Heteroaryls and uses thereof

Patent metadata

Field	Value
Publication number	US-10538533-B2
Application number	US-201715665506-A
Country	US
Kind code	B2
Filing date	Aug 1, 2017
Priority date	Jan 14, 2014
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

The present invention provides a compound of formula I:

and pharmaceutically acceptable salts thereof, wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , m, and n, are as described in the specification. Such compounds are inhibitors of VPS34 and thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

First claim

We claim:

1. A method of treating a proliferative disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, naphthyl, 3-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which being optionally substituted with 1-5 R 6 ;
R 3 is C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, naphthyl, 3-10-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which being optionally substituted with 1-5 R 6 ;
wherein:

each R 6 independently is —CN, halo or -L 3 -R 7 wherein:
L 3 is a bond, C 1-4 alkylene, —O—, —N(R x )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, N(R x )C(O)—, —N(R x )CO 2 —, —S(O) 2 NR x —, —N(R x )S(O) 2 —, —OC(O)N(R x )—, —N(R x )C(O)N(R x ), —N(R x )S(O) 2 N(R x )— or —OC(O)—;
each R x , independently, is hydrogen or C 1-4 alkyl;
R 7 is hydrogen, C 1-6 aliphatic, 3-10-membered cycloaliphatic, phenyl, naphthyl, or 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

X is a bond or C 1-4 aliphatic;
L 1 is —N(R 8 )C(O)—, —C(O)—N(R 9 )—, —N(R 10 )S(O) 2 —, —S(O) 2 NR 11 —, —C(O)—, —C(S)—, —S(O) 2 —, —O—C(O)—, —C(O)—O—, —O—S(O) 2 —, —S(O) 2 —O—, —N(R 13 )C(O)N(R 14 )—, or —N(R 15 )S(O) 2 N(R 16 )—; and wherein
each of R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , and R 16 , independently, is hydrogen or C 1-4 alkyl; or X or L 1 optionally joining with R 1 to form an optionally substituted 5-6-membered heterocyclyl;

R 2 is hydrogen or C 1-4 alkyl;
L 2 is a bond, —C(O)—, —S(O) 2 —, —C(O)—O—, —C(O)N(R y )—, or —S(O) 2 N(R y )—; wherein each R y , independently, is hydrogen or C 1-4 alkyl;
each occurrence of R 4 and R 5 , independently, is —CN, halo or -L 4 -R 17 wherein
L 4 is C 1-4 alkylene, —O—, —N(R z )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —CO 2 —, —C(O)N(R z )—, —N(R z )C(O)—,
—N(R z )C(O)O—, —S(O) 2 N(R z )—, —N(R z )S(O) 2 —, —OC(O)N(R z )—, —N(R z )C(O)N(R z )—, —N(R z )S(O) 2 N(R z )— or —OC(O)—;

each R z , independently, is hydrogen or C 1-4 alkyl, and
R 17 is hydrogen or C 1-6 aliphatic; and

each of m and n, independently, is 0-3;
provided that
if one R 4 is located at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is located, X or L 1 optionally joining with said R 4 to form an optionally substituted 5-7-membered heterocyclyl or an optionally substituted 5-6-membered heteroaryl; or
if one R 4 is located at either ring carbon adjacent to the ring nitrogen, said R 4 optionally joining with the ring nitrogen to form an optionally substituted 5-7-membered heterocyclyl or an optionally substituted 5-6-membered heteroaryl; or
if L 2 is a bond and R 3 is phenyl, naphthyl, or heteroaryl, R 2 optionally joining with a substituent of R 3 to form an optionally substituted 5-7-membered heterocyclyl or an optionally substituted 5-6-membered heteroaryl.

2. The method of claim 1 , wherein L 1 is —N(R 8 )C(O)—, —N(R 10 )S(O) 2 —, —C(O)—, or —S(O) 2 —.

3. The method of claim 2 , wherein each of R 8 and R 10 , independently, is hydrogen, methyl or ethyl.

4. The method of claim 1 , wherein R 1 is C 1-4 aliphatic, 3-6-membered cycloaliphatic, phenyl, naphthyl, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

5. The method of claim 1 , wherein R 1 is

6. The method of claim 1 , wherein X is a bond, methylene, or ethylene.

7. The method of claim 1 , wherein R 2 is hydrogen.

8. The method of claim 1 , wherein L 2 is a bond, —C(O)— or —C(O)—O—.

9. The method of claim 1 , wherein R 3 is methyl, cyclopropyl, or 6-membered heteroaryl that is optionally substituted with 1-2 R 6 .

10. The method of claim 1 , wherein R 4 is fluoro, chloro, unsubstituted C 1-3 aliphatic, trifluoromethyl, hydroxyl, methoxy, NH 2 or NH—C 1-3 aliphatic; m is 0-2; and one R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted.

11. The method of claim 1 , wherein X is a bond; C is —N(R 8 )C(O)—, —N(R 10 )S(O) 2 —, —C(O)—, or —S(O) 2 —; R 2 is hydrogen, methyl, ethyl, or cyclopropylmethyl; L 2 is a bond, —C(O)— or —C(O)—O—; R 3 is C 1-3 alkyl, cyclopropyl, or 6-membered heteroaryl, each of which being optionally substituted with 1-2 R 6 ; R 4 is fluoro, chloro, C 1-3 alkyl, trifluoromethyl, hydroxyl, methoxy, —NH 2 or —NH—C 1-3 aliphatic; m is 0-2; and one R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted: n is 0 or 1; and R 1 is

12. The method of claim 1 , wherein the compound has formula (II) below:

wherein the value of (m−1) is 0 or 1; and a first R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted, or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound has formula (VIII) below:

wherein the value of (m−1) is 0 or 1; and a first R 4 is substituted at the ring carbon between the ring nitrogen and the ring carbon to which —X-L 1 -R 1 is substituted, or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

16. The method of claim 14 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

17. The method of claim 14 , wherein the compound is

o

Assignees

• Millennium Pharm Inc

Inventors

• Bharathan Indu T
• Blackburn Chris
• Ciavarri Jeffrey P
• Chouitar Jouhara
• Cullis Courtney A
• D'Amore Natalie
• Fleming Paul E
• Gigstad Kenneth M
• Gipson Krista E
• Girard Mario
• Hu Yongbo
• Lee Janice
• Li Gang
• Rezaei Mansoureh
• Sintchak Michael D
• Soucy Francois
• Stroud Stephen G
• Vos Tricia J
• Wong Tzu-Tshin
• Xu He
• Xu Tianlin
• Ye Yingchun

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/12

  Antihypertensives · 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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title