Indazole compounds as IRAK4 inhibitors

Patent metadata

Field	Value
Publication number	US-10160753-B2
Application number	US-201515110309-A
Country	US
Kind code	B2
Filing date	Jan 7, 2015
Priority date	Jan 10, 2014
Publication date	Dec 25, 2018
Grant date	Dec 25, 2018

Abstract

The present invention provides indazole compounds of formula (I), which are therapeutically useful as kinase inhibitors, particularly IRAK4 inhibitors, wherein Z 1 , Z 2 , R 1 , R 2 , R 3 , ‘m’ and ‘n’ have the meanings given in the specification, and pharmaceutically acceptable salts or stereoisomers thereof that are useful in the treatment and prevention of diseases or disorders, in particular their use in diseases or disorders mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical compositions comprising at least one of the compounds of the compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.

First claim

We claim:

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof;
wherein
Z 1 is an optionally substituted pyridyl, oxazolyl, or furanyl;
Z 2 is an optionally substituted heterocycloalkyl or optionally substituted heteroaryl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, piperazinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl and;
R 1 is cyano, —NR a R b or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 ;
R 2 , at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;
R 3 , at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl;
R a is hydrogen or unsubstituted alkyl;
R b is hydrogen, unsubstituted alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl; and
‘m’ and ‘n’ are independently 1 or 2.

2. A compound of formula (IA)

or a pharmaceutically acceptable salt thereof;
wherein
Z 2 is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;
R 1 is alkyl, cyano, —NR a R b or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 ;
R 2 , at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;
R 3 , at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl;
R a is hydrogen or unsubstituted alkyl;
R b is hydrogen, unsubstituted alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl; and
‘m’ and ‘n’ are independently 1 or 2.

3. A compound of formula (IB)

or a pharmaceutically acceptable salt thereof,
wherein
Z 2 is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;
R 1 is alkyl, cyano, —NR a R b or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 ;
R 2 , at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;
R 3 , at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl;
R a is hydrogen or unsubstituted alkyl;
R b is hydrogen, unsubstituted alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl; and
‘m’ and ‘n’ are independently 1 or 2.

4. A compound of formula (IC)

or a pharmaceutically acceptable salt thereof;
wherein
Z 2 is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;
R 1 is alkyl, cyano, —NR a R b or optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH 2 —O-alkyl, —OP(O)(O-alkyl) 2 or —CH 2 —OP(O)(O-alkyl) 2 ;
R 2 , at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;
R 3 , at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NR a R b , hydroxyl or hydroxyalkyl;
R a is hydrogen or unsubstituted alkyl;
R b is hydrogen, unsubstituted alkyl, acyl, hydroxyalkyl, —SO 2 -alkyl or optionally substituted cycloalkyl; and
‘m’ and ‘n’ are independently 1 or 2.

5. The compound of claim 2 , wherein Z 2 is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl.

6. The compound of claim 3 , wherein Z 2 is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl.

7. The compound of claim 4 , wherein Z 2 is a 5- or 6-membered heterocycloalkyl or 5- or 6-membered heteroaryl.

8. The compound of claim 2 , wherein Z 2 is heterocycloalkyl or a direct bond.

9. The compound of claim 3 , wherein Z 2 is heterocycloalkyl or a direct bond.

10. The compound of claim 4 , wherein Z 2 is heterocycloalkyl or a direct bond.

11. The compound of claim 2 , wherein Z 2 is azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, piperazinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.

12. The compound of claim 3 , wherein Z 2 is azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, piperazinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.

13. The compound of claim 4 , wherein Z 2 is azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, tetrazolyl, thienyl, triazolyl, pyrrolyl, pyridyl, pyranyl, pyrazinyl, pyridazinyl, pyrimidyl, piperazinyl, imidazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, furanyl or pyrazolyl.

14. The compound of claim 2 , wherein Z 2 is pyridyl, pyrazolyl, pyrrolidinyl, or a direct bond.

15. The compound of claim 3 , wherein Z 2 is pyridyl, pyrazolyl, pyrrolidinyl, or a direct bond.

16. The compound of claim 4 , wherein Z 2 is pyridyl, pyrazolyl, pyrrolidinyl, or a direct bond.

Assignees

• Aurigene Discovery Tech Ltd

Inventors

• Gummadi Venkateshwar Rao
• Samajdar Susanta
• Gupta Ajay

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P7/06

  Antianaemics · CPC title