Compounds and their use as anticancer drugs

Abstract

The present invention provides compounds having the structure of formula (I) that can be used as SHP2 inhibitors, pharmaceutical compositions comprising such compounds, methods of preparing such compounds, and uses of such compounds in the treatment of cancer.

Description

Compounds and their use as anticancer drugs

[0001] Cross-references

[0002] This application claims priority to Chinese invention patent application No. 2023108367770, filed on July 7, 2023. Technical Field

[0003] The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a class of compounds with novel structures that can be used as SHP2 inhibitors, pharmaceutical compositions comprising such compounds, methods for treating or preventing SHP2-mediated diseases, particularly cancers or tumors, using such compounds, and uses of such compounds in treating or preventing SHP2-mediated diseases, particularly cancers or tumors. Background Art

[0004] Disturbances in molecular phosphorylation levels in the body often contribute to the development and progression of various diseases, such as cancer. Specifically, the phosphorylation status of tyrosine in signaling proteins plays a crucial role in the initiation, progression, and termination of many cellular signaling cascades. Tyrosine phosphorylation is regulated by protein tyrosine kinases (PTKs, phosphorylation) and protein tyrosine phosphatases (PTPs, dephosphorylation). Abnormal regulation of these two enzymes can lead to dysregulated tyrosine phosphorylation, contributing to diseases including diabetes, cancer, and autoimmune diseases.

[0005] As a member of the PTP family, protein tyrosine phosphatase 2 (SHP2) containing Src homology-2 is a 593-amino acid dephosphorylase encoded by the PTPN11 gene. SHP2 consists of two N-terminal SH2 domains, N-SH2 and C-SH2, a conserved PTP domain, and a flexible C-terminal tail. N-SH2 and C-SH2 are primarily responsible for substrate recognition, enzyme activity regulation, and binding to downstream signaling proteins. The PTP domain binds to phosphorylated tyrosine peptides and catalyzes the hydrolysis of their phosphate groups. In the ground state of SHP2, N-SH2 and C-SH2 bind to PTP, masking its catalytic active center, forming a self-inhibited inactive "closed" conformation, inhibiting the activity of the SHP2 protein, and restricting the entry of substrates into the catalytic site; under the stimulation of appropriate signaling factors such as growth factors or cytokines or in some pathogenic mutations, N-SH2 and C-SH2 leave the PTP, open the PTP active center, and expose the catalytic site, thereby catalyzing the dephosphorylation of phosphorylated substrates such as receptors, kinases, and phospholipids, and then regulating downstream signals.

[0006] SHP2 is located at the intersection of multiple signaling pathways and is a key hub connecting multiple intracellular oncogenic signaling pathways. For example, it is a convergence node in multiple signaling pathways, including the Ras-Raf-MEK-ERK, JAK-STAT, PI3K-AKT-mTOR, and PD-1 / PD-L1 pathways, and participates in regulating multiple signaling pathways in the body. Overactivated SHP2 can stimulate the activation of multiple signaling pathways, thereby driving the occurrence and progression of various cancers. In other words, the occurrence of various cancers is often closely related to the overactivation of signaling pathways regulated by SHP2. Therefore, if the activity of SHP2 can be inhibited, the survival and proliferation of tumor cells will be curbed.

[0007] However, the development of SHP2 inhibitors has been limited for a considerable period of time, and there was even a consensus within the industry that they were "undruggable." This is because early development of small-molecule SHP2 inhibitors focused on the catalytic active site, and these active site inhibitors have low biological activity. To date, the strongest inhibitor (salicylic acid active site inhibitor 11a-1) has an enzyme activity of only about 0.2 μM, and its cellular activity has not exceeded 1 μM. Furthermore, drugability is poor, with 11a-1 having an oral bioavailability of only 0.07% (J. Med. Chem. 2014, 57, 6594-6609). Furthermore, the catalytic domain of SHP2 is highly conserved, and catalytic site inhibitors generally lack selectivity, and off-target effects can lead to serious toxic reactions.

[0008] SHP2 inhibitors designed to inhibit SHP2's transition to an "open" active conformation by stabilizing its ground state, the inactive "closed" conformation, are called "allosteric inhibitors." Allosteric inhibitors bind to the interaction region of the three protein modules rather than the catalytically active center. Currently, nine allosteric inhibitors with very similar structures, led by the pioneer TNO155, have entered clinical trials. However, clinical trials of these allosteric inhibitors have shown numerous problems, including severe cardiotoxicity, low specificity, susceptibility to off-target toxicity, rapid development of drug resistance in solid tumors with mutations in the N-SH2 and C-SH2 modules that affect binding to the PTP module in the "closed" conformation, and ineffectiveness against diseases where SHP2 mutations restrict its existence to the "open" conformation, such as NS, LS, and JMML.

[0009] In contrast, despite the aforementioned drawbacks of early and current SHP2 active-center inhibitors, overcoming these shortcomings through structural optimization, coupled with the significant advantages of SHP2 active-center inhibitors over allosteric inhibitors in their mode of action, could provide a superior drug option. For example, active-center inhibitor drug molecules possess a significantly altered structural backbone, with binding characteristics consistent with those of phosphorylated tyrosine peptide fragments. This not only eliminates the inherent toxic side effects of allosteric inhibitor structures, such as cardiotoxicity caused by hERG inhibition, but also exhibits high protein binding specificity, making it less likely to produce unknown off-target effects. The mutation rate of the catalytic active center of SHP2 is low, and its binding site is distant from that of allosteric inhibitors. Therefore, active-center inhibitors develop resistance more slowly, potentially overcoming resistance to allosteric inhibitors. Furthermore, they remain effective against diseases where SHP2 mutations restrict the existence of an "open" conformation, such as NS, LS, and JMML.

[0010] Therefore, there is a great need for more structural types of compounds that serve as SHP2 active center inhibitors. It is expected that they can provide further improved inhibitory activity and other excellent properties compared to existing SHP2 active center inhibitors and allosteric inhibitors, give full play to the advantages of SHP2 active center inhibition, and overcome the defects of existing active center inhibitors and allosteric inhibitors, thereby providing more potent therapeutic drugs for clinical use.

[0011] Through in-depth research, the present inventors have addressed the above-mentioned needs. This disclosure provides novel structural inhibitor compounds with SHP2 active center inhibitory activity. Due to their improved structural pattern, these inhibitors exhibit enhanced SHP2 protein-specific inhibitory activity and inhibitory activity against related tumors, good pharmacokinetic properties (thus good drugability), excellent selectivity for SHP2 among protein phosphatases, good cardiac safety, such as reduced hERG toxicity, and reduced risk of drug interactions, compared to existing SHP2 inhibitors in the prior art, demonstrating promising application prospects.

[0012] Summary of the Invention

[0013] The present disclosure provides compounds having structural formula (I) as defined herein below,

[0014] or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof,

[0015] in:

[0016] represents a saturated, partially unsaturated, or aromatic ring system;

[0017] represents an aromatic ring system;

[0018] A1, A2, A3, A4, A5 are each independently selected from absent, C, N, O, and S, and A6 is selected from C and N, provided that (1) at most two of A1-A5 are absent, and (2) at most four of A1-A6 are heteroatoms;

[0019] R a is selected from -H, =O, =S, =N-OH, -OH, -NH2, halogen, -CN and -C optionally substituted by halogen 1-6 alkyl;

[0020] A7, A8, A9 are each independently selected from C, N, O and S, provided that at least one of A7, A8 and A9 is not C;

[0021] A 10 Selected from CR b and N;

[0022] A 11 Selected from CX and N;

[0023] R b Selected from H, halogen, CN and halogen-substituted -C 1-6 alkyl;

[0024] X is selected from H, halogen, CN, -OH, -OC 1-6 Alkyl and -C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted;

[0025] Y is selected from the group consisting of: -C 1-6 Alkyl, -(CH2) t -3-15 membered carbocyclic group, -(CH2) t -C 6-10 Aryl, -(CH2) t -5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S, -(CH2) t - a 3-15 membered heterocyclic group having 1 or more heteroatoms independently selected from N, O and S;

[0026] Z is selected from the following optionally substituted divalent groups: -C 6-10 Aryl-, -3-10 membered carbocyclyl-, -5-12 membered heteroaryl- having 1 or more heteroatoms independently selected from N, O and S, -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S;

[0027] R is selected from the group consisting of: -C 6-10aryl, -3-15 membered carbocyclyl, -5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S, -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S; and

[0028] t is each independently an integer from 0 to 3.

[0029] The present disclosure also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0030] The present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof for use as a medicament, eg, as a SHP2 inhibitor, eg, for treating and / or preventing a disease mediated by SHP2.

[0031] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing diseases mediated by SHP2, especially those diseases that benefit from SHP2 inhibition.

[0032] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing diseases mediated by SHP2, especially those diseases that benefit from SHP2 inhibition.

[0033] The present invention also provides a method for treating and / or preventing diseases mediated by SHP2, especially those that benefit from SHP2 inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, or a pharmaceutical composition comprising the same.

[0034] The present invention also provides a method for treating tumors or cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, or a pharmaceutical composition comprising the same.

[0035] The present invention also provides a method for inhibiting SHP2 activity, comprising contacting an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof with a biological sample such as a cell.

[0036] The present invention also provides use of the compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof as a research tool compound for SHP2 inhibitors.

[0037] The present invention also provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof and one or more other pharmaceutically active agents.

[0038] The present invention also provides a process for preparing the compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof.

[0039] Detailed Description of the Invention

[0040] definition

[0041] Unless otherwise indicated, the various terms used in the specification and claims have the meanings indicated below. In the absence of a specific definition for a particular term or phrase, it should be understood according to its ordinary meaning in the art. In the event of a conflict, the present specification (including definitions) will control.

[0042] In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0043] For any of the following chemical definitions, the number following the atomic symbol represents the total number of atoms of that element present in the particular chemical moiety. Additional atoms, such as H atoms or substituents as described herein, may be present as needed to satisfy the valence of the atom.

[0044] As used herein, the terms "comprising," "containing," "having," and other variations thereof are inclusive or open-ended, meaning "including but not limited to," and are not intended to exclude, for example, other additives, ingredients, integers, or steps. When an element is described as comprising a plurality of ingredients, steps, or conditions, the element may also be described as comprising any combination of the plurality of ingredients, steps, or conditions, or "consisting of" or "consisting essentially of" the plurality or combination of ingredients, steps, or conditions.

[0045] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the numerical value involved.

[0046] Unless otherwise specified, C in the definition of compounds disclosed herein n-n+m or C n -C m Including various cases from n to n+m carbons, such as C 1-6Including C1, C2, C3, C4, C5 and C6, and also including any range from n to n+m, such as C 1-6 Including C 1-2 、C 1-3 、C 1-4 、C 2-6 、C 3-6 Similarly, the definition of n-membered to n+m-membered in the compounds of the present disclosure indicates that the number of ring atoms is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 12-membered ring, etc., and also includes any range of n to n+m-membered, such as a 3-6-membered ring, a 3-8-membered ring, a 4-7-membered ring, a 4-10-membered ring, a 5-6-membered ring, a 6-8-membered ring, a 6-10-membered ring, a 6-12-membered ring, an 8-10-membered ring, etc.

