Crystalline form and salt of pyridine-n-oxide derivative, and use thereof

Abstract

The present disclosure relates to a crystalline form of a pyridine-N-oxide derivative and a preparation method therefor. Specifically, provided in the present disclosure are crystal form A, crystal form B, crystal form C, crystal form D and crystal form E of a 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamido)-2-((Z)-N'-hydroxycarbamimidoyl)pyridine1-oxide. The crystal forms have good stability and can be better used in clinical treatment.

Description

A crystalline form, salt and use of a pyridine-N-oxide derivative Technical Field

[0001] The present disclosure belongs to the field of medical technology and relates to a crystalline form of a pyridine-N-oxide diffractor, a salt thereof and uses thereof. Background Art

[0002] Nav is a type of transmembrane ion channel protein. Based on whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). Nav1.8 is a TTX-R type, encoded by the gene SCN10A, and is mainly present in trigeminal ganglion neurons and DRG neurons. It has the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rise of action potentials is mainly composed of Nav1.8 currents. In some models of neuropathic pain, nerve injury will increase the expression level of Nav1.8 in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. After carrageenan was injected into the rat paw, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice do not show normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene can cause peripheral neuropathy. Based on a series of animal studies and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy for a variety of pain types, including inflammatory pain, neuralgia, postoperative pain, and cancer pain.

[0003] PCT / CN2023 / 114740 provides a Nav1.8 inhibitor, whose chemical name is 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-((Z)-N'-hydroxycarbamimidoyl)pyridine 1-oxide, having the structure shown in Formula 1.

[0004] The crystal form of a pharmaceutically active ingredient often affects the chemical stability of the drug. Differences in crystallization and storage conditions can lead to variations in the compound's crystal structure, sometimes resulting in the formation of alternative crystal forms. Generally speaking, amorphous drug products lack a regular crystal structure and often exhibit other drawbacks, such as poor product stability, fine crystallization, difficulty in filtration, susceptibility to agglomeration, and poor flowability. Polymorphic drug forms impose varying requirements on product storage, production, and scale-up. Therefore, in-depth research into the crystal forms of these compounds is essential to improve their various properties. Summary of the Invention

[0005] The present disclosure provides a new crystalline form of the compound represented by Formula 1, which has good stability and can be better applied in clinical practice.

[0006] The crystalline form A of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.585, 11.763, 15.272, 18.662, 21.630, and 27.041.

[0007] In some embodiments, the crystalline form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.956, 7.093, 7.585, 11.763, 14.300, 15.272, 18.662, 21.630, and 27.041.

[0008] In some embodiments, the crystalline form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.956, 7.093, 7.585, 11.763, 14.300, 15.272, 18.662, 21.630, 24.349, 25.026, 25.905, and 27.041.

[0009] In some embodiments, the X-ray powder diffraction pattern of Form A of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG1 .

[0010] The present disclosure also provides a method for preparing crystalline form A of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 into methanol and stirring.

[0011] In some embodiments, the method for preparing Form A of the compound represented by Formula 1 further includes the step of adding the compound represented by Formula 1 to a water / alcohol mixed solvent and stirring, wherein the water / alcohol mixed solvent is selected from 10% water / methanol, 50% water / methanol, 80% water / methanol, and 7% water / ethanol.

[0012] The crystalline form B of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 4.834, 13.003, 16.948, 18.738, and 21.188.

[0013] In some embodiments, the crystalline form B of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 4.834, 13.003, 14.309, 15.424, 16.948, 18.738, 21.188, 22.639, and 28.062.

[0014] In some embodiments, Form B of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 4.834, 13.003, 14.055, 14.309, 15.424, 16.575, 16.948, 18.738, 19.108, 19.678, 19.950, 21.188, 22.639, 25.539, 28.062, and 31.189.

[0015] In some embodiments, the X-ray powder diffraction pattern of Form B of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG2 .

[0016] The present disclosure also provides a method for preparing the crystalline form B of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 into water, stirring, and vacuum drying.

[0017] In some embodiments, the method for preparing Form B of the compound of Formula 1 further comprises the steps of dissolving the compound of Formula 1 in tetrahydrofuran, adding water, and stirring.

[0018] The crystalline form C of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.009, 12.198, 18.422, 19.964, 23.733, and 25.818.

[0019] In some embodiments, the crystalline form C of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.009, 12.198, 14.267, 18.422, 19.964, 23.733, 25.818, 28.849, and 30.913.

[0020] In some embodiments, the X-ray powder diffraction pattern of Form C of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG3 .

[0021] The present disclosure also provides a method for preparing a crystalline form C of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to ethanol and stirring.

[0022] The crystalline form D of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.890, 12.801, 14.058, 15.731, 20.383, 22.097, and 23.634.

[0023] In some embodiments, the crystalline form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.488, 7.890, 10.200, 12.801, 14.058, 14.933, 15.731, 16.589, 19.942, 20.383, 22.097, 22.426, 23.414, 23.634, 27.134, 30.020, and 31.653.

[0024] In some embodiments, the crystalline form D of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, and has characteristic peaks at 7.488, 7.890, 10.200, 12.801, 14.058, 14.933, 15.731, 15.935, 16.589, 19.942, 20.383, 22.097, 22.426, 23.414, 23.634, 24.448, 25.636, 26.353, 27.134, 28.039, 28.807, 30.020, and 31.653.

[0025] In some embodiments, the X-ray powder diffraction pattern of Form D of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG4 .

[0026] The present disclosure also provides a method for preparing the crystalline form D of the compound represented by Formula 1, wherein the method is selected from any one of the following methods:

[0027] Method 1: Add the compound represented by Formula 1 to solvent I and stir; the solvent I is selected from one or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, and aromatic solvents;

[0028] The alcohol solvent is selected from n-propanol and isopropanol;

[0029] The ketone solvent is selected from methyl isobutyl ketone;

[0030] The ester solvent is selected from ethyl acetate and isopropyl acetate;

[0031] The ether solvent is selected from propylene glycol monomethyl ether, 1,4-dioxane, isopropyl ether, 2-methyltetrahydrofuran, and methyl tert-butyl ether;

[0032] The hydrocarbon solvent is selected from n-heptane, dichloromethane, and chloroform;

[0033] The nitrile solvent is selected from acetonitrile;

[0034] The aromatic solvent is selected from toluene;

[0035] Alternatively, method 2: dissolving the compound represented by formula 1 in solvent II, adding solvent III, and stirring, wherein the solvent II is selected from one or more of ethanol, 2-methyltetrahydrofuran, tetrahydrofuran, and 2-butanone, and the solvent III is selected from one of methyl tert-butyl ether, isopropanol, isopropyl ether, cyclohexane, and n-heptane;

[0036] Alternatively, method three: dissolving the compound represented by formula 1 in solvent IV and volatilizing the solvent, wherein the solvent IV is selected from one or more of 2-butanone, N,N-dimethylacetamide, acetone, ethyl acetate, tetrahydrofuran, and acetonitrile.

[0037] The crystalline form E of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 10.009, 16.344, 20.932, 22.602, 24.565, and 25.667.

[0038] In some embodiments, the crystalline form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 10.009, 16.344, 17.634, 19.708, 20.154, 20.932, 22.602, 23.141, 24.157, 24.565, 25.667, 26.506, 31.227, and 32.116.

[0039] In some embodiments, the crystalline form E of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, and has characteristic peaks at 10.009, 14.842, 15.415, 16.344, 17.634, 19.708, 20.154, 20.932, 22.602, 23.141, 24.157, 24.565, 25.667, 26.506, 28.781, 29.187, 29.661, 31.227, 32.116, 34.702, 35.412, and 36.123.

[0040] In some embodiments, the X-ray powder diffraction pattern of Form E of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG5 .

[0041] The present disclosure also provides a method for preparing the crystalline form E of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to 10% water / acetone and stirring.

[0042] In some embodiments, the method for preparing the crystalline form E of the compound represented by Formula 1 further comprises the steps of dissolving the compound represented by Formula 1 in acetone and volatilizing the solvent.

[0043] In some embodiments, the method for preparing the crystalline form E of the compound represented by Formula 1 further comprises the steps of dissolving the compound represented by Formula 1 in acetone, adding water, methyl tert-butyl ether or cyclohexane, and stirring.

[0044] The crystalline form F of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 12.039, 15.942, 19.256, 20.169, 20.993, and 24.293.

[0045] In some embodiments, the crystalline form F of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 12.039, 12.649, 15.942, 17.019, 17.550, 19.256, 20.169, 20.993, 24.293, 25.401, 26.517, 28.450, and 32.606.

[0046] In some embodiments, the crystalline form F of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 12.039, 12.649, 15.942, 16.330, 17.019, 17.550, 19.256, 20.169, 20.993, 22.806, 23.571, 24.293, 25.401, 26.517, 28.450, 29.153, and 32.606.

[0047] In some embodiments, the X-ray powder diffraction pattern of Form F of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG6 .

[0048] The present disclosure also provides a method for preparing the crystalline form F of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in dimethyl sulfoxide, adding water and stirring.

[0049] In some embodiments, the method for preparing Form F of the compound represented by Formula 1 further comprises the steps of dissolving the compound represented by Formula 1 in dimethyl sulfoxide and volatilizing the solvent.

[0050] The crystalline form G of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 13.853, 15.858, 19.764, 22.610, 23.919, and 28.292.

[0051] In some embodiments, the crystalline form G of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 4.606, 9.166, 10.473, 11.809, 12.740, 13.853, 14.755, 15.858, 19.764, 21.101, 22.610, 23.919, 28.292, 30.841, and 32.813.

[0052] In some embodiments, the crystalline form G of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 4.606, 9.166, 10.473, 11.809, 12.740, 13.853, 14.755, 15.858, 19.764, 21.101, 22.123, 22.610, 23.221, 23.919, 26.775, 28.292, 30.841, and 32.813.

[0053] In some embodiments, the X-ray powder diffraction pattern of Form G of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG7 .

[0054] The present disclosure also provides a method for preparing the crystalline form G of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in tetrahydrofuran and volatilizing the solvent.

[0055] The crystalline form H of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.878, 7.583, 15.302, 23.548, 27.561, and 28.276.

[0056] In some embodiments, the crystalline form H of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.878, 7.583, 9.620, 13.985, 15.302, 17.691, 19.312, 23.548, 24.842, 27.561, and 28.276.

[0057] In some embodiments, the X-ray powder diffraction pattern of Form H of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG8 .

[0058] The present disclosure also provides a method for preparing crystalline form H of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in tetrahydrofuran / ethanol (v / v=2:1) ​​and volatilizing the solvent.

[0059] The crystalline form I of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.733, 6.695, 15.840, 17.360, 18.346, and 25.687.

[0060] In some embodiments, the crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.733, 6.695, 9.180, 9.772, 10.682, 12.419, 15.840, 17.360, 18.346, 21.070, 22.629, 25.687, and 27.162.

[0061] In some embodiments, the crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.733, 6.695, 7.834, 9.180, 9.772, 10.682, 12.419, 14.769, 15.321, 15.840, 17.360, 18.346, 19.781, 20.018, 21.070, 22.629, 25.687, and 27.162.

[0062] In some embodiments, the X-ray powder diffraction pattern of Form I of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG9 .

[0063] The present disclosure also provides a method for preparing crystalline form I of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in ethyl acetate / ethanol (v / v=1:1) and volatilizing the solvent.

[0064] The crystalline form J of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.996, 7.717, 15.556, 20.746, 21.515, 22.523, 23.531, 25.814, and 27.327.

[0065] In some embodiments, Form J of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.996, 7.717, 11.060, 12.079, 12.693, 15.556, 18.496, 20.746, 21.515, 22.523, 23.531, 24.314, 25.148, 25.814, 26.605, 26.862, and 27.327.

[0066] In some embodiments, Form J of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.996, 7.717, 11.060, 12.079, 12.693, 13.859, 15.556, 17.379, 18.496, 20.746, 21.515, 22.523, 23.531, 24.314, 25.148, 25.814, 26.605, 26.862, 27.327, 28.003, 28.642, and 30.152.

[0067] In some embodiments, the X-ray powder diffraction pattern of Form J of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG10 .

[0068] The present disclosure also provides a method for preparing crystalline form J of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in acetonitrile / methanol (v / v=1:1) and volatilizing the solvent.

[0069] The crystalline form K of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 13.291, 14.032, 19.459, 20.122, 22.103, and 22.762.

[0070] In some embodiments, the crystalline form K of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 9.972, 13.291, 14.032, 14.899, 15.581, 18.865, 19.459, 20.122, 22.103, 22.762, 24.302, 26.236, 29.539, 32.179, and 33.773.

[0071] In some embodiments, the X-ray powder diffraction pattern of Form K of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG11 .

[0072] The present disclosure also provides a method for preparing a crystalline form K of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in N-methylpyrrolidone and volatilizing the solvent.

[0073] The crystalline form L of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.438, 14.121, 20.883, 21.683, and 28.129.

[0074] In some embodiments, the crystalline form L of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.438, 14.121, 14.968, 18.066, 20.883, 21.683, 22.651, 23.909, 28.129, and 28.577.

[0075] In some embodiments, the X-ray powder diffraction pattern of Form L of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG12 .

[0076] The present disclosure also provides a method for preparing a crystalline form L of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in N,N-dimethylformamide and volatilizing the solvent.

[0077] The crystalline form M of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 12.854, 15.146, 19.346, 25.229, 27.901, and 28.747.

[0078] In some embodiments, the crystalline form M of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 12.854, 15.146, 16.703, 19.346, 21.067, 22.217, 25.229, 27.901, 28.747, and 31.149.

[0079] In some embodiments, the X-ray powder diffraction pattern of Form M of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG13 .

[0080] The present disclosure also provides a method for preparing the crystalline form M of the compound represented by Formula 1, the method comprising the step of heating the crystalline form A of the compound represented by Formula 1 to 175°C.

[0081] In some embodiments, the method of preparing Form M of the compound of Formula 1 further comprises heating Form C of the compound of Formula 1 to 175°C.

[0082] In some embodiments, the method of preparing Form M of the compound of Formula 1 further comprises heating Form H of the compound of Formula 1 to 175°C.

[0083] The crystalline form N of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.885, 7.367, 12.017, 14.843, 17.518, and 24.660.

[0084] In some embodiments, the crystalline form N of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.885, 7.367, 12.017, 14.843, 17.518, 20.182, 21.270, 23.142, 24.660, 26.389, and 27.123.

[0085] In some embodiments, the crystalline form N of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.885, 7.367, 12.017, 14.843, 17.518, 20.182, 21.270, 23.142, 24.660, 26.389, 27.123, 27.935, 29.864, and 35.176.

[0086] In some embodiments, the X-ray powder diffraction pattern of Form N of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG14 .

[0087] The present disclosure also provides a method for preparing crystalline form N of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to isopropanol and stirring.

[0088] In some embodiments, the method for preparing the crystalline form N of the compound represented by Formula 1 further comprises the steps of dissolving the compound represented by Formula 1 in acetone-isopropanol (v / v=1:5) and volatilizing the solvent.

[0089] The crystalline form O of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 12.734, 13.859, 19.746, 23.841, 28.241, and 30.781.

[0090] In some embodiments, the crystalline form O of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 9.148, 10.411, 11.778, 12.734, 13.859, 15.067, 15.789, 16.775, 19.746, 23.841, 28.241, and 30.781.

[0091] In some embodiments, the crystalline form O of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 9.148, 10.411, 11.778, 12.734, 13.859, 15.067, 15.789, 16.775, 19.746, 22.122, 22.574, 23.841, 24.755, 25.601, 26.717, 28.241, and 30.781.

