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WO2025157260A1 - Sel pharmaceutiquement acceptable d'un composé inhibiteur de g12d et forme cristalline de celui-ci - Google Patents

Sel pharmaceutiquement acceptable d'un composé inhibiteur de g12d et forme cristalline de celui-ci

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Publication number
WO2025157260A1
WO2025157260A1 PCT/CN2025/074647 CN2025074647W WO2025157260A1 WO 2025157260 A1 WO2025157260 A1 WO 2025157260A1 CN 2025074647 W CN2025074647 W CN 2025074647W WO 2025157260 A1 WO2025157260 A1 WO 2025157260A1
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WO
WIPO (PCT)
Prior art keywords
cancer
methyl
compound
ray powder
fluoro
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.)
Pending
Application number
PCT/CN2025/074647
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English (en)
Chinese (zh)
Inventor
张浩宇
吴琪
拜堃
邵启云
王捷
冯君
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.)
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
Original Assignee
Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Filing date
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Application filed by Shanghai Hengrui Pharmaceutical Co Ltd, Jiangsu Hengrui Pharmaceutical Co Ltd filed Critical Shanghai Hengrui Pharmaceutical Co Ltd
Publication of WO2025157260A1 publication Critical patent/WO2025157260A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present disclosure belongs to the field of pharmaceuticals and relates to pharmaceutically acceptable salts of G12D inhibitor compounds and their preparation methods and crystal forms.
  • the KRAS protein lacks traditional small molecule binding sites on its surface and has an extremely high affinity for guanylate, making it extremely difficult to inhibit. Long considered an undruggable drug target, however, given the importance and prevalence of KRAS activation in cancer progression, KRAS has been and remains a highly sought-after target for drug development. As a mutant with widespread and overexpressed expression in various tumors, G12D, the development of inhibitors targeting it, holds significant clinical significance.
  • WO2024022444 discloses a novel G12D inhibitor compound, 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Compound A).
  • Salt formation can improve certain undesirable physicochemical or biological properties of drugs.
  • the development of salts with superior physicochemical or pharmaceutical properties compared to 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile is of great significance.
  • the present disclosure provides a pharmaceutically acceptable salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, L-tartrate, maleate, citrate, L-malate, p-toluenesulfonate, methanesulfonate, benzoate, succinate, and fumarate.
  • the chemical ratio of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile to the acid molecule is 1:0.5 to 1:3, including 1:0.5, 1:1, 1:2 or 1:3.
  • the chemical ratio of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and the acid molecule is 1:1.
  • Some embodiments provide the hydrochloride salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, wherein the chemical ratio of the compound to HCl is 1:1 to 1:2.
  • Some embodiments provide the L-tartrate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, wherein the chemical ratio of the compound to L-tartaric acid is 1:1.
  • Some embodiments provide a maleate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, wherein the chemical ratio of the compound to maleic acid is 1:1.
  • Some embodiments provide a citrate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, wherein the chemical ratio of the compound to citric acid is 1:1 to 1:2.
  • Some embodiments provide a succinate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, wherein the chemical ratio of the compound to succinic acid is 1:1.
  • Some embodiments provide a methanesulfonate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, wherein the chemical ratio of the compound to methanesulfonic acid is 1:1 to 1:2.
  • Some embodiments provide a citrate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, wherein the chemical ratio of the compound to citric acid is 1:1 or 1:2.
  • Another aspect of the present disclosure provides a pharmaceutically acceptable salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptan-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • the preparation method includes the step of forming a salt of the compound 2-amino-4-((5S, 5aS, 6S, 9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,
  • the acid used in the salt-forming reaction is selected from hydrochloric acid, sulfuric acid, phosphoric acid, L-tartaric acid, maleic acid, citric acid, L-malic acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, succinic acid and fumaric acid.
  • the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile is reacted with hydrogen chloride/ethanol solution to form a hydrochloride salt.
  • the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile is reacted with a hydrogen chloride/dioxane solution to form the hydrochloride salt.
  • the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile is reacted with a phosphoric acid/ethanol solution to form a phosphate salt.
  • the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile is reacted with an L-tartaric acid/ethanol solution to form the tartrate salt.
