[go: up one dir, main page]

WO2022199669A1 - 稠合吡啶酮类化合物盐型、晶型及其应用 - Google Patents

稠合吡啶酮类化合物盐型、晶型及其应用 Download PDF

Info

Publication number
WO2022199669A1
WO2022199669A1 PCT/CN2022/082855 CN2022082855W WO2022199669A1 WO 2022199669 A1 WO2022199669 A1 WO 2022199669A1 CN 2022082855 W CN2022082855 W CN 2022082855W WO 2022199669 A1 WO2022199669 A1 WO 2022199669A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
ray powder
powder diffraction
diffraction pattern
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/082855
Other languages
English (en)
French (fr)
Inventor
张勇
李雪健
曹程
吴迎春
程宏明
彭建彪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
Original Assignee
Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangxi Jemincare Group Co Ltd, Shanghai Jemincare Pharmaceuticals Co Ltd filed Critical Jiangxi Jemincare Group Co Ltd
Priority to CN202280020397.3A priority Critical patent/CN116964056A/zh
Publication of WO2022199669A1 publication Critical patent/WO2022199669A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • the present invention relates to the salt form, crystal form and pharmaceutical composition of the compound represented by formula (I), and its application as a KRAS inhibitor.
  • Cancer has been ranked first among the top ten causes of death in China for 31 consecutive years, among which lung cancer is one of the tumors with the highest incidence, and non-small cell lung cancer accounts for more than 80%.
  • lung cancer is one of the tumors with the highest incidence
  • non-small cell lung cancer accounts for more than 80%.
  • the research and development of innovative drugs for cancer treatment is very necessary for the company's long-term development, and has important economic and social significance.
  • pancreatic, colorectal, and lung The three cancers with the highest mortality rates in the United States (pancreatic, colorectal, and lung) also happen to be the three cancers with the most common RAS mutations, accounting for 95%, 52%, and 31%, respectively, of patients with these three cancers.
  • KRAS mutations account for the absolute majority, while NRAS mutations are more common in melanoma and acute myeloid leukemia, and HRAS mutations are more common in bladder cancer and head and neck cancer.
  • KRAS-mutant tumors are the most potentially targeted molecular subtype of non-small cell lung cancer (NSCLC), with a mutation rate of approximately 15%-25% in non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • KRAS mutations mainly occur at codons 12 and 13.
  • KRAS small molecule drugs including 10 KRAS GTPase inhibitors, 4 KRAS gene inhibitors, 2 KRAS GTPase regulators and 2 KRAS gene regulators; there is 1 such drug currently under clinical research.
  • Android Health the first KRAS inhibitor developed by a Taiwanese company, has entered the US FDA Phase II clinical trial, and AstraZeneca's inhibitor of KRAS downstream MEK, selumetinib, is also undergoing Phase II clinical trials. KRAS mutation is the most important tumor driver gene.
  • the present invention provides the sulfate salt of the compound represented by formula (I)
  • the above-mentioned sulfate salt contains sulfuric acid in an amount of 0.5 to 3.0 molar equivalents relative to compound (I).
  • the above-mentioned sulfate salt contains sulfuric acid in an amount of 0.5 to 2.5 molar equivalents relative to compound (I).
  • the above-mentioned sulfate contains 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.7, 2.9 or 3.0 molar equivalents of sulfuric acid.
  • the present invention provides the crystalline form A of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 16.80 ⁇ 0.2°, 17.75 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 13.54 ⁇ 0.2 °, 16.80 ⁇ 0.2°, 17.75 ⁇ 0.2°, 19.09 ⁇ 0.2°, 20.91 ⁇ 0.2°, 21.71 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the above-mentioned crystal form A contains 0.5-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A contains 1.0-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A contains 1.0-1.1 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I). These crystal forms A with different molar equivalents have the same characteristic peaks, for example, as shown in Figures 13-16.
  • the above crystal form A contains 1.024, 1.063, 1.075, 1.082, 1.087 or 1.108 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 5%-15%. In some embodiments of the present invention, the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 5.87%-13.23%.
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 6.6%-10.4%.
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 6.6%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4% or 10.5%.
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 6.6%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10.2%, 10.3%, 10.4% or 10.5%, these crystal forms A with different moisture contents have the same characteristic peaks, as shown in Figures 1 and 12.
  • the above-mentioned common characteristic peaks are selected from diffraction angles (2 ⁇ ): 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 16.80 ⁇ 0.2°, 17.75 ⁇ 0.2° at least 3 peaks in .
  • the above-mentioned common characteristic peaks are selected from diffraction angles (2 ⁇ ): 7.17 ⁇ 0.2°, 11.93 ⁇ 0.2°, 12.34 ⁇ 0.2°, 12.99 ⁇ 0.2°, 13.54 ⁇ 0.2°, 16.80 ⁇ 0.2° , at least 3 peaks in 17.75 ⁇ 0.2°, 19.09 ⁇ 0.2°, 20.91 ⁇ 0.2°, 21.71 ⁇ 0.2°.
  • the present invention provides the crystalline form B of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.67 ⁇ 0.2°, 8.78 ⁇ 0.2°, 10.28 ⁇ 0.2°, 11.02 ⁇ 0.2°, 12.19 ⁇ 0.2°, 15.51 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 5.67 ⁇ 0.2°, 8.78 ⁇ 0.2°, 10.28 ⁇ 0.2°, 11.02 ⁇ 0.2°, 12.19 ⁇ 0.2 °, 12.60 ⁇ 0.2°, 13.14 ⁇ 0.2°, 15.51 ⁇ 0.2°, 15.99 ⁇ 0.2°, 19.56 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 2 .
  • the above-mentioned crystal form B contains 0.8-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form B contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I).
  • the present invention provides the crystalline form C of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 5.51 ⁇ 0.2°, 7.71 ⁇ 0.2°, 11.90 ⁇ 0.2°, 13.67 ⁇ 0.2°, 15.69 ⁇ 0.2°, 20.15 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
  • the above-mentioned crystal form C contains 2.0-3.0 molar equivalents of sulfuric acid relative to compound (I).
  • the above crystal form C contains 2.3, 2.4, 2.5, 2.6 or 2.7 molar equivalents of sulfuric acid relative to compound (I).
  • the above crystal form C is tetrahydrofuran and ethyl acetate solvate
  • the content of tetrahydrofuran in the tetrahydrofuran and ethyl acetate solvate is 0-10wt%
  • the content of ethyl acetate is 0-12wt% %.
  • crystal form C can be a single solvate of ethyl acetate, that is, when the content of tetrahydrofuran is 0wt%; or crystal form C can be a single solvate of tetrahydrofuran, that is, when the content of ethyl acetate is 0wt%; Or the crystal form C is a mixed solvate of tetrahydrofuran and ethyl acetate, that is, the content of tetrahydrofuran and ethyl acetate is not 0 wt%.
  • the above crystal form C is tetrahydrofuran and ethyl acetate solvate
  • the content of tetrahydrofuran in the tetrahydrofuran and ethyl acetate solvate is 4.1wt%, 4.2wt%, 4.3wt%, 4.4wt% %, 4.5wt%, 4.6wt%, 4.7wt%, 4.8wt%, 4.9wt%, 5.0wt%, 5.1wt%, 5.2wt%, 5.3wt%, 5.4wt%, 5.5wt%, 5.6wt%, 5.7wt%, 5.8wt%, 5.9wt%, 6.0wt%
  • the content of ethyl acetate is 0.1wt%.
  • the present invention provides the crystalline form D of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 6.85 ⁇ 0.2°, 10.29 ⁇ 0.2°, 12.78 ⁇ 0.2°, 16.36 ⁇ 0.2°, 19.84 ⁇ 0.2°, 20.66 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form D are shown in Table 4 below.
  • the above-mentioned crystal form D contains 0.2-0.8 molar equivalent of sulfuric acid relative to compound (I).
  • the above crystal form D contains 0.3, 0.4, 0.5 or 0.6 molar equivalent of sulfuric acid relative to compound (I).
  • the present invention provides the crystalline form E of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 5.52 ⁇ 0.2°, 8.93 ⁇ 0.2°, 11.04 ⁇ 0.2°, 12.16 ⁇ 0.2°, 12.82 ⁇ 0.2°, 22.67 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 5.52 ⁇ 0.2°, 8.52 ⁇ 0.2°, 8.93 ⁇ 0.2°, 11.04 ⁇ 0.2°, 12.16 ⁇ 0.2 °, 12.82 ⁇ 0.2°, 14.63 ⁇ 0.2°, 15.34 ⁇ 0.2°, 16.88 ⁇ 0.2°, 22.67 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form E are shown in Table 5 below.
  • the above-mentioned crystal form E contains 0.8-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystalline form E contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form E is an ethanol solvate, and the content of ethanol in the ethanol solvate is 5%-22%.
  • the above-mentioned crystal form E is an ethanol solvate, and the content of ethanol in the ethanol solvate is 17%, 18%, 19%, 20%, 21% or 22%.
  • the present invention provides the crystalline form F of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 5.40 ⁇ 0.2°, 13.01 ⁇ 0.2°, 18.09 ⁇ 0.2°, 21.65 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form F has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form F are shown in Table 6 below.
  • the above-mentioned crystal form F contains 1.0-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form F contains 1.1, 1.2, 1.3 or 1.4 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form F is methyl isobutyl ketone and dimethyl sulfoxide solvate, and methyl isobutyl ketone and dimethyl sulfoxide solvate are among the methyl isobutyl ketone and dimethyl sulfoxide solvate.
  • the content of the base ketone is 0-12 wt %, and the content of dimethyl sulfoxide is 0-17 wt %.
  • the crystal form F can be a single solvate of methyl isobutyl ketone, that is, when the content of dimethyl sulfoxide is 0 wt%; or the crystal form F can be a single solvate of dimethyl sulfoxide, That is, when the content of methyl isobutyl ketone is 0wt%; or crystal form F is a mixed solvate of methyl isobutyl ketone and dimethyl sulfoxide, that is, the mixture of methyl isobutyl ketone and dimethyl sulfoxide. The content is not 0 wt%.
  • the above-mentioned crystal form F is methyl isobutyl ketone and dimethyl sulfoxide solvate
  • methyl isobutyl ketone and dimethyl sulfoxide solvate are among the methyl isobutyl ketone and dimethyl sulfoxide solvate.
  • the content of the base ketone is 0.5wt%, 0.6wt%, 0.7wt%, 0.8wt%, 0.9wt%, 1.0wt%, 1.1wt%, 1.2wt%, 1.3wt%, 1.4wt% or 1.5wt%, two
  • the content of methyl sulfoxide is 14.0wt%, 14.1wt%, 14.2wt%, 14.3wt%, 14.4wt%, 14.5wt%, 14.6wt%, 14.7wt%, 14.8wt%, 14.9wt% or 15.0wt% .
  • the present invention provides the crystalline form G of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 5.88 ⁇ 0.2°, 7.05 ⁇ 0.2°, 9.39 ⁇ 0.2°, 10.87 ⁇ 0.2°, 12.00 ⁇ 0.2°, 16.15 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form G are shown in Table 7 below.
  • the present invention provides the crystalline form H of the sulfate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 6.11 ⁇ 0.2°, 11.59 ⁇ 0.2°, 12.19 ⁇ 0.2°, 15.66 ⁇ 0.2°, 18.34 ⁇ 0.2°, 13.82 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 8 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form H are shown in Table 8 below.
  • the above crystal form H contains 0.5-1.5 molar equivalent of sulfuric acid relative to compound (I).
  • the above crystal form H contains 0.9, 1.0, 1.1 or 1.2 molar equivalents of sulfuric acid relative to compound (I).
  • the above-mentioned crystal form H is an anhydrous crystal form.
  • the present invention provides a benzenesulfonate salt of a compound represented by formula (I).
  • the above-mentioned benzenesulfonic acid salt contains 0.5-3.0 molar equivalent of benzenesulfonic acid relative to compound (I).
  • the above-mentioned benzenesulfonic acid salt contains 1.0-2.5 molar equivalents of benzenesulfonic acid relative to compound (I).
  • the above-mentioned benzenesulfonate contains 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.7, 2.9 or 3.0 molar equivalents of benzenesulfonic acid.
  • the present invention provides the crystal form I of the benzenesulfonate salt of the compound represented by formula (I).
  • the X-ray powder diffraction pattern of the crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 7.63 ⁇ 0.2°, 12.05 ⁇ 0.2°, 13.78 ⁇ 0.2°, 15.09 ⁇ 0.2°, 16.04 ⁇ 0.2°, 18.35 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the above-mentioned crystal form I has characteristic diffraction peaks at the following 2 ⁇ angles: 7.63 ⁇ 0.2°, 11.35 ⁇ 0.2°, 12.05 ⁇ 0.2°, 13.78 ⁇ 0.2°, 15.09 ⁇ 0.2 °, 16.04 ⁇ 0.2°, 16.65 ⁇ 0.2°, 18.35 ⁇ 0.2°, 18.87 ⁇ 0.2°, 23.53 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form I are shown in Table 9 below.
  • the above-mentioned crystal form I contains 1.5-2.5 molar equivalents of benzenesulfonic acid relative to compound (I).
  • the above-mentioned Form I contains 1.6, 1.7, 1.8, 1.9, 2.0 or 2.1 molar equivalents of sulfuric acid relative to compound (I).
  • the present invention also provides a pharmaceutical composition
  • the pharmaceutical composition contains the sulfate salt of the compound represented by the formula (I) and the benzenesulfonic acid of the compound represented by the formula (I) as described above Salt or crystal forms A to I.
  • the present invention also proposes the sulfate salt of the compound represented by the formula (I), the benzenesulfonate salt of the compound represented by the formula (I), or the crystal forms A to I or the aforementioned compound represented by the formula (I).
  • the above-mentioned KRAS-G12C-related diseases are selected from non-small cell lung cancer, colon cancer and pancreatic cancer.
  • Crystalline refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts. Crystalline forms of materials can be obtained by a number of methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, Crystallization, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding in the presence of additives such as co-crystallizing anti-molecules, among others.
  • Amorphous or “amorphous form” refers to a substance formed when its particles (molecules, atoms, ions) are arranged aperiodically in three-dimensional space, characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural features suggest that it is inextricably linked with crystalline matter. Amorphous forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol , ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran
  • Antisolvent refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent.
  • the antisolvent may comprise a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
  • Solidvate means that the crystal has a solvent on the surface, or in the lattice, or both on the surface and in the lattice, wherein the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloride Carbon, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N- Dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene and mixtures thereof and
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, or in the lattice, or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, or in the lattice, or both on the surface and in the lattice.
  • Crystalline or amorphous form can be identified by various techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • dissolution calorimetry dissolution calorimetry
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect the change of crystal form, crystallinity, crystal structure and other information, and is a common method to identify crystal form.
  • the peak positions of the XRPD patterns depend primarily on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention.
  • DSC Differential Scanning Calorimetry
  • an inert reference commonly ⁇ -Al 2 O 3
  • the melting peak heights of DSC curves depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by DSC patterns having characteristic peak positions substantially as shown in the DSC patterns provided in the accompanying drawings of the present invention.
