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METHODS FOR TREATING CANCER

20260130925 ยท 2026-05-14

    Inventors

    Cpc classification

    International classification

    Abstract

    This disclosure provides compounds of Formula (I), Formula (II), Formula (III), and pharmaceutically acceptable salts of any of the foregoing, that inhibit PI3K. These compounds are useful for treating diseases such as cancer in a subject.

    Claims

    1. A compound of Formula (I), Formula (II), or Formula (III): ##STR00388## or a pharmaceutically acceptable salt of any of the foregoing, wherein: Q is NR.sup.1A or CR.sup.1; Z is NR.sup.Z1 or CR.sup.Z2, wherein one or both of Q and Z is N; Z.sup.1 is S, S(O.sub.2), or O; each custom-character represents a single bond or a double bond; R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R.sup.1A is absent, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; R.sup.Z1 is absent, hydrogen, cyano, C1-C6 alkyl, or C1-C6 alkyl; R.sup.Z2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; each R.sup.2A is independently selected from: (i) halogen, (ii) cyano, (iii) hydroxyl, (iv) NR.sup.AR.sup.B, (v) C(O)NR.sup.AR.sup.B, ##STR00389## (vii) NHC(O)R.sup.C, (viii) C(O)NR.sup.DR.sup.E, (ix) C(O)OR.sup.F, (x) SO.sub.2R.sup.F, (xi) NHSO.sub.2R.sup.F, (xii) SO.sub.2NR.sup.FR.sup.G, (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, (xiv) C1-C6 haloalkyl, (xv) C1-C6 hydroxyalkyl, (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; each R.sup.3A and R.sup.3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.5B, or C(O)NR.sup.5AR.sup.5B; R.sup.5A and R.sup.5B are independently selected from hydrogen, CJ-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; R.sup.6 is hydrogen, halogen, or C1-C6 alkyl; R.sup.7 is hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C(O)C1-C6 alkyl, NH(CN), 5-6 membered heteroaryl, NR.sup.7AR.sup.7B, NR.sup.7AC(O)R.sup.7B, C(R.sup.A)NR.sup.7AR.sup.7B, or C(O)NR.sup.7AR.sup.7B, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.7AR.sup.7B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.7AR.sup.7B, or when each custom-character adjacent to CR.sup.7 is a single bond, R.sup.7 can be oxo; each R.sup.7A and R.sup.7B are independently selected from hydrogen, C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo; X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or ##STR00390## W is NR.sup.3B or O; Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 5-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with R.sup.Y1, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1; R.sup.Y1 is SO.sub.2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    2. The compound of claim 1, wherein the compound is a compound of Formula (II).

    3. The compound of claim 1, wherein the compound is a compound of Formula (III).

    4. The compound of claim 1 or 3, wherein Z.sup.1 is S.

    5. The compound of claim 1 or 3, wherein Z.sup.1 is O.

    6. The compound of claim 1 or 3, wherein Z.sup.1 is S(O.sub.2).

    7. The compound of claim 1, wherein the compound is a compound of Formula (I).

    8. The compound of claim 1 or 7, wherein Q is CR.sup.1.

    9. The compound of any one of claims 1-8, wherein R.sup.2 is phenyl optionally substituted with 1-3 independently selected R.sup.2A.

    10. The compound of any one of claims 1-8, wherein R.sup.2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.2A.

    11. The compound of any one of claims 1-8, wherein R.sup.2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R.sup.2A.

    12. The compound of any one of claims 1-8, wherein R.sup.2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R.sup.2A.

    13. The compound of any one of claims 1-8, wherein R.sup.2 is C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C.

    14. The compound of any one of claims 1-8, R.sup.2 is C1-C6 alkoxyalkyl

    15. The compound of any one of claims 1-14, wherein X is a bond.

    16. The compound of any one of claims 1-14, wherein X is CH.sub.2.

    17. The compound of any one of claims 1-14, wherein X is CH(CH.sub.3).

    18. The compound of any one of claims 1-14, wherein X is C(CH.sub.3).sub.2.

    19. The compound of any one of claims 1-14, wherein X is ##STR00391##

    20. The compound of any one of claims 1-19, wherein W is O.

    21. The compound of any one of claims 1-19, wherein W is NR.sup.3B.

    22. The compound of any one of claims 1-21, wherein Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y.

    23. The compound of any one of claims 1-21, wherein Y is naphthyl optionally substituted with 1-3 independently selected R.sup.Y.

    24. The compound of any one of claims 1-21, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y.

    25. The compound of any one of claims 1-24, wherein R.sup.Y is halogen.

    26. The compound of any one of claims 1-24, wherein R.sup.Y is hydroxyl.

    27. The compound of any one of claims 1-24, wherein R.sup.Y is cyano.

    28. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 haloalkyl.

    29. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 alkoxy.

    30. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 haloalkoxy.

    31. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 hydroxyalkyl.

    32. The compound of any one of claims 1-24, wherein R.sup.Y is NHC(O)R.sup.C.

    33. The compound of any one of claims 1-24, wherein R.sup.Y is C(O)NHR.sup.Y1.

    34. The compound of any one of claims 1-24, wherein R.sup.Y is CO.sub.2R.sup.A.

    35. The compound of any one of claims 1-24, wherein R.sup.Y is SO.sub.2NR.sup.FR.sup.G.

    36. The compound of any one of claims 1-24, wherein R.sup.Y is NHSO.sub.2R.sup.F.

    37. The compound of any one of claims 1-24, wherein R.sup.Y is S(O)(NR.sup.F)R.sup.G.

    38. The compound of any one of claims 1-24, wherein R.sup.Y is SO.sub.2(C1-C6 alkyl).

    39. The compound of any one of claims 1-24, wherein R.sup.Y is C(O)NR.sup.AR.sup.B.

    40. The compound of any one of claims 1-24, wherein R.sup.Y is 4-6 membered heteroaryl.

    41. The compound of any one of claims 1-24, wherein R.sup.Y is heteroaralkyl.

    42. The compound of any one of claims 1-24, wherein R.sup.Y is 4-6 membered heterocyclyl.

    43. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1.

    44. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1.

    45. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl substituted with R.sup.Y1.

    46. The compound of any one of claims 1-24, wherein R.sup.Y is C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl.

    47. The compound of any one of claims 43-45, wherein R.sup.Y1 is SO.sub.2(C1-C6 alkyl).

    48. The compound of any one of claims 43-45, wherein R.sup.Y1 is C1-C6 alkyl optionally substituted with oxo.

    49. The compound of any one of claims 43-45, wherein R.sup.Y1 is hydroxyl.

    50. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt of any of the foregoing.

    51. A compound selected from the group consisting of the compounds in Table B, or a pharmaceutically acceptable salt of any of the foregoing.

    52. A compound selected from the group consisting of the compounds in Table C, or a pharmaceutically acceptable salt of any of the foregoing.

    53. A pharmaceutical composition comprising a compound of any one of claims 1-52, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

    54. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-52, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 53.

    55. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-52, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 53.

    56. A method of treating a PI3K-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3K-associated cancer a therapeutically effective amount of a compound of any one of claims 1-52 or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 53.

    57. A method for inhibiting mutant PI3K activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-52, or a pharmaceutically acceptable salt of any of the foregoing.

    Description

    DETAILED DESCRIPTION

    [0289] This disclosure provides compounds of Formula (I), Formula (II), or Formula (III), and pharmaceutically acceptable salts of any of the foregoing, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3K). These compounds are useful for treating a disease in which increased PI3K activation contributes to the pathology, symptoms, and/or progression of the disease (e.g., cancer) in a subject.

    Formulae (I), Formula (II), and Formula (III) Compounds

    [0290] Some embodiments provide a compound of Formula (I):

    ##STR00025## [0291] or a pharmaceutically acceptable salt thereof, wherein: [0292] Q is NR.sup.1A or CR.sup.1; [0293] Z is NR.sup.Z1 or CR.sup.Z2, wherein one or both of Q and Z is N; [0294] each custom-character represents a single bond or a double bond; [0295] R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; [0296] R.sup.1A is absent, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; [0297] R.sup.Z1 is absent, hydrogen, cyano, C1-C6 alkyl, or C1-C6 alkyl; [0298] R.sup.Z2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; [0299] R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A, C1-C6 alkoxyalkyl optionally substituted with C(O)NR.sup.AR.sup.C, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; [0300] each R.sup.2A is independently selected from: [0301] (i) halogen, [0302] (ii) cyano, [0303] (iii) hydroxyl, [0304] (iv) NR.sup.AR.sup.B, [0305] (v) C(O)NR.sup.AR.sup.B2,

    ##STR00026## [0306] (vii) NHC(O)R.sup.C, [0307] (viii) C(O)NR.sup.DR.sup.E, [0308] (ix) C(O)OR.sup.F, [0309] (x) SO.sub.2R.sup.F, [0310] (xi) NHSO.sub.2R.sup.F, [0311] (xii) SO.sub.2NR.sup.FR.sup.G, [0312] (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0313] (xiv) C1-C6 haloalkyl, [0314] (xv) C1-C6 hydroxyalkyl, [0315] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, [0316] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0317] (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, [0318] (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and [0319] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; [0320] each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, SO.sub.2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; [0321] each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; [0322] each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; [0323] each R.sup.3A and R.sup.3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; [0324] R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; [0325] R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.5B, or C(O)NR.sup.5AR.sup.5B; [0326] R.sup.5A and R.sup.5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; [0327] R.sup.6 is hydrogen, halogen, or C1-C6 alkyl; [0328] R.sup.7 is hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C(O)C1-C6 alkyl, NH(CN), 5-6 membered heteroaryl, NR.sup.7AR.sup.7B, NR.sup.7AC(O)R.sup.7B, C(R.sup.A)NR.sup.7AR.sup.7B, or C(O)NR.sup.7AR.sup.7B, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.7AR.sup.7B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.7AR.sup.7B, or when each custom-character adjacent to CR.sup.7 is a single bond, R.sup.7 can be oxo; [0329] each R.sup.7A and R.sup.7B are independently selected from hydrogen, C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo; [0330] X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or

    ##STR00027## [0331] W is NR.sup.3B or O; [0332] Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; [0333] each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with R.sup.Y1, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1; [0334] R.sup.Y1 is SO.sub.2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and [0335] each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [0336] In some embodiments, Q is NR.sup.1A.

    [0337] In some embodiments Q is CR.sup.1.

    [0338] In some embodiments, Z is NR.sup.Z1.

    [0339] In some embodiments, Z is CR.sup.Z2.

    [0340] In some embodiments, Q is NR.sup.1A and Z is NR.sup.Z1.

    [0341] Some embodiments provide a compound of Formula (I-A):

    ##STR00028## [0342] or a pharmaceutically acceptable salt thereof, wherein: [0343] Q is N or CR.sup.1; [0344] R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen; [0345] R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; [0346] each R.sup.2A is independently selected from: [0347] (i) halogen, [0348] (ii) cyano, [0349] (iii) hydroxyl, [0350] (iv) NR.sup.AR.sup.B, [0351] (v) C(O)NR.sup.AR.sup.B,

    ##STR00029## [0352] (vii) NHC(O)R.sup.C, [0353] (viii) C(O)NR.sup.DR.sup.E, [0354] (ix) C(O)OR.sup.F, [0355] (x) SO.sub.2R.sup.F, [0356] (xi) NHSO.sub.2R.sup.F, [0357] (xii) SO.sub.2NR.sup.FR.sup.G, [0358] (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0359] (xiv) C1-C6 haloalkyl, [0360] (xv) C1-C6 hydroxyalkyl, [0361] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, [0362] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0363] (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, [0364] (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and [0365] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; [0366] each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; [0367] each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; [0368] each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; [0369] each R.sup.3A and R.sup.3B is independently selected from hydrogen and C1-C6 alkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; [0370] R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; [0371] R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.5B, or C(O)NR.sup.5AR.sup.5B; [0372] R.sup.5A and R.sup.5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; [0373] R.sup.6 is hydrogen, halogen, or C1-C6 alkyl; [0374] R.sup.7 is hydrogen, halogen, hydroxyl, cyano, NR.sup.7AR.sup.7B, NR.sup.7AC(O)R.sup.7B, or C(O)NR.sup.7AR.sup.7B; [0375] R.sup.7A and R.sup.7B are independently selected from hydrogen, C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo; [0376] X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or

    ##STR00030## [0377] Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; [0378] each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1; [0379] R.sup.Y1 is SO.sub.2(C1-C6 alkyl) or C1-C6 alkyl optionally substituted with oxo; and [0380] each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [0381] In some embodiments, Q is N.

    [0382] In some embodiments Q is CR.sup.1.

    [0383] Some embodiments provide a compound of Formula (II):

    ##STR00031##

    or a pharmaceutically acceptable salt thereof, wherein: [0384] R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; [0385] R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A, C1-C6 alkoxyalkyl optionally substituted with C(O)NR.sup.AR.sup.C, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; [0386] each R.sup.2A is independently selected from: [0387] (i) halogen, [0388] (ii) cyano, [0389] (iii) hydroxyl, [0390] (iv) NR.sup.AR.sup.B, [0391] (v) C(O)NR.sup.AR.sup.B,

    ##STR00032## [0392] (vii) NHC(O)R.sup.C, [0393] (viii) C(O)NR.sup.DR.sup.E, [0394] (ix) C(O)OR.sup.F, [0395] (x) SO.sub.2R.sup.F, [0396] (xi) NHSO.sub.2R.sup.F, [0397] (xii) SO.sub.2NR.sup.FR.sup.G, [0398] (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0399] (xiv) C1-C6 haloalkyl, [0400] (xv) C1-C6 hydroxyalkyl, [0401] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, [0402] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0403] (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, [0404] (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and [0405] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; [0406] each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, SO.sub.2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; [0407] each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; [0408] each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; [0409] each R.sup.3A and R.sup.3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; [0410] R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; [0411] R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.5B, or C(O)NR.sup.5AR.sup.5B; [0412] R.sup.5A and R.sup.5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; [0413] R.sup.6 is hydrogen, halogen, or C1-C6 alkyl; [0414] X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or

    ##STR00033## [0415] W is NR.sup.3B or O; [0416] Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; [0417] each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with R.sup.Y1, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1; [0418] R.sup.Y1 is SO.sub.2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and [0419] each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [0420] Some embodiments provide a compound of Formula (II-A):

    ##STR00034## [0421] or a pharmaceutically acceptable salt thereof, wherein: [0422] R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen; [0423] R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R.sup.2A, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; [0424] each R.sup.2A is independently selected from: [0425] (i) halogen, [0426] (ii) cyano, [0427] (iii) hydroxyl, [0428] (iv) NR.sup.AR.sup.B, [0429] (v) C(O)NR.sup.AR.sup.B,

    ##STR00035## [0430] (vii) NHC(O)R.sup.C, [0431] (viii) C(O)NR.sup.DR.sup.E, [0432] (ix) C(O)OR.sup.F, [0433] (x) SO.sub.2R.sup.F, [0434] (xi) NHSO.sub.2R.sup.F, [0435] (xii) SO.sub.2NR.sup.FR.sup.G, [0436] (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0437] (xiv) C1-C6 haloalkyl, [0438] (xv) C1-C6 hydroxyalkyl, [0439] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, [0440] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0441] (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, [0442] (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and [0443] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; [0444] each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; [0445] each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; [0446] each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; [0447] each R.sup.3A and R.sup.3B is independently selected from hydrogen and C1-C6 alkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; [0448] R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; [0449] R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.SB, or C(O)NR.sup.5AR.sup.5B; [0450] R.sup.5A and R.sup.5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; [0451] R.sup.6 is hydrogen, halogen, or C1-C6 alkyl; [0452] X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or

    ##STR00036## [0453] Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; [0454] each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1; [0455] R.sup.Y1 is SO.sub.2(C1-C6 alkyl) or C1-C6 alkyl optionally substituted with oxo; and [0456] each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [0457] Some embodiments provide a compound of Formula (III):

    ##STR00037##

    or a pharmaceutically acceptable salt thereof, wherein: [0458] Z.sup.1 is S, S(O.sub.2), or O; [0459] R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; [0460] R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A, C1-C6 alkoxyalkyl optionally substituted with C(O)NR.sup.AR.sup.C, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; [0461] each R.sup.2A is independently selected from: [0462] (i) halogen, [0463] (ii) cyano, [0464] (iii) hydroxyl, [0465] (iv) NR.sup.AR.sup.B, [0466] (v) C(O)NR.sup.AR.sup.B,

    ##STR00038## [0467] (vii) NHC(O)R.sup.C, [0468] (viii) C(O)NR.sup.DR.sup.E, [0469] (ix) C(O)OR.sup.F, [0470] (x) SO.sub.2R.sup.F, [0471] (xi) NHSO.sub.2R.sup.F, [0472] (xii) SO.sub.2NR.sup.FR.sup.G, [0473] (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0474] (xiv) C1-C6 haloalkyl, [0475] (xv) C1-C6 hydroxyalkyl, [0476] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, [0477] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0478] (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, [0479] (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and [0480] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; [0481] each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, SO.sub.2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; [0482] each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; [0483] each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; [0484] each R.sup.3A and R.sup.3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; [0485] R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; [0486] R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.5B, or C(O)NR.sup.5AR.sup.5B; [0487] R.sup.5A and R.sup.5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; [0488] R.sup.6 is hydrogen, halogen, or C1-C6 alkyl;

    [0489] X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or

    ##STR00039## [0490] W is NR.sup.3B or O; [0491] Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; [0492] each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with R.sup.Y1, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1; [0493] R.sup.Y1 is SO.sub.2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and [0494] each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [0495] Some embodiments provide a compound of Formula (III-A):

    ##STR00040## [0496] or a pharmaceutically acceptable salt thereof, wherein: [0497] Z is S, S(O.sub.2), or O; [0498] R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen; [0499] R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; [0500] each R.sup.2A is independently selected from: [0501] (i) halogen, [0502] (ii) cyano, [0503] (iii) hydroxyl, [0504] (iv) NR.sup.AR.sup.B, [0505] (v) C(O)NR.sup.AR.sup.B,

    ##STR00041## [0506] (vii) NHC(O)R.sup.C, [0507] (viii) C(O)NR.sup.DR.sup.E, [0508] (ix) C(O)OR.sup.F, [0509] (x) SO.sub.2R.sup.F, [0510] (xi) NHSO.sub.2R.sup.F, [0511] (xii) SO.sub.2NR.sup.FR.sup.G, [0512] (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0513] (xiv) C1-C6 haloalkyl, [0514] (xv) C1-C6 hydroxyalkyl, [0515] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, [0516] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0517] (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, [0518] (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and [0519] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; [0520] each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; [0521] each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; [0522] each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; [0523] each R.sup.3A and R.sup.3B is independently selected from hydrogen and C1-C6 alkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; [0524] R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; [0525] R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.5B, or C(O)NR.sup.5AR.sup.5B; [0526] R.sup.5A and R.sup.5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; [0527] R.sup.6 is hydrogen, halogen, or C1-C6 alkyl; [0528] X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or

    ##STR00042## [0529] Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; [0530] each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.1; [0531] R.sup.Y1 is SO.sub.2(C1-C6 alkyl) or C1-C6 alkyl optionally substituted with oxo; and [0532] each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [0533] In some embodiments, Z.sup.1 is S.

    [0534] In some embodiments, Z.sup.1 is S(O.sub.2).

    [0535] In some embodiments, Z.sup.1 is O.

    [0536] In some embodiments, R.sup.1 is hydrogen.

    [0537] In some embodiments, R.sup.1 is cyano.

    [0538] In some embodiments, R.sup.11 is C3-C6 cycloalkyl. In some embodiments, R.sup.1 is cyclopropyl or cyclobutyl.

    [0539] In some embodiments, R.sup.1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen. In some embodiments, R.sup.1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen. In some embodiments, R.sup.11 is C1-C6 alkyl substituted with phenyl substituted with halogen. In some embodiments, R.sup.1 is para-fluorobenzyl. In some embodiments, R.sup.11 is C1-C6 alkyl substituted with phenyl. In some embodiments, R.sup.1 is benzyl. In some embodiments, R.sup.1 is ethyl-1-phenyl or ethyl-2-phenyl. In some embodiments, R.sup.11 is C1-C6 alkyl. In some embodiments, R.sup.1 is methyl, ethyl, or isopropyl. In some embodiments, R.sup.1 is methyl.

    [0540] In some embodiments, R.sup.1 is C1-C6 thioalkyl. In some embodiments, R.sup.1 is C1-C3 thioalkyl. In some embodiments, R.sup.1 is thiomethyl, thioethyl, or thiopropyl. In some embodiments, R.sup.1 is methyl-thiomethyl, methyl-thioethyl, or ethyl-thiomethyl. In some embodiments, R.sup.1 is thiomethyl.

    [0541] In some embodiments, R.sup.1 is C1-C6 haloalkyl. In some embodiments, R.sup.1 is C1-C3 haloalkyl. In some embodiments, R.sup.1 is C1-C3 fluoroalkyl. In some embodiments, R.sup.1 is CF.sub.3. In some embodiments, R.sup.1 is CHF.sub.2.

    [0542] In some embodiments, R.sup.1 is C1-C6 alkoxy. In some embodiments, R.sup.1 is C1-C3 alkoxy. In some embodiments, R.sup.1 is OCH.sub.3, OCH.sub.2CH.sub.3, or OCH.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.1 is OCH.sub.3.

    [0543] In some embodiments, R.sup.1 is C1-C6 alkoxyalkyl. In some embodiments, R.sup.1 is C1-C3 alkoxyalkyl. In some embodiments, R.sup.1 is CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, or CH.sub.2CH.sub.2OCH.sub.3. In some embodiments, R.sup.1 is CH.sub.2OCH.sub.3.

    [0544] In some embodiments, R.sup.1A is absent.

    [0545] In some embodiments, R.sup.1A is hydrogen.

    [0546] In some embodiments, R.sup.1A is C1-C6 alkyl. In some embodiments, R.sup.1A is methyl, ethyl, or isopropyl. In some embodiments, R.sup.1A is methyl.

    [0547] In some embodiments, R.sup.1A is C1-C6 haloalkyl. In some embodiments, R.sup.1A is C1-C3 haloalkyl. In some embodiments, R.sup.1A is C1-C3 fluoroalkyl. In some embodiments, R.sup.1A is trifluoromethyl. In some embodiments, R.sup.1A is CHF.sub.2.

