Heteroaryl compounds as IRAK inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9969710-B2
Application number	US-201615267606-A
Country	US
Kind code	B2
Filing date	Sep 16, 2016
Priority date	Sep 18, 2015
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof, useful as IRAK inhibitors.

First claim

We claim:

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:

is a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R a is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
R b is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or R b is absent;
Ring X is selected from:

R 1 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
R 2 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
R 3 is C 1-6 aliphatic, C 3-10 aryl, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or R 3 is -haloalkyl;
R 4 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or
two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; and
p is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 , wherein

is cyclohexanone, furanone, piperidinone, pyridinone, pyrimidinone, pyrrolidinone, or oxetanyl.

3. The compound of claim 1 , wherein

is selected from:

4. The compound of claim 1 , wherein Ring X is:

5. The compound of claim 1 , wherein R 3 is C 1-6 aliphatic which is optionally substituted.

6. The compound of claim 5 , wherein R 3 is methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, t-butyl, a straight chain or branched pentyl, or a straight chain or branched hexyl; each of which is optionally substituted.

7. The compound of claim 6 , wherein R 3 is selected from:

8. The compound of claim 1 , of formula I-a,

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , of formula I-b,

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein

is selected from:

11. The compound of claim 9 , wherein R 1 is -haloalkyl.

12. The compound of claim 9 , wherein R 3 is selected from:

13. The compound of claim 1 , of formula I-c,

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from the following compounds from Table 1:

15. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

16. A method for inhibiting IRAK, or a mutant thereof, activity in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound of claim 1 or a physiologically acceptable salt thereof.

17. A method for treating an IRAK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of claim 1 .

18. The method of claim 17 , wherein the disorder is selected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh's Disease and Ulcerative Coli

Assignees

• Merck Patent Gmbh

Inventors

• Jorand-Lebrun Catherine
• Lan Ruoxi
• Chen Austin
• Clark Ryan C

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title