CROSS-REFERENCE TO RELATED APPLICATION

This application is a National Stage of International Application No. PCT/CN2018/112659, filed on Oct. 30, 2018, which claims the priority of the Chinese Patent Application No. CN201711059786.4, filed on Nov. 1, 2017, the contents of which are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present disclosure relates to salt forms and crystal forms of a class of compounds used as FGFR4 inhibitors, a preparation method thereof, and a medical use thereof.

BACKGROUND OF THE INVENTION

Fibroblast growth factor receptor 4 (FGFR4) is a kind of human protein encoded by the FGFR4 gene. This protein is a member of the fibroblast growth factor receptor family, and the homology of amino acid sequences among FGFR1-4 members is very high, with a high degree of similarity. The protein is a glycoprotein composed of an extracellular immunoglobulin (Ig)-like domain, a hydrophobic transmembrane domain and a cytoplasm portion including tyrosine kinase domain. The binding of the extramembrane domain to FGF leads to dimerization of FGFR, and the receptor undergoes autophosphorylation, thereby activating the downstream signal pathway, and finally affecting the division and variation of cells.

FGFR4 is distinctly different from FGFR1-3 in terms of genetic structure, FGFR4 has a specific structure of cysteine 552 (CYS552), thus being capable of selectively inhibiting FGFR4, rather than inhibiting the development of FGFR1-3 inhibitors, thereby reducing the potential toxicity caused by FGFR1-3 inhibition. It has been demonstrated from recent studies that FGFR4-FGF19 signal axes are closely related to liver cancer, renal cancer, colon cancer, breast cancer, etc., allowing FGFR4 to become one of the potential targets for treating liver cancer, renal cancer, colon cancer, breast cancer, etc.

In clinical applications, FGFR4 inhibitors are not limited to treatment of liver cancer with high expression of FGFR4, and may also be applied to other solid tumors with abnormal FGFR4 signal pathways, meanwhile, FGFR4 inhibitors may possibly be used in combination with other therapies. Therefore, the development of FGFR4 inhibitors has a rather extensive market space and application prospect.

SUMMARY OF THE INVENTION

For overcoming the disadvantages of the prior art, the present disclosure provides a salt form of compound as FGFR4 inhibitor, and a series of crystal forms corresponding to the salt form and free base thereof, thereby providing a plurality of candidate raw materials for the development of the FGFR4 inhibitor as clinical medicament.

For the characterization of the crystal form of a compound, those skilled in the art can understand that, for a specific crystal form of a specific compound, the 2θ angles of the respective diffraction peaks in the X-ray powder diffraction pattern thereof will deviate in duplicate trials due to the influence of equipment, operation method, sample purity, and human factors, and the deviation range (error range) is generally within ±0.2°; moreover, those skilled in the art can further understand that the stability and repeatability of the diffraction peaks will be influenced by a combination of 2θ angles, absorption intensities of the respective diffraction peaks of the X-ray powder diffraction pattern, and the like; in particular, the diffraction peaks with stronger absorption intensity, better separation and smaller 2θ angle have better stability and repeatability, and have greater possibility in characterizing the specific crystal form; as to the diffraction peaks with larger 2θ angles and/or poorer separation and/or weaker relative intensity, relatively greater fluctuation is likely to occur due to the influences of instrument equipment, operation methods, sample purity, human factors, and the like, or those diffraction peaks may not repeatedly appear in repeated trials, therefore, for those skilled in the art, such absorption peaks are not essential diffraction peaks for characterizing the crystal form. More specially, the larger 2θ angle described herein refers to the 2θ≥30°, and the peak with weaker absorption intensity refers to that its relative intensity is less than 10%.

The first object of the present disclosure is to provide a crystal form A of the compound represented by formula (I), wherein the X-ray powder diffraction pattern thereof has the most stable and repeatable characteristic diffraction peaks at the following 2θ angles: 5.58±0.2°, 21.31±0.2°, 22.97±0.2°.



Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form A has secondarily stable and repeatable 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°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form A has secondarily stable and repeatable 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°.