    [0548] In some embodiments, R.sup.1A is C1-C6 thioalkyl. In some embodiments, R.sup.1A is C1-C3 thioalkyl. In some embodiments, R.sup.1A is thiomethyl, thioethyl, or thiopropyl. In some embodiments, R.sup.1A is methyl-thiomethyl, methyl-thioethyl, or ethyl-thiomethyl. In some embodiments, R.sup.1A is thiomethyl.

    [0549] In some embodiments, R.sup.1A is C1-C6 alkoxy. In some embodiments, R.sup.1A is C1-C3 alkoxy.

    [0550] In some embodiments, R.sup.1A is OCH.sub.3, OCH.sub.2CH.sub.3, or OCH.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.1A is OCH.sub.3.

    [0551] In some embodiments, R.sup.1A is C1-C6 alkoxyalkyl. In some embodiments, R.sup.1A is C1-C3 alkoxyalkyl. In some embodiments, R.sup.1A is CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, or CH.sub.2CH.sub.2OCH.sub.3. In some embodiments, R.sup.1A is CH.sub.2OCH.sub.3.

    [0552] In some embodiments, R.sup.Z1 is absent.

    [0553] In some embodiments, R.sup.Z1 is hydrogen.

    [0554] In some embodiments, R.sup.Z1 is cyano.

    [0555] In some embodiments, R.sup.Z1 is C1-C6 alkyl. In some embodiments, R.sup.Z1 is methyl, ethyl, or isopropyl. In some embodiments, R.sup.Z1 is methyl.

    [0556] In some embodiments, R.sup.Z1 is C1-C6 haloalkyl. In some embodiments, R.sup.Z1 is C1-C3 haloalkyl. In some embodiments, R.sup.Z1 is trifluoromethyl.

    [0557] In some embodiments, R.sup.Z2 is hydrogen.

    [0558] In some embodiments, R.sup.Z2 is C1-C6 alkyl. In some embodiments, R.sup.Z2 is methyl, ethyl, or isopropyl. In some embodiments, R.sup.Z2 is methyl.

    [0559] In some embodiments, R.sup.Z2 is C1-C6 haloalkyl. In some embodiments, R.sup.Z2 is C1-C3 haloalkyl. In some embodiments, R.sup.Z2 is trifluoromethyl.

    [0560] In some embodiments, R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is phenyl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is phenyl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is phenyl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is phenyl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is phenyl.

    [0561] In some embodiments, R.sup.2 is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-10 membered heteroaryl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is 5-10 membered heteroaryl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-10 membered heteroaryl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-10 membered heteroaryl.

    [0562] In some embodiments, R.sup.2 is 6 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is 6 membered heteroaryl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 6 membered heteroaryl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is 6 membered heteroaryl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 6 membered heteroaryl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is 6 membered heteroaryl.

    [0563] In some embodiments, R.sup.2 is 9 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is 9 membered heteroaryl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 9 membered heteroaryl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is 9 membered heteroaryl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 9 membered heteroaryl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is 9 membered heteroaryl.

    [0564] In some embodiments, the heteroaryl of R.sup.2 is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, or isoquinolinyl. In some embodiments, the heteroaryl of R.sup.2 is pyridinyl or pyrimidinyl. In some embodiments, the heteroaryl of R.sup.2 is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline.

    [0565] In some embodiments, R.sup.2 is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered heterocyclyl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered heterocyclyl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered heterocyclyl.

    [0566] In some embodiments, R.sup.2 is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-8 membered heterocyclyl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is 5-8 membered heterocyclyl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-8 membered heterocyclyl.

    [0567] In some embodiments, the heterocyclyl of R.sup.2 is piperidinyl, piperazinyl, or morpholinyl.

    [0568] In some embodiments, R.sup.2 is 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered cycloalkyl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered cycloalkyl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered cycloalkyl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered cycloalkyl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is 4-10 membered cycloalkyl.

    [0569] In some embodiments, R.sup.2 is 5-7 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-7 membered cycloalkyl substituted with 1 or 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-7 membered cycloalkyl substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is 5-7 membered cycloalkyl substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-7 membered cycloalkyl optionally substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is 5-7 membered cycloalkyl.

    [0570] In some embodiments, the cycloalkyl of R.sup.2 is cyclopentyl, [1.1.1]bicyclopentyl, or cyclohexyl.

    [0571] In some embodiments, R.sup.2 is C1-C6 alkoxyalkyl optionally substituted with C(O)NR.sup.AR.sup.C. In some embodiments, R.sup.2 is C1-C6 alkoxyalkyl. In some embodiments, R.sup.2 is C1-C3 alkoxyalkyl. In some embodiments, R.sup.2 is CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2CH.sub.3, or CH.sub.2CH.sub.2OCH.sub.3. In some embodiments, R.sup.2 is CH.sub.2OCH.sub.3.

    [0572] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently halogen. In some embodiments, 1, 2, or 3 of R.sup.2A are independently fluoro or chloro. In some embodiments, 1 or 2 of R.sup.2A are independently fluoro or chloro.

    [0573] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently cyano. In some embodiments, 1 or 2 of R.sup.2A are cyano.

    [0574] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently hydroxyl. In some embodiments, 1 or 2 of R.sup.2A are hydroxyl.

    [0575] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently NR.sup.AR.sup.B. In some embodiments, 1 or 2 of R.sup.2A are independently NR.sup.AR.sup.B.

    [0576] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C(O)NR.sup.AR.sup.B. In some embodiments, 1 or 2 of R.sup.2A are independently C(O)NR.sup.AR.sup.B.

    [0577] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently

    ##STR00043##

    In some embodiments, 1 or 2 of R.sup.2A are independently

    ##STR00044##

    [0578] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently NHC(O)R.sup.C. In some embodiments, 1 or 2 of R.sup.2A are independently NHC(O)R.sup.C.

    [0579] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C(O)NR.sup.DR.sup.E. In some embodiments, 1 or 2 of R.sup.2A are independently C(O)NR.sup.DR.sup.E.

    [0580] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C(O)OR.sup.F. In some embodiments, 1 or 2 of R.sup.2A are independently C(O)OR.sup.F.

    [0581] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently SO.sub.2R.sup.F. In some embodiments, 1 or 2 of R.sup.2A are independently SO.sub.2R.sup.F.

    [0582] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently NHSO.sub.2R.sup.F. In some embodiments, 1 or 2 of R.sup.2A are independently NHSO.sub.2R.sup.F.

    [0583] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently SO.sub.2NR.sup.FR.sup.G. In some embodiments, 1 or 2 of R.sup.2A are independently SO.sub.2NR.sup.FR.sup.G.

    [0584] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B. In some embodiments, 1, 2, or 3 of R.sup.2A are independently NHC(O)C1-C6 alkyl substituted with NR.sup.AR.sup.B. In some embodiments, 1, 2, or 3 of R.sup.2A are independently NHC(O)C1-C6 alkyl. In some embodiments, 1 or 2 of R.sup.2A are independently NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B. In some embodiments, 1 or 2 of R.sup.2A are independently NHC(O)C1-C6 alkyl substituted with NR.sup.AR.sup.B. In some embodiments, 1 or 2 of R.sup.2A are independently NHC(O)C1-C6 alkyl.

    [0585] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R.sup.2A are independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R.sup.2A are trifluoromethyl.

    [0586] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R.sup.2A are independently C1-C3 hydroxyalkyl.

    [0587] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B. In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B. In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 5-10 membered heteroaryl.

    [0588] In some embodiments, 1 of R.sup.2A is 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B. In some embodiments, 1 of R.sup.2A is 5-6 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B. In some embodiments, 1 of R.sup.2A is 5-6 membered heteroaryl.

    [0589] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B. In some embodiments, 1 of R.sup.2A is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B.

    [0590] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B. In some embodiments, 1 of R.sup.2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B.

    [0591] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl substituted with NR.sup.AR.sup.B. In some embodiments, 1 of R.sup.2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl substituted with NR.sup.AR.sup.B.

    [0592] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl. In some embodiments, 1 of R.sup.2A is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl.

    [0593] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently 4-10 membered heterocyclyl.

    [0594] In some embodiments, 1 of R.sup.2A is 4-10 membered heterocyclyl.

    [0595] In some embodiments, 1, 2, or 3 of R.sup.2A are independently C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl.

    [0596] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl.

    [0597] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl.

    [0598] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, and 4-10 membered heterocyclyl.

    [0599] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkyl. In some embodiments, 1, 2, or 3 of R.sup.2A are independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of R.sup.2A are methyl. In some embodiments, 1 or 2 of R.sup.2A are independently C1-C6 alkyl. In some embodiments, 1 or 2 of R.sup.2A are independently C1-C3 alkyl. In some embodiments, 1 or 2 of R.sup.2A are methyl.

    [0600] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl.

    [0601] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkoxy substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl.

    [0602] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkoxy substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl.

    [0603] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkoxy substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl.

    [0604] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C1-C6 alkoxy.

    [0605] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

    [0606] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

    [0607] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl.

    [0608] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl.

    [0609] In some embodiments, 1, 2, 3, or 4 of R.sup.2A are independently C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R.sup.2A are independently C3-C6 cycloalkyl.

    [0610] In some embodiments, R.sup.2 is piperidinyl substituted with 1-2 independently selected R.sup.2A.

    [0611] In some embodiments, R.sup.2 is piperidinyl substituted with 2-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is morpholinyl substituted with 2-4 independently selected R.sup.2A. In some embodiments, R.sup.2 is morpholinyl. In some embodiments, R.sup.2 is piperazinyl substituted with 1-2 independently selected R.sup.2A.

    [0612] In some embodiments, R.sup.2 is phenyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is pyridinyl substituted with 1-2 independently selected R.sup.2A.

    [0613] In some embodiments, R.sup.2 is indolyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is indazolyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 7-azaindolyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 7-azaindazolyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 1,2-dihydro-3H-indazol-3-one substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is isoindolinyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is isoindolinyl. In some embodiments, R.sup.2 is 2-indolinone substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is benzimidazolyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is imidazopyridinyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is 1,3-dihydro-2H-benzo[d]imidazol-2-onyl substituted with 1-2 independently selected R.sup.2A. In some embodiments, R.sup.2 is [1,2,4]triazolo[1,5-a]pyridine substituted with 1-2 independently selected R.sup.2A.

    [0614] In some embodiments, one R.sup.2A is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, or hydroxyl, and the other R.sup.2A are independently selected from C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, hydroxyl, halogen, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B,

    ##STR00045##

    NHC(O)R.sup.C, C(O)NR.sup.DR.sup.E, C(O)OR.sup.F, SO.sub.2R.sup.F, NHSO.sub.2R.sup.F, SO.sub.2NR.sup.FR.sup.G, NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

    [0615] In some embodiments, each R.sup.2A is independently selected from halogen, methyl, ethyl, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NHOH, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, and acetyl.

    [0616] In some embodiments, 1, 2, or 3 R.sup.2A are independently selected from halogen, methyl, ethyl, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NHOH, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, and acetyl.

    [0617] In some embodiments, 1 or 2 R.sup.2A are independently selected from halogen, methyl, ethyl, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NHOH, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, and acetyl.

    [0618] In some embodiments, R.sup.2 is substituted with 1 R.sup.2A. In some embodiments, R.sup.2 is substituted with 2 independently selected R.sup.2A. In some embodiments, R.sup.2 is substituted with 3 independently selected R.sup.2A. In some embodiments, R.sup.2 is substituted with 4 independently selected R.sup.2A.

    [0619] In some embodiments, R.sup.2 is substituted with 1 R.sup.2A. In some embodiments, R.sup.2A is halogen. In some embodiments, R.sup.2A is fluoro or chloro. In some embodiments, R.sup.2A is cyano. In some embodiments, R.sup.2A is hydroxyl. In some embodiments, R.sup.2A is R.sup.2A, NR.sup.AR.sup.B. In some embodiments, R.sup.2A is C(O)NR.sup.AR.sup.B. In some embodiments, R.sup.2A is

    ##STR00046##

    In some embodiments, R.sup.2A is NHC(O)R.sup.C. In some embodiments, C(O)NR.sup.DR.sup.B. In some embodiments, R.sup.2A is C(O)OR.sup.F. In some embodiments, R.sup.2A is SO.sub.2R.sup.F. In some embodiments, R.sup.2A is NHSO.sub.2R.sup.F. In some embodiments, R.sup.2A is NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B. In some embodiments, R.sup.2A is C1-C6 haloalkyl. In some embodiments, R.sup.2A is C1-C6 hydroxyalkyl. In some embodiments, R.sup.2A is 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B. In some embodiments, R.sup.2A is 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B. In some embodiments, R.sup.2A is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B In some embodiments, R.sup.2A is 4-10 membered heterocyclyl. In some embodiments, R.sup.2A is C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl. In some embodiments, R.sup.2A is C1-C6 alkyl. In some embodiments, R.sup.2A is C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl. In some embodiments, R.sup.2A is C1-C6 alkoxy.

    [0620] In some embodiments, R.sup.2A is C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, R.sup.2A is selected from halogen, methyl, ethyl, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NHOH, SO.sub.2NH.sub.2, SO.sub.2NHCH.sub.3, SO.sub.2N(CH.sub.3).sub.2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, and acetyl.

    [0621] In some embodiments, R.sup.2 is C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C. In some embodiments, R.sup.2 is C1-C6 alkoxy substituted with C(O)NR.sup.AR.sup.C. In some embodiments, R.sup.2 is C3-C6 alkoxy substituted with C(O)NR.sup.AR.sup.C. In some embodiments, R.sup.2 is C1-C6 alkoxy.

    [0622] In some embodiments, X is a bond.

    [0623] In some embodiments, X is CH.sub.2.

    [0624] In some embodiments, X is CH(CH.sub.3).

    [0625] In some embodiments, X is C(CH.sub.3).sub.2.

    [0626] In some embodiments, X is

    ##STR00047##

    [0627] In some embodiments, W is O.

    [0628] In some embodiments, R.sup.3A is hydrogen.

    [0629] In some embodiments, R.sup.3A is C1-C6 alkyl. In some embodiments, R.sup.3A is methyl or ethyl.

    [0630] In some embodiments, R.sup.3A is methyl.

    [0631] In some embodiments, R.sup.3A is C1-C6 alkoxy. In some embodiments, R.sup.3A is C1-C3 alkoxy.

    [0632] In some embodiments, R.sup.3A is OCH.sub.3, OCH.sub.2CH.sub.3, or OCH.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.3A is OCH.sub.3.

    [0633] In some embodiments, R.sup.3A is C1-C6 haloalkyl. In some embodiments, R.sup.3A is C1-C3 haloalkyl. In some embodiments, R.sup.3A is C1-C3 fluoroalkyl. In some embodiments, R.sup.3A is CF.sub.3. In some embodiments, R.sup.3A is CHF.sub.2.

    [0634] In some embodiments, W is NR.sup.3B.

    [0635] In some embodiments, one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is C1-C6 alkyl. In some embodiments, one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is methyl. In some embodiments, each of R.sup.3A and R.sup.3B is hydrogen. In some embodiments, each of R.sup.3A and R.sup.3B is an independently selected C1-C6 alkyl. In some embodiments, each of R.sup.3A and R.sup.3B is methyl.

    [0636] In some embodiments, one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is C1-C6 alkoxy. In some embodiments, one of R.sup.3A and R.sup.3B is C1-C6 alkyl and the other of R.sup.3A and R.sup.3B is C1-C6 alkoxy. In some embodiments, R.sup.3A is C1-C6 alkoxy. In some embodiments, R.sup.3A is C1-C3 alkoxy. In some embodiments, R.sup.3A is OCH.sub.3, OCH.sub.2CH.sub.3, or OCH.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.3A is OCH.sub.3.

    [0637] In some embodiments, one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is C1-C6 haloalkyl. In some embodiments, one of R.sup.3A and R.sup.3B is C1-C6 alkyl and the other of R.sup.3A and R.sup.3B is C1-C6 haloalkyl. In some embodiments, R.sup.3A is C1-C6 haloalkyl. In some embodiments, R.sup.3A is C1-C3 haloalkyl. In some embodiments, R.sup.3A is C1-C3 fluoroalkyl. In some embodiments, R.sup.3A is CF.sub.3. In some embodiments, R.sup.3A is CHF.sub.2.

    [0638] In some embodiments, R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. In some embodiments, R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 5-6 membered heterocyclyl group.

    [0639] In some embodiments, Y is phenyl optionally substituted with R.sup.Y, naphthyl substituted with R.sup.Y, or 5-10 membered heteroaryl substituted with R.sup.Y.

    [0640] In some embodiments, Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y. In some embodiments, Y is phenyl substituted with 1 or 2 independently selected R.sup.Y.

    [0641] In some embodiments, Y is phenyl substituted with 1 R.sup.Y. In some embodiments, Y is phenyl substituted with 2 independently selected R.sup.Y. In some embodiments, Y is phenyl optionally substituted with 3 independently selected R.sup.Y. In some embodiments, Y is phenyl.

    [0642] In some embodiments, Y is naphthyl optionally substituted with 1-3 independently selected R.sup.Y. In some embodiments, Y is naphthyl substituted with 1 or 2 independently selected R.sup.Y. In some embodiments, Y is naphthyl substituted with 1 R.sup.Y. In some embodiments, Y is naphthyl substituted with 2 independently selected R.sup.Y. In some embodiments, Y is naphthyl optionally substituted with 3 independently selected R.sup.Y. In some embodiments, Y is naphthyl.

    [0643] In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y. In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R.sup.Y. In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 R.sup.Y. In some embodiments, Y is 5-10 membered heteroaryl substituted with 2 independently selected R.sup.Y. In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 3 independently selected R.sup.Y. In some embodiments, Y is 5-10 membered heteroaryl.

    [0644] In some embodiments, Y is 6 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y. In some embodiments, Y is 6 membered heteroaryl substituted with 1 or 2 independently selected R.sup.Y. In some embodiments, Y is 6 membered heteroaryl substituted with 1 R.sup.Y. In some embodiments, Y is 6 membered heteroaryl substituted with 2 independently selected R.sup.Y. In some embodiments, Y is 6 membered heteroaryl optionally substituted with 3 independently selected R.sup.Y. In some embodiments, Y is 6 membered heteroaryl.

    [0645] In some embodiments, Y is 9 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y. In some embodiments, Y is 9 membered heteroaryl substituted with 1 or 2 independently selected R.sup.Y. In some embodiments, Y is 9 membered heteroaryl substituted with 1 R.sup.Y. In some embodiments, Y is 9 membered heteroaryl substituted with 2 independently selected R.sup.Y. In some embodiments, Y is 9 membered heteroaryl optionally substituted with 3 independently selected R.sup.Y. In some embodiments, Y is 9 membered heteroaryl.

    [0646] In some embodiments, 1, 2, or 3 of R.sup.Y is independently halogen. In some embodiments, 1, 2, or 3 of R.sup.Y is independently chloro or fluoro. In some embodiments, 1 or 2 of R.sup.Y is independently chloro or fluoro.

    [0647] In some embodiments, 1, 2, or 3 of R.sup.Y is hydroxyl. In some embodiments, 1 or 2 of R.sup.Y is hydroxyl.

    [0648] In some embodiments, 1, 2, or 3 of R.sup.Y is cyano. In some embodiments, 1 or 2 of R.sup.Y is cyano.

    [0649] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 haloalkyl optionally substituted with hydroxyl. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 haloalkyl substituted with hydroxyl. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R.sup.Y is trifluoromethyl. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 haloalkyl. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R.sup.Y is trifluoromethyl.

    [0650] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkoxy. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C3 alkoxy. In some embodiments, 1 or 2 of R.sup.Y is methoxy.

    [0651] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 haloalkoxy. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C3 haloalkoxy. In some embodiments, 1 or 2 of R.sup.Y is trifluoromethoxy.

    [0652] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C3 hydroxyalkyl. In some embodiments, 1 or 2 of R.sup.Y is independently mono-hydroxyl C1-C3 alkyl. In some embodiments, 1 or 2 of R.sup.Y is independently di-hydroxyl C2-C3 alkyl.

    [0653] In some embodiments, 1, 2, or 3 of R.sup.Y is independently NHC(O)R.sup.C. In some embodiments, 1 or 2 of R.sup.Y is independently NHC(O)R.sup.C. In some embodiments, 1 of R.sup.Y is NHC(O)R.sup.C. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is NHC(O)R.sup.C.

    [0654] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C(O)NHR.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C(O)NR.sup.1. In some embodiments, 1 of R.sup.Y is C(O)NHR.sup.Y1. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is C(O)NHR.sup.Y1.

    [0655] In some embodiments, 1, 2, or 3 of R.sup.Y is independently CO.sub.2R.sup.A. In some embodiments, 1 or 2 of R.sup.Y is independently CO.sub.2R.sup.A. In some embodiments, 1 of R.sup.Y is CO.sub.2R.sup.A. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is CO.sub.2R.sup.A. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is CO.sub.2H.

    [0656] In some embodiments, 1, 2, or 3 of R.sup.Y is independently SO.sub.2NR.sup.FR.sup.G. In some embodiments, 1 or 2 of R.sup.Y is independently SO.sub.2NR.sup.FR.sup.G. In some embodiments, 1 of R.sup.Y is SO.sub.2NR.sup.FR.sup.G. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is SO.sub.2NR.sup.FR.sup.G.

    [0657] In some embodiments, 1, 2, or 3 of R.sup.Y is independently NHSO.sub.2R.sup.F. In some embodiments, 1 or 2 of R.sup.Y is independently NHSO.sub.2R.sup.F. In some embodiments, 1 of R.sup.Y is NHSO.sub.2R.sup.F. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is NHSO.sub.2R.sup.F.

    [0658] In some embodiments, 1, 2, or 3 of R.sup.Y is independently S(O)(NR.sup.F)R.sup.G. In some embodiments, 1 or 2 of R.sup.Y is independently S(O)(NR.sup.F)R.sup.G. In some embodiments, 1 of R.sup.Y is S(O)(NR.sup.F)R.sup.G. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is S(O)(NR.sup.F)R.sup.G.

    [0659] In some embodiments, 1, 2, or 3 of R.sup.Y is independently SO.sub.2(C1-C6 alkyl). In some embodiments, 1 or 2 of R.sup.Y is independently SO.sub.2(C1-C6 alkyl). In some embodiments, 1 of R.sup.Y is SO.sub.2(C1-C6 alkyl). In some embodiments, 1 or 2 of R.sup.Y is SO.sub.2CH.sub.3. In some embodiments, 1 of R.sup.Y is SO.sub.2CH.sub.3. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is SO.sub.2CH.sub.3.