  • the DSC spectrum may have experimental errors, and the peak positions and peaks of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the apparatus used in the experiments of the present invention, there is an error tolerance of ⁇ 3°C for the melting peak.
  • the glass transition refers to the transition of an amorphous substance between a highly elastic state and a glass state, which is an inherent property of the substance; its corresponding transition temperature is the glass transition temperature (Tg), which is an important part of the amorphous substance. physical properties. Glass transition is a phenomenon related to molecular motion, therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance, and is relatively insensitive to experimental details and the like.
  • the amorphous glass transition temperature (Tg) of the present invention is determined by differential scanning calorimetry (DSC) and is characterized by having a glass transition temperature of 107.44°C. Depending on the condition of the instrumentation used in the experiments of the present invention, there is a tolerance of ⁇ 3°C for the glass transition temperature.
  • DSC Differential scanning calorimetry
  • Crystal transformation Due to the transformation of the crystal form, the mechanical, electrical, magnetic and other properties of the crystal will undergo great changes.
  • DSC differential scanning calorimetry
  • the transformation process can be observed on a differential scanning calorimetry (DSC) pattern, which is characterized in that the DSC pattern has an exothermic peak reflecting the transformation process, and There are two or more endothermic peaks at the same time, which are the characteristic endothermic peaks of different crystal forms before and after transformation.
  • DSC differential scanning calorimetry
  • Thermogravimetric analysis is a technique for measuring the change of the mass of a substance with temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains water of crystallization or crystallization solvent. Case.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and between different samples.
  • the calcium salt crystal form A of the present invention loses about 5.1% in weight at a temperature of about 150°C. There is an error tolerance of ⁇ 0.3% for mass variation depending on the condition of the instrumentation used for the experiments of the present invention.
  • the 2 ⁇ values in an X-ray powder diffraction pattern are all in degrees (°).
  • the content unit “wt%” and the content unit “%” can be used interchangeably, and refer to the mass ratio (g/g), for example, in the hydrate, the moisture content of the crystal form A is 10.02%, which is It means that the ratio (g/g) of the mass of water in the crystal form A to the mass of the crystal form A is 10.02; for another example, in the solvate, the content of tetrahydrofuran in the crystal form C is 5.1wt%, which means that the crystal form The ratio (g/g) of the mass of tetrahydrofuran in Form C to the mass of the crystal form C (g/g) was 5.1.
  • a peak refers to a feature that would be recognized by those skilled in the art that would not be attributed to background noise.
  • substantially pure means that a crystalline form is substantially free of one or more other crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85% pure, or at least 90% pure, or at least 93% pure, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, said The percentage of other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • Relative intensity refers to the ratio of the intensity of the other peaks to the intensity of the first intense peak when the intensity of the first intense peak is 100% among all diffraction peaks in an X-ray powder diffraction pattern (XRPD).
  • Fig. 1 is the X-ray powder diffraction (XRPD) pattern of crystal form A;
  • Fig. 2 is the X-ray powder diffraction (XRPD) pattern of crystal form B;
  • Fig. 3 is the X-ray powder diffraction (XRPD) pattern of crystal form C;
  • Fig. 4 is the X-ray powder diffraction (XRPD) pattern of crystal form D;
  • Fig. 5 is the X-ray powder diffraction (XRPD) pattern of crystal form E;
  • Fig. 7 is the X-ray powder diffraction (XRPD) pattern of crystal form G;
  • Figure 10 is a graph showing the relationship between the days of NCI-H358 cell inoculation and body weight change after administration of the compound of formula (I);
  • Figure 11 is a graph showing the relationship between the days of inoculation of NCI-H358 cells and tumor volume after administration of the compound of formula (I);
  • Figure 12 is the X-ray powder diffraction (XRPD) pattern of crystal form A with different water contents
  • Figure 13 is an X-ray powder diffraction (XRPD) pattern of sample X-1;
  • Figure 14 is the X-ray powder diffraction (XRPD) pattern of sample X-2;
  • Figure 15 is the X-ray powder diffraction (XRPD) pattern of sample X-3;
  • Figure 16 is an X-ray powder diffraction (XRPD) pattern of sample X-4.
  • the XRPD patterns were acquired on an X-ray powder diffraction analyzer produced by PANalytacal, and the scan parameters are shown in Table 10 below.
  • TGA and DSC graphs were collected on a TA Q5000/Discovery 5500 thermogravimetric analyzer and a TA Q2000/Discovery 2500 differential scanning calorimeter, respectively, and the test parameters are listed in Table 11.
  • Dynamic moisture sorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg( NO3 ) 2 and KCl. DVS test parameters are listed in Table 12.
  • the liquid nuclear magnetic spectrum of the present invention is collected on a Bruker 400M nuclear magnetic resonance apparatus, and DMSO-d 6 is used as a solvent.
  • the PLM image of the present invention was photographed by an Olympus SZX7 stereo microscope.
  • the dissociation constant of the compound of the present invention is obtained by the Sirius pKa log P/D tester (model: T3Dt).
  • the purity test, dynamic solubility and stability test are tested by Agilent 1260 high performance liquid chromatograph, and the salt molar ratio test of ions is tested by ion chromatography.
  • the analysis conditions are shown in Table 13 and Table 14.
  • Moisture test method (KF method): the present invention adopts the volumetric method to measure the moisture in the sample.
  • the parameters are shown in Table 15 below.
  • the moisture measurement based on the Karl Fischer method may produce an error within the range of ⁇ 0.3%, so it is necessary to calculate the moisture content of the sample.
  • the value is understood to include the numerical value within the range of about ⁇ 0.3%.
  • the embodiments of the present invention disclose salt forms and crystal forms of the compound of formula (I) and their preparation methods. Those skilled in the art can learn from the content of the present invention and appropriately improve the process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications will be apparent to those skilled in the art, and they are deemed to be included in the present invention.
  • the method of the present invention has been described through preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention .
  • the raw material 8-1 (10 g, 52.351 mmol) was dissolved in thionyl chloride (30 mL), and the system was heated to 85° C. for 16 h. The system was concentrated, the residue was dissolved in 1,4 dioxane (30 mL), the solution was slowly added to stirring methanol at 0 °C, and the system was heated to 70 °C for reaction for 2 h. The system was concentrated to obtain compound 8-2.
  • the diastereomeric compound 29 was purified by SFC (ChiralPak AD, 250 ⁇ 30 mm ID, 10 ⁇ m; mobile phase: [CO 2 -ethanol (0.1% ammonia)]; % ethanol: 25%; flow rate: 60 mL/min; column temperature: 38°C). After concentration, the compound of formula (I) is obtained.
  • chromatographic column Waters XBridge 4.6*100mm, 3.5um; column temperature: 40°C; mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile: 5%-95% 7min; flow rate: 1.2mL/min. SFC 100%ee. Retention time 4.349min.
  • the water content in the crystal form A was determined by KF test. The results are shown in Table 17. The water content in the sample is 10.0% (the theoretical crystal water content in the pentahydrate is about 10.3%).
  • Reference substance stock solution (0.5mg/ml): Precisely weigh about 50mg potassium sulfate into a 100ml measuring bottle, dissolve with diluent and make up to the mark, and mix well.
  • Reference substance solution (0.05mg/ml): Precisely pipette 1ml of reference substance stock solution into a 10ml volumetric flask, dilute to volume with diluent, and mix well.
  • Control solution the same as the preparation method of the reference solution.
  • Test solution (0.2mg/ml): Precisely weigh about 20mg of the test product into a 100ml volumetric flask, dilute to the mark with diluent, and mix well. Make 2 servings.
  • Blank interference The blank solution should have no interference (if there is interference, it should not exceed 0.2% of the main peak area of the first reference solution)
  • the reference solution is injected continuously for 5 needles, and the RSD of the main peak area should be less than or equal to 5%.
  • Recovery rate The recovery rate of the main peak area in the reference solution and the control solution should be between 95% and 105%.
  • the recovery rate of the main peak area in the returned reference solution should be 95% to 105%.
  • n molecular weight of sulfate (96)
  • the relative deviation of the two results should not exceed 2.0%.
  • the molar mass of free base is 688.20g/moL, and the molar mass of sulfuric acid is 98.07g/moL.
  • the sulfate crystal form B was obtained by suspending and stirring the sulfate crystal form A in a MeOH solvent system at room temperature for about 8 days, and drying the solid sample at room temperature for about one day.
  • the sulfuric acid (4M) and the initial free state sample (the compound of formula I) were charged in a molar ratio of 0.5:1, and the solid sample was centrifuged after stirring at room temperature in THF for about 4 days, and the XRPD was tested after being vacuum-dried at room temperature for about 8 hours to obtain Amorphous samples.
  • the amorphous sample was then suspended and stirred in ACN:H 2 O (19:1, v:v) at room temperature for about 2 days to obtain Form D.
  • Form E was obtained by slowly volatilizing a sample of sulfate crystal form A in EtOH/DCM (4:1, v/v) system.
  • Form F was obtained by suspending and stirring a sample of sulfate crystal form A in a DMSO:MIBK (1:19, v:v) solvent system at room temperature for about 5 days.
  • a sample of sulfate crystal form G was obtained by antisolvent addition of the initial free state sample (compound of formula I) in the EtOH/n-Heptane system.
  • the starting sample (compound of formula I) and benzenesulfonic acid in the free state were charged at 1:2 (molar ratio), and were suspended and stirred at room temperature for about 2 days in the EtOAc solvent system.
  • the solid sample was centrifuged and vacuum-dried at room temperature for 17 hours. It was cyclically heated and suspended in EtOAc solvent system for about 4 days, and the isolated solid was obtained after vacuum drying at room temperature for about 20 hours.
  • Phosphorylated ERK levels were detected using an enzyme-linked immunosorbent (ELISA) method.
  • Phosphorylated ERK antibody (Cell Signal Technology cat. no. 4370) was diluted 1:400 in 1X blocking solution containing 0.05% Tween 20, added to a 96-well plate and incubated overnight at 4°C. Plates were washed 5 times with PBS containing 0.05% Tween 20.
  • the HRP-conjugated secondary antibody (Thermo cat# 31460) was diluted 1:10,000 in 1X blocking solution containing 0.05% Tween 20, added to a 96-well plate and incubated for 2 hours at room temperature.
  • the total number of cells in each well was detected using Gena Green staining. After the phosphorylated ERK level was detected, the 96-well plate was washed with PBS until colorless, and 0.1% kena green (Abcam catalog number ab111622) was added and incubated for 10 minutes. After washing with double-distilled water, 0.1 mol/L HCl was added and incubated for 10 minutes with shaking. OD values were read at a wavelength of 595 nm using EnVision (PerkinElmer).
  • the signal of pERK(Thr202/Tyr204) was normalized using the signal value of Gena Green and the percent inhibition after drug treatment relative to the DMSO reference was calculated. Percentage values were fitted by a four-parameter dose-response curve and IC50 values were generated. The experimental results are shown in Table 24.
  • the compounds of the present invention exhibit an excellent ability to inhibit RAS-mediated signaling.
  • the growth inhibitory ability of the compounds of the present invention on KRAS-G12C expressing cells was evaluated by measuring the cell viability and calculating the GI50 value.
  • the tumor cell line NCI-H358 (ATCC catalog number CRL-5807) expressing KRAS-G12C was cultured in RPMI medium supplemented with 10% fetal bovine serum and penicillin/streptomycin
  • the tumor cell line MIA PaCa2 (ATCC CRL-1420) expressing KRAS-G12C was supplemented with 10% fetal bovine serum (fetal bovine serum), 2.5% horse serum (horse serum) and penicillin/streptomycin double antibody (penicillin/ streptomycin) in DMEM medium.
  • Cells NCI-H358, MIA-Paca2 were seeded in black clear bottom 384-well plates (PerkinElmer cat# 6007460) at 1000 and 800 cell densities, respectively, and cells were allowed to adhere overnight (8-12 hours).
  • the experimental group was added with the compound of the invention diluted 5 times the concentration of the working solution (the final concentration contained 0.1% dimethyl sulfoxide, namely DMSO); the control group was added with the same dilution as the experimental group (final concentration with 0.1% DMSO).
  • the amount of cell proliferation was determined by measuring ATP content using Cell Titer Glo reagent (Promega Cat. No. G7572) according to the manufacturer's method.
  • the brief operation steps are: take out the cell plate and place it at room temperature to equilibrate for 30 minutes; add the same volume of Cell Titer Glo reagent as the culture; place the plate on a shaker for 2 minutes, and let the plate stand at room temperature for 10 minutes ; Use a microplate reader EnVision (PerkinElmer) to read the light signal value.
  • mice Male ICR mice were given a single dose of the test compound 1 mg/Kg (intravenous injection, solvent 5% DMSO+15% Solutol+80% saline) and 5 mg/Kg (gavage administration, solvent 1%) Tween80/2%HPMC/97%water), blood was collected via orbital vein at 5, 15, 30 min, 1, 2, 4, 6, 8, 24hr after administration, each sample was collected about 0.20mL, heparin sodium anticoagulation, collected Place on ice and centrifuge within 1 hour to separate plasma for testing. The plasma concentration of the drug was detected by liquid tandem mass spectrometry (LC/MS/MS), and the measured concentration was used to calculate the pharmacokinetic parameters. The results are shown in Table 26 and Table 27 below.
  • Cell line xenograft experiments were performed to grow NCI-H358 tumors in mice. Once tumor size reached 300 mm3 , animals were randomized and treated with vehicle control (1% Tween80 + 1% HPMC) or compound (dose: 10 mg/kg/day, 30 mg/kg/day, 100 mg/kg/day, respectively) day, orally) treatment. Tumor volume was calculated using the formula) 0.5 ⁇ length ⁇ width ⁇ width. At the end of the experiment, animals were sacrificed, tumors were collected, weighed, and stored for additional analysis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

