Cycloalkenyl hydroxamic acid derivatives and their use as histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-10793538-B2
Application number	US-201815878694-A
Country	US
Kind code	B2
Filing date	Jan 24, 2018
Priority date	Dec 20, 2012
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

Abstract

The present invention provides compounds of formula (I):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein W, X, n, s, t, and R a are as described herein. The present invention relates generally to selective inhibitors of histone deacetylase and to methods of making and using them.

First claim

What is claimed:

1. A compound of formula I:

or a pharmaceutically acceptable salt or tautomer thereof, wherein
n is 0, 1, 2, 3, 4, or 5;
t is 1, 2, 3, 4, or 5;
s is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
X is CR b R c , NR d , or S(O) z ;
W is CR e or N;
R e is hydrogen, OH, C 1 -C 4 alkyl, or halogen;
z is 0, 1, or 2;
each R a is independently selected from halogen, CN, CF 3 , OR f , OCF 3 , C(O)R g , C 1 -C 8 alkoxyl, NR h R i , C 2 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R 1 , provided that when X is CH 2 , W is CH, and n+t is 3, s is not 0;
each R b , R c , and R d is independently selected from hydrogen, halogen, CN, CF 3 , OR f , OCF 3 , C(O)R g , C 1 -C 8 alkoxyl, NR h R i , S(O) z R j , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R 1 ;
or R e is attached to R a to form a fused ring, wherein said ring is selected from C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3 to 10-membered saturated or unsaturated heterocyclic ring, 6 to 10-membered aromatic ring, and 3 to 10-membered heteroaromatic ring, wherein said fused ring is unsubstituted or substituted with one or more R 2 ;
or taken together two R a are attached to form a fused ring, wherein said ring is selected from C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3 to 10-membered saturated or unsaturated heterocyclic ring, 6 to 10-membered aromatic ring, and 3 to 10-membered heteroaromatic ring, wherein said fused ring is unsubstituted or substituted with one or more R 2 ;
or one R b , R c , or R d is attached to R e or R a to form a fused ring, wherein said ring is selected from C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3 to 10-membered saturated or unsaturated heterocyclic ring, 6 to 10-membered aromatic ring, and 3 to 10-membered heteroaromatic ring, wherein said fused ring is unsubstituted or substituted with one or more R 2 ;
or taken together two R a are attached to form a bridged ring;
or R a is attached to one R b , R c , or R d to form a bridged ring;
or R b and R c taken together with the carbon atom to which they are attached form C═O;
or two R a taken together with the carbon atom to which they are attached form a spirocyclic ring selected from a C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or 3 to 10-membered saturated or unsaturated heterocyclic ring, wherein said spirocyclic ring is unsubstituted or substituted with one or more R 2 , provided that when n is 2, t is 0, W is CH, and X is O or S, said fused ring is not unsubstituted phenyl;
or R b and R c taken together with the carbon atom to which they are attached form a spirocyclic ring selected from a C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or 3 to 10-membered saturated or unsaturated heterocyclic ring, wherein said spirocyclic ring is unsubstituted or substituted with one or more R 2 ;
each R g is selected from hydrogen, OR L , NR m R o , CF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R 3 ;
each R f , R i , R j , R L , R m , and R o is independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C(O)R p , S(O) z R jj , (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl; cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring; and heteroaromatic ring are unsubstituted or substituted with one or more R 4 ;
R h is selected from C 1 -C 8 alkyl; C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C(O)R p , S(O) z R jj , (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R 4 ;
each R p and R jj is independently selected from OR q ; NR r R u , CF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R 5 ;
each R q , R r , and R u is independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 )k-3 to 10-membered heteroaromatic ring; wherein said alkyl; alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring, and heteroaromatic ring are unsubstituted or substituted with one or more R 6 ;
each R 3 , R 4 , R 5 , and R 6 is independently selected from halogen, CF 3 , OCF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OC 1 -C 8 alkyl, NH 2 , NHC 1 -C 8 alkyl, N(C 1 -C 8 alkyl) 2 , C(O)NR v R y , C(O)R aa , and C(O)OR bb , and (CH 2 ) k -6 to 10-membered aromatic ring, wherein said aromatic ring is unsubstituted or substituted with one or more R 7 ;
R 1 is selected from halogen, CF 3 , OCF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OC 1 -C 8 alkyl, NHC 1 -C 8 alkyl, N(C 1 -C 8 alkyl) 2 , C(O)NR v R y , C(O)R aa , and C(O)OR bb , and (CH 2 ) k -6 to 10-membered aromatic ling, wherein said aromatic ring is unsubstituted or substituted with one or more R 7 ;
R 2 is selected from CF 3 , OCF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, NH 2 , NHC 1 -C 8 alkyl, N(C 1 -C 8 alkyl) 2 , C(O)NR v R y , C(O)R aa , and C(O)OR bb , and (CH 2 ) k -6 to 10-membered aromatic ring, wherein said aromatic ring is unsubstituted or substituted with one or more R 7 ;
each R v , R y , R aa , and R bb is independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring and heteroaromatic

Assignees

• Broad Inst Inc

Inventors

• Holson Edward
• Lazzaro Fanny
• Olson David
• Wagner Florence Fevrier
• Weiwer Michel

Classifications

• C07D263/16

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C2602/08

  the other ring being five-membered, e.g. indane · CPC title

• C07D309/28 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title