Thiazolopyrimidinones and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016222033-A1
Application number	US-201615094687-A
Country	US
Kind code	A1
Filing date	Apr 8, 2016
Priority date	Oct 11, 2013
Publication date	Aug 4, 2016
Grant date	—

Abstract

The present invention relates to certain thiazolopyrimidinone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.

First claim

1 . A compound of Formula (II):

wherein
R a is C 1-6 alkyl or C 2-6 alkenyl, each optionally substituted with one or more R b substituents; C 2-6 alkynyl; halo; —C(O)R c ; —NR d R e ; —C(O)NR d R e ; —C(S)NR d R e ; —C(═N—OH)—C 1-4 alkyl; —OC 1-4 alkyl; —OC 1-4 haloalkyl; —SC 1-4 alkyl; —SO 2 C 1-4 alkyl; cyano; C 3-6 cycloalkyl optionally substituted with one or more R f substituents; or a phenyl, monocyclic heteroaryl, or heterocycloalkyl ring, each ring optionally substituted with one or more R g substituents;
wherein each R b substituent is independently selected from the group consisting of —OH, —C 1-4 alkoxy, —NR d R e , —C(O)NR d R e , —SC 1-4 alkyl, —SO 2 C 1-4 alkyl, cyano, halo, C 3-6 cycloalkyl, and monocyclic heteroaryl;
R c is C 1-4 alkyl, —C 1-4 haloalkyl, C 3-6 cycloalkyl, or a monocyclic, carbon-linked heterocycloalkyl;
R d is H or C 1-4 alkyl;
R e is H; C 1-4 alkyl optionally substituted with —CN, —CF 3 , —OH, or a monocyclic heterocycloalkyl; C 3-6 cycloalkyl; —OH; or —OC 1-4 alkoxy;
or R d and R e taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C 1-4 alkyl or —OH;
each R f substituent is independently selected from the group consisting of: C 1-4 alkyl optionally substituted with —OH, cyano, or C 1-4 alkoxy; —OH; halo; C 1-4 haloalkyl; —CONH 2 ; and cyano; and
each R g substituent is independently selected from the group consisting of C 1-4 alkyl, —CF 3 , halo, —NH 2 , —OCH 3 , cyano, and —OH;

R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, halo, —OC 1-4 alkyl, —OC 1-4 haloalkyl, cyano, and —C(O)C 1-4 alkyl; or R a and R 1 taken together with the carbons to which they are attached form a 5- to 7-membered ring, optionally containing an O or NH, and optionally substituted with one or more R h substituents;
wherein each R h substituent is independently —C(O)NR i R j , cyano, or is C 1-4 alkyl optionally substituted with —OH, —OCH 3 , cyano, or —C(O)NR i R j ; or two R h groups attached to the same carbon and taken together with the carbon to which they are attached form a carbonyl or a C 3-6 cycloalkyl;
wherein R i and R j are each independently H or C 1-4 alkyl;

R 2 is —R m , —OR m , or —NR m R n ;
wherein R m is aryl or heteroaryl, each optionally substituted with one or more R s substituents;
wherein each R s substituent is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl (optionally substituted with halo), C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl-OH, C 1-4 haloalkoxy, halo, cyano, C 3-6 cycloalkyl (optionally substituted with —OH or halo), monocyclic heteroaryl, —NH 2 , —NO 2 , —NHSO 2 C 1-4 alkyl, and —SO 2 C 1-4 alkyl;

R n is H, C 1-4 haloalkyl, or C 1-4 alkyl optionally substituted with —OH or C 1-4 alkoxy;
or R m and R n taken together with the nitrogen to which they are attached form a pyrrolidine or piperidine ring, optionally substituted with C 1-4 alkyl and optionally fused to phenyl, wherein said phenyl is optionally substituted with halo;

R 3 is H or methyl; and
R 4 is H or fluoro;
or a pharmaceutically acceptable salt thereof.