提供了一种稠合吡啶酮类化合物盐型、晶型及其应用，具体地，提供了式(I)所示化合物的盐型、晶型及其用途。

Description

稠合吡啶酮类化合物盐型、晶型及其应用
本发明要求如下优先权：
CN202110321727.X，申请日：2021年03月25日；
CN202210273262.X，申请日：2022年03月18日。
技术领域
本发明涉及式(Ⅰ)所示化合物的盐型、晶型、药物组合物，以及其作KRAS抑制剂的应用。
背景技术
癌症已蝉联31年中国十大死因之首，其中肺癌是发病率最高的肿瘤之一，其非小细胞肺癌占比超过80％，同时肺癌发病率高、突变种类多。为了丰富公司的研发管线，聚焦未被满足的医疗需求，创新药的研发布局癌症治疗，对公司的长远发展非常有必要，同时有重要的经济意义和社会意义。
约3成左右癌症患者有RAS基因突变。在癌症基因的研究中，科学家早在20多年前已发现，RAS基因是包括肺癌、大肠直肠癌与胰腺癌等癌症的关键基因。
在美国，死亡率最高的三种癌症(胰腺癌、结直肠癌和肺癌)也恰好是RAS突变最多见的三种癌症，分别占这三种癌症患者数的95％、52％和31％。在胰腺癌、结直肠癌和肺癌中，KRAS突变占绝对多数，而NRAS突变多见于黑色素瘤和急性骨髓性白血病，HRAS突变多见于膀胱癌和头颈癌。
KRAS基因在亚洲人群中突变率为10–15％，KRAS在许多癌症中会发生突变，是主要癌基因之一。KRAS突变型肿瘤是最具潜在靶向性的非小细胞肺癌分子亚型(NSCLC)，其突变率在非小细胞肺癌(NSCLC)中约为15％-25％。在NSCLC的病例中，KRAS突变主要发生在12和13号密码子。最常见的密码子变异约占KRAS突变型NSCLCs的39％，是KRAS-G12C突变。
在肺腺癌中，KRAS基因的阳性概率占到了1/5-1/4，仅次于EGFR的阳性突变的概率。靶向抑制剂的缺乏使得KRAS阳性的非小细胞肺癌患者无论是在治疗还是预后都十分困难。《2013年NCCN非小细胞肺癌临床实践指南》明确指出：肺癌患者在接受EGFR-TKI治疗之前，必须进行KRAS基因检测，根据检测结果来决定是否使用EGFR-TKI靶向药物作为临床治疗措施。如果KRAS基因发生了突变，则不建议病人使用EGFR-TKI进行分子靶向治疗。
据汤森路透竞争情报药物数据库(Cortellis For CI)，目前各种与RAS基因/蛋白直接相关的药物数共有162个(数据查询时间2016年8月18日)，其中KRAS小分子药物有18个，其中包括10个KRAS GTP酶抑制剂，4个KRAS基因抑制剂，2个KRAS GTP酶调节剂和2个KRAS基因调节剂；目前临床在研的该类药物有1个。另外，台湾企业研发的首个KRAS抑制剂安卓健已进入美国FDA二期临床试验，阿斯利康研发的针对KRAS下游通路MEK的抑制剂司美替尼也在进行二期临床试验。KRAS突变是最重要的肿瘤驱动基因。这一部分突变病例在胰腺癌、肺癌及直肠胃癌中均占有一定比例。目前尚无作用于该靶点的特异性靶向药物。因此，该项目具有重要的医学研究价值和临床应用价值，对国人的医疗价值更大。开发KRAS-G12C小分子药物，其分子机制已基本阐明，药物分子结构和药效作用在现有试验条件下得到验证，具备高活性特征和成药的可能性。
发明内容
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐
Figure PCTCN2022082855-appb-000001
本发明的一些方案中，上述硫酸盐含有相对于化合物(I)为0.5～3.0摩尔当量的硫酸。
本发明的一些方案中，上述硫酸盐含有相对于化合物(I)为0.5～2.5摩尔当量的硫酸。
本发明的一些方案中，上述硫酸盐含有相对于化合物(I)为0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.7、2.9或3.0摩尔当量的硫酸。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型A。所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.2°、11.93±0.2°、12.34±0.2°、12.99±0.2°、16.80±0.2°、17.75±0.2°。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.2°、11.93±0.2°、12.34±0.2°、12.99±0.2°、13.54±0.2°、16.80±0.2°、17.75±0.2°、19.09±0.2°、20.91±0.2°、21.71±0.2°。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱具有基本上如图1所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱解析数据如下表1所示。
表1
Figure PCTCN2022082855-appb-000002
Figure PCTCN2022082855-appb-000003
本发明的一些方案中，上述晶型A含有相对于化合物(I)为0.5-1.5摩尔当量的硫酸。
本发明的一些方案中，上述晶型A含有相对于化合物(I)为1.0～1.5摩尔当量的硫酸。
本发明的一些方案中，上述晶型A含有相对于化合物(I)为1.0～1.1摩尔当量的硫酸。
本发明的一些方案中，上述晶型A含有相对于化合物(I)为0.9、1.0、1.1或1.2摩尔当量的硫酸。这些摩尔当量不同的晶型A具有相同的特征峰，例如图13-16所示。
本发明的一些方案中，上述晶型A含有相对于化合物(I)为1.024、1.063、1.075、1.082、1.087或1.108摩尔当量的硫酸。
本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为5％-15％。本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为5.87％-13.23％。
本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为6.6％-10.4％。
本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为6.6％、7.0％、7.5％、8.0％、8.5％、9.0％、9.5％、9.6％、9.7％、9.8％、9.9％、10.0％、10.1％、10.2％、10.3％、10.4％或10.5％。
本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为6.6％、7.0％、7.5％、8.0％、8.5％、9.0％、9.5％、9.6％、9.7％、9.8％、9.9％、10.0％、10.1％、10.2％、10.3％、10.4％或10.5％，这些水分含量不同的晶型A具有相同的特征峰，例如图1、12所示。
本发明的一些方案中，上述共同的特征峰为选自衍射角度(2θ)：7.17±0.2°、11.93±0.2°、12.34±0.2°、12.99±0.2°、16.80±0.2°、17.75±0.2°中的至少3个峰。
本发明的一些方案中，上述共同的特征峰为选自衍射角度(2θ)：7.17±0.2°、11.93±0.2°、12.34±0.2°、12.99±0.2°、13.54±0.2°、16.80±0.2°、17.75±0.2°、19.09±0.2°、20.91±0.2°、21.71±0.2°中的至少3个峰。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型B。所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.67±0.2°、8.78±0.2°、10.28±0.2°、11.02±0.2°、12.19±0.2°、15.51±0.2°。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.67±0.2°、8.78±0.2°、10.28±0.2°、11.02±0.2°、12.19±0.2°、12.60±0.2°、13.14±0.2°、15.51±0.2°、15.99±0.2°、19.56±0.2°。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱具有基本上如图2所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱解析数据如下表2所示。
表2
Figure PCTCN2022082855-appb-000004
本发明的一些方案中，上述晶型B含有相对于化合物(I)为0.8-1.5摩尔当量的硫酸。
本发明的一些方案中，上述晶型B含有相对于化合物(I)为0.9、1.0、1.1或1.2摩尔当量的硫酸。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型C。所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.51±0.2°、7.71±0.2°、11.90±0.2°、13.67±0.2°、15.69±0.2°、20.15±0.2°。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱具有基本上如图3所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱解析数据如下表3所示。
表3
Figure PCTCN2022082855-appb-000005
本发明的一些方案中，上述晶型C含有相对于化合物(I)为2.0-3.0摩尔当量的硫酸。
本发明的一些方案中，上述晶型C含有相对于化合物(I)为2.3、2.4、2.5、2.6或2.7摩尔当量的硫酸。
本发明的一些方案中，上述晶型C为四氢呋喃和乙酸乙酯溶剂合物，所述四氢呋喃和乙酸乙酯溶剂合物中四氢呋喃的含量为0-10wt％，乙酸乙酯的含量为0-12wt％。需要说明的是，晶型C可以为乙酸乙酯单一溶剂合物，即四氢呋喃的含量为0wt％时；或晶型C可以为四氢呋喃单一溶剂合物，即乙酸乙酯的含量为0wt％时；或晶型C为四氢呋喃和乙酸乙酯混合溶剂合物，即四氢呋喃和乙酸乙酯的含量均不为0wt％。本发明的一些方案中，上述晶型C为四氢呋喃和乙酸乙酯溶剂合物，所述四氢呋喃和乙酸乙酯溶剂合物中四氢呋喃的含量为4.1wt％、4.2wt％、4.3wt％、4.4wt％、4.5wt％、4.6wt％、4.7wt％、4.8wt％、4.9wt％、5.0wt％、5.1wt％、5.2wt％、5.3wt％、5.4wt％、5.5wt％、5.6wt％、5.7wt％、5.8wt％、5.9wt％、6.0wt％，乙酸乙酯的含量为0.1wt％。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型D。所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.85±0.2°、10.29±0.2°、12.78±0.2°、16.36±0.2°、19.84±0.2°、20.66±0.2°。
本发明的一些方案中，上述晶型D的X射线粉末衍射图谱具有基本上如图4所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型D的X射线粉末衍射图谱解析数据如下表4所示。
表4
Figure PCTCN2022082855-appb-000006
Figure PCTCN2022082855-appb-000007
本发明的一些方案中，上述晶型D含有相对于化合物(I)为0.2-0.8摩尔当量的硫酸。
本发明的一些方案中，上述晶型D含有相对于化合物(I)为0.3、0.4、0.5或0.6摩尔当量的硫酸。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型E。所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.52±0.2°、8.93±0.2°、11.04±0.2°、12.16±0.2°、12.82±0.2°、22.67±0.2°。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.52±0.2°、8.52±0.2°、8.93±0.2°、11.04±0.2°、12.16±0.2°、12.82±0.2°、14.63±0.2°、15.34±0.2°、16.88±0.2°、22.67±0.2°。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱具有基本上如图5所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱解析数据如下表5所示。
表5
Figure PCTCN2022082855-appb-000008
Figure PCTCN2022082855-appb-000009
本发明的一些方案中，上述晶型E含有相对于化合物(I)为0.8-1.5摩尔当量的硫酸。
本发明的一些方案中，上述晶型E含有相对于化合物(I)为0.9、1.0、1.1或1.2摩尔当量的硫酸。
本发明的一些方案中，上述晶型E为乙醇溶剂合物，所述乙醇溶剂合物中乙醇的含量为5％-22％。
