WO2023072188A1 - Inhibiteurs de kras g12d et leur utilisation en médecine - Google Patents

Inhibiteurs de kras g12d et leur utilisation en médecine Download PDF

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WO2023072188A1
WO2023072188A1 PCT/CN2022/127912 CN2022127912W WO2023072188A1 WO 2023072188 A1 WO2023072188 A1 WO 2023072188A1 CN 2022127912 W CN2022127912 W CN 2022127912W WO 2023072188 A1 WO2023072188 A1 WO 2023072188A1
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alkylene
alkyl
halogen
cycloalkyl
cyano
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PCT/CN2022/127912
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English (en)
Chinese (zh)
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吴颢
陈小平
路渊
徐人奇
何将旗
李波燕
赵志昌
匡翠文
夏洪峰
王冬
张洪波
湛波
张运来
王国建
杨翔
沈少聪
黄传龙
周全
王家炳
兰宏
丁列明
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贝达药业股份有限公司
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Publication of WO2023072188A1 publication Critical patent/WO2023072188A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • C07D471/02—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 system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel compound which has KRAS inhibitory activity, especially KRAS G12D inhibitory activity.
  • the invention also relates to processes for the preparation of these compounds and pharmaceutical compositions containing them.
  • RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations.
  • the most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, and the mutation at codon 12 is the most common, such as G12C, G12D or G12V.
  • KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; while MIRATI is leading the development of G12D inhibitors (WO2021041671A1).
  • MRTX1133 is a selective and reversible KRAS-G12D inhibitor, which can inhibit KRAS G12D mutant cells in activated and inactive states, but not KRAS wild-type tumor cells.
  • the specificity of MRTX1133 for KRAS G12D is more than 1000 times that of wild-type KRAS .
  • MRTX1133 has a half-life of more than 24 hours, has no potential hERG activity, and is relatively safe. At present, MRTX1133 is still in the preclinical research stage, and there is great uncertainty about whether it can be made into a drug. Therefore, it is necessary to conduct more in-depth research on KRAS-G12D inhibitors.
  • MRTX1133 has multiple chiral centers, its disassembly The synthesis cost is higher, and the production process is more complicated.
  • the present invention provides a compound represented by the general formula (I), or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, the structure of the formula (I) is:
  • A is selected from CR 6 or N;
  • B is selected from CR 7 or N;
  • R 7 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 Alkoxy is optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C alkoxy ;
  • R 1 is selected from Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano
  • R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
  • X 1 is selected from CR 8 or N;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
  • X3 is selected from CH or N;
  • X is selected from CH or N;
  • X is selected from O or S
  • L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 is selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, and the C 1-6 alkyl or C 1-6 alkoxy is optionally replaced by one or Replaced by multiple substituents selected from halogen, cyano, oxo, hydroxyl, amino or C 1-6 alkoxy;
  • R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
  • Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
  • R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n are each independently selected from 0, 1, 2, 3 or 4.
  • the compound represented by formula (I) has the following general formula (II) structure:
  • X 1 is selected from CR 8 or N;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
  • X3 is selected from CH or N;
  • X is selected from CH or N;
  • X is selected from O or S
  • L is selected from a bond, -OC 0-8 alkylene , -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene, the -OC 0-8 alkylene Alkyl, -SC 0-8 alkylene, -NH-C 0-8 alkylene or C 2-8 alkynylene is optionally substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to them form a C 3-6 cycloalkyl group;
  • R 1 is selected from Wherein R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano
  • R 13 is preferably H; wherein R 14 is selected from hydroxyl, halogen, cyano, C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, The C 3-14 cycloalkyl, 3-14 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl are optionally substituted by one or more R b ;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
  • R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituents of radicals, oxo groups, hydroxyl groups or C 1-6 alkoxyl groups;
  • Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • Each R b is independently selected from hydroxyl, C 1-3 alkyl, 3-8 membered heterocyclyl, -N(R a ) 2 , -CH 2 N(R a ) 2 ;
  • R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n are each independently selected from 0, 1, 2 or 3.
