# US 2020/0399284 A1 · Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof

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- Number: US 2020/0399284 A1
- Document ID: US20200399284A1
- Status: Published application
- Kind: A1
- Application number: 16/968,793
- 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; Yansheng Liu; Xingfu Li; Hongbo Zhang; Leifu Yang; Hailong Yang; Likai Zhou; Nanqiao Zheng; Chenming Hu; Zhanqiang Xu
- Web page: https://patentgrep.com/patent/US20200399284A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- A61K 31/4741: condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/54: having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention relates to an urea-substituted aromatic ring-linked dioxinoquinoline compound of formula (I), or a pharmaceutically acceptable salt or a hydrate 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, C-RAF, B-RAF, and RET) inhibitor is used for treating disorders related to tyrosine kinase.

## Claims

### Claim 1

A compound represented by formula (I), or a pharmaceutically acceptable salt, an isomer, a hydrate, a solvate, or a prodrug thereof,
in the formula (I),
X is O or NH;
Y is CH;
Z is CH;
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, amino substituted with mono- or di-C1-C6 alkyl or unsubstituted amino,
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 substituted with C1-C6 alkyl, or C1-C3 acyl, or is oxidized by 1 to 2 oxygen atoms;
R2 is H or halogen;
R3 is H or halogen;
R4 is H or halogen;
R5 is H, C1-C9 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, unsubstituted aryl or heteroaryl, or an aryl or heteroaryl group 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, unsubstituted amino, halogen, trifluoromethyl, aryloxy and methylsulfonyl; and
the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, which contains 1 to 3 atoms selected from the group consisting of N, O, and S in the ring.

### 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 one or more of the following: hydroxyl, C1-C3 alkoxy, C1-C3 alkylthio, amino substituted with mono- or di-C1-C3 alkyl, or unsubstituted amino, 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 substituted with C1-C3 alkyl, or C1-C3 acyl, or is oxidized by 1 to 2 oxygen atoms.

### Claim 3 (depends on 2)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 2, wherein R1 is selected from the group consisting of H, 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, diethylaminoethyl, diethylaminopropyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl, aminopropyl, aminobutyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, (3S)-3-aminobutyl, (3R)-3-aminobutyl, (3S)-3-hydroxybutyl and (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, dimethylaminopentyl, dimethylaminohexyl, 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 in R2, R3, and R4 is F, Cl or Br.

### 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, unsubstituted aryl or heteroaryl, or an aryl or heteroaryl group 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, unsubstituted amino, halogen, trifluoromethyl, aryloxy or methylsulfonyl; and
the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, which contains 1 to 2 atoms selected from the group consisting of N, O, and S in the ring.

### Claim 7 (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, unsubstituted phenyl, naphthyl or heteroaryl, or a phenyl, naphthyl or heteroaryl group substituted with one or more of the following: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, fluorine, chlorine, bromine, trifluoromethyl, phenoxy or methylsulfonyl; and
the heteroaryl group is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, and pyrrolyl.

### Claim 8 (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 selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isopenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-phenoxyphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, 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, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methoxy-pyridin-4-yl, 3-methyl-isoxazol-5-yl, and naphthalen-1-yl.

### Claim 9 (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 selected from the group consisting of butyl, isobutyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-5-(trifluoromethyl)phenyl, 2-methyl-4-(trifluoromethyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 3-methyl-5-(trifluoromethyl)phenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, and 3-chloro-4-methylphenyl.

### Claim 10

A compound represented by formula (I), or a pharmaceutically acceptable salt, an isomer, a hydrate, a solvate, or a prodrug thereof,
in the formula (I),
X is O or NH;
Y is CH;
Z is CH;
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, or 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 or halogen;
R5 is H, C1-C9 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C3-C8 cycloalkyl, unsubstituted aryl or heteroaryl, or an aryl or heteroaryl group substituted with 1 to 3 substituents —B, wherein the substituents —B are each independently hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, amino substituted with mono- or di-C1-C3 alkyl, unsubstituted amino, halogen, trifluoromethyl, aryloxy or methylsulfonyl; and
the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms, which contains 1 to 3 atoms selected from the group consisting of N, O, and S in the ring.

### Claim 11 (depends on 10)

The compound, or the pharmaceutically acceptable salt, the isomer, the hydrate, the solvate, or the prodrug thereof according to claim 10, wherein R1 is C1-C6 alkyl substituted with 1 to 3 substituents selected from the group consisting of —F, trifluoromethyl, cyano, —CONH2, —NRaRb, and 4- to 7-membered heteroalicyclic group, wherein the 4- to 7-membered heteroalicyclic group contains 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, or C1-C3 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R5 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted with C3-C6 cycloalkyl, unsubstituted phenyl, naphthyl or heteroaryl; or a phenyl, naphthyl or heteroaryl group substituted with 1 to 3 substituents —B, wherein the substituents —B are each independently methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, fluorine, chlorine, bromine, trifluoromethyl, phenoxy or methylsulfonyl; and
the heteroaryl group is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, quinazolinyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, and pyrrolyl.

### Claim at position 12

12-14. (canceled)

### Claim 15 (depends on 1)

A pharmaceutical composition, comprising the compound of Formula (I) or the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to claim 1 as an active ingredient, optionally one or more other therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.

### Claim 16 (depends on 1)

A method of treating tyrosine kinase VEGFR-2, C-RAF, B-RAF, or RET-related diseases in a subject, comprising administering to the subject the compound of Formula (I) or the pharmaceutically acceptable salt, the isomer, 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:
X is O;
Y is CH;
Z is CH;
R1 is C1-C6 alkyl
R2 is H or halogen;
R3 is H or halogen;
R4 is H or halogen;
R5 is an aryl group substituted with one or more of the following: C1-C3 alkyl, halogen, and trifluoromethyl.

### 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 methyl, ethyl, propyl, or isopropyl, and R5 is a phenyl substituted with one or more of the following: methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, and trifluoromethyl.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 19)

The compound according to claim 19 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 19)

The compound according to claim 19 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 19)

The compound according to claim 19 having the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 19)

The compound according to claim 19 having the following structure:
or a pharmaceutically acceptable salt thereof.