# US 2020/0399285 A1 · Dioxinoquinoline compounds, preparation method and uses thereof

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- Number: US 2020/0399285 A1
- Document ID: US20200399285A1
- Status: Published application
- Kind: A1
- Application number: 16/968,797
- Filed: 2019-01-25
- Published: 2020-12-24
- Earliest claimed: 2018-02-11
- Assignees: Beijing Scitech-Mq Pharmaceuticals Limited
- Applicants: Beijing Scitech-Mq Pharmaceuticals Limited
- Inventors: Qiang Zhang; Shannan Yu; Zhongxiang Wang; Shouye Feng; Yueming Sun; Yansheng Liu; Hongbo Zhang; Leifu Yang; Hailong Yang; Likai Zhou; Nanqiao Zheng; Chenming Hu; Zhanqiang Xu
- Web page: https://patentgrep.com/patent/US20200399285A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a dioxinoquinoline compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides a preparation method of the compound of formula (I) and a pharmaceutically acceptable salt thereof, as well as uses thereof as a drug, wherein the drug acting as a tyrosine kinase (i.e. VEGFR-2 and c-MET) inhibitor is used for treating disorders related to tyrosine kinase.

## Claims

### Claim 1

A compound of formula (I), or a pharmaceutically acceptable salt, an isomer, a hydrate, a solvate, or a prodrug thereof,
in the formula (I),
Q is CH;
G is O;
Z is CH;
L is selected from the group consisting of
wherein X is H or C1-C3 alkyl; Y is H or C1-C3 alkyl; n is 0 to 3, and when n is 0, L represents
R1 is H, C1-C9 alkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocyclyl, C1-C6 alkyl substituted with C3-C7 cycloalkyl, C1-C6 alkyl substituted with 4- to 7-membered heterocyclyl, or C1-C9 alkyl substituted with one or more of the following: hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio or —NR6R7,
R6 and R7 are each independently H, C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, or C1-C6 alkyl substituted with C1-C3 alkoxy;
the above 4- to 7-membered heterocyclyl is a 4- to 7-membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S, which is unsubstituted, or is substituted with C1-C3 alkyl or C1-C3 acyl, or is oxidized by 1 to 2 oxygen atoms;
R2 is H, C1-C3 alkyl or halogen;
R3 is H, C1-C3 alkyl or halogen;
R4 is H, C1-C3 alkyl or halogen;
R5 is H, C1-C9 alkyl, C3-C7 cycloalkyl, C1-C6 alkyl substituted with C3-C7 cycloalkyl, aryl, C1-C6 alkyl substituted with aryl, heteroaryl, or C1-C6 alkyl substituted with heteroaryl;
the aryl and heteroaryl are unsubstituted, or substituted with one or more of the following: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino substituted with mono- or di-C1-C3 alkyl, halogen, trifluoromethyl, aryloxy and methylsulfonyl; and
the above heteroaryl is a monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and containing 5 to 10 ring atoms.

### Claim 2 (depends on 1)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein R1 is H, C1-C6 alkyl, C3-C6 cycloalkyl, 5- to 6-membered heterocyclyl, C1-C3 alkyl substituted with C3-C6 cycloalkyl, C1-C3 alkyl substituted with 5- to 6-membered heterocyclyl, or C1-C6 alkyl substituted with the following: hydroxyl, C1-C3 alkoxy, C1-C3 alkylthio or —NR6R7,
R6 and R7 are each independently —H, C1-C3 alkyl, C1-C3 alkyl substituted with hydroxyl, or C1-C3 alkyl substituted with C1-C3 alkoxy; and the above 5- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S, which is unsubstituted, or is substituted with C1-C3 alkyl or C1-C3 acyl, or is oxidized by 1 to 2 oxygen atoms.

