# US 10,308,652 B2 · Tricyclic heterocyclic compounds useful as inhibitors of TNF

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- Number: US 10,308,652 B2
- Document ID: US10308652B2
- Status: Granted
- Kind: B2
- Application number: 15/558,708
- Filed: 2016-03-17
- Published: 2018-04-26
- Granted: 2019-06-04
- Earliest claimed: 2015-03-18
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Stephen T. Wrobleski; Gregory D. Brown; Shuqun Lin; Jingwu Duan; Zhonghui Lu; Murali T. G. Dhar; Hai-Yun Xiao; Andrew J. Tebben
- Web page: https://patentgrep.com/patent/US10308652B2

## CPC

- C07D 471/14: Ortho-condensed systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 487/06: Peri-condensed systems
- C07D 487/14: Ortho-condensed systems
- C07D 491/147: the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are compounds of Formula (I) or a salt thereof, wherein: X is N; W is: —(CR3R3)2-5-, —(CR3R3)x-Y—(CR3R3)y-, —Y—(CR3R3)2-3-Y—, —CR3R3-Y—(CR3R3)2-Y—, —Y—(CR3R3)2-Y—CR3R3-; and Y, R1, R2, R3, R5, R6, R8, x, and y 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.

## Claims

### Claim 1

A compound of Formula (I)
or a salt thereof, wherein:
X is N;
W is —CH2CH2—, —CH2CH2O—, —CH(OH)CH2O—, —C(CH3)(OH)CH2O—, —C(OH)(pyridinyl)CH2O—, —CH2CH2NH—, —CHFCH2NH—, or —CH(OH)CH2NH—;
R1 is phenyl, pyridinyl, or pyrimidinyl, each substituted 1 to 2 substituents independently selected from Cl, —CH3, —C(CH3)2OH,—C(CH2CH3)2OH, —C(CH3)(CH2CH3)OH, —CH(CH3)OCH2CH3, —OCH3, —OCH2CH3, —OCH2CH2CH3, —OCH(CH3)2, —OCH2C(CH3)3, —OCH2CH(CH3)2, —OCH2CH2OCH3, —OCH2C(CH3)2OH, —OCH2(methoxyphenyl), —S(O)2CH3, —S(O)2NH2, —S(O)2NH(CH3), —C(O)NH2, —C(O)(morpholinyl), —C(O)(methoxyazetidinyl), —C(O)NH(cyclopropyl), hydroxycyclopropyl, morpholinyl, and carboxymethyl piperazinyl;
R2 is H;
R5 is phenyl substituted with 1 to 2 substituents independently selected from F, Cl, —CH3, —CH2CH3, —CF3, —OCH3, —OCHF2, and —OCF3;
R6 is H or —CH3; and
R8 is H.

