Tricyclic modulators of tnf signaling

Patent metadata

Field	Value
Publication number	US-2016304517-A1
Application number	US-201615130362-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 invention provides tricyclic heterocyclic compounds, pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variables are defined herein. The compounds of the invention may be useful for treating immunological and oncological conditions.

First claim

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein:
R 1 is H, OH, F or optionally substituted (C 1 -C 3 )alkyl;
R 2 is optionally substituted aryl, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted heteroaryl or optionally substituted heterocyclyl; or
R 1 and R 2 together can form an optionally substituted saturated or partially saturated carbocyclic ring or optionally substituted saturated or partially saturated heterocyclic ring;
A 1 , A 2 , and A 3 are independently C(R A2 ) or N, provided that at least one is C(R A2 );
X is N and Y is C, wherein:
Z is —C(R z ) 2 — and Z 2 is —C(R z ) 2 —, —N(R z1 )— or —O—; or
Z 1 is —CH 2 — and Z 2 is —Z 2a -Z 2b ,
wherein Z 2a is attached to Z 1 and Z 2b is attached to C(R 1 )(R 2 ); and
Z 2a and Z 2b are independently —C(R z ) 2 —, —C(R z ) 2 C(R z ) 2 —, —O— or —N(R z1 )— provided that one of Z 2a and Z 2b is —C(R z ) 2 — or —C(R z ) 2 C(R z ) 2 —; or
—Z 2a -Z 2b -form —N(R z1 )C(O)— or —C(O)N(R z1 )—;

or
X is C and Y is N, provided that R 1 is not —OH or —F, wherein:
Z 1 is —C(R z ) 2 — and Z 2 is —C(R z ) 2 —; or
Z 1 is —C(R z ) 2 — and Z 2 is —Z 2a -Z 2b —
wherein Z 2a is attached to Z 1 and Z 2b is attached to C(R 1 )(R 2 ), and
Z 2a is —C(R z ) 2 —, —C(R z ) 2 C(R z ) 2 —, —O— or —N(R z1 ), and Z 2b is —C(R z ) 2 —, or
—Z 2a -Z 2b -form —N(R z1 )C(O)— or —C(O)N(R z1 )—;

R 3 is —R 3a —R 3b , wherein:
R 3a is an optionally substituted aryl, optionally substituted saturated or partially saturated heterocyclyl or optionally substituted heteroaryl;
R 3b is —CF 3 , —CN, —C(O)OH, —N(R a )(R b ), —C(O)N(R a )(R b ), —C(O)-optionally substituted heterocyclyl, —O(R a ), —S(O) 2 (C 1 -C 3 )alkyl, —S(O) 2 N(R)(R d )—, alkyl, —S(O) 2 —R c optionally substituted (C 1 -C 5 )alkyl, —(CH 2 ) p -optionally substituted (C 3 -C 6 )cycloalkyl, —(CH 2 ) p -optionally substituted heteroaryl or —(CH 2 ) p -optionally substituted saturated, unsaturated or partially saturated heterocyclyl; provided that R3 b is not methoxy when R 2 is optionally substituted phenyl;

R a and R b are independently selected from H, optionally substituted (C 1 -C 5 )alkyl, —C(O)-optionally substituted (C 1 -C 5 )alkyl, optionally substituted —(CH 2 ) p —(C 3 -C 6 )cycloalkyl and —(CH 2 ) p -optionally substituted heterocyclyl;
R c and R d are independently selected from H, optionally substituted (C 1 -C 5 )alkyl, optionally substituted —(CH 2 ) p —(C 3 -C 6 )cycloalkyl and —(CH 2 ) p -optionally substituted heterocyclyl;
R A2 is independently H, CF 3 , or (C 1 -C 3 )alkyl;
R z is independently H, F, CF 3 , —OH or (C 1 -C 3 )alkyl;
R z1 is independently H or (C 1 -C 3 )alkyl; and
p is independently 0, 1 or 2;
provided that R 2 is not phenyl substituted with —OCHF 2 ; and
provided the compound is not
1-(2-methylphenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole;
7-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole;
(1R or S)-7-(6-methylsulfonyl-3-pyridyl)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole;
[5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]methanol;
tert-butyl 4-[5-[(1R or S)-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-7-yl]-2-pyridyl]piperazine-1-carboxylate;
(1R or S)-7-[6-chloromethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole;
(1R or S)-7-[(6-(methylsulfonylmethyl)-3-pyridyl]-1-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole; or
(1R or S)-1-phenyl-7-[6-(piperazin-1-yl)pyridine-3-yl]-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole.

2 . The compound of claim 1 , wherein R 2 is phenyl, tetrahydropyranyl, pyridinyl or cyclohexyl, each of which is independently optionally substituted with 1 to 3 groups selected from halogen, —CN, —NR a , —OR a , —CF 3 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-OR a , —(C 1 -C 6 )alkylene-NR a R a , and —(C 1 -C 6 )haloalkoxy, wherein R a is H or —(C 1 -C 6 )alkyl; and
R 1 is H, OH or optionally substituted (C 1 -C 3 )alkyl; or
R 1 and R 2 together form an optionally substituted spirocycle selected from

3 . The compound of claim 1 , wherein R 2 is phenyl or cyclohexyl, each of which is independently optionally substituted with 1 to 3 groups selected from halogen, —OR a , —(C 1 -C 6 )alkyl, and —(C 1 -C 6 )haloalkoxy, and
R 1 is H, OH or CH 3 ; or
R 1 and R 2 together form

4 . The compound of claim 1 , wherein R 3a is optionally substituted phenyl, optionally substituted imidazo[4,5-b]pyridinyl, optionally substituted [1,2,5]oxadiazolo[3,4-b]pyridinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrazinyl, optionally substituted pyridin-2(1H)-one, optionally substituted 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, optionally substituted furo[3,2-b]pyridinyl, optionally substituted benzo[d][1,3]dioxolyl, optionally substituted 1H-pyrazolyl, optionally substituted 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, optionally substituted pyrrolyl, optionally substituted [1,2,5]oxadiazolo[3,4-b]pyridinyl, optionally substituted pyrido[2,3-b]pyrazinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, optionally substituted pyridin-2(1H)-onyl, or optionally substituted thienyl.

5 . The compound of claim 1 , wherein R 3b is H, CF 3 , CN, —C(O)OH, —C(O)N(R a ) 2 , optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —CH 2 -optionally substituted heteroaryl, —N(R a ) 2 , —N(R c )S(O) 2 -optionally substituted (C 1 -C 3 )alkyl, —OR a , —S-optionally substituted (C 1 -C 3 )alkyl, —S(O) 2 -optionally substituted (C 1 -C 3 )alkyl, —S(O) 2 —N(R) 2 , —S(O) 2 -morpholinyl, optionally substituted azepanyl, optionally substituted 6-azaspiro[3.4]nonanyl, optionally substituted 7-azaspiro[3.5]nonanyl, optionally substituted azaspiro[3.4]octanyl, optionally substituted azetidinyl, optionally substituted 2,7-diazaspiro[4.4]nonanyl, optionally substituted diazepanyl, optionally substituted 3,10-diazabicyclo[4.3.1]decanyl, optionally substituted oxetanyl, hexahydroimidazo[1,2-a]pyrimidin-2(3H)-one, optionally substituted imidazolyl, hexahydroimidazo[1,2-c]pyrimidin-2(3H)-one, optionally substituted hexahydroimidazo[1,5-a]pyrazin-3(2H)-one, optionally substituted hexahydroimidazo[1,5-c]pyrazin-3(2H)-one, optionally substituted morpholinyl, optionally substituted oxazolo[3,4-a]pyrazine-3-one, 1,4-oxepanyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrazinyl, optionally substituted pyrazolyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one, optionally substituted tetrahydropyranyl, thiomorpholinyl 1,1-dioxide, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, optionally substituted 1,3,8-triazaspiro[4.5]decanyl.

6 . The compound of claim 1 , wherein R 3a is optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl, optionally substituted 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, optionally substituted furo[3,2-b]pyridinyl, optionally

Assignees

• Abbvie Inc

Inventors

• Breinlinger Eric C
• Cox Phil B
• Daanen Jerome
• Dietrich Justin
• Djuric Stevan
• Dombrowski Amanda W
• Frank Kristine E
• Friedman Michael M
• Gomtsyan Arthur
• Li Huan-Qui
• Longenecker Kenton
• OSUMA Augustine
• Rowley Ann Marie
• Schmidt Robert
• Vasudevan Anil
• Wilson Noel

Classifications

• C07D471/18

  Bridged systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D498/20

  Spiro-condensed systems · CPC title