CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority of CN201810180641.8 filed on Mar. 5, 2018.

TECHNICAL FIELD

The present disclosure relates to crystal- and salt forms of a pyridoimidazole-based compound and preparation methods thereof, and relates to use of the crystal forms in preparation of a medicament against influenza virus-associated diseases.

BACKGROUND

Influenza Virus (IFV) is a segmented single-stranded antisense RNA virus that can cause influenza in humans and animals. The influenza pandemic leads to thousands of deaths, causes great social panic, and increases social instability.

Influenza will cause direct costs of lost productivity and related medical resources and indirect costs of preventive measures. In the United States, influenza has caused an estimated annual loss of about 10 billion US dollars. It is estimated that future influenza pandemics can cause hundreds of billions of dollars in direct and indirect costs. Costs of prevention are also very high. Governments around the world have spent billions of dollars in preparing and planning for a possible H5N1 avian influenza pandemic. The cost is related to the purchase of drugs and vaccines, as well as the development of disaster drills and strategies to improve border control.

Current options for flu treatment include vaccination and chemotherapy and chemoprevention with antiviral drugs. Antiviral drugs can also be used to treat influenza, in which neuraminidase inhibitors, e.g., oseltamivir (Tamiflu), have an obvious effect on influenza A virus. However, after clinical observation, it has been found that virus strains resistant to this type of neuraminidase inhibitors have appeared. In the field of anti-influenza viruses, anti-influenza virus drugs with a new mechanism of action are in urgent clinical need, which can support the use of a single drug for treatment of influenza A, or can be used in combination with other existing anti-influenza virus drugs with other mechanisms of action for prevention and treatment of influenza A.

SUMMARY

To solve the shortcomings of the prior art, the present disclosure provides a pyridoimidazole compound and its salt forms, corresponding crystal forms, and preparation methods thereof, thereby providing a plurality of raw material options for developing the pyridoimidazole compound and its salt forms as a clinical drug.

For characterization of a crystal form of a compound, persons skilled in the art can understand that for a specific crystal form of a specific compound, 2θ angles of various diffraction peaks in its X-ray powder diffraction pattern (XRPD) would have some fluctuations in repeated experiments due to the influence of instrument(s), operation method, sample purity, human factors and the like during the characterization process, and the fluctuation range (error range) is usually within ±0.2°. In addition, persons skilled in the art can also understand that the stability and repeatability of diffraction peaks would be affected by a combination of factors like 2θ angle, absorption intensity (peak height) of various diffraction peaks of the X-ray powder diffraction pattern, etc. In particular, the stronger the absorption intensity, the better the separation, and the smaller the 2θ angle, the better the stability and repeatability of the diffraction peak, and the more it can be used to characterize the specific crystal form. In contrast, diffraction peaks with larger 2θ angle and/or poorer separation and/or weaker relative intensity may be subject to relatively larger fluctuations due to the influence of instrument(s), operation method, sample purity, human factors and the like, or cannot be repeated in repeated experiments. Therefore, for those skilled in the art, such absorption peaks are not necessary diffraction peaks for characterizing the crystal form; more specifically, the present disclosure comprehensively considers factors such as 2θ angle, absorption intensity (peak height) and the like when selecting peaks, and groups them according to the stability and repeatability.

Persons skilled in the art can understand that there may be little or no difference in certain physical characteristics between different hydrates, solvates, and anhydrates of a certain compound. Specially, for the series of the compounds of the present disclosure, different hydrates, solvates, and anhydrates of the same salt form tend to have the same XRPD pattern, while the differences lie in the different DSC and/or TGA patterns thereof.

The first object of the present disclosure is to provide a series of crystal forms of the compound of Formula (I), wherein n is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4.



In particular, the crystal form A of the compound of Formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.61±0.2°, 9.27±0.2°, 14.66±0.2°; and further, the aforesaid crystal form A of the compound of Formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.61±0.2°, 9.27±0.2°, 14.66±0.2°, 16.69±0.2°, 18.65±0.2°, 19.79±0.2°, 21.85±0.2°, 24.63±0.2°.

In some embodiments of the present disclosure, the aforesaid crystal form A of the compound of Formula (I) may have XRPD analysis data as shown in Table 1. Persons skilled in the art can understand that as compared with the high volatility of the peak height, the 2θ value in the XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 1XRPD analysis data of the crystal form A of the compound of Formula (I)Full Width2θdPeakPeakat HalfNo.(±0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum14.69318.81554874012.344061.60.18426.60613.3686382177011002741521000.2637.37111.98292702921.6537820.30949.2729.530229763793693083340.245510.3968.5022854522.645941.70.171614.666.0375195256614.53810713.90.249716.2195.46052034502.574432.70.278816.6935.306321310245.8140145.10.23917.5025.0632085523.173222.70.2231018.6484.75442198314.71373350.2771119.0994.6432411100.610060.40.1531219.7934.4819241196211.12857910.40.2441320.6834.29092204792.756712.10.1991421.8464.06522015458.7232008.50.2521522.8143.89472542521.451991.90.3461623.1883.83272145603.2157475.70.4721723.6423.76012226703.893313.40.2341824.6313.61142317224.11369050.3181924.9643.56392083391.9149935.50.7422025.5163.4882532771.629811.10.1812126.3853.37512247104106953.90.2532227.1383.28322084372.564962.40.2492327.9463.191842681.536581.30.2292429.4263.0329194175125840.90.2482530.2362.95351713431.966612.40.3262631.2042.8641603171.859112.20.3132731.6752.82241591310.721790.80.2792833.022.71051521450.8271410.3142933.652.66121482011.132171.20.2693035.6232.51821431080.628821.10.4483136.2592.47551351010.622720.80.3773238.6652.3268114890.512440.50.235

In some embodiments of the present disclosure, the aforesaid crystal form A of the compound of Formula (I) has an XRPD pattern as shown inFIG.1.

