Pyridazine derivatives as RORc modulators

Patent metadata

Field	Value
Publication number	US-10280144-B2
Application number	US-201715801192-A
Country	US
Kind code	B2
Filing date	Nov 1, 2017
Priority date	May 4, 2015
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

Compounds of formula I:

or pharmaceutical salts thereof,
wherein m, A, X, Y, Z, R 1 , 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 pharmaceutically acceptable salts thereof, wherein:
A is:
a five or six membered hetereoaryl selected from: oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; and triazinyl;
a five or six membered heterocyclyl selected from: oxetanyl; azetidinyl; azepinyl; pyrrolidinyl; piperidinyl; piperazinyl; imidazolidinyl; tetrahydrofuranyl; tetrahydropyranyl; tetrahydrothienyl, 1,1-dioxo-tetrahydrothienyl; morpholinyl; thiomorpolinyl; and 1,1-dioxo-thiomorpholinyl;
phenyl; or
C 3-6 cycloalkyl;

X is: —C(O)— or —SO 2 —;
Y is: methylene
Z is:
a bond; or
methylene;

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

R 2 is:
halo;

R 3 is:
hydrogen;

R 4 is:
hydrogen;
C 1-6 alkyl; or
halo-C 1-6 alkyl;

R 5 is:
C 1-6 alkyl;
C 1-6 alkyloxy;
halo-C 1-6 alkyl;
halo-C 1-6 alkoxy;
halo;
hydroxyl;
hydroxyl-C 1-6 alkyl;
oxo;
cyano;
cyano-C 1-6 alkyl;
C 1-6 alkylsulfonyl;
C 1-6 alkylsulfonylamino;
C 3-6 cycloalkylsulfonyl;
C 3-6 cycloalkylsulfonylamino;
C 1-6 alkylsulfonyl;
C 3-6 cycloalkyl-C 1-6 alkylsulfonylamino;
C 1-6 alkylsulfonyl-C 1-6 alkyl;
amino;
aminocarbonyl;
aminosulfonyl;
C 1-6 alkylcarbonyl;
C 1-6 alkylcarbonylamino;
aminocarbonylamino;
C 1-6 alkyloxycarbonyl;
C 1-6 alkylaminosulfonyl;
phenyl which may be unsubstituted or substituted once or twice with R b ;
heteroaryl selected from: pyridinyl pyrimidinyl; pyrazinyl triazinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; oxadiazolyl; and tetrazolyl; each of which may be unsubstituted or substituted once or twice with R a ;
heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from: pyridinyl pyrimidinyl; pyrazinyl triazinyl; pyrazolyl; imidazolyl; oxazolyl; oxadiazolyl; isoxazolyl; and tetrazolyl; each of which may be unsubstituted or substituted once or twice with R a ;
heteroaryl-C 1-6 alkoxy wherein the heteroaryl is selected from: pyridinyl pyrimidinyl; pyrazinyl triazinyl; pyrazolyl; imidazolyl; oxazolyl; oxadiazolyl; isoxazolyl; and tetrazolyl; each of which may be unsubstituted or substituted once or twice with R a ;
heterocyclyl selected from: morpholinyl; pyrrolidinyl; oxetanyl; and azetidinyl each of which may be unsubstituted or substituted once or twice with R b ;

R a is:
C 1-6 alkyl;
C 3-6 cycloalkyl;
halo-C 1-6 alkyl;
halo;
hydroxyl;
hydroxyl-C 1-6 alkyl; or
oxo;

R b is:
C 1-6 alkyl;
C 1-6 alkylcarbonyl;
C 1-6 alkylsulfonyl;
halo-C 1-6 alkyl;
halo;
hydroxyl;
hydroxyl-C 1-6 alkyl; or
oxo; and

R c is:
hydroxyl;
C 1-6 alkoxy; or
amino;

provided that the compound is not N-(((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-5,6,7,8-tetrahydro-5,8-methanocinnolin-8-yl)methyl)-N-ethyl-5-methylisoxazole-3-carboxamide.

2. The compound of claim 1 , wherein:
a five or six membered hetereoaryl selected from: oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; and triazinyl; or
phenyl.

3. The compound of claim 1 , wherein A is a five or six membered hetereoaryl selected from: oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl.

4. The compound of claim 1 , wherein X is —C(O)—.

5. The compound of claim 1 , wherein X is —SO 2 —.

6. The compound of claim 1 , wherein Z is a bond.

7. The compound of claim 1 , wherein Z is methylene.

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

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

10. The compound of claim 1 , wherein R 4 is C 1-6 alkyl.

11. The compound of claim 1 , wherein the compound is of formula II

12. The compound of claim 1 , wherein the compound is of formula III

13. A composition comprising:
(a) a pharmaceutically acceptable carrier; and
(b) a compound of claim 1 .

14. A compound selected from:

Assignees

• Genentech Inc

Inventors

• Fauber Benjamin
• Crawford James J
• Bronner Sarah M
• Van Niel Monique Bodil
• Cridland Andrew
• Gancia Emanuela
• Hurley Christopher
• Killen Jonathan
• Ward Stuart

Classifications

• A61P37/02

  Immunomodulators · 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

• A61P13/12

  of the kidneys · CPC title