Agents targeting inhibitor of apoptosis proteins

Patent metadata

Field	Value
Publication number	US-11590197-B2
Application number	US-201816760646-A
Country	US
Kind code	B2
Filing date	Nov 1, 2018
Priority date	Nov 1, 2017
Publication date	Feb 28, 2023
Grant date	Feb 28, 2023

Abstract

Disclosed herein, inter alia, are methods of use and composition of novel inhibitors that target the Smac binding site of a variety of inhibitor of apoptosis proteins that contain a Bir domain, including XIAP, cIAP1, cIAP2, or other IAP proteins.

First claim

What is claimed is:

1. A compound, or a pharmaceutical salt thereof, or a prodrug thereof, having the formula:

wherein,
R 1 is —CX 1 3 , —CFHX 1 2 , —CH 2 X 1 , substituted or unsubstituted C 1 -C 4 alkyl;
L 2 is a bond, —NH—, —O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R 2 is independently cycloalkyl, aryl, or heteroaryl, wherein any cycloalkyl, aryl, or heteroaryl of R 2 is optionally substituted with one or more R 7 groups;
L 3 is a bond, —NH—, —O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted alkylarylene, substituted or unsubstituted alkylheteroarylene;
Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 3 is independently halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —CN, —OH, —NH 2 , —COH, —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCX 3 3 , —OCX 3 2 , —OCH 2 X 3 , —SO 2 X 3 , —SO 2 C═CH 2 , —NHSO 2 CH═CH 2 , —OSO 2 X 3 , —NHSO 2 X 3 , —B(OH) 2 , —CO-oxiranyl, —CO-aziridinyl, epoxidinyl, oxaziridinyl, aziridinyl, —OCH 2 C≡CH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
wherein -(Ring A)-(R 3 ) z3 is