[0092] In some embodiments, the X-ray powder diffraction pattern of Form O of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG15 .

[0093] The present disclosure also provides a method for preparing the crystalline form O of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 into water and stirring.

[0094] The crystalline form P of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 5.782, 8.372, 11.600, 17.488, 22.142, and 23.418.

[0095] In some embodiments, the crystalline form P of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.782, 8.372, 11.600, 12.676, 13.861, 14.909, 15.620, 17.488, 18.259, 19.781, 22.142, and 23.418.

[0096] In some embodiments, the crystalline form P of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.782, 8.372, 11.600, 12.676, 13.861, 14.909, 15.620, 17.488, 18.259, 19.781, 20.864, 22.142, 23.418, 25.973, 26.683, and 27.766.

[0097] In some embodiments, the X-ray powder diffraction pattern of the crystalline form P of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG16 .

[0098] The present disclosure also provides a method for preparing a crystalline form P of a compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in 10% water / isopropanol and volatilizing the solvent.

[0099] The crystalline form Q of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.284, 7.704, 18.675, 20.591, and 26.495.

[0100] In some embodiments, the crystalline form Q of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.284, 7.704, 12.452, 15.245, 18.675, 20.591, 23.508, 26.495, and 28.507.

[0101] In some embodiments, the crystalline form Q of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.284, 7.704, 9.763, 12.452, 15.245, 18.675, 20.591, 23.508, 24.643, 24.835, 26.495, 28.507, and 29.678.

[0102] In some embodiments, the X-ray powder diffraction pattern of Form Q of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG20 .

[0103] The present disclosure also provides a method for preparing the crystalline form Q of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in 7% water / ethanol and stirring.

[0104] The crystalline form R of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 12.247, 12.818, 16.149, 17.193, 20.228, and 24.467.

[0105] In some embodiments, the crystalline form R of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 10.590, 12.247, 12.818, 16.149, 17.193, 19.381, 20.228, 21.073, 21.487, 24.467, 25.695, and 26.685.

[0106] In some embodiments, the crystalline form R of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 10.590, 12.247, 12.818, 16.149, 17.193, 17.767, 19.381, 20.228, 21.073, 21.487, 24.467, 25.695, 26.446, 26.685, 29.375, 30.918, and 37.005.

[0107] In some embodiments, the X-ray powder diffraction pattern of Form R of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG21 .

[0108] The present disclosure also provides a method for preparing the crystalline form R of the compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in dimethyl sulfoxide, adding water and stirring.

[0109] The crystalline form S of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 4.729, 7.171, 9.331, 9.999, 14.447, 19.292, and 20.945.

[0110] In some embodiments, the crystalline form S of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 4.729, 7.171, 8.313, 9.331, 9.999, 11.601, 11.993, 14.447, 19.292, 20.945, 24.404, and 24.578.

[0111] In some embodiments, the crystalline form S of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 4.729, 7.171, 8.313, 9.331, 9.999, 11.601, 11.993, 14.447, 16.215, 16.499, 17.635, 19.292, 20.945, 24.404, 24.578, 25.788, 26.256, and 28.428.

[0112] In some embodiments, the X-ray powder diffraction pattern of Form S of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG. 22 .

[0113] The present disclosure also provides a method for preparing a crystalline form S of a compound represented by Formula 1, comprising the steps of dissolving the compound represented by Formula 1 in N,N-dimethylacetamide and volatilizing the solvent.

[0114] The present disclosure also provides a pharmaceutically acceptable salt of the compound represented by Formula 1, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate

[0115] The solvent used for salt formation in the present invention is selected from but not limited to ethyl acetate, 2-butanone, and tetrahydrofuran.

[0116] The present disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by Formula 1, comprising the step of reacting the compound represented by Formula 1 with an acid selected from hydrochloric acid and sulfuric acid.

[0117] In an optional embodiment, the chemical ratio of the compound represented by Formula 1 to the acid is 3:1-1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0118] In some embodiments, the chemical ratio of the compound represented by Formula 1 and hydrochloric acid is 1:1.

[0119] In some embodiments, the chemical ratio of the compound represented by Formula 1 to hydrochloric acid is 2:1.

[0120] The hydrochloride crystalline form I of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 4.708, 10.254, 11.054, 15.516, 20.304, and 24.536.

[0121] In some embodiments, the hydrochloride salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 4.708, 4.895, 10.254, 11.054, 12.272, 15.516, 15.874, 20.304, 21.001, 22.340, 23.960, and 24.536.

[0122] In some embodiments, the hydrochloride salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 4.708, 4.895, 10.254, 11.054, 12.272, 15.516, 15.874, 19.161, 19.511, 20.304, 21.001, 22.340, 23.960, 24.536, 26.176, 26.548, and 32.923.

[0123] In some embodiments, the X-ray powder diffraction pattern of Form I of the hydrochloride salt of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2θ, is shown in FIG17 .

[0124] The present disclosure also provides a method for preparing a hydrochloride crystalline form I of the compound represented by Formula 1, comprising the steps of adding the compound represented by Formula 1 to a solvent selected from ethyl acetate, 2-butanone, and tetrahydrofuran, then adding a hydrochloric acid ethanol solution, and stirring.

[0125] The sulfate crystalline form I of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 6.308, 9.813, 12.695, 17.751, 19.182, 20.699, and 23.672.

[0126] In some embodiments, the X-ray powder diffraction pattern of the sulfate salt crystalline form I of the compound represented by Formula 1, expressed in terms of a diffraction angle 2θ, is shown in FIG18 .

[0127] The present disclosure also provides a method for preparing the sulfate crystal form I of the compound represented by Formula 1, comprising adding the compound represented by Formula 1 to a solvent selected from ethyl acetate, 2-butanone, and tetrahydrofuran, then adding a sulfuric acid ethanol solution, and then adding methyl tert-butyl ether, and stirring.

[0128] In certain embodiments, the preparation method described in the present disclosure further comprises any one of the steps of crystallization, centrifugation (filtration), washing or drying.

[0129] The crystallization method of the present disclosure includes but is not limited to stirred crystallization, static crystallization or volatile crystallization. In some embodiments, the crystallization is stirred crystallization. In some embodiments, the crystallization is static crystallization.

[0130] The present disclosure also provides a pharmaceutical composition comprising any one of the aforementioned crystalline forms A to S, hydrochloride salt, sulfate salt, hydrochloride crystalline form I or sulfate crystalline form I, and a pharmaceutical excipient selected from pharmaceutically acceptable excipients.

[0131] The present disclosure also provides a pharmaceutical composition, which is prepared from any of the aforementioned crystalline forms A to S, hydrochloride, sulfate, hydrochloride crystalline form I or sulfate crystalline form I, and optionally a pharmaceutically acceptable excipient.

[0132] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing any of the aforementioned crystalline forms A to S, hydrochloride, sulfate, hydrochloride crystalline form I or sulfate crystalline form I with a pharmaceutically acceptable excipient.

[0133] The present disclosure also provides the use of any of the aforementioned crystalline forms A to S, hydrochloride salts, sulfate salts, hydrochloride crystalline form I or sulfate crystalline form I, or the aforementioned compositions, in the preparation of a composition for preventing and / or treating pain and pain-related diseases.

[0134] The use disclosed herein, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0135] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0136] Numerical values ​​in this disclosure, such as those related to substance content, are derived from measurements and calculations, and therefore inevitably have a certain degree of error. Generally speaking, ±10% is considered within a reasonable error range. While there may be some degree of error depending on the context in which they are used, this error may not exceed ±10% and may include ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0137] The starting material used in the crystal form preparation method of the present invention can be a compound in any form, including but not limited to: amorphous, any crystal form, hydrate, solvate, etc.

[0138] The drying temperature in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and can be dried under normal pressure or reduced pressure.

[0139] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be performed during the crystallization process.

[0140] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0141] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Guiding Principles for Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0142] Deliquescent: Absorbs sufficient water to form a liquid;

[0143] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0144] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0145] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0146] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0147] The "excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier that has been approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0148] Figure 1 is the XRPD spectrum of Compound 1 Form A.

[0149] Figure 2 is the XRPD spectrum of Compound 1 Form B.

[0150] Figure 3 is the XRPD spectrum of Compound 1 Form C.

[0151] Figure 4 is the XRPD spectrum of Compound 1 Form D.

[0152] Figure 5 is the XRPD spectrum of Compound 1 Form E.

[0153] Figure 6 is the XRPD spectrum of Compound 1 Form F.

[0154] Figure 7 is the XRPD spectrum of Compound 1 Form G.

[0155] Figure 8 is the XRPD spectrum of Compound 1 Form H.

[0156] Figure 9 is the XRPD spectrum of Compound 1 Form I.

[0157] Figure 10 is the XRPD spectrum of Compound 1 Form J.

[0158] Figure 11 is the XRPD spectrum of Compound 1 Form K.

[0159] Figure 12 is the XRPD spectrum of Compound 1 Form L.

[0160] Figure 13 is the XRPD spectrum of Compound 1 Form M.

[0161] Figure 14 is the XRPD spectrum of Compound 1 Form N.

[0162] Figure 15 is the XRPD spectrum of Compound 1 Form O.

[0163] Figure 16 is the XRPD spectrum of Compound 1 Form P.

[0164] Figure 17 is the XRPD spectrum of Compound 1 hydrochloride Form I.

[0165] Figure 18 is the XRPD spectrum of Compound 1 sulfate salt Form I.

[0166] FIG19 is an XRPD spectrum of the amorphous form of Compound 1.

[0167] Figure 20 is the XRPD spectrum of Compound 1 Form Q.

[0168] Figure 21 is the XRPD spectrum of Compound 1 Form R.

[0169] Figure 22 is the XRPD spectrum of Compound 1 Form S. DETAILED DESCRIPTION

[0170] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

[0171] Test conditions of the instruments used in the experiment:

[0172] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), or deuterated methanol (CD₃OD), with tetramethylsilane (TMS) as the internal standard.

[0173] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0174] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0175] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0176] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0177] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0178] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0179] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0180] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0181] XRPD is X-ray powder diffraction detection: the measurement was carried out using a BRUKER D8 X-ray diffractometer, and the specific collection information was: Cu anode (40kV, 40mA), Cu-Kα1 ray Kα2 rays Kβ rays Scanning range (2θ range): 3-40°, scanning step size 0.02, slit width (collimator) 1.0 mm.

[0182] DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C / min. The specific temperature range was referred to the corresponding spectrum (mostly 25-250 or 25-300°C), and a nitrogen purge rate of 50 mL / min.

[0183] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C / min. The specific temperature range refers to the corresponding spectrum (mostly 30-350°C), and a nitrogen purge rate of 50 mL / min.

[0184] DVS stands for dynamic moisture sorption: the test uses SMS DVS Advantage. At 25°C, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%) (the specific humidity range is subject to the corresponding spectrum, and the method listed here is mostly used). The judgment criteria are Tmax360min and dm / dt no more than 0.002%.

[0185] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0186] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0187] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0188] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0189] Where the compounds in the examples contain two or more chiral centres, the relative stereochemistry of these compounds was determined by NMR studies and / or X-ray diffraction. In these cases, the compounds are identified using the prefix "rel" followed by the R / S nomenclature, where R / S only provides relative stereochemical information and does not indicate absolute stereochemistry.

[0190] Example 1

[0191] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-((Z)-N'-hydroxycarbamimidoyl)pyridine 1-oxide 1

[0192] first step

[0193] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-1

[0194] (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-2

[0195] rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (12 g, 33.87 mmol, prepared by the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627") was separated by chiral column (Waters SFC 150, chromatographic column: DAICEL 40*250mm, 10μm; mobile phase A: supercritical CO2, mobile phase B: IPA), gradient ratio: A:B: 90:10, flow rate: 120mL / min) to obtain the title products 1b-1 (5.5g, yield: 45.8%) and 1b-2 (5.08g, yield: 42.3%).

[0196] MS m / z(ESI):353.2[M-1].

[0197] Single configuration compound (shorter retention time) 1b-1 (5.5 g, yield: 45.8%)

[0198] MS m / z(ESI):353.2[M-1].

[0199] Chiral HPLC analysis: retention time 2.414 minutes, purity: 99% (chromatographic column: DAICEL 100*3mm, 3μm; mobile phase A: supercritical CO2, mobile phase B: IPA (0.1% DEA), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5mL / min).

[0200] Single configuration compound (longer retention time) 1b-2 (5.08 g, yield: 42.3%).

[0201] MS m / z(ESI):353.2[M-1].

[0202] Chiral HPLC analysis: retention time 2.724 minutes, purity: 99% (chromatographic column: DAICEL 100*3mm, 3μm; mobile phase A: supercritical CO2, mobile phase B: IPA (0.1% DEA), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5mL / min).

[0203] Step 2

[0204] (2R,3S,4S,5R)-N-(2-cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1d

[0205] Compound 1b-1 (50 mg, 141 μmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (40 mg, 315 μmol) and 1 drop of N,N-dimethylformamide were added under ice-cooling. The reaction was restored to room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL). N,N-diisopropylethylamine (60 mg, 464 μmol) was added, and a dichloromethane solution (1 mL) of 4-aminopyridine-2-carbonitrile 1c (30 mg, 251 μmol, Shanghai Hanhong) was added dropwise under ice-cooling. The reaction was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 1d (45 mg, yield: 70%).

[0206] MS m / z(ESI):456.2[M+1].

[0207] Step 3

[0208] 2-Cyano-4-((2R,3S,4S,5R)-)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine 1-oxide 1e

[0209] Compound 1d (300 mg, 658.8 μmol) was dissolved in chloroform (6 mL), and m-chloroperbenzoic acid (268 mg, 1.3 mmol, purity 85%) was added. The reaction was stirred at 65°C for 16 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography with eluent System A to give the title compound 1e (105 mg, yield: 33.8%).

[0210] MS m / z(ESI):472.2[M+1].

[0211] Step 4

[0212] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-((Z)-N'-hydroxycarbamimidoyl)pyridine 1-oxide 1

[0213] Compound 1e (100 mg, 212.1 μmol) was dissolved in methanol (2 mL), and hydroxylamine hydrochloride (30 mg, 431.7 μmol) and N,N-diisopropylethylamine (30 mg, 232.1 μmol) were added sequentially. The reaction was stirred at 45°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min) to obtain the title compound 1 (45 mg, yield: 42%). X-ray powder diffraction analysis revealed that the product was amorphous. The XRPD spectrum is shown in Figure 19.

[0214] MS m / z(ESI):505.1[M+1].

[0215] 1 H NMR (500MHz, DMSO-d6): δ10.71(s,1H),10.16(s,1H),8.21(d,1H),8.19(d,1H),7.69(dd,1H),7.22-7.1 0(m,2H),6.78(s,2H),5.07(d,1H),4.24(dd,1H),3.95(d,3H),2.76(p,1H),1.60(s,3H),0.73(dd,3H).

[0216] Test Example 1 Determination of the inhibitory activity of the disclosed compounds on Nav1.8

[0217] The purpose of this experiment is to investigate the effects of compounds on the Nav1.8 ion channel in vitro. The Nav1.8 ion channel is stably expressed in HEK293 cells. After the Nav1.8 current stabilizes, the magnitude of the Nav1.8 current before and after compound application is compared to determine the compound's effect on the Nav1.8 channel.

[0218] 1 Experimental materials and instruments

[0219] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp 700A (Axon instrument)

[0220] 2) Digital-to-analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon instruments)

[0221] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0222] 4) Inverted microscope: TL4 (Olympus)

[0223] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0224] 6) Microelectrode glass capillary: B12024F (Wuhan Weitan Scientific Instrument Co., Ltd.)

[0225] 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

[0226] 8)TTX AF3014 (Affix Scientific)

[0227] 2 Experimental steps

[0228] 2.1 Compound preparation

[0229] Compounds used to prepare intracellular and extracellular solutions, except for NaOH and KOH used for acid-base titration, were purchased from Sigma (St. Louis, MO). The extracellular solution (mM) consisted of: NaCl, 137; KCl, 4; CaCl₂, 1.8; MgCl₂, 1; HEPES, 10; and glucose, 10; pH 7.4 (NaOH titration). The intracellular solution (mM) consisted of: aspartic acid, 140; MgCl₂, 2; EGTA, 11; and HEPES, 10; pH 7.2 (CsOH titration). All test and control compound solutions contained 1 μM TTX.

[0230] The test compound was stored at a concentration of 9 mM and dissolved in dimethyl sulfoxide (DMSO). On the day of the test, it was redissolved in the extracellular fluid to prepare the required concentration.

[0231] 2.2 Manual patch clamp test process

[0232] 1) After the compound is prepared into a solution of the specified concentration, the solution is added to each channel in order from low to high concentration, and each channel is marked.

[0233] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and place the electrode tip in contact with the cell. Set the three-way valve of the vacuum device to the three-way position. Then, apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue applying negative pressure to rupture the cell membrane, creating a current path.

[0234] 3) After the cell membrane current stabilizes, perfuse at different concentrations. If the current remains stable for at least one minute, switch to the next concentration. Each concentration should be perfused for no more than five minutes.

[0235] 4) Clean the perfusion tank. Rinse the cells in descending order of concentration, rinsing for 20 seconds at each concentration. Finally, rinse with extracellular solution for 1 minute.

[0236] 2.3 Test voltage equation (resting) and results

[0237] Cells were clamped at -80 mV and then depolarized to 10 mV with a 10-millisecond square wave to elicit Nav1.8 currents. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was measured and, after stabilization, the test compound was perfused. Once the response stabilized, the strength of the blockade was calculated.

[0238] 3. Data Analysis

[0239] Data will be stored in a computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Management will review the results. Current stability refers to the current variation within a limited range over time. The magnitude of this stable current is used to calculate the effect of the compound at that concentration.

[0240] The inhibitory activity of the disclosed compounds on Nav1.8 was determined by the above test, and the measured IC 50 See Table 1 for values.

[0241] Table 1 IC of the compounds disclosed herein for inhibition of Nav1.8 channel activity 50

[0242] Conclusion: The compounds disclosed in the present invention have a significant inhibitory effect on the activity of Nav1.8 channels.

[0243] Test Example 2 Pharmacokinetic Evaluation of the Disclosed Compounds

[0244] Dogs were used as test animals, and the drug concentrations in the plasma of the disclosed compounds at different time points after gavage (ig) were determined by LC / MS / MS to study the pharmacokinetic behavior of the disclosed compounds in dogs and evaluate their pharmacokinetic characteristics.

[0245] 1. Experimental plan

[0246] 1.1 Investigational Drugs

[0247] Compound 1.

[0248] 1.2 Experimental animals

[0249] Four dogs, half male and half female, were provided by Weifang Shengnuo Experimental Animal Breeding Co., Ltd. (License: SCXK(Beijing)2020-0009) and Beijing Xieerxin Biological Resources Research Institute Co., Ltd. (License: SCXK(Lu)20230001). All dogs were fasted overnight and then given the drug by gavage.

[0250] 1.3 Drug preparation

[0251] A certain amount of the example compounds were weighed respectively, and 5% DMSO + 20% PG + 20% PEG400 + 55% normal saline were added to prepare a 0.4 mg / mL colorless clear solution.

[0252] 1.4 Administration

[0253] The dosage was 2 mg / kg, and the administration volume was 10.0 mL / kg.

[0254] 2. Operation

[0255] Before dosing and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0, 48.0, and 72 hours after dosing, 0.5 mL of blood was collected from the forelimb vein. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored on dry ice until analysis. The entire process from blood collection to centrifugation was performed in an ice bath. Food was consumed 2 hours after dosing.

[0256] Determination of test compound levels in dog plasma after administration of various drug concentrations: 50 μL of dog plasma samples were collected at various times post-dose, vortexed with 250 μL of acetonitrile containing the internal standard (labetalol 1 μg / mL), and centrifuged at 3700 rpm for 10 minutes. 0.5 μL of the supernatant was then analyzed by LC / MS / MS.

[0257] 3. Pharmacokinetic parameter results

[0258] Table 2 Pharmacokinetic parameters of the disclosed compounds in dogs

[0259] Conclusion: The disclosed compounds have high blood concentration, high exposure, long half-life and low clearance in dogs, and have obvious pharmacokinetic advantages.

[0260] Example 2: Preparation of Form A

[0261] 5 mg of the compound represented by Formula 1 was added to 0.5 mL of methanol, stirred to crystallize, and centrifuged. The solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as Form A. The XRPD spectrum is shown in Figure 1, and the positions of its characteristic peaks are shown in Table 3. The DSC spectrum showed an endothermic peak at 133.84°C and an exothermic peak at 162.38°C. The TGA spectrum showed a weight loss of 2.66% from 32°C to 120°C.

[0262] Table 3

[0263] Example 3: Preparation of Form A

[0264] 5 mg of the compound represented by Formula 1 was added to 0.5 mL of a solvent as shown in Table 4 below, stirred for crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain a product. X-ray powder diffraction analysis showed that the product was Form A.

[0265] Table 4

[0266] Example 4: Preparation of Form B

[0267] 120 mg of the compound represented by Formula 1 was added to 1.2 mL of water, stirred to crystallize, filtered under reduced pressure, and the collected solid was dried under vacuum at 40°C to obtain the product. X-ray powder diffraction analysis identified the product as Form B. The XRPD spectrum is shown in Figure 2, and the positions of its characteristic peaks are shown in Table 5. The DSC spectrum showed an endothermic peak at 222.86°C and an exothermic peak at 227.82°C. The TGA spectrum showed a weight loss of 1.49% from 30°C to 120°C. DVS analysis showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture absorption weight gain of approximately 0.47%; under accelerated storage conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.53%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.71%. Repeated crystal form analysis after DVS analysis revealed no change in form.

[0268] Table 5

[0269] Example 5: Preparation of Form B

[0270] 100 mg of the compound represented by Formula 1 was added to 1 mL of tetrahydrofuran to dissolve the solution, 5 mL of water was added, and the mixture was stirred for crystallization. The mixture was filtered under reduced pressure, and the solid was collected and dried under vacuum to obtain the product.

[0271] Example 6: Preparation of Form C

[0272] 5 mg of the compound represented by Formula 1 was added to 0.5 mL of ethanol, stirred to crystallize, and centrifuged. The solid was collected and dried under vacuum at 40°C to obtain the product. X-ray powder diffraction analysis identified the product as Form C. The XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 6. The DSC spectrum showed an endothermic peak at 122.00°C and an exothermic peak at 160.85°C. The TGA spectrum showed a weight loss of 4.24% between 34°C and 118°C.

[0273] Table 6

[0274] Example 7: Preparation of Form D

[0275] 120 mg of the compound represented by Formula 1 was added to 1.2 mL of ethyl acetate, stirred to crystallize, filtered under reduced pressure, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as Form D. The XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 7. The DSC spectrum showed an exothermic peak at 231.17°C. The TGA spectrum showed a weight loss of 0.50% from 30°C to 120°C. DVS analysis showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample had a moisture absorption weight gain of approximately 0.13%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.20%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.52%. After DVS analysis, the crystal form was retested and no change in form was observed.

