# US 7,612,065 B2 · Inhibitors of c-JUN N-terminal kinases (JNK)

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,612,065 B2
- Document ID: US7612065B2
- Status: Granted
- Kind: B2
- Application number: 11/729,420
- Filed: 2007-03-28
- Published: 2008-02-07
- Granted: 2009-11-03
- Earliest claimed: 2007-03-28
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: Jeremy Green; Susanne Wilke; Francesco Salituro; Edmund Harrington; Jingrong Cao; Guy Bemis; Huai Gao
- Web page: https://patentgrep.com/patent/US7612065B2

## CPC

- C07D 209/40: Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
- A61P 25/16: Anti-Parkinson drugs
- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- 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 present invention relates to inhibitors of JNK, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.

## Claims

### Claim 1

A compound of the formula:
or a pharmaceutically acceptable salt thereof; wherein
Y is selected from —(CH2)-Q1; —(CO)-Q1; —(CO)NH-Q1; —(CO)—O-Q1; —(SO2)-Q1 or —(SO2)NH-Q1;
Q1 is a C1-C6 straight chain or branched alkyl or alkenyl group; a 5-7 membered aromatic or non-aromatic heterocyclic ring; or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring system, wherein said alkyl, alkenyl, ring or ring system is optionally substituted with one to four substituents, each of which is independently selected from NH2, NH—R, N(R)2, NO2, OH, OR, CF3, halo, CN, CO2H, C(O)—NH2, C(O)—NH—R, C(O)—N(R)2, C(O)—R, SR, S(O)—R, S(O)2—R, S(O)2—NH—R or —R;
W is N;
R8 is a lone pair of electrons;
A1 is CR1;
A2 is CR2;
A3 is CR3;
A4 is CR4;
R1 is —NHR5, —OR5, —SR5, or —R5;
R2, R3, and R4 are independently selected from —(CO)NH2, —(CO)NHR, —(CO)N(R)2, —NHR5, —NHCH2R5, —OR5, —SR5, —R5, —NH(CO)—R6, —NH(CO)—NHR6, —NH(CO)—NH(CO)R6, —NH(CO)—OR6, —NH(SO2)—R6, —NH(SO2)—NHR6, —C(O)OH, —C(O)OR, —(CO)-Q1, —(CO)NH-Q1, —(CO)NR-Q1, —(CO)—O-Q1, —(SO2)-Q1 or —(SO2)NH-Q1;
R5 and R6 are each independently selected from H; N(R)2, NHOH, NO2, C(O)OR or halo; a C1-C6 straight chain or branched alkyl, alkenyl or alkynyl group; a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic ring; or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring; wherein said alkyl, alkenyl, ring or ring system is optionally substituted with one to four substituents, each of which is independently selected from NH2, NHR, NHC(O)OR, N(R)2, NO2, OH, OR, CF3, halo, CN, Si(R)3, CO2H, COOR, CONH2, CONHR, CON(R)2, COR, SR, S(O)R, S(O)2R, S(O)2NHR or R;
R is a C1-C6 straight chain or branched alkyl or alkenyl group, a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or a 9-10 membered bicyclic aromatic or non-aromatic carbocyclic or heterocyclic ring system.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Y is —(CH2)-Q1 and Q1 is optionally substituted benzodioxanyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is R5.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is H, methyl, halo, optionally substituted phenyl, a monocyclic or bicyclic heterocycle, optionally substituted alkyl, alkenyl or alkynyl, or COOR.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 is R5, NH(CO)—R6, NH(SO2)—R6, —NHCH2R5, CO-Q1 or CONH-Q1.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R2 is H, halo, NO2, NH2, methyl, OCF3, —N(R)2, or substituted phenyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3 is R5, NH(CO)—R6, NH(SO2)—R6, or CONH-Q1.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3 is H, halo, methyl, CF3, optionally substituted phenyl, a heterocyclic ring, a bicyclic ring, NO2 or NH2.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R4 is R5.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R4 is H or methyl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein said compound is selected from the group consisting of:

### Claim 12 (depends on 1, 11)

A pharmaceutical composition comprising a compound according to either of claims 1 or 11 and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 12)

A method for treating Parkinson's disease in a patient in need thereof, comprising administering the pharmaceutical composition of claim 12 to the patient.

### Claim 14

A compound of the formula:
or a pharmaceutically acceptable salt thereof; wherein
Y is —(CH2)-Q1;
Q1 is benzodioxanyl, a substituted phenyl group, a substituted 5-7 membered aromatic heterocyclic ring, a 10-membered heterocyclic bicyclic ring, or a straight chain alkyl group substituted with phenyl or a heterocyclic monocyclic or bicyclic ring, wherein said phenyl or heterocyclic ring is substituted with one to four substituents, each of which is independently selected from NH2, NH—R, N(R)2, NO2, OH, OR, CF3, halo, CN, CO2H, C(O)—NH2, C(O)—NH—R, C(O)—N(R)2, C(O)—R, SR, S(O)—R, S(O)2—R, S(O)2—NH—R or —R;
R1 is R5;
R2 is OCF3, NH2, R5, NH(CO)—R6, NH(SO2)—R6, —NHCH2R5, CO-Q1 or CONH-Q1;
R3 is NH(CO)—R6, NH(SO2)—R6, CONH-Q1, H, halo, methyl, CF3, substituted or unsubstituted phenyl, a substituted or unsubstituted aromatic heterocyclic ring, an aromatic bicyclic ring, NO2 or NH2;
R4 is R5;
R5 and R6 are each independently selected from H; N(R)2, NHOH, NO2, C(O)OR or halo; a C1-C6 straight chain or branched alkyl, alkenyl or alkynyl group; a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic ring; or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring; wherein said alkyl, alkenyl, ring or ring system is optionally substituted with one to four substituents, each of which is independently selected from NH2, NHR, NHC(O)OR, N(R)2, NO2, OH, OR, CF3, halo, CN, Si(R)3, CO2H, COOR, CONH2, CONHR, CON(R)2, COR, SR, S(O)R, S(O)2R, S(O)2NHR or R; and
R is a C1-C6 straight chain or branched alkyl or alkenyl group, a 5-7 membered aromaticor non-aromatic carbocyclic or heterocyclic ring, or a 9-10 membered bicyclic aromatic or non-aromatic carbocyclic or heterocyclic ring system.

### Claim 15 (depends on 14)

The compound according to claim 14, wherein R1 is H, methyl, halo, an optionally substituted phenyl, a monocyclic or bicyclic heterocycle, a substituted or unsubstituted alkyl, alkenyl or alkynyl, or COOR.

### Claim 16 (depends on 4)

The compound according to claim 4, wherein R2 is H, halo, NO2, NH2, methyl, OCF3, —N(R)2, or substituted phenyl.

### Claim 17 (depends on 14)

The compound according to claim 14, wherein R3 is H, halo, methyl, CF3, substituted or unsubstituted phenyl, an aromatic heterocyclic ring, a bicyclic ring, NO2 or NH2.

### Claim 18 (depends on 14)

The compound according to claim 14, wherein R4 is H or methyl.

### Claim 19 (depends on 14)

The compound according to claim 14, wherein Q1 is a substituted phenyl group.

### Claim 20 (depends on 14)

The compound according to claim 14, wherein said compound is selected from the group consisting of:

### Claim 21 (depends on 14, 20)

A pharmaceutical composition comprising a compound according to either of claims 14 or 20 and a pharmaceutically acceptable carrier.

### Claim 22 (depends on 21)

A method for treating Parkinson's disease in a patient in need thereof, comprising administering the pharmaceutical composition of claim 21 to the patient.