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Title:
THIOPHENE ULK1/2 INHIBITORS AND THEIR USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2023/215494
Kind Code:
A1
Abstract:
Described herein are compounds that are ULK1/2 inhibitors and their use in the treatment of disorders such as cancers.

Inventors:
GONZALEZ-LOPEZ MARCOS (US)
VERNIER JEAN-MICHEL (US)
Application Number:
PCT/US2023/021025
Publication Date:
November 09, 2023
Filing Date:
May 04, 2023
Export Citation:
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Assignee:
ERASCA INC (US)
International Classes:
C07D513/04; A61K31/506; A61K31/55; A61K31/553; A61K31/554; A61P35/00; C07D497/04; C07D519/00
Domestic Patent References:
WO2022061273A12022-03-24
WO2020257180A12020-12-24
WO2023087027A12023-05-19
Foreign References:
KR20200016567A2020-02-17
Attorney, Agent or Firm:
BONNEFOUS, Celine M. (US)
Download PDF:
Claims:
CLAIMS 1. A compound of Formula (IVa-1), or a pharmaceutically acceptable salt thereof: Formula (IVa-1); wherein R1 is hydrogen, deuterium, halogen, C1-C4alkyl, or C1-C4haloalkyl; R2 is halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl; R3 is hydrogen, deuterium, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4haloalkyl; each R6a is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1- C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, or cycloalkyl; or two R6a are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; each R6 is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl; wherein the alkyl, cycloalkyl is optionally and independently substituted with one or more R; or two R6 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R; or two R6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; or two R6 on adjacent carbons are taken together to form a bond; each R7 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -L-O- C(=O)Ra, -L-OP(=O)(ORb)2, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R7a; or two R7 on the same atom are taken together to form an oxo; R7’ is hydrogen, -L-O-C(=O)Ra, -L-OP(=O)(ORb)2, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R7a; each R7a is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1- C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R7a on the same atom are taken together to form an oxo; p is 0-5; Y1 is -CH2-, -C(=O)-, or null; each Ra is independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3 alkylene; and each R is independently deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C3alkoxyC1-C3alkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently halogen, C1-C4alkyl, or cycloalkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently C1-C4alkyl. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IVb-1): Formula (IVb-1). 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R7 is halogen, C1-C4alkyl, or cycloalkyl. 7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R7 is C1- C4alkyl. 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein Y1 is -CH2-. 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R7’ is hydrogen, C1-C4alkyl, C1-C4haloalkyl, or C1-C4hydroxyalkyl. 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R7’ is hydrogen or C1-C4alkyl. 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R7’ is hydrogen. 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen. 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3. 14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen. 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently hydrogen or C1-C4alkyl. 16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein each R6 is hydrogen.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein each R6a is independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, or cycloalkyl. 19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein each R6a is independently hydrogen or C1-C4alkyl. 20. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein each R6a is independently hydrogen. 21. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein one R6a is hydrogen and the other R6a is C1-C4alkyl. 22. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein two R6a are taken together to form a cycloalkyl. 23. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein two R6a are taken together to form a cyclopropyl. 24. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 25. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 26. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 27. The compound of any one of claims 24-26, or a pharmaceutically acceptable salt thereof, wherein R6a is hydrogen, C1-C4alkyl, C1-C4haloalkyl, or cycloalkyl.

28. The compound of any one of claims 24-26, or a pharmaceutically acceptable salt thereof, wherein R6a is hydrogen or C1-C4alkyl. 29. The compound of any one of claims 24-26, or a pharmaceutically acceptable salt thereof, wherein R6a is hydrogen. 30. The compound of any one of claims 24-26, or a pharmaceutically acceptable salt thereof, wherein R6a is C1-C4alkyl. 31. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 32. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 33. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 34. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein . 35. A compound of Formula (III), or a pharmaceutically acceptable salt thereof: Formula (III); wherein R1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, -C(=O)NRcRd, or cycloalkyl; R3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; X is O or S; R5 is hydrogen, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -S(=O)2NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1- C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R6 is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R6 on the same carbon are taken together to form an oxo; or two R6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; Ring A is aryl or heteroaryl; each R10 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyC1-C2alkylenyloxy, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkylenyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0-4; R11 is hydrogen, -L-S(=O)Ra, -L-S(=O)2Ra, -L-S(=O)2NRcRd, -L-C(=O)Ra, -L-C(=O)ORb, -L- C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; L is absent or C1-C3 alkylene; each R12 is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R12 on the same atom are taken together to form an oxo; or two R12 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R12 on different carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; s is 0-8; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo. 36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein Ring A is 6- membered heteroaryl.

37. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl. 38. The compound of any one of claims 35-37, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2. 39. The compound of any one of claims 35-38, or a pharmaceutically acceptable salt thereof, wherein m is 0. 40. The compound of any one of claims 35-38, or a pharmaceutically acceptable salt thereof, wherein m is 1. 41. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIa): Formula (IIIa); wherein: R13 is hydrogen or R10; each R14 is independently deuterium, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; and t is 0-2. 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein R13 is R10. 43. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIb): Formula (IIIb); wherein: each R14 is independently deuterium, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; and t is 0-2. 44. The compound of any one of claims 35-43, or a pharmaceutically acceptable salt thereof, wherein each R14 is independently fluorine. 45. The compound of any of claims 35-44, or a pharmaceutically acceptable salt thereof, wherein t is 0. 46. The compound of any of claims 35-44, or a pharmaceutically acceptable salt thereof, wherein t is 1. 47. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIc): Formula (IIIc). 48. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIId): Formula (IIId). 49. The compound of any of claims 35-48, or a pharmaceutically acceptable salt thereof, wherein each R10 is independently halogen, C1-C6alkyl, or cycloalkyl. 50. The compound of any of claims 35-49, or a pharmaceutically acceptable salt thereof, wherein R10 is halogen, C1-C6alkyl, or cycloalkyl. 51. The compound of any of claims 35-50, or a pharmaceutically acceptable salt thereof, wherein R10 is halogen.

52. The compound of any of claims 35-50, or a pharmaceutically acceptable salt thereof, wherein R10 is C1-C6alkyl. 53. The compound of any of claims 35-50, or a pharmaceutically acceptable salt thereof, wherein R10 is cycloalkyl. 54. The compound of any of claims 35-53, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen. 55. The compound of any of claims 35-54, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3. 56. The compound of any of claims 35-55, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen. 57. The compound of any of claims 35-56, or a pharmaceutically acceptable salt thereof, wherein X is O. 58. The compound of any of claims 35-56, or a pharmaceutically acceptable salt thereof, wherein X is S. 59. The compound of any of claims 35-58, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. 60. The compound of any of claims 35-59, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, C1-C6alkyl, cycloalkyl, or heterocycloalkyl. 61. The compound of any of claims 35-60, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, methyl, cyclopropyl, or oxetanyl. 62. The compound of any of claims 35-61, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently hydrogen or C1-C6alkyl. 63. The compound of any of claims 35-62, or a pharmaceutically acceptable salt thereof, wherein each R6 is hydrogen. 64. The compound of any of claims 35-61, or a pharmaceutically acceptable salt thereof, wherein two R6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R. 65. The compound of any of claims 35-64, or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen, -L-C(=O)ORb, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. 66. The compound of any of claims 35-64, or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. 67. The compound of any of claims 35-64, or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R.

68. The compound of any of claims 35-64, or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-heterocycloalkyl. 69. The compound of any of claims 35-64, or a pharmaceutically acceptable salt thereof, wherein R11 is C1-C6alkyl optionally substituted with one or more R. 70. The compound of any of claims 35-64, or a pharmaceutically acceptable salt thereof, wherein R11 is -L-cycloalkyl optionally substituted with one or more R. 71. The compound of any of claims 35-64, or a pharmaceutically acceptable salt thereof, wherein R11 is -L-heterocycloalkyl optionally substituted with one or more R. 72. The compound of any of claims 35-71, or a pharmaceutically acceptable salt thereof, wherein L is absent. 73. The compound of any of claims 35-71, or a pharmaceutically acceptable salt thereof, wherein L is CH2. 74. The compound of any of claims 35-73, or a pharmaceutically acceptable salt thereof, wherein each R12 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl. 75. The compound of any of claims 35-73, or a pharmaceutically acceptable salt thereof, wherein each R12 is independently C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl. 76. The compound of any of claims 35-73, or a pharmaceutically acceptable salt thereof, wherein each R12 is independently C1-C6alkyl, or C1-C6hydroxyalkyl. 77. The compound of any of claims 35-73, or a pharmaceutically acceptable salt thereof, wherein each R12 is independently C1-C6alkyl. 78. The compound of any of claims 35-73, or a pharmaceutically acceptable salt thereof, wherein two R12 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R. 79. The compound of any of claims 35-73, or a pharmaceutically acceptable salt thereof, wherein two R12 on different carbons are taken together to form a cycloalkyl or a heterocycloalkyl. 80. The compound of any of claims 35-73, or a pharmaceutically acceptable salt thereof, wherein two R12 on different carbons are taken together to form a heterocycloalkyl. 81. The compound of any of claims 35-80, or a pharmaceutically acceptable salt thereof, wherein s is 0-2. 82. The compound of any of claims 35-80, or a pharmaceutically acceptable salt thereof, wherein s is 0 or 1. 83. The compound of any of claims 35-80, or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2. 84. A compound that is selected from a compound disclosed in the specification, or pharmaceutically acceptable salt thereof. 85. A pharmaceutical composition comprising a compound of any one of claims 1-84, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

86. A method of inhibiting a Unc-51 like autophagy activating kinase (ULK) isoform comprising contacting the ULK isoform with a compound of any one of claims 1-84, or pharmaceutically acceptable salt thereof, or pharmaceutical composition of claim 85. 87. The method of claim 86, that inhibits ULK1 and ULK2. 88. A method of treating cancer comprising administering to a subject a compound of any one of claims 1-84, or pharmaceutically acceptable salt thereof, or pharmaceutical composition of claim 85. 89. Use of a compound or pharmaceutically acceptable salt of any one of claims 1-84, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. 90. Use of a pharmaceutical composition of claim 85, in the manufacture of a medicament for the treatment of cancer.

Description:
THIOPHENE ULK1/2 INHIBITORS AND THEIR USE THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Serial No.63/338,210 filed May 4, 2022; U.S. Provisional Application Serial No.63/374,491 filed September 2, 2022; and U.S. Provisional Application Serial No. 63/383,113 filed November 10, 2022; which are hereby incorporated by reference in their entirety. FIELD OF THE DISCLOSURE [0002] The disclosure relates to ULK1/2 inhibitors and their use in the treatment of cancer sensitive to ULK1/2 inhibition. BACKGROUND [0003] Autophagy, the cell process of self-digestion, plays a role in maintaining energy homoeostasis and protein synthesis and causes degradation of long-lived proteins and damaged organelles, indicating that it plays a role in cancer, by both protecting against and promoting cell death. The autophagy-related gene (Atg) family, with more than 35 members, regulates multiple stages of the process. UNC-51-like kinase 1 (ULK1) has been demonstrated to mediate autophagy. Studies have indicated that inhibition of ULK1 promotes apoptosis and suppresses tumor growth and metastasis in cancers. Dower et al., Mol. Cancer Ther; 17(11), 2018, pp.2366-2376; Martin et al., iScience; 8, 2018, pp.74-84; Tompkins et al., Yale Journal of Biology and Medicine; 92, 2019, pp.707-718; Lin et al., Cell Death and Disease; 10, 2019, p.139. [0004] There is therefore an urgent need for developing ULK1 inhibitors for the treatment of cancers in subjects, including humans. SUMMARY OF THE DISCLOSURE [0005] The present disclosure provides novel ULK1/2 inhibitors, and their use in the treatment of cancers which are sensitive to ULK1/2 inhibition (e.g., CML). [0006] Disclosed herein is a compound of Formula (IVa-1), or a pharmaceutically acceptable salt thereof: Formula (IVa-1); wherein R 1 is hydrogen, deuterium, halogen, C1-C4alkyl, or C1-C4haloalkyl; R 2 is halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl; R 3 is hydrogen, deuterium, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4haloalkyl; each R 6a is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1- C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2- C 4 alkynyl, or cycloalkyl; or two R 6a are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; each R 6 is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl; wherein the alkyl, cycloalkyl is optionally and independently substituted with one or more R; or two R 6 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R; or two R 6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; or two R 6 on adjacent carbons are taken together to form a bond; each R 7 is independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , - NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -L-O- C(=O)R a , -L-OP(=O)(OR b )2, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; R 7’ is hydrogen, -L-O-C(=O)R a , -L-OP(=O)(OR b )2, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; each R 7a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , - NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1- C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; p is 0-5; Y 1 is -CH2-, -C(=O)-, or null; each R a is independently C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3 alkylene; and each R is independently deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C3alkoxyC1-C3alkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo. [0007] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt thereof: Formula (III); wherein R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, -C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl; X is O or S; R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -S(=O)2NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1- C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R 6 is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 6 on the same carbon are taken together to form an oxo; or two R 6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R 6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; Ring A is aryl or heteroaryl; each R 10 is independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , - NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyC1-C2alkylenyloxy, C1-C6aminoalkyl, C1- C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkylenyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0-4; R 11 is hydrogen, -L-S(=O)R a , -L-S(=O)2R a , -L-S(=O)2NR c R d , -L-C(=O)R a , -L-C(=O)OR b , -L- C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; L is absent or C1-C3 alkylene; each R 12 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 12 on the same atom are taken together to form an oxo; or two R 12 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R 12 on different carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; s is 0-8; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo. [0008] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0009] Also disclosed herein is a method of inhibiting a Unc-51 like autophagy activating kinase (ULK) isoform comprising contacting the ULK isoform with a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. [00010] In some embodiments, the method inhibits ULK1 and ULK2. [00011] Also disclosed herein is a method of treating cancer comprising administering to a subject a compound disclosed herein, or pharmaceutically acceptable salt thereof, or pharmaceutical a composition disclosed herein. [00012] Also disclosed herein is a use of a compound disclosed herein, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. [00013] Also disclosed herein is a use of a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of cancer. DETAILED DESCRIPTION OF THE DISCLOSURE [00014] “Abnormal cell growth,” as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous). Abnormal cell growth includes the abnormal growth of: (1) tumor cells (tumors) that show increased expression of ULK1 or ULK2; (2) tumors that proliferate by aberrant ULK1 or ULK2 activation; and /or (3) tumors characterized by amplification or overexpression of the genes that express ULK1 or ULK2. [00015] The term “additional anticancer agents” as used herein means any one or more therapeutic agent, other than a compound of the disclosure, that is or can be used in the treatment of cancer. In some embodiments, such additional anticancer agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like. [00016] As used herein “cancer” refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemia, lymphoma, plasmacytoma, extramedullary plasmacytoma, and myeloma. [00017] In some embodiments, the leukemia is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). [00018] In some embodiments, the lymphoma is Hodgkin lymphoma, Non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). [00019] In some embodiments, the myeloma is multiple myeloma. [00020] Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one. [00021] As used herein, the term “combination therapy” refers to the administration of a compound of the disclosure together with an at least one additional pharmaceutical or medicinal agent (e.g., one or more additional anticancer agents), either sequentially or simultaneously. [00022] As used herein, “subject” refers to a human or animal subject. In certain preferred embodiments, the subject is a human. [00023] The term “treat” or “treating” a cancer as used herein means to administer a compound of the present invention to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastases or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment,” as used herein, unless otherwise indicated, refers to the act of treating as “treating” is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject. [00024] As used herein, a “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. [00025] The terms below, as used herein, have the following meanings, unless indicated otherwise: [00026] “Oxo” refers to =O. [00027] “Carboxyl” refers to -COOH. [00028] “Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2- methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C 1 - 6 alkyl. In some embodiments, the alkyl is a C 1 - 5 alkyl. In some embodiments, the alkyl is a C 1 - 4 alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. [00029] “Alkenyl” refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. [00030] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, - CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. [00031] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. [00032] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. [00033] “Alkoxyalkyl” refers to a radical of the formula -alkyleneORa where Ra is an alkyl. In some embodiments, the alkoxyalkyl is -CH2OCH3, -CH2CH2OCH3, or -CH2CH2CH2OCH3. Unless stated otherwise specifically in the specification, an alkoxyalkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxyalkyl is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxyalkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxyalkyl is optionally substituted with halogen. [00034] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aromatic ring, which may be monocyclic or bicyclic (for example, phenyl or naphthyl). In some embodiments, the aryl is a 6-membered aromatic ring (phenyl). Aryl radicals include, but are not limited to anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Aryl radicals include, but are not limited to 1,2,3,5,6,7-hexahydro- s-indacene, 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene, 2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]naphthalene, and 1,2,3,4,5,6,7,8-octahydroanthracene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen. [00035] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6- membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl- bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. [00036] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [00037] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. [00038] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. [00039] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl. [00040] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3. [00041] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C 2 -C 8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl or a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl or a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl or a 4- to 6- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl or a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. [00042] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). In some embodiments, the heteroaryl is 1,2,3,4-tetrahydroisoquinolinyl, isoindolinyl, 2,3,4,5-tetrahydro-1H-benzo[c]azepinyl, or 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, the heteroaryl is bonded through a phenyl ring atom. Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. [00043] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons. Compounds [00044] Disclosed herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: Formula (I); wherein R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl; R 2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, -C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl; W is -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR 4 -, -S(=O)2NR 4 -, -NR 4 S(=O)2-, or -S(=O)(=NR 4 )-; X is -NR 5 -, -O-, -S-, -S(=O)2-, -C(R 6 )2-, -C(=O)-, -C(=O)NR 5 -, or null; Y is -C(R 6 ) 2 -, -O-, -NR 5 -, or null; Z is -C(R 6 ) 2 -, -NR 5 -, or null; or Y-Z is -CR 6 =CR 6 -, -CR 6 =N-, or -N=CR 6 -; V is -C(R 6 )2- or null; wherein -membered ring; R 4 is hydrogen or C1-C6alkyl; R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -S(=O)2NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1- C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R 6 is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 6 on the same atom are taken together to form an oxo; Ring A is aryl or heteroaryl; each R7 is independently halogen, -CN, -NO 2 , -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1- C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b ; each R 7a is independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; each R 7b is independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7b on the same atom are taken together to form an oxo; n is 0-7; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 - C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo. [00045] Disclosed herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: Formula (I); wherein R 1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 - C 6 heteroalkyl; R 2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, -C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; W is -C(=O)-, -S(=O)-, -S(=O)2-, -C(=O)NR 4 -, -S(=O)2NR 4 -, -NR 4 S(=O)2-, or -S(=O)(=NR 4 )-; X is -NR 5 -, -O-, -S-, -S(=O) 2 -, -C(R 6 ) 2 -, -C(=O)-, -C(=O)NR 5 -, or null; Y is -C(R 6 )2-, -NR 5 -, or null; Z is -C(R 6 )2-, -NR 5 -, or null; or Y-Z is -CR 6 =CR 6 -, -CR 6 =N-, or -N=CR 6 -; V is -C(R 6 )2- or null; wherein -membered ring; R 4 is hydrogen or C1-C6alkyl; R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C 6 alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R 6 is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 6 on the same atom are taken together to form an oxo; Ring A is aryl or heteroaryl; each R 7 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b ; each R 7a is independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; each R 7b is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7b on the same atom are taken together to form an oxo; n is 0-7; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom form an oxo. [00046] Disclosed herein are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: Formula (I); wherein R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, -C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; W is -C(=O)-, -S(=O)-, -S(=O) 2 -, -C(=O)NR 4 -, -S(=O) 2 NR 4 -, -NR 4 S(=O) 2 -, or -S(=O)(=NR 4 )-; X is -NR 5 -, -O-, -S-, -C(R 6 ) 2 -, -C(=O)-, -C(=O)NR 5 -, or null; Y is -C(R 6 )2- or null; Z is -C(R 6 )2- or null; or Y-Z is -CR 6 =CR 6 -, -CR 6 =N-, or -N=CR 6 -; V is -C(R6) 2 - or null; wherein -membered ring; R 4 is hydrogen or C 1 -C 6 alkyl; R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R 6 is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 6 on the same atom are taken together to form an oxo; Ring A is aryl or heteroaryl; each R 7 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b ; each R 7a is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; each R 7b is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7b on the same atom are taken together to form an oxo; n is 0-7; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 - C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkyl(cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(aryl), or C 1 - C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom form an oxo. [00047] In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -. In some embodiments of a compound of Formula (I), W is -S(=O)2NR 4 - or -NR 4 S(=O)2-. In some embodiments of a compound of Formula (I), W is -S(=O)2NR 4 -. In some embodiments of a compound of Formula (I), W is - NR 4 S(=O)2-. In some embodiments of a compound of Formula (I), W is -C(=O)-. In some embodiments of a compound of Formula (I), W is -S(=O)2-. In some embodiments of a compound of Formula (I), W is -S(=O)(=NR 4 )-. In some embodiments of a compound of Formula (I), X is -NR 5 -. In some embodiments of a compound of Formula (I), X is -O-. In some embodiments of a compound of Formula (I), X is -S-. In some embodiments of a compound of Formula (I), X is -C(=O)-. In some embodiments of a compound of Formula (I), X is -C(=O)NR 5 -. In some embodiments of a compound of Formula (I), X is -C(R 6 )2-. In some embodiments of a compound of Formula (I), X is null. In some embodiments of a compound of Formula (I), Y is -C(R 6 ) 2 -. In some embodiments of a compound of Formula (I), Y is -NR 5 -. In some embodiments of a compound of Formula (I), Y is -O-. In some embodiments of a compound of Formula (I), Y is null. In some embodiments of a compound of Formula (I), Z is -C(R 6 )2-. In some embodiments of a compound of Formula (I), Z is null. In some embodiments of a compound of Formula (I), Y-Z is - CR 6 =CR 6 -. In some embodiments of a compound of Formula (I), Y-Z is -CR 6 =N-. In some embodiments of a compound of Formula (I), Y-Z is -N=CR 6 -. In some embodiments of a compound of Formula (I), V is -C(R 6 )2-. In some embodiments of a compound of Formula (I), V is null. [00048] In some embodiments of a compound of Formula (I), -membered ring. In some embodiments of a compound of Formula -membered ring. In some embodiments of a compound of Formula ( membered ring. In some embodiments of a compound of Formula ( membered ring. In some embodiments of a compound of . [00049] In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is null, Y is null, and X is -C(R 6 )2-. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is null, Y is -C(R 6 ) 2 -, and X is -C(R 6 ) 2 -. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -C(R 6 )2-. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -O-. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -NR 5 -. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Y-Z is -CR 6 =CR 6 -, and X is null. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Y-Z is -CR 6 =N-, and X is null. In some embodiments of a compound of Formula (I), W is - C(=O)NR 4 -; V is null; Y-Z is -N=CR 6 -, and X is null. [00050] In some embodiments of a compound of Formula (I), W is -S(=O) 2 NR 4 -; V is null; Z is null, Y is null, and X is -C(R 6 )2-. In some embodiments of a compound of Formula (I), W is -S(=O)2NR 4 -; V is null; Z is null, Y is -C(R 6 )2-, and X is -C(R 6 )2-. In some embodiments of a compound of Formula (I), W is -S(=O) 2 NR 4 -; V is null; Z is -C(R 6 ) 2 -, Y is -C(R 6 ) 2 -, and X is -C(R 6 ) 2 -. In some embodiments of a compound of Formula (I), W is -S(=O)2NR 4 -; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -O-. In some embodiments of a compound of Formula (I), W is -S(=O)2NR 4 -; V is null; Z is -C(R 6 )2-, Y is - C(R 6 )2-, and X is -NR 5 -. In some embodiments of a compound of Formula (I), W is -S(=O)2NR 4 -; V is null; Y-Z is -CR 6 =N-, and X is null. In some embodiments of a compound of Formula (I), W is - S(=O)2NR 4 -; V is null; Y-Z is -N=CR 6 -, and X is null. [00051] In some embodiments of a compound of Formula (I), W is -NR 4 S(=O)2-; V is null; Z is null, Y is null, and X is -C(R 6 ) 2 -. In some embodiments of a compound of Formula (I), W is -NR 4 S(=O) 2 -; V is null; Z is null, Y is -C(R 6 ) 2 -, and X is -C(R 6 ) 2 -. In some embodiments of a compound of Formula (I), W is -NR 4 S(=O)2-; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -C(R 6 )2-. In some embodiments of a compound of Formula (I), W is -NR 4 S(=O)2-; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -O-. In some embodiments of a compound of Formula (I), W is -NR 4 S(=O) 2 -; V is null; Z is -C(R 6 ) 2 -, Y is - C(R 6 )2-, and X is -NR 5 -. In some embodiments of a compound of Formula (I), W is -NR 4 S(=O)2-; V is null; Y-Z is -CR 6 =N-, and X is null. In some embodiments of a compound of Formula (I), W is - NR 4 S(=O)2-; V is null; Y-Z is -N=CR 6 -, and X is null. [00052] In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is null, Y is null, and X is -C(=O)NR 5 -. In some embodiments of a compound of Formula (I), W is -C(=O)-; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -C(=O)NR 5 -. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is -C(R 6 )2-, Y is null, and X is -NR 5 -. In some embodiments of a compound of Formula (I), W is -C(=O)NR 4 -; V is null; Z is -C(R 6 )2-, Y is -C(R 6 )2-, and X is -C(=O)-.

[ [

[00062] In some embodiments of a compound of Formula (I), R 4 is hydrogen. In some embodiments of a compound of Formula (I), R 4 is C1-C6alkyl. [00063] In some embodiments of a compound of Formula (I), R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , - C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. [00064] In some embodiments of a compound of Formula (I), R 5 is hydrogen, C1-C6alkyl, C1- C6haloalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. [00065] In some embodiments of a compound of Formula (I), R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , - C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, or heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (I), R 5 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl; wherein the alkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (I), R 5 is hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I), R 5 is hydrogen. In some embodiments of a compound of Formula (I), R 5 is C1-C6alkyl. [00066] In some embodiments of a compound of Formula (I), each R 6 is independently hydrogen, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R; or two R 6 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), each R 6 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl; or two R 6 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), R 6 is independently hydrogen or C1- C6alkyl; or two R 6 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I), R 6 is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), each R 6 is hydrogen. [00067] Also disclosed herein is a compound of Formula (II), or pharmaceutically acceptable salt thereof: Formula (II); wherein R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 2 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, - C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 8 is -CN, -NR c R d , -C(=O)NR c R d , -C(=O)R a , -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , - NR b S(=O)2R a , -P(=O)(R a )2, heterocycloalkyl, or heteroaryl; wherein the heterocycloalkyl and heteroaryl is independently optionally substituted with one or more R; R 9 is hydrogen, halogen, -C(=O)NR c R d , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1- C6alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R; Ring A is aryl or heteroaryl; each R 7 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1- C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b ; each R 7a is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; each R 7b is independently halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7b on the same atom are taken together to form an oxo; n is 0-7; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo; provided that the compound is not . [00068] Also disclosed herein is a compound of Formula (II), or pharmaceutically acceptable salt thereof: Formula (II); wherein R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 2 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, - C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 8 is -CN, -NR c R d , -C(=O)NR c R d , -C(=O)R a , -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , - NR b S(=O)2R a , -P(=O)(R a )2, heterocycloalkyl, or heteroaryl; wherein the heterocycloalkyl and heteroaryl is independently optionally substituted with one or more R; R 9 is hydrogen, halogen, -C(=O)NR c R d , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1- C6alkyl(heterocycloalkyl); Ring A is aryl or heteroaryl; each R 7 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b ; each R 7a is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; each R 7b is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7b on the same atom are taken together to form an oxo; n is 0-7; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 - C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 - C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom form an oxo; provided that the compound is not . [00069] Also disclosed herein is a compound of Formula (II), or pharmaceutically acceptable salt thereof: Formula (II); wherein R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 2 is halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, - C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl; R 8 is -CN, -NR c R d , -C(=O)NR c R d , -C(=O)R a , -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , - NR b S(=O)2R a , -P(=O)(R a )2, heterocycloalkyl, or heteroaryl; wherein the heterocycloalkyl and heteroaryl is independently optionally substituted with one or more R; R 9 is hydrogen, halogen, -C(=O)NR c R d , -OR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring A is aryl or heteroaryl; each R 7 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b ; each R 7a is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; each R 7b is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7b on the same atom are taken together to form an oxo; n is 0-7; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C 6 alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom form an oxo; provided that the compound is not . [00070] In some embodiments of a compound of Formula (II), R 8 is -CN, -NR c R d , -C(=O)NR c R d , - S(=O) 2 R a , -S(=O) 2 NR c R d , -NR b S(=O) 2 R a , or -P(=O)(R a ) 2 . In some embodiments of a compound of Formula (II), R8 is -C(=O)NRcRd, -S(=O) 2 Ra, -S(=O) 2 NRcRd, -NRbS(=O) 2 Ra, or -P(=O)(Ra) 2 . In some embodiments of a compound of Formula (II), R 8 is -C(=O)NR c R d . In some embodiments of a compound of Formula (II), R 8 is -P(=O)(R a )2. In some embodiments of a compound of Formula (II), R 8 is -C(=O)R a . The compound of claim 36, or pharmaceutically acceptable salt thereof, wherein R 8 is -S(=O)R a . In some embodiments of a compound of Formula (II), R 8 is -S(=O)(=NR b )R a . In some embodiments of a compound of Formula (II), R 8 is heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (II), R 8 is heterocycloalkyl optionally substituted with one or more R. [00071] In some embodiments of a compound of Formula (II), R 9 is hydrogen, halogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II), R 9 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 - C6haloalkyl. In some embodiments of a compound of Formula (II), R 9 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II), R 9 is hydrogen. In some embodiments of a compound of Formula (II), R 9 is hydrogen, halogen, -C(=O)NR c R d , C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (II), R 9 is -C(=O)NR c R d . In some embodiments of a compound of Formula (II), R 9 is -OR a . In some embodiments of a compound of Formula (II), R 9 is -NR c R d . [00072] In some embodiments of a compound of Formula (I) or (II), R 1 is hydrogen, halogen, C1- C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is hydrogen or C 1 -C 2 alkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is hydrogen. In some embodiments of a compound of Formula (I) or (II), R 1 is C1-C4alkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is C1-C3alkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is C1-C2alkyl. In some embodiments of a compound of Formula (I) or (II), R 1 is CH3. [00073] In some embodiments of a compound of Formula (I) or (II), R 2 is hydrogen, halogen, C1- C6alkyl, C1-C6haloalkyl, -C(=O)NR c R d , or cycloalkyl. In some embodiments of a compound of Formula (I) or (II), R 2 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -C(=O)NR c R d , or cycloalkyl. In some embodiments of a compound of Formula (I) or (II), R 2 is C1-C2alkyl, C1-C2haloalkyl, -C(=O)NR c R d , or cycloalkyl. In some embodiments of a compound of Formula (I) or (II), R 2 is CF3. In some embodiments of a compound of Formula (I) or (II), R 2 is C1-C4alkyl. In some embodiments of a compound of Formula (I) or (II), R 2 is C1-C3alkyl. In some embodiments of a compound of Formula (I) or (II), R 2 is C1-C2alkyl. In some embodiments of a compound of Formula (I) or (II), R 2 is CH3. In some embodiments of a compound of Formula (I) or (II), R 2 is cyclopropyl. In some embodiments of a compound of Formula (I) or (II), R 2 is - C(=O)NH2. [00074] In some embodiments of a compound of Formula (I) or (II), R 3 is hydrogen, halogen, C1- C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (II), R 3 is hydrogen. [00075] In some embodiments of a compound of Formula (I) or (II), Ring A is heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (II), Ring A is pyrazolyl. In some embodiments of a compound of Formula (I) or (II), Ring A is phenyl. [00076] In some embodiments of a compound of Formula (I) or (II), each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C 6 alkyl(cycloalkyl), or C 1 -C 6 alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b . In some embodiments of a compound of Formula (I) or (II), each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , - C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1-C6alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b . [00077] In some embodiments of a compound of Formula (I) or (II), each R 7 is independently halogen, -CN, -OH, -OR a , -SR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b . In some embodiments of a compound of Formula (I) or (II), each R 7 is independently halogen, -CN, -OH, -OR a , -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b . In some embodiments of a compound of Formula (I) or (II), each R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b . [00078] In some embodiments of a compound of Formula (I) or (II), each R 7a is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (I) or (II), each R 7a is independently halogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound of Formula (I) or (II), each R 7a is independently C1- C6alkyl. [00079] In some embodiments of a compound of Formula (I) or (II), each R 7b is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl, is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (I) or (II), each R 7b is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl. [00080] In some embodiments of a compound of Formula (I) or (II), n is 1-4. In some embodiments of a compound of Formula (I) or (II), n is 1-3. In some embodiments of a compound of Formula (I) or (II), n is 1 or 2. In some embodiments of a compound of Formula (I) or (II), n is 1. In some embodiments of a compound of Formula (I) or (II), n is 2. In some embodiments of a compound of Formula (I) or (II), n is 3. In some embodiments of a compound of Formula (I) or (II), n is 4. [00082] wherein each R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more C1-C6alkyl. [00083] In some embodiments of a compound of Formula ( wherein: G is -CH- and K is -N- or G is -N- and K is -CH-; R 7’ is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl is optionally and independently substituted with one or more C1-C6alkyl; and R 7 is independently C1-C6alkyl, cycloalkyl, or heterocycloalkyl. [00084] In some embodiments of a compound of Formula ( wherein: Y 1 is -CH2-, -C(=O)-, or null; R 7’ is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; p is 0-5; and each R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo. [00085] In some embodiments of a compound of Formula ( wherein: Y 1 is -CH2-, -C(=O)-, or null; R 7’ is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; p is 0-5; and each R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo. [00086] In some embodiments of a compound of Formula ( wherein: R 7’ is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl. [00087] In some embodiments of a compound of Formula ( wherein: Y 1 is -CH2-, -C(=O)-, or null; R 7’ is hydrogen or C1-C6alkyl; p is 0-5; and each R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo. [00088] In some embodiments of a compound of Formula ( wherein: Y 1 is -CH2-, -C(=O)-, or null; R 7’ is hydrogen or C 1 -C 6 alkyl; p is 0-5; and each R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo. [00089] In some embodiments of a compound of Formula ( wherein: R 7’ is hydrogen or C1-C6alkyl; and R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl. [00090] In some embodiments of a compound of Formula ( wherein: R 7’ is hydrogen or C1-C6alkyl; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl. [00091] In some embodiments of a compound of Formula ( wherein: R 7’ is hydrogen or C 1 -C 6 alkyl; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl. [00092] In some embodiments of a compound of Formula ( wherein: A and B are independently selected from CH, N, and CF, with the proviso that at least one of A or B is N or CF. R 7’ is hydrogen or C 1 -C 6 alkyl; and R 7 is independently halogen, -OR a , -SR a , C1-C6alkyl, cycloalkyl, or heterocycloalkyl. [00093] In some embodiments of a compound of Formula ( wherein: A and B are independently selected from CH, N, and CF, with the proviso that at least one of A or B is N or CF. R 7’ is hydrogen or C 1 -C 6 alkyl; and R 7 is independently halogen, -OR a , -SR a , C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl. [00094] In some embodiments of a compound of Formula ( , , , , , , ,

,

, , , , , ,

, [00097] In some embodiments of a compound of Formula (I . [00098] In some embodiments of a compound of Formula (

[00099] In some embodiments of a compound of Formula (

, [000100] In some embodiments of a compound of Formula ( [000102] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt thereof: Formula (III); wherein R 1 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl; R 2 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, -C(=O)NR c R d , or cycloalkyl; R 3 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C 6 heteroalkyl; X is O or S; R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -S(=O)2NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1- C6alkyl(aryl), or C1-C6alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R 6 is independently hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 6 on the same carbon are taken together to form an oxo; or two R 6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R 6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; Ring A is aryl or heteroaryl; each R 10 is independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , - NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyC1-C2alkylenyloxy, C1-C6aminoalkyl, C1- C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkylenyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; m is 0-4; R 11 is hydrogen, -L-S(=O)R a , -L-S(=O)2R a , -L-S(=O)2NR c R d , -L-C(=O)R a , -L-C(=O)OR b , -L- C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; L is absent or C1-C3 alkylene; each R 12 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , - SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , - NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 12 on the same atom are taken together to form an oxo; or two R 12 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; or two R 12 on different carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; s is 0-8; each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1- C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo. [000103] In some embodiments of a compound of Formula (III), Ring A is heteroaryl. In some embodiments of a compound of Formula (III), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (III), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (III), Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (III), Ring A is pyrazolyl. In some embodiments of a compound of Formula (III), Ring A is phenyl or pyridinyl. In some embodiments of a compound of Formula (III), Ring A is phenyl. In some embodiments of a compound of Formula (III), Ring A is phenyl. [000104] In some embodiments of a compound of Formula (III), m is 1-4. In some embodiments of a compound of Formula (III), m is 1-3. In some embodiments of a compound of Formula (III), m is 1 or 2. In some embodiments of a compound of Formula (III), m is 0. In some embodiments of a compound of Formula (III), m is 1. In some embodiments of a compound of Formula (III), m is 2. In some embodiments of a compound of Formula (III), m is 3. [000105] In some embodiments of a compound of Formula (III), the compound is of Formula (IIIa): Formula (IIIa); wherein: R 13 is hydrogen or R 10 ; each R 14 is independently deuterium, halogen, -CN, C1-C6alkyl, or C1-C6haloalkyl; and t is 0-2. [000106] In some embodiments of a compound of Formula (IIIa), R 13 is R 10 . [000107] In some embodiments of a compound of Formula (III), the compound is of Formula (IIIb): Formula (IIIb); wherein: each R 14 is independently deuterium, halogen, -CN, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and t is 0-2. [000108] In some embodiments of a compound of Formula (IIIa) or (IIIb), each R 14 is independently deuterium, halogen, -CN, CH3, or CF3. In some embodiments of a compound of Formula (IIIa) or (IIIb), each R 14 is independently fluorine. [000109] In some embodiments of a compound of Formula (IIIa) or (IIIb), t is 0. In some embodiments of a compound of Formula (IIIa) or (IIIb), t is 1. In some embodiments of a compound of Formula (IIIa) or (IIIb), t is 2. [000110] In some embodiments of a compound of Formula (III), the compound is of Formula (IIIc): Formula (IIIc). [000111] In some embodiments of a compound of Formula (III), the compound is of Formula (IIId): Formula (IIId). [000112] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is hydrogen or C1-C2alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is hydrogen. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is C1-C4alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is C 1 -C 3 alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is C1-C2alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 1 is CH3. [000113] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -C(=O)NR c R d , or cycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C6alkyl, C1-C6haloalkyl, -C(=O)NR c R d , or cycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C6haloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C2alkyl, C1-C2haloalkyl, -C(=O)NR c R d , or cycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C2alkyl or C1- C2haloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is CF3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C 1 -C 4 alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C3alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C2alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is CH3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is cyclopropyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 2 is -C(=O)NH2. [000114] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 3 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 3 is hydrogen. [000115] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), X is O. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), X is S. [000116] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 5 is hydrogen, - C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -S(=O) 2 NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1- C6alkyl(heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), or C1- C 6 alkyl(heterocycloalkyl); wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 5 is hydrogen, C 1 -C 6 alkyl, C 1 - C6haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 5 is hydrogen, C1-C6alkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 5 is hydrogen, methyl, cyclopropyl, or oxetanyl. [000117] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 6 is independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 6 is independently hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 6 is independently hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)- (IIId), each R 6 is independently hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 6 is hydrogen. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R. [000118] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently halogen, -CN, -OH, -OR a , -SH, -SR a , -NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R. [000119] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently halogen, C 1 -C 6 alkyl, or cycloalkyl; wherein the alkyl and cycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently halogen, C1-C6alkyl, or cycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently halogen. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently C1-C6alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently cycloalkyl. [000120] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 - C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently halogen, -CN, -OH, -OR a , - NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently C1-C6alkyl, C1-C6haloalkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently C1-C6alkyl, or C1-C6hydroxyalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), each R 12 is independently C1-C6alkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 12 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 12 on different carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 12 on different carbons are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R. [000121] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 12 on different carbons are taken together to form a cycloalkyl or a heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 12 on different carbons are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), two R 12 on different carbons are taken together to form a heterocycloalkyl. [000122] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0-4. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0-3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0-2. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0 or 1. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 0. [000123] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1-7. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1-6. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1-5. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1-4. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1- 3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1 or 2. -In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 1. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 2. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 4. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 5. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), s is 6. [000124] In some embodiments of a compound of Formula (III) or (IIIa) In some embodiments of a compound of Formula ( , ,

. In some embodiments of a compound of Formula (III) or (IIIa) some embodiments of a compound of Formula ( embodiments of a compound of Formula [000125] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -L- S(=O)R a , -L-S(=O) 2 R a , -L-S(=O) 2 NR c R d , -L-C(=O)R a , -L-C(=O)OR b , -L-C(=O)NR c R d , C 1 -C 6 alkyl, C 1 - C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -L-S(=O)R a , -L- S(=O)2R a , -L-S(=O)2NR c R d , -L-C(=O)R a , -L-C(=O)OR b , -L-C(=O)NR c R d , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -L-C(=O)OR b , C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L-cycloalkyl, or - L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, C 1 -C 6 alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, C1-C6alkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is C1-C6alkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is -L-cycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is -L-heterocycloalkyl optionally substituted with one or more R. [000126] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), L is absent. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), L is C1-C3 alkylene. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), L is CH2. [000127] In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -CH3, - . In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -CH3, - some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CD 3 . In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R11 is hydrogen or -CH 3 . In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 is hydrogen. In some embodiments of a compound of Formula (III) or (IIIa)- (IIId), R 11 is -CH3. In some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 , some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 . some embodiments of a compound of Formula (III) or (IIIa)-(IIId), R 11 . [000128] In some embodiments of a compound of Formula ( [000129] In some embodiments of a compound of Formula (III) or (IIIa)- ,

,

[000130] Disclosed herein are compounds of Formula (IV), or a pharmaceutically acceptable salt thereof: Formula (IV); wherein R 1 is hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl; R 2 is halogen, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl; R 3 is hydrogen, deuterium, halogen, C1-C4alkyl, C1-C4deuteroalkyl, or C1-C4haloalkyl; X is -C(R 6a )2-, -O-, -S-, -S(=O)-, -S(=O)2-, or -NR 5 -; Y is -C(R 6b ) 2 -, -O-, -S-, -S(=O)-, -S(=O) 2 -, or -NR 5 -; R 5 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -S(=O)2NR c R d , C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2- C4alkenyl, C2-C4alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; each R 6a is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1- C 4 hydroxyalkyl, C 1 -C 4 aminoalkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 - C4alkynyl, or cycloalkyl; or two R 6a are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; each R 6b is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1- C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2- C4alkynyl, or cycloalkyl; or two R 6b are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R; each R 6 is independently hydrogen, deuterium, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, or cycloalkyl; wherein the alkyl, cycloalkyl is optionally and independently substituted with one or more R; or two R 6 on the same carbon are taken together to form a cycloalkyl optionally substituted with one or more R; or two R 6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R; or two R 6 on adjacent carbons are taken together to form a bond; Ring A is aryl or heteroaryl; each R 7 is independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , - NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -L-O- C(=O)R a , -L-OP(=O)(OR b )2, C1-C4alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 on the same atom are taken together to form an oxo; each R 7a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , - NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O) 2 R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 4 alkyl, C1-C4deuteroalkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C1- C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R; or two R 7a on the same atom are taken together to form an oxo; n is 0-7; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkoxyC1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; L is absent or C1-C3 alkylene; and each R is independently deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O) 2 NHCH 3 , -S(=O) 2 N(CH 3 ) 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OH, -C(=O)OCH 3 , C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C3alkoxyC1-C3alkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom form an oxo. [000131] In some embodiments of a compound of Formula (IV), Ring A is heteroaryl. In some embodiments of a compound of Formula (IV), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (IV), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (IV), Ring A is pyrazolyl. In some embodiments of a compound of Formula (IV), Ring A is phenyl or pyridinyl. In some embodiments of a compound of Formula (IV), Ring A is phenyl. In some embodiments of a compound of Formula (IV), Ring A is pyridinyl. In some embodiments of a compound of Formula (IV), Ring A is a bicyclic ring. In some embodiments of a compound of Formula (IV), Ring A is tetrahydroisoquinolinyl. [000132] In some embodiments of a compound of Formula (IV), n is 1-4. In some embodiments of a compound of Formula (IV), n is 1-3. In some embodiments of a compound of Formula (IV), n is 1 or 2. In some embodiments of a compound of Formula (IV), n is 1. In some embodiments of a compound of Formula (IV), n is 2. In some embodiments of a compound of Formula (IV), n is 3. In some embodiments of a compound of Formula (IV), n is 4. [000133] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, the compound is of Formula (IVa): Formula (IVa); wherein: Y 1 is -CH 2 -, -C(=O)-, or null; R 7’ is hydrogen, -L-O-C(=O)R a , -L-OP(=O)(OR b )2, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; and p is 0-5. [000134] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, the compound is of Formula (IVb): Formula (IVb); wherein: Y 1 is -CH2-, -C(=O)-, or null; and R 7’ is hydrogen, -L-O-C(=O)R a , -L-OP(=O)(OR b )2, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C 4 aminoalkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a . [000135] In some embodiments of a compound of Formula (IV), (IVa), or (IVb), X is -C(R 6a )2-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), X is -O-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), X is -S-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), X is -S(=O)-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), X is -S(=O) 2 -. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), X is -NR 5 -. [000136] In some embodiments of a compound of Formula (IV), (IVa), or (IVb), Y is -C(R 6b )2-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), Y is -O-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), Y is -S-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), Y is -S(=O)-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), Y is -S(=O)2-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), Y is -NR 5 -. [000137] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, the compound is of Formula (IVa-1): Formula (IVa-1); wherein: Y 1 is -CH 2 -, -C(=O)-, or null; R 7’ is hydrogen, -L-O-C(=O)R a , -L-OP(=O)(OR b ) 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 1 - C4aminoalkyl, C1-C4heteroalkyl, C1-C4alkoxyC1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; and p is 0-5. [000138] In some embodiments of a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, the compound is of Formula (IVb-1): Formula (IVb-1); wherein: Y 1 is -CH2-, -C(=O)-, or null; and R 7’ is hydrogen, -L-O-C(=O)R a , -L-OP(=O)(OR b )2, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1- C 4 aminoalkyl, C 1 -C 4 heteroalkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a . [000139] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 0-4. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 0-3. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 0-2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 0 or 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa- 1), p is 0. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), p is 3. [000140] In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), Y 1 is -CH2- . In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), Y 1 is -C(=O)-. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), Y 1 is null. [000141] In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, or C1- C4alkoxyC1-C4alkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen, C1-C4alkyl, C1-C4haloalkyl, or C1-C4hydroxyalkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen or C1-C4alkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen. [000142] In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen, -L-O-C(=O)R a , -L-OP(=O)(OR b )2, C1-C4hydroxyalkyl, C1-C4heteroalkyl, or C1-C4alkoxyC1- C4alkyl. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is hydrogen, -L-OP(=O)(OR b )2, C1-C4hydroxyalkyl, C1-C4heteroalkyl, or C1-C4alkoxyC1-C4alkyl. [000143] In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is defined as above and L is absent. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is defined as above and L is -CH2-. In some embodiments of a compound of Formula (IVa), (IVa-1), (IVb), or (IVb-1), R 7’ is defined as above and L is -CH2CH2-. [000144] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C4alkyl, C1- C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b . In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , - C(=O)OR b , -C(=O)NR c R d , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 aminoalkyl, C 1 - C4heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a ; or two R 7 are taken together to form a heterocycloalkyl optionally substituted with one or more R 7b . [000145] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, -CN, -OH, -OR a , -SR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1- C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R 7a . In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, -CN, -OH, -OR a , -SR a , - NR c R d , C1-C4alkyl, C1-C4haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a . In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, -OR a , -SR a , C1-C4alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 7a . [000146] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, -OR a , -SR a , C1-C4alkyl, -L-cycloalkyl, or -L-heterocycloalkyl; or two R 7 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, -OR a , C1-C4alkyl, -L-cycloalkyl, or -L- heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen, C 1 -C 4 alkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen or C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently halogen or -L-cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently C1-C4alkyl or - L-cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), each R 7 is independently C1-C4alkyl. [000147] In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), R 7 is defined as above and L is absent. In some embodiments of a compound of Formula (IV), (IVa), or (IVa-1), R 7 is defined as above and L is -CH2-. In some embodiments of a compound of Formula (IV), (IVa), or (IVa- 1), R 7 is defined as above and L is -CH2CH2-. [000148] In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is halogen, -OR a , C1- C 4 alkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is halogen, C1-C4alkyl, or -L-cycloalkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is halogen or C1-C4alkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is halogen or -L-cycloalkyl. In some embodiments of a compound of Formula (IVb) or (IVb- 1), R 7 is C1-C4alkyl or -L-cycloalkyl. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is C1-C4alkyl. [000149] In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is defined as above and L is absent. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is defined as above and L is -CH2-. In some embodiments of a compound of Formula (IVb) or (IVb-1), R 7 is defined as above and L is -CH2CH2-. [000150] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 7a is independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1- C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 7a is independently halogen, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 7a is independently C1-C4alkyl. [000151] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is hydrogen or C1-C2alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is C1-C3alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 1 is C1-C2alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa- 1), (IVb), or (IVb-1), R 1 is CH3. [000152] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C1-C2alkyl, C1-C2haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is CF3. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C1-C3alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is C1-C2alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is CH3. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 2 is cyclopropyl. [000153] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 3 is hydrogen, halogen, C1-C4alkyl, or C1-C4haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), R 3 is hydrogen. [000154] In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen, - C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -S(=O)2NR c R d , C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, C2-C4alkenyl, C2-C4alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1- C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen, C1-C4alkyl, C1- C4haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen, C1-C4alkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen, methyl, cyclopropyl, or oxetanyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is hydrogen. [000155] In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is defined as above and L is absent. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is defined as above and L is -CH2-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 5 is defined as above and L is -CH2CH2-. [000156] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6 is independently hydrogen, C1-C4alkyl, or C1-C4haloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6 is independently hydrogen or C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), two R 6 on the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), two R 6 on adjacent carbons are taken together to form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each optionally substituted with one or more R. [000157] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6a is independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1- C4heteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6a is independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6a is independently hydrogen or C 1 -C 4 alkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), each R 6a is independently hydrogen. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), one R 6a is hydrogen and the other R 6a is C1-C4alkyl. [000158] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), two R 6a are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), two R 6a are taken together to form a cyclopropyl or a cyclobutyl. In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), two R 6a are taken together to form a cyclopropyl. [000159] In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R 6b is independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1- C4heteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R 6b is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R 6b is independently hydrogen or C1-C4alkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R 6b is independently hydrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), one R 6b is hydrogen and the other R 6b is C1-C4alkyl. [000160] In some embodiments of a compound of Formula (IV), (IVa), or (IVb), two R 6b are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), two R 6b are taken together to form a cyclopropyl or a cyclobutyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), two R 6b are taken together to form a cyclopropyl. [000161] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), [000162] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), . [000163] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), . [000164] In some embodiments of a compound of Formula (IV), (IVa), (IVa-1), (IVb), or (IVb-1), . [000165] In some embodiments of a compound disclosed herein, each R a is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R a is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R a is independently C1- C 6 alkyl. [000166] In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R b is hydrogen. In some embodiments of a compound disclosed herein, each R b is independently C1-C6alkyl. [000167] In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, R c and R d are each independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, R c and R d are each hydrogen. In some embodiments of a compound disclosed herein, R c and R d are each independently C1-C6alkyl. [000168] In some embodiments of a compound disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. [000169] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is - CH2CH2-. [000170] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, and C1-C6heteroalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, - CN, -OH, -OCH3, -NH2, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, or C1- C6haloalkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCH3, -NH2, -N(CH3)2, C1-C6alkyl, or C1- C 6 haloalkyl; or two R on the same atom form an oxo. [000171] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [000172] In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 1. TABLE 1

[000173] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from: ,

,

. [000176] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from:

,

. [000177] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from:

