# US 12,180,213 B2 · Substituted pyrazoles showing serotonin 5-HT receptor activity

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- Number: US 12,180,213 B2
- Document ID: US12180213B2
- Status: Granted
- Kind: B2
- Application number: 17/889,775
- Filed: 2022-08-17
- Published: 2023-01-12
- Granted: 2024-12-31
- Earliest claimed: 2018-07-23
- Assignees: Sumitomo Pharma Co., Ltd.
- Applicants: Sumitomo Pharma Co., Ltd.
- Inventors: Hidefumi Yoshinaga; Yohei Ikuma; Junya Ikeda; Satoshi Adachi; Harunobu Mitsunuma; Yoshinori Aihara; Jeremy Besnard; Andrew Simon Bell
- Web page: https://patentgrep.com/patent/US12180213B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention relates to a medicament for treating neuropsychiatric diseases, comprising a compound of Formula (1): or a pharmaceutically acceptable salt thereof, as an active ingredient.

## Claims

### Claim 1

A compound of Formula (1):
or a pharmaceutically acceptable salt thereof,
wherein:
Ring Q1 is Formula (2):
wherein:
wherein:
Ring Q3 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, NH2, OH, OC1-6 alkyl, and C3-10 cycloalkyl;
wherein each C1-6 alkyl substituent of Ring Q3 is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and OC1-6 alkyl;
wherein each NH2 substituent of Ring Q3 is optionally and independently substituted with 1 or 2 independently selected C1-6 alkyl substituents;
wherein each OC1-6 alkyl substituent of Ring Q3 is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and a saturated 4- to 8-membered heterocyclyl; and
wherein each C3-10 cycloalkyl substituent of Ring Q3 is optionally and independently substituted with 1, 2, or 3 independently selected halogen substituents;
W is —CRCRD—;
RC is hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein the C1-6 alkyl, OC1-6 alkyl, or C30 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
RD is hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein the C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
m is 1;
bond (b) is a single bond or double bond;
X is CRE or —CRFRG;
RE is hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein the C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
RF is hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein the C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
RG is hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein the C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents; or
when RF and RG are each C1-6 alkyl, RF and RG, taken together with the carbon atom to which they are attached, form a saturated 3- to 6-membered carbocyclyl;
Y is CRH or N;
RH is hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein the C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents; and
is the point of attachment to V;
each V is independently —CRARB—;
each RA is independently hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein each C1-6 alkyl, OC1-6 alkyl, and C3-10 cycloalkyl is optionally and independently substituted with 1, 2, or 3 independently selected halogen substituents;
each RB is independently hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein each C1-6 alkyl, OC1-6 alkyl, and C3-10 cycloalkyl is optionally and independently substituted with 1, 2, or 3 independently selected halogen substituents;
n is 1 or 2;
bond (a) is a single bond or double bond;
R1a is hydrogen, halogen, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
R1b is hydrogen, halogen, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
R1c is hydrogen, halogen, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
R1d is hydrogen, halogen, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
Z is C, CR, or N;
RJ is hydrogen, C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl, wherein the C1-6 alkyl, OC1-6 alkyl, or C3-10 cycloalkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
t is 1, 2, or 3; and
Ring Q2 is Formula (3a) or Formula (3b):
wherein:
R2a is hydrogen;
R2b is hydrogen;
R2c is hydrogen;
R2d is hydrogen; and
is the point of attachment to Z;
with the provisos that:
(1) when bond (a) is a double bond, then Z is C;
(2) when bond (b) is a single bond, then X is —CRFRG—; and
(3) when bond (b) is a double bond, then X is CRES.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the compound is of Formula (1a):
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the compound is of Formula (1b):
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Q3 is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, OC1-6 alkyl, and C3-10 cycloalkyl;
wherein each C1-6 alkyl substituent of Ring Q3 is optionally and independently substituted with 1, 2, or 3 independently selected halogen substituents;
wherein each OC1-6 alkyl substituent of Ring Q3 is optionally and independently substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and a saturated 4- to 8-membered heterocyclyl; and
wherein each C3-10 cycloalkyl substituent of Ring Q3 is optionally and independently substituted with 1, 2, or 3 independently selected halogen substituents.

### Claim 5 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
bond (b) is a single bond;
X is —CRFRG—;
RF is hydrogen; and
RG is hydrogen.

### Claim 6 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Q1 is Formula (4d):
wherein:
R3a is hydrogen, halogen, cyano, C1-6 alkyl, NH2, or OC1-6 alkyl;
wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
wherein the NH2 is optionally substituted with 1 or 2 independently selected C1-6 alkyl substituents; and
wherein the OC1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
R3b is hydrogen, halogen, cyano, C1-6 alkyl, NH2, or OC1-6 alkyl;
wherein the C1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents;
wherein the NH2 is optionally substituted with 1 or 2 independently selected C1-6 alkyl substituents; and
wherein the OC1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halogen substituents; and
is the point of attachment to V.

### Claim 8 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Q1 is Formula (5e):
wherein:
R4, is C1-6 alkyl or OC1-6 alkyl; and
is the point of attachment to V.

### Claim 9 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
each RA is independently hydrogen; and
each RB is independently hydrogen.

### Claim 10 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2.

### Claim 11 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein bond (a) is a single bond.

### Claim 12 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1a is hydrogen;
R1b is hydrogen;
R1c is hydrogen; and
R1d is hydrogen.

