Publication NumberUS 20190382415
Assignees
  • THE REGENTS OF THE UNIVERSITY OF MICHIGAN
Filing StatusPatent Application
US PAIR StatusApplication Undergoing Preexam Processing
US PAIR Status Date2019-07-29
Application Number16/481501
AvailabilityUnknown
Filing Date2018-02-02
Publication Date2019-12-19

Abstract

The present disclosure provides fused 1,4-diazepines represented by Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein A. E, R1, R2, R3, R4, R5, and Ar are as defined as set forth in the specification. The present disclosure is also directed to the use of compounds having Formula (I) to treat diseases, conditions, or disorders responsive to inhibition of BET bromodomain proteins such as cancer.

Claims

  • 1. A compound having Formula I: or a pharmaceutically acceptable salt or hydrate thereof, wherein: R1 is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 haloalkyl; R2 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, —CH2C(═O)OR6, and —CH2C(═O)NR7aR7b; R3 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R4 and R4a are independently selected from the group consisting of hydrogen, halo, C1-4 alkyl, and C1-4 haloalkyl; R5 is selected from the group consisting of hydrogen, —Si(CH3)3, C1-6 alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, (heterocyclo)alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl; R6 is selected from the group consisting of hydrogen and C1-6 alkyl; R7a and R7b are each independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R7a and R7b are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclo; is a fused thienyl or fused phenyl group, wherein the fused phenyl group is additionally substituted with R4a; and A is and E is —O—; or A is and E is —N═, with the proviso that: 1) R4 is selected from the group consisting of C1-4 alkyl and C1-4 haloalkyl when R2 is hydrogen; and 2) R2 is selected from the group consisting of optionally substituted C1-4 alkyl, —CH2C(═O)OR6, and —CH2C(═O)NR7aR7b when R4 is hydrogen.
  • 2. The compound of claim 1 having Formula II: or a pharmaceutically acceptable salt or hydrate thereof.
  • 3. The compound of claim 1 having Formula III: or a pharmaceutically acceptable salt or hydrate thereof.
  • 4. The compound of claim 1 having Formula IV: or a pharmaceutically acceptable salt or hydrate thereof.
  • 5. The compound of claim 1 having Formula V: or a pharmaceutically acceptable salt or hydrate thereof.
  • 6. The compound of claim 1 having Formula VI: or a pharmaceutically acceptable salt or hydrate thereof.
  • 7. The compound of claim 1 having Formula VII: or a pharmaceutically acceptable salt or hydrate thereof.
  • 8. The compound of claim 1 having Formula VIII: or a pharmaceutically acceptable salt or hydrate thereof.
  • 9. The compound of claim 1 having Formula IX: or a pharmaceutically acceptable salt or hydrate thereof.
  • 10. The compound of claim 1 having Formula X: or a pharmaceutically acceptable salt or hydrate thereof.
  • 11. The compound of claim 1 having Formula XI: or a pharmaceutically acceptable salt or hydrate thereof.
  • 12. The compound of claim 11 having Formula XII: or a pharmaceutically acceptable salt or hydrate thereof.
  • 13. The compound of claim 12 having Formula XIV: or a pharmaceutically acceptable salt or hydrate thereof, wherein: Z is selected from the group consisting of —N═ and —CR8c═; R8a is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy; R8b is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy; and R8c is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-4 alkyl, and C1-4 alkoxy.
  • 14. The compound of claim 13 having Formula XVI: or a pharmaceutically acceptable salt or hydrate thereof.
  • 15. The compound of claims 13 or 14, or a pharmaceutically acceptable salt or hydrate thereof, wherein: R8a and R8b are independently selected from the group consisting of hydrogen and halogen; and R8c is hydrogen.
  • 16. The compound of claim 15, or a pharmaceutically acceptable salt or hydrate thereof, wherein R8b is hydrogen.
  • 17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2 is optionally substituted C1-4 alkyl.
  • 18. The compound of claim 17, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2 is methyl.
  • 19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or hydrate thereof, wherein R2 is —CH2C(═O)NR7aR7b.
  • 20. The compound of claim 19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R7a is C1-6 alkyl and R7b is hydrogen.
  • 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is selected from the group consisting of hydrogen and —Si(CH3)3.
  • 22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (hydroxy)alkyl.
  • 23. The compound of claim 22, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (hydroxy)alkyl selected from the group consisting of —CH2OH, —CH2CH2OH, and —CH2CH2CH2OH.
  • 24. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (alkoxy)alkyl.
  • 25. The compound of claim 24, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (alkoxy)alkyl selected from the group consisting of —CH2OCH3 and —CH2CH2OCH3.
  • 26. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (amino)alkyl.
