Compounds or pharmaceutically acceptable salts thereof and crystalline forms thereof

Abstract

The present disclosure provides (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one (hereinafter referred to as "Compound I") or a pharmaceutically acceptable salt thereof and a crystal form thereof. The present disclosure also provides a pharmaceutical composition comprising at least one of Compound I or a pharmaceutically acceptable salt thereof and a crystal form thereof, and a method for preparing the crystal form. The present disclosure further provides the use of Compound I or a pharmaceutically acceptable salt thereof and a crystal form thereof or a pharmaceutical composition comprising at least one of Compound I or a pharmaceutically acceptable salt thereof and a crystal form thereof in the prevention and / or treatment of a disease, particularly a disease mediated by KRAS G12C mutation. The crystal form of Compound I or a pharmaceutically acceptable salt thereof of the present disclosure is excellent in hygroscopicity, solubility and stability.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one (hereinafter referred to as “Compound I”) or a pharmaceutically acceptable salt thereof, and crystalline forms thereof. The present disclosure also relates to pharmaceutical compositions comprising at least one of Compound I or a pharmaceutically acceptable salt thereof, and crystalline forms thereof, and processes for preparing said crystalline forms. The present disclosure further relates to the use of Compound I or a pharmaceutically acceptable salt thereof, and crystalline forms thereof, or a pharmaceutical composition comprising at least one of Compound I or a pharmaceutically acceptable salt thereof, and crystalline forms thereof, for the prevention and / or treatment of a disease, in particular a disease mediated by KRAS G12C mutation. BACKGROUND

[0002] (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one (i.e. “Compound I”) has the structural formula shown below in Formula I:

[0003]

[0004] which is described in the patent application PCT / CN2022 / 074955 filed by the applicant of the present disclosure on January 29, 2021, the entire contents of which are hereby incorporated by reference in its entirety. Patent application PCT / CN2022 / 074955 discloses compounds useful as KRAS G12C inhibitors and thus can be used for the prevention and / or treatment of a disease mediated by KRAS G12C mutation, wherein Compound I and its synthetic method are disclosed in Example 22. However, this patent application does not describe Compound I or its pharmaceutically acceptable salts in crystalline solid forms, nor does it suggest one or more properties of these crystalline forms that are beneficial for formulating a pharmaceutical dosage form. In view of the usefulness of Compound I in the prevention and / or treatment of various diseases, there has been a long-felt need for polymorphic forms of Compound I or pharmaceutically acceptable salts that exhibit one or more properties (e.g. including but not limited to hygroscopicity, solubility, and stability) that are advantageous for formulating a pharmaceutical dosage form, but satisfactory results have not been achieved to date. SUMMARY

[0005] The present disclosure relates generally to Compound I or a pharmaceutically acceptable salt thereof and crystalline forms thereof.

[0006] In some embodiments, the present disclosure relates to crystalline forms of Compound I. In other embodiments, the present disclosure relates to crystalline forms of pharmaceutically acceptable salts (i.e., salt forms) of Compound I.

[0007] In some embodiments, the pharmaceutically acceptable salt of Compound I of the present disclosure is at least one selected from hydrochloride, methanesulfonate, maleate, L-tartrate, benzenesulfonate, toluenesulfonate, sulfate, hydrobromide, citrate, L-malate, L-camphorsulfonate, fumarate, and trifluoroacetate.

[0008] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate, a pharmaceutically acceptable salt of Compound I, and a pharmaceutically acceptable excipient.

[0009] In some embodiments, the present disclosure relates to a method for preparing a crystalline form of Compound I or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate, a pharmaceutically acceptable salt of Compound I, or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate, a pharmaceutically acceptable salt of Compound I, and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a disease.

[0011] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate, a pharmaceutically acceptable salt of Compound I, or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate, a pharmaceutically acceptable salt of Compound I, and a pharmaceutically acceptable excipient, for use as a KRAS G12C mutant protein inhibitor.

[0012] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate, a pharmaceutically acceptable salt of Compound I, or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate, a pharmaceutically acceptable salt of Compound I, and a pharmaceutically acceptable excipient, for use as a cell proliferation inhibitor.

[0013] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a disease mediated by KRAS G12C mutation.

[0014] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a malignant tumor (e.g., a cancer or a sarcoma).

[0015] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a malignant tumor (e.g., a cancer or a sarcoma).

[0016] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a malignant tumor (e.g., a cancer or a sarcoma).

[0017] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a malignant tumor (e.g., a cancer or a sarcoma).

[0018] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) use of a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the prevention and / or treatment of a malignant tumor (e.g., a cancer or a sarcoma).

[0019] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) use of a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I in the manufacture of a medicament for use as a KRAS G12C mutant protein inhibitor.

[0020] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) use of a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I in the manufacture of a medicament for use as a cell proliferation inhibitor.

[0021] In some embodiments, the present disclosure relates to (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I or (2) use of a pharmaceutical composition comprising at least one selected from a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of Compound I citrate salt, a pharmaceutically acceptable salt of Compound I in the manufacture of a medicament for the prevention and / or treatment of a disease mediated by KRAS G12C mutation.

[0022] In some embodiments, the present disclosure relates to a use of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the manufacture of a medicament for preventing and / or treating a malignant tumor (e.g., a cancer or a sarcoma).

[0023] In some embodiments, the present disclosure relates to a method of preventing and / or treating a disease mediated by KRAS G12C mutation, comprising administering to a subject in need thereof a therapeutically effective amount of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient.

[0024] In some embodiments, the present disclosure relates to a method of preventing and / or treating a malignant tumor (e.g., a cancer or a sarcoma), comprising administering to a subject in need thereof a therapeutically effective amount of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient.

[0025] In some embodiments, the cancer is selected from one or more of pancreatic cancer, leukemia, esophageal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, colorectal cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine cancer, and thyroid cancer.

[0026] In some embodiments, the sarcoma is osteosarcoma.

[0027] [1] A crystalline form of Compound I represented by the following formula I

[0028]

[0029] [2] The crystalline form according to [1], wherein the crystalline form is Compound I crystalline form Y1, characterized in that the Compound I crystalline form Y1 has the following features:

[0030] I) has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at diffraction angles 2Q values of 10.516°±0.2°, 18.360°±0.2° and 19.345°±0.2°; or has an XRPD pattern substantially the same as that shown in Figure 2A. Figure 1

[0031] [3] The crystalline form according to [2], characterized in that the XRPD pattern of the Compound I crystalline form Y1 has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at diffraction angles 2Q values of 10.516°±0.2°, 14.451°±0.2°, 14.889°±0.2°, 18.360°±0.2°, 19.345°±0.2°, 21.210°±0.2° and 22.070°±0.2°.

[0032] [4] The crystalline form according to [2], characterized in that the XRPD pattern of the Compound I crystalline form Y1 has characteristic peaks in the X-ray powder diffraction (XRPD) pattern at diffraction angles 2Q values of 10.516°±0.2°, 11.381°±0.2°, 12.907°±0.2°, 13.107°±0.2°, 13.729°±0.2°, 14.171°±0.2°, 14.451°±0.2°, 14.889°±0.2°, 16.672°±0.2°, 18.360°±0.2°, 18.701°±0.2°, 19.345°±0.2°, 20.367°±0.2°, 21.210°±0.2°, 21.589°±0.2°, 22.070°±0.2°, 22.467°±0.2°, 23.057°±0.2°, 23.529°±0.2°, 23.893°±0.2°, 24.675°±0.2°, 25.158°±0.2°, 26.881°±0.2°, 27.201°±0.2°, 27.822°±0.2°, 28.425°±0.2° and 35.665°±0.2°.

[0033] [5] The crystalline form according to any one of [2] to [4], characterized in that the Compound I crystalline form Y1 further has at least one feature selected from:

[0034] II) has endothermic peaks at about 58°C and about 271°C, respectively, in the differential scanning calorimetry (DSC) pattern, or has a DSC pattern substantially the same as that shown in Figure 2B. Figure 2

[0035] III) has a mass loss of about 2.8% at 30°C to 150°C in the thermogravimetric analysis (TGA) pattern, or has a TGA pattern substantially the same as that shown in Figure 2C. Figure 3 ​​a TGA pattern substantially the same as shown in FIG. 2.

[0036] [6] The crystalline form of [1], wherein the crystalline form is Compound I Form Y2, characterized in that the Compound I Form Y2 has the following characteristics:

[0037] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 18.080°±0.2°, 20.359°±0.2° and 21.180°±0.2°; or an XRPD pattern substantially the same as shown in FIG. 3. Figure 4 an XRPD pattern substantially the same as shown in FIG. 3.

[0038] [7] The crystalline form of [6], characterized in that the Compound I Form Y2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 17.220°±0.2°, 18.080°±0.2°, 20.359°±0.2°, 21.180°±0.2°, 22.660°±0.2°, 24.758°±0.2° and 28.538°±0.2°.

[0039] [8] The crystalline form of [6], characterized in that the Compound I Form Y2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.379°±0.2°, 9.597°±0.2°, 10.202°±0.2°, 11.217°±0.2°, 12.478°±0.2°, 13.762°±0.2°, 14.322°±0.2°, 15.039°±0.2°, 16.220°±0.2°, 17.220°±0.2°, 18.080°±0.2°, 19.319°±0.2°, 20.359°±0.2°, 21.180°±0.2°, 22.660°±0.2°, 23.879°±0.2°, 24.758°±0.2°, 26.119°±0.2°, 26.940°±0.2°, 28.538°±0.2°, 30.880°±0.2° and 37.501°±0.2°.

[0040] [9] A crystalline form of a pharmaceutically acceptable salt of Compound I represented by the following formula I

[0041]

[0042] The pharmaceutically acceptable salt of Compound I is at least one selected from the group consisting of a hydrochloride, a mesylate, a maleate, an L-tartrate, a besylate, a tosylate, a sulfate, a hydrobromide, a citrate, an L-malate, an L-camsylate, a fumarate and a trifluoroacetate.

[0043]

[10] The crystalline form according to [9], which is Compound I hydrochloride Form H1, characterized in that the Compound I hydrochloride Form H1 has the following characteristics:

[0044] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.425°±0.2°, 7.952°±0.2° and 14.249°±0.2°; or an XRPD pattern substantially the same as that shown in Figure 2A. Figure 5

[0045]

[11] The crystalline form according to

[10] , characterized in that the Compound I hydrochloride Form H1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.425°±0.2°, 7.952°±0.2°, 14.249°±0.2°, 17.662°±0.2°, 19.303°±0.2°, 20.647°±0.2° and 21.309°±0.2°.

[0046]

[12] The crystalline form according to

[10] , characterized in that the Compound I hydrochloride Form H1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.425°±0.2°, 6.388°±0.2°, 7.952°±0.2°, 12.443°±0.2°, 14.249°±0.2°, 14.551°±0.2°, 16.820°±0.2°, 17.662°±0.2°, 19.303°±0.2°, 20.647°±0.2°, 21.309°±0.2°, 22.151°±0.2° and 23.631°±0.2°.

[0047]

[13] The crystalline form according to any one of

[10] to

[12] , characterized in that the Compound I hydrochloride Form H1 further has at least one characteristic selected from:

[0048] II) a DSC pattern having endothermic peaks at about 54°C and about 143°C, respectively; or a DSC pattern substantially the same as that shown in Figure 3A. Figure 6

[0049] III) a TGA pattern having mass loss gradients of about 3.5% at 30°C to 105°C and about 8.1% at 105°C to 180°C; or a TGA pattern substantially the same as that shown in Figure 4A. Figure 7

[0050]

[14] The crystalline form according to [9], which is Compound I hydrochloride Form H2, characterized in that the Compound I hydrochloride Form H2 has the following characteristics:​​​

[0051] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 10.540°±0.2°, 18.422°±0.2° and 19.461°±0.2°; or having an XRPD pattern substantially the same as shown in Figure 2A. Figure 8

[0052]

[15] The crystalline form of

[14] , characterized in that the XRPD pattern of Compound I hydrochloride Form H2 has characteristic peaks at diffraction angles 2Q values of 5.648°±0.2°, 10.540°±0.2°, 14.873°±0.2°, 18.422°±0.2°, 19.461°±0.2° and 21.243°±0.2°.

[0053]

[16] The crystalline form of

[14] , characterized in that the XRPD pattern of Compound I hydrochloride Form H2 has characteristic peaks at diffraction angles 2Q values of 5.648°±0.2°, 10.540°±0.2°, 11.420°±0.2°, 13.349°±0.2°, 13.709°±0.2°, 14.873°±0.2°, 18.422°±0.2°, 19.461°±0.2°, 20.306°±0.2°, 21.243°±0.2°, 21.685°±0.2°, 22.853°±0.2°, 25.251°±0.2° and 26.840°±0.2°.

[0054]

[17] The crystalline form of any one of

[14] -

[16] , characterized in that the Compound I hydrochloride Form H2 further has at least one feature selected from:

[0055] II) a DSC pattern having an endothermic peak at about 150°C; or having a DSC pattern substantially the same as shown in Figure 3A. Figure 9

[0056] III) a TGA pattern having a mass loss of about 4.95% from 30°C to 180°C; or having a TGA pattern substantially the same as shown in Figure 4A. Figure 10

[0057]

[18] The crystalline form of [9], which is Compound I mesylate Form M1, characterized in that the Compound I mesylate Form M1 has the following features:

[0058] ​​​I) has characteristic peaks in the XRPD pattern at diffraction angles 2Q values of 16.149° ± 0.2°, 17.060° ± 0.2°, and 20.387° ± 0.2°; or has an XRPD pattern substantially the same as shown in Figure 2A. Figure 11

[0059]

[19] The crystalline form of

[18] , characterized in that the Compound I mesylate salt Form Ml has characteristic peaks in the XRPD pattern at diffraction angles 2Q values of 7.212° ± 0.2°, 10.740° ± 0.2°, 13.465° ± 0.2°, 16.149° ± 0.2°, 17.060° ± 0.2°, 20.387° ± 0.2°, and 22.026° ± 0.2°.

[0060]

[20] The crystalline form of

[18] , characterized in that the Compound I mesylate salt Form Ml has characteristic peaks in the XRPD pattern at diffraction angles 2Q values of 7.212° ± 0.2°, 9.300° ± 0.2°, 9.674° ± 0.2°, 10.740° ± 0.2°, 13.465° ± 0.2°, 14.433° ± 0.2°, 16.149° ± 0.2°, 16.576° ± 0.2°, 17.060° ± 0.2°, 17.500° ± 0.2°, 17.904° ± 0.2°, 18.501° ± 0.2°, 19.658° ± 0.2°, 20.006° ± 0.2°, 20.387° ± 0.2°, 21.149° ± 0.2°, 22.026° ± 0.2°, 22.327° ± 0.2°, 23.309° ± 0.2°, 23.650° ± 0.2°, and 24.695° ± 0.2°.

[0061]

[21] The crystalline form of any one of

[18] to

[20] , characterized in that the Compound I mesylate salt Form Ml further has at least one feature selected from:

[0062] II) has an endothermic peak at about 61 °C in the DSC pattern; or has a DSC pattern substantially the same as shown in Figure 3A. Figure 12

[0063] III) has a mass loss of about 2.04% at 30 °C to 105 °C in the TGA pattern; or has a TGA pattern substantially the same as shown in Figure 4A. Figure 13

[0064]

[22] The crystalline form of [9], which is Compound I mesylate salt Form M2, characterized in that the Compound I mesylate salt Form M2 has the following features:​​​

[0065] I) In the XRPD pattern, characteristic peaks are present at diffraction angles 2θ of 8.876°±0.2°, 17.896°±0.2°, and 18.679°±0.2°; or characteristic peaks are present at diffraction angles 2θ of 8.876°±0.2°, 17.896°±0.2°, and 18.679°±0.2°. Figure 14 The XRPD maps shown are essentially the same XRPD maps.

[0066]

[23] According to the crystal form described in

[22] , the characteristic feature is that the XRPD pattern of the crystal form M2 of compound I methanesulfonate has characteristic peaks at diffraction angles 2θ of 7.848°±0.2°, 8.876°±0.2°, 10.341°±0.2°, 14.470°±0.2°, 17.896°±0.2°, 18.679°±0.2° and 27.503°±0.2°.

[0067]

[24] According to the crystal form described in

[22] , the XRPD pattern of the methanesulfonate crystal form M2 of compound I has diffraction angles of 7.848°±0.2°, 8.876°±0.2°, 10.341°±0.2°, 11.640°±0.2°, 13.449°±0.2°, 14.470°±0.2°, 15.671°±0.2°, 17.317°±0.2°, and 17.8°±0.2° at 2θ values. Characteristic peaks are present at 96°±0.2°, 18.180°±0.2°, 18.679°±0.2°, 19.803°±0.2°, 20.847°±0.2°, 21.345°±0.2°, 21.791°±0.2°, 22.206°±0.2°, 22.850°±0.2°, 23.533°±0.2°, 25.937°±0.2°, and 27.503°±0.2°.

[0068]

[25] The crystal form according to any one of

[22] -

[24] is characterized in that the crystal form M2 of compound I methanesulfonate further has at least one feature selected from the following:

[0069] II) In the DSC spectrum, there is no obvious endothermic peak before the decomposition temperature, or it has a peak similar to... Figure 15 The DSC spectra shown are essentially the same DSC spectra; and

[0070] III) In the TGA spectrum, there is a mass loss gradient of approximately 0.96% between 30℃ and 105℃, or a gradient similar to... Figure 16 The TGA plot shown is essentially the same TGA plot.

[0071]

[26] The crystalline form according to [9], which is Compound I mesylate salt crystalline form M3, characterized in that the Compound I mesylate salt crystalline form M3 has the following characteristics:

[0072] I) an XRPD pattern substantially the same as shown in Figure 22. Figure 17

[0073]

[27] The crystalline form according to

[26] , characterized in that the Compound I mesylate salt crystalline form M3 has an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 9.343°±0.2°, 13.040°±0.2°, 14.641°±0.2°, 16.759°±0.2°, 19.799°±0.2°, 23.079°±0.2° and 24.041°±0.2°.

[0074]

[28] The crystalline form according to

[26] , characterized in that the Compound I mesylate salt crystalline form M3 has an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 9.101°±0.2°, 9.343°±0.2°, 10.221°±0.2°, 11.560°±0.2°, 12.098°±0.2°, 13.040°±0.2°, 13.579°±0.2°, 13.859°±0.2°, 14.641°±0.2°, 15.320°±0.2°, 15.599°±0.2°, 16.759°±0.2°, 18.181°±0.2°, 18.762°±0.2°, 19.799°±0.2°, 20.480°±0.2°, 20.877°±0.2°, 21.256°±0.2°, 21.761°±0.2°, 22.420°±0.2°, 23.079°±0.2°, 24.041°±0.2°, 27.141°±0.2°, 28.360°±0.2°, 29.098°±0.2°, 29.642°±0.2° and 31.701°±0.2°.

[0075]

[29] The crystalline form according to [9], which is Compound I maleate salt crystalline form MA1, characterized in that the Compound I maleate salt crystalline form MA1 has the following characteristics:

[0076] I) an XRPD pattern substantially the same as shown in Figure 23. Figure 18 ​an XRPD pattern substantially the same as that shown in Figure 2.

[0077]

[30] The crystalline form according to

[29] , characterized in that the XRPD pattern of the Compound I maleate salt crystalline form MA1 has characteristic peaks at diffraction angles 2Q values of 9.918°±0.2°, 17.780°±0.2°, 21.448°±0.2°, 22.231°±0.2° and 24.538°±0.2°.

[0078]

[31] The crystalline form according to

[29] , characterized in that the XRPD pattern of the Compound I maleate salt crystalline form MA1 has characteristic peaks at diffraction angles 2Q values of 7.990°±0.2°, 9.918°±0.2°, 10.678°±0.2°, 13.748°±0.2°, 14.249°±0.2°, 15.354°±0.2°, 16.792°±0.2°, 17.139°±0.2°, 17.780°±0.2°, 18.974°±0.2°, 19.463°±0.2°, 20.583°±0.2°, 21.448°±0.2°, 22.231°±0.2°, 24.538°±0.2°, 25.198°±0.2°, 26.060°±0.2°, 27.928°±0.2° and 30.234°±0.2°.

[0079]

[32] The crystalline form according to any one of

[29] -

[31] , characterized in that the Compound I maleate salt crystalline form MA1 further has at least one feature selected from:

[0080] II) in a DSC pattern, has endothermic peaks at about 93 °C and about 170 °C, respectively, or has a DSC pattern substantially the same as that shown in Figure 3; and Figure 19 a DSC pattern substantially the same as that shown in Figure 3; and

[0081] III) in a TGA pattern, has a mass loss of about 9.3% at 30-140 °C, or has a TGA pattern substantially the same as that shown in Figure 4. Figure 20 a TGA pattern substantially the same as that shown in Figure 4.

[0082]

[33] The crystalline form according to [9], which is Compound I L-tartrate salt crystalline form J1, characterized in that the Compound I L-tartrate salt crystalline form J1 has the following features:

[0083] I) in an XRPD pattern, has characteristic peaks at diffraction angles 2Q values of 15.760°±0.2°, 17.499°±0.2° and 23.560°±0.2°, or has an XRPD pattern substantially the same as that shown in Figure 5; and Figure 21an XRPD pattern substantially the same as that shown in FIG. 8.

[0084]

[34] The crystalline form according to

[33] , characterized in that the compound IL-tartrate salt Form J1 has characteristic peaks in an XRPD pattern at diffraction angles 2Q values of 7.880°±0.2°, 12.440°±0.2°, 15.760°±0.2°, 17.499°±0.2°, 23.560°±0.2°, 24.140°±0.2°, 25.640°±0.2° and 28.479°±0.2°.

[0085]

[35] The crystalline form according to

[33] , characterized in that the compound IL-tartrate salt Form J1 has characteristic peaks in an XRPD pattern at diffraction angles 2Q values of 5.520°±0.2°, 6.279°±0.2°, 7.880°±0.2°, 12.440°±0.2°, 13.982°±0.2°, 14.499°±0.2°, 14.919°±0.2°, 15.760°±0.2°, 17.179°±0.2°, 17.499°±0.2°, 18.561°±0.2°, 19.296°±0.2°, 19.981°±0.2°, 20.919°±0.2°, 21.641°±0.2°, 22.859°±0.2°, 23.560°±0.2°, 24.140°±0.2°, 25.640°±0.2°, 27.119°±0.2°, 28.479°±0.2°, 31.001°±0.2° and 36.181°±0.2°.

[0086]

[36] The crystalline form according to [9], which is compound IL-tartrate salt Form J2, characterized in that the compound IL-tartrate salt Form J2 has the following characteristics:

[0087] I) in an XRPD pattern, has characteristic peaks at diffraction angles 2Q values of 8.140°±0.2°, 14.120°±0.2° and 26.160°±0.2°, or has an XRPD pattern substantially the same as that shown in FIG. 10. Figure 22 an XRPD pattern substantially the same as that shown in FIG. 8

[0088]

[37] The crystalline form according to

[36] , characterized in that the compound IL-tartrate salt Form J2 has characteristic peaks in an XRPD pattern at diffraction angles 2Q values of 8.140°±0.2°, 14.120°±0.2°, 16.302°±0.2°, 21.680°±0.2°, 22.858°±0.2°, 23.679°±0.2° and 26.160°±0.2°.

[0089]

[38] The crystalline form of

[36] , characterized by an XRPD pattern of the compound IL-tartrate Form J2 having characteristic peaks at diffraction angles 2Q values of 8.140°±0.2°, 14.120°±0.2°, 15.138°±0.2°, 16.302°±0.2°, 17.501°±0.2°, 18.221°±0.2°, 18.500°±0.2°, 20.259°±0.2°, 20.721°±0.2°, 21.680°±0.2°, 22.858°±0.2°, 23.679°±0.2°, 26.160°±0.2°, 28.838°±0.2°, 31.019°±0.2°, 32.058°±0.2°, and 33.799°±0.2°.

[0090]

[39] The crystalline form of any one of

[36] -

[38] , characterized in that the compound IL-tartrate Form J2 further has at least one feature selected from:

[0091] II) an endothermic peak at about 206 °C in a DSC pattern, or a DSC pattern substantially identical to the DSC pattern shown in Figure 23 ; and

[0092] III) a mass loss gradient of about 3% at 30 °C to 170 °C in a TGA pattern, or a TGA pattern substantially identical to the TGA pattern shown in Figure 24 .

[0093]

[40] The crystalline form of [9], which is Compound I besylate Form B1, characterized in that the Compound I besylate Form B1 has the following features:

[0094] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 4.742°±0.2°, 9.477°±0.2°, and 13.504°±0.2°, or an XRPD pattern substantially identical to the XRPD pattern shown in Figure 25 .

[0095]

[41] The crystalline form of

[40] , characterized in that the XRPD pattern of the Compound I besylate Form B1 has characteristic peaks at diffraction angles 2Q values of 4.742°±0.2°, 7.149°±0.2°, 9.477°±0.2°, 10.900°±0.2°, and 13.504°±0.2°.

[0096]

[42] The crystalline form of

[40] , characterized by an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 4.742°±0.2°, 7.149°±0.2°, 9.477°±0.2°, 9.877°±0.2°, 10.900°±0.2°, 13.504°±0.2° and 20.804°±0.2° of the Compound I besylate Form B1.

[0097]

[43] The crystalline form of [9], which is Compound I besylate Form B2, characterized by the following features of the Compound I besylate Form B2:

[0098] I) an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 12.432°±0.2°, 18.292°±0.2° and 22.894°±0.2°, or an XRPD pattern essentially the same as that shown in Figure 2B of Figure 26

[0099]

[44] The crystalline form of

[43] , characterized by an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 6.788°±0.2°, 12.432°±0.2°, 18.292°±0.2°, 19.339°±0.2° and 22.894°±0.2° of the Compound I besylate Form B2.

[0100]

[45] The crystalline form of

[43] , characterized by an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 5.173°±0.2°, 6.788°±0.2°, 8.607°±0.2°, 10.677°±0.2°, 11.211°±0.2°, 12.432°±0.2°, 12.689°±0.2°, 13.734°±0.2°, 14.700°±0.2°, 15.730°±0.2°, 16.437°±0.2°, 17.364°±0.2°, 18.292°±0.2°, 19.339°±0.2°, 20.208°±0.2°, 20.543°±0.2°, 21.905°±0.2°, 22.894°±0.2°, 23.800°±0.2°, 24.453°±0.2°, 25.076°±0.2°, 25.574°±0.2°, 26.147°±0.2° and 28.396°±0.2° of the Compound I besylate Form B2.

[0101]

[46] The crystalline form of [9], which is Compound I tosylate Form T1, characterized by the following features of the Compound I tosylate Form T1: ​

[0102] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 9.554°±0.2°, 14.730°±0.2° and 24.153°±0.2°, or having an XRPD pattern substantially identical to that shown in Figure 2A. Figure 27 I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 9.554°±0.2°, 14.730°±0.2° and 24.153°±0.2°, or having an XRPD pattern substantially identical to that shown in Figure 2A.

[0103]

[47] The crystalline form of

[46] , characterized in that the Compound I tosylate salt Form T1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 9.554°±0.2°, 14.730°±0.2°, 18.763°±0.2°, 20.586°±0.2°, 21.609°±0.2° and 24.153°±0.2°.

[0104]

[48] The crystalline form of

[46] , characterized in that the Compound I tosylate salt Form T1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 4.305°±0.2°, 7.310°±0.2°, 8.213°±0.2°, 9.554°±0.2°, 12.927°±0.2°, 14.730°±0.2°, 15.495°±0.2°, 16.316°±0.2°, 17.379°±0.2°, 17.779°±0.2°, 18.763°±0.2°, 19.182°±0.2°, 19.762°±0.2°, 20.586°±0.2°, 21.609°±0.2°, 22.830°±0.2°, 24.153°±0.2°, 24.558°±0.2°, 24.916°±0.2°, 26.141°±0.2°, 27.862°±0.2° and 32.355°±0.2°.

[0105]

[49] The crystalline form of any one of

[46] -

[48] , characterized in that the Compound I tosylate salt Form T1 further has at least one feature selected from:

[0106] II) a DSC pattern having an endothermic peak at about 301 °C, or having a DSC pattern substantially identical to that shown in Figure 3A. Figure 28 II) a DSC pattern having an endothermic peak at about 301 °C, or having a DSC pattern substantially identical to that shown in Figure 3A.

[0107] III) a TGA pattern having a mass loss gradient of about 0.26% at 30-105 °C, or having a TGA pattern substantially identical to that shown in Figure 4A. Figure 29 III) a TGA pattern having a mass loss gradient of about 0.26% at 30-105 °C, or having a TGA pattern substantially identical to that shown in Figure 4A.

[0108]

[50] The crystalline form of [9], which is Compound I tosylate salt crystalline Form T2, characterized in that the Compound I tosylate salt crystalline Form T2 has the following characteristics:

[0109] I) an XRPD pattern substantially the same as shown in Figure 2A. Figure 30

[0110]

[51] The crystalline form of

[50] , characterized in that the Compound I tosylate salt crystalline Form T2 has an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 4.284°±0.2°, 7.273°±0.2°, 7.690°±0.2°, 8.715°±0.2°, 13.008°±0.2°, 16.334°±0.2° and 17.659°±0.2°.

[0111]

[52] The crystalline form of

[50] , characterized in that the Compound I tosylate salt crystalline Form T2 has an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 4.284°±0.2°, 7.273°±0.2°, 7.690°±0.2°, 8.715°±0.2°, 10.917°±0.2°, 11.280°±0.2°, 11.542°±0.2°, 12.086°±0.2°, 13.008°±0.2°, 13.746°±0.2°, 15.511°±0.2°, 16.334°±0.2°, 17.659°±0.2°, 19.882°±0.2°, 23.210°±0.2° and 25.899°±0.2°.

[0112]

[53] The crystalline form of any one of

[50] -

[52] , characterized in that the Compound I tosylate salt crystalline Form T2 further has at least one characteristic selected from:

[0113] II) a DSC pattern substantially the same as shown in Figure 3A. Figure 31

[0114] III) a TGA pattern substantially the same as shown in Figure 4A. Figure 32

[0115] ​​​

[54] The crystalline form according to [9], which is Compound I sulfate salt Form S1, characterized in that the Compound I sulfate salt Form S1 has the following characteristics:

[0116] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.146°±0.2°, 7.250°±0.2° and 18.921°±0.2°, or having an XRPD pattern essentially the same as that shown in Figure 2A. Figure 33

[0117]

[55] The crystalline form according to

[54] , characterized in that the Compound I sulfate salt Form S1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.146°±0.2°, 7.250°±0.2°, 9.177°±0.2°, 13.709°±0.2°, 16.093°±0.2°, 18.921°±0.2° and 23.033°±0.2°.

[0118]

[56] The crystalline form according to

[54] , characterized in that the Compound I sulfate salt Form S1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.146°±0.2°, 7.250°±0.2°, 9.177°±0.2°, 12.766°±0.2°, 13.709°±0.2°, 15.613°±0.2°, 16.093°±0.2°, 17.215°±0.2°, 18.921°±0.2°, 20.527°±0.2°, 21.188°±0.2°, 23.033°±0.2°, 23.994°±0.2°, 24.375°±0.2°, 24.837°±0.2° and 26.340°±0.2°.

[0119]

[57] The crystalline form according to any one of

[54] to

[56] , characterized in that the Compound I sulfate salt Form S1 further has at least one of the following characteristics:

[0120] II) a DSC pattern having an endothermic peak around about 301 °C, or having a DSC pattern essentially the same as that shown in Figure 3A. Figure 34

[0121] III) a TGA pattern having a mass loss gradient of about 0.25% from 30 °C to 105 °C, or having a TGA pattern essentially the same as that shown in Figure 4A. Figure 35

[0122] ​​​

[58] The crystalline form according to [9], which is Compound I sulfate salt Form S2, characterized in that the Compound I sulfate salt Form S2 has the following characteristics:

[0123] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.841°±0.2°, 16.160°±0.2° and 21.261°±0.2°, or an XRPD pattern substantially identical to that shown in Figure 2A. Figure 36

[0124]

[59] The crystalline form according to

[58] , characterized in that the Compound I sulfate salt Form S2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 6.842°±0.2°, 7.841°±0.2°, 13.819°±0.2°, 16.160°±0.2°, 21.261°±0.2° and 25.440±0.2°.

[0125]

[60] The crystalline form according to

[58] , characterized in that the Compound I sulfate salt Form S2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 3.360°±0.2°, 6.842°±0.2°, 7.841°±0.2°, 8.821°±0.2°, 9.637°±0.2°, 10.521°±0.2°, 11.799°±0.2°, 13.819°±0.2°, 14.594°±0.2°, 16.160°±0.2°, 17.461°±0.2°, 18.176°±0.2°, 19.105°±0.2°, 21.261°±0.2°, 22.399°±0.2°, 23.479°±0.2° and 25.440±0.2°.

[0126]

[61] The crystalline form according to [9], which is Compound I hydrobromide salt Form Br1, characterized in that the Compound I hydrobromide salt Form Br1 has the following characteristics:

[0127] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 10.475°±0.2°, 18.341°±0.2° and 19.342°±0.2°, or an XRPD pattern substantially identical to that shown in Figure 3A. Figure 37

[0128] ​​

[62] The crystalline form of

[61] , characterized by an XRPD pattern of the Compound I hydrobromide Form Brl having characteristic peaks at diffraction angles 2Q values of 8.771°±0.2°, 10.475°±0.2°, 14.792°±0.2°, 18.341°±0.2°, 19.342°±0.2°, 21.127°±0.2° and 25.097°±0.2°.

[0129]

[63] The crystalline form of

[61] , characterized by an XRPD pattern of the Compound I hydrobromide Form Brl having characteristic peaks at diffraction angles 2Q values of 5.659°±0.2°, 8.771°±0.2°, 10.475°±0.2°, 12.018°±0.2°, 13.629°±0.2°, 14.792°±0.2°, 15.319°±0.2°, 18.341°±0.2°, 19.001°±0.2°, 19.342°±0.2°, 20.228°±0.2°, 21.127°±0.2°, 21.548°±0.2°, 22.047°±0.2°, 22.411°±0.2°, 22.895°±0.2°, 23.912°±0.2°, 24.711°±0.2°, 25.097°±0.2°, 26.741°±0.2°, 27.162°±0.2°, 28.305°±0.2° and 29.187°±0.2°.

[0130]

[64] The crystalline form of any one of

[61] -

[63] , characterized in that the Compound I hydrobromide Form Brl further has at least one of the following characteristics:

[0131] II) has a DSC pattern substantially the same as shown in FIG. 2A; and Figure 38 III) has a TGA pattern substantially the same as shown in FIG. 2B.

[0132] III) has a TGA pattern substantially the same as shown in FIG. 2B. Figure 39

[0133]

[65] The crystalline form of [9], which is Compound I citrate Form Nl, characterized in that the Compound I citrate Form Nl has the following characteristics:

[0134] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 14.324°±0.2°, 17.125°±0.2° and 20.879°±0.2°, or having an XRPD pattern substantially the same as shown in FIG. 3A; and Figure 40 ​an XRPD pattern substantially the same as shown in FIG. 2.

[0135]

[66] The crystalline form of

[65] , characterized by an XRPD pattern of Compound I citrate Form Nl having characteristic peaks at diffraction angles 2Q values of 8.996° ± 0.2°, 10.083° ± 0.2°, 14.324° ± 0.2°, 17.125° ± 0.2°, 20.879° ± 0.2°, 23.798° ± 0.2°, and 27.431° ± 0.2°.

[0136]

[67] The crystalline form of

[65] , characterized by an XRPD pattern of Compound I citrate Form Nl having characteristic peaks at diffraction angles 2Q values of 7.693° ± 0.2°, 8.996° ± 0.2°, 10.083° ± 0.2°, 11.107° ± 0.2°, 12.747° ± 0.2°, 14.324° ± 0.2°, 15.116° ± 0.2°, 15.830° ± 0.2°, 16.475° ± 0.2°, 16.771° ± 0.2°, 17.125° ± 0.2°, 18.268° ± 0.2°, 19.831° ± 0.2°, 20.879° ± 0.2°, 21.571° ± 0.2°, 22.337° ± 0.2°, 22.872° ± 0.2°, 23.385° ± 0.2°, 23.798° ± 0.2°, 24.626° ± 0.2°, 26.207° ± 0.2°, 26.759° ± 0.2°, 27.431° ± 0.2°, 28.004° ± 0.2°, 28.277° ± 0.2°, 28.891° ± 0.2°, 30.530° ± 0.2°, 32.678° ± 0.2°, 34.772° ± 0.2°, 35.362° ± 0.2°, 36.546° ± 0.2°, 37.257° ± 0.2°, and 37.928° ± 0.2°.

[0137]

[68] The crystalline form of any one of

[65] -

[67] , characterized in that the Compound I citrate Form Nl further has at least one characteristic selected from:

[0138] II) exhibits dehydration upon heating to about 71 °C, or has a DSC pattern substantially the same as shown in FIG. 3; and Figure 41 a DSC pattern substantially the same as shown in FIG. 3; and

[0139] III) has a mass loss gradient of about 2.31% at 30 °C to 180 °C, or has a TGA pattern substantially the same as shown in FIG. 4. Figure 42 a TGA pattern substantially the same as shown in FIG. 4.

[0140]

[69] The crystalline form according to [9], which is Compound IL-malate Form P1, characterized in that the Compound IL-malate Form P1 has the following characteristics:

[0141] I) in the XRPD pattern, characteristic peaks XRPD at diffraction angles 2θ values of 10.477°±0.2°, 14.087°±0.2° and 22.369°±0.2°, or having an XRPD pattern substantially identical to that shown in Figure 19. Figure 45

[0142]

[70] The crystalline form according to

[69] , characterized in that the XRPD pattern of the Compound IL-malate Form P1 has characteristic peaks at diffraction angles 2θ values of 7.471°±0.2°, 10.477°±0.2°, 14.087°±0.2°, 17.275°±0.2°, 19.003°±0.2°, 22.369°±0.2° and 26.101°±0.2°.

[0143]

[71] The crystalline form according to

[69] , characterized in that the XRPD pattern of the Compound IL-malate Form P1 has characteristic peaks at diffraction angles 2θ values of 7.471°±0.2°, 8.333°±0.2°, 9.672°±0.2°, 10.200°±0.2°, 10.477°±0.2°, 14.087°±0.2°, 14.670°±0.2°, 15.211°±0.2°, 16.013°±0.2°, 16.735°±0.2°, 17.275°±0.2°, 17.500°±0.2°, 19.003°±0.2°, 19.466°±0.2°, 20.081°±0.2°, 20.506°±0.2°, 21.068°±0.2°, 21.410°±0.2°, 21.828°±0.2°, 22.369°±0.2°, 23.360°±0.2°, 23.834°±0.2°, 24.176°±0.2°, 24.996°±0.2°, 26.101°±0.2°, 26.863°±0.2°, 28.183°±0.2°, 28.424°±0.2°, 29.011°±0.2° and 29.987°±0.2°.

[0144]

[72] The crystalline form according to [9], which is Compound IL-camphorsulfonate Form Z1, characterized in that the Compound IL-camphorsulfonate Form Z1 has the following characteristics:

[0145] ​I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 6.309°±0.2°, 11.141°±0.2°, and 16.054°±0.2°, or having an XRPD pattern substantially the same as shown in Figure 2A. Figure 46

[0146]

[73] The crystalline form according to

[72] , characterized in that the compound IL-camphorsulfonate salt Form Z1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 6.309°±0.2°, 11.141°±0.2°, 14.571°±0.2°, 16.054°±0.2°, and 19.962°±0.2°.

[0147]

[74] The crystalline form according to

[72] , characterized in that the compound IL-camphorsulfonate salt Form Z1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 6.309°±0.2°, 10.600°±0.2°, 11.141°±0.2°, 14.571°±0.2°, 16.054°±0.2°, 16.834°±0.2°, and 19.962°±0.2°.

[0148]

[75] The crystalline form according to [9], which is Compound I fumarate salt Form F1, characterized in that the Compound I fumarate salt Form F1 has the following characteristics:

[0149] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 11.483°±0.2°, 14.713°±0.2°, and 18.240°±0.2°, or having an XRPD pattern substantially the same as shown in Figure 2A. Figure 47

[0150]

[76] The crystalline form according to

[75] , characterized in that the compound I fumarate salt Form F1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 9.397°±0.2°, 11.483°±0.2°, 14.713°±0.2°, 18.240°±0.2°, and 20.605°±0.2°.

[0151] ​​

[77] The crystalline form of

[75] , characterized by an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 8.432°±0.2°, 8.712°±0.2°, 9.397°±0.2°, 10.697°±0.2°, 10.978°±0.2°, 11.483°±0.2°, 12.770°±0.2°, 13.304°±0.2°, 14.383°±0.2°, 14.713°±0.2°, 15.411°±0.2°, 15.651°±0.2°, 16.178°±0.2°, 17.159°±0.2°, 17.555°±0.2°, 18.240°±0.2°, 18.619°±0.2°, 20.125°±0.2°, 20.605°±0.2°, 21.590°±0.2°, 23.192°±0.2°, and 24.537°±0.2°.

[0152]

[78] The crystalline form of [9], which is Compound I trifluoroacetate salt Form TF1, characterized in that the Compound I trifluoroacetate salt Form TF1 has the following characteristics:

[0153] I) an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 14.431°±0.2°, 17.718°±0.2°, and 18.519°±0.2°, or an XRPD pattern essentially the same as the XRPD pattern shown in Figure 48

[0154]

[79] The crystalline form of

[78] , characterized by an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 7.850°±0.2°, 10.640°±0.2°, 14.431°±0.2°, 17.718°±0.2°, 18.519°±0.2°, 20.731°±0.2°, and 27.600°±0.2°.

[0155] ​

[80] The crystalline form of

[78] , characterized by an XRPD pattern comprising characteristic peaks at diffraction angles 2Q values of 7.850°±0.2°, 8.792°±0.2°, 10.294°±0.2°, 10.640°±0.2°, 11.591°±0.2°, 12.804°±0.2°, 13.407°±0.2°, 14.431°±0.2°, 15.473°±0.2°, 15.829°±0.2°, 17.378°±0.2°, 17.718°±0.2°, 18.058°±0.2°, 18.519°±0.2°, 19.507°±0.2°, 19.897°±0.2°, 20.731°±0.2°, 21.466°±0.2°, 21.726°±0.2°, 22.716°±0.2°, 23.236°±0.2°, 23.875°±0.2°, 24.510°±0.2°, 26.039°±0.2°, 27.321°±0.2°, and 27.600°±0.2° of Compound I trifluoroacetate salt Form TF1.

[0156]

[81] The crystalline form of any one of

[78] -

[80] , characterized by further having at least one feature selected from:

[0157] II) an endothermic peak at about 239 °C in a DSC pattern, or having a DSC pattern substantially the same as the DSC pattern shown in Figure 49 ; and

[0158] III) a mass loss gradient of about 0.46% at 30-105 °C in a TGA pattern, or having a TGA pattern substantially the same as the TGA pattern shown in Figure 50 .

[0159]

[82] A method of preparing a crystalline form of Compound I of any one of [1]-[8], the method comprising: step (1) dissolving Compound I in a first solvent,

[0160] optional step (2) adding a second solvent to the solution of step (1),

[0161] step (3) crystallizing, filtering to obtain the crystalline form of Compound I.

[0162]

[83] The method of preparation of

[82] , wherein,

[0163] In the dissolution of step (1), the solution is warmed to 45-75°C (preferably 50-70°C), and the crystallization of step (3) is carried out at a temperature of 10-30°C (preferably 20-25°C).

[0164]

[84] The production method according to

[82] , wherein,

[0165] When step (2) is present, the volume ratio of the first solvent to the second solvent is 1:5 to 5:1, preferably 1:3 to 3:1, more preferably 1:2 to 2:1.

[0166]

[85] The production method according to

[82] , wherein,

[0167] After the filtration of step (3), drying is carried out, preferably vacuum drying.

[0168]

[86] A method for producing a crystal form of a pharmaceutically acceptable salt of Compound I according to any one of [9] to

[81] , the method comprising:

[0169] Step (1) dissolving Compound I in a first solvent,

[0170] Step (2) adding an acid solution,

[0171] Optional step (3) wherein a second solvent is added to the solution of step (2),

[0172] Step (4) crystallization, filtration, to obtain a crystal form of a pharmaceutically acceptable salt of Compound I.

[0173]

[87] The production method according to

[86] , wherein,

[0174] After step (2), a crystal form of a pharmaceutically acceptable salt of Compound I is added as a seed crystal.

[0175]

[88] A method for producing a crystal form of a pharmaceutically acceptable salt of Compound I according to any one of [9] to

[81] , the method comprising:

[0176] Step (1) dissolving a crystal form of a pharmaceutically acceptable salt of Compound I in a first solvent or a mixed solvent of a first solvent and a second solvent,

[0177] Step (4) crystallization, filtration, to obtain a crystal form of a pharmaceutically acceptable salt of Compound I, wherein the crystal form of a pharmaceutically acceptable salt of Compound I in step (1) is different from or the same as the crystal form of a pharmaceutically acceptable salt of Compound I as the product.

[0178]

[89] The production method according to

[88] , wherein,

[0179] After step (1), a crystal form of a pharmaceutically acceptable salt of Compound I is added as a seed crystal.

[0180]

[90] The production method according to

[86] or

[88] , wherein,

[0181] In the dissolution of step (1), the solution is warmed to 20-75°C (preferably 20-70°C), and the crystallization of step (4) is carried out at a temperature of 10-30°C (preferably 15-25°C).

[0182]

[91] The production method according to

[86] , wherein,

[0183] The acid in step (2) is at least one selected from the group consisting of hydrochloric acid, methanesulfonic acid, maleic acid, L-tartaric acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, hydrobromic acid, citric acid, L-malic acid, L-camphorsulfonic acid, fumarate, and trifluoroacetate.

[0184]

[92] The production method according to

[86] , wherein,

[0185] The solvent of the acid solution in step (2) is a third solvent.

[0186]

[93] The production method according to

[92] , wherein, the third solvent is the same as or different from the first solvent.

[0187]

[94] The production method according to

[86] or

[88] , wherein, in step (4), the volume ratio of the first solvent to the second solvent in the solution at the time of crystallization is 1:6 to 6:1, preferably 1:2 to 5:1, more preferably 1:1 to 5:1.

[0188]

[95] The production method according to

[82] ,

[86] , or

[88] , wherein, the first solvent is an organic solvent selected from the group consisting of alcohols, ketones, (cyclo)ethers, alkyl nitriles, esters, alkanes, or a mixture of two or more thereof, or a mixture of the aforementioned organic solvent and water.

[0189]

[96] The production method according to

[95] , wherein, water is not present in the first solvent,

[0190] or water is present in the first solvent, and the volume ratio of the organic solvent to water is 5:1 to 50:1, preferably 5:1 to 20:1.

[0191]

[97] The production method according to

[95] , wherein, the first solvent is at least one organic solvent selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, methanol, ethanol, isopropanol, acetonitrile, and ethyl acetate, or a mixture of the aforementioned organic solvent and water, for example, 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution, 95% (V / V) acetone aqueous solution.

[0192]

[98] The production method according to

[82] ,

[86] or

[88] , wherein the second solvent is selected from the group consisting of alkanes, ethers, esters and water, or a mixture of two or more thereof, preferably the second solvent is at least one selected from the group consisting of alkanes, ethers, esters and water.

[0193]

[99] The production method according to

[98] , wherein the second solvent is at least one selected from the group consisting of n-hexane, n-heptane, diethyl ether, methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate and water.

[0194]

[100] The production method according to

[92] , wherein the third solvent is an organic solvent selected from the group consisting of alcohols, ketones, (cyclo)ethers, alkyl nitriles, esters, alkanes, or a mixture of two or more thereof, or a mixture of the aforementioned organic solvent and water.

[0195]

[101] The production method according to

[100] , wherein the third solvent is at least one organic solvent selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, methanol, ethanol, isopropanol, acetonitrile and ethyl acetate, or a mixture of the aforementioned organic solvent and water.

[0196]

[102] The production method according to

[101] , wherein the third solvent is at least one selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, isopropanol, ethanol, acetonitrile, 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution, 95% (V / V) acetone aqueous solution, acetone-water (volume ratio 2:1), acetonitrile-water (volume ratio 6:1), acetonitrile-water (volume ratio 8:1), ethanol-water (volume ratio 10:1) and tetrahydrofuran-water (volume ratio 10:1).

[0197]

[103] The production method according to

[86] , wherein,

[0198] When the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1:1 to 50:1, preferably 2:1 to 20:1.

[0199]

[104] The production method according to

[86] , wherein,

[0200] When the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1:1 to 12:1, preferably 2:1 to 11:1.

[0201]

[105] The production method according to

[82] ,

[86] or

[88] , wherein nitrogen replacement is performed during the dissolving process of step (1).

[0202]

[106] The production method according to

[86] or

[88] , wherein, after the filtration of step (4), drying is performed, preferably vacuum drying.

[0203]

[107] A method for producing a crystal form Yl of Compound I, the method comprising: step (1) dissolving Compound I in a first solvent selected from at least one of tetrahydrofuran, 2-butanone, acetone,

[0204] step (2) adding a second solvent selected from at least one of n-heptane, methyl tert-butyl ether, water to the solution of step (1), the volume ratio of the first solvent to the second solvent being 1:5 to 5:1, preferably 1:3 to 3:1, more preferably 1:2 to 2:1,

[0205] step (3) crystallization, filtration, to obtain a crystal form Yl of Compound I.

[0206]

[108] A method for producing a citrate salt crystal form Nl of Compound I, the method comprising:

[0207] step (1) dissolving Compound I in a first solvent selected from at least one of tetrahydrofuran, acetonitrile, ethanol, acetone, 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution,

[0208] step (2) adding a citric acid or citric acid monohydrate solution, the solvent of the solution being one organic solvent selected from tetrahydrofuran, ethanol, acetone, or a mixed solution of one organic solvent selected from tetrahydrofuran, ethanol, acetone and water, preferably in the case of the mixed solution, the volume ratio of the organic solvent to water being 1:1 to 50:1, preferably 2:1 to 20:1, more preferably 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution, acetonitrile-water (8:1) mixed solution, ethanol-water (10:1) mixed solution, tetrahydrofuran-water (10:1) mixed solution,

[0209] optional step (3) wherein methyl tert-butyl ether is added as a second solvent to the solution of step (2), the volume ratio of the first solvent to the second solvent being 1:2 to 3:1, preferably 1:1 to 2:1,

[0210] step (4) crystallization, filtration, to obtain a citrate salt crystal form Nl of Compound I.

[0211]

[109] A method for producing a citrate salt crystal form Nl of Compound I, the method comprising: step (1) dissolving Compound I in acetonitrile,

[0212] step (2) adding a citric acid or citric acid monohydrate acetonitrile-water solution, wherein the volume ratio of acetonitrile to water is 6:1 to 10:1, preferably 7:1 to 9:1,

[0213] Step (4) is crystallized, filtered to obtain compound I citrate salt crystal form N1.

[0214]

[110] Single crystal of compound I, which has the following characteristics:

[0215] belongs to the orthorhombic space group P212121 with cell parameters α = 90°, β = 90 = °, γ = 90°, V =

[0216]

[111] Single crystal of compound I citrate salt, characterized in that the single crystal of compound I citrate salt has the following characteristics:

[0217] belongs to the monoclinic space group P21 with cell parameters α = 90°, β = 109.972 (2) °, γ = 90°, Z = 2.

[0218]

[112] A pharmaceutically acceptable salt of compound I, which is at least one selected from the group consisting of hydrochloride, methanesulfonate, maleate, L-tartrate, benzenesulfonate, toluenesulfonate, sulfate, hydrobromide, L-malate, L-camphorsulfonate, fumarate and trifluoroacetate.

[0219]

[113] A pharmaceutical composition comprising at least one selected from the group consisting of the compound I crystal form according to any one of [1] to [8] and the crystal form of the pharmaceutically acceptable salt of compound I according to any one of [9] to

[81] , the single crystal of compound I according to

[110] , the single crystal of compound I citrate salt according to

[111] and the pharmaceutically acceptable salt of compound I according to

[112] , and a pharmaceutically acceptable excipient.

[0220]

[114] Use of the compound I crystal form according to any one of [1] to [8], the crystal form of the pharmaceutically acceptable salt of compound I according to any one of [9] to

[81] , the single crystal of compound I according to

[110] , the single crystal of compound I citrate salt according to

[111] , the pharmaceutically acceptable salt of compound I according to

[112] or the pharmaceutical composition according to

[113] in the preparation of at least one of the following inhibitors / drugs:

[0221] 1) KRAS G12C mutant protein inhibitor;

[0222] 2) cell proliferation inhibitor;

[0223] 3) a medicament for preventing and / or treating a disease mediated by KRAS G12C mutation;

[0224] 4) a medicament for preventing and / or treating a malignant tumor, e.g., a carcinoma or a sarcoma.

[0225]

[115] The use according to

[114] , wherein the cancer is selected from one or more of pancreatic cancer, leukemia, esophageal cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), breast cancer, colorectal cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine cancer, cervical cancer, testicular cancer, brain cancer, head or neck cancer, lymphoma, and thyroid cancer.

[0226]

[116] The use according to

[114] , wherein the sarcoma is osteosarcoma. BRIEF DESCRIPTION OF DRAWINGS

[0227] Figure 1 An XRPD pattern of Compound I Form Y1 is shown.

[0228] Figure 2 A DSC pattern of Compound I Form Y1 is shown.

[0229] Figure 3 A TGA pattern of Compound I Form Y1 is shown.

[0230] Figure 4 An XRPD pattern of Compound I Form Y2 is shown.

[0231] Figure 5 An XRPD pattern of Compound I Hydrochloride Form H1 is shown.

[0232] Figure 6 A DSC pattern of Compound I Hydrochloride Form H1 is shown.

[0233] Figure 7 A TGA pattern of Compound I Hydrochloride Form H1 is shown.

[0234] Figure 8 An XRPD pattern of Compound I Hydrochloride Form H2 is shown.

[0235] Figure 9 A DSC pattern of Compound I Hydrochloride Form H2 is shown.

[0236] Figure 10 A TGA pattern of Compound I Hydrochloride Form H2 is shown.

[0237] Figure 11 An XRPD pattern of Compound I Mesylate Form M1 is shown.

[0238] Figure 12 A DSC pattern of Compound I mesylate salt Form M1 is shown.

[0239] Figure 13 A TGA pattern of Compound I mesylate salt Form M1 is shown.

[0240] Figure 14 An XRPD pattern of Compound I mesylate salt Form M2 is shown.

[0241] Figure 15 A DSC pattern of Compound I mesylate salt Form M2 is shown.

[0242] Figure 16 A TGA pattern of Compound I mesylate salt Form M2 is shown.

[0243] Figure 17 An XRPD pattern of Compound I mesylate salt Form M3 is shown.

[0244] Figure 18 An XRPD pattern of Compound I maleate salt Form MA1 is shown.

[0245] Figure 19 A DSC pattern of Compound I maleate salt Form MA1 is shown.

[0246] Figure 20 A TGA pattern of Compound I maleate salt Form MA1 is shown.

[0247] Figure 21 An XRPD pattern of Compound IL-tartrate salt Form J1 is shown.

[0248] Figure 22 An XRPD pattern of Compound IL-tartrate salt Form J2 is shown.

[0249] Figure 23 A DSC pattern of Compound IL-tartrate salt Form J2 is shown.

[0250] Figure 24 A TGA pattern of Compound IL-tartrate salt Form J2 is shown.

[0251] Figure 25 An XRPD pattern of Compound I besylate salt Form B1 is shown.

[0252] Figure 26 An XRPD pattern of Compound I besylate salt Form B2 is shown.

[0253] Figure 27 An XRPD pattern of Compound I tosylate salt Form T1 is shown.

[0254] Figure 28 A DSC pattern of Compound I tosylate Form T1 is shown.

[0255] Figure 29 A TGA pattern of Compound I tosylate Form T1 is shown.

[0256] Figure 30 An XRPD pattern of Compound I tosylate Form T2 is shown.

[0257] Figure 31 A DSC pattern of Compound I tosylate Form T2 is shown.

[0258] Figure 32 A TGA pattern of Compound I tosylate Form T2 is shown.

[0259] Figure 33 An XRPD pattern of Compound I sulfate Form S1 is shown.

[0260] Figure 34 A DSC pattern of Compound I sulfate Form S1 is shown.

[0261] Figure 35 A TGA pattern of Compound I sulfate Form S1 is shown.

[0262] Figure 36 An XRPD pattern of Compound I sulfate Form S2 is shown.

[0263] Figure 37 An XRPD pattern of Compound I hydrobromide Form Br1 is shown.

[0264] Figure 38 A DSC pattern of Compound I hydrobromide Form Br1 is shown.

[0265] Figure 39 A TGA pattern of Compound I hydrobromide Form Br1 is shown.

[0266] Figure 40 An XRPD pattern of Compound I citrate Form N1 is shown.

[0267] Figure 41 A DSC pattern of Compound I citrate Form N1 is shown.

[0268] Figure 42 A TGA pattern of Compound I citrate Form N1 is shown.

[0269] Figure 43 A single crystal structure of Compound I citrate is shown.

[0270] Figure 44 A comparison of the simulated XRPD pattern of Compound I citrate single crystal and the XRPD pattern of the citrate Form Nl prepared in Example 31 is shown.

[0271] Figure 45 The XRPD pattern of Compound IL-malate Form PI is shown.

[0272] Figure 46 The XRPD pattern of Compound IL-camphorsulfonate Form Zl is shown.

[0273] Figure 47 The XRPD pattern of Compound I fumarate Form Fl is shown.

[0274] Figure 48 The XRPD pattern of Compound I trifluoroacetate Form TF1 is shown.

[0275] Figure 49 The DSC pattern of Compound I trifluoroacetate Form TF1 is shown.

[0276] Figure 50 The TGA pattern of Compound I trifluoroacetate Form TF1 is shown.

[0277] Figure 51 The DVS pattern of Compound I Form Yl is shown.

[0278] Figure 52 The DVS pattern of Compound I mesylate Form Ml is shown.

[0279] Figure 53 The DVS pattern of Compound I mesylate Form M2 is shown.

[0280] Figure 54 The DVS pattern of Compound IL-tartrate Form J2 is shown.

[0281] Figure 55 The DVS pattern of Compound I besylate Form B2 is shown.

[0282] Figure 56 The DVS pattern of Compound I tosylate Form Tl is shown.

[0283] Figure 57 The DVS pattern of Compound I sulfate Form SI is shown.

[0284] Figure 58 The DVS pattern of Compound I citrate Form Nl is shown.

[0285] Figure 59 The DVS pattern of Compound I trifluoroacetate Form TF1 is shown.

[0286] Figure 60 Compound I citrate Form Nl was shown to be stable in crystalline form under high humidity.

[0287] Figure 61 Compound I citrate Form Nl was shown to be stable in crystalline form under high temperature.

[0288] Figure 62 Compound I citrate Form Nl was shown to be stable in crystalline form at 40 degrees Celsius.

[0289] Figure 63 Compound I citrate Form Nl was shown to be stable in crystalline form at 60 degrees Celsius.

[0290] Figure 64 A plot of mouse tumor volume change was shown.

[0291] Figure 65 A plot of single crystal structure of Compound I was shown. DETAILED DESCRIPTION

[0292] DEFINITIONS

[0293] It should be understood that the terms used herein are to be given their broadest interpretation consistent with the context in which they appear. Further, the terms used herein should not be construed to be limited to their broadest forms.

[0294] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0295] The term "comprising" encompasses "consisting of" unless otherwise specified.

[0296] As used herein, the term "crystalline form" also known as "crystaline substance" or "crystalline form" refers to a solid substance whose constituent molecules are arranged in an orderly pattern in three-dimensional space with a regular periodicity.

[0297] The term "pharmaceutical composition" as used herein refers to a preparation which is made by combining a pharmaceutically active ingredient with a pharmaceutically acceptable excipient according to some ratio, and which has a specific medical use. The pharmaceutical composition can be manufactured in the form of a pharmaceutically acceptable dosage form by any conventional technique, such as tablets, powders (including sterile powders for injection), capsules, granules, solutions, syrups, suppositories, injections, patches, etc. The pharmaceutical composition of the present disclosure can be administered to a subject (e.g., a human or a non-human mammal) by any of a variety of administration routes, including, for example, orally (e.g., in the form of tablets, capsules, powders, granules); transmucosally (e.g., sublingually, nasally, anally, rectally, or vaginally) (e.g., in the form of suppositories, creams, or foams); parenterally (e.g., intramuscularly, intravenously, intraperitoneally, subcutaneously, or intrathecally) injected; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, spray applied to the skin, or as eye drops). The pharmaceutical composition can also be formulated for inhalation administration.

[0298] The term "pharmaceutically acceptable excipient" as used herein means an excipient (also known as a carrier) that does not cause significant irritation to an organism, and does not abrogate the biological activity and properties of the administered compound. Any of the well-known pharmaceutically acceptable excipients can be used, the selection of which depends, for example, on the particular mode of administration, the influence of the excipient on the solubility and stability, the nature of the dosage form, and the like, and is within the ordinary skill of those in the art. Examples of some materials which can serve as pharmaceutically acceptable excipients include: starches, such as corn starch and potato starch; sugars, such as lactose, glucose and sucrose; cellulose and its derivatives, such as ethyl cellulose, sodium carboxymethyl cellulose, and cellulose acetate; gelatin, acacia, guar gum, tragacanth; magnesium stearate, zinc stearate, talc; water, saline; oils, such as peanut oil, cottonseed oil, olive oil, sesame oil, corn oil and soybean oil; alcohols, such as ethyl alcohol, propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; buffers, such as sodium chloride, phosphate buffer solution, and the like.

[0299] The term "prevention" as used herein refers to the prevention of the occurrence of a disease in a subject at risk of developing the disease or the recurrence of a disease that has disappeared.

[0300] The term "treatment" as used herein refers to the management and care of a subject with the aim of combating the pathology of the disease and / or prolonging the survival of the subject with the disease.

[0301] The term "disease mediated by KRAS G12C mutation" as used herein refers to a disease whose occurrence and progression is at least in part associated with KRAS G12C mutation. Exemplary diseases include, but are not limited to, malignancies, e.g., a carcinoma or a sarcoma, wherein the carcinoma includes, but is not limited to, pancreatic cancer, leukemia, esophageal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, colorectal cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine cancer, and thyroid cancer, and the sarcoma includes, but is not limited to, osteosarcoma.

[0302] The term "substantially the same" as used herein refers to the data information provided by two patterns of characterization of a crystalline form being substantially in agreement such that one of skill in the art can be confident that the two patterns are pointing to the same crystalline form. It should be understood that the use of the term "substantially the same" is intended to mean that for the same crystalline form, the 2 theta angle values, the position of the endothermic peak, and the mass loss gradient in the XRPD pattern, DSC pattern, and TGA pattern obtained in multiple runs can vary slightly due to differences in the sample, instrument, and conditions of the measurement. Thus, one of skill in the art will understand that the data in the patterns presented herein should not be interpreted as absolute, and any crystalline form that provides a pattern that is substantially the same as the data information in the patterns disclosed herein also falls within the scope of the present disclosure.

[0303] Similarly, the term "about" as used herein refers to the position of the endothermic peak and the mass loss gradient in the DSC pattern and TGA pattern can vary slightly due to differences in the sample, instrument, and conditions of the measurement, and thus the position of the endothermic peak and the mass loss gradient should not be interpreted as absolute values, but can vary slightly within a reasonable measurement error range (e.g., ±5% of the value).

[0304] The term "subject" as used herein refers to an animal individual to whom administration of a compound, a salt of a compound, a crystalline form thereof, or a pharmaceutical composition of the present disclosure is contemplated, including, but not limited to, humans and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); other mammals, such as horses, cows, pigs, sheep, goats, cats, dogs; and birds, such as chickens, ducks, geese, quail, turkeys. A preferred subject is a human.

[0305] The term "therapeutically effective amount" as used herein refers to an amount that is sufficient to affect any one or more beneficial or desired symptoms of a disease, its complications, or intermediate pathological phenotypes manifested in the course of the disease. The specific numerical value for a "therapeutically effective amount" will depend on the subject's species, the severity of the disease, the frequency of administration, the metabolic characteristics of the drug, and other factors, and can be determined by a practitioner of ordinary skill in the art according to routine practice.

[0306] It should be noted that all numerical ranges mentioned in the present disclosure represent both the endpoints of the range, all integers within the range, and sub-ranges formed by the integers.

[0307] In the course of research directed to obtaining a pharmaceutical composition based on a polymorph of Compound I or a pharmaceutically acceptable salt thereof, and a pharmaceutical preparation thereof, the inventors have conducted a careful screening of the formulation properties of polymorphs of Compound I and pharmaceutically acceptable salts thereof. As a result of the research, it has been found that the crystal forms of Compound I and pharmaceutically acceptable salts thereof have one or more properties advantageous for formulating a pharmaceutical dosage form, such as, but not limited to, hygroscopicity, solubility, and stability. Therefore, the inventors believe that the crystal forms of Compound I and pharmaceutically acceptable salts thereof can satisfy the demand of the pharmaceutical industry for a drug substance having excellent formulation properties, and thus have completed the present application.

[0308] In addition, the inventors have surprisingly found that the crystal forms of Compound I and pharmaceutically acceptable salts thereof exhibit more excellent potency than their respective amorphous compounds.

[0309] Thus, according to a first aspect of the present disclosure, there is provided a crystal form of Compound I.

[0310] In some embodiments, the crystal form of Compound I is Compound I Form Y1, characterized in that it has the following features:

[0311] I) has characteristic peaks in an X-ray powder diffraction (XRPD) pattern at diffraction angles 2θ values of 10.516° ± 0.2°, 18.360° ± 0.2°, and 19.345° ± 0.2°.

[0312] In some embodiments, the crystal form of Compound I is Compound I Form Y1, characterized in that it has an XRPD pattern substantially the same as that shown in Figure 1

[0313] In some embodiments, the XRPD pattern of Compound I Form Y1 has characteristic peaks in an X-ray powder diffraction (XRPD) pattern at diffraction angles 2θ values of 10.516° ± 0.2°, 14.451° ± 0.2°, 14.889° ± 0.2°, 18.360° ± 0.2°, 19.345° ± 0.2°, 21.210° ± 0.2°, and 22.070° ± 0.2°.

[0314] ​In some embodiments, the compound I Form Yl is characterized by an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 10.516°±0.2°, 11.381°±0.2°, 12.907°±0.2°, 13.107°±0.2°, 13.729°±0.2°, 14.171°±0.2°, 14.451°±0.2°, 14.889°±0.2°, 16.672°±0.2°, 18.360°±0.2°, 18.701°±0.2°, 19.345°±0.2°, 20.367°±0.2°, 21.210°±0.2°, 21.589°±0.2°, 22.070°±0.2°, 22.467°±0.2°, 23.057°±0.2°, 23.529°±0.2°, 23.893°±0.2°, 24.675°±0.2°, 25.158°±0.2°, 26.881°±0.2°, 27.201°±0.2°, 27.822°±0.2°, 28.425°±0.2°, and 35.665°±0.2°.

[0315] In some embodiments, the compound I Form Yl is further characterized by at least one feature selected from the following:

[0316] II) a DSC pattern having an endothermic peak at about 58 °C and about 271 °C, respectively; and

[0317] III) a TGA pattern having a mass loss of about 2.8% at 30-150 °C.

[0318] In some embodiments, the compound I Form Yl is characterized by having a DSC pattern substantially the same as the DSC pattern shown in FIG. 2. Figure 2 In some embodiments, the compound I Form Yl is characterized by having a TGA pattern substantially the same as the TGA pattern shown in FIG. 3.

[0319] In some embodiments, the compound I Form Yl is characterized by having a DSC pattern substantially the same as the DSC pattern shown in FIG. 2. Figure 3 In some embodiments, the compound I Form Yl is characterized by having a TGA pattern substantially the same as the TGA pattern shown in FIG. 3.

[0320] In some embodiments, the compound I Form Y2 is characterized by the following features:

[0321] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 18.080°±0.2°, 20.359°±0.2°, and 21.180°±0.2°.

[0322] In some embodiments, the compound I Form Y2 is characterized by having a DSC pattern substantially the same as the DSC pattern shown in FIG. 4. Figure 4an XRPD pattern substantially the same as the XRPD pattern shown in Figure 1.

[0323] In some embodiments, the XRPD pattern of the Compound I crystalline form Y2 has characteristic peaks at diffraction angles 2Q values of 17.220° ± 0.2°, 18.080° ± 0.2°, 20.359° ± 0.2°, 21.180° ± 0.2°, 22.660° ± 0.2°, 24.758° ± 0.2°, and 28.538° ± 0.2°.

[0324] In some embodiments, the XRPD pattern of the Compound I crystalline form Y2 has characteristic peaks at diffraction angles 2Q values of 7.379° ± 0.2°, 9.597° ± 0.2°, 10.202° ± 0.2°, 11.217° ± 0.2°, 12.478° ± 0.2°, 13.762° ± 0.2°, 14.322° ± 0.2°, 15.039° ± 0.2°, 16.220° ± 0.2°, 17.220° ± 0.2°, 18.080° ± 0.2°, 19.319° ± 0.2°, 20.359° ± 0.2°, 21.180° ± 0.2°, 22.660° ± 0.2°, 23.879° ± 0.2°, 24.758° ± 0.2°, 26.119° ± 0.2°, 26.940° ± 0.2°, 28.538° ± 0.2°, 30.880° ± 0.2°, and 37.501° ± 0.2°.

[0325] According to a second aspect of the present disclosure, there is provided a crystalline form of a pharmaceutically acceptable salt of Compound I.

[0326] In some embodiments, the pharmaceutically acceptable salt of Compound I is at least one selected from the group consisting of a hydrochloride salt, a mesylate salt, a maleate salt, an L-tartrate salt, a besylate salt, a tosylate salt, a sulfate salt, a hydrobromide salt, a citrate salt, an L-malate salt, an L-camphorsulfonate salt, a fumarate salt, and a trifluoroacetate salt.

[0327] In some embodiments, the crystalline form of the pharmaceutically acceptable salt of Compound I is a Compound I hydrochloride salt crystalline form.

[0328] In some embodiments, the Compound I hydrochloride salt crystalline form is Compound I hydrochloride salt crystalline form H1, characterized in that it has the following characteristics:

[0329] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.425° ± 0.2°, 7.952° ± 0.2°, and 14.249° ± 0.2°.

[0330] In some embodiments, the Compound I hydrochloride salt crystalline form is Compound I hydrochloride salt Form H1 characterized by having an XRPD pattern substantially the same as shown in FIG. 1. Figure 5

[0331] In some embodiments, the XRPD pattern of the Compound I hydrochloride salt Form H1 has characteristic peaks at diffraction angles 2Q values of 5.425° ± 0.2°, 7.952° ± 0.2°, 14.249° ± 0.2°, 17.662° ± 0.2°, 19.303° ± 0.2°, 20.647° ± 0.2°, and 21.309° ± 0.2°.

[0332] In some embodiments, the XRPD pattern of the Compound I hydrochloride salt Form H1 has characteristic peaks at diffraction angles 2Q values of 5.425° ± 0.2°, 6.388° ± 0.2°, 7.952° ± 0.2°, 12.443° ± 0.2°, 14.249° ± 0.2°, 14.551° ± 0.2°, 16.820° ± 0.2°, 17.662° ± 0.2°, 19.303° ± 0.2°, 20.647° ± 0.2°, 21.309° ± 0.2°, 22.151° ± 0.2°, and 23.631° ± 0.2°.

[0333] In some embodiments, the Compound I hydrochloride salt Form H1 further has at least one characteristic selected from the following:

[0334] II) in a DSC pattern, each of an endothermic peak at about 54 °C and at about 143 °C, respectively; and

[0335] III) in a TGA pattern, a mass loss of about 3.5% at 30 °C to 105 °C and a mass loss of about 8.1% at 105 °C to 180 °C.

[0336] In some embodiments, the Compound I hydrochloride salt Form H1 is characterized by having a DSC pattern substantially the same as shown in FIG. 2. Figure 6 In some embodiments, the Compound I hydrochloride salt Form H1 is characterized by having a TGA pattern substantially the same as shown in FIG. 3.

[0337] Figure 7 In some embodiments, the Compound I hydrochloride salt Form H1 is characterized by having a TGA pattern substantially the same as shown in FIG. 3.

[0338] In some embodiments, the Compound I hydrochloride salt Form is Compound I hydrochloride salt Form H2 characterized by having at least one characteristic selected from the following:

[0339] ​​I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 10.540° ± 0.2°, 18.422° ± 0.2°, and 19.461° ± 0.2°.

[0340] In some embodiments, the Compound I hydrochloride salt crystalline form is Compound I hydrochloride salt Form H2, characterized by an XRPD pattern substantially the same as shown in FIG. 2. Figure 8 In some embodiments, the Compound I hydrochloride salt Form H2 has an XRPD pattern substantially the same as shown in FIG. 2.

[0341] In some embodiments, the Compound I hydrochloride salt Form H2 has an XRPD pattern substantially the same as shown in FIG. 2.

[0342] In some embodiments, the Compound I hydrochloride salt Form H2 has an XRPD pattern substantially the same as shown in FIG. 2.

[0343] In some embodiments, the Compound I hydrochloride salt Form H2 further has at least one characteristic selected from the group consisting of:

[0344] II) an endothermic peak at about 150 °C in a DSC pattern; and

[0345] III) a mass loss of about 4.95% between 30 °C and 180 °C in a TGA pattern.

[0346] In some embodiments, the Compound I hydrochloride salt Form H2 is characterized by a DSC pattern substantially the same as shown in FIG. 3. Figure 9 In some embodiments, the Compound I hydrochloride salt Form H2 is characterized by a DSC pattern substantially the same as shown in FIG. 3.

[0347] In some embodiments, the Compound I hydrochloride salt Form H2 is characterized by a TGA pattern substantially the same as shown in FIG. 4. Figure 10 In some embodiments, the Compound I hydrochloride salt Form H2 is characterized by a TGA pattern substantially the same as shown in FIG. 4.

[0348] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound I mesylate salt Form.

[0349] In some embodiments, the Compound I mesylate salt crystalline form is Compound I mesylate salt Form Ml characterized in that it has at least one characteristic selected from:

[0350] I) an XRPD pattern with peaks at diffraction angles 2Q values of 16.149° ± 0.2°, 17.060° ± 0.2°, and 20.387° ± 0.2°.

[0351] In some embodiments, the Compound I mesylate salt crystalline form is Compound I mesylate salt Form Ml characterized in that it has an XRPD pattern substantially the same as that shown in Figure 11

[0352] In some embodiments, the Compound I mesylate salt Form Ml has an XRPD pattern with peaks at diffraction angles 2Q values of 7.212° ± 0.2°, 10.740° ± 0.2°, 13.465° ± 0.2°, 16.149° ± 0.2°, 17.060° ± 0.2°, 20.387° ± 0.2°, and 22.026° ± 0.2°.

[0353] In some embodiments, the Compound I mesylate salt Form Ml has an XRPD pattern with peaks at diffraction angles 2Q values of 7.212° ± 0.2°, 9.300° ± 0.2°, 9.674° ± 0.2°, 10.740° ± 0.2°, 13.465° ± 0.2°, 14.433° ± 0.2°, 16.149° ± 0.2°, 16.576° ± 0.2°, 17.060° ± 0.2°, 17.500° ± 0.2°, 17.904° ± 0.2°, 18.501° ± 0.2°, 19.658° ± 0.2°, 20.006° ± 0.2°, 20.387° ± 0.2°, 21.149° ± 0.2°, 22.026° ± 0.2°, 22.327° ± 0.2°, 23.309° ± 0.2°, 23.650° ± 0.2°, and 24.695° ± 0.2°.

[0354] In some embodiments, the Compound I mesylate salt Form Ml further has at least one characteristic selected from:

[0355] II) an endothermic peak in a DSC pattern at about 61 °C; and

[0356] III) a mass loss of about 2.04% in a TGA pattern from 30 °C to 105 °C.

[0357] ​In some embodiments, the Compound I mesylate salt crystalline form Ml is characterized by having a DSC pattern substantially the same as the DSC pattern shown in FIG. 2. Figure 12

[0358] In some embodiments, the Compound I mesylate salt crystalline form Ml is characterized by having a TGA pattern substantially the same as the TGA pattern shown in FIG. 3. Figure 13

[0359] In some embodiments, the Compound I mesylate salt crystalline form is Compound I mesylate salt Form M2, which is characterized by having at least one of the following characteristics:

[0360] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 8.876° ± 0.2°, 17.896° ± 0.2°, and 18.679° ± 0.2°.

[0361] In some embodiments, the Compound I mesylate salt crystalline form is Compound I mesylate salt Form M2, which is characterized by having an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 4. Figure 14

[0362] In some embodiments, the Compound I mesylate salt crystalline form M2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.848° ± 0.2°, 8.876° ± 0.2°, 10.341° ± 0.2°, 14.470° ± 0.2°, 17.896° ± 0.2°, 18.679° ± 0.2°, and 27.503° ± 0.2°.

[0363] In some embodiments, the Compound I mesylate salt crystalline form M2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.848° ± 0.2°, 8.876° ± 0.2°, 10.341° ± 0.2°, 11.640° ± 0.2°, 13.449° ± 0.2°, 14.470° ± 0.2°, 15.671° ± 0.2°, 17.317° ± 0.2°, 17.896° ± 0.2°, 18.180° ± 0.2°, 18.679° ± 0.2°, 19.803° ± 0.2°, 20.847° ± 0.2°, 21.345° ± 0.2°, 21.791° ± 0.2°, 22.206° ± 0.2°, 22.850° ± 0.2°, 23.533° ± 0.2°, 25.937° ± 0.2°, and 27.503° ± 0.2°.

[0364] In some embodiments, the Compound I mesylate salt crystalline form M2 further has at least one of the following characteristics: ​​​

[0365] II) In the DSC spectrum, there are no obvious endothermic peaks before the decomposition temperature; and

[0366] III) In the TGA spectrum, there is a mass loss gradient of approximately 0.96% in the range of 30℃ to 105℃.

[0367] In some embodiments, the compound I methanesulfonate crystal form M2 is characterized by having a similar Figure 15 The DSC patterns shown are essentially the same.

[0368] In some embodiments, the compound I methanesulfonate crystal form M2 is characterized by having a similar Figure 16 The TGA plot shown is essentially the same TGA plot.

[0369] In some embodiments, the crystal form of compound I methanesulfonate is crystal form M3 of compound I methanesulfonate, characterized by having the following features:

[0370] I) In the XRPD pattern, there are characteristic peaks at diffraction angles 2θ of 14.641°±0.2°, 16.759°±0.2° and 23.079°±0.2°.

[0371] In some embodiments, the crystal form of compound I methanesulfonate is crystal form M3 of compound I methanesulfonate, characterized by having the same properties as... Figure 17 The XRPD maps shown are essentially the same XRPD maps.

[0372] In some embodiments, the XRPD pattern of the methanesulfonate crystal form M3 of compound I has characteristic peaks at diffraction angles 2θ of 9.343°±0.2°, 13.040°±0.2°, 14.641°±0.2°, 16.759°±0.2°, 19.799°±0.2°, 23.079°±0.2°, and 24.041°±0.2°.

[0373] In some embodiments, the XRPD pattern of the Compound I mesylate salt Form M3 has characteristic peaks at diffraction angles 20 values of 9.101°±0.2°, 9.343°±0.2°, 10.221°±0.2°, 11.560°±0.2°, 12.098°±0.2°, 13.040°±0.2°, 13.579°±0.2°, 13.859°±0.2°, 14.641°±0.2°, 15.320°±0.2°, 15.599°±0.2°, 16.759°±0.2°, 18.181°±0.2°, 18.762°±0.2°, 19.799°±0.2°, 20.480°±0.2°, 20.877°±0.2°, 21.256°±0.2°, 21.761°±0.2°, 22.420°±0.2°, 23.079°±0.2°, 24.041°±0.2°, 27.141°±0.2°, 28.360°±0.2°, 29.098°±0.2°, 29.642°±0.2°, and 31.701°±0.2°.

[0374] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound I maleate salt Form.

[0375] In some embodiments, the Compound I maleate salt Form is Compound I maleate salt Form MA1 characterized by having an XRPD pattern substantially the same as shown in Figure 2.

[0376] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 9.918°±0.2°, 17.780°±0.2°, and 22.231°±0.2°.

[0377] In some embodiments, the Compound I maleate salt Form is Compound I maleate salt Form MA1 characterized by having an XRPD pattern substantially the same as shown in Figure 2. Figure 18

[0378] In some embodiments, the XRPD pattern of the Compound I maleate salt Form MA1 has characteristic peaks at diffraction angles 2Q values of 9.918°±0.2°, 17.780°±0.2°, 21.448°±0.2°, 22.231°±0.2°, and 24.538°±0.2°.

[0379] ​In some embodiments, the Compound I maleate salt crystalline form MA1 is characterized by having a DSC pattern substantially the same as that shown in Figure 2.

[0380] In some embodiments, the Compound I maleate salt crystalline form MA1 is further characterized by at least one feature selected from the group consisting of:

[0381] II) in a DSC pattern, each of an endothermic peak at about 93 °C and about 170 °C, respectively; and

[0382] III) in a TGA pattern, a mass loss of about 9.3% at 30 °C to 140 °C.

[0383] In some embodiments, the Compound I maleate salt crystalline form MA1 is characterized by having a DSC pattern substantially the same as that shown in Figure 2. Figure 19 In some embodiments, the Compound I maleate salt crystalline form MA1 is characterized by having a TGA pattern substantially the same as that shown in Figure 3.

[0384] Figure 20 In some embodiments, the Compound I maleate salt crystalline form MA1 is characterized by having a TGA pattern substantially the same as that shown in Figure 3.

[0385] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound IL-tartrate salt crystalline form.

[0386] In some embodiments, the Compound IL-tartrate salt crystalline form is Compound IL-tartrate salt crystalline form J1, which is characterized by having the following features:

[0387] I) in an XRPD pattern, characteristic peaks at diffraction angles 2Q values of 15.760°±0.2°, 17.499°±0.2°, and 23.560°±0.2°.

[0388] In some embodiments, the Compound IL-tartrate salt crystalline form is Compound IL-tartrate salt crystalline form J1, which is characterized by having a TGA pattern substantially the same as that shown in Figure 5. Figure 21 ​an XRPD pattern substantially the same as that shown in FIG. 1.

[0389] In some embodiments, the compound IL-tartrate salt Form J1 has an XRPD pattern with characteristic peaks at diffraction angles 2 theta values of 7.880°±0.2°, 12.440°±0.2°, 15.760°±0.2°, 17.499°±0.2°, 23.560°±0.2°, 24.140°±0.2°, 25.640°±0.2°, and 28.479°±0.2°.

[0390] In some embodiments, the compound IL-tartrate salt Form J1 has an XRPD pattern with characteristic peaks at diffraction angles 2 theta values of 5.520°±0.2°, 6.279°±0.2°, 7.880°±0.2°, 12.440°±0.2°, 13.982°±0.2°, 14.499°±0.2°, 14.919°±0.2°, 15.760°±0.2°, 17.179°±0.2°, 17.499°±0.2°, 18.561°±0.2°, 19.296°±0.2°, 19.981°±0.2°, 20.919°±0.2°, 21.641°±0.2°, 22.859°±0.2°, 23.560°±0.2°, 24.140°±0.2°, 25.640°±0.2°, 27.119°±0.2°, 28.479°±0.2°, 31.001°±0.2°, and 36.181°±0.2°.

[0391] In some embodiments, the compound IL-tartrate salt Form is Compound IL-tartrate salt Form J2, characterized by having characteristic peaks at diffraction angles 2 theta values of 8.140°±0.2°, 14.120°±0.2°, and 26.160°±0.2° in an XRPD pattern.

[0392] I) an XRPD pattern with characteristic peaks at diffraction angles 2 theta values of 8.140°±0.2°, 14.120°±0.2°, and 26.160°±0.2°.

[0393] In some embodiments, the compound IL-tartrate salt Form is Compound IL-tartrate salt Form J2, characterized by having an XRPD pattern substantially the same as that shown in FIG. 2. Figure 22 an XRPD pattern substantially the same as that shown in FIG. 1.

[0394] In some embodiments, the compound IL-tartrate salt Form J2 has a characteristic peak in its XRPD pattern at diffraction angle 2 theta values of 8.140° ± 0.2°, 14.120° ± 0.2°, 16.302° ± 0.2°, 21.680° ± 0.2°, 22.858° ± 0.2°, 23.679° ± 0.2°, and 26.160° ± 0.2°.

[0395] In some embodiments, the compound IL-tartrate salt Form J2 has a characteristic peak in its XRPD pattern at diffraction angle 2 theta values of 8.140° ± 0.2°, 14.120° ± 0.2°, 15.138° ± 0.2°, 16.302° ± 0.2°, 17.501° ± 0.2°, 18.221° ± 0.2°, 18.500° ± 0.2°, 20.259° ± 0.2°, 20.721° ± 0.2°, 21.680° ± 0.2°, 22.858° ± 0.2°, 23.679° ± 0.2°, 26.160° ± 0.2°, 28.838° ± 0.2°, 31.019° ± 0.2°, 32.058° ± 0.2°, and 33.799° ± 0.2°.

[0396] In some embodiments, the compound IL-tartrate salt Form J2 further has at least one characteristic selected from the group consisting of:

[0397] II) an endothermic peak in the DSC pattern at about 206 °C; and

[0398] III) a mass loss of about 3% in the TGA pattern from 30 °C to 170 °C.

[0399] In some embodiments, the compound IL-tartrate salt Form J2 is characterized by having a DSC pattern substantially the same as that shown in Figure 2. Figure 23

[0400] In some embodiments, the compound IL-tartrate salt Form J2 is characterized by having a TGA pattern substantially the same as that shown in Figure 3. Figure 24

[0401] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of the compound I is a compound I besylate salt Form.

[0402] In some embodiments, the compound I besylate salt Form is a compound I besylate salt Form B1, which is characterized by having the following characteristics:

[0403] ​​I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 4.742° ± 0.2°, 9.477° ± 0.2°, and 13.504° ± 0.2°.

[0404] In some embodiments, the Compound I besylate salt crystalline form is Compound I besylate salt Form B1 characterized by having an XRPD pattern substantially the same as the one set forth in FIG. 1. Figure 25

[0405] In some embodiments, the XRPD pattern of the Compound I besylate salt Form B1 has characteristic peaks at diffraction angles 2Q values of 4.742° ± 0.2°, 7.149° ± 0.2°, 9.477° ± 0.2°, 10.900° ± 0.2°, and 13.504° ± 0.2°.

[0406] In some embodiments, the XRPD pattern of the Compound I besylate salt Form B1 has characteristic peaks at diffraction angles 2Q values of 4.742° ± 0.2°, 7.149° ± 0.2°, 9.477° ± 0.2°, 9.877° ± 0.2°, 10.900° ± 0.2°, 13.504° ± 0.2°, and 20.804° ± 0.2°.

[0407] In some embodiments, the Compound I besylate salt crystalline form is Compound I besylate salt Form B2 characterized in that it has the following characteristics:

[0408] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 12.432° ± 0.2°, 18.292° ± 0.2°, and 22.894° ± 0.2°.

[0409] In some embodiments, the Compound I besylate salt crystalline form is Compound I besylate salt Form B2 characterized by having an XRPD pattern substantially the same as the one set forth in FIG. 2. Figure 26

[0410] In some embodiments, the XRPD pattern of the Compound I besylate salt Form B2 has characteristic peaks at diffraction angles 2Q values of 6.788° ± 0.2°, 12.432° ± 0.2°, 18.292° ± 0.2°, 19.339° ± 0.2°, and 22.894° ± 0.2°.

[0411] ​​In some embodiments, the XRPD pattern of the Compound I phenylsulfonic acid salt Form B2 has characteristic peaks at diffraction angles 2θ values of 5.173°±0.2°, 6.788°±0.2°, 8.607°±0.2°, 10.677°±0.2°, 11.211°±0.2°, 12.432°±0.2°, 12.689°±0.2°, 13.734°±0.2°, 14.700°±0.2°, 15.730°±0.2°, 16.437°±0.2°, 17.364°±0.2°, 18.292°±0.2°, 19.339°±0.2°, 20.208°±0.2°, 20.543°±0.2°, 21.905°±0.2°, 22.894°±0.2°, 23.800°±0.2°, 24.453°±0.2°, 25.076°±0.2°, 25.574°±0.2°, 26.147°±0.2°, and 28.396°±0.2°.

[0412] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound I toluenesulfonic acid salt Form (in the present application, toluenesulfonic acid salt is also referred to as tosylate salt).

[0413] In some embodiments, the Compound I toluenesulfonic acid salt Form is Compound I toluenesulfonic acid salt Form Tl characterized in that it has the XRPD pattern substantially the same as shown in Figure 2.

[0414] I) in an XRPD pattern, characteristic peaks at diffraction angles 2θ values of 9.554°±0.2°, 14.730°±0.2°, and 24.153°±0.2°.

[0415] In some embodiments, the Compound I toluenesulfonic acid salt Form Tl is characterized in that it has the XRPD pattern substantially the same as shown in Figure 2. Figure 27

[0416] In some embodiments, the XRPD pattern of the Compound I toluenesulfonic acid salt Form Tl has characteristic peaks at diffraction angles 2θ values of 9.554°±0.2°, 14.730°±0.2°, 18.763°±0.2°, 20.586°±0.2°, 21.609±0.2°, and 24.153°±0.2°.

[0417] ​In some embodiments, the Compound I tosylate salt Form Tl is characterized by having at least one peak in its XRPD pattern at diffraction angles 2Q values of 7.690°±0.2°, 8.715°±0.2°, and 17.659°±0.2°.

[0418] In some embodiments, the Compound I tosylate salt Form Tl is further characterized by at least one feature selected from the following:

[0419] II) an endothermic peak at about 301 °C in the DSC pattern; and

[0420] III) a mass loss gradient of about 0.26% between 30 °C and 105 °C in the TGA pattern.

[0421] In some embodiments, the Compound I tosylate salt Form Tl is characterized by having a DSC pattern substantially the same as the DSC pattern shown in Figure 2. Figure 28 In some embodiments, the Compound I tosylate salt Form Tl is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure 3.

[0422] In some embodiments, the Compound I tosylate salt Form Tl is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure 3. Figure 29 In some embodiments, the Compound I tosylate salt Form Tl is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure 3.

[0423] In some embodiments, the Compound I tosylate salt Form is Compound I tosylate salt Form T2, which is characterized by having at least one peak in its XRPD pattern at diffraction angles 2Q values of 7.690°±0.2°, 8.715°±0.2°, and 17.659°±0.2°.

[0424] I) an endothermic peak at about 301 °C in the DSC pattern; and

[0425] In some embodiments, the Compound I tosylate salt Form T2 is characterized by having a XRPD pattern substantially the same as the XRPD pattern shown in Figure 4. Figure 30 In some embodiments, the Compound I tosylate salt Form T2 is characterized by having a DSC pattern substantially the same as the DSC pattern shown in Figure 5.

[0426] In some embodiments, the Compound I mesylate Form T2 has a characteristic peak in its XRPD pattern at diffraction angle 2θ values of 4.284°±0.2°, 7.273°±0.2°, 7.690°±0.2°, 8.715°±0.2°, 13.008°±0.2°, 16.334°±0.2°, and 17.659°±0.2°.

[0427] In some embodiments, the Compound I mesylate Form T2 has a characteristic peak in its XRPD pattern at diffraction angle 2θ values of 4.284°±0.2°, 7.273°±0.2°, 7.690°±0.2°, 8.715°±0.2°, 10.917°±0.2°, 11.280°±0.2°, 11.542°±0.2°, 12.086°±0.2°, 13.008°±0.2°, 13.746°±0.2°, 15.511°±0.2°, 16.334°±0.2°, 17.659°±0.2°, 19.882°±0.2°, 23.210°±0.2°, and 25.899°±0.2°.

[0428] In some embodiments, the Compound I mesylate Form T2 further has at least one characteristic selected from the group consisting of:

[0429] II) in a DSC pattern, each of about 50 °C and about 245 °C has an endothermic peak, respectively; and

[0430] III) in a TGA pattern, has a mass loss of about 2.38% at 30 °C to 105 °C.

[0431] In some embodiments, the Compound I mesylate Form T2 is characterized by having a DSC pattern substantially the same as the DSC pattern shown in Figure Figure 31 In some embodiments, the Compound I mesylate Form T2 is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure

[0432] In some embodiments, the Compound I mesylate Form T2 is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure Figure 32 In some embodiments, the Compound I mesylate Form T2 is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure

[0433] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound I sulfate Form.

[0434] In some embodiments, the Compound I sulfate Form is Compound I sulfate Form S1, which is characterized by having at least one characteristic selected from the group consisting of:

[0435] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.146° ± 0.2°, 7.250° ± 0.2°, and 18.921° ± 0.2°.

[0436] In some embodiments, the Compound I sulfate salt crystalline form is Compound I sulfate salt Form S1 characterized by an XRPD pattern substantially the same as shown in FIG. 1. Figure 33 In some embodiments, the Compound I sulfate salt Form S1 has an XRPD pattern substantially the same as shown in FIG. 1.

[0437] In some embodiments, the Compound I sulfate salt Form S1 has an XRPD pattern substantially the same as shown in FIG. 1.

[0438] In some embodiments, the Compound I sulfate salt Form S1 has an XRPD pattern substantially the same as shown in FIG. 1.

[0439] In some embodiments, the Compound I sulfate salt Form S1 further has at least one characteristic selected from:

[0440] II) a DSC pattern having an endothermic peak near about 301 °C; and

[0441] III) a TGA pattern having a mass loss gradient of about 0.25% from 30 °C to 105 °C.

[0442] In some embodiments, the Compound I sulfate salt Form S1 is characterized by a DSC pattern substantially the same as shown in FIG. 2. Figure 34 In some embodiments, the Compound I sulfate salt Form S1 is characterized by a DSC pattern substantially the same as shown in FIG. 2.

[0443] In some embodiments, the Compound I sulfate salt Form S1 is characterized by a TGA pattern substantially the same as shown in FIG. 3. Figure 35 In some embodiments, the Compound I sulfate salt Form S1 is characterized by a TGA pattern substantially the same as shown in FIG. 3.

[0444] In some embodiments, the sulfate form of compound I is sulfate form S2, characterized by having the following features:

[0445] I) In the XRPD pattern, there are characteristic peaks at diffraction angles 2θ of 7.841°±0.2°, 16.160°±0.2° and 21.261°±0.2°.

[0446] In some embodiments, the sulfate crystal form of compound I is sulfate crystal form S2, characterized by having the same properties as... Figure 36 The XRPD maps shown are essentially the same XRPD maps.

[0447] In some embodiments, the XRPD pattern of the sulfate crystal form S2 of compound I has characteristic peaks at diffraction angles 2θ of 6.842°±0.2°, 7.841°±0.2°, 13.819°±0.2°, 16.160°±0.2°, 21.261°±0.2° and 25.440±0.2°.

