2,6,7 substituted purines as HDM2 inhibitors

Patent metadata

Field	Value
Publication number	US-9682978-B2
Application number	US-201414764616-A
Country	US
Kind code	B2
Filing date	Feb 4, 2014
Priority date	Feb 7, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present invention provides 2,6,7 substituted purines as described herein or a pharmaceutically acceptable salt thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.

First claim

What is claimed is:

1. A compound represented by Formula I:

Wherein
R 1 is selected from the group consisting of —(CR a 2 ) n COOR 11 , —(CR a 2 ) n C(O)NR c SO 2 N(R c ) 2 , and a nitrogen containing 5-membered heteroaryl and heterocyclenyl ring selected from the group consisting of tetrazolyl, oxadiazolyl, oxadiazolone, dihydro-oxadiazolyl, triazolyl, dihydro-triazolyl, and dihydro-triazolone, wherein the 5-membered ring is optionally substituted with OR c , SR c , NH 2 , nitro, CN, amide, COOR 11 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyloxy, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl-C(═O)O—, C 1 -C 6 alkyl-C(═O)—, C 2 -C 6 alkynyl, halo group, hydroxyalkoxy, —SO 2 NR c R c , —NR c SO 2 R c , C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamino or di(C 1 -C 6 )alkylamino;
R 2 is selected from the group consisting of phenyl, pyridyl, or —W—(CR a R 9 ) t R 7 , wherein W is NR c or O, wherein the phenyl or pyridyl is optionally substituted with R 12 selected from the group consisting of halo, CN, —(CR a 2 ) z COOR 10 , haloC 1 -C 6 alkyl, C 1 -C 6 alkyl, —OR c , —(CR a 2 ) z aryl, —(CR a 2 ) z heterocyclic, —(CR a 2 ) z cyclenyl, and —(CR a 2 ) z heterocyclenyl, wherein each of the alkyl, aryl, heterocyclic, cyclenyl and heterocyclenyl of R 12 is optionally substituted with OH, NH 2 , nitro, CN, CON(R c ) 2 , —(CR a 2 ) z COOR 10 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyk C 1 -C 6 haloalkyloxy, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl-C(═O)O—, C 1 -C 6 alkyl-C(═O)—, C 2 -C 6 alkynyl, halo group, hydroxyalkoxy, —NR c SO 2 R c , C 1 -C 6 alkylamino or di(C 1 -C 6 )alkylamino;
R 4 is selected from the group consisting of —(CR a 2 ) m aryl, —(CR a 2 ) m heteroaryl, —(CR a 2 ) m heterocyclic, —(CR a 2 ) m C 5 -C 6 cycloalkyl, —(CR a 2 ) m cyclohexenyl and —(CR a 2 ) m heterocyclenyl, wherein the aryl, heteroaryl, heterocyclic, cycloalkyl, cyclohexenyl, and heterocyclenyl is optionally substituted with NH 2 , nitro, CN, CON(R c ) 2 , COOR 10 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, haloC 2 -C 6 alkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkenoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyloxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkyl-C(═O)O—, C 1 -C 6 alkyl-C(═O)—, C 2 -C 6 alkynyl, halo group, hydroxyalkoxy, —SO 2 NR c R c , —NR c SO 2 R c , C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamino or di(C 1 -C 6 )alkylamino;
R 5 is independently selected from the group consisting of H, C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 8 cycloalkyl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-aryl, and —C 0 -C 6 alkylheterocyclic, wherein each of the alkyl, cycloalkyl, heteroaryl, aryl, and heterocyclic is optionally substituted with C 2 -C 3 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, OH, halo, NH 2 , C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino or COOR 11 ;
R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 8 cycloalkyl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-aryl, and —C 0 -C 6 alkylheterocyclic, wherein each of the alkyl, cycloalkyl, heteroaryl, aryl, and heterocyclic is optionally substituted with C 2 -C 3 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, OH, halo, NH 2 , C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino or COOR 11 ;
R 7 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclic, wherein each of the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclic is optionally substituted with halo, nitro, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyloxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 8 cycloalkyl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-aryl, —C 0 -C 6 alkylheterocyclic, —C 0 -C 6 alkylheterocyclenyl, —C 0 -C 6 alkylcyclenyl, —(CR a 2 ) z NR 5 R 6 , —(CR a 2 ) z NR 5 SO 2 R 6 , —(CR a 2 ) z SO 2 NR 5 R 6 , —(CR a 2 ) z C(O)R 5 , —(CR a 2 ) z C(O)OR 10 , —(CR a 2 ) z CONR 5 R 6 , —(CR a 2 ) z CONR 5 OR 6 , —(CR a 2 ) z NR 5 C(O)R 6 , —(CR a 2 ) z OR 5 , —(CR a 2 ),S(O)R c , and —(CR a 2 ) z S(O) 2 R c ;
