# US 2014/0194414 A1 · Tetracyclic compounds

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- Number: US 2014/0194414 A1
- Document ID: US20140194414A1
- Status: Published application
- Kind: A1
- Application number: 13/791,750
- Filed: 2013-03-08
- Published: 2014-07-10
- Earliest claimed: 2007-10-25
- Assignees: Medivation Technologies, Inc.
- Inventors: David T. HUNG; Andrew Asher PROTTER; Rajendra Parasmal JAIN; Sundeep DUGAR; Sarvajit CHAKRAVARTY; Sergey Olegovich BACHURIN; Anatoly Konstantinovich USTINOV; Bogdan Konstantinovich BEZNOSKO; Elena Feofanovna SHEVTSOVA; Vladimir Viktorovich GRIGORIEV
- Web page: https://patentgrep.com/patent/US20140194414A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/14: for baldness or alopecia
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- 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 27/02: Ophthalmic agents
- A61P 27/12: for cataracts
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D 471/10: Spiro-condensed systems
- C07D 471/14: 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 tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic[4,3-b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

## Claims

### Claim at position 1

1-22. (canceled)

### Claim 23

A compound of the Formula (E):
or a salt thereof,
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 or carbonylalkylenealkoxy;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or R2a and R2b are taken together with the carbon to which they are attached to form a cycloalkyl moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or R3a and R3b are taken together with the carbon to which they are attached to form a cycloalkyl moiety;
each X7, X8, X9 and X10 is independently CR4;
m and q are independently 0 or 1, provided that at least one of m and q is 1;
each R4 is independently H, hydroxyl, nitro, cyano, halo, C1-C8 perhaloalkyl, carboxy, 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;
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, C1-C8 alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, provided that at least one of R8a, R8b, R8c, R8d, R8e and R8f is other than H;
each R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl moiety or R10a and R10b are taken together with the carbon to which they are attached to form a cycloalkyl moiety; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl,
provided that (i) the compound is other than 1-propanone, 1-(2-chloro-10H-phenothiazin-10-yl)-3-(1,2,3,4-tetrahydro-2-methyl-5H-pyrido[4,3-b]indol-5-yl)-(Compound 221x) or a salt thereof, and (ii) when R1 is isopropyl and Q is substituted piperazinyl, then R8e and R8f taken together with the carbon to which they are attached do not form a carbonyl moiety.

### Claim 24 (depends on 23)

The compound of claim 23, or a salt thereof, wherein at least one of R8a, R8b, R8c, R8d, R8e and R8f is C1-C8 alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R8(a-f) to form a cycloalkyl moiety or a carbonyl moiety.

### Claim 25 (depends on 23)

The compound of claim 23, or a salt thereof, wherein at least one of R8c, R8d, R8e and R8f is other than H.

### Claim 26 (depends on 23)

The compound of claim 23, or a salt thereof, wherein at least one of R8e and R8f is other than H.

### Claim 27 (depends on 23)

The compound of claim 23, or a salt thereof, wherein at least one of R8a, R8b, R8c, R8d, R8e and R8f is substituted or unsubstituted C1-C8 alkyl.

### Claim 28 (depends on 23)

The compound of claim 23, or a salt thereof, wherein at least one of R8a, R8b, R8c, R8d, R8e and R8f is methyl.

### Claim 29 (depends on 23)

The compound of claim 23, or a salt thereof, wherein —R8cR8d-R8eR8f— and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH2—C(H)(CH3)—, —C(H)(CH3)—CH2—, —CH2—C(CH3)(CH3)—, —C(CH2CH2)—CH2— and —CH2—C(CH2CH2)—.

### Claim 30 (depends on 23)

The compound of claim 23, or a salt thereof, wherein q is 0, and m is 1.

### Claim 31 (depends on 23)

The compound of claim 23, or a salt thereof, wherein each R4 is independently H, hydroxyl, 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, thiol, carbonylalkoxy, thioalkyl, alkylsulfonylamino or acyl.

### Claim 32 (depends on 23)

The compound of claim 23, or a salt thereof, wherein each R4 is independently nitro, cyano, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, or carbonylalkylenealkoxy.

### Claim 33 (depends on 23)

The compound of claim 23, or a salt thereof, wherein X7, X8 and X10 are each CR4 where R4 is H, and X9 is CR4 where R4 is substituted or unsubstituted C1-C8 alkyl, perhaloalkyl or halo.

