Pyridazine derivatives as RORc modulators

Patent metadata

Field	Value
Publication number	US-10487068-B2
Application number	US-201715801201-A
Country	US
Kind code	B2
Filing date	Nov 1, 2017
Priority date	May 4, 2015
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

Abstract

Compounds of formula I:

or pharmaceutical salts thereof,

wherein m, n, A, R1, R 2 , R 3 , R 4 and R 5 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:
a six membered hetereoaryl selected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; and triazinyl;

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

R 2 is:
hydrogen; or
halo;

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

R 4 is:
C 1-6 alkyl;
oxo;
hydroxy;
C 1-6 alkyoxy;
C 1-6 alkyoxycarbonyl;
halo-C 1-6 alkyl;
cyano; or
halo;

R 5 is:
heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxadiazolyl, triazolyl, oxazolyl, tetrazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl and thiadiazolyl, each of which may be unsubstituted or substituted once or twice with R a ;
heterocyclyl selected from azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, morpholinyl, 1-oxa-6-azaspiro[3.3]heptanyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolinidinyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydrotriazinyl, thiomorpolinyl, 1,1-dioxo-thiomorpholinyl, and dihydropyridinyl, each of which may be unsubstituted or substituted once or twice with R a ;
cyano;
—NR b R c ;
—C 1-6 alkylene-NR b R c ;
—OR d ;
—C(O)NR e R f ;
—SO 2 NR e R f ;
—C(O)OR g ; or
hydroxy-C 1-6 alkyl;

R a is:
C 1-6 alkyl;
C 1-6 alkenyl;
C 1-6 alkynyl;
amino;
cyano;
cyano-C 1-6 alkyl;
hydroxy;
oxo;
halo;
halo-C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
hydroxy-C 1-6 alkoxy;
hydroxy-C 1-6 alkyl substituted with halo;
hydroxy-C 1-6 alkoxy substituted with halo;
aminocarbonyl;
aminocarbonyl-C 1-6 alkyl;
aminocarbonyl-C 1-6 alkoxy;
hydroxy-C 1-6 alkylaminocarbonyl;
C 1-6 alkylcarbonyl;
hydroxy-C 1-6 alkylcarbonyl;
C 3-6 cycloalkyl which may be unsubstituted or substituted once with R h ;
C 1-6 alkyoxycarbonyl;
C 1-6 alkylsulfonyl;
C 1-6 alkylsulfonyl-C 1-6 alkyl;
C 3-6 cycloalkylsulfonyl;
C 3-6 cycloalkylsulfonyl-C 1-6 alkyl;
C 3-6 cycloalkyl-C 1-6 alkylsulfonyl;
C 3-6 cycloalkyl-C 1-6 alkylsulfonyl-C 1-6 alkyl;
oxetanyl which may be unsubstituted or substituted once with R h ;

R b is:
hydrogen; or
C 1-6 alkyl;

R c is:
hydrogen;
C 1-6 alkyl;
halo-C 1-6 alkyl;
cyano-C 1-6 alkyl;
C 1-6 alkylcarbonyl;
hydroxy-C 1-6 alkylcarbonyl;
oxetanylcarbonyl;
oxetanylsulfonyl;
C 1-6 alkylsulfonyl;
C 1-6 alkylsulfonyl-C 1-6 alkyl;
hydroxyl-C 1-6 alkyl;
C 1-6 alkyoxy-C 1-6 alkyl;
C 3-6 cycloalkyl which may be unsubstituted or substituted once with R h ;
C 3-6 cycloalkyl-C 1-6 alkyl wherein the C 3-6 cycloalkyl may be unsubstituted or substituted once with R h ;
heterocyclyl selected from oxetanyl, azetidinyl, morpholinyl and tetrahydrofuranyl, each of which may be unsubstituted or substituted once or twice with R h ;
heterocyclyl-C 1-6 alkyl wherein the heterocyclyl is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once with R h ;
heteroaryl selected from pyrazinyl and triazolyl, each of which may be unsubstituted or substituted once or twice with R h ; or
heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from pyrazinyl and triazolyl, each of which may be unsubstituted or substituted once or twicewith R h ;
or R b and R c together with the nitrogen atom to which they are attached may form heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morpholinyl, thiomorpholinyl, and 1,1-dioxothiomorpholinyl, each of which heterocylcles may be unsubstituted or substituted once with R h ;

