 (s, 1H), 1.17 (t, J = 11.8 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.35FN.sub.4O.sub.5S.sub.2: 566.71; Observed: 567.2[M + H].sup.+. A-787 [01670]embedded image Yield: 8.3 mg, 1.43%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 − 7.75 (m, 4H), 7.22 (d, J = 7.9 Hz, 1H), 7.15 (s, 1H), 4.30 (s, 1H), 3.82 (d, J = 7.4 Hz, 1H), 3.49 (d, J = 7.5 Hz, 1H), 2.77 (d, J = 9.8 Hz, 3H), 2.61 (d, J = 1.4 Hz, 6H), 2.43 (d, J = 5.7 Hz, 2H), 2.40 − 2.24 (m, 4H), 1.70 (d, J = 9.4 Hz, 1H), 1.66 − 1.49 (m, 3H), 1.22 (d, J = 13.1 Hz, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.33FN.sub.4O.sub.5S.sub.2: 552.68; Observed: 553.2[M + H].sup.+. A-785 [01671]embedded image Yield: 21.7 mg, 3.75%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.25 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.18 − 7.12 (m, 1H), 6.93 (dd, J = 12.0, 8.3 Hz, 1H), 4.28 (s, 1H), 3.79 (d, J = 7.4 Hz, 1H), 3.46 (dd, J = 7.5, 1.7 Hz, 1H), 2.81 − 2.69 (m, 3H), 2.58 (s, 6H), 2.41 (d, J = 6.7 Hz, 1H), 2.36 − 2.26 (m, 4H), 1.67 (dd, J = 9.4, 2.1 Hz, 1H), 1.58 − 1.49 (m, 3H), 1.30 (s, 1H), 1.19 (dt, J = 13.2, 6.7 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.33FN.sub.4O.sub.5S.sub.2: 552.68; Observed: 553.2[M + H].sup.+.

    Example A87: Synthesis of N4-3-fluoro-2-[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)piperidin-1-yl]phenyl-N1,N1-dimethylbenzene-1,4-disulfonamide (A-778)

    [0934] ##STR01672## ##STR01673##

    Step-1. Synthesis of tert-butyl 4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)piperidine-1-carboxylate (A87.3)

    [0935] A mixture of 3-oxa-6-azabicyclo[3.1.1]heptane 4-methylbenzene-1-sulfonate (A87.2) (0.2 g, 0.737 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (A87.1) (0.2 g, 0.937 mmol), ethylbis(propan-2-yl)amine (0.109 g, 0.843 mmol) and crushed 4 Å molecular sieves (0.3 g) in DCE (30 mL) in dichloroethane (30 mL) was stirred at room temperature for 5 h. Sodium bis(acetyloxy)boranuidyl acetate (2.15 g, 10.1 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Then, the mixture was filtered through celite, celite was washed with dichloroethane (30 mL×2) and the combined filtrates were concentrated in vacuo. The residue was purified by flash chromatography (methanol/dichloromethane) to give tert-butyl 4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)piperidine-1-carboxylate (A87.3) (0.130 g, 0.438 mmol, 90% purity, 42.2% yield).

    Step-2. Synthesis of 6-[(piperidin-4-yl)methyl]-3-oxa-6-azabicyclo[3.1.1]heptane Dihydrochloride (A87.4)

    [0936] 3N HCl solution in methanol (3 mL) was added dropwise to a solution of tert-butyl 4-({3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}methyl)piperidine-1-carboxylate (A87.3) (0.13 g, 0.438 mmol) in methanol (5 mL) keeping the temperature at 0° C. The mixture was stirred at this temperature for 3 h and evaporated under reduced pressure to give 6-[(piperidin-4-yl)methyl]-3-oxa-6-azabicyclo[3.1.1]heptane dihydrochloride (A87.4) (0.1 g, 0.371 mmol, 100% purity, 85.4% yield).

    Step-3. Synthesis of give 6-[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl-3-oxa-6-azabicyclo[3.1.1]heptane (A87.6)

    [0937] Potassium carbonate (0.206 g, 1.48 mmol) was added to the solution of 6-[(piperidin-4-yl)methyl]-3-oxa-6-azabicyclo[3.1.1]heptane dihydrochloride (A87.4) (0.1 g, 0.371 mmol) and 1,2-difluoro-3-nitrobenzene (A87.5) (0.0593 g, 0.372 mmol) in DMF (10 mL). Obtained mixture was stirred at 60° C. for 10 h, cooled to room temperature and poured into water (50 mL). The product was extracted with MTBE (15 mL×3). Combined organic layers were washed with water (15 mL×3) and brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 6-[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl-3-oxa-6-azabicyclo[3.1.1]heptane as yellow crystals (A87.6) (0.09 g, 0.268 mmol, 95% purity, 59.7% yield).

    Step-4. Synthesis of 3-fluoro-2-[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)piperidin-1-yl]aniline (A87.7)

    [0938] 10% Pd/C (0.2 g) was added to a stirred solution 6-[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl-3-oxa-6-azabicyclo[3.1.1]heptane (A87.6) (0.09 g, 0.268 mmol) in methanol (1 mL) followed by addition of hydrazine hydrate (0.2016 g, 4.09 mmol) dropwise to the mixture keeping the temperature below 40° C. After refluxing for 15 h the mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure, the residue was dissolved in dichloromethane (50 mL). This solution was washed with water (50 mL×2), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 3-fluoro-2-[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)piperidin-1-yl]aniline as colorless oil (A87.7) (0.075 g, 0.245 mmol, 100% purity, 91.6% yield).

    Step-5. Synthesis of N4-3-fluoro-2-[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)piperidin-1-yl]phenyl-N1,N1-dimethylbenzene-1,4-disulfonamide (A-778)

    [0939] 4-(Dimethylsulfamoyl)benzene-1-sulfonyl chloride (A87.8) (0.0768 g, 0.27 mmol) was added to a solution of 3-fluoro-2-[4-({3-oxa-6-azabicyclo[3.1.1]heptan-6-yl}methyl)piperidin-1-yl]aniline (A87.7) (0.0752 g, 0.246 mmol), triethylamine (0.062 g, 0.612 mmol) and N,N-dimethylpyridin-4-amine (0.003 g, 0.0245 mmol) in chloroform (5 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford the product N4-3-fluoro-2-[4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-ylmethyl)piperidin-1-yl]phenyl-N1,N1-dimethylbenzene-1,4-disulfonamide (A-778). Yield: 8 mg, 5.62%; Appearance: Beige solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 7.97-7.88 (m, 4H), 7.23-7.15 (m, 2H), 6.97 (d, J=10.9 Hz, 1H), 4.12 (s, 2H), 3.62 (s, 2H), 2.74 (d, J=11.4 Hz, 2H), 2.60 (s, 6H), 2.27 (d, J=11.0 Hz, 2H), 1.72 (s, 1H), 1.56 (d, J=11.8 Hz, 2H), 1.28 (s, 3H); HPLC purity: 98.09%; LCMS Calculated for C.sub.25H.sub.33FN.sub.4O.sub.5S.sub.2: 552.68; Observed: 553.0[M+H].sup.+.

    [0940] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00032 Compound No. Structure Analytical Data A-790 [01674]embedded image Yield: 40.3 mg, 7.18%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.19 (s, 1H), 7.99 − 7.90 (m, 4H), 7.27 − 7.17 (m, 2H), 6.97 (t, J = 9.8 Hz, 1H), 3.49 (d, J = 10.1 Hz, 2H), 3.39 (d, J = 10.2 Hz, 2H), 2.98 (s, 2H), 2.78 (t, J = 11.4 Hz, 2H), 2.61 (d, J = 1.7 Hz, 6H), 2.30 (d, J = 11.7 Hz, 2H), 2.10 (d, J = 7.3 Hz, 2H), 1.81 (s, 2H), 1.66 (dd, J = 20.0, 10.1 Hz, 4H), 1.38 (s, 1H), 1.22 (t, J = 12.1 Hz, 2H) HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.35FN.sub.4O.sub.5S.sub.2: 566.71; Observed: 567.2[M + H].sup.+

    Example A88: Synthesis of N4-{3-fluoro-2-[4-({6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}methyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-791)

    [0941] ##STR01675## ##STR01676##

    Step-1. Synthesis of tert-butyl 4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)piperidine-1-carboxylate (A88.3)

    [0942] A mixture of 4-methylbenzene-1-sulfonic acid; 6-oxa-3-azabicyclo[3.1.1]heptane (A88.2) (0.5 g, 1.84 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (A88.1) (0.392 g, 1.84 mmol), ethylbis(propan-2-yl)amine (0.262 g, 2.02 mmol) and crushed 4 Å molecular sieves (0.3 g) in DCE (30 mL) was stirred at ambient temperature for 5 hours. Sodium bis(acetyloxy)boranuidyl acetate (0.781 g, 3.68 mmol) was added and the reaction was stirred at room temperature for further 16 hours. Then the mixture was filtered through celite, celite was washed with DCM (30 mL×2) and the combined filtrates were concentrated in vacuo to give tert-butyl 4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)piperidine-1-carboxylate as colorless oil (A88.3) (0.4 g, 1.34 mmol, 95% purity, 69.7% yield).

    Step-2. Synthesis of 3-[(piperidin-4-yl)methyl]-6-oxa-3-azabicyclo[3.1.1]heptane; bis(trifluoroacetic Acid) (A88.4)

    [0943] Trifluoroacetic acid (7.39 g, 64.8 mmol, 5.0 mL) was added to the stirred solution of tert-butyl 4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)piperidine-1-carboxylate (A88.3) (0.400 g, 1.34 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 4 h, then the solvent was evaporated in vacuo affording 3-[(piperidin-4-yl)methyl]-6-oxa-3-azabicyclo[3.1.1]heptane; bis(trifluoroacetic acid) as white solid (A88.4) (0.6 g, 1.41 mmol, 90% purity, 95% yield) that was used in next step without further purification.

    Step-3. Synthesis of 3-[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl-6-oxa-3-azabicyclo[3.1.1]heptane (A88.6)

    [0944] Potassium carbonate (0.781 g, 5.65 mmol) was added to the solution of 3-[(piperidin-4-yl)methyl]-6-oxa-3-azabicyclo[3.1.1]heptane; bis(trifluoroacetic acid) (A88.4) (0.6 g, 1.41 mmol) and 1,2-difluoro-3-nitrobenzene (A88.5) (0.224 g, 1.41 mmol) in DMF (10 mL). Obtained mixture was stirred at 60° C. for 10 h, then poured into water (50 mL) and extracted with MTBE (15 mL×3). Combined organic layers were washed with water (15 mL×3) and brine (20 mL), dried over sodium sulfate, filtered and evaporated to give 3-[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl-6-oxa-3-azabicyclo[3.1.1]heptane as yellow oil (A88.6) (0.42 g, 1.25 mmol, 85.4% purity, 75.8% yield) that was used in next step without further purification.

    Step-4. Synthesis of 3-fluoro-2-[4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)piperidin-1-yl]aniline (A88.7)

    [0945] 10% Palladium (0.013 g, 0.125 mmol) was added to a stirred solution 3-[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl-6-oxa-3-azabicyclo[3.1.1]heptane (A88.6) (0.42 g, 1.25 mmol) in methanol (5 mL) followed by addition of hydrazine hydrate (0.939 g, 18.76 mmol, 1.57 mL) dropwise to the mixture keeping the temperature below 40° C. After refluxing for 15 h the mixture was cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure, the residue was dissolved in DCM (50 mL). This solution was washed with water (50 mL×2), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 3-fluoro-2-[4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)piperidin-1-yl]aniline as white crystals (A88.7) (0.34 g, 1.11 mmol, 95.0% purity, 84.6% yield).

    Step-5. Synthesis of N4-{3-fluoro-2-[4-({6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}methyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-791)

    [0946] Solution of 3-fluoro-2-[4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-ylmethyl)piperidin-1-yl]aniline (A88.7) (0.15 g, 0.491 mmol), 4-(Dimethylsulfamoyl)benzene-1-sulfonyl chloride (A88.8) (0.153 g, 0.539 mmol), pyridine (96.96 mg, 1.23 mmol, 100.0 μl, 2.5 eq) and N,N-dimethylpyridin-4-amine (0.0599 g, 0.049 mmol) in chloroform (15 mL) was stirred at room temperature overnight and evaporated under reduced pressure to dryness. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to give product N4-{3-fluoro-2-[4-({6-oxa-3-azabicyclo[3.1.1]heptan-3-yl}methyl)piperidin-1-yl]phenyl}-N1,N1-dimethylbenzene-1,4-disulfonamide (A-791). Yield: 84.3 mg, 16.3%; Appearance: Orange solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.94 (d, J=8.2 Hz, 2H), 7.88 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 1H), 7.12 (d, J=7.0 Hz, 1H), 6.91 (d, J=11.1 Hz, 1H), 4.07 (d, J=10.6 Hz, 2H), 3.55 (d, J=10.6 Hz, 2H), 3.36 (d, J=6.1 Hz, 2H), 2.75 (t, J=11.0 Hz, 2H), 2.58 (s, 6H), 2.42 (d, J=6.0 Hz, 2H), 2.28 (d, J=10.8 Hz, 2H), 1.66 (d, J=7.9 Hz, 1H), 1.55 (d, J=11.3 Hz, 2H), 1.30-1.19 (m, 3H); HPLC purity: 95.59%; LCMS Calculated for C.sub.25H.sub.33FN.sub.4O.sub.5S.sub.2: 552.68; Observed: 553.2[M+H].sup.+.

    [0947] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00033 Compound No. Structure Analytical Data A-774 [01677]embedded image Yield: 77.7 mg, 20.9%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (s, 1H), 7.98 − 7.92 (m, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.13 (td, J = 8.4, 5.7 Hz, 1H), 6.78 (ddd, J = 11.6, 8.4, 1.3 Hz, 1H), 3.00 (t, J = 11.9 Hz, 2H), 2.88 (t, J = 13.3 Hz, 2H), 2.72 (s, 8H), 2.35 (dd, J = 19.0, 7.5 Hz, 4H), 2.26 (dt, J = 14.5, 7.1 Hz, 2H), 1.82 (d, J = 13.0 Hz, 2H), 1.22 (dd, J = 22.9, 11.1 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.24H.sub.31F.sub.3N.sub.4O.sub.4S.sub.2: 560.65; Observed: 561.2[M + H].sup.+. A-773 [01678]embedded image Yield: 73 mg, 22%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.18 (s, 1H), 7.99 − 7.85 (m, 4H), 7.26 − 7.15 (m, 2H), 6.98 (t, J = 10.1 Hz, 1H), 2.79 (t, J = 11.3 Hz, 2H), 2.60 (s, 6H), 2.46 (s, 1H), 2.34 (d, J = 19.1 Hz, 6H), 2.22 (d, J = 6.6 Hz, 2H), 1.85 (s, 2H), 1.69 − 1.43 (m, 5H), 1.20 (d, J = 10.8 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.33F.sub.3N.sub.4O.sub.4S.sub.2: 574.68; Observed: 575.2[M + H].sup.+. A-789 [01679]embedded image Yield: 83.2 mg, 12.6%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.16 (s, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.16 (td, J = 8.2, 5.6 Hz, 1H), 6.99 − 6.93 (m, 1H), 2.77 (t, J = 11.5 Hz, 2H), 2.58 (s, 6H), 2.43 (s, 4H), 2.29 (d, J = 11.0 Hz, 2H), 2.18 (d, J = 7.0 Hz, 2H), 1.99 − 1.85 (m, 4H), 1.53 (d, J = 12.9 Hz, 2H), 1.48 (d, J = 11.6 Hz, 1H), 1.21 − 1.12 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.33F.sub.3N.sub.4O.sub.4S.sub.2: 574.68; Observed: 575.2[M + H].sup.+.

    Example A89: Synthesis of N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (A-780)

    [0948] ##STR01680##

    Step-1. Synthesis of 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzofuran (A89.2)

    [0949] A mixture of 1-(4-bromophenyl)-2-methylpropan-2-ol (A89.1) (5 g, 21.8 mmol), Pd(OAc).sub.2 (0.489 g, 2.18 mmol), Li.sub.2CO.sub.3 (3.22 g, 43.6 mmol), and Iodobenzene diacetate (10.5 g, 32.6 mmol) in hexafluorobenzene (20 mL) was stirred at 90° C. for 36 h. After cooling to room temperature, the reaction mixture was diluted with MTBE (250 mL). This solution was washed with water (100 mL×2), brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (hexane/MTBE) that afforded 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzofuran as colorless oil (A89.2) (1.5 g, 6.60 mmol, 95% purity, 28.6% yield).

    Step-2. Synthesis of lithium 2,2-dimethyl-2,3-dihydrobenzofuran-6-sulfinate (A89.3)

    [0950] 2.5 M n-butyllithium (0.507 g, 7.92 mmol) solution in hexane (3.16 mL) was added dropwise at −78° C. to a stirred solution of 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzofuran (A89.2) (1.5 g, 6.60 mmol) in dry tetrahydrofuran (100 mL) under argon atmosphere and the reaction mixture was stirred at −78° C. for 2 h. SO.sub.2 (1.26 g, 19.7 mmol) solution in dry tetrahydrofuran (50 mL) was added at −78° C. after and the reaction mixture was allowed to warm up and stir overnight at room temperature. The suspension was concentrated under reduced pressure to give lithium 2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfinate as white solid (A89.3) (1.7 g, 7.79 mmol, 80% purity, 94.4% yield) that was used in the next step without further purification.

    Step-3. Synthesis of 2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonyl chloride (A89.4)

    [0951] Sulfuroyl dichloride (1.11 g, 8.25 mmol) was added dropwise at −10° C. to a stirred solution of lithium 2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfinate (A89.3) (1.44 g, 6.60 mmol) in dry dichloromethane (100 mL), the reaction mixture was allowed to warm up and stir for 2 h at room temperature. The organic layer was washed with water with ice (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure that afforded 2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonyl chloride as colorless oil (A89.4) (1.6 g, 6.48 mmol, 79% purity, 77.7% yield) that was used in next step without further purification.

    Step-4. Synthesis of N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (A-780)

    [0952] Pyridine (0.183 g, 2.32 mmol) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonyl chloride (A89.4) (0.458 g, 1.86 mmol) were added to a solution of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluoroaniline (A89.5) (0.5 g, 1.55 mmol) in acetonitrile (55 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile, ammonia) to afford N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-sulfonamide (A-780). Yield: 167.6 mg, 19.2%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.67 (s, 1H), 7.25 (dd, J=8.3, 2.5 Hz, 2H), 7.15 (td, J=8.2, 5.7 Hz, 1H), 7.06 (dd, J=7.7, 1.7 Hz, 1H), 7.02 (d, J=1.7 Hz, 1H), 6.90-6.86 (m, 1H), 3.50 (dtt, J=12.6, 6.6, 3.2 Hz, 2H), 2.99 (s, 2H), 2.78 (t, J=11.4 Hz, 2H), 2.71-2.64 (m, 2H), 2.28 (d, J=10.9 Hz, 2H), 2.10 (d, J=7.1 Hz, 2H), 1.58 (d, J=12.8 Hz, 2H), 1.52 (t, J=10.6 Hz, 3H), 1.35 (s, 6H), 1.24-1.17 (m, 2H), 1.01 (d, J=6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.38FN.sub.5O.sub.4S.sub.2: 531.68; Observed: 532.4[M+H].sup.+.

    Example A90: Synthesis of N-(2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamimidoyl)benzene-sulfonamide (A-769

    [0953] ##STR01681##

    Step-1&2. Synthesis of 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride (A90.3)

    [0954] 2.5 M n-butyllithium (0.382 g, 5.97 mmol) in hexane (2.38 mL) was added to a solution of 4-bromo-N′-(tert-butyldimethylsilyl)-N,N-dimethylbenzenesulfonimidamide (A90.1) (1.88 g, 4.98 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under argon atmosphere and the mixture was stirred for 1 h at −78° C. After the solution of SO.sub.2 (0.954 g, 14.9 mmol) in tetrahydrofuran (20 mL) was added to the resulting mixture at the same temperature. Then the cooling bath was removed and the mixture was allowed to warm to room temperature and stir for 12 h. The solution was evaporated in vacuo, the residue was dissolved in dichloromethane (20 mL) and N-chlorosuccinimide (0.797 g, 5.97 mmol) was added maintaining the reaction mixture temperature at 0° C. The mixture was stirred for 30 minutes, diluted with ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and the filtrate was evaporated in vacuo to give 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride as a dark resin (A90.3) (1.76 g, 4.43 mmol, 58.66% purity, 52.2% yield) that was used in the next step without further purification.

    Step-3. Synthesis of 4-(N′-(tert-butyldimethylsilyl)-N,N-dimethylsulfamimidoyl)-N-(2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)benzenesulfonamide (A90.5)

    [0955] 4-[(tert-butyldimethylsilyl)dimethyl-S-aminosulfonimidoyl]benzene-1-sulfonyl chloride (A90.3) (0.7 g, 1.76 mmol) was added to the mixture of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluoroaniline (A90.4) (0.565 g, 1.76 mmol) and pyridine (0.982 g, 12.4 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated in vacuo to give 4-(N′-(tert-butyldimethylsilyl)-N,N-dimethylsulfamimidoyl)-N-(2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)benzenesulfonamide as a dark resin (A90.5) (1.2 g, 1.75 mmol, 20% purity, 20% yield) that was used in the next step without further purification.

    Step-4. Synthesis of N-(2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamimidoyl)benzenesulfonamide (A-769)

    [0956] 1 M TBAF (0.266 g, 1.02 mmol) solution in tetrahydrofuran (1.02 mL) was added to a solution of N-(tert-butyldimethylsilyl)-4-{[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]-sulfamoyl}-N,N-dimethylbenzene-1-sulfonimidamide (A90.5) (0.7 g, 1.02 mmol) in dry tetrahydrofuran (20 mL) under argon atmosphere. The reaction mixture was stirred for 12 h at room temperature and evaporated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) that afforded the product N-(2-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamimidoyl)benzene-sulfonamide (A-769). Yield: 8.4 mg, 1.37%; Appearance: Beige solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.49 (s, 1H), 8.03-7.92 (m, 4H), 7.42 (d, J=8.2 Hz, 1H), 7.11 (td, J=8.3, 5.5 Hz, 1H), 6.81-6.71 (m, 1H), 3.69 (d, J=8.4 Hz, 2H), 3.00 (d, J=9.5 Hz, 2H), 2.69 (d, J=1.1 Hz, 8H), 2.58 (s, 1H), 2.40 (dd, J=25.9, 11.4 Hz, 2H), 2.21 (d, J=7.2 Hz, 2H), 1.81 (d, J=13.0 Hz, 2H), 1.72 (t, J=10.7 Hz, 2H), 1.18 (d, J=6.2 Hz, 8H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.38FN.sub.5O.sub.4S.sub.2: 567.74; Observed: 568.2[M+H].sup.+.

    Example A91: Synthesis of 4-(azetidine-1-sulfonyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide (A-765)

    [0957] ##STR01682## ##STR01683##

    Step-1. Synthesis of tert-butyl 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidine-1-carboxylate (A91.3)

    [0958] (2R,6S)-2,6-dimethylmorpholine (A91.2) (27.7 g, 240 mmol) and glacial acetic acid (15 mL) were added to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (A91.1) (51.1 g, 240 mmol) in dry 1,2-dichloroethane (1 L). The mixture was stirred for 6 h at room temperature and sodium triacetoxyborohydride (66.1 g, 312 mmol) was added to it. The resulting mixture was stirred for 12 h until reaction completion (LCMS control), diluted with water (0.4 L). The product was extracted with dichloromethane (1 L), the organic layer was washed with 50% sodium bicarbonate aq. solution (250 mL), brine (250 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give tert-butyl 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidine-1-carboxylate as white crystals (A91.3) (59 g, 188 mmol, 95% purity, 74.7% yield).

    Step-2. Synthesis of (2R,6S)-2,6-dimethyl-4-[(piperidin-4-yl)methyl]morpholine dihydrochloride (A91.4)

    [0959] Tert-butyl 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidine-1-carboxylate (A91.3) (59 g, 188 mmol) was added to a sat. HCl solution in dioxane (500 mL) at room temperature. The solution was stirred overnight, the precipitate was filtered, washed with MTBE (100 mL×3) and dried on air to give (2R,6S)-2,6-dimethyl-4-[(piperidin-4-yl)methyl]morpholine dihydrochloride (A91.4) (45 g, 157 mmol, 95% purity, 79.6% yield).

    Step-3. Synthesis of (2R,6S)-4-{[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-2,6-dimethylmorpholine (A91.6)

    [0960] 1,2-difluoro-3-nitrobenzene (A91.5) (10.07 g, 62.8 mmol) was added to a stirred solution of (2R,6S)-2,6-dimethyl-4-[(piperidin-4-yl)methyl]morpholine dihydrochloride (A91.4) (15.5 g, 54.3 mmol) and potassium carbonate (30.2 g, 218 mmol) in dry DMF (500 mL). The mixture was stirred at 100° C. until the reaction completion (TLC control, 24 h) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (1000 mL), the organic layer was washed with water (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The chromatographic purification (chloroform/acetonitrile) of crude product afforded (2R,6S)-4-{[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-2,6-dimethylmorpholine as a powder (A91.6) (18 g, 51.2 mmol, 95% purity, 90% yield).

    Step-4. Synthesis of (2R,6S)-4-{[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-2,6-dimethylmorpholine (A91.7)

    [0961] (2R,6S)-4-{[1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-2,6-dimethylmorpholine (A91.6) (18 g, 51.2 mmol) was dissolved in methanol (300 mL) and treated with 10% Pd/C (1.8 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control), 2 days. The catalyst was filtered off and the filtrate was evaporated to afford 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluoroaniline (A91.7) (16 g, 49.7 mmol, 80% purity by LCMS, 78.0% yield) that was used in next step without further purification.

    Step-5. Synthesis of 1-(4-bromobenzenesulfonyl)azetidine (A91.10)

    [0962] A solution of 4-bromobenzene-1-sulfonyl chloride (A91.8) (10 g, 39.1 mmol) in tetrahydrofuran (200 mL) was added dropwise to a solution of azetidine hydrochloride (A91.9) (7.31 g, 7.31 g) and triethylamine (15.7 g, 156 mmol, 21.6 mL) in water (100 mL) at 0° C. The solution was stirred for 12 hours at room temperature and evaporated. The resulting mass was suspended in water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL), 5% aq solution of hydrochloric acid (200 mL), brine (200 mL), dried over sodium sulfate and evaporated under reduced pressure to afford 1-(4-bromobenzenesulfonyl)azetidine as white powder (A91.10) (10 g, 36.2 mmol, 95% purity, 88.7% yield).

    Step-6. Synthesis of lithium-4-(azetidine-1-sulfonyl)benzene-1-sulfinate (A91.11)

    [0963] 2.5 M solution of n-butyllithium (2.54 g, 39.8 mmol, 15.9 mL) in hexane was added dropwise for 30 min to a solution of 1-(4-bromobenzenesulfonyl)azetidine (A91.10) (10 g, 36.2 mmol) in tetrahydrofuran (250 mL) maintained under nitrogen atmosphere at −78° C. The resulting solution was stirred at −78° C. for 2 h. Sulfur dioxide (23 g, 362 mmol) solution in tetrahydrofuran (200 mL) was added to the solution at −78° C. for 30 sec. After, ether (200 mL) was added and the precipitate was collected by filtration. The solid was washed with ether (100 mL×2) and dried in vacuum to give lithium-4-(azetidine-1-sulfonyl)benzene-1-sulfinate as a white solid (A91.11) (9 g, 33.6 mmol, 90% purity, 83.7% yield).

    Step-7. Synthesis of 4-(azetidine-1-sulfonyl)benzene-1-sulfonyl Chloride (A91.12)

    [0964] Sulfuroyl dichloride (2.76 g, 20.5 mmol) was added dropwise to a suspension of lithium-4-(azetidine-1-sulfonyl)benzene-1-sulfinate (A91.11) (5 g, 18.7 mmol) in dichloromethane (100 mL) at −15° C. The solution was stirred for 30 minutes at this temperature, washed with sodium bicarbonate (100 mL), water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 4-(azetidine-1-sulfonyl)benzene-1-sulfonyl chloride as white powder (A91.12) (2.5 g, 8.45 mmol, 70% purity, 31.6% yield) that was used in next step without further purification.

    Step-8. Synthesis of 4-(azetidine-1-sulfonyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide (A-765)

    [0965] 4-(azetidine-1-sulfonyl)benzene-1-sulfonyl chloride (A91.12) (0.5 g, 1.69 mmol) was added to the mixture of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluoroaniline (A91.7) (0.543 g, 1.68 mmol) and pyridine (1.39 g, 17.5 mmol) in dry acetonitrile (40 mL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile, ammonia) to afford 4-(azetidine-1-sulfonyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide (A-765). Yield: 80 mg, 7.79%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.23 (s, 1H), 7.99 (q, J=8.3 Hz, 4H), 7.20 (dt, J=22.1, 7.9 Hz, 2H), 6.96 (t, J=10.2 Hz, 1H), 3.67 (t, J=7.7 Hz, 4H), 3.51 (t, J=8.4 Hz, 2H), 2.80 (t, J=11.4 Hz, 2H), 2.69 (d, J=11.1 Hz, 2H), 2.33 (d, J=10.5 Hz, 2H), 2.11 (d, J=6.5 Hz, 2H), 1.98 (p, J=7.6 Hz, 2H), 1.54 (t, J=10.9 Hz, 5H), 1.22 (d, J=12.5 Hz, 2H), 1.03 (d, J=6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.37FN.sub.4O.sub.5S.sub.2: 580.74; Observed: 581.2[M+H].sup.+.

    Example A92: Synthesis of 4-(1-cyclopropylethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]benzene-1-sulfonamide, (A-779)

    [0966] ##STR01684##

    Step-1. Synthesis of 1-(4-bromophenyl)-1-cyclopropylethan-1-ol (A92.3)

    [0967] 2.5 M n-butyllithium (6.72 g, 105 mmol) solution in hexane (41.9 mL) was added dropwise at −78° C. to a stirred solution of 1-bromo-4-iodobenzene (A92.1) (25 g, 88.3 mmol) in dry tetrahydrofuran (500 mL) under argon atmosphere and the reaction mixture was stirred at −78° C. for 2 h. Then, the solution of 1-cyclopropylethan-1-one (A92.2) (11.1 g, 132 mmol) in dry tetrahydrofuran (50 mL) was added at −78° C., after the reaction mixture was allowed to warm up and stir overnight at room temperature. Then, it was poured in water (500 mL) and extracted with ethyl acetate (250 mL×3). The organic layer was washed with water (250 mL), brine (250 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography purification (hexane/methyl tert-butyl ether) that afforded 1-(4-bromophenyl)-1-cyclopropylethan-1-ol as colorless oil (A92.3) (17 g, 70.5 mmol, 95% purity, 75.9% yield).

    Step-2. Synthesis of 1-bromo-4-(1-cyclopropylethyl)benzene (A92.4)

    [0968] Triethylsilane (10.6 g, 91.6 mmol) and trifluoroacetic acid (16.0 g, 141 mmol) were added to a solution of 1-(4-bromophenyl)-1-cyclopropylethan-1-ol (A92.3) (17 g, 70.5 mmol) in dichloromethane (500 mL) at −78° C. and the reaction mixture was allowed to warm up to room temperature and stir for 2 h. The organic layer was washed with 10% aq. solution of NaHCO.sub.3 and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography purification (hexane/methyl tert-butyl ether) that afforded 1-bromo-4-(1-cyclopropylethyl)benzene as colorless oil (A92.4) (7.3 g, 32.4 mmol, 95% purity, 43.8% yield).

    Step-3. Synthesis of lithium 4-(1-cyclopropylethyl)benzene-1-sulfinate (A92.5)

    [0969] 2.5 M n-butyllithium (2.48 g, 38.8 mmol) solution in hexane (15.5 mL) was added dropwise at −78° C. to a stirred solution of 1-bromo-4-(1-cyclopropylethyl)benzene (A92.4) (7.3 g, 32.4 mmol) in dry tetrahydrofuran (250 mL) under argon atmosphere and the reaction mixture was stirred at −78° C. for 2 h. Solution of SO.sub.2 (6.22 g, 97.1 mmol) in dry tetrahydrofuran (100 mL) was added at −78° C., after the reaction mixture was allowed to warm up to room temperature and stir overnight. The suspension was concentrated under reduced pressure to give lithium 4-(1-cyclopropylethyl)benzene-1-sulfinate as white solid (A92.5) (7.55 g, 34.9 mmol, 87.49% purity, 94.2% yield) that was used in the next step without further purification.

    Step-4. Synthesis of 4-(1-cyclopropylethyl)benzene-1-sulfonyl chloride (A92)

    [0970] 1-chloropyrrolidine-2,5-dione (5.18 g, 38.8 mmol) was added dropwise at −10° C. to a stirred solution of lithium 4-(1-cyclopropylethyl)benzene-1-sulfinate (A92.5) (7.00 g, 32.4 mmol) in dry dichloromethane (250 mL). The reaction mixture was allowed to warm up to room temperature and stir for 2 h. The organic layer was washed with water with ice (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure that afforded 4-(1-cyclopropylethyl)benzene-1-sulfonyl chloride as colorless oil (A92.6) (7.5 g, 30.6 mmol, 74% purity, 70.0% yield) that was used in next step without further purification.

    Step-5. Synthesis of 4-(1-cyclopropylethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]benzene-1-sulfonamide (A-779)

    [0971] Pyridine (0.117 g, 1.48 mmol) and 4-(1-cyclopropylethyl)benzene-1-sulfonyl chloride (A) (0.313 g, 1.28 mmol) were added to a solution of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)aniline (0.3 g, 0.988 mmol) in acetonitrile (25 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile, ammonia) to afford 4-(1-cyclopropylethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]benzene-1-sulfonamide (A-779). Yield: 134.8 mg, 25.3%; Appearance: White solid; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.52 (s, 1H), 7.67-7.63 (m, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.38-7.34 (m, 1H), 7.11-7.08 (m, 1H), 7.05 (t, J=4.7 Hz, 2H), 3.51 (t, J=8.2 Hz, 2H), 2.67 (d, J=10.8 Hz, 2H), 2.38 (d, J=8.5 Hz, 4H), 2.10 (d, J=7.0 Hz, 2H), 2.01 (q, J=8.1, 7.7 Hz, 1H), 1.62-1.49 (m, 5H), 1.21 (d, J=7.0 Hz, 4H), 1.17 (s, 1H), 1.02 (d, J=6.2 Hz, 6H), 0.88 (dd, J=8.9, 4.6 Hz, 1H), 0.47 (dd, J=9.2, 4.3 Hz, 1H), 0.29 (dq, J=8.7, 4.8, 4.3 Hz, 1H), 0.17 (dt, J=9.6, 4.7 Hz, 1H), 0.06 (s, 1H); HPLC purity: 100%; LCMS Calculated for C.sub.29H.sub.41N.sub.3O.sub.3S: 511.72; Observed: 512.4[M+H].sup.+.

    Example A93: Synthesis of 4-(cyclopropyldifluoromethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide (A-814)

    [0972] ##STR01685## ##STR01686##

    Step-1. Synthesis of Ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (A93.2)

    [0973] 1-bromo-4-iodobenzene (A93.1) (47.2 g, 166 mmol) and ethyl 2-bromo-2,2-difluoroacetate (36.9 g, 182 mmol) were added under argon atmosphere to a suspension of activated copper powder (27.3 g, 431 mmol) in DMSO (500 mL) and the mixture was stirred at 60° C. for 12 h. After, the mixture was poured into a mixture of ice (400 g) and NH.sub.4Cl sat. aq. solution (300 mL), the product was extracted with MTBE (500 mL×3). The combined MTBE layers were washed with NH.sub.4Cl saturated aq. solution (500 mL), brine (500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (hexane/chloroform) to afford ethyl 2-(4-bromophenyl)-2,2-difluoroacetate as a light-yellow oil (A93.2) (31.3 g, 112 mmol, 95% purity, 67.6% yield).

    Step-2. Synthesis of 2-(4-bromophenyl)-1-ethoxy-2,2-difluoroethanol (A93.3)

    [0974] 1 M DIBAL (18.2 g, 128 mmol) solution in cyclohexane (128 mL) was added dropwise at −78° C. under argon atmosphere to a solution of ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (A93.2) (29.9 g, 107 mmol) in dry dichloromethane (250 mL). The reaction mixture was stirred at −78° C. for 15 min and poured in 10% HCl aq/solution (250 mL). The mixture was extracted with dichloromethane (250 mL×2), combined organic layer was washed with brine (250 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain 2-(4-bromophenyl)-1-ethoxy-2,2-difluoroethanol as a white solid (A93.3) (30.1 g, 107 mmol, 98.61% purity, 98.6% yield).

    Step-3. Synthesis of 1-bromo-4-(1,1-difluoroallyl)benzene (A93.4)

    [0975] Methyltriphenylphosphoniumiodide (151 g, 374 mmol) was suspended in dry tetrahydrofuran (500 mL) under argon atmosphere and (tert-butoxy)potassium (41.9 g, 374 mmol) was added at 0° C. over 30 min. The mixture was stirred at 0° C. for 1 h. Then, 2-(4-bromophenyl)-1-ethoxy-2,2-difluoroethanol (A93.3) (30.1 g, 107 mmol) was added to it and the mixture was stirred at room temperature for 12 h. After the reaction was diluted with water (500 mL), the product was extracted with MTBE (500 mL×2). The combined organic layer was washed with brine (500 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography (hexane/chloroform) to give 1-bromo-4-(1,1-difluoroallyl)benzene as a colorless oil (A93.4) (12.51 g, 53.6 mmol, 90% purity, 44.9% yield).

    Step-4. Synthesis of 1-bromo-4-(cyclopropyldifluoromethyl)benzene (A93.5)

    [0976] 0.8 M diazomethane (5.36 g, 127.5 mmol) solution in MTBE (159 mL) was added at −40° C. to a mixture of 1-bromo-4-(1,1-difluoroallyl)benzene (A93.4) (12.51 g, 53.6 mmol) and Pd(OAc).sub.2 (0.0572 g, 0.254 mmol) in dry MTBE (200 mL). The mixture was stirred at −40° C. until the evolution of gas was ceased (for 2 h), filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (hexane/MTBE) to give 1-bromo-4-(cyclopropyldifluoromethyl)benzene as a colorless oil (A93.5) (4.9 g, 19.8 mmol, 91% purity, 33.7% yield).

    Step-5& 6. Synthesis of 4-(cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride (A93.8)

    [0977] 2 M n-Butyllithium (1.51 g, 23.7 mmol) in hexane (9.47 mL) was added to a solution of 1-bromo-4-(cyclopropyldifluoromethyl)benzene (A93.5) (4.9 g, 19.8 mmol) in anhydrous tetrahydrofuran (50 mL) at −78° C. under argon atmosphere and the mixture was stirred for 1 h at this temperature. The solution of SO.sub.2 (3.8 g, 59.4 mmol) in tetrahydrofuran (50 mL) was added to the resulting mixture at −78° C. Then the mixture was allowed to warm to room temperature and stir for 12 h. The solution was evaporated in vacuo and the residue was dissolved in dichloromethane (20 mL) and N-chlorosuccinimide (A93.7) (3.16 g, 23.7 mmol) was added portionwise maintaining the mixture temperature at 0° C. The mixture was stirred for 30 minutes, diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was dried over sodium sulfate, filtered and the filtrate was evaporated in vacuo to give 4-(cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride as a dark resin (A93.8) (5.3 g, 19.8 mmol, 76.62% purity, 76.8% yield) which was used in the next step without further purification.

    Step-7. Synthesis of 4-(cyclopropyldifluoromethyl)-N-(2-(4-(((2S,6R)-2,6-dimethylmorpholino)-methyl)piperidin-1-yl)-3-fluorophenyl)benzenesulfonamide (A-814)

    [0978] 4-(cyclopropyldifluoromethyl)benzene-1-sulfonyl chloride (A93.8) (0.53 g, 1.98 mmol) was added to the mixture of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluoroaniline (A93.9) (0.636 g, 1.98 mmol) and pyridine (0.982, 12.4 mmol) in dry acetonitrile (20 mL). The reaction mixture was stirred for 12 h and evaporated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) that afforded 4-(cyclopropyldifluoromethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)-3-fluorophenyl]benzene-1-sulfonamide (A-814). Yield: 147.7 mg, 12.8%; Appearance: Light brown oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.90 (s, 1H), 7.87 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 7.35-7.26 (m, 1H), 7.18-7.00 (m, 3H), 3.58-3.49 (m, 2H), 2.68 (d, J=11.0 Hz, 2H), 2.41 (t, J=11.1 Hz, 2H), 2.10 (d, J=6.9 Hz, 2H), 2.07 (s, 1H), 1.74-1.64 (m, 1H), 1.57 (q, J=11.8, 10.5 Hz, 5H), 1.18 (d, J=17.8 Hz, 2H), 1.04 (d, J=6.2 Hz, 6H), 0.73-0.56 (m, 4H); HPLC purity: 96.4%; LCMS Calculated for C.sub.28H.sub.37FN.sub.3O.sub.3S: 533.67; Observed: 534.0[M+H].sup.+.

    Example A94: Synthesis of 1-(cyclopropylmethyl)-N-[2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methylpiperidin-1-yl)phenyl]-1H-pyrazole-4-sulfonamide (A-772)

    [0979] ##STR01687##

    Step-1. Synthesis of (2R,6S)-2,6-dimethyl-4-{[1-(2-nitrophenyl)piperidin-4-yl]methyl}morpholine (A94.3)

    [0980] (2R,6S)-2,6-dimethyl-4-[(piperidin-4-yl)methyl]morpholine dihydrochloride (A94.1) (1.0 g, 3.50 mmol), 1-fluoro-2-nitrobenzene (A94.2) (0.493 g, 3.50 mmol) and dipotassium carbonate (1.7 g, 12.27 mmol) were mixed in DMF (30 mL), heated to 80° C. and stirred at this temperature overnight. Completion of reaction was controlled by LCMS. Reaction mixture was cooled to room temperature, diluted with water (40 mL) and the product was extracted with ethyl acetate (30 mL×3). Combined ethyl acetate layer was washed with water (20 mL×7), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford (2R,6S)-2,6-dimethyl-4-[1-(2-nitrophenyl)piperidin-4-yl]methylmorpholine (A94.3) (1.0 g, 2.99 mmol, 100% purity, 86.2% yield).

    Step-2. Synthesis of 2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methylpiperidin-1-yl)aniline (A94.4)

    [0981] (2R,6S)-2,6-dimethyl-4-[1-(2-nitrophenyl)piperidin-4-yl]methylmorpholine (A94.3) (1 g, 2.99 mmol) was dissolved in methanol (50 mL) and treated with 10% Pd/C (0.1 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (LCMS control). The catalyst was filtered off and the filtrate was evaporated under reduced pressure to afford 2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methylpiperidin-1-yl)aniline (A94.4) (0.96 g, 3.16 mmol, 93.43% purity, 98.7% yield).

    Step-3. Synthesis of 1-(cyclopropylmethyl)-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]-1H-pyrazole-4-sulfonamide (A-772)

    [0982] Ethylbis(propan-2-yl)amine (0.261 g, 2.04 mmol) was added to a solution of 2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methylpiperidin-1-yl)aniline (A94.4) (0.413 g, 1.35 mmol) in dichloromethane (20 mL). Then 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonyl chloride (A94.5) (0.297 g, 1.35 mmol) was added in one portion. Reaction mixture was stirring at room temperature overnight and evaporated under reduced pressure. Crude product was purified by HPLC (deionized water/HPLC-grade methanol, ammonia) to give 1-(cyclopropylmethyl)-N-[2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methylpiperidin-1-yl)phenyl]-1H-pyrazole-4-sulfonamide (A-772). Yield: 398.5 mg, 57.4%; Appearance: Beige solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.32 (s, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 7.37 (dd, J=7.6, 2.0 Hz, 1H), 7.14 (dd, J=7.4, 2.0 Hz, 1H), 7.05 (pd, J=7.4, 1.8 Hz, 2H), 3.92 (d, J=7.2 Hz, 2H), 3.51 (dtt, J=12.5, 6.2, 3.3 Hz, 2H), 2.70-2.66 (m, 2H), 2.54 (d, J=11.4 Hz, 2H), 2.12 (d, J=7.3 Hz, 2H), 1.71-1.67 (m, 2H), 1.59 (td, J=7.4, 3.7 Hz, 1H), 1.54 (dd, J=11.3, 10.1 Hz, 2H), 1.29-1.21 (m, 2H), 1.11 (tt, J=7.6, 4.6 Hz, 1H), 1.01 (d, J=6.3 Hz, 6H), 0.46-0.39 (m, 2H), 0.28-0.22 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.37N.sub.5O.sub.3S: 487.66; Observed: 488.2[M+H].sup.+.

    Example A95: Synthesis of 2-cyclopropyl-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]-4-methyl-1,3-thiazole-5-sulfonamide (A-768)

    [0983] ##STR01688##

    Step-1. Synthesis of 2-cyclopropyl-4-methylthiazole (A95.3)

    [0984] The solution of cyclopropanecarbothioamide (A95.1) (3 g, 29.6 mmol) and 1-chloropropan-2-one (A95.2) (2.73 g, 29.6 mmol) in ethanol (10 mL) was refluxed for 8 h, the reaction mixture was cooled to room temperature and evaporated to dryness. The residue was treated with NaHCO.sub.3 sat. aq. solution (10 mL), the product was extracted with ethyl acetate (10 mL×2). Combined organic layer was washed with water (10 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was distilled (bp=60° C. at 1 mm Hg) to give 2-cyclopropyl-4-methylthiazole (A95.3) (3 g, 21.5 mmol, 95% purity, 69.1% yield).

