Tricyclic modulators of TNF signaling

Patent metadata

Field	Value
Publication number	US-9856253-B2
Application number	US-201615130362-A
Country	US
Kind code	B2
Filing date	Apr 15, 2016
Priority date	Apr 17, 2015
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

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

What is claimed:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is H or (C 1 -C 3 )alkyl;
R 2 is phenyl, tetrahydropyranyl, pyridinyl or cyclohexyl, each of which is optionally substituted with 1 to 3 groups selected from the group consisting of halogen, —CN, —NR f , —OR f , —CF 3 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-OR f , —(C 1 -C 6 )alkylene-NR f R f , and —(C 1 -C 6 )haloalkoxy, wherein R f is H or —(C 1 -C 6 )alkyl;
A 1 and A 2 are independently C(R A2 );
A 3 is N;
X is C and Y is N;
Z 1 is —C(R z ) 2 - and Z 2 is —C(R z ) 2 —;
R 3 is —R 3a —R 3b , wherein:
R 3a is aryl, saturated or partially saturated heterocyclyl, or heteroaryl;
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 c ) 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, or optionally substituted 1,3,8-triazaspiro[4.5]decanyl;
R a is selected from the group consisting of 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; and
R c is selected from the group consisting of 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;

provided a substituted R 3b group is substituted by one or more substituents independently selected from the group consisting of —F, —CH 3 ,—CH 2 OH, —CN, —CH 2 C(O)OCH 2 CH 3 , —C(O)CH 2 OH, —C(O)CH 3 , —C(O)OH, —NH 2 , —N(H)S(O) 2 CH 3 , —OH, and ═O;

each instance of R A2 is independently H, CF 3 , halo, or (C 1 -C 3 )alkyl;
each instance of R z is independently H, F, CF 3 , —OH or (C 1 -C 3 )alkyl; and
each instance of p is independently 0, 1 or 2;
further provided:
heterocyclyl is (i) a non-aromatic, saturated or unsaturated, monocyclic, bicyclic, tricyclic, or spirocyclic ring, having 5 to 12 ring atoms including at least one ring nitrogen, oxygen, or sulfur atom, or (ii) an azetidinyl ring; and
heteroaryl is an aromatic, monocyclic, bicyclic, or tricyclic ring, having 5 to 12 ring atoms including at least one nitrogen, oxygen, or sulfur atom.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl substituted with 1 group selected from the group consisting of halogen, —CN, —NR f ,—OR f , —CF 3 , —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkylene-OR f , —(C 1 -C 6 )alkylene-NR f R f , and -(C 1 -C 6 )haloalkoxy, wherein R f is H or —(C 1 -C 6 )alkyl; and
R 1 is H.

3. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is phenyl substituted with 1 group selected from the group consisting of halogen, —OR f ,—(C 1 -C 6 )alkyl, and —(C 1 -C 6 )haloalkoxy, and
R 1 is H.

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

5. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3b is (C 1 -C 3 )alkyl optionally substituted by one or more substituents independently selected from the group consisting of —F, —CH 3 , —CH 2 OH, —CN, —CH 2 C(O)OCH 2 CH 3 , —C(O)CH 2 OH, —C(O)CH 3 , —C(O)OH, —NH 2 , —N(H)S(O) 2 CH 3 , —OH, and ═O.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3a is phenyl, piperazinyl, piperidinyl, pyrimidinyl, pyridinyl, 3,4 -dihydro- 2H-pyrido [3,2 -b][1,4]oxazinyl, furo [3,2-b]pyridinyl, benzo[d][1,3]dioxolyl, or thienyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3b is CF 3 , CN, —C(O)OH, —C(O)N(H) 2 —C(O)N(H)(cyclopropyl), optionally substituted (C 1 -C 3 )alkyl, optionally substituted cyclobutyl, optionally substituted cyclopropyl, —N(H)(optionally substituted (C 1 -C 3 )alkyl), —N(optionally substituted (C 1 -C 3 )alkyl)) 2 , —N(H)(cyclopropyl), —N(H)(cyclopentyl), —N(R c )S(O) 2 -optionally substituted (C 1 -C 3 )alkyl, —O-tetrahydropyranyl, —O-optionally substituted (C 1 -C 3 )alkyl, —S—CH 3 , —S(O) 2 —CH 3 , —S(O) 2 —N(R c ) 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 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, or optionally substituted 1,3,8-triazaspiro[4.5]decanyl,
provided a substituted R 3b group is substituted by one or more substituents independently selected from the group consisting of —F, —CH 3 , —CH 2 OH, —CN, —CH 2 C(O)OCH 2 CH 3 , —C(O)CH 2 OH, —C(O)CH 3 , —C(O)OH, —NH 2 ,—N(H)S(O) 2 CH 3 , —OH, and ═O.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein a substituted

Assignees

• Abbvie Inc
• Abbvie Inc

Inventors

• Breinlinger Eric C
• Cox Phil B
• Dietrich Justin
• Frank Kristine E
• Friedman Michael M
• Li Huan-Qui
• Longenecker Kenton
• OSUMA Augustine
• Rowley Ann Marie
• Vasudevan Anil
• Wilson Noel

Classifications

• 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

• C07D471/18

  Bridged systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D498/18

  Bridged systems · CPC title

• C07D498/20

  Spiro-condensed systems · CPC title