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WO2021169990A1 - Inhibiteurs de kras pour le traitement de cancers - Google Patents

Inhibiteurs de kras pour le traitement de cancers Download PDF

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WO2021169990A1
WO2021169990A1 PCT/CN2021/077628 CN2021077628W WO2021169990A1 WO 2021169990 A1 WO2021169990 A1 WO 2021169990A1 CN 2021077628 W CN2021077628 W CN 2021077628W WO 2021169990 A1 WO2021169990 A1 WO 2021169990A1
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alkyl
halogen
cancer
compound
methyl
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PCT/CN2021/077628
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English (en)
Chinese (zh)
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尚尔昌
张彦涛
仲伯禹
汪瑞祥
曹宜菊
陈光明
胡旭波
王孝文
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泰励生物科技（上海）有限公司
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Publication of WO2021169990A1 publication Critical patent/WO2021169990A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a class of compounds with new structures that can be used as KRAS inhibitors, pharmaceutical compositions containing such compounds, methods for preparing such compounds, and the use of these compounds in the treatment of cancer.
  • Ras the oncogene homolog of rat sarcoma
  • Ras is activated by receiving growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration, and differentiation.
  • These regulatory functions of Ras are carried out through the "molecular switch" that is the transition between the GDP-binding state and the GTP-binding state (Alamgeer et al., Current Opin Pharmacol. 2013, 13:394-401). Ras, which binds to GDP, is in an inactive form and is in a dormant or closed state.
  • the signal system is closed, and it will be activated when exposed to some growth-promoting stimuli.
  • some growth-promoting stimuli For example, it can be induced by guanine nucleotide exchange factor (GEF).
  • GEF guanine nucleotide exchange factor
  • GDP is released and combined with GTP.
  • Ras is "turned on” and converted into the active form of Ras, which recruits and activates various downstream effectors, carries out signal transmission, and can transmit signals on the cell surface to the cytoplasm, thereby Control many key cellular processes such as differentiation, survival and proliferation (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).
  • Ras has GTPase activity, which can cleave the terminal phosphate of GTP and convert it into GDP, that is, convert itself into an inactive state.
  • the endogenous GTPase activity of Ras is very low, and the exogenous protein GAP (GTPase Activating Protein) is required to convert GTP-Ras into GDP-Ras.
  • GAP interacts with Ras and promotes the conversion of GTP to GDP. Therefore, any mutation of Ras gene that affects the interaction between Ras and GAP or the conversion of GTP to GDP will cause Ras to remain in an activated state for a long time, thereby continuously transmitting signals of growth and division to cells, stimulating cell proliferation, and ultimately leading to tumor formation And development.
  • Ras genes H-RAS, K-RAS and N-RAS which respectively encode highly homologous, approximately 21KDa HRas, NRas, and KRas proteins.
  • H-RAS Ras-RAS
  • K-RAS K-RAS
  • N-RAS N-RAS
  • Ras protein is mutated in more than 30% of cancer types, especially in pancreatic cancer (>90%), colon cancer (45%) and lung cancer (35%)
  • the mutation rate is the highest.
  • Ras tumor protein is sufficient to drive and cause many types of cancer, and the Ras oncogene is also essential for the maintenance and progression of tumors of many cancer types, such as the Ras mutation.
  • RNA intervention has been shown to slow the growth of tumors.
  • Ras mutations are most common in KRas.
  • KRas mutations can be observed in about 85% of Ras mutation-driven cancers; most Ras mutations occur in codons G12, G13 and Q61, of which about 80% of KRas mutations Occurs at the glycine of codon 12 (G12C mutation).
  • KRas mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer and cholangiocarcinoma, and can also be seen in 25% of patients with non-small cell lung cancer (McCormick, F. et al., Clinical Cancer Research 21 (8 ), 1797-1801, 2015). Therefore, the KRas mutant protein has become the most important branch in the research of Ras drug targets, and the development of its inhibitors is also regarded as a very promising research direction in the development of anti-cancer/tumor drugs.
  • Ras due to the smooth surface of Ras protein, it lacks obvious groove or pocket structure for binding small molecule inhibitors, and its affinity for guanine substrates is very high ( Picomolar level), making the development of its small molecule inhibitors into a difficult dilemma, so Ras has long been regarded as a "non-drugable" target in the industry. Nevertheless, continuous efforts to target Ras mutant proteins have achieved some encouraging results. A series of Ras inhibitors have been developed.
  • Ras They inhibit Ras, especially KRas mutations through a variety of ways, including directly targeting Ras, Inhibit the expression level of Ras, destroy the localization of Ras protein, target the synthesis of lethal components, target Ras-GEF interaction, target Ras and effector interaction, and target Ras dimerization (Zhi Tan et al., Mini-Reviews in Medicinal Chemistry, 2016, 16, 345-357).
  • Ras inhibitors that have been developed include allosteric covalent inhibitors, such as 6H05 series, quinazoline series, ARS series and tetrahydropyridopyrimidine series, and Positive binding of covalent inhibitors, these inhibitors are reviewed in the literature (Duan Ni et al., Pharmacology&Therapeutics, https://doi.org/10.1016/j.pharmthera.2019.06.007).
  • KRas inhibitors of various structural types such as CN10256421, US2019/0144444A1 and WO2019/110751A1.
  • KRas inhibitors still have problems to be solved, and their "pharmaceutical properties" are still unsatisfactory.
  • many KRas-dependent cancers are easily resistant to such targeted therapeutic agents, have side effects such as off-target effects, produce chemically active metabolites, poor metabolic stability, or produce immunogenic covalent adducts (John P.O'Bryan et al., Pharmacological Research 139 (2019) 503-511; Duan Ni et al., Pharmacology&Therapeutics, https://doi.org/10.1016/j.pharmthera.2019.06.007). Therefore, there is still a need for more alternative KRas inhibitors in clinical practice. These inhibitors are expected to have KRas inhibitory activity comparable to or improved with existing inhibitors, improved "drugability", and better safety such as less Drug interaction or metabolic properties, improved pharmacokinetic properties, and/or higher selectivity for different patient groups or specific tumor types.
  • the present invention provides a novel structural inhibitor compound having KRas mutein inhibitory activity, especially KRas-G12C inhibitory activity.
  • KRas mutein inhibitory activity especially KRas-G12C inhibitory activity.
  • These compounds of the present invention, especially the preferred compounds of the present invention have an improved structural model, and achieve the following technical effects compared with the KRas mutein inhibitors in the prior art:
  • the inventors discovered through research that the compounds defined herein, their isomers, or their pharmaceutically acceptable salts or solvates are effective KRas mutein inhibitors, capable of inhibiting KRas activity in cells, and can be used for therapy or Prevent KRas mutant protein-mediated or benefit from KRas mutant protein inhibition of diseases or disorders, especially by inhibiting KRas mutant protein to inhibit abnormal cell proliferation, thereby treating or preventing tumors or cancers.
  • the first aspect of the present invention provides a compound of formula I, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof,
  • A is selected from C-CN or N;
  • X, Y and Z are each independently selected from C, N, O or S;
  • Ring B is a heterocyclic group containing 3-12 ring atoms, which is optionally substituted with one or more R a;
  • Each occurrence of R a is independently selected from -OH, -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1 -6 alkyl) 2 , -C 1-6 alkyl, -C 3-8 cycloalkyl, halogen, -NO 2 , -CN and oxo group, where -C 1-6 alkyl or -C 3-8 cycloalkyl is optionally further substituted with R 10 , -OR 10 , halogen or -CN;
  • L is selected from the directly connected bond, -O-, -S-, -S(O) 1-2 -, -NR 10 -or -CR 8 R 9 -;
  • G is selected from -O-, -S-, -S(O) 1-2 -, -NR 10 -or -CR 8 R 9 -;
  • R 1 and R 2 are each independently selected from H, halogen, CN, NO 2 and C 1-6 alkyl optionally substituted by -OR 10 , -SR 10 , -N(R 10 ) 2 or halogen;
  • R 8 and R 9 are each independently selected from H, halogen, CN, NO 2 and C 1-6 alkyl optionally substituted by halogen or C 3-6 cycloalkyl optionally substituted by halogen or R 10;
  • R 10 is independently selected from H or C 1-6 alkyl optionally substituted by halogen;
  • R 3 is selected from - (CH 2) 0-6 -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl and a C 3-12 cycloalkyl group, each optionally Substituted by one or more substituents selected from: -OH, -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N( C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, Wherein C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl are optionally further substituted by halogen, -R 10 , -OR 10 , -SR 10 or N(R
  • R 4 is selected from C 6-12 aryl or 5-12 membered heteroaryl, each of which is optionally substituted by one or more substituents selected from the following: -OH, -SH, -NH 2 , -OC 1- 6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, -(CR 10 R 10 ) 0-1 -C(O)-N(R 10 ) 2 , -(CR 10 R 10 ) 0-1 -C(O)-OR 10 , -(CR 10 R 10 ) 0-1 -S(O) 1-2 -N(R 10 ) 2 , -(CR 10 R 10 ) 0- 1 -S(O) 1-2 -R
  • R 5 is selected from H, halogen, NO 2 , CN, C 1-6 alkyl optionally substituted by one or more halogens or C 3-8 cycloalkyl optionally substituted by one or more halogens or R 10 ;
  • n 0 or 1
  • n is selected from an integer from 0 to 3;
  • the present invention also provides the compound of formula II described herein below, its isomers, or their pharmaceutically acceptable salts or solvates.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I or formula II of the present invention, its isomers, or their pharmaceutically acceptable salts or solvates.
  • the third aspect of the present invention provides a compound of Formula I or Formula II, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof for use as a medicine.
  • the fourth aspect of the present invention provides a compound of Formula I or Formula II, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof for the treatment and/or prevention of diseases mediated by a Ras mutation, preferably a KRas mutation.
  • the fifth aspect of the present invention provides that the compound of formula I or formula II of the present invention, its isomers, or their pharmaceutically acceptable salts or solvates or pharmaceutical compositions containing them are prepared for the treatment and/or prevention of Ras mutation, preferably KRas mutation mediated disease drug use.
  • the sixth aspect of the present invention provides a method for treating and/or preventing diseases mediated by Ras mutations, preferably KRas mutations, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I or formula II of the present invention, and its isomers Body or their pharmaceutically acceptable salts or solvates or pharmaceutical compositions containing them.
  • the seventh aspect of the present invention provides a method for preparing the compound of formula I or formula II of the present invention, its isomers, or their pharmaceutically acceptable salts or solvates.
  • the eighth aspect of the present invention provides a pharmaceutical combination comprising a compound of formula I or formula II of the present invention, isomers thereof, or pharmaceutically acceptable salts or solvates thereof, and one or more other pharmaceutically active agents.
  • Ras mutant refers to a protein encoded and expressed by the Ras gene in which one or more codons are mutated, and typically includes but not limited to glycine at codon 12 of Ras, A Ras protein with mutations in glycine at codon 13 or glutamine at codon 61, such as mutated HRas, NRas, or KRas. These residues are located in the active site of Ras, and their mutations can damage the intrinsic or GAP-catalyzed GTPase activity of Ras, resulting in the persistence of Ras bound to GTP.
  • the mutation at position 12 of the codon refers to the mutation from glycine to cysteine, that is, the G12C mutation.
  • Ras mutation or “Ras mutant protein” can be used interchangeably, and generally refers to mutated HRas, NRas or KRas, such as but not limited to HRas-G12C, Nras-G12C or KRas-G12C ; Specifically refers to KRas mutant protein, more specifically refers to KRas-G12C mutant protein.
  • treatment refers to the administration of one or more of the compounds of formula I described herein, or other compounds of formula I, to a subject suffering from the disease or having symptoms of the disease, such as a mammal, such as a human.
  • the constructs or their pharmaceutically acceptable salts or solvates are used to cure, alleviate, alleviate or affect the disease or the symptoms of the disease.
  • the disease is a disease mediated by a Ras mutation as defined below, especially a tumor or cancer.
  • prevention as used herein is well known in the art, and is intended to give subjects suspected of suffering from or susceptible to diseases mediated by Ras mutations as defined herein, especially cancer or tumors, such as mammals, For example, human administration of one or more of the compounds of formula I described herein, their isomers, or their pharmaceutically acceptable salts or solvates reduces the risk of suffering from the defined disease.
  • prevention encompasses the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.
  • the terms “inhibit” and “reduce” or any variant of these terms refer to the ability of a biologically active agent to reduce the signal transduction activity of the target by directly or indirectly interacting with the target, and refers to Any measurable reduction or complete inhibition of target target activity.
  • the activity (such as KRas activity) may be reduced by about, at most, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45 %, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein.
  • selective inhibition refers to the ability of a biologically active agent to interact with a target directly or indirectly to preferentially reduce the signal transduction activity of the target target compared to off-target signal activity.
  • the compound of formula I of the present invention has the ability to selectively inhibit the G12C mutation of the KRas, HRas, or NRas proteins, and preferably selectively inhibit the G12C mutation of the KRas protein.
  • the present invention has at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% for a specific Ras mutation. , 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range of inhibitors with better activity derivable therein, or Compared with the activity against another specific Ras mutation, the specific Ras mutation (such as KRas-G12C) has at least 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250 -Or 500-fold better activity.
  • Ras mutation-mediated disease refers to a disease in which Ras mutation promotes the occurrence and development of the disease, or inhibition of Ras mutation will reduce the incidence of the disease and reduce or eliminate the disease symptoms.
  • Ras mutation-mediated disease preferably refers to a disease mediated by KRas mutation, most preferably a disease mediated by KRas-G12C, and even more preferably cancer or tumor.
  • cancer refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous cells and cancer cells and tissues.
  • the cancer or tumor includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal area Cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer , Adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CN)
  • the cancer or tumor is related to the Ras mutation, preferably to the KRas mutation, more preferably to the KRas-G12C mutation, including but not limited to the above-mentioned tumor types and their preferred ranges.