    Step-2. Synthesis of lithium 2-cyclopropyl-4-methylthiazole-5-sulfinate (A95.4)

    [0985] 2.5 M n-BuLi (1.71 g, 26.8 mmol) solution in hexane (10.7 mL) was added dropwise to the solution of 2-cyclopropyl-4-methylthiazole (A95.3) (3 g, 21.5 mmol) in tetrahydrofuran (30 mL) at −78° C., the mixture was stirred at the same temperature for 1 h, and the gaseous SO.sub.2 was bubbled through the mixture for 10 min. Then the mixture was allowed to warm to room temperature and stir overnight. The solvents were evaporated under reduced pressure to give crude lithium 2-cyclopropyl-4-methylthiazole-5-sulfinate (A95.4) (3 g, 14.3 mmol) that was used in the next step without further purification.

    Step-3. Synthesis of 2-cyclopropyl-4-methyl-1,3-thiazole-5-sulfonyl Chloride (A95.5)

    [0986] 1-chloropyrrolidine-2,5-dione (3.75 g, 28 mmol) was added portionwise to the solution of lithium 2-cyclopropyl-4-methylthiazole-5-sulfinate (A95.4) (3 g, 14.3 mmol) in tetrahydrofuran (100 mL) at 0° C., the mixture was stirred for 1 h, then water (100 mL) was added. The product was extracted with MTBE (100 mL×2), combined organic layer were washed with water (100 mL), dried over sodium sulfate, evaporated and purified by flash chromatography (hexane/chloroform) to give 2-cyclopropyl-4-methyl-1,3-thiazole-5-sulfonyl chloride (A95.5).

    Step-4. Synthesis of 2-cyclopropyl-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]-4-methyl-1,3-thiazole-5-sulfonamide (A-768)

    [0987] 2-cyclopropyl-4-methyl-1,3-thiazole-5-sulfonyl chloride (A95.5) (0.5 g, 2.10 mmol) was added to the mixture of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)aniline (A95.6) (0.637 g, 2.10 mmol) and pyridine (0.25 g, 3.15 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture was stirred overnight and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded the product 2-cyclopropyl-N-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}piperidin-1-yl)phenyl]-4-methyl-1,3-thiazole-5-sulfonamide (A-768). Yield: 139 mg, 12.5%; Appearance: Light brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.08 (s, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.17 (d, J=4.0 Hz, 2H), 7.11-7.06 (m, 1H), 3.54 (ddd, J=10.0, 6.1, 2.0 Hz, 2H), 2.70 (d, J=11.0 Hz, 2H), 2.63 (d, J=11.2 Hz, 2H), 2.54 (s, 1H), 2.37 (tt, J=8.1, 4.7 Hz, 1H), 2.24 (s, 3H), 2.12 (d, J=7.1 Hz, 2H), 1.65 (d, J=12.9 Hz, 2H), 1.56 (t, J=10.6 Hz, 3H), 1.20-1.09 (m, 4H), 1.04 (d, J=6.3 Hz, 6H), 0.98-0.92 (m, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.25H.sub.36N.sub.4O.sub.3S.sub.2: 504.71; Observed: 505.2[M+H].sup.+.

    Example A96: Synthesis of N1,N1-dimethyl-N4-[2-(morpholin-4-yl)phenyl]benzene-1,4-disulfonamide (A-815)

    [0988] ##STR01689##

    Step-1. Synthesis of 1,2-dichloro-5-methyl-3-nitrobenzene (A96.2)

    [0989] The solution of 2-chloro-4-methyl-6-nitroaniline (A96.1) (5 g, 26.7 mmol), tert-butyl nitrite (4.12 g, 40 mmol)) and copper (II) chloride (4.66 g, 34.6 mmol)) in acetonitrile (50 mL) was refluxed for 4 h, cooled to room temperature, filtered through silica pad and filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate (50 mL), this solution was washed with water (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 1,2-dichloro-5-methyl-3-nitrobenzene (A96.2) (3 g, 14.5 mmol, 90% purity, 49% yield) which was used in the next step without purification.

    Step-2. Synthesis of 4-(2-chloro-4-methyl-6-nitrophenyl)morpholine (A96.3)

    [0990] 1,2-dichloro-5-methyl-3-nitrobenzene (A96.2) (3 g, 14.5 mmol) was added to a stirred solution of morpholine (1.9 g, 21.8 mmol) and potassium carbonate (3 g, 21.8 mmol) in dry DMF (20 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in chloroform (15 mL), the organic layer was washed with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-(2-chloro-4-methyl-6-nitrophenyl)morpholine (A96.3) (2.8 g, 10.9 mmol, 90% purity, 45% yield) that was used in the next step without purification.

    Step-3. Synthesis of 3-chloro-5-methyl-2-(morpholin-4-yl)aniline (A96.4)

    [0991] Iron powder (6.08 g, 109 mmol)) and ammonium chloride (5.83 g, 109 mmol) were added at room temperature to a stirred solution of 4-(2-chloro-4-methyl-6-nitrophenyl)morpholine (A96.3) (2.8 g, 10.9 mmol)) in a mixture of ethanol (50 mL) and water (50 mL) and the resulting reaction mixture was refluxed for 6 h. After the reaction completion (TLC control) the mixture was filtered through silica and the filtrate was evaporated. The residue was treated with water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure that afforded crude 3-chloro-5-methyl-2-(morpholin-4-yl)aniline (A96.4) (1.6 g, 7.05 mmol, 90% purity, 58.2% yield) which was used in the next step without further purification.

    Step-4. Synthesis of N4-[3-chloro-5-methyl-2-(morpholin-4-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-815)

    [0992] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A96.5) (0.62 g, 2.2 mmol) was added to the mixture of 3-chloro-5-methyl-2-(morpholin-4-yl)aniline (A96.4) (0.5 g, 2.2 mmol)) and pyridine (0.261 g, 3.3 mmol) in dry tetrahydrofuran (20 mL). The reaction mixture was stirred overnight and evaporated under reduced pressure. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol) that afforded N4-[3-chloro-5-methyl-2-(morpholin-4-yl)phenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-815). Yield: 230.8 mg, 21.0%; Appearance: Yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.91 (s, 1H), 7.97-7.92 (m, 2H), 7.89 (d, J=8.6 Hz, 2H), 6.95 (s, 1H), 6.79 (d, J=3.0 Hz, 1H), 3.69 (t, J=4.4 Hz, 4H), 2.91 (t, J=4.4 Hz, 4H), 2.62 (s, 6H), 1.94 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.19H.sub.24ClN.sub.3O.sub.5S.sub.2: 473.99; Observed: 474.0[M+H].sup.+.

    Example A97: Synthesis of N1,N1-dimethyl-N4-[2-(morpholin-4-yl)phenyl]benzene-1,4-disulfonamide (A-770)

    [0993] ##STR01690##

    [0994] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A97.2) (0.354 g, 1.24 mmol) was added to the mixture 2-(morpholin-4-yl)aniline dihydrochloride (A97.1) (0.3 g, 1.19 mmol) and ethylbis(propan-2-yl)amine (A97.3) (0.23 g, 1.77 mmol) in dry acetonitrile (5 mL). The reaction mixture was stirred overnight. After completion, it was concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) to afford N1,N1-dimethyl-N4-[2-(morpholin-4-yl)phenyl]benzene-1,4-disulfonamide (A-770). Yield: 26.7 mg, 4.99%; Appearance: Light brown solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.25-7.22 (m, 1H), 7.13 (dd, J=7.0, 1.8 Hz, 2H), 7.06 (ddd, J=8.5, 6.4, 2.4 Hz, 1H), 3.58-3.47 (m, 4H), 2.59 (s, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.18H.sub.23N.sub.3O.sub.5S.sub.2: 425.52; Observed: 426.2[M+H].sup.+.

    Example A98: Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-methylpiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-781)

    [0995] ##STR01691## ##STR01692##

    Step-1. Synthesis of tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-4-methylpiperidine-1-carboxylate (A98.3)

    [0996] 1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid (A98.1) (2.0 g, 8.22 mmol), (2R,6S)-2,6-dimethylmorpholine (A98.2) (0.946 g, 8.22 mmol, 1.02 mL) and 1-methyl-1H-imidazole (2.01 g, 24.6 mmol, 1.97 mL) were dissolved in acetonitrile (20 mL) and [chloro(dimethylamino)methylidene]dimethylazanium; hexafluoro-λ.sup.5-phosphanide (3.45 g, 12.3 mmol) was added in a single portion. The reaction was stirred overnight at room temperature and concentrated under reduced pressure. Dichloromethane (20 mL) was added to the residue and the obtained solution was washed with brine (10 mL 2 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-4-methylpiperidine-1-carboxylate (A98.3) (3.4 g, 50.44% purity, 5.03 mmol, 61.2% yield).

    Step-2. Synthesis of (2R,6S)-2,6-dimethyl-4-(4-methylpiperidine-4-carbonyl)morpholine (A98.4)

    [0997] TFA (15 mL) was added in one portion to a stirred solution of tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-4-methylpiperidine-1-carboxylate (A98.3) (3.4 g, 9.98 mmol) in dichloromethane (45 mL). The resulting mixture was stirred overnight and evaporated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and saturated aqueous solution of potassium carbonate (40 mL). The organic layer was separated, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give crude (2R,6S)-2,6-dimethyl-4-(4-methylpiperidine-4-carbonyl)morpholine (A98.4) (2 g, 8.32 mmol, 86.06% purity, 71.9% yield) that was used in the next step without purification.

    Step-3. Synthesis of (2R,6S)-2,6-dimethyl-4-[(4-methylpiperidin-4-yl)methyl]morpholine (A98.5)

    [0998] LiAH.sub.4 (0.563 g, 16.6 mmol) was suspended in dry tetrahydrofuran (20 mlL, and (2R,6S)-2,6-dimethyl-4-(4-methylpiperidine-4-carbonyl)morpholine (A98.4) (2 g, 8.32 mmol) solution in tetrahydrofuran (10 mL) was added under ice-cooling dropwise keeping the temperature of mixture below 0° C. After the mixture was refluxed for 16 h, cooled to room temperature, and quenched with 2.0 M NaOH aq. solution (20 mL). The resulting mixture was stirred at room temperature for 15 min, the precipitate was filtered off and washed with THE (10 mL). The combined filtrates were concentrated under reduced pressure to give (2R,6S)-2,6-dimethyl-4-[(4-methylpiperidin-4-yl)methyl]morpholine (A98.5) (1.14 g, 5.03 mmol, 90% purity, 54.2% yield) that was used in next step without further purification.

    Step-4. Synthesis of (2R,6S)-4-{[1-(2-fluoro-6-nitrophenyl)-4-methylpiperidin-4-yl]methyl}-2,6-dimethylmorpholine (A98.7)

    [0999] 1,2-difluoro-3-nitrobenzene (A98.6) (0.8 g, 5.03 mmol) was added to a stirred solution of (2R,6S)-2,6-dimethyl-4-[(4-methylpiperidin-4-yl)methyl]morpholine (A98.5) (1.14 g, 5.03 mmol) and potassium carbonate (1.04 g, 7.54 mmol) in dry DMF (30 mL). The mixture were heated to 80° C. and stirred at this temperature till completion (overnight, TLC control). After the reaction mixture was cooled to room temperature, diluted with water (50 mL) and the product was extracted with ethyl acetate (30 mL×3). Combined ethyl acetate layers were washed with water (20 mL×7), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford (2R,6S)-4-{[1-(2-fluoro-6-nitrophenyl)-4-methylpiperidin-4-yl]methyl}-2,6-dimethylmorpholine as an orange solid (A98.7) (1.2 g, 3.28 mmol, 92.25% purity, 60.1% yield).

    Step-5. Synthesis of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-methylpiperidin-1-yl)-3-fluoroaniline (A98.8)

    [1000] 10% Pd/C (0.1 g) was added to the solution of (2R,6S)-4-{[1-(2-fluoro-6-nitrophenyl)-4-methylpiperidin-4-yl]methyl}-2,6-dimethylmorpholine (A98.7) (1.2 g, 3.28 mmol) in methanol (20 mL). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (LCMS control, overnight). The catalyst was filtered off and the filtrate was evaporated to afford 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-methylpiperidin-1-yl)-3-fluoroaniline (A98.8) (0.9 g, 2.68 mmol, 73.58% purity, 60.1% yield) that was used in next step without further purification.

    Step-6. Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-methylpiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-781)

    [1001] Pyridine (0.136 g, 1.72 mmol, 140.0 μl) was added to the mixture of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-methylpiperidin-1-yl)-3-fluoroaniline (A98.8) (0.387 g, 1.15 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A98.9) (0.357 g, 1.26 mmol) in dry acetonitrile (5 mL). The reaction mixture was stirred overnight. After completion, it was concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile) to afford N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-methylpiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-781). Yield: 127.8 mg, 18%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.23 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.3 Hz, 2H), 7.25-7.17 (m, 2H), 6.99 (ddd, J=12.3, 8.0, 1.6 Hz, 1H), 3.56 (dd, J=9.0, 5.9 Hz, 2H), 2.74 (d, J=27.9 Hz, 2H), 2.60 (s, 8H), 2.29 (s, 2H), 2.11 (s, 2H), 1.90 (t, J=10.6 Hz, 2H), 1.44 (t, J=10.4 Hz, 2H), 1.20 (d, J=12.9 Hz, 2H), 1.03 (d, J=6.2 Hz, 6H), 0.89 (s, 3H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.39FN.sub.4O.sub.5S.sub.2: 582.75; Observed: 583.2[M+H].sup.+.

    Example A99: Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-794)

    [1002] ##STR01693## ##STR01694##

    Step-1. Synthesis of tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-hydroxypiperidine-1-carboxylate (A99.3)

    [1003] tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (A99.1) (1 g, 4.68 mmol), rac-(2R,6S)-2,6-dimethylmorpholine (A99.2) (1.07 g, 9.36 mmol) and triethylamine (1.41 g, 14 mmol) were mixed in ethanol (10 mL) and stirred at 75° C. overnight. After the reaction mixture was cooled to room temperature and evaporated to dryness to give crude tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-hydroxypiperidine-1-carboxylate (A99.3) (1.6 g, 4.87 mmol, 80.0% purity, 83.6% yield) that was used in next step without further purification.

    Step-2. Synthesis of tert-butyl 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidine-1-carboxylate (A99.4)

    [1004] 4-morpholinylsulfur trifluoride (1.7 g, 9.74 mmol, 2.0 eq) was added at 0° C. to a solution of tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-hydroxypiperidine-1-carboxylate (A99.3) (1.6 g, 4.87 mmol) in anhydrous dichloromethane (10 mL). After the mixture was allowed to warm to room temperature and stir overnight. After the reaction was quenched by ice water (20 mL) and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by HPLC (deionized water/HPLC-grade acetonitrile) to give tert-butyl 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidine-1-carboxylate (A99.4) (0.58 g, 1.75 mmol, 95% purity, 34.4% yield).

    Step-3. Synthesis of (2R,6S)-4-[(4-fluoropiperidin-4-yl)methyl]-2,6-dimethylmorpholine Dihydrochloride (A99.5)

    [1005] tert-butyl 4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidine-1-carboxylate (A99.4) (0.58 g, 1.75 mmol) was dissolved in MTBE (10 mL) and 2 M HCl solution in dioxane was added (5 mL). The reaction mixture was stirred at room temperature overnight, evaporated under reduced pressure to give (2R,6S)-4-[(4-fluoropiperidin-4-yl)methyl]-2,6-dimethylmorpholine dihydrochloride (A99.5) (0.45 g, 1.48 mmol, 95% purity, 80.5% yield).

    Step-4. Synthesis of (2R,6S)-4-{[4-fluoro-1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-2,6-dimethylmorpholine (A99.7)

    [1006] 1,2-difluoro-3-nitrobenzene (A99.6) (0.115 g, 0.728 mmol), (2R,6S)-4-[(4-fluoropiperidin-4-yl)methyl]-2,6-dimethylmorpholine dihydrochloride (A99.5) (0.201 g, 0.662 mmol) and potassium carbonate (0.319 g, 2.31 mmol) were mixed in DMF (10 mL), heated to 80° C. and stirred at this temperature till completion (overnight, TLC control). After the reaction mixture was cooled to room temperature, diluted with water (20 mL) and the product was extracted with ethyl acetate (10 mL×3). Combined ethyl acetate layers were washed with water (5 mL×7), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford (2R,6S)-4-{[4-fluoro-1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-2,6-dimethylmorpholine as an orange solid (A99.7) (0.2 g, 0.541 mmol, 100% purity, 81.9% yield).

    Step-5. Synthesis of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidin-1-yl)-3-fluoroaniline (A99.8)

    [1007] 10% Pd/C (0.05 g) was added to the solution of (2R,6S)-4-{[4-fluoro-1-(2-fluoro-6-nitrophenyl)piperidin-4-yl]methyl}-2,6-dimethylmorpholine (A99.7) (0.2 g, 0.541 mmol) in methanol (10 mL). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (LCMS control, overnight). The catalyst was filtered off and the filtrate was evaporated to afford 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidin-1-yl)-3-fluoroaniline (A99.8) (0.18 g, 0.530 mmol, 99.14% purity, 97.2% yield).

    Step-6. Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-794)

    [1008] Pyridine (0.0627 g, 0.795 mmol, 70.0 μl) was added to the mixture of 2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidin-1-yl)-3-fluoroaniline (A99.8) (0.18 g, 0.53 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A99.9) (0.165 g, 0.583 mmol) in dry acetonitrile (5 mL). The reaction mixture was stirred overnight. After completion, it was concentrated in vacuo. The residue was subjected to HPLC purification (deionized water/HPLC-grade methanol, ammonia) to afford N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-fluoropiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-794). Yield: 24.7 mg, 7.54%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 7.99-7.88 (m, 4H), 7.27-7.17 (m, 2H), 6.99 (dd, J=12.1, 8.2 Hz, 1H), 3.59-3.51 (m, 2H), 2.93 (s, 2H), 2.75 (d, J=11.2 Hz, 2H), 2.62 (d, J=2.1 Hz, 6H), 2.44 (d, J=24.4 Hz, 2H), 2.22 (s, 2H), 1.76 (dd, J=23.0, 12.9 Hz, 6H), 1.04 (dd, J=6.3, 2.0 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.36F.sub.2N.sub.4O.sub.5S.sub.2: 586.72; Observed: 587.2[M+H].sup.+.

    Example A100: Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-817)

    [1009] ##STR01695## ##STR01696##

    Step-1. Synthesis of 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}pyridine (A100.3)

    [1010] Potassium tert-butylate (4.78 g, 42.6 mmol) was added at 0° C. to (2R,6S)-2,6-dimethyloxan-4-ol (A100.1) (1.85 g, 2.3 mmol) solution in DMSO (50 mL) and the mixture was stirred for 1 hour at room temperature. After it was cooled to 0° C. and 4-bromopyridine hydrochloride (A100.2) (2.39 g, 21.3 mmol) was added. The mixture was warmed to room temperature and stirred for 16 h. After monitoring by TLC, the reaction mixture was concentrated under reduced pressure. The residue was taken up in water (200 mL) and extracted with dichloromethane (200 mL×2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, concentrated under reduced pressure to give 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}pyridine (A100.3) (3.1 g, 14.9 mmol, 90% purity, 94.8% yield) that was used in next step without further purification.

    Step-2. Synthesis of 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidine (A100.4)

    [1011] 10% Pd/C (1.5 g) was added to a solution of 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}pyridine (A100.3) (3.1 g, 14.9 mmol) in ethanol (50 mL) and the mixture was hydrogenated at 80 bar and 70° C. for 3 days. After the mixture was cooled to room temperature, palladium was filtered off and the filtrate was concentrated under reduced pressure to give 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidine (A100.4) (2.5 g, 11.7 mmol, 85% purity, 66.8% yield) that was used in next step without further purification.

    Step-3. Synthesis of 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}-1-(2-fluoro-6-nitrophenyl)piperidine (A100.6)

    [1012] 1,2-difluoro-3-nitrobenzene (A100.5) (0.205 g, 1.29 mmol) was added to a stirred solution of 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidine (A100.4) (0.305 g, 1.42 mmol) and potassium carbonate (0.445 g, 3.22 mmol) in dry DMF (5 mL). The mixture was stirred at 60° C. until the reaction completion (TLC control) and concentrated under the reduced pressure. The residue was dissolved in ethyl acetate (15 mL), the organic layer was washed with water (15 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}-1-(2-fluoro-6-nitrophenyl)piperidine as an orange oil (A100.6) (0.41 g, 1.16 mmol, 95% purity, 85.6% yield).

    Step-4. Synthesis of 2-(4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidin-1-yl)-3-fluoroaniline (A100.7)

    [1013] 4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}-1-(2-fluoro-6-nitrophenyl)piperidine (A100.6) (0.41 g, 1.16 mmol) was dissolved in methanol (10 mL) and treated with 10% Pd/C (0.05 g). The resulting mixture was hydrogenated at 6 atm and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 2-(4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidin-1-yl)-3-fluoroaniline (A100.7) (0.29 g, 0.899 mmol, 95% purity, 73.5% yield).

    Step-5. Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-817)

    [1014] 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A100.8) (0.255 g, 0.899 mmol) was added to the mixture of 2-(4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidin-1-yl)-3-fluoroaniline (A100.7) (0.29 g, 0.899 mmol) and ethylbis(propan-2-yl)amine (0.173 g, 1.34 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred overnight, poured into NaHCO.sub.3 sat. aq. solution (15 mL) and extracted with dichloromethane (20 mL). Organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Resulting solid was purified by HPLC (deionized water/HPLC-grade methanol) to afford N4-[2-(4-{[(2R,6S)-2,6-dimethyloxan-4-yl]oxy}piperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-817). Yield: 84.8 mg, 15.7%; Appearance: Orange solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.35 (s, 1H), 8.02-7.89 (m, 4H), 7.25-7.15 (m, 2H), 6.96 (t, J=10.1 Hz, 1H), 3.59-3.36 (m, 6H), 2.61 (d, J=1.5 Hz, 6H), 1.87 (dd, J=13.1, 4.2 Hz, 2H), 1.70 (s, 2H), 1.52 (d, J=10.1 Hz, 2H), 1.15-1.01 (m, 6H), 0.92 (q, J=11.4 Hz, 2H); HPLC purity: 100%; LCMS Calculated for C.sub.26H.sub.36FN.sub.3O.sub.6S.sub.2: 569.71; Observed: 570.4[M+H].sup.+.

    Example A101: Synthesis of N4-[2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-786)

    [1015] ##STR01697## ##STR01698##

    Step-1. Synthesis of 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-hydroxypiperidine-1-carboxylate (A101.3)

    [1016] Tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (A101.1) (1 g, 4.68 mmol), rac-(2R,6S)-2,6-dimethylmorpholine (A101.2) (1.07 g, 9.36 mmol) and triethylamine (1.41 g, 14.05 mmol) were mixed together in ethanol (20 mL) and stirred at 75° C. overnight. Reaction mixture was cooled to room temperature, evaporated under reduced pressure to give crude tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-hydroxypiperidine-1-carboxylate (A101.3) (1.45 g, 4.41 mmol, 88.73% purity, 83.6% yield) which was used in next step without further purification.

    Step-2. Synthesis of tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidine-1-carboxylate (A101.4)

    [1017] tert-butyl-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-hydroxypiperidine-1-carboxylate (A101.3) (1.45 g, 4.43 mmol) was added at 0° C. to suspension of sodium hydride (0.211 g, 8.86 mmol) in tetrahydrofuran (50 mL). After 30 min of stirring at this temperature, iodomethane (1.57 g, 11.08 mmol) was added. The reaction mixture was stirred at room temperature overnight, cooled to 0° C. and diluted with NH.sub.4Cl sat. aq. solution (20 mL). The product was extracted with ethyl acetate (20 mL×3), combined ethyl acetate layers were dried under sodium sulfate, filtered and evaporated under reduce pressure to give crude tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidine-1-carboxylate (A101.4) (1.54 g, 4.49 mmol, 70.0% purity, 70.8% yield) that was used in next step without further purification.

    Step-3. Synthesis of give (2R,6S)-4-[(4-methoxypiperidin-4-yl)methyl]-2,6-dimethylmorpholine dihydrochloride (A101.5)

    [1018] 15 mL of HCl sat. solution in dioxane was added to solution of tert-butyl 4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidine-1-carboxylate (A101.4) (1.54 g, 4.5 mmol) in dioxane (40 mL). The reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was washed with MTBE (30 mL×2), dried on air to give (2R,6S)-4-[(4-methoxypiperidin-4-yl)methyl]-2,6-dimethylmorpholine dihydrochloride (A101.5) (1.05 g, 3.33 mmol, 95% purity, 70.7% yield).

    Step-4. Synthesis of (2R,6S)-4-[1-(2-fluoro-6-nitrophenyl)-4-methoxypiperidin-4-yl]methyl-2,6-dimethylmorpholine (A101.7)

    [1019] (2R,6S)-4-[(4-methoxypiperidin-4-yl)methyl]-2,6-dimethylmorpholine dihydrochloride (A101.5) (0.5 g, 1.58 mmol), 1,2-difluoro-3-nitrobenzene (A101.6) (0.251 g, 1.58 mmol) and dipotassium carbonate (0.764 g, 5.53 mmol) were mixed in DMF (50 mL), heated to 80° C. and stirred at this temperature overnight. Then the reaction mixture was cooled to room temperature, diluted with water (40 mL) and extracted with ethyl acetate (30 mL×3). Combined ethyl acetate layers were washed with water (15 mL×7), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford crude (2R,6S)-4-[1-(2-fluoro-6-nitrophenyl)-4-methoxypiperidin-4-yl]methyl-2,6-dimethylmorpholine (A101.7) (0.68 g, 1.78 mmol, 87.63% purity, 98.8% yield) that was used in next step without further purification.

    Step-5. Synthesis of 2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidin-1-yl)-3-fluoroaniline (A101.8)

    [1020] (2R,6S)-4-[1-(2-fluoro-6-nitrophenyl)-4-methoxypiperidin-4-yl]methyl-2,6-dimethylmorpholine (A101.7) (0.68 g, 1.78 mmol) was dissolved in MeOH (30 mL) and treated with 10% Pd/C (0.07 g). The resulting mixture was hydrogenated at ambient pressure and room temperature until the reaction was completed (TLC control). The catalyst was filtered off and the filtrate was evaporated to afford 2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidin-1-yl)-3-fluoroaniline (A101.8) (0.42 mg, 1.2 mmol, 83.7% purity, 56.1% yield) which was used in next step without further purification.

    Step-6. Synthesis of N4-[2-(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl}-4-methoxypiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-786)

    [1021] 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A101.9) (0.177 g, 0.625 mmol) was added in one portion to a solution of 2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidin-1-yl)-3-fluoroaniline (A101.8) (0.2 g, 0.569 mmol) and pyridine (0.0674 g, 0.853 mmol) in acetonitrile (10 mL). Reaction mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was purified by HPLC (deionized water/HPLC-grade acetonitrile, ammonia) to give N4-[2-(4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl-4-methoxypiperidin-1-yl)-3-fluorophenyl]-N1,N1-dimethylbenzene-1,4-disulfonamide (A-786). Yield: 31.4 mg, 8.76%; Appearance: Yellow solid; .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.28 (s, 1H), 7.97-7.93 (m, 2H), 7.89 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 6.94 (s, 1H), 3.54-3.48 (m, 2H), 3.05 (s, 3H), 2.83 (d, J=10.7 Hz, 2H), 2.77-2.73 (m, 2H), 2.58 (s, 6H), 2.27 (s, 2H), 2.13 (s, 2H), 1.75 (t, J=10.6 Hz, 2H), 1.63 (d, J=13.4 Hz, 2H), 1.57-1.49 (m, 2H), 1.01 (d, J=6.2 Hz, 6H); HPLC purity: 100%; LCMS Calculated for C.sub.27H.sub.39FN.sub.4O.sub.6S.sub.2: 598.75; Observed: 599.0[M+H].sup.+.

    Example A102: Synthesis of N4-(2-{1,7-diazaspiro[3.5]nonan-7-yl}-3-fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-816)

    [1022] ##STR01699## ##STR01700##

    Step-1. Synthesis of tert-butyl 7-(2-fluoro-6-nitrophenyl)-1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.3)

    [1023] 1,2-difluoro-3-nitrobenzene (A102.1) (0.994 g, 6.25 mmol) was added to a stirred solution of tert-butyl 1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.2) (1.7 g, 7.51 mmol) and dipotassium carbonate (1.29 g, 9.38 mmol) in dry DMF (100 mL). The mixture was stirred at 80° C. for 18 h. Then, it was cooled to room temperature, poured in water (200 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain tert-butyl 7-(2-fluoro-6-nitrophenyl)-1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.3) (2.2 g, 6.02 mmol, 95% purity, 91.6% yield).

    Step-2. Synthesis of tert-butyl 7-(2-amino-6-fluorophenyl)-1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.4)

    [1024] tert-butyl 7-(2-fluoro-6-nitrophenyl)-1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.3) (2.2 g, 6.02 mmol) was dissolved in methanol (100 mL). 10% Pd/C (0.3 g) was added to the solution and the mixture was hydrogenated at ambient pressure and room temperature for 4 h. Then it was filtered, the solid washed with methanol (50 mL) and combined filtrates were concentrated under reduced pressure to afford tert-butyl 7-(2-amino-6-fluorophenyl)-1,7-diazaspiro[3.5]nonane-1-carboxylate as white solid (A102.4) (1.95 g, 5.81 mmol, 91.57% purity, 88.5% yield) that was used in next step without further purification.

    Step-3. Synthesis of tert-butyl 7-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]-6-fluorophenyl}-1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.6)

    [1025] Pyridine (0.688 g, 8.71 mmol) and 4-(dimethylsulfamoyl)benzene-1-sulfonyl chloride (A102.5) (1.81 g, 6.39 mmol) were added to tert-butyl 7-(2-amino-6-fluorophenyl)-1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.4) (1.95 g, 5.81 mmol) in acetonitrile (100 mL). The reaction mixture was stirred at room temperature for 18 h and evaporated. The residue was purified by flash chromatography (chloroform/acetonitrile) that afforded tert-butyl 7-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]-6-fluorophenyl}-1,7-diazaspiro[3.5]nonane-1-carboxylate as white solid (A102.6) (1.5 g, 2.57 mmol, 95% purity, 42.0% yield).

    Step-4. Synthesis of N4-(2-{1,7-diazaspiro[3.5]nonan-7-yl}-3-fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-816)

    [1026] tert-butyl 7-{2-[4-(dimethylsulfamoyl)benzenesulfonamido]-6-fluorophenyl}-1,7-diazaspiro[3.5]nonane-1-carboxylate (A102.6) (1 g, 1.71 mmol) was added to trifluoroacetic acid (50 mL). The mixture was stirred at room temperature overnight. Then, it was concentrated under reduced pressure and the residue was subjected to HPLC purification (deionized water/HPLC-grade acetonitrile, ammonia) that afforded N4-(2-{1,7-diazaspiro[3.5]nonan-7-yl}-3-fluorophenyl)-N1,N1-dimethylbenzene-1,4-disulfonamide (A-816). Yield: 35.1 mg, 4.03%; Appearance: Beige solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90-7.85 (m, 2H), 7.78-7.70 (m, 2H), 6.93 (d, J=8.2 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.37 (t, J=9.7 Hz, 1H), 5.48 (s, 1H), 3.10 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.59 (d, J=2.1 Hz, 6H), 2.54 (d, J=1.8 Hz, 2H), 2.23 (s, 2H), 2.00 (s, 2H); HPLC purity: 97.36%; LCMS Calculated for C.sub.21H.sub.27FN.sub.4O.sub.4S.sub.2: 482.59; Observed: 483.4[M+H].sup.+.

    Example A103: Synthesis of N-(2-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidin]-1′-yl)phenyl)-4-(methylsulfonyl)benzenesulfonamide (A-441)

    [1027] ##STR01701## ##STR01702##

    Step-1. Synthesis of 1′-benzyl-2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one (A103.3)

    [1028] A mixture of 2-phenylacetamide (A103.1) (5 g, 36 mmol, 1 eq) and 1-benzylpiperidin-4-one (A103.2) (10.5 g, 55 mmol, 1.5 eq) in polyphosphoric acid (100 g) was heated at 100° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to 50° C. and slowly poured into ice-water mixture. The mixture was basified with 36% aqueous sodium hydroxide to pH 7 to 8 and stirred for 10 min. The resultant precipitate was filtered out, washed with water and dried under reduced pressure to afford 1′-benzyl-2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one (A103.3) (8 g, crude). This compound was used in the next step without further purification. LCMS: 307.17 [M+H].sup.+.

    Step-2. Synthesis of 1′-benzyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.4)

    [1029] To a stirred solution of 1′-benzyl-2H-spiro[isoquinoline-1,4′-piperidin]-3(4H)-one (A103.3) (2 g, 6.5 mmol, 1 eq) in THE (30 mL) was added a 2 M solution of borane dimethylsulfide (6.52 mL, 13 mmol, 2 eq) and the reaction mixture was refluxed for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, 10% aqueous HCl was added and stirred for 5 min, followed by addition of methanol and refluxed for 1 h. The reaction mixture was cooled to room temperature, poured into 10% aqueous sodium hydroxide solution and extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford 1′-benzyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.4) (1.52 g, 80%). LCMS: 293.19 [M+H].sup.+.

    Step-3. Synthesis of 1′-benzyl-2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine](A103.5)

    [1030] A solution of 1′-benzyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.4) (1 g, 3.4 mmol, 1 eq) and a 37% aqueous formaldehyde solution (4 mL) in methanol (15 mL) was stirred at room temperature for 16 h. Sodium triacetoxyborohydride (2.17 g, 10 mmol, 3 eq) was then added to the reaction mixture and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was basified with saturated aqueous NaHCO.sub.3 solution to pH 8. The reaction mixture was concentrated under reduced pressure, and the residue was treated with water and extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated and purified by combiflash chromatography on silica gel to afford 1′-benzyl-2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine](A103.5) (900 mg, 86%). LCMS: 307.21 [M+H].sup.+.

    Step-4. Synthesis of 2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.6)

    [1031] A stirred solution of 1′-benzyl-2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.5) (1.3 g, 4.2 mmol, 1 eq) in ethanol was purged with nitrogen for 5 min. 10% Palladium on carbon (400 mg, 30% w/w) and ammonium formate (2.67 g, 42 mmol, 10 eq) were then added to the reaction mixture under nitrogen atmosphere. The reaction mixture was refluxed for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was cooled to room temperature, filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to dryness to afford 2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.6) (1 g, crude). This compound was used in the next step without further purification. LCMS: 271.16 [M+H].sup.+.

    Step-5. Synthesis of 2-methyl-1′-(2-nitrophenyl)-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.8)

    [1032] To a stirred solution of 2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine](A103.6) (1 g, 4.6 mmol, 1 eq) in DMF or DMSO/CH.sub.3CN (10 mL) were added potassium carbonate/DIPEA (1.28 g, 9.2 mmol, 2 eq) and 2-fluoro nitrobenzene (A103.7) (0.649 g, 4.6 mmol, 1 eq) and the reaction mixture was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford 2-methyl-1′-(2-nitrophenyl)-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.8) (1.1 g, 71%).

    Step-6. Synthesis of 2-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidin]-1′-yl)aniline (A103.9)

    [1033] An autoclave was charged with a solution of 2-methyl-1′-(2-nitrophenyl)-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (A103.8) (500 mg, 1.4 mmol, 1 eq) in a mixture of methanol (15 mL) and DCM (5 mL) and purged with nitrogen for 5 min. 10% Palladium on carbon (200 mg, 50% moisture, 20% w/w) was then added to the reaction mixture under nitrogen atmosphere. The reaction mixture was purged with hydrogen and stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to dryness to afford 2-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidin]-1′-yl)aniline (A103.9) (450 mg, crude). This compound was used in the next step without further purification.

    Step-7. Synthesis of N-(2-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidin]-1′-yl)phenyl)-4-(methylsulfonyl)benzenesulfonamide (A-441)

    [1034] To a stirred solution of 2-(2-methyl-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidin]-1′-yl)aniline (A103.9) (250 mg, 0.813 mmol, 1 eq) in acetonitrile (5 mL) was added pyridine (0.2 mL, 2.44 mmol, 3 eq) at 0° C. and the reaction mixture was stirred for 10 min. 4-(methylsulfonyl)benzenesulfonyl chloride (A103.10) (248 mg, 0.976 mmol, 1.2 eq) was added to the reaction mixture at 0° C. The reaction mixture was allowed to attain room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by preparative SFC to afford the titled compound (A-441). Yield: 80 mg, 18.7%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.34 (bs,/1H), 8.13-8.04 (m, 4H), 7.40 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.24 (t, J=7.2 Hz, 1H), 7.20-7.03 (m, 5H), 3.21 (s, 3H), 3.12-3.06 (m, 2H), 2.97-2.88 (m, 2H), 2.76-2.70 (m, 2H), 2.33-2.27 (m, 2H), 2.19 (s, 3H), 2.08-1.98 (m, 2H), 1.82 (d, J=13.2 Hz, 2H); HPLC purity: 99.57%; LCMS calculated for C.sub.27H.sub.31N.sub.3O.sub.4S.sub.2: 525.18; Observed: 526.25 [M+H].sup.+.

