Heteroaryl compounds useful as inhibitors of sumo activating enzyme

Patent metadata

Field	Value
Publication number	US-2016009744-A1
Application number	US-201514788675-A
Country	US
Kind code	A1
Filing date	Jun 30, 2015
Priority date	Jul 1, 2014
Publication date	Jan 14, 2016
Grant date	—

Abstract

Disclosed are chemical entities which are compounds of formula (I):

or pharmaceutically acceptable salts thereof; wherein Y, R a , R a′ , R b , R c , X 1 , X 2 , X 3 , R d , Z 1 , and Z 2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. Chemical entities according to the disclosure can be 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 chemical entity which is a compound or pharmaceutically acceptable salt of formula (I):

WHEREIN:
stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry;
Y is —O—, —CH 2 —, or —N(H)—;
R a is hydrogen, fluoro, —NH 2 , or hydroxyl;
R a′ is hydrogen or fluoro, provided that when R a is —NH 2 or hydroxyl, R a′ is hydrogen;
R b is hydrogen or, together with the oxygen to which it is attached, forms a prodrug;
R c is hydrogen or C 1-4 alkyl;
R d is hydrogen, halogen, —CF 3 , or C 1-4 alkyl;
X 1 is C(H), C(F), or N;
X 2 is S or O;
X 3 is C(R x3 ) or N;
R x3 is hydrogen, methyl, or halogen;
Z 1 is hydrogen, halogen, cyano, R z3 , —S—R z3 , —S(O)—R z3 , or —S(O) 2 —R z3 ;
R z3 is an optionally substituted phenyl, an optionally substituted 5- to 7-membered cycloaliphatic, an optionally substituted 5- to 7-membered heterocyclyl, or an optionally substituted C 1-4 aliphatic;
wherein Z 1 is not hydrogen, halogen, methyl, or cyano if Z 2 is hydrogen or methyl; and
(a) Z 2 is a ring system having an optionally substituted 5- to 7-membered heterocyclyl with I-2 heteroatoms or an optionally substituted 5- to 7-membered cycloaliphatic fused to
(i) an optionally substituted 5-membered heteroaryl or an optionally substituted 6-membered aryl or heteroaryl to form a bicyclic group; or
(ii) an optionally substituted 9-membered heteroaryl or an optionally substituted 10-membered aryl or heteroaryl to form a tricyclic group;

OR
(b) Z 2 is L-R e wherein L is -L 1 -, —V 1 -L 2 -, or -L 1 -V 1 -L 2 -;

L 1 is a C 1-3 alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (R f )(R f′ ) and in which there are optionally one or two degrees of unsaturation;
each R f is independently hydrogen; hydroxyl; —N(R h )(R h′ ); C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; —O—C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; or, together with R f′ and the carbon atom to which they are attached, form C═CH 2 , or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C 1-4 alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle;
each R f′ is independently hydrogen; C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; —O—C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl; or, together with R f and the carbon atom to which they are attached, form C═CH 2 , or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C 1-4 alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle; wherein if R f is hydroxyl, R f′ is not —O—C 1-4 aliphatic optionally substituted with hydroxyl, —OCH 3 , or cyclopropyl;
R h and R h′ are each independently hydrogen or C 1-4 alkyl;
V 1 is —S—, —O—, —S(O)—, —S(O) 2 —, —C(O)— or —N(R g )—;
L 2 is a C 0-2 alkylene chain wherein one saturated carbon atom is optionally substituted by (R f )(R f′ ) ;
R is hydrogen or C 1-4 alkyl; and
either (i) R e is hydrogen, hydroxyl, halogen, —CF 3 , or an optionally substituted C 1-4 aliphatic,
with the proviso that R e is not hydrogen if R f and R f′ are present and form a ring;
OR (ii) R e is a ring chosen from optionally substituted 6-membered aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl, which is optionally fused to a second optionally substituted 6-membered aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl;

OR
(c) Z 2 is hydrogen.

