# US 11,299,475 B2 · Prostacyclin receptor agonist

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- Number: US 11,299,475 B2
- Document ID: US11299475B2
- Status: Granted
- Kind: B2
- Application number: 16/967,546
- Filed: 2019-02-02
- Published: 2021-03-25
- Granted: 2022-04-12
- Earliest claimed: 2018-02-07
- Assignees: Medshine Discovery Inc.
- Applicants: Medshine Discovery Inc.
- Inventors: Wenyuan Qian; Chundao Yang; Guanghai Xu; Jian Li; Shuhui Chen
- Web page: https://patentgrep.com/patent/US11299475B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 25/06: Antimigraine agents
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound represented by formula (I) or an isomer or a pharmaceutically acceptable salt thereof. The present invention also relates to an application of the same in preparing a drug for treating a disease related to a PGI2 receptor.

## Claims

### Claim 1

A compound represented by formula (I), an isomer or a pharmaceutically acceptable salt thereof,
wherein,
n is 1 or 2;
R1 is H or F;
each of R2 is independently selected from the group consisting of H, OH, NH2, halogen, C1-6 alkyl and C1-6 heteroalkyl, wherein C1-6 alkyl and C1-6 heteroalkyl are optionally substituted by one, two or three of Rb;
each of Rb is independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R3 is selected from the group consisting of H, OH, NH2, halogen, C1-6 alkyl and C1-6 heteroalkyl, wherein C1-6 alkyl and C1-6 heteroalkyl are optionally substituted by one, two or three of Rc;
each of Rc is independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
R4 is selected from the group consisting of OH, C1-6 alkoxy and C1-6 alkyl-S(═O)2—NH—, wherein C1-6 alkoxy and C1-6 alkyl-S(═O)2—NH— are optionally substituted by one, two or three of Rd;
each of Rd is independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
ring A is a phenyl or a 5- to 6-membered heteroaryl;
ring B is a phenyl, a 5- to 6-membered heteroaryl, a C3-6 cycloalkyl or a 3- to 6-membered heterocycloalkyl;
T1 is N or CH;
T2 is N or CH;
T3 is N or CH;
T4 is N or C(R5);
T5 is N, CH or C;
R5 is selected from the group consisting of H, OH, NH2, halogen, C1-6 alkyl and C1-6 heteroalkyl, wherein C1-6 alkyl and C1-6 heteroalkyl are optionally substituted by one, two or three of Re;
each of Re is independently selected from the group consisting of F, Cl, Br, I, OH and NH2;
each of C1-6 heteroalkyl, 3- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl respectively contains one, two or three of heteroatoms or heteroatomic groups independently selected from the group consisting of —O—, —NH—, —S— and N.

### Claim 2 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein each of R2 is independently selected from the group consisting of H, OH, NH2, halogen, C1-3 alkyl and C1-3 alkoxy, wherein C1-3 alkyl and C1-3 alkoxy are optionally substituted by one, two or three of Rb;
preferably, each of R2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, Me and
wherein Me and
are optionally substituted by one, two or three of Rb;
preferably, each of R2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH2, Me, CF3,

### Claim 3 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R3 is selected from the group consisting of H, OH, NH2, halogen, C1-3 alkyl and C1-3 alkoxy, wherein C1-3 alkyl and C1-3 alkoxy are optionally substituted by one, two or three of Rc;
preferably, R3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, Me and
wherein Me and
are optionally substituted by one, two or three of Rc;
preferably, R3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH2, Me, CF3,

### Claim 4 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R4 is selected from the group consisting of OH, C1-3 alkoxy and C1-3 alkyl-S(═O)2—NH—, wherein C1-3 alkoxy and C1-3 alkyl-S(═O)2—NH— are optionally substituted by one, two or three of Rd;
preferably, R4 is selected from the group consisting of OH,
wherein
are optionally substituted by one, two or three of Rd;
preferably, R4 is selected from the group consisting of OH,

### Claim 5 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein R5 is selected from the group consisting of H, OH, NH2, halogen, C1-3 alkyl and C1-3 alkoxy, wherein C1-3 alkyl and C1-3 alkoxy are optionally substituted by one, two or three of Re;
preferably, R5 is selected from the group consisting of H, OH, NH2, F, Cl, Br, I, Me and
wherein Me and
are optionally substituted by one, two or three of Re;
preferably, R5 is selected from the group consisting of H, OH, NH2, F, Cl, Br, I, Me and

### Claim 6 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein T1 is CH, T2 is CH and T3 is CH;
alternatively, T1 is N, T2 is CH and T3 is CH.

### Claim 7 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein T1 is CH, T2 is N, T3 is CH.

### Claim 8 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein T1 is CH, T2 is CH, T3 is N.

### Claim 9 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein the ring A is a phenyl or a pyridyl.

### Claim 10 (depends on 9)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 9, wherein the structure moiety

### Claim 11 (depends on 10)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 10, wherein the structure moiety

### Claim 12 (depends on 11)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 11, wherein the structure moiety

### Claim 13 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, wherein ring B is a phenyl, a pyridyl, a thiazolyl or a cyclohexyl.

### Claim 14 (depends on 13)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 13, wherein the structure moiety

### Claim 15 (depends on 14)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 14, wherein the structure moiety

### Claim 16 (depends on 15)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 15, wherein the structure moiety

### Claim 17 (depends on 1)

The compound represented by formula (I), the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1, which is selected from the group consisting of
wherein,
R1, R2, R3 and R4 are defined in claim 1.

### Claim 18

A compound, an isomer or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

### Claim 19 (depends on 1)

A method of modulating PGI2 receptors in a subject in need thereof, comprising administering the compound, the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject.

### Claim 20 (depends on 1)

A method for treating PGI2 receptor related disease in a subject in need thereof, comprising administering the compound, the isomer or the pharmaceutically acceptable salt thereof as defined in claim 1 to the subject, wherein the PGI2 receptor related disease is pulmonary arterial hypertension, systemic sclerosis, acute pulmonary embolism, renal failure, heart failure, rhinitis, thrombosis, arteriosclerosis, chronic thromboembolic pulmonary arterial hypertension, Raynaud's disease, headache, migraine or cardiac arrest.