    [0660] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C(O)NR.sup.AR.sup.B. In some embodiments, 1 or 2 of R.sup.Y is independently C(O)NR.sup.AR.sup.B. In some embodiments, 1 of R.sup.Y is C(O)NR.sup.AR.sup.B. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is C(O)NR.sup.AR.sup.B.

    [0661] In some embodiments, 1, 2, or 3 of R.sup.Y is independently 4-6 membered heteroaryl. In some embodiments, 1 of R.sup.Y is 4-6 membered heteroaryl. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is 4-6 membered heteroaryl.

    [0662] In some embodiments, 1, 2, or 3 of R.sup.Y is independently heteroaralkyl. In some embodiments, 1 of R.sup.Y is independently heteroaralkyl.

    [0663] In some embodiments, 1, 2, or 3 of R.sup.Y is independently 4-6 membered heterocyclyl optionally substituted with R.sup.Y1. In some embodiments, 1 of R.sup.Y is 4-6 membered heterocyclyl. In some embodiments, 1 of R.sup.Y is 4-6 membered heterocyclyl substituted with R.sup.Y1. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is 4-6 membered heterocyclyl substituted with R.sup.Y1, where R.sup.Y1 is hydroxyl. In some embodiments, R.sup.Y is

    ##STR00048##

    In some embodiments, R.sup.Y is

    ##STR00049##

    [0664] In some embodiments, Y is selected from the group consisting of:

    ##STR00050##

    [0665] In some embodiments, Y is selected from the group consisting of:

    ##STR00051##

    [0666] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl substituted with R.sup.Y1. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is C1-C6 alkyl substituted with CO.sub.2R.sup.A. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is C1-C6 alkyl substituted with CO.sub.2H.

    [0667] In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl substituted with R.sup.Y. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl.

    [0668] In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted 4-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with 4-6 membered heteroaryl substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with 4-6 membered heteroaryl.

    [0669] In some embodiments, 1, 2, or 3 of R.sup.Y is independently 5-6 membered heteroaryl. In some embodiments, 1 of R.sup.Y is 5-6 membered heteroaryl. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is 5-6 membered heteroaryl.

    [0670] In some embodiments, 1, 2, or 3 of R.sup.Y is independently heteroaralkyl. In some embodiments, 1 of R.sup.Y is independently heteroaralkyl.

    [0671] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl substituted with R.sup.Y1. In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is C1-C6 alkyl substituted with CO.sub.2R.sup.A. In some embodiments, Y is substituted with 1 R.sup.Y, and R.sup.Y is C1-C6 alkyl substituted with CO.sub.2H.

    [0672] In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl substituted with R.sup.Y. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl.

    [0673] In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted 5-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with 5-6 membered heteroaryl substituted with R.sup.Y1. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C6 alkyl substituted with 5-6 membered heteroaryl.

    [0674] In some embodiments, 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl. In some embodiments, 1 or 2 of R.sup.Y is independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of R.sup.Y is methyl.

    [0675] In some embodiments, Y is substituted with 1 R.sup.Y. In some embodiments, Y is substituted with 2 independently selected R.sup.Y. In some embodiments, Y is substituted with 3 independently selected R.sup.Y.

    [0676] In some embodiments, Y is substituted with 1 R.sup.Y. In some embodiments, R.sup.Y is halogen. In some embodiments, R.sup.Y is chloro or fluoro. In some embodiments, R.sup.Y is hydroxyl. In some embodiments, R.sup.Y is cyano. In some embodiments, R.sup.Y is C1-C6 haloalkyl optionally substituted with hydroxyl. In some embodiments, R.sup.Y is C1-C6 haloalkyl. In some embodiments, R.sup.Y is C1-C6 alkoxy. In some embodiments, R.sup.Y is C1-C6 haloalkoxy. In some embodiments, R.sup.Y is C1-C6 hydroxyalkyl. In some embodiments, R.sup.Y is NHC(O)R.sup.C. In some embodiments, R.sup.Y is C(O)NHR.sup.Y1. In some embodiments, R.sup.Y is CO.sub.2R.sup.A. In some embodiments, R.sup.Y is SO.sub.2NR.sup.FR.sup.G. In some embodiments, R.sup.Y is NHSO.sub.2R.sup.F. In some embodiments, R.sup.Y is S(O)(NR.sup.F)R.sup.G. In some embodiments, R.sup.Y is SO.sub.2(C1-C6 alkyl). In some embodiments, R.sup.Y is C(O)NR.sup.AR.sup.B. In some embodiments, R.sup.Y is 4-6 membered heteroaryl. In some embodiments, R.sup.Y is heteroaralkyl. In some embodiments, R.sup.Y is 4-6 membered heterocyclyl optionally substituted with R.sup.Y1. In some embodiments, R.sup.Y is C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1. In some embodiments, R.sup.Y is

    [0677] In some embodiments, R.sup.Y1 is SO.sub.2(C1-C6 alkyl). In some embodiments, R.sup.Y1 is SO.sub.2CH.sub.3.

    [0678] In some embodiments, R.sup.Y1 is C1-C6 alkyl optionally substituted with oxo. In some embodiments, R.sup.Y1 is C1-C6 alkyl substituted with oxo. In some embodiments, R.sup.Y1 is acetyl, 1-oxoethyl, or 1-oxopropyl. In some embodiments, R.sup.Y1 is C1-C6 alkyl. In some embodiments, R.sup.Y1 is methyl.

    [0679] In some embodiments, R.sup.4 is hydrogen.

    [0680] In some embodiments, R.sup.Y1 is hydroxyl.

    [0681] In some embodiments, R.sup.4 is C1-C6 alkyl. In some embodiments, R.sup.4 is methyl or ethyl. In some embodiments, R.sup.4 is methyl.

    [0682] In some embodiments, R.sup.4 is acrylamido.

    [0683] In some embodiments, R.sup.5 is hydrogen.

    [0684] In some embodiments, R.sup.5 is C1-C6 alkyl. In some embodiments, R.sup.5 is methyl or ethyl. In some embodiments, R.sup.5 is methyl.

    [0685] In some embodiments, R.sup.5 is cyano.

    [0686] In some embodiments, R.sup.5 is NR.sup.5AR.sup.5B.

    [0687] In some embodiments, R.sup.5 is NR.sup.5AC(O)R.sup.5B.

    [0688] In some embodiments, R.sup.5 is C(O)NR.sup.5AR.sup.5B.

    [0689] In some embodiments, one of R.sup.5A and R.sup.5B is hydrogen and the other of R.sup.5A and R.sup.5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, one of R.sup.5A and R.sup.5B is C1-C6 alkyl and the other of R.sup.5A and R.sup.5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, each of R.sup.5A and R.sup.5B is hydrogen. In some embodiments, each of R.sup.5A and R.sup.5B is an independently selected C1-C6 alkyl. In some embodiments, each of R.sup.5A and R.sup.5B is methyl. In some embodiments, the C1-C6 hydroxyalkyl of R.sup.5A and R.sup.5B is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, dihydroxypropyl or dihydroxybutyl.

    [0690] In some embodiments, R.sup.5 is acrylamido.

    [0691] In some embodiments, R.sup.6 is hydrogen.

    [0692] In some embodiments, R.sup.6 is halogen. In some embodiments, R.sup.6 is fluoro. In some embodiments, R.sup.6 is chloro.

    [0693] In some embodiments, R.sup.6 is C1-C6 alkyl. In some embodiments, R.sup.6 is methyl.

    [0694] In some embodiments, R.sup.7 is hydrogen.

    [0695] In some embodiments, R.sup.7 is halogen.

    [0696] In some embodiments, R.sup.7 is hydroxyl.

    [0697] In some embodiments, R.sup.7 is cyano.

    [0698] In some embodiments, R.sup.7 is C1-C6 alkyl. In some embodiments, R.sup.7 is methyl, ethyl, or isopropyl. In some embodiments, R.sup.7 is methyl.

    [0699] In some embodiments, R.sup.7 is C1-C6 alkoxy. In some embodiments, R.sup.7 is C1-C3 alkoxy. In some embodiments, R.sup.7 is methoxy.

    [0700] In some embodiments, R.sup.7 is C1-C6 alkoxyalkyl. In some embodiments, R.sup.7 is C1-C3 alkoxy. In some embodiments, R.sup.7 is methoxymethyl.

    [0701] In some embodiments, R.sup.7 is C1-C6 hydroxyalkyl. In some embodiments, R.sup.7 is C1-C3 hydroxyalkyl. In some embodiments, R.sup.7 is mono-hydroxyl C1-C3 alkyl. In some embodiments, R.sup.7 is di-hydroxyl C2-C3 alkyl.

    [0702] In some embodiments, R.sup.7 is C1-C6 cyanoalkyl. In some embodiments, R.sup.7 is C1-C3 cyanoalkyl. In some embodiments, R.sup.7 is cyanomethyl.

    [0703] In some embodiments, R.sup.1 is C(O)C1-C6 alkyl. In some embodiments, R.sup.1 is C(O)CH.sub.3.

    [0704] In some embodiments, R.sup.1 is NH(CN).

    [0705] In some embodiments, R.sup.7 is 5-6 membered heteroaryl. In some embodiments, R.sup.7 is a 5 membered heteroaryl. In some embodiments, R.sup.7 is a 6 membered heteroaryl.

    [0706] In some embodiments, R.sup.7 is C(NR.sup.7A)NR.sup.7AR.sup.7B.

    [0707] In some embodiments, when each --- adjacent to CR.sup.7 is a single bond, R.sup.7 is oxo.

    [0708] In some embodiments, R.sup.7 is NR.sup.7AR.sup.7B.

    [0709] In some embodiments, R.sup.7 is NR.sup.7AC(O)R.sup.7B.

    [0710] In some embodiments, R.sup.7 is C(O)NR.sup.7AR.sup.7B.

    [0711] In some embodiments, R.sup.7 is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.7AR.sup.7B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.7AR.sup.7B. In some embodiments, R.sup.7 is an unsubstituted 4-10 membered heterocyclyl. In some embodiments, R.sup.7 is 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.7AR.sup.7B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.7AR.sup.7B. In some embodiments, R.sup.7 is an unsubstituted 4-6 membered heterocyclyl. In some embodiments, R.sup.7 is 4-6 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.7AR.sup.7B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.7AR.sup.7B. In some embodiments, R.sup.7 is 4-6 membered heterocyclyl substituted with 1 substituent independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, or C1-C6 alkyl optionally substituted with C1-C6 alkoxy.

    [0712] In some embodiments, one of R.sup.7A and R.sup.7B is hydrogen and the other of R.sup.7A and R.sup.7B is C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo. In some embodiments, one of R.sup.7A and R.sup.7B is C1-C6 alkyl and the other of R.sup.7A and R.sup.7B is C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo. In some embodiments, each of R.sup.7A and R.sup.7B is hydrogen. In some embodiments, each of R.sup.7A and R.sup.7B is an independently selected C1-C6 alkyl. In some embodiments, each of R.sup.7A and R.sup.7B is methyl.

    [0713] In some embodiments, each of R.sup.A and R.sup.B are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

    [0714] In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

    [0715] In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy.

    [0716] In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.

    [0717] In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is hydroxyl. In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is C1-C6 alkoxy. In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is C3-C6 cycloalkyl. In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is C2-C6 alkenyl. In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is C1-C6 alkyl substituted with C1-C6 alkoxy.

    [0718] In some embodiments, one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is C1-C6 alkyl. In some embodiments, each of R.sup.A and R.sup.B are hydrogen. In some embodiments, each of R.sup.A and R.sup.B are an independently selected C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, each of R.sup.A and R.sup.B are an independently selected C1-C6 alkyl. In some embodiments, each of R.sup.A and R.sup.B are methyl.

    [0719] In some embodiments, R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl.

    [0720] In some embodiments, R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl.

    [0721] In some embodiments, R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with halogen, C1-C6 alkyl, or C(O)C1-C6 alkyl. In some embodiments, R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substitutents independently selected from fluoro, methyl, and acetyl.

    [0722] In some embodiments, R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. In some embodiments, R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

    [0723] In some embodiments, each R.sup.C is independently C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each R.sup.C is independently C3-C6 cycloalkyl, C(O)NR.sup.1, or a C1-C6 alkyl substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each R.sup.C is independently C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl. In some embodiments, each R.sup.C is independently C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl.

    [0724] In some embodiments, each R.sup.C is independently C3-C6 cycloalkyl. In some embodiments, each R.sup.C is independently C(O)NHR.sup.Y1. In some embodiments, each R.sup.C is independently C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each R.sup.C is independently C1-C6 alkyl substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.

    [0725] In some embodiments, one of R.sup.D and R.sup.E is hydrogen and the other of R.sup.D and R.sup.E is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, one of R.sup.D and R.sup.E is hydrogen and the other of R.sup.D and R.sup.E is hydroxyl. In some embodiments, one of R.sup.D and R.sup.E is hydrogen and the other of R.sup.D and R.sup.E is C1-C6 alkyl. In some embodiments, one of R.sup.D and R.sup.E is hydrogen and the other of R.sup.D and R.sup.E is C1-C6 alkoxy. In some embodiments, one of R.sup.D and R.sup.E is hydrogen and the other of R.sup.D and R.sup.E is hydroxyl, methyl, or methoxy. In some embodiments, each of R.sup.D and R.sup.E is hydrogen. In some embodiments, each of R.sup.D and R.sup.E is an independently selected C1-C6 alkyl. In some embodiments, each of R.sup.D and R.sup.E is methyl.

    [0726] In some embodiments, one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is phenyl or C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B. In some embodiments, one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is phenyl or C1-C6 alkyl substituted with oxo or NR.sup.AR.sup.B. In some embodiments, one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is phenyl or C1-C6 alkyl. In some embodiments, one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is phenyl. In some embodiments, one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B. In some embodiments, one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is C1-C6 alkyl substituted with oxo or NR.sup.AR.sup.B. In some embodiments, each of R.sup.F and R.sup.G is hydrogen. In some embodiments, each of R.sup.F and R.sup.G is an independently selected C1-C6 alkyl. In some embodiments, each of R.sup.F and R.sup.G is methyl.

    [0727] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A1):

    ##STR00052##

    or a pharmaceutically acceptable salt thereof.

    [0728] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A2):

    ##STR00053##

    or a pharmaceutically acceptable salt thereof.

    [0729] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B1):

    ##STR00054##

    or a pharmaceutically acceptable salt thereof.

    [0730] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B2):

    ##STR00055##

    or a pharmaceutically acceptable salt thereof.

    [0731] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B3):

    ##STR00056##

    or a pharmaceutically acceptable salt thereof.

    [0732] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B4):

    ##STR00057##

    or a pharmaceutically acceptable salt thereof.

    [0733] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-C):

    ##STR00058##

    or a pharmaceutically acceptable salt thereof.

    [0734] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-D):

    ##STR00059##

    or a pharmaceutically acceptable salt thereof.

    [0735] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-E):

    ##STR00060##

    or a pharmaceutically acceptable salt thereof.

    [0736] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-F):

    ##STR00061##

    or a pharmaceutically acceptable salt thereof.

    [0737] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-F1):

    ##STR00062##

    or a pharmaceutically acceptable salt thereof.

    [0738] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-G):

    ##STR00063##

    or a pharmaceutically acceptable salt thereof.

    [0739] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H1):

    ##STR00064##

    or a pharmaceutically acceptable salt thereof.

    [0740] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H2):

    ##STR00065##

    or a pharmaceutically acceptable salt thereof.

    [0741] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H3):

    ##STR00066##

    or a pharmaceutically acceptable salt thereof.

    [0742] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H4):

    ##STR00067##

    or a pharmaceutically acceptable salt thereof.

    [0743] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H5):

    ##STR00068##

    or a pharmaceutically acceptable salt thereof.

    [0744] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-H6):

    ##STR00069##

    or a pharmaceutically acceptable salt thereof.

    [0745] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-I1):

    ##STR00070##

    or a pharmaceutically acceptable salt thereof.

    [0746] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-I2):

    ##STR00071##

    or a pharmaceutically acceptable salt thereof.

    [0747] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-13):

    ##STR00072##

    or a pharmaceutically acceptable salt thereof.

    [0748] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-I4):

    ##STR00073##

    or a pharmaceutically acceptable salt thereof.

    [0749] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-15):

    ##STR00074##

    or a pharmaceutically acceptable salt thereof.

    [0750] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-16):

    ##STR00075##

    or a pharmaceutically acceptable salt thereof.

    [0751] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-A1):

    ##STR00076##

    or a pharmaceutically acceptable salt thereof.

    [0752] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-B):

    ##STR00077##

    or a pharmaceutically acceptable salt thereof.

    [0753] In some embodiments, the compound of Formula (II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II-C):

    ##STR00078##

    or a pharmaceutically acceptable salt thereof.

    [0754] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-A1):

    ##STR00079##

    or a pharmaceutically acceptable salt thereof.

    [0755] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-B):

    ##STR00080##

    or a pharmaceutically acceptable salt thereof.

    [0756] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-C):

    ##STR00081##

    or a pharmaceutically acceptable salt thereof.

    [0757] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-D):

    ##STR00082##

    or a pharmaceutically acceptable salt thereof.

    [0758] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-E):

    ##STR00083##

    or a pharmaceutically acceptable salt thereof.

    [0759] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III-F):

    ##STR00084##

    or a pharmaceutically acceptable salt thereof.

    Non-Limiting Exemplary Compounds

    [0760] In some embodiments, the compound is selected from the group consisting of Compounds 1-147, or a pharmaceutically acceptable salt of any of the foregoing.

    [0761] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table A, or a pharmaceutically acceptable salt of any of the foregoing.

    TABLE-US-00001 TABLE A Cmpd No. Structure 1 [00085]embedded image 2 [00086]embedded image 3 [00087]embedded image 4 [00088]embedded image 5 [00089]embedded image 6 [00090]embedded image 7 [00091]embedded image 8 [00092]embedded image 9 [00093]embedded image 10 [00094]embedded image 11 [00095]embedded image 12 [00096]embedded image 13 [00097]embedded image 14 [00098]embedded image 15 [00099]embedded image 16 [00100]embedded image 17 [00101]embedded image 18 [00102]embedded image 19 [00103]embedded image 20 [00104]embedded image 21 [00105]embedded image 22 [00106]embedded image 23 [00107]embedded image 24 [00108]embedded image 25 [00109]embedded image 26 [00110]embedded image 27 [00111]embedded image 28 [00112]embedded image 29 [00113]embedded image 30 [00114]embedded image 31 [00115]embedded image 32 [00116]embedded image 33 [00117]embedded image 34 [00118]embedded image 35 [00119]embedded image 36 [00120]embedded image 37 [00121]embedded image 38 [00122]embedded image 39 [00123]embedded image 40 [00124]embedded image 41 [00125]embedded image 42 [00126]embedded image 43 [00127]embedded image 44 [00128]embedded image 45 [00129]embedded image 46 [00130]embedded image 47 [00131]embedded image 48 [00132]embedded image 49 [00133]embedded image 50 [00134]embedded image 51 [00135]embedded image 52 [00136]embedded image 53 [00137]embedded image 54 [00138]embedded image 55 [00139]embedded image 56 [00140]embedded image 57 [00141]embedded image 58 [00142]embedded image 59 [00143]embedded image 60 [00144]embedded image 61 [00145]embedded image 62 [00146]embedded image 63 [00147]embedded image 64 [00148]embedded image 65 [00149]embedded image 66 [00150]embedded image 67 [00151]embedded image 68 [00152]embedded image 69 [00153]embedded image 70 [00154]embedded image 71 [00155]embedded image 72 [00156]embedded image 73 [00157]embedded image 74 [00158]embedded image 75 [00159]embedded image 76 [00160]embedded image 77 [00161]embedded image 78 [00162]embedded image 79 [00163]embedded image 80 [00164]embedded image 81 [00165]embedded image 82 [00166]embedded image 83 [00167]embedded image 84 [00168]embedded image 85 [00169]embedded image 86 [00170]embedded image 87 [00171]embedded image 88 [00172]embedded image 89 [00173]embedded image 90 [00174]embedded image 91 [00175]embedded image 92 [00176]embedded image 93 [00177]embedded image 94 [00178]embedded image 95 [00179]embedded image 96 [00180]embedded image 97 [00181]embedded image 98 [00182]embedded image 99 [00183]embedded image 100 [00184]embedded image 101 [00185]embedded image 102 [00186]embedded image 103 [00187]embedded image 104 [00188]embedded image 105 [00189]embedded image 106 [00190]embedded image 107 [00191]embedded image 108 [00192]embedded image 109 [00193]embedded image 110 [00194]embedded image 111 [00195]embedded image 112 [00196]embedded image 113 [00197]embedded image 114 [00198]embedded image 115 [00199]embedded image 116 [00200]embedded image 117 [00201]embedded image 118 [00202]embedded image 119 [00203]embedded image 120 [00204]embedded image 121 [00205]embedded image 122 [00206]embedded image 123 [00207]embedded image 124 [00208]embedded image 125 [00209]embedded image 126 [00210]embedded image 127 [00211]embedded image 128 [00212]embedded image 129 [00213]embedded image 130 [00214]embedded image 131 [00215]embedded image 132 [00216]embedded image 133 [00217]embedded image 134 [00218]embedded image 135 [00219]embedded image 136 [00220]embedded image 137 [00221]embedded image 138 [00222]embedded image 139 [00223]embedded image 140 [00224]embedded image 141 [00225]embedded image 142 [00226]embedded image 143 [00227]embedded image 144 [00228]embedded image 145 [00229]embedded image 146 [00230]embedded image 147 [00231]embedded image

    [0762] In some embodiments, the compound is selected from the group consisting of Compounds 148-139, or a pharmaceutically acceptable salt of any of the foregoing.

    [0763] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table B, or a pharmaceutically acceptable salt of any of the foregoing.

    TABLE-US-00002 TABLE B Example No. Structure 148 [00232]embedded image 149 [00233]embedded image 150 [00234]embedded image 151 [00235]embedded image 152 [00236]embedded image 153 [00237]embedded image 154 [00238]embedded image 155 [00239]embedded image 156 [00240]embedded image

    [0764] In some embodiments, the compound is selected from the group consisting of the Compounds 140-226, or a pharmaceutically acceptable salt of any of the foregoing.