[0047] As used herein, the term "SHP2" refers to protein tyrosine phosphatase 2 containing Src homology-2, a 593-amino acid dephosphorylase encoded by the PTPN11 gene. For purposes of the present disclosure, SHP2 may be wild-type, or any mutant or variant of SHP2 containing one or more mutations (e.g., conservative substitutions).

[0048] As used herein, the term "SHP2-mediated disease" refers to a disease in which SHP2 activity contributes to the development and progression of the disease. For purposes of this disclosure, "SHP2-mediated disease" specifically refers to a disease in which inhibition of SHP2 activity reduces the incidence of the disease, inhibits, ameliorates, slows down, or eliminates the disease and / or its symptoms, or a disease that is sensitive or responsive to SHP2 inhibition, or a disease that would benefit from SHP2 inhibition, including but not limited to proliferative, metabolic, or hematologic diseases, particularly cancer or tumor-related diseases.

[0049] As used herein, the term "cancer" or "tumor" refers to abnormal cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. For various aspects of the present disclosure, the cancers that can be treated with the compounds of the present disclosure are selected from, but are not limited to, juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, neuroblastoma, esophageal cancer, breast cancer (including triple-negative breast cancer), lung cancer (including small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma), lung adenocarcinoma, colon cancer, rectal adenocarcinoma, adenoid cystic carcinoma, gastric cancer, gastrointestinal stromal tumor, head and neck cancer (e.g., head and neck squamous cell carcinoma), ovarian cancer, prostate cancer, melanoma, skin or intraocular melanoma, soft tissue sarcoma; cancers of the oral cavity and pharynx (lip, tongue, mouth, throat, nasopharynx), stomach, small intestine, large intestine, colon, rectum, anal region, liver and biliary tract, pancreas, bone, connective tissue, skin (including epithelial cells), cancers of the vagina, vulva, cervix, uterus, endometrium, fallopian tube, urethra, penis, testicle, bladder, ureter, kidney, and other urinary tissues, including renal cell carcinoma, renal pelvis cancer, and hepatocellular carcinoma; cancers of the stomach and esophagus, the eye, brain, spinal cord, and the central and peripheral nervous systems and related structures, such as meningeal cancer, primary CNS lymphoma, oligodendroglioma, medulloblastoma, spinal tumors, brainstem glioma, or pituitary adenoma; cancers of the thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin's lymphoma, parathyroid cancer, adrenal cancer, multiple myeloma, medulloblastoma, and hematopoietic malignancies, including chronic or acute lymphocytic leukemia, chronic or acute myeloid leukemia, chronic myelomonocytic leukemia, and lymphomas, including lymphocytic, granulocytic, and monocytic, mantle cell lymphoma, and histiocytic lymphoma.

[0050] As used herein, the term "treatment" refers to administering one or more compounds described herein, or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotopic variants thereof, to a subject, such as a mammal, such as a human, suffering from the disease or symptoms of the disease, to cure, alleviate, or lessen the disease or symptoms of the disease. Preferably, the treatment is curative or ameliorative.

[0051] As used herein, the term "prevention" refers to administering one or more compounds as described herein, or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotopic variants thereof, to a subject, such as a mammal, such as a human, suspected of having or susceptible to a SHP2-mediated disease as defined herein, particularly a cancer or tumor, such that the risk of developing the defined disease is reduced or the onset of the disease is prevented. The term "prevention" encompasses the use of the compounds of the present disclosure prior to the diagnosis or determination of any clinical and / or pathological symptoms.

[0052] As used herein, the terms "inhibit" and "reduce" or any variations of these terms refer to the ability of a bioactive agent to reduce the signaling activity of a target of interest by interacting with the target, and refer to any measurable decrease or complete inhibition of the activity of a target of interest. For example, the activity (e.g., SHP2 activity) can be reduced by 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.

[0053] As used herein, the terms "selective inhibition" or "specific inhibition" refer to the ability of a bioactive agent to discriminate between potential targets, preferentially binding to the target of interest in the presence of one or more competing surrogate targets, and preferentially reducing the signaling activity of the target of interest. In some embodiments, the disclosed compounds do not detectably bind to the competing surrogate targets under conditions in which they bind to SHP2. In some embodiments, the disclosed compounds bind to SHP2 with a higher on-rate, lower off-rate, increased affinity, decreased dissociation, and / or increased stability compared to the competing surrogate targets. Specifically, relative to other PTP phosphatases, such as SHP1, HePTP, Laforin, LMPTP, LYP, PTP1B, PRL2, SSU72, VHR, FAP1, STEP, CDC14A, CD45, MEG2, PP5, etc., the compounds of the present disclosure have the ability to selectively inhibit SHP2 activity. For example, compared with the IC50 for the other specific PTP phosphatase, the IC50 value shown by the compounds of the present disclosure for SHP2 is at least about 1 times lower, for example, about 1-5 times, 5-10 times, 10-100 times lower, or even more than 100 times lower.

[0054] As used herein, the terms "subject," "individual," or "patient" refer to a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (e.g., cattle), sports animals, pets (e.g., guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In certain embodiments, the mammal is a human.

[0055] The term "therapeutically effective amount" as used herein refers to an amount or dosage that is generally sufficient to produce a beneficial therapeutic effect on a patient with a "SHP2-mediated disease" such as cancer or tumor in need of treatment. Those skilled in the art can determine the effective amount or dosage of the active ingredients of the present disclosure by conventional methods and in combination with conventional factors.

[0056] The term "drug combination" as used herein means that the compounds of the present invention can be combined with other active agents to achieve the purpose of the present invention. The other active agents can be one or more additional compounds of the present invention, or can be a second or additional (e.g., a third) compound that is compatible with the compounds of the present invention, i.e., does not adversely affect each other, or has complementary activities, such as these active agents are known to regulate other biologically active pathways, or regulate different components in the biologically active pathways involved in the compounds of the present invention, or even overlap with the biological targets of the compounds of the present invention. The other active agents can be co-administered with the compounds of the present invention in a single pharmaceutical composition, or be administered separately in different discrete units, and when administered separately, can be performed simultaneously or sequentially. The sequential administration can be close or distant in time.

[0057] As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans.

[0058] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and have sufficient purity and sufficiently low toxicity. Examples include, but are not limited to, cellulose and its derivatives (such as sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oils, polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tweens), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, etc.

[0059] As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the parent compound and are not biologically or otherwise undesirable, including acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" can be formed by compounds having a basic group with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and organic acids can be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts 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 ammoniums 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, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, triethanolamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.

[0060] The term "isomer" as used herein refers to any stereoisomer, mixture of enantiomers, including racemates, diastereomeric mixtures, geometric isomers, atropisomers and / or tautomers that may exist in the structure of a compound. For example, certain compounds of the present disclosure may contain at least one asymmetric center and thus produce stereoisomers, so the present invention covers all possible isomeric forms of the compounds defined herein, and pharmaceutically acceptable salts or solvates thereof, unless otherwise indicated. The determination and separation methods of the stereochemistry of the 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).

[0061] The compound structural formula or structural fragments used herein Indicates the absolute configuration of a stereocenter, i.e., a chiral center. Accordingly, R or S is used in the names of the compounds or intermediates provided by the present invention to indicate the absolute configuration of the chiral center.

[0062] It should be understood that when a person skilled in the art can determine, based on the structure of the compound shown herein, that the compound exists and only exists as a pair of chiral isomers, and that the compound can be easily separated based on conventional methods in the art, then the disclosure of the racemate of the compound herein (whether in terms of structural formula or chemical name) should be deemed to have disclosed each isomer of the compound separately.

[0063] As used herein, the term "isotopic variant" refers to a compound wherein one or more atoms are replaced by a corresponding isotopically enriched atom. Examples of isotopes that may be incorporated into compounds of formula (I) include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, e.g. 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F. 37 Cl and 125 I. Such isotopic variants can be used, for example, as probes in biological assays, analytical tools, or as therapeutic agents. In certain embodiments, the compounds of the present disclosure are provided in an unlabeled form. In certain embodiments, the compounds of the present disclosure also include isotopic variants in which one or more atoms present in the compound are replaced by corresponding isotopes, for example, one or more hydrogen atoms are replaced by 2 H or 3 H is replaced or one or more carbon atoms are 13 C- or 14 C-enriched carbon substitution.

[0064] As used herein, the term "solvate" refers to a solvent addition form of a compound containing a stoichiometric or non-stoichiometric amount of a solvent, including any solvated form of a compound of the present disclosure, including, for example, solvates with water, such as hydrates, or solvates with organic solvents, such as methanol, ethanol, or acetonitrile, i.e., as methanolate, ethanolate, or acetonitrile, respectively; or in the form of any polymorph. It should be understood that such solvates of the compounds of the present disclosure also include solvates of pharmaceutically acceptable salts of the compounds of the present disclosure.

[0065] The term "halogen" or "halo" as used herein means F, Cl, Br or I. Furthermore, the term "halogen-substituted" group as used herein when defining a group is intended to include monohalogenated or polyhalogenated groups in which one or more identical or different halogens replace one or more hydrogens in the corresponding group.

[0066] As used herein, the term "hydroxy" refers to an -OH group.

[0067] As used herein, the term "cyano" refers to a -CN group.

[0068] As used herein, the term "nitro" refers to a -NO2 group.

[0069] The term "alkyl" as used herein means a linear or branched monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, an alkyl group has 1-10, such as 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which include but are not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), n-hexyl, 2-methylpentyl and the like.

[0070] The term "alkoxy" as used herein means an alkyl group as defined herein that is attached to the rest of the molecule via an oxygen atom. Specifically, the alkoxy group has 1-10, e.g., 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, the term "C 1-6 Alkoxy" or "-OC 1-6 The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom, examples of which include but are not limited to -O-methyl, -O-ethyl, -O-propyl (including -O-n-propyl and -O-isopropyl), -O-butyl (including -O-n-butyl, -O-isobutyl, -O-sec-butyl or -O-tert-butyl), -O-pentyl (including -O-n-pentyl, -O-isopentyl and -O-neopentyl), -O-n-hexyl, 2-methylpentyl-O-, etc.

[0071] As used herein, the term "C optionally substituted by halogen or CN" 1-6 "Alkyl" refers to the C 1-6 Alkyl, wherein one or more (e.g. 1, 2, 3, 4 or 5) hydrogen atoms are optionally replaced by halogen and / or CN. When there are more than one halogen substituent, the halogens may be the same or different and may be located on the same or different C atoms. "C substituted by halogen or CN" 1-6Examples of "alkyl" include, but are not limited to, -CH2F, -CH2Cl, -CH2CN, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2CH2CN, -CH2CH2CF3, or -CF(CF3)2, etc.

[0072] The term "carbocyclyl" as used herein means a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic saturated or partially unsaturated non-aromatic hydrocarbon ring structure having a specified number of ring carbon atoms, in which there is no completely conjugated π electron system. A carbocyclyl group may have 3 to 15 carbon atoms (i.e., C 3-15 Carbocyclyl), for example, 3 to 10, 3 to 8, 3 to 6, 4 to 8, 5 to 10, 6 to 10, 6 to 11, 6 to 14, 6 to 15 carbon atoms, etc. The carbocyclyl in the disclosed compounds may be unsubstituted or substituted with one or more substituents as defined.