[0448] In some embodiments, the XRPD patterns of the sulfate crystal form S2 of compound I show diffraction angles of 3.360°±0.2°, 6.842°±0.2°, 7.841°±0.2°, 8.821°±0.2°, 9.637°±0.2°, 10.521°±0.2°, 11.799°±0.2°, and 13.81°±0.2°. Characteristic peaks are present at 9°±0.2°, 14.594°±0.2°, 16.160°±0.2°, 17.461°±0.2°, 18.176°±0.2°, 19.105°±0.2°, 21.261°±0.2°, 22.399°±0.2°, 23.479°±0.2°, and 25.440±0.2°.

[0449] In some embodiments, the pharmaceutically acceptable salt of compound I is in the form of compound I hydrobromide.

[0450] In some embodiments, the hydrobromide form of compound I is Br1, characterized by having features selected from the following:

[0451] I) In the XRPD pattern, there are characteristic peaks at diffraction angles 2θ of 10.475°±0.2°, 18.341°±0.2° and 19.342°±0.2°.

[0452] In some embodiments, the hydrobromide crystal form of compound I is Br1, characterized by having the same properties as... Figure 37an XRPD pattern substantially the same as that shown in FIG. 1.

[0453] In some embodiments, the XRPD pattern of the Compound I hydrobromide salt Form Br1 has characteristic peaks at diffraction angles 2Q values of 8.771° ± 0.2°, 10.475° ± 0.2°, 14.792° ± 0.2°, 18.341° ± 0.2°, 19.342° ± 0.2°, 21.127° ± 0.2°, and 25.097° ± 0.2°.

[0454] In some embodiments, the XRPD pattern of the Compound I hydrobromide salt Form Br1 has characteristic peaks at diffraction angles 2Q values of 5.659° ± 0.2°, 8.771° ± 0.2°, 10.475° ± 0.2°, 12.018° ± 0.2°, 13.629° ± 0.2°, 14.792° ± 0.2°, 15.319° ± 0.2°, 18.341° ± 0.2°, 19.001° ± 0.2°, 19.342° ± 0.2°, 20.228° ± 0.2°, 21.127° ± 0.2°, 21.548° ± 0.2°, 22.047° ± 0.2°, 22.411° ± 0.2°, 22.895° ± 0.2°, 23.912° ± 0.2°, 24.711° ± 0.2°, 25.097° ± 0.2°, 26.741° ± 0.2°, 27.162° ± 0.2°, 28.305° ± 0.2°, and 29.187° ± 0.2°.

[0455] In some embodiments, the Compound I hydrobromide salt Form Br1 further has at least one characteristic selected from:

[0456] II) an XRPD pattern substantially the same as that shown in FIG. 1. Figure 38 III) a DSC pattern substantially the same as that shown in FIG. 2.

[0457] III) a mass loss of about 2.17% between 30 °C and 105 °C in a TGA pattern.

[0458] In some embodiments, the Compound I hydrobromide salt Form Br1 is characterized by having an XRPD pattern substantially the same as that shown in FIG. 1. Figure 39 In some embodiments, the Compound I hydrobromide salt Form Br1 is characterized by having a TGA pattern substantially the same as that shown in FIG. 3.

[0459] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound I citrate Form.

[0460] In some embodiments, the Compound I citrate Form is Compound I citrate Form N1, which is characterized in that it has the following characteristics:

[0461] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 14.324° ± 0.2°, 17.125° ± 0.2°, and 20.879° ± 0.2°.

[0462] In some embodiments, the Compound I citrate salt crystalline form is Compound I citrate salt Form N1 characterized by an XRPD pattern substantially the same as shown in Figure 2. Figure 40 In some embodiments, the Compound I citrate salt Form N1 further has at least one characteristic selected from:

[0463] In some embodiments, the Compound I citrate salt Form N1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 8.996° ± 0.2°, 10.083° ± 0.2°, 14.324° ± 0.2°, 17.125° ± 0.2°, 20.879° ± 0.2°, 23.798° ± 0.2°, and 27.431° ± 0.2°.

[0464] In some embodiments, the Compound I citrate salt Form N1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.693° ± 0.2°, 8.996° ± 0.2°, 10.083° ± 0.2°, 11.107° ± 0.2°, 12.747° ± 0.2°, 14.324° ± 0.2°, 15.116° ± 0.2°, 15.830° ± 0.2°, 16.475° ± 0.2°, 16.771° ± 0.2°, 17.125° ± 0.2°, 18.268° ± 0.2°, 19.831° ± 0.2°, 20.879° ± 0.2°, 21.571° ± 0.2°, 22.337° ± 0.2°, 22.872° ± 0.2°, 23.385° ± 0.2°, 23.798° ± 0.2°, 24.626° ± 0.2°, 26.207° ± 0.2°, 26.759° ± 0.2°, 27.431° ± 0.2°, 28.004° ± 0.2°, 28.277° ± 0.2°, 28.891° ± 0.2°, 30.530° ± 0.2°, 32.678° ± 0.2°, 34.772° ± 0.2°, 35.362° ± 0.2°, 36.546° ± 0.2°, 37.257° ± 0.2°, and 37.928° ± 0.2°.

[0465] In some embodiments, the Compound I citrate salt Form N1 further has at least one characteristic selected from:

[0466] II) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 14.324° ± 0.2°, 17.125° ± 0.2°, and 20.879° ± 0.2°.

[0467] III) in the TGA plot, a mass loss gradient of about 2.31% from 30 °C to 180 °C.

[0468] In some embodiments, the Compound I citrate salt crystalline Form N1 is characterized by having a DSC plot substantially the same as the DSC plot shown in FIG. 6. Figure 41

[0469] In some embodiments, the Compound I citrate salt crystalline Form N1 is characterized by having a TGA plot substantially the same as the TGA plot shown in FIG. 7. Figure 42

[0470] In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound I L-malate Form.

[0471] In some embodiments, the Compound I L-malate Form is Compound I L-malate Form P1, which is characterized in that it has the following characteristics:

[0472] I) in the XRPD plot, characteristic peaks XRPD at diffraction angle 2 theta values of 10.477° ± 0.2°, 14.087° ± 0.2°, and 22.369° ± 0.2°.

[0473] In some embodiments, the Compound I L-malate Form is Compound I L-malate Form P1, which is characterized by having an XRPD plot substantially the same as the XRPD plot shown in FIG. 8. Figure 45

[0474] In some embodiments, the Compound I L-malate Form P1 has characteristic peaks in the XRPD plot at diffraction angle 2 theta values of 7.471° ± 0.2°, 10.477° ± 0.2°, 14.087° ± 0.2°, 17.275° ± 0.2°, 19.003° ± 0.2°, 22.369° ± 0.2°, and 26.101° ± 0.2°.

[0475] ​​​In some embodiments, the compound IL-malate salt Form PI has a characteristic XRPD pattern with peaks at diffraction angles 2Q values of 7.471°±0.2°, 8.333°±0.2°, 9.672°±0.2°, 10.200°±0.2°, 10.477°±0.2°, 14.087°±0.2°, 14.670°±0.2°, 15.211°±0.2°, 16.013°±0.2°, 16.735°±0.2°, 17.275°±0.2°, 17.500°±0.2°, 19.003°±0.2°, 19.466°±0.2°, 20.081°±0.2°, 20.506°±0.2°, 21.068°±0.2°, 21.410°±0.2°, 21.828°±0.2°, 22.369°±0.2°, 23.360°±0.2°, 23.834°±0.2°, 24.176°±0.2°, 24.996°±0.2°, 26.101°±0.2°, 26.863°±0.2°, 28.183°±0.2°, 28.424°±0.2°, 29.011°±0.2°, and 29.987°±0.2°.

[0476] In some embodiments, the compound I has a pharmaceutically acceptable salt in a crystalline form that is Compound IL-camphorsulfonate salt Form.

[0477] In some embodiments, the compound IL-camphorsulfonate salt Form is Compound IL- camphorsulfonate salt Form Z1 characterized by having the following characteristics:

[0478] I) a characteristic XRPD pattern with peaks at diffraction angles 2Q values of 6.309°±0.2°, 11.141°±0.2°, and 16.054°±0.2°.

[0479] In some embodiments, the compound IL-camphorsulfonate salt Form is Compound IL- camphorsulfonate salt Form Z1 characterized by having a XRPD pattern substantially identical to that shown in Figure Figure 46

[0480] In some embodiments, the compound IL-camphorsulfonate salt Form Z1 has a characteristic XRPD pattern with peaks at diffraction angles 2Q values of 6.309°±0.2°, 11.141°±0.2°, 14.571°±0.2°, 16.054°±0.2°, and 19.962°±0.2°.

[0481] ​In some embodiments, the compound IL-camphorsulfonic acid salt Form Zl has an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 6.309° ± 0.2°, 10.600° ± 0.2°, 11.141° ± 0.2°, 14.571° ± 0.2°, 16.054° ± 0.2°, 16.834° ± 0.2°, and 19.962° ± 0.2°.

[0482] In some embodiments, the compound I fumarate salt Form is Compound I fumarate salt Form F1 characterized by having an XRPD pattern substantially the same as that shown in Figure 18.

[0483] In some embodiments, the compound I fumarate salt Form is Compound I fumarate salt Form F1 characterized by having an XRPD pattern substantially the same as that shown in Figure 18.

[0484] I) an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 11.483° ± 0.2°, 14.713° ± 0.2°, and 18.240° ± 0.2°.

[0485] In some embodiments, the compound I fumarate salt Form is Compound I fumarate salt Form F1 characterized by having an XRPD pattern substantially the same as that shown in Figure 18. Figure 47

[0486] In some embodiments, the compound I fumarate salt Form F1 has an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 9.397° ± 0.2°, 11.483° ± 0.2°, 14.713° ± 0.2°, 18.240° ± 0.2°, and 20.605° ± 0.2°.

[0487] In some embodiments, the compound I fumarate salt Form F1 has an XRPD pattern with characteristic peaks at diffraction angles 2Q values of 8.432° ± 0.2°, 8.712° ± 0.2°, 9.397° ± 0.2°, 10.697° ± 0.2°, 10.978° ± 0.2°, 11.483° ± 0.2°, 12.770° ± 0.2°, 13.304° ± 0.2°, 14.383° ± 0.2°, 14.713° ± 0.2°, 15.411° ± 0.2°, 15.651° ± 0.2°, 16.178° ± 0.2°, 17.159° ± 0.2°, 17.555° ± 0.2°, 18.240° ± 0.2°, 18.619° ± 0.2°, 20.125° ± 0.2°, 20.605° ± 0.2°, 21.590° ± 0.2°, 23.192° ± 0.2°, and 24.537° ± 0.2°.

[0488] ​In some embodiments, the crystalline form of a pharmaceutically acceptable salt of Compound I is Compound I mesylate crystalline Form.

[0489] In some embodiments, the Compound I trifluoroacetate salt crystalline form is Compound I trifluoroacetate salt Form TF1 characterized by having at least one characteristic selected from:

[0490] I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 14.431° ± 0.2°, 17.718° ± 0.2°, and 18.519° ± 0.2° in an XRPD pattern.

[0491] In some embodiments, the Compound I trifluoroacetate salt crystalline form is Compound I trifluoroacetate salt Form TF1 characterized by having an XRPD pattern substantially the same as that shown in Figure 48

[0492] In some embodiments, the Compound I trifluoroacetate salt Form TF1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.850° ± 0.2°, 10.640° ± 0.2°, 14.431° ± 0.2°, 17.718° ± 0.2°, 18.519° ± 0.2°, 20.731° ± 0.2°, and 27.600° ± 0.2°.

[0493] In some embodiments, the Compound I trifluoroacetate salt Form TF1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.850° ± 0.2°, 8.792° ± 0.2°, 10.294° ± 0.2°, 10.640° ± 0.2°, 11.591° ± 0.2°, 12.804° ± 0.2°, 13.407° ± 0.2°, 14.431° ± 0.2°, 15.473° ± 0.2°, 15.829° ± 0.2°, 17.378° ± 0.2°, 17.718° ± 0.2°, 18.058° ± 0.2°, 18.519° ± 0.2°, 19.507° ± 0.2°, 19.897° ± 0.2°, 20.731° ± 0.2°, 21.466° ± 0.2°, 21.726° ± 0.2°, 22.716° ± 0.2°, 23.236° ± 0.2°, 23.875° ± 0.2°, 24.510° ± 0.2°, 26.039° ± 0.2°, 27.321° ± 0.2°, and 27.600° ± 0.2°.

[0494] In some embodiments, the Compound I trifluoroacetate salt Form TF1 further has at least one characteristic selected from:

[0495] ​II) an endothermic peak at about 239 °C in a DSC pattern; and

[0496] III) a mass loss gradient of about 0.46% at 30 °C to 105 °C in a TGA pattern.

[0497] In some embodiments, the compound I trifluoroacetate salt crystalline form TF1 is characterized by having a DSC pattern substantially the same as the DSC pattern shown in Figure 2. Figure 49 In some embodiments, the compound I trifluoroacetate salt crystalline form TF1 is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure 3.

[0498] In some embodiments, the compound I trifluoroacetate salt crystalline form TF1 is characterized by having a DSC pattern substantially the same as the DSC pattern shown in Figure 2. Figure 50 In some embodiments, the compound I trifluoroacetate salt crystalline form TF1 is characterized by having a TGA pattern substantially the same as the TGA pattern shown in Figure 3.

[0499] According to a third aspect of the present disclosure, there is provided a pharmaceutical composition comprising at least one selected from a crystalline form of compound I or a pharmaceutically acceptable salt thereof according to any of the embodiments described herein, a single crystal of compound I, a single crystal of compound I citrate salt, a pharmaceutically acceptable salt of compound I, and a pharmaceutically acceptable excipient.

[0500] According to a fourth aspect of the present disclosure, there is provided a method for preparing a crystalline form of compound I or a pharmaceutically acceptable salt thereof.

[0501] In the method for preparing a crystalline form of compound I or a pharmaceutically acceptable salt thereof of the present disclosure, "dissolution" means that a solute is dispersed in a solvent, optionally with stirring, and the solute is completely dissolved, partially dissolved, forms a suspension, or forms a suspension liquid.

[0502] In some embodiments, the present disclosure provides a method for preparing a crystalline form of compound I, the method comprising the step of: allowing compound I to be crystallized in an organic solvent or a mixed solvent of an organic solvent and water.

[0503] In some embodiments, the present disclosure provides a method for preparing a crystalline form of compound I, the method comprising: step (1) dissolving compound I in a first solvent,

[0504] optional step (2) wherein a second solvent is added to the solution of step (1),

[0505] step (3) crystallization, filtration, to obtain a crystalline form of compound I.

[0506] In some embodiments, in the above method for preparing a crystalline form of compound I, in the dissolution of step (1), the solution is warmed to 45-75 °C (preferably 50-70 °C), and the crystallization of step (3) is carried out at a temperature of 10-30 °C (preferably 20-25 °C).

[0507] In some embodiments, in the above method for preparing the crystalline form of Compound I, when step (2) is present, the volume ratio of the first solvent to the second solvent is 1:5 to 5:1, preferably 1:3 to 3:1, more preferably 1:2 to 2:1.

[0508] In some embodiments, in the above method for preparing the crystalline form of Compound I, after the filtration of step (3), drying is performed, preferably vacuum drying.

[0509] In some embodiments, the present disclosure provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, comprising the steps of: reacting Compound I with an acid to obtain a pharmaceutically acceptable salt of Compound I; and crystallizing the pharmaceutically acceptable salt of Compound I in an organic solvent or a mixed solvent of an organic solvent and water.

[0510] In some embodiments, the present disclosure provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, comprising: step (1) dissolving Compound I in a first solvent,

[0511] step (2) adding an acid solution,

[0512] optional step (3), wherein a second solvent is added to the solution of step (2),

[0513] step (4) crystallization, filtration to obtain a crystalline form of a pharmaceutically acceptable salt of Compound I.

[0514] In some embodiments, in the above method for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, after step (2), a crystalline form of a pharmaceutically acceptable salt of Compound I is added as a seed crystal.

[0515] In some embodiments, the present disclosure provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, comprising: step (1) dissolving a crystalline form of a pharmaceutically acceptable salt of Compound I in a first solvent or a mixed solvent of a first solvent and a second solvent,

[0516] step (4) crystallization, filtration to obtain a crystalline form of a pharmaceutically acceptable salt of Compound I, wherein the crystalline form of a pharmaceutically acceptable salt of Compound I in step (1) is different from the crystalline form of a pharmaceutically acceptable salt of Compound I as the product.

[0517] In some embodiments, the present disclosure provides a method for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, comprising: step (1) dissolving a crystalline form of a pharmaceutically acceptable salt of Compound I in a first solvent or a mixed solvent of a first solvent and a second solvent,

[0518] Step (4) is crystallization, filtration, to obtain a crystalline form of a pharmaceutically acceptable salt of Compound I, wherein the crystalline form of a pharmaceutically acceptable salt of Compound I in step (1) is the same as the crystalline form of a pharmaceutically acceptable salt of Compound I as the product.

[0519] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, after step (1), a crystalline form of a pharmaceutically acceptable salt of Compound I is added as a seed crystal.

[0520] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, in the dissolution of step (1), the solution is warmed to 20-75°C (preferably 20-70°C), and the crystallization of step (4) is carried out at a temperature of 10-30°C (preferably 15-25°C).

[0521] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, the acid in step (2) is at least one selected from the group consisting of hydrochloric acid, methanesulfonic acid, maleic acid, L-tartaric acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, hydrobromic acid, citric acid, L-malic acid, L-camphorsulfonic acid, fumarate, and trifluoroacetate.

[0522] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, the acid in step (2) is in the form of a hydrate of the acid, which is a hydrate of each acid that is conventional in the art, including but not limited to monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, etc.

[0523] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, the solvent of the acid solution in step (2) is a third solvent.

[0524] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, the third solvent is the same as the first solvent.

[0525] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, the third solvent is different from the first solvent.

[0526] In some embodiments, in the method of the present disclosure for preparing a crystalline form of a pharmaceutically acceptable salt of Compound I, in step (4), the volume ratio of the first solvent and the second solvent in the solution is 1:6-6:1, preferably 1:2-5:1, more preferably 1:1-5:1, when crystallization is carried out.

[0527] In some embodiments, in the method of preparing a crystalline form of a pharmaceutically acceptable salt of Compound I of the present disclosure, if the solvent in the third solvent is the same as the first solvent and / or the second solvent, in step (4), the first solvent in the solution upon crystallization comprises the first solvent in step (1) and the first solvent portion in the third solvent in step (2); the second solvent in the solution comprises the second solvent in step (3) and the second solvent portion in the third solvent in step (2).

[0528] In some embodiments, the first solvent of the present disclosure is an organic solvent selected from alcohols, ketones, (cyclo)ethers, alkyl nitriles, esters, alkanes, or a mixture of two or more thereof, or a mixture of the foregoing organic solvent and water.

[0529] In some embodiments, the first solvent of the present disclosure is at least one organic solvent selected from tetrahydrofuran, 2-butanone, acetone, methanol, ethanol, isopropanol, acetonitrile, and ethyl acetate, or a mixture of the foregoing organic solvent and water.

[0530] In some embodiments, when water is present in the first solvent, the volume ratio of the organic solvent to water is 5:1 to 50:1, preferably 5:1 to 20:1. It is preferred that no water is present in the first solvent.

[0531] In some embodiments, the first solvent of the present disclosure is at least one selected from tetrahydrofuran, 2-butanone, acetone, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, 85% (V / V) aqueous acetone, 90% (V / V) aqueous acetone, 95% (V / V) aqueous acetone.

[0532] In some embodiments, the second solvent of the present disclosure is selected from alkanes, ethers, esters, and water, or a mixture of two or more thereof. It is preferred that the second solvent is at least one selected from alkanes, ethers, esters, and water.

[0533] In some embodiments, the second solvent of the present disclosure is at least one selected from n-hexane, n-heptane, diethyl ether, methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate, and water.

[0534] In some embodiments, the second solvent of the present disclosure is at least one selected from n-heptane, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, and water.

[0535] In some embodiments, the third solvent of the present disclosure is an organic solvent selected from alcohols, ketones, (cyclo)ethers, alkyl nitriles, esters, alkanes, or a mixture of two or more thereof, or a mixture of the foregoing organic solvent and water.

[0536] In some embodiments, the third solvent of the present disclosure is at least one organic solvent selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, methanol, ethanol, isopropanol, acetonitrile, and ethyl acetate, or a mixture of the aforementioned organic solvent and water.

[0537] In some embodiments, in the method of the present disclosure for preparing the crystalline form of the pharmaceutically acceptable salt of Compound I, when the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1:1-50:1, preferably 2:1-20:1.

[0538] In some embodiments, in the method of the present disclosure for preparing the crystalline form of the pharmaceutically acceptable salt of Compound I, when the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1:1-12:1, preferably 2:1-11:1.

[0539] In some embodiments, the third solvent of the present disclosure is at least one selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, isopropanol, ethanol, acetonitrile, 85% (V / V) aqueous acetone, 90% (V / V) aqueous acetone, 95% (V / V) aqueous acetone, acetone-water (volume ratio 2:1), acetonitrile-water (volume ratio 6:1), acetonitrile-water (volume ratio 8:1), ethanol-water (volume ratio 10:1), and tetrahydrofuran-water (volume ratio 10:1).

[0540] In some embodiments, in the method of the present disclosure for preparing the crystalline form of Compound I or a pharmaceutically acceptable salt thereof, nitrogen replacement is performed during the dissolving process of step (1).

[0541] In some embodiments, in the method of the present disclosure for preparing the crystalline form of the pharmaceutically acceptable salt of Compound I, drying is performed after the filtration of step (4), preferably vacuum drying.

[0542] In some embodiments, the present disclosure provides a method for preparing the crystalline form Y1 of Compound I, which comprises: step (1) dissolving Compound I in a first solvent selected from at least one of tetrahydrofuran, 2-butanone, acetone,

[0543] step (2), wherein a second solvent selected from at least one of n-heptane, methyl tert-butyl ether, water is added to the solution of step (1), the volume ratio of the first solvent to the second solvent is 1:5-5:1, preferably 1:3-3:1, more preferably 1:2-2:1,

[0544] step (3) crystallization, filtration, to obtain the crystalline form Y1 of Compound I.

[0545] In some embodiments, the present disclosure provides a method for preparing the crystalline form Y2 of compound I, comprising: step (1) dissolving compound I in methanol,

[0546] Step (3) crystallization, filtration to obtain the crystalline form Y2 of compound I.

[0547] In some embodiments, the present disclosure provides a method for preparing the hydrochloride salt crystalline form H1 of compound I, comprising: step (1) dissolving compound I in tetrahydrofuran,

[0548] Step (2) adding a tetrahydrofuran solution of hydrochloric acid,

[0549] Step (3) adding n-heptane to the solution of step (2) so that the volume ratio of tetrahydrofuran to n-heptane in the solution is 4:1 to 5:1,

[0550] Step (4) crystallization, filtration to obtain the hydrochloride salt crystalline form H1 of compound I.

[0551] In some embodiments, the present disclosure provides a method for preparing the hydrochloride salt crystalline form H2 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0552] Step (2) adding an acetonitrile solution of hydrochloric acid,

[0553] Step (4) crystallization, filtration to obtain the hydrochloride salt crystalline form H2 of compound I.

[0554] In some embodiments, the present disclosure provides a method for preparing the methanesulfonic acid salt crystalline form M1 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0555] Step (2) adding an acetonitrile solution of methanesulfonic acid,

[0556] Step (4) crystallization, filtration to obtain the methanesulfonic acid salt crystalline form M1 of compound I.

[0557] In some embodiments, the present disclosure provides a method for preparing the methanesulfonic acid salt crystalline form M1 of compound I, comprising: step (1) dissolving compound I in ethyl acetate,

[0558] Step (2) adding a 2-butanone solution of methanesulfonic acid,

[0559] Step (4) crystallization, filtration to obtain the methanesulfonic acid salt crystalline form M1 of compound I.

[0560] In some embodiments, the present disclosure provides a method for preparing the methanesulfonic acid salt crystalline form M2 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0561] Step (2) adding methanesulfonic acid in acetonitrile,

[0562] Step (4) crystallization, filtration to obtain the methanesulfonic acid salt crystal form M2 of compound I.

[0563] In some embodiments, the present disclosure provides a method for preparing the methanesulfonic acid salt crystal form M3 of compound I, comprising: step (1) dissolving the methanesulfonic acid salt crystal form M2 of compound I in a mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water being 4:1-5:1,

[0564] Step (4) crystallization, filtration to obtain the methanesulfonic acid salt crystal form M3 of compound I.

[0565] In some embodiments, the present disclosure provides a method for preparing the maleic acid salt crystal form MA1 of compound I, comprising: step (1) dissolving compound I in isopropanol,

[0566] Step (2) adding isopropanol solution of maleic acid,

[0567] Step (4) crystallization, filtration to obtain the maleic acid salt crystal form MA1 of compound I.

[0568] In some embodiments, the present disclosure provides a method for preparing the L-tartaric acid salt crystal form J1 of compound I, comprising: step (1) dissolving compound I in 95% (V / V) aqueous acetone solution,

[0569] Step (2) adding 95% (V / V) aqueous acetone solution of L-tartaric acid,

[0570] Step (4) crystallization, filtration to obtain the L-tartaric acid salt crystal form J1 of compound I.

[0571] In some embodiments, the present disclosure provides a method for preparing the L-tartaric acid salt crystal form J2 of compound I, comprising: step (1) dissolving the L-tartaric acid salt crystal form J1 of compound I in a mixed solvent of methanol and ethyl acetate, the volume ratio of methanol to ethyl acetate being 1:1-3:1, preferably 1:1-2:1,

[0572] Step (4) crystallization, filtration to obtain the L-tartaric acid salt crystal form J2 of compound I.

[0573] In some embodiments, the present disclosure provides a method for preparing the benzenesulfonic acid salt crystal form B1 of compound I, comprising: step (1) dissolving compound I in acetone,

[0574] Step (2) adding acetone-water solution of benzenesulfonic acid, the volume ratio of acetone to water being 1:1-3:1, preferably 1:1-2:1,

[0575] Step (3), wherein ethyl acetate is added to the solution of step (2) to make the volume ratio of acetone to ethyl acetate in the solution 1:1-4:1, preferably 1:1-3:1,

[0576] Step (4) crystallization, filtration to obtain the benzenesulfonate salt crystal form B1 of compound I.

[0577] In some embodiments, the present disclosure provides a method for preparing the benzenesulfonate salt crystal form B1 of compound I, comprising: step (1) dissolving compound I in tetrahydrofuran,

[0578] Step (2) adding a tetrahydrofuran solution of benzenesulfonic acid,

[0579] Step (4) crystallization, filtration to obtain the benzenesulfonate salt crystal form B1 of compound I.

[0580] In some embodiments, the present disclosure provides a method for preparing the benzenesulfonate salt crystal form B2 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0581] Step (2) adding an acetonitrile solution of benzenesulfonic acid,

[0582] Step (4) crystallization, filtration to obtain the benzenesulfonate salt crystal form B2 of compound I.

[0583] In some embodiments, the present disclosure provides a method for preparing the toluenesulfonate salt crystal form T1 of compound I, comprising: step (1) dissolving compound I in acetone,

[0584] Step (2) adding an acetone solution of toluenesulfonic acid,

[0585] Step (4) crystallization, filtration to obtain the toluenesulfonate salt crystal form T1 of compound I.

[0586] In some embodiments, the present disclosure provides a method for preparing the toluenesulfonate salt crystal form T2 of compound I, comprising: step (1) dissolving compound I in acetone,

[0587] Step (2) adding an acetone solution of toluenesulfonic acid,

[0588] Step (3), wherein methyl tert-butyl ether is added to the solution of step (2) to make the volume ratio of acetone to methyl tert-butyl ether in the solution 1:1-4:1, preferably 1:1-3:1,

[0589] Step (4) crystallization, filtration to obtain the toluenesulfonate salt crystal form T2 of compound I.

[0590] In some embodiments, the present disclosure provides a method for preparing the sulfate salt crystalline form S1 of Compound I, comprising: step (1) dissolving Compound I in acetonitrile,

[0591] step (2) adding acetonitrile solution of sulfuric acid,

[0592] step (4) crystallization, filtration to obtain the sulfate salt crystalline form S1 of Compound I.

[0593] In some embodiments, the present disclosure provides a method for preparing the sulfate salt crystalline form S2 of Compound I, comprising: step (1) dissolving the sulfate salt crystalline form S1 of Compound I in 95% (V / V) aqueous tetrahydrofuran solution,

[0594] step (4) crystallization, filtration to obtain the sulfate salt crystalline form S2 of Compound I.

[0595] In some embodiments, the present disclosure provides a method for preparing the hydrobromide salt crystalline form Br1 of Compound I, comprising: step (1) dissolving Compound I in acetonitrile,

[0596] step (2) adding acetonitrile solution of hydrobromic acid,

[0597] step (4) crystallization, filtration to obtain the hydrobromide salt crystalline form Br1 of Compound I.

[0598] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystalline form N1 of Compound I, comprising:

[0599] step (1) dissolving Compound I in a first solvent selected from at least one of tetrahydrofuran, acetonitrile, ethanol, acetone, 85% (V / V) aqueous acetone solution, 90% (V / V) aqueous acetone solution,

[0600] step (2) adding citric acid or citric acid monohydrate solution, the solvent of the solution being one organic solvent selected from tetrahydrofuran, ethanol, acetone, or a mixed solution of one organic solvent selected from tetrahydrofuran, ethanol, acetone and water, preferably in the case of a mixed solution, the volume ratio of organic solvent to water is 1:1-50:1, preferably 2:1-20:1, more preferably 85% (V / V) aqueous acetone solution, 90% (V / V) aqueous acetone solution, acetonitrile-water (8:1) mixed solution, ethanol-water (10:1) mixed solution, tetrahydrofuran-water (10:1) mixed solution,

[0601] optional step (3), wherein methyl tert-butyl ether is added to the solution of step (2) as a second solvent, the volume ratio of the first solvent to the second solvent is 1:2-3:1, preferably 1:1-2:1,

[0602] Step (4) crystallization, filtration, to obtain the citrate salt crystal form N1 of compound I.

[0603] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystal form N1 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0604] Step (2) adding acetonitrile-water solution of citric acid or citric acid monohydrate, wherein the volume ratio of acetonitrile to water is 6:1-10:1, preferably 7:1-9:1,

[0605] Step (4) crystallization, filtration, to obtain the citrate salt crystal form N1 of compound I.

[0606] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystal form N1 of compound I, comprising: step (1) dissolving compound I in ethanol,

[0607] Step (2) adding ethanol-water solution of citric acid or citric acid monohydrate, wherein the volume ratio of ethanol to water is 8:1-12:1, preferably 9:1-11:1,

[0608] Step (4) crystallization, filtration, to obtain the citrate salt crystal form N1 of compound I.

[0609] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystal form N1 of compound I, comprising: step (1) dissolving compound I in tetrahydrofuran,

[0610] Step (2) adding tetrahydrofuran-water solution of citric acid or citric acid monohydrate, wherein the volume ratio of tetrahydrofuran to water is 8:1-12:1, preferably 9:1-11:1,

[0611] Step (4) crystallization, filtration, to obtain the citrate salt crystal form N1 of compound I.

[0612] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystal form N1 of compound I, comprising: step (1) dissolving compound I in tetrahydrofuran,

[0613] Step (2) adding tetrahydrofuran solution of citric acid,

[0614] Step (4) crystallization, filtration, to obtain the citrate salt crystal form N1 of compound I.

[0615] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystal form N1 of compound I, comprising: step (1) dissolving compound I in ethanol,

[0616] Step (2) adding citric acid in ethanol,

[0617] Step (4) crystallization, filtration, to obtain the citrate salt crystalline form N1 of compound I.

