Heterocyclic compounds useful as modulators of TNF alpha

Patent metadata

Field	Value
Publication number	US-10865191-B2
Application number	US-201615887214-A
Country	US
Kind code	B2
Filing date	Aug 2, 2016
Priority date	Aug 3, 2015
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

Abstract

Disclosed are compounds of Formula (I) or a salt thereof, wherein: A is CR 1 or N; B is CR 3 or N; D is CR 4 or N; L 1 is —(CR 7 R 7 ) m —; L 2 is —(CR 7 R 7 ) n —; and X, Z, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are define herein. Also disclosed are methods of using such compounds as modulators of TNFα, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt thereof, wherein:
A is CR 1 ;
B is CR 3 ;
D is CR 4 ;
X is —NR 8 —;
L 1 is a bond or —CH 2 ;
L 2 is a bond, —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH(CH 2 F)—, —CH(CHF 2 )—, —CH(CF 3 )—, —CH(CH 2 CH 3 )—, —CH(CH 2 CH 2 F)—, —CH(CH 2 CHF 2 )—, —CH(CH 2 CF 3 )—, —CH(CH 2 CH 2 OH)—, —CH(CH 2 N(CH 3 ) 2 )—, —CH(C(CH 3 ) 2 OH)—, —CH(CH 2 CH═CH 2 )—, —CH(CH 3 )CH 2 —, —CH(cyclopropyl)-, —CH(CH(CH 3 ) 2 )—, —CH(C(CH 3 ) 2 F)—, —CH(CH 3 )CH 2 CH 2 —, —CH(CH 3 )CH 2 C(OH)(phenyl)-, cyclopropyl, or cyclobutyl;
Z is a cyclic group selected from C 3-6 cycloalkyl, cyclopentenyl, phenyl, furanyl, imidazolyl, indolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, thiazolyl, and thiophenyl, wherein said cyclic group is substituted with zero to 3 R a ;
R 1 is H or F;
R 2 is (i) F, Cl, or Br; or (ii) dihydropyridinonyl, phenyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, or pyrimidinyl, each substituted with zero to 3 R 1a ;
R 3 is H, F, or Cl;
R 4 is H, F, or Cl;
R 5 is H, —OH, —CH 3 , —CH 2 OH, —CH 2 NH 2 , —CH 2 N 3 , —C(O)OH, —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , —CH 2 NH(dimethylphenyl), —C(O)NH(pyridinyl), —C(O)NH(phenyl), or —CH 2 O(pyridinyl);
R 6 is F, Cl, or —CH 3 ;
R 8 is H, —CH 3 , or —CH 2 CH 3 ;
each R 1a is independently F, —CN, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH 2 OH, —CH(CH 3 )(OH)CH 2 OH, —C(CH 2 F) 2 OH, —C(CH 3 ) 2 NHC(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 2 CH 2 CH 2 CH 2 NH 2 , —C(O)NHCH 3 , —C(O)OH, —CH(C(O)OCH 3 )CH 2 NH 2 , —CH(CH 2 OH)NHC(O)CH 3 , —CH(NH 2 )CH 2 OH, —CH(NH 2 )CH 2 C(O)OH, —CH 2 CH(NH 2 )C(O)OH, —CH 2 NH(CH 2 CH 3 ), —CH 2 NHC(O)CH 3 , —CH 2 NHC(O)NH 2 , —CH(OH)CH 2 NH(CH 3 ), —NH(CH 3 ), —NHCH 2 CH 2 OH, —NHCH 2 CH(OH)CH 2 OH, —NHCH 2 C(CH 3 ) 2 OH, —NHCH(CH 2 OH) 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(O)OH, —NHCH(CH 3 )C(O)NH 2 , —NHCH 2 CH(OH)CH 2 OH, —N(CH 3 )C(O)CH═CH 2 , —OCH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH(CH 3 ), —CH 2 (azetidinyl), —CH 2 (piperazinyl), —CH 2 (butoxycarbonylpiperazinyl), —CH(OH)(cyclopropyl), —CH(OH)CH 2 (morpholinyl), —CH(OH)CH 2 (carboxypyrrolidinyl), —NH(carbamoylcyclopropyl), C 3-6 cycloalkyl substituted with 1 to 2 substituents independently selected from —OH, —NH 2 , —NHC(O)NH 2 , —NHC(O)CH 3 , —NHCH 2 CH 2 OH, —NHS(O) 2 CH 3 , —CH 2 OH, —C(O)OH, and —C(O)CH 3 ; hydroxybutanonyl, hydroxypyrrolidinyl, carboxypyrrolidinyl, methoxycarbonylpyrrolidinyl, hydroxypropylpyrrolidinyl, hydroxypyranyl, hydroxyoxetanyl, hydroxymethylmorpholinyl, dioxohydroxytetrahydrothiopyranyl, piperidinyl substituted with 1 to 2 substituents independently selected from —NH 2 , —C(O)OH, —CH 2 C(O)OH, —C(CH 3 ) 2 OH, and —C(O)OCH 2 CH 3 ; piperazinyl substituted with zero or 1 substituent selected from —CH 2 OH, —CH 2 CN, —CH 2 C(O)OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —CH 2 C(O)NHCH 3 , —CH(C(O)OCH 3 )CH 2 NHC(O)CH 3 , —CH(C(O)OH)CH 2 NH 2 , —CH 2 C(O)NHS(O) 2 CH 3 , —CH 2 C(O)NHCH 2 C(O)OH, —CH(C(O)OH)CH 2 NHC(O)CH 3 , —CH(C(O)OH)CH 2 NHC(O)OC(CH 3 ) 3 , —C(O)OH, —C(O)CH(CH 3 )OH, —C(O)CH(NH 2 )CH 2 C(O)OH, —C(O)CH(NH 2 )CH 2 OH, —C(O)CH 2 CH 2 C(O)OH, —C(O)CH═CH 2 , —C(O)C≡CH, —CH 2 (tetrazolyl), and pyrrolidinonyl; piperazinonyl, carboxymethylpiperazinonyl, morpholinyl, dioxothiomorpholinyl, carboxyazabicyclo[3.2.1]octanyl, or pyridinyl;
each R a is independently F, Cl, Br, —CN, —OH, —CH 3 , —CH 2 CH 3 , —CH═CH 2 , —C≡C(phenyl), —CF 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH(CH 3 )OH, —CH 2 CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH 2 OH, —CH 2 CH(OH)CH 2 OH, —C(CH 3 )(OH)CH 2 OH, —CH(OH)CH(CH 3 )CH 2 CH(CH 3 ) 2 , —CH 2 NH 2 , —CH(NH 2 )CH 2 OH, —CH(NH 2 )CH(CH 3 )CH 2 CH 2 CH 3 , —CH 2 C(O)NH 2 , —CH 2 CH 2 C(O)NH 2 , —CH 2 (phenyl), —C(O)CH 3 , —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)NH(CH 2 CH 3 ), —C(O)N(CH 3 ) 2 , —C(O)CH(CH 3 )CH 2 CH 2 CH 3 , —C(O)(pyrazolyl), —C(O)(pyridinyl), —C(O)NH(phenyl), —C(O)OH, —CH 2 C(O)OH, —CH 2 CH 2 C(O)OH, —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —CH═NOH, —OCHF 2 , —OCH 3 , —OCF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 CH 2 OH, —OCH 2 C(O)OH, —OCH═CH 2 , —NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHCH(CH 3 )CH 2 CH(CH 3 )CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 CH 2 CH 2 C(O)OCH 3 , —S(O) 2 (methylpyrazolyl), oxazolidinonyl, cyclopentenyl, imidazolidine-2,4-dionyl, imidazolinonyl, methylimidazolyl, indolyl, morpholinonyl, morpholinyl, pyrazinyl, pyridazinyl, methylpyridazinyl, dimethoxypyridazinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolo[2,3-b]pyridinyl, tetrahydropyridinyl, tetrazolyl, methyltetrazolyl, thiazolyl, triazolyl, methyltriazolyl, phenyl substituted with zero to 2 substituents independently selected from F, Cl, —CN, —CH 3 , —NH 2 , —OCH 3 , and —OC(O)C(CH 3 ) 3 ; pyrazolyl substituted with zero to 2 substituents independently selected from —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —C(O)OH, —CH 2 C(O)OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 (phenyl), and —CH 2 CH 2 (morpholinyl); pyridinyl substituted with zero to 2 substituents independently selected from —CN, —CH 3 , —CH 2 CH 3 , —OCH 3 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , and —C(O)(morpholinyl); or pyrimidinyl substituted with zero to 1 substituent selected from —CH 3 , —C(CH 3 ) 2 OH, —OCH 3 , —NH 2 , —N(CH 3 ) 2 , cyclopropyl, and morpholinyl.

