Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

Patent metadata

Field	Value
Publication number	US-9303025-B2
Application number	US-201414582144-A
Country	US
Kind code	B2
Filing date	Dec 23, 2014
Priority date	Dec 4, 2008
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-2 protein.

First claim

What is claimed is:

1. A compound having Formula (III)

or a therapeutically acceptable salt thereof,
wherein
n is 0, whereby R 100 is absent;
A 1 is C(A 2 );
A 2 is H;
B 1 is NHR 1 ;
D 1 and E 1 are each H;
R 1 is R 5 , wherein R 5 is alkyl which is unsubstituted or substituted with one or two or three substituents independently selected from R 6 , R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , NHR 7 , N(R 7 ) 2 , C(O)R 7 , C(O)NH 2 , C(O)NHR 7 , C(O)N(R 7 ) 2 , NHC(O)R 7 , NR 7 C(O)R 7 , NHSO 2 R 7 , NHC(O)OR 7 , SO 2 NH 2 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , NHC(O)NH 2 , NHC(O)NHR 7 , NHC(O)CH(CH 3 )NHC(O)CH(CH 3 )NH 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br and I;
Y 1 is NO 2 ;
Z 2 is R 30 , wherein R 30 is unfused piperazinyl;
L 1 is R 37 , wherein R 37 is methylene;
Z 3 is R 40 , wherein R 40 is unfused cyclohexenyl;
R 6 is C 2 -C 5 -spiroalkyl, which is unsubstituted or substituted with OH, (O), N 3 , CN, CF 3 , CF 2 CF 3 , F, Cl, Br, I, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ;
R 7 is R 8 , R 9 , R 10 or R 11 ;
R 8 is phenyl, which is unfused or fused with benzene, heteroarene or R 8A ; R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 9 is heteroaryl, which is unfused or fused with benzene, heteroarene or R 9A ; R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl each of which is unfused or fused with benzene, heteroarene or R 10A ; R 10A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 11 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from R 12 , OR 12 , SR 12 , S(O)R 12 , SO 2 R 12 , C(O)R 12 , CO(O)R 12 , OC(O)R 12 , OC(O)OR 12 , NH 2 , NHR 12 , N(R 12 ) 2 , NHC(O)R 12 , NR 12 C(O)R 12 , NHS(O) 2 R 12 , NR 12 S(O) 2 R 12 , NHC(O)OR 12 , NR 12 C(O)OR 12 , NHC(O)NH 2 , NHC(O)NHR 12 , NHC(O)N(R 12 ) 2 , NR 12 C(O)NHR 12 , NR 12 C(O)N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , C(O)NHOH, C(O)NHOR 12 , C(O)NHSO 2 R 12 , C(O)NR 12 SO 2 R 12 , SO 2 NH 2 , SO 2 NHR 12 , SO 2 N(R 12 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 12 , C(N)N(R 12 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I;
R 12 is R 13 , R 14 , R 15 or R 16 ;
R 13 is phenyl, which is unfused or fused with benzene, heteroarene or R 13A ; R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 14 is heteroaryl, which is unfused or fused with benzene, heteroarene or R 14A ; R 14A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 15 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R 15A ; R 15A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 16 is alkyl, alkenyl or alkynyl;
at least one of R 102 is selected from the group consisting of R 50 , OR 50 , SR 50 , S(O)R 50 , SO 2 R 50 , C(O)R 50 , CO(O)R 50 , OC(O)R 50 , OC(O)OR 50 , NH 2 , NHR 50 , N(R 50 ) 2 , NHC(O)R 50 , NR 50 C(O)R 50 , NHS(O) 2 R 50 , NR 50 S(O) 2 R 50 , NHC(O)OR 50 , NR 50 C(O)OR 50 , NHC(O)NH 2 , NHC(O)NHR 50 , NHC(O)N(R 50 ) 2 , NR 50 C(O)NHR 50 , NR 50 C(O)N(R 50 ) 2 , C(O)NH 2 , C(O)NHR 50 , C(O)N(R 50 ) 2 , C(O)NHOH, C(O)NHOR 50 , C(O)NHSO 2 R 50 , C(O)NR 50 SO 2 R 50 , SO 2 NH 2 , SO 2 NHR 50 , SO 2 N(R 50 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 50 , C(N)N(R 50 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I, and the remainder of R 102 are H;
R 50 is R 51 , R 52 , R 53 or R 54 ;
