Inhibitors of IAP

Patent metadata

Field	Value
Publication number	US-8980837-B2
Application number	US-201213356556-A
Country	US
Kind code	B2
Filing date	Jan 23, 2012
Priority date	Jul 2, 2004
Publication date	Mar 17, 2015
Grant date	Mar 17, 2015

Abstract

The invention provides novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies where the compounds have the general formula I:

wherein X, Y, A, R 1 , R 2 , R 3 , R 4 , R 4 ′, R 5 , R 5 ′, R 6 and R 6 ′ are as described herein.

First claim

We claim:

1. A method for inhibiting the binding of an IAP protein to a caspase protein comprising contacting said IAP protein with a compound of formula I,

wherein
X 1 , X 2 and X 3 are independently O or S;
Y is (CHR 7 ) n , O or S; wherein n is 1 or 2 and R 7 is H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamino, alkoxy, aryloxy or aralkyloxy;
A is a 5-member heterocycle comprising 1 to 4 heteroatoms optionally substituted with amino, hydroxyl, mercapto, halogen, carboxyl, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, alkoxycarbonylamino, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonylamino or a heterocycle; wherein each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocycle substitution is optionally substituted with hydroxyl, halogen, mercapto, carboxyl, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, cycloalkyl, aryl or a heterocycle;
R 1 is H or R 1 and R 2 together form a 5-8 member ring;
R 2 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, a heterocycle or heterocyclylalkyl; each optionally substituted with hydroxyl, mercapto, halogen, amino, carboxyl, alkyl, haloalkyl, alkoxy or alkylthio;
R 3 is H or alkyl;
R 4 and R 4 ′ are independently H, hydroxyl, amino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or heteroarylalkyl wherein each alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl and heteroarylalkyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino and nitro;
R 5 , and R 5 ′ are each independently H or alkyl;
R 6 , and R 6 ′ are each independently H, alkyl, aryl or aralkyl;
and salts and solvates thereof.

2. A method for treating a disease or condition associated with the overexpression of an IAP in a mammal, comprising administering to said mammal an effective amount of a compound of formula I

wherein
X 1 , X 2 and X 3 are independently O or S;
Y is (CHR 7 ) n , O or S; wherein n is 1 or 2 and R 7 is H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamino, alkoxy, aryloxy or aralkyloxy;
A is a 5-member heterocycle comprising 1 to 4 heteroatoms optionally substituted with amino, hydroxyl, mercapto, halogen, carboxyl, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, alkoxycarbonylamino, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonylamino or a heterocycle; wherein each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocycle substitution is optionally substituted with hydroxyl, halogen, mercapto, carboxyl, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, cycloalkyl, aryl or a heterocycle;
R 1 is H or R 1 and R 2 together form a 5-8 member ring;
R 2 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, a heterocycle or heterocyclylalkyl; each optionally substituted with hydroxyl, mercapto, halogen, amino, carboxyl, alkyl, haloalkyl, alkoxy or alkylthio;
R 3 is H or alkyl;
R 4 and R 4 ′ are independently H, hydroxyl, amino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or heteroarylalkyl wherein each alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl and heteroarylalkyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino and nitro;
R 5 , and R 5 ′ are each independently H or alkyl;
R 6 , and R 6 ′ are each independently H, alkyl, aryl or aralkyl;
and salts and solvates thereof.

3. A method for treating cancer, comprising administering to said mammal an effective amount of a compound of formula I

wherein
X 1 , X 2 and X 3 are independently O or S;
Y is (CHR 7 ) n , O or S; wherein n is 1 or 2 and R 7 is H, halogen, alkyl, aryl, aralkyl, amino, arylamino, alkylamino, aralkylamino, alkoxy, aryloxy or aralkyloxy;
A is a 5-member heterocycle comprising 1 to 4 heteroatoms optionally substituted with amino, hydroxyl, mercapto, halogen, carboxyl, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, alkoxycarbonylamino, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylsulfonylamino or a heterocycle; wherein each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocycle substitution is optionally substituted with hydroxyl, halogen, mercapto, carboxyl, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, cycloalkyl, aryl or a heterocycle;
R 1 is H or R 1 and R 2 together form a 5-8 member ring;
R 2 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, a heterocycle or heterocyclylalkyl; each optionally substituted with hydroxyl, mercapto, halogen, amino, carboxyl, alkyl, haloalkyl, alkoxy or alkylthio;
R 3 is H or alkyl;
R 4 and R 4 ′ are independently H, hydroxyl, amino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or heteroarylalkyl wherein each alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl and heteroarylalkyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino and nitro;
R 5 , and R 5 ′ are each independently H or alkyl;
R 6 , and R 6 ′ are each independently H, alkyl, aryl or aralkyl;
and salts and solvates thereof.

4. The method of claim 1 , wherein ring A has the formula IIa or IIb:

wherein Q 1 is NR 8 , O or S; Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 , and Q 8 , are independently CR 9 or N; wherein R 9 is H, amino, hydroxyl, mercapto, halogen, carboxyl, amidino, guanidino, alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl or a heterocycle; wherein each alkyl, alkoxy, aryl, aryloxy, acyl, acyloxy, acylamino, cycloalkyl and heterocycle substitution is optionally substituted with hydroxyl, halogen, mercapto, carboxyl, alkyl, haloalkyl, amino, nitro, cycloalkyl, aryl or a heterocycle; R 8 is H, alkyl, acyl, aryl, cycloalkyl or a heterocycle; wherein each alkyl, aryl, cycloalkyl and heterocycle is optionally substituted with hydroxyl, halogen, mercapto, carboxyl, alkyl, haloalkyl, amino, nitro, cycloalkyl, aryl or a heterocycle; and Q 9 is CH or N.

5. The method of claim 1 , wherein ring A is selected from the group consisting of:

wherein R 8 is H, alkyl or acyl.

6. The method of claim 5 , wherein R 8 is H.

7. The method of claim 1 , wherein R 1 and R 2 together form a 5-8 member ring.

8. The method of claim 1 , wherein R 1 is H.

9. The method of claim 1 , wherein R 2 is alkyl or cycloalkyl.

10. The method of claim 1 , wherein R 2 is isopropyl, t-butyl, or cyclohexyl.

11. The method of claim 1 , wherein R 3 is methyl.

12. The method of claim 1 , wherein R 4 is H or methyl, and

Assignees

• Cohen Frederick
• Deshayes Kurt
• Fairbrother Wayne J
• Feng Bainian
• Flygare John A
• Gazzard Lewis J
• Tsui Vickie Hsiao-Wei
• Genentech Inc

Inventors

• Cohen Frederick
• Deshayes Kurt
• Fairbrother Wayne J
• Feng Bainian
• Flygare John A
• Gazzard Lewis J
• Tsui Vickie Hsiao-Wei

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title