[0276] Table 7

[0277] Example 8: Preparation of Form D

[0278] 5 mg of the compound represented by Formula 1 was added to 0.5 mL of the solvent in Table 8, stirred for crystallization, and centrifuged. The solid was collected and dried under vacuum to obtain the product.

[0279] Table 8

[0280] Example 9: Preparation of Form D

[0281] 5 mg of the compound represented by Formula 1 was added to 0.05 mL of tetrahydrofuran to dissolve the solution, and 0.5 mL of the solvent in Table 9 was added. The mixture was stirred for crystallization and centrifuged. The solid was collected and dried under vacuum to obtain the product.

[0282] Table 9

[0283] Example 10: Preparation of Form D

[0284] 5 mg of the compound represented by Formula 1 was added to 0.1 mL of 2-butanone to dissolve the solution, and 0.5 mL of the solvent in Table 10 was added. The mixture was stirred for crystallization and centrifuged. The solid was collected and dried under vacuum to obtain the product.

[0285] Table 10

[0286] Example 11: Preparation of Form D

[0287] 50 mg of the compound represented by Formula 1 was added to 1 mL of solvent A to dissolve it, and then 5 mL of solvent B was added. The solvent A and solvent B are shown in Table 11 below. The mixture was stirred for crystallization, filtered under reduced pressure, and the solid was collected and dried under vacuum to obtain the product.

[0288] Table 11

[0289] Example 12: Preparation of Form D

[0290] 5 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of the solvent in Table 12, evaporated and crystallized to obtain the product.

[0291] Table 12

[0292] Example 13: Preparation of Form E

[0293] 5 mg of the compound represented by Formula 1 was added to 0.5 mL of 10% water / acetone (v / v), stirred to crystallize, centrifuged, and the collected solid was dried under vacuum at 40°C to obtain the product. X-ray powder diffraction analysis identified the product as Form E. The XRPD spectrum is shown in Figure 5 , and the positions of its characteristic peaks are shown in Table 13. The DSC spectrum showed an endothermic peak at 141.79°C and exothermic peaks at 144.99°C and 149.99°C. The TGA spectrum showed a weight loss of 2.04% between 30°C and 100°C, and a weight loss of 4.09% between 100°C and 170°C.

[0294] Table 13

[0295] Example 14: Preparation of Form E

[0296] 5 mg of the compound shown in Formula 1 was added to 0.1 mL of acetone to dissolve the solution, and 0.5 mL of the solvent shown in Table 14 was added. The mixture was stirred for crystallization and centrifuged. The solid was collected and dried under vacuum to obtain the product.

[0297] Table 14

[0298] Example 15: Preparation of Form E

[0299] 5 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of acetone, evaporated and crystallized to obtain the product.

[0300] Example 16: Preparation of Form F

[0301] 6 mg of the compound represented by Formula 1 was added to 0.05 mL of dimethyl sulfoxide to dissolve the solution. 0.1 mL of water was added, stirred, and crystallized. The mixture was centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as Form F. The XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 15. The DSC spectrum showed an endothermic peak at 173.46°C and an exothermic peak at 216.72°C. The TGA spectrum showed a weight loss of 0.93% between 32°C and 100°C, and a weight loss of 12.24% between 100°C and 180°C.

[0302] Table 15

[0303] Example 17: Preparation of Form F

[0304] 5 mg of the compound represented by Formula 1 was dissolved in 0.05 mL of dimethyl sulfoxide, evaporated and crystallized to obtain the product.

[0305] Example 18: Preparation of Form G

[0306] 5 mg of the compound represented by Formula 1 was dissolved in 0.05 mL of tetrahydrofuran and evaporated to obtain a solid. X-ray powder diffraction analysis identified the product as Form G. The XRPD spectrum is shown in Figure 7, and the positions of its characteristic peaks are shown in Table 16. The DSC spectrum showed endothermic peaks at 62.81°C and 82.83°C, and an exothermic peak at 210.09°C. The TGA spectrum showed a weight loss of 7.39% from 30°C to 100°C.

[0307] Table 16

[0308] Example 19: Preparation of Form H

[0309] 5 mg of the compound represented by Formula 1 was dissolved in 0.05 mL of tetrahydrofuran / ethanol (v / v = 2:1) and evaporated to obtain a solid. X-ray powder diffraction analysis identified the product as Form H. The XRPD spectrum is shown in Figure 8 , and the positions of its characteristic peaks are shown in Table 17. The DSC spectrum showed endothermic peaks at 96.82°C and 123.32°C, and exothermic peaks at 158.91°C and 203.73°C. The TGA spectrum showed a weight loss of 4.70% between 30°C and 120°C.

[0310] Table 17

[0311] Example 20: Preparation of Form I

[0312] 5 mg of the compound represented by Formula 1 was dissolved in 0.25 mL of ethyl acetate / ethanol (v / v = 1:1) and evaporated to obtain a solid. X-ray powder diffraction analysis identified the product as Form I. The XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 11. The DSC spectrum showed an endothermic peak at 127.66°C and exothermic peaks at 143.55°C and 217.04°C. The TGA spectrum showed a weight loss of 4.80% from 33°C to 100°C.

[0313] Table 18

[0314] Example 21: Preparation of Form J

[0315] 5 mg of the compound represented by Formula 1 was dissolved in 0.25 mL of acetonitrile / methanol (v / v = 1:1) and evaporated to obtain a solid. X-ray powder diffraction analysis identified the product as Form J. The XRPD spectrum is shown in Figure 10 , and the positions of its characteristic peaks are shown in Table 19 .

[0316] Table 19

[0317] Example 22: Preparation of Form K

[0318] 5 mg of the compound represented by Formula 1 was dissolved in 0.05 mL of N-methylpyrrolidone and evaporated to obtain a solid. X-ray powder diffraction analysis identified the product as Form K. The XRPD spectrum is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 20.

[0319] Table 20

[0320] Example 23: Preparation of Form L

[0321] 5 mg of the compound represented by Formula 1 was dissolved in 0.05 mL of N,N-dimethylformamide and evaporated to obtain a solid. X-ray powder diffraction analysis identified the product as Form L. The XRPD spectrum is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 21. The DSC spectrum revealed an endothermic peak at 128.94°C and an exothermic peak at 219.63°C. The TGA spectrum showed a weight loss of 1.25% between 32°C and 80°C, and an 11.90% weight loss between 80°C and 160°C.

[0322] Table 21

[0323] Example 24: Preparation of Form M

[0324] Form A of the compound represented by Formula 1 was heated to 175°C to obtain the product. X-ray powder diffraction analysis identified this product as Form M. The XRPD spectrum is shown in Figure 13 , and the positions of its characteristic peaks are shown in Table 22 . The DSC spectrum revealed an exothermic peak at 201.50°C. The TGA spectrum showed a weight loss of 2.51% from 30°C to 120°C.

[0325] Table 22

[0326] Example 25: Preparation of Form M

[0327] The crystal form C of the compound represented by Formula 1 is heated to 175° C. to obtain a product. X-ray powder diffraction analysis shows that the product is crystal form M.

[0328] Example 26: Preparation of Form M

[0329] The compound of formula 1, crystal form H, was heated to 175° C. to obtain a product. X-ray powder diffraction analysis showed that the product was crystal form M.

[0330] Example 27: Preparation of Form N

[0331] 5 mg of the crystalline form of the compound represented by Formula 1 was added to 0.5 mL of isopropanol, stirred, crystallized, and centrifuged to obtain a solid. X-ray powder diffraction analysis identified this wet sample as Form N. The XRPD spectrum is shown in Figure 14 , and the positions of its characteristic peaks are shown in Table 23.

[0332] Table 23

[0333] Example 28: Preparation of Form N

[0334] 5 mg of the compound represented by Formula 1 was dissolved in 0.6 mL of acetone-isopropanol (v / v=1:5), evaporated and crystallized to obtain the product.