[0073] In some embodiments, the term "carbocyclyl" as used herein refers to a "monocyclic saturated or partially unsaturated carbocyclyl" having a specified number of ring carbon atoms. "Monocyclic saturated carbocyclyl" is also called "monocyclic cycloalkyl", for example, a 3-8 membered monocyclic saturated carbocyclyl or a 3-6 membered monocyclic saturated carbocyclyl in the compounds of the present disclosure, i.e., C 3-8 Cycloalkyl or C 3-6 Cycloalkyl, specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Monocyclic partially unsaturated carbocyclic group" is also called "monocyclic cycloalkenyl", such as 3-8 membered monocyclic partially unsaturated carbocyclic group or 3-6 membered monocyclic partially unsaturated carbocyclic group, i.e., C 3-8 Cycloalkenyl or C 3-6 Specific examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptadienyl, and the like.

[0074] In some embodiments, the term "carbocyclyl" as used herein is a "bridged saturated or partially unsaturated carbocyclyl" having a specified number of ring carbon atoms, which refers to a polycyclic carbocyclic ring that shares two carbon atoms that are not directly connected. The shared carbon atom is called a bridgehead carbon. The two bridgehead carbons may be a carbon chain or a bond, called a bridge. These groups may contain one or more double bonds but do not have a completely conjugated π electron system. It can be 5-14 members, such as 6-12 members, more preferably 5-10 members. According to the number of rings, it can be divided into bicyclic, tricyclic or polycyclic bridged carbocyclic rings, preferably bicyclic or tricyclic. For example, examples of 5-10 members, such as 5-8 members, of bridged saturated or partially unsaturated carbocyclic rings in the compounds of the present disclosure include, but are not limited to: bicyclo[1.1.0]butyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl or bicyclo[3.2.1]octyl, etc.

[0075] In some embodiments, the term "carbocyclyl" as used herein is a "spirocyclic saturated or partially unsaturated carbocyclyl" having a specified number of ring carbon atoms, meaning a polycyclic group sharing one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds but no completely conjugated π electron system. It can be 6-15 yuan, preferably 7-15 yuan, more preferably 7-11 yuan. According to the number of spiro atoms shared between rings, spiroalkyl is divided into monospiroalkyl (monospirocarbocyclyl), dispiroalkyl (dispirocarbocyclyl) or polyspiroalkyl (polyspirocarbocyclyl), preferably monospirocarbocyclyl and dispirocarbocyclyl, wherein the monospirocarbocyclyl may also be referred to as a bicyclic spirocarbocycle; more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 6 yuan monospirocarbocyclyl. The spirocarbocyclyl in the disclosed compounds can be a 6-15 membered monospirocarbocyclyl, i.e., a 6-15 membered bicyclic spirocarbocycle, preferably a 7-11 membered bicyclic spirocarbocycle. Non-limiting examples of spirocarbocyclyl include:

[0076] wait.

[0077] In some embodiments, the term "carbocyclyl" as used herein is a "fused saturated or partially unsaturated carbocyclyl" having a specified number of ring carbon atoms, meaning a carbocyclic group in which each ring in the system shares a stack of adjacent carbon atoms with other rings, which may contain one or more double bonds but does not have a completely conjugated π electron system. It can be 6-15 members, such as 5-14 members, 6-12 members, 7-14 members, preferably 7-11 members. According to the number of rings, it can be divided into bicyclic, tricyclic or polycyclic fused carbocyclic rings, preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused carbocyclic rings. Non-limiting examples of fused carbocyclic rings include

[0078] As used herein, the term "aryl" refers to a monocyclic or fused polycyclic aromatic ring structure having a specified number of ring atoms. Specifically, the term includes groups containing, for example, 6 to 10, preferably 6, ring members. Specific aryl groups include phenyl and naphthyl, with phenyl being the most specific. The aryl groups in the disclosed compounds may be unsubstituted or substituted with one or more substituents as defined.

[0079] As used herein, the term "heterocyclyl" refers to a cyclic group comprising one or more heteroatoms independently selected from O, N, and S and the specified number of ring atoms, which may be saturated or partially unsaturated and may be a monocyclic, fused, spirocyclic, or bridged polycyclic ring structure, wherein the definitions of fused heterocyclyl, spiro heterocyclyl, or bridged heterocyclyl are similar to those of "fused carbocyclyl," "spiro carbocyclyl," or "bridged carbocyclyl," except that each comprises one or more heteroatoms independently selected from O, N, and S, such as 1 to 4, 1 to 3, or 1 to 2 heteroatoms. In the case of a polycyclic heterocyclyl, it suffices that the ring structure attached to the rest of the molecule is a non-aromatic ring, and even if the ring further fused, spiro, or bridged to the non-aromatic ring is an aromatic ring, the heterocyclic ring system is still defined herein as a heterocyclyl. The heterocyclyl group can have 3 to 15 ring members (which can be referred to as a 3-15 membered heterocyclyl), for example, 3 to 10 ring members, 3 to 8 ring members, 4 to 8 ring members, 5 to 8 ring members, 5 to 10 ring members, 6 to 11 ring members, 6 to 14 ring members, 6 to 15 ring members, 7 to 15 ring members, 7 to 11 ring members, etc., for example, a monocyclic heterocyclyl, for example, a 3-8 membered or 4-8 membered monocyclic saturated heterocyclyl, or a bicyclic or tricyclic heterocyclic group, such as a 7-14 membered or 7-11 membered spiro heterocyclic group (preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered monospiro heterocyclic group), a 5-14 membered or 5-10 membered or 5-8 membered bridged heterocyclic group (preferably a bicyclic or tricyclic group), a 6-14 membered or 6-10 membered or 7-11 membered fused heterocyclic group (preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group). The heterocyclic group generally contains at least 1 and up to 4 (e.g., 1, 2, 3, or 4) heteroatoms, for example, a 3-8 membered monocyclic heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O, and S, such as a 3-8 membered monocyclic saturated heterocyclic group, or a bicyclic or tricyclic heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O, and S, such as a 7-14 membered or 7-11 membered spiroheterocyclic group, a 5-14 membered or 5-10 membered or 5-8 membered bridged heterocyclic group, a 6-14 membered or 6-10 membered or 7-11 membered fused heterocyclic group. The heterocyclic group in the compounds of the present disclosure may be unsubstituted or substituted by one or more substituents as defined.

[0080] Examples of suitable heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g., 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl, and 3-tetrahydrothiophenyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl (e.g., morpholino), thiomorpholine The heterocyclic group may be a carbon atom or a heteroatom, wherein the atom attached to the rest of the compound may be a carbon atom or a heteroatom, as long as it is chemically feasible. It is understood that structures having asymmetric centers encompass racemic and / or single enantiomeric forms thereof, e.g. Can represent

[0081] The term "heteroaryl" as used herein means a monocyclic or polycyclic aromatic ring system having 5-12 ring atoms, including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and the ring system and the rest of the molecule can be attached at a heteroatom or at a carbon atom. Specific embodiments include, for example, 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole, 1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole, pyridine, Pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, benzotriazole, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine, pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[3,4-b]pyridine Pyridine, isoindole, purine, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridazine, pyrrolo[1,2-b]pyrimidine, imidazo[1,2-c]pyrimidine, 5H-pyrrolo[3,2-b]pyrazine, 1H-pyrazolo[4,3-b]pyrazine, 1H-pyrazolo[3,4-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 1,5-naphthyridine, 2,6-naphthyridine, 2,7-naphthyridine, pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, pyrimido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine and pyrimido[4,5-d]pyrimidine. The heteroaryl groups in the disclosed compounds may be unsubstituted or substituted with one or more substituents as defined.

[0082] As used herein, the term "optionally substituted" means that one or more hydrogen atoms of the designated moiety are unsubstituted or replaced with a suitable substituent. An "optionally substituted" group may carry a stable substituent at each substitutable position of the group, for example means at least And when one or more positions in any given structure can be substituted by one or more substituents selected from a given group, the substituents can be the same or different at each position. The substituent combinations envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 identical or different substituents. In another embodiment, the optionally substituted group has 3 identical or different substituents. In another embodiment, the optionally substituted group has 4 identical or different substituents.

[0083] Many of the groups defined herein are optionally substituted, and the list of substituents given in this definitions section is merely exemplary and is not intended to limit the substituents defined elsewhere in the specification and claims.

[0084] The substituents shown as crossing chemical bonds in the cyclic structure fragments referred to herein are, for example, -(R1) t , means that the one or more R1 substituents can replace any chemically feasible one or more substitution sites in the ring, including G.

[0085] The structural fragments used in this article For example in Indicates that the fragment is attached to the rest of the molecule through any chemically feasible ring atom.

[0086] It is understood by those skilled in the art of organic synthesis that the various groups carried in the structure of the compounds of the present invention, whether unsubstituted or substituted by various defined substituents, are all based on the premise that the compound molecules are chemically feasible and stable, wherein the type and number of substituents are determined by the number and chemical valence of atoms in the group.

[0087] Technical problems solved

[0088] As described above, compounds capable of inhibiting SHP2 activity can be used to treat or prevent diseases mediated by SHP2 (e.g., cancer or tumors). Therefore, various structural types of SHP2 inhibitors have been developed in this field. However, existing SHP2 inhibitors still have problems that need to be addressed, including, for example, many inhibitors have unsatisfactory anti-tumor activity, or have toxic side effects leading to poor drug resistance, or pharmacokinetic properties that are insufficient to allow for convenient administration, i.e., poor "drugability," or undesirable drug interactions due to inhibition of the cytochrome P450 enzyme system. Furthermore, even for SHP2 inhibitors with good anti-tumor activity, there is still hope that their selective inhibitory activity against the target protein in vivo, further improved drug resistance (fewer toxic side effects or better safety), and further improved pharmacokinetic properties can be achieved through structural optimization, so as to provide more and better treatment options in the clinic.

[0089] Technical Solution

[0090] Through extensive and in-depth research, the inventors have developed a group of compounds with excellent inhibitory activity against SHP2. Through structural modification and activity verification, the inventors discovered that by modifying specific fragments at specific sites in the SHP2 inhibitor structure, they achieved further enhanced inhibitory activity against SHP2 compared to prior art inhibitors, capable of inhibiting the proliferation of various tumor cells. Furthermore, the resulting modified compounds exhibit excellent selectivity for SHP2 among numerous PTP phosphatases, significantly reduced hERG toxicity, and a favorable safety profile, with a reduced risk of drug interactions. Furthermore, they possess favorable, and even improved, pharmacokinetic properties, enabling convenient administration.

[0091] Thus, the present invention primarily provides potent and selective SHP2 inhibitors; pharmaceutical compositions containing such compounds as active ingredients; said compounds as medicaments for treating or preventing diseases, preferably tumors or cancers, mediated by SHP2 or benefiting from SHP2 inhibition; methods of using said compounds for treating or preventing diseases, preferably tumors or cancers, mediated by SHP2 or benefiting from SHP2 inhibition; and uses of said compounds in the preparation of medicaments for treating or preventing diseases, preferably tumors or cancers, mediated by SHP2 or benefiting from SHP2 inhibition.

[0092] Compounds of the Disclosure

[0093] The terms "disclosed compounds" and "compounds of the present disclosure" and the like used throughout this application, unless otherwise limited, encompass compounds defined in the various embodiments herein and preferred or exemplary embodiments thereof, and also encompass compounds formed by any combination or subcombination of the general, preferred or exemplary definitions of the various groups, including pharmaceutically acceptable salts, isomers (including atropisomers, enantiomeric mixtures, in particular racemates, diastereomeric mixtures, geometric isomers, tautomers), solvates or isotopic variants of these compounds. However, preferably, the compounds of the present disclosure and / or pharmaceutically acceptable salts or solvates thereof are used.