    [0765] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C, or a pharmaceutically acceptable salt of any of the foregoing.

    TABLE-US-00003 TABLE C Example No. Structure 157 [00241]embedded image 158 [00242]embedded image 159 [00243]embedded image 160 [00244]embedded image 161 [00245]embedded image 162 [00246]embedded image 163 [00247]embedded image 164 [00248]embedded image 165 [00249]embedded image 166 [00250]embedded image 167 [00251]embedded image 168 [00252]embedded image 169 [00253]embedded image 170 [00254]embedded image 171 [00255]embedded image 172 [00256]embedded image 173 [00257]embedded image 174 [00258]embedded image 175 [00259]embedded image 176 [00260]embedded image 177 [00261]embedded image 178 [00262]embedded image 179 [00263]embedded image 180 [00264]embedded image 181 [00265]embedded image 182 [00266]embedded image 183 [00267]embedded image 184 [00268]embedded image 185 [00269]embedded image 186 [00270]embedded image 187 [00271]embedded image 188 [00272]embedded image 189 [00273]embedded image 190 [00274]embedded image 191 [00275]embedded image 192 [00276]embedded image 193 [00277]embedded image 194 [00278]embedded image 195 [00279]embedded image 196 [00280]embedded image 197 [00281]embedded image 198 [00282]embedded image 199 [00283]embedded image 200 [00284]embedded image 201 [00285]embedded image 202 [00286]embedded image 203 [00287]embedded image 204 [00288]embedded image 205 [00289]embedded image 206 [00290]embedded image 207 [00291]embedded image 208 [00292]embedded image 209 [00293]embedded image 210 [00294]embedded image 211 [00295]embedded image 212 [00296]embedded image 213 [00297]embedded image 214 [00298]embedded image 215 [00299]embedded image 216 [00300]embedded image 217 [00301]embedded image 218 [00302]embedded image 219 [00303]embedded image 220 [00304]embedded image 221 [00305]embedded image 222 [00306]embedded image 223 [00307]embedded image 224 [00308]embedded image 225 [00309]embedded image 226 [00310]embedded image 227 [00311]embedded image 228 [00312]embedded image 229 [00313]embedded image 230 [00314]embedded image 231 [00315]embedded image 232 [00316]embedded image 233 [00317]embedded image 234 [00318]embedded image 235 [00319]embedded image 236 [00320]embedded image 237 [00321]embedded image 238 [00322]embedded image 239 [00323]embedded image 240 [00324]embedded image 241 [00325]embedded image 242 [00326]embedded image 243 [00327]embedded image

    Pharmaceutical Compositions

    [0766] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

    Methods of Treatment

    [0767] A PI3K inhibitor as used herein (e.g., compounds of Formula (I), Formula (II), Formula (III), and pharmaceutically acceptable salts of any of the foregoing) includes any compound exhibiting PI3K inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a PI3K inhibitor can be selective for a PI3K having one or more mutations.

    [0768] The ability of test compounds to act as inhibitors of PI3K may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3K inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radio ligands.

    [0769] Potency of a PI3K inhibitor as provided herein can be determined by EC.sub.50 value. A compound with a lower EC.sub.50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC.sub.50 value.

    [0770] Potency of a PI3K inhibitor as provided herein can also be determined by IC.sub.50 value. A compound with a lower IC.sub.50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC.sub.50 value. In some embodiments, the substantially similar conditions comprise determining a PI3K-dependent phosphorylation level, in vitro or in vivo.

    [0771] The selectivity between wild type PI3K and PI3K containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3K activity, and/or proliferation assays where cell proliferation is dependent on mutant PI3K kinase activity.

    [0772] In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of PI3K. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3K. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a PI3K kinase including one or more mutations, for example, the mutations in Table 1.

    [0773] In some embodiments, the compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can selectively target PI3K. For example, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can selectively target PI3K over another kinase or non-kinase target.

    [0774] In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can exhibit greater inhibition of PI3K containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1) relative to inhibition of wild type PI3K. In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3K containing one or more mutations as described herein relative to inhibition of wild type PI3K. In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can exhibit up to 1,000-fold greater inhibition of PI3K containing one or more mutations as described herein relative to inhibition of wild type PI3K. In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can exhibit up to 10,000-fold greater inhibition of PI3K having a combination of mutations described herein relative to inhibition of wild type PI3K.

    [0775] In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3K containing one or more mutations as described herein relative to inhibition of wild type PI3K. In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3K containing one or more mutations as described herein relative to inhibition of wild type PI3K. In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3K containing one or more mutations as described herein relative to inhibition of wild type PI3K. In some embodiments, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3K containing one or more mutations as described herein relative to inhibition of wild type PI3K.

    [0776] Compounds of Formula (I), Formula (II), or Formula (III), or pharmaceutically acceptable salts of any of the foregoing, are useful for treating diseases which can be treated with a PI3K inhibitor, such as PI3K-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).

    [0777] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity, or level of any of the same (a PI3K-associated cancer), for example, as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3K-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

    [0778] In certain embodiments, compounds of Formula (I), Formula (II), or Formula (III), or pharmaceutically acceptable salts of any of the foregoing, are useful for preventing diseases as defined herein such as cancer. The term preventing as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease as described herein, or a symptom thereof.

    [0779] The term PI3K-associated disease as used herein refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3K protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3K protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a PI3K-associated disease include, for example, proliferative disorders such as cancer (e.g., PI3K-associated cancer).

    [0780] The term PI3K-associated cancer as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3K-associated cancer are described herein.

    [0781] The phrase dysregulation of a PIK3CA gene, a PI3K protein, or the expression or activity or level of any of the same refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3K that includes a deletion of at least one amino acid as compared to a wild type PI3K, a mutation in a PIK3CA gene that results in the expression of PI3K with one or more point mutations as compared to a wild type PI3K, a mutation in a PIK3CA gene that results in the expression of PI3K with at least one inserted amino acid as compared to a wild type PI3K, a gene duplication that results in an increased level of PI3K in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of PI3K in a cell), an alternative spliced version of PI3K mRNA that results in PI3K having a deletion of at least one amino acid in the PI3K as compared to the wild type PI3K), or increased expression (e.g., increased levels) of a wild type PI3K in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity, or level of any of the same, can be a mutation in a PIK3CA gene that encodes a PI3K that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Non-limiting examples of PI3K point mutations/substitutions/insertions/deletions are described in Table 1.

    [0782] The term wild type describes a nucleic acid (e.g., a PIK3CA gene or a PI3K mRNA) or protein (e.g., a PI3K) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.

    [0783] The term wild type PI3K or wild-type PI3K describes a normal PI3K nucleic acid (e.g., a PIK3CA or PI3K mRNA) or protein that is found in a subject that does not have a PI3K-associated disease, e.g., a PI3K-associated cancer (and optionally also does not have an increased risk of developing a PI3K-associated disease and/or is not suspected of having a PI3K-associated disease), or is found in a cell or tissue from a subject that does not have a PI3K-associated disease, e.g., a PI3K-associated cancer (and optionally also does not have an increased risk of developing a PI3K-associated disease and/or is not suspected of having a PI3K-associated disease).

    [0784] Provided herein is a method of treating cancer (e.g., a PI3K-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3K-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3K protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the dysregulation of a PIK3CA gene, a PI3K protein, or the expression or activity or level of any of the same includes one or more a PI3K protein substitutions/point mutations/insertions. Non-limiting examples of PI3K protein substitutions/insertions/deletions are described in Table 1.

    [0785] salt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalts of any of the foregoingsalts of any of the foregoingsalt of any of the foregoingsalt of any of the foregoing

    [0786] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof.

    [0787] In some embodiments, the PI3K protein substitution/insertion/deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3K protein substitution/insertion/deletion is H1047X, where X is any amino acid other than H. In some embodiments, the PI3K protein substitution/insertion/deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3K protein substitution/insertion/deletion is E545X, where X is any amino acid other than E.

    [0788] In some embodiments, the dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity or level of any of the same, includes a splice variation in a PI3K mRNA which results in an expressed protein that is an alternatively spliced variant of PI3K having at least one residue deleted (as compared to the wild type PI3K protein) resulting in a constitutive activity of a PI3K protein domain.

    [0789] In some embodiments, the dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity or level of any of the same, includes at least one point mutation in a PIK3CA gene that results in the production of a PI3K protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3K protein that has one or more amino acids inserted or removed, as compared to the wild type PI3K protein. In some cases, the resulting mutant PI3K protein has increased activity, as compared to a wild type PI3K protein or a PI3K protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3K protein relative to a wild type PI3K protein or a PI3K protein not including the same mutation.

    [0790] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3K-associated cancer) is selected from a hematological cancer and a solid tumor.

    [0791] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3K-associated cancer) is selected from breast cancer (including both HER2.sup.+ and HER2.sup. breast cancer, ER.sup.+ breast cancer, and triple negative breast cancer), uterine cancer (including endometrial cancer), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS, including adenocarcinoma lung cancer and squamous cell lung carcinoma)), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, hepatocellular carcinoma, prostate cancer, Malignant Peripheral Nerve Sheath Tumor (MPNST), glioblastoma, cholangiocarcinoma, and pancreatic cancer.

    [0792] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3K-associated cancer) is selected from breast cancer (including both HER2.sup.+ and HER2.sup. breast cancer, ER.sup.+ breast cancer, and triple negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer.

    [0793] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3K-associated cancer) is selected from breast cancer, SCLC, NSCLC, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

    [0794] In some embodiments ofany of the methods or uses described herein, the PI3K-associated cancer is breast cancer. In some embodiments ofany of the methods or uses described herein, the PI3K-associated cancer is colorectal cancer. In some embodiments ofany of the methods or uses described herein, the PI3K-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3K-associated cancer is lung cancer.

    [0795] In some embodiments of any of the methods or uses described herein, the PI3K-associated cancer is selected from the cancers described in Table 1.

    TABLE-US-00004 TABLE 1 PI3K Protein Amino Acid Substitutions/Insertions/Deletions.sup.A Non-Limiting Amino Acid Exemplary Position Mutations Non-Limiting Exemplary PI3K Associated Cancer(s) 1043 M1043I, Breast Invasive Lobular Carcinoma M1043L, Tubular Stomach Adenocarcinoma M1043T, Uterine Endometrioid Carcinoma M1043V Mucinous Adenocarcinoma of the Colon and Rectum Papillary Thyroid Cancer Esophageal Squamous Cell Carcinoma Colon Adenocarcinoma Breast Invasive Ductal Carcinoma Bladder Urothelial Carcinoma Pancreatic Adenocarcinoma Oligodendroglioma Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma Glioblastoma Multiforme Head and Neck Squamous Cell Carcinoma 1044 N1044I, N1044K, Uterine Endometrioid Carcinoma N1044Y Breast Invasive Ductal Carcinoma 1045 D1045A, Uterine Endometrioid Carcinoma D1045V Lung Squamous Cell Carcinoma 1047 H1047L, Esophageal Squamous Cell Carcinoma H1047Q, Uterine Endometrioid Carcinoma H1047R, H1047Y Hepatocellular Carcinoma Cutaneous Melanoma Mucinous Adenocarcinoma of the Colon and Rectum Bladder Urothelial Carcinoma Cervical Squamous Cell Carcinoma Intrahepatic Cholangiocarcinoma Uterine Mixed Endometrial Carcinoma Breast Invasive Ductal Carcinoma Renal Clear Cell Carcinoma Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma Breast Invasive Lobular Carcinoma Breast Invasive Carcinoma (NOS) Astrocytoma Colon Adenocarcinoma Leiomyosarcoma Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor Oligodendroglioma Serous Ovarian Cancer Mucinous Stomach Adenocarcinoma Rectal Adenocarcinoma Intestinal Type Stomach Adenocarcinoma Diffuse Type Stomach Adenocarcinoma Prostate Adenocarcinoma Lung Adenocarcinoma Stomach Adenocarcinoma Tubular Stomach Adenocarcinoma Adrenocortical Carcinoma Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma Glioblastoma Multiforme Oligoastrocytoma 1048 H1048R Colon Adenocarcinoma Renal Clear Cell Carcinoma 1049 G1049R Intestinal Type Stomach Adenocarcinoma Bladder Urothelial Carcinoma Renal Clear Cell Carcinoma Breast Invasive Ductal Carcinoma Breast Invasive Lobular Carcinoma Uterine Endometrioid Carcinoma Colon Adenocarcinoma 1052 T1052K Hepatocellular Carcinoma Colon Adenocarcinoma 1055 M1055I Uterine Mixed Endometrial Carcinoma 1058 I1058M Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor 1065 H1065L Breast Invasive Lobular Carcinoma 1066 A1066V Uterine Mixed Endometrial Carcinoma 1068 N1068Y, Pleural Mesothelioma, Epithelioid Type N1068fs*5 Dedifferentiated Liposarcoma (Frame Shift Head and Neck Squamous Cell Carcinoma Insertion) .sup.AUnless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013). Velho S, Oliveira C, Ferreira A, Ferreira A C, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado J C, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 July; 41(11): 1649-54. doi: 10.1016/j.ejca.2005.04.022. PMID: 15994075.

    [0796] Exemplary Sequence of Human Phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1)

    TABLE-US-00005 MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQ LLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLK VIEPVGNREEKILNREIGFAIGMPVCEFDMVKDPEVQDFRRNILNVCKEA VDLRDLNSPHSRAMYVYPPNVESSPELPKHIYNKLDKGQIIVVIWVIVSP NNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLKLCVLEYQGKY ILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMD CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRD IDKIYVRTGIYHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAA RLCLSICSVKGRKGAKEEHCPLAWGNINLFDYTDTLVSGKMALNLWPVPH GLEDLLNPIGVTGSNPNKETPCLELEFDWFSSVVKFPDMSVIEEHANWSV SREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPLSEITEQEKDF LWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAME LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLV RFLLKKALTNQRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLK HLNRQVEAMEKLINLTDILKQEKKDETQKVQMKFLVEQMRRPDFMDALQG FLSPLNPAHQLGNLRLEECRIMSSAKRPLWLNWENPDIMSELLFQNNEII FKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLSIGDCVGLIEV VRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRS CAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRE RVPFVLTQDFLIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFIN LFSMMLGSGMPELQSFDDIAYIRKTLALDKTEQEALEYFMKQMNDAHHGG WTTKMDWIFHTIKQHALN

    [0797] Also provided is a method for inhibiting PI3K activity in a cell, comprising contacting the cell with a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, to a subject having a cell having aberrant PI3K activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3K-associated cancer cell. As used herein, the term contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, contacting a PI3K protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3K protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3K protein.

    [0798] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof as defined herein.

    [0799] Further provided herein is a method of increase cell death, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject, comprising administering to the subject an effective compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt of any of the foregoing, in an amount effective to increase tumor cell death.

    [0800] In some embodiments, the PI3K is human PI3K. In some embodiments, the PI3K has one or more point mutations in the PIK3CA gene. In some embodiments, the point mutations include a substitution at amino acid position 1047 of a human PI3K protein. In some embodiments, the substitution is H1047R.

    [0801] When employed as pharmaceuticals, the compounds of Formula (I), Formula (II), or Formula (III), including pharmaceutically acceptable salts of any of the foregoing, can be administered in the form of pharmaceutical compositions as described hereinsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalts of any of the foregoing.

    EMBODIMENTS

    [0802] 1. A compound of Formula (I), Formula (II), or Formula (III):

    ##STR00328##

    or a pharmaceutically acceptable salt of any of the foregoing, wherein: [0803] Q is NR.sup.1A or CR.sup.1; [0804] Z is NR.sup.Z1 or CR.sup.Z2, wherein one or both of Q and Z is N; [0805] Z.sup.1 is S, S(O.sub.2), or O; [0806] each custom-character represents a single bond or a double bond; [0807] R.sup.1 is hydrogen, cyano, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; [0808] R.sup.1A is absent, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 alkoxyalkyl; [0809] R.sup.Z1 is absent, hydrogen, cyano, C1-C6 alkyl, or C1-C6 alkyl; [0810] R.sup.Z2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; [0811] R.sup.2 is phenyl optionally substituted with 1-4 independently selected R.sup.2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R.sup.2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R.sup.2A, or C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C; [0812] each R.sup.2A is independently selected from: [0813] (i) halogen, [0814] (ii) cyano, [0815] (iii) hydroxyl, [0816] (iv) NR.sup.AR.sup.B, [0817] (v) C(O)NR.sup.AR.sup.B,

    ##STR00329## [0818] (vii) NHC(O)R.sup.C, [0819] (viii) C(O)NR.sup.DR.sup.E, [0820] (ix) C(O)OR.sup.F, [0821] (x) SO.sub.2R.sup.F, [0822] (xi) NHSO.sub.2R.sup.F, [0823] (xii) SO.sub.2NR.sup.FR.sup.G [0824] (xiii) NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0825] (xiv) C1-C6 haloalkyl, [0826] (xv) C1-C6 hydroxyalkyl, [0827] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B, [0828] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B, [0829] (xviii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl, [0830] (xix) C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl, and [0831] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; [0832] each R.sup.A and R.sup.B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl; [0833] each R.sup.C is independently selected from C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl; [0834] each R.sup.D and R.sup.E is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; [0835] each R.sup.3A and R.sup.3B is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group; [0836] R.sup.4 is hydrogen, C1-C6 alkyl, or acrylamido; [0837] R.sup.5 is hydrogen, C1-C6 alkyl, cyano, NR.sup.5AR.sup.5B, NR.sup.5AC(O)R.sup.5B, or C(O)NR.sup.5AR.sup.5B; [0838] R.sup.5A and R.sup.5B are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl; [0839] R.sup.6 is hydrogen, halogen, or C1-C6 alkyl; [0840] R.sup.7 is hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C(O)C1-C6 alkyl, NH(CN), 5-6 membered heteroaryl, NR.sup.7AR.sup.7B, NR.sup.7AC(O)R.sup.7B, C(NR.sup.7A)NR.sup.7AR.sup.7B, or C(O)NR.sup.7AR.sup.7B, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.7AR.sup.7B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.7AR.sup.7B, or when each custom-character adjacent to CR.sup.7 is a single bond, R.sup.7 can be oxo; [0841] each R.sup.7A and R.sup.7B are independently selected from hydrogen, C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo; [0842] X is a bond, CH.sub.2, CH(CH.sub.3), C(CH.sub.3).sub.2, or

    ##STR00330## [0843] W is NR.sup.3B or O; [0844] Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y, naphthyl optionally substituted with 1-3 independently selected R.sup.Y, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y; [0845] each R.sup.Y is independently selected from: halogen, cyano, hydroxyl, C1-C6 haloalkyl optionally substituted with hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, NHC(O)R.sup.C, C(O)NHR.sup.Y1, CO.sub.2R.sup.A, SO.sub.2NR.sup.FR.sup.G, NHSO.sub.2R.sup.F, S(O)(NR.sup.F)R.sup.G, SO.sub.2(C1-C6 alkyl), C(O)NR.sup.AR.sup.B, 5-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with R.sup.Y1, and C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 4-6 membered heteroaryl optionally substituted with R.sup.Y1; [0846] R.sup.Y1 is SO.sub.2(C1-C6 alkyl), hydroxyl, or C1-C6 alkyl optionally substituted with oxo; and [0847] each R.sup.F and R.sup.G is independently selected from hydrogen, phenyl, and C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [0848] 2. The compound of Embodiment 1, wherein the compound is a compound of Formula (II).

    [0849] 3. The compound of Embodiment 1, wherein the compound is a compound of Formula (III).

    [0850] 4. The compound of Embodiment 1 or 3, wherein Z.sup.1 is S.

    [0851] 5. The compound of Embodiment 1 or 3, wherein Z.sup.1 is O.

    [0852] 6. The compound of Embodiment 1 or 3, wherein Z.sup.1 is S(O.sub.2).

    [0853] 7. The compound of Embodiment 1, wherein the compound is a compound of Formula (I).

    [0854] 8. The compound of Embodiment 1 or 7, wherein Q is CR.sup.1.

    [0855] 9. The compound of any one of Embodiments 1-8 wherein R.sup.1 is hydrogen.

    [0856] 10. The compound of any one of Embodiments 1-8, wherein R.sup.1 cyano.

    [0857] 11. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C3-C6 cycloalkyl.

    [0858] 12. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 alkyl optionally substituted with phenyl optionally substituted with halogen.

    [0859] 13. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 alkyl substituted with phenyl optionally substituted with halogen.

    [0860] 14. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 alkyl substituted with phenyl substituted with halogen.

    [0861] 15. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 alkyl substituted with phenyl.

    [0862] 16. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 alkyl.

    [0863] 17. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 thioalkyl.

    [0864] 18. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 haloalkyl.

    [0865] 19. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 alkoxy.

    [0866] 20. The compound of any one of Embodiments 1-8, wherein R.sup.1 is C1-C6 alkoxyalkyl.

    [0867] 21. The compound of any one of Embodiments 1-7, wherein Q is NR.sup.1A.

    [0868] 22. The compound of Embodiment 21, wherein R.sup.1A is absent.

    [0869] 23. The compound of Embodiment 21, wherein R.sup.1A is hydrogen.

    [0870] 24. The compound of Embodiment 21, wherein R.sup.1A is C1-C6 alkyl.

    [0871] 25. The compound of Embodiment 24, wherein R.sup.1A is C1-C3 alkyl.

    [0872] 26. The compound of Embodiment 25, wherein R.sup.1A is methyl.

    [0873] 27. The compound of Embodiment 21, wherein R.sup.1A is C1-C6 haloalkyl.

    [0874] 28. The compound of Embodiment 27, wherein R.sup.1A is trifluoromethyl.

    [0875] 29. The compound of Embodiment 21, wherein R.sup.1A is C1-C6 thioalkyl.

    [0876] 30. The compound of Embodiment 21, wherein R.sup.1A is C1-C6 alkoxy.

    [0877] 31. The compound of Embodiment 21, wherein R.sup.1A is C1-C6 alkoxyalkyl.

    [0878] 32. The compound of any one of Embodiments 1 or 7-31, wherein Z is NR.sup.Z1.

    [0879] 33. The compound of Embodiment 32, wherein R.sup.Z1 is absent.

    [0880] 34. The compound of Embodiment 32, wherein R.sup.Z1 is hydrogen.

    [0881] 35. The compound of Embodiment 32, wherein R.sup.Z1 is C1-C6 alkyl.

    [0882] 36. The compound of Embodiment 32, wherein R.sup.Z1 is C1-C3 alkyl.

    [0883] 37. The compound of Embodiment 36, wherein R.sup.Z1 is methyl.

    [0884] 38. The compound of Embodiment 32, wherein R.sup.Z1 is C1-C6 haloalkyl.

    [0885] 39. The compound of Embodiment 38, wherein R.sup.Z1 is trifluoromethyl.

    [0886] 40. The compound of Embodiment 32, wherein R.sup.Z1 is cyano.

    [0887] 41. The compound of any one of Embodiments 1 or 7-31, wherein Z is CR.sup.Z2.

    [0888] 42. The compound of Embodiment 41, wherein R.sup.Z2 is hydrogen.

    [0889] 43. The compound of Embodiment 41, wherein R.sup.Z2 is C1-C6 alkyl.

    [0890] 44. The compound of Embodiment 43, wherein R.sup.Z2 is C1-C3 alkyl.

    [0891] 45. The compound of Embodiment 44, wherein R.sup.Z2 is methyl.

    [0892] 46. The compound of Embodiment 41, wherein R.sup.Z2 is C1-C6 haloalkyl.

    [0893] 47. The compound of Embodiment 46, wherein R.sup.Z2 is trifluoromethyl.

    [0894] 48. The compound of any one of Embodiments 1-47, wherein R.sup.2 is phenyl optionally substituted with 1-3 independently selected R.sup.2A.

    [0895] 49. The compound of any one of Embodiments 1-47, wherein R.sup.2 is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.2A.

    [0896] 50. The compound of any one of Embodiments 1-47, wherein R.sup.2 is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R.sup.2A.

    [0897] 51. The compound of any one of Embodiments 1-47, wherein R.sup.2 is 4-10 membered cycloalkyl optionally substituted with 1-3 independently selected R.sup.2A.

    [0898] 52. The compound of any one of Embodiments 1-51, wherein 1, 2, or 3 of R.sup.2A are independently halogen.

    [0899] 53. The compound of any one of Embodiments 1-52, wherein 1, 2, or 3 of R.sup.2A are independently cyano.

    [0900] 54. The compound of any one of Embodiments 1-53, wherein 1, 2, or 3 of R.sup.2A are independently hydroxyl.

    [0901] 55. The compound of any one of Embodiments 1-54, wherein 1, 2, or 3 of R.sup.2A are independently NR.sup.AR.sup.B.

    [0902] 56. The compound of any one of Embodiments 1-55, wherein 1, 2, or 3 of R.sup.2A are independently C(O)NR.sup.AR.sup.B.

    [0903] 57. The compound of any one of Embodiments 1-56, wherein 1, 2, or 3 of R.sup.2A are independently

    ##STR00331##

    [0904] 58. The compound of any one of Embodiments 1-57, wherein 1, 2, or 3 of R.sup.2A are independently NHC(O)R.sup.C.

    [0905] 59. The compound of any one of Embodiments 1-58, wherein 1, 2, or 3 of R.sup.2A are independently C(O)NR.sup.DR.sup.E.

    [0906] 60. The compound of any one of Embodiments 1-59, wherein 1, 2, or 3 of R.sup.2A are independently C(O)OR.sup.F.

    [0907] 61. The compound of any one of Embodiments 1-60, wherein 1, 2, or 3 of R.sup.2A are independently SO.sub.2R.sup.F.

    [0908] 62. The compound of any one of Embodiments 1-61, wherein 1, 2, or 3 of R.sup.2A are independently NHSO.sub.2R.sup.F.

    [0909] 63. The compound of any one of Embodiments 1-62, wherein 1, 2, or 3 of R.sup.2A are independently SO.sub.2NR.sup.FR.sup.G.

    [0910] 64. The compound of any one of Embodiments 1-63, wherein 1, 2, or 3 of R.sup.2A are independently NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B.

    [0911] 65. The compound of any one of Embodiments 1-64, wherein 1, 2, or 3 of R.sup.2A are independently NHC(O)C1-C6 alkyl substituted with NR.sup.AR.sup.B.

    [0912] 66. The compound of any one of Embodiments 1-65, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 haloalkyl.

    [0913] 67. The compound of any one of Embodiments 1-66, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 hydroxyalkyl.

    [0914] 68. The compound of any one of Embodiments 1-67, wherein 1, 2, or 3 of R.sup.2A are independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B.

    [0915] 69. The compound of any one of Embodiments 1-68, wherein 1, 2, or 3 of R.sup.2A are independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkyl and NR.sup.AR.sup.B.

    [0916] 70. The compound of any one of Embodiments 1-69, wherein 1, 2, or 3 of R.sup.2A are independently 5-10 membered heteroaryl.

    [0917] 71. The compound of any one of Embodiments 1-70, wherein 1, 2, or 3 of R.sup.2A are independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B.

    [0918] 72. The compound of any one of Embodiments 1-71, wherein 1, 2, or 3 of R.sup.2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.AR.sup.B.

    [0919] 73. The compound of any one of Embodiments 1-72, wherein 1, 2, or 3 of R.sup.2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G C1-C6 alkyl substituted with C1-C6 alkoxy, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl substituted with NR.sup.AR.sup.B.

    [0920] 74. The compound of any one of Embodiments 1-73, wherein 1, 2, or 3 of R.sup.2A are independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, SO.sub.2(C1-C6 alkyl), SO.sub.2NR.sup.FR.sup.G, C1-C6 alkyl, C(O)NR.sup.AR.sup.B, or NHC(O)C1-C6 alkyl.

    [0921] 75. The compound of any one of Embodiments 1-70, wherein 1, 2, or 3 of R.sup.2A are independently 4-10 membered heterocyclyl.

    [0922] 76. The compound of any one of Embodiments 1-75, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl.

    [0923] 77. The compound of any one of Embodiments 1-76, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl.

    [0924] 78. The compound of any one of Embodiments 1-77, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, C1-C6 alkoxy, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, C(O)NR.sup.AR.sup.B, or C(O)C3-C6 cycloalkyl.

    [0925] 79. The compound of any one of Embodiments 1-77, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, NR.sup.AR.sup.B, C(O)NR.sup.AR.sup.B, and 4-10 membered heterocyclyl.

    [0926] 80. The compound of any one of Embodiments 1-77, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkyl.

    [0927] 81. The compound of any one of Embodiments 1-80, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkoxy optionally substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl.

    [0928] 82. The compound of any one of Embodiments 1-81, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkoxy substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl.

    [0929] 83. The compound of any one of Embodiments 1-82, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkoxy substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl substituted with C1-C6 alkyl, aralkyl, heteroaralkyl, or C(O)C3-C6 cycloalkyl.

    [0930] 84. The compound of any one of Embodiments 1-82, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkoxy substituted with NR.sup.AR.sup.B or 4-10 membered heterocyclyl.

    [0931] 85. The compound of any one of Embodiments 1-81, wherein 1, 2, or 3 of R.sup.2A are independently C1-C6 alkoxy.

    [0932] 86. The compound of any one of Embodiments 1-85, wherein 1, 2, or 3 of R.sup.2A are independently C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

    [0933] 87. The compound of any one of Embodiments 1-86, wherein 1, 2, or 3 of R.sup.2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

    [0934] 88. The compound of any one of Embodiments 1-87, wherein 1, 2, or 3 of R.sup.2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl substituted with C1-C6 alkyl.

    [0935] 89. The compound of any one of Embodiments 1-87, wherein 1, 2, or 3 of R.sup.2A are independently C3-C6 cycloalkyl substituted with 4-10 membered heterocyclyl.

    [0936] 90. The compound of any one of Embodiments 1-86, wherein 1, 2, or 3 of R.sup.2A are independently C3-C6 cycloalkyl.

    [0937] 91. The compound of any one of Embodiments 1-47, wherein R.sup.2 is C1-C6 alkoxy optionally substituted with C(O)NR.sup.AR.sup.C.

    [0938] 92. The compound of any one of Embodiments 1-47 or 91, wherein R.sup.2 is C1-C6 alkoxy substituted with C(O)NR.sup.AR.sup.C.

    [0939] 93. The compound of any one of Embodiments 1-47 or 91, wherein R.sup.2 is C1-C6 alkoxy.

    [0940] 94. The compound of any one of Embodiments 1-47, R.sup.2 is C1-C6 alkoxyalkyl optionally substituted with C(O)NR.sup.AR.sup.C.

    [0941] 95. The compound of any one of Embodiments 1-47, R.sup.2 is C1-C6 alkoxyalkyl

    [0942] 96. The compound of any one of Embodiments 1-95, wherein X is a bond.

    [0943] 97. The compound of any one of Embodiments 1-95, wherein X is CH.sub.2.

    [0944] 98. The compound of any one of Embodiments 1-95, wherein X is CH(CH.sub.3).

    [0945] 99. The compound of any one of Embodiments 1-95, wherein X is C(CH.sub.3).sub.2.

    [0946] 100. The compound of any one of Embodiments 1-95, wherein X is

    ##STR00332##

    [0947] 101. The compound of any one of Embodiments 1-72, wherein W is O.

    [0948] 102. The compound of any one of Embodiments 1-72, wherein R.sup.3A is hydrogen.

    [0949] 103. The compound of any one of Embodiments 1-72, wherein R.sup.3A is C1-C6 alkyl.

    [0950] 104. The compound of any one of Embodiments 1-73, wherein R.sup.3A is methyl.

    [0951] 105. The compound of any one of Embodiments 1-72, wherein R.sup.3A is C1-C6 alkoxy.

    [0952] 106. The compound of any one of Embodiments 1-72, R.sup.3A is C1-C6 haloalkyl.

    [0953] 107. The compound of any one of Embodiments 1-72, wherein W is NR.sup.3B.

    [0954] 108. The compound of Embodiment 107, wherein one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is C1-C6 alkyl.

    [0955] 109. The compound of Embodiment 107-108, wherein one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is methyl.

    [0956] 110. The compound of Embodiment 107, wherein each of R.sup.3A and R.sup.3B is hydrogen.

    [0957] 111. The compound of Embodiment 107, wherein each of R.sup.3A and R.sup.3B is an independently selected C1-C6 alkyl.

    [0958] 112. The compound of Embodiment 107 or 111, wherein each of R.sup.3A and RIB is methyl.

    [0959] 113. The compound of Embodiment 107, wherein one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is C1-C6 alkoxy.

    [0960] 114. The compound of Embodiment 107, wherein one of R.sup.3A and R.sup.3B is C1-C6 alkyl and the other of R.sup.3A and R.sup.3B is C1-C6 alkoxy.

    [0961] 115. The compound of Embodiment 107, wherein each of R.sup.3A and R.sup.3B is C1-C6 alkoxy.

    [0962] 116. The compound of Embodiment 107, wherein one of R.sup.3A and R.sup.3B is hydrogen and the other of R.sup.3A and R.sup.3B is C1-C6 haloalkyl.

    [0963] 117. The compound of Embodiment 107, wherein one of R.sup.3A and R.sup.3B is C1-C6 alkyl and the other of R.sup.3A and R.sup.3B is C1-C6 haloalkyl.

    [0964] 118. The compound of Embodiment 107, wherein each of R.sup.3A and R.sup.3B is C1-C6 haloalkyl.

    [0965] 119. The compound of Embodiment 107, wherein R.sup.3A and R.sup.3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group.

    [0966] 120. The compound of any one of Embodiments 1-119, wherein Y is phenyl optionally substituted with 1-3 independently selected R.sup.Y.

    [0967] 121. The compound of any one of Embodiments 1-119, wherein Y is naphthyl optionally substituted with 1-3 independently selected R.sup.Y.

    [0968] 122. The compound of any one of Embodiments 1-119, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected R.sup.Y.

    [0969] 123. The compound of any one of Embodiments 1-122, wherein 1, 2, or 3 of R.sup.Y is independently halogen.

    [0970] 124. The compound of any one of Embodiments 1-123, wherein 1, 2, or 3 of R.sup.Y is hydroxyl.

    [0971] 125. The compound of any one of Embodiments 1-124, wherein 1, 2, or 3 of R.sup.Y is cyano.

    [0972] 126. The compound of any one of Embodiments 1-125, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 haloalkyl.

    [0973] 127. The compound of any one of Embodiments 1-126, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 alkoxy.

    [0974] 128. The compound of any one of Embodiments 1-127, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 haloalkoxy.

    [0975] 129. The compound of any one of Embodiments 1-128, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 hydroxyalkyl.

    [0976] 130. The compound of any one of Embodiments 1-129, wherein 1, 2, or 3 of R.sup.Y is independently NHC(O)R.sup.C.

    [0977] 131. The compound of any one of Embodiments 1-130, wherein 1, 2, or 3 of R.sup.Y is independently C(O)NHR.sup.Y1.

    [0978] 132. The compound of any one of Embodiments 1-131, wherein 1, 2, or 3 of R.sup.Y is independently CO.sub.2R.sup.A.

    [0979] 133. The compound of any one of Embodiments 1-132, wherein 1, 2, or 3 of R.sup.Y is independently SO.sub.2NR.sup.FR.sup.G.

    [0980] 134. The compound of any one of Embodiments 1-133, wherein 1, 2, or 3 of R.sup.Y is independently NHSO.sub.2R.sup.F.

    [0981] 135. The compound of any one of Embodiments 1-134, wherein 1, 2, or 3 of R.sup.Y is independently S(O)(NR.sup.F)R.sup.G.

    [0982] 136. The compound of any one of Embodiments 1-135, wherein 1, 2, or 3 of R.sup.Y is independently SO.sub.2(C1-C6 alkyl).

    [0983] 137. The compound of any one of Embodiments 1-136, wherein 1, 2, or 3 of R.sup.Y is independently C(O)NR.sup.AR.sup.B.

    [0984] 138. The compound of any one of Embodiments 1-137, wherein 1, 2, or 3 of R.sup.Y is independently 4-6 membered heteroaryl.

    [0985] 139. The compound of any one of Embodiments 1-138, wherein 1, 2, or 3 of R.sup.Y is independently heteroaralkyl.

    [0986] 140. The compound of any one of Embodiments 1-139, wherein 1, 2, or 3 of R.sup.Y is independently 4-6 membered heterocyclyl.

    [0987] 141. The compound of any one of Embodiments 1-140, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl optionally substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1.

    [0988] 142. The compound of any one of Embodiments 1-141, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl optionally substituted with R.sup.Y1.

    [0989] 143. The compound of any one of Embodiments 1-142, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl substituted with R.sup.Y1.

    [0990] 144. The compound of any one of Embodiments 1-143, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl substituted with CO.sub.2R.sup.A or 5-6 membered heteroaryl.

    [0991] 145. The compound of any one of Embodiments 1-144, wherein 1, 2, or 3 of R.sup.Y is independently C1-C6 alkyl.

    [0992] 146. The compound of any one of Embodiments 1-122 or 141-143, wherein R.sup.Y1 is SO.sub.2(C1-C6 alkyl).

    [0993] 147. The compound of any one of Embodiments 1-122 or 141-143, wherein R.sup.Y1 is C1-C6 alkyl optionally substituted with oxo.

    [0994] 148. The compound of any one of Embodiments 1-145, wherein 1, 2, or 3 of R.sup.Y1 is hydroxyl.

    [0995] 149. The compound of any one of Embodiments 1-148, wherein R.sup.4 is hydrogen.

    [0996] 150. The compound of any one of Embodiments 1-148, wherein R.sup.4 is C1-C6 alkyl.

    [0997] 151. The compound of any one of Embodiments 1-148, wherein R.sup.4 is acrylamido.

    [0998] 152. The compound of any one of Embodiments 1-151, wherein R.sup.5 is hydrogen.

    [0999] 153. The compound of any one of Embodiments 1-151, wherein R.sup.5 is C1-C6 alkyl.

    [1000] 154. The compound of any one of Embodiments 1-151, wherein R.sup.5 is cyano.

    [1001] 155. The compound of any one of Embodiments 1-151, wherein R.sup.5 is NR.sup.5AR.sup.5B.

    [1002] 156. The compound of any one of Embodiments 1-151, wherein R.sup.5 is C(O)NR.sup.5AR.sup.5B.

    [1003] 157. The compound of any one of Embodiments 1-151, wherein R.sup.5 is NR.sup.5AC(O)R.sup.5B.

    [1004] 158. The compound of any one of Embodiments 1-151 or 145-157, wherein one of R.sup.5A and R.sup.5B is hydrogen and the other of R.sup.5A and R.sup.5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.

    [1005] 159. The compound of any one of Embodiments 1-151 or 155-157, wherein one of R.sup.5A and R.sup.5B is C1-C6 alkyl and the other of R.sup.5A and R.sup.5B is C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.

    [1006] 160. The compound of any one of Embodiments 1-151 or 155-157, wherein each of R.sup.5A and R.sup.5B is hydrogen.

    [1007] 161. The compound of any one of Embodiments 1-151 or 155-157, wherein each of R.sup.5A and R.sup.5B is an independently selected C1-C6 alkyl.

    [1008] 162. The compound of any one of Embodiments 1-161, wherein R.sup.6 is hydrogen.

    [1009] 163. The compound of any one of Embodiments 1-161, wherein R.sup.6 is halogen.

    [1010] 164. The compound of any one of Embodiments 1-161, wherein R.sup.6 is C1-C6 alkyl.

    [1011] 165. The compound of any one of Embodiments 1-164, wherein R.sup.7 is hydrogen.

    [1012] 166. The compound of any one of Embodiments 1-164, wherein R.sup.7 is halogen.

    [1013] 167. The compound of any one of Embodiments 1-164, wherein R.sup.7 is hydroxyl.

    [1014] 168. The compound of any one of Embodiments 1-164, wherein R.sup.7 is cyano.

    [1015] 169. The compound of any one of Embodiment 1-164, wherein R.sup.7 is C1-C6 alkyl.

    [1016] 170. The compound of any one of Embodiment 1-164, wherein R.sup.7 is C1-C6 alkoxyalkyl.

    [1017] 171. The compound of any one of Embodiment 1-164, wherein R.sup.7 C1-C6 hydroxyalkyl.

    [1018] 172. The compound of any one of Embodiment 1-164, wherein R.sup.7 is C1-C6 cyanoalkyl.

    [1019] 173. The compound of any one of Embodiment 1-164, wherein R.sup.7 is C(O)C1-C6 alkyl.

    [1020] 174. The compound of any one of Embodiment 1-164, wherein R.sup.7 is NH(CN).

    [1021] 175. The compound of any one of Embodiment 1-164, wherein R.sup.7 is 5-6 membered heteroaryl.

    [1022] 176. The compound of any one of Embodiments 1-164, wherein R.sup.7 is NR.sup.7AR.sup.7B.

    [1023] 177. The compound of any one of Embodiments 1-164, wherein R.sup.7 is NR.sup.7AC(O)R.sup.7B.

    [1024] 178. The compound of any one of Embodiment 1-164, wherein R.sup.7 is C(NR.sup.7A)NR.sup.7AR.sup.7B.

    [1025] 179. The compound of any one of Embodiment 1-164, wherein R.sup.7 is 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 haloalkyl, C(O)C1-C6 alkyl, C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C(O)NR.sup.7AR.sup.7B, or NHC(O)C1-C6 alkyl optionally substituted with NR.sup.7AR.sup.7B.

    [1026] 180. The compound of any one of Embodiment 1-164, wherein each --- adjacent to CR.sup.7 is a single bond, R.sup.7 is oxo.

    [1027] 181. The compound of any one of Embodiments 1-164, wherein R.sup.7 is C(O)NR.sup.7AR.sup.7B.

    [1028] 182. The compound of any one of Embodiments 1-164 or 176-179, wherein one of R.sup.7A and R.sup.7B is hydrogen and the other of R.sup.1A and R.sup.5B is C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo.

    [1029] 183. The compound of any one of Embodiments 1-164 or 176-179, wherein one of R.sup.7A and R.sup.7B is C1-C6 alkyl and the other of R.sup.7A and R.sup.7B is C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyl optionally substituted with oxo, or C1-C6 haloalkyl optionally substituted with oxo.

    [1030] 184. The compound of any one of Embodiments 1-164 or 176-179, wherein each of R.sup.7A and R.sup.7B is hydrogen.

    [1031] 185. The compound of any one of Embodiments 1-164 or 176-179, wherein each of R.sup.7A and R.sup.7B is an independently selected C1-C6 alkyl.

    [1032] 186. The compound of any one of Embodiments 1-185, wherein each of R.sup.A and R.sup.B are independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

    [1033] 187. The compound of any one of Embodiments 1-186, wherein one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

    [1034] 188. The compound of any one of Embodiments 1-187, wherein one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl substituted with hydroxyl or C1-C6 alkoxy.

    [1035] 189. The compound of any one of Embodiments 1-188, wherein one of R.sup.A and R.sup.B is hydrogen and the other of R.sup.A and R.sup.B is hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.

    [1036] 190. The compound of any one of Embodiments 1-185, wherein R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl.

    [1037] 191. The compound of any one of Embodiments 1-185 or 190, wherein R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6 alkyl, and C(O)C1-C6 alkyl.

    [1038] 192. The compound of any one of Embodiments 1-185 or 190, wherein R.sup.A and R.sup.B together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl.

    [1039] 193. The compound of any one of Embodiments 1-176, wherein each R.sup.C is independently C3-C6 cycloalkyl, C(O)NR.sup.Y1, or a C1-C6 alkyl substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.

    [1040] 194. The compound of any one of Embodiments 1-193, wherein each R.sup.C is independently C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.

    [1041] 195. The compound of any one of Embodiments 1-193, wherein each R.sup.C is independently C3-C6 cycloalkyl, C(O)NHR.sup.Y1, or a C1-C6 alkyl substituted with NR.sup.AR.sup.B or with 4-10 membered heterocyclyl.

    [1042] 196. The compound of any one of Embodiments 1-192, wherein each R.sup.C is independently C3-C6 cycloalkyl, C(O)NR.sup.Y1, or a C1-C6 alkyl.

    [1043] 197. The compound of any one of Embodiments 1-196, wherein one of R.sup.D and R.sup.E is hydrogen and the other of R.sup.D and R.sup.E is hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy.

    [1044] 198. The compound of any one of Embodiments 1-196, wherein each of R.sup.D and R.sup.E is hydrogen.

