WO2021169990A1 - Kras inhibitors for treating cancers - Google Patents

Abstract

Compounds of formula (I) which can be used as KRAS inhibitors, isomers or pharmaceutically acceptable salts or solvates thereof, pharmaceutical compositions comprising such compounds, and use of such compounds in preparation of medicaments for treating cancers or tumors.

Description

KRAS inhibitors for cancer treatment

cross reference

This application claims the priority of the Chinese patent application 202010111297.4 filed on February 24, 2020 and the Chinese patent application 202110195075.X filed on February 22, 2021.

Technical field

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.

Background technique

Ras, the oncogene homolog of rat sarcoma, represents a group of closely related monomeric globular proteins and belongs to the family of GTPase proteins. Specifically, under normal physiological conditions, 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. At this time, the signal system is closed, and it will be activated when exposed to some growth-promoting stimuli. For example, it can be induced by guanine nucleotide exchange factor (GEF). GDP is released and combined with GTP. As a result, 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. However, 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.

Among the genes related to human tumors, there are three ubiquitously expressed Ras genes H-RAS, K-RAS and N-RAS, which respectively encode highly homologous, approximately 21KDa HRas, NRas, and KRas proteins. In 1982, researchers first discovered that Ras was mutated and activated in cancer cell lines (Chang, E.H. et al., Proceedings of the National Academy of Sciences of the United States of America, 1982, 79(16), 4848-4852). Subsequent large-scale genome sequencing studies in different cancer types revealed that 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. Transgenic and genetically engineered mouse models have also revealed that the mutated Ras 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. In cancer cell lines and cancer animal models, RNA intervention has been shown to slow the growth of tumors. These studies make Ras tumor protein a very attractive anticancer drug target widely accepted in the field of pharmacy.

Studies have shown that 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.

However, the research and development of drugs for Ras in the past 30 years has shown that 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. 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, such as inhibitors against the most common mutant protein KRas-G12C, 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). Several patent documents also describe KRas inhibitors of various structural types, such as CN10256421, US2019/0144444A1 and WO2019/110751A1.

However, the above-mentioned KRas inhibitors still have problems to be solved, and their "pharmaceutical properties" are still unsatisfactory. For example, 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. 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:

(1) It retains comparable or enhanced or even significantly enhanced KRas mutant protein and related cancer cell proliferation inhibitory activity;

(2) Different biological activity spectrum for new indications;

(3) Improved metabolic stability, leading to better pharmacokinetic properties;

(4) It has improved physical and chemical properties, and thus has good drug-making properties, such as easier absorption in the body.

Brief description of the invention

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,

in,

A is selected from C-CN or N;

X, Y and Z are each independently selected from C, N, O or S;

为单键或双键；

Single bond or double bond;

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;

W is selected from -C(O)-CR ¹ =C(R ² ) ₂ , -C(O)-C≡CR ² , -C(O)-C≡N, -S(O) _1-2 -CR ¹ = C(R ² ) ₂ , -S(O) _1-2 -C≡CR ² , -S(O) _1-2 -C≡N; or W is composed of R ¹ or R ² and ring B The N connected by W and the ring atoms adjacent to the N together form a nitrogen-containing heterocyclic ring fused with the B ring;

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;

Each occurrence of 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 ¹⁰ ) ₂ -replace;

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 ¹⁰ , where C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl are optionally further halogenated , -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ or N(R ¹⁰ ) ₂ substitution, where R ¹⁰ is as defined above for each occurrence, or two R ^10s connected to the same C are connected to them The carbon atoms together form _{a C 3-8} cycloalkyl group optionally substituted with ^{one or more R 10 or halogen;}

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} ；

m is 0 or 1;

n is selected from an integer from 0 to 3;

requirement is:

表示双键；和 When m=1, X, Y, and Z are each independently selected from C or N, and

Represents a double bond; and

When A is N and m=1, at least one of X and Y is not C.

In this aspect, 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 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.

It should be noted that the above aspects also cover such embodiments, wherein the compounds of Formula I or Formula II are the corresponding specific, preferred, more preferred or most preferred embodiments described herein, respectively.

Detailed description of the invention

definition

Unless otherwise indicated, each term used in the specification and claims has the meaning shown below. In the case that a specific term or phrase is not specifically defined, it should not be regarded as uncertain or unclear, but should be understood according to the ordinary meaning in the art. Many groups defined herein are optionally substituted. The list of substituents given in the definition section is only exemplary and is not intended to limit the substituents defined in other parts of this specification and claims.

The term "Ras mutant" or "Ras mutant protein" as used herein 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. In particular, the mutation at position 12 of the codon refers to the mutation from glycine to cysteine, that is, the G12C mutation.

For the purpose of the present invention, "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.

The term "treatment" as used herein 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. In a specific embodiment of the present invention, the disease is a disease mediated by a Ras mutation as defined below, especially a tumor or cancer.

The term "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. The term "prevention" encompasses the use of the compounds of the present invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.

As used herein, 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. For example, compared with normal conditions, 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.

The term "selective inhibition" as used herein 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. As far as the compound of formula I of the present invention is concerned, relative to the various mutations that occur in one or more codons of the Ras protein, it 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. Ability to mutate G12C. For example, compared to another specific Ras mutation, 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.

The term "Ras mutation-mediated disease" as used herein 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. For the present invention, "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.

The term "cancer" or "tumor" as used herein refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous cells and cancer cells and tissues. For the various aspects of the present invention, 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 (CNS), Primary CNS lymphoma, spinal tumor, brainstem glioma, or pituitary adenoma.

For each aspect of the present invention, preferably, 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. In certain embodiments, 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. In certain embodiments, the mammal is a human.

The term "therapeutically effective amount" as used herein 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.

The term "pharmaceutical combination" as used herein 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.

On the one hand, 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.

The term "pharmaceutically acceptable" as used herein 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.

The term "pharmaceutically acceptable salt" as used herein 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, cinnamic acid, mandelic acid, pamoic acid, Phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. "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. Accepts salts of 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.

As used herein, 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. And Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994), so the present invention covers all possible isomeric forms of the compounds of formula I or formula II defined above, and Pharmaceutically acceptable salt or solvate. For a given chemical structure, the stereoisomers are the same unless they are mirror images of each other. A specific stereoisomer can also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate. The terms "racemic mixture" and "racemate" mean an equimolar mixture of two enantiomers without optical activity.

表示立体中心即手性中心的绝对构型，相应地在本发明所提供的化合物或中间体的命名中以R和S表示关于该手性中心的绝对构型，该绝对构型的确定是本领域技术人员所熟知的。 Used in the structural formulas or structural fragments of the compounds in this article

Represents the absolute configuration of the stereocenter, that is, the chiral center. Correspondingly, in the naming of the compounds or intermediates provided by the present invention, R and S represent the absolute configuration of the chiral center. The determination of the absolute configuration is the essence Known to those skilled in the art.

指示与其交叉的键是结构片段连接于分子其余部分的键。 Used in the structural fragments involved in this article

The bond indicated to cross it is the bond that connects the structural fragment to the rest of the molecule.

The term "solvate" as used herein 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.

The term "isotopic variant" as used herein 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. Examples of 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. It should be understood that 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. For example, certain isotopic variants of the compounds of the present invention and their pharmaceutically acceptable salts incorporating radioisotopes (such as ³ H or ^{14 C) 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. Further, 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. In addition, compounds of the present invention substituted with positron emitting isotopes (such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be prepared, and they can be used in positron tomography (PET) studies for substrate receptor occupancy detection .

The term "metabolite" as used herein 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.

The term "prodrug" as used herein 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). The discussion of prodrugs can be found in Higuchi, T. et al.'s ACS Symposium Series, Volume 14, and "Bioreversible Carriers in Drug Design", Edward B. Roche, USA Pharmaceutical Association & Pergamon Press, 1987, the entire contents of which are incorporated herein by reference. The term "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. In some embodiments, 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 β-lactam, prodrugs containing optionally substituted phenoxyacetamide or prodrugs containing optionally substituted phenylacetamide, and 5-fluorocytosine and 5-fluorouridine prodrugs.

The term "pharmaceutically acceptable excipient or carrier" as used herein 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.

The term "halogen" or "halo" as used herein means F, Cl, Br, or I. In addition, the term "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.

The term "alkyl" as used herein means a saturated linear or branched monovalent hydrocarbon group, where the alkyl group may be optionally substituted. In one example, the alkyl group is 1 to 18 carbon atoms (C ₁ -C ₁₈ ). In other examples, 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 . Examples of 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 ₂ CH ₃ ), 2- Hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl ( -C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl Group (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3- Pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3 -Dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ , 1-heptyl and 1-octyl. For the purposes of the present invention, 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 , Amide group, C-carboxyl group, O-carboxyl group, nitro group and silyl group, and groups each of which is further substituted with other optional substituents, each of which is as defined herein. Examples of 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 the same list above.

The term "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. In one example, the divalent alkylene group is 1-18 carbon atoms (C ₁ -C ₁₈ ). In other examples, 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. Examples of 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.

As used herein, the term "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.

The term "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. In one example, the cycloalkyl group has 3 to 12 carbon atoms (C ₃ -C ₁₂ ). In other examples, the cycloalkyl group is a C ₃ -C ₈ , C ₃ -C ₁₀ , C ₅ -C ₁₀ or C ₃ -C ₆ ring. In other examples, the cycloalkyl group as a monocyclic ring is C ₃ -C ₈ , C ₃ -C ₆ or C ₅ -C ₆ . In another example, the cycloalkyl group is C ₇ -C ₁₂ as a bicyclic ring. In another example, the cycloalkyl group as a spiro ring system is C ₅ -C ₁₂ . Examples of 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. Examples of 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. Examples of 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. Examples of 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. For the purposes of the present invention, cycloalkyl groups are optionally substituted, and the substituents are as defined above for alkyl substituents.

The term "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. For the purposes of the present invention, aryl groups are optionally substituted, and the substituents are as defined above for alkyl substituents.

As used herein, the terms "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. In one example, 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 . In some examples, the heterocyclic group includes 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom. In other examples, 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. In another example, heterocyclyl includes 3-12 membered heterocycloalkyl, such as 4-11 membered, 3-8 membered, 5-6 membered heterocycloalkyl. In some embodiments, 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.

基、氧氮杂环庚基、二氮杂环庚基、1,4-二氮杂环庚基、二氮杂

基、硫氮杂

基、硫氮杂环庚基、四氢噻喃基、噁唑烷基、噻唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷酮基、噁唑烷酮基、咪唑烷酮基、4,5,6,7-四氢[2H]吲唑基、四氢苯并咪唑基、4,5,6,7-四氢苯并[d]咪唑基、1,6-二氢咪唑并[4,5-d]吡咯并[2,3-b]吡啶基、噻嗪基、噁嗪基、噻二嗪基、噁二嗪基、二噻嗪基、二噁嗪基、噁噻嗪基、噻三嗪基、噁三嗪基、二噻二嗪基、咪唑啉基、二氢嘧啶基、四氢嘧啶基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、噻喃基、2H-吡喃基、4H-吡喃基、二噁烷基、1,3-二氢杂环戊基、吡唑啉基、吡唑烷基、二噻烷基(dithianyl)、二硫戊环基、哌嗪酮基、哌嗪二酮基、吡唑烷基、咪唑啉基、 3-氮杂双环[3.1.0]己基、3,6-二氮杂双环[3.1.1]庚基、6-氮杂双环[3.1.1]庚基、3-氮杂双环[3.1.1]庚基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、2-氮杂双环[3.2.1]辛基、8-氮杂双环[3.2.1]辛基、2-氮杂双环[2.2.2]辛基、8-氮杂双环[2.2.2]辛基、7-氧杂双环[2.2.1]庚烷、氮杂螺[3.5]壬基、氮杂螺[2.5]辛基、氮杂螺[4.5]癸基、1-氮杂螺[4.5]癸-2-酮基、氮杂螺[5.5]十一烷基、四氢吲哚基、八氢吲哚基、四氢异吲哚基、四氢吲唑基、1,1-二氧代六氢噻喃基。 Examples of 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, oxazinyl, thiazinyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxa Cycloheptyl, thiepanyl, oxazepine

Group, oxazepin, diazacycloheptyl, 1,4-diazepanyl, diazacycloheptyl

Base, thiazepine

Group, thiazepinyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinone, oxazolidinone, imidazolidine Keto, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-di Hydroimidazo[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, Oxthiazinyl, thiatriazinyl, oxtriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrole Linyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dihydrocyclopentyl, pyrazolinyl, pyrazolidinyl , Dithianyl (dithianyl), dithiolanyl, piperazinonyl, piperazine dione, pyrazolidinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6 -Diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl Group, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl , 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5 ]Decyl, 1-azaspiro[4.5]dec-2-one, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl Hydroindazolyl, 1,1-dioxohexahydrothiopyranyl.

For the purposes of the present invention, the above-mentioned broad and specifically enumerated heterocycles are optionally substituted, and the substituents are as defined above for alkyl substituents.

The term "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. Examples of 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, pyrrolo[2,3- c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, pyrazole And [4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, Purine, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridazine, pyrrolo[1,2-b] Pyrimidine, imidazo[1,2-c]pyrimidine, 5H-pyrrolo[3,2-b]pyrazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3, 4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7 -Naphthyridine, 1,8-naphthyridine, 1,5-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3- d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, Pyrimido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine and pyrimido[4,5-d]pyrimidine.

For the purposes of the present invention, the aforementioned broad and specific heteroaryl groups are optionally substituted, and the substituents are as defined above for alkyl substituents.

The term "hydroxyl" as used herein refers to the -OH group.

The term "mercapto" as used herein refers to the -SH group.

The terms "alkoxy and alkylthio" as used herein 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.

The term "oxo" as used herein refers to =0.

The term "nitro" as used herein refers to the -NO ₂ group.

The term "cyano" as used herein refers to the -CN group.

The term "thiocarbonyl" as used herein refers to the -C=S group.

As used herein the term "azido" refers to a -N ₃ group.

The term "acyl" as used herein 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.

The term "amido" as used herein 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".

The term "acyloxy" as used herein 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".

As used herein, the term "carbamoyl" refers to -C (O) -NH _2; As used herein, the term "thiocarbamyl" refers to a -C (S) -NH _2.

The term "sulfonyl" as used herein 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".

The term "sulfonylamino" as used herein 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".

The term "sulfonyloxy" as used herein 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".

The term "amide group" as used herein refers to -C(O)-NH ₂ , where NH ₂ may be optionally substituted with an alkyl or aryl group as defined herein.

The term "carboxy" as used herein refers to the -C(O)-OH group.

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. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents.

_{Unless otherwise specified, 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. In the same way, 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. For example, 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. For example, 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.

As used in this specification and the following claims, 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. When an element is described as including a plurality of ingredients, steps or conditions, it should be understood that 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".

It should be understood that when the compound of the present invention, pharmaceutical compositions, pharmaceutical combinations, kits, and related uses and methods are described herein, 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.

Compound of the invention

The terms "compounds of the invention" and "compounds of the invention", etc. used throughout this application, unless otherwise specified, encompass the compounds of formula I or formula II (including formula Ia, Ia) defined in the various embodiments herein and their preferred embodiments. ', Ib, Ib', I-1, I-2, II-1), including its isomers, including atropisomers, enantiomeric mixtures, especially racemates, diastereomers Mixtures, geometric isomers, tautomers, solvates, metabolites, isotopic variants, salts (e.g., pharmaceutically acceptable salts), and prodrugs.

Therefore, the above-mentioned various isomers and derivatives of the compounds of the present invention are thus all encompassed within the scope of the present invention, and their respective meanings, preparations and specific examples are as defined in the "definitions" section above, or are well known in the art . In some embodiments, metabolites, isotopic variants or prodrugs, and any combination thereof are excluded as appropriate. However, it is preferably substantially pure enantiomers (enantiomerically pure), diastereomers and tautomers of the compound of formula I and/or pharmaceutically acceptable salts thereof.

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.

In one aspect, 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.

in,

A is selected from C-CN or N;

X, Y and Z are each independently selected from C, N, O or S;

为单键或双键；

Single bond or double bond;

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;

W is selected from -C(O)-CR ¹ =C(R ² ) ₂ , -C(O)-C≡CR ² , -C(O)-C≡N, -S(O) _1-2 -CR ¹ = C(R ² ) ₂ , -S(O) _1-2 -C≡CR ² , -S(O) _1-2 -C≡N; or W is composed of R ¹ or R ² and ring B The N connected by W and the adjacent ring atoms of the N together form a nitrogen-containing heterocyclic ring fused with the B ring;

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;

Each occurrence of 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 ) ₂ -replace;

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 ¹⁰ , where C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl are optionally further halogenated , -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ or N(R ¹⁰ ) ₂ substitution, where R ¹⁰ is as defined above for each occurrence, or two R ^10s connected to the same C are connected to them The carbon atoms together form _{a C 3-8} cycloalkyl group optionally substituted with ^{one or more R 10 or halogen;}

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} ；

m is 0 or 1;

n is selected from an integer from 0 to 3;

requirement is:

表示双键；和 When m=1, X, Y, and Z are each independently selected from C or N, and

Represents a double bond; and

When A is N and m=1, at least one of X and Y is not C.

In one embodiment of 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,

Wherein each group is as defined above for the compound of formula I.

优选

最优选

其中包含X、Y和Z的六元环任选被0、1、2或3个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula Ia, m=1. In a further embodiment, m=1, X is C and Y and Z are each independently selected from C or N, or m=1, X is N, and Y and Z are each independently selected from C or N. In a specific embodiment, 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.

优选

其中的五元环任选被0、1或2个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula Ia, m=0. In a further embodiment, m=0, X is C and Z is selected from C or N; or m=0, X is N and Z is selected from C or N, or m=0, X is O and Z is selected from C or N, or m=0, X is S and Z is selected from C or N. In a specific embodiment, 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.

In one embodiment of 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,

Wherein each group is as defined for the compound of formula I.

优选

各自任选被0、1或2个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula Ib, m=1. In a further embodiment, m=1, X is C, Y is N, and Z is selected from C or N; or m=1, X is N, and Y and Z are each independently selected from C or N. In a specific embodiment, 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.

优选

其中的五元环任选被0、1或2个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula Ib, m=0. In a further embodiment, m=0, X is C and Z is selected from C or N; or m=0, X is N and Z is selected from C or N; or m=0, X is O and Z is selected from C or N, or m=0, X is S and Z is selected from C or N. In a specific embodiment, 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.

In one embodiment of the compound of formula I, 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 -. Preferably 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-.

In one embodiment of the compound of formula I, L is -NR ¹⁰ -, and R ^{10 is} selected from H or C _1-6 alkyl optionally substituted by halogen, preferably R ¹⁰ is H. In this embodiment, ^{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, and each of the above-mentioned alkyl groups substituted by one or more, for example 1, 2, 3 or 4 halogens, preferably fluorine, such as trifluoromethyl, difluoromethyl, fluoromethyl, difluoro Ethyl (-CH ₂ -CHF ₂ or -CHF-CH ₂ F), trifluoropropyl (-CH(CF ₃ )(CH ₃ )), etc.

In one embodiment of the compound of formula I, L is -CR ⁸ R ⁹ -, wherein R ⁸ and R ⁹ are each independently selected from H.

In one embodiment of the compound of formula I, 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 . In this embodiment, examples of L include but are not limited to -CHCl-, -CHF-, -CCl ₂ , -CF ₂ -, preferably -CHF- or -CF ₂ -.

In one embodiment of the compound of formula I, 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. In this embodiment, 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 -.

In one embodiment of the compound of formula I, 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.} In this embodiment, 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

In one embodiment of the compound of formula I, G is -O-.

In one embodiment of the compound of formula I, G is -NR ¹⁰ -, where -NR ¹⁰ -is as defined above for the embodiment where L is -NR ¹⁰ -, preferably G is -NH-.

In the most preferred embodiment of the compound of formula I, G is -O-.

优选B环选自

最优选

该该实施方式中，B任选被0、1或2个R ^a取代，R ^a优选为H或C _1-6烷基，具体的示例包括但不限于H、甲基或乙基，最优选为H。 In an embodiment of the compound of formula I, 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. Examples of 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.

In one embodiment of the compound of formula I, W is selected from -C(O)-CR ¹ =C(R ² ) ₂ , -C(O)-C≡CR ² , -C(O)-C≡N , -S(O) _1-2 -CR ¹ =C(R ² ) ₂ , -S(O) _1-2 -C≡CR ² , -S(O) _1-2 -C≡N, where R ¹ And R ² are each independently selected from H, halogen, CN, NO ₂ and _{C 1-6} alkyl optionally substituted with ^{-OR 10} , -SR ¹⁰ , -N(R ¹⁰ ) _{2 or halogen.} Preferably W is selected from -C(O)-CR ¹ =C(R ² ) ₂ , -C(O)-C≡CR ² , -C(O)-C≡N, -S(O) ₂ -CR ¹ =C(R ² ) ₂ , more preferably -C(O)-CR ¹ =C(R ² ) ₂ , wherein R ¹ and R ² are each independently selected from H, halogen, preferably F, and optionally by -OR ¹⁰ , -N(R ¹⁰ ) ₂ or halogen, preferably C _1-6 alkyl substituted with F, preferably R ¹ and R ² are each independently selected from H, halogen, preferably F and optionally by -N(R ¹⁰ ) ₂ or halogen, preferably F-substituted C _1-6 alkyl, wherein R ¹⁰ is preferably H or C _1-6 alkyl optionally substituted by F.

In this embodiment, specific examples of W include but are not limited to -C(O)-CH=CH ₂ , -C(O)-CH=CHF, -C(O)-CF=CHF, -C(O) -CF=CH ₂ , -C(O)-CH=CH(CH ₃ ), -C(O)-CH=CH(CF ₃ ), -C(O)-C(CF ₃ )=CH(CF ₃ ), -C(O)-C(CH ₃ )=CH(CH ₂ -CH ₃ ), -C(O)-C(CH ₃ )=C(CH ₂ -CH ₂ -CH ₃ ), -C( O)-C(CF ₃ )=CH(CH ₂ -CH ₃ ), -C(O)-CH=CH(CH ₂ -CH ₂ -CH ₃ ), -C(O)-C(CH ₂ -CH ₃ )=CH ₂ , -C(O)-C(CH ₂ -CF ₃ )=CH ₂ , -C(O)-C(CH ₂ -CH ₂ -CH ₃ )=CH ₂ , -C(O) -C(CH ₂ -CH ₃ )=CH(CH ₂ -CH ₃ ), -C(O)-C(CH ₂ -CH ₃ )=CH(CH ₂ -CF ₃ ), -C(O)-CH =CH(CH ₂ -NH ₂ ), -C(O)-CH=CH(CH ₂ -N(CH ₃ ) ₂ ), -C(O)-CH=CH(CH ₂ -NH(CH ₃ )) , -C(O)-C(CH ₂ -NH(CH ₃ ))=CH(CH ₂ -CH ₃ ), -C(O)-CH=CH(CH ₂ -CH ₂ -N(CH ₃ ) ₂ ), -C(O)-CH=CH(CH ₂ -OH), -C(O)-CH=CH(CH ₂ -OCH ₃ ), -C(O)-CH=CH(CH ₂ -OCF ₃ ), -C(O)-CH=CH(CH ₂ -SH), -C(O)-CH=CH(CH ₂ -SCH ₃ ), -C(O)-C≡CF, -C(O) -C≡C-CH ₃ , -C(O)-C≡C-CF ₃ , -C(O)-C≡CC(CH ₂ -N(CH ₃ ) ₂ ), -C(O)-C≡ N, -S(O) ₂ -CH=CH ₂ , -S(O) ₂ -CF=CH ₂ , -S(O) ₂ -CH=CH(CH ₂ -CH ₃ ), -S(O) ₂ -CH=CH(CF ₃ ), -S(O) ₂ -C(CH ₃ )=CH(CH ₂ -CF ₃ ), etc.

优选5-6元含氮杂环，其中当W籍由其中的R ¹与B环形成稠合的含氮杂环 时，＝(R ²) ₂即成为该含氮杂环上携带的取代基，例如

当W籍由其中的R ²与B环形成稠合的含氮杂环时，R ¹和/或R ²即成为该含氮杂环上携带的取代基，例如

此外应当理解，该含氮杂环还可能携带R ¹和R ²各自本身所携带的一个或多个上述取代基R’，选自-OR ¹⁰、-SR ¹⁰、-N(R ¹⁰) ₂或卤素，或(R ¹或R ²为带有支链的C _1-6烷基时)被-OR ¹⁰、-SR ¹⁰、-N(R ¹⁰) ₂、卤素取代的C _1-6烷基。 In one embodiment of the compound of formula I, W is selected from -C(O)-CR ¹ =C(R ² ) ₂ , -C(O)-C≡CR ² -S(O) _1-2 -CR ¹ = C(R ² ) ₂ or -S(O) _1-2 -C≡CR ² , wherein R ¹ and R ² are each independently selected from H, halogen, CN, NO ₂ and optionally -OR ¹⁰ , -SR ¹⁰ , -N(R ¹⁰ ) ₂ or halogen-substituted C _1-6 alkyl, and W is composed of R ¹ or R ² and the N connected to W in the ring B and the adjacent ring atom of the N Together to form a 5-7 membered nitrogen-containing heterocyclic ring fused with ring B, for example

Preferably a 5-6 membered nitrogen-containing heterocyclic ring, wherein when W forms a fused nitrogen-containing heterocyclic ring ^{from R 1 and B ring therein, =(R 2} ) ₂ becomes the substituent carried on the nitrogen-containing heterocyclic ring ,E.g

When W forms a condensed nitrogen-containing heterocyclic ring ^{from R 2 and ring B, R 1} and/or R ² become the substituents carried on the nitrogen-containing heterocyclic ring, for example

In addition, it should be understood that the nitrogen-containing heterocyclic ring may also carry one or more of the above-mentioned substituents R′ carried by each of ^{R 1} and R ^{2 , selected from -OR 10} , -SR ¹⁰ , -N(R ¹⁰ ) ₂ or halo, or (R ¹ or R ² is a branched C _1-6 alkyl) is ^{-OR 10, -SR 10, -N (} R 10) 2, halo-substituted C _1-6 alkyl.

其中R ¹和R ²各自独立地选自H、卤素、CN、NO ₂和任选被-OR ¹⁰、-SR ¹⁰、-N(R ¹⁰) ₂或卤素取代的C _1-6烷基，其中R’为任选存在的R ¹或R ²本身可能携带的取代基，包括H、-OR ¹⁰、-SR ¹⁰、-N(R ¹⁰) ₂、卤素或(R ¹或R ²为带有支链的C _1-6烷基时)被-OR ¹⁰、-SR ¹⁰、-N(R ¹⁰) ₂、卤素取代的C _1-6烷基。上述优选稠合环结构W上携带的R ¹、R ²或R’的实例包括但不限于H、F、Cl、甲基、乙基、三氟甲基、二甲氨基甲基、二甲氨基乙基、氨基甲基、氨基乙基、羟基甲基、羟基乙基、甲氧基甲基等，最优选R ¹、R ²或R’均为H。 In this embodiment, specific and preferred examples of W include but are not limited to

Wherein 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. ^{Examples of 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.

In one embodiment of the compound of formula I, most preferably W is -C(O)-CR ¹ =C(R ² ) ₂ , wherein R ¹ and R ² are each independently selected from H, F, methyl and di Methylaminomethyl, most preferably R ¹ and R ² are both H.

In one embodiment of the compound of formula I, 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 membered heterocyclic group and the 5-12 membered heteroaryl group are optionally further substituted with halogen, -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ , N(R ¹⁰ ) ₂ -.

各自任选被一个或多个选自以下的取代基R ⁶和/或R ⁷取代：-OH、-NH ₂、-NHC _1-6烷基、-N(C _1-6烷基) ₂、-OC _1-6烷基、卤素、C _1-6烷基或C _3-6环烷基，其中的C _1-6烷基或C _3-6环烷基任选进一步被卤素、任选被卤素取代的C _1-6烷基、-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代；R ⁶或R ⁷的示例包括但不限于羟基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、2-甲基丙氧基、甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、三氟甲基、三氟乙基、环丙基、环丁基、一个或多个氟取代的环丙基或环丁基、三氟甲基取代的环丙基或环丁基、氨基甲基、氨基乙基、甲基氨基甲基、甲基氨基乙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基等。 In this embodiment, preferably 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 not limited to, hydroxyl, methoxy Group, ethoxy, propoxy, isopropoxy, butoxy, 2-methylpropoxy, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl , Trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, one or more fluorine-substituted cyclopropyl or cyclobutyl, trifluoromethyl-substituted cyclopropyl or cyclobutyl, aminomethyl Group, aminoethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2- (Dimethylamino)ethyl and the like.

优选

In this embodiment, more preferably 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

其中R ⁶和R ⁷各自独立地选自H、C _1-3烷基或C _3-6环烷基，其中的C _1-3烷基或C _3-6环烷基任选进一步被卤素、任选被卤素取代的C _1-6烷基、-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代，具体的示例包括但不限于甲基、三氟甲基、乙基、异丙基、环丙基、三氟甲基环丙基、氨基甲基、氨基乙基、甲基氨基甲基、甲基氨基乙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基等；更进一步优选R ³选自

其中R ⁶和R ⁷各自独立地选自H、甲基、乙基、异丙基、环丙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基。 In this embodiment, most preferably 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. Specific examples include but are not limited to

Wherein 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, methyl, ethyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl Group, 1-methyl-2-(dimethylamino)ethyl.

