Heteroaryl compounds useful as inhibitors of E1 activating enzymes

Patent metadata

Field	Value
Publication number	US-9458108-B2
Application number	US-201514827556-A
Country	US
Kind code	B2
Filing date	Aug 17, 2015
Priority date	Aug 8, 2006
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.

First claim

What is claimed is:

1. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
D is —C(R h )═;
E is —C(R h )═;
R g is hydrogen, halo,
cyano, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 ,
—NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 ,
—NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 ,
—C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 ,
—N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N (R 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , —C(R 6 )═N—OR 5 , or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl; and
each R h independently is hydrogen, halo, —CN—, —OR 5 , —N(R 4 ) 2 , —SR 6 , or an optionally substituted C 1-4 aliphatic group;
W is —CH 2 —, —CHF—, —CF 2 —, —CH(R 1 )—, —CF(R 1 )—, —NH—, —N(R 1 )—, —O—, —S—, or —NHC(O)—;
R 1 is C 1-4 aliphatic or C 1-4 fluoroaliphatic;
X is —CH 2 —, —CHF—, —CF 2 —, —NH—, or —O—;
Y is —O—, —S—, or —C(R m )(R n )—;
R a is hydrogen,
fluoro, —CN, —N 3 , —OR 5 , —N(R 4 ) 2 , —NR 4 CO 2 R 6 , —NR 4 C(O)R 5 , —C(O)N(R 4 ) 2 , —C(O) R 5 , —OC(O)N(R 4 ) 2 , —OC(O)R 5 , —OCO 2 R 6 , or a C 1-4 aliphatic or C 1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or R a and R c together form a bond;

R b is hydrogen, fluoro, C 1-4 aliphatic, or C 1-4 fluoroaliphatic;
R c is hydrogen, fluoro, —CN, —N 3 , —OR 5 , —N(R 4 ) 2 , —NR 4 CO 2 R 6 , —NR 4 C(O)R 5 , —C(O)N(R 4 ) 2 , —C(O)R 5 , —OC(O)N(R 4 ) 2 , —OC(O)R 5 , —OCO 2 R 6 , or a C 1-4 aliphatic or C 1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or R a and R o together form a bond;
R d is hydrogen, fluoro, C 1-4 aliphatic, or C 1-4 fluoroaliphatic;
R e is hydrogen, or C 1-4 aliphatic; or R e , taken together with one R f and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring; or R e , taken together with R m and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic;
R e′ is hydrogen or C 1-4 aliphatic; or R e′ , taken together with R m and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic;
each R f is independently hydrogen, fluoro, C 1-4 aliphatic, or C 1-4 fluoroaliphatic; or two R f taken together form ═O; or two R f , taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring; or one R f , taken together with R e and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
R m is hydrogen, fluoro, —N(R 4 ) 2 , or an optionally substituted C 1-4 aliphatic group; or R m and R n together form ═O or ═C(R 5 ) 2 ; or R m and R e , taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic; or R m and R e′ , taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C 1-4 aliphatic;
R n is hydrogen, fluoro, or an optionally substituted C 1-4 aliphatic group; or R m and R n together form ═O or ═C(R 5 ) 2 ;
each R 4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
R 4x is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 6-10 ar(C 1-4 )alkyl, the aryl portion of which may be optionally substituted;
R 4y is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 6-10 ar(C 1-4 )alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring; or
R 4x and R 4y , taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S; and
each R 5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R 5x independently is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or an optionally substituted C 6-10 aryl or C 6-10 ar(C 1-4 )alkyl;
each R 6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group; and
m is 1, 2, or 3.

2. The compound of claim 1 , wherein:
R g is hydrogen, C 1-6 aliphatic, C 1-6 fluoroaliphatic, halo, —R 1g , —R 2g , -T 1 -R 1g , -T 1 -R 2g , —V 1 -T 1 -R 1g , —V 1 -T 1 -R 2g , —V 1 —R 1g , or -T 1 -V 1 —R 1g ;
T 1 is a C 1-6 alkylene chain substituted with 0-2 independently selected R 3a or R 3b , wherein the alkylene chain optionally is interrupted by —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )—C(═NR 4 )—, —N(R 4 )CO 2 —, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —OC(O)—, —OC(O)N(R 4 )—, —C(O)—, —CO 2 —, —C(O)N(R 4 )—, —C(═NR 4 )—N(R 4 )—, —C(NR 4 )═N(R 4 )—, —C(═NR 4 )—O—, or —C(R 6 )═N—O—, and wherein T 1 or a portion thereof optionally forms part of a 3-7 membered ring;
V 1 is —C(R 5 )═C(R 5 )—, —C≡C—, —O—, —S—, —S(O)—, —S(O) 2 —, —SO 2 N(R 4 )—, —N(R 4 )—, —N(R 4 )C(O)—, —NR 4 C(O)N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )C(═NR 4 )—, —N(R 4 )CO 2 —, —N(R 4 )SO 2 —, —N(R 4 )SO 2 N(R 4 )—, —OC(O)—, —OC(O)N(R 4 )—, —C(O)—, —CO 2 —, —C(O)N(R 4 )—, —C(O)N(R 4 )—O—, —C(O)N(R 4 )C(═NR 4 )—N(R 4 )—, —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)—, —C(═NR 4 )—N(R 4 )—, —C(NR 4 )═N(R 4 )—, —C(═NR 4 )—O—, or —C(R 6 )═N—O—;
each R 1g independently is an optionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;
each R 2g independently is —NO 2 , —CN, —C(R 5 )═C(R 5 ) 2 , —C≡C—R 5 , —OR 5 , —SR 6 , —S(O)R 6 , —SO 2 R 6 , —SO 2 N(R 4 ) 2 , —N(R 4 ) 2 , —NR 4 C(O)R 5 , —NR 4 C(O)N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—R 6 , —NR 4 CO 2 R 6 , —N(R 4 )SO 2 R 6 , —N(R 4 )SO 2 N(R 4 ) 2 , —O—C(O)R 5 , —OCO 2 R 6 , —OC(O)N(R 4 ) 2 , —C(O)R 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(O)N(R 4 )—OR 5 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , —C(═NR 4 )—N(R 4 ) 2 , —C(═NR 4 )—OR 5 , —N(R 4 )—N(R 4 ) 2 , —N(R 4 )—OR 5 , —C(═NR 4 )—N(R 4 )—OR 5 , or —C(R 6 )═N—OR 5 ;
each R 3a independently is —F, —OH, —O(C 1-4 alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-4 alkyl)-, —CO 2 H, —CO 2 (C 1-4 alkyl), —C(O)NH 2 , or —C(O)NH(C 1-4 alkyl);
each R 3b independently is a C 1-3 aliphatic optionally substituted with R 3a or R 7 , or two substituents R 3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring; and
each R 7 independently is an

Assignees

• Millennium Pharm Inc

Inventors

• Claiborne Christopher F
• Critchley Stephen
• Langston Steven P
• Mizutani Hirotake
• Olhava Edward J
• Peluso Stephane
• Vyskocil Stepan
• Weatherhead Gabriel S

Classifications

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title