CN113637005A

CN113637005A - KRAS inhibitors for cancer treatment

Info

Publication number: CN113637005A
Application number: CN202110203951.9A
Authority: CN
Inventors: 尚尔昌; 张彦涛; 仲伯禹; 汪瑞祥; 曹宜菊; 陈光明; 胡旭波; 王孝文
Original assignee: Taili Biotechnology Shanghai Co ltd
Current assignee: Taili Biotechnology Shanghai Co ltd
Priority date: 2020-02-24
Filing date: 2021-02-24
Publication date: 2021-11-12
Also published as: TW202140450A; WO2021169990A1

Abstract

The present invention relates to compounds of formula I, isomers thereof or pharmaceutically acceptable salts or solvates thereof, useful as KRAS inhibitors, pharmaceutical compositions comprising such compounds and the use of these compounds in the treatment of cancer or tumors.

Description

KRAS inhibitors for cancer treatment

Technical Field

The present invention relates to the field of pharmaceutical chemistry. More particularly, the present invention relates to a class of compounds having novel structures useful as KRAS inhibitors, pharmaceutical compositions comprising such compounds, methods of preparing such compounds and the use of such compounds in the treatment of cancer.

Background

Ras, a rat sarcoma oncogene homolog, represents a group of closely related monomeric globular proteins belonging to the gtpase family of proteins. Specifically, under normal physiological conditions, Ras is activated upon receipt of growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration and differentiation. These regulatory functions of Ras are performed by switching between GDP-binding and GTP-binding states, i.e., a "molecular switch" (Alamgeer et al, Current Opin Pharmacol.2013, 13: 394-401). Ras bound to GDP is an inactive form, either dormant or off, when the signaling system is turned off and activated when exposed to some pro-stimulatory stimulus, e.g., it can be induced by guanine nucleotide exchange factor (GEF) to release GDP and bind to GTP, with the result that Ras is thereby turned "on" and converted to Ras active form, which recruits and activates various downstream effectors for signaling, and can transmit signals from the cell surface into the cytoplasm, thereby controlling numerous critical cellular processes such as differentiation, survival and proliferation (Zhi Tan et al, Mini-Reviews in Medicinal Chemistry,2016,16, 345-.

Ras has gtpase activity and can cleave the terminal phosphate of GTP to convert it to GDP, i.e., convert itself to an inactive state. However, Ras has very low endogenous GTPase activity, and conversion of GTP-Ras to GDP-Ras requires the exogenous protein GAP (GTPase activating protein). GAP interacts with Ras and promotes conversion of GTP to GDP. Thus, any Ras gene mutation that affects Ras interaction with GAP or conversion of GTP to GDP results in Ras being in an active state for a long period of time, thereby continuously signaling growth and division to the cell, stimulating the cell to proliferate continuously, and ultimately leading to tumor formation and development.

Among the human tumor-associated genes, there are three ubiquitously expressed Ras genes, H-RAS, K-RAS and N-RAS, which encode highly homologous, approximately 21kDa, HRas, NRas, KRas proteins, respectively. In 1982, the researchers first discovered Ras activation of mutations 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 genome sequencing studies in different cancer types revealed that Ras proteins mutated in more than 30% of cancer types, with the highest mutation rates especially in pancreatic (> 90%), colon (45%) and lung (35%) cancers. Transgenic and genetically engineered mouse models have also revealed that mutated Ras proteins are sufficient to drive and trigger multiple types of cancer, and that Ras oncogenes are also critical for the maintenance and progression of tumors of multiple cancer types, e.g., in Ras mutated cancer cell lines and cancer animal models, RNA intervention has been shown to slow tumor growth. These studies have made Ras tumor proteins a very attractive target for anticancer drugs well-accepted in the pharmaceutical field.

Studies have shown that Ras mutations are most common in KRas, and KRas mutations can be observed in approximately 85% of Ras mutation-driven cancers; the vast majority of Ras mutations occur at codons G12, G13, and Q61, with about 80% of KRas mutations occurring again at the glycine of codon 12 (G12C mutation). KRas mutations are common in pancreatic, lung adenocarcinoma, colorectal, gall bladder, thyroid, and bile duct cancers, and are also found in 25% of non-small cell lung Cancer patients (McCormick, f. et al, Clinical Cancer Research 21(8), 1797-. Therefore, KRas mutant protein has become the most important branch in Ras drug target research, and the development of inhibitors thereof is also regarded as a very promising development direction in the development of anticancer/tumor drugs.

However, the last three decades of drug development for Ras have shown that Ras has long been considered as an "unprofitable" target in the industry because of its smooth surface, lack of significant groove or pocket structures for binding small molecule inhibitors, and its very high affinity (on the picomolar scale) for guanine substrates, which has led to the development of its small molecule inhibitors into problematic predicaments. Nevertheless, continuing efforts to target Ras muteins have led to some encouraging efforts, and a series of Ras inhibitors have been developed that inhibit Ras, and in particular KRas mutations, through a variety of pathways, including direct targeting of Ras, inhibition of Ras expression levels, disruption of Ras protein localization, targeting synthetic lethal components, targeting Ras-GEF interactions, targeting Ras and effector interactions, and targeting 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 mutein KRas-G12C, including allosteric covalent inhibitors, such as the 6H05 series, the quinazoline series, the ARS series, and the tetrahydropyridopyrimidine series, as well as forward binding covalent 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, among others.

However, the aforementioned KRas inhibitors still have problems that are being solved and their "druggability" is still unsatisfactory. For example, many KRas-dependent cancers are susceptible to drug resistance, side effects such as off-target effects, chemically active metabolites, poor metabolic stability, or immunogenic covalent adducts for such targeted Therapeutics (John P.O' Bryan et al, Pharmacological Research 139(2019) 503-511; Duan Ni et al, Pharmacological & Therapeutics, https:// doi. org/10.1016/j. pharmatherma.2019.06.007). Thus, there remains a clinical need for more alternative KRas inhibitors that are expected to have KRas inhibitory activity comparable to or improved by existing inhibitors, improved "druggability", better safety such as less drug interactions or metabolic properties, improved pharmacokinetic properties, and/or greater selectivity for different patient populations or specific tumor types.

The present invention provides novel structural inhibitor compounds having KRas mutein inhibitory activity, in particular KRas-G12C inhibitory activity. These compounds of the invention, in particular the preferred compounds of the invention, have an improved structural pattern, which allows the following technical effects to be achieved compared to the KRas mutein inhibitors known from the prior art:

(1) retains comparable or enhanced, even significantly enhanced, KRas muteins and related cancer cell proliferation inhibitory activity;

(2) different spectrum of biological activity for new indications;

(3) has improved metabolic stability, thereby leading to better pharmacokinetic properties;

(4) has improved physicochemical properties, and thus has good drug properties, such as easier absorption in vivo.

Brief description of the invention

The present inventors have found through studies that the compounds defined herein, isomers thereof, or pharmaceutically acceptable salts or solvates thereof are effective KRas mutein inhibitors, capable of inhibiting KRas activity in a cell, and are useful for treating or preventing diseases or disorders mediated by or benefiting from KRas mutein inhibition, in particular, tumors or cancers, by inhibiting abnormal cell proliferation through inhibition of KRas mutein.

In a first aspect, the present invention provides a compound of formula I, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof,

wherein the content of the first and second substances,

a is selected from C-CN or N;

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

is a single bond or a double bond;

ring B is a heterocyclic group containing 3-12 ring atoms, optionally substituted with one or more R^aSubstitution;

R^aeach occurrence is independently selected from-OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6Alkyl, -C_3-8Cycloalkyl, halogen, -NO₂-CN and oxo, where-C is present_1-6Alkyl or-C_3-8Cycloalkyl is optionally substitutedFurther by R¹⁰、-OR¹⁰Halogen or-CN;

w is selected from the group consisting of-C (O) -CR¹＝C(R²)₂、-C(O)-C≡CR²、-C(O)-C≡N、-S(O)_1-2-CR¹＝C(R²)₂、-S(O)₁-2-C≡CR²、 -S(O)₁-2-C ≡ N; or W is represented by R in¹Or R²Together with the N to which W is attached in ring B and the ring atoms adjacent to the N form a nitrogen-containing heterocycle fused to ring B;

l is selected from the group consisting of a direct bond, -O-, -S-, -S (O)₁-2-、-NR¹⁰-or-CR⁸R⁹-；

G is selected from-O-, -S (O)₁-2-、-NR¹⁰-or-CR⁸R⁹-；

R¹And R²Each independently selected from H, halogen, CN, NO₂And optionally is-OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Or halogen-substituted C_1-6An alkyl group;

R⁸and R⁹Each independently selected from H, halogen, CN, NO₂And C optionally substituted by halogen_1-6Alkyl or optionally substituted by halogen or R¹⁰Substituted C_3-6A cycloalkyl group;

R¹⁰each occurrence is independently selected from H or C optionally substituted with halogen _1-6An alkyl group;

R³is selected from- (CH)₂)_0-6-R^3’Wherein R is^3’Selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl and C_3-12Cycloalkyl, each optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, wherein C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted with haloElement, -R¹⁰、-OR¹⁰、-SR¹⁰Or N (R)¹⁰)₂-substitution;

R⁴is selected from C_6-12Aryl or 5-12 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, - (CR)¹⁰R¹⁰)_0-1-C(O)-N(R¹⁰)₂、 -(CR¹⁰R¹⁰)₀-1-C(O)-OR¹⁰、-(CR¹⁰R¹⁰)₀-1-S(O)₁-2-N(R¹⁰)₂、-(CR¹⁰R¹⁰)₀-1-S(O)₁-2-R¹⁰Wherein C is_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰Or N (R)¹⁰)₂Is substituted in which R¹⁰In each occurrence, two R's as defined above, or linked to the same C¹⁰Together with the carbon atom to which they are attached form an optionally substituted R¹⁰Or halogen-substituted C_3-8A cycloalkyl group;

R⁵selected from H, halogen, NO₂CN, C optionally substituted by one or more halogens _1-6Alkyl or optionally substituted by one or more halogens or R¹⁰Substituted C_3-8A cycloalkyl group;

m is 0 or 1;

n is an integer from 0 to 3;

with the following conditions:

when m is 1, each X, Y, Z is independently selected from C or N, and

represents a double bond; and

when a is N and m is 1, at least one of X and Y is not C.

The present invention also provides in this aspect a compound of formula II, isomers thereof, or pharmaceutically acceptable salts or solvates thereof, as described herein below.

In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or formula II of the present invention, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof.

A third aspect of the 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 medicament.

In a fourth aspect, the present invention provides a compound of formula I or formula II, 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.

In a fifth aspect, the present invention provides the use of a compound of formula I or formula II, or an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, of the present invention in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by Ras mutations, preferably KRas mutations.

In a sixth aspect, the present invention provides a method for treating and/or preventing a disease mediated by Ras mutations, preferably KRas mutations, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or formula II of the present invention, isomers thereof or pharmaceutically acceptable salts or solvates thereof or a pharmaceutical composition comprising the same.

In a seventh aspect, the present invention provides a process for the preparation of a compound of formula I or formula II, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, according to the present invention.

In an eighth aspect, the present invention provides a pharmaceutical combination comprising a compound of formula I or formula II, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more other pharmaceutically active agents of the present invention.

It is to be noted that the above aspects also encompass embodiments wherein the compound of formula I or formula II, respectively, is a corresponding specific, preferred, more preferred or most preferred embodiment described herein.

Detailed Description

Definition of

Unless otherwise indicated, each term used in the specification and claims has the following meaning. Where a particular term or phrase is not specifically defined, it should not be considered uncertain or clear, but rather should be understood according to ordinary meanings in the art. Many of the groups defined herein are optionally substituted and the list of substituents given in this definition section are exemplary only and are not intended to limit the substituents defined elsewhere in this specification and claims.

The term "Ras mutation" or "Ras mutein" as used herein refers to a protein encoded and expressed by a Ras gene in which one or more codons have been mutated, typically including, but not limited to, a Ras protein in which the glycine at codon 12, the glycine at codon 13, or the glutamine at codon 61 has been mutated, such as a mutated HRas, NRas, or KRas. These residues are located in the active site of Ras, and mutations that impair Ras' intrinsic or GAP-catalyzed GTPase activity, leading to the persistence of GTP-bound Ras. In particular, the mutation at codon position 12 refers to a glycine to cysteine mutation, i.e. the G12C mutation.

For the purposes of the present invention, "Ras mutation" or "Ras mutein" are used interchangeably and refer generally to a mutated HRas, NRas or KRas, such as but not limited to HRas-G12C, NRas-G12C or KRas-G12C; in particular to KRas muteins, more particularly to KRas-G12C muteins.

The term "treating" or "treatment" as used herein refers to administering one or more compounds of formula I, isomers thereof, or pharmaceutically acceptable salts or solvates thereof, as described herein, to a subject, e.g., a mammal, e.g., a human, suffering from, or having symptoms of, the disease, for the purpose of curing, alleviating, or otherwise affecting the disease or symptoms of the disease. In a specific embodiment of the invention, the disease is a Ras mutation mediated disease, as defined below, in particular a tumor or cancer.

The term "prevention" as used herein is well known in the art and is the administration of one or more compounds of formula I, isomers thereof or pharmaceutically acceptable salts or solvates thereof as described herein to a subject, e.g., a mammal, e.g., a human, suspected of suffering from or susceptible to a disease mediated by a Ras mutation as defined herein, particularly a cancer or tumor, such that the risk of suffering from the defined disease is reduced. The term "prevention" encompasses the use of a compound of the invention prior to diagnosis or determination of any clinical and/or pathological condition.

The terms "inhibit" and "reduce," or any variant of these terms, as used herein, refer to the ability of a biologically active agent to reduce the signaling activity of a target of interest by interacting directly or indirectly with the target, and to any measurable reduction or complete inhibition of the activity of the target of interest. For example, it may be an amount of reduction in activity (e.g., KRas activity) of about, up to about, 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, as compared to normal.

The term "selective inhibition" as used herein refers to the ability of a biologically active agent to preferentially reduce the signaling activity of a target of interest, as compared to off-target signaling activity, by interacting directly or indirectly with the target. For the compounds of formula I of the present invention, they have the ability to selectively inhibit the G12C mutation of a KRas, HRas or NRas protein, preferably the G12C mutation of KRas protein, relative to the various mutations at one or more codons of Ras protein. For example, the invention for a particular Ras mutation compared to another specific Ras mutation, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or can be derived from any range of better activity inhibitors, or with another specific Ras mutation compared to the activity of at least 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-or 500-fold better activity for a particular Ras mutation (such as KRas-G12C).

The term "Ras mutation mediated disease" as used herein refers to a disease in which Ras mutation contributes to the development and progression of the disease, or inhibition of Ras mutation reduces the incidence of disease, reduces or eliminates disease symptoms. For the purposes of the present invention, "Ras mutation-mediated disease" preferably refers to KRas mutation-mediated disease, most preferably KRas-G12C-mediated disease, 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 cancerous 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, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, carcinoma of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the Central Nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma or pituitary adenoma.

For the various aspects of the invention, preferably, the cancer or tumor is associated with Ras mutations, preferably KRas mutations, more preferably KRas-G12C mutations, including but not limited to the above tumor types and their preferred ranges. Particularly preferred tumors of the present invention include lung, colon, pancreatic and ovarian cancers.

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 (e.g., cattle), sport animals, pets (e.g., 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 in a patient having a cancer or tumor in need of treatment. The effective amount or dosage of the active ingredients of the present invention can be determined by one skilled in the art by conventional methods, in combination with conventional influencing factors.

The term "pharmaceutical combination" as used herein means that the compounds of the present invention can be used in combination with other active agents for the purpose of the present invention. The additional active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., third) compound that is compatible with, i.e., does not adversely affect, or has complementary activity to, the compounds of the invention, e.g., such that the agent is known to modulate other bioactive pathways, or to modulate different components of, or even overlap with, the biological target of the compounds of the invention. Such active agents are suitably present in combination in an effective amount to achieve the intended purpose. The additional active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or separately administered in separate discrete units from the compounds of the present invention, either simultaneously or sequentially when administered separately. The sequential administration may be close in time or remote in time.

In one aspect, other active agents that can be used in combination with the compounds of the invention include, but are not limited to, chemotherapeutic agents, therapeutic antibodies, and radiation therapies, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, topoisomerase inhibitors, anti-hormonal agents, angiogenesis inhibitors, cytotoxic agents, and compounds that disrupt or inhibit the Ras-Raf-ERK or PI3K-AKT-TOR signaling pathway. Examples of such other active agents for use 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 means molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered in suitable amounts to an animal such as a human.

The term "pharmaceutically acceptable salts" as used herein refers to those salts, including acid addition salts and base addition salts, which retain the biological effectiveness and properties of the parent compound and are not biologically or otherwise undesirable. "pharmaceutically acceptable acid addition salts" can be formed from compounds having a free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, or organic acids which 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, and the like. "pharmaceutically acceptable base addition salts" include those derived from salts of inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, as well as salts derived from pharmaceutically acceptable 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, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

The term "isomer" as used herein refers to any stereoisomer, mixture of enantiomers, including racemates, mixture of diastereomers, geometric isomers, atropisomers and/or tautomers of a compound that may exist on a structure. Methods for determining and isolating the Stereochemistry of such isomers are well known to those skilled in the art (S.P. 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), and the invention encompasses all possible isomeric forms of the Compounds of formula I or formula II defined above, as well as pharmaceutically acceptable salts or solvates thereof. For a given chemical structure, unless mirror images of each other, the stereoisomers are identical. A particular stereoisomer may also be referred to as an enantiomer, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate. The terms "racemic mixture" and "racemate" mean an equimolar mixture of two enantiomers, free of optical activity.

Structural formula or structural fragment of compound used in the invention

Denotes the absolute configuration of a stereocenter, i.e. a chiral center, and accordingly denotes the absolute configuration for this chiral center in the nomenclature of the compounds or intermediates provided by the present invention as R and S, the determination of which is well known to the person skilled in the art.

The term "- - - - - -" as used herein in reference to a structural fragment indicates that the bond across which it crosses is the bond that the structural fragment is attached to the rest of the molecule.

The term "solvate" as used herein refers to a solvent addition form comprising a stoichiometric or non-stoichiometric amount of solvent, including any solvated form of the compounds of the invention, including, for example, solvates with water, such as hydrates, or with organic solvents, such as methanol, ethanol or acetonitrile, i.e., as methanolates, ethanolates or acetonitriles, respectively; or in the form of any polymorph. It will be understood that such solvates of the compounds of the invention also include solvates of pharmaceutically acceptable salts of the compounds of the invention.

The term "isotopic variation" as used herein refers to a compound containing an unnatural proportion of an isotope on one or more of the atoms making up the compound. The compounds of the invention may contain non-daily moieties on one or more of the atoms that make up the compound The isotopic variation of the atomic isotopes, to form compounds of the present invention or pharmaceutically acceptable salts thereof, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Examples of isotopes and pharmaceutically acceptable salts thereof which may be incorporated into compounds of the invention include, for example²H、³H、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. It will be appreciated 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 with incorporation therein of radioactive isotopes (e.g. of the type³H or¹⁴C) Certain isotopic variations of those compounds of the present invention and pharmaceutically acceptable salts thereof, are useful in drug and/or substrate tissue distribution studies. Tritium generation³H and carbon-14 i.e¹⁴The C isotope is particularly preferred because of its ease of preparation and detectability. In addition, with isotopes such as deuterium²H substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances. Alternatively, positron emitting isotopes (e.g. prepared) ¹¹C、¹⁸F、¹⁵O and¹³n) substituted compounds of the invention, which are useful in Positron Emission Tomography (PET) studies for substrate receptor occupancy detection.

The term "metabolite" as used herein means a product of a particular compound or salt thereof produced via in vivo metabolism. Such products may, for example, result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Metabolite products are typically identified as follows: preparation of radiolabeled isotopes of the compounds of the invention (e.g.¹⁴C or³H) Administered to an animal such as rat, mouse, guinea pig, monkey, or human at a detectable dose (e.g., greater than about 0.5mg/kg) for a time sufficient for metabolism to occur (typically about 30 seconds to 30 hours) and from the urineBlood or other biological samples. Metabolite structure is determined in a conventional manner, e.g. MS, LC/MS or NMR analysis. Typically, metabolite analysis is performed in the same manner as conventional pharmacokinetic studies well known to those skilled in the art. Metabolite products, so long as they are not otherwise found in vivo, can be used in diagnostic assays for therapeutic dosages of the compounds of the present invention.

The term "prodrug" as used herein refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound as described herein, e.g., a compound of formula I or II. Thus, 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 an active compound in vivo, e.g., by hydrolysis. Prodrug compounds generally provide the advantages of solubility, histocompatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, h., Design of produgs (1985), pages 7-9, 21-24 (Elsevier, Amsterdam.) the discussion of Prodrugs can be found in Higuchi, ACS Symposium Series, t. et al, volume 14, and "bioreversible carrier in drug Design", Edward B. roche, U.S. Pharmaceutical Association & Pergamon Press, 1987), the entire contents of which are incorporated herein by reference. The term "prodrug" is also meant to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound as described herein are typically prepared by modifying functional groups present in the active compound such that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is bonded to any group that, when the prodrug is administered to a mammal, cleaves to form a free hydroxy, free amino, or free mercapto group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxyl functional groups, or acetamide, formamide and benzamide derivatives of amine functional groups in the active compound. In some embodiments, prodrugs include phosphate-containing prodrugs, borate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β -lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 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 filler or gel materials, suitable for human use, and of sufficient purity and sufficiently low toxicity, examples of which include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., magnesium stearate), calcium sulfate, vegetable oils, polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, and the like), emulsifiers (e.g., tweens), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, and the like.

The term "halogen" or "halo" as used herein means F, Cl, Br or I. Furthermore, the term "halogen-substituted" group is intended to include monohalogenated or polyhalogenated groups, wherein one or more of the same or different halogens substitute for one or more hydrogens in the group.

The term "alkyl" as used herein means a saturated straight or branched chain monovalent hydrocarbon group, wherein the alkyl group may be optionally substituted. In one example, alkyl is 1 to 18 carbon atoms (C)₁-C₁₈). In other examples, alkyl is C₁-C₁₂、C₁-C₁₀、C₁-C₈、 C₁-C₆、C₁-C₅、C₁-C₄Or C₁-C₃. 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)₂CH(CH₃)₂) 2-butyl (-CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (-C (CH)₃)₃) 1-pentyl group, 2-pentyl group (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃1-heptyl and 1-octyl. For the purposes of the present invention, optional substituents on alkyl include cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, mercapto, amino, alkoxy, alkylthio, mono-or dialkylamino, aryloxy, arylthio, halogen, cyano, carbonyl, thiocarbonyl, azido, alkanoyl, arylacyl, alkylamido, arylamido, alkanoyloxy, arylacyloxy, alkylsulfonyl, arylsulfonyl, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, C-carbamoyl, N-carbamoyl, C-thiocarbamoyl, N-thiocarbamoyl, amido, C-carboxy, O-carboxy, nitro and silyl, and groups each of which is further substituted with the remaining optional substituents, wherein each type of group is as defined herein. Examples of substituents include, but are not limited to, one or more Independently selected from the group consisting of: halogen, OH, SH, CN, NH₂、NHCH₃、N(CH₃)₂、NO₂、N₃、C(O)CH₃COOH, C (O) -amino, OCOCH₃Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methylsulfonylamino, SO₂Phenyl, piperidinyl, piperazinyl and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic moieties may optionally be further substituted, such as by one or more substituents selected from the same list above.

The term "alkylene" as used herein means a divalent group derived from the removal of 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 to 18 carbon atoms (C)₁-C₁₈). In other examples, the divalent alkylene is C₀-C₆、C₀-C₅、C₀-C₃、C₀-C₁、C₁-C₁₂、C₁-C₁₀、C₁-C₈、C₁-C₆、C₁-C₅、C₁-C₄、 C₁-C₃Or C₁-C₂For example, the compounds R of the formula I according to the invention³"- (CH) in definition₂)_0-6”。C₀Alkylene means a bond. Examples of alkylene groups include methylene (-CH)₂-), 1-ethyl (-CH (CH)₃) -, (1, 2-ethyl (-CH))₂CH₂-), 1-propyl (-CH (CH)₂CH₃) -), 2-propyl (-C (CH)₃)₂-), 1, 2-propyl (-CH (CH)₃)CH₂-), 1, 3-propyl (-CH)₂CH₂CH₂-), 1-Dimethylethyl-1, 2-yl (-C (CH) ₃)₂CH₂-), 1, 4-butyl (-CH)₂CH₂CH₂CH₂-) and the like.

The term "amino" as used herein refers to a primary amine (i.e., -NH) that may be optionally substituted₂) Secondary amines (i.e., -NRH), tertiary amines (i.e., -NRR), and quaternary amines (i.e., -N (+) RRR), wherein each R is the same or different and is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclyl, wherein alkyl, cycloalkyl, aryl, and heterocyclyl are defined herein. Specific secondary and tertiary amines are alkylamines, dialkylamines, arylamines, diarylamines, aralkylamines, and diarylalkylamines, wherein 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 may be an all-carbon monocyclic, fused, spiro or bridged ring. In one example, the cycloalkyl group has 3 to 12 carbon atoms (C)₃-C₁₂). In other examples, cycloalkyl is C₃-C₈、C₃-C₁₀、C₅-C₁₀Or C₃-C₆Of (2) a ring of (a). In other examples, cycloalkyl as a monocyclic ring is C₃-C₈、C₃-C₆Or C₅-C₆. In another example, cycloalkyl is C as bicyclic₇-C₁₂. In another example, cycloalkyl as a spiro ring system is C ₅-C₁₂. 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-enyl, cyclohexyl, 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 cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4]、 [4,5]、[5,5]、[5,6]Or [6,6 ]]A ring system. Examples of bridged bicyclic cycloalkyls 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 is optionally substituted, substituentsAs defined above for the alkyl substituents.

The term "aryl" as used herein means an all-carbon, monocyclic or fused polycyclic aromatic group having 6 to 14 carbon atoms. Examples include C_6-10Aryl radical, C_6-12Aryl radical, C_5-12And (4) an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracyl, phenanthryl, tetracenyl, 1,2,3, 4-tetrahydronaphthyl, 1H-indenyl, 2, 3-dihydro-1H-indenyl, and the like, with phenyl or naphthyl being preferred. Aryl groups in the definition of compounds herein are optionally substituted with one or more, e.g. 1,2,3,4 or 5, substituents, e.g. 1-2, 1-3 or 1-4 substituents. For the purposes of the present invention, aryl is optionally substituted, the substituents being as defined above for the alkyl substituents.

The terms "heterocyclyl" or "heterocycle" or "heterocycloalkyl" as used herein, are used interchangeably and mean any monocyclic, fused, spiro or bridged ring, saturated or unsaturated non-aromatic ring system having from 3 to 20 ring atoms (e.g., 3-5, 3-8, 3-12, 4-7, 4-10, 5-12 ring atoms) wherein the ring atoms contain, in addition to carbon, at least one heteroatom selected from nitrogen, oxygen or sulfur, regardless of where the ring system is attached to the remainder of the molecule, and any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO)₂) And any nitrogen heteroatom may be optionally quaternized. In one example, heterocyclyl includes 3-12 ring atoms ("members") and includes monocyclic, fused or spiro ring systems in which the ring atoms are carbon and at least one heteroatom selected from nitrogen, oxygen or sulfur. In some examples, heterocyclyl includes 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom. In other examples, heterocyclyl includes 3-to 8-membered, 3-to 7-membered, 3-to 6-membered, or 4-to 6-membered monocyclic, e.g., 3-membered monocyclic, 4-membered monocyclic, 5-6-membered monocyclic, having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur. In another example, heterocyclyl includes 3-12 membered heterocycloalkyl, such as 4-11 membered, 3-8 membered, 5-6 membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a "nitrogen-containing heterocycle" that includes at least one nitrogen in the ring system. In one example, heterocyclyl includes 0-3 double bonds.

Examples of heterocycles include, but are not limited toLimited to oxiranyl, aziridinyl, thiepinyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithiocyclobutyl, 1, 3-dithiocyclobutyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuryl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidyl, oxazinanyl, thiazinyl, thiohexoxanyl, homopiperazinyl, homopiperidinyl, azepanyl, thiepanyl, oxacycloheptyl, azetidinyl, oxetanyl, and the like

A group, an oxazepinyl group, a diazepanyl group, a 1, 4-diazepanyl group, a diazepine group

Radical, sulfur nitrogen hetero

A group, a thiazepine group, a tetrahydrothiopyranyl group, an oxazolidinyl group, a thiazolidinyl group, an isothiazolidinyl group, a 1, 1-dioxoisothiazolidinonyl group, an oxazolidinonyl group, an imidazolidinonyl group, a 4,5,6, 7-tetrahydro [2H ] group]Indazolyl, tetrahydrobenzimidazolyl, 4,5,6, 7-tetrahydrobenzo [ d ]]Imidazolyl, 1, 6-dihydroimidazo [4,5-d ]Pyrrolo [2,3-b]Pyridyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dihydroheterocyclopentyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiopentinyl, piperazinonyl, piperazindionyl, pyrazolidinyl, imidazolinyl, 3-azabicyclo [ 3.1.0.0]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, 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 ]]Decan-2-onyl, azaspiro [5.5 ]]Undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1-dioxohexahydrothiopyranyl.