[0335] Example 29: Preparation of Form O

[0336] 5 mg of the compound represented by Formula 1 was added to 0.5 mL of water, stirred, crystallized, and centrifuged to obtain a solid. X-ray powder diffraction analysis identified the wet sample as Form O. The XRPD spectrum is shown in Figure 15 , and the positions of its characteristic peaks are shown in Table 24.

[0337] Table 24

[0338] Example 30: Preparation of Form P

[0339] 5 mg of the compound of Formula 1 was dissolved in 0.5 mL of 10% water / isopropanol (v / v) and evaporated to obtain a solid. X-ray powder diffraction analysis identified the product as Form P. The XRPD spectrum is shown in Figure 16 , and the positions of its characteristic peaks are shown in Table 25 .

[0340] Table 25

[0341] Example 31: Preparation of Hydrochloride Form I

[0342] To 150 mg of the compound represented by Formula 1, 1.5 mL of ethyl acetate and 156.2 μL of a 2M hydrochloric acid-ethanol solution were added. The mixture was stirred to crystallize, centrifuged, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as hydrochloride Form I. The XRPD spectrum is shown in Figure 17, and the positions of its characteristic peaks are shown in Table 26. Ion chromatography analysis revealed a chloride ion content of 6.9%. The DSC spectrum showed an exothermic peak at 204.34°C. The TGA spectrum showed a weight loss of 1.90% between 30°C and 120°C, and a weight loss of 11.98% between 120°C and 210°C. DVS analysis revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample experienced a moisture gain of approximately 0.23%; under accelerated storage conditions (i.e., 70% RH), the moisture gain was approximately 0.32%; and under extreme conditions (90% RH), the moisture gain was approximately 0.71%. The crystal form was retested after DVS detection and the crystal form remained unchanged.

[0343] Table 26

[0344] Example 32: Preparation of Hydrochloride Form I

[0345] 7 mg of the compound represented by Formula 1 was added to 0.1 mL of 2-butanone and 7.29 μL of a 2M hydrochloric acid ethanol solution. The mixture was stirred for crystallization and centrifuged. The solid was collected and dried under vacuum to obtain the product.

[0346] Example 33: Preparation of Hydrochloride Form I

[0347] 7 mg of the compound represented by Formula 1 was added to 0.1 mL of tetrahydrofuran and 7.29 μL of a 2M hydrochloric acid ethanol solution. The mixture was stirred for crystallization and centrifuged. The solid was collected and dried under vacuum to obtain the product.

[0348] Example 34: Preparation of Sulfate Crystal Form I

[0349] 7 mg of the compound represented by Formula 1 was added to 0.1 mL of 2-butanone and 7.29 μL of a 2M sulfuric acid ethanol solution to dissolve the solution. 0.5 mL of methyl tert-butyl ether was added and stirred to crystallize. The mixture was centrifuged and the solid was collected and dried under vacuum to obtain the product.

[0350] X-ray powder diffraction analysis identified the product as sulfate salt Form I. The XRPD spectrum is shown in Figure 18 , and the locations of its characteristic peaks are shown in Table 27 . Ion chromatography analysis revealed a sulfate ion content of 9.6%. DSC analysis revealed an exothermic peak at 174.29°C. TGA analysis revealed a weight loss of 5.30% between 30°C and 120°C, and a weight loss of 7.16% between 120°C and 210°C.

[0351] Table 27

[0352] Example 35: Preparation of Sulfate Crystal Form I

[0353] 7 mg of the compound of Formula 1 was added to 0.1 mL of tetrahydrofuran, followed by 7.29 μL of a 2M ethanolic sulfuric acid solution. The solution was dissolved, and 0.5 mL of methyl tert-butyl ether was added. The mixture was stirred to crystallize, centrifuged, and the solid collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was sulfate salt Form I.

[0354] Example 36: Preparation of amorphous

[0355] 50 mg of the compound represented by Formula 1 was dissolved in 10 mL of dichloromethane / ethanol (v / v=1:1) and the mixture was spin-dried to obtain a solid.

[0356] X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum was shown in FIG19 .

[0357] Example 37: Preparation of Form Q

[0358] 10 mg of the compound represented by Formula 1 was dissolved in 7% water / ethanol (v / v) at 40°C, cooled to 5°C, stirred to crystallize, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as Form Q. The XRPD spectrum is shown in Figure 20, and the positions of its characteristic peaks are shown in Table 28. The DSC spectrum revealed an endothermic peak at 116.67°C. The TGA spectrum showed a weight loss of approximately 3.50% between 43°C and 139°C.

[0359] Table 28

[0360] Example 38: Preparation of Form R

[0361] Dissolve 10 mg of the compound represented by Formula 1 in 0.1 mL of dimethyl sulfoxide (DMSO), add 0.3 mL of water, stir at room temperature to crystallize, centrifuge, and vacuum dry to obtain a solid. X-ray powder diffraction analysis identified the product as Form R. The XRPD spectrum is shown in Figure 21, and the positions of its characteristic peaks are shown in Table 29. The DSC spectrum reveals an endothermic peak at 178.51°C. The TGA spectrum shows a weight loss of approximately 0.25% between 38°C and 108°C, and a weight loss of approximately 13.30% between 108°C and 173°C.

[0362] Table 29

[0363] Example 39: Preparation of Form S

[0364] 10 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of N,N-dimethylacetamide at room temperature and allowed to evaporate and solidify at room temperature to obtain a solid product. X-ray powder diffraction analysis identified the product as Form S. The XRPD spectrum is shown in Figure 22, and the positions of its characteristic peaks are shown in Table 30. The DSC spectrum revealed an endothermic peak at 90.82°C. The TGA spectrum showed a weight loss of approximately 0.52% between 34°C and 81°C, and a weight loss of approximately 15.62% between 81°C and 135°C.

[0365] Table 30

[0366] Example 40: Study on Stability of Influencing Factors

[0367] Form B, Form D and Form I hydrochloride were laid out in an open container and their stability was investigated under high temperature (40°C, 60°C) and high humidity (RH 75%, RH 92.5%) conditions for one month.

[0368] Table 31

[0369] Table 32

[0370] Table 33

[0371] Conclusion: Form B, Form D and hydrochloride Form I have good physical and chemical stability under high temperature and high humidity conditions.

[0372] Experimental Example 41: Long-term / accelerated stability

[0373] The stability of Form B, Form D and Hydrochloride Form I were investigated under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively.

[0374] Table 34

[0375] Table 35

[0376] Table 36

[0377] Conclusion: Form B and Form D showed good physical and chemical stability under long-term accelerated conditions for 6 months. Hydrochloride Form I showed good physical and chemical stability under long-term conditions for 3 months.

Claims

1. A crystalline form A of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ has characteristic peaks at 7.585, 11.763, 15.272, 18.662, 21.630, and 27.041, preferably at 5.956, 7.093, 7.585, 11.763, 14.300, 15.272, 18.662, and 21.630, more preferably at 5.956, 7.093, 7.585, 11.763, 14.300, 15.272, 18.662, and 21.

630.

2. The crystalline form A according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG1 .

3. A method for preparing Form A according to claim 1 or 2, comprising adding the compound represented by Formula 1 to methanol or a water / alcohol mixed solvent and stirring, wherein the water / alcohol mixed solvent is selected from 10% water / methanol, 50% water / methanol, 80% water / methanol, and 7% water / ethanol.

4. A crystalline form B of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ has characteristic peaks at 4.834, 13.003, 16.948, 18.738, and 21.188, preferably at 4.834, 13.003, 14.309, 15.424, 16.948, 18.738, 21.188, 22.639, and 28.062, more preferably at 4.834, 13.003, 14.055, 14.309, 15.424, 16.575, 16.948, 18.738, 19.108, 19.678, 19.950, 21.188, 22.639, 25.539, 28.062, and 31.

189.

