# US 11,897,864 B2 · Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases

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- Number: US 11,897,864 B2
- Document ID: US11897864B2
- Status: Granted
- Kind: B2
- Application number: 17/938,835
- Filed: 2022-10-07
- Published: 2023-05-11
- Granted: 2024-02-13
- Earliest claimed: 2009-05-26
- Assignees: AbbVie Inc.; Genentech, Inc.; The Walter and Eliza Hall Institute of Medical Research
- Applicants: AbbVie Inc.; Genentech, Inc.; The Walter and Eliza Hall Institute of Medical Research
- Inventors: Milan Bruncko; Hong Ding; George A. Doherty; Steven W. Elmore; Lisa A. Hasvold; Laura Hexamer; Aaron R. Kunzer; Xiaohong Song; Andrew J. Souers; Gerard M. Sullivan; Zhi-Fu Tao; Gary T. Wang; Le Wang; Xilu Wang; Michael D. Wendt; Robert Mantei; Todd M. Hansen
- Web page: https://patentgrep.com/patent/US11897864B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- C07D 209/82: Carbazoles; Hydrogenated carbazoles
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 1

A compound having Formula (II)
or a therapeutically acceptable salt thereof, wherein:
n is 0;
A1 is C(A2);
A2, D1, and E1 are H;
B1 is NHR1;
Y1 is NO2;
R1 is methyl, which is substituted with one heterocycloalkyl;
Z2 is piperazinyl;
L1 is methylene;
Z3 is cycloalkenyl substituted with R57A and R57;
R57A is spiroalkyl; and
R57 is phenyl substituted with one Cl.

### Claim 2 (depends on 1)

The compound of claim 1, or the therapeutically acceptable salt thereof, wherein the one heterocycloalkyl is tetrahydropyranyl.

### Claim 3 (depends on 1)

The compound of claim 1, or the therapeutically acceptable salt thereof, wherein the one heterocycloalkyl is 1,4-dioxanyl.

### Claim 4 (depends on 1)

The compound of claim 1, or the therapeutically acceptable salt thereof, wherein R57A is C2-C5-spiroalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or the therapeutically acceptable salt thereof, wherein Z3 is cyclohexenyl.

### Claim 6 (depends on 5)

The compound of claim 5, or the therapeutically acceptable salt thereof, wherein R57A is C2-C5-spiroalkyl.

### Claim 7 (depends on 6)

The compound of claim 6, or the therapeutically acceptable salt thereof, wherein the one heterocycloalkyl is 1,4-dioxanyl.

### Claim 8 (depends on 1)

The compound of claim 1, or the therapeutically acceptable salt thereof, wherein the compound is:
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.

### Claim 9

A compound having Formula (II)
or a therapeutically acceptable salt thereof, wherein:
n is 0;
A1 is C(A2);
A2, D1, and E1 are H;
B1 is OR1 or NHR1;
Y1 is NO2;
R1 is methyl, which is substituted with one R10;
R10 is cycloalkyl or heterocycloalkyl;
wherein R10 is unsubstituted or substituted with one or two of independently selected from cycloalkyl, heterocycloalkyl, alkyl, alkoxy, OH, or F;
Z2 is piperazinyl;
L1 is methylene;
Z3 is cycloalkenyl substituted with R57A and R57;
R57A is spiroalkyl; and
R57 is phenyl substituted with one Cl.

### Claim 10 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein B1 is OR1.

### Claim 11 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein B1 is NHR1.

### Claim 12 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein R10 is cycloalkyl.

### Claim 13 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein R10 is cyclohexyl.

### Claim 14 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein R10 is heterocycloalkyl.

### Claim 15 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein R10 is tetrahydropyranyl.

### Claim 16 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein R10 is 1,4-dioxanyl.

### Claim 17 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein R57A is C2-C5-spiroalkyl.

### Claim 18 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein Z3 is cyclohexenyl.

### Claim 19 (depends on 18)

The compound of claim 18, or the therapeutically acceptable salt thereof, wherein R57A is C2-C5-spiroalkyl.

### Claim 20 (depends on 19)

The compound of claim 19, or the therapeutically acceptable salt thereof, wherein B1 is OR1.

### Claim 21 (depends on 19)

The compound of claim 19, or the therapeutically acceptable salt thereof, wherein B1 is NHR1.

### Claim 22 (depends on 21)

The compound of claim 21, or the therapeutically acceptable salt thereof, wherein R10 is cycloalkyl.

### Claim 23 (depends on 22)

The compound of claim 22, or the therapeutically acceptable salt thereof, wherein R10 is cyclohexyl.

### Claim 24 (depends on 21)

The compound of claim 21, or the therapeutically acceptable salt thereof, wherein R10 is heterocycloalkyl.

### Claim 25 (depends on 24)

The compound of claim 24, or the therapeutically acceptable salt thereof, wherein R10 is tetrahydropyranyl.

### Claim 26 (depends on 24)

The compound of claim 24, or the therapeutically acceptable salt thereof, wherein R10 is 1,4-dioxanyl.

### Claim 27 (depends on 9)

The compound of claim 9, or the therapeutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide;
trans-4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; and
4-(4-{[8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide.