# US 11,440,903 B2 · Salt form and crystal form of compound as FGFR4 inhibitor and preparation method thereof

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- Number: US 11,440,903 B2
- Document ID: US11440903B2
- Status: Granted
- Kind: B2
- Application number: 16/759,734
- Filed: 2018-10-30
- Published: 2021-03-25
- Granted: 2022-09-13
- Earliest claimed: 2017-11-01
- Assignees: Guangdong Zhongsheng Pharmaceutical Co., Ltd; Guangdong Xianqiang Pharmaceutical Co., Ltd
- Applicants: Guangdong Zhongsheng Pharmaceutical Co., Ltd; Guangdong Xianqiang Pharmaceutical Co., Ltd
- Inventors: Chaofeng Long; Yang Zhang; Zhengxia Chen; Xiaoxin Chen; Zhuowei Liu; Meibi Dai; Zhiqiang Liu; Shuhui Chen
- Web page: https://patentgrep.com/patent/US11440903B2

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention provides a salt form, a crystal form, and a preparation method of a compound as an FGFR4 inhibitor and medical uses thereof.

## Claims

### Claim 1

A crystal form A, B, C or D of the compound represented by formula (I),
wherein (i) the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.58±0.2°, 12.43±0.2°, 14.56±0.2°, 18.47±0.2°, 20.23±0.2°, 21.31±0.2°, 22.97±0.2°, 25.44±0.2°;
(ii) the X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.27±0.2°, 12.59±0.2°, 15.21±0.2°, 15.98±0.2°, 18.47±0.2°, 20.90±0.2°, 21.78±0.2°, 27.69±0.2°;
(iii) the X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.35±0.2°, 8.38±0.2°, 10.50±0.2°, 12.25±0.2°, 12.82±0.2°, 13.45±0.2°, 16.36±0.2°, 18.65±0.2°; and
(iv) the X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at the following 2θ angles: 5.68±0.2°, 12.53±0.2°, 14.68±0.2°, 18.55±0.2°, 20.33±0.2°, 21.41±0.2°, 23.05±0.2°, 25.52±0.2°.

