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WO2022206723A1 - 杂环类衍生物、其制备方法及其医药上的用途 - Google Patents

杂环类衍生物、其制备方法及其医药上的用途 Download PDF

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Publication number
WO2022206723A1
WO2022206723A1 PCT/CN2022/083546 CN2022083546W WO2022206723A1 WO 2022206723 A1 WO2022206723 A1 WO 2022206723A1 CN 2022083546 W CN2022083546 W CN 2022083546W WO 2022206723 A1 WO2022206723 A1 WO 2022206723A1
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Prior art keywords
alkyl
group
halogen
pharmaceutically acceptable
cancer
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PCT/CN2022/083546
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English (en)
French (fr)
Inventor
陈友喜
龚亮
向清
毛文涛
赵雯雯
赵伟峰
程超英
和燕玲
叶成
钱文建
陈磊
Original Assignee
浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Priority to CN202280006415.2A priority Critical patent/CN116113632A/zh
Publication of WO2022206723A1 publication Critical patent/WO2022206723A1/zh

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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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed 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 heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as a K-Ras GTPase inhibitor.
  • RAS represents a group of closely related monomeric globular proteins (21 kDa molecular weight) that have 189 amino acids and are associated with the plasma membrane and bind GDP or GTP. Under normal developmental or physiological conditions, RAS is activated upon receipt of growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration, and differentiation. RAS acts as a molecular switch, and the on/off state of RAS proteins is determined by nucleotide binding, with the active signaling conformation bound to GTP and the inactive conformation bound to GDP. When RAS contains bound GDP, it is in a dormant or quiescent or off state and is "inactive".
  • RAS When cells respond to exposure to certain growth-promoting stimuli, RAS is induced to convert bound GDP to GTP. With GTP bound, RAS is "on” and is able to interact with and activate other proteins (its “downstream targets”).
  • the RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP and thereby turn itself into the off state. Switching RAS off requires exogenous proteins called GTPases activating proteins (GAPs), which interact with RAS and greatly facilitate the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus an extended signal to the cell that tells it to continue growing and split. So these signals allow cells to grow and divide, and overactive RAS signaling may ultimately lead to cancer.
  • the RAS protein contains a G domain responsible for the enzymatic activity of RAS, guanine nucleotide binding and hydrolysis (GTPase reaction), and it also includes a C-terminal extension called the "CAAX box" that can is post-translationally modified and targets the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate-binding loop (P-loop).
  • P-loop represents the pocket in the protein that binds nucleotides, and this is a rigid part of a domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine-12, Threonine-26 and Lysine-16).
  • the G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are the dynamic part of the protein, since the dynamic part switches between rest and load states capability is often denoted as a "spring loaded” mechanism.
  • the main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the ⁇ -phosphate of GTP, which allows switch I and switch II regions, respectively, to maintain their active conformations. After hydrolysis of GTP and release of phosphate, both relax to the inactive GDP conformation.
  • KRAS mutations are prevalent in the three most lethal cancer types in the United States: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%). KRAS mutations are also found in other cancer types including carcinoma, diffuse large B-cell lymphoma, rhabdomyosarcoma, squamous cell carcinoma of the skin, cervical cancer, testicular germ cell carcinoma, etc., while breast, ovarian, and brain cancers Rarely found ( ⁇ 2%).
  • KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D.
  • the increased frequency of allele-specific mutations is mostly due to classic smoking-induced mutations (G:C to T:A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT) to GTT) mutation.
  • KRAS mutations in lung cancer including G12C
  • KRAS mutations frequently co-occur with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with mutated RAS to transform cells into highly malignant and aggressive tumor cells.
  • KRas G12D inhibitors At present, there is fierce competition for clinical development of KRas G12D inhibitors at home and abroad. Among them, MRTX-1133, a KRas G12D inhibitor developed by Mirati Therapeutics Inc, has entered the preclinical stage for the treatment of colorectal tumors, non-small cell lung cancer and pancreatic cancer. . At present, there are a few patent applications for KRas G12D inhibitors published, including WO2021041671 of Mirati Therapeutics Inc. Although some progress has been made in the research and application of KRas G12D inhibitors, the room for improvement is still huge, and it is still necessary to continue the research and development of new KRas G12D inhibitors.
  • the object of the present invention is to provide a compound represented by the general formula (A-I) or (A-II), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
  • Ring A is independently selected from 5-6 membered heteroaryl group or 5-10 membered monocyclic heterocyclic group; preferably 6-7 membered monocyclic heterocyclic group; wherein said heteroaryl, monocyclic heterocyclic group contains one or more N or O atoms;
  • Rings B are each independently selected from aryl, heteroaryl, or fused rings;
  • Ring C is each independently selected from a 6-8 membered heterocyclic group containing 2 nitrogen atoms;
  • Q 1 is selected from N or CR a ; Q 1 is preferably N;
  • Q 2 is each independently selected from N, C or CR a ;
  • Y is each independently selected from a bond, O or NR;
  • Each E is independently selected from a hydrogen atom or
  • R a is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkoxy or cyano; wherein said alkyl or alkoxy is optionally further selected by one or more selected from halogen, hydroxyl, substituted by cyano, alkyl or alkoxy substituents;
  • R b is selected from a hydrogen atom or an alkyl group
  • R c is selected from hydrogen atom, halogen, cyano, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further selected by one or more of halogen, hydroxy, cyano, alkyl or alkoxy substituted by the substituent of oxy; R c is preferably halogen, more preferably fluorine or chlorine;
  • R d and R e are the same or different, each independently selected from hydrogen atom, halogen, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further selected by one or more selected from halogen, hydroxyl, substituted by cyano, alkyl or alkoxy substituents;
  • R and R together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group; preferably cyclopropyl;
  • R f is selected from hydrogen atom or cycloalkyl, wherein said cycloalkyl is preferably cyclopropyl;
  • R 1 is each independently selected from a hydrogen atom, -L-alkyl, -L-halogen, -L-OR 5 , -L-NR 6 R 7 , -LC(O)OR 5 , -LC(O)NR 6 R 7 , -L-cycloalkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-fused ring or wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused ring is optionally further substituted by one or more substituents selected from R g ;
  • L is each independently selected from a bond or a C 1 -C 6 alkylene group, wherein said alkylene group is optionally further substituted with one or more R D ;
  • R D is each independently selected from a hydrogen atom, halogen, hydroxy or hydroxymethyl
  • the two R Ds attached to the same carbon atom together form a cycloalkyl group with the attached carbon atom; preferably cyclopropyl;
  • R 2 are the same or different, each independently selected from hydrogen atom, halogen, hydroxyl, alkyl or alkoxy, preferably hydrogen atom or alkyl;
  • any two R2 together with the atoms to which they are attached form a cycloalkyl or heterocyclyl
  • R 6 and R 7 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from R;
  • R 8 , R 9 and R 10 are each independently selected from hydrogen atom, halogen, alkyl, amino, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl, wherein said alkyl, cycloalkane radical, heterocyclyl, benzyl, aryl, or heteroaryl optionally further selected by one or more groups selected from hydroxy, halo, nitro, amino, cyano, alkyl, aminoalkyl, alkoxy, cycloalkane substituted by substituents of radical, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;
  • n is each independently selected from 0, 1, 2, 3 or 4;
  • n is each independently selected from 0, 1, 2 or 3;
  • k is each independently selected from 0, 1 or 2;
  • r is each independently selected from 0, 1 or 2.
  • the present invention provides a compound represented by general formula (A-I) or (A-II), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is of general formula (I) or ( The compound shown in II) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:
  • ring A, ring B, X 1 , X 2 , Y, Q 1 , Q 2 , R 1 , R 2 , R 3 , R 4 , m, n and k are as defined in general formula (AI) or (A -II).
  • the present invention provides a compound represented by the general formula (I) or (II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (III) and (IV) , (V) or (VI) compounds or their stereoisomers, tautomers or their pharmaceutically acceptable salts:
  • ring B, X 1 , X 2 , Y, Q 1 , Q 2 , R 1 , R 2 , R 3 , R 4 , m and n are as defined in general formula (AI) or (A-II) described.
  • the present invention provides a compound represented by the general formula (A-I) or (A-II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (VII), ( A compound represented by VIII) or (IX) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
  • ring B, X 1 , X 2 , Y, Q 1 , Q 2 , R 1 , R 2 , R 3 , R 4 , m and n are as defined in general formula (AI) or (A-II) .
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • Q 1 is selected from N;
  • Q 2 is selected from C
  • X 1 and X 2 are each independently selected from N or CR c ;
  • R c is selected from a hydrogen atom or halogen, preferably halogen, more preferably fluorine or chlorine.
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • Q 1 is selected from N;
  • Q 2 is selected from C
  • X 1 is selected from CR c ;
  • X 2 is selected from N;
  • R c is selected from halogen, preferably fluorine or chlorine, more preferably fluorine.
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • X 1 and X 2 are each independently selected from CR d Re ;
  • R d and Re are selected from hydrogen atoms
  • R d and R e together with the carbon atom to which they are attached form a 3-5 membered monocyclic cycloalkyl or 3-5 membered monocyclic heterocyclyl; preferably cyclopropyl.
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • X 2 connected is selected from double bonds
  • X 2 is selected from N;
  • Q 2 is selected from N.
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • L is selected from a bond or a C 1 -C 3 alkylene group, wherein said alkylene group is optionally further substituted by one or more R D ;
  • R D is each independently selected from a hydrogen atom, halogen, hydroxy or hydroxymethyl
  • two R Ds attached to the same carbon atom together form a cycloalkyl group; preferably cyclopropyl.
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • L is selected from bond, -CH 2 -, -CH 2 CH 2 - or
  • the present invention provides a general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein R 1 is selected from:
  • the present invention provides a general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX), or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein R 4 is the same or different, each independently selected from hydrogen atom, alkyl group, halogen, alkoxy group , alkynyl, hydroxy, amino, hydroxyalkyl, haloalkyl or haloalkoxy; R 4 is preferably a hydrogen atom, methyl, fluorine, chlorine, bromine, iodine, hydroxy, amino, hydroxymethyl or ethynyl.
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • Ring B is selected from phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, indolyl, indazolyl, benzothiazolyl, tetralinyl,
  • Ring B is preferably naphthyl or benzothiazolyl.
