# US 8,569,287 B2 · Azepino[4,5-B]indoles and methods of use

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- Number: US 8,569,287 B2
- Document ID: US8569287B2
- Status: Granted
- Kind: B2
- Application number: 12/610,152
- Filed: 2009-10-30
- Published: 2010-06-17
- Granted: 2013-10-29
- Earliest claimed: 2008-10-31
- Assignees: Medivation Technologies, Inc.
- Applicants: David T. Hung; Andrew Asher Protter; Rajendra Parasmal Jain; Sarvajit Chakravarty
- Inventors: David T. Hung; Andrew Asher Protter; Rajendra Parasmal Jain; Sarvajit Chakravarty
- Web page: https://patentgrep.com/patent/US8569287B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This disclosure relates to new azepino[4,5-b]indole compounds that may be used to modulate a histamine receptor in an individual. Novel compounds are described, including new 1,2,3,4,5,6-tetrahydroazepino[4,5-b]indoles. Pharmaceutical compositions are also provided.

## Claims

### Claim 1

A compound of formula (I):
wherein:
R1 is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy;
each R2a, R2b, R3a and R3b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R2 or R3 to form a cycloalkyl moiety or a carbonyl moiety;
each R10a, R10b, R11a and R11b is independently H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C1-C8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is taken together with the carbon to which it is attached and a geminal R10 or R11 to form a cycloalkyl moiety or a carbonyl moiety;
each X7, X8, X9 and X10 is independently N or CR4;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 perhaloalkoxy, C1-C8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
m is 1;
q is 0;
each R8c, R8d, R8e and R8f is independently H, hydroxyl, alkoxy, halo, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety; and
Q is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;
provided that (i) at least one of X7, X8, X9 and X10 is N, or (ii) at least one of R8c, R8d, R8e and R8f is hydroxyl,
or a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, or a salt thereof, wherein X7, X8, X9 and X10 are CR4.

### Claim 3 (depends on 1)

The compound of claim 1, or a salt thereof, wherein at least one of X7, X8, X9 and X10 is N.

### Claim 4 (depends on 1)

The compound of claim 1, or a salt thereof, wherein each R4 is independently H, halo, unsubstituted C1-C4 alkyl, C1-C4 perhaloalkyl or a substituted or unsubstituted aryl.

### Claim 5 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is H, substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl.

### Claim 6 (depends on 1)

The compound of claim 1, or a salt thereof, wherein R1 is methyl, ethyl, cyclopropyl, propylate, trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl, hydroxycyclopent-2-yl, hydroxycycloprop-2-yl, 1-hydroxy- 1-methylcycloprop-2-yl, or 1-hydroxy- 1 ,2,2-trimethyl-cycloprop-3-yl.

### Claim 7 (depends on 1)

The compound of claim 1, or a salt thereof, wherein:
each R2a and R2b is independently H, unsubstituted C1-C8 alkyl, halo or R2a and R2b are taken together to form a carbonyl moiety; and
each R3a and R3b is independently H, unsubstituted C1-C8 alkyl, halo or R3a and R3b are taken together to form a carbonyl moiety.

### Claim 8 (depends on 7)

The compound of claim 7, or a salt thereof, wherein each of R2a, R2b, R3a and R3b is H.

### Claim 9 (depends on 1)

The compound of claim 1, or a salt thereof, wherein each R10a, R10b, R10b R11b is independently H, bromo, methyl, hydroxyl or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl or R11a and R11b are taken together with the carbon to which they are attached to form a carbonyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a salt thereof, wherein:
R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl or substituted or unsubstituted aryl;
each R2a and R2b is independently H, methyl, fluoro or R2a and R2b are taken together to form a carbonyl moiety;
each R3a and R3b is independently H or fluoro;
each R10a and R10b is independently H, fluoro or methyl or R10a and R10b are taken together to form a carbonyl; and
each R11a and R11b is independently H, fluoro or methyl or R10a and R10b are taken together to form a carbonyl.

### Claim 11 (depends on 1)

The compound of claim 1, or a salt thereof, wherein Q is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group.

### Claim 12 (depends on 1)

The compound of claim 1, or a salt thereof, wherein:
R1 is a substituted or unsubstituted C1-C8 alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl;
each R2a and R2b is independently H, unsubstituted C1-C8 alkyl or halo;
each R2a and R2b is independently H or halo;
each X7, X8, X9 and X10 is CR4;
each R10a, R10b, R11a and R11b is independently H or methyl; and
Q is a substituted or unsubstituted aryl.

### Claim 13 (depends on 1)

A method of modulating a histamine receptor in an individual comprising administering to an individual in need thereof a compound according to claim 1, or a salt thereof.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

A kit comprising a compound according to claim 1, or a salt thereof.

### Claim 16 (depends on 10)

The compound of claim 10, or a salt thereof, wherein Q is a substituted or unsubstituted pyridyl, or a substituted or unsubstituted phenyl.