本发明的一些方案中，上述晶型E为乙醇溶剂合物，所述乙醇溶剂合物中乙醇的含量为17％、18％、19％、20％、21％或22％。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型F。所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.40±0.2°、13.01±0.2°、18.09±0.2°、21.65±0.2°。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱具有基本上如图6所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱解析数据如下表6所示。
表6
Figure PCTCN2022082855-appb-000010
Figure PCTCN2022082855-appb-000011
本发明的一些方案中，上述晶型F含有相对于化合物(I)为1.0-1.5摩尔当量的硫酸。
本发明的一些方案中，上述晶型F含有相对于化合物(I)为1.1、1.2、1.3或1.4摩尔当量的硫酸。
本发明的一些方案中，上述晶型F为甲基异丁基酮和二甲基亚砜溶剂合物，所述甲基异丁基酮和二甲基亚砜溶剂合物中甲基异丁基酮的含量为0-12wt％，二甲基亚砜的含量为0-17wt％。需要说明的是，晶型F可以为甲基异丁基酮单一溶剂合物，即二甲基亚砜的含量为0wt％时；或晶型F可以为二甲基亚砜单一溶剂合物，即甲基异丁基酮的含量为0wt％时；或晶型F为甲基异丁基酮和二甲基亚砜混合溶剂合物，即甲基异丁基酮和二甲基亚砜的含量均不为0wt％。
本发明的一些方案中，上述晶型F为甲基异丁基酮和二甲基亚砜溶剂合物，所述甲基异丁基酮和二甲基亚砜溶剂合物中甲基异丁基酮的含量为0.5wt％、0.6wt％、0.7wt％、0.8wt％、0.9wt％、1.0wt％、1.1wt％、1.2wt％、1.3wt％、1.4wt％或1.5wt％，二甲基亚砜的含量为14.0wt％、14.1wt％、14.2wt％、14.3wt％、14.4wt％、14.5wt％、14.6wt％、14.7wt％、14.8wt％、14.9wt％或15.0wt％。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型G。所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.88±0.2°、7.05±0.2°、9.39±0.2°、10.87±0.2°、12.00±0.2°、16.15±0.2°。
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱具有基本上如图7所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱解析数据如下表7所示。
表7
Figure PCTCN2022082855-appb-000012
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的硫酸盐的晶型H。所述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.11±0.2°、11.59±0.2°、12.19±0.2°、15.66±0.2°、18.34±0.2°、13.82±0.2°。
本发明的一些方案中，上述晶型H的X射线粉末衍射图谱具有基本上如图8所示的X射线粉末衍射 图谱。
本发明的一些方案中，上述晶型H的X射线粉末衍射图谱解析数据如下表8所示。
表8
Figure PCTCN2022082855-appb-000013
本发明的一些方案中，上述晶型H含有相对于化合物(I)为0.5-1.5摩尔当量的硫酸。
本发明的一些方案中，上述晶型H含有相对于化合物(I)为0.9、1.0、1.1或1.2摩尔当量的硫酸。
本发明的一些方案中，上述晶型H为无水晶型。
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物的苯磺酸盐。
本发明的一些方案中，上述苯磺酸盐含有相对于化合物(I)为0.5-3.0摩尔当量的苯磺酸。
本发明的一些方案中，上述苯磺酸盐含有相对于化合物(I)为1.0-2.5摩尔当量的苯磺酸。
本发明的一些方案中，上述苯磺酸盐含有相对于化合物(I)为0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.7、2.9或3.0摩尔当量的苯磺酸。
在本发明的另一方面，本发明提供了式(Ⅰ)所示化合物的苯磺酸盐的晶型I。所述晶型I的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.63±0.2°、12.05±0.2°、13.78±0.2°、15.09±0.2°、16.04±0.2°、18.35±0.2°。
本发明的一些方案中，上述晶型I的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.63±0.2°、11.35±0.2°、12.05±0.2°、13.78±0.2°、15.09±0.2°、16.04±0.2°、16.65±0.2°、18.35±0.2°、18.87±0.2°、23.53±0.2°。
本发明的一些方案中，上述晶型I的X射线粉末衍射图谱具有基本上如图9所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型I的X射线粉末衍射图谱解析数据如下表9所示。
表9
Figure PCTCN2022082855-appb-000014
Figure PCTCN2022082855-appb-000015
本发明的一些方案中，上述晶型I含有相对于化合物(I)为1.5-2.5摩尔当量的苯磺酸。
本发明的一些方案中，上述晶型I含有相对于化合物(I)为1.6、1.7、1.8、1.9、2.0或2.1摩尔当量的硫酸。
在本发明的再一方面，本发明还提出了药物组合物，所述药物组合物含有如前面所述的式(Ⅰ)所示化合物的硫酸盐、式(Ⅰ)所示化合物的苯磺酸盐或晶型A～I。
在本发明的再一方面，本发明还提出了如前面所述的式(Ⅰ)所示化合物的硫酸盐、式(Ⅰ)所示化合物的苯磺酸盐或晶型A～I或前面所述的药物组合物在制备预防和/或治疗用作KRAS-G12C相关疾病的药物中的用途。
本发明的一些方案中，上述KRAS-G12C相关疾病选自非小细胞肺癌，结肠癌和胰腺癌。
定义和说明
除非另有说明，本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质，但是本发明中描述的是优选的方法、设备和物质。
“晶型”或“结晶形式”是指具有高度规则化学结构的固体，包括，但不限于，单组分或者多组分晶体，和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶，例如，在纳米孔或者毛细管中，在表面或者模板上结晶，例如，在聚合物上，在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、 反应结晶、反溶剂添加、研磨和溶剂滴研磨等。
“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。物质的无定形形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，骤冷法、反溶剂絮凝法、球磨法、喷雾干燥法、冷冻干燥法、湿法制粒法和固体分散体技术等等。
“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、l-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。
“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。
“溶剂化物”是指晶体在表面上、或在晶格中、或者在表面上和在晶格中具有溶剂，其中，所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯曱烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、或在晶格中、或者在表面上和在晶格中的溶剂是水。在物质的表面上、或在晶格中、或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。
晶型或无定形可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施例中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本发明试验所用仪器状况，衍射峰存在±0.2°的误差容限。
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al 2O 3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施例中，本发明所述晶型的特征在于具有特征峰位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本发明试验所用仪器状况，熔化峰存在±3℃的误差容限。
玻璃态转变是指非晶态物质在高弹态和玻璃态之间的转变，是该物质的固有性质；它所对应的转变温度为玻璃化转变温度(Tg)，是非晶态物质的一个重要物理性质。玻璃化转变是与分子运动有关的现象，因而，玻璃化转变温度(Tg)主要取决于物质的结构，而对实验细节等相对不敏感。在一些实施例中，本发明所述无定形的玻璃化转变温度(Tg)通过差示扫描量热法(DSC)测定，其特征在于具有107.44℃的玻璃化转变温度。根据本发明试验所用仪器状况，玻璃化转变温度存在±3℃的误差容限。
差示扫描量热(DSC)还可用于检测分析晶型是否有转晶或混晶现象。
化学组成相同的固体，在不同的热力学条件下，常会形成晶体结构不同的同质异构体，或称为变体，这种现象称为同质多晶或同质多相现象。当温度和压力条件变化时，变体之间会发生相互转变，此现象称为晶型转变。由于晶型转变，晶体的力学、电学、磁学等性能会发生巨大的变化。当晶型转变的温度在可测范围内时，在差示扫描量热(DSC)图上可观察到这一转变过程，其特征在于，DSC图具有反映这一转变过程的放热峰，且同时具有两个或多个吸热峰，分别为转变前后的不同晶型的特征吸热峰。本发明化合物的晶型或无定形在适当条件下可发生晶型转变
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。在一些实施例中，本发明所述的钙盐晶型A在温度150℃左右失重5.1％左右。根据本发明试验所用的仪器状况，质量变化存在±0.3％的误差容限。
在本发明的上下文中，X射线粉末衍射图中的2θ值均以度(°)为单位。
需要说明的是，在含量单位“wt％”和含量单位“％”可互换使用，是指质量比(g/g)，例如在水合物中，晶型A的水分含量为10.02％，是指该晶型A中水的质量与该晶型A的质量的比例(g/g)为10.02；又例如在溶剂合物中，晶型C中四氢呋喃的含量为5.1wt％，是指该晶型C中四氢呋喃的质量与该晶型C的质量的比例(g/g)为5.1。
需要说明的是“
Figure PCTCN2022082855-appb-000016
是R构型的轴手性对映体”。
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。
“基本上纯净的”是指一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
“基本上不含”是指一种或多种其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于4％，或少于3％，或少于2％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
“相对强度”是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
附图说明
图1为晶型A的X射线粉末衍射(XRPD)图；
图2为晶型B的X射线粉末衍射(XRPD)图；
图3为晶型C的X射线粉末衍射(XRPD)图；
图4为晶型D的X射线粉末衍射(XRPD)图；
图5为晶型E的X射线粉末衍射(XRPD)图；
图6为晶型F的X射线粉末衍射(XRPD)图；
图7为晶型G的X射线粉末衍射(XRPD)图；
图8为晶型H的X射线粉末衍射(XRPD)图；
图9为晶型I的X射线粉末衍射(XRPD)图；
图10为给药式(I)化合物后NCI-H358细胞接种天数与体重变化的关系图；
图11为给药式(I)化合物后NCI-H358细胞接种天数与肿瘤体积的关系图；
图12为晶型A不同水含量的X射线粉末衍射(XRPD)图；
图13为样品X-1的X射线粉末衍射(XRPD)图；
图14为样品X-2的X射线粉末衍射(XRPD)图；
图15为样品X-3的X射线粉末衍射(XRPD)图；
图16为样品X-4的X射线粉末衍射(XRPD)图。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
XRPD图在PANalytacal生产的X射线粉末衍射分析仪上采集，扫描参数如下表10所示。
表10
Figure PCTCN2022082855-appb-000017
Figure PCTCN2022082855-appb-000018
TGA和DSC图分别在TA Q5000/Discovery 5500热重分析仪和TA Q2000/Discovery 2500差示扫描量热仪上采集，表11列出了测试参数。
表11
参数 TGA DSC mDSC
方法 线性升温 线性升温 调制升温
样品盘 铝盘，敞开 铝盘，压盖/不压盖 铝盘，压盖
温度范围 室温-设置终点温度 25℃-设置终点温度 25℃-设置终点温度
扫描速率(℃/min) 10 10 3