  • the present invention provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or ( The compound shown in IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, wherein:
  • the present invention provides a compound represented by general formula (I) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
  • the present invention provides a compound represented by general formula (II), (IV), (V) or (VI) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
  • the present invention provides a compound represented by general formula (VII), (VIII) or (IX) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective dose of general formula (A-I), (A-II), (I), (II), (III), (IV) ), (V), (VI), (VII), (VIII) or (IX) described compounds or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carrier, excipient, or a combination thereof.
  • the present invention provides a method for inhibiting KRas G12D enzyme, wherein the method comprises: administering to a patient a pharmaceutical composition containing an effective dose of the general formula (A-I), (A) -II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) described compound or its stereoisomer, Tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the present invention also provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) Or the compound described in (IX) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition (for example, the pharmaceutical composition described in the foregoing technical scheme) is prepared for treatment by KRas Use in the medicine of the disease mediated by G12D mutation, wherein the disease mediated by KRas G12D mutation is selected from cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, Pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, skin squamous cell carcinoma, adrenal neuroblastoma , myeloid leuk
  • the present invention provides a kind of general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII),
  • the compound described in (VIII) or (IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition is prepared Use in KRas G12D inhibitors.
  • Another aspect of the present invention relates to a method of preventing and/or treating a disease mediated by KRas G12D mutation, comprising administering to a patient a therapeutically effective amount of formula (A-I), (A-II), (I), The compound described in (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or its stereoisomer, tautomer or its isomers A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same (for example, the pharmaceutical composition described in the aforementioned technical solutions).
  • said disease mediated by KRas G12D mutation is selected from cancer, wherein said cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma , cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glial Blastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer and lung cancer; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
  • the present invention also provides a general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) Or the compound described in (IX) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition (for example, the pharmaceutical composition described in the aforementioned technical scheme) is used in the preparation of a treatment for cancer.
  • the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma , uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer cancer, rectal cancer and lung cancer; wherein the lung cancer is preferably non-small cell lung cancer or small cell lung cancer.
  • the present invention also provides a method of preventing and/or treating cancer, comprising administering to a patient a therapeutically effective dose of general formulae (A-I), (A-II), (I), (II), (III), (IV) ), (V), (VI), (VII), (VIII) or (IX) described compound or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition (For example, the pharmaceutical compositions described in the aforementioned technical solutions).
  • the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer carcinoma, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer and Lung cancer; wherein the lung cancer is preferably non-small cell lung cancer.
  • compositions of the present invention can be topical, oral, transdermal, rectal, vaginal, parenteral, intranasal, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal , intraperitoneal, subcutaneous, substratum corneum, or by inhalation.
  • Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • the formulations of the present invention are suitably presented in unit dosage form, and such formulations may be prepared by any method well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with carrier materials to produce a single dosage form can vary depending upon the host treated and the particular mode of administration.
  • the amount of active ingredient which, in combination with a carrier material, can produce a single dosage form generally refers to that amount of compound which produces a therapeutic effect.
  • Dosage forms for topical or transdermal administration of the compounds of this invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and it can be mixed with any preservatives, buffers or propellants that may be required.
  • the compounds of the present invention When the compounds of the present invention are administered in pharmaceutical form to humans and animals, the compounds may be provided alone or in a pharmaceutical composition containing in combination with a pharmaceutically acceptable carrier active ingredient, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.
  • a pharmaceutically acceptable carrier active ingredient for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.
  • Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and derivatives thereof such as carboxylate (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and Suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol , mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) seaweed (16) pyrogen-free water; (17) isotonic saline; (18) Ring
  • antioxidants examples include, but are not limited to: (1) water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; ( 2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like
  • Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (B
  • Solid dosage forms may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or the following Any one of: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as carboxymethyl cellulose, alginate, Gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) humectants, such as cetyl alcohol and glycerol monostearate; (8)
  • Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene Methanol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran methanol, polyethylene Diols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as water or other solvents
  • solubilizers and emulsifiers such as ethanol
  • Suspensions in addition to the active compounds, may also contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar and tragacanth and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar-agar and tragacanth and mixtures thereof.
  • Ointments, pastes, creams and gels can contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, poly Ethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, poly Ethylene glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • the sprays can contain other customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the "bond” means that the indicated substituent does not exist, and both end portions of the substituent are directly connected to form a bond.
  • Alkyl when taken as a group or part of a group is meant to include C1 - C20 straight or branched chain aliphatic hydrocarbon groups. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are 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, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preferred are C2 - C10 alkynyl groups, more preferably C2 - C6 alkynyl groups, and most preferably C2 - C4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spirocyclic carbocyclic rings. Preferably it is C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons.
  • spiro atom carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthryl.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.2.1]octyl Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocycle,” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclyl in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, piperidinyl , 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl .
  • Heterocyclyl groups can be substituted or unsubstituted.
  • “Spiroheterocyclyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and single rings share one atom with each other, and the ring contains one or more double bonds, but no An aromatic system with fully conjugated pi electrons in one ring, wherein one or more ring atoms are selected from nitrogen, oxygen, or a heteroatom of S(O) r (wherein r is selected from 0, 1, or 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has complete Conjugated pi-electron aromatic systems wherein one or more ring atoms are selected from nitrogen, oxygen or heteroatoms of S(O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine or
  • “Bridged heterocyclyl” refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may be Aromatic systems containing one or more double bonds but none of the rings have fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo Cyclo[3.3.2]decyl.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are naphthyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include but are not limited to furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiazolyl oxadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl,
  • Heteroaryl groups can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring is not completely conjugated A pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2), and the remaining ring atoms are carbon .
  • the condensed ring preferably includes a bicyclic or tricyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl means a group in which an alkyl group is optionally further substituted with one or more halogens, wherein alkyl is as defined herein.
  • Hydroalkyl refers to a group in which an alkyl group is optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
  • Aminoalkyl refers to a group in which an alkyl group is optionally further substituted with one or more amino groups, wherein alkyl is as defined herein.
  • Methods refers to a group in which the methyl group is optionally further substituted with one or more hydroxy groups.
  • Haloalkoxy refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Carboxylate means -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
  • DMSO dimethyl sulfoxide
  • BOC refers to t-butoxycarbonyl
  • Ts refers to p-toluenesulfonyl.
  • T3P refers to propylphosphoric anhydride.
  • DPPA diphenylphosphoryl azide
  • DEA diethylamine
  • TBS refers to t-butyldimethylsilyl
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • R 6 and R 7 together with the atoms to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O) r , and the
  • R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group , aryl or heteroaryl are optionally further selected from one or more groups selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , substituted by a substituent of a carboxyl group or a carboxylate group;
  • r 0, 1 or 2.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers, and atropisomers and geometric (conformational) isomers and Their mixtures, such as racemic mixtures, are within the scope of the present invention.
  • the structures depicted herein also include all isomeric (eg, diastereomeric, enantiomeric, and atropisomeric and geometric (conformational) isomeric forms of such structures; for example, , the R and S configuration of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers.
  • isomeric eg, diastereomeric, enantiomeric, and atropisomeric and geometric (conformational) isomeric forms of such structures; for example, , the R and S configuration of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers.
  • the individual stereoisomers of the compounds of the present invention as well as Enantiomeric mixtures, diastereomeric mixtures and geometric (conformational) isomer mixtures are all within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Represented by the general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) Pharmaceutically acceptable salts of the compounds can be metal salts, amine salts with suitable acids.
  • “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 physiologically pharmaceutically acceptable carriers and excipients Form.
  • 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 preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (IA) and the compound of general formula (IB) are subjected to a Suzuki coupling reaction under the action of a palladium catalyst and a basic reagent to obtain a compound of general formula (IC); the compound of general formula (IC) is further deprotected to obtain Compounds of general formula (I);
  • X is a leaving group, preferably chlorine
  • PG is a protecting group, preferably tert-butoxycarbonyl
  • M is selected from -B(OH) 2 , -BF 3 K or
  • Ring A, ring B, R 1 to R 4 , X 1 , X 2 , Q 1 , Q 2 , Y, k, m and n are as defined in the general formula (I).
  • the preparation method of the compound described in the general formula (II) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • X is a leaving group, preferably chlorine
  • PG is a protecting group, preferably tert-butoxycarbonyl
  • M is selected from -B(OH) 2 , -BF 3 K or
  • Ring A, ring B, R 1 to R 4 , X 1 , X 2 , Q 2 , Y, k, m and n are as defined in the general formula (II).
  • Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • CD3OD Deuterated methanol.
  • the compound was purified using column chromatography and thin layer chromatography eluent system, wherein the system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane And ethyl acetate system, D: dichloromethane and ethanol system, wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagents can also be added for conditions, such as acetic acid or triethylamine.
  • reaction solution was extracted with ethyl acetate (100 mL ⁇ 1), the organic phase was washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (2-((7-bromo-6-chloro-8 -Fluoro-3-nitroquinolin-4-yl)amino)ethyl)carbamate tert-butyl ester 1c (680 mg, 1.47 mmol), yield 99.70%, the product was directly carried out to the next step without purification.
  • reaction solution was filtered while hot, the filter cake was washed with methanol (20 mL), the filtrate was spun to remove methanol, extracted with ethyl acetate (100 mL ⁇ 1), the organic phase was washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, reduced was concentrated under pressure to give tert-butyl (2-((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl)amino)ethyl)carbamate 1d (636 mg, 1.47 mmol) as The yield was 100.00%, and the product was directly carried out to the next step without purification.
  • reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: system A) to obtain the product 3-bromo-2-chloro-4-fluoro-10,11-dihydropyrazino [1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate tert-butyl ester 1 h (140 mg, 307.21 ⁇ mol), 80.33% yield.
  • reaction solution was concentrated under reduced pressure, the system was made basic with saturated sodium carbonate solution, extracted with ethyl acetate (100 mL ⁇ 1), the organic phase was washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 4-(2-Chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl )-5,7-difluorobenzo[d]thiazol-2-amine (45 mg, 88.66 ⁇ mol), 58.61% yield.
  • 2-Amino-4-bromo-6-fluoro-benzonitrile 2a (4 g, 18.60 mmol, commercially available) was added to concentrated sulfuric acid (10 mL), and the temperature was raised to 65° C. to react for 3 hours.
  • the reaction solution was cooled to room temperature, poured into ice water (100 mL), adjusted to alkaline with saturated aqueous sodium carbonate solution, extracted with ethyl acetate (100 mL ⁇ 1), the organic phase was washed with saturated brine (100 mL ⁇ 3), Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude product 2-amino-4-bromo-6-fluorobenzamide 2b (4 g, 17.16 mmol), yield 92.27%, the product was directly carried out without purification one-step reaction.
  • reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: system B) to obtain 4-(7-bromo-2-chloro-5-fluoroquinazolin-4-yl) - tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 2f (40 mg, 67.80 ⁇ mol), 20.06% yield.
  • reaction solution was added with water (5 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent).
  • reaction solution was cooled to room temperature, water (5 mL) was added, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH3CN ) to give 5-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroazin-7a(5H)-yl)methoxy)-8,8a, 9,10,11,12-Hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl ) Naphthalen-2-ol 2 (1 mg, 1.78 ⁇ mol), 8.38% yield.
  • Test Example 1 Determination of the Inhibitory Activity of the Compounds of the Invention on p-ERK1/2 in AGS Cells
  • AGS human gastric adenocarcinoma
  • This method uses the Advanced phospho-ERK1/2 (Thr202/tyr204) kit (Cat. No. 64AERPEH) from Cisbio.
  • Kit instructions for detailed experimental operations, please refer to the kit instructions.
  • AGS cells (containing KRAS G12D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • AGS cells were cultured in F12K complete medium containing 10% fetal bovine serum, 100 U penicillin and 100 ⁇ g/mL streptomycin.
  • AGS cells were plated in 96-well plates at 40,000 cells per well, and the medium was complete medium, and cultured overnight in a 37°C, 5% CO 2 incubator.
  • the test compound was dissolved in DMSO to prepare a 10 mM stock solution, then diluted with F12K complete medium, and 100 ⁇ L of F12K complete medium containing the corresponding concentration of the test compound was added to each well.
  • the final concentration range of the test compound in the reaction system After culturing in a cell incubator for 3 hours, discard the cell supernatant, wash the cells with ice-bathed PBS, and then add 50 ⁇ l of 1 ⁇ cell phospho/total protein lysis buffer (Advanced phospho-ERK1 /2 kit components) were lysed, the 96-well plate was placed on ice for half an hour, and then the lysate was detected according to the instructions of the Advanced phospho-ERK1/2 (Thr202/tyr204) kit.
  • 1 ⁇ cell phospho/total protein lysis buffer Advanced phospho-ERK1 /2 kit components
  • the fluorescence intensity of each well at 620nm and 665nm was measured on a microplate reader in TF-FRET mode, and the fluorescence intensity ratio of 665/620 in each well was calculated.
  • the percentage inhibition rate of the test compound at each concentration was calculated, and the numerical-inhibition rate was subjected to nonlinear regression analysis with the test compound concentration by GraphPad Prism 5 software. , to obtain the IC50 value of the compound.
  • the compound of the present invention has a significant inhibitory effect on the activity of p-ERK1/2 in AGS cells, preferably, the compound has an IC 50 ⁇ 500 nM, more preferably, the compound has an IC 50 ⁇ 200 nM.
  • Test Example 2 Determination of Inhibition of AsPC-1 Cell Proliferation by Compounds of the Invention
  • AsPC-1 human metastatic pancreatic adenocarcinoma
  • AsPC-1 cells (containing KRAS G12D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, 100 ⁇ g/mL streptomycin and 1 mM Sodium Pyruvate middle. cell viability through Assays were performed with the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).
  • test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with culture medium to prepare a test sample.
  • the final concentration of the compound was in the range of 1000nM-0.015nM .
  • Cells in logarithmic growth phase were seeded into 96-well cell culture plates at a density of 800 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, followed by the addition of test compounds for 120 hours. After the incubation, 50 ⁇ L of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes.
  • the luminescence value of each well of the sample was read on a microplate reader using Luminescence mode.
  • the percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO), and then a nonlinear regression analysis was performed in the GraphPad Prism 5 software with the compound concentration logarithm-inhibition rate to obtain the compound inhibiting cell proliferation. the IC50 value.
  • the compound of the present invention has a significant inhibitory effect on the proliferation of AsPC-1 cells, preferably, the compound has an IC 50 ⁇ 500nM, more preferably, the compound has an IC 50 ⁇ 200nM.
  • Test Example 3 Determination of the inhibitory ability of the compounds of the present invention on the interaction between KRAS G12D and RAF1 protein
  • the following method was used to determine the ability of the compounds of the invention to block the KRAS G12D:RAF1 protein interaction under in vitro conditions.
  • This method uses the KRAS-G12C/SOS1BINDING ASSAY KITS kit (63ADK000CB21PEG) from Cisbio Company, and the detailed experimental operation refers to the kit instructions.
  • the wells emit fluorescence intensities at wavelengths of 620 nm and 665 nm, and the 665/620 fluorescence intensity ratio of each well is calculated.
  • the compound of the present invention has a good inhibitory ability on the interaction between KRAS G12D and RAF1 protein.
  • Test Example 4 Determination of Inhibition of AGS Cell Proliferation by Compounds of the Invention
  • AGS cells (containing KRAS G12D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in F12K medium containing 10% fetal bovine serum, 100 U penicillin and 100 ⁇ g/mL streptomycin. cell viability through Assays were performed with the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).
  • test compound was first dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with culture medium to prepare a test sample.
  • the final concentration of the compound was in the range of 1000nM-0.015nM .
  • Cells in logarithmic growth phase were seeded into 96-well cell culture plates at a density of 500 cells per well, cultured overnight at 37°C in a 5% CO2 incubator, followed by the addition of test compounds for 72 hours. After the incubation, 50 ⁇ L of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then allowed to stand for 10 minutes.
  • the luminescence value of each well of the sample was read on a microplate reader using Luminescence mode.
  • the percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO), and then a nonlinear regression analysis was performed in the GraphPad Prism 5 software with the compound concentration logarithm-inhibition rate to obtain the compound inhibiting cell proliferation.
  • the IC50 values are shown in Table 2.
  • the compound of the present invention has a good inhibitory effect on the proliferation of AGS cells.

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Abstract

本发明涉及杂环类衍生物、其制备方法及其在医药上的应用。具体而言，本发明涉及一种通式(A-I)或(A-II)所示的杂环类衍生物、其制备方法以及它们作为治疗剂、特别是作为KRas G12D抑制剂的用途，其中通式(A-I)或(A-II)中的各取代基的定义与说明书中的定义相同，

Description

杂环类衍生物、其制备方法及其医药上的用途 技术领域
本发明涉及一种杂环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为K-Ras GTP酶抑制剂的用途。
背景技术
RAS代表一组紧密相关的单体球状蛋白质(21kDa分子量)，其具有189个氨基酸且与质膜相连并且结合GDP或GTP。在正常发育或生理条件下，RAS接收生长因子和各种其它细胞外信号而被激活，负责调节细胞生长、存活、迁移和分化等功能。RAS起分子开关作用，RAS蛋白的开/关状态通过核苷酸结合确定，活性信号传导构象结合GTP，非活性构象结合GDP。当RAS包含结合的GDP时，其处于休眠或静止或关闭状态，并且是“非活化的”。当细胞暴露于某些生长促进刺激物进行响应时，RAS被诱导将结合的GDP转换为GTP。随着GTP被结合，RAS是“开启的”，并且能够与其它蛋白相互作用且活化其它蛋白(其“下游靶标”)。RAS蛋白本身具有极低的将GTP水解回到GDP并由此将自身变为关闭状态的固有能力。将RAS转换为关闭需要称作GTP酶激活蛋白(GAPs)的外源性蛋白，其与RAS相互作用并且能大大促进GTP向GDP的转化。任何在RAS中的影响其与GAP相互作用或将GTP转化回到GDP的能力的突变，将会导致所述蛋白的延长的活化，并且因此产生到细胞的延长的信号，该信号告知其继续生长和分裂。因此这些信号会使得细胞生长和分裂，过度活化的RAS信号转导可能最终导致癌症。