For the purposes of the present invention, the above broad and specific list of heterocycles is optionally substituted, with the substituents being as defined above for the alkyl substituents.

The term "heteroaryl" as used herein means any mono-, bi-or tricyclic ring system having 5-12 ring atoms containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, wherein at least one ring is a 5-or 6-membered aromatic ring, which ring system may be attached to the remainder of the molecule either at an aromatic or non-aromatic ring moiety, and the point of attachment may be at a heteroatom or at a carbon atom, and any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO)₂) And any nitrogen heteroatom may be optionally quaternized. Particular embodiments include 4-7, 4-10, 5-7, 5-12 membered heteroaryl. 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-oxadiazole, 1-oxa-2, 4-oxadiazole, 1-oxa-2, 5-oxadiazole, 1-oxa-3, 4-oxadiazole, 1-thia-2, 3-oxadiazole, 1-thia-2, 4-diazoles, 1-thia-2, 5-diazoles, 1-thia-3, 4-diazoles, tetrazoles, pyridines, pyridazines, pyrimidines, pyrazines, benzofurans, benzothiophenes, indoles, benzimidazoles, indazoles, benzotriazoles, 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, pyrazine and derivatives thereof,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]A pyrimidine.

For the purposes of the present invention, the heteroaryl groups broadly and specifically enumerated above are optionally substituted as defined above for the alkyl substituents.

The term "hydroxy" as used herein refers to an-OH group.

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

The terms "alkoxy, alkylthio" as used herein refer to hydroxy or mercapto, respectively, wherein H is substituted by alkyl as defined herein; the terms "aryloxy, arylthio" as used herein refer to a strong group or a mercapto group, respectively, wherein H is substituted by an aryl group as defined herein.

The term "oxo" as used herein means ═ O.

The term "nitro" as used herein means-NO₂A group.

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

The term "thiocarbonyl" as used herein refers to a — C ═ S group.

The term "azido" as used herein refers to-N₃A group.

The term "acyl" as used herein refers to rc (o) -, wherein R may be alkyl or aryl as defined herein, which correspond to the terms "alkanoyl" and "arylamino" as used herein, respectively.

The term "acylamino" as used herein refers to RC (O) -NH-, wherein R may be alkyl or aryl as defined herein, which corresponds to the terms "alkylamido" and "arylamido", respectively, as used herein.

The term "acyloxy", as used herein, refers to RC, (O) -O-, where R may be an alkyl or aryl group, as defined herein, which corresponds to the terms "alkanoyloxy" and "aryloyloxy", respectively, as used herein.

The term "carbamoyl" as used herein refers to-C (O) -NH₂(ii) a The term "thiocarbamoyl" as used herein means-C (S) -NH₂。

The term "sulfonyl", as used herein, refers to-S (O)₂-R, wherein R may be alkyl or aryl as defined herein, which correspond to the terms "alkylsulfonyl" and "arylsulfonyl", respectively, as used herein.

The term "sulfonamido", as used herein, refers to RS (O)₂-NH-, wherein R may be an alkyl or aryl group as defined herein, which corresponds to the terms "alkylsulfonylamino" and "arylsulfonylamino", respectively, as used herein.

The term "sulfonyloxy" as used herein refers to RS (O)₂-O-, wherein R may be an alkyl or aryl group as defined herein, which corresponds to the terms "alkylsulfonyloxy" and "arylsulfonyloxy", respectively, as used herein.

The term "amido" as used herein refers to-C (O) -NH₂In which NH₂May be optionally substituted with alkyl or aryl groups 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 a group may be unsubstituted or substituted with one or more substituents (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) as set forth for that 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 in the definition of the compounds of the invention_n-n+mOr C_n-C_mIncluding n to n + m carbons, e.g. C_1-6Comprising C₁、C₂、C₃、C₄、C₅And C₆Also included are any ranges of n to n + m, e.g. C_1-6Comprising C_1-2、C_1-3、C_1-4、C_2-6、C_3-6And the like. Similarly, n-to n + m-membered in the definition of the compounds of the present invention means that the number of ring atoms is n to n + m, for example, 3-to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 12-membered rings and the like, and any range of n to n + m-membered rings is also included, for example, 3-to 12-membered rings include 3-to 6-membered rings, 3-to 9-membered rings, 5-to 6-membered rings, 5-to 7-membered rings, 6-to 8-membered rings, 6-to 10-membered rings and the like.

As used in this specification and the claims that follow, the word "comprise", and variations of the word such as "comprises" and "comprising", means "including but not limited to", and is not intended to exclude, for example, other additives, components, integers or steps. When an element is described as comprising a plurality of components, steps or conditions, it is to be understood that the element can also be described as comprising any combination of the plurality of components, steps or conditions, or "consisting of" or "consisting essentially of the plurality or combination of components, steps or conditions.

It is to be understood that the dosages referred to when describing the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations, kits and related uses and methods comprising the same, are based on the weight of the free form, excluding any salt, hydrate or solvate thereof, unless the specification indicates that the dosage is based on the weight of the salt, hydrate or solvate.

Compounds of the invention

The terms "compound of the invention" and the like, as used throughout this application, unless otherwise indicated, encompass compounds of formula I or formula II (including formula Ia, Ia ', Ib', I-1, I-2, II-1), as defined in the various embodiments herein and preferred embodiments thereof, including isomers thereof, including atropisomers, enantiomeric mixtures, particularly racemates, diastereomeric mixtures, geometric isomers, tautomers, solvates, metabolites, isotopic variations, salts (e.g., pharmaceutically acceptable salts), and prodrugs.

Accordingly, the above-mentioned isomers and derivatives of the compounds of the invention are thus included within the scope of the present invention, the respective meanings, preparations and embodiments thereof being as defined above in the "definitions" section or being well known to the skilled person. In some embodiments, metabolites, isotopic variants or prodrugs, and any combinations thereof, are excluded as appropriate. However, substantially pure enantiomers (enantiomerically pure), diastereomers and tautomers of the compounds of formula I and/or pharmaceutically acceptable salts thereof are preferred.

The invention also encompasses N-oxides of the compounds of the invention, provided that these compounds contain a basic nitrogen atom, such as that present in nitrogen-containing heterocycles. Certain compounds of the present invention may exist in polymorphic or amorphous forms and are therefore also within the scope of the present invention.

In one aspect, the invention provides a group of compounds having a structure shown in formula I, isomers thereof or pharmaceutically acceptable salts or solvates thereof, which can inhibit the activity of KRas muteins, especially KRas-G12C

Wherein the content of the first and second substances,

a is selected from C-CN or N;

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

is a single bond or a double bond;

R^aeach time goes outEach independently at the occurrence is selected from-OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6Alkyl, -C_3-8Cycloalkyl, halogen, -NO₂-CN and oxo, where-C is present_1-6Alkyl or-C_3-8Cycloalkyl is optionally further substituted by R¹⁰、-OR¹⁰Halogen or CN;

w is selected from the group consisting of-C (O) -CR¹＝C(R²)₂、-C(O)-C≡CR²、-C(O)-C≡N、-S(O)_1-2-CR¹＝C(R²)₂、-S(O)_1-2-C≡CR²、 -S(O)_1-2-C ≡ N; or W is represented by R in¹Or R²Together with the N to which W is attached in ring B and the ring atoms adjacent to the N form a nitrogen-containing heterocycle fused to ring B;

l is selected from the group consisting of a direct bond, -O-, -S-, -S (O) _1-2-、-NR¹⁰-or-CR⁸R⁹-；

G is selected from-O-, -S (O)_1-2-、-NR¹⁰-or-CR⁸R⁹-；

R⁸and R⁹Each independently selected from H, halogen, CN, NO₂And C optionally substituted by halogen_1-6Alkyl or optionally substituted by halogen or R¹⁰Substituted C_3-8A cycloalkyl group;

R¹⁰each occurrence is independently selected from H or C optionally substituted with halogen_1-6An alkyl group;

R³is selected from- (CH)₂)_0-6-R^3’Wherein R is^3’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: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, wherein C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰Or N (R)¹⁰)₂-substitution;

R⁴is selected from C_6-12Aryl or 5-12 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, - (CR) ¹⁰R¹⁰)_0-1-C(O)-N(R¹⁰)₂、 -(CR¹⁰R¹⁰)_0-1-C(O)-OR¹⁰、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-N(R¹⁰)₂、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-R¹⁰Wherein C is_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰Or N (R)¹⁰)₂Is substituted in which R¹⁰In each occurrence, two R's as defined above, or linked to the same C¹⁰Together with the carbon atom to which they are attached form an optionally substituted R¹⁰Or halogen-substituted C_3-8A cycloalkyl group;

R⁵selected from H, halogen, CN, NO₂C optionally substituted by one or more halogens_1-6Alkyl or optionally substituted by one or more halogens or R¹⁰Substituted C_3-8A cycloalkyl group;

m is 0 or 1;

n is an integer from 0 to 3;

with the following conditions:

when m is 1, each X, Y, Z is independently selected from C or N, and

represents a double bond; and

when a is N and m is 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',

wherein the individual radicals are as defined above for the compounds of the formula I.

In one embodiment of the compound of formula Ia, m is 1. In further embodiments, 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 particular embodiment, the fused bicyclic moiety of formula Ia is such as, but not limited to:

Preference is given to

Most preferably

Wherein the six-membered ring comprising X, Y and Z is optionally substituted with 0, 1, 2 or 3R⁵Substituted, preferably by 0 or 1R⁵Substituted, R⁵Selected from halogens, preferably F or Cl.

In one embodiment of the compound of formula Ia, m is 0. In further embodiments, 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 particular embodiment, the fused bicyclic moiety of formula Ia is such as, but not limited to:

preference is given to

Wherein the five-membered ring is optionally substituted by 0, 1 or 2R⁵Substituted, preferably by 0 or 1R⁵Substituted, R⁵Selected from halogens, 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,

wherein the individual radicals are as defined for the compounds of the formula I.

In an embodiment of a compound of formula Ib, m ═ 1. In further embodiments, 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 particular embodiment, fused bicyclic moiety of formula Ib, for example, but not limited to

Preference is given to

Each optionally substituted by 0, 1 or 2R⁵Substituted, preferably by 0 or 1R⁵Substituted, R⁵Selected from halogens, preferably F or Cl.

In one embodiment of the compounds of formula Ib, m is 0. In further embodiments, 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 such as, but not limited to:

preference is given to

In one embodiment of the compounds of formula I, L is a direct bond. In one embodiment of the compounds of formula I, L is-O-. In one embodiment of compounds of formula I, L is-S-, -SO-, or-S (O)₂-. In one embodiment of the compounds of formula I, L is-NR¹⁰-. In one embodiment of the compounds of formula I, L is-CR⁸R⁹-. Preferably L is selected from the group consisting of a direct bond, -O-, -S-, -NR-¹⁰-or-CR⁸R⁹-, more preferably L is selected from the group consisting of a direct bond, -O-, -S-or-NH-or-CR⁸R⁹-, most preferably L is selected from the group consisting of a direct bond, -O-, -S-or-NH-.

In one embodiment of the compounds of formula I, L is-NR ¹⁰-, and R¹⁰Selected from H or C optionally substituted by halogen_1-6Alkyl, preferably R¹⁰Is H. In this embodiment, R¹⁰Examples of (A) include, but are not limited to, H, methyl, ethyl, 1-propyl, isopropyl, 1-butyl2-methyl-1-propyl group, 2-butyl group, 2-methyl-2-propyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-1-butyl group, 2-methyl-1-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 3-methyl-3-pentyl group, 2, 3-dimethyl-2-butyl group, 3-dimethyl-2-butyl group, and the abovementioned individual alkyl radicals substituted by one or more, for example 1, 2,3 or 4, halogen, preferably fluorine, such as trifluoromethyl, difluoromethyl, fluoromethyl, difluoroethyl (-CH)₂-CHF₂or-CHF-CH₂F) Trifluoropropyl (-CH (CF)₃)(CH₃) Etc.).

In one embodiment of the compounds of formula I, L is-CR⁸R⁹-, wherein R⁸And R⁹Each independently selected from H.

In one embodiment of the compounds of formula I, L is-CR⁸R⁹-, wherein R⁸And R⁹Each 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、-CF₂-, preferably-CHF-or-CF₂-。

In one embodiment of the compounds of formula I, L is-CR⁸R⁹-, wherein R⁸And R⁹Each independently selected from halogen or C optionally substituted by halogen, preferably F_1-6An alkyl group. In this embodiment, examples of L include, but are not limited to, -CHCl-, -CHF-, -CCl₂、-CF₂-、-CH(CH₃)-、-C(CH₃)₂、-CH(CH₂-CH₃)-、-CH(CF₃)、-CH(CHF₂)、-CH(CH₂-CF₃)-、 -C(CH₃)(CH₂-CH₃)-、-C(CF₃)(CH₃)-、-C(CHF)(CF₃) -, preferably-CHF-or-CF₂-。

In one embodiment of the compounds of formula I, L is-CR⁸R⁹-, wherein R⁸And R⁹Each independently selected from H, optionally halogenatedPlain, preferably F-substituted C_1-6Alkyl or optionally substituted by halogen, preferably F or R¹⁰Substituted C_3-8A cycloalkyl group. In this embodiment, examples of L include, but are not limited to, -CH₂-、-CH(CH₃)-、-C(CH₃)₂、-CH(CH₂-CH₃)-、-CH(CF₃)、 -CH(CHF₂)、-CH(CH₂-CF₃)-、-C(CH₃)(CH₂-CH₃)-、-C(CF₃)(CH₃)-、-C(CHF)(CF₃) -, -CH (cyclopropyl) -, wherein the cyclopropyl group may be optionally substituted, such as but not limited to

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

In one embodiment of the compounds of formula I, G is-NR¹⁰-, wherein-NR¹⁰-as above for L is-NR¹⁰As defined in the embodiments of (a) and (b), preferably G is-NH-.

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

In one embodiment of the compounds of formula I, ring B is heterocyclyl containing 3 to 12 ring atoms, especially a saturated 4 to 7 membered monocyclic heterocycle containing two N atoms, or a 7 to 10 membered saturated spiro, fused or bridged ring containing two nitrogen atoms, each optionally substituted with one or more R ^aAnd (4) substitution. Examples of B rings include, but are not limited to

Preferably the B ring is selected from

Most preferably

In this embodiment, B is optionally substituted with 0, 1 or 2R^aSubstituted, R^aPreferably H or C_1-6Specific examples of alkyl groups include, but are not limited to, H, methyl or ethyl, with H being most preferred.

In an embodiment of compounds of formula I, W is selected from the group consisting of-C (O) -CR¹＝C(R²)₂、-C(O)-C≡CR²、-C(O)-C≡N、 -S(O)_1-2-CR¹＝C(R²)₂、-S(O)_1-2-C≡CR²、-S(O)_1-2-C ≡ N, wherein R is¹And R²Each independently selected from H, halogen, CN, NO₂And optionally is-OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Or halogen-substituted C_1-6An alkyl group. Preferably W is selected from the group consisting of-C (O) -CR¹＝C(R²)₂、-C(O)-C≡CR²、-C(O)-C≡N、-S(O)₂-CR¹＝C(R²)₂More preferably-C (O) -CR¹＝C(R²)₂Wherein R is¹And R²Each independently selected from H, halogen, preferably F, and optionally-OR¹⁰、-N(R¹⁰)₂Or halogen, preferably F-substituted C_1-6Alkyl, preferably R¹And R²Each independently selected from H, halogen, preferably F and optionally-N (R)¹⁰)₂Or halogen, preferably F-substituted C_1-6Alkyl radical, wherein R¹⁰Preferably H or C optionally substituted by F_1-6An alkyl group.

In this embodiment, specific examples of W include, but are not limited to, -c (o) -CH ═ CH₂、-C(O)-CH＝CHF、 -C(O)-CF＝CHF、-C(O)-CF＝CH₂、-C(O)-CH＝CH(CH₃)、-C(O)-CH＝CH(CF₃)、 -C(O)-C(CF₃)＝CH(CF₃)、-C(O)-C(CH₃)＝CH(CH₂-CH₃)、-C(O)-C(CH₃)＝C(CH₂-CH₂-CH₃)、 -C(O)-C(CF₃)＝CH(CH₂-CH₃)、-C(O)-CH＝CH(CH₂-CH₂-CH₃)、-C(O)-C(CH₂-CH₃)＝CH₂、 -C(O)-C(CH₂-CF₃)＝CH₂、-C(O)-C(CH₂-CH₂-CH₃)＝CH₂、-C(O)-C(CH₂-CH₃)＝CH(CH₂-CH₃)、 -C(O)-C(CH₂-CH₃)＝CH(CH₂-CF₃)、-C(O)-CH＝CH(CH₂-NH₂)、-C(O)-CH＝CH(CH₂-N(CH₃)₂)、 -C(O)-CH＝CH(CH₂-NH(CH₃))、-C(O)-C(CH₂-NH(CH₃))＝CH(CH₂-CH₃)、 -C(O)-CH＝CH(CH₂-CH₂-N(CH₃)₂)、-C(O)-CH＝CH(CH₂-OH)、-C(O)-CH＝CH(CH₂-OCH₃)、 -C(O)-CH＝CH(CH₂-OCF₃)、-C(O)-CH＝CH(CH₂-SH)、-C(O)-CH＝CH(CH₂-SCH₃)、-C(O)-C≡CF、 -C(O)-C≡C-CH₃、-C(O)-C≡C-CF₃、-C(O)-C≡C-C(CH₂-N(CH₃)₂)、-C(O)-C≡N、-S(O)₂-CH＝CH₂、 -S(O)₂-CF＝CH₂、-S(O)₂-CH＝CH(CH₂-CH₃)、-S(O)₂-CH＝CH(CF₃)、-S(O)₂-C(CH₃)＝CH(CH₂-CF₃) And the like.

In an embodiment of compounds of formula I, W is selected from the group consisting of-C (O) -CR¹＝C(R²)₂、-C(O)-C≡CR² -S(O)_1-2-CR¹＝C(R²)₂or-S (O)_1-2-C≡CR²Wherein R is¹And R²Each independently selected from H, halogen, CN, NO₂And optionally is-OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Or halogen-substituted C_1-6Alkyl, and W is represented by R in¹Or R²Together with the N to which W is attached in the B ring and the ring atoms adjacent to this N form a 5-to 7-membered nitrogen-containing heterocyclic ring condensed with the B ring, e.g.

Preferably a 5-6 membered nitrogen containing heterocycle wherein when W is represented by R¹When a condensed nitrogen-containing heterocyclic ring is formed with ring B, (R)²)₂I.e. as substituents carried on the nitrogen-containing heterocyclic ring, e.g.

When W is present in R²When a condensed nitrogen-containing heterocyclic ring is formed with ring B, R¹And/or R²I.e. as substituents carried on the nitrogen-containing heterocyclic ring, e.g.

It is furthermore understood that the nitrogen-containing heterocycle may also carry R¹And R²Each carrying on its own one OR more of the abovementioned substituents R' selected from-OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Or halogen, or (R)¹Or R²Is C with a branched chain_1-6Alkyl) by-OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Halogen-substituted C_1-6An alkyl group.

In this embodiment, specific and preferred examples of W include, but are not limited to

Wherein R is¹And R²Each independently selected from H, halogen, CN, NO₂And optionally is-OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Or halogen-substituted C_1-6Alkyl, wherein R' is optionally present R¹Or R²Substituents which may be carried on themselves, including H, -OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Halogen or (R)¹Or R²Is C with a branched chain_1-6Alkyl) by-OR¹⁰、-SR¹⁰、-N(R¹⁰)₂Halogen-substituted C_1-6An alkyl group. R carried on the above-mentioned preferred fused ring structure W¹、R²Examples of R 'or R' include, but are not limited to, H, F, Cl, methyl, ethyl, trifluoromethyl, dimethylaminomethyl, dimethylaminoethyl, aminomethyl, aminoethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, and the like, with R being most preferred ¹、R²Or R' are both H.

In one embodiment of the compounds of formula I, most preferably W is-C (O) -CR¹＝C(R²)₂Wherein R is¹And R²Each independently selected from H, F, methyl and dimethylaminomethyl, most preferably R¹And R²Are all H.

In one embodiment of the compounds of formula I, R³Is- (CH)₂)_0-6-R^3’Is preferably- (CH)₂)_0-3-R^3’More preferably- (CH)₂)_0-1-R^3’Wherein R is^3’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: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, wherein C_1-6Alkyl radical, C_3-8Alkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、 -OR¹⁰、-SR¹⁰、N(R¹⁰)₂-substitution.

In this embodiment, R is preferred³Is- (CH)₂)_0-3-R^3’Wherein R is^3’Selected from 3-12 membered heterocyclic group (preferably 3-7 membered heterocyclic group) or 5-12 membered heteroaryl group (preferably 5-10 membered heteroaryl group), specific examples include but are not limited to

Each optionally substituted by one or more substituents R selected from⁶And/or R⁷And (3) substitution: -OH, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-OC_1-6Alkyl, halogen, C_1-6Alkyl or C_3-6Cycloalkyl radicals, in which C is_1-6Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, C optionally substituted by halogen _1-6Alkyl, -NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substitution; r⁶Or R⁷Examples of (b) include, but are not limited to, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-methylpropoxy, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, one or more fluoro-substituted cyclopropyl or cyclobutyl, trifluoromethyl-substituted cyclopropyl or cyclobutyl, aminomethyl, aminoethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl, and the like.

In this embodiment, R is more preferred³Is- (CH)₂)_0-1-R^3’Wherein R is^3’Selected from 3-12 membered heterocyclyl (preferably 3-7 membered heterocyclyl) or 5-12 membered heteroaryl (preferably 5-10 membered heteroaryl), each optionally substituted with one or more substituents selected from: -OC_1-6Alkyl, halogen (preferably F), C_1-6Alkyl or C_3-6Cycloalkyl radicals, in which C is_1-6Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, C optionally substituted by halogen_1-6Alkyl, -NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂And (4) substitution. Specific examples include, but are not limited to

Preference is given to

In this embodiment, R is most preferred ³Is- (CH)₂)_0-1-R^3’Wherein R is^3’Selected from 3-12 membered heterocyclyl (preferably 3-7 membered heterocyclyl) or 5-12 membered heteroaryl (preferably 5-10 membered heteroaryl), each optionally substituted with one or more substituents selected from: -OC_1-6Alkyl, halogen (preferably F), C_1-3Alkyl or C_3-6Cycloalkyl radicals, in which C is_1-3Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, C optionally substituted by halogen_1-6Alkyl, -NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂And (4) substitution. Specific examples include, but are not limited to

Wherein R is⁶And R⁷Each independently selected from H, C_1-3Alkyl or C_3-6Cycloalkyl radicals, in which C is_1-3Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, C optionally substituted by halogen_1-6Alkyl, -NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Specific examples include, but are not limited to, methyl, trifluoromethyl, ethyl, isopropyl, cyclopropyl, trifluoromethylcyclopropyl, aminomethyl, aminoethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl, and the like; further preferred is R³Is selected from

Wherein R is⁶And R⁷Each independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl.

In a preferred example of this embodiment, R³Is composed of

In another preferred example, R³Is composed of

In another preferred example, R³Is composed of

Wherein R is⁶Is C_1-3Alkyl or C_3-6Cycloalkyl, optionally further substituted by-NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Such as, but not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl.

In one embodiment of the compounds of formula I, R⁴Is selected from C_6-12Aryl, preferably phenyl or naphthyl, each of which is optionally substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, - (CR)¹⁰R¹⁰)_0-1-C(O)-N(R¹⁰)₂、-(CR¹⁰R¹⁰)_0-1-C(O)-OR¹⁰、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-N(R¹⁰)₂、 -(CR¹⁰R¹⁰)_0-1-S(O)_1-2-R¹⁰Wherein C is_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclylAnd 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰、N(R¹⁰)₂Is substituted in which R¹⁰In each occurrence two R's as defined above for a compound of formula I, or attached to the same C¹⁰Together with the carbon atom to which they are attached form an optionally substituted R¹⁰Or halogen-substituted C_3-8A cycloalkyl group.

In this embodiment, R⁴Preferably phenyl, optionally substituted with one or more substituents selected from: -OH, -NH₂、 -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, C_1-6Alkyl, 5-6 membered heteroaryl, - (CR)¹⁰R¹⁰)_0-1-C(O)-N(R¹⁰)₂Wherein C is_1-6Alkyl and 5-6 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-N(R¹⁰)₂Substituted, or two R attached to the same C¹⁰Together with the carbon atom to which they are attached form an optionally substituted R¹⁰Or halogen-substituted C_3-6Cycloalkyl, wherein R¹⁰At each occurrence as defined above for compounds of formula I. Preferably R⁴Substituted with one or more substituents selected from: -OH, -NH₂Methylamino, dimethylamino, diethylamino, methylethylamino, fluoro, chloro, CN, methyl, ethyl, propyl, isopropyl, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2, 3-triazole, 1,3, 4-triazole, 1-oxa-2, 3-oxadiazole, 1-oxa-2, 4-oxadiazole, 1-oxa-2, 5-oxadiazole, 1-oxa-3, 4-oxadiazole, 1-thia-2, 3-oxadiazole, 1-thia-2, 4-oxadiazole, 1-thia-2, 5-oxadiazole, 1-thia-3, 4-oxadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, -c (o) -NH.₂、

Wherein C is_1-6Alkyl and 5-6 membered heteroaryl optionally further substituted by fluorine, chlorine, trifluoromethyl, methyl, ethyl, isopropyl or-NH ₂And (4) substitution. Specific examples include, but are not limited to

Wherein the substituent R¹¹、R¹²And R¹³Each independently selected from H, halogen (preferably fluoro or chloro), CN, C optionally substituted by halogen (preferably fluoro or chloro)_1-6Alkyl, OH, -NH₂C optionally substituted by halogen, preferably fluorine or chlorine_1-6Alkoxy or C optionally substituted by halogen, preferably fluorine or chlorine_3-6A cycloalkyl group; preferably, R¹¹Selected from CN, halogen (preferably fluorine or chlorine) or C_1-6Alkyl radical, R¹²Selected from H, NH₂Or halogen (preferably fluorine or chlorine), R¹³Selected from halogen, OH or NH₂. Specific examples are

In this embodiment, R⁴Preferably, it is

Wherein R is¹¹Selected from halogen (preferably fluorine or chlorine) or CN, R¹²Selected from H, halogen (preferably fluorine or chlorine) or-NH₂，R¹³Selected from halogen, OH or NH₂。

In one embodiment of the compounds of formula I, R⁴Selected from 5-12 membered heteroaryl (preferably 5-10 membered heteroaryl), 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-oxadiazole, 1-oxa-2, 4-oxadiazole, 1-oxa-2, 5-oxadiazole, 1-oxa-3, 4-oxadiazole, 1-thia-2, 3-oxadiazole, 1-thia-2, 4-oxadiazole, 1-thia-2, 5-oxadiazole, 1-thia-3, 4-oxadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, pyridine, pyrimidine, pyrazine, imidazole, oxazole, thiazole, and oxadiazole, Indole and 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]A pyrimidine, each optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C) _1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, - (CR)¹⁰R¹⁰)_0-1-C(O)-N(R¹⁰)₂、 -(CR¹⁰R¹⁰)_0-1-C(O)-OR¹⁰、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-N(R¹⁰)₂、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-R¹⁰Wherein C is_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰、 N(R¹⁰)₂Is substituted in which R¹⁰In each occurrence two R's as defined above for a compound of formula I, or attached to the same C¹⁰Together with the carbon atom to which they are attached form an optionally substituted R¹⁰Or halogen-substituted C_3-6A cycloalkyl group; preferably substituted with one or more substituents selected from: -OH, -NH₂、-OC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, oxo or C_1-6An alkyl group.

In this embodiment, R⁴Preferably a 5-12 membered heteroaryl (preferably a 5-10 membered heteroaryl) selected from:

wherein the substituent R¹¹、R¹²And R¹³Each independently selected from halogen (preferably fluorine or chlorine), C optionally substituted by halogen (preferably fluorine or chlorine)_1-6Alkyl, OH, -NH₂C optionally substituted by halogen, preferably fluorine or chlorine_1-6Alkoxy or C optionally substituted by halogen, preferably fluorine or chlorine_3-6Cycloalkyl, preferably each independently selected from halogen (preferably fluoro or chloro) or C optionally substituted by halogen (preferably fluoro or chloro)_1-6An alkyl group. Specific examples of 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 with one or more fluorine or chlorine, and cyclopropyl, cyclobutyl, cyclopentyl substituted with one or more fluorine or chlorine. R ⁴Specific examples of (d) are:

preferably, R⁴Is selected from C₆Aryl or 5-to 10-membered heteroaryl (preferably benzoheteroaryl containing 1 or 2N atoms), optionally substituted by halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -OH, -NH₂-, CN or oxo, wherein C_1-6Alkyl is optionally further substituted by halogen, -OH, -O-C_1-6Alkyl or N (R)¹⁰)₂And (4) substitution. R⁴More preferably

Wherein R is¹¹Selected from halogen (preferably fluorine or chlorine) or CN, R¹²Selected from H, halogen (preferably fluorine or chlorine) or-NH₂，R¹³Selected from halogen, OH or NH₂Specific examples are given above for R⁴Shown; or R⁴More preferably

Wherein the substituent R¹¹Or R¹²Each independently selected from halogen (preferably fluorine or chlorine) or C optionally substituted by halogen (preferably fluorine or chlorine)_1-6Alkyl, specific examples of substituents include, but are not limited to: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, and ethyl, propyl, or butyl substituted with one or more of fluorine or chlorine; specific R⁴Examples include

Most preferred is R⁴Is selected from

In one embodiment of the compounds of formula I, R⁵Is selected from H. In another embodiment of the compounds of formula I, R⁵Is halogen, in particular fluorine, chlorine, bromine, iodine, preferably F or Cl, most preferably Cl. In another embodiment of the compounds of formula I, R ⁵Is nitro or cyano. In another embodiment of the compounds of formula I, R⁵Is C optionally substituted by one or more halogens_1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyl substituted with 1-3 fluorines or chlorines, ethyl substituted with 1-5 fluorines or chlorines, propyl substituted with 1-7 fluorines or chlorines, and the like. In another embodiment of the compounds of formula I, R⁵Is C optionally substituted by one or more halogens or by halogen_1-6Alkyl substituted C_3-8Cycloalkyl, examples include, but are not limited to, cyclopropyl optionally substituted with 1 to 4 fluoro or chloro, cyclopropyl optionally substituted with 1 to 3 fluoro or chloro substituted methyl.