### Claim 17 (depends on 1, 10)

The compound of claim 1 or 10, or a salt thereof, wherein —R8cR8dR8eR8f— and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH2—C(H)(OH)—, —CH2—C(OH)(CH3)—, —CH2—C(H)(CH3)—, —C(H)(CH3)—CH2—, —CH2—C(CH3)(CH3)—, —C(CH2CH2)—CH2—, and —CH2—C(CH2CH2)—.

### Claim 18 (depends on 17)

The compound of claim 17, or a salt thereof, wherein —R8cR8dR8eR8f— and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH2—C(H)(OH)— and —CH2—C(OH)(CH3)—.

### Claim 19 (depends on 1)

The compound of claim 1, or a salt thereof, wherein:
R1 is CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH;
each R2a, R2b, R3a, R3b, R10a, R11a and R11b is H;
each X7, X8, X9 and X10 is CR4;
each R4 is independently H, CH3, CF3, Cl, F, or —NHCH3;
each R8c, R8d, R8e and R8f is independently H, hydroxyl, unsubstituted C1-C4 alkyl or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety; and
Q is a substituted or unsubstituted pyridyl, or a substituted or unsubstituted phenyl.

### Claim 20 (depends on 19)

The compound of claim 19, or a salt thereof, wherein:
R1 is CH3;
R8c and R8d are both H;
R8e and R8f are independently H, OH or CH3;
X7, X8 and X10 are each CR4, wherein R4 is H; and
X9 is CR4 where R4 is CH3, Cl, or F.

### Claim 21 (depends on 19, 20)

The compound of claim 19 or 20, or a salt thereof, wherein Q is 3-pyridyl or 4-pyridyl, each of which can be substituted with one, two or three moieties selected from C1-C4 alkyl, halo, perhaloalkyl and perhaloalkoxy.

### Claim 22 (depends on 21)

The compound of claim 21, or a salt thereof, wherein Q is 3-pyridyl, 6-methyl-3-pyridyl or 4-pyridyl.

### Claim 23 (depends on 19, 20)

The compound of claim 19 or 20, or a salt thereof, wherein Q is phenyl which can be substituted with one, two or three moieties selected from C1-C4 alkyl, halo, perhaloalkyl and perhaloalkoxy.

### Claim 24 (depends on 1)

The compound of claim 1, or a salt thereof, wherein the compound is selected from the group consisting of:

### Claim 25

A compound of formula (I):
wherein:
R1 is CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH;
each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is H;
each X7, X8, X9 and X10 is CR4;
each R4 is independently H, CH3, CF3, Cl, F, or —NHCH3;
m is 1;
q is 0;
each R8c, R8d, R8e and R8f is independently H, hydroxyl, unsubstituted C1-C4 alkyl or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety, provided that at least one of R8c, R8d, R8e and R8f is other than H; and
Q is 3-pyridyl or 4-pyridyl, each of which can be substituted with one, two or three moieties selected from the group consisting of C1-C4 alkyl, halo, perhaloalkyl and perhaloalkoxy;
or a salt thereof.

### Claim 26 (depends on 25)

The compound of claim 25, or a salt thereof, wherein Q is 3-pyridyl, 6-methyl-3-pyridyl or 4-pyridyl.

### Claim 27 (depends on 25)

The compound of claim 25, or a salt thereof, wherein:
R1 is CH3;
R8c and R8d are both H;
R8e and R8f are independently H, OH or CH3;
X7, X8 and X10 are each CR4, wherein R4 is H;
X9 is CR4 where R4 is CH3, Cl, or F; and
Q is 3-pyridyl or 4-pyridyl, each of which can be substituted with one, two or three moieties selected from the group consisting of C1-C4 alkyl, halo, perhaloalkyl and perhaloalkoxy.

### Claim 28 (depends on 27)

The compound of claim 27, or a salt thereof, wherein Q is 3-pyridyl, 6-methyl-3-pyridyl or 4-pyridyl.

### Claim 29

A compound of formula (I):
wherein:
R1 is CH3, —CH2CH2F, —CH2CF3, or —CH2CH2C(CH3)2OH;
each R2a, R2b, R3a, R3b, R10a, R10b, R11a and R11b is H;
X7, X8 and X10 are each CR4, wherein R4 is H;
X9 is CR4 where R4 is CH3, Cl, or F; and
m is 1;
q is 0;
each R8c, R8d, R8e and R8f is independently H, hydroxyl, unsubstituted C1-C4 alkyl or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety, provided that at least one of R8c, R8d, R8e and R8f is other than H; and
Q is phenyl which can be substituted with one, two or three moieties selected from the group consisting of C1-C4 alkyl, halo, perhaloalkyl and perhaloalkoxy;
or a salt thereof.

### Claim 30 (depends on 29)

The compound of claim 29, or a salt thereof, wherein:
R1 is CH3;
R8c and R8d are both H;
R8e and R8f are independently H, OH or CH3;
Q is phenyl which can be substituted with one, two or three moieties selected from the group consisting of C1-C4 alkyl, halo, perhaloalkyl and perhaloalkoxy.