    [1045] 199. The compound of any one of Embodiments 1-196, wherein each of R.sup.D and R.sup.E is an independently selected C1-C6 alkyl.

    [1046] 200. The compound of any one of Embodiments 1-196, wherein one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is phenyl or C1-C6 alkyl optionally substituted with oxo or NR.sup.AR.sup.B.

    [1047] 201. The compound of any one of Embodiments 1-196, wherein one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is phenyl or C1-C6 alkyl substituted with oxo or NR.sup.AR.sup.B 202. The compound of any one of Embodiments 1-196, wherein one of R.sup.F and R.sup.G is hydrogen and the other of R.sup.F and R.sup.G is phenyl or C1-C6 alkyl.

    [1048] 203. The compound of any one of Embodiments 1-196, wherein each of R.sup.F and R.sup.G is hydrogen.

    [1049] 204. The compound of any one of Embodiments 1-196, wherein each of R.sup.F and R.sup.G is an independently selected C1-C6 alkyl.

    [1050] 205. A compound selected from the group consisting of the compounds in Table A, Table B, or Table C, or a pharmaceutically acceptable salt of any of the foregoing.

    [1051] 206. A pharmaceutical composition comprising a compound of any one of Embodiments 1-205, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients.

    [1052] 207. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-205, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Embodiment 206.

    [1053] 208. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3K protein, or expression or activity or level of any of the same, and (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-205, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Embodiment 206.

    [1054] 209. A method of treating a PI3K-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3K-associated cancer a therapeutically effective amount of a compound of any one of Embodiments 1-205 or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of Embodiment 206.

    [1055] 210. A method for inhibiting mutant PI3K activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-205, or a pharmaceutically acceptable salt of any of the foregoing.

    [1056] salt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoingsalt of any of the foregoing

    EXAMPLES

    Preparation of Compounds

    [1057] The starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent. LCMS spectra were obtained on a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector.

    [1058] The general methods for the preparation of the compounds of Formula (I), Formula (II), or Formula (III), have been described in an illustrative manner and are intended to be descriptive, rather than limiting. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use provided herein, may be made without departing from the spirit and scope thereof.

    Example 1: Synthesis of Compound 9: 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00333##

    Step 1Synthesis of 8-bromo-6-methyl-2-(pyridin-4-yl)quinazolin-4-ol

    ##STR00334##

    [1059] A mixture of 2-amino-3-bromo-5-methyl-benzamide (1.8 g, 8.7 mmol) (prepared according to the procedure in WO20075668), CuO (1.32 g, 16.6 mmol) and pyridine-4-carbaldehyde (1.12 g, 10.5 mmol) in dimethylacetamide (DMA, 50 mL) was stirred at 135 C. for 16 hours under O.sub.2 atmosphere. After cooling to room temperature, the reaction was poured into water (100 mL). The suspension was filtered and the filter cake was dried in vacuo to give 8-bromo-6-methyl-2-(pyridin-4-yl)quinazolin-4-ol (360 mg, crude) as a white solid that required no further purification. MS: m/z 318.1 (M+H.sup.+).

    Step 2Synthesis of 1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-one

    ##STR00335##

    [1060] A mixture of 8-bromo-6-methyl-2-(4-pyridyl)quinazolin-4-ol (190 mg, 601 mol), tributyl(1-ethoxyvinyl)stannane (543 mg, 1.5 mmol) and Pd(dppf)Cl.sub.2 (44 mg, 60 umol) in dioxane (10 mL) was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (1 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 10 mL 10% KF solution, stirred at room temperature over 2 hours. The mixture was extracted with EtOAc (20 mL3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give 1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-one (110 mg, 60%) as a white solid. MS: m/z 280.1 (M+H.sup.+).

    Step 3Synthesis of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-one

    ##STR00336##

    [1061] To a solution of 1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-one (110 mg, 508 mol), K.sub.2CO.sub.3 (105 mg, 763 mol) in DMF (10 mL) was added BnBr (83 mg, 483 mol). The reaction mixture was heated to 65 C. for 2 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was added water (20 mL) and extracted with EtOAc (20 mL3). The combined organic layers were washed with brine (20 mL3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-one (180 mg, 44%) as a white solid. MS: m/z 370.1 (M+H.sup.+).

    Step 4Synthesis of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-amine

    ##STR00337##

    [1062] To a solution of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-one (180 mg, 327 mmol), NH.sub.4OAc (252 mg, 3.27 mmol) in MeOH (10 mL) was added NaBH.sub.3CN (62 mg, 980 umol). The reaction was heated to 40 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-amine (62 mg, 52%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.81 (d, J=6.0 Hz, 2H), 8.41 (d, J=6.4 Hz, 2H), 7.96 (s, 1H), 7.91 (s, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.48-7.42 (m, 1H), 7.38 (d, J=7.2 Hz, 1H), 5.82 (s, 2H), 5.28-5.16 (m, 1H), 2.53 (s, 3H), 1.50 (d, J=6.4 Hz, 3H). MS: m/z 371.1 (M+H.sup.).

    Step 5Synthesis of tert-butyl 2-((1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoate

    ##STR00338##

    [1063] A mixture of 1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethan-1-amine (50 mg, 135 umol), tert-butyl 2-bromobenzoate (103 mg, 2.1 mmol), Cs.sub.2CO.sub.3 (176 mg, 540 umol), Pd.sub.2(dba).sub.3 (13 mg, 14 umol), Xantphos (16 mg, 27 umol) in dioxane (5 mL) was stirred at 100 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give the title compound (22 mg, 30%) as a white solid. MS: m/z 547.3 (M+H.sup.+).

    Step 6Synthesis of tert-butyl 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoate

    ##STR00339##

    [1064] To a solution of tert-butyl 2-((1-(4-(benzyloxy)-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoate (54 mg, 99 umol) in MeOH (5 mL) was added wet Pd/C (10 mg, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 0.5 hours under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to afford tert-butyl 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoate (12 mg, 27%) as yellow oil that required no further purification. MS: m/z 457.2 (M+H.sup.+).

    Step 7Synthesis of 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00340##

    [1065] To a mixture of tert-butyl 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoate (12 mg, 26 umol) in DCM (1.5 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (acetonitrile 32%-62%/0.225% formic acid in water) to give 2-((1-(4-hydroxy-6-methyl-2-(pyridin-4-yl)quinazolin-8-yl)ethyl)amino)benzoic acid (2.4 mg, 24%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.78 (s, 1H), 8.81 (d, J=6.0 Hz, 2H), 8.49 (d, J=6.0 Hz, 1H), 8.22 (d, J=6.0 Hz, 2H), 7.88 (s, 1H), 7.81-7.76 (m, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.23-7.15 (m, 1H), 6.56-6.45 (m, 2H), 5.72-5.57 (m, 1H), 2.40 (s, 3H), 1.62 (d, J=6.4 Hz, 3H). MS: m/z 401.2 (M+H.sup.+).

    Example 2: Synthesis of Compound 20: 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino)benzoic acid

    ##STR00341##

    Step 1Synthesis of (3-bromo-5-methylphenyl)methanamine

    ##STR00342##

    [1066] To a solution of 3-bromo-5-methyl-benzonitrile (5 g, 26 mmol) in THE (50 mL) was added borane tetrahydrofuran complex (33 mL, 33 mmol, 1M in THF) at room temperature. The mixture was heated to 70 C. and stirred for 2 hours. After cooling to room temperature, the mixture was quenched with MeOH (20 mL), then the mixture was heated to 70 C. and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give (3-bromo-5-methylphenyl)methanamine (3 g, 58%) as yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.33 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 3.65 (s, 2H), 2.27 (s, 3H). MS: m/z 202.0 (M+H.sup.+).

    Step 2Synthesis of N-(3-bromo-5-methylbenzyl)-2,2-dimethoxyacetamide

    ##STR00343##

    [1067] A mixture of (3-bromo-5-methylphenyl)methanamine (3 g, 15 mmol) and methyl 2,2-dimethoxyacetate (2.2 mL, 18 mmol) was heated to 130 C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% EtOAc in petroleum ether) to give N-(3-bromo-5-methylbenzyl)-2,2-dimethoxyacetamide (4.3 g, 88%) as yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.25 (s, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 6.92-6.81 (m, 1H), 4.76 (s, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.42 (s, 6H), 2.32 (s, 3H). MS: m/z 302.0 (M+H.sup.+).

    Step 3Synthesis of 5-bromo-7-methylisoquinolin-3-ol and 7-bromo-5-methylisoquinolin-3-ol

    ##STR00344##

    [1068] A solution of N-(3-bromo-5-methylbenzyl)-2,2-dimethoxyacetamide (4.3 g, 14 mmol) in conc. H.sub.2SO.sub.4 (12 mL, 230 mmol) was stirred at room temperature for 16 h. The reaction mixture was added to ice water (20 mL) slowly and the mixture was adjusted to pH 7-8 with 1M aqueous NaOH solution, then extracted with EtOAc (60 mL3). The combined organic layers were washed with brine (50 mL2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 5-bromo-7-methylisoquinolin-3-ol and 7-bromo-5-methylisoquinolin-3-ol (3.1 g, crude, mixture of two isomers, inseparable) as yellow solids that required no further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.99 (s, 1H), 8.87 (s, 1H), 8.05-7.84 (m, 1H), 7.76-7.54 (m, 1H), 6.95-6.88 (m, 1H), 2.41 (s, 3H). MS: m/z 239.9 (M+H.sup.).

    Step 4Synthesis of 5-bromo-7-methylisoquinolin-3-yl trifluoromethanesulfonate

    ##STR00345##

    [1069] To a solution of 5-bromo-7-methylisoquinolin-3-ol and 7-bromo-5-methylisoquinolin-3-ol (1 g, 4.2 mmol, mixture of two isomers) in DCM (15 mL) was added pyridine (1 mL, 12.6 mmol) and Tf.sub.2O (1.8 g, 6.3 mmol). The mixture was stirred at 0 C. for 2 hours. The reaction was quenched with water (30 mL) and extracted with DCM (60 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-2% EtOAc in petroleum ether) to give 5-bromo-7-methylisoquinolin-3-yl trifluoromethanesulfonate (600 mg, 37%) as a yellow solid, which was further confirmed by NOESY. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.97 (s, 1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 2.58 (s, 3H). MS: m/z 369.9 (M+H.sup.+).

    Step 5Synthesis of 4-(5-bromo-7-methylisoquinolin-3-yl)morpholine

    ##STR00346##

    [1070] A mixture of 5-bromo-7-methylisoquinolin-3-yl trifluoromethanesulfonate (500 mg, 1.4 mmol), Pd.sub.2(dba).sub.3 (124 mg, 135 mol), Xantphos (156 mg, 270 mol), Cs.sub.2CO.sub.3 (1.3 g, 4.1 mmol) and morpholine (130 mg, 1.5 mmol) in dioxane (20 mL) was stirred at 80 C. for 3 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was quenched with water (30 mL) and extracted with EtOAc (50 mL3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-25% EtOAc in petroleum ether) to give 4-(5-bromo-7-methylisoquinolin-3-yl)morpholine (170 mg, 37%) as a yellow solid. MS: m/z 309.0 (M+H.sup.+).

    Step 6Synthesis of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-one

    ##STR00347##

    [1071] A mixture of 4-(5-bromo-7-methylisoquinolin-3-yl)morpholine (170 mg, 0.6 mmol), tributyl(1-ethoxyvinyl)stannane (354 uL, 1 mmol) and Pd(dppf)Cl.sub.2 (40 mg, 55 mol) in dioxane (10 mL) was degassed and purged with N.sub.2 atmosphere for 3 times. The reaction mixture was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, HCl (2 mL, 1 M) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was added 20 mL 10% KF aqueous solution, stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% EtOAc in petroleum ether) to give 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-one (120 mg, 50%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.89 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 3.90-3.88 (m, 4H), 3.62-3.60 (m, 4H), 2.72 (s, 3H), 2.52 (s, 3H). MS: m/z 271.1 (M+H.sup.+).

    Step 7Synthesis of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-amine

    ##STR00348##

    [1072] To a solution of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-one (110 mg, 407 mol), NH.sub.4OAc (470 mg, 6 mmol) and AcOH (47 L, 814 mol) in MeOH (5 mL). The mixture was stirred at room temperature for 0.5 hours, then NaBH.sub.3CN (77 mg, 1 mmol) was added. The reaction was heated to 60 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to give 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-amine (50 mg, 36%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.89 (s, 1H), 7.63 (s, 1H), 7.52 (s, 1H), 7.00 (s, 1H), 4.66 (q, J=6.4 Hz, 1H), 3.78-3.75 (m, 4H), 3.48-3.46 (m, 4H), 2.41 (s, 3H), 1.33 (d, J=6.4 Hz, 3H). MS: m/z 272.3 (M+H.sup.).

    Step 8Synthesis of tert-butyl 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino)benzoate

    ##STR00349##

    [1073] A mixture of 1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethan-1-amine (50 mg, 184 mol), Pd.sub.2(dba).sub.3 (17 mg, 18 mol), Xantphos (21 mg, 37 mol), Cs.sub.2CO.sub.3 (180 mg, 553 mol) and tert-butyl 2-iodobenzoate (112 mg, 369 mol) in dioxane (5 mL) was stirred at 110 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was diluted with water (15 mL) and extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% EtOAc in petroleum ether) to give tert-butyl 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino)benzoate (40 mg, 46%) as yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.94 (s, 1H), 8.18 (d, J=6.4 Hz, 1H), 7.76 (dd, J=8.0, 1.2 Hz, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 7.19-7.15 (m, 1H), 7.11 (s, 1H), 6.54-6.50 (m, 1H), 6.40 (d, J=8.4 Hz, 1H), 5.36-5.29 (m, 1H), 3.78-3.75 (m, 4H), 3.51-3.49 (m, 4H), 2.33 (s, 3H), 1.59 (d, J=6.4 Hz, 3H), 1.57 (s, 9H). MS: m/z 448.1 (M+H.sup.+).

    Step 9Synthesis of 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino) benzoic acid

    ##STR00350##

    [1074] To a mixture of tert-butyl 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino)benzoate (40 mg, 89 mol) in DCM (1.5 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 40-70%/0.225% formic acid in water) to give 2-((1-(7-methyl-3-morpholinoisoquinolin-5-yl)ethyl)amino) benzoic acid (16 mg, 44%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.93 (s, 1H), 8.46 (s, 1H), 7.81-7.79 (m, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 7.18-7.14 (m, 1H), 7.11 (s, 1H), 6.52-6.48 (m, 1H), 6.36 (d, J=8.4 Hz, 1H), 5.35-5.29 (m, 1H), 3.76 (t, J=4.8 Hz, 4H), 3.50 (t, J=4.8 Hz, 4H), 2.33 (s, 3H), 1.57 (d, J=6.8 Hz, 3H). MS: m/z 392.1 (M+H.sup.+).

    Example 3: Synthesis of Compound 26: 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00351##

    Step 1Synthesis of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one

    ##STR00352##

    [1075] To a mixture of methyl 2-amino-3-bromo-5-methylbenzoate (3 g, 12.3 mmol) (prepared according to the procedure in CN111440161) and 4,4-dimethylpiperidine-1-carbonitrile (2.55 g, 18.5 mmol) in THE (40 mL) was added NaH (983 mg, 24.8 mmol, 60% purity). The reaction mixture was heated to 90 C. for 5 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was quenched water (50 mL) and extracted with EtOAc (50 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (1.5 g, 35%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.39 (s, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 3.70-3.63 (m, 4H), 2.32 (s, 3H), 1.40-1.33 (m, 4H), 0.96 (s, 6H). MS: m/z 352.0 (M+H.sup.+).

    Step 2Synthesis of 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one

    ##STR00353##

    [1076] A mixture of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (650 mg, 1.87 mmol), tributyl(1-ethoxyvinyl)stannane (1.90 g, 5.26 mmol) and Pd(dppf)Cl.sub.2 (272 mg, 0.4 mmol) in dioxane (6 mL) was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (2 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 20 mL 10% KF solution, stirred at room temperature over 2 hours. The mixture was extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (450 mg, 51%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.45 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 3.66-3.60 (m, 4H), 2.73 (s, 3H), 2.35 (s, 3H), 1.41-1.35 (m, 4H), 0.97 (s, 6H). MS: m/z 314.1 (M+H.sup.+).

    Step 3Synthesis of 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-6-methylquinazolin-4(31)-one

    ##STR00354##

    [1077] To a solution of 8-acetyl-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (0.6 g, 1.91 mmol) in MeOH (10 mL) was added NaBH.sub.4 (150 mg, 3.96 mmol) at 0 C. The mixture was stirred at 0 C. for 2 hours under N.sub.2 atmosphere. The reaction was quenched with saturated aqueous (sat. aq.) NH.sub.4Cl (3 mL), diluted with water (20 mL), extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give 2-(4,4-dimethylpiperidin-1-yl)-8-(1-hydroxyethyl)-6-methylquinazolin-4(3H)-one (460 mg, 76%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.26 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 5.36-5.27 (m, 1H), 5.11 (d, J=4.4 Hz, 1H), 3.62-3.55 (m, 4H), 2.34 (s, 3H), 1.41-1.31 (m, 7H), 0.97 (s, 6H). MS: m/z 316.2 (M+H.sup.+).

    Step 4Synthesis of 8-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one

    ##STR00355##

    [1078] To a solution of 2-(4,4-dimethyl-1-piperidyl)-8-(1-hydroxyethyl)-6-methyl-3H-quinazolin-4-one (460 mg, 1.46 mmol) in DCM (6 mL) was added PBr.sub.3 (592.16 mg, 2.19 mmol) at 0 C. The reaction mixture was stirred at 0 C. for 1 hour under N.sub.2 atmosphere. The mixture was quenched with sat. aq. NaHCO.sub.3 (20 mL), extracted with DCM (30 mL2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give 8-(1-bromoethyl)-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (500 mg, crude) as a yellow solid that required no further purification.

    Step 5Synthesis of tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate

    ##STR00356##

    [1079] To a solution of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-6-methyl-3H-quinazolin-4-one (0.4 g, 1.06 mmol) in DMF (4 mL) was added tert-butyl 2-aminobenzoate (613 mg, 3.17 mmol). The mixture was stirred at 90 C. for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (40 mL2). The combined organic layers were washed with brine (30 mL3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 85%-100%/0.225% formic acid in water) to give tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (30 mg, 7%) as yellow oil. MS: m/z 491.4 (M+H.sup.+).

    Step 6Synthesis of tert-butyl 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate

    ##STR00357##

    [1080] To a solution of tert-butyl 2-((1-(2-(4,4-dimethylpiperidin-1-yl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (30 mg, 61 mol) in DMF (1 mL) was added BOP (35 mg, 79 mol), DBU (14 mg, 92 mol), NaCN (10 mg, 183 mol,) and 18-crown-6 (48 mg, 182 mol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was added water (20 mL) and extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (30 mL3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% EtOAc in petroleum ether) to give tert-butyl 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate (18 mg, 59%) as a yellow solid. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.88-7.85 (m, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.61-7.59 (m, 1H), 7.24-7.20 (m, 1H), 6.83-6.77 (m, 2H), 5.65-5.59 (m, 1H), 3.94-3.88 (m, 4H), 2.41 (s, 3H), 1.82 (d, J=5.2 Hz, 3H), 1.60 (s, 9H), 1.48-1.43 (m, 4H) 1.05 (s, 6H). MS: m/z 500.1 (M+H.sup.+).

    Step 7Synthesis of 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00358##

    [1081] To a solution of tert-butyl 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate (18 mg, 36 umol) in DCM (2 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 85%-100%/0.225% formic acid in water) to give 2-((1-(4-cyano-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoic acid (2.7 mg, 19%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.70 (s, 1H), 8.48 (s, 1H), 7.79 (d, J=6.4 Hz, 1H), 7.64 (s, 1H), 7.56 (s, 1H), 7.16 (s, 1H), 6.52-6.48 (m, 1H), 6.40 (s, 1H), 5.43 (s, 1H), 3.89 (s, 4H), 2.39 (s, 3H), 1.60 (d, J=6.4 Hz, 3H), 1.46-1.40 (m, 4H), 1.01 (s, 6H). MS: m/z 444.2 (M+H.sup.+).

    Example 4: Synthesis of Compound 32: (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00359##

    Step 1Synthesis of 8-bromo-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one

    ##STR00360##

    [1082] A mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (2.3 g, 9.5 mmol) (prepared according to the procedure in Eur. J. Med. Chem., 2021, 225, 113764), 4-fluorobenzaldehyde (2 g, 16.1 mmol) and CuO (1.5 g, 18.9 mmol) in DMA (20 mL) was stirred at 135 C. for 16 hours under O.sub.2 atmosphere. After cooling to room temperature, the reaction was poured into water (50 mL), the suspension was filtered and the filter cake was dried in vacuo to give 8-bromo-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (1.3 g, crude) as a white solid that required no further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99 (s, 1H), 7.95 (s, 1H), 7.79-7.74 (m, 2H), 7.44-7.35 (m, 2H), 3.35 (s, 3H), 2.45 (s, 3H). MS: m/z 347.0 (M+H.sup.+).

    Step 2Synthesis of 8-acetyl-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one

    ##STR00361##

    [1083] A mixture of 8-bromo-2-(4,4-dimethylpiperidin-1-yl)-6-methylquinazolin-4(3H)-one (1.28 g, 3.69 mmol), tributyl(1-ethoxyvinyl)stannane (4 mL, 11.85 mmol) and Pd(dppf)Cl.sub.2 (270 mg, 0.37 mmol) in dioxane (10 mL) was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (5 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 40 mL 10% KF solution, stirred at room temperature over 2 hours. The mixture was extracted with EtOAc (50 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give 8-acetyl-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (500 mg, 44%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.15 (d, J=1.2 Hz, 1H), 7.84-7.74 (m, 3H), 7.43-7.37 (m, 2H), 3.40 (s, 3H), 2.71 (s, 3H), 2.49 (s, 3H). MS: m/z 311.1 (M+H.sup.+).

    Step 3Synthesis of 8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one

    ##STR00362##

    [1084] To a solution of 8-acetyl-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (180 mg, 0.58 mmol), NH.sub.4OAc (447 mg, 5.8 mmol) in MeOH (10 mL) was added NaBH.sub.3CN (110 mg, 1.74 mmol). The reaction was heated to 40 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give 8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (160 mg, 88%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.88 (s, 1H), 7.81-7.77 (m, 3H), 7.43-7.37 (m, 2H), 4.88-4.82 (m, 1H), 3.38 (s, 3H), 2.47 (s, 3H), 1.36 (d, J=6.8 Hz, 3H). MS: m/z 312.2 (M+H.sup.+).