在结构上，RAS蛋白包含负责RAS的酶促活性——鸟嘌呤核苷酸结合和水解(GTP酶反应)的G结构域，其还包括含称为“CAAX盒”的C端延伸区，可被转译后修饰并且使该蛋白靶向膜。G结构域在尺寸上大约为21-25kDa并含有磷酸结合环(P-环)。P-环表示蛋白中结合核苷酸的囊袋，并且这是具有保守氨基酸残基的结构域的刚性部分，所述保守氨基酸残基为核苷酸结合和水解所必需的(甘氨酸-12、苏氨酸-26和赖氨酸-16)。G结构域还含有所谓的开关I区(残基30-40)和开关II区(残基60-76)，均为蛋白的动态部分，由于该动态部分在静止和负载状态之间进行转换的能力而常常被表示为“弹簧加载”机制。主要相互作用为由苏氨酸-35和甘氨酸-60与GTP的γ-磷酸所形成的氢键，其使开关I区和开关II区分别维持它们的活性构象。在水解GTP和释放磷酸盐之后，此两者松弛成无活性的GDP构象。
在RAS家族成员中，致癌突变最常见于KRAS(85％)，而NRAS(12％)和HRAS(3％)则较为少见。KRAS突变在美国三大致命癌症类型中普遍存在：胰腺癌(95％)、结肠直肠癌(45％)和肺癌(25％)，在包括多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌等在内的其他癌症类型中也发现KRAS突变，而在乳腺癌、卵巢癌和脑癌中很少发现(<2％)。在非小细胞肺癌(NSCLC)中，KRAS G12C是最常见的突变，占所有KRAS突变的近一半，其次是G12V和G12D。在 非小细胞肺癌中，特定等位基因突变频率的增加多来自经典的由吸烟诱导的典型突变(G:C至T:A置换)，从而导致了KRAS G12C(GGT至TGT)和G12V(GGT至GTT)突变。
大型基因组学研究表明，肺癌KRAS突变，包括G12C，与NSCLC中其它已知的驱动致癌突变相互排斥，包括EGFR、ALK、ROS1、RET和BRAF，表明KRAS突变在肺癌中的独特性。而同时，KRAS突变经常与某些共突变同时发生，例如STK11、KEAP1和TP53，它们与突变的RAS合作将细胞转化为高度恶性和侵袭性的肿瘤细胞。
三种RAS癌基因构成了人类癌症中突变最频繁的基因家族。令人失望的是，尽管经过三十多年的研究努力，临床上仍然没有有效的抗RAS疗法，使用小分子靶向该基因是项挑战。因此，本领域迫切需要用于靶向RAS(例如，K-RAS，H-RAS和/或N-RAS)的小分子并且利用其治疗多种疾病，例如癌症。
目前，国内外对于KRas G12D抑制剂的临床开发竞争激烈，其中Mirati Therapeutics Inc公司研发的KRas G12D抑制剂MRTX-1133已经进入临床前阶段，用于治疗大肠肿瘤、非小细胞肺癌和胰腺癌等疾病。目前公开为数不多的KRas G12D抑制剂专利申请，其中包括Mirati Therapeutics Inc公司的WO2021041671。虽然KRas G12D抑制剂的研究和应用已取得一定的进展，但是提高的空间仍然巨大，仍有必要继续研究和开发新的KRas G12D抑制剂。
发明内容
本发明的目的在于提供一种通式(A-I)或(A-II)所示的化合物、或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022083546-appb-000001
其中：
Figure PCTCN2022083546-appb-000002
根据需要选自单键或双键，以使其连接的每个原子呈现正常价态；
环A各自独立地选自5～6元杂芳基或5～10元单环杂环基；优选为6～7元单环杂环基；其中所述的杂芳基、单环杂环基内含有一个或多个N或O原子；
环B各自独立地选自芳基、杂芳基或稠合环；
环C各自独立地选自一个含有2个氮原子的6～8元的杂环基；
Q 1选自N或CR a；Q 1优选为N；
Q 2各自独立地选自N、C或CR a；
Y各自独立地选自键、O或NR b；
X 1、X 2各自独立地选自N、C＝O、CR c或CR dR e；
E各自独立地选自氢原子或
Figure PCTCN2022083546-appb-000003
R a相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基或氰基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；
R b选自氢原子或烷基；
R c选自氢原子、卤素、氰基、烷基或烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R c优选为卤素，更优选为氟或氯；
R d和R e相同或不同，各自独立地选自氢原子、卤素、烷基或烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；
或者，R d和R e与所连接的碳原子一起形成一个环烷基或杂环基；优选为环丙基；
R f选自氢原子或环烷基，其中所述的环烷基优选为环丙基；
R 1各自独立地选自氢原子、-L-烷基、-L-卤素、-L-OR 5、-L-NR 6R 7、-L-C(O)OR 5、-L-C(O)NR 6R 7、-L-环烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-稠合环或
Figure PCTCN2022083546-appb-000004
其中所述的烷基、环烷基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个选自R g的取代基所取代；
R g相同或不同，各自独立地选自烷基、卤素、苄基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NHC(O)NR 6R 7、-NHC(＝NH)NR 6R 7、-OC(O)NR 6R 7、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7或-S(O) rR 5，其中所述的烷基、苄基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、卤代烷基、羟烷基、苄基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-OSi(R 5) 3、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NHC(O)NR 6R 7、-NHC(＝NH)NR 6R 7、-OC(O)NR 6R 7、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7、-NHS(O) rR 5或-S(O) rR 5的取代基所取代；
L各自独立地选自键或C 1-C 6亚烷基，其中所述的亚烷基任选进一步被一个或多个R D所取代；
R D各自独立地选自氢原子、卤素、羟基或羟甲基；
或者，连接于同一碳原子的两个R D与所连接的碳原子一起形成一个环烷基；优选为环丙基；
R 2相同或不同，各自独立地选自氢原子、卤素、羟基、烷基或烷氧基，优选为氢原子或烷基；
或者，任意的两个R 2与其所连接的原子一起形成一个环烷基或杂环基；
R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基或＝O；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R 3优选为氢原子、甲基或＝O；
R 4各自独立地选自氢原子、烷基、卤素、硝基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7或-S(O) rR 5；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7或-S(O) rR 5的取代基所取代；
R 5各自独立地选自氢原子、卤素、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2R 8、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
R 6和R 7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自R h的取代基所取代；
R h相同或不同，各自独立地选自羟基、卤素、硝基、氰基、烷基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 8、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10；其中所述的烷基、环烷基、杂环基、芳基、杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
或者，R 6和R 7与它们相连接的原子一起形成一个4～8元杂环基，其中4～8元杂环基内含有一个或多个N、O或S(O) r，并且所述的4～8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-CH 2NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
R 8、R 9和R 10各自独立地选自氢原子、卤素、烷基、氨基、环烷基、杂环基、苄基、 芳基或杂芳基，其中所述的烷基、环烷基、杂环基、苄基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、氨基烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；
m各自独立地选自0、1、2、3或4；
n各自独立地选自0、1、2或3；
k各自独立地选自0、1或2；
r各自独立地选自0、1或2。
本发明提供一种通式(A-I)或(A-II)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其为通式(I)或(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022083546-appb-000005
其中：环A、环B、X 1、X 2、Y、Q 1、Q 2、R 1、R 2、R 3、R 4、m、n和k的定义如通式(A-I)或(A-II)中所述。
本发明提供一种通式(I)或(II)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其为通式(III)、(IV)、(V)或(VI)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022083546-appb-000006
Figure PCTCN2022083546-appb-000007
其中：环B、X 1、X 2、Y、Q 1、Q 2、R 1、R 2、R 3、R 4、m和n的定义如通式(A-I)或(A-II)中所述。
本发明提供一种通式(A-I)或(A-II)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其为通式(VII)、(VIII)或(IX)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
Figure PCTCN2022083546-appb-000008
其中：环B、X 1、X 2、Y、Q 1、Q 2、R 1、R 2、R 3、R 4、m和n的定义如通式(A-I)或(A-II)所述。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
Figure PCTCN2022083546-appb-000009
均选自双键；
Q 1选自N；
Q 2选自C；
X 1、X 2各自独立地选自N或CR c；
R c选自氢原子或卤素，优选为卤素，更优选为氟或氯。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
Figure PCTCN2022083546-appb-000010
均选自双键；
Q 1选自N；
Q 2选自C；
X 1选自CR c；
X 2选自N；
R c选自卤素，优选为氟或氯，更优选为氟。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
Figure PCTCN2022083546-appb-000011
均选自单键；
X 1、X 2各自独立地选自CR dR e；
R d和R e选自氢原子；
或者，R d和R e与所连接的碳原子一起形成一个3～5元单环环烷基或3～5元单环杂环基；优选为环丙基。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
X 2所连
Figure PCTCN2022083546-appb-000012
选自双键；
X 1和Q 2之间
Figure PCTCN2022083546-appb-000013
选自单键；
X 1选自C＝O；
X 2选自N；
Q 2选自N。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
R 1选自-L-杂环基；其中所述的杂环基任选进一步被一个或多个选自烷基、卤素、烷氧基或＝O的取代基所取代；其中所述的卤素优选为氟；
L选自键或C 1-C 3亚烷基，其中所述的亚烷基任选进一步被一个或多个R D所取代；
R D各自独立地选自氢原子、卤素、羟基或羟甲基；
或者，连接于同一碳原子的两个R D与所连接的碳原子一起形成一个环烷基；优选为环丙基。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
L选自键、-CH 2-、-CH 2CH 2-或
Figure PCTCN2022083546-appb-000014
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中R 1选自：
Figure PCTCN2022083546-appb-000015
Figure PCTCN2022083546-appb-000016
Figure PCTCN2022083546-appb-000017
Figure PCTCN2022083546-appb-000018
Figure PCTCN2022083546-appb-000019
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基或＝O；R 3优选为氢原子、甲基或＝O。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中R 4相同或不同，各自独立地选自氢原子、烷基、卤素、烷氧基、炔基、羟基、氨基、羟烷基、卤代烷基或卤代烷氧基；R 4优选为氢原子、甲基、氟、氯、溴、碘、羟基、氨基、羟甲基或乙炔基。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
环B选自苯基、萘基、吡啶基、喹啉基、异喹啉基、吲哚基、吲唑基、苯并噻唑基、四氢化萘基、
Figure PCTCN2022083546-appb-000020
环B优选为萘基或苯并噻唑基。
本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示的化合物、或其立体异构体、互变异构体或其可药用的盐，其中：
Figure PCTCN2022083546-appb-000021
选自以下基团：
Figure PCTCN2022083546-appb-000022
本发明提供一种通式(I)或(III)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
Figure PCTCN2022083546-appb-000023
选自以下基团：
Figure PCTCN2022083546-appb-000024
本发明提供一种通式(II)、(IV)、(V)或(VI)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
Figure PCTCN2022083546-appb-000025
选自以下基团：
Figure PCTCN2022083546-appb-000026
本发明提供一种通式(VII)、(VIII)或(IX)所示的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
