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WO2022121839A1 - Dérivé de pyrido[2,3-d]pyrimidin-2(1h)-one, son procédé de préparation et son application - Google Patents

Dérivé de pyrido[2,3-d]pyrimidin-2(1h)-one, son procédé de préparation et son application Download PDF

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Publication number
WO2022121839A1
WO2022121839A1 PCT/CN2021/135713 CN2021135713W WO2022121839A1 WO 2022121839 A1 WO2022121839 A1 WO 2022121839A1 CN 2021135713 W CN2021135713 W CN 2021135713W WO 2022121839 A1 WO2022121839 A1 WO 2022121839A1
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alkyl
deuterium
substituted
cancer
cyano
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PCT/CN2021/135713
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English (en)
Chinese (zh)
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寻国良
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN202180051991.4A priority Critical patent/CN116171155B/zh
Publication of WO2022121839A1 publication Critical patent/WO2022121839A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, in particular to a pyrido[2,3-d]pyrimidin-2(1H)-one derivative and a preparation method and application thereof.
  • the RAS gene family contains HRAS, KRAS and NRAS, which are frequently mutated in cancer as oncogenes. 20-30% of human tumors have mutated RAS proteins. Activated RAS proteins lead to malignant phenotypes of cancer cells, including dysregulation of cell growth and programmed cell death, increased invasiveness and neovascularization. Due to its high affinity for GTP/GDP and lack of a clear binding pocket, the development of drugs targeting RAS proteins has been slow.
  • RAS proteins function as molecular switches, alternating between a GDP-bound inactive state and a GTP-bound activated state.
  • RAS protein After stimulation by exogenous growth factors, RAS protein is converted from an inactive GDP-binding form to an activated GTP-binding form through the promotion of guanine nucleotide exchange factors (GEFs), which can bind and activate downstream signaling pathways.
  • GEFs guanine nucleotide exchange factors
  • GAP GTPase activating/accelerating protein
  • K-RAS is the most frequently mutated subtype in the RAS family in human cancers, including pancreatic cancer (71%), small bowel cancer (35%), colon cancer (35%), biliary tract cancer (26%), and endometrial cancer (17%) and lung cancer (19%).
  • pancreatic cancer 71%
  • small bowel cancer 35%
  • colon cancer 35%
  • biliary tract cancer 26%
  • endometrial cancer 17%)
  • lung cancer (19%).
  • G12D/G12V/G12C/G13D are the most common mutation types of K-RAS in pancreatic, lung and colorectal cancers.
  • the activity has a strong inhibitory effect and can be widely used in the preparation of drugs for the treatment of cancers or tumors mediated at least in part by the K-RAS G12C mutation, especially for the treatment of the lungs, liver and gallbladder, gastrointestinal tract, blood system, skin, bone, Drugs for genitourinary tract, nervous system, gynecological and adrenal-related malignancies or cancers are expected to be developed into a new generation of K-RAS G12C inhibitor drugs.
  • a first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X is CH or N
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1- 4 -alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl and -SF 5 ;
  • R 3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3 -6 cycloalkyl, 4-6 membered heterocyclyl and -SF5 ;
  • R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl and -SF 5 ,
  • Each R 6 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl , -SF 5 , C 2-4 alkynyl, cyano substituted C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, halo substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl, Alternatively, when m ⁇ 2, the two R 6 together with the moiety to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • n 0, 1, 2, 3 or 4.
  • R 1 and R 2 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl , C 1-4 alkyl, C 3-6 cycloalkyl and -SF 5 ;
  • R 3 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl and -SF 5 ;
  • R 4 is selected from C 1-4 alkyl, cyano-substituted C 1-4 alkyl, hydroxy-substituted C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3 -6 cycloalkyl, 4-6 membered heterocyclyl and C 1-4 alkoxy;
  • R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkoxy, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3 -6 cycloalkyl, 4-6 membered heterocyclyl and -SF5 ;
  • Each R 6 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-2 alkyl, cyano-substituted C 1-2 alkyl, C 3-6 cycloalkyl, halo-substituted C 1- 2 alkyl and deuterium substituted C 1-2 alkyl.
  • the compound of formula (I) has the following compound structure of formula (II):
  • X is CH or N
  • Each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, methyl, ethyl, isopropyl, cyclopropyl and -SF5 ;
  • R 2 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl and -SF 5 ;
  • R3 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, isopropyl, cyclopropyl and -SF5 ;
  • R 4 is selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, di-deuteromethyl, cyclopropyl, cyclobutyl, azetidinyl, oxa cyclobutyl, methoxy, ethoxy and isopropoxy;
  • R 5 is selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, methoxy, ethoxy, isopropoxy, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl radical, di-deuteromethyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl and -SF5 ;
  • R 6a , R 6b , R 6c are each independently selected from hydrogen, deuterium, fluorine, cyano, methyl, cyanomethyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
  • the compound of formula (I) has the following structure of compound of formula (III):
