# US 9,434,693 B2 · Substituted pyrazoles as N-type calcium channel blockers

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- Number: US 9,434,693 B2
- Document ID: US9434693B2
- Status: Granted
- Kind: B2
- Application number: 13/968,465
- Filed: 2013-08-16
- Published: 2014-06-12
- Granted: 2016-09-06
- Earliest claimed: 2012-08-16
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Mark Wall; Nalin Subasinghe; Zhihua Sui; Christopher Flores
- Web page: https://patentgrep.com/patent/US9434693B2

## CPC

- C07D 231/22: with aryl radicals attached to ring nitrogen atoms
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/18: Antioxidants, e.g. antiradicals (preparations for protection against sunlight A61Q17/00)
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 33/14: Ectoparasiticides, e.g. scabicides
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: wherein R1, R2, ring A, and G are defined herein.

## Claims

### Claim 1

A compound of Formula (I)
wherein
R1 is selected from the group consisting of C1-4alkyl, C1-4alkoxy, di(C1-4alkyl)amino, chloro, trifluoromethoxy, trifluoromethyl, and cyano;
ring A is phenyl or a heteroaryl selected from the group consisting of pyridinyl, thienyl, benzofuranyl, quinolinyl, and indolyl;
R2 is selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-4alkylthio, cyano, fluoro, chloro, hydroxy, and di(C1-4alkyl)amino;
G is G1, G2, G3, or G4;
wherein
Q is selected from the group consisting of O, S, SO2, N—R4, CH2,CH(R5), CF2, C(CH3)2, C(O), and a spirofused
W is selected from the group consisting of O, S, CH(OH), C(O), S(O), SO2, and N—R4;
R3 and R4 are each independently selected from the group consisting of 2,2,2-trifluoroethyl, di(C1-4alkyl)aminocarbonyl, N-methoxy-N-methylaminocarbonyl, phenylcarbonyl, C1-4alkylcarbonyl, trifluoromethylcarbonyl, C1-4alkoxycarbonyl, C3-7cycloalkylsulfonyl, trifluoromethylsulfonyl, and 3,5-dimethylisoxazol-4-ylsulfonyl;
R5 is trifluoromethylcarbonylamino, amino, or C1-4alkoxycarbonylamino; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R1 is selected from the group consisting of C1-4alkyl, C1-4alkoxy, chloro, trifluoromethoxy, trifluoromethyl, and cyano.

### Claim 3 (depends on 2)

The compound of claim 2 wherein R1 is selected from the group consisting of C1-4alkyl, C1-4alkoxy, chloro, and trifluoromethyl.

### Claim 4 (depends on 3)

The compound of claim 3 wherein R1 is selected from the group consisting of methyl, ethyl, methoxy, and isopropyloxy.

### Claim 5 (depends on 1)

The compound of claim 1 wherein ring A is phenyl.

### Claim 6 (depends on 5)

The compound of claim 5 wherein ring A is phenyl substituted at the 4-position.

### Claim 7 (depends on 1)

The compound of claim 1 wherein R2 is selected from the group consisting of C1-4alkoxy, cyano, and chloro.

### Claim 8 (depends on 7)

The compound of claim 7 wherein R2 is selected from the group consisting of methoxy, cyano, and chloro.

### Claim 9 (depends on 1)

The compound of claim 1 wherein G is G1, G2, G3, or G4;
wherein
Q is selected from the group consisting of O, S, SO2, N—R4, CH2, CH(R5), CF2, C(CH3)2, C(O), and a spirofused
W is selected from the group consisting of O, S, CH(OH), C(O), S(O), and SO2;
R3 and R4 are each independently selected from the group consisting of 2,2,2-trifluoroethyl, di(C1-4alkyl)aminocarbonyl, N-methoxy-N-methylaminocarbonyl, phenylcarbonyl, C1-4alkylcarbonyl, trifluoromethylcarbonyl, C1-4alkoxycarbonyl, C3-7cycloalkylsulfonyl, trifluoromethylsulfonyl, and 3,5-dimethylisoxazol-4-ylsulfonyl; and
R5 is trifluoromethylcarbonylamino or C1-4alkoxycarbonylamino.