### Claim 13 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
Z is CRJ; and
RJ is hydrogen.

### Claim 14 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N.

### Claim 15 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Q2 is Formula (3a):

### Claim 16 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring Q2 is Formula (3b):

### Claim 17 (depends on 1)

A drug comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

### Claim 18 (depends on 1)

A medicament comprising a pharmaceutically acceptable excipient, at least one drug, and a compound according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient;
wherein each drug is independently selected from the group consisting of an adrenaline beta receptor antagonist, an analgesic drug, an anticonvulsant, an antidementia drug, an antidepressant drug, an antiemetic drug, an antiepileptic drug, an antimigraine drug, an antiparkinsonian drug, an antischizophrenic agent, an anxiolytic drug, a dopamine receptor agonist, a dopamine supplement, a hormone preparation, a drug for treating a mood disorder, and a sleep-inducing drug.

### Claim 19 (depends on 1)

A method for treating a central nervous system disease, central nervous system disorder, mental disease, or mental disorder in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The method according to claim 19, wherein the central nervous system disease, central nervous system disorder, mental disease, or mental disorder is selected from the group consisting of a behavioral disorder due to psychoactive substance use, a behavioral disorder with onset usually occurring in childhood, a behavioral disorder with onset usually occurring in adolescence, a degenerative disease of the central nervous system, a delusional disorder, an emotional disorder with onset usually occurring in childhood, an emotional disorder with onset usually occurring in adolescence, an extrapyramidal movement disorder, a mental disorder due to psychoactive substance use, a mood affective disorder, a neurotic disorder, an organic mental disorder, a pervasive developmental disorder, schizophrenia, a schizotypal disorder, sexual dysfunction not caused by an organic disorder or organic disease, a sleep disorder, a somatoform disorder, and a stress-related disorder.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the sleep disorder is a nonorganic sleep disorder.

### Claim 22 (depends on 19)

The method according to claim 19, wherein the central nervous system disease, central nervous system disorder, mental disease, or mental disorder is selected from the group consisting of aggression associated with Alzheimer's disease, agitation associated with Alzheimer's disease, a bipolar disorder with a psychotic feature, a depressive disorder with a psychotic feature, irritation associated with Alzheimer's disease, a negative symptom of schizophrenia, a positive symptom of schizophrenia, a psychopathic symptom associated with Alzheimer's disease, a psychopathic symptom associated with dementia, a psychopathic symptom associated with Parkinson's disease, and schizophrenia.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the psychopathic symptom associated with dementia is a psychopathic symptom associated with dementia with Lewy bodies.

### Claim 24 (depends on 22)

The method according to claim 22, wherein the psychopathic symptom associated with Parkinson's disease is a psychopathic symptom associated with Parkinson's disease with dementia.

### Claim 25 (depends on 19)

The method according to claim 19, wherein the central nervous system disease, central nervous system disorder, mental disease, or mental disorder is selected from the group consisting of aggression associated with Alzheimer's disease, agitation associated with Alzheimer's disease, irritation associated with Alzheimer's disease, a psychopathic symptom associated with Alzheimer's disease, a psychopathic symptom associated with dementia, and schizophrenia.

### Claim 26 (depends on 25)

The method according to claim 25, wherein the psychopathic symptom associated with dementia is a psychopathic symptom associated with dementia with Lewy bodies.

### Claim 27 (depends on 1)

A method for treating a central nervous system disease, central nervous system disorder, mental disease, or mental disorder in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of at least one drug and a compound according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient;
wherein each drug is independently selected from the group consisting of an adrenaline beta receptor antagonist, an analgesic drug, an anticonvulsant, an antidementia drug, an antidepressant drug, an antiemetic drug, an antiepileptic drug, an antimigraine drug, an antiparkinsonian drug, an antischizophrenic agent, an anxiolytic drug, a dopamine receptor agonist, a dopamine supplement, a hormone preparation, a drug for treating a mood disorder, and a sleep-inducing drug.

### Claim 28 (depends on 1, 27)

The method according to claim 27, wherein at least one drug is administered to the patient first and the compound according to claim 1, or a pharmaceutically acceptable salt thereof, is administered to the patient second.

### Claim 29 (depends on 1, 27)

The method according to claim 27, wherein the compound according to claim 1, or a pharmaceutically acceptable salt thereof, is administered to the patient first and at least one drug is administered to the patient second.

### Claim 30 (depends on 1, 27)

The method according to claim 27, wherein at least one drug and the compound according to claim 1, or a pharmaceutically acceptable salt thereof, are administered to the patient concurrently.

### Claim 31 (depends on 1)

A method for treating a central nervous system disease, central nervous system disorder, mental disease, or mental disorder in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a medicament comprising a pharmaceutically acceptable excipient, at least one drug, and a compound according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient;
wherein each drug is independently selected from the group consisting of an adrenaline beta receptor antagonist, an analgesic drug, an anticonvulsant, an antidementia drug, an antidepressant drug, an antiemetic drug, an antiepileptic drug, an antimigraine drug, an antiparkinsonian drug, an antischizophrenic agent, an anxiolytic drug, a dopamine receptor agonist, a dopamine supplement, a hormone preparation, a drug for treating a mood disorder, and a sleep-inducing drug.