,

[000178] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from: ,

Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [000179] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds [000180] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. [000181] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein. [000182] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [000183] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [000184] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [000185] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate. [000186] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1 - carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein and their pharmaceutically acceptable acid addition salts. [000187] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4, and the like. [000188] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [000189] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [000190] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers [000191] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Method of treatment [000192] Disclosed herein is a method of inhibiting a Unc-51 like autophagy activating kinase (ULK) isoform comprising contacting the ULK isoform with a compound disclosed herein or pharmaceutically acceptable salt thereof. In some embodiments, the method inhibits ULK1 and/or ULK2. [000193] Disclosed herein is a method of selectively inhibiting a Unc-51 like autophagy activating kinase (ULK) isoform comprising selectively contacting the ULK isoform with a compound disclosed herein or pharmaceutically acceptable salt thereof. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salt thereof, selectively inhibit Unc-51 like autophagy activating kinase (ULK) over other kinases. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salt thereof, selectively inhibit Unc-51 like autophagy activating kinase (ULK) over AMP-activated protein kinase (AMPK). [000194] Disclosed herein is a method of treating cancer comprising administering to a subject a compound disclosed herein or pharmaceutically acceptable salt thereof. [000195] Disclosed herein is a method of treating cancer sensitive to ULK1/2 inhibition in a subject in need thereof. Some embodiments of the disclosure include methods for treating abnormal cell growth in a subject comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. In certain such embodiments, the abnormal cell growth is cancer, and in certain of those embodiments the cancer is lung cancer, pancreatic cancer, skin cancer, including melanoma, cancer of the head or neck, ovarian cancer, rectal cancer, colon cancer, breast cancer, cancer of the thyroid gland, chronic or acute leukaemia, and renal cell carcinoma. Such cancers may be KRAS associated cancers. In some embodiments, the cancer comprises a solid tumor. Of particular interest are cancers such as lung cancer, non-small cell lung cancer, colon cancer, rectal, colorectal, gastric, stomach, oesophageal cancer, salivary gland cancer, pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC), AML, CML, and ovarian cancer. In some embodiment the method of treating cancer is a method of treating chronic myeloid leukaemia. In some embodiments, the cancer comprises a liquid tumor. In some embodiments, the cancer is chronic myeloid leukaemia. [000196] In some embodiments, one or more compounds disclosed herein are administered to subjects having cancer that comprises one or more alterations in the MAPK pathway, including cancers having alternations in one or more of the RAS, SHP2, RAF, MEK, and ERK pathways. In some embodiments, the cancer in the subject has one or more alterations in the RAS pathway. In some embodiments, the cancer in the subject has one or more alterations in the RAF pathway. In some embodiments, the cancer in the subject has one or more alterations in the MEK pathway. In some embodiments, the cancer in the subject has one or more alterations in the ERK pathway. In some embodiments, one or more compounds disclosed herein are administered to subjects having cancer that is driven by cellular signalling in the MAPK pathway. [000197] In some embodiments, one or more compounds disclosed herein are administered to subjects having cancer that comprises one or more alterations in the PI3K-AKT pathway, including cancers having alternations in one or more of the PI3K, PTEN, and AKT pathways. In some embodiments, the cancer in the subject has one or more alterations in the PI3K pathway. In some embodiments, the cancer in the subject has one or more alterations in the PTEN pathway. In some embodiments, the cancer in the subject has one or more alterations in the AKT pathway. [000198] In some embodiments, one or more compounds disclosed herein are administered to subjects having cancer that comprises one or more alterations in the mTOR pathway. [000199] In some embodiments, the cancer in the subject has one or more alterations in the RAS pathway, including mutations to KRAS, including G12C, G12D, and G12V mutations. KRAS inhibitors that may be used in combination with the compounds disclosed herein include, but are not limited to, one or more of AMG 510, MRTX849, and GDC-6036. [000200] In some embodiments, the cancer in the subject has one or more alterations in the RAF pathway, including mutations to BRAF, including BRAF V600E. [000201] In some embodiments, the cancer in the subject has one or more alterations in the ERK pathway. [000202] In some embodiments, the cancer in the subject has one or more alterations in the MEK pathway. [000203] Within the scope of the present disclosure, beneficial or desired clinical results in a subject to which a compound of the disclosure is administered, alone or in the form of a pharmaceutically acceptable composition, include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of a tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression of the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and/or prolonging survival of subjects the cancer. Positive therapeutic effects in cancer can be measured in a number of ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med.50 Suppl.1:1S-10S (2009). For example, with respect to tumor growth inhibition (T/C), according to the National Cancer Institute (NCI) standards, a T/C less than or equal to 42% is the minimum level of anti-tumor activity. A T/C<10% is considered a high anti-tumor activity level, with T/C (%)=median tumor volume of the treated/median tumor volume of the control.times.100. [000204] In some embodiments, the treatment achieved by treatment as disclosed herein is defined by reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression free survival (PFS), disease free survival (DFS) and overall survival (OS). PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time subjects have experienced a CR or PR, as well as the amount of time subjects have experienced stable disease (SD). DFS refers to the length of time during and after treatment that the subject remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated subjects or subjects. In some embodiments, response to a combination of the disclosure is any of PR, CR, PFS, DFS, OR, or OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria. [000205] The treatment regimen relating to a compound of the disclosure, or a pharmaceutical composition comprising a compound of the disclosure, that is effective to treat cancer in a subject may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student's t-test, the chi2-test the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat-testy and the Wilcon on-test. Dosing [000206] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [000207] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition. [000208] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. [000209] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. [000210] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms. [000211] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. [000212] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day. [000213] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage, or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [000214] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD10 and the ED90. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized. [000215] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal. [000216] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day. [000217] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year. Routes of Administration [000218] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. [000219] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, the compound described herein is administered topically. Pharmaceutical Compositions/Formulations [000220] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof is administered to animals. In some embodiments, the compounds are administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration. [000221] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [000222] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof. [000223] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. [000224] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes. [000225] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [000226] Pharmaceutical compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. [000227] Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms. Combination [000228] Disclosed herein are methods of treating a disease or disorder associated with modulating autophagy via inhibition of ULK1 and/or ULK2,with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent. [000229] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein. [000230] In some embodiments, the additional therapeutic agent is an additional anticancer agent. Such additional anticancer agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases and/or phosphatases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like. In some embodiments, the additional anti-cancer agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is selected from imatinib and nilotinib. In some embodiments the additional therapeutic agent is radiotherapy. [000231] In some embodiments, the additional therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib, or talazoparib. [000232] In some embodiments, the additional therapeutic agent is a BRAF inhibitor. In some embodiments, the BRAF inhibitor is encorafenib, dabrafenib, or vemurafenib. [000233] In some embodiments, the additional therapeutic agent is an ERK inhibitor. In some embodiments, the ERK inhibitor is ulixertinib, ASN007, LY3214996, AZ13767370, MK-8353, or LTT462. [000234] In some embodiments, the additional therapeutic agent is a MEK inhibitor. In some embodiments, the MEK inhibitor is trametinib, binimetinib, cobimetinib, or selumetinib. [000235] In some embodiments, the additional therapeutic agent is mammalian target of rapamycin inhibitor (mTOR). In some embodiments, the mTOR inhibitor is sirolimus, everolimus, temsirolimus, or ridaforolimus (AP23573 and MK-8669). [000236] In some embodiments, the additional therapeutic agent is an anti-angiogenesis agent. In some embodiments, the additional therapeutic agent is a VEGF inhibitor, VEGFR inhibitor, PDGFR inhibitor, sunitinib, bevacizumab, axitinib, SU 14813 (Pfizer), or AG 13958 (Pfizer). In some embodiments, the additional therapeutic agent is sorafenib. [000237] In some embodiments, the additional therapeutic agent is a so-called signal transduction inhibitor (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include for example kinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors. More specifically signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, ERBB family inhibitors, IGF1R inhibitors, MEK, c-Kit inhibitors, Erk1/2 inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and so called multi-targeted kinase inhibitors. [000238] In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is selected from imatinib and nilotinib. EXAMPLES Example 1: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide Step 1: N-(4-chlorophenethyl)-2,2,2-trifluoroacetamide [000239] 2-(4-Chlorophenyl)ethylamine (642 mmol) was dissolved in dichloromethane (1.2 L) and triethylamine (107 mL) was added in one portion. The mixture was cooled down to 0 °C and trifluoroacetic anhydride (771 mmol) was added dropwise over 40 minutes while maintaining the reaction temperature below 5 °C. The reaction mixture was stirred at 0–5 °C for 15 minutes and quenched with water. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford the title compound in 99% yield. This material was used in the next step without purification. m/z (ESI, -ve) = 250.6 (M-H). Step 2: 1-(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoro ethan-1-one [000240] N-[2-(4-chlorophenyl)ethyl]-2,2,2-trifluoroacetamide (636.56 mmol) was suspended in acetic acid (173 mL) and paraformaldehyde (1.27 mol) was added in one portion. The mixture was cooled down to 10 °C and concentrated sulfuric acid (218 mL) was added dropwise over 85 minutes maintaining the temperature below 15 °C. The reaction mixture was stirred at 50-60 °C for 1 hour and then cooled down to room temperature and stirred for another 16 hours. The reaction mixture was poured on ice and the aqueous layer was separated and extracted with dichloromethane three times. The combined organic layers were combined, washed with a saturated solution of sodium carbonate, dried over sodium sulfate, and evaporated to afford a crude that was triturated with 10% ethyl acetate in hexane, filtered, washed with n-hexane and dried. The title compound was isolated in 60% yield. m/z (ESI, +ve)= 264.1 [M+H] + . Step 3: 1-(7-chloro-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-t rifluoroethan-1-one [000241] 1-(7-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-triflu oroethan-1-one (152 mmol) was dissolved in sulfuric acid (374 mL). The solution was cooled down to -20 °C and fuming nitric acid (6.5 mL) was added dropwise over 30 min while keeping the temperature at -20 °C. After 15 minutes, the reaction was quenched with ice-water (1.5 L) and the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound in 79% yield. m/z (ESI, -ve) = 307.1 (M-H)-. Step 4: 1-(6-amino-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-t rifluoroethan-1-one [000242] To a solution of 1-(7-chloro-6-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2, 2-trifluoroethan-1- one (120 mmol) in ethanol (928 mL), iron powder (608 mmol) was added in small portions. Acetic acid (14 mL) and 6N aqueous HCl (5 mL) were added and the resulting reaction mixture was heated at 70 °C for 2 hours. The crude reaction mixture was cooled down to room temperature, filtered through a pad of celite and rinsed with ethanol. The filtrate was concentrated to obtain a dark brown semisolid that was purified by chromatography (20% ethyl acetate in hexanes) to afford the title compound in 96% yield. m/z (ESI, +ve)= 279.1 [M+H] + . Step 5: 1-(7-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000243] 1-(6-amino-7-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2, 2-trifluoroethan-1-one (34.7 mmol) was dissolved in 2,4-dichloro-5-(trifluoromethyl)pyrimidine (191 mmol) and the mixture was stirred at 70°C for 24 hours. The reaction mixture was diluted with dichloromethane, celite was added and the solvent was evaporated under reduced pressure. Purification by silica gel chromatography (20% ethyl acetate in hexanes) afforded the title compound in 37% yield. m/z (ESI, +ve)= 459.1 [M+H] + . Step 6: Methyl 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000244] A solution of 1-(7-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (0.41 mmol), triethylamine (0.83 mmol), Pd(dppf)Cl 2 (0.041 mmol) and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester (0.50 mmol) in 1,4-dioxane (2.0 mL) and water (0.4 mL) was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (70% ethyl acetate in hexanes) to afford the title compound in 40% yield. m/z (ESI, -ve)= 563.3 (M-H)-. Step 7: [000245] Methyl 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate (0.88 mmol) was suspended in 7N solution of ammonia in methanol (2.53 mL). The reaction mixture was stirred at 90°C for 48 hours and the volatiles removed under reduced pressure to afford a residue that was triturated with methanol and purified by HPLC. The title compound was isolated in 30% yield. m/z (ESI, +ve)= 454.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.78 (s, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 3.96 (s, 2H), 3.06 (t, J = 6.0 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H). Example 2: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-N,N-dimethylthiophene-3-car boxamide Step 1: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylic acid [000246] A solution of methyl 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carb oxylate (0.16 mmol) in ethanol (1.9 mL), was treated with a 4M aqueous solution of LiOH (0.19 mL) and the reaction mixture was stirred at room temperature for 1 hour. Evaporation of volatiles under reduced pressure afforded the title compound in quantitative yield. This material was used in the next step without further purification. m/z (ESI, +ve)= 455.1 [M+H]+ Step 2: 5-(2-((2-(tert-butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydrois oquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid [000247] To a solution of 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid (0.16 mmol) in acetonitrile (3.7 mL) was added di-tert-butyl dicarbonate (0.33 mmol) and triethylamine (0.069 mL). The reaction mixture was stirred at room temperature for 1 hour and the volatiles were removed under reduced pressure to afford the title compound in quantitative yield. This material was used in the next step without further purification. m/z (ESI, -ve)= 553.3 (M-H)- Step 3: tert-butyl 7-chloro-6-((4-(4-(dimethylcarbamoyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli ne-2(1H)-carboxylate [000248] A solution of O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (0.33 mmol), 5-(2-((2-(tert-butoxycarbonyl)-7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)thiophene-3-carboxylic acid (0.16 mmol), triethylamine (0.046 mL) and methylamine (2M in THF, 0.165 mL) in acetonitrile (1.8 mL) was stirred at room temperature for 30 minutes. Evaporation of volatiles afforded a residue that was dissolved in dichloromethane and water. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (70% hexanes in ethyl acetate) to afford the title compound in 93% yield. m/z (ESI, -ve)= 580.5 (M-H)-. Step 4: [000249] A solution of tert-butyl 7-chloro-6-((4-(4-(dimethylcarbamoyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli ne-2(1H)-carboxylate (0.12 mmol) in 1,4- dioxane (1.4 mL) was treated with a 4N aqueous solution of HCl (1.4 mL) and the solution was stirred at room temperature overnight. Evaporation of volatiles afforded a residue that was purified by HPLC. The title compound was isolated in 19% yield. m/z (ESI, +ve)= 482.2 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 9.99 (s, 1H), 8.97 (s, 2H), 8.80 (s, 1H), 8.15 (d, J = 1.3 Hz, 1H), 7.77 (d, J = 1.3 Hz, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 4.31 (s, 2H), 3.42 (t, J = 6.3 Hz, 2H), 3.02 (m, 8H). Example 3: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-N,N-dimethylthiophene-2-car boxamide Step 1: 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-2-carboxylic acid [000250] The title compound was prepared analogously to Example 1, step 6, where 4- (methoxycarbonyl)thiophene-2-boronic acid pinacol ester was substituted with 5-carboxylthiophene-2- boronic acid pinacol ester. The title compound was isolated in 23% yield. m/z (ESI, +ve)= 551.3 [M+H] + . Step 2: [000251] 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-2-carboxylic acid (0.15 mmol) was treated with SOCl2 (0.11 mL) and the mixture was stirred at 60°C for 1 hour and concentrated to dryness. The resulting residue was dissolved in THF (2.4 mL) and a 2M solution of dimethylamine in THF (0.76 mL) was added. This mixture was stirred at room temperature for 1 hour. Potassium carbonate (0.76 mmol) and water (0.6 mL) were added and the reaction mixture was stirred at 50°C overnight, concentrated under reduced pressure and the residue purified by preparative HPLC to afford the title compound in 2% yield. m/z (ESI, +ve)= 482.14 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.48 (s, 1H), 7.64 (d, J = 3.9 Hz, 1H), 7.54 (d, J = 4.1 Hz, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 3.84 (s, 2H), 2.94 (t, J = 5.8 Hz, 2H), 2.68 (d, J = 5.6 Hz, 2H). Example 4: 2-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one Step 1: 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000252] A solution of 1-(7-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (3.26 mmol), 1,4-bis(diphenylphosphino)butane (0.65 mmol), palladium (II) acetate (0.65 mmol) and hexamethylditin (9.80 mmol) in 1,4-dioxane (30 mL) was stirred at 95 ˚C for 24 hours. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by silica gel chromatography (hexanes with 10% of triethylamine) to afford the title compound in 32% yield. m/z (ESI, +ve)= 590.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.56 (s, 1H), 7.60 – 7.47 (m, 2H), 4.77 (d, J = 12.4 Hz, 3H), 3.82 (q, J = 5.8 Hz, 2H), 2.95 – 2.85 (m, 2H), 0.31 (s, 9H). Step 2: 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000253] A mixture of CuI (0.037 mmol), PdCl2(PPh3)2 (0.009 mmol), 2-bromo-6,7-dihydrothieno[3,2- C]pyridin-4(5H)-one (0.22 mmol) and 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin- 2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoro ethan-1-one (0.18 mmol) in 1,4-dioxane (2.8 mL) was stirred at 100°C for 2 hours. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford the title compound in 47% yield. m/z (ESI, +ve)= 576.2 [M+H] + . Step 3: [000254] Potassium carbonate (0.36 mmol) was added to a stirred solution of 2-(2-((7-chloro-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one (0.073 mmol) in a mixture of ethanol (1.2 mL) and water (0.12 mL) and the reaction mixture was stirred at 70°C for 1 hour. Evaporation of volatiles afforded a residue that was purified by HPLC. The title compound was isolated in 21% yield. m/z (ESI, +ve)= 480.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.25 (s, 2H), 7.88 – 7.75 (m, 2H), 7.34 (s, 1H), 7.26 (s, 1H), 3.92 (m, 2H), 3.04 (m, 6H), 2.74 (m, 2H). Example 5: 5-(2-((2-(azetidin-3-yl)-7-chloro-1,2,3,4-tetrahydroisoquino lin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide Step 1: tert-butyl 3-(6-((4-(4-carbamoylthiophen-2-yl)-5-(trifluoromethyl)pyrim idin-2-yl)amino)-7- chloro-3,4-dihydroisoquinolin-2(1H)-yl)azetidine-1-carboxyla te [000255] To a stirred solution of tert-butyl 3-oxoazetidine-1-carboxylate (0.41 mmol) and 5-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)thiophene-3- carboxamide (0.34 mmol) in dichloromethane (3.4 mL), triethylamine (0.49 mL) and NaBH(OAc)3 (1.69 mmol) were added in one portion. The reaction mixture was stirred at room temperature overnight, diluted with water and the organic layer separated, dried over sodium sulfate, and concentrated to dryness. The crude material was purified by silica gel chromatography (0 to 100% ethyl acetate in hexanes) to afford the title compound in 93% yield. m/z (ESI, +ve)= 609.3 [M+H] + . Step 2: [000256] A solution of tert-butyl 3-(6-((4-(4-carbamoylthiophen-2-yl)-5-(trifluoromethyl)pyrim idin-2- yl)amino)-7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)azetidine -1-carboxylate (0.071 mmol) was treated with a 4N solution of HCl in 1,4-dioxane (0.8 mL). The reaction was stirred at room temperature for 1 hour, the volatiles were removed under reduced pressure and the resulting crude material was purified by preparative HPLC to afford the title compound in 40% yield. m/z (ESI, +ve)= 509.4 [M+H] + . Example 6: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-N-methylthiophene-3-carboxa mide Step 1: tert-butyl 7-chloro-6-((4-(4-(methylcarbamoyl)thiophen-2-yl)-5-(trifluo romethyl)pyrimidin- 2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate [000257] The title compound was prepared analogously to Example 3, where the solution of dimethylamine was replaced with a 2M solution of methylamine in THF. The title compound was isolated in 53% yield. m/z (ESI, -ve) = 566.6 (M-H)-. Step 2: [000258] The title compound was prepared analogously to Example 2 where tert-butyl 7-chloro-6-((4-(4- (dimethylcarbamoyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinoline- 2(1H)-carboxylate was replaced with tert-butyl 7-chloro-6-((4-(4-(methylcarbamoyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli ne-2(1H)-carboxylate. The title compound was isolated in 40% yield. m/z (ESI, +ve)= 468.10 [M+H] + . MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 8.76 (s, 1H), 8.47 (d, J = 4.6 Hz, 1H), 8.42 – 8.28 (m, 3H), 8.01 (s, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 3.87 (s, 3H), 2.97 (s, 3H), 2.75 (d, J = 4.5 Hz, 3H), 2.70 (s, 2H). Example 7: 5-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)thiophene-3- carboxamide Step 1: 1-(5-chloroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000259] 5-Chloroisoindoline (5.69 mmol) and triethylamine (2.4 mL) were dissolved in dichloromethane (28 mL). The solution was cooled down to -10°C and trifluoroacetic anhydride (8.53 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature, stirred at that temperature for 1 hour and quenched with water. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound in 77% yield, which was used in the next step without further purification. m/z (ESI, +ve)= 250.0 [M+H] + Step 2: 1-(5-chloro-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-o ne [000260] 1-(5-Chloro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroeth an-1-one (4.37 mmol) was stirred in H 2 SO 4 (12 mL) at 0°C until the starting material is completely dissolved. The solution was cooled down to -20°C and 90% fuming HNO3 (0.43 mL) was added. The reaction mixture was stirred at -20°C for 1 hour and quenched by addition of ice. The mixture was extracted with dichloromethane three times and the combined organic layers were washed with a saturated solution of NaHCO3, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound in 98% yield, which was used in the next step without purification. m/z (ESI, +ve)= 293.1 [M+H] + . Step 3: 1-(5-amino-6-chloroisoindolin-2-yl)-2,2,2-trifluoroethan-1-o ne [000261] 1-(5-chloro-6-nitro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trif luoroethan-1-one (4.23 mmol), acetic acid (0.50 mL) and iron powder (21.3 mmol) were suspended in EtOH (63.5 mL). The mixture was stirred at 80°C for 1.5 hours and the volatiles were removed under reduced pressure to afford a residue that was filtered through a pad of celite and rinsed with ethyl acetate. Evaporation of volatiles afforded the title compound in 96% yield. m/z (ESI, +ve)= 265.0 [M+H] + . Step 4: 1-(5-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)isoindolin-2-yl)-2,2,2- trifluoroethan-1-one [000262] A mixture of 1-(5-amino-6-chloro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trif luoroethan-1-one (4.12 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (28.8 mmol) was stirred at 60°C overnight. The reaction mixture was diluted with dichloromethane (3 mL) and the insoluble material was filtered off. The filtrate was concentrated and purified by chromatography in silica gel (50-100% dichloromethane in hexanes) to afford the title compound in 26% yield. m/z (ESI, +ve)= 445.7 [M+H] + . Step 5: Methyl-5-(2-((6-chloro-2-(2,2,2-trifluoroacetyl)isoindolin-5 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000263] The title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(5-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)isoindolin-2- yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 72% yield. m/z (ESI, +ve)= 551.9 [M+H] + . Step 6: [000264] The title compound was prepared analogously to Example 1 where methyl 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with methyl-5-(2-((6-chloro-2-(2,2,2-trifluoroacetyl)isoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxylate. The title compound was isolated in 83% yield. m/z (ESI, +ve)= 440.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.76 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 4.14 (s, 4H). Example 8: 7-chloro-N-(4-(4-(4,5-dihydrooxazol-2-yl)thiophen-2-yl)-5-(t rifluoromethyl)pyrimidin- 2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine Step 1: 5-bromothiophene-3-carboxylic acid [000265] Methyl 2-bromothiophene-4-carboxylate (13.6 mmol) and LiOH (20.4 mmol) were dissolved in THF (30 mL) and water (30 mL) and the solution stirred at 50 ˚C for 2 hours. The THF was removed under reduced pressure and the aqueous solution was acidified with concentrated aqueous HCl to pH=3. The resulting white solid was filtered, washed with water, and dried under high vacuum. The title compound was isolated in 87% yield. m/z (ESI, -ve) = 206.9 (M-H)-. Step 2: 5-Bromo-N-(2-hydroxyethyl)thiophene-3-carboxamide [000266] Over a solution of 5-bromothiophene-3-carboxylic acid (11.4 mmol) in dichloromethane (47 mL) and 3 drops of DMF at 0 ˚C, oxalyl chloride (17.1 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes, the volatiles were removed under reduced pressure and the residue re-dissolved in dichloromethane (25 mL). This new solution was added over a solution of ethanolamine (0.76 mL) and triethylamine (3.2 mL) in dichloromethane (25 mL) precooled to 0˚C. The reaction was allowed to warm up to room temperature and stirred for one hour. Evaporation of volatiles and purification of the crude material by silica gel (0-100% ethyl acetate in hexanes) afforded the title compound in 46% yield. m/z (ESI, +ve)= 251.9 [M+H] + . Step 3: 2-(5-Bromothiophen-3-yl)-4,5-dihydrooxazole [000267] 5-Bromo-N-(2-hydroxyethyl)thiophene-3-carboxamide (1.9 mmol) was suspended in dichloromethane (10 mL). Triethylamine (0.69 mL) was added and the mixture was cooled to 0 ˚C. Methanesulfonyl chloride (0.19 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Evaporation of volatiles under reduced pressure afforded a residue that was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford the title compound in 50% yield. m/z (ESI, +ve)= 234.4 [M+H] + . Step 4: 1-(7-Chloro-6-((4-(4-(4,5-dihydrooxazol-2-yl)thiophen-2-yl)- 5-(trifluoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one [000268] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-(5-bromothiophen-3-yl)-4,5- dihydrooxazole. The title compound was isolated in 32% yield. m/z (ESI, +ve)= 576.8 [M+H] + . Step 5: [000269] 1-(7-Chloro-6-((4-(4-(4,5-dihydrooxazol-2-yl)thiophen-2-yl)- 5-(trifluoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one (0.064 mmol) was suspended in a 7N solution of ammonia in methanol (2 mL) and the reaction mixture was stirred at 50 ˚C for 2 hours. The solvent was removed under reduced pressure and the crude was purified by preparative TLC (dichloromethane with 5% of a 3M solution of ammonia in methanol) to afford the title compound in 32% yield. m/z (ESI, +ve)= 479.87 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.78 (s, 1H), 8.34 (d, J = 1.1 Hz, 1H), 8.01 (s, 1H), 7.27 (d, J = 32.8 Hz, 2H), 4.39 (t, J = 9.5 Hz, 2H), 3.94 (t, J = 9.4 Hz, 2H), 3.85 (s, 1H), 2.95 (t, J = 5.8 Hz, 2H), 2.73 – 2.63 (m, 2H). Example 9: 5-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxamide Step 1: 7-Ethyl-6-nitro-1,2,3,4-tetrahydroisoquinoline [000270] 1-(7-chloro-6-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2, 2-trifluoroethan-1-one (3.24 mmol), Pd(dppf) 2 Cl 2 complex with dichloromethane (0.16 mmol), potassium phosphate tribasic (16.2 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (0.26 mmol) and ethylboronic acid (9.72 mmol) were suspended in toluene (20 mL) and water (3 mL) and the mixture was stirred at 100°C overnight. The reaction was cooled down to room temperature and washed with water and 1N aqueous HCl. The pH of the organic layer was made alkaline (pH>10) by the addition 15% aqueous solution of NaOH, the organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound in 61% yield. m/z (ESI, +ve)= 207.1 [M+H] + . Step 2: 1-(7-ethyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000271] A -10°C solution of 7-ethyl-6-nitro-1,2,3,4-tetrahydroisoquinoline (1.96 mmol) and triethylamine (0.55 mL) in dichloromethane (9 mL) was treated with trifluoroacetic anhydride (2.94 mmol) and the resulting mixture was stirred at room temperature for one hour. The reaction was quenched with water and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (10-60% ethyl acetate in hexanes) to afford the title compound in 67% yield. m/z (ESI, -ve) = 301.2 (M-H)-. Step 3: 1-(6-Amino-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000272] A mixture of 1-(7-ethyl-6-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2 -trifluoroethan-1-one (1.31 mmol), iron powder (6.55 mmol) and acetic acid (0.15 mL) was suspended in ethanol (20 mL) and heated at 80°C overnight. Evaporation of volatiles under reduced pressure afforded a residue that was suspended in ethyl acetate and filtered through silica gel. The filtrate was concentrated and the crude material was purified by silica gel chromatography (10-60% ethyl acetate in hexanes) to afford the title compound in 58% yield. m/z (ESI, +ve)= 273.2 [M+H] + Step 4: 1-(6-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-e thyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000273] A solution of 1-(6-Amino-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one (0.73 mmol) in 2,4-dichloro-5-(trifluoromethyl)pyrimidine (4.70 mmol) was heated at 50 °C overnight. The insoluble materials were filtered and the solvent was removed under reduced pressure. Purification by silica gel chromatography afforded the title compound in 39% yield. m/z (ESI, +ve)= 453.9 [M+H] + . Step 5: [000274] The title compound was prepared analogously to Example 1 where methyl 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with methyl 5-(2-((7-ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)thiophene-3-carboxylate. The title compound was isolated in 26% yield. m/z (ESI, +ve)= 448.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.67 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 3.98 (s, 2H), 3.09 (s, 2H), 2.76 (s, 2H), 2.60 – 2.54 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H). Step 5: Methyl 5-(2-((7-ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroi soquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000275] The title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 11-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7- ethyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 75% yield. m/z (ESI, +ve)= 559.9 [M+H] + . Example 10: 5-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide Step 1: 1-(7-Cyclopropyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2, 2,2-trifluoroethan-1-one [000276] The title compound was prepared analogously to Example 9, step 1, where ethylboronic acid was replaced with potassium cyclopropyltrifluoroborate. The title compound was isolated in 72% yield. m/z (ESI, +ve)= 315.1 [M+H] + . Step 2: 1-(6-Amino-7-cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2, 2,2-trifluoroethan-1-one [000277] The title compound was prepared analogously to Example 9, step 3, where 1-(7-ethyl-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne was replaced with 1-(7-cyclopropyl-6- nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one. The title compound was isolated in 79% yield. m/z (ESI, +ve)= 285.3 [M+H] + . Step 3: 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-c yclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000278] The title compound was prepared analogously to example 9, step 4, where 1-(6-amino-7-ethyl- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-amino-7- cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoro ethan-1-one. The title compound was isolated in 33% yield. m/z (ESI, +ve)= 465.2 [M+H] + . Step 4: Methyl 5-(2-((7-cyclopropyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetra hydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carb oxylate [000279] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-c yclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 66% yield. m/z (ESI, +ve)= 571.9 [M+H] + . Step 5: [000280] The title compound was prepared analogously to Example 1 where methyl 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with methyl 5-(2-((7-cyclopropyl-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-carboxylate. The title compound was isolated in 27% yield. m/z (ESI, +ve)= 460.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 8.75 (s, 1H), 8.41 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 6.87 (s, 1H), 4.22 (s, 2H), 3.38 (t, J = 6.3 Hz, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.09 – 1.92 (m, 1H), 0.95 – 0.80 (m, 2H), 0.67 – 0.52 (m, 2H). Example 11: 5-(2-((7-chloro-2-(1-methylazetidin-3-yl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide [000281] To a stirred solution of 1-methylazetidin-3-one hydrochloride (0.17 mmol) and 5-(2-((7-chloro- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-carboxamide (0.14 mmol) in dichloromethane (1.4 mL), triethylamine (0.20 mL) and NaBH(OAc)3 (0.69 mmol) were added in one portion. The reaction mixture was stirred at room temperature overnight and quenched with water. The organic layer was separated and dried over sodium sulfate and concentrated to dryness. The crude product was purified by preparative HPLC to afford the title compound in 5% yield. m/z (ESI, +ve)= 523.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.77 (s, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.37 (d, J = 6.0 Hz, 2H), 7.27 (s, 1H), 3.47 (t, J = 6.6 Hz, 2H), 3.43 (s, 2H), 3.02 (p, J = 6.5 Hz, 1H), 2.85 (t, J = 6.7 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H), 2.25 (s, 3H). Example 12: 5-(2-((6-chloro-2-(1-methylazetidin-3-yl)isoindolin-5-yl)ami no)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide [000282] 5-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)thiophene-3- carboxamide (0.21 mmol), 1-methylazetidin-3-one hydrochloride (0.42 mmol) and sodium cyanoborohydride (0.42 mmol) were dissolved in methanol (2 mL). The reaction was stirred at 50°C for 3 hours and purified by silica gel chromatography (dichloromethane with 10-40% of a 0.6M methanolic solution of ammonia). The product was dried and a second purification was carried out by eluting the dissolved compound through a NH2-silica cartridge using methanol as solvent. The title compound was isolated in 32% yield. m/z (ESI, +ve)= 509.14 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.76 (s, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 3.83 (s, 4H), 3.45 – 3.38 (m, 3H), 3.05 – 2.94 (m, 2H), 2.26 (s, 3H). Example 13: 5-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide Step 1: Methyl 5-(2-((7-Ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000283] Methyl 5-(2-((7-ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroi soquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate (0.69 mmol) was dissolved in THF (8 mL) and a 0.3M aqueous solution of LiOH (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour followed by the addition of acetic acid (0.12 mL) and a 37% aqueous solution of formaldehyde (0.072mL). After 10 minutes, sodium cyanoborohydride (1.39 mmol) was added and one hour later all volatiles were removed under reduced pressure to afford a solid that was taken up in dichloromethane and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated to afford the title compound in 84% yield. m/z (ESI, +ve)= 477.4 [M+H] + Step 2: 5-(2-((7-Ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid [000284] Methyl 5-(2-((7-Ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate (0.58 mmol) was dissolved in THF (5.6 mL) and a 1M aqueous solution of LiOH (1.4 mL) was added. The reaction was stirred at room temperature overnight and the pH of the mixture was decreased to 4 by the addition of a 1M aqueous solution of HCl. The solvents were removed under reduced pressure affording the title compound in 96% yield. This material was used in the next step without further purification. m/z (ESI, +ve)= 463.3 [M+H] + . Step 3: [000285] 5-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid hydrochloride (0.56 mmol) was dissolved in DMF (6.9 mL) and triethylamine (0.23 mL), a 0.4 N solution of ammonia in 1,4-dioxane (4.2 mL) and HATU (1.68 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, the volatiles were removed under reduced pressure and the residue was taken up in water and filtered. The crude material was purified by silica gel chromatography (dichloromethane with 10-50% of a 0.6M methanolic solution of ammonia) to afford the title compound in 52% yield. m/z (ESI, +ve)= 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.71 (s, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.37 (s, 1H), 7.16 (s, 1H), 6.98 (s, 1H), 3.69 (s, 2H), 2.92 – 2.75 (m, 4H), 2.56 (q, J = 8.5, 8.0 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H). Example 14: 5-(2-((7-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxamide Step 1: Methyl 5-(2-((7-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000286] The title compound was prepared analogously to Example 13, step 1, where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with methyl 5-(2-((7-cyclopropyl-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-carboxylate. The title compound was isolated in 99% yield. m/z (ESI, +ve)= 489.4 [M+H] + . Step 2: 5-(2-((7-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid [000287] The title compound was prepared analogously to Example 13, step 2, where methyl 5-(2-((7- ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin-4-yl)thiophene- 3-carboxylate was replaced with methyl 5-(2-((7-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin- 6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carb oxylate. The title compound was isolated in 98% yield. m/z (ESI, +ve)= 475.3 [M+H] + . Step 3: [000288] A solution of 5-(2-((7-cyclopropyl-2-methyl-1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid hydrochloride (0.36 mmol), triethylamine (0.15 mL) in DMF (4 mL) was treated with a 0.4 N solution of ammonia in 1,4-dioxane (2.7 mL) and HATU (1.08 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and the solid residue was suspended in water and filtered. Purification by preparative HPLC afforded the title compound in 15% yield. m/z (ESI, +ve)= 474.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.64 (s, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 8.29 (s, 2H), 8.01 (s, 1H), 7.96 (s, 1H), 7.38 (s, 1H), 7.18 (s, 1H), 6.67 (s, 1H), 3.44 (s, 2H), 2.79 (t, J = 5.8 Hz, 2H), 2.58 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 2.00 – 1.86 (m, 1H), 0.84 – 0.76 (m, 2H), 0.59 – 0.51 (m, 2H). Example 15: N-(4-(4-aminothiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-y l)-7-chloro-1,2,3,4- tetrahydroisoquinolin-6-amine Step 1: tert-Butyl (5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydr oisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)ca rbamate [000289] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-4-(N-tert- butyloxycarbonylamino)thiophene. The title compound was isolated in 28% yield. m/z (ESI, +ve)= 623.3 [M+H] + . Step 2: [000290] tert-Butyl-(5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3, 4-tetrahydroisoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)carbamate (0.038 mmol) was dissolved in a 2M solution of HCl in diethyl ether (2 mL) and the reaction was stirred at room temperature for 2 hours. After evaporation of volatiles, the residue was redissolved in a 7N solution of ammonia in methanol (0.55 mL) and the reaction was stirred for 16 hours. The solvents were removed under reduced pressure and the crude material was purified by HPLC to afford the title compound in 49% yield. m/z (ESI, +ve)= 424.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.69 (s, 1H), 8.18 (s, 1H), 7.42 (s, 1H), 7.28 (d, J = 6.0 Hz, 2H), 6.37 (d, J = 1.4 Hz, 1H), 5.06 (s, 2H), 3.97 (s, 2H), 3.08 (s, 2H), 2.78 (s, 2H). Example 16: N-(5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)methanesulfona mide Step 1: tert-butyl (5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydr oisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)ca rbamate [000291] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-4-(N-tert- butyloxycarbonylamino)thiophene. The title compound was isolated in 92% yield. m/z (ESI, +ve)= 622.2 [M+H] + Step 2: 1-(6-((4-(4-aminothiophen-2-yl)-5-(trifluoromethyl)pyrimidin -2-yl)amino)-7-chloro-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000292] The title compound was prepared analogously to Example 5 where tert-butyl 3-(6-((4-(4- carbamoylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-7-chloro-3,4-dihydroisoquinolin- 2(1H)-yl)azetidine-1-carboxylate was replaced with tert-butyl (5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophen-3-yl)carbamate. The title compound was isolated in 92% yield. m/z (ESI, +ve)= 522.2 [M+H] + . Step 3: [000293] To the stirred suspension of N-(4-(4-aminothiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-y l)- 7-chloro-1,2,3,4-tetrahydroisoquinolin-6-amine hydrochloride (0.096 mmol) in dichloromethane (1.0 mL), triethylamine (0.028 mL) and methanesulfonyl chloride (0.007 mL) were added. The reaction mixture was stirred at room temperature overnight and the volatiles were removed under reduced pressure to afford a residue that was treated with a 7N solution of ammonia in methanol (1.4 mL). The resulting reaction was stirred at 50°C for 2 hours, concentrated to dryness and purified by silica gel chromatography (dichloromethane with a 10% methanolic solution of ammonia) to afford the title compound in 52% yield. m/z (ESI, +ve)= 501.8 NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.75 (s, 1H), 7.63 (s, 1H), 7.33 (d, J = 1.5 Hz, 2H), 7.22 (s, 1H), 3.86 (s, 2H), 2.97 (d, J = 10.2 Hz, 5H), 2.71 (d, J = 5.9 Hz, 3H). Example 17: 5-(2-((6-Chloro-2-methylisoindolin-5-yl)amino)-5-(trifluorom ethyl)pyrimidin-4- yl)thiophene-3-carboxamide [000294] 5-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)thiophene-3- carboxamide (0.16 mmol) and formaldehyde (37 wt. % in water, 0.02 mL) were dissolved in methanol (2.4 mL) and stirred at room temperature for 10 minutes. Sodium cyanoborohydride (0.33 mmol) was added and the reaction was stirred for another hour. After evepaoration of volatiles under reduced pressure, the crude material was purified by HPLC to afford the title compound in 12% yield. m/z (ESI, +ve)= 454.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.77 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.47 (s, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 3.91 (s, 4H), 2.55 (s, 3H). Example 18: 7-Chloro-N-(4-(4-(oxazol-2-yl)thiophen-2-yl)-5-(trifluoromet hyl)pyrimidin-2-yl)- 1,2,3,4-tetrahydroisoquinolin-6-amine Step 1: 2-(5-Bromothiophen-3-yl)oxazole [000295] 2-(5-Bromothiophen-3-yl)-4,5-dihydro-1,3-oxazole (1.08 mmol) and 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone (1.62 mmol) in 1,4-dioxane (5.0 mL) were stirred at 100 °C for 2 hours. The reaction mixture was concentrated and purified by silica gel chromatography (0-100% dichloromethane in hexanes) to afford the title compound in 36% yield. m/z (ESI, +ve)= 232.0 [M+H]+. Step 2: 1-(7-Chloro-6-((4-(4-(oxazol-2-yl)thiophen-2-yl)-5-(trifluor omethyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000296] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-(5-bromothiophen-3-yl)oxazole. The title compound was isolated in 20% yield. m/z (ESI, +ve)= 574.8 [M+H] + . Step 3: [000297] The title compound was prepared analogously to Example 1 where methyl-5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 1-(7-chloro-6-((4-(4-(oxazol-2-yl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli n-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 56% yield. m/z (ESI, +ve)= 478.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.80 (s, 1H), 8.48 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 0.8 Hz, 1H), 8.12 (s, 1H), 7.36 (d, J = 0.8 Hz, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 3.85 (s, 2H), 2.95 (t, J = 5.8 Hz, 2H), 2.70 (m, 3H). Example 19: 5-(2-((6-Cyclopropyl-2-methylisoindolin-5-yl)amino)-5-(trifl uoromethyl)pyrimidin-4- yl)thiophene-3-carboxamide Step 1: 1-(5-Cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000298] The title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne and ethylboronic acid were replaced with 1-(5-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one and cyclopropylboronic acid. The title compound was isolated in 52% yield. m/z (ESI, +ve)= 256.1 [M+H] + . Step 2: 1-(5-Cyclopropyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroetha n-1-one [000299] The title compound was prepared analogously to Example 1, step 3, where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-cyclopropylisoindolin-2- yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 31% yield. m/z (ESI, +ve)= 301.2 [M+H] + . Step 3: 1-(5-Amino-6-cyclopropylisoindolin-2-yl)-2,2,2-trifluoroetha n-1-one [000300] A solution of 1-(5-cyclopropyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroetha n-1-one (2.40 mmol) in methanol (29 mL) was hydrogenated in the presence of 10% palladium on carbon (0.72 mmol) for two hours. The reaction was filtered through celite and concentrated to afford the title compound in 93% yield. m/z (ESI, +ve)= 271.2 [M+H] + . Step 4: 1-(5-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-c yclopropylisoindolin-2-yl)- 2,2,2-trifluoroethan-1-one [000301] The title compound was prepared analogously to Example 1, step 5, where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(5-amino-6- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 34% yield. m/z (ESI, +ve)= 451.1 [M+H] + . Step 5: Methyl 5-(2-((6-cyclopropyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-y l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000302] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 73% yield. m/z (ESI, +ve)= 557.3 [M+H] + . Step 6: [000303] The title compound was prepared analogously to Example 13 where 5-(2-((7-ethyl-2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-carboxylic acid hydrochloride was replaced with 5-(2-((6-cyclopropyl-2-methylisoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid. The title compound was isolated in 49% yield. m/z (ESI, +ve)= 460.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.75 (s, 1H), 8.40 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.04 (s, 1H), 4.48 (s, 4H), 2.97 (s, 3H), 2.02 (m, 1H), 0.96 – 0.81 (m, 2H), 0.66 – 0.54 (m, 2H). Example 20: 5-(2-((6-Ethyl-2-methylisoindolin-5-yl)amino)-5-(trifluorome thyl)pyrimidin-4- yl)thiophene-3-carboxamide Step 1: 1-(5-Bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000304] The title compound was prepared analogously to Example 7, step 1 where 5-chloroisoindoline was replaced with 5-bromoisoindoline. The title compound was isolated in 96% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.69 – 7.59 (m, 1H), 7.53 (dd, J = 8.2, 1.9 Hz, 1H), 7.41 – 7.30 (m, 1H), 5.01 (d, J = 12.0 Hz, 2H), 4.81 (d, J = 12.8 Hz, 2H). Step 2: 1-(5-Ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000305] The title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne was replaced with 1-(5-bromoisoindolin-2- yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 97% yield. m/z (ESI, +ve)= 244.1 [M+H] + . Step 3: 1-(5-Ethyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e [000306] The title compound was prepared analogously to Example 7, step 2, where 1-(5-chloro-2,3- dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-Ethylisoindolin-2-yl)-2,2,2- trifluoroethan-1-one. The title compound was isolated in 41% yield. m/z (ESI, +ve)= 289.2 [M+H] + . Step 4: 1-(5-Amino-6-ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e [000307] A solution of 1-(5-ethyl-6-nitro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifl uoroethan-1-one (4.10 mmol) in methanol (47 mL) was hydrogenated in the presence of 10% palladium on carbon (130 mg) for 2 hours. The reaction was filtered through celite and the solvents were removed under reduced pressure to afford the title compound in 93% yield. m/z (ESI, +ve)= 259.1 [M+H] + . Step 5: 1-(5-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-e thylisoindolin-2-yl)-2,2,2- [000308] The title compound was prepared analogously to Example 7, step 4, where 1-(5-amino-6- chloro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1- one was replaced with 1-(5-amino-6- ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 23% yield. m/z (ESI, +ve)= 439.1 [M+H] + . Step 6: Methyl 5-(2-((6-ethyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000309] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-e thylisoindolin-2- yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 55% yield. m/z (ESI, +ve)= 545.2 [M+H] + . Step 7: Methyl 5-(2-((6-ethyl-2-methylisoindolin-5-yl)amino)-5-(trifluorome thyl)pyrimidin-4- yl)thiophene-3-carboxylate [000310] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with methyl 5-(2-((6-ethyl-2-(2,2,2-trifluoroacetyl)isoindolin-5- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-carb oxylate. The title compound was isolated in 99% yield. m/z (ESI, +ve)= 463.3 [M+H] + . Step 8: 5-(2-((6-Ethyl-2-methylisoindolin-5-yl)amino)-5-(trifluorome thyl)pyrimidin-4-yl)thiophene- 3-carboxylic acid [000311] The title compound was prepared analogously to Example 2, step 1 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with methyl 5-(2-((6-ethyl-2-methylisoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate. The title compound was isolated in 99% yield. m/z (ESI, +ve)= 449.3 [M+H] + . Step 9: [000312] The title compound was prepared analogously to Example 13 where 5-(2-((7-ethyl-2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4- yl)thiophene-3-carboxylic acid hydrochloride was replaced with 5-(2-((6-ethyl-2-methylisoindolin-5-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid. The title compound was isolated in 49% yield. m/z (ESI, +ve)= 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.39 (s, 1H), 7.21 (s, 1H), 7.16 (s, 1H), 3.83 (s, 4H), 2.59 (t, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H). Example 21: 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methyl-6,7-dihydrothieno[ 3,2-c]pyridin-4(5H)-one Step 1: 2-Bromo-5-methyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000313] Cesium carbonate (2.15 mmol), 2-bromo-6,7-dihydrothieno[3,2-c]pyridin-4(5h)-one (0.43 mmol) and methyl iodide (0.14 mL) were suspended in DMF (2.0 mL) and the mixture stirred at 40 ˚C overnight. The volatiles were removed under reduced pressure, the residue was taken up in dichloromethane and water, the organic layer was separated, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (50% ethyl acetate in hexanes) afforded the title compound in 52% yield. m/z (ESI, +ve)= 247.9 [M+H] + . Step 2: 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methyl-6,7-dihydrothieno[ 3,2-c]pyridin-4(5H)-one [000314] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5-methyl-6,7-dihydrothieno[3,2- c]pyridin-4(5H)-one. The title compound was isolated in 62% yield. m/z (ESI, +ve)= 588.4 [M+H] + . Step 3: [000315] The title compound was prepared analogously to Example 13 where methyl 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-5-methyl-6,7-dihydrothieno[3,2- c]pyridin-4(5H)-one. The title compound was isolated in 36% yield. m/z (ESI, +ve)= 493.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.83 (s, 1H), 8.76 (s, 1H), 7.84 (s, 1H), 7.34 (s, 1H), 7.27 (s, 1H), 3.93 (s, 2H), 3.64 (t, J = 6.8 Hz, 4H), 3.14 (t, J = 6.8 Hz, 2H), 3.02 (s, 1H), 2.97 (s, 3H), 2.75 (s, 2H). Example 22: 2-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-ethyl-6,7-dihydrothieno[3 ,2-c]pyridin-4(5H)-one Step 1: 2-bromo-5-ethyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000316] The title compound was prepared analogously to Example 21, step1 where methyl iodide was replaced with ethyl iodide. The title compound was isolated in 45% yield. m/z (ESI, +ve)= 260.0 [M+H] + Step 2: 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-ethyl-6,7-dihydrothieno[3 ,2-c]pyridin-4(5H)-one [000317] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5-ethyl-6,7-dihydrothieno[3,2- c]pyridin-4(5H)-one. The title compound was isolated in 65% yield. m/z (ESI, +ve)= 604.1 [M+H] + . Step 3: [000318] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-5-ethyl-6,7-dihydrothieno[3,2- c]pyridin-4(5H)-one. The title compound was isolated in 77% yield. m/z (ESI, +ve)= 508.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.75 (s, 1H), 7.84 (s, 1H), 7.29 (s, 1H), 7.22 (s, 1H), 3.84 (s, 2H), 3.64 (t, J = 6.8 Hz, 2H), 3.45 (q, J = 7.1 Hz, 2H), 3.18 – 3.06 (m, 2H), 2.94 (t, J = 5.8 Hz, 2H), 2.68 (t, J = 5.9 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H). Example 23: 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-o ne Step 1: 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-o ne [000319] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromothieno[3,2-c]pyridin-4(5h)-one. The title compound was isolated in 39% yield. m/z (ESI, +ve)= 574.2 [M+H] + . Step 2: [000320] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)thieno[3,2-c]pyridin-4(5H)-one. The title compound was isolated in 25% yield. m/z (ESI, +ve)= 478.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 9.90 (s, 1H), 8.78 (s, 1H), 8.06 (s, 1H), 7.39 (d, J = 11.5 Hz, 2H), 7.33 (s, 1H), 6.87 (d, J = 7.0 Hz, 1H), 4.03 (s, 2H), 3.13 (s, 2H), 2.82 (s, 2H). Example 24: 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[2,3-d]pyridazin-4(5H) -one Step 1: 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thieno[2,3-d]pyridazin-4(5H) -one [000321] The title compound was prepared analogously to Example 4, step 2, where ethyl 2- chlorooxazole-4-carboxylate was replaced with 2-bromothieno[2,3-D]pyridazine-4(5H)-one. The title compound was isolated in 48% yield. m/z (ESI, +ve)= 575.2 [M+H] + . Step 2: [000322] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)thieno[2,3-d]pyridazin-4(5H)-one. The title compound was isolated in 27% yield. m/z (ESI, +ve)= 479.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 4.13 (s, 2H), 3.22 (d, J = 6.4 Hz, 2H), 2.91 (s, 2H). Example 25: 5-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carbonitrile Step 1: 5-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carbonitrile [000323] The title compound was prepared analogously to Example 1, step 6, where 4- (methoxycarbonyl)thiophene-2-boronic acid pinacol ester was replaced with 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3-thiophenecarbonitrile. The title compound was isolated in 9% yield. m/z (ESI, +ve)= 532.1 [M+H] + . Step 2: [000324] The title compound was prepared analogously to Example 8, where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced was replaced with 5-(2-((7-chloro-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)thiophene- 3-carbonitrile. The title compound was isolated in 12% yield. m/z (ESI, +ve)= 436.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.84 (s, 1H), 8.82 (s, 1H), 7.91 (s, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 3.84 (m, 2H), 2.94 (m, 2H), 2.67 (m, 2H). Example 26: 4-(4-Carbamoylthiophen-2-yl)-2-((7-chloro-1,2,3,4-tetrahydro isoquinolin-6- yl)amino)pyrimidine-5-carboxamide Step 1: Methyl 5-(5-carbamoyl-2-chloropyrimidin-4-yl)thiophene-3-carboxylat e [000325] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 2,4- dichloropyrimidine-5-carboxamide and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester. The title compound was isolated in 35% yield. m/z (ESI, +ve)= 298.1 [M+H] + . Step 2: Methyl 5-(5-carbamoyl-2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3, 4-tetrahydroisoquinolin- 6-yl)amino)pyrimidin-4-yl)thiophene-3-carboxylate [000326] A solution of methyl 5-(5-carbamoyl-2-chloropyrimidin-4-yl)thiophene-3-carboxylat e (0.34 mmol), 1-(6-amino-7-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2, 2-trifluoroethan-1-one (0.67 mmol) and (1S)-(+)-10-camphorsulfonic acid (0.672 mmol) in N-methylpyrrolidone (2.5 mL) was stirred in a sealed tube at 100°C overnight. Additional (1S)-(+)-10-camphorsulfonic acid (0.67 mmol) was added and the reaction was continued at 100°C for 24 hours. A third batch of (1S)-(+)-10-camphorsulfonic acid (0.67 mmol) was added and the reaction was continued at 100°C for another 24 hours. The reaction was cooled down to room temperature and a saturated aqueous solution of NaHCO3 (50 mL) was added. The precipitate was collected by filtration and triturated with dichloromethane to afford the title compound in 75% yield. m/z (ESI, +ve)= 540.2 [M+H] + . Step 3: Methyl 5-(5-carbamoyl-2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4- yl)thiophene-3-carboxylate [000327] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with methyl 5-(5-carbamoyl-2-((7-chloro-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)py rimidin-4-yl)thiophene-3-carboxylate. The title compound was isolated in 99% yield. m/z (ESI, +ve)= 444.1 [M+H] + . Step 4: tert-Butyl 6-((5-carbamoyl-4-(4-(methoxycarbonyl)thiophen-2-yl)pyrimidi n-2-yl)amino)-7- chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate [000328] The title compound was prepared analogously to Example 2, step 2, where 5-(2-((7-chloro- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-carboxylic acid was replaced with methyl 5-(5-carbamoyl-2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)thiophene-3-carboxylate. The title compound was isolated in 99% yield. m/z (ESI, +ve)= 544.2 [M+H] + . Step 5: 5-(2-((2-(tert-Butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydrois oquinolin-6-yl)amino)-5- carbamoylpyrimidin-4-yl)thiophene-3-carboxylic acid [000329] The title compound was prepared analogously to Example 2, step 1, where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with tert-butyl 6-((5-carbamoyl-4-(4- (methoxycarbonyl)thiophen-2-yl)pyrimidin-2-yl)amino)-7-chlor o-3,4-dihydroisoquinoline-2(1H)- carboxylate. The title compound was isolated in 99% yield. m/z (ESI, +ve)= 530.2 [M+H] + . Step 6: tert-Butyl 6-((5-carbamoyl-4-(4-carbamoylthiophen-2-yl)pyrimidin-2-yl)a mino)-7-chloro- 3,4-dihydroisoquinoline-2(1H)-carboxylate [000330] The title compound was prepared analogously to Example 13 where 5-(2-((7-ethyl-2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-carboxylic acid hydrochloride was replaced with 5-(2-((2-(tert-Butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydrois oquinolin- 6-yl)amino)-5-carbamoylpyrimidin-4-yl)thiophene-3-carboxylic acid. The title compound was isolated in 16% yield. m/z (ESI, +ve)= 529.2 [M+H] + . Step 7: [000331] The title compound was prepared analogously to Example 5 where tert-butyl 3-(6-((4-(4- carbamoylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-7- chloro-3,4-dihydroisoquinolin- 2(1H)-yl)azetidine-1-carboxylate was replaced with tert-butyl 6-((5-carbamoyl-4-(4-carbamoylthiophen- 2-yl)pyrimidin-2-yl)amino)-7-chloro-3,4-dihydroisoquinoline- 2(1H)-carboxylate. The title compound was isolated in 21% yield. m/z (ESI, +ve)= 429.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.41 (s, 1H), 8.32 (d, J = 1.3 Hz, 1H), 8.26 (s, 1H), 8.11 (d, J = 1.3 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.88 (s, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 3.94 (s, 2H), 3.06 (t, J = 5.9 Hz, 3H), 2.77 (t, J = 6.0 Hz, 2H). Example 27: 5-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-sulfonamide Step 1: Methyl 5-bromo-3-sulfamoylthiophene-2-carboxylate [000332] Methyl 5-bromo-3-(chlorosulfonyl)thiophene-2-carboxylate (2.48 mmol) was dissolved in a 0.4 N solution of ammonia in 1,4-dioxane (15.5 mL) and the reaction was stirred at room temperature for 20 minutes. Volatiles were removed under reduced pressure and the resulting residue was dissolved in dichloromethane and washed with water. The organic layer was dried with sodium sulfate, filtered, and concentrated to afford the title compound in 96% yield. m/z (ESI, +ve)= 300.0 [M+H] + . Step 2: 5-bromo-3-sulfamoylthiophene-2-carboxylic acid [000333] The title compound was prepared analogously to Example 8, step 1, where methyl 2- bromothiophene-4-carboxylate was replaced with methyl 5-bromo-3-sulfamoylthiophene-2-carboxylate. The title compound was isolated in 57% yield. m/z (ESI, -ve) = 284.0 (M-H)-. Step 3: 5-Bromothiophene-3-sulfonamide [000334] 5-Bromo-3-sulfamoylthiophene-2-carboxylic acid (1.05 mmol) was dissolved in DMSO (6.0 mL) and acetic acid (0.006 mL) and silver (I) carbonate (0.052 mmol) were added. The reaction mixture was stirred overnight at 100°C and quenched with water. Extraction with dichloromethane, filtration and concentration under reduced pressure afforded a crude material that was purified by silica gel chromatography (20-80% ethyl acetate in hexanes). The title compound was isolated in 50% yield. m/z (ESI, +ve)= 242.0 [M+H] + . Step 4: 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-sulfonamide [000335] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 5-bromothiophene-3-sulfonamide. The title compound was isolated in 48% yield. m/z (ESI, +ve)= 586.1 [M+H] + . Step 5: [000336] The title compound was prepared analogously to Example 4 where 2-(2-((7-chloro-2-(2,2,2- trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-6,7- dihydrothieno[3,2-c]pyridin- 4(5H)-one was replaced with 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-sulfonamide. The title compound was isolated in 40% yield. m/z (ESI, +ve)= 490.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.79 (s, 1H), 8.34 (d, J = 1.3 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 2H), 7.29 (s, 1H), 7.21 (s, 1H), 3.84 (s, 2H), 2.93 (s, 2H), 2.68 (s, 2H). Example 28: 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thien o[3,2-c]azepin-4-one Step 1: 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thien o[3,2-c]azepin-4-one [000337] The title compound was prepared analogously to Example 4, step 2, where ethyl 2- chlorooxazole-4-carboxylate was replaced with 2‐bromo‐4H,5H,6H,7H,8H‐thieno[3,2‐c]azepin‐4‐one . The title compound was isolated in 24% yield. m/z (ESI, +ve)= 590.0 [M+H] + . Step 2: [000338] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-5,6,7,8-tetrahydro-4H-thieno[3,2- c]azepin-4-one. The title compound was isolated in 54% yield. m/z (ESI, +ve)= 494.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.73 (s, 1H), 8.03 (t, J = 5.3 Hz, 1H), 7.91 (s, 1H), 7.33 (s, 1H), 7.22 (s, 1H), 3.85 (s, 2H), 3.16 (tt, J = 5.4, 3.2 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 5.8 Hz, 2H), 2.69 (t, J = 6.1 Hz, 2H), 1.99 (ddd, J = 10.3, 8.5, 5.1 Hz, 2H). Example 29: 2-(2-((7-Cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one Step 1: 2-(2-((7-Cyclopropyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetra hydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000339] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 1-(6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-cyclopropy l-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H,5H,6H,7H- thieno[3,2- c]pyridin-4-one, respectively. The title compound was isolated in 30% yield. m/z (ESI, +ve)= 582.2 [M+H] + . Step 2: [000340] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- (4-(4,5-dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl )pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-cyclopropyl-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one. The title compound was isolated in 41% yield. m/z (ESI, +ve)= 486.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.71 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.14 (s, 1H), 6.65 (s, 1H), 3.79 (s, 2H), 3.47 (td, J = 6.9, 2.6 Hz, 2H), 3.05 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.66 (d, J = 5.9 Hz, 2H), 1.93 (m, 1H), 0.85 – 0.76 (m, 2H), 0.59 – 0.49 (m, 2H). Example 30: 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[3,2-c]pyridi n-4(5H)-one Step 1: 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[3,2-c]pyridi n-4(5H)-one [000341] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5-methyl-4H,5H-thieno[3,2- c]pyridin-4-one. The title compound was isolated in 45% yield. m/z (ESI, +ve)= 588.1 [M+H] + . Step 2: [000342] The title compound was prepared analogously to Example 13 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-5-methylthieno[3,2-c]pyridin- 4(5H)-one. The title compound was isolated in 56% yield. m/z (ESI, +ve)= 492.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.79 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.36 (s, 1H), 7.28 (s, 1H), 6.95 (d, J = 7.2 Hz, 1H), 3.93 (s, 2H), 3.52 (s, 4H, overlapped with water signal), 3.03 (m, 2H), 2.76 m, 2H). Example 31: 2-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[2,3-d]pyrida zin-4(5H)-one Step 1: 2-Bromo-5-methylthieno[2,3-d]pyridazin-4(5H)-one [000343] A solution of 2-bromothieno[2,3-D]pyrazin-4(5H)-one (0.65 mmol) and dimethylformamide- dimethyl acetal (0.97 mmol) in DMF (3 mL) was stirred at 160°C for 2 hours in a sealed pressure tube. The reaction mixture was cooled down and concentrated to dryness. The crude was purified by silica gel chromatography (0-50% ethyl acetate in hexanes) to afford the title compound in 72% yield. m/z (ESI, +ve)= 246.9 [M+H]+. Step 2: 2-(2-((7-Chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5-methylthieno[2,3-d]pyrida zin-4(5H)-one [000344] The title compound was prepared analogously to Example 6, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5-methyl-4H,5H-thieno[2,3- d]pyridazin-4-one. The title compound was isolated in 72% yield. m/z (ESI, +ve)= 589.1 [M+H] + . Step 3: [000345] The title compound was prepared analogously to Example 13, where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-5-methylthieno[2,3-d]pyridazin- 4(5H)-one. The title compound was isolated in 38% yield. m/z (ESI, +ve)= 493.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.88 (s, 1H), 8.65 (s, 1H), 8.06 (s, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 4.15 (s, 2H), 3.74 (s, 3H), 3.25 (t, J = 6.1 Hz, 4H, overlapped with H2O), 2.90 (t, J = 6.2 Hz, 2H). Example 32: 7-Chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoro methyl)pyrimidin-2-yl)- 1,2,3,4-tetrahydroisoquinolin-6-amine Step 1: 2-(Methoxycarbonyl)thiophene-3-sulfinic acid [000346] A suspension of Na 2 SO 3 (15 mmol) and NaHCO3 (16 mmol) in water (30.0 mL) was heated at 40 ˚C and methyl 3-chlorosulfonylthiophene-2-carboxylate (12 mmol) was added in small portions. The reaction mixture was stirred at 40 ˚C for one additional hour, cooled down to room temperature and filtered. The aqueous layer was acidified with a 1M aqueous solution of HCl and extracted with dichloromethane twice. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 70% yield. m/z (ESI, +ve)= 207.0 [M+H] + . Step 2: Methyl 3-(methylsulfonyl)thiophene-2-carboxylate [000347] To a solution of 2-(methoxycarbonyl)thiophene-3-sulfinic acid (8.8 mmol) in DMF (18.0 mL), cesium carbonate (17.5 mmol) and methyl iodide (1.1 mL) were added. The reaction mixture was stirred at room temperature for 2 hours, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford the title compound in 52% yield. m/z (ESI, +ve)= 221.0 [M+H] + . Step 3: Methyl 5-bromo-3-(methylsulfonyl)thiophene-2-carboxylate [000348] Methyl 3-(methylsulfonyl)thiophene-2-carboxylate (1.36 mmol) was dissolved in TFA (6.0 mL) and H2SO4 (13.6 mmol). The reaction mixture was cooled down to -15°C and N-bromosuccinimide (1.49 mmol) was added in small portions over 15 minutes. The cooling bath was removed and the solution was stirred at room temperature for one hour. The reaction was quenched with water, extracted with dichloromethane three times, the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford a residue that was purified by silica gel chromatography (30% ethyl acetate in hexanes). The title compound was isolated in 42% yield. m/z (ESI, +ve)= 300.8 [M+H] + . Step 4: 5-Bromo-3-(methylsulfonyl)thiophene-2-carboxylic acid [000349] A 2.2 M aqueous solution of LiOH (0.5 mL) was added over a solution of methyl 5-bromo-3- methanesulfonylthiophene-2-carboxylate (0.56 mmol) in methanol (3.4 mL) and the reaction was stirred at room temperature for one hour. After evaporation of volatiles under reduced pressure, the crude was dissolved in water and the pH was made acidic by the addition of a 1M aqueous solution of HCl. The precipitate was filtered affording title compound in 93% yield. 1 H NMR (400 MHz, DMSO-d6) δ 14.9 - 13.9 (bs, 1H), 7.60 (s, 1H), 3.47 (s, 3H). Step 5: 2-Bromo-4-(methylsulfonyl)thiophene [000350] 5-Bromo-3-methanesulfonylthiophene-2-carboxylic acid (0.52 mmol) was dissolved in DMSO (1.0 mL). Acetic acid (0.006 mL) and silver carbonate (0.025 mmol) were added and the reaction mixture was stirred at 100°C for 2 hours. Dilution with water yielded a precipitate that was filtered to afford the title compound in 47% yield. Step 6: 1-(7-Chloro-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifl uoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one [000351] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-4-(methylsulfonyl)thiophene. The title compound was isolated in 44% yield. m/z (ESI, +ve)= 585.0 [M+H] + Step 7: [000352] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-chloro-6-((4-(4-(methylsulfonyl)thiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoq uinolin-2(1H)-yl)-2,2,2-trifluoroethan-1- one. The title compound was isolated in 24% yield. m/z (ESI, +ve)= 489.18 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.83 (s, 1H), 8.68 (d, J = 1.2 Hz, 1H), 7.90 (s, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 4.02 (s, 2H), 3.30 (s, 3H), 3.13 (t, J = 6.1 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H), 2.08 (s, 1H). Example 33: 2-(2-((6-Chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one Step 1: 2-(2-((6-Chloro-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl)ami no)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000353] The title compound was prepared analogously to Example 14, step 2, where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(5-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 90% yield. m/z (ESI, +ve)= 562.0 [M+H] + . Step 2: [000354] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((6-chloro-2-(2,2,2- trifluoroacetyl)isoindolin-5-yl)amino)-5-(trifluoromethyl)py rimidin-4-yl)-6,7-dihydrothieno[3,2- c]pyridin-4(5H)-one. The title compound was isolated in 26% yield. m/z (ESI, +ve)= 466.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.75 (s, 1H), 8.18 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.49 (s, 1H), 7.48 (s, 1H), 4.16 (s, 4H), 3.46 (td, J = 6.8, 2.6 Hz, 2H), 3.04 (t, J = 6.7 Hz, 2H). Example 34: 2-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin- 4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one Step 1: 2-(2-((7-Ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroi soquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000355] The title compound was prepared analogously to Example 14, step 2, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 24% yield. m/z (ESI, +ve)= 570.2 [M+H] + . Step 2: [000356] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-6,7-dihydrothieno[3,2-c]pyridin- 4(5H)-one. The title compound was isolated in 40% yield. m/z (ESI, +ve)= 474.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.70 (s, 1H), 8.35 (s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 3.95 (s, 2H), 3.50 - 3.44 (m, 2H, overlapped with water signal), 3.08 – 3.00 (m, 4H), 2.75 (s, 2H), 2.62 – 2.54 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H). Example 35: 2-(2-((7-(Methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)ami no)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one Step 1: 2,2,2-Trifluoro-1-(7-(methylthio)-6-nitro-3,4-dihydroisoquin olin-2(1H)-yl)ethan-1-one [000357] 1-(7-Chloro-6-nitro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2, 2-trifluoroethan-1-one (3.2 mmol) was dissolved in DMSO (20 mL) and. NaSMe (3.6 mmol) was added in one portion. After 16 hours at room temperature, the reaction was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated. Purification in silica gel (15-30% ethyl acetate in hexanes) afforded the title compound in 28% yield. m/z (ESI, +ve)= 319.1 [M+H] + Step 2: 1-(6-Amino-7-(methylthio)-3,4-dihydroisoquinolin-2(1H)-yl)-2 ,2,2-trifluoroethan-1-one [000358] The title compound was prepared analogously to Example 9, step 3, where 1-(7-ethyl-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne was replaced with 2,2,2-Trifluoro-1-(7- (methylthio)-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1 -one. The title compound was isolated in 84% yield. m/z (ESI, +ve)= 291.1 [M+H] + Step 3: 1-(6-((4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-( methylthio)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000359] The title compound was prepared analogously to Example 9, step 4, where 1-(6-amino-7-ethyl- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-amino-7- (methylthio)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluor oethan-1-one. The title compound was isolated in 22% yield. m/z (ESI, +ve)= 471.1 [M+H] + Step 4: 2-(2-((7-(Methylthio)-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetr ahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000360] The title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 1-(6-((4- Chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-(methylthi o)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H,5H,6H,7H- thieno[3,2- c]pyridin-4-one. The title compound was isolated in 46% yield. m/z (ESI, +ve)= 588.1 [M+H] + . Step 5: [000361] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 2-(2-((7-(Methylthio)-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-6,7-dihydrothieno[3,2- c]pyridin-4(5H)-one. The title compound was isolated in 50% yield. m/z (ESI, +ve)= 492.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.59 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 3.99 (s, 2H), 3.47 (td, J = 6.8, 2.6 Hz, 2H), 3.06 (q, J = 7.5, 6.9 Hz, 4H), 2.75 (t, J = 5.8 Hz, 2H), 2.36 (s, 3H). Example 36: 2-(2-((2-Cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one Step 1: 2-Cyclopropyl-4-(4-methylpiperazin-1-yl)aniline [000362] A solution of 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (7.65 mmol) in methanol (10 mL) at 0 ˚C, was treated with NH 4 Cl (2.33 mmol) and the reaction mixture was stirred at 0 ˚C for 10 minutes. Zinc dust (76.5 mmol) was added slowly and after 15 minutes the reaction mixture was allowed to warm to room temperature and stirred overnight. Filtration through celite and evaporation of volatiles afforded a residue that was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford the title compound in 53% yield. m/z (ESI, +ve)= 232.2 [M+H] + Step 2: 4-Chloro-N-(2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)- 5- (trifluoromethyl)pyrimidin-2-amine [000363] A 0.7 M solution of ZnCl2 in THF (6.8 mL) was added dropwise over a solution of 2,4- dichloro-5-trifluoromethyl-pyrimidine (2.17 mmol) in dichloroethane (9 mL) and tert-butanol (1.5 mL). The reaction mixture was stirred at 0 ˚C for 1 hour and a solution of 2-cyclopropyl-4-(4-methylpiperazin- 1-yl)aniline (2.16 mmol) in dichloroethane (2.5 mL) and tert-butanol (2.5 mL) was added, followed by triethylamine (0.42 mL). After 16 hours at room temperature, the reaction was concentrated under reduced pressure and the crude was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford the title compound in 12% yield. m/z (ESI, +ve)= 412.3 [M+H] + . Step 3: [000364] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 4-chloro-N-(2- cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)-5-(trifluorome thyl)pyrimidin-2-amine and dihydrothienopyridin-4-one-2-boronic acid pinacol ester, respectively. The title compound was isolated in 11% yield. m/z (ESI, +ve)= 529.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ .53 (s, 1H), 8.67 (s, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.20 (d, J = 9.8 Hz, 1H), 6.77 (d, J = 9.3 Hz, 1H), 6.48 (s, 1H), 3.46 (s, 2H), 3.11 (m, 4H), 3.04 (s, 2H), 2.45 (m, 5H), 2.22 (s, 3H), 1.93 (s, 1H), 0.84–0.76 (m, 2H), 0.65–0.57 (m, 2H). Example 37: 5-(2-((2-Ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(tr ifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxamide Step 1: 1-Methyl-4-(4-nitro-3-vinylphenyl)piperazine [000365] A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (16.7 mmol), potassium vinyltrifluoroborate (25.0 mmol), potassium carbonate (49.9 mmol) and Pd(dppf)Cl2-dichloromethane complex (0.83 mmol) in DMSO (35 mL), was stirred at 80 ˚C for 3 hours. The reaction was cooled down to room temperature, diluted with water and extracted with dichloromethane three times. The combined organic layers were concentrated and the resulting crude purified by silica gel chromatography (0-8% MeOH in dichloromethane) to afford the title compound in 92% yield. Step 2: 2-Ethyl-4-(4-methylpiperazin-1-yl)aniline [000366] The title compound was prepared analogously to Example 19, step 3 where 1-(5-cyclopropyl- 6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-methyl-4-(4-nitro-3- vinylphenyl)piperazine. The title compound was isolated in 89% yield m/z (ESI, +ve)= 220.5 [M+H] + Step 3: 4-Chloro-N-(2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)-5-(tri fluoromethyl)pyrimidin-2- amine [000367] The title compound was prepared analogously to Example 36, step 2, where 2-cyclopropyl-4- (4-methylpiperazin-1-yl)aniline was replaced with 2-ethyl-4-(4-methylpiperazin-1-yl)aniline. The title compound was isolated in 53% yield. m/z (ESI, +ve)= 400.5 [M+H] + . Step 4: Methyl 5-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylate [000368] The title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one was substituted with 4-chloro-N-(2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)-5- (trifluoromethyl)pyrimidin-2-amine. The title compound was isolated in 28% yield. m/z (ESI, +ve)= 506.6 [M+H] + . Step 5: 5-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(tr ifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylic acid [000369] The title compound was prepared analogously to Example 2, step 1 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was substituted with methyl 5-(2-((2-ethyl-4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene -3-carboxylate. The title compound was isolated in 28% yield. m/z (ESI, +ve)= 492.3 [M+H] + . Step 6: [000370] The title compound was prepared analogously to Example 13, where 5-(2-((7-ethyl-2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)thiophene-3-carboxylic acid hydrochloride was replaced with 5-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)thiophene-3-carboxylic acid. The title compound was isolated in 16% yield. m/z (ESI, +ve)= 491.2 [M+H] + . 1 H NMR (300 MHz, MeOH-d4) δ .8.56 (s, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.25 (s, 1H), 6.97 – 6.81 (m, 2H), 3.23 (d, J = 5.2 Hz, 4H), 2.74 – 2.54 (m, 6H), 2.39 (s, 3H), 1.17 (t, J = 7.6 Hz, 3H). Example 38: (5-(2-((7-Chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)thiophen-3-yl)dimethylphosph ine oxide Step 1: Dimethyl(thiophen-3-yl)phosphine oxide [000371] A solution of 3-iodothiophene (4.76 mmol), dimethylphosphine oxide (4.32 mmol), triethylamine (0.75 mL), Pd2(dba)3 (0.044 mmol) and Xantphos (0.044 mmol) in 1,4-dioxane (22 mL), was stirred at room temperature for 20 hours. The reaction was concentrated and purified by silica gel chromatography (3-5% methanol in dichloromethane) to afford the title compound in 55% yield. Step 2: (5-Iodothiophen-3-yl)dimethylphosphine oxide [000372] A solution of 3‐(dimethylphosphoryl)thiophene in ethanol (6.6 mL) was treated with I2 (0.94 mmol) and H5IO6 (1.09 mmol) at room temperature. The resulting mixture was stirred at 80°C for 30 minutes and at room temperature overnight. The reaction was concentrated under reduced pressure and the residue purified by silica gel chromatography (5% methanol in dichloromethane) to afford the title compound in 55% yield. Step 3: 1-(7-Chloro-6-((4-(4-(dimethylphosphoryl)thiophen-2-yl)-5-(t rifluoromethyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one [000373] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 4‐(dimethylphosphoryl)‐2‐iodothiophene. The title compound was isolated in 50% yield. m/z (ESI, +ve)= 583.0 [M+H] + . Step 4: [000374] The title compound was prepared analogously to Example 8 where 1-(7-chloro-6-((4-(4-(4,5- dihydrooxazol-2-yl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-chloro-6-((4-(4- (dimethylphosphoryl)thiophen-2-yl)-5-(trifluoromethyl)pyrimi din-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 52% yield. m/z (ESI, +ve)= 487.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.78 (s, 1H), 8.35 (dd, J = 7.1, 1.2 Hz, 1H), 7.85 (d, J = 4.1 Hz, 1H), 7.31 (s, 1H), 7.22 (s, 1H), 3.85 (s, 2H), 3.01 – 2.89 (m, 2H), 2.72 – 2.64 (m, 2H), 1.67 (d, J = 13.6 Hz, 6H). Example 39: 2-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(tr ifluoromethyl)pyrimidin- 4-yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000375] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin- 2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 4-chloro-N-[2- ethyl-4-(4-methylpiperazin-1-yl)phenyl]-5-(trifluoromethyl)p yrimidin-2-amine and 2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-4H,5H,6H,7H-thieno[3,2- c]pyridin-4-one, respectively. The title compound was isolated in 10% yield. m/z (ESI, +ve)= 517.1 [M+H] + . 1 H NMR (300 MHz, MeOH-d4) δ 8.54 (s, 1H), 8.01 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.99–6.84 (m, 2H), 3.60 (t, J = 6.9 Hz, 2H), 3.36 (s, 5H), 3.10 (d, J = 5.3 Hz, 5H), 2.71 (s, 3H), 2.63 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). Example 43: 2-(2-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one Step 1: 1-(6-amino-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-t rifluoroethan-1-one [000376] The title compound was prepared analogously to Example 1, steps 1-4, where 2-(4- chlorophenyl)ethylamine was replaced with 2-(4-fluorophenyl)ethan-1-amine in step 1. MS (ESI) m/z: 263.0 [M+H] + . Step 2: 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-f luoro-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000377] The title compound was prepared analogously to Example 1, step 5, where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(6-amino-7- fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan -1-one. The title compound was isolated in 30% yield. MS (ESI) m/z: 443.0 [M+H] + . Step 3: 2-(2-((7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000378] The title compound was prepared analogously to Example 1, step 6 where 4- (methoxycarbonyl)thiophene-2-boronic acid pinacol ester was replaced with 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4H,5H,6H,7H-thieno[3,2-c]pyridin-4-one. The title compound was isolated in 37% yield. MS (ESI) m/z: 560.2 [M+H] + . Step 4: 2-(2-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one [000379] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 2-(2-((7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-6,7-dihydrothieno[3,2-c]pyridin- 4(5H)-one. The title compound was isolated in 15% yield. MS (ESI) m/z: 463.8 [M+H] + .1H-NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.76 (s, 1H), 8.42 (s, 2H), 7.84 (s, 1H), 7.79 (s, 1H), 7.30 (s, 1H), 6.98 (d, J = 11.0 Hz, 1H), 3.06 (t, J = 6.7 Hz, 2H). Example 46: 2-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thien o[3,2-c]azepin-4-one Step 1: 1-(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoro ethan-1-one [000380] Trifluoroacetic anhydride (72 mmol) was added over a 0°C solution of 6-chloro-1,2,3,4- tetrahydroisoquinoline (60 mmol) and triethylamine (119 mmol) in dichloromethane (300 mL) and stirred for one hour. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 96% yield. MS (ESI) m/z: 263.9 [M+H] + . Step 2: 1-(6-chloro-7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-t rifluoroethan-1-one [000381] The title compound was prepared analogously to Example 1, step 3 where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-chloro-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 79% yield. MS (ESI) m/z: 307.1 [M+H] + . Step 3: 1-(7-amino-6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-t rifluoroethan-1-one [000382] The title compound was prepared analogously to Example 1, step 4 where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne was replaced with 1-(6-chloro-7-nitro-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 96% yield. MS (ESI) m/z: 279.1 [M+H] + . Step 4: 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000383] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(7-amino-6- chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan -1-one. The title compound was isolated in 49% yield. MS (ESI) m/z: 459.0 [M+H] + . Step 5: 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetr ahydro-4H-thieno[3,2-c]azepin- 4-one [000384] A solution of 2-bromo-4H,5H,6H,7H,8H-thieno[3,2-c]azepin-4-one (0.41 mmol), potassium acetate (0.61 mmol), bis(pinacolato)diboron (0.45 mmol), tricyclohexylphosphine (0.03 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.012 mmol) in 1,4-dioxane (2 mL) was microwaved at 120 °C for 25 minutes. The solids were filtered off and the volatiles were removed under reduced pressure to afford a residue that was redissolved in dichloromethane (3mL). Addition of hexanes (30 mL) and storage of this mixture at -20 °C afford a grey solid that was filtered and dried. The title compound was isolated in 63% yield. MS (ESI) m/z: 294.1 [M+H] + . Step 6: 2-(2-((6-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thien o[3,2-c]azepin-4-one [000385] The title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 1-(6-chloro-7- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihy droisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetr ahydro-4H- thieno[3,2-c]azepin-4-one. The title compound was isolated in 29% yield. MS (ESI) m/z: 590.0 [M+H] + . Step 7: 2-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one [000386] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 2-(2-((6-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-5,6,7,8-tetrahydro-4H-thieno[3,2- c]azepin-4-one. The title compound was isolated in 31% yield. MS (ESI) m/z: 494.08 [M+H] + . (400 MHz, DMSO-d 6 ) δ 1.95 – 2.07 (m, 2H), 2.73 (t, J = 5.9 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 3.13 – 3.19 (m, 2H), 3.89 (s, 2H), 7.28 (s, 1H), 7.31 (s, 1H), 7.91 (s, 1H), 8.03 (t, J = 5.3 Hz, 1H), 8.26 (s, 1H), 8.73 (s, 1H), 9.76 (s, 1H). Example 48: 2-(2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one Step 1: tert-butyl 4-(3-cyclopropyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carbox ylate [000387] 3-Cyclopropyl-4-nitro-1H-pyrazole (13 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (14 mmol) and triphenylphosphine (40 mmol) were dissolved in THF (22.0 mL) and the mixture was cooled down to 0 °C. A 40% solution of DEAD in toluene (40 mmol) was added dropwise over 25 minutes and the reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to afford the title compound in 51% yield. (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 4.32 (tt, J = 11.6, 4.0 Hz, 1H), 4.02 (d, J = 13.3 Hz, 2H), 2.86 (s, 2H), 2.05 – 1.91 (m, 2H), 1.75 (qd, J = 12.2, 4.4 Hz, 2H), 1.41 (s, 9H), 1.31 – 1.10 (m, 1H), 1.05 – 0.96 (m, 2H), 0.87 (dq, J = 5.0, 3.7 Hz, 2H). Step 2: tert-butyl 4-(4-amino-3-cyclopropyl-1H-pyrazol-1-yl)piperidine-1-carbox ylate [000388] A suspension of tert-butyl 4-(3-cyclopropyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carbox ylate (6.3 mmol) and 10% palladium on carbon (0.075 mmol) in methanol was hydrogenated at room temperature for 48 hours. The catalyst was filtered through celite and the volatiles were removed under reduced pressure to afford the title compound in 99% yield. MS (ESI) m/z: 307.3 [M+H] + . Step 3: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-c yclopropyl-1H- pyrazol-1-yl)piperidine-1-carboxylate [000389] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with tert-butyl 4-(4- amino-3-cyclopropyl-1H-pyrazol-1-yl)piperidine-1-carboxylate . The title compound was isolated in 27% yield. MS (ESI) m/z: 485.4 [M+H] + . Step 4: tert-butyl 4-(3-cyclopropyl-4-((4-(4-oxo-4,5,6,7-tetrahydrothieno[3,2-c ]pyridin-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piper idine-1-carboxylate [000390] The title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with tert-butyl 4-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclop ropyl-1H-pyrazol-1-yl)piperidine-1- carboxylate and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H,5H,6H,7H- thieno[3,2-c]pyridin-4- one. The title compound was isolated in 23% yield. MS (ESI) m/z: 602.3 [M+H] + . Step 5: 2-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000391] A solution of tert-butyl 4-(3-cyclopropyl-4-((4-(4-oxo-4,5,6,7-tetrahydrothieno[3,2-c ]pyridin- 2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1- yl)piperidine-1-carboxylate (0.39 mmol) in methanol (3 mL) was treated with a 4M solution of HCl in dioxane (4.8 mL). After 10 minutes, the volatiles were removed under reduced pressure to afford the title compound in 99% yield. MS (ESI) m/z: 504.3 [M+H] + . Step 6: 2-(2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothieno[3,2-c]pyr idin-4(5H)-one [000392] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 2-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-6,7-dihydrothie no[3,2-c]pyridin-4(5H)-one. The title compound was isolated in 6% yield. MS (ESI) m/z: 518.2 [M+H] + . (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.47 (s, 0H), 8.74 (d, J = 11.5 Hz, 1H), 8.00 (s, 1H), 7.91 – 7.71 (m, 2H), 4.00 (s, 1H), 3.50 (td, J = 6.8, 2.6 Hz, 2H), 3.15 – 3.00 (m, 2H), 2.87 (d, J = 11.1 Hz, 2H), 2.23 (s, 3H), 2.16 – 1.80 (m, 7H), 0.84 – 0.66 (m, 4H). Example 49: 2-(2-((6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thien o[3,2-c]azepin-4-one [000393] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 2-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thi eno[3,2-c]azepin-4-one. The title compound was isolated in 63% yield. MS (ESI) m/z: 508.1 [M+H] + . (400 MHz, DMSO-d6) δ 1.95 – 2.06 (m, 2H), 2.35 (s, 3H), 2.61 (t, J = 5.9 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 3.14 – 3.19 (m, 2H), 3.49 (s, 2H), 7.23 – 7.37 (m, 2H), 7.91 (s, 1H), 8.03 (t, J = 5.4 Hz, 1H), 8.16 (s, 1H), 8.73 (s, 1H), 9.76 (s, 1H). Example 53: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1,2,3,4-tetrahydro-5H-thien o[2,3-e][1,4]diazepin-5-one Step 1: tert-butyl (3-(((1,3-dioxolan-2-yl)methyl)carbamoyl)-5-bromothiophen-2- yl)carbamate [000394] A solution of 5-bromo-2-{[(tert-butoxy)carbonyl]amino}thiophene-3-carboxyl ic acid (1.34 mmol), 1-(1,3-dioxolan-2-yl)methanamine (5.21 mmol) and triethylamine (8.69 mmol) in acetonitrile (28 ml) was treated with HCTU (8.69 mmol) and the reaction mixture was stirred at room temperature for 10 minutes, concentrated under vacuum and the resulting residue was suspended in dichloromethane (8 mL). The insoluble materials were filtered off, the filtrate was concentrated and the resulting residue was purified by silica gel chromatography to afford the title compound in 82% yield. MS (ESI) m/z: 408.0 [M+H] + . Step 2: tert-butyl (5-bromo-3-((2-oxoethyl)carbamoyl)thiophen-2-yl)carbamate [000395] tert-butyl (3-(((1,3-dioxolan-2-yl)methyl)carbamoyl)-5-bromothiophen-2- yl)carbamate (0.88 mmol) was dissolved in methanol (20.0 mL) and 37% methanolic solution of hydrochloric acid (88 mmol). After 2 hours, the reaction mixture was quenched by addition of 1M aqueous sodium hydroxide and the methanol was removed under reduced pressure. The resulting aqueous solution was extracted with dichloromethane three times and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 62% yield. Step 3: 7-bromo-1,2,3,4-tetrahydro-5H-thieno[2,3-e][1,4]diazepin-5-o ne [000396] A solution of tert-butyl (5-bromo-3-((2-oxoethyl)carbamoyl)thiophen-2-yl)carbamate (0.28 mmol), acetic acid (0.017 ml) and sodium cyanoborohydride (0.42 mmol) in methanol (3.54 mL) was stirred at 45°C for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (1-10% methanol in dichloromethane) to afford the title compound in 25% yield. MS (ESI) m/z: 248.0 [M+H] + . Step 4: 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1,2,3,4-tetrahydro-5H-thien o[2,3-e][1,4]diazepin-5-one [000397] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 7-bromo-1,2,3,4-tetrahydro-5H-thieno[2,3- e][1,4]diazepin-5-one. The title compound was isolated in 7% yield. MS (ESI) m/z: 591.0 [M+H] + . Step 5: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-1,2,3,4-tetrahydro-5H-thieno[2,3-e][1,4]diazepin-5-one [000398] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-1,2,3,4-tetrahydro-5H-thieno[2,3- e][1,4]diazepin-5-one. The title compound was isolated in 17% yield. MS (ESI) m/z: 495.1 [M+H] + .1H- NMR (400 MHz, DMSO-d6) δ 2.75 (t, J = 5.8 Hz, 2H), 3.00 (t, J = 5.9 Hz, 2H), 3.31 (m, 2H), 3.41 (m, 2H), 3.88 (s, 2H), 7.21 (s, 1H), 7.40 (s, 1H), 7.73 (t, J = 5.1 Hz, 1H), 7.90 (s, 1H), 8.23 (s, 1H), 8.54 (s, 1H), 8.63 (t, J = 3.7 Hz, 1H), 9.34 (s, 1H). Example 59: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophene -2-carboxamide Step 1: Methyl 3-(methylsulfonyl)thiophene-2-carboxylate [000399] To a solution of sodium bicarbonate (8.73 mmol) in water (5 mL) was added sodium sulfite (8.31 mmol). Methyl 3-chlorosulfonylthiophene-2-carboxylate (4.15 mmol) and ethanol (2.5 mL) were added and the reaction was stirred at 50 °C for 45 minutes. The volatiles were removed under reduced pressure and the resulting residue was dissolved in DMF (7.5 mL) and treated with iodomethane (20.8 mmol). After 15 minutes, the reaction was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (10-30% ethyl acetate in hexanes). The title compound was isolated in 77% yield. MS (ESI) m/z: 221.0[M+H] + . Step 2: Methyl 5-bromo-3-(methylsulfonyl)thiophene-2-carboxylate [000400] 1-Bromopyrrolidine-2,5-dione (10.0 mmol) and sulfuric acid (45.4 mmol) were added over a solution of methyl 3-methylsulfonylthiophene-2-carboxylate (4.54 mmol) in acetic acid (10 mL). The mixture was stirred at 60 °C for 12 hours, quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by semi- preparative reverse phase-HPLC. The title compound was isolated in 22% yield. MS (ESI) m/z: 299.0[M+H] + . Step 3: 5-Bromo-3-(methylsulfonyl)thiophene-2-carboxylic acid [000401] To a solution of methyl 5-bromo-3-methylsulfonyl-thiophene-2-carboxylate (1.00 mmol) in methanol (3 mL) and water (0.6 mL) was added sodium hydroxide (2.01 mmol). The mixture was stirred at 25 °C for 2 hours, quenched with water and the pH adjusted to 3 with a 1M aqueous solution of hydrochloric acid. The resulting aqueous solution was extracted with ethyl acetate three times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 91% yield. MS (ESI) m/z: 285.2 [M+H] + . Step 4: 5-Bromo-3-(methylsulfonyl)thiophene-2-carboxamide [000402] A solution of 5-bromo-3-methylsulfonyl-thiophene-2-carboxylic acid (0.10 mmol) in thionyl chloride (1 mL) was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure and the resulting residue was treated with a solution of ammonium hydroxide (1.15 mmol) in THF (1 mL) precooled to 0 °C. The mixture was stirred at 25 °C for 1 hour, concentrated and purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound in 61% yield. MS (ESI) m/z: 283.8 [M+H] + . Step 5: 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophene -2-carboxamide [000403] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 5-bromo-3-(methylsulfonyl)thiophene-2- carboxamide. The title compound was isolated in 22% yield. MS (ESI) m/z: 628.1 [M+H] + . Step 6: 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-3-(methylsulfonyl)thiophene-2-carboxamide [000404] A solution of 5-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfon yl)thiophene-2-carboxamide (0.03 mmol) in ethanol (1 mL) was treated with a solution of potassium carbonate (0.19 mmol) in water (0.25 mL). After 12 hours, the reaction was concentrated and purified by semi-preparative reverse phase-HPLC to afford the title compound in 31% yield. MS (ESI) m/z: 532.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.08 - 9.92 (m, 1H), 8.84 (s, 1H), 8.41 (s, 1H), 8.31 - 8.17 (m, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 3.89 (s, 3H), 3.43 (s, 2H), 2.98 (s, 2H), 2.71 (s, 2H). Example 60: 2-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydro-5H-thieno[2,3-b ][1,4]oxathiepine 4,4-dioxide Step 1: 3-(thiophen-3-ylsulfanyl)propan-1-ol [000405] 3-bromothiophene (3.00 g, 1.0 eq) was dissolved in diethyl ether (21 mL) and cooled down to - 76°C. A 1.6 M solution of n-BuLi in hexanes (12.60 mL) was added dropwise for 10 minutes and after 30 minutes, sulphur (649 mg, 1.10 eq) was added in one portion. After 30 minutes, the reaction was allowed to warm to room temperature during 1 hour. The mixture was cooled down to -30°C and 3- bromopropanol (2.43 g) was added dropwise. The cooling bath was removed and the reaction was allowed to warm up to room temperature and stirring continued for another 48 hours. Saturated ammonium chloride and ethyl acetate were added and the layers separated. The aqueous layer was extracted with ethyl acetate twice and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to afford the title compound in 60% yield. This crude material was used in the next step without further purification. MS (ESI) m/z: 175.1 [M+H] + . Step 2: 3-[(2-bromothiophen-3-yl)sulfanyl]propan-1-ol [000406] NBS (2.47 g, 1.05 eq) was added portion wise during 5 minutes to a 0°C solution of 3- (thiophen-3-ylsulfanyl)propan-1-ol (2.47 g) in dichloromethane (86 mL). After 90 minutes the reaction was diluted with dichloromethane and washed with a half-saturated solution of sodium thiosulfate. The aqueous layer was extracted with dichloromethane twice and the combined organic layers were washed with 1M NaOH and water, dried over sodium sulfate, filtered, and evaporated to afford the title compound in 88% yield. This crude material was used in the next step without further purification. MS (ESI) m/z: 252.9/254.9 [M+H] + . Step 3: 5H,6H,7H-thieno[2,3-b][1,4]oxathiepine [000407] A mixture of 3-(thiophen-3-ylsulfanyl)propan-1-ol (11.3 mmol), cesium carbonate (22.5 mmol), CuI (1.24 mmol) and phenanthroline (2.25 mmol) in toluene (43 mL) was heated at 110 °C for 21 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate, filtered through celite, and eluted with methanol. The volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography (0-5% methanol in dichloromethane). The title compound was isolated in 42% yield. MS (ESI) m/z: 172.7 [M+H] + . Step 4: 2-bromo-5H,6H,7H-4λ⁶-thieno[2,3-b][1,4]oxathiepine-4,4-di one [000408] MCPBA (85 mg) was added to a 0°C solution of 5H,6H,7H-thieno[2,3-b][1,4]oxathiepine (26 mg) in dichloromethane (1.0 mL). After 10 minutes, the cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction was diluted with saturated NaHCO3 and dichloromethane and the pH of the aqueous layer adjusted to10 by the addition of 1M aqueous solution of NaOH. The organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (2% ethyl acetate in dichloromethane). The title compound in 51% yield. MS (ESI) m/z: 202.7 [M-H]-. Step 5: 1-(7-chloro-6-((4-(4,4-dioxido-6,7-dihydro-5H-thieno[2,3-b][ 1,4]oxathiepin-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli n-2(1H)-yl)-2,2,2-trifluoroethan-1- one [000409] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 2-bromo-5H,6H,7H-4λ⁶-thieno[2,3- b][1,4]oxathiepine-4,4-dione. The title compound was isolated in 24% yield. MS (ESI) m/z: 627.9 [M+H] + . Step 6: 2-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-6,7-dihydro-5H-thieno[2,3-b][1,4]oxathiepine 4,4-dioxide [000410] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 1-(7-chloro-6-((4-(4,4-dioxido-6,7-dihydro-5H- thieno[2,3-b][1,4]oxathiepin-2-yl)-5-(trifluoromethyl)pyrimi din-2-yl)amino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 45% yield. MS (ESI) m/z: 531.1 [M+H] + .1H-NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.76 (s, 1H), 8.34 (s, 2H), 7.63 (s, 1H), 7.28 (d, J = 6.2 Hz, 2H), 4.50 (t, J = 5.0 Hz, 2H), 3.92 (s, 2H), 3.68 – 3.64 (m, 2H), 3.01 (m, 2H), 2.73 (m, 2H), 2.35 (m, 2H). Example 63: 5-(2-((7-Chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophene -2-carboxamide [000411] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 5-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3-(methylsulfonyl)thiophe ne-2-carboxamide. The title compound was isolated in 54% yield. MS (ESI) m/z: 546.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 10.01 (d, J = 3.6 Hz, 1H), 8.84 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 7.34 (s, 1H), 7.28 (d, J = 6.4 Hz, 1H), 3.94 (s, 1H), 3.49 (s, 1H), 3.43 (s, 3H), 3.04 (t, J = 5.6 Hz, 1H), 2.82 (t, J = 5.2 Hz, 1H), 2.75 (t, J = 5.2 Hz, 1H), 2.59 (d, J = 6.0 Hz, 1H), 2.46 - 2.33 (m, 3H). Example 64: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2, 3-f][1,4]thiazepine 1,1-dioxide Step 1: Methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2 -carboxylate [000412] To a solution of sodium bicarbonate (262 mmol) and sodium sulfite (249 mmol) in water (200 mL) was added methyl 3-chlorosulfonylthiophene-2-carboxylate (125 mmol), methyl 3- chlorosulfonylthiophene-2-carboxylate (125 mmol) and ethyl alcohol (100 mL). The reaction mixture was heated at 50 °C for 45 minutes and concentrated to dryness. The residue was suspended in DMF (300 mL) and tert-butyl-N-(2-bromoethyl)carbamate (249 mmol) was added. After 12 hours, the volatiles were removed under reduced pressure and the residue was treated with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative HPLC. The title compound was isolated in 10% yield. MS (ESI) m/z: 250.1 [M+H] + . Step 2: Methyl 3-((2-aminoethyl)sulfonyl)thiophene-2-carboxylate [000413] A 10 °C solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2 - carboxylate (11.5 mmol) in dichloromethane (18 mL) was treated with TFA (122 mmol) and the reaction was stirred for 1 hour. Evaporation of volatiles under reduced pressure afforded the title compound, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 - 8.10 (m, 1H), 7.58 (d, J = 5.2 Hz, 1H), 4.00 - 3.94 (m, 2H), 3.89 (s, 3H), 3.16 - 3.06 (m, 2H). Step 3: 3,4-Dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000414] A mixture of methyl 3-(2-aminoethylsulfonyl)thiophene-2-carboxylate (5.50 mmol) and potassium carbonate (16.5 mmol) in ethyl alcohol (10 mL) was stirred at 70°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound in 88% yield which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (brs, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.50 (d, J = 5.2 Hz, 1H), 3.88 - 3.80 (m, 2H), 3.66 - 3.60 (m, 2H). Step 4: 2,3,4,5-Tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide [000415] A mixture of 1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one (4.60 mmol) and borane tetrahydrofuran complex (1 M, 20 mL) was stirred at 70°C for 12 hours. The reaction was cooled down to 0°C and methanol was added (10mL). After 10 minutes, the volatiles were removed under reduced pressure and the crude material was purified by preparative TLC (10% methanol in dichloromethane) to afford the title compound in 60% yield, which was used into the next step without further purification. MS (ESI) m/z: 203.8 [M+H] + . Step 5: 1-(1,1-Dioxido-2,3-dihydrothieno[2,3-f][1,4]thiazepin-4(5H)- yl)-2,2,2-trifluoroethan-1-one [000416] A 0°C solution of 2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide (1.67 mmol) and triethylamine (3.35 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic anhydride (2.01 mmol). The mixture was stirred at 10 °C for 1 hour and the pH adjusted to 5 by the addition of ammonium chloride. The solids were filtered off and the solution was concentrated under reduced pressure to afford the title compound, which was used into the next step without further purification. MS (ESI) m/z: 300.0 [M+H] + . Step 6: 1-(7-bromo-1,1-dioxido-2,3-dihydrothieno[2,3-f][1,4]thiazepi n-4(5H)-yl)-2,2,2- trifluoroethan-1-one [000417] A solution of 1-(1,1-dioxido-2,3-dihydrothieno[2,3-f][1,4]thiazepin-4(5H)- yl)-2,2,2- trifluoroethan-1-one (1.40 mmol), N-bromosuccinimide (1.40 mmol) and acetic acid (10 mL) was treated with sulfuric acid (19 mmol) and the mixture was stirred at 60 °C for 12 hours. The pH was brought up to 7 by the addition of sodium bicarbonate, diluted with ethyl acetate and filtered. Evaporation of volatiles under reduced pressure afforded a residue that was purified by preparative TLC (25% ethyl acetate in hexanes) to afford the title compound in 40% yield. MS (ESI) m/z: 378.0 [M+H] + . Step 7: 1-(7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahy droisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-1,1-dioxido-2,3-dihydrothie no[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2- trifluoroethan-1-one [000418] The title compound was prepared analogously to Example 4, step 2, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 1-(7-bromo-1,1-dioxido-2,3- dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2-trifluoro ethan-1-one. The title compound was isolated in 87% yield. MS (ESI) m/z: 722.0 [M+H] + . Step 8: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide [000419] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-(7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-1,1-dioxido-2,3- dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2-trifluoro ethan-1-one. The title compound was isolated in 54% yield. MS (ESI) m/z: 530.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.03 - 9.84 (m, 1H), 8.79 (s, 1H), 8.32 - 8.27 (m, 1H), 7.84 - 7.79 (m, 1H), 7.35 - 7.31 (m, 1H), 7.30 - 7.27 (m, 1H), 4.09 (s, 2H), 3.96 (s, 2H), 3.43 - 3.39 (m, 2H), 3.37 - 3.33 (m, 2H), 3.08 - 3.00 (m, 2H), 2.79 - 2.73 (m, 2H). Example 68: 2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoro methyl)pyrimidin-2-yl)-7- (methylthio)-1,2,3,4-tetrahydroisoquinolin-6-amine Step 1: 2,2,2-trifluoro-1-(7-(methylthio)-6-nitro-3,4-dihydroisoquin olin-2(1H)-yl)ethan-1-one [000420] To a solution of 2,2,2-trifluoro-1-[7-chloro-6-nitro-1,2,3,4-tetrahydroisoqui nolin-2-yl]ethan-1- one (16 mmol) in dimethyl sulfoxide (100 ml), sodium thiomethoxide (24 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 3 hours, diluted with dichloromethane (200 mL) and treated with a solution of 15 g of K 3 PO 4 in 150 ml of water. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford a crude material that was purified by silica gel chromatography (dichloromethane) to afford the title compound in 62% yield. MS (ESI) m/z: 319.5 [M-H]-. Step 2: 1-(6-amino-7-(methylthio)-3,4-dihydroisoquinolin-2(1H)-yl)-2 ,2,2-trifluoroethan-1-one [000421] The title compound was prepared analogously to Example 1, step 4 where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne was replaced with 2,2,2-trifluoro-1-(7- (methylthio)-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1 -one. The title compound was isolated in 77% yield. MS (ESI) m/z: 289.5 [M-H]-. Step 3: 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-( methylthio)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000422] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(6-amino-7- (methylthio)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluor oethan-1-one. The title compound was isolated in 40% yield. MS (ESI) m/z: 469.5 [M-H]-. Step 4: 2,2,2-trifluoro-1-(6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5 -(trifluoromethyl)pyrimidin-2- yl)amino)-7-(methylthio)-3,4-dihydroisoquinolin-2(1H)-yl)eth an-1-one [000423] The title compound was prepared analogously to Example 1, step 6 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 1-(6-{[4- chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-7-(methylsul fanyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)- 2,2,2-trifluoroethan-1-one and 2-(4-methanesulfonylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2 - dioxaborolane. The title compound was isolated in 29% yield. MS (ESI) m/z: 596.9 [M+H] + . Step 5: N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)py rimidin-2-yl)-7-(methylthio)- 1,2,3,4-tetrahydroisoquinolin-6-amine epared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 2,2,2-trifluoro-1-(6-((4-(4-(methylsulfonyl)thiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-(methylthio)- 3,4-dihydroisoquinolin-2(1H)-yl)ethan-1- one. The title compound was isolated in 98% yield. MS (ESI) m/z: 501.0 [M+H] + . Step 6: 2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoro methyl)pyrimidin-2-yl)-7- (methylthio)-1,2,3,4-tetrahydroisoquinolin-6-amine [000425] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-7-(methylthio)-1,2,3,4-tetr ahydroisoquinolin-6-amine. The title compound was isolated in 31% yield. MS (ESI) m/z: 515.1 [M+H] + .1H-NMR (300 MHz, DMSO-d6) δ 2.36 (s, 6H), 2.60 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H), 3.28 (s, 3H), 3.52 (s, 2H), 7.08 (s, 1H), 7.16 (s, 1H), 7.87 (s, 1H), 8.21 (s, 1H), 8.64 (d, J = 1.4 Hz, 1H), 8.77 (s, 1H), 9.74 (s, 1H). Example 69: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2, 3-f][1,4]thiazepine 1,1-dioxide Step 1: 7-bromo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide [000426] The title compound was prepared analogously to Example 59, step 6, where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-(7-bromo-1,1-dioxido-2,3- dihydrothieno[2,3-f][1,4]thiazepin-4(5H)-yl)-2,2,2-trifluoro ethan-1-one. The title compound was isolated. MS (ESI) m/z: 284.0 [M+H] + . Step 2: tert-butyl 7-bromo-2,3-dihydrothieno[2,3-f][1,4]thiazepine-4(5H)-carbox ylate 1,1-dioxide [000427] A 0 °C solution of 7-bromo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide (2.0 mmol), trimethylamine (4.0 mmol) in dichloromethane (6 mL) was treated with di-tert-butyldicarbonate (2.60 mmol). The reaction mixture was stirred at 10 °C for 2 hours, quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude material that was purified by preparative TLC (25% ethyl acetate in hexanes). The title compound was isolated in 67% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.39 (m, 1H), 4.68 - 4.57 (m, 2H), 3.97 - 3.88 (m, 2H), 3.64 - 3.49 (m, 2H), 1.36 (s, 9H). Step 3: tert-butyl 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2,3-dihydrothie no[2,3-f][1,4]thiazepine-4(5H)- carboxylate 1,1-dioxide [000428] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with tert-butyl 7-bromo-2,3-dihydrothieno[2,3- f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide. The title compound was isolated in 68% yield. MS (ESI) m/z: 726.0 [M+H] + . Step 4: tert-butyl 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydrothieno[2,3-f][1, 4]thiazepine-4(5H)-carboxylate 1,1- dioxide [000429] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with tert-butyl 7-(2-((7-chloro-2-(2,2,2- trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-2,3- dihydrothieno[2,3-f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide. The title compound was isolated in 87% yield. MS (ESI) m/z: 630.1 [M+H] + . Step 5: tert-butyl 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydrothieno[2,3-f][1, 4]thiazepine-4(5H)-carboxylate 1,1- dioxide [000430] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with tert-butyl 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-2,3-dihydrothie no[2,3-f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide. The title compound was isolated in 88% yield. MS (ESI) m/z: 644.0 [M+H] + . Step 6: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2, 3-f][1,4]thiazepine 1,1-dioxide [000431] The title compound was prepared analogously to Example 64, step 2 where methyl 3-((2-((tert- butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2-carboxylate was replaced with tert-butyl 7-(2-((7- chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3- dihydrothieno[2,3-f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide. The title compound was isolated in 31% yield. MS (ESI) m/z: 544.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.75 - 8.70 (m, 1H), 8.16 - 8.09 (m, 2H), 7.77 - 7.71 (m, 1H), 7.14 - 7.08 (m, 1H), 4.31 - 4.27 (m, 2H), 3.67 - 3.63 (m, 2H), 3.60 - 3.55 (m, 2H), 3.34 - 3.30 (m, 2H), 3.02 - 2.96 (m, 2H), 2.78 - 2.73 (m, 2H), 2.54 - 2.46 (m, 3H). Example 71: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[3,2-f][1, 4]oxazepin-5(2H)-one Step 1: 2-(2-hydroxyethoxy)thiophene-3-carboxylic acid [000432] Potassium tert-butoxide (72.4 mmol) was dissolved in ethylene glycol (11 mL) and copper(I) iodide (2.42 mmol) and 2-bromo-3-thiophenecarboxylic acid (24 mmol) were added portion-wise. The reaction mixture was stirred at 120 °C for 3 hours. The mixture was cooled down to room temperature and the pH made neutral by the addition of formic acid. The solution was diluted with methanol and filtered through celite. The volatiles were removed under reduced pressure and the crude material was purified by silica gel chromatography (0-5% methanol in dichloromethane). The title compound was isolated in 15% yield. MS (ESI) m/z: 189.3 [M+H] + . Step 2: 2-(2-hydroxyethoxy)thiophene-3-carboxamide [000433] A solution of 2-(2-hydroxyethoxy)thiophene-3-carboxylic acid (4.67 mmol), triethylamine (26.3 mmol) and HCTU (14.0 mmol) in DMF (13 ml) was treated with a 0.4 M solution of ammonia in dioxane (22.7 mmol). After 1 hour, a second portion of HCTU (14.0 mmol) and 0.4 M solution of ammonia in dioxane (22.7 mmol) was added and stirring continued overnight. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (5- 10% dichloromethane in methanol) to afford the title compound in 95% yield. MS (ESI) m/z: 188.0 [M+H] + . Step 3: 2-((3-carbamoylthiophen-2-yl)oxy)ethyl methanesulfonate [000434] A solution of 2-(2-hydroxyethoxy)thiophene-3-carboxamide (2.67 mmol) and DIPEA (3.73 mmol) in dichloromethane (7.5 ml) was cooled to 0 ˚C and methanesulfonyl chloride (3.20 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour.0.4 additional equivalents of DIPEA and 0.2 additional equivalents of methanesulfonyl chloride were added and stirring continued for another hour. The reaction was quenched with water and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and filtered. Evaporation of volatiles under reduced pressure afforded the title compound in 91% yield. This material was used in the following step without further purification. MS (ESI) m/z: 266.0 [M+H] + . Step 4: 3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one [000435] 60% Sodium hydride (2.92 mmol) was added to a solution of 2-((3-carbamoylthiophen-2- yl)oxy)ethyl methanesulfonate (2.44 mmol) in DMF (14 mL). After 12 hours, the reaction was acidified by the addition of acetic acid (0.07 mL) and the volatiles were removed under reduced pressure. The crude material was purified by silica gel chromatography to afford the title compound in 66% yield. MS (ESI) m/z: 169.9 [M+H] + . Step 5: 7-bromo-3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one [000436] NBS (1.52 mmol) was added to a solution of 3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one (1.60 mmol) in dichloromethane (0.3 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (0-10% methanol in 1M solution of ammonia in methanol). The title compound was isolated in 87% yield. MS (ESI) m/z: 250.4 [M+H] + . Step 6: 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[3,2-f][1, 4]oxazepin-5(2H)-one [000437] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 7-bromo-3,4-dihydrothieno[3,2- f][1,4]oxazepin-5(2H)-one. The title compound was isolated in 48% yield. MS (ESI) m/z: 592.6 [M+H] + . Step 7: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-3,4-dihydrothieno[3,2-f][1,4]oxazepin-5(2H)-one [000438] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[3,2- f][1,4]oxazepin-5(2H)-one. The title compound was isolated in 90% yield. MS (ESI) m/z: 496.4 [M+H] + . 1H-NMR (300 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.68 (s, 1H), 8.18 (m, 1H), 7.88 (s, 1H), 7.30 (m, 1H), 7.22 (s, 1H), 4.53 (m, 2H), 3.86 (s, 2H), 3.49 (m, 2H), 2.96 (m, 2H), 2.69 (m, 2H). Example 72: 6-ethyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluorom ethyl)pyrimidin-2- yl)isoindolin-5-amine Step 1: 1-(5-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000439] Triethylamine (76 mmol) was added to a solution of 5-bromo-2,3-dihydro-1H-isoindole (50 mmol) in dichloromethane (120 mL). The resulting solution was cooled down to 0°C and trifluoroacetic anhydride (56 mmol) were added dropwise maintaining the temperature of the reaction mixture below 5°C. After 2 hours, the reaction was quenched with water, the organic layer was separated and washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a residue that was purified by silica gel chromatography (30% ethyl acetate in hexanes). The title compound was isolated in 75% yield.1H-NMR (300 MHz, DMSO-d6) δ 7.63 (dd, J = 7.6, 1.7 Hz, 1H), 7.53 (dd, J = 8.2, 1.9 Hz, 1H), 7.36 (dd, J = 8.1, 6.3 Hz, 1H), 5.01 (d, J = 12.0 Hz, 2H), 4.81 (d, J = 12.8 Hz, 2H). Step 2: 1-(5-ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000440] A mixture of 1-(5-bromo-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroetha n-1-one (18 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.4 mmol), ethylboronic acid (35 mmol), potassium phosphate tribasic (53 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.88 mmol) in toluene (104 mL)and water (16 ml) was stirred at 80 °C for 4 hours. The reaction mixture was cooled down to room temperature and washed with water. The organic layer was concentrated and the resulting crude material was purified by silica gel chromatography (dichloromethane) to afford the title compound in 89% yield. MS (ESI) m/z: 244.0 [M-H]-. Step 3: 1-(5-ethyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e [000441] A solution of 1-(5-ethyl-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroetha n-1-one (16 mmol) in acetic anhydride (22 ml) was cooled down to -30°C. Nitric acid (0.83 mL) was added slowly over 10 minutes. The reaction mixture warmed up to room temperature and stirred for 2 hours. Methanol (15 mL) was added and the mixture stirred for another 30 minutes. Evaporation of the volatiles under reduced pressure afforded a residue that was partitioned between water and dichloromethane. The organic layer was separated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0- 30% ethyl acetate in hexanes). The title compound was isolated in 45% yield.1H-NMR (300 MHz, CDCl3) δ 1.30 (m, 3H), 2.94 (m, 2H), 4.95 (s, 2H), 5.07 (s, 2H), 7.32 (d, J = 15.5 Hz, 1H), 7.84 (d, J = 12.3 Hz, 1H). Step 4: 1-(5-amino-6-ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e [000442] A solution of 1-(5-ethyl-6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e (7.14 mmol) in methanol (42 mL) was hydrogenated in the presence of 10% palladium on carbon (0.21 mmol) for 12 hours. The mixture was filtered through celite and the methanol was evaporated. The crude material was purified by silica gel chromatography (20-60% ethyl acetate in hexanes) to afford the title compound in 55% yield. MS (ESI) m/z: 257.6 [M-H]-. Step 5: 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-e thylisoindolin-2-yl)-2,2,2- trifluoroethan-1-one [000443] The title compound was prepared analogously to Example 1, step 5, where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(5-amino-6- ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 36% yield. MS (ESI) m/z: 439.0 [M+H] + . Step 6: 1-(5-ethyl-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(triflu oromethyl)pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000444] The title compound was prepared analogously to Example 1, step 6, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one and 4-(methoxycarbonyl)thiophene-2-boronic acid pinacol ester were replaced with 1-(5-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-ethylisoin dolin-2-yl)-2,2,2-trifluoroethan-1-one and 2-(4-methanesulfonylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2 -dioxaborolane. The title compound was isolated in 8% yield. MS (ESI) m/z: 565.0 [M+H] + . Step 7: 6-ethyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluorom ethyl)pyrimidin-2- yl)isoindolin-5-amine [000445] The title compound was prepared analogously to Example 1, step 7, where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 1-(5-ethyl-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)isoindolin-2-yl)-2,2,2 -trifluoroethan-1-one. The title compound was isolated in 15% yield. MS (ESI) m/z: 469.1 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ 1.09 (t, J = 7.5 Hz, 3H), 2.59 (q, J = 7.5 Hz, 2H), 3.28 (s, 3H), 4.19 (s, 4H), 7.23 (s, 1H), 7.26 (s, 1H), 7.87 (s, 1H), 8.33 (s, 2H), 8.63 (s, 1H), 8.76 (s, 1H), 9.83 (s, 1H). Example 73: 6-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoro methyl)pyrimidin-2- yl)isoindolin-5-amine [000446] The title compound was prepared analogously to Example 72, where 5-bromo-2,3-dihydro-1H- isoindole was replaced with 5-chloro-2,3-dihydro-1H-isoindole in step 1. MS (ESI) m/z: 473.2 [M-H]-. 1H-NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.82 (s, 1H), 8.66 (d, J = 1.4 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.48 (d, J = 5.3 Hz, 2H), 4.15 (s, 4H), 3.29 (s, 3H). Example 75: 7-chloro-N-(4-(5-(3,6-dihydro-2H-pyran-4-yl)-4-(methylsulfon yl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine Step 1: 2,5-dibromo-3-(methylthio)thiophene [000447] To a solution of 3-methylsulfanylthiophene (38 mmol) in dichloromethane (50 mL) was added 1-bromopyrrolidine-2,5-dione (84 mmol). After 12 hours the volatiles were removed under reduced pressure and the resulting residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether). The title compound was isolated in 74% yield. 1 H NMR (400MHz, CDCl 3 ) δ 6.90 (s, 1H), 2.45 (s, 3H). Step 2: 2,5-dibromo-3-(methylsulfonyl)thiophene [000448] To a 0 °C solution of 2,5-dibromo-3-methylsulfanyl-thiophene (14 mmol) in dichloromethane (40 mL) was added meta-chloroperoxybenzoic acid (28 mmol). The mixture was stirred at 25 °C for 2 hours and quenched by the addition of saturated aqueous solution of sodium sulfite (100 mL). The mixture was extracted with dichloromethane three times and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (10-50% ethyl acetate in petroleum ether). The title compound was isolated in 74% yield. 1 H NMR (400MHz, CDCl3) δ 7.38 (s, 1H), 3.18 (s, 3H). Step 3: 4-(5-bromo-3-(methylsulfonyl)thiophen-2-yl)-3,6-dihydro-2H-p yran [000449] A mixture of 2,5-dibromo-3-methylsulfonyl-thiophene (0.62 mmol), 2-(3,6-dihydro-2H-pyran- 4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.62 mmol), potassium phosphate (1.87 mmol) and tetrakis[triphenylphosphine]palladium(0) (0.06 mmol) in dioxane (2 mL) and water (0.4 mL) was stirred at 80 °C for 1 hour. The mixture was purified by preparative TLC (33% ethyl acetate in petroleum ether, Rf = 0.32). The title compound was isolated in 59% yield. 1 H NMR (400MHz, CDCl3) δ 7.37 (s, 1H), 6.24 - 6.21 (m, 1H), 4.31 (q, J = 2.8 Hz, 2H), 3.91 (t, J = 5.2 Hz, 2H), 3.08 (s, 3H), 2.52 (dt, J = 2.4, 4.8 Hz, 2H). Step 4: 1-(7-chloro-6-((4-(5-(3,6-dihydro-2H-pyran-4-yl)-4-(methylsu lfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli n-2(1H)-yl)-2,2,2-trifluoroethan-1- one [000450] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 4-(5-bromo-3-(methylsulfonyl)thiophen-2-yl)- 3,6-dihydro-2H-pyran. The title compound was isolated in 62% yield. MS (ESI) m/z: 667.0 [M+H] + Step 5: 7-chloro-N-(4-(5-(3,6-dihydro-2H-pyran-4-yl)-4-(methylsulfon yl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine [000451] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-(7-chloro-6-((4-(5-(3,6-dihydro-2H- pyran-4-yl)-4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromet hyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 42% yield. MS (ESI) m/z: 571.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.91 (d, J = 2.0 Hz, 1H), 8.80 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 6.36 (s, 1H), 4.24 (d, J = 2.8 Hz, 2H), 3.88 (s, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.26 (s, 3H), 2.98 (t, J = 5.6 Hz, 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.53 - 2.51 (m, 2H). Example 77: 6-chloro-2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)isoindolin-5-amine [000452] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 6-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)isoindolin-5-amine. The title compound was isolated in 21% yield. MS (ESI) m/z: 487.1 [M+H] + .1H-NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 8.83 (s, 1H), 8.66 (d, J = 1.4 Hz, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.44 (s, 2H), 3.82 (d, J = 4.2 Hz, 3H), 2.49 (s, 3H). Example 80: 6-fluoro-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluorom ethyl)pyrimidin-2-yl]-2- methyl-2,3-dihydro-1H-isoindol-5-amine Step 1: 1-(5-amino-6-fluoro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trif luoroethan-1-one [000453] The title compound was prepared analogously to Example 72 following steps 1, 3 and 4, where 5-bromo-2,3-dihydro-1H-isoindole was replaced with 5-fluoro-2,3-dihydro-1H-isoindole in step 1. MS (ESI) m/z: 249.0 [M+H] + . Step 2: 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-f luoroisoindolin-2-yl)-2,2,2- trifluoroethan-1-one [000454] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(5-amino-6- fluoro-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1- one. The title compound was isolated in 33% yield. MS (ESI) m/z: 429.0 [M+H] + Step 3: 2,2,2-trifluoro-1-(5-fluoro-6-((5-(trifluoromethyl)-4-(trime thylstannyl)pyrimidin-2- yl)amino)isoindolin-2-yl)ethan-1-one [000455] A mixture of 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-f luoroisoindolin-2- yl)-2,2,2-trifluoroethan-1-one (4.18 mmol), 1,4-bis(diphenylphosphino)butane (0.83 mmol), hexamethylditin (12.5 mmol) and palladium (II) acetate (0.83 mmol) in dioxane (36 mL) was stirred at 95 ˚C overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (10% triethylamine in hexanes) to afford the title compound in 75% yield. MS (ESI) m/z: 558.9 [M+H] + . Step 4: 2,2,2-trifluoro-1-(5-fluoro-6-((4-(4-(methylsulfonyl)thiophe n-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)isoindolin-2-yl)ethan- 1-one [000456] The title compound was prepared analogously to Example 4, step 2 where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-bromo-6,7-dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 2,2,2- trifluoro-1-(5-fluoro-6-((5-(trifluoromethyl)-4-(trimethylst annyl)pyrimidin-2-yl)amino)isoindolin-2- yl)ethan-1-one and 2-bromo-4-methanesulfonylthiophene. The title compound was isolated in 78% yield. MS (ESI) m/z: 555.1 [M+H] + . Step 5: 6-fluoro-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluorom ethyl)pyrimidin-2-yl]-2,3- dihydro-1H-isoindol-5-amine [000457] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 2,2,2-trifluoro-1-(5-fluoro-6-((4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)isoindolin-2-yl)ethan-1-one. The title compound was isolated in 86% yield. MS (ESI) m/z: 459.4 [M+H] + .1H-NMR (400 MHz, DMSO-d 6 ) δ 8.84 (s, 1H), 8.67 (d, J = 1.4 Hz, 1H), 8.23 (s, 1H), 7.90 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 10.2 Hz, 1H), 4.17 (d, J = 7.4 Hz, 4H), 3.30 (s, 3H), 2.55 (s, 1H). Step 6: 6-fluoro-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluorom ethyl)pyrimidin-2-yl]-2- methyl-2,3-dihydro-1H-isoindol-5-amine [000458] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 6-fluoro-N-[4-(4-methanesulfonylthiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-2,3-dihydro-1H-isoindol-5-a mine. The title compound was isolated in 47% yield. MS (ESI) m/z: 473.3 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.83 (s, 1H), 8.66 (d, J = 1.3 Hz, 1H), 8.15 (s, 0H), 7.89 (s, 1H), 7.43 (d, J = 7.1 Hz, 1H), 7.19 (d, J = 10.2 Hz, 1H), 3.82 (d, J = 7.2 Hz, 4H), 3.29 (s, 3H). Example 82: -[2-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-3,4-dihydro-2H-th ieno[2,3-f][1,4]thiazepin-5-one Step 1: 8-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin -5-one [000459] A solution of 1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-one (13.8 mmol), N- bromosuccinimide (24.8 mmol) in acetic acid (30 mL) was treated with sulfuric acid (56.3 mmol) and the mixture was stirred at 60 °C for 12 hours. The pH was made neutral by the addition of sodium bicarbonate and the mixture was diluted with ethyl acetate, filtered, and concentrated. The residue was purified by preparative HPLC. The title compound was isolated in 10% yield. MS (ESI) m/z: 295.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.86 - 8.80 (m, 1H), 7.69 (s, 1H), 3.93 - 3.86 (m, 2H), 3.69 - 3.64 (m, 2H). Step 2: 7-[2-[[7-chloro-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-iso quinolin-6-yl]amino]-5- (trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-3,4-dihydro-2H-th ieno[2,3-f][1,4]thiazepin-5-one [000460] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 8-bromo-1,1-dioxo-3,4-dihydro-2H- thieno[2,3-f][1,4]thiazepin-5-one. The title compound was isolated in 24% yield. MS (ESI) m/z: 639.9 [M+H] + Step 3: 7-[2-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl]-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin-5-o ne [000461] The title compound was prepared analogously to Example 59, step 6, where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 7-[2-[[7-chloro-2-(2,2,2-trifluoroacetyl)- 3,4-dihydro-1H-isoquinolin-6-yl]amino]-5-(trifluoromethyl)py rimidin-4-yl]-1,1-dioxo-3,4-dihydro-2H- thieno[2,3-f][1,4]thiazepin-5-one. The title compound was isolated in 62% yield. MS (ESI) m/z: 544.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.16 - 9.72 (m, 1H), 8.90 (s, 1H), 8.83 (s, 1H), 7.85 (s, 1H), 7.29 (s, 1H), 7.21 (s, 1H), 4.42 (s, 1H), 3.91 - 3.87 (m, 2H), 3.83 (s, 2H), 3.67 (s, 2H), 2.92 (t, J = 5.4 Hz, 2H), 2.67 (s, 3H). Example 83: 7-Chloro-N-[4-(4-methylsulfonyl-5-morpholino-2-thienyl)-5- (trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinol in-6-amine Step 1: 4-(5-bromo-3-methylsulfonyl-2-thienyl)morpholine [000462] A solution of 2,5-dibromo-3-methylsulfonyl-thiophene (1.72 mmol) in 1-methyl-2- pyrrolidinone (2.5 mL) was treated with morpholine (13.7 mmol) and N,N-diisopropylethylamine (13.75 mmol). The mixture was stirred at 135 °C for 1 hour. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (33% ethyl acetate in hexanes). The title compound was isolated in 45% yield. MS (ESI) m/z: 326.0[M+H] + . Step 2: 1-[7-chloro-6-[[4-(4-methylsulfonyl-5-morpholino-2-thienyl)- 5-(trifluoromethyl)pyrimidin- 2-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro -ethanone [000463] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 4-(5-bromo-3-methylsulfonyl-2- thienyl)morpholine. The title compound was isolated in 63% yield. MS (ESI) m/z: 670.2 [M+H]+. Step 3: 7-Chloro-N-[4-(4-methylsulfonyl-5-morpholino-2-thienyl)-5-(t rifluoromethyl)pyrimidin-2- yl]-1,2,3,4-tetrahydroisoquinolin-6-amine [000464] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-[7-chloro-6-[[4-(4-methylsulfonyl-5- morpholino-2-thienyl)-5-(trifluoromethyl)pyrimidin-2-yl]amin o]-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2- trifluoro-ethanone. The title compound was isolated in 39% yield. MS (ESI) m/z: 574.1 NMR (400MHz, DMSO-d6) δ 9.74 (s, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 3.90 (s, 2H), 3.81 - 3.76 (m, 4H), 3.36 - 3.33 (m, 4H), 3.29 (s, 3H), 3.00 (t, J = 5.6 Hz, 2H), 2.76 - 2.70 (m, 2H). Example 85: 7-chloro-N-[4-(1,1-dioxo-3,4-dihydro-2H-thieno[2,3-b][1,4,5] oxathiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinol in-6-amine Step 1: 2,5-dibromo-N-(2-hydroxyethyl)thiophene-3-sulfonamide [000465] A 0 °C solution of 2,5-dibromothiophene-3-sulfonyl chloride (5.29 mmol) and triethylamine (15.9 mmol) in dichloromethane (20 mL) was treated with 2-aminoethanol (4.76 mmol). The mixture was stirred at 20 °C for 1 hour. The volatiles were removed under reduced pressure and the crude material purified by silica column chromatography (60% ethyl acetate in petroleum ether) to afford the title compound in 93% yield. Step 2: 7-bromo-3,4-dihydro-2H-thieno[2,3-b][1,4,5]oxathiazepine 1,1-dioxide [000466] A mixture of 2,5-dibromo-N-(2-hydroxyethyl)thiophene-3-sulfonamide (0.82 mmol), ethane- 1,2-diol (1.5 mL), cuprous iodide (0.16 mmol) and cesium carbonate (2.47 mmol) in DMF (3 mL) was stirred at 120 °C for 12 hours. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (33% ethyl acetate in hexanes). The title compound was isolated in 9% yield. 1 H NMR (400 MHz, CDCl3) δ 6.71 (s, 1 H), 5.59 (s, 1 H), 4.35 (t, J = 4.4 Hz, 2 H), 3.66 (s, 2 H). Step 3: 1-[7-chloro-6-[[4-(1,1-dioxo-3,4-dihydro-2H-thieno[2,3-b][1, 4,5]oxathiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl]amino]-3,4-dihydro-1H-isoqui nolin-2-yl]-2,2,2-trifluoro-ethanone [000467] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 7-bromo-3,4-dihydro-2H-thieno[2,3- b][1,4,5]oxathiazepine 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 627.9 [M+H] + . Step 4: 7-chloro-N-[4-(1,1-dioxo-3,4-dihydro-2H-thieno[2,3-b][1,4,5] oxathiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinol in-6-amine [000468] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 1-[7-chloro-6-[[4-(1,1-dioxo-3,4-dihydro- 2H-thieno[2,3-b][1,4,5]oxathiazepin-7-yl)-5-(trifluoromethyl )pyrimidin-2-yl]amino]-3,4-dihydro-1H- isoquinolin-2-yl]-2,2,2-trifluoro-ethanone. The title compound was isolated in 42% yield. MS (ESI) m/z: 532.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1 H), 8.16 (s, 1 H), 7.68 (s, 1 H), 7.36 (s, 1 H), 7.01 (s, 1 H), 4.36 - 4.35 (m, 2 H), 4.03 (s, 2 H), 3.67 (s, 2 H), 3.33 (s, 2 H), 3.05 (s, 2 H). Example 86: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5 (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000469] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 7-chloro-N-[4-(1,1-dioxo-3,4-dihydro-2H-thieno[2,3- b][1,4,5]oxathiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-y l]-1,2,3,4-tetrahydroisoquinolin-6-amine. The title compound was isolated in 40% yield. MS (ESI) m/z: 558.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.2220 (s, 1H), 10.08 - 10.00 (m, 1H), 8.91 - 8.84 (m, 2H), 7.89 - 7.86 (m, 1H), 7.58 - 7.53 (m, 1H), 7.51 - 7.49 (m, 1H), 4.60 - 4.48 (m, 1H), 4.37 - 4.28 (m, 1H), 3.93 - 3.89 (m, 2H), 3.71 - 3.64 (m, 3H), 3.51 - 3.46 (m, 1H), 3.14 - 3.07 (m, 2H), 2.97 - 2.94 (m, 3H). Example 88: 6-cyclopropyl-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifl uoromethyl)pyrimidin-2- yl]-2-methyl-2,3-dihydro-1H-isoindol-5-amine Step 1: 1-(5-amino-6-cyclopropyl-2,3-dihydro-1H-isoindol-2-yl)-2,2,2 -trifluoroethan-1-one [000470] The title compound was prepared analogously to Example 72, steps 1-4 where ethylboronic acid was replaced with cyclopropylboronic acid in step 2. The title compound was isolated. MS (ESI) m/z: 271.2 [M+H] + . Step 2: 1-(5-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-6-c yclopropyl-2,3-dihydro-1H- isoindol-2-yl)-2,2,2-trifluoroethan-1-one [000471] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(5-amino-6- cyclopropyl-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroeth an-1-one. The title compound was isolated in 24% yield. MS (ESI) m/z: 451.2 [M+H] + . Step 3: 1-(5-cyclopropyl-6-{[5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2-yl]amino}-2,3- dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one [000472] The title compound was prepared analogously to Example 80, step 3 where 1-(5-{[4-chloro-5- (trifluoromethyl)pyrimidin-2-yl]amino}-6-fluoro-2,3-dihydro- 1H-isoindol-2-yl)-2,2,2-trifluoroethan-1- one was replaced with 1-(5-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-6-c yclopropyl-2,3- dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 10% yield. MS (ESI) m/z: 580.8 [M+H] + . Step 4: 1-(5-cyclopropyl-6-{[4-(4-methanesulfonylthiophen-2-yl)-5-(t rifluoromethyl)pyrimidin-2- yl]amino}-2,3-dihydro-1H-isoindol-2-yl)-2,2,2-trifluoroethan -1-one [000473] The title compound was prepared analogously to Example 4, step 2 where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-bromo-6,7-dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 1-(5- cyclopropyl-6-{[5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl]amino}-2,3-dihydro-1H- isoindol-2-yl)-2,2,2-trifluoroethan-1-one and 2-bromo-4-methanesulfonylthiophene. The title compound was isolated in 98% yield. MS (ESI) m/z: 577.0 [M+H] + . Step 5: 6-cyclopropyl-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifl uoromethyl)pyrimidin-2-yl]- 2,3-dihydro-1H-isoindol-5-amine [000474] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 1-(5-cyclopropyl-6-{[4-(4-methanesulfonylthiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2,3-dihydro-1H- isoindol-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 99% yield. MS (ESI) m/z: 481.4 [M+H] + . Step 6: 6-cyclopropyl-N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifl uoromethyl)pyrimidin-2-yl]-2- methyl-2,3-dihydro-1H-isoindol-5-amine [000475] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 6-cyclopropyl-N-[4-(4-methanesulfonylthiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-2,3-dihydro-1H-isoindol-5-a mine. The title compound was isolated in 25% yield. MS (ESI) m/z: 495.1 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ 0.58 (m, 2H), 0.82 (m, 2H), 1.96 (m, 1H), 2.53 (s, 3H), 3.28 (s, 3H), 3.86 (s, 4H), 6.88 (s, 1H), 7.26 (s, 1H), 7.87 (s, 1H), 8.15 (s, 1H), 8.64 (s, 1H), 8.77 (s, 1H), 9.84 (s, 1H). Example 95: 7-chloro-2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine [000476] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with 7-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine. The title compound was isolated in 15% yield. MS (ESI) m/z: 503.1 [M+H] + .1H-NMR ((400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.83 (s, 1H), 8.66 (d, J = 1.3 Hz, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 3.29 (s, 3H), 2.83 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 5.9 Hz, 2H), 2.35 (s, 3H). Example 101: N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyr imidin-2-yl]-1,2,3,4- tetrahydroisoquinolin-7-amine Step 1: 1-(7-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-1,2 ,3,4-tetrahydroisoquinolin-2- yl)-2,2,2-trifluoroethan-1-one [000477] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(7-amino- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne. The title compound was isolated in 42% yield. Step 2: 2,2,2-trifluoro-1-(7-{[4-(4-methanesulfonylthiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2- yl]amino}-1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one [000478] The title compound was prepared analogously to Example 4, step 2 where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 2-bromo-6,7-dihydrothieno[3,2-C]pyridin-4(5H)-one were replaced with 1-(7- {[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2- trifluoroethan-1-one and (4-methanesulfonylthiophen-2-yl)trimethylstannane. The title compound was isolated in 83% yield. MS (ESI) m/z: 551.6 [M+H] + . Step 3: N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyr imidin-2-yl]-1,2,3,4- tetrahydroisoquinolin-7-amine [000479] The title compound was prepared analogously to Example 1, step 7 where methyl 5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophene-3-carboxylate was replaced with 2,2,2-trifluoro-1-(7-{[4-(4-methanesulfonylthiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-1,2,3,4-tetrahy droisoquinolin-2-yl)ethan-1-one. The title compound was isolated in 90% yield. MS (ESI) m/z: 455.1 [M+H] + .1H-NMR (300 MHz, DMSO-d6) δ 2.75 (d, J = 6.2 Hz, 2H), 3.08 (m, 2H), 3.32 (s, 3H), 4.01 (s, 2H), 7.11 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.3, 2.2 Hz, 1H), 7.54 (s, 1H), 7.93 (s, 1H), 8.27 (s, 1H), 8.72 (d, J = 1.3 Hz, 1H), 8.88 (s, 1H), 10.38 (s, 1H). Example 102: N-[4-(4-methanesulfonylthiophen-2-yl)-5-(trifluoromethyl)pyr imidin-2-yl]-2-methyl- 1,2,3,4-tetrahydroisoquinolin-7-amine [000480] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with N-[4-(4-methanesulfonylthiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl]-1,2,3,4-tetrahydroisoquinol in-7-amine. The title compound was isolated in XX% yield. MS (ESI) m/z: 469.1 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ 2.39 (s, 3H), 2.66 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 3.32 (s, 3H), 3.57 (s, 2H), 7.10 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.51 (s, 1H), 7.93 (s, 1H), 8.15 (s, 2H), 8.73 (d, J = 1.4 Hz, 1H), 8.87 (s, 1H), 10.36 (s, 1H). Example 116: 7-[2-[(7-chloro-2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)ami no]-5- (trifluoromethyl)pyrimidin-4-yl]-4-methyl-1,1-dioxo-2,3-dihy drothieno[2,3-f][1,4]thiazepin-5-one Step 1: 7-bromo-4-methyl-1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thia zepin-5-one [000481] A 0 °C solution of 7-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin -5-one (0.34 mmol) and DMF (3 mL) was treated with 60% sodium hydride (0.37 mmol). After 30 minutes, iodomethane (0.34 mmol) was added and the reaction was stirred at 20°C for 12 hours. LCMS (EW33254-140-P1A) showed 43.03% of desired compound formed. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (100% ethyl acetate). The title compound was isolated in 81% yield. MS (ESI) m/z: 310.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.95 (s, 1H), 3.94 - 3.93 (m, 2H), 3.92 - 3.90 (m, 2H), 3.06 - 3.06 (m, 3H). Step 2: 7-[2-[[7-chloro-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-iso quinolin-6-yl]amino]-5- (trifluoromethyl)pyrimidin-4-yl]-4-methyl-1,1-dioxo-2,3-dihy drothieno[2,3-f][1,4]thiazepin-5-one [000482] The title compound was prepared analogously to Example 4, step 2 where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 7-bromo-4-methyl-1,1-dioxo-2,3- dihydrothieno[2,3-f][1,4]thiazepin-5-one. The title compound was isolated in 56% yield. MS (ESI) m/z: 654.0 [M+H] + . Step 3: 7-[2-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5- (trifluoromethyl)pyrimidin-4- yl]-4-methyl-1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thiazepi n-5-one [000483] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 7-[2-[[7-chloro-2-(2,2,2-trifluoroacetyl)- 3,4-dihydro-1H-isoquinolin-6-yl]amino]-5-(trifluoromethyl)py rimidin-4-yl]-4-methyl-1,1-dioxo-2,3- dihydrothieno[2,3-f][1,4]thiazepin-5-one. The title compound was isolated in 47% yield. MS (ESI) m/z: 558.1 [M+H] + . Step 4: 7-[2-[(7-chloro-2-methyl-3,4-dihydro-1H-isoquinolin-6-yl)ami no]-5- (trifluoromethyl)pyrimidin-4-yl]-4-methyl-1,1-dioxo-2,3-dihy drothieno[2,3-f][1,4]thiazepin-5-one [000484] A mixture of 7-[2-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]-4-methyl-1,1-dioxo-2,3-dihy drothieno[2,3-f][1,4]thiazepin-5-one (0.04 mmol) and paraformaldehyde (0.45 mmol) in methanol (1 mL) was stirred at 10 °C for 1 hour. Sodium cyanoborohydride (0.07 mmol) was added to the solution and the reaction was stirred at 10 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford a crude product that was purified by preparative HPLC. The title compound was isolated in 31% yield. MS (ESI) m/z: 572.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 10.05 - 9.94 (m, 1H), 8.90 (s, 1H), 7.84 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 4.59 - 4.45 (m, 1H), 4.37 - 4.27 (m, 1H), 4.01 - 3.95 (m, 2H), 3.92 - 3.86 (m, 2H), 3.77 - 3.64 (m, 1H), 3.18 - 3.03 (m, 6H), 2.96 (s, 3H). [000485] Characterization Data for examples 40-120 are provided below in Table 2. Table 2