  • the solvent used in the salt-forming reaction is at least one selected from methanol, ethanol, acetonitrile, ethyl acetate, methyl isobutyl ketone and 2-methyltetrahydrofuran.
  • the present disclosure also provides a crystalline form A of the hydrochloride salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ having characteristic peaks at 4.765, 9.445, 14.148, 14.671, and 18.874.
  • the hydrochloride salt form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.765, 9.058, 9.445, 14.148, 14.671, and 18.874.
  • the X-ray powder diffraction pattern of the hydrochloride salt form A expressed in terms of a diffraction angle 2 ⁇ is shown in FIG1 .
  • the present disclosure also provides a method for preparing the hydrochloride salt form A of the aforementioned compound, comprising the steps of: (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and methanol; and (b) adding an HCl/dioxane solution and stirring.
  • the present disclosure also provides a hydrochloride salt form B of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees has characteristic peaks at 5.048, 8.691, 10.031, 14.977, 16.254, and 19.987.
  • the hydrochloride salt form B has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.048, 8.691, 10.031, 12.987, 14.977, 16.254, 19.737, and 19.987.
  • the hydrochloride salt form B has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 5.048, 8.691, 10.031, 12.987, 14.977, 16.254, 17.138, 19.737, 19.987, and 28.214.
  • the X-ray powder diffraction pattern of the hydrochloride salt form B expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG2 .
  • the present disclosure also provides a method for preparing the hydrochloride form B of the aforementioned compound, comprising the steps of: (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and acetonitrile; and (b) adding an HCl/dioxane solution and stirring.
  • the present disclosure also provides a hydrochloride salt form C of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 17.222, 7.804, and 7.526.
  • the X-ray powder diffraction pattern of the hydrochloride salt form C expressed in terms of a diffraction angle 2 ⁇ is shown in FIG3 .
  • the present disclosure also provides a method for preparing the hydrochloride salt form C of the aforementioned compound, comprising the steps of: (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and ethyl acetate; and (b) adding an HCl/dioxane solution and stirring.
  • the present disclosure also provides a sulfate salt crystalline form A of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees having characteristic peaks at 4.722, 9.103, 12.864, 14.146, 14.704, and 18.899.
  • the sulfate salt crystal form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.722, 9.103, 12.864, 14.146, 14.704, 17.681, 18.899, and 20.897.
  • the sulfate salt crystal form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.722, 9.103, 12.864, 14.146, 14.704, 17.681, 18.899, 20.897, 22.102, and 25.406.
  • the X-ray powder diffraction pattern of the sulfate salt crystal form A expressed in terms of a diffraction angle 2 ⁇ is shown in FIG4 .
  • the present disclosure also provides a method for preparing the sulfate salt crystal form A of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S, 5aS, 6S, 9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and acetonitrile, and (b) adding a sulfuric acid/ethanol solution and stirring.
  • the present disclosure also provides a phosphate crystal form A of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees has characteristic peaks at 4.735, 9.012, 14.150, 14.661, and 18.894.
  • the phosphate crystal form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.735, 9.012, 11.783, 12.846, 14.150, 14.661, and 18.894.
  • the phosphate crystal form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.735, 9.012, 11.783, 12.846, 14.150, 14.661, 18.894, 20.947, and 22.072.
  • the X-ray powder diffraction pattern of the phosphate crystal form A expressed in terms of a diffraction angle 2 ⁇ is shown in FIG5 .
  • the present disclosure also provides a method for preparing the phosphate salt A crystal form of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and ethanol, and (b) adding phosphoric acid and stirring.
  • the present disclosure also provides a phosphate form B of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, and an X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees, having characteristic peaks at 5.001, 8.678, 11.020, 12.981, 14.846, and 19.704.
  • the phosphate B crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.001, 8.678, 11.020, 12.981, 14.846, 16.242, 19.704, and 21.356.
  • the phosphate B crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.001, 8.678, 11.020, 12.981, 14.846, 16.242, 16.723, 19.704, 21.356, and 22.508.
  • the X-ray powder diffraction pattern of the phosphate B crystal form expressed in terms of a diffraction angle 2 ⁇ is shown in FIG6 .