### Claim 34 (depends on 33)

The compound of claim 33, or a salt thereof, wherein X9 is CR4 where R4 is methyl, CF3, CH2F, CHF2, chloro or fluoro.

### Claim 35 (depends on 26)

The compound of claim 26, wherein X7, X8 and X10 are each CR4 where R4 is H, and X9 is CR4 where R4 is substituted or unsubstituted C1-C8 alkyl, perhaloalkyl, or halo.

### Claim 36 (depends on 35)

The compound of claim 35, or a salt thereof, wherein X9 is CR4 where R4 is methyl, CHF2, CH2F, CF3, chloro or fluoro.

### Claim 37 (depends on 23)

The compound of claim 23, or a salt thereof, wherein each R2a, R2b, R3a, R3b, R10a and R10b is independently H, substituted or unsubstituted C1-C8 alkyl, or halo.

### Claim 38 (depends on 37)

The compound of claim 37, or a salt thereof, wherein each R2a, R2b, R3a, R3b, R10a and R10b is H.

### Claim 39 (depends on 23)

The compound of claim 23, or a salt thereof, wherein Q is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

### Claim 40 (depends on 39)

The compound of claim 39, or a salt thereof, wherein Q is selected from the group consisting of:
wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino.

### Claim 41 (depends on 23)

The compound of claim 23, or a salt thereof, wherein Q is pyridyl, phenyl, pyrimidinyl, or pyrazinyl.

### Claim 42 (depends on 23)

The compound of claim 23, or a salt thereof, wherein Q is unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.

### Claim 43 (depends on 42)

The compound of claim 42, or a salt thereof, wherein Q is selected from the group consisting of:
wherein each R9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino.

### Claim 44 (depends on 23)

The compound of claim 23, or a salt thereof, wherein:
at least one of R8c, R8d, R8e and R8f is C1-C8 alkyl;
X7, X8 and X10 are each CR4 where R4 is H;
X9 is CR4 where R4 is substituted or unsubstituted C1-C8 alkyl, perhaloalkyl, or halo; and
R1 is substituted or unsubstituted C1-C8 alkyl.

### Claim 45 (depends on 23)

The compound of claim 23, or a salt thereof, wherein:
at least one of R8c, R8d, R8e and R8f is methyl, ethyl or cyclopropyl;
X7, X8 and X10 are each CR4 where R4 is H;
X9 is CR4 where R4 is methyl, CHF2, CH2F, CF3, chloro or fluoro; and
R1 is methyl or cyclopropyl.

### Claim 46 (depends on 23)

The compound of claim 23, or a salt thereof, wherein the compound has one or more of the following structural features:
R1 is methyl;
Q is a substituted or unsubstituted pyridyl; and
X9 is CR4 where R4 is halo, a substituted or unsubstituted C1-C8 alkyl, or perhaloalkyl.

### Claim 47 (depends on 27)

The compound of claim 27, or a salt thereof, wherein the compound has one or more of the following structural features:
R1 is methyl;
Q is a substituted or unsubstituted pyridyl; and
X9 is CR4 where R4 is halo, a substituted or unsubstituted C1-C8 alkyl, or perhaloalkyl.

### Claim 48 (depends on 23)

The compound of claim 23, or a salt thereof, wherein the compound has one or more of the following structural features:
R1 is methyl;
Q is a substituted or unsubstituted phenyl; and
X9 is CR4 where R4 is halo, a substituted or unsubstituted C1-C8 alkyl, or perhaloalkyl.

### Claim 49 (depends on 23)

The compound of claim 23, or a salt thereof, wherein:
R1 is methyl or ethyl;
each R8c, R8d, R8e and R8f is independently H or C1-C8 alkyl;
X7 is CR4 where R4 is H;
X8 and X10 are independently CR4 where R4 is H or halo;
X9 is CR4 where R4 is halo, methyl, trifluoromethyl or ethyl; and
Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl, provided that when X9 is CR4 where R4 is halo, then only one of X8 and X10 is CR4 where R4 is halo.

### Claim 50 (depends on 23)

The compound of claim 23, or a salt thereof, wherein:
R1 is unsubstituted C1-C8 alkyl;
each of R2a, R2b, R3a, R3b, R10a and R10b is H; H and
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, C1-C8 alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R8(a-f) to form a cycloalkyl moiety or a carbonyl moiety.

