Histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-10981933-B2
Application number	US-201916299423-A
Country	US
Kind code	B2
Filing date	Mar 12, 2019
Priority date	Feb 28, 2011
Publication date	Apr 20, 2021
Grant date	Apr 20, 2021

Abstract

This invention relates to generally inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3).

First claim

We claim:

1. A compound of the formula (I):

wherein:
Ar′/Het′ is:
phenyl which is optionally substituted with from 1-3 R p ; provided that the point of connection on said phenyl to U and the point of connection on said phenyl to the amide carbonyl do not result in a 1,2-relation to one another on said phenyl; wherein R p at each occurrence is, independently, selected from H, F, chloro, CH 3 , CF 3 , OCH 3 , OCF 3 , and OCHF 2 ;
R1 is:
(i) hydrogen; or
(ii) C6-C10 aryl, which is optionally substituted with from 1-3 R q ; or
(iii) monocyclic or bicyclic heteroaryl having from 5-10 ring atoms, which is optionally substituted with from 1-3 R q ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q , and S; or
(iv) heterocyclyl having from 4-10 ring atoms, which is optionally substituted with from 1-3 R q ; wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q , and S; and
each occurrence of R q is independently selected from the group consisting of:
(C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—;
—N*(R q′ ) 2 , wherein R q′ —N*—R q′ together form a saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms is/are optionally a heteroatom independently selected from NH, N(alkyl), O, and S (—N*(R q′ ) 2 ;
formyl; formyl(C 1 -C 4 ) alkyl; cyano; cyano(C 1 -C 4 ) alkyl;
benzyl; benzyloxy;
heterocyclyl-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, and S, and when said alkyl portion is present, said alkyl portion serves as the point of attachment to R1; otherwise in the case of CO alkyl, a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R1;
phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—R q″ , and S, each of which is optionally substituted with from 1-3 R q″ ;
SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and
nitro;
each occurrence of R q″ is independently selected from the group consisting of:
halogen;
C1-C6 alkyl; fluoro(C1-C6)alkyl;
hydroxyl;
hydroxy(C 1 -C 4 )alkyl;
C1-C6 alkoxy; fluoro(C1-C6)alkoxy;
(C1-C6 alkyl)C(O)—;
(C1-C6 alkyl)NH—; (C1-C6 alkyl) 2 N—;
formyl; formyl(C1-C4) alkyl; cyano; cyano(C1-C4) alkyl;
benzyl; benzyloxy;
heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atoms is/are a heteroatom independently selected from NH, N(alkyl), O, and S, and when said alkyl portion is present, said alkyl portion serves as the point of attachment to R1; otherwise in the case of CO alkyl, a heterocyclyl carbon ring atom serves as the point of attachment of the heterocyclyl to R1;
phenyl or heteroaryl having from 5-6 ring atoms, wherein from 1-4 of the ring atoms is/are a heteroatom independently selected from O, N, N—H, N—(C1-C6 alkyl), and S;
SO 2 —(C1-C6)alkyl; SO—(C1-C6)alkyl; and
nitro;
U is ═CR r or U′—C(R s ) 2 — or C(R s ) 2 —U′;
wherein:
R r is hydrogen, F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;
each occurrence of R S is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; or
R s —C—R s together form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O) m , (m=0-2); and NR u ; and m is 0-2;
each occurrence of R u is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R v , C(═O)O(C1-C6 alkyl), C(═O)N(R w ) 2 , and SO 2 —R v ; wherein R v is selected from C1-C6 alkyl, CH 2 -(heteroaryl having 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R W is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl having 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; wherein the aryl and heteroaryl portion in R v and R w are optionally substituted with one or more independently selected substituents selected from F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;
U′ is a bond; O; NR u ; S(O) m ; CH 2 ; or U″—CH 2 —; wherein U″ is O; NR u ; or S(O) m , and each m is independently 0-2;
Cy is C4-C10 cycloalkyl or saturated heterocyclyl having 4-10 ring atoms, each of which is optionally substituted with from 1-3 R x , in which from 1-3 heteroatoms are independently selected from O, N—H, NR′″, and S(O), wherein m is 0-2; wherein each occurrence of R x is independently selected from F, OH, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; wherein R x′ is defined as R q″ ; and

wherein when the heterocyclyl contains a secondary amine as part of its structure, then:
(i) V is linked through the nitrogen of the secondary amine portion of the heterocyclyl; and
(ii) U is linked to Cy via a Cy ring carbon atom; wherein the bond between U and the Cy ring carbon is a single or double bond;
V is:
(i) —V′—C(R y ) 2 — or —C(R y ) 2 —V′—; or
(ii) O, NR z , or S(O) m , and m is 0-2; or
(iii) —CH═CH—, C═O, C(R y ) 2 —C(═O), —C(═O)—C(R y ) 2 —, —SO 2 NR z , NR z SO 2 , —C(═O)NR z , or NR Z C(═O); wherein:
each occurrence of R y is independently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH 2 , OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, and cyano; or
R y —C—R y together form C3-C6 cycloalkyl or heterocyclyl having 3-6 ring atoms, in which one of the heterocyclyl ring atoms is selected from O; S(O) m , and NR aa ; and m is 0-2;
each occurrence of R z and R aa is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R v , C(═O)O(C1-C6 alkyl), C(═O)N(R w ) 2 , and SO 2 —R v , wherein R v is selected from C1-C6 alkyl, CH 2 -(heteroaryl having 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R w is independently selected from H, C1-C6 alkyl, CH 2 -(heteroaryl having 5-10 ring atoms), CH 2 —(C6-C10 aryl), and C6-C10 aryl;
V′ is a bond; O; NR u ; S(O) m ; —C(O)—O—(CR y 2 ) 0-2 —, —(CR y 2 ) 0-2 —O—C(O)—, C(R y ) 2 , C(R y ) 2 —C(R y ) 2 ; —(R y ) 2 —V″; or V″—C(R Y ) 2 —; wherein V″ is O; NR z ; or S(O) m ; each occurrence of R y is independently defined as above; and each m is independently 0-2;
R2 is selected from H, F, CI, CF 3 , CF 2 CF 3 , CH 2 CF 3 , OCF 3 , OCHF 2 , phenyl; phenyl substituted with from 1-3 substituents independently selected from F, OH, C1-C6 alkyl, fluoro(C1-C6) alkyl C3-C6 cycloalkyl, NH 2 , C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; thienyl; thiazolyl; and pyrazol-1-yl; and
R3 is H, F, or Cl;
or a pharmaceutically acceptable salt thereof.

2. The compound or salt according to claim 1 , wherein Cy is a saturated heterocyclyl including 4-10 ring atoms, optionally substituted with from 1-3 R x , in which from 1-3 heteroatoms are independently selected from O, N—H, NR x″ , and S(O) m ; and m is 0-2.

3. The compound or salt according to claim 1 , wherein Cy is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, isoxazolidinyl, thiazolidinonyl, imidazolidinonyl, pyrrolidinonyl.

4. The compound or salt according to claim 3 , wherein Cy is azetidinyl, pyrrolidinyl or piperidinyl.

Assignees

• Biomarin Pharm Inc

Inventors

• Jacques Vincent
• Rusche James R
• Peet Norton P
• Singh Jasbir

Classifications

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D261/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D277/30

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