Further, in an embodiment of the present disclosure, the analytical data of the XRPD pattern of the crystal form A are as shown in Table 1:

TABLE 1XRPD Analytical Data of the Crystal Form A of theCompound Represented by Formula (I)2θd-RelativeAngleSpacingIntensityNumber(°)(Å)(%)15.58315.81657.9210.9468.07637.6311.5127.68035.1412.4277.11721.3512.7656.929224.56136.804546714.5626.077910.2815.6915.64315.1916.665.31697.51017.964.93486.71118.474.799824.31219.5984.525961320.2294.3862291420.9994.227113.21521.3114.165847.91622.443.9587131722.9733.86821001824.8643.57816.51925.4383.498659.42027.1363.283412.52127.6073.22848.42227.8713.19856.12328.8183.09557.32429.4473.03085.92531.3432.85163.82631.7882.81273.92732.2472.77374.32832.5842.745811.3

Further, in an embodiment of the present disclosure, the XRPD pattern of the crystal form A is as shown inFIG. 1.

In some embodiments of the present disclosure, the differential scanning calorimetric curve of the crystal form A has an endothermic peak with an onset of 174.46° C.±3° C.

Furthermore, in an embodiment of the present disclosure, the DSC pattern of the crystal form A is as shown inFIG. 2.

In some embodiments of the present disclosure, 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.

Further, in an embodiment of the present disclosure, the TGA pattern of the crystal form A is as shown inFIG. 3.

The second object of the present disclosure is to provide a crystal form B of the compound represented by formula (I), wherein the X-ray powder diffraction pattern thereof has the most stable and repeatable characteristic diffraction peaks at the following 2θ angles: 9.27±0.2°, 12.59±0.2°, 15.98±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form B has secondarily stable and repeatable 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°, 21.79±0.2°, 27.69±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form B has secondarily stable and repeatable 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°.

Further, in an embodiment of the present disclosure, the analytical data of the XRPD pattern of the crystal form B are as shown in Table 2:

TABLE 2XRPD Analytical Data of the Crystal Form Bof the Compound Represented by Formula (I)2θd-RelativeAngleSpacingIntensityNumber(°)(Å)(%)16.14914.36167.627.04412.53872.239.2729.530466.2412.1157.299413512.5877.0265100613.976.3347715.2125.81969.3815.9825.54121.4918.4684.800315.31019.3834.57565.41119.7134.49979.91220.014.43365.71320.94.246856.31421.5084.12819.31521.7854.076233.21622.3023.98295.11722.5963.931812.71822.8533.888111.11923.4043.797972024.1563.681226.62124.3943.645928.72224.6853.60358.42325.1823.53367.42426.3653.37768.62527.6933.218624.12628.7773.09976.82729.8562.99013.22831.4822.83935.42932.0962.78641.43033.4352.67787.43135.6272.51793.43236.5152.45874.33337.0272.42595.53438.0182.36494.3

Further, in an embodiment of the present disclosure, the XRPD pattern of the crystal form B is as shown inFIG. 4.

In some embodiments of the present disclosure, the differential scanning calorimetric curve of the crystal form B has an endothermic peak with an onset of 178.04° C.±3° C.

Further, in an embodiment of the present disclosure, the DSC pattern of the crystal form B is as shown inFIG. 5.

In some embodiment of the present disclosure, 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.

Further, in an embodiment of the present disclosure, the TGA pattern of the crystal form B is as shown inFIG. 6.

The third object of the present disclosure is to provide a crystal form C of the compound represented by formula (I), wherein the X-ray powder diffraction pattern thereof has the most stable and repeatable characteristic diffraction peaks at the following 2θ angles: 4.35±0.2°, 10.50±0.2°, 12.25±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form C has secondarily stable and repeatable 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°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form C has secondarily stable and repeatable 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°.