### Claim 3 (depends on 1)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein R1 is selected from the group consisting of one or more of the following: methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrol-1-ylethyl, tetrahydropyrrol-1-ylpropyl, piperidin-1-ylethyl, piperidin-1-ylpropyl, piperazin-1-ylethyl, piperazin-1-ylpropyl, morpholin-4-ylethyl, morpholin-4-ylpropyl, methylpiperazin-4-ylethyl, methylpiperazin-4-ylpropyl, N-formylpiperazin-4-ylethyl, N-formylpiperazin-4-ylpropyl, N-acetylpiperazin-4-ylethyl, N-acetylpiperazin-4-ylpropyl, (1,1-dioxothiomorpholin)-4-ylethyl, (1,1-dioxothiomorpholin)-4-ylpropyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl, diethylaminoethyl, diethylaminopropyl, hydroxyethyl, hydroxypropyl, hydroxyethylaminoethyl, hydroxypropylaminoethyl, hydroxyethylaminopropyl, methoxyethylaminoethyl, methoxypropylaminoethyl, methoxyethylaminopropyl, aminoethyl, aminopropyl, aminobutyl, N-methyl-N-hydroxyethylaminoethyl, N-methyl-N-hydroxypropylaminoethyl, N-methyl-N-hydroxyethylaminopropyl, N-methyl-N-methoxyethylaminoethyl, N-methyl-N-methoxypropylaminoethyl, N-methyl-N-methoxyethylaminopropyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, (3S)-3-aminobutyl, (3R)-3-aminobutyl, (3S)-3-hydroxybutyl or (3R)-3-hydroxybutyl.

### Claim 4 (depends on 1)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein R1 is selected from the group consisting of butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, 4,4-dimethylpiperidin-1-ylethyl, 4,4-dimethylpiperidin-1-ylpropyl, and oxetan-3-yl.

### Claim 5 (depends on 1)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein the halogen described in R2, R3, and R4 is Cl or F.

### Claim 6 (depends on 1)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein R5 is —H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted with C3-C6 cycloalkyl, aryl, C1-C3 alkyl substituted with aryl, heteroaryl, or C1-C3 alkyl substituted with heteroaryl, wherein the aryl and heteroaryl are substituted with one or more of the following: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino substituted with mono- or di-C1-C3 alkyl, halogen, trifluoromethyl, aryloxy and methylsulfonyl; and the heteroaryl is a monocyclic or bicyclic group containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, and containing 5 to 10 ring atoms.

### Claim 7 (depends on 6)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 6, wherein R5 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-(trifluoromethyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 3-chloro-4-(trifluoromethyl)phenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, benzyl, phenethyl, 4-fluorobenzyl, naphthalen-1-yl, 3-methyl-isoxazol-5-yl, 4-phenoxyphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3-methoxybenzyl or 4-methoxybenzyl.

### Claim 8

A compound of formula (I), or a pharmaceutically acceptable salt, an isomer, a hydrate, a solvate, or a prodrug thereof,
in the formula (I),
Q is CH;
G is O;
Z is CH;
L is selected from the group consisting of
wherein X is H or C1-C3 alkyl; Y is H or C1-C3 alkyl; n is 0 to 3, and when n is 0, L represents
R1 is C1-C6 alkyl substituted with 1 to 3 substituents selected from the group consisting of C1-C3 acyl, halogen, trifluoromethyl, cyano, —CONH2, —NRaRb and 4- to 7-membered heteroalicyclic group, wherein the 4- to 7-membered heteroalicyclic group is a 4- to 7-membered heteroalicyclic group containing 1 to 2 atoms selected from the group consisting of N, O, and S as ring atoms, and the 4- to 7-membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-C3 alkyl, hydroxyl, —NH2, and C1-C3 acyl,
Ra and Rb are each independently —H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted with C1-C3 alkoxy, C1-C6 alkyl substituted with C1-C3 alkylthio, C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R2, R3, and R4 are each independently H, C1-C3 alkyl or halogen;
R5 is —H, C1-C9 alkyl, C3-C7 cycloalkyl, C1-C6 alkyl substituted with C3-C7 cycloalkyl, aryl, C1-C6 alkyl substituted with aryl, heteroaryl, or C1-C6 alkyl substituted with heteroaryl;
the aryl and heteroaryl are unsubstituted, or are substituted with 1 to 3 substituents selected from the group consisting of one or more of the following: hydroxyl, amino, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino substituted with mono- or di-C1-C3 alkyl, halogen, trifluoromethyl, and methylsulfonyl; and
the above heteroaryl is a monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S and containing 5 to 10 ring atoms.