  • Particularly preferred tumors of the present invention include lung cancer, colon cancer, pancreatic cancer and ovarian cancer.
  • the term "subject”, “individual” or “patient” as used herein refers to a vertebrate.
  • the vertebrate is a mammal.
  • Mammals include, but are not limited to, farm animals (such as cows), sports animals, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats.
  • the mammal is a human.
  • terapéuticaally effective amount refers to an amount or dose that is generally sufficient to produce a beneficial therapeutic effect on cancer or tumor patients in need of treatment.
  • Those skilled in the art can determine the effective amount or dosage of the active ingredient in the present invention by conventional methods and combined with conventional influencing factors.
  • pharmaceutical combination means that the compound of the present invention can be combined with other active agents to achieve the purpose of the present invention.
  • the other active agent may be one or more additional compounds of the present invention, or may be a second or additional (e.g., third ) Compounds, for example, these active agents are known to modulate other biologically active pathways, or modulate different components in the biologically active pathways involved in the compounds of the present invention, or even overlap with the biological targets of the compounds of the present invention.
  • Such active agents are suitably present in combination in an effective amount to achieve the intended purpose.
  • the other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or administered separately from the compound of the present invention in separate discrete units, and when administered separately, they may be administered simultaneously or sequentially.
  • the sequential administration may be close or distant in time.
  • other active agents that can be used in combination with the compounds of the present invention include, but are not limited to, chemotherapeutics, therapeutic antibodies, and radiotherapy, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, topoisomerase inhibition Drugs, antihormonal drugs, angiogenesis inhibitors, cytotoxic agents, and compounds that disrupt or inhibit the Ras-Raf-ERK or PI3K-AKT-TOR signaling pathway.
  • examples of the other active agents used in combination with the compounds of the present invention are well known in the art and include the list as disclosed in WO2019/051291A1, which is incorporated herein by reference.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce adverse, allergic or other adverse reactions when administered to animals such as humans in appropriate amounts.
  • pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness and properties of the parent compound and are not biologically or otherwise undesirable, including acid addition salts and base addition salts.
  • “Pharmaceutically acceptable acid addition salts” can be formed by compounds with free bases and inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids can be selected from aliphatic , Alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, Maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., as well as those derived from pharmaceutically acceptable salts.
  • organic non-toxic bases including but not limited to primary, secondary and tertiary amines, substituted ammonium, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, Diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histamine Acid, caffeine, procaine, hybamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purine, piperazine, piperidine, N- Ethyl piperidine, polyamine resin, etc.
  • substituted ammonium including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammoni
  • the term "isomer” refers to any stereoisomer, mixture of enantiomers, including racemates, mixtures of diastereomers, geometric isomers, and hindrances that may exist in the structure of a compound. Isomers and/or tautomers.
  • the stereochemistry determination and separation methods of the isomers are well known to those skilled in the art (SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.
  • the bond indicated to cross it is the bond that connects the structural fragment to the rest of the molecule.
  • solvate refers to a solvent addition form containing stoichiometric or non-stoichiometric solvents, including any solvated form of the compounds of the present invention, including, for example, solvates with water, such as hydrates, Or a solvate with an organic solvent, such as methanol, ethanol or acetonitrile, namely as methanolate, ethanolate or acetonitrile respectively; or in the form of any polymorph. It should be understood that such solvates of the compounds of the present invention also include solvates of pharmaceutically acceptable salts of the compounds of the present invention.
  • isotopic variant refers to a compound that contains isotopes in unnatural proportions on one or more of the atoms constituting the compound.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound, thereby forming an isotopic variation of the compound of the present invention or a pharmaceutically acceptable salt thereof, whether it is radioactive or not, it is intended Within the scope of the present invention.
  • isotopes that can be incorporated into the compounds of the present invention and pharmaceutically acceptable salts thereof include, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S , 18 F and 36 Cl.
  • isotopic variations of the compounds of the present invention and pharmaceutically acceptable salts thereof can generally be prepared by conventional methods using appropriate isotopic variations of suitable reagents.
  • certain isotopic variants of the compounds of the present invention and their pharmaceutically acceptable salts incorporating radioisotopes can be used in drug and/or substrate tissue distribution studies. Tritium generation, 3 H and carbon-14, 14 C isotopes are particularly preferred due to their ease of preparation and detectability.
  • substitution with isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and therefore in some circumstances be preferred.
  • compounds of the present invention substituted with positron emitting isotopes can be prepared, and they can be used in positron tomography (PET) studies for substrate receptor occupancy detection .
  • PET positron tomography
  • metabolite refers to a product produced by metabolism of a specific compound or its salt in the body. Such products may, for example, originate from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the applied compound.
  • Metabolite products are typically identified as follows: prepare a radiolabeled isotope (for example 14 C or 3 H) of the compound of the present invention, and administer it to animals such as rats, mice, and guinea pigs at a detectable dose (for example, greater than about 0.5 mg/kg) , Monkeys or humans, given enough time for metabolism to occur (usually about 30 seconds to 30 hours) and separate its conversion products from urine, blood or other biological samples.
  • the structure of metabolites is determined in a conventional manner, such as MS, LC/MS or NMR analysis. Generally, metabolite analysis is performed in the same manner as conventional pharmacokinetic studies well known to those skilled in the art.
  • the metabolite product as long as it is not found in the body in other ways, can be used in the diagnostic determination of the therapeutic dose of the compound of the present invention.
  • prodrug refers to a compound that can be converted into a biologically active compound described herein, such as a compound of formula I or II, under physiological conditions or by solvolysis. Therefore, the term “prodrug” refers to a precursor of a pharmaceutically acceptable biologically active compound. In some aspects, the prodrug is inactive when administered to a subject, but is converted to the active compound in the body, for example, by hydrolysis. Prodrug compounds usually provide advantages in solubility, tissue compatibility or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pages 7-9, pages 21-24 (Elsevier , Amsterdam).
  • prodrugs also means to include any covalently bonded carriers that are released in vivo when such prodrugs are administered to a mammalian subject Active compound.
  • the prodrugs of the active compound as described herein are usually prepared by modifying the functional groups present in the active compound so that the modification can be cleaved into the parent active compound in routine operations or in vivo.
  • Prodrugs include such A compound in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free sulfhydryl group when the prodrug is administered to a mammal.
  • Examples of prodrugs include, but are not limited to, acetates of hydroxyl functional groups , Formate and benzoate derivatives, or acetamide, formamide and benzamide derivatives of amine functional groups in active compounds.
  • prodrugs include phosphate-containing prodrugs, Borate prodrugs, thiophosphate/ester-containing prodrugs, sulfate/ester-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, Prodrugs of ⁇ -lactam, prodrugs containing optionally substituted phenoxyacetamide or prodrugs containing optionally substituted phenylacetamide, and 5-fluorocytosine and 5-fluorouridine prodrugs.
  • pharmaceutically acceptable excipient or carrier refers to one or more compatible solid or liquid fillers or gel substances, suitable for human use, and having sufficient purity and sufficiently low toxicity Examples include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oils, polyols (Such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives Wait.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, cellulose acetate, etc.
  • gelatin talc
  • solid lubricants such as magnesium stearate
  • calcium sulfate such as magnesium stearate
  • vegetable oils such as
  • halogen or "halo” as used herein means F, Cl, Br, or I.
  • halogen substituted group is intended to include monohalogenated or polyhalogenated groups in which one or more of the same or different halogen substitutes for one or more hydrogens in the group.
  • alkyl as used herein means a saturated linear or branched monovalent hydrocarbon group, where the alkyl group may be optionally substituted.
  • the alkyl group is 1 to 18 carbon atoms (C 1 -C 18 ).
  • the alkyl group is C 1 -C 12 , C 1 -C 10, C 1 -C 8 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 or C 1 -C 3 .
  • alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl (-CH(CH 3 ) 2 ), 1-butyl, 2-methyl-1-propyl (-CH 2 CH(CH 3 ) 2 ), 2-butyl (-CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (-C(CH 3 ) 3 ), 1-pentyl, 2-Pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH
  • optional substituents on the alkyl group include cycloalkanes Group, aryl, heteroaryl, heterocyclic, hydroxyl, mercapto, amino, alkoxy, alkylthio, mono- or dialkylamino, aryloxy, arylthio, halogen, cyano, carbonyl, sulfur Carbonyl, azido, alkyl acyl, aryl acyl, alkyl amido, aryl amido, alkyl acyloxy, aryl acyloxy, alkylsulfonyl, arylsulfonyl, alkylsulfonyl Acyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, C-carbamoyl, N-carbamoyl, C-thiocarbamoyl, N-thiocarbamoyl , Am
  • substituents include But not limited to one or more groups independently selected from: Halogen, OH, SH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , NO 2 , N 3 , C(O)CH 3 , COOH, C(O)-amino, OCOCH 3 , methyl, ethyl Group, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, Difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO 2 , phenyl, piperidinyl, piperazinyl and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic moieties can be optionally further substituted , As substituted by one or more substituents selected from
  • alkylene as used herein means a divalent group obtained by removing two hydrogen atoms from the same or two different carbon atoms of an alkyl group as defined above.
  • the divalent alkylene group is 1-18 carbon atoms (C 1 -C 18 ).
  • the divalent alkylene group is C 0 -C 6 , C 0 -C 5 , C 0 -C 3 , C 0 -C 1 , C 1 -C 12 , C 1 -C 10, C 1 -C 8, C 1 -C 6, C 1 -C 5, C 1 -C 4, C 1 -C 3 or C 1 -C 2, for example 3 of the present invention is defined by the formula I compounds of R "- (CH 2 ) 0-6 ".
  • C 0 alkylene means a bond.
  • alkylene groups include methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3 )-), (1,2-ethyl (-CH 2 CH 2 -), 1,1 -Propyl (-CH(CH 2 CH 3 )-), 2,2-propyl (-C(CH 3 ) 2 -), 1,2-propyl (-CH(CH 3 )CH 2 -), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,1-dimethylethyl-1,2-yl (-C(CH 3 ) 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -) and so on.
  • amino refers to primary amines (i.e. -NH 2 ), secondary amines (i.e. -NRH), tertiary amines (i.e. -NRR) and quaternary amines (i.e. -N(+)RRR), which may be optionally substituted , wherein each R is the same or different and is selected from alkyl, cycloalkyl, aryl and heterocyclyl, wherein alkyl, cycloalkyl, aryl and heterocyclyl are as defined herein.
  • Specific secondary and tertiary amines are alkyl amines, dialkyl amines, aryl amines, diaryl amines, aralkyl amines and diaralkyl amines, where the alkyl and aryl moieties may be optionally substituted.
  • Specific secondary and tertiary amines include, but are not limited to, methylamine, ethylamine, propylamine, isopropylamine, aniline, benzylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, and the like.
  • cycloalkyl as used herein means a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group, which can be an all-carbon monocyclic, fused ring, spiro ring or bridged ring.
  • the cycloalkyl group has 3 to 12 carbon atoms (C 3 -C 12 ).
  • the cycloalkyl group is a C 3 -C 8 , C 3 -C 10 , C 5 -C 10 or C 3 -C 6 ring.
  • the cycloalkyl group as a monocyclic ring is C 3 -C 8 , C 3 -C 6 or C 5 -C 6 .
  • the cycloalkyl group is C 7 -C 12 as a bicyclic ring.
  • the cycloalkyl group as a spiro ring system is C 5 -C 12 .
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3- Alkenyl, cyclohexyl, per-deuterated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl Cycloheptatriene, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.
  • spirocycloalkyl groups include, but are not limited to, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.
  • cycloalkyl groups are optionally substituted, and the substituents are as defined above for alkyl substituents.
  • aryl as used herein means an all-carbon, monocyclic or fused polycyclic aromatic group, having 6-14 carbon atoms. Examples include C 6-10 aryl, C 6-12 aryl, C 5-12 aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, phenanthryl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1H-indenyl, 2,3 -Dihydro-1H-indenyl, etc., preferably phenyl or naphthyl.
  • Aryl groups in the definition of compounds herein are optionally substituted with one or more, for example 1, 2, 3, 4 or 5 substituents, for example 1-2, 1-3 or 1-4 substituents.
  • substituents are as defined above for alkyl substituents.
  • heterocyclyl or “heterocycle” or “heterocycloalkyl” are used interchangeably and mean any monocyclic, fused ring, spiro or bridged ring, saturated or unsaturated non-aromatic ring System with 3 to 20 ring atoms (for example, 3-5, 3-8, 3-12, 4-7, 4-10, 5-12 ring atoms), wherein the ring atoms include at least one in addition to carbon Heteroatoms selected from nitrogen, oxygen or sulfur, regardless of where the ring system is connected to the rest of the molecule, and any nitrogen or sulfur heteroatoms can be optionally oxidized (for example, NO, SO, SO 2 ), and any aza The atoms can optionally be quaternized.
  • the heterocyclic group includes 3-12 ring atoms ("members”) and includes monocyclic, fused ring, or spiro ring systems, where the ring atoms are carbon and at least one heteroatom selected from nitrogen, oxygen, or sulfur .
  • the heterocyclic group includes 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom.
  • the heterocyclic group includes 3- to 8-membered, 3- to 7-membered, 3- to 8-membered, 3- to 7-membered, 3- to 8-membered, 3- to 7-membered, 3-to- To 6-membered or 4- to 6-membered monocyclic ring, for example, 3-membered monocyclic ring, 4-membered monocyclic ring, 5-6 membered monocyclic ring.
  • heterocyclyl includes 3-12 membered heterocycloalkyl, such as 4-11 membered, 3-8 membered, 5-6 membered heterocycloalkyl.