Example 121: N-(2-chloro-5-(1-methylazetidin-3-yl)phenyl)-4-(4-(methylsul fonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine Step 1: tert-butyl 3-(2-tosylhydrazineylidene)azetidine-1-carboxylate [000486] A mixture of p-toluenesulfonyl hydrazide (16.31 g, 87.6 mmol, 1.0 eq) and t-butyl 3- oxoazetidine-1-carboxylate (15.00 g, 87.6 mmol, 1.0 eq) in toluene (262 mL) was stirred at 110 °C for 2 h. The reaction mixture was filtered and the solid residue was dried overnight under vacuum to afford the title compound in 88% yield. MS (ESI) m/z: 240.0 [M+H-Boc]+. Step 2: tert-butyl 3-(3-amino-4-chlorophenyl)azetidine-1-carboxylate [000487] To a solution of tert-butyl 3-[(4-methylbenzenesulfonamido)imino]azetidine-1-carboxylate (6.00 g, 18 mmol, 1.00 eq) in anhydrous dioxane (126 mL), 3-amino-4-chlorophenylboronic acid (4.54 g, 26.516 mmol, 1.5 eq) and Cs2CO3 (8.64 g, 26.516 mmol) were added. The reaction mixture was refluxed at 110 °C for 30 h. The reaction mixture was and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-30% ethyl acetate in hexanes). The title compound was isolated in 30% yield. MS (ESI) m/z: 277.0 [M+H-Boc]+. Step 3: tert-butyl 3-(4-chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino) phenyl)azetidine-1-carboxylate [000488] To a 0°C solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (0.219 mmol) in dichloroethane/t-BuOH (1.2 mL/0.2 mL), a 0.7 M solution of ZnCl2 in THF (0.69 mL) was added. The reaction mixture was stirred at 0°C for 1 hour and a solution of tert-butyl 3-(3-amino-4- chlorophenyl)azetidine-1-carboxylate (0.219 mmol) in dichloroethane /t-BuOH [0.31 mL/0.31 mL] was added. Over the resulting mixture, diisopropylethylamine (0.241 mmol) was added dropwise and the reaction was stirred overnight at room temperature. Water was added and the resulting solution was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (10% methanol in dichloromethane). The title compound was isolated in 21% yield. m/z (ESI, +ve)= 408.8 [M+H] + . Step 4: tert-butyl 3-(4-chloro-3-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifl uoromethyl)pyrimidin- 2-yl)amino)phenyl)azetidine-1-carboxylate [000489] A mixture of tert-butyl 3-(4-chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino) phenyl)azetidine-1-carboxylate (1.47 mmol), trimethyl(4-(methylsulfonyl)thiophen-2-yl)stannane (1.91 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.073 mmol) in dioxane (7 mL) was stirred at 100 °C for 16 hours. Evaporation of volatiles under reduced pressure afforded a residue that was purified by silica gel chromatography (0-60% ethyl acetate in hexanes). The title compound was isolated in 69% yield. m/z (ESI, +ve)= 489.0 (M+H-Boc) + . Step 5: N-(5-(azetidin-3-yl)-2-chlorophenyl)-4-(4-(methylsulfonyl)th iophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine [000490] A 4M solution of HCl in methanol (5 mL) was added over a solution of tert-butyl 3-(4-chloro- 3-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)p yrimidin-2-yl)amino)phenyl)azetidine-1- carboxylate (1 mmol) in methanol (6 mL). After 90 minutes the volatiles were removed under reduced pressure to afford the title compound which was used in the next step without further purification. m/z (ESI, +ve)= 489.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.65 (d, J = 1.3 Hz, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 8.3, 2.2 Hz, 1H), 4.04 (d, J = 3.3 Hz, 3H), 3.86 (s, 2H), 3.29 (s, 3H). Example 122: N-(2-chloro-5-(1-methylazetidin-3-yl)phenyl)-4-(4-(methylsul fonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine [000491] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with N-(5- (azetidin-3-yl)-2-chlorophenyl)-4-(4-(methylsulfonyl)thiophe n-2-yl)-5-(trifluoromethyl)pyrimidin-2- amine. The title compound was isolated in 46% yield. m/z (ESI, +ve)= 503.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.84 (s, 1H), 8.66 (d, J = 1.3 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 8.3, 2.2 Hz, 1H), 3.78 – 3.64 (m, 3H), 3.28 (s, 3H), 3.24 (d, J = 6.4 Hz, 2H), 2.33 (s, 3H). Example 123: N-(1-(azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-4-(4-(methyls ulfonyl)thiophen-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine Step 1: tert-butyl 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate [000492] A solution of 3-methyl-4-nitro-1H-pyrazole (15.7 mmol) in THF (24 mL) was treated with 1- Boc-3-hydroxyazetidine (18.9 mmol) and triphenylphosphine (6.19 mmol). The mixture was cooled down to 0 °C and a 40% solution of diethylazodiacarboxylate in toluene (24 mmol) was added slowly. The reaction was stirred at room temperature overnight and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (15-30% ethyl acetate in hexanes). The title compound was isolated in 45% yield. m/z (ESI, +ve)= 227.0 (M+H-Boc) + . Step 2: tert-butyl 3-(4-amino-3-methyl-1H-pyrazol-1-yl)azetidine-1-carboxylate [000493] The title compound was prepared analogously to Example 19, step 3 where 1-(5-cyclopropyl- 6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with tert-butyl 3-(3-methyl-4-nitro-1H- pyrazol-1-yl)azetidine-1-carboxylate. The title compound was isolated in 94% yield. 1 H NMR (300 MHz, DMSO-d 6 ) δ 1.41 (s, 9H), 2.04 (s, 3H), 3.70 (s, 2H), 4.03 (br.s, 2H), 4.18 (t, J = 8.3 Hz, 2H), 4.92 (m, 1H), 7.06 (s, 1H). Step 3: tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-m ethyl-1H-pyrazol-1- yl)azetidine-1-carboxylate [000494] The title compound was prepared analogously to Example 121, step 3, where tert-butyl 3-(3- amino-4-chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 3-(4-amino-3-methyl-1H- pyrazol-1-yl)azetidine-1-carboxylate. The title compound was isolated in 64% yield.1H-NMR (300 MHz, DMSO-d6) δ 1.40 (s, 9H), 2.16 (s, 3H), 4.10 (s, 2H), 4.25 (t, J = 8.3 Hz, 2H), 5.13 (m, 1H), 7.97 (m, 1H), 8.71 (m, 1H), 10.07 (s, 1H). Step 4: tert-butyl 3-(3-methyl-4-((4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azeti dine-1-carboxylate [000495] The title compound was prepared analogously to Example 121, step 4 where tert-butyl 3-(4- chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate was replaced with tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-m ethyl-1H-pyrazol- 1-yl)azetidine-1-carboxylate. The title compound was isolated in 68% yield. m/z (ESI, -ve)= 557.1 (M- H)-. Step 5: N-(1-(azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-4-(4-(methyls ulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine [000496] The title compound was prepared analogously to Example 48, step 5 where tert-butyl 4-(3- cyclopropyl-4-((4-(4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyri din-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate was replaced with tert-butyl 3-(3-methyl-4-((4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)-1H-pyrazol-1-yl)azetidine-1- carboxylate. The title compound was isolated in 98% yield. m/z (ESI, +ve)= 459.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 2.19 (m, 3H), 3.31 (s, 3H), 4.05 (m, 4H), 5.20 (m, 1H), 7.90 (s, 1H), 8.04 (m, 1H), 8.28 (s, 1H), 8.69 (s, 1H), 8.80 (m, 1H), 9.83 (m, 1H). Example 124: N-(3-methyl-1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000497] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with N-(1- (azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-4-(4-(methylsulfon yl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine. The title compound was isolated in 50% yield. m/z (ESI, +ve)= 473.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 2.16 (m, 3H), 2.34 (s, 3H), 3.31 (s, 3H), 3.36 (m, 2H), 3.70 (t, J = 6.7 Hz, 2H), 4.86 (p, J = 6.8 Hz, 1H), 8.02 (m, 2H), 8.77 (m, 2H), 9.79 (m, 1H). Example 125: 7-(2-((7-chloro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroi soquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2 -carboxylate [000498] A mixture of methyl 3-chlorosulfonylthiophene-2-carboxylate (125 mmol), sodium sulfite (249 mmol), sodium bicarbonate (262 mmol) in ethanol (100 mL) and water (200 mL) was heated at 50 °C for 45 minutes. The mixture was concentrated under reduced pressure and the residue was taken up in DMF (300 mL) and treated with tert-butyl N-(2-bromoethyl)carbamate (249 mmol) and KI (374 mmol). After 12 hours, the organic volatiles were evaporated and the resulting aqueous mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative HPLC. The title compound was isolated in 90% yield. MS (ESI) m/z: 250.1[M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 - 8.01 (m, 1H), 7.54 - 7.50 (m, 1H), 6.88 - 6.78 (m, 1H), 3.87 (s, 3H), 3.80 - 3.73 (m, 2H), 3.29 - 3.21 (m, 2H), 1.31 (s, 9H). Step 2: methyl 3-((2-aminoethyl)sulfonyl)thiophene-2-carboxylate [000499] A 10 °C solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2 - carboxylate (37 mmol) in dichloromethane (30 mL) was treated with TFA (405 mmol). Evaporation of volatiles afforded the title compound which was used in the next step without further purification. MS (ESI) m/z: 250.0[M+H] + . Step 3: 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000500] A mixture of methyl 3-((2-aminoethyl)sulfonyl)thiophene-2-carboxylate (39 mmol) and potassium carbonate (154 mmol) in ethanol was refluxed for 12 hours. The reaction was cooled down to room temperature, filtered and concentrated under reduced pressure to afford the title compound that was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.82 - 8.63 (m, 1H), 8.05 - 8.01 (m, 1H), 7.53 - 7.49 (m, 1H), 3.87 - 3.81 (m, 2H), 3.66 - 3.59 (m, 2H). Step 4: 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000501] A solution of 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (28 mmol) in sulfuric acid (6 mL) and acetic acid (60 mL) was treated with N-bromosuccinimide (50 mmol) and the reaction was stirred at 60 °C for 12 hours. The mixture was cooled down to room temperature and the pH was neutralized by the addition of sodium bicarbonate. DMF added and the insoluble materials were filtered. The resulting solution was concentrated under reduced pressure to afford a residue that was purified by preparative HPLC. The title compound was isolated in 17% yield. MS (ESI) m/z: 295.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.89 - 8.80 (m, 1H), 7.70 (s, 1H), 3.93 - 3.87 (m, 2H), 3.70 - 3.63 (m, 2H). Step 5: 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000502] A mixture of 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.68 mmol), 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (0.68 mmol), tetrakis[triphenylphosphine]palladium(0) (0.07 mmol) and CuI (0.68 mmol) in dioxane (6 mL) was stirred at 120 °C for 12 hours. The reaction was concentrated and the residue was taken up in water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (ethyl acetate). The title compound was isolated in 23% yield. MS (ESI) m/z: 639.9 [M+H] + . Step 6: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000503] A mixture of 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.16 mmol) and potassium carbonate (0.94 mmol) in ethanol (2 mL) and water was stirred at 50 °C for 12 hours. The mixture was concentrated and the residue was purified by preparative TLC (ethyl acetate) to afford the title compound in 55% yield. MS (ESI) m/z: 544.0 [M+H] + . Step 7: 7-(2-((7-chloro-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroi soquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000504] Triethylamine (0.30 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.14 mmol) were added over a solution of 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide in acetonitrile (1 mL). The reaction was stirred at 50 °C for 2 hours and concentrated under reduced pressure. The residue was taken up in water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by HPLC. The title compound was isolated in 18% yield. MS (ESI) m/z: 626.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.90 - 8.83 (m, 2H), 7.86 (s, 1H), 7.38 (br s, 1H), 7.30 (s, 1H), 3.91 - 3.87 (m, 2H), 3.86 - 3.83 (m, 2H), 3.68 - 3.65 (m, 2H), 3.41 - 3.34 (m, 2H), 2.97 - 2.91 (m, 2H), 2.86 - 2.80 (m, 2H). Example 126: 7-(2-((7-chloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000505] A solution of 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide (0.07 mmol) in THF (0.3 mL) and methanol (0.3 mL) was treated with acetic acid (0.007 mmol) and (1- ethoxycyclopropoxy)-trimethyl-silane (0.14 mmol). After 1 hour, sodium cyanoborohydride (0.10 mmol) was added and the reaction stirred at 60 °C for 12 hours. The reaction was quenched with water and concentrated. The crude residue was purified by preparative HPLC to afford the title compound in 22% yield. MS (ESI) m/z: 584.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.87 - 8.82 (m, 2H), 7.86 (s, 1H), 7.36 - 7.28 (m, 2H), 3.91 - 3.87 (m, 2H), 3.74 - 3.70 (m, 2H), 3.68 - 3.64 (m, 2H), 2.86 - 2.82 (m, 2H), 2.80 - 2.76 (m, 2H), 1.84 - 1.78 (m, 1H), 0.54 - 0.47 (m, 2H), 0.44 - 0.38 (m, 2H). Example 127: 8-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoro methyl)pyrimidin-2-yl)- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-amine Step 1: 1-(8-chloro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2 -trifluoroethan-1-one [000506] A 0 °C solution of 8-chloro-2,3,4,5-tetrahydro-1H-benzo[c]azepine (56 mmol) in dichloromethane (200 mL) was treated with trifluoroacetic anhydride (67 mmol) and triethylamine (112 mmol). After 8 hours at room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 96% yield. MS (ESI) m/z: 278.0 [M+H] + . Step 2: 1-(8-chloro-7-nitro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-y l)-2,2,2-trifluoroethan-1-one [000507] The title compound was prepared analogously to Example 1, step 3 where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(8-chloro-1,3,4,5-tetrahydro- 2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 97% yield. MS (ESI) m/z: 323.1 [M+H] + . Step 3: 1-(7-amino-8-chloro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-y l)-2,2,2-trifluoroethan-1-one [000508] The title compound was prepared analogously to Example 1, step 4 where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne was replaced with 1-(8-chloro-7-nitro- 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroet han-1-one. The title compound was isolated in 97% yield. MS (ESI) m/z: 293.0 [M+H] + . Step 4: 1-(8-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-1,3,4,5-tetrahydro-2H- benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-one [000509] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(7-amino-8- chloro-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trif luoroethan-1-one. The title compound was isolated in 90% yield. MS (ESI) m/z: 473.0 [M+H] + . Step 5: 1-(8-chloro-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)-1,3,4,5- tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-on e [000510] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(8-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-1,3,4,5- tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-trifluoroethan-1-on e. The title compound was isolated in 70% yield. Step 6: 1-(8-chloro-7-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifl uoromethyl)pyrimidin-2- yl)amino)-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)-2,2,2-t rifluoroethan-1-one [000511] The title compound was prepared analogously to Example 125, step 5, where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced with 2-bromo-4-(methylsulfonyl)thiophene and 1-(8-chloro-7-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-1,3,4,5-tetrahydro-2 H-benzo[c]azepin-2-yl)-2,2,2- trifluoroethan-1-one. The title compound was isolated in 62% yield. MS (ESI) m/z: 599.1 [M+H] + . Step 7: 8-chloro-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoro methyl)pyrimidin-2-yl)-2,3,4,5- tetrahydro-1H-benzo[c]azepin-7-amine [000512] A solution of 1-(8-chloro-7-((4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1,3,4,5-tetrahydro-2H -benzo[c]azepin-2-yl)-2,2,2-trifluoroethan- 1-one (0.03 mmol) in ethanol (5 mL) and water (1 mL) was treated with potassium carbonate (0.25 mmol). After 10 hours, the solids were filtered and the volatiles removed under reduced pressure. The crude was purified by HPLC to afford the title compound in 7% yield. MS (ESI) m/z: 502.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.77 (s, 1H), 8.31- 8.30 (m, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.79 (s, 1H), 7.21 (s, 1H), 3.91 (s, 2H), 3.29 - 3.20 (m, 2H), 3.16 (s, 3H), 3.06 - 2.95 (m, 2H), 1.85 - 1.74 (m, 2H) Example 128: N-(3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl) -4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine Step 1: tert-butyl 4-(3-cyclopropyl-4-((4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piper idine-1-carboxylate [000513] The title compound was prepared analogously to Example 121, step 4 where tert-butyl 3-(4- chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate was replaced with 4-(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-c yclopropyl-1H-pyrazol-1- yl)piperidine-1-carboxylate. The title compound was isolated in 96% yield. MS (ESI) m/z: 611.9 [M+H] + . Step 2: N-(3-Cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4-(4-(m ethylsulfonyl)thiophen-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine [000514] The title compound was prepared analogously to Example 48, step 5 where tert-butyl 4-(3- cyclopropyl-4-((4-(4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyri din-2-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate was replaced with tert-butyl 4-(3-cyclopropyl-4-((4- (4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-yl)amino)-1H-pyrazol-1-yl)piperidine- 1-carboxylate. The title compound was isolated in 84% yield. MS (ESI) m/z: 513.0 [M+H] + . 1 NMR:(300 MHz, DMSO-d6) δ 0.75 (m, 4H), 1.99 (m, 5H), 2.83 (t, J = 11.7 Hz, 2H), 3.22 (m, 2H), 3.31 (s, 3H), 4.25 (s, 1H), 7.94 (m, 2H), 8.37 (s, 1H), 8.71 (m, 1H), 8.80 (m, 1H), 9.82 (m, 1H). Example 129: N-(3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl) -4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000515] The title compound was prepared analogously to Example 13, step 1 where methyl 5-(2-((7- ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoli n-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxylate was replaced with N-(3-Cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-4- (4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-amine. The title compound was isolated in 43% yield. MS (ESI) m/z: 527.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 0.72 (m, 4H), 1.96 (m, 7H), 2.21 (s, 3H), 2.85 (d, J = 10.9 Hz, 2H), 3.30 (s, 3H), 3.96 (m, 1H), 7.92 (m, 2H), 8.16 (s, 1H), 8.71 (m, 1H), 8.80 (m, 1H), 9.77 (m, 1H). Example 130: N-(1-(azetidin-3-yl)-3-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(me thylsulfonyl)thiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine [000516] The title compound was prepared analogously to Example 123, where 3-methyl-4-nitro-1H- pyrazole was replaced with 3-cyclopropyl-4-nitro-1H-pyrazole in step 1. MS (ESI) m/z: 408.15 [M+H] +. 1 H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.57 (s, 1H), 9.27 (s, 1H), 8.81 (d, J =22.6 Hz, 1H), 8.70 (s, 1H), 8.05 (d, J = 23.5 Hz, 1H), 7.91 (s, 1H), 5.32 (m, 1H), 4.30 (m,4H), 3.31 (s, 3H), 2.08 (m, 1H), 0.83 (m, 4H). Example 131: 6-cyclopropyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trif luoromethyl)pyrimidin- 2-yl)isoindolin-5-amine Step 1: 1-(5-cyclopropyl-6-((4-(4-(methylsulfonyl)thiophen-2-yl)-5-( trifluoromethyl)pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000517] The title compound was prepared analogously to Example 121, step 4 where tert-butyl 3-(4- chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-c yclopropylisoindolin-2-yl)- 2,2,2-trifluoroethan-1-one. The title compound was isolated in 72% yield. MS (ESI) m/z: 575.0 [M-H]-. Step 2: 6-cyclopropyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trif luoromethyl)pyrimidin-2- yl)isoindolin-5-amine [000518] The title compound was prepared analogously to Example 15, step 1 where tert-butyl-(5-(2-((7- chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)thiophen-3-yl)carbamate was replaced with 1-(5-cyclopropyl-6-((4-(4-(methylsulfonyl)thiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)isoindolin-2-yl) -2,2,2-trifluoroethan-1-one. The title compound was isolated in 34% yield. MS (ESI) m/z: 481.15 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.77 (s, 1H), 8.63 (s, 1H), 8.29 (s, 1H), 7.87 (s, 1H), 7.30 (s, 1H), 6.94 (s, 1H), 4.16 (s, 4H), 3.28 (s, 3H), 1.96 (td, J = 8.5, 4.3 Hz, 1H), 0.91 – 0.74 (m, 2H), 0.65 – 0.51 (m, 2H). Example 132: 7-cyclopropyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trif luoromethyl)pyrimidin- 2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine [000519] The title compound was prepared analogously to Example 131, where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-cyclopropylisoindol in-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 7-cyclopropyl-N-(4-methyl-5-(trifluoromethyl)pyrimidin-2-yl) -1,2,3,4- tetrahydroisoquinolin-6-amine. The title compound was isolated. MS (ESI) m/z: 495.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 0.54 (m, 2H), 0.79 (m, 2H), 1.92 (m, 1H), 2.44 (brs, 1H), 2.64 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 5.8 Hz, 2H), 3.28 (s, 3H), 3.79 (s, 2H), 6.63 (s, 1H), 7.10 (brs, 1H), 7.87 (s, 1H), 8.64 (s, 1H), 8.77 (s, 1H), 9.75 (s, 1H). Example 133: 8-chloro-2-methyl-N-(4-(4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-benzo [c]azepin-7-amine [000520] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 8-chloro-N- (4-(4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyri midin-2-yl)-2,3,4,5-tetrahydro-1H- benzo[c]azepin-7-amine. The title compound was isolated in 32% yield. MS (ESI) m/z: 517.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.78 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.82 (s, 1H), 7.24 (s, 1H), 3.83 (s, 2H), 3.16 (s, 3H), 3.09 (d, J = 2.4 Hz, 2H), 3.00 - 2.85 (m, 2H), 2.38 (s, 3H), 1.86 (s, 2H). Example 134: 7-(2-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000521] The title compound was prepared analogously to Example 4, where 1-(7-chloro-6-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli n-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-f luoro-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 1. The title compound was isolated. MS (ESI) m/z: 626.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.13 - 8.97 (m, 2H), 8.92 - 8.84 (m, 2H), 7.89 (s, 1H), 7.57 - 7.50 (m, 1H), 7.28 - 7.23 (m, 1H), 4.31 - 4.27 (m, 2H), 3.93 - 3.89 (m, 2H), 3.70 - 3.65 (m, 2H), 3.43 - 3.39 (m, 2H), 3.02 - 2.97 (m, 2H). Example 135: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 7-Bromo-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide [000522] A 0 °C solution of 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.20 mmol) in DMF (3 mL) was treated with 60% NaH in mineral oil (0.37 mmol). After 30 minutes, ethyl iodide (0.20 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (50% ethyl acetate in hexanes). The title compound was isolated in 55% yield. MS (ESI) m/z: 323.0 [M+H] + . Step 2: 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000523] The title compound was prepared analogously to Example 125, step 5 where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced with 7-bromo-4-ethyl-1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thiaz epin-5-one and 1-[7- chloro-6-[[5-(trifluoromethyl)-4-trimethylstannyl-pyrimidin- 2-yl]amino]-3,4-dihydro-1H-isoquinolin-2- yl]-2,2,2-trifluoro-ethanone. The title compound was isolated in 16% yield. MS (ESI) m/z: 668.0 [M+H] + . Step 3: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-ethyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000524] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-4-ethyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 25% yield. MS (ESI) m/z: 572.0[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.03 (brd, J = 3.2 Hz, 2H), 8.88 (brs, 1H), 7.83 (s, 1H), 7.50 (brd, J = 4.6 Hz, 2H), 4.31 (s, 2H), 3.98 - 3.86 (m, 4H), 3.52 (d, J = 7.2 Hz, 2H), 3.41 (s, 2H), 3.00 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H). Example 136: N-(5-(azetidin-3-yl)-2-methylphenyl)-4-(4-(methylsulfonyl)th iophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine [000525] The title compound was prepared analogously to Example 121, where 3-amino-4- chlorophenylboronic acid was replaced with 3-amino-4-methylphenylboronic acid in step 2. The title compound was isolated. MS (ESI) m/z: 481.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.80 (s, 1H), 8.65 (d, J = 1.4 Hz, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.39 (s, 1H), 7.29 – 7.08 (m, 2H), 3.77 (t, J = 7.4 Hz, 2H), 3.66 (t, J = 7.6 Hz, 1H), 3.29 (d, J = 4.4 Hz, 5H), 2.38 (s, 3H), 2.20 (s, 3H). Example 137: N-(2-Methyl-5-(1-methylazetidin-3-yl)phenyl)-4-(4-(methylsul fonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine [000526] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with N-(5- (azetidin-3-yl)-2-methylphenyl)-4-(4-(methylsulfonyl)thiophe n-2-yl)-5-(trifluoromethyl)pyrimidin-2- amine. The title compound was isolated in 33% yield. m/z (ESI, +ve)= 483.0 [M+H] + 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.80 (s, 1H), 8.65 (d, J = 1.4 Hz, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.39 (s, 1H), 7.29 – 7.08 (m, 2H), 3.77 (t, J = 7.4 Hz, 2H), 3.66 (t, J = 7.6 Hz, 1H), 3.29 (d, J = 4.4 Hz, 5H), 2.38 (s, 3H), 2.20 (s, 3H). Example 138: 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 1-(7-ethyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000527] A mixture of 1-(7-bromo-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-tr ifluoro-ethanone (2.83 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.14 mmol) in dioxane (100 mL), was treated with a 1M solution of diethylzinc in hexanes (8.5 mL) and the resulting solution was stirred at 60 °C for 11 hours. The reaction was cooled down to room temperature, poured into ice- water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (10-50% ethyl acetate in hexanes). The title compound was isolated in 30% yield. 1 H NMR (400MHz, CDCl3) δ 7.77 - 7.74 (m, 1H), 7.18 - 7.12 (m, 1H), 4.87 - 4.77 (m, 2H), 3.94 - 3.85 (m, 2H), 3.06 - 2.97 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 1.31 - 1.24 (m, 3H). Step 2: 1-(6-amino-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000528] The title compound was prepared analogously to Example 19, step 3 where 1-(5-cyclopropyl- 6-nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-ethyl-6-nitro-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 95% yield. 1 H NMR (400MHz, DMSO-d6) δ 6.77 (d, J = 3.6 Hz, 1H), 6.41 (d, J = 4.4 Hz, 1H), 4.82 - 4.72 (m, 2H), 4.59 - 4.53 (m, 2H), 3.75 - 3.69 (m, 2H), 2.77 - 2.67 (m, 2H), 2.40 (q, J = 7.6 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). Step 3: 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-e thyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000529] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(6-amino-7- ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one. The title compound was isolated in 43% yield. MS (ESI) m/z: 453.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.55 - 8.51 (m, 1H), 7.58 - 7.52 (m, 1H), 7.16 (s, 1H), 7.10 - 7.03 (m, 1H), 4.81 - 4.74 (m, 2H), 3.92 - 3.83 (m, 2H), 3.00 - 2.93 (m, 2H), 2.70 - 2.59 (m, 2H), 1.26 - 1.21 (m, 3H). Step 4: 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000530] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one (3.26 mmol), 1,4-bis(diphenylphosphino)butane was replaced with 1-(6-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-7-ethyl-3,4-dihydrois oquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1- one. The title compound was isolated in 23% yield. MS (ESI) m/z: 583.2 [M+H] + . Step 5: 7-(2-((7-ethyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroi soquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000531] The title compound was prepared analogously to Example 125, step 5 where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced with 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7- ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin- 2-yl)amino)-3,4-dihydroisoquinolin-2(1H)- yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 70% yield. MS (ESI) m/z: 634.1 [M+H] + . Step 6: 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin-4-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000532] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 7-(2-((7-ethyl-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 55% yield. MS (ESI) m/z: 538.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.74 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.05 (s, 1H), 7.47 (s, 1H), 7.17 (s, 1H), 4.35 (s, 2H), 3.79 (s, 4H), 3.50 (t, J = 6.4 Hz, 2H), 3.14 (t, J = 6.0 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H). Example 139: 7-(2-((7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000533] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 11% yield. m/z (ESI, +ve)= 542.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 10.18 - 9.95 (m, 1H), 8.96 - 8.81 (m, 2H), 7.91 - 7.83 (m, 1H), 7.60 - 7.50 (m, 1H), 7.28 - 7.21 (m, 1H), 4.60 - 4.20 (m, 2H), 3.95 - 3.89 (m, 2H), 3.75 - 3.60 (m, 2H), 3.30 - 3.21 (m, 2H), 3.12 - 3.05 (m, 2H), 2.94 (s, 3H). Example 140: 7-(2-((7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 7-Bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide [000534] The title compound was prepared analogously to Example 135, step 1 where ethyl iodide was replaced with methyl iodide. The title compound was isolated in 64% yield. m/z (ESI, +ve)= 310.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 3.98 - 3.93 (m, 2H), 3.93 - 3.88 (m, 2H), 3.05 (s, 3H). Step 2: 7-(2-((7-fluoro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000535] The title compound was prepared analogously to Example 125, step 5 where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced with 7-Bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide and 2,2,2-trifluoro-1-(7-fluoro-6-((5-(trifluoromethyl)-4-(trime thylstannyl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)ethan-1-one. The title compound was isolated in 75% yield. MS (ESI) m/z: 638.1 [M+H] + . Step 3: 7-(2-((7-fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide [000536] The title compound was prepared analogously to Example 59, step 6 where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with -(2-((7-fluoro-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 64% yield. MS (ESI) m/z: 542.1 [M+H] + . Step 4: 7-(2-((7-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000537] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- fluoro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 22% yield. m/z (ESI, +ve)= 556.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (br s, 1H), 10.07 (br s, 1H), 8.91 (s, 1H), 7.85 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 10.8 Hz, 1H), 4.59 - 4.42 (m, 1H), 4.38 - 4.21 (m, 1H), 4.01 - 3.94 (m, 2H), 3.93 - 3.86 (m, 2H), 3.77 - 3.63 (m, 1H), 3.44 - 3.39 (m, 1H), 3.14 - 3.03 (m, 5H), 2.96 (s, 3H). Example 141: 7-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: tert-butyl 4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate [000538] The title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2- yl)-2,2,2-trifluoroethan-1-one was replaced with tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-c yclopropyl-1H-pyrazol-1- yl)piperidine-1-carboxylate. The title compound was isolated in 28% yield. m/z (ESI, +ve)= 617.2 [M+H] + . Step 2: tert-butyl 4-(3-cyclopropyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5-t etrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)-1H-pyrazol-1-yl)piperidine-1- [000539] The title compound was prepared analogously to Example 125, step 5 where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced with 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide and tert-butyl 4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)piperidine-1-carboxylate. The title compound was isolated in 48% yield. m/z: 682.1 [M+H] + . Step 3: 7-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000540] The title compound was prepared analogously to Example 64, step 2 where methyl 3-((2-((tert- butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2-carboxylate was replaced with tert-butyl 4-(3- cyclopropyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5-tetrah ydrothieno[2,3-f][1,4]thiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piper idine-1-carboxylate. The title compound was isolated in 48% yield. m/z: 582.1 [M+H] +. 1 H NMR (400MHz, methanol-d4) δ 8.77 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 4.49-4.44 (m, 1H), 4.00-3.98 (m, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.59 (d, J = 12.8 Hz, 2H), 3.28-3.24 (m, 2H), 3.21 (s, 3H), 2.42-2.39 (m, 2H), 2.27 (d, J = 10.8 Hz, 2H), 1.96-1.91 (m, 1H), 0.91 (d, J = 8.4 Hz, 2H), 0.82 (d, J = 3.2 Hz, 2H). Example 142: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000541] The title compound was prepared analogously to Example 17, where 5-(2-((6- chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxamide was replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide. The title compound was isolated . m/z (ESI, +ve)= 586.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 10.02 - 9.84 (m, 1H), 8.91 - 8.85 (m, 1H), 7.84 (s, 1H), 7.56 - 7.51 (m, 1H), 7.49 (s, 1H), 3.96 - 3.86 (m, 4H), 3.55 - 3.49 (m, 2H), 3.12 - 3.04 (m, 2H), 2.99 - 2.89 (m, 3H), 2.57 - 2.54 (m, 4H), 1.16 (t, J = 7.6 Hz, 3H). Example 143: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide Step 1: 7-bromo-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1- dioxide [000542] The title compound was prepared analogously to Example 158, step 1 where bromocyclobutane was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonate. The title compound was isolated in 68% yield. MS (ESI) m/z: 377.9 [M+H] + . Step 2: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]th iazepin-5(2H)-one 1,1-dioxide [000543] The title compound was prepared analogously to Example 135, where ethyl iodide was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonate in step 1, and 7-bromo-4-ethyl-1,1-dioxo- 2,3-dihydrothieno[2,3-f][1,4]thiazepin-5-one was replaced with 7-bromo-4-(2,2,2-trifluoroethyl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 2. The title compound was isolated. m/z (ESI, +ve)= 626.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.15 - 8.99 (m, 1H), 8.90 (s, 1H), 7.86 (s, 1H), 7.53 - 7.48 (m, 2H), 4.48 - 4.40 (m, 2H), 4.34 - 4.28 (m, 2H), 4.12 - 4.04 (m, 2H), 3.98 - 3.92 (m, 2H), 3.45 - 3.41 (m, 2H), 3.04 - 2.97 (m, 2H). Example 144: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000544] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-4-(2,2,2- trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide. The title compound was isolated in 43% yield. m/z (ESI, +ve)= 640.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 10.00 (br s, 1H), 8.91 (s, 1H), 7.86 (s, 1H), 7.54 - 7.49 (m, 2H), 4.59 - 4.50 (m, 1H), 4.48 - 4.40 (m, 2H), 4.37 - 4.27 (m, 1H), 4.11 - 4.05 (m, 2H), 3.98 - 3.92 (m, 2H), 3.75 - 3.65 (m, 1H), 3.46 - 3.41 (m, 1H), 3.13 - 3.04 (m, 2H), 2.96 (s, 3H). Example 145: N-(3-cyclopropyl-1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)- 4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000545] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with N-(1- (azetidin-3-yl)-3-cyclopropyl-1H-pyrazol-4-yl)-4-(4-(methyls ulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine. The title compound was isolated in 9% yield. m/z (ESI, +ve)= 499.5 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.85 (d, J = 82.2 Hz, 1H), 8.88 – 8.67 (m, 2H), 8.16 (s, 1H), 7.94 (d, J = 14.3 Hz, 1H), 4.83 (q, J = 6.8 Hz, 1H), 3.70 (t, J = 7.3 Hz, 3H), 3.31 (s, 3H), 2.35 (s, 3H), 2.09 – 1.86 (m, 1H), 0.87 – 0.68 (m, 4H). Example 146: 7-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000546] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 45% yield. m/z (ESI, +ve)= 552.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.71 (s, 1H), 8.52 (s, 1H), 8.06 - 7.98 (m, 1H), 7.36 (d, J = 5.2 Hz, 1H), 7.07 (s, 1H), 3.93 (s, 2H), 3.78 (s, 4H), 3.07 (s, 4H), 2.72 - 2.60 (m, 5H), 1.21 - 1.14 (m, 3H). Example 147: 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000547] The title compound was prepared analogously to Example 138, where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 5. The title compound was isolated in 44% yield. m/z (ESI, +ve)= 552.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.73 (s, 1H), 7.99 (s, 1H), 7.43 (s, 1H), 7.16 (s, 1H), 4.32 (s, 2H), 3.98 - 3.90 (m, 2H), 3.89 - 3.81 (m, 2H), 3.47 (t, J = 5.6 Hz, 2H), 3.19 (s, 3H), 3.11 (s, 2H), 2.68 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). Example 148: 7-(2-((7-ethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000548] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 69% yield. m/z (ESI, +ve)= 566.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.70 (s, 1H), 8.51 (s, 1H), 7.98 (s, 1H), 7.34 (s, 1H), 7.07 (s, 1H), 3.92 (s, 4H), 3.87 - 3.81 (m, 2H), 3.18 (s, 3H), 3.06 (s, 4H), 2.70 - 2.61 (m, 5H), 1.17 (t, J = 7.6 Hz, 3H). Example 149: 7-(2-((2-chloro-5-(piperidin-4-yl)phenyl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 4-(3-amino-4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxy late [000549] A solution of 5-bromo-2-chloroaniline (0.48 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.58 mmol), bis-triphenylphosphine- palladium(II) chloride (0.05 mmol), sodium carbonate (2.4 mmol) in DMF (2mL) and water (1.2 mL) was refluxed for 1 hour. The reaction was cooled down to room temperature and concentrated. The crude product was purified by preparative TLC (30% ethyl acetate in hexanes) to afford the title compound in [000550] A solution of tert-butyl 4-(3-amino-4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxy late (9.71 mmol) in methanol (60 mL) was hydrogenated for 15 minutes in the presence of 10% Pd on carbon (600 mg). After filtration through celite and evaporation of volatiles, the crude product was purified by silica gel chromatography (10-20% ethyl acetate in hexanes) to afford the title compound in 50% yield. Step 3: tert-butyl 4-(4-chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)piperidine-1-carboxylate [000551] The title compound was prepared analogously to tert-butyl 3-(4-chloro-3-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino) phenyl)azetidine-1-carboxylate where tert-butyl 3-(3-amino-4- chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 4-(3-amino-4- chlorophenyl)piperidine-1-carboxylate. The title compound was isolated in 63% yield. Step 4: tert-butyl 4-(4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2- yl)amino)phenyl)piperidine-1-carboxylate [000552] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-on was replaced with tert-butyl 4-(4-chloro-3-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)piperidine-1-carboxylate. The title compound was isolated in 53% yield. Step 5: 7-(2-((2-chloro-5-(piperidin-4-yl)phenyl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000553] The title compound was prepared analogously to Example 125, step 5, where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced with tert-butyl 4-(4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2- yl)amino)phenyl)piperidine-1-carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide. The title compound was isolated in 53% yield. MS (ESI) m/z: 585.9 [M+H- Boc] + . Step 6: 7-(2-((2-chloro-5-(piperidin-4-yl)phenyl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000554] A solution of 7-(2-((2-chloro-5-(piperidin-4-yl)phenyl)amino)-5-(trifluoro methyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide (0.10 mmol) in dichloromethane (2 mL) and TFA (1mL) was stirred for one hour. Evaporation of the volatiles under reduced pressure and purification of the resulting crude material by HPLC, afforded the title compound in 3% yield. MS (ESI) m/z: 585.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1 H), 8.11 (s, 1 H), 8.05 (s, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.12 (dd, J = 8.4, 2.0 Hz, 1 H), 3.99 - 3.96 (m, 2 H), 3.90 - 3.87 (m, 2 H), 3.57 (d, J = 12.4 Hz, 2 H), 3.23 - 3.17 (m, 5H), 3.07 - 3.03 (m, 1 H), 2.20 - 2.16 (m, 2 H), 2.04 - 2.00 (m, 2 H). Example 150: 7-(2-((2-chloro-5-(1-methylpiperidin-4-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000555] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with -(2-((2- chloro-5-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)py rimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 54% yield. m/z (ESI, +ve)= 598.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1 H), 8.16 (s, 1 H), 8.06 (s, 1 H), 7.77 - 7.73 (m, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.12 (dd, J = 8.4, 2.0 Hz, 1 H), 4.01 - 3.98 (m, 2 H), 3.91 - 3.88 (m, 2 H), 3.68 (d, J = 12.4 Hz, 2 H), 3.22 - 3.19 (m, 5 H), 3.01 - 2.96 (m, 1 H), 2.96 (s, 3 H), 2.24 - 2.21 (m, 2 H), 2.11 - 2.08 (m, 2 H). Example 151: 7-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 4-(3-cyclopropyl-4-((4-(1,1-dioxido-5-oxo-2,3,4,5-tetrahydro thieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)-1H-pyrazol-1-yl)piperidine-1- [000556] The title compound was prepared analogously to Example 141, where 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 47% yield. Step 2: 7-(2-((3-cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000557] The title compound was prepared analogously to Example 149, step 5 where 7-(2-((2-chloro-5- (piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 4-(3-cyclopropyl-4-((4-(1,1-dioxido- 5-oxo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)piperidine-1-carboxylate. The title compound was isolated in 88% yield. m/z (ESI, +ve)= 568.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.72 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 4.46-4.41 (m, 1H), 3.83 (s, 4H), 3.58 (d, J = 12.8 Hz, 2H), 3.23 (t, J = 12.4 Hz, 2H), 2.41-2.22 (m, 4H), 1.96-1.91 (m, 1H), 0.92-0.82 (m, 4H). Example 152: 7-(2-((3-cyclopropyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000558] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((3- cyclopropyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(tri fluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 38% yield. m/z (ESI, +ve)= 582.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.75 (s, 1H), 8.51 (s, 0.9H), 8.13 (s, 1H), 8.06 (s, 1H), 4.32-4.26 (m, 1H), 3.81 (s, 4H), 3.38 (d, J = 11.6 Hz, 2H), 2.85 (t, J = 11.2 Hz, 2H), 2.69 (s, 3H), 2.35-2.27 (m, 2H), 2.25-2.18 (m, 2H), 1.94-1.89 (m, 1H), 0.91-0.89 (m, 2H), 0.82 (d, J = 2.8 Hz, 2H). Example 153: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(cyclopropylmethyl)-3,4-d ihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide Step 1: 7-Bromo-4-(cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]t hiazepin-5(2H)-one 1,1- dioxide [000559] The title compound was prepared analogously to Example 135, step 1 where ethyl iodide was replaced with (bromomethyl)cyclopropane. The title compound was isolated in 52% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 4.00 - 3.95 (m, 2H), 3.94 - 3.90 (m, 2H), 3.48 - 3.41 (m, 1H), 3.30 - 3.26 (m, 1H), 1.10 - 0.99 (m, 1H), 0.54 - 0.47 (m, 2H), 0.32 - 0.27 (m, 2H). Steps 2-3: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-4-(cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thi azepin-5(2H)-one 1,1-dioxide [000560] The title compound was prepared analogously to Example 135, steps 2-3, where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- (cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide in step 2. The title compound was isolated. m/z (ESI, +ve)= 626.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.13 - 9.06 (m, 1H), 8.89 (s, 1H), 7.85 (s, 1H), 7.54 - 7.46 (m, 2H), 4.35 - 4.27 (m, 2H), 3.99 - 3.93 (m, 4H), 3.43 - 3.37 (m, 4H), 3.06 - 2.95 (m, 2H), 1.12 - 1.03 (m, 1H), 0.56 - 0.49 (m, 2H), 0.36 - 0.29 (m, 2H). Example 154: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(cyclopropylmethyl)-3,4-d ihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000561] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-4- (cyclopropylmethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide. The title compound was isolated in 52% yield. m/z (ESI, +ve)= 612.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 10.09 (brs, 1H), 8.90 (brs, 1H), 7.85 (s, 1H), 7.56 - 7.51 (m, 1H), 7.49 (s, 1H), 4.62 - 4.44 (m, 1H), 4.40 - 4.25 (m, 1H), 4.00 - 3.91 (m, 4H), 3.76 - 3.63 (m, 1H), 3.51 - 3.44 (m, 1H), 3.16 - 3.05 (m, 2H), 2.96 (s, 3H), 2.55 - 2.52 (m, 2H), 1.13 - 1.01 (m, 1H), 0.57 - 0.49 (m, 2H), 0.36 - 0.27 (m, 2H). Example 155: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide [000562] A mixture of 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (2.8 mmol), cyclopropylboronic acid (8.3 mmol), copper diacetate (2.8 mmol), pyridine (13.8 mmol) and 4A molecular sieves (1.8 g) in 1,2-dichloroethane (6 mL) was stirred at 80 °C for 12 hours under air. Additional copper acetate was added (2.8 mmol) and stirring continued at 80 °C for another 12 hours. The mixture was cooled down, filtered, and concentrated to afford a residue that was purified by preparative TLC (66% ethyl acetate in hexanes). The title compound was isolated in 17% yield. MS (ESI) m/z: 258.1[M+H] + . Step 2: 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide [000563] A solution of 4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide (0.85 mmol) in acetic acid (2 mL) was treated with N-bromosuccinimide (1.71 mmol) and sulfuric acid (8.6 mmol). The mixture was stirred at 60 °C for 12 hours, cooled down to room temperature and poured over ice-water. The solution was extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (70% ethyl acetate in hexanes). The title compound was isolated in 84% yield. MS (ESI) m/z: 336.0 [M+H] + . [000564] Step 3: 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000565] A solution of 1-(7-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (0.03 mmol) and 7-bromo-4-cyclopropyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.03 mmol) in dioxane (1 mL) was treated with copper (I) iodide (0.03 mmol) and tetrakis[triphenylphosphine]palladium (0) (0.003 mmol). The mixture was heated at 120 °C for 12 hours, cooled down to room temperature and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (66% ethyl acetate in hexanes). The title compound was isolated in 46% yield. MS (ESI) m/z: 680.3[M+H] + . Step 4: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2 H)-one 1,1-dioxide [000566] A mixture of 7-(2-((7-chloro-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro isoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3 ,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide (0.01 mmol) and potassium carbonate (0.09 mmol) in acetonitrile (2 mL) and water (0.5 mL) was stirred at room temperature for 12 hours. After evaporation of volatiles, the crude product was purified by preparative HPLC to afford the title compound in 91% yield. MS (ESI) m/z: 584.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.80 (s, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.31 (s, 1H), 4.15 (s, 2H), 4.02 - 3.95 (m, 2H), 3.80 - 3.75 (m, 2H), 3.34 - 3.32 (m, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.94 - 2.86 (m, 1H), 0.93 - 0.89 (m, 4H). Example 156: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000567] The title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated in 68% yield. MS (ESI) m/z: 557.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.10 - 9.06 (m, 1H), 8.88 (s, 1H), 7.84 (s, 1H), 7.51 (s, 2H), 4.34 - 4.27 (m, 2H), 3.99 - 3.94 (m, 2H), 3.92 - 3.87 (m, 2H), 3.44 - 3.39 (m, 2H), 3.10 - 3.06 (m, 3H), 3.03 - 2.97 (m, 2H). Example 157: 7-(2-((6-fluoroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000568] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 2,2,2-trifluoro-1-(5-fluoro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)isoindolin-2-yl)ethan -1-one and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 528.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 8.03 (s, 1 H), 7.34 (d, J = 10.4 Hz, 1H), 4.65 (d, J = 6.4 Hz, 4H), 3.96 (d, J = 5.6 Hz, 2H), 3.89 - 3.88 (m, 2H), 3.20 (s, 3H). Example 158: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothi eno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 7-bromo-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000569] A -20 °C solution of 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.34 mmol) in DMF (2.5 mL) was treated with 60% NaH (0.51 mmol). After 30 minutes, bromocyclobutane (1.0 mmol) was added and the reaction as stirred at 80 °C for 12 hours. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (50% ethyl acetate in hexanes). The title compound was isolated in 15% yield. MS (ESI) m/z: 350.0 [M+H] + . Steps 2-3: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5( 2H)-one 1,1-dioxide [000570] The title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated in 54% yield. MS (ESI) m/z: 598.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.04 - 9.00 (m, 1H), 8.92 - 8.84 (m, 1H), 7.86 - 7.81 (m, 1H), 7.53 - 7.46 (m, 2H), 4.73 - 4.60 (m, 1H), 4.34 - 4.25 (m, 2H), 3.98 - 3.84 (m, 4H), 3.44 - 3.41 (m, 2H), 3.04 - 2.96 (m, 2H), 2.27 - 2.18 (m, 2H), 2.17 - 2.09 (m, 2H), 1.73 - 1.60 (m, 2H). Example 159: 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000571] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(7-amino-6- chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan -1-one. The title compound was isolated in 32% yield. MS (ESI) m/z: 459.0 [M+H] + . Step 2: 1-(6-chloro-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000572] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 26% yield after purification by neutral alumina. MS (ESI) m/z: 589.0 [M+H] + . Step 3-4: 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide [000573] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-chloro-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated in 58% yield. MS (ESI) m/z: 694.0 [M+H] + . Example 160: 7-(2-((6-ethylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyri midin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 4-methyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]t hiazepin-5(2H)-one 1,1-dioxide [000574] A mixture of 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide (2.9 mmol), hexamethylditin (5.8 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.14 mmol) in dioxane (10 mL) was stirred at 90 °C for 12 hours. The reaction was concentrated under reduced pressure and the crude material purified by silica gel chromatography (0-100% ethyl acetate) to afford the title compound in 35% yield. MS (ESI) m/z: 395.90 [M+H] + . Steps 2 and 3: 7-(2-((6-ethylisoindolin-5-yl)amino)-5-(trifluoromethyl)pyri midin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000575] The title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one were replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6- ethylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one and 4-methyl-7-(trimethylstannyl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 536.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.80 (s, 1H), 7.81 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 4.06 (m, 4H), 3.96 (bs, 2H), 3.89 (bs, 2H), 3.08 (s, 3H), 2.59 (q, J = 7.4 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H). Example 161: 4-methyl-7-(2-((7-(methylthio)-1,2,3,4-tetrahydroisoquinolin -6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000576] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 4-methyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]t hiazepin-5(2H)- one 1,1-dioxide and 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-( methylthio)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 570.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 8.82 (s, 1H), 7.82 (s, 1H), 7.09 (d, J = 21.0 Hz, 2H), 3.96 (d, J = 5.8 Hz, 2H), 3.93 – 3.82 (m, 5H), 3.08 (d, J = 3.5 Hz, 3H), 2.96 (t, J = 5.8 Hz, 2H), 2.70 – 2.64 (m, 2H), 2.37 (s, 3H). Example 162: 7-(2-((7-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000577] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide and acetaldehyde. The title compound was isolated in 69% yield. m/z (ESI, +ve)= 585.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (br s, 1H), 8.85 (s, 1H), 7.82 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 3.98 - 3.94 (m, 2H), 3.90 - 3.86 (m, 2H), 3.57 - 3.53 (m, 2H), 3.07 (s, 3H), 2.83 - 2.78 (m, 2H), 2.66 - 2.63 (m, 2H), 2.60 - 2.56 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). Example 163: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e ][1,4]oxathiepine 1,1-dioxide Step 1: 2-((3-bromothiophen-2-yl)methoxy)ethan-1-ol [000578] To a solution of ethane-1,2-diol (135 mmol) in dimethylsulfoxide (50 mL) was added potassium tert-butoxide (35 mmol) and 3-bromo-2-(chloromethyl)thiophene (27 mmol). A solution of tetrabutylammonium iodide (2.69 mmol) in dimethylsulfoxide (10 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (17% ethyl acetate in hexanes). The title compound was isolated in 58% yield. Step 2: S-(2-((3-bromothiophen-2-yl)methoxy)ethyl) ethanethioate [000579] To a 0 °C solution of triphenylphosphine (31 mmol) in THF (20 mL) was added dropwise a solution of diisopropylazodicarboxylate (31 mmol) in THF (8 mL). After 1 hour, a solution of 2-((3- bromothiophen-2-yl)methoxy)ethan-1-ol (16 mmol) in THF (8 mL) was added dropwise at 0 °C, followed by ethanethioic S-acid (31 mmol). The reaction was stirred at room temperature for 2 hours and the volatiles were removed under reduced pressure. The crude material was purified by preparative TLC (9% ethyl acetate in hexanes). The title compound was isolated in 39% yield. Step 3: 2-((3-Bromothiophen-2-yl)methoxy)ethane-1-thiol [000580] A solution of S-(2-((3-bromothiophen-2-yl)methoxy)ethyl) ethanethioate (6.1 mmol) in methanol (1 mL) was treated with 1M aqueous NaOH (18 mmol). After 1 hour the reaction was concentrated to afford the title compound. This material was used in the next step without further purification. MS (ESI) m/z: 252.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 7.30 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 5.2 Hz, 1H), 4.69 (s, 2H), 3.67 (t, J = 6.4 Hz, 2H), 2.76 - 2.70 (m, 2H), 1.63 (t, J = 8.0 Hz, 1H). Step 4: 2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine [000581] A solution of 2-((3-bromothiophen-2-yl)methoxy)ethane-1-thiol (4.7 mmol), N,N- diisopropylethylamine (14 mmol), tris(dibenzylidenacetone)dipalladium (0.47 mmol) and Xantphos (0.47 mmol) in dioxane (20 mL) was stirred at 120 °C for 8 hours. After evaporation of volatiles under reduced pressure, the residue was purified by silica gel chromatography (9% ethyl acetate in hexanes). The title compound was isolated in 53% yield. Step 5: 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine [000582] The title compound was prepared analogously to Example 125, step 4, where 3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 2,3-dihydro-5H-thieno[3,2- e][1,4]oxathiepine. The title compound was isolated in 34% yield. 1 H NMR (400 MHz, CDCl 3 ) δ = 6.97 (s, 1H), 4.70 (s, 2H), 4.22 - 4.20 (m, 2H), 2.82 - 2.80 (m, 2H). Step 6: 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide [000583] To a 0 °C solution of 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine (0.80 mmol) in dichloromethane (1 mL) was added meta-chloroperoxybenzoic acid (0.74 mmol). After 20 minutes, the reaction was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (25 % ethyl acetate in hexanes). The title compound was isolated in 66% yield. Step 7 and 8: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e ][1,4]oxathiepine 1,1-dioxide [000584] The title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo- 2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 531.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.75 (s, 1H), 8.14 (s, 2H), 7.74 (s, 1H), 7.13 (s, 1H), 5.00 (s, 2H), 4.47 - 4.44 (m, 2H), 4.03 (s, 2H), 3.45 - 3.43 (m, 2H), 3.22 - 3.19 (m, 2H), 2.91 - 2.88 (m, 2H), 1.36 - 1.25 (m, 1H). Example 164: 7-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 1-(5-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)isoindolin-2- yl)-2,2,2-trifluoroethan-1-one [000585] The title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2- yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-chloro-6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)isoindolin-2-yl)-2,2,2- trifluoroethan-1-one. The title compound was isolated in 32% yield. MS (ESI) m/z: 574.9 [M+H] + . Step 2: 7-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000586] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(5-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 544.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.79 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.35 (s, 1H), 4.34 (d, J = 1.1 Hz, 2H), 4.26 (s, 2H), 3.96 - 3.90 (m, 2H), 3.75 (s, 2H), 3.26 (s, 3H), 1.30 - 1.24 (m, 1H). Example 165: 7-(2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-m ethyl-1H-pyrazol-1- yl)piperidine-1-carboxylate [000587] The title compound was prepared analogously to Example 123 (steps 1-3), where 1-Boc-3- hydroxyazetidine was replaced with tert-butyl 4-hydroxypiperidine-1-carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 405.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.61 - 8.43 (m, 1H), 7.79 (s, 1H), 7.43 (s, 1H), 4.47 - 4.19 (m, 1H), 4.04 (d, J = 10.5 Hz, 2H), 2.90 (s, 2H), 2.13 (s, 1H), 2.00 (s, 3H), 1.94 - 1.65 (m, 3H), 1.50 - 1.32 (m, 9H). Step 2: tert-butyl 4-(3-methyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)- 1H-pyrazol-1-yl)piperidine-1-carboxylate [000588] The title compound was prepared analogously to Example 160, step 1, where 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 4-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl -1H-pyrazol-1-yl)piperidine-1-carboxylate. The title compound was isolated in 42% yield. MS (ESI) m/z: 591.2 [M+H] + . Step 3: 7-(2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000589] The title compound was prepared analogously to Example 149, steps 4-5, where tert-butyl 4- (4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimi din-2-yl)amino)phenyl)piperidine-1- carboxylate and 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with tert-butyl 4-(3-methyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)-1H- pyrazol-1-yl)piperidine-1-carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide in step 4. The title compound was isolated. MS (ESI) m/z: 542.2[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.58 (d, J = 0.8 Hz, 1H), 8.10 (s, 1H), 7.91 (s, 1H), 4.27 (m, 1H), 3.78 (s, 4H), 3.23 (m, 2H), 2.86 - 2.75 (m, 2H), 2.18 (s, 5H), 2.02 - 1.91 (m, 2H). Example 166: 4-methyl-7-(2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000590] The title compound was prepared analogously to Example 149, steps 4-5, where tert-butyl 4- (4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimi din-2-yl)amino)phenyl)piperidine-1- carboxylate was replaced with tert-butyl 4-(3-methyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)pipe ridine-1-carboxylate and 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 4. The title compound was isolated. MS (ESI) m/z: 556.0[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.56 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 4.34 - 4.26 m, 1H), 3.98 - 3.89 (m, 2H), 3.84 - 3.76 (m, 2H), 3.16 (s, 3H), 3.03 - 2.71 (m, 2H), 2.21 ( d, J = 11.6 Hz, 2H), 2.16 (s, 3H), 2.06 - 1.96 (m, 2H), 1.27 (s, 2H). Example 167: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000591] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 83% yield. m/z (ESI, +ve)= 598.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.78 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.25 (s, 1H), 3.97 (t, J = 6.0 Hz, 2H), 3.80 - 3.75 (m, 2H), 3.62 (s, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.94 - 2.87 (m, 1H), 2.81 - 2.75 (m, 2H), 2.47 (s, 3H), 0.93 - 0.89 (m, 4H). Example 168: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothi eno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000592] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 28% yield. m/z (ESI, +ve)= 612.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.87 (s, 1H), 7.83 (s, 1H), 7.34 (s, 1H), 7.28 (s, 1H), 4.72 - 4.63 (m, 1H), 3.94 - 3.89 (m, 2H), 3.88 - 3.81 (m, 2H), 3.54 - 3.49 (m, 2H), 2.87 - 2.79 (m, 2H), 2.65 - 2.58 (m, 2H), 2.39 - 2.34 (m, 3H), 2.24 - 2.18 (m, 2H), 2.17 - 2.12 (m, 2H), 1.71 - 1.63 (m, 2H). Example 169: 7-(2-((7-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothi eno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000593] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((7- chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 50% yield. m/z (ESI, +ve)= 572.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (br s, 1H), 8.85 (s, 1H), 7.82 (br s, 1H), 7.32 (s, 1H), 7.31 - 7.27 (m, 1H), 3.99 - 3.94 (m, 2H), 3.91 - 3.85 (m, 2H), 3.49 - 3.46 (m, 2H), 3.08 - 3.06 (m, 3H), 2.87 - 2.81 (m, 2H), 2.61 - 2.59 (m, 2H), 2.34 (s, 3H). Example 170: 7-(2-((4-cyclopropylisoindolin-5-yl)amino)-5-(trifluoromethy l)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 1-(5-amino-4-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e [000594] To a 0 °C solution 1-(5-aminoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one (27 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (27 mmol) and the reaction mixture was stirred for 2 hours. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (5-10% ethyl acetate in hexanes) to afford the title compound in 50% yield. MS (ESI) m/z: 308.9 [M+H] +.1 H NMR (400 MHz, DMSO-d6) 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J = 8.8 Hz, 1H), 7.19 - 6.96 (m, 1H), 6.85 - 6.66 (m, 1H), 5.41 (d, J = 13.0 Hz, 2H), 5.02 - 4.81 (m, 2H), 4.80 - 4.56 (m, 2H). Step 2: 1-(5-amino-4-cyclopropylisoindolin-2-yl)-2,2,2-trifluoroetha n-1-one [000595] The title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne and ethylboronic acid were replaced with 1-(5-amino-4-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e, and potassium cyclopropyltrifluoroborate. The title compound was isolated in 19% yield. MS (ESI) m/z: 271.1 [M+H] + . Step 3: 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-c yclopropylisoindolin-2-yl)- 2,2,2-trifluoroethan-1-one [000596] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(5-amino-4- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 50% yield. MS (ESI) m/z: 451.0[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 8.93-8.55 (m, 1H), 8.11-8.07 (m, 1H), 7.24- 7.09 (m, 1H), 5.04-4.98 (m, 2H), 4.91-4.85 (m, 2H), 1.80-1.72 (m, 1H), 1.16-1.07 (m, 2H), 0.70-0.61 (m, 2H). Step 4: 1-(4-cyclopropyl-5-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one [000597] The title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2- yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4-c yclopropylisoindolin-2-yl)-2,2,2- trifluoroethan-1-one. The title compound was isolated in 24% yield. MS (ESI) m/z: 580.9[M+H] + . Step 5: 7-(2-((4-cyclopropylisoindolin-5-yl)amino)-5-(trifluoromethy l)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000598] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(4-cyclopropyl-5-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 550.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.73 (s, 1H), 7.99 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.36 (s, 2H), 4.23 (s, 2H), 3.95-3.92 (m, 2H), 3.86-3.83 (m, 2H), 3.18 (s, 3H), 1.83-1.76 (m, 1H), 0.91-0.86 (m, 2H), 0.55-0.51 (m, 2H). Example 171: 4-methyl-7-(2-((2-methyl-7-(methylthio)-1,2,3,4-tetrahydrois oquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000599] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 4-methyl-7- (2-((7-(methylthio)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )-5-(trifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 16% yield. MS (ESI) m/z= 584.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.82 (s, 1H), 7.81 (s, 1H), 7.16 (s, 1H), 7.09 (s, 1H), 3.95 (d, J = 5.5 Hz, 2H), 3.89 (s, 2H), 3.51 (s, 2H), 3.07 (s, 3H), 2.80 (s, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.36 (d, J = 5.1 Hz, 5H). Example 172: 7-(2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000600] The title compound was prepared analogously to Example 123, where 1-Boc-3- hydroxyazetidine was replaced with tert-butyl (2-hydroxyethyl)(methyl)carbamate in step 1 and trimethyl(4-(methylsulfonyl)thiophen-2-yl)stannane with 4-methyl-7-(trimethylstannyl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 4. The title compound was isolated. MS (ESI) m/z= 528.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.80 (d, J = 69.8 Hz, 1H), 8.82 (d, J = 12.9 Hz, 1H), 8.00 – 7.75 (m, 2H), 4.07 (t, J = 6.4 Hz, 2H), 4.02 – 3.95 (m, 2H), 3.89 (d, J = 6.1 Hz, 2H), 3.08 (d, J = 6.6 Hz, 3H), 2.85 (q, J = 6.5 Hz, 2H), 2.28 (s, 3H), 2.13 (d, J = 6.8 Hz, 3H). Example 173: 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroe than-1-one [000601] To a solution of 7-bromo-1,2,3,4-tetrahydroisoquinoline (60 mmol) in dichloromethane (150 mL) was added pyridine (181 mmol), followed by dimethylaminopyridine (3.0 mmol) and trifluoroacetic anhydride (72 mmol). The mixture was stirred for 2 hours, quenched with water, and extracted with dichloromethane three times. The combined organic layers were washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated to afford a residue that was purified by silica gel chromatography (0-12% ethyl acetate in hexanes). The title compound was isolated in 97% yield. MS (ESI) m/z: 309.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ = 7.65 - 7.21 (m, 2H), 7.21 - 6.98 (m, 1H), 4.79 - 4.69 (m, 2H), 3.85 - 3.74 (m, 2H), 2.86 (q, J = 5.6 Hz, 2H). Step 2: 1-(7-bromo-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000602] The title compound was prepared analogously to Example 1, step 3, where 1-(7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(7-bromo-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 80% yield. MS (ESI) m/z: 353.09 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 17.6 Hz, 2H), 4.92 - 4.78 (m, 2H), 3.86 - 3.78 (m, 2H), 3.01 - 2.92 (m, 2H). Step 3: 1-(7-cyclopropyl-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2, 2,2-trifluoroethan-1-one [000603] A mixture of 1-(7-bromo-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-tr ifluoro-ethanone (8.10 mmol), cyclopropylboronic acid (32 mmol), tricyclohexylphosphane (1.61 mmol), diacetoxypalladium (0.81 mmol) and potassium phosphate (32.3 mmol) in toluene (30 mL) was stirred at 110 °C for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative TLC (25% ethyl acetate in hexanes) to afford the title compound in 20% yield. 1 H NMR (400MHz, CDCl3) δ 7.71 - 7.66 (m, 1H), 6.98 - 6.92 (m, 1H), 4.86 - 4.73 (m, 2H), 3.89 (td, J = 6.0, 18.0 Hz, 2H), 3.06 - 2.95 (m, 2H), 2.44 - 2.33 (m, 1H), 1.11 - 1.02 (m, 2H), 0.73 - 0.64 (m, 2H). Step 4: 1-(6-amino-7-cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2, 2,2-trifluoroethan-1-one [000604] To a solution of 1-(7-cyclopropyl-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2, 2,2-trifluoro- ethanone (1.91 mmol) in a mixture of ethanol (5.6 mL) and water (1.4 mL) was added iron powder (9.55 mmol) and ammonium chloride (9.55 mmol). The mixture was stirred at 70 °C for 2 hours, cooled down to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography (0- 32% ethyl acetate in hexanes) to afford the title compound in 65% yield. MS (ESI) m/z: 285.0[M+H] + . Step 5: 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-c yclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000605] A mixture of 1-(6-amino-7-cyclopropyl-3,4-dihydro-1H-isoquinolin-2-yl)-2, 2,2-trifluoro- ethanone (1.23 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (6.16 mmol) was stirred at 70 °C for 12 hours. The reaction was cooled down to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography (0-32% ethyl acetate in hexanes) to afford the title compound in 52% yield. MS (ESI) m/z: 465.1[M+H] + . Step 6: 1-(7-cyclopropyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000606] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-c yclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 16% yield. MS (ESI) m/z: 595.1 [M+H] + . Steps 7-8: 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000607] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 4-methyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]t hiazepin-5(2H)- one 1,1-dioxide and 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-c yclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 564.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 0.55 (m, 2H), 0.79 (m, 2H), 1.92 (m, 1H), 2.64 (t, J = 5.8 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H), 3.07 (s, 3H), 3.79 (s, 2H), 3.89 (m, 2H), 3.95 (m, 2H), 6.64 (s, 1H), 7.10 (s, 1H), 7.81 (s, 1H), 8.80 (s, 1H), 9.84 (s, 1H). Example 174: 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethylphenyl)piperazine-1-carboxylate [000608] The title compound was prepared analogously to Example 121, step 3, where tert-butyl 3-(3- amino-4-chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 4-(4-amino-3- ethylphenyl)piperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 485.9 [M+H] + Step 2: tert-butyl 4-(3-ethyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5-tetrahy drothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)piperazine-1-carboxylate [000609] The title compound was prepared analogously to Example 155, step 3, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one were replaced with tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-ethylphenyl)piperazine-1-carboxylate and 4-methyl-7-(trimethylstannyl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated in 83% yield. MS (ESI) m/z: 681.2 [M+H] + . Step 3: 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000610] The title compound was prepared analogously to Example 5, step 2 where tert-butyl 3-(6-((4- (4-carbamoylthiophen-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)-7-chloro-3,4-dihydroisoquinolin- 2(1H)-yl)azetidine-1-carboxylate was replaced with tert-butyl 4-(3-ethyl-4-((4-(4-methyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(t rifluoromethyl)pyrimidin-2- yl)amino)phenyl)piperazine-1-carboxylate. The title compound was isolated in 98% yield. MS (ESI) m/z: 581.0 [M+H] + . 1 H NMR (400 MHz, CD3CN) δ 8.67 (s, 1H), 7.87 (s, 2H), 7.23 (s, 1H), 6.89 (d, J = 3.0 Hz, 1H), 6.82 (dd, J = 8.6, 3.0 Hz, 1H), 3.84 (s, 2H), 3.73 (t, J = 5.5 Hz, 2H), 3.24 – 3.16 (m, 4H), 3.10 (s, 3H), 3.02 (dt, J = 4.9, 3.4 Hz, 3H), 2.65 (d, J = 5.0 Hz, 1H), 2.58 (q, J = 7.5 Hz, 2H), 1.14 (td, J = 7.5, 1.9 Hz, 3H). Example 175: 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000611] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-(2,2,2-trifluoroethyl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 620.1 [M+H] + . 1 H NMR (400MHz, methanol-d 4 ) δ 8.70 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 7.28 - 7.18 (m, 1H), 7.02 (s, 1H), 4.36 (d, J = 9.2 Hz, 2H), 4.08 (t, J = 5.6 Hz, 2H), 4.00 (s, 2H), 3.85 - 3.81 (m, 2H), 3.14 - 3.10 (m, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.65 - 2.60 (m, 2H), 1.18 - 1.15 (m, 3H). Example 176: 4-methyl-7-(2-((5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000612] The title compound was prepared following the synthetic procedure described in Example 166. The title compound was isolated. MS (ESI) m/z: 556.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 7.96 (s, 1H), 7.50 (s, 1H), 4.49 - 4.33 (m, 1H), 3.97 - 3.89 (m, 2H), 3.84 - 3.76 (m, 2H), 3.17 (s, 3H), 2.92 (dt, J = 2.9, 12.8 Hz, 2H), 2.21 (s, 3H), 2.19 - 2.13 (m, 2H), 2.06 (d, J = 10.0 Hz, 2H), 1.33 - 1.23 (m, 2H). Example 177: 7-(2-((6-cyclopropylisoindolin-5-yl)amino)-5-(trifluoromethy l)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000613] The title compound was prepared analogously to Example 170, where 1-(5-amino-4- bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6-bromoisoindolin-2-yl)- 2,2,2-trifluoroethan-1-one in step 2. The title compound was isolated. MS (ESI) m/z: 550.1 [M+H] + . 1 H NMR (400MHz, methanol-d 4 ) δ 8.73 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.06 (s, 1H), 4.27 (s, 2H), 4.23 (s, 2H), 3.95-3.93 (m, 2H), 3.86-3.84 (m, 2H), 3.19 (s, 3H), 2.00-1.96 (m, 1H), 0.97-0.92 (m, 2H), 0.67- 0.63 (m, 2H). Example 178: 7-(2-((5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000614] The title compound was prepared using the same synthetic procedure described in the preparation of Example 165. The title compound was isolated. MS (ESI) m/z: 542.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.02 (s, 1H), 7.49 (s, 1H), 4.38 (m, 1H), 3.76 (d, J = 2.8 Hz, 4H), 3.24 (s, 2H), 2.88 - 2.80 (m, 2H), 2.21 (s, 3H), 2.13 (m, 2H), 2.04 - 2.00 (m, 2H). Example 179: 7-(2-((2-ethyl-6-methylisoindolin-5-yl)amino)-5-(trifluorome thyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 1-(5-amino-6-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e [000615] To a 0 °C solution 1-(5-aminoisoindolin-2-yl)-2,2,2-trifluoroethan-1-one (27 mmol) in acetonitrile (100 mL) was added N-bromosuccinimide (27 mmol) and the reaction mixture was stirred for 2 hours. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford the title compound in 50% yield. MS (ESI) m/z: 308.9 [ 7.38 (d, J = 8.8 Hz, 1H), 7.19 - 6.96 (m, 1H), 6.85 - 6.66 (m, 1H), 5.41 (d, J = 13.0 Hz, 2H), 5.02 - 4.81 (m, 2H), 4.80 - 4.56 (m, 2H). Step 2: 1-(5-amino-6-methylisoindolin-2-yl)-2,2,2-trifluoroethan-1-o ne [000616] The title compound was prepared analogously to Example 9, step 1, where 1-(7-chloro-6-nitro- 1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-o ne and ethylboronic acid were replaced with 1-(5-amino-6-bromoisoindolin-2-yl)-2,2,2-trifluoroethan-1-on e and 2,4,6-trimethyl-1,3,5,2,4,6- trioxatriborinane. The title compound was isolated in 28% yield. MS (ESI) m/z: 245.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.92 (d, J = 10.8 Hz, 1H), 6.57 (d, J = 10.5 Hz, 1H), 4.93 (s, 2H), 4.85 (d, J = 14.1 Hz, 2H), 4.66 (d, J = 12.3 Hz, 2H), 2.06 (s, 3H). Steps 3-5: 7-(2-((2-ethyl-6-methylisoindolin-5-yl)amino)-5-(trifluorome thyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000617] The title compound was prepared analogously to Example 170, steps 3-5, where 1-(5-amino-4- cyclopropylisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 1-(5-amino-6-methylisoindolin- 2-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated. MS (ESI) m/z: 524.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.77 (s, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 4.63 (d, J = 7.0 Hz, 4H), 3.99 - 3.95 (m, 2H), 3.90 - 3.86 (m, 2H), 3.21 (s, 3H), 2.36 (s, 3H). Example 180: 7-(2-((6-chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000618] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(5-chloro-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2- yl)amino)isoindolin-2-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 530.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.79 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.45 (s, 1H), 4.22 (d, J = 11.5 Hz, 4H), 3.84 - 3.76 (m, 4H). Example 181: 7-(2-((6-chloro-2-methylisoindolin-5-yl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000619] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((6- chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 32% yield. m/z (ESI, +ve)= 558.0 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.79 (s, 1H), 8.01 (s, 1H), 7.77 (s, 1H), 7.41 (s, 1H), 3.98 - 3.92 (m, 6H), 3.87 - 3.83 (m, 2H), 3.19 (s, 3H), 2.61 (s, 3H). Example 182: 7-(2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000620] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((3- methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 10% yield. m/z (ESI, +ve)= 555.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.59 (s, 1H), 8.08 (s, 1H), 7.88 (s, 1H), 4.29 - 4.17 (m, 1H), 3.81 - 3.75 (m, 5H), 3.17 (br d, J = 12.4 Hz, 2H), 2.47 (s, 4H), 2.28 - 2.22 (m, 2H), 2.20 - 2.16 (m, 5H). Example 183: 4-methyl-7-(2-((3-methyl-1-(1-methylpiperidin-4-yl)-1H-pyraz ol-4-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000621] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 4-methyl-7- (2-((3-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(t rifluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 47% yield. m/z (ESI, +ve)= 570.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 4.21 - 4.09 (m, 1H), 3.96 - 3.88 (m, 2H), 3.86 - 3.76 (m, 2H), 3.18 (s, 3H), 3.07 (d, J = 11.9 Hz, 2H), 2.38 (s, 3H), 2.36 - 2.25 (m, 2H), 2.24 - 2.18 (m, 2H), 2.17 (s, 3H), 2.16 - 2.05 (m, 2H). Example 184: 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000622] The title compound was prepared analogously to Example 138, where diethylzinc was replaced with methylboronic acid in step 1 and 7-bromo-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide and 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one with 1-(6-{[4-chloro-5- (trifluoromethyl)pyrimidin-2-yl]amino}-7-methyl-1,2,3,4-tetr ahydroisoquinolin-2-yl)-2,2,2- trifluoroethan-1-one and 4-methyl-7-(trimethylstannyl)-2H,3H,4H,5H-1λ⁶-thieno[2,3- f][1,4]thiazepine- 1,1,5-trione, respectively, in step 5. The title compound was isolated. m/z (ESI, +ve)= 538.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 2.15 (s, 3H), 2.66 (m, 2H), 2.93 (t, J = 5.8 Hz, 2H), 3.07 (s, 3H), 3.81 (s, 2H), 3.89 (m, 2H), 3.96 (m, 2H), 6.91 (s, 1H), 7.09 (s, 1H), 7.81 (s, 1H), 8.81 (s, 1H), 9.82 (s, 1H). Example 185: 7-(2-((2-ethyl-7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000623] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 64% yield. m/z (ESI, +ve)= 566.2 [M+H] + . 1 H NMR (300 MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3H), 2.27 (s, 3H), 2.70 (d, J = 7.2 Hz, 2H), 2.88 (m, 2H), 3.00 (m, 2H), 3.23 (s, 3H), 3.72 (m, 4H), 3.90 (t, J = 5.7 Hz, 2H), 6.94 (s, 1H), 7.18 (s, 1H), 7.58 (s, 1H), 8.06 (s, 1H), 8.69 (s, 1H). Example 186: 7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000624] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 19% yield. 1 H NMR (400 MHz, DMSO-d6) δ 0.56 (m, 2H), 0.81 (m, 2H), 1.09 (t, J = 7.1 Hz, 3H), 1.93 (s, 1H), 2.47 (d, J = 7.4 Hz, 2H), 2.62 (t, J = 5.9 Hz, 2H), 2.77 (m, 2H), 3.07 (s, 3H), 3.49 (s, 2H), 3.88 (m, 2H), 3.95 (m, 2H), 6.69 (s, 1H), 7.15 (s, 1H), 7.81 (s, 1H), 8.81 (s, 1H), 9.86 (s, 1H). Example 187: 7-(2-((1-(2-(dimethylamino)ethyl)-3-methyl-1H-pyrazol-4-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000625] The title compound was prepared analogously to Example 123, where 1-Boc-3- hydroxyazetidine was replaced with tert-butyl (2-hydroxyethyl)(methyl)carbamate in step 1 and tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-m ethyl-1H-pyrazol-1-yl)azetidine-1- carboxylate in step 1 and trimethyl(4-(methylsulfonyl)thiophen-2-yl)stannane with 4-methyl-7- (trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5( 2H)-one 1,1-dioxide in step 4. The title compound was isolated. m/z (ESI, +ve)= 543.9 [M+H] + . MHz, DMSO-d6) δ 9.89 (m, 1H), 8.83 (m, 1H), 7.89 (m, 1H), 7.84 (s, 1H), 4.11 (t, J= 6.5 Hz, 2H), 4.03 – 3.85 (m, 4H), 3.09 (d, J = 8.0 Hz, 3H), 2.64 (t, J = 6.6 Hz, 2H), 2.18 (s, 6H), 2.13 (d, J = 9.9 Hz, 3H). Example 188: 7-(2-((2-ethyl-7-(methylthio)-1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000626] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-methyl-7-(2-((7-(methylthio)-1,2,3,4-tetrahydroisoquinolin -6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 23% yield. m/z (ESI, +ve)= 598.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.82 (s, 1H), 7.81 (s, 1H), 7.15 (s, 1H), 7.11 (m, 1H), 3.92 (m, 4H), 3.58 (s, 2H), 3.07 (s, 3H), 2.78 (m, 2H), 2.66 (m, 2H), 2.37 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H). Example 189: 7-(2-((2-chloro-5-(piperazin-1-yl)phenyl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000627] The title compound was prepared analogously to Example 149, steps 3-6, where tert-butyl 4- (3-amino-4-chlorophenyl)piperidine-1-carboxylate was replaced with tert-butyl 4-(3-amino-4- chlorophenyl)piperazine-1-carboxylate in step 3. The title compound was isolated. MS (ESI) m/z: 587.0 [M+H] + . 1 H NMR (400 MHz, methanol-d 4 ) δ 8.83 (s, 1H), 8.02 (s, 1H), 7.76 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 2.8, 8.8 Hz, 1H), 4.83 (br d, J = 3.6 Hz, 2H), 4.59 (s, 2H), 3.99 - 3.93 (m, 2H), 3.90 - 3.84 (m, 2H), 3.44 - 3.38 (m, 4H), 3.20 (s, 3H). Example 190: 7-(2-((2-ethyl-6-fluoroisoindolin-5-yl)amino)-5-(trifluorome thyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000628] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((6-fluoroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 11% yield. m/z (ESI, +ve)= 556.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.80 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.19 (d, J = 10.4 Hz, 1H), 4.58 (s, 2H), 4.19 (d, J = 5.6 Hz, 2H), 3.94 (d, J = 5.6 Hz, 2H), 3.89 - 3.84 (m, 2H), 3.19 (s, 3H), 3.08 - 2.98 (m, 2H), 1.32 - 1.27 (m, 3H). Example 191: 7-(2-((4-cyclopropyl-2-ethylisoindolin-5-yl)amino)-5-(triflu oromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide [000629] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((4-cyclopropylisoindolin-5-yl)amino)-5-(trifluoromethy l)pyrimidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 52% yield. m/z (ESI, +ve)= 578.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.73 (s, 1H), 7.99 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.10 (s, 2H), 3.96 (s, 2H), 3.94-3.92 (m, 2H), 3.85-3.83 (m, 2H), 3.18 (s, 3H), 2.89-2.84 (m, 2H), 1.82-1.78 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 0.91-0.87 (m, 2H), 0.55-0.51 (m, 2H). Example 192: 7-(2-((2-ethyl-6-methylisoindolin-5-yl)amino)-5-(trifluorome thyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000630] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-methyl-7-(2-((6-methylisoindolin-5-yl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 52% yield. m/z (ESI, +ve)= 552.2 [M+H] + . 1 H NMR (400 MHz, methanol-d 4 ) δ 8.72 (d, J = 0.9 Hz, 1H), 8.00 (s, 1H), 7.39 (s, 1H), 7.21 (s, 1H), 4.04 - 3.92 (m, 6H), 3.88 - 3.81 (m, 2H), 3.20 (s, 3H), 2.86 (q, J = 7.3 Hz, 2H), 2.30 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H). Example 193: 7-(2-((2-chloro-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000631] The title compound was prepared analogously to Example 189, where tert-butyl 4-(3-amino-4- chlorophenyl)piperazine-1-carboxylate was replaced with tert-butyl 4-(4-amino-3- chlorophenyl)piperazine-1-carboxylate. The title compound was isolated. m/z (ESI, +ve)= 586.9 [M+H] + . 1 H NMR 1 H NMR (400 MHz, acetonitrile-d3) δ 8.75 (s, 1H), 7.92 (s, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 9.0, 2.8 Hz, 1H), 3.90 – 3.85 (m, 2H), 3.77 (dd, J = 6.5, 4.8 Hz, 2H), 3.13 (d, J = 5.7 Hz, 8H), 2.96 – 2.91 (m, 4H). Example 194: 7-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000632] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((2- chloro-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)py rimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated. m/z (ESI, +ve)= 602.0 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d 3 ) δ 8.76 (s, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 6.97 (dd, J = 9.0, 2.9 Hz, 1H), 3.91 – 3.85 (m, 2H), 3.77 (t, J = 5.7 Hz, 2H), 3.25 – 3.20 (m, 4H), 3.14 (s, 3H), 2.56 – 2.50 (m, 4H), 2.30 (s, 3H). Example 195: 7-(2-((2-chloro-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000633] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((2-chloro-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated. m/z (ESI, +ve)= 615.1 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 8.75 (s, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 9.0, 2.8 Hz, 1H), 3.88 (t, J = 5.7 Hz, 2H), 3.77 (dd, J = 6.5, 4.8 Hz, 2H), 3.26 – 3.19 (m, 4H), 3.13 (s, 3H), 2.58 (t, J = 5.1 Hz, 4H), 2.49 – 2.42 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H). Example 196: 7-(2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000634] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 7-(2-((2- ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyr imidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 36% yield. m/z (ESI, +ve)= 595.4 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 8.66 (s, 1H), 7.87 (s, 2H), 7.22 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 2.9 Hz, 1H), 6.81 (dd, J = 8.7, 2.9 Hz, 1H), 3.84 (s, 2H), 3.73 (t, J = 5.7 Hz, 2H), 3.22 – 3.14 (m, 4H), 3.10 (s, 3H), 2.57 (q, J = 7.5 Hz, 2H), 2.53 – 2.46 (m, 4H), 2.25 (s, 3H), 1.13 (t, J = 7.5 Hz, 3H). Example 197: 7-(2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(tri fluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000635] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 64% yield. m/z (ESI, +ve)= 609.2 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.78 (s, 1H), 7.79 (s, 1H), 7.13 (s, 1H), 6.91 – 6.71 (m, 2H), 3.94 (s, 3H), 3.21 – 2.97 (m, 9H), 2.37 (q, J = 7.2 Hz, 2H), 1.06 (dt, J = 13.2, 7.3 Hz, 7H). Two protons of methylene groups are masked by DMSO signal at 2.5 ppm. Example 198: 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 4-ethyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]th iazepin-5(2H)-one 1,1-dioxide [000636] The title compound was prepared analogously to Example 160, step 1 where 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with appropriate starting material. The title compound was isolated in 99% yield. MS (ESI) m/z: 325.9 [M+H] + . Step 2: 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000637] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 4-ethyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]th iazepin-5(2H)- one 1,1-dioxide and 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-c yclopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 578.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 8.81 (s, 1H), 7.82 (s, 1H), 7.11 (s, 1H), 6.65 (s, 1H), 3.91 (d, J = 10.2 Hz, 4H), 3.80 (s, 2H), 3.53 (q, J = 7.1 Hz, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.65 (q, J = 6.5, 5.7 Hz, 2H), 1.92 (d, J = 5.2 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H), 0.87 – 0.76 (m, 2H), 0.56 (dt, J = 5.3, 2.9 Hz, 2H). Example 199: 7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000638] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 69% yield. m/z (ESI, +ve)= 606.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.82 (s, 1H), 7.82 (s, 1H), 7.15 (s, 1H), 6.70 (s, 1H), 3.91 (d, J = 10.7 Hz, 4H), 3.56 – 3.47 (m, 4H), 2.77 (s, 2H), 2.63 (t, J = 5.8 Hz, 2H), 1.93 (s, 1H), 1.13 (dt, J = 27.4, 7.1 Hz, 6H), 0.85 – 0.79 (m, 2H), 0.60 – 0.53 (m, 2H). Example 200: 7-(2-((6-chloro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 5-chloro-N1-methyl-4-nitrobenzene-1,2-diamine [000639] To a solution of 4-chloro-2-fluoro-5-nitroaniline (33 mmol) and methylamine hydrochloride (130 mmol) in acetonitrile (100 mL) was added triethylamine (198 mmol). The mixture was stirred at 100 °C for 8 hours. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (30% ethyl acetate in hexanes). The title compound was isolated in 53% yield. 1 H NMR (400 MHz, CDCl3) δ = 7.55 (s, 1H), 6.58 (s, 1H), 2.96 (s, 3H). Step 2: 6-chloro-1-methyl-5-nitro-1H-benzo[d][1,2,3]triazole [000640] To a 0 °C solution of 5-chloro-N1-methyl-4-nitrobenzene-1,2-diamine (17 mmol) in acetic acid (22 mL) and water (11 mL) was added sodium nitrite (26 mmol). After 1 hour the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 79% yield. (400 MHz, CDCl3) δ = 8.63 (s, 1H), 7.74 (s, 1H), 4.36 (s, 3H). Step 3: 6-chloro-1-methyl-1H-benzo[d][1,2,3]triazol-5-amine [000641] To a solution of 6-chloro-1-methyl-5-nitro-1H-benzo[d][1,2,3]triazole (14 mmol) in ethanol (40 mL) and water (15 mL) was added ammonium hydrochloride (27 mmol) and iron (68 mmol). The mixture was stirred at 80 °C for 2 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford the title compound in 72% yield. MS (ESI) m/z: 183.2 [M+H] + . Step 4: 6-chloro-N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-me thyl-1H- benzo[d][1,2,3]triazol-5-amine [000642] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 6-chloro-1- methyl-1H-benzo[d][1,2,3]triazol-5-amine. The title compound was isolated in 20% yield. MS (ESI) m/z: 363.0 [M+H] + . Step 5: 6-chloro-1-methyl-N-(5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2-yl)-1H- benzo[d][1,2,3]triazol-5-amine [000643] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one (3.26 mmol), 1,4-bis(diphenylphosphino)butane was replaced with 6-chloro-N-(4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)-1-methyl-1H-benzo[d][1,2,3] triazol-5-amine. The title compound was isolated. Step 6: 7-(2-((6-chloro-1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000644] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 6-chloro-1-methyl-N-(5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)-1H-benzo[d][1,2,3]triazol-5-amine and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 558.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 10.28 (brs, 1H), 8.88 (s, 1H), 8.26 (d, J = 13.6 Hz, 2H), 7.82 (s, 1H), 4.33 (s, 3H), 3.98 - 3.82 (m, 4H), 3.05 (s, 3H). Example 201: 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000645] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(6-chloro-7-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 584.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (br s, 1H), 8.85 (s, 1H), 7.80 (br s, 1H), 7.34 - 7.17 (m, 2H), 3.92 - 3.84 (m, 4H), 3.84 - 3.77 (m, 2H), 2.96 - 2.90 (m, 2H), 2.89 - 2.83 (m, 1H), 2.73 - 2.68 (m, 2H), 2.55 (br s, 1H), 0.83 - 0.75 (m, 4H). Example 202: 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothi eno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000646] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-chloro-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 598.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 8.86 (s, 1H), 7.82 (s, 1H), 7.33 - 7.20 (m, 2H), 4.73 - 4.61 (m, 1H), 3.95 - 3.89 (m, 2H), 3.89 - 3.84 (m, 2H), 3.84 - 3.77 (m, 2H), 2.97 - 2.87 (m, 2H), 2.72 - 2.67 (m, 2H), 2.47 - 2.45 (m, 1H), 2.26 - 2.18 (m, 2H), 2.17 - 2.10 (m, 2H), 1.73 - 1.61 (m, 2H). Example 203: 7-(2-((7-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclobutyl-3,4-dihydrothi eno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000647] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-cyclobutyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 35% yield. m/z (ESI, +ve)= 626.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 10.07 (s, 1H), 8.86 (s, 1H), 7.82 (s, 1H), 7.37 - 7.27 (m, 2H), 4.70 - 4.63 (m, 1H), 3.93 - 3.89 (m, 2H), 3.89 - 3.82 (m, 3H), 3.65 - 3.54 (m, 1H), 3.30 - 3.28 (m, 4H), 2.88 - 2.77 (m, 2H), 2.24 - 2.18 (m, 1H), 2.16 - 2.12 (m, 2H), 1.70 - 1.64 (m, 2H), 1.14 - 1.09 (m, 3H). Example 204: 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-ethyl-3,4-dihydrothieno[2 ,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000648] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 4-ethyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]th iazepin-5(2H)- one 1,1-dioxide and 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 572.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.86 (s, 1H), 7.83 (s, 1H), 7.26 (d, J = 13.8 Hz, 2H), 3.92 (dd, J = 8.0, 4.5 Hz, 4H), 3.83 (s, 2H), 3.53 (q, J = 7.2 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.7 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H). Example 205: 7-(2-((2-(cyclopropylmethyl)-7-methyl-1,2,3,4-tetrahydroisoq uinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000649] To a solution of 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide (0.22 mmol) in methanol (1.2 mL) and THF (1.2 mL), acetic acid (0.026 mL) and sodium cyanoborohydride (0.33 mmol) were added. The reaction mixture was cooled down to -30 °C and cyclopropanecarboxaldehyde (0.265 mmol) was added. The reaction mixture was stirred at –30 °C for 5 minutes, then the cooling bath was removed and the reaction mixture was allowed to reach room temperature and stirred for one additional hour. The reaction mixture was diluted with water, extracted with dichloromethane three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 32% yield. MS (ESI) m/z: 592.2 [M+H] + . 1 H NMR (300 MHz, acetonitrile-d3) δ 8.71 (s, 1H), 7.93 (d, J = 17.6 Hz, 2H), 7.29 (s, 1H), 6.98 (s, 1H), 3.84 (d, J = 6.1 Hz, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.64 (s, 2H), 3.10 (s, 3H), 2.85 (t, J = 5.9 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.39 (d, J = 6.6 Hz, 2H), 2.21 (s, 3H), 0.95 (s, 1H), 0.54 (d, J = 7.8 Hz, 2H), 0.17 (d, J = 5.0 Hz, 2H). Example 206: 7-(2-((2-chloro-4-(4-(cyclopropylmethyl)piperazin-1-yl)pheny l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000650] The title compound was prepared analogously to Example 205, where 4-methyl-7-(2-((7- methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2-chloro-4- (piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 51% yield. MS (ESI) m/z: 641.1 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 8.72 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.95 (dd, J = 8.9, 2.8 Hz, 1H), 3.88 – 3.80 (m, 2H), 3.74 (dd, J = 6.5, 4.8 Hz, 2H), 3.22 – 3.17 (m, 4H), 3.11 (s, 3H), 2.65 – 2.59 (m, 4H), 2.25 (d, J = 6.6 Hz, 2H), 0.92 – 0.81 (m, 1H), 0.55 – 0.44 (m, 2H), 0.16 – 0.07 (m, 2H). Example 207: 4-cyclopropyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide [000651] To a solution of 7-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin -5-one (1.35 mmol) and cyclopropylboronic acid (4.05 mmol) in 1,2-dichloroethane (2 mL) and DMF (0.6 mL) was added copper diacetate (1.35 mmol), pyridine (8.10 mmol) and 4A molecular sieve (1.2 g). The mixture was stirred at 80 °C for 12 hours under air. The mixture was filtered and concentrated under vacuum to afford a residue that was purified by semi-preparative reverse phase-HPLC. The title compound was isolated in 66% yield. MS (ESI) m/z: 336.0[M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.44 (s, 1H), 3.99 - 3.91 (m, 2H), 3.62 (dd, J = 5.2, 6.4 Hz, 2H), 2.92 - 2.83 (m, 1H), 0.97 - 0.91 (m, 2H), 0.90 - 0.85 (m, 2H). Step 2: 4-cyclopropyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000652] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin- 2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoro ethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 578.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.68 (d, J = 1.2 Hz, 1H), 7.97 (s, 1H), 7.33 - 7.16 (m, 1H), 7.01 (s, 1H), 4.01 - 3.93 (m, 4H), 3.79 - 3.74 (m, 2H), 3.14 (t, J = 5.6 Hz, 2H), 2.94 - 2.85 (m, 3H), 2.63 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H), 0.92 - 0.88 (m, 4H). Example 208: 4-cyclobutyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000653] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 592.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.74 - 8.64 (m, 1H), 7.97 (s, 1H), 7.30 - 7.19 (m, 1H), 7.00 (s, 1H), 4.78 - 4.71 (m, 1H), 3.99 (s, 2H), 3.96 - 3.91 (m, 2H), 3.76 (m 2H), 3.14 - 3.10 (m, 2H), 2.88 - 2.82 (m, 2H), 2.62 (m, 2H), 2.33 - 2.25 (m, 4H), 1.82 - 1.73 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H). Example 209: 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000654] The title compound was prepared analogously to Example 155, where 1-(7-chloro-6-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(7-cyclopropyl-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 590.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.73 (s, 1H), 7.99 (s, 1H), 7.50 - 7.40 (m, 1H), 6.80 (s, 1H), 4.01 - 3.94 (m, 4H), 3.76 (m, 2H), 3.16 - 3.11 (m, 2H), 2.94 - 2.86 (m, 3H), 1.96 - 1.86 (m, 1H), 0.93 - 0.88 (m, 6H), 0.65 - 0.57 (m, 2H). Example 210: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 7-bromo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazep in-5(2H)-one 1,1-dioxide [000655] A mixture of 7-bromo-1,1-dioxo-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepin -5-one (1.02 mmol), 3-bromooxetane (1.92 mmol), cesium carbonate (2.03 mmol) and DMF (5 mL) was stirred at 60°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude product that was purified by preparative TLC (50% of ethyl acetate in hexanes). The title compound was isolated in 13% yield as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (s, 1H), 5.28 - 5.17 (m, 1H), 4.74 - 4.69 (m, 2H), 4.68 - 4.63 (m, 2H), 4.06 - 3.98 (m, 4H). Step 2: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide [000656] The title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 600.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.86 (s, 1H), 7.84 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 5.27 - 5.18 (m, 1H), 4.76 - 4.67 (m, 4H), 4.05 - 3.98 (m, 4H), 3.88 - 3.84 (m, 2H), 2.98 - 2.92 (m, 2H), 2.69 (br t, J = 5.6 Hz, 2H). Example 211: 7-(2-((6-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000657] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide and acetaldehyde. The title compound was isolated in 69% yield. m/z (ESI, +ve)= 586.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (br s, 1H), 8.85 (s, 1H), 7.82 (s, 1H), 7.31 (s, 2H), 3.98 - 3.92 (m, 2H), 3.91 - 3.84 (m, 2H), 3.57 - 3.50 (m, 2H), 3.09 - 3.03 (m, 3H), 2.85 - 2.79 (m, 2H), 2.68 - 2.65 (m, 2H), 2.53 - 2.52 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H). Example 212: 7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1: 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroe than-1-one [000658] A 0 °C solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (47 mmol) in dichloromethane (100 mL) was treated with pyridine (94 mmol), N,N-dimethylaminopyridine (2.4 mmol) and trifluoroacetic anhydride (57 mmol) and triethylamine (112 mmol). After 12 hours at room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-10% ethyl acetate in hexanes) to afford the title compound in 94% yield. MS (ESI) m/z: 307.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.37-7.33 (m, 2H), 7.05-6.99 (m, 1H), 4.74-4.69 (m, 2H), 3.89-3.82 (m, 2H), 2.96-2.92 (m, 2H). Step 2: 1-(6-bromo-7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000659] 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroe than-1-one (44 mmol) was dissolved in sulfuric acid (130 mL). The solution was cooled down to 0 °C and fuming nitric acid (2 mL) was added dropwise over 30 min while keeping the temperature at 0 °C. After 60 minutes, the reaction was quenched with ice-water and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound in 95% yield. MS (ESI) m/z: 353.9 [M+H] + . (400MHz, CDCl3) δ 7.69 (s, 1H), 7.57-7.55 (m, 1H), 4.78-4.75 (m, 2H), 3.91-3.85 (m, 2H), 3.02-2.97 (m, 2H). Step 3: 2,2,2-trifluoro-1-(7-nitro-6-vinyl-3,4-dihydroisoquinolin-2( 1H)-yl)ethan-1-one [000660] A solution of 1-(6-bromo-7-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-tr ifluoro-ethanone (17 mmol) and tributyl(vinyl)stannane (25 mmol) in dioxane (60 mL) was treated with tetrakis(triphenylphosphine) palladium(0) (1.7 mmol) and copper iodide (17 mmol). The mixture was stirred at 120 °C for 12 hours, cooled down to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-6% ethyl acetate in hexanes). The title compound was isolated in 58% yield. MS (ESI) m/z: 301.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.04-7.98 (m, 1H), 7.65 (s, 1H), 7.04-6.96 (m, 1H), 5.88 (d, J = 17.2 Hz, 1H), 5.49 (d, J = 11.2 Hz, 1H), 4.88-4.83 (m, 2H), 3.84-3.82 (m, 2H), 3.05-3.00 (m, 2H). Step 4: 1-(7-amino-6-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000661] A solution of 2,2,2-trifluoro-1-(7-nitro-6-vinyl-3,4-dihydroisoquinolin-2( 1H)-yl)ethan-1-one (9.33 mmol) in methanol (30 mL) was hydrogenated in the presence of 10% palladium on carbon (1.0 g) for two hours. The reaction was filtered through celite and concentrated. Purification by silica gel chromatography (0-12% ethyl acetate in hexanes) afforded the title compound in 85% yield. MS (ESI) m/z: 273.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 6.74-6.73 (m, 1H), 6.41 (s, 1H), 4.75 (s, 2H), 4.56 (s, 2H), 3.75-3.73 (m, 2H), 2.75-2.69 (m, 2H), 2.40 (q, J = 14.8, 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H). Step 5: 1-(7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-e thyl-3,4-dihydroisoquinolin- 2(1H)-yl)-2,2,2-trifluoroethan-1-one [000662] 1-(7-amino-6-ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-tr ifluoro-ethanone (7.0 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (35 mmol) were heated at 70 °C for 3 hours. The mixture was cooled down and purified by silica gel chromatography (0-10% ethyl acetate in hexanes). The title compound was isolated in 39% yield. MS (ESI) m/z: 453.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.13 (s, 1H), 8.65 (br s, 1H), 7.19-7.16 (m, 1H), 7.14-7.13 (m, 1H), 4.71-4.69 (m, 2H), 3.83-3.80 (m, 2H), 2.93-2.88 (m, 2H), 2.54-2.52 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H). Step 6: 1-(6-ethyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000663] To a solution of 1-[7-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-e thyl-3,4-dihydro- 1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (3.1 mmol) and trimethyl(trimethylstannyl)stannane (12.4 mmol) in dioxane (10 mL) was added palladium diacetate (0.62 mmol) and 1,4- bis(diphenylphosphino)butane (0.62 mmol). The mixture was stirred at 95 °C for 12 hours. The mixture was cooled down to room temperature and quenched with water, extracted with ethyl acetate and the combined organic layers were washed with brine and dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by neutral alumina chromatography (0- 5% ethyl acetate in hexanes). The title compound was isolated in 62% yield. MS (ESI) m/z: 583.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ 9.35-9.32 (m, 1H), 8.48 (s, 1H), 7.29 (s, 1H), 7.09 (d, J = 3.2 Hz, 1H), 4.71-4.69 (m, 2H), 3.82-3.79 (m, 2H), 2.92-2.88 (m, 2H), 2.59-2.55 (m, 2H), 1.10-1.06 (m, 3H), 0.28 (d, J = 4.0 Hz, 9H). Steps 7-8: 7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-( trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide [000664] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-ethyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 552.3 [M+H] + . 1 H NMR (400MHz, methanol-d 4 ) δ 8.68 (s, 1H), 7.98 (s, 1H), 7.18 (s, 1H), 7.07 (s, 1H), 4.00 (s, 2H), 3.95-3.92 (m, 2H), 3.85-3.83 (m, 2H), 3.18 (s, 3H), 3.13 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.63 (q, J = 15.2, 7.2 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). Example 213: 7-(2-((7-chloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000665] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2 H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 69% yield. m/z (ESI, +ve)= 612.2 [M+H] + . 1 H NMR (400MHz, methanol- d 4 ) δ 8.83 (s, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 4.39 (s, 2H), 4.02 - 3.97 (m, 2H), 3.79 (t, J = 6.0 Hz, 2H), 3.56 (s, 2H), 3.35 - 3.32 (m, 2H), 3.28 - 3.23 (m, 2H), 2.94 - 2.87 (m, 1H), 1.45 (t, J = 7.2 Hz, 3H), 0.93 - 0.90 (m, 4H). Example 214: 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000666] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 4-methyl-7-(trimethylstannyl)-2H,3H,4H,5H-1λ⁶-thieno[2,3- f][1,4]thiazepine-1,1,5-trione and 1-(6-chloro-7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)a mino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 626.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.87 (s, 1H), 7.85 (s, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 4.45 (q, J = 9.5 Hz, 2H), 4.08 (t, J = 5.7 Hz, 2H), 3.93 (t, J = 5.6 Hz, 2H), 3.83 (s, 2H), 2.93 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 5.9 Hz, 2H). Example 215: 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000667] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 4-methyl-7-(trimethylstannyl)-2H,3H,4H,5H-1λ⁶-thieno[2,3- f][1,4]thiazepine-1,1,5-trione and 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7- cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoro ethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 632.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.83 (s, 1H), 7.84 (s, 1H), 7.09 (s, 1H), 6.65 (s, 1H), 4.45 (q, J = 9.5 Hz, 2H), 4.07 (s, 2H), 3.94 (d, J = 5.9 Hz, 2H), 3.80 (s, 2H), 2.92 (t, J = 5.8 Hz, 2H), 2.65 (s, 2H), 0.86 – 0.77 (m, 2H), 0.59 – 0.50 (m, 2H). Example 216: 4-methyl-7-(2-((7-methyl-2-(oxetan-3-ylmethyl)-1,2,3,4-tetra hydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000668] To a solution of 4-methyl-7-(2-((7-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide (0.22 mmol) in methanol (1.2 mL) and THF (1.2 mL), acetic Acid (0.44 mmol) and sodium cyanoborohydride (0.33 mmol) were added. The reaction mixture was cooled down to -30 °C and oxetane-3-carbaldehyde (0.25 mmol) was added. The reaction mixture was stirred at –30 °C for 5 minutes and at room temperature for one hour. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative HPLC. The title compound was isolated in 29% yield. MS (ESI) m/z: 608.0 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d 3 ) δ 8.74 (s, 1H), 7.96 (s, 1H), 7.92 (d, J = 0.9 Hz, 1H), 7.30 (s,1H), 6.98 (s, 1H), 4.75 (dd, J = 7.8, 5.8 Hz, 2H), 4.39 (t, J = 6.0 Hz, 2H), 3.92 – 3.83 (m, 2H), 3.76 (dd, J = 6.5, 4.7 Hz, 2H), 3.54 (s, 2H), 3.13 (s, 3H), 2.84 (m, 4H), 2.69 (t, J = 5.9 Hz, 2H), 2.23 (s,3H). Example 217: 7-(2-((2-chloro-4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pheny l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000669] The title compound was prepared analogously to Example 216, where 4-methyl-7-(2-((7- methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluor omethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2-chloro-4- (piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 66% yield. MS (ESI) m/z: 657.2 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 8.75 (s, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.96 (dd, J = 9.0, 2.8 Hz, 1H), 4.73 (ddd, J = 7.8, 5.9, 2.2 Hz, 2H), 4.35 (t, J = 6.1 Hz, 2H), 3.88 (s, 2H), 3.77 (dd, J = 6.5, 4.7 Hz, 2H), 3.28 (q, J = 7.1 Hz, 1H), 3.19 (t, J = 5.1 Hz, 4H), 3.14 (d, J = 2.2 Hz, 3H), 2.74 (d, J = 7.6 Hz, 2H), 2.54 (t, J = 4.9 Hz, 4H). Example 218: 4-cyclobutyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquino lin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000670] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(7-cyclopropyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 604.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.72 (s, 1H), 7.99 (s, 1H), 7.42 (d, J = 1.2 Hz, 1H), 6.78 (s, 1H), 4.76 (s, 1H), 3.98 - 3.93 (m, 4H), 3.79 - 3.74 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 5.6 Hz, 2H), 2.32 - 2.25 (m, 4H), 1.95 - 1.87 (m, 1H), 1.85 - 1.74 (m, 2H), 0.93 - 0.87 (m, 2H), 0.63 - 0.58 (m, 2H). Example 219: 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000671] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(7-cyclopropyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 606.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.82 (s, 1H), 7.82 (s, 1H), 7.20 (s, 1H), 6.76 (s, 1H), 5.27 - 5.18 (m, 1H), 4.77 - 4.65 (m, 4H), 4.06 - 3.96 (m, 6H), 3.18 - 3.12 (m, 3H), 2.84 - 2.78 (m, 2H), 2.00 - 1.92 (m, 1H), 0.86 - 0.80 (m, 2H), 0.60 - 0.51 (m, 2H). Example 220: 4-cyclopropyl-7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000672] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-ethyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 578.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.69 (s, 1H), 7.97 (s, 1H), 7.27 (s, 1H), 7.12 (s, 1H), 4.13 (s, 2H), 3.98 - 3.95 (m, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.27 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 5.2 Hz, 1H), 2.65 (q, J = 15.2, 7.6 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H), 0.91 - 0.89 (m, 4H). Example 221: 4-cyclobutyl-7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7- yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000673] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-ethyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 592.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.71 (s, 1H), 7.98 (s, 1H), 7.32 (s, 1H), 7.15 (s, 1H), 4.75 (d, J = 9.2 Hz, 1H), 4.20 (s, 2H), 3.96 - 3.94 (m, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.37 - 3.34 (m, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.66 (q, J = 15.2, 7.6 Hz, 2H), 2.31 - 2.26 (m, 4H), 1.83 - 1.74 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H). Example 222: 7-(2-((2,7-diethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000674] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide and acetaldehyde. The title compound was isolated in 48% yield. m/z (ESI, +ve)= 580.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.71 (s, 1H), 7.98 (s, 1H), 7.45 - 7.25 (m, 1H), 7.13 (s, 1H), 4.19 - 4.01 (m, 2H), 3.93 (d, J = 5.0 Hz, 2H), 3.85 (d, J = 5.5 Hz, 2H), 3.29 - 3.20 (m, 2H), 3.18 (s, 3H), 3.15 - 2.99 (m, 4H), 2.66 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.6 Hz, 3H). Example 223: 7-(2-((2-(cyclopropylmethyl)-7-ethyl-1,2,3,4-tetrahydroisoqu inolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000675] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 44% yield. m/z (ESI, +ve)= 606.2 [M+H] + 1 H NMR (400 MHz, methanol-d 4 ) δ 8.72 (s, 1H), 7.99 (s, 1H), 7.48 - 7.31 (m, 1H), 7.12 (s, 1H), 4.12 (s, 2H), 3.98 - 3.92 (m, 2H), 3.88 - 3.81 (m, 2H), 3.24 (d, J = 5.9 Hz, 2H), 3.19 (s, 3H), 3.10 (d, J = 5.4 Hz, 2H), 2.82 (d, J = 5.1 Hz, 2H), 2.67 (q, J = 7.7 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H), 1.16 - 1.09 (m, 1H), 0.72 (dd, J = 1.3, 7.8 Hz, 2H), 0.37 (d, J = 4.5 Hz, 2H). Example 224: 4-cyclopropyl-7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 1-(7-amino-6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one [000676] To a solution of 1-(6-bromo-7-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1- one (20 mmol) in ethanol (60 mL) and water (30 mL) was added iron (99 mmol) and ammonium chloride (40 mmol). The mixture was stirred at 70 °C for 2 hours, cooled down to room temperature and filtered. Evaporation of volatiles afforded a crude product that was used into the next step without further purification. The title compound was isolated in 73% yield. 1 H NMR (400 MHz, CDCl3) δ = 7.26 - 7.20 (m, 1H), 6.58 - 6.51 (m, 1H), 4.67 - 4.54 (m, 2H), 3.88 - 3.79 (m, 2H), 2.86 - 2.80 (m, 2H). Step 2: 1-(7-amino-6-cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2, 2,2-trifluoroethan-1-one [000677] To a solution of 1-(7-amino-6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1- one (14 mmol) and cyclopropylboronic acid (58 mmol) in toluene (100 mL) was added tricyclohexylphosphane (3 mmol), potassium phosphate (58 mmol) and diacetoxypalladium (1.5 mmol). The mixture was stirred at 110 °C for 12 hours, cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure and the crude was purified by silica gel chromatography (25 % ethyl acetate in hexanes). The title compound was isolated in 54% yield. MS (ESI) m/z: 285.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 6.65 (s, 1H), 6.45 (s, 1H), 4.73 (s, 2H), 4.56 (s, 2H), 3.74 (d, J = 4.8 Hz, 2H), 2.77 - 2.70 (m, 2H), 1.67 - 1.59 (m, 1H), 0.88 - 0.83 (m, 2H), 0.44 - 0.40 (m, 2H). Step 3-4: 1-(6-cyclopropyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000678] The title compound was prepared analogously to Example 212, steps 5-6, where 1-(7-amino-6- ethyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethan one was replaced with 1-(7-amino-6- cyclopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoro ethan-1-one in step 4. The title compound was isolated in 31% yield. MS (ESI) m/z: 593.2 [M+H] + . Example 5-6: 4-cyclopropyl-7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000679] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-cyclopropyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 590.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.73 (s, 1H), 8.08 (s, 1H), 7.84 (s, 2H), 6.93(s, 1H), 4.12 -3.97 (m, 2H), 3.96 – 3.94 (m, 2H), 3.67 - 3.64 (m, 2H), 3.18 - 3.15 (m, 2H), 2.93 - 2.90 (m, 1H), 3.80 - 2.77 (m, 2H), 1.85 - 1.82 (m, 1H), 1.05 - 1.04 (m, 2H), 1.03 – 1.02 (m, 2H), 0.95 - 0.89 (m, 2H), 0.70 - 0.69 (m, 2H). Example 225: 4-cyclobutyl-7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquino lin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000680] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-cyclopropyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-cyclobutyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 604.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.73 (s, 1H), 8.09 (s, 1H), 7.85 (d, J = 5.6 Hz, 2H), 6.93 (s, 1H), 5.00 - 4.68 (m, 1H), 4.15 (s, 2H), 3.96 - 3.84 (m, 2H), 3.68 (t, J = 5.6 Hz, 2H), 3.21 (t, J = 5.6 Hz, 2H), 2.81 (t, J = 5.6 Hz, 2H), 2.43 - 2.31 (m, 2H), 2.17 - 2.12 (m, 2H), 1.79 (s, 1H), 1.26 (s, 2H), 1.10 - 1.01 (m, 2H), 0.95 - 0.82 (m, 1H), 0.74 - 0.62 (m, 2H). Example 226: 4-cyclobutyl-7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000681] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclobutyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquino lin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 24% yield. m/z (ESI, +ve)= 623.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.73 (s, 1H), 8.00 (s, 1H), 7.51 - 7.43 (m, 1H), 6.83 (s, 1H), 4.75 (s, 1H), 3.99 - 3.92 (m, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.65 (s, 2H), 2.97 (d, J = 5.6 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H), 2.65 (q, J = 7.2 Hz, 2H), 2.33 - 2.26 (m, 4H), 1.97 - 1.87 (m, 1H), 1.85 - 1.75 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H), 0.94 - 0.88 (m, 2H), 0.65 - 0.60 (m, 2H). Example 227: 7-(2-((7-chloro-2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquino lin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000682] To a solution of 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.02 mmol) and 1-bromo-2-fluoroethane (0.02 mmol) in DMF (1 mL) was added potassium carbonate (0.03 mmol) and sodium iodide (0.002 mmol). The mixture was stirred at 60 °C for 8 hours, cooled down to room temperature and filtered. The filtrate was concentrated and the crude material purified by preparative HPLC. The title compound was isolated in 37% yield. MS (ESI) m/z: 630.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.79 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.17 (s, 1H), 4.96 - 4.66 (m, 2H), 4.06 - 3.96 (m, 2H), 3.96 - 3.72 (m, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.33 - 2.96 (m, 6H), 2.96 - 2.89 (m, 1H), 1.00 - 0.93 (m, 4H). Example 228: 4-cyclopropyl-7-(2-((2,7-diethyl-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000683] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 17% yield. m/z (ESI, +ve)= 606.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.71 (s, 1H), 7.97 (s, 1H), 7.37 (d, J = 0.8 Hz, 1H), 7.11 (s, 1H), 4.02 (s, 2H), 3.96 (t, J = 6.0 Hz, 2H), 3.78 - 3.74 (m, 2H), 3.16 (d, J = 4.8 Hz, 2H), 3.09 (d, J = 4.8 Hz, 2H), 2.97 (d, J = 7.2 Hz, 2H), 2.89 (d, J = 5.6 Hz, 1H), 2.69-2.63 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H), 0.92 - 0.88 (m, 4H). Example 229: 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000684] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(7-ethyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 557.9 [M+1] +.1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.80 (br s, 1H), 7.83 (s, 1H), 7.12 (br s, 1H), 6.98 (s, 1H), 5.28 - 5.17 (m, 1H), 4.77 - 4.72 (m, 2H), 4.71 - 4.65 (m, 2H), 4.06 - 3.97 (m, 4H), 3.96 - 3.93 (m, 2H), 3.18 - 3.15 (m, 2H), 3.09 - 3.03 (m, 2H), 2.77 - 2.69 (m, 2H), 2.58 - 2.54 (m, 1H), 1.07 (t, J = 7.6 Hz, 3H). Example 230: 7-(2-((6-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000685] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-chloro-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 600.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.86 (s, 1H), 7.84 (s, 1H), 7.32 - 7.21 (m, 2H), 5.26 - 5.18 (m, 1H), 4.76 - 4.67 (m, 4H), 4.05 - 3.97 (m, 4H), 3.89 - 3.83 (m, 2H), 3.01 - 2.94 (m, 2H), 2.76 - 2.68 (m, 2H). Example 231: 7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000686] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-cyclopropyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 564.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.72 (s, 1H), 8.00 (s, 1H), 7.48 - 7.34 (m, 1H), 6.85 (s, 1H), 4.64 - 4.55 (m, 1H), 4.02 (s, 2H), 3.97 - 3.92 (m, 2H), 3.87 - 3.83 (m, 2H), 3.18 (s, 3H), 3.13 (t, J = 6.0 Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 1.97 - 1.89 (m, 1H), 0.95 - 0.89 (m, 2H), 0.65 - 0.59 (m, 2H). Example 232: 7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000687] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-cyclopropyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-(2,2,2- trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 632.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.74 (s, 1 H), 8.02 (s, 1 H), 7.41 - 7.28 (m, 1 H), 6.85 (s, 1 H), 4.37 (q, J = 9.2 Hz, 2 H), 4.09 (d, J = 5.2 Hz, 2 H), 4.00 (s, 2 H), 3.84 (t, J = 5.6 Hz, 2 H), 3.11 (t, J = 6.0 Hz, 2 H), 2.82 (t, J = 5.6 Hz, 2 H), 1.94 - 1.90 (m, 1 H), 0.93 - 0.90 (m, 2 H), 0.63 - 0.60 (m, 2 H). Example 233: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydr oisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000688] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 69% yield. m/z (ESI, +ve)= 618.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.74 (s, 1H), 7.99 (s, 1H), 7.54 (s, 1H), 6.87 (s, 1H), 3.97 (t, J = 5.6 Hz, 2H), 3.83 (s, 2H), 3.80 - 3.75 (m, 2H), 3.02 (dd, J = 4.4, 10.0 Hz, 4H), 2.90 (td, J = 2.8, 5.2 Hz, 1H), 2.82 (q, J = 7.2 Hz, 2H), 1.95 - 1.88 (m, 1H), 1.29 - 1.24 (m, 3H), 0.95 - 0.89 (m, 6H), 0.66 - 0.60 (m, 2H). Example 234: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-(oxetan-3-ylmethyl)-1,2 ,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000689] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and oxetane-3-carbaldehyde. The title compound was isolated in 42% yield. m/z (ESI, +ve)= 660.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.77 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 6.94 (s, 1H), 4.92 (s, 2H), 4.56 (t, J = 6.4 Hz, 2H), 4.21 (s, 1H), 4.01 - 3.94 (m, 2H), 3.82 - 3.73 (m, 3H), 3.67 - 3.59 (m, 1H), 3.54 (d, J = 6.4 Hz, 2H), 3.42 (d, J = 2.0 Hz, 2H), 3.19 (t, J = 5.6 Hz, 2H), 2.95 - 2.87 (m, 1H), 2.03 - 1.93 (m, 1H), 1.01 - 0.95 (m, 2H), 0.94 - 0.90 (m, 4H), 0.68 - 0.62 (m, 2H). Example 235: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-(cyclopropylmethyl)-1,2 ,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000690] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 99% yield. m/z (ESI, +ve)= 644.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.76 (s, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 6.92 (s, 1H), 4.59 (s, 2H), 4.12 (s, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.81 - 3.74 (m, 2H), 3.18 - 3.09 (m, 2H), 2.94 - 2.83 (m, 3H), 1.97 - 1.94 (m, 1H), 1.18 - 1.09 (m, 1H), 0.98 - 0.90 (m, 6H), 0.77 - 0.72 (m, 2H), 0.67 - 0.62 (m, 2H), 0.43 - 0.35 (m, 2H). Example 236: 7-(2-((7-cyclopropyl-2-(2-fluoroethyl)-1,2,3,4-tetrahydroiso quinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000691] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((7-cyclopropyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 41% yield. MS (ESI) m/z: 610.2 [M+H] + . 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.85 (s, 1H), 8.12 (s, 1H), 7.59 (d, J = 1.6 Hz, 1H), 6.93 (s, 1H), 4.87 - 4.85 (m, 1H), 4.75 - 4.73 (m, 1H), 4.13 - 4.03 (m, 2H), 3.99 - 3.93 (m, 2H), 3.85 (s, 2H), 3.31 (s, 3H), 3.15 - 2.98 (m, 6H), 2.09 - 2.02 (m, 1H), 1.05 - 1.02 (m, 2H), 0.74 (dd, J = 1.6, 5.2 Hz, 2H). Example 237: 7-(2-((7-chloro-2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquino lin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000692] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 34% yield. MS (ESI) m/z: 604.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.79 (s, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.24 (s, 1H), 4.74 (s, 1H), 4.61 (d, J = 4.8 Hz, 1H), 4.58 (s, 2H), 3.94 (d, J = 5.6 Hz, 2H), 3.86 (d, J = 5.2 Hz, 2H), 3.75 (s, 2H), 3.19 (s, 3H), 2.87 (d, J = 4.8 Hz, 4H). Example 238: 7-(2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trif luoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide Step 1: tert-butyl 4-(3-bromo-4-nitrophenyl)piperazine-1-carboxylate [000693] A solution of 2-bromo-4-fluoro-1-nitro-benzene (86 mmol), tert-butyl piperazine-1-carboxylate (95 mmol) and potassium carbonate (173 mmol) in DMF (190 mL) was stirred at 60 °C for 12 hours. The mixture was cooled down to room temperature and poured over ice-water, which resulted in formation of yellow precipitate. The precipitate was filtered and dried under vacuum. The title compound was isolated in 90% yield. 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 9.2 Hz, 1 H), 7.06 (d, J = 2.4 Hz, 1 H), 6.76 (dd, J = 9.2, 2.4 Hz, 1 H), 3.61 - 3.59 (m, 4 H), 3.40 - 3.38 (m, 4 H), 1.49 (s, 9H). Step 2: tert-butyl 4-(3-cyclopropyl-4-nitrophenyl)piperazine-1-carboxylate [000694] The title compound was prepared analogously to Example 224, step 2, where 1-(7-amino-6- bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl 4-(3- bromo-4-nitrophenyl)piperazine-1-carboxylate. The title compound was isolated in 56% yield. 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 9.2 Hz, 1 H), 6.68 (dd, J = 9.2, 2.8 Hz, 1 H), 6.54 (d, J = 2.8 Hz, 1 H), 3.60 - 3.58 (m, 4 H), 3.36 - 3.33 (m, 4 H), 2.64 - 2.58 (m, 1 H), 1.06 - 1.04 (m, 2 H), 0.69 - 0.66 (m, 2 H). Step 3: tert-butyl 4-(4-amino-3-cyclopropylphenyl)piperazine-1-carboxylate [000695] The title compound was prepared analogously to Example 224, step 1 where 1-(6-bromo-7- nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl 4-(3- cyclopropyl-4-nitrophenyl)piperazine-1-carboxylate. The title compound was isolated in 71% yield. MS (ESI) m/z: 318.2 [M+H] + . Step 4: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- cyclopropylphenyl)piperazine-1-carboxylate [000696] The title compound was prepared analogously to Example 121, step 3, where tert-butyl 3-(3- amino-4-chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 4-(4-amino-3- cyclopropylphenyl)piperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 498.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.53 (s, 1 H), 7.91 - 7.72 (m, 1 H), 7.65 - 7.48 (m, 1 H), 6.93 - 6.66 (m, 2 H), 3.59 (s, 4 H), 3.12 (s, 4 H), 1.92 - 1.77 (m, 1 H), 1.02 (d, J = 7.6 Hz, 2 H), 0.69 (d, J = 4.4 Hz, 2 H). Step 5: tert-butyl 4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)phenyl)piperazine-1-carboxylate [000697] The title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2- yl)-2,2,2-trifluoroethan-1-one was replaced with tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- cyclopropylphenyl)piperazine-1-carboxylate. The title compound was isolated in 66% yield. MS (ESI) m/z: 628.3 [M+H] + . Step 6: 7-(2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trif luoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000698] The title compound was prepared analogously to Example 149, steps 5-6, where tert-butyl 4- (4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimi din-2-yl)amino)phenyl)piperidine-1- carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide were replaced with tert-butyl 4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)phenyl)piperazine-1-carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 5. The title compound was isolated. MS (ESI) m/z: 593.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.75 - 8.60 (m, 1 H), 7.98 (s, 1 H), 7.47 - 7.27 (m, 1 H), 6.87 (dd, J = 8.8, 2.4 Hz, 1 H), 6.66 (d, J = 2.4 Hz, 1 H), 3.92 (s, 2 H), 3.18 (s, 3 H), 3.15 - 3.10 (m, 4 H), 3.00 - 2.95 (m, 4 H), 2.00 - 1.90 (m, 1 H), 0.93 - 0.86 (m, 3 H), 0.68 - 0.61 (m, 2 H). Example 239: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000699] The title compound was prepared analogously to Example 238, where 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 4-(3-cyclopropyl- 4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)a mino)phenyl)piperazine-1-carboxylate in step 5. The title compound was isolated in 43% yield. MS (ESI) m/z: 619.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1 H), 8.05 (s, 1 H), 7.90 - 7.88 (m, 1 H), 7.68 - 7.65 (m, 1 H), 6.90 - 6.88 (m, 1 H), 6.76 (s, 1 H), 3.93 (d, J = 6.0 Hz, 2 H), 3.64 (t, J = 5.6 Hz, 2 H), 3.14 (d, J = 4.4 Hz, 4 H), 3.06 (d, J = 5.2 Hz, 4 H), 2.93 - 2.89 (m, 1 H), 1.92 - 1.85 (m, 1 H), 1.03 - 1.01 (m, 2 H), 0.97 - 0.94 (m, 4 H),0.72 - 0.71 (m, 2 H). Example 240: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperidin-4-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 4-(4-amino-3-cyclopropylphenyl)piperidine-1-carboxylate [000700] The title compound was prepared analogously to Example 224, step 2 where 1-(7-amino-6- bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl 4-(4- amino-3-bromophenyl)piperidine-1-carboxylate. The title compound was isolated in 71% yield.. MS (ESI) m/z: 261.3 [M-55] + . Step 2: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- cyclopropylphenyl)piperidine-1-carboxylate [000701] The title compound was prepared analogously to Example 121, step 3, where tert-butyl 3-(3- amino-4-chlorophenyl)azetidine-1-carboxylate was replaced with tert-butyl 4-(4-amino-3- cyclopropylphenyl)piperidine-1-carboxylate. The title compound was isolated in 24% yield. 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.13 (dd, J = 1.6, 8.4 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 4.25 (d, J = 12.4 Hz, 2H), 2.80 (t, J = 12.4 Hz, 2H), 2.67 2.58 (m, 1H), 1.86 - 1.79 (m, 3H), 1.68 - 1.60 (m, 2H), 1.50 (s, 9H), 1.07 - 1.02 (m, 2H), 0.73 - 0.68 (m, 2H). Step 3: tert-butyl 4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)phenyl)piperidine-1-carboxylate [000702] The title compound was prepared analogously to Example 80, step 3 where 1-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-fluoroisoindolin-2- yl)-2,2,2-trifluoroethan-1-one was replaced with tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- cyclopropylphenyl)piperidine-1-carboxylate. The title compound was isolated in 41% yield as a colorless oil. MS (ESI) m/z: 627.3 [M+H] + . Step 4-5: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperidin-4-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000703] The title compound was prepared analogously to Example 238, steps 6-7, where tert-butyl 4- (3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)p yrimidin-2-yl)amino)phenyl)piperazine-1- carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide were replaced with tert-butyl 4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)phenyl)piperidine-1-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 6. The title compound was isolated. MS (ESI) m/z: 618.2 [M+H] + . 1 H NMR (400 MHz,CDCl3) δ 8.75 (s, 1H), 8.11 - 8.06 (m, 2H), 7.88 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.59 - 3.52 (m, 2H), 3.04 (dt, J = 4.0, 12.4 Hz, 2H), 2.94 - 2.90 (m, 1H), 2.78 - 2.72 (m, 1H), 2.10 - 2.04 (m, 4H), 1.88 (d, J = 5.2 Hz, 1H), 1.10 - 1.06 (m, 2H), 0.98 - 0.92 (m, 4H), 0.74 - 0.70 (m, 2H). Example 241: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(1-(cyclopropylmethyl)p iperidin-4- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000704] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperidin-4-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 57% yield. m/z (ESI, +ve)= 672.2 [M+H] + 1 H NMR (400 MHz,CDCl3) δ 8.73 (s, 1H), 8.07 - 8.03 (m, 2H), 7.85 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.45 - 3.36 (m, 2H), 2.96 - 2.90 (m, 1H), 2.62 - 2.48 (m, 3H), 2.40 - 2.28 (m, 2H), 2.08 - 1.97 (m, 3H), 1.91 (s, 2H), 1.08 - 1.02 (m, 3H), 0.98 - 0.93 (m, 4H), 0.72 (d, J = 5.2 Hz, 2H), 0.64 (d, J = 7.6 Hz, 2H), 0.25 (d, J = 5.2 Hz, 2H). Example 242: 4-cyclopropyl-7-(2-((2-(cyclopropylmethyl)-7-ethyl-1,2,3,4-t etrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000705] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 47% yield. m/z (ESI, +ve)= 632.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.72 (s, 1H), 7.98 (s, 1H), 7.43 - 7.33 (m, 1H), 7.12 (s, 1H), 4.59 (s, 2H), 4.15 - 4.07 (m, 2H), 3.96 (s, 2H), 3.81 - 3.73 (m, 2H), 3.26 (s, 2H), 3.10 (s, 2H), 2.90 (s, 1H), 2.83 (d, J = 6.4 Hz, 2H), 2.67 (d, J = 7.6 Hz, 2H), 1.29 (s, 2H), 1.19 (t, J = 7.2 Hz, 3H), 1.14 - 1.08 (m, 1H), 0.91 (s, 2H), 0.72 (d, J = 6.8 Hz, 2H), 0.39 - 0.35 (m, 2H). Example 243: 7-(2-((7-chloro-2-(2-fluoroethyl)-1,2,3,4-tetrahydroisoquino lin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000706] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 4-cyclopropyl-7-(2-((7- ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoro methyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 39% yield. MS (ESI) m/z: 624.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.69 (s, 1H), 7.97 (s, 1H), 7.26 (s, 1H), 7.03 (s, 1H), 4.75 (t, J = 4.8 Hz, 1H), 4.63 (t, J = 4.8 Hz, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.79 (s, 2H), 3.75 (t, J = 6.0 Hz, 2H), 2.99-2.96 (m, 3H), 2.93-2.89 (m, 4H), 2.63 (q, J = 15.2, 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H), 0.91-0.89 (m, 4H). Example 244: 7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000707] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide and acetaldehyde. The title compound was isolated in 82% yield. m/z (ESI, +ve)= 634.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.82 (br s, 1H), 7.83 (s, 1H), 7.16 (br s, 1H), 6.70 (s, 1H), 5.27 - 5.18 (m, 1H), 4.76 - 4.67 (m, 4H), 4.05 - 3.96 (m, 4H), 3.61 - 3.51 (m, 2H), 2.83 - 2.75 (m, 2H), 2.70 - 2.66 (m, 1H), 2.59 - 2.54 (m, 1H), 1.92 - 1.89 (m, 3H), 1.11 (t, J = 6.8 Hz, 3H), 0.83 - 0.78 (m, 2H), 0.58 - 0.53 (m, 2H). Example 245: 7-(2-((7-cyclopropyl-2-ethyl-1,2,3,4-tetrahydroisoquinolin-6 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000708] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide and acetaldehyde. The title compound was isolated. m/z (ESI, +ve)= 661.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.83 (s, 1H), 7.84 (s, 1H), 7.16 (s, 1H), 6.70 (s, 1H), 4.44 (d, J = 9.5 Hz, 2H), 4.06 (s, 2H), 3.93 (s, 2H), 3.50 (s, 2H), 2.78 (s, 2H), 2.63 (s, 2H), 1.93 (d, J = 9.0 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H), 0.88 – 0.79 (m, 2H), 0.61 – 0.54 (m, 2H). Example 246: 7-(2-((7-chloro-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoq uinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000709] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 10% yield. m/z (ESI, +ve)= 612.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.87 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 3.96 (d, J = 6.0 Hz, 2H), 3.89 (d, J = 6.3 Hz, 2H), 3.64 (s, 2H), 3.08 (s, 3H), 2.82 (d, J = 5.7 Hz, 2H), 2.73 (t, J = 5.7 Hz, 2H), 2.37 (d, J = 6.6 Hz, 2H), 0.93 (d, J = 5.2 Hz, 1H), 0.56 – 0.48 (m, 2H), 0.20 – 0.10 (m, 2H). Example 247: 4-cyclopropyl-7-(2-((7-(methylthio)-1,2,3,4-tetrahydroisoqui nolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 4-cyclopropyl-7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1- dioxide [000710] A solution of 7-bromo-4-cyclopropyl-2H,3H,4H,5H-1λ⁶-thieno[2,3-f][1,4]t hiazepine-1,1,5- trione (3.1 mmol) in dioxane (21 ml) was treated with hexamethylditin (6.2 mmol) and tetrakis(triphenylphosphine)palladium (0.16 mmol). The reaction mixture was stirred overnight at 95°C, cooled down to room temperature and filtered through celite. The volatiles were removed under reduced pressure and the residue purified by silica gel chromatography (0-30% of ethyl acetate in dichloromethane) to afford the title compound in 74% yield. m/z (ESI, +ve)= 421.9 [M+H] + . Step 2: 4-Cyclopropyl-7-(2-((7-(methylthio)-2-(2,2,2-trifluoroacetyl )-1,2,3,4-tetrahydroisoquinolin- 6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000711] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 1-(6-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-7- (methylsulfanyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-t rifluoroethan-1-one in step 3. The title compound was isolated in 94% yield. MS (ESI) m/z: 692.2 [M+H] + . Step 3: 4-cyclopropyl-7-(2-((7-(methylthio)-1,2,3,4-tetrahydroisoqui nolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000712] A solution of 4-cyclopropyl-7-(2-{[7-(methylsulfanyl)-2-(2,2,2-trifluoroac etyl)-1,2,3,4- tetrahydroisoquinolin-6-yl]amino}-5-(trifluoromethyl)pyrimid in-4-yl)-2H,3H,4H,5H-1λ⁶-thieno[2,3- f][1,4]thiazepine-1,1,5-trione (0.44 mmol) in dichloromethane (3 mL), was treated with a 7M solution of ammonia in methanol (6.3 mL). After1 hour at room temperature, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (0-20% of 0.7M NH3 in MeOH in DCM). The title compound was isolated in 70% yield. MS (ESI) m/z: 696.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 2.15 (s, 3H), 2.66 (m, 2H), 2.93 (t, J = 5.8 Hz, 2H), 3.07 (s, 3H), 3.81 (s, 2H), 3.89 (m, 2H), 3.96 (m, 2H), 6.91 (s, 1H), 7.09 (s, 1H), 7.81 (s, 1H), 8.81 (s, 1H), 9.82 (s, 1H). Example 248: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-isopropyl-1,2,3,4-tetra hydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000713] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetone. The title compound was isolated in 86% yield. m/z (ESI, +ve)= 632.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.76 (s, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 6.93 (s, 1H), 4.12 (s, 2H), 3.97 (t, J = 5.6 Hz, 2H), 3.80 - 3.74 (m, 2H), 3.41 - 3.34 (m, 1H), 3.28 - 3.26 (m, 1H), 3.17 - 3.09 (m, 2H), 2.94 - 2.87 (m, 1H), 2.00 - 1.90 (m, 2H), 1.34 (d, J = 6.4 Hz, 6H), 0.98 - 0.93 (m, 2H), 0.92 - 0.89 (m, 4H), 0.67 - 0.61 (m, 2H). Example 249: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-(2-fluoroethyl)-1,2,3,4 -tetrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000714] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 4-cyclopropyl-7-(2-((7- cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(tri fluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 51% yield. MS (ESI) m/z: 636.2[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.75 (s, 1H), 7.99 (s, 1H), 7.57 (s, 1H), 6.88 (s, 1H), 4.92 (d, J = 3.2 Hz, 1H), 4.73 (t, J = 4.4 Hz, 1H), 4.04 (s, 2H), 4.01 - 3.95 (m, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.26 - 3.16 (m, 4H), 3.10 (d, J = 5.6 Hz, 2H), 2.95 - 2.87 (m, 1H), 1.99 - 1.89 (m, 1H), 0.95 - 0.88 (m, 6H), 0.64 (d, J = 4.0 Hz, 2H). Example 250: 7-(2-((2-cyclopropyl-4-(4-(cyclopropylmethyl)piperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000715] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trif luoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 96% yield. m/z (ESI, +ve)= 647.2 [M+H] + . 1 H NMR (400 MHz, MeOD, 298 K) δ 8.70 (s, 1H), 8.07 (s, 1H), 7.91 - 7.87 (m, 1H), 7.72 - 6.90 (m, 1H), 6.89 (d, J = 2.8 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 3.99 - 3.85 (m, 2H), 3.80 - 3.68 (m, 2H), 3.44 - 3.32 (m, 4H), 3.25 (s, 3H), 3.09 (s, 4H), 2.67 (d, J = 7.2 Hz, 2H), 1.95 - 1.82 (m, 1H), 1.26 (s, 2H), 1.09 - 0.98 (m, 2H), 0.96 - 0.79 (m, 1H), 0.75 - 0.60 (m, 4H), 0.29 (d, J = 5.2 Hz, 2H). Example 251: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(4-(cyclopropylmethyl)p iperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000716] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 57% yield. m/z (ESI, +ve)= 719.3 [M+H] + . Example 252: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(1-methylpiperidin-4-yl )phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000717] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide was replaced with 4- cyclopropyl-7-(2-((2-cyclopropyl-4-(piperidin-4-yl)phenyl)am ino)-5-(trifluoromethyl)pyrimidin-4-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 59% yield. m/z (ESI, +ve)= 632.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.74 (s, 1H), 8.12 - 7.96 (m, 2H), 7.87 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.57 - 3.42 (m, 2H), 2.98 - 2.88 (m, 1H), 2.74 (s, 3H), 2.68 - 2.56 (m, 2H), 2.21 - 2.08 (m, 3H), 2.01 (s, 3H), 1.26 (s, 2H), 1.09 - 0.95 (m, 4H), 0.75 - 0.70 (m, 2H). Example 253: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(1-ethylpiperidin-4-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000718] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperidin-4-yl)phenyl) amino)-5-((difluoro-l3- methyl)-l2-fluoraneyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 58% yield. m/z (ESI, +ve)= 646.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.16 - 8.02 (m, 2H), 7.88 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.08 (s, 1H), 3.97 (t, J = 6.0 Hz, 2H), 3.72 - 3.56 (m, 4H), 3.17 - 3.02 (m, 2H), 2.98 - 2.91 (m, 1H), 2.81 - 2.71 (m, 2H), 2.42 - 2.20 (m, 3H), 2.11 - 2.05 (m, 2H), 1.89 - 1.84 (m, 1H), 1.46 (t, J = 7.2 Hz, 3H), 1.26 (s, 2H), 1.12 - 0.96 (m, 4H), 0.73 (q, J = 5.2 Hz, 2H). Example 254: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(1-(oxetan-3-ylmethyl)p iperidin-4- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000719] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperidin-4-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and oxetane-3-carbaldehyde. The title compound was isolated in 79% yield. m/z (ESI, +ve)= 688.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.07 (s, 2H), 7.86 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.06 (s, 1H), 5.03 - 4.69 (m, 4H), 4.52 - 4.42 (m, 3H), 3.99 - 3.90 (m, 3H), 3.65 (t, J = 6.0 Hz, 2H), 3.41 - 3.27 (m, 1H), 3.26 - 2.90 (m, 4H), 2.82 (d, J = 5.6 Hz, 2H), 2.49 (dd, J = 6.4, 12.0 Hz, 1H), 2.16 - 2.07 (m, 2H), 1.26 (s, 2H), 1.06 - 0.96 (m, 4H), 0.76 - 0.68 (m, 2H). Example 255: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(4-ethylpiperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000720] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 73% yield. m/z (ESI, +ve)= 647.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1 H), 8.05 (s, 1 H), 7.92 - 7.88 (m, 1 H), 7.70 - 7.68 (m, 1 H), 6.91 - 6.89 (m, 1 H), 6.76 (d, J = 2.4 Hz, 1 H), 3.96 - 3.93 (m, 2 H), 3.66 (t, J = 6.0 Hz, 2 H), 3.29 - 3.27 (m, 4 H), 2.93 - 2.91 (m, 1 H), 2.74 - 2.72 (m, 4 H), 2.62 - 2.58 (m, 2 H), 1.71 - 1.70 (m, 1 H), 1.21 (t, J = 7.2 Hz, 3 H), 1.04 - 0.99 (m, 2 H), 0.95 - 0.94 (m, 4 H), 0.72 - 0.70 (m, 2 H). Example 256: 7-(2-((7-cyclopropyl-2-(cyclopropylmethyl)-1,2,3,4-tetrahydr oisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000721] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 20% yield. m/z (ESI, +ve)= 660.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.82 (s, 1H), 7.82 (s, 1H), 7.16 (s, 1H), 6.71 (s, 1H), 5.24 – 5.20 (m, 1H), 4.75 – 4.67 (m, 4H), 4.41 – 4.00 (m, 4H), 3.58 (s, 1H), 2.81 – 2.78 (m, 3H), 2.3 (s, 1H), 1.99 – 1.91 (m, 2H), 1.04 – 1.03 (m, 2H), 0.87 – 0.80 (m, 3H), 0.58- 0.57 (m, 4H), 0.17 (s, 2H). Example 257: 7-(2-((7-cyclopropyl-2-(oxetan-3-ylmethyl)-1,2,3,4-tetrahydr oisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000722] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(piperidin-4-yl)phenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and oxetane-3-carbaldehyde. The title compound was isolated in 28% yield. m/z (ESI, +ve)= 676.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.81 (brs, 1H), 7.82 (s, 1H), 7.12 (s, 1H), 6.66 (s, 1H), 5.24-5.20 (m, 1H), 4.76-4.65 (m, 4H), 4.30 (t, J = 6.0 Hz, 2H), 4.01-3.90 (m, 4H), 3.45 (s, 2H), 3.33-3.30 (m, 1H), 2.78-2.73 (m, 4H), 2.61-2.56 (m, 2H), 1.95-1.90 (m, 1H), 0.82-0.79 (m, 2H), 0.56-0.50 (m, 2H). Example 258: 7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(2,2,2-trifluoroethyl)-3, 4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000723] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-ethyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-(2,2,2-trifluoroethyl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 620.1 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.70 (s, 1H), 8.00 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 4.36 (q, J = 18.4, 9.2 Hz, 2H), 4.13 (s, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.84 (t, J = 5.6 Hz, 2H), 3.27 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.65 (q, J = 14.8, 7.2 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). Example 259: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- methylpyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 2-chloro-5-methyl-4-(trimethylstannyl)pyrimidine [000724] To a solution of 2,4-dichloro-5-methyl-pyrimidine (13 mmol) in dioxane (10 mL), hexamethylditin (25 mmol) and tetrakis(triphenylphosphine)palladium (0.61 mmol) were added in one portion. The reaction mixture was stirred overnight at 90°C, cooled down to room temperature and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography (0-50% ethyl acetate in hexanes ) to afford the title compound in 60% yield. m/z (ESI, +ve)= 292.9 [M+H] + . 1 H NMR (300 MHz, CDCl3) δ 0.42 (s, 9H), 2.32 (s, 3H), 8.21 (s, 1H). Step 2: 7-(2-chloro-5-methylpyrimidin-4-yl)-4-methyl-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000725] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 2-chloro-5-methyl-4-(trimethylstannyl)pyrimidine and 7-bromo-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated in 42% yield. MS (ESI) m/z: 358.0 [M+H] + . Step 3: 7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-( trifluoromethyl)pyrimidin-4-yl)- 4-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-f][1,4]thiaze pin-5(2H)-one 1,1-dioxide [000726] To a solution of 7-(2-chloro-5-methylpyrimidin-4-yl)-4-methyl-2H,3H,4H,5H-1λ ⁶-thieno[2,3- f][1,4]thiazepine-1,1,5-trione (0.27 mmol) in dioxane (2.0 mL), 1-(6-amino-7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one (0.32 mmol), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (0.054 mmol), cesium carbonate (0.54 mmol) and bis(dibenzylideneacetone)palladium(0) (0.027 mmol) were added. The reaction mixture was stirred overnight at 100°C, cooled down to room temperature and filtered. The filtrate was concentrated and the crude was purified by silica gel chromatography (0-35% ethyl acetate in dichloromethane) to afford the title compound in 18% yield. MS (ESI) m/z: 504.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.47 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 7.17 (s, 1H), 3.98 – 3.87 (m, 4H), 3.82 (s, 2H), 3.57 (s, 2H), 3.09 (s, 3H), 2.94 (t, J = 5.9 Hz, 2H), 2.69 (d, J = 5.5 Hz, 2H), 2.44 (s, 3H). Example 260: 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- methylpyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide [000727] The title compound was prepared analogously to Example 259, where 7-bromo-4-cyclopropyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-cyclopropyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 2 and 1-(6-amino-7-chloro-1,2,3,4- tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroethan-1-one with 7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin- 6-amine in step 3. The title compound was isolated. MS (ESI) m/z: 536.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 0.54 (m, 2H), 0.80 (m, 6H), 1.94 (m, 1H), 2.42 (s, 3H), 2.67 (m, 2H), 2.91 (m, 3H), 3.78 (s, 2H), 3.86 (s, 4H), 6.65 (s, 1H), 7.42 (s, 1H), 7.80 (s, 1H), 8.43 (s, 1H), 8.62 (s, 1H). Example 261: 4-cyclopropyl-7-(5-cyclopropyl-2-((7-cyclopropyl-1,2,3,4-tet rahydroisoquinolin-6- yl)amino)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiaze pin-5(2H)-one 1,1-dioxide [000728] The title compound was prepared analogously to Example 260, where 2,4-dichloro-5-methyl- pyrimidine was replaced with 2,4-dichloro-5-cyclopropylpyrimidine in step 1. The title compound was isolated. MS (ESI) m/z: 562.4 [M+H] + . (300 MHz, DMSO-d6) δ 0.54 (m, 2H), 0.78 (m, 8H), 1.01 (m, 2H), 1.99 (m, 2H), 2.66 (t, J = 5.9 Hz, 2H), 2.91 (m, 3H), 3.78 (s, 2H), 3.87 (s, 4H), 6.64 (s, 1H), 7.40 (s, 1H), 8.21 (s, 1H), 8.40 (s, 1H), 8.68 (s, 1H). Example 262: 7-(2-((6-ethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000729] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-ethyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 594.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.79 (s, 1H), 7.83 (s, 1H),7.08 - 7.03 (m, 2H), 5.26 - 5.19 (m, 1H), 4.76 - 4.68 (m, 4H), 4.02 (s, 4H), 3.91 (s, 2H), 3.06 (t, J = 4.8 Hz, 2H), 2.76 (d, J = 4.8 Hz, 2H), 2.54 - 2.52 (m, 3H), 1.08 (t, J = 7.6 Hz, 3H). Example 263: 4-cyclopropyl-7-(2-((7-isopropyl-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 2,2,2-trifluoro-1-(6-nitro-7-(prop-1-en-2-yl)-3,4-dihydroiso quinolin-2(1H)-yl)ethan-1-one [000730] The title compound was prepared analogously to Example 212, step 3 where 1-(6-bromo-7- nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethan one and tributyl(vinyl)stannane were replaced with 1-(7-bromo-6-nitro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-tr ifluoroethan-1-one and tributyl(prop-1-en-2-yl)stannane. The title compound was isolated in 49% yield. MS (ESI) m/z: 315.1 [M+H] + . Step 2: 1-(6-amino-7-(prop-1-en-2-yl)-3,4-dihydroisoquinolin-2(1H)-y l)-2,2,2-trifluoroethan-1-one [000731] To a solution of 2,2,2-trifluoro-1-(6-nitro-7-(prop-1-en-2-yl)-3,4-dihydroiso quinolin-2(1H)- yl)ethan-1-one (3.1 mmol) in methanol (30 mL) was added 10% palladium on carbon (300 mg). The mixture was hydrogenated at 50 psi for 2 hours, filtered through celite and concentrated to afford a residue that was purified by preparative. The title compound was isolated in 45% yield as a purple oil. MS (ESI) m/z: 285.5[M+H] + . Step 3: 1-(6-amino-7-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2, 2-trifluoroethan-1-one [000732] To a solution of 1-(6-amino-7-isopropenyl-3,4-dihydro-1H-isoquinolin-2-yl)-2, 2,2-trifluoro- ethanone (1.1 mmol) in methanol (20 mL) was hydrogenated at 50 psi in the presence of 10% palladium on carbon (100 mg) for 12 hours. The mixture was filtered through celite and concentrated to afford the title compound in 83% yield. MS (ESI) m/z: 287.1[M+H] + . Step 4: 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-i sopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000733] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with 1-(6-amino-7- isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one. The title compound was isolated in 25% yield. MS (ESI) m/z: 467.3[M+H] + . Step 5: 2,2,2-trifluoro-1-(7-isopropyl-6-((5-(trifluoromethyl)-4-(tr imethylstannyl)pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one [000734] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-i sopropyl-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 31% yield as a colorless oil. MS (ESI) m/z: 597.3 [M+H] + . Step 6-7: 4-cyclopropyl-7-(2-((7-isopropyl-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000735] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 2,2,2-trifluoro-1-(7-isopropyl-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)ethan-1-one in step 3. The title compound was isolated. MS (ESI) m/z: 592.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.71 (s, 1H), 8.06 (s, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.26 - 7.16 (m, 1H), 7.09 (s, 1H), 4.39 (s, 2H), 3.95 (t, J = 5.6 Hz, 2H), 3.64 (t, J = 5.6 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.21 (t, J = 5.6 Hz, 2H), 3.17 - 3.08 (m, 1H), 2.95 - 2.88 (m, 1H), 1.26 (s, 6H), 0.98 - 0.91 (m, 4H). Example 264: 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 4-(4-nitro-3-vinylphenyl)piperazine-1-carboxylate [000736] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one, and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with tributyl(vinyl)stannane and tert-butyl 4-(3-bromo-4-nitrophenyl)piperazine-1- carboxylate in step 3. The title compound was isolated. 1 H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9 H) 3.39 - 3.45 (m, 4 H) 3.58 - 3.64 (m, 4 H) 5.42 (dd, J = 10.8, 1.2 Hz, 1 H) 5.61 (dd, J = 17.2, 1.2 Hz, 1 H) 6.72 - 6.87 (m, 2 H) 7.37 (dd, J = 17.2, 10.8 Hz, 1 H) 8.06 (d, J = 9.2 Hz, 1 H). Step 2: tert-butyl 4-(4-amino-3-ethylphenyl)piperazine-1-carboxylate [000737] The title compound was prepared analogously to Example 263, step 5 where 1-(6-amino-7- isopropenyl-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro -ethanone was replaced with tert-butyl 4-(4- nitro-3-vinylphenyl)piperazine-1-carboxylate. The title compound was isolated in 66% yield. MS (ESI) m/z: 306.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 1.25 (t, J = 7.6 Hz, 3 H) 1.49 (s, 9 H) 2.51 (q, J = 7.6 Hz, 2 H) 2.99 (br s, 4 H) 3.55 - 3.67 (m, 4 H) 6.56 - 6.73 (m, 2 H) 6.76 (br s, 1 H). Step 3: tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethylphenyl)piperazine-1-carboxylate [000738] The title compound was prepared analogously to Example 1, step 5 where 1-(6-amino-7- chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2,2,2-trifluoroet han-1-one was replaced with tert-butyl 4-(4- amino-3-ethylphenyl)piperazine-1-carboxylate. The title compound was isolated in 42% yield. MS (ESI) m/z: 486.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 1.22 (t, J = 7.6 Hz, 3 H) 1.50 (s, 9 H) 2.60 (q, J = 7.6 Hz, 2 H) 3.17 (d, J = 4.4 Hz, 4 H) 3.59 (d, J = 4.4 Hz, 4 H) 6.77 - 6.91 (m, 2 H) 7.04 (br s, 1 H) 7.32 - 7.55 (m, 1 H) 8.48 (s, 1 H). Step 4: tert-butyl 4-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2- yl)amino)phenyl)piperazine-1-carboxylate [000739] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethylphenyl)piperazine-1-carboxylate. The title compound was isolated in 44% yield. MS (ESI) m/z: 614.4 [M+H] + . Step 5: 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino) -5-(trifluoromethyl)pyrimidin- 4-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000740] The title compound was prepared analogously to Example 149, steps 5-6, where tert-butyl 4- (4-chloro-3-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimi din-2-yl)amino)phenyl)piperidine-1- carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide were replaced with tert-butyl 4-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2- yl)amino)phenyl)piperazine-1-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 5. The title compound was isolated. MS (ESI) m/z: 607.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.90 - 0.97 (m, 4 H) 1.23 (t, J = 7.6 Hz, 4 H) 2.62 - 2.67 (m, 2 H) 2.87 - 2.94 (m, 1 H) 3.15 - 3.51 (m, 8 H) 3.64 (t, J = 5.6 Hz, 2 H) 3.93 (br s, 2 H) 6.79 - 6.93 (m, 2 H) 7.15 (br s, 1 H) 7.40 - 7.67 (m, 1 H) 8.03 (s, 1 H) 8.66 (s, 1 H). Example 265: 4-cyclopropyl-7-(2-((4-(4-(cyclopropylmethyl)piperazin-1-yl) -2-ethylphenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000741] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 53% yield. m/z (ESI, +ve)= 661.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.26 (d, J = 4.0 Hz, 2 H) 0.65 (d, J=7.2 Hz, 2 H) 0.89 - 1.09 (m, 5 H) 1.23 (t, J = 7.6 Hz, 3 H) 2.56 - 2.70 (m, 4 H) 2.83 - 3.07 (m, 5 H) 3.38 (br s, 4 H) 3.64 (t, J = 5.6 Hz, 2 H) 3.93 (br s, 2 H) 6.77 - 6.95 (m, 2 H) 7.10 (br s, 1 H) 7.39 - 7.70 (m, 1 H) 8.02 (s, 1 H) 8.66 (s, 1 H). Example 266: 4-cyclopropyl-7-(2-((2-ethyl-4-(4-(oxetan-3-ylmethyl)piperaz in-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000742] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and oxetane-3-carbaldehyde. The title compound was isolated in 46% yield. m/z (ESI, +ve)= 677.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.87 - 1.02 (m, 4 H) 1.22 (t, J = 7.6 Hz, 3 H) 2.53 - 2.71 (m, 6 H) 2.78 - 2.95 (m, 3 H) 3.24 (br s, 4 H) 3.30 - 3.40 (m, 1 H) 3.64 (t, J = 5.2 Hz, 2 H) 3.91 (d, J = 6.8 Hz, 2 H) 4.45 - 4.49 (m, 2 H) 4.85 (dd, J = 7.6, 6.0 Hz, 2 H) 6.83 (br s, 2 H) 7.11 (br s, 1 H) 7.32 - 7.65 (m, 1 H) 8.02 (s, 1 H) 8.65 (s, 1 H). Example 267: 4-cyclopropyl-7-(2-((2-ethyl-7-isopropyl-1,2,3,4-tetrahydroi soquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000743] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-isopropyl-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 85% yield. m/z (ESI, +ve)= 620.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.05 (s, 1H), 7.62 - 7.39 (m, 1H), 7.23 - 7.19 (m, 1H), 7.04 (s, 1H), 4.05 - 3.89 (m, 4H), 3.64 (t, J = 5.8 Hz, 2H), 3.20 - 3.04 (m, 5H), 2.99 - 2.89 (m, 3H), 1.41 - 1.36 (m, 3H), 1.25 (d, J = 6.8 Hz, 6H), 0.98 - 0.92 (m, 4H). Example 268: 4-cyclopropyl-7-(2-((2-(cyclopropylmethyl)-7-isopropyl-1,2,3 ,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000744] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-isopropyl-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 84% yield. m/z (ESI, +ve)= 646.4 [M+H] + . 1 H NMR (400 MHz,CDCl 3 ) δ 8.68 (s, 1H), 8.04 (s, 1H), 7.58 - 7.40 (m, 1H), 7.37 - 7.28 (m, 1H), 7.23 - 7.17 (m, 1H), 7.04 (s, 1H), 4.00 - 3.84 (m, 4H), 3.64 (t, J = 5.6 Hz, 2H), 3.11 (d, J = 6.8 Hz, 1H), 3.09 - 2.95 (m, 4H), 2.93 - 2.88 (m, 1H), 2.69 - 2.57 (m, 2H), 1.25 (d, J = 6.8 Hz, 6H), 1.10 - 1.05 (m, 1H), 0.98 - 0.92 (m, 4H), 0.66 (d, J = 7.6 Hz, 2H), 0.28 (d, J = 4.8 Hz, 2H). Example 269: 4-cyclopropyl-7-(2-((7-isopropyl-2-(oxetan-3-ylmethyl)-1,2,3 ,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000745] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-isopropyl-1,2,3,4-tetrahydroisoquinol in-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and cycloprooxetane-3-carbaldehyde. The title compound was isolated in 79% yield. MS (ESI) m/z: 662.2 [M+H] + . 1 H NMR (400 MHz,CDCl3) δ 8.59 (s, 1H), 7.97 (s, 1H), 7.43 - 7.21 (m, 1H), 7.10 - 7.03 (m, 1H), 6.91 (s, 1H), 4.81 - 4.72 (m, 3H), 4.41 (t, J = 6.0 Hz, 2H), 3.87 - 3.83 (m, 2H), 3.62 - 3.46 (m, 4H), 3.34 - 3.22 (m, 1H), 3.07 - 2.96 (m, 1H), 2.86 - 2.81 (m, 4H), 2.71 - 2.59 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.92 - 0.85 (m, 4H). Example 270: 7-(2-((6-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000746] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(6-cyclopropyl-7-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-bromo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 3. The title compound was isolated. MS (ESI) m/z: 606.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.76 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 6.96 (s, 1H), 5.29 (t, J = 7.2 Hz, 1H), 4.91 (s, 2H), 4.84 (s, 2H), 4.30 (s, 2H), 4.07-4.04 (m, 2H), 3.91- 3.89 (m, 2H), 3.43 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H), 2.00-1.93 (m, 1H), 0.99-0.94 (m, 2H), 0.67-0.63 (m, 2H). Example 271: 4-cyclopropyl-7-(2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000747] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and acetaldehyde. The title compound was isolated in 58% yield. m/z (ESI, +ve)= 635.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.87 - 1.00 (m, 4 H) 1.19 - 1.30 (m, 6 H) 2.64 (q, J = 7.6 Hz, 2 H) 2.69 - 2.79 (m, 2 H) 2.79 - 3.00 (m, 5 H) 3.37 (br s, 4 H) 3.64 (t, J = 5.6 Hz, 2 H) 3.93 (br s, 2 H) 6.77 - 6.92 (m, 2 H) 7.08 (br s, 1 H) 7.37 - 7.70 (m, 1 H) 8.03 (s, 1 H) 8.66 (s, 1 H). Example 272: 4-cyclopropyl-7-(2-((2-ethyl-4-(4-isopropylpiperazin-1-yl)ph enyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000748] To a solution of 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide (0.03 mmol) in methyl alcohol (1 mL) and acetic acid (0.1 mL) was added acetone (0.10 mmol). The mixture was stirred at room temperature for 30 minutes and sodium cyanoborohydride (0.07 mmol) was added. After 1 hour, the reaction was filtered and concentrated to afford a residue that was purified by preparative TLC. The title compound was isolated in 59% yield. MS (ESI) m/z: 649.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.79 (br s, 4 H) 1.01 (d, J = 6.4 Hz, 6 H) 1.08 (t, J = 7.6 Hz, 3 H) 2.52 - 2.62 (m, 6 H) 2.65 - 2.73 (m, 1 H) 2.87 (br dd, J = 5.6, 3.6Hz, 1 H) 3.13 (d, J = 4.0 Hz, 4 H) 3.78 - 3.97 (m, 4 H) 6.66 - 6.89 (m, 2 H) 6.98 - 7.30 (m, 1 H) 7.64 - 7.91 (m, 1 H) 8.53 - 8.96 (m, 1 H) 9.52 - 9.82 (m, 1 H). Example 273: 4-cyclopropyl-7-(2-((7-(trifluoromethoxy)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1-5: 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-( trifluoromethoxy)-3,4- dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one [000749] The title compound was prepared analogously to Example 1, steps 1-5, where 2-(4- chlorophenyl)ethylamine was replaced with 2-[4-(trifluoromethoxy)phenyl]ethanamine in step 1. The title compound was isolated. MS (ESI) m/z: 509.0 [M+H] + . Step 6: 7-(trifluoromethoxy)-N-(5-(trifluoromethyl)-4-(trimethylstan nyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-amine [000750] The title compound was prepared analogously to Example 4, step 1 where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 1-(6-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-( trifluoromethoxy)- 3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated in 27% yield. MS (ESI) m/z: 639.0 [M+H] + . Step 7: 4-cyclopropyl-7-(2-((7-(trifluoromethoxy)-1,2,3,4-tetrahydro isoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000751] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 7-(trifluoromethoxy)-N-(5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquino lin-6-amine in step 3. The title compound was isolated. MS (ESI) m/z: 634.1 [M+H] +. 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.63 (s, 1H), 7.02 (s, 1H), 4.11 (s, 2H), 3.97 (t, J = 5.6 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.29 (t, J = 5.6 Hz, 2H), 3.07 - 2.99 (m, 2H), 2.96 - 2.92 (m, 1H), 1.01 - 0.91 (m, 4H). Example 274: 7-(2-((2-(cyclopropylmethyl)-7-ethyl-1,2,3,4-tetrahydroisoqu inolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000752] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide and cyclopropanecarbaldehyde. The title compound was isolated in 56% yield. m/z (ESI, +ve)= 648.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.71 (s, 1H), 8.01 (s, 1H), 7.36 - 7.26 (m, 1H), 7.08 (s, 1H), 5.32 - 5.25 (m, 1H), 4.04 (t, J = 5.6 Hz, 2H), 3.96 (s, 2H), 3.90 - 3.86 (m, 2H), 3.08 - 3.03 (m, 4H), 2.68 - 2.60 (m, 4H), 1.29 (s, 3H), 1.17 (t, J = 7.6 Hz, 3H), 1.11 - 1.04 (m, 1H), 0.93 - 0.84 (m, 1H), 0.70 - 0.64 (m, 2H), 0.34 - 0.29 (m, 2H). Example 275: 7-(2-((7-ethyl-2-(oxetan-3-ylmethyl)-1,2,3,4-tetrahydroisoqu inolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000753] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide and oxetane-3- carbaldehyde. The title compound was isolated in 48% yield. m/z (ESI, +ve)= 664.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.69 (s, 1H), 8.00 (s, 1H), 7.24 (s, 1H), 7.01 (s, 1H), 5.30 (t, J = 7.2 Hz, 1H), 4.81 - 4.77 (m, 1H), 4.75 - 4.69 (m, 1H), 4.59 - 4.53 (m, 1H), 4.52 - 4.46 (m, 3H), 4.02 (d, J = 5.6 Hz, 2H), 3.89 - 3.84 (m, 2H), 3.76 (d, J = 6.4 Hz, 1H), 3.63 (s, 2H), 3.46 - 3.39 (m, 1H), 3.17 - 3.06 (m, 1H), 2.96 - 2.90 (m, 4H), 2.80 - 2.74 (m, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). Example 276: 2-(7-cyclopropyl-6-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3, 4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)- yl)acetonitrile [000754] A mixture of 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide (0.02 mmol), 2-bromoacetonitrile (0.03 mmol) and triethylamine (0.05 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 12 hours. The mixture was filtered and concentrated, and the residue was purified by preparative TLC (15% methanol in dichloromethane). The title compound was isolated in 47% yield. MS (ESI) m/z: 629.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.75 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 6.89 (s, 1H), 3.96 (t, J = 5.6 Hz, 2H), 3.80 (s, 2H), 3.76 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.12 - 3.04 (m, 2H), 2.98 - 2.89 (m, 3H), 1.88 - 1.82 (m, 1H), 1.09 - 1.03 (m, 2H), 1.00 - 0.93 (m, 4H), 0.71 - 0.65 (m, 2H). Example 277: 4-cyclopropyl-7-(2-((7-ethyl-2-(oxetan-3-ylmethyl)-1,2,3,4-t etrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000755] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-( trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide and oxetane-3- carbaldehyde. The title compound was isolated in 21% yield. m/z (ESI, +ve)= 648.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.73 - 8.65 (m, 1H), 7.97 (s, 1H), 7.25 - 7.24 (m, 1H), 7.02 (s, 1H), 4.56 - 4.44 (m, 4H), 3.95 (m, 2H), 3.77 - 3.72 (m, 3H), 3.66 - 3.61 (m, 2H), 3.45 - 3.39 (m, 1H), 2.95 - 2.92 (m, 4H), 2.80 - 2.75 (m, 2H), 2.66 - 2.60 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H), 0.92 - 0.89 (m, 4H). Example 278: 2-(7-cyclopropyl-6-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3, 4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)- yl)acetamide [000756] To a solution of 4-cyclopropyl-7-[2-[(7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6- yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-2,3-d ihydrothieno[2,3-f][1,4]thiazepin-5-one (0.05 mmol) in N,N-dimethylformamide (0.5 mL) was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.10 mmol) and 2-bromoacetamide (0.13 mmol). The mixture was stirred for 12 hours, filtered and concentrated. The residue was purified by preparative TLC (15% methanol in dichloromethane). The title compound was isolated in 48% yield. MS (ESI) m/z: 646.2 [M+H] + . 1 H NMR (400MHz, CD3OD) 8.74 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 6.81 (s, 1H), 3.99 (t, J = 5.6 Hz, 2H), 3.85 - 3.73 (m, 4H), 3.25 (s, 2H), 3.06 - 2.96 (m, 2H), 2.96 - 2.86 (m, 3H), 2.03 - 1.87 (m, 1H), 0.94 - 0.92 (m, 4H), 0.69 - 0.59 (m, 2H). Example 279: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-((3-methyloxetan-3-yl)m ethyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000757] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and 3- methyloxetane-3-carbaldehyde. The title compound was isolated in 63% yield. m/z (ESI, +ve)= 674.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.09 (s, 1H), 7.96 - 7.90 (m, 1H), 7.89 - 7.85 (m, 1H), 6.84 (s, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.41 (d, J = 5.6 Hz, 2H), 3.96 (t, J = 6.0 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.51 (s, 2H), 2.97 - 2.92 (m, 3H), 2.75 (s, 2H), 2.66 (t, J = 5.6 Hz, 2H), 1.84 - 1.83 (m, 1H), 1.45 (s, 3H), 1.04 - 1.02 (m, 2H), 0.99 - 0.95 (m, 4H), 0.69 - 0.68 (m, 2H). Example 280: 2-(4-(4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3,4,5-tetrahy drothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)-3-ethylphenyl)piperazin-1- yl)acetamide [000758] The title compound was prepared analogously to Example 278, where 4-cyclopropyl-7-[2-[(7- cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-5-(tri fluoromethyl)pyrimidin-4-yl]-1,1-dioxo-2,3- dihydrothieno[2,3-f][1,4]thiazepin-5-one was replaced with 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 36% yield. MS (ESI) m/z: 664.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ ppm 0.89 - 1.00 (m, 4 H) 1.24 (t, J = 7.6 Hz, 3 H) 2.65 (q, J = 7.6 Hz, 2 H) 2.71 - 2.80 (m, 4 H) 2.87 - 2.97 (m, 1 H) 3.11 (s, 2 H) 3.21 - 3.32 (m, 4 H) 3.64 (br t, J = 6.0 Hz, 2 H) 3.93 (br s, 2 H) 5.36 - 5.52 (m, 1 H) 6.85 (br d, J = 2.4 Hz, 2 H) 6.98 - 7.14 (m, 2 H) 7.38 - 7.70 (m, 1 H) 8.04 (s, 1 H) 8.67 (s, 1 H). Example 281: 4-cyclopropyl-7-(2-((4-(1-(2,2-difluoroethyl)piperidin-4-yl) -2-ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000759] The title compound was prepared analogously to Example 240, where tert-butyl 4-(4-amino-3- cyclopropylphenyl)piperidine-1-carboxylate was replaced with tert-butyl 4-(4-amino-3- ethylphenyl)piperidine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 606.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.88 (s, 1H), 8.79 (s, 1H), 7.79 (s, 1H), 7.32 (s, 1H), 7.15 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 3.87 (s, 4H), 3.39 (s, 1H), 3.01 (t, J = 11.2 Hz, 2H), 2.87 (d, J = 12.4 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.51 (s, 1H), 1.96 (d, J = 12.4 Hz, 2H), 1.87 - 1.77 (m, 2H), 1.11 (t, J = 7.6 Hz, 3H), 0.79 (s, 4H). Step 2: 4-cyclopropyl-7-(2-((4-(1-(2,2-difluoroethyl)piperidin-4-yl) -2-ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000760] To a solution of 4-cyclopropyl-7-[2-[2-ethyl-4-(4-piperidyl)anilino]-5- (trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrothieno [2,3-f][1,4]thiazepin-5-one (0.13 mmol) in dichloromethane (1 mL) was added triethylamine (0.40 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (0.14 mmol). The mixture was stirred at 50 °C for 2 hours, cooled down to room temperature and concentrated. The residue was purified by preparative TLC (5% methanol in dichloromethane) to afford the title compound in 38% yield. MS (ESI) m/z: 670.3 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.66 (s, 1H), 7.96 (s, 1H), 7.33 (d, J = 6.4 Hz, 1H), 7.20 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.02 (tt, J = 55.6, 4.0 Hz, 1H), 3.95 (s, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.10 (d, J = 11.2 Hz, 2H), 2.90 - 2.87 (m, 1H), 2.80 (m, 2H), 2.66 (q, J = 7.6 Hz, 2H), 2.58 - 2.53 (m, 1H), 2.40 - 2.34 (m, 2H), 1.86 - 1.80 (m, 4H), 1.18 (t, J = 7.6 Hz, 3H), 0.90 - 0.89 (m, 4H). Example 282: 4-cyclopropyl-7-(2-((2-ethyl-4-(1-(2-fluoroethyl)piperidin-4 -yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000761] The title compound was prepared analogously to Example 281, where 2,2-difluoroethyl trifluoromethanesulfonate was replaced with 1-bromo-2-fluoro-ethane in step 2. The title compound was isolated in 32% yield. MS (ESI) m/z: 652.2[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.66 (s, 1H), 7.96 (s, 1H), 7.34 - 7.33 (m, 1H), 7.21 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.69 (t, J = 4.8 Hz, 1H), 4.57 (t, J = 4.8 Hz, 1H), 4.00 – 3.00 (m, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.14 (d, J = 11.6 Hz, 2H), 2.91 - 2.88 (m, 1H), 2.82 (t, J = 4.8 Hz, 1H), 2.74 (t, J = 4.8 Hz, 1H), 2.66 (q, J = 7.6 Hz, 2H), 2.62 - 2.55 (m, 1H), 2.32 - 2.25 (m, 2H), 1.90 - 1.83 (m, 4H), 1.18 (t, J = 7.6 Hz, 3H), 0.91 - 0.90 (m, 4H). Example 283: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- cyclopropylpyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide [000762] The title compound was prepared analogously to Example 259, where 2,4-dichloro-5-methyl- pyrimidine was replaced with 2,4-dichloro-5-cyclopropyl-pyrimidine in step 1. The title compound was isolated. 1 H NMR (400MHz, DMSO-d6) δ 8.93 (S, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 7.58 (S, 1H), 7.28 (s, 1H), 4.02-3.86 (m, 6H), 3.10 (d, J= 8.5 Hz, 5H), 2.80 (t, J= 6.1 Hz, 2H), 2.11-1.99 (m, 1H), 1.03 (q, J=5.6, 4.9 Hz, 2H), 0.78 (q, J= 5.3 Hz, 2H). Example 284: 2-(7-cyclopropyl-6-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-oxo-2, 3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)acetamide [000763] To a solution of 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.04 mmol) in dimethylformamide (1 mL) was added 2-bromoacetamide (0.06 mmol) and potassium carbonate (0.08 mmol). The mixture was stirred at room temperature for one hour, concentrated and the residue purified by preparative TLC (95% dichloromethane in methanol). The title compound was isolated in 84% yield. MS (ESI) m/z: 663.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.13 (s, 1H), 7.99 - 7.85 (m, 2H), 6.87 (s, 1H), 5.56 - 5.50 (m, 1H), 5.50 - 5.44 (m, 1H), 5.04 (t, J = 7.4 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.14 (t, J = 6.0 Hz, 2H), 3.80 (t, J = 5.8 Hz, 2H), 3.75 (s, 2H), 3.25 (s, 2H), 3.06 - 3.00 (m, 2H), 2.97 - 2.88 (m, 2H), 1.06 - 1.03 (m, 2H), 0.70 - 0.66 (m, 2H) Example 285: 2-(7-cyclopropyl-6-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-oxo-2, 3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)acetonitrile [000764] The title compound was prepared analogously to Example 284, where 7-(2-((7-cyclopropyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 2-bromoacetamide were replaced with 7- (2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino) -5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide and 2-bromoacetonitrile. The title compound was isolated in 87 % yield. MS (ESI) m/z: 645.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 6.88 (s, 1H), 5.60 - 5.49 (m, 1H), 5.04 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.81 - 3.77 (m, 2H), 3.76 (s, 2H), 3.73 (s, 2H), 3.08 - 2.99 (m, 2H), 2.93 - 2.86 (m, 2H), 1.88 - 1.79 (m, 1H), 1.08 - 1.01 (m, 2H), 0.72 - 0.65 (m, 2H). Example 286: 7-(2-((7-cyclopropyl-2-((3-methyloxetan-3-yl)methyl)-1,2,3,4 -tetrahydroisoquinolin- 6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-y l)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000765] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide and 3-methyloxetane-3-carbaldehyde. The title compound was isolated in 60% yield. m/z (ESI, +ve)= 690.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.75 (s, 1H), 8.12 (s, 1H), 7.98 - 7.75 (m, 2H), 6.83 (s, 1H), 5.55 (quin, J = 6.8 Hz, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (br t, J = 6.8 Hz, 2H), 4.57 (br d, J = 5.2 Hz, 2H), 4.40 (d, J = 5.6 Hz, 2H), 4.13 (br t, J = 5.6 Hz, 2H), 3.79 (br t, J = 5.6 Hz, 2H), 3.51 (s, 2H), 2.95 (br s, 2H), 2.75 (s, 2H), 2.71 - 2.61 (m, 2H), 1.88 - 1.77 (m, 1H), 1.45 (s, 3H), 1.03 (br d, J = 7.6 Hz, 2H), 0.68 (br d, J = 4.8 Hz, 2H). Example 287: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-(2-hydroxy-2-methylprop yl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000766] A solution of 4-cyclopropyl-7-[2-[(7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrothieno [2,3-f][1,4]thiazepin-5-one (0.051 mmol), 2,2-dimethyloxirane (0.51 mmol) and triethylamine (0.25 mmol) in ethanol (1 mL) was stirred at 80 °C for 12 hours. The crude was purified directly by preparative TLC (10% methanol in dichloromethane) to afford the title compound in 64% yield. MS (ESI) m/z: 662.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 6.85 (s, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.80 (s, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.99 - 2.91 (m, 5H), 2.52 (s, 2H), 1.87 - 1.82 (m, 1H), 1.23 (s, 6H), 1.05 - 1.03 (m, 2H), 0.96 - 0.93 (m, 4H), 0.69 - 0.68 (m, 2H). Example 288: 4-cyclopropyl-7-(2-((2-ethyl-4-(1-(2,2,2-trifluoroethyl)pipe ridin-4-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000767] The title compound was prepared analogously to Example 281, where 2,2-difluoroethyl trifluoromethanesulfonate was replaced with 2,2,2-trifluoroethyl trifluoromethanesulfonate in step 2. The title compound was isolated in 27% yield. MS (ESI) m/z: 688.3 [M+H] + . 1 H NMR (400MHz, methanol- d4) δ 8.66 (s, 1H), 7.96 (s, 1H), 7.33 (s, 1H), 7.20 (s, 1H), 7.14 (dd, J = 8.0, 1.6 Hz, 1H), 4.58 (s, 1H), 3.94 (d, J = 4.8 Hz, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.10 (m, 4H), 2.92 - 2.87 (m, 1H), 2.66 (q, J = 14.8, 7.2 Hz, 2H), 2.57 - 2.48 (m, 3H), 1.86 - 1.82 (m, 4H), 1.18 (t, J = 7.6 Hz, 3H), 0.91 - 0.89 (m, 4H). Example 289: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-(oxetan-3-yl)-1,2,3,4-t etrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000768] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and oxetan-3-one. The title compound was isolated in 65% yield. m/z (ESI, +ve)= 646.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.89 - 8.74 (m, 1H), 7.80 (s, 1H), 7.27 - 7.10 (m, 1H), 6.70 (s, 1H), 4.68 - 4.59 (m, 2H), 4.58 - 4.50 (m, 2H), 3.96 - 3.76 (m, 5H), 3.65 - 3.48 (m, 4H), 2.91 - 2.76 (m, 3H), 2.01 - 1.84 (m, 1H), 0.86 - 0.74 (m, 6H), 0.61 - 0.49 (m, 2H). Example 290: 7-(2-((7-cyclopropyl-2-(2-fluoroethyl)-1,2,3,4-tetrahydroiso quinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000769] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((7-cyclopropyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 40% yield. MS (ESI) m/z: 651.1 MHz, CDCl3-d) δ, 0.65 - 0.70 (m, 2 H) 0.98 - 1.05 (m, 2 H) 1.79 - 1.86 (m, 1 H) 2.87 (br t, J=5.6 Hz, 3 H) 2.93 (t, J=4.8 Hz, 1 H) 3.00 (br t, J=5.2 Hz, 2 H) 3.71 (s, 2 H) 3.77 - 3.82 (m, 2 H) 4.14 (t, J=5.6 Hz, 2 H) 4.59 - 4.65 (m, 1 H) 4.71 - 4.77 (m, 3 H) 5.04 (t, J=7.6 Hz, 2 H) 5.56 (t, J=6.4 Hz, 1 H) 6.86 (s, 1 H) 7.85 (br s, 1 H) 7.90 (br s, 1 H) 8.12 (s, 1 H) 8.70 - 8.79 (m, 1 H). Example 291: 7-(2-((7-cyclopropyl-2-(2-hydroxy-2-methylpropyl)-1,2,3,4-te trahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000770] To a solution of 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.07 mmol) and 2,2-dimethyloxirane (0.07 mmol) in ethanol (3 mL) was added triethylamine (0.33 mmol).and the mixture was stirred at 80 °C for 12 hours. The reaction was concentrated under reduced pressure to afford a residue that was purified by preparative TLC (10%methanol in dichloromethane) to afford the title compound in 53% yield. MS (ESI) m/z: 678.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 8.13 (s, 1H), 8.08 - 7.95 (m, 1H), 7.92 - 7.74 (m, 1H), 6.87 (s, 1H), 5.57 - 5.49 (m, 1H), 5.04 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.15 (t, J = 6.0 Hz, 2H), 3.79 (t, J = 6.0 Hz, 4H), 3.29 - 2.89 (m, 4H), 2.87 - 2.39 (m, 2H), 1.86 - 1.81 (m, 1H), 1.37 - 1.25 (m, 6H), 1.06 (d, J = 7.6 Hz, 2H), 0.72 - 0.66 (m, 2H). Example 292: 7-(2-((7-cyclopropyl-2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoqu inolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000771] The title compound was prepared analogously to Example 17, where 5-(2-((6-chloroisoindolin- 5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)thiophene-3-ca rboxamide and formaldehyde were replaced with 7-(2-((7-cyclopropyl-2-(oxetan-3-yl)-1,2,3,4-tetrahydroisoqu inolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide and oxetan-3-one. The title compound was isolated in 49% yield. m/z (ESI, +ve)= 662.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.85 (br s, 1H), 6.85 (s, 1H), 5.60 - 5.48 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.80 - 4.71 (m, 6H), 4.14 (t, J = 6.0 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.70 (t, J = 6.4 Hz, 1H), 3.48 (s, 2H), 3.00 (br t, J = 5.6 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 1.86 - 1.79 (m, 1H), 1.05 - 1.00 (m, 2H), 0.70 - 0.63 (m, 2H). Example 293: 4-Cyclopropyl-7-(2-((2,7-dicyclopropyl-1,2,3,4-tetrahydroiso quinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000772] To a solution of 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothie no[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.07 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was added (1- ethoxycyclopropoxy)trimethylsilane (0.14 mmol), acetic acid (0.1 mL) and sodium cyanoborohydride (0.10 mmol). The mixture was stirred at 80 °C for 12 hours, cooled down to room temperature and purified by preparative TLC (9% methanol in dichloromethane) to afford the title compound in 50% yield. MS (ESI) m/z: 630.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.73 (s, 1H), 8.08 (s, 1H), 8.01 - 7.92 (m, 1H), 7.91 - 7.83 (m, 1H), 6.88 (s, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.91 - 3.70 (m, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.15 - 2.95 (m, 2H), 2.95 - 2.90 (m, 1H), 1.90 - 1.75 (m, 2H), 1.26 (s, 2H), 1.08 - 1.00 (m, 2H), 1.00 - 0.84 (m, 5H), 0.70 - 0.66 (m, 2H), 0.65 - 0.44 (m, 3H). Example 294: 4-Cyclopropyl-7-(2-((4-(4-cyclopropylpiperazin-1-yl)-2-ethyl phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000773] A solution of 4-cyclopropyl-7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide (0.07 mmol) and cyclopropylboronic acid (0.07 mmol) in dichloroethane (2 mL) was treated with sodium carbonate (0.19 mmol), 2-(2-pyridyl)pyridine (0.13 mmol) and copper acetate (0.13 mmol). The mixture was stirred at 60 °C for 2 hours, cooled down to room temperature, filtered and concentrated under reduced pressure to afford a residue that was purified by preparative HPLC. The title compound was isolated in 27% yield. MS (ESI) m/z: 647.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.39 - 0.61 (m, 3 H) 0.75 - 0.97 (m, 4 H) 1.05 - 1.24 (m, 4 H) 1.40 - 1.59 (m, 2 H) 2.51 - 2.60 (m, 2 H) 2.67 - 2.88 (m, 4 H) 3.05 - 3.27 (m, 4 H) 3.47 - 3.60 (m, 2 H) 3.79 - 3.92 (m, 2 H) 6.67 - 6.84 (m, 2 H) 6.89 - 7.09 (m, 1 H) 7.31 - 7.67 (m, 1 H) 7.87 - 8.03 (m, 1 H) 8.49 - 8.69 (m, 1 H). Example 295: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydro-2H-thieno[3,2-f ][1,5,2]dithiazepine 1,1,5,5-tetraoxide Step 1: 3-Bromothiophene-2-sulfonyl chloride [000774] A 0° C solution of 3-bromothiophene (123 mmol) in dichloromethane (200 mL) was treated with a solution of sulfurochloridic acid (491 mmol) in dichloromethane (200 mL). The reaction was allowed to reach 25 °C over 30 minutes and stirring continued for another 4 hours. The mixture was poured into ice water and extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel column chromatography (0-15% ethyl acetate in hexanes). The title compound was isolated as a colorless oil in 57% yield. 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H). Step 2: 3-Bromo-N-(4-methoxybenzyl)thiophene-2-sulfonamide [000775] To a 0 °C solution of 3-bromothiophene-2-sulfonyl chloride (57 mmol) in dichloromethane (150 mL) was added (4-methoxyphenyl)methanamine (68 mmol) and triethylamine (68 mmol). The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure to afford a residue that was purified by silica gel column chromatography (5-25% ethyl acetate in hexanes). The title compound was isolated in 91% yield. 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 5.2 Hz, 1H), 7.19 - 7.13 (m, 2H), 7.10 (d, J = 5.2 Hz, 1H), 6.87 - 6.80 (m, 2H), 5.18 (t, J = 5.6 Hz, 1H), 4.15 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H). Step 3: 3-((2-Hydroxyethyl)thio)-N-(4-methoxybenzyl)thiophene-2-sulf onamide [000776] To a solution of 3-bromo-N-(4-methoxybenzyl)thiophene-2-sulfonamide (51 mmol) and 2- mercaptoethan-1-ol (77 mmol) in dioxane (200 mL) was added N,N-diisopropylethyl amine (154 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.28 mmol). The mixture was stirred at 130 °C, cooled down to room temperature and diluted with water. The mixture was extracted with ethyl acetate twice, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a residue that was purified by preparative TLC (35% ethyl acetate in hexanes). The title compound was isolate din 79% yield. 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 5.2 Hz, 1H), 7.17 - 7.09 (m, 3H), 6.82 (d, J = 8.4 Hz, 2H), 5.50 (t, J = 5.6 Hz, 1H), 4.13 - 4.10 (m, 2H), 3.79 (s, 3H), 3.65 (q, J = 5.6 Hz, 2H), 3.06 (t, J = 5.6 Hz, 2H), 2.65 (t, J = 6.0 Hz, 1H). Step 4: 2-(4-Methoxybenzyl)-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithi azepine 1,1-dioxide [000777] To a solution of 3-((2-hydroxyethyl)thio)-N-(4-methoxybenzyl)thiophene-2-sulf onamide (41 mmol) in tetrahydrofuran (150 mL) was added triphenylphosphine (49 mmol) and diisopropylazodicarboxylate (49 mmol). The mixture was stirred at 25 °C for 30 minutes, diluted with water and extracted with ethyl acetate three times. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel column chromatography (0-25% ethyl acetate in hexanes). The title compound was isolated in 79% yield. NMR (400 MHz, CDCl3) δ 7.36 (d, J = 5.2 Hz, 1H), 7.21 - 7.19 (m, 2H), 6.95 (d, J = 5.2 Hz, 1H), 6.85 - 6.78 (m, 2H), 4.91 (td, J = 6.4, 12.4 Hz, 4H), 4.23 (s, 2H), 3.74 (s, 3H), 3.71 (td, J = 2.4, 5.2 Hz, 2H), 2.96 - 2.89 (m, 2H). Step 5: 7-Iodo-2-(4-methoxybenzyl)-3,4-dihydro-2H-thieno[3,2-f][1,5, 2]dithiazepine 1,1-dioxide [000778] To a -40 °C solution of 2-(4-methoxybenzyl)-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithi azepine 1,1-dioxide (0.59 mmol) in tetrahydrofuran (5 mL) was added a 1.5 M solution of 2,2,6,6- tetramethylpiperidinylmagnesium chloride lithium chloride complex in THF/toluene (1.56 mL). After 30 minutes at room temperature, the mixture was cooled down to -70 °C and iodine (1.17 mmol) in tetrahydrofuran (5 mL) was added dropwise. After 1 hour at room temperature the reaction mixture was poured into water, extracted with ethyl acetate twice and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (25% ethyl acetate in hexanes). The title compound was isolated in 37% yield as a colorless oil. 1H NMR (400 MHz, CDCl 3 ) δ 7.27 - 7.23 (m, 2H), 7.18 (s, 1H), 6.92 - 6.87 (m, 2H), 4.31 (s, 2H), 3.82 (s, 3H), 3.76 (td, J = 2.4, 5.2 Hz, 2H), 3.04 - 2.94 (m, 2H). Step 6: 7-Iodo-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1-dioxide [000779] Trifluoroacetic acid (2 mL) was added to a solution of 7-iodo-2-(4-methoxybenzyl)-3,4- dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1-dioxide (0.14 mmol) in dichloromethane (2 mL). After 2 hours the reaction was concentrated under reduced pressure and the residue was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (s, 1H), 7.35 (s, 1H), 3.61 (s, 2H), 2.98 (td, J = 2.4, 4.8 Hz, 2H). Step 7: 7-Iodo-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1,5,5-tetraoxide [000780] A 0 °C solution of 7-iodo-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1-dioxide (0.14 mmol) in dichloromethane (1 mL) was treated with meta-chloroperoxybenzoic acid (0.30 mmol). After 30 minutes the reaction was quenched with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (50% ethyl acetate in hexanes). The title compound was isolated in 59% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.74 (s, 1H), 3.80 (d, J = 4.4 Hz, 2H), 3.73 - 3.65 (m, 2H). Steps 8-9: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1,5,5-tetraoxide [000781] The title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with 7-iodo- 3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1,5,5-tetraoxide in step 3. The title compound was isolated. MS (ESI) m/z: 580.0 [M+H] + . (400 MHz, DMSO-d6) δ 10.08 (d, J = 1.2 Hz, 1H), 8.92 - 8.90 (m, 1H), 7.90 (s, 1H), 7.41 - 7.33 (m, 1H), 7.29 (s, 1H), 3.95 (s, 2H), 3.79 (d, J = 4.4 Hz, 2H), 3.69 - 3.65 (m, 2H), 3.05 (t, J = 5.2 Hz, 2H), 2.79 - 2.74 (m, 2H). Example 296: 7-(2-((4-(1-(2,2-difluoroethyl)piperidin-4-yl)-2-ethylphenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000782] The title compound was prepared analogously to Example 281, step 2, where 4-cyclopropyl-7- [2-[2-ethyl-4-(4-piperidyl)anilino]-5-(trifluoromethyl)pyrim idin-4-yl]-1,1-dioxo-2,3-dihydrothieno[2,3- f][1,4]thiazepin-5-one was replaced with 7-(2-((2-ethyl-4-(piperidin-4-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide. The title compound was isolated in 19% yield. MS (ESI) m/z: 686.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 9.83 (s, 1H), 8.78 (bs, 1H), 7.82 (s, 1H), 7.25 - 7.22 (m, 1H), 7.17 (d, J = 1.6 Hz, 1H), 7.11 - 7.08 (m, 1H), 6.15 (tt, J = 55.6, 4.4 Hz, 1H), 5.24 - 5.21 (m, 1H), 4.75 - 4.68 (m, 4H), 4.02 (s, 4H), 3.01 (d, J = 11.2 Hz, 2H), 2.75 (td, J = 15.6, 4.0 Hz, 2H), 2.61 - 2.57 (m, 2H), 2.33 - 2.24 (m, 3H), 1.76 - 1.65 (m, 4H), 1.10 (t, J = 7.6 Hz, 3H). Example 297: 4-Cyclopropyl-7-(2-((7-cyclopropyl-2-((4,4-dimethyloxetan-2- yl)methyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000783] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-bromo-2-fluoroethane were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and (4,4- dimethyloxetan-2-yl)methyl 4-methylbenzenesulfonate. The title compound was isolated in 16% yield. MS (ESI) m/z: 688.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.74 (s, 1H), 8.08 (s, 1H), 8.04 - 7.95 (m, 1H), 7.88 (s, 1H), 6.88 (s, 1H), 5.18 - 4.80 (m, 1H), 4.07 - 3.93 (m, 2H), 3.89 - 3.53 (m, 4H), 3.31 - 2.78 (m, 7H), 2.61 - 2.45 (m, 1H), 2.29 - 2.14 (m, 1H), 1.87 - 1.79 (m, 1H), 1.49 (s, 3H), 1.42 (s, 3H), 1.07 - 1.01 (m, 2H), 1.00 - 0.93 (m, 4H), 0.72 - 0.64 (m, 2H). Example 298: 7-(2-((2-Ethyl-4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phe nyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: Methyl 3-iodothiophene-2-carboxylate [000784] To a solution of methyl 3-aminothiophene-2-carboxylate (118 mmol) in acetonitrile (400 mL) was added diiodomethane (353 mmol) and tert-butyl nitrite (177 mmol). The reaction mixture was stirred at 50 °C for 1 hour, cooled down to room temperature, quenched with aqueous sodium sulfite and concentrated under vacuum. The aqueous phase was extracted with ethyl acetate three times, the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (1% ethyl acetate in hexanes) to afford the title compound in 99% yield. 1 H NMR (400 MHz, CDCl3) δ = 7.45 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 3.91 (s, 3H). Step 2: Methyl 3-((2-hydroxyethyl)thio)thiophene-2-carboxylate [000785] A mixture of methyl 3-iodothiophene-2-carboxylate (120 mmol), 2-mercaptoethan-1-ol (139 mmol), tris(dibenzylidenacetone)dipalladium (12 mmol), (9,9-dimethyl-9H-xanthene-3,5- diyl)bis(diphenylphosphine) (12 mmol) and N,N’-diisopropylethylamine (361 mmol) in dioxane (350 mL) was stirred at 130 °C for 4 hours. The resulting mixture was cooled down to room temperature, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (5-40% ethyl acetate in hexanes) to afford the title compound in 65% yield. MS (ESI) m/z: 219.0 [M+H] + . Step 3: methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)thiophene-2-c arboxylate [000786] To a 0 °C solution of methyl 3-((2-hydroxyethyl)thio)thiophene-2-carboxylate (78 mmol) and imidazole (235 mmol) in dichloromethane (200 mL) was added tert-butylchlorodimethylsilane (118 mmol). The reaction mixture was stirred at room temperature for 12 hours, quenched with water and extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-3% ethyl acetate in hexanes). The title compound was isolated in 99% yield. MS (ESI) m/z: 333.1 [M+Na]+. 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 5.2 Hz, 1H), 3.95 - 3.76 (m, 5H), 3.17 (t, J = 7.2 Hz, 2H), 0.90 (s, 9H), 0.07 (s, 6H). Step 4: Methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-5-iodothioph ene-2-carboxylate [000787] To a -40 °C solution of methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)thiophene-2- carboxylate (75 mmol) in tetrahydrofuran (300 mL) was added a 1.5M solution of lithium chloro- (2,2,6,6-tetramethyl-1-piperidyl)magnesium chloride in THF (150 mL) and the reaction was stirred at this temperature for 30 minutes. A 1M THF solution of iodine (150 mmol) was added dropwise and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (1-5% ethyl acetate in hexanes) to afford the title compound in 81% yield. MS (ESI) m/z: 459.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 3.91 - 3.76 (m, 5H), 3.14 (t, J = 6.8 Hz, 2H), 0.90 (s, 9H), 0.08 (s, 6H). Step 5: Methyl 3-((2-hydroxyethyl)thio)-5-iodothiophene-2-carboxylate [000788] To a solution of methyl 3-((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)-5-iodothioph ene-2- carboxylate (61 mmol) in THF (200 mL) was added a 1M solution of tetrabutylammonium fluoride in THF (40 mL). After 2 hours, the mixture was diluted with ethyl acetate and washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (5-30% ethyl acetate in hexanes). The title compound was isolated in 55% yield. MS (ESI) m/z: 344.8 [M+H] + . 1 H NMR (400 MHz, methanol-d 4 ) δ 7.35 (s, 1H), 3.82 (s, 3H), 3.76 (t, J = 6.8 Hz, 2H), 3.16 (t, J = 6.8 Hz, 2H). Step 6: Methyl 3-((2-bromoethyl)thio)-5-iodothiophene-2-carboxylate [000789] To a 0 °C solution of methyl 3-((2-hydroxyethyl)thio)-5-iodothiophene-2-carboxylate (15 mmol) in dichloromethane (60 mL) was added carbon tetrabromide (22 mmol) and triphenylphosphine (22 mmol). The reaction mixture was stirred at 45 °C for 1 hour, concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (3-10% ethyl acetate in hexanes) to afford the title compound in 88% yield. 1 H NMR (400 MHz, methanol-d4) δ = 7.32 (s, 1H), 3.83 (s, 3H), 3.64 - 3.56 (m, 2H), 3.53 - 3.45 (m, 2H). Step 7: Methyl 3-((2-(cyclopropylamino)ethyl)thio)-5-iodothiophene-2-carbox ylate [000790] To a solution of methyl 3-((2-bromoethyl)thio)-5-iodothiophene-2-carboxylate (491 mmol) and cyclopropanamine (0.98 mmol) in acetonitrile (2 mL) was added potassium carbonate (1.47 mmol). The reaction mixture was stirred at 80 °C for 12 hours, cooled down to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by preparative TLC (50% ethyl acetate in hexanes). The title compound was isolated in 32% yield. MS (ESI) m/z: 383.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.38 (s, 1H), 3.83 (s, 3H), 3.20 - 3.12 (m, 2H), 3.02 - 2.84 (m, 2H), 2.23 - 2.20 (m, 1H), 0.59 - 0.46 (m, 2H), 0.45 - 0.26 (m, 2H). Step 8: 3-((2-(Cyclopropylamino)ethyl)thio)-5-iodothiophene-2-carbox ylic acid [000791] Lithium hydroxide monohydrate (3.4 mmol) was added to a solution of methyl 3-((2- (cyclopropylamino)ethyl)thio)-5-iodothiophene-2-carboxylate (2.27 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature for 12 hours and the volatiles removed under reduced pressure to afford the title compound, which was used in the next step without further purification. MS (ESI) m/z: 370.1 [M+H] + . Step 9: 4-Cyclopropyl-7-iodo-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one [000792] A solution of 3-((2-(cyclopropylamino)ethyl)thio)-5-iodothiophene-2-carbox ylic acid (2.20 mmol) and HATU (3.29 mmol) in DMF (10 mL) was treated with N,N’-diisopropylethylamine (6.6 mmol). After 1 hour, the reaction was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (5-20% ethyl acetate in hexanes) to afford the title compound in 61% yield. MS (ESI) m/z: 352.1 [M+H] + . Step 10: 4-Cyclopropyl-7-iodo-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000793] To a 0 °C solution of 4-cyclopropyl-7-iodo-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one (0.071 mmol) in dichloromethane (1 mL) was added 85% 3-chloroperbenzoic acid (0.21 mmol). After 12 hours, the reaction was quenched with water and extracted with dichloromethane twice. The combined organic layers were washed with saturated sodium sulfite, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (33% ethyl acetate in hexanes). The title compound was isolated in 73% yield. MS (ESI) m/z: 383.9 [M+H] + 1 H NMR (400 MHz, methanol-d 4 ) δ 7.61 (s, 1H), 4.02 - 3.93 (m, 2H), 3.79 - 3.72 (m, 2H), 2.91 - 2.87 (m, 1H), 0.92 - 0.87 (m, 4H). Steps 11-14: 7-(2-((2-Ethyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide [000794] The title compound was prepared analogously to Example 240, steps 2-5, where tert-butyl 4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyc lopropylphenyl)piperidine-1-carboxylate was replaced with tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethyllphenyl)piperidine-1-carboxylate in step 2 and 7-bromo-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 4. The title compound was isolated. MS (ESI) m/z: 622.2[M+H] + . Step 15: 7-(2-((2-ethyl-4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phe nyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000795] compound was prepared analogously to Example 281, where 4-cyclopropyl-7-[2-[2- ethyl-4-(4-piperidyl)anilino]-5-(trifluoromethyl)pyrimidin-4 -yl]-1,1-dioxo-2,3-dihydrothieno[2,3- f][1,4]thiazepin-5-one and 2,2-difluoroethyl trifluoromethanesulfonate were replaced with 7-(2-((2-ethyl- 4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin -4-yl)-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 2,2,2-trifluoroethyl trifluoromethanesulfonate. The title compound was isolated in 40% yield. MS (ESI) m/z: 704.3[M+H] +. 1 H NMR (400MHz, DMSO-d6) δ 9.84 (s, 1H), 8.79 (s, 1H), 7.82 (s, 1H), 7.25 (s, 1H), 7.17 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 5.22 (t, J = 6.8 Hz, 1H), 4.75 - 4.67 (m, 4H), 4.01 (d, J = 4.0 Hz, 4H), 3.20 (q, J = 20.4, 10.0 Hz, 2H), 3.02 (d, J = 11.6 Hz, 2H), 2.59 - 2.55 (m, 2H), 2.46 - 2.43 (m, 3H), 1.76 - 1.66 (m, 4H), 1.10 (t, J = 7.2 Hz, 3H). Example 299: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-(2-fluoro-2-methylpropy l)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000796] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-bromo-2-fluoroethane were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and 2- fluoro-2-methylpropyl trifluoromethanesulfonate. The title compound was isolated in 36% yield. MS (ESI) m/z: 664.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.80 (br s, 1H), 7.80 (s, 1H), 7.16 (brs, 1H), 6.66 (s, 1H), 3.91 - 3.82 (m, 4H), 3.65 - 3.60 (m, 2H), 2.90 - 2.84 (m, 1H), 2.78 - 2.76 (m, 2H), 2.65 - 2.62 (m, 1H), 2.59 - 2.57 (m, 1H), 2.08 - 2.05 (m, 2H), 1.96 - 1.88 (m, 1H), 1.34 (d, J = 21.6 Hz, 6H), 0.83 - 0.76 (m, 3H), 0.59 - 0.53 (m, 2H). Example 300: 7-(2-((7-cyclopropyl-2-(2-fluoro-2-methylpropyl)-1,2,3,4-tet rahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000797] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-bromo-2-fluoroethane were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide and 2-fluoro-2- methylpropyl trifluoromethanesulfonate. The title compound was isolated in 56% yield. MS (ESI) m/z: 680.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.75 (s, 1H), 8.12 (s, 1H), 8.09 - 7.73 (m, 2H), 6.86 (s, 1H), 5.55 (t, J = 6.8 Hz, 1H), 5.04 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.14 (br t, J = 5.6 Hz, 2H), 3.79 (br t, J = 6.0 Hz, 4H), 3.28 - 2.88 (m, 4H), 2.87 - 2.57 (m, 2H), 1.86 - 1.79 (m, 1H), 1.50 - 1.46 (m, 3H), 1.42 (br d, J = 1.2 Hz, 3H), 1.05 - 1.00 (m, 2H), 0.68 (br d, J = 4.8 Hz, 2H). Example 301: 7-(2-((2,7-dicyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000798] The title compound was prepared analogously to Example 293, where 4-cyclopropyl-7-(2-((7- cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(tri fluoromethyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((7-cyclopropyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 41% yield. MS (ESI) m/z: 646.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.11 (s, 1H), 7.98 - 7.77 (m, 2H), 6.87 (s, 1H), 5.63 - 5.47 (m, 1H), 5.04 (t, J = 7.4 Hz, 2H), 4.78 - 4.70 (m, 4H), 4.13 (t, J = 5.8 Hz, 2H), 3.86 - 3.75 (m, 4H), 3.03 - 2.96 (m, 3H), 1.85 - 1.80 (m, 1H), 1.05 - 1.00 (m, 2H), 0.71 - 0.66 (m, 2H), 0.66 - 0.54 (m, 4H). Example 302: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2-methyl-3,4-dihydro-2H-thi eno[3,2-f][1,5,2]dithiazepine 1,1,5,5- tetraoxide Step 1: 7-Iodo-2-methyl-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazep ine 1,1,5,5-tetraoxide [000799] The title compound was prepared analogously to Example 135, step 1, where 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and ethyl iodide were replaced with 7-iodo- 3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1,5,5-tetraoxide and methyl iodide. The title compound was isolated in 39% yield. MS (ESI) m/z: 394.9 [M+H] + . Step 2: 7-(2-((7-chloro-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-2-methyl-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1,5,5-tetraoxide [000800] The title compound was prepared analogously to Example 155, steps 3-4, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-iodo-2- methyl-3,4-dihydro-2H-thieno[3,2-f][1,5,2]dithiazepine 1,1,5,5-tetraoxide in step 3. The title compound was isolated. MS (ESI) m/z: 594.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.24 - 9.97 (m, 1H), 8.97 - 8.82 (m, 1H), 7.99 (s, 1H), 7.44 - 7.32 (m, 1H), 7.29 (s, 1H), 4.08 (d, J = 2.0 Hz, 2H), 4.01 - 3.88 (m, 4H), 3.03 (s, 2H), 2.86 (s, 3H), 2.75 (d, J = 4.4 Hz, 2H). Example 303: 4-cyclopropyl-7-(2-((2-cyclopropyl-5,6,7,8-tetrahydro-1,7-na phthyridin-3-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 3-amino-2-cyclopropyl-5,8-dihydro-1,7-naphthyridine-7(6H)-ca rboxylate [000801] The title compound was prepared analogously to Example 173, where 1-(7-bromo-6-nitro-3,4- dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone was replaced with tert-butyl 3-amino-2-bromo-5, 8-dihydro-1, 7-naphthyridine-7(6H)-carboxylate. The title compound was isolated in 81% yield. MS (ESI) m/z: 290.1 [M+H] + . Steps 2-4: tert-butyl 2-cyclopropyl-3-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3,4,5 - tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)-5,8-dihydro- 1,7-naphthyridine-7(6H)-carboxylate [ as prepared analogously to Example 137, steps 3-5, where 1-(6-amino-7- ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl 3-amino- 2-cyclopropyl-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylat e in step 3 and 7-bromo-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 5. The title compound was isolated. MS (ESI) m/z: 691.3 [M+H] + . Step 5: 4-cyclopropyl-7-(2-((2-cyclopropyl-5,6,7,8-tetrahydro-1,7-na phthyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000803] The title compound was prepared analogously to Example 149, step 6, where 7-(2-((2-chloro- 5-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin -4-yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 2-cyclopropyl-3-((4-(4-cyclopropyl- 1,1-dioxido-5-oxo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiaze pin-7-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate. The title compound was isolated in 59% yield. MS (ESI) m/z: 591.0 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ ppm 0.94 (t, J=4.4 Hz, 2 H) 0.95 - 0.99 (m, 2 H) 1.01 - 1.04 (m, 2 H) 1.06 (dt, J=4.4, 2.49 Hz, 2 H) 2.02 - 2.09 (m, 1 H) 2.87 - 2.96 (m, 3 H) 3.21 (t, J=6.0 Hz, 2 H) 3.65 (t, J=6.4 Hz, 2 H) 3.96 (t, J=6.0 Hz, 2 H) 4.06 (s, 2 H) 7.65 (br s, 1 H) 7.99 (br s, 1 H) 8.07 (s, 1 H) 8.74 (s, 1 H). Example 304: 7-(2-((2-cyclopropyl-5,6,7,8-tetrahydro-1,7-naphthyridin-3-y l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000804] The title compound was prepared analogously to Example 303 where 7-bromo-4-cyclopropyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-iodo-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 4. The title compound was isolated. MS (ESI) m/z: 607.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ ppm 1.00 - 1.08 (m, 4 H) 2.01 - 2.06 (m, 1 H) 2.91 - 2.97 (m, 2 H) 3.23 (t, J=5.8 Hz, 2 H) 3.79 (t, J=5.8 Hz, 2 H) 4.08 (s, 2 H) 4.14 (t, J=5.8 Hz, 2 H) 4.73 (t, J=6.8 Hz, 2 H) 5.03 (t, J=7.6 Hz, 2 H) 5.45 - 5.61 (m, 1 H) 7.60 (br s, 1 H) 7.96 (s, 1 H) 8.11 (s, 1 H) 8.76 (s, 1 H). Example 305: 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl (1S,4S)-5-(3-cyclopropyl-4-nitrophenyl)-2,5-diazabicyclo[2.2 .1]heptane-2- carboxylate Cesium carbonate (166 mmol) was added to a solution of 2-cyclopropyl-4-fluoro-1-nitrobenzene (55 mmol) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (61 mmol) in DMF (100 mL). [000805] The reaction mixture was stirred at 80 °C for 12 hours, cooled down to room temperature, diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (2-15% ethyl acetate in hexanes). The title compound was isolated in 90% yield. MS (ESI) m/z: 360.2 [M+H]+. 1H NMR (400 MHz, methanol-d 4 ) δ = 7.97 (d, J = 9.1 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 4.68 (s, 1H), 4.59 (s, 1H), 3.60 (d, J = 9.8 Hz, 1H), 3.50 - 3.39 (m, 1H), 3.28 (s, 1H), 3.23 (t, J = 8.8 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.01 (s, 2H), 1.53 - 1.33 (m, 9H), 1.05 - 0.95 (m, 2H), 0.70 (t, J = 5.5 Hz, 2H). Step 2: tert-butyl (1S,4S)-5-(4-amino-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2 .1]heptane-2- carboxylate [000806] The title compound was prepared analogously to Example 173, step 4, where 1-(7-cyclopropyl- 6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-eth anone was replaced with tert-butyl (1S,4S)-5- (3-cyclopropyl-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane -2-carboxylate. The title compound was isolated in 94% yield. MS (ESI) m/z: 330.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.88 - 6.45 (m, 1H), 6.26 - 6.02 (m, 1H), 5.78 - 5.48 (m, 1H), 4.67 - 4.13 (m, 2H), 3.64 - 3.33 (m, 2H), 3.28 - 2.93 (m, 2H), 2.07 - 1.47 (m, 3H), 1.46 - 1.25 (m, 9H), 0.84 (d, J = 4.0 Hz, 2H), 0.54 (s, 2H). Step 3: tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate [000807] A mixture of tert-butyl (1S,4S)-5-(4-amino-3-cyclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (46 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (232 mmol) was stirred at 70 °C for 12 hours. he resulting mixture was cooled down to room temperature, concentrated and the residue was purified by flash silica gel column chromatography (2- 10% ethyl acetate in hexanes) to give an inseparable mixture of two regioisomers. The mixture was further purified by reverse phase preparative HPLC (60-90% acetonitrile in water containing 0.2% formic acid as additive). Most of the acetonitrile was removed under reduced pressure and the pH of the resulting suspension was adjusted to 8-9 with aqueous saturated solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate twice, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 11% yield. MS (ESI) m/z: 510.4 [M+H] + . (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.75 - 8.46 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.08 (s, 1H), 4.57 - 4.32 (m, 2H), 3.58 - 3.47 (m, 1H), 3.27 (d, J = 11.2 Hz, 1H), 3.21 - 3.15 (m, 1H), 2.95 (s, 1H), 1.88 (m, 3H), 1.36 (m, 9H), 0.78 (d, J = 8.4 Hz, 2H), 0.61 (s, 2H). Step 4: tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethy lstannyl)pyrimidin-2- yl)amino)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylat e [000808] The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate. The purification of this compound was carried out using neutral alumina. The title compound was isolated in 87% yield. MS (ESI) m/z: 640.4 [M+H] + . Step 5: tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate [000809] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate. The title compound was isolated in 87% yield. MS (ESI) m/z: 731.5 [M+H] + . 1 H NMR (400 MHz, methanol-d 4 ) δ 8.85 - 8.43 (m, 1H), 7.96 (s, 1H), 7.37 - 7.11 (m, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.25 (s, 1H), 4.54 - 4.43 (m, 2H), 4.05 - 3.85 (m, 2H), 3.80 - 3.74 (m, 2H), 3.60 (t, J = 7.2 Hz, 1H), 3.44 - 3.36 (m, 2H), 3.08 (t, J = 9.2 Hz, 1H), 2.90 - 2.85 (s, 1H), 2.12 - 1.87 (m, 3H), 1.56 - 1.35 (m, 9H), 1.02 - 0.79 (m, 6H), 0.64 (t, J = 5.9 Hz, 2H). Step 6: 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000810] To a solution of tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo- 2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifl uoromethyl)pyrimidin-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (0.23 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (13.5 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The volatiles were removed under reduced pressure and the residue was diluted with water and the pH of the resulting solution was adjusted to 8-9 by the addition of saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted with ethyl acetate twice, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound in 95% yield. MS (ESI) m/z: 631.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.84 - 8.54 (m, 1H), 7.96 (s, 1H), 7.40 - 7.02 (m, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.27 (s, 1H), 4.72 - 4.38 (m, 2H), 4.04 - 3.89 (m, 2H), 3.87 - 3.70 (m, 3H), 3.62 (m, 1H), 3.10 - 2.90 (m, 3H), 2.02 - 1.89 (m, 2H), 1.82 (m, 1H), 0.93 - 0.84 (m, 6H), 0.71 - 0.55 (m, 2H). Example 306: 4-Cyclopropyl-7-(2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromet hyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000811] To a solution of 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2- cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-cyclopropyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.067 mmol), paraformaldehyde (0.67 mmol) and acetic acid (0.007 mmol) in methanol (1 mL) was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (0.20 mmol) was added and the reaction was stirred for two additional hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford a residue that was purified by preparative TLC (10%methanol in dichloromethane). The title compound was isolated in 73% yield. MS (ESI) m/z: 645.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.72 - 8.66 (m, 1H), 7.95 (s, 1H), 7.38 - 7.20 (m, 1H), 6.68 - 6.50 (m, 1H), 6.32 (s, 1H), 4.64 - 4.53 (m, 2H), 3.96 - 3.90 (m, 2H), 3.77 - 3.74 (m, 2H), 3.74 - 3.63 (m, 1H), 3.40 - 3.32 (m, 3H), 3.27 - 3.11 (m, 1H), 2.92 - 2.79 (m, 3H), 2.31 - 2.21 (m, 1H), 1.94 (s, 2H), 0.91 - 0.85 (m, 6H), 0.68 - 0.60 (m, 2H). Example 307: 7-(2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-cyclo propylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl (1R,5S)-3-(3-cyclopropyl-4-nitrophenyl)-3,8-diazabicyclo[3.2 .1]octane-8- carboxylate [000812] The title compound was prepared analogously to Example 305, step 1, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate. The title compound was isolated in 71% yield. MS (ESI) m/z: 374.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 9.2 Hz, 1H), 6.80 (dd, J = 9.2, 2.8 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 4.28 - 4.19 (m, 2H), 3.71 (d, J = 11.2 Hz, 2H), 2.97 - 2.90 (m, 2H), 2.49 - 2.44 (m, 1H), 1.90 - 1.78 (m, 2H), 1.73 - 1.63 (m, 2H), 1.41 (s, 9H), 0.98 - 0.92 (m, 2H), 0.78 - 0.73 (m, 2H). Step 2: tert-butyl (1R,5S)-3-(4-amino-3-cyclopropylphenyl)-3,8-diazabicyclo[3.2 .1]octane-8- carboxylate [000813] The title compound was prepared analogously to Example 173, step 4, where 1-(7-cyclopropyl- 6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-eth anone was replaced tert-butyl (1R,5S)-3-(3- cyclopropyl-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-c arboxylate. The title compound was isolated in 85% yield. MS (ESI) m/z: 344.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.55 - 6.46 (m, 2H), 6.38 (d, J = 2.0 Hz, 1H), 4.52 - 4.35 (m, 2H), 4.22 - 4.12 (m, 2H), 3.24 - 3.16 (m, 2H), 2.64 - 2.56 (m, 2H), 1.84 - 1.75 (m, 4H), 1.69 - 1.61 (m, 1H), 1.40 (s, 9H), 0.84 - 0.77 (m, 2H), 0.51 - 0.44 (m, 2H). Step 3: tert-butyl (1R,5S)-3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- cyclopropylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyla te [000814] A mixture of tert-butyl 3-(4-amino-3-cyclopropyl-phenyl)-3,8-diazabicyclo[3.2.1]octa ne-8- carboxylate (27.1 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (135 mmol) was stirred at 70°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative-HPLC. The title compound was isolated in 20% yield. MS (ESI) m/z: 524.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.74 - 8.49 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 1.6 Hz, 1H), 4.26 - 4.14 (m, 2H), 3.53 - 3.45 (m, 2H), 2.81 - 2.70 (m, 2H), 1.89 - 1.73 (m, 5H), 1.41 (s, 9H), 0.81 - 0.73 (m, 2H), 0.65 - 0.57 (m, 2H). Step 4: tert-butyl (1R,5S)-3-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethy lstannyl)pyrimidin- 2-yl)amino)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyla te [000815] The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl (1R,5S)-3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- cyclopropylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxyla te. The purification of this compound was carried out using neutral alumina. The title compound was isolated in 88% yield. MS (ESI) m/z: 654.1 [M+H] + . Step 5: tert-butyl (1R,5S)-3-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate [000816] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with tert-butyl (1R,5S)-3-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-3,8-diazabicy clo[3.2.1]octane-8-carboxylate. The title compound was isolated in 43% yield. MS (ESI) m/z: 745.3 [M+H] + . Step 6: 7-(2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-cyclo propylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000817] The title compound was prepared analogously to Example 305, step 6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (1R,5S)-3-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(t rifluoromethyl)pyrimidin-2- yl)amino)phenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate . The title compound was isolated in 48% yield. MS (ESI) m/z: 645.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.87 - 8.61 (m, 1H), 7.78 (s, 1H), 7.25 - 7.05 (m, 1H), 6.73 - 6.61 (m, 1H), 6.36 (s, 1H), 3.92 - 3.82 (m, 4H), 3.70 - 3.62 (m, 3H), 3.54 - 3.50 (m, 2H), 2.91 - 2.83 (m, 1H), 2.82 - 2.75 (m, 2H), 1.94 - 1.88 (m, 1H), 1.82 - 1.69 (m, 4H), 0.84 - 0.74 (m, 6H), 0.64 - 0.57 (m, 2H). Example 308: (R)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3-methylpiperazin- 1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl (R)-4-(3-cyclopropyl-4-nitrophenyl)-2-methylpiperazine-1-car boxylate [000818] The title compound was prepared analogously to Example 305, step 1, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-2- methylpiperazine-1-carboxylate. The title compound was isolated in 79% yield. MS (ESI) m/z: 362.1 [M+H] + . Step 2: tert-butyl (R)-4-(4-amino-3-cyclopropylphenyl)-2-methylpiperazine-1-car boxylate [000819] The title compound was prepared analogously to Example 173, step 4, where 1-(7-cyclopropyl- 6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-eth anone was replaced with tert-butyl (R)-4-(3- cyclopropyl-4-nitrophenyl)-2-methylpiperazine-1-carboxylate. The title compound was isolated in 78% yield. MS (ESI) m/z: 332.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 6.56 (d, J = 2.4 Hz, 1H), 6.55 (s, 1H), 6.44 (d, J = 2.4 Hz, 1H), 4.59 - 4.51 (m, 2H), 4.18-4.10 (m, 1H), 3.75 (d, J = 13.2 Hz, 1H), 3.24 (d, J = 11.2 Hz, 1H), 3.14 (m, 1H), 3.10 - 3.04 (m, 1H), 2.59 -2.55 (m, 1H), 2.42 - 2.35 (m, 1H), 1.69 - 1.62 (m, 1H), 1.42 (s, 9H), 1.22 (d, J = 6.4 Hz, 3H), 0.84 - 0.81 (m, 2H), 0.50 - 0.46 (m , 2H). Step 3: tert-butyl (R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- cyclopropylphenyl)-2-methylpiperazine-1-carboxylate [000820] The title compound was prepared analogously to Example 305, step 3, where tert-butyl (1S,4S)-5-(4-amino-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2 .1]heptane-2-carboxylate was replaced with tert-butyl (R)-4-(4-amino-3-cyclopropylphenyl)-2-methylpiperazine-1-car boxylate. The title compound was isolated in 20% yield. MS (ESI) m/z: 512.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.97 (s, 1H), 8.80 - 8.53 (m, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.87 - 6.67 (m, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.24 - 4.15 (m, 1H), 3.79 (d, J = 13.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.46 (d, J = 11.2 Hz, 2H), 3.23 - 3.10 (m, 1H), 2.82 - 2.78 (m, 1H), 2.60 (m, 1H), 1.92 – 1.80 (m, 1H), 1.42 (s, 9H), 1.21 - 1.19 (m, 1H), 1.22 - 1.18 (m, 1H), 0.86 - 0.75 (m, 2H), 0.61 (d, J = 3.6 Hz, 2H). Step 4: tert-butyl (R)-4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylsta nnyl)pyrimidin-2- yl)amino)phenyl)-2-methylpiperazine-1-carboxylate [000821] The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl (R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- cyclopropylphenyl)-2-methylpiperazine-1-carboxylate. The purification of this compound was carried out using neutral alumina. The title compound was isolated in 39% yield. MS (ESI) m/z: 642.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.19 (s, 1H), 8.51 - 8.33 (m, 1H), 7.21 (d, J = 4.0 Hz, 1H), 6.74 - 6.70 (m, 1H), 6.43 (d, J = 2.4 Hz, 1H), 4.20 (d, J = 3.6 Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.42 (d, J = 12.0 Hz, 1H), 3.18 - 3.11 (m, 1H), 2.78 - 2.74 (m, 1H), 2.59 - 2.53 (m, 1H), 1.93 - 1.86 (m, 1H), 1.42 (s, 9H), 1.19 (d, J = 1.2 Hz, 3H), 0.81 - 0.77 (m, 2H), 0.61 - 0.58 (m, 2H), 0.28 (s, 9H). Step 5: tert-butyl (R)-4-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo- 2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-2- methylpiperazine-1-carboxylate [000822] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with tert-butyl (R)-4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2-methylpiper azine-1-carboxylate. The title compound was isolated in 66% yield. MS (ESI) m/z: 733.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.80 - 8.71 (m, 1H), 7.78 (s, 1H), 7.19 - 7.14 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 4.22 – 4.20 (m, 1H), 3.86 – 3.81 (m, 4H), 3.79 (d, J = 13.2 Hz, 1H), 3.55 – 3.45 (m, 1H), 3.20 - 3.16 (m, 1H), 2.88 – 2.81 (m, 1H), 2.80 – 2.75 (m, 1H), 2.62 – 2.59 (m, 1H), 1.99 – 1.91 (m, 2H), 1.42 (s, 9 H), 1.21 – 1.19 (m, 3H), 0.87 – 0.79 (m, 6H), 0.64 – 0.62 (m, 4H). Step 6: (R)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3-methylpiperazin- 1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000823] The title compound was prepared analogously to Example 305, step 6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (R)-4-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo- 2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifl uoromethyl)pyrimidin-2-yl)amino)phenyl)-2- methylpiperazine-1-carboxylate. The title compound was isolated in 24% yield. MS (ESI) m/z: 633.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.70 (s, 1H), 8.06 (s, 1H), 8.00 - 7.85 (m, 1H), 7.77 - 7.60 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 5.45 - 5.26 (m, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.65 (t, J = 6.0 Hz, 2H), 3.60 - 3.51 (m, 2H), 3.28 - 3.09 (m, 2H), 2.95 - 2.86 (m, 2H), 2.65 - 2.53 (m, 1H), 2.23 (t, J = 7.6 Hz, 1H), 2.05 - 2.00 (m, 1H), 1.32 (s, 3H), 1.06 - 1.02 (m, 2H), 0.98 - 0.95 (m, 2H), 0.89 - 0.85 (m, 2H), 0.71 (d, J = 5.6 Hz, 2H). Example 309: (R)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3,4-dimethylpipera zin-1-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000824] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-4- cyclopropyl-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)p henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 35% yield. MS (ESI) m/z: 647.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.69 (s, 1H), 8.05 (s, 1H), 7.98 - 7.80 (m, 1H), 7.78 - 7.60 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 3.94 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 3.52 (d, J = 11.2 Hz, 1H), 3.45 (d, J = 11.6 Hz, 1H), 2.95 (d, J = 3.6 Hz, 1H), 2.94 - 2.90 (m, 2H), 2.60 - 2.53 (m, 1H), 2.51 - 2.42 (m, 1H), 2.37 (s, 3H), 2.34 - 2.27 (m, 1H), 1.93 - 1.85 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H), 1.06 - 1.00 (m, 2H), 0.95 (d, J = 4.4 Hz, 4H), 0.75 - 0.68 (m, 2H). Example 310: 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopro pylphenyl)-4-chloro-5- (trifluoromethyl)pyrimidin-2-amine [000825] The title compound was prepared analogously to Example 305, step 6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptan e-2-carboxylate. The title compound was isolated in 97% yield. MS (ESI) m/z: 410.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.25 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 8.4 Hz, 2.8, 1H), 6.31 (d, J = 2.4 Hz, 1H), 4.67 (s, 2H), 3.74 (dd, J = 10.8, 2.4 Hz, 1H), 3.41 - 3.35 (m, 2H), 2.30 (d, J = 10.8 Hz, 1H), 2.13 - 1.99 (m, 2H), 1.94 - 1.87 (m, 1H), 0.88 (d, J = 8.4 Hz, 2H), 0.68 - 0.59 (m, 2H). Step 2: 1-((1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl )amino)-3-cyclopropylphenyl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,2,2-trifluoroethan-1-o ne [000826] The title compound was prepared analogously to Example 9, step 2, where 7-ethyl-6-nitro- 1,2,3,4-tetrahydroisoquinoline was replaced with N-(4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2- cyclopropylphenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-a mine. The title compound was isolated in 60% yield. MS (ESI) m/z: 506.3 NMR (400 MHz, methanol-d4) δ 8.72 - 8.20 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.63 - 6.45 (m, 1H), 6.40 - 6.18 (m, 1H), 5.06 - 4.90 (m, 1H), 4.64 (d, J = 14.8 Hz, 1H), 3.84 - 3.62 (m, 2H), 3.59 (s, 1H), 3.15 (d, J = 9.6 Hz, 1H), 2.26 - 2.02 (m, 2H), 1.94 - 1.80 (m, 1H), 0.89 - 0.84 (m, 2H), 0.73 - 0.58 (m, 2H). Step 3: 1-((1S,4S)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trime thylstannyl)pyrimidin-2- yl)amino)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,2,2-t rifluoroethan-1-one

