Solid forms of ras inhibitor

Abstract

The present invention relates to novel solid forms of compound (I), (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide, and the processes for their preparation and their use in pharmaceutical composition.

Description

[0001] Case 39453 Solid forms of RAS inhibitor The present invention relates to novel solid forms of compound (I), (1r,2R,3S)-N- [(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17- dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide, and the processes for their preparation and their use in pharmaceutical composition. BACKGROUND OF THE INVENTION RAS is one of the most well-known proto-oncogenes. Approximately 30% of human cancers contain mutations in three most notable members, KRAS, HRAS, and NRAS, making them the most prevalent oncogenic drivers. KRAS mutations are generally associated with poor prognosis, especially in colorectal cancer, pancreatic cancer, lung cancers. As the most frequently mutated RAS isoform, KRAS has been intensively studied in the past years. Among the most commonly occurring KRAS alleles (including G12D, G12V, G12C, G13D, G12R, G12A, G12S, Q61H, etc), G12C, G12D, G12V represent more than half of all KRAS-driven cancers across colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma (LUAD). Of note, KRAS wild-type amplifications are also found in around 7% of all KRAS-altered cancers (ovarian, esophagogastric, uterine), ranking among the top alterations. All RAS proteins belong to a protein family of small GTPases that hydrolyze GTP to GDP. KRAS is structurally divided into an effector binding lobe followed by the allosteric lobe and a carboxy-terminal region that is responsible for membrane anchoring. The effector lobe comprises the P-loop, switch I, and switch II regions. The switch I / II loops play a critical role in KRAS downstream signaling through mediating protein–protein interactions with effector proteins that include RAF in the mitogen-activated protein kinase (MAPK) pathway or PI3K in the phosphatidylinositol 3‑kinase (PI3K) / protein kinase B (AKT) pathway. KRAS protein switches between an inactive to an active form via binding to GTP and GDP, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), such as Son Of Sevenless Homolog 1 (SOS1), or GTPase-activating proteins (GAPs) that involve catalyzing the exchange of GDP for GTP, potentiating intrinsic GTPase activity or accelerating RAS-mediated GTP hydrolysis. In response to extracellular stimuli, the inactive RAS-GDP is converted to active RAS-GTP which directly binds to RAF RAS binding domains (RAFRBD), recruiting RAF kinase family from cytoplasm to membranes, where they dimerize and become active. The activated RAF subsequently carries out a chain of phosphorylation reactions to its downstream Mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK), and propagates the growth signal. Of the RAF family of protein kinases (three known isoforms ARAF, BRAF, CRAF / RAF1), BRAF is most frequently mutated and remains the most potent activator of MEK. Despite that individual RAS and RAF family members revealed distinct binding preferences, all RAFs possess the conserved RBD for forward transmission of MAPK singnaling, frequently used for characterizing KRAS inhibition (e.g. KRAS-BRAFRBDherein). For KRAS, mutations at positions 12, 13, 61, and 146 lead to a shift toward the active KRAS form through impairing nucleotide hydrolysis or activating nucleotide exchange, leading to hyper-activation of the MAPK pathway that results in tumorigenesis. Compound (I) is a RAS inhibitor as described in International application No. PCT / CN2024 / 076886. Solid forms of such compound, and pharmaceutical composition comprising such solid forms are desired herein which may be useful in the commercial manufacturing process. SUMMARY OF THE INVENTION The present invention relates to novel solid forms of compound (I),

[0002] , (1r,2R,3S)-N-[(7S,13S) 1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]-2,3-dimethyl-cyclopropanecarboxamide, and the processes for their preparation and their use in pharmaceutical composition. In another embodiment, Mesylate salt Form C, Besylate Salt Form I or Tosylate Salt Form C of compound (I) showed improved stability compared to other solid forms of compound (I). They also showed improved hygroscopicity compared to other solid forms. In addition, they showed improved processability given that it is easier to be purified and isolated from solvent compared to other solid forms of Compound (I), and that the bulk powders have higher densities and are easier to handle and process during downstream manufacture such as blending and tableting. SOLID FORMS The present invention relates to a solid form of compound (I),

[0003] , or salt, solvate or Form Amorphous, Mesylate salt Form C, Besylate Salt Form I, Tosylate Salt Form C, Mesylate salt Form E, Free Base Form H, Free Base Form A, Besylate Salt Form F or Tosylate Salt Form A. In a further embodiment, the solid form of compound (I) is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 8.3°±0.2°, 11.2°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 19.6°±0.2°, 19.8°±0.2° and 24.3°±0.2°. In a further embodiment, the solid form of compound (I) is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 13.2°±0.2°, 14.2°±0.2°, 17.9°±0.2°, 19.4°±0.2° and 20.1°±0.2°. In a further embodiment, the solid form of compound (I) is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.3°±0.2°, 11.2°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 19.6°±0.2°, 19.8°±0.2° and 24.3°±0.2°. In a further embodiment, the solid form of compound (I) is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.3°±0.2°, 11.2°±0.2°, 13.2°±0.2°, 14.2°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 17.9°±0.2°, 19.4°±0.2°, 19.6°±0.2°, 19.8°±0.2°, 20.1°±0.2° and 24.3°±0.2°. In a further embodiment, the solid form of compound (I) is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.2. In a further embodiment, the solid form of compound (I) is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 5.9°±0.2°, 12.4°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 19.9°±0.2° and 21.8°±0.2°. In a further embodiment, the solid form of compound (I) is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 21.1°±0.2°, 20.5°±0.2°, 23.7°±0.2°, 10.8°±0.2°, 13.7°±0.2° and 18.5°±0.2°. In another embodiment, the solid form of compound (I) is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.9°±0.2°, 12.4°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 19.9°±0.2° and 21.8°±0.2°. In a further embodiment, the solid form of compound (I) is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 5.9°±0.2°, 10.8°±0.2°, 12.4°±0.2°, 13.7°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 18.5°±0.2°, 19.9°±0.2°, 20.5°±0.2°, 21.1°±0.2°, 21.8°±0.2° and 23.7°±0.2°. In a further embodiment, the solid form of compound (I) is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.7. In a further embodiment, the solid form of compound (I) is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 8.7°±0.2°, 12.0°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 15°±0.2° and 19.7°±0.2°. In a further embodiment, the solid form of compound (I) is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 4.3°±0.2°, 7.1°±0.2°, 11.4°±0.2°, 15.9°±0.2°, 16.6°±0.2° and 21.6°±0.2°. In another embodiment, the solid form of compound (I) is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 8.7°±0.2°, 12.0°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 15°±0.2° and 19.7°±0.2°. In a further embodiment, the solid form of compound (I) is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.3°±0.2°, 7.1°±0.2°, 8.7°±0.2°, 11.4°±0.2°, 12.0°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 15°±0.2°, 15.9°±0.2°, 16.6°±0.2°, 19.7°±0.2° and 21.6°±0.2°. In a further embodiment, the solid form of compound (I) is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.11. In a further embodiment, the solid form of compound (I) is Mesylate salt Form E that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 7.5°±0.2°, 8.2°±0.2°, 14.4°±0.2°, 17.4°±0.2°, 18.7°±0.2° and 22.0°±0.2°. In a further embodiment, the solid form of compound (I) is Mesylate salt Form E that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 10.9°±0.2°, 11.7°±0.2°, 16.7°±0.2°, 18.1°±0.2°, 19.5°±0.2° and 22.3°±0.2°. In another embodiment, the solid form of compound (I) is Mesylate salt Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.5°±0.2°, 8.2°±0.2°, 14.4°±0.2°, 17.4°±0.2°, 18.7°±0.2° and 22.0°±0.2°. In a further embodiment, the solid form of compound (I) is Mesylate salt Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.5°±0.2°, 8.2°±0.2°, 10.9°±0.2°, 11.7°±0.2°, 14.4°±0.2°, 16.7°±0.2°, 17.4°±0.2°, 18.1°±0.2°, 18.7°±0.2°, 19.5°±0.2°, 22.0°±0.2°, 22.3°±0.2° and 24.8°±0.2°. In a further embodiment, the solid form of compound (I) is Mesylate salt Form E that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.3. In a further embodiment, the solid form of compound (I) is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 4.0°±0.2°, 12.1°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 17.8°±0.2° and 19.3°±0.2°. In a further embodiment, the solid form of compound (I) is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 8.1°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 17.2°±0.2°, 18.9°±0.2° and 24.7°±0.2°. In another embodiment, the solid form of compound (I) is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2- theta at 4.0°±0.2°, 12.1°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 17.8°±0.2° and 19.3°±0.2°. In a further embodiment, the solid form of compound (I) is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2- theta at 4.0°±0.2°, 8.1°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 16.2°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 17.8°±0.2°, 18.9°±0.2°, 19.3°±0.2° and 24.7°±0.2°. In a further embodiment, the solid form of compound (I) is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.5. In a further embodiment, the solid form of compound (I) is Free Base Form A that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 4.6°±0.2°, 6°±0.2°, 6.1°±0.2°, 6.9°±0.2°, 8.1°±0.2° and 9.0°±0.2°. In a further embodiment, the solid form of compound (I) of compound (I) is Free Base Form A that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 10.1°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 16.9°±0.2°, 17.1°±0.2° and 20.8°±0.2°. In another embodiment, the solid form of compound (I) of compound (I) is Free Base Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.6°±0.2°, 6°±0.2°, 6.1°±0.2°, 6.9°±0.2°, 8.1°±0.2° and 9.0°±0.2°. In a further embodiment, the solid form of compound (I) of compound (I) is Free Base Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.6°±0.2°, 6°±0.2°, 6.1°±0.2°, 6.9°±0.2°, 8.1°±0.2°, 9.0°±0.2°, 10.1°±0.2°, 12.2°±0.2°, 12.9°±0.2°, 16.9°±0.2°, 17.1°±0.2° and 20.8°±0.2°. In a further embodiment, the solid form of compound (I) is Free Base Form A that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.4. In a further embodiment, the solid form of compound (I) is Besylate Salt Form F that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 7.7°±0.2°, 10.9°±0.2°, 12.7°±0.2°, 15.6°±0.2°, 16°±0.2° and 19.7°±0.2°. In a further embodiment, the solid form of compound (I) of compound (I) is Besylate Salt Form F that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 10.1°±0.2°, 11.5°±0.2°, 13.5°±0.2°, 13.8°±0.2°, 16.4°±0.2° and 17.8°±0.2°. In another embodiment, the solid form of compound (I) of compound (I) is Besylate Salt Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.7°±0.2°, 10.9°±0.2°, 12.7°±0.2°, 15.6°±0.2°, 16°±0.2° and 19.7°±0.2°. In a further embodiment, the solid form of compound (I) of compound (I) is Besylate Salt Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 7.7°±0.2°, 10.1°±0.2°, 10.9°±0.2°, 11.5°±0.2°, 12.7°±0.2°, 13.5°±0.2°, 13.8°±0.2°, 15.6°±0.2°, 16°±0.2°, 16.4°±0.2°, 17.8°±0.2° and 19.7°±0.2°. In a further embodiment, the solid form of compound (I) is Besylate Salt Form F that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.9. In a further embodiment, the solid form of compound (I) is Tosylate Salt Form A that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 4.6°±0.2°, 5.0°±0.2°, 12.4°±0.2°, 13.2°±0.2°, 14.3°±0.2° and 19.5°±0.2°. In a further embodiment, the solid form of compound (I) of compound (I) is Tosylate Salt Form A that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 5.6°±0.2°, 7.8°±0.2°, 9.2°±0.2°, 9.6°±0.2°, 16.3°±0.2° and 17.2°±0.2°. In another embodiment, the solid form of compound (I) of compound (I) is Tosylate Salt Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.6°±0.2°, 5.0°±0.2°, 12.4°±0.2°, 13.2°±0.2°, 14.3°±0.2° and 19.5°±0.2°. In a further embodiment, the solid form of compound (I) of compound (I) is Tosylate Salt Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2-theta at 4.6°±0.2°, 5.0°±0.2°, 5.6°±0.2°, 7.8°±0.2°, 9.2°±0.2°, 9.6°±0.2°, 12.4°±0.2°, 13.2°±0.2°, 14.3°±0.2°, 16.3°±0.2°, 17.2°±0.2° and 19.5°±0.2°. In a further embodiment, the solid form of compound (I) is Tosylate Salt Form A that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.13. In another embodiment, the present invention relates to a process for the preparation of the Form Amorphous of compound (I), comprising: (a) compound (I) in any other free base forms was dissolved in a mixture solvent of acetonitrile and water ; (b) solid was collected after the above solution was lyophilized. In another embodiment, the present invention relates to a process for the preparation of the Form Amorphous of compound (I), comprising: (a) compound (I) in any other free base forms was dissolved in dichloromethane; (b) solid was collected after the above solution was concentrated using a rotary evaporator. In another embodiment, the present invention relates to a process for the preparation of the Form Amorphous of compound (I), comprising: (a) compound (I) in any other free base forms was dissolved in acetone; (b) solid was collected after the above solution was concentrated using a rotary evaporator. In another embodiment, the present invention relates to a process for the preparation of the Form Amorphous of compound (I), comprising: (a) compound (I) in any other free base forms was dissolved in ethyl acetate; (b) solid was collected after the above solution was concentrated using a rotary evaporator. In another embodiment, the present invention relates to a process for the preparation of the Mesylate salt Form C of compound (I), comprising: (a) compound (I) was dissolved in acetone, or heptane, or MTBE, or a mixture solvent thereof; (b) methanesulfonic acid in acetone, or heptane, or MTBE, or a mixture solvent thereof was added; (c) solid was collected after drying. In another embodiment, the present invention relates to a process for the preparation of the Mesylate salt Form E of compound (I), comprising: (a) a solution of compound (I) in Mesylate salt Form C was prepared in acetone and stirred at 50℃; (b) solid was collected after drying. In another embodiment, the present invention relates to a process for the preparation of the Besylate Salt Form I of compound (I), comprising: (a) a solution of compound (I) and benzenesulfonic acid was prepared in acetone, and stirred at room temperature; (b) solid was collected after drying. In another embodiment, the present invention relates to a process for the preparation of the Tosylate Salt Form C of compound (I), comprising: (a) a solution of compound (I) and p-toluenesulfonic acid was prepared in acetone, and stirred at room temperature; (b) solid was collected after drying. In another embodiment, the present invention relates to a process for the preparation of the Free Base Form H of compound (I), comprising: (a) compound (I) was suspended in a mixture solvent of dioxane / cyclohexane; (b) solid was collected and dried; (c) dried solid was treated with THF / heptane to form a slurry, which was stirred at room temperature for 3 days; (d) the solid was dried under vacuum at 40 °C for overnight. In another embodiment, the present invention relates to a pharmaceutical composition comprising the crystalline form, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for the manufacture of a medicament for treating a KRAS G12C protein-related disease. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for treating a KRAS G12C, G12D and G12V protein-related disease. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for inhibiting the propagating oncogenic MAPK and PI3K signaling. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for the treatment or prophylaxis of cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for the treatment or prophylaxis of cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma ovarian cancer and endometrial cancer. In a further embodiment, the present invention relates to the use, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer. In a further embodiment, the present invention relates to the use of the solid form, or the pharmaceutical composition for the treatment or prophylaxis of primary central nervous system (CNS) tumors harboring RAS mutations or RAS driven cancers with brain metastases; wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer. In a further embodiment, the present invention relates to the use, wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is non- small cell lung cancer. ABBREVIATIONS DVS dynamic vapor sorption EtOAc or EA ethyl acetate HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate) HPLC high performance liquid chromatography HOBt N-hydroxybenzotriazole KRAS Kirsten Rat Sarcoma Viral Oncogene Homolog NMR nuclear magnetic resonance NMM N-Methylmorpholine NPLC Normal phase liquid chromatography XRPD X-ray powder diffraction DESCRIPTION OF THE FIGURES FIG.1. X-ray powder diffraction pattern for Form Amorphous of Compound (I) FIG.1a. Dynamic vapor sorption for Free Base Amorphous of Compound (I) FIG.2. X-ray powder diffraction pattern for Mesylate salt Form C of Compound (I) FIG.2a. Dynamic vapor sorption for Mesylate Salt Form C of Compound (I) FIG.3. X-ray powder diffraction pattern for Mesylate salt Form E of Compound (I) FIG.3a. Dynamic vapor sorption for Mesylate Salt Form E of Compound (I) FIG.4. X-ray powder diffraction pattern for Free Base Form A of Compound (I) FIG.5. X-ray powder diffraction pattern for Free Base Form H of Compound (I) FIG.6. Dynamic vapor sorption for Free Base Form H of Compound (I) FIG.7. X-ray powder diffraction pattern for Besylate Salt Form I of Compound (I) FIG.8. Dynamic vapor sorption for Besylate Salt Form I of Compound (I) FIG.9. X-ray powder diffraction pattern for Besylate Salt Form F of Compound (I) FIG.10. Dynamic vapor sorption for Besylate Salt Form F of Compound (I) FIG.11. X-ray powder diffraction pattern for Tosylate Salt Form C of Compound (I) FIG.12. Dynamic vapor sorption for Tosylate Salt Form C of Compound (I) FIG.13. X-ray powder diffraction pattern for Tosylate Salt Form A of Compound (I) FIG.14. Dynamic vapor sorption for Tosylate Salt Form A of Compound (I) EXAMPLES The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Synthesis of Compound (I) (1r,2R,3S)-N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3- pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]-2,3-dimethyl-cyclopropanecarboxamide To a solution of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (Intermediate E, 20 mg) and (1r,2S,3R)-2,3-dimethylcyclopropanecarboxylic acid (CAS 34669-51-7) ( 4.3 mg) in DMF (0.2 mL) were added DIEA (14 µL), HATU (18.5 mg) at 0 °C. After being stirred at 20 °C for 1 h, the reaction mixture was diluted with water (15 mL), extracted with EtOAc (15 mL, three times). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to get a residue. The residue was purified by prep-HPLC to afford compound (I) (7.3 mg) as a white solid. MS calc’d 837.4 (MH+), measured 837.4 (MH+).1H NMR (400 MHz, Methanol-d4) δ = 8.33 - 8.25 (m, 2H), 7.37 (s, 1H), 7.29 (s, 1H), 7.17 (d, J = 2.8 Hz, 1H), 5.72 - 5.64 (m, 1H), 4.47 (br s, 2H), 4.36 - 4.24 (m, 2H), 4.17 - 4.08 (m, 2H), 3.66 - 3.62 (m, 2H), 3.54 - 3.45 (m, 1H), 3.34 - 3.26 (m, 5H), 3.18 - 3.13 (m, 1H), 3.02 - 2.85 (m, 3H), 2.73 - 2.61 (m, 5H), 2.50 (br d, J = 14.3 Hz, 1H), 2.38 (s, 3H), 2.25 - 2.15 (m, 1H), 2.12 - 2.02 (m, 2H), 1.82 (br d, J = 13.3 Hz, 1H), 1.71 - 1.58 (m, 1H), 1.49 (dq, J = 3.6, 12.5 Hz, 1H), 1.36 - 1.31 (m, 3H), 1.30 - 1.21 (m, 2H), 1.08 - 0.94 (m, 8H), 0.86 - 0.81 (m, 3H), 0.46 - 0.40 (m, 3H). Intermediate E (7S,13S)-7- 17,17-dimethyl- 8,14-dione The Intermediate Y POCl3LDA TFA, Et3SiH DMF THF DCM E3 E4E5 Step 1: Preparation of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8- yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1). To a solution of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (Intermediate Z, 26.1 g, 68.8 mmol) in DMF (400 mL) were added 6-bromo-8-iodo- 1,2,3,4-tetrahydroquinoline (Intermediate Y, 23.3 g, 68.8 mmol), TEA (47.9 mL, 343.9 mmol), CuI (1.3 g, 6.88 mmol) and Pd(PPh3)2Cl2 (4.8 g, 6.88 mmol). The reaction mixture was degassed and purged with nitrogen for three times and then it was stirred at 25 °C for 12 hrs. After the reaction was completed, the reaction mixture was poured into water (1.4 L), and extracted with EtOAc (800 mL, three times). The combined organic layer was washed with brine (800 mL, four times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5-[2-(6-bromo-1,2,3,4- tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1, 30.0 g) as a yellow solid. MS calc’d 589.2 (MH+), measured 589.2(MH+). Step 2: Preparation of benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2). To a solution of benzyl 4-[5-[2-(6-bromo-1,2,3,4-tetrahydroquinolin-8-yl)ethynyl]-6-[(1S)- 1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E1, 27.0 g, 45.8 mmol) in DMF (270 mL) was added PdCl2 (1.6 g, 9.16 mmol) in one portion. The reaction mixture was degassed and purged with nitrogen for three times and then heated to 70 °C for 16 hrs. After being cooled to the room temperature, the mixture was poured into water (800 mL), and extracted with EtOAc (300 mL, three times). The combined organic layer was washed with brine (300 mL, three times), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2, 19.2 g) as a yellow solid. MS calc’d 589.2 (MH+), measured 589.2 (MH+). Step 3: Preparation of benzyl 4-[5-(6-bromo-3-formyl-1-azatricyclo[6.3.1.04,12]dodeca- 2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E3). Phosphorus oxychloride (30.4 mL, 325.69 mmol) was added into DMF (350 mL) dropwise slowly at 0°C. After being stirred at 0 °C for 0.5 h, the reaction mixture was added with a solution of benzyl 4-[5-(6-bromo-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6- [(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E2, 19.2 g, 32.57 mmol) in DMF (150 mL) dropwise at 0 ºC. The reaction mixture was heated to 45 °C, and then stirred for another 1 h. The reaction was quenched with sat. NaHCO3aq. solution (1.5 L), extracted with EtOAc (500 mL, three times). The organic phase was washed with brine (500 mL, three times), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[5-(6-bromo-3-formyl-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E3, 14.6 g) as a yellow solid. MS calc’d 616.9 (MH+), measured 617.2 (MH+). Step 4: Preparation of benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3- 4,12 oxo-propyl)-1-azatricyclo[6.3.1.0 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1- methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E4) To a solution of methyl isobutyrate (13.4 g, 131.17 mmol) in THF (150 mL) was added LDA (65.58 mL, 131.17 mmol) dropwise at -70 °C under nitrogen atmosphere. After being stirred for 0.5 h, the reaction mixture was added with a solution of benzyl 4-[5-(6-bromo-3- formyl-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl)-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E3, 13.5 g, 21.86 mmol) in THF (50 mL) dropwise at -70 °C. The reaction mixture was then allowed warm up to room temperature and stirred for 1 h. After the reaction was completed, the mixture was quenched with sat. NH4Cl (600 mL) aqueous solution and extracted with EtOAc (200 mL, three times). The organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo-propyl)-1- 4,12 azatricyclo[6.3.1.0 ]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E4, 14.01 g) as a yellow gum. MS calc’d 719.3 (MH+), measured 719.2 (MH+). Step 5: Preparation of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)- 1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E5) To a solution of benzyl 4-[5-[6-bromo-3-(1-hydroxy-3-methoxy-2,2-dimethyl-3-oxo- propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E4, 14.0 g, 19.45 mmol) and Et3SiH (18.1 g, 155.63 mmol) in DCM (280 mL) was added TFA (57.8 mL, 778.15 mmol) at 0 °C. After being stirred at 25°C for 12 hrs, the reaction mixture was concentrated under vacuum to give a residue, which was diluted with sat. NaHCO3 aq. until pH=9 and extracted with EtOAc (300 mL, three times). The combined organic layer was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column to afford benzyl 4-[5-[6- bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)- tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E5, 14 g) as a yellow gum. MS calc’d 703.2 (MH+), measured 703.2 (MH+). Step 6: Preparation of benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)- 1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E6) To a solution of benzyl 4-[5-[6-bromo-3-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E5, 14.0 g, 19.9 mmol) in THF (150 mL) was added lithium borohydride (99.48 mL, 198.96 mmol) dropwise under N2 at 0°C. After being stirred at 20 °C for 15 hrs, the reaction was quenched by sat. NH4Cl aq. (600 mL) at 0 °C and the resultant mixture was extracted with EtOAc (100mL, three times). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to afford benzyl 4-[(5M)-5-[6- bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E6, 7 g, faster eluted) as a yellow solid. MS calc’d 675.3 (MH+), measured 675.2 (MH+). Step 7: Preparation of benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2- yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7) To a solution of benzyl 4-[(5M)-5-[6-bromo-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound E6, 7.0 g, 10.36 mmol) and bis(pinacolato)diboron (3.95 g, 15.54 mmol) in toluene (140 mL) was added KOAc (2.56 g, 26.05 mmol) and Pd(dppf)Cl2 (760.87 mg, 1.04 mmol). The mixture was degassed and purged with nitrogen for three times and stirred at 75 °C for 16 hrs. After being cooled to the room temperature, the reaction mixture was filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl- propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca- 2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 7.3 g) as a yellow solid. MS calc’d 723.4 (MH+), measured 723.4 (MH+). Step 8: Preparation of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4- benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2- dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2- (tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8) To a solution of benzyl 4-[(5M)-5-[3-(3-hydroxy-2,2-dimethyl-propyl)-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-2-yl]-6- [(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E7, 6.8 g, 9.41 mmol) and methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B, 4.9 g, 10.35 mmol) in toluene (90 mL) / 1,4-dioxane (30 mL) / water (30 mL) was added K3PO4 (5.0 g, 23.52 mmol) and Pd(dtbpf)Cl2 (613.2 mg, 0.94 mmol) in one portion. The mixture was degassed and purged with nitrogen for three times and then stirred at 70 °C for 15 hrs. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. The residue was purified by column chromatography to afford methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]-3- pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen- 6-yl]thiazol-2-yl]-2-(tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g) as a yellow solid. MS calc’d 993.7 (MH+), measured 993.7 (MH+). Step 9: Preparation of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1- yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9) To the mixture of methyl (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1- yl)-2-[(1S)-1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1- azatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (compound E8, 8.1 g, 8.16 mmol) in DCE (160 mL) was added trimethyltin hydroxide (5.9 g, 32.62 mmol) in one portion. After being stirred at 60 °C for 16 hrs, the reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under vacuum to afford (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)-1- methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca- 2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 7.9 g) as a brown solid. MS calc’d 979.5 (MH+), measured 979.5 (MH+). Step 10: Preparation of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)- 17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (compound E10) To a solution of (3S)-1-[(2S)-3-[4-[(2M)-2-[5-(4-benzyloxycarbonylpiperazin-1-yl)-2-[(1S)- 1-methoxyethyl]-3-pyridyl]-3-(3-hydroxy-2,2-dimethyl-propyl)-1-azatricyclo[6.3.1.04,12]dodeca- 2,4(12),5,7-tetraen-6-yl]thiazol-2-yl]-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylic acid (compound E9, 6.8 g, 6.94 mmol) in DCM (700 mL) was added DIEA (24.2 mL, 138.89 mmol), EDCI (19.9 g, 104.17 mmol) and HOBt (2.4 g, 17.36 mmol) at 0°C. After being stirred at 30 °C for 15 hrs, the reaction mixture was poured into water (500 mL), and extracted with EtOAc (300 mL, three times). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum to give a residue, which was purified by silica column to afford benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound E10, 5.6 g) as a yellow solid. MS calc’d 961.5 (MH+), measured 961.5 (MH+). Step 11: Preparation of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen- 7-yl]carbamate (compound E11) To a solution of benzyl 4-[(5M)-5-[(7S,13S)-7-(tert-butoxycarbonylamino)-17,17-dimethyl- 8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaen-20-yl]-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound E10, 5.6 g, 5.83 mmol) and formaldehyde (1.9 g, 23.3 mmol) in methanol (150 mL) was added Pd(OH)2 on activated carbon (3.0 g, 2.91 mmol) under nitrogen atmosphere. The reaction mixture was degassed and purged with H2 for three times and then it was stirred at 35 °C for 15 hrs under H2(15psi). After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give a residue. EtOAc (50 mL) and water (50 mL) were added into the residue and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL, twice). The combined organic layer was washed with brine (60 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum to give tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamate (compound E11, 3.9 g) as a yellow solid which was used in the next step without further purification. MS calc’d 841.5 (MH+), measured 841.4 (MH+). Step 12: Preparation of (7S,13S)-7-amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaene- 8,14-dione (Intermediate E) To a solution of tert-butyl N-[(7S,13S)-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4- methylpiperazin-1-yl)-3-pyridyl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31- tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta-1(28),2,5(31),19,25(29),26-hexaen-7- yl]carbamate (compound E11, 3.9 g, 4.6 mmol) in DCM (30 mL) was added TFA (15.0 mL) in one portion. After being stirred at 25°C for 1 h, the mixture was poured into water (100 mL) and extracted with EtOAc (200 mL). The organic phase was washed with water (50 mL, twice). The combined aqueous phase was basified with sat. NaHCO3 aq. until pH = 9 and extracted with EtOAc (100 mL, three times). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford (7S,13S)-7- amino-(20M)-20-[2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)-3-pyridyl]-17,17- dimethyl-15-oxa-4-thia-9,21,30,31-tetrazahexacyclo[23.3.1.12,5.19,13.019,27.021,26]hentriaconta- 1(28),2,5(31),19,25(29),26-hexaene-8,14-dione (Intermediate E, 2.95 g) as a yellow solid. MS calc’d 741.5 (MH+), measured 741.4 (MH+). Intermediate Y 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline The compound was prepared scheme: NIS To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline (compound Y1, 40.0 g, 188.6 mmol) in DMF (1.3 L) was added NIS (42.4 g, 188.6 mmol) portion-wise at 0 °C. After being stirred for 2 h at 25 °C, the reaction mixture was poured into water (4 L) and extracted with EtOAc (2 L, three times). The combined organic layer was washed with brine (2 L, three times), dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by reversed phase chromatography to give 6-bromo-8-iodo-1,2,3,4-tetrahydroquinoline (Intermediate Y, 37 g) as a brown gum. MS calc’d 337.9 (MH+), measured 338.0 (MH+). Intermediate Z Benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1-carboxylate The compound Z was prepared according to the following scheme: -3- pyridyl]piperazine-1-carboxylate (compound A5) To a solution of 3-bromo-5-iodo-2-[(1S)-1-methoxyethyl]pyridine (compound A3, 660 mg, 1.9 mmol, CAS 2641451-76-3, PBWZ170, PharmaBlock (Nanjing) R&D Co. Ltd) and 1-Cbz- piperazine (compound A4, 425.1 mg, 1.9 mmol) in toluene (10 mL) were added cesium carbonate (1.6 g, 4.83 mmol), (R)-BINAP (60.1 mg, 0.1 mmol) and palladium (II) acetate (43.3 mg, 0.19 mmol). After being stirred at 100 °C for 12 hrs under N2 protection, the mixture was filtered and then the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (EA / PE: 0-50%) to afford benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (compound A5, 740 mg) as a yellow solid. MS calc’d 434.1 (MH+), measured 434.1 (MH+). Step 2: Preparation of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound Z1) To a solution of benzyl 4-[5-bromo-6-[(1S)-1-methoxyethyl]-3-pyridyl]piperazine-1- carboxylate (compound A5, 33.0 g, 75.98 mmol) in DMF (1 L) was added trimethylsilylacetylene (85.9 mL, 607.83 mmol), Pd(PPh3)2Cl2(5.3 g, 7.6 mmol), CuI (1.5 g, 7.6 mmol) and TEA (52.9 mL, 379.9 mmol) under a nitrogen atmosphere. The reaction mixture was degassed and purged with nitrogen for three times and then it was stirred at 100 °C for 12 hrs. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered and the filtrate was added with H2O (3 L). The reaction mixture was extracted with EtOAc (1 L, three times). The combined organic layer was washed with brine (3 L), dried over Na2SO4, filtered and concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound Z1, 21.0 g) as a yellow solid. MS calc’d 452.2 (MH+), measured 452.2 (MH+). Step 3: Preparation of benzyl 4-[5-ethynyl-6-[(1S)-1-methoxyethyl]-3- pyridyl]piperazine-1-carboxylate (intermediate Z) To a solution of benzyl 4-[6-[(1S)-1-methoxyethyl]-5-(2-trimethylsilylethynyl)-3- pyridyl]piperazine-1-carboxylate (compound Z1, 31 g, 68.6 mmol) in Methanol (500 mL) was added potassium fluoride (8.1 g, 139.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was concentrated under vacuum to give a residue, which was purified by column chromatography to afford benzyl 4-[5-ethynyl-6-[(1S)-1- methoxyethyl]-3-pyridyl]piperazine-1-carboxylate (intermediate Z, 25 g) as a brown solid. MS calc’d 380.2 (MH+), measured 380.2 (MH+). Intermediate B Methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate The intermediate B was scheme:

[0004] Step 1: Preparation of (4-bromothiazol-2-yl)methanol (compound B2) To a solution of 4-bromothiazole-2-carboxaldehyde (compound B1 ̧ 6.0 g, 31.25 mmol)in methanol (70 mL) was added sodium borohydride (1.7 g, 46.87 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was quenched with water (300 mL) at 0 °C and the reaction mixture was extracted by ethyl acetate (200 mL, three times). The combined organic phase was washed with brine (150 mL, twice), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford (4-bromothiazol-2-yl)methanol (compound B2, 6g) as colorless oil. Step 2: Preparation of 4-bromo-2-(bromomethyl)thiazole (compound B3) To a solution of (4-bromothiazol-2-yl)methanol (compound B2, 6.0 g, 30.92 mmol) in DCM (80 mL) was added CBr4 (15.4 g, 46.38 mmol) and triphenylphosphine (12.1 g, 46.38 mmol) at 0 °C. After being stirred at 25 °C for 1 hour, the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether (0~10%) to afford 4-bromo-2-(bromomethyl)thiazole (compound B3, 6.0 g) as yellow oil. MS calc’d 255.9 (MH+), measured 255.9 (MH+). Step 3: Preparation of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl]methyl]thiazole (compound B5) To a mixture of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (compound B4, 4.3 g, 23.45 mmol) in THF (60 mL) was added n-butyllithium (10 mL, 25.22 mmol, 2.5 M) at -78 °C slowly. After addition, the mixture was stirred for 0.5 hour at -78 °C.4-bromo-2- (bromomethyl)thiazole (compound B3, 5.4 g, 21.02 mmol) was added into above mixture at - 78 °C which was stirred for another 1 hour. The reaction was quenched with saturated solution of NH4Cl (100 mL), and the reaction mixture was extracted with EtOAc (100 mL, twice). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by reversed- phase chromatography to afford 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl]methyl]thiazole (compound B5, 3.6 g) as yellow oil. MS calc’d 360 (MH+), measured 359.9 (MH+). Step 4: Preparation of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6) To a solution of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2- yl]methyl]thiazole (compound B5, 3.6 g, 10 mmol) in ACN (20 mL) was added hydrochloric acid (66.6 mL, 0.3 M). The mixture was stirred at 25 °C for 2 hours. The mixture was basified by saturated solution of NaHCO3 until pH=8. The mixture was extracted with EtOAc (80 mL, six times). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford methyl (2S)-2-amino-3-(4-bromothiazol-2- yl)propanoate (compound B6, 3.1 g) as yellow oil. MS calc’d 264.9 (MH+), measured 264.9 (MH+). Step 5: Preparation of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound B7) To a solution of methyl (2S)-2-amino-3-(4-bromothiazol-2-yl)propanoate (compound B6, 3.1 g, 11.69 mmol) in DCM (40 mL) were added TEA (2.9 g, 29.23 mmol) and (Boc)2O (3.8 g, 17.54 mmol). After being stirred at 30 °C for 12 hours, the mixture was concentrated under vacuum. The residue was purified by silica gel column, eluted with ethyl acetate in petroleum ether (0~30%) to afford methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound B7, 3.2 g) as yellow oil. MS calc’d 387(MNa+), measured 386.9 (MNa+). Step 6: Preparation of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)- propanoic acid (compound B8) To a solution of methyl (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoate (compound B7, 3.2 g, 8.76 mmol) in THF (30 mL), methanol (2 mL) and water (10 mL) was added lithium hydroxide (0.4 mL, 43.81 mmol). After being stirred at 25 °C for 1 hour, the reaction mixture was acidified by 1 M solution of HCl until pH=5. The mixture was extracted with EtOAc (40 mL, twice). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford (2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoic acid (compound B8, 3.1 g) as yellow oil. MS calc’d 373(MNa+), measured 372.9 (MNa+). Step 7: Preparation of methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2-(tert- butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (Intermediate B) To a solution of (2S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (compound B8, 3.1 g, 8.83 mmol) in DCM (50 mL) was added methyl (3S)- hexahydropyridazine-3-carboxylate;hydrochloride (compound B9, 2.4 g, 13.24 mmol), EDCI (3.4 g, 17.65 mmol), 1-Hydroxybenzotriazole (238.5 mg, 1.77 mmol) and NMM (9.92 mL, 88.26 mmol) at 0 °C. After being stirred at 25 °C for 1 hour, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL, three times). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column and eluted with ethyl acetate in petroleum ether (10~30%) to afford methyl (3S)-1-[(2S)-3-(4-bromothiazol-2-yl)-2- (tert-butoxycarbonylamino)propanoyl]hexahydropyridazine-3-carboxylate (intermediate B, 2.4 g). MS calc’d 477(MH+), measured 476.9 (MH+). Example 1: Form Amorphous Preparation of Form Amorphous of compound (I): A solution of 10 mg of compound (I) in any other free base forms in 1 mL mixture solvents of acetonitrile and water (50:50, v:v) was lyophilized to dryness. The solid was analyzed by XRPD. The result is shown in FIG.1. Characterization method: Bruker D8 Advance X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was 40 KV and tube current was 40 mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.02° at a scanning speed of 6° / min. Example 2: Form Amorphous Alternative preparation of Form Amorphous of compound (I): A solution of 10 mg of compound (I) in any other free base forms in 1 mL dichloromethane was rapidly evaporated using a rotary evaporator. The solid was dried at 30 °C for overnight. The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in FIG.1 and confirmed to be Form Amorphous of compound (I). Example 3: Form Amorphous Alternative preparation of Form Amorphous of compound (I): A solution of 10 mg of compound (I) in any other free base forms in 1 mL acetone was rapidly evaporated using a rotary evaporator. The solid was dried at 30 °C for overnight. The solid was analyzed by XRPD. The XRPD pattern of the solid was the same as that in FIG.1 and confirmed to be Form Amorphous of compound (I). Example 4: Form Amorphous Alternative preparation of Form Amorphous of compound (I): A solution of 10 mg of compound (I) in any other free base forms in 1 mL ethyl acetate was rapidly evaporated using a rotary evaporator. The solid was dried at 30 °C for overnight. The solid was analyzed by XRPD. The XRPD pattern of the solid was the same as that in FIG.1 and confirmed to be Form Amorphous of compound (I). Example 5: Mesylate salt Form C Preparation of Mesylate salt Form C of compound (I): A solution of 21.4 mg of Form Amorphous of compound (I) as prepared in Example 1 was prepared in 0.2 mL acetone. To the solution, another solution of 2.4 mg of methanesulfonic acid (1.05 eq.) in 0.2 mL acetone was added, and the mixture was stirred at room temperature for 2 days. The solid was dried at room temperature for overnight then further dried under vacuum for overnight. The solid was analyzed by XRPD. The XRPD pattern of Mesylate salt Form C of compound (I) is shown in FIG. 2. Major peaks and their related intensities in the XRPD pattern are shown in Table 1. Mesylate salt Form C was a hydrate, and the stoichiometry of compound (I) : methanesulfonic acid : water is 1:1:X (wherein 0<X≤2). The crystal structure information of Mesylate salt Form C was summarized in Table 2. The solvent used in the synthesis of Mesylate salt Form C was replaced with heptane, MTBE, mixture of acetone and heptane, mixture of acetone and MTBE, and mixture of acetone and water in other batches. Characterization method: Bruker D8 Advance X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was 40 KV and tube current was 40 mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.02° at a scanning speed of 6° / min. Table 1. X-ray powder diffraction peaks of Mesylate salt Form C of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 4.9 15 21.5 27 8.3 67 22.1 15 9.8 12 22.5 22 9.9 16 22.5 22 11.2 100 23.3 21 11.6 14 24.3 67 12.4 8 25.2 20 13.2 44 26.3 25 14.2 44 27.1 13 15.2 75 28.0 10 16.1 57 28.8 10 16.4 16 29.4 8 16.8 14 30.1 12 17.6 29 31.5 8 17.9 40 31.9 11 19.4 49 32.6 10 19.6 54 35.4 8 19.8 59 38.0 7 20.1 31 Table 2. Unit cell parameters of mesylate Salt Form C. Temperature, K 83 Space group P21 a, Å 15.8 b, Å 8.65 c, Å 18.1 α, ° 90 β, ° 103.4 γ, ° 90 V, Å32411.2 Example 6: Mesylate salt Form E Preparation of Mesylate salt Form E of compound (I): 20 mg of Mesylate salt Form C of compound (I) as prepared in Example 5 in 0.5 mL anhydrous acetone was stirred for 24 h at 50℃. The solid was dried at room temperature for overnight then further dried under vacuum for overnight. The solid was collected for XRPD analysis. The XRPD pattern of Mesylate salt Form E of compound (I) is shown in FIG.3. Major peaks and their related intensities in the XRPD pattern are shown in Table 3. Characterization method: Bruker D8 Advance X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was 40 KV and tube current was 40 mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.02° at a scanning speed of 6° / min. Table 3. X-ray powder diffraction peaks of Mesylate salt Form E of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 4.9 16 16.2 8 6.3 8 16.4 10 7.3 10 16.7 27 7.5 52 16.9 16 8.2 100 17.4 54 9.8 11 18.1 43 10.9 28 18.7 59 11.1 24 18.9 19 11.6 11 19.5 37 11.7 41 19.7 19 12.1 23 20.4 15 12.2 11 21.4 24 12.5 5 22.0 45 12.9 15 22.3 39 13.1 20 22.6 17 13.3 21 23.4 24 14.4 46 24.8 27 14.6 21 25.8 22 15.1 9 28.6 10 15.4 25 33.8 5 Example 7: Free Base Form H Preparation of Free Base Form H of compound (I): A suspension of 1 g of compound (I) was stirred in 5 mL mixture solvents of dioxane / cyclohexane (1:1 v / v), then the solid was collected and dried before re-slurry in THF / heptane until precipitation. The