  • the heterocycloalkyl group is a "nitrogen-containing heterocyclic ring" that includes at least one nitrogen in the ring system. In one example, the heterocyclic group includes 0-3 double bonds.
  • heterocycles include, but are not limited to, oxirane, aziridinyl, thietanyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithia Cyclobutyl, 1,3-dithiaetanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidine Pyridinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl Pyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,
  • the above-mentioned broad and specifically enumerated heterocycles are optionally substituted, and the substituents are as defined above for alkyl substituents.
  • heteroaryl as used herein means any mono-, bi- or tricyclic ring system having 5-12 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, at least one of which The ring is a 5- or 6-membered aromatic ring.
  • the ring system and the rest of the molecule can be connected in an aromatic or non-aromatic ring part, and the point of attachment can be on a heteroatom or on a carbon atom, and any nitrogen or Sulfur heteroatoms can optionally be oxidized (e.g. NO, SO, SO 2 ), and any nitrogen heteroatoms can optionally be quaternized.
  • Specific embodiments include 4-7, 4-10, 5-7, 5-12 membered heteroaryl groups.
  • heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole, 1-oxa-3,4-diazole, 1- Thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole, pyridine , Pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, benzotriazole, pyrrolo[2,3-b]pyridine, pyr
  • the aforementioned broad and specific heteroaryl groups are optionally substituted, and the substituents are as defined above for alkyl substituents.
  • hydroxyl refers to the -OH group.
  • mercapto refers to the -SH group.
  • alkoxy and alkylthio refer to the hydroxyl group or mercapto group in which H is substituted by an alkyl group as defined herein; the terms “aryloxy and arylthio” as used herein respectively refer to the H is a strong group or mercapto group substituted with an aryl group as defined herein.
  • nitro refers to the -NO 2 group.
  • cyano refers to the -CN group.
  • azido refers to a -N 3 group.
  • acyl refers to RC(O)-, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the terms “alkyl acyl” and “arylamino” as used herein, respectively.
  • amido refers to RC(O)-NH-, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the terms “alkylamido” and "aryl” as used herein, respectively. Amido".
  • acyloxy refers to RC(O)-O-, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the terms “alkyl acyloxy” and “alkyl acyloxy” as used herein, respectively.
  • Aryl acyloxy refers to RC(O)-O-, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the terms “alkyl acyloxy” and “alkyl acyloxy” as used herein, respectively.
  • Aryl acyloxy refers to RC(O)-O-, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the terms “alkyl acyloxy” and “alkyl acyloxy” as used herein, respectively.
  • Aryl acyloxy refers to RC(O)-O-, where R can be an alkyl group or an aryl group as defined herein, which correspond
  • carbamoyl refers to -C (O) -NH 2;
  • thiocarbamyl refers to a -C (S) -NH 2.
  • sulfonyl refers to -S(O) 2 -R, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the terms “alkylsulfonyl” and “aryl” as used herein, respectively. Sulfonyl".
  • sulfonylamino refers to RS(O) 2 -NH-, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the terms “alkylsulfonylamino” and "Arylsulfonylamino".
  • sulfonyloxy refers to RS(O) 2 -O-, where R can be an alkyl group or an aryl group as defined herein, which corresponds to the term “alkylsulfonyloxy” as used herein, respectively. "And “arylsulfonyloxy”.
  • amide group refers to -C(O)-NH 2 , where NH 2 may be optionally substituted with an alkyl or aryl group as defined herein.
  • the term "optionally substituted” as used herein, unless otherwise indicated, means that the group may be unsubstituted or be substituted by one or more (e.g. 0, 1, 2, 3, 4, or 5 or more, or derivatized therein Any range of) is substituted with the listed substituents for the group, wherein the substituents may be the same or different.
  • the optionally substituted group has 1 substituent.
  • the optionally substituted group has 2 substituents.
  • the optionally substituted group has 3 substituents.
  • the optionally substituted group has 4 substituents.
  • the optionally substituted group has 5 substituents.
  • C n-n+m or C n -C m in the definition of the compound of the present invention includes various cases of n to n+m carbons, for example, C 1-6 includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 , including any range from n to n+m, for example, C 1-6 includes C 1-2 , C 1-3 , C 1-4 , C 2-6 , C 3-6 etc.
  • n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms is from n to n+m.
  • a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring.
  • Rings, 12-membered rings, etc. also include any range from n to n+m.
  • 3-12-membered rings include 3-6-membered rings, 3-9-membered rings, 5-6-membered rings, and 5-7-membered rings , 6-7 membered ring, 6-8 membered ring and 6-10 membered ring, etc.
  • the word “comprises” and variations of the word such as “includes” and “containing” means “including but not limited to” and is not intended to exclude, for example, other additives , Ingredients, integers or steps.
  • the element can also be described as including any combination of the plurality of ingredients, steps or conditions, or “consisting of multiple or combined ingredients, Consisting of steps or conditions” or “essentially consisting of multiple or combined components, steps or conditions”.
  • the dosages involved are based on the weight of the free form and do not include any salts, hydrates or hydrates thereof. Solvates, unless the instructions indicate that the dosage is based on the weight of the salt, hydrate or solvate.
  • the present invention also encompasses the N-oxides of the compounds of the present invention, as long as these compounds contain basic nitrogen atoms, such as nitrogen atoms present in nitrogen-containing heterocycles. Certain compounds of the present invention may exist in polymorphic or amorphous forms, and therefore fall within the scope of the present invention.
  • the present invention provides a group of compounds of formula I, their isomers, or their pharmaceutically acceptable salts or solvates that can inhibit the activity of KRas mutein, especially the activity of KRas-G12C.
  • A is selected from C-CN or N;
  • X, Y and Z are each independently selected from C, N, O or S;
  • Ring B is a heterocyclic group containing 3-12 ring atoms, which is optionally substituted with one or more R a;
  • Each occurrence of R a is independently selected from -OH, -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1 -6 alkyl) 2 , -C 1-6 alkyl, -C 3-8 cycloalkyl, halogen, -NO 2 , -CN and oxo group, where -C 1-6 alkyl or -C 3-8 cycloalkyl is optionally further substituted with R 10 , -OR 10 , halogen or CN;
  • L is selected from the directly connected bond, -O-, -S-, -S(O) 1-2 -, -NR 10 -or -CR 8 R 9 -;
  • G is selected from -O-, -S-, -S(O) 1-2 -, -NR 10 -or -CR 8 R 9 -;
  • R 1 and R 2 are each independently selected from H, halogen, CN, NO 2 and C 1-6 alkyl optionally substituted by -OR 10 , -SR 10 , -N(R 10 ) 2 or halogen;
  • R 8 and R 9 are each independently selected from H, halogen, CN, NO 2 and C 1-6 alkyl optionally substituted by halogen or C 3-8 cycloalkyl optionally substituted by halogen or R 10;
  • R 10 is independently selected from H or C 1-6 alkyl optionally substituted by halogen;
  • R 3 is selected from - (CH 2) 0-6 -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl and 3-12 membered cycloalkyl, each optionally Substituted by one or more substituents selected from: -OH, -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N( C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, Wherein C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl are optionally further substituted by halogen, -R 10 , -OR 10 , -SR 10 or N(R 10
  • R 4 is selected from C 6-12 aryl or 5-12 membered heteroaryl, each of which is optionally substituted by one or more substituents selected from the following: -OH, -SH, -NH 2 , -OC 1- 6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, -(CR 10 R 10 ) 0-1 -C(O)-N(R 10 ) 2 , -(CR 10 R 10 ) 0-1 -C(O)-OR 10 , -(CR 10 R 10 ) 0-1 -S(O) 1-2 -N(R 10 ) 2 , -(CR 10 R 10 ) 0- 1 -S(O) 1-2 -R
  • R 5 is selected from H, halogen, CN, NO 2 , C 1-6 alkyl optionally substituted by one or more halogens or C 3-8 cycloalkyl optionally substituted by one or more halogens or R 10 ;
  • n 0 or 1
  • n is selected from an integer from 0 to 3;
  • the compound of formula I it is a compound of formula Ia, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, preferably a compound of formula Ia', an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • Acceptable salt or solvate
  • m 1.
  • the fused bicyclic moiety of formula Ia is for example but not limited to: Preferred Most preferred The six-membered ring containing X, Y and Z is optionally substituted with 0, 1, 2 or 3 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • m 0.
  • the fused bicyclic moiety of formula Ia is for example but not limited to: Preferred The five-membered ring is optionally substituted by 0, 1, or 2 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • the compound of formula I it is a compound of formula Ib, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, preferably a compound of formula Ib', an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • Acceptable salt or solvate
  • m 1.
  • X is C
  • Y is N
  • Z is selected from C or N; or
  • X is N
  • Y and Z are each independently selected from C or N.
  • the fused bicyclic moiety of formula Ib is, for example, but not limited to Preferred Each is optionally substituted by 0, 1 or 2 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • m 0.
  • the fused bicyclic moiety of formula Ib is for example but not limited to: Preferred The five-membered ring is optionally substituted by 0, 1, or 2 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • L is a directly connected bond. In one embodiment of the compound of formula I, L is -O-. In one embodiment of the compound of formula I, L is -S-, -SO- or -S(O) 2 -. In one embodiment of the compound of formula I, L is -NR 10 -. In one embodiment of the compound of formula I, L is -CR 8 R 9 -.
  • L is selected from a directly connected bond, -O-, -S-, -NR 10 -or -CR 8 R 9 -, more preferably L is selected from a directly connected bond, -O-, -S- or -NH- Or -CR 8 R 9 -, most preferably L is selected from directly connected bond, -O-, -S- or -NH-.
  • L is -NR 10 -
  • R 10 is selected from H or C 1-6 alkyl optionally substituted by halogen, preferably R 10 is H.
  • examples of R 10 include, but are not limited to, H, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl , 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl -1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- Methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2 -Butyl
  • L is -CR 8 R 9 -, wherein R 8 and R 9 are each independently selected from H.
  • L is -CR 8 R 9 -, wherein R 8 and R 9 are each independently selected from H or halogen, preferably halogen, such as fluorine, chlorine, bromine or iodine, most preferably F .
  • examples of L include but are not limited to -CHCl-, -CHF-, -CCl 2 , -CF 2 -, preferably -CHF- or -CF 2 -.
  • L is -CR 8 R 9 -, wherein R 8 and R 9 are each independently selected from halogen or C 1-6 alkyl optionally substituted by halogen, preferably F.
  • examples of L include, but are not limited to, -CHCl-, -CHF-, -CCl 2 , -CF 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 , -CH(CH 2 -CH 3 )-, -CH(CF 3 ), -CH(CHF 2 ), -CH(CH 2 -CF 3 )-, -C(CH 3 )(CH 2 -CH 3 )-, -C(CF 3 )(CH 3 )-, -C(CHF)(CF 3 )-, preferably -CHF- or -CF 2 -.
  • L is -CR 8 R 9 -, wherein R 8 and R 9 are each independently selected from H, C 1-6 alkyl optionally substituted by halogen, preferably F, or any C 3-8 cycloalkyl substituted by halogen, preferably F or R 10 is selected.
  • examples of L include but are not limited to -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 , -CH(CH 2 -CH 3 )-, -CH(CF 3 ), -CH(CHF 2 ), -CH(CH 2 -CF 3 )-, -C(CH 3 )(CH 2 -CH 3 )-, -C(CF 3 )(CH 3 )-, -C( CHF)(CF 3 )-, -CH(cyclopropyl)-, wherein the cyclopropyl group can be optionally substituted, such as but not limited to
  • G is -O-.
  • G is -NR 10 -, where -NR 10 -is as defined above for the embodiment where L is -NR 10 -, preferably G is -NH-.
  • G is -O-.
  • ring B is a heterocyclic group containing 3-12 ring atoms, especially a saturated 4-7 membered monocyclic heterocyclic ring containing two N atoms, or containing two nitrogen atoms 7-10 membered saturated spiro ring, a fused or bridged ring, each optionally substituted with one or more substituents R a.
  • B-rings include, but are not limited to Preferably ring B is selected from Most preferred The this embodiment, B is optionally substituted with 0, 1, or 2 R a, R a is preferably H or C 1-6 alkyl group, specific examples include, but are not limited to H, methyl or ethyl, most preferably For H.
  • R 1 and R 2 are each independently selected from H, halogen, CN, NO 2 and C 1-6 alkyl optionally substituted by -OR 10 , -SR 10 , -N(R 10 ) 2 or halogen, wherein R'is an optional substituent that may be carried by R 1 or R 2 itself, including H, -OR 10 , -SR 10 , -N(R 10 ) 2 , halogen or (R 1 or R 2 is a support chain C 1-6 alkyl) is -OR 10, -SR 10, -N ( R 10) 2, halo-substituted C 1-6 alkyl.
  • R 1 , R 2 or R'carried on the above-mentioned preferred fused ring structure W include, but are not limited to, H, F, Cl, methyl, ethyl, trifluoromethyl, dimethylaminomethyl, dimethylamino Ethyl, aminomethyl, aminoethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, etc., most preferably R 1 , R 2 or R'are all H.