In this embodiment, R⁵Most preferred is H, chloro, fluoro, 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, having the structure of formula I-1, capable of inhibiting KRas mutein activity, in particular KRas-G12C activity,

wherein the content of the first and second substances,

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;

is a single bond or a double bond;

ring B is selected from

R¹And R²Each independently selected from H, halogen and optionally-OR ¹⁰or-N (R)¹⁰)₂Substituted C_1-6An alkyl group;

l is selected from the group consisting of a direct bond, -O-, -S-or-CR⁸R⁹-；

G is selected from-O-or-NR¹⁰-；

R⁸And R⁹Each independently selected from H, halogen and C optionally substituted by halogen_1-6An alkyl group;

R³is- (CH)₂)_0-3-R^3’Wherein R is^3’Selected from the following 3-12 membered heterocyclyl or 5-12 membered heteroaryl:

each optionally substituted by one or more substituents R selected from⁶And/or R⁷And (3) substitution: -OH, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-OC_1-6Alkyl, halogen, C_1-6Alkyl or C_3-6Cycloalkyl radicals, in which C is_1-6Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, C optionally substituted by halogen_1-6Alkyl, -NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substitution;

R⁴is selected from

Wherein the substituent R¹¹、R¹²And R¹³Each independently selected from H, halogen, C optionally substituted by halogen_1-6Alkyl, OH, -NH₂C optionally substituted by halogen_1-6Alkoxy or C optionally substituted by halogen_3-6A cycloalkyl group;

R⁵selected from H or halogen;

m is 0 or 1;

n is an integer from 0 to 3;

with the following conditions:

when m is 1, X is selected from C or N, and

represents a double bond;

when a is N and m is 1, at least one of X and Y is not C.

In one embodiment of the compounds of formula I-1, A is C-CN.

In one embodiment of the compounds of formula I-1, A is N.

In one embodiment, when m ═ 1, X, Y, Z are each independently selected from C or N, and

represents a double bond.

In one embodiment of the compounds of formula I-1, wherein the fused bicyclic moiety comprising X, Y, Z and A is selected from

In one embodiment of the compounds of formula I-1, wherein the fused bicyclic moiety comprising X, Y, Z and A is preferably selected from

Most preferably

Wherein the ring containing X, Y and Z is optionally substituted with 0, 1, 2 or 3R⁵Substituted, preferably by 0 or 1R⁵Substituted, R⁵Selected from halogens, preferably F or Cl.

In one embodiment of the compounds of formula I-1, ring B is

In one embodiment of the compounds of formula I-1, L is-O-.

In one embodiment of the compounds of formula I-1, L is a direct bond.

In one embodiment of the compounds of formula I-1, G is-O-.

In one embodiment of the compounds of formula I-1, G is-NH-.

In one embodiment of the compounds of formula I-1, R³Is selected from

Wherein R is⁶And R⁷Each independently selected from H, C_1-3Alkyl or C_3-6Cycloalkyl, each optionally halogen-, optionally halogen-substituted C_1-6Alkyl, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Substitution; preferably each independently selected from the group consisting of H, methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethylcyclopropyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl.

In one embodiment of the compounds of formula I-1, R³Is selected from

Wherein R is⁶And R⁷Each independently selected from H, methyl, ethyl, isopropyl or cyclopropyl.

In a preferred embodiment of the compounds of formula I-1, R³Is composed of

In another preferred embodiment, R³Is composed of

In another preferred embodiment, R³Is composed of

In one embodiment of the compounds of formula I-1, R³Is selected from

Preference is given to

In one embodiment of the compounds of formula I-1, R⁴Is selected from

Most preferred is R⁴Is selected from

The most preferred compound of the present invention is one embodiment of the compound of formula I-2 below, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof,

wherein the various radicals are as defined hereinbefore for the general, specific or preferred embodiments of the compounds of formula I-1.

In this respect, the invention also provides a group of compounds of formula II, isomers thereof or pharmaceutically acceptable salts or solvates thereof, which are capable of inhibiting the activity of KRas muteins, in particular KRas-G12C,

wherein:

a is C-CN or N;

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

is a single bond or a double bond;

R^aeach occurrence is independently selected from-OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-C_1-6Alkyl, -C_3-8Cycloalkyl, halogen, -NO₂-CN and oxo, where-C is present_1-6Alkyl or-C_3-8Cycloalkyl is optionally further substituted by R¹⁰、-OR¹⁰Halogen or CN;

w is selected from the group consisting of-C (O) -CR ¹＝C(R²)₂、-C(O)-C≡CR²、-C(O)-C≡N、-S(O)_1-2-CR¹＝C(R²)₂、-S(O)_1-2-C≡CR²、 -S(O)_1-2-C ≡ N; or W is represented by R in¹Or R²Together with N to which W is attached in the B ring and the ring atoms adjacent to this N form a ring condensed with the B ringA nitrogen-containing heterocycle;

g is selected from-O-, -S (O)_1-2-、-NR¹⁰-or-CR⁸R⁹-；

e is selected from H, halogen or-L-R³；

L is selected from the group consisting of a direct bond, -O-, -S-, -S (O)_1-2-、-NR¹⁰-or-CR⁸R⁹-；

R³Is selected from-C_0-6alkylene-R^3’Wherein R is^3’Selected from 3-12 membered heterocyclic group, 5-12 membered heteroaryl group, 3-12 membered cycloalkyl group, C_1-6Alkyl or C_6-12Aryl, each optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, wherein C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰Or N (R)¹⁰)₂-substitution;

R⁴is selected from C_6-12Aryl or 5-12 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, - (CR) ¹⁰R¹⁰)_0-1-C(O)-N(R¹⁰)₂、 -(CR¹⁰R¹⁰)_0-1-C(O)-OR¹⁰、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-N(R¹⁰)₂、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-R¹⁰Wherein C is_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰、 N(R¹⁰)₂Is substituted in which R¹⁰In each occurrence, two R's as defined above, or linked to the same C¹⁰Together with the carbon atom to which they are attached form an optionally substituted R¹⁰Or halogen-substituted C_3-8A cycloalkyl group;

m is 0 or 1;

n is an integer from 0 to 3;

with the following conditions:

when m is 1, each X, Y, Z is independently selected from C or N, and

represents a double bond; and

when a is N and m is 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.

In one embodiment of the compounds of formula II, A is C-CN. In further embodiments, 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, of formula II Fused bicyclic moieties such as, but not limited to, the corresponding examples given above for compounds of formula Ia; most preferably

In one embodiment of the compounds of formula II, A is C-CN. In further embodiments, 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 particular 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; preference is given to

In one embodiment of the compounds of formula II, a is N. In further embodiments, 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 particular embodiment, fused bicyclic moieties of formula II such as, but not limited to, the corresponding examples given above for compounds of formula Ib, are preferred

Each optionally substituted by 0, 1 or 2R ⁵Substituted, preferably by 0 or 1R⁵Substituted, R⁵Selected from halogens, preferably F or Cl.

In one embodiment of the compounds of formula II, a is N. In further embodiments, 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 particular embodiment, fused bicyclic moieties of formula II such as, but not limited to, compounds of formula Ib, supraThe corresponding examples given; preference is given to

In a preferred embodiment of the compounds of formula II, the fused bicyclic moiety of formula II is selected from

More preferably

Wherein the ring containing X, Y and Z is optionally substituted with 0 or 1R⁵Substituted, R⁵Selected from halogens, preferably F or Cl.

In any of the embodiments of compounds of formula II above, ring B is heterocyclyl containing 3-12 ring atoms, particularly a saturated 4-7 membered monocyclic heterocycle containing two N atoms, or a 7-10 membered saturated spiro, fused, or bridged ring containing two N atoms, each optionally substituted with one or more R^aAnd (4) substitution. Examples of B rings include, but are not limited to, the corresponding examples given above for B ring of compounds of formula I, most preferably

Optionally substituted by 1-2R^aSubstituted, R^aPreferably C_1-6Alkyl, most preferably CH₃。

In any of the embodiments of the compounds of formula II above, W has each of the specific embodiments, preferred embodiments and examples thereof given above for the compound of formula I for W; most preferably W is-C (O) -CR¹＝C(R²)₂Wherein R is¹And R²Each independently selected from H, F, methyl and dimethylaminomethyl, most preferably R¹And R²Are all H.

In any of the embodiments of the compounds of formula II above, L has each of the specific embodiments, preferred embodiments and examples thereof given above for the compounds of formula I for L; most preferably, L is absent, -O-, -NH-, or-S-.

In any embodiment of the compounds of formula II above, E is-L-R³L is absent; or E is-L-R³L is-O-; or E is-L-R³L is-NH-; or E is-L-R³L is-S-.

In any embodiment of the compounds of formula II above, R³Having the formula I compounds given above for R³And preferred embodiments and examples thereof.

Alternatively, or additionally, in any embodiment of the compounds of formula II above, R³is-C_0-6alkylene-R^3’preferably-C_0-3alkylene-R³', most preferably-R³', wherein R³' is selected from 3-12 membered heterocyclic group, 5-12 membered heteroaryl group or C _6-10Aryl, each optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, wherein C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰Or N (R)¹⁰)₂-substitution; preferably each substituted with one or more substituents selected from: -OC_1-6Alkyl, halogen (preferably F), C_1-6Alkyl or C_3-6Cycloalkyl radicals, in which C is_1-6Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, -NH₂、-OC_1-6Alkyl radical, C_1-6Alkyl, -NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂And (4) substitution. Specific embodiments include, but are not limited to

Wherein R is⁶And R⁷Each independently selected from: -OH, -NH₂、-NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂、-OC_1-6Alkyl, halogen, C_1-6Alkyl or C_3-6Cycloalkyl radicals, in which C is_1-6Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, C optionally substituted by halogen_1-6Alkyl, -OC_1-6Alkyl, -NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substitution; r⁶Or R⁷Examples of (b) include, but are not limited to, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-methylpropoxy, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, one or more fluoro-substituted cyclopropyl or cyclobutyl, trifluoromethyl-substituted cyclopropyl or cyclobutyl, aminomethyl, aminoethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl, and the like.

In this embodiment, specific R³Examples include, but are not limited to

In this embodiment, R is preferred^3’Selected from 3-7 membered heterocyclyl, 5-10 membered heteroaryl or C₆Aryl, each optionally substituted by C_1-6Alkyl, -O-C_1-6Alkyl or C_3-6Cycloalkyl substitution, wherein C_1-6Alkyl or C_3-6Cycloalkyl is optionally further substituted by C_1-6Alkyl, -O-C_1-6Alkyl or-N (R)¹⁰)₂Substituted, in particular R³Is selected from

(example ofSuch as

)、

(e.g. in

Wherein R is⁶Is selected from C_1-6Alkyl or C_3-6Cycloalkyl, optionally further substituted by C_1-6Alkyl or N (R)¹⁰)₂Substituted, R⁷Is selected from C_1-6Alkyl or-O-C_1-6An alkyl group; r⁶Or R⁷Examples of (b) 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, and the like. Specific examples are

In a preferred example of this embodiment, R³Is composed of

In another preferred example, R³Is composed of

In another preferred example, R³Is composed of

Wherein R is⁶Is C_1-6Alkyl or C_3-6Cycloalkyl, optionally further substituted by-NH ₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substituents such as methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl. In another preferred example, R³Is composed of

Wherein R is⁶Is C_1-6Alkyl, optionally further substituted by-NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substitution, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl; most preferred is R⁶is-N (C)_1-6Alkyl radical)₂Substituted C_1-3An alkyl group.

In any embodiment of the compounds of formula II above, R⁴Having the formula I compounds given above for R⁴And preferred embodiments and examples thereof. Preferably, R⁴Is selected from C₆Aryl or 5-to 10-membered heteroaryl (preferably benzoheteroaryl containing 1 or 2N atoms), optionally substituted by halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -OH, -NH₂-, CN or oxo, wherein C_1-6Alkyl is optionally further substituted by halogen, -OH, -O-C_1-6Alkyl or N (R)¹⁰)₂And (4) substitution.

In any embodiment of the compounds of formula II above, R ⁵Having the formula I compounds given above for R⁵And preferred embodiments and examples thereof.

Preferably, the compound of formula II described above is a compound of formula II-1, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof,

wherein:

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;

is a single bond or a double bond;

ring B is

R¹And R²Each independently selected from H, halogen and optionally-OR¹⁰CN or-N (R)¹⁰)₂Substituted C_1-6An alkyl group;

e is-L-R³；

L is selected from the group consisting of a direct bond, -O-, -NH-, or-S-;

g is-O-or-NH-;

R³is-C_0-3alkylene-R^3’Wherein R is^3’Selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl or C_6-10Aryl, each optionally substituted by halogen, C_1-6Alkyl, -O-C_1-6Alkyl or C_3-6Cycloalkyl substitution, wherein C_1-6Alkyl or C_3-6Cycloalkyl optionally further substituted by halogen, C_1-6Alkyl, -O-C_1-6Alkyl or N (R)¹⁰)₂Substitution;

R⁴is selected from C_6-12Aryl or 5-12 membered heteroaryl, optionally substituted by halogen, C_1-6Alkyl, -OH, -NH₂-、-NH(C_1-6Alkyl) -, -N (C)_1-6Alkyl radical)₂-, oxo, CN, -O-C_1-6Alkyl or C_3-6Cycloalkyl substitution, wherein C_1-6Alkyl or C_3-6Cycloalkyl is optionally further substituted by halogen, -OH, -O-C _1-6Alkyl radical, C_1-6Alkyl or N (R)¹⁰)₂Substitution;

R⁵selected from H or halogen;

m is 0 or 1;

n is an integer from 0 to 3;

with the following conditions:

when m is 1, X is selected from C or N, and

represents a double bond; and

when a is N and m is 1, at least one of X and Y is not C.

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

In an embodiment of the compounds of formula II-1 above, wherein the fused bicyclic moiety is selected from

More preferably

In any of the embodiments of the compounds of formula II-1 above, R³Selected from the corresponding R above for each embodiment of the compound of formula II³The definitions given. Preferably, R³is-R^3’Wherein R is^3’Selected from 3-7 membered heterocyclyl, 5-10 membered heteroaryl or C₆Aryl, each optionally substituted by C_1-6Alkyl, -O-C_1-6Alkyl or C_3-6Cycloalkyl substitution, wherein C_1-6Alkyl or C_3-6Cycloalkyl is optionally further substituted by C_1-6Alkyl, -O-C_1-6Alkyl or-N (R)¹⁰)₂Substitution; more preferably, R³Is selected from

Wherein R is⁶Is selected from C_1-6Alkyl or C_3-6Cycloalkyl, optionally further substituted by C_1-6Alkyl or N (R)¹⁰)₂Substituted, R⁷Is selected from C_1-6Alkyl radical, R⁶Or R⁷Examples of (b) 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 the like. Most preferably, in one particular embodiment, R ³Is composed of

In another specific embodiment, R³Is composed of

In another specific embodiment, R³Is composed of

Wherein R is⁶Is C_1-6Alkyl or C_3-6Cycloalkyl, optionally further substituted by-NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substituents such as methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl. In another specific embodiment, R³Is composed of

Wherein R is⁶Is C_1-6Alkyl, optionally further substituted by-NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substituents such as methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl. Further most preferred is R⁶is-N (C)_1-6Alkyl radical)₂Substituted C_1-3An alkyl group.

In any of the embodiments of the compounds of formula II-1 above, R⁴Selected from the corresponding R above for each embodiment of the compound of formula II⁴The definitions given. Preferably, R⁴Is selected from C₆Aryl or 5-to 10-membered heteroaryl (preferably benzoheteroaryl containing 1 or 2N atoms), optionally substituted by halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -OH, -NH₂-, CN or oxo, wherein C_1-6Alkyl is optionally further substituted by halogen, -OH, -O-C _1-6Alkyl or N (R)¹⁰)₂And (4) substitution. More preferably, R⁴Is selected from

Wherein R is¹¹、R¹²And R¹³Each independently selected from halogen (preferably fluorine or chlorine), CN, C optionally substituted by halogen (preferably fluorine or chlorine)_1-6Alkyl, OH, -NH₂Or C optionally substituted by halogen, preferably fluorine or chlorine_1-6An alkoxy group; preferably, wherein R¹¹Selected from halogen (preferably fluorine or chlorine) or CN, R¹²Selected from H or halogen (preferably fluorine or chlorine) or-NH₂，R¹³Selected from halogen, OH or NH₂(ii) a Or R⁴Is selected from

Wherein R is¹¹Or R¹²Each independently selected from halogen (preferably fluorine or chlorine) or optionally halogen (preferablyFluorine or chlorine) substituted C_1-6Specific examples of alkyl groups include, but are not limited to: fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, and ethyl, propyl or butyl substituted with one or more fluorine or chlorine, with R being particularly preferred⁴Examples include

Most preferred is R⁴Is selected from

In any of the embodiments of the compounds of formula II-1 above, n is 0; or n is 1, and R⁵Selected from F or Cl.

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

It is to be understood that the compounds of formula I and formula II of the present invention encompass each of the above independent embodiments, as well as any combination or sub-combination of the above embodiments, and also any combination of any of the above preferred, more preferred, or most preferred definitions.

It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention, unless specifically stated.

Specific embodiments of the compounds of the present invention described above include, but are not limited to, the compounds of synthetic examples a1-145 and example B1-8 below, isomers thereof, or pharmaceutically acceptable salts or solvates thereof:

preferred embodiments of the compounds of the present invention include the compounds of synthetic 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 example B2, isomers thereof or pharmaceutically acceptable salts or solvates thereof, hereinafter.

The compounds of the invention and their various embodiments as defined herein above are Ras mutation inhibitors, particularly KRas mutation inhibitors. As shown in the active examples section below, the compounds of the invention, especially the compounds specifically exemplified herein above and below, show an inhibitory effect on Ras mutations, especially the KRas G12C mutation, in the indicated cellular assay, with an IC50 in the range of 0.1nM to 10. mu.M, e.g., 0.1nM to 5. mu.M, 0.1nM to 1. mu.M, 1nM to 5. mu.M, 1nM to 1. mu.M, 1nM to 0.5. mu.M, preferably in the range of 0.1nM to 0.5. mu.M or 1nM to 0.5. mu.M. The compounds of the invention are therefore useful for treating or preventing 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, most preferably KRas G12C mutations, or diseases or disorders in which Ras mutations, preferably KRas mutations, most preferably KRas G12C mutant activity play a role or are implicated, in particular for treating or preventing tumors or cancers by inhibiting Ras mutations, preferably KRas mutations, most preferably KRas G12C mutations.

In addition to exhibiting Ras mutation, preferably KRas, and most preferably KRas G12C mutation inhibitory activity, the compounds defined herein and various embodiments thereof, particularly the example compounds, have improved structural patterns that retain comparable or enhanced, even significantly enhanced, KRas mutein and related cancer cell proliferation inhibitory activity over prior art existing KRas mutein inhibitors; have different biological activity profiles and can be used for new indications; has improved metabolic stability, thereby leading to better pharmacokinetic properties; and has improved physicochemical properties, thereby having good drug properties, such as easier absorption in vivo, etc.

Based on the above, the invention also provides the technical scheme of the following aspects.

In one aspect, the present invention provides a compound of the invention, isomers thereof, or pharmaceutically acceptable salts or solvates thereof, for use as a medicament.

In another aspect, the present invention provides a compound 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 compositions and their administration

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof as defined above, and a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical compositions of the invention are useful for treating or preventing diseases mediated by Ras mutations, particularly KRas mutations, preferably KRas G12C mutations, such as tumors or cancers.

The above-described Pharmaceutical compositions of the present invention may be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20 th edition.

The administration and administration of the pharmaceutical compositions of the present invention are in accordance with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of agent delivery, the method of administration, the schedule of administration, and other factors well known to practitioners of the physician. The optimal dose level and frequency of administration of the pharmaceutical compositions of the present invention will be determined by clinical trials as required in the pharmaceutical arts. Typically, for example, the daily dose for oral administration ranges from about 0.001mg to about 100mg per kg of body weight of the patient, often from 0.01mg to about 50mg per kg of body weight, e.g., from 0.1 to 10mg per kg of body weight, preferably from about 0.01 to about 35mg per kg of body weight, taken in single or divided doses. For a 70kg human subject, a suitable dosage range is from about 0.07 to about 7000 mg/day, preferably from about 0.7 to about 2500 mg/day. It will be appreciated that it may be necessary in some cases to use dosages outside these limits.

The compositions of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhalation and epidural and intranasal, and if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In some embodiments, oral administration is employed.

The compositions of the present invention may be administered in any convenient form of administration, such as tablets, powders, capsules, lozenges, granules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. The compositions may contain conventional ingredients for pharmaceutical formulations such as diluents (e.g., glucose, lactose or mannitol), carriers, pH adjusting agents, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavoring agents, other known additives and other active agents. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al, Ansel's Pharmaceutical Delivery Forms and Drug Delivery systems, Philadelphia: Lippincott, Williams & Wilkins, 2004.

Methods of treatment and uses

As mentioned above, the compounds of the present invention and the compounds of various embodiments thereof, particularly the compounds specifically prepared and characterized in the examples, exhibit inhibitory effects on Ras mutations, particularly KRas G12C mutations.

Thus, in another aspect, the invention provides a method of inhibiting a KRas mutation, particularly KRas G12C, in a cell, comprising contacting the cell with a compound of the invention, isomers thereof or pharmaceutically acceptable salts or solvates thereof to inhibit the activity of a KRas mutation, particularly KRas G12C, in the cell.

Based on the same properties, the present invention accordingly provides a method of inhibiting abnormal cell growth in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the present invention, its isomer, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the present invention, its isomer, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method for treating and/or preventing a disease mediated by Ras mutations, preferably KRas mutations, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, its isomers, or pharmaceutically acceptable salts or solvates thereof, or a pharmaceutical composition comprising a compound of the present invention, its isomers, or pharmaceutically acceptable salts or solvates thereof.

In another aspect, the invention provides the use of a compound of the invention, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, for inhibiting KRas mutations, in particular KRas G12C, in a cell, or for inhibiting abnormal cell growth in a mammal, or for the treatment and/or prevention of a disease mediated by Ras mutations, preferably KRas mutations.

In another aspect, the invention provides the use of a compound of the invention, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising a compound of the invention, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by a Ras mutation, preferably a KRas mutation.

For the above-described respective methods and use solutions provided by the invention, the abnormal cell growth or disease mediated by Ras mutations, preferably KRas mutations, is particularly referred to as cancer or tumor. Preferably, the abnormal cell growth or cancer or tumor is associated with a KRas mutation, more preferably with a KRas-G12C mutation, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the Central Nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma or pituitary adenoma.

For each of the methods and use embodiments provided herein above, the abnormal cell growth or disease mediated by Ras mutation, preferably KRas mutation, more preferably KRas-G12C is particularly preferred for lung, colon, pancreatic and ovarian cancer.

Thus, in a preferred embodiment of this aspect, the present invention provides the above-described methods and use solutions for treating or preventing cancer or tumor by inhibiting KRas-G12C mutation. In a still further preferred embodiment, the present invention provides the above-described methods and use protocols for treating or preventing lung, colon, pancreatic and ovarian cancer by inhibiting the KRas-G12C mutation.

Pharmaceutical combination

The compounds of the present invention may be administered as the sole active ingredient or in combination with additional drugs or therapies.

Thus, in another aspect, the present invention provides a pharmaceutical combination comprising or consisting of a compound of the present invention, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof and a further active agent. The pharmaceutical combination is useful for inhibiting abnormal cell growth in a mammal, or for treating and/or preventing diseases mediated by Ras mutations, preferably KRas mutations.

The additional active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g., third) compound that is compatible with, i.e., does not adversely affect, or has complementary activity to, the compounds of the invention, e.g., the active agents may be compounds known to modulate other pathways of biological activity, or may be compounds that modulate different components of the pathway of biological activity to which the compounds of the invention relate, or even compounds that overlap with the biological target of the compounds of the invention.

In a particular embodiment, other active agents that can be used in combination with the compounds of the present invention include, but are not limited to, chemotherapeutic agents, therapeutic antibodies, and radiation therapies, such as alkylating agents, antimetabolites, cell cycle inhibitors, mitotic inhibitors, topoisomerase inhibitors, anti-hormonal agents, angiogenesis inhibitors, cytotoxic agents, and compounds that disrupt or inhibit the Ras-Raf-ERK or PI3K-AKT-TOR signaling pathway. Examples of such other active agents for use 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 may be administered simultaneously, separately or sequentially with the compounds of the present invention by the same or different routes of administration. The further active agents may be co-administered with the compounds of the invention in a single pharmaceutical composition or separately administered in separate discrete units from the compounds of the invention, e.g. a combination product, preferably in kit form, which when administered separately may be simultaneous or sequential, which sequential administration may be close in time or remote in time. They may be prepared and/or formulated by the same or different manufacturers. Furthermore, the compound of the invention and the other active agent may be administered (i) prior to delivery of the combination product to a physician (e.g., in the case of a kit comprising a compound of the invention and an additional pharmaceutical agent); (ii) by the physician himself (or under the direction of the physician) immediately before administration; (iii) the combination therapy is added by the patient himself, for example together during the sequential administration of the compounds of the invention and the other active agents.

The compounds of the present invention may also be combined with anti-tumor therapies including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.

Thus, in a further aspect, the invention also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, and means for separately containing the compositions, such as a container, a divided bottle or a discrete foil package, e.g. a blister package for packaging tablets, capsules and the like. The kit of the invention is particularly suitable for administration of different dosage forms, such as oral dosage forms and parenteral dosage forms, or for administration of different compositions at different dosage intervals.

For the above-described technical solutions of the pharmaceutical compositions, pharmaceutical combinations or kits of the invention, wherein abnormal cell growth or diseases mediated by Ras mutations, preferably KRas mutations, are involved are as defined above for the methods and uses of the invention.

With respect to the above-described compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations and kits of the present invention, preferably the compounds of the present invention, isomers thereof or pharmaceutically acceptable salts or solvates thereof, as described herein above, more preferably the compounds as defined in the embodiment of formula II-1 and the specific compounds listed herein above; most preferably the "most preferred compounds of the invention", isomers thereof or pharmaceutically acceptable salts or solvates thereof, listed above.

When a dose of a drug or a pharmaceutically acceptable salt thereof is described herein, it is understood that the dose is based on the weight of the free base, excluding any hydrates or solvates thereof, unless the specification states that the dose is based on the weight of the salt, hydrate or solvate.

Process for the preparation of the compounds of the invention

In another aspect, the invention also provides a process for the preparation of a compound as defined herein.

The compounds of the present invention, isomers thereof, or pharmaceutically acceptable salts or solvates thereof can be prepared by a variety of methods, including the methods given below, the methods given in the examples, or methods similar thereto. The following illustrates a general synthetic scheme for synthesizing the compounds of the present invention.

For each reaction step of each general synthetic scheme, suitable reaction conditions are known to those skilled in the art or can be routinely determined. The process steps for the synthesis of the compounds of the invention may be carried out under reaction conditions known per se, including those specifically mentioned, in the absence or generally in the presence of a solvent or diluent, including, for example, solvents or diluents which are inert with respect to the reagents used and which dissolve the reagents used, in the absence or presence of a catalyst, condensing agent or neutralizing agent (for example, ion exchangers, such as cation exchangers, for example H) ⁺Forms), at reduced, normal or elevated temperature (e.g. from about-100 ℃ to about 190 ℃, including for example from about-78 ℃ to about 150 ℃, such as from about 0 ℃ to about 125 ℃, room temperature, -20 to 40 ℃ or reflux temperature), depending on the nature of the reaction and/or reactants, at atmospheric pressure or in a closed vessel, as appropriateUnder pressure and/or under an inert atmosphere, for example an argon or nitrogen atmosphere.

Depending on the reactivity of the compounds used, the above reaction will generally be carried out at a temperature between room temperature and the boiling temperature of the solvent used.

The starting materials and reagents used in preparing these compounds are generally commercially available or can be prepared by the methods described below, by methods analogous to those set forth below, or by methods known in the art.

Unless otherwise indicated in the description of the process, solvents suitable for use in any particular reaction include those of: those solvents specifically mentioned, or for example water; esters, such as lower alkyl lower alkanoates, e.g., ethyl acetate; ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example 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, for example pyridine or triethylamine; carboxylic anhydrides, such as lower alkanoic acid anhydrides, e.g., acetic anhydride; cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane; or mixtures of these solvents, for example aqueous solutions. Such solvent mixtures can also be used for work-up, for example by chromatography or partitioning.

