IP Library › Granted Patent US 11,021,468

Granted Patent B2

US 11,021,468 · App. 15/563,056 · Granted Jun 1, 2021

TGF-ß inhibitors

Inventors: Marina Gelman (San Francisco, CA); Pingyu Ding (Foster City, CA); Todd Kinsella (Redwood City, CA); Rajinder Singh (Belmont, CA); Somasekhar Bhamidipati (Foster City, CA); Jeffrey Clough (Redwood City, CA)

Assignee: Rigel Pharmaceuticals, Inc.

C07D403/12 A61P35/02 C07D401/12 C07D471/04

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Quick Facts

Patent No.: US 11,021,468
App. No.: 15/563,056
Granted: Jun 1, 2021
Kind: B2

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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.

Claims (103)

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:

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

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 .

Assignments (2)

SECURITY INTEREST Recorded Aug 25, 2022

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL TRUST

Reel/Frame 061327/0712 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2018

From: GELMAN, MARINA; DING, PINGYU; KINSELLA, TODD; SINGH, RAJINDER; BHAMIDIPATI, SOMASEKHAR; CLOUGH, JEFFREY

To: RIGEL PHARMACEUTICALS, INC.

Reel/Frame 045129/0364 →

Continuity (2)

Provisional Application 62141441 · Apr 1, 2015

Related Publication 20180339979A1 · Nov 29, 2018