Macrocyclic compounds as IRAK1/4 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9708324-B2
Application number	US-201615016569-A
Country	US
Kind code	B2
Filing date	Feb 5, 2016
Priority date	Feb 5, 2015
Publication date	Jul 18, 2017
Grant date	Jul 18, 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 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 , —SO 2 R 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 —N(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 compound of claim 1 , wherein Ring A 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.

3. The compound of claim 2 , wherein Ring A is

4. The compound 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.

5. The compound of claim 4 , wherein Ring B is phenyl or pyridinyl.

6. The compound 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.

7. The compound of claim 6 , wherein Ring C is pyrazolidinyl, pyrazolinyl, or pyrazolyl; each of which is optionally substituted.

8. The compound of claim 1 , wherein X is absent.

9. The compound of claim 8 , wherein X is —CH═CH—, —C≡C—, —O—, —S—, —SO 2 —, —SO—, —CO 2 —, —OC(O)N(Me)-, or —N(Me)-.

10. The compound of claim 1 , wherein Y is absent.

11. The compound of claim 10 , wherein Y is an optionally substituted divalent phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from Table 1

Assignees

• Merck Patent Gmbh

Inventors

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

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · 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

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title