If desired, the starting materials and intermediates in the synthetic reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. If the intermediates and the final product are obtained in solid form, purification can also be carried out by recrystallization or aging. The materials may be characterized using conventional methods including physical constants and spectroscopic 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.

One skilled in the art will recognize whether a stereocenter is present in the compounds of the present invention. The mixture of isomers formed can be separated into the individual isomers, e.g. diastereoisomers or enantiomers, or into any desired mixture of isomers, e.g. racemates or mixtures of diastereomers, at all stages of the reaction, see e.g. E.L.Eliel, S.H. Wilen and L.N.Mander "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994).

In certain specific cases, it may be necessary to protect certain reactive groups with appropriate protecting groups to avoid side reactions with other reactive groups that may be present in the compounds of the invention and that may compete or interfere with the reaction. By way of example only, if one or more of the radicals in the compounds of the invention is or includes the group C (O) OH, NH ₂Or OH and the groups have similar or even stronger reactivity than the desired reaction sites, it may be advantageous to protect these groups before the desired reaction takes place. 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 for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T.Greene and P.Wuts, Protective Groups in Organic Synthesis (3 rd edition), John Wiley&Sons, NY (1999).

The invention also relates to a preparation method which comprises the following steps: wherein a compound obtainable in any step of the preparation processes and schemes described below in intermediate form is used as starting material and the remaining process steps are carried out, or wherein the starting material is formed in situ under the reaction conditions or is used in the form of a derivative, e.g. in protected form or in salt form, or a compound obtainable according to the process of the invention is generated under the process conditions and is further processed in situ.

The compounds of the invention may be prepared according to the following scheme, wherein variables are as defined above if not otherwise indicated.

Synthesis scheme I:

wherein R is³And R⁴As defined above for each embodiment of formula I, II or of compounds of formula I-1, II-1; y corresponds to B as defined above for the various embodiments of formula I, II or of the compounds of formula I-1, II-1; x corresponds to L as defined above for each embodiment of formula I, II or of compounds of formula I-1, II-1; PG is a protecting group.

In step A, R⁴Introduction of groups can be achieved by aromatic nucleophilic substitution reactions, the reaction conditions required for such reactions being well known to those skilled in the art. The resulting nitro compound is then reduced according to step B to give amino compound 3. The latter is subjected to an amine acid condensation in step C to give compound 4. Compound 4 cyclizes under the appropriate basic conditions to produce compound 5. Compound 5 is subjected to a chlorination reaction to give compound 6. The compound 6 reacts with a fragment Y with different protecting groups by substitution to give a compound 7, which is then introduced by nucleophilic substitution or catalytic coupling reactions in which X is selected from-O-, -S-, -S (O)_1-2-、 -NR¹⁰-or-CR⁸R⁹R of (A-C)³-X group to give compound 8. Compound 8 is deprotected (e.g., Boc, etc.) to provide compound 9. Acylation of compound 9 with an acid chloride or carboxylic acid gives compounds of general formula I, which correspond to a subset of the compounds of the invention wherein a is C-CN.

Typical reaction conditions and/or reagents used for nucleophilic substitution, nitration reduction, condensation reaction, cyclization, catalytic coupling, and acylation reactions involved in this synthesis scheme 1 are well known in the art, are within the routine experience of those skilled in the art, or can be determined by those skilled in the art with appropriate changes based on typical conditions in the art for such reactions, based on the substitution pattern of the starting materials and target products used.

Synthesis scheme II:

the compounds of formula II can be synthesized according to the following general procedure.

Compound 3 is chlorinated by step J to give compound 10. The subsequent synthesis from compound 10 to the molecule of formula II is identical to that in synthesis scheme I, which corresponds to a subset of the compounds of the invention wherein a is C-CN.

Synthesis scheme III:

the compounds of formula III can be synthesized according to the following general procedure.

Wherein R is³、R⁴And R⁵As defined above for each embodiment of formula I, II or of compounds of formula I-1, II-1; y corresponds to B as defined above for the various embodiments of formula I, II or of the compounds of formula I-1, II-1; PG is a protecting group.

Compounds 7 or 14 can be obtained by scheme I or scheme II. In step K, compound 7 or 14 is reacted with R wherein X is boronic acid or pinacolboronic ester³Coupling of the-X group (e.g., palladium-catalyzed carbon-carbon bond coupling) affords compound 17. Compound 17 was then deprotected and acylated according to the procedure of synthesis scheme 1, step I, to give compounds of general formula III, which correspond to a subset of the compounds of the invention wherein a is C-CN.

Synthetic examples

The present invention will be further described with reference to the following examples. It should be noted that the following examples are illustrative and should not be construed as limiting the scope of the present invention.

In describing the embodiments and the specific examples that follow, the following abbreviations are used herein:

AcOH (acetic acid); ag₂O (silver oxide); aq (aqueous solution); BINAP (1, 1' -bi-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(deuterated chloroform); mCPBA (m-chloroperoxybenzoic acid); CS₂(carbon disulfide); cs₂CO₃(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 (dimethyl sulfoxide); DMSO-d₆(hexa-deuterated dimethyl sulfoxide); DPPA (diphenylphosphoryl azide); EA (ethyl acetate); EDTA-K2 (dipotassium ethylenediaminetetraacetate); EtOH (ethanol); FCC (flash column chromatography); FeCl₃(ferric chloride); g (grams); h (hours); HATU (2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate); HCl (hydrogen chloride); h₂O (water); h₂SO₄(sulfuric acid); IV (intravenous administration); k₂CO₃(potassium carbonate); KI (potassium iodide); KOH (potassium hydroxide); LCMS (liquid mass on line); LC-MS/MS (liquid spectrum-mass spectrum online); LDA (lithium diisopropylamide); LiAlH₄(lithium aluminum hydride); LiCl (lithium chloride); LiOH (lithium hydroxide); MeCN (acetonitrile); MeI (methyl iodide); MeOH (methanol); methanol-d₄(tetradeuterated methanol); mg (milligrams); MHz (megahertz); min (minutes); mL (milliliters); mmol (millimole); MTBE (methyl tert-butyl ether); m/z (mass to charge ratio); n is a radical of ₂(nitrogen); NaCl (sodium chloride); NaH (sodium hydride); NaHCO 2₃(sodium bicarbonate); NaNO₂(sodium nitrite); NaOH (sodium hydroxide); na (Na)₂SO₃(sodium sulfite); na (Na)₂SO₄(sodium sulfate); na (Na)₂S₂O₃(sodium thiosulfate); na (Na)₂S₂O₄(sodium dithionate); NBS (bromosuccinimide); NCCH₂CO₂H (2-cyanoacetic acid);NCS (chlorosuccinimide); NH (NH)₃(ammonia); NH (NH)₄Cl (ammonium chloride); NH (NH)₂NH₂(hydrazine); NMI (N-methylimidazole); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance); Pd/C (palladium on carbon); pd₂(dba)₃(tris (dibenzylideneacetone) dipalladium); pd (OAc)₂(palladium acetate); PE (petroleum ether); PEG (polyethylene glycol); PCl₅(phosphorus pentachloride); PO (oral administration); POCl₃(phosphorus oxychloride); PPTS (pyridine p-toluenesulfonate); i-Pr₂NH (diisopropylamine); r.t. (room temperature); SiO 2₂(silica gel); SnCl₂(stannous chloride); TCFH (N, N' -tetramethylformamidine hexafluorophosphate); TEA/Et₃N (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TLC (thin layer chromatography); TsOH (p-toluenesulfonic acid); uL (microliter); uM (micromolar concentration); xanth-Phos (4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene)); zn (CN)₂(zinc cyanide); BBr₃(boron tribromide); BCl₃(boron trichloride); CDI (N, N' -carbonyldiimidazole); CuIsine (cuprous iodide); pd (dppf) Cl ₂(1,1' -bis-diphenylphosphinoferrocene palladium dichloride); pd (PPh)₃)₄Tetrakis (triphenylphosphine) palladium.

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

Experimental procedures without specific conditions noted in the following examples are generally carried out according to conventional conditions for such reactions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight. Unless otherwise specified, the ratio of liquids is by volume.

The experimental materials and reagents used in the following examples are commercially available, prepared according to methods of the prior art or prepared according to methods similar to those disclosed herein, unless otherwise specified.

In the following examples of the present invention,¹the H-NMR spectrum was obtained with Bruker AVANCE^III(400MHz) chemical shifts were recorded relative to the deuterated solvent peak (CDCl)₃:δ＝7.26ppm；CD₃OD:δ＝3.31ppm；DMSO-d₆δ 2.50ppm) is represented by δ (ppm); mass spectra were recorded using an agilent 1200 liquid chromatography + agilent G6100 mass spectrometer LCMS lc.

Synthesis of intermediate a

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

Step A4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

TsOH (4.08g, 23.7mmol) was added to a mixture of 4-bromo-5-methyl-1H-indazole (50.0g, 236.9mmol) and DHP (25.9g, 308.1mmol) in DCM (500 mL). The mixture was stirred at 20 ℃ for 12h to give a dark brown solution. The reaction was monitored by LCMS and the desired product was about 65% and starting material was about 35%. Another batch of DHP (7.97g, 94.8mmol) was added. The mixture was stirred at 20 ℃ for 2 h. LCMS monitor reaction completion. The reaction mixture was concentrated under reduced pressure. FCC purification (SiO)₂PE/EA 1/0-4/1) to give 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (54.0g, 77% yield) as a white solid.

Step B5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol

KOH (41.1g, 731.8mmol) was dissolved in H₂O (1100mL) and the resulting solution was added to a solution containing 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (54.0g,182.9mmol), Pd₂(dba)₃(3.35g, 3.66mmol) and t-BuXphos (4.66g, 11.0mmol) in dioxane (1100 mL). In N₂The mixture was stirred at 90 ℃ for 2h under protection to give a dark brown mixture. The reaction was monitored by LCMS for completion and the reaction mixture was adjusted to pH 2-3 with 1N aqueous HCl. The resulting mixture was extracted with EA (3X 1000 mL). The organic phase was washed with saturated aqueous NaCl solution and anhydrous Na ₂SO₄Drying, filtering, and concentrating under reduced pressure. FCC purification (SiO)₂PE/EA 10/1-1/1) yielded 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol as a yellow solid (28.0g, yield 68%).¹H NMR(400MHz,DMSO-d₆)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 A1-tert-butyl-2-methyl- (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylate

A solution of DAST (2.96g, 18.4mmol) in DCM (50mL) was added dropwise to a solution of 1-tert-butyl-2-methyl- (S) -4-oxopyrrolidine-1, 2-dicarboxylate (3.0g, 12.33mmol) in DCM (150mL) at 0 deg.C. Stirring overnight at room temperature gave a yellow solution. The completion of the reaction was monitored by TLC and the reaction mixture was slowly poured into saturated NaHCO at 0 deg.C₃Aqueous (100mL) and then extracted with DCM (2X 100 mL). The organic phase obtained is treated with Na₂SO₄Dried, filtered and concentrated under reduced pressure. Purification by FCC (SiO)₂PE/EA 1/0-0/1) gave 1-tert-butyl-2-methyl- (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylate as a colorless liquid (1.8g, yield 55.0%).

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

At 0 deg.C, LiAlH₄(543mg, 14.7mmol) was added portionwise to a solution of 1-tert-butyl-2-methyl- (S) -4, 4-difluoropyrrolidine-1, 2-dicarboxylate (1.3g, 4.90mmol) in THF (40 mL). The resulting mixture was stirred at 0 ℃ for 2 h. TLC monitored completion of reaction at 0 deg.C H is added into the lower reaction mixture in turn₂O(0.55mL)、15％NaOH(aq，0.55mL)、 H₂The reaction was quenched with O (1.65 mL). The resulting mixture was stirred at room temperature for 0.5h, then filtered and the filtrate was concentrated under reduced pressure. Purification by FCC (SiO)₂PE/EA 1/0-0/1) to give (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol (340mg, yield 45.9%) as a colorless liquid.¹H NMR(400MHz,CDCl₃)δ3.80–3.71(m,1H),3.49–3.36(m,2H),2.80–2.65(m, 2H),2.52–2.23(m,6H).¹⁹F NMR(376MHz,CDCl₃)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 of intermediate b, 1-tert-butyl-2-methyl- (2S,4R) -4-hydroxypyrrolidine-1, 2-dicarboxylate was used instead of 1-tert-butyl-2-methyl- (S) -4-oxopyrrolidine-1, 2-dicarboxylate in step A to give intermediate c (2S,4S) -4-fluoro-1-methylpyrrolidin-2-yl) methanol.¹H NMR(400MHz,CDCl₃)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).¹⁹F NMR(376MHz, CDCl₃)δ-168.61.

Synthesis of intermediate d

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

Step A1-tert-butyl-2-methyl- (2S,4R) -4-methoxypyrrolidine-1, 2-dicarboxylic acid

To 1-tert-butyl-2-methyl- (2)S,4R) -4-hydroxypyrrolidine-1, 2-dicarboxylic acid (3.0g, 12.23mmol) and Ag₂To a solution of O (8.5g, 36.69mmol) in MeCN (50mL) was added MeI (18.06g, 127.2 mmol). The mixture was stirred at 25 ℃ for 3 days to give a dark brown solution. TLC monitored the reaction was complete, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Purification by FCC (SiO) ₂PE/EA 1/0 to 0/1) to give 1- (tert-butyl) 2-methyl (2S,4R) -4-methoxypyrrolidine-1, 2-dicarboxylic acid as a colorless oil (1.97g, yield 62.1%).

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

(2S,4R) -4-methoxy-1-methylpyrrolidin-2-yl) methanol using step B of the intermediate B synthetic procedure¹H NMR(400MHz,CDCl₃)δ3.92–3.82(m,1H),3.68(dd,J＝11.1,3.3Hz,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 A3-bromo-5-fluoro-2-methylaniline

To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (10.0g, 42.7mmol) in MeOH (100mL) at 20 deg.C was added SnCl in portions₂-2H₂O (33.8g, 149.6 mmol). The mixture was then stirred at 70 ℃ for 8h to give a yellow suspension. LCMS showed reaction completion. The reaction mixture was concentrated and the residue was separated between 10% aqueous NaOH (200mL) and EA (200 mL). The mixture was stirred at room temperature for 10min, the layers were separated and the aqueous phase was extracted with EA (2 × 200 ml). The organic phases were combined and anhydrous Na₂SO₄Drying, filtering, and vacuum concentrating to obtain yellow liquid3-bromo-5-fluoro-2-methylaniline (9.00g, crude) 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 (8.00g, 39.2mmol) in DMF (80mL) was added NCS (6.28g, 47.1 mmol). The resulting mixture was stirred at 20 ℃ for 60 h. LCMS monitors the reaction for completion and H is added to the reaction mixture ₂O (150 mL). The mixture was extracted with EA (3 × 100 mL). Organic phase in anhydrous Na₂SO₄Drying, filtering and vacuum concentrating. FCC purification (SiO)₂EA/PE ═ 0 to 20%), yielding 3-bromo-4-chloro-5-fluoro-2-methylaniline as a dark brown solid (3.70g, 39.6% yield over two steps).¹H NMR:(400MHz,DMSO-d₆)δ6.62(d,J＝11.6Hz,1H),5.66(br s,2H),2.18(d, J＝0.6Hz,3H).

Step C4-bromo-5-chloro-6-fluoro-1H-indazole

To a solution of 3-bromo-4-chloro-5-fluoro-2-methylaniline (2.00g, 8.39mmol) in AcOH (20mL) was added NaNO₂(810.1mg, 11.7 mmol). The mixture was stirred at 20 ℃ for 12h to give a dark brown solution. LCMS monitored completion of reaction and reaction mixture was concentrated in vacuo. Residue is in H₂O (50mL) and EA (50mL) were separated and the aqueous phase was extracted with EA (2X 50 mL). Anhydrous Na for organic phase₂SO₄Drying, filtering and vacuum concentrating. Purification of the residue by FCC (SiO)₂EA/PE 0-10%) gave 4-bromo-5-chloro-6-fluoro-1H-indazole (900.0mg, yield 43.0%) as a yellow solid.¹H NMR:(400 MHz,DMSO-d₆)δ13.82-13.56(m,1H),8.18-7.97(m,1H),7.79-7.60(m,1H).

Step D4-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 (500.0mg, 2.00mmol) and DHP (219.2mg, 2.61mmol) in DCM (5mL) was added TsOH (34.5mg, 200.4 umol). The mixture was stirred at 20 ℃ for 12h to give a light brown solution. TLC monitored the reaction was complete and the reaction mixture was concentrated under reduced pressure. The residue obtained is purified by FCC (SiO) ₂EA/PE ═ 0 to 10%) to give 4-bromo-5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole as a red solid (337.0mg, yield 50.4%).¹H NMR:(400 MHz,DMSO-d₆)δ8.15(s,1H),7.98(dd,J＝0.8,9.4Hz,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 E5-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), Pd₂(dba)₃To a solution of (603.9mg, 659.5umol) and t-BuXphos (840.2mg, 1.98mmol) in dioxane (200mL) was added a solution of KOH (7.40g, 131.9mmol) in water (200 mL). In N₂The mixture was stirred at 90 ℃ for 2h under protection to give a brown mixture. The reaction was monitored by LCMS for completion and adjusted to pH 2-3 with 1N aqueous HCl. The resulting mixture was extracted with EA (3 × 200 ml). The obtained organic phase was treated with anhydrous Na₂SO₄Drying, filtering, and concentrating under reduced pressure. Purification of the residue by FCC (SiO)₂EA/PE ═ 0 to 30%) yielded 5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol as a yellow solid (5.30g, yield 55.9%).¹H NMR:(400MHz,DMSO-d₆)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 A4-chloro-2, 6-difluorobenzaldehyde

To a solution of 1-chloro-3, 5-difluorobenzene (10.0g, 67.3mmol) in THF (100mL) at-70 deg.C was added n-BuLi (2.5M, 32.3mL) dropwise. Stirring at-70 deg.C for 30m After in, DMF (9.84g, 134.6mmol) was added dropwise. The resulting mixture was stirred at-70 ℃ for a further 1.5 h. The reaction mixture was poured into saturated NH₄Aqueous Cl (300mL) and the mixture adjusted to pH 3 with 1N aqueous HCl. The mixture was extracted with EA (100mL), and the resulting organic phase was washed with saturated aqueous NaCl solution (50mL) and anhydrous Na₂SO₄Drying, filtration and concentration under reduced pressure gave 4-chloro-2, 6-difluorobenzaldehyde (11.0g, crude) as a yellow solid which was used directly in the next step.¹H NMR:(400MHz,CDCl₃)δ10.40-10.14(m,1H),7.16-6.92(m,2H).

Step B6-chloro-4-fluoro-1H-indazole

Reacting NH₂NH₂-H₂O (9.55g, 186.9mmol) was added to dioxane (120mL) of 4-chloro-2, 6-difluorobenzaldehyde (11.0g, 62.3mmol) and the mixture was heated to 100 ℃ and stirred for 16 h. The reaction mixture is poured into H₂In O (300mL), a yellow precipitate formed. Filtering the mixture with H₂The filter cake was washed with O (100mL) and dried in vacuo. The solid was dissolved in MTBE (300mL) and the mixture was filtered to remove insoluble material. The filtrate was concentrated under reduced pressure to give 6-chloro-4-fluoro-1H-indazole (8.50g, yield 79.9%) as a yellow solid, which was used directly in the next step.¹H NMR(400MHz,DMSO-d₆)δ13.56(br s, 1H),8.24(s,1H),7.52(s,1H),7.08(dd,J＝1.4,9.9Hz,1H).

Step C6-chloro-4-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

PPTS (1.53g, 6.10mmol) and DHP (12.6g, 150.1mmol) were added sequentially to a solution of 6-chloro-4-fluoro-1H-indazole (8.00g, 46.9mmol) in THF (150mL) at 15 deg.C, and the mixture was heated to 60 deg.C and stirred for 16H. LCMS monitored completion of reaction and mixture was concentrated under reduced pressure. The residue was in EA (100mL) and H ₂O (30 mL). The organic phase was washed with saturated aqueous NaCl solution (30mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. Purification of the residue by FCC (SiO)₂EA/PE ═ 0 to 6.3%) to give 6-chloro-4-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5.50g, yield 70.4%) as a white solid.¹H NMR:(400MHz,CDCl₃)δ8.14-7.98(m,1H),7.51-7.37(m,1H),6.87(dd,J＝1.4,9.4Hz, 1H),5.68(dd,J＝2.8,9.3Hz,1H),4.10-3.98(m,1H),3.77(ddd,J＝3.0,10.2,11.7Hz,1H),2.62- 2.41(m,1H),2.23-2.02(m,2H),1.83-1.67(m,3H).

Step D5, 6-dichloro-4-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

n-BuLi (2.5M, 25.1mL) was added dropwise to i-Pr at-40 to-30 deg.C₂NH (6.36g, 62.8mmol) in THF (80 mL). Stirring the mixture for 0.5h at the temperature of between 40 ℃ below zero and 30 ℃ below zero to obtain LDA solution. The resulting LDA solution was cooled to-70 to-65 ℃ and a solution of 6-chloro-4-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (8.00g, 31.4mmol) in THF (40mL) was added dropwise for 1H. After the dropwise addition is completed, the reaction system is stirred for 1h at-40 to-30 ℃. Then cooled to-70-65 ℃ and a solution of 1,1,1,2,2, 2-hexachloroethane (11.9g, 50.3mmol) in THF (20mL) was added dropwise over 1 h. After the addition was complete, the resulting mixture was stirred at-70 to-65 ℃ for 2 h. With saturated NH₄The reaction was quenched with aqueous Cl (100mL) and the resulting mixture was extracted with EA (300 mL). The resulting organic phase was washed with saturated aqueous NaCl solution (100mL) and anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. Purification of the residue by FCC (SiO)₂EA/PE ═ 0 to 5%) to give 5, 6-dichloro-4-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (4.00g, yield 44.0%).¹H NMR:(400MHz,CDCl₃)δ8.08(d,J＝0.6Hz, 1H),7.62(s,1H),5.68(dd,J＝2.7,8.9Hz,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 E5, 6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol

5, 6-dichloro-4-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (15.0g, 51.8mmol), KOH (11.6g, 207.5mmol) and H were reacted at 20 deg.C₂O (3.74g, 207.5mmol) was added to DMSO (50.0mL) and the resulting mixture was stirred at 80 ℃ for 5 h. The completion of the reaction was monitored by TLC and the reaction mixture was adjusted to pH 5-6 with 1N aqueous HCl. Subjecting the mixture to hydrogenation with H₂O (50mL) was diluted and extracted with EA (2 × 150 mL). The organic phase was washed with saturated aqueous NaCl solution (100mL) and anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by FCC (SiO)₂，EA/PE＝0-5%) to give 5, 6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol as an off-white solid (11.2g, yield 75.2%)¹H NMR:(400MHz, CDCl₃)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 A1-bromo-2-chloro-5-fluoro-3-toluene

2-bromo-4-fluoro-6-methylaniline (10.0g, 49.0mmol) was added to concentrated HCl (60mL) and H₂O (60 mL). The resulting mixture was stirred at 60 ℃ for 1h and then cooled to 0 ℃. Addition of NaNO ₂(4.06g, 58.8mmol) of H₂O (20mL) solution, and the mixture was stirred at 0 ℃ for 15 min. The mixture was then added to a solution of CuCl (7.28g, 73.5mmol) in concentrated HCl (100 mL). The resulting mixture was stirred at 70 ℃ for 30min to give a brown mixture. LCMS showed reaction completion. The reaction mixture was cooled to room temperature and extracted with DCM (3 × 200 mL). Anhydrous Na for organic phase₂SO₄Drying, filtration and concentration under reduced pressure gave 1-bromo-2-chloro-5-fluoro-3-toluene as a brownish black oil (crude 9.53g, 87.0% yield) which was used directly in the next step.¹H NMR:(400MHz,CDCl₃)δ7.22(dd,J＝3.0,7.8Hz,1H),6.93(dd,J＝2.4,8.6Hz,1H),2.48- 2.37(m,3H).

Step B2-bromo-3-chloro-6-fluoro-4-methylbenzaldehyde

LDA (2.0M, 20.1mL) was added to a solution of 1-bromo-2-chloro-5-fluoro-3-toluene (9.00g, 40.3mmol) in THF (90mL) at-65 ℃. The mixture was stirred at-65 ℃ for 40min and then added dropwiseDMF (4.27g, 58.5 mmol). The mixture was stirred at-65 ℃ for 1h to give a dark brown solution. TLC monitoring of the reaction completion, the reaction mixture was poured into H₂O (100mL) and extracted with EA (3 × 100 mL). The obtained organic phase was treated with anhydrous Na₂SO₄Drying, filtering and concentrating. Purification of the residue by FCC (SiO)₂EA/PE ═ 0 to 5%) to give 2-bromo-3-chloro-6-fluoro-4-methylbenzaldehyde as a pale yellow solid (8.30g, yield 81.9%). ¹H NMR:(400MHz,CDCl₃)δ10.34-10.24(m,1H),7.08(d,J＝10.5Hz,1H),2.51(s,3H).

Step C4-bromo-5-chloro-6-methyl-1H-indazole

2-bromo-3-chloro-6-fluoro-4-methylbenzaldehyde (8.00g, 31.8mmol) and NH₂NH₂-H₂A solution of O (19.5g, 381.7mmol) in DMSO (160mL) was stirred at 130 ℃ for 3h to give a yellow solution. LCMS monitors the reaction for completion and H is added to the reaction mixture₂O (200mL) and the mixture was extracted with DCM (2 × 200 mL). The resulting organic phase was washed with saturated aqueous NaCl (3X200mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO)₂THF/PE ═ 0 to 20%) to give 4-bromo-5-chloro-6-methyl-1H-indazole (5.50g, yield 70.4%) as an off-white solid.¹H NMR:(400MHz,CDCl₃)δ 10.84-9.68(m,1H),8.02(d,J＝0.9Hz,1H),7.33(d,J＝0.9Hz,1H),2.56(d,J＝0.9Hz,3H).

Step D4-bromo-5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a solution of 4-bromo-5-chloro-6-methyl-1H-indazole (5.00g, 20.4mmol) in DCM (50mL) was added PPTS (511.8mg, 2.04mmol) and DHP (5.14g, 61.1mmol) in that order, and the resulting mixture was stirred at 20 ℃ for 12H to give a yellow solution. TLC showed consumption of starting material and found two new spots. The reaction was warmed to 40 ℃ and stirred for 12 h. TLC showed the reaction was complete. Adding H to the reaction mixture₂O (50mL), separated and the aqueous phase extracted with DCM (2 × 50 mL). The obtained organic phase was treated with anhydrous Na₂SO₄Drying, filtering, and concentrating under reduced pressure. The residue was purified by FCC (SiO) ₂THF/PE ═ 0-3%) to give 4-bromo-5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5) as a white solid.70g, yield 81.7%).¹H NMR:(400 MHz,CDCl₃)δ7.99-7.88(m,1H),7.42(s,1H),5.65(dd,J＝2.8,9.0Hz,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 E5-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), Pd₂(dba)₃To a solution of (450.1mg, 491.5umol) and t-BuXphos (626.1mg, 1.47mmol) in dioxane (160mL) was added KOH (5.52g, 98.3mmol) in H₂O (160mL) solution. In N₂The mixture was stirred at 90 ℃ for 2h under protection to give a brown mixture. LCMS monitored completion of the reaction, the reaction mixture was adjusted to pH 2-3 with 1N aqueous HCl and the resulting mixture was extracted with EA (3x200 mL). Anhydrous Na for organic phase₂SO₄Drying, filtering and concentrating. Purification of the residue by FCC (SiO)₂EA/PE ═ 0 to 30%) yielded 5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol as a yellow solid (4.10g, yield 58.9%).¹H NMR:(400MHz,DMSO-d₆)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 A4-chloro-2-fluoro-5-methylaniline

To 1-chloro-5-fluoro-2-methyl-4To a solution of nitrobenzene (20.0g, 105.5mmol) in EtOH (100mL) was added concentrated HCl (8.79 mL). The mixture was heated to 80 ℃ and iron powder (20.6g, 369.3mmol) was added slowly. The resulting mixture was stirred at the same temperature for 1 h. LCMS showed reaction complete, system was cooled to 25 deg.C, diluted with EA (300mL) and saturated NaHCO ₃Basification of the aqueous solution to pH 8-9. 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 (500mL) and anhydrous Na₂SO₄Drying, filtering, and concentrating under reduced pressure. The crude product obtained was used directly in the next step as a yellow solid, 4-chloro-2-fluoro-5-methylaniline (16.0g, crude).¹H NMR:(400MHz,DMSO-d₆)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

NBS (71.4g, 401.0mmol) was added slowly to a solution of 4-chloro-2-fluoro-5-methylaniline (64.0g, 401.0mmol) in DMF (800mL) at 0 deg.C, then the mixture was heated to 25 deg.C and stirred for 1 h. TLC showed the reaction was complete. With EA (1000mL) and H₂The reaction mixture was treated with O (1000mL), separated, and the organic phase was washed with saturated aqueous NaCl solution (1000mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue (SiO) by FCC₂PE/EA-1/0 to 20/1) gave 2-bromo-4-chloro-6-fluoro-3-methylaniline (70.0g, 62.6% yield in two steps) as a yellow solid.¹H NMR:(400MHz,DMSO-d₆)δ 7.28(d,J＝10.9Hz,1H),5.44(br s,2H),2.35(s,3H).

