# US 10,246,448 B2 · 4-hydroxy-2-phenyl-1,3-thiazol-5-yl methanone derivatives as TRPM8 antagonists

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- Number: US 10,246,448 B2
- Document ID: US10246448B2
- Status: Granted
- Kind: B2
- Application number: 16/061,850
- Filed: 2016-12-16
- Published: 2018-11-08
- Granted: 2019-04-02
- Earliest claimed: 2015-12-21
- Assignees: Dompé Farmaceutici S.P.A.
- Applicants: Dompé Farmaceutici S.P.A.
- Inventors: Andrea Aramini; Gianluca Bianchini; Samuele Lillini
- Web page: https://patentgrep.com/patent/US10246448B2

## CPC

- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to compounds acting as antagonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), and having formula (I): Said compounds are useful in the treatment of diseases associated with activity of TRPM8 such as pain, ischaemia, neurodegeneration, stroke, psychiatric disorders, itch, irritable bowel diseases, cold-induced and/or exacerbated-respiratory disorders, urological disorders, corneal disorders associated to disturbances in the production of the tears and/or altered blinking such as epiphora and dry eye disease.

## Claims

### Claim 1

A compound of formula (I):
wherein
R1 is an unsubstituted or substituted 5, 6 or 7-membered, aliphatic or aromatic heterocycle group having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S; and
R2 is selected from the group consisting of hydrogen, C1-C2 alkyl, F, Cl and OH;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 is selected from the group consisting of oxazolidinyl, oxolanyl, pyrrolidinyl, oxazinanyl, morpholinyl, piperidinyl, methylpyrrolidinyl, pyrrolyl, methylpyrrolyl, furanyl, thiophenyl, pyridinyl, imidazolyl, pyrazolyl, oxadiazolyl and oxazolyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 is selected from the group consisting of 1,2-oxazolidin-2-yl, 1,3-oxazolidin-3-yl, oxolan-2-yl, pyrrolidin-1-yl, 1,2-oxazinan-2-yl, 1,3-oxazinan-3-yl, morpholin-4-yl, piperidin-1-yl, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl, 1H-pyrrol-2-yl, 1-methyl-1H-pyrrol-2-yl, furan-2-yl, thiophen-2-yl, 1H-pyrrol-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-imidazol-1-yl and 1H-pyrazol-1-yl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the 5, 6 or 7-membered, aliphatic or aromatic heterocycle is unsubstituted.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein the 5, 6 or 7-membered, aliphatic or aromatic heterocycle is substituted with one or more groups independently selected from C1-C3 alkyl, cycloalkyl, Cl and F or the heterocycle is substituted with a saturated cyclic moiety.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein the saturated cyclic moiety is cyclobutane, cyclopentane or cyclohexane.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R2 is F or OH.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein R2 is 3-F or 2-OH.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
R1 is oxazolidinyl and R2 is F or OH,
or
R1 is oxolanyl and R2 is F or OH,
or
R1 is pyrrolidinyl and R2 is F or OH,
or
R1 is oxazinanyl and R2 is F or OH,
or
R1 is morpholinyl and R2 is F or OH,
or
R1 is piperidinyl and R2 is F or OH,
or
R1 is methylpyrrolidinyl and R2 is F or OH,
or
R1 is pyrrolyl and R2 is F or OH,
or
R1 is methylpyrrolyl and R2 is F or OH,
or
R1 is furanyl and R2 is F or OH,
or
R1 is thiophenyl and R2 is F or OH,
or
R1 is pyridinyl and R2 is F or OH,
or
R1 is imidazolyl and R2 is F or OH,
or
R1 is pyrazolyl and R2 is F or OH.

### Claim 10 (depends on 1)

The compound according to claim 1, which is selected from the group consisting of:
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1,2-oxazolidin-2-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](1,2-oxazolidin-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1,3-oxazolidin-3-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](1,3-oxazolidin-3-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](oxolan-2-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](oxolan-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](pyrrolidin-1-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](1,2-oxazinan-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1,2-oxazinan-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1,3-oxazinan-3-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](1,3-oxazinan-3-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](morpholin-4-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](morpholin-4-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](piperidin-1-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](pyrrolidin-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1-methylpyrrolidin-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1H-pyrrol-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1-methyl-1H-pyrrol-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](furan-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](thiophen-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1H-pyrrol-1-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](pyridin-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](pyridin-3-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](pyridin-4-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1H-imidazol-1-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1H-pyrazol-1-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1,2-oxazepan-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](5-oxa-6-azaspiro[2.4]heptan-6-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](5-methyl-1,2-oxazolidin-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](hexahydro-2H-cyclopenta[d][1,2]oxazol-2-yl)methanone,
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1H-1,2,3-triazol-1-yl)methanone and
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1-methyl-1H-tetrazol-5-yl)methanone.

### Claim 11 (depends on 1)

The compound according to claim 1, which is selected from the group consisting of:
[2-(3-fluorophenyl)-4-hydroxy-1,3-thiazol-5-yl](1,2-oxazolidin-2-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](1,2-oxazolidin-2-yl)methanone,
[4-hydroxy-2-(2-hydroxyphenyl)-1,3-thiazol-5-yl](1,2-oxazinan-2-yl)methanone and
[2-(3-fluorphenyl)-4-hydroxy-1,3-thiazol-5-yl](1,2-oxazinan-2-yl)methanone.

### Claim 12 (depends on 1)

A method of treating a disease associated with the overexpression and/or hyperactivity of TRPM8, wherein the disease is selected from the group consisting of pain, itch, irritable bowel diseases, cold induced and/or exhacerbated respiratory disorders, ischaemia, stroke, urological disorders, psychiatric disorders and corneal disorders associated with disturbances in the production of the tears and/or altered blinking in a subject in need thereof, comprising administration of an effective amount of the compound according to claim 1.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the disease is selected from the group consisting of chronic pain, cancer pain, neuropathic pain, cold allodynia, postoperative pain, neuralgia, neuropathies, diabetic neuropathy, fibromyalgia, algesia, pain associated with nerve injury, migraine, headache, pain associated with osteoarthritis and rheumatoid arthritis, itch, irritable bowel disease, painful bladder syndrome, interstitial cystitis, detrusor overactivity, urinary incontinence, neurogenic detrusor overactivity, idiopathic detrusor overactivity, benign prostatic hyperplasia, lower urinary tract disorders, anxiety, depression and cold-induced/or exhacerbated pulmonary hypertension, COPD, asthma, epiphora and dry eye disease.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising as the active ingredient at least one compound according to claim 1 in combination with pharmaceutically acceptable excipients and/or diluents.