  • the compound represented by formula (I) has the following structure of general formula (III):
  • X 1 is selected from CR 8 or N;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy base;
  • X3 is selected from CH or N;
  • X is selected from CH or N;
  • X is selected from O or S
  • L is selected from a bond, -OC 0-4 alkylene , -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene, the -OC 0-4 alkylene Alkyl, -SC 0-4 alkylene, -NH-C 0-4 alkylene or C 2-4 alkynylene is optionally substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, A cyano group, a hydroxyl group or a C 1-6 alkyl group, or two R 10 on the same carbon atom together with the atoms connected to it form a 3-6 membered cycloalkyl group;
  • R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R1 is H;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 or R 7 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxy, amino or C 1-6 alkoxy;
  • R 5 is selected from H, C 1-6 alkyl or C 3-14 cycloalkyl, and the C 1-6 alkyl or C 3-14 cycloalkyl is optionally replaced by one or more selected from halogen, cyano Substituent group, oxo group, hydroxyl group or C 2-6 alkoxyl group;
  • Each R a is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R c and R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n is selected from 0, 1, 2 or 3.
  • the compound represented by formula (I) has the following structure of formula (IV):
  • X 1 is selected from CR 8 or N;
  • R 8 is selected from H, amino, substituted amino, cyano, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
  • B is selected from CR 7 or N;
  • R 7 is selected from H, halogen, cyano or C 1-6 alkyl;
  • X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, hydroxyl, C 1-6 alkoxy, cyano or C 1-6 alkyl;
  • A is selected from CR 6 or N;
  • R 6 is selected from H, halogen, cyano or C 1-6 alkyl;
  • L is selected from bond, O, S, NR 10 , -OC 1-4 alkylene or C 2-4 alkynylene, said -OC 1-4 alkylene or C 2-4 alkynylene optionally Substituted by one or more R 10 ;
  • R 10 is selected from H, halogen, cyano, hydroxyl or C 1-6 alkyl, or two R 10 on the same carbon atom together with the atoms connected to form 3-6 Cycloalkyl;
  • R is selected from H, hydroxyl, cyano, halogen or C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl or cyano; preferably R 13 is H;
  • R 2 is selected from -OR a , -OC(O)N(R a ) 2 , -N(R a ) 2 , -NR a C(O)R a , -NR a C(O)N(R a ) 2.
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 12 , said R 12 is selected from C 1-6 alkyl or C 3-8 cycloalkyl, R 12 is optionally replaced by one or more Substituents selected from hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy or cyclopropyl;
  • R 4 or R 5 are each independently selected from H, cyano, hydroxyl, halogen, C 1-6 alkyl or C 2-6 alkoxy, the C 1-6 alkyl or C 2-6 alkoxy optionally substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl or C2-6alkoxy ;
  • n is selected from 0, 1, 2, 3 or 4.
  • the X 2 is selected from CR 9 or N;
  • R 9 is selected from H, halogen, cyano or C 1-6 alkyl;
  • R is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R ;
  • the X 1 is selected from CR 8 or N;
  • R a each independently selected from H or C 1-6 alkyl.
  • the X 2 is selected from CR 9 or N; R 9 is cyano.
  • the L is selected from a bond, preferred
  • the R is selected from preferably
  • the R 3 is selected from H, halogen or -OR 12 , and the R 12 is selected from C 1-6 Alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl.
  • the R 4 is selected from H, halogen or C 1-6 alkyl.
  • the R 5 is selected from H or C 1-6 alkyl; preferably H.
  • the R 7 is selected from H, halogen or C 1-6 alkyl; preferably H.
  • the m is selected from 1 or 2; preferably 1.
  • n is selected from 1 or 2; preferably 1.
  • the compound represented by formula (I) has the following formula (IA) or (IB) structure:
  • each substituent is as defined in formula (I).