### Claim 10 (depends on 1)

The compound of Formula (I) as in claim 1
wherein
R1 is selected from the group consisting of C1-4alkyl, C1-4alkoxy, chloro, trifluoromethoxy, trifluoromethyl, and cyano;
ring A is phenyl or a heteroaryl selected from the group consisting of pyridinyl, thienyl, benzofuranyl, quinolinyl, and indolyl;
R2 is selected from the group consisting of C1-4alkoxy, cyano, and chloro;
G is G1, G2, G3, or G4;
wherein
Q is selected from the group consisting of O, S, SO2, N—R4, CH2, CH(R5), CF2, C(CH3)2, C(O), and a spirofused
W is selected from the group consisting of O, S, CH(OH), C(O), S(O), and SO2;
R3 and R4 are each independently selected from the group consisting of 2,2,2-trifluoroethyl, di(C1-4alkyl)aminocarbonyl, N-methoxy-N-methylaminocarbonyl, phenylcarbonyl, C1-4alkylcarbonyl, trifluoromethylcarbonyl, C1-4alkoxycarbonyl, C3-7cycloalkylsulfonyl, trifluoromethylsulfonyl, and 3,5-dimethylisoxazol-4-ylsulfonyl;
R5 is trifluoromethylcarbonylamino or C1-4alkoxycarbonylamino;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 1)

The compound of Formula (I) as in claim 1
wherein
R1 is selected from the group consisting of C1-4alkyl, C1-4alkoxy, chloro, and trifluoromethyl;
ring A is phenyl;
R2 is selected from the group consisting of C1-4alkoxy, cyano, and chloro;
G is G1, G2, G3, or G4;
wherein
Q is selected from the group consisting of O, S, SO2, N—R4, CH2, CH(R5), CF2, C(CH3)2, C(O), and a spirofused
W is selected from the group consisting of O, S, CH(OH), C(O), S(O), and SO2;
R3 and R4 are each independently selected from the group consisting of 2,2,2-trifluoroethyl, di(C1-4alkyl)aminocarbonyl, N-methoxy-N-methylaminocarbonyl, phenylcarbonyl, C1-4alkylcarbonyl, trifluoromethylcarbonyl, C1-4alkoxycarbonyl, C3-7cycloalkylsulfonyl, trifluoromethylsulfonyl, and 3,5-dimethylisoxazol-4-ylsulfonyl;
R5 is trifluoromethylcarbonylamino or C1-4alkoxycarbonylamino;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

### Claim 12 (depends on 1)

The compound of Formula (I) as in claim 1
wherein
R1 is selected from the group consisting of methyl, ethyl, methoxy, and isopropyloxy;
ring A is phenyl substituted at the 4-position;
R2 is selected from the group consisting of methoxy, cyano, and chloro;
G is G1, G2, G3, or G4;
wherein
Q is selected from the group consisting of O, S, SO2, N—R4, CH2, CH(R5), CF2, C(CH3)2, C(o), and a spirofused
W is selected from the group consisting of O, S, CH(OH), C(O), S(O), and SO2;
R3 and R4 are each independently selected from the group consisting of 2,2,2-trifluoroethyl, di(C1-4alkyl)aminocarbonyl, N-methoxy-N-methylaminocarbonyl, phenylcarbonyl, C1-4alkylcarbonyl, trifluoromethylcarbonyl, C1-4alkoxycarbonyl, C3-7cycloalkylsulfonyl, trifluoromethylsulfonyl, and 3,5-dimethylisoxazol-4-ylsulfonyl;
R5 is trifluoromethylcarbonylamino or C1-4alkoxycarbonylamino;
and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof.

