9H-pyrimido[4,5-B]indoles and related analogs as BET bromodomain inhibitors

Patent metadata

Field	Value
Publication number	US-9580430-B2
Application number	US-201514633360-A
Country	US
Kind code	B2
Filing date	Feb 27, 2015
Priority date	Feb 28, 2014
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

The present disclosure provides substituted 9H-pyrimido[4,5-b]indoles and 5H-pyrido[4,3-b]indoles and related analogs represented by Formula I:

and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R 1a , A, B 1 , B 2 , G, X 1 , Y 1 , Y 2 , and Y 3 are as defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a condition or disorder responsive to inhibition of BET bromodomains. Compounds of the present disclosure are especially useful for treating cancer.

First claim

What is claimed is:

1. A compound having Formula I:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
wherein:
B 1 is —N═ or —C(R 1b )—;
B 2 is —N═ or —C(R 1c )—;
Y 1 is —N═;
Y 2 is —C(R 2b )═;
Y 3 is —N═;
G is selected from the group consisting of halo, hydroxy, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl)alkyl, —OS(═O) 2 CF 3 , and —Z—R 3 ;
R 1a is selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino, and halo;
R 1b is selected from the group consisting of hydrogen and halo;
R 1c is selected from the group consisting of hydrogen and fluoro;
R 2b is selected from the group consisting of hydrogen, amino, optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, heteroalkyl, (heterocyclo)alkyl, (amino)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, and carboxamido;
R 3 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclo;
A is selected from the group consisting of

X 2 is selected from the group consisting of —O—, —S—, and —N(R 5c1 )—;
R 5c1 is selected from the group consisting of hydrogen and alkyl;
R 4a and R 4b are independently selected from the group consisting of hydrogen, halo, haloalkyl, and alkyl;
X 1 is —N(R 5a1 )—;
Z is selected from the group consisting of —C(═O)—, —O—, —S—, —SO 2 —, and —N(R 5b1 )—;
R 5a1 is hydrogen; and
R 5b1 is selected from the group consisting of hydrogen and alkyl, with the provisos that:
a) when G is halo, hydroxy, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl)alkyl, or —OS(═O) 2 CF 3 then either B 1 or B 2 , or both, is —N═; or
b) when G is halo, hydroxy, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, aralkyl, (heteroaryl)alkyl, or —OS(═O) 2 CF 3 , then either R 1b or R 1c , or both, is fluoro.

2. A compound having Formula II:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
R 1 is selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, alkylthio, amino, and halo;
R 2 is selected from the group consisting of hydrogen, amino, alkyl, hydroxyalkyl, alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, and carboxamido;
R 3 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclo;
A is selected from the group consisting of:

R 4a and R 4b are independently selected from the group consisting of hydrogen and alkyl;
X 2 is selected from the group consisting of —O—, —S—, and —N(R 5c1 )—; and
R 5c1 is selected from the group consisting of hydrogen and alkyl;
X 1 is —N(R 5a1 )—;
Y 1 is —N═;
Z is selected from the group consisting of —O—, —S—, —SO 2 —, and —N(R 5b1 )—;
R 5a1 is hydrogen; and
R 5b1 is selected from the group consisting of hydrogen and alkyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
R 2 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, (heterocyclo)alkyl, alkoxyalkyl, (amino)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, and carboxamido; and
R 3 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclo.

4. The compound of claim 2 having Formula IV:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

5. The compound of claim 2 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Z is —NH—.

6. The compound of claim 2 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 2 is alkyl.

7. The compound of claim 2 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 3 is optionally substituted 5-membered heteroaryl selected from the group consisting of:

R 5a , R 5b , R 5c are each independently selected from the group consisting of hydrogen, halo, cyano, alkylcarbonyl, alkoxycarbonyl, haloalkyl, optionally substituted alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, aralkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, and carboxamido;
X 3 is selected from the group consisting of —O—, —S—, and —N(R 5d )—;
R 5d is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (amino)alkyl, aralkyl, (heterocyclo)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, carboxamido, (carboxamido)alkyl, and —C(═O)R 5e ; and
R 5e is selected from the group consisting of alkyl and alkoxy.

8. The compound of claim 2 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, having Formula IX:

9. The compound of claim 8 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5a , R 5c , and R 5d are independently selected from the group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl.

10. The compound of claim 9 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R 1 is —OCH 3 , R 2 is selected from the group consisting of —CH 3 and —CH 2 OCH 3 ; and Z is —N(H)—.

11. The compound of claim 2 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, having Formula XVIII:

12. The compound of claim 11 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R 5f is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl.

13. The compound of claim 12 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: R 1 is —OCH 3 ; R 2 is selected from the group consisting of —CH 3 and —CH 2 OCH 3 ; and Z is —N(H)—.

14. The compound of claim 4 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from the group consisting of:
N-(3-cyclopropyl- 1 -methyl-1H-pyrazol-5-yl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2-methyl-9H-pyrimido[4,5-b]indol-4-amine;
N-(3-cyclopropyl-1-ethyl-1H-pyrazol

Assignees

• Univ Michigan Regents

Inventors

• Wang Shaomeng
• Zhao Yujun
• Zhou Bing
• Aguilar Angelo
• Liu Liu
• Bai Longchuan
• Mceachern Donna
• Sun Duxin
• Wen Bo
• Luo Ruijuan
• Zhao Ting
• Chinnaiyan Arul
• Asangani Irfan A
• Stuckey Jeanne
• Meagher Jennifer Lynn
• Ran Xu
• Hu Yang

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D487/14

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title