5. The crystal form B according to claim 4, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG2 .

6. A method for preparing the crystalline form B according to claim 4 or 5, wherein the method is selected from any one of the following methods: Method 1: Dissolve the compound represented by formula 1 in tetrahydrofuran, add water and stir; Alternatively, method 2: add the compound represented by formula 1 into water and stir.

7. A crystalline form C of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ has characteristic peaks at 6.009, 12.198, 18.422, 19.964, 23.733, and 25.818, preferably at 6.009, 12.198, 14.267, 18.422, 19.964, 23.733, 25.818, 28.849, and 30.

913.

8. The crystalline form C according to claim 7, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG3 .

9. A method for preparing the crystalline form C according to claim 7 or 8, comprising the steps of adding the compound represented by Formula 1 to ethanol and stirring.

10. A crystalline form D of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ has characteristic peaks at 7.890, 12.801, 14.058, 15.731, 20.383, 22.097, and 23.634, preferably at 7.488, 7.890, 10.200, 12.801, 14.058, 14.933, 15.731, 16.589, 19.942, 20.383, 22.097, 22.426, 23.414, 23.634, 27.134, and 30. 020 and 31.653, and more preferably there are characteristic peaks at 7.488, 7.890, 10.200, 12.801, 14.058, 14.933, 15.731, 15.935, 16.589, 19.942, 20.383, 22.097, 22.426, 23.414, 23.634, 24.448, 25.636, 26.353, 27.134, 28.039, 28.807, 30.020, and 31.

653.

11. The crystalline form D according to claim 10, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG4 .

12. A method for preparing the crystalline form D according to claim 10 or 11, wherein the method is selected from any one of the following methods: Method 1: Add the compound represented by Formula 1 to solvent I and stir; the solvent I is selected from one or more of alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, and aromatic solvents; The alcohol solvent is selected from n-propanol and isopropanol; The ketone solvent is selected from methyl isobutyl ketone; The ester solvent is selected from ethyl acetate and isopropyl acetate; The ether solvent is selected from propylene glycol monomethyl ether, 1,4-dioxane, isopropyl ether, 2-methyltetrahydrofuran, and methyl tert-butyl ether; The hydrocarbon solvent is selected from n-heptane, dichloromethane, and chloroform; The nitrile solvent is selected from acetonitrile; The aromatic solvent is selected from toluene; Alternatively, method 2: dissolving the compound represented by formula 1 in solvent II, adding solvent III, and stirring, wherein the solvent II is selected from one or more of ethanol, 2-methyltetrahydrofuran, tetrahydrofuran, and 2-butanone, and the solvent III is selected from one of methyl tert-butyl ether, isopropanol, isopropyl ether, cyclohexane, and n-heptane; Alternatively, method three: dissolving the compound represented by formula 1 in solvent IV and volatilizing the solvent, wherein the solvent IV is selected from one or more of 2-butanone, N,N-dimethylacetamide, acetone, ethyl acetate, tetrahydrofuran, and acetonitrile.

13. A crystalline form E of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 10.009, 16.344, 20.932, 22.602, 24.565, and 25.667, preferably at 10.009, 16.344, 17.634, 19.708, 20.154, 20.932, 22.602, 23.141, 24.157, 24.565, 25.667, 26.506, 31.227, 32.116 There are characteristic peaks at, more preferably at 10.009, 14.842, 15.415, 16.344, 17.634, 19.708, 20.154, 20.932, 22.602, 23.141, 24.157, 24.565, 25.667, 26.506, 28.781, 29.187, 29.661, 31.227, 32.116, 34.702, 35.412, and 36.

123.

14. The crystalline form E according to claim 13, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG5 .

15. A method for preparing the crystalline form E according to claim 13 or 14, wherein the method is selected from any one of the following methods: Method 1: Add the compound of formula 1 to 10% water / acetone and stir; Alternatively, method 2: dissolving the compound represented by formula 1 in acetone and evaporating the solvent; Alternatively, method three: dissolve the compound represented by formula 1 in acetone, add water, methyl tert-butyl ether or cyclohexane, and stir.

16. A crystalline form H of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 5.878, 7.583, 15.302, 23.548, 27.561, and 28.276, preferably at 5.878, 7.583, 9.620, 13.985, 15.302, 17.691, 19.312, 23.548, 24.842, 27.561, and 28.

276.

17. The crystalline form H according to claim 16, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG8 .

18. A method for preparing the crystalline form H according to claim 16 or 17, comprising dissolving the compound represented by Formula 1 in tetrahydrofuran / ethanol (v / v = 2:1) and volatilizing the solvent.

19. A crystalline form M of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed in terms of a diffraction angle 2θ has characteristic peaks at 12.854, 15.146, 19.346, 25.229, 27.901, and 28.747, preferably at 12.854, 15.146, 16.703, 19.346, 21.067, 22.217, 25.229, 27.901, 28.747, and 31.

149.

20. The crystalline form M according to claim 19, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG13 .

21. A method for preparing the crystalline form M according to claim 19 or 20, comprising heating the crystalline form A, crystalline form C or crystalline form H of the compound represented by Formula 1 to 175°C.

22. A crystalline form O of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 12.734, 13.859, 19.746, 23.841, 28.241, and 30.781, preferably at 9.148, 10.411, 11.778, 12.734, 13.859, 15.067, 15.789, 16.775, 19.746, 23.841, 28.241, and 30.

781. .241, and 30.781, and more preferably, there are characteristic peaks at 9.148, 10.411, 11.778, 12.734, 13.859, 15.067, 15.789, 16.775, 19.746, 22.122, 22.574, 23.841, 24.755, 25.601, 26.717, 28.241, and 30.

781.

23. The crystalline form O according to claim 22, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG15 .

24. A method for preparing the crystalline form O according to claim 22 or 23, comprising the steps of adding the compound represented by formula 1 to water and stirring.

25. A pharmaceutically acceptable salt of the compound represented by formula 1, wherein the pharmaceutically acceptable salt is selected from hydrochloride and sulfate.

26. The pharmaceutically acceptable salt according to claim 25, characterized in that The chemical ratio of the compound represented by Formula 1 to the acid is 3:1-1:3, preferably 2:1-1:2, more preferably 2:1 or 1:

1.

27. The method for preparing the pharmaceutically acceptable salt according to claim 25 or 26, comprising the step of reacting the compound represented by formula 1 with an acid selected from hydrochloric acid and sulfuric acid.

28. A hydrochloride crystalline form I of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 4.708, 10.254, 11.054, 15.516, 20.304, and 24.536, preferably at 4.708, 4.895, 10.254, 11.054, 12.272, 15.516, 15.874, 20.304, 21.001, 22.340, and 23. 960, and 24.536, and more preferably, there are characteristic peaks at 4.708, 4.895, 10.254, 11.054, 12.272, 15.516, 15.874, 19.161, 19.511, 20.304, 21.001, 22.340, 23.960, 24.536, 26.176, 26.548, and 32.

923.

29. The hydrochloride crystalline form I according to claim 28, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG17 .

30. A method for preparing the hydrochloride salt form I according to claim 28 or 29, comprising adding the compound represented by Formula 1 to a solvent V, then adding a hydrochloric acid ethanol solution, and stirring, wherein the solvent V is selected from one of ethyl acetate, 2-butanone, and tetrahydrofuran.

31. The crystal form according to any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, and 28-29, wherein the 2θ angle error range is ±0.

20.

32. A pharmaceutical composition comprising the crystalline form of any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, 28-29, or the pharmaceutically acceptable salt of claims 25-26, and optionally a pharmaceutically acceptable excipient.

33. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystalline form of any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, 28-29, or the pharmaceutically acceptable salt of claims 25-26 with a pharmaceutically acceptable excipient.

34. Use of the crystalline form of any one of claims 1-2, 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 22-23, 28-29, or the pharmaceutical composition of claim 32 in the preparation of a medicament for treating and / or preventing pain and pain-related diseases.

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