### Claim 13 (depends on 1)

The compound of Formula (I) as in claim 1
selected from the group consisting of
tert-Butyl 4-{[5-(4-chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}piperidine -1-carboxylate;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}cyclohexanone;
1-Acetyl-4-{[5-(4-chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}piperidine;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N,N -dimethylpiperidine-1-carboxamide;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-(tetrahydro-2H-pyran-4-yloxy)-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-(tetrahydro-2H-thiopyran-4-yloxy)-1H-pyrazole;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-1-(2,2,2-trifluoroethyl)piperidine;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-1-(trifluoroacetyl)piperidine;
5-(4-Chlorophenyl)-3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-1-(2-methoxyphenyl)-1H-pyrazole;
tert-Butyl(cis-4-{[5-(4-chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}cyclohexyl)carbamate;
cis-4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}cyclohexanamine;
N-(cis-4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}cyclohexyl)-2,2,2-trifluoroacetamide;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-1-[(trifluoromethyl)sulfonyl]piperidine;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-1-(cyclopropylsulfonyl)piperidine;
5-(4-Chlorophenyl)-3-[(4,4-difluorocyclohexyl)oxy]-1-(2-methoxyphenyl)-1H-pyrazole;
5-(4-Chlorophenyl)-3-(1,4-dioxaspiro[4.5]dec-8-yloxy)-1-(2-ethylphenyl)-1H-pyrazole;
tert-Butyl 4-{[5-(4-chlorophenyl)-1-(2-ethylphenyl)-1H-pyrazol-3-yl]oxy}piperidine-1-carboxylate;
4-{[5-(4-Chlorophenyl)-1-(2-ethylphenyl)-1H-pyrazol-3-yl]oxy}-1-(methylsulfonyl)piperidine;
4-({5-(4-Chlorophenyl)-1-[2-(1-methylethoxy)phenyl]-1H-pyrazol-3-yl}oxy)-1-(methylsulfonyl)piperidine;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-1-[(1-methylethyl)sulfonyl]piperidine;
tert-Butyl 3-{[5-(4-chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}azetidine-1-carboxylate;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-[(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy]-1H-pyrazole;
4-{[1-(2-tert-Butoxyphenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy}-1-(methylsulfonyl)piperidine;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-({1-[(1-methylethyl)sulfonyl]azetidin-3-yl }oxy)-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-{[1-(methylsulfonyl)azetidin-3-yl]oxy}-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-{[1-(phenylcarbonyl)azetidin-3-yl]oxy}-1H-pyrazole;
4-({5-(4-Chlorophenyl)-1-[2-(1-methylethoxy)phenyl]-1H-pyrazol-3-yl}oxy)-1-[(1-methylethyl)sulfonyl]piperidine;
3-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)- 1H-pyrazol-3-yl]oxy}-N-methoxy-N-methylazetidine-1-carboxamide;
4-[(3-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}azetidin-1-yl)sulfonyl]-3,5-dimethylisoxazole;
1-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-3-[(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy]-1H-pyrazole;
1-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-3-[(2,2,6,6-tetramethyltetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazole;
1-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-3-[(2,2,6,6-tetramethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazole;
1-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-3-[(2,2,6,6-tetramethyl-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazole;
1-(2-Methoxyphenyl)-5-(4-methoxyphenyl)-3-[(2,2,6,6-tetramethyl-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-[(2,2,6,6-tetramethyltetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-[(2,2,6,6-tetramethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-{[(1s)-2,2,6,6-tetramethyl-1-oxidotetrahydro-2H-thiopyran-4-yl]oxy}-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-{[(1r)-2,2,6,6-tetramethyl-1-oxidotetrahydro-2H-thiopyran-4-yl]oxy}-1H-pyrazole;
5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-3-[(2,2,4,4-tetramethyloxetan-3-yl)methoxy]-1H-pyrazole;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-2,2,6,6-tetramethylcyclohexanone;
4-{[5-(4-Chlorophenyl)-1-(2-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-2,2,6,6-tetramethylcyclohexanol;
4-{1-(2-Methoxyphenyl)-3-[(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)oxy]-1H-pyrazol-5-yl }benzonitrile;
4-{1-(2-Methoxyphenyl)-3-[(2,2,6,6-tetramethyltetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazol-5-yl }benzonitrile;
4-{1-(2-Methoxyphenyl)-3-[(2,2,6,6-tetramethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-1H-pyrazol-5-yl }benzonitrile;
4-[1-(2-Methoxyphenyl)-3-{[(1s)-2,2,6,6-tetramethyl-1-oxidotetrahydro-2H-thiopyran-4-yl]oxy}-1H-pyrazol-5-yl]benzonitrile;
and pharmaceutically acceptable salt forms thereof.

### Claim 14 (depends on 1, 13)

A pharmaceutical composition comprising a compound of claim 1 or 13 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and a pharmaceutically acceptable diluent.

### Claim 15 (depends on 14)

A pharmaceutical composition of claim 14, wherein the composition is a solid oral dosage form.

### Claim 16 (depends on 14)

A pharmaceutical composition of claim 14, wherein the composition is a syrup, an elixir or a suspension.

### Claim 17 (depends on 1, 13)

A method for treating inflammatory pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 13.

### Claim 18 (depends on 17)

The method of claim 17 wherein the inflammatory pain is due to inflammatory bowel disease, visceral pain, migraine, post-operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pain, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic/overactive bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache or arachnoiditis.

### Claim 19 (depends on 1, 13)

A method for treating neuropathic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 13.

### Claim 20 (depends on 19)

The method of claim 19 wherein the neuropathic pain is cancer pain, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), chemotherapy-induced pain, pain chronification, radicular pain, HIV pain, spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian neuralgia.