# US 10,118,920 B2 · Isoxazolyl substituted benzimidazoles

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- Number: US 10,118,920 B2
- Document ID: US10118920B2
- Status: Granted
- Kind: B2
- Application number: 15/567,768
- Filed: 2016-04-20
- Published: 2018-05-10
- Granted: 2018-11-06
- Earliest claimed: 2015-04-20
- Assignees: Cellcentric GmbH & Co. KG
- Applicants: Cellcentric Ltd
- Inventors: Neil Anthony Pegg; David Michel Adrien Taddei; Stuart Thomas Onions; Eric Sing Yuen Tse; Richard James Brown; David Kenneth Mycock; David Cousin; Anil Patel
- Web page: https://patentgrep.com/patent/US10118920B2

## CPC

- C07D 413/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- C07D 403/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound which is a benzimidazolyl isoxazole of formula (I): wherein: R0 and R, which are the same or different, are each H or C1-6 alkyl; R9, R9 and R9, which are the same or different, are each H or F; X is -(alkn-, -alk-C(═O)—NR—, -alk-NR—C(═O)— or -alk-C(═O)—; R1 is selected from —S(═O)2R′; a 4- to 6-membered, C-linked heterocyclic group which is unsubstituted or substituted; and an N-linked spiro group of the following formula: R2 and R2′, which are the same or different, are each H or C1-6 alkyl, or R2 and R2′ form, together with the C atom to which they are attached, a C3-6 cycloalkyl group; R3 and R3, which are the same or different, are each H, C1-6 alkyl, OH or F; R4 is phenyl or a 5- to 12-membered, N-containing heteroaryl group and is unsubstituted or substituted; alk is C1-6 alkylene; R′ is C1-6 alkyl; and n is 0 or 1; or a pharmaceutically acceptable salt thereof. The compound has activity in modulating the activity of p300 and/or CBP and is used to treat cancer, particularly prostate cancer.

## Claims

### Claim 1

A compound which is a benzimidazolyl isoxazole of formula (I):
wherein:
R0 and R, which are the same or different, are each H or C1-6 alkyl;
R9, R9′ and R9″, which are the same or different, are each H or F;
X is -(alk)n-, -alk-C(═O)—NR—, -alk-NR—C(═O)— or -alk-C(═O)—;
R1 is selected from —S(═O)2R′, a 4- to 6-membered, C-linked heterocyclic group which is unsubstituted or substituted and an N-linked spiro group of the following formula:
R2 and R2′, which are the same or different, are each H or C1-6 alkyl; or R2 and R2′ form, together with the C atom to which they are attached, a C3-6 cycloalkyl group;
R3 and R3′, which are the same or different, are each H, C1-6 alkyl, OH or F;
R4 is phenyl or a 5- to 12-membered, N-containing heteroaryl group and is unsubstituted or substituted;
alk is C1-6 alkylene;
R′ is C1-6 alkyl; and
n is 0 or 1;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein the benzimidazolyl isoxazole has the following formula (Ia):
wherein each of R9, R9′, R9″, X, R1, R2, R2′, R3, R3′ and R4 is as defined in claim 1 for formula (I).

### Claim 3 (depends on 1)

A compound according to claim 1 wherein the benzimidazolyl isoxazole has the following formula (Ib):
wherein:
R9, R9′ and R9″ are as defined above for formula (I);
X′ is C1-3 alkylene or —(CH2)—C(═O)—NH—;
R2′ is H, Me or Et;
R5 is H and R6 is —S(═O)2Me, or R5 and R6 form, together with the carbon atom to which they are attached, a heterocyclic group selected from pyrrolidinyl, thiopyranyl, pyranyl and piperidinyl, which group is unsubstituted or substituted;
W is C or N; and
R7 and R8 form, together with the C or N atom to which they are attached, a group selected from phenyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, pyrrolopyridinyl and quinoxalinyl, which group is unsubstituted or substituted.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R2 is H, R2′ is C1-6 alkyl, the C—R2′ bond is CR2′ and the compound is the R enantiomer.