Figure PCTCN2022083546-appb-000027
选自以下基团：
Figure PCTCN2022083546-appb-000028
本发明的典型化合物包括但不限于：
Figure PCTCN2022083546-appb-000029
Figure PCTCN2022083546-appb-000030
Figure PCTCN2022083546-appb-000031
Figure PCTCN2022083546-appb-000032
Figure PCTCN2022083546-appb-000033
Figure PCTCN2022083546-appb-000034
或其立体异构体、互变异构体或其可药用的盐。
注：如果在画出的结构和给出的该结构的名称之间有差异，则画出的结构将给予更大的权重。
在另一方面，本发明提供一种药物组合物，所述的药物组合物含有有效剂量的通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
在另一方面，本发明提供一种抑制KRas G12D酶的方法，其中所述的方法包括：给予患者一种药物组合物，所述的药物组合物含有有效剂量的通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
本发明还提供了一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物(例如前述技术方案所述的药物组合物)在制备治疗由KRas G12D突变介导的疾病的药物中的用途，其中所述的由KRas G12D突变介导的疾病选自癌症，其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、结直肠癌、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，优选为胰腺癌、结直肠癌、直肠癌和肺癌；其中所述的肺癌选自非小细胞肺癌或小细胞肺癌。
在另一方面，本发明提供一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物(例如前述技术方案所述的药物组合物)在制备KRas G12D抑制剂中的用途。
本发明的另一方面涉及一种预防和/或治疗由KRas G12D突变介导的疾病的方法，其包括向患者施用治疗有效剂量的通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所述的化合物或其立体异构体、互变异构体或其可药用的盐、或包含其的药物组合物(例如前述技术方案所述的药物组合物)。其中所述的由KRas G12D突变介导的疾病选自癌症，其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、结直肠癌、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，优选为胰腺癌、结直肠癌、直肠癌和肺癌；其中所述的肺癌选自非小细胞肺癌或小细胞肺癌。
本发明还提供了一种通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物(例如前述技术方案所述的药物组合物)在制备治疗癌症的药物中的用途，其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、结直肠癌、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，优选为胰腺癌、结直肠癌、直肠癌和肺癌；其中所述的肺癌优选为非小细胞肺癌或小细胞 肺癌。
本发明还提供了一种预防和/或治疗癌症的方法，包括向患者施用治疗有效剂量的通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所述的化合物或其立体异构体、互变异构体或其可药用的盐，或其药物组合物(例如前述技术方案所述的药物组合物)。其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、结直肠癌、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，优选为胰腺癌、结直肠癌、直肠癌和肺癌；其中所述的肺癌优选为非小细胞肺癌。
本发明的药物制剂可以经局部、口服、经皮、经直肠、经阴道、非经肠、鼻内、肺内、眼内、静脉内、肌肉内、动脉内、鞘内、囊内、皮内、腹膜内、皮下、角质层下或者通过吸入进行给药。含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊、或糖浆剂或酏剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。
本发明的制剂适合以单位计量的形式存在，并且所述制剂可借由在制药技术中所众所周知的任何方法进行制备。能够通过与载体物质进行组合，从而产生单一剂型的活性成分的量可以依据所治疗的宿主及特定给药模式而变化。能够通过与载体物质进行组合从而产生单一剂型的活性成分的量通常指的是能够产生治疗效果的化合物的量。
用于本发明化合物的局部或者透皮给药的剂型可包括粉末、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴片及吸入剂。活性化合物可在无菌条件下与药学上可接受的载剂进行混合，并且其可与可能需要的任何防腐剂、缓冲剂或者推进剂进行混合。
当本发明的化合物以药物的形式对人类及动物进行给药时，所述化合物可进行单独提供或者以药物组合物的形式提供，所述药物组合物含有与药学上可接受的载剂进行组合的活性成分，例如0.1％至99.5％(更优选地，0.5％至90％)的活性成分。
药学上可接受的载剂的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉及马铃薯淀粉；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；(4)粉末状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨糖醇、甘露糖醇及聚乙二醇；(12)酯，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液(Ringer's solution)；(19)乙醇；(20)磷酸盐缓冲溶液；(21)环糊精，例如连接于纳米粒子的靶向配体，例如AccurinsTM；及(22)用于药物制剂中的其它无毒兼容物质，例如聚合物基组合物。
药学上可接受的抗氧化剂的实例包括但不限于：(1)水溶性抗氧化剂，例如抗坏血酸、 半胱胺酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠及其类似物；(2)油溶性抗氧化剂，例如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、五倍子酸丙酯、α-生育酚及其类似物；及(3)金属螯合剂，例如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其类似物。固体剂型(例如胶囊、锭剂丸剂、糖衣锭、粉末、颗粒剂及其类似物)可包括一种或者多种药学上可接受的载剂，例如柠檬酸钠或者磷酸二钙，和/或以下任意其中之一：(1)填充剂或增量剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或者硅酸；(2)黏合剂，例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯啶酮、蔗糖和/或阿拉伯胶；(3)保湿剂，例如甘油；(4)崩解剂，例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠；(5)溶解阻滞剂，例如石蜡；(6)吸收加速剂，例如四级铵化合物；(7)湿润剂，例如十六醇及甘油单硬脂酸酯；(8)吸收剂，例如高岭土及膨润土；(9)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物；和(10)着色剂。液体剂型可包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性成分之外，液体剂型可含有通常用于本技术领域中的惰性稀释剂，例如水或其它溶剂；增溶剂及乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙脂、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油、及芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇以及脱水山梨醇的脂肪酸酯、及其混合物。
除活性化合物之外，悬浮液也可含有悬浮剂，例如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇及脱水山梨醇酯、微晶纤维素、氢氧化铝氧化物、膨润土、琼脂及黄蓍胶及其混合物。
除活性化合物之外，软膏剂、糊剂、乳膏剂以及凝胶剂也可含有赋形剂，例如动物脂肪及植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧、膨润土、硅酸、滑石及氧化锌或者其混合物。
除活性化合物之外，粉末及喷雾剂也可以含有赋形剂，例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末或者上述这些物质的混合物。所述喷雾剂可以含有其它的常用推进剂，例如氯氟烃、以及挥发性的未被取代的烃，例如丁烷及丙烷。
发明的详细说明
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：
“键”是指标示的取代基不存在，该取代基的两端部分直接连接成键。
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的脂肪烃基团。优选为C 1-C 10烷基，更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基 可以是取代或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。烯基可以是任选取代的或未取代的。
“炔基”是指含有一个碳碳三键的脂肪烃基团，可为直链也可以带有支链。优先选择的是C 2-C 10的炔基，更优选C 2-C 6炔基，最优选C 2-C 4炔基。炔基基团的实施例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C 3-C 12环烷基，更优选为C 3-C 8环烷基，最优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于：螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元，含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接碳原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，都是指非芳香性杂环基，其中一个或多个成环的原子是杂原子，如氧、氮、硫原子等，包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双或三环，其可以包含1,2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基、氧杂环丁烷基、硫代吗啉基、四氢吡喃 基、1,1-二氧代硫代吗啉基、哌啶基、2-氧代哌啶基、吡咯烷基、2-氧代吡咯烷基、哌嗪-2-酮、8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。
“螺杂环基”指5至18元，两个或两个以上环状结构，且单环之间彼此共用一个原子的多环基团，环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) r(其中r选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于：1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的全碳多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) r(其中r选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基，3-氮杂二环[3.1.0]己基，八氢苯并[b][1,4]二噁英(dioxine)或
Figure PCTCN2022083546-appb-000035
“桥杂环基”指5至14元，5至18元，含有两个或两个以上环状结构，彼此共用两个不直接相连接的原子的多环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) r(其中r选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于：2-氮杂二环[2.2.1]庚基，2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基，比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为萘基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或8至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。优选为双环杂芳基，“杂芳基”的实施例包括但不限于呋喃基、吡啶基、2-氧代-1,2-二氢吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异噁唑基、噁唑基、噁二唑基、咪唑基、吡咯基、吡唑基、三唑基、四氮唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、苯并间二氧杂环戊烯基、苯并噻吩基、苯并咪唑基、吲哚基、异吲哚基、1,3-二氧代-异吲 哚基、喹啉基、吲唑基、苯并异噻唑基、苯并噁唑基、苯并异噁唑基、
Figure PCTCN2022083546-appb-000036
杂芳基可以是取代或未取代的。
“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但至少一个环不具有完全共轭的π电子的芳香系统，其中环原子选自0个、一个或多个选自氮、氧或S(O) r(其中r选自0、1或2)的杂原子，其余环原子为碳。稠合环优选包括双环或三环的稠合环，其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环。优选为7至14元，更优选为8至10元。“稠合环”的实施例包括但不限于：
Figure PCTCN2022083546-appb-000037
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤代烷基”是指烷基任选进一步被一个或多个卤素所取代的基团，其中烷基见本文有关定义。
“羟烷基”是指烷基任选进一步被一个或多个羟基所取代的基团，其中烷基见本文有关定义。
“氨基烷基”是指烷基任选进一步被一个或多个氨基所取代的基团，其中烷基见本文有关定义。
“羟甲基”指甲基任选进一步被一个或多个羟基所取代的基团。
“卤代烷氧基”是指(烷基-O-)的烷基任选进一步被一个或多个卤素所取代的基团，其中烷氧基见本文有关定义。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“苄基”指-CH 2-苯基。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基，其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“BOC”指叔丁氧基羰基。
“Ts”指对甲苯磺酰基。
“T3P”指丙基磷酸酐。
“DPPA”指叠氮磷酸二苯酯。
“DEA”指二乙胺。
“X-PHOS Pd G2”氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)。
“MOM”指甲氧基甲基。
“TBS”指叔丁基二甲基甲硅烷基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7或-S(O) rR 5的取代基所取代；
R 5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