[0094] The present disclosure also encompasses N-oxides of the disclosed compounds, provided that these compounds contain basic nitrogen atoms, such as those present in nitrogen-containing heterocycles, and are chemically and biologically feasible. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms, and thus they also fall within the scope of the present invention.

[0095] The present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof,

[0096] or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof,

[0097] in:

[0098] represents a saturated, partially unsaturated, or aromatic ring system;

[0099] represents an aromatic ring system;

[0100] A1, A2, A3, A4, A5 are each independently selected from absent, C, N, O, and S, and A6 is selected from C and N, provided that (1) at most two of A1-A5 are absent, and (2) at most four of A1-A6 are heteroatoms;

[0101] R a is selected from -H, =O, =S, =N-OH, -OH, -NH2, halogen, -CN and -C optionally substituted by halogen 1-6 alkyl;

[0102] A7, A8, A9 are each independently selected from C, N, O and S, provided that at least one of A7, A8 and A9 is not C;

[0103] A 10 Selected from CR b and N;

[0104] A 11 Selected from CX and N;

[0105] R b Selected from H, halogen, CN and halogen-substituted -C 1-6 alkyl;

[0106] X is selected from H, halogen, CN, -OH, -OC 1-6 Alkyl and -C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted;

[0107] Y is selected from the group consisting of: -C 1-6 Alkyl, -(CH2) t -3-15 membered carbocyclic group, -(CH2) t -C 6-10 Aryl, -(CH2) t -5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S, -(CH2) t - a 3-15 membered heterocyclic group having 1 or more heteroatoms independently selected from N, O and S;

[0108] Z is selected from the following optionally substituted divalent groups: -C 6-10 Aryl-, -3-10 membered carbocyclyl-, -5-12 membered heteroaryl- having 1 or more heteroatoms independently selected from N, O and S, -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S;

[0109] R is selected from the group consisting of: -C 6-10 aryl, -3-15 membered carbocyclyl, -5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S, -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S; and

[0110] t is an integer from 0 to 3, each independently.

[0111] In a further embodiment of the present disclosure, in the compound of formula (I), Y is selected from the following optionally substituted groups:

[0112] -C 1-6 alkyl,

[0113] -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring,

[0114] -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon ring-,

[0115] -(CH2) t-6-15 membered spiro ring or fused saturated or partially unsaturated carbon ring,

[0116] -(CH2) t -C 6-10 Aryl,

[0117] -(CH2) t - a 5-12 membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S,

[0118] -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S;

[0119] -(CH2) t - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S;

[0120] -(CH2) t - a 6-15 membered spirocyclic or fused saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O and S.

[0121] In a further embodiment of the present disclosure, in the compound of formula (I), Z is selected from the following optionally substituted divalent groups: -C 6-10 Aryl-,

[0122] -3-8 membered monocyclic saturated or partially unsaturated carbon ring-,

[0123] -5-10 membered bridged saturated or partially unsaturated carbon ring-

[0124] -5-12 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S-,

[0125] - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S,

[0126] - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S,

[0127] - a 6-15 membered spirocyclic or fused saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O and S.

[0128] In a further embodiment of the present disclosure, in the compound of formula (I), R is selected from the following groups which are optionally substituted:

[0129] -C 6-10 Aryl,

[0130] -3-8 membered monocyclic saturated or partially unsaturated carbon ring,

[0131] -5-10 membered bridged saturated or partially unsaturated carbon ring,

[0132] -6-15 membered spiro ring or fused saturated or partially unsaturated carbocyclic ring,

[0133] - a 5-12 membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S,

[0134] - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S,

[0135] - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S,

[0136] - a 6-15 membered spirocyclic or fused saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O and S.

[0137] In some embodiments of the compound of Formula (I), 0-3 R a substituted, five-membered or six-membered saturated, partially unsaturated or aromatic group containing 1-4 ring heteroatoms selected from N, O and S; preferably optionally substituted with 0-3 R a substituted, five-membered partially unsaturated or aromatic group containing 2-4 ring heteroatoms selected from N, O and S; more preferably optionally substituted with 0-1 R a A substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S; most preferably optionally substituted with 0-1 R a A substituted five-membered aromatic group containing 3-4 nitrogen heterocyclic atoms.

[0138] In some embodiments of the compound of Formula (I), A6 is C.

[0139] In some embodiments of the compound of Formula (I), R a is H; in some embodiments, R a =O or =S; in some embodiments, R a is -OH or -NH2; in some embodiments, R a is halogen, -CN or -C1-6 alkyl optionally substituted by halogen. a is selected from -H, =O, =S, -OH, -NH2, -CN and -C1-6 alkyl optionally substituted by halogen, further selected from -H, -CN, halogen, =O and -C1-6 alkyl optionally substituted by halogen 1-6 In some embodiments, R aSubstitution is on a ring carbon atom.

[0140] In some embodiments of the compound of formula (I), the ring formed by A1-A6 is triazolyl and A6 is C, for example By 1 R a Substituted, the R a is selected from H, halogen, CN and -C optionally substituted by halogen 1-6 Alkyl, preferably selected from halogen, CN and -C 1-6 Alkyl, most preferably -C substituted by halogen 1-6 Alkyl, such as -CF3.

[0141] In some embodiments of the compound of formula (I), the ring formed by A1-A6 is tetrazolyl

[0142] In some embodiments of the compound of formula (I), the ring formed by A1-A6 is a five-membered partially unsaturated ring containing 3-4 ring heteroatoms selected from N, O and S, such as but not limited to Preferred

[0143] In this embodiment, the exemplary Including but not limited to Preferred More preferred

[0144] In some embodiments of the compound of Formula (I), is a fused heteroaromatic ring substituted by Y containing 1 to 3 heteroatoms selected from N, O and S.

[0145] In some embodiments, A 10 CR b And A 11 is CX; in some embodiments, A 10 and A 11 One of them is a nitrogen atom and the other is a carbon atom, for example, A 10 N and A 11 is CX; in some embodiments, A 10 and A 11 All are nitrogen atoms.

[0146] In some embodiments, one of A7 and A9 is a heteroatom selected from N, O and S, the other is a carbon atom, and A8 is a carbon atom; preferably, A7 is selected from CY and NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom, and A8 is a carbon atom; further preferably, Y is connected to the A7 ring atom.

[0147] In this embodiment, the exemplary Including but not limited to Preferred More preferred

[0148] In some embodiments of the compound of Formula (I), R b is H; in some embodiments, R b is halogen, preferably F; in some embodiments, R b is CN; in some embodiments, R b -C substituted with halogen 1-6 Alkyl, for example -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CF(CF3)2, preferably -CF3.

[0149] In some embodiments of the compound of Formula (I), X is H.

[0150] In some embodiments of the compound of formula (I), X is halogen selected from F, Cl, Br, I; preferably F.

[0151] In some embodiments of the compound of Formula (I), X is CN.

[0152] In some embodiments of the compound of Formula (I), X is -OH.

[0153] In some embodiments of the compound of Formula (I), X is -OC 1-6 Alkyl, optionally substituted with halogen or CN; for example, but not limited to -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -O-CH2F, -O-CH2Cl, -O-CHF2, -O-CF3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CN, -O-CH2CH2CN.

[0154] In some embodiments of the compound of Formula (I), X is -C 1-6Alkyl, optionally substituted with halogen or CN; for example, but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-CN, -CH2CH2-CN, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CF(CF3)2.

[0155] In a preferred embodiment, X is selected from H, halogen and -OH, more preferably F.

[0156] In some embodiments of the compound of Formula (I), Y is -C 1-6 Alkyl, optionally substituted by halogen or CN and wherein any carbon atom is optionally replaced by NR', O or S, preferably -C substituted by halogen or CN 1-6 Alkyl, more preferably -C 1-6 Alkyl; for example, but not limited to -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)(CH3), -CH2CH2CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2-CN, -CH2CH2-CN, -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CF(CF3)2, - CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2-SCH3, -CH2-S-CH2CH3, -CH2CH2-S-CH3, -CH2CH2-S-C H2CH3, -CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-NH-CH2CH3, -CH2CH2-NH-CH3, -CH2CH2-NH-CH2CH3, -CH2CH2-N(CH3)-CH2CH3.

[0157] In some embodiments of the compound of formula (I), Y is -(CH2) t -3-15 membered carbocyclic group, specifically -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, more specifically -(CH2) t -3-6 membered monocyclic saturated carbon ring, optionally substituted by -C 1-6Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 Alkyl is optionally substituted with halogen or CN; for example but not limited to Preferred

[0158] In some embodiments of the compound of formula (I), Y is -(CH2) t -3-15 membered carbocyclic group, specifically -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon ring, more specifically -(CH2) t -5-8 membered bicyclic bridged saturated carbon ring, optionally substituted by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 The alkyl group is optionally substituted with halogen or CN; wherein the bridged carbon ring is, for example but not limited to

[0159] In some embodiments of the compound of formula (I), Y is -(CH2) t -3-15 membered carbocyclic group, specifically -(CH2) t -6-15 membered spiro ring or fused saturated or partially unsaturated carbocyclic ring, more specifically -(CH2) t -7-11 membered bicyclic spiro ring or fused saturated carbocyclic ring, optionally substituted by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 The alkyl group is optionally substituted by halogen or CN; the group may also be represented by wherein k is an integer of 0-2, m and n are each independently an integer of 1-3, l is an integer of 1-4, r and p are each independently an integer of 0-3, q is an integer of 1-4, optionally containing one or more double bonds (non-aromatic), and optionally replaced by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substitution; In this embodiment, the carbocycle of Y is more specifically a 7-11 membered bicyclic spirocyclic saturated carbocycle (wherein k is 0-2, m and n are each independently an integer of 1-2, and l is an integer of 1-3) or a 7-11 membered bicyclic fused saturated carbocycle (wherein r is an integer of 0-1, p is an integer of 0-2, and q is an integer of 1 to 3); wherein the spirocarbocycle and the fused carbocycle are, for example, but not limited to or the exemplary groups containing one or two carbon-carbon double bonds.

[0160] In some embodiments of the compound of formula (I), Y is -(CH2) t -C 6-10 Aryl, specifically -(CH2) t -phenyl, optionally substituted by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 Alkyl is optionally substituted with halogen or CN; for example but not limited to Preferred

[0161] In some embodiments of the compound of formula (I), Y is -(CH2) t -5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S, specifically -(CH2) t -5-12 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, more specifically -(CH2) t -5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, optionally substituted by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 Alkyl is optionally substituted with halogen or CN; wherein heteroaryl is, for example but not limited to, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

[0162] The heteroaryl group and the rest of the molecule can be connected at a heteroatom or a carbon atom of the heteroaryl group.

