# US 9,433,626 B2 · Pyrido[4,3-B]indole and pyrido[3,4-B]indole derivatives and methods of use

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- Number: US 9,433,626 B2
- Document ID: US9433626B2
- Status: Granted
- Kind: B2
- Application number: 14/701,244
- Filed: 2015-04-30
- Published: 2015-11-26
- Granted: 2016-09-06
- Earliest claimed: 2010-02-18
- Assignees: Medivation Technologies, Inc.
- Applicants: Medivation Technologies, Inc.
- Inventors: Sarvajit Chakravarty; Barry Patrick Hart; Rajendra Parasmal Jain
- Web page: https://patentgrep.com/patent/US9433626B2

## CPC

- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- 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 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/497: containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/14: Ortho-condensed systems
- C07D 471/18: Bridged systems
- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 487/14: Ortho-condensed systems
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This disclosure is directed to pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives. 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 1

A method of treating schizophrenia in an individual comprising administering to an individual in need thereof an effective amount of a compound of formula (IA):
or a pharmaceutically acceptable salt thereof;
wherein:
R1 is H, hydroxyl, 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, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R1 and R2a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R1 and R4a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety;
each R2a and R2b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl, or R2a and R2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R2a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R2a and R3a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R2a and R4a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety;
each R3a and R3b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl, or R3a and R3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R3a and R1 are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety, or R3a and R2a are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R3a and R4a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
each R4a and R4b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, or heterocyclyl, or R4a and R4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R4a and R1 are taken together to form an ethylene (—CH2CH2—) moiety or a propylene (—CH2CH2CH2—) moiety, or R4a and R2a are taken together to form a methylene (—CH2—) moiety or an ethylene (—CH2CH2—) moiety, or R4a and R3a are taken together to form a propylene (—CH2CH2CH2—) moiety or a butylene (—CH2CH2CH2CH2—) moiety;
R5 is H or unsubstituted C1-C8 alkyl;
each X1, X2 and X3 is independently N, CH or CR6;
each m, n, o and p is independently 0 or 1;
each R6 is independently 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, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted 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, R8f, R8g and R8h is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C8 alkenyl, C1-C8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C8 alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety, or is taken together with a geminal R8(a-h) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH2CH2O—, or is taken together with a geminal R8(a-h) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R8(a-h) and the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or is taken together with a vicinal R8(a-h) to form a bond provided that when an R8(a-h) is taken together with a vicinal R8(a-h) to form a bond, the geminal R8(a-h) is other than hydroxyl; and
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, wherein R9 is H or a substituted or unsubstituted C1-C8 alkyl and R10a and R10b are taken together with the carbon to which they are attached to form a substituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclyl moiety;
provided that (i) at least one of X1, X2 and X3 is N or CR6, and (ii) when at least one of X1, X2 and X3 is CH or CR6, then provisions (1)-(4) apply:
(1) when each m, n, o and p is 0 and R5 is H, then Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, acyloxy, cyano, alkynyl, acylamino, a group of the formula —CR9═CR10aR10b, or amino substituted with one or two substituted or unsubstituted C1-C8 alkyl;
(2) when each m, n, o and p is 0 and R5 is methyl, then Q is substituted or unsubstituted aryl other than unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, alkynyl, aminocarbonylalkoxy, a group of the formula —CR9═CR10aR10b, or amino substituted with one or two substituted or unsubstituted C1-C8 alkyl;
(3) wherein at least one of m, n, o and p is 1 and R5 is H, then Q substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b; and
(4) wherein at least one of m, n, o and p is 1 and R5 is methyl, then Q substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted heterocyclyl other than a substituted piperazinyl, aminoacyl, acyloxy, carboxyl, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a group of the formula —CR9═CR10aR10b, or amino substituted with one or two substituted or unsubstituted C1-C8 alkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is of formula (C1), (C2), (C3), (C4) or (C5):
wherein:
R1 is H or substituted or unsubstituted C1-C8 alkyl;
R5 is H or unsubstituted C1-C8 alkyl;
R6 is H, halo, or substituted or unsubstituted C1-C8 alkyl;
R8c is H, OH or substituted or unsubstituted C1-C8 alkyl;
R8d is H or substituted or unsubstituted C1-C8 alkyl, and the bond indicates the presence of either an E or Z double bond configuration;
Y is O or NR11;
each R11, R12a and R12b is independently H or substituted or unsubstituted C1-C8 alkyl;
each X1 and X3 is independently CH or N; and
D is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
provided that when the compound is of the formula (C5), D is other than unsubstituted phenyl.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound is of the formula (C1).

### Claim 4 (depends on 2)

The method of claim 2, wherein the compound is of the formula (C2).

### Claim 5 (depends on 2)

The method of claim 2, wherein the compound is of the formula (C3).

### Claim 6 (depends on 2)

The method of claim 2, wherein the compound is of the formula (C4).

### Claim 7 (depends on 2)

The method of claim 2, wherein the compound is of the formula (C5).

### Claim 8 (depends on 1)

The method of claim 1, wherein R1 is H or methyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein R5 is H or methyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein X1 is CH.

### Claim 11 (depends on 1)

The method of claim 1, wherein X3 is CH.

### Claim 12 (depends on 1)

The method of claim 1, wherein R6 is H, chloro or methyl.

### Claim 13 (depends on 12)

The method of claim 12, wherein R6 is methyl.

### Claim 14 (depends on 3)

The method of claim 3, wherein R8c is H, OH or methyl.

### Claim 15 (depends on 14)

The method of claim 14, wherein R8d is H or unsubstituted C1-C8 alkyl.

### Claim 16 (depends on 4)

The method of claim 4, wherein R8d is H or methyl.

### Claim 17 (depends on 6)

The method of claim 6, wherein Y is NR11.

### Claim 18 (depends on 17)

The method of claim 17, wherein R11 is H or methyl.

### Claim 19 (depends on 17)

The method of claim 17, wherein each R12a and R12b is H.

### Claim 20 (depends on 17)

The method of claim 17, wherein D is selected from the group consisting of phenyl, 4-fluorophenyl, pyridin-4-yl, pyridine-3-yl, 6-methylpyridin-3-yl, thiophen-2-yl, thiazol-2-yl, and 4-phenylthiazol-2-yl.

### Claim 21 (depends on 2)

The method of claim 2, wherein D is selected from the group consisting of 4-fluorophenyl, pyridin-4-yl, pyridine-3-yl, 6-methylpyridin-3-yl, thiophen-2-yl, thiazol-2-yl, and 4-phenylthiazol-2-yl.

### Claim 22 (depends on 1)

The method of claim 1, wherein Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

### Claim 23

A method of treating schizophrenia in an individual comprising administering to an individual in need thereof an effective amount of a compound selected from the group consisting of compounds 2, 5-22, 28-35, 39, 42-44, 47-50, 53-59, 62-65, 68-89, 105-112, 115-117, 119-121, and 149-154;
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 23)

The method of claim 23, wherein the compound is selected from the group consisting of compounds 2, 5-22, 28-35, 39, and 42;
or a pharmaceutically acceptable salt thereof.