Further, in an embodiment of the present disclosure, the analytical data of the XRPD pattern of the crystal form C are as shown in Table 3:

TABLE 3XRPD Analytic Data of the Crystal Form C of theCompound Represented by Formula (I)2θd-RelativeAngleSpacingIntensityNumber(°)(Å)(%)14.35220.285313.628.37810.544615.3310.4968.421625.7411.8387.469772.1512.2537.2178100612.8246.897429.9713.4536.576518.3814.1316.26227.7916.3595.414115.11016.6375.324111117.0475.19719.91217.6855.0118.51317.924.9458131418.6474.754528.21519.0064.66564.41619.4194.56736.81719.7894.4827121820.2074.390926.61920.5224.324133.92020.9794.2319.22121.1944.1885172221.6284.105462322.1814.004314.22422.5783.93493.22523.2313.8257102623.8383.729622.92724.653.608621.22824.9843.561110.52925.6733.467116.23026.1693.402519.13126.4653.36519.53227.1583.28085.53327.6023.2294.63428.0253.18139.43528.6793.110211.53628.9143.085313.33730.6292.91645.33831.0522.87768.53932.7052.73595.74035.8212.504810.3

Further, in an embodiment of the present disclosure, the XRPD pattern of the crystal form C is as shown inFIG. 7.

In some embodiments of the present disclosure, the differential scanning calorimetric curve of the crystal form C has an endothermic peak with an onset of 179.19° C.±3° C.

Further, in an embodiment of the present disclosure, the DSC pattern of the crystal form C is as shown inFIG. 8.

In some embodiments of the present disclosure, 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.

Further, in an embodiment of the present disclosure, the TGA pattern of the crystal form C is as shown inFIG. 9.

The fourth object of the present disclosure is to provide a crystal form D of the compound represented by formula (I), wherein the X-ray powder diffraction pattern thereof has the most stable and repeatable characteristic diffraction peaks at the following 2θ angles: 5.68±0.2°, 14.68±0.2°, 23.05±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form D has secondarily stable and repeatable 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°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form D has secondarily stable and repeatable 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°.

Further, in an embodiment of the present disclosure, the analytical data of the XRPD pattern of the crystal form D are as shown in Table 4:

TABLE 4XRPD Analytical Data of the Crystal Form D of theCompound Represented by Formula (I)2θd-RelativeAngleSpacingIntensityNumber(°)(Å)(%)15.67915.548611.7211.0088.03059.5311.5597.64924.8412.5277.060531.8512.8646.876232.4613.0616.772653.2714.6796.029614.5815.7865.60926916.8095.270110.31018.0764.90359.21118.5494.779532.71219.6574.51256.51320.3254.3657371420.9794.23118.31521.4094.147155.21622.2813.98665.41722.5753.9354191823.0493.85551001924.9643.563922.42025.5173.48867.42126.0973.41173.62226.413.3724.62327.2543.269419.12427.653.22358.92527.9813.18617.52628.8953.08749.72729.5443.02172831.7752.81385.62932.6432.7409163033.6922.65795.73134.3832.60614.33234.7372.58045.53336.872.43585.33437.9362.36985.63538.6012.33054.6

Further, in an embodiment of the present disclosure, the XRPD pattern of the crystal form D is as shown inFIG. 10.

In some embodiments of the present disclosure, the differential scanning calorimetric curve of the crystal form D has an endothermic peak with an onset of 179.17° C.±3° C.

Further, in an embodiment of the present disclosure, the DSC pattern of the crystal form D is as shown inFIG. 11.

In some embodiments of the present disclosure, the thermogravimetric analysis curve of the crystal form D has a weight loss of 0.6366% at 196.80° C.±3° C.

Further, in an embodiment of the present disclosure, the TGA pattern of the crystal form D is as shown inFIG. 12.

The fifth object of the present disclosure is to provide a compound represented by formula (II)



Researchers have found through solubility experiments that the compound represented by formula (II) has a relatively good solubility in a simulated gastric fluid (SGF) and in fasting or satiety state simulated intestinal fluid (FaSSIF). Therefore, the compound represented by formula (II) has a prospect to be developed as medicaments.

The sixth object of the present disclosure is to provide a crystal form E of the compound represented by formula (II), wherein the X-ray powder diffraction pattern thereof has the most stable and repeatable characteristic diffraction peaks at the following 2θ angles: 5.95±0.2°, 11.77±0.2°, 22.42±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form E has secondarily stable and repeatable 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°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form E has secondarily stable and repeatable 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°.

