Bicyclic heterocyclyl derivatives as IRAK4 inhibitors

Patent metadata

Field	Value
Publication number	US-9732095-B2
Application number	US-201515111000-A
Country	US
Kind code	B2
Filing date	Jan 12, 2015
Priority date	Jan 13, 2014
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

The present invention provides bicyclic heterocyclyl kinase enzyme inhibitor compounds of formula (I), which are therapeutically useful as kinase inhibitors, particularly IRAK4 inhibitors, wherein A, Y, Z, X 1 , X 2 , R 1 , R 3 , ‘m’, ‘n’ and ‘p’ have the meanings given in the specification and pharmaceutically acceptable salt or stereoisomer thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical composition comprising at least one of the compounds of compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

First claim

We claim:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein
X 1 and X 3 independently are CH or N; X 2 is CR 2 or N; provided one and not more than one of X 1 , X 2 or X 3 is N;
A is O or S;
Y is —CH 2 — or O;
Z is aryl or heterocyclyl;
R 1 , at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ;
R 2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or —NR a R b ; wherein the substituent is alkyl, amino, halo or hydroxyl;
R 3 , at each occurrence, is alkyl or hydroxyl;
R a and R b are independently hydrogen, alkyl, acyl or heterocyclyl;
‘m’ and ‘n’ are independently 0, 1 or 2;
‘p’ is 0 or 1.

2. The compound of claim 1 , wherein
A is O or S;
Y is —CH 2 — or O;
Z is aryl or heterocyclyl;
R 1 , at each occurrence, is independently halo or optionally substituted heterocyclyl, wherein the substituent is alkyl, aminoalkyl, halo, or NR a R b ; where R a and R b are independently hydrogen, alkyl, or heterocyclyl;
R 2 is hydrogen, cycloalkyl, heterocyclyl or NR a R b ;
m is 0; and
n is 1.

3. The compound of claim 1 , wherein
A is O or S;
Y is —CH 2 — or O;
Z is aryl or heterocyclyl;
R 1 , at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or NR a R b ; where R a and R b are independently hydrogen, alkyl, or heterocyclyl;
R 2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl or NR a R b , where the substituent is selected from amino, halo or hydroxyl;
‘m’ and ‘n’ are independently 0, 1 or 2; and
‘p’ is 0 or 1.

4. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the group

wherein R 2 is as defined in claim 1 .

5. The compound of claim 1 , wherein Z is aryl or 5- or 6-membered heterocyclyl.

6. The compound of claim 1 , wherein Z is an optionally substituted heterocyclyl selected from phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl or azabicyclo[3.2.1]octanyl; each of which is optionally substituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen, alkyl or acyl.

7. The compound of claim 1 represented by formula (IA):

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein A, Y, R 1 , R 2 , R 3 , ‘m’, ‘p’ and ‘n’ are same as defined in claim 1 .

8. The compound of claim 7 , wherein
A is O or S;
Y is —CH 2 — or O;
R 1 , at each occurrence, is independently halo or optionally substituted heterocyclyl, wherein the substituent is alkyl, aminoalkyl, halo, or NR a R b ; where R a and R b are independently hydrogen, alkyl, or heterocyclyl;
R 2 is hydrogen, cycloalkyl, heterocyclyl or NR a R b ;
m is 0; and
n is 1.

9. The compound of claim 7 , wherein
A is O or S;
Y is —CH 2 — or O;
R 1 , at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or NR a R b ; where R a and R b are independently hydrogen, alkyl, or heterocyclyl;
R 2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl or NR a R b , where the substituent is selected from amino, halo or hydroxyl; and
‘m’ and ‘n’ are independently 0, 1 or 2.

10. The compound of claim 1 , represented by (TB):

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein A, Y, R 1 , R 2 and ‘n’ are same as defined in claim 1 .

11. The compound of claim 10 , wherein
A is O or S;
Y is —CH 2 — or O;
R 1 , at each occurrence, is independently halo or optionally substituted heterocyclyl, wherein the substituent is alkyl, aminoalkyl, halo, or NR a R b ; where R a and R b are independently hydrogen, alkyl, or heterocyclyl;
R 2 is hydrogen, cycloalkyl, heterocyclyl or NR a R b ; and
n is 1.

12. The compound of claim 10 , wherein
A is O or S;
Y is —CH 2 — or O;
R 1 , at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or NR a R b ; where R a and R b are independently hydrogen, alkyl, or heterocyclyl; and
R 2 is hydrogen, cycloalkyl, optionally substituted heterocyclyl or NR a R b , where the substituent is selected from amino, halo or hydroxyl.

13. The compound of formula (I) according to claim 1 , is a compound of formula (IC)

or a pharmaceutically acceptable salt or a stereoisomer thereof;
wherein A, Y, R 1 , R 2 and ‘n’ are same as defined in claim 1 .

14. The compound of claim 1 , wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen or acyl.

15. The compound of claim 2 , wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen or acyl.

16. The compound of claim 3 , wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen or acyl.

17. The compound of claim 8 , wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen or acyl.

18. The compound of claim 9 , wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen or acyl.

19. The compound of claim 11 , wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen or acyl.

20. The compound of claim 12 , wherein R 1 is optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or —NR a R b ; R a and R b are independently hydrogen or acyl.

21. The compound of cla

Assignees

• Aurigene Discovery Tech Ltd

Inventors

• Gummadi Venkateshwar Rao
• Samajdar Susanta

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/08

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/06

  Antianaemics · CPC title