# US 2023/0054070 A1 · Sigma ligand compounds and uses thereof

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- Number: US 2023/0054070 A1
- Document ID: US20230054070A1
- Status: Published application
- Kind: A1
- Application number: 17/400,207
- Filed: 2021-08-12
- Published: 2023-02-23
- 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/US20230054070A1

## 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 prodrug, 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;
each R2 independently is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, —C(O)C1-C6alkyl, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, —C(O)N(C1-C6alkyl)2, 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 alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, 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, or aryl 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;
or
R7 and R8, together with the carbon atom they are attached, form a C3-C6 cycloalkyl optionally substituted with one or more OH, halogen, or C1-C6 alkoxyl;
m is 0, 1, 2, or 3;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4; 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 prodrug, 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;
each R2 independently is H, OH, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, —C(O)C1-C6alkyl, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, —C(O)N(C1-C6alkyl)2, 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 alkyl, alkenyl, alkynyl, haloalkyl, alkoxyl, haloalkoxyl, cycloalkyl, 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;
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, 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;
m is 0, 1, 2, or 3;
n is 0, 1, 2, or 3;
p is 0, 1, 2, 3, or 4; and
q is 1, 2, 3, or 4.

### 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 at position 5

-11. (canceled)

### Claim 12 (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 13 (depends on 1)

The compound of claim 1, wherein X2 is absent.

### Claim at position 8

-20. (canceled)

### Claim 21 (depends on 1)

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

### Claim 22 (depends on 1)

The compound of claim 1, wherein R1 is halogen.

### Claim 23 (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 24

(canceled)

### Claim 25 (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 26

(canceled)

### Claim 27 (depends on 1)

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

### Claim at position 16

-35. (canceled)

### Claim 36 (depends on 1)

The compound of claim 1, wherein 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.

### Claim at position 18

-39. (canceled)

### Claim 40 (depends on 1)

The compound of claim 1, wherein R2 is

### Claim at position 20

-53. (canceled)

### Claim 54 (depends on 1)

The compound of claim 1, wherein m is 1 and n is 1.

### Claim 55 (depends on 1)

The compound of claim 1, wherein m is 1 and n is 2.

### Claim at position 23

-58. (canceled)

### Claim 59 (depends on 1)

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

### Claim 60 (depends on 1)

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

### Claim 61 (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 62 (depends on 1)

The compound of claim 1, wherein R5 is —C(O)OC1-C6 alkyl, —C(O)NH2, —C(O)NHC1-C6 alkyl, or —C(O)N(C1-C6alkyl)2.

### Claim 63 (depends on 1)

The compound of claim 1, wherein R6 is OH or halogen.

### Claim 64 (depends on 1)

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

### Claim 65 (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 66 (depends on 1)

The compound of claim 1, wherein R6 is —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)NHC1-C6alkyl, or —C(O)N(C1-C6alkyl)2.

### Claim 67 (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 68 (depends on 1)

The compound of claim 1, wherein R6 is

### Claim at position 34

-72. (canceled)

### Claim 73 (depends on 1)

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

### Claim 74

(canceled)

### Claim 75 (depends on 1)

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

### Claim 76 (depends on 1)

The compound of claim 1, wherein the compound is
or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein X1, X2, R1, R2, R5, and p are as described in claim 1.

### Claim at position 39

-86. (canceled)

### Claim 87 (depends on 1)

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

### Claim 88 (depends on 1)

The compound of claim 1, wherein the compound is
or a prodrug, solvate, or pharmaceutically acceptable salt thereof, wherein X1, X2, R1, R2, R5, and p are as described in claim 1.

### Claim at position 42

-100. (canceled)

### Claim 101

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

### Claim at position 44

-103. (canceled)

### Claim 104 (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 105 (depends on 1)

A method of treating or preventing a viral infection in a subject, or an illness resulting from the viral infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

### Claim 106 (depends on 105)

The method of claim 105, wherein the viral infection is caused by a coronavirus, herpes simplex virus, human immunodeficiency virus, influenza, or human papillomavirus.

### Claim 107 (depends on 106)

The method of claim 106, wherein the coronavirus is SARS-CoV-2.

### Claim 108 (depends on 107)

The method of claim 107, wherein the illness resulting from the viral infection is severe acute respiratory syndrome or COVID-19.

### Claim 109 (depends on 1)

A method of treating Alzheimer's disease comprising administering to an individual in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

### Claim 110 (depends on 1)

A method of treating a disease, or symptom of a disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein said disease or symptom of a disease is anxiety, depression, emotional abnormality, schizophrenia, narcotic intoxication, narcotic addiction, sharp pain, dyskinesia, cerebrovascular disease, epilepsy, dementia, Parkinson's syndrome, attention deficit disorder, irritable bowel syndrome, irritable colon, spastic colon, colitis mucosus, enterocolitis, diverticulitis, dysentery, hypertension, arrhythmia, angina pectoris, amyotrophic lateral sclerosis (ALS), Huntington disease, stroke, retinal degeneration, or cognitive impairment in neuropsychiatric diseases.

### Claim 111 (depends on 1)

A method of treating or preventing pain in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

### Claim 112 (depends on 111)

The method of claim 111, wherein the pain is acute pain, chronic pain, toxic pain, neuropathic pain, nociceptive pain, inflammatory pain, post-operative pain, visceral pain, chemotherapy-induced pain, peripheral neuropathy, fibromyalgia, or a combination thereof.

### Claim 113 (depends on 1)

A method of promoting an antihyperalgesic effect in a subject suffering from hyperalgesia comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

### Claim 114 (depends on 1)

A method of reducing sensitivity to pain in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

### Claim 115 (depends on 1)

A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, or solvate thereof.

### Claim 116 (depends on 115)

The method of claim 115, wherein the cancer is breast cancer, prostate cancer, colon cancer, rectal cancer, pancreatic cancer, liver cancer, bladder cancer, thyroid cancer, kidney cancer, skin cancer, non-Hodgkin lymphoma, or uterine cancer.