# US 12,006,300 B2 · Sigma ligand compounds and uses thereof

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- Number: US 12,006,300 B2
- Document ID: US12006300B2
- Status: Granted
- Kind: B2
- Application number: 17/400,207
- Filed: 2021-08-12
- Published: 2023-02-23
- Granted: 2024-06-11
- Earliest claimed: 2020-08-14
- Assignees: Minerva Neurosciences, Inc.
- Applicants: Minerva Neurosciences, Inc.
- Inventors: Remy Luthringer; Nadine Noel; Florent Schmitt; Sandra Werner; Hans Maag; Jay Saoud
- Web page: https://patentgrep.com/patent/US12006300B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- C07D 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 217/08: with a hetero atom directly attached to the ring nitrogen atom
- C07D 223/16: Benzazepines; Hydrogenated benzazepines
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates to compounds of Formula (I): and their prodrugs, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of their preparation. The compounds disclosed herein are useful for modulating Sigma receptors and have antiviral activity, and may also be useful in the treatment and/or prevention of pain disorders, neurological disorders (e.g., Parkinson's disease and Alzheimer's disease), and cancer.

## Claims

### Claim 1

A compound of Formula (I):
or a solvate or pharmaceutically acceptable salt thereof, wherein
X1 is absent, —(CR3R4)q—, —O—, —S(O)2—, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, —C(O)NR3—, —C(O)O—, or —OC(O)—;
X2 is absent, —(CR3R4)q—, —O—, —S(O2)—, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, —C(O)NR3—, —C(O)O—, or —OC(O)—;
R1 is H, OH, halogen, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 12-membered heteroaryl comprising 1-6 heteroatoms selected from N, O, and S, 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl of any of the foregoing is optionally substituted with one or more R5;
R2 is C6-C10 aryl, 5- to 12-membered heteroaryl comprising 1-6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the aryl, heteroaryl, or heterocycloalkyl of any of the foregoing is optionally substituted with one or more R6;
each R3 independently is H, halogen, or C1-C6 alkyl;
each R4 independently is H, halogen, or C1-C6 alkyl;
each R5 independently is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C10 aryl, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl of any of the foregoing is optionally substituted with one or more —C(O)C1-C6alkyl, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, or —C(O)N(C1-C6alkyl)2;
each R6 independently is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C10 aryl, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocycloalkyl of any of the foregoing is optionally substituted with one or more —C(O)C1-C6 alkyl, —C(O)OC1-C6 alkyl, —C(O)NH2, —C(O)NHC1-C6 alkyl, or —C(O)N(C1-C6alkyl)2;
R7 is C1-C6 alkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl;
R8 is C1-C6 alkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl;
m is 1;
n is 2;
p is 1; and
each q independently is 1, 2, 3, or 4.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is a compound of Formula (Ia):
or a solvate or pharmaceutically acceptable salt thereof, wherein
X1 is absent, (CR3R4)q, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, or —C(O)O—;
R1 is H, OH, halogen, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl of any of the foregoing is optionally substituted with one or more R5;
R2 is C6-C10 aryl, 5- to 12-membered heteroaryl comprising 1-6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the aryl, heteroaryl, or heterocycloalkyl of any of the foregoing is optionally substituted with one or more R6;
each R3 independently is H or halogen;
each R4 independently is H or halogen;
each R5 independently is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, or C6-C10 aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl of any of the foregoing is optionally substituted with one or more —C(O)C1-C6alkyl, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, or —C(O)N(C1-C6alkyl)2; and
each R6 independently is OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C10 aryl, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl of any of the foregoing is optionally substituted with one or more —C(O)C1-C6alkyl, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, or —C(O)N(C1-C6alkyl)2.

### Claim 3 (depends on 1)

The compound of claim 1, wherein X1 is (CR3R4)q, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, or —C(O)O—.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X1 is absent.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X2 is (CR3R4)q, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, or —C(O)O—.