[0163] In some embodiments of the compound of formula (I), Y is -(CH2) t - a 3-15 membered heterocyclic group having one or more heteroatoms independently selected from N, O and S, specifically -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S, more specifically -(CH2) t- a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S, optionally substituted by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 Alkyl is optionally substituted with halogen or CN; heterocycles such as, but not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g., 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl, and 3-tetrahydrothiophenyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl (e.g., morpholino), thiomorpholinyl, dioxanyl, piperazinyl, or azepanyl, diazepanyl such as 1,4-diazepanyl, and pyrrolinyl (e.g., 1-pyrrolinyl, 2-pyrrolidinyl, 3-pyrrolinyl, 4-pyrrolinyl, or 5-pyrrolinyl), dihydrofuranyl (e.g., 1-dihydrofuranyl, 2-dihydrofuranyl, 3-dihydrofuranyl, 4-dihydrofuranyl, or 5-dihydrofuranyl), dihydrothiophenyl (e.g., 1-dihydrothiophenyl, 2-dihydrothiophenyl, 3-dihydrothiophenyl, or 4-dihydrothiophenyl), tetrahydropyridinyl (e.g., 1-, 2-, 3-, 4-, 5-, or 6-tetrahydropyridinyl), oxenyl, dihydropyranyl (e.g., 4-dihydropyranyl), or dihydrothiopyranyl (e.g., 4-dihydrothiopyranyl), wherein the heterocyclic radical and the rest of the molecule can be attached at a heteroatom or carbon atom of the heterocyclic ring, and wherein substituents can be substituted at ring carbon atoms or ring heteroatoms, as long as it is chemically feasible.

[0164] In some embodiments of the compound of formula (I), Y is -(CH2) t - a 3-15 membered heterocyclic group having one or more heteroatoms independently selected from N, O and S, specifically -(CH2) t - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, more specifically -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S, optionally substituted by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 The alkyl group is optionally substituted with halogen or CN; wherein the bridged heterocycle is, for example, but not limited to The heterocyclic group and the rest of the molecule can be connected at a heteroatom or a carbon atom of the heterocyclic ring, and the substituents thereon can be substituted on the ring carbon atom or the ring heteroatom, as long as it is chemically feasible.

[0165] In some embodiments of the compound of formula (I), Y is -(CH2) t - a 3-15 membered heterocyclic group having one or more heteroatoms independently selected from N, O and S, specifically -(CH2) t - a 6-15 membered spirocyclic or fused saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O and S, more specifically -(CH2) t -7-11 membered bicyclic spiro ring or fused saturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, optionally substituted by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, wherein t is preferably 0 or 1, wherein -C 1-6 The alkyl group is optionally substituted by halogen or CN; the group may also be represented by wherein 1-4 ring atoms, preferably 1-3, more preferably 1-2 ring atoms may be replaced by heteroatoms independently selected from N, O, S, k is an integer of 0-2, m, n are each independently an integer of 1-3, l is an integer of 1-4, r and p are each independently an integer of 0-3, q is an integer of 1-4, optionally containing 1 or more double bonds (non-aromatic), and optionally replaced by -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl substituted, where -C 1-6 The alkyl group is optionally substituted with halogen or CN; the heterocycle in this embodiment is more specifically a 7-11 membered bicyclic spirocyclic saturated heterocycle (wherein k is 0-2, m and n are each independently an integer of 1-2, and l is an integer of 1-3) or a 7-11 membered bicyclic fused saturated heterocycle (wherein r is an integer of 0-1, p is an integer of 0-2, and q is an integer of 1 to 3), wherein t is preferably 0 or 1; the spiro heterocycle and fused heterocycle are, for example, but not limited to: The heterocyclic group and the rest of the molecule can be attached at any available heteroatom or carbon atom in the entire heterocyclic ring, and the substituents thereon can be substituted at the ring carbon atom or ring heteroatom, as long as it is chemically feasible.

[0166] In an embodiment of the compound of formula (I), preferably Y is selected from the group consisting of: -C 1-6 Alkyl, -(CH2) t -3-15 membered carbocyclyl and -(CH2) t -C 6-10Aryl; more preferably Y is selected from the following groups which are optionally substituted: -C 1-6 Alkyl, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon ring and -(CH2) t -C 6-10 Aryl; further preferably Y is selected from the following groups optionally substituted: -C 1-6 Alkyl, -(CH2) t -3-6 membered monocyclic saturated carbocyclic ring, -(CH2) t -5-8 membered bicyclic bridged saturated carbocyclic ring and -(CH2) t -phenyl.

[0167] In an embodiment of the compound of formula (I), preferably t in Y is 0-2, more preferably 0-1.

[0168] In an embodiment of the compound of formula (I), each cyclic group of Y is optionally replaced by one or more independently selected from -C 1-6 Alkyl, -OH or -OC 1-6 Alkyl radical substitution, wherein Y and its substituents appear in -C 1-6 Alkyl or -(CH2) t -optionally substituted by halogen or CN and wherein any carbon chain atom is optionally replaced by NR', O or S, wherein R' is selected from H or -C 1-6 Alkyl; preferably Y's -C 1-6 The alkyl group is optionally substituted by halogen or CN, and the cyclic group of Y is optionally substituted by 1-3, preferably 1 or 2, more preferably 1 selected from -C 1-6 Alkyl and -OC 1-6 Alkyl groups substituted, where -C 1-6 Alkyl and -OC 1-6 Non-limiting examples of alkyl groups are as defined above for substituent X. In which Y is -(CH2) t In the embodiment of the -3-15 membered carbocyclic group, when t is 0 and the 3-15 membered carbocyclic ring is a 3-6 membered monocyclic saturated carbocyclic ring, the carbocyclic ring optionally carries a substituent C 1-6 Alkyl, preferably the C 1-6 When present, the alkyl group is substituted at the ring carbon atom which connects the carbocyclic ring to the rest of the molecule.

[0169] In some embodiments of the compound of Formula (I), Z is -C 6-10 Aryl-, optionally substituted with halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl substitution, where the -C 1-6 Alkyl is optionally substituted with halogen or CN; for example but not limited to Preferred

[0170] In some embodiments of the compound of formula (I), Z is -3-10 membered carbocyclyl-, specifically -3-8 membered monocyclic saturated or partially unsaturated carbocyclic-, more specifically -3-6 membered monocyclic saturated or partially unsaturated carbocyclic, optionally substituted by halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl substituted, where -C 1-6 Alkyl is optionally substituted with halogen or CN; for example but not limited to It should be noted that the divalent attachment points of these carbocyclic rings to the rest of the molecule are merely exemplary, and the carbocyclic ring can be attached to the rest of the molecule at any chemically feasible group.

[0171] In some embodiments of the compound of formula (I), Z is -3-10 membered carbocyclyl-, specifically -5-10 membered bridged saturated or partially unsaturated carbocyclic-, more specifically -5-8 membered bicyclic bridged saturated carbocyclic ring, optionally substituted by halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl substituted, where -C 1-6 The alkyl group is optionally substituted with halogen or CN; wherein the bridged carbon ring is, for example but not limited to

[0172] In some embodiments of the compound of formula (I), Z is -5-12 membered heteroaryl- having 1 or more heteroatoms independently selected from N, O and S, specifically 5-12 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, more specifically 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, optionally substituted by halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl substituted, where -C 1-6 The alkyl group is optionally substituted with halogen or CN; examples of the heteroaryl group are as shown above for Y as “a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S”, except that it is a divalent group, and the heteroaryl group and the rest of the molecule can be connected at a heteroatom or a carbon atom of the heteroaryl group, and the substituents therein can be substituted on a ring carbon atom or a ring heteroatom, as long as it is chemically feasible.

[0173] In some embodiments of the compound of formula (I), Z is a divalent 3-15 membered heterocyclic group having 1 or more heteroatoms independently selected from N, O and S, specifically a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, more specifically a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S, optionally substituted by halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl substituted, where -C 1-6 The alkyl group is optionally substituted with halogen or CN; examples of the heterocycle are as shown above for Y as "a 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S", except that it is a divalent group, and the heterocyclic group and the rest of the molecule can be connected at a heteroatom or a carbon atom of the heterocycle, and the substituents can be substituted at ring carbon atoms or ring heteroatoms, as long as it is chemically feasible.

[0174] In some embodiments of the compound of formula (I), Z is -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S, specifically -5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, more specifically -5-8 membered bridged saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S, optionally substituted by halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl substituted, where -C 1-6 The alkyl group is optionally substituted with halogen or CN; examples of the bridged heterocycle are as shown above for Y as the "5-10 membered bridged saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O and S", except that it is a divalent group, and the heterocyclic group and the rest of the molecule can be connected at a heteroatom or a carbon atom of the heterocyclic ring, and the substituents can be substituted at ring carbon atoms or ring heteroatoms, as long as it is chemically feasible.

[0175] In some embodiments of the compound of formula (I), Z is -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S, specifically -6-15 membered spiro ring or fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O and S, more specifically -7-11 membered bicyclic spiro ring or fused saturated heterocycle having 1-3 heteroatoms independently selected from N, O and S, optionally substituted by halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl substituted, where -C 1-6The alkyl group is optionally substituted with halogen or CN; wherein examples of spiroheterocycles and fused heterocycles are as shown above for Y as “a 6-15 membered spirocycle or a fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O and S”, except that it is a divalent group, and wherein the heterocyclic group and the rest of the molecule can be attached at a heteroatom or a carbon atom of the heterocycle, and wherein the substituents can be substituted at ring carbon atoms or ring heteroatoms, as long as it is chemically feasible.

[0176] In some embodiments of the compound of formula (I), preferably Z is selected from optionally substituted -C 6-10 Aryl-, -3-10 membered carbocyclyl- and -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S; more preferably Z is selected from optionally substituted -C 6-10 Aryl-, -3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring-, -5-10 membered bridged saturated or partially unsaturated carbocyclic ring- and -3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S; further preferably, Z is selected from optionally substituted phenyl, -3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring-, -5-8 membered bridged saturated carbocyclic ring- and -4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S; most preferably, Z is phenyl.

[0177] In an embodiment of the compound of formula (I), Z is optionally replaced by one or more independently selected from halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl group substituted, where -C 1-6 Alkyl is optionally substituted with halogen or CN; for example, Z is optionally substituted with 1-2, preferably 1, selected from halogen, -C 1-6 Alkyl and -OC 1-6 In one embodiment, Z is unsubstituted.

[0178] In some embodiments of the compound of Formula (I), R is optionally substituted -C 6-10 Aryl, preferably

[0179] In some embodiments of the compound of formula (I), R is an optionally substituted 3-15 membered carbocyclyl, specifically a 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring, more specifically -(CH2) t -3-6 membered monocyclic saturated carbocyclic ring; the 3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring is for example but not limited to

[0180] In some embodiments of the compound of formula (I), R is an optionally substituted 3-15 membered carbocyclic ring, specifically a 5-10 membered bridged saturated or partially unsaturated carbocyclic ring, more specifically a 5-8 membered bicyclic bridged saturated carbocyclic ring; the 5-10 membered bridged saturated or partially unsaturated carbocyclic ring is, for example, but not limited to

[0181] In some embodiments of the compound of formula (I), R is an optionally substituted 3-15 membered carbocyclic group, specifically a 6-15 membered spirocyclic ring or a fused saturated or partially unsaturated carbocyclic ring, more specifically a 7-11 membered bicyclic spirocyclic ring or a fused saturated carbocyclic ring; the 6-15 membered spirocyclic ring or the fused saturated or partially unsaturated carbocyclic ring may also be represented by wherein k is an integer from 0 to 2; m and n are each independently an integer from 1 to 3, l is an integer from 1 to 4, r and p are each independently an integer from 0 to 3, q ​​is an integer from 1 to 4, optionally containing one or more double bonds (non-aromatic), and in this embodiment, R is more specifically an optionally substituted 7-11-membered bicyclic spirocyclic saturated carbocycle (wherein k is 0 to 2, m and n are each independently an integer from 1 to 2, and l is an integer from 1 to 3) or a 7-11-membered bicyclic fused saturated carbocycle (wherein r is an integer from 0 to 1, p is an integer from 0 to 2, and q is an integer from 1 to 3); the spirocarbocycle and fused carbocycle are, for example, but not limited to, the groups exemplified above for the “6-15-membered spirocyclic or fused saturated or partially unsaturated carbocycle” of Y.

[0182] In some embodiments of the compound of formula (I), R is an optionally substituted 5-12 membered heteroaryl group having 1 or more heteroatoms independently selected from N, O and S, specifically a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group having 1-4 heteroatoms independently selected from N, O and S, more specifically a 5-6 membered monocyclic heteroaryl group having 1-4 heteroatoms independently selected from N, O and S; wherein the heteroaryl group can be connected to the rest of the molecule through a ring carbon atom or a ring heteroatom, and specific examples are as exemplified above for the heteroaryl group of Y, such as thienyl, pyrazolyl, etc.

[0183] In some embodiments of the compound of formula (I), R is an optionally substituted 3-15 membered heterocyclic group having 1 or more heteroatoms independently selected from N, O and S, specifically a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, more specifically a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S; wherein the heterocyclic ring is, for example, but not limited to, the groups exemplified above for “a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S” for Y, such as oxetanyl, tetrahydropyranyl, morpholinyl, oxolanyl, oxetanyl, piperidinyl, pyrrolidinyl, azetidinyl and the like.

[0184] In some embodiments of the compound of formula (I), R is an optionally substituted 3-15 membered heterocyclic group having 1 or more heteroatoms independently selected from N, O and S, specifically a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, more specifically a 5-8 membered bicyclic bridged saturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S; examples of the bridged heterocyclic ring are as shown above for Y's "5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S", for example

[0185] In a further embodiment, the bridged heterocycle is connected to the rest of the molecule via a nitrogen heteroatom. In a further embodiment, the bridged heterocycle is unsubstituted. In a further embodiment, the bridged heterocycle is substituted with 1-3 substituents independently selected from the group consisting of halogen, CN, -C 1-6 Alkyl, - containing 1-3 heteroatoms independently selected from N, O and S 4-7 membered monocyclic saturated heterocyclic ring, wherein the C 1-6 The alkyl group is optionally further substituted with halogen, -OH or -OC 1-6 Alkyl substitution.

[0186] In some embodiments of the compound of formula (I), R is an optionally substituted 3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S, specifically a 6-15 membered spiro ring or a fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O and S, more specifically a 7-11 membered bicyclic spiro ring or a fused saturated heterocycle having 1-3 heteroatoms independently selected from N, O and S; wherein the spiroheterocycle and the fused heterocycle are, for example, but not limited to, those shown above for Y as “a 6-15 membered spiro ring or a fused saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from N, O and S”.

[0187] In some embodiments of the compound of formula (I), the 3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S, including the above embodiments, of R is attached to the rest of the molecule through a ring heteroatom.

[0188] In an embodiment of the compound of formula (I), preferably R is selected from the following groups which are optionally substituted: - a 5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S and - a 3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S; more preferably R is selected from the following groups which are optionally substituted: - a 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S, - a 5-10 membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O and S R is preferably selected from the following groups optionally substituted: - a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, - a 4-7 membered monocyclic saturated or unsaturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, - a 5-8 membered bicyclic bridged saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, - and - a 7-11 membered spiro or fused saturated heterocycle having 1-3 heteroatoms independently selected from N, O and S.

[0189] In the embodiment of the compound of formula (I), the optional substituents carried on each type of R group are 0 to 4, preferably 0 to 3, more preferably 0-2 groups independently selected from the following groups: halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t- a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein two substituents attached to the same ring carbon atom can form a 3-8 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached, and the -C in the substituent is 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The alkynyl or cyclic groups are each independently optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: halogen, CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein two substituents attached to the same carbon atom can form a 3-6 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached, and C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substitution; the substituents include but are not limited to -OH, -CN, F, Cl, -CH3, -CF3, -CH2CH3, -CH=CH2, -CH=CHCH3, -CH=CHF, -C≡CH, -CH2CF3, -CH2CH2CH3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH(OH)(CF3)-, -C(CH3)(OH)(CH3), -CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH2C(CH3)(OH)CH3, -CH2CH2C(CH3)(OH)CH3, -CH2CN, -CH2-OCH3, -CH2-OCH2CH3, -CH2CH2-OCH3, -NH2, -NHCH3, -NCH3CH3, The substituents of R may be substituted on ring carbon atoms or ring heteroatoms, as long as it is chemically feasible.

[0190] In an embodiment of the compound of formula (I), it is preferred that t in the R substituent is 0-2, more preferably 0-1.

[0191] In some embodiments of the compound of formula (I), R has the formula (A) in,

[0192] f is selected from an integer from 0 to 3, preferably an integer from 0 to 2;

[0193] t is selected from an integer from 0 to 3, preferably an integer from 0 to 1;

[0194] G is selected from O, N-R2 and CR3R4; preferably O and CR3R4, most preferably CR3R4;

[0195] R1 is selected from H and optionally halogen, CN, -OH or -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, wherein two R1 attached to the same ring carbon atom can form together with the carbon atom to which they are attached a 3-8 membered saturated spirocarbocyclic ring; preferably R1 is selected from H and optionally substituted by -OH or -OC 1-6 Alkyl-substituted-C 1-6 Alkyl; most preferably R1 is selected from H and -C 1-6 alkyl;

[0196] R3 and R4 are each independently selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atoms to which they are attached form a 3-8 membered saturated spirocarbocyclic ring, and the -C in the substituent is 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The alkynyl or cyclic groups are each independently optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, halogen, CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atom to which they are attached form a 3-6 membered saturated spirocarbocyclic ring, and C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably selected from H, halogen, CN, -C 1-6Alkyl, - containing 1-2 heteroatoms independently selected from N, O and S 4-7 membered monocyclic saturated heterocyclic ring, wherein the C 1-6 The alkyl group is optionally further substituted with halogen, -OH or -OC 1-6 Alkyl substitution;

[0197] R2 is selected from H, -C 1-6 Alkyl, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl or cyclic group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, -C 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably a group selected from the following: H, -C 1-6 Alkyl, - containing 1-2 heteroatoms independently selected from N, O and S 4-7 membered monocyclic saturated heterocyclic ring, wherein the C 1-6 The alkyl group is optionally substituted with halogen, -OH or -OC 1-6 Alkyl substitution;

[0198] When f is 0, G is -CH2-.

[0199] In some embodiments of formula (A), when G is CR3R4, one of R3 and R4 is selected from H, halogen and -C 1-6 Alkyl, the other selected from -C 1-6 Alkyl; in some embodiments of formula (A), one of R3 and R4 is selected from H and -C 1-6 alkyl, and the other is CN; in some embodiments of formula (A), one of R3 and R4 is H, and the other is a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S.

[0200] In a further such embodiment, R is selected from Optionally substituted by R1 to R4 as defined above, preferably substituted by 1 to 3 of the preferred R1 to R4 above; exemplary groups of R1 to R4 are as shown above for the substituents carried on R, preferably exemplary groups of R1 to R4 are -OH, -CN, F, Cl, -CH3, -CF3, -CH2CH3, -CH2CF3, -CH2CH2CH3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH(OH)(CF3)-, -C(CH3)(OH)(CH3), -CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH2C(CH3)(OH)CH3, -CH2CH2C(CH3)(OH)CH3, -CH2CN, -CH2-OCH3, -CH2-OCH2CH3, -CH2CH2-OCH3, More preferably, -CN, F, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2C(CH3)(OH)CH3, -CH2CH2C(CH3)(OH)CH3, -CH(OH)CH2CH3, -CH(OH)(CF3)-, -C(CH3)(OH)(CH3), -CH2-OCH3.

[0201] In further such embodiments, exemplary groups for R include, but are not limited to:

[0202] In some embodiments of the compound of formula (I), R has the formula

[0203] in:

[0204] k is an integer of 0-2, m and n are each independently an integer of 1-3, and l is an integer of 1-4. Preferably, k is an integer of 0-2, m and n are each independently an integer of 1-2, and l is an integer of 1-3;

[0205] r and p are each independently an integer from 0 to 3, q ​​is an integer from 1 to 4, preferably r is an integer from 0 to 1, p is an integer from 0 to 2 and q is an integer from 1 to 3;

[0206] t is selected from an integer from 0 to 3, preferably an integer from 0 to 1;

[0207] G is selected from O, N-R2 and CR3R4, preferably O and CR3R4;

[0208] R1 is selected from H and optionally halogen, CN, -OH or -OC1-6 Alkyl-substituted-C 1-6 Alkyl, wherein two R1 attached to the same ring carbon atom can form together with the carbon atom to which they are attached a 3-8 membered saturated spirocarbocyclic ring; preferably R1 is selected from H and optionally substituted by -OH or -OC 1-6 Alkyl-substituted-C 1-6 Alkyl; more preferably R1 is H;

[0209] R3 and R4 are each independently selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atoms to which they are attached form a 3-8 membered saturated spirocarbocyclic ring, and the -C in the substituent is 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The alkynyl or cyclic groups are each independently optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, halogen, CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atom to which they are attached form a 3-6 membered saturated spirocarbocyclic ring, and C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably selected from H, -OH, -C 1-6 Alkyl, where the C 1-6 The alkyl group is optionally further substituted with halogen, -OH or -OC 1-6 Alkyl substitution;

[0210] R2 is selected from H, -C 1-6 Alkyl, -(CH2) t-3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl or cyclic group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, -C 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably a group selected from the following: selected from H, -C 1-6 Alkyl, where C 1-6 The alkyl group is optionally further substituted with halogen, -OH or -OC 1-6 Alkyl substitution.

[0211] In some embodiments of Formula (B) and Formula (C), when G is O, R1 is H.

[0212] In some embodiments of formula (B) and formula (C), when G is CR3R4, one of R3 and R4 is selected from -OH and -C substituted with -OH. 1-6 alkyl, the other selected from H and -C optionally substituted by halogen 1-6 alkyl.

[0213] In a further such embodiment, R is selected from Preferred Optionally substituted by R1 to R4 as defined above, preferably substituted by 1 to 3 of the above preferred R1 to R4; exemplary groups of R1 to R4 are as shown above for the substituents carried on R, and exemplary groups of preferred R1 to R4 include but are not limited to H, -OH, -CH3, -CF3, -CH2OH, -C(CH3)(OH)(CH3).

