IP Library › Granted Patent US 9,546,150

Granted Patent B2

US 9,546,150 · App. 14/241,923 · Granted Jan 17, 2017

Substituted quinazolin-4-ones for inhibiting ubiquitin specific protease 7

Inventors: Frédéric Colland (Puiseux en France, FR); Marie-Edith Gourdel (Savigny le Temple, FR)

Assignee: HYBRIGENICS SA

C07D401/06 A61K31/517 A61K45/06 C07D239/88 C07D239/91 C07D409/14

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Quick Facts

Patent No.: US 9,546,150
App. No.: 14/241,923
Granted: Jan 17, 2017
Kind: B2

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Abstract

The present invention relates to quinazolin-4-one compounds of formula (I′), their process of preparation and uses thereof. These compounds are useful as selective and reversible inhibitors of ubiquitin specific proteases, particularly USP7, for treating e.g. cancer, neurodegenerative diseases, inflammatory disorders and viral infections.

Claims (97)

1. A compound of formula (I′):

wherein

R 1 , each identical or different, is selected from the group consisting of halogen, linear or branched (C 1 -C 6 ) alkyl, OR, NRR′, CN, CF 3 , C(O)R, C(O)OR, C(O)NRR′, NO 2 , (C 1 -C 6 )alkylene-OR, (C 1 -C 6 )alkylene-NRR′, (C 1 -C 6 )alkylene-CO 2 R, (C 1 -C 6 )alkylene-CONRR′, —O—(C 1 -C 6 )alkylene-CO 2 R, —O—(C 1 -C 6 )alkylene-CONRR′, CO 2 —(C 1 -C 6 )alkylene-OR, CO 2 —(C 1 -C 6 )alkylene-NRR′, C(O)NH—(C 1 -C 6 )alkylene-OR, CONH—(C 1 -C 6 )alkylene-NRR′, and NHC(O)R;

L 1 is linear or branched (C 1 -C 6 )alkylene optionally substituted by one or more of ═O, CN, C(O)R, C(O)OR, or C(O)NRR′, or linear or branched CH 2 (C 1 -C 6 )alkylene, wherein the later (C 1 -C 6 )alkylene is optionally substituted by one or more of halogen, OR, NRR′ or CF 3 ;

q is 0, 1, 2, 3 or 4;

X′ is CR 7 ;

R 7 is OR, halogen, linear or branched (C 1 -C 6 )alkyl-OR, C(O)OR, C(O)NRR′, CN or OPO 3 H 2 ;

n is 0, 1 or 2;

p is 1, 2 or 3;

R 3 , R 4 , R 8′ and R 8 , each identical or different, are selected from the group consisting of H, linear or branched (C 1 -C 6 )alkyl, halogen, OH, —O—(C 1 -C 6 )alkyl, NRR′, CN, CF 3 , OR, C(O)R, C(O)OR and C(O)NRR′;

A is selected from the group consisting of —C(O)—, —C(O)NH—, —S(O) 2 — and —S(O) 2 NH—;

L 2 is linear or branched (C 1 -C 6 )alkylene optionally interrupted by at least one heteroatom selected from the group consisting of O, N and S and/or optionally substituted by: R, OR, NRR′, (C 1 -C 6 )alkyl-OR, (C 1 -C 6 )alkyl-NRR′, OC(O)R, NHC(O)R, NHC(O)NRR′, CN or C(═NH)NHOR;

R 6 is selected from the group consisting of H, aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is monocyclic or polycyclic and is optionally substituted by one or more of linear or branched (C 1 -C 6 )alkyl, halogen, NRR′, CN, CF 3 , OR, ═O, C(O)R, C(O)OR, NHC(O)R, OC(O)R or C(O)NRR′; and

each R and R′, identical or different, are independently selected from the group consisting of H, linear or branched (C 1 -C 6 )alkyl, aryl, heterocyclyl, heteroaryl, linear or branched —(C 1 -C 6 )alkyl-aryl, linear or branched —(C 1 -C 6 )alkyl-heterocyclyl and linear or branched —(C 1 -C 6 )alkyl-heteroaryl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof;

with the exception of:

(i) q is 0, L′ is CH 2 , X′ is CR 7 , where R 7 is OH, A is —C(O)—, L 2 is CH 2 CH 2 and R 6 is 3-methylpiperidin-1-yl; and

(ii) q is 1, L′ is CH 2 , X′ is CR 7 , where R 7 is OH, A is —C(O)—, L 2 is CH(CH 2 CH 3 ) 2 and, at C-7, R 1 — is Cl.

