Indazolones as modulators of TNF signaling

Patent metadata

Field	Value
Publication number	US-10273238-B2
Application number	US-201715852179-A
Country	US
Kind code	B2
Filing date	Dec 22, 2017
Priority date	Apr 17, 2015
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

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 or stereoisomer thereof, wherein:
X is —CR 4 , and 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; and
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 the group consisting of H, optionally substituted (C 1 -C 5 )alkyl, and —(CH 2 ) n -optionally substituted heterocyclyl;
each instance of R 4 is independently H, halo, CF 3 , or (C 1 -C 3 )alkyl;
each instance of R z is independently H, halo, CF 3 , or (C 1 -C 3 )alkyl;
n is 1; and
p is 0 or 1;
wherein heterocyclyl is:
a non-aromatic monocyclic, bicyclic, tricyclic, or spirocyclic ring having 5 to 12 ring atoms which include at least one nitrogen, oxygen, or sulfur ring atom; or
an azetidinyl ring.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, 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; and
R a and R b are independently selected from the group consisting of H, optionally substituted (C 1 -C 5 )alkyl, and —(CH 2 ) n -optionally substituted heterocyclyl.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein E is CH 2 , and G is CH or N.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CH, Y is CH, and Z is CR 4 .

5. The compound according to claim 4 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is F.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein X is CH, Y is CH, and Z is CH.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein E is CH 2 , and G is N.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, 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 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted phenyl.

10. The compound according to claim 9 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted by one or more substituents independently selected from the group consisting of —CF 3 , —CN, —C(O)NH 2 , —OCHF 2 , —OCH 3 , and (C 1 -C 3 )alkyl.

11. The compound according to claim 10 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is optionally substituted by one or more substituents independently selected from the group consisting of —CH 3 and —OCHF 2 .

12. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is optionally substituted pyrimidinyl or optionally substituted dihydropyranyl.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, 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 , or a pharmaceutically acceptable salt or stereoisomer thereof, 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 14 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R a is H or (C 1 -C 3 )alkyl, R b is (C 1 -C 3 )alkyl, methoxypropyl, 5-oxopyrrolidin-3-ylmethyl, or tetrahydrofuranyl, and R 2b is optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2a is optionally substituted pyrimidinyl.

17. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2b is optionally substituted morpholinyl, optionally substituted piperidinyl, or 1,1-dioxidothiomorpholinyl.

18. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
X is CH;
Y is CH;
Z is CR 4 , wherein R 4 is H or F;
A is —C(R z ) 2 — wherein R z is H;
E is CH 2 ;
G is N;
R 1 is phenyl optionally substituted by one or more substituents independently selected from the group consisting of —CF 3 , —CN, —C(O)NH 2 , —OCHF 2 , —OCH 3 , and (C 1 -C 3 )alkyl;
R 2 is —R 2a —R 2b , wherein R 2a is pyrimidinyl, and R 2b is selected from the group consisting of:
—N(R a )(R b ) wherein R a is H or (C 1 -C 3 )alkyl, and R b is (C 1 -C 3 )alkyl, methoxypropyl, 5-oxopyrrolidin-3-ylmethyl, or tetrahydrofuranyl;
(C 1 -C 3 )alkyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
7-azaspiro[3.5]nonanyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
morpholinyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
piperazinyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
piperidinyl optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl;
hexahydroimidazo[1,5-a]pyrazin-3(2H)-one optionally substituted by —CH 2 OH, —C(OH)(CH 3 ) 2 , —C(O)CH 3 , —C(O)OH, —OH, or alkoxyalkyl; and
pyrrolidinyl 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 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein optionally substituted refers to substitution with one or more substituents selected from the group consisting of (C 1 -C 8 )alkyl; (C 2 -C 8 )alkenyl; (C 2 -C 8 )alkynyl; (C 3 -C 10 )cycloalkyl; F; Cl; Br; I; halogenated (C 1 -C 8 )alkyl; —O—(C 1 -C 8 )alkyl; ═O; ═CH 2 ; —OH; —CH 2 OH; —CH 2 OCH 3 ; —CH 2 NH 2 ; (C 1 -C 4 )alkyl-OH; —CH 2 CH 2 OCH 2 CH 3 ; —S—(C 1 -C 8 )alkyl; —SH; —NH(C 1 -C 8 )alkyl; —N((C 1 -C 8 )alkyl) 2 ; —NH 2 ; —C(O)NH 2 ; —CH 2 NHC(O)(C 1 -C 4 )alkyl; —CH 2 NHC(O)CH 2 Cl; —CH 2 NHC(O)CH 2 CN; —CH 2 NHC(O)CH 2 CH 2 N(CH 3 ) 2 ; —CH 2 NHC(O)C(═CH 2 )CH 3 ; —CH 2 NHC(O)(C 2 -C 4 )alkynyl; —CH

Assignees

• Abbvie Inc

Inventors

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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

• A61P27/14

  Decongestants or antiallergics · CPC title