在另一个优选示例中，R ³为

在另一个优选示例中，R ³为

其中R ⁶为C _1-3烷基或C _3-6环烷基，任选进一步被-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代，例 如但不限于甲基、乙基、丙基、异丙基、环丙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基。 In a preferred example of this embodiment, 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.

In one embodiment of the compound of formula I, 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(O) _1-2 -R ¹⁰ , where C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group and 5- The 12-membered heteroaryl group is optionally further substituted with halogen, -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ , N(R ¹⁰ ) ₂ , wherein ^{each occurrence of R 10} is as defined above for the compound of formula I, or is connected ^{Two R 10} on the same C together with the carbon atom to which they are attached form _{a C 3-8} cycloalkyl group optionally substituted with ^{one or more R 10 or halogen.}

其中的C _1-6烷基和5-6元杂芳基任选进一步被氟、氯、三氟甲基、甲基、乙基、异丙基或-NH ₂取代。具体的实例包括但不限于

其中的取代基R ¹¹、R ¹²和R ¹³各自独立地选自H、卤素(优选氟或氯)、CN、任选被卤素(优选氟或氯)取代的C _1-6烷基、OH、-NH ₂、任选被卤素(优选氟或氯)取代的C _1-6烷氧基或任选被卤素(优选氟或氯)取代的C _3-6环烷基；优选地，R ¹¹选自CN、卤素(优选氟或氯)或C _1-6烷基，R ¹²选自H、NH ₂或卤素(优选氟或氯)，R ¹³选自卤素、OH或NH ₂。具体的示例有

In this embodiment, 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. Preferably 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, tetrazole, pyridine , Pyridazine, pyrimidine, pyrazine, -C(O)-NH ₂ ,

The C _1-6 alkyl group and 5-6 membered heteroaryl group may be further substituted with fluorine, chlorine, trifluoromethyl, methyl, ethyl, isopropyl or -NH ₂ . Specific examples include but are not limited to

The substituents 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

其中R ¹¹选自卤素(优选氟或氯)或CN，R ¹²选自H、卤素(优选氟或氯)或-NH ₂，R ¹³选自卤素、OH或NH ₂。 In this embodiment, 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 .

In an embodiment of the compound of formula I, 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 , Benzimidazole, indazole, benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3 ,2-b]pyridine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c ]Pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[3,4-b]pyridine, isoindole, purine, indolizine, imidazo[1,2-a]pyridine, imidazo [1,5-a]pyridine, pyrazolo[1,5-a]pyridazine, pyrrolo[1,2-b]pyrimidine, imidazo[1,2-c]pyrimidine, 5H-pyrrolo[3 ,2-b]pyrazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3,4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, Quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 1,5-naphthyridine, 2 ,6-naphthyridine, 2,7-naphthyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2 ,3-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrimido[5,4-d]pyrimidine, pyrazino[2,3- b] pyrazine and pyrimido[4,5-d]pyrimidine, each of which is 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 ring Alkyl, 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 ¹⁰ , where C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered hetero The aryl group is optionally further substituted with halogen, -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ , N(R ¹⁰ ) ₂ , wherein ^{each occurrence of R 10} is as defined above for the compound of formula I, or is connected to the same The two R ¹⁰ on C together with the carbon atom to which they are attached form a C _3-6 ^{cycloalkyl group optionally substituted by one or more R 10} or halogen; preferably substituted by one or more substituents selected from : -OH, -NH ₂ , -OC _1-6 alkyl, -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , halogen, CN, oxo or C _1-6 alkyl.

其中的取代基R ¹¹、R ¹²和R ¹³各自独立地选自卤素(优选氟或氯)、任选被卤素(优选氟或氯)取代的C _1-6烷基、OH、-NH ₂、任选被卤素(优选氟或氯)取代的C _1-6烷氧基或任选被卤素(优选氟或氯)取代的C _3-6环烷基，优选各自独立地选自卤素(优选氟或氯)或任选被卤素(优选氟或氯)取代的C _1-6烷基。具体的取代基示例包括但不限于：氟、氯、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、氟甲基、二氟甲基、三氟甲基，以及被一个或多个氟或氯取代的乙基、丙基或丁基，以及环丙基、环丁基、环戊基，以及被一个或多个氟或氯取代的环丙基、环丁基、环戊基。R ⁴的具体示例有：

In this embodiment, 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). Examples of specific 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. Specific examples of R ^{4 are:}

其中R ¹¹选自卤素(优选氟或氯)或CN，R ¹²选自H、卤素(优选氟或氯)或-NH ₂，R ¹³选自卤素、OH或NH ₂，具体的示例如上文对R ⁴所示；或者R ⁴更优选为

其中的取代基R ¹¹或R ¹²各自独立地选自卤素(优选氟或氯)或任选被卤素(优选氟或氯)取代的C _1-6烷基，具体的取代基示例包括但不限于：氟、氯、甲基、乙基、丙基、异丙基、氟甲基、二氟甲基、三氟甲基，以及被一个或多个氟或氯取代的乙基、丙基或丁基；具体的R ⁴示例包括

最优选R ⁴选自

Preferably, 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} 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). Examples of specific 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基; specific examples ^{of R 4 include}

Most preferably R ^{4 is} selected from

In the embodiment of a compound of formula I, R ⁵ is selected from H. In another embodiment of the compounds of Formula I, R ⁵ is halogen, particularly fluoro, chloro, bromo, iodo, preferably F or Cl, most preferably Cl. In another embodiment of the compound of Formula I, R ⁵ is nitro or cyano. In another embodiment of the compound of formula I, 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. . In another embodiment of the compound of formula I, 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.

In this embodiment, R ^{5 is} most preferably H, chlorine, fluorine, methyl or cyclopropyl.

Preferably, 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,

in,

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;

为单键或双键；

Single bond or double bond;

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;

Each occurrence of R ¹⁰ is independently selected from H or C _1-6 alkyl optionally substituted by halogen;

各自任选被一个或多个选自以下的取代基R ⁶和/或R ⁷取代：-OH、-NH ₂、-NHC _1-6烷基、-N(C _1-6烷基) ₂、-OC _1-6烷基、卤素、C _1-6烷基或C _3-6环烷基，其中的C _1-6烷基或C _3-6环烷基任选进一步被卤素、任选被卤素取代的C _1-6烷基、-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代； 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;

其中的取代基R ¹¹、R ¹²和R ¹³各自独立地选自H、卤素、任选被卤素取代的C _1-6烷基、OH、-NH ₂、任选被卤素取代的C _1-6烷氧基或任选被卤素取代的C _3-6环烷基； 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;

m is 0 or 1;

n is selected from an integer from 0 to 3;

requirement is:

表示双键； When m=1, X is selected from C or N, and

Represents a double bond;

When A is N and m=1, at least one of X and Y is not C.

In a specific embodiment of the compound of formula I-1, A is C-CN.

In a specific embodiment of the compound of formula I-1, A is N.

表示双键。 In one embodiment, when m=1, X, Y, and Z are each independently selected from C or N, and

Represents a double bond.

In a specific embodiment of the compound of formula I-1, wherein the fused bicyclic moiety containing X, Y, Z and A is selected from

其中包含X、Y和Z的六元环任选被0、1、2或3个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。

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.

其中的五元环任选被0、1或2个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In a specific embodiment of the compound of formula I-1, wherein the fused bicyclic moiety containing X, Y, Z and A is selected from

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.

最优选

其中包含X、Y和Z的环任选被0、1、2或3个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In a specific embodiment of the compound of formula I-1, 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.

In a specific embodiment of the compound of formula I-1, ring B is

In a specific embodiment of the compound of formula I-1, L is -O-.

In a specific embodiment of the compound of formula I-1, L is a directly connected bond.

In a specific embodiment of the compound of formula I-1, G is -O-.

In a specific embodiment of the compound of formula I-1, G is -NH-.

其中R ⁶和R ⁷各自独立地选自H、C _1-3烷基或C _3-6环烷基，各自任选被卤素、任选被卤素取代的C _1-6烷基、-NH ₂、-NHC _1-6烷基、-N(C _1-6烷基) ₂取代；优选各自独立地选自H、甲基、三氟甲基、乙基、丙基、异丙基、环丙基、三氟甲基环丙基、氨基甲基、甲基氨基甲基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基。 In a specific embodiment of the compound of formula I-1, 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.

其中R ⁶和R ⁷各自独立地选自H、甲基、乙基、异丙基或环丙基。 In a specific embodiment of the compound of formula I-1, R ^{3 is} selected from

Wherein R ⁶ and R ⁷ are each independently selected from H, methyl, ethyl, isopropyl or cyclopropyl.

在另一个优选实施方式中，R ³为

在另一个优选实施方式中，R ³为

其中R ⁶为C _1-3烷基或C _3-6环烷基，任选进一步被-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代，例如但不限于甲基、乙基、丙基、异丙基、环丙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基。 In a preferred embodiment of the compound of formula I-1, 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.

In a specific embodiment of the compound of formula I-1, R ^{3 is} selected from

In a specific embodiment of the compound of formula I-1, R ^{4 is} selected from

最优选R ⁴选自

Most preferably 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,

Wherein each group is as defined above for the general, specific or preferred embodiment of the compound of formula I-1.

In this regard, 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,

in:

A is C-CN or N;

X, Y and Z are each independently selected from C, N, O or S;

为单键或双键；

Single bond or double bond;

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;

W is selected from -C(O)-CR ¹ =C(R ² ) ₂ , -C(O)-C≡CR ² , -C(O)-C≡N, -S(O) _1-2 -CR ¹ = C(R ² ) ₂ , -S(O) _1-2 -C≡CR ² , -S(O) _1-2 -C≡N; or W is composed of R ¹ or R ² and ring B The N connected by W and the adjacent ring atoms of the N together form a nitrogen-containing heterocyclic ring fused with the B ring;

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 , -OR ¹⁰ , -SR ¹⁰ or N(R ¹⁰ ) ₂ -substituted;

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 ¹⁰ , where C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl are optionally further halogenated , -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ , N(R ¹⁰ ) ₂ substitution, where R ¹⁰ is as defined above each time it appears, or two R ¹⁰ connected to the same C and their connected The carbon atoms together form _{a C 3-8} cycloalkyl group optionally substituted with ^{one or more R 10 or halogen;}

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;

Each occurrence of R ¹⁰ is independently selected from H or C _1-6 alkyl optionally substituted by halogen;

m is 0 or 1;

n is selected from an integer from 0 to 3;

requirement is:

表示双键；和 When m=1, X, Y, and Z are each independently selected from C or N, and

Represents a double bond; and

When A is N and m=1, at least one of X and Y is not C.

In a most preferred embodiment of the compound of formula II, G is O.

其中包含X、Y和Z的六元环任选被0、1、2或3个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula II, A is C-CN. In a further embodiment, m=1, X is C and Y and Z are each independently selected from C or N, or m=1, X is N, and Y and Z are each independently selected from C or N. In a specific embodiment, 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.

其中的五元环任选被0、1或2个R ⁵取代，优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula II, A is C-CN. In a further embodiment, m=0, X is C and Z is selected from C or N; or m=0, X is N and Z is selected from C or N, or m=0, X is O and Z is selected from C or N, or m=0, X is S and Z is selected from C or N. In a specific embodiment, 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.

各自任选被0、1或2个R ⁵取代、优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula II, A is N. In a further embodiment, m=1, X is C, Y is N, and Z is selected from C or N; or m=1, X is N, and Y and Z are each independently selected from C or N. In a specific embodiment, 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.

其中的五元环任选被0、1或2个R ⁵取代、优选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In one embodiment of the compound of formula II, A is N. In a further embodiment, m=0, X is C and Z is selected from C or N; or m=0, X is N and Z is selected from C or N; or m=0, X is O and Z is selected from C or N, or m=0, X is S and Z is selected from C or N. In a specific embodiment, 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.

更优选

其中包含X、Y和Z的环任选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In a preferred embodiment of the compound of formula II, 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.

任选被1-2个R ^a取代，R ^a优选为C _1-6烷基，最优选为CH ₃。 In any embodiment of the above formula II compound, 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. Examples of 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.

In any embodiment of the compound of formula II above, W has the specific embodiments, preferred embodiments and examples thereof for W given above for the compound of formula I; most preferably W is -C(O)-CR ¹ = C(R ² ) ₂ , wherein R ¹ and R ² are each independently selected from H, F, methyl and dimethylaminomethyl, most preferably R ¹ and R ² are both H.

In any of the above-mentioned embodiments of the compound of formula II, 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-.

In any embodiment of the compound of formula II above, 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-.

In any of the above-mentioned embodiments of the compound of formula II, R ³ has the specific embodiments and preferred embodiments and examples thereof ^{for R 3} given above for the compound of formula I.

其中R ⁶和R ⁷各自独立地选自：-OH、-NH ₂、-NHC _1-6烷基、-N(C _1-6烷基) ₂、-OC _1-6烷基、卤素、C _1-6烷基或C _3-6环烷基，其中的C _1-6烷基或C _3-6环烷基任选进一步被卤素、任选被卤素取代的C _1-6烷基、-OC _1-6烷基、-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代；R ⁶或R ⁷的示例包括但不限于羟基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、2-甲基丙氧基、甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、三氟甲基、三氟乙基、环丙基、环丁基、一个或多个氟取代的环丙基或环丁基、三氟甲基取代的环丙基或环丁基、氨基甲基、氨基乙基、甲基氨基甲基、甲基氨基乙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基等。 Or/further, in any embodiment of the compound of formula II above, 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 and 5-12 membered heteroaryl group are optionally further substituted with halogen, -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ or N(R ¹⁰ ) ₂ -; preferably each is substituted by one or more One substituent selected from the following: -OC _1-6 alkyl, halogen (preferably F), C _1-6 alkyl or C _3-6 cycloalkyl, wherein C _1-6 alkyl or C _{3- The 6-} cycloalkyl group is optionally further substituted with halogen, -NH ₂ , -OC _1-6 alkyl, C _1-6 alkyl, -NHC _1-6 alkyl, or -N(C _1-6 alkyl) ₂ . Specific implementations include but are not limited to

Wherein 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 Methyl, trifluoroethyl, cyclopropyl, cyclobutyl, one or more fluorine-substituted cyclopropyl or cyclobutyl, trifluoromethyl-substituted cyclopropyl or cyclobutyl, aminomethyl, amino Ethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2-(dimethyl (Amino) ethyl and the like.

In this embodiment, specific ^{examples of R 3} include but are not limited to

(例如

)、

(例如

)、

其中R ⁶选自C _1-6烷基或C _3-6环烷基，任选进一步被C _1-6烷基或N(R ¹⁰) ₂取代，R ⁷选自C _1-6烷基或-O-C _1-6烷基；R ⁶或R ⁷的示例包括但不限于甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、2-甲基丙氧基、环丙基、环丁基、氨基甲基、氨基乙基、甲基氨基甲基、甲基氨基乙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基等。具体的示例有

In this embodiment, preferably 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, sec-butyl, tert-butyl, methoxy, ethoxy , Propoxy, isopropoxy, butoxy, 2-methylpropoxy, cyclopropyl, cyclobutyl, aminomethyl, aminoethyl, methylaminomethyl, methylaminoethyl, Dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2-(dimethylamino)ethyl, etc. Specific examples are

在另一个优选示例中，R ³为

在另一个优选示例中，R ³为

其中R ⁶为C _1-6烷基或C _3-6环烷基，任选进一步被-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代，例如甲基、乙基、丙基、异丙基、环丙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基) 乙基、1-甲基-2-(二甲基氨基)乙基。在另一个优选示例中，R ³为

其中R ⁶为C _1-6烷基，任选进一步被-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代，例如甲基、乙基、丙基、异丙基、环丙基、氨基甲基、甲基氨基甲基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基；最优选R ⁶为被-N(C _1-6烷基) ₂取代的C _1-3烷基。 In a preferred example of this embodiment, 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. In another preferred example, 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.

In any of the above-mentioned embodiments of the compound of formula II, R ⁴ has the specific embodiments and preferred embodiments and examples thereof ^{for R 4} given above for the compound of formula I. Preferably, 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.

In any of the above-mentioned embodiments of the compound of formula II, R ⁵ has the specific embodiments and preferred embodiments and examples thereof ^{for R 5} given above for the compound of formula I.

Preferably, the compound of formula II mentioned above is the compound of formula II-1, its isomers, or their pharmaceutically acceptable salts or solvates,

in:

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;

为单键或双键；

Single bond or double bond;

Ring B is

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-;

Each occurrence of 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;

m is 0 or 1;

n is selected from an integer from 0 to 3;

requirement is:

表示双键；和 When m=1, X is selected from C or N, and

Represents a double bond; and

When A is N and m=1, at least one of X and Y is not C.

In one embodiment of the compound of formula II-1, A is C-CN. In another embodiment of the compound of formula II-1, A is N.

更优选

其中包含X、Y和Z的环任选被0或1个R ⁵取代，R ⁵选自卤素，优选F或Cl。 In the embodiment of the compound of formula II-1 above, wherein the fused bicyclic structure moiety 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.

其中R ⁶选自C _1-6烷基或C _3-6环烷基，任选进一步被C _1-6烷基或N(R ¹⁰) ₂取代，R ⁷选自C _1-6烷基，R ⁶或R ⁷的示例包括但不限于甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、环丙基、环丁基、氨基甲基、氨基乙基、甲基氨基甲基、甲基氨基乙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基等。最优选地，在一种具体的实施方式中，R ³为

在另一种具体的实施方式中，R ³为

在另一种具体的实施方式中，R ³为

其中R ⁶为C _1-6烷基或C _3-6环烷基，任选进一步被-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代，例如甲基、乙基、丙基、异丙基、环丙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基。在另一种具体的实施方式中，R ³为

其中R ⁶为C _1-6烷基，任选进一步被-NH ₂、-NHC _1-6烷基或-N(C _1-6烷基) ₂取代，例如甲基、乙基、丙基、异丙基、环丙基、二甲基氨基甲基、二甲基氨基乙基、1-(二甲基氨基)乙基、1-甲基-2-(二甲基氨基)乙基。进一步最优选R ⁶为被-N(C _1-6烷基) ₂取代的C _1-3烷基。 In any embodiment of the compound of formula II-1 ^{above, R 3 is} selected from the definition given ^{above for the corresponding R 3 of} each embodiment of the compound of formula II. Preferably, 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 to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, aminomethyl, aminoethyl , Methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino)ethyl, 1-methyl-2-(dimethylamino) ) Ethyl and so on. Most preferably, in a 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. In another specific embodiment, 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.

其中R ¹¹、R ¹²和R ¹³各自独立地选自卤素(优选氟或氯)、CN、任选被卤素(优选氟或氯)取代的C _1-6烷基、OH、-NH ₂或任选被卤素(优选氟或氯)取代的C _1-6烷氧基；优选地，其中R ¹¹选自卤素(优选氟或氯)或CN，R ¹²选自H或卤素(优选氟或氯)或-NH ₂，R ¹³选自卤素、OH或NH ₂；或者R ⁴选自

其中R ¹¹或R ¹²各自独立地选自卤素(优选氟或氯)或任选被卤素(优选氟或氯)取代的C _1-6烷基，具体的示例包括但不限于：氟、氯、甲基、乙基、丙基、异丙基、氟甲基、二氟甲基、三氟甲基，以及被一个或多个氟或氯取代的乙基、丙基或丁基，具体的优选R ⁴示例包括

最优选R ⁴选自

In any of the above embodiments of the compound of formula II-1, R ^{4 is} selected from the definitions given ^{above for the corresponding R 4 of} each embodiment of the compound of formula II. Preferably, 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. More preferably, 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). Specific examples 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, specifically preferred R ⁴ examples include

Most preferably R ^{4 is} selected from

In any embodiment of the compound of formula II-1 above, n is 0; or n is 1, and R ^{5 is} selected from F or Cl.

In any embodiment of the compound of formula II-1 above, G is O.

It should be noted that the compound of formula I and the compound of formula II of the present invention cover each of the above independent specific embodiments, any combination or sub-combination of each of the above specific embodiments, and any of the above preferred, more preferred or The most preferred embodiment is constituted by any combination of the definitions.

It is particularly considered that, unless otherwise specified, any limitations discussed regarding one embodiment of the present invention can be applied to any other embodiment of the present invention.

The above-mentioned specific embodiments of the compounds of the present invention include, but are not limited to, the compounds of Synthesis Examples A1-145 and Example B1-8, their isomers, or their pharmaceutically acceptable salts or solvates:

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. As shown in the Activity Examples section below, 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 μM For example, 0.1 nM to 5 μM, 0.1 nM to 1 μM, 1 nM to 5 μM, 1 nM to 1 μM, 1 nM to 0.5 μM, preferably in the range of 0.1 nM to 0.5 μM or 1 nM to 0.5 μM. Therefore, 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, Or 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.

In addition to showing Ras mutation, preferably KRas, and most preferably KRas G12C mutation inhibitory activity, 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.

Based on the above, the present invention also provides the following technical solutions in various aspects.

In one aspect, 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.

In another aspect, 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.

Pharmaceutical composition and its administration

In another aspect, 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.

The above-mentioned pharmaceutical 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. Generally, for example, 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. kg body weight, taken in single or divided doses. For a 70 kg human subject, 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.

The 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.

The 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, 2004.

Treatment methods and uses

As described above, 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.

Therefore, in another aspect, 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.

Based on the same properties, 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.

In another aspect, 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.

In another aspect, 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. Use of the pharmaceutical composition of the drug for inhibiting KRas mutations in cells, especially KRas G12C, or for inhibiting abnormal cell growth in mammals, or for treating and/or preventing diseases mediated by Ras mutations, preferably KRas mutations .

In another aspect, 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.

For the various methods and use technical solutions provided by the present invention, the abnormal cell growth or diseases mediated by Ras mutations, preferably KRas mutations, especially refer to cancer or tumors. Preferably, 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, kidney cells Carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal tumor, brainstem glioma, or pituitary adenoma.

For the various methods and use technical solutions provided by the present invention, the abnormal cell growth or diseases mediated by Ras mutations, preferably KRas mutations, more preferably KRas-G12C, are particularly preferably lung cancer, colon cancer, pancreatic cancer and ovarian cancer. cancer.

Therefore, in a preferred embodiment of this aspect, 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. In a further preferred embodiment, 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.

Drug combination

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.

Therefore, in another aspect, 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.

In a specific embodiment, 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. 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. When administered separately, they may be administered simultaneously or Carried out one after the other, the sequential administration may be close or distant in time. They can be made and/or formulated by the same or different manufacturers. Moreover, 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.

Therefore, in another aspect, 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.

Regarding the above-mentioned technical solutions of the pharmaceutical composition, drug combination or kit of the present invention, 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.

For the above-mentioned compounds of the present invention, pharmaceutical compositions, methods, uses, pharmaceutical combinations and kits, the above-mentioned compounds of the present invention, isomers thereof, or their pharmaceutically acceptable salts or solvates are preferred, and more preferred The compounds defined in the specific embodiments of Formula II-1 and the specific compounds listed above; most preferably the "most preferred compounds of the present invention" listed above, their isomers or their pharmaceutically acceptable salts or Solvate.

When 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.

Preparation method of the compound of the present invention

On the other hand, the present invention also provides a method for preparing the compound defined in the present invention.

The compounds of the present invention, their isomers, or their pharmaceutically acceptable salts or solvates 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.

For each reaction step of each general synthesis scheme, appropriate 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). And can dissolve the reagents used in the solvent or diluent), in the absence or presence of catalysts, condensing agents or neutralizing agents (for example, ion exchangers, such as cation exchangers, such as H ⁺ form), according to the reaction And/or 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.

Depending on the reactivity of the compound used, 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.

Unless otherwise stated in the description of the method, 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 anhydrides, such as acetic anhydride; cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isoamyl Alkane; or a mixture of these solvents, such as an aqueous solution. Such solvent mixtures can also be used for post-treatment, such as post-treatment by chromatography or partitioning.

If necessary, 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.

Those skilled in the art can recognize whether there are stereocenters in the compounds of the present invention. At all stages of the reaction, 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.

In some specific cases, 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. As an example only, if 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.

Synthesis Scheme I:

Wherein 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.

In 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. Then according to step B, the obtained nitro compound is reduced to obtain the amino compound 3. The latter 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. Compound 6 and fragment Y with different protective groups are substituted to obtain compound 7, and the latter is introduced through nucleophilic substitution or catalytic coupling reaction, wherein X is selected from -O-, -S-, -S(O) _1- The R ³ _{-X group of 2} -, -NR ¹⁰ -or -CR ⁸ R ⁹ -, to give compound 8. Compound 8 is deprotected (such as Boc, etc.) to obtain compound 9. Compound 9 undergoes an acylation reaction with acid chloride or carboxylic acid to obtain the compound represented by general formula I, which corresponds to a subset of the compounds of the present invention in which A is C-CN.

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.

Synthesis Scheme II:

Compounds of general formula II can be synthesized according to the following general methods.

Wherein 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.

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.

Synthesis Scheme III:

Compounds of general formula III can be synthesized according to the following general methods.

Wherein 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. In 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. Then, according to the process of 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.

Synthesis Example

In the following, the present invention will be further described in conjunction with the embodiments. It should be noted that the following embodiments are exemplary and should not be regarded as limiting the protection scope of the present invention.

In the description of the embodiments and subsequent specific examples herein, the following abbreviations are used:

AcOH (acetic acid); Ag ₂ O (silver oxide); aq (aqueous solution); BINAP (1,1'-bin-2-naphthol); Boc (tert-butoxycarbonyl); n-BuLi (n-butyl lithium) ); t-BuOK (potassium tert-butoxide); t-BuXphos ((2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) ( 2'-amino-1,1'-biphenyl-2-yl)); CDCl ₃ (deuterochloroform); mCPBA (m-chloroperoxybenzoic acid); CS ₂ (carbon disulfide); Cs ₂ CO ₃ (cesium carbonate ); CuCl (cuprous chloride); CuI (cuprous iodide); DAST (diethylaminosulfur trifluoride); DCM (dichloromethane); DHP (3,4-dihydro-2H-pyran) ); DIEA (N,N-diisopropylethylamine); DMA (N,N-dimethylacetamide); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); DMSO-d ₆ (hexadeuterated dimethyl sulfoxide); DPPA (diphenyl azide phosphate); EA (ethyl acetate); EDTA-K2 (dipotassium ethylenediaminetetraacetic acid); EtOH (ethanol); FCC (Fast Column Chromatography); FeCl ₃ (ferric chloride); g (gram); h (hour); HATU (2-(7-azabenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate); HCl (hydrogen chloride); H ₂ O (water); H ₂ SO ₄ (sulfuric acid); IV (intravenous administration); K ₂ CO ₃ (potassium carbonate); KI (Potassium iodide); KOH (potassium hydroxide); LCMS (liquid mass spectrometry); LC-MS/MS (liquid spectrometry-mass spectrometry-mass spectrometry); LDA (lithium diisopropylamide); LiAlH ₄ (lithium tetrahydroaluminum ); LiCl (lithium chloride); LiOH (lithium hydroxide); MeCN (acetonitrile); MeI (methyl iodide); MeOH (methanol); Methanol-d ₄ (tetradeuterated methanol); mg (mg); MHz( Megahertz); min (minutes); mL (milliliters); mmol (millimoles); MTBE (methyl tert-butyl ether); m/z (mass-to-charge ratio); N ₂ (nitrogen); NaCl (sodium chloride ); NaH (sodium hydride); NaHCO ₃ (sodium bicarbonate); NaNO ₂ (sodium nitrite); NaOH (sodium hydroxide); Na ₂ SO ₃ (sodium sulfite); Na ₂ SO ₄ (sodium sulfate); Na ₂ S ₂ O ₃ (sodium thiosulfate); Na ₂ S ₂ O ₄ (sodium dithionite); NBS (bromosuccinimide); NCCH ₂ CO ₂ H (2-cyanoacetic acid); NCS ( Chlorosuccinimide); NH ₃ (ammonia); NH ₄ Cl (ammonium chloride); NH ₂ NH ₂ (hydrazine); NMI (N-methylimidazole); NMP (N-methylpyrrolidone); NMR( Nuclear magnetic resonance); Pd/C (palladium on carbon); Pd ₂ (dba) ₃ (tris(dibenzylideneacetone) two palladium); Pd(OAc) ₂ (palladium acetate); PE (petroleum ether); PEG (poly Ethylene glycol); PCl ₅ (phosphorus pentachloride); PO (oral administration); POCl ₃ (phosphorus oxychloride); PPTS (pyridine p-toluenesulfonate); i-Pr ₂ NH (diisopropylamine) ;Rt (room temperature); SiO ₂ (silica gel); SnCl ₂ (stannous chloride); TCFH (N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate); TEA/Et ₃ N (Triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid); uL (microliter); uM (micromolar concentration); Xant-Phos( 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)); Zn(CN) ₂ (zinc cyanide); BBr ₃ (boron tribromide); BCl ₃ (trichloro Boron); CDI (N,N'-carbonyldiimidazole); CuIsine (cuprous iodide); Pd(dppf)Cl ₂ (1,1'-bisdiphenylphosphine ferrocene dichloride palladium); Pd(PPh ₃ ) ₄ tetrakis(triphenylphosphine)palladium.

In the following examples, the names and structures of the synthesized target compounds are given. Any deviation between the name and the structure is not intentional, in this case the structure is decisive.

The experimental methods that do not indicate specific conditions in the following examples usually follow the conventional conditions of this type of reaction or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the ratio of the liquid is the volume ratio.

The 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.