[0618] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystalline form N1 of compound I, comprising: step (1) dissolving compound I in acetone,

[0619] Step (2) adding citric acid in acetone,

[0620] Step (4) crystallization, filtration, to obtain the citrate salt crystalline form N1 of compound I.

[0621] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystalline form N1 of compound I, comprising: step (1) dissolving compound I in 90% (V / V) aqueous acetone solution,

[0622] Step (2) adding citric acid or citric acid monohydrate in 90% (V / V) aqueous acetone solution,

[0623] Step (4) crystallization, filtration, to obtain the citrate salt crystalline form N1 of compound I.

[0624] In some embodiments, the present disclosure provides a method for preparing the citrate salt crystalline form N1 of compound I, comprising: step (1) dissolving compound I in 85% (V / V) aqueous acetone solution,

[0625] Step (2) adding citric acid or citric acid monohydrate in 85% (V / V) aqueous acetone solution, and then adding the citrate salt crystalline form N1 as a seed crystal,

[0626] Step (3), wherein methyl tert-butyl ether is added to the solution of step (2), and the volume ratio of 85% (V / V) aqueous acetone solution to methyl tert-butyl ether in the solution is 1:1-4:1, preferably 1:1-3:1,

[0627] Step (4) crystallization, filtration, to obtain the citrate salt crystalline form N1 of compound I.

[0628] In some embodiments, the present disclosure provides a method for preparing the L-malate salt crystalline form P1 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0629] Step (2) adding L-malic acid in acetonitrile-water solution, wherein the volume ratio of acetonitrile to water is 4:1-8:1, preferably 5:1-7:1,

[0630] Step (4) crystallization, filtration, to obtain the L-malate salt crystal form P1 of compound I.

[0631] In some embodiments, the present disclosure provides a method for preparing the L-malate salt crystal form P1 of compound I, comprising: step (1) dissolving compound I in acetone,

[0632] Step (2) adding an acetonitrile-water solution of L-malic acid, wherein the volume ratio of acetonitrile to water is 4:1-8:1, preferably 5:1-7:1,

[0633] Step (4) crystallization, filtration, to obtain the L-malate salt crystal form P1 of compound I.

[0634] In some embodiments, the present disclosure provides a method for preparing the L-camphorsulfonic acid salt crystal form Z1 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0635] Step (2) adding an acetonitrile-water solution of L-camphorsulfonic acid, wherein the volume ratio of acetonitrile to water is 6:1-10:1, preferably 7:1-9:1,

[0636] Step (3), wherein methyl tert-butyl ether is added to the solution of step (2), so that the volume ratio of acetonitrile to methyl tert-butyl ether in the solution is 1:1-4:1, preferably 1:1-2:1,

[0637] Step (4) crystallization, filtration, to obtain the L-camphorsulfonic acid salt crystal form Z1 of compound I.

[0638] In some embodiments, the present disclosure provides a method for preparing the fumarate salt crystal form F1 of compound I, comprising: step (1) dissolving compound I in tetrahydrofuran,

[0639] Step (2) adding a tetrahydrofuran solution of fumaric acid,

[0640] Step (3), wherein isopropyl acetate is added to the solution of step (2), so that the volume ratio of tetrahydrofuran to isopropyl acetate in the solution is 1:1-4:1, preferably 1:1-3:1,

[0641] Step (4) crystallization, filtration, to obtain the fumarate salt crystal form F1 of compound I.

[0642] In some embodiments, the present disclosure provides a method for preparing the trifluoroacetate salt crystal form TF1 of compound I, comprising: step (1) dissolving compound I in acetonitrile,

[0643] Step (2) adding an acetonitrile solution of trifluoroacetic acid,

[0644] Step (4) was crystallized, filtered to obtain a trifluoroacetate salt crystal form TF1 of compound I.

[0645] According to a fifth aspect of the present disclosure, there is provided a single crystal of compound I having the following characteristics:

[0646] belongs to the orthorhombic space group P212121 with cell parameters α = 90°, β = 90°, γ = 90°, Z = 4.

[0647] According to a sixth aspect of the present disclosure, there is provided a single crystal of compound I citrate having the following characteristics:

[0648] belongs to the monoclinic space group P21 with cell parameters α = 90°, β = 109.972(2)°, γ = 90°, Z = 2.

[0649] According to a seventh aspect of the present disclosure, there is provided a pharmaceutically acceptable salt of compound I, which is at least one selected from the group consisting of a hydrochloride, a methanesulfonate, a maleate, an L-tartrate, a benzenesulfonate, a toluenesulfonate, a sulfate, a hydrobromide, an L-malate, an L-camphorsulfonate, a fumarate, and a trifluoroacetate.

[0650] According to an eighth aspect of the present disclosure, there is provided (1) a crystal form of compound I or a pharmaceutically acceptable salt thereof, a single crystal of compound I, a single crystal of compound I citrate, a pharmaceutically acceptable salt of compound I, or (2) a pharmaceutical composition comprising at least one selected from the group consisting of the crystal form of compound I or a pharmaceutically acceptable salt thereof, the single crystal of compound I, the single crystal of compound I citrate, the pharmaceutically acceptable salt of compound I, and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a disease.

[0651] According to a ninth aspect of the present disclosure, there is provided (1) a crystal form of compound I or a pharmaceutically acceptable salt thereof, a single crystal of compound I, a single crystal of compound I citrate, a pharmaceutically acceptable salt of compound I, or (2) a pharmaceutical composition comprising at least one selected from the group consisting of the crystal form of compound I or a pharmaceutically acceptable salt thereof, the single crystal of compound I, the single crystal of compound I citrate, the pharmaceutically acceptable salt of compound I, and a pharmaceutically acceptable excipient, for use as a KRAS G12C mutant protein inhibitor.

[0652] According to a tenth aspect of the present disclosure, there is provided (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use as a cell proliferation inhibitor.

[0653] According to an eleventh aspect of the present disclosure, there is provided (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a disease mediated by KRAS G12C mutation.

[0654] According to a twelfth aspect of the present disclosure, there is provided (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use in the prevention and / or treatment of a malignant tumor, for example, a cancer or a sarcoma.

[0655] According to a thirteenth aspect of the present disclosure, there is provided (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use as a KRAS G12C mutant protein inhibitor.

[0656] According to a fourteenth aspect of the present disclosure, there is provided (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient, for use as a cell proliferation inhibitor.

[0657] According to a fifteenth aspect of the present disclosure, there is provided a use of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the prevention and / or treatment of a disease mediated by KRAS G12C mutation.

[0658] According to a sixteenth aspect of the present disclosure, there is provided a use of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the prevention and / or treatment of a malignant tumor (e.g., a cancer or a sarcoma).

[0659] According to a seventeenth aspect of the present disclosure, there is provided a use of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the manufacture of a medicament for use as a KRAS G12C mutant protein inhibitor.

[0660] According to an eighteenth aspect of the present disclosure, there is provided a use of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the manufacture of a medicament for use as a cell proliferation inhibitor.

[0661] According to a nineteenth aspect of the present disclosure, there is provided a use of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the manufacture of a medicament for the prevention and / or treatment of a disease mediated by KRAS G12C mutation.

[0662] According to a twentieth aspect of the present disclosure, there is provided a use of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient in the manufacture of a medicament for preventing and / or treating a malignant tumor (e.g., a cancer or a sarcoma).

[0663] According to a twenty-first aspect of the present disclosure, there is provided a method for preventing and / or treating a disease mediated by KRAS G12C mutation, which comprises administering to a subject in need thereof a therapeutically effective amount of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient.

[0664] According to a twenty-second aspect of the present disclosure, there is provided a method for preventing and / or treating a malignant tumor (e.g., a cancer or a sarcoma), which comprises administering to a subject in need thereof a therapeutically effective amount of (1) a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I or (2) a pharmaceutical composition comprising at least one selected from the group consisting of a crystalline form of Compound I or a pharmaceutically acceptable salt thereof, a single crystal of Compound I, a single crystal of citrate salt of Compound I, a pharmaceutically acceptable salt of Compound I and a pharmaceutically acceptable excipient.

[0665] In any of the above aspects, the cancer can be selected from one or more of pancreatic cancer, leukemia, esophageal cancer, lung cancer (e.g., non-small cell lung cancer), breast cancer, colorectal cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine cancer, and thyroid cancer.

[0666] In any of the above aspects, the sarcoma can be osteosarcoma.

[0667] Embodiment

[0668] The following specific examples are provided to enable those skilled in the art to more clearly understand the present disclosure. It is noted that these examples are set forth merely for purposes of illustration and are not intended to limit the scope of the application.

[0669] Instrument and analytical conditions:

[0670] X-ray powder diffraction (XRPD):

[0671] Instrument: Bruker D8 advance, Cu / Ka radiation, voltage 40 kV, current 40 mA, scan range 3°-40°, step: 0.02°, scan rate: 0.1 s / step.

[0672] Differential scanning calorimetry (DSC):

[0673] Instrument: DSC Q2000, nitrogen protection, flow rate 50 ml / min, temperature range: 25-350 °C, heating rate: 10 °C / min.

[0674] Thermogravimetric analysis (TGA):

[0675] Instrument: TGA 55, nitrogen protection, flow rate 50 ml / min, temperature range: 30-400 °C, heating rate: 10 °C / min.

[0676] X-ray single crystal diffraction (SCXRD):

[0677] Rigaku Oxford Diffraction XtaLAB Synergy four-circle diffractometer, equipped with one HyPix-6000 HE area detector. Low temperature system: Oxford Cryostream 800. Cu: 50 W, Micro focus source: with multilayer mirror (p-CMF). Distance between crystal and CCD detector: d = 35 mm. Tube voltage: 50 kV. Tube current: 1 mA.

[0678] Dynamic vapor sorption (DVS):

[0679] DVS graphs were collected on an Intrinsic dynamic vapor sorption instrument produced by SMS (Surface Measurement Systems Ltd.). The method parameters of the dynamic vapor sorption instrument are as follows: temperature: 25 °C; relative humidity range: 0% RH-95% RH-0% RH; gradient steps: 5% RH; equilibration conditions: <0.02% / min.

[0680] Example 1

[0681] Preparation of (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6- hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8- oxo-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one (Compound I)

[0682]

[0683] According to Example 22 of patent application PCT / CN2022 / 074955, Compound I is prepared, in particular as described below.

[0684] (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2- methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c- tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one

[0685]

[0686] Step 1: (S)-tert-butyl 2-vinylpyrrolidine-1-carboxylate

[0687]

[0688] Potassium tert-butoxide (27.03 g, 240.91 mmol, 2 eq) was dissolved in tetrahydrofuran (240 mL), methyltriphenylphosphonium bromide (88.21 g, 246.93 mmol, 2.05 eq) was added, and after nitrogen replacement, the reaction was carried out at 80 °C for 1 h and then cooled to 0 °C. A solution of (S)-tert-butyl-2-formylpyrrolidine-1-carboxylate (24 g, 120.45 mmol, 1 eq) in tetrahydrofuran (240 mL) was added dropwise. The reaction was carried out at room temperature for 2.5 h. TLC (petroleum ether: ethyl acetate = 5:1) was used to monitor the completion of the reaction. The reaction was quenched with water (150 mL), extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-tert-butyl-2-vinylpyrrolidine-1-carboxylate (44 g, yield 97%) as a colorless oil.

[0689] 1 H NMR (400 MHz, CDC13) δ 5.66 (br s, 1H), 4.97 (br d, J = 9.6 Hz, 2H), 4.35 - 4.09 (m, 1H), 3.32 (br s, 2H), 2.01 - 1.84 (m, 1H), 1.83 - 1.68 (m, 2H), 1.67 - 1.55 (m, 1H), 1.37 (br s, 9H).

[0690] Step 2: (2S)-tert-butyl-2-(1,2-dihydroxyethyl)pyrrolidine-1-carboxylate

[0691]

[0692] (S)-tert-butyl-2-vinylpyrrolidine-1-carboxylate (8 g, 40.55 mmol, 1 eq) was dissolved in a mixture of tert-butanol (168 mL), tetrahydrofuran (48 mL) and water (24 mL), 4-methylmorpholine N-oxide (14.25 g, 121.66 mmol, 3 eq) and potassium osmate dihydrate (1.49 g, 4.06 mmol, 0.1 eq) were added, and the reaction was carried out at room temperature overnight. TLC (petroleum ether: tetrahydrofuran = 2:1) was used to monitor the completion of the reaction. The reaction was quenched with saturated sodium sulfite solution (480 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give (2S)-tert-butyl-2-(1,2-dihydroxyethyl)pyrrolidine-1-carboxylate (9.5 g) as a light yellow oil. The crude product was directly used in the next step.

[0693] 1H NMR (400 MHz, CDC13) δ 4.03-3.80 (m, 1H), 3.70-3.01 (m, 7H), 2.12-1.65 (m, 4H), 1.50-1.44 (m, 9H).

[0694] Step 3: Compound 22-3-1 and Compound 22-3-2

[0695] (S)-tert-Butyl-2-((S)-2-((tert-butyldimethylsilyl)oxy)-l-hydroxyethyl)pyrrolidine-l- carboxylate and (S)-tert-Butyl-2-((R)-2-((tert-butyldimethylsilyl)oxy)-l- hydroxyethyl)pyrrolidine-l-carboxylate

[0696]

[0697] The crude (2S)-tert-butyl-2-(l,2-dihydroxyethyl)pyrrolidine-l-carboxylate (9.50 g, 40.56 mmol, 1 eq) was dissolved in dichloromethane (300 mL), and imidazole (5.52 g, 81.11 mmol, 2 eq) and tert-butyldimethylsilyl chloride (6.72 g, 44.61 mmol, 1.1 eq) were added, and the reaction was allowed to proceed at room temperature overnight. TLC (petroleum ether: tetrahydrofuran = 3: 1) was used to monitor the completion of the reaction, and the reaction solution was quenched with water (300 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (tetrahydrofuran / petroleum ether: 0-10%) to obtain the first fraction of Compound 22-3-1 (6.5 g, yield 46.38%, light yellow solid) and the second fraction of Compound 22-3-2 (4.2 g, yield 29.97%, light yellow solid).

[0698] Compound 22-3-1:

[0699] 1 H NMR (400 MHz, CDC13) δ 4.03-3.80 (m, 1H), 3.70-3.01 (m, 7H), 2.12-1.65 (m, 4H), 1.50-1.44 (m, 9H).

[0700] Compound 22-3-2:

[0701] 1H NMR (400 MHz, CDC13) δ 4.53 (br s, 1H), 4.03-3.90 (m, 1H), 3.74-3.36 (m, 4H), 3.35-3.25 (m, 1H), 2.00-1.71 (m, 4H), 1.46 (s, 9H), 0.91-0.88 (m, 9H), 0.11-0.05 (m, 6H).

[0702] Step 4: Compound 22-4-1 and Compound 22-4-2

[0703] (S)-2-((tert-butyldimethylsilyl)oxy)-1-((S)-1-methylpyrrolidin-2-yl)ethanol and (R)-2-((tert-butyldimethylsilyl)oxy)-1-((S)-1-methylpyrrolidin-2-yl)ethanol

[0704]

[0705] Lithium tetrahydroaluminate (1.27 g, 33.43 mmol, 3 eq) was dissolved in tetrahydrofuran (40 mL), after nitrogen replacement, it was cooled to 0 °C. Compound 22-3-1 (3.85 g, 11.14 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL), it was added to the reaction solution slowly at 0 °C. The reaction was carried out at 70 °C overnight. TLC (petroleum ether: tetrahydrofuran: ammonia water = 2:1:0.015) was used to monitor the reaction completion. The reaction was quenched by adding water, 15% sodium hydroxide solution and water to the reaction solution successively at 0 °C, it was dried by adding sodium sulfate, concentrated after filtration, the crude product (1.65 g) was obtained as light yellow oil. The crude product was dissolved in dichloromethane (32 mL), imidazole (1.52 g, 22.31 mmol, 2 eq) and tert-butyldimethylsilyl chloride (1.85 g, 12.27 mmol, 1.1 eq) were added, the reaction was carried out at room temperature overnight. TLC (petroleum ether: tetrahydrofuran: ammonia water = 3:1:0.02) was used to monitor the reaction completion, the reaction was quenched by water, extracted by dichloromethane, washed by saturated brine, dried by anhydrous sodium sulfate, concentrated after filtration, the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia water) / petroleum ether: 0-50%], compound 22-4-1 (2 g, yield 69.09%) was obtained as light yellow oil.

[0706] 1H NMR (400 MHz, CDC13) δ 3.76 (dt, J = 2.9, 6.1 Hz, 1H), 3.71 - 3.63 (m, 1H), 3.51 (dd, J = 5.9, 10.0 Hz, 1H), 3.18 - 2.94 (m, 2H), 2.35 - 2.27 (m, 4H), 2.26 - 2.18 (m, 1H), 1.85 - 1.74 (m, 1H), 1.72 - 1.57 (m, 3H), 0.88 (s, 9H), 0.05 (s, 6H).

[0707] Lithium tetrahydroaluminate (329.48 mg, 8.68 mmol, 3 eq) was dissolved in tetrahydrofuran (10 mL) and cooled to 0 °C under nitrogen. Compound 22-3-2 (1 g, 2.89 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL) and added slowly to the reaction solution at 0 °C. The reaction was carried out at 70 °C overnight. TLC (petroleum ether: tetrahydrofuran: ammonia water = 2: 1: 0.015) was used to monitor the completion of the reaction. The reaction was quenched by adding water, 15% sodium hydroxide solution and water successively at 0 °C, and then the reaction solution was dried over sodium sulfate after being warmed to room temperature. The crude product (350 mg) was obtained as a light yellow oil after filtration and concentration. The crude product was dissolved in dichloromethane (7 mL), and then imidazole (328.21 mg, 4.82 mmol, 2 eq) and tert-butyldimethylsilyl chloride (1.399 g, 2.65 mmol, 1.1 eq) were added. The reaction was carried out at room temperature overnight. The completion of the reaction was monitored by TLC (petroleum ether: tetrahydrofuran: ammonia water = 3: 1: 0.02). The reaction solution was quenched with water, and then extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Compound 22-4-2 (400 mg, yield 63.96%) was obtained as a light yellow oil after column purification [tetrahydrofuran (containing 0.5% ammonia water) / petroleum ether: 0-50%].

[0708] 1 H NMR (400 MHz, CDC13) δ 3.57 (d, J = 6.0 Hz, 2H), 3.46 - 3.40 (m, 1H), 3.05 (td, J = 4.7, 9.5 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.44 (s, 3H), 2.36 - 2.26 (m, 1H), 1.97 - 1.85 (m, 1H), 1.78 - 1.67 (m, 2H), 1.66 - 1.56 (m, 1H), 0.90 - 0.87 (m, 9H), 0.06 (s, 6H).

[0709] Step 5: Compound 22-5-1 and Compound 22-5-2

[0710] (2R,4aR)-tert-butyl-10-bromo-7-((S)-2-((tert-butyldimethylsilyl)oxy)-l-((S)-l- methylpyrrolidin-2-yl)ethoxy)-l l-chloro-9-fluoro-2-methyl-5-oxo-4,4a,5,6-tetrahydro-lH- pyrrolo[l',2':4,5]pyrrolo[2,3-c]quinoline-3(2H)-carboxylate and (2R,4aR)-tert-butyl-10-bromo- 7-((R)-2-((tert-butyldimethylsilyl)oxy)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)-l l-chloro-9- fluoro-2-methyl-5-oxo-4,4a,5,6-tetrahydro-lH-pyrrolo[l',2':4,5]pyrrolo[2,3-c]quinoline-3(2H)- carboxylate

[0711]

[0712] Sodium hydride (751.49 mg, 18.79 mmol, 60% content, 3 eq) was dissolved in toluene (50 mL), after nitrogen replacement, it was cooled to 0 °C. Compound 22-4-1 (1.95 g, 7.52 mmol, 1.2 eq) was dissolved in toluene (25 mL), which was added slowly to the reaction solution at 0 °C. After 30 min at 0 °C, (2R,4aR)-tert-butyl-10-bromo-7, 11-dichloro-9-fluoro-2-methyl-5-oxo- 4,4a,5,6-tetrahydro-lH-pyrrolo[l',2':4,5]pyrrolo[2,3-c]quinoline-3(2H)-carboxylate (3.35 g, 6.26 mmol, 1 eq) was added, and the reaction was carried out at 50 °C overnight. The reaction was monitored by LCMS, and the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography [tetrahydrofuran (containing 0.5% ammonia water) / petroleum ether: 0-70%] to give compound 22-5-1 (3.7 g, yield 78.02%) as a brown solid.

[0713] MS m / z: 756.1 / 758.1 [M+H] + .

[0714] 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 5.81 (br s, 1H), 4.71 - 4.50 (m, 1H), 4.34 - 4.10 (m, 1H), 3.83 (br d, J = 5.6 Hz, 2H), 3.48 - 3.36 (m, 1H), 3.27 (br d, J = 13.5 Hz, 1H), 3.06 - 2.93 (m, 1H), 2.90 - 2.75 (m, 2H), 2.39 - 2.33 (m, 3H), 2.23 (br s, 1H), 2.06 (q, J = 8.3 Hz, 1H), 1.73 - 1.53 (m, 4H), 1.44 (br d, J = 11.5 Hz, 12H), 0.71 (s, 9H), -0.03 (d, J = 11.3 Hz, 6H).

[0715] Sodium hydride (4.09 g, 102.14 mmol, 60% purity, 3 eq) was dissolved in toluene (150 mL), and after nitrogen substitution, it was cooled to 0 °C. Compound 22-4-2 (10.6 g, 40.85 mmol, 1.2 eq) was dissolved in toluene (50 mL), and it was slowly added dropwise to the reaction solution at 0 °C. After 30 minutes of reaction at 0 °C, (2R,4aR)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-2-methyl-5-oxo-4,4a,5,6-tetrahydro-1H- pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylate (18.19 g, 34.05 mmol, 1 eq) was added, and the reaction was carried out at 50 °C overnight. The reaction was monitored by LCMS, and after completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography [methanol (containing 0.5% ammonia water) / petroleum ether: 0-5%] to obtain compound 22-5-2 (4.3 g, yield 16.68%) as a yellow solid.

[0716] MS m / z: 756.3 / 758.3 [M+H] + .

[0717] 1H NMR (400 MHz, CDC13) δ 8.56-8.33 (m, 1H), 7.81 (d, J = 1.3 Hz, 1H), 5.54 (br s, 1H), 4.92 (br d, J = 13.6 Hz, 1H), 4.52 (br s, 1H), 4.30 (br s, 1H), 4.08-3.85 (m, 2H), 3.72-3.35 (m, 3H), 3.21-2.81 (m, 4H), 2.50 (br s, 2H), 2.30 (br s, 1H), 2.05-1.68 (m, 3H), 1.57-1.43 (m, 12H), 0.90-0.69 (m, 9H), 0.13-0.06 (m, 6H).

[0718] Step 6: Compound 22-6-1 and Compound 22-6-2

[0719] (2R,4aR)-tert-Butyl-10-bromo-11-chloro-9-fluoro-7-((S)-2-hydroxy-l-((S)-l- methylpyrrolidin-2-yl)ethoxy)-2-methyl-5-oxo-4,4a,5,6-tetrahydro-lH-pyrrolo[l',2':4,5] pyrrolo[2,3-c]quinoline-3(2H)-carboxylate and (2R,4aR)-tert-Butyl-10-bromo-11-chloro-9- fluoro-7-((R)-2-hydroxy-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)-2-methyl-5-oxo-4,4a,5,6- tetrahydro-lH-pyrrolo[l',2':4,5]pyrrolo[2,3-c]quinoline-3(2H)-carboxylate

[0720]

[0721] Compound 22-5-1 (3.5 g, 4.62 mmol, 1 eq) was dissolved in tetrahydrofuran (42 mL), tetrabutylammonium fluoride solution (1 M, 6.93 mL, 1.5 eq) was added, stirred at room temperature for 4 hours, LCMS detected that the reaction was complete, the reaction liquid was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 22-6-1 crude (3.2 g), light brown solid, which was directly used in the next step.

[0722] MS m / z: 642.2 / 644.2 [M+H] + .

[0723] Compound 22-6-2 (550 mg, yield 64.77%) was obtained as a yellow solid by dissolving compound 22-5-2 (1 g, 1.32 mmol, 1 eq) in tetrahydrofuran (5 mL), adding a solution of tetrabutylammonium fluoride (1 M, 2.38 mL, 1.8 eq), stirring at room temperature for 1 hour, detecting that the reaction was complete by LCMS, extracting the reaction liquid with water and ethyl acetate, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering and concentrating, and purifying the residue by column chromatography [methanol (containing 0.5% ammonia water) / dichloromethane: 0-5%].

[0724] MS m / z: 642.0 / 644.0 [M+H] + .

[0725] 1 H NMR (400 MHz, CDC13) δ 8.86 (br s, 1H), 7.82 (br s, 1H), 5.72 (br s, 1H), 5.00-4.70 (m, 1H), 4.55-4.25 (m, 1H), 4.14 (dd, J = 6.4, 11.7 Hz, 1H), 3.93 (dd, J = 4.0, 11.5 Hz, 1H), 3.82-3.19 (m, 4H), 3.14-2.82 (m, 3H), 2.75 (br s, 3H), 2.62-2.40 (m, 1H), 2.19-1.69 (m, 4H), 1.62-1.46 (m, 12H).

[0726] Step 7: Compound 22-7-1 and compound 22-7-2

[0727] (2R,4aR,7R)-tert-Butyl-11-bromo-12-chloro-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate and (2R,4aR,7S)-tert-Butyl-11-bromo-12-chloro-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate

[0728]

[0729] Triphenylphosphine (1.41 g, 5.37 mmol, 3 eq) was dissolved in tetrahydrofuran (30 mL), diisopropyl azodicarboxylate (1.09 g, 5.37 mmol, 3 eq) was added at 0 °C, and the reaction was stirred at 0 °C for 30 min. Compound 22-6-1 (1.15 g, 1.79 mmol, 1 eq) was dissolved in tetrahydrofuran (6 mL) and added dropwise to the reaction at 0 °C, and the reaction was stirred at room temperature overnight. The reaction was monitored by LCMS to be complete, and the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by HPLC to give compound 22-7-1 (260 mg, yield 23.26%) as a light yellow solid.

[0730] MS m / z: 624.2 / 626.2 [M+H] + .

[0731] 1 H NMR (400 MHz, DMSO-d6) d 7.82 (s, 1H), 4.72 - 4.52 (m, 2H), 4.38 - 4.10 (m, 2H), 3.96 - 3.80 (m, 1H), 3.48 (br d, J = 11.0 Hz, 1H), 3.09 - 2.94 (m, 2H), 2.87 (br d, J = 12.0 Hz, 1H), 2.73 (td, J = 4.7, 9.0 Hz, 1H), 2.42 - 2.37 (m, 3H), 2.31 - 2.23 (m, 1H), 2.04 - 1.91 (m, 1H), 1.88 - 1.67 (m, 3H), 1.47 - 1.41 (m, 12H).

[0732] HPLC separation conditions:

[0733] Column: YMC Triart C 18 250*50mm*7um;

[0734] Mobile Phase A: Water (0.05% ammonia hydroxide v / v), Mobile Phase B: ACN;

[0735] % Mobile Phase B: 54% - 94% in 9 min.

[0736] Triphenylphosphine (673.11 mg, 2.57 mmol, 3 eq) was dissolved in tetrahydrofuran (3 mL), diisopropyl azodicarboxylate (518.93 mg, 2.57 mmol, 3 eq) was added at 0 °C, and the reaction was stirred at 0 °C for 30 min. Compound 22-6-2 (550 mg, 0.855 mmol, 1 eq) was dissolved in tetrahydrofuran (4.5 mL) and added dropwise to the reaction solution at 0 °C, and the reaction was stirred at room temperature overnight. The reaction was monitored by LCMS to be complete, and the reaction solution was filtered and concentrated. The residue was purified by column chromatography [methanol (containing 0.5% ammonia water) / dichloromethane: 0-5%] and then by HPLC to give compound 22-7-2 (435 mg, yield 81.37%) as a white solid.

[0737] MS m / z: 624.1 / 626.1 [M+H] + .

[0738] 1 H NMR (400 MHz, CDC13) δ 7.82 (d, J = 1.8 Hz, 1H), 5.02 - 4.90 (m, 1H), 4.83 (br s, 1H), 4.59 - 4.24 (m, 1H), 4.12 (br dd, J = 5.8, 13.8 Hz, 1H), 3.94 (dd, J = 3.3, 13.8 Hz, 1H), 3.79 - 3.19 (m, 3H), 3.08 - 2.93 (m, 2H), 2.88 (q, J = 7.5 Hz, 1H), 2.61 (br s, 3H), 2.50 - 2.35 (m, 1H), 2.10 - 1.74 (m, 4H), 1.52 (br s, 9H), 1.26 (d, J = 6.3 Hz, 3H).

[0739] HPLC separation conditions:

[0740] Column: YMC Triart C 18 250*50mm*7um;

[0741] Mobile Phase A: Water (0.225% FA), Mobile Phase B: ACN;

[0742] % Mobile Phase B: 29%-69%, 9 min.

[0743] Step 8: Compound 22-8-1, Compound 22-8-2 and Compound 22-8-3

[0744] (2R,4aR,7R)-tert-butyl-12-chloro-10-fluoro-11-((R)-2-fluoro-6-hydroxyphenyl)- 2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa- 3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate, (2R,4aR,7R)-tert-butyl-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)- 2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa- 3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate and (2R,4aR,7S)-tert-butyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2- methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa- 3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate

[0745]

[0746]

[0747] Compound 22-8-1 (80 mg, 27.21% yield, yellowish solid) and compound 22-8-2 (100 mg, 34.02% yield, yellowish solid) were obtained by dissolving compound 22-7-1 (280 mg, 0.448 mmol, 1 eq), potassium (2-fluoro-6-hydroxyphenyl)trifluoroborate (390.70 mg, 1.79 mmol, 4 eq), potassium carbonate (185.77 mg, 1.34 mmol, 3 eq) in a mixture of dioxane (4.5 mL) and water (1.5 mL), adding 2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (74.95 mg, 0.090 mmol, 0.2 eq), and after nitrogen replacement, reacting at 80 °C for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated, and the crude product was purified by plate separation (petroleum ether: tetrahydrofuran: ammonia water = 1:2:0.015) to obtain compound 22-8-1 (80 mg, 27.21% yield, yellowish solid) and compound 22-8-2 (100 mg, 34.02% yield, yellowish solid).

[0748] Compound 22-8-1:

[0749] MS m / z: 656.3 / 658.3 [M+H] + .

[0750] Compound 22-8-2:

[0751] MS m / z: 656.3 / 658.3 [M+H] + .

[0752] Compound 22-7-2 (400 mg, 0.64007 mmol, 1 eq), potassium trifluoroborate (2-fluoro-6-hydroxyphenyl) salt (558.14 mg, 2.56 mmol, 4 eq), potassium carbonate (265.39 mg, 1.92 mmol, 3 eq) were dissolved in a mixture of dioxane (4.5 mL) and water (1.5 mL), and then 2-dicyclohexylphosphino-2',6'-d iisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (107.07 mg, 0.12801 mmol, 0.2 eq) was added. After replacement of nitrogen, the reaction was carried out at 80 °C for 5 hours. The reaction was monitored by LCMS. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography [tetrahydrofuran (containing 0.5% ammonia water) / petroleum ether: 0-66%] to obtain compound 22-8-3 (220 mg, yield 52.39%) as a yellow solid.

[0753] MS m / z: 656.3 / 658.3 [M+H] + .