    Step 4Synthesis of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate

    ##STR00363##

    [1085] A mixture of 8-(1-aminoethyl)-2-(4-fluorophenyl)-3,6-dimethylquinazolin-4(3H)-one (160 mg, 514 mol), tert-butyl 2-iodobenzoate (391 mg, 1.28 mmol), Pd.sub.2(dba).sub.3 (47 mg, 51 mol), Xantphos (60 mg, 103 mol) and Cs.sub.2CO.sub.3 (502 mg, 1.54 mmol) in dioxane (5 mL) was stirred at 100 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (180 mg, 71%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.24 (d, J=6.8 Hz, 1H), 7.93-7.84 (m, 3H), 7.73 (dd, J=8.0, 1.6 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.44-7.38 (m, 2H), 7.22-7.13 (m, 1H), 6.55-6.42 (m, 2H), 5.47-5.36 (m, 1H), 3.41 (s, 3H), 2.40 (s, 3H), 1.59-1.53 (m, 12H). MS: m/z 488.2 (M+H.sup.+).

    Step 5Synthesis of 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00364##

    [1086] To a mixture of tert-butyl 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (100 mg, 205 mol) in DCM (2 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 51%-81%/0.225% formic acid in water) to give 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (65 mg, 73%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.69 (s, 1H), 8.52-8.31 (m, 1H), 7.88-7.83 (m, 3H), 7.78 (dd, J=8.0, 1.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.45-7.38 (m, 2H), 7.19-7.13 (m, 1H), 6.52-6.46 (m, 1H), 6.41 (d, J=8.4 Hz, 1H), 5.50-5.43 (m, 1H), 3.41 (s, 3H), 2.39 (s, 3H), 1.53 (d, J=6.8 Hz, 3H). MS: m/z 432.2 (M+H.sup.+).

    Step 6Synthesis of (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00365##

    [1087] 2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino) benzoic acid (65 mg, 151 umol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250 mm*30 mm, 10 um); Supercritical CO.sub.2/EtOH+0.1% NH.sub.3.Math.H.sub.2O=75/25; 70 mL/min) to afford (R)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (19 mg, first peak) and (S)-2-((1-(2-(4-fluorophenyl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (16 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.51-8.39 (m, 1H), 7.88-7.82 (m, 3H), 7.78 (dd, J=8.0, 1.6 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.45-7.37 (m, 2H), 7.19-7.12 (m, 1H), 6.51-6.45 (m, 1H), 6.40 (d, J=8.4 Hz, 1H), 5.49-5.43 (m, 1H), 3.41 (s, 3H), 2.38 (s, 3H), 1.53 (d, J=6.8 Hz, 3H). MS: m/z 432.2 (M+H.sup.+).

    Example 5: Synthesis of Compound 33: (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00366##

    Step 1Synthesis of 1,3-dimethyl-1H-indazole-5-carbaldehyde

    ##STR00367##

    [1088] To a stirred solution of 5-bromo-1,3-dimethyl-indazole (2 g, 8.89 mmol) in dry THF (20 mL) was added n-BuLi (4.27 mL, 10.68 mmol, 2.5 M in hexane) at 78 C. under N.sub.2 atmosphere. The resulting reaction mixture was stirred at this temperature for 15 minutes. Then dry DMF (685 uL, 8.89 mmol) was added to the reaction mixture at 78 C. The mixture was stirred at this temperature for 2 hours. After complete consumption of the starting material, the reaction mixture was quenched with water (30 mL), extracted with EtOAc (50 mL2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give 1,3-dimethyl-1H-indazole-5-carbaldehyde (1.5 g, 96%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.01 (s, 1H), 8.38 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 4.00 (s, 3H), 2.54 (s, 3H). MS: m/z 175.1 (M+H.sup.+).

    Step 2Synthesis of 8-bromo-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazolin-4(3H)-one

    ##STR00368##

    [1089] A mixture of 2-amino-3-bromo-N,5-dimethylbenzamide (1.5 g, 6.17 mmol) (prepared according to the procedure in Eur. J Med. Chem., 2021, 225, 113764), 1,3-dimethyl-1H-indazole-5-carbaldehyde (1.29 g, 7.40 mmol) and CuO (982 mg, 12.34 mmol) in DMA (30 mL) was stirred at 135 C. for 16 hours under O.sub.2 atmosphere. After cooling to room temperature, the reaction was poured into water (100 mL), extracted with EtOAc (100 mL2). The combined organic layers were washed with brine (100 mL3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give 8-bromo-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazolin-4(3H)-one (1.5 g, 61%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.99 (s, 1H), 7.71 (s, 1H), 7.70 (d, J=1.2 Hz, 1H), 4.03 (s, 3H), 3.40 (s, 3H), 2.53 (s, 3H), 2.47 (s, 3H). MS: m/z 397.1 (M+H.sup.+).

    Step 3Synthesis of 8-acetyl-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazolin-4(3H)-one

    ##STR00369##

    [1090] A mixture of 8-bromo-2-(1,3-dimethylindazol-5-yl)-3,6-dimethyl-quinazolin-4-one (400 mg, 1.01 mmol), tributyl(1-ethoxyvinyl)stannane (1.09 g, 3.02 mmol), Pd(dppf)Cl.sub.2 (74 mg, 101 mol) in dioxane (10 mL) was stirred at 90 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction mixture was added 1M HCl in water (5 mL) and stirred at room temperature for 0.5 hours. The reaction mixture was added 50 mL 10% KF solution, stirred at room temperature over 2 hours. The mixture was extracted with EtOAc (60 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give 8-acetyl-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazolin-4(3H)-one (200 mg, 51%) as yellow oil. MS: m/z 361.2 (M+H.sup.+).

    Step 4Synthesis of 8-(1-aminoethyl)-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazolin-4(3H)-one

    ##STR00370##

    [1091] To a solution of 8-acetyl-2-(1,3-dimethylindazol-5-yl)-3,6-dimethyl-quinazolin-4-one (700 mg, 1.94 mmol), NH.sub.4OAc (1.50 g, 19.42 mmol) in MeOH (10 mL) was added NaBH.sub.3CN (336 mg, 5.83 mmol). The reaction was heated to 40 C. for 16 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was diluted with water (30 mL), extracted with EtOAc (50 mL3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM) to give 8-(1-aminoethyl)-2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethylquinazolin-4(3H)-one (250 mg, 36%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (s, 1H), 7.85 (s, 1H), 7.78 (d, J-1.6 Hz, 1H), 7.73-7.67 (m, 2H), 4.85-4.67 (m, 1H), 4.02 (s, 3H), 3.42 (s, 3H), 2.52 (s, 3H), 2.47 (s, 3H), 2.11 (s, 2H), 1.31 (d, J=6.4 Hz, 3H). MS: m/z 362.3 (M+H.sup.+).

    Step 5Synthesis of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate

    ##STR00371##

    [1092] A mixture of 8-(1-aminoethyl)-2-(1,3-dimethylindazol-5-yl)-3,6-dimethyl-quinazolin-4-one (250 mg, 692 mol), tert-butyl 2-iodobenzoate (421 mg, 1.38 mmol), Pd.sub.2(dba).sub.3 (63 mg, 69 mol), Xantphos (80 mg, 138 mol) and Cs.sub.2CO.sub.3 (676 mg, 2.08 mmol) in dioxane (10 mL) was stirred at 100 C. for 3 hours under N.sub.2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (350 mg, 94%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (d, J=6.8 Hz, 1H), 8.14 (s, 1H), 7.88 (d, J=0.8 Hz, 1H), 7.80-7.77 (m, 1H), 7.74-7.71 (m, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.21-7.15 (m, 1H), 6.54-6.40 (m, 2H), 5.51-5.43 (m, 1H), 3.47 (s, 3H), 2.53 (s, 3H), 2.40 (s, 3H), 1.99 (s, 3H), 1.57 (d, J=6.8 Hz, 3H), 1.52 (s, 9H). MS: m/z 538.2 (M+H.sup.+).

    Step 6Synthesis of 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00372##

    [1093] To a mixture of tert-butyl 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate (350 mg, 651 mol) in DCM (3 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 51%-81%/0.225% formic acid in water) to give 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (150 mg, 41%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.68 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.78-7.75 (m, 1H), 7.74-7.71 (m, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.17 (s, 1H), 6.55-6.39 (m, 2H), 5.51-5.49 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.54 (d, J=6.8 Hz, 3H). MS: m/z 482.3 (M+H.sup.+).

    Step 7Synthesis of (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid & (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00373##

    [1094] 2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (150 mg, 312 mol) was separated by using chiral SFC (DAICEL CHIRALCEL AD (250 mm*30 mm, 10 um); Supercritical CO.sub.2/EtOH+0.1% NH.sub.3.Math.H.sub.2O=55/45; 70 mL/min) to afford (R)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (60 mg, first peak) and (S)-2-((1-(2-(1,3-dimethyl-1H-indazol-5-yl)-3,6-dimethyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid (59 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Second peak: .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.51-8.35 (m, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.82-7.70 (m, 3H), 7.57 (d, J=1.8 Hz, 1H), 7.23-7.10 (m, 1H), 6.54-6.40 (m, 2H), 5.53-5.42 (m, 1H), 4.03 (s, 3H), 3.47 (s, 3H), 2.53 (s, 3H), 2.39 (s, 3H), 1.54 (d, J=6.8 Hz, 3H). MS: m/z 482.2 (M+H.sup.+).

    Example 6: Synthesis of Compound 62: 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00374##

    Step 1Synthesis of methyl 2-amino-3-bromo-5-methylbenzoate

    ##STR00375##

    [1095] To a solution of 2-amino-3-bromo-5-methyl-benzoic acid (30 g, 130.4 mmol) in MeOH (100 mL) was slowly added concentrated H.sub.2SO.sub.4 (30 mL, 562.8 mmol) dropwise with stirring at room temperature. After the addition, the reaction was heated to 50 C. and stirred for 16 h. After cooling to room temperature, the reaction solution was slowly poured into ice water (60 mL). The mixture was adjusted to pH 7 with aqueous NaOH (2M), then extracted with EtOAc (200 mL3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give the title compound (30 g, 94% yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59 (s, 1H), 7.51 (s, 1H), 6.47 (s, 2H), 3.81 (s, 3H), 2.17 (s, 3H).

    Step 2Synthesis of 8-bromo-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one

    ##STR00376##

    [1096] To a solution of methyl 2-amino-3-bromo-5-methyl-benzoate (15 g, 61.45 mmol) and isoindoline-2-carbonitrile (13.29 g, 92.18 mmol) in THF (30 mL) was added NaH (4.92 g, 122.91 mmol) with stirring at room temperature. The mixture was heated to 70 C. for 3 h under N.sub.2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with sat. aq. NH.sub.4Cl (40 mL), then extracted with EtOAc (100 mL3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give the title compound (11 g, 50%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.49 (s, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.43-7.40 (m, 2H), 7.34-7.31 (m, 2H), 4.90 (s, 4H), 2.34 (s, 3H).

    Step 3Synthesis of 8-acetyl-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one

    ##STR00377##

    [1097] A mixture of 8-bromo-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one (24.0 g, 67.4 mmol), tributyl(1-ethoxyvinyl)stannane (37.8 g, 104.6 mmol), Pd(dppf)Cl.sub.2 (2.46 g, 3.37 mmol) in dioxane (300 mL) was stirred at 90 C. for 16 h under N.sub.2 atmosphere. After cooling to room temperature, the mixture was quenched with 200 mL of 10% KF aqueous solution and stirred for 30 min. The mixture was extracted with EtOAc (300 mL2). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a crude product (23 g) as a yellow solid. The crude product was dissolved in dioxane (300 mL), then added aqueous HCl (1M, 40 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered to give the title compound (21 g, crude) as a gray solid that required no further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (s, 1H), 7.54-7.30 (m, 5H), 4.98 (s, 4H), 2.84 (s, 3H), 2.42 (s, 3H). MS: m/z 320.2 (M+H.sup.+).

    Step 4Synthesis of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H.SUB.1.)-one

    ##STR00378##

    [1098] To a solution of 8-acetyl-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one (16.0 g, 50.1 mmol) in MeOH (30 mL) was added NaBH.sub.4 (3.61 g, 95.4 mmol) at 0 C. The mixture was stirred at room temperature for 2 h under N.sub.2 atmosphere. The mixture was quenched with sat. aq. NH.sub.4Cl (30 mL) at 0 C., diluted with water (30 mL). The mixture was stirred at 0 C. for 10 min. The suspension solution was filtered, the filter cake was washed with water (30 mL2) and dried in vacuo to give the title compound (14 g, crude) as a yellow solid that required no further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.62 (s, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 7.44-7.39 (m, 2H), 7.34-7.30 (m, 2H), 5.45-5.33 (m, 1H), 5.23 (s, 1H), 4.87 (s, 4H), 2.34 (s, 3H), 1.41 (d, J=6.0 Hz, 3H). MS: m/z 322.2 (M+H.sup.+).

    Step 5Synthesis of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one

    ##STR00379##

    [1099] To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one (1.1 g, 3.4 mmol) in DCM (33 mL) was slowly added PBr.sub.3 (926 mg, 3.4 mmol) at 0 C. under N.sub.2 atmosphere. The mixture was stirred at 0 C. for 1 h. After the reaction was completed, the reaction mixture was concentrated to give the title compound (1.31 g, crude) that required no further purification.

    Step 6Synthesis of tert-butyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoate

    ##STR00380##

    [1100] The solution of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methylquinazolin-4(3H)-one (1.31 g, 3.4 mmol) in dioxane (11 mL) was adjusted to pH 8 with DIPEA at 0 C. The mixture was added tert-butyl 2-aminobenzoate (1.32 g, 6.8 mmol) and heated to 90 C. for 16 h under N.sub.2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (1 g, 40%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.37 (s, 1H), 8.34-8.27 (m, 1H), 7.75-7.70 (m, 2H), 7.66-7.62 (m, 1H), 7.41-7.40 (m, 2H), 7.34-7.32 (m, 2H), 7.25-7.17 (m, 1H), 6.61-6.55 (m, 1H), 6.50-6.44 (m, 1H), 5.42-5.35 (m, 1H), 5.02-4.90 (m, 4H), 2.28 (s, 3H), 1.61 (d, J=6.8 Hz, 3H), 1.53 (s, 9H). MS: m/z 497.3 (M+H.sup.+).

    Step 7Synthesis of tert-butyl 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate

    ##STR00381##

    [1101] To a solution of tert-butyl 2-((1-(4-hydroxy-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate (30 mg, 60 umol) in DMF (3 mL) was added K.sub.2CO.sub.3 (25 mg, 0.18 mmol) and iodoethane (10 mg, 66 mol). The mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction was added water (20 mL) and extracted with EtOAc (20 mL3). The combined organic layers were washed with brine (20 mL3), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% EtOAc in petroleum ether) to give the title compound (23 mg, 73%) as yellow oil, which was further confirmed by 2D NMR (.sup.13C NMR). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.40 (d, J=7.6 Hz, 1H), 7.75-7.70 (m, 1H), 7.60 (s, 1H), 7.49-7.45 (m, 3H), 7.35-7.31 (m, 2H), 7.22-7.15 (m, 1H), 6.60 (d, J=8.4 Hz, 1H), 6.49-6.45 (m, 1H), 5.51-5.47 (m, 1H), 5.02-4.89 (m, 4H), 4.64 (q, J=7.2 Hz, 2H), 2.33 (s, 3H), 1.67 (d, J=6.8 Hz, 3H), 1.53 (s, 9H), 1.48 (t, J=7.2 Hz, 3H). MS: m/z 525.3 (M+H.sup.+).

    Step 8Synthesis of 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00382##

    [1102] To a mixture of tert-butyl 2-((1-(4-ethoxy-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 80 umol) in DCM (3 mL) was added TFA (0.5 mL, 6.9 mmol).

    [1103] The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 75%-100%/0.225% formic acid in water) to give the title compound (7 mg, 19%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.63 (s, 1H), 8.63 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.50-7.43 (m, 3H), 7.36-7.33 (m, 2H), 7.23-7.16 (m, 1H), 6.56 (d, J=8.8 Hz, 1H), 6.47 (t, J=7.6 Hz, 1H), 5.54-5.50 (m, 1H), 5.11-4.87 (m, 4H), 4.63 (q, J=7.2 Hz, 2H), 2.33 (s, 3H), 1.65 (d, J=6.4 Hz, 3H), 1.48 (t, J=7.2 Hz, 3H). MS: m/z 469.1 (M+H.sup.+).

    Example 7: Synthesis of Compound 63: 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00383##

    Step 1Synthesis of tert-butyl 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate

    ##STR00384##

    [1104] To a solution of tert-butyl 2-((1-(4-hydroxy-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate (150 mg, 302 mol) in acetonitrile (6 mL) was added BOP (200 mg, 453 mol) and DBU (138 mg, 906 mol). The mixture was stirred at room temperature for 10 min, azetidin-3-ol (44 mg, 604 mol,) was added. The final mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to give the title compound (110 mg, 81%) as a white solid. MS: m/z 552.1 (M+H.sup.+).

    Step 2Synthesis of 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoic acid

    ##STR00385##

    [1105] To a mixture of tert-butyl 2-((1-(4-(3-hydroxyazetidin-1-yl)-2-(isoindolin-2-yl)-6-methylquinazolin-8-yl)ethyl)amino)benzoate (70 mg, 80 umol) in DCM (2 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 26%-56%/0.225% formic acid in water) to give the title compound (11 mg, 56%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.78-7.73 (m, 1H), 7.65-7.53 (m, 1H), 7.47-7.39 (m, 3H), 7.35-7.28 (m, 3H), 7.20-7.12 (m, 1H), 6.53 (d, J=8.0 Hz, 1H), 6.47-6.43 (m, 1H), 5.81-5.77 (m, 1H), 5.57-5.48 (m, 1H), 4.98-4.81 (m, 4H), 4.72-4.65 (m, 2H), 4.23-4.13 (m, 2H), 2.29 (s, 3H), 1.61 (d, J=6.4 Hz, 3H). MS: m/z 496.1 (M+H.sup.+).

    Example 8: Preparation of (S)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (Compound 159) and (S)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (Compound 157)

    ##STR00386##

    Step 1: Synthesis of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-ol

    [1106] To a solution of 3-bromo-2-fluoro-5-methyl-benzaldehyde (3 g, 13.8 mmol) in THF (20 mL) was added MeMgBr (3 M in THF, 9.22 mL) at 0 C. The reaction was stirred at 0 C. for 2 h under a N.sub.2 atmosphere. The mixture was quenched with sat. aq. NH.sub.4Cl (20 mL), diluted with water (20 mL), extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give the title compound (2.5 g, 78%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.25-7.12 (m, 2H), 5.08 (q, J=6.4 Hz, 1H), 1.97 (s, 3H), 1.42 (d, J=6.4 Hz, 3H).

    Step 2: Synthesis of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-one

    [1107] To a solution of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-ol (2.8 g, 12.01 mmol) in DCM (20 mL) was added Dess-Martin (7.6 g, 18 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with sat. aq. Na.sub.2S.sub.2O.sub.3 (20 mL), diluted with water (20 mL), extracted with DCM (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to give the title compound (2.6 g, 93%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) =7.59-7.39 (m, 2H), 2.64 (d, J=5.2 Hz, 3H), 2.34 (s, 3H).

    Step 3: Synthesis of 8-bromo-2-mercapto-6-methyl-4H-thiochromen-4-one

    [1108] To a solution of 1-(3-bromo-2-fluoro-5-methylphenyl)ethan-1-one (3.1 g, 13.42 mmol) in DMF (12 mL) and PhMe (8 mL) was added NaH (1.07 g, 26.8 mmol, 60% purity) and CS.sub.2 (2.04 g, 26.8 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with sat. aq. NH.sub.4Cl (20 mL), diluted with water (20 mL), extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (3 g, 78%) as a yellow solid. MS: m/z 572.8 (2M+H.sup.+).

    Step 4: Synthesis of 8-bromo-2-(ethylthio)-6-methyl-4H-thiochromen-4-one

    [1109] To a solution of 8-bromo-2-mercapto-6-methyl-4H-thiochromen-4-one (2.5 g, 8.7 mmol) in DCM (20 mL) was added EtI (2.72 g, 17.41 mmol) and Et.sub.3N (2.4 mL, 17.41 mmol). The mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (2.5 g, 91%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.21-8.08 (m, 1H), 8.01-7.88 (m, 1H), 6.99 (s, 1H), 3.30-3.24 (m, 2H), 2.45-2.41 (m, 3H), 1.36-1.29 (m, 3H). MS: m/z 315.0 (M+H.sup.+).

    Step 5: Synthesis of 8-bromo-2-(ethylsulfonyl)-6-methyl-4H-thiochromen-4-one

    [1110] To a solution of 8-bromo-2-(ethylthio)-6-methyl-4H-thiochromen-4-one (2.3 g, 7.20 mmol) in AcOH (15 mL) was added H.sub.2O.sub.2 (1.80 g, 15.84 mmol). The mixture was stirred at 60 C. for 2 h. After cooling to room temperature, the mixture was filtered. The crude filter was concentrated in vacuo to give title compound (2.4 g, crude) as a yellow solid. MS: m/z 348.9 (M+H.sup.+).

    Step 6: Synthesis of 8-bromo-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one

    [1111] To a solution of 8-bromo-2-(ethylsulfonyl)-6-methyl-4H-thiochromen-4-one (1.2 g, 3.46 mmol) in t-BuOH (10 mL) was added isoindoline (823 mg, 6.9 mmol). The mixture was stirred at 130 C. for 36 h. After cooling to room temperature, the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (1.2 g, 93%) as a black solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.14 (s, 1H), 7.83 (s, 1H), 7.45-7.42 (m, 2H), 7.38-7.34 (m, 2H), 5.89 (s, 1H), 4.88 (s, 4H), 2.41 (s, 3H). MS: m/z 371.8 (M+H.sup.+).