    [1035] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00034 Compound No. Structure Yields/Analytical data A-348 [01703]embedded image Yield: 45 mg, 12.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.30 (bs, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 4.0 Hz, 1H), 7.35 − 7.30 (m, 2H), 7.24 − 7.20 (m, 1H), 7.19 − 7.13 (m, 1H), 7.11 − 8.06 (m, 1H), 6.55 − 6.50 (m, 1H), 3.23 (s, 3H), 2.85 (s, 3H), 2.64 − 2.56 (m, 2H), 1.88 − 1.78 (m, 2H), 1.53 (d, J = 12.8 Hz, 2H), (s, 2H merged with the moisture peak, m, 2H merged with the solvent peak); HPLC purity: 99.79%; LCMS calculated for C.sub.25H.sub.28N.sub.4O.sub.4S.sub.2: 512.16; Observed: 513.25 [M + H].sup.+. A-398 [01704]embedded image Yield: 14 mg, 2.73%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (bs, 1H), 8.16 (s, 1H, formate salt), 8.10 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.34 − 7.25 (m, 3H), 7.17 − 7.04 (m, 3H), 7.02 (d, J = 7.6 Hz, 1H), 3.45 (s, 2H), 3.20 (s, 3H), 2.75 (t, J = 11.6 Hz, 2H), 2.62 (s, 2H), 2.39 − 2.31 (m, 2H), 2.35 (s, 3H), 2.11 − 2.02 (m, 2H), 1.55 (d, J = 13.2 Hz, 2H); HPLC purity: 97.94%; LCMS calculated for C.sub.27H.sub.31N.sub.3O.sub.4S.sub.2: 525.18; Observed: 526.25 [M + H].sup.+. A-402 [01705]embedded image Yield: 200 mg, 57%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.36 (bs, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.0 Hz, 2H), 7.40 − 7.32 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.20 − 7.05 (m, 5H), 3.85 − 3.79 (m, 2H), 3.22 (s, 3H), 2.85 (t, J = 11.2 Hz, 2H), 2.77 − 2.71 (m, 2H), 2.30 (d, J = 10.4 Hz, 2H), 2.14-2.03 (m, 2H), 1.69 (d, J = 13.2 Hz, 2H); HPLC purity: 99.86%; LCMS calculated for C.sub.26H.sub.28N.sub.2O.sub.5S.sub.2: 512.14; Observed: 513.20 [M + H].sup.+. A-481 [01706]embedded image Yield: 260 mg, 74.7%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.37 (bs, 1H), 8.11 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.36 − 7.26 (m, 3H), 7.20 − 7.05 (m, 3H), 7.01 (d, J = 12 Hz, 1H), 4.69 (s, 2H), 3.90 (s, 2H), 3.20 (s, 3H), 2.74 (t, J = 12.0 Hz, 2H), 2.35 (d, J = 11.2 Hz, 2H), 2.13 − 2.04 (m, 2H), 1.52 (d, J = 12.8 Hz, 2H); HPLC purity: 99.64%; LCMS calculated for C.sub.26H.sub.28N.sub.2O.sub.5S.sub.2: 512.14; Observed: 513.25 [M + H].sup.+. A-492 [01707]embedded image Yield: 6 mg, 7%; Appearance: Off white solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.20 (bs, 1H), 8.06 − 7.97 (m, 4H), 7.61 (dd, J = 1.2, 8.0 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.20 − 7.06 (m, 4H), 6.78 (t, J = 12 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 3.18 (t, J = 6.0 Hz, 2H), 3.03 (s, 3H), 2.90 (s, 3H), 2.85 (t, J = 11.2 Hz, 2H), 2.33 (d, J = 11.6 Hz, 2H), 2.17 − 2.07 (m, 2H), 2.04 − 1.98 (m, 2H), 1.70 (d, J = 13.2 Hz, 2H); HPLC purity: 97.78%; LCMS calculated for C.sub.27H.sub.31N.sub.3O.sub.4S.sub.2: 525.18; Observed: 526.25 [M + H].sup.+. A-470 [01708]embedded image Yield: 100 mg, 25.6; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.36 (bs, 1H), 8.03 (d, J = 7.6 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.14 − 7.02 (m, 3H), 3.03 − 2.94 (m, 1H), 2.61 (s, 6H), 2.59 − 2.52 (m, 4H), 1.79 − 1.65 (m, 2H), 1.49 (d, J = 12.0 Hz, 2H), 1.11 (s, 9H); HPLC purity: 99.73%; LCMS Calculated for C.sub.24H.sub.33N.sub.3O.sub.5S.sub.2: 507.19; Observed: 508.25 [M + H].sup.+. A-352 [01709]embedded image Yield: 60 mg, 33%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 7.97 (s, 4H), 7.27 − 7.14 (m, 3H), 3.87 − 3.78 (m, 2H), 3.20 − 3.19 (m, 2H), 2.64 (s, 6H), 2.34 − 2.24 (m, 2H), 1.19 (s, 9H), (2H merged with the moisture peak); HPLC purity: 99.79%; LCMS Calculated for C.sub.23H.sub.31ClN.sub.4O.sub.5S.sub.2: 542.14; Observed: 543.25 [M + H].sup.+. A-353 [01710]embedded image Yield: 100 mg, 30%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.18 (bs, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.12 − 7.07 (m, 2H), 7.07 − 7.00 (M, 1H), 2.62 (s, 8H), 2.39 (t, J = 11.6 Hz, 2H), 1.52 (d, J = 12.0 Hz, 2H), 1.35 − 1.22 (m, 2H), 1.02 − 0.92 (m, 1H), 0.86 (s, 9H); HPLC purity: 99 40%; LCMS Calculated for C.sub.23H.sub.33N.sub.3O.sub.4S.sub.2 479.19; Observed: 480.70 [M + H].sup.+. A-361 [01711]embedded image Yield: 460 mg, 71%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.19 (bs, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.13 − 7.00 (m, 3H), 6.67 (s, 1H), 2.62 (s, 6H), 2.50 − 2.38 (m, 4H), 2.04 − 1.95 (m, 2H), 1.44 − 1.34 (m, 2H), 1.27 (s, 9H), 1.09 (s, 3H); HPLC purity: 99.76%; LCMS Calculated for C.sub.25H.sub.36N.sub.4O.sub.5S.sub.2 536.21; Observed: 537.55 [M + H].sup.+. A-360 [01712]embedded image Yield: 47 mg, 17%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.23 (bs, 1H), 8.0 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.27 (dd, J = 1.6, 8.0 Hz, 1H), 7.14 − 7.07 (m, 1H), 7.07 − 6.97 (m, 2H), 2.84 (s, 3H), 2.63 (s, 6H), 2.47 − 2.35 (m, 4H), 2.10 (d, J = 13.2 Hz, 2H), 1.51 − 1.42 (m, 2H), 1.31 (s, 9H), 1.18 (s, 3H); HPLC purity: 99.94%; LCMS Calculated for C.sub.26H.sub.38N.sub.4O.sub.5S.sub.2: 550.23; Observed: 551.35 [M + H].sup.+. A-354 [01713]embedded image Yield: 120 mg, 16.1%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.44 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.08 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 3.92 (d, J = 11.6 Hz, 2H), 3.71 (s, 2H), 3.10 (d, J = 11.6 Hz, 2H), 2.64 (s, 6H), 1.79 − 1.72 (m, 2H), 1.56 − 1.50 (m, 2H), 1.20 (s, 9H); HPLC purity: 97 18%; LCMS Calculated for C.sub.25H.sub.34N.sub.4O.sub.5S.sub.2 534.20; Observed: 535.25 [M + H].sup.+. A-407 [01714]embedded image Yield: 56 mg, 17.6%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.27 (bs, 1H), 8.55 (s, 1H), 8.49 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.38 (dd, J = 4.8, 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.20 − 7.04 (m, 4H), 6.49 (d, J = 10.8 Hz, 1H), 6.44 − 6.36 (m, 1H), 4.39 (s, 2H), 3.30 (s, 2H), 3.23 (s, 3H), 2.55 − 2.42 (m, 4H), 1.90 − 1.80 (m, 2H), 1.50 (d, J = 12.8 Hz, 2H); HPLC purity: 99.62%; LCMS Calculated for C.sub.31H.sub.31FN.sub.4O.sub.4S.sub.2: 606.18; Observed: 607.30 [M + H].sup.+. A-403 [01715]embedded image Yield: 40 mg, 12.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.30 (bs, 1H), 8.54 − 8.50 (m, 2H), 8.12 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.34 − 7.28 (m, 3H), 7.20 − 7.04 (m, 4H), 6.43 − 6.35 (m, 2H), 4.40 (s, 2H), 3.24 (s, 3H), 2.58 − 2.40 (m, 4H), 1.93 − 1.82 (m, 2H), 1.54 (d, J = 12.8 Hz, 2H), (2H merged with the moisture peak); HPLC purity: 98.54%; LCMS calculated for C.sub.31H.sub.31FN.sub.4O.sub.4S.sub.2: 606.18; Observed: 607.30 [M + H].sup.+. A-466 [01716]embedded image Yield: 67.7 mg, 21.1%; Appearance: Pale brown solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.28 (bs, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.24 − 7.00 (m, 4H), 6.37 − 6.28 (m, 2H), 3.52 (t, J = 5.2 Hz, 2H), 3.40 (s, 2H), 3.29 (m, 2H), 3.27 (s, 3H), 3.23 (s, 3H), 2.62 − 2.52 (m, 2H), 2.50 − 2.44 (m, 2H), 1.88 − 1.78 (m, 2H), 1.48 (d, J = 13.2 Hz, 2H); HPLC purity: 99 61%; LCMS calculated for C.sub.28H.sub.32FN.sub.3O.sub.5S.sub.2: 573.18; Observed: 574.20 [M + H].sup.+. A-467 [01717]embedded image Yield: 120 mg, 38.2%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.28 (bs, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.10 − 7.04 (m, 1H), 7.02 (t, 6.8 Hz, 1H), 6.35 − 6.29 (m, 2H), 4.08 − 4.00 (m, 1H), 3.76 (q, J = 6.8 Hz, 1H), 3.63 (q, J = 6.4 Hz, 1H), 3.48 − 3.40 (m, 2H), 3.23 (s, 3H), 3.19 (d, J = 3.6 Hz, 1H), 3.15 − 3.08 (m, 1H), 2.61 − 2.43 (m, 4H), 2.00 − 1.90 (m, 1H), 1.90 − 1.73 (m, 4H), 1.57 − 1.43 (m, 3H); HPLC purity: 99.81%; LCMS Calculated for C.sub.30H.sub.34FN.sub.3O.sub.5S.sub.2 599.19; Observed: 599.80 [M + H].sup.+. A-423 [01718]embedded image Yield: 120 mg, 38.2%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.28 (bs, 1H), 8.12 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 6.4 Hz, 1H), 7.11 − 7.00 (m, 2H), 6.37 − 6.30 (m, 2H), 3.82 − 3.73 (m, 2H), 3.65 (q, J = 8.0 Hz, 1H), 3.41 − 3.35 (m, 2H), 3.23 (s, 3H), 3.08 − 3.04 (m, 2H), 2.69 − 2.53 (m, 3H), 2.50 − 2.43 (m, 2H), 2.02 − 1.93 (m, 1H), 1.90 − 1.76 (m, 2H), 1.61 − 1.51 (m, 1H), 1.48 (bd, J = 12.4 Hz, 2H), (.sup.1H merged with the moisture peak); HPLC purity: 98.05%; LCMS Calculated for C.sub.30H.sub.34FN.sub.3O.sub.5S.sub.2: 599.19; Observed: 600.10 [M + H].sup.+. A-468 [01719]embedded image Yield: 100 mg, 21.4%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (bs, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 1.6, 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.18 − 7.12 (m, 1H), 7.10 − 7.04 (m, 2H), 6.43 − 6.35 (m, 2H), 3.43 − 3.34 (m, 3H), 3.30 (s, 2H), 3.23 (s, 3H), 3.18 − 3.11 (m, 1H), 2.64 − 2.50 (m, 2H), 2.00 − 1.78 (m, 3H), 1.69 − 1.59 (m, 1H), 1.50 (bd, J = 12.4 Hz, 2H), 1.37 − 1.27 (m, 1H); HPLC purity: 99.86%; LCMS Calculated for C.sub.29H.sub.30F.sub.3N.sub.3O.sub.4S.sub.2: 605.16; Observed: 605.95 [M + H].sup.+. A-469 [01720]embedded image Yield: 136.6 mg, 35.6%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.29 (bs, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.47 (bs, 1H), 7.35 − 7.23 (m, 3H), 7.17 − 7.06 (m, 2H), 6.91 − 6.84 (m, 1H), 5.32 (bs, 1H), 3.90 − 3.72 (m, 6H), 3.22 (s, 3H), 2.64 − 2.54 (m, 2H), 2.50 − 2.43 (m, 2H), 2.25 − 2.14 (m, 1H), 2.08-1.98 (m, 1H), 1.91 (t, J = 11.6 Hz, 2H), 1.53 (d, J = 12.8 Hz, 2H); HPLC purity: 96.48%; LCMS calculated for C.sub.30H.sub.32FN.sub.3O.sub.7S.sub.2: 629.17; Observed: 630.25 [M + H].sup.+. A-442 [01721]embedded image Yield: 209.6 mg, 43.6%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.27 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.47 (bs, 1H), 7.37 − 7.30 (m, 2H), 7.28 − 7.23 (m, 1H), 7.18 − 8.08 (m, 2H), 6.91 − 6.83 (m, 1H), 5.32 (bs, 1H), 3.90 − 3.72 (m, 6H), 2.64 − 2.54 (m, 2H), 2.58 (s, 6H), 2.50 − 2.40 (m, 2H), 2.25 − 2.13 (m, 1H), 2.09 − 1.98 (m, 1H), 1.98 − 1.87 (m, 2H), 1.50 (d, J = 12.4 Hz, 2H); HPLC purity: 99.62%; LCMS calculated for C.sub.31H.sub.35FN.sub.4OS.sub.2: 658.19; Observed: 659.25 [M + H].sup.+. A-408 [01722]embedded image Yield: 90 mg, 39%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.80 (bs, 1H), 8.56 (s, 1H), 7.80 − 7.73 (m, 2H), 7.70 (d, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 6.8 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.09 − 7.00 (m, 2H), 5.25 (s, 1H), 2.94 (t, J = 11.2 Hz, 2H), 2.46 − 2.30 (m, 4H), 2.32 (s, 3H), 1.55 (d, J = 13.2 Hz, 2H); HPLC purity: 98.74%; LCMS Calculated for C.sub.23H.sub.24FN.sub.3O.sub.3S: 441 15; Observed: 442.20 [M + H].sup.+. A-409 [01723]embedded image Yield: 95 mg, 40%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.70 (bs, 1H), 8.56 (s, 1H), 7.79 − 7.70 (m, 4H), 7.34 − 7.29 (m, 1H), 7.21 − 7.17 (m, 1H), 7.08 − 7.02 (m, 4H), 5.26 (s, 1H), 3.77 (s, 3H), 2.95 (t, J = 11.2 Hz, 2H), 2.46 − 2.30 (m, 4H), 1.56 (d, J = 12.4 Hz, 2H); HPLC purity: 99.38%; LCMS Calculated for C.sub.23H.sub.24FN.sub.3O.sub.4S: 457.15; Observed: 458.25 [M + H].sup.+. A-414 [01724]embedded image Yield: 10 mg, 5.4%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.18 (bs, 1 H), 7.98 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.19 − 7.06 (m, 3H), 5.66 (s, 1H), 3.32 − 3.23 (m, 4H), 2.77 − 2.64 (m, 4H), 2.71 (s, 6H), 1.54 (s, 9H); HPLC purity: 98.07%; LCMS Calculated for C.sub.25H.sub.34N.sub.6O.sub.4S.sub.2: 546.21; Observed: 547.20 [M + H].sup.+. A-482 [01725]embedded image Yield: 200 mg, 21.7%; Appearance: Pale yellow solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (bs, 1H), 8.03 − 7.92 (m, 4H), 7.57 (s, 2H), 7.47 (t, J = 8.4 Hz, 1H), 7.38 (d, J = 10.4 Hz, 1H), 7.35 − 7.30 (m, 2H), 7.23 − 7.05 (m, 3H), 2.89 − 2.79 (m, 1H), 2.68 − 2.50 (m, 4H), 1.92 − 1.80 (m, 2H), 1.68 − 1.60 (m, 2H); HPLC purity: 98.43%; LCMS calculated for C.sub.23H.sub.23ClFN.sub.3O.sub.4S.sub.2: 523.08; Observed: 524.20 [M + H].sup.+. A-424 [01726]embedded image Yield: 98.4 mg, 24.7%; Appearance: Gray solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.18 (br s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.70 − 7.65 (m, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.40 − 7.29 (m, 3H), 7.20 − 7.06 (m, 3H), 2.87 − 2.77 (m, 1H), 2.65 − 2.56 (m, 2H), 2.55 − 2.50 (m, 2H), 2.37 (d, J = 4.8 Hz, 3H), 1.88 − 1.75 (m, 2H), 1.60 (d, J = 11.6 Hz, 2H); HPLC purity: 99.56%; LCMS calculated for C.sub.24H.sub.25ClFN.sub.3O.sub.4S.sub.2: 537.10; Observed: 538.15 [M + H].sup.+. A-637 [01727]embedded image Yield: 0.5 g, 18%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.56-1.67 (m, 2H) 1.70- 1.87 (m, 2H) 2.55-2.71 (m, 4H) 2.82 (t, J = 11.25 Hz, 1H) 3.41-3.53 (m, 2H) 3.65 (q, J = 5.87 Hz, 2H) 4.80 − 4.89 (m, 1H) 7.05 − 7.22 (m, 3H) 7.27 − 7.49 (m, 4H) 7.98 − 8.11 (m, 4H) 9.17 − 9.32 (m, 1H); HPLC purity: 98.82%; LCMS Calculated for C.sub.25H.sub.26ClFN.sub.2O.sub.5S.sub.2 553.06; Observed: 553.07 [M + H].sup.+. A-701 [01728]embedded image Yield: 0.165 g, 26%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.25 (bs, 1H), 8.07 (q, J = 7.84 Hz, 4H), 7.47 − 7.36 (m, 2H), 7.32-7.30 (m, 2H), 7.19 − 7.05 (m, 3H), 3.64 − 3.61 (m, 2H), 3.57 − 3.54 (m, 2H), 2.95 (s, 3H), 2.85 − 2.79 (m, 1H), 2.65 − 2.60 (m, 4H), 1.86 − 1.78 (m, 2H), 1.64 − 1.61 (m, 2H); HPLC purity: 98.80%; LCMS Calculated for C.sub.26H.sub.28ClFN.sub.2O.sub.5S.sub.2 566.11; Observed: 566.95 [M + H].sup.+. A-502 [01729]embedded image Yield: 0.06 g, 59%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (s, 1H), 7.99 − 7.82 (m, 4H), 7.34 − 7.28 (m, 4H), 7.27 − 7.21 (m, 1H), 7.10 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.85 (t, J = 8.0 Hz, 1H), 3.59 (s, 2H), 3.12 (t, J = 7.2 Hz, 2H), 2.75 − 2.70 (m, 2H), 2.68 − 2.58 (m, 2H), 2.62 (s, 6H), 2.57 − 2.50 (m, 2H), 2.46 − 2.40 (m, 2H); HPLC purity: 97.51%; LCMS calculated for C.sub.27H.sub.32N.sub.4O.sub.4S.sub.2: 540.19; Observed: 541.30 [M + H].sup.+. A-483 [01730]embedded image Yield: 120 mg, 32.7%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (br s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.37 − 7.32 (m, 1H), 7.23 − 7.18 (m, 1H), 7.09 − 7.03 (m, 2H), 3.28 (s, 3H), 3.12 (s, 2H), 2.50 − 2.43 (m, 2H), 2.37 − 2.30 (m, 2H), 1.56 − 1.48 (m, 2H), 1.30 − 1.20 (m, 2H), 1.24 (s, 9H), 0.93 (s, 3H); HPLC purity: 97.99%; LCMS calculated for C.sub.24H.sub.34N.sub.2O.sub.3S: 430.23; Observed: 431.35 [M + H].sup.+. A-489 [01731]embedded image Yield: 80 mg, 28.2%; Appearance: Colorless oil; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.54 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.41 − 7.36 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.23 − 7.18 (m, 1H), 7.09 − 7.03 (m, 2H), 3.27 (s, 3H), 3.12 (s, 2H), 2.47 − 2.41 (m, 2H), 2.37 − 2.30 (m, 2H), 1.60 − 1.50 (m, 2H), 1.31 − 1.23 (m, 2H), 0.93 (s, 3H), 0.80 (s, 9H), (2H merged with the solvent peak); HPLC purity: 99.68%; LCMS calculated for C.sub.25H.sub.36N.sub.2O.sub.3S: 444.24; Observed: 445.60 [M + H].sup.+. A-555 [01732]embedded image Yield: 110 mg, 17.5%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.48 (br s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.34 − 7.24 (m, 1H), 7.23 − 7.18 (m, 1H), 7.06 − 6.99 (m, 4H), 3.85 (d, J = 6.8 Hz, 2H), 3.29 (s, 3H), 3.14 (s, 2H), 2.57 − 2.40 (m, 4H), 1.64 − 1.53 (m, 2H), 1.35 − 1.29 (m, 2H), 1.23 − 1.13 (m, 1H), 0.95 (s, 3H), 0.58 − 0.50 (m, 2H), 0.32 − 0.27 (m, 2H); HPLC purity: 99.35%; LCMS calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444 21; Observed: 445.20 [M + H].sup.+. A-518 [01733]embedded image Yield: 400 mg, 53%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (bs, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.20 − 7.00 (m, 3H), 3.55 − 3.43 (m, 4H), 3.27 (s, 3H), 3.19 (s, 2H), 2.61 (s, 6H), 2.50 − 2.40 (m, 2H), 1.54 − 1.45 (m, 2H), 1.30 − 1.20 (m, 2H), 0.92 (s, 3H), (2H merged with the solvent peak); HPLC purity: 99.85%; LCMS calculated for C.sub.24H.sub.35N.sub.3O.sub.6S.sub.2: 525.20; Observed: 526.15 [M + H].sup.+. A-519 [01734]embedded image Yield: 86 mg, 9.76%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.12 (bs, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2Hz, 1H), 3.58 − 3.50 (m, 6H), 3.44 (t, J = 4.4 Hz, 2H), 3.24 (s, 3H), 3.20 (s, 2H), 2.61 (s, 6H), 2.55 − 2.40 (m, 4H), 1.54 − 1.45 (m, 2H), 1.30 − 1.21 (m, 2H), 0.92 (s, 3H); HPLC purity: 99.77%; LCMS calculated for C.sub.26H.sub.39N.sub.3O.sub.7S.sub.2: 569.22; Observed: 570.35 [M + H].sup.+. A-520 [01735]embedded image Yield: 169 mg, 29%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.75 (s, 1H), 7.66 (s, 1H), 1.49 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.64 − 3.60 (m, 4H), 2.90 − 2.84 (m, 4H), 2.42 − 2.37 (m, 4H), 2.24 (s, 3H), 2.06 − 1.98 (m, 2H); HPLC purity: 99.97%; LCMS calculated for C.sub.20H.sub.24N.sub.2O.sub.3S: 372.15; Observed: 373.20 [M + H].sup.+. A-521 [01736]embedded image Yield: 786 mg, 13.7%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.80 (s, 1H), 7.67 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 6.65 (dd, J = 3.2, 8.8 Hz, 1H), 3.69 (s, 3H), 3.65 − 3.60 (m, 4H), 2.89 − 2.82 (m, 4H), 2.38 − 2.33 (m, 4H), 2.04 − 1.95 (m, 2H); HPLC purity: 99.93%; LCMS calculated for C.sub.20H.sub.2N.sub.2O.sub.4S: 388.15; Observed: 389.20 [M + H].sup.+. A-699 [01737]embedded image Yield: 10.01 mg, 22%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.13 − 5.04 (m, 1H), 3.29 (s, 3H), 3.13 (bs, 2H), 2.60 (s, 6H), 1.73 (d, J = 6.8 Hz, 3H), 1.61 − 1.34 (m, 3H), 1.30 − 1.20 (m, 2H), 0.92 (s, 3H), (3H merged with the solvent peak); HPLC purity: 98.45%; LCMS calculated for C.sub.24H.sub.34N.sub.2O.sub.5S.sub.2: 494.19; Observed: 496.39 [M + H].sup.+. Chiral HPLC details: Method: Mobile Phase: A) CO2 B) MEOH + 0.1% TFA; Gradient: 25-30% B in 5 min, hold 30% Btill 9 min, 30- 25% B at 10min, hold 25% B till 12 Min. Column: YMC CHIRALART CELLULOSE-SC(250 × 4.6 mm, 5u); Wavelength: 249 nm; Flow: 3 mL/min: retention time: 6.0. A-586 [01738]embedded image Yield: 280 mg; 57%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.20 (s, 1H), 7.96 − 7.90 (m, 2H), 7.69 − 7.64 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.10 − 7.00 (m, 2H), 4.83 (s, 2H), 3.27 (s, 3H), 3.14 (s, 2H), 3.12 (s, 3H), 2.79 − 2.69 (m, 4H), 1.64 − 1.54 (m, 2H), 1.39 − 1.30 (m, 2H), 0.97 (s, 3H); HPLC purity: 99.13%; LCMS calculated for C.sub.22H.sub.30N.sub.2O.sub.5S.sub.2: 466.16; Observed: 467.90 [M + H].sup.+; A-570 [01739]embedded image Yield: 100 mg; 32%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 7.37 − 7.32 (m, 3H), 7.28 − 7.22 (m, 4H), 7.10 − 7.04 (m, 2H), 4.62 (s, 2H), 3.57 (s, 2H), 2.66 (t, J = 4.8 Hz, 4H), 1.63 (s, 2H), 1.61 − 1.53 (m, 4H), 1.19 (s, 6H); HPLC purity: 99 47%; LCMS calculated for C.sub.23H.sub.30N.sub.2O.sub.3S: 414.20; Observed: 415.10 [M + H].sup.+. A-639 [01740]embedded image Yield: 0.074 g, 25%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (bs, 1H), 7.98 (s, 1H), 7.79 − 7.74 (m, 2H), 7.29-7.27 (m, 2H), 7.20 − 7.18 (m, 2H), 7.12 − 7.02 (m, 2H), 3.26 (s, 3H), 3.08 (s, 2H), 3.04 (s, 2H), 2.56 − 2.53 (m, 1H), 2.47 − 2.42 (m, 2H), 1.50 − 1.44 (m, 2H), 1.23 − 1.20 (m, 6H), 0.90 (s, 3H); HPLC purity: 97.15%; LCMS Calculated for C.sub.25H.sub.32N.sub.2O.sub.4S: 456.60; Observed: 456.9 [M + H].sup.+. A-638 [01741]embedded image Yield: 0.114 g, 41%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (bs, 1H), 7.99 (s, 1H), 7.79 − 7.75 (m, 2H), 7.30 − 7.28 (m, 1H), 7.15-7.03 (m, 3H), 3.53 (s, 2H), 3.04 (s, 2H), 2.46 (t, J = 5.4 Hz, 4H), 1.58 (s, 2H), 1.56 − 1.48 (m, 4H), 1.17 (s, 6H), 1.13 (s, 6H); HPLC purity: 99.73%; LCMS Calculated for C.sub.27H.sub.34N.sub.2O.sub.4S: 482.64; Observed: 483.2 [M + H].sup.+. A-730 [01742]embedded image Yield: 0.03 g, 8%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.15 (bs, 1H), 8.00 − 7.98 (m, 2H), 7.92 − 7.90 (m, 2H), 7.27- 7.29 (m, 1H), 7.11 − 7.05 (m, 3H), 6.14 (s, 1H), 3.70 − 3.63 (m, 2H), 3.37 − 3.31 (m, 2H), 2.61 (s, 6H), 2.60 − 2.49 (m, 2H), 2.43 − 2.40 (m, 2H), 1.57 (d, J = 10 Hz, 3H), 1.25 − 1.23 (m, 2H); HPLC purity: 99 54%; LCMS Calculated for C.sub.22H.sub.29F.sub.2N.sub.3O.sub.5S.sub.2 517.61; Observed: 518.05 [M + H].sup.+. A-703 [01743]embedded image Yield: 2.0 g, 44%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.33 (s, 1H), 8.00 − 7.98 (m, 2H), 7.93 − 7.90 (m, 2H), 7.31- 7.29 (m, 1H), 7.17 − 7.06 (m, 3H), 4.12 (q, J = 7.2 Hz, 2H), 2.73 (s, 1H), 2.68 − 2.61 (m, 9H), 2.41 (d, J = 11.2 Hz, 2H), 1.94 − 1.84 (m, 4H), 1.23 (t, J = 12 Hz, 3H); HPLC purity: 97.82%; LCMS Calculated for C.sub.23H.sub.3FN.sub.3O.sub.6S.sub.2 527.63; Observed: 528.0 [M + H].sup.+. A-722 [01744]embedded image Yield: 0.05 g, 13%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (bs, 1H), 8.01 − 7.98 (m, 2H), 7.93 − 7.91 (m, 2H), 7.30- 7.28 (m, 1H), 7.15 − 7.04 (m, 3H), 4.51 (t, J = 5 Hz, 1H), 3.59 (q, J = 6.24 Hz, 2H), 2.66 − 2.61 (m, 8H), 2.38 (d, J = 10.8 Hz, 2H), 1.86 − 1.65 (m, 6H); HPLC purity: 97.82%; LCMS Calculated for C.sub.21H.sub.28FN.sub.3O.sub.5S.sub.2 485.59; Observed: 486.15 [M + H].sup.+. A-472 [01745]embedded image Yield: 50 mg, 9.61%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.41 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.63 − 7.57 (m, 1H), 7.34 − 7.28 (m, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.02 − 6.98 (m, 1H), 6.89 − 6.82 (m, 1H), 3.13 (s, 3H), 3.02 − 2.92 (m, 2H), 2.73 − 2.64 (m, 2H), 2.58 (s, 6H), 1.91 − 1.82 (m, 2H), 1.78 − 1.68 (m, 2H); HPLC purity: 99.59%; LCMS calculated for C.sub.27H.sub.29FN.sub.4O.sub.5S.sub.2: 572.16; Observed: 573.25 [M + H].sup.+. A-473 [01746]embedded image Yield: 48 mg, 17.9%; Appearance: 1.6 Hz, 1H), 8.34 (dd, J = 2.8, 8.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.30 − 7.24 (m, 2H), 7.16 (t, J = 8.0 Hz, 1H), 7.11 − 7.05 (m, 1H), 2.90 − 2.82 (m, 2H), 2.76 − 2.69 (m, 2H), 2.59 (s, 6H), 2.46 − 2.40 (m, 2H), 1.72 (d, J = 13.2 Hz, 2H); HPLC purity: 99.44%; LCMS Calculated for C.sub.25H.sub.25FN.sub.4O.sub.6S.sub.2: 560.12; Observed: 561.15 [M + H].sup.+. A-401 [01747]embedded image Yield: 600 mg, 41%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.50-1.60 (m, 2H) 2.19 − 2.28 (m, 2H) 2.35 (d, J = 10.76 Hz, 2H) 2.58 (s, 6H) 2.95 (t, J = 11.25 Hz, 2H) 5.43 (s, 1H) 7.03 − 7.22 (m, 3H) 7.27 − 7.35 (m, 1H) 7.55 − 7.62 (m, 1H) 7.88 − 7.94 (m, 2H) 7.95 − 7.99 (m, 2H) 8.43 (s, 1H) 8.48 − 8.51 (m, 1H) 9.26 (s, 1H); HPLC purity: 99.93%; LCMS calculated for C.sub.24H.sub.27FN.sub.4O.sub.5S.sub.2: 534.14; Observed: 535.18 [M + H].sup.+. A-355 [01748]embedded image Yield: 200 mg, 19%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.80 (d, J = 12.23 Hz, 2H) 2.21 − 2.35 (m, 3H) 2.60 (s, 6H) 2.93 (t, J = 10.52 Hz, 2H) 5.25 (s, 1H) 7.01 − 7.21 (m, 4H) 7.22-7.35 (m, 1H) 7.38- 7.47 (m, 1 H) 7.70 (dd, J = 11.74, 8.31 Hz, 1 H) 7.91 (d, J = 8.31 Hz, 2 H) 8.01 (d, J = 8.31 Hz, 2 H) 8.40 (d, J = 3.91 Hz, 1 H) 9.30 (s, 1 H); HPLC purity: 99.02%; LCMS calculated for C.sub.24H.sub.27FN.sub.4O.sub.5S.sub.2: 534.14; Observed: 535.25 [M + H].sup.+. A-412 [01749]embedded image Yield: 50 mg, 7%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.45-1.58 (m, 2H) 1.76- 1.94 (m, 2H) 2.58 (s, 6H) 2.77 (s, 3H) 3.24 (s, 2H) 7.03-7.17 (m, 2H) 7.19- 7.23 (m, 2H) 7.34 (d, J = 1.83 Hz, 1H) 7.84 (s, 1H) 7.86-7.95 (m, 2H) 7.97- 8.05 (m, 3H) 9.30 (brs, 1H) 4H’s are merged in solvent peak; HPLC purity: 99.28%; LCMS calculated for C.sub.26H.sub.31N.sub.5O.sub.4S.sub.2: 541.18; Observed: 542.25 [M + H].sup.+. A-724 [01750]embedded image Yield: 80 mg, 11%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.18 (s, 6H) 1.52 − 1.66 (m, 6H) 2.62 (s, 6H) 2.79 − 2.90 (m, 2H) 2.91 − 3.00 (m, 2H) 3.56 (s, 2H) 7.11 − 7.18 (m, 1H) 7.20 − 7.27 (m, 1H) 7.56 − 7.59 (m, 1H) 7.92-7.98 (m, 4H) 9.72 (s, 1H); HPLC purity: 99.57%; LCMS calculated for C.sub.25H.sub.32N.sub.4O.sub.5S.sub.2: 532.18; Observed: 533.10 [M + H].sup.+. A-653 [01751]embedded image Yield: 50 mg, 12%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.18 (s, 6H) 1.38-1.65 (m, 6H) 2.52-2.60 (m, 2H) 2.66 (s, 6H) 3.54 (s, 2H) 6.99-7.07 (m, 1H) 7.09- 7.17 (m, 1H) 7.18-7.21 (m, 1 H) 7.24 (d, J = 7.83 Hz, 1H) 7.70 (d, J = 8.31 Hz, 1 H) 7.84 (d, J = 9.29 Hz, 1 H) 7.92 − 8.03 (m, 1 H) 9.48 (s, 1H) 2H’s are merged in solvent peak; HPLC purity: 98.31%; LCMS calculated for C.sub.24H.sub.32FN.sub.3O.sub.5S.sub.2: 525.18; Observed: 526.45 [M + H].sup.+. A-652 [01752]embedded image Yield: 0.9 g, 49%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.10-1.20 (m, 2H) 1.48- 1.56 (m, 4H) 2.24-2.32 (m, 2H) 2.61 (s, 6H) 3.06-3.15 (m, 2H) 7.11 − 7.26 (m, 3H) 7.9-7.98 (m, 4H) 9.23 (s, 1H); HPLC purity: 99.34%; LCMS calculated for C.sub.19H.sub.24ClN.sub.3O.sub.4S.sub.2: 457.09; Observed: 458.30 [M + H].sup.+. A-615 [01753]embedded image Yield: 100 mg, 9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.18 (s, 6H) 1.44 − 1.64 (m, 6H) 2.44 (s, 2H) 2.61 (s, 6H) 3.53 (s, 2H) 6.94-7.02 (m, 1H) 7.12 − 7.28 (m, 2H) 7.90 − 7.95 (m, 2H) 7.95- 8.02 (m, 2H) 9.29 (brs, 1H) 2H’s are merged in solvent peak; HPLC purity: 98.95%; LCMS calculated for C.sub.24H.sub.32FN.sub.3O.sub.5S.sub.2: 525.18; Observed: 526.2 [M + H].sup.+. A-702 [01754]embedded image Yield: 35 mg, 11%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.19 (s, 6H) 1.52-1.58 (m, 2H) 1.62 (s, 2H) 2.78 (s, 4H) 3.32 (s, 2H) 3.55 (s, 2H) 4.67 (s, 2H) 6.83 − 6.95 (m, 1H) 7.12-7.20 (m, 2H) 7.27 (d, J = 2.93 Hz, 2H) 7.35 (d, J = 2.93 Hz, 3H) 8.27 (s, 1H); HPLC purity: 99.64%; LCMS calculated for C.sub.23H.sub.29FN.sub.2O.sub.3S: 432.19; Observed: 433.1 [M + H].sup.+. A-685 [01755]embedded image Yield: 158 mg, 40%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.95 (s, 3H) 1.22-1.37 (m, 2H) 1.57 (t, J = 9.05 Hz, 2H) 1.78 (dt, J =l 5.65, 7.83 Hz, 2H) 2.35 − 2.47 (m, 2H) 2.51-2.64 (m, 6H) 3.14 (s, 2H) 3.29 (s, 3H) 6.98 (d, J = 7.83 Hz, 1H) 7.01-7.11 (m, 2H) 7.13-7.23 (m, 1H) 7.25 (s, 1H) 7.27 (s, 2H) 8.60 (s, 1H); HPLC purity: 98 59%; LCMS calculated for C.sub.24H.sub.30N.sub.2O.sub.5S: 458.19; Observed: 459.15 [M + H].sup.+. A-723 [01756]embedded image Yield: 35 mg, 9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.18 (s, 6H) 1.44 − 1.64 (m, 6H) 2.44 (s, 2H) 2.61 (s, 6H) 3.53 (s, 2H) 6.94-7.02 (m, 1H) 7.12 − 7.28 (m, 2H) 7.90 − 7.95 (m, 2H) 7.95- 8.02 (m, 2H) 9.29 (brs, 1H) 2H’s are merged in solvent peak; HPLC purity: 99.68%; LCMS calculated for CH.sub.32N.sub.2O.sub.5S: 484.20; Observed: 485.25 [M + H].sup.+. A-655 [01757]embedded image Yield: 35 mg, 9%; Appearance: Sticky White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.92 (s, 3H) 1.18- 1.31 (m, 2H) 1.40 (s, 6H) 1.46-1.59 (m, 2H) 2.27-2.38 (m, 2H) 2.44 (d, J = 8.80 Hz, 2H) 2.94 (s, 3H) 3.15 (m, 2H) 3.28 (s, 3H) 7.06 (dd, J = 5.62, 3.67 Hz, 2H) 7.15 − 7.24 (m, 1H) 7.32 − 7.41 (m, 1H) 7.52 (d, J = 8.31 Hz, 2H) 7.72 (d, J = 8.31 Hz, 2H) 8.65 (s, 1H); HPLC purity: 99.68%; LCMS calculated for C.sub.24H.sub.34N.sub.2O.sub.4S: 446.22; Observed: 447.45 [M + H].sup.+. A-656 [01758]embedded image Yield: 22 mg, 6%; Appearance: Sticky white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.18 (s, 6H) 1.40 (s, 6H) 1.48 − 1.56 (m, 4H) 1.60 (s, 2H) 2.27-2.39 (m, 4H) 2.94 (s, 3H) 3.55 (s, 2H) 7.00 − 7.10 (m, 2H) 7.10 − 7.17 (m, 1H) 7.34 − 7.39 (m, 1H) 7.53 (d, J = 8.31 Hz, 2H) 7.72 (d, J = 8.80 Hz, 2H) 8.71 (s, 1H); HPLC purity: 99.27%; LCMS calculated for C.sub.26H.sub.36N.sub.2O.sub.4S: 472.24; Observed: 473.30 [M + H].sup.+. A-704 [01759]embedded image Yield: 50 mg, 14%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.19 (s, 6H) 1.53 − 1.69 (m, 12H) 2.45 (t, J = 5. 14 Hz, 4H) 3.57 (s, 2H) 6.93 (d, J = 8.80 Hz, 1H) 7.06 (dd, J = 5.87, 3.91 Hz, 2H) 7.16 (dd, J = 5.87, 3.42 Hz, 1H) 7.20 − 7.25 (m, 2H) 7.28 − 7.38 (m, 1H) 8.61 (s, 1H); HPLC purity: 99.36%; LCMS calculated for C.sub.25H.sub.32N.sub.2O.sub.5S: 472.20; Observed: 473.20 [M + H].sup.+. A-721 [01760]embedded image Yield: 30 mg, 8%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.95 (s, 3H) 1.21-1.38 (m, 2H) 1.52-1.60 (s, 2H) 1.64 (s, 6H) 2.39 − 2.61 (m, 4H) 3.14 (s, 2H) 3.28 (s, 3H) 6.93 (d, J = 7.83 Hz, 1H) 7.00 − 7.10 (m, 2 H) 7.17 − 7.27 (m, 3H) 7.29 − 7.36 (m, 1H) 8.56 (s, 1H).; HPLC purity: 99.53%; LCMS calculated for C.sub.23H.sub.30N.sub.2O.sub.5S: 446.19; Observed: 447.20 [M + H].sup.+. A-633 [01761]embedded image Yield: 57 mg, 15%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.92 (s, 3H) 1.18-1.31 (m, 2H) 1.34 (s, 6H) 1.47-1.60 (m, 2H) 2.25 − 2.35 (m, 2H) 2.38 − 2.47 (m, 2H) 2.83 (s, 3H) 3.12 (s, 2H) 3.27 (s, 3H) 7.03 − 7.12 (m, 2H) 7.17 − 7.25 (m, 1H) 7.37 − 7.42 (m, 1H) 7.51 − 7.55 (m, 1H) 7.57 − 7.65 (m, 2H) 7.71 (d, J = 7.83 Hz, 1H) 8.60 (s, 1H); HPLC purity: 99.47%; LCMS calculated for C.sub.24H.sub.34N.sub.2O.sub.4S: 446.22; Observed: 447.0 [M + H].sup.+. A-634 [01762]embedded image Yield: 27 mg, 7%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.18 (s, 6H) 1.34 (s, 6H) 1.47-1.58 (m, 4H) 1.60 (s, 2H) 2.35 (t, J = 5.14 Hz, 4 H) 2.83 (s, 3H) 3.55 (s, 2H) 7.00-7.11 (m, 2H) 7.12 − 7.18 (m, 1H) 7.40 (dd, J = 7.34, 1.96 Hz, 1H) 7.48 − 7.57 (m, 1H) 7.61 (d, J = 12.23 Hz, 2H) 7.72 (d, J = 7.83 Hz, 1 H) 8.66 (s, 1H); HPLC purity: 99.82%; LCMS calculated for C.sub.26H.sub.36N.sub.2O.sub.4S: 472.24; Observed: 473.15 [M + H].sup.+. A-635 [01763]embedded image Yield: 0.116 g; 32%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.45 (s, 1H), 7.63 (s, 1H), 7.48 (bd, J = 8.4 Hz, 1H), 7.36 (bd, J = 8.4 Hz, 1H), 7.18 − 7.15 (m, 1H), 7.05 (bs, 2H), 6.78 − 6.76 (m, 1H), 3.57 (s, 2H), 3.00 (s, 2H), 2.43 (bs, 4H), 1.63 (s, 6H), 1.61 − 1.39 (m, 6H), 1.19 (s, 6H); HPLC purity: 98.93%; LCMS calculated for C.sub.26H.sub.34N.sub.2O.sub.4S: 470.63; Observed: 471.1 [M + H].sup.+. A-613 [01764]embedded image Yield: 0.016 g, 8%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97 (s, 1H), 7.60 (m, 3H), 7.14 − 7.08 (m, 2H), 7.04 − 7.00 (m, 1H), 6.68 − 6.66 (m, 1H), 3.39 (s, 3H), 3.18 (s, 2H), 2.97 (s, 2H), 2.63 − 2.58 (m, 2H), 2.46 − 2.44 (m, 2H), 1.67 − 1.61 (m, 2H), 1.49 − 1.39 (m, 8H), 1.03 (s, 3H); HPLC purity: 97.98%; LCMS calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444.59; Observed: 445.0 [M + H].sup.+. A-640 [01765]embedded image Yield: 0.042 g, 37%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.60 (s, 1H), 7.66 (s, 1H), 7.54 − 7.53 (bd, J = 7.2 Hz, 1H), 7.45 − 7.43 (bd, J = 7.6 Hz, 1H), 7.21 − 7.19 (bd, J = 8 Hz, 1H), 7.16 − 7.12 (m, 1H), 7.02 − 6.98 (m, 1H), 6.79 − 6.77 (m, 1H), 3.60 − 3.53 (m, 2H), 3.00 (s, 2H), 2.91 − 2.84 (m, 3H), 2.78 − 2.76 (m, 1H), 2.12 − 2.07 (m, 1H), 1.84 − 1.83 (m, 2H), 1.72 − 1.67 (m, 1H), 1.54 − 1.51 (m, 1H), 1.38 (s, 8H), 0.97 − 0.94 (m, 1H); HPLC purity: 99.04%; LCMS calculated for C.sub.24H.sub.30N.sub.2O.sub.4S: 442.57; Observed: 442.8 [M + H].sup.+. A-654 [01766]embedded image Yield: 0.06 g, 32%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.31-1.50 (m, 10H) 1.50 − 1.61 (m, 4H) 3.01 (s, 2H) 3.46 − 3.61 (m, 4H) 6.70 − 6.81 (m, 1H) 6.99 − 7.10 (m, 2H) 7.16 − 7.24 (m, 1H) 7.35 (d, J = 6.36 Hz, 1H) 7.47 (d, J = 1.83 Hz, 1H) 7.59-7.68 (m, 1H) 8.36 − 8.49 (m, 1H) 4H’s are merged in solvent peak; HPLC purity: 99.72%; LCMS calculated for C.sub.25H.sub.32N.sub.2O.sub.4S: 456.60; Observed: 456.9 [M + H].sup.+. A-632 [01767]embedded image Yield: 0.062 g, 33.51%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.13-1.18 (m, 2H) 1.39 (s, 6H) 1.43-1.69 (m, 4H) 2.34 (d, J = 10.27 Hz, 1H) 2.58 (d, J = 10.27 Hz, 1H) 3.01 (s, 2H) 3.30 (s, 4H) 3.38-3.56 (m, 2H) 3.63-3.71 (m, 2H) 6.70-6.85 (m, 1H) 6.99-7.12 (s, 2H) 7.12-7.17 (m, 1H) 7.34 (d, J = 5.87 Hz, 1H) 7.51 (d, J = 7.34 Hz, 1H) 7.58-7.68 (m, 1H) 8.04-8.12 (m, 1H); HPLC purity: 98.25%; LCMS calculated for C.sub.25H.sub.32N.sub.2O.sub.4S: 456.60; Observed: 457.1 [M + H].sup.+. A-636 [01768]embedded image Yield: 0.074 g, 26%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.39 (s, 6H) 1.49-1.70 (m, 8H) 1.75-1.93 (m, 2H) 3.01 (s, 2H) 6.78 (d, J = 8.31 Hz, 1H) 7.01-7.10 (m, 2H) 7.11-7.17 (m, 1H) 7.28-7.37 (m, 1H) 7.43-7.52 (m, 1H) 7.64 (s, 1H) 8.60 (s, 1H). 2H’s merged in solvent peak; HPLC purity: 99.12%; LCMS calculated for C.sub.23H.sub.28N.sub.2O.sub.3S: 450.54; Observed: 450.8 [M + H].sup.+. A-631 [01769]embedded image Yield: 0.05 g, 9.02%; Appearance: Colourless sticky solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.09 (t, J = 6.85 Hz, 3H) 1.20-1.41 (m, 8H) 1.43-1.51 (m, 3H) 1.53-1.66 (m, 2H) 2.45 (d, J = 6.36 Hz, 4H) 2.99 (s, 2H) 3.34-3.47 (m, 4H) 6.70-6.79 (m, 1H) 6.98-7.08 (m, 2H) 7.13 (d, J = 5.38 Hz, 1H) 7.35 (d, J = 7.83 Hz, 1H) 7.39-7.49 (m, 1H) 7.62 (s, 1H) 8.39 (s, 1H); HPLC purity: 99.80%; LCMS calculated for C.sub.25H.sub.34N.sub.2O.sub.4S: 458.62; Observed: 459.50 [M + H].sup.+. A-614 [01770]embedded image Yield: 11.31 mg, 3.55%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.24- 1.36 (m, 2H) 1.39 (s, 6H) 1.55-1.66 (m, 4H) 3.00 (s, 2H) 3.23 (d, J = 5.38 Hz, 2H) 3.25 (s, 3H) 6.77 (d, J = 8.31 Hz, 1H) 6.98-7.08 (m, 2H) 7.10-7.16 (m, 1H) 7.35 (d, J = 6.85 Hz, 1H) 7.47 (d, J = 7.34 Hz, 1H) 7.62 (s, 1H) 8.43 (s, 1H). 3H’s are merged in solvent peak; HPLC purity: 97.73%; LCMS calculated for C.sub.23H.sub.30N.sub.2O.sub.4S: 430.56; Observed: 431.1 [M + H].sup.+. A-686 [01771]embedded image Yield: 0.043 g, 7%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 1.61-1.75 (m, 2H) 1.75 − 1.85 (m, 2H) 2.35-2.45 (m, 4H) 2.62 (s, 6H) 3.36 − 3.47 (m, 2H) 6.99 − 7.20 (m, 2H) 7.23 − 7.32 (m, 2H) 7.81 − 7.94 (m, 2 H) 7.96-8.04 (m, 2H) 9.33 (s, 1H). 3H′ are merged in solvent peak; HPLC purity: 98.76%; LCMS calculated for C.sub.21H.sub.28FN.sub.3O.sub.5S.sub.2: 485.59; Observed: 486.1 [M + H].sup.+. A-438 [01772]embedded image Yield: 7.6 g, 71%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.92 (s, 3H), 1.19-1.29 (m, 2H), 1.45-1.55 (m, 2H), 2.39-2.50 (m, 4H), 2.61 (s, 6H), 3.11 (s, 2H), 3.27 (s, 3H), 7.00-7.06 (m, 1H), 7.12 (t, J = 7.34 Hz, 1H), 7.15-7.21 (m, 1H), 7.26 (d, J = 7.83 Hz, 1H), 7.87-7.94 (m, 2H), 7.96-8.02 (m, 2H), 9.06-9.21 (m, 1H); HPLC purity : 99.87%; LCMS calculated for C.sub.22H.sub.31N.sub.3O.sub.5S.sub.2: 481.17; Observed: 482.35 [M + H].sup.+. A-727 [01773]embedded image Yield: 0.040 g, 18.18%; Appearance: Off white sticky solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.95 (s, 3H) 1.31 (d, 13.20 Hz, 2H) 1.52-1.63 (m, 2H) 2.43 (d, J = 6.85 Hz, 2H) 2.52-2.60 (m, 2H) 2.79 (t, J = 5.38 Hz, 2H) 3.14 (s, 2H) 3.29 (s, 3H) 3.85 (t, J = 5.62 Hz, 2H) 4.68 (s, 2H) 7.01-7.08 (m, 2H) 7.13-7.22 (m, 2H) 7.26-7.33 (m, 1H) 7.51 (d, J = 7.82 Hz, 1H) 7.60 (s, 1H) 8.63 (s, 1H); HPLC purity: 99.25%; LCMS calculated for C.sub.23H.sub.30N.sub.2O.sub.4S: 430.56; Observed: 431.08 [M + H].sup.+. A-726 [01774]embedded image Yield: 0.042 g; 16%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.19 (s, 6H) 1.50-1.68 (m, 6H) 2.35-2.46 (m, 4H) 2.71-2.85 (m, 2H) 3.57 (s, 2H) 3.85 (s, 2H) 4.68 (s, 2H) 6.99-7.09 (m, 2H) 7.18 (d, J = 7.82 Hz, 2H) 7.31 (s, 1H) 7.51 (d, J = 6.85 Hz, 1H) 7.56-7.66 (m, 1H) 8.68 (s, 1H); HPLC purity: 97.19%; LCMS calculated for C.sub.25H.sub.32N.sub.2O.sub.4S: 456.60; Observed: 457.05 [M + H].sup.+. A-683 [01775]embedded image Yield: 0.085 g, 44.97%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.93 (s, 3H) 1.19-1.31 (m, 2H) 1.35 (s, 6H) 1.47-1.60 (m, 2H) 2.33-2.44 (m, 2H) 3.12 (s, 2H) 3.27 (s, 3H) 4.95 (s, 2H) 7.01-7.09 (m, 2H) 7.17-7.24 (m, 1H) 7.30-7.37 (m, 1H) 7.42 (d, J = 7.83 Hz, 1H) 7.60 (s, 1H) 7.65-7.73 (m, 1H) 8.61 (brs, 1H), 2H’s are merged in to solvent peak; HPLC purity: 98.97%; LCMS calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444.59; Observed: 445.25 [M + H].sup.+. A-682 [01776]embedded image Yield: 0.05 g, 24%; Appearance: Off white semisolid; .sup.1H NMR ((400 MHz, DMSO-d.sub.6) δ 0.93 (s, 3H) 1.25 (d, J = 13.21 Hz, 2H) 1.38 (s, 6H) 1.42 − 1.56 (m, 2H) 2.30-2.39 (m, 2H) 2.46 (d, J = 9.29 Hz, 2H) 3.12 (s, 2H) 3.28 (s, 3H) 4.94 (s, 2H) 7.02-7.11 (m, 2H) 7.21 (dd, J = 6.60, 2.69 Hz, 1H) 7.30- 7.37 (m, 1H) 7.41 (d, J = 8.31 Hz, 1H) 7.61 (d, J = 8.31 Hz, 1H) 7.70 (s, 1H) 8.66 (s, 1H); HPLC purity: 96.83%; LCMS calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444.59; Observed: 445.55 [M + H].sup.+. A-700 [01777]embedded image Yield: 0.04 g; 11%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.18 (s, 6H) 1.38 (s, 6H) 1.46-1.56 (m, 4H) 1.57-1.64 (m, 2H) 2.28-2.41 (m, 4H) 3.55 (s, 2H) 4.94 (s, 2H) 6.98-7.09 (m, 2H) 7.12-7.19 (m, 1H) 7.30-7.37 (m, 1H) 7.41 (d, J = 7.83 Hz, 1H) 7.62 (d, J = 7.83 Hz, 1H) 7.70 (s, 1H) 8.72 (brs, 1H); HPLC purity: 98.22%; LCMS calculated for C.sub.26H.sub.34N.sub.2O.sub.4S: 470.63; Observed: 471.1 [M + H].sup.+. A-720 [01778]embedded image Yield: 0.061 g, 17%; Appearance: Off white solid; .sup.1H NMR (400 MHz, CHLOROFORM-d) δ 1.30 (s, 6 H) 1.38 − 1.50 (m, 6 H) 1.62 − 1.77 (m, 4 H) 2.49 (br t, J = 5.14 Hz, 4 H) 2.99 (s, 2 H) 3.72 (s, 2 H) 4.77 (s, 2 H) 6.96 − 7.05 (m, 1 H) 7.06 − 7.31 (m, 4 H) 7.59 (br d, J = 1.82 Hz, 1 H). 2H’s merged in to solvent peak; HPLC purity: 99.80%; LCMS calculated for C.sub.26H.sub.34N.sub.2O.sub.4S: 470.63; Observed: 471.1 [M + H].sup.+. A-605 [01779]embedded image Yield: 0.2 g, 35%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.39 (bs, 1H), 8.04 − 8.02 (m, 2H), 7.94 − 7.92 (m, 2H), 7.23 (q, J = 4.8 Hz , 1H), 7.15 − 7.12 (m, 1H), 6.97 − 6.93 (m, 1H), 3.53 (s, 2H), 2.61 (s, 6H), 2.34 (bs, 4H), 1.58 (s, 2H), 1.54 − 1.49 (m, 4H), 1.17 (s, 6H); HPLC purity: 99.72%; LCMS Calculated for C.sub.24H.sub.32FN.sub.3O.sub.5S.sub.2 525.65; Observed: 526.25 [M + H].sup.+. A-606 [01780]embedded image Yield: 0.11 g, 39%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.31 (bs, 1H), 7.91 (s, 4H), 7.19 (q, J = 5.6 Hz , 1H), 6.93 − 6.82 (m, 2H), 3.48 (s, 2H), 2.61 (s, 6H), 2.45 (s, 4H, merged in solvent peak) 1.54 (s, 2H), 1.42 (bd, J = 3.2 Hz, 4H), 1.15 (s, 6H); HPLC purity: 99.82%; LCMS Calculated for C.sub.24H.sub.32FN.sub.3O.sub.5S.sub.2: 525.65; Observed: 526.25 [M + H].sup.+. A-735 [01781]embedded image Yield: 100 mg, 21%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.66 (d, J = 13.2 Hz, 1H), 7.98 (q, J = 10 Hz, 4H), 7.22 − 7.15 (m, 4H), 3.64-3.56 (m, 2H), 3.37 (bs, 1H), 2.90 (bs, 1H), 2.63 (s, 6H), 2.45 − 2.31 (m, 2H), 1.80 − 1.63 (m, 4H), 1.22 (s, 3H), 1.20 (s, 3H). HPLC purity: 99.54%; LCMS calculated for C.sub.24H.sub.31N.sub.3O.sub.6S.sub.2: 521.17; Observed: 522.20 [M + H].sup.+. A-734 [01782]embedded image Yield: 15 mg, 5%; Appearance: White solid; : .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.17 (s, 1H), 7.98 (q, J = 5.2 Hz, 4H), 7.06 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 10 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 3.72 (s, 2H), 3.27 (s, 3H), 3.16 (s, 2H), 2.63 (s, 6H), 1.79 − 1.78 (m, 2H), 1.60-1.53 (m, 6H), 0.86 (s, 3H). HPLC purity: 99.37%; LCMS calculated for C.sub.24H.sub.33N.sub.3O.sub.5S.sub.2: 507.19; Observed: 575.45 [M + H].sup.+. A-738 [01783]embedded image Yield: 93 mg, 49%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 8.6 (s, 1H), 7.34 − 7.28 (m, 2H), 7.24 − 7.18 (m, 2H), 7.08 − 7.03 (m, 3H), 3.28 (s, 3H), 3.13 (s, 2H), 3.02 (s, 2H), 2.51 (s, 2H), 2.48 − 2.38 (m, 2H), 1.61 − 1.53 (m, 2H), 1.38 (s, 6H), 1.35 − 1.28 (m, 2H), 0.94 (s, 3H). HPLC purity: 98.85%; LCMS calculated for C.sub.24H.sub.32N.sub.2O.sub.4S: 444.21; Observed: 445.15 [M + H].sup.+. A-739 [01784]embedded image Yield: 15 mg, 13%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.17 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.27 (d, J = δ Hz, 1H), 7.12 − .05 (m, 3H), 3.69 (d, J = 5.6 Hz, 2H), 2.61 (s, 6H), 2.58 − 2.53 (m, 2H), 2.44 − 2.41 (m 2H), 1.79 (t,J = 13.2 Hz, 3H), 1.59 (d, J = 9.6 Hz, 3H), 1.34-1.29 (m, 2H); HPLC purity: 97.41%; LCMS calculated for C.sub.22H.sub.29F.sub.2N.sub.3O.sub.5S.sub.2 517.15; Observed: 518.0 [M + H].sup.+. A-745 [01785]embedded image Yield: 100 mg, 33%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.01 (s, 1H), 8.05 (d, J = 8 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.18 − 7.08 (m, 2H), 3.28 (s, 3H), 3.04 (s, 2H), 3.01 − 2.99 (m, 1H), 2.57 (s, 7H), 1.82 (d, J = 10.8 Hz, 1H), 1.61 − 1.55 (m, 1H), 1.39 − 1.30 (m, 2H), 1.13 (d, J = 12 Hz, 1H), 0.97 (s, 3H), 0.41 (d, J = 6Hz, 3H) HPLC purity: 98.72%; LCMS calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.19; Observed: 496.20 [M + H].sup.+. A-809 [01786]embedded image Yield: 46 mg; 22%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.97 (s, 1H), 8.25 (s, 1H), 8.02 (d, J = 6.4 Hz, 2H), 7.95 (d, J = 6.4 Hz, 2H), 7.28 (d, J = 6.4 Hz, 1H), 7.11 (t, J = 6.0 Hz, 1H), 6.99 (d, J = 6.0 Hz, 1H), 2.74 − 2.68 (m, 4H), 2.65 (s, 9H), 1.56 − 1.38 (m, 6H); HPLC purity: 99.72%; LCMS calculated for C.sub.21H.sub.28N.sub.4O.sub.5S.sub.2: 480.60; Observed: 481.2 [M + H].sup.+. A-812 [01787]embedded image Yield: 70 mg; 18%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.2 (brs, 1H), 7.97 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.23 − 7.20 (m, 2H), 3.03 (s, 1H), 2.70 (s, 6H), 2.46 (t, J = 5.6 Hz, 4H), 1.64-1.54 (m, 6H), HPLC purity: 98.7%; LCMS calculated for C.sub.21H.sub.25N.sub.3O.sub.4S.sub.2: 447.13; Observed: 448.2 [M + H].sup.+ A-753 [01788]embedded image Yield: 0.045 g, 13%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.64 (s, 1H), 8.02 (q, J = 8.52 Hz, 4H), 7.44 (d, J = 7.6 Hz, 1H), 7.26 − 6.98 (m, 3H), 3.61 − 3.54 (m, 2H), 3.07 − 2.96 (m, 2H), 2.71 (bs, 2H), 2.64 (s, 6H), 1.62 − 1.60 (m, 6H), 1.21 (s, 6H); HPLC purity: 97.16%; LCMS calculated for C.sub.25H.sub.33F.sub.2N.sub.3O.sub.5S.sub.2: 557.18; Observed: 558.00 [M + H].sup.+. A-764 [01789]embedded image Yield: 0.155 g, 33%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.49 (s, 1H), 7.99 − 7.92 (m, 4H), 7.26 − 7.19 (m, 2H), 7.02 − 6.97 (m, 1H), 3.31 (s, 3H), 2.88 − 2.75 (m, 4H), 2.61 (s, 6H), 2.38 (bs, 2H), 1.84 − 1.77 (m, 4H); HPLC purity: 99.55%; LCMS calculated for C.sub.22H.sub.27FN.sub.4O.sub.6S.sub.2: 526.14 Observed: 527.00 [M + H].sup.+. A-736 [01790]embedded image Yield: 0.009 g, 2%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.19 (s, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.97 (d, J = 8 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.22-7.04 (m, 3H), 3.69 (t, J = 8 Hz, 4H), 3.27 (s, 3H), 3.10 (s, 2H), 1.99 − 1.96 (m, 2H), 1.53-1.47 (m, 2H), 1.27 − 1.23 (m, 2H), 0.91 (s, 3H). 4H’s are merged in to solvent peak; HPLC purity: 99.84%; LCMS calculated for C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2: 493.17; Observed: 494.25 [M + H].sup.+. A-868 [01791]embedded image Yield: 0.1 g, 13.88%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.30 (brs, 1 H), 7.96 (d, J = 14.18 Hz, 4 H), 7.25 − 7.13 (m, 2 H), 7.0 − 6.92 (m, 1 H), 3.58 − 3.48 (m, 2 H), 2.87 − 2.69 (m, 4 H), 2.61 (s, 6 H), 2.40 − 2.32 (m, 2 H), 2.20 − 2.12 (m, 1 H), 1.81 (t, J = 9.54 Hz, 2 H), 1.62 − 1.51 (m, 4 H), 1.07 (d, J = 4.40 Hz, 6 H); HPLC purity: 99.75%; LCMS calculated for C.sub.25H.sub.35FNO.sub.5S.sub.2: 554.20 Observed: 555.25 [M + H].sup.+.