  • the present disclosure also provides a method for preparing the phosphate B crystal form of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and acetonitrile, and (b) adding phosphoric acid and stirring.
  • the present disclosure also provides a crystalline form A of the L-tartrate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ having characteristic peaks at 5.687, 7.991, 10.409, and 12.828.
  • the L-tartrate salt form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.687, 7.991, 10.409, 12.828, 16.244, 20.083, and 21.427.
  • the X-ray powder diffraction pattern of the L-tartrate salt form A expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG7 .
  • the present disclosure also provides a method for preparing the L-tartrate salt form A of the aforementioned compound, comprising the steps of mixing the compound 2-amino-4-((5S, 5aS, 6S, 9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and a solvent (1), (b) adding L-tartaric acid, and stirring, wherein the solvent (1) is selected from methanol.
  • the present disclosure also provides a crystalline form A of the citrate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ having characteristic peaks at 7.276, 15.823, 17.940, 18.247, 19.645, and 21.863.
  • the citrate salt form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.276, 15.823, 17.940, 18.247, 19.645, 21.863, 30.027, and 35.408.
  • the citrate salt form A has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 5.120, 7.276, 15.823, 17.305, 17.940, 18.247, 19.645, 21.863, 30.027, and 35.408.
  • the X-ray powder diffraction pattern of the citrate salt form A expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG8 .
  • the present disclosure also provides a method for preparing the citrate salt form A of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and ethyl acetate, and (b) adding citric acid and stirring.
  • the present disclosure also provides a citrate salt form B of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees having characteristic peaks at 8.663, 19.723, 14.863, and 10.973.
  • the citrate salt form B has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.663, 10.973, 14.863, 16.264, 19.723, and 22.586.
  • the X-ray powder diffraction pattern of the citrate salt form B expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG9 .
  • the present disclosure also provides a method for preparing the citrate salt form B of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and acetonitrile, and (b) adding citric acid and stirring.
  • the present disclosure also provides a citrate salt form C of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees having characteristic peaks at 7.076, 7.483, 15.665, 17.203, and 19.775.
  • the citrate salt form C has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.952, 7.076, 7.483, 13.147, 15.665, 17.203, and 19.775.
  • the citrate salt form C has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.952, 7.076, 7.483, 13.147, 15.665, 16.499, 17.203, 17.746, and 19.775.
  • the X-ray powder diffraction pattern of the citrate salt form C expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG10 .
  • the present disclosure also provides a citrate salt form D of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ degrees having characteristic peaks at 4.728, 9.421, 14.12, 14.619, and 18.856.
  • the citrate salt form D has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 4.728, 9.421, 14.12, 14.619, 18.856, 20.922, 29.106, and 33.272.
  • the X-ray powder diffraction pattern of the citrate salt form D expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG11 .
  • the present disclosure also provides a method for preparing the citrate D crystalline form of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and ethanol, and (b) adding citric acid and stirring.
  • the present disclosure also provides a crystalline form A of the methanesulfonate of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ having characteristic peaks at 7.553, 9.757, and 13.097.
  • the mesylate salt form A has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 7.553, 9.757, 13.097, 16.859, 18.394, 19.738, 20.429, and 21.082.
  • the X-ray powder diffraction pattern of the mesylate salt form A expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG12 .
  • the present disclosure also provides a method for preparing a crystalline form A of a mesylate salt of the aforementioned compound, comprising the steps of mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and a solvent (2), (b) adding methanesulfonic acid, and then adding a solvent (3), and stirring, wherein the solvent (2) is selected from 2-methyltetrahydrofuran, and the solvent (3) is selected from n-h
  • the present disclosure also provides a crystalline form A of the benzoate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ having characteristic peaks at 7.515, 8.359, and 11.945.
  • the benzoate salt form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.515, 8.002, 8.359, 11.945, 12.920, and 18.970.
  • the X-ray powder diffraction pattern of the benzoate salt form A expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG13 .
  • the present disclosure also provides a method for preparing a crystalline form A of the benzoate salt of the aforementioned compound, comprising the steps of mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and a solvent (4), (b) adding benzoic acid, and stirring, wherein the solvent (4) is selected from methyl isobutyl ketone or 2-methyltetrahydrofuran.