### Claim 9 (depends on 8)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 8, wherein R1 is C1-C6 alkyl substituted with 1 to 3 substituents selected from the group consisting of C1-C3 acyl, —F, trifluoromethyl, cyano, —CONH2, —NRaRb or 4- to 7-membered heteroalicyclic group, wherein the 4- to 7-membered heteroalicyclic group is a 4- to 7-membered heteroalicyclic group containing 1 to 2 atoms selected from the group consisting of N, O, and S as ring atoms, and the 4- to 7-membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of —F, C1-C3 alkyl, hydroxyl, —NH2, and C1-C3 acyl,
Ra and Rb are each independently —H, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted with C1-C3 alkoxy, C1-C3 alkyl substituted with C1-C3 alkylthio, C1-C3 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R2, R3 and R4 are each independently —H, —F or —Cl;
R5 is —H, aryl, C1-C3 alkyl substituted with aryl, heteroaryl, or C1-C3 alkyl substituted with heteroaryl, wherein the aryl and heteroaryl are unsubstituted, or are substituted with 1 to 3 substituents selected from the group consisting of one or more of the following: hydroxyl, amino, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino substituted with mono- or di-C1-C3 alkyl, halogen, trifluoromethyl and methylsulfonyl; and the heteroaryl is a monocyclic or bicyclic group containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, and containing 5 to 10 ring atoms.

### Claim at position 10

10-13. (canceled)

### Claim 14 (depends on 1)

A pharmaceutical composition, consisting of the compound of formula (I), or the pharmaceutically acceptable salt, the hydrate, or the prodrug thereof according to claim 1 and pharmaceutically acceptable carrier(s) or excipient(s).

### Claim 15

(canceled)

### Claim 16 (depends on 1)

A method of treating tyrosine kinase VEGFR-2 and/or c-MET-related diseases in a subject, comprising administering to the subject the compound of formula (I), or the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein the diseases include ocular fundus disease, psoriasis, rheumatic arthritis, atherosclerosis, pulmonary fibrosis, liver fibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary cancer and sarcoma, and cholangiocarcinoma.

### Claim 17 (depends on 1)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein:
Q is CH;
G is O;
Z is CH;
L represents
R1 is C1-C6 alkyl, or C1-C6 alkyl substituted with 4- to 7-membered heterocyclyl;
the above 4- to 7-membered heterocyclyl is a 4- to 7-membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S;
R2 is H or halogen;
R3 is H or halogen;
R4 is H or halogen;
R5 is aryl, wherein the aryl is unsubstituted, or substituted with one or more halogen.

### Claim 18 (depends on 17)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 17, wherein: R1 is C1-C6 alkyl, or C1-C3 alkyl substituted with 5- to 6-membered heterocyclyl,
the above 5- to 6-membered heterocyclyl is a 5- to 6-membered heterocyclyl containing 1 to 2 atoms selected from the group consisting of N, O, and S.

### Claim 19 (depends on 17)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 17, wherein: R1 is selected from the group consisting of one or more of the following: methyl, ethyl, propyl, isopropyl, tetrahydropyrrol-1-ylethyl, tetrahydropyrrol-1-ylpropyl, piperidin-1-ylethyl, piperidin-1-ylpropyl, piperazin-1-ylethyl, piperazin-1-ylpropyl, morpholin-4-ylethyl, morpholin-4-ylpropyl, methylpiperazin-4-ylethyl, methylpiperazin-4-ylpropyl, N-formylpiperazin-4-ylethyl, N-formylpiperazin-4-ylpropyl, N-acetylpiperazin-4-ylethyl, N-acetylpiperazin-4-ylpropyl, (1,1-dioxothiomorpholin)-4-ylethyl, and (1,1-dioxothiomorpholin)-4-ylpropyl.

### Claim 20 (depends on 1)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 1, wherein the compound is selected from the group consisting of:

### Claim 21 (depends on 20)

The compound according to claim 20, wherein the compound has the following structure:
or the pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 20)

The compound according to claim 20, wherein the compound has the following structure:
or the pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 20)

The compound according to claim 20, wherein the compound has the following structure:
or the pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 20)

The compound according to claim 20, wherein the compound has the following structure:
or the pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 20)

The compound according to claim 20, wherein the compound has the following structure:
or the pharmaceutically acceptable salt thereof.