R 6和R 7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个 或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
或者，R 6和R 7与它们相连接的原子一起形成一个4～8元杂环基，其中4～8元杂环基内含有一个或多个N、O或S(O) r，并且所述的4～8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
R 8、R 9和R 10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；
r为0、1或2。
本发明化合物可以含有不对称中心或手性中心，因此以不同的立体异构体形式存在。所预期的是，本发明化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物，如外消旋体混合物，均在本发明的范围内。
除非另外指出，本发明描述的结构还包括此结构的所有异构体(如，非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式；例如，各不对称中心的R和S构型，(Z)和(E)双键异构体，以及(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本发明范围内。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(A-I)、(A-II)、(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022083546-appb-000038
通式(IA)化合物和通式(IB)化合物在钯催化剂及碱性试剂的作用下进行Suzuki偶联反应，得到通式(IC)化合物；通式(IC)化合物进一步脱去保护基，得到通式(I)化合物；
其中：
X为离去基团，优选为氯；
PG为保护基，优选为叔丁氧基羰基；
M选自-B(OH) 2、-BF 3K或
Figure PCTCN2022083546-appb-000039
环A、环B、R 1～R 4、X 1、X 2、Q 1、Q 2、Y、k、m和n的定义如通式(I)中所述。
本发明通式(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2022083546-appb-000040
通式(IIA)化合物和通式(IB)化合物在钯催化剂及碱性试剂的作用下进行Suzuki偶联反应，得到通式(IIC)化合物；通式(IIC)化合物进一步脱去保护基，得到通式(II)化合物；
其中：
X为离去基团，优选为氯；
PG为保护基，优选为叔丁氧基羰基；
M选自-B(OH) 2、-BF 3K或
Figure PCTCN2022083546-appb-000041
环A、环B、R 1～R 4、X 1、X 2、Q 2、Y、k、m和n的定义如通式(II)中所述。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
实施例给出了通式(I)和(II)所表示的代表性化合物的制备及相关结构鉴定数据。必须说 明，下述实施例是用于说明本发明而不是对本发明的限制。 1HNMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1HNMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于上海皓鸿生物医药科技有限公司，上海韶远试剂有限公司，上海毕得医药科技有限公司，萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。
CD 3OD：氘代甲醇。
CDCl 3：氘代氯仿。
DMSO-d 6：氘代二甲基亚砜。
实施例中无特殊说明，反应中的溶液是指水溶液。
对化合物进行纯化，采用柱层析和薄层色谱法的洗脱剂体系，其中该体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷和乙酸乙酯体系，D：二氯甲烷和乙醇体系，其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行条件，如醋酸或三乙胺等。
室温：20℃～30℃。
实施例1
4-(2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl)-5,7-difluorobenzo[d]thiazol-2-amine
4-(2-氯-4-氟-8,9,10,11-四氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-3-基)-5,7-二氟苯并[d]噻唑-2-胺
Figure PCTCN2022083546-appb-000042
Figure PCTCN2022083546-appb-000043
第一步
tert-butyl(2-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)ethyl)carbamate
(2-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)乙基)氨基甲酸叔丁酯
将7-溴-4,6-二氯-8-氟-3-硝基喹啉1a(500mg,1.47mmol,根据公开专利WO2019110751A1制备)和(2-氨基乙基)氨基甲酸叔丁酯1b(282.79mg,1.77mmol)加入乙腈(8.54mL)中，冷却至0℃，加入N,N-二异丙基乙胺(570.29mg,4.41mmol,729.27μL)，转至室温反应过夜。反应液用乙酸乙酯萃取(100mL×1)，有机相用饱和食盐水洗(100mL×1)，无水硫酸钠干燥，减压浓缩，得到(2-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)乙基)氨基甲酸叔丁酯1c(680mg,1.47mmol)，产率99.70％，产物不经纯化，直接进行下一步反应。
LCMS:463.0[M+1] +
第二步
tert-butyl(2-((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl)amino)ethyl)carbamate(2-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)乙基)氨基甲酸叔丁酯
将(2-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)乙基)氨基甲酸叔丁酯1c(680mg,1.47 mmol)、铁粉(409.52mg,7.33mmol)和氯化铵(392.22mg,7.33mmol)加入甲醇(10mL)和水(2mL)的混合溶剂中，加热回流4小时。反应液趁热过滤，滤饼用甲醇洗(20mL)，滤液旋除甲醇后用乙酸乙酯萃取(100mL×1)，有机相用饱和食盐水洗(100mL×1)，无水硫酸钠干燥，减压浓缩，得到(2-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)乙基)氨基甲酸叔丁酯1d(636mg,1.47mmol)，产率100.00％，产物不经纯化，直接进行下一步反应。
LCMS:433.0[M+1] +
第三步
tert-butyl (2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate
(2-(7-溴-8-氯-2-(氯甲基)-6-氟-1H-咪唑并[4,5-c]喹啉-1-基)乙基)氨基甲酸叔丁酯
将(2-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)乙基)氨基甲酸叔丁酯1d(300mg,691.72μmol)加入二氯甲烷(5mL)中，加入三乙胺(139.99mg,1.38mmol)，室温下滴加2-氯乙酰氯(156.25mg,1.38mmol)的二氯甲烷溶液(2mL)，继续室温反应过夜，LCMS检测有很多中间体没有关环，反应液用二氯甲烷萃取(50mL×1)，有机相用饱和食盐水洗(100mL×2)，无水硫酸钠干燥，浓缩，所得的残余物加入醋酸(5mL)中，加热至50℃反应2小时，反应液冷却至室温，体系用饱和碳酸钠溶液调至碱性，乙酸乙酯萃取(100mL×1)，有机相用饱和食盐水洗(100mL×1)，无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得到产物(2-(7-溴-8-氯-2-(氯甲基)-6-氟-1H-咪唑并[4,5-c]喹啉-1-基)乙基)氨基甲酸叔丁酯1e(190mg,386.05μmol)，产率57.58％。
LCMS:492.7[M+1] +
第四步
2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethan-1-amine
2-(7-溴-8-氯-2-(氯甲基)-6-氟-1H-咪唑并[4,5-c]喹啉-1-基)乙-1-胺
将(2-(7-溴-8-氯-2-(氯甲基)-6-氟-1H-咪唑并[4,5-c]喹啉-1-基)乙基)氨基甲酸叔丁酯1e(190mg,386.05μmol)加入二氯甲烷(4mL)中，加入氯化氢的二氧六环溶液(4M,2mL)，室温反应1小时。反应液减压浓缩，得到2-(7-溴-8-氯-2-(氯甲基)-6-氟-1H-咪唑并[4,5-c]喹啉-1-基)乙-1-胺1f(151mg,385.15μmol)，产率99.77％，产物不经纯化，直接进行下一步反应。
LCMS:393.0[M+1] +
第五步
3-bromo-2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolone
3-溴-2-氯-4-氟-8,9,10,11-四氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉
将2-(7-溴-8-氯-2-(氯甲基)-6-氟-1H-咪唑并[4,5-c]喹啉-1-基)乙-1-胺1f(151mg,385.15μmol)、碘化钾(6.39mg,38.52μmol)和碳酸钾(106.46mg,770.30μmol)加入乙腈(5mL)中， 加热回流3小时。冷却至室温，反应液用乙酸乙酯萃取(100mL×1)，有机相用饱和食盐水洗(100mL×1)，无水硫酸钠干燥，减压浓缩，得到3-溴-2-氯-4-氟-8,9,10,11-四氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉1g(136mg,382.46μmol)，产率99.30％，产物不经纯化，直接进行下一步反应。
LCMS:355.0[M+1] +
第六步
tert-butyl 3-bromo-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate
3-溴-2-氯-4-氟-10,11-二氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-9(8H)-羧酸叔丁酯
将3-溴-2-氯-4-氟-8,9,10,11-四氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉1g(136mg,382.46μmol)、三乙胺(77.40mg,764.92μmol)和二碳酸二叔丁酯(100.17mg,458.95μmol)加入二氯甲烷(5mL)中，室温反应2小时。反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)分离纯化，得到产物3-溴-2-氯-4-氟-10,11-二氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-9(8H)-羧酸叔丁酯1h(140mg,307.21μmol)，产率80.33％。
LCMS:456.8[M+1] +
第七步
tert-butyl 3-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate
3-(2-((叔丁氧羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)-2-氯-4-氟-10,11-二氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-9(8H)-羧酸叔丁酯
将(2-((叔丁氧羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)硼酸1i(152.12mg,460.82μmol,根据公开专利US20200115375A1制备)、3-溴-2-氯-4-氟-10,11-二氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-9(8H)-羧酸叔丁酯1h(140mg,307.21μmol)、碳酸钠(65.13mg,614.43μmol)和四三苯基膦钯(35.50mg,30.72μmol)加入二氧六环(4mL)和水(1mL)的混合溶液中，氩气保护，加热至110℃反应过夜。反应液冷却，乙酸乙酯萃取(100mL×1)，有机相用饱和食盐水洗(100mL×1)，无水硫酸钠干燥，减压浓缩，得到的残留物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)得到产物3-(2-((叔丁氧羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)-2-氯-4-氟-10,11-二氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-9(8H)-羧酸叔丁酯1j(100mg,151.26μmol)，产率49.24％。
LCMS:660.8[M+1] +
第八步
4-(2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl)-5,7-difluorobenzo[d]thiazol-2-amine
4-(2-氯-4-氟-8,9,10,11-四氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-3-基)-5,7-二氟苯并[d]噻唑-2-胺
将3-(2-((叔丁氧羰基)氨基)-5,7-二氟苯并[d]噻唑-4-基)-2-氯-4-氟-10,11-二氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-9(8H)-羧酸叔丁酯1j(100mg,151.26μmol)加入二氯甲烷(5mL)中，加入氯化氢的1,4-二氧六环溶液(4M,3mL)，室温反应3小时。反应液减压浓缩，体系用饱和碳酸钠溶液调至碱性，乙酸乙酯萃取(100mL×1)，有机相用饱和食盐水洗(100mL×1)，无水硫酸钠干燥，减压浓缩得产物4-(2-氯-4-氟-8,9,10,11-四氢吡嗪并[1',2':1,2]咪唑并[4,5-c]喹啉-3-基)-5,7-二氟苯并[d]噻唑-2-胺(45mg,88.66μmol),产率58.61％。
LCMS:461.0[M+1]
实施例2
5-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol
5-氟-4-(2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8,8a,9,10,11,12-六氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-5-基)萘-2-醇
Figure PCTCN2022083546-appb-000044
Figure PCTCN2022083546-appb-000045
第一步
2-amino-4-bromo-6-fluorobenzamide
2-氨基-4-溴-6-氟苯甲酰胺
将2-氨基-4-溴-6-氟-苯甲腈2a(4g,18.60mmol,市售)加入浓硫酸(10mL)中，升温至65℃反应3小时。反应液冷却至室温，倒入冰水(100mL)中，以饱和碳酸钠水溶液调节pH至碱性，以乙酸乙酯萃取(100mL×1)，有机相用饱和食盐水洗(100mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到粗品产物2-氨基-4-溴-6-氟苯甲酰胺2b(4g,17.16mmol)，产率92.27％，产物不经纯化，直接进行下一步反应。
LCMS:233.0[M+1] +
第二步
7-bromo-5-fluoroquinazoline-2,4-diol
7-溴-5-氟喹唑啉-2,4-二醇