  • R 3 is -(CH 2 ) 0-6 -R 3' , preferably -(CH 2 ) 0-3 -R 3' , more preferably -(CH 2 ) 0- 1 -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl and 3-12 membered cycloalkyl, each optionally substituted with one or more substituents selected from Substitution: -OH, -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl, wherein C 1-6 alkyl, C 3 The -8 alkyl group, the 3-12
  • R 3 is - (CH 2) 0-3 -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl (preferably 3-7 membered heterocyclyl), or 5-12 Membered heteroaryl groups (preferably 5-10 membered heteroaryl groups), specific examples include but are not limited to Each is optionally substituted by one or more substituents R 6 and/or R 7 selected from: -OH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl or C 3-6 cycloalkyl is optionally further halogenated, optionally Halogen-substituted C 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 substitution; examples of R 6 or R 7 include, but are
  • R 3 is - (CH 2) 0-1 -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl (preferably 3-7 membered heterocyclyl) or 5- 12-membered heteroaryl groups (preferably 5-10 membered heteroaryl groups), each optionally substituted by one or more substituents selected from the group consisting of: -OC 1-6 alkyl, halogen (preferably F), C 1-6 Alkyl group or C 3-6 cycloalkyl group, wherein C 1-6 alkyl group or C 3-6 cycloalkyl group is optionally further substituted by halogen, C 1-6 alkyl group optionally substituted by halogen, -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 substitution. Specific examples include but are not limited to Preferred
  • R 3 is - (CH 2) 0-1 -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl (preferably 3-7 membered heterocyclyl) or 5- 12-membered heteroaryl groups (preferably 5-10 membered heteroaryl groups), each optionally substituted by one or more substituents selected from the following: -OC 1-6 alkyl, halogen (preferably F), C 1-3 Alkyl group or C 3-6 cycloalkyl group, wherein C 1-3 alkyl group or C 3-6 cycloalkyl group is optionally further substituted by halogen, C 1-6 alkyl group optionally substituted by halogen, -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 substitution.
  • R 3' is selected from 3-12 membered heterocyclyl (preferably 3-7 membered heterocyclyl) or 5- 12-membered heteroaryl groups (preferably 5-10 membered heteroaryl groups), each optionally substituted
  • R 6 and R 7 are each independently selected from H, C 1-3 alkyl or C 3-6 cycloalkyl, wherein C 1-3 alkyl or C 3-6 cycloalkyl is optionally further halogenated, C 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 optionally substituted by halogen, specific examples include but are not limited to methyl, trifluoro Methyl, ethyl, isopropyl, cyclopropyl, trifluoromethylcyclopropyl, aminomethyl, aminoethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, two Methylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2-(dimethylamino)ethyl, etc.; more preferably R 3 is selected from Wherein R 6 and R 7 are each independently selected from H, C 1-3
  • R 3 is In another preferred example, R 3 is In another preferred example, R 3 is In another preferred example, R 3 is Wherein R 6 is C 1-3 alkyl or C 3-6 cycloalkyl, optionally further substituted by -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 , for example but Not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2 -(Dimethylamino)ethyl.
  • R 4 is selected from C 6-12 aryl, preferably phenyl or naphthyl, each of which is optionally substituted by one or more substituents selected from: -OH,- SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxygen Generation, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group, 5-12 membered heteroaryl, -(CR 10 R 10 ) 0-1 -C(O)-N (R 10 ) 2 , -(CR 10 R 10 ) 0-1 -C(O)-OR 10 , -(CR 10 R 10 ) 0-1 -S(O) 1-2 -N(R 10 ) 2 , -(CR 10 R 10 ) 0-1 -S
  • R 4 is preferably phenyl, optionally substituted by one or more substituents selected from the group consisting of -OH, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkane Group) 2 , halogen, CN, C 1-6 alkyl, 5-6 membered heteroaryl, -(CR 10 R 10 ) 0-1 -C(O)-N(R 10 ) 2 , where C 1
  • the -6 alkyl group and the 5-6 membered heteroaryl group are optionally further substituted by halogen, -R 10 , -N(R 10 ) 2 , or two R 10 connected to the same C and the carbon atom to which they are connected Together to form a C 3-6 cycloalkyl group optionally substituted with one or more R 10 or halogen, wherein each occurrence of R 10 is as defined above for the compound of formula I.
  • R 4 is substituted by one or more substituents selected from the group consisting of -OH, -NH 2 , methylamino, dimethylamino, diethylamino, methylethylamino, fluorine, chlorine, CN, methyl, ethyl Group, propyl, isopropyl, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole, 1-oxa-3,4-diazole, 1- Thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, te
  • R 11 , R 12 and R 13 are each independently selected from H, halogen (preferably fluorine or chlorine), CN, C 1-6 alkyl optionally substituted by halogen (preferably fluorine or chlorine), OH, -NH 2 , C 1-6 alkoxy optionally substituted by halogen (preferably fluorine or chlorine) or C 3-6 cycloalkyl optionally substituted by halogen (preferably fluorine or chlorine); preferably, R 11 is selected From CN, halogen (preferably fluorine or chlorine) or C 1-6 alkyl, R 12 is selected from H, NH 2 or halogen (preferably fluorine or chlorine), and R 13 is selected from halogen, OH or NH 2 . Specific examples are
  • R 4 is preferably Wherein R 11 is selected from halogen (preferably fluorine or chlorine) or CN, R 12 is selected from H, halogen (preferably fluorine or chlorine) or -NH 2 , and R 13 is selected from halogen, OH or NH 2 .
  • R 4 is selected from 5-12 membered heteroaryl groups (preferably 5-10 membered heteroaryl groups), specific examples include but are not limited to pyrrole, furan, thiophene, pyrazole, imidazole , Isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2, 4-diazole, 1-oxa-2,5-diazole, 1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4- Diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole ,
  • R 4 is preferably a 5-12 membered heteroaryl group selected from the following (preferably a 5-10 membered heteroaryl group):
  • the substituents R 11 , R 12 and R 13 are each independently selected from halogen (preferably fluorine or chlorine), C 1-6 alkyl optionally substituted by halogen (preferably fluorine or chlorine), OH, -NH 2 , C 1-6 alkoxy optionally substituted by halogen (preferably fluorine or chlorine) or C 3-6 cycloalkyl optionally substituted by halogen (preferably fluorine or chlorine), preferably each independently selected from halogen (preferably fluorine) Or chlorine) or C 1-6 alkyl optionally substituted by halogen (preferably fluorine or chlorine).
  • substituents include but are not limited to: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl , Trifluoromethyl, and ethyl, propyl or butyl substituted by one or more fluorine or chlorine, as well as cyclopropyl, cyclobutyl, cyclopentyl, and substituted by one or more fluorine or chlorine Cyclopropyl, cyclobutyl, cyclopentyl.
  • R 4 are:
  • R 4 is selected from a C 6 aryl group or a 5-10 membered heteroaryl group (preferably a benzoheteroaryl group containing 1 or 2 N atoms), optionally substituted by halogen, C 1-6 alkyl, -OC 1-6 alkyl, -OH, -NH 2 -, CN or oxo substituted, wherein C 1-6 alkyl is optionally further substituted by halogen, -OH, -OC 1-6 alkyl or N(R 10 ) 2 Replace.
  • a C 6 aryl group or a 5-10 membered heteroaryl group preferably a benzoheteroaryl group containing 1 or 2 N atoms
  • R 4 is more preferably Wherein R 11 is selected from halogen (preferably fluorine or chlorine) or CN, R 12 is selected from H, halogen (preferably fluorine or chlorine) or -NH 2 , R 13 is selected from halogen, OH or NH 2 , specific examples are as described above R 4 is represented; or R 4 is more preferably
  • the substituents R 11 or R 12 are each independently selected from halogen (preferably fluorine or chlorine) or C 1-6 alkyl optionally substituted by halogen (preferably fluorine or chlorine).
  • substituents include but are not limited to :Fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, and ethyl, propyl or butyl substituted by one or more fluorine or chlorine ⁇ ; specific examples of R 4 include Most preferably R 4 is selected from
  • R 5 is selected from H.
  • R 5 is halogen, particularly fluoro, chloro, bromo, iodo, preferably F or Cl, most preferably Cl.
  • R 5 is nitro or cyano.
  • R 5 is C 1-6 alkyl optionally substituted with one or more halogens, examples include but are not limited to methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, methyl substituted by 1-3 fluorine or chlorine, ethyl substituted by 1-5 fluorine or chlorine, propyl substituted by 1-7 fluorine or chlorine, etc. .
  • R 5 is a C 3-8 cycloalkyl optionally substituted by one or more halogens or a C 1-6 alkyl optionally substituted by halogen, examples include but not Limited to cyclopropyl optionally substituted with 1-4 fluorine or chlorine, cyclopropyl optionally substituted with 1-3 fluorine or chlorine substituted methyl.
  • R 5 is most preferably H, chlorine, fluorine, methyl or cyclopropyl.
  • the first aspect of the present invention provides a compound of formula I, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof capable of inhibiting the activity of KRas mutein, especially the activity of KRas-G12C, which has the formula I-1 structure,
  • A is selected from C-CN or N;
  • X is selected from C, N, O or S
  • Y and Z are each independently selected from C or N;
  • Ring B is selected from
  • R 1 and R 2 are each independently selected from H, halogen, and C 1-6 alkyl optionally substituted by -OR 10 or -N(R 10 ) 2;
  • L is selected from directly connected bond, -O-, -S- or -CR 8 R 9 -;
  • G is selected from -O- or -NR 10 -;
  • R 8 and R 9 are each independently selected from H, halogen, and C 1-6 alkyl optionally substituted by halogen;
  • R 10 is independently selected from H or C 1-6 alkyl optionally substituted by halogen;
  • R 3 is - (CH 2) 0-3 -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl or 5-12 membered heteroaryl group: Each is optionally substituted by one or more substituents R 6 and/or R 7 selected from: -OH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl or C 3-6 cycloalkyl is optionally further halogenated, optionally Halogen-substituted C 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 substitution;
  • R 4 is selected from The substituents R 11 , R 12 and R 13 are each independently selected from H, halogen, C 1-6 alkyl optionally substituted by halogen, OH, -NH 2 , C 1-6 optionally substituted by halogen Alkoxy or C 3-6 cycloalkyl optionally substituted by halogen;
  • R 5 is selected from H or halogen
  • n 0 or 1
  • n is selected from an integer from 0 to 3;
  • X is selected from C or N, and Represents a double bond
  • A is C-CN.
  • A is N.
  • X, Y, and Z are each independently selected from C or N, and Represents a double bond.
  • the six-membered ring containing X, Y and Z is optionally substituted with 0, 1, 2 or 3 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • the fused bicyclic moiety containing X, Y, Z and A is preferably selected from Most preferred
  • the ring containing X, Y and Z is optionally substituted with 0, 1, 2 or 3 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • ring B is
  • L is -O-.
  • L is a directly connected bond.
  • G is -O-.
  • G is -NH-.
  • R 3 is selected from Wherein R 6 and R 7 are each independently selected from H, C 1-3 alkyl or C 3-6 cycloalkyl, each of which is optionally halogen, C 1-6 alkyl optionally substituted by halogen, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 substitution; preferably each independently selected from H, methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl Group, trifluoromethylcyclopropyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl- 2-(Dimethylamino)ethyl.
  • R 3 is selected from Wherein R 6 and R 7 are each independently selected from H, methyl, ethyl, isopropyl or cyclopropyl.
  • R 3 is In another preferred embodiment, R 3 is In another preferred embodiment, R 3 is In another preferred embodiment, R 3 is Wherein R 6 is C 1-3 alkyl or C 3-6 cycloalkyl, optionally further substituted by -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 , for example but Not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2 -(Dimethylamino)ethyl.
  • R 3 is selected from
  • R 4 is selected from
  • R 4 is selected from
  • the most preferred compound of the present invention is a specific embodiment of the compound of the following formula I-2, its isomers, or their pharmaceutically acceptable salts or solvates,
  • the present invention also provides a group of compounds of formula II, isomers thereof, or their pharmaceutically acceptable salts or solvates that can inhibit the activity of KRas mutein, especially the activity of KRas-G12C,
  • A is C-CN or N;
  • X, Y and Z are each independently selected from C, N, O or S;
  • Ring B is a heterocyclic group containing 3-12 ring atoms, which is optionally substituted with one or more R a;
  • Each occurrence of R a is independently selected from -OH, -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1 -6 alkyl) 2 , -C 1-6 alkyl, -C 3-8 cycloalkyl, halogen, -NO 2 , -CN and oxo group, where -C 1-6 alkyl or -C 3-8 cycloalkyl is optionally further substituted with R 10 , -OR 10 , halogen or CN;
  • G is selected from -O-, -S-, -S(O) 1-2 -, -NR 10 -or -CR 8 R 9 -;
  • R 1 and R 2 are each independently selected from H, halogen, CN, NO 2 and C 1-6 alkyl optionally substituted by -OR 10 , -SR 10 , -N(R 10 ) 2 or halogen;
  • E is selected from H, halogen or -LR 3 ;
  • L is selected from the directly connected bond, -O-, -S-, -S(O) 1-2 -, -NR 10 -or -CR 8 R 9 -;
  • R 3 is selected from -C 0-6 alkylene -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, C 1- 6 alkyl groups or C 6-12 aryl groups, each optionally substituted by one or more substituents selected from the group consisting of -OH, -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 Alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3- 12-membered heterocyclic group and 5-12-membered heteroaryl group, in which C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl are optionally further Halogen, -R 10
  • R 4 is selected from C 6-12 aryl or 5-12 membered heteroaryl, each of which is optionally substituted by one or more substituents selected from the following: -OH, -SH, -NH 2 , -OC 1- 6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , halogen, CN, NO 2 , oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, -(CR 10 R 10 ) 0-1 -C(O)-N(R 10 ) 2 , -(CR 10 R 10 ) 0-1 -C(O)-OR 10 , -(CR 10 R 10 ) 0-1 -S(O) 1-2 -N(R 10 ) 2 , -(CR 10 R 10 ) 0- 1 -S(O) 1-2 -R
  • R 5 is selected from H, halogen, CN, NO 2 , C 1-6 alkyl optionally substituted by one or more halogens or C 3-8 cycloalkyl optionally substituted by one or more halogens or R 10 ;
  • R 8 and R 9 are each independently selected from H, halogen, CN, NO 2 and C 1-6 alkyl optionally substituted by halogen or C 3-8 cycloalkyl optionally substituted by halogen or R 10;
  • R 10 is independently selected from H or C 1-6 alkyl optionally substituted by halogen;
  • n 0 or 1
  • n is selected from an integer from 0 to 3;
  • G is O.