R 51 is phenyl, which is unfused or fused with benzene, heteroarene or R 51A ; R 51A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 52 is heteroaryl, which is unfused or fused with benzene, heteroarene or R 52A ; R 52A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 53 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 53A ; R 53A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 54 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from R 55 , OR 55 , SR 55 , S(O)R 55 , SO 2 R 55 , C(O)R 55 , CO(O)R 55 , OC(O)R 55 , OC(O)OR 55 , NH 2 , NHR 55 , N(R 55 ) 2 , NHC(O)R 55 , NR 55 C(O)R 55 , NHS(O) 2 R 55 , NR 55 S(O) 2 R 55 , NHC(O)OR 55 , NR 55 C(O)OR 55 , NHC(O)NH 2 , NHC(O)NHR 55 , NHC(O)N(R 55 ) 2 , NR 55 C(O)NHR 55 , NR 55 C(O)N(R 55 ) 2 , C(O)NH 2 , C(O)NHR 55 , C(O)N(R 55 ) 2 , C(O)NHOH, C(O)NHOR 55 , C(O)NHSO 2 R 55 , C(O)NR 55 SO 2 R 55 , SO 2 NH 2 , SO 2 NHR 55 , SO 2 N(R 55 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 55 , C(N)N(R 55 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I;
R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
wherein each cyclic moiety represented by R 8 , R 9 , R 10 , R 13 , R 14 , R 15 , R 40 , R 51 , R 52 , R 53 and R 55 is independently unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R 57A , R 57 , OR 57 , SR 57 , S(O)R 57 , SO 2 R 57 , C(O)R 57 , CO(O)R 57 , OC(O)R 57 , OC(O)OR 57 , NH 2 , NHR 57 , N(R 57 ) 2 , NHC(O)R 57 , NR 57 C(O)R 57 , NHS(O) 2 R 57 , NR 57 S(O) 2 R 57 , NHC(O)OR 57 , NR 57 C(O)OR 57 , NHC(O)NH 2 , NHC(O)NHR 57 , NHC(O)N(R 57 ) 2 , NR 57 C(O)NHR 57 , NR 57 C(O)N(R 57 ) 2 , C(O)NH 2 , C(O)NHR 57 , C(O)N(R 57 ) 2 , C(O)NHOH, C(O)NHOR 57 , C(O)NHSO 2 R 57 , C(O)NR 57 SO 2 R 57 , SO 2 NH 2 , SO 2 NHR 57 , SO 2 N(R 57 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 57 , C(N)N(R 57 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;
R 57A is spirocyclyl;
R 57 is R 58 , R 59 , R 60 or R 61 ;
R 58 is phenyl, which is unfused or fused with benzene, heteroarene or R 58A ; R 58A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 59 is heteroaryl, which is unfused or fused with benzene, heteroarene or R 59A ; R 59A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 60 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 60A ; R 60A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 61 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three substituents independently selected from R 62 , OR 62 , SR 62 , S(O)R 62 , SO 2 R 62 , C(O)R 62 , CO(O)R 62 , OC(O)R 62 , OC(O)OR 62 , NH 2 , NHR 62 , N(R 62 ) 2 , NHC(O)R 62 , NR 62 C(O)R 62 , NHS(O) 2 R 62 , NR 62 S(O) 2 R 62 , NHC(O)OR 62 , NR 62 C(O)OR 62 , NHC(O)NH 2 , NHC(O)NHR 62 , NHC(O)N(R 62 ) 2 , NR 62 C(O)NHR 62 , NR 62 C(O)N(R 62 ) 2 , C(O)NH 2 , C(O)NHR 62 , C(O)N(R 62 ) 2 , C(O)NHOH, C(O)NHOR 62 , C(O)NHSO 2 R 62 , C(O)NR 62 SO 2 R 62 , SO 2 NH 2 , SO 2 NHR 62 , SO 2 N(R 62 ) 2 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 62 , C(N)N(R 62 ) 2 , CNOH, CNOCH 3 , OH, (O), CN, N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br and I;
R 62 is R 63 , R 64 , R 65 or R 66 ;
R 63 is phenyl, which is unfused or fused with benzene, heteroarene or R 63A ; R 63A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 64 is heteroaryl, which is unfused or fused with benzene, heteroarene or R 64A ; R 64A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 65 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloa

Assignees

• Abbvie Inc

Inventors

• Bruncko Milan
• Ding Hong
• Doherty George A
• Elmore Steven W
• Hasvold Lisa
• Hexamer Laura
• Kunzer Aaron R
• Mantei Robert A
• Park Cheol-Min
• Song Xiaohong
• Souers Andrew J
• Sullivan Gerard M
• Tao Zhi-Fu
• Wang Gary T
• Wang Le
• Wang Xilu
• Wendt Michael D

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title