# US 10,308,617 B2 · Triazole benzamide derivatives and the compositions and methods of treatment regarding the same

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- Number: US 10,308,617 B2
- Document ID: US10308617B2
- Status: Granted
- Kind: B2
- Application number: 15/614,371
- Filed: 2017-06-05
- Published: 2018-05-03
- Granted: 2019-06-04
- Earliest claimed: 2016-06-03
- Assignees: An2H Discovery Limited
- Applicants: An2H Discovery Limited
- Inventors: Jennifer Johnston; Albert W. Garofalo; Paul Ross Fatheree
- Web page: https://patentgrep.com/patent/US10308617B2

## CPC

- C07D 249/14: Nitrogen atoms
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure is directed to triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

## Claims

### Claim 1

A compound of formula (IA):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4 —;
R1 and R2 are each phenyl, substituted with one or more R5a;
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5a is each independently I, Br, Cl, F, C1-C6 alkyl, C1-C3 haloalkyl, —(C1-C6)-O—(C1-C6), C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH;
R5b is each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OH, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1 wherein the compound has the structure of formula (IB):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4—;
R1 and R2 are each phenyl, substituted with one or more R5a;
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5a is each independently C1-C6 alkyl;
R5b is each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OH, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound has the structure of formula (IC):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4—;
R1 and R2 are each phenyl, substituted with one or more R5a, wherein at least one of R1 and R2is
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5a is each independently I, Br, Cl, F, C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH;
R5b is each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OH, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound has the structure of formula (ID):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4—;
R1 and R2 are each
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5b is each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OH, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound has the structure of formula (IE):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L 3 is a bond;
M1 and M2 are each —NHC(O)—;
R1 and R2 are each
R3 is phenyl, optionally substituted with one or more R5b; and
R5b is each independently I, Br, Cl, F, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound has the structure of formula (IG):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each —NHC(O)—;
R1 and R2 are each
R3 is phenyl; and
R5a a is each independently C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH.

### Claim 7 (depends on 5)

The compound of claim 5, wherein the compound has the structure of formula (IF):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each —NHC(O)—;
R1 and R2 are each
R3 is phenyl, optionally substituted with one or more R5b; and
R5b is each independently C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH.

### Claim 8

A compound having one of the following structures:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 9 (depends on 8)

The compound of claim 8 having the following structure:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of claim 1, wherein the compound has the structure of formula (IA):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4—;
R1 and R2 are each phenyl, substituted with one or more R5a;
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5a is each independently I, Br, Cl, F, C1-C6 alkyl, C1-C3 haloalkyl, —(C1-C6)-O—(C1-C6), C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH;
R5b is each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OH, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10, wherein the compound has the structure of formula (IB):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4—;
R1 and R2 are each phenyl, substituted with one or more R5a;
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5a is each independently C1-C6 alkyl;
R5b is each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OH, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 12 (depends on 10)

The pharmaceutical composition of claim 10, wherein the compound has the structure of formula (IC):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4—;
R1 and R2 are each phenyl, substituted with one or more R5a, wherein at least one of R1 and R2 is
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5a is each independently I, Br, Cl, F, C1-C6 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH;
R5bis each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OH, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 13 (depends on 10)

The pharmaceutical composition of claim 10, wherein the compound has the structure of formula (ID):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3 is a bond;
M1 and M2 are each independently selected from —NR4C(O)— or —C(O)NR4—;
R1 and R2 are each
R3 is phenyl, optionally substituted with one or more R5b;
R4 is each independently H or C1-C3 alkyl;
R5b is each independently I, Br, Cl, F, CN, CONH2, CONHR6, CONR6R6, COOH, NH2, NHR6, NO2, NR6R6, OR6, —COOR6, OSO3R6, oxo, R6, SH, SO2R6, SO3H, SO3R6, or SR6; and
R6 is each independently alkyl or haloalkyl.

### Claim 14 (depends on 10)

The pharmaceutical composition of claim 10, wherein the compound has the structure of formula (IE):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L3is a bond;
M1 and M2 are each —NHC(O)—;
R1 and R2 are each
R3 is phenyl, optionally substituted with one or more R5b; and
R5b is each independently I, Br, Cl, F, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, OH, or COOH.

### Claim 15 (depends on 8)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any compound claim 8.

### Claim 16 (depends on 10)

The pharmaceutical composition of claim 10, wherein the compound has the following structure:
or a pharmaceutically acceptable salt or solvate thereof.