# US 2021/0332012 A1 · N-substituted indoles and other heterocycles for treating brain disorders

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- Number: US 2021/0332012 A1
- Document ID: US20210332012A1
- Status: Published application
- Kind: A1
- Application number: 17/345,471
- Filed: 2021-06-11
- Published: 2021-10-28
- Earliest claimed: 2019-02-27
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: David E. OLSON; Lee DUNLAP; Florence Wagner
- Web page: https://patentgrep.com/patent/US20210332012A1

## CPC

- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61P 25/24: Antidepressants
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 209/18: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/30: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D 209/34: in position 2
- C07D 209/36: in position 3, e.g. adrenochrome
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 491/044: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- 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

The present invention provides N-substituted indoles and other heterocycles and methods of using the compounds for treating brain disorders.

## Claims

### Claim 1

A compound of Formula I:
wherein:
X is CR3;
R1a and R1b are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, or C4-14 alkyl-cycloalkyl;
R1c is C1-6 alkyl, C3-8 cycloalkyl, or C4-14 alkyl-cycloalkyl;
alternatively, two of R1a, R1b, and R1c are combined with the atoms to which they are attached to form a C3-12 heterocycloalkyl;
R2, R3, R4, R5, R6 and R7 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C1-6 haloalkyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, —OR8a, —NO2, —CN, —C(O)R8b, —C(O)OR8b, —OC(O)R8b, —OC(O)OR8b, —N(R8bR8c), —N(R8b)C(O)R8c, —C(O)N(R8bR8c), —N(R8b)C(O)OR8c, —OC(O)N(R8bR8c), —N(R8b)C(O)N(R8cR8d), —C(O)C(O)N(R8bR8c), —S(O2)R8b, —S(O)2N(R8bR8c), C3-8 cycloalkyl, C3-14 alkyl-cycloalkyl, C4-10 heterocycloalkyl, C4-16 alkyl-heterocycloalkyl, C6-12 aryl, C7-18 alkyl-aryl, C5-10 heteroaryl, or C4-16 alkyl-heteroaryl;
R8a is C3-8 cycloalkyl, C3-14 alkyl-cycloalkyl, C4-10 heterocycloalkyl, C4-16 alkyl-heterocycloalkyl, C6-12 aryl, C7-18 alkyl-aryl, C5-10 heteroaryl, or C4-16 alkyl-heteroaryl;
R8b, R8c and R8d are each independently H or C1-6 alkyl;
alternatively, one of R1a, R1b, or R1c is combined with R2 to form a C5-12 heterocycloalkyl;
alternatively, R2 and R3 are combined with the atoms to which they are each attached to form a C4-8 cycloalkyl, C4-10 heterocycloalkyl, or C6-12 aryl;
alternatively, R4 and R5, R5 and R6, or R6 and R7 are combined with the atoms to which they are each attached to form a C4-6 cycloalkyl, C4-6 heterocycloalkyl, C6-12 aryl, or C5-10 heteroaryl; and
L is C1-6 alkylene,
or pharmaceutically acceptable salts and isomers thereof,
wherein when R1a, R1b and R1c are each Me, L is methylene, X is CR3 and R2, R3, R4, R5, R6 and R7 are hydrogen, then the compound is
and
wherein the compound is other than

### Claim 2 (depends on 1)

The compound of claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 2)

The compound of claim 2, which is
or a pharmaceutically acceptable salt thereof.

### Claim 13

A compound of Formula II:
wherein:
X is CR3;
R1a and R1b are each independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, or C4-14 alkyl-cycloalkyl;
alternatively, R1a and R1b are combined with the atoms to which they are attached to form a C3-12 heterocycloalkyl;
R2, R3, R4, R5, R6 and R7 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C1-6 haloalkyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, —OR8a, —NO2, —CN, —C(O)R8b, —C(O)OR8b, —OC(O)R8b, —OC(O)OR8b, —N(R8bR8c), —N(R8b)C(O)R8c, —C(O)N(R8bR8c), —N(R8b)C(O)OR8c, —OC(O)N(R8bR8c), —N(R8b)C(O)N(R8cR8d), —C(O)C(O)N(R8bR8c), —S(O2)R8b, —S(O)2N(R8bR8c), C3-8 cycloalkyl, C3-14 alkyl-cycloalkyl, C4-10 heterocycloalkyl, C4-16 alkyl-heterocycloalkyl, C6-12 aryl, C7-18 alkyl-aryl, C5-10 heteroaryl, or C4-16 alkyl-heteroaryl;
R8a is C3-8 cycloalkyl, C3-14 alkyl-cycloalkyl, C4-10 heterocycloalkyl, C4-16 alkyl-heterocycloalkyl, C6-12 aryl, C7-18 alkyl-aryl, C5-10 heteroaryl, or C4-16 alkyl-heteroaryl;
R8b, R8c and R8d are each independently H or C1-6 alkyl;
alternatively, one of R1a or R1b is combined with R2 to form a C5-12 heterocycloalkyl;
alternatively, R2 and R3 are combined with the atoms to which they are each attached to form a C4-8 cycloalkyl, C4-10 heterocycloalkyl, or C6-12 aryl;
alternatively, R4 and R5, R5 and R6, or R6 and R7 are combined with the atoms to which they are each attached to form a C4-6 cycloalkyl, C4-6 heterocycloalkyl, C6-12 aryl, or C5-10 heteroaryl; and
L is C1-6 alkylene,
or pharmaceutically acceptable salts and isomers thereof,
wherein when R1a and R1b are both Me, and L is methylene, then at least one of R2, R3, R4, R5, R6, and R7 is not hydrogen and the compound is other than:
wherein when R1a and R1b are Me, L is ethylene, and X is CR3, then at least one of R2, R3, R4, R5, R6 and R7 is not hydrogen;
wherein when R1c is hydrogen, and R5 is Br, Cl, F, —NH2, —NO2, or C1-3 alkoxy, then at least one of R2, R3, R4, R6, or R7 is not hydrogen; and
wherein when R1c is hydrogen and R5 is F, then at least one of R2, R3, R4, R6, or R7 is not hydrogen and R6 is not F.

### Claim 14 (depends on 13)

The compound of claim 13, selected from the group consisting of:

### Claim 15 (depends on 14)

The compound of claim 14, which is
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 14)

The compound of claim 14, which is
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A method for treating a brain disorder, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein the brain disorder is a psychological disorder, depression, addiction, anxiety, or post-traumatic stress disorder.

### Claim 19 (depends on 18)

The method of claim 18, wherein the brain disorder is depression or addiction.

### Claim 20 (depends on 17)

The method of claim 17, wherein the brain disorder is treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

### Claim 21 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of a compound selected from claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 21)

The pharmaceutical composition of claim 21, selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 23 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is
or a pharmaceutically acceptable salt thereof.