Macrocyclic compounds as IRAK1/4 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9815836-B2
Application number	US-201715620049-A
Country	US
Kind code	B2
Filing date	Jun 12, 2017
Priority date	Feb 5, 2015
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

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 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:
Ring A is a 5-membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen oxygen, or sulfur, or a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
Ring B is a 6-membered aryl, or a 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted;
Ring C is a 5-membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted;
X is absent, —CH═CH—, —C≡C—, —O—, —S—, —SO 2 —, —SO—, —C(O)—, —CO 2 —, —C(O)N(R)—, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —NRSO 2 —, or —N(R)—;
Y is absent, a divalent C 3-10 aryl, a divalent 3-8 membered saturated or partially unsaturated carbocyclic ring, a divalent 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a divalent 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
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
each R is independently —OR c , —SR c , —SOR c , —SOR c , —C(O)R c , —CO 2 R c , —C(O)N(R)R c , —OC(O)N(R)R c , —NRC(O)R c , —NRC(O)N(R)R c , —NRSO 2 R c , or —Ni(R)R c ;
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;
R a is H or optionally substituted C 1-6 aliphatic;
R b is H or optionally substituted C 1-6 aliphatic;
each R c is independently H or optionally substituted C 1-6 aliphatic;
n is 1, 2, 3, 4, or 5;
p is 0, 1, 2, 3, or 4; and
r is 0, 1, or 2.

2. The method of claim 1 , wherein the disorder is selected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease Cronh's Disease and Ulcerative, 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, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer's disease, and Cancer.

3. The method of claim 1 , wherein Ring A is pyrazolidinyl, pyrazolinyl, or pyrazolyl; each of which is optionally substituted.

4. The method of claim 3 , wherein Ring A is

5. The method of claim 1 , wherein Ring B is phenyl, 2H,6H-1,5,2-dithiazinyl, pyrimidinyl, pyranyl, pyrazinyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, or triazinyl; each of which is optionally substituted.

6. The method of claim 5 , wherein Ring B is phenyl or pyridinyl.

7. The method of claim 5 , wherein Ring B is

8. The method of claim 1 , wherein Ring C is imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which is optionally substituted.

9. The method of claim 8 , wherein Ring C is pyrazolidinyl, pyrazolinyl, or pyrazolyl; each of which is optionally substituted.

10. The method of claim 5 , wherein Ring C is

11. The method of claim 1 , wherein X is absent.

12. The method of claim 1 , wherein X is —CH═CH—, —C≡C—, —O—, —S—, —SO 2 —, —SO—, —CO 2 —, —OC(O)N(Me)-, or —N(Me)-.

13. The method of claim 1 , wherein Y is absent.

14. The method of claim 1 , wherein Y is an optionally substituted divalent pyrrolidine, piperidine, or morpholine.

15. The method of claim 14 , wherein Y is

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound is of formula I-d,

or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the compound is selected from Table 1

Assignees

• Merck Patent Gmbh

Inventors

• Chen Xiaoling
• Yu Henry
• Lan Ruoxi
• Jorand-Lebrun Catherine
• Johnson Theresa L
• Goutopoulos Andreas

Classifications

• 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

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title