In some embodiments of the present disclosure, the aforesaid crystal form A of the compound of Formula (I) has a differential scanning calorimetry (DSC) curve with a starting point of an endothermic peak at 185.46° C.±3° C.; and further, in some embodiments of the present disclosure, the crystal form A of the compound of Formula (I) has a DSC pattern as shown inFIG.2.

In some embodiments of the present disclosure, the aforesaid crystal form A of the compound of Formula (I) has a thermogravimetric analysis curve (TGA) at 120.00° C.±3° C. with a weight loss of 2.479%; and further, in some embodiments of the present disclosure, the crystal form A of the compound of Formula (I) has a TGA pattern as shown inFIG.3.

In some embodiments of the present disclosure, in the aforesaid crystal form A of the compound of Formula (I), the compound of Formula (I) has a structure as represented by Compound 1:



In particular, the crystal form B of the compound of Formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 7.14±0.2°, 11.19±0.2°, 22.39±0.2°; and further, the aforesaid crystal form B of the compound of Formula (I) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 7.14±0.2°, 11.19±0.2°, 12.00±0.2°, 17.28±0.2°, 18.84±0.2°, 22.39±0.2°, 26.90±0.2°, 27.95±0.2°.

In some embodiments of the present disclosure, the aforesaid crystal form B of the compound of Formula (I) may have XRPD analysis data as shown in Table 2. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 20 value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 2XRPD analysis data of the crystal form B of the compound of Formula (I)Full Width2θdPeakPeakat HalfNo.(±0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum17.14312.3657290169331.42440524.90.24228.66210.19942313877.254185.50.235311.1927.8992264325060.24633747.30.239412.0037.3676262165530.72245722.90.228514.0766.286422162911.792409.40.247614.5126.09882222544.774947.70.495715.2225.8159257376735043.60.157815.9125.56522101663.115721.60.159916.5465.35342641673.115601.60.1571017.2765.12882761347252948130.10.3681118.0884.9003409111520.71253912.80.1891218.8374.7069304147927.43649037.30.4141319.554.53733810825670.60.0881419.9644.4437280130824.22182722.30.281520.5364.32133051673.128012.90.2821621.1664.1941245981.88480.90.1451722.3933.96692825395100978841000.3051822.8083.8956339137325.44007540.90.491923.6583.75763014538.41492615.20.5532024.0323.6999274105219.52147021.90.3432125.0373.55372331051.97970.80.1272225.4973.49062512224.1488750.372325.8713.4412712264.255485.70.4122426.5623.35327268112.62454025.10.6052526.8983.3119259170331.633293340.3282627.9463.1901242115021.31992820.40.2912729.5663.018823748891032510.50.3552830.1812.9587255901.77380.80.1382930.8892.89242302544.733563.40.2223031.7592.81522673346.248424.90.2433132.2942.7698219268572247.40.4533232.6872.7374239106214311.50.2273333.42.68062301542.920122.10.2193434.2462.61622483596.770557.20.333534.7212.58152151592.960196.10.6363636.2252.47771972384.454865.60.38737382.3661901883.574417.60.665

In some embodiments of the present disclosure, the aforesaid crystal form B of the compound of Formula (I) has an XRPD pattern as shown inFIG.4.

In some embodiments of the present disclosure, the aforesaid crystal form B of the compound of Formula (I) has a differential scanning calorimetry curve with an endothermic peak at 101.04° C.±3° C. and a starting point of an endothermic peak at 188.30° C.±3° C.; and further, in some embodiments of the present disclosure, the crystal form B of the compound of Formula (I) has a DSC pattern as shown inFIG.5.

In some embodiments of the present disclosure, the aforesaid crystal form B of the compound of Formula (I) has a thermogravimetric analysis curve with a weight loss of 4.087% at 154.18° C.±3° C. and a weight loss of up to 4.610% at 196.80° C.±3° C.; and further, in some embodiments of the present disclosure, the crystal form B of the compound of Formula (I) has a TGA pattern as shown inFIG.6.

In some embodiments of the present disclosure, in the aforesaid crystal form B of the compound of Formula (I), the compound of Formula (I) has a structure as represented by Compound 2:



The second object of the present disclosure is to provide a compound as represented by Formula (II) as below and a series of corresponding crystal forms thereof, wherein n2is selected from 1; and m2is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4.



Further, the present disclosure further provides a crystal form C of the compound of Formula (II) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 8.00±0.2°, 15.06±0.2°, 15.84±0.2°. Further, the aforesaid crystal form C of the compound of Formula (II) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 5.90±0.2°, 6.52±0.2°, 8.00±0.2°, 12.28±0.2°, 15.06±0.2°, 15.84±0.2°, 21.22±0.2°, 26.82±0.2°.

