Benzazole compounds and methods for making and using the compounds

Patent metadata

Field	Value
Publication number	US-10065946-B2
Application number	US-201615226625-A
Country	US
Kind code	B2
Filing date	Aug 2, 2016
Priority date	Aug 4, 2015
Publication date	Sep 4, 2018
Grant date	Sep 4, 2018

Abstract

Disclosed are novel benzazole compounds and compositions comprising the compounds. The compounds are useful as kinase inhibitors including interleukin receptor associated kinases (IRAK) inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

First claim

We claim:

1. A compound having a formula

or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide thereof, wherein:
X is O;
Y is O and Z is CR 9 ; or
Y is S and Z is N;
Het-1 is pyrazolyl;
R 1 and R 2 independently are H, aliphatic, heteroaliphatic, heterocyclyl, aryl, araliphatic, or together with the nitrogen to which they are attached, form a heterocyclic ring;
R 3 , R 4 , R 5 , R 6 and R 9 independently are H, aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl;
R 7 is H, aliphatic, heteroaliphatic, heterocyclyl, aryl or araliphatic;
each R 8 independently is aliphatic, halo, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl or haloalkyl; and
m is from 0 to 3.

2. The compound of claim 1 , wherein Het-1 is selected from

and
R 10 is selected from H, aliphatic, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl.

3. The compound of claim 1 , wherein

is selected from

4. The compound of claim 2 , wherein:
each R 8 independently is selected from halo, C 1-6 haloalkyl, C 1-6 alkyl, —OC 1-6 alkyl, amino or —CH 2 OP(O)(OR 24 ) 2 ; and
each R 24 independently is H, C 1-6 alkyl or a counterion forming a pharmaceutically acceptable base addition salt with the phosphate moiety.

5. The compound of claim 4 , wherein at least one R 8 is —NH 2 , —CH 3 , CF 3 , —CF 2 H or —CH 2 CF 3 .

6. The compound of claim 1 , wherein the compound has a formula

7. The compound of claim 1 , wherein the compound has formula selected from

and
R 10 is selected from H, aliphatic, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, or haloalkyl.

8. The compound of claim 1 , wherein the compound has a formula selected from

R 10 is H, aliphatic, aryl or heterocyclyl; and
R 11 , R 12 , and R 13 independently are H, aliphatic, halogen, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, or haloalkyl.

9. The compound of claim 8 , wherein the compound has a formula selected from

10. The compound of claim 8 , wherein the compound has a formula selected from

11. The compound of claim 1 , wherein R 5 is amino, aryl or heteroaryl.

12. The compound of claim 11 , wherein R 5 is amino having a formula —NRR wherein each R independently is aliphatic, or both R groups together with the nitrogen attached thereto form a heterocyclic ring.

13. The compound of claim 12 , wherein R 5 is a cyclic amino selected from

14. The compound of claim 11 , wherein R 5 is

15. The compound of claim 1 , wherein R 1 and R 2 independently are H, aliphatic, heteroaliphatic, or together with the nitrogen attached thereto forms a heteroaliphatic ring.

16. The compound of claim 15 , wherein R 1 is H or alkyl, and R 2 is aliphatic or heteroaliphatic.

17. The compound of claim 1 , wherein R 1 and R 2 , together with the nitrogen attached thereto, are selected from

R a is aliphatic, haloalkyl or acyl;
n is 1 or 2; and
p is 0, 1 or 2.

18. The compound of claim 17 , wherein:
R a is CH 3 , CF 3 , CF 2 H, or R b C(O)—; and
R b is aliphatic or haloalkyl.

19. A compound selected from
I-3: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-4: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;
I-7: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-8: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]thiazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;
I-12: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-13: N-(2-morpholino-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;
I-16: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-17: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;
I-20: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-21: N-(2-(4-methylpiperazin-1-yl)-5-(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;
I-23: N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-25: N-(5-(4-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-27: N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-29: N-(5-(4,4-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-31: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-32: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-3-yl)furan-2-carboxamide;
I-35: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-36: N-(2,5-di(piperidin-1-yl)benzo[d]oxazol-6-yl)-2-(1H-pyrazol-3-yl)thiazole-4-carboxamide;
I-38: N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-40: N-(5-(3-fluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-42: N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-44: N-(5-(3,3-difluoropiperidin-1-yl)-2-morpholinobenzo[d]oxazol-6-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;
I-46: N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]oxazol-6-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-47: N-(2-morpholino-5-(pyrrolidin-1-yl)benzo[d]ox

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Yen Rose
• Chen Yan
• Singh Rajinder
• Taylor Vanessa

Classifications

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P37/02

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• A61P35/04

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• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P37/06

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