2 . The chemical entity of claim 1 , wherein:
(a) Z 2 is a ring system having a 5- to 7-membered heterocyclyl with 1-2 heteroatoms or a 5- to 7-membered cycloaliphatic fused to
(i) a 5-membered heteroaryl or a 6-membered aryl or heteroaryl to form a bicyclic group; or
(ii) a 9-membered heteroaryl or a 10-membered aryl or heteroaryl to form a tricyclic group;
wherein the ring system is optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, C 1-4 aliphatic, C 1-4 fluoroaliphatic, C 1-4 alkoxy, C 1-4 fluoroalkoxy, —S—C 1-4 aliphatic, —S—C 1-4 fluoroaliphatic, —N(R z7 ) 2 , —C(O)R z8 , —S(O)R z8 , —S(O) 2 R z8 , —C(O) 2 R z7 , —C(O)N(R z7 ) 2 , —S(O) 2 N(R z7 ) 2 , —OC(O)N(R z7 ) 2 , —N(R z7 )C(O)R z8 , —N(R z7 )SO 2 R z8 , —N(R z7 )C(O)OR z8 , T 2 -R z9 , a 5- to 6-membered heteroaryl, a 6-membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and the ring system is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or a spirocyclic 4- to 6-membered heterocycle; each occurrence of R z7 is independently hydrogen or C 1-4 alkyl; each occurrence of R z8 is independently C 1-4 alkyl; T 2 is a C 1-2 alkylene chain; R z9 is cyano, —N(R z7 ) 2 , —OR z7 , —C(O)R z8 , —C(O) 2 R z7 , or —C(O)N(R z7 ) 2 ;
OR
(b) Z 2 is L-R e wherein either:
(i) R e is hydrogen, hydroxyl, halogen, —CF 3 , or C 1-4 aliphatic optionally substituted with one or more hydroxyl, halogen, or C 1-4 aliphatic,

with the proviso that R e is not hydrogen if R f and R f′ are present and form a ring;
OR (ii) R e is a ring chosen from 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, which is optionally fused to a second 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 7-membered cycloaliphatic, or 4- to 7-membered heterocyclyl, R e being optionally substituted by 1-3 independent occurrences of halogen, hydroxyl, cyano, C 1-4 aliphatic, C 1-4 fluoroaliphatic, C 1-4 alkoxy, C 1-4 fluoroalkoxy, S—C 1-4 aliphatic, S—C 1-4 fluoroaliphatic, —N(R z7 ) 2 , —C(O)R z8 , —S(O)R z8 , —S(O) 2 R z8 , —C(O) 2 R z7 , —C(O)N(R z7 ) 2 , —S(O) 2 N(R z7 ) 2 , —OC(O)N(R z7 ) 2 , —N(R z7 )C(O)R z8 , —N(R z7 )SO 2 R z8 , —N(R z7 )C(O)OR z8 , T 2 -R z9 , a 5- to 6-membered heteroaryl, a 6-membered aryl, a 3- to 6-membered cycloaliphatic, or a 4- to 6-membered heterocyclyl; and which is optionally substituted at one saturated carbon with oxo, a spirocyclic 3- to 6-membered carbocycle, or a spirocyclic 4- to 6-membered heterocycle;

each occurrence of R z7 is independently hydrogen or C 1-4 alkyl;
each occurrence of R z8 is independently C 1-4 alkyl;
T 2 is a C 1 -C 2 alkylene chain; and
R z9 is cyano, —NO 2 , —N(R z7 ) 2 , —OR z7 , —C(O)R z8 , —C(O) 2 R z7 , or —C(O)N(R z7 ) 2 .

3 . The chemical entity of claim 1 , wherein L is —C(R f )(R f′ )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(═CH 2 )—, —C(R f )(R f′ )—C(═CH 2 )—, —C(R f )(R f′ )—C≡C—, —C(R f )(R f′ )—O—, —C(R f )(R f′ )—S—, —C(R f )(R f′ )—N(R g )—, —C(R f )(R f′ )—N(R g )—CH 2 —, —C(R f )(R f′ )—CH 2 —, —C(R f )(R f′ )—CH 2 —CH 2 —, or —C(O)—C(R f )(R f′ )—.

4 . The chemical entity of claim 1 , wherein:
Z 1 is hydrogen, halogen, cyano, R z3 , —S(O)—R z3 , or —S(O) 2 —R z3 ; R z3 is a phenyl, 5- to 7-membered cycloaliphatic, 5- to 7-membered heterocyclyl, or C 1-4 aliphatic, any of which may be substituted with one or more independently selected R z4 ; R z4 is hydroxyl, halogen, cyano, C 1-4 aliphatic, C 1-4 fluoroaliphatic, C 1-4 alkoxy, C 1-4 fluoroalkoxy, —N(R z5 ) 2 , —C(O)R z6 , —C(O) 2 R z5 , 5- or 6-membered

Assignees

• Millennium Pharm Inc

Inventors

• Duffey Matthew O
• England Dylan
• Freeze Scott
• Hu Zhigen
• Langston Steven
• Mcintyre Charles
• Mizutani Hirotake
• Ono Koji
• 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

• C07D409/14

  containing three or more hetero rings · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title