[0214] In further such embodiments, exemplary groups for R include, but are not limited to:

[0215] In a further embodiment of the compound of formula (I), there is provided a compound of formula (I), or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein:

[0216] 0-1 R is optional a A substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S; preferably optionally substituted with 0-1 R a substituted, containing 3-4 nitrogen heterocyclic atoms; most preferably optionally 0-1 R a a substituted five-membered aromatic group containing four nitrogen heteroatoms;

[0217] R a Selected from -H, -CN, halogen, =O and -C substituted by halogen 1-6 Alkyl, preferably H;

[0218] One of A7 and A9 is a heteroatom selected from N, O and S, the other is C, and A8 is a carbon atom; preferably, A7 is selected from CY and NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom, and A8 is a carbon atom;

[0219] A 10 Selected from CR b and N, A 11 Selected from CX and N; preferably A 10 CR b And A 11 For CX;

[0220] R b Selected from H, halogen, CN and halogen-substituted -C 1-6 Alkyl, preferably H;

[0221] X is selected from H, halogen and -OH, preferably halogen;

[0222] Y is selected from the group consisting of the following optionally substituted groups:

[0223] -C 1-6 alkyl,

[0224] -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring,

[0225] -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon ring-,

[0226] -(CH2) t -C 6-10 Aryl,

[0227] Z is selected from the following optionally substituted divalent groups:

[0228] -C 6-10 Aryl-,

[0229] -3-8 membered monocyclic saturated or partially unsaturated carbon ring-,

[0230] -5-10 membered bridged saturated or partially unsaturated carbon ring-

[0231] - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S;

[0232] R is selected from the following optionally substituted groups:

[0233] - a 5-12 membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S,

[0234] - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S;

[0235] - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S;

[0236] - a 6-15 membered spirocyclic or fused saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O and S; and

[0237] t is an integer from 0 to 3.

[0238] In these further embodiments, each cyclic group of Y is independently optionally substituted with 1-3 -C 1-6 Alkyl, OH or -OC 1-6 Alkyl substitution, where Y and its substituents appear in -C 1-6 Alkyl or -(CH2) t -optionally substituted by halogen or CN and wherein any carbon chain atom is optionally replaced by NR', O or S, R' is selected from H or -C 1-6 Alkyl, as generally or specifically exemplified above for the substituents of Y; preferably each cyclic group of Y is independently optionally substituted by 1 or 2, more preferably by 1 -C 1-6 Alkyl or -OC 1-6 Alkyl substitution, where Y and its substituents appear in -C 1-6 Alkyl or -(CH2) t - is optionally substituted with halogen. Wherein Y is -(CH2) t In the embodiment of the -carbocyclic group, preferably t is 0 and the carbocyclic ring is a 3-6 membered monocyclic saturated carbocyclic ring, which optionally carries a substituent C 1-6 Alkyl, more preferably the C1-6 When present, the alkyl group is substituted at the ring carbon atom which connects the carbocyclic ring to the rest of the molecule.

[0239] In these further embodiments, each cyclic group of Z is independently optionally substituted by one or more independently selected from halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl group substituted, where -C 1-6 The alkyl group is optionally substituted with halogen or CN, as generally or specifically exemplified above for the substituents of Z; preferably Z is optionally substituted with 1-2, preferably 1, selected from halogen, -C 1-6 Alkyl and -OC 1-6 In one embodiment, Z is unsubstituted.

[0240] In these further embodiments, the optional substituents carried by the R group are 0 to 4, preferably 0 to 3, more preferably 0-2 groups independently selected from the following groups: halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein two substituents attached to the same ring carbon atom can form a 3-8 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached, and the -C in the substituent is 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The alkynyl or cyclic groups are each independently optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted, as generally or specifically exemplified above for the substituents of R; preferably a group selected from the following: halogen, CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) t- a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein two substituents attached to the same carbon atom can form a 3-6 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached, and C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substitution; examples of the substituents are, for example, but not limited to, the general and specific definitions of R-carrying substituents above, preferred exemplary groups include -OH, -CN, F, Cl, -CH3, -CF3, -CH2CH3, -CH2CF3, -CH2CH2CH3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH(OH)(CF3)-, -C(CH3)(OH)(CH3), -CH2CH(OH)CH3, -CH(OH)CH2CH3, -CH2C(CH3)(OH)CH3, -CH2CH2C(CH3)(OH)CH3, -CH2CN, -CH2-OCH3, -CH2-OCH2CH3, -CH2CH2-OCH3, More preferably, -CN, F, -OH, -CH3, -CF3, -CH2CH3, -CH2CF3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2C(CH3)(OH)CH3, -CH2CH2C(CH3)(OH)CH3, -CH(OH)CH2CH3, -CH(OH)(CF3)-, -C(CH3)(OH)(CH3), -CH2-OCH3.

[0241] The present disclosure also provides a compound of formula (I-1), or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof,

[0242] Among them, A1~A 11 、R a , Y, R and t are each as defined above for compounds of formula (I) in general and in specific embodiments; wherein Preferably, 0-1 R a substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S; more preferably optionally substituted with 0-1 R a A substituted five-membered aromatic group containing 3-4 nitrogen heteroatoms; most preferably a five-membered aromatic group containing 4 nitrogen heteroatoms; 11 Preferably CX, A 10 Selected from N and CR b, A8 is C, R b Preferably, A7 is selected from CY or NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom. Specifically, formula (I-1) can be the following compound:

[0243] Where X, Y, R b and R are each as defined above for the compounds of formula (I) in general and in specific embodiments, respectively.

[0244] The present invention also provides a compound of formula (I-2), or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof,

[0245] Among them, A1~A 11 、R a , Y, G, R1, t and f are each as defined above for compounds of formula (I) in general and in specific embodiments; wherein Preferably, 0-1 R a substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S; more preferably optionally substituted with 0-1 R a A substituted five-membered aromatic group containing 3-4 nitrogen heteroatoms; most preferably a five-membered aromatic group containing 4 nitrogen heteroatoms; 11 Preferably CX, A 10 Selected from N and CR b , A8 is C, R b Preferably, A7 is selected from CY or NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom. Specifically, formula (I-2) can be the following compound:

[0246] Where X, Y, R b Each is as defined above for compounds of formula (I) in general and in specific embodiments, wherein As defined above for the general and specific embodiments given for the structural fragments of formula (A) respectively.

[0247] The present invention also provides a compound of formula (I-3), or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof,

[0248] Among them, A1~A 11 、R a , Y, G, R1, t, m, k, n and l are each as defined above for compounds of formula (I) in general and in specific embodiments; wherein Preferably, 0-1 R a substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S; more preferably optionally substituted with 0-1 R a A substituted five-membered aromatic group containing 3-4 nitrogen heteroatoms; most preferably a five-membered aromatic group containing 4 nitrogen heteroatoms; 11 Preferably CX, A 10 Selected from N and CR b , A8 is C, R b Preferably, A7 is selected from CY or NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom. Specifically, formula (I-3) can be the following compound:

[0249] Where X, Y, R b Each is as defined above for compounds of formula (I) in general and in specific embodiments, wherein As defined above for the general and specific embodiments given for the structural fragments of formula (B) respectively.

[0250] The present invention also provides a compound of formula (I-4), or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof,

[0251] Among them, A1~A 11 、R a , Y, G, R1, t, r, p and q are each as defined above for compounds of formula (I) in general and in specific embodiments; wherein Preferably, 0-1 R a substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S; more preferably optionally substituted with 0-1 R a A substituted five-membered aromatic group containing 3-4 nitrogen heteroatoms; most preferably a five-membered aromatic group containing 4 nitrogen heteroatoms; 11 Preferably CX, A 10 Selected from N and CR b , A8 is C, A7 is selected from CY or NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom. Specifically, formula (I-4) can be the following compound:

[0252] Where X, Y, R b Each is as defined above for compounds of formula (I) in general and in specific embodiments, wherein As defined above for the general and specific embodiments given for the structural fragments of formula (C) respectively.

[0253] In specific embodiments, the present disclosure provides compounds of Examples 1-134 below, or or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotopic variant thereof.

[0254] It should be noted that the compounds disclosed herein encompass the above-mentioned independent embodiments or specific embodiments, and also encompass embodiments consisting of any combination or sub-combination of the above-mentioned embodiments or specific embodiments, and also encompass embodiments consisting of any combination of any of the above-mentioned preferred or exemplary embodiments.

[0255] Advantageous Effects of the Invention

[0256] As previously mentioned, SHP2 is known to play a key role in tumorigenesis and a variety of other diseases. We have surprisingly discovered that by introducing low-ionization "conditionally" acidic groups into the molecular structure to avoid highly ionizable strongly acidic groups, the resulting compounds of the present disclosure not only overcome the permeability / transport issues of existing active-site inhibitors, but also bind strongly to the active-site catalytic domain of the SHP2 enzyme, resulting in potent inhibition. Furthermore, they exhibit highly selective inhibition of SHP2, thus showing potential value as anti-proliferative and / or anti-invasive drugs for the prevention, control, and / or treatment of related diseases, particularly neoplastic diseases. In particular, the compounds of the present disclosure are expected to be useful in preventing or treating diseases mediated by SHP2 or that benefit from SHP2 inhibition, such as those defined below, particularly cancer or tumors.

[0257] Specifically, it has been found through research that the compounds disclosed herein can achieve one or more of the following technical effects:

[0258] Potent SHP2 inhibitory activity: The compounds of the present disclosure, especially the compounds specifically exemplified above and below, show generally enhanced inhibitory activity in a SHP2 enzyme inhibition assay relative to the prior art inhibitor 11a-1, with IC50 values ​​against the SHP2 catalytic domain ranging from 0.001 to 1 μM, e.g., 0.001 to 0.5 μM, 0.001 to 0.1 μM, 0.001 to 0.05 μM, 0.01 to 1 μM, 0.01 to 0.5 μM, 0.01 to 0.1 μM, preferably 0.01 to 0.5 μM, more preferably 0.01 to 0.2 μM, as generally demonstrated in Activity Example 1; and / or

[0259] Potent tumor cell proliferation inhibitory activity: The compounds disclosed herein, especially the compounds specifically exemplified above and below, show significantly enhanced proliferation inhibitory activity in a variety of tumor cell lines that rely on SHP2 for growth compared to the prior art inhibitor 11a-1, with IC50 values ​​generally ranging from 0.001 to 1 μM, for example, 0.001 to 0.5 μM, 0.001 to 0.2 μM, 0.001 to 0.1 μM, 0.01 to 0.5 μM, 0.01 to 0.2 μM, 0.01 to 0.1 μM, 0.05 to 0.1 μM, preferably 0.01 to 0.5 μM, more preferably 0.01 to 0.1 μM, as demonstrated in Activity Example 2; and / or

[0260] Broad-spectrum tumor cell inhibitory activity: The compounds disclosed herein, especially the compounds specifically exemplified above and below, exhibit cell proliferation inhibitory activity in a variety of tumor cell lines spanning solid tumors and hematological tumors, with IC50 values ​​generally ranging from 0.001 to 1 μM, for example, 0.001 to 0.5 μM, 0.001 to 0.2 μM, 0.01 to 0.2 μM, 0.01 to 0.1 μM, preferably 0.01 to 0.5 μM, more preferably 0.01 to 0.1 μM, as demonstrated in Activity Example 3; and / or

[0261] Good pharmacokinetic properties, such as a longer t compared to the prior art inhibitor 11a-1 1 / 2 , which can, for example, increase the dosing interval and enable patients to have better compliance; with a significantly increased oral AUC 0-t , is expected to have higher bioavailability, as demonstrated in Active Example 4; and / or

[0262] Demonstrating excellent selective inhibitory activity against SHP2 in the tyrosine phosphatase panel, as demonstrated in Activity Example 5; and / or

[0263] It has satisfactory cardiac safety, with no inhibitory activity on hERG at a concentration of 10 μM; and has a low risk of drug interactions, with no significant inhibitory effect on key CYP isoforms of drug metabolism, as demonstrated in Activity Examples 6-7.