将2-氨基-4-溴-6-氟苯甲酰胺2b(1g,4.29mmol)加入乙腈(5mL)中，依次加入4-二甲氨基吡啶(1.05g,8.58mmol)，三光气(636.70mg,2.15mmol)，室温反应4小时，LCMS监控反应完全。反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到7-溴-5-氟喹唑啉-2,4-二醇2c(400mg,1.54mmol)，产率35.99％。
LCMS:259.0[M+1] +
第三步
7-bromo-2,4-dichloro-5-fluoroquinazoline
7-溴-2,4-二氯-5-氟喹唑啉
将7-溴-5-氟喹唑啉-2,4-二醇2c(300mg,1.16mmol)加入乙腈(6mL)中，室温搅拌下，依次加入三氯氧磷(4.43g,28.95mmol)和N,N-二异丙基乙胺(1.50g,11.58mmol)，升温至80℃反应2小时，LCMS监控反应完全。反应液冷却至室温，减压浓缩，得到粗品产物7-溴-2,4-二氯-5-氟喹唑啉2d，产物不经纯化，直接进行下一步反应。
第四步
tert-butyl 4-(7-bromo-2-chloro-5-fluoroquinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate
4-(7-溴-2-氯-5-氟喹唑啉-4-基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)哌嗪-1-羧酸叔丁酯
将3-(((叔丁基二甲基甲基硅烷基)氧基)甲基)哌嗪-1-羧酸叔丁酯2e(111.70mg,337.93μmol,根据公开专利WO2003051797制备)加入二氯甲烷(2mL)中，氩气保护，冷却至-40℃，滴加N,N-二异丙基乙胺(436.73mg,3.38mmol)，反应液升至室温搅拌过夜，第二天反应液再次冷却至-40℃，滴加N,N-二异丙基乙胺(436.73mg,3.38mmol)，然后滴加新制的7-溴-2,4-二氯-5-氟喹唑啉2d(100mg,337.93μmol)的二氯甲烷溶液(2mL)，反应液升至室温反应过夜，LCMS监控反应完全。反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到4-(7-溴-2-氯-5-氟喹唑啉-4-基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)哌嗪-1-羧酸叔丁酯2f(40mg,67.80μmol)，产率20.06％。
LCMS:589.0[M+1] +
第五步
tert-butyl 4-(7-bromo-5-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate
4-(7-溴-5-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)哌嗪-1-羧酸叔丁酯
将((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇2g(16.19mg,101.70μmol,根据公开专利WO2020146613制备)加入到四氢呋喃(5mL)中，氩气保护，加入氢化钠(4.07mg,169.49μmol)，降温至0℃下反应30分钟，然后加入4-(7-溴-2-氯-5-氟喹唑啉-4-基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)哌嗪-1-羧酸叔丁酯2f(40mg,67.80μmol)，升温至70℃下反应过夜，LCMS监控反应完全。反应液降至室温，加入水(5mL)淬灭反应，以乙酸乙酯萃取(10mL×3)，合并有机相，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到4-(7-溴-5-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)哌嗪-1-羧酸叔丁酯2h(30mg,42.09μmol)，产率62.08％。
LCMS:713.0[M+1] +
第六步
tert-butyl 5-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate
5-溴-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8a,9,11,12-四氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-10(8H)-羧酸叔丁酯
将4-(7-溴-5-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3-(((叔丁基二甲基甲硅烷基)氧基)甲基)哌嗪-1-羧酸叔丁酯2h(55mg,77.17μmol)加入到四氢呋喃(5mL)中，加入四丁基氟化铵(40.35mg,154.33μmol)，室温反应过夜。反应液加入水(5mL)，以乙酸乙酯萃取(10mL×3)，合并有机相，以无水硫酸钠干燥，过滤，减压 浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到产物5-溴-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8a,9,11,12-四氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-10(8H)-羧酸叔丁酯2i(30mg,51.86μmol)，产率67.21％。
LCMS:578.0[M+1] +
第七步
tert-butyl 5-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate
5-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8a,9,11,12-四氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-10(8H)-羧酸叔丁酯
将5-溴-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8a,9,11,12-四氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-10(8H)-羧酸叔丁酯2i(18mg,31.12μmol)加入到1,4-二氧六环(1mL)和水(0.2mL)的混合溶剂中，依次加入2-(8-氟-3-甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷2j(12.40mg,37.34μmol,根据公开专利WO2021041671A1制备)、碳酸钠(9.90mg,93.35μmol)和四(三苯基膦)钯(3.60mg,3.11μmol)，氩气保护，升温至80℃反应2小时。反应液降至室温，加入水(5mL)，以乙酸乙酯萃取(10mL×3)，合并有机相，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)分离纯化，得到5-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8a,9,11,12-四氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-10(8H)-羧酸叔丁酯2k(15mg,21.31μmol)，产率68.48％。
LCMS:704.0[M+1] +
第八步
5-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol
5-氟-4-(2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8,8a,9,10,11,12-六氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-5-基)萘-2-醇
将5-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8a,9,11,12-四氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉-10(8H)-羧酸叔丁酯2k(15mg,21.31μmol)加入到乙腈(1mL)中，搅拌，加入氯化氢的1,4-二氧六环溶液(4M,0.5mL)，室温反应3小时，LCMS监控反应完全。反应液减压浓缩，得到的残留物通过制备液相分离纯化(分离柱AKZONOBEL Kromasil；250×21.2mm I.D.；5μm，20mL/min；流动相A：0.05％TFA+H 2O，流动相B：CH 3CN)，得到5-氟-4-(2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8,8a,9,10,11,12-六氢吡嗪并[2',1':3,4][1,4]氧氮杂卓并[5,6,7-de]喹唑啉 -5-基)萘-2-醇2(1mg,1.78μmol)，产率8.38％。
LCMS:560.0[M+1] +
生物学评价
测试例1、本发明化合物对AGS细胞中p-ERK1/2抑制活性的测定
以下方法用于测定本发明化合物对AGS(人胃腺癌)细胞中p-ERK1/2抑制活性。本方法使用Cisbio公司的Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒(货号64AERPEH)，详细实验操作可参考试剂盒说明书。AGS细胞(含有KRAS G12D突变)购于中国科学院上海生命科学研究院细胞资源中心。
将实验流程简述如下：AGS细胞培养于含10％胎牛血清、100U青霉素和100μg/mL链霉素的F12K完全培养基中。AGS细胞按每孔40000个铺于96孔板中，培养基为完全培养基，在37℃，5％CO 2培养箱内培养过夜。将受试化合物溶解于DMSO中制备为10mM贮存液，随后使用F12K完全培养基进行稀释，每孔加入100μL含对应浓度受试化合物的F12K完全培养基，受试化合物在反应体系中的终浓度范围为1000nM-0.015nM，置于细胞培养箱培养3小时后，弃去细胞上清，使用冰浴的PBS清洗细胞，之后每孔加入50μl的1×cell phospho/total protein lysis buffer(Advanced phospho-ERK1/2试剂盒组分)进行裂解，96孔板置于冰上裂解半小时，随后参照Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒说明书检测裂解液。最后在酶标仪以TF-FRET模式上测定在304nm的激发波长下，各孔发射波长为620nm和665nm的荧光强度，并计算各孔665/620的荧光强度比值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算受试化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以受试化合物浓度对数值-抑制率进行非线性回归分析，获得化合物的IC 50值。
本发明化合物对AGS细胞中p-ERK1/2活性具有明显的抑制作用，优选地，化合物的IC 50<500nM，更优选地，化合物的IC 50<200nM。
测试例2、本发明化合物对AsPC-1细胞增殖抑制的测定
以下方法用于测定本发明化合物对AsPC-1(人转移胰腺腺癌)细胞增殖的影响。AsPC-1细胞(含有KRAS G12D突变)购于中国科学院上海生命科学研究院细胞资源中心，培养于含10％胎牛血清、100U青霉素，100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640培养基中。细胞活力通过
Figure PCTCN2022083546-appb-000046
Luminescent Cell Viability Assay试剂盒(Promega，货号G7573)进行测定。
实验方法按照试剂盒说明书的步骤操作，简述如下：受试化合物首先溶解于DMSO中制备为10mM贮存液，随后以培养基进行稀释，配制成测试样品，化合物的终浓度范围在1000nM-0.015nM。将处于对数生长期的细胞以800个细胞每孔的密度接种至96孔细胞培养板中，在37℃，5％CO 2培养箱中培养过夜，随后加入受试化合物后继续培养120小时。培养结束后，向每孔加入50μL体积的CellTiter-Glo检测液，震荡5分钟后静置10分钟， 随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.3％DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率，之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析，获得化合物抑制细胞增殖的IC 50值。
本发明化合物对AsPC-1细胞增殖具有明显的抑制作用，优选地，化合物的IC 50<500nM，更优选地，化合物的IC 50<200nM。
测试例3、本发明化合物对KRAS G12D与RAF1蛋白相互作用的抑制能力测定
以下方法用于测定本发明化合物在体外条件下阻断KRAS G12D：RAF1蛋白相互作用的能力。本方法使用Cisbio公司的KRAS-G12C/SOS1BINDING ASSAY KITS试剂盒(63ADK000CB21PEG)，详细实验操作参考试剂盒说明书。
将实验流程简述如下：使用diluent buffer(货号62DLBDDF)配制Tag1-RAF1和Tag2-KRAS-G12D蛋白为5X的工作液浓度备用。受试化合物溶解于DMSO中制备为10mM贮存液，随后使用diluent buffer进行稀释备用。首先向孔中加入2μL受试化合物(反应体系终浓度为10000nM-0.1nM)，随后加入4μL Tag1-RAF1 5X的工作液和4μL Tag2-KRAS-G12D 5X的工作液，离心并混匀，静置15分钟；随后加入10μL预混匀的anti-Tag1-Eu 3+和anti-Tag2-XL665，室温下孵育4小时；最后使用酶标仪以TF-FRET模式上测定在304nm的激发波长下，各孔发射波长为620nm和665nm的荧光强度，并计算各孔665/620的荧光强度比值。通过与对照组(0.1％DMSO)的荧光强度比值进行比较，计算受试化合物在各浓度下的百分比抑制率，并通过GraphPad Prism 5软件以受试化合物浓度对数值-抑制率进行非线性回归分析，获得化合物的IC 50值，见下表1。
表1 本发明化合物对KRAS G12D与RAF1蛋白相互作用的抑制能力的IC 50数据
实施例编号 IC 50(nM)
2 648
结论：本发明化合物对KRAS G12D与RAF1蛋白相互作用具有较好的抑制能力。
测试例4、本发明化合物对AGS细胞增殖抑制的测定
以下方法用于测定本发明化合物对AGS细胞增殖的影响。AGS细胞(含有KRAS G12D突变)购于中国科学院上海生命科学研究院细胞资源中心，培养于含10％胎牛血清、100U青霉素和100μg/mL链霉素的F12K培养基中。细胞活力通过
Figure PCTCN2022083546-appb-000047
Luminescent Cell Viability Assay试剂盒(Promega，货号G7573)进行测定。
实验方法按照试剂盒说明书的步骤操作，简述如下：受试化合物首先溶解于DMSO中制备为10mM贮存液，随后以培养基进行稀释，配制成测试样品，化合物的终浓度范围在1000nM-0.015nM。将处于对数生长期的细胞以500个细胞每孔的密度接种至96孔细胞培养板中，在37℃，5％CO 2培养箱中培养过夜，随后加入受试化合物后继续培养72小时。培养 结束后，向每孔加入50μL体积的CellTiter-Glo检测液，震荡5分钟后静置10分钟，随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.3％DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率，之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析，获得化合物抑制细胞增殖的IC 50值，见表2。
表2 本发明化合物对AGS细胞增殖抑制的IC 50数据
实施例编号 IC 50(nM)
2 630
结论：本发明化合物对AGS细胞有较好的增殖抑制作用。
除非特别限定，本发明所用术语均为本领域技术人员通常理解的含义。
本发明所描述的实施方式仅出于示例性目的，并非用以限制本发明的保护范围，本领域技术人员可在本发明的范围内作出各种其他替换、改变和改进，因而，本发明不限于上述实施方式，而仅由权利要求限定。

Claims (24)

  1. 一种通式(A-I)或(A-II)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2022083546-appb-100001
    其中：
