Pyridazinone macrocycles as IRAK inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-10517872-B2
Application number	US-201715450463-A
Country	US
Kind code	B2
Filing date	Mar 6, 2017
Priority date	Feb 6, 2015
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

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, selected from Systemic Lupus Erythematosus, and Lupus nephritis, said method comprising: administering to said patient a compound of formula I,

wherein:
Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is optionally substituted;
X is absent, C(O)—, —CO 2 —, —C(O)N(R)—, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —(CRR) m C(O)—, —(CRR) m CO 2 —, —(CRR) m C(O)N(R)—, —(CRR) m OC(O)N(R)—, —(CRR) m NRC(O)—, or —(CRR) m NRC(O)N(R)—;
Y is an optionally substituted C 1 -6 aliphatic;
Z is O—, 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, and sulfur; each of which is optionally substituted;
W is CR or N;
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, and 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, and sulfur; each of which is optionally substituted;
each R 1 is independently —R, halogen, —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, —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 4 is —R, halogen, —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 m is independently 1 or 2; and
n is 0, 1, 2, 3, 4, or 5;
or a physiologically acceptable salt thereof.

2. The method of claim 1 , wherein ring A is furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, or 1,3,4-triazolyl; each of which is optionally substituted.

3. The method of claim 2 , wherein ring A is pyrazolyl; which is optionally substituted.

4. The method of claim 3 , wherein Ring A is selected from the group consisting of

5. The method of claim 1 , wherein X is absent, —C(O)N(R)—, or —(CRR) m C(O)N(R)—, wherein m is 1.

6. The method of claim 5 , wherein X is

7. The method of claim 1 , wherein Y is methylene, ethylene, propylene, i-propylene, n-butylene, or s-butylene; each of which is optionally substituted.

8. The method of claim 1 , wherein Z is —O—, a divalent C 3-10 aryl, a divalent 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 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.

9. The method of claim 8 , wherein Z is —O—,

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

14. The method of claim 1 , wherein the administering results in an inhibition of IRAK in said patient.

15. The method of claim 14 , wherein the IRAK is IRAK1 and/or IRAK4.

16. A method for treating an IRAK 1- and/or IRAK 4-mediated disorder in a patient in need thereof, comprising:
administering to said patient a compound of formula I,

thereby inhibiting said IRAK 1 and/or IRAK 4 in said patient,
wherein said disorder is Systemic Lupus Erythematosus, or Lupus nephritis,
wherein:
Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; which is optionally substituted;
X is absent, C(O)—, —CO 2 —, —C(O)N(R)—, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —(CRR) m C(O)—, —(CRR) m CO 2 —, —(CRR) m C(O)N(R)—, —(CRR) m OC(O)N(R)—, —(CRR) m NRC(O)—, or —(CRR) m NRC(O)N(R)—;
Y is an optionally substituted C 1-6 aliphatic;
Z is —O—, 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, and sulfur; each of which is optionally substituted;
W is CR or N;
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, and 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 p

Assignees

• Merck Patent Gmbh

Inventors

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

Classifications

• A61P43/00

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

• A61P37/02

  Immunomodulators · 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title