  • A is C-CN.
  • the fused bicyclic moiety of formula II is such as but not limited to the corresponding examples given above for the compound of formula Ia; most preferably The six-membered ring containing X, Y and Z is optionally substituted with 0, 1, 2 or 3 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • A is C-CN.
  • the fused bicyclic moiety of formula II is such as but not limited to the corresponding examples given above for the compound of formula Ia; preferably The five-membered ring is optionally substituted by 0, 1, or 2 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • A is N.
  • the fused bicyclic moiety of formula II is such as but not limited to the corresponding examples given above for the compound of formula Ib, preferably Each is optionally substituted by 0, 1 or 2 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • A is N.
  • the fused bicyclic moiety of formula II is such as but not limited to the corresponding examples given above for the compound of formula Ib; preferably The five-membered ring is optionally substituted by 0, 1 or 2 R 5 , preferably 0 or 1 R 5 , R 5 is selected from halogen, preferably F or Cl.
  • the fused bicyclic moiety of formula II is selected from More preferred
  • the ring containing X, Y and Z is optionally substituted with 0 or 1 R 5 , and R 5 is selected from halogen, preferably F or Cl.
  • ring B is a heterocyclic group containing 3-12 ring atoms, especially a saturated 4-7 membered monocyclic heterocyclic ring containing two N atoms, or containing two N atoms 7-10 membered saturated spiro ring atoms, fused or bridged ring, each optionally substituted with one or more substituents R a.
  • the B ring include but are not limited to the corresponding examples given above for the B ring of the compound of formula I, most preferably Optionally substituted with 1-2 R a, R a is preferably C 1-6 alkyl, most preferably CH 3.
  • L has the specific embodiments, preferred embodiments and examples thereof for L given above for the compound of formula I; most preferably L is absent, -O-, -NH- or -S-.
  • E is -LR 3 and L is absent; or E is -LR 3 and L is -O-; or E is -LR 3 and L is -NH-; or E is -LR 3 and L is -S-.
  • R 3 has the specific embodiments and preferred embodiments and examples thereof for R 3 given above for the compound of formula I.
  • R 3 is -C 0-6 alkylene-R 3' , preferably -C 0-3 alkylene-R 3 ', most preferably -R 3 ', wherein R 3 'is selected from 3-12 membered heterocyclic group, 5-12 membered heteroaryl group or C 6-10 aryl group, each of which is optionally substituted by one or more substituents selected from the following: -OH , -SH, -NH 2 , -OC 1-6 alkyl, -SC 1-6 alkyl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , halogen, CN, NO 2 , Oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl, of which C 1-6 alkyl, C 3-8 cycloalkane Group, 3-12 membered heterocyclic group
  • R 6 and R 7 are each independently selected from: -OH, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, halogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein C 1-6 alkyl or C 3-6 cycloalkyl is optionally further substituted by halogen, C 1-6 alkyl optionally substituted by halogen,- OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 substitution; examples of R 6 or R 7 include but are not limited to hydroxyl, methoxy, ethyl Oxy, propoxy, isopropoxy, butoxy, 2-methylpropoxy, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, trifluoro
  • R 3 include but are not limited to
  • R 3 ' is selected from 3-7 membered heterocyclyl, 5-10 membered heteroaryl, or a C 6 aryl group, each optionally substituted with C 1-6 alkyl, -OC 1-6 alkyl Group or C 3-6 cycloalkyl group, wherein the C 1-6 alkyl group or C 3-6 cycloalkyl group is optionally further substituted by C 1-6 alkyl group, -OC 1-6 alkyl group or -N(R 10 ) 2 substitution, specifically, R 3 is selected from (E.g ), (E.g ), Wherein R 6 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, optionally further substituted by C 1-6 alkyl or N(R 10 ) 2 , R 7 is selected from C 1-6 alkyl or -OC 1-6 alkyl; examples of R 6 or R 7 include but are not limited to methyl, ethyl, propyl, isopropyl, butyl,
  • R 3 is In another preferred example, R 3 is In another preferred example, R 3 is In another preferred example, R 3 is Wherein R 6 is C 1-6 alkyl or C 3-6 cycloalkyl, optionally further substituted by -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 , for example, methyl Group, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino) ethyl, 1-methyl-2-(di Methylamino)ethyl.
  • R 3 is Where R 6 is C 1-6 alkyl, optionally further substituted by -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 , such as methyl, ethyl, propyl, Isopropyl, cyclopropyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2- (Dimethylamino)ethyl; most preferably R 6 is C 1-3 alkyl substituted with -N(C 1-6 alkyl) 2.
  • R 4 has the specific embodiments and preferred embodiments and examples thereof for R 4 given above for the compound of formula I.
  • R 4 is selected from a C 6 aryl group or a 5-10 membered heteroaryl group (preferably a benzoheteroaryl group containing 1 or 2 N atoms), optionally substituted by halogen, C 1-6 alkyl, -OC 1-6 alkyl, -OH, -NH 2 -, CN or oxo substituted, wherein C 1-6 alkyl is optionally further substituted by halogen, -OH, -OC 1-6 alkyl or N(R 10 ) 2 Replace.
  • R 5 has the specific embodiments and preferred embodiments and examples thereof for R 5 given above for the compound of formula I.
  • the compound of formula II mentioned above is the compound of formula II-1, its isomers, or their pharmaceutically acceptable salts or solvates,
  • A is C-CN or N;
  • X is selected from C, N, O or S
  • Y and Z are each independently selected from C or N;
  • R 1 and R 2 are each independently selected from H, halogen, and C 1-6 alkyl optionally substituted by -OR 10 , CN or -N(R 10 ) 2;
  • E is -LR 3 ;
  • L is selected from directly connected bond, -O-, -NH- or -S-;
  • G is -O- or -NH-
  • R 10 is independently selected from H or C 1-6 alkyl optionally substituted by halogen;
  • R 3 is -C 0-3 alkylene -R 3 ', wherein R 3' is selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl, or C 6-10 aryl group, each optionally substituted with halogen , C 1-6 alkyl, -OC 1-6 alkyl or C 3-6 cycloalkyl substituted, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is optionally further substituted by halogen, C 1- 6 alkyl, -OC 1-6 alkyl or N(R 10 ) 2 substitution;
  • R 4 is selected from C 6-12 aryl or 5-12 membered heteroaryl, optionally substituted by halogen, C 1-6 alkyl, -OH, -NH 2 -, -NH(C 1-6 alkyl)- , -N(C 1-6 alkyl) 2 -, oxo, CN, -OC 1-6 alkyl or C 3-6 cycloalkyl substituted, where C 1-6 alkyl or C 3-6 ring
  • the alkyl group is optionally further substituted by halogen, -OH, -OC 1-6 alkyl, C 1-6 alkyl or N(R 10 ) 2 ;
  • R 5 is selected from H or halogen
  • n 0 or 1
  • n is selected from an integer from 0 to 3;
  • X is selected from C or N, and Represents a double bond
  • A is C-CN. In another embodiment of the compound of formula II-1, A is N.
  • R 3 is selected from the definition given above for the corresponding R 3 of each embodiment of the compound of formula II.
  • R 3 is -R 3 ', wherein R 3' is selected from 3-7 membered heterocyclyl, 5-10 membered heteroaryl, or a C 6 aryl group, each optionally substituted with C 1-6 alkyl, - OC 1-6 alkyl or C 3-6 cycloalkyl substituted, wherein C 1-6 alkyl or C 3-6 cycloalkyl is optionally further substituted by C 1-6 alkyl, -OC 1-6 alkyl Or -N(R 10 ) 2 substitution; more preferably, R 3 is selected from Wherein R 6 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, optionally further substituted by C 1-6 alkyl or N(R 10 ) 2 , R 7 is selected from C 1-6 alkyl, Examples of R 6 or R 7 include, but are not limited
  • R 3 is In another specific embodiment, R 3 is In another specific embodiment, R 3 is In another specific embodiment, R 3 is Wherein R 6 is C 1-6 alkyl or C 3-6 cycloalkyl, optionally further substituted by -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 , for example, methyl Group, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2-(di Methylamino)ethyl.
  • R 3 is Where R 6 is C 1-6 alkyl, optionally further substituted by -NH 2 , -NHC 1-6 alkyl or -N(C 1-6 alkyl) 2 , such as methyl, ethyl, propyl, Isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2-(dimethylamino)ethyl. More preferably, R 6 is C 1-3 alkyl substituted with -N(C 1-6 alkyl) 2.
  • R 4 is selected from the definitions given above for the corresponding R 4 of each embodiment of the compound of formula II.
  • R 4 is selected from a C 6 aryl group or a 5-10 membered heteroaryl group (preferably a benzoheteroaryl group containing 1 or 2 N atoms), optionally substituted by halogen, C 1-6 alkyl, -OC 1-6 alkyl, -OH, -NH 2 -, CN or oxo substituted, wherein C 1-6 alkyl is optionally further substituted by halogen, -OH, -OC 1-6 alkyl or N(R 10 ) 2 Replace.
  • R 4 is selected from Wherein R 11 , R 12 and R 13 are each independently selected from halogen (preferably fluorine or chlorine), CN, C 1-6 alkyl optionally substituted by halogen (preferably fluorine or chlorine), OH, -NH 2 or any C 1-6 alkoxy substituted by halogen (preferably fluorine or chlorine); preferably, wherein R 11 is selected from halogen (preferably fluorine or chlorine) or CN, and R 12 is selected from H or halogen (preferably fluorine or chlorine) Or -NH 2 , R 13 is selected from halogen, OH or NH 2 ; or R 4 is selected from Wherein R 11 or R 12 are each independently selected from halogen (preferably fluorine or chlorine) or C 1-6 alkyl optionally substituted by halogen (preferably fluorine or chlorine).
  • R 4 is selected from
  • n is 0; or n is 1, and R 5 is selected from F or Cl.
  • G is O.
  • Preferred specific embodiments of the compounds of the present invention include the following synthesis examples A1, A3, A4, A6-16, A28, A30, A51-53, A55-56, A65-66, A69-70, A81, A103, A105- 107, A112-114, A116, A118-120, A122, A130-131, A136-137, A144 and the compound of Example B2, its isomers, or their pharmaceutically acceptable salts or solvates.
  • the compounds of the present invention defined herein above and various specific embodiments thereof are Ras mutations, especially KRas mutation inhibitors.
  • the compounds of the present invention especially the compounds specifically exemplified in the context of this article, have shown inhibitory effects on Ras mutations, especially KRas G12C mutations in the indicated cell assays, with IC50 in the range of 0.1 nM to 10 ⁇ M
  • IC50 in the range of 0.1 nM to 10 ⁇ M
  • 0.1 nM to 5 ⁇ M 0.1 nM to 1 ⁇ M, 1 nM to 5 ⁇ M, 1 nM to 1 ⁇ M, 1 nM to 0.5 ⁇ M, preferably in the range of 0.1 nM to 0.5 ⁇ M or 1 nM to 0.5 ⁇ M.
  • the compounds of the present invention can be used to treat or prevent diseases mediated by Ras mutations, preferably KRas mutations, most preferably KRas G12C mutations, for example, diseases or disorders that can be treated by inhibiting Ras mutations, preferably KRas mutations, and most preferably KRas G12C mutations,
  • Ras mutation, preferably KRas mutation, most preferably KRas G12C mutation activity plays a role or is involved in the disease or disorder, especially by inhibiting Ras mutation, preferably KRas mutation, most preferably KRas G12C mutation to treat or prevent tumor or cancer.
  • the compounds defined herein and various specific embodiments thereof, especially the example compounds have improved structural models, compared with the prior art.
  • the KRas mutant protein inhibitors retain comparable or enhanced or even significantly enhanced KRas mutant protein and related cancer cell proliferation inhibitory activities; have different biological activity profiles and can be used for new indications; have improved metabolic stability , Resulting in better pharmacokinetic properties; and improved physical and chemical properties, which has good drug-making properties, such as easier absorption in the body.
  • the present invention provides a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof for use as a medicine.
  • the present invention provides compounds of the present invention, isomers thereof, or pharmaceutically acceptable salts or solvates thereof for use in the treatment and/or prevention of diseases mediated by Ras mutations, preferably KRas mutations.
  • the present invention provides a pharmaceutical composition, which comprises the above-defined compound of the present invention, its isomers, or their pharmaceutically acceptable salts or solvates, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition of the present invention can be used to treat or prevent diseases mediated by Ras mutations, especially KRas mutations, preferably diseases mediated by KRas G12C mutations, such as tumors or cancers.
  • composition of the present invention can be formulated by techniques known to those skilled in the art, such as the technique disclosed in Remington's Pharmaceutical Sciences 20th Edition.
  • the administration and administration of the pharmaceutical composition of the present invention conform to good medical practice. Factors that need to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the location of drug delivery, the method of administration, the schedule of administration, and other factors well known to medical practitioners.
  • the optimal dosage level and frequency of administration of the pharmaceutical composition of the present invention will be determined through clinical trials required in the field of pharmacy.
  • the daily dose for oral administration ranges from about 0.001 mg to about 100 mg per kg of patient body weight, usually 0.01 mg to about 50 mg per kg body weight, such as 0.1 to 10 mg per kg body weight, preferably about 0.01 to about 35 mg per kg body weight.
  • a suitable dosage range is about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. It should be understood that it may be necessary in some cases to use dosages that exceed these limits.
  • composition of the present invention can be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhalation And epidural and intranasal, and if local treatment is needed, intralesional administration can also be taken.
  • Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In some embodiments, oral administration is used.
  • composition of the present invention can be administered in any convenient administration form, such as tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches Wait.
