Heteroaryl compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-2016221966-A1
Application number	US-201615133755-A
Country	US
Kind code	A1
Filing date	Apr 20, 2016
Priority date	Mar 15, 2013
Publication date	Aug 4, 2016
Grant date	—

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

First claim

We claim:

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is —NR 4 , N, —CR 4 R 4′ , or —CR 4 ;
X 2 is —NR 5 , N, —CR 5 R 5′ , or —CR 5 ;
X 3 is N or CR 6
X 4 is N or CR 7 ;
X 5 is N, C, or CH; wherein at least one of X 1 , X 2 , X 3 , X 4 , or X 5 is N;
G is H, O, OR, or N(R)(R);
Ring A is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 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; or
two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocylic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 1 is a warhead group; wherein R 1 is attached to an atom adjacent to the atom where T is attached;
each R 2 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 3 is hydrogen, C 2-6 alkenyl, —W-Cy, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from halogen, —CN, oxo, —OR′, or —C(O)O(C 1-6 alkyl);
W is absent or is a bivalent C 1-3 alkylene chain optionally substituted with one or more R″ and
wherein one methylene unit of W is optionally replaced with —O—, —S—, or —NR′—;
each R′ is independently hydrogen or C 1-6 alkyl;
each R″ is independently halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from halogen, —CN, oxo, or —OR′;
Cy is phenyl, C 3-7 cycloalkyl, or a 3-7 membered monocyclic or 5-10 membered bicyclic saturated, partially unsaturated, or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy is optionally substituted with 1-3 R x ;
each R x is independently H, —CN, oxo, —NH 2 , C 1-6 alkyl, halogen, —OR′, —N(R′) 2 , —NHC(O)(C 1-6 alkyl), —C(O)N(R′) 2 , —C(O)O(C 1-6 alkyl), —NHSO 2 (C 1-6 alkyl), or —SO 2 N(R′) 2 ;
or R 3 is absent if not allowed by valence;
each of R 4 and R 4′ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring which is optionally bridged, a 4-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring, which is optionally bridged;
each of R 5 and R 5′ 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 ;
Y is O or NR a ;
R a is hydrogen or an optionally substituted C 1-6 aliphatic group;
T is a covalent bond or a bivalent straight or branched, saturated or unsaturated C 1-6 hydrocarbon chain wherein one or more methylene units are optionally replaced by —O—, —S—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)N(R)—, —S(O)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, or —N(R)SO 2 N(R)—;
q is 0-6; and
each of R 6 and R 7 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 .

2 . The compound according to claim 1 , wherein Ring A is an optionally substituted phenyl group.

3 . The compound according to claim 1 , wherein Ring A is an optionally substituted a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring.

4 . The compound according to claim 1 , wherein Ring A is phenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclobutyl, cyclopropyl, pyridine, pyrmidine, pyrazine, pyridazine, pyrrole, pyrazole, piperidine, piperidin-one, pyrrolidine, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene dioxide, or cyclobutene dione.

5 . The compound according to claim 1 , wherein Ring A is

6 . The compound according to claim 5 , wherein each R 2 is hydrogen.

7 . The compound according to claim 5 , wherein each R 2 is independently —R.

8 . The compound according to claim 5 , wherein each R 2 is independently 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 .

9 . The compound according to claim 5 , wherein each R 2 is independently —CH 3 , —Cl, —F, —CF 3 , or —OMe; or is selected from

10 . The compound according to claim 1 , wherein Ring A is selected from:

11 . The compound according to claim 1 , wherein R 3 is hydrogen.

12 . The compound according to claim 1 , wherein R 3 is C 2-6 alkenyl, —W-Cy, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from halogen, —CN, oxo, —OR′, or —C(O)O(C 1-6 alkyl).

13 . The compound according to claim 1 , wherein R 3 is

14 . The compound according to claim 1 , wherein R 4 is an optionally substituted phenyl.

15 . The compound according to claim 1 , wherein R 4 is an o

Assignees

• Celgene Avilomics Res Inc
• Sanofi Sa

Inventors

• D'Agostino Laura Akullian
• Sjin Robert Tjin Tham
• Niu Deqiang
• Mcdonald Joseph John
• Zhu Zhendong
• Liu Haibo
• Mazdiyasni Hormoz
• Petter Russell C
• Singh Juswinder
• Barrague Matthieu
• Gross Alexandre
• Munson Mark

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C12Y207/10001

  Receptor protein-tyrosine kinase (2.7.10.1) · CPC title

• C07D239/80 Primary

  Oxygen atoms · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title