In the following examples, the ¹ H-NMR spectrum was ^{recorded with Bruker AVANCE III} (400MHz), and the chemical shifts are relative to the peak of the deuterated solvent (CDCl ₃ : δ = 7.26 ppm; CD ₃ OD: δ = 3.31 ppm; DMSO- d ₆ : δ = 2.50 ppm) means δ (ppm); the mass spectrum is recorded by Aglient 1200 liquid chromatography + Aglient G6100 mass spectrometry LCMS LC/MS.

Synthesis of intermediate a

5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

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. Purified by FCC (SiO ₂ , PE/EA=1/0～4/1), a white solid 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indyl was obtained Azole (54.0 g, yield 77%).

Step B: 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

KOH (41.1 g, 731.8 mmol) was dissolved in H ₂ O (1100 mL), and the resulting solution was added to the solution containing 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl) -1H-indazole (54.0 g, 182.9 mmol), Pd ₂ (dba) ₃ (3.35 g, 3.66 mmol) and t-BuXphos (4.66 g, 11.0 mmol) in dioxane (1100 mL). Under the _{protection of N 2} , the mixture was stirred at 90° C. for 2 h to obtain a dark brown mixture. The completion of the reaction was monitored by LCMS, and the reaction mixture was adjusted to pH=2-3 with 1N HCl aqueous solution. The resulting mixture was extracted with EA (3×1000 mL). The organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. FCC purification (SiO ₂ , PE/EA=10/1～1/1) to obtain yellow solid 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (28.0g, yield 68%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.79-9.59 (m, 1H), 8.24-8.05 (m, 1H), 7.16-7.07 (m, 1H), 7.07-6.96 (m, 1H), 5.75 -5.64(m,1H),3.93-3.81 (m,1H),3.76-3.62(m,1H),2.44-2.31(m,1H),2.07-1.96(m,1H),1.96-1.86(m, 1H),1.81-1.65(m,1H),1.63-1.49(m,2H).LCMS(m/z):232.9(M+H).

Synthesis of intermediate b

(S)-(4,4-Difluoro-1-methylpyrrolidin-2-yl)methanol

Step A: 1-tert-Butyl-2-methyl-(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate

At 0°C, a solution of DAST (2.96g, 18.4mmol) in DCM (50mL) was added dropwise to 1-tert-butyl-2-methyl-(S)-4-oxopyrrolidine-1,2-dicarboxylate The acid ester (3.0 g, 12.33 mmol) in DCM (150 mL). Stir at room temperature overnight to obtain a yellow solution. The completion of the reaction was monitored by TLC, and the reaction mixture was slowly poured into a saturated aqueous NaHCO ₃ solution (100 mL) at 0° C., and then extracted with DCM (2×100 mL). ₂ SO ₄ dried organic phase with Na, filtered, and concentrated under reduced pressure. Purified by FCC (SiO ₂ , PE/EA=1/0～0/1) to obtain colorless liquid 1-tert-butyl-2-methyl-(S)-4,4-difluoropyrrolidine-1,2 -Dicarboxylic acid ester (1.8 g, yield 55.0%).

Step B: (S)-(4,4-Difluoro-1-methylpyrrolidin-2-yl)methanol

At 0°C, _{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. The resulting mixture was stirred at room temperature for 0.5 h, then filtered, and the filtrate was concentrated under reduced pressure. Purified by FCC (SiO ₂ , PE/EA = 1/0～0/1) to obtain colorless liquid (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (340mg , Yield 45.9%). ¹ H NMR (400MHz, CDCl ₃ ) δ 3.80–3.71(m,1H), 3.49–3.36(m,2H), 2.80–2.65(m,2H), 2.52–2.23(m,6H). ¹⁹ F NMR (376MHz, CDCl ₃ )δ-92.56(d,J=229.6Hz), -96.40(d,J=229.9Hz).

Synthesis of intermediate c

(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol

According to the synthesis method of intermediate b, use 1-tert-butyl-2-methyl-(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate instead of 1-tert-butyl in step A 2-methyl-(S)-4-oxopyrrolidine-1,2-dicarboxylate to give intermediate c(2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl ) Methanol. ¹ H NMR(400MHz, CDCl ₃ )δ5.19–4.96(m,1H), 3.77–3.66(m,1H), 3.47(dd,J＝11.1,2.1Hz,1H), 3.39–3.27(m,1H) ), 2.52–2.03(m,8H). ¹⁹ F NMR(376MHz, CDCl ₃ )δ-168.61.

Synthesis of intermediate d

(2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol

Step A: 1-tert-Butyl-2-methyl-(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylic acid

To 1-tert-butyl-2-methyl-(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid (3.0g, 12.23mmol) and Ag ₂ O (8.5g, 36.69mmol) MeI (18.06 g, 127.2 mmol) was added to the MeCN (50 mL) solution. The mixture was stirred at 25°C for 3 days to obtain a dark brown solution. The completion of the reaction was monitored by TLC, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Purified by FCC (SiO ₂ , PE/EA=1/0～0/1) to obtain colorless oily 1-(tert-butyl)2-methyl(2S,4R)-4-methoxypyrrolidine-1 ,2-Dicarboxylic acid (1.97g, yield 62.1%).

Step B: (2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol

Use step B in the synthesis method of intermediate b to obtain (2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol ¹ H NMR (400MHz, CDCl ₃ ) δ3.92-3.82( m, 1H), 3.68 (dd, J = 11.1, 3.3 Hz, 1H), 3.44–3.37 (m, 2H), 3.30 (s, 3H), 2.69–2.59 (m, 1H), 2.56–2.42 (m, 1H), 2.39-2.31(m, 4H), 2.13-1.99(m, 1H), 1.90-1.80(m, 1H).

Synthesis of intermediate e

5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

Step A: 3-Bromo-5-fluoro-2-methylaniline

At 20°C, to a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (10.0g, 42.7mmol) in MeOH (100mL), SnCl ₂ -2H ₂ O (33.8 g, 149.6 mmol). The mixture was then stirred at 70°C for 8 h to obtain a yellow suspension. LCMS showed that the reaction was complete. The reaction mixture was concentrated, and the residue was separated between 10% aqueous NaOH (200 mL) and EA (200 mL). The mixture was stirred at room temperature for 10 min, the layers were separated, and the aqueous phase was extracted with EA (2x200ml). The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to obtain the compound yellow liquid 3-bromo-5-fluoro-2-methylaniline (9.00 g, crude product), which was used directly in the next step.

Step B: 3-bromo-4-chloro-5-fluoro-2-methylaniline

To a solution of 3-bromo-5-fluoro-2-methylaniline (8.00 g, 39.2 mmol) in DMF (80 mL) was added NCS (6.28 g, 47.1 mmol). The resulting mixture was stirred at 20°C for 60 h. The completion of the reaction was monitored by LCMS, and H ₂ O (150 mL) was added to the reaction mixture. The mixture was extracted with EA (3x100 mL). The organic phase was dried over anhydrous Na ₂ SO _4, filtered, and concentrated in vacuo. Purified by FCC (SiO ₂ , EA/PE=0-20%), 3-bromo-4-chloro-5-fluoro-2-methylaniline (3.70 g, two-step yield 39.6%) was obtained as a dark brown solid. ¹ H NMR: (400MHz, DMSO-d ₆ )δ6.62(d,J=11.6Hz,1H), 5.66(br s,2H), 2.18(d,J=0.6Hz,3H).

Step C: 4-Bromo-5-chloro-6-fluoro-1H-indazole

To a solution of 3-bromo-4-chloro-5-fluoro-2-methylaniline (2.00 g, 8.39 mmol) in AcOH (20 mL) was added NaNO ₂ (810.1 mg, 11.7 mmol). The mixture was stirred at 20°C for 12 h to obtain a dark brown solution. The completion of the reaction was monitored by LCMS, and the reaction mixture was concentrated in vacuo. The residue was separated between H ₂ O (50 mL) and EA (50 mL), and the aqueous phase was extracted with EA (2×50 mL). The organic phase was dried over anhydrous Na ₂ SO _4, filtered, and concentrated in vacuo. The residue was purified by FCC (SiO ₂ , EA/PE=0-10%) to obtain 4-bromo-5-chloro-6-fluoro-1H-indazole (900.0 mg, yield 43.0%) as a yellow solid. ¹ H NMR: (400MHz, DMSO-d ₆ ) δ 13.82-13.56 (m, 1H), 8.18-7.97 (m, 1H), 7.79-7.60 (m, 1H).

Step D: 4-Bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (500.0 mg, 2.00 mmol) and DHP (219.2 mg, 2.61 mmol) in DCM (5 mL) was added TsOH (34.5 mg, 200.4 umol). The mixture was stirred at 20°C for 12 h to obtain a light brown solution. The completion of the reaction was monitored by TLC, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by FCC (SiO ₂ , EA/PE=0～10%) to obtain 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H as a red solid -Indazole (337.0 mg, yield 50.4%). ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.15 (s, 1H), 7.98 (dd, J = 0.8, 9.4 Hz, 1H), 5.90-5.82 (m, 1H), 3.94-3.82 (m, 1H), 3.80-3.71 (m, 1H), 2.44-2.27 (m, 1H), 2.10-1.92 (m, 2H), 1.65-1.64 (m, 1H), 1.80-1.64 (m, 1H), 1.65- 1.53(m,1H).

Step E: 5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

To 4-bromo-5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (11.0g, 33.0mmol _{), Pd 2} (dba) _{3 (603.9mg} , 659.5umol) and t-BuXphos (840.2mg, 1.98mmol) in dioxane (200mL) solution was added KOH (7.40g, 131.9mmol) in water (200mL) solution. Under the _{protection of N 2} , the mixture was stirred at 90° C. for 2 h to obtain a brown mixture. The completion of the reaction was monitored by LCMS, and the reaction solution was adjusted to pH=2-3 with 1N HCl aqueous solution. The resulting mixture was extracted with EA (3x200ml). The obtained organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE=0-30%) to obtain 5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4 as a yellow solid -Alcohol (5.30 g, yield 55.9%). ¹ H NMR: (400MHz, DMSO-d ₆ )δ11.40(s,1H), 8.41-8.14(m,1H), 7.26(d,J=9.4Hz,1H), 5.87-5.63(m,1H) ,3.86(br d,J=12.3Hz,1H),3.79-3.66(m,1H),2.42-2.25(m,1H),2.08-1.99(m,1H),1.97-1.87(m,1H), 1.80-1.63(m,1H),1.63-1.48(m,2H).LCMS(m/z):271.0(M+H).

Synthesis of intermediate f

5,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

Step A: 4-chloro-2,6-difluorobenzaldehyde

At -70°C, n-BuLi (2.5M, 32.3 mL) was added dropwise to a solution of 1-chloro-3,5-difluorobenzene (10.0 g, 67.3 mmol) in THF (100 mL). After stirring for 30 min at -70°C, DMF (9.84 g, 134.6 mmol) was added dropwise. The resulting mixture was continuously stirred at -70°C for 1.5 h. The reaction mixture was poured into saturated _{aqueous NH 4} Cl solution (300 mL), and the mixture was adjusted to pH=3 with 1 N aqueous HCl solution. The mixture was extracted with EA (100 mL), the resulting organic phase was washed with saturated aqueous NaCl (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a yellow solid 4-chloro-2,6-difluorobenzaldehyde (11.0 g, crude product), used directly in the next step. ¹ H NMR: (400MHz, CDCl ₃ ) δ 10.40-10.14 (m, 1H), 7.16-6.92 (m, 2H).

Step B: 6-chloro-4-fluoro-1H-indazole

NH ₂ NH ₂ -H ₂ O (9.55 g, 186.9 mmol) was added to 4-chloro-2,6-difluorobenzaldehyde (11.0 g, 62.3 mmol) in dioxane (120 mL), and the mixture Heat to 100°C and stir for 16h. The reaction mixture was poured into H ₂ O (300 mL) and a yellow precipitate formed. The mixture was filtered, the _{filter cake was washed with H 2} O (100 mL) and dried in vacuum. The solid was dissolved in MTBE (300 mL), and then the mixture was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure to obtain a yellow solid 6-chloro-4-fluoro-1H-indazole (8.50 g, yield 79.9%), which was directly used in the next step. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.56 (br s, 1H), 8.24 (s, 1H), 7.52 (s, 1H), 7.08 (dd, J = 1.4, 9.9 Hz, 1H).

Step C: 6-Chloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Add PPTS (1.53g, 6.10mmol) and DHP (12.6g, 150.1mmol) to a solution of 6-chloro-4-fluoro-1H-indazole (8.00g, 46.9mmol) in THF (150mL) at 15°C. Then the mixture was heated to 60°C and stirred for 16h. LCMS monitored the completion of the reaction, and the mixture was concentrated under reduced pressure. The residue was separated between EA (100 mL) and H ₂ O (30 mL). The organic phase was washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE=0～6.3%) to obtain white solid 6-chloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5.50 g, yield 70.4%). ¹ H NMR: (400MHz, CDCl ₃ )δ8.14-7.98 (m, 1H), 7.51-7.37 (m, 1H), 6.87 (dd, J = 1.4, 9.4 Hz, 1H), 5.68 (dd, J = 2.8, 9.3 Hz, 1H), 4.10-3.98 (m, 1H), 3.77 (ddd, J = 3.0, 10.2, 11.7 Hz, 1H), 2.62-2.41 (m, 1H), 2.23-2.02 (m, 2H) ,1.83-1.67(m,3H).

Step D: 5,6-Dichloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

At -40 to -30°C, 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. Then it was cooled to -70～-65°C, and a solution of 1,1,1,2,2,2-hexachloroethane (11.9g, 50.3mmol) in THF (20mL) was added dropwise thereto for 1h. After the addition was complete, the resulting mixture was stirred at -70～-65°C for 2h. The reaction was quenched with saturated _{aqueous NH 4} Cl (100 mL), and the resulting mixture was extracted with EA (300 mL). The resulting organic phase was washed with saturated aqueous NaCl (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE=0～5%) to obtain 5,6-dichloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole ( 4.00g, yield 44.0%). ¹ H NMR: (400MHz, CDCl ₃ )δ8.08 (d, J = 0.6Hz, 1H), 7.62 (s, 1H), 5.68 (dd, J = 2.7, 8.9 Hz, 1H), 4.08-3.96 (m ,1H),3.82-3.72(m,1H),2.56-2.44(m,1H),2.22-2.07(m,2H),1.84-1.68(m,3H).

Step E: 5,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

At 20°C, 5,6-dichloro-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (15.0g, 51.8mmol), KOH (11.6g, 207.5 mmol) and H ₂ O (3.74 g, 207.5 mmol) were added to DMSO (50.0 mL), and the resulting mixture was stirred at 80° C. for 5 h. The completion of the reaction was monitored by TLC, and the reaction mixture was adjusted to pH=5-6 with 1N HCl aqueous solution. The mixture was _{diluted with H 2} O (50 mL) and extracted with EA (2×150 mL). The organic phase was washed with saturated aqueous NaCl (100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by FCC (SiO ₂ , EA/PE=0 to 5%) to obtain an off-white solid 5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-ol (11.2g, yield 75.2%) ¹ H NMR: (400MHz, CDCl ₃ )δ8.17-7.95 (m, 1H), 7.36 (d, J = 0.7Hz, 1H), 6.50-6.08(m,1H), 5.64(dd,J=2.6,9.2Hz,1H), 4.18-3.93(m,1H), 3.82-3.72(m,1H), 2.58-2.44(m,1H), 2.23-2.05(m,2H),1.84-1.64(m,3H).LCMS(m/z): 287.0(M+H).

Synthesis of intermediate g

5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

Step A: 1-bromo-2-chloro-5-fluoro-3-toluene

2-Bromo-4-fluoro-6-methylaniline (10.0 g, 49.0 mmol) was added to _{a mixture of concentrated HCl (60 mL) and H 2} O (60 mL). The resulting mixture was stirred at 60°C for 1 h and then cooled to 0°C. A solution of NaNO ₂ (4.06 g, 58.8 mmol) in H ₂ O (20 mL) was added, and the mixture was stirred at 0° C. for 15 min. This mixture was then added to a solution of CuCl (7.28 g, 73.5 mmol) in concentrated HCl (100 mL). The resulting mixture was stirred at 70°C for 30 min to obtain a brown mixture. LCMS showed that the reaction was complete. The reaction mixture was cooled to room temperature and extracted with DCM (3x200 mL). The organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 1-bromo-2-chloro-5-fluoro-3-toluene (crude 9.53g, yield 87.0%), which was used directly Next step. ¹ H NMR: (400MHz, CDCl ₃ ) δ 7.22 (dd, J = 3.0, 7.8 Hz, 1H), 6.93 (dd, J = 2.4, 8.6 Hz, 1H), 2.48-2.37 (m, 3H).

Step B: 2-Bromo-3-chloro-6-fluoro-4-methylbenzaldehyde

At -65°C, to a solution of 1-bromo-2-chloro-5-fluoro-3-toluene (9.00 g, 40.3 mmol) in THF (90 mL) was added LDA (2.0M, 20.1 mL). The mixture was stirred at -65°C for 40 min, and then DMF (4.27 g, 58.5 mmol) was added dropwise. The mixture was stirred at -65°C for 1 h to obtain a dark brown solution. The completion of the reaction was monitored by TLC, the reaction mixture was poured into H ₂ O (100 mL) and extracted with EA (3×100 ml). The obtained organic phase was dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by FCC (SiO ₂ , EA/PE=0~5%) to obtain 2-bromo-3-chloro-6-fluoro-4-methylbenzaldehyde (8.30 g, yield 81.9%) as a pale yellow solid. ¹ H NMR: (400MHz, CDCl ₃ ) δ 10.34-10.24 (m, 1H), 7.08 (d, J = 10.5 Hz, 1H), 2.51 (s, 3H).

Step C: 4-Bromo-5-chloro-6-methyl-1H-indazole

Combine 2-bromo-3-chloro-6-fluoro-4-methylbenzaldehyde (8.00g, 31.8mmol) and NH ₂ NH ₂ -H ₂ O (19.5g, 381.7mmol) in DMSO (160mL) solution in 130 Stir at ℃ for 3h to obtain a yellow solution. The completion of the reaction was monitored by LCMS, H ₂ O (200 mL) was added to the reaction mixture and the mixture was extracted with DCM (2×200 mL). The resulting organic phase was washed with saturated aqueous NaCl (3×200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , THF/PE=0-20%) to obtain 4-bromo-5-chloro-6-methyl-1H-indazole (5.50 g, yield 70.4%) as an off-white solid. ¹ H NMR: (400MHz, CDCl ₃ ) δ 10.84-9.68 (m, 1H), 8.02 (d, J = 0.9 Hz, 1H), 7.33 (d, J = 0.9 Hz, 1H), 2.56 (d, J ＝0.9Hz,3H).

Step D: 4-Bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To 4-bromo-5-chloro-6-methyl-1H-indazole (5.00g, 20.4mmol) in DCM (50mL) solution was added PPTS (511.8mg, 2.04mmol) and DHP (5.14g, 61.1mmol) ), the resulting mixture was stirred at 20°C for 12 h to obtain a yellow solution. TLC showed that the raw material was consumed and two new spots were found. The reaction system was heated to 40°C and stirred for 12h. TLC showed that the reaction was complete. _{H 2} O (50 mL) was added to the reaction mixture, separated, and the aqueous phase was extracted with DCM (2×50 mL). The obtained organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , THF/PE=0~3%) to obtain 4-bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H as a white solid -Indazole (5.70 g, yield 81.7%). ¹ H NMR: (400MHz, CDCl ₃ ) δ7.99-7.88 (m, 1H), 7.42 (s, 1H), 5.65 (dd, J = 2.8, 9.0 Hz, 1H), 5.02-4.75 (m, 1H) ,4.09-3.94(m,1H),3.88(ddd,J=3.4,7.3,10.9Hz,1H), 3.73(ddd,J=3.1,9.9,11.5Hz,1H),3.64-3.44(m,1H) ,2.56(s,3H),2.54-2.43(m,1H),2.22-2.00(m,2H),1.96-1.45(m,8H).

Step E: 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

To 4-bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.10g, 24.6mmol), Pd ₂ (dba) ₃ (450.1 mg, 491.5umol) and t-BuXphos (626.1mg, 1.47mmol) in dioxane (160mL) solution was added KOH (5.52g, 98.3mmol) in H ₂ O (160mL) solution. Under N ₂ protection, the mixture was stirred at 90° C. for 2 h to obtain a brown mixture. The completion of the reaction was monitored by LCMS, the reaction mixture was adjusted to pH=2-3 with 1N HCl aqueous solution, and the resulting mixture was extracted with EA (3×200 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by FCC (SiO ₂ , EA/PE=0-30%) to obtain 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- as a yellow solid 4-alcohol (4.10g, yield 58.9%). ¹ H NMR: (400MHz,DMSO-d ₆ )δ10.59(s,1H), 8.16(s,1H), 7.15(s,1H), 5.70(dd,J=2.4,9.7Hz,1H), 3.86 (br d,J=12.3Hz,1H),3.76-3.65(m,1H),2.40(s,3H),2.38-2.29(m,1H),2.07-1.96(m,1H),1.96-1.86( m,1H),1.81-1.64(m,1H),1.63-1.50(m,2H).LCMS(m/z):266.8(M+H).

Synthesis of intermediate h

6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

Step A: 4-Chloro-2-fluoro-5-methylaniline

To a solution of 1-chloro-5-fluoro-2-methyl-4-nitrobenzene (20.0 g, 105.5 mmol) in EtOH (100 mL) was added concentrated HCl (8.79 mL). The mixture was heated to 80°C and iron powder (20.6 g, 369.3 mmol) was slowly added. The resulting mixture was stirred at the same temperature for 1 h. LCMS showed that the reaction was complete, the system was cooled to 25° C., diluted with EA (300 mL), and basified to pH=8-9 _{with saturated aqueous NaHCO 3 solution.} The two layers were separated, and the aqueous layer was extracted with EA (2x300 mL). The combined organic phases were washed with saturated aqueous NaCl solution (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The resulting crude product, a yellow solid 4-chloro-2-fluoro-5-methylaniline (16.0 g, crude product) was used directly in the next step. ¹ H NMR: (400MHz, DMSO-d ₆ )δ7.08(d, J=11.0Hz,1H), 6.70(d,J=9.8Hz,1H), 5.20(s,2H), 2.15(s,3H) ).

Step B: 2-Bromo-4-chloro-6-fluoro-3-methylaniline

At 0° C., to a solution of 4-chloro-2-fluoro-5-methylaniline (64.0 g, 401.0 mmol) in DMF (800 mL) was slowly added NBS (71.4 g, 401.0 mmol), and then the mixture was heated to 25 ℃, and stirred for 1h. TLC showed that the reaction was complete. The reaction mixture was treated with EA (1000 mL) and H ₂ O (1000 mL), separated, and the organic phase was washed with saturated aqueous NaCl (1000 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , PE/EA=1/0 to 20/1) to obtain 2-bromo-4-chloro-6-fluoro-3-methylaniline as a yellow solid (70.0g, the yield of two steps was 62.6% ). ¹ H NMR: (400MHz, DMSO-d ₆ ) δ 7.28 (d, J = 10.9 Hz, 1H), 5.44 (br s, 2H), 2.35 (s, 3H).

Step C: 3-Bromo-1-chloro-5-fluoro-4-iodo-2-toluene

2-Bromo-4-chloro-6-fluoro-3-methylaniline (74.0 g, 310.3 mmol) was added to an aqueous solution (840 mL) of _{concentrated H 2} SO _{4 (208 mL).} Stir at 25°C for 10 min, then cool to 5°C. A solution of NaNO ₂ (23.6 g, 341.3 mmol) in H ₂ O (75 mL) was added dropwise. The resulting mixture was stirred at 5°C for 20 min, and then added to a solution of KI (206.0 g, 1.24 mol) in H ₂ O (160 mL). The resulting mixture was stirred at 5°C for 20 min, and then heated to 25°C and stirred for 18 h. TLC showed that the reaction was complete, _{the reaction was quenched with H 2} O (500 mL), and the resulting mixture was extracted with EA (2×1000 mL). The organic phase was washed with saturated _{aqueous Na 2} SO ₃ (500 mL) and saturated aqueous NaCl (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , PE/EA=1/0 to 50/1) to obtain 3-bromo-1-chloro-5-fluoro-4-iodo-2-toluene (69.0 g, yield 60.5%) as a yellow solid ). ¹ H NMR: (400MHz, DMSO-d ₆ ) δ 7.57 (d, J = 7.8 Hz, 1H), 2.53-2.45 (m, 3H).

Step D: 2-Bromo-4-chloro-6-fluoro-3-methylbenzaldehyde

At -78°C, to a solution of 3-bromo-1-chloro-5-fluoro-4-iodo-2-toluene (68.0g, 194.6mmol) in THF (500mL) was added dropwise n-BuLi (2.5M, 77.9 mL). The mixture was stirred at the same temperature for 30 min. DMF (15.7 g, 214.1 mmol) was added dropwise, and the mixture was stirred at -78° C. for 20 min to obtain a yellow solution. TLC monitors the completion of the reaction. The reaction was quenched with saturated _{aqueous NH 4} Cl (200 mL). _{H 2} O (200 mL) was added to the system and extracted with EA (2×300 mL). The resulting organic layer was washed with saturated aqueous NaCl (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , PE/EA=1/0 to 20/1) to obtain 2-bromo-4-chloro-6-fluoro-3-methylbenzaldehyde as a yellow solid (38.0 g, yield 57.1%) .

Step E: 4-Bromo-6-chloro-5-methyl-1H-indazole

NH ₂ NH ₂ -H ₂ O (90.8 g, 1.81 mol) was added to a solution of 2-bromo-4-chloro-6-fluoro-3-methylbenzaldehyde (38.0 g, 151.1 mmol) in DMSO (800 mL). The resulting mixture was stirred at 130°C for 3h. LCMS showed that the product had formed, the _{reaction mixture was treated with EA (2000 mL) and H 2} O (1000 mL), separated, the organic phase was washed with saturated aqueous NaCl (2×1000 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain 4-bromo-6-chloro-5-methyl-1H-indazole (23.5 g, yield 51.5%) as a yellow solid. ¹ H NMR: (400MHz, DMSO-d ₆ ) δ 13.44 (br s, 1H), 8.10-7.90 (m, 1H), 7.78-7.56 (m, 1H), 2.50 (br s, 3H).

Step F: 4-Bromo-6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a solution of 4-bromo-6-chloro-5-methyl-1H-indazole (22.0g, 89.6mmol) and PPTS (2.25g, 8.96mmol) in DCM (400mL) was added DHP (22.6g, 268.8mmol) . The reaction mixture was stirred at 40°C for 5 h. LCMS showed that the reaction was complete, and the reaction system was washed with saturated aqueous NaCl (150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE=0～5%) to obtain 4-bromo-6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H as a yellow solid -Indazole (21.0 g, yield 71.1%). ¹ H NMR:(400MHz,DMSO-d ₆ )δ8.46(s,1H),7.84(s,1H),5.76(dd,J=2.6,9.7Hz,1H),3.99(br d,J=11.0 Hz, 1H), 3.78-3.65 (m, 1H), 2.49 (s, 3H), 2.27-2.15 (m, 1H), 2.09-1.91 (m, 2H), 1.79-1.65 (m, 1H), 1.64- 1.56 (m, 2H).

Step G: 6-Chloro-5-methyl-1H-indazol-4-ol

To 4-bromo-6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (11.0g, 33.4mmol), Pd ₂ (dba) ₃ (611.2 mg, 667.4umol) and t-BuXphos (850.3mg, 2.00mmol) in dioxane (220mL) solution was added KOH (7.50g, 133.5mmol) in H ₂ O (220mL) solution. The resulting mixture was stirred at 90°C for 2 h under the protection of nitrogen to obtain a brown mixture. LCMS showed that the reaction was complete, and the reaction mixture was adjusted to pH=2-3 with 1N HCl aqueous solution. The mixture was extracted with EA (300 mL). The resulting organic phase was washed with saturated aqueous NaCl (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE=0-50%) to obtain 6-chloro-5-methyl-1H-indazol-4-ol (6.00 g, yield 98.5%) as a yellow solid. LCMS(m/z): 182.9(M+H).

Step H: 6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)-1H- Indazole

To a solution of 6-chloro-5-methyl-1H-indazol-4-ol (6.00 g, 32.9 mmol) and PPTS (825.7 mg, 3.3 mmol) in DCM (150 mL) was added DHP (8.29 g, 98.6 mmol) . The reaction mixture was stirred at 40°C for 5 h. LCMS showed that the reaction was complete. The reaction solution was washed with saturated aqueous NaCl (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE=0～10%) to obtain 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(( Tetrahydro-2H-pyran-2-yl)oxy)-1H-indazole (6.20 g, yield 48.4%). LCMS(m/z): 351.1(M+H).

Step I: 6-Chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol

At 0℃, add 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy) To a solution of -1H-indazole (6.10 g, 17.4 mmol) in dioxane (18 mL) was added 4N HCl/dioxane (8 mL). The reaction mixture was stirred at 0°C for 10 min. TLC showed that the reaction was complete. The reaction mixture was adjusted to pH=9 with saturated aqueous NaHCO ₃ solution, and then extracted with EA (100 mL). The resulting organic phase was washed with saturated aqueous NaCl (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO ₂ , EA/PE = 0-15%) to obtain a yellow solid 6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-alcohol (2.10 g, yield 43.6%). ¹ H NMR: (400MHz, DMSO-d ₆ ) δ10.37 (s, 1H), 8.20 (s, 1H), 7.32 (s, 1H), 5.78-5.70 (m, 1H), 3.91-3.80 (m, 1H), 3.73(td,J=6.9,11.3Hz,1H),2.41-2.28(m,1H),2.25(s,3H),2.07-1.98(m,1H),1.96-1.87(m,1H) ,1.80-1.66(m,1H),1.62-1.52(m,2H).LCMS(m/z):266.8(M+H).