Step C3-bromo-1-chloro-5-fluoro-4-iodo-2-toluene

2-bromo-4-chloro-6-fluoro-3-methylaniline (74.0g, 310.3mmol) was added to concentrated H₂SO₄(208mL) in an aqueous solution (840 mL). Stirred at 25 ℃ for 10min and then cooled to 5 ℃. Dropwise adding NaNO₂(23.6g, 341.3mmol) of H₂O (75mL) solution. The resulting mixture was stirred at 5 ℃ for 20min, then added to KI (206.0g, 1.24mol) in H ₂O (160mL) solution. The resulting mixture was stirred at 5 ℃ for 20min, then warmed to 25 ℃ and stirred for 18 h. TLC showed complete reaction with H₂The reaction was quenched with O (500mL) and extracted with EA (2X1000mL)The resulting mixture was taken. The organic phase is saturated with Na₂SO₃Washed with aqueous solution (500mL) and saturated aqueous NaCl solution (500mL) over anhydrous Na₂SO₄Drying, filtering, and concentrating under reduced pressure. Purification of the residue (SiO) by FCC₂PE/EA-1/0 to 50/1) gave 3-bromo-1-chloro-5-fluoro-4-iodo-2-toluene (69.0g, yield 60.5%) as a yellow solid.¹H NMR:(400MHz,DMSO-d₆)δ7.57(d,J＝7.8Hz,1H),2.53-2.45(m,3H).

Step D of 2-bromo-4-chloro-6-fluoro-3-methylbenzaldehyde

To a solution of 3-bromo-1-chloro-5-fluoro-4-iodo-2-toluene (68.0g, 194.6mmol) in THF (500mL) at-78 deg.C was added n-BuLi (2.5M, 77.9mL) dropwise. The mixture was stirred at the same temperature for 30 min. DMF (15.7g, 214.1mmol) was added dropwise and the mixture was stirred at-78 ℃ for 20min to give a yellow solution. TLC monitored the reaction completion. With saturated NH₄The reaction was quenched with aqueous Cl (200 mL). Adding H into the system₂O (200mL) and extracted with EA (2X 300 mL). The resulting organic layer was washed with saturated aqueous NaCl solution (150mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. Purification of the residue (SiO) by FCC₂PE/EA-1/0 to 20/1) gave 2-bromo-4-chloro-6-fluoro-3-methylbenzaldehyde as a yellow solid (38.0g, yield 57.1%).

Step E4-bromo-6-chloro-5-methyl-1H-indazole

Reacting NH₂NH₂-H₂O (90.8g, 1.81mol) was added to a DMSO (800mL) solution of 2-bromo-4-chloro-6-fluoro-3-methylbenzaldehyde (38.0g, 151.1 mmol). The resulting mixture was stirred at 130 ℃ for 3 h. LCMS shows product formation with EA (2000mL) and H₂The reaction mixture was treated with O (1000mL), separated, and the organic phase was washed with saturated aqueous NaCl (2X1000mL), anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO)₂EA/PE 0-20%) gave 4-bromo-6-chloro-5-methyl-1H-indazole (23.5g, yield 51.5%) as a yellow solid.¹H NMR:(400MHz,DMSO-d₆)δ13.44 (br s,1H),8.10-7.90(m,1H),7.78-7.56(m,1H),2.50(br s,3H).

Step F4-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, 268.8 mmol). The reaction mixture was stirred at 40 ℃ for 5 h. LCMS showed the reaction was complete and the reaction was washed with saturated aqueous NaCl (150mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by FCC (SiO)₂EA/PE ═ 0 to 5%) yielded 4-bromo-6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole as a yellow solid (21.0g, yield 71.1%).¹H NMR:(400MHz,DMSO-d₆)δ8.46(s,1H),7.84(s,1H),5.76(dd,J＝2.6, 9.7Hz,1H),3.99(br d,J＝11.0Hz,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 G6-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), Pd₂(dba)₃(611.2mg, 667.4umol) and t-BuXphos (850.3mg, 2.00mmol) in dioxane (220mL) was added KOH (7.50g, 133.5mmol) in H₂O (220mL) solution. The resulting mixture was stirred at 90 ℃ for 2h under nitrogen to give a brown mixture. LCMS showed the reaction was complete and the reaction mixture was adjusted to pH 2-3 with 1N aqueous HCl. The mixture was extracted with EA (300 mL). The resulting organic phase was washed with saturated aqueous NaCl (100mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by FCC (SiO)₂EA/PE 0-50%) gave 6-chloro-5-methyl-1H-indazol-4-ol as a yellow solid (6.00g, 98.5% yield). LCMS (M/z):182.9(M + H).

Step H6-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 (6.00g, 32.9mmol) and PPTS (825.7mg, 3.3mmol) in DCM (150mL) was added DHP (8.29g, 98.6 mmol). The reaction mixture was stirred at 40 ℃ for 5 h. LCMS showed reaction complete. The reaction solution was washed with saturated aqueous NaCl solution (100mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by FCC (SiO) ₂EA/PE of 0-10%) to give 6-chloro-5-methyl as a yellow oily substance-1- (tetrahydro-2H-pyran-2-yl) -4- ((tetrahydro-2H-pyran-2-yl) oxy) -1H-indazole (6.20g, yield 48.4%). LCMS (M/z):351.1(M + H).

Step I6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol

To a solution of 6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -4- ((tetrahydro-2H-pyran-2-yl) oxy) -1H-indazole (6.10g, 17.4mmol) in dioxane (18mL) at 0 ℃ was added 4N HCl/dioxane (8 mL). The reaction mixture was stirred at 0 ℃ for 10 min. TLC showed the reaction was complete. With saturated NaHCO₃The reaction mixture was adjusted to pH 9 with aqueous solution and then extracted with EA (100 mL). The resulting organic phase was washed with saturated aqueous NaCl (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by FCC (SiO)₂EA/PE ═ 0 to 15%) yielded 6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol as a yellow solid (2.10g, yield 43.6%).¹H NMR:(400MHz,DMSO-d₆)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

To a solution of methyl 3-fluoro-2-nitrobenzoate (2.1g, 10.55mmol) and 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol (2.45g, 10.55mmol) in DMF (20mL) at room temperature was added K₂CO₃(3.60g, 22.15 mmol). Heating the mixture to 60 ℃ and stirring 1And 6 h. After cooling to room temperature, the mixture is poured into H₂O (100mL) and extracted with EA (3X 30 mL). The organic phase was washed with saturated aqueous NaCl (2 × 50mL), anhydrous Na₂SO₄Drying, FCC purification (SiO)₂EA/PE ═ 0-30%) yielded methyl 3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2-nitrobenzoate as a pale yellow solid (3.40g, 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

A mixture of 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) was stirred in a reaction flask equipped with a hydrogen balloon at room temperature for 40H. After completion of the reaction monitored by LCMS, the mixture was filtered. The filtrate was concentrated to give methyl 2-amino-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate as a pale yellow solid (3.10g, yield 98%). LCMS (M/z):382.2(M + H).

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

NMI (2.0g, 24.4mmol) was added to a solution of methyl 2-amino-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate (3.10g, 8.13mmol), cyanoacetic acid (1.38g, 16.3mmol) and TCFH (3.42g, 12.19mmol) in MeCN (30mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS for completion, the mixture was poured into saturated aqueous NaCl (50mL) and extracted with EA (2 × 30 mL). The resulting organic phase was washed with saturated aqueous NaCl solution (2X25mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The obtained crude product is treated with FCC (SiO)₂EA/PE ═ 0-60%) purified to give methyl 2- (2-cyanoacetylamino) -3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate as a pale yellow solid (3.50g, 96% yield). LCMS (M/z):449.2(M + H), 471.1(M + Na).

Step D2, 4-dihydroxy-8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) quinoline-3-carbonitrile

To a solution of methyl 2- (2-cyanoacetamido) -3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate (4.1g, 9.14mmol) in THF (50mL) at 0 ℃ was added t-BuOK (2.0g, 18.28 mmol). The mixture was stirred at 0 ℃ for 2 h. After LCMS monitoring reaction completion, pour mixture into H ₂O (100mL) and acidified to pH 4 with 1N aqueous HCl, a solid formed. The combined system was extracted with EA (3 × 25mL), the resulting organic phase was washed with saturated aqueous NaCl (2 × 20mL), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 2, 4-dihydroxy-8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) quinoline-3-carbonitrile as an off-white solid (3.5g, 92% yield). LCMS (M/z):417.0(M + H), 439.0(M + Na).

Step E2, 4-dichloro-8- ((5-methyl-1H-indazol-4-yl) oxy) quinoline-3-carbonitrile

To a solution of 2, 4-dihydroxy-8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) quinoline-3-carbo-nitrile (800mg, 1.92mmol) in toluene (20mL) was added POCl₃(4mL) and N, N-diethylaniline (0.5 mL). The resulting mixture was heated at 100 ℃ with stirring for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Subjecting the obtained crude product to FCC (SiO)₂EA/PE ═ 0-80%) purified to give 2, 4-dichloro-8- ((5-methyl-1H-indazol-4-yl) oxy) quinoline-3-carbonitrile as a yellow solid (425mg, yield 60%). LCMS (M/z):369.0(M + H).

Step F tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate

To a solution of 2, 4-dichloro-8- ((5-methyl-1H-indazol-4-yl) oxy) quinoline-3-carbonitrile (425mg, 1.15mmol) and N-Boc-piperazine (321mg, 1.73mmol) in DMA (2mL) was added DIEA (300mg, 2.3mmol) dropwise. The mixture was stirred at room temperature for 2 h. After LCMS monitoring reaction completion, pour mixture into H ₂O (30 mL). The precipitate formed is collected by filtration and passed through FCC (SiO)₂EA/PE ═ 0-70%) to give tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (300mg, yield 50%) as a pale yellow solid. 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-methylpyrrolidin-2-yl) methoxy) quinoline-3-carbonitrilecarboxylate

Step A (S) -tert-butyl 4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate

To a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (44mg, 0.38mmol) in THF (3mL) at room temperature was added NaH (10mg, 0.4 mmol). The resulting mixture was stirred at the same temperature for 5min, then tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (100mg, 0.19mmol) was added and the resulting mixture was stirred at room temperature for an additional 1H. After completion of the reaction, it was quenched by addition of saturated aqueous NaCl and extracted with EA (2 × 20 mL). Washing the organic phase with saturated aqueous NaCl solution and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure to give crude yellow solid tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate (115mg, crude) which was used directly 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-carbonitril

TFA (2mL) was added to a solution of (S) -tert-butyl 4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate (110mg, 0.18mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give (S) -8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) quinoline-3-carbonitrile (90mg, crude) as a pale yellow oil which was 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-methylpyrrolidin-2-yl) methoxy) quinoline-3-carbonitrile formate salt

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 at 0 deg.C₃To an aqueous solution (5mL) was added a solution of acryloyl chloride (25mg, 0.28mmol) in EA (1 mL). The mixture was stirred vigorously for 15 min. After completion of the reaction, 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 give (S) -4- (4-acryloylpiperazin-1-yl) -8- (5-methyl-1H-indazol-4-yl) oxy) -2- (1-methylpyrrolidin-2-yl) methoxy) quinoline-3-carbonitrile formate as a white solid (32mg, 31% of the total yield in the three steps). ¹H NMR(400MHz,DMSO-d₆)δ13.04(s,1H),7.81 (d,J＝8.4Hz,1H),7.42(t,J＝8.1Hz,1H),7.35–7.17(m,3H),7.02(s,1H),6.91(dd,J＝16.7, 10.4Hz,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.75(dd,J＝10.4,2.4Hz,1H),4.06(dd,J＝11.0,4.8 Hz,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＝8.7Hz,1H),1.84(dt,J＝12.4,8.5Hz,1H),1.74–1.59(m,2H),1.52(dt, J＝14.2,6.7Hz,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-carbonitril-e

Step A and step B:

preparation of the 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 as described in reference to example 1, using (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol instead of (S) - (1-methylpyrrolidin-2-yl) methanol in step a. 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

A solution of acryloyl chloride (14.3mg, 0.16mmol) in DCM (0.5mL) was added dropwise to a solution of (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 (84mg, 0.16mmol) and DIEA (447mg, 3.46mmol) in DCM (2.5mL) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 30 min. The reaction was diluted with EA (30mL) and H₂O (20mL) wash, saturated aqueous NaCl (2X20mL) wash and Na anhydrous₂SO₄And (5) drying. After filtration and removal of the solvent under reduced pressure, the residue was purified by preparative high performance liquid chromatography to give (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 as a white solid (37mg, 40% of the total yield in three steps). ¹H NMR(400MHz,DMSO-d₆)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＝ 16.7,10.4Hz,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.75(dd,J＝10.4,2.4Hz,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).¹⁹F NMR(376MHz,DMSO-d₆)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

Preparation of example A3 reference was made to example A2, wherein ((2S,4S) -4-fluoro-1-carbaldehyde was used in step AMethylpyrrolidin-2-yl) methanol instead of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol.¹H NMR(400MHz,Methanol-d₄)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).¹⁹F 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

Preparation of example a4 As described in reference example a2, (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol was used in place of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol in step a.¹H NMR(400MHz,Methanol-d₄)δ7.89(d, J＝8.3Hz,1H),7.58–7.16(m,4H),7.05–6.76(m,2H),6.30(d,J＝16.7Hz,1H),5.83(d,J＝ 10.7Hz,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-carbonitril-e

Preparation of example A5 As described in example A2 ((2S,4R) -4-methoxy-1-methylpyrrolidin-2-yl) methanol was used in step A instead of (S) - (4, 4-difluoro-1-)Methylpyrrolidin-2-yl) methanol.¹H NMR(400MHz,Methanol-d₄)δ 7.97(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

Preparation of intermediate a2 described with reference to the synthesis of intermediate a1, 5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol was used in step a instead of 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

Preparation of example a6 tert-butyl 4- (2-chloro-8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate a2) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1) as described in example a 1.¹H NMR(400MHz,DMSO-d₆) δ13.36(s,1H),8.00–7.93(m,1H),7.83(d,J＝7.6Hz,1H),7.57(t,J＝8.1Hz,1H),7.34(d,J＝ 8.8Hz,1H),6.91(dd,J＝16.6,10.4Hz,1H),6.77(s,1H),6.19(dd,J＝16.6,2.4Hz,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).¹⁹F NMR(376MHz,DMSO-d₆)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

Preparation of example a7 as described in example a1, in step a tert-butyl 4- (2-chloro-8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate a2) was used instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1), and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol is used instead of (S) - (1-methylpyrrolidin-2-yl) methanol. ¹H NMR(400MHz,DMSO-d₆)δ13.35(s, 1H),8.00(d,J＝8.5Hz,1H),7.82(d,J＝7.7Hz,1H),7.59(t,J＝8.1Hz,1H),7.33(d,J＝8.8Hz, 1H),6.92(dd,J＝16.6,10.4Hz,1H),6.55(s,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.76(dd,J＝ 10.4,2.4Hz,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).¹⁹F NMR(376MHz,DMSO-d₆)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-carboxylic acid tert-butyl ester

Preparation of intermediate A3 described with reference to the synthesis of intermediate a1, 6-chloro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol was used in step a 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

Preparation of example A8 tert-butyl 4- (2-chloro-8- ((6-chloro-5-methyl-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate A3) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1) as described in example a 1.¹H NMR(400MHz, DMSO-d₆)δ13.14(s,1H),7.88(d,J＝8.3Hz,1H),7.57(d,J＝7.6Hz,1H),7.49(t,J＝8.1Hz, 1H),7.43(s,1H),6.91(dd,J＝16.6,10.4Hz,1H),6.83(s,1H),6.19(dd,J＝16.6,2.4Hz,1H), 5.75(dd,J＝10.4,2.4Hz,1H),3.95–3.76(m,5H),3.72(dd,J＝11.0,6.5Hz,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

Preparation of example a9 as described in example a1, tert-butyl 4- (2-chloro-8- ((6-chloro-5-methyl-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate A3) was used instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1) in step a, and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol is used instead of (S) - (1-methylpyrrolidin-2-yl) methanol. ¹H NMR(400MHz,DMSO-d₆)δ 13.20(s,1H),7.97(d,J＝8.3Hz,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＝16.6,2.3Hz,1H),5.82(dd,J＝10.3,2.4Hz,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-carboxylic acid tert-butyl ester

Preparation of intermediate a4 described with reference to the synthesis of intermediate a1, 5-chloro-6-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol was used in step a 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

Preparation of example a10 as described in example a2, in step a tert-butyl 4- (2-chloro-8- ((5-chloro-6-methyl-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate a4) was used instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1) and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol was used instead of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol.¹H NMR(400MHz,DMSO-d₆)δ13.12(s,1H),7.93(dd,J＝8.5,1.3Hz,1H),7.67(dd,J＝7.7,1.2Hz,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

Preparation of example a11 referring to the description in example a2, tert-butyl 4- (2-chloro-8- ((5-chloro-6-methyl-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate a4) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1), and (S) - (1-methylpyrrolidin-2-yl) methanol is used instead of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol.¹H NMR(400MHz,Methanol-d₄)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 ester

Preparation of intermediate a5 described with reference to the synthesis of intermediate a1, 5, 6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol was 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-methylpyrrolidin-2-yl) methoxy) quinoline-3-carbonitril

Preparation of example a12 referring to the description in example a2, tert-butyl 4- (2-chloro-3-cyano-8- ((5, 6-dichloro-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a5) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1), and (S) - (1-methylpyrrolidin-2-yl) methanol is used instead of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol. ¹H NMR(400MHz,DMSO-d₆)δ13.38(s, 1H),7.95(dd,J＝8.5,1.3Hz,1H),7.81(dd,J＝7.8,1.2Hz,1H),7.62–7.49(m,2H),6.91(dd,J ＝16.6,10.4Hz,1H),6.77(s,1H),6.19(dd,J＝16.7,2.4Hz,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

Preparation of example a13 as described in example a2, tert-butyl 4- (2-chloro-3-cyano-8- ((5, 6-dichloro-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a5) was used instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1) in step a, and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol is used instead of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol.¹H NMR(400MHz,DMSO-d₆)δ 13.37(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＝ 16.6,10.4Hz,1H),6.58(s,1H),6.19(dd,J＝16.6,2.4Hz,1H),5.76(dd,J＝10.4,2.4Hz,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

Step A and step B:

the synthesis of methyl 2-amino-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate was done according to steps a and B in the synthesis of intermediate a 1.

Step C methyl 2-amino-5-chloro-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate

NCS (700mg, 5.24mmol) was added portionwise to a solution of methyl 2-amino-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate (2.0g, 5.24mmol) in DMF (10mL) at room temperature. The resulting mixture was stirred at 60 ℃ for 48 h. After cooling to room temperature, the mixture is poured into H ₂O (100mL) and extracted with EA (3 × 30 mL). The resulting organic phase was washed with saturated aqueous NaCl solution (40mL) and anhydrous Na₂SO₄Drying, filtering, and concentrating under reduced pressure. The obtained crude product is passed through FCC (SiO)₂EA/PE ═ 0-100%) purified to give methyl 2-amino-5-chloro-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate as a yellow solid (1.5g, 69% yield). 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) piperazine-1-carboxylic acid tert-butyl ester (intermediate A6)

Subsequent synthesis of intermediate a6 described with reference to the synthesis of intermediate a1, methyl 2-amino-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate was replaced in step C with methyl 2-amino-5-chloro-3- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) benzoate. 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

Preparation of example a14 referring to the description in example a2, tert-butyl 4- (2, 6-dichloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a6) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1), and (S) - (1-methylpyrrolidin-2-yl) methanol is used instead of (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol. ¹H NMR(400MHz,DMSO-d₆)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＝16.6,2.4Hz,1H),5.74(dd,J＝10.4,2.4Hz,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

Preparation of intermediate a7 described with reference to the synthesis of intermediate a6, 5, 6-dichloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol was 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

Synthesis of example a15 referring to the description in example a1, tert-butyl 4- (2, 6-dichloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a7) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1), and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol is used instead of (S) - (1-methylpyrrolidin-2-yl) methanol.¹H NMR (400MHz, methanol-d)₄)δ7.97(d,J＝ 2.3Hz,1H),7.67(d,J＝2.2Hz,1H),7.59(d,J＝1.0Hz,1H),7.02(s,1H),6.87(dd,J＝16.8,10.7 Hz,1H),6.30(dd,J＝16.8,2.0Hz,1H),5.84(dd,J＝10.7,2.0Hz,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

Preparation of example a16 reference was made to example a2, where 4- (2, 6-dichloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) was used in step a) Oxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate a6) was used in place 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 (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol was used instead of (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol.¹H 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

To a solution of (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 was added DIEA (36mg, 0.28mmol) dropwise at 0 ℃. After the addition was complete, the mixture was stirred at 20 ℃ for 1h, the reaction was diluted with EA (30mL), washed with water (2X20mL), saturated aqueous NaCl (2X20mL), anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting crude product was purified by preparative high performance liquid chromatography to give (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 (16mg, yield 20%). ¹H NMR (400MHz, methanol-d)₄)δ7.88(dd,J＝8.4,1.2Hz,1H),7.45(t,J＝8.1Hz,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＝3.9Hz,1H), 4.06–3.99(m,1H),3.96(d,J＝5.0Hz,4H),3.77(d,J＝2.7Hz,4H),3.07(td,J＝8.8,8.0,4.0Hz, 1H),2.74(s,1H),2.49(s,3H),2.42(s,3H),2.37(s,1H),2.03(dd,J＝12.6,8.3Hz,1H),1.87– 1.77(m,2H),1.65(dd,J＝13.0,6.6Hz,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-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinoline-3-carbonitrile

Example A18 preparation reference example A17 used (E) -4- (dimethylamino) -2-butenoic acid instead of 2-fluoroacrylic acid.¹H NMR (400MHz, methanol-d)₄)δ7.88(dd,J＝8.5,1.3Hz,1H),7.44(t,J＝8.1Hz,1H),7.39– 7.22(m,3H),7.05(s,1H),6.87(dt,J＝15.2,6.4Hz,1H),6.79–6.69(m,1H),4.27(dd,J＝11.5, 3.9Hz,1H),4.01(d,J＝20.3Hz,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＝8.9Hz,1H),2.33(s,6H),2.03(dd, J＝12.6,8.3Hz,1H),1.87–1.76(m,2H),1.65(dd,J＝12.9,6.6Hz,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-pyrazol-4-yl) quinoline-3-carbonitrile

Step A tert-butyl 4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- (1-methyl-1H-pyrazol-4-yl) quinolin-4-yl) piperazine-1-carboxylate

In N₂Tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (80mg, 0.15mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (29.1mg, 0.23mmol), Pd (PPh) with protection₃)₄(35.6mg, 0.031mmol) and K₂CO₃A solution of (42.6mg, 0.31mmol) of ethylene glycol dimethyl ether in water (20:1, 6mL) was stirred at 85 ℃ for 3 h. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was purified by adding EA (30mL) and H₂Partition between O (20mL) and separate the organic phase. The organic phase obtained is H₂O (20mL) and saturated aqueous NaCl (2X20mL) were washed sequentially with anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The resulting crude tert-butyl 4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- (1-methyl-1H-pyrazol-4-yl) quinolin-4-yl) piperazine-1-carboxylate (230mg, crude) was directly charged to the next step. LCMS (M/z):565.3(M + H).

Step B and C4- (4-acryloylpiperazin-1-yl) -8- ((5-methyl-1H-indazol-4-yl) oxy) -2- (1-methyl-1H-pyrazol-4-yl) quinoline-3-carbonitrile

Subsequent synthesis steps B and C of example a19 referring to the description in example a2, tert-butyl 4- (3-cyano-2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate was replaced in step B by tert-butyl 4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- (1-methyl-1H-pyrazol-4-yl) quinolin-4-yl) piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ8.24(s,1H),8.05(s,1H),7.89(dd,J＝8.6,1.2Hz, 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＝16.8,1.9Hz,1H),5.82(dd,J＝10.6,1.9Hz,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-methylisoindolin-4-yl) oxy) quinoline-3-carbonitrile

Step A: 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

In N₂Under protection, tert-butyl 4- (2-chloro-8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (150mg,0.27mmol), 2-methylisoindolin-4-ol (80.3mg,0.54mmol), CuI (10.3mg,0.05mmol), N ¹-benzyl-N²- (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (22.2mg,0.06mmol) and K₂CO₃A solution of (111.6mg,0.81mmol) in DMSO (2mL) was stirred at 100 ℃ for 3 h. The reaction system was treated with EA (30mL) and H₂Diluted O (30mL), filtered over celite and the filtrate extracted with EA (3 × 30 mL). The organic layer was washed with saturated aqueous NaCl solution and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. Subjecting the crude product to FCC (SiO)₂MeOH/DCM ═ 0-20%) to give tert-butyl 4- (8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -3-cyano-2- ((2-methylisoindolin-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (70mg, yield 39%). LCMS (M/z):670.2(M + H).

Step B and C4- (4-acryloylpiperazin-1-yl) -8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -2- ((2-methylisoindol-4-yl) oxy) quinoline-3-carbonitrile

Subsequent syntheses of example a20 described in reference to example a2, tert-butyl 4- (8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -3-cyano-2- ((2-methylisoindolin-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate was used in step B instead of tert-butyl (S) -4- (3-cyano-2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate. ¹H NMR (400MHz, methanol-d)₄)δ8.09(dd,J＝8.5,1.3Hz,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＝6.9,2.0 Hz,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).¹⁹F 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-isopropylisoindolin-4-yl) oxy) quinoline-3-carbonitrile

Preparation of example A21 As described in reference example A20, 2-isopropylindolin-4-ol was used instead of 2-methylisoindoline-4-ol in step A.¹H NMR(400MHz,DMSO-d₆)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＝16.6,2.5Hz,1H), 5.77(dd,J＝10.4,2.4Hz,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).¹⁹F NMR(376MHz,DMSO-d₆)δ-115.00. LCMS(m/z):652.2(M+H).

The following compounds of example a22 through example a61 were also prepared and characterized according to a method analogous to the synthesis of the above-described compound of the example a series:

example A62

4- (4-acryloylpiperazin-1-yl) -8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -2- ((2-methylpyridin-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

In N₂Under 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),Cs₂CO₃(176mg，0.54mmol)、 Pd(OAc)₂A solution of (12mg, 0.054mmol) and BINAP (33mg, 0.054mmol) in dioxane (10mL) was stirred with heating at 100 ℃ for 16 h. After cooling to room temperature, it was filtered through celite. Concentrating the filtrate to obtain FCC (SiO) ₂MeOH/DCM ═ 0-30%) purified to give 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 as a pale yellow solid (30mg, yield 17.72%). LCMS (M/z):629.1(M + H).

Step B and C4- (4-acryloylpiperazin-1-yl) -8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -2- ((2-methylpyridin-3-yl) amino) quinoline-3-carbonitrile

Subsequent synthesis of example a62 reference was made to example a2, using tert-butyl 4- (8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -3-cyano-2- ((2-methylpyridin-3-yl) amino) quinolin-4-yl) piperazine-1-carboxylate in step B instead of tert-butyl (S) -4- (3-cyano-2- ((4, 4-difluoro-1-methylpyrrolidin-2-yl) methoxy) -8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate. LCMS (M/z):583.1(M + H).

The following compounds of example a63 through example a80 were also prepared and characterized according to a method analogous to the synthesis of the above-described compound of the example a series:

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

To methyl 3-amino-4-bromothiophene-2-carboxylate (500mg,2.12mmol), 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol (492mg,2.12mmol), N at room temperature¹,N²Bis (naphthalen-1-ylmethyl) oxamide (150mg,0.40mmol), sodium tert-butoxide (407mg,4.24mmol),

to a solution of molecular sieves (500mg) in 1, 4-dioxane (10mL) was added cuprous iodide (38mg,0.20 mmol). The mixture was heated to 110 ℃ and stirred for 16 h. Cooling to room temperature, filtering to obtain filtrate, concentrating, and purifying by FCC (SiO)₂EA/PE ═ 0-100%) yielded methyl 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) thiophene-2-carboxylate (120mg, yield 15%) as a yellow solid. 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

The subsequent synthesis of example a81 was described with reference to intermediate a1 and example a 2.¹H NMR (400MHz, methanol-d)₄)δ7.39–7.26(m,3H),7.20(s,1H),6.83(dd,J＝16.8,10.6Hz,1H),6.26(dd,J＝16.8,1.9 Hz,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＝10.5,6.0Hz,1H),2.73(dd,J＝11.5,6.3Hz,1H),2.53(dd,J＝10.4, 4.3Hz,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).

The following compounds of example a82 through example a109 were also prepared and characterized according to a method analogous to the synthesis of the above-described compound of example a series:

examples A110 and A111

Or

4- (4-acryloylpiperazin-1-yl) -8- ((5-chloro-6-fluoro-1-methyl-1H-indol-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-methylpyrrolidin-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-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester.