  • the compound represented by formula (I) has the following formula (IC) or (ID) structure:
  • the compound represented by formula (I) has the following formula (IC-3) structure:
  • R 13 is selected from H
  • R 3 is selected from H, C 1-6 alkyl or halogen
  • R is selected from H, cyano, hydroxyl or halogen
  • R is selected from H, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl,
  • R c or R d are each independently selected from H, halogen, C 0-3 alkylene C 3-6 cycloalkyl, C 0-3 alkylene C 6-8 aryl, C 1-6 alkyl or C 1-6 haloalkyl; or, R c and R d form a 3-8 membered heterocyclic group or a C 3-8 cycloalkyl group together with the carbon atom to which they are attached;
  • n is selected from 0, 1, 2, 3 or 4.
  • the alkene structure in the present invention compares with The chiral fluorine atom structure not only reduces the chiral center, but also has a simple synthesis process and greatly reduces production costs, which is conducive to large-scale industrial production, and some of the compounds such as etc., the activity of KRAS G12D is generally higher than that of chiral fluorine compounds.
  • the compound in general formula (I), (II), (III) or (IV), is selected from:
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound represented by formula (I), or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt, optionally Further include pharmaceutically acceptable auxiliary materials.
  • the present invention provides the compound represented by formula (I), or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, or the application of its pharmaceutical composition in the preparation of medicine.
  • the application in the preparation of medicaments is the application in the preparation of medicaments for treating and/or preventing cancer.
  • the application in the preparation of the medicament is the application in the preparation of a medicament for treating and/or preventing diseases mediated by KRAS G12D.
  • the KRAS G12D-mediated disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing diseases, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), or its stereoisomers, tautomers, Deuterated substances or pharmaceutically acceptable salts, or pharmaceutical compositions containing them.
  • the present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12D, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I), or its stereoisomer, Tautomers, deuterated substances or pharmaceutically acceptable salts, or pharmaceutical compositions containing them.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any one represented by structural formula (I), or its stereoisomers, tautomers, deuteriums, or medicinal salt, or a pharmaceutical composition containing it.
  • the KRAS G12D-mediated disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • halogen refers to fluorine, chlorine, bromine or iodine, unless otherwise specified.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like.
  • “1-6” in “C 1-6 alkyl” refers to a group comprising 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
  • alkylene refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the point of attachment of the alkylene to the rest of the compound. Similarly, “C 1-6 " in C 1-6 alkylene refers to an alkylene group containing 1, 2, 3, 4, 5 or 6 carbon atoms, including but not limited to methylene, 1, 2-ethylene, 1,3-propylene or 1,2-isopropylidene.
  • alkoxy refers to the oxygen ether form of the aforementioned linear or branched alkyl, ie -O-alkyl.
  • aryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted aromatic group including 6-14 membered monocyclic or condensed rings.
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group.
  • Preferred are phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl, where the ring bonded to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
  • heterocyclyl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is Saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 14 carbon atoms, wherein the nitrogen or sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatoms may be optionally quaternized .
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl.
  • the heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring bonded to the parent structure is the heterocyclyl.
  • heteroaryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- to 14-membered benzo
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl.
  • the heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring where the ring attached to the parent structure is a heteroaryl ring.
  • cycloalkyl refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • the cycloalkyl group may be fused to an aryl, heterocyclyl, or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl group.
  • substituted means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents.
  • substituents include, but are not limited to, H, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-OR b , -C 0-6 alkylene- OC(O)N(R b ) 2 , -C 0-6 alkylene-N(R b ) 2 , -C 0-6 alkylene-NR b C(O)R b , -C 0-6 Alkylene-NR b C(O)N(R b ) 2 , -C 0-6 Alkylene-NR b S(O)R b , -C 0-6 Alkylene-NR b S(O) 2 R b , -C 0-6 alkylene-S(O) 2 R b , -C 0-6 alkylene-S(O)
  • Each R b is independently selected from H, halogen, hydroxyl, amino, oxo, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkane Base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 heteroalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper (superior and subvalent), ferric, ferrous, lithium, magnesium, manganese (superior and subvalent), potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Nontoxic organic bases from which pharmaceutically acceptable salts can be derived include primary, secondary and tertiary amines, also cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine acid, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
  • ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylamino
  • the compound provided by the present invention is a base
  • its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, Cyclohexanesulfonic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoro
  • prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted in vivo into the desired compound.