    Example A104: Synthesis of N1-(2-(4-(tert-butyl)-4-hydroxypiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-471)

    [1036] ##STR01792## ##STR01793##

    Step-1. Synthesis of 8-(2-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A104.3)

    [1037] To a stirred solution of 1,4-dioxa-8-azaspiro[4.5]decane (A104.1) (5 g, 34.9 mmol, 1 eq) in DMF (50 mL), potassium carbonate (14.4 g, 105 mmol, 3 eq) and 1-fluoro-2-nitrobenzene (A104.2) (5.42 g, 38.4 mmol, 1.1 eq) were added at room temperature. The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with cold water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford 8-(2-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A104.3) (9.08 g, 98.5%). LCMS: 265.11 [M+H].sup.+.

    Step-2. Procedure for the synthesis of 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline (A104.4)

    [1038] A stirred solution of 8-(2-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (A104.3) (9.08 g, 34.3 mmol, 1 eq) in methanol (50 mL) was purged with nitrogen for 5 min. 10% Palladium on carbon (2 g, 22% w/w) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was purged with hydrogen and hydrogenated at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrated was concentrated under reduced pressure to dryness to afford 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline (A104.4) (7.7 g, crude which was used in the next step without further purification. LCMS: 235.14 [M+H].sup.+.

    Step-3. Procedure for the synthesis of N1-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A104.6)

    [1039] To a stirred solution of 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline (A104.4) (1.5 g, 6.4 mmol, 1 eq) in acetonitrile (20 mL), pyridine (1.51 mL, 19.2 mmol, 3 eq) followed by 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A104.5) (2 g, 7 mmol, 1.1 eq) were added at room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford N1-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A104.6) (2.5 g, 81.4%). LCMS: 482.13 [M+H].sup.+.

    Step-4. Procedure for the synthesis of N1,N1-dimethyl-N4-(2-(4-oxopiperidin-1-yl)phenyl)benzene-1,4-disulfonamide (A104.7)

    [1040] To a stirred solution of N1-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A104.6) (2.8 g, 5.8 mmol, 1 eq) in methanol (14 mL), 2 M aqueous HCl (14 mL) was added and the reaction mixture was stirred at 60° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford N1,N1-dimethyl-N4-(2-(4-oxopiperidin-1-yl)phenyl)benzene-1,4-disulfonamide (A104.7) (2 g, 78.7%). LCMS: 438.11 [M+H].sup.+.

    Step-5. Procedure for the synthesis of N1-(2-(4-(tert-butyl)-4-hydroxypiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-471)

    [1041] To a stirred solution N1,N1-dimethyl-N4-(2-(4-oxopiperidin-1-yl)phenyl)benzene-1,4-disulfonamide (A104.7) (250 mg, 0.57 mmol, 1 eq) in THE (5 mL) was added a 1.7 M solution of tert-butyl lithium in pentane (1 mL, 1.7 mmol, 1.7 mmol, 3 eq) at −78° C. under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was slowly quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash chromatography on silica gel followed by reverse phase preparative HPLC to afford N1-(2-(4-(tert-butyl)-4-hydroxypiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-471). Yield: 35 mg, 6.18%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (bs, 1H), 7.97 (d, J=7.6 Hz, 2H), 7.91 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 1H), 7.14-7.00 (m, 3H), 3.80 (s, 1H), 2.76 (t, J=11.2 Hz, 2H), 2.61 (s, 6H), 2.33-2.24 (m, 2H), 1.69-1.60 (m, 2H), 1.32 (d, J=12.8 Hz, 2H), 0.88 (s, 9H); HPLC purity: 99.72%; LCMS Calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.19; Observed: 496.25 [M+H].sup.+.

    Example A105: Synthesis of 4-((2-(4-benzylpiperazin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesul fonamide (A-406) and 4-((1-(2-(4-benzylpiperazin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-465)

    [1042] ##STR01794## ##STR01795##

    Step-1. Procedure for the synthesis of 2-(4-benzylpiperazin-1-yl)benzaldehyde (A105.3)

    [1043] To a stirred solution of 2-fluorobenzaldehyde (A105.1) (5 g, 40.3 mmol, 1 eq) and 1-benzylpiperazine (A105.2) (7.8 g, 44 mmol, 1.1 eq) in DMF (50 mL) was added potassium carbonate (16.67 g, 120 mmol, 3 eq) at room temperature and the reaction mixture was stirred at 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with cold water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford 2-(4-benzylpiperazin-1-yl)benzaldehyde (A105.3) (4.35 g, 38%). LCMS: 281.16 [M+H].sup.+.

    Step-2. Procedure for the Synthesis of (2-(4-benzylpiperazin-1-yl)phenyl)methanol (A105.4)

    [1044] To a stirred solution of 2-(4-benzylpiperazin-1-yl)benzaldehyde (A105.3) (4.3 g, 15.3 mmol, 1 eq) in a mixture of methanol (25 mL) and THE (25 mL) was added sodium borohydride (0.87 g, 23 mmol, 1.5 eq) in portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford the titled (2-(4-benzylpiperazin-1-yl)phenyl)methanol (A105.4) (4 g, crude). This compound was used in the next step without further purification. LCMS: 283.17 [M+H].sup.+.

    Step-3. Procedure for the Synthesis of 1-benzyl-4-(2-(bromomethyl)phenyl)piperazine (A105.5)

    [1045] To a stirred solution of (2-(4-benzylpiperazin-1-yl)phenyl)methanol (A105.4) (3 g, 10.6 mmol, 1 eq) in DCM (60 ML) was added pyridine (1.71 mL, 21.2 mmol, 2 eq) followed by phosphorous tribromide (4.31 g, 15.9 mmol, 1.5 eq) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford 1-benzyl-4-(2-(bromomethyl)phenyl)piperazine (A105.5) (3.5 g, crude). This compound was used in the next step without further purification. LCMS: 345.09 [M+H].sup.+.

    Step-4. Procedure for the Synthesis of 4-((2-(4-benzylpiperazin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-406)

    [1046] To a stirred solution of 1-benzyl-4-(2-(bromomethyl)phenyl)piperazine (A105.5) (3 g, 8.7 mmol, 1 eq) and sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A105.6) (2.35 g, 8.7 mmol, 1 eq) in DMF (60 mL) was added TBAI (0.32 g, 0.87 mmol, 0.1 eq) and the reaction mixture was stirred at 100° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ice-cold water. The resultant precipitate was filtered out, washed water and dried under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford 4-((2-(4-benzylpiperazin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-406). Yield: 1.5 g, 33%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.87 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.42 (d, J=7.6 Hz, 1H), 7.16-7.22 (m, 6H), 7.15 (t, J=7.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 4.75 (s, 2H), 3.49 (s, 2H), 2.61 (s, 6H), 2.48-2.25 (m, 8H); HPLC purity: 99.67%; LCMS Calculated for C.sub.26H.sub.31N.sub.3O.sub.4S.sub.2: 513.18; Observed: 514.30 [M+H].sup.+.

    [1047] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00035 Compound No. Structure Yields/Analytical data A-493 [01796]embedded image Yield: 600 mg, 39%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.85 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 6.8 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.73 (s, 2H), 3.28 (s, 3H), 3.11 (s, 2H), 2.62 (s, 6H), 2.46- 2.39 (m, 2H), 2.33-2.25 (m, 2H), 1.44-1.35 (m, 2H), 1.23-1.16 (m, 2H), 0.91 (s, 3H); HPLC purity: 99.95%; LCMS calculated for C.sub.23H.sub.32N.sub.2O.sub.5S.sub.2: 480.18; Observed: 480.80 [M + H].sup.+. A-598 [01797]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 7.2 Hz, 1H), 7.42-7.30 (m, 6H), 7.21-7.16 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 5.09 (s, 2H), 4.80 (s, 2H), 3.38 (bs, 4H), 2.63 (s, 6H), 2.43- 2.37 (m, 4H); HPLC purity: 99.76%; LCMS calculated for C.sub.27H.sub.31N.sub.3O.sub.6S.sub.2: 557.17; Observed: 558.10 [M + H].sup.+. A-599 [01798]embedded image Yield: 15 mg, 13%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.87 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 4.75 (s, 2H), 2.63 (s, 6H), 2.47-2.39 (m, 4H), 2.36-2.20 (m, 4H), 2.06 (d, J = 7.2 Hz, 2H), 1.79-1.69 (m, 1H), 0.85 (d, J = 6.4 Hz, 6H); HPLC purity: 99.73%; LCMS calculated for C.sub.23H.sub.33N.sub.3O.sub.4S.sub.2: 479.19; Observed: 480.25 [M + H].sup.+.

    Step-5. Procedure for the synthesis of 4-((1-(2-(4-benzylpiperazin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-465)

    [1048] To a stirred solution of 4-((2-(4-benzylpiperazin-1-yl)benzyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-406) (300 mg, 0.58 mmol, 1 eq) in THE (10 mL) was added a 60% suspension of sodium hydride in mineral oil (210 mg, 1.75 mmol, 3 eq) at 0° C. and the reaction mixture was stirred at the same temperature for 30 min. Methyl iodide (0.072 mL, 1.16 mmol, 2 eq) was then added dropwise to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirred for overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel followed by reverse phase preparative HPLC to afford the titled compound (A-465). Yield: 30 mg, 10%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.78 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.37-7.29 (m, 4H), 7.28-7.17 (m, 3H), 6.96 (d, J=8.4 Hz, 1H), 5.12 (q, J=7.6 Hz, 1H), 3.53 (q, J=12.8 Hz, 2H), 2.73-2.64 (m, 2H), 2.58 (s, 6H), 1.72 (d, J=7.2 Hz, 3H), (6H merged with the solvent/moisture peaks); HPLC purity: 99.58%; LCMS Calculated for C.sub.27H.sub.33N.sub.3O.sub.4S.sub.2: 527.19; Observed: 528.25 [M+H].sup.+.

    [1049] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00036 Compound No. Structure Yields/Analytical data A-474 [01799]embedded image Yield: 15 mg, 29%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.83 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.33-7.20 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 5.22 (q, J = 6.8 Hz, 1H), 2.71-2.59 (m, 2H), 2.62 (s, 6H), 1.72 (d, J = 7.2 Hz, 3H), 1.20 (s, 9H), (6H merged with the solvent/moisture peaks); HPLC purity: 99.31%; LCMS Calculated for C.sub.25H.sub.35N.sub.3O.sub.5S.sub.2: 521.20; Observed: 522.48 [M + H].sup.+. A-491 [01800]embedded image Yield: 60 mg, 27%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.18(t, J = 7.2 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 5.13-5.04 (m, 1H), 3.29 (s, 3H), 3.13 (bs, 2H), 2.60 (s, 6H), 1.73 (d, J = 6.8 Hz, 3H), 1.61-1.34 (m, 3H), 1.30-1.20 (m, 2H), 0.92 (s, 3H), (3H merged with the solvent peak); HPLC purity: 98.45%; LCMS calculated for C.sub.24H.sub.34N.sub.2O.sub.5S.sub.2: 494.19; Observed: 496.39 [M + H].sup.+. A-556 [01801]embedded image Yield: 80 mg, 19%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.69-7.63 (m, 3H), 7.42-7.27 (m, 6H), 7.25-7.20 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.23 (q, J = 7.2 Hz, 1H), 5.15 (s, 2H), 4.09 (bs, 2H), 3.04 (bs, 2H), 2.85-2.40 (m, 4H), 2.69 (s, 6H), 1.80 (d, J = 7.6 Hz, 3H); HPLC purity: 99 81%; LCMS calculated for C.sub.28H.sub.33N.sub.3O.sub.6S.sub.2: 571.18; Observed: 572.10 [M + H].sup.+. A-604 [01802]embedded image Yield: 25 mg, 16%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.79 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 5.12 (q, J = 7.2 Hz, 1H), 2.72-2.63 (m, 2H), 2.60 (s, 6H), 2.40 (bs, 4H), 2.10 (d, J = 7.2 Hz, 2H), 1.80-1.70 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H), 0.86 (d, J = 6.4 Hz, 6H), (2H merged with the solvent peak); HPLC purity: 97.70%; LCMS calculated for C.sub.24H.sub.35N.sub.3O.sub.4S.sub.2: 493.21; Observed: 494.30 [M + H].sup.+. A-603 [01803]embedded image Yield: 25 mg, 12%; Appearance: White solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71-7.61 (m, 5H), 7.32- 7.27 (m, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.19 (q, J = 7.6 Hz, 1H), 4.69 (q, J = 6.8 Hz, 2H), 4.60 (t, J = 5.6 Hz, 2H), 3.53 (quint, J = 5.6 Hz, 1H), 2.90- 2.50 (m, 5H), 2.68 (s, 6H), 2.20 (bs, 3H), 1.83 (d, J = 7.2 Hz, 3H); HPLC purity: 99.89%; LCMS calculated for C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2: 493.17; Observed: 494.20 [M + H].sup.+. A-737 [01804]embedded image Yield: 0.05 g, 16.12%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (q, J = 9.4 Hz, 4H), 7.19 (t, J = 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 14.4 Hz, 1H), 4.76 (q, J = 7.2 Hz, 1H), 3.55 (s, 2H), 3.18-3.13 (m, 4H), 2.60 (s, 6H), 1.61-1.56 (m, 9H), 1.19 (s, 6H); HPLC purity: 95.51%; LCMS calculated for C.sub.26H.sub.35FN.sub.2O.sub.5S.sub.2: 538.20 Observed: 539.25 [M + H].sup.+.

    Example A106: Synthesis of 4-((3-(1-(2,6-difluorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-503)

    [1050] ##STR01805## ##STR01806##

    Step-1. Synthesis of 4-((3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A106.3)

    [1051] To a stirred solution of 3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (A106.1) (0.7 g, 3.48 mmol, 1 eq) in DCM (15 mL) was added TBA.HSO.sub.4 (0.177 g, 0.522 mmol, 0.15 eq) and KOH (0.39 g, 6.96 mmol, 2 eq) followed by 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A106.2) (1.08 g, 3.83 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography on silica gel to afford 4-((3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A106.3) (0.5 g, 33%). LCMS: 451.0 (bromo pattern).

    Step-2. Synthesis of 4-((3-(1-(2,6-difluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A106.5)

    [1052] To a stirred solution of 4-((3-bromo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A106.3) (0.5 g, 1.12 mmol, 1 eq), 1-(2,6-difluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (A106.4) (0.387 g, 1.17 mmol, 1.05 eq), in 1,4-Dioxane (10 mL) was added Cs.sub.2CO.sub.3 (2 M in H.sub.2O, 1 mL, 2.008 mmol, 1.8 eq) and KOH (0.39 g, 6.96 mmol, 2 eq) followed by Pd(PPh.sub.3).sub.2C.sub.12 (1.08 g, 3.83 mmol, 1.1 eq), after degassing with argon for 20 minutes. The reaction mixture was stirred 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography on silica gel to afford 4-((3-(1-(2,6-difluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A106.5) (0.3 g, 48%).

    Step-3. Synthesis of 4-((3-(1-(2,6-difluorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-503)

    [1053] To a stirred solution of 4-((3-(1-(2,6-difluorophenyl)-1,2,3,6-tetrahydropyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A106.5) (0.2 g, 0.355 mmol, 1 eq) in MeOH:EtOAc (1:1, 10 mL) was added PtO.sub.2 (0.1 g) under N2 atmosphere. The reaction mixture was hydrogenated (100 psi) at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite and the celite bed was washed with EtOAc. The filtrate was concentrated under reduced pressure to dryness. The crude product was purified by prep-HPLC to afford 4-((3-(1-(2,6-difluorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-503). Yield: 0.04 g, 20%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03-8.01 (m, 2H), 7.95-7.93 (m, 2H), 7.04-7.01 (m, 3H), 4.85 (s, 1H), 3.18-3.15 (m, 2H), 3.04-2.98 (m, 4H), 2.87-2.84 (m, 2H), 2.61 (s, 7H), 1.79-1.75 (m, 4H), 1.65-1.53 (m, 2H); HPLC purity: 99.26%; LCMS Calculated for C.sub.25H.sub.29F.sub.2N.sub.5O.sub.4S.sub.2: 565.65; Observed: 566.20 [M+H].sup.+.

    [1054] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00037 Compound No. Structure Yields/Analytical data A-504 [01807]embedded image Yield: 0.004 g, 3%; Appearance: White solid; (400 MHz, CHLORO- FORM-d) δ 1.78-1.91 (m, 4 H) 1.94-2.09 (m, 2 H) 2.41-2.50 (m, 2 H) 2.66-2.72 (m, 1H) 2.77 (s, 6 H) 2.92 (br t, J = 5.62 Hz, 2 H) 3.20 (br t, J = 11.49 Hz, 2 H) 3.30-3.41 (m, 2 H) 6.81-6.89 (m, 2 H) 6.92- 7.01 (m, 1 H) 7.92 (d, J = 8.31 Hz, 2 H) 8.13 (d, J = 8.80 Hz, 2 H). 2H′s are merged in to solvent peak; HPLC purity: 99%; LCMS Calculated for C.sub.26H.sub.30F.sub.2N.sub.4O.sub.4S.sub.2: 564.67; Observed: 565.20 [M + H].sup.+. A-533 [01808]embedded image Yield: 0.02 g, 12%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.63-1.72 (m, 2H) 1.73-1 83 (m, 2H) 2.64 (s, 6H) 2.65-2.77 (m, 1H) 2.81-2.88 (m, 2H) 2.90-2.98 (m, 2H) 3.03- 3.13 (m, 2H) 3.14-3.23 (m, 2H) 3.62-3.68 (m, 2H) 6.97-7.12 (m, 4H) 8.00 (d, J = 8.31 Hz, 2 H) 8.14 (d, J = 8.31 Hz, 2 H); HPLC purity: 97%; LCMS Calculated for C.sub.25H.sub.29F.sub.2N.sub.5O.sub.4S.sub.2: 565.65; Observed: 566.4 [M + H].sup.+.

    Example A107: Synthesis of N,N-dimethyl-4-(2,2,2-trifluoro-1-((2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)amino)ethyl)benzenesulfonamide (A-684)

    [1055] ##STR01809## ##STR01810##

    Step-1. Synthesis of (Z)-1-(4-bromophenyl)-2,2,2-trifluoro-N-(2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)ethan-1-imine (A107.3)

    [1056] To a stirred solution of 2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A107.1) (0.5 g, 2.134 mmol, 1 eq) in dry toluene (5 mL) was added trimethylaluminium (4.2 mL, 8.54 mmol, 4 eq) under argon atmosphere at 0° C. and stirred for 15 minutes at the same temperature. To the resultant reaction mixture was added a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one (A107.2) (0.65 g, 2.56 mmol, 1.2 eq) in toluene and stirred at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was quenched with ice cold water, basified with saturated NaHCO.sub.3 solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel using (EtOAc/n-Hexane: 2-5%) as eluent to afford (Z)-1-(4-bromophenyl)-2,2,2-trifluoro-N-(2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)ethan-1-imine (A107.3) (0.5 g, 50%) as a yellow semisolid. LCMS: 470.95 [M+H].sup.+.

    Step-2. Synthesis of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A107.4)

    [1057] To a stirred solution of (Z)-1-(4-bromophenyl)-2,2,2-trifluoro-N-(2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)ethan-1-imine (A107.3) (0.5 g, 1.065 mmol, 1 eq) in THF (10 mL) was added Borane.DMS, 1 M solution in THE (2.1 mL, 4.26 mmol, 4 eq). The reaction mixture was stirred at reflux temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was slowly quenched with MeOH, concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A107.4) (0.45 g, 89.6%). This compound was used in the next step without further purification. LCMS: 472.95 [M+H].sup.+.

    Step-3. Synthesis of N-(1-(4-benzylthio)phenyl)-2,2,2-trifluoroethyl)-2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A107.6)

    [1058] To a stirred solution of N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A107.4) (0.45 g, 0.954 mmol, 1 eq), benzyl mercaptan (A107.5) (0.166 g, 1.336 mmol, 1.4 eq) and DIPEA (0.44 mL, 2.38 mmol, 2.5 eq) in 1,4-Dioxane (10 mL) were added Pd.sub.2(dba).sub.3 (0.026 g, 0.029 mmol, 0.03 eq) and xantphos (0.039 g, 0.067 mmol, 0.07 eq) and the mixture was degassed for 15 minutes using argon. The resulting reaction mixture was stirred at 100° C. for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash using (EtOAc/n-hexane: 1-5%) as eluent to afford N-(1-(4-benzylthio)phenyl)-2,2,2-trifluoroethyl)-2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A107.6) (0.5 g, crude) as a yellow oil. LCMS: 515.1 [M+H].sup.+.

    Step-4. Synthesis of 4-(2,2,2-trifluoro-1-((2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)amino)ethyl)benzenesulfonyl chloride (A107.7)

    [1059] To a stirred solution of N-(1-(4-benzylthio)phenyl)-2,2,2-trifluoroethyl)-2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)aniline (A107.6) (0.5 g, 0.97 mmol, 1 eq) in AcOH:H.sub.2O (1:1, 10 mL) was added NBS (0.35 g, 1.95 mmol, 2 eq) and stirred at 0° C. for 1 h. To the resultant reaction mixture was added NBS (0.35 g, 1.95 mmol, 2 eq) again and stirred at 0° C. for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with H.sub.2O, basified with saturated solution of NaHCO.sub.3, extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford 4-(2,2,2-trifluoro-1-((2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)amino)ethyl)benzenesulfonyl chloride (A107.7) (0.4 g, crude) as yellow semisolid. This compound was used in the next step without further purification.

    Step-5. Synthesis of N,N-dimethyl-4-(2,2,2-trifluoro-1-((2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)amino)ethyl)benzenesulfonamide (A-684)

    [1060] To a stirred solution of 4-(2,2,2-trifluoro-1-((2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)amino)ethyl)benzenesulfonyl chloride (A107.7) (0.4 mg, 0.81 mmol, 1 eq) in THE (5 mL), pyridine (0.128 g, 1.628 mmol, 2 eq) followed dimethylamine in THE (2 M, 200 mg, 0.74 mmol, 1 eq) were added at 0° C. and the reaction mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using (EtOAc/n-hexane: 20-30%) as eluent followed by recrystallization with MeOH and dried to afford N,N-dimethyl-4-(2,2,2-trifluoro-1-((2-(4-(methoxymethyl)-4-methylpiperidin-1-yl)phenyl)amino)ethyl)benzenesulfonamide (A-684). Yield: 29 mg, 7.9%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.83-7.77 (m, 4H), 7.12 (d, J=7.2 Hz, 1H), 6.92-6.88 (m, 1H), 6.80-6.78 (m, 1H), 6.71 (t, J=7.4 Hz, 1H), 5.85-5.83 (m, 1H), 5.78-5.76 (m, 1H), 3.29 (s, 3H), 3.18 (s, 2H), 2.82-2.80 (s, 2H), 2.66-2.63 (m, 2H), 2.60 (s, 6H), 1.66-1.61 (m, 2H), 1.43 (bs, 2H), 1.00 (s, 3H); HPLC purity: 99.78%; LCMS calculated for C.sub.24H.sub.32F.sub.3N.sub.3O.sub.3S: 499.59; Observed: 500.1 [M+H].sup.+.

    Example A108: Syntheses of N1-(2-(4-(2-hydroxypropan-2-yl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-522), N1-(2-(4-(1-hydroxycyclopropyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-558), and N1-(2-(4-(1-hydroxyethyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-557)

    [1061] ##STR01811##

    Step-1. Synthesis of N1-(2-(4-(2-hydroxypropan-2-yl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-522)

    [1062] To a stirred solution of methyl 1-(2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)-4-methylpiperidine-4-carboxylate (A108.1) (100 mg, 0.2 mmol, 1 eq) in THE (5 mL) was added a 1.4 M solution of methylmagnesium bromide solution in THE (1.44 mL, 2 mmol, 10 eq) at −78° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with cold water. The resultant solid was filtered out and dried under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford N1-(2-(4-(2-hydroxypropan-2-yl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-522). Yield: 35 mg, 35%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.02 (br s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.25 (d, J=6.8 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.10 (t, J=7.2 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 4.06 (s, 1H), 2.67-2.56 (m, 2H), 2.60 (s, 6H), 2.40-2.32 (m, 2H), 1.90-1.80 (m, 2H), 1.15-1.05 (m, 2H), 1.07 (s, 6H), 0.88 (s, 3H); HPLC purity: 99.68%; LCMS calculated for C.sub.23H.sub.33N.sub.3O.sub.5S.sub.2: 495.19; Observed: 496.40 [M+H].sup.+.

    Step-2. Synthesis of N1-(2-(4-(1-hydroxycyclopropyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-558)

    [1063] To a stirred solution of methyl 1-(2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)-4-methylpiperidine-4-carboxylate (A108.1) (200 mg, 0.4 mmol, 1 eq) in THE (15 mL) was added titanium tetraisopropoxide (0.735 mL, 2.4 mmol, 6 eq) and the reaction mixture was stirred at room temperature for 5 min. To the resulting reaction mixture, a 3 M solution of ethylmagnesium bromide solution in THF (0.404 mL, 1.2 mmol, 3 eq) was added at room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 1N aqueous HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by Combiflash chromatography on silica gel to afford N1-(2-(4-(1-hydroxycyclopropyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-558). Yield: 20 mg, 10%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.10 (br s, 1H), 8.00 (d, J=7.6 Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.26 (d, J=7.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 7.04 (t, J=7.2 Hz, 1H), 4.95 (s, 1H), 2.67-2.59 (m, 2H), 2.61 (s, 6H), 2.37 (d, J=11.2 Hz, 2H), 1.60-1.50 (m, 2H), 1.18 (d, J=12.8 Hz, 2H), 0.96 (s, 3H), 0.63-0.59 (m, 2H), 0.47-0.42 (m, 2H); HPLC purity: 99.71%; LCMS calculated for C.sub.23H.sub.31N.sub.3O.sub.5S.sub.2: 493.17; Observed: 492.20 [M+H].sup.+.

    Step-3. Synthesis of N1-(2-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A108.2)

    [1064] To a stirred solution of compound 1-(2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)phenyl)-4-methylpiperidine-4-carboxylate (A108.1) (800 mg, 1.61 mmol, 1 eq) in THE (10 mL) was added a 2 M solution of lithium aluminium hydride (0.88 mL, 1.77 mmol, 1.1 eq) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.4 solution, filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by combiflash chromatography on silica gel to afford N1-(2-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A108.2) (750 mg, 88.3%). LCMS: 468.15 [M+H].sup.+.

    Step-4. Synthesis of N1-(2-(4-formyl-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A108.3)

    [1065] To a stirred solution of N1-(2-(4-(hydroxymethyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A108.2) (750 mg, 1.6 mmol, 1 eq) in DMSO (5 mL), pyridine sulfur trioxide (1.27 g, 8 mmol, 5 eq) and triethyl amine (1.21 mL, 8 mmol, 5 eq) at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by combiflash chromatography on silica gel to afford N1-(2-(4-formyl-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A108.3) (600 mg, 80.3%). LCMS: 466.14 [M+H].sup.+.

    Step-5. Synthesis of NJ-(2-(4-(1-hydroxyethyl)-4-methylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-557)

    [1066] To a stirred solution of compound (A108.3) (200 mg, 0.429 mmol, 1 eq) in THE (2 mL) was added a 1.4 M solution of methyl magnesium bromide solution in THF (0.46 mL, 0.64 mmol, 1.5 eq) at −78° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford the titled compound (A-557). Yield: 30 mg, 14.6%; Appearance: Off white solid; 1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (bs, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.0 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 4.35 (d, J=5.2 Hz, 1H), 2.61 (s, 6H), 2.60-2.50 (m, 2H), 2.46-2.35 (m, 2H), 1.60-1.48 (m, 2H), 1.35 (d, J=12.4 Hz, 1H), 1.10 (d, J=13.2 Hz, 1H), 0.99 (d, J=6.4 Hz, 3H), 0.81 (s, 3H), (1H merged with the moisture peak); HPLC purity: 98.93%; LCMS calculated for C.sub.22H.sub.31N.sub.3O.sub.5S.sub.2: 481.17; Observed: 482.40 [M+H].sup.+.

    Example A109: Synthesis of 4-((1-(2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-801, A-803 & A-804)

    [1067] ##STR01812## ##STR01813##

    Step-1. Synthesis of ethyl 1-(2-acetyl-6-fluorophenyl)piperidine-4-carboxylate (A109.3)

    [1068] To a stirred solution of ethyl piperidine-4-carboxylate (A109.1) (0.6 g, 3.84 mmol, 1.2 eq) and 1-(2,3-difluorophenyl)ethan-1-one (A109.2) (0.5 g, 3.2 mmol, 1 eq) in DMF (15 mL) was added potassium carbonate (0.88 g, 6.41 mmol, 2 eq) at room temperature and the reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with cold water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford ethyl 1-(2-acetyl-6-fluorophenyl)piperidine-4-carboxylate (A109.3) (0.6 g, 53.5%) as colorless oil. LCMS: 294.2 [M+H].sup.+.

    Step-2. Synthesis of ethyl 1-(2-fluoro-6-(1-hydroxyethyl)phenyl)piperidine-4-carboxylate (A109.4)

    [1069] To a stirred solution of ethyl 1-(2-acetyl-6-fluorophenyl)piperidine-4-carboxylate (A109.3) (0.6 g, 2.04 mmol, 1 eq) in THE (25 mL) was added sodium borohydride (0.077 g, 2.04 mmol, 1 eq) in portions at 0° C. The reaction mixture was warmed to room temperature and stirred for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by combiflash chromatography to afford ethyl 1-(2-fluoro-6-(1-hydroxyethyl)phenyl)piperidine-4-carboxylate (A109.4) (0.5 g, 83.3%) as a thick liquid. LCMS: 295.65 [M+H].sup.+.

    Step-3. Synthesis of ethyl 1-(2-fluoro-6-(1-((methylsulfonyl)oxy)ethyl)phenyl)piperidine-4-carboxylate (A109.5)

    [1070] To a stirred solution of ethyl 1-(2-fluoro-6-(1-hydroxyethyl)phenyl)piperidine-4-carboxylate (A109.4) (0.5 g, 1.69 mmol, 1 eq) in DCM (15 mL), triethyl amine (0.46 mL, 3.38 mmol, 2 eq) and methanesulfonyl chloride (0.16 mL, 2.03 mmol, 1.2 eq) were added at 0° C. and the reaction mixture was stirred at same temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with saturated solution of NaHCO.sub.3, separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford ethyl 1-(2-fluoro-6-(1-((methylsulfonyl)oxy)ethyl)phenyl)piperidine-4-carboxylate (A109.5) (0.5 g, crude) as a yellow oil. This compound was used in the next step without further purification. LCMS: No ionization.

    Step-4. Synthesis of ethyl 1-(2-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)ethyl)-6-fluorophenyl)piperidine-4-carboxylate (A109.7)

    [1071] To a stirred solution of ethyl 1-(2-fluoro-6-(1-((methylsulfonyl)oxy)ethyl)phenyl)piperidine-4-carboxylate (A109.5) (0.5 g, 1.34 mmol, 1 eq) and sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A109.6) (0.36 g, 1.34 mmol, 1 eq) in DMF (25 mL) was added potassium carbonate (0.36 g, 2.68 mmol, 2 eq) at room temperature and the reaction mixture was stirred at 50° C. for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with cold water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by combiflash chromatography to afford ethyl 1-(2-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)ethyl)-6-fluorophenyl)piperidine-4-carboxylate (A109.7) (0.28 g, 40%) as an off-white solid. LCMS: 527.33 [M+H].sup.+.

    Step-5. Synthesis of 4-((1-(3-fluoro-2-(4-formylpiperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A109.8)

    [1072] To a stirred solution of ethyl 1-(2-(1-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonyl)ethyl)-6-fluorophenyl)piperidine-4-carboxylate (A109.7) (0.28 g, 0.53 mmol, 1 eq) in DCM (15 mL), was added DIBAL (0.22 g, 1.59 mmol, 3 eq) at −78° C. The reaction mixture was stirred at same temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with 1N HCl and extracted with dichloromethane. The combined organic layers were washed with brine, separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by combiflash chromatography to afford 4-((1-(3-fluoro-2-(4-formylpiperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A109.8) (0.2 g, 91%) as an off-white solid. LCMS: 483.18 [M+H].sup.+.

    Step-6. Synthesis of 4-((1-(2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-801, A-803 & A-804)

    [1073] To a stirred solution of 4-((1-(3-fluoro-2-(4-formylpiperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A109.8) (0.2 g, 0.41 mmol, 1 eq) in MeOH (10 mL) was added 4,4-difluoropiperidine (A109.9) (0.05 g, 0.41 mmol, 1 eq) and the reaction mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (0.052 g, 0.82 mmol, 2 eq) was added at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash chromatography, followed by reverse phase preparative HPLC to afford 4-((1-(2-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidin-1-yl)-3-fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-801) (350 mg). The compound A-801 (329 mg) was given for chiral separation to afford titled compounds A-803 and A-804.

    [1074] A-801: Yield: 0.35 g, 73%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (d, J=8 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.44-7.38 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.14 (m, 1H), 5.38-5.32 (m, 1H), 2.90-2.76 (m, 2H), 2.72-2.66 (m, 1H), 2.61 (s, 6H), 2.48-2.42 (m, 4H), 2.24 (d, J=7.2 Hz, 2H), 2.00-1.86 (m, 4H), 1.76-1.64 (m, 5H), 1.58-1.46 (m, 2H) 1.24-1.14 (m, 1H), 1.04-0.98 (m, 1H). HPLC purity: 99.55%; LCMS calculated for C.sub.27H.sub.36F.sub.3N.sub.3O.sub.4S.sub.2: 587.21 Observed: 588.1 [M+H].sup.+.

    [1075] A-803: Yield: 0.048 g, 13.7%; Appearance: Off-white solid; 1H NMR (400 MHz, DMSO.sub.6) S 7.89 (d, J=7.2 Hz, 2H), 7.77 (d, J=6.8 Hz, 2H), 7.41 (d, J=6.4 Hz, 1H), 7.34-7.26 (m, 1H), 7.19-7.14 (m, 1H), 5.35-5.33 (m, 1H), 2.86-2.76 (m, 2H), 2.72-2.68 (m, 1H), 2.61 (s, 6H), 2.48-2.40 (m, 4H), 2.24 (d, J=4.8 Hz, 2H), 2.00-1.86 (m, 4H), 1.74-1.62 (m, 5H), 1.58-1.42 (m, 2H), 1.24-1.14 (m, 1H), 1.02-0.99 (m, 1H); HPLC purity: 99.79%; LCMS calculated for C.sub.27H.sub.36F.sub.3N.sub.3O.sub.4S.sub.2:587.21 Observed: 588.1 [M+H].sup.+. Method for chiral sepn: Column: DIACEL CHIRALPAK-IG, 250 mm*4.6 mm, 5 u; Mobile Phase: A: n-HEXANE:MTBE (60:40)+0.1% TFA B: ETHANOL, Flow rate: 1.00 mL/min, Isocratic: 10% B, Ret. Time: 12.48.