In some embodiments of the present disclosure, the aforesaid crystal form C of the compound of Formula (II) may have XRPD analysis data as shown in Table 3. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θ value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 3XRPD analysis data of crystal form C of the compound of Formula (II)Full Width2θdPeakPeakat HalfNo.(±0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum15.89614.9784339190924586.10.21726.52513.535933028613.5434010.70.25437.6511.5464301467221755143.20.6348.00411.03632812121100405921000.321510.6478.3027201170825396.30.25611.6157.6124210753.580720.18712.2857.198822533215.7652916.10.33812.8346.89212171316.2412910.20.528913.9776.3308227693.37091.70.1721015.0645.876429839618.7673616.60.2851115.8375.591431833215.7531413.10.2681217.0365.20032681316.219054.70.2441317.8884.95442721195.614583.60.2051419.7624.48882321145.418654.60.2741521.2184.183926226112.3629415.50.4041621.8714.06042631225.831297.70.431724.5663.6207225542.57121.80.2211825.443.4983275753.58472.10.1891926.0313.42023261245.831857.80.4312026.8223.32123061537.2633015.60.6942131.1482.869215783.711892.90.2562232.9432.7167189502.45281.30.1772337.9242.3705148512.411502.80.3782438.0662.362147622.911662.90.315

Further, in some embodiments of the present disclosure, the aforesaid crystal form C of the compound of Formula (II) has an XRPD pattern as shown inFIG.7.

Further, in some embodiments of the present disclosure, the aforesaid crystal form C of the compound of Formula (II) has a differential scanning calorimetry curve with an endothermic peak at 193.754° C.±3° C. and with an endothermic peak at 235.53° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form C of the compound of Formula (II) has a DSC pattern as shown inFIG.8.

Further, in some embodiments of the present disclosure, the aforesaid crystal form C of the compound of Formula (II) has a thermogravimetric analysis curve with a weight loss of 5.000% at 117.79° C.±3° C. and a weight loss of up to 12.377% at 222.15° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form C of the compound of Formula (II) has a TGA pattern as shown inFIG.9.

In some embodiments of the present disclosure, in the aforesaid crystal form C of the compound of Formula (II), the compound of Formula (II) is a compound II-1 as shown below:



Further, the present disclosure further provides a crystal form D of the compound of Formula (II) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.96±0.2°, 10.31±0.2°, 14.95±0.2°; and further, the aforesaid crystal form D of the compound of Formula (II) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.96±0.2°, 9.44±0.2°, 10.31±0.2°, 14.95±0.2°, 17.38±0.2°, 20.67±0.2°, 21.89±0.2°, 22.72±0.2°. In some embodiments of the present disclosure, the aforesaid crystal form D of the compound of Formula (II) may have XRPD analysis data as shown in Table 4. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θ value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 4XRPD analysis data of the crystal form D of the compound of Formula (II)Full Width2θdPeakPeakat HalfNo.(0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum16.95812.6937327105041001076341000.17229.4449.35672154754.542453.90.15310.3118.5723200139713.31451313.50.174412.1287.29171672402.3213120.149512.8196.89991581341.3107910.135614.9465.9227192144713.81876217.40.217715.3225.77812201572151816116.90.194815.8925.57192301801.716531.50.154916.2685.44392012742.633623.10.2061017.3765.0993149421444004.10.1751118.6984.74171333493.340103.70.1931219.724.4983140950.9104710.1851320.6664.2944150124911.915103140.2031421.894.0569166142813.61594314.80.1871522.7173.91111545535.352774.90.161623.8063.73461381121.19620.90.1441724.633.6114138930.9210220.3791824.9073.57191341021212020.3481925.7923.45141414984.747804.40.1612026.7043.33551553633.536563.40.1692127.4523.24621491391.312341.10.1492228.2023.1616149312345104.20.2422328.5953.1191135206262775.80.5112428.9663.07991452862.761645.70.3612530.8432.89671271881.836853.40.3292631.1982.8645112320382347.60.4312731.752.8161342742.619541.80.122832.5842.74581092041.926852.50.2212934.3592.6079961291.224162.20.3143035.1682.5497100590.66450.60.1833135.8162.505901431.427442.50.3223237.1962.415285580.6211820.6123337.5692.392184700.7210620.504

In some embodiments of the present disclosure, the aforesaid crystal form D of the compound of Formula (II) has an XRPD pattern as shown inFIG.10.

In some embodiments of the present disclosure, the aforesaid crystal form D of the compound of Formula (II) has a differential scanning calorimetry curve with an endothermic peak at 193.68° C.±3° C.; and further, in some embodiments of the present disclosure, the crystal form D of the compound of Formula (II) has a DSC pattern as shown inFIG.11.

In some embodiments of the present disclosure, the aforesaid crystal form D of the compound of Formula (II) has a thermogravimetric analysis curve with a weight loss of 0.231% at 78.99° C.±3° C. and a weight loss of up to 5.826% at 198.74° C.±3° C.; and further, in some embodiments of the present disclosure, the crystal form D of the compound of Formula (II) has a TGA pattern as shown inFIG.12.

In some embodiments of the present disclosure, in the aforesaid crystal form D of the compound of Formula (II), the compound of Formula (II) has the structure of Compound II-2.



The third object of the present disclosure is to provide a compound of Compound 3 and its crystal forms.



