HDAC inhibitors

Patent metadata

Field	Value
Publication number	US-9725407-B2
Application number	US-201615004039-A
Country	US
Kind code	B2
Filing date	Jan 22, 2016
Priority date	Oct 6, 2006
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Compounds of formula (I) inhibit HDAC activity:

wherein A, B and D independently represent ═C— or ═N—; W is a divalent radical —CH═CH— or CH 2 CH 2 —; R 1 is an ester group; R 2 is the side chain of a natural or non-natural alpha-amino acid; z is 0 or 1; and Y, L 1 , and X 1 are as defined in the claims.

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
one of A, B, and D is ═N— and the others are each ═C—;
W is a divalent radical —CH 2 CH 2 —;
R 1 is an ester group of formula —(C═O)OR 9 , wherein R 9 is R 20 R 21 R 22 C, wherein:
(i) R 20 is hydrogen or (C 1 -C 3 )alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - or (C 2 -C 3 )alkenyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b -wherein a and b are independently 0 or 1 and Z 1 is —O—, —S—, or —NR c — wherein R c is hydrogen or (C 1 -C 3 )alkyl; and R 21 and R 22 are independently hydrogen or (C 1 -C 3 )alkyl—;
(ii) R 20 is hydrogen or R 12 R 13 N—(C 1 -C 3 )alkyl-wherein R 12 is hydrogen or (C 1 -C 3 )alkyl and R 13 is hydrogen or (C 1 -C 3 )alkyl; or R 12 and R 13 together with the nitrogen to which they are attached form an monocyclic heterocyclic ring of 5- or 6-ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R 21 and R 22 are independently hydrogen or (C 1 -C 3 )alkyl-; or
(iii) R 20 and R 21 taken together with the carbon to which they are attached form an monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms, and R 22 is hydrogen;

R 2 is benzyl, phenyl, cyclohexylmethyl, cyclohexyl, pyridin-3-ylmethyl, tert-butoxymethyl, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, or phenylethyl;
Y is a bond, —S(═O) 2 —, —C(═S)—NR 3 , —C(═NH)NR 3 , or —S(═O) 2 NR 3 —, wherein R 3 is hydrogen or C 1 -C 6 alkyl;
L 1 is a divalent radical of formula -(Alk 1 ) m (Q) n (Alk 2 ) p - , wherein:
m, n and p are independently 0 or 1,
Q is (i) an optionally substituted divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, or (ii), in the case where both m and p are 0, a divalent radical of formula —X 2 -Q 1 - or -Q 1 -X 2 — wherein X 2 is —O—, —S— or —NR A — wherein R A is hydrogen or C 1 -C 3 alkyl, and Q 1 is an divalent mono- or bicyclic carbocyclic or heterocyclic radical having 5-13 ring members, and
Alk 1 and Alk 2 independently represent divalent C 3 -C 7 cycloalkyl radicals, or straight or branched, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene radicals which may optionally contain or terminate in —O—, —S—, or —NR A —, wherein R A is hydrogen or C 1 -C 3 alkyl;

X 1 represents a bond, —C(═O)—, —S(═O) 2 —, —NR 4 C(═O)—, —C(═O)NR 4 —, —NR 4 C(═O)NR 5 —, —NR 4 S(═O) 2 —, or —S(═O) 2 NR 4 —, wherein R 4 and R 5 are independently hydrogen or C 1 -C 6 alkyl; and
z is 0 or 1;
and wherein when Y is a bond and m, n and p are each 0, X 1 does not represent —C(═O)—.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein the radical HONHC(═O)—W— is attached to the ring containing A, B, and D in a position meta- or para- to the radical R 1 R 2 CHNHYL 1 X 1 [CH 2 ] z —.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein the radical R 1 R 2 CHNHYL 1 X 1 [CH 2 ] z —, is selected from:
R 1 R 2 CHNHSO 2 —, R 1 R 2 CHNHCH 2 —, R 1 R 2 CHNH(CH 2 ) 3 O—, and the following:

4. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein the radical —YL 1 X 1 [CH 2 ] z — is —CH 2 —.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein R 9 is methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- or 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl or methoxyethyl.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein R 9 is cyclopentyl.

7. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein R 2 is phenyl, benzyl, phenylethyl, tert-butoxymethyl or iso-butyl.

8. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein R 2 is —CH(CH 3 ) 2 , cyclohexyl, —CH 2 O(t-Bu), —CH 2 S(t-Bu), or phenyl.

9. The compound or pharmaceutically acceptable salt thereof according to claim 1 wherein the compound has the formula (IB):

wherein:
W is a divalent radical —CH 2 CH 2 —;
R 1 is an ester group of formula —(C═O)OR 9 , wherein R 9 is R 20 R 21 R 22 C, wherein:
(i) R 20 is hydrogen or (C 1 -C 3 )alkyl-(Z 1 ) a —[(C 1 -C 3 )alkyl] b - or (C 2 -C 3 )alkenyl-(Z 1 ) a— [(C 1 -C 3 )alkyl] b - wherein a and b are independently 0 or 1 and Z 1 is —O—, —S—,or —NR c — wherein R c is hydrogen or (C 1 -C 3 )alkyl; and R 21 and R 22 are independently hydrogen or (C 1 -C 3 )alkyl-;
(ii) R 20 is hydrogen or R 12 R 13 N—(C 1 -C 3 )alkyl- wherein R 12 is hydrogen or (C 1 -C 3 )alkyl and R 13 is hydrogen or (C 1 -C 3 )alkyl; or R 12 and R 13 together with the nitrogen to which they are attached form an monocyclic heterocyclic ring of 5- or 6- ring atoms or bicyclic heterocyclic ring system of 8 to 10 ring atoms, and R 21 and R 22 are independently hydrogen or (C 1 -C 3 )alkyl-; or
(iii) R 20 and R 21 taken together with the carbon to which they are attached form an monocyclic carbocyclic ring of from 3 to 7 ring atoms or bicyclic carbocyclic ring system of 8 to 10 ring atoms, and R 22 is hydrogen;

R 2 is benzyl, phenyl, cyclohexylmethyl, cyclohexyl, pyridin-3-ylmethyl, tert-butoxymethyl, iso-butyl, sec-butyl, tert-butyl, 1 -benzylthio-1 -methylethyl, 1 -methylthio-1-methylethyl, 1-mercapto-1-methylethyl, or phenylethyl.

10. The compound or pharmaceutically acceptable salt thereof according to claim 9 wherein R 9 is methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, cyclohexyl, allyl, phenyl, benzyl, 2-, 3- or 4-pyridylmethyl, N-methylpiperidin-4-yl, tetrahydrofuran-3-yl or methoxyethyl.

11. The compound or pharmaceutically acceptable salt thereof according to claim 9 wherein R 9 is cyclopentyl.

12. The compound or pharmaceutically acceptable salt thereof according to claim 9 wherein R 2 is phenyl, benzyl, phenylethyl, tert-butoxymethyl or iso-butyl.

13. The compound or pharmaceutically acceptable salt thereof according to claim 9 wherein R 2 is —CH(CH 3 ) 2 , cyclohexyl, —CH 2 O(t-Bu), —CH 2 S(t-Bu), or phenyl.

14. The compound according to claim 1 selected from the group consisting of:
Cyclopentyl (2S)-cyclohexyl[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino]acetate,
tert-Butyl (2S)-[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino](phenyl)acetate,
Cyclopentyl (2S)-[({6-[3-(hydroxyamino)-3-oxopropyl]pyridin-3-yl}methyl)amino](phenyl)acetate,
tert-Butyl N-({6-[3-(hydroxyamino)-3 -oxopropyl]pyridin-3-yl}methyl)-L-leucinate,
Cyclopentyl (2S)-cyclohexyl[({5-[3-(hydroxyamino)-3oxopropyl]pyridin-2-yl}methyl)amino]acetate, and
tert-Butyl N-({5-[3-(hydroxyamino)-3-oxopropyl]pyridin-2yl}methyl)-L-leucinate,
or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 , together with a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 9 ,

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Davidson Alan Hornsby
• Moffat David Festus Charles
• Day Francesca Ann
• Donald Alastair David Graham

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title