Synthesis of intermediate A1

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: Methyl 3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-nitrobenzoate

At room temperature, add methyl 3-fluoro-2-nitrobenzoate (2.1g, 10.55mmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole _{K 2} CO ₃ (3.60 g, 22.15 mmol) was added to a solution of -4-ol (2.45 g, 10.55 mmol) in DMF (20 mL). The mixture was heated to 60°C and stirred for 16 h. After cooling to room temperature, the mixture was poured into H ₂ O (100 mL) and extracted with EA (3×30 mL). The organic phase was washed with saturated aqueous NaCl (2x50mL), dried with anhydrous Na ₂ SO ₄ , and purified by FCC (SiO ₂ , EA/PE=0-30%) to obtain a pale yellow solid 3-((5-methyl-1-( Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-nitrobenzoic acid methyl ester (3.40 g, yield 78%). LCMS(m/z): 412.2(M+H), 434.1(M+Na).

Step B: Methyl 2-amino-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzoate

Methyl 3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-nitrobenzoate (3.40g , 8.26mmol) and Pd/C (500mg) in MeOH (30mL) mixture was stirred at room temperature for 40h in a reaction flask equipped with a hydrogen balloon. After the completion of the reaction monitored by LCMS, the mixture was filtered. The filtrate was concentrated to obtain a pale yellow solid 2-amino-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzoic acid methyl ester Esters (3.10 g, yield 98%). LCMS(m/z): 382.2(M+H).

Step C: 2-(2-Cyanoacetamido)-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy ) Methyl benzoate

At room temperature, NMI (2.0g, 24.4mmol) was added to 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). The resulting organic phase was washed with saturated aqueous NaCl (2×25 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude product was purified with FCC (SiO ₂ , EA/PE=0-60%) to obtain a pale yellow solid 2-(2-cyanoacetamido)-3-((5-methyl-1-(tetrahydro-2H- Methyl pyran-2-yl)-1H-indazol-4-yl)oxy)benzoate (3.50 g, yield 96%). LCMS (m/z): 449.2 (M+H), 471.1 (M+Na).

Step D: 2,4-Dihydroxy-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline- 3-carbon nitrile

At 0 ℃, to 2-(2-cyanoacetamido)-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl ) To a THF (50 mL) solution of methyl oxy)benzoate (4.1 g, 9.14 mmol) was added t-BuOK (2.0 g, 18.28 mmol). The mixture was stirred at 0°C for 2 h. After the completion of the reaction was monitored by LCMS, the mixture was poured into H ₂ O (100 mL), and acidified with 1N HCl aqueous solution to pH=4, and a solid was formed. The mixed system was extracted with EA (3x25mL), the resulting organic phase was washed with saturated aqueous NaCl (2x20mL), dried with anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain an off-white solid 2,4-dihydroxy-8-((5-form Base-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile (3.5 g, yield 92%). LCMS (m/z): 417.0 (M+H), 439.0 (M+Na).

Step E: 2,4-Dichloro-8-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile

To 2,4-dihydroxy-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinoline-3- To a solution of carbonitrile (800 mg, 1.92 mmol) in toluene (20 mL) was added POCl ₃ (4 mL) and N,N-diethylaniline (0.5 mL). The resulting mixture was heated and stirred at 100° C. for 16 h. After cooling to room temperature, it was concentrated under reduced pressure. The obtained crude product was purified by FCC (SiO ₂ , EA/PE=0-80%) to obtain 2,4-dichloro-8-((5-methyl-1H-indazol-4-yl)oxy)quine as a yellow solid Phloline-3-carbonitrile (425 mg, yield 60%). LCMS(m/z): 369.0(M+H).

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

To 2,4-dichloro-8-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile (425mg, 1.15mmol) and N-Boc-piperazine ( DIEA (300 mg, 2.3 mmol) was added dropwise to a solution of 321 mg, 1.73 mmol) in DMA (2 mL). The mixture was stirred at room temperature for 2h. After the completion of the reaction monitored by LCMS, the mixture was poured into H ₂ O (30 mL). The formed precipitate was collected by filtration and purified by FCC (SiO ₂ , EA/PE=0-70%) to obtain 4-(2-chloro-3-cyano-8-((5-methyl-1H) as a pale yellow solid -Indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (300 mg, yield 50%). LCMS(m/z): 519.0(M+H).

Example A1

(S)-4-(4-acryloylpiperazin-1-yl)-8-(5-methyl-1H-indazol-4-yl)oxy)-2-(1-methylpyrrolidine- 2-yl)methoxy)quinoline-3-carbonitrile formate

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

At room temperature, to a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (44 mg, 0.38 mmol) in THF (3 mL) was added NaH (10 mg, 0.4 mmol). The resulting mixture was stirred at the same temperature for 5 min, and then 4-(2-chloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl was added ) Tert-butyl piperazine-1-carboxylate (100 mg, 0.19 mmol), and the resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, it was quenched by adding saturated aqueous NaCl solution, and extracted with EA (2×20 mL). The organic phase was washed with a saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain the crude yellow solid (S)-4-(3-cyano-8-((5-methyl-1H-indyl) (Azol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (115mg, crude ), directly used in the next step. LCMS(m/z): 598.2(M+H).

Step B: (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-4 -(Piperazin-1-yl)quinoline-3-carbonitrile

Add TFA (2mL) to (S)-4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrole) Alk-2-yl)methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.18 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to obtain (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl) as a pale yellow oil )Methoxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile (90mg, crude product), used directly in the next step. LCMS(m/z): 498.1(M+H).

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

At 0 ℃, to (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy )-4-(piperazin-1-yl)quinoline-3-carbonitrile (90mg, 0.18mmol) in EA (5mL) and saturated NaHCO ₃ aqueous solution (5mL) was added with acryloyl chloride (25mg, 0.28mmol) in EA (1mL) Solution. The mixture was stirred vigorously for 15 min. After the reaction was completed, the EA layer was separated and washed with saturated aqueous NaCl (2×15 mL). After concentration under reduced pressure, the crude product was purified by preparative high performance liquid chromatography to obtain a white solid (S)-4-(4-acryloylpiperazin-1-yl)-8-(5-methyl-1H-indazol-4-yl) )Oxy)-2-(1-methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile formate (32mg, 31% total yield for three steps). ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.04 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.35–7.17 (m, 3H), 7.02 (s, 1H), 6.91 (dd, J = 16.7, 10.4 Hz, 1H), 6.19 (dd, J = 16.7, 2.4 Hz, 1H), 5.75 (dd, J = 10.4, 2.4 Hz, 1H) ),4.06(dd,J=11.0,4.8Hz,1H),3.98–3.77(m,5H), 3.64(s,4H), 3.00–2.82(m,1H), 2.50–2.42(m,1H), 2.34 (s, 3H), 2.29 (s, 3H), 2.14 (q, J = 8.7 Hz, 1H), 1.84 (dt, J = 12.4, 8.5 Hz, 1H), 1.74-1.59 (m, 2H), 1.52 (dt, J=14.2, 6.7 Hz, 1H). LCMS (m/z): 552.3 (M+1).

Example A2

(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

Steps A and B:

Compound (S)-2-((4,4-Difluoro-1-methylpyrrolidin-2-yl)methoxy)-8-((5-methyl-1H-indazol-4-yl) (Oxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile was prepared as described in Example 1, and (S)-(4,4-difluoro-1-methyl) was used in step A. (S)-(1-methylpyrrolidin-2-yl)methanol instead of (S)-(1-methylpyrrolidin-2-yl)methanol. LCMS(m/z): 534.3(M+H).

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

At 0°C, a solution of acryloyl chloride (14.3 mg, 0.16 mmol) in DCM (0.5 mL) was added dropwise to (S)-2-((4,4-difluoro-1-methylpyrrolidine-2- Yl)methoxy)-8-((5-methyl-1H-indazol-4-yl)oxy)-4-(piperazin-1-yl)quinoline-3-carbonitrile (84mg, 0.16 mmol) and DIEA (447 mg, 3.46 mmol) in DCM (2.5 mL). The resulting mixture was stirred at 0°C for 30 min. 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%). ¹ H NMR(400MHz,DMSO-d ₆ )δ13.07(s,1H), 7.80(dd,J=8.4,1.3Hz,1H),7.46-7.37(m,1H),7.34-7.20(m,3H ), 7.06 (s, 1H), 6.91 (dd, J = 16.7, 10.4 Hz, 1H), 6.19 (dd, J = 16.7, 2.4 Hz, 1H), 5.75 (dd, J = 10.4, 2.4 Hz, 1H) , 4.32(dd,J=11.5,4.2Hz,1H),4.02(dd,J=11.5,5.3Hz,1H),3.91–3.80(m,4H),3.70–3.59(m,4H),3.32–3.25 (m,1H), 2.87–2.75(m,1H), 2.66–2.55(m,1H), 2.46–2.36(m,1H), 2.32(s,3H), 2.28(s,3H), 2.21–2.02 (m, 1H). ¹⁹ F NMR(376MHz, DMSO-d ₆ )δ-90.05(d, J=226.2Hz), -95.27(d,J=226.1Hz).LCMS(m/z): 588.3(M +H).

Example A3

4-(4-acryloylpiperazin-1-yl)-2-((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8-((5- Methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A3 refers to the description in Example A2. In step A, ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol was used instead of (S)-(4,4). -Difluoro-1-methylpyrrolidin-2-yl)methanol. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.90–7.81(m,1H),7.48–7.41(m,1H),7.35(dd,J=8.3,1.5Hz,1H),7.32–7.24(m ,2H),7.06(s,1H),6.93-6.81(m,1H),6.30(dd,J=16.8,2.0Hz,1H), 5.83(dd,J=10.6,1.9Hz,1H), 5.26- 5.03(m,1H), 4.30(dd,J=11.5,4.0Hz,1H), 4.16–4.06(m,1H), 4.03–3.91(m,4H), 3.80–3.69(m,4H), 3.31– 3.23(m,1H), 2.90--2.75(m,1H), 2.62--2.55(m,1H), 2.53(s,3H), 2.51--2.43(m,1H), 2.42(s,3H), 1.99-- 1.75 (m, 1H). ¹⁹ F NMR (376MHz, methanol-d ₄ ) δ-169.94.LCMS (m/z): 570.2 (M+H).

Example A4

4-(4-acryloylpiperazin-1-yl)-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-8-((5 -Methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A4 refers to the description in Example A2. In step A, (3R,4R)-4-methoxy-1-methylpyrrolidin-3-ol was used instead of (S)-(4,4- Difluoro-1-methylpyrrolidin-2-yl)methanol. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.89(d,J＝8.3Hz,1H), 7.58–7.16(m,4H), 7.05–6.76(m,2H), 6.30(d,J＝16.7 Hz, 1H), 5.83 (d, J = 10.7 Hz, 1H), 5.10 (s, 1H), 4.19–3.52 (m, 10H), 3.13–2.92 (m, 1H), 2.83–2.63 (m, 1H) ,2.57--1.97(m,9H).LCMS(m/z):568.3(M+H).

Example A5

4-(4-acryloylpiperazin-1-yl)-2-((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-8-(( 5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A5 refers to the description in Example A2. In step A, ((2S,4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol was used instead of (S)-(4 ,4-Difluoro-1-methylpyrrolidin-2-yl)methanol. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.97(dd,J＝8.1,1.7Hz,1H), 7.60–7.49(m,2H),7.24(s,1H), 6.86(dd,J＝16.8 ,10.6Hz,1H), 6.70(s,1H), 6.28(dd,J=16.7,2.0Hz,1H), 5.82(dd,J=10.6,1.9Hz,1H), 4.88–4.75(m,2H) ,4.05–3.90(m,5H), 3.82–3.68(m,4H), 3.23(s,3H), 3.04(dd,J＝10.3,6.1Hz,1H),2.58(d,J＝0.9Hz,4H ),2.43--2.32(m,1H),2.22(s,3H).LCMS(m/z):582.2(M+H).

Synthesis of intermediate A2

4-(2-chloro-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester

The preparation of intermediate A2 refers to the synthesis of intermediate A1. In 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. LCMS (m/z): 557.1 (M+H).

Example A6

(S)-4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-2-((1- (Methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile

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). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.36 (s, 1H), 8.00–7.93 (m, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 16.6, 10.4 Hz, 1H), 6.77 (s, 1H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.76(dd,J=10.5,2.4Hz,1H), 4.02–3.71(m,5H), 3.65(s,4H), 3.33(s,1H), 2.90(m,1H), 2.36(m,1H) ,2.23(s,3H),2.13(m,1H),1.90–1.74(m,1H),1.64(m,2H),1.38(dt,J=12.9,6.7Hz,1H). ¹⁹ F NMR(376MHz ,DMSO-d ₆ )δ-115.81.LCMS(m/z):590.1(M+H).

Example A7

4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-2-((3R,4R)-4 -Methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A7 refers to the description in Example A1. In 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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.35 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 8.1Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 16.6, 10.4 Hz, 1H), 6.55 (s, 1H), 6.19 (dd, J = 16.7, 2.4 Hz, 1H), 5.76 (dd, J = 10.4, 2.4 Hz, 1H), 4.61 (s, 1H), 3.99–3.76 (m, 5H), 3.67 (s, 4H), 3.33 (s, 1H), 3.09 (s , 3H), 3.02 (m, 1H), 2.20-2.10 (m, 5H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-115.56.LCMS (m/z): 606.2 (M+H).

Synthesis of intermediate A3

4-(2-Chloro-8-((6-chloro-5-methyl-1H-indazol-4-yl)oxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxy Tert-butyl ester

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

(S)-4-(4-acryloylpiperazin-1-yl)-8-((6-chloro-5-methyl-1H-indazol-4-yl)oxy)-2-((1 -Methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile

The preparation of 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). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.14 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 8.1Hz, 1H), 7.43 (s, 1H), 6.91 (dd, J = 16.6, 10.4 Hz, 1H), 6.83 (s, 1H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.75 ( dd, J = 10.4, 2.4 Hz, 1H), 3.95–3.76 (m, 5H), 3.72 (dd, J = 11.0, 6.5 Hz, 1H), 3.63 (s, 4H), 2.89 (dt, J = 8.9, 4.4Hz, 1H), 2.43 (s, 3H), 2.25 (s, 3H), 2.19-2.06 (m, 1H), 1.89-1.76 (m, 1H), 1.70-1.58 (m, 2H), 1.52-1.42 (m,1H).LCMS(m/z): 586.2(M+H).

Example A9

4-(4-acryloylpiperazin-1-yl)-8-((6-chloro-5-methyl-1H-indazol-4-yl)oxy)-2-((3R,4R)- 4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A9 refers to the description in Example A1. In 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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.20 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.68-7.54 (m, 2H), 7.49 (s, 1H), 6.98 ( dd, J = 16.6, 10.4 Hz, 1H), 6.73 (s, 1H), 6.25 (dd, J = 16.6, 2.3 Hz, 1H), 5.82 (dd, J = 10.3, 2.4 Hz, 1H), 4.83 (s ,1H),4.05–3.83(m,5H),3.72(s,4H),3.20(s,3H),3.08(dd,J=9.6,6.7Hz,1H),2.50(s,3H),2.42– 2.00(m,6H).LCMS(m/z):602.1(M+H).

Synthesis of intermediate A4

4-(2-Chloro-8-((5-chloro-6-methyl-1H-indazol-4-yl)oxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxy Tert-butyl ester

The preparation of 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

4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-methyl-1H-indazol-4-yl)oxy)-2-((3R,4R)- 4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A10 refers to that described in Example A2. In 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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.12 (s, 1H), 7.93 (dd, J = 8.5, 1.3 Hz, 1H), 7.67 (dd, J = 7.7, 1.2 Hz, 1H), 7.54 ( t,J=8.1Hz,1H),7.27(s,1H),6.91(dd,J=16.7,10.4Hz,1H),6.62(s,1H),6.19(dd,J=16.7,2.4Hz,1H ), 5.76(dd,J=10.4,2.4Hz,1H), 4.67(s,1H), 3.94–3.79(m,5H), 3.72–3.58(m,4H), 3.10(s,3H), 2.98( dd,J=9.6,6.6Hz,1H),2.56–2.52(m,4H),2.20–1.89(m,5H).LCMS(m/z):602.3(M+H).

Example A11

(S)-4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-methyl-1H-indazol-4-yl)oxy)-2-((1 -Methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile

The preparation of 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. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.94(dd,J=7.8,2.0Hz,1H), 7.69–7.41(m,2H),7.24(s,1H),6.99–6.78(m,2H ), 6.28(dd,J=16.8, 2.0Hz,1H), 5.82(dd,J=10.6,2.0Hz,1H),4.07(d,J=11.0Hz,1H),4.00–3.92(m,4H) ,3.87-3.61(m,5H),3.08-2.96(m,1H),2.66-2.58(m,1H),2.55(s,3H),2.41(s,3H),2.36-2.25(m,1H) ,2.08–1.88(m,1H),1.86–1.70(m,2H),1.63–1.45(m,1H).LCMS(m/z): 586.2(M+H).

Synthesis of intermediate A5

4-(2-chloro-3-cyano-8-((5,6-dichloro-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert Butyl

The preparation of 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

(S)-4-(4-acryloylpiperazin-1-yl)-8-((5,6-dichloro-1H-indazol-4-yl)oxy)-2-((1-methyl Pyrrolidin-2-yl) methoxy) quinoline-3-carbonitrile

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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 7.95 (dd, J = 8.5, 1.3 Hz, 1H), 7.81 (dd, J = 7.8, 1.2 Hz, 1H), 7.62- 7.49 (m, 2H), 6.91 (dd, J = 16.6, 10.4 Hz, 1H), 6.77 (s, 1H), 6.19 (dd, J = 16.7, 2.4 Hz, 1H), 5.75 (dd, J = 10.4, 2.4Hz, 1H), 3.92--3.80 (m, 4H), 3.79--3.71 (m, 1H), 3.69--3.57 (m, 4H), 3.62--3.51 (m, 1H), 2.91--2.83 (m, 1H) ,2.39--2.30(m,1H),2.21(s,3H),2.17-2.03(m,1H),1.87-1.74(m,1H),1.70-1.57(m,2H),1.49-1.35(m, 1H).LCMS(m/z):606.0(M+H).

Example A13

4-(4-acryloylpiperazin-1-yl)-8-((5,6-dichloro-1H-indazol-4-yl)oxy)-2-((3R,4R)-4- Methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A13 refers to that described in Example A2. In 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. ¹ H NMR(400MHz,DMSO-d ₆ )δ13.37(s,1H),7.99(dd,J=8.5,1.3Hz,1H),7.85-7.79(m,1H),7.62-7.55(m,2H ), 6.91 (dd, J = 16.6, 10.4 Hz, 1H), 6.58 (s, 1H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.76 (dd, J = 10.4, 2.4 Hz, 1H) , 4.65–4.41(m,1H), 3.94–3.78(m,5H), 3.73–3.61(m,4H), 3.09(s,3H), 3.07–2.99(m,1H), 2.08(s,3H) ,2.06–1.99(m,2H).LCMS(m/z): 622.2(M+H).

Synthesis of intermediate A6

4-(2,6-Dichloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester

Steps A and B:

Synthesis of methyl 2-amino-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy) benzoate according to the intermediate Steps A and B in the synthesis of A1 are completed.

Step C: 2-Amino-5-chloro-3-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)benzoic acid Methyl ester

At room temperature, NCS (700 mg, 5.24 mmol) was added to 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) in DMF (10 mL). The resulting mixture was stirred at 60°C for 48h. After cooling to room temperature, 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. The resulting crude product was purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a yellow solid 2-amino-5-chloro-3-((5-methyl-1-(tetrahydro-2H-pyran- Methyl 2-yl)-1H-indazol-4-yl)oxy)benzoate (1.5 g, yield 69%). LCMS(m/z): 416.1(M+H).

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. In 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. LCMS (m/z): 553.2, 555.2 (M+H).

Example A14

(S)-4-(4-acryloylpiperazin-1-yl)-6-chloro-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1 -Methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile

The preparation of Example A14 refers to that described in Example A2. In 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. ¹ H NMR(400MHz,DMSO-d ₆ )δ13.14(s,1H), 7.72(d,J=2.3Hz,1H), 7.36–7.22(m,3H), 7.15(d,J=2.2Hz, 1H), 6.95–6.82 (m, 1H), 6.18 (dd, J = 16.6, 2.4 Hz, 1H), 5.74 (dd, J = 10.4, 2.4 Hz, 1H), 4.20–4.07 (m 1H), 4.04– 3.93 (m, 1H), 3.92-3.77 (m, 4H), 3.70-3.56 (m, 4H), 2.97-2.86 (m, 1H), 2.36-2.23 (m, 6H), 2.19-1.78 (m, 3H) ),1.71-1.59(m,2H),1.58-1.48(m,1H).LCMS(m/z):586.2(M+H).

Synthesis of intermediate A7

4-(2,6-Dichloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester

The preparation of 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. LCMS(m/z): 609.0(M+H).

Example A15

4-(4-acryloylpiperazin-1-yl)-6-chloro-8-((5,6-dichloro-1H-indazol-4-yl)oxy)-2-((3R, 4R )-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile

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. ¹ H NMR (400MHz, methanol-d ₄ ) δ 7.97 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.02 (s, 1H), 6.87 (dd, J = 16.8, 10.7 Hz, 1H), 6.30 (dd, J = 16.8, 2.0 Hz, 1H), 5.84 (dd, J = 10.7, 2.0 Hz, 1H), 4.67 ( s,1H), 4.14–3.88(m,5H), 3.76(s,4H), 3.23(s,3H), 3.12(dd,J=10.2,6.3Hz,1H), 2.61–2.41(m,1H) ,2.41-2.13(m,5H).LCMS(m/z):656.0,658.0(M+H).

Example A16

4-(4-acryloylpiperazin-1-yl)-6-chloro-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-8 -((5-Methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A16 refers to that described in Example A2. In 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. ¹ H NMR(400MHz, methanol-d ₄ )δ7.79(s,1H), 7.41–7.29(m,2H), 7.18(s,1H), 7.07(s,1H), 6.86(dd,J=16.8 ,10.6Hz,1H),6.28(dd,J=16.8,1.8Hz,1H),5.82(dd,J=10.7,1.8Hz,1H),5.23-5.14(m,1H),4.09-4.03(m, 1H), 4.00–3.93(m, 4H), 3.77–3.68(m, 4H), 3.34(s, 3H), 3.00(dd, J = 10.5, 6.0Hz, 1H), 2.91–2.80(m, 1H) ,2.54(dd,J=10.5,4.3Hz,1H),2.47–2.40(m,1H),2.37(s,3H),2.29(s,3H).LCMS(m/z):602.1(M+H ).

Example A17

(S)-4-(4-(2-Fluoroacryloyl)piperazin-1-yl)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-(( 1-Methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile

At 0 ℃, to (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy )-4-(piperazin-1-yl)quinoline-3-carbonitrile (70mg, 0.14mmol), 2-fluoroacrylic acid (12.6mg, 0.14mmol) and HATU (80mg, 0.21mmol) in DMF solution. DIEA (36 mg, 0.28 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 20°C for 1 h, the reaction system was diluted with EA (30 mL), washed with water (2×20 mL), saturated NaCl aqueous solution (2×20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude product was purified by preparative high performance liquid chromatography to obtain (S)-4-(4-(2-fluoroacryloyl)piperazin-1-yl)-8-((5-methyl-1H-indazole-4 -Yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile (16 mg, yield 20%). ¹ H NMR (400MHz, methanol-d ₄ ) δ 7.88 (dd, J = 8.4, 1.2 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 7.39-7.22 (m, 3H), 7.06 ( s, 1H), 5.40–5.32 (m, 1H), 5.31–5.23 (m, 1H), 4.26 (d, J = 3.9 Hz, 1H), 4.06–3.99 (m, 1H), 3.96 (d, J = 5.0Hz, 4H), 3.77 (d, J = 2.7 Hz, 4H), 3.07 (td, J = 8.8, 8.0, 4.0 Hz, 1H), 2.74 (s, 1H), 2.49 (s, 3H), 2.42 ( s, 3H), 2.37 (s, 1H), 2.03 (dd, J = 12.6, 8.3 Hz, 1H), 1.87-1.77 (m, 2H), 1.65 (dd, J = 13.0, 6.6 Hz, 1H). LCMS (m/z): 570.0(M+H).

Example A18

(S,E)-4-(4-(4-(dimethylamino)but-2-enolyl)piperazin-1-yl)-8-((5-methyl-1H-indazole-4 -Yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)quinoline-3-carbonitrile

The preparation of Example A18 was as described in Example A17, using (E)-4-(dimethylamino)-2-butenoic acid instead of 2-fluoroacrylic acid. ¹ H NMR (400MHz, methanol-d ₄ ) δ 7.88 (dd, J = 8.5, 1.3 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.39-7.22 (m, 3H), 7.05 ( s, 1H), 6.87 (dt, J = 15.2, 6.4 Hz, 1H), 6.79-6.69 (m, 1H), 4.27 (dd, J = 11.5, 3.9 Hz, 1H), 4.01 (d, J = 20.3 Hz ,5H), 3.75(s, 4H), 3.23(dd,J=6.3,1.2Hz,2H),3.07(dt,J=9.7,4.7Hz,1H),2.72(s,1H),2.48(s, 3H), 2.42 (s, 3H), 2.37 (d, J = 8.9 Hz, 1H), 2.33 (s, 6H), 2.03 (dd, J = 12.6, 8.3 Hz, 1H), 1.87–1.76 (m, 2H ), 1.65 (dd, J = 12.9, 6.6 Hz, 1H). LCMS (m/z): 609.0 (M+H).

Example A19

4-(4-acryloylpiperazin-1-yl)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-(1-methyl-1H-pyrazole- 4-yl)quinoline-3-carbonitrile

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

Under N ₂ protection, 4-(2-chloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine- Tert-butyl 1-carboxylate (80mg, 0.15mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid ( _{29.1mg, 0.23mmol), Pd(PPh 3} ) ₄ (35.6mg, 0.031mmol) ) And K ₂ CO ₃ (42.6 mg, 0.31 mmol) in ethylene glycol dimethyl ether/water (20:1, 6 mL) solution was stirred at 85° C. for 3 h. After the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was _{partitioned between EA (30 mL) and H 2} O (20 mL), and the organic phase was separated. The obtained organic phase _{was washed sequentially with H 2} O (20 mL) and saturated aqueous NaCl (2×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting crude 4-(3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)quine The tert-butyl lin-4-yl)piperazine-1-carboxylate (230 mg, crude product) was directly put into the next step. LCMS (m/z): 565.3 (M+H).

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

The subsequent synthetic steps B and C of Example A19 are described in Example A2. In 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. ¹ H NMR (400MHz, methanol-d ₄ ) δ 8.24 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J = 8.6, 1.2 Hz, 1H), 7.50-7.43 (m, 1H), 7.42–7.38(m,1H),7.36–7.30(m,2H),7.11–7.06(m,1H), 6.87(dd,J=16.8,10.6Hz,1H), 6.29(dd,J=16.8,1.9 Hz, 1H), 5.82 (dd, J = 10.6, 1.9 Hz, 1H), 4.02–3.97 (m, 4H), 3.95 (s, 3H), 3.83–3.75 (m, 4H), 2.37 (s, 3H) .LCMS(m/z): 519.2(M+H).

Example A20

4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-2-((2-methylisoindyl) (Dolin-4-yl)oxy)quinoline-3-carbonitrile

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

Under N ₂ protection, 4-(2-chloro-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3-cyanoquinolin-4-yl) Tert-butyl piperazine-1-carboxylate (150mg, 0.27mmol), 2-methylisoindolin-4-ol (80.3mg, 0.54mmol), CuI (10.3mg, 0.05mmol), N ¹ -benzyl -N ² -(5-methyl-[1,1'-biphenyl]-2-yl)oxamide (22.2mg, 0.06mmol) and K ₂ CO ₃ (111.6mg, 0.81mmol) in DMSO (2mL ) The solution was stirred at 100°C for 3h. The 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. The crude product was purified by FCC (SiO ₂ , MeOH/DCM=0-20%) to obtain brown solid 4-(8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3 -Cyano-2-((2-methylisoindolin-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (70 mg, yield 39%). LCMS (m/z): 670.2 (M+H).

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

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. Base-2-((2-methylisoindolin-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of (S)-4-(3-cyano Base-2-((4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-8-((5-methyl-1H-indazol-4-yl)oxy) Quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR (400MHz, methanol-d ₄ ) δ 8.09 (dd, J = 8.5, 1.3 Hz, 1H), 7.76-7.68 (m, 1H), 7.67-7.57 (m, 1H), 7.16-7.07 (m ,2H),7.00–6.83(m,2H),6.60(dd,J=6.9,2.0Hz,1H),6.44(s,1H),6.32(dd,J=16.8,2.0Hz,1H),5.86( dd,J=10.6,2.0Hz,1H), 4.08–3.99(m,4H), 3.96(s,2H), 3.90–3.80(m,4H), 3.45(s,2H), 2.46(s,3H) ^.19 F NMR(376MHz, methanol-d ₄ )δ-115.04.LCMS(m/z): 624.1(M+H).