### Claim 2 (depends on 1)

The crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 1, wherein (i) the analytical data of the XRPD pattern of the crystal form A are as shown in the table below:
2θ
Relative
Angle
Intensity
Number
(°)
(%)
1
5.583
7.9
2
10.946
7.6
3
11.512
5.1
4
12.427
21.3
5
12.765
24.5
6
13
46
7
14.562
10.2
8
15.691
5.1
9
16.66
7.5
10
17.96
6.7
11
18.47
24.3
12
19.598
6
13
20.229
29
14
20.999
13.2
15
21.311
47.9
16
22.44
13
17
22.973
100
18
24.864
16.5
19
25.438
59.4
20
27.136
12.5
21
27.607
8.4
22
27.871
6.1
23
28.818
7.3
24
29.447
5.9
25
31.343
3.8
26
31.788
3.9
27
32.247
4.3
28
32.584
11.3;
(ii) the analytical data of the XRPD pattern of the crystal form B are as shown in the table below:
2θ
Relative
Angle
Intensity
Number
(°)
(%)
1
6.149
7.6
2
7.044
2.2
3
9.272
66.2
4
12.115
13
5
12.587
100
6
13.97
7
7
15.212
9.3
8
15.982
21.4
9
18.468
15.3
10
19.383
5.4
11
19.713
9.9
12
20.01
5.7
13
20.9
56.3
14
21.508
9.3
15
21.785
33.2
16
22.302
5.1
17
22.596
12.7
18
22.853
11.1
19
23.404
7
20
24.156
26.6
21
24.394
28.7
22
24.685
8.4
23
25.182
7.4
24
26.365
8.6
25
27.693
24.1
26
28.777
6.8
27
29.856
3.2
28
31.482
5.4
29
32.096
1.4
30
33.435
7.4
31
35.627
3.4
32
36.515
4.3
33
37.027
5.5
34
38.018
4.3;
(iii) the analytical data of the XRPD pattern of the crystal form C is as shown in the table below:
2θ
Relative
Angle
Intensity
Number
(°)
(%)
1
4.352
13.6
2
8.378
15.3
3
10.496
25.7
4
11.838
72.1
5
12.253
100
6
12.824
29.9
7
13.453
18.3
8
14.131
7.7
9
16.359
15.1
10
16.637
11
11
17.047
19.9
12
17.685
8.5
13
17.92
13
14
18.647
28.2
15
19.006
4.4
16
19.419
6.8
17
19.789
12
18
20.207
26.6
19
20.522
33.9
20
20.979
9.2
21
21.194
17
22
21.628
6
23
22.181
14.2
24
22.578
3.2
25
23.231
10
26
23.838
22.9
27
24.65
21.2
28
24.984
10.5
29
25.673
16.2
30
26.169
19.1
31
26.465
9.5
32
27.158
5.5
33
27.602
4.6
34
28.025
9.4
35
28.679
11.5
36
28.914
13.3
37
30.629
5.3
38
31.052
8.5
39
32.705
5.7
40
35.821
10.3
and
(iv) the analytical data of the XRPD pattern of the crystal form D is as shown in the table below:
2θ
Relative
Angle
Intensity
Number
(°)
(%)
1
5.679
11.7
2
11.008
9.5
3
11.559
4.8
4
12.527
31.8
5
12.864
32.4
6
13.061
53.2
7
14.679
14.5
8
15.786
6
9
16.809
10.3
10
18.076
9.2
11
18.549
32.7
12
19.657
6.5
13
20.325
37
14
20.979
18.3
15
21.409
55.2
16
22.281
5.4
17
22.575
19
18
23.049
100
19
24.964
22.4
20
25.517
67.4
21
26.097
3.6
22
26.41
4.6
23
27.254
19.1
24
27.65
8.9
25
27.981
7.5
26
28.895
9.7
27
29.544
7
28
31.775
5.6
29
32.643
16
30
33.692
5.7
31
34.383
4.3
32
34.737
5.5
33
36.87
5.3
34
37.936
5.6
35
38.601
4.6.

### Claim 3 (depends on 2)

The crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 2, wherein (i) the XRPD pattern of the crystal form A is as shown in FIG. 1;
(ii) the XRPD pattern of the crystal form B is as shown in FIG. 4;
(iii) the XRPD pattern of the crystal form C is as shown in FIG. 7; and
(iv) the XRPD pattern of the crystal form D is as shown in FIG. 10.

### Claim 4 (depends on 1)

The crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 1, wherein (i) the differential scanning calorimetric curve of the crystal form A has an endothermic peak with an onset of 174.46° C.±3° C.;
(ii) the differential scanning calorimetric curve of the crystal form B has an endothermic peak with an onset of 178.04° C.±3° C.;
(iii) the differential scanning calorimetric curve of the crystal form C has an endothermic peak with an onset of 179.19° C.±3° C.; and
(iv) the differential scanning calorimetric curve of the crystal form D has an endothermic peak with an onset of 179.17° C.±3° C.

### Claim 5 (depends on 4)

The crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 4, wherein
(i) the DSC pattern of the crystal form A is as shown in FIG. 2;
(ii) the DSC pattern of the crystal form B is as shown in FIG. 5;
(iii) the DSC pattern of the crystal form C is as shown in FIG. 8; and
(iv) the DSC pattern of the crystal form D is as shown in FIG. 11.