Further, in an embodiment of the present disclosure, the analytical data of the XRPD pattern of the crystal form E are as shown in Table 5:

TABLE 5XRPD Analytical Data of the Crystal Form E of theCompound Represented by Formula (II)2θd-RelativeAngleSpacingIntensityNumber(°)(Å)(%)15.9514.840648.3210.7528.22153.8311.7727.511242.8411.9787.382819.5512.5297.059136.9617.5995.03534.1718.5284.784727.8819.2814.599627.1920.1114.41176.61020.4454.34034.21120.7814.271241221.1154.20459.71321.4954.130720.71421.9854.039715.51522.4183.96271001623.013.861918.41723.9423.713718.61824.3533.6519331925.0633.5515.22025.3033.5176.92125.7563.456129.22226.0733.41487.12326.3683.377292426.6813.3383112527.1163.285714.42628.6533.11298.72729.4233.03322.42830.0232.973911.42930.8282.898110.63031.3412.851817.43131.9332.800293232.4642.75566.43332.8412.72484.73433.3152.68724.93534.9742.563427.33637.6392.38787.6

Further, in an embodiment of the present disclosure, the XRPD pattern of the crystal form E is as shown inFIG. 13.

In some embodiments of the present disclosure, 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.

Further, in an embodiment of the present disclosure, the DSC pattern of the crystal form E is as shown inFIG. 14.

In some embodiments of the present disclosure, the thermogravimetric analysis curve of the crystal form E has a TGA curve with 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.

Further, in an embodiment of the present disclosure, the TGA pattern of the crystal form E is as shown inFIG. 15.

The seventh object of the present disclosure is to provide a crystal form F of the compound represented by formula (II), wherein the X-ray powder diffraction pattern thereof has the most stable and repeatable characteristic diffraction peaks at the following 2θ angles: 6.04±0.2°, 9.21±0.2°, 12.51±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form F has secondarily stable and repeatable 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°, 20.84±0.2°, 21.67±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form F has secondarily stable and repeatable 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°.

Further, in an embodiment of the present disclosure, the analytical data of the XRPD pattern of the crystal form F are as shown in Table 6:

TABLE 6XRPD Analytical Data of Crystal Form F of the CompoundRepresented by Formula (II)2θd-RelativeAngleSpacingIntensityNumber(°)(Å)(%)16.03614.629119.829.2099.5948100312.0177.358917412.5097.070598.6513.8896.37097.9615.1145.85729.1715.8855.574522.1818.3524.830215.2919.2864.598441019.714.500412.61120.0274.437.21220.8394.259251.11321.6694.097732.71422.3243.97915.91522.5943.932114.71623.3483.80697.61724.1363.684228.51824.6473.6099.31925.0483.55224.52026.2883.38737.32127.1363.283442227.6493.223618.32328.4813.13134.12428.8313.09416.22529.7812.99753.22631.4792.83964.92733.3542.68415.92833.5882.66594.82936.5112.45894.73036.9442.43114.23137.9532.36882.8

Further, in an embodiment of the present disclosure, the XRPD pattern of the crystal form F is as shown inFIG. 16.

In some embodiments of the present disclosure, the differential scanning calorimetric curve of the crystal form F has an endothermic peak with an onset of 155.72° C.±3° C.

Further, in an embodiment of the present disclosure, the DSC pattern of the crystal form F is as shown inFIG. 17.

In some embodiments of the present disclosure, the TGA 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.

Further, in an embodiment of the present disclosure, the TGA pattern of the crystal form F is as shown inFIG. 18.

The eighth object of the present disclosure is to provide a compound represented by formula (III)



Researchers have found through solubility experiments that the compound represented by formula (III) also has a relatively good solubility in a simulated gastric fluid (SGF) and in fasting or satiety state simulated intestinal fluid (FaSSIF). Therefore, the compound represented by formula (III) also has a prospect to be developed as medicaments.

The ninth object of the present disclosure is to provide a crystal form G of the compound represented by formula (III), wherein the X-ray powder diffraction pattern thereof has the most stable and repeatable characteristic diffraction peaks at the following 2θ angles: 5.86±0.2°, 11.62±0.2°, 22.81±0.2°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form G has secondarily stable and repeatable 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°.

Further, in some embodiments of the present disclosure, the X-ray powder diffraction pattern of the crystal form G has secondarily stable and repeatable 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°.