    Step 7: Synthesis of 8-acetyl-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one

    [1112] To a solution of 8-bromo-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one (1 g, 2.69 mmol) in dioxane (10 mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 (188 mg, 268 mol) and tributyl(1-ethoxyvinyl)stannane (1.94 g, 5.37 mmol). The mixture was stirred at 100 C. for 16 h under N.sub.2 atmosphere. After cooling to room temperature. Aq. HCl (1M, 2 mL) was added and the mixture was stirred at 50 C. for additional 3 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-30% EtOAc in petroleum ether) to give the title compound (800 mg, 88%) as colorless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.43 (s, 1H), 8.29 (s, 1H), 7.45-7.42 (m, 2H), 7.37-7.34 (m, 2H), 5.76-5.75 (m, 1H), 4.83 (s, 4H), 2.72 (s, 3H), 2.47 (s, 3H). MS: m/z 336.1 (M+H.sup.+).

    Step 8: Synthesis of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one

    [1113] To a solution of 8-acetyl-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one in MeOH (5 mL) was added NaBH.sub.4 (45 mg, 1.2 mmol) at 0 C. The mixture was stirred at 0 C. for 2 h under N.sub.2 atmosphere. The reaction was quenched with sat. aq. NH.sub.4Cl (2 mL), diluted with water (20 mL), extracted with EtOAc (10 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (0.18 g, 89%) as a yellow solid. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.16, (s, 1H), 8.13 (s, 1H), 7.44-7.40 (m, 2H), 7.35-7.32 (m, 2H), 6.03 (s, 1H), 5.49 (s, 4H), 4.77-4.74 (m, 1H), 2.41 (s, 3H), 1.61-1.54 (m, 3H). MS: m/z 338.2 (M+H.sup.+).

    Step 9: Synthesis of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one

    [1114] To a solution of 8-(1-hydroxyethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one (150 mg, 444 umol) in DCM (3 mL) was added PBr.sub.3 (120 mg, 666 umol) at 0 C. The mixture was stirred at 0 C. for 1 h under N.sub.2 atmosphere. The reaction was concentrated in vacuo to give the title compound (2.25 g, crude) as a yellow solid. MS: m/z 400.1 (M+H.sup.+).

    Step 10: Synthesis of tert-butyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoate

    [1115] To a solution of 8-(1-bromoethyl)-2-(isoindolin-2-yl)-6-methyl-4H-thiochromen-4-one (50 mg, 125 umol) in DMF (2 mL) was added tert-butyl 2-aminobenzoate (48 mg, 250 umol). The mixture was stirred at 100 C. for 2 h. The reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (25 mg, 39%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.29 (d, J=5.6 Hz, 1H), 8.05 (m, 1H), 7.78 (d, J=6.8 Hz, 1H), 7.51 (s, 1H), 7.45-7.32 (m, 4H), 7.25-7.18 (m, 1H), 6.61-6.52 (m, 1H), 6.32 (d, J=8.4 Hz, 1H), 5.90 (s, 1H), 5.04-4.93 (m, 1H), 4.91-4.80 (m, 4H), 2.34 (s, 3H), 1.66 (d, J=6.8 Hz, 3H), 1.60 (s, 9H). MS: m/z 513.1 (M+H.sup.+).

    Step 11: Synthesis of 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid

    [1116] To a solution of tert-butyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoate (25 mg, 49 umol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-10% MeOH in DCM (1% AcOH)) to give the title compound (20 mg, 89%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.85 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 7.88-7.78 (m, 1H), 7.50-7.47 (m, 1H), 7.47-7.42 (m, 2H), 7.40-7.34 (m, 2H), 7.23-7.21 (m, 1H), 6.62-6.48 (m, 1H), 6.35-6.24 (m, 1H), 5.92 (s, 1H), 5.03-4.95 (m, 1H), 4.93-4.83 (m, 4H), 2.34 (s, 3H), 1.63 (d, J=6.8 Hz, 1H). MS: m/z 457.1 (M+H.sup.+).

    Step 12: Synthesis of (R)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (Compound 159) and (S)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (Compound 157)

    [1117] 2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (20 mg, 43 umol) was separated by using chiral SFC (DAICEL CHIRALCEL J (250 mm*30 mm, 10 um); Supercritical CO.sub.2/EtOH+0.1% NH.sub.3H.sub.2O=55/45; 60 ml/min) to afford (R)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (8 mg, first peak) and (S)-2-((1-(2-(isoindolin-2-yl)-6-methyl-4-oxo-4H-thiochromen-8-yl)ethyl)amino)benzoic acid (7 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer.

    [1118] Compound 159: .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.87 (s, 1H), 8.59 (s, 1H), 8.06 (s, 1H), 7.83 (d, J=5.6 Hz, 1H), 7.50-7.47 (m, 1H), 7.47-7.42 (m, 2H), 7.40-7.34 (m, 2H), 7.22-7.20 (m, 1H), 6.62-6.48 (m, 1H), 6.35-6.24 (m, 1H), 5.93 (s, 1H), 5.03-4.95 (m, 1H), 4.93-4.83 (m, 4H), 2.34 (s, 3H), 1.63 (d, J=6.8 Hz, 1H). MS: m/z 457.1 (M+H.sup.+).

    Example 9: Preparation of (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 158)

    ##STR00387##

    Step 1: Synthesis of 2,4-dibromo-3-(methoxymethoxy)-6-methylpyridine

    [1119] To a solution of 2,4-dibromo-6-methyl-pyridin-3-ol (3.4 g, 12.7 mmol) in DCM (30 mL) was added DIEA (3.33 mL, 19.1 mmol) and bromo(methoxy)methane (1.25 mL, 15.3 mmol) dropwise at room temperature. After the addition, the reaction was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL), extracted with DCM (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% ethyl acetate in petroleum ether) to give the title compound (3.7 g, 93%) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (s, 1H), 5.19 (s, 2H), 3.73 (s, 3H), 2.50 (s, 3H).

    Step 2: Synthesis of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-ol

    [1120] To a solution of 2,4-dibromo-3-(methoxymethoxy)-6-methylpyridine (3.7 g, 11.9 mmol) in THF (40 mL) was added n-BuLi (2.5 M, 5.71 mL) dropwise at 78 C. under N.sub.2 atmosphere. After the addition, the mixture was stirred at 78 C. for 10 min. Then acetaldehyde (5 M, 7.14 mL) was added to the mixture dropwise. The mixture was stirred at room temperature for 16 h. The mixture was quenched with sat. aq. NH.sub.4Cl (30 mL) and extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-20% ethyl acetate in petroleum ether) to give the title compound (1.67 g, 51%) as yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.22 (s, 1H), 5.22-5.16 (m, 2H), 5.10 (d, J=6.4 Hz, 1H), 3.64 (s, 3H), 2.86 (d, J=3.6 Hz, 1H), 2.52 (s, 3H), 1.51 (d, J=6.4 Hz, 3H). MS: m/z 276.1 (M+H.sup.+).

    Step 3: Synthesis of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-one

    [1121] To a solution of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-ol (1.67 g, 6.05 mmol) in DCM (30 mL) was added Dess-Martin (3.08 g, 7.26 mmol) in portions at 0 C. After the addition, the mixture was stirred at room temperature for 16 h. The mixture was quenched with sat. aq. Na.sub.2S.sub.2O.sub.3 (20 mL) and washed with sat. aq. NaHCO.sub.3 (100 mL). The mixture was extracted with DCM (100 mL2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-12% ethyl acetate in petroleum ether) to give the title compound (1.4 g, 84%) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.13 (s, 1H), 5.09 (s, 2H), 3.51 (s, 3H), 2.61 (s, 3H), 2.55 (s, 3H). MS: m/z 274.1 (M+H.sup.+).

    Step 4: Synthesis of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-1-one

    [1122] To a solution of 1-(2-bromo-3-(methoxymethoxy)-6-methylpyridin-4-yl)ethan-1-one (1 g, 3.65 mmol) in DCM (5 mL) was added HCl (5 mL, 4M in dioxane). After the addition, the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove the solvent. The residue was dissolved in EtOAc (30 mL), washed with saturated NaHCO.sub.3 (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-12% EtOAc in petroleum ether) to give the title compound (294 mg, 35%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 12.03 (s, 1H), 7.34 (s, 1H), 2.69 (s, 3H), 2.55 (s, 3H). MS: m/z 230.0 (M+H.sup.+).

    Step 5: Synthesis of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)-3-(pyridin-4-yl)propane-1,3-dione

    [1123] To a solution of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)ethan-1-one (1 g, 4.35 mmol) in THF (15 mL) was added LiHMDS (1 M, 13.9 mL) at 78 C. The reaction mixture was stirred at 0 C. for 1 hour. Then the mixture was cooled to 78 C. and to the mixture was added methyl pyridine-4-carboxylate (0.62 mL, 5.22 mmol) dropwise. The mixture was stirred at room temperature for 16 h. The reaction was quenched with aq. HCl (1M, 10 mL) and extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo to give the title compound (1.34 g, crude) as a yellow solid that required no further purification. MS: m/z 337.0 (M+H.sup.+).

    Step 6: Synthesis of 8-bromo-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one

    [1124] To a mixture of 1-(2-bromo-3-hydroxy-6-methylpyridin-4-yl)-3-(pyridin-4-yl)propane-1,3-dione (1.34 g, 4.00 mmol) in AcOH (10 mL) was added H.sub.2SO.sub.4 (0.42 mL, 8.00 mmol). After the addition, the mixture was stirred at 80 C. for 3 h. The mixture was cooled to room temperature and poured into ice-water (30 mL). The mixture was basified with sat. aq. NaHCO.sub.3 to pH7, extracted with EtOAc (50 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-50% EtOAc in petroleum ether) to give the title compound (696 mg, 55%) as a brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.90-8.83 (m, 2H), 8.09-8.03 (m, 2H), 7.78 (s, 1H), 7.45 (s, 1H), 2.60 (s, 3H). MS: m/z 317.0 (M+H.sup.+).

    Step 7: Synthesis of 8-(1-ethoxyvinyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one

    [1125] A mixture of tributyl(1-ethoxyvinyl)stannane (1.64 g, 4.54 mmol), 8-bromo-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one (696 mg, 2.19 mmol), Pd(dppf)Cl.sub.2 (160 mg, 219 umol) in dioxane (10 mL) was degassed with N.sub.2 for 3 times and stirred at 100 C. for 16 h. The mixture was cooled to room temperature. The mixture was poured into 10% KF solution (20 mL) and stirred for 30 min. The mixture was extracted with EtOAc (30 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified with silica gel chromatography (solvent gradient: 0-60% EtOAc in petroleum ether) to give the title compound (545 mg, 80%) as a brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.87-8.84 (m, 2H), 8.87-8.84 (m, 1H), 7.88-7.83 (m, 3H), 6.99 (s, 1H), 4.91 (d, J=2.8 Hz, 1H), 4.74 (d, J=2.8 Hz, 1H), 4.17-4.11 (m, 2H), 2.72 (s, 3H), 1.49 (t, J=7.2 Hz, 3H). MS: m/z 309.1 (M+H.sup.+).

    Step 8: Synthesis of 8-acetyl-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one

    [1126] To a solution of 8-(1-ethoxyvinyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one in THE (10 mL) was added aq. HCl (1M, 3 mL). After the addition, the reaction mixture was stirred at room temperature for 3 h. The mixture was basified with sat. aq. NaHCO.sub.3 to pH 7. Then the mixture was extracted with EtOAc (20 mL2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated to give the title compound (495 mg, 99%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.88-8.85 (m, 2H), 8.15-8.12 (m, 2H), 8.04 (s, 1H), 7.47 (s, 1H), 2.74 (s, 3H), 2.68 (s, 3H). MS: m/z 281.1 (M+H.sup.+).

    Step 9: Synthesis of 8-(1-aminoethyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one

    [1127] A mixture of 8-acetyl-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one (100 mg, 356 umol) and NH.sub.4OAc (275 mg, 3.57 mmol) in MeOH (4 mL) was stirred at room temperature for 1 h. Then to the mixture was added NaBH.sub.3CN (67.3 mg, 1.07 mmol). The resulting mixture was stirred at 60 C. for 4 h. The mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to give the title compound (62 mg, 62%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.90-8.82 (m, 2H), 8.27 (s, 2H), 8.12-8.06 (m, 2H), 7.84 (s, 1H), 7.44 (s, 1H), 5.30-5.22 (m, 1H), 2.68 (s, 3H), 1.61 (d, J=6.8 Hz, 3H). MS: m/z 282.1 (M+H.sup.+).

    Step 10: Synthesis of tert-butyl 2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate

    [1128] A mixture of 8-(1-aminoethyl)-6-methyl-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-4-one (80 mg, 284 umol), tert-butyl 2-iodobenzoate (173 mg, 569 umol), Pd.sub.2(dba).sub.3 (26 mg, 28.4 umol), Xantphos (33 mg, 56.9 umol) and Cs.sub.2CO.sub.3 (278 mg, 853 umol) in dioxane (2 mL) was degassed with N.sub.2 for 3 times. Then the reaction mixture was stirred at 100 C. for 16 h. The mixture was cooled to room temperature, quenched with water (20 mL). The mixture was extracted with EtOAc (20 mL2). The combined organic layers were washed with brine (20 mL2), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-60% EtOAc in petroleum ether) to give the title compound (114 mg, 88%) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.88-8.82 (m, 2H), 8.63 (d, J=7.6 Hz, 1H), 8.15-8.09 (m, 2H), 7.76-7.72 (m, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 7.32 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.58-6.54 (m, 1H), 5.56-5.44 (m, 1H), 2.62 (s, 3H), 1.68 (d, J=6.4 Hz, 3H), 1.51 (s, 9H). MS: m/z 458.0 (M+H.sup.+).

    Step 11: Synthesis of tert-butyl (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate and tert-butyl (S)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate

    [1129] Tert-butyl 2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate (80 mg, 174.86 umol) was separated by prep.SFC (column: DAICEL CHIRALPAK IC(250 mm*30 mm, 10 um), Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=40/60, 80 mL/min) to give tert-butyl (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate (27 mg, 34%) and tert-butyl (S)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate (27 mg, 34%) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m/z 402.0 (M+H.sup.+).

    Step 12: Synthesis of (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoic acid trifluoroacetate (Compound 158)

    [1130] To a solution of tert-butyl tert-butyl (R)-2-((1-(6-methyl-4-oxo-2-(pyridin-4-yl)-4H-pyrano[2,3-c]pyridin-8-yl)ethyl)amino)benzoate (27 mg, 59.01 umol) in DCM (1 mL) was added TFA (1 mL). After the addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated to remove the solvent. The residue was triturated in MeOH (3 mL). The mixture was basified with 1M LiOH to pH 8 and acidified with formic acid to pH 5. To the mixture was added water (2 mL). The mixture was extracted with EtOAc (20 mL3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to give the title compound (14 mg, 59%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.00 (s, 1H), 8.84 (d, J=5.2 Hz, 2H), 8.15-8.05 (m, 2H), 7.83-7.76 (m, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 7.35-7.28 (m, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.57-6.53 (m, 1H), 5.55-5.44 (m, 1H), 2.62 (s, 3H), 1.65 (d, J=6.4 Hz, 3H). MS: m/z 402.0 (M+H.sup.+).

    [1131] Compounds of Formula (III) in Table C can be prepared analogously to Example 8 and 9.

    [1132] Compounds of Formula (I) in Table A can be prepared analogously to Examples 1-7

    [1133] Compounds of Formula (I) in Table D below were prepared analogously to Examples 1-7.

    TABLE-US-00006 TABLE D Cmpd. No. Characterization Data 5 LC-MS: (M + H)+ found 455.1 6 LC-MS: (M + H)+ found 441.1 8 LC-MS: (M + H)+ found 419.2 10 LC-MS: (M + H)+ found 419.2 11 LC-MS: (M + H)+ found 435.3 17 LC-MS: (M + H)+ found 409.1 18 LC-MS: (M + H)+ found 409.1 19 LC-MS: (M + H)+ found 409.1 23 LC-MS: (M + H)+ found 462.1 24 LC-MS: (M + H)+ found 468.2 32 LC-MS: (M + H)+ found 432.1 33 LC-MS: (M + H)+ found 482.1 34 LC-MS: (M + H)+ found 602.3 36 LC-MS: (M + H)+ found 425.3 46 LC-MS: (M + H)+ found 449.1 51 LC-MS: (M + H)+ found 440.2 57 LC-MS: (M + H)+ found 392.1 61 LC-MS: (M + H)+ found 444.3 63 LC-MS: (M + H)+ found 496.1 65 LC-MS: (M + H)+ found 496.1 69 LC-MS: (M + H)+ found 481.3 71 LC-MS: (M + H)+ found 496.1 73 LC-MS: (M + H)+ found 467.3 74 LC-MS: (M + H)+ found 407.1 76 LC-MS: (M + H)+ found 431.2 78 LC-MS: (M + H)+ found 454.1 81 LC-MS: (M + H)+ found 424.3 84 LC-MS: (M + H)+ found 451.1 86 LC-MS: (M + H)+ found 481.1 87 LC-MS: (M + H)+ found 481.1 89 LC-MS: (M + H)+ found 424.3 128 LC-MS: (M + H)+ found 456.1 131 LC-MS: (M + H)+ found 391.1 132 LC-MS: (M + H)+ found 407.2 133 LC-MS: (M + H)+ found 481.2 134 LC-MS: (M + H)+ found 481.3 135 LC-MS: (M + H)+ found 429.1 136 LC-MS: (M + H)+ found 455.1 137 LC-MS: (M + H)+ found 415.2 138 LC-MS: (M + H)+ found 440.1 139 LC-MS: (M + H)+ found 414.1 140 LC-MS: (M + H)+ found 463.4 141 LC-MS: (M + H)+ found 414.2 142 LC-MS: (M + H)+ found 450.1 143 LC-MS: (M + H)+ found 440.1 144 LC-MS: (M + H)+ found 496.1 145 LC-MS: (M + H)+ found 455.1 146 LC-MS: (M + H)+ found 497.1 147 LC-MS: (M + H)+ found 469.1

    Biochemical Assays

    PI3K cellular assay experimental procedure:
    SKBR3 or T47D cells are seeded in DMEM containing 10% FBS at 25 k cells/well into 96-well cell culture format. Cells are incubated overnight at 37 C. in a 5% CO2 incubator and the following day cell media is aspirated, adherent cells are washed 1 with room temperature PBS prior to serum-free media application. Cells are returned to 37 C. 5% CO2 incubator and incubated a further 16 hrs. Compounds are added to serum starved adherent cells with a top dose of 10,000 nM and 3 multiple dose reductions for a minimum dose of 0.5 nM diluted in DMSO. Cell/compound incubation continues for 1 hr in a 37 C., 5% CO2 incubator prior to 10 minute PIK3CA stimulation with 20 ng/ml EGF. Cells treated with 0.1% DMSO and 20 ng/mL EGF are employed as negative control, cells treated with 10 uM Alpelisib and 20 ng/mL EGF are employed as a positive control. After 10 mins, plates are removed from incubator and cells are lysed with buffer and shaking 45 minutes. 20 L of lysate is transferred to an opti-384 plate and 2.5 l of Phospho-AKT d2 antibody with 2.5 l of Phospho-AKT Eu Cryptate solution in the detection buffer are added to each well. 384 well plate is left overnight at room temperature before reading HTRF on an Envision plate reader.

    [1134] The biological activity of certain compounds using the assays described above is shown in Table 2. The ranges are as follows: [1135] for T47D pAKT IC.sub.50 (nM): A denotes <750 nM; B denotes 750 nMIC.sub.50<2,000 nM; C denotes 2,000 nM. ND denotes value not determined with that assay for the specified compound; [1136] for T47D (H1047R) selectivity over SKBR3 (WT): A denotes >20-fold; B denotes 20-foldvalue>5-fold; C denotes 5-fold. ND denotes value not determined with that assay for the specified compound; [1137] for PI3K H1047R ADP-Glo (PI/PS) IC.sub.50 (nM): A denotes <1,000 nM; B denotes 1,000 nMIC.sub.50<10,000 nM; C denotes 10,000 nM. ND denotes value not determined with that assay for the specified compound; and [1138] for PI3K H1047R ADP-Glo (PI/PS) IC.sub.50: H1047R Selectivity: A denotes >20-fold; B denotes 20-foldvalue>5-fold; C denotes 5-fold. ND denotes value not determined with that assay for the specified compound.

    TABLE-US-00007 TABLE 2 Biological Activity of Selected Compounds T47D pAKT S473 T47D pAKT S473 PI3K H1047R HTRF IC50 HTRF IC.sub.50 (H1047R): ADP-Glo PI3K H1047R (H1047R): T47D (H1047R) (PI/PS) IC.sub.50: ADP-Glo (PI/PS) Cmpd. Average selectivity Average IC.sub.50: H1047R No. IC.sub.50 (nM) over SKBR3 (WT) IC.sub.50 (nM) Selectivity 1 C C ND ND 2 C C ND ND 3 C C ND ND 4 C C ND ND 5 B B C ND 6 C C ND ND 7 C C ND ND 8 A A A B 9 A B ND ND 10 A A A A 11 B B ND ND 12 C C ND ND 17 A B ND ND 18 C C ND ND 19 B B B B 21 C C ND ND 23 C C ND ND 24 A A ND ND 26 C C C C 30 B B ND ND 32 A A A A 33 A A A B 34 C C ND ND 35 C C ND ND 36 B B ND ND 37 A A A A 38 A A A A 39 C C ND ND 40 A A A A 41 C C C ND 46 C C ND ND 51 A A A A 57 A A A A 58 C C C ND 59 B B ND ND 60 C C C ND 61 A A ND ND 63 B B ND ND 65 B B ND ND 69 B B ND ND 71 C C ND ND 73 A A A A 74 A A A A 75 B B C ND 76 A A A A 77 A A A A 78 A A A A 79 C C C ND 80 C C C ND 81 A A A A 82 A A A A 83 C C C C 84 A A A A 85 C B B C 86 A A ND ND 87 A A ND ND 88 A A A A 89 A A ND ND 128 A A ND ND 131 A A ND ND 132 A A ND ND 133 A A ND ND 134 A A ND ND 135 A A ND ND 136 A A ND ND 137 A A ND ND 138 A A ND ND 139 B B ND ND 140 A B ND ND 141 A B ND ND 142 A A ND ND 143 A A ND ND 144 B B ND ND 145 A B ND ND 146 A A ND ND 147 C C ND ND