  • the present disclosure also provides a crystalline form A of the succinate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ having characteristic peaks at 7.943, 10.351, 12.828, 16.138, 19.832, and 21.057.
  • the succinate salt form A has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.943, 10.351, 12.828, 13.212, 16.138, 19.832, 21.057, and 23.619.
  • the succinate salt form A has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 6.685, 7.943, 10.351, 12.828, 13.212, 16.138, 19.832, 21.057, 21.465, and 23.619.
  • the X-ray powder diffraction pattern of the succinate salt form A expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG14 .
  • the present disclosure also provides a method for preparing a crystalline form A of the succinate salt of the aforementioned compound, comprising the steps of mixing the compound 2-amino-4-((5S, 5aS, 6S, 9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and a solvent (5), (b) adding succinic acid, and stirring, wherein the solvent (5) is selected from methyl isobutyl ketone.
  • the present disclosure also provides a crystalline form B of the succinate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, the X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ having characteristic peaks at 7.189, 7.976, 8.802, 10.681, and 15.899.
  • the succinate salt form B has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.189, 7.976, 8.802, 10.681, 15.899, 22.331, and 28.635.
  • the succinate salt form B has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 4.420, 4.989, 7.189, 7.976, 8.802, 10.681, 15.899, 22.331, and 28.635.
  • the X-ray powder diffraction pattern of the succinate salt form B expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG15 .
  • the present disclosure also provides a method for preparing the succinate salt form B of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S, 5aS, 6S, 9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and acetonitrile, and (b) adding succinic acid and stirring.
  • the present disclosure also provides a crystalline form C of the succinate salt of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle 2 ⁇ , having characteristic peaks at 5.179, 7.238, 7.525, 13.268, 15.91, and 17.916.
  • the succinate salt form C has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.179, 7.238, 7.525, 13.268, 15.91, 16.681, 17.357, and 17.916.
  • the succinate salt form C has an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , with characteristic peaks at 5.179, 7.238, 7.525, 8.693, 10.064, 13.268, 15.91, 16.681, 17.357, 17.916, and 19.45.
  • the X-ray powder diffraction pattern of the succinate salt form C expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG16 .
  • the present disclosure also provides a method for preparing the succinate salt crystal form C of the aforementioned compound, comprising the steps of (a) mixing the compound 2-amino-4-((5S, 5aS, 6S, 9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptylcyclo-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and ethyl acetate, and (b) adding succinic acid and stirring.
  • the present invention discloses an X-ray powder diffraction pattern of the aforementioned crystal form expressed in terms of a diffraction angle 2 ⁇ , wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • the present disclosure also provides a complex comprising the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and saccharin.
  • the chemical ratio of the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanaptho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile to the saccharin molecule is 1:1.
  • the present disclosure also provides a method for preparing a complex, which includes the step of mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile with saccharin.
  • a method for preparing a complex comprises the steps of mixing the compound 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methylnaphtho[1,8-ab]heptyl-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile and a solvent (6), (b) adding saccharin, and then adding a solvent (7), and stirring, wherein the solvent (6) is selected from methanol or 2-methyltetrahydrofuran, and the solvent (7) is selected from isopropyl ether or n-heptane.
  • the preparation method disclosed herein further comprises any one of the steps of stirring and dissolving or heating and dissolving, crystallizing, filtering, washing or drying.
  • the crystallization includes but is not limited to stirring crystallization, such as dissolution crystallization.
  • the drying method includes but is not limited to forced air drying and vacuum drying.
  • the drying temperature is generally 25°C to 100°C, preferably 30°C to 70°C, such as 40°C, 50°C or 60°C.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or a complex and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a pharmaceutical composition prepared from the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or the complex and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or the complex with a pharmaceutically acceptable excipient.
  • the present disclosure also provides the use of the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or the complex, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease or condition mediated by KRAS G12D.
  • the disease or condition mediated by KRAS G12D is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma.
  • the present disclosure also provides the use of the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or the complex, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a tumor.
  • the tumor is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neuro
  • the present disclosure also provides a method for preventing and/or treating a disease or condition mediated by KRAS G12D, which comprises administering the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or the complex, or the aforementioned pharmaceutical composition to a patient.