保护气体 氮气 氮气 氮气
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl，Mg(NO 3) 2和KCl的潮解点校正。DVS测试参数列于表12。
表12
Figure PCTCN2022082855-appb-000019
本发明液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d 6作为溶剂。
本发明PLM图通过Olympus SZX7体式显微镜拍摄。
本发明化合物解离常数由Sirius pKa log P/D tester(model:T3Dt)测试得到。
本发明试验中纯度测试、动态溶解度和稳定性测试是由安捷伦1260高效液相色谱仪测试，离子的成盐摩尔比测试是由离子色谱测试，分析条件如表13和表14所示。
表13
Figure PCTCN2022082855-appb-000020
表14
离子色谱仪 ThermoFisher ICS-1100
色谱柱 IonPac AS18 Analytical Column,250*4mm
流动相 25mM NaOH
进样体积 25μL
流速 1.0mL/min
温度 35℃
柱温 35℃
电流 80mA
运行时间 SO 4 2-:13.0min
水分测试方法(KF法)：本发明采用容量法进行测定样品中的水分，参数见下表15，基于卡氏法的水分测定可能产生±0.3％的范围内的误差，因此需将水分含量的值理解为亦包含±0.3％左右的范围内的数值在内者。
表15
仪器 852型卡尔费休水分滴定仪(万通)
滴定剂 容量法滴定剂(Honeywell-Fluka)
溶剂 无水甲醇(Scharlau)
本发明采用的溶剂缩写或英文的中文含义如下表16所示：
表16
英文 中文 英文 中文
MeOH 甲醇 1,4-Dioxane 1,4-二氧六环
EtOH 乙醇 ACN 乙腈
IPA 异丙醇 DCM 二氯甲烷
Acetone 丙酮 CHCl 3 三氯甲烷
MIBK 甲基异丁基酮 Toluene 甲苯
EtOAc 乙酸乙酯 n-Heptane 正庚烷
IPAc 乙酸异丙酯 DMSO 二甲基亚砜
MTBE 甲基叔丁基醚 Anisole 苯甲醚
THF 四氢呋喃 CPME 环戊基甲醚
2-MeTHF 2-甲基四氢呋喃 H 2O 水
本发明实施例公开了式(I)化合物的盐型、晶型以及它们的制备方法。本领域技术人员可以借鉴本发明内容，适当改进工艺参数来实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明中。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步理解本发明，下面结合实施例对本发明进行详细说明。
实施例1：式(Ⅰ)化合物的制备
步骤1：化合物8-2的制备
Figure PCTCN2022082855-appb-000021
将原料8-1(10g,52.351mmol)溶于二氯亚砜(30mL)，将体系加热至85℃反应16h。将体系浓缩，剩余物溶于1,4二氧六环(30mL)，0℃条件下，将该溶液慢慢加入搅拌的甲醇中，将体系加热至70℃反应2h。将体系浓缩得化合物8-2。
步骤2：化合物8-3的制备
Figure PCTCN2022082855-appb-000022
将化合物8-2(4g,19.4mmol)溶于甲醇(50mL)，向其中滴加甲醇钠的甲醇溶液(4mL,21.3mmol)，将体系室温(20℃)反应3h。将体系浓缩，倒入水(50mL)中，用乙酸乙酯(50mL x 3)萃取，合并的有机相经无水硫酸钠干燥，过滤，滤液浓缩得粗品8-3。
MS(ESI)m/z(M+H) +＝202.0.
步骤3：化合物8-4的制备
Figure PCTCN2022082855-appb-000023
室温(20℃)条件下，将化合物8-3(1.48g,7.36mmol)，化合物3-9(1.11g,7.36mmol),醋酸钯(165mg,0.736mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(425mg,0.735mmol)，碳酸铯(4.8g,14.73mmol)溶于二氧六环(15mL),氮气氛围下，将体系升温至110℃搅拌4h。将体系冷却至室温，浓缩得粗品。粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～20％)得化合物8-4。
MS(ESI)m/z(M+H) +＝316.0。
步骤4：化合物8-5的制备
Figure PCTCN2022082855-appb-000024
将化合物8-4(1.58g,4.80mmol)溶于N,N-二甲基甲酰胺(15mL)，向其中加入N-氯代丁二酰亚胺(0.706g,5.28mmol),将体系升温至80℃反应5h。将体系冷却至室温，倒入水(50mL)中，用乙酸乙酯(50mL x 3)萃取，合并的有机相经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～5％)得化合物8-5。
MS(ESI)m/z(M+H) +＝350.0
步骤5：化合物8-6的制备
Figure PCTCN2022082855-appb-000025
室温(20℃)条件下，将化合物8-5(6.3g,7.82mmol)溶于N,N-二甲基甲酰胺(30mL),0℃条件下，向其中分批加入氢化钠(2.17g,54.15mmol),加毕，将体系0℃反应30min，向其中滴加乙酰氯(3.85 mL，54.15mmol)。向体系依次加入水(30mL)及碳酸钾的饱和水溶液，将体系室温(20℃)反应3h。用EA(100mL x 2)萃取后，水相用盐酸(4N)调节pH 4～5后，用乙酸乙酯(100mL x 4)萃取，合并有机相经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经中压柱层析纯化(甲醇/二氯甲烷(v/v)＝0～5％)得化合物8-6。
MS(ESI)m/z(M+H) +＝360.0.
步骤6：化合物8-7的制备
Figure PCTCN2022082855-appb-000026
将化合物8-6(1.86g,5.18mmol)溶于冰醋酸(30mL)，室温(20℃)条件下，向体系滴加硝酸(15mL)。滴加完毕后，将体系在室温(20℃)搅拌2h。将体系浓缩除去大部分冰醋酸，剩余物倒入冰水(25mL)中，调节pH至5～6，过滤，滤饼水洗后干燥，得化合物8-7。
MS(ESI)m/z(M+H) +＝405.0.
步骤7：化合物8-8的制备
Figure PCTCN2022082855-appb-000027
将化合物8-7(1g,2.47mmol)溶于醋酸(6mL)和氢溴酸(8mL)的混合溶液。将体系升温至100℃反应16h。将体系旋干得化合物8-8。
MS(ESI)m/z(M+H) +＝391.0.
步骤8：化合物8-9的制备
Figure PCTCN2022082855-appb-000028
将化合物8-8(2.0g,5.13mmol)及N,N-二异丙基乙胺(5mL,30.7mmol)溶于乙腈(6mL)，室温条件(20℃)下，向其中加入三氯氧磷(7mL,77mmol)。加毕，将体系升温至80℃搅拌2h。将体系浓缩得粗品。粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～50％)得化合物8-9。
MS(ESI)m/z(M+H) +＝427.0.
步骤9：化合物25-1的制备
Figure PCTCN2022082855-appb-000029
将化合物8-9(426mg,1.0mmol)，7-1(286mg,1.1mmol)，N,N-二异丙基乙基胺(0.2mL)溶于乙腈(10mL)中，将体系升温至100℃搅拌4h。体系浓缩得粗品。粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～35％)得化合物25-1。
MS(ESI)m/z(M+H) +＝649.0。
步骤10：化合物25-2的制备
Figure PCTCN2022082855-appb-000030
将化合物25-1(326mg,0.502mmol)，铁粉(200mg，3.6mmol)溶于乙酸(15mL)中，氮气氛围下，将体系升温至85℃搅拌1h。体系经硅藻土过滤，滤液浓缩，残余物溶于乙酸乙酯，用饱和碳酸氢钠洗涤，有机相经无水硫酸钠干燥，过滤，滤液浓缩得化合物25-2。不经进一步纯化直接用于下一步反应。
MS(ESI)m/z(M+H) +＝587.0。
步骤11：化合物25-3的制备
Figure PCTCN2022082855-appb-000031
将化合物25-2(277mg,0.5mmol),化合物2-3(282mg，1mmol)，四(三苯基膦)钯(150mg，0.125mmol),碳酸钾(138mg，1mmol)溶于二氧六环(18mL)和水(1.8mL)的混合溶液中。氮气氛围下，将体系升温至100℃搅拌反应2h。体系浓缩得粗品，粗品经中压柱层析纯化(乙酸乙酯/石油醚(v/v)＝0～50％)得化合物25-3。
MS(ESI)m/z(M+H) +＝707.2。
步骤12：化合物29-1的制备
Figure PCTCN2022082855-appb-000032
将化合物25-3(700mg,1mmol)及碳酸铯(977mg,3mmol)溶于N,N-二甲基甲酰胺(20mL)中，室温(25℃)条件下，向其中加入化合物26-1(432mg,3mmol)。加毕，氮气氛围下，将体系升温至120℃搅拌2h。将体系过滤，滤液浓缩得粗品，粗品经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝1/10)，得化合物29-1。
MS(ESI)m/z(M+H) +＝778.2.
步骤13：化合物29-2的制备
Figure PCTCN2022082855-appb-000033
将化合物29-1(150mg,0.2mmol),盐酸(6N,7mL)加入甲醇(0.6mL)及四氢呋喃(6mL)的混合溶液。将体系升温至55℃反应10min。体系浓缩得粗品化合物29-2，不经进一步纯化直接用于下一步反应。
MS(ESI)m/z(M+H) +＝634.2.
步骤14：化合物29的制备
Figure PCTCN2022082855-appb-000034
将化合物29-2(140mg,0.2mmol)溶于二氯甲烷(10mL)中，将体系冷却至0℃，向其中滴加三乙胺(0.3mL，2.1mmol)和丙烯酰氯(27mg，0.3mmol),将体系在0℃反应0.5h。将体系用甲醇淬灭后，浓缩得粗品。粗品溶于甲醇(5mL)中，向其中加入碳酸钾(140mg),加毕，将体系在室温(20℃)条件下搅拌30min。将体系用盐酸调节pH～6，用二氯甲烷(20mL)与水(20mL)分液萃取，有机相经无水硫酸钠干燥，过滤，滤液浓缩得粗品，粗品经高效制备液相纯化(分离条件：色谱柱Welch
Figure PCTCN2022082855-appb-000035
C18  21.2×250mm,10μm；柱温：25℃；流动相:水(10mM/L NH 4HCO 3)-乙腈；乙腈40％-60％9min；流速30mL/min)得化合物29。
MS(ESI)m/z(M+H) +＝688.2.
步骤15：式(I)化合物的制备
Figure PCTCN2022082855-appb-000036
非对映异构体化合物29经SFC纯化(ChiralPak AD,250×30mm I.D.,10μm；流动相:[CO 2-乙醇(0.1％氨水)]；乙醇％:25％；流速:60mL/min；柱温:38℃)。浓缩后，得式(I)化合物。
式(I)化合物:
1H NMR(400MHz,DMSO-d 6)δ10.18(brs,1H),8.45(d,J＝4.9Hz,1H),8.26(s,1H),7.29–7.20(m,2H),7.04(dd,J＝16.8,10.4Hz,0.75H),6.86(dd,J＝17.6,10.4Hz,0.25H),6.72–6.60(m,2H),6.14(d,J＝16.4Hz,1H),5.75(d,J＝10.7Hz,1H),5.03(d,J＝13.8Hz,0.25H),4.80(d,J＝7.8Hz,0.75H),4.61(d,J＝14.1Hz,1H),4.43–4.30(m,1H),4.28–4.15(m,1H),4.04–3.89(m,1H),3.75(dd,J＝14.5,4.4Hz,1H),3.28–3.10(m,2H),2.75–2.65(m,1H),2.39–2.28(m,1H),2.28–2.17(m,1H),2.06–1.96(m,6H),1.81(d,J＝9.5Hz,3H),1.53(d,J＝6.8Hz,3H),1.11(d,J＝6.9Hz,3H),0.95(d,J＝6.6Hz,3H).
MS(ESI)m/z(M+H) +＝688.3.
HPLC保留时间5.269min。
分离条件：色谱柱：Waters XBridge 4.6*100mm,3.5um；柱温：40℃；流动相:水(10mM碳酸氢铵)-乙腈；乙腈:5％-95％7min；流速：1.2mL/min。SFC 100％ee.保留时间4.349min。
分离条件：色谱柱：ChiralPak AD-3,150×4.6mm I.D.,3μm；流动相:[CO 2-乙醇(0.05％DEA)]；乙醇％:5％-40％5min，40％2.5min，5％2.5min；流速:2.5mL/min；柱温:35℃。
实施例2：晶型A的制备及鉴定
