# US 10,479,798 B2 · Six-membered ring benzo derivatives as DPP-4 inhibitor and use thereof

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- Number: US 10,479,798 B2
- Document ID: US10479798B2
- Status: Granted
- Kind: B2
- Application number: 15/523,058
- Filed: 2015-10-30
- Published: 2017-11-02
- Granted: 2019-11-19
- Earliest claimed: 2014-10-31
- Assignees: East China University of Science and Technology; Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Applicants: East China University of Science and Technology; Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Inventors: Honglin Li; Hualiang Jiang; Yufang Xu; Jia Li; Zhenjiang Zhao; Jingya Li; Hongling Xu; Shiliang Li
- Web page: https://patentgrep.com/patent/US10479798B2

## CPC

- C07D 493/04: Ortho-condensed systems
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/48: of the pancreatic hormones
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 221/10: Aza-phenanthrenes
- C07D 311/60: with aryl radicals attached in position 2
- C07D 311/92: Naphthopyrans; Hydrogenated naphthopyrans
- C07D 335/04: condensed with carbocyclic rings or ring systems
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to six-membered ring benzo derivatives as a DPP-4 inhibitor and a use thereof. In particular, the present invention relates to a compound as shown in formula I, a pharmaceutical composition containing the compound as shown in formula I and a use of the compound in the preparation of drugs for treating DPP-4 related diseases or inhibiting DPP-4.

## Claims

### Claim 1

A compound having formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
wherein:
X is O
A is a benzene ring with 1 to 5 substituents, wherein each substituent is independently a halogen, a cyano, a hydroxy, a C1-6 alkyl, a C1-6 alkyl substituted by halogen, a C1-6 alkoxy, or a C1-6 alkoxy substituted by halogen;
A is a nitrogen-containing, or sulfur-containing five-membered or six-membered saturated or unsaturated heterocycle with 1 to 4 substituents, wherein each substituent is independently a halogen, a cyano, or a boronic acid group; or
A is a heterocycle selected from the following structures:
R is H, a halogen, a cyano, a hydroxy, a C1-6 alkyl, C1-6 alkyl with 1 to 5 F atoms, C1-6 alkoxy, or C1-6 alkoxy with 1 to 5 F atoms;
n is an integer of 1-2;
Ring B is an aromatic benzene ring, an aromatic heterocycle, a saturated or unsaturated 5-membered or 6-membered ring, a nitrogen-, oxygen-, or sulfur-containing five- or six-membered saturated or unsaturated heterocycle;
R1 is independently selected from the group consisting of a halogen, a cyano, a hydroxy, a C1-6 alkyl, a C1-6 alkyl group containing 1 to 5 F atoms, a C1-6 alkoxy, a C1-10 alkylcarbonyloxy, a C1-3 alkoxymethoxy, a disubstituted OCH2CH2O and OCH2O, COOH, a C1-6 alkoxycarbonyl, a carbamoyl, a methylcarbamido, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, an amino, a NR2R3, a C1-5alkylcarboxamido, a C3-5 alkyllactam group, a C1-6 alkylsulfonamido, a C3-5 alkylsultam group, a mercapto, a C1-6 alkylthio, a C1-6 alkylthio containing 1 to 5 F atoms, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, a C3-5 cycloalkylsulfonyl, and a C1-5alkylsulfinyl, a N-propanesulfonyllactam group, a N-butanesulfonyllactam group, and a 3-pyrazolylamino;
m is an integer of 1 to 4; and
R2, R3 are independently selected from a C1-6 alkyl, or R2 and R3 together form a substituted or unsubstituted 5- or 6-membered heterocycloalkyl, or a substituted or unsubstituted 5-or 6-membered heterocycle group additionally containing N or O.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (II):
wherein,
X is O
A is a benzene ring with 1 to 5 substituents, wherein each substituent is independently a halogen, a cyano, a hydroxy, a C1-6 alkyl, a C1-6 alkyl substituted by halogen, a C1-6 alkoxy, or a C1-6 alkoxy substituted by halogen;
R4 is H, a hydroxyl, F, or a cyano;
R5 is a halogen, a cyano, a hydroxyl, a mercapto, a C1-6 alkyl group, a C1-6 alkyl group containing 1 to 5 F atoms, a C1-6 alkoxy, a C1-10 alkylcarbonyloxy, a C1-3 alkoxymethyloxy, COOH, a C1-6 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a C1-6 alkylthio, a C1-6 alkylthio containing 1 to 5 F atoms, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, an amino, an acetylamino, a methanesulfonamido, a methylcarbamido, a N-propanesulfonyllactam group, a N-butanesulfonyllactam group, a 4-morpholinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
q is an integer of 1-4.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (II):
wherein,
X is O
A is a benzene ring with 1 to 5 substituents, wherein each substituent is independently a halogen, a cyano, a hydroxy, a C1-6 alkyl, a C1-6 alkyl substituted by halogen, a C1-6 alkoxy, or a C1-6 alkoxy substituted by halogen;
R4 is H, a hydroxyl, F, or a cyano;
R5 is a halogen, a cyano, a hydroxyl, a mercapto, a C1-6 alkyl group, a C1-6 alkyl group containing 1 to 5 F atoms, a C1-6 alkoxy, a C1-3 alkoxymethyloxy, COOH, a C1-6 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a C1-6 alkylthio,-a C1-6 alkylthio containing 1 to 5 F atoms, a C1-6 alkylsulfinyl, a C1-6 alkylsulfonyl, an amino, an acetylamino, a methanesulfonamido, a methylcarbamido, a N-propanesulfonyllactam group, a N-butanesulfonyllactam group, a 4-morpholinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
q is an integer of 1-4.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (III):
wherein
X is O
R4 is H or a hydroxyl;
R6, R7 are independently a hydrogen, a halogen, a cyano, a hydroxy, a mercapto, a C1-2 alkoxy, a C1-2 alkylcarbonyloxy, a C1-3 alkoxymethoxy, COOH, a C1-2 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a methylthio, a methylsulfinyl, a methanesulfonyl, an amino, acetamido, methanesulfonamido, a methylcarbamido, N-propanesulfonyllactam group, N-butanesulfonyllactam group, a 4-morphinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
R8, R9 and R10 are independently H, Cl, F, or a cyano.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the compound is shown in general formula (III):
wherein
X is O;
R4 is H or a hydroxyl;
R6, R7 are independently selected from a hydrogen, a halogen, a cyano, a hydroxy, a mercapto, a C1-2 alkoxy, a C1-3 alkoxymethoxy, COOH, a C1-2 alkoxycarbonyl, a carbamoyl, a cyanomethylcarbonyl, an acetamidomethylcarbonyl, a 2-pyrrocarbonyl, a methoxycarbonylmethyl, a 4-pyranylcarbonyl, a 4-morpholinecarbonyl, a 1-piperazinecarbonyl, a methylthio, a methylsulfinyl, a methanesulfonyl, an amino, acetamido, methanesulfonamido, a methylcarbamido, N-propanesulfonyllactam group, N-butanesulfonyllactam group, a 4-morphinyl, a N-methylpiperazin-4-yl, a piperazinyl, a 3-methanesulfonylpiperazinyl, a 3,3-difluorotetrahydropyrrolyl, a 2-aminoformylpiperidyl, or a 3-pyrazolylamino; and
R8, R9 and R10 are independently H, Cl, F, or a cyano.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the C1-6 alkyl substituted by halogen is C1-6 alkyl substituted by F; and the C1-6 alkoxy substituted by halogen is C1-6 alkoxy substituted by F.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the C1-6 alkyl substituted by halogen is C1-6 alkyl substituted by 1 to 5 F; and the C1-6 alkoxy substituted by halogen is C1-6 alkoxy substituted by 1 to 5 F.