[0754] Step 9: Compound 22-9-1, compound 22-9-2 and compound 22-9-3

[0755] (2R,4aR,7R)-12-chloro-10-fluoro-11-((R)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1- methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de] anthracen-5(1H)-one, (2R,4aR,7R)-12-chloro-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1- methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de] anthracen-5(1H)-one and (2R,4aR,7S)-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1- methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de] anthracen-5(1H)-one

[0756]

[0757]

[0758] Compound 22-9-1 (80 mg, 0.122 mmol, 1 eq) was dissolved in dichloromethane (1.2 mL), trifluoroacetic acid (0.4 mL) was added, and stirring was performed at room temperature for 1 hour. The reaction was monitored by LCMS to be complete, and the reaction solution was concentrated to obtain compound 22-9-1 crude (120 mg) as a light brown oil, which was directly used in the next step.

[0759] MS m / z: 556.3 / 558.3 [M+H] + .

[0760] The synthetic method of compound 22-9-1 was adopted to prepare compound 22-9-2 crude (135 mg) as a light brown oil using compound 22-8-2 as the raw material.

[0761] MS m / z: 556.3 / 558.3 [M+H] + .

[0762] The synthetic method of compound 22-9-1 was adopted to prepare compound 22-9-3 crude (260 mg) as a light brown oil using compound 22-8-3 as the raw material.

[0763] MS m / z: 556.3 / 558.3 [M+H] + .

[0764] Step 10: Compound 22-P1, compound 22-P2, compound 22-P3 and compound 22-P4

[0765] (2R,4aR,7R)-3-acryloyl-12-chloro-10-fluoro-11-((R)-2-fluoro-6-hydroxyphenyl)- 2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c- tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one, (2R,4aR,7R)-3-acryloyl-12-chloro-10- fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)- 2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one, (2R,4aR,7S)-3-acryloyl-12-chloro-10-fluoro-11-((R)-2-fluoro-6-hydroxyphenyl)-2- methyl-7-((S)-1-methylpyrrolidin-2-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c- tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one and (2R,4aR,7S)-3-acryloyl-12-chloro-10- fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)- 2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracen-5(1H)-one

[0766]

[0767] Compound 22-9-1 crude (120 mg, 0.122 mmol, 1 eq) and triethylamine (98.70 mg, 0.975 mmol, 8 eq) were dissolved in dichloromethane (2 mL), acryloyl chloride (11.04 mg, 0.122 mmol, 1 eq) was added slowly at -70 °C, and the reaction was allowed to proceed at -70 °C for 30 min. The reaction was complete as detected by LCMS. The reaction solution was quenched with saturated brine and extracted with dichloromethane, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and amine methanol solution (7 M, 2 mL, 14 mmol) was added to the residue at room temperature. The reaction was allowed to proceed for half an hour, and the reaction was complete as detected by LCMS. The reaction solution was concentrated, and the residue was purified by HPLC to obtain compound 22-P1 (16.5 mg, yield: 22.1%) as a white solid.

[0768] MS m / z: 610.3 / 612.3 [M+H] + .

[0769] 19F NMR (376 MHz, CDC13) δ -112.10 (s, IF), -116.84 (s, IF).

[0770] 1 H NMR (400 MHz, CDC13) δ 7.86 (s, IH), 7.37 - 7.28 (m, IH), 6.99 (br dd, J=10.8, 16.7 Hz, IH), 6.87 (br d, J=8.1 Hz, IH), 6.78 (br t, J=8.4 Hz, IH), 6.36 (br d, J=17.0 Hz, IH), 5.81 (br d, J=11.1 Hz, IH), 4.95 (br s, IH), 4.85 - 4.68 (m, 2H), 4.24 (br s, IH), 3.89 - 3.77 (m, IH), 3.74 (br s, IH), 3.37 - 2.85 (m, 5H), 2.67 - 2.32 (m, 4H), 2.16 - 1.75 (m, 4H), 1.68 - 1.61 (m, 3H).

[0771] HPLC separation conditions:

[0772] Column: Phenomenex Gemini-NX 80*40mm*3um;

[0773] Mobile phase A: Water (0.05% ammonia hydroxide v / v), Mobile phase B: ACN;

[0774] Flow B%: 29% - 69% in 9 min.

[0775] Compound 22-P2 (15.8 mg, yield 17.0%) was prepared using the synthetic method of compound 22-P1 with compound 22-9-2 crude as starting material and purified by HPLC, white solid.

[0776] MS m / z: 610.3 / 612.3 [M+H] + .

[0777] 19 F NMR (376 MHz, CDC13) δ -112.30 (s, IF), -116.53 (s, IF).

[0778] 1H NMR (400 MHz, CDC13) δ 7.79 (s, 1H), 7.33-7.27 (m, 1H), 7.06-6.83 (m, 2H), 6.75 (br t, J = 8.6 Hz, 1H), 6.34 (br d, J = 16.6 Hz, 1H), 5.78 (br d, J = 10.9 Hz, 1H), 5.48-4.87 (m, 1H), 4.77 (br t, J = 12.4 Hz, 2H), 4.28 (br s, 1H), 3.86-3.61 (m, 2H), 3.41-2.85 (m, 5H), 2.70-2.40 (m, 4H), 2.16-1.78 (m, 4H), 1.63 (br d, J = 6.5 Hz, 3H).

[0779] HPLC separation conditions:

[0780] Column: Phenomenex Gemini-NX 80*40mm*3um;

[0781] Mobile phase A: Water (0.05% ammonia hydroxide v / v), Mobile phase B: ACN;

[0782] % of mobile phase B: 28%-68%, 9 min.

[0783] Compound 22-9-3 crude (186 mg, 0.3345 mmol, 1 eq) and triethylamine (270.81 mg, 2.68 mmol, 8 eq) were dissolved in dichloromethane (3 mL), acryloyl chloride (60.56 mg, 0.6691 mmol, 2 eq) was added slowly at -70 °C, and the reaction was carried out at -70 °C for 30 min. The reaction was detected to be complete by LCMS. The reaction solution was quenched with saturated brine, extracted with dichloromethane, washed with saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and addition of amine methanol solution (7M, 2 mL, 14 mmol) to the residue at room temperature were carried out, the reaction was monitored by LCMS, and the reaction was complete after half an hour. The reaction solution was concentrated, and the residue was purified by HPLC twice to obtain compound 22-P3 (30 mg, yield 13.92%, white solid) and compound 22-P4 (35 mg, yield 17.02%, white solid).

[0784] HPLC separation conditions:

[0785] Column: Phenomenex Gemini NX-C18 (75*30mm*3um);

[0786] Mobile phase A: Water (0.05% ammonia hydroxide v / v), Mobile phase B: ACN;

[0787] Mobile phase B%: 36-76%, 9 min.

[0788] Column: Phenomenex Gemini NX-C18 (75*30mm*3um);

[0789] Mobile phase A: Water (0.225% FA), Mobile phase B: ACN;

[0790] Mobile phase B%: 10-50%, 9 min.

[0791] Compound 22-P3:

[0792] MS m / z: 610.0 / 612.0 [M+H] + .

[0793] 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (br s, 1H), 7.83 (br s, 1H), 7.41 - 7.28 (m, 1H), 7.07 - 6.74 (m, 3H), 6.14 (dd, J=2.1, 16.7 Hz, 1H), 5.81 - 5.66 (m, 1H), 5.17 - 4.35 (m, 3H), 4.16 - 3.98 (m, 2H), 3.87 - 3.68 (m, 2H), 3.33 - 2.92 (m, 3H), 2.73 - 2.59 (m, 1H), 2.33 (br s, 3H), 2.25 - 2.10 (m, 1H), 1.84 (br s, 1H), 1.75 - 1.61 (m, 3H), 1.57 - 1.39 (m, 3H).

[0794] 19 F NMR (376 MHz, DMSO-d6) δ -113.71 (s, 1F), -119.41 (s, 1F).

[0795] Compound 22-P4:

[0796] MS m / z: 610.0 / 612.0 [M+H] + .

[0797] 1H NMR (400 MHz, DMSO-d6) δ 10.32 (br s, 1H), 7.84 (br s, 1H), 7.33 (q, J = 7.9 Hz, 1H), 7.08 - 6.73 (m, 3H), 6.15 (dd, J = 2.1, 16.7 Hz, 1H), 5.83 - 5.67 (m, 1H), 5.19 - 4.36 (m, 3H), 4.17 - 3.99 (m, 2H), 3.89 - 3.71 (m, 2H), 3.22 - 2.83 (m, 3H), 2.71 - 2.57 (m, 1H), 2.33 (s, 3H), 2.24 - 2.10 (m, 1H), 1.83 (br d, J = 4.0 Hz, 1H), 1.75 - 1.60 (m, 3H), 1.59 - 1.43 (m, 3H).

[0798] 19 F NMR (376 MHz, DMSO-d6) δ -113.71 (s, IF), -119.63 (s, IF).

[0799] Retention time (compound 22-P3): 1.238 min; retention time (compound 22-P4): 0.927 min.

[0800] Column: Chiralpak IG-350*4.6 mm I.D, 3 um

[0801] Mobile phase: A: C02B: Ethanol (0.05% DEA); Isocratic: 40% B

[0802] Flow rate: 4 mL / min

[0803] Column temperature: 35 °C

[0804] ABPR: 1500 psi.

[0805] A sample of 15 mg of compound 22-P2 was dissolved in 900 pL of methanol / ethyl acetate / acetonitrile (1:4:4) at room temperature, and the sample solution was placed in a 4 mL semi-sealed sample bottle and slowly evaporated at room temperature. A colorless block single crystal was obtained the next day. This single crystal sample was used for single crystal X-ray diffraction analysis.

[0806] The results show that the single crystal structure belongs to the orthorhombic P212121 space group with cell parameters a = 90°, b = 90°, g = 90°, Z = 4. Details are shown in Table 1. Figure 65 The absolute configuration of compound 22-P2 is shown in Formula I according to the single crystal spectrum and X-ray single crystal diffraction data.

[0807] Compound 22-P2 was prepared into citrate single crystal according to the preparation method of Example 25, and the single crystal diffraction analysis was carried out, and the pattern thereof is shown in Figure 43 The X-ray single crystal diffraction data of the compound 22-P2 is monoclinic P21 space group, and the cell parameters are a = 8. 030(2) A, b = 12. 858(3) A, c = 20. 858(5) A, a = 90°, β = 109. 972(2) °, γ = 90°, V = 2 1 1 1 1(7) A3, Z = 2. The absolute configuration of the compound 22-P2 is shown in formula I according to the single crystal pattern and the X-ray single crystal diffraction data.

[0808] Example 2

[0809] Preparation of compound I crystal form Y1

[0810] 5.01 g of compound I was added into a 100 mL reaction bottle, 30 mL of tetrahydrofuran was added, stirred, replaced by nitrogen, and warmed to 55-60 °C. After dissolution, 30 mL of n-heptane was added dropwise. After the dropwise addition was completed, the temperature was maintained and stirred for 2-3 hours, slowly cooled to 20-25 °C, filtered, and the filter cake was washed with 5 mL of n-heptane and then dried under suction. After being dried under vacuum at 50 °C for 40-48 hours, 3.81 g of crystal form Y1 was obtained, with a yield of 76%. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 1 to 3

[0811] Example 3

[0812] Preparation of compound I crystal form Y1

[0813] 5.12 g of compound I was added into a 100 mL reaction bottle, 30 mL of tetrahydrofuran was added, stirred, replaced by nitrogen, and warmed to 55-60 °C. After dissolution, 40 mL of water was added dropwise. After the dropwise addition was completed, the temperature was maintained and stirred for 2-3 hours, slowly cooled to 20-25 °C, filtered, and the filter cake was washed with 5 mL of tetrahydrofuran aqueous solution (volume ratio of tetrahydrofuran: water = 3:4) and then dried under suction. After being dried under vacuum at 50 °C for 40-48 hours, 4.20 g of crystal form Y1 was obtained, with a yield of 82%. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 1 to 3

[0814] Example 4

[0815] Preparation of compound I crystal form Y1

[0816] ​​​Into a 2L reaction flask, 100.05g of Compound I was added, 600mL of 2-butanone was added, stirred, replaced by nitrogen, and warmed to 65-70°C. After dissolution, 800mL of methyl tert-butyl ether was added dropwise. After the dropwise addition was completed, the mixture was stirred for 2-3 hours, slowly cooled to 20-25°C, filtered, the filter cake was rinsed with 100mL of methyl tert-butyl ether, and then dried under suction, and dried under vacuum at 50°C for 40-48 hours to obtain 80.04g of Form Y1, with a yield of 80%. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 1 to 3

[0817] Example 5

[0818] Preparation of Compound I Form Y1

[0819] Into a 10L reaction kettle, 500.66g of Compound I was added, 3L of acetone was added, stirred, replaced by nitrogen, and warmed to 50-55°C. After dissolution, 1.75L of water was added dropwise. After the dropwise addition was completed, the mixture was stirred for 2-3 hours, slowly cooled to 20-25°C, filtered, the filter cake was rinsed with 500mL of an aqueous acetone solution (volume ratio of acetone: water 6:3.5), and then dried under suction, and dried under vacuum at 50°C for 40-48 hours to obtain 425.56g of Form Y1, with a yield of 85%. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 1 to 3

[0820] Example 6

[0821] Preparation of Compound I Form Y2

[0822] Into a 100mL reaction flask, 5.03g of Compound I was added, 50mL of methanol was added, stirred, replaced by nitrogen, and warmed to 55-60°C. After stirring for 2-3 hours, the mixture was slowly cooled to 20-25°C, filtered, the filter cake was rinsed with 5mL of methanol, and then dried under suction, and dried under vacuum at 50°C for 40-48 hours to obtain 4.53g of Form Y2, with a yield of 90%. The XRPD pattern thereof is shown in Figure 4

[0823] Example 7

[0824] Preparation of Compound I Hydrochloride Form H1

[0825] ​​​Into a 100 mL reaction flask, 3.025 g of Compound I was added, 30 mL of tetrahydrofuran was added, stirred, replaced by nitrogen, and warmed to 35-40 °C. After dissolution, a solution of hydrochloric acid (0.190 g, 1.05 eq) in tetrahydrofuran (12 mL) was added dropwise. After the addition was completed, the stirring was continued for 5-6 hours. 9 mL of n-heptane was added, and the stirring was continued for 12-24 hours while slowly cooling to 20-25 °C. Filtration was performed, the filter cake was washed with n-heptane, and then dried under suction. The filter cake was dried under vacuum at 50 °C for 40-48 hours to obtain 2.612 g of hydrochloride salt Form H1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 1, 2, and 3, respectively. Figures 5 to 7

[0826] Example 8

[0827] Preparation of Compound I hydrochloride salt Form H2

[0828] Into a 50 mL reaction flask, 1.017 g of Compound I was added, 10.2 mL of acetonitrile was added, stirred, replaced by nitrogen, and warmed to 45-50 °C. A solution of hydrochloric acid (0.061 g, 1.00 eq) in acetonitrile (10.2 mL) was added dropwise. After the addition was completed, the stirring was continued for 12-24 hours while slowly cooling to 20-25 °C. Filtration was performed, the filter cake was washed with acetonitrile, and then dried under suction. The filter cake was dried under vacuum at 50 °C for 40-48 hours to obtain 0.862 g of hydrochloride salt Form H2. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 4, 5, and 6, respectively. Figures 8 to 10

[0829] Example 9

[0830] Preparation of Compound I methanesulfonic acid salt Form M1

[0831] Into a 50 mL reaction flask, 0.998 g of Compound I was added, 10 mL of acetonitrile was added, stirred, replaced by nitrogen, and warmed to 45-50 °C. A solution of methanesulfonic acid (0.165 g, 1.05 eq) in acetonitrile (4 mL) was added dropwise. After the addition was completed, the stirring was continued for 12-24 hours while slowly cooling to 20-25 °C. Filtration was performed, the filter cake was washed with acetonitrile, and then dried under suction. The filter cake was dried under vacuum at 50 °C for 40-48 hours to obtain 0.928 g of methanesulfonic acid salt Form M1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 7, 8, and 9, respectively. Figures 11 to 13

[0832] Example 10

[0833] Preparation of Compound I methanesulfonic acid salt Form M1

[0834] ​​​Into a 50 mL reaction vial, 1.066 g of Compound I was added, followed by 16 mL of ethyl acetate, stirred, purged with nitrogen, warmed to 45-50 °C, and a solution of methanesulfonic acid (0.176 g, 1.05 eq) in 2-butanone (5.3 mL) was added dropwise. After the addition was completed, the mixture was stirred for 12-24 h, slowly cooled to 20-25 °C, filtered, the filter cake was rinsed with ethyl acetate and then suction dried, and vacuum dried at 50 °C for 40-48 h to give 0.984 g of methanesulfonate salt Form Ml. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in FIGS. 1-3, respectively. Figures 11 to 13

[0835] Example 11

[0836] Preparation of Compound I methanesulfonate salt Form M2

[0837] Into a 50 mL reaction vial, 1.056 g of Compound I was added, followed by 10.6 mL of acetonitrile, stirred, purged with nitrogen, and a solution of methanesulfonic acid (0.174 g, 1.05 eq) in acetonitrile (10.6 mL) was added dropwise at 20-25 °C. After the addition was completed, the mixture was warmed to 45-50 °C, stirred for 1-2 h, slowly cooled to 20-25 °C, filtered, the filter cake was rinsed with acetonitrile and then suction dried, and vacuum dried at 50 °C for 40-48 h to give 0.963 g of methanesulfonate salt Form M2. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in FIGS. 4-6, respectively. Figures 14 to 16

[0838] Example 12

[0839] Preparation of Compound I methanesulfonate salt Form M3

[0840] Into a 25 mL reaction vial, 0.522 g of methanesulfonic acid Form M2 was added, followed by 2.6 mL of acetonitrile, 0.78 mL of water, stirred at 20-25 °C, purged with nitrogen, and 0.52 mL of acetonitrile was added dropwise after dissolution. After the addition was completed, seed crystal (Form M2) was added, the mixture was warmed to 45-50 °C, stirred for 1-2 h, slowly cooled to 20-25 °C, filtered, the filter cake was rinsed with acetonitrile and then suction dried, and vacuum dried at 50 °C for 40-48 h to give 0.310 g of methanesulfonate salt Form M3. The XRPD pattern thereof is shown in FIG. 7. Figure 17

[0841] Example 13

[0842] Preparation of Compound I maleate salt Form MA1

[0843] ​​​Into a 50 mL reaction bottle, 1.117 g of Compound I was added, 16.8 mL of isopropanol was added, stirred, replaced by nitrogen, warmed to 45-50 °C, and a solution of maleic acid (0.223 g, 1.05 eq) in isopropanol (5.6 mL) was added dropwise. After the dropwise addition was completed, the stirring was continued for 12-24 hours, and the temperature was slowly lowered to 20-25 °C. The filter cake was washed with isopropanol and then dried under suction. The product was dried under vacuum at 50 °C for 40-48 hours to obtain 1.133 g of maleate salt Form MA1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 1-3, respectively. Figures 18 to 20

[0844] Example 14

[0845] Preparation of Compound I L-tartrate salt Form J1

[0846] Into a 25 mL reaction bottle, 1.051 g of Compound I was added, 9.5 mL of 95% acetone was added, stirred, replaced by nitrogen, warmed to 35-40 °C, and a solution of L-tartaric acid (0.271 g, 1.05 eq) in 95% acetone (3.2 mL) was added dropwise. After the dropwise addition was completed, the stirring was continued for 12-24 hours, and the temperature was slowly lowered to 20-25 °C. The filter cake was washed with acetone and then dried under suction. The product was dried under vacuum at 50 °C for 40-48 hours to obtain 1.109 g of L-tartrate salt Form J1. The XRPD pattern thereof is shown in Fig. 4. Figure 21

[0847] Example 15

[0848] Preparation of Compound I L-tartrate salt Form J2

[0849] Into a 25 mL reaction bottle, 0.984 g of L-tartrate salt Form J1 was added, 6.4 mL of methanol and 3.4 mL of ethyl acetate were added, stirred, replaced by nitrogen, warmed to 55-60 °C, dissolved, and stirred for half an hour. The temperature was slowly lowered to 20-25 °C, and the filter cake was washed with ethyl acetate and then dried under suction. The product was dried under vacuum at 50 °C for 40-48 hours to obtain 0.782 g of L-tartrate salt Form J2. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 5-7, respectively. Figures 22 to 24

[0850] Example 16

[0851] Preparation of Compound I benzenesulfonate salt Form B1

[0852] ​​​Into a 25 mL reaction vial, 0.508 g of Compound I was added, 5.1 mL of acetone was added, stirred, replaced by nitrogen, warmed to 35-40 °C, and a solution of benzenesulfonic acid (0.138 g, 1.05 eq) in acetone-water (1.5 mL, 2:1 by volume) was added dropwise. After the addition was completed, the mixture was stirred for 4-8 hours, 2.5 mL of ethyl acetate was added, and the mixture was stirred for 12-24 hours. The mixture was slowly cooled to 20-25 °C, filtered, and the filter cake was washed with ethyl acetate and then dried under suction. The filter cake was dried under vacuum at 50 °C for 40-48 hours to give 0.506 g of benzenesulfonic acid salt Form B1. The XRPD pattern thereof is shown in Figure 25 .

[0853] Example 17

[0854] Preparation of Compound I benzenesulfonic acid salt Form B1

[0855] Into a 25 mL reaction vial, 0.520 g of Compound I was added, 5.2 mL of tetrahydrofuran was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of benzenesulfonic acid (0.141 g, 1.05 eq) in tetrahydrofuran (2.1 mL) was added dropwise. After the addition was completed, the mixture was stirred for 12-24 hours. The mixture was slowly cooled to 20-25 °C, filtered, and the filter cake was washed with tetrahydrofuran and then dried under suction. The filter cake was dried under vacuum at 50 °C for 40-48 hours to give 0.487 g of benzenesulfonic acid salt Form B1.

[0856] Example 18

[0857] Preparation of Compound I benzenesulfonic acid salt Form B2

[0858] Into a 25 mL reaction vial, 1.046 g of Compound I was added, 10. mL of acetonitrile was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of benzenesulfonic acid (0.284 g, 1.05 eq) in acetonitrile (4.2 mL) was added dropwise. After the addition was completed, the mixture was stirred for 12-24 hours. The mixture was slowly cooled to 20-25 °C, filtered, and the filter cake was washed with acetonitrile and then dried under suction. The filter cake was dried under vacuum at 50 °C for 40-48 hours to give 1.102 g of benzenesulfonic acid salt Form B2. The XRPD pattern thereof is shown in Figure 26 .

[0859] Example 19

[0860] Preparation of Compound I toluenesulfonic acid salt Form T1

[0861] Into a 25 mL reaction bottle, 1.131 g of Compound I was added, 15.8 mL of acetone was added, stirred, replaced by nitrogen, and warmed to 35-40 °C. A solution of toluenesulfonic acid monohydrate (0.370 g, 1.05 eq) in acetone (3.4 mL) was added dropwise. After the addition was completed, the stirring was continued for 12-24 hours, and the temperature was slowly lowered to 20-25 °C. The filter cake was washed with acetone and then dried under suction. The product was dried under vacuum at 50 °C for 40-48 hours to obtain 1.269 g of toluenesulfonic acid salt Form T1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 1-3, respectively. Figures 27 to 29

[0862] Example 20

[0863] Preparation of Compound I toluenesulfonic acid salt Form T2

[0864] Into a 50 mL reaction bottle, 1.015 g of Compound I was added, 14.2 mL of acetone was added, stirred, replaced by nitrogen, and a solution of toluenesulfonic acid monohydrate (0.332 g, 1.05 eq) in acetone (3 mL) was added dropwise at 20-25 °C. After the addition was completed, the stirring was continued for 4-5 hours, 8 mL of methyl tert-butyl ether was added dropwise, and the stirring was continued for 2-3 hours. The filter cake was washed with methyl tert-butyl ether and then dried under suction. The product was dried under vacuum at 50 °C for 40-48 hours to obtain 1.192 g of toluenesulfonic acid salt Form T2. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 4-6, respectively. Figures 30 to 32

[0865] Example 21

[0866] Preparation of Compound I toluenesulfonic acid salt Form T2

[0867] Into a 25 mL reaction bottle, 0.326 g of toluenesulfonic acid salt Form T2 was added, 15 mL of 95% acetone was added, stirred, replaced by nitrogen, and warmed to 40-45 °C. The stirring was continued for 15 hours, and the temperature was slowly lowered to 20-25 °C. The filter cake was washed with acetone and then dried under suction. The product was dried under vacuum at 50 °C for 40-48 hours to obtain 0.264 g of toluenesulfonic acid salt Form T2. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 7-9, respectively. Figures 30 to 32

[0868] Example 22

[0869] Preparation of Compound I sulfate salt Form S1

[0870] ​​​Into a 25 mL reaction bottle, 0.989 g of Compound I was added, 11.9 mL of acetonitrile was added, stirred, replaced by nitrogen, warmed to 50-55 °C, and a solution of sulfuric acid (0.170 g, 1.05 eq) in acetonitrile (4 mL) was added dropwise. After the dropwise addition was completed, the stirring was continued for 12-24 hours, slowly cooled to 20-25 °C, filtered, the filter cake was washed with acetonitrile and then dried under suction, and dried at 50 °C under vacuum for 40-48 hours to obtain 1.001 g of the sulfate salt Form S1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 33 to 35

[0871] Example 23

[0872] Preparation of Compound I sulfate salt Form S2

[0873] Into a 50 mL reaction bottle, 0.556 g of the sulfate salt Form S1 was added, 22 mL of 95% tetrahydrofuran was added, stirred, replaced by nitrogen, warmed to reflux, and after the system was dissolved, the stirring was continued for half an hour, slowly cooled to 20-25 °C, filtered, the filter cake was washed with tetrahydrofuran and then dried under suction, and dried at 50 °C under vacuum for 40-48 hours to obtain 0.334 g of the sulfate salt Form S2. The XRPD pattern thereof is shown in Figure 36

[0874] Example 24

[0875] Preparation of Compound I hydrobromide salt Form Br1

[0876] Into a 25 mL reaction bottle, 0.895 g of Compound I was added, 10.7 mL of acetonitrile was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of hydrobromic acid (0.125 g, 1.05 eq) in acetonitrile (3.6 mL) was added dropwise. After the dropwise addition was completed, the stirring was continued for 12-24 hours, slowly cooled to 20-25 °C, filtered, the filter cake was washed with acetonitrile and then dried under suction, and dried at 50 °C under vacuum for 40-48 hours to obtain 0.901 g of the hydrobromide salt Form Br1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 37 to 39

[0877] Example 25

[0878] Preparation of Compound I citrate salt Form N1, preparation of a single crystal of Compound I citrate salt

[0879] ​​​Take 1.230 g of compound I into a 50 mL reaction bottle, add 12.3 mL of acetonitrile, stir, replace with nitrogen, and warm to 40-45 °C. Add a solution of citric acid monohydrate (0.445 g, 1.05 eq) in acetonitrile-water (8.6 mL, 8:1 by volume) dropwise. After the dropwise addition is complete, incubate with stirring for 12-24 hours, slowly cool to 20-25 °C, filter, rinse the filter cake with acetonitrile, and then dry under suction. Dry the filter cake at 50 °C under vacuum for 40-48 hours to obtain 1.369 g of citrate salt Form N1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 40 to 42

[0880] Take 20 mg of the above citrate salt Form N1, dissolve in 1 mL of dichloromethane / methanol (1:1 by volume) at room temperature, and place the sample solution in a 4 mL semi-sealed sample bottle. Slowly evaporate at room temperature to obtain block-shaped crystals for single crystal analysis. The single crystal pattern is shown in Figure 43 α = 90°, β = 109.972 (2) °, γ = 90°, Z = 2.

[0881] Example 26

[0882] Preparation of citrate salt Form N1 of compound I

[0883] Take 0.622 g of compound I into a 25 mL reaction bottle, add 6.2 mL of ethanol, stir, replace with nitrogen, and warm to 40-45 °C. Add a solution of citric acid monohydrate (0.225 g, 1.05 eq) in ethanol-water (4.7 mL, 10:1 by volume) dropwise. After the dropwise addition is complete, incubate with stirring for 12-24 hours, slowly cool to 20-25 °C, filter, rinse the filter cake with ethanol, and then dry under suction. Dry the filter cake at 50 °C under vacuum for 40-48 hours to obtain 0.661 g of citrate salt Form N1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 40 to 42

[0884] Example 27

[0885] Preparation of citrate salt Form N1 of compound I

[0886] ​​​Into a 25 mL reaction vial, 0.451 g of Compound I was added, followed by 4.5 mL of tetrahydrofuran, stirring, nitrogen replacement, and dropwise addition of a tetrahydrofuran-water solution (3.6 mL, 10:1 by volume) of citric acid monohydrate (0.163 g, 1.05 eq) at 20-25 °C. After the dropwise addition was completed, stirring was continued for 12-24 hours, followed by filtration, suction-drying of the filter cake after rinsing with tetrahydrofuran, and vacuum drying at 50 °C for 40-48 hours to obtain 0.490 g of citrate salt Form N1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 1, 2, and 3, respectively. Figures 40 to 42

[0887] Example 28

[0888] Preparation of Compound I citrate salt Form N1

[0889] Into a 50 mL reaction vial, 0.773 g of Compound I was added, followed by 7.7 mL of tetrahydrofuran, stirring, nitrogen replacement, and dropwise addition of a tetrahydrofuran solution (8 mL) of citric acid anhydrous (0.255 g, 1.05 eq) at 40-45 °C. After the dropwise addition was completed, stirring was continued for 12-24 hours, followed by slow cooling to 20-25 °C, filtration, suction-drying of the filter cake after rinsing with tetrahydrofuran, and vacuum drying at 50 °C for 40-48 hours to obtain 0.881 g of citrate salt Form N1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 4, 5, and 6, respectively. Figures 40 to 42

[0890] Example 29

[0891] Preparation of Compound I citrate salt Form N1

[0892] Into a 50 mL reaction vial, 0.773 g of Compound I was added, followed by 7.7 mL of tetrahydrofuran, stirring, nitrogen replacement, and dropwise addition of a tetrahydrofuran solution (8 mL) of citric acid anhydrous (0.255 g, 1.05 eq) at 40-45 °C. After the dropwise addition was completed, stirring was continued for 12-24 hours, followed by slow cooling to 20-25 °C, filtration, suction-drying of the filter cake after rinsing with tetrahydrofuran, and vacuum drying at 50 °C for 40-48 hours to obtain 0.881 g of citrate salt Form N1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figs. 4, 5, and 6, respectively. Figures 40 to 42

[0893] Example 30

[0894] Preparation of Compound I citrate salt Form N1

[0895] ​​​1.001 g of compound I was added to a 50 mL reaction flask, followed by 10 mL of acetone. The mixture was stirred, purged with nitrogen, and heated to 40–45 °C. A 12 mL solution of anhydrous citric acid (0.330 g, 1.05 eq) in acetone was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 12–24 hours. The temperature was then slowly lowered to 20–25 °C, and the mixture was filtered. The filter cake was washed with acetone and dried under vacuum at 50 °C for 40–48 hours to obtain 1.090 g of citrate crystal form N1. Its XRPD, DSC, and TGA spectra are shown below. Figures 40 to 42 As shown.

[0896] In Examples 28-30, the source of the water of crystallization in crystal form N1 is water present as an impurity in compound I and / or solvent and / or solid anhydrous citric acid used in the crystallization process.

[0897] Example 31

[0898] Preparation of compound I citrate crystal form N1

[0899] 45.12 g of compound I was added to a 1 L reaction flask, followed by 450 mL of 90% acetone. The mixture was stirred, purged with nitrogen, and heated to 45–50 °C. A 90% acetone solution (225 mL) of citric acid monohydrate (15.54 g, 1.00 eq) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 4–8 hours. The temperature was then slowly lowered to 35–40 °C, and stirred for 12–24 hours. The temperature was then slowly lowered to 20–25 °C, and the mixture was filtered. The filter cake was washed with 45 mL of acetone and dried under vacuum at 50 °C for 40–48 hours to obtain 52.51 g of citrate crystal form N1. Its XRPD, DSC, and TGA spectra are shown below. Figures 40 to 42 As shown.