    [1076] A-804: Yield: 0.05 g, 14.2%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (d, J=7.6 Hz, 2H), 7.78 (d, J 8 Hz, 2H), 7.41 (d, J=7.2 Hz, 1H), 7.33-7.28 (m, 1H), 7.20-7.16 (m, 1H), 5.35-5.33 (m, 1H), 2.86-2.76 (m, 2H), 2.69-2.66 (m, 1H), 2.61 (s, 6H), 2.48-2.39 (m, 4H), 2.24 (d, J=5.6 Hz, 2H), 2.00-1.86 (m, 4H), 1.71-1.65 (m, 5H) 1.55-1.48 (m, 2H), 1.23-1.17 (m, 1H), 1.02-0.99 (m, 1H); HPLC purity: 95.15%; LCMS calculated for C.sub.27H.sub.36F.sub.3N.sub.3O.sub.4S.sub.2: 587.21; Observed: 588.1 [M+H].sup.+. Method for chiral sepn: Column: DIACEL CHIRALPAK-IG, 250 mm*4.6 mm, 5 u; Mobile Phase: A: n-HEXANE:MTBE (60:40)+0.1% TFA B: ETHANOL, Flow rate: 1.00 mL/min, Isocratic: 10% B, Ret. Time: 17.61.

    [1077] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00038 Compound No. Structure Yields/Analytical data A-802 [01814]embedded image Yield: 0.202 g, 34.2%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 8 Hz, 1H), 7.33-7.28 (m, 1H), 7.20- 7.15 (m, 1H), 5.37 (q, J = 7.2 Hz, 1H), 2.87-2.68 (m, 4H), 2.66-2.65 (m, 3H), 2.61 (s, 6H), 2.33 (d, J = 6.8 Hz, 2H), 2.27-2.16 (m, 2H), 1.70-1.65 (m, 5H), 1.57-1.54 (m, 1H), 1.48-1.40 (m, 1H), 1.20-1.17 (m, 1H), 1.03-1.00 (m, 1H); HPLC purity: 99.86%; LCMS calculated for C.sub.26H.sub.34F.sub.3N.sub.3O.sub.4S.sub.2: 573.19 Observed: 574.1 [M + H].sup.+. A-805 [01815]embedded image Yield: 0.042 g, 23.3%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.33-7.28 (m, 1H), 7.20- 7.15 (m, 1H), 5.37 (q, J = 7.2 Hz, 1H), 2.878-2.76 (m, 4H), 2.68 (t, J = 7.2 Hz, 3H), 2.61 (s, 6H), 2.33 (d, J = 6.8 Hz, 2H), 2.27-2.18 (m, 2H), 1.70-1.65 (m, 5H), 1.57-1.53 (m, 1H), 1.48-1.40 (m, 1H), 1.20-1.18 (m, 1H), 1.03-1.00 (m, 1H) ; HPLC purity: 99.37%; LCMS calculated for C.sub.26H.sub.34F.sub.3N.sub.3O.sub.4S.sub.2: 573.19 Observed: 574.1 [M + H].sup.+. Method for Chiral sepn: Column: DIACEL CHIRALPAK-IG, 250 mm * 4.6 mm, 5u, Mobile Phase: A: n-HEXANE + 0.1% TFA, B: ETHANOL, Flow rate: 1.0 mL/min, Isocratic: 8% B, Ret. Time: 9.48. A-806 [01816]embedded image Yield: 0.022 g, 12.2%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8 Hz, 1H), 7.33-7.28 (m, 1H), 7.20- 7.15 (m, 1H), 5.37 (q, J = 6.8 Hz 1H), 2.87-2.77 (m, 4H), 2.68 (t, J = 7.20 Hz, 3H), 2.61 (s, 6H), 2.33 (d, J = 6.8 Hz, 2H), 2.28-2.17 (m, 2H), 1.72-1.65 (m, 5H), 1.57-1.54 (m, 1H), 1.50-1.38 (m, 1H), 1.23-1.18 (m, 1H), 1.03-1.00 (m, 1H) ; HPLC purity: 99.75%; LCMS calculated for C.sub.26H.sub.34F.sub.3N.sub.3O.sub.4S.sub.2: 573.19 Observed: 574.11 [M + H].sup.+. Method for Chiral sepn: Column: DIACEL CHIRALPAK-IG, 250 mm * 4.6 mm, 5u, Mobile Phase: A: n-HEXANE + 0.1 % TFA, B: ETHANOL, Flow rate: 1.0 mL/min, Isocratic: 8% B, Ret. Time: 11.63. A-782 [01817]embedded image Yield: 0.025 g, 13.8%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.41 (d, J = 8 Hz, 1H), 7.31-7.29 (m, 1H), 7.22- 7.14 (m, 1H), 5.35 (q, J = 7.2 Hz, 1H), 3.58-3.50 (m, 2H), 2.79-2.65 (m, 5H), 2.61 (s, 6H), 2.16-2.10 (m, 2H), 1.70-1.62 (m, 5H), 1.60-1.53 (m, 4H), 1.04 (d, J = 5.2 Hz, 6H). HPLC purity: 99.80%; LCMS calculated for C.sub.28H.sub.40N.sub.3O.sub.5FS.sub.2: 581.24; Observed: 582.2 [M + H].sup.+. Method of chiral sepn: Column: DIACEL CHIRAL- PAK-IG, 250 mm * 4.6 mm , 5u, Mobile Phase: A: n-HEXANE + 0.1% TFA B: ETHANOL, Flow rate: 1.0 mL/min, Isocratic: 20% B, Ret. Time: 19.64 A-783 [01818]embedded image Yield: 0.028 g, 15.5%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.90 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8 Hz, 1H), 7.31-7.29 (m, 1H), 7.12- 7.14 (m, 1H), 5.35 (q, J = 7.2 Hz, 1H), 3.58-3.48 (m, 2H), 2.90-2.64 (m, 5H), 2.61 (s, 6H), 2.14 (d, J = 6 Hz, 2H), 1.72-1.62 (m, 5H), 1.58-1.48 (m, 4H), 1.04 (d, J = 6.4 Hz, 6H). HPLC purity: 99 80%; LCMS calculated for C.sub.28H.sub.40N.sub.3O.sub.5FS.sub.2: 581.24; Observed: 582.36 [M + H].sup.+. Method of chiral sepn: Column: DIACEL CHIRAL- PAK-IG, 250 mm * 4.6 mm , 5u, Mobile Phase: A: n-HEXANE + 0.1% TFA B: ETHANOL, Flow rate: 1.0 mL/min, Isocratic: 20% B, Ret. Time: 25.52 A-800 [01819]embedded image Yield: 0.2 g, 32%; Appearance: Off- white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 8.13 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.42-7.40 (m, 1H), 7.32-7.27(m, 1H), 7.19-7.13 (m, 1H), 5.36 (q, J = 7.04 Hz, 1H), 3.53- 3.49 (m, 2H), 2.83-2.63 (m, 4H), 2.12 (d, J = 6.2 Hz, 2H), 1.66 (d, J = 7.2 Hz, 4H), 1.57-1.46 (m, 5H), 1.17-1.14 (m, 1H), 1.03 (d, J = 6 Hz, 6H), 0.95- 0.93 (m, 1H). HPLC purity: 98 72%; LCMS calculated for C.sub.27H.sub.35 F.sub.3N.sub.2O.sub.5S.sub.2: 588.19; Observed: 589.1 [M + H].sup.+. A-807 [01820]embedded image Yield: 26 mg; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 8.15 (d, J = 7.6 Hz, 2H), 7.91 (d, J = 8 Hz, 2H), 7.44-7.41 (m, 1H), 7.33- 7.28 (m, 1H), 7.20-7.15 (m, 1H), 5.36 (q, J = 7.2 Hz, 1H), 3.53 (bs, 2H), 2.82-2.67 (m, 4H), 2.13 (d, J = 6 Hz, 2H), 1.68 (d, J = 7.2 Hz, 4H), 1.55- 1.48 (m, 5H), 1.22-1.16 (m, 1H), 1.04 (d, J = 6 Hz, 6H), 0.97-0.94 (m, 1H). HPLC purity: 99.29%; Chiral HPLC purity: 98.87%; LCMS calculated for C.sub.27H.sub.35 F.sub.3N.sub.2O.sub.5S.sub.2: 588.19; Observed: 589.1 [M + H].sup.+. Method for chiral sepn: Column: DIACEL CHIRAL- PAK-IG, 250 mm * 4.6 mm, 5u, Mobile Phase: A: n-HEXANE + 0.1% TFA, B: Iso-Propyl-Alcohol, Flow rate: 1.00 mL/min, Isocratic: 20% B, Ret. Time: 17.37 A-808 [01821]embedded image Yield: 17 mg; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 8.15 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.54-7.15 (m, 3H), 5.36 (q, J = 7 Hz, 1H), 3.58-3.50 (m, 2H), 2.82-2.68 (m, 4H), 2.14 (d J = 6.4 Hz, 2H), 1.68 (d, J = 7.2 Hz, 4H), 1.56-1.48 (m, 5H), 1.23-1.16 (m, 1H), 1.05 (d, J = 6.4 Hz, 6H), 0.97-0.94 (m, 1H). HPLC purity: 98.99%; Chiral HPLC purity: 97.36%; LCMS calculated for C.sub.27H.sub.35F.sub.3N.sub.2O.sub.5S.sub.2: 588.19; Observed: 589.1 [M + H].sup.+. Method for chiral sepn: Column: DIACEL CHIRALPAK-IG, 250 mm * 4.6 mm, 5u, Mobile Phase: A: n-HEXANE + 0.1% TFA, B: Iso- Propyl-Alcohol, Flow rate: 1.00 mL/min, Isocratic: 20% B, Ret. Time: 25.72. A-839 [01822]embedded image Yield: 940 mg. 98%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (d, J = 7.34 Hz, 2 H), 7.76 (d, J = 7.34 Hz, 2 H), 7.41 (d, J = 7.34 Hz, 1 H), 7.34-7.24 (m, 1 H), 7.20-7.14 (m, 1 H), 5.36-5.32 (m, 1 H), 3.48 (d, J = 9.78 Hz, 2 H), 3.37 (d, J = 9.78 Hz, 2 H), 2.96 (bs, 2 H), 2.90-2.73 (m, 2 H), 2.69-2.66 (m, 1 H), 2.61 (s, 6 H), 2.16-2.06 (m, 2 H), 1.84-1.75 (m, 3 H), 1.72-1.62 (m, 6 H), 1.61-1.54 (m, 1 H), 1.47- 1.30 (m, 1 H), 1.25-1.14 (m, 1 H), 1.01 (d, J = 10.76 Hz, 1 H): HPLC purity: 99.83%; LCMS calculated for C.sub.28H.sub.38FN.sub.3O.sub.5S.sub.2: 579.22 Observed: 580.1 [M + H].sup.+. A-832 [01823]embedded image Yield: 12.82 mg, 12%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 7.34 Hz, 2 H), 7.78 (d, J = 7.34 Hz, 2 H), 7.42 (d, J = 7.34 Hz, 1 H), 7.34-7.28 (m, 1 H), 7.21-7.15 (m, 1 H), 5.25-5.44 (m, 1 H), 3.50 (d, J = 9.78 Hz, 2 H), 3.40 (d, J = 9.78 Hz, 2 H), 3.00-2.95 (m, 2 H), 2.88-2.74 (m, 2 H), 2.71- 2.67 (m, 1 H), 2.62 (s, 6 H), 2.17- 2.06 (m, 2 H), 1.85-1.75 (m, 3 H), 1.70-1.64 (m, 6 H), 1.62-1.57 (m, 1 H), 1.44-1.34 (m 1 H), 1.25-1.14 (m, 1 H), 1.10-0.96 (m, 1 H); HPLC purity: 99.53%; LCMS calculated for C.sub.28H.sub.38FN.sub.3O.sub.5S.sub.2: 579.22 Observed: 580.1 [M + H].sup.+. Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm * 4.6 mm , 5u; Mobile Phase: A: n-HEXANE + 0.1 % TFA; B: DCM:MEOH(50:50); Flow rate: 1.00 mL/min; Isocratic: 20% B; Retention time: 24.377 A-855 [01824]embedded image Yield: 9.13 mg, 1%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 8 Hz, 2 H), 7.78 (d, J = 8 Hz, 2 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.34-7.28 (m, 1 H), 7.20-7.15 (m, 1 H), 5.38-5.34 (m, 1 H), 3.51 (d, J = 9.6 Hz, 2 H), 3.41 (d, J = 9.6 Hz, 2 H), 3.01-2.96 (m, 2 H), 2.90-2.74 (m, 2 H), 2.72-2.68 (m, 1 H), 2.62 (s, 6 H), 2.15-2.09 (m, 2 H), 1.86-1.76 (m, 3 H), 1.72-1.65 (m, 6H), 1.64-1.57 (m, 1 H), 1.44-1.34 (m, 1 H), 1.24-1.19 (m, 1 H), 1.02- 0.99 (m, 1 H); HPLC purity: 98 41%; LCMS calculated for C.sub.28H.sub.28FN.sub.3O.sub.5S.sub.2: 579.22 Observed: 580.1 [M + H].sup.+. METHOD: Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm * 4.6 mm, 5u; Mobile Phase: A: n- HEXANE + 0.1% TFA; B: DCM: MEOH(50:50); Flow rate: 1.00 mL/min; Isocratic: 20% B; Ret. Time: 26.374. A-837 [01825]embedded image Yield: 0.4 g. 69%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (d, J = 8.31 Hz, 2 H), 7.77 (d, J = 8.31 Hz, 2 H), 7.41 (d, J = 7.82 Hz, 1 H), 7.32-7.27 (m, 1 H), 7.19-7.14 (m, 1 H), 5.37 (q, J = 7.01 Hz, 1 H), 4.41 (d, J = 5.87 Hz, 2 H), 3.30-2.88 (m, 2 H), 2.84-2.76 (m, 3 H), 2.69 (d, J = 11.74 Hz, 1 H), 2.61 (s, 6 H), 2.57-2.52 (m, 2 H), 2.43-2.37 (m, 2 H), 2.20-2.15 (m, 1 H), 1.74-1.70 (m, 1 H), 1.66 (d, J = 7.34 Hz, 3 H), 1.56 (d, J = 11.25 Hz, 2H), 1.24-1.18 (m, 1 H), 1.04-0.99 (m, 1 H).; HPLC purity: 98.44%; LCMS calculated for C.sub.27H.sub.36F.sub.3N.sub.3O.sub.5S.sub.2: 565.21 Observed: 566.1 [M + H].sup.+. A-848 [01826]embedded image Yield: 0.0426 g, 12%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 8 Hz, 2 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.34-7.27 (m, 1 H), 7.21-7.14 (m, 1 H), 5.41-5.33 (m, 1 H), 4.42 (d, J = 5.2 Hz, 2 H), 3.03 (dd, J = 10,51, 5.14 Hz, 2 H), 2.95- 2.76 (m, 3 H), 2.72-2.67 (m, 1 H), 2.62 (s, 6 H), 2.58-2.56 (m, 2 H), 2.44 (d, J = 6.8 Hz, 2 H), 2.20 (d, J = 7.2 Hz, 1 H), 1.70-1.80 (m, 2 H), 1.67 (d, J = 7.34 Hz, 3 H), 1.60-1.52 (m, 2 H), 1.28-1.18 (m, 1 H), 1.05 (d, J = 10.27 Hz, 1 H); HPLC purity: 99.68%; LCMS calculated for C.sub.27H.sub.36F.sub.3N.sub.3O.sub.5S.sub.2: 565.21 Observed: 566.1 [M + H].sup.+. METHOD: Column: YMC CHIRAL ART CELLULOSE- SC, 250 mm * 4.6 mm , 5u; Mobile Phase: A: n-HEXANE + 0. 1% Iso- propyl-amine; B: DCM:MEOH (50:50); Flow rate: 1.00 mL/min; Isocratic: 20% B; Ret. Time: 24.387. A-849 [01827]embedded image Yield: 0.021 g. 6%; Appearance: Off white solid: .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.91 (d, J = 8.31 Hz, 2 H), 7.79 (d, J = 8.31 Hz, 2 H), 7.42 (d, J = 7.82 Hz, 1 H), 7.37-7.25 (m, 1 H), 7.24-7.11 (m, 1 H), 5.37 (q, J = 7.2 Hz, 1 H), 4.42 (d, J = 5.87 Hz, 2 H), 3.03 (dd, J = 10.51, 5.14 Hz, 2 H), 2.95-2.76 (m, 3 H), 2.74-2.66 (m, 1 H), 2.62 (s, 6 H), 2.60-2.55 (m, 2 H), 2.44 (d, J = 6.85 Hz, 2 H), 2.19 (d, J = 7.6 Hz, 1 H), 1.79-1.70 (m, 2 H), 1.67 (d, J = 7.34 Hz, 3 H), 1.60-1.52 (m, 2 H), 1.28-1.18 (m, 1 H), 1.05 (d, J = 10.8 Hz, 1 H): HPLC purity: 96.86%; LCMS calculated for C.sub.27H.sub.36F.sub.3N.sub.3O.sub.5S.sub.2: 565.21 Observed: 566.1 [M + H].sup.+. METHOD: Column: YMC CHIRAL ART CELLULOSE- SC, 250 mm * 4.6 mm , 5u; Mobile Phase: A: n-HEXANE + 0.1% Iso- propyl-amine; B: DCM:MEOH (50:50) Flow rate: 1.00 mL/min; Isocratic: 20% B; Ret. Time: 27.739. A-860 [01828]embedded image Yield: 0.25 g. 35.5%: Appearance: White solid: .sup.1H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (d, J = 2.93 Hz, 4 H), 7.47 (d, J = 7.82 Hz, 1 H), 7.22-7.15 (m, 1 H), 6.98 (dd, J = 11.25, 8.80 Hz, 1 H), 5.51-5.45 (m, 1 H), 4.24 (d, J = 10 Hz, 2 H), 3.72 (d, J = 10.27 Hz, 2 H), 3.51- 3.42 (m, 2 H), 2.93 (t, J = 11.00 Hz, 2 H), 2.70 (s, 6 H), 2.64 (d, J = 7.83 Hz, 2 H), 2.58-2.50 (m, 2 H), 1.84 (d, J = 8.31 Hz, 1 H), 1.75 (d, J = 6.85 Hz, 6 H), 1.47-1.35 (m, 1 H), 1.30-1.23 (m, 1 H), 1.09-0.98 (m, 1 H): HPLC purity: 96.95%; LCMS calculated for C.sub.27H.sub.36FN.sub.3O.sub.5S.sub.2: 565.21 Observed: 566.1 [M + H].sup.+. A-869 [01829]embedded image Yield: 0.042 g, 5.97%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 8.17 (s, 1 H), 7.89 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 8 Hz, 2 H), 7.42 (d, J = 7.34 Hz, 1 H), 7.36-7.26 (m, 1 H), 7.21-7.15 (m, 1 H), 5.36 (d, J = 6.85 Hz, 1 H), 4.11 (d, J = 10.27 Hz, 2 H), 3.63-3.55 (m, 3 H), 3.45- 3.40 (m, 4 H), 2.87-2.68 (m, 3 H), 2.62 (s, 6 H), 1.75-1.65 (m, 6 H), 1.58 (d, J = 11.25 Hz, 1 H), 1.37-1.21 (m, 2 H), 1.10-1.01 (m, 1 H); HPLC purity: 100.00%; LCMS calculated for C.sub.27H.sub.36FN.sub.3O.sub.5S.sub.2: 565.21 Observed: 566.1 [M + H].sup.+. Method: Mobile Phase: A) CO2 B) MEOH + 0.1% NH3; Gradient: 35-50% B in 5 min, hold 50% B till 9 min, 50-35% B at 10 min, hold 35% B till 12 Min. Column: DIACEL CH1RALPAK- IG(250 4.6 mm, 5u); Wavelength: 241 nm; Flow: 5 mL/min; Ret. Time: 5.66. A-870 [01830]embedded image Yield: 0.019 g, 2.70%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 8.17 (s, 1 H), 7.89 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 8 Hz, 2 H), 7.42 (d, J = 7.34 Hz, 1 H), 7.36-7.26 (m, 1 H), 7.21-7.15 (m, 1 H), 5.35 (d, J = 7.2 Hz, 1 H), 4.11 (d, J = 10.27 Hz, 2 H), 3.63-3.55 (m, 3 H), 3.45- 3.40 (m, 4 H), 2.87-2.68 (m, 3 H), 2.62 (s, 6 H), 1.75-1.65 (m, 6 H), 1.58 (d, J = 11.25 Hz, 1 H), 1.37- 1.20 (m, 2 H), 1.10-1.01 (m, 1 H); HPLC purity: 96.11%; LCMS calculated for C.sub.27H.sub.36FN.sub.3O.sub.5S.sub.2: 565.21 Observed: 566.1 [M + H].sup.+. Method: Mobile Phase: A) CO2 B) MEOH + 0.1% NH3; Gradient: 35-50% B in 5 min, hold 50% B till 9 min, 50-35% B at 10 min, hold 35% B till 12 Min. Column: DIACEL CHIRALPAK-IG (250 × 4.6 mm, 5u); Wavelength: 241 nm; Flow: 5 mL/min; Ret. Time: 6.03. A-859 [01831]embedded image Yield: 0 234 g, 38.3%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 7.89 (d, J = 8.31 Hz, 2 H), 7.78 (br d, J = 4.89 Hz, 2 H), 7.45- 7.38 (m, 1 H), 7.36-7.27 (m, 1 H), 7.22-7.12 (m, 1 H), 5.35 (d, J = 7.34 Hz, 1 H), 3.94-3.84 (m, 2 H), 2.88- 2.67 (m, 3 H), 2.61 (s, 6 H), 2.40-2.30 (m, 2 H), 2.19-1.98 (m, 4 H), 1.66 (d, J = 4.89 Hz, 4 H), 1.59-1.42 (m, 2 H), 1.12 (d, J = 5.38 Hz, 6 H), 1.07-0.93 (m, 1 H), HPLC purity: 99.83%; LCMS calculated for C.sub.28H.sub.40FN.sub.3O.sub.5S.sub.2: 581.24 Observed: 582.2 [M + H].sup.+.

    Example A110: Syntheses of Rel-N-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-810 & A-811)

    [1078] ##STR01832## ##STR01833##

    Step-1. Synthesis of Rel-4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-2,6-dimethylmorpholine (A110.3)

    [1079] To a stirred solution of 1,2-difluoro-3-nitrobenzene (A110.1) (1 g, 6.4 mmol, 1 eq) and Rel-(2S,6R)-2,6-dimethyl-4-(piperidin-4-ylmethyl)morpholine (A110.2) (2 g, 6.4 mmol, 1 eq) in DMF (20 mL) was added potassium carbonate (2.67 g, 19.41 mmol, 3 eq) at room temperature and the reaction mixture was stirred at 90° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with cold water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford Rel-4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-2,6-dimethylmorpholine (A110.3) (1.2 g, 54.5%) as yellow solid LCMS: 352.0 [M+H].sup.+.

    Step-2. Synthesis of Rel-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A110.4)

    [1080] An autoclave was charged with a solution of Rel-4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-2,6-dimethylmorpholine (A110.3) (1.2 g, 3.41 mmol, 1 eq) in MeOH (12 mL) and purged with nitrogen for 5 min. 20% Palladium on carbon (0.24 g, 20% w/w) was then added to the reaction mixture under nitrogen atmosphere. The reaction mixture was purged with hydrogen and stirred at room temperature for 6 h under hydrogen atmosphere at 100 psi. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure to afford Rel-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A110.4) (0.95 g, 95%) as a colorless semi solid. LCMS: 322.15 [M+H].sup.+.

    Step-3. Synthesis of Rel-N-((dimethylamino)(4-(N-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)sulfamoyl)phenyl)(oxo)-λ.SUP.6.-6-sulfaneylidene)-2,2,2-trifluoroacetamide (A110.6)

    [1081] To a stirred solution of Rel-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A110.4) (0.3 g, 0.93 mmol, 1 eq) in acetonitrile (10 mL), pyridine (0.147 g, 1.86 mmol, 2 eq) was added at 0° C. 4-(N,N-dimethyl-N′-(2,2,2-trifluoroacetyl)sulfamidimidoyl)benzenesulfonyl chloride (A110.5) (0.42 g, 1.12 mmol, 1.2 eq) was added and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and purified by combiflash to afford Rel-N-((dimethylamino)(4-(N-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)sulfamoyl)phenyl)(oxo)-λ.sup.6-sulfaneylidene)-2,2,2-trifluoroacetamide (A110.6) (0.19 g, 30.6%) as an off-white solid.

    Step-4. Synthesis of Rel-N-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-810 & A-811)

    [1082] To a stirred solution of Rel-N-((dimethylamino)(4-(N-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)sulfamoyl)phenyl)(oxo)-λ.sup.6-sulfaneylidene)-2,2,2-trifluoroacetamide (A110.6) (0.18 g, 0.27 mmol, 1 eq) in MeOH (5 mL) sodium carbonate (0.06 g, 0.54 mmol, 2 eq) was added and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by trituration with methanol, filtered, dried and purified by chiral HPLC to afford Rel-N-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-810 & A-811).

    [1083] A-810: Yield: 0.025 g, 16.2%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.07 (s, 1H), 7.92 (s, 4H), 7.25-7.18 (m, 2H), 6.98-6.90 (m, 1H), 4.66 (s, 1H), 3.54 (t, J=6.4 Hz, 2H), 2.82 (t, J=10.4 Hz, 2H), 2.71 (d, J=10.8 Hz, 2H), 2.53 (s, 6H), 2.36-2.24 (m, 2H), 2.12 (d, J=6.4 Hz, 2H), 1.58-1.51 (m, 5H), 1.04 (d, J=6.4 Hz, 6H). HPLC purity: 98.84%; LCMS calculated for C.sub.26H.sub.38N.sub.5O.sub.4FS.sub.2: 567.23; Observed: 568.8 [M+H].sup.+. Method for chiral sepn: Column: YMC CHIRAL ART CELLULOSE SC, 250 mm*4.6 mm, 5 u, Mobile Phase: A: n-HEXANE+MTBE (50:50)+0.1% Iso-propyl-amine, B: DCM:MEOH (50:50), Flow rate: 1.00 mL/min, Isocratic: 10% B, Ret. Time: 8.685

    [1084] A-811: Yield: 0.015 g, 9.7%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.07 (s, 1H), 7.91 (s, 4H), 7.24-7.08 (m, 2H), 6.94-6.84 (m, 1H), 4.64 (s, 1H), 3.58-3.48 (m, 2H), 2.86-2.76 (m, 2H), 2.71 (d, J=10.4 Hz, 2H), 2.53 (s, 6H), 2.38-2.28 (m, 2H), 2.12 (d, J=6.4 Hz, 2H), 1.58-1.50 (m, 5H), 1.04 (d, J=6.4 Hz, 6H). HPLC purity: 99.14%; LCMS calculated for C.sub.26H.sub.38N.sub.5O.sub.4FS.sub.2: 567.23; Observed: 568.1 [M+H].sup.+. Method for chiral sepn: Column: YMC CHIRAL ART CELLULOSE SC, 250 mm*4.6 mm, 5 u, Mobile Phase: A: n-HEXANE+MTBE (50:50)+0.100 Iso-propyl-amine, B: DCM:MEOH (50:50), Flow rate: 1.00 mL/min, Isocratic: 10% B, Ret. Time: 10.12.

    [1085] The following examples were prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00039 Compound No. Structure Yields/Analytical data A-841 [01834]embedded image .sup.1H NMR (400 MHz, DMSO.sub.6) δ 8.13 (bs, 1 H), 8.10-8.04 (m, 2 H), 7.99-7.93 (m, 2 H), 7.22-7.12 (m, 2 H), 6.97-6.90 (m, 1 H), 4.45 (bs, 1 H), 3.56-3.49 (m, 3 H), 3.07 (s, 3 H), 2.83-2.77 (m, 2 H), 2.72 (d, J = 6.36 Hz, 2 H), 2.45-2.31 (m, 2 H), 2.11 (d, J = 6.4 Hz, 2H), 1.60-1.50 (m, 5 H), 1.27-1.15 (m, 2 H), 1.03 (d, J = 5.6 Hz, 6 H); HPLC purity: 99.49%; LCMS calculated for C.sub.25H.sub.35FN.sub.4O.sub.4S.sub.2: 538.21 Observed: 539.1 [M + H].sup.+. A-846 [01835]embedded image Yield: 30 mg; 3.5%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.13 (br s, 1 H), 8.09 (d, J = 7.82 Hz, 2 H), 7.97 (d, J = 8.4 Hz, 2 H), 7.24-7.16 (m, 2 H), 6.95 (dd, J = 11.25, 8.80 Hz, 1 H), 4.45 (br s, 1 H), 3.56-3.53 (m, 2 H), 3.09 (s, 3 H), 2.82 (t, J = 10.76 Hz, 2 H), 2.72 (d, J = 10.76 Hz, 2 H), 2.42-2.37 (m, 2 H), 2.13 (d, J = 5.38 Hz, 2 H), 1.61-1.58 (m, 5 H), 1.22-1.99 (m, 2 H), 1.05 (d, J = 5.87 Hz, 6 H); HPLC purity: 99.27%; Chiral HPLC purity: 99.76%; LCMS calculated for C.sub.25H.sub.35FN.sub.4O.sub.4S.sub.2: 538.70; Observed: 539.1 [M + H].sup.+. Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm * 4.6 mm, 5u; Mobile Phase: A: n-HEXANE + 0.1% Iso-propyl-amine; B: DCM: MeOH(50:50); Flow rate: 1.00 mL/min; Isocratic: 25% B; Ret. Time: 12.437. A-847 [01836]embedded image Yield: 28 mg; 3.3%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.12 (br s, 1 H), 8.09 (d, J = 8.31 Hz, 2 H), 7.98 (d, J = 8.31 Hz, 2 H), 7.23-7.16 (m, 2 H), 6.97-6.92 (m, 1 H), 4.45 (br s, 1 H), 3.56-3.53 (m, 2 H), 3.09 (s, 3 H), 2.83 (t, J = 10.51 Hz, 2 H), 2.71 (d, J = 10.27 Hz, 2 H), 2.49- 2.37 (m, 2 H), 2.13 (d, J = 6.36 Hz, 2 H), 1.61-1.53 (m, 5 H), 1.21 (d, J = 11.25 Hz, 2 H), 1.05 (d, J = 6.36 Hz, 6 H); HPLC purity: 99.60%; Chiral HPLC purity: 99.04%; LCMS cal- culated for C.sub.25H.sub.35FN.sub.4O.sub.4S.sub.2: 538.70; Observed: 539.1 [M + H].sup.+. Column: YMC CHIRAL ART CELLULOSE- SC, 250 mm * 4.6 mm, 5u; Mobile Phase: A: n-HEXANE + 0.1% Iso- propyl-amine; B: DCM:MeOH (50:50); Flow rate. 1.00 mL/min; Isocratic: 25% B, Ret. Time: 13.884. A-867 [01837]embedded image Yield: 0.040 g, 22%); Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.25 (brs, 1H), 8.14 (s, 1H), 7.93 (bs, 4 H), 7.26 (d, J = 7.82 Hz, 1 H), 7.22-7.16 (m, 1 H), 7.01-6.92 (m, 1 H), 4.67 (s, 1 H), 3.60-3.51 (m, 2 H), 3.20 (s, 3 H), 2.81-2.70 (m, 2 H), 2.54 (s, 4 H), 2.46-2.40 (m, 2 H), 2.38-2.22 (m, 2 H), 2.16 (d, J = 4.4 Hz, 2 H), 1.66-1.54 (m, 2 H), 1.42-1.30 (m, 1 H), 1.29-1.17 (m, 2 H), 0.94 (s, 6 H). 2 exchangeable proton not seen; HPLC purity: 99.88%; LCMS calculated for C.sub.26H.sub.38FN.sub.5O.sub.4S.sub.2: 567.23 Observed: 568.1 [M + H].sup.+. A-858 [01838]embedded image Yield: 0.2 g, 48%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.11 (br s, 1 H), 7.92 (s, 4 H), 7.29-7.11 (m, 2 H), 7.00-6.91 (m, 1 H), 4.66 (s, 1 H), 3.52 (bs, 4 H), 2.75-2.88 (m, 2 H), 2.53 (s, 6 H), 2.27 (t, J = 10.76 Hz, 2 H), 1.49-1.22 (m, 5 H), 0.60-0.52 (m, 2 H), 0.49-0.41 (m, 2 H). 4 H’s are merged into solvent peak; HPLC purity: 99.55%; LCMS calculated for C.sub.26H.sub.36FN.sub.5O.sub.4S.sub.2: 565.22 Observed: 566.1 [M + H].sup.+. A-844 [01839]embedded image Yield: 0.2 g, 49.18%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.05 (bs, 1 H), 7.93 (s, 4 H), 7.29-7.22 (m, 1 H), 7.21-7.14 (m, 1 H), 6.96 (dd, J = 1.25, 8.80 Hz, 1 H), 4.66 (s, 1 H), 4.22-4.14 (m, 2 H), 2.78 (t, J = 10.76 Hz, 2 H), 2.53 (s, 6 H), 2.38-2.22 (m, 3 H), 2.16-2.04 (m, 4 H), 1.84-1.78 (m, 2 H), 1.74-1.65 (m, 3 H), 1.57 (d, J = 12.23 Hz, 2 H), 1.51-1.42 (m, 1 H), 1.30-1.16 (m, 2 H); HPLC purity: 98.6%; LCMS calculated for C.sub.26H.sub.36FN.sub.5O.sub.4S.sub.2: 565.22 Observed: 566.1 [M + H].sup.+. A-852 [01840]embedded image Yield: 0.018 g; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.05 (bs, 1H), 8.93-9.13 (m, 1 H), 7.91 (bs, 4 H), 7.26-7.14 (m, 2 H), 7.00-6.89 (m, 1 H), 4.65 (bs, 1 H), 4.21-4.14 (m, 2 H), 2.84-2.72 (m, 2 H), 2.37-2.22 (m, 2 H), 2.16-2.05 (m, 4 H), 1.79 (d, J = 5.87 Hz, 2 H), 1.74-1.62 (m, 2 H), 1.56 (d, J = 11.74 Hz, 2 H), 1.50-1.42 (m, 1 H), 1.30-1.16 (m, 2 H). 7H’s are merged into solvent peak; HPLC purity: 96.78%; LCMS calculated for C.sub.26H.sub.36FN.sub.5O.sub.4S.sub.2: 565.22 Observed: 566.1 [M + H].sup.+. METHOD: Column : YMC CHIRAL ART CELLULOSE- SC, 250 mm * 4.6 mm, 5u; Mobile Phase: A: n-HEXANE + 0.1% Iso-propyl-amine; B: DCM:MEOH (50:50)Flow rate: 1.00 mL/min; Isocratic: 25% B; Ret. Time: 16.399. A-853 [01841]embedded image Yield: 0.017 g; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO.sub.6) δ 9.04 (bs, 1 H), 7.91 (bs, 4 H), 7.25-7.14 (m, 2 H), 6.99-6.84 (m, 1 H), 4.65 (bs, 1 H), 4.20-4.12 (m, 2 H), 2.77 (t, J = 10.03 Hz, 2 H), 2.39-2.22 (m, 2 H), 2.15-2.05 (m, 4 H), 1.82-1.75 (m, 2 H), 1.74-1.64 (m, 2 H), 1.60-1.40 (m, 3 H), 1.28-1.12 (m, 2 H). 8H’s are merged into solvent peak; HPLC purity: 97.34%; LCMS calculated for C.sub.26H.sub.36FN.sub.5O.sub.4S.sub.2: 565.22 Observed: 566.1 [M + H].sup.+. METHOD: Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm * 4.6 mm , 5u; Mobile Phase: A: n- HEXANE + 0.1% Iso-propyl-amine; B: DCM:MEOH(50:50); Flow rate: 1.00 mL/min; Isocratic: 25% B, Ret. Time: 18.274.

    Example A111: Synthesis of 4-((1-(3-cyano-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-842, A-854 and A-845)

    [1086] ##STR01842## ##STR01843##

    Step-1. Synthesis of 1-(3-bromo-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethan-1-one (A111.3)

    [1087] To a stirred solution of cis-2,6-dimethyl-4-(piperidin-4-ylmethyl)morpholine trifluoroacetate salt (A111.2) (7.0 g, 21.4 mmol, 1 eq), 1-(3-bromo-2-fluorophenyl)ethan-1-one (A111.1) (4.65 g, 21.4 mmol, 1 eq) in DMF (40 mL) was added K.sub.2CO.sub.3 (11.85 g, 84.0 mmol, 4 eq). The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford 1-(3-bromo-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethan-1-one (A111.3) (3.5 g, 39%). LCMS: 411.0 [M+H].sup.+.

    Step-2. Synthesis of 3-acetyl-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)benzonitrile (A111.4)

    [1088] To a stirred solution of 1-(3-bromo-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethan-1-one (A111.3) (3.5 g, 8.5 mmol, 1 eq) in NMP (10 mL) was added CuCN (3.5 g, 8.5 mmol, 1 eq) at room temperature. The reaction mixture was stirred at 140° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude was purified by flash column chromatography to afford 3-acetyl-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)benzonitrile (A111.4) (1.7 g, 55%). LCMS: 355.84 [M+H].sup.+.

    Step-3. Synthesis of 2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-(1-hydroxyethyl)benzonitrile (A111.5)

    [1089] To a stirred solution of 3-acetyl-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)benzonitrile (A111.4) (1.7 g, 4.78 mmol, 1 eq) in THE (30 mL) and MeOH (10 mL) was added NaBH.sub.4 (0.35 g, 9.57 mmol, 2 eq) at 0° C. The resulting reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford 2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-(1-hydroxyethyl)benzonitrile (A111.5) (1.2 g, 70%). This compound was used in the next step without further purification. LCMS: 357.90 [M+H].sup.+.

    Step-4. Synthesis of 1-(3-cyano-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethyl methanesulfonate (A111.6)

    [1090] To a stirred solution of 2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-(1-hydroxyethyl)benzonitrile (A111.5) (1.0 g, 2.8 mmol, 1 eq) in DCM (50 mL) was added Et.sub.3N (1.17 mL, 8.4 mmol, 3 eq) followed by MsCl (0.32 mL, 4.2 mmol, 1.5 eq) and catalytic quantity of DMAP at 0° C. The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford 1-(3-cyano-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethyl methanesulfonate (A111.6) (1.2 g, crude). This compound was used in the next step without further purification.

    Step-5. Synthesis of 4-((1-(3-cyano-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-842, A-854 and A-845)

    [1091] To a stirred solution of 1-(3-cyano-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethyl methanesulfonate (A111.6) (1.2 g, 2.7 mmol, 1 eq), sodium 4-(N,N-dimethylsulfamoyl)benzenesulfinate (A111.7) (0.89 g, 3.3 mmol, 1.2 eq) in DMF (20 mL) was added K.sub.2CO.sub.3 (1.14 g, 8.2 mmol, 3 eq). The reaction mixture was stirred at 70° C. for 12 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography followed by reverse phase preparative HPLC to afford 4-((1-(3-cyano-2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)phenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonamide (A-842) (0.38 g, 23%). A-842 (200 mg) was further purified by chiral separation to afford A-854 and A-845.

    [1092] A-842: Yield: 0.38 g, 23%; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .sup.1H NMR (400 MHz, CHLOROFORM-d) δ 7.94-7.90 (m, 3H), 7.79-7.75 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 5.27 (q, J=7.2 Hz, 1H), 3.56-3.52 (m, 2H), 2.97-2.92 (m, 1H), 2.77-2.69 (m, 3H), 2.64 (s, 6H), 2.17 (d, J=6.8 Hz, 2H), 1.87-1.85 (m, 1H), 1.76-1.64 (m, 4H), 1.61-1.53 (m, 4H), 1.24-1.17 (m, 1H), 1.06 (d, J=6.0 Hz, 6H); HPLC purity: 99.46%; LCMS calculated for C.sub.29H.sub.40N.sub.4O.sub.5S.sub.2: 588.24 Observed: 589.1 [M+H].sup.+.

    [1093] A-854: Yield: 0.03 g; Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.92 (d, J=6.4 Hz, 3H), 7.76 (d, J=6.4 Hz, 3H), 7.46 (t, J=7.38 Hz, 1H), 5.25 (d, J=6.8 Hz, 1H), 3.60-3.48 (m, 2H), 3.25-3.15 (m, 2H), 2.95 (t, J=11.2 Hz, 1H), 2.78-2.69 (m, 3H), 2.64 (s, 6H), 2.16 (d, J=4.8 Hz, 2H), 1.86 (d, J=8.39 Hz, 1H), 1.76-1.51 (m, 8H), 1.26-1.15 (m, 1H), 1.05 (d, J=5.6 Hz, 6H); HPLC purity: 98.99%; LCMS calculated for C.sub.29H.sub.40N.sub.4O.sub.5S.sub.2: 588.24 Observed: 589.1 [M+H].sup.+. METHOD: Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm*4.6 mm, 5 u; Mobile Phase: A: n-HEXANE+0.1% TFA; B:DCM:MEOH (50:50); Flow rate: 1.00 mL/min; Isocratic: 20% B; Ret. Time: 18.472

    [1094] A-845: Yield: 0.021 g; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96-7.88 (m, 3H), 7.81-7.73 (m, 3H), 7.46 (t, J=7.6 Hz, 1H), 7.2 (d, J=7.12 Hz, 1H), 3.58-3.48 (m, 2H), 3.24-3.20 (m, 1H), 2.96-2.90 (m, 1H), 2.80-2.68 (m, 3H), 2.63 (s, 6H), 2.16 (d, J=6.4 Hz, 2H), 1.92-1.79 (m, 1H), 1.77-1.71 (m, 1H), 1.68 (d, J=6.8 Hz, 3H), 1.64-1.51 (m, 3H), 1.27-1.19 (m, 1H), 1.05 (d, J=5.6 Hz, 6H); HPLC purity: 97.28%; LCMS calculated for C.sub.29H.sub.40N.sub.4O.sub.5S.sub.2: 588.24 Observed: 589.1 [M+H].sup.+. METHOD: Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm*4.6 mm, Su; Mobile Phase: A: n-HEXANE+0.1% TFA; B:DCM:MEOH (50:50); Flow rate: 1.00 mL/min; Isocratic: 20% B; Ret. Time: 19.642.

    Example A112: Synthesis of trans-N-(2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(methylsulfonyl)benzenesulfonamide (A-838)

    [1095] ##STR01844##

    Step-1. Synthesis of rel-2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A112.2)

    [1096] To a stirred solution of rel-4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-3,5-dimethylmorpholine (A112.1) (0.28 g, 0.8 mmol, 1 eq) in MeOH (5 mL) was added Pd/C (20%, 0.2 g) under nitrogen atmosphere. The resulting reaction mixture was hydrogenated at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford rel-2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A112.2) (0.26 g, crude). This compound was used in the next step without further purification. LCMS: 322.20 [M+H].sup.+.

    Step-2. Synthesis of rel-N-(2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(methylsulfonyl)benzenesulfonamide (A-838)

    [1097] To a stirred solution of rel-2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A112.2) (0.26 g, 0.81 mmol, 1 eq) and 4-(methylsulfonyl)benzenesulfonyl chloride (A112.3) (0.25 g, 0.98 mmol, 1.2 eq) in acetonitrile (5 mL) was added pyridine (0.13 g, 1.62 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography by using (EtOAc/n-hexane: 20%) as eluent followed by reverse phase preparative HPLC to afford rel-N-(2-(4-((3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(methylsulfonyl)benzenesulfonamide (A-838). Yield: 0.035 g, 8%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.21 (bs, 1H), 8.09 (d, J=7.6 Hz, 2H), 8.01 (d, J=8 Hz, 2H), 7.20-7.13 (m, 1H), 6.99-6.89 (m, 1H), 3.58-3.50 (m, 2H), 3.26 (s, 3H), 3.23-3.20 (m, 1H), 2.84-2.68 (m, 4H), 2.45-2.38 (m, 2H), 2.32 (d, J=9.78 Hz, 1H), 1.61 (d, J=12.4, 1H), 1.54 (d, J=11.6, 1H), 1.42-1.32 (m, 1H), 1.24-1.12 (m, 3H), 0.90 (d, J=5.87 Hz, 6H); HPLC purity: 97.11%; LCMS calculated for C.sub.25H.sub.34FN.sub.3O.sub.5S.sub.2:539.19, Observed: 540.95 [M+H].sup.+.

    [1098] The following example was prepared using standard chemical manipulations and procedures similar to those used for the preparation of the previous example.

    TABLE-US-00040 Compound No. Structure Yields/Analytical data A-866 [01845]embedded image Yield: 0.25 g, 23%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.43 (brs, 1H), 8.28-8.21 (m, 2 H), 8.20-8.13 (m, 2 H), 7.59- 7.19 (t, 3 H), 7.10-7.00 (m, 1 H), 3.61 (d, J = 8.80 Hz, 2 H), 3.34-3.25 (m, 2 H), 2.89-2.70 (m, 4 H), 2.49-2.37 (m, 2 H), 2.34-2.24 (m, 1 H), 2.22-2.12 (m, 1 H), 1.64 (d, J = 11.74 Hz, 1 H), 1.55 (d, J = 10.27 Hz, 1 H), 1.48-1.36 (m, 1 H), 1.34-1.14 (m, 2H), 0.97 (d, J = 5.38 Hz, 6 H); HPLC purity: 98.38%; LCMS calculated for C.sub.25H.sub.32F.sub.3N.sub.3O.sub.5S.sub.2: 575.17, Observed: 576.0 [M + H].sup.+.

