# US 10,308,628 B2 · Heterocyclic compounds and methods for their use

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- Number: US 10,308,628 B2
- Document ID: US10308628B2
- Status: Granted
- Kind: B2
- Application number: 15/556,593
- Filed: 2016-03-09
- Published: 2018-03-01
- Granted: 2019-06-04
- Earliest claimed: 2015-03-12
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Jane Brown; Thomas David McCarthy; Alan Naylor; John Paul Watts
- Web page: https://patentgrep.com/patent/US10308628B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/12: Keratolytics, e.g. wart or anti-corn preparations
- 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 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 29/02: without antiinflammatory effect
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- 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 compounds of formula (I), as described herein, 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 Ring G is a 5 to 8 membered ring and
X is absent or is selected from —(CR6R7)n—, —W—, —(CR6R7)m—W—, —W—(CR6R7)m— and —(CR6R7)p—W—(CR6R7)p—;
Y is —CR8CR9— wherein R8 and R9 together with the carbon atoms to which they are attached form an optionally substituted aromatic or heteroaromatic ring or ring system;
Z is absent or is selected from —CR4R5—, —CR6R7CR4R5—, —W—CR4R5—;
W is selected from —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —NR10—, —C(O)N(R11)—, —N(R11)C(O)—, —C(O)O—, —OC(O)—, —S(O)2N(R11)—, —N(R11)S(O)2—, —N(R11)C(O)N(R11)— and —N(R11)S(O)2N(R11)—;
R1 is selected from —CO2H, —CH2CO2H, —C(O)C(O)OH, —CH2OH, —C(O)NH2, — CN, —CH2C(O)NH2, —CH2CN, a carboxylic acid bioisostere and —CH2carboxylic acid bioisostere;
R2 is selected from hydrogen, alkyl, alkenyl, alkynyl, —C1-6alkyleneR12, —C2-6alkenyleneR12 and —C2-6alkynyleneR12;
R3 is selected from —C(O)CH(aryl)(aryl) and —C(O)N(aryl)(aryl);
Each R4 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, —OC(R14)3, —CN, —NO2, —N(R13)2, —CO2R13, — C(O)R13, —C(O)N(R13)2, —S(O)2R13, —S(O)2N(R13)2, —C(R14)3, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl, or R4 and R5 taken together form a carbonyl group;
R6 and R7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, —OR13, —SR13, halo, —CN, —NO2, —N(R13)2, —CO2R13, —C(O)R13, —C(O)N(R13)2, —S(O)2R13, S(O)2N(R13)2, —C(R14)3, —OC(R14)3, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl, or R6 and R7 taken together form a carbonyl group;
R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —C(R14)3, —C(O)R13, —C(O)N(R13)2, —S(O)R13, —S(O)2R13, —S(O)2N(R13)2 and —CO2R13;
R11 is selected from hydrogen and alkyl;
R12 is selected from cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl;
Each R13 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl;
Each R14 is independently selected from hydrogen and halo;
n is selected from an integer from 1 to 4;
m is selected from an integer from 1 to 3;
p is selected from an integer of 1 or 2;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl may be optionally substituted; or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of formula (I), according to claim 1,
wherein Ring G is a 5 to 8 membered ring and
X is —(CR6R7)n— or —(CR6R7)m—W—;
Y is —CR8CR9— wherein R8 and R9 together with the carbon atoms to which they are attached form an optionally substituted phenyl;
Z is absent;
W is —O— or —S(O)2—;
R1 is —CO2H or a carboxylic acid bioisostere;
R2 is hydrogen;
R3 is —C(O)CH(aryl)(aryl);
R4 and R5 are hydrogen;
R6 and R7 are hydrogen;
n is selected from an integer from 1 to 4;
m is selected from an integer from 1 to 3;
or
a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R1 is —CO2H or 13 C(O)NHSO2C3-8cycloalkyl, or
a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R3 is —C(O)CH(phenyl)(phenyl), or
a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein n is 1, 2 or 4, or
a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