Further, a crystal form E of Compound 3 has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 8.10±0.2°, 9.60±0.2°, 22.97±0.2°; and further, the crystal form E of Compound 3 has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 8.10±0.2°, 9.60±0.2°, 16.09±0.2°, 17.61±0.2°, 18.42±0.2°, 22.97±0.2°, 23.58±0.2°, 25.14±0.2°. In some embodiments of the present disclosure, the crystal form E of Compound 3 may have XRPD analysis data as shown in Table 5. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 20 value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 5XRPD analysis data of the crystal form E of Compound 3Full Width2θdPeakPeakat HalfNo.(±0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum18.10410.9007220203088.61523669.80.12629.5999.2062199221296.61721878.90.13139.8338.987919665328.56318290.162411.0667.98881731355.912345.70.153511.7127.549717631813.9247611.30.131612.4877.082517249121.4373117.10.127712.9786.815816131113.6234210.70.126813.7076.455115347320.74368200.155915.7535.620816798743.112876590.2191016.0935.5028177190883.31676976.80.1471116.7225.297318563727.8437920.10.1151216.9965.212417785237.2761734.90.151317.6125.0316171158669.310697490.1131418.4154.813815697342.5890840.80.1531519.2274.612516870330.7528224.20.1261619.5424.538715934014.8399818.30.1971720.0774.419118046420.3347215.90.1251820.3514.3601177111148.5771735.40.1161921.5134.127115584837620928.50.1232022.2044.000421164728.3581626.70.1512122.5953.9322551827.910284.70.0952222.9743.86791792290100218231000.162323.2543.8222341697.4224310.30.2232423.5853.769222220296.22102596.30.162524.1993.674818351122.3427419.60.142624.9073.571916853423.3706232.40.2222725.1433.5389163157568.81495568.50.1592825.5953.4775155753.38623.90.1932926.0733.414814633414.62842130.1433026.7653.3281142723.15882.70.1373127.2523.2696169230102174100.1583227.5073.241811124.9109050.1633327.8853.196915132314.1495022.70.2573428.4173.138220649421.6300713.80.1023528.9323.083515340217.6359316.50.153629.5643.0191371717.5234910.80.233730.0762.968812328012.2439020.10.2633831.0552.87741191034.58473.90.1383931.6732.82271601466.4249111.40.2864032.2632.77241251506.6374217.10.4184132.5392.74951531767.7173580.1654233.1162.70291201074.77903.60.1244334.4142.60381101255.5259411.90.3484435.3642.536100723.1259211.90.6044535.6342.51741031386274212.60.3334635.7352.51051031225.3272012.50.3744737.2362.412710568313796.30.344837.8512.374911369310454.80.2544938.1242.3586115552.410494.80.325038.9532.3103112713.18844.10.209

In some embodiments of the present disclosure, the aforesaid crystal form E of Compound 3 has an XRPD pattern as shown inFIG.13.

In some embodiments of the present disclosure, the aforesaid crystal form E of Compound 3 has a differential scanning calorimetry curve with a starting point of an endothermic peak at 258.27° C.±3° C.; and further, in some embodiments of the present disclosure, the crystal form E of Compound 3 has a DSC pattern as shown inFIG.14.

In some embodiments of the present disclosure, the aforesaid crystal form E of Compound 3 has a thermogravimetric analysis curve with a weight loss of 0.905% at 121.35° C.±3° C.; and further, in some embodiments of the present disclosure, the crystal form E of Compound 3 has a TGA pattern as shown inFIG.15.

The fourth object of the present disclosure is to provide a compound of Formula (III) as shown below and its crystal forms,



wherein,

n3is selected from 1;

m3is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4.

In particular, the present disclosure further provides a crystal form F of the compound of Formula (III) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.47±0.2°, 9.11±0.2°, 9.90±0.2°; and further, the aforesaid crystal form F of the compound of Formula (III) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.47±0.2°, 9.11±0.2°, 9.90±0.2°, 15.85±0.2°, 16.28±0.2°, 19.40±0.2°, 20.37±0.2°, 24.10±0.2°.

In some embodiments of the present disclosure, the aforesaid crystal form F of the compound of Formula (III) may have XRPD analysis data as shown in Table 6. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θ value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 6XRPD analysis data of crystal form F of the compound of Formula (III)Full Width2θdPeakPeakat HalfNo.(±0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum14.47719.72176461272.636597.70.48326.46713.65573714830100477861000.16639.1099.700926367514585512.30.14549.8958.931924687218.1852717.80.164511.1897.90111835014020.80.135611.7797.5069178581.22200.50.064712.8996.85761862685.520414.30.128814.4736.11511989527021.50.124915.345.77142632455.18681.80.0591015.8545.585519978816.31057522.10.2251116.2855.43842311593.37691.60.0811217.4165.08781972465.126155.50.1781317.8854.95531972284.721944.60.1611418.6934.7431972555.325625.40.1681519.4024.57122023958.247249.90.2011620.3744.35531763657.641198.60.1891721.3774.1532155611.36681.40.1841822.2213.9972153430.94410.90.1721923.2353.82511861693.515243.20.1512023.593.7682177601.211612.40.3242124.0993.68981784068.4588812.30.2432224.7073.60031801513.19241.90.1032326.3683.3772139911.914663.10.272427.6083.22841521723.620134.20.1962528.1593.16631282364.95256110.3732629.8622.9896112440.912992.70.4952731.772.814299450.97051.50.2632832.3272.76797360.74310.90.2012935.3342.538178591.27561.60.2153037.4972.3965785017931.70.266

In some embodiments of the present disclosure, the aforesaid crystal form F of the compound of Formula (III) has an XRPD pattern as shown inFIG.16.

In some embodiments of the present disclosure, the aforesaid crystal form F of the compound of Formula (III) has a differential scanning calorimetry curve with an endothermic peak at 78.73° C.±3° C., a starting point of an endothermic peak at 222.37° C.±3° C., and an exothermic peak at 245.01° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form F of the compound of Formula (III) has a DSC pattern as shown inFIG.17.

In some embodiments of the present disclosure, the aforesaid crystal form F of the compound of Formula (III) has a thermogravimetric analysis curve with a weight loss of 1.192% at 39.57° C.±3° C., a weight loss of up to 3.683% at 81.27° C.±3° C., and a weight loss of up to 6.023% at 199.63° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form F has a TGA pattern as shown inFIG.18.