### Claim 5 (depends on 1)

A compound according to claim 1 which is selected from:
4-(2-(1-(3-fluoro-4-methoxyphenyl)propan-2-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1-(1-methylpyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-(1-(4-chloro-3-fluorophenyl)propan-2-yl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(5-(3,5-dimethylisoxazol-4-yl)-2-(1-(3-fluoro-4-methoxyphenyl)propan-2-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
4-(2-(1-(4-fluorophenyl)propan-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
3,5-dimethyl-4-(2-(1-(pyridin-2-yl)propan-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)isoxazole;
4-(2-(1-(3-fluoro-4-methoxyphenyl)propan-2-yl)-1-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
1-(4-((2-(1-(4-chlorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)piperidin-1-yl)ethan-1-one;
4-(2-(1-(3-fluoro-4-methoxyphenyl)propan-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-(1-(4-chlorophenyl)propan-2-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-(1-(3-chloro-4-(trifluoromethoxy)phenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
4-(2-(1-(3-chloro-4-(difluoromethoxy)phenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
4-(2-(3,4-dichlorophenethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
4-(2-(4-ethylphenethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
3,5-dimethyl-4-(2-(2-(quinoxalin-2-yl)ethyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-benzo[d]imidazol-5-yl)isoxazole;
2-(5-(3,5-dimethylisoxazol-4-yl)-2-(3-fluoro-4-methoxyphenethyl)-1H-benzo[d]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide;
2-(5-(3,5-dimethylisoxazol-4-yl)-2-(3-fluoro-4-methoxyphenethyl)-1H-benzo[d]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide;
2-(5-(3,5-dimethylisoxazol-4-yl)-2-(1-(3-fluoro-4-methoxyphenyl)propan-2-yl)-1H-benzo[d]imidazol-1-yl)-N-(tetrahydrofuran-3-yl)acetamide;
4-(2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-(1-(4-chlorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
(R)-4-(2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
(S)-4-(2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
3-(2-((R)-1-(3-chloro-4-(difluoromethoxy)phenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
3-(2-((S)-1-(3-chloro-4-(difluoromethoxy)phenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
4-(2-((R)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-((S)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-1-((R)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
(R)-4-(2-(1-(4-chlorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
(S)-4-(2-(1-(4-chlorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
4-(2-((R)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-1-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
4-(2-((S)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-1-((S)-1-(methylsulfonyl)pyrrolidin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
(R)-4-(2-(1-(4-chloro-3-fluorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
(S)-4-(2-(1-(4-chloro-3-fluorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
((R)-3-(2-((R)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
((R)-3-(2-((S)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
(R)-3-(2-((R)-1-(4-chlorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
(R)-4-(5-(3,5-dimethylisoxazol-4-yl)-2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
(S)-4-(5-(3,5-dimethylisoxazol-4-yl)-2-(1-(3-fluoro-4-(trifluoromethoxy)phenyl)propan-2-yl)-1H-benzo[d]imidazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide;
(S)-3-(2-((R)-1-(4-chlorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
(S)-3-(2-((R)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
(S)-3-(2-((R)-1-(4-chloro-3-fluorophenyl)propan-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)tetrahydrothiophene 1,1-dioxide;
(R)-4-(2-(1-(4-chloro-3-fluorophenyl)propan-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
(S)-4-(2-(1-(4-chloro-3-fluorophenyl)propan-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole;
and the pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 1)

A process for producing a compound as defined in claim 1, which process comprises treating a compound of formula (II):
wherein each of R1, R2, R2′, R3, R3′, R4, R9, R9′ and R9″ is as defined above for formula (I), with a boronic acid of formula (III):
in which each of R0 and R is as defined in claim 1 for formula (I), in the presence of Pd(PPh3)4 and Na2CO3 in aqueous ethanol.

### Claim 7 (depends on 6)

A process according to claim 6, which further comprises converting the resulting benzimidazolyl isoxazole of formula (I) into a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound as defined in claim 1.

### Claim 9 (depends on 1)

A compound as defined in claim 1 for use in the treatment of the human or animal body by therapy.

### Claim 10 (depends on 1)

A compound as defined in claim 1 for use as a modulator of p300 and/or CBP activity.

### Claim 11 (depends on 1)

A compound as defined in claim 1 for use in treating cancer.

### Claim 12 (depends on 11)

A compound for use according to claim 11, wherein the cancer is a cancer that expresses AR.

### Claim 13 (depends on 1)

Use of a compound as defined in claim 1 in the manufacture of a medicament for use as a modulator of p300 and/or CBP activity.

### Claim 14 (depends on 1)

A method of treating cancer, which method comprises administering to a patient in need thereof a compound as defined in claim 1.

### Claim 15 (depends on 14)

A method according to claim 14 wherein said compound is administered concurrently or sequentially with radiotherapy; or is administered concurrently, sequentially or as a combined preparation with another chemotherapeutic agent or agents.

### Claim 16 (depends on 1)

A product comprising
(i) a compound as defined in claim 1; and
(ii) a chemotherapeutic agent;
for separate, simultaneous or sequential administration in the prophylactic or therapeutic treatment of cancer.