  • any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers.
  • the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.
  • substitution of compounds of formula (I) with heavier isotopes may afford certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or their pharmaceutically acceptable salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • compositions comprising "a” pharmaceutically acceptable excipient may be interpreted to mean that the pharmaceutical composition includes “one or more” pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, Subcutaneous, intravenous administration.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described in .
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • Step I Compound A-1 is reacted with Obtain compound A-2 through substitution reaction;
  • Step II compound A-2 is under the effect of Pd catalyst such as Pd(dtbpf)Cl 2 , and compound The corresponding groups were introduced through Suzuki coupling reaction;
  • Pd catalyst such as Pd(dtbpf)Cl 2
  • Step III The target compound A can be obtained by removing the TG protecting group of compound A-3 under acidic conditions such as the action of TFA.
  • DABCO triethylenediamine
  • DBU 1,8-diazabicycloundec-7-ene
  • CPME cyclopentyl methyl ether
  • m-CPBA m-chloroperoxybenzoic acid
  • DIEA N,N-Diisopropylethylamine
  • Dioxane dioxane
  • POCl 3 phosphorus oxychloride
  • THF Tetrahydrofuran
  • TFA trifluoroacetic acid
  • Pre-TLC preparation of thin-layer plates
  • TosMIC p-Methylsulfonylmethylisonitrile
  • DMSO dimethyl sulfoxide
  • Pd(dtbpf)Cl 2 dichloro[1,1'-bis(er-tert-butylphosphine)ferrocenepalladium(II);
  • Pd(DPEPhos)Cl 2 bis(diphenylphosphine phenyl ether) dichloropalladium(II);
  • CataCXium A Pd G3 [n-butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate;
  • Pre-HPLC high performance liquid phase preparation method.
  • Bis(imidazol-1-yl)methanone (2.70 g) was added to compound 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (4.0 g) in THF (20 mL) at room temperature, N-ethyl-N-isopropylpropan-2-amine (1.4 g) was added thereto, and the mixture was moved to 50° C. for 2 hours.
  • the compound 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid was almost completely converted into an intermediate product, and then the mixture was added dropwise into iced ammonia water (35 mL), and stirred for 5 min to complete the reaction.
  • compound M6-4 (187g) and difluoromethyl (2-pyridyl) sulfone (184g) were dissolved in anhydrous DMF (1.4L), and potassium tert-butoxide (107g) was added dropwise at -50°C DMF (460mL) solution, after the dropwise addition, control the temperature and react at -40°C for 2 hours. After the reaction, add saturated ammonium chloride solution dropwise at -50°C until the solution becomes weakly acidic, then naturally warm to room temperature and react for 18 hours. , filtered to obtain the filtrate, added EA (1.4 L) to dilute, then filtered to obtain the filtrate, and concentrated.
  • compound M7-1 (0.3g) was dissolved in tetrahydrofuran, lithium aluminum hydride (123mg) was added under ice bath, and then a solution of borane in tetrahydrofuran (3.2mL) was added, and the reaction was quenched with water immediately after 1 minute. Quench the reaction until bubbles no longer emerge, add 15% sodium hydroxide (0.3mL), then add water (0.9mL), after stirring and quenching completely, add sodium sulfate to dry, filter to obtain the filtrate, concentrate to obtain the product M12 (80mg, 33% yield).
