Heteroaryl compounds as IRAK inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10030013-B2
Application number	US-201715701842-A
Country	US
Kind code	B2
Filing date	Sep 12, 2017
Priority date	Nov 20, 2014
Publication date	Jul 24, 2018
Grant date	Jul 24, 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 method for treating an IRAK-mediated disorder selected from: Psoriatic arthritis, Osteoarthritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, and DIRA (Deficiency of IL-1 Receptor Antagonist), in a patient in need thereof, comprising the step of administering to said patient a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:
X is CR or N;
A is O, S, SO 2 , SO, —NRC(O), —NRSO 2 , or N(R); or A is absent;
R 3 is H, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or R 3 is 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
when A is —NRC(O), —NRSO 2 , or N(R); then R and R 3 , together with the atoms to which each is attached, may form 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;
X′ is CR or N;
Ring Z is 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;
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 a is absent, —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 ;
Ring Y is an optionally substituted pyridyl, pyrazole or thiadiazole;
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 b is absent, —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;

wherein when X is N and A is absent, then R 3 is not H.

2. The method of claim 1 , wherein X is CH.

3. The method of claim 1 , wherein X is N.

4. The method of claim 1 , wherein A is O or N(R), or A is absent.

5. The method of claim 1 , wherein R 3 is H, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or R 3 is -haloalkyl, —C(O)R, —CO 2 R, or —C(O)N(R) 2 .

6. The method of claim 5 , wherein R 3 is C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

7. The method of claim 1 , wherein A-R 3 is —H, —CH 3 , —CF 3 ,

8. The method of claim 1 , wherein Ring Z is:

wherein X is O, S or NR 1 ; Y is C or N; and T is C or N.

9. The method of claim 8 , wherein Ring Z is

10. The method of claim 1 , wherein Ring Y is

11. The method of claim 1 , wherein the compound of formula I is a compound of formula I-b,

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the compound of formula I is a compound of formula I-c,

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is selected from:

Assignees

• Merck Patent Gmbh

Inventors

• Jorand-Lebrun Catherine
• Jones Reinaldo
• Won Annie Cho
• Nguyen Ngan
• Johnson Theresa L
• Deselm Lizbeth Celeste
• Panda Kausik

Classifications

• A61P43/00

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

• A61P37/06

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

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · 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