R 9 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl, and heterocyclic, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic is optionally substituted with —C 0 -C 6 alkylOR c , C 0 -C 6 alkylN(R c ) 2 , COOR 10 , nitro, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyloxy, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkyl-C(═O)O—, C 1 -C 6 alkyl-C(═O)—, C 2 -C 6 alkynyl, halo group, hydroxyalkoxy, —SO 2 NR c R c , —NR c SO 2 R c , C 1 -C 6 alkylsulfonyl, heterocylic, or C(O)NHR c ;
R 10 is independently selected from the group consisting of C 1 -C 6 alkyl, —(CR c 2 ) z C 3 -C 8 cycloalkyl, —(CR c 2 ) z -heteroaryl, —(CR c 2 ) z -aryl, and —(CR c 2 ) z -heterocyclic, wherein each of the heteroaryl, aryl, heterocyclic, cycloalkyl and alkyl is optionally substituted with C 1 -C 6 alkyl, OH, halo, or haloC 1 -C 6 alkyl;
R 11 is independently selected from the group consisting of H, C 1 -C 6 alkyl, —(CR c 2 ) z C 3 -C 8 cycloalkyl, —(CR c 2 ) z heteroaryl, —(CR c 2 ) z aryl, and —(CR c 2 ) z heterocyclic wherein each of the heteroaryl, aryl, heterocyclic, cycloalkyl and alkyl is optionally substituted with C 1 -C 6 alkyl, OH, halo, or haloC 1 -C 6 alkyl;
R a is independently H, OR c , NH 2 , halo, C 1 -C 3 alkyl, or C 2 -C 3 alkenyl, said alkyl or alkenyl is optionally substituted with OH, C 1 -C 4 alkoxy, NH 2 , halo, haloC 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 4 alkenyl;
R c is independently H or C 1 -C 3 alkyl optionally substituted with C 2 -C 3 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, OH, halo, NH 2 , C 1 -C 3 alkylamino, or C 1 -C 3 dialkylamino;
n is independently 0, 1, 2 or 3;
m is independently 0, 1 or 2;
t is independently 0, 1, or 2;
z is independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein
R 1 is selected from the group consisting of COOR 11 and a nitrogen containing 5-membered heterocyclenyl ring selected from the group consisting of
oxadiazolone and dihydro-triazolone, wherein the 5-membered ring is optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyloxy, or halo group;
R 2 is selected from the group consisting of phenyl, pyridyl, or W—(CR a R 9 )R 7 , wherein W is NR c or O, wherein the phenyl and pyridyl is optionally substituted with R 12 selected from the group consisting of halo, CN, haloC 1 -C 6 alkyl, C 1 -C 6 alkyl, and —OR c , wherein the alkyl of R 12 is optionally substituted with OH, CN, halo, haloC 1 -C 6 alkyl, or CON(R c ) 2 ;
R 4 is selected from the group consisting of —(CR a 2 )aryl, —(CR a 2 )C 5 -C 6 cycloalkyl, and —(CR a 2 )cyclohexenyl, wherein each of the aryl, cycloalkyl, and cyclohexenyl is optionally substituted with CN, C 1 -C 3 alkoxy, C 1 -C 3 alkyl, haloC 2 -C 3 alkenyl, C 2 -C 3 alkenyl, C 2 -C 3 alkenoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkyloxy, C 1 -C 3 hydroxyalkyl, C 2 -C 3 alkynyl, or halo group;
R 7 is C 3 -C 5 cycloalkyl optionally substituted with halo, nitro, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyloxy, C 1 -C 6 alkyl, or —(CR a 2 ) z OR c ;
R 9 is H, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl, wherein the alkyl is optionally substituted with OR c , N(R c ) 2 , heterocyclic, C(O)NHCH 2 CH 2 OH, C(O)NH 2 , or C(O)NHC 1 -C 3 alkyl;
R 10 is C 1 -C 3 alkyl optionally substituted with OH or halo;
R 11 is independently selected from the group consisting of H and C 1 -C 3 alkyl,

Assignees

• Merck Sharp & Dohme

Inventors

• Christopher Matthew P
• Fradera Llinas Francesc Xavier
• Machacek Michelle
• Martinez Michelle
• Reutershan Michael Hale
• Shizuka Manami
• Sun Binyuan
• Thompson Christopher Francis
• Trotter B Wesley
• Voss Matthew E
• Yang Liping

Classifications

• C07D473/30

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

• C07D473/34 Primary

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

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title