[000827] The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced 1-((1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl )amino)-3- cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,2,2 -trifluoroethan-1-one. The purification of this compound was carried out using neutral alumina. The title compound was isolated in 93% yield. MS (ESI) m/z: 634.1 [M+H] + . NMR (400 MHz, methanol-d4) δ 8.52 - 8.28 (m, 1H), 7.47 - 7.10 (m, 1H), 6.58 - 6.40 (m, 1H), 6.27 (dd, J = 6.0, 2.8 Hz, 1H), 4.98 (s, 1H), 4.62 (d, J = 14.4 Hz, 1H), 3.81 - 3.60 (m, 2H), 3.58 (s, 1H), 3.13 (dd, J = 8.8, 4.0 Hz, 1H), 2.28 - 2.01 (m, 2H), 1.93 - 1.84 (m, 1H), 0.88 - 0.84 (m, 4H), 0.64 - 0.61 (m, 2H), 0.45 - 0.16 (m, 7H). Step 4: 7-(2-((2-cyclopropyl-4-((1S,4S)-5-(2,2,2-trifluoroacetyl)-2, 5-diazabicyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000828] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-((1S,4S)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2,5-diazabicy clo[2.2.1]heptan-2-yl)-2,2,2- trifluoroethan-1-one and 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepi n-5(2H)-one 1,1- dioxide. The title compound was isolated in 72% yield. MS (ESI) m/z: 743.4 [M+H] + . Step 5: 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000829] The title compound was prepared analogously to Example 59, step 6, where 5-(2-((7-chloro-2- (2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-3- (methylsulfonyl)thiophene-2-carboxamide was replaced with 7-(2-((2-cyclopropyl-4-((1S,4S)-5-(2,2,2- trifluoroacetyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 97% yield. MS (ESI) m/z: 647.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.75 - 8.52 (m, 1H), 7.99 (s, 1H), 7.35 - 7.23 (m, 1H), 6.65 - 6.51 (m, 1H), 6.32 (s, 1H), 5.38 - 5.14 (m, 1H), 4.63 (s, 3H), 4.37 (s, 2H), 4.10 - 4.00 (m, 2H), 3.89 (d, J = 4.8 Hz, 2H), 3.73 (d, J = 8.8 Hz, 2H), 3.35 (s, 2H), 3.27 (s, 1H), 2.26 (d, J = 10.1 Hz, 1H), 2.08 - 1.95 (m, 2H), 0.89 (m, 2H), 0.69 - 0.61 (m, 2H). Example 311: 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydro-2H-thieno[3,2-f ][1,5,2]dithiazepine 1,1,5,5-tetraoxide [000830] The title compound was prepared analogously to Example 155, steps 3-4, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 1-(7-cyclopropyl-6-((5-(trifluoromethyl)-4-(trimethylstannyl )pyrimidin-2- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroet han-1-one and 7-iodo-3,4-dihydro-2H- thieno[3,2-f][1,5,2]dithiazepine 1,1,5,5-tetraoxide in step 3. The title compound was isolated. MS (ESI) m/z: 586.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.79 (s, 1H), 7.85 (s, 1H), 7.38 - 7.06 (m, 1H), 6.72 (s, 1H), 3.93 (s, 2H), 3.75 - 3.70 (m, 2H), 3.56 (d, J = 5.2 Hz, 2H), 3.08 - 3.05 (m, 2H), 2.76 (s, 2H), 1.96 - 1.92 (m, 1H), 0.85 - 0.80 (m, 2H), 0.59 - 0.52 (m, 2H). Example 312: 7-(2-((7-cyclopropyl-2-(2-(trifluoromethoxy)ethyl)-1,2,3,4-t etrahydroisoquinolin-6- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000831] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-bromo-2-fluoroethane were replaced with 7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amin o)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide and 1-bromo-2- (trifluoromethoxy)ethane. The title compound was isolated in 7% yield. MS (ESI) m/z: 718.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 6.86 (s, 1H), 5.58 - 5.51 (m, 1H), 5.04 (t, J = 7.4 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.17 (t, J = 5.8 Hz, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.79 (t, J = 5.8 Hz, 2H), 3.69 (s, 2H), 3.03 - 2.91 (m, 2H), 2.87 (td, J = 5.8, 14.2 Hz, 4H), 1.88 - 1.76 (m, 1H), 1.06 - 1.01 (m, 2H), 0.70 - 0.64 (m, 2H). Example 313: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-d iazabicyclo[3.2.1]octan- 3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-di hydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000832] The title compound was prepared analogously to Example 306 where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-cyclopropylphe nyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide. The title compound was isolated in 80% yield. MS (ESI) m/z: 659.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.88 - 8.59 (m, 1H), 7.86 - 7.68 (m, 1H), 7.22 - 7.03 (m, 1H), 6.70 - 6.56 (m, 1H), 6.40 - 6.28 (m, 1H), 3.96 - 3.79 (m, 4H), 3.21 - 3.17 (m, 2H), 2.96 - 2.74 (m, 4H), 2.22 (s, 3H), 2.06 - 1.82 (m, 4H), 1.68 - 1.57 (m, 2H), 0.86 - 0.76 (m, 6H), 0.65 - 0.55 (m, 2H). Example 314: 4-cyclopropyl-7-(2-((7-cyclopropyl-2-(2-(trifluoromethoxy)et hyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000833] The title compound was prepared analogously to Example 227, where 7-(2-((7-chloro-1,2,3,4- tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimid in-4-yl)-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-bromo-2-fluoroethane were replaced with 4-cyclopropyl-7-(2-((7-cyclopropyl-1,2,3,4-tetrahydroisoquin olin-6-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide and 1- bromo-2-(trifluoromethoxy)ethane. The title compound was isolated in 7% yield. MS (ESI) m/z: 702.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.08 (s, 1H), 7.99 - 7.83 (m, 2H), 6.86 (s, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.96 (t, J = 5.8 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.69 (s, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.03 - 2.95 (m, 2H), 2.94 - 2.91 (m, 1H), 2.88 (d, J = 5.4 Hz, 2H), 1.89 - 1.78 (m, 1H), 1.06 - 1.01 (m, 2H), 0.99 - 0.93 (m, 4H), 0.71 - 0.65 (m, 2H). Example 315: (R)-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000834] The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclop ropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-4-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2-methylpiperazine-1-carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 649.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.71 (s, 1H), 8.09 (s, 1H), 7.95 - 7.82 (m, 1H), 7.78 - 7.59 (m, 1H), 6.89 - 6.87 (m, 1H), 6.75 (s, 1H), 5.63 - 5.49 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.17 - 4.07 (m, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.51 (d, J = 10.4 Hz, 2H), 3.20 - 3.11 (m, 1H), 3.10 - 2.96 (m, 2H), 2.80 - 2.66 (m, 1H), 2.45 - 2.32 (m, 1H), 2.02 - 1.78 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H), 1.05 - 0.99 (m, 2H), 0.92 - 0.86 (m, 1H), 0.74 - 0.69 (m, 2H). Example 316: (R)-7-(2-((2-cyclopropyl-4-(3,4-dimethylpiperazin-1-yl)pheny l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000835] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(t rifluoromethyl)pyrimidin-4-yl)-4-(oxetan- 3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 89% yield. MS (ESI) m/z: 663.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.70 (s, 1H), 8.09 (s, 1H), 7.92 - 7.80 (m, 1H), 7.77 - 7.58 (m, 1H), 6.92 - 6.84 (m, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.62 - 5.49 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.57 - 3.39 (m, 2H), 3.00 - 2.87 (m, 2H), 2.55 (t, J = 10.4 Hz, 1H), 2.48 - 2.41 (m, 1H), 2.37 (s, 3H), 2.30 - 2.20 (m, 1H), 1.94 - 1.82 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 1.07 - 1.00 (m, 2H), 0.74 - 0.67 (m, 2H). Example 317: 7-(2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2. 2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000836] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylph enyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide. The title compound was isolated in 19% yield. MS (ESI) m/z: 661.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.78 - 8.58 (m, 1H), 8.01 (s, 1H), 7.37 - 7.17 (m, 1H), 6.61 - 6.52 (m, 1H), 6.31 (s, 1H), 5.35 - 5.26 (m, 1H), 4.92 (s, 2H), 4.84 - 4.83 (m, 2H), 4.58 - 4.43 (m, 2H), 4.13 - 4.02 (m, 2H), 4.00 - 3.94 (m, 1H), 3.92 - 3.86 (m, 2H), 3.69 - 3.59 (m, 1H), 3.38 (s, 1H), 3.08 (d, J = 10.4 Hz, 1H), 2.68 (s, 3H), 2.22 - 2.17 (m, 1H), 2.05 - 1.94 (m, 2H), 0.89 (m, 2H), 0.66 (m, 2H). Example 318: 7-(2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-cyclo propylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000837] The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclop ropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,5S)-3-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 3,8-diazabicyclo[3.2.1]octane-8- carboxylate. The title compound was isolated. MS (ESI) m/z: 661.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.85 - 8.62 (m, 1H), 7.89 - 7.71 (m, 1H), 7.22 - 7.04 (m, 1H), 6.67 - 6.60 (m, 1H), 6.33 (s, 1H), 5.28 - 5.17 (m, 1H), 4.79 - 4.64 (m, 4H), 4.10 - 3.90 (m, 4H), 3.59 - 3.53 (m, 2H), 3.42 - 3.39 (m, 2H), 2.78 - 2.70 (m, 2H), 2.02 - 1.97 (m, 1H), 1.74 - 1.64 (m, 4H), 0.87 - 0.83 (m, 1H), 0.81 - 0.76 (m, 2H), 0.63 - 0.57 (m, 2H). Example 319: 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl (1S,4S)-5-(3-bromo-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate [000838] The title compound was prepared analogously to Example 305, step 1, where 2-cyclopropyl-4- fluoro-1-nitrobenzene, cesium carbonate and DMF were replaced with 2-bromo-4-fluoro-1-nitrobenzene, potassium carbonate and NMP. The title compound was isolated in 99% yield. MS (ESI) m/z: 398.1 [M+H] + . Step 2: tert-butyl (1S,4S)-5-(4-nitro-3-vinylphenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate [000839] The title compound was prepared analogously to Example 212, step 3, where 1-(6-bromo-7- nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethan one was replaced with tert-butyl (1S,4S)-5- (3-bromo-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-car boxylate. The title compound was isolated in 58% yield. MS (ESI) m/z: 346.2 [M+H] + . Step 3: tert-butyl (1S,4S)-5-(4-amino-3-ethylphenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate [000840] The title compound was prepared analogously to Example 212, step 4, where 2,2,2-trifluoro-1- (7-nitro-6-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one was replaced with tert-butyl (1S,4S)-5-(4- nitro-3-vinylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbox ylate. The title compound was isolated in 93% yield. MS (ESI) m/z: 318.2 [M+H] + . Step 4: tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-ethylphenyl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [000841] The title compound was prepared analogously to Example 305, step 3, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-cyclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1S,4S)-5-(4-amino-3- ethylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated in 99% yield. MS (ESI) m/z: 498.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.76 - 8.48 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.56 - 6.42 (m, 2H), 4.56 - 4.36 (m, 2H), 3.60 - 3.49 (m, 1H), 3.29 - 3.15 (m, 2H), 2.98 (d, J = 0.8 Hz, 1H), 2.46 - 2.43 (m, 2H), 1.95 - 1.86 (m, 2H), 1.37 (d, J = 17.6 Hz, 9H), 1.07 (t, J = 7.2 Hz, 3H). Step 5: tert-butyl (1S,4S)-5-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstann yl)pyrimidin-2- yl)amino)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylat e [000842] The title compound was prepared analogously to Example 305, step 4, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-cyclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1S,4S)-5-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)-2,5-di azabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated in 37% yield. MS (ESI) m/z: 626.4 [M+H] + . Step 6: tert-butyl (1S,4S)-5-(4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3,4,5-te trahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)-3-ethylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate [000843] The title compound was prepared analogously to Example 305, step 5, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethy lstannyl)pyrimidin-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1S,4S)-5-(3-ethyl-4-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)p henyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate. The title compound was isolated in 79% yield. MS (ESI) m/z: 719.4 [M+H] + Step 7: 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000844] The title compound was prepared analogously to Example 305, step 6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (1S,4S)-5-(4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)-3-ethylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated in 70% yield. MS (ESI) m/z: 619.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.99 (s, 1H), 7.34 - 7.28 (m, 1H), 7.04 (s, 1H), 6.50 (s, 2H), 4.45 (s, 1H), 4.40 - 4.21 (m, 1H), 3.93 (s, 2H), 3.82 - 3.73 (m, 1H), 3.63 (s, 2H), 3.43 - 3.18 (m, 4H), 2.91 (dd, J = 4.0, 8.0 Hz, 1H), 2.58 (q, J = 7.2 Hz, 2H), 2.26 - 2.05 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H), 0.97 (d, J = 6.8 Hz, 2H), 0.88 (d, J = 7.2 Hz, 2H). Example 320: 7-(2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3. 2.1]octan-3- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000845] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-cyclopropylphe nyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide. The title compound was isolated in 23% yield. MS (ESI) m/z: 675.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.87 - 8.61 (m, 1H), 7.88 - 7.73 (m, 1H), 7.20 - 7.00 (m, 1H), 6.67 - 6.59 (m, 1H), 6.35 (s, 1H), 5.30 - 5.15 (m, 1H), 4.79 - 4.62 (m, 4H), 4.14 - 3.89 (m, 4H), 3.50 - 3.43 (m, 1H), 3.17 - 3.14 (m, 2H), 2.88 - 2.82 (m, 2H), 2.40 - 2.35 (m, 2H), 2.33 (s, 3H), 2.02 - 1.95 (m, 2H), 1.74 - 1.63 (m, 2H), 0.88 - 0.82 (m, 1H), 0.81 - 0.76 (m, 2H), 0.64 - 0.57 (m, 2H). Example 321: 4-cyclopropyl-7-(2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabi cyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000846] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 55% yield. MS (ESI) m/z: 633.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.10 - 7.91 (m, 1H), 7.34 - 7.29 (m, 1H), 7.05 - 6.92 (m, 1H), 6.51 (br s, 2H), 4.55 - 4.29 (m, 1H), 3.99 - 3.90 (m, 2H), 3.63 (br d, J = 6.4 Hz, 4H), 3.18 - 3.07 (m, 1H), 2.95 - 2.90 (m, 1H), 2.85 - 2.69 (m, 2H), 2.63 - 2.57 (m, 2H), 2.26 - 2.14 (m, 2H), 2.07 (s, 3H), 1.27 (s, 3H), 0.93 - 0.88 (m, 4H). Example 322: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000847] The title compound was prepared analogously to Example 319, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated. MS (ESI) m/z: 619.3 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.65 (s, 1H), 7.99 (br s, 1H), 7.29 (br d, J = 9.6 Hz, 1H), 7.09 - 7.00 (m, 1H), 6.50 (br s, 2H), 4.60 - 4.14 (m, 2H), 3.93 (m, 2H), 3.64 (m, 2H), 3.59 - 3.34 (m, 2H), 3.34 - 2.97 (m, 2H), 2.96 - 2.89 (m, 1H), 2.60 - 2.55 (m, 2H), 2.24 - 2.15 (m, 2H), 1.19 (br t, J = 7.2 Hz, 3H), 0.98 (m, 2H), 0.88 (m, 2H). Example 323: 4-cyclopropyl-7-(2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabi cyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000848] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 50% yield. MS (ESI) m/z: 633.4 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.65 (s, 1H), 8.01 - 7.96 (m, 1H), 7.31 (br d, J = 9.2 Hz, 1H), 7.04 (br d, J = 2.8 Hz, 1H), 6.51 (br s, 2H), 4.50 - 4.36 (m, 1H), 4.02 - 3.97 (m, 1H), 3.97 - 3.89 (m, 2H), 3.62 (br s, 2H), 3.61 - 3.56 (m, 2H), 3.16 (br d, J = 10.0 Hz, 1H), 2.99 - 2.85 (m, 2H), 2.80 (br d, J = 2.4 Hz, 2H), 2.60 (br d, J = 7.6 Hz, 2H), 2.31 - 2.21 (m, 3H), 1.23 - 1.18 (m, 3H), 0.94 - 0.89 (m, 4H). Example 324: 7-(2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-ethyl phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000849] The title compound was prepared analogously to Example 319, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 633.5 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.03 (s, 1H), 7.63 - 7.36 (m, 1H), 7.06 (s, 1H), 6.82 - 6.71 (m, 2H), 4.07 (s, 2H), 3.93 (s, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.54 (d, J = 10.4 Hz, 2H), 3.31 (d, J = 11.2 Hz, 2H), 2.91 (d, J = 3.2, 6.4 Hz, 2H), 2.67 - 2.61 (m, 2H), 2.22 - 2.17 (m, 2H), 2.14 - 2.08 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 0.98 - 0.91 (m, 4H). Example 325: 4-cyclopropyl-7-(2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabi cyclo[3.2.1]octan-3- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000850] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-ethylphenyl)am ino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 67% yield. MS (ESI) m/z: 647.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.03 (s, 1H), 7.67 - 7.32 (m, 1H), 7.07 - 6.98 (m, 1H), 6.81 - 6.73 (m, 2H), 3.93 (s, 2H), 3.81 - 3.69 (m, 2H), 3.64 (t, J = 6.0 Hz, 4H), 3.49 (d, J = 11.6 Hz, 2H), 2.95 - 2.86 (m, 1H), 2.79 - 2.65 (m, 3H), 2.65 - 2.59 (m, 2H), 2.27 - 2.18 (m, 2H), 2.16 - 2.06 (m, 2H), 1.25 - 1.22 (m, 3H), 0.97 - 0.92 (m, 4H). Example 326: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-((3S,5R)-3,5-dimethylpi perazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000851] The title compound was prepared analogously to Example 308, where tert-butyl (R)-2- methylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-2,6-dimethylpiperazine-1- carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 647.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1 H) 8.05 (s, 1 H) 7.54 - 7.98 (m, 2 H) 6.75 (br d, J = 2.0 Hz, 1 H) 3.94 (t, J = 6.0 Hz, 2 H) 3.64 (t, J = 6.0 Hz, 2 H) 6.81 - 6.96 (m, 1 H) 3.52 (br d, J = 10.0 Hz, 2 H) 3.04 - 3.17 (m, 2 H) 2.86 - 2.98 (m, 1 H) 2.30 - 2.46 (m, 2 H) 1.89 - 1.93 (m, 1 H) 1.21 (d, J = 6.4 Hz, 6 H) 1.00 - 1.08 (m, 2 H) 0.92 - 0.99 (m, 4 H) 0.84 - 0.92 (m, 1 H) 0.69 - 0.75 (m, 2 H). Example 327: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-((3S,5S)-3,5-dimethylpi perazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000852] The title compound was prepared analogously to Example 308, where tert-butyl (R)-2- methylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6S)-2,6-dimethylpiperazine-1- carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 647.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.74 (s, 1H), 8.89 - 8.64 (m, 1H), 7.85 - 7.71 (m, 1H), 7.28 - 7.00 (m, 1H), 6.73 (br d, J = 6.8 Hz, 1H), 6.43 (br s, 1H), 4.01 - 3.70 (m, 4H), 3.17 (br d, J = 5.2 Hz, 2H), 3.10 (dd, J = 3.2, 11.3 Hz, 2H), 2.91 - 2.81 (m, 1H), 2.72 (dd, J = 6.4, 11.4 Hz, 2H), 1.95 - 1.88 (m, 1H), 1.10 (d, J = 6.4 Hz, 6H), 0.83 - 0.76 (m, 6H), 0.65 - 0.57 (m, 2H). Example 328: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-((3S,5S)-3,4,5-trimethy lpiperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000853] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 4- cyclopropyl-7-(2-((2-cyclopropyl-4-((3S,5S)-3,5-dimethylpipe razin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 98% yield. MS (ESI) m/z: 661.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.73 - 8.65 (m, 1H), 8.05 (s, 1H), 7.94 - 7.69 (m, 1H), 7.30 - 7.27 (m, 1H), 6.93 - 6.81 (m, 1H), 6.71 (br s, 1H), 3.94 (br t, J = 5.6 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 3.30 - 3.21 (m, 2H), 3.08 - 2.85 (m, 5H), 2.39 (s, 3H), 1.90 (br s, 1H), 1.15 (d, J = 6.0 Hz, 6H), 1.05 - 1.01 (m, 2H), 0.98 - 0.93 (m, 4H), 0.74 - 0.69 (m, 2H). Example 329: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000854] The title compound was prepared analogously to Example 305, steps 1-3, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate in step 1 and Example 310, where tert-butyl (1S,4S)-5-(4-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropy lphenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptan e-2-carboxylate. The title compound was isolated. MS (ESI) m/z: 631.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 8.76 - 8.56 (m, 1H), 7.96 (s, 1H), 7.40 - 7.13 (m, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.28 (s, 1H), 4.74 - 4.50 (m, 1H), 3.99 - 3.88 (m, 3H), 3.76 (s, 2H), 3.64 (d, J = 8.4 Hz, 1H), 3.15 - 3.02 (m, 3H), 2.90 (s, 1H), 2.07 - 1.86 (m, 3H), 0.92 - 0.84 (m, 6H), 0.70 - 0.60 (m, 2H). Example 330: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromet hyl)pyrimidin-4-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000855] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylph enyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide. The title compound was isolated in 77% yield. MS (ESI) m/z: 645.4[M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 8.78 - 8.55 (m, 1H), 7.95 (s, 1H), 7.37 - 7.17 (m, 1H), 6.57 (d, J = 6.4 Hz, 1H), 6.31 (s, 1H), 4.81 - 4.63 (m, 1H), 4.19 - 4.03 (m, 1H), 3.95 (s, 2H), 3.80 - 3.65 (m, 3H), 3.40 - 3.36 (m, 1H), 3.22 - 3.08 (m, 1H), 2.91 - 2.77 (m, 3H), 2.33 - 2.11 (m, 2H), 2.01 - 1.89 (m, 3H), 0.94 - 0.86 (m, 6H), 0.69 - 0.63 (m, 2H). Example 331: (S)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3-methylpiperazin- 1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000856] The title compound was prepared analogously to Example 308, where tert-butyl (R)-2- methylpiperazine-1-carboxylate was replaced with tert-butyl (S)-2-methylpiperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 633.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.06 (s, 1H), 7.98 - 7.83 (m, 1H), 7.80 - 7.58 (m, 1H), 6.97 - 6.84 (m, 1H), 6.76 (s, 1H), 3.94 (t, J = 5.6 Hz, 2H), 3.65 (t, J = 5.6 Hz, 2H), 3.53 (d, J = 12.2 Hz, 2H), 3.25 - 3.16 (m, 1H), 3.15 - 3.02 (m, 2H), 2.95 - 2.89 (m, 1H), 2.86 - 2.77 (m, 1H), 2.49 (t, J = 10.6 Hz, 1H), 1.96 - 1.90 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H), 1.06 - 1.00 (m, 2H), 0.99 - 0.92 (m, 4H), 0.75 - 0.68 (m, 2H). Example 332: (S)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3,4-dimethylpipera zin-1-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000857] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (S)-4- cyclopropyl-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)p henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 18% yield. MS (ESI) m/z: 647.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 8.05 (s, 1H), 7.99 - 7.80 (m, 1H), 7.79 - 7.50 (m, 1H), 6.98 - 6.81 (m, 1H), 6.75 (d, J = 1.4 Hz, 1H), 3.94 (t, J = 5.6 Hz, 2H), 3.64 (t, J = 6.2 Hz, 2H), 3.56 - 3.49 (m, 1H), 3.49 - 3.42 (m, 1H), 2.96 - 2.88 (m, 3H), 2.59 - 2.50 (m, 1H), 2.48 - 2.40 (m, 1H), 2.36 (s, 3H), 2.31 - 2.22 (m, 1H), 1.97 - 1.77 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H), 1.07 - 1.00 (m, 2H), 0.99 - 0.92 (m, 4H), 0.72 (d, J = 4.6 Hz, 2H). Example 333: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000858] The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclop ropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,4R)-5-(4-amino-3- cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate. The title compound was isolated. MS (ESI) m/z: 647.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.07 (s, 1H), 7.73 - 7.60 (m, 1H), 7.58 - 7.38 (m, 1H), 6.57 - 6.45 (m, 1H), 6.32 (s, 1H), 5.46 (m, 1H), 5.02 (t, J = 7.2 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.38 (s, 1H), 4.21 - 3.97 (m, 2H), 3.77 (m, 3H), 3.68 (d, J = 9.6 Hz, 1H), 3.20 – 2.90 (m, 3H), 2.06 - 1.99 (m, 3H), 0.98 (d, J = 8.4 Hz, 2H), 0.74 - 0.65 (m, 2H). Example 334: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2. 2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000859] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylph enyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide. The title compound was isolated in 51% yield MS (ESI) m/z: 661.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 8.83 - 8.59 (m, 1H), 7.98 (s, 1H), 7.42 - 7.20 (m, 1H), 6.57 (s, 1H), 6.32 (s, 1H), 5.36 - 5.15 (m, 1H), 4.96 - 4.88 (m, 2H), 4.70 - 4.56 (m, 1H), 4.06 - 3.99 (m, 2H), 3.89 (d, J = 4.8 Hz, 2H), 3.76 - 3.70 (m, 2H), 3.63 - 3.43 (m, 1H), 3.40 - 3.33 (m, 2H), 3.27 - 3.18 (m, 1H), 3.03 - 2.73 (m, 3H), 2.33 - 2.24 (m, 2H), 2.08 - 1.97 (m, 1H), 1.94 - 1.90 (m, 1H), 0.89 - 0.86 (m, 2H), 0.68 - 0.62 (m, 2H). Example 335: 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000860] The title compound was prepared analogously to Example 310, where with tert-butyl (1S,4S)- 5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-c yclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1S,4S)-5-(4-amino-3- ethylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated. MS (ESI) m/z: 635.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.04 (br s, 1H), 7.33 (d, J = 9.2 Hz, 1H), 7.04 (br s, 1H), 6.49 (s, 2H), 5.60 - 5.41 (m, 1H), 5.01 (br t, J = 7.2 Hz, 2H), 4.73 - 4.62 (m, 2H), 4.49 (br s, 1H), 4.39 - 4.25 (m, 1H), 4.13 - 4.02 (m, 2H), 3.82 - 3.70 (m, 3H), 3.36 (br d, J = 5.6 Hz, 3H), 2.62 - 2.56 (m, 2H), 2.23 - 2.14 (m, 2H), 1.19 (br t, J = 7.6 Hz, 3H). Example 336: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000861] The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclop ropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,4R)-5-(4-amino-3- ethylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated. MS (ESI) m/z: 635.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ, 8.66 (s, 1H), 8.06 (br d, J = 2.0 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.04 - 6.90 (m, 1H), 6.51 - 6.44 (m, 2H), 5.58 - 5.47 (m, 1H), 5.08 - 4.96 (m, 2H), 4.78 - 4.67 (m, 2H), 4.41 - 4.33 (m, 1H), 4.19 - 4.01 (m, 2H), 3.96 - 3.66 (m, 4H), 3.24 - 3.08 (m, 2H), 3.08 - 3.01 (m, 1H), 2.63 - 2.53 (m, 2H), 2.05 - 1.95 (m, 2H), 1.21 (br t, J = 7.6 Hz, 3H). Example 337: 7-(2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-ethyl phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000862] The title compound was prepared analogously to Example 319, steps 1-4, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate and Example 310, where tert-butyl (1S,4S)-5-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2,5-diazabicyclo[2.2.1]heptane-2- carboxylate was replaced with tert-butyl (1R,5S)-3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-ethylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-car boxylate. The title compound was isolated. MS (ESI) m/z: 649.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.07 (s, 1H), 7.60 - 7.28 (m, 1H), 7.02 (d, J = 2.4, 7.6 Hz, 1H), 6.77 - 6.71 (m, 2H), 5.60 - 5.48 (m, 1H), 5.02 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.11 (s, 2H), 3.86 (s, 2H), 3.77 (d, J = 4.8 Hz, 2H), 3.54 - 3.47 (m, 2H), 3.13 (d, J = 11.2 Hz, 2H), 2.63 (q, J = 7.6 Hz, 2H), 2.05 (s, 4H), 1.22 (t, J = 7.6 Hz, 3H). Example 338: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000863] The title compound was prepared analogously to Example 329, where tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate. The title compound was isolated. MS (ESI) m/z: 631.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (s, 1H), 8.04 (s, 1H), 7.88 - 7.41 (m, 2H), 6.73 - 6.60 (m, 1H), 6.50 (s, 1H), 4.04 - 3.89 (m, 4H), 3.67 - 3.56 (m, 6H), 2.97 - 2.87 (m, 1H), 2.85 - 2.77 (m, 1H), 1.96 - 1.93 (m, 1H), 1.70 - 1.61 (m, 1H), 1.33 - 1.22 (m, 1H), 1.03 - 0.91 (m, 6H), 0.75 - 0.68 (m, 2H). Example 339: 4-cyclopropyl-7-(2-((2-cyclopropyl-4-(6-methyl-3,6-diazabicy clo[3.1.1]heptan-3- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000864] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylphenyl)ami no)-5-(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 90% yield. MS (ESI) m/z: 645.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (s, 1H), 8.04 (s, 1H), 7.94 - 7.43 (m, 2H), 6.78 - 6.64 (m, 1H), 6.53 (s, 1H), 4.15 - 4.00 (m, 2H), 3.98 - 3.87 (m, 2H), 3.77 - 3.62 (m, 4H), 3.61 - 3.46 (m, 2H), 2.97 - 2.84 (m, 2H), 2.70 (s, 3H), 1.97 - 1.89 (m, 1H), 1.87 - 1.76 (m, 1H), 1.06 - 0.91 (m, 6H), 0.76 - 0.69 (m, 2H). Example 340: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000865] The title compound was prepared analogously to Example 329, where tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate in step 1 and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide was replaced with 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepi n-5(2H)-one 1,1- dioxide in step 7. The title compound was isolated. MS (ESI) m/z: 647.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.08 (s, 1H), 7.86 - 7.41 (m, 2H), 6.66 (d, J = 8.4 Hz, 1H), 6.49 (s, 1H), 5.57 - 5.48 (m, 1H), 5.02 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.17 - 4.00 (m, 2H), 3.94 - 3.86 (m, 2H), 3.81 - 3.72 (m, 2H), 3.62 - 3.50 (m, 4H), 2.82 - 2.68 (m, 1H), 1.97 - 1.89 (m, 1H), 1.68 - 1.60 (m, 2H), 1.03 - 0.96 (m, 2H), 0.75 - 0.66 (m, 2H). Example 341: (S)-7-(2-((2-Cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000866] The title compound was prepared analogously to Example 308, steps 1-3, where tert-butyl (R)- 2-methylpiperazine-1-carboxylate was replaced with tert-butyl (S)-2-methylpiperazine-1-carboxylate and Example 310, steps 1-3, where with tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptan e-2-carboxylate was replaced with tert- butyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3-cyclopropylphenyl)-2- methylpiperazine-1-carboxylate, Example 310, steps 4-5, where 1-((1S,4S)-5-(3-cyclopropyl-4-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)p henyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- 2,2,2-trifluoroethan-1-one was replaced with (S)-1-(4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2-methylpiper azin-1-yl)-2,2,2-trifluoroethan-1-one in step 4. The title compound was isolated. MS (ESI) m/z: 649.1[M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.09 (s, 1H), 7.96 - 7.81 (m, 1H), 7.72 - 7.45 (m, 1H), 6.94 - 6.85 (m, 1H), 6.78 - 6.69 (m, 1H), 5.59 - 5.50 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.51 (d, J = 11.8 Hz, 2H), 3.20 - 2.93 (m, 3H), 2.79 - 2.64 (m, 1H), 2.36 (t, J = 10.8 Hz, 1H), 1.94 - 1.82 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H), 1.08 - 0.97 (m, 2H), 0.77 - 0.65 (m, 2H). Example 342: (S)-7-(2-((2-cyclopropyl-4-(3,4-dimethylpiperazin-1-yl)pheny l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000867] The title compound was prepared analogously to Example 306 where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (S)-7-(2- ((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(t rifluoromethyl)pyrimidin-4-yl)-4-(oxetan- 3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 42% yield. MS (ESI) m/z: 663.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.09 (s, 1H), 7.96 - 7.82 (m, 1H), 7.75 - 7.52 (m, 1H), 6.95 - 6.82 (m, 1H), 6.74 (s, 1H), 5.61 - 5.49 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.82 - 3.74 (m, 2H), 3.60 - 3.42 (m, 2H), 2.96 - 2.88 (m, 2H), 2.59 - 2.50 (m, 1H), 2.48 - 2.39 (m, 1H), 2.36 (s, 3H), 2.32 - 2.22 (m, 1H), 1.93 - 1.83 (m, 1H), 1.17 (d, J = 6.0 Hz, 3H), 1.06 - 0.98 (m, 2H), 0.74 - 0.66 (m, 2H). Example 343: 4-Cyclopropyl-7-(2-((2-cyclopropyl-4-((3S,5R)-3,4,5-trimethy lpiperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000868] The title compound was prepared analogously to Example 306 where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 4- cyclopropyl-7-(2-((2-cyclopropyl-4-((3S,5R)-3,5-dimethylpipe razin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 42% yield. MS (ESI) m/z: 661.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.69 (s, 1 H) 8.05 (s, 1 H) 7.93 (br s, 1 H) 7.71 (br s, 1 H) 6.88 (br d, J = 8.4 Hz, 1 H) 3.84 - 4.04 (m, 2 H) 3.64 (br t, J = 6.0 Hz, 2 H) 3.48 (br d, J = 11.2 Hz, 2 H) 2.81 - 3.02 (m, 1 H) 2.73 (br s, 2 H) 2.45 (br s, 4 H) 1.80 - 1.96 (m, 2 H) 1.19 - 1.35 (m, 7 H) 0.88 - 1.09 (m, 7 H) 0.62 - 0.81 (m, 2 H). Example 344: 7-(2-((2-Cyclopropyl-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)p henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000869] The title compound was prepared analogously to Example 341, where tert-butyl (S)-2- methylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6S)-2,6-dimethylpiperazine-1- carboxylate. The title compound was isolated. MS (ESI) m/z: 663.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.71 (s, 1H), 8.09 (s, 1H), 7.94 - 7.79 (m, 1H), 7.78 - 7.57 (m, 1H), 6.86 (br d, J = 8.4 Hz, 1H), 6.71 (br s, 1H), 5.55 (quin, J = 7.2 Hz, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (br t, J = 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.54 - 3.37 (m, 2H), 3.26 (dd, J = 3.2, 11.6 Hz, 2H), 2.91 (dd, J = 6.4, 11.6 Hz, 2H), 1.89 - 1.87 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H), 1.05 - 1.00 (m, 2H), 0.75 - 0.68 (m, 2H). Example 345: (R)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3-(hydroxymethyl)p iperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide Step 1: tert-butyl (R)-4-(3-cyclopropyl-4-nitrophenyl)-2-(hydroxymethyl)piperaz ine-1-carboxylate [000870] The title compound was prepared analogously to Example 305, step 1, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-2- (hydroxymethyl)piperazine-1-carboxylate. The title compound was isolated in 68% yield. MS (ESI) m/z: 378.2 [M+H] + Step 2: tert-butyl (R)-2-(acetoxymethyl)-4-(3-cyclopropyl-4-nitrophenyl)piperaz ine-1-carboxylate [000871] To a solution of tert-butyl (2R)-4-(3-cyclopropyl-4-nitro-phenyl)-2- (hydroxymethyl)piperazine-1-carboxylate (19 mmol) in dichloromethane (70 mL) was added triethylamine (37 mmol) and acetyl chloride (20 mmol). The mixture was stirred at 0 °C for 30 minutes, partitioned between ethyl acetate and water, the organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was used in the next step without further purification. The title compound was isolated. MS (ESI) m/z: 420.2 [M+H] + . Steps 3-7: (R)-(4-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo -2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2- yl)amino)phenyl)piperazin-2-yl)methyl acetate [000872] The title compound was prepared analogously to Example 308, steps 2-6 where with tert-butyl (R)-4-(3-cyclopropyl-4-nitrophenyl)-2-methylpiperazine-1-car boxylate was replaced with tert-butyl (R)- 2-(acetoxymethyl)-4-(3-cyclopropyl-4-nitrophenyl)piperazine- 1-carboxylate. The title compound was isolated. MS (ESI) m/z: 691.3 [M+H] + . Step 8: (R)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3-(hydroxymethyl)p iperazin-1-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000873] To a solution of (R)-(4-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo -2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)piperazin-2- yl)methyl acetate (0.17 mmol) in ethyl alcohol (1 mL) and water (0.2 mL), was added potassium carbonate (0.51 mmol). The mixture was stirred at 50 °C for 12 hours. The reaction mixture was cooled down to room temperature, filtered and concentrated under reduced pressure to afford a residue that was purified by preparative TL. The title compound was isolated in 32% yield. MS (ESI) m/z: 649.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.69 (s, 1 H) 8.05 (s, 1 H) 7.48 - 7.96 (m, 2 H) 6.89 (br d, J=8.0 Hz, 1 H) 6.75 (d, J=2.4 Hz, 1 H) 3.94 (br t, J=6.0 Hz, 2 H) 3.74 - 3.82 (m, 1 H) 3.59 - 3.71 (m, 3 H) 3.51 (br d, J=11.6 Hz, 2 H) 2.99 - 3.34 (m, 3 H) 2.79 - 2.97 (m, 2 H) 2.67 (br t, J=10.8 Hz, 1 H) 1.82 - 1.92 (m, 1 H) 1.18 - 1.32 (m, 2 H) 0.99 - 1.07 (m, 2 H) 0.93 - 0.98 (m, 3 H) 0.65 - 0.75 (m, 2 H). Example 346: 7-(2-((2-Ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]he ptan-2-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihyd rothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000874] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 83% yield. MS (ESI) m/z: 649.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.05 (br s, 1H), 7.35 (br d, J = 8.0 Hz, 1H), 7.03 (br s, 1H), 6.56 - 6.44 (m, 2H), 5.59 - 5.40 (m, 1H), 4.99 (br d, J = 6.8 Hz, 2H), 4.74 (q, J = 7.2 Hz, 2H), 4.52 - 4.39 (m, 1H), 4.16 - 3.95 (m, 3H), 3.85 - 3.72 (m, 3H), 3.69 - 3.54 (m, 2H), 3.41 - 3.28 (m, 1H), 2.76 (br d, J = 1.6 Hz, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.37 - 2.23 (m, 2H), 1.23 - 1.19 (m, 3H) Example 347: 7-(2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]he ptan-2-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihyd rothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000875] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced 7-(2-((4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide. The title compound was isolated in 76% yield. MS (ESI) m/z: 649.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.66 (s, 1H), 8.04 (br s, 1H), 7.31 (br d, J = 9.6 Hz, 1H), 7.02 (br s, 1H), 6.51 (br s, 2H), 5.52 - 5.39 (m, 1H), 5.02 - 4.93 (m, 2H), 4.80 - 4.71 (m, 2H), 4.52 - 4.39 (m, 1H), 4.24 - 4.06 (m, 2H), 4.04 - 3.96 (m, 1H), 3.91 - 3.68 (m, 3H), 3.68 - 3.58 (m, 2H), 3.23 - 3.15 (m, 1H), 2.83 - 2.74 (m, 2H), 2.65 - 2.55 (m, 3H), 2.27 - 2.20 (m, 2H), 1.20 (br t, J = 7.2 Hz, 3H). Example 348: 7-(2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oc tan-3-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihyd rothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000876] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-ethylphenyl)am ino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 54% yield. MS (ESI) m/z: 663.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.07 (s, 1H), 7.51 - 7.36 (m, 1H), 7.07 - 7.00 (m, 1H), 6.79 - 6.73 (m, 2H), 5.59 - 5.47 (m, 1H), 5.02 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.10 (d, J = 1.6 Hz, 2H), 3.80 - 3.70 (m, 4H), 3.67 - 3.54 (m, 2H), 3.52 - 3.47 (m, 2H), 2.80 - 2.66 (m, 3H), 2.65 - 2.60 (m, 2H), 2.26 - 2.09 (m, 4H), 1.23 - 1.20 (m, 3H). Example 349: 7-(2-((2-cyclopropyl-4-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihyd rothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000877] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylphenyl)ami no)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 33% yield. MS (ESI) m/z: 661.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.08 (s, 1H), 7.87 - 7.43 (m, 2H), 6.74 - 6.62 (m, 1H), 6.51 (br.s., 1H), 5.60 - 5.48 (m, 1H), 5.06 - 4.99 (m, 2H), 4.77 - 4.70 (m, 2H), 4.18 - 4.06 (m, 2H), 3.81 - 3.75 (m, 2H), 3.74 - 3.69 (m, 2H), 3.60 - 3.54 (m, 2H), 3.39 - 3.29 (m, 2H), 2.67 - 2.56 (m, 1H), 2.15 (s, 3H), 1.97 - 1.88 (m, 1H), 1.63 - 1.60 (m, 1H), 1.05 - 0.96 (m, 2H), 0.77 - 0.69 (m, 2H). Example 350: 7-(2-((2-cyclopropyl-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)p henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000878] The title compound was prepared analogously to Example 344, where tert-butyl (2S,6S)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-2,6-dimethylpiperazine-1- carboxylate. The title compound was isolated. MS (ESI) m/z: 663.3 [M+H] + 1 H NMR (400 MHz, CDCl3) δ ppm 8.71 (s, 1 H) 8.09 (s, 1 H) 7.81 - 7.96 (m, 1 H) 7.65 - 7.78 (m, 1 H) 6.88 (br d, J = 8 Hz, 1 H) 6.75 (br d, J = 2.00 Hz, 1 H) 5.55 (quin, J = 6.8 Hz, 1 H) 5.04 (t, J = 7.60 Hz, 2 H) 4.74 (t, J = 6.8 Hz, 2 H) 4.11 (br d, J = 5.6 Hz, 2 H) 3.78 (br t, J = 6 Hz, 2 H) 3.51 (br d, J = 10 Hz, 2 H) 3.04 - 3.16 (m, 2 H) 2.37 (br t, J = 10.8 Hz, 2 H) 1.84 - 1.92 (m, 1 H) 1.21 (br d, J =6.4 Hz, 6 H) 1.00 - 1.06 (m, 2 H) 0.88 - 0.92 (m, 1 H) 0.69 - 0.74 (m, 2 H). Example 351: 7-(2-((2-cyclopropyl-4-((3S,5S)-3,4,5-trimethylpiperazin-1-y l)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000879] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2- cyclopropyl-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)ami no)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 677.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.71 (s, 1H), 8.09 (s, 1H), 7.95 - 7.78 (m, 1H), 7.58 (s, 1H), 6.87 (br d, J = 9.2 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 5.61 - 5.46 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (br t, J = 6.0 Hz, 2H), 3.81 - 3.73 (m, 2H), 3.44 - 3.27 (m, 2H), 3.26 - 2.99 (m, 4H), 2.61 - 2.43 (m, 3H), 1.90 - 1.86 (m, 1H), 1.28 - 1.24 (m, 6H), 1.05 - 0.99 (m, 2H), 0.72 - 0.65 (m, 2H). Example 352: (R)-4-cyclopropyl-7-(2-((2-cyclopropyl-4-(3-(hydroxymethyl)- 4-methylpiperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000880] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-(4-(3- cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3,4,5-t etrahydrothieno[2,3-f][1,4]thiazepin-7-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-y l)methyl acetate and Example 345, step 8, where (R)-(4-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo -2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)piperazin-2-yl)methyl acetate was replaced with (R)-(4-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo -2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-1- methylpiperazin-2-yl)methyl acetate. The title compound was isolated in 26% yield. MS (ESI).m/z: 663.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.70 (s, 1 H) 8.05 (s, 1 H) 7.80 - 7.97 (m, 1 H) 7.57 - 7.77 (m, 1 H) 6.84 - 6.98 (m, 1 H) 6.76 (d, J=2.4Hz, 1 H) 3.88 - 4.04 (m, 3 H) 3.59 - 3.70 (m, 3 H) 3.43 - 3.56 (m, 2 H) 2.85 - 3.06 (m, 4 H) 2.59 (td, J = 11.6, 2.8 Hz, 1 H) 2.35 - 2.48 (m, 4 H) 1.89 (br d, J = 5.6 Hz, 1 H) 1.00 - 1.06 (m, 2 H) 0.92 - 0.99 (m, 4 H) 0.68 - 0.74 (m, 2 H). Example 353: (S)-4-cyclopropyl-7-(2-((2-ethyl-4-(3-methylpiperazin-1-yl)p henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000881] The title compound was prepared analogously to Example 319, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (S)-2-methylpiperazine-1- carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 621.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.03 (s, 1H), 7.55 - 7.51 (m, 1H), 7.06 - 7.01 (m, 1H), 6.87 - 6.82 (m, 2H), 3.93 – 3.92 (m, 2H), 3.64 - 3.57 (m, 4H), 3.22 - 3.19 (m, 1H), 3.12 - 3.00 (m, 2H), 2.93 - 2.90 (m, 2H), 2.65 - 2.53 (m, 3H), 1.24 - 1.22 (m, 3H), 0.97 - 0.89 (m, 7H). Example 354: (S)-7-(2-((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000882] The title compound was prepared analogously to Example 319, steps 1-4, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (S)-2- methylpiperazine-1-carboxylate in step 1 and Example 341, steps 4-8, where tert-butyl (S)-4-(4-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropy lphenyl)-2-methylpiperazine-1- carboxylate was replaced with tert-butyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- ethylphenyl)-2-methylpiperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 637.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.06 (s, 1H), 7.54 - 7.46 (m, 1H), 7.07 (s, 1H), 6.85 (d, J = 2.4 Hz, 2H), 5.57 - 5.50 (m, 1H), 5.02 (t, J = 7.2 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.10 (s, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.57 (d, J = 12.0 Hz, 2H), 3.21 - 3.17 (m, 1H), 3.16 - 2.99 (m, 2H), 2.82 - 2.79 (m, 1H), 2.64 (q, J = 7.6 Hz, 2H), 2.45 (t, J = 11.2 Hz, 1H), 2.15 - 2.14 (m, 1H), 1.26 - 1.25 (m, 3H), 1.21 - 1.19 (m, 3H). Example 355: (R)-7-(2-((2-ethyl-4-(3-(hydroxymethyl)piperazin-1-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Steps 1-2: tert-butyl (R)-4-(3-ethyl-4-nitrophenyl)-2-(hydroxymethyl)piperazine-1- carboxylate The title compound was prepared analogously to Example 345, step 1, where 2-cyclopropyl-4-fluoro-1- nitrobenzene and tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate were replaced with 2-ethyl- 4-fluoro-1-nitrobenzene and tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 366.2 [M+H] + [000883] Step 3: tert-butyl (R)-2-(acetoxymethyl)-4-(3-ethyl-4-nitrophenyl)piperazine-1- carboxylate The title compound was prepared analogously to Example 345, step 2, where tert-butyl (R)-4-(3- cyclopropyl-4-nitrophenyl)-2-(hydroxymethyl)piperazine-1-car boxylate was replaced with tert-butyl (R)- 4-(3-ethyl-4-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carb oxylate. The title compound was isolated in 89% yield. MS (ESI) m/z: 408.3 [M+H] + . [000884] Steps 4-5: tert-butyl (R)-2-(acetoxymethyl)-4-(4-((4-chloro-5-(trifluoromethyl)pyr imidin- 2-yl)amino)-3-ethylphenyl)piperazine-1-carboxylate [000885] The title compound was prepared analogously to Example 319, steps 3-4, where tert-butyl (1S,4S)-5-(4-nitro-3-vinylphenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate was replaced with tert- butyl (R)-2-(acetoxymethyl)-4-(3-ethyl-4-nitrophenyl)piperazine-1- carboxylate. The title compound was isolated. MS (ESI) m/z: 558.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.80 - 8.37 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.47 - 4.30 (m, 2H), 4.29 - 4.19 (m, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.72 - 3.50 (m, 2H), 3.18 (s, 1H), 2.79 (d, J = 10.4 Hz, 1H), 2.70 - 2.56 (m, 1H), 2.49 - 2.45 (m, 2H), 2.01 (s, 3H), 1.42 (s, 9H), 1.07 (t, J = 7.6 Hz, 3H). Steps 6-9: (R)-(4-(3-ethyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-oxo-2,3 ,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-1-(2,2,2- trifluoroacetyl)piperazin-2-yl)methyl acetate [000886] The title compound was prepared analogously to Example 310, steps 1-4, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-cyclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-2-(acetoxymethyl)-4-(4-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylpheny l)piperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 684.3 [M+H] + . Step 10: (R)-7-(2-((2-ethyl-4-(3-(hydroxymethyl)piperazin-1-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000887] The title compound was prepared analogously to Example 345, step 8, where (R)-(4-(3- cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5-oxo-2,3,4,5-t etrahydrothieno[2,3-f][1,4]thiazepin-7-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-y l)methyl acetate was replaced with (R)-(4- (3-ethyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-oxo-2,3,4,5-te trahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-(2,2,2-trifl uoroacetyl)piperazin-2-yl)methyl acetate. The title compound was isolated in 47% yield. MS (ESI) m/z: 653.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.06 (s, 1H), 7.52 (d, J = 2.8, 3.6 Hz, 1H), 7.10 (s, 1H), 6.93 - 6.79 (m, 2H), 5.61 - 5.41 (m, 1H), 5.01 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.09 (s, 2H), 4.04 - 3.97 (m, 1H), 3.95 - 3.87 (m, 1H), 3.77 (t, J = 5.6 Hz, 2H), 3.70 - 3.61 (m, 2H), 3.58 - 3.51 (m, 1H), 3.49 - 3.41 (m, 1H), 3.32 - 3.20 (m, 2H), 3.14 - 3.08 (m, 1H), 2.64 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). Example 356: 4-cyclopropyl-7-(2-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)- 2-ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000888] The title compound was prepared analogously to Example 319, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (2S,6S)-2,6-dimethylpiperazine-1- carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 635.4 [M+H] + 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.72 - 8.56 (m, 1H), 7.95 (s, 1H), 7.35 - 7.26 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.00 – 3.87 (m, 2H), 3.80 – 3.75 (m, 2H), 3.65 – 3.55 (m, 2H), 3.40 - 3.36 (m, 2H), 3.09 - 3.05 (m, 2H), 2.95 – 2.85 (m, 1H), 2.63 (q, J = 7.6 Hz, 2H), 1.39 (d, J = 6.8 Hz, 6H), 1.17 (t, J = 7.6 Hz, 3H), 0.94 - 0.85 (m, 4H). Example 357: 7-(2-((2-cyclopropyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-y l)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000889] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2- cyclopropyl-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)phenyl)ami no)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 70% yield. MS (ESI) m/z: 677.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.71 (s, 1 H) 8.10 (s, 1 H) 7.83 - 7.99 (m, 1 H) 7.60 - 7.80 (m, 1 H) 6.83 - 6.93 (m, 1 H) 6.70 - 6.78 (m, 1 H) 5.47 - 5.63 (m, 1 H) 5.03 (t, J = 7.60 Hz, 2 H) 4.74 (t, J = 6.80 Hz, 2 H) 4.08 - 4.15 (m, 2 H) 3.78 (t, J = 6.00 Hz, 2 H) 3.45 - 3.53 (m, 2 H) 2.65 - 2.85 (m, 2 H) 2.40 - 2.54 (m, 3 H) 1.22 - 1.29 (m, 6 H) 1.01 - 1.06 (m, 2 H) 0.81 - 0.93 (m, 2 H) 0.69 - 0.74 (m, 2 H). Example 358: (R)-7-(2-((2-cyclopropyl-4-(3-(hydroxymethyl)piperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000890] The title compound was prepared analogously to Example 308, steps 2-3, where with tert-butyl (R)-4-(3-cyclopropyl-4-nitrophenyl)-2-methylpiperazine-1-car boxylate was replaced with tert-butyl (R)- 2-(acetoxymethyl)-4-(3-cyclopropyl-4-nitrophenyl)piperazine- 1-carboxylate and Example 310, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-cyclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-2-(acetoxymethyl)-4-(4-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropy lphenyl)piperazine-1-carboxylate. The title compound was isolated. MS (ESI).m/z: 665.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (br s, 1 H) 8.64 - 8.91 (m, 1 H) 7.81 (br s, 1 H) 7.06 - 7.28 (m, 1 H) 6.78 (dd, J = 8.8, 2.4 Hz, 1 H) 6.49 (br s, 1 H) 4.94 - 5.40 (m, 2 H) 4.60 - 4.81 (m, 4 H) 4.02 (br s, 4 H) 3.46 - 3.73 (m, 4 H) 3.14 (br d, J = 11.6 Hz, 1 H) 2.89 - 3.08 (m, 2 H) 2.64 - 2.77 (m, 1 H) 1.89 - 1.96 (m, 1 H) 0.77 - 0.84 (m, 2 H) 0.58 - 0.65 (m, 2 H). Example 359: (R)-4-cyclopropyl-7-(2-((2-ethyl-4-(3-methylpiperazin-1-yl)p henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000891] The title compound was prepared analogously to Example 319, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-2-methylpiperazine-1- carboxylate. The title compound was isolated. MS (ESI) m/z: 621.2 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.03 (s, 1H), 7.74 - 7.36 (m, 1H), 7.05 (s, 1H), 6.90 - 6.81 (m, 2H), 3.92 (d, J = 5.2 Hz, 2H), 3.67 - 3.59 (m, 3H), 3.28 - 3.21 (m, 1H), 3.18 - 3.08 (m, 2H), 2.95 - 2.87 (m, 2H), 2.71 - 2.39 (m, 5H), 1.25 (m, 6H), 0.97 - 0.88 (m, 4H). Example 360: (R)-4-cyclopropyl-7-(2-((4-(3,4-dimethylpiperazin-1-yl)-2-et hylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000892] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-4- cyclopropyl-7-(2-((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl) amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 28% yield. MS (ESI) m/z: 635.2 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.03 (s, 1H), 7.78 - 7.34 (m, 1H), 7.12 - 7.00 (m, 1H), 6.87 - 6.81 (m, 2H), 3.93 – 3.82 (m, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.59 - 3.54 (m, 1H), 3.52 - 3.48 (m, 1H), 3.02 - 2.88 (m, 3H), 2.67 - 2.60 (m, 3H), 2.54 - 2.46 (m, 1H), 2.40 – 2.30 (m, 4H), 1.26 - 1.19 (m, 6H), 0.98 - 0.92 (m, 4H). Example 361: (S)-4-cyclopropyl-7-(2-((4-(3,4-dimethylpiperazin-1-yl)-2-et hylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000893] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (S)-4- cyclopropyl-7-(2-((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl) amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 50% yield. MS (ESI) m/z: 635.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.03 (s, 1H), 7.57 - 7.52 (m, 1H), 7.05 (s, 1H), 6.86 - 6.84 (m, 2H), 3.93 - 3.92 (m, 2H), 3.65 - 3.52 (m, 4H), 3.37 – 3.11 (m, 2H), 2.92 - 2.91 (m, 1H), 2.67 - 2.62 (m, 1H), 2.65 - 2.62 (m, 4H), 2.52 (s, 3H), 1.29 - 1.27 (m, 3H), 1.24 - 1.22 (m, 3H), 0.97 - 0.93 (m, 4H). Example 362: (S)-7-(2-((4-(3,4-dimethylpiperazin-1-yl)-2-ethylphenyl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000894] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (S)-7-(2- ((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(trifluo romethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 40% yield. MS (ESI) m/z: 651.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (s, 1H), 8.07 (s, 1H), 7.53 - 7.49 (m, 1H), 7.03 - 7.01 (m, 1H), 6.86 - 6.84 (m, 2H), 5.57 - 5.52 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.18 – 4.07 (m, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.59 - 3.50 (m, 2H), 3.03 - 3.01 (m, 2H), 2.64 (q, J = 7.6 Hz, 3H), 2.63 - 2.30 (m, 5H), 1.23 (m, J = 7.6 Hz, 6H). Example 363: 4-cyclopropyl-7-(2-((2-ethyl-4-((3S,5S)-3,4,5-trimethylpiper azin-1-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000895] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 4- cyclopropyl-7-(2-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-2- ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 65% yield. MS (ESI) m/z: 649.4[M+H] + .1H-NMR (400MHz, methanol-d 4 ) δ 8.71 - 8.56 (m, 1H), 7.95 (s, 1H), 7.27 - 7.17 (m, 1H), 6.88 - 6.83 (m, 2H), 3.98 – 3.89 (m, 2H), 3.78 – 3.70 (m, 2H), 3.29 - 3.26 (m, 2H), 3.08 - 2.98 (m, 4H), 2.90 - 2.89 (m, 1H), 2.52 (q, J = 7.6 Hz, 2H), 2.42 (s, 3H), 1.20 - 1.15 (m, 9H), 0.90 - 0.89 (m, 4H). Example 364: 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide [000896] The title compound was prepared analogously to Example 319, steps 1-4, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl piperazine-1- carboxylate and Example 341, steps 4-8, where tert-butyl (S)-4-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2-methylpiperazine-1-carboxylate was replaced with tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethylphenyl)piperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 623.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J = 7.6 Hz, 3 H) 2.64 (q, J = 7.6 Hz, 2 H) 3.00 - 3.16 (m, 4 H) 3.17 - 3.30 (m, 4 H) 3.77 (br t, J = 5.6 Hz, 2 H) 4.11 (br s, 2 H) 4.73 (t, J = 6.8 Hz, 2 H) 5.03 (t, J = 7.6 Hz, 2 H) 5.54 (quin, J = 6.8 Hz, 1 H) 6.85 (br d, J = 2.4 Hz, 2 H) 7.04 (br s, 1 H) 7.39 - 7.61 (m, 1 H) 8.07 (s, 1 H) 8.68 (s, 1 H). Example 365: (R)-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000897] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with tert-butyl (R)-4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2-methylpiper azine-1-carboxylate and 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and Example 305, step 6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (R)-4-(3-cyclopropyl-4-((4-(4-methyl-1,1-dioxido-5-oxo- 2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifl uoromethyl)pyrimidin-2-yl)amino)phenyl)-2- methylpiperazine-1-carboxylate. The title compound was isolated in 68% yield. MS (ESI) m/z: 707.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.70 (s, 1H), 8.08 (s, 1H), 7.95 - 7.82 (m, 1H), 7.72 - 7.63 (m, 1H), 6.93 - 6.82 (m, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.42 - 4.28 (m, 1H), 4.02 - 3.94 (m, 1H), 3.94 - 3.84 (m, 2H), 3.79 - 3.70 (m, 2H), 3.50 (d, J = 10.8 Hz, 1H), 3.36 (d, J = 12.0 Hz, 1H), 3.26 (s, 3H), 3.25 - 3.20 (m, 1H), 2.93 (dd, J = 11.6, 3.6 Hz, 1H), 2.78 - 2.72 (m, 1H), 1.93 - 1.83 (m, 1H), 1.50 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H), 1.07 - 0.98 (m, 2H), 0.76 - 0.68 (m, 2H). Example 366: 4-cyclopropyl-7-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)- 2-ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000898] The title compound was prepared analogously to Example 319, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (2S,6R)-2,6-dimethylpiperazine-1- carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 635.4 [M+H] + 1 H NMR (400 MHz, CDCl3-d) δ, 8.69 (s, 1H), 8.06 (s, 1H), 7.66 - 7.48 (m, 1H), 7.12 - 7.02 (m, 1H), 6.94 - 6.84 (m, 2H), 3.95 (br s, 2H), 3.69 - 3.55 (m, 4H), 3.38 - 3.22 (m, 2H), 2.93 (br s, 1H), 2.77 - 2.58 (m, 4H), 1.34 - 1.25 (m, 9H), 0.96 (br d, J = 5.2 Hz, 4H). Example 367: 4-cyclopropyl-7-(2-((2-ethyl-4-((3S,5R)-3,4,5-trimethylpiper azin-1-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000899] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 4- cyclopropyl-7-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2- ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 78% yield. MS (ESI) m/z: 649.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.66 (s, 1H), 8.03 (s, 1H), 7.65 - 7.34 (m, 1H), 7.22 - 7.00 (m, 1H), 6.88 - 6.80 (m, 2H), 3.92 (br s, 2H), 3.63 (br t, J = 5.8 Hz, 2H), 3.54 - 3.49 (m, 2H), 2.95 - 2.87 (m, 1H), 2.76 - 2.69 (m, 2H), 2.67 - 2.62 (m, 2H), 2.61 - 2.52 (m, 2H), 2.42 (s, 3H), 1.27 - 1.22 (m, 9H), 0.98 - 0.91 (m, 4H). Example 368: 7-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-ethylphenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 4-chloro-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-ethylph enyl)-5- (trifluoromethyl)pyrimidin-2-amine [000900] The title compound was prepared analogously to Example 305, step 6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (2S,6R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-ethylphenyl)-2,6-dimethylpiperazine-1-carboxylat e. The title compound was isolated. MS (ESI) m/z: 414.2 [M+H] + . Step 2: (9H-fluoren-9-yl)methyl (2S,6R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)- 3-ethylphenyl)-2,6-dimethylpiperazine-1-carboxylate [000901] To a 0°C solution of 4-chloro-N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-ethylph enyl)-5- (trifluoromethyl)pyrimidin-2-amine (2.42 mmol) and 9H-fluoren-9-ylmethyl carbonochloridate (3.62 mmol) in water (4 mL) and tetrahydrofuran (20 mL), was added potassium carbonate (12.1 mmol). The mixture was stirred for 30 minutes and the volatiles were removed under reduced pressure. The title compound was isolated and was used into the next step without further purification. MS (ESI) m/z: 636.2 [M+H] + . Step 3: (9H-Fluoren-9-yl)methyl (2S,6R)-4-(3-ethyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2,6-dimethylp iperazine-1-carboxylate [000902] The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with (9H-fluoren-9-yl)methyl (2S,6R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin- 2-yl)amino)-3-ethylphenyl)-2,6-dimethylpiperazine-1-carboxyl ate. The title compound was isolated in 8% yield. MS (ESI) m/z: 766.3 [M+H] + . Step 4: (9H-fluoren-9-yl)methyl (2S,6R)-4-(3-ethyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-oxo- 2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-2,6- dimethylpiperazine-1-carboxylate [000903] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with (9H-Fluoren-9-yl)methyl (2S,6R)-4-(3-ethyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2,6-dimethylp iperazine-1-carboxylate and 7-iodo-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 33% yield. MS (ESI) m/z: 873.2 [M+H] + . Step 5: 7-(2-((4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-ethylphenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000904] To a solution of 9H-fluoren-9-ylmethyl (2S,6R)-4-[3-ethyl-4-[[4-[4-(oxetan-3-yl)-1,1,5-trioxo- 2,3-dihydrothieno[2,3-f][1,4]thiazepin-7-yl]-5-(trifluoromet hyl)pyrimidin-2-yl]amino]phenyl]-2,6- dimethyl-piperazine-1-carboxylate (0.02 mmol) in tetrahydrofuran (1 mL) was added piperidine (0.05 mmol). After 2 hours the volatiles were removed under reduced pressure and the residue was purified by preparative TLC (50 % methanol in dichloromethane). The title compound was isolated in 92% yield. MS (ESI) m/z: 651.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.67 (s, 1H), 8.07 (s, 1H), 7.62 - 7.33 (m, 1H), 7.11 - 6.98 (m, 1H), 6.87 - 6.82 (m, 2H), 5.54 (br t, J = 6.8 Hz, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.77 - 4.71 (m, 2H), 4.10 (br s, 2H), 3.76 (br t, J = 5.6 Hz, 2H), 3.60 - 3.52 (m, 2H), 3.08 (br s, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2.36 (t, J = 11.2 Hz, 2H), 1.26 - 1.17 (m, 9H). Example 369: 7-(2-((2-ethyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phen yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000905] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 87% yield. MS (ESI) m/z: 665.3 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.68 (s, 1H), 8.08 - 8.05 (m, 1H), 7.59 - 7.43 (m, 1H), 7.09 (br d, J = 4.4 Hz, 1H), 6.86 - 6.82 (m, 2H), 5.52 (br s, 1H), 5.02 (br t, J = 7.2 Hz, 2H), 4.74 (br t, J = 6.8 Hz, 2H), 4.09 (br s, 2H), 3.76 (br s, 2H), 3.54 (br d, J = 10.8 Hz, 2H), 2.89 - 2.81 (m, 2H), 2.80 - 2.68 (m, 2H), 2.64 (br d, J = 7.6 Hz, 2H), 2.53 (br s, 3H), 1.33 (br d, J = 4.4 Hz, 6H), 1.24 - 1.22 (m, 3H). Example 370: 7-(2-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-2-ethylphenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000906] The title compound was prepared analogously to Example 337, where tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate was replaced with tert-butyl (2S,6S)-2,6-dimethylpiperazine-1- carboxylate. The title compound was isolated. MS (ESI) m/z: 651.4[M+H] + 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.70 - 8.64 (m, 1H), 8.03 - 7.93 (m, 1H), 7.29 - 7.26 (m, 1H), 6.92 - 6.86 (m, 2H), 5.32 - 5.27 (m, 1H), 4.91 - 4.87 (m, 4H), 4.15 – 3.95 (m, 2H), 3.92 – 3.80 (m, 2H), 3.61 - 3.56 (m, 2H), 3.39 - 3.35 (m, 2H), 3.08 - 3.04 (m, 2H), 2.66 - 2.60 (m, 2H), 1.40 - 1.38 (m, 6H), 1.19 - 1.15 (m, 3H). Example 371: (S)-4-(3-cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-ox o-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2- yl)amino)phenyl)piperazine-2-carboxamide Steps 1-3: 1-(tert-butyl) 2-Methyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- cyclopropylphenyl)piperazine-1,2-dicarboxylate