### Claim 2

The compound or a salt thereof, wherein said compound is:
(+/−)-9-(2-(difluoromethoxy)phenyl)-2-(6-methoxypyridin-3-yl)-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazine (1); (+/−)-2-(4-(9-(2-(difluoromethoxy)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)propan-2-ol (2); (+/−)-2-(5(9-(2-(difluoromethoxy)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2]pyridazin-2-yl)pyrimidin-2-yl)propan-2-ol (3); (+/')-cis and trans-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (4 and 5); cis-(6R,9R)-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl) phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (6); cis-(6S,9S)-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (7); (+/−)-cis-2-(4-((6S,9S)-9-(2-(difluoromethoxy) phenyl)-6-fluoro-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2- yl)phenyl) propan-2-ol (8); (+/−)-trans-2-(4-(9-(2-(difluoromethoxy)phenyl)-6-fluoro-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)propan-2-ol (9); (+/−)-cis-2-(5-(9-(2-(difluoromethoxy)phenyl)-6-fluoro-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)propan-2-ol (10); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-6-fluoro-2-(6-methoxypyridin-3-yl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazine (11); cis-(1S,4S)-2-(4-(9-(2-(difluoromethoxy)phenyl)-6-fluoro-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)propan-2-ol (12); cis-(1R,4R)-2-(4-(9-(2-(difluoromethoxy)phenyl)6-fluoro-6,7,8,9-tetrahydropyrido[′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)propan-2-ol (13); trans-(6R,9S)-9-(2-(difluoromethoxy) phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (14); trans-(6S,9R)-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (15); cis-(6R,9S)-9-(2-(difluoromethoxy)phenyl)-2-(6-methoxypyridin-3-yl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (16); 9-(2-(difluoromethoxy) phenyl)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (17); (4-(9-(2-(difluoromethoxy)phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3 :4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)(3-methoxyazetidin-1-yl) methanone (18); (4-(9-(2-(difluoromethoxy)phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)(morpholino)methanone (19); N-cyclopropyl-4-(9-(2-(difluoromethoxy)phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)benzamide (20); N-cyclopropyl-5-(9-(2-(difluoromethoxy) phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl) picolinamide (21); 2-(4-(5-(9-(2-(difluoromethoxy)phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)piperazin-1-yl)acetic acid (22); (+/−)-trans-9-(4-fluoro-2-methoxyphenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (23); (+/−)-trans-9-(2-ethylphenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (24); (+/−)-cis-9-(2-ethylphenyl)-2-(4-(2-hydroxypropan-2-yl) phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (25); 2-(4-(2-hydroxypropan-2-yl)phenyl)-9-(2-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (26); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-isobutoxyphenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (27); (+/−)-trans-9-(5-chloro-2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (28); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxy-2-methylpropoxy)phenyl)-6,7,8,9tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (29); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-6,7,8,9tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (30); (+/−)-cis-9-(2(difluoromethoxy)phenyl)-2-(4-ethoxyphenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo [1,2-b]pyridazin-6-ol (31); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-isopropoxyphenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (32); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-propoxyphenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (33); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-methoxyethoxy)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (34); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(1-ethoxyethyl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (35); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(1-hydroxycyclopropyl)phenyl)-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (36); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-((2-methoxybenzyl)oxy)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (37); (+/−)-trans-9-(4-fluoro-2-methylphenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (38); (+/−)-cis-9-(4-fluoro-2-(trifluoromethyl)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (39); (+/−)-cis-4-(9-(2-(difluoromethoxy)phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)-N-methylbenzenesulfonamide (40); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(methylsulfonyl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (41); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(neopentyloxy)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (42); (+/−)-cis-9-(4-fluoro-2-methylphenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (43); (+/−)-trans-9-(4-fluoro-2-methylphenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (44); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-morpholinophenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (45); (+/−)-cis-4-(9-(2-(difluoromethoxy)phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)benzenesulfonamide (46); (+/−)-cis-(2-chloro-4-(9-(2-(difluoromethoxy) phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)(morpholino)methanone (47); (+/−)-cis-2-chloro-4-(9-(2-(difluoromethoxy) phenyl)-6-hydroxy-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl) benzamide (48); (+/−)-cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(3-hydroxypentan-3-yl) phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (49); (+/−) cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxybutan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (50); (+/−)-trans-9-(2-(difluoromethoxy)phenyl)-2-(6-methoxypyridin-3-yl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (51); (+/−)trans-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxy-2-methylpropoxy)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (52); (+/−)-trans-9-(2,5-dimethylphenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (53); (+/−)-cis-9-(5-chloro-2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (54); (+/−)trans-9-(5-chloro-2-(trifluoromethyl)phenyl)-2-(4-(2-hydroxypropan-2-yl) phenyl)-6,7,8,9-tetrahydropyrido[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (55); (+/−)trans-9-(5-chloro-2-methoxyphenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,7,8,9-tetrahydropyrido [4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (56); rac-(6S,9S)-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-7,9-dihydro-6H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (57); cis-9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6,9-dihydro-7H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (58); 9-(2(difluoromethoxy) phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-methyl-6,9-dihydro-7H-pyrano[4′,3′:4,5] imidazo[1,2-b]pyridazin-6-ol (59); 9-(2-(difluoromethoxy)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-6-(pyridin-4-yl)-6,9-dihydro-7H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (60); cis-9-(2-(difluoromethoxy)phenyl)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6,9-dihydro-7H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (61); cis-9-(2-(difluoromethoxy) phenyl)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-6,9-dihydro-7H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazin-6-ol (61); 2-(4-(9-(2-(difluoromethoxy)phenyl)-7,9-dihydro-6H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)phenyl)propan-2-ol (62); 2-(5-(9-(2-(difluoromethoxy)phenyl)-7,9-dihydro-6H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazin-2-yl)pyrimidin-2-yl)propan-2-ol (63); or 9-(2-(difluoromethoxy)phenyl)-2-(1-methyl-1H-pyrazol-4yl)-7,9-dihydro-6H-pyrano[4′,3′:4,5]imidazo[1,2-b]pyridazine (64).

### Claim 3 (depends on 1)

A pharmaceutical composition comprising one or more compounds according to claim 1 or a salt thereof; and a pharmaceutically acceptable carrier or diluent.