Pyridazine derivatives as RORc modulators

Patent metadata

Field	Value
Publication number	US-9981916-B2
Application number	US-201414533358-A
Country	US
Kind code	B2
Filing date	Nov 5, 2014
Priority date	Nov 5, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

Compounds of the formula I:

or a pharmaceutical salt thereof,

wherein X, Ar 1 , R1, 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 II

or a pharmaceutical salt thereof,
wherein:
R 4 is:
halo-C 1-6 alkyl;
halo;
hydroxy;
hydroxy-C 1-6 alkyl;
C 1-6 alkoxy-C 1-6 alkyl;
C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl;
cyano;
cyano- C 1-6 alkyl;
aminosulfonylC 1-6 alkyl
—(CR f R g ) m NR h R i ;
—(CR f R g ) m —C(O)—NR j R k ;
—(CR f R g ) m —C(O)—R m ;
—(CR f R g ) m —NR p —C(O)—R n ;
—(CR f R g ) m —O—C(O)—R n ;
a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl,
a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, oxo, C 3-6 cycloalky, halo-C 1-6 alkyl, amino, N—C 1-6 alkyl-amino, N,N-di-C 1-6 alkyl-amino amino-C 1-6 alkyl, cyano-C 1-6 alkyl, or C 1-6 alkoxycarbonyl;
heteroaryl-CH 2 —, wherein the heteroaryl moiety is selected from pyrazolyl and oxadiazolyl, each of which may be unsubstituted or substituted one or more times with C 1-6 alkyl, hydroxy-C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, or oxo;
heteroaryloxy-CH 2 —, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C 1-6 alkyl, hydroxy-C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, or oxo;
phenyl-C 1-6 alkoxy- CH 2 —, wherein the phenyl moiety may be unsubstituted or substituted one or more times with C 1-6 alkoxy-carbonyl, carboxy, or aminocarbonyl;
heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with with C 1-6 alkyl, or oxo; or
heterocyclyl- CH 2 —, wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholin-4-yl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C 1-6 alkyl, oxo, morpholinylethyl, or cyano;

m is from 0 to 2;
R 8 and R 9 are halo, or one of; R 8 and R 9 is halo and the other is hydrogen;

R f and R g each independently is:
hydrogen; or
C 1-6 alkyl;
R h is:
hydrogen;
C 1-6 alkyl;
C 1-6 alkoxy-C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
amino-C 1-6 alkyl;
N—C 1-6 alkyl-amino-C 1-6 alky;
N,N-di-C 1-6 alkyl-amino-C 1-6 alkyl; or
halo-C 1-6 alkyl;

R i is:
C 1-6 alkyl;
C 1-6 alkoxy-C 1-6 alkyl;
halo-C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
C 1-6 alkylsulfonyl;
C 1-6 alkylcarbonyl;
hydroxy-C 1-6 alkoxy;
aminocarbonyl-C 1-6 alkyl,
hydroxy-C 1-6 alkyl-carbonyl,
cyano-C 1-6 alkyl;
oxetanyl;
C 1-6 alkylsulfonyl;
halo-C 1-6 alkylsulfonyl; or
heteroaryl selected from oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which which may be unsubstituted or substituted one or more times with C 1-6 alkyl, hydroxy-C 1-6 alkyl, oxo, or halo-C 1-6 alkyl;

R j is:
hydrogen;
C 1-6 alkyl; or
benzyl

R k is:
hydrogen;
C 1-6 alkyl;
halo-C 1-6 alkyl;
cyano-C 1-6 alkyl;
hydroxy-C 1-6 alkoxy;
C 1-6 alkoxy;
C 3-6 cycloalkyl;
C 3-6 cycloalkyl-C 1-6 alkyl;
heteroaryl selected from oxadiazolyl, or pyridinyl, each of which which may be unsubstituted or substituted one or more times with C 1-6 alkyl, cyano, C 1-6 alkylsulfonyl, or halo;
phenyl which which may be unsubstituted or substituted one or more times with C 1-6 alkylsulfonyl; or
benzyl, the phenyl portion of which which may be unsubstituted or substituted one or more times with C 1-6 alkyl, halo,