R 4 is independently hydrogen, halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —CN, —OH, —NH 2 , —COH, —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCX 4 3 , —OCHX 4 2 , —OCH 2 X 4 , —NHC(NH)NH 2 , —SO 2 X 4 , —SO 2 CH═CH 2 , —NHSO 2 CH═CH 2 , —OSO 2 X 4 , —NHSO 2 X 4 , —B(OH) 2 , —CO-oxiranyl, —CO-aziridinyl, epoxidinyl, oxaziridinyl, aziridinyl, —OCH 2 C≡CH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is independently hydrogen, halogen, —CX 5 3 , —CHX 5 2 , —CH 2 X 5 , —CN, —OH, —NH 2 , —COH, —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCX 5 3 , —OCHX 5 2 , —OCH 2 X 5 , —NHC(NH)NH 2 , —SO 2 X 5 , —SO 2 CH═CH 2 , —NHSO 2 CH═CH, —OSO 2 X 5 , —NHSO 2 X 5 , —B(OH) 2 , —CO-oxiranyl, —CO-aziridinyl, epoxidinyl, oxaziridinyl, aziridinyl, —OCH 2 C≡CH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L 6 is a bond or unsubstituted methylene;
R 6 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or un substituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 is independently halogen, —CX 7 3 , —CHX 7 2 , —CH 2 X 7 , —CN, —OH, —NH 2 , —COH, —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHN H 2 , —NH C(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCX 7 3 , —OCHX 7 2 , —OCH 2 X 7 , —NHC(NH)NH 2 , —N═C(NH 2 ) 2 , —CH 2 SO 3 − , —PO 3 −2 , —SO 3 − , —SO 2 NH 2 , —CH 2 PO 3 −2 , —CH 2 SO 2 NH 2 , —NHC(O)CHCH 2 , —NHC(O)CH 2 Cl, —B(OH) 2 , —SO 2 X 7 , —OSO 2 X 7 , —NHSO 2 X 7 , —SO 2 CH═CH 2 , —NHSO 2 CH═CH 2 , —CO-oxiranyl, —CO-aziridinyl, epoxidinyl, oxaziridinyl, aziridinyl, —OCH 2 C≡CH, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein any alkyl, heteroalkyl, cycloalkyl, heterocyloalkyl, aryl, or heteroaryl of R 7 is optionally substituted with one or more R 8 groups;
R 8 is independently halogen, —CX 8 3 , —CHX 8 2 , —CH 2 X 8 , —CN, —OH, —NH 2 , —COH, —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHN H 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCX 8 3 , —OCHX 8 2 , —OCH 2 X 8 , —NHC(NH)NH 2 , —N═C(NH 2 ) 2 , —CH 2 SO 3 − , —PO 3 −2 , —SO 3 − , —SO 2 NH 2 , —CH 2 PO 3 −2 , —CH 2 SO 2 NH 2 , —NHC(O)CHCH 2 , —NHC(O)CH 2 Cl, —B(OH) 2 , —SO 2 X 8 , —OSO 2 X 8 , —NHSO 2 X 8 , —SO 2 CH═CH 2 , —NHSO 2 CH═CH 2 , —CO-oxiranyl, —CO-aziridinyl, epoxidinyl, oxaziridinyl, aziridinyl, —OCH 2 C≡CH, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein any alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of R 8 is optionally substituted with one or more R 8 groups;
R 9 is independently halogen, —CX 9 3 , —CHX 9 2 , —CH 2 X 9 , —CN, —OH, —NH 2 , —COH, —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHN H 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCX 9 3 , —OCHX 9 2 , —OCH 2 X 9 , —NHC(NH)NH 2 , —N═C(NH 2 ) 2 , —CH 2 SO 3 − , —PO 3 −2 , —SO 3 − , —SO 2 NH 2 , —CH 2 PO 3 −2 , —CH 2 SO 2 NH 2 , —NHC(O)CHCH 2 , —NHC(O)CH 2 Cl, —B(OH) 2 , —SO 2 X 9 , —OSO 2 X 9 , —NHSO 2 X 9 , —SO 2 CH═CH 2 , —NHSO 2 CH═CH 2 , —CO-oxiranyl, —CO-aziridinyl, epoxidinyl, oxaziridinyl, aziridinyl, —OCH 2 C≡CH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
each X 1 , X 2 , X 3 , X 4 , X 5 , X 7 , X 8 , and X 9 is independently —F, —Cl, —Br, or —I; and
z3 is independently an integer from 0 to 3.

2. The compound, or a pharmaceutical salt thereof, or a prodrug thereof, of claim 1 , wherein R 8 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

3. The compound, or a pharmaceutical salt thereof, or a prodrug thereof, of claim 1 , wherein R is —CH 3 , —C 2 H 5 , —CF 3 , —CH 2 F, —CHF 2 , —CH 2 CF 3 , —CF 2 CH 3 , —CH 2 OH, —CF 2 OH, or —CHFOH.

4. The compound, or a pharmaceutical salt thereof, or a prodrug thereof, of claim 1 , wherein L 2 is a bond, —NH—, —O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, —(CH 2 ) 1-5 —, —(CH 2 ) 1-5 O—, —(CH 2 ) 1-5 NHC(O)—, —(CH 2 ) 1-5 S—, —(CH 2 ) 1-5 C(O)NH—, —O(CH 2 ) 1-5 —, —(CH 2 ) 1-5 NH—, —(CH 2 ) 1-5 NHCH 2 —, or —(CH 2 ) 1-5 C(O)—.

5. The compound, or a pharmaceutical salt thereof, or a prodrug thereof, of claim 1 , wherein R 2 is independently unsubstituted tetrazolyl, unsubstituted aziridinyl, unsubstituted oxiranyl, unsubstituted epoxidinyl, 4-pyridyl that is

Assignees

• Univ California

Inventors

• Pellecchia Maurizio
• Baggio Carlo
• Gambini Luca
• Udompholkul Parima

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07K5/10

  Tetrapeptides · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K38/07

  Tetrapeptides · CPC title