# US 2016/0257656 A1 · Heterocyclic compounds and methods for their use

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- Number: US 2016/0257656 A1
- Document ID: US20160257656A1
- Status: Published application
- Kind: A1
- Application number: 15/149,641
- Filed: 2016-05-09
- Published: 2016-09-08
- Earliest claimed: 2012-01-25
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Thomas David McCarthy; Alan Naylor
- Web page: https://patentgrep.com/patent/US20160257656A1

## CPC

- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 35/00: Antineoplastic agents
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 243/08: not condensed with other rings
- C07D 295/185: from aliphatic carboxylic acids
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to heterocyclic compounds useful for antagonising angiotensin II Type 2 (AT2) receptor. More particularly the invention relates to piperazine and diazepine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT2 receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.

## Claims

### Claim 1

A compound of formula (I):
wherein
X is —CHR4—, —CH2CHR4— or —C(═O)—;
R1 is —C(═O)CHR5R6, —C(═O)NR5R6, —C(═O)CH2CHR5R6, —C(═O)CH═CR5R6, —C(═S)CHR5R6, —C(═S)NR5R6, —C(═S)CH2CHR5R6, —C(═S)CH═CR5R6, —C(═NR7)CHR5R6, —C(═NR7)NR5R6, —C(═NR7)CH2CHR5R6 or —C(═NR7)CH═CR5R6;
R2 is —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —C(═O)R8, —C(═O)NHR7, —SO2N(R7)2, —W-cycloalkyl, —W-cycloalkenyl, —W-aryl, —W-heterocyclyl, —W-heteroaryl, —W—Z—Y-cycloalkyl, —W—Z—Y-cycloalkenyl, —W—Z—Y-aryl, —W—Z—Y-heterocyclyl or —W—Z—Y-heteroaryl;
R3 is a carboxylic acid, —CH2CO2H, —C(═O)C(═O)OH, —C(═O)NH2, —CH2C(═O)NH2, —CN, —CH2CN, a carboxylic acid bioisostere or a —CH2-carboxylic acid bioisotere;
R4 is hydrogen or together with R2 forms a fused cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring optionally substituted with one or two substituents selected from —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —C1-6alkyleneR9, —C2-6alkenyleneR9, —C2-6alkynyleneR9, —OC0-6alkyleneR9, —OC2-6alkenyleneR9, —OC2-6alkynyleneR9, —C(═O)C0-6alkyleneR9, —C(═O)C2-6alkenyleneR9, —C(═O)C2-6alkynyleneR9, —C(═O)OC0-6alkyleneR9, —C(═O)OC2-6alkenyleneR9, —C(═O)OC2-6alkynyleneR9, —SO2NHC0-6alkyleneR9, —SO2NHC2-6alkenyleneR9, —SO2NHC2-6alkynyleneR9, —NHSO2C0-6alkyleneR9, —NHSO2C2-6alkenyleneR9, —NHSO2C2-6alkynyleneR9, —NH(═O)NHR10, —NHC(═O)OR10 or —CH(OH)CH(OH)R10;
R5 and R6 are independently selected from hydrogen, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —CH2cycloalkyl, —CH2cycloalkenyl, —CH2aryl, —CH2heterocyclyl and —CH2heteroaryl; provided that both R5 and R6 are not hydrogen;
R7 is hydrogen, —C1-6alkyl, aryl or —C1-6alkylenearyl;
R8 is —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, aryl or —C2-6alkylenearyl;
R9 is cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl;
R10 is —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl;
W is a covalent bond, —SO—, —SO2— —C(═O)—, —C(═O)N(H)—, —C1-4alkylene-, —C2-4alkenylene-, —C2-4alkynylene-, —C1-3alkyleneQC1-3 alkylene-, —C1-4alkyleneQ-, —C2-4alkenyleneQ- or —C2-4alkynyleneQ-;
Z is -cycloalkyl-, -cycloalkenyl-, -aryl-, -heterocyclyl- or -heteroaryl-;
Y is a covalent bond, —O—, —S—, —SO—, —SO2— —N(R7)—, —C(═O)—, —N(R7)C(═O)—, —C(═O)N(R7)—, —C1-3alkylene-, —C2-3alkenylene-, —C2-3alkynylene-, —C1-3alkyleneQC1-3alkylene-, -QC1-4alkylene-, -QC2-4 alkenylene-, -QC2-4alkynylene-, —C1-4alkyleneQ-, —C2-4alkenyleneQ-, —C2-4alkynyleneQ- -QC1-4 alkyleneQ-, -QC2-4alkenyleneQ- or -QC2-4alkynyleneQ-; and
Q is —O—, —S—, —SO—, —SO2— —N(R7)—, —C(═O)—, —N(R7)C(═O)— or —C(═O)N(R7)—;
wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl is optionally substituted;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein X is —CH2— or —CH2CH2—.