NaH (24mg, 60% w/w,0.6mmol) was added to a solution of tert-butyl 4- (2-chloro-8- ((5-chloro-6-fluoro-1H-indazol-4-yl) oxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (330mg,0.6mmol) and iodomethane (100mg, 0.7mmol) in anhydrous tetrahydrofuran (5mL) with stirring in an ice bath. The ice bath was removed and the temperature was slowly raised to room temperature with stirring. After TLC monitoring of the reaction completion, (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol (210mg, 1.6mmol) and NaH (64mg, 60% w/w, 1.6mmol) were added sequentially and the resulting mixture was stirred further until LCMS monitoring of the reaction completion. The reaction was quenched by the addition of water (5mL), the organic phase was collected by liquid separation, and the aqueous phase was extracted with EA (10 mL. times.3). The combined organic phases were washed with saturated aqueous NaCl solution (30mL) and anhydrous Na ₂SO₄Drying, filtering, and concentrating under reduced pressure. The crude product was used in the next step without purification.

And step B and step C: 4- (4-acryloylpiperazin-1-yl) -8- ((5-chloro-6-fluoro-1-methyl-1H-indol-4-yl) oxy) -2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinoline-3-carbonitrile (example A110) and 4- (4-acryloylpiperazin-1-yl) -8- ((5-chloro-6-fluoro-2-methyl-2H-indazol-4-yl) oxy) -2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinoline-3-carbonitrile (example A111).

Examples a110 and subsequent synthesis of example a111 referring to the synthesis of example A1, tert-butyl 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-carboxylate 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) quina -tert-butyl quinolin-4-yl) piperazine-1-carboxylate instead of tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate. In the case of the embodiment a110 or a111,¹H NMR(400MHz,DMSO-d₆)δ7.92(dd,J＝8.5,1.4Hz,1H),7.63(dd, J＝7.8,1.2Hz,1H),7.57–7.49(m,1H),7.43–7.34(m,1H),7.25(s,1H),6.91(dd,J＝16.6,10.4 Hz,1H),6.19(dd,J＝16.6,2.4Hz,1H),5.75(dd,J＝10.4,2.4Hz,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)；

in the case of either embodiment a111 or a110, ¹H NMR(400MHz,DMSO-d₆)δ7.99(dd,J＝8.5,1.3Hz,1H),7.83(dd, J＝7.7,1.2Hz,1H),7.68–7.50(m,2H),6.91(dd,J＝16.7,10.4Hz,1H),6.53(s,1H),6.19(dd,J ＝16.7,2.4Hz,1H),5.76(dd,J＝10.4,2.4Hz,1H),4.55(s,1H),4.05–3.79(m,8H),3.67(s,4H), 3.08(s,3H),3.01(dd,J＝9.7,6.6Hz,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

Synthesis of intermediate A8 described with reference to the synthesis of compound 2, 4-dichloro-8- ((5-methyl-1H-indazol-4-yl) oxy) quinoline-3-carbonitrile, using 2-fluoro-6-methoxyphenol in step a 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

4- (2-chloro-3-cyano-8- (2-fluoro-6-hydroxyphenoxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

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

Boron trichloride (7.0mL, 1M n-hexane solution, 7.0mmol) was added slowly dropwise to a solution of 2, 4-dichloro-8- (2-fluoro-6-methoxyphenoxy) quinoline-3-carbonitrile (1.0g,2.7mmol) in DCM (20mL) with stirring in an ice bath. After the dropwise addition, the temperature is raised to 50 ℃ for reaction for 48 hours. Reaction completion was monitored by LCMS, the system was cooled to room temperature and saturated NaHCO was added slowly₃The reaction was quenched with aqueous solution (10mL), the organic phase was collected by liquid separation, and the aqueous phase was extracted with DCM (10 mL. times.3). The combined organic phases were washed with saturated aqueous NaCl (30mL) and anhydrous Na₂SO₄And (5) drying. Filtering, concentrating to obtain crude product, and FCC (SiO)₂EA/PE ═ 0-80%) to give 2, 4-dichloro-8- (2-fluoro-6-hydroxyphenoxy) quinoline-3-carbonitrile (900mg, yield 93%). LCMS (M/z) 349.1(M + H). step B: 4- (2-chloro-3-cyano-8- (2-fluoro-6-hydroxyphenoxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

N, N-diisopropylethylamine (532mg, 4.1mmol) was added to a solution of 2, 4-dichloro-8- (2-fluoro-6-hydroxyphenoxy) quinoline-3-carbonitrile (900mg, 2.6mmol) and piperazine-1-carboxylic acid tert-butyl ester (563mg, 3.0 mmol) in THF (20mL) with stirring at room temperature, the resulting solution was stirred at room temperature for 3h, the reaction was monitored by LCMS for completion, the reaction system was washed with saturated aqueous NaCl (15mL), the aqueous phase was extracted with EA (10 mL. times.3), the organic phases were combined, anhydrous Na₂SO₄And (5) drying. Concentrating the crude product with FCC (SiO)₂EA/PE ═ 0-80%) to give 4- (2-chloro-3-cyano-8- (2-fluoro-6-hydroxy)Phenoxy) 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-carbonitrile

Step A: 4- (3-cyano-2- (3- ((dimethylamino) methyl) phenyl) -8- (2-fluoro-6-hydroxyphenoxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a microwave reaction tube containing magnetons, tert-butyl 4- (2-chloro-3-cyano-8- (2-fluoro-6-hydroxyphenoxy) quinolin-4-yl) piperazine-1-carboxylate (150mg,0.3mmol), (3- ((dimethylamino) methyl) phenyl) boronic acid (72mg,0.4mmol), Pd (dppf) Cl ₂(11mg,15umol) and K₂CO₃(81mg, 0.6mmol) of DME/H₂O (v/v ═ 10:1,2.75mL) solution. After nitrogen substitution, the system was heated at 90 ℃ for 1 hour by microwave reaction. Cooled to room temperature, EA (20mL) was added to dilute the system, washed with saturated aqueous NaCl (15 mL. times.2), anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the obtained crude product with FCC (SiO)₂MeOH/DCM ═ 0-50%) purification afforded tert-butyl 4- (3-cyano-2- (3- ((dimethylamino) methyl) phenyl) -8- (2-fluoro-6-hydroxyphenoxy) quinolin-4-yl) piperazine-1-carboxylate (135mg, yield 75%). LCMS (M/z):598.6(M + H).

And step B and step C: 4- (4-Acryloylpiperazin-1-yl) -2- (3- ((dimethylamino) methyl) phenyl) -8- (2-fluoro-6-hydroxyphenoxy) quinoline-3-carbonitrile

Subsequent synthesis steps B and C of example a112 as described in reference example A1, 4- (3-cyano-2- (3- ((dimethylamino) methyl) phenyl) -8- (2-fluoro-6-hydroxyphenoxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester was used in step B 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.¹H NMR (400MHz, chloroform-d) δ 8.04-7.91 (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). ¹⁹F NMR (376MHz, chloroform-d) delta-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) quinoline-3-carbonitril

Synthesis of example a113 as described for the synthesis of example a112, (3- (1- (dimethylamino) ethyl) phenyl) boronic acid was used in place of (3- ((dimethylamino) methyl) phenyl) boronic acid in step a.¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H), 7.84(d,J＝8.5Hz,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＝10.4,2.4 Hz,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-methylpyrrolidin-3-yl) oxy) quinoline-3-carbonitril e

Synthesis of example a114 as described in the synthesis of example A1, tert-butyl 4- (2-chloro-3-cyano-8- (2-fluoro-6-hydroxyphenoxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a9) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate A1) and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol instead of (S) - (1-methylpyrrolidin-3-olMethylpyrrolidin-2-yl) methanol.¹H NMR(400MHz,DMSO-d₆)δ10.14(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＝10.8,6.1Hz,1H),2.60(dd,J＝10.7,3.0Hz,1H),2.31(dd,J＝9.8,4.9Hz,1H),2.23(s,3H).¹⁹F NMR(376MHz,DMSO-d₆)δ-130.63.LCMS(m/z):548.5(M+H).

The following compound of example a115 was also prepared and characterized according to a method analogous to the synthesis of the above-described compound of example a series:

synthesis of intermediate A10

4- (2-chloro-8- (3-chloro-2-fluoro-6-methoxyphenoxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Synthesis of intermediate a10 as described for the synthesis of intermediate a1, 2-fluoro-6-methoxyphenol was used in place of 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol in step a. 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-carbonitril-e

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

Synthesis of the Compound 4- (4-acryloylpiperazin-1-yl) -8- (3-chloro-2-fluoro-6-methoxyphenoxy) -2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinoline-3-carbo-nitrile As described for the synthesis of example A1, tert-butyl 4- (2-chloro-8- (3-chloro-2-fluoro-6-methoxyphenoxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate A10) was used in step A instead of 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinoline- 4-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate A1). In step C, the crude product of 4- (4-acryloylpiperazin-1-yl) -8- (3-chloro-2-fluoro-6-methoxyphenoxy) -2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinoline-3-carbonitril is used directly in the subsequent reaction without being prepared by high performance liquid chromatography. 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-carbonitril-e

The crude compound obtained above (300mg, crude) was dissolved in DCM (5mL) and cooled to-70 ℃ with a dry ice/ethanol solution. BBr is added into the system dropwise under stirring₃(0.96mL, 10mmol), after the addition was complete, the reaction was allowed to warm to room temperature and stirring continued for 30min, and reaction completion was monitored by LCMS. Adding saturated NaHCO into the system₃The reaction was quenched with aqueous solution (5mL), the organic phase was collected by separation, the aqueous phase was extracted with DCM (5 mL. times.2), the organic phases were combined, anhydrous Na₂SO₄And (5) drying. Filtration and concentration under reduced pressure gave a crude product which was purified by high performance liquid chromatography to give 4- (4-acryloylpiperazin-1-yl) -8- (3-chloro-2-fluoro-6-hydroxyphenoxy) -2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinoline-3-carbo-nitrile as a white solid (8.2mg, 2.3% of the four-step total yield).¹H 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＝9.0,1.9Hz,1H),6.30(dd,J＝16.7,2.0Hz,1H), 5.83(dd,J＝10.6,1.9Hz,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＝11.5,6.2Hz,1H),3.09(dd,J＝ 10.5,6.0Hz,1H),2.72(dd,J＝11.5,3.0Hz,1H),2.62(dd,J＝10.5,4.4Hz,1H),2.39(s,3H).¹⁹F 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-2-carboxylic acid tert-butyl ester

Synthesis of intermediate a11 as described for the synthesis of intermediate a1, 2-fluoro-6-methoxyphenol was used in place of 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol in step a; in step F, tert-butyl 2, 7-diazaspiro [3.5] nonane-2-carboxylate is used instead of tert-butyl piperazine-1-carboxylate. 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-carbonitril

Synthesis of example A117 As described for the synthesis of example A116, in step A7- (2-chloro-3-cyano-8- (2-fluoro-6-methoxyphenoxy) quinolin-4-yl) -2, 7-diazaspiro [3.5] cyclo]Nonane-2-carboxylic acid tert-butyl ester (intermediate A11) instead of tert-butyl 4- (2-chloro-8- (3-chloro-2-fluoro-6-methoxyphenoxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate A10).¹H NMR(400MHz,DMSO-d₆)δ7.60(d,J＝8.5Hz,1H),7.36–7.28(m,1H),7.13–7.04(m,1H), 6.93(d,J＝7.8Hz,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＝9.8,4.9Hz,1H),2.24(s,3H),2.01(t,J＝5.6Hz, 4H).¹⁹F NMR(376MHz,DMSO-d₆)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-methylpyrrolidin-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

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

And B: 4- (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

Tert-butyl 4- (7-bromo-6-chloro-3-cyano-8-fluoro-2- (((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (600mg,1mmol), HCOOH (138mg,3mmol), Pd (PPh)₃)₄(116mg,0.1mmol), Et₃N(203mg,2mmol) in DMF (15mL), twice with nitrogen, and heating to 55 deg.C and stirring for 6 h. After the reaction, the reaction solution was poured into water (100mL), EA (50 mL. times.2) was extracted, the extract was collected and concentrated to obtain a crude product, which was then subjected to FCC (SiO)₂THF/DCM ═ 0-30%) to give tert-butyl 4- (6-chloro-3-cyano-8-fluoro-2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (500mg, yield 96%) as a yellow solid.

And 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

Tert-butyl 4- (6-chloro-3-cyano-8-fluoro-2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (200mg,0.38mmol), 2-fluoro-6-methoxyphenol (109mg,0.76mmol), Cs₂CO₃(376mg,1.1mmol) was dissolved in DMF (8mL) and stirred overnight at 110 ℃. After the reaction was completed, the reaction solution was poured into water (50mL), extracted with ethyl acetate (30mL × 3), and the extract was collected and concentrated to obtain 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) as a yellow solid which was directly fed to 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-carbonitril-e

Synthesis of example a118 as described for the synthesis of example a116, tert-butyl 4- (2, 6-dichloro-3-cyano-8- (2-fluoro-6-methoxyphenoxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a12) was used in step B instead of tert-butyl 4- (8- (3-chloro-2-fluoro-6-methoxyphenoxy) -3-cyano-2- (((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)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＝5.6,2.8 Hz,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＝10.8,2.9Hz,1H),2.30(dd,J＝9.9,4.9 Hz,1H),2.23(s,3H).¹⁹F NMR(376MHz,DMSO-d₆)δ-130.68.LCMS(m/z):582.5(M+H).

Synthesis of intermediate A13

4- (8-bromo-2-chloro-3-cyanoquinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Step A: 3-bromo-2- (2-cyanoacetamido) benzoic acid methyl ester

TCFH (195g, 695mmol) was added portionwise to a solution of methyl 2-amino-3-bromobenzoate (80g, 348mmol), 2-cyanoacetic acid (59.2g, 695mmol) and 1-methylimidazole (85.6g, 1.04mol) in acetonitrile (1000mL) at room temperature under a blanket of nitrogen. The resulting mixture was stirred at rt for 12h and LCMS monitored for completion. Acetonitrile was removed by concentration under reduced pressure, and the system was diluted with water (1000mL) and extracted with DCM (500 mL. times.2). The organic phases were combined, washed with brine and anhydrous Na ₂SO₄And (5) drying. Filtering, concentrating to obtain crude product, and FCC (SiO)₂EA/PE ═ 0-30%) purified to give methyl 3-bromo-2- (2-cyanoacetamido) benzoate (60g, 58% yield) as a yellow solid.

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

Potassium tert-butoxide (41.5g, 370mmol) was added slowly to a solution of methyl 3-bromo-2- (2-cyanoacetamido) benzoate (55g, 185mmol) in THF (500mL) and the mixture stirred at room temperature for an additional 1 h. TLC monitoring of the reaction completion, filtration, and additional slurrying of the resulting solid with water gave a crude yellow solid (51g, crude) 8-bromo-2, 4-dihydroxyquinoline-3-carbonitrile which was used directly in the next step.

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

8-bromo-2, 4-dihydroxyquinoline-3-carbonitrile (50g, 189mmol) was slowly added to phosphorus oxychloride (187mL, 2.01mol) at room temperature. The reaction solution was heated to 110 ℃ and stirred for 12 h. LCMS monitor reaction completion. After distilling off the phosphorus oxychloride, the crude product was dissolved in DCM (500mL) and the DCM solution was poured slowly into the ice-water mixture (1000 mL). The system was extracted with DCM (500 mL. times.3), the organic phases were combined, washed with saturated aqueous NaCl solution (500mL), anhydrous Na₂SO₄And (5) drying. Filtered and concentrated under reduced pressure to give the crude product (50g, 88% yield) which was used directly in the next reaction.

Step D: 4- (8-bromo-2-chloro-3-cyanoquinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

DIEA (53.5g, 414mmol) was added to a solution of 8-bromo-2, 4-dichloroquinoline-3-carbonitrile (50g, 166mmol) and piperazine-1-carboxylic acid tert-butyl ester (55.5g, 298mmol) in THF (500mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for a further 12 h. LCMS monitored completion of reaction and concentrated under reduced pressure to remove THF. Water (500mL) was added to the system to dilute the mixture, and the mixture was extracted with DCM (500 mL. times.2). The organic phases were combined, washed with saturated aqueous NaCl solution and anhydrous Na₂SO₄Drying, filtering, concentrating under reduced pressure and pulping the crude product with methyl tert-butyl ether to obtain yellow solid tert-butyl 4- (8-bromo-2-chloro-3-cyanoquinolin-4-yl) piperazine-1-carboxylate (60g, 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) piperazine-1-carboxylic acid tert-butyl ester

Step A: 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

NaH (32mg, 60% w/w,0.80mmol) was added to a solution of (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol (96mg, 0.73mmol) in THF (3mL), stirred at room temperature for 5min, and tert-butyl 4- (8-bromo-2-chloro-3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate A13, 300mg,0.66mmol) was added. After the reaction system was stirred at room temperature for 1 hour, a saturated aqueous solution (20mL) of ammonium chloride was added to the reaction system to conduct the extraction reaction. The mixture was extracted with EA (15 mL. times.2), washed with saturated brine (20 mL. times.2), and dried over anhydrous Na ₂SO₄After drying, filtration and concentration, tert-butyl 4- (8-bromo-3-cyano-2- (((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate was obtained as a pale yellow solid (300mg, yield 83%) which was used directly in the next step.

And B: 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

Tert-butyl 4- (8-bromo-3-cyano-2- (((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (300mg,0.73mmol), Pd₂dba₃(67mg,0.073mmol), tBuXphos (46mg,0.11mmol) and KOH (205mg,3.66mmol) were dissolved in 6mL dioxane and 2mL water and stirred at 90 ℃ for 2h under nitrogen. After the reaction was finished and cooled to the greenhouse, 1N HCl was added to adjust the pH to 7. The mixture was extracted with EA (15 mL. times.2), the organic phases were combined, washed with saturated aqueous NaCl solution (20 mL. times.2), anhydrous Na₂SO₄Drying, concentrating, and FCC (SiO)₂MeOH/DCM ═ 0-20%) to give tert-butyl 4- (3-cyano-8-hydroxy-2- (((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (250mg, yield 94%) as a white solid. 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-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 4- (3-cyano-8-hydroxy-2- (((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (250mg,0.52mmol), 1-chloro-2, 3-difluoro-4-nitrobenzene (110mg,0.57mmol) and potassium carbonate (143mg, 1.0mmol) in DMF (5mL) was stirred at 70 ℃ for 2 h. After the reaction was completed and cooled to a room temperature, the reaction mixture was poured into 30mL of water, the mixture was extracted with EA (25 mL. times.2), washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, concentrated, and passed through FCC (SiO)₂MeOH/DCM ═ 0-20%) to give 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 as a yellow solid (270mg, yield 79%). LCMS (M/z):657.6(M + H).

And B: 8- (3-chloro-2-fluoro-6-nitrophenoxy) -2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) -4- (piperazin-1-yl) quinoline-3-carbonitril

Tert-butyl 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-carboxylate (270mg,0.41mmol) was added portionwise to TFA (3mL) at room temperature, the resulting mixture was stirred for 1h at room temperature and LCMS monitored for reaction completion. The crude product is obtained after decompression and concentration and is directly used for the next reaction. LCMS (M/z):557.5(M + H).

And C: 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

The crude product from the previous step was dissolved in EA (10mL), and a saturated aqueous solution of sodium hydrogencarbonate (10mL) was added thereto, and acryloyl chloride (51mg,0.41mmol) was added dropwise to the reaction mixture with stirring while cooling in an ice bath. After stirring for another 15min while cooling on ice, saturated aqueous ammonium chloride (5mL) was added and the reaction was quenched. The EA phase was separated, the aqueous phase was extracted once with EA (10mL), and the organic phases were combined and washed with saturated brine (15mL) 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-carbonitril-e was obtained as a pale yellow solid (250mg, yield 99%) and 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

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) were dissolved in MeOH (15mL) and the resulting mixture was reacted at 70 ℃ for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and then filtered through celite. After the filtrate was concentrated to dryness, EA (25mL) and water (25mL) were added, the organic phase was separated and collected, and the aqueous phase was extracted once with EA (10 mL). The combined organic phases were washed with saturated brine (15mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by preparative high performance liquid chromatography to give 4- (4-acryloylpiperazin-1-yl) -8- (6-amino-3-chloro-2-fluorophenoxy) -2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinoline-3-carbonitril-e as a white solid (35mg, 15% yield). ¹H NMR(400MHz,DMSO-d₆)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＝9.8,6.5Hz,1H),2.88(dd,J＝10.9,6.1Hz, 1H),2.63(dd,J＝10.9,2.9Hz,1H),2.31(dd,J＝9.8,5.1Hz,1H),2.24(s,3H).¹⁹F NMR(376 MHz,DMSO-d₆)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-methylpyrrolidin-3-yl) oxy) quinoline-3-carbonitril-e

Synthesis of example a120 as described for the synthesis of example a119, 1, 2-difluoro-3-nitrobenzene was used in place of 1-chloro-2, 3-difluoro-4-nitrobenzene in step a.¹H NMR(400MHz,DMSO-d₆)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, 6.1Hz,1H),2.66(dd,J＝10.7,3.0Hz,1H),2.34(dd,J＝9.9,5.0Hz,1H),2.25(s,3H).¹⁹F NMR (376MHz,DMSO-d₆)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-carboxylic acid tert-butyl ester

Under the protection of nitrogen, 4- (8-bromo-2-chloro-3-cyano-4-quinolyl) 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, 66.2mmol) in MeCN (1700mL)/H₂To the O (400mL) solution, K was added₂CO₃(14.1g, 102mmol) and Pd (PPh)₃)₄(2.94g,2.55 mmol). The resulting mixture was heated to 40 ℃ for 24h and LCMS monitored for completion. Concentrating the mixture under reduced pressure to remove CAN, adding H₂O (500mL), DCM (1000 mL. times.2) and the combined organic phases were dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to obtainCrude product, FCC (SiO)₂EA/PE ═ 0-50%) to give tert-butyl 4- (8-bromo-3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate as a yellow solid (39g, 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-carboxylic acid tert-butyl ester

Tert-butyl 4- (8-bromo-3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (34g, 60.4mmol) was dissolved in H₂O (600mL) and 1, 4-dioxane (600 mL). KOH (13.6g, 242mmol), Pd was added under nitrogen₂dba₃(1.11g, 1.21mmol) and tBuXphos (1.54g, 3.63 mmol). The resulting mixture was heated to 90 ℃ and stirred for 2 h. The solvent was removed by concentration under reduced pressure, and the mixture was cooled to room temperature, adjusted to pH 7 with 1N hydrochloric acid, and the system was extracted with DCM (500mL × 2). The combined organic phases were washed with saturated brine (500mL) and dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to obtain crude product, and FCC (SiO)₂EA/PE 0-40%) to give a pale yellow solid (12.1g, 40% yield). LCMS (M/z):500.2(M + H).

Example A121

4- (4-acryloylpiperazin-1-yl) -8- ((2-amino-7-fluoropheno [ 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-fluorophenothiazol-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, a round-bottomed flask containing magnetons was charged with tert-butyl 4- (8-bromo-3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (intermediate A15, 300mg,0.53mmol), (7-fluoro-4-hydroxybenzo [ d ] b]Thiazol-2-yl) carbamic acid tert-butyl ester (230mg,0.81mmol), CuI (21mg,0.11mmol), N¹-benzyl-N²- (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (73mg,0.21mmol), potassium carbonate (221mg,1.60 mmol). After purging with nitrogen three times, DMSO (3ml) was added, and the reaction was heated to 100 ℃ and stirred for 16 hours. After LCMS monitoring reaction, pouring the reaction liquid into water, and filtering to obtain crude product of FCC (SiO)₂EA/PE ═ 0-80%) to give tert-butyl 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-carboxylate (150mg, yield 37%). LCMS (M/z):766.3(M + H).

Step B and step C: 4- (4-acryloylpiperazin-1-yl) -8- ((2-amino-7-fluoropheno [ d ] thiazol-4-yl) oxy) -2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinoline-3-carbonitrile

Subsequent synthesis of example a121 reference was made to the procedure described in example A1 using tert-butyl 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-carboxylate in step B instead of tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate. ¹H NMR(400MHz,DMSO-d₆)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＝7.6Hz,1H),6.18(d,J＝ 16.6Hz,1H),5.74(d,J＝10.4Hz,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

Synthesis of example a122 as described for the synthesis of example a121, in step a 7-fluoro-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol was used instead of (7-fluoro-4-hydroxybenzo [ d [ -d ]]Thiazol-2-yl) carbamic acid tert-butyl ester.¹H NMR (400MHz,Methanol-d₄)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＝11.2Hz,1H),6.97(d,J＝7.9Hz,1H),6.88(dd,J＝16.8,10.6Hz,1H),6.30(d,J＝ 16.7Hz,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

Synthesis of tert-butyl 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-carboxylate As described in reference example A121, tert-butyl (7-fluoro-4-hydroxybenzo [ d ] thiazol-2-yl) carbamate was replaced in step A with 2- ((4-methoxybenzyl) oxy) -6-methylquinolin-5-ol.

And B: 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

Tert-butyl 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-carboxylate (130mg,0.167mmol) was dissolved in 1mL of TFA and heated to 120 ℃ by microwave for 1 h. The crude product obtained after desolventizing was used directly in the next reaction.

And 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 As described in reference example A1, 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 was used instead of (S) -8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) quinoline-3-carbonitrile.¹H NMR(400MHz,DMSO-d₆)δ11.91(s,1H), 8.33(s,2H),7.83(d,J＝8.5Hz,1H),7.60(d,J＝9.7Hz,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＝16.7,10.5Hz,1H),6.68 (d,J＝7.8Hz,1H),6.41(d,J＝9.8Hz,1H),6.19(dd,J＝16.7,2.4Hz,1H),5.75(dd,J＝10.4,2.4 Hz,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, a reaction flask with a lid and equipped with magnetons was charged with tert-butyl 4- (3-cyano-8-hydroxy-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (intermediate A16, 50mg,0.1mmol), 6-bromo-5-methylpyrazin-2-amine (23mg, 0.12mmol), CuI (19mg,0.1mmol), N ¹-benzyl-N²- (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (21mg, 0.06mmol), K₃PO₄(64mg,0.3 mmol). After purging with nitrogen three times, DMSO (2ml) was added, and the reaction was heated to 120 ℃ and stirred for 16 hours. After completion of the reaction was monitored by LCMS, the reaction mixture was poured into water (6mL), EA (6 mL. times.3) was extracted, and the organic phases were combined, washed with saturated brine (10 mL. times.3), and dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to obtain crude product, and treating with FCC (SiO)₂MeOH/DCM ═ 0-20%) to give 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

Subsequent synthesis of example a124 as described in example A1, tert-butyl 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-carboxylate was used in step B instead of tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate. ¹H NMR (400MHz, methanol-d)₄)δ8.10(d,J＝8.2Hz,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 of examples A125-127 was carried out as described 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-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

At room temperature, a reaction flask with a cover and a magneton was charged with tert-butyl 4- (3-cyano-8-hydroxy-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (intermediate A16, 100mg,0.2mmol), 4-chloro-5-methylpyrimidin-2-amine (34mg,0.24mmol), Ag₂O (73.8mg,0.6mmol), DMF (5 ml). The resulting mixture was heated to 120 ℃ and the reaction was stirred. After completion of the reaction was monitored by LCMS, the reaction mixture was poured into water (15 mL. times.3), EA (15 mL. times.3) was extracted, and the organic phases were combined, washed with saturated brine (15 mL. times.3), and dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to obtain crude product, and treating with FCC (SiO)₂MeOH/DCM ═ 0-20%) to give 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

Subsequent synthesis of example a128 as described in example A1, tert-butyl 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-carboxylate was used in step B instead of tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate. 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-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3-cyano-8-hydroxy-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (intermediate A16, 200mg,0.400mmol) and 6-amino-3-chloro-2-fluorobenzonitrile (102mg,0.598mmol) in DMF (3mL) at room temperature was added K ₂CO₃(166mg,1.20 mmol). The mixture was heated to 60 ℃ and stirred for 16 h. After cooling to room temperature, the mixture is poured into H₂O (30mL) and extracted with EA (8 mL. times.3). The organic phase was washed with saturated aqueous NaCl solution (8 mL. times.2) and anhydrous Na₂SO₄Drying, FCC purification (SiO)₂EA/PE ═ 0-100%) to give 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 as a pale yellow solid (140mg, 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

Subsequent synthesis of example a129 tert-butyl 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-carboxylate was used in step B instead of tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate, as described in example A1.¹H NMR(400MHz,DMSO-d₆)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＝9.2Hz,1H),6.52(s,2H),6.18(dd,J＝16.7,2.4 Hz,1H),5.75(dd,J＝10.5,2.4Hz,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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3-cyano-8-hydroxy-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (intermediate A16, 800mg,1.60mmol) and 3-fluoro-4-methyl-2-nitroaniline (408mg,2.40mmol) in DMF (10mL) at room temperature was added K₂CO₃(662mg,4.80 mmol). The mixture was heated to 60 ℃ and stirred for 16 h. After cooling to room temperature, the mixture is poured into H₂O (100mL) and extracted with EA (30 mL. times.3). The organic phase was washed with saturated aqueous NaCl solution (20X 2mL) and anhydrous Na₂SO₄Drying, FCC purification (SiO)₂EA/PE ═ 0-100%) to give 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 as a pale yellow solid (650mg, yield 62%). LCMS (M/z):650.5(M + H).

