Heteroaryl inhibitors of sumo activating enzyme

Patent metadata

Field	Value
Publication number	US-9695154-B2
Application number	US-201414901809-A
Country	US
Kind code	B2
Filing date	Jul 1, 2014
Priority date	Jul 2, 2013
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

Disclosed are compounds of formula (I); or a pharmaceutically acceptable salt thereof; wherein Y, R a , R a′ , R c , R f , X 2 , R d , R d′ , R e , R e′ , m, and G have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry, useful as inhibitors of Sumo Activating Enzyme (SAE). Further provided are pharmaceutical compositions comprising a compound of the disclosure and methods of using the compositions in the treatment of proliferative, inflammatory, cardiovascular and neurodegenerative diseases or disorders.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry;
Y is —O—, —CH 2 —, —N(H)—;
R a is hydrogen, fluoro, —NH 2 , or —OH;
R a′ is hydrogen, or fluoro; provided that when R a is —NH 2 or —OH, R a′ is hydrogen;
R c is hydrogen or C 1-4 alkyl;
X 1 is C(H), C(F) or N;
X 2 is C(R d ) or N;
each occurrence of R d is independently hydrogen, halogen, cyano, C 1-4 aliphatic, or C 1-4 fluoroaliphatic;
R d′ is hydrogen, halogen, cyano, C 1-4 aliphatic, C 1-4 fluoroaliphatic, or -T 2 -R 3 ;
T 2 is a C 1 -C 2 alkylene chain optionally substituted with 0-3 independent occurrences of R 3c ;
R 3 is —CN, —NO 2 , —N(R 3a ) 2 , —OR 3a , —C(O)R 3b , —C(O)OR 3a , —C(O)N(R 3a ) 2 , or —S(O) 2 N(R 3a ) 2 ;
each occurrence of R 3a is independently hydrogen or C 1-4 alkyl;
R 3b is C 1-4 alkyl;
each occurrence of R 3c is independently C 1-4 alkyl;
R e is hydrogen or C 1-4 alkyl;
R e′ is hydrogen or C 1-4 alkyl; or R e is taken together with R e′ to form a 3-6 membered cycloaliphatic ring;
m is 0-2;
R f is hydrogen, chloro or C 1-4 alkyl;
G is R 1 or -L 1 -R 1 ;
L 1 is

—C(O)—, or —SO 2 —; provided that when L 1 is —SO 2 —, m is zero;
R 1 is an optionally substituted group selected from C 1-6 aliphatic, 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 1 is optionally substituted with n occurrences of R 2 ; wherein each occurrence of R 2 is independently —R 2a , -T 1 -R 2d , -T 1 -R 2a , or —V 1 -T 1 -R 2d ;
n is 1-5;
each occurrence of R 2a is independently halogen, —CN, —NO 2 , —R 2c , —N(R 2b ) 2 , —OR 2b , —SR 2c , —S(O)R 2c , —S(O) 2 R 2c , —C(O)R 2b , —C(O)OR 2b , —C(O)N(R 2b ) 2 , —S(O) 2 N(R 2b ) 2 , —OC(O)N(R 2b ) 2 , —N(R 2e )C(O)R 2b , —N(R 2e )SO 2 R 2c , —N(R 2e )C(O)OR 2b , —N(R 2e )C(O)N(R 2b ) 2 , —N(R 2e )SO 2 N(R 2b ) 2 , or Si(R 2c ) 3 , or an optionally substituted C 1 -C 6 aliphatic or C 1 -C 6 haloaliphatic;
each occurrence of R 2b is independently hydrogen or an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 haloaliphatic, 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R 2b , taken together with a nitrogen atom to which they are bound, form an optionally substituted 4- to -7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, and sulfur;
each occurrence of R 2c is independently an optionally substituted group selected from C 1 -C 6 aliphatic, C 1 -C 6 haloaliphatic, 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each occurrence of R 2d is independently hydrogen or an optionally substituted group selected from 3- to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each occurrence of R 2e is independently hydrogen or an optionally substituted C 1-6 aliphatic group;
each occurrence of V 1 is independently —N(R 2e )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 2e )—, —S(O) 2 N(R 2e )—, —OC(O)N(R 2e )—, —N(R 2e )C(O)—, —N(R 2e )SO 2 —, —N(R 2e )C(O)O—, —N(R 2e )C(O)N(R 2e )—, —N(R 2e )SO 2 N(R 2e )—, —OC(O)—, or —C(O)N(R 2e )—O—; and
T 1 is an optionally substituted C 1 -C 6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R 4 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(O)O—, —C(O)N(R 4 )—, —S(O) 2 N(R 4 )—, —OC(O)N(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )SO 2 —, —N(R 4 )C(O)O—, —N(R 4 )C(O)N(R 4 )—, —N(R 4 )S(O) 2 N(R 4 )—, —OC(O)—, or —C(O)N(R 4 )—O— or wherein T 1 or a portion thereof optionally forms part of an optionally substituted 3- to -7 membered cycloaliphatic or heterocyclyl ring, wherein R 4 is hydrogen or an optionally substituted C 1-4 aliphatic group.

2. The compound of claim 1 , wherein Y is —O—.

3. The compound of claim 1 , wherein X 1 is N.

4. The compound of claim 1 , wherein:
m is 1 or 2;
R e is hydrogen, methyl, or ethyl; and
R e′ is hydrogen.

5. The compound of claim 1 , represented by formula (III):

or a pharmaceutically acceptable salt thereof;
wherein:
stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

6. The compound of claim 5 , represented by formulas (IV-a)-(IV-c):

or a pharmaceutically acceptable salt thereof;
wherein:
stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry.

7. The compound of claim 5 , wherein:
X 1 is N;
X 2 is N; and
m is 1 or 2.

8. The compound of claim 5 , wherein:
X 1 is N;
X 2 is C(R d ); and
m is 1 or 2.

9. The compound of claim 8 , wherein m is 1.

10. The compound of claim 5 , wherein:
R e is hydrogen, methyl, or ethyl; and
R e′ is hydrogen.

11. The compound of claim 10 , wherein R e is hydrogen.

12. The compound of claim 5 , wherein each occurrence of R d is independently hydrogen, chloro, bromo, fluoro, methyl, ethyl, or trifluoromethyl.

13. The compound of claim 12 , wherein R d is hydrogen.

14. The compound of claim 5 , wherein R d′ is hydrogen, chloro, bromo, fluoro, methyl, ethyl, or trifluoromethyl.

15. The compound of claim 14 , wherein R d′ is hydrogen or methyl.

16. The compound of claim 1 , wherein G is R 1 .

17. The compound of claim 16 , wherein R 1 is 3 to 10-membered cycloaliphatic, 4- to 10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R 1 is unsubstituted or substituted with n occurrences of R 2 .

18. The compound of claim 16 , wherein R 1 is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzthiazolyl, b

Assignees

• Millennium Pharm Inc

Inventors

• Duffey Matthew O
• England Dylan B
• Hu Zhigen
• Ito Mitsuhiro
• Langston Steven P
• Mcintyre Charles
• Mizutani Hirotake
• Xu He

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title