Indazolones as modulators of tnf signaling

Patent metadata

Field	Value
Publication number	US-2016304526-A1
Application number	US-201615130323-A
Country	US
Kind code	A1
Filing date	Apr 15, 2016
Priority date	Apr 17, 2015
Publication date	Oct 20, 2016
Grant date	—

Abstract

The disclosure provides compounds of Formula (I)

pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the disclosure are useful for treating immunological and oncological conditions.

First claim

What is claimed:

1 . A compound of Formula (I),

or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein:
X, Y and Z are independently CR 4 or N;
provided that Y and Z are not both N;

A is —C(R z ) 2 —;
E is CH 2 or O and G is CH; or
E is CH 2 and G is CH or N;
R 1 is optionally substituted aryl or optionally substituted heteroaryl;
R 2 is —R 2a -R 2b , wherein:
R 2a is an optionally substituted saturated, unsaturated or partially saturated heterocyclyl or optionally substituted heteroaryl;
R 2b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 5 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) p -optionally substituted heteroaryl or —(CH 2 ) p -optionally substituted heterocyclyl; wherein
R a and R b are independently selected from H, optionally substituted (C 1 -C 5 )alkyl, and —(CH 2 ) n -optionally substituted heterocyclyl;

R 4 is independently H, halo, CF 3 , or (C 1 -C 3 )alkyl;
R z is independently H, halo, CF 3 , or (C 1 -C 3 )alkyl;
n is 0 or 1; and
p is 0 or 1.

2 . The compound according to claim 1 wherein:
R 2b is —N(R a )(R b ), —O(R a ), optionally substituted (C 1 -C 5 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, or —(CH 2 ) p -optionally substituted heterocyclyl; wherein
R a and R b are independently selected from H, optionally substituted (C 1 -C 5 )alkyl, and —(CH 2 ) n -optionally substituted heterocyclyl.

3 . The compound according to claim 1 wherein E is CH 2 .

4 . The compound according to claim 1 wherein X is CH, Y is CH and Z is CR 4 .

5 . The compound according to claim 1 wherein R 4 is F.

6 . The compound according to claim 1 wherein X is CH, Y is CH and Z is CH.

7 . The compound according to claim 1 wherein G is N.

8 . The compound according to claim 1 wherein R 1 is optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted pyrimidinyl or optionally substituted thiazolyl.

9 . The compound according to claim 1 wherein R 1 is optionally substituted phenyl.

10 . The compound according to claim 1 wherein R 1 is optionally substituted by one or more substituents independently selected from —CF 3 , —CN, —C(O)NH 2 , —OCHF 2 , —OCH 3 , or (C 1 -C 3 )alkyl.

11 . The compound according to claim 1 wherein R 1 is optionally substituted by one or more substituents independently selected from —CH 3 or —OCHF 2 .

12 . The compound according to claim 1 wherein R 2a is optionally substituted pyrimidinyl or optionally substituted dihydropyranyl.

13 . The compound according to claim 1 wherein R 2a is 1,2,4-oxadiazolyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, or optionally substituted 1,2,4-thiadiazolyl.

14 . The compound according to claim 1 wherein R 2b is N(R a )(R b ), optionally substituted (C 1 -C 4 )alkyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, 1,1-dioxidothiomorpholinyl, optionally substituted hexahydroimidazo[1,5-a]pyrazin-3(2H)-one, optionally substituted 7-azaspiro[3.5]nonane, or optionally substituted pyrrolidinyl.

15 . The compound according to claim 1 wherein R 2b is —N(R a )(R b ), optionally substituted (C 1 -C 3 )alkyl, optionally substituted 7-azaspiro[3.5]nonanyl, optionally substituted morpholinyl, 1,1-dioxidothiomorpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, hexahydroimidazo[1,5-a]pyrazin-3(2H)-one, or optionally substituted pyrrolidinyl; wherein R a is H or (C 1 -C 3 )alkyl, and R b is optionally substituted (C 1 -C 3 )alkyl, methoxypropyl, -5-oxopyrrolidin-3-ylmethyl, or tetrahydrofuranyl.

16 . The compound according to claim 1 wherein R 2b is optionally substituted (C 1 -C 3 )alkyl, —CH 2 -pyrazolyl or —CH 2 -triazolyl.

17 . The compound according to claim 1 wherein R 2b is optionally substituted (C 1 -C 3 )alkyl, optionally substituted 7-azaspiro[3.5]nonanyl, optionally substituted morpholinyl, or hexahydroimidazo[1,5-a]pyrazin-3(2H)-one.

18 . The compound according to claim 1 wherein R 2b is optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl.

19 . The compound according to claim 1 wherein R 2b is optionally substituted by one or more substituents independently selected from CH 3 , —C(O)CH 2 OH, —C(O)CH 3 .

20 . The compound according to claim 1 wherein the compound is:
3-(2-(Difluoromethoxy)phenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-morpholinopyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
1-(5-(3-(2-(difluoromethoxy)phenyl)-9-oxo-1,2,3,9-tetrahydropyrazolo[1,2-a]indazol-6-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(methoxymethyl)pyrrolidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((R)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((S)-2-(hydroxymethyl)morpholino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(Difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
3-(2-(difluoromethoxy)phenyl)-6-(2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((S)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((S)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((R)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-((((R)-5-oxopyrrolidin-3-yl)methyl)amino)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(R)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluoromethoxy)phenyl)-6-(2-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-(difluorometboxy)phenyl)-6-(2-((S)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyrimidin-5-yl)-2,3-dihydropyrazolo[1,2-a]indazol-9(1H)-one;
(S)-3-(2-

Assignees

• Abbvie Inc

Inventors

• Breinlinger Eric
• Burchat Andrew
• Dietrich Justin
• Friedman Michael
• Ihle David
• Kinsman David
• Mullen Kelly
• OSUMA Augustine
• Vasudevan Anil
• Wilson Noel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P27/14

  Decongestants or antiallergics · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title