And B: 4- (3-cyano-8- (2, 3-diamino-6-methylphenoxy) -2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 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-carboxylate (400mg,0.61mmol) and ammonium chloride (132mg,2.47mmol) in MeOH (10mL) at room temperature was added iron powder (103mg,1.84 mmol). The mixture was heated to 80 ℃ and stirred for 16 h. After cooling to room temperature and suction filtration, the filtrate was spin-dried and concentrated to give tert-butyl 4- (3-cyano-8- (2, 3-diamino-6-methylphenoxy) -2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (340mg, 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-carbo-nitrile

Step A: 4- (3-cyano-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) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3-cyano-8- (2, 3-diamino-6-methylphenoxy) -2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (340mg,0.55mmol) in THF (5mL) at room temperature was added CDI (178mg, 1.10 mmol)mmol). The mixture was heated to 80 ℃ and stirred for 16 h. After cooling to room temperature, the mixture is poured into H₂O (20mL) and extracted with EA (10 mL. times.3). The organic phase was washed with saturated aqueous NaCl solution (5 mL. times.2), anhydrous Na₂SO₄Drying and concentrating to obtain 4- (3-cyano-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) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (200mg, 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-carbo-nitrile

Subsequent Synthesis of example A130 As described in example A1, 4- (3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) -8- ((5-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] is used in step B]Imidazol-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.¹H NMR(400MHz,DMSO-d₆)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-benzimidazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3-cyano-8- (2, 3-diamino-6-methylphenoxy) -2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (180mg,0.29mmol) and trimethyl orthoformate (62mg,0.58mmol) in THF (3mL) at room temperature was added dropwise one drop of concentrated hydrochloric acid. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was poured into H₂O (10mL) and extracted with EA (5 mL. times.3). The organic phase was washed with saturated aqueous NaCl solution (5 mL. times.2), anhydrous Na ₂SO₄Drying and concentration gave tert-butyl 4- (3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) -8- ((5-methyl-1H-benzimidazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (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

Subsequent synthesis of example a130 the procedure described in example A1 was followed, using tert-butyl 4- (3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) -8- ((5-methyl-1H-benzimidazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate in step B instead of tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate.¹H NMR(400MHz,DMSO-d₆)δ12.53(s,1H),8.11–8.01(m,1H),7.79(dd,J ＝17.3,8.6Hz,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-benzo [ d ] [1,2,3] triazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4- (3-cyano-8- (2, 3-diamino-6-methylphenoxy) -2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (180mg,0.29mmol) and sodium nitrite (40mg,0.58mmol) in THF (3mL) at room temperature was added dropwise one drop of glacial acetic acid. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was poured into H ₂O (10mL) and extracted with EA (5 mL. times.3). The organic phase was washed with saturated aqueous NaCl solution (5 mL. times.2), anhydrous Na₂SO₄Drying and concentrating to obtain 4- (3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) -8- ((5-methyl-1H-benzo [ d)][1,2,3]Triazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (150mg, 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

Subsequent Synthesis of example A130 As described in example A1, 4- (3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) -8- ((5-methyl-1H-benzo [ d ] is used in step B][1,2,3]Triazol-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.¹H NMR(400MHz,DMSO-d₆)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, 2.4Hz,1H),5.76(dd,J＝10.4,2.4Hz,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

To a mixed solution of tert-butyl 4- (3-cyano-8- (2, 3-diamino-6-methylphenoxy) -2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinolin-4-yl) piperazine-1-carboxylate (530mg,0.85mmol) in methanol and water (v/v ═ 1:1,6mL) was added bromoacetonitrile (113mg,0.94mmol) at room temperature. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the mixture was poured into H₂O (20mL) and extracted with EA (10 mL. times.3). The organic phase was washed with saturated aqueous NaCl solution (5 mL. times.2), anhydrous Na₂SO₄Drying and concentrating to obtain 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 (120mg, yield 22%). 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

Subsequent Synthesis of example A130 As described in example A1, 4- (8- ((2-amino-5-methyl-1H-benzo [ d ] is used in step B]Imidazol-4-yl) oxy) -3-cyano-2- (2-methyl-1, 2,3, 4-tetrahydroisoquinolin-5-yl) quinoline-tert-butyl quinolin-4-yl) piperazine-1-carboxylate instead of tert-butyl (S) -4- (3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) quinolin-4-yl) piperazine-1-carboxylate. ¹H 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 of examples A134-135 was carried out as described in example A19.

Synthesis of intermediate A18

4- (2-chloro-3-cyano-6-fluoro-8- (2-fluoro-6-methoxyphenoxy) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Step A: 2-amino-5-fluoro-3- (2-fluoro-6-methoxyphenoxy) benzoic acid methyl ester

Methyl 2-amino-3-bromo-5-fluorobenzoate (1.0g,4.03mmol), 2-fluoro-6-methoxyphenol (688mg,4.84mmol), CuI (153mg,0.81mmol), N¹-benzyl-N²- (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (555mg,1.62mmol), K₂CO₃(2.14g,12.09mmol) was dissolved in DMSO (10mL), replaced with nitrogen twice, and the temperature was raised to 100 ℃ for reaction for 24 hours. After the reaction is finished, the reaction is carried outPouring the reaction solution into water (100mL), extracting with ethyl acetate (50mL × 3), collecting extractive solution, concentrating to obtain crude product, and FCC (SiO)₂EA/PE ═ 0-25%) to give methyl 2-amino-5-fluoro-3- (2-fluoro-6-methoxyphenoxy) benzoate (1.6g, crude) as a brown solid. 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-carboxylic acid tert-butyl ester

Subsequent synthetic steps of intermediate a18 were performed as described in the synthesis of intermediate a 1. LCMS (M/z):531.3(M + H).

Example A136

Synthesis of example a136 as described for the synthesis of example a116, tert-butyl 4- (2-chloro-3-cyano-6-fluoro-8- (2-fluoro-6-methoxyphenoxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a18) was used in step a instead of tert-butyl 4- (2-chloro-8- (3-chloro-2-fluoro-6-methoxyphenoxy) -3-cyanoquinolin-4-yl) piperazine-1-carboxylate (intermediate a 10).¹H NMR(400MHz, DMSO-d₆)δ7.47–7.33(m,1H),7.18–7.06(m,1H),6.96–6.78(m,4H),6.19(dd,J＝16.6,2.4 Hz,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).¹⁹F NMR(376MHz,DMSO-d₆)δ-113.41,-130.70.LCMS(m/z):566.5 (M+H).

Synthesis of intermediate A19

4- (8-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Synthesis of intermediate a19 as described for the synthesis of intermediate a13, methyl 2-amino-3-bromo-5-fluorobenzoate was used instead of methyl 2-amino-3-bromobenzoate in step a. 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) quinolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Step a tert-butyl 4- (8-bromo-2-chloro-3-cyano-6-fluoroquinolin-4-yl) piperazine-1-carboxylate (intermediate a19) was used instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate a1) and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol was used instead of (S) - (1-methylpyrrolidin-2-yl) methanol, as described in example a1 step a. LCMS (M/z):564.2,566.2(M + H).

And 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

To a round bottom flask with magnetons placed at room temperature was added tert-butyl 4- (8-bromo-3-cyano-6-fluoro-2- ((3R,4R) -4-methoxy-1-methylpyrrolidin-3-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (250mg,0.44mmol), 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol (205mg,0.88mmol), CuI (16.8mg,0.88mmol), N¹-benzyl-N²- (5-methyl- [1,1' -biphenyl)]-2-yl) oxamide (36.6mg,0.10mmol), potassium carbonate (183.6mg,1.32 mmol). After purging with nitrogen three times, DMSO (3ml) was added, and the reaction was heated to 100 ℃ and stirred for 16 hours. After LCMS monitoring reaction, pouring the reaction liquid into water, and filtering to obtain crude product of FCC (SiO)₂EA/PE ═ 0-80%) purification,tert-butyl 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-carboxylate (40mg, yield 12.6%) was obtained. 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

Example a137 subsequent synthetic procedure the use of tert-butyl 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-carboxylate 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 was described in example A1, step B and step C -1-carboxylic acid tert-butyl ester.¹H 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, 2.0Hz,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

4- (2-chloro-3-cyano-8- (2-fluoro-6-methoxyphenoxy) -1, 7-naphthyridin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Synthesis of intermediate a20 as described for the intermediate synthesis, methyl 2-chloro-3-nitrosoisonicotinate was used in step a instead of methyl 3-fluoro-2-nitrobenzoate; and 2-fluoro-6-methoxyphenol 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol was used. 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-methylpyrrolidin-3-yl) oxy) -1, 7-naphthyridine-3-carbonitrile

Synthesis of example a138 as described for the synthesis of example A1, tert-butyl 4- (2-chloro-3-cyano-8- (2-fluoro-6-methoxyphenoxy) -1, 7-naphthyridin-4-yl) piperazine-1-carboxylate (intermediate a20) was used in step a instead of tert-butyl 4- (2-chloro-3-cyano-8- ((5-methyl-1H-indazol-4-yl) oxy) quinolin-4-yl) piperazine-1-carboxylate (intermediate A1), and (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol is used instead of (S) - (1-methylpyrrolidin-2-yl) methanol. ¹H NMR(400MHz,DMSO-d₆)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 ＝16.6,2.4Hz,1H),5.75(dd,J＝10.4,2.3Hz,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).

The following examples a139 to a145 compounds were also prepared and characterized according to a method analogous to the synthesis of the example a series of compounds described above:

synthesis of intermediate B-1

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

Step A4- ((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 a solution of 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol in THF (15 mL). The mixture was stirred at r.t. for 2 h. After TLC monitoring was complete, the mixture was diluted with EA (50mL), washed with saturated aqueous NaCl (3 × 30mL) and washed with anhydrous Na₂SO₄And (5) drying. The mixture was concentrated under reduced pressure and the crude product was purified by FCC (EA/PE ═ 0-30%) to give a yellow solid 4- ((2-chloro-3-nitropyridin-4-yl) oxy) -5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H indazole (2.66g, 88% yield). LCMS (M/z):389.1(M + H).

Step B4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -3-nitropyridinecarbonitrile

In N₂Under 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)、Pd₂(dba)₃A solution of (118mg, 0.128mmol) and Xant Phos (149mg, 0.257mmol) in NMP (5mL) was microwaved at 150 ℃ for 0.5 h. After completion of TLC monitoring, the mixture was filtered through Celite and washed with H₂The filtrate was treated with O (20mL) and extracted with EA (3 × 25 mL). The resulting organic phase was washed with saturated aqueous NaCl (3X30mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude product was purified by FCC (EA/PE ═ 0-30%) to give 4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -3-nitropyridinenitrile (0.83g, 85% yield) as a yellow solid. LCMS (M/z):380.1(M + H),402.1(M + Na).

Step C3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridinecarbonitrile

To a solution of 4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -3-nitromethylpyridinecarbonitrile (1.09g, 2.87mmol) in THF/EtOH (18mL, 1:1) at 0 deg.C was added Na rapidly₂S₂O₄(2.98g, 17.24mmol) of H₂O (9mL) solution. After the reaction system was stirred at 0 ℃ for 15min, the mixture was diluted with EA (50mL) and successively with H₂O (30mL) wash, saturated aqueous NaCl solution (30mL) wash, anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the product was purified by FCC (MeOH/DCM ═ 1% to 10%) to give 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridinecarbonitrile as a yellow solid (0.82g, yield 81%). LCMS (M/z):350.3(M + H).

Step D8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyrido [3,2-D ] pyrimidine-2, 4-dithiol

At room temperature, adding CS₂(3.92g, 51.5mmol) was added to 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridine carbonitrile (1.8g, 5.15mmol) and K₂CO₃(2.14g, 15.5mmol) in DMSO (11mL) and then heated to 50 ℃ and stirred for 3 h. After completion, the mixture was cooled to room temperature and poured into H with vigorous stirring₂O (75 mL). The resulting clear solution was adjusted to pH 7 with 1N aqueous HCl and the precipitate formed was collected by filtration. The filter cake was washed with water and dried in vacuo to give 8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridine [3,2-d as a dark green solid]Pyrimidine-2, 4-dithiol (1.62g, 73% yield). LCMS (M/z):426(M + H).

Step E8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2, 4-bis (methylthio) pyridine [3,2-d ] pyrimidine

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

Step F tert-butyl 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-carboxylate

Reacting 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 K₂CO₃A solution of (490mg, 3.53mmol) in DMSO (3mL) was heated to 120 ℃ and stirred for 23 h. The mixture was then cooled to room temperature, poured into ice water (20mL) and extracted with EA (3 × 20 mL). The resulting organic phase was washed with saturated aqueous NaCl (3 × 20mL) and with anhydrous Na₂SO₄And (5) drying. The solvent was removed in vacuo and the resulting crude was purified by preparative TLC (MeOH/DCM ═ 1:20) to give 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylthio) pyridine [3, 2-d) as a yellow solid]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (262mg, yield 40%). LCMS (M/z):592.3(M + H).

Step G tert-butyl 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylsulfonyl) pyridine [3,2-d ] pyrimidin-4-yl) piperazine-1-carboxylate

4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylthio) pyridine [3, 2-d) at 0 ℃ ]A solution of t-butyl pyrimidin-4-yl) piperazine-1-carboxylate (380mg, 0.64mmol) in DCM (5mL) was added to a solution of mCPBA (148mg,0.64mmol) in DCM (3 mL). The resulting mixture was stirred at 0 ℃ for 30min, then r.t. for 1 h. After completion of LCMS monitoring, the mixture was diluted with DCM (30mL) and in turn saturated Na₂S₂O₃Aqueous solution (20mL), saturated NaHCO₃Aqueous solution (20mL), saturated aqueous NaCl solution (20mL) wash, anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure to give 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) as a yellow solid) -2- (methylsulfonylidene) pyrido [3,2-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (390mg, crude) was 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 tert-butyl 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-carboxylate

NaH (38.5mg,0.96mmol) was added to a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (110.9mg, 0.96mmol) in THF (2mL) at room temperature. Stirring at room temperature for 30min, and adding 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylsulfonyl) pyridine [3,2-d ]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (390mg, 0.64mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for a further 1 h. The reaction was then diluted with EA (30mL) and washed with saturated aqueous NaCl (2X20mL) and anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure to give crude 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]T-butyl pyrimidin-4-yl) piperazine-1-carboxylate (422mg, crude) was directly charged 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

TFA (2.4mL) was added to a solution of tert-butyl 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-carboxylate (422mg, 0.64mmol) in DCM (6mL) at room temperature. The reaction was stirred at room temperature for 1H and concentrated under reduced pressure to give (S) -8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) pyridine [3,2-d ] pyrimidine (377mg, crude) as a dark yellow solid which was directly charged to the next step. LCMS (M/z):475.3(M + H).

Step C (S) -1- (4- (8- ((5-methyl-1H-indazozol-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

A solution of acryloyl chloride (32.7mg, 0.75mmol) in DCM (2mL) 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 at 0 deg.C]Pyrimidine (304mg, 0.64mmol) and DIEA (407mg, 6.4mmol) in DCM (5 mL). The resulting mixture was stirred at 0 ℃ for 50 min. The mixture was diluted with EA (30mL) and H₂O (20mL), saturated aqueous NaCl (2X20mL) and anhydrous Na₂SO₄And (5) drying. The solvent was removed under reduced pressure and the crude product was purified by preparative high performance liquid chromatography to give (S) -1- (4- (8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyridine [3,2-d as a white solid]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one formate (50mg, yield 15%).¹H NMR(400MHz,Methanol-d₄)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＝16.8,10.6 Hz,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-indazol-4-yl) oxy) pyridine [3,2-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Preparation of example B2 as described for the synthesis of example B1, (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol was used in step a instead of (S) - (1-methylpyrrolidin-2-yl) methanol. ¹H NMR(400MHz,Methanol-d₄)δ8.34(d,J＝ 5.0Hz,1H),7.66(s,1H),7.54–7.35(m,2H),6.86(dd,J＝16.8,10.6Hz,1H),6.60(d,J＝5.0Hz, 1H),6.29(dd,J＝16.8,2.0Hz,1H),5.82(dd,J＝10.7,2.0Hz,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- (methylsulfinylidene) pyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester

Step A3-bromo-5-fluoroisonicotinic acid ethyl ester

In N₂LDA (1.58g, 14.77mmol) was added to a solution of 3-bromo-5-fluoropyridine (2.0g, 11.36mmol) in anhydrous THF (18mL) cooled to-78 deg.C under an atmosphere. The mixture was stirred at-78 ℃ for 45 min. Ethyl thiocyanate (1.24g, 12.50mmol) was slowly added dropwise to the above solution at the same temperature, and then the mixture was stirred at-78 ℃ for 20 min. With saturated NaHCO₃The reaction was quenched with aqueous solution (5mL) and extracted with EA (2 × 15 mL). The organic layer was washed with anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude product was purified by FCC (EA/PE ═ 0-7%) to give ethyl 3-bromo-5-fluoroisonicotinate as a pale yellow oil (2.2g, yield 78%). 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) isonicotinite

Ethyl 3-bromo-5-fluoroisonicotinite (1g, 4.03mmol), 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol (1.03g, 4.43mmol) and Cs₂CO₃The mixture in anhydrous DMF (10mL) was stirred at 100 ℃ for 16 h. After completion, the mixture was filtered. The filtrate was diluted with EA (20mL), washed with saturated aqueous LiCl (2X15mL) and anhydrous Na ₂SO₄And (5) drying. Filtration and concentration under reduced pressure, and the crude product purified by FCC (EA/PE ═ 0-15%) gave ethyl 3-bromo-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) isonicotinate (1.5g, yield 80%) as a pale yellow oil. LCMS (M/z):460.1, 462.1(M + H).

Step C3-bromo-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) isonicotinic acid

To a solution of 3-bromo-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazon-4-yl) oxy) isonicotinic acid ethyl ester (1.5g, 3.26mmol) in anhydrous EtOH (5mL) was added LiOH (390mg, 16.29mmol) in H₂O (5mL) solution. The resulting mixture was stirred at 70 ℃ for 1 h. After completion, the mixture was concentrated to remove EtOH and the residual liquid was adjusted to pH 7-8 with 4N aqueous HCl. 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) oxy) isonicotinic acid as a white solid (1.0g, 71% yield). LCMS (M/z):432.1, 434.1(M + H).

Step D3-bromo-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridin-4-amine

To a solution of 3-bromo-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazox-4-yl) oxy) isonicotinic acid (1.5g, 3.50mmol) in toluene (10mL) was added TEA (1.9 mL). The mixture was stirred at r.t. until the solid was completely dissolved. DPPA (2.89g, 10.5mmol) and H were then added ₂O (5 mL). The mixture was stirred at 100 ℃ for 16h before extraction with EA (2 × 15 mL). The resulting organic phase was washed with saturated aqueous NaCl solution (2X10mL), anhydrous Na₂SO₄And (5) drying. Filtering, concentrating, and purifying with FCC (EA/PE 0-40%) to obtain white solid 3-bromo-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl)) -1H-indazol-4-yl) oxy) pyridin-4-amine (650mg, yield 46%). LCMS (M/z):403.2,405.2(M + H).

Step E4-amino-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) nicotinonitrile

Reacting 3-bromo-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridin-4-amine, Zn (CN)₂(175mg, 1.49mmol),Pd₂(dba)₃A solution of (68mg,0.075mmol) and Xant-Phos (86mg,0.149mmol) in NMP (5mL) was microwaved to 150 ℃ for 1 h. The reaction was diluted with EA (15mL) and washed with saturated aqueous LiCl (2 × 10 mL). Organic phase with FCC (SiO)₂EA/PE ═ 0-50%) purified to give 4-amino-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) nicotinonitrile as a white solid (500mg, 96% yield). LCMS (M/z):350.3(M + H).

Step F8- ((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, adding K₂CO₃(521mg,3.77mmol) and CS ₂(957mg,12.57mmol) was added to a solution of 4-amino-5- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) nicotinonitrile (440mg,1.26mmol) in DMSO (3 mL). The reaction mixture was stirred at 50 ℃ for 2H, cooled to room temperature and poured H₂In O (20mL), a precipitate was formed by stirring for 30 min. The precipitate was collected by filtration and dried in vacuo to give 8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridine [4,3-d as a yellow solid]Pyrimidine-2, 4(1H, 3H) -dithione (530mg, yield 99%). LCMS (M/z):426.1(M + H).

Step G8- ((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, adding CH₃I (386.9mg,2.73mmol) was added dropwise to 8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyridine [4,3-d]Pyrimidine-2, 4(1H, 3H) -dithione (580mg,1.36mmol), 1N NaOH (1.6mL) and H₂O (2 mL). The mixture was stirred at room temperature for 2 h. Followed by extraction with EA (2 × 15 mL). The combined organic phases were washed with brine and anhydrous Na₂SO₄Drying, filtering and concentratingCondensed with FCC (SiO)₂EA/PE ═ 0-50%) purified to give 8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2, 4-bis (methylthio) pyridine [4, 3-d) as a yellow solid ]Pyrimidine (300mg, yield 49%). LCMS (M/z):454.0(M + H).

Step H tert-butyl 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-carboxylate

At room temperature, adding K₂CO₃(91mg,0.66mmol) and piperazine-1-carboxylic acid tert-butyl ester (246mg,1.32mmol) 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). The reaction was stirred at 120 ℃ for 6 h. The reaction was then cooled to room temperature, diluted with EA (20mL) and washed with saturated aqueous LiCl (2 × 15 mL). Concentrating the organic phase and then using FCC (SiO)₂EA/PE ═ 0-60%) purified to give 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylthio) pyridine [4, 3-d) as an off-white solid]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (340mg, yield 87%). LCMS (M/z):592.2(M + H).

Step I tert-butyl 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylsulfonylidene) pyridine [4,3-d ] pyrimidin-4-yl) piperazine-1-carboxylate

mCPBA (103mg,0.51mmol) was added to 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylthio) pyridine [4,3-d ] at room temperature ]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (300mg,0.51mmol) in DCM (3 mL). The reaction was stirred at room temperature for 2h and then saturated Na was added₂SO₃The reaction was quenched with aqueous solution (20mL) and extracted with EA (10 × 2 mL). The organic phase was concentrated to give 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylsulfonylidene) pyridine [4, 3-d) as a yellow solid]Tert-butyl pyrimidin-4-yl) piperazine-1-carboxylate (210mg, 68% yield) was fed as crude product to 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-indazol-4-yl) oxy) pyridine [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Preparation of example B3 as described in reference example B1, in step a, 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylsulfonyl) 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- (methylsulfinylidene) pyridine [3,2-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate B1) with (3R,4R) -4-methoxy-1-methylpyrrolidin-3-ol instead of (S) - (1-methylpyrrolidin-2-yl) methanol. ¹H NMR(400MHz,Methanol-d₄)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 A1, 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 ℃ for 6 h. The reaction system was cooled to room temperature and poured into H₂In the presence of O (1000mL),a yellow precipitate formed. Filtering, collecting precipitate, and vacuum drying to obtain yellow solid 1, 7-dihydropyrimidine [5,4-d ]]Pyrimidine-2, 4,8(3H) -trione (19.7g, yield 75%). LCMS (M/z):181.1(M + H).

Step B2, 4, 8-trichloropyrimidine [5,4-d ] pyrimidine

1, 7-dihydropyrimidine [5,4-d ]]Pyrimidine-2, 4,8(3H) -trione (3.0g,16.6mmol), PCl₅(14.9g 71.6mmol) and POCl₃(100mL) the mixture was heated to 120 ℃ and stirred overnight. The reaction was concentrated under reduced pressure and poured into a mixture of ice water (200 mL). The resulting mixture was extracted with EA (3 × 100 mL). The organic layer was washed with saturated aqueous NaCl (3X100mL) and anhydrous Na₂SO₄Drying, filtering and concentrating under reduced pressure. The obtained crude product is treated with FCC (SiO)₂EA/PE ═ 0-5%) to give 2,4, 8-trichloropyrimidine [5,4-d ] as a pale yellow solid]Pyrimidine (2.2g, yield 56.4%). LCMS (M/z):235.1(M + H).

Step C tert-butyl 4- (2, 8-dichloropyrimidine [5,4-d ] pyrimidin-4-yl) piperazine-1-carboxylate

TEA (2.14g,21.2mmol) was added to 2,4, 8-trichloropyrimidine [5,4-d ] at room temperature]Pyrimidine (2.0g,8.4mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.42g,7.6mmol) in THF (30mL) and the mixture was stirred at room temperature for 2 h. After TLC monitoring the reaction was complete, the system was poured into a mixture of ice water (200mL) and extracted with EA (3 × 100 mL). The combined organic phases were washed with saturated aqueous NaCl (3X100mL) and anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The crude product is treated with FCC (SiO)₂EA/PE ═ 0-20%) purified to give a pale yellow solid (2.7g, 84% yield). LCMS (M/z):385.2(M + H).

Step D4- (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, adding Cs₂CO₃(1.26g,3.89mmol) was added to 4- (2, 8-dichloropyrimidine [5,4-d ]]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.0g,2.59mmol) and 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol (542.8mg, 2.3mmol) in DMA (5 mL). The reaction mixture was stirred at 60-80 ℃ overnight. The reaction was poured into a mixture of ice water (200mL) and extracted with EA (3 × 100 mL). The organic phases are combined Washed with saturated aqueous NaCl (2X100mL) anhydrous Na₂SO₄And (5) drying. Filtering, concentrating, and treating with FCC (SiO)₂EA/PE ═ 0-20%) purified to give 4- (2-chloro-8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) pyrimidine [5, 4-d) as a pale yellow solid]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-indazozol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin [5,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Step A tert-butyl 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-carboxylate

(S) - (1-methylpyrrolidin-2-yl) methanol (198mg 1.72mmol) and K are added at room temperature₂CO₃(237.8mg,1.72mmol) was 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-carboxylic acid tert-butyl ester (500mg,0.86mmol) in DMF (5mL) and the reaction was stirred at 80 ℃ overnight. After completion of the reaction, it was cooled to room temperature, poured into a mixture of ice and water (100mL) and extracted with EA (3 × 50 mL). The organic phase was washed with saturated aqueous NaCl (2 × 50mL), anhydrous Na ₂SO₄Drying, filtering, and concentrating under reduced pressure. The obtained crude product is treated with FCC (SiO)₂EA/PE ═ 0-100% and MeOH/DCM ═ 10% in this order) to afford 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) as a pale yellow solid]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (200mg, yield 35%). LCMS (M/z):660.0(M + H).

Steps B and C (S) -1- (4- (8- ((5-methyl-1H-indazozol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin [5,4-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

Subsequent synthesis of example B4 referring to example B1, 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 ] pyrimidine was used in step B]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester 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.¹H NMR (400MHz, methanol-d)₄)δ8.50(s,1H),8.43(s,1H),7.74(d,J＝1.0Hz,1H),7.47–7.44(m,1H),7.40–7.37(m,1H),6.83 (dd,J＝16.8,10.6Hz,1H),6.28(dd,J＝16.7,1.9Hz,1H),5.81(dd,J＝10.6,1.9Hz,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, to 4- (2, 8-dichloropyrimidine [5,4-d ]]To a solution of tert-butyl pyrimidin-4-yl) piperazine-1-carboxylate (1.0g, 2.59mmol) and 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (539.9mg, 2.33mmol) in DMA (5mL) was added DIEA (671mg, 5.19 mmol). The mixture was stirred at 100 ℃ overnight. After completion, the mixture was poured into ice water (200mL) and extracted with EA (3 × 100 mL). The organic phase obtained is washed with saturated aqueous NaCl solution (2X100ml) and driedNa₂SO₄Dried, filtered and concentrated under reduced pressure. Subjecting the crude product to FCC (SiO)₂EA/PE ═ 0-20%) purified to give 4- (2-chloro-8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) amino) pyrimidine [5, 4-d) as a pale yellow solid]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (1.2g, yield 80%). LCMS (M/z):580.3(M + H).

Example B5

(S) -1- (4- (8- ((5-methyl-1H-indazozol-4-yl) amino) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin [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- (methylsulfinylidene) pyridine [3,2-d ]Pyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate B1).¹H 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＝16.7,10.6Hz,1H),6.27(dd,J＝ 16.8,1.9Hz,1H),5.80(dd,J＝10.6,2.0Hz,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 diformate

Step A4, 5-dibromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one

4, 5-dibromopyridin-3 (2H) -one (5) (50.0g, 196.94mmol), 4-methoxybenzyl chloride (32.39, 206.79mmol), tetrabutylammonium bromide (3.17g, 9.85mmol) and K₂CO₃A solution of (54.44g, 393.89mmol) in MeCN (500mL) was stirred at 60 ℃ 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 was sonicated in MeOH, and the solid was collected by filtration. The resulting solid was washed with a small amount of MeOH and dried in vacuo to give 4, 5-dibromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (50.0g, yield 68%) as a light brown solid.¹H NMR (400MHz, chloroform-d) δ ppm 7.78(1H, s),7.40(2H, d, J ═ 8.6Hz),6.85(2H, d, J ═ 8.8Hz),5.25(2H, s),3.78(3H, s); LCMS (M/z):373.0(M + H).

Step B4-amino-5-bromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one

The reaction mixture was charged with 4, 5-dibromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (15.0g,40.10mmol) and NH ₃A sealed tube of-MeOH (80mL, 7mol/L) was heated to 90 deg.C, stirred for 18h and then slowly cooled to room temperature. The reaction was filtered and the filter cake was washed with MeOH. The resulting solid was dried in vacuo to give 4-amino-5-bromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (5.0g, 40% yield) as a yellow solid. LCMS (M/z):310.0(M + H).