    Figure PCTCN2022083546-appb-100002
    根据需要选自单键或双键，以使其连接的每个原子呈现正常价态；
    环A各自独立地选自5～6元杂芳基或5～10元单环杂环基；优选为6～7元单环杂环基；其中所述的杂芳基、单环杂环基内含有一个或多个N或O原子；
    环B各自独立地选自芳基、杂芳基或稠合环；
    环C各自独立地选自一个含有2个氮原子的6～8元的杂环基；
    Q 1选自N或CR a；Q 1优选为N；
    Q 2各自独立地选自N、C或CR a；
    Y各自独立地选自键、O或NR b；
    X 1、X 2各自独立地选自N、C＝O、CR c或CR dR e；
    E各自独立地选自氢原子或
    Figure PCTCN2022083546-appb-100003
    R a相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基或氰基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；
    R b选自氢原子或烷基；
    R c选自氢原子、卤素、氰基、烷基或烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R c优选为卤素，更优选为氟或氯；
    R d和R e相同或不同，各自独立地选自氢原子、卤素、烷基或烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；
    或者，R d和R e与所连接的碳原子一起形成一个环烷基或杂环基；优选为环丙基；
    R f选自氢原子或环烷基，其中所述的环烷基优选为环丙基；
    R 1各自独立地选自氢原子、-L-烷基、-L-卤素、-L-OR 5、-L-NR 6R 7、-L-C(O)OR 5、-L-C(O)NR 6R 7、-L-环烷基、-L-杂环基、-L-芳基、-L-杂芳基、-L-稠合环或
    Figure PCTCN2022083546-appb-100004
    其中所述的烷基、环烷基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个选自R g的取代基所取代；
    R g相同或不同，各自独立地选自烷基、卤素、苄基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NHC(O)NR 6R 7、-NHC(＝NH)NR 6R 7、-OC(O)NR 6R 7、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7或-S(O) rR 5，其中所述的烷基、苄基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、卤代烷基、羟烷基、苄基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-OSi(R 5) 3、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NHC(O)NR 6R 7、-NHC(＝NH)NR 6R 7、-OC(O)NR 6R 7、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7、-NHS(O) rR 5或-S(O) rR 5的取代基所取代；
    L各自独立地选自键或C 1-C 6亚烷基，其中所述的亚烷基任选进一步被一个或多个R D所取代；
    R D各自独立地选自氢原子、卤素、羟基或羟甲基；
    或者，连接于同一碳原子的两个R D与所连接的碳原子一起形成一个环烷基；优选为环丙基；
    R 2相同或不同，各自独立地选自氢原子、卤素、羟基、烷基或烷氧基，优选为氢原子或烷基；
    或者，任意的两个R 2与其所连接的原子一起形成一个环烷基或杂环基；
    R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基或＝O；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R 3优选为氢原子、甲基或＝O；
    R 4各自独立地选自氢原子、烷基、卤素、硝基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7或-S(O) rR 5；其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 5、-C(O)R 5、-C(O)OR 5、-NHC(O)R 5、-NHC(O)OR 5、-NR 6R 7、-C(O)NR 6R 7、-CH 2NHC(O)OR 5、-CH 2NR 6R 7或-S(O) rR 5的取代基所取代；
    R 5各自独立地选自氢原子、卤素、烷基、环烷基、杂环基、芳基或杂芳基，其中所述 的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2R 8、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
    R 6和R 7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自R h的取代基所取代；
    R h相同或不同，各自独立地选自羟基、卤素、硝基、氰基、烷基、环烷基、杂环基、芳基、杂芳基、＝O、-OR 8、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10；其中所述的烷基、环烷基、杂环基、芳基、杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
    或者，R 6和R 7与它们相连接的原子一起形成一个4～8元杂环基，其中4～8元杂环基内含有一个或多个N、O或S(O) r，并且所述的4～8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-C(O)R 8、-C(O)OR 8、-OC(O)R 8、-NR 9R 10、-CH 2NR 9R 10、-C(O)NR 9R 10、-SO 2NR 9R 10或-NR 9C(O)R 10的取代基所取代；
    R 8、R 9和R 10各自独立地选自氢原子、卤素、烷基、氨基、环烷基、杂环基、苄基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、苄基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、氨基烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代；
    m各自独立地选自0、1、2、3或4；
    n各自独立地选自0、1、2或3；
    k各自独立地选自0、1或2；
    r各自独立地选自0、1或2。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(I)或(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2022083546-appb-100005
    其中：环A、环B、X 1、X 2、Y、Q 1、Q 2、R 1、R 2、R 3、R 4、m、n和k的定义如权利要求1中所述。
  3. 根据权利要求2所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(III)、(IV)、(V)或(VI)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2022083546-appb-100006
    其中：环B、X 1、X 2、Y、Q 1、Q 2、R 1、R 2、R 3、R 4、m和n的定义如权利要求1中所述。
  4. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其为通式(VII)、(VIII)或(IX)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2022083546-appb-100007
    其中：环B、X 1、X 2、Y、Q 1、Q 2、R 1、R 2、R 3、R 4、m和n的定义如权利要求1中所述。
  5. 根据权利要求1～4任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
    Figure PCTCN2022083546-appb-100008
    均选自双键；
    Q 1选自N；
    Q 2选自C；
    X 1、X 2各自独立地选自N或CR c；
    R c选自氢原子或卤素，优选为卤素，更优选为氟或氯。
  6. 根据权利要求1～4任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
    Figure PCTCN2022083546-appb-100009
    均选自双键；
    Q 1选自N；
    Q 2选自C；
    X 1选自CR c；
    X 2选自N；
    R c选自卤素，优选为氟或氯，更优选为氟。
  7. 根据权利要求1～4任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
    Figure PCTCN2022083546-appb-100010
    均选自单键；
    X 1、X 2各自独立地选自CR dR e；
    R d和R e选自氢原子；
    或者，R d和R e与所连接的碳原子一起形成一个3～5元单环环烷基或3～5元单环杂环基；优选为环丙基。
  8. 根据权利要求1～4任一项所述的化合物或其立体异构体、互变异构体或其可药用的 盐，
    其中：
    X 2所连
    Figure PCTCN2022083546-appb-100011
    选自双键；
    X 1和Q 2之间
    Figure PCTCN2022083546-appb-100012
    选自单键；
    X 1选自C＝O；
    X 2选自N；
    Q 2选自N。
  9. 根据权利要求1～8任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
    R 1选自-L-杂环基；其中所述的杂环基任选进一步被一个或多个选自烷基、卤素、烷氧基或＝O的取代基所取代；其中所述的卤素优选为氟；
    L选自键或C 1-C 3亚烷基，其中所述的亚烷基任选进一步被一个或多个R D所取代；
    R D各自独立地选自氢原子、卤素、羟基或羟甲基；
    或者，连接于同一碳原子的两个R D与所连接的碳原子一起形成一个环烷基；优选为环丙基。
  10. 根据权利要求9所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：L选自键、-CH 2-、-CH 2CH 2-或
    Figure PCTCN2022083546-appb-100013
  11. 根据权利要求1～8任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 1选自：
    Figure PCTCN2022083546-appb-100014
    Figure PCTCN2022083546-appb-100015
    Figure PCTCN2022083546-appb-100016
    Figure PCTCN2022083546-appb-100017
    Figure PCTCN2022083546-appb-100018
  12. 根据权利要求1～11任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：R 3相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基或＝O；R 3优选为氢原子、甲基或＝O。
  13. 根据权利要求1～12任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：R 4相同或不同，各自独立地选自氢原子、烷基、卤素、烷氧基、炔基、羟基、氨基、羟烷基、卤代烷基或卤代烷氧基；R 4优选为氢原子、甲基、氟、氯、溴、碘、羟基、氨基、羟甲基或乙炔基。
  14. 根据权利要求1～13任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
    环B选自苯基、萘基、吡啶基、喹啉基、异喹啉基、吲哚基、吲唑基、苯并噻唑基、四氢化萘基、
    Figure PCTCN2022083546-appb-100019
    环B优选为萘基或苯并噻唑基。
  15. 根据权利要求1～13任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：
    Figure PCTCN2022083546-appb-100020
    选自以下基团：
    Figure PCTCN2022083546-appb-100021
  16. 根据权利要求2或3所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：所述的通式(I)或(III)中的
    Figure PCTCN2022083546-appb-100022
    选自以下基团：
    Figure PCTCN2022083546-appb-100023
  17. 根据权利要求2或3所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：所述的通式(II)、(IV)、(V)或(VI)中的
    Figure PCTCN2022083546-appb-100024
    选自以下基团：
    Figure PCTCN2022083546-appb-100025
  18. 根据权利要求4所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中：所述的通式(VII)、(VIII)或(IX)中的
    Figure PCTCN2022083546-appb-100026
    选自以下基团：
    Figure PCTCN2022083546-appb-100027
  19. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中所述的化合物为：
    Figure PCTCN2022083546-appb-100028
    Figure PCTCN2022083546-appb-100029
  20. 一种药物组合物，所述的药物组合物含有有效剂量的根据权利要求1～19任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
  21. 根据权利要求1～19任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求20所述的药物组合物在制备KRas G12D抑制剂中的用途。
  22. 根据权利要求1～19任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求20所述的药物组合物在制备治疗由KRas G12D突变介导的疾病的药物中的用途，其中所述的由KRas G12D突变介导的疾病选自癌症，其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、结直肠癌、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，优选为胰腺癌、结直肠癌、直肠癌或肺癌。
  23. 根据权利要求1～19任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，或根据权利要求20所述的药物组合物在制备治疗癌症的药物中的用途，其中所述的癌症选自心脏粘液瘤、肺癌、胃癌、结直肠癌、直肠癌、胰腺癌、前列腺癌、膀胱癌、肝细胞癌、胆管癌、软骨肉瘤、多发性骨髓瘤、子宫癌、宫颈癌、精原细胞瘤、恶性黑色素瘤、皮肤鳞状细胞癌、肾上腺成神经细胞瘤、骨髓性白血病、急性淋巴细胞白血病或胶质母细胞瘤，优选为胰腺癌、结直肠癌、直肠癌或肺癌。
  24. 根据权利要求22或23所述的用途，其中所述的肺癌选自非小细胞肺癌或小细胞肺癌。
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