2. The compound according to claim 1 , wherein A is —C(O)—.

3. The compound according to claim 1 , wherein L 1 is CH 2 .

4. The compound according to claim 1 , wherein L 2 is linear or branched (C 1 -C 6 )alkylene.

5. The compound according to claim 1 , wherein R 1 , each identical or different, is selected from the group consisting of linear or branched (C 1 -C 6 )alkyl, halogen, OR, NRR′, CN, CF 3 , C(O)R, C(O)OR, C(O)NRR′ and NHC(O)R.

6. The compound according to claim 1 , wherein R 1 , each identical or different, is selected from the group consisting of linear or branched C 1 -C 6 (alkyl), halogen, OH and linear or branched —O—(C 1 -C 6 )alkyl.

7. The compound according to claim 1 , wherein R 3 , R 4 , R 8 , and R 8′ , each identical or different, are selected from the group consisting of H, —O—(C 1 -C 6 )alkyl, and OH.

8. The compound according to claim 1 , wherein R 6 is selected from the group consisting of aryl, heteroaryl, cycloalkyl and H, wherein the aryl, heteroaryl or cycloalkyl is optionally substituted by halogen or linear or branched O—(C 1 -C 6 )alkyl.

9. The compound according to claim 1 , wherein R 7 is OR or OPO 3 H 2 .

10. The compound according to claim 1 , wherein R 7 is OH.

11. The compound according to claim 1 , wherein p is 2 and n is 2.

12. The compound according to claim 1 , wherein the sum of p and n is 4.

13. The compound according to claim 1 , selected from the group consisting of:

3-({4-hydroxy-1-[3-(2-methoxyphenyl)propanoyl]piperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-one;

3-({1-[2-(3-fluorophenoxy)acetyl]-4-hydroxypiperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-one;

3-{[4-hydroxy-1-(2-methylpropanoyl)piperidin-4-yl]methyl}-6, 7-dimethoxy-3,4-dihydroquinazolin-4-one;

3-{[4-hydroxy-1-(2-methylpropanoyl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one;

4-hydroxy-1-([2-methyl-3-(thiophen-2-yl)propanoyl]piperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-one;

7-chloro-3-{[1-(3-cyclopentylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one;

3-{[1-(3-cyclopentylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one;

7-chloro-3-{[4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one;

3-{[4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one;

7-chloro-3-({4-hydroxy-1-[2-methyl-3-(thiophen-2-yl)propanoyl]piperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-one;

3-({4-hydroxy-1-[3-(thiophen-2-yl)propanoyl]piperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-one;

3-{[1-(2-benzylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one; and

3-{[1-(2-benzylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-7-chloro-3,4-dihydroquinazolin-4-one;

or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

14. A process for preparing a compound of formula (I′) according to claim 1 ,

comprising the step of:

reacting a compound of formula (IIa)

wherein n, p, q, L 1 , R 1 , R 3 , R 4 , R 8 , R 8′ and X′ are as defined in claim 1 ,

with a compound of formula (III)

Y-A-L 2 -R 6 (III),

wherein Y is halogen, OH, tosylate or mesylate and A, L 2 and R 6 are as defined in claim 1 .

15. A process for preparing a compound of formula (I′) according to claim 1 ,

comprising the step of:

reacting a compound of formula (IV)

wherein q and R 1 are as defined in claim 1 ,

with a compound of formula (Va)

wherein Y is epoxy, halogen, tosylate or mesylate and n, p, A, L 1 , L 2 , R 3 , R 4 , R 6 , R 8 , R 8 and X′ are as defined in claim 1 .