  • the composition may contain conventional components in pharmaceutical preparations, such as diluents (such as glucose, lactose or mannitol), carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, Wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids, coloring agents, perfuming agents, flavoring agents, other known additives and other active agents.
  • Suitable carriers and excipients are well known to those skilled in the art and detailed in, for example, Ansel, Howard C., etc., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,
  • the compounds of the present invention and the compounds of various specific embodiments, especially the compounds specifically prepared and characterized in the examples, show an inhibitory effect on the Ras mutation, especially the KRas G12C mutation.
  • the present invention provides a method for inhibiting KRas mutations in cells, especially KRas G12C, which comprises contacting cells with a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof In order to inhibit the KRas mutation in the cell, especially the activity of KRas G12C.
  • the present invention correspondingly provides a method for inhibiting the growth of abnormal cells in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, its isomers or their pharmaceutically acceptable salts Or a solvate, or a pharmaceutical composition containing the compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method for the treatment and/or prevention of diseases mediated by Ras mutations, preferably KRas mutations, comprising administering to a subject in need a therapeutically effective amount of a compound of the present invention, its isomers or them A pharmaceutically acceptable salt or solvate, or a pharmaceutical composition comprising a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides the compound of the present invention, its isomers, or their pharmaceutically acceptable salts or solvates, or the compounds of the present invention, its isomers, or their pharmaceutically acceptable salts or solvates.
  • the present invention provides a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a compound of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof, or Use of the solvated pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of diseases mediated by Ras mutations, preferably KRas mutations.
  • the abnormal cell growth or diseases mediated by Ras mutations especially refer to cancer or tumors.
  • the abnormal cell growth or cancer or tumor is related to KRas mutation, more preferably related to KRas-G12C mutation, including but not limited to lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanin Tumor, uterine cancer, ovarian cancer, rectal cancer, anal area cancer, stomach cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vagina cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine Cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer,
  • the abnormal cell growth or diseases mediated by Ras mutations are particularly preferably lung cancer, colon cancer, pancreatic cancer and ovarian cancer. cancer.
  • the present invention provides the above-mentioned methods and technical solutions for the treatment or prevention of cancer or tumors by inhibiting KRas-G12C mutation.
  • the present invention provides the above methods and technical solutions for the treatment or prevention of lung cancer, colon cancer, pancreatic cancer and ovarian cancer by inhibiting KRas-G12C mutation.
  • the compound of the present invention can be administered as the sole active ingredient, or can be administered in combination with another drug or therapy.
  • the present invention provides a pharmaceutical combination comprising the compound of the present invention, its isomers, or their pharmaceutically acceptable salts or solvates and other active agents, or both.
  • the drug combination is used to inhibit the growth of abnormal cells in mammals, or to treat and/or prevent diseases mediated by Ras mutations, preferably KRas mutations.
  • the other active agent may be one or more additional compounds of the present invention, or may be a second or additional (e.g., third ) Compounds, for example, these active agents may be compounds known to modulate other biologically active pathways, or may be compounds that modulate different components in the biologically active pathways involved in the compounds of the present invention, or even the biological targets of the compounds of the present invention. Overlapping compounds.
  • other active agents that can be used in combination with the compounds of the present invention include, but are not limited to, chemotherapeutics, therapeutic antibodies, and radiotherapy, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, Topoisomerase inhibitors, antihormonal drugs, angiogenesis inhibitors, cytotoxic agents, and compounds that disrupt or inhibit the Ras-Raf-ERK or PI3K-AKT-TOR signaling pathway.
  • chemotherapeutics such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, Topoisomerase inhibitors, antihormonal drugs, angiogenesis inhibitors, cytotoxic agents, and compounds that disrupt or inhibit the Ras-Raf-ERK or PI3K-AKT-TOR signaling pathway.
  • examples of the other active agents used in combination with the compounds of the present invention are well known in the art and include the list as disclosed in WO2019/051291A1, which is incorporated herein by reference.
  • the other active agents used in combination with the present invention can be administered simultaneously, separately or sequentially with the compound of the present invention through the same or different administration routes.
  • the other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or may be administered separately from the compound of the present invention in separate discrete units, such as a combination product, preferably in the form of a kit.
  • a combination product preferably in the form of a kit.
  • the sequential administration may be close or distant in time. They can be made and/or formulated by the same or different manufacturers.
  • the compound of the present invention and other active agents can be (i) before sending the combined product to the physician (for example, in the case of a kit containing the compound of the present invention and another drug); (ii) before administration The physician himself (or under the guidance of the physician); (iii) the patient himself, for example, is added to the combination therapy together during the sequential administration of the compound of the present invention and other active agents.
  • the compounds of the present invention can also be combined with anti-tumor therapies, including but not limited to surgery, radiation therapy, transplantation (such as stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.
  • anti-tumor therapies including but not limited to surgery, radiation therapy, transplantation (such as stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.
  • the present invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains the compound of the present invention, its isomers or their pharmaceutically acceptable salts or Solvates, and devices that hold the compositions separately, such as containers, sub-bottles, or discrete foil packages, such as blister packs for packaging tablets, capsules, and the like.
  • the kit of the present invention is particularly suitable for administering different dosage forms, such as oral dosage forms and parenteral dosage forms, or for administering different compositions at different dosage intervals.
  • the abnormal cell growth or the disease mediated by Ras mutation preferably KRas mutation, is as defined above for the method and use of the present invention.
  • compositions, methods, uses, pharmaceutical combinations and kits for the above-mentioned compounds of the present invention, isomers thereof, or their pharmaceutically acceptable salts or solvates are preferred, and more preferred
  • the dosage of a drug or a pharmaceutically acceptable salt thereof is described herein, it should be understood that the dosage is based on the weight of the free base, excluding any hydrate or solvate thereof, unless the instructions indicate that the dosage is based on a salt, hydrate or solvent The weight of the material.
  • the present invention also provides a method for preparing the compound defined in the present invention.
  • the compounds of the present invention can be prepared by a variety of methods, including the methods given below, the methods given in the examples or similar methods.
  • the following exemplifies a general synthetic scheme for the synthesis of the compounds of the present invention.
  • reaction conditions are known to those skilled in the art or can be routinely determined.
  • the method steps used to synthesize the compounds of the present invention can be under reaction conditions known per se (including those specifically mentioned), in the absence or usually in the presence of a solvent or diluent (including, for example, inert to the reagents used).
  • ion exchangers such as cation exchangers, such as H + form
  • the nature of the reactants is at a reduced, normal or elevated temperature (e.g., about -100°C to about 190°C, including, for example, about -78°C to about 150°C, for example, about 0°C to about 125°C, room temperature , -20 to 40°C or reflux temperature), under atmospheric pressure or in a closed container, under pressure when appropriate, and/or under an inert atmosphere such as argon or nitrogen.
  • ion exchangers such as cation exchangers, such as H + form
  • the above-mentioned reaction will usually be carried out at a temperature between room temperature and the boiling temperature of the solvent used.
  • the raw materials and reagents used in the preparation of these compounds are generally commercially available, or can be prepared by the methods described below, methods similar to those given below, or methods known in the art.
  • solvents suitable for those solvents for any particular reaction include: those specifically mentioned, or, for example, water; esters, such as lower alkanoic acid lower alkyl esters, such as ethyl acetate Esters; ethers, such as aliphatic ethers, such as diethyl ether, or cyclic ethers, such as tetrahydrofuran or dioxane; liquid aromatic hydrocarbons, such as benzene or toluene; alcohols, such as methanol, ethanol, or 1- or 2- Propanol; Nitriles, such as acetonitrile; halogenated hydrocarbons, such as dichloromethane or chloroform; amides, such as dimethylformamide, N-methylpyrrolidin-2-one or dimethylacetamide; bases, Such as heterocyclic nitrogen bases, such as pyridine or triethylamine; carboxylic acid anhydrides, such as lower alkanoic acid an
  • the raw materials and intermediates in the synthesis reaction process can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. If the intermediates and final products are obtained in solid form, purification can also be carried out by recrystallization or aging.
  • the material can be characterized by conventional methods including physical constants and spectral data.
  • the reaction mixture is worked up in a conventional manner, for example, by mixing with water, separating the phases, and where appropriate, purifying the crude product by chromatography.
  • the resulting mixture of isomers can be separated into individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, such as For mixtures of racemates or diastereomers, see, for example, "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994) by EL Eliel, SH Wilen and LNMander.
  • protecting groups it may be necessary to use appropriate protecting groups to protect specific reactive groups to avoid side reactions with other reactive groups, which may be present in the compounds of the present invention and may compete or interfere reaction.
  • one or more groups in the compound of the present invention are or contain the group C(O)OH, NH 2 or OH and the group has similar or even stronger reactivity than the desired reaction position, then It is advantageous to protect these groups before the desired reaction occurs. In these cases, it may be necessary to perform an additional deprotection step to remove these protecting groups after the desired reaction is complete.
  • Suitable protecting groups and methods of using such suitable protecting groups to protect and deprotect different substituents are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd edition) , John Wiley & Sons, NY (1999).
  • the present invention also relates to a preparation method in which a compound that can be obtained in the form of an intermediate in any step in each preparation method and process described below is used as a starting material and the remaining method steps are carried out, or in which the starting material is
  • the compound formed in situ under the reaction conditions or used in the form of derivatives, for example in protected form or salt form, or obtainable according to the method of the present invention is produced under the conditions of the method and is further processed in situ.
  • the compounds of the present invention can be prepared according to the following scheme, wherein if not otherwise specified, the variables are as defined above.
  • R 3 and R 4 are as defined above for the respective embodiments of the compounds of formula I, II or formula I-1, II-1; Y corresponds to the above for the compounds of formula I, II or formula I-1, II-1 B as defined in each embodiment of; X corresponds to L as defined above for each embodiment of the compound of formula I, II or formula I-1, II-1; PG is a protecting group.
  • step A the introduction of the R 4 group can be achieved through an aromatic nucleophilic substitution reaction, and those skilled in the art are familiar with the reaction conditions required for this type of reaction.
  • step B the obtained nitro compound is reduced to obtain the amino compound 3.
  • step C realizes the amino acid condensation through step C to obtain compound 4.
  • Compound 4 is cyclized to compound 5 under proper basic conditions.
  • Compound 5 is chlorinated to obtain compound 6.
  • the typical reaction conditions and/or reagents used in the nucleophilic substitution, nitration reduction, condensation reaction, cyclization, catalytic coupling and acylation reaction involved in the synthesis scheme 1 are well known in the art and belong to the routine of those skilled in the art.
  • the range of experience may be determined by those skilled in the art based on typical conditions for such reactions in the field, based on the raw materials used and the substitution pattern of the target product and making appropriate changes.
  • R 3 and R 4 are as defined above for the respective embodiments of the compounds of formula I, II or formula I-1, II-1; Y corresponds to the above for the compounds of formula I, II or formula I-1, II-1 B as defined in each embodiment of; X corresponds to L as defined above for each embodiment of the compound of formula I, II or formula I-1, II-1; PG is a protecting group.
  • step J Compound 3 is chlorinated by step J to obtain compound 10.
  • the subsequent synthetic method from compound 10 to the molecule shown in general formula II is consistent with the synthetic method in synthetic scheme I, which corresponds to a subset of the compounds of the invention in which A is C-CN.
  • R 3 , R 4 and R 5 are as defined above for the respective embodiments of formula I, II or formula I-1, II-1; Y corresponds to the above for formula I, II or formula I-1, II -1 B as defined in each embodiment of the compound; PG is a protecting group.
  • Compound 7 or 14 can be obtained by Scheme I or Scheme II.
  • step K compound 7 or 14 is coupled with the R 3 -X group where X is boronic acid or pinacol boron ester (such as palladium-catalyzed carbon-carbon bond coupling) to obtain compound 17.
  • X is boronic acid or pinacol boron ester (such as palladium-catalyzed carbon-carbon bond coupling)
  • step I of synthetic scheme 1 compound 17 was deprotected and acylated to obtain the compound represented by general formula III, which corresponds to a subset of the compounds of the present invention in which A is C-CN.
  • experimental materials and reagents used in the following examples can be obtained from commercial channels, prepared according to the method of the prior art, or prepared according to a method similar to that disclosed in the present application unless otherwise specified.
  • Step A 4-Bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • TsOH (4.08 g, 23.7 mmol) was added to a mixture of 4-bromo-5-methyl-1H-indazole (50.0 g, 236.9 mmol) and DHP (25.9 g, 308.1 mmol) in DCM (500 mL). The mixture was stirred at 20°C for 12 h to obtain a dark brown solution. The reaction was monitored by LCMS, and the target product accounted for about 65%, and the raw material accounted for about 35%. Another batch of DHP (7.97 g, 94.8 mmol) was added. The mixture was stirred at 20°C for 2 h. LCMS monitors the completion of the reaction. The reaction mixture was concentrated under reduced pressure.
  • Step B 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol
  • Step A 1-tert-Butyl-2-methyl-(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate
  • Step B (S)-(4,4-Difluoro-1-methylpyrrolidin-2-yl)methanol
  • LiAlH 4 (543 mg, 14.7 mmol) was added to 1-tert-butyl-2-methyl-(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate in batches (1.3 g, 4.90 mmol) in THF (40 mL). The resulting mixture was continuously stirred at 0°C for 2 h. The completion of the reaction was monitored by TLC, and H 2 O (0.55 mL), 15% NaOH (aq, 0.55 mL), and H 2 O (1.65 mL) were sequentially added to the reaction mixture at 0° C. to quench the reaction.