Example A21

4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-2-((2-isopropyl iso Indolin-4-yl)oxy)quinoline-3-carbonitrile

The preparation of Example A21 refers to that described in Example A20. In step A, 2-isoindolin-4-ol was used instead of 2-methylisoindolin-4-ol. ¹ H NMR(400MHz,DMSO-d ₆ )δ13.26(s,1H), 8.03(d,J=8.4Hz,1H), 7.74–7.68(m,1H), 7.63–7.54(m,1H), 7.16(d,J=8.7Hz,1H), 7.09–7.02(m,2H), 6.94(dd,J=16.7,10.5Hz,1H), 6.61(dd,J=6.0,3.0Hz,1H), 6.41 (s, 1H), 6.21 (dd, J = 16.6, 2.5 Hz, 1H), 5.77 (dd, J = 10.4, 2.4 Hz, 1H), 3.98–3.86 (m, 4H), 3.82 (s, 2H), 3.80–3.74(m,4H),3.31(s,2H),2.47–2.41(m,1H),0.97(d,J=6.2Hz,6H). ¹⁹ F NMR(376MHz,DMSO-d ₆ )δ- 115.00.LCMS(m/z): 652.2(M+H).

According to a method similar to the synthetic method of the above-mentioned Example A series of compounds, the following compounds of Example A22 to Example A61 were also prepared and characterized:

Example A62

4-(4-acryloylpiperazin-1-yl)-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-2-((2-methylpyridine- 3-yl)amino)quinoline-3-carbonitrile

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

Under N ₂ protection, 4-(2-chloro-8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)-3-cyanoquinolin-4-yl) Piperazine-1-carboxylate (150mg, 0.27mmol), 2-methylpyridin-3-amine (87mg, 0.81mmol), Cs ₂ CO ₃ (176mg, 0.54mmol), Pd(OAc) ₂ (12mg, A dioxane (10 mL) solution of 0.054 mmol) and BINAP (33 mg, 0.054 mmol) was heated and stirred at 100° C. for 16 h. After cooling to room temperature, filter with Celite. The filtrate was concentrated and _{purified by FCC (SiO 2} , MeOH/DCM=0-30%) to obtain a pale yellow solid 4-(8-((5-chloro-6-fluoro-1H-indazol-4-yl)oxy)- Tert-butyl 3-cyano-2-((2-methylpyridin-3-yl)amino)quinolin-4-yl)piperazine-1-carboxylate (30 mg, 17.72% yield). LCMS (m/z): 629.1 (M+H).

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

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. Base-2-((2-methylpyridin-3-yl)amino)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester instead of (S)-4-(3-cyano-2- ((4,4-Difluoro-1-methylpyrrolidin-2-yl)methoxy)-8-((5-methyl-1H-indazol-4-yl)oxy)quinoline-4 -Yl)piperazine-1-carboxylic acid tert-butyl ester. LCMS(m/z): 583.1(M+H).

According to a method similar to the synthesis method of the above-mentioned Example A series of compounds, the following compounds of Example A63 to Example A80 were also prepared and characterized:

Example A81

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

Step A: 3-Amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxylic acid Methyl ester

分子筛(500mg)的1,4-二氧六环(10mL)溶液中加入碘化亚铜(38mg,0.20mmol)。将混合物在加热至110℃并搅拌16h。冷却至室温后，抽滤得到滤液，浓缩，通过FCC纯化(SiO ₂，EA/PE＝0-100％)得到黄色固体3-氨基-4-((5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)氧基)噻吩-2-羧酸甲酯(120mg，收率15％)。LCMS(m/z):388.2(M+H)。 At room temperature, to 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (500mg, 2.12mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- Indazol-4-ol (492mg, 2.12mmol), N ¹ , N ² -bis(naphthalene-1-ylmethyl)oxamide (150mg, 0.40mmol), sodium tert-butoxide (407mg, 4.24mmol),

A solution of molecular sieve (500mg) in 1,4-dioxane (10mL) was added with cuprous iodide (38mg, 0.20mmol). The mixture was heated to 110°C and stirred for 16 h. After cooling to room temperature, the filtrate was filtered off with suction, concentrated, and purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a yellow solid 3-amino-4-((5-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxylic acid methyl ester (120 mg, yield 15%). LCMS (m/z): 388.2 (M+H).

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

For the subsequent synthesis method of Example A81, refer to the description in Intermediate A1 and Example A2. ¹ H NMR (400MHz, methanol-d ₄ ) δ 7.39–7.26 (m, 3H), 7.20 (s, 1H), 6.83 (dd, J = 16.8, 10.6 Hz, 1H), 6.26 (dd, J = 16.8 ,1.9Hz,1H),5.80(dd,J=10.6,1.9Hz,1H),5.11–5.06(m,1H),4.08–4.00(m,1H),3.97–3.79(m,8H),3.35( s, 3H), 2.97 (dd, J = 10.5, 6.0 Hz, 1H), 2.73 (dd, J = 11.5, 6.3 Hz, 1H), 2.53 (dd, J = 10.4, 4.3 Hz, 1H), 2.39 (s ,3H), 2.32(dd,J=11.6,3.0Hz,1H),2.28(s,3H).LCMS(m/z): 574.0(M+H).

According to a method similar to the synthetic method of the above-mentioned Example A series of compounds, the following compounds of Example A82 to Example A109 were also prepared and characterized:

Examples A110 and A111

或者

or

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 or 4-(4-acryloylpiperazin-1-yl)-8- ((5-Chloro-6-fluoro-2-methyl-2H-indazol-4-yl)oxy)-2-((3R,4R)-4-methoxy-1-methylpyrrolidine- 3-yl)oxy)quinoline-3-carbonitrile

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

Under ice bath stirring, NaH (24mg, 60%w/w, 0.6mmol) was added to 4-(2-chloro-8-((5-chloro-6-fluoro-1H-indazol-4-yl) (Oxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (330 mg, 0.6 mmol) and methyl iodide (100 mg, 0.7 mmol) in anhydrous tetrahydrofuran (5 mL). Remove the ice bath, slowly warm to room temperature and stir. After the completion of the reaction monitored by TLC, (3R, 4R)-4-methoxy-1-methylpyrrolidin-3-ol (210mg, 1.6mmol) and NaH (64mg, 60% w/w, 1.6mmol) were added in sequence , The resulting mixture continued to be stirred until the completion of the reaction was monitored by LCMS. The reaction was quenched by adding water (5 mL), the organic phase was separated and the aqueous phase was extracted with EA (10 mL×3). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was directly used in the next step without purification.

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)

The subsequent synthesis methods of Example A110 and Example A111 refer to the synthesis of Example A1. In 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-methylpyrrolidin-2-yl)methoxy)quinoline -4-yl)piperazine-1-carboxylic acid tert-butyl ester. Example A110 or A111, ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.92 (dd, J = 8.5, 1.4 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.57-7.49 (m,1H),7.43-7.34(m,1H),7.25(s,1H),6.91(dd,J=16.6,10.4Hz,1H),6.19(dd,J=16.6,2.4Hz,1H), 5.75 (dd, J = 10.4, 2.4 Hz, 1H), 4.81 (s, 1H), 3.99–3.79 (m, 8H), 3.66 (s, 4H), 3.14 (s, 3H), 3.01 (dd, J = 9.8,6.7Hz,1H),2.40–1.98(m,5H).LCMS(m/z): 620.3(M+H);

Example A111 or A110, ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.99 (dd, J = 8.5, 1.3 Hz, 1H), 7.83 (dd, J = 7.7, 1.2 Hz, 1H), 7.68-7.50 (m, 2H), 6.91 (dd, J = 16.7, 10.4 Hz, 1H), 6.53 (s, 1H), 6.19 (dd, J = 16.7, 2.4 Hz, 1H), 5.76 (dd, J = 10.4, 2.4 Hz, 1H), 4.55 (s, 1H), 4.05-3.79 (m, 8H), 3.67 (s, 4H), 3.08 (s, 3H), 3.01 (dd, J = 9.7, 6.6 Hz, 1H), 2.17 –1.96(m,5H).LCMS(m/z): 620.3(M+H).

Synthesis of intermediate A8

2,4-Dichloro-8-(2-fluoro-6-methoxyphenoxy)quinoline-3-carbonitrile

The synthesis of 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. LCMS(m/z): 363.1(M+H).

Synthesis of intermediate A9

Tert-Butyl 4-(2-chloro-3-cyano-8-(2-fluoro-6-hydroxyphenoxy)quinolin-4-yl)piperazine-1-carboxylate

Step A: 2,4-Dichloro-8-(2-fluoro-6-hydroxyphenoxy)quinoline-3-carbonitrile

With stirring in an ice bath, boron trichloride (7.0 mL, 1M n-hexane solution, 7.0 mmol) was slowly added dropwise to 2,4-dichloro-8-(2-fluoro-6-methoxyphenoxy)quine In DCM (20 mL). After the dropwise addition was completed, the temperature was raised to 50°C and reacted for 48 hours. LCMS monitored the completion of the reaction, cooled the system to room temperature, slowly added saturated aqueous NaHCO ₃ (10 mL) to quench the reaction, separated the organic phase, and extracted the aqueous phase with DCM (10 ml×3). The organic phases were combined, washed with saturated aqueous NaCl (30 mL), and dried over anhydrous Na ₂ SO ₄ . Filter and concentrate to obtain the crude product and _{purify by FCC (SiO 2} , EA/PE=0-80%) to obtain 2,4-dichloro-8-(2-fluoro-6-hydroxyphenoxy)quinoline-3-carbon Nitrile (900 mg, yield 93%). LCMS(m/z): 349.1(M+H).

Step B: tert-Butyl 4-(2-chloro-3-cyano-8-(2-fluoro-6-hydroxyphenoxy)quinolin-4-yl)piperazine-1-carboxylate

Under stirring at room temperature, 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). The organic phases were combined and dried with anhydrous Na ₂ SO _4. The crude product obtained by concentration was purified with FCC (SiO ₂ , EA/PE=0-80%), Obtain 4-(2-chloro-3-cyano-8-(2-fluoro-6-hydroxyphenoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (1.05g, yield 81%).LCMS (m/z): 499.1 (M+H).

Example A112

4-(4-acryloylpiperazin-1-yl)-2-(3-((dimethylamino)methyl)phenyl)-8-(2-fluoro-6-hydroxyphenoxy)quinoline- 3-carbon nitrile

Step A: 4-(3-cyano-2-(3-((dimethylamino)methyl)phenyl)-8-(2-fluoro-6-hydroxyphenoxy)quinolin-4-yl) Tert-butyl piperazine-1-carboxylate

Add 4-(2-chloro-3-cyano-8-(2-fluoro-6-hydroxyphenoxy)quinolin-4-yl)piperazine-1- Tert-butyl carboxylate (150mg, 0.3mmol), (3-((dimethylamino)methyl)phenyl)boronic acid ( _{72mg, 0.4mmol), Pd(dppf)Cl 2} (11mg, 15umol) and K ₂ CO ₃ (81 mg, 0.6 mmol) in DME/H ₂ O (v/v=10:1, 2.75 mL) solution. After nitrogen replacement, the system was heated in microwave at 90°C for 1 h. Cool to room temperature, add EA (20 mL) to dilute the system, wash with saturated aqueous NaCl (15 mL×2), and dry with anhydrous Na ₂ SO ₄ . The crude product obtained by filtration and concentration was purified with FCC (SiO ₂ , MeOH/DCM=0-50%) to obtain 4-(3-cyano-2-(3-((dimethylamino)methyl)phenyl)-8 -(2-Fluoro-6-hydroxyphenoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (135 mg, yield 75%). LCMS(m/z): 598.6(M+H).

Steps B and C: 4-(4-acryloylpiperazin-1-yl)-2-(3-((dimethylamino)methyl)phenyl)-8-(2-fluoro-6-hydroxyphenoxy) Yl)quinoline-3-carbonitrile

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. ¹ H NMR(400MHz, chloroform-d) δ8.04-7.91(m,3H), 7.85(d,J=8.5Hz,1H), 7.71-7.52(m,4H), 7.03-6.88(m,1H) ,6.73-6.55(m,3H),6.38(d,J=16.7Hz,1H),5.80(d,J=10.4Hz,1H),4.12-3.69(m,10H),2.83-2.52(m,6H ) .LCMS (m / z): 598.6 (m + H) 19 F NMR (376MHz, cHLOROFORM -d) δ-75.46, -127.98.LCMS ( m / z):. 552.5 (m + H).

Example A113

4-(4-acryloylpiperazin-1-yl)-2-(3-(1-(dimethylamino)ethyl)phenyl)-8-(2-fluoro-6-hydroxyphenoxy)quine Phenyl-3-carbonitrile

The synthesis of Example A113 refers to the synthesis of Example A112. In step A, (3-(1-(dimethylamino)ethyl)phenyl)boronic acid was used instead of (3-((dimethylamino)methyl)benzene.基)Boric acid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.18 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.71–7.62 (m, 1H), 7.58– 7.45(m,3H), 7.19–7.08(m,1H), 7.00(d,J=7.8Hz,1H), 6.97–6.79(m,3H), 6.20(dd,J=16.6,2.4Hz,1H) ,5.76(dd,J=10.4,2.4Hz,1H),3.90(s,4H),3.72(s,4H),3.42–3.34(m,1H),2.16(s,6H),1.33(d,J =6.6Hz,3H).LCMS(m/z):566.5(M+H).

Example A114

4-(4-acryloylpiperazin-1-yl)-8-(2-fluoro-6-hydroxyphenoxy)-2-((3R,4R)-4-methoxy-1-methylpyrrole (Alk-3-yl)oxy)quinoline-3-carbonitrile

The synthesis of Example A114 refers to the synthesis described in Example A1. In 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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.14 (s, 1H), 7.71-7.61 (m, 1H), 7.38-7.28 (m, 1H), 7.14-7.01 (m, 1H), 6.97-6.85 (m,2H),6.84-6.70(m,2H),6.18(dd,J=16.7,2.4Hz,1H), 5.74(dd,J=10.4,2.4Hz,1H),5.40-5.29(m,1H ),3.99–3.92(m,1H),3.91–3.79(m,4H),3.62(s,4H),3.33(s,3H),3.02(dd,J=9.9,6.5Hz,1H),2.87( dd, J = 10.8, 6.1 Hz, 1H), 2.60 (dd, J = 10.7, 3.0 Hz, 1H), 2.31 (dd, J = 9.8, 4.9 Hz, 1H), 2.23 (s, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ )δ-130.63.LCMS(m/z): 548.5(M+H).

According to a method similar to the synthetic method of the above-mentioned Example A series of compounds, the following Example A115 compounds were also prepared and characterized:

Synthesis of intermediate A10

Tert-Butyl 4-(2-chloro-8-(3-chloro-2-fluoro-6-methoxyphenoxy)-3-cyanoquinolin-4-yl)piperazine-1-carboxylate

The synthesis of intermediate A10 refers to the synthesis of intermediate A1. In step A, 2-fluoro-6-methoxyphenol is used instead of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazol-4-ol. LCMS (m/z): 457.1 (M+H).

Example A116

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

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

Compound 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-methoxyphenoxy)-2-((3R,4R)-4-methoxy For the synthesis of phenyl-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile, refer to the synthesis described in Example A1. In 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 . After filtration and concentration under reduced pressure, the crude product obtained was purified by high performance liquid chromatography to obtain 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-hydroxyphenoxy) as a white solid )-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile (8.2mg, total yield of four steps 2.3%) . ¹ H NMR(400MHz, methanol-d ₄ )δ7.83-7.76(m,1H), 7.39(t,J=8.2Hz,1H), 7.21-7.10(m,2H), 6.87(dd,J=16.8 , 10.6Hz, 1H), 6.79 (dd, J = 9.0, 1.9 Hz, 1H), 6.30 (dd, J = 16.7, 2.0 Hz, 1H), 5.83 (dd, J = 10.6, 1.9 Hz, 1H), 5.35 (dt,J=5.4,2.4Hz,1H), 4.12(ddd,J=6.2,4.3,1.8Hz,1H), 3.97(d,J=5.5Hz,4H), 3.75(s,4H), 3.43( s, 3H), 3.18 (dd, J = 11.5, 6.2 Hz, 1H), 3.09 (dd, J = 10.5, 6.0 Hz, 1H), 2.72 (dd, J = 11.5, 3.0 Hz, 1H), 2.62 (dd , J = 10.5, 4.4 Hz, 1H), 2.39 (s, 3H). ¹⁹ F NMR (376MHz, methanol-d ₄ ) δ-132.78.LCMS (m/z): 582.5 (M+H).

Synthesis of intermediate A11

7-(2-Chloro-3-cyano-8-(2-fluoro-6-methoxyphenoxy)quinolin-4-yl)-2,7-diazaspiro[3.5]nonane- Tert-Butyl 2-carboxylate

The synthesis of intermediate A11 refers to the synthesis of intermediate A1. In 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. LCMS(m/z): 553.2(M+H).

Example A117

4-(2-acryloyl-2,7-diazaspiro[3.5]non-7-yl)-8-(2-fluoro-6-hydroxyphenoxy)-2-((3R,4R)- 4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile

The synthesis of Example A117 refers to the synthesis method of Example A116. In 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). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.60(d,J=8.5Hz,1H), 7.36–7.28(m,1H), 7.13–7.04(m,1H), 6.93(d,J=7.8 Hz,1H), 6.87–6.75(m,2H), 6.42–6.32(m,1H), 6.13(dd,J=16.9,2.3Hz,1H), 5.69(dd,J=10.2,2.3Hz,1H) ,5.38–5.30(m,1H),4.07(s,2H),3.98–3.90(m,1H), 3.77(s,2H), 3.67–3.50(m,5H), 3.32(s,3H),3.02 (dd,J=9.9,6.5Hz,1H), 2.87(dd,J=10.8,6.1Hz,1H), 2.60(dd,J=10.7,3.0Hz,1H), 2.31(dd,J=9.8,4.9 Hz, 1H), 2.24 (s, 3H), 2.01 (t, J = 5.6 Hz, 4H). ¹⁹ F NMR(376MHz, DMSO-d ₆ )δ-30.57.LCMS(m/z): 588.6(M+ H).

Synthesis of intermediate A12

4-(6-chloro-3-cyano-8-(2-fluoro-6-methoxyphenoxy)-2-(((3R,4R)-4-methoxy-1-methylpyrrole (Alk-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

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

At 0℃, NaH (647mg, 60% w/w, 19mmol) was added to (3R, 4R)-4-methoxy-1-methylpyrrolidin-3-ol (707mg, 6.3mmol) and tetrahydrofuran In the mixed solution, react for 10 minutes, 4-(7-bromo-2,6-dichloro-3-cyano-8-fluoroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (3.2 g, 6.3 mmol, purity 85%) was added to the reaction system and stirred at 0°C for 20 minutes. After the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL), extracted with EA (50 mL×3), and the extract was collected and concentrated to obtain 4-(7-bromo-6-chloro-3-cyano) as a yellow solid -8-Fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert Butyl ester (1.6g, yield 51%). LCMS (m/z): 598.4 (M+H).

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

Put 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 (600mg, 1mmol), HCOOH (138mg, 3mmol), Pd(PPh ₃ ) ₄ (116mg, 0.1mmol), Et ₃ N (203mg, 2mmol) was dissolved in DMF (15mL), replaced with nitrogen twice, heated to 55°C and stirred for 6h. After the reaction, the reaction solution was poured into water (100mL), EA (50mL×2) was extracted, the extract was collected and concentrated to obtain a crude product, which was then purified by FCC (SiO ₂ , THF/DCM=0-30%) to obtain Yellow solid 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 (500mg, yield 96%).

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

Put 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 (200mg, 0.38mmol), 2-fluoro-6-methoxyphenol (109mg, 0.76mmol), Cs ₂ CO ₃ (376mg, 1.1mmol) dissolved in DMF (8mL) and heated to 110°C and stirred overnight. After the reaction, the reaction solution was poured into water (50mL) and extracted with ethyl acetate (30mL×3). The extract was collected and concentrated to obtain a yellow solid 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 (320mg, crude product), directly put into the next step without purification.

Example A118

4-(4-acryloylpiperazin-1-yl)-6-chloro-8-(2-fluoro-6-hydroxyphenoxy)-2-((3R,4R)-4-methoxy-1 -Methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile

The synthesis of 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. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.64(d,J=2.2Hz,1H), 7.12(q,J=7.7Hz,1H), 6.94–6.79(m,4H), 6.19(dd, J = 16.7, 2.4Hz, 1H), 5.75 (dd, J = 10.4, 2.4Hz, 1H), 5.31 (dd, J = 5.6, 2.8Hz, 1H), 3.98–3.92 (m, 1H), 3.84 (d ,J＝18.2Hz,5H),3.63(s,4H),3.32(s,3H),3.03(dd,J＝9.8,6.5Hz,1H),2.85(dd,J＝10.9,6.1Hz,1H) , 2.61 (dd, J = 10.8, 2.9 Hz, 1H), 2.30 (dd, J = 9.9, 4.9 Hz, 1H), 2.23 (s, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ )δ-130.68 .LCMS(m/z): 582.5(M+H).

Synthesis of intermediate A13

Tert-Butyl 4-(8-bromo-2-chloro-3-cyanoquinolin-4-yl)piperazine-1-carboxylate

Step A: Methyl 3-bromo-2-(2-cyanoacetamido)benzoate

Under nitrogen protection at room temperature, TCFH (195g, 695mmol) was added to methyl 2-amino-3-bromobenzoate (80g, 348mmol), 2-cyanoacetic acid (59.2g, 695mmol) and 1-methyl in batches. Imidazole (85.6 g, 1.04 mol) in acetonitrile (1000 mL). The resulting mixture was stirred at room temperature for 12 h, and the completion of the reaction was monitored by LCMS. Concentrate under reduced pressure to remove acetonitrile, add water (1000 mL) to dilute the system, and extract with DCM (500 mL×2). The organic phases were combined, washed with saturated brine, and dried over anhydrous Na ₂ SO ₄ . The crude product obtained by filtration and concentration was purified by FCC (SiO ₂ , EA/PE=0-30%) to obtain methyl 3-bromo-2-(2-cyanoacetamido)benzoate (60g, yield 58%) as a yellow solid ).

Step B: 8-bromo-2,4-dihydroxyquinoline-3-carbonitrile

Potassium tert-butoxide (41.5g, 370mmol) was slowly added to a solution of methyl 3-bromo-2-(2-cyanoacetamido)benzoate (55g, 185mmol) in THF (500mL), and the resulting mixture was continued at room temperature Stir for 1h. The completion of the reaction was monitored by TLC, filtered, and the obtained solid was slurried with water to obtain a crude yellow solid (51 g, crude product) 8-bromo-2,4-dihydroxyquinoline-3-carbonitrile and used directly in the next step.

Step C: 8-bromo-2,4-dichloroquinoline-3-carbonitrile

At room temperature, 8-bromo-2,4-dihydroxyquinoline-3-carbonitrile (50 g, 189 mmol) was slowly added to phosphorus oxychloride (187 mL, 2.01 mol). The reaction solution was heated to 110°C and stirred for 12h. LCMS monitors the completion of the reaction. After the phosphorus oxychloride was distilled off, the crude product was dissolved in DCM (500 mL), and the DCM solution was slowly poured into an ice-water mixture (1000 mL). The system was extracted with DCM (500 mL×3), the organic phases were combined, washed with saturated aqueous NaCl (500 mL), and dried over anhydrous Na ₂ SO ₄ . It was filtered and concentrated under reduced pressure to obtain the crude product (50 g, yield 88%), which was directly used in the next reaction.

Step D: tert-Butyl 4-(8-bromo-2-chloro-3-cyanoquinolin-4-yl)piperazine-1-carboxylate

At room temperature, under nitrogen protection, DIEA (53.5g, 414mmol) was added to 8-bromo-2,4-dichloroquinoline-3-carbonitrile (50g, 166mmol) and piperazine-1-carboxylic acid tert-butyl ester ( 55.5 g, 298 mmol) in THF (500 mL). The reaction mixture was continuously stirred at room temperature for 12 h. LCMS monitored the completion of the reaction, and concentrated under reduced pressure to remove THF. The system was diluted by adding water (500 mL), and then extracted with DCM (500 mL×2). The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product obtained was slurried with methyl tert-butyl ether to obtain a yellow solid 4-(8-bromo-2-chloro-3- Cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (60 g, yield 80%). LCMS (m/z): 453.0 (M+H).

Synthesis of intermediate A14

4-(3-cyano-8-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piper Oxazine-1-carboxylic acid tert-butyl ester

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

Add NaH (32mg, 60% w/w, 0.80mmol) to (3R, 4R)-4-methoxy-1-methylpyrrolidin-3-ol (96mg, 0.73mmol) in THF (3mL) After stirring for 5 min at room temperature, add 4-(8-bromo-2-chloro-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A13, 300mg, 0.66mmol )join in. After the reaction system was stirred at room temperature for 1 h, a saturated aqueous solution of ammonium chloride (20 mL) was added to extract the reaction. The mixture was extracted with EA (15 mL×2), washed with saturated brine (20 mL×2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain 4-(8-bromo-3-cyano-2- (((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (300mg, yield 83%), directly used in the next step.

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

The 4-(8-bromo-3-cyano-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl) Tert-butyl piperazine-1-carboxylate (300mg, 0.73mmol), Pd ₂ dba ₃ (67mg, 0.073mmol), tBuXphos (46mg, 0.11mmol) and KOH (205mg, 3.66mmol) dissolved in 6mL dioxane And 2mL of water, stirring at 90°C for 2h under nitrogen protection. After the reaction was cooled to the greenhouse, 1N HCl was added to adjust the pH to 7. The mixture was extracted with EA (15mL×2), the organic phases were combined, washed with saturated aqueous NaCl (20mL×2), dried with anhydrous Na ₂ SO ₄ , concentrated and purified by FCC (SiO ₂ , MeOH/DCM=0-20%) , A white solid 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 (250 mg, yield 94%). LCMS (m/z): 484.5 (M+H).

Example A119

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

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

The 4-(3-cyano-8-hydroxy-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl) Piperazine-1-carboxylic acid tert-butyl ester (250mg, 0.52mmol), 1-chloro-2,3-difluoro-4-nitrobenzene (110mg, 0.57mmol) and potassium carbonate (143mg, 1.0mmol) in DMF (5mL) The solution was stirred and reacted at 70°C for 2h. After the reaction was cooled to the greenhouse, the reaction mixture was poured into 30 mL of water, the mixture was extracted with EA (25 mL×2), washed with saturated brine (20 mL×2), dried with anhydrous sodium sulfate, concentrated and passed through FCC (SiO ₂ , MeOH) /DCM=0-20%) to obtain a yellow solid 4-(8-(3-chloro-2-fluoro-6-nitrophenoxy)-3-cyano-2-(((3R,4R) -4-Methoxy-1-methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (270 mg, yield 79%). LCMS (m/z): 657.6 (M+H).

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

At room temperature, the 4-(8-(3-chloro-2-fluoro-6-nitrophenoxy)-3-cyano-2-(((3R,4R)-4-methoxy-1- Methylpyrrolidin-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (270mg, 0.41mmol) was added to TFA (3mL) in portions, and the resulting mixture was at room temperature Stirring was continued for 1 h, and LCMS monitored the reaction to be complete. The crude product was obtained after concentration under reduced pressure, which was directly used in the next reaction. LCMS(m/z): 557.5(M+H).

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. After concentration under reduced pressure, 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-nitrophenoxy)-2-((3R, 4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile (250mg, yield 99%), used directly in the next step. LCMS (m/z): 611.6 (M+H).

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

Add 4-(4-acryloylpiperazin-1-yl)-8-(3-chloro-2-fluoro-6-nitrophenoxy)-2-((3R,4R)-4-methoxy -1-Methylpyrrolidin-3-yl)oxy)quinoline-3-carbonitrile (250mg, 0.41mmol), iron powder (114mg, 2.0mmol) and ammonium chloride (219mg, 4.1mmol) dissolved in MeOH (15mL), the resulting mixture was reacted at 70°C for 2h. After the reaction was cooled to room temperature, the reaction solution was filtered through Celite. After the filtrate was concentrated to dryness, EA (25 mL) and water (25 mL) were added, the organic phase was separated and collected, and the aqueous phase was extracted once with EA (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain 4-(4-acryloylpiperazin-1-yl) as a white solid -8-(6-Amino-3-chloro-2-fluorophenoxy)-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quine Phloline-3-carbonitrile (35mg, yield 15%). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.77–7.68(m,1H), 7.42–7.33(m,1H), 7.18–7.05(m,2H), 6.90(dd,J=16.7, 10.4Hz ,1H), 6.67(dd,J＝9.0,1.7Hz,1H), 6.19(dd,J＝16.7,2.4Hz,1H), 5.75(dd,J＝10.4,2.4Hz,1H),5.51–5.42( m,2H), 5.40-5.33(m,1H), 4.03-3.95(m,1H), 3.93-3.79(m,4H), 3.72-3.57(m,4H), 3.32(s,3H), 3.04( dd, J = 9.8, 6.5 Hz, 1H), 2.88 (dd, J = 10.9, 6.1 Hz, 1H), 2.63 (dd, J = 10.9, 2.9 Hz, 1H), 2.31 (dd, J = 9.8, 5.1 Hz , 1H), 2.24 (s, 3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-133.43.LCMS (m/z): 581.2 (M+H).