  • R 1 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl and cyclopropyl;
  • R is selected from hydrogen , deuterium, fluorine, chlorine, cyano, hydroxy, methyl and cyclopropyl;
  • R is selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, methyl and cyclopropyl;
  • R 4 is selected from methyl, ethyl, isopropyl, tri-deuteromethyl, di-deuteromethyl and cyclopropyl;
  • R 6a , R 6b , R 6c are each independently selected from hydrogen, deuterium and methyl.
  • the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
  • the second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
  • R is H or amino protecting group, preferably, the amino protecting group is tert-butoxycarbonyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and m are as in formula (I) Compounds described.
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a compound of the aforementioned formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for the treatment of tumors or cancers mediated at least in part by K-RAS G12C mutation use in.
  • the cancer or tumor is selected from lung cancer or cancer, hepatobiliary cancer or cancer, gastrointestinal cancer or cancer, hematological cancer or cancer, sarcoma, skin cancer or cancer, bone cancer or cancer Malignant tumors or cancers of the medium, genitourinary tract malignancies or cancers, nervous system malignancies or cancers, gynecological malignancies or cancers and adrenal malignancies or cancers.
  • the lung cancer and cancer are selected from bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell or adenocarcinoma), non-small cell lung cancer, bronchial carcinoma, bronchial gland carcinoma tumor, sarcoma, lymphoma, cartilaginous hamartoma or mesothelioma;
  • bronchial carcinoma squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell or adenocarcinoma
  • non-small cell lung cancer bronchial carcinoma, bronchial gland carcinoma tumor, sarcoma, lymphoma, cartilaginous hamartoma or mesothelioma
  • the hepatobiliary malignancies and cancers are selected from liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder carcinoma, ampullary carcinoma or cholangiocarcinoma;
  • the gastrointestinal malignancies and cancers are selected from the group consisting of esophageal malignancies and cancers (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma or lymphoma), gastric malignancies and cancers (carcinoma, lymphoma or leiomyosarcoma), pancreatic malignancies and cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, uveoma), small bowel (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma , hemangiomas, lipomas, neurofibromas, fibroids), colorectal malignancies and cancers (adenocarcinoma, adenoma, adenoma, tubular adenoma) or leiomyoma;
  • Said hematological malignancy or cancer is selected from acute or chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease or non-Hodgkin's disease Chikin lymphoma;
  • the sarcoma is selected from the group consisting of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyomas, fibroma, lipoma and teratoma;
  • the skin malignancy or cancer is selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, nevus hyperplasia, lipoma, hemangioma, dermatofibroma, keloid, or psoriasis;
  • the malignant tumor or cancer in the bone is selected from osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma , benign chondroma, chondroblastoma, chondromucosal fibroma, osteoid osteoma or giant cell tumor;
  • the urogenital malignancy or cancer is selected from the group consisting of renal malignancies or cancers (adenocarcinoma, Wilms tumor or Wilms tumor), lymphoma, leukemia, bladder or urinary tract malignancies or cancers (squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), prostate malignancy or cancer (adenocarcinoma or sarcoma), testicular malignancy or cancer (blood cancer, teratoma, embryonal carcinoma or teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, Fibroma, fibroadenoma, adenomatous tumor or lipoma;
  • the nervous system malignancies and cancers are selected from the group consisting of osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans, meningiomas, meningiosarcomas, gliomas, astrocytomas, medulloblastomas, glia Plasma tumor, ependymoma, genital tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glial tumor or sarcoma;
  • the gynecological malignancy or cancer is selected from endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma or unclassified carcinoma), granular-schwannoma, Leydig cell tumor, sarcolemma, malignant tumor Teratoma, squamous cell carcinoma, fibroepithelial carcinoma, adenocarcinoma, melanoma, clear cell carcinoma, squamous cell carcinoma, grape sarcoma, or fallopian tube carcinoma;
  • the adrenal malignancy or cancer is selected from neuroblastoma.
  • a fifth aspect of the present invention provides a compound of the aforementioned formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the treatment of tumors or cancers mediated at least in part by K-RAS G12C mutation medicine.
  • a sixth aspect of the present invention provides a method of preventing and/or treating a tumor or cancer mediated at least in part by K-RAS G12C mutation, comprising administering to a patient a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable compound thereof Accept the salt, or the aforementioned pharmaceutical composition.
  • the inventors of the present application have developed a pyrido[2,3-d]pyrimidin-2(1H)-one derivative for the first time after extensive and in-depth research.
  • the series of compounds of the present invention have a strong inhibitory effect on K-RAS enzymatic and cellular activities, and can be widely used in the preparation of medicines for the treatment of cancers or tumors at least partially mediated by K-RAS G12C mutation, especially for the treatment of lung, Drugs for hepatobiliary, gastrointestinal, blood system, skin, bone, genitourinary tract, nervous system, gynecological and adrenal-related malignancies or cancers are expected to be developed into a new generation of K-RAS G12C inhibitor drugs. On this basis, the present invention has been completed.