A compound according to claim 1 which is a compound of formula (II):
wherein
X is selected from —(CR6R7)n—, —W—, —(CR6R7)m—W—, —W—(CR6R7)m— and —(CR6R7)p—W—(CR6R7)p—;
Ar is an aromatic or heteroaromatic ring or ring system;
R1 is selected from —CO2H, —CH2CO2H, —C(O)C(O)OH, —CH2OH, —C(O)NH2,— CN, —CH2C(O)NH2, —CH2CN, a carboxylic acid bioisostere and —CH2carboxylic acid bioisostere;
R2 is selected from hydrogen, alkyl, alkenyl, alkynyl, —C1-6alkyleneR12, —C2-6alkenyleneR12 and —C2-6alkynyleneR12;
R3 is selected from —C(O)CH(aryl)(aryl) and —C(O)N(aryl)(aryl);
Each R4 and R5 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, —OC(R14)3, —CN, —NO2, —N(R13)2, —CO2R13, —C(O)R13, —C(O)N(R13)2, —S(O)2R13, —S(O)2N(R13)2, —C(R14)3, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl, or R4 and R5 taken together from a carbonyl group;
R6 and R7 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, —OR13, —SR13, halo, —CN, —NO2, —N(R13)2, —CO2R13, —C(O)R13, —C(O )N(R13)2, —S(O)2R13, S(O)2N(R13 )2, —C(R14)3, —OC(R14)3, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl, or R6 and R7 taken together form a carbonyl group;
W is selected from —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —NR10—, —C(O)N(R11)—, —N(R11)C(O)—, —C(O)O—, —OC(O)—, —S(O)2N(R11)—, —N(R11)S(O)2—, —N(R11)C(O)N(R11)— and —N(R11)S(O)2N(R11)—;
R10 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —C(R14)3, —C(O)R13, —C(O)N(R13)2, —S(O)R13, —S(O)2R13, —S(O)2N(R13)2 and —CO2R13;
R11 is selected from hydrogen and alkyl;
R12 is selected from cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl;
Each R13 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl;
Each R14 is independently selected from hydrogen and halo;
Each R15 is independently selected from —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —OR13, —SR13, halo, —CN, —NO2, —N(R13)2, —CO2R13, —CON(R13)2, —C(O)R13, —S(O)2R13, —S(O)2N(R13)2, —C(R14)3, —OC(R14)3, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl;
m is selected from an integer from 1 to 3;
n is selected from an integer from 1 to 4;
p is selected from an integer of 1 or 2; and
q is 0 or an integer of 1 to 4;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl may be optionally substituted; or
a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 7)

A compound of formula (II), according to claim 7,
wherein
X is —(CR6R7)n— or —(CR6R7)m—W—;
Ar is an aromatic ring system;
R1 is —CO2H or a carboxylic acid bioisostere;
R2 is hydrogen;
R3 is —C(O)CH(aryl)(aryl);
R4 and R5 are hydrogen;
R6 and R7 are hydrogen;
W is —O— or —S(O)2—;
R13 is alkyl;
Each R15 is independently selected from —C1-6alkyl, —OR13, halo and —CN;
m is selected from an integer from 1 to 3;
n is selected from an integer from 1 to 4;
q is 0 or an integer of 1 to 4;
or
a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 7)

A compound according to claim 7, wherein
R1 is —CO2H or —C(O)NHSO2C3-8cycloalkyl;
R3 is —C(O)CH(phenyl)(phenyl); and
Ar is phenyl; or
a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 7)

A compound according to claim 7, wherein
n is 1, 2 or 4;
m is 1 or 2; and
q is 1 or 2; or
a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

A compound accordingly to claim 1, wherein the compound is selected from the group consisting of:
(2S,4R)-4-(7,8-Difluoro-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-1-(2,2-diphenylacetyl)piperidine-2-carboxylic acid;
(2S,4R)-1-(2,2-Diphenylacetyl)-4-(8-fluoro-3,4 dihydrobenzo[b][1,4]oxazepin-5(2H) -yl)piperidine-2-carboxylic acid;
(2S,4R)-1-(2,2-Diphenylacetyl)-4-(7-fluoro-3,4dihydrobenzo[b][1,4]oxazepin-5(2H) -yl)piperidine-2-carboxylic acid;
(2S,4R)-4-(3,4-Dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)-1-(2,2-diphenylacetyl)piperidine-2-carboxylic acid; and
(2S,4R)-1-(2,2-diphenylacetyl)-4-(7-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)piperidine-2-carboxylic acid,
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

A pharmaceutical composition comprising an effective amount of a compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 1)

A compound accordingly to claim 1, wherein the compound is selected from the group consisting of:
(2S,4R)-1-(2,2-diphenylacetyl)-4-(2,3,4,5 -tetrahydro-1H-benzo[b] azepin-1-yl)piperidine -2carboxylic acid;
(2S,4R)-4-(7,8-difluoro-2,3 ,4, 5-tetrahydro-1H-benzo[b]azepin-1-yl)-1-(2,2-diphenylacetyl)piperidine-2-carboxylic acid;
(2S,4R)-1-(2,2-diphenylacetyl)-4-(7-fluoro-2,3 ,4,5 -tetrahydro-1H-benz[b]azepin-1-yl)piperidine-2-carboxylic acid;
(2S,4R)-1-(2,2-diphenylacetyl)-4-(8-fluoro-2,3 ,4,5 -tetrahydro-1H-benzo[b]azepin-1-yl)piperidine-2-carboxylic acid; and
(2S,4S)-1-(2,2-diphenylacetyl)-4-(8-fluoro-2,3 ,4,5 -tetrahydro-1H-benzo[b]azepin-1-yl)piperidine-2-carboxylic acid,
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

A pharmaceutical composition comprising an effective amount of a compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.