[000907] The title compound was prepared analogously to Example 305, steps 1-3, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with 1-(tert-butyl) 2-methyl (S)- piperazine-1,2-dicarboxylate. The title compound was isolated. MS (ESI) m/z: 556.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.78 - 8.40 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.0, 8.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.87 - 4.59 (m, 1H), 3.99 (t, J = 13.2 Hz, 1H), 3.80 (d, J = 12.4 Hz, 1H), 3.68 (d, J = 5.2 Hz, 3H), 3.62 - 3.50 (m, 1H), 3.23 - 3.03 (m, 1H), 2.91 (t, J = 10.4 Hz, 1H), 2.76 - 2.58 (m, 1H), 1.96 - 1.79 (m, 1H), 1.48 - 1.34 (m, 9H), 0.86 - 0.76 (m, 2H), 0.58 (d, J = 4.8 Hz, 2H). Steps 4-6: 1-((9H-Fluoren-9-yl)methyl) 2-methyl (S)-4-(3-cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1- dioxido-5-oxo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepin- 7-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)piperazine-1,2-dicarboxylate [000908] The title compound was prepared analogously to Example 368, steps 2-4, where 4-chloro-N- (4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-ethylphenyl)-5-(tr ifluoromethyl)pyrimidin-2-amine was replaced with 1-(tert-butyl) 2-Methyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- cyclopropylphenyl)piperazine-1,2-dicarboxylate. The title compound was isolated. MS (ESI) m/z: 915.5 [M+H] + . Step 7: (S)-4-(3-Cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-ox o-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)piperazine-2-carboxamide [000909] To a solution of 1-((9H-fluoren-9-yl)methyl) 2-methyl (S)-4-(3-cyclopropyl-4-((4-(4-(oxetan- 3-yl)-1,1-dioxido-5-oxo-2,3,4,5-tetrahydrothieno[2,3-f][1,4] thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin- 2-yl)amino)phenyl)piperazine-1,2-dicarboxylate (0.02 mmol) in acetonitrile (0.5 mL) was added ammonia in methanol (7 M, 3 mL). The mixture was stirred at 50 °C for 12 hours, cooled down to room temperature and the volatiles removed under reduced pressure. The residue was purified by preparative TLC (15% methanol in dichloromethane). The title compound was isolated in 43% yield. MS (ESI) m/z: 678.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.91 - 8.63 (m, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.33 (s, 1H), 7.24 - 7.08 (m, 2H), 6.76 (J = 2.4, 8.8 Hz, 1H), 6.48 (s, 1H), 5.30 - 5.13 (m, 1H), 4.76 - 4.64 (m, 4H), 4.01 (d, J = 1.2 Hz, 4H), 3.50 ( J = 2.4, 11.6 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.77 - 2.66 (m, 3H), 2.49 - 2.47 (m, 2H), 2.36 - 2.30 (m, 1H), 0.84 - 0.79 (m, 2H), 0.64 - 0.58 (m, 2H). Example 372: (S)-4-(3-Cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-ox o-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-1- methylpiperazine-2-carboxamide [000910] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (S)-4-(3- Cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-oxo-2,3,4,5 -tetrahydrothieno[2,3-f][1,4]thiazepin-7- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin e-2-carboxamide. The title compound was isolated in 43% yield. MS (ESI) m/z: 692.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.94 - 8.63 (m, 1H), 7.92 - 7.75 (m, 1H), 7.32 (s, 1H), 7.14 (s, 2H), 6.76 (d, J = 2.4, 8.8 Hz, 1H), 6.47 (s, 1H), 5.28 - 5.15 (m, 1H), 4.79 - 4.59 (m, 4H), 4.00 (d, J = 2.4 Hz, 4H), 3.56 ( d, J = 11.2 Hz, 1H), 2.88 ( d, J = 11.2 Hz, 1H), 2.79 - 2.59 (m, 3H), 2.48 - 2.45 (m, 2H), 2.20 (s, 3H), 1.95 - 1.89 (m, 1H), 0.80 (d, J = 1.6, 8.6 Hz, 2H), 0.65 - 0.59 (m, 2H) Example 373: (S)-4-(3-cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-ox o-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-N- methylpiperazine-2-carboxamide [000911] The title compound was prepared analogously to Example 371, where 1-((9H-fluoren-9- yl)methyl) 2-methyl (S)-4-(3-cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-ox o-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)piperazine- 1,2-dicarboxylate was replaced with 1-((9H-fluoren-9-yl)methyl) 2-methyl (S)-4-(3-cyclopropyl-4-((4- (4-(oxetan-3-yl)-1,1-dioxido-5-oxo-2,3,4,5-tetrahydrothieno[ 2,3-f][1,4]thiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1,2- dicarboxylate. The title compound was isolated in 29% yield. MS (ESI) m/z: 692.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.76 ( s, 1H), 8.90 - 8.66 (m, 1H), 7.82 ( d, J = 4.0 Hz, 2H), 7.29 - 7.07 (m, 1H), 6.75 (d, J = 2.4, 8.8 Hz, 1H), 6.49 - 6.41 (m, 1H), 5.27 - 5.16 (m, 1H), 4.78 - 4.67 (m, 4H), 4.00 ( s, 4H), 3.50 - 3.43 (m, 1H), 2.98 - 2.92 (m, 1H), 2.79 - 2.67 (m, 3H), 2.63 (d, J = 4.8 Hz, 3H), 2.48 - 2.48 (m, 2H), 1.97 - 1.86 (m, 1H), 0.83 - 0.78 (m, 2H), 0.60 (q, J = 5.2 Hz, 2H). Example 374: (R)-7-(2-((4-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-3 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 2-Chloro-4-cyclopropyl-5-nitropyridine [000912] A mixture of 2,4-dichloro-5-nitropyridine (124 mmol), cyclopropylboronic acid (137 mmol), 1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (6.22 mmol) and sodium carbonate (149 mmol) in toluene (288 mL) and water (96 mL) was stirred at 90°C for 12 hours and cooled down to room temperature. Evaporation of volatiles under reduced pressure afforded a residue that was purified by silica gel column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 59% yield. MS (ESI) m/z: 199.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 -d) δ, 0.89 - 0.97 (m, 2 H) 1.26 - 1.35 (m, 2 H) 2.55 (tt, J=8.8, 5.2 Hz, 1 H) 6.95 (s, 1 H) 8.85 (s, 1 H). [000913] Steps 2-9: (R)-7-(2-((4-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-3 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000914] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 2-chloro-4-cyclopropyl-5-nitropyridine and tert-butyl (R)-2-methylpiperazine-1- carboxylate and Example 368, steps 1-5, where tert-butyl (2S,6R)-4-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)-2,6-di methylpiperazine-1-carboxylate was replaced with tert-butyl (R)-4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -4- cyclopropylpyridin-2-yl)-2-methylpiperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 650.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ,0.72 - 0.78 (m, 2 H) 0.99 - 1.08 (m, 2 H) 1.27 (br d, J=6.0 Hz, 3 H) 1.84 - 1.93 (m, 1 H) 2.57 - 2.72 (m, 1 H) 2.93 - 3.10 (m, 3 H) 3.21 (br d, J=8.0 Hz, 1 H) 3.77 (br t, J=5.2 Hz, 2 H) 4.11 (br d, J=5.2 Hz, 3 H) 4.15 - 4.22 (m, 1 H) 4.73 (t, J=6.8 Hz, 2 H) 5.03 (t, J=7.6 Hz, 2 H) 5.48 - 5.59 (m, 1 H) 6.28 (s, 1 H) 7.18 (br s, 1 H) 8.07 (s, 1 H) 8.37 - 8.46 (m, 1 H) 8.70 (s, 1 H). Example 375: (R)-7-(2-((2-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-3 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000915] The title compound was prepared analogously to Example 374, step 1, where 2,4-dichloro-5- nitropyridine was replaced with 2,6-dichloro-3-nitropyridine, Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and DMF were replaced with 6-chloro-2-cyclopropyl-3-nitropyridine, tert-butyl (R)-2-methylpiperazine- 1-carboxylate and NMP in step 1 and Example 310, where tert-butyl (1S,4S)-5-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2,5-diazabicyclo[2.2.1]heptane-2- carboxylate was replaced with tert-butyl (R)-4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -6- cyclopropylpyridin-2-yl)-2-methylpiperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 650.4 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.72 - 8.55 (m, 1H), 7.98 (s, 1H), 7.49 (s, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.28 (s, 1H), 4.90 - 4.86 (m, 4H), 4.24 (d, J = 13.6 Hz, 2H), 4.10 – 3.95 (m, 2H), 3.90 – 3.80 (m, 2H), 3.30 (s , 1H), 3.20 - 3.18 (m, 1H), 3.10 – 3.06 (s, 1H), 2.99 - 2.91 (m, 2H), 2.65 (t, J = 12.0 Hz, 1H), 2.14 - 2.07 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 1.04 – 0.95 (m, 2H), 0.85 - 0.82 (m, 2H). Example 376: (R)-7-(2-((2-cyclopropyl-6-(3,4-dimethylpiperazin-1-yl)pyrid in-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000916] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)amino )-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 85% yield. MS (ESI) m/z: 664.4 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.77 - 8.57 (m, 1H), 7.98 (s, 1H), 7.47 (s, 1H), 6.60 (d, J = 8.8 Hz, 1H), 5.38 – 5.25 (m, 1H), 4.89 - 4.86 (m, 4H), 4.17 - 4.01 (m, 4H), 3.94 – 3.80 (m, 2H), 3.01 - 2.89 (m, 2H), 2.62 (dd, J = 12.8, 10.0 Hz, 1H), 2.42 – 2.30 (s, 4H), 2.28 - 2.21 (m, 1H), 2.12 - 2.06 (m, 1H), 1.17 (d, J = 6.0 Hz, 3H), 1.04 – 0.98 (m, 2H), 0.85 - 0.80 (m, 2H). Example 377: 7-(2-((2-Cyclopropyl-4-(2,6-diazaspiro[3.3]heptan-2-yl)pheny l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000917] The title compound was prepared analogously to Example 305, steps 1-3, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and DMF were replaced with tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate and NMP in step 1 and Example 310, where tert-butyl (1S,4S)-5- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyc lopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl 6-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2,6-diazaspiro[3.3]heptane-2-carboxylate. The title compound was isolated. MS (ESI) m/z: 647.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.65 - 0.71 (m, 2 H) 0.95 - 1.02 (m, 2 H) 1.85 - 1.88 (m, 1 H) 3.77 (br t, J = 5.6 Hz, 2 H) 3.82 - 3.95 (m, 3 H) 3.99 (s, 4 H) 4.02 - 4.20 (m, 3 H) 4.74 (t, J = 6.8 Hz, 2 H) 5.03 (t, J = 7.6 Hz, 2 H) 5.48 - 5.60 (m, 1 H) 6.21 (br s, 1 H) 6.39 (br d, J = 8.4 Hz, 1 H) 7.37 - 7.81 (m, 2 H) 8.08 (s, 1 H) 8.68 (s, 1 H). Example 378: (R)-7-(2-((2-cyclopropyl-4-(3,4-dimethylpiperazin-1-yl)pheny l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000918] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(t rifluoromethyl)pyrimidin-4-yl)-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 28% yield. MS (ESI) m/z: 621.4 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.74 - 8.52 (m, 1H), 7.98 (s, 1H), 7.51 - 7.30 (m, 1H), 6.87 (dd, J = 8.4, 2.4 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 3.95 - 3.89 (m, 2H), 3.87 - 3.82 (m, 2H), 3.56 - 3.48 (m, 2H), 3.18 (s, 3H), 2.98 - 2.92 (m, 1H), 2.85 (m, 1H), 2.52 - 2.42 (m, 2H), 2.36 (s, 3H), 2.35 – 2.34 (m, 1H), 2.00 - 1.89 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.92 - 0.86 (m, 2H), 0.68 - 0.59 (m, 2H) Example 379: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000919] The title compound was prepared analogously to Example 305, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and DMF were replaced with tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and NMP in step 1 and 7-bromo-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide in step 5. The title compound was isolated. MS (ESI) m/z: 605.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.95 - 8.57 (m, 1H), 7.93 – 7.66 (m, 1H), 7.24 - 6.97 (m, 1H), 6.52 - 6.35 (m, 1H), 6.24 - 6.00 (m, 1H), 4.49 (br s, 1H), 4.05 (s, 1H), 4.00 - 3.81 (m, 4H), 3.55 (br d, J = 8.0 Hz, 1H), 3.10 – 3.03 (m, 5H), 3.01 - 2.97 (m, 1H), 1.97 (br d, J = 9.8 Hz, 1H), 1.93 - 1.85 (m, 1H), 1.78 (br d, J = 10.0 Hz, 1H), 0.80 (br d, J = 8.4 Hz, 2H), 0.61 (br s, 2H). Example 380: (S)-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000920] The title compound was prepared analogously to Example 308, steps 1-3, where tert-butyl (R)- 2-methylpiperazine-1-carboxylate was replaced with tert-butyl (S)-2-methylpiperazine-1-carboxylate in step 1 and Example 310, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptan e-2-carboxylate was replaced with tert- butyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3-cyclopropylphenyl)-2- methylpiperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 607.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 8.08 (s, 1H), 7.95 - 7.86 (m, 1H), 7.75 - 7.59 (m, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 3.95 - 3.87 (m, 2H), 3.77 - 3.68 (m, 2H), 3.53 (d, J = 12.0 Hz, 2H), 3.30 (s, 3H), 3.22 - 3.16 (m, 1H), 3.09 (m, 2H), 2.86 - 2.72 (m, 1H), 2.47 (t, J = 10.8 Hz, 1H), 1.90 - 1.86 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.07 - 1.01 (m, 2H), 0.76 - 0.68 (m, 2H). Example 381: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000921] The title compound was prepared analogously to Example 308, steps 1-3, where tert-butyl (R)- 2-methylpiperazine-1-carboxylate was replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate in step 1, and Example 305, steps 4-6, where tert-butyl (1S,4S)-5-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2,5-diazabicyclo[2.2.1]heptane-2- carboxylate was replaced with tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- cyclopropylphenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxyl ate. The title compound was isolated. MS (ESI) m/z: 510.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.06 (s, 1H), 7.83 - 7.42 (m, 2H), 6.73 - 6.64 (m, 1H), 6.50 (s, 1H), 4.12 - 4.01 (m, 2H), 3.94 - 3.86 (m, 2H), 3.76 - 3.70 (m, 2H), 3.68 - 3.59 (m, 4H), 3.24 (s, 3H), 2.93 - 2.81 (m, 1H), 1.95 - 1.90 (m, 1H), 1.03 - 0.98 (m, 2H), 0.93 - 0.79 (m, 2H), 0.74 - 0.69 (m, 2H). Example 382: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-cycl opropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-di hydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide Steps 1-4: tert-butyl (1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-4- cyclopropylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-ca rboxylate [000922] The title compound was prepared analogously to Example 374, steps 1-4, where tert-butyl (R)- 2-methylpiperazine-1-carboxylate was replaced with tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate. The title compound was isolated. MS (ESI) m/z: 511.2 [M+H]+ Steps 5-9: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-cycl opropylpyridin-3-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothien o[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000923] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylp henyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with tert-butyl (1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-4-cyclopropylpyridin-2-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate in step 1 and 7-iodo- 4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide was replaced with 7- bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 361.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.67 (br s, 1 H) 8.28 (s, 1 H) 8.04 (br s, 1 H) 7.27 - 7.30 (m, 1 H) 5.94 (br t, J = 6.4 Hz, 1 H) 4.90 (br s, 1 H) 4.31 (br d, J = 1.6 Hz, 1 H) 3.92 (br d, J = 1.6 Hz, 2 H) 3.75 (br d, J = 1.6 Hz, 2 H) 3.49 - 3.67 (m, 2 H) 3.15 - 3.35 (m, 5 H) 1.83 - 1.96 (m, 3 H) 1.00 (br d, J = 9.2 Hz, 2 H) 0.76 (br d, J = 5.2 Hz, 2 H). Example 383: 7-(2-((6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-cyclopropylp yridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Steps 1-3: tert-butyl 3-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4- cyclopropylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-ca rboxylate [000924] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 2-chloro-4-cyclopropyl-5-nitropyridine and tert-butyl 3,6-diazabicyclo[3.1.1]heptane- 6-carboxylate. The title compound was isolated. MS (ESI) m/z: 511.4 [M+H] + . Steps 4-6: 7-(2-((6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-cyclopropylp yridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000925] The title compound was prepared analogously to Example 305, steps 4-6, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-cyclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl 3-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4-cyclopropylpyridin- 2-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate in step 4 and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide was replaced with 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1- dioxide in step 5. The title compound was isolated. MS (ESI) m/z: 606.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.26 - 7.12 (m, 1H), 6.14 (s, 1H), 4.28 - 4.06 (m, 2H), 4.01 - 3.77 (m, 6H), 3.76 - 3.70 (m, 2H), 3.24 (s, 3H), 3.05 - 2.87 (m, 1H), 1.94 - 1.88 (m, 1H), 1.79 - 1.69 (m, 1H), 1.02 (q, J = 6.4 Hz, 2H), 0.81 - 0.72 (m, 2H). Example 384: 7-(2-((6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-cyclopropylp yridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000926] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylp henyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with tert-butyl 3-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4- cyclopropylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-ca rboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 648.2 [M+H] + . (400 MHz, CDCl3) δ 8.69 (d, J = 3.6 Hz, 1H), 8.40 (s, 1H), 8.12 - 8.01 (m, 1H), 7.24 - 7.12 (m, 1H), 6.21 - 6.08 (m, 1H), 5.58 - 5.45 (m, 1H), 5.02 (t, J = 7.2 Hz, 2H), 4.75 - 4.68 (m, 2H), 4.51 (d, J = 5.6 Hz, 2H), 4.12 - 4.08 (m, 2H), 4.07 - 3.97 (m, 3H), 3.83 - 3.68 (m, 3H), 3.20 (d, J = 2.4, 5.6 Hz, 1H), 1.94 - 1.87 (m, 2H), 1.07 - 1.02 (m, 2H), 0.79 - 0.74 (m, 2H). Example 385: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl (1R,4R)-5-(6-cyclopropyl-5-nitropyridin-2-yl)-2,5-diazabicyc lo[2.2.1]heptane-2- carboxylate [000927] A solution of 6-chloro-2-cyclopropyl-3-nitro-pyridine (25 mmol), tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (25 mmol) and N,N’-diisopropylethylamine (50 mmol) in acetonitrile (100 mL) was stirred at 80 °C for 12 hours. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (30% ethyl acetate in hexanes). The title compound was isolated in 77% yield. MS (ESI) m/z: 361.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.2 Hz, 1H), 6.08 (d, J = 9.2 Hz, 1H), 4.95 - 4.87 (m, 1H), 4.70 - 4.56 (m, 1H), 3.54 - 3.30 (m, 4H), 3.17 - 3.11 (m, 1H), 1.97 - 1.94 (m, 2H), 1.44 (s, 9H), 1.20 – 1.17 (m, 2H), 1.05 (dd, J = 8.0, 3.2 Hz, 2H). Step 2: tert-butyl (1R,4R)-5-(5-amino-6-cyclopropylpyridin-2-yl)-2,5-diazabicyc lo[2.2.1]heptane-2- carboxylate [000928] A solution of tert-butyl (1R,4R)-5-(6-cyclopropyl-5-nitro-2-pyridyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (19.4 mmol), iron powder (97.1 mmol) and ammonia hydrochloride (97.1 mmol) in ethanol (80 mL) and water (20 mL) was stirred at 80 °C for 5 hours. The reaction mixture was cooled down to room temperature, filtered and concentrated. The residue was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford the title compound in 99% yield. MS (ESI) m/z: 331.1 [M+H] + Step 3: tert-butyl (1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-6- cyclopropylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-ca rboxylate [000929] To a solution of tert-butyl (1R,4R)-5-(5-amino-6-cyclopropyl-2-pyridyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (19.4 mmol) and N,N’-diisopropylethylamine (21.3 mmol) in tert-butanol (65 mL) was added 2,4-dichloro-5-(trifluoromethyl)pyrimidine (21.3 mmol). The mixture was stirred for 1 hour, quenched with water and extracted with ethyl acetate three times. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by preparative HPLC to afford the title compound in 72% yield. MS (ESI) m/z: 511.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.46 (s, 1H), 7.18 - 7.09 (m, 1H), 6.15 (d, J = 8.4 Hz, 1H), 4.85 - 4.79 (m, 1H), 4.65 - 4.50 (m, 1H), 3.52 - 3.32 (m, 4H), 1.99 – 1.95 (m, 1H), 1.90 (d, J = 11.2 Hz, 2H), 1.47 – 1.44 (m, 9H), 1.12-1.00 (m, 2H), 0.92 – 0.78 (m, 2H). Step 4: N-(6-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopro pylpyridin-3-yl)-4-chloro-5- (trifluoromethyl)pyrimidin-2-amine [000930] A solution of tert-butyl (1R,4R)-5-[5-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]am ino]-6- cyclopropyl-2-pyridyl]-2,5-diazabicyclo[2.2.1]heptane-2-carb oxylate (6.85 mmol) in dichloromethane (70 mL) and trifluoroacetic acid (35 mL) was stirred at room temperature for 1 hour. The mixture was concentrated to afford the title compound in 97% yield. MS (ESI) m/z: 411.1 [M+H] + . Step 5: 1-((1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl )amino)-6-cyclopropylpyridin- 2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,2,2-trifluoroeth an-1-one