### Claim 6 (depends on 1)

The crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 1, wherein the thermogravimetric analysis curve of the crystal form A has a weight loss of 0.02335% occurred at 120.00° C.±3° C., and an additional weight loss of 0.2869% occurred at 200.85° C.±3° C.;
(ii) the thermogravimetric analysis curve of the crystal form B has a weight loss of 0.8093% occurred at 120.00° C.±3° C., and an additional weight loss of 1.128% occurred at 200.04° C.±3° C.;
(iii) the thermogravimetric analysis curve of the crystal form C has a weight loss of 0.4101% occurred at 120.00° C.±3° C., and an additional weight loss of 0.2938% occurred at 200.31° C.±3° C.; and
(iv) the thermogravimetric analysis curve of the crystal form D has a weight loss of 0.6366% occurred at 196.80° C.±3° C.

### Claim 7 (depends on 6)

The crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 6, wherein
(i) the TGA pattern of the crystal form A is as shown in FIG. 3;
(ii) the TGA pattern of the crystal form B is as shown in FIG. 6;
(iii) the TGA pattern of the crystal form C is as shown in FIG. 9; and
(iv) the TGA pattern of the crystal form D is as shown in FIG. 12.

### Claim 8 (depends on 1)

A method for preparing a crystal form B of the compound represented by formula (I) as defined in claim 1, comprising preparing the crystal form B by adding the compound represented by formula (I) into a solvent, heating and stirring, or by carrying out recrystallization, wherein the solvent is selected from: methanol, ethanol, acetone, tetrahydrofuran, isopropanol or ethanol-water, the stirring temperature is 10° C. to 45° C., the time for slurrying with stirring is 10 hours to 60 hours, and the weight-volume ratio of the compound to the solvent is 1:8-15 g/mL.

### Claim 9 (depends on 1)

The crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 1, wherein (i) the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2θ angles: 5.58±0.2°, 12.43±0.2°, 12.77±0.2°, 13.00±0.2°, 14.56±0.2°, 18.47±0.2°, 20.23±0.2°, 21.00±0.2°, 21.31±0.2°, 22.44±0.2°, 22.97±0.2°, 24.86±0.2°, 25.44±0.2°, 27.14±0.2°;
(ii) the X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at the following 2θ angles: 9.27±0.2°, 12.12±0.2°, 12.59±0.2°, 15.21±0.2°, 15.98±0.2°, 18.47±0.2°, 20.90±0.2°, 21.79±0.2°, 22.60±0.2°, 22.85±0.2°, 24.16±0.2°, 24.39±0.2°, 27.69±0.2°;
(iii) the X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2θ angles: 4.35±0.2°, 8.38±0.2°, 10.50±0.2°, 11.84±0.2°, 12.25±0.2°, 12.82±0.2°, 13.45±0.2°, 16.36±0.2°, 16.64±0.2°, 17.05±0.2°, 17.92±0.2°, 18.65±0.2°, 19.79±0.2°, 20.21±0.2°, 20.52±0.2°, 21.19±0.2°, 22.18±0.2°, 23.23±0.2°, 23.84±0.2°, 24.65±0.2°, 25.67±0.2°, 26.17±0.2°, 28.91±0.2°; and
(iv) the X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at the following 2θ angles: 5.68±0.2°, 12.53±0.2°, 13.06±0.2°, 14.68±0.2°, 16.81±0.2°, 18.55±0.2°, 20.33±0.2°, 20.98±0.2°, 21.41±0.2°, 22.58±0.2°, 23.05±0.2°, 24.96±0.2°, 25.52±0.2°, 27.25±0.2°.

### Claim 10 (depends on 1)

A method for treating FGFR4 related disease in a subject in need thereof, comprising administering an effective amount of the crystal form A, B, C or D of the compound represented by formula (I) as defined in claim 1 to the subject.

### Claim 11

A compound represented by formula (II) or crystal form E or F thereof,
wherein the X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at the following 2θ angles: 5.95±0.2°, 11.77±0.2°, 12.53±0.2°, 18.53±0.2°, 19.28±0.2°, 21.12±0.2°, 22.42±0.2°, 25.76±0.2°; and
the X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2θ angles: 6.04±0.2°, 9.21±0.2°, 12.02±0.2°, 12.51±0.2°, 15.88±0.2°, 18.35±0.2°, 20.84±0.2°, 21.67±0.2°.