solid was then collected and dried again and stirred in mixture solvents of methanal / water (2:3 v / v). The slurry was stirred at room temperature for 3 days. The solid was dried under vacuum at 40 °C for overnight. The solid was collected for XRPD analysis and DVS analysis. The XRPD pattern of Free Base Form H of compound (I) is shown in FIG.5. Major peaks and their related intensities in the XRPD pattern are shown in Table 4. The DVS characterization result of Free Base Form H of compound (I) is shown in FIG. 6. Free Base Form H is a monohydrate of compound (I). Its crystal structure information was summarized in Table 5. Characterization method: Bruker D8 Advance X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was 40 KV and tube current was 40 mA. Scan range was from 3 to 40 degree 2-theta. The step size was 0.02° at a scanning speed of 6° / min. Table 4. X-ray powder diffraction peaks of Free Base Form H of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 4.0 100 19.3 46 6.3 7 19.9 5 8.1 13 20.3 11 8.7 9 20.8 8 11.6 6 21.5 5 12.1 27 22.2 8 13.0 14 22.7 11 13.8 20 23.7 7 14.3 5 24.7 12 15.0 10 25.4 7 16.2 23 26.1 4 16.8 7 27.5 5 17.2 23 27.8 5 17.6 27 29.6 4 17.8 34 35.7 5 18.9 13 Table 5. Unit cell parameters of free base Form H. Temperature, K 83 Space group P21 a, Å 14.4 b, Å 7.1 c, Å 22.1 α, ° 90 β, ° 104.8 γ, ° 90 V, Å32186 Example 8: Free Base Form A Preparation of Free Base Form A of compound (I): A solution of 100 mg of compound (I) in free base amorphous or any other free base forms was prepared in 0.5 mL tetrahydrofuran. The solution was then evaporated at room temperature. The resulting solid was analyzed by XRPD. The XRPD pattern of Free Base Form A of compound (I) is shown in FIG. 4. Major peaks and their related intensities in the XRPD pattern are shown in Table 6. Free Base Form A is a solvate hydrate that can be formed with different types of solvates, such as dioxane, heptane, acetone, cyclohexane, and water, etc. One example of its crystal structure is summarized in Table 7, which is a solvate hydrate containing solvent molecules of heptane, acetone and water. Table 6. X-ray powder diffraction peaks of Free Base Form A of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 4.6 100 17.7 15 6.0 68 18.1 16 6.1 70 18.6 20 6.9 27 19.4 22 8.1 53 20.0 16 9.0 34 20.8 25 10.1 22 21.6 15 11.3 19 21.9 15 12.2 24 22.2 13 12.9 25 23.0 15 14.0 16 24.8 11 14.6 19 25.3 9 16.22 20 26.2 7 16.9 22 29.0 6 17.1 23 29.5 6 Table 7. Unit cell parameters of an example of free base Form A. Temperature, K 83 Space group P62 a, Å 36.4 b, Å 36.4 c, Å 22.3 α, ° 90 β, ° 90 γ, ° 120 V, Å325638 Example 9: Besylate Salt Form I Preparation of Besylate Salt Form I of compound (I): A solution of 33.5 mg of compound (I) in free base amorphous or any other free base forms and 7.0 mg benzenesulfonic acid was prepared in 1.0 mL acetone. The solution was stirred at room temperature for 2 days. The resulting solid was collected and dried under vacuum at room temperature for overnight. The solid was collected for XRPD analysis and DVS analysis. The XRPD pattern of Besylate Salt Form H of compound (I) is shown in FIG. 7. Major peaks and their related intensities in the XRPD pattern are shown in Table 8. Table 8. X-ray powder diffraction peaks of Besylate Salt Form I of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 5.9 31 18.5 21 10.8 24 19.9 50 12.4 48 20.5 26 13.7 23 21.1 27 16.2 46 21.8 32 16.5 100 23.7 25 Example 10: Besylate Salt Form F Preparation of Besylate Salt Form F of compound (I): A solution of 33.3 mg of compound (I) in free base amorphous or any other free base forms and 7.3 mg benzenesulfonic acid was prepared in 1.0 mL acetonitrile and was stirred at room temperature for 2 days. The resulting solid was collected and dried under vacuum at room temperature for overnight, then heated to 170 °C and cooled to room temperature for XRPD analysis and DVS analysis. The XRPD pattern of Besylate Salt Form F of compound (I) is shown in FIG. 9. Major peaks and their related intensities in the XRPD pattern are shown in Table 9. Table 9. X-ray powder diffraction peaks of Besylate Salt Form F of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 7.7 100 15.6 36 10.1 13 16.0 16 10.9 40 16.4 15 11.5 14 17.8 13 12.7 44 19.7 20 13.5 13 25.7 10 13.8 12 Example 11: Tosylate Salt Form C Preparation of Tosylate Salt Form C of compound (I): A solution of 33.3 mg of compound (I) in free base amorphous or any other free base forms and 7.3 mg p-toluenesulfonic acid was prepared in 1.0 mL acetonitrile and was stirred at room temperature for 2 days. The resulting solid was collected and dried under vacuum at room temperature for overnight, then heated to 170 °C and cooled to room temperature for XRPD analysis and DVS analysis. The XRPD pattern of Tosylate Salt Form C of compound (I) is shown in FIG. 11. Major peaks and their related intensities in the XRPD pattern are shown in Table 10. Table 10. X-ray powder diffraction peaks of Tosylate Salt Form C of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 4.3 29 15.0 51 7.1 26 15.9 32 8.7 60 16.6 24 11.4 33 19.7 35 12.0 81 21.6 32 13.1 100 24.5 24 14.4 45 25.2 23 Example 12: Tosylate Salt Form A Preparation of Tosylate Salt Form A of compound (I): A solution of 33.7 mg of compound (I) in free base amorphous or any other free base forms and 8.4 mg p-toluenesulfonic acid was prepared in 1.0 mL t-butanol and was stirred at room temperature for 2 days. The resulting solid was collected and dried under vacuum at room temperature then used for XRPD analysis and DVS analysis. The XRPD pattern of Tosylate Salt Form A of compound (I) is shown in FIG. 13. Major peaks and their related intensities in the XRPD pattern are shown in Table 11. Table 11. X-ray powder diffraction peaks of Tosylate Salt Form A of compound (I) Pos. [°2-theta] Rel. Int. [%] Pos. [°2-theta] Rel. Int. [%] 4.6 42 13.2 26 5.0 100 14.3 31 5.6 18 16.3 14 7.8 22 17.2 22 9.2 19 18.3 13 9.6 14 19.5 31 12.4 28 Example 13: hygroscopicity analysis of the forms Experimental protocols: DVS analysis was carried out using a Surface Measurement System DVS Intrinsic Plus analyzer (SMS, UK). The instrument balance was calibrated with standard weights. Approximately 10-40 mg of sample was loaded into a pan for analysis. The sample was analyzed at 25 °C from 60% to 0% RH (desorption cycle), 0% to 90% RH (sorption cycle), 90% to 0% RH (desorption cycle), 0% to 90% RH (sorption cycle), 90% to 0% RH (desorption cycle) and 0% to 60% RH (adsorption cycle), at 10% relative humidity (RH) steps. The equilibrium criterion at each step was 0.002% weight change (dm / dt) with a maximum hold of 180 min if the equilibrium criterion was not met. The solid form of the resulting sample after DVS runs was characterized using XRPD. Results: The table below summarizes hygroscopicity of some solid forms of Compound (I) by listing the corresponding weight gain from 0% to 90% RH based on DVS data and the solid form change after DVS measurements. Table 12. Hygroscopicity of solid forms of Compound (I) Solid form Weight gain from 0% to 90% RH Resulting solid form Free Base Amorphous 8-10% No form change Free Base Form H 2-3% No form change Mesylate salt Form C 4-5% No form change Mesylate salt Form E 12-14% No form change Besylate salt Form I 6-7% No form change Besylate salt Form F 12-13% No form change Tosylate salt Form C 8-9% No form change Tosylate salt Form A 18-22% No form change Individual characterization: Free Base Amorphous of compound (I) presents 8-10% weight gain from 0 to 90% RH. Its DVS characterization is shown in FIG.1a. Mesylate Salt Form C of compound (I) presents 4-5% weight gain from 0 to 90% RH. Its DVS characterization is shown in FIG.2a. Mesylate Salt Form E of compound (I) presents 12-14% weight gain from 0 to 90% RH. Its DVS characterization is shown in FIG.3a. Free Base Form H of compound (I) presents 2-3% weight gain from 0 to 90% RH. The DVS characterization result of Free Base Form H of compound (I) is shown in FIG.6. Besylate Salt Form I of compound (I) presents 6-7% weight gain from 0 to 90% RH. The DVS characterization result of Besylate Salt Form H of compound (I) is shown in FIG.8. Besylate Salt Form F of compound (I) presents 12-13% weight gain from 0 to 90% RH. The DVS characterization result of Besylate Salt Form F of compound (I) is shown in FIG.10. Tosylate Salt Form C of compound (I) presents 8-9% weight gain from 0 to 90% RH. The DVS characterization result of Tosylate Salt Form C of compound (I) is shown in FIG.12. Tosylate Salt Form A of compound (I) presents 18-22% weight gain from 0 to 90% RH. The DVS characterization result of Tosylate Salt Form A of compound (I) is shown in FIG.14. Conclusion: Hygroscopicity is the tendency of a solid substance to uptake moisture from the surrounding environment. It is an essential property of a pharmaceutical solid because water content can impact stability and manufacturability of a solid. Generally speaking, solid forms that have low and consistent weight gain are preferred. For free base forms of Compound (I), free base Form H was preferred over free base amorphous; for mesylate salt form of Compound (I), mesylate salt Form C was preferred over mesylate salt Form E; for besylate salt forms of Compound (I), besylate salt Form I is preferred over besylate salt Form F; for tosylate salt forms of Compound (I), tosylate salt Form C is preferred over tosylate salt Form A. These superior forms are less hygroscopic, and have relatively consistent weight gain at given relative humidity levels. The low and consistent water uptake is expected to reduce analytical variations in water content and assay results, and as a result, lead to accurate API dispensing during drug product manufacture.