[000931] To a 0 °C solution of 4-chloro-N-[2-cyclopropyl-6-[(1R,4R)-2,5-diazabicyclo[2.2.1] heptan-2- yl]-3-pyridyl]-5-(trifluoromethyl)pyrimidin-2-amine (6.67 mmol) and triethylamine (20 mmol) in dichloromethane (40 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (8.00 mmol). The mixture was stirred at room temperature for 2 hours, quenched with water and extracted with dichloromethane twice. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to afford the title compound in 74% yield. MS (ESI) m/z: 507.2 [M+H] + . Step 6: 1-((1R,4R)-5-(6-cyclopropyl-5-((5-(trifluoromethyl)-4-(trime thylstannyl)pyrimidin-2- yl)amino)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2 ,2,2-trifluoroethan-1-one [000932] To a solution of 1-[(1R,4R)-5-[5-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl ]amino]-6- cyclopropyl-2-pyridyl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2 ,2,2-trifluoro-ethanone (2.96 mmol) in dioxane (15 mL) was added 4-diphenylphosphanylbutyl(diphenyl)phosphane (0.59 mmol), diacetoxy palladium (0.59 mmol) and trimethyl(trimethylstannyl)stannane (7.40 mmol). The mixture was stirred at 95 °C for 12 hours, quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by flash chromatography (neutral alumina, 8 % ethyl acetate in hexanes). The title compound was isolated in 43% yield. MS (ESI) m/z: 637.2 [M+H] + . Step 7: 7-(2-((2-cyclopropyl-6-((1R,4R)-5-(2,2,2-trifluoroacetyl)-2, 5-diazabicyclo[2.2.1]heptan-2- yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide

[000933] A solution of 1-[(1R,4R)-5-[6-cyclopropyl-5-[[5-(trifluoromethyl)-4-trimet hylstannyl- pyrimidin-2-yl]amino]-2-pyridyl]-2,5-diazabicyclo[2.2.1]hept an-2-yl]-2,2,2-trifluoro-ethanone (0.20 mmol), 7-iodo-4-(oxetan-3-yl)-1,1-dioxo-2,3-dihydrothieno[2,3-f][1, 4]thiazepin-5-one (0.20 mmol), cuprous iodide (0.20 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.020 mmol) in dioxane (4 mL) was stirred at 80 °C for 12 hours. The mixture was cooled down to room temperature, filtered and concentrated. The residue was purified by preparative TLC (60 % ethyl acetate in hexanes) to afford the title compound in 58% yield. MS (ESI) m/z: 744.2 [M+H] + . Step 8: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylpyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000934] A solution of 7-[2-[[2-cyclopropyl-6-[(1R,4R)-5-(2,2,2-trifluoroacetyl)-2, 5- diazabicyclo[2.2.1]heptan-2-yl]-3-pyridyl]amino]-5-(trifluor omethyl)pyrimidin-4-yl]-4-(oxetan-3-yl)- 1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thiazepin-5-one (0.11 mmol) and potassium carbonate (1.15 mmol) in acetonitrile (1 mL), ethanol (1 mL), and water (1 mL) was stirred for 12 hours. The mixture was purified by preparative TLC (10 % methanol in dichloromethane) to afford the title compound in 40% yield. MS (ESI) m/z: 648.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.06 (s, 1H), 7.55 - 7.52 (m, 1H), 7.20 - 7.05 (m, 1H), 6.23 - 6.21 (m, 1H), 5.54 - 5.53 (m, 1H), 5.05 - 5.01 (m, 2H), 4.80 – 4.68 (m, 2H), 4.10 - 4.09 (m, 3H), 3.81 - 3.72 (m, 2H), 3.65 - 3.61 (m, 1H), 3.39 - 3.37 (m, 1H), 3.20 - 3.19 (m, 2H), 2.02 - 2.01 (m, 3H), 1.09 - 1.05 (m, 2H), 0.89 - 0.86 (m, 2H). Example 386: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-cycl opropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000935] The title compound was prepared analogously to Example 374, where tert-butyl (R)-2- methylpiperazine-1-carboxylate was replaced with tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate. The title compound was isolated. MS (ESI) m/z: 648.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.68 - 0.79 (m, 2 H) 0.94 - 1.05 (m, 2 H) 1.86 (br d, J = 6.0 Hz, 3 H) 3.14 (s, 2 H) 3.29 (br d, J = 9.6 Hz, 1 H) 3.62 (br d, J = 9.2 Hz, 1 H) 3.77 (br s, 2 H) 3.96 (br s, 1 H) 4.11 (br d, J = 1.2 Hz, 2 H) 4.66 - 4.83 (m, 3 H) 5.02 (td, J = 7.2, 1.6 Hz, 2 H) 5.43 - 5.64 (m, 1 H) 5.93 (s, 1 H) 7.14 - 7.25 (m, 1 H) 8.06 (br s, 1 H) 8.27 (s, 1 H) 8.68 (s, 1 H). [000936] Example 387: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2- cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5-(4-((4-chloro- 5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl )-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate was replaced with tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated. MS (ESI) m/z: 647.3[M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 8.08 (s, 1H), 7.86 - 7.45 (m, 2H), 6.57 – 6.48 (m, 1H), 6.37 - 6.19 (m, 1H), 5.63 - 5.43 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.31 (s, 1H), 4.16 – 4.07 (m, 2H), 3.85 - 3.72 (m, 3H), 3.69 - 3.61 (m, 1H), 3.16 - 3.09 (m, 1H), 3.08 - 3.01 (m, 1H), 2.97 (d, J = 8.8 Hz, 1H), 1.89 - 1.82 (m, 1H), 1.36 - 1.24 (m, 2H), 1.02 - 0.93 (m, 2H), 0.74 - 0.61 (m, 2H). [000937] Example 388: (R)-7-(2-((2-cyclopropyl-4-(3-(hydroxymethyl)-4-methylpipera zin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-cyclopropyl-4-(3-(hydroxymethyl)piperazin-1-yl)phenyl)am ino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide. The title compound was isolated in 31% yield. MS (ESI) m/z: 679.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.73 (s, 1 H) 8.10 (s, 1 H) 7.94 (d, J = 8.8 Hz, 1 H) 7.71 (s, 1 H) 6.89 - 6.98 (m, 1 H) 6.78 (br d, J = 4.0 Hz, 1 H) 5.45 - 5.60 (m, 1 H) 5.03 (t, J = 7.2 Hz, 2 H) 4.70 - 4.80 (m, 2 H) 4.19 - 4.28 (m, 1 H) 4.09 - 4.15 (m, 2 H) 4.01 (br dd, J = 12.4, 1.6 Hz, 1 H) 3.72 - 3.85 (m, 3 H) 3.57 - 3.69 (m, 4 H) 3.18 - 3.26 (m, 1 H) 3.01 (s, 3 H) 1.83 - 1.91 (m, 1 H) 1.01 - 1.11 (m, 2 H) 0.65 - 0.75 (m, 2 H). Example 389: (R)-7-(2-((4-(3,4-dimethylpiperazin-1-yl)-2-ethylphenyl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000938] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(trifluo romethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 20% yield. MS (ESI) m/z: 651.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.07 (s, 1H), 7.60 - 7.39 (m, 1H), 7.11 - 6.98 (m, 1H), 6.88 - 6.80 (m, 2H), 5.56 – 5.52 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.21 – 4.07 (m, 2H), 3.78 – 3.70 (m, 2H), 3.61 - 3.46 (m, 2H), 3.08 - 2.89 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H), 2.60 – 2.55 (m, 1H), 2.53 - 2.44 (m, 1H), 2.42 - 2.31 (m, 4H), 1.27 - 1.23 (m, 3H), 1.22 - 1.18 (m, 3H). Example 390: (S)-4-(3-cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-ox o-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-N,1- dimethylpiperazine-2-carboxamide [000939] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (S)-4-(3- cyclopropyl-4-((4-(4-(oxetan-3-yl)-1,1-dioxido-5-oxo-2,3,4,5 -tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-N-methylpipe razine-2-carboxamide. The title compound was isolated in 37% yield. MS (ESI) m/z: 706.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.77 ( s, 1H), 8.82 - 8.70 (m, 1H), 7.88 - 7.80 (m, 2H), 7.19 - 7.10 (m, 1H), 6.75 (d, J = 2.4, 8.8 Hz, 1H), 6.45 ( s, 1H), 5.21 ( s, 1H), 4.74 - 4.68 (m, 4H), 4.00 ( s, 4H), 3.54 ( s, 1H), 2.88 (br d, J = 11.2 Hz, 1H), 2.74 - 2.65 (m, 3H), 2.61 (d, J = 4.8 Hz, 3H), 2.47 - 2.45 (m, 2H), 2.14 (s, 3H), 1.92 - 1.88 (m, 1H), 0.80 - 0.77 (m, 2H), 0.62 - 0.59 (m, 2H). Example 391: (R)-7-(2-((4-cyclopropyl-6-(3,4-dimethylpiperazin-1-yl)pyrid in-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000940] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((4-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)amino )-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 91% yield. MS (ESI) m/z: 664.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 0.70 - 0.80 (m, 2 H) 0.99 - 1.08 (m, 2 H) 1.22 (br d, J=5.2 Hz, 3 H) 1.82 - 1.92 (m, 1 H) 2.16 - 2.54 (m, 5 H) 2.68 - 2.87 (m, 1 H) 2.91 - 3.05 (m, 1 H) 3.08 - 3.27 (m, 1 H) 3.78 (br d, J=5.6 Hz, 2 H) 4.01 - 4.19 (m, 4 H) 4.73 (t, J=6.8 Hz, 2 H) 5.02 (t, J=7.6 Hz, 2 H) 5.54 (m, J=6.4 Hz, 1 H) 6.28 (s, 1 H) 7.20 (br s, 1 H) 8.06 (s, 1 H) 8.41 (br s, 1 H) 8.69 (s, 1 H). Example 392: 7-(2-((2-cyclopropyl-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2 -yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000941] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2- cyclopropyl-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated in 29% yield. MS (ESI) m/z: 661.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 0.63 - 0.71 (m, 2 H) 0.94 - 1.02 (m, 2 H) 1.85 - 1.90 (m, 1 H) 2.37 (s, 3 H) 3.45 (s, 4 H) 3.77 (br t, J = 6.0 Hz, 2 H) 3.95 (s, 4 H) 4.06 - 4.14 (m, 2 H) 4.74 (t, J = 6.8 Hz, 2 H) 5.03 (t, J = 7.6 Hz, 2 H) 5.54 (quin, J = 6.8 Hz, 1 H) 6.19 (br s, 1 H) 6.39 (br d, J = 8.4 Hz, 1 H) 7.36 - 7.80 (m, 2 H) 8.07 (s, 1 H) 8.68 (s, 1 H). Example 393: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2. 2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000942] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylph enyl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide. The title compound was isolated in 54% yield. MS (ESI) m/z: 619.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.06 (s, 1H), 7.83 - 7.70 (m, 1H), 7.64 - 7.49 (m, 1H), 6.58 - 6.46 (m, 1H), 6.37 - 6.29 (m, 1H), 4.37 - 4.26 (m, 1H), 3.97 - 3.87 (m, 2H), 3.79 - 3.70 (m, 3H), 3.54 - 3.42 (m, 2H), 3.25 (s, 3H), 3.20 - 3.09 (m, 1H), 2.98 - 2.78 (m, 1H), 2.60 - 2.48 (m, 3H), 2.24 - 2.14 (m, 1H), 2.08 - 2.02 (m, 1H), 1.90 - 1.86 (m, 1H), 1.04 - 0.99 (m, 2H), 0.72 - 0.65 (m, 2H). Example 394: 7-(2-((2-cyclopropyl-4-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothien o[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000943] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylphenyl)ami no)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 32% yield. MS (ESI) m/z: 619.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.06 (s, 1H), 7.92 - 7.38 (m, 2H), 6.74 - 6.65 (m, 1H), 6.52 (s, 1H), 3.95 - 3.86 (m, 2H), 3.79 - 3.68 (m, 4H), 3.62 - 3.55 (m, 2H), 3.42 - 3.31 (m, 2H), 3.25 (s, 3H), 2.72 - 2.60 (m, 1H), 2.18 (s, 3H), 1.96 - 1.89 (m, 1H), 1.66 - 1.62 (m, 1H), 1.06 - 0.95 (m, 2H), 0.79 - 0.70 (m, 2H). Example 395: 7-(2-((6-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-di hydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000944] The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5-(4- ((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclop ropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,4R)-5-(5-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-6-cyclopropylpyridin- 2-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate in step 1 and 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepi n-5(2H)-one 1,1- dioxide was replaced with 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1- dioxide in step 4. The title compound was isolated. MS (ESI) m/z: 606.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.03 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.26 - 6.22 (m, 1H), 4.88 (s, 1H), 4.38 - 4.34 (m, 1H), 3.93 - 3.91 (m, 2H), 3.73 - 3.59 (m, 4H), 3.57 - 3.30 (m, 1H), 3.30 - 3.28 (m, 1H), 3.24 (s, 3H), 2.17 (s, 1H), 2.06 - 2.02 (m, 2H), 1.09 - 1.01 (m, 2H), 0.90 - 0.87s (m, 2H). Example 396: 7-(2-((2-Cyclopropyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2. 2.1]heptan-2- yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000945] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylpy ridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 38% yield. MS (ESI) m/z: 620.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.04 (s, 1H), 7.60 - 7.53 (m, 1H), 7.16 - 7.13 (m, 1H), 6.22 - 6.21 (m, 1H), 4.70 (s, 1H), 3.91 - 3.87 (m, 2H), 3.72 - 3.63 (m, 4H), 3.40 - 3.32 (m, 1H), 3.23 (s, 3H), 3.06 - 3.05 (m, 1H), 2.88 - 2.66 (m, 1H), 2.51 (s, 3H), 2.03 - 2.02 (m, 1H), 1.97 - 1.88 (m, 2H), 1.11 - 1.07 (m, 2H), 0.89 - 0.86 (m, 2H). Example 397: 7-(2-((6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp yridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000946] The title compound was prepared analogously to Example 375, steps 2-4, where tert-butyl (R)- 2-methylpiperazine-1-carboxylate was replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate and Example 308, steps 4-6, where tert-butyl (R)-4-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2-methylpiperazine-1-carboxylate was replaced with tert-butyl 3-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6-c yclopropylpyridin- 2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate. The title compound was isolated. MS (ESI) m/z: 606.3[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.72 - 8.58 (m, 1H), 8.00 - 7.96 (m, 1H), 7.52 - 7.46 (m, 1H), 6.49 - 6.47 (m, 1H), 4.18 – 4.08 (m, 2H), 3.95 - 3.78 (m, 8H), 3.16 (s, 3H), 2.89 - 2.83 (m, 1H), 2.15 - 2.09 (m, 1H), 1.82 - 1.79 (m, 1H), 1.13 – 1.04 (m, 2H), 0.83 (dd, J = 7.6, 2.8 Hz, 2H). Example 398: 7-(2-((2-cyclopropyl-6-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)pyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-di hydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000947] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide. The title compound was isolated in 33% yield. MS (ESI) m/z: 620.3[M+H] + . 1 H NMR (400MHz, methanol) δ 8.73 - 8.55 (m, 1H), 8.00 - 7.95 (m, 1H), 7.54 - 7.42 (m, 1H), 6.46 (s, 1H), 3.97 - 3.60 (m, 10H), 3.20 - 3.15 (m, 3H), 2.67 - 2.61 (m, 1H), 2.31 - 2.23 (m, 4H), 1.75 - 1.66 (m, 1H), 1.14 – 1.05 (m, 2H), 0.84 – 0.82 (m 2H). Example 399: 7-(2-((6-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp yridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000948] The title compound was prepared analogously to Example 375, where tert-butyl (R)-2- methylpiperazine-1-carboxylate was replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate in step 2. The title compound was isolated. MS (ESI) m/z: 648.1[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.72 - 8.55 (m, 1H), 8.01 - 7.97 (m, 1H), 7.50 - 7.44 (m, 1H), 6.44 (d, J = 8.8 Hz, 1H), 5.30 - 5.25 (m, 1H), 4.07 - 3.97 (m, 4H), 3.92 - 3.85 (m, 2H), 3.82 - 3.72 (m, 4H), 2.82 - 2.77 (m, 1H), 2.14 - 2.08 (m, 1H), 1.73 - 1.71 (m, 1H), 1.15 – 1.02 (m, 2H), 0.82 (dd, J = 7.6, 2.8 Hz, 2H). Example 400: 7-(2-((2-Cyclopropyl-6-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)pyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000949] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- (3,6-Diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide. The title compound was isolated in 30% yield. MS (ESI) m/z: 662.3[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.69 (s, 1H), 8.07 (s, 1H), 7.68 - 7.53 (m, 1H), 7.24 - 7.15 (m, 1H), 6.38 (d, J = 8.0 Hz, 1H), 5.56 - 5.50 (m, 1H), 5.08 – 4.97 (m, 2H), 4.73 (t, J = 6.4 Hz, 2H), 4.13 - 4.08 (m, 2H), 3.90 - 3.72 (m, 6H), 3.62 - 3.57 (m, 2H), 2.78 - 2.71 (m, 1H), 2.26 (s, 3H), 2.06 - 2.05 (m, 1H), 1.76 - 1.62 (m, 1H), 1.17 - 1.14 (m, 2H), 0.92 - 0.88 (m, 2H). Example 401: 7-(2-((4-cyclopropyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2. 2.1]heptan-2-yl)pyridin- 3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000950] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-cyclopropylpy ridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 11% yield. MS (ESI).m/z: 665.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.68 (s, 1 H) 8.27 (s, 1 H) 8.04 (br s, 1 H) 7.18 (s, 1 H) 5.97 (br s, 1 H) 4.68 - 4.86 (m, 1 H) 3.66 - 3.93 (m, 6 H) 3.39 - 3.50 (m, 1 H) 3.07 - 3.28 (m, 5 H) 2.51 - 2.70 (m, 3 H) 2.10 - 2.18 (m, 1 H) 1.84 - 1.87 (m, 2 H) 0.96 - 1.06 (m, 2 H) 0.71 - 0.78 (m, 2 H). Example 402: 7-(2-((4-cyclopropyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2. 2.1]heptan-2-yl)pyridin- 3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-y l)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000951] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-cyclopropylpy ridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide. The title compound was isolated in 68% yield. MS (ESI) m/z: 662.1 [M+H] + 1 H NMR (400 MHz, CDCl3) δ ppm 0.67 - 0.78 (m, 2 H) 1.00 (br dd, J = 6.0, 2.4 Hz, 2 H) 1.85 (ddd, J = 13.6, 8.0, 5.2 Hz, 2 H) 2.07 (br d, J = 10.2 Hz, 1 H) 2.51 (br s, 3 H) 2.68 - 2.94 (m, 1 H) 2.96 - 3.13 (m, 1 H) 3.33 - 3.47 (m, 1 H) 3.63 (br d, J = 14.4 Hz, 2 H) 3.76 (br s, 2 H) 4.02 - 4.19 (m, 2 H) 4.67 - 4.80 (m, 3 H) 5.02 (br t, J = 7.6 Hz, 2 H) 5.44 - 5.64 (m, 1 H) 5.95 (s, 1 H) 7.14 (br s, 1 H) 8.06 (br s, 1 H) 8.27 (s, 1 H) 8.68 (s, 1 H). Example 403: 7-(2-((4-cyclopropyl-6-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)pyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-di hydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [000952] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-cyclopropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide. The title compound was isolated in 39% yield. MS (ESI) m/z: 620.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.06 (s, 1H), 7.20 (s, 1H), 6.16 (s, 1H), 4.05 - 3.93 (m, 2H), 3.91 (s, 2H), 3.83 - 3.64 (m, 6H), 3.24 (s, 3H), 2.97 - 2.82 (m, 1H), 2.34 (s, 3H), 2.10 - 2.05 (m, 1H), 1.96 - 1.93 (m, 1H), 1.08 - 1.02 (m, 2H), 0.79 (d, J = 5.4 Hz, 2H). Example 404: (R)-N-(2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000953] The title compound was prepared analogously to Example 308, where 7-bromo-4-cyclopropyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 2-bromo-4- (methylsulfonyl)thiophene in step 5. The title compound was isolated. MS (ESI) m/z: 538.2 [M+1H]+. 1 H NMR (400 MHz, methanol-d4) δ = 8.75 - 8.57 (m, 1H), 8.46 (s, 1H), 8.00 (s, 1H), 7.51 - 7.33 (m, 1H), 6.87 (dd, J = 8.8, 2.8 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 3.55 (t, J = 10.4 Hz, 2H), 3.18 (s, 3H), 3.12 (d, J = 2.4 Hz, 1H), 3.05 - 2.97 (m, 2H), 2.71 -2.64 (m, 1H), 2.43 - 2.34 (m, 1H), 2.00 - 1.92 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 0.93 - 0.86 (m, 2H), 0.69 - 0.60 (m, 2H). Example 405: N-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylpheny l)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000954] The title compound was prepared analogously to Example 308, where with tert-butyl (R)-4-(3- cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyri midin-2-yl)amino)phenyl)-2- methylpiperazine-1-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin - 5(2H)-one 1,1-dioxide were replaced with tert-butyl 3-[3-cyclopropyl-4-[[5-(trifluoromethyl)-4- trimethylstannyl-pyrimidin-2-yl]amino]phenyl]-3,6-diazabicyc lo[3.1.1]heptane-6-carboxylate and 2- bromo-4-methylsulfonyl-thiophene. The title compound was isolated. MS (ESI) m/z: 536.2[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.66 - 8.58 (m, 1H), 8.43 - 8.41 (m, 1H), 7.99 (s, 1H), 7.42 - 7.24 (m, 1H), 6.65 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 4.02 - 3.81 (m, 2H), 3.62 - 3.56 (m, 4H), 3.17 (s, 3H), 2.80 - 2.68 (m, 1H), 2.00 - 1.93 (m, 1H), 1.71 (d, J = 9.2 Hz, 1H), 0.90 - 0.85 (m, 2H), 0.68 - 0.64 (m, 2H). Example 406: (R)-7-(2-((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000955] The title compound was prepared analogously to Example 319, steps 1-4, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-2- methylpiperazine-1-carboxylate and Example 310, where tert-butyl (1S,4S)-5-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2,5-diazabicyclo[2.2.1]heptane-2- carboxylate was replaced with tert-butyl (R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- ethylphenyl)-2-methylpiperazine-1-carboxylate in step 1. The title compound was isolated. MS (ESI) m/z: 637.3 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.07 (s, 1H), 7.56 - 7.42 (m, 1H), 7.08 - 6.98 (m, 1H), 6.84 (br s, 2H), 5.61 - 5.48 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.10 (br d, J = 3.6 Hz, 2H), 3.77 (br t, J = 5.4 Hz, 2H), 3.57 (br d, J = 11.6 Hz, 2H), 3.22 - 3.14 (m, 1H), 3.12 - 3.01 (m, 2H), 2.81 (dt, J = 11.4, 3.2, Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 2.46 (br t, J = 10.8 Hz, 1H), 1.25 - 1.19 (m, 6H). Example 407: (R)-4-cyclopropyl-7-(2-((2-ethyl-4-(3-(hydroxymethyl)piperaz in-1-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide [000956] The title compound was prepared analogously to Example 355, where 7-iodo-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 4-cyclopropyl-7-iodo- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 637.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.03 (s, 1H), 7.56 - 7.41 (m, 1H), 7.08 (br s, 1H), 6.91 - 6.79 (m, 2H), 3.97 - 3.87 (m, 3H), 3.79 (br dd, J = 6.8, 11.2 Hz, 1H), 3.63 (br t, J = 5.6 Hz, 4H), 3.38 (br d, J = 12.0 Hz, 1H), 3.32 - 3.26 (m, 1H), 3.21 - 3.12 (m, 2H), 2.94 - 2.89 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H), 0.98 - 0.90 (m, 4H). Example 408: (R)-4-cyclopropyl-7-(2-((2-ethyl-4-(3-(hydroxymethyl)-4-meth ylpiperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihy drothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide [000957] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-4- cyclopropyl-7-(2-((2-ethyl-4-(3-(hydroxymethyl)piperazin-1-y l)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide. MS (ESI) m/z: 651.5 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.02 (s, 1H), 7.59 - 7.34 (m, 1H), 7.18 - 7.03 (m, 1H), 6.93 - 6.80 (m, 2H), 4.01 (br dd, J = 4.0, 12.0 Hz, 1H), 3.93 (br s, 2H), 3.77 - 3.67 (m, 1H), 3.67 - 3.52 (m, 4H), 3.52 - 3.46 (m, 1H), 3.23 - 2.97 (m, 3H), 2.90 (br s, 1H), 2.81 - 2.69 (m, 1H), 2.66 - 2.61 (m, 2H), 2.56 (br s, 3H), 2.10 - 2.06 (m, 1H), 1.23 (br t, J = 7.6 Hz, 3H), 0.97 - 0.90 (m, 4H). Example 409: (R)-7-(2-((2-Ethyl-4-(3-(hydroxymethyl)-4-methylpiperazin-1- yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000958] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-ethyl-4-(3-(hydroxymethyl)piperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 667.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.07 (s, 1H), 7.58 - 7.37 (m, 1H), 7.07 (br s, 1H), 6.93 - 6.77 (m, 2H), 5.59 - 5.43 (m, 1H), 5.02 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.10 (br s, 2H), 4.01 (dd, J = 4.0, 12.0 Hz, 1H), 3.76 (m, 2H), 3.69 (br d, J = 12.0 Hz, 1H), 3.57 (br t, J = 12.0 Hz, 2H), 3.19 - 2.97 (m, 3H), 2.77 - 2.65 (m, 2H), 2.65 - 2.58 (m, 2H), 2.54 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H). Example 410: 7'-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyc lopropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2'H-spiro[cyclopropane-1,3' -thieno[2,3-f][1,4]thiazepin]-5'(4'H)- one 1',1'-dioxide [000959] A solution of 2-methoxycarbonylthiophene-3-sulfinic acid (5.53 mmol), tert-butyl N-[1- (bromomethyl)cyclopropyl]carbamate (6.6 mmol), and cesium carbonate (11 mmol) in DMF (15mL) was stirred at 100 °C for 1 hour. The reaction was cooled down to room temperature, diluted with water and extracted with ethyl acetate three times. The combined organic layers were collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (60% ethyl acetate in hexanes) to afford the title compound in 50% yield. MS (ESI) m/z: 398.3 [M+Na]+ Step 2: 2'H-spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thiazepin]-5'( 4'H)-one 1',1'-dioxide [000960] A solution of methyl 3-(((1-((tert- butoxycarbonyl)amino)cyclopropyl)methyl)sulfonyl)thiophene-2 -carboxylate (0.53 mmol) in 1,4 dioxane (2mL) was treated with 4N aqueous HCl (3 mL) and the reaction was monitored by LCMS until complete consumption of starting material was observed. The reaction was concentrated under reduced pressure, treated with saturated aqueous solution of sodium carbonate and stirred at 50 °C for 12 hours. The reaction mixture was cooled in an ice bath and the resulting solid was filtered to afford the title compound in 80% yield. MS (ESI) m/z: 244.0 [M+H] + Step 3: 7'-bromo-2'H-spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thiaz epin]-5'(4'H)-one 1',1'-dioxide [000961] A -10 °C solution of 2'H-spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thiazepin]-5'( 4'H)-one 1',1'- dioxide (0.77 mmol) in trifluoroacetic acid (5 mL) was treated with concentrated sulfuric acid (1.5 mmol). N-bromosuccinimide (1.2 mmol) was added and stirring continued for another 36 hours. The pH of the reaction was made neutral by the addition of sodium bicarbonate and the mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by preparative HPLC to afford the title compound in 48% yield. MS (ESI) m/z: 321.9 [M+H] + Steps 4: tert-butyl (1R,4R)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethy lstannyl)pyrimidin- 2-yl)amino)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate [000962] The title compound was prepared analogously to Example 4, where 1-(7-chloro-6-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli n-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate. The title compound was isolated as a pale yellow oil. MS (ESI) m/z: 640.2 [M+H] + Step 5: tert-butyl (1R,4R)-5-(3-cyclopropyl-4-((4-(1',1'-dioxido-5'-oxo-4',5'-d ihydro-2'H- spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thiazepin]-7'-yl)- 5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylat e [000963] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with tert-butyl (1R,4R)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate and 7'- bromo-2'H-spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thiazepi n]-5'(4'H)-one 1',1'-dioxide. The title compound was isolated as a pale yellow solid. MS (ESI) m/z: 717.2 [M+H]+ Step 6: 7'-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyc lopropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2'H-spiro[cyclopropane-1,3' -thieno[2,3-f][1,4]thiazepin]-5'(4'H)- one 1',1'-dioxide [000964] The title compound was prepared analogously to Example 149, step 6, where 7-(2-((2-chloro- 5-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin -4-yl)-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl (1R,4R)-5-(3-cyclopropyl-4-((4- (1',1'-dioxido-5'-oxo-4',5'-dihydro-2'H-spiro[cyclopropane-1 ,3'-thieno[2,3-f][1,4]thiazepin]-7'-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-2,5-diazabicyc lo[2.2.1]heptane-2-carboxylate. MS (ESI) m/z: 631.1 [M+H] + Example 411: 7-(2-((2-cyclopropyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2. 2.1]heptan-2-yl)pyridin- 3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-y l)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000965] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylpy ridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide. The title compound was isolated in 33% yield as an orange solid. MS (ESI) m/z: 662.2 [M+H] + [000966] 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.08 - 8.05 (m, 1H), 7.54 - 7.53 (m, 1H), 7.12 - 7.11 (m, 1H), 6.29 - 6.21 (m, 1H), 5.51 - 5.48 (m, 1H), 5.03 - 4.98 (m, 2H), 4.75 - 4.72 (m, 3H), 4.12 - 4.10 (m, 3H), 3.78 - 3.73 (m, 3H), 3.68 - 3.28 (m, 2H), 3.22 - 2.90 (m, 1H), 2.70 - 2.63 (m, 3H), 2.05 - 2.01 (m, 3H), 1.08 - 1.03 (m, 2H), 0.89 - 0.87 (m, 2H). Example 412: 7-(2-((4-cyclopropyl-6-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)pyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000967] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-cyclopropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide. The title compound was isolated in 22% yield as a pale yellow solid. MS (ESI) m/z: 662.2 [M+H] + [000968] 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.46 - 8.35 (m, 1H), 8.08 (s, 1H), 7.21 - 7.14 (m, 1H), 6.16 (s, 1H), 5.59 - 5.48 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.16 - 4.08 (m, 2H), 4.05 - 3.83 (m, 2H), 3.78 (s, 4H), 3.73 - 3.57 (m, 2H), 2.99 - 2.80 (m, 1H), 2.43 - 2.16 (m, 3H), 1.94 - 1.88 (m, 1H), 1.08 - 1.02 (m, 2H), 0.81 - 0.76 (m, 2H) Example 413: N-(4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopro pylphenyl)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000969] The title compound was prepared analogously to Example 329, where 7-bromo-4-cyclopropyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 2-bromo-4- (methylsulfonyl)thiophene. The title compound was isolated in 25% yield as an orange solid. MS (ESI) m/z: 536.2[M+H] + [000970] 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.97 - 7.58 (m, 1H), 7.57 - 7.30 (m, 1H), 6.40 ( d, J = 8.4 Hz, 1H), 6.33 ( s, 1H), 4.34 (s, 1H), 3.90 (s, 1H), 3.76 - 3.63 (m, 1H), 3.22 - 3.16 (m, 1H), 3.14 (s, 3H), 3.13 - 3.04 (m, 2H), 2.03 - 1.98 (m, 1H), 2.00 ( d, J = 8.4 Hz, 2H), 1.06 - 0.94 (m, 2H), 0.75 - 0.64 (m, 2H) Example 414: N-(2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1] heptan-2-yl)phenyl)-4- (4-(methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimid in-2-amine [000971] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with N-(4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylph enyl)-4-(4-(methylsulfonyl)thiophen-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine. The title compound was isolated in 57% yield as an orange solid. [000972] MS (ESI) m/z: 550.2[M+H] + [000973] 1 H NMR (400 MHz, CDCl3) δ 8.71 - 8.61 (m, 1H), 8.29 - 8.21 (m, 1H), 8.07 - 7.96 (m, 1H), 7.92 - 7.66 (m, 1H), 7.59 - 7.39 (m, 1H), 6.54 - 6.48 (m, 1H), 6.38 - 6.30 (m, 1H), 4.30 ( s, 1H), 3.86 - 3.65 (m, 1H), 3.55 - 3.42 (m, 2H), 3.23 - 3.07 (m, 4H), 2.98 - 2.77 (m, 1H), 2.61 - 2.44 (m, 3H), 2.23 - 2.12 (m, 1H), 2.06 - 2.01 (m, 1H), 1.91 - 1.87 (m, 1H), 1.00 ( d, J = 8.4 Hz, 2H), 0.73 - 0.65 (m, 2H). Example 415: (R)-N-(2-chloro-4-(3-methylpiperazin-1-yl)phenyl)-4-(4-(meth ylsulfonyl)thiophen-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine [000974] The title compound was prepared analogously to Example 413, where 2-cyclopropyl-4-fluoro- 1-nitrobenzenewas replaced with 2-chloro-4-fluoro-1-nitrobenzene. The title compound was isolated as a pale yellow solid. MS (ESI) m/z: 531.1[M+H] + [000975] 1 H NMR (400 MHz, CDCl3) δ (ppm) = 8.71 (s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.60 (br s, 1H), 6.99 (d, J = 2.8 Hz, 1H), 6.93 (dd, J = 2.8, 9.2 Hz, 1H), 3.52 (br d, J = 12.0 Hz, 2H), 3.23 - 3.13 (m, 4H), 3.09 - 2.97 (m, 2H), 2.78 (dt, J = 3.2, 11.6 Hz, 1H), 2.50 - 2.39 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H). Example 416: N-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-chlorophenyl)-4- (4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000976] The title compound was prepared analogously to Example 381, where 2-cyclopropyl-4-fluoro- 1-nitrobenzenewas replaced with 2-chloro-4-fluoro-1-nitrobenzene and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide with 2-bromo-4-(methylsulfonyl)thiophene. The title compound was isolated as an orange solid. MS (ESI) m/z: 530.2 [M+H] + [000977] 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.26 (s, 1H), 8.04 (s, 2H), 7.50 ( s, 1H), 6.80 (d, J = 2.8 Hz, 1H), 6.72 (d, J = 2.8, 9.2 Hz, 1H), 4.01 ( d, J = 6.0 Hz, 2H), 3.61 (s, 4H), 3.15 - 3.13 (m, 3H), 2.89 - 2.81 (m, 1H), 1.66 ( d, J = 8.8 Hz, 1H) Example 417: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-chlo rophenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000978] The title compound was prepared analogously to Example 310, where 2-cyclopropyl-4-fluoro- 1-nitrobenzene and tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 2-chloro-4-fluoro-1-nitrobenzene and tert- butyl (1R,4R)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 641.1 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 1.75 (br d, J = 9.2 Hz, 1 H) 1.87 - 1.94 (m, 1 H) 2.89 - 3.05 (m, 3 H) 3.53 (br d, J = 7.6 Hz, 1 H) 3.87 - 4.13 (m, 5 H) 4.48 (br s, 1 H) 4.63 - 4.80 (m, 4 H) 5.21 (br d, J = 2.4 Hz, 1 H) 6.59 (dd, J = 8.8, 2.4 Hz, 1 H) 6.73 (br s, 1 H) 7.24 (br s, 1 H) 7.65 - 7.96 (m, 1 H) 8.53 - 9.05 (m, 1 H) 9.67 - 10.04 (m, 1 H). Example 418: N-(4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-chloroph enyl)-4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine [000979] The title compound was prepared analogously to Example 329, where 2-cyclopropyl-4-fluoro- 1-nitrobenzene was replaced with 2-chloro-4-fluoro-1-nitrobenzene and 7-bromo-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide with 2-bromo-4-(methylsulfonyl)thiophene. The title compound was isolated as an orange solid. MS (ESI) m/z: 530.1 [M+H] + 1 H NMR (400 MHz, CDCl3) δ ppm 1.90 - 1.96 (m, 2 H) 3.04 - 3.23 (m, 6 H) 3.65 (dd, J = 9.2, 1.6 Hz, 1 H) 3.96 (br s, 1 H) 4.33 (s, 1 H) 6.55 (dd, J = 8.8, 2.4 Hz, 1 H) 6.63 (d, J = 2.8 Hz, 1 H) 7.47 (br s, 1 H) 7.83 - 7.98 (m, 1 H) 8.03 (s, 1 H) 8.27 (s, 1 H) 8.69 (s, 1 H). Example 419: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000980] The title compound was prepared analogously to Example 379, where 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 7-bromo-5-oxo- 2,3-dihydrothieno[2,3-f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 591.1 [M+H] + [000981] 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.08 (s, 1H), 7.56 - 7.41 (m, 1H), 7.41 - 7.27 (m, 1H), 6.54 - 6.44 (m, 1H), 6.29 (d, J = 2.3 Hz, 1H), 4.38 – 4.18 (m, 1H), 4.02 - 3.83 (m, 2H), 3.82 - 3.48 (m, 4H), 3.47 - 2.91 (m, 3H), 2.26 (m, 1H), 1.91 - 1.78 (m, 2H), 0.97 - 0.83 (m, 2H), 0.70 - 0.57 (m, 2H) Example 420: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [000982] The title compound was prepared analogously to Example 381, where 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 7-bromo-5-oxo- 2,3-dihydrothieno[2,3-f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 591.3[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.72 - 8.58 (m, 1H), 8.02 (s, 1H), 7.39 - 7.32 (m, 1H), 6.75 - 6.67 (m, 1H), 6.46 (s, 1H), 4.40 - 4.30 (m, 2H), 3.83 - 3.71 (m, 8H), 2.98 - 2.92 (m, 1H), 2.03 - 1.92 (m, 2H), 0.92 - 0.87 (m, 2H), 0.70 - 0.66 (m, Example 421: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(methyl-d3)-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide

