Thiazolopyrimidinones and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9988400-B2
Application number	US-201615094687-A
Country	US
Kind code	B2
Filing date	Apr 8, 2016
Priority date	Oct 11, 2013
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

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

First claim

The invention claimed is:

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 phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, indolyl, indazolyl, quinolinyl, or isoquinolinyl, 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 claim 1 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 1-4 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 phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, indolyl, indazolyl, quinolinyl, or isoquinolinyl, 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 a pharmaceutically acceptable salt thereof, wherein R a is C 1-6 alkyl optionally substituted with one or more R b substituents.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a is C 1-6 alkyl optionally substituted with one or two R b substituents.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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 claim 1 , or a pharmaceutically acceptable salt thereof, 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 claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R b is independently —OH,

Assignees

• Genentech Inc

Inventors

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

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P29/00

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

• A61P25/16

  Anti-Parkinson drugs · CPC title