Further, in an embodiment of the present disclosure, the analytical data of the XRPD pattern of the crystal form G are as shown in Table 7:

TABLE 7XRPD Analytic Data of Crystal Form G of the CompoundRepresented by Formula (III)2θd-RelativeAngleSpacingIntensityNumber(°)(Å)(%)15.85715.076930.6210.5588.37196.1311.6247.606737.4412.317.184322.8519.224.614133620.0284.429726.3720.8394.259143.6821.1754.192322.3921.634.105114.41022.1864.00364.71122.8123.89511001223.6823.753830.61324.7463.594853.31425.1753.53456.61526.2293.394826.91626.8213.321217.51727.3333.26015.51828.9683.07978.51929.1683.05914.52030.2982.947510.62130.6122.9189.12231.5992.829117.22331.8682.80586.92432.7072.73583.62535.152.55119.52637.8972.37215.32738.8232.31777.9

Further, in an embodiment of the present disclosure, the XRPD pattern of the crystal form G is as shown inFIG. 19.

In some embodiments of the present disclosure, the differential scanning calorimetric curve of the crystal form G has an endothermic peak at 164.93° C.±3° C.

Further, in an embodiment of the present disclosure, the DSC pattern of the crystal form G is as shown inFIG. 20.

In some embodiments of the present disclosure, 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.

Further, in an embodiment of the present disclosure, the TGA pattern of the crystal form G is as shown inFIG. 21.

The last object of the present disclosure is to further provide a method for preparing a crystal form B of the compound represented by formula (I), 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.

In some embodiments of the present disclosure, in the preparation method, the solvent is selected from: methanol, ethanol, acetone, tetrahydrofuran, isopropanol or ethanol-water.

In some embodiments of the present disclosure, in the preparation method, the stirring temperature is selected to be 10° C. to 45° C.

In some embodiments of the present disclosure, in the preparation method, the slurrying time is 10 hours to 60 hours.

In some embodiments of the present disclosure, in the preparation method, the weight-volume ratio of the compound to the solvent is 1:8-15 g/mL.

The present disclosure further provides the use of the compounds or the crystal forms A-G in the manufacture of a medicament for treating FGFR4 related disease.

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific phrase or term without specific definition should not be considered uncertain or unclear, but should be understood in line with its ordinary meaning. When a trade name is used herein, it is intended to refer to the corresponding commercially available product or its active ingredient(s).

The intermediate compound(s) of the present disclosure can be prepared by a variety of synthetic methods well known by those skilled in the art, including the specific embodiments as listed below, the embodiments formed by a combination of those embodiments with other chemical synthesis methods, as well as equivalent alternatives well known by those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present disclosure.

The chemical reaction(s) of the specific embodiments of the present disclosure is carried out in a suitable solvent which should be suitable for the chemical changes of the present disclosure and the required reagents and materials. In order to obtain the compounds of the present disclosure, those skilled in the art sometimes need to modify or make selection on the synthesis steps or the reaction process based on the existing embodiments.

Hereinafter the present disclosure will be described in details by reference to the embodiments which do not indicate any limitation to the present disclosure.

All the solvents used in the present disclosure are commercially available, and can be used without further purification.

The following abbreviations are used in the present disclosure: r.t. represents room temperature; THF represents tetrahydrofuran; NMP represents N-methylpyrrolidone; MeSO3H represents methanesulfonic acid; DME represents 1,2-dimethoxyethane; DCM represents dichloromethane; Xphos represents 2-dicyclohexylphosphino-2′4′6′-tri-isopropylbiphenyl; EtOAc represents ethyl acetate; MeOH represents methanol; acetone represents propanone; 2-Me-THF represents 2-methyltetrahydrofuran; IPA represents isopropanol; m-CPBA represents 3-chloroperoxybenzoic acid; Pd(dppf)Cl2represents [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride; DIEA represents N,N-diisopropylethylamine; DMSO represents dimethylsulfoxide; HEPES represents 4-hydroxyethylpiperazine ethanesulfonic acid; and EGTA represents ethylene glycol bis(2-aminoethyl ether) tetraacetic acid.

Compounds are named manually or by ChemDraw® software, and commercially available compounds are named with supplier catalog names.