  • Step A 1-tert-Butyl-2-methyl-(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylic acid
  • Step D 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • Step E 5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol
  • Step A 4-chloro-2,6-difluorobenzaldehyde
  • Step C 6-Chloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • Step D 5,6-Dichloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • n-BuLi 2.5M, 25.1 mL was added dropwise to a solution of i-Pr 2 NH (6.36 g, 62.8 mmol) in THF (80 mL). After stirring for 0.5 h at -40 to -30°C, an LDA solution was obtained. The resulting LDA solution was cooled to -70 ⁇ -65°C, and 6-chloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.00g, 31.4 mmol) in THF (40 mL) for 1 h. After the dropwise addition is completed, the reaction system is stirred at -40 to -30°C for 1 h.
  • Step D 4-Bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • Step F 4-Bromo-6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • Step H 6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)-1H- Indazole
  • Step B Methyl 2-amino-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzoate
  • Step C 2-(2-Cyanoacetamido)-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy ) Methyl benzoate
  • NMI 2-amino-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4 -Yl)oxy)benzoic acid methyl ester (3.10 g, 8.13 mmol), cyanoacetic acid (1.38 g, 16.3 mmol) and TCFH (3.42 g, 12.19 mmol) in MeCN (30 mL).
  • the resulting mixture was stirred at room temperature for 16 h.
  • the completion of the reaction was monitored by LCMS, the mixture was poured into saturated aqueous NaCl (50 mL) and extracted with EA (2 ⁇ 30 mL).
  • Step D 2,4-Dihydroxy-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline- 3-carbon nitrile
  • Step F 4-(2-Chloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester
  • Step A (S)-4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidine-2- (Yl)methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-4 -(Piperazin-1-yl)quinoline-3-carbonitrile
  • Step C (S)-4-(4-acryloylpiperazin-1-yl)-8-(5-methyl-1H-indazol-4-yl)oxy)-2-(1-methyl (Pyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile formate
  • Step C (S)-4-(4-acryloylpiperazin-1-yl)-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-8 -((5-Methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile
  • the reaction system was diluted with EA (30 mL), washed with H 2 O (20 mL), washed with saturated aqueous NaCl (2 ⁇ 20 mL) and dried with anhydrous Na 2 SO 4 . After filtering and removing the solvent under reduced pressure, the residue was purified by preparative high performance liquid chromatography to obtain a white solid (S)-4-(4-acryloylpiperazin-1-yl)-2-((4,4-di Fluoro-1-methylpyrrolidin-2-yl)methoxy)-8-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile (37mg, three Step total yield 40%).
  • Example A3 refers to the description in Example A2.
  • step A ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol was used instead of (S)-(4,4). -Difluoro-1-methylpyrrolidin-2-yl)methanol.
  • Example A4 refers to the description in Example A2.
  • step A (3R,4R)-4-methoxy-1-methylpyrrolidin-3-ol was used instead of (S)-(4,4- Difluoro-1-methylpyrrolidin-2-yl)methanol.
  • Example A5 refers to the description in Example A2.
  • step A ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol was used instead of (S)-(4 ,4-Difluoro-1-methylpyrrolidin-2-yl)methanol.
  • the preparation of intermediate A2 refers to the synthesis of intermediate A1.
  • step A 5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4- Alcohol replaces 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol.
  • Example A6 The preparation of Example A6 was as described in Example A1, and 4-(2-chloro-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)- 3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A2) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H- Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1).
  • Example A7 refers to the description in Example A1.
  • step A 4-(2-chloro-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy) was used -3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A2) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H -Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (3R, 4R)-4-methoxy-1- Methylpyrrolidin-3-ol replaces (S)-(1-methylpyrrolidin-2-yl)methanol.
  • the preparation of intermediate A3 refers to the synthesis of intermediate A1, and 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4 is used in step A -Alcohol instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol.
  • LCMS (m/z): 553.0 (M+H).
  • Example A8 refers to that described in Example A1, using 4-(2-chloro-8-((6-chloro-5-methyl-1H-indazol-4-yl)oxy) in step A -3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A3) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H -Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1).
  • Example A9 refers to the description in Example A1.
  • step A tert-butyl 4-(2-chloro-8-((6-chloro-5-methyl-1H-indazol-4-yl )Oxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A3) instead of 4-(2-chloro-3-cyano-8-((5- Methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (3R,4R)-4-methoxy Yl-1-methylpyrrolidin-3-ol instead of (S)-(1-methylpyrrolidin-2-yl)methanol.
  • intermediate A4 refers to the synthesis of intermediate A1, and 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4 is used in step A. -Alcohol instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol. LCMS(m/z): 553.2(M+H).
  • Example A10 refers to that described in Example A2.
  • step A 4-(2-chloro-8-((5-chloro-6-methyl-1H-indazol-4-yl)oxy )-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A4) instead of 4-(2-chloro-3-cyano-8-((5-methyl- 1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (3R,4R)-4-methoxy-1 -Methylpyrrolidin-3-ol instead of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol.
  • Example A11 refers to that described in Example A2, using 4-(2-chloro-8-((5-chloro-6-methyl-1H-indazol-4-yl)oxy) in step A -3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A4) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H -Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (S)-(1-methylpyrrolidine-2- Yl)methanol instead of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol.
  • intermediate A5 refers to the synthesis of intermediate A1, and 5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol is used in step A Instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol.
  • LCMS m/z: 573.2, 575.1 (M+H).
  • Example A12 The preparation of Example A12 was as described in Example A2, using 4-(2-chloro-3-cyano-8-((5,6-dichloro-1H-indazol-4-yl) in step A (Oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A5) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H-indyl) (Azol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1) with (S)-(1-methylpyrrolidin-2-yl) Methanol replaces (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol.
  • Example A13 refers to that described in Example A2.
  • step A 4-(2-chloro-3-cyano-8-((5,6-dichloro-1H-indazol-4-yl )Oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A5) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H- Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (3R, 4R)-4-methoxy-1-methyl Pyrrolidin-3-ol instead of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol.
  • NCS 700 mg, 5.24 mmol
  • 2-amino-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)oxy)benzoic acid methyl ester 2.0 g, 5.24 mmol
  • DMF 10 mL
  • the resulting mixture was stirred at 60°C for 48h.
  • the mixture was poured into H 2 O (100 mL) and extracted with EA (3 ⁇ 30 mL).
  • the obtained organic phase was washed with saturated aqueous NaCl (40 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step D to Step G 4-(2,6-Dichloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piper Tert-Butyl oxazine-1-carboxylate (Intermediate A6)
  • the subsequent synthesis method of intermediate A6 refers to the synthesis of intermediate A1.
  • step C 2-amino-5-chloro-3-((5-methyl-1-(tetrahydro-2H-pyran-2 -Yl)-1H-indazol-4-yl)oxy)methyl benzoate instead of 2-amino-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazol-4-yl)oxy)benzoic acid methyl ester.
  • Example A14 refers to that described in Example A2.
  • step A 4-(2,6-dichloro-3-cyano-8-((5-methyl-1H-indazol-4-yl )Oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A6) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H- Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (S)-(1-methylpyrrolidin-2-yl) ) Methanol instead of (S)-(4,4-Difluoro-1-methylpyrrolidin-2-yl)methanol.
  • intermediate A7 refers to the synthesis of intermediate A6, and 5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol is used in step A Instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol.
  • Example A15 The synthesis of Example A15 was as described in Example A1, and 4-(2,6-dichloro-3-cyano-8-((5-methyl-1H-indazol-4-yl )Oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A7) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H- Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (3R, 4R)-4-methoxy-1-methyl Pyrrolidin-3-ol replaces (S)-(1-methylpyrrolidin-2-yl)methanol.
  • Example A16 refers to that described in Example A2.
  • step A 4-(2,6-dichloro-3-cyano-8-((5-methyl-1H-indazole-4- Yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A6) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H -Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and use (3R, 4R)-4-methoxy-1 -Methylpyrrolidin-3-ol instead of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol.
  • Example A18 The preparation of Example A18 was as described in Example A17, using (E)-4-(dimethylamino)-2-butenoic acid instead of 2-fluoroacrylic acid.
  • Step A 4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl) Quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Steps B and C 4-(4-acryloylpiperazin-1-yl)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-(1-methyl- 1H-pyrazol-4-yl)quinoline-3-carbonitrile
  • step B 4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy Yl)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of 4-(3-cyano-2-(( 4,4-Difluoro-1-methylpyrrolidin-2-yl)methoxy)-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl ) Tert-butyl piperazine-1-carboxylate.
  • Step A 4-(8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3-cyano-2-((2-methylisoindoline-4 -Yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • reaction system was diluted with EA (30 mL) and H 2 O (30 mL), filtered with Celite, and the filtrate was extracted with EA (3 ⁇ 30 mL). The resulting organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • Steps B and C 4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-2-((2 -Methylisoindol-4-yl)oxy)quinoline-3-carbonitrile
  • Example A20 The subsequent synthesis of Example A20 refers to that described in Example A2, and 4-(8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3-cyano was used in step B.
  • Example A21 refers to that described in Example A20.
  • 2-isoindolin-4-ol was used instead of 2-methylisoindolin-4-ol.
  • Example A22 to Example A61 were also prepared and characterized:
  • Step A 4-(8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3-cyano-2-((2-methylpyridin-3-yl) (Amino)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Steps B and C 4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-2-((2 -Methylpyridin-3-yl)amino)quinoline-3-carbonitrile
  • Example A62 The subsequent synthesis of Example A62 was as described in Example A2, and 4-(8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3-cyano was used in step B.
  • Example A63 to Example A80 were also prepared and characterized:
  • Step A 3-Amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxylic acid Methyl ester
  • Step B to Step G 7-(4-acryloylpiperazin-1-yl)-5-(3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)- 3-((5-methyl-1H-indazol-4-yl)oxy)thiophene[3,2-b]pyridine-6-carbonitrile
  • Example A82 to Example A109 were also prepared and characterized:
  • Step A 4-(8-((5-chloro-6-fluoro-1-methyl-1H-indazol-4-yl)oxy)-3-cyano-2-((3R,4R)- 4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester and 4-(8-((5-chloro-6 -Fluoro-2-methyl-2H-indazol-4-yl)oxy)-3-cyano-2-((3R,4R)-4-methoxy-1-methylpyrrolidine-3- (Yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Steps B and C 4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1-methyl-1H-indolazol-4-yl)oxy) -2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile (Example A110) and 4-(4-acryloyl Piperazin-1-yl)-8-((5-chloro-6-fluoro-2-methyl-2H-indazol-4-yl)oxy)-2-((3R,4R)-4-methyl (Oxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile (Example A111)
  • Example A110 and Example A111 refer to the synthesis of Example A1.
  • step B 4-(8-((5-chloro-6-fluoro-1-methyl-1H-indazole- 4-yl)oxy)-3-cyano-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piper Oxazine-1-carboxylic acid tert-butyl ester and 4-(8-((5-chloro-6-fluoro-2-methyl-2H-indazol-4-yl)oxy)-3-cyano-2- ((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of (S)-4 -(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1
  • intermediate A8 refers to the synthesis of 2,4-dichloro-8-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile, in step A Use 2-fluoro-6-methoxyphenol instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol.
  • Step B tert-Butyl 4-(2-chloro-3-cyano-8-(2-fluoro-6-hydroxyphenoxy)quinolin-4-yl)piperazine-1-carboxylate
  • N,N-diisopropylethylamine (532mg, 4.1mmol) was added to the dissolved 2,4-dichloro-8-(2-fluoro-6-hydroxyphenoxy)quinoline-3 -Carbonitrile (900mg, 2.6mmol) and piperazine-1-carboxylic acid tert-butyl ester (563mg, 3.0mmol in THF (20mL) solution.
  • the resulting solution was stirred at room temperature for 3h, LCMS monitored the completion of the reaction.
  • the reaction system was saturated with NaCl
  • the aqueous solution (15 mL) was washed, and the aqueous phase was extracted with EA (10 mL ⁇ 3).
  • Step A 4-(3-cyano-2-(3-((dimethylamino)methyl)phenyl)-8-(2-fluoro-6-hydroxyphenoxy)quinolin-4-yl) Tert-butyl piperazine-1-carboxylate
  • Steps B and C 4-(4-acryloylpiperazin-1-yl)-2-(3-((dimethylamino)methyl)phenyl)-8-(2-fluoro-6-hydroxyphenoxy) Yl)quinoline-3-carbonitrile
  • Example A112 The subsequent synthetic steps B and C of Example A112 are described in Example A1, and 4-(3-cyano-2-(3-((dimethylamino)methyl)phenyl)-8 is used in step B.
  • -(2-Fluoro-6-hydroxyphenoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of (S)-4-(3-cyano-8-((5-methyl -1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Example A113 refers to the synthesis of Example A112.
  • step A (3-(1-(dimethylamino)ethyl)phenyl)boronic acid was used instead of (3-((dimethylamino)methyl)benzene. ⁇ )Boric acid.
  • Example A114 refers to the synthesis described in Example A1.
  • step A 4-(2-chloro-3-cyano-8-(2-fluoro-6-hydroxyphenoxy)quinoline-4- Yl) piperazine-1-carboxylic acid tert-butyl ester (Intermediate A9) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy )Quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1), and replaced with (3R,4R)-4-methoxy-1-methylpyrrolidin-3-ol (S )-(1-Methylpyrrolidin-2-yl)methanol.
  • Example A115 compounds were also prepared and characterized:
  • the synthesis of intermediate A10 refers to the synthesis of intermediate A1.
  • 2-fluoro-6-methoxyphenol is used instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazol-4-ol.
  • Step A to Step C 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-methoxyphenoxy)-2-((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile
  • step A 4-(2-chloro-8-(3- Chloro-2-fluoro-6-methoxyphenoxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A10) instead of 4-(2-chloro- Tert-Butyl 3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylate (Intermediate A1). It is not prepared by high performance liquid chromatography in step C, and the crude product 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-methoxyphenoxy) is obtained by the reaction. -2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile was directly used in the subsequent reaction. LCMS(m/z): 596.5(M+H).
