# US 11,078,194 B2 · Salt form and crystal form serving as FGFR and VEGFR inhibitor compounds, and preparation method therefor

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- Number: US 11,078,194 B2
- Document ID: US11078194B2
- Status: Granted
- Kind: B2
- Application number: 16/770,196
- Filed: 2018-12-07
- Published: 2020-11-19
- Granted: 2021-08-03
- Earliest claimed: 2017-12-07
- Assignees: Harbin Zhenbao Pharmaceutical Co., Ltd.
- Applicants: Harbin Zhenbao Pharmaceutical Co., Ltd.
- Inventors: Zhengxia Chen; Yang Zhang; Meibi Dai; Hongfei Cheng; Suqin Yang; Wenju Li; Jian Li; Shuhui Chen
- Web page: https://patentgrep.com/patent/US11078194B2

## CPC

- C07D 405/14: containing three or more hetero rings
- A61P 35/00: Antineoplastic agents
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed in the present invention are a salt form and a crystal form serving as FGFR and VEGFR inhibitor compounds, a preparation method therefor, and medical uses thereof.

## Claims

### Claim 1

A crystal form of a compound of formula (II), (III), or (IV):
wherein the crystal form is a crystal form G of the compound of formula (II) or a crystal form I of the compound of formula (III) or a crystal form J of the compound of formula (IV), wherein:
the X-ray powder diffraction pattern of the crystal form G of the compound of formula (II) comprises characteristic diffraction peaks at the following angle 2θ: 7.39±0.2°, 19.07±0.2°, and 20.04±0.2°;
the X-ray powder diffraction pattern of the crystal form I of the compound of formula (III) comprises characteristic diffraction peaks at the following angle 2θ: 6.73±0.2°, 11.66±0.2°, and 19.51±0.2°;
and the X-ray powder diffraction pattern of the crystal form J of the compound of formula (IV) comprises characteristic diffraction peaks at the following angle 2θ: 4.99±0.2°, 11.32±0.2°, and 19.95±0.2°.

### Claim 2 (depends on 1)

The crystal form of the compound of formula (II), (III), or (IV) as defined in claim 1, wherein:
the X-ray powder diffraction pattern of the crystal form G of the compound of formula (II) comprises characteristic diffraction peaks at the following angle 2θ: 7.39±0.2°, 19.07±0.2°, 20.04±0.2°, 21.05±0.2°, 21.76±0.2°, 25.64±0.2°, 26.23±0.2°, and 27.16±0.2°;
and/or, the X-ray powder diffraction pattern of the crystal form I of the compound of formula (III) comprises characteristic diffraction peaks at the following angle 2θ: 6.73±0.2°, 11.66±0.2°, 14.28±0.2°, 14.99±0.2°, 16.39±0.2°, 19.51±0.2°, 23.34±0.2°, and 25.61±0.2°;
and/or, the X-ray powder diffraction pattern of the crystal form J of the compound of formula (IV) comprises characteristic diffraction peaks at the following angle 2θ: 4.99±0.2°, 6.90±0.2°, 9.9±0.2°, 10.73±0.2°, 11.32±0.2°, 14.41±0.2°, 16.73±0.2°, and 19.95±0.2°.

### Claim 3 (depends on 2)

The crystal form of the compound of formula (II), (III), or (IV) as defined in claim 2, wherein:
the XRPD pattern of the crystal form G of the compound of formula (II) is as shown in FIG. 11;
and/or, the XRPD pattern of the crystal form I of the compound of formula (III) is as shown in FIG. 17;
and/or, the XRPD pattern of the crystal form J of the compound of formula (IV) is as shown in FIG. 21.

### Claim 4 (depends on 1)

The crystal form of the compound of formula (II), (III), or (IV) as defined in claim 1, wherein:
the differential scanning calorimetry curve of the crystal form G of the compound of formula (II) has an onset point of an endothermic peak at 278.70° C.±3° C., and has an onset point of an exothermic peak at 285.46° C.±3° C.;
and/or, the thermogravimetric analysis curve of the crystal form G of the compound of formula (II) has a weight loss of 3.870% occurred at 120° C.±3° C. and a weight loss of 1.170% occurred at 221.76° C.±3° C.;
and/or, the differential scanning calorimetry curve of the crystal form I of the compound of formula (III) has an onset point of an endothermic peak at 32.94° C.±3° C. and 204.62° C.±3° C., respectively;
and/or, the thermogravimetric analysis curve of the crystal form I of the compound of formula (III) has a weight loss of 0.8601% occurred at 85.39° C.±3° C. and a weight loss of 2.264% occurred at 184.93° C.±3° C.;
and/or, the differential scanning calorimetry curve of the crystal form J of the compound of formula (IV) has an onset point of an endothermic peak at 33.34° C.±3° C. and 194.84° C.±3° C., respectively;
and/or, the thermogravimetric analysis curve of the crystal form J of the compound of formula (IV) has a weight loss of 1.357% occurred at 120° C.±3° C. and a weight loss of 0.8330% occurred at 177.11° C.±3° C.

### Claim 5 (depends on 4)

The crystal form of the compound of formula (II), (III), or (IV) as defined in claim 4, wherein the DSC pattern of the crystal form G of the compound of formula (II) is as shown in FIG. 12;
and/or, the TGA pattern of the crystal form G of the compound of formula (II) is as shown in FIG. 13.

### Claim 6 (depends on 4)

The crystal form of the compound of formula (II), (III), or (IV) as defined in claim 4, wherein the DSC pattern of the crystal form I of the compound of formula (III) is as shown in FIG. 18;
and/or, the TGA pattern of the crystal form I of the compound of formula (III) is as shown in FIG. 19.

### Claim 7 (depends on 4)

The crystal form of the compound of formula (II), (III), or (IV) as defined in claim 4, wherein the DSC pattern of the crystal form J of the compound of formula (IV) is as shown in FIG. 22;
and/or, the TGA pattern of the crystal form J of the compound of formula (IV) is as shown in FIG. 23.

### Claim 8 (depends on 1)

A process for preparing the crystal form G of the compound of formula (II), as defined in claim 1, the process comprising:
adding the compound of formula (II) into ethanol to form a mixture,
adding hydrochloric acid/ethyl acetate dropwise to the mixture,
heating and stirring the mixture,
cooling the mixture to room temperature, and
filtering the mixture to obtain the crystal form G of the compound of formula II:

### Claim 9 (depends on 8)

The process as defined in claim 8, wherein the heating and stirring is performed at a temperature of 85° C. to 95° C.

### Claim 10 (depends on 1)

A method for inhibiting tyrosine kinase in a subject in need thereof, comprising: administering an effective amount of the crystal form of the compound of formula (II), (Ill), or (IV) as defined in claim 1 to the subject.