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group, preferably a straight chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms or 1 to 2 carbon atoms and branched alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl,
  • C 1-10 alkyl refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups
  • C 1-8 alkyl refers to straight-chain alkyl groups including 1 to 8 carbon atoms and A branched-chain alkyl group
  • C 0-8 alkyl refers to a straight-chain alkyl group of 0 to 8 carbon atoms and a branched alkyl group
  • C 1-4 alkyl refers to a group containing 1 to 4 carbon atoms
  • C 1-2 alkyl group refers to the straight-chain alkyl group including 1 to 2 carbon atoms and the branched-chain alkyl group
  • C 0 alkyl group refers to the number of carbon atoms The number is 0.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated ⁇ electron system, and the cycloalkyl group is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 10 or 3 to 8 or 3 Cycloalkyl of up to 6 carbon atoms, for example, "C 3-10 cycloalkyl” refers to a cycloalkyl group including 3 to 10 carbon atoms, “C 3-8 cycloalkyl” refers to a cycloalkyl group including 3 to 8 carbon atoms Atom cycloalkyl, "C 3-6 cycloalkyl” refers to a cycloalkyl group comprising 3 to 6 carbon atoms
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
  • a heterocyclyl group includes 3 to 10 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl” refers to a ring group containing 3 to 6 ring atoms, "4-6 membered hetero
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • Spiroheterocyclyl groups include, but are not limited to:
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • Aryl or “aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 5-10 or 5-8 carbons, for example, "C 5-10 aryl” refers to all-carbon aryl groups containing 5-10 carbons, Including but not limited to phenyl and naphthyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O)r (where r is the integer 0 , 1, 2) heteroatoms, preferably a heteroaromatic system containing 5-10 or 5-8 ring atoms, for example, a 5-10 membered heteroaryl group refers to a heteroaromatic system containing 5-10 ring atoms , including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons
  • C 2-10 alkenyl refers to a straight-chain or branched alkenyl containing 2-10 carbons
  • C 2-4 alkenyl refers to a straight or branched alkenyl containing 2-4 carbons .
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons,
  • a C2-10 alkynyl group refers to a straight or branched chain alkynyl group containing 2 to 10 carbons
  • a C2-4 alkynyl group refers to a straight chain or branched chain alkynyl group containing 2 to 4 carbons.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above, eg, "C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, C 1-4 alkoxy "Oxy” refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • Cycloalkoxy refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, "C 3-10 cycloalkoxy” refers to a cycloalkyloxy group containing 3-10 carbons, Including, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Heterocyclyloxy refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, and heterocyclyloxy, including but not limited to azetidinyloxy, oxetanyloxy, nitrogen Heterocyclopentyloxy, nitrogen, oxhexyloxy, etc.
  • C 1-10 alkanoyl refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, usually also expressed as "C 0-9 -C(O)-", for example, "C 1 -C (O)-” means acetyl; “C2 - C(O)-” means propionyl; “C3 - C(O)-” means butyryl or isobutyryl.
  • C 1-4 means “C 1-4 alkyl”
  • C 0-4 means “C 0-4 alkyl”
  • C 1-8 means C 1-8 alkyl
  • C 0-8 means C 0-8 alkyl
  • C 1-10 means “C 1-10 alkyl”, as defined above.
  • Each R 7 is independently hydrogen, deuterium, hydroxy, halogen, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3- 10 -cycloalkoxy, 3-10-membered heterocyclyl, 3-10-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered Heteroaryloxy and -NR 10 R 11 , the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3- 10 cycloalkyl, C 3-10 cycloalkoxy, 3-10-membered heterocyclyl, 3-10-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered Heteroaryl, 5-10-member
  • Each R 8 is each independently hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl and 5-10-membered heteroaryl, the above-mentioned groups are optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3- 10 cycloalkyl, C 3-10 cycloalkoxy, 3-10-membered heterocyclyl, 3-10-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered Heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 10 R 11 ;
  • Each R 9 is independently hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 ring Alkyl, C 3-10 cycloalkoxy, 3-10-membered heterocyclyl, 3-10-membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryloxy, 5-10-membered heteroaryl group, 5-10-membered heteroaryloxy and -NR 10 R 11 , the above-mentioned groups are optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 aryl, C 5-10 aryl substituted by the substituents of oxy, 5-10-membered hetero
  • Each R 10 , R 11 is independently hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 membered aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl , p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monosubstituted C 1-10 alkylamino, disubstituted C 1-10 alkylamino and C 1-10 alkanoyl, the above-mentioned groups are optional is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C 1-10 alky