In particular, the present disclosure further provides a crystal form G of the compound of Formula (III) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.23±0.2°, 7.20±0.2°, 14.30±0.2°. Further, the aforesaid crystal form G of the compound of Formula (III) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 6.23±0.2°, 7.20±0.2°, 7.81±0.2°, 11.22±0.2°, 12.38±0.2°, 14.30±0.2°, 15.90±0.2°, 18.97±0.2°.

In some embodiments of the present disclosure, the aforesaid crystal form G of the compound of Formula (III) may have XRPD analysis data as shown in Table 7. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θ value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 7XRPD analysis data of the crystal form G of the compound of Formula (III)Full Width2θdPeakPeakat Half#(±0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum14.80618.37214171168.591550.13225.93314.884635033824.71170164.20.5836.2314.1754338117986.21650490.60.23546.52713.531332614710.8259614.20.29657.19712.27292901367100182231000.22367.80911.312226038528.2417622.90.18279.59.30192101359.97584.20.09489.98.9269200654.85983.30.154910.1828.6802196624.55693.10.1541011.2177.881718428220.6313017.20.1861111.7857.5029193876.412366.80.2381212.3837.142218944232.34194230.1591312.9156.8488181574.24332.40.1271413.3276.638318616712.214718.10.1481513.9186.357620330822.5376820.70.2051614.2986.1896199101374.11187965.20.1971714.6346.047920234024.9533029.20.2631815.6175.669421219714.4372220.40.3171915.8955.571121163946.7998254.80.2622016.4395.388226614.57884.30.2172116.7375.29272189675583.10.0972217.0715.1897220604.42471.40.0692317.5555.0477213725.35092.80.1192417.9314.9428212846.110725.90.2142518.1774.8763212533.99695.30.3072618.9694.674620370251.4913550.10.2182719.9214.45321881047.6258114.20.4162820.1734.398218316412258614.20.2642921.0654.2141781279.316148.90.2133021.9844.039718818713.7229912.60.2063122.4013.965619218913.8554530.40.4923222.6793.91751971309.5445224.40.5743322.8163.89431981027.5312917.20.5143423.5283.7781911299.413027.10.1693525.3193.514717838027.8772542.40.3413626.1073.410419116512.12726150.2773727.3153.2622202977.110465.70.1813828.0633.17720120815.2442924.30.3573928.7533.102318932223.6422523.20.224030.2732.9499179523.811696.40.3774130.9052.891165906.614407.90.2684231.4542.8418173866.39275.10.1814333.082.705712954413697.50.4254433.432.6782122624.5239713.20.6484535.0192.5602118453.39715.30.3624635.4022.5334119493.69835.40.3364736.1722.4812123584.27123.90.2064836.7212.4454121624.54242.30.1154937.7492.3811118463.44292.40.1565038.5082.3359116493.63221.80.11

Further, in some embodiments of the present disclosure, the aforesaid crystal form G of the compound of Formula (III) has an XRPD pattern as shown inFIG.19.

In some embodiments of the present disclosure, the aforesaid crystal form G of the compound of Formula (III) has a differential scanning calorimetry curve with an endothermic peak at 70.13° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form G of the compound of Formula (III) has a DSC pattern as shown inFIG.20.

In some embodiments of the present disclosure, the aforesaid crystal form G of the compound of Formula (III) has a thermogravimetric analysis curve as shown inFIG.21.

In some embodiments of the present disclosure, in the aforesaid crystal forms F and G of the compound of Formula (III), the compound of Formula (III) has a structure of compound



The fourth object of the present disclosure is to further provide a compound as represented by Formula (IV):



wherein,

n4is selected from 1;

m4is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4.

In particular, the present disclosure further provides a crystal form H of the compound of Formula (IV) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.71±0.2°, 5.56±0.2°, 18.16±0.2°, and further, the aforesaid crystal form H of the compound of Formula (IV) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.71±0.2°, 5.56±0.2°, 7.98±0.2°, 8.97±0.2°, 18.16±0.2°, 22.42±0.2°, 26.37±0.2°, 27.10±0.2°.

Further, in some embodiments of the present disclosure, the aforesaid crystal form H of the compound of Formula (IV) may have XRPD analysis data as shown in Table 8. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θvalue in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 8XRPD analysis data of the crystal form H of the compound of Formula (IV)Full Width2θdPeakPeakat HalfNo.(±0.2°)(Å)BackgroundHeightHeight %AreaArea %Maximum14.7118.746769818101002732278.80.25325.55915.8846325153084.5346601000.3837.98411.065125419610.827287.90.23348.9719.849323619210.626607.70.232512.5437.05131545433831.10.119613.3616.6212156502.835810.12714.3526.16651941075.919765.70.31815.1865.82931941417.822616.50.269916.1255.4921168472.65181.50.1851016.7435.29061631558.625777.40.2791118.1634.880215826714.81195934.50.7511218.5184.787520324713.61135132.70.771319.1514.6305296874.85011.40.0971419.6594.512226794.427287.90.5791519.9214.45332081156.426497.60.3861622.423.962213219911583316.80.4911723.2683.81971365532880.80.0881826.3673.377318828916564216.30.3271927.0973.28811991015.6478913.80.7952027.5743.2322231643.510072.90.2642128.3553.1449173502.84671.30.1572229.3193.0437148703.922416.50.5372330.0352.9727154613.420455.90.5622432.922.7185109412.33851.10.157

Further, in some embodiments of the present disclosure, the aforesaid crystal form H of the compound of Formula (IV) has an XRPD pattern as shown inFIG.22.

