TGF-ß inhibitors

Patent metadata

Field	Value
Publication number	US-11021468-B2
Application number	US-201615563056-A
Country	US
Kind code	B2
Filing date	Mar 29, 2016
Priority date	Apr 1, 2015
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

Disclosed are aryl pyrimidine compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure (I) and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein A, Z, R and R′ are as described herein. In certain embodiments, a compound disclosed herein inhibits the activity of one or more members of the TGF-β superfamily, and can be used to treat disease by blocking such activity.

First claim

What is claimed:

1. A compound having the structure of formula (IV):

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
Z is:
a)

wherein
R 2 is —C(O)CH 2 NR b 2 ,
wherein R b is C 1-6 alkyl; and
R 3 is C 1-6 alkyl; or

b)

wherein
R 2 is hydrogen or —OR b ,
wherein R b is hydrogen or C 1-6 alkyl; and
n is 0, 1 or 2;

R and R′ are independently hydrogen or C 1-6 alkyl;
R 1 is halogen, cyano, or C 1-6 alkyl; and
m is 0, 1 or 2.

2. The compound of claim 1 , wherein the compound has the structure

3. A compound having the structure of formula (II):

or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof,
wherein
R and R′ are independently hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 1 is halogen, cyano, —SR a , —N(R a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl,
wherein each R a is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
m is 0, 1, 2, 3 or 4;
X is N or C(H);
R 2 is hydrogen, —C(O)CH 2 NR b 2 , —CH 2 —OP(O)(OR c ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, or heteroaryl,
wherein each R b is independently hydrogen or C 1-6 alkyl, and
wherein each R c is independently hydrogen or C 1-6 alkyl; and
R 3 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl or heteroaryl.

4. The compound of claim 3 , having the structure of formula (IIa):

wherein
R is hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 1 is halogen, cyano, C 1-6 alkyl, —NH 2 , C 1-6 haloalkyl or C 3-6 cycloalkyl;
m is 0, 1, 2, 3 or 4;
R 2 is hydrogen, C 1-6 alkyl, —C(O)CH 2 NR b 2 , —CH 2 OP(O)(OR c ) 2 , C 1-6 haloalkyl, or C 5-6 heteroaryl,
wherein each R b is independently hydrogen or C 1-6 alkyl, and
wherein each R c is independently hydrogen or C 1-6 alkyl; and
R 3 is halogen, C 1-6 alkyl or C 1-6 haloalkyl.

5. The compound of claim 4 , wherein
R is hydrogen, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 1 is halogen, cyano, C 1-6 alkyl or —NH 2 ,
wherein R a is C 1-6 alkyl;
m is 0, 1, 2, 3 or 4;
R 2 is hydrogen, C 1-6 alkyl, —C(O)CH 2 NR b 2 , or —CH 2 OP(O)(OR c ) 2 ,
wherein each R b is independently hydrogen or C 1-6 alkyl, and
wherein each R c is independently hydrogen or C 1-6 alkyl; and
R 3 is halogen or C 1-6 alkyl.

6. The compound of claim 3 , wherein the compound has the structure

7. A compound selected from:
2-(Dimethylamino)-1-(5-((2-(2,5-dimethylphenyl)pyrimidin-4-yl)amino)-1H-indazol-1-yl)ethan-1-one;
N-(2-(3,4-Difluorophenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(4-Fluorophenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(5-Fluoro-2-(4-fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(3-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(4-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(3-Methylphenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(2-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-Phenylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(2-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-(2-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(5-fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3,5-Difluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Fluoro-4-methoxyphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Cyanophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2,5-Dimethylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Aminophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-(methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-(3-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(5-Fluoro-2-phenylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2,5-Dimethylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Aminophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(3-Trifluoromethylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Methoxy-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-2-methylphenyl)pyrimidin-4-yl)-6,7-dimethoxyquinolin-4-amine;
N-(2-(2-Fluoro-5-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(3-Methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(4-Fluorophenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(2,5-Dimethylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;
6-Fluoro-N-(2-(3-fluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(2,5-dimethylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(3,4-difluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
6-Fluoro-N-(2-(4-fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;
N-(2-(2-Fluorophenyl)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine;
N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine;
or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof.

8. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, carrier, or excipient and a compound according to claim 3 .

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Gelman Marina
• Ding Pingyu
• Kinsella Todd
• Singh Rajinder
• Bhamidipati Somasekhar
• Clough Jeffrey

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title