Example A120

4-(4-acryloylpiperazin-1-yl)-8-(2-amino-6-fluorophenoxy)-2-((3R,4R)-4-methoxy-1-methylpyrrole (Alk-3-yl)oxy)quinoline-3-carbonitrile

The synthesis of Example A120 refers to the synthesis of Example A119. In step A, 1,2-difluoro-3-nitrobenzene was used instead of 1-chloro-2,3-difluoro-4-nitrobenzene. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.74–7.66(m,1H), 7.41–7.30(m,1H), 7.03–6.86(m,3H), 6.65(d,J=8.2Hz,1H ), 6.55–6.43(m,1H), 6.19(dd,J=16.7,2.4Hz,1H), 5.76(dd,J=10.4,2.4Hz,1H), 5.49–5.39(m,1H), 5.27( s,2H),4.03-3.96(m,1H),3.93-3.78(m,4H),3.70-3.58(m,4H),3.35(s,3H),3.04(dd,J=9.9,6.5Hz, 1H), 2.94 (dd, J = 10.9, 6.1 Hz, 1H), 2.66 (dd, J = 10.7, 3.0 Hz, 1H), 2.34 (dd, J = 9.9, 5.0 Hz, 1H), 2.25 (s, 3H ). ¹⁹ F NMR(376MHz, DMSO-d ₆ )δ-131.57.LCMS(m/z): 574.5(M+H).

Synthesis of intermediate A15

4-(8-Bromo-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1- Tert-butyl carboxylate

Under the protection of nitrogen, in 4-(8-bromo-2-chloro-3-cyano-4-quinolinyl) piperazine-1-carboxylic acid tert-butyl ester (23g, 50.9mmol) and 2-methyl-5 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (18.1g, To a MeCN (1700 mL)/H ₂ O (400 mL) solution of _{66.2 mmol), K 2} CO ₃ (14.1 g, 102 mmol) and Pd(PPh ₃ ) ₄ (2.94 g, 2.55 mmol) were added. The resulting mixture was heated to 40°C to react for 24 hours, and LCMS monitored the completion of the reaction. After the mixture was concentrated under reduced pressure to remove CAN, H ₂ O (500 mL) and DCM (1000 mL×2) were added for extraction, and the combined organic phase was dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by FCC (SiO ₂ , EA/PE=0-50%) to obtain 4-(8-bromo-3-cyano-2-(2-methyl-1, 2,3,4-Tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (39 g, yield 45%). LCMS(m/z): 562.1(M+H).

Synthesis of intermediate A16

4-(3-cyano-8-hydroxy-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1- Tert-butyl carboxylate

The 4-(8-bromo-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1 -Tert-butyl carboxylate (34 g, 60.4 mmol) was dissolved in a _{mixed solution of H 2} O (600 mL) and 1,4-dioxane (600 mL). KOH (13.6g, 242mmol), Pd ₂ dba ₃ (1.11g, 1.21mmol) and tBuXphos (1.54g, 3.63mmol) were added under nitrogen protection. The resulting mixture was heated to 90°C and stirred for 2h. Concentrate under reduced pressure to remove about 600 mL of solvent, cool to room temperature, adjust pH to 7 with 1N hydrochloric acid, and extract the system with DCM (500 mL×2). The combined organic phase was washed with saturated brine (500 mL), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the crude product was purified by FCC (SiO ₂ , EA/PE=0-40%) to obtain a pale yellow solid (12.1 g, yield 40%). LCMS (m/z): 500.2 (M+H).

Example A121

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

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

At room temperature, add 4-(8-bromo-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-5- Yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A15, 300mg, 0.53mmol), (7-fluoro-4-hydroxybenzo[d]thiazol-2-yl)amino Tert-Butyl formate (230mg, 0.81mmol), CuI (21mg, 0.11mmol), N ¹ -benzyl-N ² -(5-methyl-[1,1'-biphenyl]-2-yl)oxamide (73mg, 0.21mmol), potassium carbonate (221mg, 1.60mmol). After the nitrogen was pumped three times, DMSO (3ml) was added, and the reaction system was heated to 100°C and stirred for 16h. After the reaction was monitored by LCMS, the reaction solution was poured into water, and the crude product obtained by suction filtration was purified by FCC (SiO ₂ , EA/PE=0-80%) to obtain 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 (150 mg, yield 37%). LCMS(m/z): 766.3(M+H).

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

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. 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-methylpyrrolidine-2- (Yl)methoxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.86(d,J=8.5Hz,1H), 7.82–7.72(m,2H), 7.58–7.49(m,1H), 7.45–7.37(m,1H) ), 7.36–7.27(m,2H), 7.27–7.19(m,1H), 7.05–6.95(m,1H), 6.89(dd,J=16.6,10.4Hz,1H), 6.79(d,J=7.6 Hz, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.74 (d, J = 10.4 Hz, 1H), 3.92–3.79 (m, 4H), 3.74–3.56 (m, 6H), 2.90–2.71 (m, 2H), 2.59--2.53 (m, 2H), 2.35 (s, 3H). LCMS (m/z): 620.4 (M+H).

Example A122

4-(4-acryloylpiperazin-1-yl)-8-((7-fluoro-5-methyl-1H-indazol-4-yl)oxy)-2-(2-methyl-1 ,2,3,4-Tetrahydroisoquinolin-5-yl)quinoline-3-carbonitrile

The synthesis of Example A122 refers to the synthesis of Example A121. In 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. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.95(d,J=8.7Hz,1H), 7.58–7.43(m,2H), 7.34(s,1H), 7.26(s,1H), 7.11( d, J = 11.2 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.88 (dd, J = 16.8, 10.6 Hz, 1H), 6.30 (d, J = 16.7 Hz, 1H), 5.83 ( d, J = 10.7Hz, 1H), 4.01 (s, 4H), 3.84 (s, 4H), 3.76 (s, 2H), 2.85-2.67 (m, 4H), 2.46 (s, 3H), 2.28 (s ,3H).LCMS(m/z): 602.4(M+H).

Example A123

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 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

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 is synthesized as described in Example A121, in step A Use 2-((4-methoxybenzyl)oxy)-6-methylquinolin-5-ol instead of (7-fluoro-4-hydroxybenzo[d]thiazol-2-yl) carbamate 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

Add 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)tert-butyl piperazine-1-carboxylate (130mg, 0.167mmol) dissolved in 1mL TFA, microwave Heat to 120°C and react for 1h. The crude product obtained after desolvation was directly used in the next reaction.

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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.91 (s, 1H), 8.33 (s, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 9.7 Hz, 1H) ,7.52(d,J=8.5Hz,1H),7.50–7.42(m,1H),7.37–7.28(m,2H),7.22(dd,J=8.3,4.5Hz,2H),6.91(dd,J = 16.7, 10.5 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.41 (d, J = 9.8 Hz, 1H), 6.19 (dd, J = 16.7, 2.4 Hz, 1H), 5.75 (dd ,J=10.4,2.4Hz,1H),3.93-3.82(m,4H),3.74-3.68(m,4H),3.63-3.59(m,2H),2.82-2.73(m,2H),2.61-2.55 (m,2H),2.35(s,3H),2.09(s,3H).LCMS(m/z): 611.5(M+H).

Example A124

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

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

At room temperature, add 4-(3-cyano-8-hydroxy-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-5) into a capped reaction flask equipped with a magnet. -Yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A16, 50mg, 0.1mmol), 6-bromo-5-methylpyrazine-2-amine (23mg, 0.12mmol ), CuI (19mg, 0.1mmol), N ¹ -benzyl-N ² -(5-methyl-[1,1'-biphenyl]-2-yl)oxamide (21mg, 0.06mmol), K ₃ PO ₄ (64mg, 0.3mmol). After the nitrogen was pumped three times, DMSO (2ml) was added, and the reaction system was heated to 120°C and stirred for 16h. After LCMS monitoring the completion of the reaction, the 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. Filtered and concentrated under reduced pressure to obtain a crude product, which was purified by FCC (SiO ₂ , MeOH/DCM=0-20%) to obtain 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 ( 45mg, yield 74%). LCMS(m/z): 607.5(M+H).

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

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. -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. ¹ H NMR (400MHz, methanol-d ₄ ) δ 8.10 (d, J = 8.2 Hz, 1H), 7.75-7.61 (m, 2H), 7.43 (s, 1H), 7.28-7.12 (m, 3H), 6.87(dd,J=16.8,10.6Hz,1H),6.30(d,J=16.7Hz,1H),5.83(d,J=10.6Hz,1H),3.99(s,4H),3.80(s,4H ), 3.68(s, 2H), 2.64–2.54(m, 2H), 2.54–2.46(m, 2H), 2.42(s, 6H). LCMS(m/z): 561.5(M+H).

The synthesis method of Examples A125-127 was completed with reference to the description in Example A124.

Example A128

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

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

At room temperature, add 4-(3-cyano-8-hydroxy-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-5) into a capped reaction flask equipped with a magnet. -Yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A16, 100mg, 0.2mmol), 4-chloro-5-methylpyrimidin-2-amine (34mg, 0.24mmol) , Ag ₂ O (73.8 mg, 0.6 mmol), DMF (5 ml). The resulting mixture was heated to 120°C and stirred for reaction. After LCMS monitoring the completion of the reaction, the 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. It was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by FCC (SiO ₂ , MeOH/DCM=0-20%) to obtain 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 (55mg , Yield 45%). LCMS(m/z): 607.5(M+H).

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

The subsequent synthesis method of Example A128 refers to that described in Example A1. In 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. LCMS(m/z): 561.4(M+H).

Example A129

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

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

At room temperature, to 4-(3-cyano-8-hydroxy-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl) Piperazine-1-carboxylic acid tert-butyl ester (Intermediate A16, 200mg, 0.400mmol) and 6-amino-3-chloro-2-fluorobenzonitrile (102mg, 0.598mmol) in DMF (3mL) solution was added K ₂ CO ₃ (166 mg, 1.20 mmol). The mixture was heated to 60°C and stirred for 16 h. After cooling to room temperature, the mixture was poured into H ₂ O (30 mL) and extracted with EA (8 mL×3). The organic phase was washed with a saturated aqueous NaCl solution (8mL×2), dried with anhydrous Na ₂ SO ₄ , and purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a pale yellow solid 4-(8-(3-amino) -6-Chloro-2-cyanophenoxy)-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinoline-4- Yl)piperazine-1-carboxylic acid tert-butyl ester (140 mg, yield 54%). LCMS(m/z): 650.4(M+H)

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

The subsequent synthesis method of Example A129 refers to that described in Example A1. In 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. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.89(d,J=8.5Hz,1H), 7.60–7.46(m,2H), 7.33–7.19(m,3H), 7.04–6.85(m,2H ), 6.73 (d, J = 9.2 Hz, 1H), 6.52 (s, 2H), 6.18 (dd, J = 16.7, 2.4 Hz, 1H), 5.75 (dd, J = 10.5, 2.4 Hz, 1H), 3.95 --3.81(m,4H),3.77–3.65(m,4H),3.58(s,2H),2.77–2.61(m,2H),2.57–2.51(m,2H),2.33(s,3H).LCMS (m/z): 604.4(M+H).

Synthesis of intermediate A17

4-(3-cyano-8-(2,3-diamino-6-methylphenoxy)-2-(2-methyl-1,2,3,4-tetrahydroisoquinoline-5 -Yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

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

At room temperature, to 4-(3-cyano-8-hydroxy-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl) Piperazine-1-carboxylic acid tert-butyl ester (Intermediate A16, 800mg, 1.60mmol) and 3-fluoro-4-methyl-2-nitroaniline (408mg, 2.40mmol) in DMF (10mL) solution was added K ₂ CO ₃ (662 mg, 4.80 mmol). The mixture was heated to 60°C and stirred for 16 h. After cooling to room temperature, the mixture was poured into H ₂ O (100 mL) and extracted with EA (30 mL×3). The organic phase was washed with a saturated aqueous NaCl solution (20×2 mL), dried over anhydrous Na ₂ SO ₄ , and purified by FCC (SiO ₂ , EA/PE=0-100%) to obtain a pale yellow solid 4-(8-(3-amino) -6-Chloro-2-cyanophenoxy)-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinoline-4- Yl)piperazine-1-carboxylic acid tert-butyl ester (650 mg, yield 62%). LCMS(m/z): 650.5(M+H).

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

At room temperature, add 4-(8-(3-amino-6-methyl-2-nitrophenoxy)-3-cyano-2-(2-methyl-1,2,3,4- Tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (400mg, 0.61mmol) and ammonium chloride (132mg, 2.47mmol) in MeOH (10mL) Iron powder (103mg, 1.84mmol) was added. The mixture was heated to 80°C and stirred for 16h. After cooling to room temperature, after suction filtration, the filtrate was spin-dried and concentrated to obtain 4-(3-cyano-8-(2,3-diamino-6-methylphenoxy)-2-(2-methyl) -1,2,3,4-Tetrahydroisoquinolin-5-yl)quinolin-4-yl)tert-butyl piperazine-1-carboxylate (340 mg, yield 89%). LCMS (m/z): 620.6 (M+H).

Example A130

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

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

At room temperature, to 4-(3-cyano-8-(2,3-diamino-6-methylphenoxy)-2-(2-methyl-1,2,3,4-tetrahydro To a solution of isoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (340 mg, 0.55 mmol) in THF (5 mL) was added CDI (178 mg, 1.10 mmol). The mixture was heated to 80°C and stirred for 16h. After cooling to room temperature, the mixture was poured into H ₂ O (20 mL) and extracted with EA (10 mL×3). The organic phase was washed with a saturated aqueous NaCl solution (5 mL×2), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydro Isoquinolin-5-yl)-8-((5-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)oxy)quinoline-4 -Yl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, yield 56%). LCMS(m/z): 646.5(M+H).

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

The subsequent synthesis method of Example A130 refers to that described in Example A1. In 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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.75-10.67 (m, 2H), 7.84-7.78 (m, 1H), 7.50-7.44 (m, 1H), 7.30-7.27 (m, 2H), 7.24 –7.19(m,1H), 6.94–6.87(m,2H), 6.82–6.77(m,1H), 6.70(d,J=7.9Hz,1H), 6.18(dd,J=16.6,2.3Hz,1H ), 5.75(dd,J=10.5,2.4Hz,1H), 3.93–3.83(m,4H), 3.71–3.65(m,4H), 3.60–3.57(m,2H), 2.76–2.70(m,2H) ), 2.57--2.54(m,2H),2.34(s,3H),1.99(s,3H).LCMS(m/z): 600.5(M+H).

Example A131

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

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

At room temperature, to 4-(3-cyano-8-(2,3-diamino-6-methylphenoxy)-2-(2-methyl-1,2,3,4-tetrahydro Isoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (180mg, 0.29mmol) and trimethyl orthoformate (62mg, 0.58mmol) in THF (3mL) solution Add a drop of concentrated hydrochloric acid dropwise. The mixture was stirred at room temperature for 2h. After the reaction was completed, the mixture was poured into H ₂ O (10 mL) and extracted with EA (5 mL×3). The organic phase was washed with a saturated aqueous NaCl solution (5 mL×2), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydro Isoquinolin-5-yl)-8-((5-methyl-1H-benzimidazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (150mg , Yield 82%). LCMS (m/z): 630.6 (M+H).

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

The subsequent synthesis method of Example A130 refers to that described in Example A1. In 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. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 8.11-8.01 (m, 1H), 7.79 (dd, J = 17.3, 8.6 Hz, 1H), 7.54-7.35 (m, 2H) ), 7.33–7.25(m,2H), 7.24–7.13(m,2H), 6.90(dd,J=16.7,10.5Hz,1H), 6.68–6.59(m,1H), 6.18(dd,J=16.7 ,2.4Hz,1H),5.75(d,J=10.6Hz,1H),3.93-3.81(m,4H),3.73-3.65(m,4H),3.57(s,2H),2.79-2.65(m, 2H),2.58--2.52(m,2H),2.33(s,3H),2.20--2.11(m,3H).LCMS(m/z):584.5(M+H).

Example A132

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

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

At room temperature, to 4-(3-cyano-8-(2,3-diamino-6-methylphenoxy)-2-(2-methyl-1,2,3,4-tetrahydro Isoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (180mg, 0.29mmol) and sodium nitrite (40mg, 0.58mmol) in THF (3mL) solution are added dropwise A drop of glacial acetic acid. The mixture was stirred at room temperature for 2h. After the reaction was completed, the mixture was poured into H ₂ O (10 mL) and extracted with EA (5 mL×3). The organic phase was washed with a saturated aqueous NaCl solution (5 mL×2), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain 4-(3-cyano-2-(2-methyl-1,2,3,4-tetrahydro Isoquinolin-5-yl)-8-((5-methyl-1H-benzo[d][1,2,3]triazol-4-yl)oxy)quinolin-4-yl)piper Tert-butyl oxazine-1-carboxylate (150 mg, yield 82%). LCMS (m/z): 631.6 (M+H).

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

The subsequent synthesis method of Example A130 refers to that described in Example A1. In 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. ¹ H NMR(400MHz,DMSO-d ₆ )δ7.87(d,J=8.2Hz,1H), 7.76–7.66(m,1H), 7.59–7.39(m,3H), 7.37–7.17(m,3H) ), 6.97–6.79 (m, 2H), 6.19 (dd, J = 16.6, 2.4 Hz, 1H), 5.76 (dd, J = 10.4, 2.4 Hz, 1H), 3.97–3.83 (m, 4H), 3.80– 3.63(m,6H), 2.74–2.65(m,2H), 2.57–2.53(m,2H), 2.48–2.36(m,3H), 2.30–2.20(m,3H).LCMS(m/z): 585.5(M+H).

Example A133

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

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

At room temperature, to 4-(3-cyano-8-(2,3-diamino-6-methylphenoxy)-2-(2-methyl-1,2,3,4-tetrahydro Isoquinolin-5-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (530mg, 0.85mmol) in a mixed solution of methanol and water (v/v=1:1, 6mL) Bromoacetonitrile (113 mg, 0.94 mmol) was added. The mixture was stirred at room temperature for 4h. After the reaction was completed, the mixture was poured into H ₂ O (20 mL) and extracted with EA (10 mL×3). The organic phase was washed with a saturated aqueous NaCl solution (5 mL×2), dried over anhydrous Na ₂ SO ₄ , and concentrated to obtain 4-(8-((2-amino-5-methyl-1H-benzo[d]imidazole-4) -Yl)oxy)-3-cyano-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)quinolin-4-yl)piperazine-1- Tert-butyl carboxylate (120mg, 22% yield). LCMS(m/z): 645.6(M+H).

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

The subsequent synthesis method of Example A130 refers to that described in Example A1. In 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. ¹ H NMR(400MHz, methanol-d ₄ )δ8.47(s,2H), 7.85(d,J=8.5Hz,1H), 7.48–7.42(m,3H), 7.36–7.32(m,1H), 7.09(d,J=8.0Hz,1H), 7.00(d,J=8.1Hz,1H), 6.88–6.80(m,2H), 6.28(d,J=16.7Hz,1H), 5.81(d,J =10.5Hz,1H), 4.00–3.96(m,4H), 3.83–3.79(m,4H), 3.26–3.21(m,4H), 3.07–3.03(m,2H), 2.81(s,3H), 2.13(s,3H).LCMS(m/z): 599.5(M+H).

The synthesis method of Examples A134-135 was completed with reference to the description in Example A19.

Synthesis of intermediate A18

Tert-Butyl 4-(2-chloro-3-cyano-6-fluoro-8-(2-fluoro-6-methoxyphenoxy)quinolin-4-yl)piperazine-1-carboxylate

Step A: Methyl 2-amino-5-fluoro-3-(2-fluoro-6-methoxyphenoxy)benzoate

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. After the reaction, the reaction solution was poured into water (100mL), extracted with ethyl acetate (50mL×3), the extract was collected and concentrated to obtain a crude product, which was purified by FCC (SiO ₂ , EA/PE=0-25%). A brown solid, methyl 2-amino-5-fluoro-3-(2-fluoro-6-methoxyphenoxy)benzoate (1.6 g, crude product) was obtained. LCMS (m/z): 310.2 (M+H).

Step B to Step E: 4-(2-chloro-3-cyano-6-fluoro-8-(2-fluoro-6-methoxyphenoxy)quinolin-4-yl)piperazine-1- Tert-butyl carboxylate

The subsequent synthesis steps of Intermediate A18 were performed as described in the synthesis of Intermediate A1. LCMS (m/z): 531.3 (M+H).

Example A136

The synthesis of Example A136 refers to the synthesis method described in Example A116, and 4-(2-chloro-3-cyano-6-fluoro-8-(2-fluoro-6-methoxyphenoxy) was used in step A. )Quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A18) instead of 4-(2-chloro-8-(3-chloro-2-fluoro-6-methoxyphenoxy) ) Tert-Butyl-3-cyanoquinolin-4-yl)piperazine-1-carboxylate (Intermediate A10). ¹ H NMR(400MHz,DMSO-d ₆ )δ7.47–7.33(m,1H), 7.18–7.06(m,1H), 6.96–6.78(m,4H), 6.19(dd,J=16.6, 2.4Hz ,1H), 5.83--5.67(m,1H), 5.36--5.25(m,1H), 3.98--3.91(m,1H), 3.90--3.80(m,4H), 3.69--3.56(m,5H), 3.32 (s,3H),3.07–2.99(m,1H), 2.90–2.81(m,1H), 2.65–2.57(m,1H), 2.37–2.27(m,1H), 2.24(s,3H). ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-113.41, -130.70.LCMS (m/z): 566.5 (M+H).

Synthesis of intermediate A19

Tert-Butyl 4-(8-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl)piperazine-1-carboxylate

The synthesis of intermediate A19 refers to the synthesis of intermediate A13. In step A, methyl 2-amino-3-bromo-5-fluorobenzoate is used instead of methyl 2-amino-3-bromobenzoate. LCMS (m/z): 469.0, 471.0 (M+H).

Example A137

4-(4-acryloylpiperazin-1-yl)-6-fluoro-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-8 -((5-Methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile

Step A: 4-(8-Bromo-3-cyano-6-fluoro-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)quinoline -4-yl) piperazine-1-carboxylic acid tert-butyl ester

Step A Refer to Example A1, Step A, using 4-(8-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (middle Body A19) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxy Acid tert-butyl ester (Intermediate A1), and use (3R, 4R)-4-methoxy-1-methylpyrrolidin-3-ol instead of (S)-(1-methylpyrrolidin-2-yl ) Methanol. LCMS (m/z): 564.2, 566.2 (M+H).

Step B: 4-(3-cyano-6-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-8-(( 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, add 4-(8-bromo-3-cyano-6-fluoro-2-((3R,4R)-4-methoxy-1-methylpyrrole) into a round bottom flask equipped with a magnet Alkyl-3-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (250mg, 0.44mmol), 5-methyl-1-(tetrahydro-2H-pyran-2 -Radical) -1H-indazol-4-ol (205mg, 0.88mmol), CuI (16.8mg, 0.88mmol), N ¹ -benzyl-N ² -(5-methyl-[1,1'-linked Benzene]-2-yl)oxamide (36.6 mg, 0.10 mmol), potassium carbonate (183.6 mg, 1.32 mmol). After the nitrogen was pumped three times, DMSO (3ml) was added, and the reaction system was heated to 100°C and stirred for 16h. After the reaction was monitored by LCMS, the reaction solution was poured into water, and the crude product obtained by suction filtration was purified by FCC (SiO ₂ , EA/PE=0-80%) to obtain 4-(3-cyano-6-fluoro-2-( ((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-8-((5-methyl-1-(tetrahydro-2H-pyran-2- (Yl)-1H-indazol-4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (40 mg, yield 12.6%). LCMS(m/z): 716.3(M+H).

Step C and Step D: 4-(4-acryloylpiperazin-1-yl)-6-fluoro-2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl )Oxy)-8-((5-methyl-1H-indazol-4-yl)oxy)quinoline-3-carbonitrile

The subsequent synthetic steps of Example A137 refer to the steps B and C of Example A1, using 4-(3-cyano-6-fluoro-2-(((3R,4R)-4-methoxy-1- Methylpyrrolidin-3-yl)oxy)-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-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)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR(400MHz, methanol-d ₄ )δ7.52(dd,J=9.7,2.8Hz,1H), 7.40(m,J=8.5Hz,1H), 7.36(m,J=8.5Hz,1H) ,7.22(s,1H),6.96(m,J=9.3Hz,1H),6.88(dd,J=16.8,10.6Hz,1H),6.31(dd,J=16.8,1.9Hz,1H),5.84( dd, J = 10.6, 2.0 Hz, 1H), 5.22 (m, 1H), 4.08 (m, 1H), 3.99 (m, 4H), 3.73 (m, 4H), 3.37 (s, 3H), 3.03 (m ,J＝10.6,6.0Hz,1H),2.91(m,1H),2.58(m,J＝10.6,4.1Hz,1H),2.49(m,1H),2.39(s,3H),2.32(s, 3H).LCMS(m/z): 584.1(M+H).

Synthesis of intermediate A20

Tert-Butyl 4-(2-chloro-3-cyano-8-(2-fluoro-6-methoxyphenoxy)-1,7-naphthyridin-4-yl)piperazine-1-carboxylate

The synthesis of intermediate A20 refers to the synthesis of intermediates. In step A, methyl 2-chloro-3-nitroisonicotinate was used instead of methyl 3-fluoro-2-nitrobenzoate; and 2-fluoro- 6-Methoxyphenol 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol. LCMS(m/z): 514.4(M+H).

Example A138

4-(4-acryloylpiperazin-1-yl)-8-(2-fluoro-6-hydroxyphenoxy)-2-(((3R,4R)-4-methoxy-1-methyl (Pyrrolidin-3-yl)oxy)-1,7-naphthyridin-3-carbonitrile

The synthesis of Example A138 refers to the synthesis of Example A1, and 4-(2-chloro-3-cyano-8-(2-fluoro-6-methoxyphenoxy)-1,7 is used in step A -Naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A20) instead of 4-(2-chloro-3-cyano-8-((5-methyl-1H-indazole- 4-yl)oxy)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate A1) with (3R,4R)-4-methoxy-1-methylpyrrolidine -3-ol instead of (S)-(1-methylpyrrolidin-2-yl)methanol. ¹ H NMR(400MHz,DMSO-d ₆ )δ9.99(s,1H), 7.97–7.82(m,1H), 7.50(d,J=5.8Hz,1H), 7.21–7.03(m,1H), 6.99–6.73 (m, 3H), 6.18 (dd, J = 16.6, 2.4 Hz, 1H), 5.75 (dd, J = 10.4, 2.3 Hz, 1H), 5.57–5.41 (m, 1H), 3.97 (s, 1H), 3.91–3.79(m,4H), 3.73–3.62(m,4H), 3.39(s,3H), 3.09–3.00(m,1H), 3.00–2.90(m,1H), 2.76–2.63( m,1H), 2.40–2.31(m,1H), 2.31–2.14(m,3H).LCMS(m/z): 549.5(M+H).

According to a method similar to the synthetic method of the above-mentioned Example A series of compounds, the following compounds of Example A139 to Example A145 were also prepared and characterized:

Synthesis of intermediate B-1

4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylsulfoxide) Pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

Step A: 4-((2-chloro-3-nitropyridin-4-yl)oxy)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To a solution of 2,4-dichloro-3-nitropyridine (1.50g, 7.77mmol) and NaH (0.20g, 8.55mmol) in THF (30mL) was added dropwise 5-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-ol in THF (15 mL). The mixture was stirred at rt for 2h. After completion of TLC monitoring, the mixture was diluted with EA (50 mL), washed with saturated aqueous NaCl (3×30 mL) and dried with anhydrous Na ₂ SO ₄ . The mixture was concentrated under reduced pressure, and the resulting crude product was purified by FCC (EA/PE=0-30%) to obtain 4-((2-chloro-3-nitropyridin-4-yl)oxy)-5-methyl as a yellow solid -1-(Tetrahydro-2H-pyran-2-yl)-1H indazole (2.66 g, yield 88%). LCMS (m/z): 389.1 (M+H).

Step B: 4-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-3-nitropyridinenitrile

Under N ₂ protection, 4-((2-chloro-3-nitropyridin-4-yl)oxy)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazole (1.0g, 2.57mmol), Zn(CN) ₂ (301mg, 2.57mmol), Pd ₂ (dba) ₃ (118mg, 0.128mmol) and Xant Phos (149mg, 0.257mmol) in NMP (5mL) The solution was heated in microwave at 150°C for 0.5h. After completion of TLC monitoring, the mixture was filtered through celite, the filtrate was treated with H ₂ O (20 mL), and extracted with EA (3×25 mL). The resulting organic phase was washed with saturated aqueous NaCl (3×30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by FCC (EA/PE=0-30%) to obtain a yellow solid 4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl )Oxy)-3-nitropyridinenitrile (0.83g, yield 85%). LCMS (m/z): 380.1 (M+H), 402.1 (M+Na).

Step C: 3-Amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyridinenitrile

At 0 ℃, to 4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-3-nitromethyl A solution of pyridine nitrile (1.09 g, 2.87 mmol) in THF/EtOH (18 mL, 1:1) was quickly added with a solution of Na ₂ S ₂ O ₄ (2.98 g, 17.24 mmol) in H ₂ O (9 mL). After the reaction system was stirred at 0°C for 15 min, the mixture was diluted with EA (50 mL), washed with H ₂ O (30 mL), saturated aqueous NaCl (30 mL), and dried with anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure, and the product was purified with FCC (MeOH/DCM=1%-10%) to give a yellow solid 3-amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2- (Yl)-1H-indazol-4-yl)oxy)pyridinenitrile (0.82 g, yield 81%). LCMS (m/z): 350.3 (M+H).