[0900] Example 32

[0901] Preparation of compound I citrate crystal form N1

[0902] 50.05 g of compound I was added to a 2 L reaction flask, followed by 400 mL of 85% acetone. The mixture was stirred, purged with nitrogen, and heated to 45–50 °C. A 250 mL solution of 85% acetone in citric acid monohydrate (17.24 g, 1.00 eq) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 1–2 hours. 0.05 g of citrate crystal form N1 was added as a seed crystal, and the mixture was kept at this temperature and stirred for another 4–8 hours. The temperature was then slowly lowered to 35–40 °C, and 350 mL of methyl tert-butyl ether was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 12–24 hours, then slowly lowered to 15–25 °C. The mixture was filtered, and the filter cake was washed with 50 mL of methyl tert-butyl ether and dried under vacuum at 50 °C for 40–48 hours to obtain 57.55 g of citrate crystal form N1. Its XRPD, DSC, and TGA spectra are shown below. Figures 40 to 42 As shown.

[0903] Example 33

[0904] Preparation of Compound I L-malate salt Form P1

[0905] Into a 25 mL reaction vial, 0.481 g of Compound I was added, 4.8 mL of acetonitrile was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of L-malic acid (0.111 g, 1.05 eq) in acetonitrile-water (2.4 mL, 6:1 by volume) was added dropwise. After the addition was completed, the mixture was stirred at the same temperature for 12-24 hours, slowly cooled to 20-25 °C, filtered, the filter cake was washed with acetonitrile and then dried under vacuum at 50 °C for 40-48 hours to give 0.470 g of L-malate salt Form P1. The XRPD pattern thereof is shown in Figure 6. Figure 45

[0906] Example 34

[0907] Preparation of Compound I L-malate salt Form P1

[0908] Into a 8 mL reaction vial, 0.276 g of Compound I was added, 2.8 mL of acetone was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of L-malic acid (0.064 g, 1.05 eq) in acetonitrile-water (0.8 mL, 6:1 by volume) was added dropwise. After the addition was completed, the mixture was stirred at the same temperature for 12-24 hours, slowly cooled to 20-25 °C, filtered, the filter cake was washed with acetone and then dried under vacuum at 50 °C for 40-48 hours to give 0.266 g of L-malate salt Form P1. The XRPD pattern thereof is shown in Figure 7. Figure 45

[0909] Example 35

[0910] Preparation of Compound I L-camphorsulfonate salt Form Z1

[0911] Into a 25 mL reaction vial, 0.385 g of Compound I was added, 3.9 mL of acetonitrile was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of L-camphorsulfonic acid (0.154 g, 1.05 eq) in acetonitrile-water (1.5 mL, 8:1 by volume) was added dropwise. After the addition was completed, the mixture was stirred at the same temperature for 12-24 hours, 2.7 mL of methyl tert-butyl ether was added dropwise, stirred at the same temperature for 1-2 hours, slowly cooled to 20-25 °C, filtered, the filter cake was washed with methyl tert-butyl ether and then dried under vacuum at 50 °C for 40-48 hours to give 0.424 g of L-camphorsulfonate salt Form Z1. The XRPD pattern thereof is shown in Figure 8. Figure 46

[0912] Example 36

[0913] Preparation of Compound I fumarate salt Form F1​​​

[0914] Into a 25 mL reaction bottle, 0.391 g of Compound I was added, 3.9 mL of tetrahydrofuran was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of fumaric acid (0.078 g, 1.05 eq) in tetrahydrofuran (3.9 mL) was added dropwise. After the dropwise addition was completed, the mixture was stirred at 40-45 °C for 12-24 h, 2.7 mL of isopropyl acetate was added dropwise, and the mixture was stirred at 40-45 °C for 1-2 h. The mixture was slowly cooled to 20-25 °C, filtered, and the filter cake was washed with isopropyl acetate and then dried under vacuum at 50 °C for 40-48 h to obtain 0.372 g of fumarate salt Form F1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figure 47

[0915] Example 37

[0916] Preparation of Compound I trifluoroacetate salt Form TF1

[0917] Into a 25 mL reaction bottle, 0.391 g of Compound I was added, 3.9 mL of tetrahydrofuran was added, stirred, replaced by nitrogen, warmed to 40-45 °C, and a solution of fumaric acid (0.078 g, 1.05 eq) in tetrahydrofuran (3.9 mL) was added dropwise. After the dropwise addition was completed, the mixture was stirred at 40-45 °C for 12-24 h, 2.7 mL of isopropyl acetate was added dropwise, and the mixture was stirred at 40-45 °C for 1-2 h. The mixture was slowly cooled to 20-25 °C, filtered, and the filter cake was washed with isopropyl acetate and then dried under vacuum at 50 °C for 40-48 h to obtain 0.372 g of fumarate salt Form F1. The XRPD pattern, DSC pattern, and TGA pattern thereof are shown in Figures 48 to 50

[0918] Example 38

[0919] Proliferation inhibition activity of Compound I on Ba / F3 KRAS-G12C, NCI-H358, and MIA PaCa-2 cells containing KRAS G12C mutation

[0920] This example was used to determine the proliferation inhibition activity of Compound I prepared according to Example 1 on Ba / F3 KRAS-G12C cell strain stably expressing KRAS G12C mutant protein of mouse original B cell Ba / F3, non-small cell lung cancer NCI-H358 cell strain expressing KRAS G12C mutant protein, and pancreatic cancer MIA PaCa-2 cell strain in vitro.

[0921] Cell source: Ba / F3 KRAS-G12C was purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., item number KC-1260; NCI-H358 was purchased from Shanghai Di Jin Biotechnology Co., Ltd.; MIA PaCa-2 was purchased from Shanghai Di Ao Biotechnology Co., Ltd.

[0922] ​​Cells in logarithmic growth phase were inoculated in 96-well plates (5000, 3000, 1000 cells / well for Ba / F3 KRAS-G12C, NCI-H358, MIAPaCa-2 cells respectively, 90 μl / well), after incubation at 37℃, 5% CO2 for 1 day, gradient-diluted compound I was added. Specifically as follows: Compound I stock solution (10 mM) dissolved in DMSO in advance was diluted by 4 times to 10 gradient concentrations, and diluted to 10 times of the desired concentration in another 96-well plate with culture medium, then 10 μl / well of compound I solution was added to the 96-well plate inoculated with cells, i.e. to reach the desired concentration (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Three replicates were set for each concentration, and blank controls were set. After incubation at 37℃, 5% CO2 for 72 h, 50 μl 2.0 reagent (luciferase ATP bioluminescence detection reagent, purchased from Promega, item No. G9243) was added to each well, and shaken for 2 min, after incubation at room temperature for 8 min, the fluorescence intensity was detected (the light collection time was 100 ms). The inhibition rate of compound I at each concentration on cell proliferation was calculated (cell proliferation inhibition rate = [(luminescence intensity 72小时培养基对照组 - luminescence intensity 72小时化合物I组 ) / (luminescence intensity 72小时培养基对照组 - luminescence intensity 0小时培养基对照组 )] x 100%), the data was analyzed using GraphPad Prism 5.0 software, the dose-effect curve was fitted by nonlinear S curve regression, and the IC 50 value of compound I was calculated, the results are shown in Table 1.

[0923] Table 1

[0924]

[0925] The test results show that compound I has good proliferation inhibition activity on Ba / F3 KRAS-G12C, NCI-H358 and MIAPaCa-2 cells containing KRAS G12C mutation.

[0926] Example 39

[0927] Hygroscopicity test

[0928] This example investigates the hygroscopicity of part of the crystal forms of the present disclosure.

[0929] The test method of hygroscopicity is specifically described as follows: a certain amount of sample was placed in a dynamic vapor sorption (DVS) instrument, under the condition of 25℃, it experienced a cycle of 0%-95%-0% relative humidity change, and the weight gain at 80% relative humidity was used to evaluate the hygroscopicity of the sample.

[0930] The hygroscopicity test results of the tested crystalline forms are shown in Table 2 below:

[0931] Table 2

[0932]

[0933] As can be seen from the hygroscopicity data in Table 2, the tested crystalline forms of Compound I and its pharmaceutically acceptable salts have low hygroscopicity (the weight gain at 80% relative humidity is in the range of 0.30%-3.83%). Among the tested crystalline forms, citrate crystalline form N1 has the lowest weight gain at 80% relative humidity (0.30%), which indicates that this crystalline form has extremely low hygroscopicity.

[0934] Example 40

[0935] Solubility test

[0936] This example investigates the solubility of some crystalline forms of the present disclosure.

[0937] The method of the solubility test is described in detail as follows: an appropriate amount of each substance is weighed and placed in a brown volumetric flask, different solvents are added, and ultrasonic is applied for 20s to make it uniformly dispersed. After being shaken at 25°C and 200rpm for 24h, it is taken out and centrifuged at 12000rpm for 10min. The supernatant is aspirated and diluted with the corresponding solvent to a certain multiple, and then the concentration is determined by HPLC. The residual solid is subjected to XRPD detection to investigate the change of crystalline form.

[0938] The solubility of Compound I crystalline form Y1, tosylate crystalline form T1 and citrate crystalline form N1 in water at 25°C is shown in Table 3 below:

[0939] Table 3

[0940]

[0941] As can be seen from the solubility data in Table 3, the solubility of citrate crystalline form N1 in water at 25°C is significantly better than that of Compound I crystalline form Y1 and tosylate crystalline form T1. In addition, XRPD characterization shows that the three crystalline forms do not undergo crystalline transformation after being shaken in water at 25°C for 24h.

[0942] Example 41

[0943] Stability test

[0944] This example investigates the stability of Compound I citrate crystalline form N1 of the present disclosure.

[0945] The method of the stability test is described as follows: citrate Form N1 was left open at high humidity (25°C, 92.5% RH), high temperature (60°C), 40°C / 75% RH and 60°C / 92.5% RH, respectively, and its crystal form and chemical purity were monitored, and the results are shown in Table 4 below:

[0946] Table 4

[0947]

[0948] From the stability data in Table 4, it can be seen that Compound I citrate Form N1 shows unexpectedly excellent crystal and chemical stability.

[0949] Example 42

[0950] Testing the anti-tumor effect of the crystal form of Compound I and its pharmaceutically acceptable salts in NCI-H358 tumor model

[0951] This experiment is used to evaluate the anti-tumor effect of the crystal form of Compound I and its pharmaceutically acceptable salts in the human non-small cell lung cancer cell line NCI-H358 subcutaneous xenograft BALB / c female nude mouse animal model.

[0952] Experimental animals: BALB / c nude mice, female, 8-9 weeks (mouse age at the time of tumor cell inoculation), body weight 13.8-17.7 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Shanghai Branch.

[0953] Animal modeling and random grouping: NCI-H358 cells were cultured and expanded to 5 T175 cm 2 flasks, the cells were collected, resuspended, counted with serum-free medium RPMI-1640, and 1:1 added with Matrigel, and inoculated subcutaneously in the right front of BALB / c nude mice at 5x10 6 mm, according to the tumor size, randomly divided into 3 experimental groups. Each group of 5. The day of grouping was defined as day 0, i.e. D0. 3

[0954] Experimental scheme: BALB / c nude mice were subcutaneously inoculated with NCI-H358 cells to establish a cell line xenograft tumor model. The test was divided into a 10 mg / kg group of Compound I Form Y1, a 10 mg / kg group of Compound I citrate Form N1, and a vehicle group, each group of 5, orally administered, the administration volume was 10 μL / g, the vehicle group was given an equal amount of vehicle (10% dimethylacetamide + 5% polyethylene glycol (15)-hydroxystearate + 85% phosphate buffer), administered once a day, for two weeks. During the entire experiment, the tumor size of the mice was measured twice a week, and whether toxic reactions occurred was observed. ​

[0955] The formula for calculating the tumor volume (TV) is: TV = 1 / 2 x a x b x b, wherein a and b represent the length and width of the tumor, respectively.

[0956] The tumor volume change curves of the three experimental groups are shown in Figure 2. Figure 64 .

[0957] The results show that in the human non-small cell lung cancer cell line NCI-H358 subcutaneous xenograft BALB / c female nude mouse animal model, the crystal forms of compound I and its pharmaceutically acceptable salts (especially compound I crystal form Y1 and compound I citrate crystal form N1) exhibit good anti-tumor effect.

[0958] The above embodiments and examples are provided to enable those skilled in the art to more clearly understand the spirit and effects of the present disclosure. However, these embodiments and examples are only for illustrative purposes, and by no means limit the claims of the present disclosure.

[0959] All publications cited in the specification are hereby incorporated by reference in their entirety. It will be apparent to those skilled in the art that certain modifications and improvements can be made to the embodiments and examples of the present disclosure without departing from the spirit or scope of the appended claims.

Claims

1. A crystalline form of Compound I of Formula I ###0001### Compound I 2. The crystalline form of claim 1, wherein the crystalline form is Compound I Form Yl, characterized by The crystalline form of Compound I Y1 has the following characteristics: I) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at diffraction angles 2Q values of 10.516° ± 0.2°, 18.360° ± 0.2°, and 19.345° ± 0.2°.

3. The morphic form of claim 2, characterized by an X-ray diffraction pattern substantially in accordance with Figure 8, The XRPD pattern of the crystalline form of Compound I Y1 has characteristic peaks at diffraction angles 2Q values of 10.516° ± 0.2°, 14.451° ± 0.2°, 14.889° ± 0.2°, 18.360° ± 0.2°, 19.345° ± 0.2°, 21.210° ± 0.2°, and 22.070° ± 0.2°.

4. The morphic form of claim 2, characterized by an X-ray diffraction pattern substantially in accordance with Figure 8, The XRPD pattern of the crystalline form of Compound I Y1 has characteristic peaks at diffraction angles 2Q values of 10.516° ± 0.2°, 11.381° ± 0.2°, 12.907° ± 0.2°, 13.107° ± 0.2°, 13.729° ± 0.2°, 14.171° ± 0.2°, 14.451° ± 0.2°, 14.889° ± 0.2°, 16.672° ± 0.2°, 18.360° ± 0.2°, 18.701° ± 0.2°, 19.345° ± 0.2°, 20.367° ± 0.2°, 21.210° ± 0.2°, 21.589° ± 0.2°, 22.070° ± 0.2°, 22.467° ± 0.2°, 23.057° ± 0.2°, 23.529° ± 0.2°, 23.893° ± 0.2°, 24.675° ± 0.2°, 25.158° ± 0.2°, 26.881° ± 0.2°, 27.201° ± 0.2°, 27.822° ± 0.2°, 28.425° ± 0.2°, and 35.665° ± 0.2°.

5. The morphic form of claim any one of claims 2-4, characterized by, The crystalline form of Compound I Y1 further has at least one characteristic selected from the group consisting of: II) a differential scanning calorimetry (DSC) pattern having endothermic peaks at 58°C and 271°C, respectively; and III) a thermogravimetric analysis (TGA) pattern having a mass loss of 2.8% from 30°C to 150°C.

6. The morphic form of claim any one of claims 2-4, characterized by, The crystalline form of Compound I Y1 further has at least one characteristic selected from the group consisting of: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 1 ; has a DSC pattern substantially the same as the DSC pattern shown in Figure 2; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 3.

7. The crystalline form of claim 1, wherein the crystalline form is Compound I Form Y2, characterized by The crystalline form of Compound I Y2 has the following characteristics: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 18.080° ± 0.2°, 20.359° ± 0.2°, and 21.180° ± 0.2°.

8. The morphic form of claim 7, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30, The XRPD pattern of the Compound I crystalline form Y2 has characteristic peaks at diffraction angles 2Q values of 17.220°±0.2°, 18.080°±0.2°, 20.359°±0.2°, 21.180°±0.2°, 22.660°±0.2°, 24.758°±0.2° and 28.538°±0.2°.

9. The morphic form of claim 7, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30, The XRPD pattern of the Compound I crystalline form Y2 has characteristic peaks at diffraction angles 2Q values of 7.379°±0.2°, 9.597°±0.2°, 10.202°±0.2°, 11.217°±0.2°, 12.478°±0.2°, 13.762°±0.2°, 14.322°±0.2°, 15.039°±0.2°, 16.220°±0.2°, 17.220°±0.2°, 18.080°±0.2°, 19.319°±0.2°, 20.359°±0.2°, 21.180°±0.2°, 22.660°±0.2°, 23.879°±0.2°, 24.758°±0.2°, 26.119°±0.2°, 26.940°±0.2°, 28.538°±0.2°, 30.880°±0.2° and 37.501°±0.2°.

10. The crystalline form of claim 1, wherein the crystalline form is Compound I Form Y2, characterized by The Compound I crystalline form Y2 has the following characteristics: has substantially the same XRPD pattern as that shown in Figure 4.

11. A crystalline form of a pharmaceutically acceptable salt of Compound I of the following formula I The pharmaceutically acceptable salt of Compound I is at least one selected from the group consisting of hydrochloride, mesylate, maleate, L-tartrate, besylate, tosylate, sulfate, hydrobromide, citrate, L-malate, L-camsylate, fumarate and trifluoroacetate.

12. The crystalline form of claim 11, which is Compound I hydrochloride Form H1, characterized by, The Compound I hydrochloride crystalline form H1 has the following characteristics: I) characteristic peaks at diffraction angles 2Q values of 5.425°±0.2°, 7.952°±0.2° and 14.249°±0.2° in the XRPD pattern.

13. The morphic form of claim 12, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. The XRPD pattern of the Compound I hydrochloride crystalline form H1 has characteristic peaks at diffraction angles 2Q values of 5.425°±0.2°, 7.952°±0.2°, 14.249°±0.2°, 17.662°±0.2°, 19.303°±0.2°, 20.647°±0.2° and 21.309°±0.2°.

14. The morphic form of claim 12, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. The Compound I hydrochloride salt crystalline Form Hl has at least one characteristic selected from the following:

15. The morphic form of claim any one of claims 12-14, characterized by, I) an XRPD pattern with peaks at diffraction angles 2Q values of 5.425°±0.2°, 6.388°±0.2°, 7.952°±0.2°, 12.443°±0.2°, 14.249°±0.2°, 14.551°±0.2°, 16.820°±0.2°, 17.662°±0.2°, 19.303°±0.2°, 20.647°±0.2°, 21.309°±0.2°, 22.151°±0.2°, and 23.631°±0.2°. The Compound I hydrochloride salt crystalline Form Hl further has at least one characteristic selected from the following: II) a DSC pattern with endothermic peaks at 54 °C and 143 °C, respectively; and 16. The morphic form of claim any one of claims 12-14, characterized by, III) a TGA pattern with a mass loss gradient of 3.5% at 30 °C to 105 °C and a mass loss gradient of 8.1% at 105 °C to 180 °C. The Compound I hydrochloride salt crystalline Form Hl further has at least one characteristic selected from the following: an XRPD pattern substantially the same as the XRPD pattern shown in Figure 5; a DSC pattern substantially the same as the DSC pattern shown in Figure 6; and 17. The crystalline form of claim 11, which is Compound I hydrochloride Form H2, characterized by, a TGA pattern substantially the same as the TGA pattern shown in Figure 7. The Compound I hydrochloride salt crystalline Form H2 has the following characteristics:

18. The morphic form of claim 17, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. I) an XRPD pattern with peaks at diffraction angles 2Q values of 10.540°±0.2°, 18.422°±0.2°, and 19.461°±0.2°.

19. The morphic form of claim 17, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. The Compound I hydrochloride salt crystalline Form H2 has at least one characteristic selected from the following:

20. The morphic form of any one of claims 17-19, characterized by, I) an XRPD pattern with peaks at diffraction angles 2Q values of 5.648°±0.2°, 10.540°±0.2°, 14.873°±0.2°, 18.422°±0.2°, 19.461°±0.2°, and 21.243°±0.2°. The Compound I hydrochloride salt crystalline Form H2 has at least one characteristic selected from the following: I) an XRPD pattern with peaks at diffraction angles 2Q values of 5.648°±0.2°, 10.540°±0.2°, 11.420°±0.2°, 13.349°±0.2°, 13.709°±0.2°, 14.873°±0.2°, 18.422°±0.2°, 19.461°±0.2°, 20.306°±0.2°, 21.243°±0.2°, 21.685°±0.2°, 22.853°±0.2°, 25.251°±0.2°, and 26.840°±0.2°.

21. The morphic form of any one of claims 17-19, characterized by, The Compound I hydrochloride salt crystalline Form H2 further has at least one characteristic selected from the following: II) a DSC pattern with an endothermic peak at 150 °C; and III) a TGA pattern with a mass loss gradient of 4.95% at 30 °C to 180 °C. The Compound I hydrochloride salt crystalline Form H2 further has at least one characteristic selected from the following: an XRPD pattern substantially the same as the XRPD pattern shown in Figure 8; a DSC pattern substantially the same as the DSC pattern shown in Figure 9; and a TGA pattern substantially the same as the TGA pattern shown in Figure 10. has an XRPD pattern substantially the same as that shown in Figure 11; has a TGA pattern substantially the same as that shown in Figure 12.

22. The crystalline form of claim 11, which is Compound I mesylate salt Form Ml, characterized by: The Compound I mesylate salt crystalline Form Ml has the following characteristics: I) an XRPD pattern having peaks at diffraction angles 2Q values of 16.149° ± 0.2°, 17.060° ± 0.2°, and 20.387° ± 0.2°.

23. The morphic form of claim 22, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. The XRPD pattern of the Compound I mesylate salt crystalline Form Ml has peaks at diffraction angles 2Q values of 7.212° ± 0.2°, 10.740° ± 0.2°, 13.465° ± 0.2°, 16.149° ± 0.2°, 17.060° ± 0.2°, 20.387° ± 0.2°, and 22.026° ± 0.2°.

24. The morphic form of claim 22, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. The XRPD pattern of the Compound I mesylate salt crystalline Form Ml has peaks at diffraction angles 2Q values of 7.212° ± 0.2°, 9.300° ± 0.2°, 9.674° ± 0.2°, 10.740° ± 0.2°, 13.465° ± 0.2°, 14.433° ± 0.2°, 16.149° ± 0.2°, 16.576° ± 0.2°, 17.060° ± 0.2°, 17.500° ± 0.2°, 17.904° ± 0.2°, 18.501° ± 0.2°, 19.658° ± 0.2°, 20.006° ± 0.2°, 20.387° ± 0.2°, 21.149° ± 0.2°, 22.026° ± 0.2°, 22.327° ± 0.2°, 23.309° ± 0.2°, 23.650° ± 0.2°, and 24.695° ± 0.2°.

25. The morphic form of claim any one of claims 22-24, characterized by, The Compound I mesylate salt crystalline Form Ml further has at least one characteristic selected from the following: II) a DSC pattern having an endothermic peak at 61 °C; and III) a TGA pattern having a mass loss of 2.04% between 30 °C and 105 °C.

26. The morphic form of any one of claims 22-24, characterized by, The Compound I mesylate salt crystalline Form Ml further has at least one characteristic selected from the following: an XRPD pattern substantially the same as that shown in Figure 11; a DSC pattern substantially the same as that shown in Figure 12; and a TGA pattern substantially the same as that shown in Figure 13.

27. The crystalline form of claim 11, which is Compound I mesylate salt Form M2, characterized by: The Compound I mesylate salt crystalline Form M2 has the following characteristics: I) an XRPD pattern having peaks at diffraction angles 2Q values of 8.876° ± 0.2°, 17.896° ± 0.2°, and 18.679° ± 0.2°.

28. The morphic form of claim 27, characterized by an X-ray diffraction pattern substantially in accordance with Figure 33. The XRPD pattern of the Compound I mesylate salt crystalline Form M2 has peaks at diffraction angles 2Q values of 7.848° ± 0.2°, 8.876° ± 0.2°, 10.341° ± 0.2°, 14.470° ± 0.2°, 17.896° ± 0.2°, 18.679° ± 0.2°, and 27.503° ± 0.2°.

29. The morphic form of claim 27, characterized by an X-ray diffraction pattern substantially in accordance with Figure 30. The XRPD pattern of the Compound I mesylate salt crystalline Form M2 has characteristic peaks at diffraction angles 2Θ values of 7.848°±0.2°, 8.876°±0.2°, 10.341°±0.2°, 11.640°±0.2°, 13.449°±0.2°, 14.470°±0.2°, 15.671°±0.2°, 17.317°±0.2°, 17.896°±0.2°, 18.180°±0.2°, 18.679°±0.2°, 19.803°±0.2°, 20.847°±0.2°, 21.345°±0.2°, 21.791°±0.2°, 22.206°±0.2°, 22.850°±0.2°, 23.533°±0.2°, 25.937°±0.2°, and 27.503°±0.2°.

30. The morphic form of claim any one of claims 27-29, characterized by, The Compound I mesylate salt crystalline Form M2 further has at least one characteristic selected from the following: II) no significant endothermic peak prior to decomposition temperature in the DSC pattern; and III) a mass loss gradient of 0.96% at 30°C to 105°C in the TGA pattern.

31. The morphic form of claim any one of claims 27-29, characterized by, The Compound I mesylate salt crystalline Form M2 further has at least one characteristic selected from the following: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 14; has a DSC pattern substantially the same as the DSC pattern shown in Figure 15; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 16.

32. The crystalline form of claim 11, which is Compound I mesylate salt Form M3, characterized by: The Compound I mesylate salt crystalline Form M3 has the following characteristics: I) in the XRPD pattern, characteristic peaks at diffraction angles 2Θ values of 14.641°±0.2°, 16.759°±0.2°, and 23.079°±0.2°.

33. The morphic form of claim 32, characterized by: The XRPD pattern of the Compound I mesylate salt crystalline Form M3 has characteristic peaks at diffraction angles 2Θ values of 9.343°±0.2°, 13.040°±0.2°, 14.641°±0.2°, 16.759°±0.2°, 19.799°±0.2°, 23.079°±0.2°, and 24.041°±0.2°.

34. The morphic form of claim 32, characterized by: The XRPD pattern of said compound I mesylate salt crystalline form M3 has characteristic peaks at diffraction angles 2Q values of 9.101°±0.2°, 9.343°±0.2°, 10.221°±0.2°, 11.560°±0.2°, 12.098°±0.2°, 13.040°±0.2°, 13.579°±0.2°, 13.859°±0.2°, 14.641°±0.2°, 15.320°±0.2°, 15.599°±0.2°, 16.759°±0.2°, 18.181°±0.2°, 18.762°±0.2°, 19.799°±0.2°, 20.480°±0.2°, 20.877°±0.2°, 21.256°±0.2°, 21.761°±0.2°, 22.420°±0.2°, 23.079°±0.2°, 24.041°±0.2°, 27.141°±0.2°, 28.360°±0.2°, 29.098°±0.2°, 29.642°±0.2° and 31.701°±0.2°.

35. The crystalline form of claim 11, which is Compound I mesylate salt Form M3, characterized by: Said compound I mesylate salt crystalline form M3 has the following characteristics: has substantially the same XRPD pattern as the XRPD pattern shown in Figure 17.

36. The crystalline form of claim 11, which is Compound I maleate salt Form MA1, characterized by: Said compound I maleate salt crystalline form MA1 has the following characteristics: I) in the XRPD pattern, characteristic peaks at diffraction angles 2Q values of 9.918°±0.2°, 17.780°±0.2° and 22.231°±0.2°.

37. The morphic form of claim 36, characterized by: The XRPD pattern of said compound I maleate salt crystalline form MA1 has characteristic peaks at diffraction angles 2Q values of 9.918°±0.2°, 17.780°±0.2°, 21.448°±0.2°, 22.231°±0.2° and 24.538°±0.2°.

38. The morphic form of claim 36, characterized by: The XRPD pattern of said compound I maleate salt crystalline form MA1 has characteristic peaks at diffraction angles 2Q values of 7.990°±0.2°, 9.918°±0.2°, 10.678°±0.2°, 13.748°±0.2°, 14.249°±0.2°, 15.354°±0.2°, 16.792°±0.2°, 17.139°±0.2°, 17.780°±0.2°, 18.974°±0.2°, 19.463°±0.2°, 20.583°±0.2°, 21.448°±0.2°, 22.231°±0.2°, 24.538°±0.2°, 25.198°±0.2°, 26.060°±0.2°, 27.928°±0.2° and 30.234°±0.2°.

39. The morphic form of claim any one of claims 36-38, characterized by, Said compound I maleate salt crystalline form MA1 further has at least one characteristic selected from: II) in the DSC pattern, two endothermic peaks at 93 °C and 170 °C, respectively; and III) in the TGA pattern, a weight loss of about 0.5% up to 100 °C. III) has a mass loss gradient of 9.3% in the TGA pattern between 30 °C and 140 °C.

40. The morphic form of any one of claims 36-38, characterized by, The compound I maleate salt crystalline form MA1 further has at least one characteristic selected from: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 18; has a DSC pattern substantially the same as the DSC pattern shown in Figure 19; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 20.

41. The crystalline form of claim 11, which is Compound IL-tartrate salt Form J1, characterized by, The compound I L-tartrate salt crystalline form J1 has the following characteristics: I) has characteristic peaks in the XRPD pattern at diffraction angles 2Q values of 8.140° ± 0.2°, 14.120° ± 0.2°, and 26.160° ± 0.2°.

42. The Form of claim 41, characterized by: The XRPD pattern of the compound I L-tartrate salt crystalline form J2 has characteristic peaks in the XRPD pattern at diffraction angles 2Q values of 8.140° ± 0.2°, 14.120° ± 0.2°, 16.302° ± 0.2°, 21.680° ± 0.2°, 22.858° ± 0.2°, 23.679° ± 0.2°, and 26.160° ± 0.2°.

43. The Form of claim 41, characterized by: The XRPD pattern of the compound I L-tartrate salt crystalline form J2 has characteristic peaks in the XRPD pattern at diffraction angles 2Q values of 8.140° ± 0.2°, 14.120° ± 0.2°, 16.302° ± 0.2°, 21.680° ± 0.2°, 22.858° ± 0.2°, 23.679° ± 0.2°, and 26.160° ± 0.2°.

44. The crystalline form of claim 11, which is Compound IL-tartrate salt Form J1, characterized by, ​ ​ 45. The crystalline form of claim 11, which is Compound IL-tartrate salt Form J2, characterized by, ​ ​ 46. The Form of claim 45, characterized by: ​ 47. The Form of claim 45, characterized by: The XRPD pattern of the compound IL-tartrate salt Form J2 has characteristic peaks at diffraction angles 2Q values of 8.140°±0.2°, 14.120°±0.2°, 15.138°±0.2°, 16.302°±0.2°, 17.501°±0.2°, 18.221°±0.2°, 18.500°±0.2°, 20.259°±0.2°, 20.721°±0.2°, 21.680°±0.2°, 22.858°±0.2°, 23.679°±0.2°, 26.160°±0.2°, 28.838°±0.2°, 31.019°±0.2°, 32.058°±0.2°, and 33.799°±0.2°.

48. The crystalline form of any one of Claims 45-47, characterized by, The compound IL-tartrate salt Form J2 further has at least one characteristic selected from the following: II) an endothermic peak at 206°C in the DSC pattern; and III) a 3% mass loss gradient from 30°C to 170°C in the TGA pattern.

49. The crystalline form of any one of Claims 45-47, characterized by, The compound IL-tartrate salt Form J2 further has at least one characteristic selected from the following: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 22; has a DSC pattern substantially the same as the DSC pattern shown in Figure 23; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 24.

50. The crystalline form of claim 11, which is Compound I besylate Form B1, characterized by, The compound I besylate salt Form B1 has the following characteristics: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 4.742°±0.2°, 9.477°±0.2°, and 13.504°±0.2°.

51. The Form of claim 50, characterized by: The XRPD pattern of the compound I besylate salt Form B1 has characteristic peaks at diffraction angles 2Q values of 4.742°±0.2°, 7.149°±0.2°, 9.477°±0.2°, 10.900°±0.2°, and 13.504°±0.2°.