or R j and R k together with the atoms to which they are attached may form a four to seven membered heterocyclyl selected from:
azetidinyl,
morpholinyl,
pyrolidinyl,
azabicyclo[3.1.0]hexanyl,
piperidinyl,
piperazinyl,
2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,
3-azabicyclo[3.1.0]hexanyl,
2-azabicyclo[2.1.1]hexanyl,
tetrahydro-1H-furo[3,4-c]pyrrolyl,
2-oxa-6-azaspiro[3.4]octanyl,
5-oxa-2-azaspiro[3.4]octanyl,
2-azabicyclo[3.1.0]hexanyl,
2,5-diazabicyclo[2.2.1]heptanyl,
2-azaspiro[3.3]heptanyl,
7-azabicyclo[2.2.1]heptanyl, or
8-azabicyclo[3.2.1]octanyl,
each of which may be unsubstituted or substituted one or more times with
C 1-6 alkyl,
halo,
amino,
N—C 1-6 alkyl-amino,
N,N-di-C 1-6 alkyl-amino,
hydroxy,
C 1-6 alkoxy-carbonyl,
C 1-6 alkoxy,
C 1-6 alkylsulfonyl,
hydroxy-C 1-6 alkyl,
C 1-6 alkoxy-C 1-6 alkyl,
halo-C 1-6 alkyl,
cyano,
cyano-C 1-6 alkyl,
amino-carbonyl,
N—C 1-6 alkyl-amino-carbonyl,
N,N-di-C 1-6 alkyl-amino-carbonyl,
C 1-6 alkyl-carbonyl-amino,
C 1-6 alkoxy-carbonyl-amino,
C 1-6 alkoxy-carbonyl-amino-C 1-6 alkyl,
benzyloxy,
pyrrolidinyl which may be unsubstituted or substituted one or more times with C 1-6 alkyl or halo; or
heteroaryl selected from pyrazolyl, pyrimidinyl, each of which may be unsubstituted or substituted one or more times with C 1-6 alkyl, oxo or halo;

R m is:
hydrogen;
C 1-6 alkyl;
cyano-C 1-6 alkyl;
halo-C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
C 1-6 alkoxy;
C 3-6 cycloalkyl;
C 3-6 cycloalkyl-C 1-6 alkyl;
C 1-6 alkoxy-C 1-6 alkyl; hydroxy-C 1-6 alkyl
amino-C 1-6 alkyl;
heteroaryl selected from pyridinyl, indolyl, and indolinyl; each of which which may be unsubstituted or substituted one or more times with C 1-6 alkyl, halo, cyano, halo-C 1-6 alkyl, or C 1-6 alkyl-sulfonyl
phenyl which which may be unsubstituted or substituted one or more times with C 1-6 alkyl,
phenyl-C 1-6 alkyl wherein the phenyl portion thereof may be unsubstituted or substituted one or more times with C 1-6 alkyl, or
heterocyclyl selected from azetidinyl, or oxetanyl, each of which which may be unsubstituted or substituted one or more times with C 1-6 alkyl, halo, cyano, or halo-C 1-6 alkyl,

R n is:
hydrogen;
C 1-6 alkyl;
halo-C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
hydroxy-C 1-6 alkoxy;
C 3-6 cycloalkyl;
C 3-6 cycloalkyl-C 1-6 alkyl;
C 1-6 alkoxy,
C 1-6 alkoxy-C 1-6 alkyl;
hydroxy-C 1-6 alkyl,
amino,
N—C 1-6 alkyl-amino,
N,N-di-C 1-6 alkyl-amino,
amino-C 1-6 alkyl,
N—C 1-6 alkyl-amino-C 1-6 alkyl,
N,N-di-C 1-6 alkyl-amino-C 1-6 alkyl,
amino-carbonyl-C 1-6 alkyl,
N—C 1-6 alkyl-amino-carbonyl-C 1-6 alkyl,
N,N-di-C 1-6 alkyl-amino-carbonyl-C 1-6 alkyl,
amino-carbonyl-amino-C 1-6 alkyl,
5-methylisoxazole-3-yl;
cyano-C 1-6 alkyl;
C 1-6 alkylsulfonyl;
C 1-6 alkylcarbonyl-amino-C 1-6 alkyl, or
C 1-6 alkylsulfonyl-C 1-6 alkyl; and

R p is:
hydrogen;
C 1-6 alkyl;
halo-C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
C 1-6 alkoxycarbonyl-C 1-6 alkyl; or
cyano-C 1-6 alkyl.

2. The compound of claim 1 , wherein R 8 and R 9 are fluoro.

3. The compound of claim 1 , wherein R 4 is:
—(CR f R g ) m NR h R i ;
—(CR f R g ) m —C(O)—NR j R k ;
—(CR f R g ) m —C(O)—R m ;
—(CR f R g ) m —NR p —C(O)—R n ;
—(CR f R g ) m —O—C(O)—R n ;
a six membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl,
a five membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, oxo, C 3-6 cycloalky, halo-C 1-6 alkyl, amino, N—C 1-6 alkyl-amino, N,N-di-C 1-6 alkyl-amino amino-C 1-6 alkyl, cyano-C 1-6 alkyl, or C 1-6 alkoxycarbonyl;
heteroaryl-C 1-6 alkyl, wherein the C 1-6 alkyl moiety may be unsubstituted or substituted one or more times with hydroxy or C

Assignees

• Genentech Inc

Inventors

• Bodil Van Niel Monique
• Cridland Andrew
• Fauber Benjamin
• Gobbi Alberto
• Hurley Christopher
• Hurst David
• Killen Jonathan
• Maxey Robert
• Ward Stuart

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

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

• A61P17/06

  Antipsoriatics · CPC title