称取500.2mg游离态起始物料(式I化合物)于20mL玻璃瓶中，加入4mL THF/toluene(1:1,v/v)。量取180μL的4M硫酸于20-mL玻璃瓶中，加入6mL THF/toluene(1:1,v/v)进行稀释。磁力搅拌(～750rpm)下向游离态中逐滴加入稀释后的硫酸溶液(酸与游离态投料摩尔比约为1.1:1)。室温下悬浮搅拌约1天后，所得固体经抽滤分离、室温真空干燥2天，收集固体。
XRPD结构如图1所示。
通过KF测试对晶型A中水含量进行了测定，结果如表17所示，样品中水含量为10.0％(五水合物中的理论结晶水含量约为10.3％)。
表17
Figure PCTCN2022082855-appb-000037
备注： *：滴定时所用的平均滴定度为4.7976mg/mL。
用同样的方法同样制备了另外两批次晶型，鉴定其均为晶型A，对其进行水分测定，其结果如下表18所示。
表18
样品 XPRD图谱 水含量(％) *
1 图12(样品1) 10.4％
2 图12(样品2) 6.6％
硫酸含量测定方法：
仪器设备：
离子色谱仪、十万分之一电子天平、超声仪。
试剂和对照品：
表19
名称 级别
水 纯化水
硫酸钾 分析纯
色谱条件：
表20
名称 参数
色谱柱 Dionex IonPac AS11-HC,4*250mm,13μm
保护柱 Dionex IonPac AG11-HC,4*50mm,13μm
淋洗液 30mM KOH
流速 1.3ml/min
运行时间 12min
进样体积 25μl
柱温 35℃
抑制器型号 AERS_4mm
溶液配制：
稀释剂/空白溶液：水。
对照品储备液(0.5mg/ml)：精密称定约50mg硫酸钾置100ml量瓶中，用稀释剂溶解并定容到刻度，混匀。
对照品溶液(0.05mg/ml)：精密移取1ml对照品储备液置10ml量瓶中，用稀释剂定容到刻度，混匀。
控制溶液：同对照品溶液配制方法。
供试品溶液(0.2mg/ml)：精密称定约20mg供试品置100ml量瓶中，用稀释剂定容到刻度，混匀。配制2份。
进样序列：
系统平衡后按以下序列进样，每进12针供试品溶液后或序列结束后返进一针对照品溶液。
表21
溶液名称 进样针数
空白溶液 ≥1
对照品溶液 5
控制溶液 1
供试品溶液1 1
供试品溶液2 1
(返进)对照品溶液 1
系统适用性：
空白干扰：空白溶液应无干扰(若有干扰，不得过第一针对照品溶液主峰峰面积的0.2％)
重复性：对照品溶液连续进样5针，主峰峰面积RSD应≤5％。
回收率：对照品溶液和控制溶液中主峰峰面积的回收率应在95％～105％之间。返进对照品溶液中主峰峰面积的回收率应在95％～105％％。
Figure PCTCN2022082855-appb-000038
A CS：控制溶液中目标物峰面积
C RS：对照品溶液中目标物的浓度，mg/ml
Figure PCTCN2022082855-appb-000039
对照品溶液连续进样5次的目标物峰面积的平均值
C CS：控制溶液中目标物的浓度，mg/ml
Figure PCTCN2022082855-appb-000040
A RS：返进对照品溶液中目标物峰面积
Figure PCTCN2022082855-appb-000041
对照品溶液连续进样5次的目标物峰面积的平均值
结果计算
Figure PCTCN2022082855-appb-000042
A SPL：供试品溶液中目标物峰面积
C RS：对照品溶液中目标物的浓度，mg/ml
P：对照品的含量，％
Figure PCTCN2022082855-appb-000043
对照品溶液连续进样5次的目标物峰面积的平均值
C SPL：供试品溶液的浓度，mg/ml
Figure PCTCN2022082855-appb-000044
m：硫酸的分子量(98)
n：硫酸根的分子量(96)
报告方式
取平均值报告结果，保留4位有效数字；
两次结果相对偏差应不得过2.0％。
以上述方法对另四批次的晶型，鉴定其均为晶型A，对其进行硫酸含量测定，其结果如下表22所示。
表22
样品 XPRD图谱 游离碱(式I所示化合物)含量％ 硫酸含量％ 硫酸：游离碱摩尔比
X-1 图13 77.69 11.98 1：1.082
X-2 图14 76.92 11.91 1：1.087
X-3 图15 76.21 12.03 1：1.108
X-4 图16 76.00 11.64 1：1.075
备注:游离碱摩尔质量为688.20g/moL，硫酸摩尔质量为98.07g/moL。
实施例3：晶型A固态稳定性实验
将硫酸盐晶型A样品及游离态样品(式I化合物)在25℃/60％RH和40℃/75％RH条件下敞口放置1周及2周后，通过XRPD和HPLC检测样品的物理和化学稳定性。同时，对硫酸盐晶型A样品增加了25℃/60％RH和40℃/75％RH条件下敞口放置1个月及60℃闭口放置24小时的稳定性考察。稳定性试验结果汇总于表23。结果显示硫酸盐晶型A样品在测试条件下未观察到晶型变化，HPLC纯度未见明显下降。游离态样品在稳定性试验后仍为无定形，同时在测试条件下观察到约1.5～3.9area％的HPLC纯度下降。
表23
Figure PCTCN2022082855-appb-000045
Figure PCTCN2022082855-appb-000046
实施例4：晶型B的制备及鉴定
由硫酸盐晶型A在MeOH溶剂体系中室温悬浮搅拌约8天，固体样品于室温下晾干约1天后得到硫酸盐晶型B。
XRPD结构如图2所示。
实施例5：晶型C的制备及鉴定
由硫酸(4M)及起始游离态样品(式I化合物)以摩尔比2.5:1投料，在THF中室温悬浮搅拌约4天后离心分离固体样品，并于室温真空干燥约8小时后再用EtOAc经三次涡旋、离心后得到。
XRPD结构如图3所示。经HPLC/IC测试，样品中酸:游离态摩尔比为2.5。
实施例6：晶型D的制备及鉴定
由硫酸(4M)及起始游离态样品(式I化合物)以摩尔比0.5:1投料，在THF中室温悬浮搅拌约4天后离心分离固体样品，并于室温真空干燥约8小时后测试XRPD，得到无定形样品。再将该无定形样品在ACN:H 2O(19:1,v:v)中室温悬浮搅拌约2天得到晶型D。
XRPD结构如图4所示。经HPLC/IC测试，样品中酸:游离态摩尔比为0.5。
实施例7：晶型E的制备及鉴定
由硫酸盐晶型A样品在EtOH/DCM(4:1,v/v)体系中缓慢挥发得到晶型E。
XRPD结构如图5所示。
实施例8：晶型F的制备及鉴定
由硫酸盐晶型A样品在DMSO:MIBK(1:19,v:v)溶剂体系中室温悬浮搅拌约5天后得到晶型F。
XRPD结构如图6所示。经HPLC/IC测试，样品中酸:游离态摩尔比为1.3。
实施例9：晶型G的制备及鉴定
硫酸盐晶型G样品通过起始游离态样品(式I化合物)在EtOH/n-Heptane体系中反溶剂添加得到。
XRPD结构如图7所示。
实施例10：晶型H的制备及鉴定
通过硫酸盐晶型A在氮气保护下高温脱水并降温至30℃得到。
XRPD结构如图8所示。
实施例11：晶型I的制备及鉴定
由游离态起始样品(式I化合物)及苯磺酸以1:2(摩尔比)投料，在EtOAc溶剂体系中室温悬浮搅拌约2天，固体样品离心分离并于室温真空干燥17小时后，再将其在EtOAc溶剂体系中循环升降温悬浮搅拌 约4天后，分离固体经室温真空干燥约20小时后得到。
XRPD结构如图9所示。
效果实施例：
实验例1：RAS介导的信号转导的抑制
如下评定并证明本文所公开的化合物抑制RAS介导的信号传导的能力。表达突变型RAS(G12C)的细胞NCI-H358(ATCC目录号CRL-5807)利用含10％的胎牛血清，盘尼西林/链霉素双抗的RPMI培养基培养。细胞按每孔40,000个细胞铺于96孔板(Corning目录号3699)中，静置过夜使其附着于板底上。用本发明化合物或不用本发明化合物(二甲基亚砜，DMSO)对细胞进行处理，并保证DMSO的终浓度为0.5％。2小时处理后，去除培养基，加入4％多聚甲醛(Beyotime目录号E672002-0100)，静置20分钟。细胞固定后使用PBS清洗，用预冷的甲醇孵育10分钟以通透细胞膜。加入1X封闭缓冲液(Thermo目录号37520)孵育1小时阻断非特异性抗体的结合。
磷酸化ERK水平的检测使用酶联免疫吸附(ELISA)方法。磷酸化ERK抗体(Cell Signal Technology目录号4370)用含0.05％吐温20的1X封闭液按1：400稀释，加入96孔板并在4℃孵育过夜。用含0.05％吐温20的PBS将板子洗5遍。偶联HRP的二抗(Thermo目录号31460)用含0.05％吐温20的1X封闭液按1：10,000稀释，加入96孔板并在室温孵育2小时。用含0.05％吐温的PBS将板子洗5遍，加入TMB(Thermo目录号4816)并在室温孵育15分钟。加入1mol/L H2SO4中止反应，使用EnVision(PerkinElmer)在450nm波长处读OD值。
每孔细胞总数的检测使用健那绿染色法。检测完磷酸化ERK水平的96孔板用PBS清洗至无色，加入0.1％健那绿(Abcam目录号ab111622)孵育10分钟。用双蒸水清洗后加入0.1mol/L HCl振荡孵育10分钟。使用EnVision(PerkinElmer)在595nm波长处读OD值。
pERK(Thr202/Tyr204)的信号使用健那绿的信号值进行归一，并计算药物处理后相对于DMSO参照的抑制百分比。百分比数值通过四参数的剂量反应曲线拟合并生成IC50值。实验结果如表24所示。
表24
化合物编号 p-ERK IC50(NCI H358,μM)
ARS-1620 0.325
式(I)化合物 0.009
本发明化合物表现出优异的抑制RAS介导的信号传导的能力。
实验例2：抑制表达KRAS-G12C肿瘤细胞系的生长能力实验
通过测定细胞活率并计算GI50值来评价本发明化合物对表达KRAS-G12C细胞的生长抑制能力。
肿瘤细胞系NCI-H358(ATCC目录号CRL-5807)表达KRAS-G12C，使用添加有10％胎牛血清(fetal bovine serum)和盘尼西林/链霉素双抗(penicillin/streptomycin)的RPMI培养基培养；肿瘤细胞系MIA PaCa2(ATCC CRL-1420)表达KRAS-G12C，使用添加有10％胎牛血清(fetal bovine serum)、2.5％马血清(horse serum)和盘尼西林/链霉素双抗(penicillin/streptomycin)的DMEM培养基培养。
将细胞NCI-H358、MIA-Paca2分别以1000、800个的细胞密度接种于黑色透明底384孔板(PerkinElmer目录号6007460)中，并允许细胞贴壁过夜(8-12小时)。细胞贴壁后，实验组加入稀释后的5倍于工作液 浓度的本发明化合物(终浓度含0.1％二甲基亚砜，即DMSO)；对照组加入与实验组相同的稀释液(终浓度含0.1％DMSO)。72小时后，使用Cell Titer Glo试剂(Promega目录号G7572)按说明书方法检测ATP含量来测定细胞增殖量。简要操作步骤为：将细胞板取出并置于常温平衡30分钟；加入与培养物等体积的Cell Titer Glo试剂；将培养板置于摇床上震荡裂解2分钟；将培养板在常温静置10分钟；利用酶标仪EnVision(PerkinElmer)读取光信号值。
所有实验组数据利用DMSO组计算各自抑制百分率，利用数据处理软件GraphPad分析9个按1/3倍比稀释的化合物剂量浓度产生的抑制率计算出GI50。实验结果如表25所示。
表25
化合物编号 GI 50(NCI-H358,μM) GI 50(MIA-Paca2,μM)
ARS-1620 0.51 1.21
式(I)化合物 0.007 0.004
实验例3 药代动力学实验：
本实验例对小鼠通过静脉注射和口服给药进行了体内药代动力学评价。
实验方法和条件：雄性ICR小鼠，分别单次给予待测化合物1mg/Kg(静脉注射，溶剂5％DMSO+15％Solutol+80％saline)和5mg/Kg(灌胃给药，溶剂1％Tween80/2％HPMC/97％water)，给药后5,15,30min,1,2,4,6,8,24hr经眼眶静脉采血，每个样品采集约0.20mL，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆待测。血浆中血药浓度的检测采用液相串联质谱法(LC/MS/MS)，测得浓度用以计算药代动力学参数。结果如下表26和表27所示。
表26：静脉给药(1mg/kg)的药代动力学
化合物 T 1/2(hr) AUC inf(ng*hr/mL) Vz(mL/Kg) Cl(mL/min/kg)
AMG 510 0.26 176.19 2159.04 94.59
式(I)化合物 1.43 368.33 5615.42 45.25
表27：灌胃注射给药(5mg/kg)的药代动力学
化合物 T 1/2(hr) C max(ng/mL) AUC inf(ng*hr/mL) F(％)
AMG 510 0.57 177.00 155.14 17.61
式(I)化合物 1.06 108.72 421.20 22.87
结论：可见本发明化合物在小鼠体内药代吸收良好，具有药代动力学优势。
实验例4 异种移植实验
Nu/Nu Nude雌性小鼠(n＝7-10)以每笼五只动物关养且使其自由接近自来水和商业鼠粮(Harlan Teklad 22/5啮齿动物饲料-8640)。进行细胞系异种移植实验，使NCI-H358肿瘤在小鼠中生长。一旦肿瘤尺寸达到300mm 3，动物经随机分组且用溶媒对照(1％Tween80+1％HPMC)或化合物(剂量分别为：10毫克/千克/天，30毫克/千克/天，100毫克/千克/天，口服)治疗。使用式)0.5X长度X宽度X宽度计算肿瘤体积。在实验结束时，杀死动物，收集肿瘤，称重，且储存用于另外的分析。
其中施用式(I)化合物后，其小鼠体重变化的结果如图10所示，肿瘤体积变化的结果如图11所示。