    Example A113: Synthesis of N1-(5-fluoro-4-(piperidin-1-yl)pyridin-3-yl)-N.SUP.4.,N.SUP.4.-dimethylbenzene-1,4-disulfonamide (A-856)

    [1099] ##STR01846##

    Step-1. Synthesis of 3-bromo-5-fluoro-4-iodopyridine (A113.2)

    [1100] To a stirred solution of 3-bromo-5-fluoropyridine (A113.1) (4.0 g, 22.72 mmol, 1 eq) in THF (10 mL) was added LDA (1 M in THF, 34 mL, 34 mmol, 1.5 eq) at −78° C. followed by the addition of iodine (6.9 gm in THF, 27.2 mmol, 1.2 eq) at the same temperature after stirring for 15 minutes. The reaction mixture was stirred at −78° C. for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture slowly quenched with saturated NH.sub.4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford 3-bromo-5-fluoro-4-iodopyridine (A113.2) (6.1 g, 89.70%). LCMS: 301.65 [M+H].sup.+.

    Step-2. Synthesis of 3-bromo-5-fluoro-4-(piperidin-1-yl)pyridine (A113.3)

    [1101] To a stirred solution of 3-bromo-5-fluoro-4-iodopyridine (A113.2) (5.1 g, 16.94 mmol, 1 eq), piperidine (1.7 g, 20.33 mmol, 1.2 eq) in DMF (60 mL) was added K.sub.2CO.sub.3 (4.6 g, 33.8 mmol, 2 eq). The reaction mixture was stirred at 150° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford 3-bromo-5-fluoro-4-(piperidin-1-yl)pyridine (A113.3) (2.0 g, 45.76%). LCMS: 259.1 [M+H].sup.+.

    Step-3. Synthesis of N-(5-fluoro-4-(piperidin-1-yl)pyridine-3-yl)-1,1-diphenylmethanimine (A113.5)

    [1102] To a stirred solution of 3-bromo-5-fluoro-4-(piperidin-1-yl)pyridine (A113.3) (1.8 g, 6.97 mmol, 1 eq) in toluene (25 mL) was added diphenylmethanimine (A113.4) (1.5 g, 8.37 mmol, 1.2 eq), cesium carbonate (4.5 g, 13.95 mmol, 2 eq) at room temperature, degassed for 20 minutes by using nitrogen gas followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (0.32 g, 0.35 mmol, 0.05 eq) and BINAP (0.433 g, 0.7 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting reaction mixture was stirred at 100° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford N-(5-fluoro-4-(piperidin-1-yl)pyridine-3-yl)-1,1-diphenylmethanimine (A113.5) (1.4 g, 56%). LCMS: 359.76 [M+H].sup.+.

    Step-4. Synthesis of 5-fluoro-4-(piperidin-1-yl)pyridine-3-amine (A113.6)

    [1103] To a stirred solution of N-(5-fluoro-4-(piperidin-1-yl)pyridine-3-yl)-1,1-diphenylmethanimine (A113.5) (0.7 g, 1.95 mmol, 1 eq) in THE (10 mL) was added aqueous HCl (2 M, 2.9 mL, 5.85 mmol, 3 eq) at 0° C. The reaction mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched by using saturated sodiumbicarbonate solution and extracted with ethylacetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford to afford 5-fluoro-4-(piperidin-1-yl)pyridine-3-amine (A113.6) (0.3 g, 78.94%). LCMS: 195.68 [M+H].sup.+.

    Step-5. Synthesis of N-(5-fluoro-4-(piperidin-1-yl)pyridin-3-yl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-856)

    [1104] To a stirred solution of 5-fluoro-4-(piperidin-1-yl)pyridine-3-amine (A113.6) (0.3 g, 1.54 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A113.7) (0.653 g, 2.31 mmol, 1.5 eq) in acetonitrile (10 mL) was added pyridine (0.243 g, 3.08 mmol, 2 eq) and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure, quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash followed by preparative HPLC to afford N1-(5-fluoro-4-(piperidin-1-yl)pyridin-3-yl)-N.sup.4,N4-dimethylbenzene-1,4-disulfonamide (A-856). Yield: 0.065 g, 9.5%; Appearance: Off white solid; 1H NMR (400 MHz, DMSO-d.sub.6) δ 9.98 (bs, 1H), 8.19 (d, J=2.93 Hz, 1H), 8.00-7.89 (m, 4H), 7.63 (s, 1H), 3.05-2.98 (m, 4H), 2.64 (s, 6H), 1.55-1.48 (m, 6H); HPLC purity: 99.40%; LCMS calculated for C.sub.18H.sub.23FN.sub.4O.sub.4S.sub.2: 442.11 Observed: 442.9 [M+H].sup.+.

    Example A114: Synthesis of 4-(((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (A-884)

    [1105] ##STR01847## ##STR01848##

    Step-1. Synthesis of tert-butyl 4,4-difluoropiperidine-1-carboxylate (A114.2)

    [1106] To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (A114.1) (3.0 g, 15.06 mmol, 1 eq) in DCM (30 mL) was added DAST (5.2 mL, 45.19 mmol, 3 eq) at −40° C. The resulting reaction mixture was stirred at −40° C. for 2 h and then at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution and extracted with DCM. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford tert-butyl 4,4-difluoropiperidine-1-carboxylate (A114.2) (2.5 g, 75%) as an off white solid.

    Step-2. Synthesis of 4,4-difluoropiperidine TFA Salt (A114.3)

    [1107] To a stirred solution of tert-butyl 4,4-difluoropiperidine-1-carboxylate (A114.2) (1.5 g, 6.78 mmol, 1 eq) in DCM (15 mL) was added TFA (7.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford 4,4-difluoropiperidine TFA Salt (A114.3) (3.0 g, crude). This compound was used in the next step without further purification.

    Step-3. Synthesis of 1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethan-1-one (A114.5)

    [1108] To a stirred solution of 4,4-difluoropiperidine TFA Salt (A114.3) (2.0 g, 8.50 mmol, 1 eq) and 1-(2,3-difluorophenyl)ethan-1-one (A114.4) (1.46 g, 9.35 mmol, 1.1 eq) in DMF (20 mL) was added K.sub.2CO.sub.3 (2.35 g, 17.01 mmol, 2 eq). The reaction mixture was stirred at 120° C. for 12 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude was purified by column chromatography to afford 1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethan-1-one (A114.5) (1.0 g, 46%) as a pale brown oil. LCMS: 258.11 [M+H].sup.+.

    Step-4. Synthesis of (S)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethan-1-ol (A114.6)

    [1109] To a stirred solution of 1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethan-1-one (A114.5) (1.0 g, 3.88 mmol, 1 eq) in THE (20 mL) was added (R)-2-Methyl-CBS-oxazaborolidine (1 M in Toluene, 0.8 mL, 0.77 mmol, 0.2 eq) at −40° C. The reaction mixture was allowed to stir for 5 min, and then BH.sub.3.DMS (2 M in THF, 3.9 mL, 7.77 mmol, 2.0 eq) was added dropwise at −40° C. The reaction mixture was stirred at −40° C. for 1 h and then at the same temperature for 30 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0° C. and quenched with dropwise addition of MeOH and water. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude was purified by column chromatography to afford (S)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethan-1-ol (A114.6) (0.85 g, 85%) as an off white solid. LCMS: 260.12 [M+H].sup.+.

    Step-5. Synthesis of (R)—S-(1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl) ethanethioate (A114.8)

    [1110] To a stirred solution of Triphenyl phosphine (1.72 g, 6.56 mmol, 2 eq) in THE (20 mL) was added DIAD (1.2 mL, 6.23 mmol, 1.9 eq) dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min. and then a mixture of (S)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethan-1-ol (A114.6) (850 mg, 3.28 mmol, 1 eq) and ethanethioic S-acid (A114.7) (0.45 mL, 5.90 mmol, 1.8 eq) dissolved in THE (5 mL) were added at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude was purified by column chromatography to afford (R)—S-(1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl) ethanethioate (A114.8) (700 mg, 67%) as an yellow oil. LCMS: 318.11 [M+H].sup.+.

    Step-6. Synthesis of (R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethane-1-thiol (A114.9)

    [1111] To a stirred solution of (R)—S-(1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl) ethanethioate (A114.8) (700 mg, 2.20 mmol, 1 eq) in THE (15 mL) was added a 1 M solution of lithium aluminium hydride (4.4 mL, 4.41 mmol, 2 eq) dropwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with EtOAc and ice-water. The resulting solution was then extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude was purified by column chromatography to afford (R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethane-1-thiol (A114.9) (535 mg, 88%) as a pale yellow oil. LCMS: 276.10 [M+H].sup.+.

    Step-7. Synthesis of N-((4-(((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl)thio)phenyl)(dimethylamino)(oxo)-l6-sulfaneylidene)-2,2,2-trifluoroacetamide (A114.11)

    [1112] A pyrex tube was charged with (R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethane-1-thiol (A114.9) (524.5 mg, 1.90 mmol, 1.05 eq), N-((4-bromophenyl)(dimethylamino)(oxo)-16-sulfaneylidene)-2,2,2-trifluoroacetamide (A114.10) (650 mg, 1.81 mmol, 1 eq), and DIPEA (0.63 mL, 3.63 mmol, 2 eq) in 1,4-dioxane (20 mL). The tube was sealed with a septum and the reaction mixture was purged with argon for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (49.9 mg, 0.05 mmol, 0.03 eq) and Xantphos (63 mg, 0.10 mmol, 0.06 eq) were added to the reaction mixture under an argon atmosphere. The tube was then fitted with a screw cap and the reaction mixture was heated at 80° C. for 5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with water. The resulting solution was extracted in ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel to afford N-((4-(((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl)thio)phenyl)(dimethylamino)(oxo)-16-sulfaneylidene)-2,2,2-trifluoroacetamide (A114.11) (900 mg, 90%) as a pale brown semi-solid. LCMS: 604.25 [M+H].sup.+.

    Step-8. Synthesis of 4-(((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (A-884)

    [1113] To a stirred solution of N-((4-(((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl)thio)phenyl)(dimethylamino)(oxo)-16-sulfaneylidene)-2,2,2-trifluoroacetamide (A114.11) (400 mg, 0.72 mmol, 1 eq) in MeOH:H.sub.2O (6.4 mL: 1.6 mL) was added oxone (667 mg, 2.16 mmol, 3 eq) at 0° C. The reaction mixture was warmed to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice-water. The resulting precipitate was filtered and washed with aqueous saturated NaHCO.sub.3 solution and water. The obtained solid was dried under vacuum and purified by reverse phase preparative HPLC followed by Chiral HPLC to afford 4-(((R)-1-(2-(4,4-difluoropiperidin-1-yl)-3-fluorophenyl)ethyl)sulfonyl)-N,N-dimethylbenzenesulfonimidamide (A-884). Yield: 13.4 mg, 4%; Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94 (d, J=8.31 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.40-7.34 (m, 2H), 7.24-7.19 (m, 1H), 5.45-5.43 (m, 1H), 4.63 (br s, 1H), 3.03-3.00 (m, 2H), 2.90-2.80 (m, 1H), 2.56 (s, 6H), 2.35-2.09 (m, 1H), 2.10-1.82 (m, 4H), 1.63 (br d, J=7.34 Hz, 3H); HPLC purity: 99.62%; Chiral HPLC purity: 98.27%; LCMS calculated for C.sub.2H.sub.6F.sub.3N.sub.3O.sub.3S.sub.2: 489.57; Observed: 490.25 [M+H].sup.+. Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm*4.6 mm, 5 u; Mobile Phase: A: n-HEXANE+MTBE (50:50)+0.1% Iso-propyl-amine; B:DCM:MEOH (50:50); Flow rate: 1.00 mL/min; Isocratic: 10% B; Ret. Time: 11.590.

    Example A115: Synthetic Scheme for Synthesis of rel-N′-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-843)

    [1114] ##STR01849## ##STR01850##

    Step-1. Synthesis of Ethyl 1-(2-fluoro-6-nitrophenyl)piperidine-4-carboxylate (A115.3)

    [1115] To a stirred solution of ethyl piperidine-4-carboxylate (A115.1) (11.8 g, 75.06 mmol, 1.2 eq) and 1,2-difluoro-3-nitrobenzene (A115.2) (10.0 g, 62.9 mmol, 1 eq) in DMF (50 mL) was added K.sub.2CO.sub.3 (17.3 g, 125.8 mmol, 2 eq). The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude was purified by column chromatography to afford ethyl 1-(2-fluoro-6-nitrophenyl)piperidine-4-carboxylate (A115.3) (12 g, 66.6%). LCMS: 297.18 [M+H].sup.+.

    Step-2. Synthesis of ethyl 1-(2-amino-6-fluorophenyl)piperidine-4-carboxylate (A115.4)

    [1116] An autoclave was charged with a solution of ethyl 1-(2-fluoro-6-nitrophenyl)piperidine-4-carboxylate (A115.3) (12.0 g, 40.54 mmol, 1 eq) in methanol (100 mL) and the reaction mixture was purged with nitrogen for 5 min. 20% Palladium on carbon (1.0 g, 20% w/w) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was purged with hydrogen and stirred at room temperature for 12 h under hydrogen atmosphere (100 psi). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the Celite pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to afford ethyl 1-(2-amino-6-fluorophenyl)piperidine-4-carboxylate (A115.4) (10.0 g, crude, 93.4%). This compound was used in the next step without further purification. LCMS: 266.79 [M+H].sup.+.

    Step-3. Synthesis of Ethyl 1-(2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-6-fluorophenyl)piperidine-4-carboxylate (A15.6)

    [1117] To a stirred solution of ethyl 1-(2-amino-6-fluorophenyl)piperidine-4-carboxylate (A115.4) (1.0 g, 3.76 mmol, 1 eq) and 4-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride (A115.5) (1.28 g, 4.14 mmol, 1.1 eq) in acetonitrile (25 mL) was added pyridine (0.6 mL, 7.52 mmol, 2 eq) and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash chromatography on silica gel to afford ethyl 1-(2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-6-fluorophenyl)piperidine-4-carboxylate (A115.6) (1.2 g, 62.5%). LCMS: 514.1 [M+H].sup.+.

    Step-4. Synthesis of N′-(3-fluoro-2-(4-formylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A115.7)

    [1118] To a stirred solution of ethyl 1-(2-((4-(N,N-dimethylsulfamoyl)phenyl)sulfonamido)-6-fluorophenyl)piperidine-4-carboxylate (A115.6) (1.0 g, 1.95 mmol, 1 eq) in DCM (50 mL) was added DIBAL-H (1 M, 10 mL, 5.85 mmol, 3 eq) at −78° C. and the reaction mixture was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with 1N HCl and extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash chromatography on silica gel to afford N1-(3-fluoro-2-(4-formylpiperidin-1-yl)phenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A115.7) (0.8 g, 87.9%).

    Step-5. Synthesis of rel-N′-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-843)

    [1119] To a stirred solution of N1-(3-fluoro-2-(4-formylpiperidin-1-yl)phenyl)-N4,N.sup.4-dimethylbenzene-1,4-disulfonamide (A115.7) (0.5 g, 1.04 mmol, 1 eq) in MeOH (20 mL) was added 2,6-dimethylmorpholine (A115.8) (0.14 g, 1.25 mmol, 1.2 eq) at room temperature, stirred for 30 minutes followed by addition of NaCNBH.sub.3 (0.134 g, 2.1 mmol, 2 eq) at 0° C. and stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to obtain the crude product, which was purified by combiflash chromatography followed by reverse phase preparative HPLC to afford rel-N1-(2-(4-((2,6-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-N4,N4-dimethylbenzene-1,4-disulfonamide (A-843) (0.075 g, 12.5%) and A-755 (0.125 g, 20.8%). A-843: Yield: 0.075 g, 12.5%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6).sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.17 (s, 1H), 7.98-7.90 (m, 4H), 7.26-7.15 (m, 2H), 7.02-6.94 (m, 1H), 3.90-3.85 (m, 2H), 2.79 (br t, J=10.27 Hz, 2H), 2.60 (s, 6H), 2.36-2.25 (m, 3H), 2.15-2.02 (m, 4H), 1.59-1.48 (m, 3H), 1.27-1.15 (m, 2H), 1.12 (d, J=6.36 Hz, 6H); HPLC purity: 99.57%; LCMS calculated for C.sub.26H.sub.37FN.sub.4O.sub.5S.sub.2: 568.22 Observed: 569.20 [M+H].sup.+.

    Example A116: Synthesis of N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide, Isomer-I (A-871) and Isomer-II (A-872)

    [1120] ##STR01851## ##STR01852##

    Step-1. Synthesis of Synthesis of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (A116.2)

    [1121] To a stirred solution of compound A116.1 (6.0 g, 26.2 mmol, 1 eq) in DCM (50 mL) was added N,O-dimethoxyhydroxyamine (3.3 g, 34.0 mmol, 1.3 eq) and EDC.HCl (11.91 g, 62 mmol, 2.4 eq) at 0° C. followed by the addition of NMM (3.93 g, 39.0 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford title compound A116.2 (6.72 g, 94.38%). LCMS: No ionization.

    Step-2. Synthesis of tert-butyl 4-acetylpiperidine-1-carboxylate (A116.3)

    [1122] To a stirred solution of compound A116.2 (6.6 g, 24.26 mmol, 1 eq) in THF (40 mL) was added methyl magnesium bromide (3 M, 48 mL) −5° C. in 30 minutes. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was slowly quenched with saturated NH.sub.4Cl solution (50 mL) at 0° C. and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness to afford crude of the titled compound A116.3 (4.68 g, 85.09%). LCMS: No ionization.

    Step-3. Synthesis of tert-butyl 4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidine-1-carboxylate (A116.4)

    [1123] To a stirred solution of compound A116.3 (3.5 g, 15.41 mmol, 1 eq) in THE (100 mL) was added compound A116.3A (2.1 g, 18.5 mmol, 1.2 eq) and titanium isopropoxide (13.1 g, 46.23 mmol, 3 eq) at 0° C. and stirred at room temperature for 1 h. To the resultant reaction mixture was added NaCNBH.sub.3 (2.4 g, 38.52 mmol, 2.5 eq) portionwise at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure, quenched with cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford the titled compound A116.4 (2.5 g, 50%). LCMS: 327.1 [M+H].sup.+.

    Step-3A. Synthesis of (2S,6R)-2,6-dimethyl-4-(1-(piperidin-4-yl)ethyl)morpholine Hydrochloride (A116.5)

    [1124] To a stirred solution of compound A116.4 (2.5 g, 7.67 mmol, 1 eq) in dioxane (15 mL) was added 4 M HCl in dioxane (20 mL). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to dryness to afford the titled compound A116.5 (2.0 g, 76.9%, crude). This compound was used in the next step without further purification. LCMS: No ionization.

    Step-4. Synthesis of (2S,6R)-4-(1-(1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)ethyl)-2,6-dimethylmorpholine (A116.7A & A116.7B)

    [1125] To a stirred solution of compound A116.5 (2.0 g, 5.88 mmol, 1 eq), compound A116.6 (1.02 g, 6.47 mmol, 1.1 eq) in DMF (20 mL) was added K.sub.2CO.sub.3 (1.62 g, 11.77 mmol, 2 eq). The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford title compound A116.7 (racemic compound) (2.0 g, 95.2%). LCMS: 366.1 [M+H].sup.+. The compound A116.7 (racemic compound) (2.0 g) was given for chiral separation to afford titled compounds A116.7A Pk-I (RT=? min, 1.0 g), LCMS: 366.2 [M+H].sup.+; A116.7B Pk-II (RT=? min, 1.0 g), LCMS: 366.2 [M+H].sup.+.

    Step-5A. Synthesis of 2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3-fluoroaniline (A116.8A)

    [1126] To a stirred solution of compound A116.7A (1.0 g, 2.74 mmol, 1 eq) in MeOH (15 mL) was added Pd/C (20%, 0.1 g) under nitrogen atmosphere. The resulting reaction mixture was hydrogenated (50 psi) at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford the crude of the titled compound A116.8A (0.9 g, crude). This compound was used in the next step without further purification. LCMS: 336.2 [M+H].sup.+.

    Step-5B. Synthesis of 2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3-fluoroaniline (A116.8B)

    [1127] To a stirred solution of compound A116.7B (1.0 g, 2.74 mmol, 1 eq) in MeOH (15 mL) was added Pd/C (20%, 0.1 g) under nitrogen atmosphere. The resulting reaction mixture was hydrogenated (50 psi) at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford the crude of the titled compound A116.8B (0.9 g, crude). This compound was used in the next step without further purification. LCMS: 336.2 [M+H].sup.+.

    Step-6A. Synthesis of N-((dimethylamino)(4-(N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3-fluorophenyl)sulfamoyl)phenyl)(oxo)-λ6-sulfaneylidene)-2,2,2-trifluoroacetamide (A116.9A)

    [1128] To a stirred solution of compound A116.8A (0.5 g, 1.49 mmol, 1 eq) and compound A116.Int-10 (0.676 g, 1.79 mmol, 1.2 eq) in acetonitrile (10 mL) was added pyridine (0.235 mg, 2.98 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford the titled compound A116.9A (0.35 g, 35%). LCMS: 678.1 [M+H].sup.+.

    Step-6B. Synthesis of N-((dimethylamino)(4-(N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3-fluorophenyl)sulfamoyl)phenyl)(oxo)-26-sulfaneylidene)-2,2,2-trifluoroacetamide (A116.9B)

    [1129] To a stirred solution of compound A116.8B (0.4 g, 1.1 mmol, 1 eq) and compound A116.Int-10 (0.496 g, 1.3 mmol, 1.1 eq) in acetonitrile (5 mL) was added pyridine (0.173 g, 2.2 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford the titled compound A116.9B (0.4 g, 49.5%). LCMS: 678.05 [M+H].sup.+.

    Step-7A. Synthesis of N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-871)

    [1130] To a stirred solution of the mixture of the compound A116.9A (0.35 g, 0.52 mmol, 1 eq) in MeOH (10 mL) was added Na.sub.2CO.sub.3 (0.11 g, 1.032 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash to afford the titled compound, racemic mixture, A-871 (170 mg, 56.6%), out of which 150 mg was given for chiral separation to afford A-871A (0.053 g) and A-871B (0.051 g). A-871: Yield: 170 mg, 56.6%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (bs, 1H), 7.93 (bs, 4H), 7.28-7.14 (m, 2H), 6.98-6.91 (m, 1H), 4.67 (bs, 1H), 3.59-3.50 (m, 1H), 3.49-3.40 (m, 1H), 2.85-2.73 (m, 2H), 2.54 (s, 6H), 2.40-2.30 (m, 1H), 2.39-2.29 (m, 1H), 2.28-2.17 (m, 1H), 1.89-1.81 (m, 1H), 1.73 (t, J=10.2 Hz, 1H), 2.58-2.50 (m, 1H), 1.39-1.17 (m, 4H), 1.04 (s, 6H), 0.87 (d, J=5.87 Hz, 3H); HPLC purity: 95.52%; LCMS calculated for C.sub.27H.sub.40FN.sub.5O.sub.4S.sub.2: 581.25, Observed: 582.2 [M+H].sup.+.

    Step-7B. Synthesis of N-(2-(4-(1-((2S,6R)-2,6-dimethylmorpholino)ethyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-872)

    [1131] To a stirred solution of the mixture of the compound A116.9B (0.4 g, 0.59 mmol, 1 eq) in MeOH (10 mL) was added Na.sub.2CO.sub.3 (0.125 g, 1.18 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash to afford the titled compound A-872 (200 mg, 58.3%), out of which 170 mg which was given for chiral separation to afford the compounds A-872A (0.048 g) and A-872B (0.036 g). A-872: Yield: 200 mg, 58.3%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (bs, 1H), 7.93 (bs, 4H), 7.28-7.14 (m, 2H), 7.00-6.9-(m, 1H), 4.67 (s, 1H), 3.59-3.51 (m, 1H), 3.50-3.41 (m, 1H), 2.85-2.73 (m, 2H), 2.54 (s, 6H), 2.40-2.30 (m, 2H), 2.39-2.29 (m, 1H), 2.18-2.06 (m, 1H), 1.89-1.81 (m, 1H), 1.73 (t, J=10.2 Hz, 1H), 2.58-2.50 (m, 1H), 1.39-1.17 (m, 3H), 1.04 (t, J=5.62 Hz, 6H), 0.87 (d, J=6.36 Hz, 3H); HPLC purity: 96.63%; LCMS calculated for C.sub.27H.sub.40FN.sub.5O.sub.4S.sub.2: 581.25, Observed: 582.1 [M+H].sup.+.

    Example A117: Synthesis of N-(2-(4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-840, A-833, A-834, A-835, and A-836)

    [1132] ##STR01853## ##STR01854##

    Step-1. Synthesis of trans-tert-butyl 4-((3,5-dimethylmorpholino)methyl)piperidine-1-carboxylate (A117.3)

    [1133] To a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (A117.1) (5.0 g, 23.4 mmol, 1 eq) in MeOH (100 mL) was added 3,5-dimethylmorpholine (A117.2) (4.0 g, 35.0 mmol, 1.5 eq) at room temperature and stirred at room temperature for 1 h. To the resultant reaction mixture was added NaCNBH.sub.3 (3.69 g, 58.6 mmol, 2.5 eq) portionwise at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure, quenched with cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford trans-tert-butyl 4-((3,5-dimethylmorpholino)methyl)piperidine-1-carboxylate (A117.3) (0.80 g, 9%) as a colourless oil. LCMS: NA.

    Step-2. Synthesis of trans-3,5-dimethyl-4-(piperidin-4-ylmethyl)morpholine.TFA salt (A117.4)

    [1134] To a stirred solution of rel-tert-butyl 4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidine-1-carboxylate (A117.3) (0.8 g, 2.56 mmol, 1 eq) in DCM (10 mL) was added TFA (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to dryness to afford trans-(3,5-dimethyl-4-(piperidin-4-ylmethyl)morpholine TFA salt (A117.4) (0.8 g, crude). This compound was used in the next step without further purification.

    Step-3A & 3B: Procedure for the Synthesis of trans-4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-3,5-dimethylmorpholine (A117.6)

    [1135] To a stirred solution of trans-3,5-dimethyl-4-(piperidin-4-ylmethyl)morpholine TFA salt (A117.4) (0.8 g, 2.4 mmol, 1 eq), 1,2-difluoro-3-nitrobenzene (A117.5) (0.43 g, 2.6 mmol, 1.1 eq) in DMF (20 mL) was added K.sub.2CO.sub.3 (1.01 g, 7.36 mmol, 3 eq). The reaction mixture was stirred at 80° C. for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography to afford trans-4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-3,5-dimethylmorpholine (A117.6) (0.65 g, 75%). LCMS: 352.0 [M+H].sup.+. Trans-4-((1-(2-fluoro-6-nitrophenyl)piperidin-4-yl)methyl)-3,5-dimethylmorpholine (A117.6) (0.65 g) was further purified by chiral Prep. HPLC to afford individual enantiomers of A117.6A Pk-I (0.25 g) and A117.6B Pk-II (0.28 g).

    Step-4A. Synthesis of 2-(4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A117.7A Pk-I)

    [1136] To a stirred solution of compound A117.6A Pk-I (0.25 g, 0.7 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (20%, 0.1 g) under nitrogen atmosphere. The resulting reaction mixture was hydrogenated (50 psi) at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford the crude of the titled compound A117.7A Pk-I (0.22 g, crude). This compound was used in the next step without further purification. LCMS: 321.72 [M+H].sup.+.

    Step-4B. Synthesis of 2-(4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluoroaniline (A117.7B Pk-II)

    [1137] To a stirred solution of compound A117.6B Pk-II (0.29 g, 0.8 mmol, 1 eq) in MeOH (20 mL) was added Pd/C (20%, 0.12 g) under nitrogen atmosphere. The resulting reaction mixture was hydrogenated (50 psi) at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford the crude of the titled compound A117.7B Pk-II (0.25 g, crude). This compound was used in the next step without further purification. LCMS: 322.25 [M+H].sup.+.

    Step-5A. Synthesis of N-((dimethylamino)(4-(N-(2-(4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)sulfamoyl)phenyl)(oxo)-26-sulfaneylidene)-2,2,2-trifluoroacetamide, (A117.9A Pk-I)

    [1138] To a stirred solution of compound A117.7A Pk-I (0.5 g, 1.56 mmol, 1 eq) and compound A117.8 (0.71 g, 1.87 mmol, 1.2 eq) in acetonitrile (10 mL) was added pyridine (0.36 mL, 4.67 mmol, 3 eq) at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography by using (EtOAc/n-Hexane: 20-30%) as eluent to afford the titled compound A117.9A Pk-I (0.35 g, 35%) as a yellow solid. LCMS: 664.0 [M+H].sup.+.

    Step-5B. Synthesis of N-((dimethylamino)(4-(N-(2-(4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)sulfamoyl)phenyl)(oxo)-26-sulfaneylidene)-2,2,2-trifluoroacetamide, (A117.9B Pk-II)

    [1139] To a stirred solution of compound A117.7B Pk-II (0.5 g, 1.56 mmol, 1 eq) and compound A117.8 (0.71 g, 1.87 mmol, 1.2 eq) in acetonitrile (10 mL) was added pyridine (0.36 mL, 4.67 mmol, 3 eq) at 0° C. and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography by using (EtOAc/n-Hexane: 20-30%) as eluent to afford the titled compound A117.9B Pk-II (0.27 g, 27%). LCMS: 664.0 [M+H].sup.+.

    Step-6A. Synthesis of N-(2-(4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-840, A-833, and A-834)

    [1140] To a stirred solution of the mixture of the compound A117.9A Pk-I (0.35 g, 0.53 mmol, 1 eq) in MeOH (10 mL) was added Na.sub.2CO.sub.3 (0.112 g, 1.054 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash to afford the titled compound A-840 (35 mg, 23%), which was further purified by chiral prep.HPLC to afford titled compounds A-833 (0.018 g) and A-834 (0.015 g).

    [1141] A-833: Yield: 0.018 g; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (s, 1H), 7.96-7.89 (m, 4H), 7.26-7.23 (m, 1H), 7.17 (d, J=5.87 Hz, 1H), 6.98-6.90 (m, 1H), 4.67 (s, 1H), 3.54 (dd, J=10.51, 2.20 Hz, 1H), 3.26-3.20 (m, 2H), 2.85-2.65 (m, 3H), 2.54 (s, 6H), 2.44-2.41 (m, 1H), 2.38-2.28 (m, 2H), 2.14 (dd, J=12.47, 5.14 Hz, 1H), 1.66-1.54 (m, 2H), 1.45-1.32 (m, 1H), 1.30-1.14 (m, 2H), 0.91 (d, J=6.36 Hz, 6H); HPLC purity: 97.36%; LCMS calculated for C.sub.26H.sub.38FN.sub.5O.sub.4S.sub.2: 567.23, Observed: 568.1 [M+H].sup.+.

    [1142] METHOD, Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm*4.6 mm, 5μ, Mobile Phase: A: n-HEXANE+0.1% Iso-propyl-amine; B:DCM:MEOH (50:50), Flow rate: 1.00 mL/min, Isocratic: 25% B, Ret. Time: 13.141

    [1143] A-834: Yield: 0.015; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (s, 1H), 7.96-7.89 (m, 4H), 7.27-7.22 (m, 1H), 7.21-7.14 (m, 1H), 6.98-6.90 (m, 1H), 4.67 (s, 1H), 3.55 (dd, J=10.76, 1.96 Hz, 1H), 3.25-3.20 (m, 2H), 2.86-2.68 (m, 3H), 2.54 (s, 6H), 2.47-2.25 (m, 3H), 2.14 (dd, J=12.47, 5.14 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.55 (d, J=12.0 Hz, 1H), 1.45-1.32 (m, 1H), 1.32-1.15 (m, 2H), 0.91 (d, J=5.87 Hz, 6H); HPLC purity: 98.44%; LCMS calculated for C.sub.26H.sub.38FN.sub.5O.sub.4S.sub.2: 567.23, Observed: 568.2 [M+H].sup.+.

    [1144] METHOD, Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm*4.6 mm, 5μ, Mobile Phase: A: n-HEXANE+0.1% Iso-propyl-amine; B:DCM:MEOH (50:50), Flow rate: 1.00 mL/min, Isocratic: 25% B, Ret. Time: 14.668

    Step-6B. Synthesis of N-(2-(4-(((3S,5S)-3,5-dimethylmorpholino)methyl)piperidin-1-yl)-3-fluorophenyl)-4-(N,N-dimethylsulfamidimidoyl)benzenesulfonamide (A-835 and A-836)

    [1145] To a stirred solution of the mixture of the compound A117.9B Pk-II (0.25 g, 0.38 mmol, 1 eq) in MeOH (5 mL) was added Na.sub.2CO.sub.3 (0.080 g, 0.75 mmol, 2 eq) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to dryness. The crude product was purified by combiflash to afford the titled compound A117.10 (150 mg, 70%), which was further purified by chiral prep.HPLC to afford titled compounds A-835 (0.013 g) and A-836 (0.009 g).

    [1146] A-836: Yield: 0.013 g; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (s, 1H), 7.98-7.88 (m, 4H), 7.28-7.22 (m, 1H), 7.21-7.15 (m, 1H), 6.98-6.90 (m, 1H), 4.67 (bs, 1H), 3.58-3.51 (m, 1H), 3.25-3.18 (m, 2H), 2.84-2.59 (m, 3H), 2.52 (s, 6H), 2.47-2.25 (m, 3H), 2.17-2.12 (m, 1H), 1.64 (d, J=11.6 Hz, 1H), 1.55 (d, J=11.2 Hz, 1H), 1.32-1.46 (m, 1H), 1.30-1.12 (m, 2H), 0.91 (d, J=5.87 Hz, 6H); HPLC purity: 99.23%; LCMS calculated for C.sub.26H.sub.38FN.sub.5O.sub.4S.sub.2: 567.23, Observed: 568.1 [M+H].sup.+.

    [1147] METHOD, Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm*4.6 mm, 5 u, Mobile Phase: A: n-HEXANE+0.1% Iso-propyl-amine; B:DCM:MEOH (50:50), Flow rate: 1.00 mL/min, Isocratic: 30% B, Ret. Time: 10.356

    [1148] A-836: Yield: 0.009 g; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (s, 1H), 7.98-7.88 (m, 4H), 7.26-7.21 (m, 1H), 7.20-7.14 (m, 1H), 6.98-6.90 (m, 1H), 4.67 (s, 1H), 3.54 (dd, J=10.51, 2.20 Hz, 2H), 3.27-3.19 (m, 1H), 2.82-2.69 (m, 3H) 2.53 (s, 6H), 2.46-2.30 (m, 3H), 2.14 (dd, J=12.72, 5.38 Hz, 1H), 1.68-1.52 (m, 2H), 1.45-1.34 (m, 1H), 1.30-1.12 (m, 2H), 0.91 (d, J=6.36 Hz, 6H); HPLC purity: 99.24%; LCMS calculated for C.sub.26H.sub.38FN.sub.5O.sub.4S.sub.2: 567.23, Observed: 568.2 [M+H].sup.+.

    [1149] METHOD, Column: YMC CHIRAL ART CELLULOSE-SC, 250 mm*4.6 mm, 5 u, Mobile Phase:A: n-HEXANE+0.1% Iso-propyl-amine; B:DCM:MEOH (50:50), Flow rate: 1.00 mL/min, Isocratic: 30% B, Ret. Time: 11.523

    Example A118

    [1150] The following compounds were prepared according to methods described herein using standard chemical transformations known to one of skill in the art.