Step D: 8-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[3,2-d]pyrimidine -2,4-Dithiol

At room temperature, CS ₂ (3.92g, 51.5mmol) was added to 3-amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)oxy)pyridinenitrile (1.8 g, 5.15 mmol) and K ₂ CO ₃ (2.14 g, 15.5 mmol) in DMSO (11 mL) solution, and then heated to 50° C. and stirred for 3 h. After completion, the mixture was cooled to room temperature and poured into H ₂ O (75 mL) with vigorous stirring. The resulting clear solution was adjusted to pH=7 with 1N HCl aqueous solution, and the formed precipitate was collected by filtration. The filter cake was washed with water and dried in vacuo to obtain 8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyridine as a dark green solid [3,2-d]pyrimidine-2,4-dithiol (1.62g, yield 73%). LCMS(m/z): 426(M+H).

Step E: 8-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,4-bis(methylthio) )Pyridine[3,2-d]pyrimidine

The 8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrido[3,2-d]pyrimidine-2 ,4-Dithiol was dissolved in an aqueous NaOH solution (0.4N, 10 mL), and the resulting mixture was stirred at rt for 10 min. Then MeI (1.1 g, 7.52 mmol) was added to the above solution and stirred at the same temperature for 1 h. The formed precipitate was collected by filtration, washed with water and dried under vacuum to give 8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)oxy)-2,4-bis(methylthio)pyridine[3,2-d]pyrimidine (1.48 g, yield 87%). LCMS(m/z): 454.1(M+H).

Step F: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylthio )Pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

8-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,4-bis(methylthio)pyridine [3,2-d]pyrimidine (500mg, 1.10mmol), piperazine-1-carboxylic acid tert-butyl ester (330mg, 1.76mmol) and K ₂ CO ₃ (490mg, 3.53mmol) in DMSO (3mL) solution was heated to Stir at 120°C for 23h. Then the mixture was cooled to room temperature, poured into ice water (20 mL), and extracted with EA (3×20 mL). The resulting organic phase was washed with saturated aqueous NaCl (3×20 mL) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under vacuum, and the resulting crude product was purified by preparative TLC (MeOH/DCM=1:20) to obtain 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2) as a yellow solid -Yl)-1H-indazol-4-yl)oxy)-2-(methylthio)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (262mg , Yield 40%). LCMS(m/z): 592.3(M+H).

Step G: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methyl Sulfonyl)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At 0°C, 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-( (Methylthio)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (380mg, 0.64mmol) in DCM (5mL) was added to mCPBA (148mg, 0.64mmol) DCM (3mL) solution. The resulting mixture was stirred at 0°C for 30 min, and then at rt for 1 h. After the completion of LCMS monitoring, the mixture was diluted with DCM (30 mL), and washed with saturated _{aqueous Na 2} S ₂ O ₃ (20 mL), saturated aqueous NaHCO ₃ (20 mL), saturated aqueous NaCl (20 mL), and anhydrous Na ₂ SO ₄ dry. The solvent was removed under reduced pressure to give a yellow solid 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2 -(Methylsulfoxide)pyrido[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (390mg, crude product), used directly in the next step. LCMS(m/z): 608.3(M+H).

Example B1

(S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy )Pyridine[3,2-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one formate

Step A: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-((S) -1-Methylpyrrolidin-2-yl)methoxy)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, NaH (38.5 mg, 0.96 mmol) was added to a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (110.9 mg, 0.96 mmol) in THF (2 mL). After stirring for 30 min at room temperature, 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2- (Methylsulfoxy)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (390 mg, 0.64 mmol) in THF (3 mL). The resulting mixture was continuously stirred at room temperature for 1 h. Then the reaction solution was diluted with EA (30 mL), washed with saturated aqueous NaCl (2×20 mL), and dried with anhydrous Na ₂ SO ₄ . After the solvent was removed under reduced pressure, the crude product 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2- ((S)-1-Methylpyrrolidin-2-yl)methoxy)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (422mg, crude product) directly Go to the next step. LCMS (m/z): 659.5 (M+H).

Step B: (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-4 -(Piperazin-1-yl)pyridine[3,2-d]pyrimidine

At room temperature, TFA (2.4mL) was added to 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy Yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester ( 422 mg, 0.64 mmol) in DCM (6 mL). The reaction system was stirred at room temperature for 1 h and then concentrated under reduced pressure to obtain a dark yellow solid (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidine) -2-yl)methoxy)-4-(piperazin-1-yl)pyridine[3,2-d]pyrimidine (377mg, crude product), directly put into the next step. LCMS(m/z): 475.3(M+H).

Step C: (S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl )Methoxy)pyridine[3,2-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one formate

At 0°C, a solution of acryloyl chloride (32.7 mg, 0.75 mmol) in DCM (2 mL) was added dropwise to (S)-8-((5-methyl-1H-indazol-4-yl)oxy)- 2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)pyridine[3,2-d]pyrimidine (304mg, 0.64mmol) and DIEA (407mg, 6.4 mmol) in DCM (5 mL). The resulting mixture was stirred at 0°C for 50 min. The mixture was diluted with EA (30 mL), washed with H ₂ O (20 mL), saturated aqueous NaCl (2×20 mL) and dried over anhydrous Na ₂ SO ₄ . After the solvent was removed under reduced pressure, the crude product was purified by preparative high performance liquid chromatography to obtain (S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)oxy) as a white solid -2-((1-Methylpyrrolidin-2-yl)methoxy)pyridine[3,2-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one Formate (50mg, yield 15%). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.56(brs,1H), 8.37(d,J=5.1Hz,1H),7.72(s,1H),7.51(d,J=8.5Hz,1H) ,7.44(d,J＝8.6Hz,1H), 6.85(dd,J＝16.8,10.6Hz,1H), 6.61(d,J＝5.1Hz,1H), 6.29(dd,J＝16.8,2.0Hz, 1H), 5.82(dd,J=10.7,1.9Hz,1H), 4.82–4.52(m,6H), 3.95–3.85(m,4H), 3.60–3.46(m,2H), 2.98-2.89(m, 4H),2.35-2.28(m,4H),2.14-1.93(m,3H).LCMS(m/z):529.3(M+H)

Example B2

1-(4-(2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-8-((5-methyl-1H-indazole -4-yl)oxy)pyridine[3,2-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

The preparation of Example B2 refers to the synthesis of Example B1. In step A, (3R, 4R)-4-methoxy-1-methylpyrrolidin-3-ol was used instead of (S)-(1-methyl Pyrrolidin-2-yl)methanol. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.34(d,J=5.0Hz,1H),7.66(s,1H),7.54-7.35(m,2H),6.86(dd,J=16.8,10.6 Hz, 1H), 6.60 (d, J = 5.0 Hz, 1H), 6.29 (dd, J = 16.8, 2.0 Hz, 1H), 5.82 (dd, J = 10.7, 2.0 Hz, 1H), 5.47–5.36 (m ,1H),4.75–4.48(m,4H),4.21–4.03(m,1H),3.96–3.80(m,4H), 3.47(s,3H), 3.27(dd,J=11.1,6.2Hz,1H ),3.05(dd,J=10.6,5.9Hz,1H),2.82-2.65(m,2H),2.43(s,3H),2.29(s,3H).LCMS(m/z): 545.3(M+ H).

Synthesis of intermediate B2

4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylsulfoxide) Pyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

Step A: Ethyl 3-bromo-5-fluoroisonicotinate

Under N ₂ atmosphere, to a solution of 3-bromo-5-fluoropyridine (2.0 g, 11.36 mmol) in anhydrous THF (18 mL) cooled to -78° C. was added LDA (1.58 g, 14.77 mmol). The mixture was stirred at -78°C for 45 min. Ethyl cyanocarbonate (1.24g, 12.50mmol) was slowly added dropwise to the above solution at the same temperature, and then the mixture was stirred at -78°C for 20min. The reaction was quenched with saturated aqueous NaHCO ₃ (5 mL) and extracted with EA (2×15 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude product was purified by FCC (EA/PE=0-7%) to obtain ethyl 3-bromo-5-fluoroisonicotinate (2.2 g, yield 78%) as a pale yellow oil. LCMS (m/z): 248.1, 250.1 (M+H).

Step B: Ethyl 3-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)isonicotinate

Ethyl 3-bromo-5-fluoroisonicotinate (1g, 4.03mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol ( A mixture of 1.03 g, 4.43 mmol) and Cs ₂ CO ₃ in anhydrous DMF (10 mL) was stirred at 100° C. for 16 h. After completion, the mixture was filtered. The filtrate was diluted with EA (20 mL), washed with saturated LiCl aqueous solution (2×15 mL), and dried over anhydrous Na ₂ SO ₄ . Filtration, concentration under reduced pressure, the obtained crude product was purified by FCC (EA/PE=0-15%) to obtain a pale yellow oily 3-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran) -2-yl)-1H-indazol-4-yl)oxy)isonicotinic acid ethyl ester (1.5 g, yield 80%). LCMS (m/z): 460.1, 462.1 (M+H).

Step C: 3-Bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)isonicotinic acid

To 3-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)ethyl isonicotinate (1.5 g, 3.26 mmol) in anhydrous EtOH (5 mL) solution was added LiOH (390 mg, 16.29 mmol) in H ₂ O (5 mL) solution. The resulting mixture was stirred at 70°C for 1 h. After completion, the mixture was concentrated to remove EtOH, and the remaining liquid was adjusted to pH 7-8 with 4N HCl aqueous solution. The precipitate was collected by filtration and dried under vacuum to give 3-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl as a white solid )Oxy)isonicotinic acid (1.0 g, yield 71%). LCMS(m/z): 432.1, 434.1(M+H).

Step D: 3-Bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyridin-4-amine

To 3-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)isonicotinic acid (1.5g, TEA (1.9 mL) was added to a toluene (10 mL) solution of 3.50 mmol). The mixture was stirred at rt until the solids were completely dissolved. Then DPPA (2.89 g, 10.5 mmol) and H ₂ O (5 mL) were added. The mixture was stirred at 100°C for 16 h, before being extracted with EA (2x15 mL). The obtained organic phase was washed with saturated aqueous NaCl (2×10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration, the crude product was purified with FCC (EA/PE=0-40%) to obtain 3-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl) as a white solid -1H-indazol-4-yl)oxy)pyridine-4-amine (650 mg, yield 46%). LCMS (m/z): 403.2, 405.2 (M+H).

Step E: 4-Amino-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)nicotinonitrile

Add 3-bromo-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyridin-4-amine, Zn( A solution of CN) ₂ (175 mg, 1.49 mmol), Pd ₂ (dba) ₃ (68 mg, 0.075 mmol) and Xant-Phos (86 mg, 0.149 mmol) in NMP (5 mL) was heated to 150°C for 1 h in microwave. The reaction system was diluted with EA (15 mL), and washed with saturated LiCl aqueous solution (2×10 mL). The organic phase was _{purified by FCC (SiO 2} , EA/PE=0-50%) to obtain a white solid 4-amino-5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-Indazol-4-yl)oxy)nicotinonitrile (500mg, yield 96%). LCMS (m/z): 350.3 (M+H).

Step F: 8-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyridine[4,3-d]pyrimidine- 2,4(1H,3H)-Dithione

At room temperature, K ₂ CO ₃ (521 mg, 3.77 mmol) and CS ₂ (957 mg, 12.57 mmol) were added to 4-amino-5-((5-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)oxy)nicotinonitrile (440 mg, 1.26 mmol) in DMSO (3 mL). The reaction mixture was stirred at 50° C. for 2 hours and then cooled to room temperature, poured into H ₂ O (20 mL), and stirred for 30 minutes to produce precipitation. The precipitate was collected by filtration and dried in vacuo to obtain 8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyridine [4, 3-d] Pyrimidine-2,4(1H,3H)-dithione (530 mg, yield 99%). LCMS(m/z): 426.1(M+H).

Step G: 8-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,4-bis(methylthio) )Pyridine[4,3-d]pyrimidine

At room temperature, CH ₃ I (386.9 mg, 2.73 mmol) was added dropwise to 8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4- Yl)oxy)pyridine[4,3-d]pyrimidine-2,4(1H,3H)-dithione (580mg, 1.36mmol), 1N NaOH (1.6mL) and H ₂ O (2mL) solution . The resulting mixture was stirred at room temperature for 2h. Then it was extracted with EA (2x15mL). The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, and then _{purified with FCC (SiO 2} , EA/PE=0-50%) to obtain a yellow solid 8-((5-methyl-1-(tetrahydro -2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,4-bis(methylthio)pyridine[4,3-d]pyrimidine (300mg, yield 49% ). LCMS(m/z): 454.0(M+H).

Step H: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylthio )Pyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, K ₂ CO ₃ (91 mg, 0.66 mmol) and tert-butyl piperazine-1-carboxylate (246 mg, 1.32 mmol) were added to 8-((5-methyl-1-(tetrahydro-2H- Pyran-2-yl)-1H-indazol-4-yl)oxy)-2,4-bis(methylthio)pyridine[4,3-d]pyrimidine (300mg, 0.66mmol) in DMA (2.5 mL) in solution. The reaction system was stirred at 120°C for 6h. Then the reaction system was cooled to room temperature, diluted with EA (20 mL), and washed with saturated LiCl aqueous solution (2×15 mL). The organic phase was concentrated and _{purified with FCC (SiO 2} , EA/PE=0-60%) to obtain an off-white solid 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl) )-1H-indazol-4-yl)oxy)-2-(methylthio)pyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (340mg, Yield 87%). LCMS(m/z): 592.2(M+H).

Step 1: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methyl Sulfonyl)pyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, add mCPBA (103mg, 0.51mmol) to 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) (Oxy)-2-(methylthio)pyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.51 mmol) in DCM (3 mL). After the resulting reaction system was stirred at room temperature for 2 h, the _{reaction was quenched with saturated aqueous Na 2} SO ₃ (20 mL), and extracted with EA (10×2 mL). The organic phase was concentrated to obtain a yellow solid 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2- The crude product of (methylsulfoxy)pyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (210mg, yield 68%) was directly put into the next step. LCMS(m/z): 608.3(M+H).

Example B3

1-(4-(2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-8-((5-methyl-1H-indazole- 4-yl)oxy)pyridine(4,3-d)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

The preparation of Example B3 refers to that described in Example B1. In step A, 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indyl) (Azol-4-yl)oxy)-2-(methylsulfoxide)pyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate B2) instead of 4 -(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylsulfoxide)pyridine [3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate B1) with (3R,4R)-4-methoxy-1-methylpyrrolidine-3 -Alcohol instead of (S)-(1-methylpyrrolidin-2-yl)methanol. ¹ H NMR(400MHz,Methanol-d ₄ )δ9.05(s,1H),7.95(s,1H),7.39(d,J=2.5Hz,3H), 6.84(dd,J=16.8,10.6Hz, 1H), 6.31(dd,J=16.8,2.0Hz,1H),5.83(dd,J=10.7,2.0Hz,1H),5.32–5.17(m,1H),4.22–4.11(m,4H),4.11 –4.03(m,1H),3.99–3.89(m,4H),3.39(s,3H),3.03(dd,J=10.5,6.0Hz,1H),2.96(dd,J=11.3,6.2Hz,1H ), 2.63--2.53(m,2H),2.39(s,3H),2.34(s,3H).LCMS(m/z): 545.3(M+H).

Synthesis of intermediate B3

4-(2-Chloro-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrimidine[5,4- d)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

Step A: 1,7-dihydropyrimidine[5,4-d]pyrimidine-2,4,8(3H)-trione

A mixture of 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (25g, 146.2mmol) and formamide (300mL) was stirred at 170°C for 6h. The reaction system was cooled to room temperature and poured into H ₂ O (1000 mL), and a yellow precipitate formed. The precipitate was collected by filtration and dried under vacuum to obtain 1,7-dihydropyrimidine[5,4-d]pyrimidine-2,4,8(3H)-trione (19.7g, yield 75%) as a yellow solid. LCMS(m/z): 181.1(M+H).

Step B: 2,4,8-trichloropyrimidine[5,4-d]pyrimidine

Combine 1,7-dihydropyrimidine[5,4-d]pyrimidine-2,4,8(3H)-trione (3.0g, 16.6mmol), PCl ₅ (14.9g 71.6mmol) and POCl ₃ (100mL) The mixture was heated to 120°C and stirred overnight. The reaction system was concentrated under reduced pressure and poured into a mixture of ice water (200 mL). The resulting mixture was extracted with EA (3x100 mL). The organic layer was washed with saturated aqueous NaCl solution (3×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The obtained crude product was purified by FCC (SiO ₂ , EA/PE=0-5%) to obtain 2,4,8-trichloropyrimidine [5,4-d]pyrimidine (2.2 g, yield 56.4%) as a pale yellow solid. LCMS(m/z): 235.1(M+H).

Step C: 4-(2,8-Dichloropyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, add TEA (2.14g, 21.2mmol) to 2,4,8-trichloropyrimidine [5,4-d]pyrimidine (2.0g, 8.4mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.42 g, 7.6 mmol) in THF (30 mL), and the mixture was stirred at room temperature for 2 h. After TLC monitoring the completion of the reaction, the system was poured into a mixture of ice water (200 mL) and extracted with EA (3×100 mL). After the combined organic phase was washed with saturated aqueous NaCl (3×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a pale yellow solid (2.7 g, yield 84%). LCMS(m/z): 385.2(M+H).

Step D: 4-(2-Chloro-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrimidine [5 ,4-d)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, add Cs ₂ CO ₃ (1.26g, 3.89mmol) to tert-butyl 4-(2,8-dichloropyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (1.0g, 2.59mmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (542.8mg 2.3mmol) in DMA (5mL) solution . The reaction mixture was stirred at 60-80°C overnight. The reaction system was poured into a mixture of ice water (200 mL), and extracted with EA (3×100 mL). The combined organic phase was washed with saturated aqueous NaCl (2×100 mL), and dried over anhydrous Na ₂ SO ₄ . After filtration and concentration, the crude product was purified with FCC (SiO ₂ , EA/PE=0-20%) to obtain a pale yellow solid 4-(2-chloro-8-((5-methyl-1-(tetrahydro-2H-pyridine) (Pyran-2-yl)-1H-indazol-4-yl)oxy)pyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (1.1g, yield 73 %). LCMS(m/z): 581.0(M+H).

Example B4

(S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy Yl)pyrimidine[5,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-((S) -1-Methylpyrrolidin-2-yl)methoxy)pyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, (S)-(1-methylpyrrolidin-2-yl)methanol (198mg 1.72mmol) and K ₂ CO ₃ (237.8mg, 1.72mmol) were added to 4-(2-chloro-8-( (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)pyrimidine[5,4-d]pyrimidin-4-yl)piperazine -1- tert-butyl carboxylate (500 mg, 0.86 mmol) in DMF (5 mL), and the reaction system was stirred at 80° C. overnight. After the reaction was completed, it was cooled to room temperature, the system was poured into a mixture of ice and water (100 mL), and extracted with EA (3×50 mL). The organic phase was washed with saturated aqueous NaCl (2×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The resulting crude product was purified with FCC (SiO ₂ , EA/PE=0-100% and MeOH/DCM=10% eluted sequentially) to obtain a pale yellow solid 4-(8-((5-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine[5,4 -d] pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, yield 35%). LCMS(m/z): 660.0(M+H).

Steps B and C: (S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidine-2 -Yl)methoxy)pyrimidine[5,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

The subsequent synthesis method of Example B4 refers to Example B1. In step B, 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole- 4-yl)oxy)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxy Instead of 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(( S)-1-Methylpyrrolidin-2-yl)methoxy)pyridine[3,2-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR (400MHz, methanol-d ₄ ) δ 8.50 (s, 1H), 8.43 (s, 1H), 7.74 (d, J = 1.0 Hz, 1H), 7.47-7.44 (m, 1H), 7.40- 7.37 (m, 1H), 6.83 (dd, J = 16.8, 10.6 Hz, 1H), 6.28 (dd, J = 16.7, 1.9 Hz, 1H), 5.81 (dd, J = 10.6, 1.9 Hz, 1H), 4.83 (dd,J=12.5,3.2Hz,1H), 4.69–4.49(m,5H), 3.97–3.81(m,4H), 3.75–3.65(m,1H), 3.65–3.53(m,1H), 3.14 --3.03(m,1H),2.98(s,3H),2.40-2.30(m,1H),2.26(s,3H),2.16-1.97(m,3H).LCMS(m/z):530.2(M +H).

Synthesis of intermediate B4

4-(2-Chloro-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)amino)pyrimidine[5,4-d ]Pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, add 4-(2,8-dichloropyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (1.0g, 2.59mmol) and 5-methyl- To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (539.9 mg, 2.33 mmol) in DMA (5 mL) was added DIEA (671 mg, 5.19 mmol). The mixture was stirred at 100°C overnight. After completion, the mixture was poured into ice water (200 mL) and extracted with EA (3×100 mL). The organic phase was washed with saturated aqueous NaCl (2 x 100 mL), dried over anhydrous dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by FCC (SiO ₂ , EA/PE=0-20%) to obtain a pale yellow solid 4-(2-chloro-8-((5-methyl-1-(tetrahydro-2H-pyran-2- (Yl)-1H-indazol-4-yl)amino)pyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (1.2 g, yield 80%). LCMS(m/z): 580.3(M+H).

Example B5

(S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)amino)-2-((1-methylpyrrolidin-2-yl)methoxy )Pyrimidine[5,4-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Preparation of Example B5 Referring to Example B1, in step A, 4-(2-chloro-8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- Indazol-4-yl)amino)pyrimidine[5,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate B4) instead of 4-(8-((5-methyl -1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylsulfoxide)pyridine[3,2-d]pyrimidine-4 -Yl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate B1). ¹ H NMR(400MHz, methanol-d ₄ )δ8.53(s,1H), 8.19(s,1H), 7.82(s,1H), 7.47(d,J=8.6Hz,1H), 7.39(d, J = 8.5Hz, 1H), 6.83 (dd, J = 16.7, 10.6 Hz, 1H), 6.27 (dd, J = 16.8, 1.9 Hz, 1H), 5.80 (dd, J = 10.6, 2.0 Hz, 1H), 4.65–4.46(m,6H), 3.98–3.75(m,4H), 3.30–3.26(m,1H), 3.12(s,1H), 2.77–2.59(m,4H), 2.36(s,3H), 2.27–2.12(m,1H),2.01–1.77(m,3H).LCMS(m/z): 529.3(M+H).

Example B6

(S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy )Pyrimidine[4,5-d]pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one dicarboxylate

Step A: 4,5-Dibromo-2-(4-methoxybenzyl)pyridazine-3(2H)-one

Combine 4,5-dibromopyridine-3(2H)-one (5) (50.0g, 196.94mmol), 4-methoxybenzyl chloride (32.39, 206.79mmol), tetrabutylammonium bromide (3.17g) , 9.85 mmol) and K ₂ CO ₃ (54.44 g, 393.89 mmol) in MeCN (500 mL) were stirred at 60° C. for 12 h. The mixture was cooled to room temperature and then filtered through Celite. The solvent was removed under reduced pressure, the resulting crude product was sonicated in MeOH, and the solid was collected by filtration. The obtained solid was washed with a small amount of MeOH and dried in vacuum to obtain a light brown solid 4,5-dibromo-2-(4-methoxybenzyl)pyridazine-3(2H)-one (50.0g, yield 68%) ). ¹ H NMR (400MHz, chloroform-d) δppm 7.78 (1H, s), 7.40 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.8 Hz), 5.25 (2H, s), 3.78(3H,s); LCMS(m/z): 373.0(M+H).

Step B: 4-Amino-5-bromo-2-(4-methoxybenzyl)pyridazine-3(2H)-one

Put 4,5-dibromo-2-(4-methoxybenzyl)pyridazine-3(2H)-one (15.0g, 40.10mmol) and NH ₃ -MeOH (80mL, 7mol/L) The sealed tube was heated to 90°C and stirred for 18 hours and then slowly cooled to room temperature. The reaction system was filtered, and the filter cake was washed with MeOH. The obtained solid was dried under vacuum to obtain 4-amino-5-bromo-2-(4-methoxybenzyl)pyridazine-3(2H)-one (5.0 g, yield 40%) as a yellow solid. LCMS(m/z): 310.0(M+H).

Step C: 5-Amino-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-4-carbonitrile

Add cyanide to the DMF (12mL) solution containing 4-amino-5-bromo-2-(4-methoxybenzyl)pyridazine-3(2H)-one (1.50g, 4.84mmol) Cuprous chloride (0.519 g, 5.80 mmol). The reaction was heated in a microwave oven at 200°C for 1 h. _{Then, a solution of H 2} O (50 mL) containing FeCl ₃ (10.0 g) and concentrated HCl (12N, 3.0 mL) was added and stirred at 70° C. for 15 min, and then cooled to room temperature. The mixture was filtered and the solid was washed with water to give a yellow solid 5-amino-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-4-carbonitrile (1.2g, yield 97%). ¹ H NMR(400MHz, CDCl ₃ )δ7.45(s,1H), 7.36(d,J=8.4Hz,2H), 6.85(d,J=8.3Hz,2H), 5.20(s,2H), 5.16 (s, 2H), 3.78 (s, 3H); LCMS (m/z): 257.1 (M+H).

Step D: 7-(4-methoxybenzyl)-2,4-dithio-1,3,4,7-tetrahydropyrimidine[4,5-d]pyridazine-8(2H)-one

Anhydrous EtOH (60 mL) and KOH (85% purity, 3.19 g, 48.39 mmol) were placed in a 500 mL glass reactor, and the mixture was heated to 25-30°C to dissolve KOH. CS ₂ (3.68 g, 48.39 mmol) was added, and the mixture was stirred at 25-30° C. for 0.5 h to obtain a yellow suspension. Then 5-amino-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazine-4-carbonitrile (6.20g, 24.19mmol), 95% EtOH (60mL) And H ₂ O (12 mL) were sequentially added to the mixture. After refluxing for 21h, the mixture was cooled to room temperature. The mixture was filtered, the solid was collected and washed with water. The solid was dried in vacuum to obtain a yellow solid 7-(4-methoxybenzyl)-2,4-dithio-1,3,4,7-tetrahydropyrimidine[4,5-d]pyridazine- 8(2H)-ketone (8.0 g crude product, yield 99%). LCMS (m/z): 333.0 (M+H).

Step E: 7-(4-methoxybenzyl)-2,4-bis(methylthio)pyrimidine[4,5-d]pyridazin-8(7H)-one

Place 7-(4-methoxybenzyl)-2,4-dithio-1,3,4-,7-tetrahydropyrimidinyl[4,5-d]pyridazine in a 500mL glass reactor in sequence -8(2H)-1 (8g, 24.19mmol), H ₂ O (150mL) and NaOH (2.42g, 60.47mmol), heated to 25-30°C to dissolve. Then immediately MeI (6.87 g, 48.38 mmol) was added to the mixture. After stirring for 1 hour, the clear solution became turbid. The mixture was filtered, the solid was collected and washed with water. The obtained solid was dried in vacuum to obtain 7-(4-methoxybenzyl)-2,4-bis(methylthio)pyrimidin[4,5-d]pyridazine-8(7H)-one as a yellow solid (2.5g, yield 29%). LCMS(m/z): 361.0(M+H).

Step F: 2,4-bis(methylthio)pyrimidine[4,5-d]pyridazine-8(7H)-one

Add cerium ammonium nitrate (19.01g, 34.68mmol) to 7-(4-methoxybenzyl)-2,4-bis(methylthio)pyrimidine[4,5-d]pyridazine-8(7H) -Ketone (2.5 g, 6.94 mmol) in MeCN (200 mL)/H ₂ O (40 mL) mixture solution, stirred at room temperature for 18 h. The mixture was filtered, the precipitate was collected and washed with water. The obtained solid was dried in vacuum to obtain 2,4-bis(methylthio)pyrimidin[4,5-d]pyridazin-8(7H)-one (1.5g, yield 90%) as a yellow solid. LCMS(m/z): 241.0(M+H).

Step G: 8-Chloro-2,4-bis(methylthio)pyrimidine[4,5-d]pyridazine

2,4-bis (methylthio) pyrimido [4,5-d] pyridazine -8 (7H) - one (1.10g, 4.58mmol) was heated with a mixture of POCl ₃ (12mL) with stirring to 125 ℃ 16h. _{The excess POCl 3 was} removed under reduced pressure, and the obtained crude product was purified with FCC (SiO ₂ , EA/PE=0-20%) to obtain 8-chloro-2,4-bis(methylthio)pyrimidine [4,5-d] as a yellow solid Pyridazine (270mg, yield 23%). LCMS(m/z): 259.0(M+H).

Step H: 8-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,4-bis(methylthio) )Pyrimidine[4,5-d]pyridazine

In 8-chloro-2,4-bis(methylthio)pyrimidine[4,5-d]pyridazine (270mg, 1.04mmol), 5-methyl-1-(tetrahydro-2H-pyran-2- To the DMA (10 mL) solution of -1H-indazol-4-ol (218 mg, 0.94 mmol), Cs ₂ CO ₃ (509 mg, 1.57 mmol) was added. The reaction system was stirred at room temperature for 4 h, H ₂ O (10 mL) was added, and extracted with EA (3×10 mL). The organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated under reduced pressure and then _{purified with FCC (SiO 2} , EA/PE=0-30%) to obtain a yellow solid 8-((5-methyl- 1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2,4-bis(methylthio)pyrimidine[4,5-d]pyridazine (370mg, yield 78%). LCMS(m/z): 455.1(M+H).