  • the present disclosure also provides a method for preventing and/or treating tumors, which comprises administering to a patient the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or the complex, or the aforementioned pharmaceutical composition.
  • the tumor is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, testi
  • the present disclosure also provides the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or complex, or the aforementioned pharmaceutical composition for preventing and/or treating diseases or conditions mediated by KRAS G12D.
  • the present disclosure also provides the aforementioned pharmaceutically acceptable salt, or the aforementioned crystal form, or the complex, or the aforementioned pharmaceutical composition for preventing and/or treating tumors.
  • the tumor is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, gli
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • the numerical values in this disclosure are instrumental measurements or calculated values after instrumental measurement, and are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used must be considered.
  • the total impurity content which is a value with an error variation of no more than plus or minus 10% after measurement, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.
  • the "differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • the drying temperature in the present disclosure is generally 25°C-100°C, preferably 30°C-70°C, and can be dried under normal pressure or reduced pressure.
  • a “complex” refers to a substance in which two compounds of different types are connected by non-covalent bonds.
  • the two compounds are connected by at least one of hydrogen bonds, van der Waals forces, or ⁇ - ⁇ forces.
  • compositions include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.
  • Figure 1 is the XRPD spectrum of Form A of the hydrochloride salt of Compound A.
  • Figure 2 is the XRPD spectrum of the hydrochloride form B of compound A.
  • Figure 3 is the XRPD spectrum of Form C of the hydrochloride salt of Compound A.
  • Figure 4 is the XRPD spectrum of the sulfate salt form A of compound A.
  • Figure 5 is the XRPD spectrum of the phosphate A crystal form of compound A.
  • Figure 6 is an XRPD spectrum of the phosphate B crystal form of compound A.
  • Figure 7 is the XRPD spectrum of L-tartrate salt Form A of Compound A.
  • Figure 8 is an XRPD spectrum of Form A of the citrate salt of Compound A.
  • Figure 9 is an XRPD spectrum of the citrate salt Form B of Compound A.
  • Figure 10 is an XRPD spectrum of Form C of the citrate salt of Compound A.
  • Figure 11 is the XRPD spectrum of the citrate salt Form D of Compound A.
  • FIG12 is an XRPD spectrum of Form A of the mesylate salt of Compound A.
  • Figure 13 is an XRPD spectrum of Form A of the benzoate salt of Compound A.
  • Figure 14 is an XRPD spectrum of the succinate salt Form A of Compound A.
  • Figure 15 is an XRPD spectrum of the succinate salt Form B of Compound A.
  • Figure 16 is an XRPD spectrum of Form C of the succinate salt of Compound A.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS measurements were performed using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS instrument (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), a Waters ACQuity UPLC-QD/SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q 15 Exactive).
  • HPLC determinations were performed using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6 mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6 mm column).
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: ⁇ /2 ⁇ , scanning range: 3-48°.
  • DSC stands for differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min, 25-300°C or 25-350°C, and a nitrogen purge rate of 50 mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C/min. The specific temperature range was referred to the corresponding spectrum, and the nitrogen purge rate was 50 mL/min.
  • DVS dynamic moisture adsorption: using Surface Measurement Systems instrinsic, humidity starts from 50%, the humidity range is 0%-95%, the step is 10%, the judgment standard is each gradient mass change dM/dT ⁇ 0.002%, TMAX 360min, two cycles.
  • the known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.
  • the reaction progress in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.
  • the crude compound 1a (2 g, 8 mmol) was dissolved in phosphorus oxychloride (25 mL), and N,N-diisopropylethylamine (5.16 g, 40 mmol) was added. The reaction was stirred at 110°C for 14 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. The mixture was stirred for 2 hours and then filtered. The filter cake was washed with water and dried to obtain the crude title compound 1b (1.5 g). The product was used directly in the next step without purification.
  • the crude compound 1k (40 mg, 44.1 ⁇ mol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added. After stirring for 1 hour, the reaction was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 ⁇ m; mobile phase: aqueous phase (10 mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL/min) to give the title compound A (2 mg, yield: 6.4%).
  • the inhibitory effect of the disclosed compounds on the KRAS target was evaluated by testing the 3D proliferation inhibitory effect of the disclosed compounds on GP2d and AGS cells.