Step C5-amino-1- (4-methoxybenzyl) -6-oxo-1, 6-dihydropyridazine-4-carbonitrile

To a solution of 4-amino-5-bromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (1.50g, 4.84mmol) in DMF (12mL) was added cuprous cyanide (0.519g, 5.80mmol) to the microwave tube. The reaction was heated in a microwave oven at 200 ℃ for 1 h. Then adding FeCl₃(10.0g), concentrated HCl (12N, 3.0mL) in H₂O (50mL) solution and stirred at 70 ℃ for 15min, then cooled to room temperature. The mixture was filtered and the solid was washed with water to give 5-amino-1- (4-methoxybenzyl) -6-oxo-1, 6-dihydropyridazine-4-carbonitrile (1.2g, yield 97%) as a yellow solid.¹H NMR(400MHz,CDCl₃)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 D7- (4-methoxybenzyl) -2, 4-dithio-1, 3,4, 7-tetrahydropyrimidin [4,5-D ] pyridazin-8 (2H) -one

In a 500mL glass reactor, anhydrous EtOH (60mL) and KOH (85% purity, 3.19g, 48.39mmol) were placed, and the mixture was heated to 25-30 ℃ to dissolve the KOH. Addition of CS ₂(3.68g, 48.39mmol) and the mixture was stirred at 25-30 ℃ for 0.5h to give a yellow suspension. 5-amino-1- (4-methoxybenzyl) -6-oxo-1, 6-dihydropyridazine-4-carbonitril-e (6.20g, 24.19mmol), 95% EtOH (60mL) and H₂O (12mL) was added to the mixture in succession. After refluxing for 21h, the mixture was cooled to room temperature. The mixture was filtered, the solid collected and washed with water. The solid was dried in vacuo to give 7- (4-methoxybenzyl) -2, 4-dithio-1, 3,4, 7-tetrahydropyrimidine [4,5-d ] as a yellow solid]Pyridazin-8 (2H) -one (8.0g crude, 99% yield). LCMS (M/z):333.0(M + H).

Step E7- (4-methoxybenzyl) -2, 4-bis (methylthio) pyrimidin-4, 5-d-pyridazin-8 (7H) -one

In a 500mL glass reactor, 7- (4-methoxybenzyl) -2, 4-dithio-1, 3, 4-, 7-tetrahydropyrimidinyl [4,5-d ] is placed in sequence]Pyridazine-8 (2H) -1(8g, 24.19mmol), H₂O (150mL) and NaOH (2.42g, 60.47mmol) were dissolved by heating to 25-30 ℃. MeI (6.87g, 48.38mmol) was then added to the mixture immediately. After stirring for 1h, the clear solution became cloudy. The mixture was filtered, the solid collected and washed with water. The resulting solid was dried in vacuo to give 7- (4-methoxybenzyl) -2, 4-bis (methylthio) pyrimidine [4,5-d as a yellow solid ]Pyridazin-8 (7H) -one (2.5g, 29% yield). LCMS (M/z):361.0(M + H).

Step F2, 4-bis (methylthio) pyrimidin-4, 5-d-pyridazin-8 (7H) -one

Cerium ammonium nitrate (19.01g, 34.68mmol) was added to 7- (4-methoxybenzyl) -2, 4-bis (methylthio) pyrimidine [4,5-d]Pyridazin-8 (7H) -ones (2.5g, 6.94mmol) in MeCN (200mL)/H₂O (40mL) mixture solution was stirred at room temperature for 18 h. The mixture was filtered, the precipitate collected and washed with water. The resulting solid was dried in vacuo to give 2, 4-bis (methylthio) pyrimidine [4,5-d as a yellow solid]Pyridazin-8 (7H) -one (1.5g,yield 90%). LCMS (M/z):241.0(M + H).

Step G8-chloro-2, 4-bis (methylthio) pyrimidine [4,5-d ] pyridazine

2, 4-bis (methylthio) pyrimidine [4,5-d]Pyridazin-8 (7H) -ones (1.10g,4.58mmol) with POCl₃(12mL) the mixture was heated to 125 ℃ and stirred for 16 h. Removing excess POCl under reduced pressure₃The obtained crude product is treated with FCC (SiO)₂EA/PE ═ 0-20%) purified to give 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 H8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2, 4-bis (methylthio) pyrimidine [4,5-d ] pyridazine

In the presence of 8-chloro-2, 4-bis (methylthio) pyrimidine [4,5-d]Pyridazine (270mg, 1.04mmol), 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol (218mg, 0.94mmol) in DMA (10mL) solution, Cs was added ₂CO₃(509mg, 1.57 mmol). The reaction system is stirred for 4H at room temperature, H is added₂O (10mL), extracted with EA (3X10 mL). The organic phase was washed with saturated aqueous NaCl solution, anhydrous Na₂SO₄Drying, filtering, concentrating under reduced pressure, and adding FCC (SiO)₂EA/PE ═ 0-30%) purified to give 8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2, 4-bis (methylthio) pyrimidine [4, 5-d) as a yellow solid]Pyridazine (370mg, yield 78%). LCMS (M/z):455.1(M + H).

Step I tert-butyl 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-carboxylate

Mixing Cs₂CO₃(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 piperazine-1-carboxylic acid tert-butyl ester (150mg, 0.805mmol) in DMA (10mL) and the mixture was stirred at room temperature for 18 h. Adding H into the system₂O (10mL) and extracted with EA (3 × 10 mL). The organic phase was washed with saturated aqueous NaCl solution, anhydrous Na₂SO₄Drying, filtering, concentrating, and adding FCC (SiO)₂EA/PE ═ 0-50%) purified to give 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran) as a yellow solid-2-yl) -1H-indazol-4-yl) oxy) -2- (methylthio) pyrimidine [4,5-d ]Pyridazin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (230mg, yield 48%). LCMS (M/z): 592.2(M + H).

Step J tert-butyl 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-carboxylate

To 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylthio) pyrimidine [4,5-d]To a solution of pyridazin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.337mmol) in DCM (10mL) was added mCPBA (209mg, 75% purity, 0.911mmol), and the mixture was stirred at room temperature for 2.5 h. DCM (20mL) was added and saturated NaHCO₃Aqueous (2 × 10mL) wash, then saturated aqueous NaCl, anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate, and FCC (SiO)₂EA/PE ═ 0-80%) purified to give 4- (8- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) -2- (methylsulfonyl) pyrimidine [4, 5-d) as a yellow solid]Pyridazin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (160mg, yield 84%). LCMS (M/z):625.2(M + H).

Step K tert-butyl 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-carboxylate

To a solution of (S) - (1-methylpyrrolidin-2-yl) methanol (48mg, 0.416mmol) in THF (5mL) at room temperature was added NaH (60%, 17mg, 0.416mmol) and stirred for 30 min. 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 (100mg, 0.19mmol) was added to the above solution, and the resulting mixture was stirred at room temperature for 1 h. Saturated aqueous NaCl (3 drops) was added to quench the reaction. The mixture is mixed with anhydrous Na₂SO₄Drying, concentrating to obtain crude product, and subjecting the crude product to FCC (SiO)₂MeOH/DCM ═ 0-10%) purified to give 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) pyrimidine as a yellow solid]Pyridazin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (100mg, 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

TFA (1mL) was added to a solution of tert-butyl 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-carboxylate (100mg, 0.151mmol) in DCM (2mL) at room temperature and the resulting mixture was stirred at room temperature for 1H. The solvent was removed by concentration under reduced pressure to give (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) as a pale yellow oil, which was directly charged to the next step. LCMS (M/z):476.2(M + H).

Step M (S) -1- (4- (8- ((5-methyl-1H-indazozol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidine [4,5-d ] pyridazin-4-yl) piperazin-1-yl) propan-2-en-1-one diformate

Reacting (S) -8- ((5-methyl-1H-indazol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) pyrimidine [4,5-d]A solution of pyridazine (72mg, 0.151mmol) and DIEA (97.95mg, 0.757mmol) in DCM (5mL) was stirred at room temperature for 10 min. After cooling to 0 deg.C, acryloyl chloride (13.72mg, 0.151mmol) was added dropwise and the resulting mixture stirred vigorously for 15 min. After the reaction was complete, saturated NaHCO was added₃Aqueous (5mL) and the reaction was extracted with DCM (3 × 10 mL). Washing the obtained organic phase with saturated NaCl aqueous solution (10mL), concentrating under reduced pressure, and purifying the crude product by preparative high performance liquid chromatography to obtain white solid (S) -1- (4- (8- ((5-methyl-1H-indazozol-4-yl) oxy) -2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidine [4,5-d]Pyridazin-4-yl) piperazin-1-yl) prop-2-en-1-one diformate (6mg, yield 7%).¹H NMR (400MHz, methanol-d)₄)δ 9.02(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＝10.6,1.9Hz, 1H),4.84(dd,J＝12.3,3.7Hz,1H),4.71(dd,J＝12.3,6.7Hz,1H),4.07(d,J＝5.9Hz,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-indazol-4-yl) oxy) thieno [3,2-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one

The synthesis of the compound methyl 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) thiophene-2-carboxylate is described in reference to step a of example a 81. LCMS (M/z):388.2(M + H).

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

To a solution of methyl 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) thiophene-2-carboxylate (380mg,0.98mmol) in THF (5mL) and water (1mL) was added lithium hydroxide (47mg,1.96mmol) at room temperature. The mixture was heated to 70 ℃ and stirred for 2 h. After cooling to room temperature, extraction with EA (10 mL. times.3) and washing of the organic phase with saturated aqueous NaCl solution (10mL) anhydrous Na₂SO₄Drying, spin-dry concentration afforded 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) thiophene-2-carboxylic acid as a yellow solid (360mg, 98% yield). LCMS (M/z) 374.1(M + H)

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

To 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) thiophene-2-carboxylic acid (360mg,0.96mmol), ammonium chloride (10mg,1.93mmol), DIPEA (478uL,2.89 mm) at room temperature ol) in DMF (4mL)) was added HATU (550mg,1.44 mmol). The mixture was heated to 50 ℃ and stirred for 2 h. After cooling to room temperature, the mixture was poured into water (20mL), extracted with EA (10 mL. times.3), and the organic phase was washed with saturated aqueous NaCl (10mL), anhydrous Na₂SO₄Dried, concentrated by rotary drying to give 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) thiophene-2-carboxamide (340mg, yield 95%) as a yellow liquid. 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

To a solution of 3-amino-4- ((5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxy) thiophene-2-carboxamide (340mg,0.91mmol) in DMF (4mL) was added CDI (740mg,4.56mmol) at room temperature. The mixture was heated to 80 ℃ and stirred for 2 h. After cooling to room temperature, the mixture was poured into water (20mL), extracted with EA (10 mL. times.3), and the organic phase was washed with saturated aqueous NaCl (10mL), anhydrous Na₂SO₄Drying, spin-drying and concentrating to obtain 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, crop). 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

The subsequent synthetic steps of example B7 were described with reference to intermediate a1 and example a 2.¹H NMR (400MHz, methanol-d)₄)δ7.50(s,1H),7.40–7.34(m,2H),6.90–6.78(m,2H),6.29(d,J＝16.8Hz,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).

Following a procedure analogous to that described above for the synthesis of the example B series of compounds, the following compounds were also prepared and characterized:

active examples

Example 1 inhibitory Effect of the Compounds of the present invention on the proliferation of KRas G12C mutant cells

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

[ test methods ]: using Promega corporation

The Luminescent Cell Viability Assay kit evaluates the inhibitory activity of compounds on NCI-H358 Cell proliferation.

[ Main instruments ]: spectramax M3 multifunctional microplate reader from Molecular Devices.

[ test materials ]: NCI-H358 cell line (center for cell resources of institute of basic medicine, national academy of medical sciences, resources: 3111C0001CCC000470), 96-well transparent flat-bottomed black-walled cell culture plate (Greiner Bio one, cat #655096), RPMI-1640media (GE, cat # SH30809.01), fetal bovine serum FBS (Thermo Fisher, cat #10099-,

Luminescent Cell Viability Assay kit (Promega, cat # G7573), PBS (Solarbio, cat # P1020), pancreatin (Thermo Fisher, cat #25200072), DMSO (Sigma, cat # D2650), Methylcellulose (Sigma, cat # 9004-67-5).

[ Experimental procedures ]: to a 96-well cell culture plate, 180. mu.L of cell suspension (10% FBS RPMI1640 solution containing 1% methylcellulose) was added to make the cell density in the cell culture plate 1500 viable cells/well. A control group (i.e., a culture medium control) containing no cells, no compound, and only 3D complete medium (10% FBS RPMI1640 solution containing 1% methylcellulose) was set, and a control group (i.e., a cell control) containing no compound and cells was set. Compound AMG510 or the following reference compound was used as a positive control during the assay. The cell plates were placed in a cell incubator for overnight incubation. A 10-fold solution of the drug (10% FBS in RPMI1640 solution with 1% DMSO) was prepared with a maximum concentration of 10 μ M, 3.16-fold gradient dilution, for a total of 9 concentrations. To a 96-well plate seeded with cells, 20 μ L of drug solution was added per well, working concentrations of compounds: mu.M, 3.16-fold gradient dilution, 9 concentrations, three duplicate wells per compound, with a DMSO content of 0.1%, were prepared in the same manner and solutions of compound AMG510 or the following reference compounds were added to the positive control wells. The cell plate is placed in a cell incubator to be continuously cultured for 120 h. In the final detection, the CellTiter-Glo reagent is melted, the cell plate is moved to room temperature and balanced for 30min, 100 mu L of CellTiter-Glo is added into each hole of the cell plate, the cell plate is vibrated on an orbital shaker for 5min to fully lyse the cells, the cell plate is placed at room temperature for 20min to stabilize the luminescent signal, and the luminescent value of each hole is scanned by a multifunctional microplate reader at full wavelength.

Representative example compounds and reference compounds, and the following compound AMG510 served as positive controls.

AMG510：

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

Reference compound 1:

prepared according to a synthetic method analogous to that of example 1L in US20190233440 using 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol instead of 5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol in step 1.¹H NMR(400MHz,DMSO-d₆)δ13.04(s,1H),7.78(d,J＝8.3 Hz,1H),7.45–7.11(m,4H),6.95(s,1H),6.84(dd,J＝16.6,10.4Hz,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 2:

synthesized as described in example 7E of US 20190233440.

[ data analysis ] the cell inhibitory rate and IC under the action of each compound were calculated using the following formulas₅₀：

Inhibition rate [ < 1 > - (Lum) ]_{Drug to be tested}-Lum_{Culture fluid control})/(Lum_{Cell controls}-Lum_{Culture fluid control})】×100％

IC was calculated by fitting compound concentration and cytostatic correlation curves using a four parameter Logistic model in nonlinear regression analysis in GraphPad Prism 7.0 software₅₀Values, the fitting model used was:

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

[ test results ] the compounds of the present invention showed higher anti-cell proliferation activity against KRas G12C mutated NCI-H358 human non-small cell lung cancer cells, preferably with inhibition rates > 20%, > 30%, > 40%, > 50%, > 60%, more preferably with inhibition rates > 70%, > 80%, > 90%. Specific data are shown in tables 1-2.

TABLE 1 inhibition of NCI-H358 cell proliferation by A series of compounds of examples (1. mu.M inhibition)

TABLE 2 inhibitory Activity of the compounds of the B series of examples on NCI-H358 cell proliferation (1. mu.M concentration inhibition)

Compound (I)	% inhibition (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: and (4) not measuring.

Example 2 preliminary rat pharmacokinetic Studies of Compounds of the invention

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

Adult male SD rats were used as test animals and were administered by intravenous Injection (IV) and oral administration (PO). IV sample configuration 1mg/mL 1% NMP/19% PEG 400/80% (20% Captisol in 50mM citrate buffer pH 5) clear solution; the PO samples were prepared as 1mg/mL clear aqueous solutions of 2% HPMC/1% Tween 80. The administration dose is 1mg/kg in group IV; PO 5 mg/kg. Blood samples were collected at 0.08330, 25, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose i.v. group; blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours in the oral administration group, respectively. The collected blood sample was placed in an EDTA-K2 anticoagulation tube, and plasma was collected by centrifugation. The plasma was subjected to acetonitrile to precipitate proteins, centrifuged to collect the supernatant for LC-MS/MS analysis.

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

Example 3 rat Cassette administration (Cassette) of Compounds of the invention pharmacokinetic Properties

The pharmacokinetic profile of some of the compounds of the invention was evaluated by a rat Cassette pharmacokinetic experiment (Nagilla r. et al, j.pharm.sci.2011,100, 3862-3874.).

[ test materials ]: male SD rats, week old: at 6-8 weeks, a weight of 220-; tolbutamide (Tolbutamide) (alatin, cat # H1401054); sulfobutyl beta cyclodextrin (Captisol, a noontian organism, shandong coast, cat # 20191013); propylene glycol (15) stearate (Solutol, melphalan bio, cat # S0206A); DMSO (Vetec corporation, cat # WXBD 0293V); acetonitrile (Sigma-Aldrich, cat # WXBD 1744V); methanol (Sigma-Aldrich, cat # WXBD 2831V).

[ Experimental procedures ]: the compound combination is prepared into a solvent of 5% DMSO/10% Solutol/85% (20% Captisol), the concentration of each compound is 1mg/mL finally, the pharmaceutical preparation is injected into SD rats according to the tail vein injection volume of 1mL/kg, blood is collected from external jugular vein puncture at 5min,15min,30min,1h,2h,4h,8h and 24h respectively, centrifugation is carried out at low temperature for 20 min, and plasma is collected and stored at-20 ℃ for detection.

[ sample analysis ]: establishment of compound LC-MS/MS analysis method

Preparing a standard curve: sucking 20 mu L of 1mg/mL DMSO stock solution of each compound, transferring the compound into 900 mu L of 50% methanol working solution, diluting step by step to obtain a standard curve working solution with the concentration of 20000, 10000, 5000, 1000, 500, 100, 50, 20 and 10ng/mL, sucking 5 mu L of the standard curve working solution and mixing with 45 mu L of rat blank plasma to obtain a standard curve with the concentration of 2000, 1000, 500, 100, 50, 10, 5, 2 and 1ng/mL, and using the standard curve for quantifying unknown samples.

Sample pretreatment: adding 250 mu L of acetonitrile containing tolbutamide as an internal standard as a precipitator into 50 mu L of unknown plasma samples and standard curve samples, precipitating plasma proteins, extracting a compound to be detected in the plasma, centrifuging at low temperature for 20 minutes, taking supernate, mixing the supernate with 0.1% formic acid aqueous solution, sucking 5 mu L of sample injection, and analyzing the drug blood concentration by adopting LC-MS.

[ data processing ]: and drawing a standard curve by using mass spectrometry software Analyst 1.6.1, quantifying an unknown sample, and calculating pharmacokinetic parameters by using Winnonlin 8.2 according to the concentration of the drug of the unknown sample at each time point.

[ Experimental results ]: the experimental results show that the compounds of the invention show good or even improved pharmacokinetic properties in the cassette dosing pharmacokinetic evaluation.

Table 2.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which they pertain. The contents of the references disclosed, which are contained in the literature references discussed in the sentence in which the reference is based, are also individually and specifically incorporated by reference herein.

Claims

1. A compound of formula I, isomers thereof or pharmaceutically acceptable salts or solvates thereof,

wherein the content of the first and second substances,

a is selected from C-CN or N;

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

is a single bond or a double bond;

w is selected from the group consisting of-C (O) -CR¹＝C(R²)₂、-C(O)-C≡CR²、-C(O)-C≡N、-S(O)_1-2-CR¹＝C(R²)₂、-S(O)_1-2-C≡CR²、-S(O)_1-2-C ≡ N; or W is represented by R in¹Or R²Together with the N to which W is attached in ring B and the ring atoms adjacent to the N form a nitrogen-containing heterocycle fused to ring B;

G is selected from-O-, -S (O)_1-2-、-NR¹⁰-or-CR⁸R⁹-；

R³is selected from- (CH)₂)_0-6-R^3’Wherein R is^3’Selected from 3-12 membered heterocyclyl, 5-12 membered heteroaryl and C_3-12Cycloalkyl, each optionally substituted with one or more substituents selected from: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, wherein C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰Or N (R)¹⁰)₂-substitution;

R⁴is selected from C_6-12Aryl or 5-12 membered heteroaryl, each of which is optionally substituted by one or more groups selected fromThe following substituents: -OH, -SH, -NH₂、-OC_1-6Alkyl, -SC_1-6Alkyl, -NHC_1-6Alkyl, -N (C)_1-6Alkyl radical)₂Halogen, CN, NO₂Oxo, C_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, - (CR) ¹⁰R¹⁰)_0-1-C(O)-N(R¹⁰)₂、-(CR¹⁰R¹⁰)_0-1-C(O)-OR¹⁰、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-N(R¹⁰)₂、-(CR¹⁰R¹⁰)_0-1-S(O)_1-2-R¹⁰Wherein C is_1-6Alkyl radical, C_3-8Cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl optionally further substituted by halogen, -R¹⁰、-OR¹⁰、-SR¹⁰、N(R¹⁰)₂Is substituted in which R¹⁰In each occurrence, two R's as defined above, or linked to the same C¹⁰Together with the carbon atom to which they are attached form an optionally substituted R¹⁰Or halogen-substituted C_3-8A cycloalkyl group;

R⁵selected from H, halogen, NO₂CN, C optionally substituted by one or more halogens_1-6Alkyl or optionally substituted by one or more halogens or R¹⁰Substituted C_3-8A cycloalkyl group;

m is 0 or 1;

n is an integer from 0 to 3;

with the following conditions:

when m is 1, each X, Y, Z is independently selected from C or N, and

represents a double bond; and

when a is N and m is 1, at least one of X and Y is not C.

2. A compound according to claim 1 of formula Ia or Ib,

isomers thereof or pharmaceutically acceptable salts or solvates thereof.

3. A compound according to claim 2, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, which is a compound of formula Ia, wherein the fused bicyclic ring moieties are each independently selected from

Most preferably

Wherein the ring containing X, Y and Z is optionally substituted with 0, 1, 2 or 3R⁵And (4) substitution.

4. A compound according to claim 2, isomers thereof or pharmaceutically acceptable salts or solvates thereof, which is a compound of formula Ib, wherein the fused bicyclic ring moieties are each independently selected from

Each optionally substituted by 0, 1 or 2R⁵And (4) substitution.

5. A compound according to any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the group consisting of a direct bond, -O-, -S-, or-NR¹⁰-。

6. The compound, isomer thereof, or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 5, wherein ring B is selected from the group consisting of

Preference is given to

Wherein each B is optionally substituted with R^aIs substituted in which R^aPreferably H or C_1-6Alkyl, most preferably H or CH₃。

7. The compound, isomer thereof, or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 6, wherein W is-C (O) -CR¹＝C(R²)₂Wherein R is¹And R²Each independently selected from H, F, methyl and dimethylaminomethyl, most preferably R¹And R²Are all H.

8. A compound according to any one of claims 1 to 7, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R³Is- (CH)₂)_0-3-R^3’Wherein R is^3’Selected from the following 3-12 membered heterocyclyl or 5-12 membered heteroaryl:

wherein R is⁶And R⁷Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, dimethylaminomethyl, dimethylaminoethyl, 1- (dimethylamino) ethyl, 1-methyl-2- (dimethylamino) ethyl.

9. A compound according to claims 1-8, isomers thereof or pharmaceutically acceptable salts or solvates thereof, wherein R⁴Is selected from

Wherein R is¹¹Selected from halogen (preferably fluorine or chlorine) or CN, R¹²Selected from H, halogen (preferably fluorine or chlorine) or-NH₂，R¹³Selected from halogen, OH or NH₂(ii) a Or R⁴Is selected from

Wherein R is¹¹Or R¹²Each independently selected from halogen or C optionally substituted by halogen_1-6An alkyl group.

10. A compound according to claim 9, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is selected from

11. A compound according to any one of claims 1 to 10, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R⁵Selected from H, halogen, C_1-3Alkyl or C_3-6A cycloalkyl group; h, chlorine, fluorine, methyl or cyclopropyl are preferred.

12. The compound, isomer thereof, or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 11, wherein G is-O-.

13. A compound of formula II-1, isomers thereof or pharmaceutically acceptable salts or solvates thereof,

wherein:

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;

is a single bond or a double bond;

ring B is

e is-L-R³；

L is selected from a direct bond, -O-, -NH-, or-S-;

g is-O-or-NH-;

R⁴is selected from C_6-12Aryl or 5-12 membered heteroaryl, optionally substituted by halogen, C_1-6Alkyl, -OH, -NH₂-、-NH(C_1-6Alkyl) -, -N (C)_1-6Alkyl radical)₂-, oxo, CN, -O-C_1-6Alkyl or C_3-6Cycloalkyl substitution, wherein C_1-6Alkyl or C_3-6Cycloalkyl is optionally further substituted by halogen, -OH, -O-C_1-6Alkyl radical, C_1-6Alkyl or N (R)¹⁰)₂Substitution;

R⁵selected from H or halogen;

m is 0 or 1;

n is an integer from 0 to 3;

with the following conditions:

when m is 1, X is selected from C or N, and

represents a double bond; and

when a is N and m is 1, at least one of X and Y is not C.

14. A compound, isomer thereof, or pharmaceutically acceptable salt or solvate thereof according to claim 13, wherein the fused bicyclic moiety is selected from

More preferably

Wherein the ring containing X, Y and Z is substituted by 0 or 1R ⁵Substituted, R⁵Selected from halogens, preferably F or Cl.

15. A compound according to any one of claims 13 to 14, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein G is O.

16. A compound, isomer thereof, or a pharmaceutically acceptable salt or solvate thereof according to any of claims 13 to 15, wherein R³is-R^3’Wherein R is^3’Selected from 3-7 membered heterocyclyl, 5-10 membered heteroaryl or C₆Aryl, each optionally substituted by C_1-6Alkyl, -O-C_1-6Alkyl or C_3-6Cycloalkyl substitution, wherein C_1-6Alkyl or C_3-6Cycloalkyl is optionally further substituted by C_1-6Alkyl, -O-C_1-6Alkyl or-N (R)¹⁰)₂Substitution; preferably, R³Is selected from

Wherein R is⁶Is C_1-6Alkyl or C_3-6Cycloalkyl, optionally further substituted by-NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂Substitution; or

Wherein R is⁶Is C_1-6Alkyl, optionally further substituted by-NH₂、-NHC_1-6Alkyl or-N (C)_1-6Alkyl radical)₂And (4) substitution.

17. A compound, isomer thereof, or a pharmaceutically acceptable salt or solvate thereof according to any of claims 13 to 16, wherein R⁴Is selected from C₆Aryl or 5-to 10-membered heteroaryl, optionally substituted by halogen, C_1-6Alkyl, -O-C_1-6Alkyl, -OH, -NH₂-, CN or oxo, wherein C_1-6Alkyl is optionally further substituted by halogen, -OH, -O-C_1-6Alkyl or N (R)¹⁰)₂Substitution; preferably, R ⁴Is selected from

Wherein R is¹¹Or R¹²Each independently selected from halogen (preferably fluorine or chlorine) or optionally halogen (preferablyFluorine or chlorine) substituted C_1-6An alkyl group.

18. A compound, isomer thereof, or a pharmaceutically acceptable salt or solvate thereof according to any of claims 13 to 17, wherein R⁵Is H or halogen.

19. A compound, isomer thereof or pharmaceutically acceptable salt or solvate thereof selected from the group consisting of the compounds of examples 1-145 of the specification, isomer thereof or pharmaceutically acceptable salt or solvate thereof.

20. A compound according to any one of claims 1 to 19, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

21. A compound of any one of claims 1-19, an isomer thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a disease mediated by a K-RAS G12C, H-RAS G12C, or N-RAS G12C mutation, preferably a K-RAS G12C mutation, in a subject in need thereof.

22. A pharmaceutical composition comprising a compound of any one of claims 1-19, isomers thereof, or pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable excipient or carrier.

23. Use of a compound of any one of claims 1-19, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition of claim 22 for the manufacture of a medicament for the treatment or prevention of a disease mediated by a K-RAS G12C, H-RAS G12C or N-RAS G12C mutation, preferably a K-RAS G12C mutation, in a subject in need thereof.

24. A method of treating or preventing a disease mediated by a K-RAS G12C, H-RAS G12C or N-RAS G12C mutation, preferably a K-RAS G12C mutation, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-19, an isomer thereof or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition of claim 22.

25. The use of claim 23 or the method of claim 24, wherein the disease mediated by a mutation of K-RAS G12C, H-RAS G12C or N-RAS G12C, preferably a mutation of K-RAS G12C, is selected from the group consisting of tumors or cancers of the lung, bone, pancreas, skin, head and neck, skin or intraocular melanoma, uterine, ovarian, rectal, anal region, stomach, colon, breast, fallopian tube, endometrial, cervical, vaginal, vulvar, Hodgkin's disease, esophageal, small intestine, endocrine, thyroid, parathyroid, adrenal, soft tissue sarcoma, urethral, penile, prostate, chronic or acute leukemia, lymphocytic lymphomas, bladder, renal or ureteral, renal cell, renal, Central Nervous System (CNS), Primary CNS lymphoma, spinal tumor, brain stem glioma or pituitary adenoma.

26. The use or method of claim 25, wherein the disease mediated by a K-RAS G12C, H-RAS G12C or N-RAS G12C mutation, preferably a K-RAS G12C mutation, is selected from pancreatic cancer, colorectal cancer and lung cancer.