52. The Form of claim 50, characterized by: The XRPD pattern of the compound I besylate salt Form B1 has characteristic peaks at diffraction angles 2Q values of 4.742°±0.2°, 7.149°±0.2°, 9.477°±0.2°, 9.877°±0.2°, 10.900°±0.2°, 13.504°±0.2°, and 20.804°±0.2°.

53. The crystalline form of claim 11, which is Compound I besylate Form B1, characterized by: The compound I besylate salt Form B1 has the following characteristics: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 25.

54. The crystalline form of claim 11, which is Compound I besylate Form B2, characterized by: The compound I besylate salt Form B2 has the following characteristics: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 12.432°±0.2°, 18.292°±0.2°, and 22.894°±0.2°.

55. The Form of claim 54, characterized by: The XRPD pattern of the Compound I besylate salt crystalline form B2 has characteristic peaks at diffraction angles 2Q values of 6.788°±0.2°, 12.432°±0.2°, 18.292°±0.2°, 19.339°±0.2° and 22.894°±0.2°.

56. The Form of claim 54, characterized by: The XRPD pattern of the Compound I besylate salt crystalline form B2 has characteristic peaks at diffraction angles 2Q values of 5.173°±0.2°, 6.788°±0.2°, 8.607°±0.2°, 10.677°±0.2°, 11.211°±0.2°, 12.432°±0.2°, 12.689°±0.2°, 13.734°±0.2°, 14.700°±0.2°, 15.730°±0.2°, 16.437°±0.2°, 17.364°±0.2°, 18.292°±0.2°, 19.339°±0.2°, 20.208°±0.2°, 20.543°±0.2°, 21.905°±0.2°, 22.894°±0.2°, 23.800°±0.2°, 24.453°±0.2°, 25.076°±0.2°, 25.574°±0.2°, 26.147°±0.2° and 28.396°±0.2°.

57. The crystalline form of claim 11, which is Compound I besylate Form B2, characterized by: The Compound I besylate salt crystalline form B2 has the following characteristics: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 26.

58. The crystalline form of claim 11, which is Compound I tosylate salt Form Tl, characterized by: The Compound I tosylate salt crystalline form T1 has the following characteristics: I) characteristic peaks in an XRPD pattern at diffraction angles 2Q values of 9.554°±0.2°, 14.730°±0.2° and 24.153°±0.2°.

59. The Form of claim 58, characterized by: The XRPD pattern of the Compound I tosylate salt crystalline form T1 has characteristic peaks at diffraction angles 2Q values of 9.554°±0.2°, 14.730°±0.2°, 18.763°±0.2°, 20.586°±0.2°, 21.609±0.2° and 24.153°±0.2°.

60. The Form of claim 58, characterized by: The Compound I tosylate salt crystalline form Tl has at least one characteristic selected from the following:

61. The morphic form of any one of claims 58-60, characterized by, II) an endothermic peak at 301 °C in the DSC pattern; and III) a mass loss gradient of 0.26% between 30 °C and 105 °C in the TGA pattern. The Compound I tosylate salt crystalline form Tl has at least one characteristic selected from the following:

62. The morphic form of any one of claims 58-60, characterized by, has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 27; has a DSC pattern substantially the same as the DSC pattern shown in Figure 28; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 29. The Compound I tosylate salt crystalline form T2 has the following characteristics:

63. The crystalline form of claim 11, which is Compound I tosylate salt Form T2, characterized by: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.690° ± 0.2°, 8.715° ± 0.2°, and 17.659° ± 0.2°. The Compound I tosylate salt crystalline form T2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 4.284° ± 0.2°, 7.273° ± 0.2°, 7.690° ± 0.2°, 8.715° ± 0.2°, 13.008° ± 0.2°, 16.334° ± 0.2°, and 17.659° ± 0.2°.

64. The Form of claim 63, characterized by: The Compound I tosylate salt crystalline form T2 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 4.284° ± 0.2°, 7.273° ± 0.2°, 7.690° ± 0.2°, 8.715° ± 0.2°, 10.917° ± 0.2°, 11.280° ± 0.2°, 11.542° ± 0.2°, 12.086° ± 0.2°, 13.008° ± 0.2°, 13.746° ± 0.2°, 15.511° ± 0.2°, 16.334° ± 0.2°, 17.659° ± 0.2°, 19.882° ± 0.2°, 23.210° ± 0.2°, and 25.899° ± 0.2°.

65. The Form of claim 63, characterized by: ​ 66. The crystalline form of any one of claims 63-65, characterized by, The Compound I besylate salt crystalline Form T2 further has at least one characteristic selected from: II) an endothermic peak in the DSC pattern at 50 °C and 245 °C, respectively; and III) a 2.38% mass loss in the TGA pattern from 30 °C to 105 °C.

67. The Form of any one of claims 63-65, characterized by: The Compound I besylate salt crystalline Form T2 further has at least one characteristic selected from: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 30; has a DSC pattern substantially the same as the DSC pattern shown in Figure 31; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 32.

68. The crystalline form of claim 11, which is Compound I sulfate salt Form S1, characterized by, The Compound I sulfate salt crystalline Form S1 has the following characteristics: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.146° ± 0.2°, 7.250° ± 0.2°, and 18.921° ± 0.2°.

69. The Form of claim 68, characterized by: The Compound I sulfate salt crystalline Form S1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.146° ± 0.2°, 7.250° ± 0.2°, 9.177° ± 0.2°, 13.709° ± 0.2°, 16.093° ± 0.2°, 18.921° ± 0.2°, and 23.033° ± 0.2°.

70. The Form of claim 68, characterized by: The Compound I sulfate salt crystalline Form S1 has an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 5.146° ± 0.2°, 7.250° ± 0.2°, 9.177° ± 0.2°, 12.766° ± 0.2°, 13.709° ± 0.2°, 15.613° ± 0.2°, 16.093° ± 0.2°, 17.215° ± 0.2°, 18.921° ± 0.2°, 20.527° ± 0.2°, 21.188° ± 0.2°, 23.033° ± 0.2°, 23.994° ± 0.2°, 24.375° ± 0.2°, 24.837° ± 0.2°, and 26.340° ± 0.2°.

71. The morphic form of any one of claims 68-70, characterized by an X-ray diffraction pattern substantially in accordance with Figure 34. The Compound I sulfate salt crystalline Form S1 further has at least one characteristic selected from: II) an endothermic peak in the DSC pattern at 301 °C; and III) a 0.25% mass loss in the TGA pattern from 30 °C to 105 °C.

72. The morphic form of any one of claims 68-70, characterized by, The Compound I sulfate salt crystalline Form S1 further has at least one characteristic selected from: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 33; has a DSC pattern substantially the same as the DSC pattern shown in Figure 34; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 35.

73. The crystalline form of claim 11, which is Compound I sulfate salt Form S2, characterized by: The Compound I sulfate salt crystalline Form S2 has the following characteristics: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 7.841° ± 0.2°, 16.160° ± 0.2°, and 21.261° ± 0.2°.

74. The Form of claim 73, characterized by: The XRPD pattern of the compound I sulfate salt crystalline form S2 has characteristic peaks at diffraction angles 2Q values of 6.842°±0.2°, 7.841°±0.2°, 13.819°±0.2°, 16.160°±0.2°, 21.261°±0.2° and 25.440±0.2°.

75. The Form of claim 73, characterized by: The XRPD pattern of the compound I sulfate salt crystalline form S2 has characteristic peaks at diffraction angles 2Q values of 3.360°±0.2°, 6.842°±0.2°, 7.841°±0.2°, 8.821°±0.2°, 9.637°±0.2°, 10.521°±0.2°, 11.799°±0.2°, 13.819°±0.2°, 14.594°±0.2°, 16.160°±0.2°, 17.461°±0.2°, 18.176°±0.2°, 19.105°±0.2°, 21.261°±0.2°, 22.399°±0.2°, 23.479°±0.2° and 25.440±0.2°.

76. The crystalline form of claim 11, which is Compound I sulfate salt Form S2, characterized by, The compound I sulfate salt crystalline form S2 has the following characteristics: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 36.

77. The crystalline form of claim 11, which is Compound I hydrobromide crystalline Form Br1, characterized by: The compound I hydrobromide salt crystalline form Br1 has the following characteristics: I) in an XRPD pattern, characteristic peaks at diffraction angles 2Q values of 10.475°±0.2°, 18.341°±0.2° and 19.342°±0.2°.

78. The Form of claim 77, characterized by: The XRPD pattern of the compound I hydrobromide salt crystalline form Br1 has characteristic peaks at diffraction angles 2Q values of 8.771°±0.2°, 10.475°±0.2°, 14.792°±0.2°, 18.341°±0.2°, 19.342°±0.2°, 21.127°±0.2° and 25.097°±0.2°.

79. The Form of claim 77, characterized by: The XRPD pattern of the compound I hydrobromide salt crystalline form Br1 has characteristic peaks at diffraction angles 2Q values of 5.659°±0.2°, 8.771°±0.2°, 10.475°±0.2°, 12.018°±0.2°, 13.629°±0.2°, 14.792°±0.2°, 15.319°±0.2°, 18.341°±0.2°, 19.001°±0.2°, 19.342°±0.2°, 20.228°±0.2°, 21.127°±0.2°, 21.548°±0.2°, 22.047°±0.2°, 22.411°±0.2°, 22.895°±0.2°, 23.912°±0.2°, 24.711°±0.2°, 25.097°±0.2°, 26.741°±0.2°, 27.162°±0.2°, 28.305°±0.2° and 29.187°±0.2°.

80. The morphic form of any one of claims 77-79, characterized by, The compound I hydrobromide salt crystalline form Br1 further has at least one characteristic selected from: II) has a DSC pattern substantially the same as the DSC pattern shown in Figure 38; and III) has a mass loss gradient of 2.17% between 30 °C and 105 °C in a TGA pattern.

81. The morphic form of any one of claims 77-79, characterized by, The compound I hydrobromide salt crystalline form Br1 further has at least one characteristic selected from: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 37; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 39.

82. The crystalline form of claim 11, which is Compound I citrate salt Form Nl, characterized by: The compound I citrate salt crystalline form N1 has the following characteristics: I) has characteristic peaks in an XRPD pattern at diffraction angles 2Q values of 14.324° ± 0.2°, 17.125° ± 0.2°, and 20.879° ± 0.2°.

83. The Form of claim 82, characterized by: The compound I citrate salt crystalline form N1 has characteristic peaks in an XRPD pattern at diffraction angles 2Q values of 8.996° ± 0.2°, 10.083° ± 0.2°, 14.324° ± 0.2°, 17.125° ± 0.2°, 20.879° ± 0.2°, 23.798° ± 0.2°, and 27.431° ± 0.2°.

84. The Form of claim 82, characterized by: The compound I citrate salt crystalline form N1 has characteristic peaks in an XRPD pattern at diffraction angles 2Q values of 7.693° ± 0.2°, 8.996° ± 0.2°, 10.083° ± 0.2°, 11.107° ± 0.2°, 12.747° ± 0.2°, 14.324° ± 0.2°, 15.116° ± 0.2°, 15.830° ± 0.2°, 16.475° ± 0.2°, 16.771° ± 0.2°, 17.125° ± 0.2°, 18.268° ± 0.2°, 19.831° ± 0.2°, 20.879° ± 0.2°, 21.571° ± 0.2°, 22.337° ± 0.2°, 22.872° ± 0.2°, 23.385° ± 0.2°, 23.798° ± 0.2°, 24.626° ± 0.2°, 26.207° ± 0.2°, 26.759° ± 0.2°, 27.431° ± 0.2°, 28.004° ± 0.2°, 28.277° ± 0.2°, 28.891° ± 0.2°, 30.530° ± 0.2°, 32.678° ± 0.2°, 34.772° ± 0.2°, 35.362° ± 0.2°, 36.546° ± 0.2°, 37.257° ± 0.2°, and 37.928° ± 0.2°.

85. The Form of any one of claims 82-84, characterized by: The compound I citrate salt crystalline form N1 further has at least one characteristic selected from: II) shows dehydration upon heating to 71 °C in a DSC pattern; and III) has a mass loss gradient of 2.31% between 30 °C and 180 °C in a TGA pattern.

86. The morphic form of any one of claims 82-84, characterized by, The compound I citrate salt crystalline form N1 further has at least one characteristic selected from: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 40; has an XRPD pattern substantially the same as that shown in Figure 41. has a TGA pattern substantially the same as that shown in Figure 42.

87. The crystal form according to claim 11, wherein it is the crystal form P1 of compound IL-malate, characterized in that, The compound IL-malate Form P1 has the following characteristics: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 10.477° ± 0.2°, 14.087° ± 0.2°, and 22.369° ± 0.2°.

88. The Form of claim 87, characterized by: The XRPD pattern of the compound IL-malate Form P1 has characteristic peaks at diffraction angles 2Q values of 7.471° ± 0.2°, 10.477° ± 0.2°, 14.087° ± 0.2°, 17.275° ± 0.2°, 19.003° ± 0.2°, 22.369° ± 0.2°, and 26.101° ± 0.2°.

89. The crystal form according to claim 87, characterized in that, The XRPD pattern of the compound IL-malate Form P1 has characteristic peaks at diffraction angles 2Q values of 7.471° ± 0.2°, 8.333° ± 0.2°, 9.672° ± 0.2°, 10.200° ± 0.2°, 10.477° ± 0.2°, 14.087° ± 0.2°, 14.670° ± 0.2°, 15.211° ± 0.2°, 16.013° ± 0.2°, 16.735° ± 0.2°, 17.275° ± 0.2°, 17.500° ± 0.2°, 19.003° ± 0.2°, 19.466° ± 0.2°, 20.081° ± 0.2°, 20.506° ± 0.2°, 21.068° ± 0.2°, 21.410° ± 0.2°, 21.828° ± 0.2°, 22.369° ± 0.2°, 23.360° ± 0.2°, 23.834° ± 0.2°, 24.176° ± 0.2°, 24.996° ± 0.2°, 26.101° ± 0.2°, 26.863° ± 0.2°, 28.183° ± 0.2°, 28.424° ± 0.2°, 29.011° ± 0.2°, and 29.987° ± 0.2°.

90. The crystalline form of claim 11, which is Compound IL-malate salt Form P1, characterized by, The compound IL-malate Form P1 has the following characteristics: has an XRPD pattern substantially the same as that shown in Figure 45.

91. The morphic form of claim 11, which is compound IL-camphorsulfonic acid salt Form Zl, characterized by: The compound IL-camphorsulfonate Form Z1 has the following characteristics: I) an XRPD pattern having characteristic peaks at diffraction angles 2Q values of 6.309° ± 0.2°, 11.141° ± 0.2°, and 16.054° ± 0.2°.

92. The Form of claim 91, characterized by: The XRPD pattern of the compound IL-camphorsulfonate Form Z1 has characteristic peaks at diffraction angles 2Q values of 6.309° ± 0.2°, 11.141° ± 0.2°, 14.571° ± 0.2°, 16.054° ± 0.2°, and 19.962° ± 0.2°.

93. The Form of claim 91, characterized by: The XRPD pattern of said compound IL-camphorsulfonic acid salt Form Z1 has characteristic peaks at diffraction angles 2Q values of 6.309°±0.2°, 10.600°±0.2°, 11.141°±0.2°, 14.571°±0.2°, 16.054°±0.2°, 16.834°±0.2° and 19.962°±0.2°.

94. The crystalline form of claim 11, which is compound IL-camphorsulfonic acid salt Form Zl, characterized in that, Said compound IL-camphorsulfonic acid salt Form Z1 has the following characteristics: has substantially the same XRPD pattern as the one set forth in Figure 46.

95. The crystal form according to claim 11, which is the crystal form F1 of compound I fumarate, characterized in that, Said compound I fumaric acid salt Form F1 has the following characteristics: I) in the XRPD pattern, characteristic peaks at diffraction angles 2Q values of 11.483°±0.2°, 14.713°±0.2° and 18.240°±0.2°.

96. The Form of claim 95, characterized by: The XRPD pattern of said compound I fumaric acid salt Form F1 has characteristic peaks at diffraction angles 2Q values of 9.397°±0.2°, 11.483°±0.2°, 14.713°±0.2°, 18.240°±0.2° and 20.605°±0.2°.

97. The Form of claim 95, characterized by: The XRPD pattern of said compound I fumaric acid salt Form F1 has characteristic peaks at diffraction angles 2Q values of 8.432°±0.2°, 8.712°±0.2°, 9.397°±0.2°, 10.697°±0.2°, 10.978°±0.2°, 11.483°±0.2°, 12.770°±0.2°, 13.304°±0.2°, 14.383°±0.2°, 14.713°±0.2°, 15.411°±0.2°, 15.651°±0.2°, 16.178°±0.2°, 17.159°±0.2°, 17.555°±0.2°, 18.240°±0.2°, 18.619°±0.2°, 20.125°±0.2°, 20.605°±0.2°, 21.590°±0.2°, 23.192°±0.2° and 24.537°±0.2°.

98. The crystal form according to claim 11, which is the crystal form F1 of compound I fumarate, characterized in that, Said compound I fumaric acid salt Form F1 has the following characteristics: has substantially the same XRPD pattern as the one set forth in Figure 47.

99. The crystalline form of claim 11, which is Compound I trifluoroacetate salt Form TF1, characterized by: Said compound I trifluoroacetate salt Form TF1 has the following characteristics: I) in the XRPD pattern, characteristic peaks at diffraction angles 2Q values of 14.431°±0.2°, 17.718°±0.2° and 18.519°±0.2°.

100. The crystal form according to claim 99, characterized in that, The XRPD pattern of said compound I trifluoroacetate salt Form TF1 has characteristic peaks at diffraction angles 2Q values of 7.850°±0.2°, 10.640°±0.2°, 14.431°±0.2°, 17.718°±0.2°, 18.519°±0.2°, 20.731°±0.2° and 27.600°±0.2°.

101. The morphic form of claim 99, characterized by: The XRPD pattern of said compound I trifluoroacetate salt crystalline form TF1 has characteristic peaks at diffraction angles 2Q values of 7.850°±0.2°, 8.792°±0.2°, 10.294°±0.2°, 10.640°±0.2°, 11.591°±0.2°, 12.804°±0.2°, 13.407°±0.2°, 14.431°±0.2°, 15.473°±0.2°, 15.829°±0.2°, 17.378°±0.2°, 17.718°±0.2°, 18.058°±0.2°, 18.519°±0.2°, 19.507°±0.2°, 19.897°±0.2°, 20.731°±0.2°, 21.466°±0.2°, 21.726°±0.2°, 22.716°±0.2°, 23.236°±0.2°, 23.875°±0.2°, 24.510°±0.2°, 26.039°±0.2°, 27.321°±0.2°, and 27.600°±0.2°.

102. The morphic form of any one of claims 99-101, characterized by, Said compound I trifluoroacetate salt crystalline form TF1 further has at least one feature selected from the following: II) an endothermic peak at 239°C in the DSC pattern; and III) a mass loss of 0.46% at 30°C to 105°C in the TGA pattern.

103. The morphic form of any one of claims 99-101, characterized by, Said compound I trifluoroacetate salt crystalline form TF1 further has at least one feature selected from the following: has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 48; has a DSC pattern substantially the same as the DSC pattern shown in Figure 49; and has a TGA pattern substantially the same as the TGA pattern shown in Figure 50.

104. A method of preparing a crystalline form of Compound I of any one of claims 1-10, the method comprising: Step (1) dissolving compound I in a first solvent, Optionally, step (2) adding a second solvent to the solution of step (1), Step (3) crystallization, filtration, to obtain the crystalline form of compound I.

105. The method of preparation according to claim 104, wherein, In the dissolving of step (1), the solution is warmed to 45-75°C, and the crystallization of step (3) is carried out at a temperature of 10-30°C.

106. The method of preparation according to claim 104, wherein, When step (2) is present, the volume ratio of the first solvent to the second solvent is 1:5 to 5:

1.

107. The method of preparation according to claim 104, wherein, After the filtration of step (3), drying is carried out.

108. The method of manufacturing of claim 104, wherein, has at least one feature selected from the following: In the dissolving of step (1), the solution is warmed to 50-70°C, and the crystallization of step (3) is carried out at a temperature of 20-25°C; when step (2) is present, the volume ratio of the first solvent to the second solvent is 1:2 to 2:1; and After the filtration of step (3), vacuum drying is carried out.

109. A method of preparing a crystalline form of a pharmaceutically acceptable salt of compound I according to any one of claims 11-103, the method comprising: Step (1) dissolving compound I in a first solvent, Step (2) adding an acid solution, Optional step (3) wherein a second solvent is added to the solution of step (2), Step (4) crystallization, filtration, to obtain a crystal form of the pharmaceutically acceptable salt of Compound I.

110. The production method according to claim 109, wherein, After step (2), a crystal form of the pharmaceutically acceptable salt of Compound I is added as a seed crystal.

111. A method for producing a crystal form of the pharmaceutically acceptable salt of Compound I according to any one of claims 11 to 103, the method comprising: Step (1) dissolving a crystal form of the pharmaceutically acceptable salt of Compound I in a first solvent or a mixed solvent of the first solvent and a second solvent, Step (4) crystallization, filtration, to obtain a crystal form of the pharmaceutically acceptable salt of Compound I, wherein the crystal form of the pharmaceutically acceptable salt of Compound I in step (1) is different from or the same as the crystal form of the pharmaceutically acceptable salt of Compound I as a product.

112. The production method according to claim 111, wherein, After step (1), a crystal form of the pharmaceutically acceptable salt of Compound I is added as a seed crystal.

113. The production method according to claim 109 or 111, wherein, In the dissolving of step (1), the solution is warmed to 20 to 75°C, and the crystallization of step (4) is performed at a temperature of 10 to 30°C.

114. The production method according to claim 109, wherein, The acid in step (2) is hydrochloric acid, methanesulfonic acid, maleic acid, L-tartaric acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, hydrobromic acid, citric acid, L-malic acid, L-camphorsulfonic acid, fumaric acid, or trifluoroacetic acid.

115. The production method according to claim 109, wherein, The solvent of the acid solution in step (2) is a third solvent.

116. The method of manufacturing according to claim 115, wherein, The third solvent is the same as or different from the first solvent.

117. The method of manufacturing according to claim 109 or 111, wherein, In the crystallization of step (4), the volume ratio of the first solvent to the second solvent in the solution is 1:6 to 6:

1.

118. The method of manufacturing according to claim 109 or 111, wherein, has at least one feature selected from the group consisting of, in the dissolving of step (1), the solution is warmed to 20 to 70°C, and the crystallization of step (4) is performed at a temperature of 15 to 25°C; in the crystallization of step (4), the volume ratio of the first solvent to the second solvent in the solution is 1:1 to 5:

1.

119. The method of making of claim 104, 109, or 111, wherein, The first solvent is an organic solvent selected from the group consisting of an alcohol, a ketone, an ether, an alkyl nitrile, an ester, an alkane, or a mixture of two or more thereof, or a mixture of the aforementioned organic solvent and water.

120. The method of manufacturing according to claim 119, wherein, The ether is a cyclic ether.

121. The method of manufacturing according to claim 119, wherein, Water is not present in the first solvent.

122. The method of manufacturing according to claim 119, wherein, Water is present in the first solvent, and the volume ratio of the organic solvent to water is 5:1 to 50:

1.

123. The method of manufacturing of claim 119, wherein, Water is present in the first solvent, and the volume ratio of the organic solvent to water is 5:1 to 20:

1.

124. The method of manufacturing of claim 119, wherein, The first solvent is at least one organic solvent selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, methanol, ethanol, isopropanol, acetonitrile, and ethyl acetate, or a mixture of the aforementioned organic solvent and water.

125. The method of manufacturing according to claim 119, wherein, The first solvent is 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution, or 95% (V / V) acetone aqueous solution.

126. The method of manufacturing of claim 104, 109, or 111, wherein, The second solvent is at least one selected from the group consisting of alkanes, ethers, esters, and water, or a mixture of two or more thereof.

127. The method of making of claim 104, 109, or 111, wherein, The second solvent is at least one selected from the group consisting of alkanes, ethers, esters, and water.

128. The method of manufacturing according to claim 126, wherein, The second solvent is at least one selected from the group consisting of n-hexane, n-heptane, diethyl ether, methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate, and water.

129. The method of manufacturing of claim 115, wherein, The third solvent is an organic solvent selected from the group consisting of alcohols, ketones, ethers, alkyl nitriles, esters, alkanes, or a mixture of two or more thereof, or a mixture of the aforementioned organic solvent and water.

130. The method of manufacturing according to claim 129, wherein, The ether is a cyclic ether.

131. The method of manufacturing according to claim 129, wherein, The third solvent is at least one organic solvent selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, methanol, ethanol, isopropyl alcohol, acetonitrile, and ethyl acetate, or a mixture of the aforementioned organic solvent and water.

132. The method of manufacturing according to claim 131, wherein, The third solvent is at least one selected from the group consisting of tetrahydrofuran, 2-butanone, acetone, isopropyl alcohol, ethanol, acetonitrile, 85% (V / V) aqueous acetone, 90% (V / V) aqueous acetone, 95% (V / V) aqueous acetone, acetone-water at a volume ratio of 2:1, acetonitrile-water at a volume ratio of 6:1, acetonitrile-water at a volume ratio of 8:1, ethanol-water at a volume ratio of 10:1, and tetrahydrofuran-water at a volume ratio of 10:

1.

133. The production method according to claim 109, wherein, When the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1:1 to 50:

1.

134. The production method according to claim 109, wherein, When the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 2:1 to 20:

1.

135. The production method according to claim 109, wherein, When the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 1:1 to 12:

1.

136. The production method according to claim 109, wherein, When the solvent of the acid solution of step (2) is a mixed solvent of an organic solvent and water, the volume ratio of the organic solvent to water is 2:1 to 11:

1.

137. The method of manufacturing of claim 104, 109, or 111, wherein, During the dissolving process of step (1), nitrogen replacement is performed.

138. The method of manufacturing according to claim 109 or 111, wherein, After the filtration of step (4), drying is performed.

139. The method of manufacturing according to claim 109 or 111, wherein, After the filtration of step (4), vacuum drying is performed.

140. A method of preparing crystalline Form Yl of Compound I, the method comprising: Step (1) dissolves compound I in a first solvent selected from at least one of tetrahydrofuran, 2-butanone, and acetone, Step (2), wherein a second solvent selected from at least one of n-heptane, methyl tert-butyl ether, and water is added to the solution of step (1), the volume ratio of the first solvent to the second solvent being 1:5 to 5:1, Step (3) crystallization, filtration, to obtain a crystal form Yl of compound I.

141. A method of preparing crystalline Form Yl of Compound I, the method comprising: Step (1) dissolves compound I in a first solvent selected from at least one of tetrahydrofuran, 2-butanone, and acetone, Step (2), wherein a second solvent selected from at least one of n-heptane, methyl tert-butyl ether, and water is added to the solution of step (1), the volume ratio of the first solvent to the second solvent being 1:2 to 2:1, Step (3) crystallization, filtration, to obtain a crystal form Yl of compound I.

142. A method for preparing the citrate salt Form Nl of Compound I, the method comprising: Step (1) dissolving Compound I in a first solvent selected from at least one of tetrahydrofuran, acetonitrile, ethanol, acetone, 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution, Step (2) adding a solution of citric acid or citric acid monohydrate, the solvent of the solution being an organic solvent selected from one of tetrahydrofuran, ethanol, acetone, Optional Step (3), wherein methyl tert-butyl ether is added to the solution of Step (2) as a second solvent, the volume ratio of the first solvent to the second solvent being 1:2 to 3:1, Step (4) crystallization, filtration to obtain the citrate salt Form Nl of Compound I.

143. A method for preparing the citrate salt Form Nl of Compound I, the method comprising: Step (1) dissolving Compound I in a first solvent selected from at least one of tetrahydrofuran, acetonitrile, ethanol, acetone, 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution, Step (2) adding a solution of citric acid or citric acid monohydrate, the solvent of the solution being a mixed solution of an organic solvent selected from one of tetrahydrofuran, ethanol, acetone and water, Optional Step (3), wherein methyl tert-butyl ether is added to the solution of Step (2) as a second solvent, the volume ratio of the first solvent to the second solvent being 1:1 to 2:1, Step (4) crystallization, filtration to obtain the citrate salt Form Nl of Compound I.

144. The method of claim 143, wherein, In Step (2), the volume ratio of the organic solvent to water is 1:1 to 50:

1.

145. The method of claim 143, wherein, In Step (2), the solvent of the solution is 85% (V / V) acetone aqueous solution, 90% (V / V) acetone aqueous solution, a mixed solution of acetonitrile-water at a ratio of 8:1, a mixed solution of ethanol-water at a ratio of 10:1, or a mixed solution of tetrahydrofuran-water at a ratio of 10:

1.

146. A method of preparing Citrate Form Nl of Compound I, the method comprising: Step (1) dissolving Compound I in acetonitrile, Step (2) adding a solution of citric acid or citric acid monohydrate in acetonitrile-water, wherein the volume ratio of acetonitrile to water is 6:1 to 10:1, Step (4) crystallization, filtration to obtain the citrate salt Form Nl of Compound I.

147. A method of preparing Citrate Form Nl of Compound I, the method comprising: Step (1) dissolving Compound I in acetonitrile, Step (2) adding a solution of citric acid or citric acid monohydrate in acetonitrile-water, wherein the volume ratio of acetonitrile to water is 7:1 to 9:1, Step (4) crystallization, filtration to obtain the citrate salt Form Nl of Compound I.

148. A single crystal of Compound I, having the following characteristics: Belongs to the orthorhombic space group P2i2i2i, cell parameters α = 90°, β = 90°, γ = 90°, Z = 4.

149. A single crystal of Compound I citrate characterized by, The single crystal of the citrate salt of Compound I has the following characteristics: belongs to the monoclinic space group P21 and has a unit cell parameter of α = 90°, β = 109.972(2)°, γ = 90°, Z = 2.

150. A pharmaceutically acceptable salt of Compound I, the salt being at least one selected from the group consisting of hydrochloride, methanesulfonate, maleate, L-tartrate, benzenesulfonate, toluenesulfonate, sulfate, hydrobromide, L-malate, L-camphorsulfonate, fumarate and trifluoroacetate.

151. A pharmaceutical composition comprising at least one of a crystalline form of Compound I according to any one of claims 1-10, a crystalline form of a pharmaceutically acceptable salt of Compound I according to any one of claims 11-103, a single crystal of Compound I according to claim 148, a single crystal of a citrate salt of Compound I according to claim 149, and a pharmaceutically acceptable salt of Compound I according to claim 150, and a pharmaceutically acceptable excipient.

152. Use of a crystalline form of Compound I according to any one of claims 1-10, a crystalline form of a pharmaceutically acceptable salt of Compound I according to any one of claims 11-103, a single crystal of Compound I according to claim 148, a single crystal of a citrate salt of Compound I according to claim 149, a pharmaceutically acceptable salt of Compound I according to claim 150, and a pharmaceutical composition according to claim 151 in the manufacture of at least one of the following inhibitors / drugs: 1) a KRAS G12C mutant protein inhibitor; 2) a cell proliferation inhibitor; 3) a drug for preventing and / or treating a disease mediated by KRAS G12C mutation; 4) a drug for preventing and / or treating a malignant tumor.

153. The use according to claim 152, wherein the inhibitor / drug is a drug for preventing and / or treating a cancer or a sarcoma.

154. The use according to claim 153, wherein the cancer is selected from one or more of pancreatic cancer, leukemia, esophageal cancer, lung cancer, breast cancer, colorectal cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine cancer, cervical cancer, testicular cancer, brain cancer, head or neck cancer, lymphoma, and thyroid cancer.

155. The use according to claim 153, wherein the sarcoma is osteosarcoma.

156. The use according to claim 154, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.

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