N1-pyrazolospiroketone acetyl-CoA carboxylase inhibitors

Patent metadata

Field	Value
Publication number	US-10822335-B2
Application number	US-201916371896-A
Country	US
Kind code	B2
Filing date	Apr 1, 2019
Priority date	Sep 30, 2010
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The invention provides a compound of Formula (I)

or a pharmaceutically acceptable salt of the compound, wherein R 1 , R 2 , R 3 , Z, A 1 , L and A 2 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase enzyme(s) in an animal.

First claim

What is claimed is:

1. A method for treating nonalcoholic fatty liver disease (NAFLD) in a human comprising the step of administering to the human in need of such treatment a therapeutically effective amount of a compound of Formula (I)

or a pharmaceutically acceptable salt thereof; wherein
R 1 is (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, tetrahydrofuranyl or oxetanyl; wherein said (C 1 -C 6 )alkyl is optionally substituted with 1 to 3 substituents independently selected from (C 1 -C 3 )alkoxy, hydroxy, fluoro, phenyl, tetrahydrofuranyl or oxetanyl;
R 2 is hydrogen, halo, (C 1 -C 3 )alkyl, or cyano;
R 3 are each independently hydrogen or (C 1 -C 3 )alkyl;
L is a direct bond or a (C 1 -C 6 )alkylene wherein one carbon of the (C 1 -C 6 )alkylene is optionally replaced by —C(O)—, —C(O)NH—, —NHC(O)—, —O—, —S—, NH or N(C 1 -C 3 )alkyl;
Z is CH 2 or O;
A 1 and A 2 are each independently (C 6 -C 10 )aryl, 5 to 12 membered heteroaryl or 8 to 12 membered fused heterocyclicaryl; wherein said (C 6 -C 10 )aryl, 5 to 12 membered heteroaryl or 8 to 12 membered fused heterocyclicaryl are each optionally substituted with one to three substituents independently selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halo, amino, (C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, hydroxy, cyano and amido wherein the alkyl portion of the (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylamino and di(C 1 -C 3 )alkylamino are optionally substituted with one to five fluoro; and wherein one of A 1 or A 2 is substituted by CO 2 R 4 , (C 1 -C 6 )CO 2 R 4 ; and
R 4 is H.

2. The method of claim 1 wherein R 1 is isopropyl or t-butyl; R 2 is hydrogen; each R 3 is hydrogen; A 1 is phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, indolyl, benzopyrazinyl, benzoimidazolyl, benzoimidazolonyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, indazolyl, indolinonyl, naphthyridinyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, oxo-dihydroquinolinonyl, isoquinolinyl, isoquinolinonyl, dihydroisoquinonyl or oxo-dihydroisoquinonyl, wherein A 1 is optionally substituted with one to three substituents independently selected from fluoro, chloro, methyl, methoxy, amino, methylamino, dimethylamino, amido or cyano; and L is a direct bond or O; or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 wherein R 1 is isopropyl or t-butyl; R 2 is hydrogen; each R 3 is hydrogen; A 1 is phenyl, pyridinyl, indazolyl, indolyl, benzoimidazolyl, pyrrolopyridinyl or pyrrolopyrimidinyl, wherein A 1 is optionally substituted with one methyl, methoxy, methylamino or dimethylamino; and L is a direct bond or O; or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 wherein R 1 is isopropyl or t-butyl; R 2 is hydrogen; each R 3 is hydrogen; A 1 is phenyl, pyridinyl, indazolyl, indolyl, benzoimidazolyl, pyrrolopyridinyl or pyrrolopyrimidinyl, wherein A1 is optionally substituted with one methyl, methoxy, methylamino or dimethylamino; L is a direct bond, and A 2 is phenyl substituted with CO 2 H; or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 wherein R 1 is isopropyl or t-butyl; R 2 is hydrogen; each R 3 is hydrogen; A 1 is pyridinyl optionally substituted with methylamino or dimethylamino; L is a direct bond, and A 2 is phenyl substituted with CO 2 H; or a pharmaceutically acceptable salt thereof.

6. A method for treating nonalcoholic fatty liver disease (NAFLD) in a human comprising the step of administering to the human in need of such treatment a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.

Assignees

• Pfizer

Inventors

• Didiuk Mary Theresa
• Dow Robert Lee
• Griffith David Andrew

Classifications

• A61K31/519

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

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61P43/00

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