    TABLE-US-00041 Compound No. Structure Analytical data A-956 [01855]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (br s, 1 H), 7.93 (s, 4 H), 7.24-7.19 (m, 2 H), 6.98-6.95 (m, 1 H), 3.33-3.50 (m, 2 H), 2.82-2.75 (m, 2 H), 2.70-7.62 (m, 5 H), 2.54 (s, 6 H), 2.36-2.29 (m, 2 H), 2.16-7.10 (m, 2 H), 1.61-1.52 (m, 5H), 1.28-1.17 (m, 2 H), 1.03 (s, 6 H) 2H’s are merged in solvent peak; HPLC purity: 99.76%; LCMS calculated for C.sub.28H.sub.42FN.sub.5O.sub.6S.sub.2: 627.26, for free base 581.25; Observed: 582.1 [M + H].sup.+. A-957 [01856]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96-7.94 (m, 2H), 7.63 (d, J = 8.0 Hz, 1 H), 7.40-7.33 (m, 2 H), 7.27-7.22 (m, 1 H), 5.43 (q, J = 7.6 Hz, 1 H), 3.78- 3.57 (m, 5 H), 3.43-3.38 (m, 3 H), 3.12-2.98 (m, 2 H), 2.59-2.56 (m, 1 H), 1.76-1.73 (m, 1 H), 1.61 (d, J = 7.2 Hz, 3 H); HPLC purity: 95.86%; LCMS calculated for C.sub.20H.sub.22FNO.sub.5S.sub.2: 439.09, Observed: 440.1 [M + H].sup.+. A-958 [01857]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (d, J = 2.4 Hz, 1 H), 7.95 (d, J = 2.4 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H), 4.71 (q, J = 7.2 Hz, 1 H), 2.90-2.87 (m, 1H), 2.62 (s, 6 H), 2.61- 2.45 (m, 4H), 2.37-2.32 (m, 2H), 2.24- 2.17 (m, 3 H), 1.96-1.88 (m, 4 H), 1.81 (d, J = 7.2 Hz, 3 H), 1.71-1.50 (m, 3 H), 1.31-1.23 (m, 1 H), 0.95-0.87 (m, 1H); HPLC purity: 99.03%; LCMS calculated for: 604.18 Observed: 605.2 [M + H].sup.+; HPLC purity: 99.03%; LCMS calculated for C.sub.26H.sub.33ClF.sub.2N.sub.4O.sub.4S.sub.2: 604.18, Observed: 605.2 [M + H].sup.+. A-959 [01858]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.78-7.73 (m, 2 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.35-7.28 (m, 1 H), 7.21-7.15 (m, 1 H), 5.33 (q, J = 6.8 Hz, 1 H), 4.84 (s, 1H), 3.53-3.49 (m, 2 H), 2.88-2.60 (m, 4 H), 1.45-1.79 (m, 8 H), 1.43-1.09 (m, 3 H); HPLC purity: 98.19%; LCMS calculated for C.sub.21H.sub.25FN.sub.2O.sub.3S.sub.2: 436.13, Observed: 437.2 [M + H].sup.+. A-960 [01859]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.78-7.73 (m, 2 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.35-7.28 (m, 1 H), 7.21-7.15 (m, 1 H), 5.33 (q, J = 6.8 Hz, 1 H), 4.84 (s, 1H), 3.53- 3.49 (m, 2 H), 2.88-2.60 (m, 4 H), 1.45-1.79 (m, 8 H), 1.43-1.09 (m, 3 H); HPLC purity: 97.97%; LCMS calculated for C.sub.21H.sub.25FN.sub.2O.sub.3S.sub.2: 436.13, Observed: 437.1 [M + H].sup.+. A-961 [01860]embedded image Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 6.8 Hz, 2H), 7.735 (d, J = 6.8 Hz, 2H), 7.40 (d, J = 6.4 Hz, 1H), 7.32-7.26 (m, 1H), 7.2-7.12 (m, 1H), 5.40-5.25 (m, 1H), 4.69 (br s, 1H), 3.30-3.15 (m, 2H), 2.90-2.60 (m, 3H), 2.55 (s, 6H), 1.8-1.6 (m, 5H), 1.52 (d, J = 9.6 Hz, 1H), 1.49-1.30 (m, 1H), 1.30-1.10 (11H); HPLC purity: 97.22%; LCMS calculated for C.sub.26H.sub.18FN.sub.3O.sub.4S.sub.2: 539.23, Observed: 540.1 [M + H].sup.+. A-962 [01861]embedded image Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 6.8 Hz, 2H), 7.735 (d, J = 6.8 Hz, 2H), 7.40 (d, J = 6.4 Hz, 1H), 7.32- 7.26 (m, 1H), 7.2-7.12 (m, 1H), 5.40- 5.25 (m, 1H), 4.69 (brs, 1H), 3.30- 3.15 (m, 2H), 2.90-2.60 (m, 3H), 2.55 (s, 6H), 1.8-1.6 (m, 5H), 1.52 (d, J = 9.6 Hz, 1H), 1.49-1.30 (m, 1H), 1.30- 1.10 (m, 11H); HPLC purity: 98.78%; LCMS calculated for C.sub.26H.sub.38FN.sub.3O.sub.4S.sub.2: 539.23, Observed: 540.1 [M + H].sup.+. A-963 [01862]embedded image Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.69 (m, 4H), 7.42-6.99 (m, 4H), 5.81 (t, J = 56 8 Hz, 1H), 5.32-5.25 (m, 1H), 3.10-2.90 (m, 2H), 2.60-2.50 (m, 1 H), 1 75-1.42 (m, 6H), 1.30 (d, J = 13.2 Hz, 1H), 1.175 (d, J = 12.4 Hz, 1H), 1.0 (s, 3H); HPLC purity: 99.81%; LCMS calculated for C.sub.22H.sub.24F.sub.5NO.sub.2S: 461.14, Observed: 462.0 [M + H].sup.+. A-964 [01863]embedded image Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.69 (m, 4H), 7.42-6.99 (m, 4H), 5.81 (t, J = 56.8 Hz, 1H), 5.32-5.25 (m, 1H), 3.10-2.90 (m, 2H), 2.60-2.50 (m, 1H), 1.75-1.42 (m, 6H), 1.30 (d, J = 13.2 Hz, 1H), 1.175 (d, J = 12.4 Hz, 1H), 1.0 (s, 3H); HPLC purity: 99.70%; LCMS calculated for C.sub.22H.sub.24F.sub.5NO.sub.2S: 461.14, Observed: 462.0 [M + H].sup.+. A-965 [01864]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.43 (br d, J = 8.00 Hz, 2 H), 7.41-7.33 (m, 3 H), 7.18-7.15 (m, 1 H), 7.20-7.10 (m, 1 H), 5.28 (q, J = 8 Hz, 1 H), 3.59-3.48 (m, 2 H), 3.40 (br d, J = 8 Hz, 2 H), 2.98 (br s, 2 H), 2.83 (br t, J = 12 Hz, 2 H), 2.70-2.65 (m, 1 H), 2.36 (s, 3 H), 2.18-2.04 (m, 2 H), 1.90-1.78 (m, 4 H), 1.72-1.64 (m, 3 H), 1.58 (d, J = 8.0 Hz, 3H), 1.40-1.38 (m, 1 H), 1.24-1.12 (m, 1 H) 1.08-0.98 (m, 1 H); HPLC purity: 96.67%; LCMS calculated for C.sub.27H.sub.35FN.sub.2O.sub.3S: 486.24, Observed: 487.3 [M + H].sup.+. A-966 [01865]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96-7.94 (m, 2H), 7.63 (d, J = 8.0 Hz, 1 H), 7.40-7.33 (m, 2 H), 7.27-7.22 (m, 1 H), 5.43 (q, J = 7.2 Hz, 14.4 Hz, 1 H), 3.78-3.57 (m, 5 H), 3.43-3.38 (m, 3 H), 3.12-2.98 (m, 2 H), 2.59-2.56 (m, 1 H), 1.76-1.73 (m, 1 H), 1.61 (d, J = 7.2 Hz, 3 H); HPLC purity: 98.04%; LCMS calculated for C.sub.20H.sub.22FNO.sub.5S.sub.2: 439.09, Observed: 440.0 [M + H].sup.+. A-967 [01866]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96-7.94 (m, 2H), 7.63 (d, J = 8.0 Hz, 1 H), 7.40-7.35 (m, 2 H), 7.27-7.22 (m, 1 H), 5.43 (q, J = 7.2 Hz, 1 H), 3.74- 3.57 (m, 5 H), 3.43-3.31 (m, 3 H), 3.12-2.98 (m, 2 H), 2.59-2.55 (m, 1 H), 1.76-1.70 (m, 1 H), 1.61 (d, J = 7.25 Hz, 3 H); HPLC purity: 98.43%; LCMS calculated for C.sub.20H.sub.22FNO.sub.5S.sub.2: 439.09, Observed: 440.1 [M + H].sup.+. A-971 [01867]embedded image Appearance: White solid; 1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (d, J = 7.2 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.15-7.04 (m, 1H), 6.92 (t, J = 10.4 Hz, 1H), 6.14 (t, J = 53.6 Hz, 1H), 5.50-5.40 (m, 1H), 3.32-3.22 (br t, 1H), 3.16-3.06 (m, 1H), 2.98-2.82 (m, 2H), 1.845 (d, J = 11.6 Hz, 1H), 1.73 (br s, 3 H), 1.68-1.58 (m, 4H), 1.45-1.34 (m, 1H); HPLC purity: 99.45%; LCMS calculated for C.sub.20H.sub.22F.sub.3NO.sub.2S.sub.2: 429.10, Observed: 430.0 [M + H].sup.+. A-972 [01868]embedded image Appearance: White solid; 1H NMR (400 MHz, CDCl.sub.3) δ 7.99 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8 Hz, 2H), 7.22- 7.18 (m, 2H), 7.05-6.99 (m, 1H), 6.20 (t, J = 53.2 Hz, 1H), 4.85 (q, J = 7.2 Hz, 1H), 3.05-2.90 (m, 2H), 2.69 (d, J = 11.2 Hz, 1H), 1.86 (d, J = 11.2 Hz, 1H), 1.76 (d, J = 11.6 Hz, 1H), 1.70- 1.55 (m, 4H), 1.54-1.48 (m, 2H), 1.30- 1.15 (m, 2H); HPLC purity: 99.32%; LCMS calculated for C.sub.20H.sub.22F.sub.3NO.sub.3S.sub.2: 445.10, Observed: 445.9 [M + H].sup.+. A-973 [01869]embedded image Appearance: White solid; 1H NMR (400 MHz, CDCl.sub.3) δ 8.0 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz, 1H), 7.26-7.19 (m, 1H), 7.02-6.97 (m, 1H), 6.20 (t, J = 53.6 Hz, 1H), 5.49 (q, J = 7.4 Hz, 1H), 2.92- 2.84 (m, 2H), 2.58 (d, J = 10.8 Hz, 1H), 1.78-1.70 (m, 4H), 1.68-1 60 (m, 1H), 1.55-1.46 (m, 3H), 1.30-1.15 (m, 2H); HPLC purity: 99.80%; LCMS calculated for C.sub.20H.sub.22F.sub.3NO.sub.4S.sub.2: 461.09, Observed: 461.9 [M + H].sup.+. A-974 [01870]embedded image Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.40 (d, J = 8 Hz, 1H), 7.36-7.30 (m, 1H), 7.23-7.18 (m, 1H), 5.84 (t, J = 56.8 Hz, 1H), 5.35 (q, J = 7.2 Hz, 1H), 4.75 (brs, 1H), 3.10-2.92 (m, 2H), 2.62-2.50 (m, 7H), 1.80-1.5 (m, 6H), 1.31 (d, J = 12.8 Hz, 1H), 1.20 (d, J = 12.8 Hz, 1H), 1.0 (s, 3H); HPLC purity: 98.62%; LCMS calculated for C.sub.23H.sub.30F.sub.3N.sub.3O.sub.3S.sub.2: 517.17, Observed: 518.1 [M + H].sup.+. A-975 [01871]embedded image Appearance: White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H), 7.40 (d, J = 8Hz, 1H), 7.36-7.30 (m, 1H), 7.23-7.18 (m, 1H), 5.84 (t, J = 56 8 Hz, 1H), 5.35 (q, J = 7.2 Hz, 1H), 4.70 (brs, 1H), 3.07-2.95 (m, 2H), 2.62-2.50 (m, 7H), 1.80-1.5 (m, 6H), 1.31 (d, J = 12.8 Hz, 1H), 1.20 (d, J = 12.8 Hz, 1H), 1.0 (s, 3H); HPLC purity: 99.07%; LCMS calculated for C.sub.23H.sub.30F.sub.3N.sub.3O.sub.3S.sub.2: 517.17, Observed: 518.3 [M + H ].sup.+. A-976 [01872]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.33-6.90 (m, 3 H), 5.45-5.35 (m, 1 H), 3.19-3.16 (m, 2 H), 2.75-2.62 (m, 3 H), 1.69-1.61 (m, 5 H), 1.48 (d, J = 12.4 Hz, 1H), 1.82-1.72 (m, 1 H), 1.25-1.09 (m, 10 H), 1.08-0.94 (m, 1 H); HPLC purity: 99.69%; LCMS calculated for C.sub.25H.sub.32F.sub.3NO.sub.3S: 483.21, Observed: 484.2 [M + H].sup.+. A-977 [01873]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.33-6.90 (m, 3 H), 5.45-5.35 (m, 1 H), 3.19-3.16 (m, 2H), 2.75-2.62 (m, 3 H), 1.69-1.61 (m, 5 H), 1.48 (d, J = 12.4 Hz, 1H), 1.82-1.72 (m, 1 H), 1.25-1.09 (m, 10 H), 1.08-0.94 (m, 1 H); HPLC purity: 98.88%; LCMS calculated for C.sub.25H.sub.32F.sub.3NO.sub.3S: 483.21, Observed: 484.1 [M + H].sup.+. A-978 [01874]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (d, J = 2.4 Hz, 1 H), 7.95 (d, J = 2.4 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H), 4.71 (q, J = 7.2 Hz, 1 H), 2.90-2.87 (m, 1H), 2.62 (s, 6 H), 2.61- 2.45 (m, 4 H), 2.37-2.32 (m, 2 H), 2.24-2.17 (m, 3 H), 1.96-1.88 (m, 4 H), 1.81 (d, J = 7.2 Hz, 3 H), 1.71-1.50 (m, 3 H), 1.28-1.22 (m, 1 H), 0.95-0.89 (m, 1 H); HPLC purity: 97.72%; LCMS calculated for: 604.18 Observed: 605.2 [M + H].sup.+; HPLC purity: 97.72%; LCMS calculated for C.sub.26H.sub.35ClF.sub.2N.sub.4O.sub.4S.sub.2: 604.18, Observed: 605.2 [M + H].sup.+. A-979 [01875]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.21 (d, J = 2.4 Hz, 1 H), 7.95 (d, J = 2.4 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.8 Hz, 2 H), 4.71 (q, J = 6.8 Hz, 1 H), 2.90-2.87 (m, 1 H), 2.62 (s, 6 H), 2.61- 2.45 (m, 4 H), 2.37-2.32 (m, 2 H), 2.24-2.17 (m, 3 H), 1.96-1 88 (m, 4 H), 1.81 (d, J = 7.2 Hz, 3 H), 1.71-1.50 (m, 3 H), 1.28-1.22 (m, 1 H), 0.95-0.89 (m, 1H); HPLC purity: 97.73%; LCMS calculated for C.sub.26H.sub.35ClF.sub.2N.sub.4O.sub.4S.sub.2: 604.18, Observed: 605.2 [M + H].sup.+. A-980 [01876]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (d, J = 8 Hz, 2 H), 7.80 (d, J = 8 Hz, 2 H), 7.41- 7.18 (m, 3 H), 5.39-5.32 (m, 1 H), 3.88-3.81 (m, 1 H), 3.69-3.62 (m, 1 H), 3.49-3.32 (m, 2 H), 2.88-2.55 (m, 3 H), 2.30-2.19 (m, 2 H), 1.79-0.86 (m, 10 H); HPLC purity: 99.66%; LCMS calculated for C.sub.22H.sub.27FN.sub.2O.sub.3S.sub.2: 450.14, Observed: 451.2 [M + H].sup.+. A-981 [01877]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (d, J = 8 Hz, 2 H), 7.80 (d, J = 8 Hz, 2 H), 7.41- 7.18 (m, 3 H), 5.40-5.30 (m, 1 H), 3.88-3.80 (m, 1 H), 3.68-3.60 (m, 1 H), 3.49-3.35 (m, 2 H), 2.88-2.55 (m, 3 H), 2.30-2.25 (m, 2 H), 1.78-1.16 (m, 10 H); HPLC purity: 99.78%; LCMS calculated for C.sub.22H.sub.27FN.sub.2O.sub.3S.sub.2: 450.14, Observed: 451.2 [M + H].sup.+. A-982 [01878]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01-7.89 (m, 4 H), 7.50 (dd, J = 7.83 Hz, 0.98 Hz, 1 H), 7.37-7.35 (m, 1 H), 7.24-7.21 (m, 1 H), 4.63 (d, J = 10.88 Hz, 1 H), 2.99- 2.79 (m, 2 H), 2.69-2.61 (m, 7 H), 2.18 (br d, J = 10.39 Hz, 1H), 1.73 (br d, J = 12.23 Hz, 1 H), 1.63-1.39(m, 5 H), 1.30-1.17 (m, 1 H), 0.70-0.61 (m, 1 H), 0.55-0.46 (m, 1 H), 0.22-0.11 (m, 1 H), 0.12-0.02 (m, 1 H); HPLC purity: 100.00%; LCMS calculated for C.sub.23H.sub.29FN.sub.2O.sub.4S.sub.2: 480.16; Observed: 481.2 [M + H].sup.+. A-983 [01879]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03-7.88 (m, 4 H), 7.50 (dd, J = 7.89, 1.04 Hz, 1 H), 7.37-7.34 (m, 1 H), 7.24-7.21 (m, 1 H), 4.63 (d, J = 10.88 Hz, 1 H), 2.97-2.80 (m, 2 H), 2.64 (s, 7 H), 2.19 (br d, J = 10.03 Hz, 1H), 1.73 (br d, J = 12.96 Hz, 1 H), 1.64-1.40 (m, 5 H), 1.28-1.19 (m, 1 H), 0.70-0.60 (m, 1 H), 0.55-0.46 (m, 1 H), 0.18-0.14 (m, 1 H), 0.12-0.03 (m, 1 H); HPLC purity: 97.10%; LCMS calculated for C.sub.23H.sub.29FN.sub.2O.sub.4S.sub.2: 480.16; Observed: 481.2 [M + H].sup.+. A-986 [01880]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (s, 1H), 8.43 (d, J = 3.2 Hz, 1H), 7.93-7.86 (m, 4 H), 5.16-5.08 (m, 1 H), 3.40-2.60(m, 10H), 2.17-2.00 (m, 4 H), 1.78 (d, J = 7.6 Hz, 3 H); HPLC purity: 97.73%; LCMS calculated for C.sub.20H.sub.24F.sub.3N.sub.3O.sub.4S.sub.2: 491.12, Observed: 490.0 [M − H].sup.−. A-987 [01881]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16 (br d, J = 3.55 Hz, 1 H), 7.91 (br d, J = 7.09 Hz, 1 H), 7.77 (br d, J = 7.82 Hz, 2 H), 7.62 (br d, J = 7.83 Hz, 2 H), 7.18-7.08 (m, 1 H), 4.77 (br d, J = 6.85 Hz, 1 H), 2.88 (br d, J = 11.98 Hz, 1 H), 2.61 (s, 6 H), 2.58-2.30 (m, 4 H), 2.25 (br d, J = 6.60 Hz, 2 H), 2.16 (br d, J = 11.86 Hz, 1 H), 2.01-1.87 (m, 5 H), 1.80 (d, J = 6.97 Hz, 3 H), 1.75-1.56 (m, 2 H), 1.54-1.46 (m, 1 H), 1.34-1.14 (m, 2 H), 1.02-0.89 (m, 1 H); HPLC purity: 99.89%, LCMS calculated for C.sub.26H.sub.36F.sub.2N.sub.4O.sub.4S.sub.2: 570.21; Observed: 571.3 [M + H].sup.+. A-988 [01882]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.84 (d, J = 8.4 Hz, 2 H), 7.66 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.09-6.99 (m, 2 H), 5.24 (q, J = 7.2 Hz, 1 H), 4.69 (bs, 1H), 3.30-3.22 (m, 2 H), 2.53 (s, 6 H), 2.01-1.95 (m, 1 H), 1.84-1.76 (m, 1 H), 1.74 (d, J = 7.2 Hz, 3H), 1.79-1.48 (m, 7 H), 1.49-1.36 (m, 1 H); HPLC purity: 98.33%; LCMS calculated for C.sub.23H.sub.30FN.sub.3O.sub.3S.sub.2: 479.17 Observed: 480.1 [M + H].sup.+. A-989 [01883]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.83 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.09-6.84 (m, 2 H), 5.24 (q, J = 7.2 Hz, 1 H), 4.70 (bs, 1H), 3.31-3.22 (m, 2 H), 2.66 (s, 6H), 2.01-1.95 (m, 1 H), 1.84-1.76 (m, 1 H), 1.74 (d, J = 7.2 Hz, 3H), 1.79- 1.48 (m, 7 H) 1.49-1.36 (m, 1 H); HPLC purity: 97.71%; LCMS calcu- lated for C.sub.23H.sub.30FN.sub.3O.sub.3S.sub.2: 479.17 Observed: 480.1 [M + H].sup.+. A-990 [01884]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (d, J = 1.6 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.72 (d, J = 2 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 4.79 (q, J = 14.0 Hz, 1 H), 2.81 (br d J = 12.4 Hz, 1 H), 2.68-2.61 (m, 7 H), 2.45 (br s, 4 H), 2.32-2.23 (m, 6 H), 2.05 (br d J = 12.4 Hz, 1 H), 1.97-1.90 (m, 4 H), 1.77 (d, J = 7.2 Hz, 3 H), 1.69 (br d J = 12.4 Hz, 1 H), 1.58 (br d J = 12.4 Hz, 1 H), 1.49-1.47 (m, 1 H), 1.27-1.23 (m, 1 H), 0.90-1.02 (m, 1 H); HPLC purity: 99.90%; LCMS calculated for C.sub.27H.sub.38F.sub.2N.sub.4O.sub.4S.sub.2: 584.23; Observed: 585.2 [M + H].sup.+. A-991 [01885]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (d, J = 8.8 Hz, 2 H), 7.80 (d, J = 8.8 Hz, 2 H), 7.40 (dd, J = 8.0, 2.4 Hz, 1 H), 7.34- 7.28 (m, 1H), 7.22-7.16 (m, 1 H), 5.36 (q, J = 8.0 Hz, 1 H), 3.86-3.81 (m, 1H), 3.67-3.62 (m, 1H), 3.41 (t, J = 8.0 Hz, 2H), 2.85-2.76 (m, 2H), 2.68-2.63 (m, 1 H), 2.30-2.18 (m, 2 H), 1.82-1.68 (m, 2H), 1.63 (d, J = 8.0 Hz, 3H), 1.57-1.46 (m, 3 H), 1.39-1.30 (m, 1 H), 1.24-1.13 (m, 1 H); HPLC purity: 99.73%; LCMS calculated for C.sub.22H.sub.27FN.sub.2O.sub.3S.sub.2; 450.14 Observed: 451.0 [M + H].sup.+. A-992 [01886]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (d, J = 8.4 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 7.2 Hz, 1 H), 7.34-7.28 (m, 1 H), 7.22-7.16 (m, 1 H), 5.36 (q, J = 8.0 Hz, 1 H), 3.86-3.79 (m, 1 H), 3.67-3.62 (m, 1H), 3.44-3.31 (m, 2H), 2.85-2.76 (m, 2H), 2.68-2.64 (m, 1 H), 2.30-2.18 (m, 2 H), 1.77-1.68 (m, 2H), 1.62 (d, J = 7.2 Hz, 3H), 1.57-1.46 (m, 3 H), 1.39-1.30 (m, 1 H), 1.24-1.16 (m, 1 H), HPLC purity: 99.78%; LCMS calculated for C.sub.22H.sub.27FN.sub.2O.sub.3S.sub.2: 450.14 Observed: 451.1 [M + H].sup.+. A-993 [01887]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.22 (d, J = 2.57 Hz, 1 H), 7.89 (d, J = 2.57 Hz, 1 H), 7.31-7.24 (m, 2 H), 7.11-7.03 (m, 1 H), 4.58 (q, J = 7.21 Hz, 1 H), 2.90- 2.77 (m, 5 H), 2.63-2.54 (m, 1 H), 2.34- 2.27 (m, 5 H), 2.21 (d, J = 7.09 Hz, 3 H), 2.05-1.86 (m, 6 H), 1.73 (d, J = 7.21 Hz, 3 H), 1.67-1.59 (m, 2 H), 1.51-1.48 (m, 1 H), 1.24-1.13 (m, 1 H), 0.89-0.77 (m, 1 H); HPLC purity: 98.19%; LCMS calculated for C.sub.27H.sub.34ClF.sub.2N.sub.3O.sub.2S: 537.20; Observed 538.2 [M + H].sup.+. A-994 [01888]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (d, J = 2.50 Hz, 1 H), 7.90 (d, J = 2.63 Hz, 1 H), 7.29-7.25 (m, 2 H), 7.07 (dd, J = 8.0, 1.2 Hz, 1H), 4.58 (d, J = 7.38 Hz, 1 H), 2.89-2.80 (m, 5 H), 2.62-2.58 (m, 1 H), 2.52-2.46 (m, 4 H), 2.39-2.24 (m, 2 H), 2.23 (d, J = 7.2 Hz, 2H), 2.03- 1.89 (m, 6 H), 1.73 (d, J = 7.25 Hz, 3 H), 1.71-1.56 (m, 3 H), 1.24-1.11 (m, 1 H), 0.88-0.80 (m, 1 H); HPLC purity: 99.76%; LCMS calculated for C.sub.27H.sub.34ClF.sub.2N.sub.3O.sub.2S: 537.20; Observed: 538.2 [M + H].sup.+. A-995 [01889]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (d, J = 1.6 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.72 (d, J = 2 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 4.79 (d, J = 14.0 Hz, 1 H), 2.81 (br d) J = 12.4 Hz, 1 H), 2.68-2.61 (m, 7 H), 2.45 (br s, 4 H), 2.32-2.23 (m, 6 H), 2.05 (br d J = 12.4 Hz, 1 H), 1.97- 1.90 (m, 4 H), 1.77 (d, J = 7.2 Hz, 3 H), 1.69 (br d J = 12.4 Hz, 1 H), 1.58 (br d J = 12.4 Hz, 1 H), 1.49-1.47 (m, 1 H), 1.27-1.23 (m, 1 H), 1.02-0.90 (m, 1 H); HPLC purity: 96.77%; LCMS calculated for C.sub.27H.sub.38F.sub.2N.sub.4O.sub.4S.sub.2: 584.23; Observed: 585.2 [M + H].sup.+. HPLC purity: 99.76%; LCMS calculated for C.sub.27H.sub.34ClF.sub.2N.sub.3O.sub.2S: 537.20; Observed 538.2 [M + H].sup.+. A-996 [01890]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64 (s, 1H), 8.34 (d, J = 3.2 Hz, 1H) 7.85-7.79 (m, 4 H), 5.18-5.08 (m, 1 H), 3.08-2.88 (m, 2 H), 2.81-2.72 (m, 8 H), 2.58-2.51 (m, 5 H), 2.29-2.55 (m, 2 H), 2.42-2.25 (m, 1 H), 2.05-1.96 (m, 4 H), 1.85-1.72 (m, 6 H); HPLC purity: 97.64%; LCMS calculated for C.sub.26H.sub.35F.sub.3N.sub.4O.sub.4S.sub.2: 588.21, Observed: 589.25 [M − H].sup.−. A-997 [01891]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.74 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.32-6.99 (m, 3 H), 5.33-5.28 (m, 1 H), 2.84-2.75 (m, 2H), 2.70-2.68 (m, 1 H), 2.50-2.42 (m, 4 H), 2.24 (d, J = 7.2 Hz, 2H), 2.00-1.86 (m, 4 H), 1.74-1.66 (m, 2 H), 1.63 (d, J = 6.8 Hz, 3H), 1.56-1.42 (m, 2 H), 1.23- 1.15 (m, 1 H), 1.06-0.71 (m, 1 H); HPLC purity: 100%; LCMS calculated for C.sub.26H.sub.31F.sub.5N.sub.2O.sub.2S: 530.20, Observed: 531.1 [M + H].sup.+. A-998 [01892]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.74 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.32-6.99 (m, 3H), 5.33-5.28 (m, 1H), 2.84-2.75 (m, 2 H), 2.70-2.68 (m, 1 H), 2.50-2.42 (m, 4 H), 2.24 (d, J = 7.2 Hz, 2H), 2.00-1.86 (m, 4 H), 1.74-1.66 (m, 2 H), 1.63 (d, J = 6.8 Hz, 3H), 1.56-1.42 (m, 2 H), 1.23- 1.15 (m, 1 H), 1.06-0.71 (m, 1 H); HPLC purity: 98.91%; LCMS calculated for C.sub.26H.sub.31F.sub.5N.sub.2O.sub.2S: 530.20, Observed: 531.1 [M + H].sup.+. A-999 [01893]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 7.70 (s, 1 H), 7.29 (s, 1 H), 7.26 (d, J = 8.0 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 4.70 (q, J = 14.4 hz, 1 H), 2.89-2.79 (m, 5 H), 2.71-2.55 (m, 2 H), 2.69-2.62 (m, 4 H), 2.38-2.12 (m, 6 H), 2.03-1.91 (m, 6 H), 1.70 (d, J = 7.2 Hz, 4 H), 1.61 (br d J = 12.0 Hz, 1 H), 1.49 (br s, 1 H), 1.25-1.18 (m, 1 H), 0.93-0.85 (m, 1 H); HPLC purity: 98.73%; LCMS calculated for C.sub.28H.sub.37F.sub.2N.sub.3O.sub.2S: 517.26; Observed: 518.2 [M + H].sup.+. A-1000 [01894]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.04 (s, 1 H), 7.70 (s, 1 H), 7.29 (s, 1 H), 7.26 (d, J = 8.0 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 4.70 (q, J = 14.4 Hz, 1 H), 2.89-2.79 (m, 5 H), 2.71-2.55 (m, 2 H), 2.52-2.40 (m, 3 H), 2.39-2.13 (m, 7 H), 2.03-1.91 (m, 6 H), 1.70 (d, J = 7.2 Hz, 4 H), 1.61 (br d J = 12.0 Hz, 1 H), 1.49 (br s 1 H), 1.25-1.18 (m, 1 H), 0.93-0.85 (m, 1 H); HPLC purity: 99.36%; LCMS calculated for C.sub.28H.sub.37F.sub.2N.sub.3O.sub.2S: 517.26; Observed: 518.2 [M + H].sup.+.

    Example A119

    [1151] The following compounds were prepared according to methods described herein using standard chemical transformations known to one of skill in the art.

    TABLE-US-00042 Compound No. Structure Analytical data A-828 [01895]embedded image Yield: 0.038 g, 6.13%; Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO- d.sub.6) δ 7.46 (s, 1 H), 7.41-7.37 (m, 1 H), 7.33-7.25 (m, 2 H), 7.19-7.11 (m, 2 H), 5.25 (q, J = 7.17 Hz, 1 H), 3.56-3.49 (m, 2 H), 2.92-2.78 (m, 6 H), 2.72-2.62 (m, 3 H), 2.12 (d, J = 6.85 Hz, 2 H), 2.08-2.98 (m, 2H), 1.79 (d, J = 10.76 Hz, 1 H), 1.69 (d, J = 11.74 Hz, 1 H), 1.62-1.49 (m, 7H), 1.18-1.11 (m, 1 H), 1.04 (d, J = 6.36 Hz, 6 H), 0.98-0.94 (m, 1 H); HPLC purity: 99.23%; LCMS calculated for C.sub.29H.sub.39FN.sub.2O.sub.3S: 514.27 Observed: 515.1 [M + H].sup.+. A-871A [01896]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.09 (brs, 1 H), 8.01-7.80 (m, 4 H), 7.27-7.08 (m, 2 H), 6.97-6.80 (m, 1 H), 4.65 (s, 1 H) 3.60- 3.49 (m, 1 H), 3.47-3.38 (m, 1 H), 2.90- 2.73 (m, 2 H), 2.54 (s, 6 H), 2.42-2.29 (m, 3 H), 2.29-2.15 (m, 1H), 2.14-2.02 (m, 1 H), 1.92-1.79 (m, 1 H), 1.77-1.64 (m, 1 H), 1.60-1.44 (m, 1 H), 1.40-1.13 (m, 4 H), 1.04 (d, J = 5.62 Hz, 6 H), 0.86 (d, J = 5.87 Hz, 3 H); HPLC purity: 100%; LCMS calculated for C.sub.27H.sub.40FN.sub.5O.sub.4S.sub.2: 581.25, Observed: 582.1 [M + H].sup.+. A-871B [01897]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (brs, 1 H), 8.04-7.83 (m, 4 H), 7.29-7.10 (m, 2 H), 7.01-6.88 (m, 1 H), 4.66 (s, 1 H), 3.59- 3.49 (m, 1 H), 3.49-3.39 (m, 1 H), 2.88- 2.72 (m, 2 H), 2.54 (s, 6 H), 2.39-2.28 (m, 3 H), 2.24 (d, J = 7.34 Hz, 1 H), 2.15- 2.01 (m, 1H), 1.86 (d, J = 11.25 Hz, 1H), 1.77-1.64 (m, 1 H), 1.58-1.43 (m, 1 H), 1.40-1.12 (m, 4 H), 1.04 (d, J = 6.11 Hz, 6 H), 0.86 (d, J = 6.36 Hz, 3 H); HPLC purity: 99.32%; LCMS calculated for C.sub.27H.sub.40FN.sub.5O.sub.4S.sub.2: 581.25, Observed: 582.1 [M + H].sup.+. A-872A [01898]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.05 (s, 1H), 8.00-7.86 (m, 4 H), 7.28-7.08 (m, 2 H), 7.00-6.87 (m, 1 H), 4.66 (s, 1 H), 3.60- 3.49 (m, 1 H), 3.49-3.39 (m, 1 H), 2.82- 2.72 (m, 2 H), 2.54 (s, 6 H), 2.40-2.28 (m, 3 H), 2.27-2.16 (m, 1 H), 2.16-2.01 (m, 1 H), 1.92-1.78 (m, 1 H), 1.78-1.65 (m, 1 H), 1.57-1.44 (m, 1 H), 1.42-1.15 (m, 4 H), 1.04 (d, J = 6. 11 Hz, 6 H), 0.86 (d, J = 6.36 Hz, 3 H); HPLC purity: 96.45%; LCMS calculated for C.sub.27H.sub.40FN.sub.5O.sub.4S.sub.2: 581.25, Observed: 582.1 [M + H].sup.+. A-872B [01899]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (s, 1 H), 8.00-7.85 (m, 4 H), 7.30-7.07 (m, 2 H), 7.02-6.83 (m, 1 H), 4.66 (s, 1 H), 3.62- 3.50 (m, 1 H), 3.49-3.38 (m, 1 H), 2.87- 2.72 (m, 2 H), 2.54 (s, 6 H), 2.41-2.29 (m, 3 H), 2.27-2.16 (m, 1 H), 2.10 (t, J = 10.27 Hz, 1 H), 1.85 (d, J = 11.25 Hz, 1 H), 1.73 (t, J = 10.27 Hz, 1 H), 1.53 (d, J = 10.76 Hz, 1 H), 1.39-1.15 (m, 4 H) 1.04 (d, J = 6.11 Hz, 6 H), 0.86 (d, J = 6.36 Hz, 3 H); HPLC purity: 98.50%; LCMS calculated for C.sub.27H.sub.40FN.sub.5O.sub.4S.sub.2: 581.25, Observed: 582.1 [M + H].sup.+. A-885 [01900]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96-7.83 (m, 2H), 7.78 (d, J = 7.82 Hz, 2 H), 7.46-7.35 (m, 1 H), 7.33-7.24 (m, 1 H), 7.21-7.07 (m, 1 H), 5.43-5.26 (m, 1 H), 3.95-3.82 (m, 2 H), 2.94-2.65 (m, 5 H), 2.62 (s, 6 H), 2.40-2.25 (m, 2 H), 2.18-1.98 (m, 5 H), 1.65 (s, 3 H), 1.57-1.39 (m, 1 H), 1.26-1.15 (m, 1 H), 1.13 (d, J = 5.87 Hz, 6 H), 1.05-0.91 (m, 1 H); HPLC purity: 95.50%; LCMS calculated for C.sub.26H.sub.40FN.sub.3O.sub.5S.sub.2: 581.24 Observed: 582.6 [M + H].sup.+. A-890 [01901]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94 (d, J = 8.31 Hz, 2 H), 7.88-7.74 (m, 2 H), 7.45-7.29 (m, 2 H), 7.26-7.12 (m, 1 H), 5.51-5.36 (m, 1 H), 4.75 (s, 1 H), 3.10-2.89 (m, 3 H), 2.87-2.75 (m, 1 H), 2.56 (s, 6 H), 2.35-1.83 (m, 4 H), 1.62, 1.64 (s, 3 H); HPLC purity: 97.56%; LCMS calculated for C.sub.21H.sub.26F.sub.3N.sub.3O.sub.3S.sub.2: 489.14 Observed: 490.20 [M + H].sup.+. A-892 [01902]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.92 (d, J = 6.36 Hz, 2 H), 7.78 (d, J = 6.85 Hz, 2 H), 7.46- 7.35 (m, 1 H), 7.34-7.24 (m, 1 H), 7.18 (d, J = 9.78 Hz, 1 H), 5.43-5.29 (m, 1 H), 4.71 (s, 1 H), 3.63-3.46 (m, 4 H), 2.98- 2.75 (m, 2 H), 2.75-2.64 (m, 1 H), 2.56 (s, 6 H), 2.01-1.83 (m, 1 H), 1.71-1.52 (m, 4H), 1.51-1.33 (m, 2H), 1.30-1.12 (m, 2 H), 0.54-0.70 (m, 2 H), 0.52-0.32 (m, 2 H). 4H's are merged in to solvent peak; HPLC purity: 100%; LCMS calculated for C.sub.26H.sub.39FN.sub.4O.sub.4S.sub.2: 578.24 Observed: 579.1 [M + H].sup.+. A-893 [01903]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 7.93 (d, J = 7.82 Hz, 2 H), 7.84-7.70 (m, 2 H), 7.39 (d, J = 7.34 Hz, 1 H), 7.30 (d, J = 4.89 Hz, 1 H), 7.22-7.08 (m, 1 H), 5.42-5.28 (m, 1 H), 4.68 (s, 1 H), 3.60-3.46 (m, 4 H), 2.93-2.74 (m, 3 H), 2.70 (d, J = 11.74 Hz, 2 H), 2.56 (s, 6 H), 1.95 (d, J = 9.29 Hz, 2 H), 1.62, 1.64 (s, 3 H), 1.58-1.52 (m, 1 H), 1.50-1.33 (m, 2 H), 1.31-1.09 (m, 3 H). 4H's are merged in to solvent peak; HPLC purity: 97.56%; LCMS calculated for C.sub.26H.sub.39FN.sub.4O.sub.4S.sub.2: 578.24 Observed: 579.1 [M + H].sup.+. A-894 [01904]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 8.31 Hz, 2 H), 7.78-7.64 (m, 2 H), 7.40 (d, J = 7.82 Hz, 1 H), 7.33-7.23 (m, 1 H), 7.22-7.09 (m, 1 H), 5.45-5.28 (m, 1 H), 4.71 (brs, 1 H), 2.88-2.70 (m, 2 H), 2.70- 2.61 (m, 1 H), 2.54 (s, 6 H), 1.72 (d, J = 9.78 Hz, 2 H), 1.65, 1.63 (s, 3 H), 1.59- 1.48 (m, 2 H), 1.46-1.30 (m, 2 H), 1.26- 1.08 (m, 1 H); HPLC purity: 99.94%; LCMS calculated for C.sub.21H.sub.28FN.sub.3O.sub.3S.sub.2: 453.16 Observed: 454.1 [M + H].sup.+. A-895 [01905]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 8.31 Hz, 2 H), 7.74 (d, J = 7.82 Hz, 2 H), 7.40 (d, J = 7.34 Hz, 1 H), 7.29 (d, J = 4.89 Hz, 1 H), 7.20-7.09 (m, 1 H), 5.45-5.27 (m, 1 H), 4.66 (s, 1 H), 2.88-2.71 (m, 2 H), 2.70-2.60 (m, 1 H), 2.54 (s, 6 H), 1.78- 1.67 (m, 2 H), 1.63, 1.65 (s, 3 H) 1.59- 1.31 (m, 4 H), 1.25-1.07 (m, 1H); HPLC purity: 96.49%; LCMS calculated for C.sub.21H.sub.28FN.sub.3O.sub.3S.sub.2: 453.16 Observed: 454.1 [M + H].sup.+. A-901 [01906]embedded image Yield: 30 mg; 17% Appearance: white solid; .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.28 (br d, J = 17.39 Hz, 1H), 1.55 (s, 2 H), 1.68 (br d, J = 11.59 Hz, 2 H), 1.80 (br d, J = 10.43 Hz, 1 H), 2.21 (br d, J = 8.69 Hz, 2 H), 2.70 (s, 6 H), 3.31 (s, 1 H), 3.41 (br t, J = 11.59 Hz, 2H), 7.18-7.09 (m, 2 H), 7.67 (br d, J = 7.53 Hz, 1 H), 7.81 (d, J = 8.11 Hz, 2 H), 7.93 (d, J = 8.11 Hz, 2 H), 8.77 (br s, 1 H); HPLC purity: 99.59%; LCMS calculated for C.sub.21H.sub.25N.sub.3O.sub.4S.sub.2: 447.57; Observed: 448.1 [M + H].sup.+. A-902 [01907]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94-7.82 (m, 2 H), 7.73 (d, J = 7.82 Hz, 2 H), 7.41 (d, J = 7.34 Hz, 1 H), 7.34-7.23 (m, 1 H), 7.20-7.08 (m, 1 H), 5.42-5.26 (m, 1 H), 4.72 (s, 1 H), 3.61-3.45 (m, 2 H), 2.90-2.75 (m, 2 H), 2.74-2.64 (m, 3 H), 2.54 (s, 6 H), 2.21-2.04 (m, 2 H), 1.77-1.70 (m, 1 H), 1.64, 1,66 (s, 3 H), 1.58-1.41 (m, 4 H), 1.30-1.10 (m, 2 H) 1.04 (d, J = 5.87 Hz, 6 H), 0.92-0.82 (m, 1 H); HPLC purity: 100%; LCMS calculated for C.sub.26H.sub.41FN.sub.4O.sub.4S.sub.2: 580.26 Observed: 581.1 [M + H].sup.+. A-903 [01908]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00-7.81 (m, 2 H), 7.77-7.61 (m, 2 H), 7.41 (d, J = 6.36 Hz, 1 H), 7.35-7.22 (m, 1 H), 7.21-7.08 (m, 1 H), 5.41-5.23 (m, 1 H), 4.72 (s, 1 H), 3.59-3.46 (m, 2 H), 2.92-2.62 (m, 6 H), 2.54 (s, 6 H), 2.18-2.08 (m, 2 H), 1.79- 1.45 (m, 8 H), 1.28-1.11 (m, 2 H), 1.04 (br d, J = 4.32 Hz, 6 H); HPLC purity: 96.70%; LCMS calculated for C.sub.26H.sub.41FN.sub.4O.sub.4S.sub.2: 580.26 Observed: 581.1 [M + H].sup.+. A-904 [01909]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (d, J = 7.34 Hz, 2 H), 7.81 (d, J = 7.34 Hz, 2 H), 7.40 (d, J = 6.85 Hz, 1 H), 7.31 (d, J = 4.89 Hz, 1 H), 7.22-7.11 (m, 1 H), 5.34 (d, J = 6.36 Hz, 1 H), 3.52 (d, J = 9.29 Hz, 3H), 3.40 (d, J = 9.29 Hz, 5H), 3.27 (s, 3 H), 3.01 (s, 2 H), 2.91-2.75 (m, 2 H), 2.75-2.63 (m, 2 H), 2.12 (dd, J = 15.89, 6.11 Hz, 2 H), 1.89-1.74 (m, 2 H), 1.75-1.49 (m, 5 H), 1.40-1.31 (m, 1 H), 1.28-1.10 (m, 1 H), 1.02-0.93 (m, 1 H); HPLC purity: 99.30%; LCMS calculated for C.sub.28H.sub.37FN.sub.2O.sub.7S.sub.2: 596.20, for free base 550.20; Observed: 551.1 [M + H].sup.+. A-905 [01910]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.19-8.06 (m, 1 H), 7.50-7.21 (m, 6H), 7.20-7.05 (m, 1 H), 5.35-5.19 (q, 1 H), 3.59-3.46 (m, 4H), 3.05-2.90 (m, 2H), 2.88-2.76 (m, 2 H), 2.72-2.59 (m, 1 H), 2.36 (s, 3 H), 2.20-2.01 (m, 2 H), 1.94-1.74 (m, 4 H), 1.70 (d, J = 5.87 Hz, 2 H), 1.58 (d, J = 5.87 Hz, 5H), 1.44-1.30 (m, 1 H), 1.23-1.10 (m, 1 H), 1.03 (d, J = 9.78 Hz, 1 H); HPLC purity: 98.06%; LCMS calculated for C.sub.28H.sub.37FN.sub.2O.sub.5S: 532.24, for free base 486.24; Observed: 487.2 [M + H].sup.+. A-906 [01911]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.14 (br s, 1H), 7.78-7.57 (m, 4 H), 7.41 (d, J = 7.34 Hz, 1 H), 7.34-6.99 (m, 3H), 5.37-5.21 (m, 1 H), 3.53 (d, J = 9.78 Hz, 3 H), 3.41 (d, J = 9.78 Hz, 2 H), 3.07-2.94 (m, 2 H), 2.89-2.73 (m, 2 H), 2.72-2.59 (m, 1 H), 2.24-2.03 (m, 2 H), 1.91-1.75 (m, 3 H), 1.71 (d, J = 5.87 Hz, 3 H), 1.65-1.48 (m, 4H), 1.39 (d, J = 2.45 Hz, 1 H), 1.26-1.11 (m, 1 H), 1.05-0.91 (m, 1 H); HPLC purity: 96.61%; LCMS calculated for C.sub.28H.sub.35F.sub.3N.sub.2O.sub.3S: 568.22 Observed: 523.1 [M + H].sup.+. A-911 [01912]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.99-7.84 (m, 2H), 7.83-7.69 (m, 2H), 7.41 (d, J = 6.85 Hz, 1 H), 7.31 (d, J = 4.89 Hz, 1H), 7.23- 7.07 (m, 1 H), 5.45-5.28 (m, 1H), 2.90- 2.71 (m, 2 H), 2.62 (s, 7H), 1.77-1.60 (m, 4 H), 1.57 (brs, 2 H) 1.47-1.09 (m, 3 H), 1 proton merged in solvent; HPLC purity: 98.70%; LCMS Calculated for C.sub.21H.sub.27FN.sub.2O.sub.4S.sub.2: 454.14 Observed: 455.1 [M + H].sup.+. A-912 [01913]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (d, J = 7.82 Hz, 2 H), 7.79 (d, J = 7.82 Hz, 2 H), 7.41 (d, J = 6.85 Hz, 1 H), 7.31 (d, J = 4.89 Hz, 1 H), 7.23-7.09 (m, 1 H), 5.37 (d, J = 7.34 Hz, 1 H), 2.89-2.72 (m, 3 H), 2.62 (s, 6 H), 1.66 (d, J = 6.85 Hz, 4 H), 1.61-1.50 (m, 2 H), 1.49-1.27 (m, 2 H), 1.27-1.09 (m, 2 H); HPLC purity: 98.66%; LCMS calculated for C.sub.21H.sub.27FN.sub.2O.sub.4S.sub.2: 454.14 Observed: 455.1 [M + H].sup.+. A-913 [01914]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.16-8.02 (m, 2 H), 7.88-7.72 (m, 2 H), 7.46-7.23 (m, 2 H), 7.22-7.10 (m, 1 H), 5.44-5.26 (m, 1 H), 3.50 (d, J = 9.29 Hz, 2 H), 3.40 (d, J = 9.29 Hz, 2 H), 3.04-2.92 (m, 2 H), 2.92-2.62 (m, 5 H), 2.12 (dd, J = 15.89, 6.11 Hz, 2 H), 1.89-1.49 (m, 8 H), 1.45- 1.31 (m, 1H), 1.28-1.10 (m, 1 H), 0.97 (d, J = 10.27 Hz, 1 H). 3H's are merged in to solvent peak; HPLC purity: 95.73%; LCMS calculated for C.sub.27H.sub.35FN.sub.2O.sub.5S.sub.2: 550.20 Observed: 551.6 [M + H].sup.+. A-914 [01915]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (d, J = 6.36 Hz, 2 H), 7.81 (d, J = 6.36 Hz, 2 H), 7.45-7.37 (m, 1 H), 7.35-7.23 (m, 1 H), 7.19 (d, J = 8.80 Hz, 1 H), 5.34 (d, J = 5.87 Hz, 1 H), 3.50 (d, J = 9.29 Hz, 2 H), 3.40 (d, J = 8.80 Hz, 2 H), 3.19-3.09 (m, 1 H), 3.04-2.92 (m, 2 H), 2.91-2.61 (m, 3 H), 2.20-2.01 (m, 2 H), 1.90-1.49 (m, 9 H), 1.45-1.30 (m, 1H), 1.26-1.09 (m, 1 H), 0.97 (d, J = 11.25 Hz, 1 H), 3H's are merged in to solvent peak; HPLC purity: 97.57%; LCMS calculated for C.sub.27H.sub.35FN.sub.2O.sub.5S.sub.2: 550.20 Observed: 551.6 [M + H].sup.+. A-920 [01916]embedded image Yield: 70 mg, 43%; Appearance: White solid .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.93- 7.87 (m, 2H), 7.54-7.50 (m, 1H), 7.41 (dd, J = 7.83, 1.10 Hz, 1 H), 7.33-7.30 (m, 1H), 7.23-7.17 (m, 1H), 5.35 (q, J = 7.25 Hz, 1H), ), 3.7--3.64 (m, 2H), 3.42-3.36 (m, 2H), 2.87-2.74 (m, 2H), 2.68-2.65 (m, 1H), 1.73 (br d, J = 8.68 Hz, 2 H), 1.64 (d, J = 7.21 Hz, 3 H); 1.59-1.46 (m, 3H); 1.36-1.14 (m, 2 H); HPLC purity: 96.10%; LCMS calculated for C.sub.21H.sub.24FNO.sub.4S.sub.2: 437.54; Observed: 438.1 [M + H].sup.+. A-921 [01917]embedded image Appearance: Off white solid; 1H NMR (400 MHz, DMSO-d.sub.6) δ 9.37 (s, 1 H), 7.98-7.89 (m, 4 H), 7.35-6.83 (m, 4 H), 2.80 (br s, 4 H), 2.62 (s, 6 H), 1.58-1.41 (m, 6 H); HPLC purity: 98.91%; LCMS calculated for C.sub.22H.sub.25F.sub.2N.sub.3O.sub.4S.sub.2: 497.58 Observed: 498.2 [M + H].sup.+. A-922 [01918]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08-7.89 (m, 2 H), 7.85-7.71 (m, 2 H), 7.41 (d, J = 6.36 Hz, 1 H), 7.30 (d, J = 4.40 Hz, 1 H), 7.18 (d, J = 10.76 Hz, 1 H), 4.52-4.37 (m, 1 H), 2.88-2.59 (m, 4 H), 1.81-1.30 (m, 10 H), 1.28-1.14 (m, 1 H), 1.15-1.0 (m, 6 H); HPLC purity: 98.60%; LCMS calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S.sub.2: 452.16 Observed: 452.69 [M + H].sup.+. A-923 [01919]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.99 (d, J = 5.38 Hz, 2 H), 7.85-7.66 (m, 2 H), 7.40 (br s, 1 H), 7.34-7.22 (m, 1 H), 7.18 (d, J = 9.29 Hz, 1 H), 5.39 (d, J = 4.89 Hz, 1 H), 4.43 (s, 1 H), 2.78 (brs, 2 H), 2.67 (brs, 2 H) 1.79-1.27 (m, 9H), 1.21 (d, J = 15.65 Hz, 1 H), 1.09 (s, 6 H); HPLC purity: 100%; LCMS calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S.sub.2: 452.16 Observed: 453.1 [M + H].sup.+. A-924 [01920]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.43 (br d, J = 8.00 Hz, 2 H), 7.41-7.32 (m, 3 H), 7.31-7.24 (m, 1 H), 7.14 (br dd, J = 12.01, 8.38 Hz, 1 H), 5.28 (q, J = 7.05 Hz, 1 H), 3.50 (br d, J = 9.63 Hz, 2 H), 2.98 (br s, 2 H), 2.83 (br t, 2H), 2.68 (br d, J = 12.26 Hz, 1 H), 2.36 (s, 4 H), 2.18-2.04 (m, 2 H), 1.90-1.78 (m, 4 H), 1.72-1.56 (m, 6 H), 1.38 (br d, J = 3.38 Hz, 1 H), 1.26-1.12 (m, 2 H), 1.08-0.97 (m, 1 H); HPLC purity: 100%; LCMS calculated for C.sub.27H.sub.35FN.sub.2O.sub.3S: 486.65 Observed: 487.3 [M + H].sup.+. A-925 [01921]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (d, J = 7.34 Hz, 2 H), 7.86-7.71 (m, 2 H), 7.47-7.11 (m, 3 H), 6.01-5.64 (m, 1 H), 5.35 (d, J = 6.36 Hz, 1 H), 3.13-2.86 (m, 3 H), 2.62 (s, 6 H), 1.80-1.46 (m, 6 H), 1.36-1.12 (m, 2 H), 1.01 (s, 3 H); HPLC purity: 100%; LCMS calculated for C.sub.23H.sub.29F.sub.3N.sub.2O.sub.4S.sub.2: 518.15 Observed: 519.1 [M + H].sup.+. A-926 [01922]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08-7.91 (m, 2 H), 7.79 (d, J = 5.87 Hz, 2 H), 7.41 (d, J = 5.38 Hz, 1 H), 7.30 (d, J = 4.89 Hz, 1 H), 7.22- 7.05 (m, 1 H), 5.39 (d, J = 5.87 Hz, 1 H), 4.48 (s, 1 H), 2.92-2.60 (m, 4 H), 1.82- 1.31 (m, 9 H), 1.23-1.15 (m, 1 H), 1.15- 0.99 (m, 6H); HPLC purity: 96.41%; LCMS calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S.sub.2: 452.16 Observed: 453.1 [M + H].sup.+. A-927 [01923]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.06-7.89 (m, 2 H), 7.78 (d, J = 6.85 Hz, 2 H), 7.47-7.35 (m, 1 H), 7.30 (d, J = 3.42 Hz, 1 H), 7.18 (d, J = 11.25 Hz, 1 H), 5.48-5.30 (m, 1 H), 4.43 (s, 1 H), 3.55-3.38 (m, 2 H), 2.88- 2.71 (m, 1 H), 2.70-2.60 (m, 1 H), 1.80- 1.28 (m, 9 H), 1.18-1.06 (m, 6 H), 1.04- 0.92 (m, 1 H); HPLC purity: 94.87%; LCMS calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S.sub.2: 452.16 Observed: 453.1 [M + H].sup.+. A-928 [01924]embedded image Appearance: White sticky solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.08-7.89 (m, 2 H), 7.79 (d, J = 6.36 Hz, 2 H), 7.40 (brs, 1 H), 7.30 (d, J = 3.91 Hz, 1 H), 7.18 (d, J = 9.78 Hz, 1 H), 5.47-5.26 (m, 1 H), 4.48 (s, 1 H) 3.53-3.40 (m, 1 H), 2.80 (d, J = 5.87 Hz, 2 H), 2.72-2.61 (m, 1 H), 1.85-1.31 (m, 8 H), 1.23-1.15 (m, 1H), 1.15-1.05 (m, 6 H), 1.04-0.94 (m, 1 H); HPLC purity: 99.30%; LCMS calculated for C.sub.22H.sub.29FN.sub.2O.sub.3S.sub.2: 452.16 Observed: 453.1 [M + H].sup.+. A-929 [01925]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (d, J = 8.31 Hz, 2 H), 7.75 (d, J = 8.31 Hz, 2 H), 7.41 (d, J = 7.83 Hz, 1 H), 7.33-7.24 (m, 1 H), 7.20-7.08 (m, 1 H), 5.38 (q, J = 7.01 Hz, 1 H), 4.71 (s, 1 H), 2.87-2.72 (m, 2 H), 2.69-2.61 (m, 1 H), 2.55 (s, 6 H), 1.76- 1.68 (m, 2 H), 1.65 (d, J = 6.36 Hz, 3 H), 1.60-1.28 (m, 4 H), 1.25-1.10 (m, 1 H); HPLC purity: 99.66%; LCMS calculated for C.sub.21H.sub.28FN.sub.3O.sub.3S.sub.2: 453.16 Observed: 454.1 [M + H].sup.+. A-930 [01926]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.91 (d, J = 8.31 Hz, 2 H), 7.75 (d, J = 8.31 Hz, 2 H), 7.41 (d, J = 7.83 Hz, 1 H), 7.33-7.24 (m, 1 H), 7.20-7.08 (m, 1 H), 5.38 (q, J = 7.01 Hz, 1 H), 4.71 (s, 1 H), 2.87-2.72 (m, 2 H), 2.69-2.61 (m, 1 H), 2.55 (s, 6 H), 1.76- 1.68 (m, 2 H), 1.65 (d, J = 6.36 Hz, 3 H), 1.60-1.28 (m, 4 H), 1.25-1.10 (m, 1H); HPLC purity: 100%; LCMS calculated for C.sub.21H.sub.28FN.sub.3O.sub.3S.sub.2: 453.16 Observed: 454.1 [M + H].sup.+. A-931 [01927]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95-7.82 (m, 2 H), 7.78-7.62 (m, 2 H), 7.41 (d, J = 7.34 Hz, 1 H), 7.30 (d, J = 5.38 Hz, 1 H), 7.21- 7.07 (m, 1 H), 5.41-5.25 (m, 1 H), 4.67 (s, 1 H), 3.62-3.45 (m, 3 H), 2.93-2.62 (m, 6 H), 2.55 (s, 6 H), 2.18-2.05 (m, 2 H), 1.79-1.43 (m, 8 H), 1.24-1.12 (m, 1 H), 1.04 (d, J = 5.38 Hz, 6 H); HPLC purity: 97.59%; LCMS calculated for C.sub.28H.sub.41FN.sub.4O.sub.4S.sub.2: 580.26 Observed: 581.6 [M + H].sup.+. A-932 [01928]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.93 (d, J = 7.34 Hz, 2 H), 7.77 (d, J = 7.83 Hz, 2 H), 7.43- 7.29 (m, 2 H), 7.25-7.11 (m, 1 H), 5.42- 5.29 (m, 1 H), 4.70 (s, 1 H), 3.58-3.41 (m, 2 H), 2.99-2.74 (m, 3 H), 2.56 (s, 6 H), 2.36 (d, J = 18.10 Hz, 1 H), 1.94-1.69 (m, 2 H), 1.66 (d, J = 6.36 Hz, 3 H), 1.51- 1.32 (m, 1H); HPLC purity: 95.41%; LCMS calculated for C.sub.22H.sub.27F.sub.4N.sub.3O.sub.3S.sub.2: 521.14 Observed: 522.1 [M + H].sup.+. A-933 [01929]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.86-7.76 (m, 2 H), 7.97-7.87 (m, 2 H), 7.47-7.28 (m, 2 H), 7.25-7.11 (m, 1 H), 6.02-5.61 (m, 1 H), 5.42-5.25 (m, 1 H), 3.56-3.40 (m, 1 H), 3.12-2.87 (m, 2 H), 2.62 (s, 6 H), 1.78- 1.43 (m, 6 H), 1.36-1.13 (m, 2 H), 1.09- 0.93 (m, 3 H); HPLC purity: 94.19%; LCMS calculated for C.sub.23H.sub.29F.sub.3N.sub.2O.sub.4S.sub.2: 518.15 Observed: 519.0 [M + H].sup.+. A-935 [01930]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.0-7.83 (m, 2 H), 7.77 (d, J = 7.34 Hz, 2 H), 7.45-7.27 (m, 2 H), 7.21 (d, J = 9.78 Hz, 1 H), 5.41-5.24 (m, 1 H), 4.71 (s, 1 H), 3.0-2.71 (m, 3 H), 2.56 (s, 6 H), 2.42-2.27 (m, 2H), 1.99- 1.85 (m, 1 H), 1.78 (br d, J = 8.80 Hz, 1 H), 1.66-1.52 (m, 4H), 1.49-1.33 (m, 1 H); HPLC purity: 96.37%; LCMS calculated for C.sub.22H.sub.27F.sub.4N.sub.3O.sub.3S.sub.2: 521.14 Observed: 522.1 [M + H].sup.+. A-936 [01931]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.94 (d, J = 8.31 Hz, 2 H), 7.83 (d, J = 8.31 Hz, 2 H), 7.42-7.28 (m, 2 H), 7.22 (dd, J = 11.74, 8.31 Hz, 1 H), 5.43 (q, J = 6.85 Hz, 1 H), 4.70 (s, 1 H), 3.09-2.93 (m, 2 H), 2.81 (d, J = 7.82 Hz, 1 H), 2.56 (s, 6 H), 2.35-2.11 (m, 1 H), 2.08-1.83 (m, 4 H), 1.63 (d, J = 6.85 Hz, 3 H); HPLC purity: 98.00%; LCMS calculated for C.sub.21H.sub.26F.sub.3N.sub.3O.sub.3S.sub.2: 489.14 Observed: 490.1 [M + H].sup.+. A-937 [01932]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (d, J = 8.51 Hz, 2H), 7.85 (d, J = 8.50 Hz, 2 H), 7.43 (d, J = 7.00 Hz, 1 H), 7.31 (td, J = 8.00, 5.38 Hz, 1 H), 7.19-7.16 (m, 1 H), 7.10- 6.80 (m, 1 H), 5.95 (s, 1 H), 5.37 (q, J = 7.25 Hz, 1 H), 2.81-2.70 (m, 2 H), 2.68-2.60 (m, 1 H), 1.74-1.64 (m, 4 H), 1.60-1.50 (m, 3 H), 1.43-1.08 (m, 3 H); HPLC purity: 95.26%; LCMS calculated for C.sub.20H.sub.23F.sub.3N.sub.2O.sub.3S.sub.2: 460.53 Observed: 461.2 [M + H].sup.+. A-938 [01933]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (d, J = 8.50 Hz, 2 H), 7.85 (d, J = 8.50 Hz, 2 H), 7.43 (dd, J = 7.88, 1.00 Hz, 1 H), 7.31 (td, J = 8.04, 5.44 Hz, 1 H), 7.22-7.13 (m, 1 H), 7.09-6.79 (m, 1 H), 5.92 (s, 1 H), 5.37 (q, J = 7.17 Hz, 1 H), 2.75 (br dd, J = 10.26, 6.50 Hz, 2 H), 2.67 (br s, 1 H), 1.73-1.64 (m, 4 H), 1.56 (br d, J = 7.50 Hz, 3 H), 1.46-1.38 (m, 1 H), 1.37-1.26 (m, 1 H), 1.22-1.09 (m, 1 H); ; HPLC purity: 98.64%; LCMS calculated for C.sub.20H.sub.23F.sub.3N.sub.2O.sub.3S.sub.2: 460.53 Observed: 461.2 [M + H].sup.+. A-939 [01934]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (d, J = 8.44 Hz, 2 H), 7.85 (d, J = 8.44 Hz, 2 H), 7.43 (d, J = 6.97 Hz, 1 H), 7.31 (td, J = 8.01, 5.38 Hz, 1 H), 7.19-7.16 (m, 1 H), 7.10- 6.80 (m, 1 H), 5.95 (s, 1 H), 5.37 (q, J = 7.21 Hz, 1 H), 2.82-2.60 (m, 3 H), 1.74-1.63 (m, 4 H), 1.60-1.49 (m, 3 H), 1.43-1.09 (m, 3 H); HPLC purity: 99.70%; LCMS calculated for C.sub.20H.sub.23F.sub.3N.sub.2O.sub.3S.sub.2: 460.53 Observed: 461.1 [M + H].sup.+. A-940 [01935]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.10 (d, J = 8.31 Hz, 2 H), 7.85 (d, J = 8.31 Hz, 2 H), 7.43 (d, J = 7.46 Hz, 1 H), 7.32-7.29 (m, 1 H), 7.17 (dd, J = 11.98, 8.68 Hz, 1 H), 7.09- 6.79 (m, 1 H), 5.92 (s, 1 H), 5.37 (q, J = 7.17 Hz, 1 H), 2.80-2.61 (m, 3 H), 1.66 (br d, J = 7.21 Hz, 4 H), 1.56 (br s, 3 H), 1.46-1.09 (m, 3 H); HPLC purity: 98.56%; LCMS calculated for C.sub.20H.sub.23F.sub.3N.sub.2O.sub.3S.sub.2: 460.53 Observed: 461.1 [M + H].sup.+. A-941 [01936]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.49-8.30 (m, 2 H), 7.49-7.15 (m, 3 H), 5.97 (q, J = 7.21 Hz, 1 H), 2.99-2.86 (m, 8 H), 2.82-2.65 (m, 2 H), 1.77 (br d, J = 12.51 Hz, 1 H), 1.68-1.53 (m, 7 H), 1.33-1.19 (m, 1 H); HPLC purity: 99.66%; LCMS calculated for C.sub.19H.sub.25FN.sub.4O.sub.4S.sub.2: 456.13 Observed: 457.1 [M + H].sup.+. A-942 [01937]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.92 (d, J = 6.85 Hz, 2 H), 7.78 (d, J = 7.34 Hz, 2 H), 7.40 (d, J = 6.36 Hz, 1 H), 7.35-7.26 (m, 1 H), 7.25-7.10 (m, 1 H), 6.01-5.62 (m, 1 H), 5.35 (d, J = 6.36 Hz, 1 H), 4.68 (s, 1 H), 3.11-2.89 (m, 2 H), 2.61-2.53 (m, 6 H), 1.77-1.46 (m, 6 H), 1.35-1.10 (m, 3 H), 1.07-0.94 (m, 3 H); HPLC purity: 96.63%; LCMS calculated for C.sub.23H.sub.30F.sub.3N.sub.3O.sub.3S.sub.2: 517.17 Observed: 518.1 [M + H].sup.+. A-943 [01938]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97-7.84 (m, 2 H), 7.83-7.67 (m, 2 H), 7.47-7.36 (m, 1 H), 7.35-7.24 (m, 1 H), 7.23-7.11 (m, 1 H), 6.02-5.63 (m, 1 H), 5.42-5.27 (m, 1 H), 4.72 (s, 1 H), 3.12-2.87 (m, 3 H), 2.55 (s, 6 H), 1.78-1.48 (m, 6 H), 1.32 (d, J = 12.23 Hz, 1 H), 1.25-1.12 (m, 1 H), 1.07-0.94 (m, 3 H); HPLC purity: 97.90%; LCMS calculated for C.sub.23H.sub.30F.sub.3N.sub.3O.sub.3S.sub.2: 517.17 Observed: 518.5 [M + H].sup.+. A-944 [01939]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 6.85 Hz, 2 H), 7.81-7.63 (m, 2 H), 7.45-7.39 (m, 1 H), 7.35-7.26 (m, 1 H), 7.23-7.05 (m, 1 H), 5.44-5.27 (m, 1 H), 4.65 (s, 1 H), 3.97-3.85 (m, 1 H), 3.54-3.38 (m, 2 H), 3.16-2.82 (m, 4 H), 2.54 (s, 6 H), 1.71-1.49 (m, 4 H), 1.49-1.33 (m, 3 H), 1.28 (d, J = 12.23 Hz, 1 H), 1.19-1.04 (m, 3 H), 1.01-0.84 (m, 3 H); HPLC purity: 95.12%; LCMS calculated for C.sub.25H.sub.36FN.sub.3O.sub.4S.sub.2: 525.21 Observed: 526.1 [M + H].sup.+. A-945 [01940]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 7.82 Hz, 2 H), 7.76 (d, J = 7.83 Hz, 2 H), 7.40 (d, J = 6.85 Hz, 1 H), 7.34-7.24 (m, 1 H), 7.22-7.08 (m, 1 H), 5.41-5.28 (m, 1 H), 4.71 (s, 1 H), 3.52-3.37 (m, 2 H), 3.14- 2.89 (m, 4 H), 2.54 (s, 6 H), 1.69-1.57 (m, 4 H), 1.57-1.47 (m, 1 H), 1.43 (d, J = 8.31 Hz, 2 H), 1.31-1.19 (m, 2 H), 1.18-1.06 (m, 3 H), 1.0-0.86 (m, 3 H); HPLC purity: 94.01%; LCMS calculated for C.sub.25H.sub.36FN.sub.3O.sub.4S.sub.2: 525.21 Observed: 526.1 [M + H].sup.+. A-946 [01941]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98-7.82 (m, 2 H), 7.73 (d, J = 7.34 Hz, 2 H), 7.46-7.34 (m, 1 H), 7.30 (d, J = 4.89 Hz, 1 H), 7.22-7.07 (m, 1 H), 5.42-5.25 (m, 1 H), 4.66 (s, 1 H), 3.20 (d, J = 5.38 Hz, 3 H), 2.93-2.62 (m, 4 H), 2.55 (s, 6 H), 1.83-1.58 (m, 5 H), 1.68-1.48 (m, 1 H), 1.45-1.30 (m, 1 H), 1.14 (s, 9 H); HPLC purity: 98.48%; LCMS calculated for C.sub.26H.sub.38FN.sub.3O.sub.4S.sub.2: 539.23 Observed: 540.1 [M + H].sup.+. A-947 [01942]embedded image Yield: 46 mg (46%); Appearance: off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.80- 7.72 (m, 2H), 7.49 (d, J = 8.07 Hz, 1H), 7.41 (d, J = 6.97 Hz, 1H), 7.33-7.29 (m, 1H), 7.20-7.16 (m, 1H), 5.33 (q, J = 7.17 Hz, 1H), 4.85 (br s, 1H), 3.54-3.48 (m, 2H), 3.28 (br s, 1H), 2.84-2.75 (m, 2H), 2.69-2.61 (m, 1H), 1.77-1.45 (m, 8H), 1.37-1.26 (m, 2H), 1.25-1.14 (m, 1H); HPLC purity: 98.7%; LCMS calculated for C.sub.21H.sub.25FN.sub.2O.sub.3S.sub.2: 436.56; Observed: 437.1 [M + H].sup.+. A-948 [01943]embedded image Yield: 34 mg (34%); Appearance: off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.81- 7.71 (m, 2H), 7.49-7.45 (m, 1H), 7.41 (dd, J = 7.82, 1.06 Hz, 1H), 7.32-7.29 (m, 1H), 7.20-7.16 (m, 1H), 5.33 (q, J = 7.17 Hz, 1H), 4.82 (s, 1H), 3.54-3.47 (m, 2H), 3.35 (br s, 1H), 3.28 (br s, 1H), 2.84-2.74 (m, 2H), 2.69-2.62 (m, 1H), 1.72 (br t, J = 9.69 Hz, 2H), 1.63 (d, J = 7.25 Hz, 3H), 1.60-1.47 (m, 3H), 1.37-1.12 (m, 2H); HPLC purity: 97.60%; LCMS calculated for C.sub.21H.sub.25FN.sub.2O.sub.3S.sub.2: 436.56; Observed: 437.1 [M + H].sup.+. A-949 [01944]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.90 (d, J = 8.51 Hz, 2 H), 7.72 (d, J = 8.50 Hz, 2 H), 7.49 (d, J = 7.75 Hz, 1 H), 7.06-7.03 (m, 1 H), 6.94-6.90 (m, 1 H), 5.43 (q, J = 7.25 Hz, 1 H), 3.37-3.34 (m, 1 H), 3.22-3.18 (m, 1 H), 2.68 (s, 6 H), 2.15-2.05 (m, 1 H), 2.01-1.90 (m, 1 H), 1.84-1.79 (m, 3H), 1.79-1.58 (m, 7 H), 1.50-1.40 (m, 1 H), 1 proton merged in solvent; HPLC purity: 98.10%; LCMS calculated for C.sub.23H.sub.30FN.sub.3O.sub.3S.sub.2: 479.63 Observed: 480.2 [M + H].sup.+. A-950 [01945]embedded image Appearance: Off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.86 (br d, J = 7.82 Hz, 2 H), 7.68 (br d, J = 7.70 Hz, 2 H), 7.41 (br d, J = 6.97 Hz, 1 H), 6.98- 7.12 (m, 2 H), 5.26 (br d, J = 6.97 Hz, 1 H), 4.68 (br s, 1 H), 3.16-3.27 (m, 2 H), 2.55-2.70 (m, 6 H), 1.98 (br d, J = 4.77 Hz, 1 H), 1.76 (br d, J = 6.72 Hz, 5 H), 1.69-1.62 (m, 4 H), 1.59-1.48 (m, 3 H); HPLC purity: 98.37%; LCMS calculated for C.sub.23H.sub.30FN.sub.3O.sub.3S.sub.2: 479.63 Observed: 480.2 [M + H].sup.+. A-951 [01946]embedded image Yield: 160 mg (30%); Appearance: off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96 (q, J = 8.64 Hz, 4H), 7.52-7.47 (m, 1H), 7.37-7.34 (m, 1H), 7.24-7.21 (m, 1H), 4.63 (d, J = 10.88 Hz, 1H), 2.99-2.78 (m, 2H), 2.63 (s, 6H), 2.19 (br d, J = 10.39 Hz, 1H), 1.73 (br d, J = 12.35 Hz, 1H), 1.64-1.39 (m, 5H), 1.31-1.16 (m, 2H), 0.72-0.45 (m, 2H), 0.18-0.14 (m, 1H), -0.01 to -0.12 (m, 1H); HPLC purity: 97.60%; LCMS calculated for C.sub.23H.sub.29FN.sub.2O.sub.4S.sub.2: 480.61; Observed: 481.2 [M + H].sup.+. A-952 [01947]embedded image Yield: 0.15 g (29%); Appearance: off white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71- 9.46 (m, 1H), 8.01-7.89 (m, 5H), 7.23 (d, J = 1.71 Hz, 1H), 3.16 (br d, J = 11.13 Hz, 2H), 2.64 (s, 6H), 2.45 (br s, 5H), 2.19-2.10 (m, 5H), 2.0-1.85 (m, 5H), 1.61-1.44 (m, 3H), 1.07-0.91 (m, 2H); HPLC purity: 99.26%; LCMS calculated for C.sub.25H.sub.35F.sub.2N.sub.5O.sub.4S.sub.2: 571.70; Observed: 572.2 [M + H].sup.+. A-953 [01948]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.95-7.80 (m, 2 H), 7.78-7.63 (m, 2 H), 7.41 (d, J = 7.34 Hz, 1 H), 7.34-7.22 (m, 1 H), 7.20-7.06 (m, 1 H), 5.40-5.26 (m, 1 H), 4.70 (s, 1 H), 3.22-3.09 (m, 2 H), 2.91-2.61 (m, 3 H), 2.55 (s, 6 H), 1.78-1.59 (m, 5 H), 1.56- 1.18 (m, 4 H), 1.14 (s, 9 H); HPLC purity: 96.82%; LCMS calculated for C.sub.26H.sub.38FN.sub.3O.sub.4S.sub.2: 539.23 Observed: 540.1 [M + H].sup.+. A-954 [01949]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.90 (d, J = 7.82 Hz, 2 H), 7.80-7.63 (m, 2 H), 7.47-7.35 (m, 1 H), 7.31 (d, J = 4.40 Hz, 1 H), 7.23-7.08 (m, 1 H), 5.44-5.25 (m, 1 H), 4.71 (s, 1 H), 3.56-3.38 (m, 2 H), 3.17-2.85 (m, 4 H), 2.55 (s, 6 H), 1.70-1.52 (m, 4 H), 1.49-1.34 (m, 2 H), 1.32-1.03 (m, 6 H), 1.0-0.87 (m, 3 H); HPLC purity: 99.70%; LCMS calculated for C.sub.25H.sub.36FN.sub.3O.sub.4S.sub.2: 525.21 Observed: 526.1 [M + H].sup.+. A-955 [01950]embedded image Appearance: White solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97-7.82 (m, 2 H), 7.80-7.66 (m, 2 H), 7.47-7.36 (m, 1 H), 7.31 (d, J = 4.89 Hz, 1 H), 7.23-7.08 (m, 1 H), 5.44-5.26 (m, 1 H), 4.67 (s, 1 H), 3.53-3.40 (m, 2 H), 3.14-2.88 (m, 4 H), 2.55 (s, 6 H), 1.73-1.35 (m, 6 H), 1.34- 1.21 (m, 2 H), 1.18-1.03 (m, 4 H), 1.0- 0.86 (m, 3 H); HPLC purity: 98.96%; LCMS calculated for C.sub.25H.sub.36FN.sub.3O.sub.4S.sub.2: 525.21 Observed: 526.1 [M + H].sup.+. A-1001 [01951]embedded image Appearance: Off-white solid; .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.00 (d, J = 8.4 Hz, 2 H), 7.82 (d, J = 7.6 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 1H), 7.24-7.18 (m, 1 H), 7.06- 6.98 (m, 1 H), 5.46-5.37 (m, 1 H), 4.18-4.06 (m, 2H), 3.51 (d, J = 11.6 Hz, 2 H), 3.09-2.91 (m, 4 H), 2.70 (s, 7 H), 2.40-2.21 (m, 3 H), 1.78-1.71 (m, 2 H), 1.66 (d, J = 7.2 Hz, 3 H), 1.46-1.28 (m, 2 H), 1.26-1.22 (m, 7 H), 1 H merged in solvent peak; HPLC purity: 99.71%; LCMS calculated for C.sub.28H4.sub.1FN.sub.4O.sub.4S.sub.2: 580.26 Observed: 581.1 [M + H].sup.+. A-1002 [01952]embedded image Appearance: Off-white solid; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.38 (d, J = 8.0 Hz, 1H), 7.30-7.23 (m, 3H), 7.17- 7.10 (m, 1 H), 6.93 (d, J = 8.4 Hz, 2 H), 5.28-5.18 (m, 1 H), 3.58-3.48 (m, 2 H), 3.28 (s, 6 H), 2.82 (t, J = 11 Hz, 2 H), 2.64-2.62 (m, 3 H), 2.12 (d, J = 6.4 Hz, 2 H), 1.88 (d, J = 10.4 Hz, 1 H), 1.69 (bd, J = 11.6 Hz, 1 H), 1.60-1.50 (m, 7 H), 1.19-1.11 (m, 1H), 1.04 (d, J = 6.4 Hz, 6 H), 1.01-0.98 (m, 1 H); HPLC purity: 95.95%; LCMS calculated for C.sub.28H.sub.40FN.sub.3O.sub.4S.sub.2: 565.24 Observed: 566.1 [M + H].sup.+.