16. A compound of formula (I′)

wherein

each identical or different, is selected from the group consisting of halogen, R, OR, NRR′, CN, CF 3 , C(O)R, C(O)OR, C(O)NRR′, NO 2 , (C 1 -C 6 )alkylene-OR, (C 1 -C 6 )alkylene-NRR′, (C 1 -C 6 )alkylene-CO 2 R, (C 1 -C 6 )alkylene-CONRR′, —O—(C 1 -C 6 )alkylene-CO 2 R, —O—(C 1 -C 6 )alkylene-CONRR′, CO 2 —(C 1 -C 6 )alkylene-OR, CO 2 -(C 1 -C 6 )alkylene-NRR′, C(O)NH—(C 1 -C 6 )alkylene-OR, CONH—(C 1 -C 6 )alkylene-NRR′, OCF 3 , SO 2 R, SO 3 H, SO 2 NR, NHSO 2 R, C≡CH, (R 10 )C═C(R 11 ) 2 , (R 10 ) 2 C═C(R 11 ), (C 1 -C 6 )alkylene-COR, NHC(O)R, and (C 1 -C 6 )alkyl interrupted by at least one heteroatom selected from the group consisting of O, N and S;

q is 0, 1, 2, 3 or 4;

X′ is CR 7 ;

R 7 is OR, halogen, linear or branched (C 1 -C 6 )alkyl-OR, C(O)OR, C(O)NRR′, CN, OR 9 , NRR′ or SR;

n is 0, 1 or 2;

p is 1, 2 or 3;

A is selected from the group consisting of —C(O)—, —C(O)NH—, —S(O) 2 — and —S(O) 2 NH—;

L 2 is linear or branched (C 1 -C 6 )alkylene optionally interrupted by at least one heteroatom selected from the group consisting of O, NR and S and/or optionally substituted by: R, OR, NRR′, (C 1 -C 6 )alkyl-OR, (C 1 -C 6 )alkyl-NRR′, OC(O)R, NHC(O)R, NHC(O)NRR′, CN or C(═NH)NHOR;

R 6 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclyl and H, wherein the aryl, heteroaryl, cycloalkyl or heterocyclyl is monocyclic or polycyclic and is optionally substituted by one or more of linear or branched (C 1 -C 6 )alkyl, halogen, NRR′, CN, CF 3 , OR, ═O, C(O)R, C(O)OR, NHC(O)R, OC(O)R, linear or branched (C 2 -C 6 )alkenylene or C(O)NRR′;

each R and R′, identical or different, are independently selected from the group consisting of H, linear or branched (C 1 -C 6 )alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, linear or branched —(C 1 -C 6 )alkyl-aryl, linear or branched —(C 1 -C 6 )alkyl-heterocyclyl and linear or branched —(C 1 -C 6 )alkyl-heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by OH, CO 2 H, C(O)NH 2 or NH 2 ;

R 9 is selected from the group consisting of —C(O)R, —C(O)NHR, —C(O)OR, —C(O)CH 2 NRR′, —C(O)CH 2 CH 2 CO 2 R, —C(O)CH 2 SO 3 H, —C(O)—(C 5 H 4 N) and —PO 3 H 2 ;

each R 10 independently is selected from the group consisting of a bond and a linear or branched (C 1 -C 6 )alkyl; and

each R 11 independently is selected from the group consisting of a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl and an aryl, wherein the alkyl or aryl is optionally substituted by OH, NH 2 , C(O)OH or C(O)NH;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

17. The compound according to claim 16 , wherein L 2 is linear or branched (C 1 -C 6 )alkylene.

18. The compound according to claim 16 , selected from the group consisting of:

3-({4-hydroxy-1-[3-(2-methoxyphenyl)propanoyl]piperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-one;

7-chloro-3-{[1-(2-ethylbutanoyl)-4-hydroxypiperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one;

3-({1-[2-(3-fluorophenoxy)acetyl]-4-hydroxypiperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-one;

3-{[4-hydroxy-1-(2-methylpropanoyl)piperidin-4-yl]methyl}-6,7-dimethoxy-3,4-dihydroquinazolin-4-one;