Claims (29)

  1. 式(Ⅰ)所示化合物的硫酸盐，
    Figure PCTCN2022082855-appb-100001
  2. 根据权利要求1所述的硫酸盐，其特征在于，所述硫酸盐含有相对于化合物(I)为0.5～3.0摩尔当量的硫酸。
  3. 式(Ⅰ)所示化合物的硫酸盐的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.2°、11.93±0.2°、12.34±0.2°、12.99±0.2°、16.80±0.2°、17.75±0.2°。
  4. 根据权利要求3所述的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.17±0.2°、11.93±0.2°、12.34±0.2°、12.99±0.2°、13.54±0.2°、16.80±0.2°、17.75±0.2°、19.09±0.2°、20.91±0.2°、21.71±0.2°。
  5. 根据权利要求4所述的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱具有基本上如图1所示的X射线粉末衍射图谱。
  6. 式(Ⅰ)所示化合物的硫酸盐的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.67±0.2°、8.78±0.2°、10.28±0.2°、11.02±0.2°、12.19±0.2°、15.51±0.2°。
  7. 根据权利要求6所述的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.67±0.2°、8.78±0.2°、10.28±0.2°、11.02±0.2°、12.19±0.2°、12.60±0.2°、13.14±0.2°、15.51±0.2°、15.99±0.2°、19.56±0.2°。
  8. 根据权利要求6所述的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱具有基本上如图2所示的X射线粉末衍射图谱。
  9. 式(Ⅰ)所示化合物的硫酸盐的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.51±0.2°、7.71±0.2°、11.90±0.2°、13.67±0.2°、15.69±0.2°、20.15±0.2°。
  10. 根据权利要求9所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱具有基本上如图3所示的X射线粉末衍射图谱。
  11. 式(Ⅰ)所示化合物的硫酸盐的晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.85±0.2°、10.29±0.2°、12.78±0.2°、16.36±0.2°、19.84±0.2°、20.66±0.2°。
  12. 根据权利要求11所述的晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱具有基本上如图4所示的X射线粉末衍射图谱。
  13. 式(Ⅰ)所示化合物的硫酸盐的晶型E，其特征在于，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.52±0.2°、8.93±0.2°、11.04±0.2°、12.16±0.2°、12.82±0.2°、22.67±0.2°。
  14. 根据权利要求13所述的晶型E，其特征在于，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有 特征衍射峰：5.52±0.2°、8.52±0.2°、8.93±0.2°、11.04±0.2°、12.16±0.2°、12.82±0.2°、14.63±0.2°、15.34±0.2°、16.88±0.2°、22.67±0.2°。
  15. 根据权利要求13所述的晶型E，其特征在于，所述晶型E的X射线粉末衍射图谱具有基本上如图5所示的X射线粉末衍射图谱。
  16. 式(Ⅰ)所示化合物的硫酸盐的晶型F，其特征在于，所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.40±0.2°、13.01±0.2°、18.09±0.2°、21.65±0.2°。
  17. 根据权利要求16所述的晶型F，其特征在于，所述晶型F的X射线粉末衍射图谱具有基本上如图6所示的X射线粉末衍射图谱。
  18. 式(Ⅰ)所示化合物的硫酸盐的晶型G，其特征在于，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.88±0.2°、7.05±0.2°、9.39±0.2°、10.87±0.2°、12.00±0.2°、16.15±0.2°。
  19. 根据权利要求18所述的晶型G，其特征在于，所述晶型G的X射线粉末衍射图谱具有基本上如图7所示的X射线粉末衍射图谱。
  20. 式(Ⅰ)所示化合物的硫酸盐的晶型H，其特征在于，所述晶型H的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.11±0.2°、11.59±0.2°、12.19±0.2°、15.66±0.2°、18.34±0.2°、13.82±0.2°。
  21. 根据权利要求20所述的晶型H，其特征在于，所述晶型H的X射线粉末衍射图谱具有基本上如图8所示的X射线粉末衍射图谱。
  22. 式(Ⅰ)所示化合物的苯磺酸盐。
  23. 根据权利要求22所述的苯磺酸盐，其特征在于，所述苯磺酸盐含有相对于化合物(I)为0.5-3.0摩尔当量的苯磺酸。
  24. 式(Ⅰ)所示化合物的苯磺酸盐的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.63±0.2°、12.05±0.2°、13.78±0.2°、15.09±0.2°、16.04±0.2°、18.35±0.2°。
  25. 根据权利要求24所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：7.63±0.2°、11.35±0.2°、12.05±0.2°、13.78±0.2°、15.09±0.2°、16.04±0.2°、16.65±0.2°、18.35±0.2°、18.87±0.2°、23.53±0.2°。
  26. 根据权利要求25所述的晶型I，其特征在于，所述晶型I的X射线粉末衍射图谱具有基本上如图9所示的X射线粉末衍射图谱。
  27. 一种药物组合物，其特征在于，所述药物组合物含有如权利要求1-2所述的式(Ⅰ)所示化合物的硫酸盐或如权利要求3-5所述的晶型A或如权利要求6-8所述的晶型B或如权利要求9-10所述的晶型C或如权利要求11-12所述的晶型D或如权利要求13-15所述的晶型E或如权利要求16-17所述的晶型F或如权利要求18-19所述的晶型G或如权利要求20-21所述的晶型H或如权利要求22-23所述的式(Ⅰ)所示化合物的苯磺酸盐或如权利要求24-26所述的晶型I。
  28. 如权利要求1-2所述的式(Ⅰ)所示化合物的硫酸盐或如权利要求3-5所述的晶型A或如权利要求6-8所述的晶型B或如权利要求9-10所述的晶型C或如权利要求11-12所述的晶型D或如权利要求13-15所述的晶型E或如权利要求16-17所述的晶型F或如权利要求18-19所述的晶型G或如权利要求20-21所述的晶型H或如权利要求22-23所述的式(Ⅰ)所示化合物的苯磺酸盐或如权利要求24-26所述的晶型I或如权利要求27所述的药物组合物在制备预防和/或治疗用作KRAS-G12C相关疾病的药物中的用途。
  29. 根据权利要求28所述的用途，其特征在于，所述的KRAS-G12C相关疾病选自非小细胞肺癌，结肠癌和胰腺癌。
PCT/CN2022/082855 2021-03-25 2022-03-24 稠合吡啶酮类化合物盐型、晶型及其应用 Ceased WO2022199669A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280020397.3A CN116964056A (zh) 2021-03-25 2022-03-24 稠合吡啶酮类化合物盐型、晶型及其应用