  • Halo-substituted C 1-4 alkyl refers to 1-4 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine, or iodine atoms, including but not limited to difluoromethyl (-CHF 2 ), dichloromethyl (-CHCl 2 ), dibromomethyl (-CHBr 2 ), trifluoromethyl (-CF 3 ), trichloromethyl (-CCl 3 ), tribromomethyl (-CBr 3 ) etc.
  • Halo-substituted C 1-4 alkoxy refers to a 1-4 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
  • Deuterium substituted C1-4 alkyl refers to a 1-4 carbon alkyl group in which the hydrogen on the alkyl group is optionally replaced by a deuterium atom. Including, but not limited to, deuteromethyl ( -CH2D ), dideuteromethyl ( -CHD2 ), trideuteromethyl ( -CD3 ), and the like.
  • Deuterium substituted C 1-4 alkoxy refers to a 1-4 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to mono-deuteromethoxy, di-deuteromethoxy, tri-deuteromethoxy and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • MeOH refers to methanol.
  • KF refers to potassium fluoride.
  • KHMDS refers to potassium hexamethyldisilazide.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted .
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
  • Stereoisomer its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories.
  • the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations.
  • geometric isomers also known as cis-trans isomers, which are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers, if the compound of the present invention contains a double bond, if not specified, it can be understood as containing E and/or Z form.
  • Stereoisomers with different optical properties due to the absence of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations.
  • the "stereoisomer" can be understood to include one or more of the above-mentioned enantiomers, configuration isomers and conformation isomers unless otherwise specified, preferably R configuration type.
  • “Pharmaceutically acceptable salts” in the present invention refer to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400/500 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS internal standard For tetramethylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the first step the synthesis of 2,4-dibromopyridin-3-amine
  • the third step Synthesis of 4-(1-ethoxyvinyl)-2-(prop-1-en-2-yl)pyridin-3-amine
  • the fourth step the synthesis of 1-(3-amino-2-(prop-1-en-2-yl)pyridin-4-yl)ethane-1-one
  • the fifth step the synthesis of 1-(3-amino-2-isopropylpyridin-4-yl) ethane-1-ol
  • the sixth step the synthesis of 1-(3-amino-2-isopropylpyridin-4-yl) ethane-1-one
  • the first step synthesis of N-((4-acetyl-2-isopropylpyridin-3-yl)carbamoyl)-2,6-dichloro-5-fluoronicotinamide
  • the third step tert-butyl (S)-4-(1-(4-acetyl-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1, Synthesis of 2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
  • Example 1 1-(4-Acetyl-2-isopropylpyridin-3-yl)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6- Preparation of fluoro-7-(2-fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the first step tert-butyl (3S)-4-(1-(4-acetyl-2-isopropylpyridin-3-yl)-6-fluoro-7-(2-fluoro-6-hydroxybenzene Synthesis of yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate
  • the third step 1-(4-acetyl-2-isopropylpyridin-3-yl)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6- Synthesis of Fluoro-7-(2-Fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • Embodiment 1-R and 1-S are obtained through SFC separation on the basis of embodiment 1 preparation, and separation condition is as follows:
  • the first step tert-butyl (3S)-4-((E)-(((4-acetyl-2-isopropylpyridin-3-yl)carbamoyl)imino)(2,5- Synthesis of Dichloro-6-(2-fluoro-6-(methoxymethoxy)phenyl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate
  • the second step tert-butyl (3S)-4-(1-(4-acetyl-2-isopropylpyridin-3-yl)-6-chloro-7-(2-fluoro-6-(methyl) Oxymethoxy)phenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate synthesis
  • the fourth step 1-(4-acetyl-2-isopropylpyridin-3-yl)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6- Synthesis of Chloro-7-(2-Fluoro-6-hydroxyphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • cells When cell confluence was about 80%, cells were detached with 0.25% trypsin. The isolated cells were resuspended in 5 mL of fresh cell culture medium and centrifuged to collect the cells. Simultaneously count the number of cells. The cells were then suspended in medium concentration medium. Cells were placed in 96-well plates at 1500 cells/well for H358 and 500 cells/well for MIAPACA-2. The 96-well plate was placed in an incubator at 37°C and incubated overnight.
  • a 10-point serial dilution was made at a ratio of 1:3 from a 2 mM stock.
  • 5X compound-containing medium was transferred to corresponding wells of 96 wells.
  • the final peak compound concentration was 10 ⁇ M and the final concentration of DMSO was 0.5%.
  • the 96-well plate was placed in a 37°C incubator for 5 days.
  • Percent inhibition (%) at each compound concentration was calculated from the signal in HPE and ZPE control wells and the fluorescence signal in individual compound wells contained in each assay plate. ZPE control wells containing enzyme and substrate showed 0% inhibition, and HPE control wells containing only substrate showed 100% inhibition.
  • the concentration of compound required for 50% inhibition ( IC50 ) was determined using a four-parameter log-dose-response equation from the concentration of the test compound and the percent inhibition value. Endpoint values ( IC50 ) for reference compounds were evaluated in each experiment as a quality control measure. The experiment was considered acceptable if the endpoint value was within three times the expected value.
  • the series of compounds of the present invention have a strong inhibitory effect on the activity of K-RAS cells.