  • 27. The compound of claim 26, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (amino)alkyl selected from the group consisting of —CH2N(H)CH3 and —CH2N(CH3)2.
  • 28. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (heterocyclo)alkyl.
  • 29. The compound of claim 28, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is (heterocyclo)alkyl selected from the group consisting of:
  • 30. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted C3-8 cycloalkyl.
  • 31. The compound of claim 30, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted C3-8 cycloalkyl selected from the group consisting of:
  • 32. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted 4- to 8-membered heterocyclo.
  • 33. The compound of claim 32, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted 4- to 8-membered heterocyclo selected from the group consisting of:
  • 34. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted phenyl.
  • 35. The compound of claim 34, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted phenyl selected from the group consisting of:
  • 36. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted heteroaryl.
  • 37. The compound of claim 34, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted heteroaryl selected from the group consisting of:
  • 38. The compound of claim 36, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted 5-membered heteroaryl.
  • 39. The compound of claim 38, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted 5-membered heteroaryl selected from the group consisting of:
  • 40. The compound of claim 36, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted 6-membered heteroaryl.
  • 41. The compound of claim 40, or a pharmaceutically acceptable salt or hydrate thereof, wherein R5 is optionally substituted 6-membered heteroaryl selected from the group consisting of:
  • 42. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, which is any one or more of the compounds of Table 1.
  • 43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient.
  • 44. A method of treating a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-42, or a pharmaceutically acceptable salt or hydrate thereof, wherein the subject has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • 45. The method claim 44, wherein the subject has cancer.
  • 46. The method of claim 45, wherein the cancer is selected from any one or more of the cancers of Table 2.
  • 47. The method of claim 45, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukaemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • 48. The method of any one of claims 44-47 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.
  • 49. The pharmaceutical composition of claim 43 for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • 50. The pharmaceutical composition of claim 49 for use in treating cancer.
  • 51. The pharmaceutical composition of claim 50, wherein the cancer is selected from any one or more of the cancers of Table 2.
  • 52. The pharmaceutical composition of claim 50, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukaemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • 53. A compound of any one of claims 1-42, or a pharmaceutically acceptable salt or hydrate thereof, for use in treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • 54. The compound of claim 53 for use in treating cancer.
  • 55. The compound of claim 54, wherein the cancer is selected from any one or more of the cancers of Table 2.
  • 56. The compound of claim 54, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukaemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • 57. Use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a medicament for treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • 58. The use of claim 57 for treatment of cancer.
  • 59. The use of claim 58, wherein the cancer is selected from any one or more of the cancers of Table 2.
  • 60. The use of claim 58, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukaemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • 61. A kit comprising the compound of any one of claims 1-42, or a pharmaceutically acceptable salt or hydrate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or hydrate thereof, to a subject having cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.
  • 62. The kit of claim 61, wherein the subject has cancer.
  • 63. The kit of claim 62, wherein the cancer is selected from any one or more of the cancers of Table 2.
  • 64. The kit of claim 62, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.
  • 65. The kit of any one of claims 61-64 further comprising one or more additional therapeutic agents.
  • 66. A compound of Table 5 or a pharmaceutically acceptable salt or hydrate thereof.
  • 67. A pharmaceutical composition comprising a compound of any one of claims 1-42 and 66, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient.
  • 68. A method of treating a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-42 and 66, or a pharmaceutically acceptable salt or hydrate thereof, wherein the subject has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

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