# US 2014/0194411 A1 · Benzazepines as serotonin 5-ht2c receptor ligands and uses thereof

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- Number: US 2014/0194411 A1
- Document ID: US20140194411A1
- Status: Published application
- Kind: A1
- Application number: 14/138,866
- Filed: 2013-12-23
- Published: 2014-07-10
- Earliest claimed: 2012-12-21
- Assignees: ABT Holding Company
- Applicants: ABT Holding Company
- Inventors: Mike Robarge; John Harrington; David Gerrish; John Mecom
- Web page: https://patentgrep.com/patent/US20140194411A1

## CPC

- C07D 223/32: containing carbocyclic rings other than six-membered
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/30: for treating abuse or dependence
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 491/052: the oxygen-containing ring being six-membered
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are benzazepine compounds. These compounds are serotonin receptor (5-HT2c) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT2c) is desired (e.g. addiction, anxiety, depression, obesity, and others).

## Claims

### Claim 1

A compound of the formula
where
R1 is selected from the group consisting of H, alkyl, perhaloalkyl, alkanoyl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
R2 and R3 are independently selected from the group consisting of H, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, CN, OR8, NR8R9, SR8, OCOR10, CONR8R9, NR8COR10, NR8CO2R10, SO2NR8R9, SO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
R4 and R5 together with the atoms which they are attached form a 5- or 6-membered carbocycle, benzofuran, dihydrobenzofuran or benzopyrane ring, substituted with one or more of each of R11a, R11b, R12a, R12b, R13a, R13b, R14a, and R14b;
R6a and R6b are independently selected from the group consisting of H, OR8, aryl, and heteroaryl; or Rha and R6b taken together are —CH2CH2—;
R7a and R7b are independently selected from the group consisting of H, OR8, aryl, and heteroaryl; or R7a and R7b taken together are —CH2CH2—;
R8 is selected from the group consisting of H, C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
R9 is selected from the group consisting of H, C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, alkylaryl, and C1-8 alkylheteroaryl;
R10 is selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
R11a and R11b are independently selected from the group consisting of H, halogen, C1-4 alkyl, perhaloalkyl, aryl, and heteroaryl;
R12a and R12b are independently selected from the group consisting of H, halogen C1-8 alkyl, perhalo alkyl, aryl, and heteroaryl, with the proviso that when the formula is
then R12b is not present;
R13a and R13b are independently selected from the group consisting of H, halogen, C1-8 alkyl, perhaloalkyl, aryl, and heteroaryl;
R14a and R14b are independently selected from the group consisting of H, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl (preferably CF3), CN, OR8, NR8R9, SRR, OCOR10, OCONR8R9, CONR8R9, NR8COR10, NR8CO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8alkylheteroaryl, with the proviso that when the formula is
then R14b is not present;
or an isomer or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound as in claim 1, wherein R1 is H.

### Claim 3 (depends on 1)

A compound as in claim 1 wherein said compound has the formula:

### Claim 4 (depends on 1)

A compound as in claim 1 wherein said compound has the formula:

### Claim 5 (depends on 1)

A compound as in claim 1 wherein said compound has the formula:
wherein X is C, S, SO2 or O.

### Claim 6 (depends on 1)

A compound as in claim 1 wherein said compound has the formula:
wherein X is C, S, SO2 or O.

### Claim 7 (depends on 1)

A compound as in claim 1, wherein said compound has one of the formulas:
wherein
X is C, S, SO2 or O;
R1 is H;
R2 and R3 are independently selected from the group consisting of H and halogen;
R11a, R11b, R12a, R12b, R13a and R13b are independently selected from the group consisting of H and halogen; and
R14a and R14b are independently selected from the group consisting of H, halogen, C1-8 alkyl, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
with the proviso that when the formula is
then R12b and R14b are not present,
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein R1, R2, R3, R6a, R6b, R7a, R7b are H; and R4 and R5 together with the atoms which they are attached form a 5-membered carbocycle ring, substituted with one or more of each of R11a, R11b, R12a, R12b, R14a, and R14b.

### Claim 9 (depends on 8)

A compound according to claim 8, wherein R11a and R11b are both H.

### Claim 10 (depends on 8)

A compound according to claim 8, wherein R12a and R12b are both F.

### Claim 11 (depends on 8)

A compound according to claim 8, wherein R14a is aryl and R14b is H.

### Claim 12 (depends on 1)

A compound according to claim 1, wherein said compound is selected from the group consisting of:
1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Methyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Ethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Cyclopropyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Propyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
4-Chloro-1-ethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Ethyl-4-iodo-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Ethyl-4-fluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
4-Chloro-1-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
4-Fluoro-1-pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1,1-Dimethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-o-tolyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-m-tolyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-p-tolyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-(3-trifluoromethyl-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-(3-trifluoromethoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-(4-fluoro-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-(3-fluoro-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Cyclopropyl-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-(3-Chloro-phenyl)-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-(4-Chloro-phenyl)-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-(2-methoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-(3-methoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-(4-methoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-pyridin-4-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
4-Chloro-2,2-difluoro-1-pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Ethyl-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1-methyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Benzyl-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1,1-dimethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1,1-Dimethyl-4-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Ethyl-1,2,7,8,9,10-hexahydro-6H-3-oxa-8-aza-cyclohepta[e]indene;
1-Ethyl-2,3,8,9,10,11-hexahydro-1H,7H-4-oxa-9-aza-cyclohepta[a]naphthalene;
2,2-Difluoro-1-methoxy-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Phenyl-7,8,9,10-tetrahydro-6H-3-oxa-8-aza-cyclohepta[e]indene;
1-Thiazol-2-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
1-Ethoxy-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
2,2-Difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene; and
1-Methoxy-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein said compound is 1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.

### Claim 14 (depends on 1)

A compound according to claim 1, wherein said compound is 1-Ethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.

### Claim 15 (depends on 1)

A compound according to claim 1, wherein said compound is 1-Phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.

### Claim 16 (depends on 1)

A compound according to claim 1, wherein said compound is 4-Chloro-1-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.

### Claim 17 (depends on 1)

A compound according to claim 1, wherein said compound is 2,2-Difluoro-1-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.

### Claim 18 (depends on 1)

A compound according to claim 1, wherein said compound is 4-Chloro-2,2-difluoro-1-pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 1)

A method of treating a disease, disorder and/or condition in a patient wherein modulation of a 5-HT2c function is desired comprising administering an effective amount of at least one compound of claim 1 to a patient in need of such treatment.