Pyridazine derivatives as RORc modulators

Patent metadata

Field	Value
Publication number	US-11008312-B2
Application number	US-201916398795-A
Country	US
Kind code	B2
Filing date	Apr 30, 2019
Priority date	Nov 1, 2016
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

Compounds of formula I:

or pharmaceutical salts thereof,

wherein m, n, p, q A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis.

First claim

What is claimed is:

1. A compound of formula I

or a pharmaceutical salt thereof,
wherein:
A is hetereoaryl selected from:
pyridinyl;
pyrimidinyl;
pyridazinyl; and
pyrazinyl;

B is piperidinyl or heteroaryl wherein the heteroaryl selected from the group consisting of:
oxazolyl;
isoxazolyl;
thiazolyl;
isothiazolyl;
pyrrolyl;
imidazolyl;
pyridazolyl;
triazolyl;
oxadiazolyl;
thiadiazolyl;
pyridinyl;
pyrimidinyl;
pyrazinyl;
pyridazinyl; and
2,3-dihydro-1H-imidazo[4,5-b]pyridinyl;

m is: 0; 1; or 2;
n is: 0; or 1;
p is: 0; or 1;
q is: 0; or 1;
R 1 is:
halo;

R 2 is:
hydrogen;
halo; or
methoxy;

R 3 is:
hydrogen;
cyano;
C 1-6 alkyl; or
halo;

R 4 is:
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;
C 2-6 alkenyl;
cyano;
hydroxyl-C 1-6 alkyl wherein the C 1-6 alkyl moiety may be unsubstituted or substituted one or more times with halo;
C 1-6 alkoxyC 1-6 alkyl wherein the C 1-6 alkyl moieties may be unsubstituted or substituted one or more times with halo;
oxo;
hydroxy;
C 1-6 alkylsulfinyl;
halo;

R 5 is:
—(CR a1 R a2 ) p —NR b R c ;
—(CR a1 R a2 ) p —SO 2 —R d ;
—(CR a1 R a2 ) p —C(O)—R e ;
—(CR a1 R a2 ) p —NR b —SO 2 —R d ;
—(CR a1 R a2 ) p —NR b —C(O)—R e ;
—(CR a1 R a2 ) p —NR b —(CHR c ) q —SO 2 —R d ;
—(CR a1 R a2 ) p NR b —(CHR c q —C(O)—R e ;
—(CR a1 R a2 ) p —CN;
—C 2-6 alkenyl-CN;
—(CR a1 R a2 ) p —Z;
—(CR a1 R a2 ) p —SO 2 —Z;
C 1-6 alkylsulfonimidamido; or
C 1-6 alkylsulfonimidoylC 1-6 alkyl;

R 6 is:
C 1-6 alkyl;
halo; or
hydroxyl;

R 7 is:
C 1-6 alkyl;
C 1-6 alkoxy;
halo; or
hydroxyl;

Z is:
C 3-6 cycloalkyl which may be unsubstituted or substituted once or twice with R f ;
a four or five membered heterocyclyl selected from azetidinyl, oxetanyl, thietanyl or tetrahydrothiophenyl, each of which may be unsubstituted or substituted once or twice with R f ;
C 1-6 alkyl-heterocyclyl wherein the heterocyclyl is a four or five membered heterocyclyl selected from azetidinyl, oxetanyl, thietanyl or tetrahydrothiophenyl, each of which may be unsubstituted or substituted once or twice with R f ; or
C 1-6 alkylcarbonylaminoC 1-6 alkyl;

p is: 0; 1; 2; or 3
q is: 1; or 2;
R a1 is:
hydrogen;
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;

R a2 is:
hydrogen;
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo; or
hydroxyl;
or R a1 and R a2 may together form a ═CH 2 group;

R b is:
hydrogen;
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo; or
hydroxyl-C 1-6 alkyl wherein the C 1-6 alkyl moiety may be unsubstituted or substituted one or more times with halo;

R c is:
hydrogen; or
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;

R d is:
C 1-6 alky which may be unsubstituted or substituted one or more times with halo;
C 3-6 cycloalkyl;
C 3-6 cycloalkyl-C 1-6 alkyl;
hydroxyC 1-6 alkyl; or
NR b R c ;

R e is:
C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;
C 1-6 alkoxy;
hydroxyl-C 3-6 alkyl or
hydroxyl; or
NR b R c ; and

R f is: C 1-6 alkyl which may be unsubstituted or substituted one or more times with halo;
halo;
oxo;
cyanoC 1-6 alkyl;
hydroxy;
—CH 2 COOH;
hydroxyC 1-6 alkyl; or
C 1-6 alkylsulfonylC 1-6 alkyl;

and wherein the compound is selected from:
3-[2-[6[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]oxetan-3-ol;
[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methanamine;
N-[[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methyl]methanesulfonamide;
2,2,2-trifluoro-N-[[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methyl]ethanamine;
[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methylurea;
(2S)-2-[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]propane-1,2-diol;
(S)-cyclopropyl-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methanol;
(R)-cyclopropyl-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methanol;
(1R)-2,2-difluoro-1-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]ethanol;
(1S)-2,2-difluoro-1-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]ethanol
(1S)-2-methyl-1-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]propan-1-ol;
2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]-4-[(1R)-1-methylsulfonylethyl]oxazole;
2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]-4-[(1S)-1-methylsulfonylethyl]oxazole;
4-(isopropylsulfonylmethyl)-2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazole;
(2S)-2-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]propanamide;
(2R)-2-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]propanamide;
N-(2-hydroxyethyl)-2-[2-[6-[(1R,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]acetamide;
3-[4-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]pyrazol-1-yl]propanenitrile;
(2R)-1-[4-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]pyrazol-1-yl]propan-2-ol;
(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-1-[6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]pyrazin-2-yl]-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene;
(2S)-1-[4-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]pyrazol-1-yl]propan-2-ol;
N-[(1R)-1-[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]ethyl]methanesulfonamide;
[5-methyl-2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methanol;
5-methyl-4-(methylsulfonylmethyl)-2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazole;
ethyl N-[[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyrazin-2-yl]oxazol-4-yl]methyl]carbamate;
[2-[6-[(1S,8R)-5-(2,6-difluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-1-yl]pyraz

Assignees

• Genentech Inc

Inventors

• Bronner Sarah M
• Crawford James J
• Cridland Andrew
• Cyr Patrick
• Fauber Benjamin
• Gancia Emanuela
• Gobbi Alberto
• Hurley Christopher
• Killen Jonathan
• Lee Wendy
• Rene Olivier
• Van Niel Monique Bodil
• Ward Stuart
• Winship Paul
• Zbieg Jason

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title