2 . A compound of Formula (I):

wherein
R a is C 1-6 alkyl optionally substituted with one or more R b substituents; C 2-6 alkenyl; C 2-6 alkynyl; halo; —C(O)R c ; —NR d R e ; —C(O)NR d R e ; —C(S)NR d R e ; —C(═N—OH)—C 1-4 alkyl; —SO 2 C 1-4 alkyl; cyano; C 3-6 cycloalkyl optionally substituted with one or more R f substituents; or a phenyl, monocyclic heteroaryl, or heterocycloalkyl ring, each ring optionally substituted with one or more R g substituents;
wherein each R b substituent is independently selected from the group consisting of —OH, —C 1-4 alkoxy, —NR d R e , —C(O)NR d R e , —SC 1-4 alkyl, —SO 2 C 1-4 alkyl, cyano, halo, and monocyclic heteroaryl;
R c is C 1-4 alkyl, —C 1-4 haloalkyl, C 3-6 cycloalkyl, or a monocyclic, carbon-linked heterocycloalkyl;
R d is H or C 1-4 alkyl;
R e is H; C 1-4 alkyl optionally substituted with —CN, —CF 3 , —OH, or a monocyclic heterocycloalkyl; C 3-6 cycloalkyl; —OH; or —OC 1-4 alkoxy;
or R d and R e taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C 1-4 alkyl or —OH;
each R f substituent is independently selected from the group consisting of: C 1-4 alkyl optionally substituted with —OH, cyano, or C 1-4 alkoxy; C 1-4 haloalkyl; —CONH 2 ; and cyano; and
each R g substituent is independently selected from the group consisting of C 1-4 alkyl, —CF 3 , halo, —NH 2 , —OCH 3 , cyano, and —OH;

R 1 is selected from the group consisting of H, C 1-6 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl; or R a and R 1 taken together with the carbons to which they are attached form a 5- to 7-membered ring, optionally containing an O or NH, and optionally substituted with one or more R h substituents;
wherein each R h substituent is independently —C(O)NR i R j , cyano, or is C 1 -4alkyl optionally substituted with —OH, —OCH 3 , cyano, or —C(O)NR i R j ; or two R h groups attached to the same carbon and taken together with the carbon to which they are attached form a carbonyl or a C 3-6 cycloalkyl;
wherein R i and R j are each independently H or C 1-4 alkyl;

R 2 is —R m , —OR m , or —NR m R n ;
wherein R m is aryl or heteroaryl, each optionally substituted with one or more R s substituents;
wherein each R s substituent is independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl-OH, C 1-4 haloalkoxy, halo, cyano, C 3-6 cycloalkyl, —NHSO 2 C 1-4 alkyl, and —SO 2 C 1-4 alkyl;

R n is H, C 1-4 haloalkyl, or C 1-4 alkyl optionally substituted with —OH or C 1-4 alkoxy;
or R m and R n taken together with the nitrogen to which they are attached form a pyrrolidine or piperidine ring, optionally substituted with C 1-4 alkyl and optionally fused to phenyl, wherein said phenyl is optionally substituted with halo;

R 3 is H or methyl; and
R 4 is H or fluoro;
or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 or claim 2 , wherein R a is C 1-6 alkyl optionally substituted with one or more R b substituents.

4 . The compound of any one of claims 1 - 3 , wherein R a is C 1-6 alkyl optionally substituted with one or two R b substituents.

5 . The compound of any one of claims 1 - 4 , wherein R a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or isopentyl, each optionally substituted with one or more R b substituents.

6 . The compound of any one of claims 1 - 5 , wherein each R b is independently —OH, methoxy, ethoxy, —NR d R e , —C(O)NR d R e , thiomethyl, thioethyl, methanesulfonyl, ethanesulfonyl, cyano, fluoro, chloro, bromo, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, oxazolyl, or thiazolyl.

7 . The compound of any one of claims 1 - 6 , wherein each R b is independently —OH, —C(O)NHCH 3 , —CF 3 , methoxy, ethoxy, fluoro, —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —N(CH 3 ) 2 , methanesulfonyl, thiomethyl, cyano, pyrazolyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, azetidinyl, 3-hydroxyazetidinyl, pyrrolidinyl, or hydroxyethylamino.

8 . The compound of claim 1 or claim 2 , wherein R a is C 1-6 alkenyl or C 1-6 alkynyl.

9 . The compound of any one of claims 1 , 2 , or 8 , wherein R a is ethenyl, iso

Assignees

• Genentech Inc

Inventors

• Yu Jiang
• Wu Guosheng
• Yuen Po-Wai
• Villemure Elisia
• Schwarz Jacob
• Ly Cuong
• Sellers Benjamin
• Matthew Volgraf

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title

• A61P25/22

  Anxiolytics · CPC title