### Claim 51 (depends on 50)

The compound of claim 50, or a salt thereof, wherein —R8cR8d-R8eR8f— and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH2—C(H)(CH3)—, —C(H)(CH3)—CH2—, —CH2—C(CH3)(CH3)—, —C(CH2CH2)—CH2— and —CH2—C(CH2CH2)—.

### Claim 52 (depends on 50)

The compound of claim 50, or a salt thereof, wherein Q is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

### Claim 53

A compound of the formula (B):
or a salt thereof,
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 or carbonylalkylenealkoxy;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano or nitro or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety;
each X7, X8, X9 and X10 is 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;
each R8c, R8d, R8e and R8f is independently H, C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R8 to form a cycloalkyl moiety or a carbonyl moiety, provided that at least one of R8c, R8d, R8e and R8f is other than H;
each R10a and R10b is independently H, halo, a substituted or unsubstituted C1-C8 alkyl, hydroxyl, alkoxyl or R10a and R10b are taken together with the carbon to which they are attached to form a carbonyl; and
Q is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl,
provided that when R1 is isopropyl and Q is substituted piperazinyl, then R8e and R8f taken together with the carbon to which they are attached do not form a carbonyl moiety.

### Claim 54 (depends on 53)

The compound of claim 53, or a salt thereof, wherein at least one of R8a, R8b, R8c, R8d, R8e and R8f is C1-C8 alkyl, C1-C8 perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R8(a-f) to form a cycloalkyl moiety or a carbonyl moiety.

### Claim 55 (depends on 53)

The compound of claim 53, or a salt thereof, wherein at least one of R8e and R8f is other than H.

### Claim 56 (depends on 53)

The compound of claim 53, or a salt thereof, wherein at least one of R8c, R8d, R8e and R8f is C1-C8 alkyl.

### Claim 57 (depends on 53)

The compound of claim 53, or a salt thereof, wherein —R8cR8d-R8eR8f— and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH2—C(H)(CH3)—, —C(H)(CH3)—CH2—, —CH2—C(CH3)(CH3)—, —C(CH2CH2)—CH2— and —CH2—C(CH2CH2)—.

### Claim 58 (depends on 53)

The compound of claim 53, or a salt thereof, wherein:
R1 is substituted or unsubstituted C1-C8 alkyl;
X7 is CR4 where R4 is H;
X8 and X10 are independently CR4 where R4 is H or halo;
X9 is CR4 where R4 is halo, methyl, CHF2, CH2F, CF3, or ethyl; and
Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl, provided that when X9 is CR4 where R4 is halo, then only one of X8 and X10 is CR4 where R4 is halo.

### Claim 59 (depends on 53)

The compound of claim 53, or a salt thereof, wherein:
R1 is unsubstituted C1-C8 alkyl;
each of R2a, R2b, R3a, R3b, R10a and R10b is H; and
each R8a, R8b, R8c, R8d, R8e and R8f is independently H, C1-C8 alkyl, or is taken together with the carbon to which it is attached and a geminal R8(a-f) to form a cycloalkyl moiety or a carbonyl moiety.

### Claim 60 (depends on 53)

The compound of claim 53, or a salt thereof, wherein:
Q is 3-pyridyl, 4-pyridyl or 6-methyl-3-pyridyl; and
X9 is CR4 where R4 is chloro, methyl, CHF2, CH2F, or CF3.

### Claim 61 (depends on 53)

The compound of claim 53, or a salt thereof, wherein
Q is an unsubstituted 3-pyridyl;
X9 is CR4 where R4 is methyl, CHF2, CH2F or CF3; and
R1 is methyl.

### Claim 62 (depends on 23)

A pharmaceutical composition comprising a compound according to claim 23, or a salt thereof, and a pharmaceutically acceptable carrier.

### Claim 63 (depends on 23)

A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of compound according to claim 23, or a salt thereof.

### Claim 64 (depends on 23)

A kit comprising a compound according to claim 23, or a salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.

### Claim 65 (depends on 59)

A pharmaceutical composition comprising a compound according to claim 59, or a salt thereof, and a pharmaceutically acceptable carrier.

### Claim 66 (depends on 59)

A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of compound according to claim 59, or a salt thereof.

### Claim 67 (depends on 59)

A kit comprising a compound according to claim 59, or a salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.