2,6,7,8 substituted purines as HDM2 inhibitors

Patent metadata

Field	Value
Publication number	US-9540377-B2
Application number	US-201414762827-A
Country	US
Kind code	B2
Filing date	Jan 29, 2014
Priority date	Jan 30, 2013
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

The present invention provides 2,6,7,8 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 C 1 -C 6 alkyl, —(CR a 2 ) n COOR 11 , —(CR a 2 ) n NR 5 SO 2 R 6 , —(CR a 2 ) n SO 2 NR 5 R 6 , —(CR a 2 ) n C(O)NR c SO 2 N(R c ) 2 , —(CR a 2 ) n C(O)R 5 , —(CR a 2 ) n CONR 5 R 6 , —(CR a 2 ) n CONR 5 SO 2 R 6 , —(CR a 2 ) n CONR 5 OR 6 , —(CR a 2 ) n OR 5 , —(CR a 2 ) n S(O)R c , —(CR a 2 ) n S(O) 2 R c , and nitrogen containing 5 or 6-membered heteroaryl, heterocyclic and heterocyclenyl ring, wherein the alkyl and 5 or 6-membered ring can be 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 aryl, heteroaryl, C 3 -C 8 cycloalkyl, —W—(CR a R 9 ) t R 7 , and heterocyclic, wherein W is NR c or O, wherein the aryl, heteroaryl, cycloalkyl or heterocyclic is optionally substituted with R 12 selected from the group consisting of halo, CN, haloC 1 -C 6 alkyl, C 1 -C 6 alkyl, —(CR a 2 ) z OR 8 , —(CR a 2 ) z NHR 8 , —(CR a 2 ) z C(O)NR c R c , —(CR a 2 ) z COOR 10 , —(CR a 2 ) z S(O) 2 R c , —(CR a 2 ) z aryl, —(CR a 2 ) z heteroaryl, —(CR a 2 ) z heterocyclic, —(CR a 2 ) z C 3 -C 8 cycloalkyl, —(CR a 2 ) z cyclenyl, and —(CR a 2 ) z heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl and heterocyclenyl of R 12 can be 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 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 3 is selected from the group consisting of —(CR a 2 ) q NR c R 8 , —(CR a 2 ) q OR 8 , —(CR a 2 ) q SR 8 , —(CR a 2 ) q C(O)R 8 , —(CR a 2 ) q S(O)R 8 , —(CR a 2 ) q S(O) 2 R 8 , —(CR a 2 ) q CONR c R 8 , —(CR a 2 ) q NR c C(O)R 8 , -T-C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -T-aryl, -T-heteroaryl, -T-heterocyclic, -T-C 3 -C 8 cycloalkyl, -T-cyclenyl, and -T-heterocyclenyl,
wherein the alkyl, alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl and heterocyclenyl can be optionally substituted with halo, SR c , OR c , haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, —(CR a 2 ) z CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(CR a 2 ) z C(O)OR 10 , —(CR a 2 ) z C(O)R 8 , —(CR a 2 ) z OR 8 , —(CR a 2 ) z NR c R 8 , —(CR a 2 ) z S(O) 2 R 8 , —(CR a 2 ) z C(O)NR c R 8 , —(CR a 2 ) z aryl, —(CR a 2 ) z heteroaryl, —(CR a 2 ) z C 3 -C 8 cycloalkyl, —(CR a 2 ) z heterocyclic,
—(CR a 2 ) z heterocyclenyl, —(CR a 2 ) z cyclenyl, —(CR a 2 ) z SO 2 NR c R 8 , or —(CR a 2 ) z O(CR a 2 ) z D(CR a 2 ) v Q, said alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic, heterocyclenyl and cyclenyl can further be optionally substituted with SH, OH, NH 2 , nitro, CN, CON(R) 2 , COOR 10 C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, 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 4 is selected from the group consisting of C 1 -C 6 alkyl, —(CR a 2 ) m aryl, —(CR a 2 ) m heteroaryl, —(CR a 2 ) m heterocyclic, —(CR a 2 ) m C 3 -C 8 cycloalkyl, —(CR a 2 ) m cyclenyl, and —(CR a 2 ) m heterocyclenyl, wherein the alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, cyclenyl, and heterocyclenyl can be optionally substituted with OH, SH, 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 the alkyl, cycloalkyl, heteroaryl, aryl, and heterocyclic can be 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 the alkyl, cycloalkyl, heteroaryl, aryl, and heterocyclic can be 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 the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclic can be 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)OR 6 , —(CR a 2 ) z NR 5 C(O)R 6 , —(CR a 2 ) z OR 5 , —(CR a 2 ) z S(O)R c , and —(CR a 2 ) z S(O) 2 R c ;
R 8 is independently selected from the group consisting of H, —(CR a 2 ) s -heteroaryl, —(CR a 2 ) s -aryl, —(CR a 2 ) s -heterocyclic, —(CR a 2 ) s -heterocyclenyl, —(CR a 2 ) s -cyclenyl, —(CR a 2 ) s C 3 -C 8 cycloalkyl, and C 1 -C 6 alkyl, wherein the heteroaryl, aryl, heterocyclic, heterocyclenyl, cyclenyl, cycloalkyl, and alkyl can be optionally substituted with OH, —N(R c ) 2 , NH 2 , nitro, CN, CON(R c ) 2 , COOR 10 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, 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 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, heteroaryl, aryl, heterocyclic, heterocyclenyl, or cyclenyl;
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 the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic can be optionally substituted with —C 0 -C 6 alkylOR c , C 0 -C 6 alkylN(R) 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 -he

Assignees

• Merck Sharp & Dohme

Inventors

• Cammarano Carolyn Michele
• Christopher Matthew P
• Dinsmore Christopher
• Doll Ronald J
• Fradera Llinas Francesc Xavier
• Li Chaomin
• Machacek Michelle
• Martinez Michelle
• Nair Latha G
• Pan Weidong
• Reutershan Michael Hale
• Shizuka Manami
• Steinhuebel Dietrich P
• Sun Binyuan
• Thompson Christopher Francis
• Trotter B Wesley
• Wang Yaolin
• Yang Liping
• Bogen Stephane L
• Voss Matthew E
• Panda Jagannath
• Kurissery Anthappan Tony

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D473/34

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

• C07D473/30

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

• C07D473/16

  two nitrogen atoms · CPC title

• C07D473/00 Primary

  Heterocyclic compounds containing purine ring systems · CPC title