    Analytical Instrumentation and Purification:

    [1152] NMR Instrument Details: Varian 400 MHz, Probe-1: Auto XID Probe 2: ATB.

    [1153] LCMS Instrument Details: Shimadzu LCMS-2010EV system coupled to SPD-M20A PDA and ELS detectors. Softa model 400.

    [1154] LCMS Method 1—Acidic Conditions [1155] Column: X-Select C18 CSH (3.0*50) mm 2.5μ; Make: Waters [1156] Mobile Phase A: 0.05% formic acid in water:Acetonitrile (95:5); pH=3.5 [1157] Mobile Phase B: 0.05% formic acid in Acetonitrile [1158] Column oven temperature: 5° C. [1159] Flow rate: 1.2 ml/minute [1160] PDA: 210 nm Maxplot [1161] Gradient program:

    TABLE-US-00043 Time(min) A % B % 0.0 100 0 2.0 2 98 3.0 2 98 3.2 100 0 4.0 100 0 [1162] MS Parameters [1163] Mode: Dual (+/−) [1164] Detector voltage: 1.5 KV [1165] Scan rang: 80-2000 amu [1166] Scan speed: 2000

    [1167] LCMS Method 2—Basic Conditions [1168] Column: X-Select C18 CSH (3.0*50) mm 2.5 μm; Make: Waters [1169] Mobile Phase A: 5 mM Ammonium Bicarb; pH=8.8 [1170] Mobile Phase B: Acetonitrile [1171] Column oven temperature: 5° C. [1172] Flow rate: 1.2 ml/minute [1173] PDA: 210 nm Maxplot [1174] Gradient program:

    TABLE-US-00044 Time(min) A % B % 0.0 100 0 2.0 2 98 3.0 2 98 3.2 100 0 4.0 100 0 [1175] MS Parameters [1176] Mode: Dual (+/−) [1177] Detector voltage: 1.5 KV [1178] Scan rang: 80-2000 amu [1179] Scan speed: 2000

    [1180] HPLC Method 1—Acidic Conditions [1181] Column: X-Select CSH C.sub.18 (4.6*150) mm; 5μ; Make: Waters [1182] Mobile Phase: A—0.1% Formic acid in water:Acetonitrile (95:05); pH=3.5 [1183] B—Acetonitrile [1184] Flow Rate: 1.0. mL/minute [1185] PDA: 210 nm maxplot [1186] Gradient program:

    TABLE-US-00045 Time(min) A % B % 0.0 95 5 1.0 95 5 8.0 0 100 12.0 0 100 14.0 95 5 18.0 95 5

    [1187] HPLC Method 2—Basic Conditions [1188] Column: Xbridge C18 (4.6*150) mm, 5μ; Make: Waters [1189] Mobile Phase A—0.1% NH.sub.3 in water; pH=9.5 [1190] B—Acetonitrile [1191] Flow Rate: 1.2. mL/minute [1192] PDA: 210 nm maxplot [1193] Gradient program:

    TABLE-US-00046 Time(min) A % B % 0.0 98 2 6.0 0 85 8.0 0 85 9.0 0 100 12.0 0 100 14.0 98 2 18.0 98 2

    Biological Activity

    [1194] For the TFEB nuclear translocation assay, HeLa wt or HeLa TRPML1 KO cells were plated at 2700 cells/well into black-walled, 384-well Cell carrier Ultra tissue culture treated plates in complete media and incubated overnight. The next day, cells are treated for 2 hrs with compounds and incubated at 37° C. Cells were then fixed for 30 minutes at room temperature in 4% final PFA and washed five times with 90 μL PBS. PBS is aspirated from the wells and the cells are blocked with 7.5 μL blocking buffer (1:1 PBS/Odyssey block buffer containing 0.1% triton x-100 and 1% goat serum). After 30-60 minutes of block, 7.5 μL of primary anti-TFEB (rabbit) antibody is added for a final dilution of 1:200 antibody in 15 μL blocking buffer. Plates are incubated overnight at 4° C. The following day, plates are washed again into PBS, 90 μL with 5 washes, all PBS is aspirated from the wells and the cells are incubated for 1 hr in 1:1000 goat-anti rabbit Alexa 488 secondary antibody, also containing 10 μg/mL Hoechst 33342. After the 1 hr room temperature incubation, plates are washed a final time into PBS, sealed with foil and imaged with an automated epifluorescence microscopy (PerkinElmer Operetta CLS). Four different fields were imaged per well using ×20 magnification for DAPI and FITC filter sets. Images were quantified using PerkinElmer Harmony software, briefly: apply flatfield correction (basic/advanced) for input images. Use the Find Nuclei building block with channel set at Hoechst to find the nuclei. Use the Find cytoplasm building block with channel set to Alexa 488 to find the cytoplasm. Use select cell region with Channel set at Alexa 488 and region of interest as Nuclei and define outer border at 0 μm and inner at 45 μm to cover complete nuclei. Use select cell region with Channel set at Alexa 488 and region of interest as ring region and define outer border at −5 μm and inner at 0 μm to define a ring around the nucleus. Use the find calculate intensity parameter to calculate intensity of the nuclear region and the ring region. Define results as Number of nuclei and ratio of A/B where A is Intensity of Nuclei and B is intensity of the ring region.

    [1195] Table 1 shows the activity of selected compounds of this invention in TFEB assays. The compound numbers correspond to the compound numbers above in Tables A or B. Compounds having an activity designated as “++++” provided an AC.sub.50 of ≤2.00 μM; compounds having an activity designated as “+++” provided an AC.sub.50 of 2.01-8.00 μM; compounds having an activity designated as “++” provided an AC.sub.50 of 8.01-9.99 μM; and compounds having an activity designated as “+” provided an AC.sub.50 of ≥10.00 μM.

    TABLE-US-00047 TABLE 1 Compound TFEB AC.sub.50 (μM) A-1 ++++ A-2 ++++ A-3 ++++ A-4 ++++ A-5 +++ A-6 + A-7 ++++ A-8 + A-9 ++++ A-10 ++++ A-11 ++++ A-12 ++++ A-13 ++++ A-14 +++ A-15 + A-16 +++ A-17 +++ A-18 ++++ A-19 ++++ A-20 ++++ A-21 +++ A-22 +++ A-23 ++++ A-24 ++++ A-25 ++++ A-26 ++++ A-27 +++ A-28 ++++ A-29 + A-30 ++++ A-31 ++++ A-32 ++++ A-33 + A-34 ++++ A-35 + A-36 ++++ A-37 +++ A-38 ++++ A-39 +++ A-40 +++ A-41 + A-42 + A-43 ++++ A-44 ++++ A-45 +++ A-46 + A-47 ++++ A-48 + A-49 + A-50 +++ A-51 +++ A-52 ++++ A-53 +++ A-54 + A-55 ++++ A-56 +++ A-57 +++ A-58 + A-59 + A-60 +++ A-61 + A-62 ++ A-63 +++ A-64 + A-65 + A-66 + A-67 + A-68 + A-69 +++ A-70 ++++ A-71 + A-72 ++++ A-73 ++++ A-74 +++ A-75 + A-76 + A-77 ++++ A-78 + A-79 + A-80 +++ A-81 + A-82 + A-83 ++++ A-84 + A-85 + A-86 + A-87 + A-88 +++ A-89 ++++ A-90 +++ A-91 + A-92 ++++ A-93 + A-94 +++ A-96 + A-97 + A-98 ++++ A-99 ++++ A-100 ++++ A-101 +++ A-102 +++ A-103 ++++ A-104 ++++ A-105 + A-106 + A-107 + A-108 ++++ A-109 ++++ A-110 + A-111 + A-112 ++++ A-113 ++++ A-114 + A-115 ++++ A-116 + A-117 + A-118 +++ A-119 ++++ A-120 ++++ A-121 ++++ A-122 + A-123 +++ A-124 ++++ A-128 + A-129 + A-130 + A-131 ++++ A-132 ++++ A-133 + A-134 + A-135 + A-136 ++++ A-137 +++ A-138 ++++ A-139 + A-140 ++++ A-141 ++++ A-142 +++ A-143 ++++ A-144 + A-145 + A-146 ++++ A-147 +++ A-148 ++++ A-149 ++++ A-150 ++++ A-151 +++ A-152 + A-153 +++ A-154 ++++ A-155 +++ A-156 +++ A-157 ++++ A-158 ++++ A-159 +++ A-160 +++ A-161 +++ A-162 +++ A-163 + A-164 + A-165 +++ A-166 +++ A-167 +++ A-168 + A-169 + A-170 ++++ A-171 +++ A-172 +++ A-173 ++++ A-174 +++ A-175 ++++ A-176 + A-177 + A-178 ++++ A-179 ++++ A-180 ++ A-181 +++ A-182 ++++ A-183 ++++ A-184 ++++ A-185 ++++ A-186 + A-187 + A-188 + A-189 ++++ A-190 ++++ A-191 +++ A-192 + A-193 + A-194 + A-195 +++ A-196 ++++ A-197 + A-198 ++++ A-199 + A-200 +++ A-201 +++ A-202 + A-203 +++ A-204 ++++ A-205 ++++ A-206 + A-207 ++++ A-208 ++++ A-209 ++++ A-210 ++++ A-211 ++++ A-212 ++++ A-213 ++++ A-214 ++++ A-215 ++++ A-216 ++++ A-217 ++++ A-218 ++++ A-219 + A-220 + A-221 ++++ A-222 ++++ A-223 +++ A-224 + A-225 +++ A-226 ++++ A-227 + A-228 ++++ A-229 ++++ A-230 + A-231 ++++ A-232 + A-233 + A-234 + A-235 + A-236 + A-237 + A-238 + A-239 + A-240 + A-241 + A-242 + A-243 ++++ A-244 + A-245 ++++ A-246 ++++ A-247 ++++ A-248 + A-249 + A-250 + A-251 ++++ A-252 ++++ A-253 ++++ A-254 ++++ A-255 + A-256 + A-257 ++++ A-258 ++++ A-259 + A-260 + A-261 + A-262 + A-263 + A-264 + A-265 + A-266 + A-267 + A-268 ++++ A-269 + A-270 + A-271 ++++ A-272 + A-273 + A-274 + A-275 + A-276 + A-277 + A-278 + A-279 + A-280 + A-281 + A-282 +++ A-283 + A-284 + A-285 + A-286 + A-287 + A-288 ++++ A-289 + A-290 + A-291 ++++ A-292 ++++ A-293 + A-294 + A-295 +++ A-296 +++ A-297 + A-298 ++++ A-299 + A-300 +++ A-301 ++++ A-302 + A-303 ++ A-304 ++++ A-305 +++ A-306 + A-307 +++ A-308 +++ A-309 +++ A-310 ++++ A-311 +++ A-312 + A-313 ++++ A-314 + A-315 + A-316 +++ A-317 +++ A-318 +++ A-319 ++++ A-320 + A-321 + A-322 ++ A-323 +++ A-324 + A-325 + A-326 + A-327 + A-328 + A-329 + A-330 + A-331 ++++ A-332 +++ A-333 + A-334 +++ A-335 + A-336 ++++ A-337 ++ A-338 +++ A-339 +++ A-340 + A-341 ++++ A-342 ++ A-343 +++ A-344 +++ A-345 +++ A-346 ++++ A-347 ++++ A-348 ++ A-349 + A-350 +++ A-351 + A-352 +++ A-353 ++++ A-354 + A-355 +++ A-356 +++ A-357 + A-358 + A-359 ++++ A-360 ++++ A-361 ++++ A-362 ++++ A-363 + A-364 + A-365 + A-366 + A-367 +++ A-368 +++ A-369 + A-370 ++++ A-371 ++++ A-372 +++ A-390 ++++ A-391 +++ A-392 +++ A-393 ++ A-394 +++ A-395 + A-396 ++++ A-397 +++ A-398 +++ A-399 ++++ A-400 +++ A-401 + A-402 +++ A-403 +++ A-404 +++ A-405 +++ A-406 +++ A-407 ++++ A-408 + A-409 + A-410 +++ A-411 ++++ A-412 ++++ A-413 ++ A-414 ++++ A-415 ++++ A-416 +++ A-417 +++ A-418 +++ A-419 ++++ A-420 +++ A-421 ++++ A-422 ++++ A-423 ++++ A-424 +++ A-425 +++ A-426 ++++ A-427 +++ A-428 ++++ A-429 +++ A-430 +++ A-431 +++ A-432 +++ A-433 +++ A-434 ++++ A-435 ++++ A-436 +++ A-437 +++ A-438 ++++ A-439 ++++ A-440 ++++ A-441 +++ A-442 ++++ A-443 +++ A-444 ++++ A-445 ++++ A-446 +++ A-447 +++ A-448 ++++ A-449 +++ A-450 ++ A-451 ++++ A-452 ++ A-453 +++ A-454 ++++ A-455 +++ A-456 ++++ A-457 +++ A-458 +++ A-459 +++ A-460 ++++ A-461 +++ A-462 +++ A-463 +++ A-464 +++ A-465 ++++ A-466 ++++ A-467 ++++ A-468 ++++ A-469 ++++ A-470 ++++ A-471 ++++ A-472 ++++ A-473 +++ A-474 +++ A-475 ++++ A-476 +++ A-477 +++ A-478 +++ A-479 ++++ A-480 +++ A-481 ++++ A-482 +++ A-483 ++++ A-484 +++ A-485 +++ A-486 +++ A-487 ++++ A-488 ++ A-489 +++ A-490 + A-491 ++++ A-492 ++++ A-493 ++++ A-494 ++++ A-495 ++ A-496 ++++ A-497 ++++ A-498 ++++ A-499 ++++ A-500 +++ A-501 +++ A-502 ++++ A-503 ++++ A-504 ++++ A-505 +++ A-506 ++++ A-507 +++ A-508 +++ A-509 +++ A-510 ++++ A-511 ++++ A-512 +++ A-513 +++ A-514 ++++ A-515 +++ A-516 +++ A-517 +++ A-518 ++++ A-519 ++++ A-520 ++++ A-521 ++++ A-522 +++ A-523 ++++ A-524 ++++ A-525 ++++ A-526 +++ A-527 +++ A-528 +++ A-529 +++ A-530 +++ A-531 ++++ A-532 ++++ A-533 +++ A-534 +++ A-535 +++ A-536 ++ A-537 ++ A-538 ++++ A-539 ++++ A-540 ++++ A-541 ++++ A-542 ++++ A-543 ++++ A-544 ++++ A-545 ++++ A-546 ++++ A-547 ++++ A-548 ++++ A-549 +++ A-550 ++++ A-551 ++++ A-552 ++++ A-553 +++ A-554 ++++ A-555 +++ A-556 ++++ A-557 +++ A-558 +++ A-559 +++ A-560 ++++ A-561 +++ A-562 ++++ A-563 + A-564 ++++ A-565 ++ A-566 +++ A-567 + A-568 ++ A-569 ++ A-570 ++++ A-571 +++ A-572 +++ A-573 ++ A-574 +++ A-575 ++ A-576 + A-577 +++ A-578 +++ A-579 +++ A-580 ++ A-581 +++ A-582 +++ A-583 + A-584 ++++ A-585 ++++ A-586 ++ A-587 +++ A-588 ++++ A-589 ++++ A-590 +++ A-591 + A-592 ++ A-593 +++ A-594 +++ A-595 +++ A-596 +++ A-597 ++ A-598 ++++ A-599 +++ A-600 + A-601 +++ A-602 +++ A-603 +++ A-604 ++++ A-605 ++++ A-606 +++ A-607 +++ A-608 ++++ A-609 ++ A-610 +++ A-611 ++++ A-612 +++ A-613 ++++ A-614 ++++ A-615 ++++ A-616 +++ A-617 +++ A-618 +++ A-619 +++ A-620 ++++ A-621 ++++ A-622 +++ A-623 +++ A-624 +++ A-625 ++++ A-626 ++++ A-627 +++ A-628 +++ A-629 +++ A-630 ++++ A-631 ++++ A-632 ++++ A-633 +++ A-634 +++ A-635 +++ A-636 ++++ A-637 + A-638 +++ A-639 + A-640 +++ A-641 ++ A-642 ++++ A-643 ++++ A-644 +++ A-645 ++ A-646 +++ A-647 ++ A-648 ++++ A-649 +++ A-650 ++++ A-651 ++++ A-652 ++++ A-653 +++ A-654 ++++ A-655 +++ A-656 +++ A-657 ++ A-658 ++++ A-659 +++ A-660 ++ A-661 +++ A-662 ++++ A-663 ++++ A-664 ++++ A-665 +++ A-666 +++ A-667 +++ A-668 +++ A-669 ++++ A-670 +++ A-671 ++++ A-672 ++++ A-673 +++ A-674 ++++ A-675 ++++ A-676 +++ A-677 ++++ A-678 ++++ A-679 ++++ A-680 ++ A-681 ++++ A-682 +++ A-683 +++ A-684 +++ A-685 ++++ A-686 ++++ A-687 ++++ A-688 +++ A-689 + A-690 +++ A-691 +++ A-692 +++ A-693 +++ A-694 ++++ A-695 ++++ A-696 ++++ A-697 +++ A-698 ++++ A-699 +++ A-700 +++ A-701 ++++ A-702 ++++ A-703 ++++ A-704 ++++ A-705 ++ A-706 ++++ A-707 +++ A-708 ++++ A-709 +++ A-710 ++ A-711 ++++ A-712 +++ A-713 ++++ A-714 ++ A-715 ++++ A-716 +++ A-717 +++ A-718 ++++ A-719 ++++ A-720 +++ A-721 ++++ A-722 + A-723 ++++ A-724 ++++ A-725 ++ A-726 +++ A-727 +++ A-728 +++ A-729 +++ A-730 ++++ A-731 + A-732 +++ A-733 +++ A-734 ++++ A-735 + A-736 ++++ A-737 + A-738 ++++ A-739 ++++ A-740 ++ A-741 ++++ A-742 ++++ A-743 + A-744 + A-745 + A-746 ++++ A-747 + A-748 ++++ A-749 +++ A-750 ++++ A-751 + A-752 ++++ A-753 ++++ A-754 +++ A-755 ++++ A-756 +++ A-757 ++++ A-758 ++++ A-759 ++++ A-760 +++ A-761 + A-762 ++++ A-763 ++++ A-764 +++ A-765 ++++ A-766 ++++ A-767 ++++ A-768 ++++ A-769 ++++ A-770 + A-771 ++++ A-772 ++ A-773 ++++ A-774 ++++ A-775 ++ A-776 ++++ A-777 ++++ A-778 ++++ A-779 ++++ A-780 ++++ A-781 ++++ A-782 ++++ A-783 ++++ A-784 ++++ A-785 ++++ A-786 ++++ A-788 ++++ A-789 ++++ A-790 ++++ A-791 + A-792 + A-793 +++ A-794 ++++ A-795 ++ A-796 + A-797 ++++ A-798 ++++ A-799 ++++ A-800 ++++ A-801 ++++ A-802 ++++ A-803 ++++ A-804 ++++ A-805 ++++ A-806 ++++ A-807 ++++ A-808 ++++ A-809 + A-810 ++++ A-811 ++++ A-812 ++++ A-813 + A-814 ++++ A-815 + A-816 + A-817 ++++ A-818 ++++ A-819 + A-820 + A-821 ++++ A-822 +++ A-823 + A-824 ++++ A-825 ++++ A-826 ++++ A-827 + A-828 ++++ A-829 ++++ A-830 ++++ A-831 ++++ A-832 ++++ A-833 ++++ A-834 ++++ A-835 ++++ A-836 +++ A-837 ++++ A-838 ++++ A-839 ++++ A-840 ++++ A-841 +++ A-842 ++++ A-843 ++++ A-844 ++++ A-845 +++ A-846 +++ A-847 + A-848 ++++ A-849 +++ A-850 +++ A-851 ++++ A-852 ++++ A-853 ++++ A-854 ++++ A-855 +++ A-856 + A-857 ++++ A-858 ++++ A-859 ++++ A-860 +++ A-861 ++++ A-862 ++++ A-863 ++++ A-864 ++++ A-865 ++++ A-866 ++++ A-867 ++++ A-868 ++++ A-869 +++ A-870 + A-871 ++++ A-871A ++++ A-871B ++++ A-872 ++++ A-872A ++++ A-872B ++++ A-873 + A-874 +++ A-875 + A-876 + A-877 ++++ A-878 ++++ A-879 ++++ A-880 ++++ A-881 ++++ A-882 ++++ A-883 ++++ A-885 ++++ A-886 ++++ A-887 ++++ A-888 +++ A-889 +++ A-890 +++ A-891 + A-892 ++ A-893 + A-894 +++ A-895 + A-896 ++++ A-897 ++++ A-898 + A-899 + A-900 + A-901 ++++ A-902 + A-903 + A-904 +++ A-905 ++++ A-906 ++++ A-907 ++++ A-908 +++ A-909 +++ A-910 +++ A-911 ++++ A-912 ++++ A-913 ++++ A-914 + A-915 + A-916 + A-917 +++ A-918 ++++ A-919 ++++ A-920 + A-921 ++++ A-922 + A-923 + A-924 ++++ A-925 ++++ A-926 + A-927 + A-928 +++ A-929 ++++ A-930 +++ A-931 ++++ A-932 ++++ A-933 ++++ A-934 + A-935 ++++ A-936 ++++ A-937 +++ A-938 + A-939 +++ A-940 ++++ A-941 +++ A-946 ++++ A-952 ++++ A-956 ++++ A-957 + A-958 ++++ A-959 + A-960 + A-961 + A-962 ++++ A-963 +++ A-964 ++++ A-965 + A-966 + A-967 + A-968 ++++ A-969 ++++ A-970 ++++ A-971 +++ A-972 +++ A-973 ++++ A-974 ++++ A-975 + A-976 ++++ A-977 +++ A-978 ++++ A-979 +++ A-980 + A-981 + A-982 ++++ A-983 ++++ A-984 ++++ A-985 ++++ A-986 + A-987 ++++ A-988 + A-989 ++ A-990 ++++ A-991 +++ A-992 + A-993 ++++ A-994 ++++ A-995 + A-996 ++++ A-997 ++++ A-998 +++ A-999 ++++ A-1000 + A-1001 ++++ A-1002 +