In some embodiments of the present disclosure, the aforesaid crystal form H of the compound of Formula (IV) has a differential scanning calorimetry curve with an endothermic peak at 141.17° C.±3° C., an endothermic peak at 243.06° C.±3° C., and an exothermic peak at 257.74° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form H of the compound of Formula (IV) has a DSC pattern as shown inFIG.23.

In some embodiments of the present disclosure, the aforesaid crystal form H of the compound of Formula (IV) has a thermogravimetric analysis curve with a weight loss of 1.328% at 73.74±3° C., a weight loss of up to 4.986% at 207.43° C.±3° C., and a weight loss of up to 5.627% at 249.40° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form H of the compound of Formula (IV) has a TGA pattern as shown inFIG.24.

In particular, the present disclosure further provides a crystal form I of the compound of Formula (IV) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.89±0.2°, 6.19±0.2°, 7.45±0.2°; and further, the aforesaid crystal form I of the compound of Formula (IV) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.89±0.2°, 6.19±0.2°, 7.45±0.2°, 16.23±0.2°, 18.28±0.2°, 18.95±0.2°, 26.31±0.2°, 27.04±0.2°. In some embodiments of the present disclosure, the aforesaid crystal form I of the compound of Formula (IV) may have XRPD analysis data as shown in Table 9. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θ value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 9XRPD analysis data of the crystal form I of the compound of Formula (IV)Full WidthdPeakPeakat HalfNo.2θ(Å)BackgroundHeightHeight %AreaArea %Maximum14.88918.06043772218100315361000.23826.18814.271430154024.3589218.70.18337.45211.852824352423.6590118.70.18949.7179.0947164612.814224.50.39159.9688.866160482.2126440.441612.2257.23381501084.910073.20.156714.5296.0914164532.414924.70.472815.0225.89281791456.5221870.256915.8145.5992168863.9187960.3661016.2265.45811641305.917545.60.2261118.284.84931861697.6597518.90.5931218.9544.67831831516.8607219.30.6741319.8224.47541631064.814414.60.2281420.9234.2422134964.39653.10.1691521.8214.06961358849623.10.1831622.5753.9353135612.864520.1771723.3843.801129472.15241.70.1871826.3073.38491481516.826858.50.2981927.0353.29551661526.925718.20.2842028.123.1707168733.313084.10.32129.982.9781153823.721356.80.4372235.3662.535992361.64501.40.212338.4372.34105421.93331.10.133

Further, in some embodiments of the present disclosure, the aforesaid crystal form I of the compound of Formula (IV) has an XRPD pattern as shown inFIG.25.

In some embodiments of the present disclosure, the aforesaid crystal form I of the compound of Formula (IV) has a differential scanning calorimetry curve with an endothermic peak at 86.86° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form I of the compound of Formula (IV) has a DSC pattern as shown inFIG.26.

In some embodiments of the present disclosure, the aforesaid crystal form I of the compound of Formula (IV) has a thermogravimetric analysis curve with a weight loss of 1.298% at 46.81° C.±3° C., a weight loss of up to 3.607% at 89.20° C.±3° C. and a weight loss of up to 4.641% at 169.65° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form I of the compound of Formula (IV) has a TGA pattern as shown inFIG.27.

In particular, the present disclosure further provides a crystal form J of the compound of Formula (IV) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.97±0.2°, 16.33±0.2°, 23.92±0.2°; and further, the aforesaid crystal form J of the compound of Formula (IV) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.97±0.2°, 6.19±0.2°, 16.33±0.2°, 19.15±0.2°, 19.84±0.2°, 21.02±0.2°, 22.68±0.2°, 23.92±0.2°. Further, in some embodiments of the present disclosure, the aforesaid crystal form J of the compound of Formula (IV) may have XRPD analysis data as shown in Table 10. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θ value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 10XRPD analysis data of the crystal formJ of the compound of Formula (IV)FullWidthPeakat Half2θBack-PeakHeightAreaMaxi-#(±0.2°)d (Å)groundHeight%Area%mum14.96717.77814375372100779521000.24326.19114.2641356269529563.80.18439.948.8913169841.617762.30.354411.7737.5108145741.414531.90.329514.5696.07471451232.315041.90.205615.0435.88441511492.828163.60.317715.7395.6258158440.879110.301816.3265.42491423095.851086.60.277918.3784.82341651643.128063.60.2871019.1484.63131722244.260407.70.4521119.8394.47151452113.930163.90.241221.0214.22271222775.245685.90.2761321.7284.0869123490.93130.40.1071422.6793.91761231693.119472.50.1931523.4483.79081261272.418902.40.251623.9223.71671109681845435.80.0791726.3283.3823127105228103.60.4491827.0373.2952124951.841315.30.7291928.0433.1792128801.520332.60.4262028.6823.1098134430.84720.60.1842129.8952.98631271001.913931.80.2342230.9962.8827120641.2152320.3992334.4092.604296490.97100.90.2432439.372.286797370.72330.30.106

Further, in some embodiments of the present disclosure, the aforesaid crystal form J of the compound of Formula (IV) has an XRPD pattern as shown inFIG.28.

In some embodiments of the present disclosure, the aforesaid crystal form J of the compound of Formula (IV) has a differential scanning calorimetry curve with an endothermic peak at 61.29° C.±3° C., an endothermic peak at 86.40° C.±3° C., and an endothermic peak at 151.50° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form J of the compound of Formula (IV) has a DSC pattern as shown inFIG.29.

In some embodiments of the present disclosure, the aforesaid crystal form J of the compound of Formula (IV) has a thermogravimetric analysis curve with a weight loss of 3.412% at 220.12° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form J of the compound of Formula (IV) has a TGA pattern as shown inFIG.30.