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202110321727.X 2021-03-25
CN202110321727 2021-03-25
CN202210273262 2022-03-18
CN202210273262.X 2022-03-18

Publications (1)

Publication Number Publication Date
WO2022199669A1 true WO2022199669A1 (zh) 2022-09-29

Family

ID=83396351

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/082855 Ceased WO2022199669A1 (zh) 2021-03-25 2022-03-24 稠合吡啶酮类化合物盐型、晶型及其应用

Country Status (3)

Country Link
CN (1) CN116964056A (zh)
TW (1) TW202246267A (zh)
WO (1) WO2022199669A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019110751A1 (en) * 2017-12-08 2019-06-13 Astrazeneca Ab Tetracyclic compounds as inhibitors of g12c mutant ras protein, for use as anti-cancer agents
WO2020239123A1 (zh) * 2019-05-31 2020-12-03 上海翰森生物医药科技有限公司 芳香杂环类衍生物调节剂、其制备方法和应用
CN112300194A (zh) * 2019-07-30 2021-02-02 上海凌达生物医药有限公司 一类稠环吡啶酮类化合物、制备方法和用途
WO2021052499A1 (zh) * 2019-09-20 2021-03-25 上海济煜医药科技有限公司 稠合吡啶酮类化合物及其制备方法和应用
WO2021083167A1 (zh) * 2019-10-30 2021-05-06 劲方医药科技(上海)有限公司 取代的杂环并环类化合物，其制法与医药上的用途
WO2022037630A1 (zh) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 四环类衍生物、其制备方法及其医药上的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019110751A1 (en) * 2017-12-08 2019-06-13 Astrazeneca Ab Tetracyclic compounds as inhibitors of g12c mutant ras protein, for use as anti-cancer agents
WO2020239123A1 (zh) * 2019-05-31 2020-12-03 上海翰森生物医药科技有限公司 芳香杂环类衍生物调节剂、其制备方法和应用
CN112300194A (zh) * 2019-07-30 2021-02-02 上海凌达生物医药有限公司 一类稠环吡啶酮类化合物、制备方法和用途
WO2021052499A1 (zh) * 2019-09-20 2021-03-25 上海济煜医药科技有限公司 稠合吡啶酮类化合物及其制备方法和应用
WO2021083167A1 (zh) * 2019-10-30 2021-05-06 劲方医药科技(上海)有限公司 取代的杂环并环类化合物，其制法与医药上的用途
WO2022037630A1 (zh) * 2020-08-21 2022-02-24 浙江海正药业股份有限公司 四环类衍生物、其制备方法及其医药上的用途

Also Published As

Publication number Publication date
CN116964056A (zh) 2023-10-27
TW202246267A (zh) 2022-12-01

Similar Documents

Publication Publication Date Title
US10000496B2 (en) Compositions useful for treating disorders related to kit and PDGFR
EP3176173B1 (en) Crystalline free bases of c-met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof
CN107286077A (zh) 一种选择性的c-kit激酶抑制剂
CN112888690B (zh) 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途
CN114315837A (zh) 一种erk抑制剂的结晶形式及其制备方法
CN112142675B (zh) 一种作为jak激酶抑制剂的小分子化合物及其用途
KR20230051207A (ko) Jak 억제제의 염 형태, 결정형, 이의 제조방법 및 이의 용도
CN111205290B (zh) 一种jak激酶抑制剂的结晶形式及其制备方法
CA3239187A1 (en) Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof
CN117043163A (zh) 吡咯并嘧啶类或吡咯并吡啶类衍生物及其医药用途
WO2022199669A1 (zh) 稠合吡啶酮类化合物盐型、晶型及其应用
AU2017239301A1 (en) Crystalline forms of hydrochloride of drug for treating or preventing JAK-associated disease and preparation method thereof
WO2023011428A1 (zh) Ripk1抑制剂的晶型及其酸式盐和其酸式盐的晶型
WO2022171117A1 (zh) 含氮稠杂环化合物的盐、晶型及其制备方法、药物组合物和用途
EP3632912B1 (en) Pyridoquinazoline derivatives useful as protein kinase inhibitors
CN116178433A (zh) Axl激酶抑制剂的盐及其制备方法和用途
EP4596553A1 (en) Salt of dioxane quinoline compound, crystal form thereof, preparation methods therefor and uses thereof
TWI777438B (zh) N- (苯基磺醯基) 苯甲醯胺類化合物的結晶形式
CN111303024A (zh) 一种喹啉结构的pan-KIT激酶抑制剂及其用途
TW201829398A (zh) 酪胺酸蛋白激酶調節劑、晶型及其用途
CN116514726A (zh) 嘧啶类衍生物及其用途
CN115515954A (zh) 6-氯-7-(4-(4-氯苄基)哌嗪-1-基)-2-(1,3-二甲基-1h-吡唑-4-基)-3h-咪唑并[4,5-b]吡啶的盐和多晶型形式
HK40050133B (zh) 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途
HK40050133A (zh) 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途
BR112019024892B1 (pt) Inibidores da proteína quinase

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22774323

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280020397.3

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22774323

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 22774323

Country of ref document: EP

Kind code of ref document: A1