X-Ray Powder Diffractometer (XRPD) Method of the Present Invention

Instrument model: Bruker D8 advance X-ray diffractometer

Test method: About 10-20 mg sample was used for XRPD detection.

The detailed XRPD parameters are as follows:

X-ray tube: Cu, kα, (λ=1.54056).

X-ray tube voltage: 40 kV, X-ray tube current: 40 mA

Divergence slit: 0.60 mm

Detector slit: 10.50 mm

Anti-scattering slit: 7.10 mm

Scan range: 4-40 deg

Step size: 0.02 deg

Step length: 0.12 second

Rotation speed of sample tray: 15 rpm

Those skilled in the art can understand that, during the analysis process of the obtained XRPD pattern, the relevant data can be subjected to appropriate scientific processing, such as baseline correction processing, in order to reduce errors.

Differential Scanning Calorimeter (DSC) Method of the Present Invention

Instrument model: TA Q2000 Differential Scanning calorimeter

Test method: A sample (about 1 mg) was placed into a DSC aluminum crucible for test, under the condition of 50 mL/min N2, the sample was heated at a heating rate of 10° C./min from 30° C. (room temperature) to 300° C. (or 350° C.).

Thermal Gravimetric Analyzer (TGA) Method of the Present Invention

Instrument model: TA Q5000IR TGA Instrument

Test method: A sample (2-5 mg) was placed in a TGA platinum crucible for test, under the condition of 25 mL/min N2, the sample was heated at a heating rate of 10° C./min from room temperature to 300° C. or a weight loss of 20%.

X-Ray Powder Diffractor (XRPD)

Test conditions: About 10-20 mg sample was used for XRPD detection.

X-ray tube: Cu, K-Alpha, (u, K-Alp)

X-ray tube voltage: 40 kV, X-ray tube current: 40 mA

Divergence slit: 0.60 mm

Detector slit: 10.50 mm

Anti-scattering slit: 7.10 mm

Scan range: 4-40 deg

Step length: 0.02 deg

Rate: 0.12 S

Rotation speed of sample tray: 15 rpm

High Performance Liquid Chromatograph (HPLC)

The analytical method is as follows:

TABLE 8-1Method for Measuring Content by HPLC Analysis*Agilent 1200 High PerformanceLiquid ChromatographInstrument(PDS-PF-HPLC-02 or PDS-PF-HPLC-01)ColumnAscentis Express C18 (4.6 × 150 mm,2.7 μm) (PDS-HPLC-Mobile phase A0.1% phosphoric acid aqueous solutionMobile phase B100% acetonitrileFlow rate1 mL/minInjection volume10 μLDetection280 nmwavelengthColumn40° C.DiluentN,N-dimethylformamide:acetonitrile 50/50 (v/v) oracetonitrile: water 1/1 (v/v)GradientMobileMobileelutionTimephasephaseprocedure(min)A (%)B (%)0.00901013.0059515.0059515.01901018.009010*The method was used for detecting the crystal forms B and E in the specific embodiments.

TABLE 8-2Method for Measuring Content by HPLC Analysis **Agilent 1200 HighInstrumentPerformance Liquid ChromatographColumnAgilent Eclipse C18 (4.6 × 150 mm, 3.5 μm)Mobile phase A0.04% trifluoroacetic acid solutionMobile phase B100% acetonitrileFlow rate1 mL/minInjection volume10 μLDetection wavelength230 nmColumn temperature40° C.Diluentacetonitrile: water 50/50 (v/v)Gradient elutionMobileMobileprocedureTimephase Aphase B0.00752550.00307055.00158555.017525607525** The method was used for detecting the crystal forms A, C, D, and F in thespecific embodiments.

Technical Effects

The crystal forms of the compounds represented by formula (I), (II) or (III) as described in the present disclosure have good stability and are easy to be made into medicaments; the core structure of the compound of the present disclosure having acrylamide and fluoroolefin bond can result in a series of highly FGFR4-selective compounds, which exhibits excellent inhibitory activity on FGFR4 kinase, but have no activity on the subtype of FGFR1 kinase, and the selectivity is at least 10 times or even more than 100 times.