In particular, the present disclosure further provides the crystal form K of the compound of Formula (IV) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.83±0.2°, 7.39±0.2°, 14.80±0.2°; further, the aforesaid crystal form K of the compound of Formula (IV) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 4.83±0.2°, 7.39±0.2°, 11.61±0.2°, 14.81±0.2°, 16.19±0.2°, 18.50±0.2°, 19.29±0.2°, 20.86±0.2°.

In some embodiments of the present disclosure, the aforesaid crystal form K of the compound of Formula (IV) may have XRPD analysis data as shown in Table 11. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θvalue in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 11XRPD analysis data of the crystal formK of the compound of Formula (IV)FullWidthPeakat Half2θBack-PeakHeightAreaMaxi-No.(±0.2°)d (Å)groundHeight%Area%mum14.82718.28984885225100542671000.17425.98914.74573831663.220083.70.20337.39311.94822641203231168821.50.16349.8149.00531731522.917263.20.19511.147.936169460.952710.192611.6127.61411621653.233436.20.34714.2046.2304153791.513192.40.28814.4736.11511471482.835876.60.406914.8075.97781502534.8432280.2861015.0425.8848161921.833566.20.6121116.1875.4712140315647908.80.2551218.4994.79231861843.542487.80.3871318.9334.68351411873.69242170.8291419.2874.59821742264.350229.30.3731519.664.51171801082.110021.80.1561620.8634.25421222464.738367.10.2611722.483.95171171001.913302.50.2231823.2923.81591141342.620383.80.2551926.2453.392897460.9109620.3992026.5043.360297501109620.3672127.8413.2018102701.315762.90.3772228.4773.131711850155010.1842334.2152.618578390.79061.70.389

Further, in some embodiments of the present disclosure, the aforesaid crystal form K of the compound of Formula (IV) has an XRPD pattern as shown inFIG.31.

In some embodiments of the present disclosure, the aforesaid crystal form K of the compound of Formula (IV) has a differential scanning calorimetry curve as shown inFIG.32.

In some embodiments of the present disclosure, the aforesaid crystal form K of the compound of Formula (IV) has a thermogravimetric analysis curve with a weight loss of 3.442% at 83.69° C.±3° C. and a weight loss of up to 4.947% at 183.76° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form K of the compound of Formula (IV) has a TGA pattern as shown inFIG.33.

In some embodiments of the present disclosure, in the aforesaid crystal forms H and K of the compound of Formula (IV), the compound of Formula (IV) has a structural formula of Compound IV-1.



In some embodiments of the present disclosure, in the aforesaid crystal forms I and J of the compound of Formula (IV), the compound of Formula (IV) has a structural formula of Compound IV-2.



The fifth object of the present disclosure is to further provide a compound of Formula (V) as below and its crystal forms,



wherein,

n5is selected from 0.5 and 1;

m5is selected from 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4.

In particular, the present disclosure further provides the crystal form L of the compound of Formula (V) having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 10.39±0.2°, 18.04±0.2°, 20.31±0.2°; and further, the aforesaid crystal form L of the compound of Formula (V) has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ angles of 7.91±0.2°, 10.39±0.2°, 14.18±0.2°, 16.01±0.2°, 16.47±0.2°, 18.04±0.2°, 20.31±0.2°, 21.91±0.2°. Further, in some embodiments of the present disclosure, the aforesaid crystal form L of the compound of Formula (V) may have XRPD analysis data as shown in Table 12. Persons skilled in the art can understand that as compared with the peak height with higher volatility, the 2θ value in XRPD analysis data is more suitable for characterization of the crystal form due to its smaller volatility.

TABLE 12XRPD analysis data of the crystal formL of the compound of Formula (V)FullWidthPeakat Half2θBack-PeakHeightAreaMaxi-#(±0.2°)d (Å)groundHeight%Area%mum17.90611.17424728645.5430938.80.253210.3938.504917462098.7986288.80.267311.7887.501154518.110539.50.346413.6266.49331437712.3125011.30.272514.186.240614125440.4446940.20.295615.0495.8822133629.95274.70.143715.7745.613313714322.8444940.10.522816.0125.530614424839.5525547.30.355916.4665.37916019531.1181516.30.1561017.1645.1617164548.62932.60.0911118.0444.9121153628100111051000.2961219.864.466915811217.8147713.30.2211320.3114.368713128946823874.20.4781420.8294.261216614422.9152713.80.1781521.914.053213731950.8493644.40.2591622.5383.941813920232.2349031.40.291723.1943.8318122132211332120.1691824.593.61731418112.95034.50.1041925.1243.541613814523.1272124.50.3152025.4173.5014149599.4152613.70.4342125.8943.4381417111.310809.70.2552226.353.379512214923.7231020.80.262328.1043.172510813120.9317228.60.4062428.6323.115111313621.7251522.60.312529.8212.993691386.18177.40.362631.3952.8479811518.3322729.10.472732.482.754397406.42942.60.1232834.2572.615488619.710959.90.3012935.3992.533684426.710529.50.423039.3832.28673436.87546.80.294

In some embodiments of the present disclosure, the aforesaid crystal form L of the compound of Formula (V) has an XRPD pattern as shown inFIG.34.

In some embodiments of the present disclosure, the aforesaid crystal form L of the compound of Formula (V) has a differential scanning calorimetry curve with an endothermic peak at 168.08° C.±3° C., and a starting point of an endothermic peak at 204.17° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form L of the compound of Formula (V) has a DSC pattern as shown inFIG.35.