### Claim 8 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the C1-6 alkyl substituted by halogen is C1-6 alkyl substituted by F; and the C1-6 alkoxy substituted by halogen is C1-6 alkoxy substituted by F.

### Claim 9 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the C1-6 alkyl substituted by halogen is C1-6 alkyl substituted by 1 to 5 F; and the C1-6 alkoxy substituted by halogen is C1-6 alkoxy substituted by 1 to 5 F.

### Claim 10 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein wherein the C1-6 alkyl substituted by halogen is C1-6 alkyl substituted by F; and the C1-6 alkoxy substituted by halogen is C1-6 alkoxy substituted by F.

### Claim 11 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof, wherein the C1-6 alkyl substituted by halogen is C1-6 alkyl substituted by 1 to 5 F; and the C1-6 alkoxy substituted by halogen is C1-6 alkoxy substituted by 1 to 5 F.

### Claim 12

A compound selected from the following group, or a pharmaceutically acceptable salt or prodrug thereof:

### Claim 13

A compound selected from the following group, or a pharmaceutically acceptable salt or prodrug thereof:

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

### Claim 15 (depends on 14)

The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in a dosage form suitable for oral administration.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, wherein the dosage form suitable for oral administration is a tablet, a solution, a suspension, a capsules, a granule, or a powder.

### Claim 17 (depends on 1)

A preparation method of a compound of claim 1, wherein the method includes following steps:
wherein X, A, R, B, and R1 are defined in claim 1.