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Abstract

L'invention concerne un dérivé de pyrido[2,3-d]pyrimidin-2(1H)-one, son procédé de préparation et son application. Le dérivé est utilisé pour préparer des médicaments destinés à traiter des cancers ou des tumeurs au moins partiellement médiés par la mutation de K-RAS G12C, en particulier des médicaments pour le traitement des cancers du poumon, du foie et de la vésicule biliaire, du tractus gastrointestinal, du système sanguin, de la peau, des os, du tractus urogénital, du système nerveux, du système reproducteur féminin et des glandes surrénales, et des tumeurs malignes associées, et est susceptible d'être développé dans une nouvelle génération de médicaments inhibiteurs de K-RAS G12C.
PCT/CN2021/135713 2020-12-08 2021-12-06 Dérivé de pyrido[2,3-d]pyrimidin-2(1h)-one, son procédé de préparation et son application WO2022121839A1 (fr)

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Citations (5)

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WO2018119183A2 (fr) * 2016-12-22 2018-06-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2018217651A1 (fr) * 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019213516A1 (fr) * 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
CN111051306A (zh) * 2017-09-08 2020-04-21 美国安进公司 Kras g12c的抑制剂及其使用方法
WO2020239077A1 (fr) * 2019-05-29 2020-12-03 上海翰森生物医药科技有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son application

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US20130324520A1 (en) * 2011-02-14 2013-12-05 Sloan-Kettering Institute For Cancer Research Rxrg modulators for the treatment of cancer
WO2016161361A1 (fr) * 2015-04-03 2016-10-06 Nantbioscience, Inc. Compositions et méthodes de ciblage de k-ras mutant
SG11202012697QA (en) * 2018-01-19 2021-02-25 Medshine Discovery Inc Pyridone-pyrimidine derivative acting as krasg12c mutein inhibitor
CN111868058B (zh) * 2018-05-25 2023-06-13 上海和誉生物医药科技有限公司 一种fgfr抑制剂、其制备方法和在药学上的应用
CN113396147B (zh) * 2019-05-31 2024-06-18 上海翰森生物医药科技有限公司 芳香杂环类衍生物调节剂、其制备方法和应用

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WO2018119183A2 (fr) * 2016-12-22 2018-06-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2018217651A1 (fr) * 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
CN111051306A (zh) * 2017-09-08 2020-04-21 美国安进公司 Kras g12c的抑制剂及其使用方法
WO2019213516A1 (fr) * 2018-05-04 2019-11-07 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2020239077A1 (fr) * 2019-05-29 2020-12-03 上海翰森生物医药科技有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son application

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