Fused 1,4-diazepines as BET bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-11046709-B2
Application number	US-201816481501-A
Country	US
Kind code	B2
Filing date	Feb 2, 2018
Priority date	Feb 3, 2017
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

The present disclosure provides fused 1,4-diazepines represented by Formula (I): and the pharmaceutically acceptable salts and solvates thereof, wherein A, E, R 1 , R 2 , R 3 , R 4 , R 5 , 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.

First claim

The invention claimed is:

1. A compound having Formula I:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
R 2 is selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, —CH 2 C(═O)OR 6 , and —CH 2 C(═O)NR 7a R 7b ;
R 3 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R 4 is selected from the group consisting of hydrogen, halo, C 1-4 alkyl, and C 1-4 haloalkyl;
R 5 is selected from the group consisting of hydrogen, —Si(CH 3 ) 3 , C 1-6 alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, (heterocyclo)alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl;
R 6 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 7a and R 7b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
R 7a and R 7b are taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclo;

is a fused thienyl R 4a ; and
A is

and E is —N═,
with the proviso that:
1) R 4 is selected from the group consisting of C 1-4 alkyl and C 1-4 haloalkyl when R 2 is hydrogen; and
2) R 2 is selected from the group consisting of optionally substituted C 1-4 alkyl, —CH 2 C(═O)OR 6 , and —CH 2 C(═O)NR 7a R 7b when R 4 is hydrogen.

2. The compound of claim 1 having Formula V:

or a pharmaceutically acceptable salt or hydrate thereof.

3. The compound of claim 1 having Formula XI:

or a pharmaceutically acceptable salt or hydrate thereof.

4. The compound of claim 3 having Formula XII:

or a pharmaceutically acceptable salt or hydrate thereof.

5. The compound of claim 4 having Formula XIV:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Z is selected from the group consisting of —N═ and —CR 8c ═;
R 8a is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R 8b is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy; and
R 8c is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

6. The compound of claim 5 having Formula XVI:

or a pharmaceutically acceptable salt or hydrate thereof.

7. The compound of claim 5 , or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R 8a and R 8b are independently selected from the group consisting of hydrogen and halogen; and
R 8c is hydrogen.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, which is

9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient.

10. A method of treating a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , 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.

11. The method of claim 10 , wherein the cancer is selected from any one or more of the cancers of adrenal cancer, lymphoepithelioma, acinic cell carcinoma, lymphoma, acoustic neuroma, acute lymphocytic leukemia, acral lentigious melanoma, acute myelogeous leukemia, acrospiroma, chronic lymphocytic leukemia, acute eosinophilic leukemia, liver cancer, acute erythroid leukemia, small cell lung cancer, acute lymphoblastic leukemia, non-small cell lung cancer, acute megakaryoblastic leukemia, MALT lymphoma, acute monocytic leukemia, malignant fibrous histiocytoma, acute promyelocytic leukemia, malignant peripheral nerve sheath tumor, adenocarcinoma, malignant triton tumor, adenoid cystic carcinoma, mantle cell lymphoma, adenoma, marginal zone B-cell lymphoma, adenomatoid odontogenic tumor, mast cell leukemia, adenosquamous carcinoma, mediastinal germ cell tumor, adipose tissue neoplasm, medullary carcinoma of the breast, adrenocortical carcinoma, medullary thyroid cancer, adult T-cell leukemia/lymphoma, medulloblastoma, aggressive NK-cell leukemia, melanoma, AIDS-related lymphoma, meningioma, alveolar rhabdomyosarcoma, merkel cell cancer, alveolar soft part sarcoma, mesothelioma, ameloblastic fibroma, metastatic urothelial carcinoma, anaplastic lame cell lymphoma, mixed Mullerian tumor, anaplastic thyroid cancer, mucinous tumor, angioimmunoblastic T-cell lymphoma, multiple myeloma, angiomyolipoma, muscle tissue neoplasm, angiosarcoma, mycosis fungoides, astrocytoma, myxoid liposarcoma, atypical teratoid rhabdoid tumor, myxoma, B-cell chronic lymphocytic leukemia, myxosarcoma, B-cell prolymphocytic leukemia, nasopharyngeal carcinoma, B-cell lymphoma, neurinoma, basal cell carcinoma, neuroblastoma, biliary tract cancer, neurofibroma, bladder cancer, neuroma, blastoma, nodular melanoma, bone cancer, ocular cancer, Brenner tumor, oligoastrocytoma, Brown tumor, oligodendroglioma, Burkitt's lymphoma, oncocytoma, breast cancer, optic nerve sheath meningioma, br

Assignees

• Univ Michigan Regents

Inventors

• Wang Shaomeng
• Hu Jiantao
• Xu Fuming

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D498/12 Primary

  in which the condensed system contains three hetero rings · CPC title

• C07D495/14

  Ortho-condensed systems · CPC title