Step 1: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylthio )Pyrimidine[4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

Cs ₂ CO ₃ (393mg, 1.21mmol) was added to 8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy) -2,4-bis(methylthio)pyrimidine[4,5-d]pyridazine (366mg, 0.805mmol) and tert-butyl piperazine-1-carboxylate (150mg, 0.805mmol) in DMA (10mL) In the middle, the mixture was stirred at room temperature for 18h. _{H 2} O (10 mL) was added to the system and extracted with EA (3×10 mL). The organic phase was washed with saturated aqueous NaCl solution, dried with anhydrous Na ₂ SO ₄ , filtered, concentrated and _{purified with FCC (SiO 2} , EA/PE=0-50%) to obtain a yellow solid 4-(8-((5-methyl -1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylthio)pyrimidine[4,5-d]pyridazine-4- Yl)piperazine-1-carboxylic acid tert-butyl ester (230 mg, yield 48%). LCMS(m/z): 592.2(M+H).

Step J: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylsulfon Yl)pyrimidine[4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

To 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylthio)pyrimidine [4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.337mmol) in DCM (10mL) was added mCPBA (209mg, 75% purity, 0.911mmol), The mixture was stirred at room temperature for 2.5 h. DCM (20 mL) was added, washed with saturated aqueous NaHCO ₃ (2×10 mL), then washed with saturated aqueous NaCl, and dried with anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated and _{purified by FCC (SiO 2} , EA/PE=0-80%) to obtain a yellow solid 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl) )-1H-indazol-4-yl)oxy)-2-(methylsulfo)pyrimidine[4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (160mg , Yield 84%). LCMS(m/z): 625.2(M+H).

Step K: 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-((S) -1-Methylpyrrolidin-2-yl)methoxy)pyrimidine[4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

At room temperature, to (S)-(1-methylpyrrolidin-2-yl)methanol (48mg, 0.416mmol) in THF (5mL) was added NaH (60%, 17mg, 0.416mmol) and stirred for 30min . Then 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-(methylsulfonyl )Pyrimidine[4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.19 mmol) was added to the above solution, and the resulting mixture was stirred at room temperature for 1 h. A saturated aqueous NaCl solution (3 drops) was added to quench the reaction. The mixture was dried with anhydrous Na ₂ SO ₄ and concentrated to obtain a crude product, which was purified by FCC (SiO ₂ , MeOH/DCM=0-10%) to obtain a yellow solid 4-(8-((5-methyl-1-( Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)pyrimidine[ 4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, yield 73%). LCMS (m/z): 660.3 (M+H).

Step L: (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-4 -(Piperazin-1-yl)pyrimidine[4,5-d]pyridazine

At room temperature, add TFA (1mL) to 4-(8-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy) -2-((S)-1-Methylpyrrolidin-2-yl)methoxy)pyrimidine[4,5-d]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (100mg , 0.151 mmol) in DCM (2 mL), and the resulting mixture was stirred at room temperature for 1 h. Concentrate under reduced pressure to remove the solvent to obtain a pale yellow oil (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl) )Methoxy)-4-(piperazin-1-yl)pyrimidine[4,5-d]pyridazine (72mg, crude product), the crude product was directly put into the next step. LCMS(m/z): 476.2(M+H).

Step M: (S)-1-(4-(8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl )Methoxy)pyrimidine[4,5-d]pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one dicarboxylate

Add (S)-8-((5-methyl-1H-indazol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-( A solution of piperazin-1-yl)pyrimidine[4,5-d]pyridazine (72 mg, 0.151 mmol) and DIEA (97.95 mg, 0.757 mmol) in DCM (5 mL) was stirred at room temperature for 10 min. After cooling to 0°C, acryloyl chloride (13.72 mg, 0.151 mmol) was added dropwise, and the resulting mixture was stirred vigorously for 15 min. After the reaction was completed, a saturated aqueous NaHCO ₃ solution (5 mL) was added, and the reaction system was extracted with DCM (3×10 mL). The obtained organic phase was washed with saturated aqueous NaCl solution (10 mL), and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to obtain a white solid (S)-1-(4-(8-((5-methyl-1H-indida) (Azol-4-yl)oxy)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidine[4,5-d]pyridazin-4-yl)piperazin-1-yl ) Prop-2-en-1-one dicarboxylate (6 mg, yield 7%). ¹ H NMR(400MHz, methanol-d ₄ )δ9.02(s,1H),8.50(s,2H),7.80(d,J=0.9Hz,1H),7.46(d,J=8.4Hz,1H) ,7.38(d,J＝8.5Hz,1H), 6.78(dd,J＝16.8,10.6Hz,1H), 6.24(dd,J＝16.8,2.0Hz,1H), 5.78(dd,J＝10.6,1.9 Hz, 1H), 4.84 (dd, J = 12.3, 3.7 Hz, 1H), 4.71 (dd, J = 12.3, 6.7 Hz, 1H), 4.07 (d, J = 5.9 Hz, 4H), 3.86 (d, J =5.4Hz,4H),3.70(s,1H),3.63-3.55(m,1H),3.14-3.04(m,1H),2.98(s,3H),2.44-2.33(m,1H),2.26( s,3H),2.15-1.98(m,3H).LCMS(m/z):530.3(M+H).

Example B7

1-(4-(2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-7-((5-methyl-1H-indazole- 4-yl)oxy)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step A: 3-Amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxylic acid Methyl ester

Compound 3-amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxylic acid methyl ester For the synthesis method of, refer to step A in Example A81. LCMS (m/z): 388.2 (M+H).

Step B: 3-Amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxylic acid

At room temperature, to 3-amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophen-2- Lithium hydroxide (47 mg, 1.96 mmol) was added to a solution of methyl carboxylate (380 mg, 0.98 mmol) in THF (5 mL) and water (1 mL). The mixture was heated to 70°C and stirred for 2 h. After cooling to room temperature, it was extracted with EA (10 mL x 3), the organic phase was washed with saturated aqueous NaCl (10 mL), dried over anhydrous Na ₂ SO ₄ , spin-dried and concentrated to obtain a yellow solid 3-amino-4-((5-methyl Base-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxylic acid (360 mg, yield 98%). LCMS(m/z): 374.1(M+H)

Step C: 3-Amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophene-2-carboxamide

At room temperature, to 3-amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophen-2- To a solution of carboxylic acid (360mg, 0.96mmol), ammonium chloride (10mg, 1.93mmol), DIPEA (478uL, 2.89mmol) in DMF (4mL)) was added HATU (550mg, 1.44mmol). The mixture was heated to 50 °C and stirred for 2 h. After cooling to room temperature, the mixture was poured into water (20 mL), extracted with EA (10 mL x 3), the organic phase was washed with saturated aqueous NaCl (10 mL), dried with anhydrous Na ₂ SO ₄ , spin-dried and concentrated to obtain a yellow liquid 3-amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophen-2-carboxamide (340mg, Yield 95%). LCMS(m/z): 373.1(M+H)

Step D: 7-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thieno[3,2-d]pyrimidine -2,4(1H,3H)-dione

At room temperature, to 3-amino-4-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thiophen-2- CDI (740 mg, 4.56 mmol) was added to a DMF (4 mL) solution of formamide (340 mg, 0.91 mmol). The mixture was heated to 80 °C and stirred for 2 h. After cooling to room temperature, the mixture was poured into water (20 mL), extracted with EA (10 mL x 3), the organic phase was washed with saturated aqueous NaCl (10 mL), dried with anhydrous Na ₂ SO ₄ , spin-dried and concentrated to obtain a yellow liquid 7-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)oxy)thieno[3,2-d]pyrimidine-2, 4(1H,3H)-dione (450mg, crude). LCMS(m/z): 399.0(M+H)

Step E to Step I: 1-(4-(2-((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-7-((5-methyl -1H-indazol-4-yl)oxy)thieno[3,2-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

For the subsequent synthesis steps of Example B7, refer to the description of Intermediate A1 and Example A2. ¹ H NMR (400MHz, methanol-d ₄ ) δ 7.50 (s, 1H), 7.40-7.34 (m, 2H), 6.90-6.78 (m, 2H), 6.29 (d, J = 16.8 Hz, 1H), 5.82(d,J=10.8Hz,1H), 5.28–5.21(m,1H), 4.21–4.10(m,4H), 4.09–4.04(m,1H), 3.94–3.82(m,4H), 3.41( s,3H),3.11-2.95(m,2H),2.71-2.55(m,2H),2.43--2.30(m,6H).LCMS(m/z):530.3(M+H).

According to the method similar to the synthetic method of the above-mentioned Example B series compound, the following compounds were also prepared and characterized:

Active Example

Example 1: The inhibitory effect of the compound of the present invention on the proliferation of KRas G12C mutant cells

This experiment verified the inhibitory effect of the compound of the present invention on the proliferation of KRas G12C mutant NCI-H358 human non-small cell lung cancer cells.

Luminescent Cell Viability Assay试剂盒评估化合物对NCI-H358细胞增殖的抑制活性。 [Test method]: Use Promega's

The Luminescent Cell Viability Assay kit evaluates the compound's inhibitory activity on the proliferation of NCI-H358 cells.

[Main instrument]: Spectramax M3 multifunctional microplate reader from Molecular Devices.

Luminescent Cell Viability Assay试剂盒(Promega公司，货号#G7573)，PBS(Solarbio公司，货号#P1020)，胰酶(Thermo Fisher，货号#25200072)，DMSO(Sigma公司，货号#D2650),甲基纤维素Methylcellulose(SIGMA，货号#9004-67-5)。 [Test materials]: NCI-H358 cell line (Cell Resource Center, Institute of Basic Medicine, Chinese Academy of Medical Sciences, resource number: 3111C0001CCC000470), 96-well transparent flat-bottomed black-walled cell culture plate (Greiner Bio one, catalog #655096), RPMI- 1640media (GE company, product number #SH30809.01), fetal bovine serum FBS (Thermo Fisher company, product number #10099-141),

Luminescent Cell Viability Assay Kit (Promega, Product Number #G7573), PBS (Solarbio, Product Number #P1020), Pancreatin (Thermo Fisher, Product Number #25200072), DMSO (Sigma, Product Number #D2650), Methyl Cellulose Methylcellulose (SIGMA, article number #9004-67-5).

[Experimental procedure]: Add 180 μL of cell suspension (RPMI1640 solution containing 1% methylcellulose and 10% FBS) to a 96-well cell culture plate to make the cell density in the cell culture plate 1500 viable cells/well. Set a control group (ie culture medium control) without cells, without compounds, and only 3D complete medium (1% methylcellulose in 10% FBS in RPMI1640 solution), and set without compounds and cells Control group (i.e. cell control). During the determination, the compound AMG510 or the following reference compound was used as a positive control. Place the cell plate in a cell incubator overnight. Prepare a 10-fold drug solution (RPMI1640 solution containing 1% DMSO and 10% FBS), the highest concentration is 10 μM, 3.16-fold gradient dilution, a total of 9 concentrations. Add 20 μL of drug solution to each well of a 96-well plate seeded with cells. The working concentration of the compound is: 1 μM, 3.16-fold gradient dilution, a total of 9 concentrations, each compound is set to three multiple wells, and the DMSO content is 0.1%. Prepare and add a solution of compound AMG510 or the following reference compound to the positive control well. The cell plate was placed in a cell incubator and continued to be cultured for 120 hours. For endpoint detection, melt the CellTiter-Glo reagent and move the cell plate to room temperature to equilibrate for 30 minutes, add 100 μL of CellTiter-Glo to each well of the cell plate, shake on an orbital shaker for 5 minutes to fully lyse the cells, and place the cell plate on To stabilize the luminescence signal at room temperature for 20 minutes, scan the luminescence value of each well with a multi-function microplate reader at full wavelength.

[Test samples] Representative example compounds and reference compounds, as well as the following compound AMG510 as positive controls.

AMG510: (Canon J et al., Nature.2019,575(7781):217-223.)

根据类似于US20190233440中实施例1L的合成方法，在步骤1中使用5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-醇代替5-氯-6-氟-1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-醇制备。 ¹H NMR(400MHz,DMSO-d ₆)δ13.04(s,1H),7.78(d,J＝8.3Hz,1H),7.45–7.11(m,4H),6.95(s,1H),6.84(dd,J＝16.6,10.4Hz,1H),6.17(d,J＝17.0Hz,1H),5.75(d,J＝10.5Hz,1H),4.92(s,1H),3.93–3.87(m,1H),3.87–3.71(m,6H),3.21(s,3H),2.99–2.90(m,2H),2.33(s,3H),2.30–2.19(m,3H),2.14(s,3H).LCMS(m/z):544.2(M+H). Reference compound 1:

According to the synthesis method similar to Example 1L in US20190233440, 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol was used in step 1 instead of 5-chloro -6-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol preparation. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.45-7.11 (m, 4H), 6.95 (s, 1H), 6.84 ( dd, J = 16.6, 10.4 Hz, 1H), 6.17 (d, J = 17.0 Hz, 1H), 5.75 (d, J = 10.5 Hz, 1H), 4.92 (s, 1H), 3.93–3.87 (m, 1H) ), 3.87--3.71 (m, 6H), 3.21 (s, 3H), 2.99 - 2.90 (m, 2H), 2.33 (s, 3H), 2.30 - 2.19 (m, 3H), 2.14 (s, 3H). LCMS(m/z): 544.2(M+H).

按照US20190233440的实施例7E所述方法合成。 Reference compound 2:

It was synthesized according to the method described in Example 7E of US20190233440.

[Data analysis] Use the following formula to calculate the cell inhibition rate and IC ₅₀ under the action of each compound:

Inhibition rate% = [1-(Lum _{test drug -Lum culture medium control} )/(Lum _{cell control-} Lum _{culture medium control} )]×100%

The four-parameter Logistic model in the nonlinear regression analysis in GraphPad Prism 7.0 software was used to fit the correlation curve of compound concentration and cell inhibition rate to calculate the IC ₅₀ value. The fitting model used was:

Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

[Experimental results] The compound of the present invention shows high anti-cell proliferation activity against KRas G12C mutant NCI-H358 human non-small cell lung cancer cells, and the preferred inhibition rate is >20%, >30%, >40%, >50%, >60%, more preferably the inhibition rate is >70%, >80%, >90%. The specific data is shown in Table 1-2.

Table 1. Inhibitory activity of A series of example compounds on the proliferation of NCI-H358 cells (inhibition rate of 1 μM concentration)

Compound Inhibition rate% (1uM) IC50(μM) Example 1 70.6 0.734 Example 2 <10 ND Example 3 62 0.745 Example 4 96.1 0.022 Example 5 40.6 1.04 Example 6 75.6 0.269 Example 7 97.4 0.012 Example 8 84.8 0.205 Example 9 98.2 0.004 Example 10 98.3 0.022 Example 11 72.4 0.247 Example 12 80.1 0.197 Example 13 98.8 0.008 Example 14 60.3 0.212 Example 15 95.2 0.023 Example 16 97.6 0.020 Example 17 <10 ND Example 18 14 ND Example 19 32.5 ND Example 20 77.6 ND Example 21 69.6 ND Example 22 47.9 ND Example 24 34.0 ND Example 28 91.6 0.101 Example 29 67.6 ND

Example 30 92.9 0.042 Example 31 50.3 ND Example 32 14.9 ND Example 33 <10 ND Example 36 33.7 ND Example 51 62.2 ND Example 52 61.5 ND Example 53 88.0 ND Example 55 91.6 0.063 Example 56 81.4 0.090 Example 63 43.2 ND Example 65 91.7 0.166 Example 66 85.0 0.371 Example 69 82.5 ND Example 70 81.9 ND Example 72 39.1 ND Example 81 96.2 0.052 Example 84 48.6 ND Example 85 59.6 ND Example 86 55.5 ND Example 87 26.0 ND Example 88 53.4 ND Example 89 47.9 ND Example 90 27.1 ND Example 91 <10 ND Example 92 52.1 ND Example 93 26.4 ND Example 95 16.5 ND Example 96 25.8 ND Example 97 18.2 ND Example 98 <10 ND Example 99 25.0 ND Example 100 49.3 ND Example 101 57.7 ND

Example 102 52.6 ND Example 103 92.0 0.055 Example 105 70.5 ND Example 106 85.3 ND Example 107 96.5 0.014 Example 110 45.3 ND Example 111 38.1 ND Example 112 39.8 ND Example 113 76.3 ND Example 114 86.1 0.105 Example 115 36.6 ND Example 116 73.2 ND Example 117 36.2 ND Example 118 75.3 ND Example 119 82.1 0.221 Example 120 81.9 0.224 Example 121 23.9 ND Example 122 43.3 ND Example 123 11.5 ND Example 124 16.6 ND Example 125 <10 ND Example 126 <10 ND Example 127 <10 ND Example 128 25.1 ND Example 129 62.3 ND Example 130 <10 ND Example 131 <10 ND Example 132 <10 ND Example 133 <10 ND Example 134 31.8 ND Example 135 <10 ND Example 136 92.7 0.091 Example 137 98.3 0.009 Example 138 <10 ND

Example 139 <10 ND Example 140 25.0 ND Example 141 <10 ND Example 142 <10 ND Example 143 40.5 ND Example 144 81.9 ND Example 145 39.1 ND Reference compound 1 77.7 0.228 Reference compound 2 76.4 ND AMG510 98.8 0.010

Table 2. Inhibitory activity of the example compounds of series B on the proliferation of NCI-H358 cells (inhibition rate of 1 μM concentration)

Compound % Inhibition rate (1uM) IC50(μM) Example 1 12 1.87 Example 2 81.5 0.170 Example 3 68.4 0.342 Example 4 <10 ND Example 5 <10 ND Example 6 <10 ND Example 7 47.6 ND

ND: Not determined.

Example 2: Preliminary rat pharmacokinetic study of the compound of the present invention

The pharmacokinetic characteristics of some compounds of the present invention were evaluated through rat pharmacokinetic experiments.

Adult male SD rats were used as test animals, and they were administered by intravenous injection (IV) and oral administration (PO). The IV sample configuration is 1 mg/mL 1% NMP/19% PEG400/80% (20% Captisol in 50 mM citrate buffer pH ~ 5) clear solution; the PO sample configuration is 1 mg/mL 2% HPMC/1% Tween80 is a clear aqueous solution. The dosage is 1 mg/kg in the IV group; 5 mg/kg in the PO group. Blood samples were collected at 0.08330, 25, 0.5, 1, 2, 4, 6, 8, and 24 hours in the intravenous injection group after administration; blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 24 in the oral administration group, respectively Collect blood samples within hours. The collected blood samples were placed in an EDTA-K2 anticoagulation tube and centrifuged to collect plasma. The obtained plasma was precipitated with acetonitrile, and the supernatant was collected by centrifugation for LC-MS/MS analysis.

Preliminary experimental results show that the compounds of the present invention show good or even improved pharmacokinetic properties.

Example 3: Cassette pharmacokinetic properties of the compound of the present invention in rats

The pharmacokinetic characteristics of some compounds of the present invention were evaluated through the rat Cassette pharmacokinetic experiment (Nagilla R. et al., J. Pharm. Sci. 2011, 100, 3862-3874.).

[Test materials]: Male SD rats, age: 6-8 weeks, weight 220-250g, purchased from Zhaoyan (Suzhou) New Drug Research Center Co., Ltd.; Tolbutamide (Aladdin, item number H1401054) ; Sulfobutyl β-cyclodextrin (Captisol, Shandong Binzhou Zhiyuan Biological, Product No. 20191013); Propylene Glycol (15) Stearate (Solutol, Meilun Biological, Product No. S0206A); DMSO (Vetec Company, Product No. WXBD0293V); Acetonitrile (Sigma-Aldrich, catalog number WXBD1744V); methanol (Sigma-Aldrich, catalog number WXBD2831V).

[Experimental procedure]: The compound combination is formulated into a solvent of 5% DMSO/10% Solutol/85% (20% Captisol), and the final concentration of each compound is 1 mg/mL, and the pharmaceutical preparation is in accordance with the injection volume of 1 mL/kg The tail vein was injected into SD rats, and blood was collected from the external jugular vein at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h. The blood was centrifuged at low temperature for 20 minutes, and the plasma was collected and stored at -20°C for testing.

[Sample analysis]: Establish a compound LC-MS/MS analysis method

Standard curve preparation: Pipette 20μL 1mg/mL DMSO stock solution of each compound, transfer it to 900μL 50% methanol working solution, and dilute step by step to obtain a concentration of 20000, 10000, 5000, 1000, 500, 100, 50, 20 , 10ng/mL standard curve working solution, and then draw 5μL standard curve working solution and 45μL rat blank plasma to get a standard concentration of 2000, 1000, 500, 100, 50, 10, 5, 2, 1ng/mL Curve, used to quantify unknown samples.

Sample pretreatment: 50μL of unknown plasma sample and standard curve sample, add 250μL of acetonitrile containing tolbutamide as an internal standard as a precipitant to precipitate plasma proteins, extract the test compound in the plasma, centrifuge at low temperature for 20 minutes, and take the supernatant. The supernatant was mixed with an aqueous solution of 0.1% formic acid, 5 μL was drawn into the sample, and the plasma concentration of the drug was analyzed by LC-MS.

[Data processing]: Use the mass spectrometry software Analyst 1.6.1 to draw a standard curve, quantify the unknown sample, and use Winnonlin 8.2 to calculate the pharmacokinetic parameters based on the drug concentration of the unknown sample at each time point.

[Experimental results]: The experimental results show that the compound of the present invention shows good or even improved pharmacokinetic properties in the pharmacokinetic evaluation of cassette administration.

Table 2.

Example T _1/2 (h) AUC _0-t (ng·hr/mL) Cl(mL/min/kg) A55 1.43 186 98.3 A103 2.26 172 80.8 A112 2.77 497 33.3 A114 1.89 447 36.5 A116 10.1 824 19.5 A118 1.79 531 31.7 A122 1.33 249 65.5 A130 1.14 662 25

A131 1.36 370 43.8 A136 0.74 306 54.1 AMG510 0.49 231 71.8

Throughout this application, various publications are cited. The disclosures of these publications are incorporated into this application as a whole by reference in order to more fully describe their technical level. The contents discussed in the sentences on which the references are contained in the published references are also individually and specifically incorporated herein by reference.

Claims (26)

The compound of formula I, its isomers or their pharmaceutically acceptable salts or solvates,

in, A is selected from C-CN or N; X, Y and Z are each independently selected from C, N, O or S;

Single bond or double bond; 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; W is selected from -C(O)-CR ¹ =C(R ² ) ₂ , -C(O)-C≡CR ² , -C(O)-C≡N, -S(O) _1-2 -CR ¹ = C(R ² ) ₂ , -S(O) _1-2 -C≡CR ² , -S(O) _1-2 -C≡N; or W is composed of R ¹ or R ² and ring B The N connected by W and the ring atoms adjacent to the N together form a nitrogen-containing heterocyclic ring fused with the B ring; 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; Each occurrence of 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 ¹⁰ ) ₂ -replace; 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 ¹⁰ , where C _1-6 alkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group and 5-12 membered heteroaryl are optionally further halogenated , -R ¹⁰ , -OR ¹⁰ , -SR ¹⁰ , N(R ¹⁰ ) ₂ substitution, where R ¹⁰ is as defined above each time it appears, or two R ¹⁰ connected to the same C and their connected The carbon atoms together form _{a C 3-8} cycloalkyl group optionally substituted with ^{one or more R 10 or halogen;} 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} ； m is 0 or 1; n is selected from an integer from 0 to 3; requirement is: When m=1, X, Y, and Z are each independently selected from C or N, and

Represents a double bond; and When A is N and m=1, at least one of X and Y is not C. The compound according to claim 1, which is of formula Ia or formula Ib,

Its isomers or their pharmaceutically acceptable salts or solvates. The compound according to claim 2, its isomer, or their pharmaceutically acceptable salt or solvate, which is a compound of formula Ia, wherein the fused bicyclic moieties are each independently selected from

Most preferred

Which includes X, Y and Z rings are optionally substituted 2 or 3 R ^5. The compound according to claim 2, its isomer, or their pharmaceutically acceptable salt or solvate, which is a compound of formula Ib, wherein the fused bicyclic moieties are each independently selected from

Each optionally substituted with 1 or 2 R ^5. The compound, its isomers, or their pharmaceutically acceptable salts or solvates according to any one of claims 1 to 4, wherein L is selected from a directly connected bond, -O-, -S- or -NR ^10- . The compound, its isomers, or their pharmaceutically acceptable salts or solvates according to any one of claims 1 to 5, wherein the B ring is selected from

Preferred

Wherein each B is optionally substituted with R ^a, wherein R ^a is preferably H or C _1-6 alkyl, most preferably H or CH _3. The compound, isomers thereof, or pharmaceutically acceptable salts or solvates thereof according to any one of claims 1 to 6, wherein W is -C(O)-CR ¹ =C(R ² ) ₂ , wherein R ¹ and R ² are each independently selected from H, F, methyl and dimethylaminomethyl, most preferably R ¹ and R ² are both H. The compound, its isomers, or their pharmaceutically acceptable salts or solvates according to any one of claims 1-7, wherein R ³ is -(CH ₂ ) _0-3 -R ^3' , wherein R ^3' Selected from the following 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups:

Wherein R ⁶ and R ⁷ are each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1-(dimethylamino) Ethyl, 1-methyl-2-(dimethylamino)ethyl. The compound according to claims 1-8, its isomers, or their pharmaceutically acceptable salts or solvates, wherein R ^{4 is} selected from

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 ; or R ^{4 is} selected from

Wherein R ¹¹ or R ¹² are each independently selected from halogen or C _1-6 alkyl optionally substituted by halogen. The compound according to claim 9, its isomer, or their pharmaceutically acceptable salt or solvate, wherein R ^{4 is} selected from

The compound, isomers thereof, or pharmaceutically acceptable salts or solvates thereof according to any one of claims 1-10, wherein R ^{5 is} selected from H, halogen, C _1-3 alkyl or C _3-6 ring Alkyl; preferably H, chlorine, fluorine, methyl or cyclopropyl. The compound, isomer thereof, or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-11, wherein G is -O-. The compound of formula II-1, its isomers, or their pharmaceutically acceptable salts or solvates,

in: 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;

Single bond or double bond; Ring B is

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; E is -LR ³ ; L is selected from directly connected bond, -O-, -NH- or -S-; G is -O- or -NH-; Each occurrence of 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; m is 0 or 1; n is selected from an integer from 0 to 3; requirement is: When m=1, X is selected from C or N, and

Represents a double bond; and When A is N and m=1, at least one of X and Y is not C. The compound according to claim 13, its isomer, or their pharmaceutically acceptable salt or solvate, wherein the fused bicyclic moiety is selected from

More preferred

The ring containing X, Y, and Z is substituted with 0 or 1 R ⁵ , and R ^{5 is} selected from halogen, preferably F or Cl. The compound, its isomer, or their pharmaceutically acceptable salt or solvate according to any one of claims 13-14, wherein G is O. A compound according to any one of claims 13 to 15, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R ³ is -R ^{3 ',} wherein R ^3' is selected from 3-7 membered heterocyclic ring Group, 5-10 membered heteroaryl group or C ₆ aryl group, each optionally substituted by C _1-6 alkyl, -OC _1-6 alkyl or C _3-6 cycloalkyl, wherein C _1-6 alkane 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 ; preferably, R ^{3 is} selected from

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 ; or

Wherein R ⁶ is C _1-6 alkyl, optionally further substituted by -NH ₂ , -NHC _1-6 alkyl or -N(C _1-6 alkyl) ₂ . The compound according to any one of claims 13-16, its isomers, or their pharmaceutically acceptable salts or solvates, wherein R ^{4 is} selected from C ₆ aryl or 5-10 membered heteroaryl, optionally 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 substitution; preferably, R ^{4 is} selected from

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 ; 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). The compound, its isomers, or their pharmaceutically acceptable salts or solvates according to any one of claims 13-17, wherein R ⁵ is H or halogen. The compound, its isomers, or their pharmaceutically acceptable salts or solvates are selected from the compounds of Examples 1-145 of the specification, their isomers, or their pharmaceutically acceptable salts or solvates. The compound according to any one of claims 1-19, its isomer, or their pharmaceutically acceptable salt or solvate, which is used as a medicine. The compound of any one of claims 1-19, its isomers, or their pharmaceutically acceptable salts or solvates, which are used for the treatment or prevention of K-RAS G12C, H-RAS G12C in individuals in need Or N-RAS G12C mutation, preferably K-RAS G12C mutation mediated disease. A pharmaceutical composition comprising the compound of any one of claims 1-19, its isomers, or their pharmaceutically acceptable salts or solvates, and a pharmaceutically acceptable excipient or carrier. The compound of any one of claims 1-19, its isomer, or their pharmaceutically acceptable salt or solvate or the pharmaceutical composition of claim 22 is prepared for the treatment or prevention of K -RAS G12C, H-RAS G12C or N-RAS G12C mutation, preferably K-RAS G12C mutation mediated disease medicine. A method for treating or preventing diseases mediated by K-RAS G12C, H-RAS G12C, or N-RAS G12C mutations, preferably K-RAS G12C mutations, in an individual in need thereof, comprising administering to the individual an effective amount of the claims The compound of any one of 1-19, its isomer, or their pharmaceutically acceptable salt or solvate, or the pharmaceutical composition of claim 22. The use of claim 23 or the method of claim 24, wherein the disease mediated by K-RAS G12C, H-RAS G12C or N-RAS G12C mutation, preferably K-RAS G12C mutation is selected from the following tumors or cancers: 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 bowel 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 (CNS), primary CNS lymphoma, spinal tumor, brainstem glioma or Pituitary adenoma. The use or method of claim 25, wherein the disease mediated by K-RAS G12C, H-RAS G12C or N-RAS G12C mutation, preferably K-RAS G12C mutation is selected from pancreatic cancer, colorectal cancer and lung cancer.