  • Step D 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-hydroxyphenoxy)-2-((3R,4R)-4-methoxy (1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile
  • the crude compound (300 mg, crude product) obtained above was dissolved in DCM (5 mL) and cooled to -70°C with a dry ice/ethanol solution. Under stirring, BBr 3 (0.96 mL, 10 mmol) was added dropwise to the system. After the addition was completed, the reaction system was moved to room temperature and stirring continued for 30 min. The completion of the reaction was monitored by LCMS. A saturated NaHCO 3 aqueous solution (5 mL) was added to the system to quench the reaction, the organic phase was separated and collected, the aqueous phase was extracted with DCM (5 mL ⁇ 2), the organic phases were combined, and dried over anhydrous Na 2 SO 4 .
  • the synthesis of intermediate A11 refers to the synthesis of intermediate A1.
  • step A 2-fluoro-6-methoxyphenol is used instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazol-4-ol; 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester is used in step F instead of piperazine-1-carboxylic acid tert-butyl ester.
  • Example A117 refers to the synthesis method of Example A116.
  • step A 7-(2-chloro-3-cyano-8-(2-fluoro-6-methoxyphenoxy)quinoline- 4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Intermediate A11) instead of 4-(2-chloro-8-(3-chloro-2-fluoro- 6-Methoxyphenoxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A10).
  • Step A 4-(7-Bromo-6-chloro-3-cyano-8-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl) (Oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B 4-(6-Chloro-3-cyano-8-fluoro-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline -4-yl) piperazine-1-carboxylic acid tert-butyl ester
  • Step C 4-(6-Chloro-3-cyano-8-(2-fluoro-6-methoxyphenoxy)-2-(((3R,4R)-4-methoxy-1- (Methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Example A118 refers to the synthesis method described in Example A116, and 4-(2,6-dichloro-3-cyano-8-(2-fluoro-6-methoxyphenoxy) was used in step B.
  • Quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A12) instead of 4-(8-(3-chloro-2-fluoro-6-methoxyphenoxy)-3-cyanide 2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step D tert-Butyl 4-(8-bromo-2-chloro-3-cyanoquinolin-4-yl)piperazine-1-carboxylate
  • Step A 4-(8-Bromo-3-cyano-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-4- Yl) piperazine-1-carboxylic acid tert-butyl ester
  • Step B 4-(3-cyano-8-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-4- Yl) piperazine-1-carboxylic acid tert-butyl ester
  • Step A 4-(8-(3-chloro-2-fluoro-6-nitrophenoxy)-3-cyano-2-(((3R,4R)-4-methoxy-1-methyl Pyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B 8-(3-Chloro-2-fluoro-6-nitrophenoxy)-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy Yl)-4-(piperazin-1-yl)quinoline-3-carbonitrile
  • Step C 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-nitrophenoxy)-2-((3R,4R)-4-methyl (Oxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile
  • the crude product from the previous step was dissolved in EA (10 mL), saturated aqueous sodium bicarbonate solution (10 mL) was added, and acryloyl chloride (51 mg, 0.41 mmol) was added dropwise to the reaction solution under cooling and stirring in an ice bath. After stirring for 15 min under the ice bath, saturated aqueous ammonium chloride solution (5 mL) was added to quench the reaction. The EA phase was separated, the aqueous phase was extracted once with EA (10 mL), the organic phases were combined and washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate.
  • Step D 4-(4-Acryloylpiperazin-1-yl)-8-(6-amino-3-chloro-2-fluorophenoxy)-2-((3R,4R)-4-methoxy (1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile
  • Example A120 refers to the synthesis of Example A119.
  • step A 1,2-difluoro-3-nitrobenzene was used instead of 1-chloro-2,3-difluoro-4-nitrobenzene.
  • Step A 4-(8-((2-((tert-butoxycarbonyl)amino)-7-fluorobenzothiazol-4-yl)oxy)-3-cyano-2-(2-methyl- 1,2,3,4-Tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-8-((2-amino-7-fluorobenzo[d]thiazol-4-yl)oxy)-2-( 2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinoline-3-carbonitrile
  • Example A121 The subsequent synthesis method of Example A121 refers to the description in Example A1, and 4-(8-((2-((tert-butoxycarbonyl)amino)-7-fluorobenzothiazol-4-yl) was used in step B.
  • Example A122 refers to the synthesis of Example A121.
  • step A 7-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4- Alcohol replaces tert-butyl (7-fluoro-4-hydroxybenzo[d]thiazol-2-yl)carbamate.
  • Step A 4-(3-cyano-8-((2-((4-methoxybenzyl)oxy)-6-methylquinolin-5-yl)oxy)-2-(2 -Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B 8-((2-hydroxy-6-methylquinolin-5-yl)oxy)-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-5- Yl)-4-(piperazin-1-yl)quinoline-3-carbonitrile
  • Step C 4-(4-Acryloylpiperazin-1-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8-((6 -Methyl-2-oxo-1,2-dihydroquinolin-5-yl)oxy)quinoline-3-carbonitrile diformate
  • Step C refers to the description in Example A1, using 8-((2-hydroxy-6-methylquinolin-5-yl)oxy)-2-(2-methyl-1,2,3,4- Tetrahydroisoquinolin-5-yl)-4-(piperazin-1-yl)quinoline-3-carbonitrile instead of (S)-8-((5-methyl-1H-indazol-4-yl) )Oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile.
  • Step A 4-(8-((6-amino-3-methylpyrazin-2-yl)oxy)-3-cyano-2-(2-methyl-1,2,3,4- Tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • reaction solution was poured into water (6 mL), extracted with EA (6 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (10 mL ⁇ 3), and dried with anhydrous sodium sulfate.
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-8-((6-amino-3-methylpyrazin-2-yl)oxy)-2-(2-methyl -1,2,3,4-tetrahydroisoquinolin-5-yl)quinoline-3-carbonitrile
  • Example A124 The subsequent synthesis method of Example A124 refers to the description in Example A1, and 4-(8-((6-amino-3-methylpyrazin-2-yl)oxy)-3-cyano group is used in step B.
  • Step A 4-(8-((2-Amino-5-methylpyrimidin-4-yl)oxy)-3-cyano-2-(2-methyl-1,2,3,4-tetra (Hydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • reaction solution was poured into water (15 mL), extracted with EA (15 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (15 mL ⁇ 3), and dried with anhydrous sodium sulfate.
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-8-((2-amino-5-methylpyrimidin-4-yl)oxy)-2-(2-methyl -1,2,3,4-Tetrahydroisoquinolin-5-yl)quinoline-3-carbonitrile
  • Example A128 The subsequent synthesis method of Example A128 refers to that described in Example A1.
  • step B 4-(8-((2-amino-5-methylpyrimidin-4-yl)oxy)-3-cyano- 2-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of (S)-4- (3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline- 4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step A 4-(8-(3-Amino-6-chloro-2-cyanophenoxy)-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroiso Quinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-8-(3-amino-6-chloro-2-cyanophenoxy)-2-(2-methyl-1 ,2,3,4-Tetrahydroisoquinolin-5-yl)quinoline-3-carbonitrile
  • Example A129 The subsequent synthesis method of Example A129 refers to that described in Example A1.
  • step B 4-(8-(3-amino-6-chloro-2-cyanophenoxy)-3-cyano-2- (2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of (S)-4-(3 -Cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline-4- Yl) tert-butyl piperazine-1-carboxylate.
  • Step A 4-(8-(3-Amino-6-methyl-2-nitrophenoxy)-3-cyano-2-(2-methyl-1,2,3,4-tetrahydro (Isoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B 4-(3-cyano-8-(2,3-diamino-6-methylphenoxy)-2-(2-methyl-1,2,3,4-tetrahydroisoquine (A-line-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step A 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8-((5-methyl-2-oxy (2,3-Dihydro-1H-benzo[d]imidazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8- ((5-Methyl-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-4-yl)oxy)quinoline-3-carbonitrile
  • Example A130 The subsequent synthesis method of Example A130 refers to that described in Example A1.
  • step B 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline- 5-yl)-8-((5-methyl-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-4-yl)oxy)quinolin-4-yl)piper Instead of (S)-4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1- Methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step A 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8-((5-methyl-1H-benzene (B-imidazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8- ((5-Methyl-1H-benzo(d)imidazol-4-yl)oxy)quinoline-3-carbonitrile
  • Example A130 The subsequent synthesis method of Example A130 refers to that described in Example A1.
  • step B 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline- 5-yl)-8-((5-methyl-1H-benzimidazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of (S)-4 -(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline -4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step A 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8-((5-methyl-1H-benzene And [d][1,2,3]triazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8- ((5-Methyl-1H-benzo[d][1,2,3]triazol-4-yl)oxy)quinoline-3-carbonitrile
  • Example A130 The subsequent synthesis method of Example A130 refers to that described in Example A1.
  • step B 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline- 5-yl)-8-((5-methyl-1H-benzo[d][1,2,3]triazol-4-yl)oxy)quinolin-4-yl)piperazine-1- Tert-butyl carboxylate instead of (S)-4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidine) -2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Step A 4-(8-((2-Amino-5-methyl-1H-benzo[d]imidazol-4-yl)oxy)-3-cyano-2-(2-methyl-1 ,2,3,4-Tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
  • Step B and Step C 4-(4-acryloylpiperazin-1-yl)-8-((2-amino-5-methyl-1H-benzo[d]imidazol-4-yl)oxy) -2-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinoline-3-carbonitrile
  • Example A130 The subsequent synthesis method of Example A130 refers to that described in Example A1.
  • step B 4-(8-((2-amino-5-methyl-1H-benzo[d]imidazol-4-yl)oxy Yl)-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl Ester instead of (S)-4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl) )Methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester.
  • Methyl 2-amino-3-bromo-5-fluorobenzoate (1.0g, 4.03mmol), 2-fluoro-6-methoxyphenol (688mg, 4.84mmol), CuI (153mg, 0.81mmol), N 1 -benzyl-N 2 -(5-methyl-[1,1'-biphenyl]-2-yl)oxamide ( 555mg, 1.62mmol), K 2 CO 3 (2.14g, 12.09mmol) dissolved in Replace with nitrogen twice in DMSO (10 mL), and raise the temperature to 100°C to react for 24 hours.

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Abstract

Composés de formule (I) qui peuvent être utilisés en tant qu'inhibiteurs de KRAS, isomères ou sels ou solvates pharmaceutiquement acceptables de ceux-ci, des compositions pharmaceutiques comprenant de tels composés, et l'utilisation de tels composés dans la préparation de médicaments pour le traitement de cancers ou de tumeurs.
PCT/CN2021/077628 2020-02-24 2021-02-24 Inhibiteurs de kras pour le traitement de cancers WO2021169990A1 (fr)

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WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023055904A1 (fr) * 2020-10-20 2023-04-06 TRUETIVA, Inc. Antagonistes de kras
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
CN116115618A (zh) * 2021-11-15 2023-05-16 石药集团中奇制药技术（石家庄）有限公司 一种治疗肿瘤的药物
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2024026423A1 (fr) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Dérivés de quinoléine substitués utiles comme inhibiteurs de pi3k
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
WO2024102421A2 (fr) 2022-11-09 2024-05-16 Revolution Medicines, Inc. Composés, complexes, et leurs procédés de préparation et d'utilisation
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024207892A1 (fr) * 2023-04-04 2024-10-10 泰励生物科技（上海）有限公司 Composés ayant une activité contre des tumeurs avec mutation de kras
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
US12122787B2 (en) 2019-09-20 2024-10-22 Shanghai Jemincare Pharmaceuticals Co., Ltd Fused pyridone compound, and preparation method therefor and use thereof
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2024167922A3 (fr) * 2023-02-07 2024-11-14 Board Of Regents, The University Of Texas System Composés hétérocycliques utilisés en tant qu'inhibiteurs de nras
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras

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Cited By (32)

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US11932633B2 (en) 2018-05-07 2024-03-19 Mirati Therapeutics, Inc. KRas G12C inhibitors
US12208099B2 (en) 2018-09-10 2025-01-28 Mirati Therapeutics, Inc. Combination therapies
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
US11964989B2 (en) 2019-08-29 2024-04-23 Mirati Therapeutics, Inc. KRas G12D inhibitors
US12122787B2 (en) 2019-09-20 2024-10-22 Shanghai Jemincare Pharmaceuticals Co., Ltd Fused pyridone compound, and preparation method therefor and use thereof
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2022060836A1 (fr) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Dérivés d'indole servant d'inhibiteurs dans le traitement du cancer
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2023055904A1 (fr) * 2020-10-20 2023-04-06 TRUETIVA, Inc. Antagonistes de kras
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2022235870A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras pour le traitement du cancer
WO2022235864A1 (fr) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Inhibiteurs de ras
WO2023060253A1 (fr) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Inhibiteurs de ras
CN116115618A (zh) * 2021-11-15 2023-05-16 石药集团中奇制药技术（石家庄）有限公司 一种治疗肿瘤的药物
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024026423A1 (fr) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Dérivés de quinoléine substitués utiles comme inhibiteurs de pi3k
WO2024081674A1 (fr) 2022-10-11 2024-04-18 Aadi Bioscience, Inc. Polythérapies pour le traitement du cancer
WO2024102421A2 (fr) 2022-11-09 2024-05-16 Revolution Medicines, Inc. Composés, complexes, et leurs procédés de préparation et d'utilisation
WO2024167922A3 (fr) * 2023-02-07 2024-11-14 Board Of Regents, The University Of Texas System Composés hétérocycliques utilisés en tant qu'inhibiteurs de nras
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024207892A1 (fr) * 2023-04-04 2024-10-10 泰励生物科技（上海）有限公司 Composés ayant une activité contre des tumeurs avec mutation de kras
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras

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