### Claim 12 (depends on 11)

The compound represented by formula (II) or crystal form E or F thereof as defined in claim 11, wherein (i) the analytical data of the XRPD pattern of the crystal form E is as shown in the table below:
2θ
Relative
Angle
Intensity
Number
(°)
(%)
1
5.95
48.3
2
10.752
3.8
3
11.772
42.8
4
11.978
19.5
5
12.529
36.9
6
17.599
4.1
7
18.528
27.8
8
19.281
27.1
9
20.111
6.6
10
20.445
4.2
11
20.781
24
12
21.115
59.7
13
21.495
20.7
14
21.985
15.5
15
22.418
100
16
23.01
18.4
17
23.942
18.6
18
24.353
33
19
25.063
15.2
20
25.303
6.9
21
25.756
29.2
22
26.073
7.1
23
26.368
9
24
26.681
11
25
27.116
14.4
26
28.653
8.7
27
29.423
2.4
28
30.023
11.4
29
30.828
10.6
30
31.341
17.4
31
31.933
9
32
32.464
6.4
33
32.841
4.7
34
33.315
4.9
35
34.974
27.3
36
37.639
7.6.
and
(ii) the analytical data of the XRPD pattern of the crystal form F is as shown in the table below:
2θ
Relative
Angle
Intensity
Number
(°)
(%)
1
6.036
19.8
2
9.209
100
3
12.017
17
4
12.509
98.6
5
13.889
7.9
6
15.114
9.1
7
15.885
22.1
8
18.352
15.2
9
19.286
4
10
19.71
12.6
11
20.027
7.2
12
20.839
51.1
13
21.669
32.7
14
22.324
5.9
15
22.594
14.7
16
23.348
7.6
17
24.136
28.5
18
24.647
9.3
19
25.048
4.5
20
26.288
7.3
21
27.136
4
22
27.649
18.3
23
28.481
4.1
24
28.831
6.2
25
29.781
3.2
26
31.479
4.9
27
33.354
5.9
28
33.588
4.8
29
36.511
4.7
30
36.944
4.2
31
37.953
2.8.

### Claim 13 (depends on 12)

The compound represented by formula (II) or crystal form E or F thereof as defined in claim 12, wherein (i) the XRPD pattern of the crystal form E is as shown in FIG. 13; and
(ii) the XRPD pattern of the crystal form F is as shown in FIG. 16.

### Claim 14 (depends on 11)

The compound represented by formula (II) or crystal form E or F thereof as defined in claim 11, wherein (i) the differential scanning calorimetric curve of the crystal form E has an endothermic peak with an onset of 193.78° C.±3° C. and an exothermic peak at 198.70° C.±3° C.; and
(ii) the differential scanning calorimetric curve of the crystal form F has an endothermic peak with an onset of 155.72° C.±3° C.

### Claim 15 (depends on 14)

The compound represented by formula (II) or crystal form E or F thereof as defined in claim 14, wherein
(i) the DSC pattern of the crystal form E is as shown in FIG. 14; and
(ii) the DSC pattern of the crystal form F is as shown in FIG. 17.

### Claim 16 (depends on 11)

The compound represented by formula (II) or crystal form E or F thereof as defined in claim 11, wherein (i) the thermogravimetric analysis curve of the crystal form E has a weight loss of 1.086% occurred at 170.64° C.±3° C., and an additional weight loss of 1.652% occurred at 210.29° C.±3° C.; and
(ii) the thermogravimetric analysis curve of the crystal form F has a weight loss of 0.6525% occurred at 120° C.±3° C., and an additional weight loss of 1.138% occurred at 205.16° C.±3° C.

### Claim 17 (depends on 16)

The compound represented by formula (II) or crystal form E or F thereof as defined in claim 16, wherein (i) the TGA pattern of the crystal form E is as shown in FIG. 15; and
(ii) the TGA pattern of the crystal form F is as shown in FIG. 18.