R d is:
C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
C 1-6 alkyoxy-C 1-6 alkyl;
aminocarbonyl-C 1-6 alkyl; or
heteroaryl selected from pyridinyl, pyrimidinyl and pyrazinyl;

R e is:
hydrogen;
C 1-6 alkyl; or
hydroxy-C 1-6 alkyl;

R f is:
hydrogen;
C 1-6 alkyl;
halo-C 1-6 alkyl;
cyano-C 1-6 alkyl;
hydroxyl-C 1-6 alkyl;
C 1-6 alkyoxy;
C 1-6 alkyoxy-C 1-6 alkyl;
C 1-6 alkylsulfonyl-C 1-6 alkyl;
C 3-6 cycloalkyl which may be unsubstituted or substituted once with R h ;
C 3-6 cycloalkyl-C 1-6 alkyl wherein the C 3-6 cycloalkyl may be unsubstituted or substituted once with R h ;
heterocyclyl selected from oxetanyl, azetidinyl, morpholinyl and tetrahydrofuranyl, each of which may be unsubstituted or substituted once or twice with R h ;
heterocyclyl-C 1-6 alkyl wherein the heterocyclyl is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once with R h ;
heteroaryl selected from pyrazinyl and triazolyl, each of which may be unsubstituted or substituted once or twice with R h ; or
heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from pyrazinyl and triazolyl, each of which may be unsubstituted or substituted once or twicewith R h ;
or R e and R f together with the nitrogen atom to which they are attached may form heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morpholinyl, thiomorpholinyl, and 1,1-dioxothiomorpholinyl, each of which heterocylcles may be unsubstituted or substituted once with R h ;

R g is:
hydrogen; or
C 1-6 alkyl;

R h is:
C 1-6 alkyl;
cyano;
hydroxy;
aminocarbonyl;
oxo; or
hydroxy-C 1-6 alkyl.

2. The compound of claim 1 , wherein A is a six membered hetereoaryl selected from:
pyridinyl; pyrimidinyl; and pyrazinyl.

3. The compound of claim 1 , wherein m is 0 or 1.

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

5. The compound of claim 1 , wherein R 3 is hydrogen.

6. The compound of claim 1 , wherein R 4 is: C 1-6 alkyl; oxo; halo; or cyano.

7. The compound of claim 1 , wherein R 5 is:
heteroaryl selected from pyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, oxazolyl, tetrazolyl, imidazolyl, pyrazolyl, and isoxazolyl, each of which may be unsubstituted or substituted once or twice with R a ;
heterocyclyl selected from azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, morpholinyl, 1-oxa-6-azaspiro 3.3 heptanyl, piperazinyl, piperidinyl, and dihydropyridinyl, each of which may be unsubstituted or substituted once or twice with R a ;
—NR b R c ;
—C(O)NR e R f ; or
-hydroxy-C 1-6 alkyl.

8. The compound of claim 1 , wherein R a is:
cyano-C 1-6 alkyl;
halo-C 1-6 alkyl;
hydroxy-C 1-6 alkyl;
hydroxy-C 1-6 alkoxy;
hydroxy-C 1-6 alkyl substituted with halo; or hydroxy-C 1-6 alkoxy substituted with halo.

9. The compound of claim 1 , wherein R 5 is:

10. The compound of claim 1 , wherein said compound is of formula III

11. The compound of claim 1 , wherein sa

Assignees

• Genentech Inc

Inventors

• Fauber Benjamin
• Van Niel Monique Bodil
• Cridland Andrew
• Hurley Christopher
• Killen Jonathan
• Ward Stuart

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D413/14

  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