[000983] The title compound was prepared analogously to Example 140, where iodomethane was replaced with iodomethane-d3. The title compound was isolated as a yellow solid. MS (ESI) m/z: 313.0 [M+H] + Step 2: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(methyl-d3)-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000984] The title compound was prepared analogously to Example 308, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4-(methyl-d3)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 608.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (s, 1H), 8.04 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.53 (br s, 1H), 6.55 - 6.48 (m, 1H), 6.35 - 6.27 (m, 1H), 3.90 (br d, J = 6.0 Hz, 2H), 3.76 - 3.68 (m, 3H), 3.39 - 3.28 (m, 3H), 2.14 (br s, 2H), 1.93 - 1.77 (m, 2H), 0.97 (br d, J = 8.4 Hz, 2H), 0.70 - 0.63 (m, 2H). Example 422: (R)-7-(2-((2-chloro-4-(3-methylpiperazin-1-yl)phenyl)amino)- 5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000985] The title compound was prepared analogously to Example 308, where 2-cyclopropyl-4-fluoro- 1-nitrobenzene and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 2-chloro-4-fluoro-1-nitrobenzene and 7-iodo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 642.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm) = 8.75 (s, 1H), 8.14 - 8.02 (m, 2H), 7.67 - 7.56 (m, 1H), 7.02 - 6.87 (m, 2H), 5.60 - 5.49 (m, 1H), 5.04 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.13 (br t, J = 6.0 Hz, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.54 (br d, J = 11.2 Hz, 2H), 3.28 - 3.19 (m, 1H), 3.15 - 3.02 (m, 2H), 2.95 - 2.83 (m, 1H), 2.55 (br t, J = 11.6 Hz, 1H), 1.26 (br d, J = 6.4 Hz, 3H). Example 423: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-chlorophenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000986] The title compound was prepared analogously to Example 308, where 2-cyclopropyl-4-fluoro- 1-nitrobenzene and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1- dioxide were replaced with 2-chloro-4-fluoro-1-nitrobenzene and 7-iodo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 641.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.09 (s, 1H), 7.96 - 7.86 (m, 1H), 7.59 - 7.44 (m, 1H), 6.79 (s, 1H), 6.72 ( d, J = 8.8 Hz, 1H), 5.61 - 5.48 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.12 ( t, J = 5.2 Hz, 2H), 3.94 ( d, J = 5.6 Hz, 2H), 3.78 ( t, J = 5.6 Hz, 2H), 3.62 - 3.50 (m, 4H), 2.79 (q, J = 6.8 Hz, 1H), 1.63 ( d, J = 8.8 Hz, 1H) Example 424: (S)-7-(2-((2-cyclopropyl-4-(3-(hydroxymethyl)piperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000987] The title compound was prepared analogously to Example 345, where tert-butyl (R)-2- (hydroxymethyl)piperazine-1-carboxylate was replaced with tert-butyl (S)-2-(hydroxymethyl)piperazine- 1-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide with 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI).m/z: 623.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.70 (s, 1 H) 8.07 (s, 1 H) 7.89 (br dd, J = 6.4, 2.8 Hz, 1 H) 7.61 - 7.77 (m, 1 H) 6.84 - 6.96 (m, 1 H) 6.75 (d, J = 2.4 Hz, 1 H) 3.91 (br t, J = 5.6 Hz, 2 H) 3.79 - 3.86 (m, 1 H) 3.68 - 3.78 (m, 3 H) 3.47 - 3.57 (m, 2 H) 3.17 - 3.33 (m, 5 H) 3.06 - 3.15 (m, 1 H) 2.87 - 2.98 (m, 1 H) 2.75 (br t, J = 11.2 Hz, 1 H) 1.83 - 1.93 (m, 1 H) 0.99 - 1.07 (m, 2 H) 0.67 - 0.74 (m, 2 H) Example 425: (S)-(4-(3-cyclopropyl-4-((4-(4-(methylsulfonyl)thiophen-2-yl )-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-yl) methanol [000988] The title compound was prepared analogously to Example 424, where 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 2-bromo-4- (methylsulfonyl)thiophene. The title compound was isolated as a yellow solid. MS (ESI) m/z: 554.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.69 (s, 1 H) 8.26 (s, 1 H) 8.04 (s, 1 H) 7.83 - 7.99 (m, 1 H) 7.59 - 7.75 (m, 1 H) 6.89 (br d, J = 8.0 Hz, 1 H) 6.77 (br s, 1 H) 3.76 - 3.84 (m, 1 H) 3.66 - 3.74 (m, 1 H) 3.51 (br t, J = 9.2 Hz, 2 H) 3.26 (br d, J = 12.0 Hz, 1 H) 3.05 - 3.20 (m, 5 H) 2.87 (td, J = 11.6, 2.8 Hz, 1 H) 2.69 (t, J = 10.8 Hz, 1 H) 1.84 - 1.94 (m, 1 H) 0.99 - 1.08 (m, 2 H) 0.67 - 0.75 (m, 2 H) Example 426: 7-(2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)- 4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide [000989] The title compound was prepared analogously to Example 305, steps 1-5, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with morpholine and 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide with 7-iodo-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 636.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.72 (s, 1H), 8.10 (s, 1H), 7.96 - 7.87 (m, 1H), 7.76 - 7.63 (m, 1H), 6.93 - 6.83 (m, 1H), 6.80 - 6.70 (m, 1H), 5.58 - 5.51 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.14 – 4.11 (m, 2H), 3.90 (s, 4H), 3.78 (t, J = 5.8 Hz, 2H), 3.18 (s, 4H), 1.91 - 1.87 (m, 1H), 1.11 – 0.95 (m, 2H), 0.74 – 0.70 (m, 2H) Example 427: (S)-7-(2-((2-cyclopropyl-4-(2-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [000990] The title compound was prepared analogously to Example 374, steps 2-9, where 2-chloro-4- cyclopropyl-5-nitropyridine was replaced with 2-cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (R)- 2-methylpiperazine-1-carboxylate with tert-butyl (S)-3-methylpiperazine-1-carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 649.3[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.72 (s, 1H), 8.09 (s, 1H), 7.97 - 7.85 (m, 1H), 7.74 (s, 1H), 6.95 - 6.86 (m, 1H), 6.77 (d, J = 2.0 Hz, 1H), 5.58 - 5.50 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.74 - 3.70 (m, 1H), 3.23 - 3.01 (m, 5H), 2.92 - 2.85 (m, 1H), 1.91 - 1.84 (m, 1H), 1.08 - 1.00 (m, 5H), 0.74 - 0.66 (m, 2H). Example 428: (R)-7-(2-((2-cyclopropyl-4-(2-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one [000991] The title compound was prepared analogously to Example 374, steps 2-9, where 2-chloro-4- cyclopropyl-5-nitropyridine was replaced with 2-cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (R)- 2-methylpiperazine-1-carboxylate with tert-butyl (R)-3-methylpiperazine-1-carboxylate. The title compound was isolated. MS (ESI) m/z: 649.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.73 (s, 1H), 8.10 (s, 1H), 7.99 - 7.93 (m, 1H), 7.75 - 7.74 (m, 1H), 6.94 (dd, J = 8.8, 2.0Hz, 1H), 6.81 - 6.80 (m, 1H), 5.55 (t, J = 6.8 Hz, 1H), 5.04 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.13 (t, J = 5.6 Hz, 2H), 3.83 - 3.69 (m, 3H), 3.36 - 3.06 (m, 5H), 2.95 (dd, J = 5.6, 12.4 Hz, 1H), 1.90 - 1.84 (m, 1H), 1.08 (d, J = 6.4 Hz, 3H), 1.06 - 1.03 (m, 2H), 0.76 - 0.66 (m, 2H) Example 429: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-2,3,4,5-tet rahydrothieno[2,3-f][1,4]thiazepine 1,1- dioxide [000992] A solution of 7-bromo-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide (0.53 mmol) and oxetan-3-one (1.06 mmol) in 1,2-dichloroethane (3 mL) was stirred at 60 °C for 30 minutes. Sodium triacetyloxyborohydride (1.59 mmol) was added and the reaction mixture was stirred at 60 °C for 1 hour. The volatiles were removed under reduced pressure and the crude residue was purified by preparative- TLC (50% ethyl acetate in petroleum ether) to afford the title compound in 56% yield. MS (ESI) m/z: 339.9 [M+H] + Steps 2-3: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-2,3,4,5-tet rahydrothieno[2,3-f][1,4]thiazepine 1,1- dioxide [000993] The title compound was prepared analogously to Example 333, where 7-iodo-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-(oxetan-3- yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 633.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.68 (s, 1H), 8.64 (s, 1H), 8.06 (s, 1H), 7.70 - 7.64 (m, 1H), 7.45 - 7.42 (m, 1H), 6.47 (dd, J = 8.4, 2.4 Hz, 1H), 6.32 (s, 1H), 4.61 (q, J = 6.4 Hz, 4H), 4.33 (s, 1H), 4.20 (s, 2H), 3.89 - 3.80 (m, 2H), 3.68 - 3.66 (m, 1H), 3.49 - 3.47 (m, 2H), 3.25 - 3.23 (m, 2H), 3.15 - 3.12 (m, 2H), 3.06 (d, J = 8.8 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.89 - 1.88 (m, 2H), 1.00 - 0.98 (m, 2H), 0.71 - 0.66 (m, 2H). Example 430: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-2,3,4,5-tet rahydrothieno[2,3-f][1,4]thiazepine 1,1- dioxide [000994] The title compound was prepared analogously to Example 340, where 7-iodo-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-(oxetan-3- yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 633.4[M+H] + . 1 H NMR (400MHz, methanol-d 4 ) δ 8.63 - 8.56 (m, 1H), 7.94 (s, 1H), 7.45 - 7.17 (m, 1H), 6.66 (dd, J = 8.4, 2.4 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 4.63 - 4.49 (m, 4H), 4.26 - 4.15 (m, 2H), 4.13 - 4.01 (m, 2H), 3.88 - 3.84 (m, 1H), 3.70 - 3.60 (m, 4H), 3.47 - 3.40 (m, 2H), 3.38 - 3.33 (m, 2H), 2.87 - 2.77 (m, 1H), 2.00 - 1.93 (m, 1H), 1.78 (d, J = 9.2 Hz, 1H), 0.91 - 0.86 (m, 2H), 0.68 - 0.64 (m, 2H). Example 431: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000995] The title compound was prepared analogously to Example 308, where 2-cyclopropyl-4-fluoro- 1-nitrobenzene, tert-butyl (R)-2-methylpiperazine-1-carboxylate and 7-bromo-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with 2-cyclopropyl-4-fluoro-1- nitrobenzene, tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated. MS (ESI) m/z: 593.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.65 (s, 1H), 8.03 (br s, 1H), 7.41 - 7.29 (m, 1H), 7.14 - 6.98 (m, 1H), 6.51 - 6.43 (m, 2H), 4.36 (br s, 1H), 4.01 - 3.94 (m, 1H), 3.89 (br d, J = 2.0 Hz, 2H), 3.72 (br s, 3H), 3.27 - 3.18 (m, 4H), 3.18 - 3.06 (m, 2H), 2.60 (q, J = 7.6 Hz, 2H), 2.03 - 1.98 (m, 2H), 1.97 - 1.90 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H) Example 432: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-chlorophenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000996] The title compound was prepared analogously to Example 381, where 2-cyclopropyl-4-fluoro- 1-nitrobenzene was replaced with 2-chloro-4-fluoro-1-nitrobenzene. The title compound was isolated. MS (ESI) m/z: 599.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.06 (s, 1H), 7.94 ( d, J = 8.4 Hz, 1H), 7.59 - 7.48 (m, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.73 ( d, J = 9.6 Hz, 1H), 4.13 ( d, J = 6.0 Hz, 2H), 3.90 ( t, J = 5.6 Hz, 2H), 3.79 - 3.60 (m, 6H), 3.24 (s, 3H), 2.98 - 2.87 (m, 1H), 1.72 ( d, J = 9.2 Hz, 1H) Example 433: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-chlo rophenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [000997] The title compound was prepared analogously to Example 393, where 2-cyclopropyl-4-fluoro- 1-nitrobenzene was replaced with 2-chloro-4-fluoro-1-nitrobenzene. The title compound was isolated. MS (ESI) m/z: 599.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 1.98 - 2.09 (m, 2 H) 3.12 - 3.23 (m, 3 H) 3.25 (s, 3 H) 3.61 - 3.68 (m, 1 H) 3.71 - 3.81 (m, 2 H) 3.85 - 3.97 (m, 2 H) 4.06 (br s, 1 H) 4.36 (s, 1 H) 6.49 - 6.61 (m, 1 H) 6.63 (d, J = 2.8 Hz, 1 H) 7.50 (br s, 1 H) 7.87 (d, J = 8.8 Hz, 1 H) 8.06 (s, 1 H) 8.70 (s, 1 H) Example 434: 4-cyclopropyl-7-(2-((3-cyclopropyl-5,6,7,8-tetrahydro-1,6-na phthyridin-2-yl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][ 1,4]thiazepin-5(2H)-one 1,1-dioxide

[000998] To a solution of methyl 2-chloro-6-methoxy-pyridine-3-carboxylate (89 mmol), 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (179 mmol), and potassium carbonate (179 mmol) in dioxane (200 mL) and water (40 mL) was added (1,1’-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (5.47 mmol). The mixture was stirred at 100 °C, cooled down to room temperature, filtered and the filtrate was diluted with water and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was purified by silica gel column chromatography (0-1% ethyl acetate in hexanes) to afford the title compound as a colorless oil. 1H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J = 8.8 Hz, 1H), 7.79 -7.72 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.61 - 6.56 (m, 1H), 5.58 (dd, J = 10.4, 2.4 Hz, 1H), 4.03 (s, 3H), 3.90 (s, 3H). Step 2: 2-methoxy-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5 (6H)-one [000999] To a solution of methyl 6-methoxy-2-vinyl-pyridine-3-carboxylate (12 mmol) in N,N- dimethylacetamide (7.5 mL) was added 4-methoxybenzylamine (31 mmol). The mixture was stirred at 150 °C for 2 hours under microwave irradiation, filtered and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-33% ethyl acetate in hexanes). The title compound was isolated in 78% yield as a white solid. MS (ESI) m/z: 299.1 [M+H] + Step 3: 2-hydroxy-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5 (6H)-one [0001000] A mixture of 2-methoxy-6-[(4-methoxyphenyl)methyl]-7,8-dihydro-1,6-naphth yridin-5-one (64 mmol) and sodium iodide (255 mmol) in acetonitrile (200 mL) was stirred for 5 minutes. Chlorotrimethylsilane (255 mmol) was added and the reaction was stirred at 100 °C for 15 minutes. The mixture was cooled down to room temperature, filtered and concentrated to afford a residue that was purified by silica gel chromatography (0-12 % methanol in dichloromethane). The title compound was isolated in 82% yield as a white solid. MS (ESI) m/z: 285.1 [M+H] + Step 4: 3-bromo-2-hydroxy-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphth yridin-5(6H)-one [0001001] N-bromosuccinimide (56 mmol) was added to a 0 °C solution of 2-hydroxy-6-[(4- methoxyphenyl)methyl]-7,8-dihydro-1,6-naphthyridin-5-one (56 mmol) and chloroform (160 mL). After two hours the volatiles were removed under reduced pressure to afford a residue that was dissolved in water and ethyl acetate. The organic layer was separated and the aqueous was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative-HPLC to afford the title compound as a yellow solid. MS (ESI) m/z: 363.0 [M+H] + Step 5: 3-bromo-2-chloro-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthy ridin-5(6H)-one [0001002] Dichlorophosphorylbenzene (978 mmol) was added to 3-bromo-2-hydroxy-6-[(4- methoxyphenyl)methyl]-7,8-dihydro-1,6-naphthyridin-5-one (38 mmol) dropwise at 0 °C. The reaction was gradually warmed to room temperature and stirred at 160 °C for 2 hours. The mixture was cooled down to room temperature, filtered and concentrated to afford a residue that was purified by preparative- HPLC to afford the title compound in 49% yield as yellow oil. MS (ESI) m/z: 263.0 [M+H] + Step 6: 2-amino-3-bromo-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyr idin-5(6H)-one [0001003] A solution of 3-bromo-2-chloro-6-[(4-methoxyphenyl)methyl]-7,8-dihydro-1,6 -naphthyridin- 5-one (22 mmol) and aqueous ammonium hydroxide (160 mL) in isopropyl alcohol (80 mL) was stirred in an autoclave at 100 °C for 12 hours. The solvent was removed and the resulting residue was taken up in water (80 mL) and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (100 % ethyl acetate in hexanes). The title compound was isolated in 37% yield as a yellow oil. MS (ESI) m/z: 361.9 [M+H] + Step 7: 2-amino-3-cyclopropyl-6-(4-methoxybenzyl)-7,8-dihydro-1,6-na phthyridin-5(6H)-one [0001004] A mixture of 2-amino-3-bromo-6-[(4-methoxyphenyl)methyl]-7,8-dihydro-1,6- naphthyridin- 5-one (9.0 mmol), cyclopropylboronic acid (13 mmol), (1,1’- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (9.0 mmol) and lithium hydroxide (18 mmol) in water (30 mL) and dioxane (30 mL) was stirred at 100 °C for 12 hours. The reaction was cooled to room temperature and the volatiles removed under reduced pressure to afford a residue that was diluted with water 50 mL and extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (100 % ethyl acetate). The title compound was isolated in 61% yield as a yellow solid. MS (ESI) m/z: 324.1 [M+H] + Step 8: 3-cyclopropyl-6-(4-methoxybenzyl)-5,6,7,8-tetrahydro-1,6-nap hthyridin-2-amine [0001005] A 2.5M THF solution of lithium aluminium hydride (13.5 mL) was added to a 0 °C solution of 2-amino-3-cyclopropyl-6-[(4-methoxyphenyl)methyl]-7,8-dihydr o-1,6-naphthyridin-5-one (6.7 mmol) in THF (20 mL). The mixture was then stirred at 60 °C for 3 hours, cooled down to room temperature and quenched by aqueous saturated potassium sodium tartrate solution (15 mL), after 30 minutes, water was added and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-10% methanol in dichloromethane). The title compound was isolated in 80% yield as a white solid. MS (ESI) m/z: 310.1 [M+H] + Step 9: N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-3-cyclopropyl -5,6,7,8-tetrahydro-1,6- naphthyridin-2-amine [0001006] The title compound was prepared analogously to Example 385, step 3, where tert-butyl (1R,4R)-5-(5-amino-6-cyclopropyl-2-pyridyl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate was replaced with 3-cyclopropyl-6-(4-methoxybenzyl)-5,6,7,8-tetrahydro-1,6-nap hthyridin-2-amine. The title compound was isolated as a yellow oil in 37% yield. MS (ESI) m/z: 370.2 [M+H] + Step 10-11: 3-cyclopropyl-N-(5-(trifluoromethyl)-4-(trimethylstannyl)pyr imidin-2-yl)-5,6,7,8- tetrahydro-1,6-naphthyridin-2-amine [0001007] The title compound was prepared analogously to Example 385, steps 5-6, where 1-chloro-N- [2-cyclopropyl-6-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl ]-3-pyridyl]-5-(trifluoromethyl)pyrimidin- 2-amine (6.67 mmol) was replaced with N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-3-cyclopropyl - 5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine. The title compound was isolated as a yellow oil. MS (ESI) m/z: 500.0 [M+H] + . Step 12: 4-cyclopropyl-7-(2-((3-cyclopropyl-5,6,7,8-tetrahydro-1,6-na phthyridin-2-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-3,4-dihydrothieno[2,3-f][1, 4]thiazepin-5(2H)-one 1,1-dioxide [0001008] The title compound was prepared analogously to Example 155, step 3, where 1-(7-chloro-6- ((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)ami no)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2- trifluoroethan-1-one was replaced with 3-cyclopropyl-N-(5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)-5,6,7,8-tetrahydro-1,6-nap hthyridin-2-amine. The title compound was isolated as a yellow solid. MS (ESI) m/z: 591.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ (ppm) = 8.67 (s, 1H), 8.04 (s, 1H), 7.20 – 7.05 (m, 1H), 5.09 – 4.92 (m, 1H), 4.87 - 4.86 (m, 2H), 4.23 (s, 2H), 3.96 (t, J = 6.0 Hz, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.96 - 2.91 (m, 3H), 2.03 - 1.99 (m, 1H), 0.99 - 0.94 (m, 6H), 0.66 - 0.61 (m, 2H) Example 435: 7-(2-((2-cyclopropyl-4-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001009] The title compound was prepared analogously to Example 319, step 1, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with 2-oxa-5,8- diazaspiro[3.5]nonane. The title compound was isolated as a yellow oil in 53% yield. Step 2: 1-(8-(3-cyclopropyl-4-nitrophenyl)-2-oxa-5,8-diazaspiro[3.5] nonan-5-yl)-2,2,2- trifluoroethan-1-one [0001010] The title compound was prepared analogously to Example 1, step 1, where 2-(4- chlorophenyl)ethylamine was replaced with 8-(3-cyclopropyl-4-nitrophenyl)-2-oxa-5,8- diazaspiro[3.5]nonane. The title compound was isolated as a yellow oil in 62% yield. MS (ESI) m/z: 386.1[M+H] + Step 3: 1-(8-(4-amino-3-cyclopropylphenyl)-2-oxa-5,8-diazaspiro[3.5] nonan-5-yl)-2,2,2- trifluoroethan-1-one [0001011] The title compound was prepared analogously to Example 173, step 4, where 1-(7- cyclopropyl-6-nitro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-t rifluoro-ethanone was replaced with 1-(8- (3-cyclopropyl-4-nitrophenyl)-2-oxa-5,8-diazaspiro[3.5]nonan -5-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated as a brown oil in 74% yield. 1 H NMR (400 MHz, CDCl 3 ): δ 6.73 - 6.52 (m, 3H), 4.95 - 4.85 (m, 2H), 4.60 - 4.52 (m, 2H), 3.57 - 3.50 (m, 2H), 3.45 (s, 2H), 3.00 (t, J = 4.8 Hz, 2H), 1.75 - 1.59 (m, 1H), 0.98 - 0.88 (m, 2H), 0.66 - 0.58 (m, 2H). Step 4-7: 7-(2-((2-cyclopropyl-4-(2-oxa-5,8-diazaspiro[3.5]nonan-8-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001012] The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyc lopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with 1-(8-(4-amino-3-cyclopropylphenyl)-2-oxa- 5,8-diazaspiro[3.5]nonan-5-yl)-2,2,2-trifluoroethan-1-one. The title compound was isolated as a red solid. MS (ESI) m/z: 677.2[M+H] + . 1 H NMR 8.72 (s, 1H), 8.10 (s, 1H), 8.00 - 7.85 (m, 1H), 7.76 - 7.62 (m, 1H), 6.92 (d, J = 9.6 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 5.64 - 5.48 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.61 (d, J = 6.8 Hz, 2H), 4.52 (d, J = 6.8 Hz, 2H), 4.13 (t, J = 5.4 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.37 (s, 2H), 3.13 - 3.07 (m, 2H), 3.05 - 2.97 (m, 2H), 1.93 - 1.86 (m, 1H), 1.09 - 1.02 (m, 2H), 0.76 - 0.70 (m, 2H). Example 436: (S)-7-(2-((2-cyclopropyl-4-(3-(hydroxymethyl)piperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001013] The title compound was prepared analogously to Example 345, where (R)-(4-(3-cyclopropyl- 4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)a mino)phenyl)piperazin-2-yl)methanol and 7- bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide were replaced with (S)-(4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylst annyl)pyrimidin-2- yl)amino)phenyl)piperazin-2-yl)methanol and 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI).m/z: 665.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.71 (s, 1 H) 8.09 (s, 1 H) 7.87 (br dd, J = 6.8, 2.8 Hz, 1 H) 7.60 - 7.72 (m, 1 H) 6.89 (br d, J = 8.4 Hz, 1 H) 6.75 (br s, 1 H) 5.54 (quin, J = 7.6 Hz, 1 H) 5.03 (t, J = 7.6 Hz, 2 H) 4.74 (t, J = 6.8 Hz, 2 H) 4.11 (br d, J = 5.6 Hz, 2 H) 3.71 - 3.89 (m, 4 H) 3.47 - 3.58 (m, 2 H) 3.29 - 3.39 (m, 1 H) 3.08 - 3.28 (m, 2 H) 2.92 - 3.04 (m, 1 H) 2.74 - 2.86 (m, 1 H) 1.89 (br s, 1 H) 0.99 - 1.09 (m, 2 H) 0.66 - 0.74 (m, 2 H) Example 437: 7-[2-(2-cyclopropyl-4-piperazin-1-yl-anilino)-5-(trifluorome thyl)pyrimidin-4-yl]-4- (oxetan-3-yl)-1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thiazep in-5-one [0001014] The title compound was prepared analogously to Example 305, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl piperazine-1-carboxylate and 7- bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide with 7-iodo-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 635.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.78 (s, 1H), 8.91 - 8.62 (m, 1H), 7.89 - 7.66 (m, 1H), 7.31 - 7.02 (m, 1H), 6.75 (dd, J = 8.4, 2.4 Hz, 1H), 6.46 (s, 1H), 5.28 - 5.10 (m, 1H), 4.78 - 4.66 (m, 4H), 4.11 - 3.93 (m, 4H), 3.10 - 3.03 (m, 4H), 2.96 – 2.82 (m, 4H), 1.95 - 1.88 (m, 1H), 0.84 - 0.78 (m, 2H), 0.65 - 0.59 (m, 2H). Example 438: (R)-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-2,3,4,5-tet rahydrothieno[2,3-f][1,4]thiazepine 1,1- dioxide [0001015] The title compound was prepared analogously to Example 315, where 7-iodo-4-(oxetan-3- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-(oxetan- 3-yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 857.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.67 (s, 1H), 8.08 (s, 1H), 7.89 – 7.85 (m, 2H), 7.59 – 7.56 (m, 2H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 4.65 – 4.59 (m, 4H), 4.21 (s, 2H), 3.90 – 3.86 (m, 1H), 3.53 – 3.48 (m, 4H), 3.27 – 3.24 (m, 3H), 3.08 – 3.15 (m, 2H), 2.88 – 2.76 (m, 1H), 2.52 – 2.40 (m, 1H), 1.91 – 1.88 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.04 – 1.01 (m, 2H), 0.72 - 0.69 (m, 2H). Example 439: 7-(2-((2-cyclopropyl-4-(2,6-diazaspiro[3.4]octan-6-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1-3: tert-butyl 6-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- cyclopropylphenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate [0001016] The title compound was prepared analogously to Example 305, steps 1-3, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl 2,6- diazaspiro[3.4]octane-2-carboxylate. The title compound was isolated as a yellow oil. MS (ESI) m/z: 344.2 [M+H] + Steps 4-8: 7-(2-((2-cyclopropyl-4-(2,6-diazaspiro[3.4]octan-6-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001017] The title compound was prepared analogously to Example 310, where tert-butyl (1S,4S)-5- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyc lopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl 6-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2,6-diazaspiro[3.4]octane-2-carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 661.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 0.60 - 0.70 (m, 2 H) 0.79 - 0.88 (m, 2 H) 1.92 - 2.01 (m, 1 H) 2.25 (br t, J = 6.8 Hz, 2 H) 3.26 - 3.33 (m, 4 H) 3.74 (br d, J = 8.0 Hz, 2 H) 3.83 (br d, J = 6.4 Hz, 2 H) 4.00 - 4.18 (m, 4 H) 4.78 (br d, J = 5.2 Hz, 4 H) 5.15 - 5.37 (m, 1 H) 6.11 (br s, 1 H) 6.41 (dd, J = 8.4, 2.4 Hz, 1 H) 7.02 - 7.33 (m, 1 H) 7.72 - 8.00 (m, 1 H) 8.65 - 9.01 (m, 1 H) 9.77 (br d, J = 2.8 Hz, 1 H) Example 440: (R)-7-(2-((2-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-3 -yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001018] The title compound was prepared analogously to Example 308, where 4-chloro-2- cyclopropyl-1-nitrobenzene was replaced with 6-chloro-2-cyclopropyl-3-nitropyridine and 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide with 7-iodo-4-(oxetan-3-yl)- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 608.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4): δ 8.82 - 8.52 (m, 1H), 8.02 - 7.92 (m, 1H), 7.55 - 7.37 (m, 1H), 6.68 - 6.57 (m, 1H), 4.25 - 4.17 (m, 2H), 3.97 - 3.80 (m, 4H), 3.22 - 3.08 (m, 4H), 2.98 - 2.82 (m, 3H), 2.61 - 2.48 (m, 1H), 2.15 - 2.07 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H), 1.03 - 0.98 (m, 2H), 0.87 - 0.81 (m, 2H) Example 441: 7'-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyc lopropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4'-methyl-2'H-spiro[cyclopr opane-1,3'-thieno[2,3- f][1,4]thiazepin]-5'(4'H)-one 1',1'-dioxide Step 1: 7'-bromo-4'-methyl-2'H-spiro[cyclopropane-1,3'-thieno[2,3-f] [1,4]thiazepin]-5'(4'H)-one 1',1'-dioxide [0001019] A solution of 7'-bromo-2'H-spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thiaz epin]-5'(4'H)-one 1',1'-dioxide (0.35 mmol) in DMF (10 mL) was treated with cesium carbonate (0.71mmol) and methyl iodide (0.71 mmol) and the mixture was heated at 50 °C for 18 hours. The reaction was cooled down to room temperature and extracted three times with ethyl acetate. The combined organic layers were collected, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a residue that was purified by silica gel chromatography (40% ethyl acetate in hexanes) to afford the title compound in 98% yield . MS (ESI) m/z: 335.9 [M+H] + Step 2-3: 7'-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyc lopropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4'-methyl-2'H-spiro[cyclopr opane-1,3'-thieno[2,3- f][1,4]thiazepin]-5'(4'H)-one 1',1'-dioxide [0001020] The title compound was prepared analogously to Example 410, steps 5-6, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7'-bromo- 4'-methyl-2'H-spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thia zepin]-5'(4'H)-one 1',1'-dioxide. The title compound was isolated as a pale yellow solid. MS (ESI) m/z: 631.2 [M+H] + Example 442: 7-(2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]he ptan-2-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothien o[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001021] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 16% yield as a pale yellow solid. MS (ESI) m/z: 607.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.68 (s, 1H), 8.08 - 8.05 (m, 1H), 7.59 - 7.43 (m, 1H), 7.09 (br d, J = 4.4 Hz, 1H), 6.86 - 6.82 (m, 2H), 5.52 (br s, 1H), 5.02 (br t, J = 7.2 Hz, 2H), 4.74 (br t, J = 6.8 Hz, 2H), 4.09 (br s, 2H), 3.76 (br s, 2H), 3.54 (br d, J = 10.8 Hz, 2H), 2.89 - 2.81 (m, 2H), 2.80 - 2.68 (m, 2H), 2.64 (br d, J = 7.6 Hz, 2H), 2.53 (br s, 3H), 1.33 (br d, J = 4.4 Hz, 6H), 1.24 - 1.22 (m, 3H) Example 443: (R)-7-(2-((2-cyclopropyl-4-(4-(2-methoxyethyl)-3-methylpiper azin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001022] To a solution of (R)-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (0.05 mmol) in acetonitrile (0.5 mL) was added potassium carbonate (0.14 mmol) and 1-bromo- 2-methoxyethane (0.05 mmol). The mixture was stirred at 100 °C for 8 hours, cooled down to room temperature and concentrated under reduced pressure to afford a residue that was purified by preparative- TLC (17% methanol in dichloromethane), followed by a second purification by preparative-HPLC. The title compound was isolated in 35% yield as an orange solid. MS (ESI) m/z: 707.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.71 (s, 1H), 8.09 (s, 1H), 7.97 - 7.81 (m, 1H), 7.76 - 7.61 (m, 1H), 6.89 - 6.87 (m, 1H), 6.74 - 6.73 (m, 1H), 5.56 - 5.53(m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.91 - 3.48 (m, 6H), 3.46 - 3.29 (m, 3H), 3.39 (s, 3H), 3.24 - 2.81 (m, 3H), 2.78 - 2.31 (m, 2H), 1.95 - 1.82 (m, 1H), 1.43 - 1.11 (m, 3H), 1.09 - 0.98 (m, 2H), 0.76 - 0.65 (m, 2H) Example 444: (R)-7-(2-((2-cyclopropyl-4-(4-(2-hydroxyethyl)-3-methylpiper azin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001023] The title compound was prepared analogously to Example 443, where 1-bromo-2- methoxyethane was replaced with 2-bromoethan-1-ol. The title compound was isolated as an orange solid. MS (ESI) m/z: 693.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.71 (s, 1H), 8.09 (s, 1H), 7.96 - 7.81 (m, 1H), 7.76 - 7.61 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.58 - 5.51 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.86 - 3.66 (m, 4H), 3.48 – 3.38 (m, 2H), 3.28 - 3.03 (m, 3H), 2.98 - 2.79 (m, 2H), 2.75 - 2.41 (m, 2H), 1.97 - 1.85 (m, 1H), 1.33 - 1.20 (m, 3H), 1.09 - 1.00 (m, 2H), 0.75 - 0.67 (m, 2H) Example 445: (S)-7-(2-((2-Cyclopropyl-4-(3-(methoxymethyl)piperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide

[0001024] To a 0 °C solution of (S)-4-(3-cyclopropyl-4-nitrophenyl)-2-(hydroxymethyl)piperaz ine-1- carboxylate (7.3 mmol) and methyl 4-methylbenzenesulfonate (29 mmol) in dimethylformamide (30 mL) was added potassium tert-butoxide (14.5 mmol) and after 10 minutes the reaction was quenched with water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel column chromatography (10-25% ethyl acetate in hexanes). The title compound was isolated in 95% yield as a yellow oil. MS (ESI) m/z: 392.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 9.2 Hz, 1H), 6.65 (dd, J = 2.8, 9.2 Hz, 1H), 6.52 (d, J = 2.8 Hz, 1H), 4.36 - 4.21 (m, 1H), 4.13 (q, J = 7.2 Hz, 1H), 4.03 - 3.90 (m, 2H), 3.80 - 3.67 (m, 1H), 3.52 - 3.36 (m, 2H), 3.35 (s, 3H), 3.23 - 3.03 (m, 3H), 2.61 (tt, J = 5.6, 8.4 Hz, 1H), 1.64 (br s, 1H), 1.50 (s, 9H), 1.09 - 1.00 (m, 2H), 0.72 - 0.63 (m, 2H) Step 2: tert-butyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- cyclopropylphenyl)-2-(methoxymethyl)piperazine-1-carboxylate [0001025] The title compound was prepared analogously to Example 305, steps 2-3, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-nitrophenyl)-2,5-diazabicyclo[2.2 .1]heptane-2-carboxylate was replaced with tert-butyl (S)-4-(3-cyclopropyl-4-nitrophenyl)-2-(methoxymethyl)piperaz ine-1-carboxylate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 542.2[M+H] + Steps 3-7: (S)-7-(2-((2-Cyclopropyl-4-(3-(methoxymethyl)piperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001026] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with tert-butyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3- cyclopropylphenyl)-2-(methoxymethyl)piperazine-1-carboxylate . The title compound was isolated as an orange solid. MS (ESI) m/z: 679.3[M+H] + / 1 H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.09 (s, 1H), 7.95 - 7.52 (m, 2H), 6.88 (br d, J = 8.4 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 5.59 - 5.49 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.12 (br t, J = 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.55 - 3.45 (m, 3H), 3.45 - 3.38 (m, 4H), 3.22 - 3.12 (m, 2H), 3.05 (dt, J = 2.8, 11.5 Hz, 1H), 2.87 - 2.77 (m, 1H), 2.56 (t, J = 10.8 Hz, 1H), 1.91 - 1.84 (m, 1H), 1.06 - 0.99 (m, 2H), 0.73 - 0.67 (m, 2H). Example 446: (R)-7-(2-((2-cyclopropyl-4-(3-(methoxymethyl)piperazin-1-yl) phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001027] The title compound was prepared analogously to Example 445, where (S)-4-(3-cyclopropyl- 4-nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate was replaced with (R)-4-(3-cyclopropyl-4- nitrophenyl)-2-(hydroxymethyl)piperazine-1-carboxylate. The title compound was isolated as an orange solid. MS (ESI).m/z: 679.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.71 (s, 1 H) 8.09 (s, 1 H) 7.81 - 7.96 (m, 1 H) 7.59 - 7.78 (m, 1 H) 6.83 - 6.93 (m, 1 H) 6.75 (br d, J = 2.0 Hz, 1 H) 5.55 (quin, J = 6.8 Hz, 1 H) 5.03 (t, J = 7.6 Hz, 2 H) 4.74 (t, J = 6.8 Hz, 2 H) 4.12 (br t, J = 5.6 Hz, 2 H) 3.78 (t, J = 5.6 Hz, 2 H) 3.43 - 3.56 (m, 4 H) 3.41 (s, 3 H) 3.13 - 3.26 (m, 2 H) 3.00 - 3.11 (m, 1 H) 2.78 - 2.90 (m, 1 H) 2.59 (t, J = 10.8 Hz, 1 H) 1.87 (br d, J = 5.6 Hz, 1 H) 0.97 - 1.08 (m, 2 H) 0.67 - 0.76 (m, 2 H) Example 447: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-meth ylpyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Steps 1-3: tert-butyl (1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-4- methylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxy late [0001028] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene was replaced with 2-fluoro-4-methyl-5-nitropyridine. The title compound was isolated as a yellow solid. MS (ESI) m/z: 757.1[M+H] + Steps 4-8: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-meth ylpyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001029] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with tert-butyl (1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-4-methylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hepta ne-2-carboxylate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 621.1[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 8.73 - 8.59 (m, 1H), 8.21 (br s, 1H), 8.05 (br s, 1H), 7.26 - 7.08 (m, 1H), 6.32 (s, 1H), 5.61 - 5.45 (m, 1H), 5.11 - 4.98 (m, 2H), 4.90 (br s, 1H), 4.73 (br s, 2H), 4.37 (br s, 1H), 4.14 - 4.09 (m, 1H), 3.78 (br d, J = 1.6 Hz, 2H), 3.65 (br d, J = 5.6 Hz, 2H), 3.35 - 3.22 (m, 2H), 3.17 - 3.08 (m, 2H), 2.24 (br s, 3H), 1.93 - 1.83 (m, 1H). Example 448: 7-[2-[4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methy l-anilino]-5- (trifluoromethyl)pyrimidin-4-yl]-4-(oxetan-3-yl)-1,1-dioxo-2 ,3-dihydrothieno[2,3-f][1,4]thiazepin-5- one Steps 1-3: tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- methylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0001030] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 4-fluoro-2-methyl-1-nitrobenzene and tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated as a yellow semisolid. MS (ESI) m/z: 484.3[M+H] + Steps 4-8: 7-[2-[4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methy l-anilino]-5- (trifluoromethyl)pyrimidin-4-yl]-4-(oxetan-3-yl)-1,1-dioxo-2 ,3-dihydrothieno[2,3-f][1,4]thiazepin-5- one [0001031] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-methylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-c arboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 621.2[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.70 - 8.54 (m, 1H), 7.98 (s, 1H), 7.25 - 7.10 (m, 1H), 6.58 (s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 5.35 - 5.20 (m, 1H), 4.95 - 4.88 (m, 2H), 4.84 - 4.79 (m, 2H), 4.53 (s, 1H), 4.16 - 4.12 (m, 1H), 4.08 - 3.96 (m, 2H), 3.92 - 3.83 (m, 2H), 3.68 (d, J = 8.4 Hz, 1H), 3.28 - 3.25 (m, 1H), 3.20 - 3.15 (m, 2H), 2.22 (s, 3H), 2.17 - 2.12 (m, 1H), 1.97 - 1.90 (m, 1H). Example 449: 7-[2-[4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methy l-anilino]-5- (trifluoromethyl)pyrimidin-4-yl]-4-methyl-1,1-dioxo-2,3-dihy drothieno[2,3-f][1,4]thiazepin-5-one [0001032] The title compound was prepared analogously to Example 305, where 2-cyclopropyl-4- fluoro-1-nitrobenzene, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with 4-fluoro- 2-methyl-1-nitrobenzene, tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide, respectively. The title compound was isolated as an orange solid. MS (ESI) m/z: 579.2[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.69 - 8.54 (m, 1H), 7.96 (s, 1H), 7.19 - 7.13 (m, 1H), 6.55 - 6.50 (m, 2H), 4.45 - 4.40 (m, 1H), 3.94 - 3.85 (m, 5H), 3.63 (d, J = 8.8 Hz, 1H), 3.17 (s, 3H), 3.13 - 3.07 (m, 2H), 3.02 - 3.00 (m, 1H), 2.21 (s, 3H), 2.06 - 1.99 (m, 1H), 1.84 (d, J = 9.6 Hz, 1H). Example 450: 7-(2-((4-(azetidin-3-yl)-2-cyclopropylphenyl)amino)-5-(trifl uoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide [0001033] A solution of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (65 mmol), tert-butyl 3- iodoazetidine-1-carboxylate (50 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (0.50 mmol), (1,2- dimethoxyethane)dichloronickel(II) (2.5 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.5 mmol), and tris- (trimethylsilyl)silane (50 mmol) in ethylene glycol dimethyl ether (3 mL) was irradiated with a 34 W blue LED lamp (7 cm away) for 14 hours while keeping the reaction temperature at 25 °C. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-20% ethyl acetate in hexanes). The title compound was isolated in 68% yield as yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.09 (d, J = 8.8 Hz, 1H), 7.29 – 7.27 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 2.0, 8.8 Hz, 1H), 6.93 (s, 1H), 4.29 - 4.25 (m, 2H), 3.90 - 3.87 (m, 3H), 1.50 (s, 9H), 1.43 (s, 9H). Step 2: tert-butyl 3-(4-((tert-butoxycarbonyl)amino)-3-cyclopropylphenyl)azetid ine-1-carboxylate [0001034] The title compound was prepared analogously to Example 374, step 1, where 2,4-dichloro-5- nitropyridine was replaced with tert-butyl 3-(4-((tert-butoxycarbonyl)amino)-3-chlorophenyl)azetidine-1 - carboxylate. The title compound was isolated as a yellow oil in 81% yield. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.94 (d, J = 8.4 Hz, 1H), 7.15 (dd, J = 2.0, 8.4 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 4.29 (t, J = 8.4 Hz, 2H), 3.94 - 3.91 (m, 2H), 3.70 - 3.61 (m, 1H), 1.78 - 1.71 (m, 1H), 1.55 (s, 9H), 1.47 (s, 9H), 1.02 - 0.97 (m, 2H), 0.67 - 0.63 (m, 2H). Step 3-4: (9H-fluoren-9-yl)methyl 3-(4-amino-3-cyclopropylphenyl)azetidine-1-carboxylate [0001035] The title compound was prepared analogously to Example 368, steps 1-2, where tert-butyl (2S,6R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-ethylphenyl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl 3-(4-((tert-butoxycarbonyl)amino)-3- cyclopropylphenyl)azetidine-1-carboxylate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 411.1 [M+H] + . Step 5: (9H-fluoren-9-yl)methyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- cyclopropylphenyl)azetidine-1-carboxylate [0001036] The title compound was prepared analogously to Example 385, where tert-butyl (1R,4R)-5- (5-amino-6-cyclopropyl-2-pyridyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate was replaced with (9H- fluoren-9-yl)methyl 3-(4-amino-3-cyclopropylphenyl)azetidine-1-carboxylate. The title compound was isolated as a yellow oil. MS (ESI) m/z: 591.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ = 10.18 (s, 1H), 8.66 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.45 - 7.39 (m, 2H), 7.37 - 7.29 (m, 3H), 7.18 - 7.16 (m, 1H), 6.91 (s, 1H), 4.36 - 4.24 (m, 5H), 3.89 - 3.78 (m, 3H), 1.97 - 1.88 (m, 1H), 0.88 - 0.80 (m, 2H), 0.64 - 0.63 (m, 2H). Steps 6-8: 7-(2-((4-(azetidin-3-yl)-2-cyclopropylphenyl)amino)-5-(trifl uoromethyl)pyrimidin-4-yl)- 4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide [0001037] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with (9H-fluoren-9-yl)methyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-cyclopropylphenyl)azetidine-1-carboxylate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 606.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.04 - 9.86 (m, 1H), 8.87 - 8.78 (m, 1H), 7.83 - 7.80 (m, 1H), 7.83 (s, 1H), 7.43 - 7.35 (m, 1H), 7.24 - 7.19 (m, 1H), 7.01 (br s, 1H), 5.27 - 5.17 (m, 1H), 4.77 - 4.65 (m, 4H), 4.17 - 4.08 (m, 2H), 4.07 - 3.96 (m, 5H), 3.96 - 3.88 (m, 2H), 2.03 - 1.98 (m, 1H), 0.89 - 0.84 (m, 2H), 0.70 - 0.62 (m, 2H). Example 451: 7-(2-((4-cyclopropyl-6-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)pyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl) -2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepine 1,1-dioxide [0001038] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-cyclopropylpyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]thia zepine 1,1-dioxide. The title compound was isolated in 60% yield as a yellow solid. MS (ESI) m/z: 648.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.60 - 8.29 (m, 1H), 8.06 (s, 1H), 7.25 - 7.08 (m, 1H), 6.19 (s, 1H), 4.65 - 4.56 (m, 4H), 4.22 - 4.14 (m, 4H), 3.92 - 3.77 (m, 5H), 3.51 - 3.45 (m, 2H), 3.27 - 3.21 (m, 2H), 3.10 - 2.99 (m, 1H), 2.48 - 2.41 (m, 2H), 1.97 - 1.91 (m, 2H), 1.85 - 1.80 (m, 1H), 1.12 - 1.05 (m, 2H), 0.83 - 0.75 (m, 2H) Example 452: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4-meth ylpyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001039] The title compound was prepared analogously to Example 447, where 7-iodo-4-(oxetan-3- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 580.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (br s, 1H), 8.14 (s, 1H), 8.03 (br s, 1H), 7.27 - 6.92 (m, 1H), 6.28 (s, 1H), 4.75 (s, 1H), 4.07 - 3.82 (m, 3H), 3.74 (br s, 2H), 3.63 (br d, J = 8.8 Hz, 1H), 3.32 (br d, J = 9.2 Hz, 1H), 3.24 (br s, 3H), 3.14 (br s, 2H), 2.21 (s, 3H), 1.98 - 1.87 (m, 2H) Example 453: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lpyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Steps 1-3: tert-butyl (1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-6- ethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxyl ate [0001040] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene was replaced with 6-chloro-2-ethyl-3-nitropyridine and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate with tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 499.2 [M+H] + Steps 4-8: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lpyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001041] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with tert-butyl (1R,4R)-5-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-6-ethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan e-2-carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 636.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.06 (s, 1H), 7.54 - 7.47 (m, 1H), 7.06 – 6.92 (m, 1H), 6.26 (d, J = 7.2 Hz, 1H), 5.57 – 5.46 (m, 1H), 5.02 (t, J = 7.2 Hz, 2H), 4.82 (s, 1H), 4.72 (t, J = 6.8 Hz, 2H), 4.18 – 4.04 (m, 2H), 3.89 – 3.85 (m, 1H), 3.82 - 3.70 (m, 2H), 3.63 (d, J = 9.2 Hz, 1H), 3.28 (d, J = 7.6 Hz, 1H), 3.13 (s, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1.95 - 1.92 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H). Example 454: 7-(2-((6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-ethylpyridin -3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001042] The title compound was prepared analogously to Example 453, where tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H )-one 1,1-dioxide respectively. The title compound was isolated as a yellow solid. MS (ESI) m/z: 594.3[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.76 - 8.54 (m, 1H), 7.97 (s, 1H), 7.60 - 7.53 (m, 1H), 6.70 - 6.50 (m, 1H), 4.44 (d, J = 5.2 Hz, 2H), 4.12 - 4.08 (m, 2H), 3.98 - 3.84 (m, 6H), 3.22 - 3.12 (m, 3H), 3.05 - 2.99 (m, 1H), 2.72 (q, J = 7.2 Hz, 2H), 2.01 - 1.92 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H). Example 455: (R)-7-(2-((2-ethyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001043] The title compound was prepared analogously to Example 305, where 2-cyclopropyl-4- fluoro-1-nitrobenzene, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with 6-chloro- 2-ethyl-3-nitropyridine, tert-butyl (R)-2-methylpiperazine-1-carboxylate and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 510.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (s, 1H), 8.04 (s, 1H), 7.77 - 7.60 (m, 1H), 7.04 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.35 - 4.22 (m, 2H), 3.96 - 3.83 (m, 2H), 3.79 - 3.70 (m, 2H), 3.28 - 3.20 (m, 4H), 3.16 - 3.00 (m, 3H), 2.71 (q, J = 7.6 Hz, 3H), 1.32 - 1.24 (m, 6H). Example 456: (R)-7-(2-((2-cyclopropyl-3-methoxy-4-(3-methylpiperazin-1-yl )phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one Step 1: 2-cyclopropyl-3,4-difluoro-1-nitrobenzene [0001044] To a solution of 2-bromo-3,4-difluoro-1-nitrobenzene (8.40 mmol) and cyclopropylboronic acid (11 mmol) in toluene (20 mL) and water (2 mL) was added palladium acetate (0.42 mmol), tricyclohexyl phosphine (0.84 mmol) and potassium phosphate (25 mmol). The mixture was stirred at 110 °C for 12 hours, cooled down to room temperature, diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-10% ethyl acetate in hexanes). The title compound was isolated in 72% yield as yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 - 7.61 (m, 1H), 7.32 - 7.17 (s, 1H), 2.21 - 2.10 (m, 1H), 1.21 - 1.14 (m, 2H), 0.81 - 0.73 (m, 2H) Step 2: tert-butyl (R)-4-(3-cyclopropyl-2-fluoro-4-nitrophenyl)-2-methylpiperaz ine-1-carboxylate [0001045] The title compound was prepared analogously to Example 305, step 1, where 2-cyclopropyl- 4-fluoro-1-nitrobenzene, cesium carbonate and DMF were replaced with 2-cyclopropyl-3,4-difluoro-1- nitrobenzene, potassium carbonate and NMP. The title compound was isolated in 83% yield as a pale yellow solid. MS (ESI) m/z: 380.1 [M+H] + Step 3: tert-butyl (R)-4-(3-cyclopropyl-2-methoxy-4-nitrophenyl)-2-methylpipera zine-1- carboxylate [0001046] To a solution of tert-butyl (R)-4-(3-cyclopropyl-2-fluoro-4-nitrophenyl)-2-methylpiperaz ine- 1-carboxylate (1.55 mmol) in methanol (0.5 mL) and 1-methylpyrrolidin-2-one (6 mL) was added sodium methoxide (1.87 mmol). The reaction was stirred at 140 °C for 1 hour, cooled down to room temperature and diluted with water. The mixture was extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-30% ethyl acetate in hexanes). The title compound was isolated in 49% yield as yellow solid. MS (ESI) m/z: 392.2 [M+H] + Steps 4-10: (R)-7-(2-((2-cyclopropyl-3-methoxy-4-(3-methylpiperazin-1-yl )phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001047] The title compound was prepared analogously to Example 385, steps 2-8, where tert-butyl (1R,4R)-5-(6-cyclopropyl-5-nitro-2-pyridyl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-4-(3-cyclopropyl-2-methoxy-4-nitrophenyl)-2-methylpipera zine-1-carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 679.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 5.55 (t, J = 6.8 Hz, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.13 (br t, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.79 (t, J = 5.6 Hz, 2H), 3.46 (d, J = 12.0 Hz, 2H), 3.31 (d, J = 11.2 Hz, 2H), 3.20 (t, J = 10.4 Hz, 1H), 2.96 (t, J = 10.8 Hz, 1H), 2.69 (t, J = 10.8 Hz, 1H), 1.64 (t, J = 6.0 Hz, 1H), 1.35 (d, J = 6.4 Hz, 3H), 1.18 - 1.12 (m, 2H), 0.76 (q, J = 5.2 Hz, 2H) Example 457: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropyl-3- methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(o xetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001048] The title compound was prepared analogously to Example 456, where tert-butyl (S)-3- methylpiperazine-1-carboxylate was replaced with tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 677.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.71 (s, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 5.53 ( t, J = 6.8 Hz, 1H), 5.02 (t, J = 7.2 Hz, 2H), 4.73 (t, J = 6.8 Hz, 2H), 4.53 (s, 1H), 4.33 ( s, 1H), 4.12 ( t, J = 5.6 Hz, 2H), 3.81 - 3.72 (m, 6H), 3.55 - 3.45 (m, 2H), 3.36 ( d, J = 10.4 Hz, 1H), 2.15 ( d, J = 4.0 Hz, 2H), 1.66 - 1.61 (m, 1H), 1.11 ( d, J = 8.4 Hz, 2H), 0.84 - 0.79 (m, 1H), 0.74 - 0.68 (m, 1H) Example 458: 7-(2-((6-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lpyridin-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001049] The title compound was prepared analogously to Example 305, where 2-cyclopropyl-4- fluoro-1-nitrobenzene, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with 6-chloro- 2-ethyl-3-nitropyridine, tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 594.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.04 (s, 1H), 7.56 - 7.49 (m, 1H), 6.96 (s, 1H), 6.32 – 6.20 (m, 1H), 4.82 (s, 1H), 3.96 – 3.88 (m, 3H), 3.78 - 3.69 (m, 2H), 3.68 – 3.58 (m, 1H), 3.30 - 3.25 (m, 1H), 3.28 (s, 3H), 3.18 – 3.08 (m, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1.94 - 1.93 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H). Example 459: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-(2-hydroxyethyl)-2,5-diaza bicyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001050] The title compound was prepared analogously to Example 443, where (R)-7-(2-((2- cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(trifl uoromethyl)pyrimidin-4-yl)-4-(oxetan-3- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-bromo-2-methoxyethane were replaced with 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 2-bromoethan-1-ol. The title compound was isolated as an orange solid. MS (ESI) m/z: 693.2 [M+H] + .. 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.06 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 2.8 Hz, 1H), 4.48 – 4.43 (m, 1H), 4.33 - 4.32 (m, 1H), 3.93 - 3.90 (m, 4H), 3.75 - 3.66 (m, 5H), 3.24 (s, 3H), 3.17 – 3.05 (m, 2H), 2.48 - 2.47 (m, 1H), 2.27 - 2.25 (m, 1H), 1.92 - 1.85 (m, 2H), 1.01 (d, J = 8.4 Hz, 2H), 0.70 – 0.67 (m, 2H). Example 460: (R)-7-(2-((2-cyclopropyl-6-(3,4-dimethylpiperazin-1-yl)pyrid in-3-yl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001051] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)amino )-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 89% yield as a pale yellow solid. MS (ESI) m/z: 608.4[M+H] + . 1 H NMR (400 MHz, methanol-d 4 ): δ 8.68 - 8.54 (m, 1H), 7.99 (s, 1H), 7.46 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 4.30 - 4.14 (m, 3H), 4.09 (d, J = 12.8 Hz, 1H), 3.60 - 3.50 (m, 2H), 3.45 - 3.37 (m, 2H), 3.01 - 2.92 (m, 2H), 2.66 - 2.60 (m, 1H), 2.45 - 2.36 (m, 1H), 2.38 (s, 3H), 2.36 - 2.26 (m, 4H), 2.12 - 2.06 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H), 1.04 - 0.96 (m, 2H), 0.86 - 0.78 (m, 2H). Example 461: (R)-7-(2-((2-cyclopropyl-4-(2-methylmorpholino)phenyl)amino) -5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001052] The title compound was prepared analogously to Example 305, where tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with (R)-2-methylmorpholine and 7-iodo-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 650.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.10 (s, 1H), 7.91 - 7.90 (m, 1H), 7.88 - 7.74 (m, 1H), 6.91 - 6.86 (m, 1H), 6.76 - 6.75 (m, 1H), 5.57 - 5.53 (m, 1H), 5.04 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.13 (br t, J = 5.6 Hz, 2H), 4.04 - 4.02 (m, 1H), 3.80 - 3.77 (m, 4H), 3.48 - 3.43 (m, 2H), 2.86 - 2.85 (m, 1H), 2.54 - 2.52 (m, 1H), 1.91 - 1.87 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H), 1.05 (br d, J = 6.8 Hz, 2H), 0.72 (br d, J = 5.2 Hz, 2H). Example 462: 7-(2-((2-cyclopropyl-4-((4aS,7aR)-hexahydrofuro[3,4-b]pyrazi n-1(2H)- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (example 462a) and 7-(2-((2-cyclopropyl-4-((4aR,7aS)- hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)phenyl)amino)-5-(triflu oromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide (example 462b) Step 1-3: 1-((4aR,7aS)-4-(4-amino-3-cyclopropylphenyl)hexahydrofuro[3, 4-b]pyrazin-1(2H)-yl)- 2,2,2-trifluoroethan-1-one and 1-((4aS,7aR)-4-(4-amino-3-cyclopropylphenyl)hexahydrofuro[3, 4- b]pyrazin-1(2H)-yl)-2,2,2-trifluoroethan-1-one [0001053] The title compounds were prepared as a 1:1 mixture of enantiomers following the synthetic procedure described in Example 435, steps 1-3, where 2-oxa-5,8-diazaspiro[3.5]nonane was replaced with syn-octahydrofuro[3,4-b]pyrazine. The racemate was isolated as a yellow oil. MS (ESI) m/z: 356.1[M+H] + Steps 4-8: 7-(2-((2-cyclopropyl-4-((4aS,7aR)-hexahydrofuro[3,4-b]pyrazi n-1(2H)-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihyd rothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide (example 462a) and 7-(2-((2-cyclopropyl-4-((4aR,7aS)-hexahydrofuro[3,4-b]pyrazi n- 1(2H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (example 462b) [0001054] The title compounds were prepared as a racemic mixture following the synthetic procedure described in Example 310, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2.1]heptan e-2-carboxylate was replaced with the racemic mixture of 1-((4aR,7aS)-4-(4-amino-3-cyclopropylphenyl)hexahydrofuro[3, 4-b]pyrazin-1(2H)- yl)-2,2,2-trifluoroethan-1-one and 1-((4aS,7aR)-4-(4-amino-3-cyclopropylphenyl)hexahydrofuro[3, 4- b]pyrazin-1(2H)-yl)-2,2,2-trifluoroethan-1-one. The title compounds were isolated as single enantiomers after purification of the racemic mixture by SFC (column: DAICEL CHIRALPAK AS (250mm*30mm,10um); mobile phase: CO2-MeOH (0.1%NH3H2O); B%: 45%, isocratic elution mode). [0001055] Example 462a: MS (ESI) m/z: 677.3 [M+H] + . 1 H NMR (400 MHz, CDCl3): 8.71 (s, 1H), 8.09 (s, 1H), 7.92 - 7.79 (m, 1H), 7.71 - 7.52 (m, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 5.65 - 5.46 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.48 - 4.32 (m, 1H), 4.19 - 4.08 (m, 2H), 4.04 (dd, J = 9.6, 4.2 Hz, 1H), 3.95 (t, J = 8.0 Hz, 1H), 3.87 (d, J = 9.2 Hz, 1H), 3.82 - 3.74 (m, 3H), 3.56 (t, J = 4.0 Hz, 1H), 3.42 - 3.32 (m, 1H), 3.25 (d, J = 11.8 Hz, 1H), 3.15 - 2.95 (m, 2H), 1.95 - 1.88 (m, 1H), 1.09 - 0.99 (m, 2H), 0.74 - 0.65 (m, 2H). [0001056] Example 462b: MS (ESI) m/z: 677.3 [M+H] + . 1 H NMR (400 MHz, CDCl3): 8.70 (s, 1H), 8.09 (s, 1H), 7.90 - 7.76 (m, 1H), 7.72 - 7.55 (m, 1H), 6.84 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 5.62 - 5.45 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.44 - 4.33 (m, 1H), 4.12 (t, J = 4.8 Hz, 2H), 4.03 (dd, J = 9.2, 4.0 Hz, 1H), 3.95 (t, J = 8.0 Hz, 1H), 3.83 - 3.71 (m, 4H), 3.52 (t, J = 4.2 Hz, 1H), 3.35 (d, J = 10.8 Hz, 1H), 3.22 (d, J = 11.2 Hz, 1H), 3.09 - 2.92 (m, 2H), 1.92 - 1.85 (m, 1H), 1.03 (d, J = 7.6 Hz, 2H), 0.75 - 0.55 (m, 2H). Example 463: 7-(2-((2-ethyl-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: 7-(2-((4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperazin -1-yl)-2-ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide

[0001057] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide and 2-((tert- butyldimethylsilyl)oxy)acetaldehyde. The title compound was isolated in 93% yield as a yellow oil. MS (ESI) m/z: 781.3 [M+H] + Step 2: 7-(2-((2-ethyl-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001058] The title compound was prepared analogously to Example 298, step 5, where methyl 3-((2- ((tert-butyldimethylsilyl)oxy)ethyl)thio)-5-iodothiophene-2- carboxylate was replaced with 7-(2-((4-(4-(2- ((tert-butyldimethylsilyl)oxy)ethyl)piperazin-1-yl)-2-ethylp henyl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 667.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.67 (s, 1 H) 8.06 (s, 1 H) 7.51 (s, 1 H) 7.05 (s, 1 H) 6.85 (s, 2 H) 5.51 (m, 1 H) 5.02 (t, J = 7.6 Hz, 2 H) 4.72 (t, J = 6.8 Hz, 2 H) 4.12 (s, 2 H) 3.78 - 3.76 (m, 2 H) 3.72 - 3.70 (m, 2 H) 3.36 - 3.28 (m, 4 H) 2.75 - 2.73 (m, 4 H) 2.68~2.62 (m, 4, H) 1.23 (m, 3 H). Example 464: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2, 3-f][1,4]thiazepine 1,1-dioxide Steps 1-3: tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- ethylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0001059] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylatewere replaced with 2-ethyl-4-fluoro-1-nitrobenzene and tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate. The title compound was isolated as a pale yellow oil. MS (ESI) m/z: 498.2 [M+H] + Steps 4-8: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2, 3-f][1,4]thiazepine 1,1-dioxide [0001060] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate and 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepi n-5(2H)-one 1,1-dioxide were replaced with tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3- ethylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and tert-butyl 7-bromo-2,3- dihydrothieno[2,3-f][1,4]thiazepine-4(5H)-carboxylate 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 565.3[M+23]+. 1 H NMR (400 MHz, DMSO-d6) δ 9.81 - 9.26 (m, 2H), 9.06 - 8.55 (m, 2H), 7.80 (br s, 1H), 7.30 - 6.90 (m, 1H), 6.72 - 6.30 (m, 2H), 4.62 (br s, 1H), 4.43 (br s, 1H), 4.41 - 4.20 (m, 2H), 3.75 - 3.45 (m, 5H), 3.30 - 3.20 (m, 2H), 3.16 - 2.96 (m, 1H), 2.13 (br d, J = 10.4 Hz, 1H), 1.94 (br d, J = 10.4 Hz, 1H), 1.73 - 1.48 (m, 1H), 1.08 (t, J = 7.6 Hz, 3H) Example 465: 7-(2-((4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-cy clopropylphenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihyd rothieno[2,3-f][1,4]thiazepin-5(2H)-one [0001061] The title compound was prepared analogously to Example 305, steps 1-5, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with (1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptane and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide with 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepi n-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 648.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.08 (s, 1H), 7.86 - 7.37 (m, 2H), 6.62 - 6.49 (m, 1H), 6.37 (br s, 1H), 5.54 (quin, J = 6.8 Hz, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.66 (s, 1H), 4.42 (br s, 1H), 4.10 (br d, J = 5.2 Hz, 2H), 3.96 - 3.91 (m, 1H), 3.89 - 3.84 (m, 1H), 3.77 (br t, J = 5.6 Hz, 2H), 3.58 (br d, J = 8.8 Hz, 1H), 3.19 (br d, J = 8.8 Hz, 1H), 2.11 - 1.94 (m, 2H), 1.92 - 1.83 (m, 1H), 1.07 - 0.91 (m, 2H), 0.76 - 0.64 (m, 2H) Example 466: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-(methyl-d3)-2,5-diazabicyc lo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001062] To a solution of 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2- cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (0.33 mmol) in acetonitrile (0.5 mL) was added potassium carbonate (0.50 mmol) and methyl-d34-methylbenzenesulfonate (0.33 mmol). The mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure to afford a residue that was purified by preparative-TLC (15% methanol in dichloromethane) to afford the title compound in 19% yield as a yellow solid. MS (ESI) m/z: 622.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.74 - 8.62 (m, 1H), 8.13 - 8.00 (m, 1H), 7.82 - 7.62 (m, 1H), 7.59 - 7.35 (m, 1H), 6.60 - 6.44 (m, 1H), 6.40 - 6.28 (m, 1H), 4.41 - 4.23 (m, 1H), 3.97 - 3.77 (m, 3H), 3.76 - 3.70 (m, 2H), 3.55 - 3.45 (m, 2H), 3.29 - 3.16 (m, 4H), 3.00 - 2.77 (m, 1H), 2.31 - 2.14 (m, 1H), 2.13 - 2.01 (m, 1H), 1.91 - 1.85 (m, 1H), 1.00 (d, J = 1.6, 8.3 Hz, 2H), 0.69 (t, J = 5.6 Hz, 2H) Example 467: 7-chloro-N-(4-(5-methyl-4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine Step 1: 2-methyl-3-(methylthio)thiophene [0001063] 3-(Methylthio)thiophene (7.7 mmol) was added dropwise over a -78 °C THF solution of 2M BuLi in hexanes (8.1 mmol). After 2 hours, methyl iodide (10 mmol) was added and the mixture was allowed to reach room temperature over 1 hour. The reaction was quenched with 1M aqueous HCl, diluted with water and extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound which was used in the next step without further purification. MS (ESI) m/z: 145.0 [M+H]+ Step 2: 2-methyl-3-(methylsulfonyl)thiophene To a solution of 2-methyl-3-(methylthio)thiophene (7.5 mmol) in acetic acid (22.0 mL), 30% aqueous hydrogen peroxide (45 mmol) was added. The reaction mixture was stirred at 50°C for 4 hours, cooled down to room temperature and quenched with water. The mixture was extracted three times with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-30% ethyl acetate in cyclohexane). The title compound was isolated in 25% yield as colorless oil. MS (ESI) m/z: 177.0 [M+H]+ Step 3: 5-bromo-2-methyl-3-(methylsulfonyl)thiophene [0001064] 2-Methyl-3-(methylsulfonyl)thiophene (1.9 mmol) and NBS (2.1 mmol) were added over a solution of concentrated sulfuric acid (19 mmol) in acetic acid (7 mL). After 2 hours the reaction was poured over ice and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (30-80% ethyl acetate in cyclohexane). The title compound was isolated in 84% yield as a pale yellow oil. 1 H NMR (300 MHz, CDCl3) δ 2.69 (s, 3H), 3.05 (s, 3H), 7.26 (s, 1H). Step 4: trimethyl(5-methyl-4-(methylsulfonyl)thiophen-2-yl)stannane The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoli n-2(1H)-yl)-2,2,2-trifluoroethan-1-one was replaced with 5-bromo-2-methyl-3-(methylsulfonyl)thiophene. The title compound was isolated as a colorless solid.1H-NMR (300 MHz, CDCl3) δ 0.38 (s, 9H), 2.76 (s, 3H), 3.06 (s, 3H), 7.35 (s, 1H). Steps 5-6: 7-chloro-N-(4-(5-methyl-4-(methylsulfonyl)thiophen-2-yl)-5-( trifluoromethyl)pyrimidin- 2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine [0001066] The title compound was prepared analogously to Example 4, steps 2-3, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one and 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one were replaced with 2,2,2-trifluoro-1-[7-chloro-6-nitro-1,2,3,4-tetrahydroisoqui nolin-2-yl]ethan-1-one and trimethyl(5-methyl-4-(methylsulfonyl)thiophen-2-yl)stannane. The title compound was isolated as a pale yellow solid. MS (ESI) m/z: 503.1 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ 2.67 (t, J = 5.9 Hz, 2H), 2.73 (s, 3H), 2.94 (t, J = 5.8 Hz, 2H), 3.25 (s, 3H), 3.84 (s, 2H), 7.21 (s, 1H), 7.29 (s, 1H), 7.80 (s, 1H), 8.77 (s, 1H), 9.84 (s, 1H). Example 468: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(methyl-d3)-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001067] The title compound was prepared analogously to Example 305, steps 4-6, where tert-butyl (1S,4S)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-cyclopropylphenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with tert-butyl 3-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate and 7-bromo-4-(methyl-d3)-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide. The title compound was isolated as a pale yellow solid. MS (ESI) m/z: 608.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.84 - 8.50 (m, 1H), 7.97 (s, 1H), 7.45 - 7.11 (m, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.42 (s, 1H), 3.95 - 3.81 (m, 6H), 3.63 – 3.55 (m, 4H), 2.78 - 2.69 (m, 1H), 1.99 - 1.92 (m, 1H), 1.70 (d, J = 8.0 Hz, 1H), 0.91 - 0.85 (m, 2H), 0.70 - 0.64 (m, 2H). Example 469: 7-(2-((2-cyclopropyl-4-(6-methyl-3,6-diazabicyclo[3.1.1]hept an-3-yl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-(methyl-d3)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001068] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- (3,6-diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylphenyl)ami no)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (methyl-d3)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 33% yield as a pale yellow solid. MS (ESI) m/z: 622.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.68 (s, 1H), 8.07 (s, 1H), 8.01 - 7.27 (m, 2H), 6.75 - 6.63 (m, 1H), 6.57 - 6.46 (m, 1H), 3.98 - 3.79 (m, 4H), 3.74 (t, J = 5.6 Hz, 2H), 3.62 (d, J = 11.2 Hz, 2H), 3.49 - 3.36 (m, 2H), 2.93 - 2.62 (m, 1H), 2.24 (s, 3H), 2.01 - 1.81 (m, 2H), 1.05 - 0.99 (m, 2H), 0.77 - 0.70 (m, 2H) Example 470: 7-(2-((2-cyclopropyl-4-(6-(methyl-d3)-3,6-diazabicyclo[3.1.1 ]heptan-3- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001069] The title compound was prepared analogously to Example 466, where 7-(2-((4-((1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4-(3,6- diazabicyclo[3.1.1]heptan-3-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 622.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.07 (s, 1H), 7.93 - 7.48 (m, 2H), 6.75 - 6.66 (m, 1H), 6.54 (s, 1H), 4.24 - 4.08 (m, 2H), 3.94 - 3.86 (m, 2H), 3.78 - 3.73 (m, 2H), 3.71 - 3.59 (m, 3H), 3.25 (s, 3H), 3.09 - 2.94 (m, 1H), 1.96 - 1.90 (m, 3H), 1.07 - 0.99 (m, 2H), 0.77 - 0.69 (m, 2H). Example 471: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001070] To a solution of 7-iodo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1- dioxide (0.28 mmol) in tetrahydrofuran (3 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo- 1,3,2,4dithiadiphosphetane (0.28 mmol). The reaction was stirred at 50°C for 12 hours, cooled down to room temperature and quenched with aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (20-100% ethyl acetate in hexanes). The title compound was isolated in 77% yield as yellow solid. MS (ESI) m/z: 373.9 [M+H] + Step 2: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001071] The title compound was prepared analogously to Example 431, where 7-bromo-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-iodo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide. The title compound was isolated as an orange solid. Example 472: 7-(2-((2-cyclopropyl-4-((4aS,7aR)-4-methylhexahydrofuro[3,4- b]pyrazin-1(2H)- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (example 472a) and 7-(2-((2-cyclopropyl-4-((4aR,7aS)-4- methylhexahydrofuro[3,4-b]pyrazin-1(2H)-yl)phenyl)amino)-5-( trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide (example 472b) [0001072] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with a 1:1 racemic mixture of 7-(2-((2-cyclopropyl-4-((4aS,7aR)-hexahydrofuro[3,4-b]pyrazi n-1(2H)- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 7-(2-((2-cyclopropyl-4-((4aR,7aS)-hexahydrofuro[3,4- b]pyrazin-1(2H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidi n-4-yl)-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The racemate was purified by chiral SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um); mobile phase: [CO2-MeOH (0.1%NH3H2O)]; B%: 45%, isocratic elution mode) to afford the title compounds as individual enantiomers as orange solids. [0001073] Example 472a: MS (ESI) m/z: 691.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): 8.70 (s, 1H), 8.09 (s, 1H), 7.92 - 7.74 (m, 1H), 7.71 - 7.53 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 5.62 - 5.47 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.52 - 4.38 (m, 1H), 4.20 - 4.06 (m, 3H), 3.99 - 3.87 (m, 2H), 3.83 - 3.71 (m, 3H), 3.43 (d, J = 11.6 Hz, 1H), 3.23 (t, J = 10.6 Hz, 1H), 2.99 (d, J = 10.6 Hz, 1H), 2.79 - 2.61 (m, 1H), 2.52 - 2.40 (m, 1H), 2.37 (s, 3H), 1.92 - 1.82 (m, 1H), 1.03 (d, J = 8.0 Hz, 2H), 0.70 (t, J = 5.6 Hz, 2H). [0001074] Example 472b: MS (ESI) m/z: 691.3 [M+H] + . 1 H NMR (400 MHz, CDCl3): 8.70 (s, 1H), 8.09 (s, 1H), 7.96 - 7.76 (m, 1H), 7.73 - 7.49 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 5.65 - 5.45 (m, 1H), 5.03 (t, J = 7.2 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.56 - 4.38 (m, 1H), 4.19 - 4.03 (m, 3H), 4.00 - 3.87 (m, 2H), 3.82 - 3.66 (m, 3H), 3.43 (d, J = 12.0 Hz, 1H), 3.29 - 3.15 (m, 1H), 2.99 (d, J = 11.2 Hz, 1H), 2.78 – 2.65 (m, 1H), 2.49 - 2.35 (m, 1H), 2.37 (s, 3H), 1.93 - 1.85 (m, 1H), 1.10 - 0.97 (m, 2H), 0.75 - 0.64 (m, 2H). Example 473: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-ethylphenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Steps 1-3: tert-butyl 6-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-e thylphenyl)-3,6- diazabicyclo[3.1.1]heptane-3-carboxylate [0001075] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 2-ethyl-4-fluoro-1-nitrobenzene and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3- carboxylate. The title compound was isolated as a yellow oil. MS (ESI) m/z: 498.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.80 (s, 1H), 8.71 - 8.51 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.54 - 6.39 (m, 2H), 4.36 - 4.23 (m, 2H), 3.82 - 3.65 (m, 2H), 3.30 - 3.20 (m, 2H), 2.63 - 2.56 (m, 1H), 2.49 - 2.43 (m, 2H), 1.53 (d, J = 8.4 Hz, 1H), 1.32 (s, 9H), 1.06 (t, J = 7.6 Hz, 3H). Steps 4-8: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-ethylphenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001076] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with tert-butyl 6-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethylphenyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 635.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.69 (s, 1H), 8.05 (s, 1H), 7.03 (s, 1H), 6.43 - 6.40 (m, 2H), 5.58 - 5.49 (m, 1H), 5.18 - 4.97 (m, 2H), 4.80 - 4.58 (m, 2H), 4.41 - 4.32 (m, 2H), 4.19 - 4.12 (m, 2H), 3.84 - 3.71 (m, 4H), 3.46 - 3.37 (m, 1H), 3.01 - 2.90 (m, 1H), 2.67 - 2.53 (m, 3H), 1.24 - 1.12 (m, 4H). Example 474: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-chlorophenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Steps 1-3: tert-butyl 6-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-e thylphenyl)-3,6- diazabicyclo[3.1.1]heptane-3-carboxylate [0001077] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 2-chloro-4-fluoro-1-nitrobenzene and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3- carboxylate. The title compound was isolated as a yellow oil. MS (ESI) m/z: 634.2 [M+H] + Steps 4-8: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-chlorophenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001078] The title compound was prepared analogously to Example 368, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate and 7-iodo-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepi n-5(2H)-one 1,1-dioxide were replaced with tert-butyl 6-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-e thylphenyl)- 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate and 7-bromo-4-methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 599.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.72 (s, 1H), 8.07 (s, 1H), 7.99 - 7.82 (m, 1H), 7.48 (s, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.8, 2.4 Hz, 1H), 4.25 (d, J = 6.0 Hz, 2H), 3.93 - 3.90 (m, 2H), 3.75 – 3.72 (m, 2H), 3.60 (d, J = 12.8 Hz, 2H), 3.25 (s, 3H), 3.12 (d, J = 12.8 Hz, 2H), 2.88 - 2.81 (m, 1H), 2.16 - 2.08 (m, 1H) Example 475: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-ethylphenyl) amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide The title compound was prepared analogously to Example 474, where 2-chloro-4-fluoro-1-nitrobenzene was replaced with 2-ethyl-4-fluoro-1-nitrobenzene. The title compound was isolated as an orange solid. [0001079] MS (ESI) m/z: 593.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.67 (s, 1H), 8.03 (s, 1H), 7.26 - 7.21 (m, 1H), 7.03 (s, 1H), 6.48 - 6.41 (m, 2H), 4.34 (s, 2H), 3.97 - 3.87 (m, 2H), 3.80 - 3.66 (m, 4H), 3.51 - 3.36 (m, 2H), 3.22 (s, 3H), 2.98 - 2.84 (m, 2H), 2.57 (q, J = 7.2 Hz, 2H), 2.38 - 2.27 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H). Example 476: 7-(2-((2-ethyl-6-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]he ptan-2-yl)pyridin-3- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-di hydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide [0001080] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((6- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethylpyridin- 3-yl)amino)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide. The title compound was isolated in 70% yield as an orange solid. MS (ESI) m/z: 608.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.04 (s, 1H), 7.61 - 7.53 (m, 1H), 6.94 (s, 1H), 6.29 - 6.27 (m, 1H), 4.77 (s, 1H), 3.92 - 3.87 (m, 2H), 3.75 - 3.61 (m, 4H), 3.43 - 3.39 (m, 1H), 3.24 (s, 3H), 3.05 - 3.03 (m, 1H), 2.88 - 2.70 (m, 1H), 2.68 (q, J = 7.6 Hz, 2H), 2.48 (s, 3H), 2.05 – 1.85 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H). Example 477: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-chlorophenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001081] The title compound was prepared analogously to Example 473, where 2-ethyl-4-fluoro-1- nitrobenzene was replaced with 2-chloro-4-fluoro-1-nitrobenzene. The title compound was isolated as an orange solid. MS (ESI) m/z: 641.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.73 (s, 1H), 8.10 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.53 - 7.51 (m, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.64 – 6.52 (m, 1H), 5.56 - 5.51 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 6.8 Hz, 2H), 4.22 (d, J = 6.8 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.53 (d, J = 12.4 Hz, 2H), 3.11 - 3.08 (m, 1H), 3.00 (d, J = 13.2 Hz, 2H), 2.83 - 2.78 (m, 1H), 1.87-1.82 (m, 1H). Example 478: (R)-7-(2-((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-2,3,4,5-tetrahydrothieno[2, 3-f][1,4]thiazepine 1,1-dioxide [0001082] The title compound was prepared analogously to Example 359, where 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with tert-butyl 7- bromo-2,3-dihydrothieno[2,3-f][1,4]thiazepine-4(5H)-carboxyl ate 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 567.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 8.05 (s, 1H), 7.67 - 7.39 (m, 1H), 7.08 - 6.92 (m, 1H), 6.90 - 6.78 (m, 2H), 4.27 (s, 2H), 3.66 - 3.60 (m, 2H), 3.56 (d, J = 11.8 Hz, 2H), 3.33 - 3.27 (m, 2H), 3.24 - 3.16 (m, 1H), 3.13 - 3.04 (m, 2H), 2.82 (td, J = 11.4, 2.8, 1H), 2.64 (q, J = 7.6 Hz, 2H), 2.54 - 2.43 (m, 1H), 1.26 - 1.23 (m, 3H), 1.22 - 1.20 (m, 3H). Example 479: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-(2-methoxyethyl)-2,5-diaza bicyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide

[0001083] The title compound was prepared analogously to Example 443, where (R)-7-(2-((2- cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(trifl uoromethyl)pyrimidin-4-yl)-4-(oxetan-3- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4-((1R,4R)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amin o)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 663.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ): δ 8.67 (s, 1H), 8.06 (s, 1H), 7.83 - 7.65 (m, 1H), 7.63 - 7.49 (m, 1H), 6.56 - 6.44 (m, 1H), 6.31 ( d, J = 1.2 Hz, 1H), 4.22 (s, 1H), 3.97 - 3.85 (m, 2H), 3.78 - 3.71 (m, 2H), 3.69 - 3.63 (m, 1H), 3.50 - 3.37 (m, 4H), 3.35 (s, 3H), 3.25 (s, 3H), 3.18 - 3.02 (m, 1H), 2.85 - 2.59 (m, 3H), 2.08 – 1.96 (m, 1H), 1.95 - 1.81 (m, 2H), 0.99 (d, J = 8.0 Hz, 2H), 0.77 - 0.56 (m, 2H). Example 480: (R)-N-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)- 4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine (example 480a) and (S)-N-(2- chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(4-(met hylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine (example 480b) Steps 1-3: 4-chloro-N-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phe nyl)-5- (trifluoromethyl)pyrimidin-2-amine [0001084] The title compound was prepared analogously to Example 305, steps 1-3, where 2- cyclopropyl-4-fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 2-chloro-4-fluoro-1-nitrobenzene and N,N-dimethylpyrrolidin-3-amine. The title compound was isolated as a yellow oil. MS (ESI) m/z: 520.1 [M+H] + Step 4: N-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-5-(t rifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-amine [0001085] The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with 4-chloro-N-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phe nyl)-5- (trifluoromethyl)pyrimidin-2-amine. The title compound was isolated as a pale yellow oil. MS (ESI) m/z: 550.1 [M+H] + Step 5: (R)-N-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)- 4-(4- (methylsulfonyl)thiophen-2-yl)-5-(trifluoromethyl)pyrimidin- 2-amine (example 480a) and (S)-N-(2- chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(4-(met hylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine (example 480b) [0001086] The title compound was prepared as a 1:1 mixture of enantiomers following the synthetic procedure described in Example 155, step 3, where 1-(7-chloro-6-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinol in-2(1H)-yl)-2,2,2-trifluoroethan-1-one and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide were replaced with N-(2-chloro-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-5-(t rifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-amine and 2-bromo-4-(methylsulfonyl)thiophene. The title compounds were isolated as individual enantiomers by purification of the racemic mixture by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO2-i- PrOH(0.1%NH3H2O)];B%:35%, isocratic elution mode). [0001087] Example 480a: MS (ESI) m/z: 546.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.68 (s, 1 H) 8.25 (s, 1 H) 8.03 (s, 1 H) 7.78 - 7.97 (m, 1 H) 7.39 - 7.56 (m, 1 H) 6.61 (d, J = 2.0 Hz, 1 H) 6.53 (br d, J = 9.2 Hz, 1 H) 3.42 - 3.56 (m, 2 H) 3.29 - 3.40 (m, 1 H) 3.23 (br t, J = 8.4 Hz, 1 H) 3.10 - 3.17 (m, 3 H) 2.92 - 3.00 (m, 1 H) 2.38 (s, 6 H) 2.27 (dt, J = 12.0, 6.0 Hz, 1 H) 1.97 - 2.07 (m, 1 H) [0001088] Example 480b: MS (ESI) m/z: 546.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.62 - 8.81 (m, 1 H) 8.25 (br s, 1 H) 7.99 - 8.14 (m, 1 H) 7.76 - 7.97 (m, 1 H) 7.38 - 7.58 (m, 1 H) 6.47 - 6.74 (m, 2 H) 3.43 - 3.60 (m, 2 H) 3.29 - 3.40 (m, 1 H) 3.11 - 3.27 (m, 4 H) 2.85 - 3.02 (m, 1 H) 2.32 - 2.49 (m, 6 H) 2.21 - 2.31 (m, 1 H) 1.93 - 2.05 (m, 1 H) Example 481: (S)-7-(2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylpheny l)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (example 481a) and (R)-7-(2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylpheny l)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothien o[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (example 481b) [0001089] The title compounds were prepared as a 1:1 mixture of enantiomers analogously to Example 480, where 2-chloro-4-fluoro-1-nitrobenzene and 2-bromo-4-(methylsulfonyl)thiophene were replaced with 2-ethyl-4-fluoro-1-nitrobenzene and 7-bromo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide. The title compounds were isolated as single enantiomers by purification of the racemic mixture by SFC (column: DAICEL CHIRALPAK AD(250 mm × 30 mm, 10 um); mobile phase: 60% carbon dioxide in ethanol + ammonia water, isocratic elution mode). [0001090] Example 481a: MS (ESI) m/z: 609.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 -d) δ, 1.20 (t, J=7.6Hz, 3 H) 1.88 - 2.06 (m, 1 H) 2.24 (dt, J=11.6, 5.6Hz, 1 H) 2.36 (br s, 6 H) 2.60 (q, J=7.6Hz, 2 H) 2.80 - 3.01 (m, 1 H) 3.22 (br s, 4 H) 3.30 - 3.40 (m, 1 H) 3.41 - 3.60 (m, 2 H) 3.70 (br s, 2 H) 3.80 - 4.00 (m, 2 H) 6.38 - 6.49 (m, 2 H) 6.88 - 7.05 (m, 1 H) 7.34 - 7.44 (m, 1 H) 8.02 (br s, 1 H) 8.62 (s, 1 H) [0001091] Example 481b: MS (ESI) m/z: 609.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 1.21 (t, J=7.6Hz, 3 H) 1.89 - 2.07 (m, 1 H) 2.25 (dt, J=11.6, 5.6Hz, 1 H) 2.37 (br s, 6 H) 2.61 (q, J=7.6Hz, 2 H) 2.81 - 3.02 (m, 1 H) 3.23 (br s, 4 H) 3.31 - 3.41 (m, 1 H) 3.42 - 3.61 (m, 2 H) 3.71 (br s, 2 H) 3.81 - 4.01 (m, 2 H) 6.39 - 6.50 (m, 2 H) 6.89 - 7.06 (m, 1 H) 7.35 - 7.45 (m, 1 H) 8.03 (br s, 1 H) 8.63 (s, 1 H) Example 482: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001092] The title compound was prepared analogously to Example 473, where 2-ethyl-4-fluoro-1- nitrobenzene was replaced with 2-cyclopropyl-4-fluoro-1-nitrobenzene. The title compound was isolated as an orange solid. MS (ESI) m/z: 510.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.08 (s, 1H), 7.75 - 7.68 (m, 1H), 7.60 – 7.53 (m, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 5.56 – 5.51 (m, 1H), 5.01 (t, J = 7.6 Hz, 2H), 4.73 (t, J = 6.4 Hz, 2H), 4.21 (d, J = 6.0 Hz, 2H), 4.10 (d, J = 5.2 Hz, 2H), 3.77 (t, J = 6.0 Hz, 2H), 3.51 (d, J = 12.8 Hz, 2H), 2.98 (d, J = 12.4 Hz, 2H), 2.80 – 2.76 (m, 1H), 1.88 – 1.82 (m, 3H), 1.01 – 0.98 (m, 2H), 0.68 – 0.65 (m, 2H). Example 483: 7-(2-((2-ethyl-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001093] The title compound was prepared analogously to Example 364, where tert-butyl piperazine- 1-carboxylate was replaced with 1-(2-methoxyethyl)piperazine. The title compound was isolated as an orange solid. MS (ESI) m/z: 680.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.67 (s, 1 H) 8.06 (s, 1 H) 7.38 - 7.57 (m, 1 H) 7.05 (br s, 1 H) 6.85 (br d, J = 2.4 Hz, 2 H) 5.54 (quin, J = 6.8 Hz, 1 H) 5.03 (t, J = 7.6 Hz, 2 H) 4.73 (t, J = 6.8 Hz, 2 H) 4.10 (br s, 2 H) 3.70 - 3.83 (m, 2 H) 3.61 (br t, J = 5.2 Hz, 2 H) 3.39 (s, 3 H) 3.25 - 3.34 (m, 4 H) 2.67 - 2.82 (m, 6 H) 2.63 (q, J = 7.6 Hz, 2 H) 1.23 (t, J = 7.6 Hz, 3 H) Example 484: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-(2-methoxyethyl)-2,5-diaza bicyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide

[0001094] The title compound was prepared analogously to Example 443, where (R)-7-(2-((2- cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(trifl uoromethyl)pyrimidin-4-yl)-4-(oxetan-3- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4-((1R,4R)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amin o)-5-(trifluoromethyl)pyrimidin-4-yl)-4- (oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 705.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.08 (s, 1H), 7.83 - 7.34 (m, 2H), 6.55 - 6.43 (m, 1H), 6.32 (s, 1H), 5.58 - 5.49 (m, 1H), 5.03 (t, J = 7.6 Hz, 2H), 4.74 (t, J = 7.6 Hz, 2H), 4.28 - 4.19 (m, 1H), 4.16 - 4.06 (m, 2H), 3.81 - 3.74 (m, 2H), 3.57 - 3.40 (m, 3H), 3.39 - 3.25 (m, 1H), 3.36 (s, 3H), 3.23 - 3.06 (m, 1H), 2.92 - 2.58 (m, 3H), 2.18 - 1.90 (m, 2H), 1.90 - 1.84 (m, 1H), 1.70 - 1.61 (m, 1H), 1.04 - 0.94 (m, 2H), 0.73 - 0.63 (m, 2H). Example 485: 7-(2-((4-(3-(dimethylamino)azetidin-1-yl)-2-ethylphenyl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Steps 1-5: tert-butyl (1-(3-ethyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5-tetrah ydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)azetidin-3-yl)carbamate [0001095] The title compound was prepared analogously to Example 480, where 2-chloro-4-fluoro-1- nitrobenzene and N,N-dimethylpyrrolidin-3-amine were replaced with 2-ethyl-4-fluoro-1-nitrobenzene and tert-butyl azetidin-3-ylcarbamate. The title compound was isolated as a yellow solid. MS (ESI).m/z: 667.4 [M+H] + Step 6: 7-(2-((4-(3-aminoazetidin-1-yl)-2-ethylphenyl)amino)-5-(trif luoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001096] The title compound was prepared analogously to Example 305, step 6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((4-(4-cyclopropyl-1,1-dioxido-5- oxo-2,3,4,5-tetrahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-2,5-diazabicyclo[2.2.1]heptane- 2-carboxylate was replaced with tert-butyl (1-(3-ethyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)azetidin-3- yl)carbamate. The title compound was isolated as an orange solid. MS (ESI).m/z: 567.3 [M+H] + Step 7: 7-(2-((4-(3-(dimethylamino)azetidin-1-yl)-2-ethylphenyl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001097] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4-(3- aminoazetidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 39% yield as a pale yellow solid. MS (ESI).m/z: 595.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.65 (s, 1 H) 8.04 (br s, 1 H) 7.28 - 7.46 (m, 2 H) 6.99 (dt, J=4.0, 2.4 Hz, 1 H) 6.30 - 6.46 (m, 2 H) 4.01 (br d, J=4.0 Hz, 2 H) 3.89 (br d, J=0.8 Hz, 2 H) 3.69 - 3.81 (m, 4 H) 3.24 (br s, 3 H) 2.56 - 2.64 (m, 2 H) 2.23 - 2.41 (m, 6 H) 1.21 (td, J=8.0, 2.0 Hz, 3 H) Example 486: (R)-7-(2-((2-ethyl-4-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl )phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001098] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with (R)-7-(2- ((2-ethyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(trifluo romethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 26% yield as an orange solid. MS (ESI) m/z: 651.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.67 (s, 1H), 8.05 (s, 1H), 7.53 - 7.46 (m, 1H), 7.03 (s, 1H), 6.85 - 6.83 (m, 2H), 4.76 - 4.62 (m, 4H), 3.89 - 3.71 (m, 5H), 3.50 - 3.40 (m, 2H), 3.24 (s, 3H), 3.15 - 2.98 (m, 1H), 2.79 - 2.76 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.25 - 2.35 (m, 1H), 1.24 (t, J = 7.6 Hz, 3H), 1.02 (s, 3H). Example 487: 7-(2-((2-ethyl-4-((1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2 .2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001099] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4- ((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)a mino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated in 39% yield as an orange solid. MS (ESI) m/z: 649.3 [M+H] + 1 H NMR (400 MHz, CDCl3) δ,8.76 - 8.61 (m, 1H), 8.15 - 7.98 (m, 1H), 7.47 - 7.36 (m, 1H), 7.08 - 6.92 (m, 1H), 6.56 - 6.38 (m, 2H), 4.85 - 4.68 (m, 2H), 4.66 - 4.48 (m, 2H), 4.45 - 4.28 (m, 1H), 4.15 - 4.00 (m, 1H), 3.96 - 3.83 (m, 2H), 3.77 - 3.69 (m, 2H), 3.55 - 3.44 (m, 1H), 3.30 - 3.21 (m, 3H), 3.19 (br d, J = 2.4 Hz, 2H), 2.70 - 2.57 (m, 2H), 2.17 - 1.96 (m, 2H), 1.29 (br s, 2H), 1.27 - 1.19 (m, 3H) Example 488: 7-(2-((4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-cyclopropylp henyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001100] The title compound was prepared analogously to Example 474, where 2-chloro-4-fluoro-1- nitrobenzene was replaced with 2-cyclopropyl-4-fluoro-1-nitrobenzene. The title compound was isolated as an orange solid. MS (ESI) m/z: 605.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.06 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.58 - 7.50 (m, 1H), 6.54 - 6.47 (m, 1H), 6.31 (d, J = 2.4 Hz, 1H), 4.26 - 4.18 (m, 2H), 3.93 - 3.88 (m, 2H), 3.75 - 3.71 (m, 2H), 3.58 - 3.48 (m, 2H), 3.25 (s, 3H), 3.08 - 2.96 (m, 2H), 2.86 - 2.75 (m, 1H), 1.93 - 1.82 (m, 3H), 1.04 - 0.94 (m, 2H), 0.70 - 0.63 (m, 2H). Example 489: (S)-7-(2-((2-ethyl-4-(2-methylpiperazin-1-yl)phenyl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001101] The title compound was prepared analogously to Example 305, where 2-cyclopropyl-4- fluoro-1-nitrobenzene, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with 2- cyclopropyl-4-fluoro-1-nitrobenzene, tert-butyl (S)-3-methylpiperazine-1-carboxylate and 7-bromo-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 595.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.05 (s, 1H), 7.61 - 7.47 (m, 1H), 7.05 (s, 1H), 6.88 - 6.79 (m, 2H), 3.94 - 3.85 (m, 2H), 3.83 - 3.77 (m, 1H), 3.76 - 3.69 (m, 2H), 3.24 (s, 3H), 3.23 - 3.06 (m, 4H), 3.04 - 2.96 (m, 1H), 2.94 - 2.87 (m, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H). Example 490: 7-(2-((4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2-ethylph enyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001102] A 0 °C solution of (2R,6S)-1-benzyl-4-(phenylsulfonyl)piperazine-2,6-dicarboxyl ate (11 mmol) in tetrahydrofuran (100 mL) was treated with a 2.5M solution of lithium aluminum hydride in THF (43 mL). The mixture was stirred at room temperature for 12 hours, quenched with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a colorless solid which was used in the next step without further purification. MS (ESI) m/z: 237.1 [M+H] + Step 2: ((2R,6S)-1-benzyl-4-(3-ethyl-4-nitrophenyl)piperazine-2,6-di yl)dimethanol [0001103] The title compound was prepared analogously to Example 305, step 1, where tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 2-cyclopropyl-4-fluoro-1-nitrobenzene, cesium carbonate and DMF were replaced with ((2R,6S)-1-benzylpiperazine-2,6-diyl)dimethanol, 2-ethyl-4- fluoro-1-nitrobenzene, potassium carbonate and NMP. The title compound was isolated in 58% yield as a pale yellow solid. MS (ESI) m/z: 386.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 -d) δ, 1.23 - 1.33 (m, 3 H) 2.99 (q, J=7.2 Hz, 2 H) 3.09 - 3.17 (m, 2 H) 3.44 - 3.54 (m, 4 H) 3.57 - 3.68 (m, 4 H) 3.87 (s, 2 H) 6.50 (d, J=2.4 Hz, 1 H) 6.56 (dd, J=9.2, 2.4 Hz, 1 H) 7.30 - 7.41 (m, 5 H) 8.06 (d, J=9.2 Hz, 1 H). Step 3: 9-benzyl-7-(3-ethyl-4-nitrophenyl)-3-oxa-7,9-diazabicyclo[3. 3.1]nonane [0001104] To a solution of ((2R,6S)-1-benzyl-4-(3-ethyl-4-nitrophenyl)piperazine-2,6-di yl)dimethanol (3.4 mmol) in N-methylpyrrolidone (30 mL) was added a solution of dichlorosulfoxide (3.4 mmol) in toluene (6 mL). The reaction was stirred at 170 °C for 3 hours, cooled down to room temperature and diluted with water. The mixture was extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (33% ethyl acetate in hexanes). The title compound was isolated in 28% yield as yellow solid. MS (ESI) m/z: 368.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 -d) δ, 1.30 (t, J=7.2 Hz, 3 H) 2.96 (br s, 2 H) 3.04 (q, J=7.2 Hz, 2 H) 3.53 - 3.63 (m, 4 H) 3.87 (d, J=11.2 Hz, 2 H) 3.93 (s, 2 H) 4.03 (br d, J=11.2 Hz, 2 H) 6.63 (d, J=2.8 Hz, 1 H) 6.68 (dd, J=9.2, 2.8 Hz, 1 H) 7.28 - 7.47 (m, 5 H) 8.12 (d, J=9.2 Hz, 1 H). Step 4: 4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2-ethylaniline [0001105] The title compound was prepared analogously to Example 19, where 1-(5-cyclopropyl-6- nitroisoindolin-2-yl)-2,2,2-trifluoroethan-1-one was replaced with 9-benzyl-7-(3-ethyl-4-nitrophenyl)-3- oxa-7,9-diazabicyclo[3.3.1]nonane. The title compound was isolated as a brown oil. MS (ESI) m/z: 248.1 [M+H] + Step 5: tert-butyl 7-(4-amino-3-ethylphenyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan e-9-carboxylate [0001106] The title compound was prepared analogously to Example 69, step 2, where 1-bromo- 2,3,4,5-tetrahydrothieno[2,3-f][1,4]thiazepine 1,1-dioxide was replaced with 4: 4-(3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)-2-ethylaniline. The title compound was isolated in 25% yield as a yellow oil. MS (ESI) m/z: 348.3 [M+H] + Step 6: tert-butyl 7-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-e thylphenyl)-3-oxa- 7,9-diazabicyclo[3.3.1]nonane-9-carboxylate [0001107] The title compound was prepared analogously to Example 305, step 3, where tert-butyl (1S,4S)-5-(4-amino-3-cyclopropylphenyl)-2,5-diazabicyclo[2.2 .1]heptane-2-carboxylate was replaced with tert-butyl 7-(4-amino-3-ethylphenyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan e-9-carboxylate. The title compound was isolated as a brown solid in 22% yield. MS (ESI) m/z: 528.1 [M+H] + Step 7: tert-butyl 7-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2- yl)amino)phenyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carbo xylate [0001108] The title compound was prepared analogously to Example 4, step 1, where 1-(7-chloro-6-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroi soquinolin-2(1H)-yl)-2,2,2-trifluoroethan- 1-one was replaced with tert-butyl 7-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3- ethylphenyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxyla te. The title compound was isolated in 92% yield as a pale yellow oil. MS (ESI) m/z: 658.2 [M+H] + Step 8-9: 7-(2-((4-(3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-2-ethylph enyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001109] The title compound was prepared analogously to Example 305, steps 5-6, where tert-butyl (1S,4S)-5-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethy lstannyl)pyrimidin-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl 7-(3-ethyl-4-((5-(trifluoromethyl)- 4-(trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-3-oxa-7,9-d iazabicyclo[3.3.1]nonane-9-carboxylate in step 5. MS (ESI) m/z: 623.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 1.13 (t, J=7.6 Hz, 3 H) 2.51 (q, J=7.6 Hz, 2 H) 3.14 (s, 3 H) 3.30 (br s, 2 H) 3.37 (br d, J=11.6 Hz, 2 H) 3.58 - 3.65 (m, 2 H) 3.74 - 3.84 (m, 4 H) 3.94 - 4.02 (m, 2 H) 4.06 - 4.15 (m, 2 H) 6.69 - 6.80 (m, 3 H) 7.46 (d, J=8.8 Hz, 1 H) 8.06 (s, 1 H) 8.46 (s, 1 H). Example 491: 7-(2-((2-ethyl-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino )-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001110] The title compound was prepared analogously to Example 17, where 5-(2-((6- chloroisoindolin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl)thiophene-3-carboxamide and formaldehyde were replaced with 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and oxetan-3-one. The title compound was isolated as an orange solid. MS (ESI).m/z: 637.3 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ = 8.67 (s, 1H), 8.05 (s, 1H), 7.66 - 7.39 (m, 1H), 7.04 (br s, 1H), 6.90 - 6.80 (m, 2H), 4.76 - 4.66 (m, 4H), 3.90 (br s, 2H), 3.75 - 3.70 (m, 2H), 3.60 (br s, 1H), 3.32 - 3.19 (m, 7H), 2.64 (q, J = 7.6 Hz, 2H), 2.54 (br s, 4H), 1.24 (t, J = 7.6 Hz, 3H) Example 492: 7-(2-((2-cyclopropyl-4-(2-oxopiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide Step 1: tert-butyl 4-(4-amino-3-chlorophenyl)-3-oxopiperazine-1-carboxylate [0001111] To a solution of 2-chloro-4-iodoaniline (15.8 mmol) and tert-butyl 3-oxopiperazine-1- carboxylate (15.8 mmol) in dioxane (80 mL) was added cuprous iodide (1.6 mmol), potassium carbonate (32 mmol) and N,N'-dimethylethane-1,2-diamine (15.8 mmol). The reaction was stirred at 120 °C for 5 hours, cooled down to room temperature, diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (5-40% ethyl acetate in hexanes). The title compound was isolated in 91% yield as yellow solid. MS (ESI) m/z: 326.1 [M+H] + Step 2: tert-butyl 4-(4-amino-3-cyclopropylphenyl)-3-oxopiperazine-1-carboxylat e [0001112] The title compound was prepared analogously to Example 456, step 1, where 2-bromo-3,4- difluoro-1-nitrobenzene was replaced with tert-butyl 4-(4-amino-3-chlorophenyl)-3-oxopiperazine-1- carboxylate. The title compound was isolated as a yellow oil in 14% yield. 1 H NMR (400 MHz, CDCl3) δ 6.99 - 6.83 (m, 2H), 6.71 (d, J = 9.2 Hz, 1H), 4.23 (s, 2H), 3.79 - 3.72 (m, 2H), 3.68 - 3.58 (m, 2H), 1.72 - 1.66 (m, 1H), 1.50 (s, 9H), 0.94 - 0.84 (m, 2H), 0.69 - 0.52 (m, 2H). Step 3: 1-(2-((2-cyclopropyl-4-(2-oxopiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4- yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide [0001113] The title compound was prepared analogously to Example 385, step 3, where tert-butyl (1R,4R)-5-(5-amino-6-cyclopropyl-2-pyridyl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate was replaced with tert-butyl 4-(4-amino-3-cyclopropylphenyl)-3-oxopiperazine-1-carboxylat e. The title compound was isolated as an orange solid in 59% yield. MS (ESI) m/z: 762.2 [M+H] + Step 4-8: 7-(2-((2-cyclopropyl-4-(2-oxopiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin- 4-yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide [0001114] The title compound was prepared analogously to Example 385, where tert-butyl (2S,6R)-4- (4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-eth ylphenyl)-2,6-dimethylpiperazine-1- carboxylate was replaced with 1-(2-((2-cyclopropyl-4-(2-oxopiperazin-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4-dihydro thieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide. Example 493: 7-(2-((2-ethyl-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001115] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 2-((tert- butyldimethylsilyl)oxy)acetaldehyde. The title compound was isolated as an orange solid. MS (ESI) m/z: 625.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.67 (s, 1 H) 8.05 (s, 1 H) 7.61 (s, 1 H) 7.06 (s, 1 H) 6.85 (m, 2 H) 3.90 (br s, 2 H) 3.74 (br s, 4 H) 3.30 (br s, 4 H) 3.24 (s, 3 H) 2.78 (br s, 4 H) 2.71 (br s, 2 H) 2.64 (q, J = 7.6 Hz, 2 H) 1.23 (t, J = 7.6 Hz, 3 H) Example 494: 7-(2-((2-ethyl-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide

[0001116] The title compound was prepared analogously to Example 305, steps 1-5, where 2- cyclopropyl-4-fluoro-1-nitrobenzene, tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin -5(2H)-one 1,1-dioxide were replaced with 2-ethyl-4-fluoro-1-nitrobenzene, 1-(2-methoxyethyl)piperazine and 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 639.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ, 8.66 (s, 1H), 8.05 (s, 1H), 7.65 - 7.36 (m, 1H), 7.09 - 6.97 (m, 1H), 6.85 (br s, 2H), 3.89 (br s, 2H), 3.74 (br d, J = 5.2 Hz, 2H), 3.62 - 3.54 (m, 2H), 3.39 (s, 3H), 3.28 (br s, 4H), 3.25 (s, 3H), 2.73 - 2.59 (m, 8H), 1.23 (t, J = 7.6 Hz, 3H) Example 495: (R)-7-(2-((2-ethyl-4-(2-(methoxymethyl)piperazin-1-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001117] The title compound was prepared analogously to Example 305, step 1, where 2-cyclopropyl- 4-fluoro-1-nitrobenzene and DMF were replaced with 2-ethyl-4-fluoro-1-nitrobenzene and NMP. The title compound was isolated in 24% yield as a brown oil. MS (ESI) m/z: 366.3 [M+H] + Step 2: tert-butyl (R)-4-(3-ethyl-4-nitrophenyl)-3-(methoxymethyl)piperazine-1- carboxylate To a 0 °C solution of tert-butyl (3R)-4-(3-ethyl-4-nitro-phenyl)-3-(hydroxymethyl)piperazine- 1- carboxylate (2.1 mmol) and potassium tert-butoxide (4.2 mmol) in dimethylformamide (10 mL) was added methyl 4-methylbenzenesulfonate (2.6 mmol). After 15 minutes, the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (20% ethyl acetate in hexanes). The title compound was isolated in 77% yield as yellow solid. MS (ESI) m/z: 380.2 [M+H] + Steps 3-5: tert-butyl (R)-4-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)p yrimidin-2- yl)amino)phenyl)-3-(methoxymethyl)piperazine-1-carboxylate [0001118] The title compound was prepared analogously to Example 319, steps 3-5, where tert-butyl (1S,4S)-5-(4-nitro-3-vinylphenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate was replaced with tert- butyl (R)-4-(3-ethyl-4-nitrophenyl)-3-(methoxymethyl)piperazine-1- carboxylate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 660.4 [M+H] + Steps 6-7: (R)-7-(2-((2-ethyl-4-(2-(methoxymethyl)piperazin-1-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001119] The title compound was prepared analogously to Example 319, steps 6-7, where tert-butyl (1S,4S)-5-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstann yl)pyrimidin-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-4-cyclopropyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with tert-butyl (R)-4-(3-ethyl-4-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)p henyl)-3-(methoxymethyl)piperazine-1- carboxylate and 7-iodo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 625.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.79 - 8.61 (m, 1H), 8.09 - 8.03 (m, 1H), 7.74 - 7.44 (m, 1H), 7.12 - 7.03 (m, 1H), 6.90 - 6.83 (m, 2H), 3.99 - 3.94 (m, 1H), 3.94 - 3.85 (m, 2H), 3.81 - 3.72 (m, 3H), 3.41 (br d, J = 14.4 Hz, 6H), 3.36 - 3.34 (m, 3H), 3.27 - 3.20 (m, 4H), 2.66 (q, J = 7.6 Hz, 2H), 1.26 - 1.22 (m, 3H) Example 496: 7-chloro-N-(4-(5-chloro-4-(methylsulfonyl)thiophen-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine [0001120] To a solution of 2-bromo-4-(methylthio)thiophene (12 mmol) in acetic acid (25 mL) was added 1-chloropyrrolidine-2,5-dione (12 mmol). After 12 hours, the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-5% ethyl acetate in hexanes). The title compound was isolated in 52% yield as a white solid. 1 H NMR (400 MHz, CDCl3) δ 6.90 (s, 1H), 2.53 - 2.38 (m, 3H) Step 2: 5-bromo-2-chloro-3-(methylsulfonyl)thiophene [0001121] To a solution of 5-bromo-2-chloro-3-(methylthio)thiophene (0.41 mmol) in dichloromethane (2 mL) was added m-chloroperoxybenzoic acid (1.1 mmol). After 12 hours, the reaction was quenched with sodium sulfite, neutralized with sodium bicarbonate, diluted with water, and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (25% ethyl acetate in hexanes). The title compound was isolated in 62% yield as colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 3.33 (s, 3H) Steps 3-4: 7-chloro-N-(4-(5-chloro-4-(methylsulfonyl)thiophen-2-yl)-5-( trifluoromethyl)pyrimidin- 2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine [0001122] The title compound was prepared analogously to Example 4, steps 2-3, where 2-bromo-6,7- dihydrothieno[3,2-C]pyridin-4(5H)-one was replaced with 5-bromo-2-chloro-3- (methylsulfonyl)thiophene. The title compound was isolated as a pink solid. MS (ESI) m/z: 523.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (br d, J = 1.6 Hz, 1H), 8.83 (s, 1H), 7.81 (s, 1H), 7.42 - 7.17 (m, 2H), 4.08 - 3.74 (m, 2H), 3.32 - 3.29 (m, 3H), 3.01 (br s, 2H), 2.76 - 2.67 (m, 2H). Example 497: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001123] The title compound was prepared analogously to Example 379, where 7-bromo-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-iodo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 621.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.87 - 8.65 (m, 1H), 7.81 - 7.67 (m, 1H), 7.23 - 7.03 (m, 1H), 6.51 - 6.37 (m, 1H), 6.16 - 6.06 (m, 1H), 4.59 - 4.46 (m, 1H), 4.21 - 4.16 (m, 1H), 4.16 (br s, 2H), 4.10 - 3.99 (m, 2H), 3.61 - 3.47 (m, 4H), 3.14 - 3.01 (m, 3H), 2.01 (br d, J = 9.2 Hz, 1H), 1.90 (br s, 1H), 1.83 (br d, J = 10.8 Hz, 1H), 2.04 - 1.77 (m, 1H), 0.81 (br d, J = 7.6 Hz, 2H), 0.61 (br d, J = 2.8 Hz, 2H). Example 498: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e ][1,4]oxathiepine 1,1-dioxide [0001124] 2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine (2.32 mmol) was dissolved in acetonitrile (10 mL) and the resulting solution was cooled down to 0 °C. N-bromosuccinimide (2.79 mmol) was added and the mixture was stirred at 50 °C for 8 hours. The reaction was cooled down to room temperature and the volatiles were removed under reduced pressure to afford a residue that was purified by preparative TLC (95% ethyl acetate in hexanes). The title compound was isolated in 34% yield as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 6.97 (s, 1H), 4.70 (s, 2H), 4.22 - 4.20 (m, 2H), 2.82 - 2.80 (m, 2H) Step 2: 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide [0001125] To a 0 °C solution of 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine (3.2 mmol) in dichloromethane (15 mL) was added meta-chloroperoxybenzoic acid (7.1 mmol) in small portions. The mixture was allowed to reach room temperature and stirring continued for another 18 hours. The reaction was poured into aqueous sodium sulfite and extracted with ethyl acetate twice. The combined organic layers were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by preparative TLC (25 % ethyl acetate in hexanes). The title compound was isolated in 97% yield as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 7.44 (s, 1H), 4.87 (s, 2H), 4.40 (m, 2H), 3.38 (m, 2H) Step 3: tert-butyl (1R,4R)-5-(3-bromo-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate [0001126] Cesium carbonate (119 mmol) was added over a solution of 2-bromo-4-fluoro-1- nitrobenzene (59 mmol) and tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (65 mmol) in 1-methylpyrrolidin-2-one (150 mL). The mixture was stirred at 80 °C for 12 hours. The reaction was diluted with ethyl acetate and water, the organic layer was separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-33% ethyl acetate in hexanes). The title compound was isolated in 97% yield as a yellow solid. MS (ESI) m/z: 398.0 [M+H] + Step 4: tert-butyl (1R,4R)-5-(4-nitro-3-vinylphenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate [0001127] A mixture of tert-butyl (1R,4R)-5-(3-bromo-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]hep tane- 2-carboxylate (38 mmol), tributyl(vinyl)stannane (57 mmol), copper(I) iodide (38 mmol) and tetrakis(triphenylphosphine) palladium(0) (3.8 mmol) in dioxane (150 mL) was stirred at 120°C for 12 hours. The reaction was cooled down to room temperature and quenched by the addition of an aqueous solution of potassium fluoride. The mixture was extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford a residue that was purified by silica gel chromatography (5-33%, ethyl acetate in hexanes). The title compound was isolated in 99% yield as a yellow oil. MS (ESI) m/z: 346.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 6.51 (br d, J = 7.2 Hz, 1H), 6.25 (br s, 2H), 4.40 - 4.13 (m, 4H), 3.53 - 3.42 (m, 1H), 3.36 - 3.26 (m, 2H), 2.81 (br s, 1H), 2.41 (br d, J = 6.8 Hz, 2H), 1.88 - 1.76 (m, 2H), 1.38 - 1.30 (m, 9H), 1.10 (t, J = 7.6 Hz, 3H). Step 5: tert-butyl (1R,4R)-5-(4-amino-3-ethylphenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate [0001128] A mixture of tert-butyl (1R,4R)-5-(4-nitro-3-vinylphenyl)-2,5-diazabicyclo[2.2.1]hep tane-2- carboxylate (28 mmol) and 10% palladium on carbon (1 gram) in methanol (100 mL) was hydrogenated at 50 psi for 12 hours. The reaction was filtered through celite and the volatiles were removed under reduce pressure to afford a residue that was purified by silica gel chromatography (10-30% ethyl acetate in hexanes). The title compound was isolated in 44% yield as a yellow oil. MS (ESI) m/z: 318.1 [M+H] + Step 6: tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-ethylphenyl)- 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0001129] A mixture of tert-butyl (1R,4R)-5-(4-amino-3-ethylphenyl)-2,5-diazabicyclo[2.2.1]hep tane- 2-carboxylate (12 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (60 mmol) was stirred at 70 °C for 2 hours under nitrogen atmosphere. The mixture was cooled down to room temperature and diluted with water and ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-15% ethyl acetate in hexanes). A second purification by preparative HPLC afford the title compound in 34% yield as a yellow oil. MS (ESI) m/z: 498.2 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ,9.81 (s, 1H), 8.69 - 8.52 (m, 1H), 7.01 (br d, J = 8.4 Hz, 1H), 6.48 - 6.44 (m, 2H), 4.52 - 4.38 (m, 2H), 3.61 - 3.47 (m, 1H), 3.38 - 3.16 (m, 4H), 2.98 (br s, 1H), 1.92 (br s, 2H), 1.37 (br d, J = 17.6 Hz, 9H), 1.07 (br t, J = 7.6 Hz, 3H). Step 7: tert-butyl (1R,4R)-5-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstann yl)pyrimidin-2- yl)amino)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylat e [0001130] To a solution of tert-butyl (1R,4R)-5-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-ethylphenyl)-2,5-diazabicyclo[2.2.1]heptane-2-ca rboxylate (0.50 mmol) in dioxane (5 mL) was added hexamethylditin (1.5 mmol), palladium acetate (0.10 mmol) and 4- diphenylphosphanylbutyl(diphenyl)phosphane (0.10 mmol) and the resulting mixture was stirred at 95 °C for 12 hours. The reaction mixture was cooled down to room temperature, diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by aluminum oxide chromatography (1-13% ethyl acetate in hexanes). The title compound was isolated in 61% yield as yellow solid. MS (ESI) m/z: 628.2 [M+H] + Step 8: tert-butyl (1R,4R)-5-(4-((4-(1,1-dioxido-2,3-dihydro-5H-thieno[3,2-e][1 ,4]oxathiepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)-2,5-di azabicyclo[2.2.1]heptane-2- [0001131] A mixture of 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide (0.24 mmol), tert-butyl (1R,4R)-5-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstann yl)pyrimidin-2- yl)amino)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylat e (0.24 mmol), tetrakis(triphenylphosphine) palladium(0) (0.02mmol) and copper (I) iodide (0.24 mmol) in dioxane (2 mL), was stirred at 120 °C for 12 hours. The reaction mixture was cooled down to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (50% ethyl acetate in hexanes). The title compound was isolated in 81% yield as yellow solid. MS (ESI) m/z: 666.2 [M+H] + [0001132] Step 9: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e ][1,4]oxathiepine 1,1-dioxide A 0 °C solution of tert-butyl (1R,4R)-5-(4-((4-(1,1-dioxido-2,3-dihydro-5H-thieno[3,2-e][1 ,4]oxathiepin- 7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl )-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (0.20 mmol) in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (12 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure to afford a residue that was purified by preparative TLC (15% methanol in dichloromethane). The title compound was isolated in 91% yield as an orange solid. MS (ESI) m/z: 566.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ , 8.61 (s, 1H), 8.09 (s, 1H), 7.54 - 7.28 (m, 1H), 6.97 - 6.89 (m, 1H), 6.51 - 6.43 (m, 2H), 4.97 (s, 2H), 4.48 (s, 1H), 4.42-4.43 (m, 2H), 4.34 - 4.30 (m, 1H), 3.71 - 3.65 (m, 1H), 3.53 - 3.46 (m, 1H), 3.42 - 3.32 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 2.18 - 2.09 (m, 2H), 1.29 - 1.23 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H) Example 499: 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e ][1,4]oxathiepine 1,1-dioxide [0001133] The title compound was prepared analogously to Example 498, where tert-butyl (1R,4R)-5- (3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrimid in-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (1R,4R)-5-(3-cyclopropyl-4-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)p henyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 578.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ = 8.65 - 8.57 (m, 1H), 8.02 - 7.98 (m, 1H), 7.41 - 7.25 (m, 1H), 6.59 - 6.55 (m, 1H), 6.33 - 6.31 (m, 1H), 4.96 - 4.95 (m, 2H), 4.62 (s, 1H), 4.39 - 4.37 (m, 2H), 4.33 (s, 1H), 3.72 (dd, J = 2.4, 10.4 Hz, 1H), 3.52 - 3.51 (m, 2H), 3.29 - 3.28 (m, 2H), 3.27 - 3.20 (m, 1H), 2.24 (d, J = 10.8 Hz, 1H), 1.99 (d, J = 10.4 Hz, 1H), 1.97 - 1.91 (m, 1H), 1.38 - 1.25 (m, 1H), 0.94 - 0.85 (m, 3H), 0.72 - 0.57 (m, 2H) Example 500: 2-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydro-5H-thieno[2,3-b ][1,4]oxathiepine 4,4-dioxide [0001134] The title compound was prepared analogously to Example 496, step 2, where 5-bromo-2- chloro-3-(methylthio)thiophene was replaced with 2-bromo-6,7-dihydro-5H-thieno[2,3- b][1,4]oxathiepine. The title compound was isolated as a white solid. MS (ESI) m/z: 282.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.19 (s, 1H), 4.43 - 4.36 (m, 2H), 3.62 - 3.54 (m, 2H), 2.35 - 2.24 (m, 2H). Step 2: 2-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydro-5H-thieno[2,3-b ][1,4]oxathiepine 4,4-dioxide [0001135] The title compound was prepared analogously to Example 499, where tert-butyl (1R,4R)-5- (3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)p yrimidin-2-yl)amino)phenyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate and 7-bromo-2,3-dihydro-5H-thieno[3,2-e][1,4]oxathiepine 1,1-dioxide were replaced with tert-butyl (1R,4R)-5-(3-ethyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2,5-diazabicy clo[2.2.1]heptane-2-carboxylate and 2- bromo-6,7-dihydro-5H-thieno[2,3-b][1,4]oxathiepine 4,4-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 578.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.70 - 8.39 (m, 1H), 7.76 (s, 1H), 7.46 - 7.16 (m, 1H), 6.56 (dd, J =8.4, 1.6 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 4.59 (s, 1H), 4.48 (d, J = 4.2 Hz, 2H), 4.26 (s, 1H), 3.71 (dd, J =10.4, 2.4 Hz, 1H), 3.54 - 3.49 (m, 2H), 3.28 - 3.21 (m, 3H), 2.49 - 2.42 (m, 2H), 2.21 (d, J = 10.4 Hz, 1H), 2.01 - 1.92 (m, 2H), 0.91 - 0.85 (m, 2H), 0.69 - 0.61 (m, 2H). Example 501: 7-(2-((2-ethyl-4-((4aS,7aR)-hexahydrofuro[3,4-b]pyrazin-1(2H )-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide (example 501a) and 7-(2-((2-ethyl-4-((4aR,7aS)-hexahydrofuro[3,4-b]pyrazin-1(2H )- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (example 501b) [0001136] The title compounds were prepared analogously to Example 306, where 7-(2-((4-((1S,4S)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amin o)-5-(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with a 1:1 racemic mixture of 7-(2-((2-ethyl-4-((4aS,7aR)-4-(2,2,2-trifluoroacetyl)hexahyd rofuro[3,4-b]pyrazin- 1(2H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 7-(2-((2-ethyl-4-((4aR,7aS)-4-(2,2,2- trifluoroacetyl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)phenyl) amino)-5-(trifluoromethyl)pyrimidin-4-yl)- 4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The racemate was purified by chiral SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um); mobile phase: [CO2-MeOH (0.1%NH3H2O)]; B%: 45%, isocratic elution mode) to afford the title compounds as individual enantiomers as orange solids. [0001137] Example 501a: MS (ESI) m/z: 623.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.05 (s, 1H), 7.53 - 7.38 (m, 1H), 7.07 - 7.06 (m, 1H), 6.87 – 6.72 (m, 2H), 4.44 - 4.39 (m, 1H), 4.05 - 3.98 (m, 2H), 3.98 – 3.83 (m, 2H), 3.83 - 3.73 (m, 4H), 3.52 (t, J = 4.0 Hz, 1H), 3.42 - 3.39 (m, 1H), 3.24 (s, 3H), 3.22 – 3.16 (m, 1H), 3.08 - 2.96 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). [0001138] Example 501b: MS (ESI) m/z: 623.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.05 (s, 1H), 7.53 - 7.46 (m, 1H), 7.08 - 7.01 (m, 1H), 6.87 – 6.75 (m, 2H), 4.44 - 4.39 (m, 1H), 4.03 - 3.98 (m, 2H), 3.98 – 3.85 (m, 2H), 3.84 - 3.73 (m, 4H), 3.53 (t, J = 4.0 Hz, 1H), 3.42 - 3.39 (m, 1H), 3.24 (s, 3H), 3.22 – 3.16 (m, 1H), 3.09 - 2.96 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). Example 502: (R)-7-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-2,3-dihydro-5H-thieno[3,2-e ][1,4]oxathiepine 1,1-dioxide [0001139] The title compound was prepared analogously to Example 308, where 2-ethyl-4-fluoro-1- nitrobenzene was replaced with 2-cyclopropyl-4-fluoro-1-nitrobenzene and 7-bromo-4-cyclopropyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-bromo-2,3-dihydro-5H- thieno[3,2-e][1,4]oxathiepine 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 580.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.63 (s, 1H), 7.99 (s, 1H), 7.45 - 7.41 (m, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 4.96 (s, 2H), 4.38 - 4.36 (m, 2H), 3.61 - 3.50 (m, 4H), 3.20 - 3.16 (m, 1H), 3.10 - 3.01 (m, 2H), 2.79 - 2.72 (m, 1H), 2.44 (t, J = 11.2 Hz, 1H), 1.97 - 1.92 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 0.92 - 0.88 (m, 2H), 0.66 - 0.64 (m, 2H). Example 503: 2-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydro-5H-thieno[2,3-b ][1,4]oxathiepine 4,4-dioxide [0001140] The title compound was prepared analogously to Example 410, where 7'-bromo-2'H- spiro[cyclopropane-1,3'-thieno[2,3-f][1,4]thiazepin]-5'(4'H) -one 1',1'-dioxide was replaced with 2- bromo-6,7-dihydro-5H-thieno[2,3-b][1,4]oxathiepine 4,4-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 578.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.70 - 8.39 (m, 1H), 7.76 (s, 1H), 7.46 - 7.16 (m, 1H), 6.56 (dd, J =8.4, 1.6 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 4.59 (s, 1H), 4.48 (d, J = 4.2 Hz, 2H), 4.26 (s, 1H), 3.71 (dd, J =10.4, 2.4 Hz, 1H), 3.54 - 3.49 (m, 2H), 3.28 - 3.21 (m, 3H), 2.49 - 2.42 (m, 2H), 2.21 (d, J = 10.4 Hz, 1H), 2.01 - 1.92 (m, 2H), 0.91 - 0.85 (m, 2H), 0.69 - 0.61 (m, 2H). Example 504: 7-(2-((2-ethyl-4-((1R,4R)-5-(2-methoxyethyl)-2,5-diazabicycl o[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001141] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 2-methoxyacetaldehyde. The title compound was isolated in 30% yield as a pale yellow solid. MS (ESI) m/z: 651.2 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.65 (s, 1H), 8.04 (br s, 1H), 7.50 - 7.27 (m, 1H), 7.06 - 6.90 (m, 1H), 6.52 - 6.41 (m, 2H), 4.26 (br s, 1H), 3.98 - 3.82 (m, 2H), 3.80 - 3.65 (m, 3H), 3.53 - 3.38 (m, 4H), 3.36 (s, 3H), 3.24 (br s, 3H), 3.19 - 3.11 (m, 1H), 2.80 (br s, 2H), 2.75 - 2.66 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.07 (br d, J = 6.4 Hz, 1H), 2.00 - 1.90 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H). Example 505: 7-chloro-N-(4-(4-(methylsulfonyl)-5-(trifluoromethyl)thiophe n-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine [0001142] To a solution of 3-(methylthio)thiophene (23 mmol) in acetic acid (30 mL) was added N- iodosuccinimide (23 mmol). After 12 hours, the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-5% ethyl acetate in hexanes). The title compound was isolated in 98% yield as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (d, J = 5.6 Hz, 1H), 6.93 (d, J = 5.6 Hz, 1H), 2.50 (s, 3H). Step 2: 3-(Methylthio)-2-(trifluoromethyl)thiophene [0001143] To a solution of 2-iodo-3-(methylthio)thiophene (7.8 mmol), tetrabutylammonium iodide (3.4 mmol) and copper(I) iodide (10 mmol) in HMPA (10 mL) was added methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (72 mmol) and the mixture was stirred at 90 °C for one hour. The mixture was cooled down to room temperature diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-10% ethyl acetate in hexanes). The title compound was isolated in 26% yield as a brown oil. Step 3: 5-iodo-3-(methylthio)-2-(trifluoromethyl)thiophene [0001144] To a -70 °C solution of 3-(methylthio)-2-(trifluoromethyl)thiophene (1.72 mmol) in tetrahydrofuran (5 mL) was added iodine (3.43 mmol). After 30 minutes, lithium diisopropylamide (2 M in THF, 1.3 mL) was added and the reaction was stirred at 25 °C for one hour. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by semi-preparative reverse phase HPLC (64-94% acetonitrile+0.2% formic acid in water). The title compound was isolated in 52% yield as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 2.58 (s, 3H). Step 4: 5-iodo-3-(methylsulfonyl)-2-(trifluoromethyl)thiophene [0001145] The title compound was prepared analogously to Example 162, step 6, where 7-bromo-2,3- dihydro-5H-thieno[3,2-e][1,4]oxathiepine was replaced with 5-iodo-3-(methylthio)-2- (trifluoromethyl)thiophene. The title compound was isolated as a colorless oil in 57% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.98 - 7.80 (m, 1H), 3.36 (s, 3H) Steps 5-6: 7-chloro-N-(4-(4-(methylsulfonyl)-5-(trifluoromethyl)thiophe n-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine [0001146] The title compound was prepared analogously to Example 125, steps 5-6, where 7-bromo- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 5-iodo-3- (methylsulfonyl)-2-(trifluoromethyl)thiophene. The title compound was isolated as a yellow solid. MS (ESI) m/z: 557.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.31 - 9.99 (m, 1H), 8.91 (br s, 1H), 7.99 (s, 1H), 7.42 (br s, 1H), 7.37 (s, 1H), 4.08 (s, 2H), 3.38 (s, 3H), 3.18 (br t, J = 5.6 Hz, 2H), 2.83 (br t, J = 5.6 Hz, 2H) Example 506: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-(2-hydroxyethyl)-2,5-diaza bicyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-(oxeta n-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide

[0001147] The title compound was prepared analogously to Example 443, where 1-bromo-2- methoxyethane was replaced with 2-bromoethanol. The title compound was isolated as an orange solid in 36% yield. MS (ESI) m/z: 691.4[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.76 - 8.55 (m, 1H), 8.01 (s, 1H), 7.34 - 7.22 (m, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.36 - 5.29 (m, 1H), 4.92 - 4.88 (m, 4H), 4.49 (s, 1H), 4.15 - 4.10 (m, 1H), 4.09 - 4.00 (m, 2H), 3.94 - 3.85 (m, 2H), 3.76 - 3.72 (m, 2H), 3.61 - 3.58 (m, 1H), 3.45 (d, J = 10.4 Hz, 1H), 3.27 - 3.24 (m, 1H), 3.20 - 3.10 (m, 1H), 3.05 - 2.95 (m, 2H), 2.19 - 2.12 (m, 2H), 1.97 - 1.93 (m, 1H), 0.89 (dd, J = 8.4, 1.6 Hz, 2H), 0.70 - 0.64 (m, 2H). Example 507: (S)-7-(2-((2-ethyl-4-(4-(2-hydroxyethyl)-2-methylpiperazin-1 -yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001148] To a solution of 2-ethyl-4-fluoro-1-nitro-benzene (14.8 mmol) and tert-butyl (3S)-3- methylpiperazine-1-carboxylate (14.8 mmol) in dimethylsulfoxide (40 mL) was added potassium carbonate (30 mmol). The mixture was stirred at 120 °C for 12 hours, cooled down to room temperature, diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-10% ethyl acetate in hexanes). The title compound was isolated in 17% yield as yellow solid. MS (ESI) m/z: 350.3[M+H] + Step 2-3: tert-butyl (S)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino) -3-ethylphenyl)-3- methylpiperazine-1-carboxylate [0001149] The title compound was prepared analogously to Example 385, steps 2-3, where tert-butyl (1R,4R)-5-(6-cyclopropyl-5-nitro-2-pyridyl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate was replaced with tert-butyl (3S)-4-(3-ethyl-4-nitro-phenyl)-3-methyl-piperazine-1-carbox ylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 500.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H), 8.65 - 8.57 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.79 - 6.74 (m, 2H), 3.99 - 3.84 (m, 2H), 3.71 (d, J = 12.4 Hz, 1H), 3.30 – 3.17 (m, 2H), 3.04 (s, 2H), 2.50 - 2.45 (m, 2H), 1.42 (s, 9H), 1.07 (t, J = 7.4 Hz, 3H), 0.91 (d, J = 6.0 Hz, 3H) Step 4: tert-butyl (S)-4-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)p yrimidin-2- yl)amino)phenyl)-3-methylpiperazine-1-carboxylate [0001150] The title compound was prepared analogously to Example 385, step 6, where 1-[(1R,4R)-5- [5-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-cyc lopropyl-2-pyridyl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]-2,2,2-trifluoro-ethanone was replaced with tert-butyl (S)-4-(4-((4-chloro- 5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)-3-me thylpiperazine-1-carboxylate. The title compound was isolated as a green solid in 54% yield. MS (ESI) m/z: 629.9 [M+H] + Step 5: tert-butyl (S)-4-(3-ethyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5-tet rahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-3-methylpiperazine-1- carboxylate [0001151] The title compound was prepared analogously to Example 385, step 7, where 1-[(1R,4R)-5- [6-cyclopropyl-5-[[5-(trifluoromethyl)-4-trimethylstannyl-py rimidin-2-yl]amino]-2-pyridyl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]-2,2,2-trifluoro-ethanone (0.20 mmol) and 7-iodo-4-(oxetan-3-yl)-1,1- dioxo-2,3-dihydrothieno[2,3-f][1,4]thiazepin-5-one were replaced with tert-butyl (S)-4-(3-ethyl-4-((5- (trifluoromethyl)-4-(trimethylstannyl)pyrimidin-2-yl)amino)p henyl)-3-methylpiperazine-1-carboxylate and 7-iodo-4-methyl-1,1-dioxo-2,3-dihydrothieno[2,3-f][1,4]thiaz epin-5-one. The title compound was isolated as an orange solid. MS (ESI) m/z: 695.3 [M+H] + Step 6: (S)-7-(2-((2-ethyl-4-(2-methylpiperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin-4- yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-on e 1,1-dioxide [0001152] The title compound was prepared analogously to Example 64, step 2, where methyl 3-((2- ((tert-butoxycarbonyl)amino)ethyl)sulfonyl)thiophene-2-carbo xylate was replaced with tert-butyl (S)-4- (3-ethyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5-tetrahydr othieno[2,3-f][1,4]thiazepin-7-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-3-methylpipera zine-1-carboxylate. The title compound was isolated as an orange solid. MS (ESI) m/z: 595.3 [M+H] + Step 7: (S)-7-(2-((2-ethyl-4-(4-(2-hydroxyethyl)-2-methylpiperazin-1 -yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001153] The title compound was prepared analogously to Example 443, where 1-bromo-2- methoxyethane was replaced with 2-bromoethanol. The title compound was isolated as an orange solid in 38% yield. MS (ESI) m/z: 639.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.72 - 8.60 (m, 1H), 7.97 (s, 1H), 7.33 - 7.24 (m, 1H), 7.00 – 6.94 (m, 2H), 3.97 - 3.87 (m, 2H), 3.89 – 3.83 (m, 2H), 3.82 – 3.67 (m, 3H), 3.25 – 3.20 (m, 2H), 3.17 (s, 3H), 3.04 - 2.69 (m, 6H), 2.63 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H), 1.06 (d, J = 6.4 Hz, 3H), Example 508: (S)-7-(2-((2-ethyl-4-(4-(2-methoxyethyl)-2-methylpiperazin-1 -yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001154] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with (S)-7-(2-((2-ethyl-4-(2-methylpiperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide and 2- methoxyacetaldehyde. The title compound was isolated in 89% yield as a pale yellow solid. MS (ESI) m/z: 653.3 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (s, 1H), 8.05 (s, 1H), 7.64 - 7.43 (m, 1H), 7.04 (br. S., 1H), 6.94 - 6.79 (m, 2H), 3.93 - 3.87 (m, 2H), 3.85 - 3.78 (m, 1H), 3.75 - 3.71 (m, 2H), 3.63 - 3.50 (m, 2H), 3.40 (s, 3H), 3.33 - 3.25 (m, 1H), 3.24 (s, 3H), 3.20 - 3.11 (m, 1H), 2.88 - 2.76 (m, 1H), 2.73 - 2.54 (m, 6H), 2.52 - 2.40 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 1.18 - 1.02 (m, 3H). Example 509: (S)-7-(2-((2-ethyl-4-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl )phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001155] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with (S)-7-(2-((2-ethyl-4-(2-methylpiperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide and oxetan-3-one. The title compound was isolated in 74% yield as an orange solid. MS (ESI) m/z: 651.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.05 (s, 1H), 7.62 - 7.43 (m, 1H), 7.05 (s, 1H), 6.91 - 6.80 (m, 2H), 4.74 - 4.61 (m, 4H), 3.93 - 3.84 (m, 3H), 3.75 - 3.70 (m, 2H), 3.58 - 3.46 (m, 1H), 3.31 - 3.23 (m, 4H), 3.22 - 3.14 (m, 1H), 2.72 - 2.60 (m, 3H), 2.51 - 2.39 (m, 2H), 2.34 - 2.20 (m, 1H), 1.24 (t, J = 7.6 Hz, 3H), 1.15 (d, J = 5.6 Hz, 3H). Example 510: 7-(2-((2-ethyl-4-((1R,4R)-5-(2-methoxyethyl)-2,5-diazabicycl o[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001156] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-ethy lphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1- dioxide and 2-methoxyacetaldehyde. The title compound was isolated in 53% yield as a pale yellow solid. MS (ESI) m/z: 667.3 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 8.56 (s, 1H), 7.89 (br s, 1H), 7.40 - 7.20 (m, 1H), 7.03 - 6.82 (m, 1H), 6.38 (s, 2H), 4.67 - 4.40 (m, 2H), 4.21 (br s, 1H), 4.03 (br s, 2H), 3.73 (br s, 2H), 3.55 (br s, 3H), 3.46 - 3.34 (m, 4H), 3.29 (s, 3H), 3.18 - 3.12 (m, 1H), 2.90 - 2.72 (m, 4H), 2.55 - 2.50 (m, 2H), 1.17 - 1.12 (m, 3H) Example 511: 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4- methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001157] The title compound was prepared analogously to Example 174, where tert-butyl 4-(4-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylpheny l)piperazine-1-carboxylate and 4-methyl- 7-(trimethylstannyl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide were replaced with tert-butyl 4-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstannyl)pyrim idin-2- yl)amino)phenyl)piperazine-1-carboxylate and 7-iodo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepine- 5(2H)-thione 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 597.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.65 (s, 1 H) 7.98 (s, 1 H) 7.39 - 7.66 (m, 1 H) 7.01 (br d, J = 3.6 Hz, 1 H) 6.81 - 6.91 (m, 2 H) 4.11 (br s, 2 H) 3.81 (br t, J = 5.6 Hz, 2 H) 3.63 (s, 3 H) 3.15 - 3.24 (m, 4 H) 3.02 - 3.12 (m, 4 H) 2.64 (q, J = 7.6 Hz, 2 H) 1.24 (t, J = 7.6 Hz, 3 H) Example 512: 7-(2-((2-ethyl-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001158] compound was prepared analogously to example 494, where 7-bromo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-iodo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 655.2 [M+H] +. 1 H NMR (400 MHz, CDCl 3 -d) δ ,8.65 (s, 1H), 7.98 (s, 1H), 7.57 - 7.30 (m, 1H), 7.00 (br d, J = 2.4 Hz, 1H), 6.89 - 6.82 (m, 2H), 4.11 (br s, 2H), 3.81 (br t, J = 5.2 Hz, 2H), 3.63 (s, 3H), 3.58 (t, J = 5.2 Hz, 2H), 3.39 (s, 3H), 3.30 - 3.22 (m, 4H), 2.72 - 2.58 (m, 8H), 1.23 (t, J = 7.6 Hz, 3H) Example 513: 7-(2-((2-cyclopropyl-4-((1R,4R)-5-(2-methoxyethyl)-2,5-diaza bicyclo[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepine-5(2H)-thione 1,1-dioxide

[0001159] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with 7-(2-((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1- dioxide and 2-methoxyacetaldehyde. The title compound was isolated in 47% yield as a pale yellow solid. MS (ESI) m/z: 679.2[M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 8.66 (s, 1H), 7.98 (s, 1H), 7.88 - 7.62 (m, 1H), 7.61 - 7.45 (m, 1H), 6.57 - 6.41 (m, 1H), 6.37 - 6.24 (m, 1H), 4.21 (br s, 1H), 4.11 (br s, 2H), 3.82 (br d, J = 5.6 Hz, 2H), 3.67 (br d, J = 2.8 Hz, 1H), 3.64 (s, 3H), 3.48 - 3.36 (m, 4H), 3.35 (s, 3H), 3.21 - 3.05 (m, 1H), 2.88 - 2.56 (m, 3H), 2.13 - 1.99 (m, 1H), 1.97 - 1.83 (m, 2H), 1.05 - 0.95 (m, 2H), 0.75 - 0.64 (m, 2H) Example 514: 7-cyclopropyl-N-(4-(5-methyl-4-(methylsulfonyl)thiophen-2-yl )-5- (trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinol in-6-amine [0001160] The title compound was prepared analogously to Example 132, where trimethyl(4- (methylsulfonyl)thiophen-2-yl)stannane was replaced with trimethyl(5-methyl-4- (methylsulfonyl)thiophen-2-yl)stannane. The title compound was isolated as an orange solid. MS (ESI) m/z: 509.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 0.54 (m, 2H), 0.79 (m, 2H), 1.92 (m, 1H), 2.64 (t, J = 5.8 Hz, 2H), 2.72 (s, 3H), 2.93 (t, J = 5.8 Hz, 2H), 3.25 (s, 3H), 3.79 (s, 2H), 6.65 (s, 1H), 7.13 (brs, 1H), 7.80 (s, 1H), 8.64 (s, 1H), 9.79 (s, 1H). Example 515: (R)-2-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydro-5H-thieno[2,3-b ][1,4]oxathiepine 4,4-dioxide Steps 1-3: (9H-fluoren-9-yl)methyl (R)-4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4- (trimethylstannyl)pyrimidin-2-yl)amino)phenyl)-2-methylpiper azine-1-carboxylate [0001161] The title compound was prepared analogously to Example 368, steps 1-3, where tert-butyl (2S,6R)-4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)am ino)-3-ethylphenyl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (R)-4-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-cyclopropylphenyl)- 2-methylpiperazine-1-carboxylate Steps 4-5: (R)-2-(2-((2-cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-6,7-dihydro-5H-thieno[2,3-b ][1,4]oxathiepine 4,4-dioxide [0001162] The title compound was prepared analogously to Example 368, steps 4-5, where (9H- Fluoren-9-yl)methyl (2S,6R)-4-(3-ethyl-4-((5-(trifluoromethyl)-4-(trimethylstann yl)pyrimidin-2- yl)amino)phenyl)-2,6-dimethylpiperazine-1-carboxylate and 7-iodo-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide were replaced with (9H-fluoren-9-yl)methyl (R)-4-(3-cyclopropyl-4-((5-(trifluoromethyl)-4-(trimethylsta nnyl)pyrimidin-2-yl)amino)phenyl)-2- methylpiperazine-1-carboxylate and 2-bromo-6,7-dihydro-5H-thieno[2,3-b][1,4]oxathiepine 4,4-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 580.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.61 - 8.53 (m, 1H), 7.76 (s, 1H), 7.44 - 7.31 (m, 1H), 6.87 (dd, J = 8.8, 2.8 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 4.56 - 4.44 (m, 2H), 3.58 - 3.49 (m, 4H), 3.13 - 3.06 (m, 1H), 3.02 - 2.92 (m, 2H), 2.73 - 2.64 (m, 1H), 2.50 - 2.42 (m, 2H), 2.40 - 2.31 (m, 1H), 1.98 - 1.89 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H), 0.92 - 0.86 (m, 2H), 0.67 - 0.61 (m, 2H). Example 516: (R)-7-(2-((2-ethyl-4-(2-(hydroxymethyl)piperazin-1-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide Step 1-4: tert-butyl (R)-3-(acetoxymethyl)-4-(4-((4-chloro-5-(trifluoromethyl)pyr imidin-2- yl)amino)-3-ethylphenyl)piperazine-1-carboxylate [0001163] The title compound was prepared analogously to Example 345, steps 1-4, where tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate was replaced with tert-butyl (R)-3- (hydroxymethyl)piperazine-1-carboxylate in step 1. The title compound was isolated as a orange semisolid. MS (ESI).m/z: 558.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 8.67 - 8.55 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.78 - 6.75 (m, 2H), 4.24 – 4.05 (m, 2H), 4.05 -3.96 (m, 2H), 3.41 - 3.36 (m, 2H), 3.28 – 3.15 (m, 1H), 3.15 – 2.96 (m, 2H), 2.50 - 2.49 (m, 2H), 1.84 (s, 3H), 1.41 (s, 9H), 1.07 (t, J = 7.6 Hz, 3H). Step 5: (R)-(1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino )-3-ethylphenyl)piperazin-2- yl)methyl acetate [0001164] The title compound was prepared analogously to Example 385, step 4, where tert-butyl (1R,4R)-5-[5-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]am ino]-6-cyclopropyl-2-pyridyl]-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate was replaced with tert-butyl (R)-3-(acetoxymethyl)-4-(4-((4- chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylpheny l)piperazine-1-carboxylate. The title compound was isolated as a brown oil. MS (ESI) m/z: 458.2 [M+H] + Step 6: (R)-(1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino )-3-ethylphenyl)-4-(2,2,2- trifluoroacetyl)piperazin-2-yl)methyl acetate [0001165] The title compound was prepared analogously to Example 9, step 2, where 7-ethyl-6-nitro- 1,2,3,4-tetrahydroisoquinoline was replaced with (R)-(1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-ethylphenyl)piperazin-2-yl)methyl acetate. The title compound was isolated as a yellow oil. MS (ESI) m/z: 554.2 [M+H] + Step 7-8: (R)-(1-(3-ethyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5-te trahydrothieno[2,3- f][1,4]thiazepin-7-yl)-5-(trifluoromethyl)pyrimidin-2-yl)ami no)phenyl)-4-(2,2,2- trifluoroacetyl)piperazin-2-yl)methyl acetate [0001166] The title compound was prepared analogously to Example 385, steps 6-7, where 1-[(1R,4R)- 5-[5-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-6-c yclopropyl-2-pyridyl]-2,5- diazabicyclo[2.2.1]heptan-2-yl]-2,2,2-trifluoro-ethanone was replaced with (R)-(1-(4-((4-chloro-5- (trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)-4-(2,2 ,2-trifluoroacetyl)piperazin-2-yl)methyl acetate and 7-iodo-4-(oxetan-3-yl)-1,1-dioxo-2,3-dihydrothieno[2,3-f][1, 4]thiazepin-5-one was replaced with 7-iodo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H) -one 1,1-dioxide. The title compound was isolated as a yellow solid. MS (ESI) m/z: 749.3 [M+H] + Step 9: (R)-7-(2-((2-ethyl-4-(2-(hydroxymethyl)piperazin-1-yl)phenyl )amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001167] A solution of (R)-(1-(3-ethyl-4-((4-(4-methyl-1,1-dioxido-5-oxo-2,3,4,5- tetrahydrothieno[2,3-f][1,4]thiazepin-7-yl)-5-(trifluorometh yl)pyrimidin-2-yl)amino)phenyl)-4-(2,2,2- trifluoroacetyl)piperazin-2-yl)methyl acetate (0.073 mmol) in dioxane (3 mL) was added a 12M aqueous solution of hydrochloric acid (0.3 mL). The reaction mixture was stirred at 80 °C for 1 hour, cooled to room temperature and neutralized with saturated sodium bicarbonate. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue that was purified by HPLC. The title compound was isolated as an orange solid in 31% yield. MS (ESI) m/z: 611.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.02 (s, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.02 (s, 1H), 6.93 – 6.79 (m, 2H), 4.03 - 3.93 (m, 1H), 3.94 – 3.82 (m, 3H), 3.81 - 3.75 (m, 1H), 3.73 - 3.68 (m, 2H), 3.52 - 3.24 (m, 5H), 3.20 (s, 3H), 3.11 - 3.01 (m, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H) Example 517: (S)-7-(2-((2-ethyl-4-(2-methylpiperazin-1-yl)phenyl)amino)-5 - (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001168] The title compound was prepared analogously to Example 489, where 7-bromo-4-methyl- 3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-iodo-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 611.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.98 (s, 1H), 7.55 - 7.51 (m, 1H), 7.03 (s, 1H), 6.92 – 6.80 (m, 2H), 4.18 – 4.07 (m, 2H), 3.83 - 3.77 (m, 3H), 3.63 (s, 3H), 3.22 - 3.09 (m, 4H), 3.04 - 3.02 (m, 1H), 2.91 (dd, J = 12.0, 4.0 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H). Example 518: (S)-7-(2-((2-ethyl-4-(4-(2-methoxyethyl)-2-methylpiperazin-1 -yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001169] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with (S)-7-(2-((2-ethyl-4-(2-methylpiperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepine-5(2H) -thione 1,1-dioxide and 2- methoxyacetaldehyde. The title compound was isolated in 56% yield as an orange solid. MS (ESI) m/z: 669.2 [M+H] + . 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.70 - 8.60 (m, 1H), 7.92 - 7.90 (m, 1H), 7.30 - 7.26 (m, 1H), 7.00 - 6.93 (m, 2H), 4.19 - 4.11 (m, 2H), 3.96 - 3.87 (m, 2H), 3.72 - 3.63 (m, 1H), 3.61 - 3.59 (m, 2H), 3.56 (s, 3H), 3.37 (s, 3H), 3.19 - 3.11 (m, 2H), 2.77 - 2.54 (m, 8H), 1.18 (t, J = 7.6 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H) Example 519: 7-(2-((2-ethyl-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am ino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001170] The title compound was prepared analogously to Example 463, where 7-(2-((2-ethyl-4- (piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2-ethyl-4-(piperazin-1- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3-f][1,4]thiazepine- 5(2H)-thione 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 641.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 8.66 (s, 1 H) 7.98 (s, 1 H) 7.41 - 7.63 (m, 1 H) 6.98 - 7.04 (m, 1 H) 6.86 (br d, J = 2.0 Hz, 2 H) 4.11 (br d, J = 4.8 Hz, 2 H) 3.77 - 3.87 (m, 4 H) 3.64 (s, 3 H) 3.36 - 3.47 (m, 4 H) 2.80 - 3.02 (m, 6 H) 2.61 - 2.68 (m, 2 H) 1.24 (br t, J = 7.6 Hz, 3 H) Example 520: 7-(2-((2-ethyl-4-((4aS,7aR)-4-(2-hydroxyethyl)hexahydrofuro[ 3,4-b]pyrazin-1(2H)- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (example 520a) and 7-(2-((2-ethyl-4-((4aR,7aS)-4-(2- hydroxyethyl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)phenyl)ami no)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide (example 520b) [0001171] The title compounds were prepared as a racemic mixture analogously to example 463, where 7-(2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluorom ethyl)pyrimidin-4-yl)-4-(oxetan-3-yl)-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((2-ethyl-4- (hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)phenyl)amino)-5-(trifl uoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compounds were isolated as single enantiomers after resolution of the racemic mixture by SFC (column: DAICEL CHIRALPAK AS (250mm*30mm,10um), 55% ethanol (0.1%ammonium hydroxide)] in CO2. [0001172] First eluting enantiomer (absolute stereochemistry undetermined): MS (ESI) m/z: 667.2 [M+H] + 1 H NMR (400 MHz, CD3OD) δ 8.79 - 8.50 (m, 1H), 7.97 (s, 1H), 7.33 - 7.17 (m, 1H), 6.97 - 6.85 (m, 2H), 4.74 - 4.62 (m, 1H), 4.22 - 4.13 (m, 1H), 4.03 - 3.88 (m, 4H), 3.87 - 3.74 (m, 5H), 3.58 - 3.38 (m, 3H), 3.29 - 3.23 (m, 1H), 3.21 - 3.06 (m, 4H), 2.91 - 2.71 (m, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). [0001173] Second eluting enantiomer (absolute stereochemistry undetermined): MS (ESI) m/z: 667.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.78 - 8.49 (m, 1H), 7.96 (s, 1H), 7.33 - 7.17 (m, 1H), 6.96 - 6.86 (m, 2H), 4.76 - 4.62 (m, 1H), 4.26 - 4.15 (m, 1H), 4.05 - 3.89 (m, 4H), 3.87 - 3.74 (m, 5H), 3.61 - 3.43 (m, 3H), 3.29 - 3.25 (m, 1H), 3.22 - 3.11 (m, 4H), 3.02 - 2.80 (m, 2H), 2.63 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). Example 521: 7-(2-((2-ethyl-4-((4aS,7aR)-4-(2-methoxyethyl)hexahydrofuro[ 3,4-b]pyrazin-1(2H)- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide (example 521a) and 7-(2-((2-ethyl-4-((4aR,7aS)-4-(2- methoxyethyl)hexahydrofuro[3,4-b]pyrazin-1(2H)-yl)phenyl)ami no)-5-(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)- one 1,1-dioxide (example 521b) [0001174] The title compounds were prepared as a racemic mixture analogously to example 306, where 7-(2-((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-cycl opropylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-cyclopropyl-3,4-dihydroth ieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide and paraformaldehyde were replaced with 7-(2-((2-ethyl-4-(hexahydrofuro[3,4-b]pyrazin-1(2H)- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3-f][1,4]thiazepin- 5(2H)-one 1,1-dioxide and 2-methoxyacetaldehyde. The title compounds were isolated as single enantiomers after resolution of the racemic mixture by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um) using as mobile phase 60% acetonitrile/ethanol (containing 0.1% ammonium hydroxide) in CO2. [0001175] First eluting enantiomer (absolute stereochemistry undetermined): MS (ESI) m/z: 681.4[M+H] + . 1 H NMR (400MHz, methanol-d 4 ) δ 8.72 - 8.55 (m, 1H), 7.97 (s, 1H), 7.26 - 7.17 (m, 1H), 6.91 - 6.85 (m, 2H), 4.54 - 4.48 (m, 1H), 4.07 (dd, J = 9.6, 1.6 Hz, 1H), 3.95 - 3.84 (m, 6H), 3.75 - 3.71 (m, 1H), 3.59 (t, J = 5.6 Hz, 2H), 3.43 - 3.40 (m, 1H), 3.37 (s, 3H), 3.20 - 3.15 (m, 5H), 3.05 - 3.03 (m, 1H), 2.87 (dt, J = 13.6, 6.0 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.53 - 2.46 (m, 2H), 1.17 (t, J = 7.6 Hz, 3H). [0001176] Second eluting enantiomer (absolute stereochemistry undetermined): MS (ESI) m/z: 681.4[M+H] + . 1 H NMR (400MHz, methanol-d4) δ 8.72 - 8.54 (m, 1H), 7.97 (s, 1H), 7.28 - 7.18 (m, 1H), 6.94 - 6.86 (m, 2H), 4.54 - 4.48 (m, 1H), 4.07 (dd, J = 9.6, 1.6 Hz, 1H), 3.95 - 3.84 (m, 6H), 3.75 - 3.71 (m, 1H), 3.59 (t, J = 5.6 Hz, 2H), 3.43 - 3.40 (m, 1H), 3.37 (s, 3H), 3.20 - 3.15 (m, 5H), 3.05 - 3.03 (m, 1H), 2.88 (dt, J = 13.6, 6.0 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.53 - 2.46 (m, 2H), 1.17 (t, J = 7.6 Hz, 3H). Example 522: 7-(2-((2-ethyl-4-(3-(methylamino)pyrrolidin-1-yl)phenyl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001177] The title compound was prepared analogously to Example 305, where 2-cyclopropyl-4- fluoro-1-nitrobenzene and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate were replaced with 2-ethyl-4-fluoro-1-nitrobenzene and tert-butyl methyl(pyrrolidin-3-yl)carbamate in step 1 and 7- bromo-4-cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5 (2H)-one 1,1-dioxide was replaced with 7- iodo-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-o ne 1,1-dioxide in step 5. The title compound was isolated as a yellow solid. MS (ESI) m/z: 595.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 1.20 (t, J=7.6 Hz, 3 H) 1.87 - 2.10 (m, 1 H) 2.20 - 2.35 (m, 1 H) 2.48 - 2.66 (m, 5 H) 3.15 - 3.40 (m, 5 H) 3.42 - 3.60 (m, 3 H) 3.73 (s, 2 H) 3.80 - 4.03 (m, 2 H) 6.40 - 6.50 (m, 2 H) 7.05 (br s, 1 H) 7.31 - 7.45 (m, 1 H) 8.02 (d, J=1.6 Hz, 1 H) 8.63 (s, 1 H). Example 523: 7-(2-((2-ethyl-4-(3-((2-methoxyethyl)(methyl)amino)pyrrolidi n-1-yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001178] The title compound was prepared analogously to Example 306, where 7-(2-((4-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-cyclopropylphenyl)amino)-5 -(trifluoromethyl)pyrimidin-4-yl)-4- cyclopropyl-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and paraformaldehyde were replaced with 7-(2-((2-ethyl-4-(3-(methylamino)pyrrolidin-1-yl)phenyl)amin o)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 2-methoxyacetaldehyde. The title compound was isolated in 87% yield as a pale yellow solid. MS (ESI) m/z: 653.3 [M+H] + . 1 H NMR (400 MHz, CDCl3-d) δ, 1.22 (t, J=7.6 Hz, 3 H) 1.93 - 2.07 (m, 1 H) 2.23 (dd, J=3.2 Hz, 1 H) 2.38 (s, 3 H) 2.61 (q, J=7.6 Hz, 2 H) 2.72 (s, 2 H) 3.24 (s, 5 H) 3.30 - 3.37 (m, 1 H) 3.39 (s, 3 H) 3.45 - 3.61 (m, 4 H) 3.73 (s, 2 H) 3.81 - 4.01 (m, 2 H) 6.40 - 6.52 (m, 2 H) 6.92 - 7.07 (m, 1 H) 7.41 (dd, J=4.0, 2.8 Hz, 1 H) 8.04 (s, 1 H) 8.63 (s, 1 H). Example 524: 7-(2-((4-(3-aminopyrrolidin-1-yl)-2-ethylphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepin-5(2H)-one 1,1- dioxide [0001179] The title compound was prepared analogously to Example 522, where tert-butyl methyl(pyrrolidin-3-yl)carbamate was replaced with tert-butyl pyrrolidin-3-ylcarbamate. The title compound was isolated as a yellow solid. MS (ESI) m/z: 581.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ = 8.82 - 8.44 (m, 1H), 8.09 - 7.86 (m, 1H), 7.27 - 7.04 (m, 1H), 6.64 - 6.44 (m, 2H), 4.02 - 3.76 (m, 5H), 3.65 - 3.52 (m, 2H), 3.42 - 3.34 (m, 2H), 3.24 - 3.09 (m, 3H), 2.68 - 2.56 (m, 2H), 2.47 - 2.35 (m, 1H), 2.12 - 2.00 (m, 1H), 1.17 (t, J = 7.6 Hz, 3H). Example 525: 7-(2-((2-ethyl-4-((1R,4R)-5-(2-hydroxyethyl)-2,5-diazabicycl o[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide [0001180] The title compound was prepared analogously to Example 463, where 7-(2-((2-ethyl-4- (piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4-((1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)amino)-5-(trif luoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide. The title compound was isolated as an orange solid. MS (ESI) m/z: 637.4 [M+H] +. (400 MHz, CDCl 3 ) δ, 8.65 (s, 1H), 8.08 - 8.01 (m, 1H), 7.41 - 7.29 (m, 1H), 7.02 - 6.93 (m, 1H), 6.48 (br s, 2H), 4.40 - 4.25 (m, 1H), 4.00 - 3.85 (m, 2H), 3.85 - 3.62 (m, 6H), 3.57 (br s, 2H), 3.48 - 3.34 (m, 1H), 3.22 (br s, 3H), 3.06 - 2.70 (m, 4H), 2.60 (q, J = 7.6 Hz, 2H), 1.21 (br t, J = 7.6 Hz, 3H). Example 526: 7-(2-((2-ethyl-4-((1R,4R)-5-(2-hydroxyethyl)-2,5-diazabicycl o[2.2.1]heptan-2- yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-4-methyl -3,4-dihydrothieno[2,3- f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001181] The title compound was prepared analogously to Example 463, where 7-(2-((2-ethyl-4- (piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4 -yl)-4-(oxetan-3-yl)-3,4-dihydrothieno[2,3- f][1,4]thiazepin-5(2H)-one 1,1-dioxide was replaced with 7-(2-((4-((1R,4R)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-2-ethylphenyl)amino)-5-(trif luoromethyl)pyrimidin-4-yl)-4-methyl-3,4- dihydrothieno[2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide. The title compound was isolated as a white solid. MS (ESI) m/z: 653.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ, 8.64 (s, 1H), 8.06 - 7.89 (m, 1H), 7.50 - 7.29 (m, 1H), 7.07 - 6.89 (m, 1H), 6.58 - 6.41 (m, 2H), 4.33 - 4.26 (m, 1H), 4.19 - 4.03 (m, 2H), 3.86 - 3.75 (m, 2H), 3.62 (br s, 4H), 3.59 - 3.53 (m, 2H), 3.50 (br d, J = 9.6 Hz, 1H), 3.30 (br d, J = 9.2 Hz, 1H), 3.05 - 2.97 (m, 1H), 2.82 - 2.71 (m, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.11 - 1.98 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H). Example 527: (S)-7-(2-((2-ethyl-4-(4-(2-hydroxyethyl)-2-methylpiperazin-1 -yl)phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)-4-methyl-3,4-dihydrothieno[ 2,3-f][1,4]thiazepine-5(2H)-thione 1,1-dioxide [0001182] The title compound was prepared analogously to Example 443, where (R)-7-(2-((2- cyclopropyl-4-(3-methylpiperazin-1-yl)phenyl)amino)-5-(trifl uoromethyl)pyrimidin-4-yl)-4-(oxetan-3- yl)-3,4-dihydrothieno[2,3-f][1,4]thiazepin-5(2H)-one 1,1-dioxide and 1-bromo-2-methoxyethane were replaced with (S)-7-(2-((2-ethyl-4-(2-methylpiperazin-1-yl)phenyl)amino)-5 -(trifluoromethyl)pyrimidin- 4-yl)-4-methyl-3,4-dihydrothieno[2,3-f][1,4]thiazepine-5(2H) -thione 1,1-dioxide and 2-bromoethan-1-ol. The title compound was isolated as an orange solid. MS (ESI) m/z: 655.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ = 8.66 (s, 1H), 7.98 (s, 1H), 7.61 - 7.39 (m, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.90 – 6.74 (m, 2H), 4.17 - 4.06 (m, 2H), 3.95 - 3.87 (m, 1H), 3.81 (t, J = 5.2 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.63 (s, 3H), 3.35 - 3.25 (m, 1H), 3.23 - 3.13 (m, 1H), 2.93 - 2.83 (m, 1H), 2.73 - 2.56 (m, 6H), 2.52 - 2.43 (m, 1H), 1