Claims

1. CLAIMS 1. A solid form of compound (I), (I), or salt, solvate orForm Amorphous, Mesylate salt Form C, Besylate Salt Form I, Tosylate Salt Form C or Free Base Form H.

2. A solid form according to claim 1, wherein the solid form is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 8.3°±0.2°, 11.2°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 19.6°±0.2°, 19.8°±0.2° and 24.3°±0.2°.

3. A solid form according to claim 2, wherein the solid form is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 13.2°±0.2°, 14.2°±0.2°, 17.9°±0.2°, 19.4°±0.2° and 20.1°±0.2°.

4. A solid form according to claim 2 or 3, wherein the solid form is Mesylate salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.

1.

5. A solid form according to claim 1, wherein the solid form is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 5.9°±0.2°, 12.4°±0.2°, 16.2°±0.2°, 16.5°±0.2°, 19.9°±0.2° and 21.8°±0.2°.

6. A solid form according to claim 5, wherein the solid form is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 21.1°±0.2°, 20.5°±0.2°, 23.7°±0.2°, 10.8°±0.2°, 13.7°±0.2° and 18.5°±0.2°.

7. A solid form according to claim 5 or 6, wherein the solid form is Besylate Salt Form I that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.

7.

8. A solid form according to claim 1, wherein the solid form is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 8.7°±0.2°, 12.0°±0.2°, 13.1°±0.2°, 14.4°±0.2°, 15°±0.2° and 19.7°±0.2°.

9. A solid form according to claim 5, wherein the solid form is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 4.3°±0.2°, 7.1°±0.2°, 11.4°±0.2°, 15.9°±0.2°, 16.6°±0.2° and 21.6°±0.2°.

10. A solid form according to claim 5 or 6, wherein the solid form is Tosylate Salt Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.

11.

11. A solid form according to claim 1, wherein the solid form is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern comprising 3 or more characteristic peaks expressed in degrees 2-theta selected from 4.0°±0.2°, 12.1°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 17.8°±0.2° and 19.3°±0.2°.

12. A solid form according to claim 11, wherein the solid form is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern with one or more additional characteristic peaks expressed in degrees 2-theta selected from 8.1°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 17.2°±0.2°, 18.9°±0.2° and 24.7°±0.2°13. A solid form according to claim 11 or 12, wherein the solid form is Free Base Form H that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.

5.

14. A process for the preparation of the Form Amorphous of compound (I) according to claim 1, comprising: (a) compound (I) in any other free base forms was dissolved in a mixture solvent of acetonitrile and water; (b) solid was collected after the above solution was lyophilized.

15. A process for the preparation of the Form Amorphous of compound (I) according to claim 1, comprising: (a) compound (I) in any other free base forms was dissolved in dichloromethane; (b) solid was collected after the above solution was concentrated using a rotary evaporator.

16. A process for the preparation of the Form Amorphous of compound (I) according to claim 1, comprising: (a) compound (I) in any other free base forms was dissolved in acetone; (b) solid was collected after the above solution was concentrated using a rotary evaporator.

17. A process for the preparation of the Form Amorphous of compound (I) according to claim 1, comprising: (a) compound (I) in any other free base forms was dissolved in ethyl acetate; (b) solid was collected after the above solution was concentrated using a rotary evaporator.

18. A process for the preparation of the Mesylate salt Form C of compound (I) according to any one of claims 1 to 4, comprising: (a) compound (I) was dissolved in acetone, or heptane, or MTBE, or a mixture solvent thereof; (b) methanesulfonic acid in acetone, or heptane, or MTBE, or a mixture solvent thereof was added; (c) solid was collected after drying.

19. A process for the preparation of the Mesylate salt Form E of compound (I) according to any one of claims 5 to 7, comprising: (a) a solution of compound (I) in Mesylate salt Form C was prepared in acetone, and stirred at 50℃; (b) solid was collected after drying.

20. A process for the preparation of the Besylate Salt Form I of compound (I) according to any one of claims 5 to 7, comprising: (a) a solution of compound (I) and benzenesulfonic acid was prepared in acetone, and stirred at room temperature; (b) solid was collected after drying.

21. A process for the preparation of the Tosylate Salt Form C of compound (I) according to any one of claims 8 to 10, comprising: (a) a solution of compound (I) and p-toluenesulfonic acid was prepared in acetone, and stirred at room temperature; (b) solid was collected after drying.

22. A process for the preparation of the Free Base Form H of compound (I) according to any one of claims 11 to 13, comprising: (a) compound (I) was suspended in a mixture solvent of dioxane / cyclohexane; (b) solid was collected and dried; (c) dried solid was treated with THF / heptane to form a slurry, which was stirred at room temperature for 3 days; (d) the solid was dried under vacuum at 40 °C for overnight.

23. A pharmaceutical composition comprising the crystalline form of any one of the claims 1 to 7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

24. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for the manufacture of a medicament for treating a KRAS G12C protein-related disease.

25. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for treating a KRAS G12C, G12D and G12V protein-related disease.

26. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for inhibiting RAS interaction with downstream effectors, wherein the downstream effectors are RAF and PI3K.

27. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for inhibiting the propagating oncogenic MAPK and PI3K signaling.

28. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for the treatment or prophylaxis of cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

29. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for the preparation of a medicament for the treatment or prophylaxis of cancers in a subject in need thereof, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of V8A, V9Y, S17E, A59T, T58I, D69P, M72I, S65W, R68S, D92R, H95N, Y96D, Q99W and F156L.

30. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for the treatment or prophylaxis of KRAS mutation driven cancers, wherein the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, melanoma ovarian cancer and endometrial cancer.

31. The use according to claim 29, wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer.

32. The use of the solid form of any one of claims 1 to 13, or the pharmaceutical composition of claim 23 for the treatment or prophylaxis of primary central nervous system (CNS) tumors harboring RAS mutations or RAS driven cancers with brain metastases; wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is selected from pancreatic adenocarcinoma, colorectal cancer, non-small cell lung cancer.

33. The use according to claim 31; wherein the CNS tumor is primary melanocytic tumors of the CNS harboring NRAS mutation; wherein the cancer is non-small cell lung cancer.

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