  • Embodiment 1 Compound 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3 -Synthesis of carbonitrile
  • Example 148 Compound 7-(2-amino-3-cyano-7-fluorobenzothiophen-4-yl)-4-((1R,5S)-3,8-diazacyclo[3.2.1 Synthesis of ]octane-3-yl)-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoroquinoline-3-carbonitrile
  • Example 149 Compound 3-((7-(2-amino-3-cyano-7-fluorobenzothiophen-4-yl)-4-((1R,5S)-3,8-diazacyclo Synthesis of [3.2.1] octane-3-yl)-6-chloro-3-cyano-8-fluoroquinolin-2-yl)amino)-N,N-dimethylpropylamine
  • Example 162 Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2-Oxytrihydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile synthesis
  • Example 163 Compound 4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-2-((2-(di Fluoromethylene)tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene -Synthesis of 3-carbonitrile
  • Example 180 Compound 4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile synthesis
  • Example 181 2-Amino-4-(6-chloro-4-((1-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-2-((2R, 7aS) of the compound Synthesis of -2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile
  • Example 187 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-( Synthesis of (2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile
  • Example 188 Compound 4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-2-((2-( Difluoromethyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoroquinazolin-7-yl)-2-aminobenzo[b]thiophene-3-carbonitrile Synthesis
  • the KRas-G12D mutant tumor cell AGS ( CRL-1739 TM ) were spread in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and placed in a cell culture incubator for overnight culture.
  • the compounds to be tested were added to the 96-well plate at the final concentrations of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, and 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37 °C After 96 hours, add 50 ⁇ L of Cell-titer GLO working solution to each well, shake and mix well, and incubate at room temperature for 10 minutes. Read the Luminescence luminescence value on a multi-functional microplate reader, and convert the luminescence value data into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • KRas-G12D mutant tumor cells AGS CRL-1739 TM
  • Panc 04.03 CRL-2555 TM
  • CRL-2555 TM Two kinds of KRas-G12D mutant tumor cells AGS ( CRL-1739 TM ) or Panc 04.03 ( CRL-2555 TM ) were plated in a 96-well plate at a cell density of 5 ⁇ 10 4 /well, and placed in a cell culture incubator for overnight culture.
  • the compounds to be tested were added to the 96-well plate according to the final concentration of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and incubated After 3 hours, use the lysis buffer (50 ⁇ L) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit to extract the protein lysate of each treated cell sample in the 96-well plate, use the BCA method to quantify the protein lysate, and use The analysis buffer dilutes the protein sample concentration to 0.1 ⁇ g/ ⁇ L.
  • MSD Meso Scale Discovery
  • p-ERK% value ((2 ⁇ phosphorylation signal value)/(phosphorylation signal value+total signal value)) ⁇ 100
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • the second group G2 is compound 163 single drug.
  • the third group G3 is compound 188 single drug.
  • the fourth group G4 is compound 1 single drug.
  • PO oral gavage
  • Bid administration twice a day
  • the tumor size and the body weight of the mice were measured twice a week, and each administration was referred to the body weight of the animal on the day.
  • tumor growth inhibition rate (Tumor growth inhibition) of each administration group is shown in Table 6.

Abstract

L'invention concerne des composés représentés par la formule (I) ayant une activité de modulation de KRAS G12D, une méthode de préparation desdits composés, des compositions pharmaceutiques comprenant lesdits composés, et une utilisation de ceux-ci dans la préparation d'un médicament pour le traitement ou la prévention de maladies médiées par la KRAS G12D.
PCT/CN2022/127912 2021-10-29 2022-10-27 Inhibiteurs de kras g12d et leur utilisation en médecine WO2023072188A1 (fr)

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WO2023179703A1 (fr) * 2022-03-24 2023-09-28 Beigene , Ltd. Composés hétérocycliques, compositions de ceux-ci et méthodes de traitement associés
WO2024008178A1 (fr) * 2022-07-08 2024-01-11 贝达药业股份有限公司 Inhibiteur de kras g12d et son application en médecine
WO2024008179A1 (fr) * 2022-07-07 2024-01-11 Beigene, Ltd. Composés hétérocycliques, compositions à base de ceux-ci et procédés de traitement associés
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024054926A1 (fr) * 2022-09-07 2024-03-14 Bristol-Myers Squibb Company Inhibiteurs de kras g12d
WO2024061365A1 (fr) * 2022-09-22 2024-03-28 成都奥睿药业有限公司 Composé pyrimidine à cycle condensé, son procédé de préparation et son utilisation
WO2024067714A1 (fr) * 2022-09-30 2024-04-04 泰励生物科技（上海）有限公司 Composés ayant une activité tumorale mutante anti-kras

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