  • GP2d cells were cultured in complete medium (DMEM/high glucose medium (Hyclone, SH30243.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded at a density of 1000 cells/well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 ⁇ L of cell suspension was added to each well, centrifuged at 2000 rpm for 5 minutes at room temperature, and then incubated overnight at 37°C in a 5% CO2 incubator.
  • complete medium DMEM/high glucose medium (Hyclone, SH30243.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV).
  • GP2d cells were seeded at a density of 1000 cells/well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 ⁇ L of cell suspension
  • AGS cells were cultured in complete medium (RPMI1640 medium (Hyclone, SH30809.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV).
  • complete medium RPMI1640 medium (Hyclone, SH30809.01) supplemented with 10% fetal bovine serum (Corning, 35-076-CV).
  • AGS cells were seeded at a density of 1000 cells/well in a 96-well low attachment plate (Corning, CLS7007-24EA) using complete medium. 90 ⁇ L of cell suspension was added to each well. After centrifugation at 2000 rpm for 5 minutes at room temperature, the cells were incubated overnight at 37°C in a 5% CO2 incubator.
  • 3D Cell Viability Assay reagent (Promega, G9682) was shaken at room temperature in the dark for 25 minutes, then pipetted to mix thoroughly and 100 ⁇ L was transferred from each well to a white opaque 96-well plate (PerkinElmer, 6005290). The luminescence signal was read using a multi-function microplate reader (PerkinElmer, EnVision2105).
  • the IC50 values of the inhibitory activity of the compounds were calculated using Graphpad Prism software.
  • the IC50 value of the inhibitory activity of compound AGP2d on 3D cell proliferation was 0.4 nM.
  • a 20 mM DMSO-dissolved test compound was diluted with DMSO to a starting concentration of 2 mM. This was then serially diluted 5-fold to a total of nine concentration points, with DMSO as a control. The serially diluted compound was then further diluted 20-fold with culture medium. 10 ⁇ L of the test compound diluted with culture medium was added to each well of the plate for a final concentration of 10 ⁇ M starting at the 10 ⁇ M concentration and then serially diluted 5-fold to a total of nine concentration points. The wells containing 0.5% DMSO were set as vehicle control wells, and the wells containing only culture medium and 0.5% DMSO were set as blank control wells.
  • DMSO concentration in each well was 0.5%. After centrifugation at 2500 rpm for 3 minutes, the cell plate was placed in a 37°C, 5% CO2 incubator for 5 days. On the seventh day, the 96-well cell culture plate was removed and 50 ⁇ L of the luminescent cell activity detection reagent CellTiter- 3D Cell Viability Assay (Promega, G9683) was shaken at room temperature in the dark for 25 minutes. After mixing by pipetting up and down, 100 ⁇ L was transferred to each well of a white opaque OptiPlate TM -96-well plate (PerkinElmer, 6005290). Luminescence signals were read using a multi-function microplate reader (PerkinElmer, EnVision 2105).
  • GraphPad Prism software was used to plot inhibition rate curves based on compound concentrations and calculate compound IC50 values.
  • Compound A had an IC50 of 3.7 nM.
  • X-ray powder diffraction analysis revealed no obvious characteristic peaks in the XRPD spectrum, and ion chromatography analysis revealed a sulfate ion content of 19.77%.
  • the XRPD spectrum of the product is shown in FIG4 , and the positions of the characteristic peaks are shown in Table 4 , which is defined as sulfate crystal form A.
  • X-ray powder diffraction analysis revealed no obvious characteristic peaks in the XRPD spectrum, and ion chromatography analysis revealed a phosphate ion content of 23.33%.
  • the DSC spectrum showed endothermic peaks at 76.00°C, 128.84°C, and 190.18°C.
  • the TGA spectrum showed a weight loss of 3.47% from 32°C to 134°C and a weight loss of 1.75% from 134°C to 203°C.
  • X-ray powder diffraction analysis revealed no obvious characteristic peaks in the XRPD spectrum, and ion chromatography analysis revealed a maleate ion content of 13.16%.
  • X-ray powder diffraction analysis revealed no obvious characteristic peaks in the XRPD spectrum, and ion chromatography analysis revealed a citrate ion content of 20.60%.
