# US 7,612,212 B2 · Substituted hydantoins

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- Number: US 7,612,212 B2
- Document ID: US7612212B2
- Status: Granted
- Kind: B2
- Application number: 11/657,800
- Filed: 2007-01-25
- Published: 2007-08-23
- Granted: 2009-11-03
- Earliest claimed: 2006-02-22
- Assignees: Hoffmann-La Roche Inc.
- Inventors: Shaoqing Chen; Nicholas J. S. Huby; Norman Kong; Steven Gregory Mischke; John Anthony Moliterni; Hong Wang; Zhuming Zhang
- Web page: https://patentgrep.com/patent/US7612212B2

## CPC

- C07D 233/76: with substituted hydrocarbon radicals attached to the third ring carbon atom
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 233/78: Radicals substituted by oxygen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- 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 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 407/04: directly linked by a ring-member-to-ring-member bond
- C07D 407/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of the formula methods for the preparation thereof, and methods for their use. The compounds are useful in treating diseases characterized by the hyperactivity of MEK. Accordingly the compounds are useful in the treatment of diseases, such as cancer, cognitive and CNS disorders, and inflammatory/autoimmune diseases.

## Claims

### Claim 1

A compound of formula I:
wherein:
R1 is selected from the group consisting of bromo, iodo, ethynyl, cycloalkyl, alkoxy, azetidinyl, acetyl, heterocycyl, cyano, straight-chained alkyl and branched-chain alkyl;
R2 is selected from the group consisting of hydrogen, chloro, fluoro, and alkyl;
R3 is selected from the group consisting of hydrogen and fluoro;
R4 is selected from the group consisting of optionally substituted aryl, alkyl, and cycloalkyl;
R5 is selected from the group consisting of hydrogen and
wherein R6 is selected from the group consisting of hydroxyl, alkoxy, cycloalkyl, trihaloalkyl, alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, and trihaloalkyl; or
R6 and R7 can together form a cycloalkyl group and R8 is hydrogen;
and pharmaceutically acceptable salts or esters thereof.

### Claim 2 (depends on 1)

The compound of claim 1 with the formula:
wherein:
R1 is selected from the group consisting of bromo, iodo, ethynyl, cycloalkyl, alkoxy, acetyl, alkylthio, heterocycyl, cyano, straight-chained lower alkyl and branched-chain lower alkyl;
R2 is selected from the group consisting of hydrogen, chloro, fluoro, and lower alkyl;
R3 is selected from the group consisting of hydrogen and fluoro;
R4 is selected from the group consisting of optionally substituted aryl, lower alkyl, and cycloalkyl;
R5 is selected from the group consisting of hydrogen and
wherein R6 is selected from the group consisting of hydroxyl, alkoxy, cycloalkyl, trihalo lower alkyl, lower alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, and trihalo lower alkyl; or
R6 and R7 can together form a cycloalkyl group and R8 is hydrogen;
and pharmaceutically acceptable salts or esters thereof.

### Claim 3 (depends on 2)

The compound of claim 2 wherein R1 is selected from the group consisting of iodo, ethynyl, and cyclopropyl.

### Claim 4 (depends on 3)

The compound of claim 3 wherein R2 is selected from the group consisting of hydrogen, chloro, and fluoro.

### Claim 5 (depends on 4)

The compound of claim 4 wherein R3 is hydrogen.

### Claim 6 (depends on 5)

The compound of claim 5 wherein R5 is
and R7 and R8 are independently selected from the group consisting of hydrogen and methyl.

### Claim 7 (depends on 6)

The compound of claim 6 wherein R4 is optionally substituted aryl.

### Claim 8 (depends on 7)

The compound of claim 7 wherein R1 is selected from the group consisting of iodo, ethynyl, and cyclopropyl, R2 is selected from the group consisting of hydrogen, fluoro, and chloro, R3 is hydrogen, R4 is optionally substituted phenyl, R5 is
R6 is optionally substituted phenyl, R7 is methyl, and R8 is hydrogen.

### Claim 9 (depends on 8)

The compound of claim 8 wherein R4 is phenyl substituted with alkoxy.

### Claim 10 (depends on 9)

The compound of claim 9 wherein R1 is iodo and R2 is selected from the group consisting of chloro and fluoro.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R6 is phenyl and R4 is phenyl substituted with a member selected from a 2,3-dihydroxy-propoxy group and a 2-hydroxy-ethoxy group.

### Claim 12

A compound selected from the group consisting of:
(2S,3S)—N-(4-Bromo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyramide;
(2S,3S)—N-(4-Iodo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-butyramide;
(2S,3S)—N-(4-Ethynyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide;
(2R,3S)—N-(4-Ethynyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide;
(2S,3S)—N-(2-Chloro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide;
(2S,3S)-2-{(R)-4-[4-(2-Hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-N-(4-iodo-2-methyl-phenyl)-3-phenyl-butyramide;
(2S,3S)—N-(2-Chloro-4-iodo-phenyl)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide;
(2S,3S)—N-(2-Chloro-4-iodo-phenyl)-2-{(R)-4-[4-((S)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide;
(2S,3S)-2-{(R)-2,5-Dioxo-4-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-phenyl]-imidazolidin-1-yl}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide;
(2S,3S)-2-((R)-2,5-Dioxo-4-thiophen-3-yl-imidazolidin-1-yl)-N-(4-iodo-phenyl)-3-phenyl-butyramide;
(S)-2-[(R)-4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-propionamide;
(S)-2-[(R)-4-(4-Acetylamino-phenyl)-2,5-dioxo-imidazolidin-1-yl]-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-propionamide;
(4-{(R)-1-[(1S,2S)-1-(2-Fluoro-4-iodo-phenylcarbamoyl)-2-phenyl-propyl]-2,5-dioxo-imidazolidin-4-yl}-phenoxymethyl)-phosphonic acid dimethyl ester;
(2S,3S)—N-(2-Fluoro-4-iodo-phenyl)-2-((R)-4-isopropyl-2,5-dioxo-imidazolidin-1-yl)-3-phenyl-butyramide;
(S)—N-(2-Fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-methyl-butyramide;
(S)—N-(2-Fluoro-4-iodo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-o-tolyl-propionamide;
(S)—N-(2-Fluoro-4-iodo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-m-tolyl-propionamide;
(S)—N-(2-Fluoro-4-iodo-phenyl)-2-[(R)-4-(4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-p-tolyl-propionamide; and
(S)—N-(4-Cyclopropyl-2-fluoro-phenyl)-3-(4-fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy-1-hydroxymethyl-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-propionamide.

### Claim 13

A compound selected from the group consisting of:
(2S,3S)—N-(2-Fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide;
(2S,3S)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-N-(2-fluoro-4-iodo-phenyl)-3-phenyl-butyramide;
(2S,3S)—N-(2-Chloro-4-iodo-phenyl)-2-{(R)-4-[4-((R)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide;
(2S,3S)—N-(2-Chloro-4-iodo-phenyl)-2-{(R)-4-[4-((S)-2,3-dihydroxy-propoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide; and
(2S,3S)—N-(4-Cyclopropyl-2-fluoro-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, excipient, or adjuvant.

### Claim 15 (depends on 11)

A pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable diluent, excipient, or adjuvant.

### Claim 16 (depends on 13)

A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable diluent, excipient, or adjuvant.