2. The compound according to claim 1 or a salt thereof, wherein:
X is —NR 8 —;
L 1 is a bond;
L 2 is —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH(CH 2 F)—, —CH(CHF 2 )—, —CH(CF 3 )—, —CH(CH 2 CH 3 )—, —CH(CH 2 CH 2 F)—, —CH(CH 2 CHF 2 )—, —CH(CH 2 CF 3 )—, —CH(CH 2 CH 2 OH)—, —CH(CH 2 N(CH 3 ) 2 )—, —CH(C(CH 3 ) 2 OH)—, —CH(CH 3 )CH 2 —, —CH(cyclopropyl)-, —CH(CH(CH 3 ) 2 )—, —CH(C(CH 3 ) 2 F)—, or —CH(CH 3 )CH 2 CH 2 —;
Z is a cyclic group selected from piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, or pyrimidinyl, each substituted with zero to 3 R a ;
each R a is independently F, Cl, Br, —CN, —OH, C 1-2 alkyl, —CF 3 , —CH═CH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH(CH 3 )OH, —CH 2 CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —C(CH 3 )(OH)CH 2 OH, —CH(OH)CH 2 OH, —CH 2 CH(OH)CH 2 OH, —CH 2 CH 2 C(O)OH, —CH(NH 2 )CH 2 OH, —CH 2 (phenyl), —CH 2 C(O)NH 2 , —CH 2 C(O)OH, —CH 2 CH 2 C(O)NH 2 , —OCH 3 , —OCHF 2 , —OCF 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 CH 2 OH, —OCH 2 C(O)OH, —OCH═CH 2 , —C≡C(phenyl), —CH═N—OH, —C(O)OH, —C(O)CH 3 , —C(O)OCH 3 , —C(O)OC(CH 3 ) 3 , —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)NH(CH 2 CH 3 ), —C(O)N(CH 3 ) 2 , —C(O)NH(phenyl), —C(O)(pyrazolyl), —C(O)(pyridinyl), —NH 2 , —CH 2 NH 2 , —NHC(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 CH 2 CH 2 C(O)OCH 3 , —S(O) 2 (methylpyrazolyl), cyclopentenyl, phenyl, methylphenyl, cyanophenyl, aminophenyl, butoxycarbonyl phenyl, methoxyphenyl, oxazolidinonyl, indolyl, methylimidazolyl, imidazolinonyl, imidazolidine-2,4-dionyl, pyrazinyl, pyridazinyl, methylpyridazinyl, dimethoxypyridazinyl, pyrrolidinyl, pyrrolidinonyl, chlorophenyl, fluorophenyl, morpholinyl, morpholinonyl, methyltriazolyl, triazolyl, tetrazolyl, methyltetrazolyl, tetrahydropyridinyl, pyrrolo[2,3-b]pyridinyl, pyrazolyl substituted with zero to 2 substituents independently selected from —CH 3 , —CH 2 CH 3 , —CHF 2 , —CF 3 , —CH 2 C(CH 3 ) 2 OH, —CH 2 C(O)OH, —CH 2 (phenyl), —C(O)OH, and —CH 2 CH 2 (morpholinyl); pyrimidinyl substituted with zero to one substituent selected from —NH 2 , —N(CH 3 ) 2 , —CH 3 , —C(CH 3 ) 2 OH, —OCH 3 , cyclopropyl, and morpholinyl; or pyridinyl substituted with zero to 2 substituents independently selected from —CN, —CH 3 , —CH 2 CH 3 , —OCH 3 , —NH 2 , —NH(CH 3 ), —N(CH 3 ) 2 , and —C(O)(morpholinyl);
R 2 is dihydropyridinonyl, phenyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, or pyrimidinyl, each substituted with zero to 3 R 1a ; and
R 8 is

Assignees

• Bristol Myers Squibb Co

Inventors

• Xiao Hai-Yun
• Dhar T G Murali
• Li Ning
• Duan Jingwu
• Jiang Bin
• Lu Zhonghui
• Ngu Khehyong
• Pitts William J
• Tino Joseph A

Classifications

• A61P29/00

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

• C07D215/44

  with aryl radicals attached to said nitrogen atoms · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D215/42

  attached in position 4 · CPC title