In some embodiments of the present disclosure, the aforesaid crystal form L of the compound of Formula (V) has a thermogravimetric analysis curve with a weight loss of 0.830% at 80.19° C.±3° C., a weight loss of up to 3.058% at 149.87° C.±3° C., and a weight loss of up to 4.648% at 201.25° C.±3° C.; and further, in some embodiments of the present disclosure, the aforesaid crystal form L of the compound of Formula (V) has a TGA pattern as shown inFIG.36.

Further, in some embodiments of the present disclosure, in the aforesaid crystal form L of the compound of Formula (V), the compound of Formula (V) is Compound V-1.



The present disclosure further provides use of the aforesaid crystal forms in preparation of anti-influenza drugs.

Technical Effect

The crystal forms provided in the present disclosure have good stability, low moisture absorption, and good prospect as drugs.

In particular, the present disclosure provides free form, potassium salt form, sodium salt form, calcium salt form, hydrochloride salt form, and tosylate salt form of a pyrazolopyridine compound, as well as crystal forms corresponding to the free form and various salt forms. Further experiments indicate that the resultant crystal forms of the free form and the various salt forms all have relatively high stability, and show that the impurity content does not change significantly during storage at high temperature and high humidity, and the crystal forms remain substantially unchanged, and thus it appears that these crystal forms have better properties for drug formation; in addition, for some of the aforesaid crystal forms, they can also be used as intermediate crystal forms to prepare other stable crystal forms.

In addition, the compounds of the present disclosure also show positive effects in the tests of inhibiting influenza virus replication at cellular level, and the corresponding salt forms and their crystal forms can be understood to also have positive effects that are substantially consistent with the free form of the compounds.

Definitions and Explanations

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A specific phrase or term should not be deemed indefinite or unclear without specific definition, but understood in accordance with its ordinary meaning. When a trade name is used herein, it is intended to refer to the corresponding commercial product or its active ingredient.

The intermediate compounds of the present disclosure can be prepared by various synthetic methods which are well known to those skilled in the art, including the specific embodiments as listed below, the embodiments formed by combining the specific embodiments with other chemical synthesis methods, and equivalent alternatives which are well known to those skilled in the art. The preferred embodiments include, but are not limited to the examples of the present disclosure.

The chemical reactions of the specific embodiments of the present disclosure are performed in suitable solvent(s) which must 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 select the synthesis steps or the reaction schemes based on the existing embodiments.

Hereinafter the present disclosure will be described in details by ways of examples. These examples are not intended to limit the present disclosure in any manner.

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

The following abbreviates are used in the present disclosure: DMF represents dimethylformamide; MsOH represents methanesulfonic acid; EtOH represents ethanol; and NaOH represents sodiumhydroxide.

The compounds are named manually or by ChemDraw® software, while commercially available compounds are used with their supplier catalog names.

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

Instrument Model: Bruker D8 advance X-ray diffractometer

Detection Method: About 10-20 mg of sample is used in XRPD detection.

Detailed XRPD parameters are as follows:

Light Tube: Cu, kα, (λ=1.54056 {acute over (Å)}).

Light Tube Voltage: 40 kV, Light Tube Current: 40 mA

Divergence Slit: 0.60 mm

Detector Slit: 10.50 mm

Anti-Scatter Slit: 7.10 mm

Scanned Range: 4-40 deg

Step Size: 0.02 deg

Step Length: 0.12 sec

Rotating Speed of Sample Disc: 15 rpm

Differential Scanning Calorimeter (DSC) Method of the Present Disclosure

Instrument Model: TA Q2000 differential scanning calorimeter

Detection Method: A sample (˜1 mg) is placed in a DSC aluminum pot for detection, for which the sample is heated from 30° C. to 280° C., at a heating rate of 10° C./min, under the condition of 50 mL/min N2.

Thermal Gravimetric Analyzer (TGA) Method of the Present Disclosure

Instrument Model: TA Q5000IR thermal gravimetric analyzer

Detection Method: A sample (2-5 mg) is placed in a TGA platinum pot for detection, for which the sample is heated from room temperature to 300° C., at a heating rate of 10° C./min, under the condition of 25 mL/min N2.

High Performance Liquid Chromatograph (HPLC)

The analytic method is as follows:

TABLE 13Detection and Analysis Method of Content of Crystal Form A and Related MaterialsInstrumentAgilent 1200 High Performance Liquid ChromatographColumnAscentis Express C18, 4.6 × 150 mm, 2.7 μm (94#)Mobile Phase A0.1% aqueous solution of phosphoric acidMobile Phase BAcetonitrile solutionFlowrate1.2 mL/minInjection Volume5.0 μLDetection Wavelength210 nmColumn Temperature40° C.DiluentAcetonitrile:pure water = 3/1 (v/v)Sample Concentration0.5 mg/mLGradient Elution ProcedureTime (min)Mobile Phase A (%)Mobile Phase B (%)0.00851525.0059527.0059527.01851530.008515

TABLE 14Detection and Analysis Method of Content of Crystal Form B and Related MaterialsInstrumentAgilent 1200 High Performance Liquid ChromatographColumnAgilent Eclipse plus C18, 4.6 × 150 mm, 3.5 μm (150#)Mobile Phase A0.04% aqueous solution of trifluoroacetic acidMobile Phase BAcetonitrile solutionFlowrate1.0 mL/minInjection Volume10.0 μlDetection Wavelength220 nmColumn Temperature40° C.DiluentEthanol-water (80:20)HPLC save path:E:\ PDS-NDL\ 2017\Formulation internal\FL056Gradient Elution ProcedureTime (min)Mobile Phase A (%)Mobile Phase B (%)0.00901050.00109055.00109055.01901060.009010

