US 10,308,652 B2Granted

Tricyclic heterocyclic compounds useful as inhibitors of TNF

AssigneeBristol-Myers Squibb Company

InventorsStephen T. Wrobleski, Gregory D. Brown, Shuqun Lin, Jingwu Duan, Zhonghui Lu, Murali T. G. Dhar, Hai-Yun Xiao, Andrew J. Tebben

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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.

Claims3

Dependent claims

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.

6 more elements

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).

61 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/558,708Filed 17 Mar 2016 · us provisional application
Priority: 18 Mar 2015
Published: US 2018/0111937 A126 Apr 2018
Granted: 4 Jun 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07D 471/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 37/00
Drugs for immunological or allergic disorders
C07D 487/06
In which the condensed system contains two hetero rings: peri-condensed systems

Family

Application62/134,779Us provisional application · filed 18 Mar 2015
US 2018/0111937 A1Pre-grant publication · published 26 Apr 2018
US 10,308,652 B2This patent

From the US filing history. Foreign family members aren’t listed.

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