### Claim 3 (depends on 2)

A compound according to claim 2 wherein X is —CH2—.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R1 is —C(═O)CH(aryl)(aryl), —C(═O)CH(aryl)(cycloalkyl), —C(═O)CH(cycloalkyl)(cycloalkyl), —C(═O)N(aryl)(aryl), —C(═O)N(aryl)(cycloalkyl) or —C(═O)N(cycloalkyl)(cycloalkyl) wherein each aryl or cycloalkyl is optionally substituted with one or more substituents selected from —C1-3alkyl, —OC1-3 alkyl and halo.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein R1 is —C(═O)CH(phenyl)(phenyl), —C(═O)CH(phenyl)(cyclohexyl), —C(═O)CH(cyclohexyl)(cyclohexyl), —C(═O)N(phenyl)(phenyl), —C(═O)N(phenyl)(cyclohexyl) or —C(═O)N(cyclohexyl)(cyclohexyl) wherein each phenyl or cyclohexyl is optionally substituted with one or more substituents selected from —C1-3alkyl, —OC1-3alkyl and halo.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein R2 is —C1-6alkyl, —C2-6alkenyl, -cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, heterocyclylaryl, —C1-4alkylenecycloalkyl, —C1-4alkylenecycloalkenyl, —C1-4alkylenearyl, —C1-4alkyleneheterocyclyl, —C1-4alkyleneheteroaryl, —C2-4alkenylenecycloalkyl, —C2-4alkenylenecycloalkenyl, —C2-4alkenylenearyl, —C2-4alkenyleneheterocyclyl, —C2-4alkenyleneheteroaryl, —C2-4alkynylenecycloalkyl, —C2-4alkynylenecycloalkenyl, —C2-4alkynylenearyl, —C2-4alkynyleneheterocyclyl, —C2-4alkynyleneheteroaryl, -heterocyclylaryl, heteroarylaryl, -heterocyclylC1-3 alkylenearyl, —C1-3alkyleneheterocyclylaryl, —C1-3 alkyleneheteroarylaryl, —CH2C(═O)NHCH2cycloalkyl, —CH2C(═O)NHCH2cycloalkenyl, —CH2C(═O)NHCH2aryl, —CH2C(═O)NHCH2heterocyclyl, —CH2C(═O)NHCH2heteroaryl, —C(═O)NHC1-3alkylenecycloalkyl, —C(═O)NHC1-3 alkylenecycloalkenyl, —C(═O)NHC1-3 alkylenearyl, —C(═O)NHC1-3 alkyleneheterocyclyl, —C(═O)NHC1-3alkyleneheteroaryl, —CH2SO2C1-3 alkylenecycloalkyl, —CH2SO2C1-3 alkylenecycloalkenyl, —CH2SO2C1-3 alkylenearyl, —CH2SO2C1-3alkyleneheterocyclyl, —CH2SO2C1-3alkyleneheteroaryl, —CH2OC1-3alkylenecycloalkyl, —CH2OC1-3 alkylenecycloalkenyl, —CH2OC1-3 alkylenearyl, —CH2OC1*3 alkyleneheterocyclyl or —CH2OC1-3alkyleneheteroaryl; wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one or two substituents.

### Claim 7 (depends on 6)

A compound according to claim 6 wherein R2 is phenyl, benzyl, —CH2CH2phenyl, —CH2CH═CH-phenyl, —CH2C≡C-phenyl, —CH2C≡C-4-fluorophenyl, —CH2CH2C≡C-phenyl, —CH2CH2C≡C-4-fluorophenyl, —CH2CH2CH2phenyl, -2-methylbutyl, -5-(3-methyl-1-phenylpyrazole), -3-(1,5-diphenylpyrazole), -3-(5-phenylpyrazole), -3-(5-methyl-1-phenylpyrazole), 3-(5-(1-methylethyl)-1-phenylpyrazole, -2-(5-phenyloxazole), -5-(5-benzyloxazole), -5-(1-benzyl-3-methylpyrazole), -3-(1-benzyl-5-methylpyrazole, —CH2-4-(2-phenyloxazole), -5-(1-benzyl)-3-trifluoromethylpyrazole and -5-(1-benzyl-3-methylpyrazole, wherein each cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl is optionally substituted.

### Claim 8 (depends on 1)

A compound according to claim 1 wherein R3 is —CO2H, —CH2CO2H, —C(═O)NH2, —CN, —C(═O)C(═O)OH, —C(═O)NHSO2C1-6alkyl, —C(═O)NHSO2phenyl, —C(O)NHSO2N(CH3)2, —C(═O)NHSO2CF3—SO3H or —PO3H2.

### Claim 9 (depends on 8)

A compound according to claim 8 wherein R3 is —CO2H.

### Claim 10 (depends on 1)

A compound according to claim 1 wherein R4 is H.

### Claim 11 (depends on 1)

A compound according to claim 1 wherein R2 and R4 together form a fused aryl, heterocyclyl or heteroaryl ring optionally substituted with one or two substituents selected from -aryl, —C1-3alkylenearyl, —Oaryl, —OC1-3alkylenearyl and —C(═O)OC1-3alkylenearyl.

### Claim 12 (depends on 11)

A compound according to claim 11 wherein R2 and R4 together form a fused heterocyclyl or heteroaryl ring optionally substituted with phenyl, benzyl, —Obenzyl, or —CO2benzyl.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 1)

A method of treating or preventing neuropathic pain or inflammatory pain in a subject comprising administering a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

A method of treating or preventing a condition characterized by neuronal hypersensitivity, impaired nerve conduction velocity, a cell proliferative disorder, a disorder associated with an imbalance between bone resorption and bone formation or a disorder associated with aberrant nerve regeneration in a subject comprising administering a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A method of producing analgesia in a subject comprising administering a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.