  • X-ray powder diffraction analysis revealed an XRPD spectrum as shown in Figure 10 , with characteristic peak positions shown in Table 10 , defining it as citrate crystal form C. Nuclear magnetic resonance results showed a citric acid content of 29.0%.
  • X-ray powder diffraction analysis revealed no obvious characteristic peaks in the XRPD spectrum, and ion chromatography analysis revealed a malate ion content of 25.05%.
  • X-ray powder diffraction analysis identified the product as mesylate salt Form A.
  • the XRPD spectrum is shown in Figure 12, and the locations of its characteristic peaks are shown in Table 12.
  • Ion chromatography analysis revealed a mesylate ion content of 14.96%.
  • the DSC spectrum showed endothermic peaks at 178.17°C and 250.19°C, and an exothermic peak at 206.70°C.
  • the TGA spectrum revealed a weight loss of 2.19% between 30°C and 168°C.
  • X-ray powder diffraction analysis identified the product as succinate Form A.
  • the XRPD spectrum is shown in Figure 14, and the locations of its characteristic peaks are shown in Table 14.
  • Ion chromatography analysis revealed a succinate ion content of 13.38%.
  • the DSC spectrum showed an endothermic peak at 175.31°C.
  • the TGA spectrum revealed a weight loss of 1.75% from 30°C to 122°C.
  • the XRPD spectrum of the product is shown in Figure 16 and the characteristic peak positions are shown in Table 16.
  • the product is defined as succinate C crystal form.
  • the NMR results show that the succinic acid content is 25.3%.
  • X-ray powder diffraction analysis revealed no obvious characteristic peaks in the XRPD spectrum, and ion chromatography analysis revealed a fumarate ion content of 11.40%.
  • the above-mentioned salt was spread out in the open and the stability of the samples was examined under high temperature (40°C, 60°C) and high humidity (RH 75%, RH 92.5%) conditions.
  • the sampling period was 30 days.
  • succinate crystal form A showed good physical and chemical stability under high temperature 40°C and 60°C and high humidity 75% and 92.5% for 30 days.
  • Test Example 4 Long-term accelerated test

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Abstract

La présente divulgation concerne un sel pharmaceutiquement acceptable d'un composé inhibiteur de G12D et une forme cristalline de celui-ci. Plus particulièrement, la présente invention concerne un sel de 2-amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluorométhylène)pipéridin-1-yl)méthyl)cyclopropyl)méthoxy)-1-fluoro-5-méthyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-méthanonaphto[1,8-ab]cycloheptén-2-yl)-7-fluorobenzo[b]thiophène-3-carbonitrile et une forme cristalline de celui-ci.
PCT/CN2025/074647 2024-01-26 2025-01-24 Sel pharmaceutiquement acceptable d'un composé inhibiteur de g12d et forme cristalline de celui-ci Pending WO2025157260A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022188729A1 (fr) * 2021-03-07 2022-09-15 Jacobio Pharmaceuticals Co., Ltd. Dérivés cycliques fusionnés utiles en tant qu'inhibiteurs de kras g12d
WO2023001123A1 (fr) * 2021-07-19 2023-01-26 上海艾力斯医药科技股份有限公司 Nouveau dérivé de pyridopyrimidine
WO2023103906A1 (fr) * 2021-12-07 2023-06-15 贝达药业股份有限公司 Inhibiteur ciblant la kras g12d et son utilisation en médecine
WO2024022444A1 (fr) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Composé cyclique fusionné, son procédé de préparation et son application médicinale

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022188729A1 (fr) * 2021-03-07 2022-09-15 Jacobio Pharmaceuticals Co., Ltd. Dérivés cycliques fusionnés utiles en tant qu'inhibiteurs de kras g12d
WO2023001123A1 (fr) * 2021-07-19 2023-01-26 上海艾力斯医药科技股份有限公司 Nouveau dérivé de pyridopyrimidine
WO2023103906A1 (fr) * 2021-12-07 2023-06-15 贝达药业股份有限公司 Inhibiteur ciblant la kras g12d et son utilisation en médecine
WO2024022444A1 (fr) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Composé cyclique fusionné, son procédé de préparation et son application médicinale

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