### Claim 6 (depends on 1)

The compound of claim 1, wherein X2 is absent.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 is H or OH.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1 is halogen.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl of any of the foregoing is optionally substituted with one or more R5.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is C6-C10 aryl, 5- to 12-membered heteroaryl comprising 1-6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the aryl, heteroaryl, or heterocycloalkyl of any of the foregoing is optionally substituted with one or more R5.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R1 is H, OH, methyl,

### Claim 12 (depends on 1)

The compound of claim 1, wherein R2 is

### Claim 13 (depends on 1)

The compound of claim 1, wherein R5 is OH or halogen.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R5 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R5 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R6 is OH.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R6 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

### Claim 18 (depends on 1)

The compound of claim 1, wherein R6 is C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein R6 is a 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the heterocycloalkyl is optionally substituted with one or more —C(O)C1-C6alkyl, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, or —C(O)N(C1-C6alkyl)2.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R6 is

### Claim 21 (depends on 1)

The compound of claim 1, wherein R7 and R8 are each methyl.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound is a compound of Formula (III):
or a solvate or pharmaceutically acceptable salt thereof, wherein X1, R1, and R2 are as described in claim 1.

### Claim 23 (depends on 1)

The compound of claim 1, wherein the compound is
or a solvate or pharmaceutically acceptable salt thereof, wherein X1, X2, R1, R2, and R6 are as described in claim 1.

### Claim 24

A compound that is:
or a solvate or pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or carrier.

### Claim 26 (depends on 1)

The compound of claim 1, wherein R2 is or

### Claim 27 (depends on 1)

The compound of claim 1, wherein the compound is
or a solvate or pharmaceutically acceptable salt thereof, wherein X1, R1, R2, and R6 are as described in claim 1.

### Claim 28

A compound of Formula (I):
or a solvate or pharmaceutically acceptable salt thereof, wherein
X1 is absent, —(CR3R4)q—, —O—, —S(O)2—, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, —C(O)NR3—, —C(O)O—, or —OC(O)—;
X2 is absent, —(CR3R4)q—, —O—, —S(O2)—, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, —C(O)NR3—, —C(O)O—, or —OC(O)—;
R1 is H, OH, halogen, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 12-membered heteroaryl comprising 1-6 heteroatoms selected from N, O, and S, 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl of any of the foregoing is optionally substituted with one or more R5;
R2 is
each R3 independently is H, halogen, or C1-C6 alkyl;
each R4 independently is H, halogen, or C1-C6 alkyl;
each R5 independently is OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C6-C10 aryl, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or aryl of any of the foregoing is optionally substituted with one or more —C(O)C1-C6alkyl, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, or —C(O)N(C1-C6alkyl)2;
R7 is C1-C6 alkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl;
R8 is C1-C6 alkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl; and
each q independently is 1, 2, 3, or 4.

### Claim 29 (depends on 28)

The compound of claim 28, wherein R5 is OH or halogen.

### Claim 30 (depends on 28)

The compound of claim 28, wherein X1 is (CR3R4)q, —C(O)—, —C(S)—, —S(O)—, —S(O)2, —NR3C(O)—, or —C(O)O—.

### Claim 31 (depends on 28)

The compound of claim 28, wherein X1 is absent.

### Claim 32 (depends on 28)

The compound of claim 28, wherein X2 is (CR3R4)q, —C(O)—, —C(S)—, —S(O)—, —NR3C(O)—, or —C(O)O—.

### Claim 33 (depends on 28)

The compound of claim 28, wherein X2 is absent.

### Claim 34

The compound of 28, wherein R1 is H, OH, or halogen.

### Claim 35 (depends on 28)

The compound of claim 28, wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, or C3-C6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, or cycloalkyl of any of the foregoing is optionally substituted with one or more R5.

### Claim 36 (depends on 28)

The compound of claim 28, wherein R1 is C6-C10 aryl, 5- to 12-membered heteroaryl comprising 1-6 heteroatoms selected from N, O, and S, or 5- to 14-membered saturated or unsaturated heterocycloalkyl comprising 1-5 heteroatoms selected from N, O, and S; wherein the aryl, heteroaryl, or heterocycloalkyl of any of the foregoing is optionally substituted with one or more R5.

### Claim 37 (depends on 28)

The compound of claim 28, wherein R7 and R8 are each methyl.

### Claim 38 (depends on 28)

The compound of claim 28, wherein the compound is a compound of Formula (II):
or a solvate or pharmaceutically acceptable salt thereof, wherein X1, R1, and R2 are as described in claim 28.

### Claim 39 (depends on 28)

The compound of claim 28, wherein the compound is
or a solvate or pharmaceutically acceptable salt thereof, wherein X1, X2, R1, and R2 are as described in claim 28.

### Claim 40 (depends on 28)

The compound of claim 28, wherein the compound is
or a solvate or pharmaceutically acceptable salt thereof, wherein R2 is as described in claim 28.

### Claim 41 (depends on 28)

A pharmaceutical composition comprising the compound of claim 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent and/or carrier.