### Claim 18 (depends on 11)

The compound represented by formula (II) or crystal form E or F thereof as defined in claim 11, wherein the X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at the following 2θ angles: 5.95±0.2°, 11.77±0.2°, 11.98±0.2°, 12.53±0.2°, 18.53±0.2°, 19.28±0.2°, 20.78±0.2°, 21.12±0.2°, 21.50±0.2°, 21.99±0.2°, 22.42±0.2°, 23.01±0.2°, 23.94±0.2°, 24.35±0.2°, 25.06±0.2°, 25.76±0.2°, 27.12±0.2°; and
the X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2θ angles: 6.04±0.2°, 9.21±0.2°, 12.02±0.2°, 12.51±0.2°, 15.89±0.2°, 18.35±0.2°, 19.71±0.2°, 20.84±0.2°, 21.67±0.2°, 22.59±0.2°, 24.14±0.2°, 27.64±0.2°.

### Claim 19 (depends on 11)

A method for treating FGFR4 related disease in a subject in need thereof, comprising administering an effective amount of the compound represented by formula (II) or crystal form E or F thereof as defined in claim 11 to the subject.

### Claim 20

A compound represented by formula (III) or crystal form G thereof,
wherein the X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2θ angles: 5.86±0.2°, 11.62±0.2°, 12.31±0.2°, 19.22±0.2°, 20.03±0.2°, 22.81±0.2°, 23.68±0.2°, 24.75±0.2°.

### Claim 21 (depends on 20)

The compound represented by formula (III) or crystal form G thereof as defined in claim 20, wherein the analytical data of the XRPD pattern of the crystal form G is as shown in the table below:
2θ
Relative
Angle
Intensity
Number
(°)
(%)
1
5.857
30.6
2
10.558
6.1
3
11.624
37.4
4
12.31
22.8
5
19.22
33
6
20.028
26.3
7
20.839
43.6
8
21.175
22.3
9
21.63
14.4
10
22.186
4.7
11
22.812
100
12
23.682
30.6
13
24.746
53.3
14
25.175
6.6
15
26.229
26.9
16
26.821
17.5
17
27.333
5.5
18
28.968
8.5
19
29.168
4.5
20
30.298
10.6
21
30.612
9.1
22
31.599
17.2
23
31.868
6.9
24
32.707
3.6
25
35.15
19.5
26
37.897
5.3
27
38.823
7.9.

### Claim 22 (depends on 20)

The compound represented by formula (III) or crystal form G thereof as defined in claim 20, wherein the differential scanning calorimetric curve of the crystal form G has an endothermic peak with an onset of 164.93° C.±3° C.

### Claim 23 (depends on 20)

The compound represented by formula (III) or crystal form G thereof as defined in claim 20, wherein the thermogravimetric analysis curve of the crystal form G has a weight loss of 0.2051% occurred at 120° C.±3° C., and an additional weight loss of 2.867% occurred at 218.92° C.±3° C.

### Claim 24 (depends on 20)

A method for treating FGFR4 related disease in a subject in need thereof, comprising administering an effective amount of the compound represented by formula (III) or crystal form G thereof as defined in claim 20 to the subject.

### Claim 25 (depends on 20)

The compound represented by formula (III) or crystal form G thereof as defined in claim 20, wherein the X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2θ angles: 5.86±0.2°, 11.62±0.2°, 12.31±0.2°, 19.22±0.2°, 20.03±0.2°, 20.84±0.2°, 21.18±0.2°, 21.63±0.2°, 22.81±0.2°, 23.68±0.2°, 24.75±0.2°, 26.23±0.2°, 26.82±0.2°.

### Claim 26 (depends on 20)

The compound represented by formula (III) or crystal form G thereof as defined in claim 20, wherein the XRPD pattern of the crystal form G is as shown in FIG. 19;
the DSC curve of the crystal form G is as shown in FIG. 20; or
the TGA pattern of the crystal form G is as shown in FIG. 21.