# US 9,040,706 B2 · Pyrrolidine inhibitors of IAP

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- Number: US 9,040,706 B2
- Document ID: US9040706B2
- Status: Granted
- Kind: B2
- Application number: 14/088,110
- Filed: 2013-11-22
- Published: 2014-03-20
- Granted: 2015-05-26
- Earliest claimed: 2004-12-20
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Frederick Cohen; Vickie Hsiao-Wei Tsui; Cuong Ly; John A. Flygare
- Web page: https://patentgrep.com/patent/US9040706B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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 A, Q, X1, X2, Y, R1, R2, R3, R4, R4′, R5, R6 and R6′ are as described herein.

## Claims

### Claim 1

A method of inducing apoptosis in a cell comprising introducing into said cell a compound of Formula I:
wherein
A is thiazole;
ring A and Q together are selected from the group consisting of:
Q is (a) alkyl, wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, or —NR8—C(NH)—; and the alkyl is optionally substituted with one or more halogen, cyano, nitro, optionally substituted carbocycle, or optionally substituted heterocycle; or
(b) a carbocycle or heterocycle optionally substituted with one or more halogen, nitro, cyano, oxo, alkyl, carbocycle, or heterocycle;
wherein one or more CH2 groups of the alkyl substituent on Q is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O— or —O—C(O)—, and the alkyl is optionally substituted with one or more halogen, cyano, nitro, an optionally substituted carbocycle, or an optionally substituted heterocycle; and
wherein the carbocycle or heterocycle substituents on Q are optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, carbocycle, or heterocycle;
X1 and X2 are each independently O or S;
Y is CH2;
R1 is H, or R1 and R2 together form a 5-8 member ring;
R2 is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle, or heterocyclylalkyl, each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, sulfonyl, amino, or nitro;
R3 is H or alkyl optionally substituted with halogen or hydroxyl; or R3 and R4 together form a 3-6 member heterocycle;
R3′ is H, or R3 and R3′ together form a 3-6 member carbocycle;
R4 is H, hydroxyl, amino, alkyl, carbocycle, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy or heterocycloalkyloxycarbonyl; wherein each alkyl, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy and heterocycloalkyloxycarbonyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino, or nitro; or R4 and R4′ together form a heterocycle;
R4′ is H;
R5 is H or alkyl;
R6 and R6′ are each independently H, alkyl, aryl or aralkyl;
R7 in each instance is independently H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, a heterocycle, or —U—V;
wherein U is —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—; and
V is alkyl, a carbocycle, or a heterocycle;
and wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—; and an alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
R8 is H, alkyl, a carbocycle, or a heterocycle; wherein one or more CH2 groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, or —C(O)—; and said alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
wherein each alkyl is independently a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon group, having up to 12 carbon atoms;
or a salt thereof.

### Claim 2

A method of sensitizing a cell to an apoptotic signal comprising introducing into said cell a compound of Formula I:
wherein
A is thiazole;
ring A and Q together are selected from the group consisting of:
Q is (a) alkyl, wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, or —NR8—C(NH)—; and the alkyl is optionally substituted with one or more halogen, cyano, nitro, optionally substituted carbocycle, or optionally substituted heterocycle; or
(b) a carbocycle or heterocycle optionally substituted with one or more halogen, nitro, cyano, oxo, alkyl, carbocycle, or heterocycle;
wherein one or more CH2 groups of the alkyl substituent on Q is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—, and the alkyl is optionally substituted with one or more halogen, cyano, nitro, an optionally substituted carbocycle, or an optionally substituted heterocycle; and
wherein the carbocycle or heterocycle substituents on Q are optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, carbocycle, or heterocycle;
X1 and X2 are each independently O or S;
Y is CH2;
R1 is H, or R1 and R2 together form a 5-8 member ring;
R2 is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle, or heterocyclylalkyl, each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, sulfonyl, amino, or nitro;
R3 is H or alkyl optionally substituted with halogen or hydroxyl; or R3 and R4 together form a 3-6 member heterocycle;
R3′ is H, or R3 and R3′ together form a 3-6 member carbocycle;
R4 is H, hydroxyl, amino, alkyl, carbocycle, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy or heterocycloalkyloxycarbonyl; wherein each alkyl, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy, and heterocycloalkyloxycarbonyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino, or nitro; or R4 and R4′ together form a heterocycle;
R4′ is H;
R5 is H or alkyl;
R6 and R6′ are each independently H, alkyl, aryl or aralkyl;
R7 in each instance is independently H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, a heterocycle, or —U—V;
wherein U is —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—; and
V is alkyl, a carbocycle, or a heterocycle;
and wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—; and an alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
R8 is H, alkyl, a carbocycle, or a heterocycle; wherein one or more CH2 groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, or —C(O)—; and said alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
wherein each alkyl is independently a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon group, having up to 12 carbon atoms;
or a salt thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein said apoptotic signal is induced by contacting said cell with cytarabine, fludarabine, 5-fluoro-2′-deoxyuridine, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, colcemid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasterid, taxotere, mitomycin C, or Apo2L/TRAIL, or with radiation.

### Claim 4

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
A is thiazole;
ring A and Q together are selected from the group consisting of:
Q is (a) alkyl, wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, or —NR8—C(NH)—; and the alkyl is optionally substituted with one or more halogen, cyano, nitro, optionally substituted carbocycle, or optionally substituted heterocycle; or
(b) a carbocycle or heterocycle optionally substituted with one or more halogen, nitro, cyano, oxo, alkyl, carbocycle, or heterocycle;
wherein one or more CH2 groups of the alkyl substituent on Q is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—, and the alkyl is optionally substituted with one or more halogen, cyano, nitro, an optionally substituted carbocycle, or an optionally substituted heterocycle; and
wherein the carbocycle or heterocycle substituents on Q are optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, carbocycle, or heterocycle;
X1 and X2 are each independently O or S;
Y is CH2;
R1 is H, or R1 and R2 together form a 5-8 member ring;
R2 is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle, or heterocyclylalkyl, each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, sulfonyl, amino, or nitro;
R3 is H or alkyl optionally substituted with halogen or hydroxyl; or R3 and R4 together form a 3-6 member heterocycle;
R3′ is H, or R3 and R3′ together form a 3-6 member carbocycle;
R4 is H, hydroxyl, amino, alkyl, carbocycle, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy or heterocycloalkyloxycarbonyl; wherein each alkyl, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy, and heterocycloalkyloxycarbonyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino, or nitro; or R4 and R4′ together form a heterocycle;
R4′ is H;
R5 is H or alkyl;
R6 and R6′ are each independently H, alkyl, aryl, or aralkyl;
R7 in each instance is independently H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, a heterocycle, or —U—V;
wherein U is —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—; and
V is alkyl, a carbocycle, or a heterocycle;
and wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—; and an alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
R8 is H, alkyl, a carbocycle, or a heterocycle; wherein one or more CH2 groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, or —C(O)—; and said alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
wherein each alkyl is independently a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon group, having up to 12 carbon atoms;
or a salt thereof.