[0264] Based on the beneficial effects of the above compounds of the present invention, the present invention also provides the following technical solutions in various aspects.

[0265] Compounds of the present disclosure for use in therapy or as a medicament

[0266] In one aspect, the present disclosure provides the above-mentioned compounds of the present disclosure, preferably pharmaceutically acceptable salts or solvates thereof, for use as medicaments, in particular as SHP2 inhibitors.

[0267] In another aspect, the present disclosure provides a compound of the present disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, for use in treating and / or preventing a disease mediated by SHP2 or that benefits from SHP2 inhibition.

[0268] In a specific embodiment, the present disclosure provides compounds of the present disclosure for use in treating and / or preventing diseases in which abnormal SHP2 activity promotes the occurrence and development of the disease or in which inhibition of SHP2 activity reduces the incidence of the disease, reduces or eliminates the symptoms of the disease, wherein the disease is selected from, but not limited to, cancer or tumor, cardiovascular disease, immune disorder, fibrosis, eye disorder, systemic lupus erythematosus, diabetes, neutropenia or a combination thereof; preferably, the disease is selected from Noonan syndrome (NS), Leopard syndrome (LS), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and a combination thereof.

[0269] Pharmaceutical compositions and their administration

[0270] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) as defined above, preferably a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition of the present disclosure can be used to treat or prevent diseases mediated by SHP2, such as tumors or cancers.

[0271] The above-mentioned pharmaceutical compositions of the present disclosure can be prepared by technology known to those skilled in the art, such as technology disclosed in Remington's Pharmaceutical Sciences the 20th edition. For example, tablets, powders, capsules, lozenges, granules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. can be formulated. The compositions can contain conventional components in pharmaceutical preparations, such as diluents (such as glucose, lactose or mannitol), carriers, pH regulators, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavorings, flavorings, 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 in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004.

[0272] The administration and use of the disclosed pharmaceutical compositions are in accordance with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the location of the agent being delivered, the method of administration, the administration schedule, and other factors well known to physician practitioners. The optimal dosage level and frequency of administration of the disclosed compounds or pharmaceutical compositions can be determined by those skilled in the art through standard tests in the field of pharmaceutical research.

[0273] The compositions of the present disclosure can be administered in any suitable manner, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhalation, epidural, and intranasal, and for local treatment, intralesional administration can also be employed. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In a preferred embodiment, the pharmaceutical compositions of the present disclosure are administered orally.

[0274] When administering the compounds of the present disclosure to human subjects, the daily dosage is generally determined by the prescribing physician based on the individual patient's age, weight, sex, and severity of the disease. Typically, dosage levels of about 0.1 mg / kg to about 150 mg / kg body weight are useful for treating the aforementioned diseases. For a 70 kg human subject, a suitable dosage range for the compounds of the present disclosure can be routinely determined by one skilled in the art, for example, 1-1000 mg / day.

[0275] When dosages of a drug or a pharmaceutically acceptable salt thereof are described herein, it is understood that the dosage is based on the weight of the free base and does not include any hydrate or solvate thereof unless the specification indicates that the dosage is based on the weight of the salt, hydrate or solvate.

[0276] Treatment methods and uses

[0277] As described above and demonstrated in the examples below, the compounds disclosed herein and various embodiments thereof, particularly the compounds prepared and characterized in the examples, exhibit potent and selective inhibition of SHP2. Inhibition of SHP2 activity further leads to ERK dephosphorylation and inhibition of the cancer-promoting functions of the RAS-RAF-ERK pathway.

[0278] Therefore, on the other hand, the present disclosure provides medical uses of the compounds of the present disclosure, preferably pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising the same, or the pharmaceutical combinations of the present disclosure described below, for inhibiting the abnormal activity of SHP2 in cells, especially for inhibiting abnormal cell proliferation in mammals, or for treating and / or preventing diseases mediated by SHP2, especially those diseases that benefit from SHP2 inhibition.

[0279] On the other hand, the present disclosure also provides a method for inhibiting abnormal cell proliferation in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same.

[0280] On the other hand, the present disclosure provides a method for treating and / or preventing diseases mediated by SHP2, particularly those that benefit from SHP2 inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, or a pharmaceutical combination of the present disclosure described below.

[0281] In another aspect, the present invention provides the use of a compound of the present disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing diseases mediated by SHP2, especially those diseases that benefit from SHP2 inhibition.

[0282] Based on the same properties, the present disclosure also provides a method for inhibiting SHP2 activity, particularly an in vitro method, comprising contacting a compound of the present disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, with a sample or applying it to a sample (e.g., a biological sample), specifically including cells, cellular or subcellular extracts, and / or biomolecules in an artificial environment. Specifically, the present disclosure also provides the in vitro use of a compound of the present disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, as a SHP2 inhibitor in research, particularly as a research tool compound for inhibiting SHP2.

[0283] For each method and use technical solution provided by the present disclosure, the disease mediated by SHP2 is selected from: cancer or tumor, cardiovascular disease, immune disorder, fibrosis, eye disorder, systemic lupus erythematosus, diabetes, neutropenia or a combination thereof. Preferably, the disease is selected from Noonan syndrome (NS), Leopard syndrome (LS), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and a combination thereof. Preferably, any one of the cancers is a primary cancer or a cancer metastasis.

[0284] SHP2-mediated diseases also specifically refer to diseases caused by abnormal cell proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues, particularly cancers or tumors. The cancers or tumors can be solid tumors or hematological malignancies, and can be hormone-dependent or hormone-resistant. In certain embodiments, the cancer is a drug-resistant phenotype of a cancer disclosed herein or known in the art, and can be primary or metastatic. Therefore, the compounds, compositions, combinations, and methods disclosed herein can be used to treat precancerous neoplasia, tumor growth, tumor invasion, tumor metastasis, and angiogenesis.

[0285] Cancers that can be treated with the compounds of the present disclosure are selected from, but are not limited to, juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), neuroblastoma, esophageal cancer, breast cancer (including triple-negative breast cancer), lung cancer (including small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma), lung adenocarcinoma, colon cancer, rectal adenocarcinoma, adenoid cystic carcinoma, gastric cancer, gastrointestinal stromal tumor, head and neck cancer (e.g., head and neck squamous cell carcinoma), ovarian cancer, prostate cancer, melanoma, skin or intraocular melanoma, soft tissue sarcoma; oral and pharyngeal (lip, tongue, mouth, throat, nasopharynx), stomach, small intestine, large intestine, colon, rectum, anal region cancer, liver and biliary tract, pancreas, bone, connective tissue, skin (including epithelial cell cancers) cancers of the vagina, vulva, cervix, uterus, endometrium, fallopian tube, urethra, penis, testicles, bladder, ureters, kidneys, and other urinary tissues, including renal cell carcinoma, renal pelvis cancer, and hepatocellular carcinoma; cancers of the stomach, esophagus, eye, brain, spinal cord, and central and peripheral nervous systems and related structures, such as meningeal cancer, primary CNS lymphoma, oligodendroglioma, medulloblastoma, spinal tumors, brainstem glioma, or pituitary adenoma; cancers of the thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin's lymphoma, parathyroid cancer, adrenal cancer, multiple myeloma, medulloblastoma, and hematopoietic malignancies, including chronic or acute lymphocytic leukemia, chronic or acute myeloid leukemia, chronic myelomonocytic leukemia, and lymphomas, including lymphocytic, granulocytic, and monocytic, mantle cell lymphoma, and histiocytic lymphoma.

[0286] Therefore, in a preferred embodiment of this aspect, the present disclosure provides the above-mentioned various methods and use technical solutions for treating or preventing cancer or tumors by inhibiting SHP2 activity. In a further preferred embodiment, the present disclosure provides the above-mentioned various methods and use technical solutions for treating or preventing Noonan syndrome (NS), Leopard syndrome (LS), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and combinations thereof by inhibiting SHP2 activity.

[0287] Drug combinations

[0288] The compounds of the present disclosure may be administered as the sole active ingredient or in combination with another drug or therapy.

[0289] Therefore, in another aspect, the present disclosure provides a pharmaceutical combination comprising a compound of the present disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, and another active agent, or consisting of both. The pharmaceutical combination is used to treat and / or prevent diseases mediated by SHP2.

[0290] The other active agent can be one or more additional compounds of the present disclosure, or can be a second or additional (e.g., a third) compound that is compatible with the compounds of the present disclosure, i.e., does not adversely affect each other, or has complementary activities. For example, these active agents can be compounds that are known to modulate other biological activity pathways, or can be compounds that modulate different components in the biological activity pathway involved in the compounds of the present disclosure.

[0291] In some embodiments of the present disclosure, other active agents that can be used in combination with the compounds of the present disclosure include, but are not limited to, alkylating agents, antimetabolites, antimitotic agents, checkpoint inhibitors, topoisomerase inhibitors, cytotoxic antibiotics, aromatase inhibitors, angiogenesis inhibitors, antisteroids or antiandrogens, mTOR inhibitors, tyrosine kinase inhibitors, and the like.

[0292] The compounds of the present disclosure may also be combined with anti-tumor therapies including, but not limited to, surgery, radiation therapy, transplantation (eg, stem cell transplantation, bone marrow transplantation), tumor immunotherapy, chemotherapy, and the like.

[0293] Other active agents used in combination with the compounds of the present invention can be administered simultaneously, separately or sequentially with the compounds of the present invention by the same or different routes of administration. The other active agents can be co-administered with the compounds of the present invention in a single pharmaceutical composition, or be administered separately in different discrete units, such as a combination product, preferably in the form of a medicine box, which can be administered simultaneously or sequentially when administered separately, and the sequential administration can be close or distant in time. They can be prepared and / or formulated by the same or different manufacturers. Moreover, the compounds of the present invention and the other active agents can be (i) administered before the combination product is sent to the physician (e.g., in the case of a medicine box comprising a compound of the present invention and another drug); (ii) administered by the physician himself (or under the guidance of a physician) before administration; (iii) administered by the patient himself, such as during the sequential administration of the compounds of the present invention and the other active agents, in a combination therapy.

[0294] Therefore, in another aspect, the present disclosure also provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present disclosure or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotopic variant thereof, and a device for separately containing the compositions, such as a container, a sub-bottle, or a separate foil package, and instructions for use. The kit of the present disclosure is particularly suitable for administering different dosage forms, such as an oral dosage form and a parenteral dosage form, or for administering different compositions at different dosage intervals.

[0295] With respect to the technical solutions of the pharmaceutical composition, drug combination or drug kit disclosed above, the diseases mediated by SHP2 involved therein are as defined above for the methods and uses disclosed herein.

[0296] For the above-mentioned compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations and kits of the present disclosure, the compounds of the Examples herein are preferred.

[0297] Preparation method of the compound of the present invention

[0298] In another aspect, the present disclosure also provides a process for preparing the defined compound.

[0299] The compounds of the present disclosure can be prepared by a variety of methods, including the general methods given below, the methods disclosed in the Examples, or methods analogous thereto.

[0300] Standard synthetic methods and operations for preparing organic compounds and functional group conversions and operations are known in the art and can be found in standard textbooks, such as Smith MB, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 7th edition, Wiley, 2013). For each reaction step of each general synthesis scheme, appropriate reaction conditions are known to those skilled in the art or can be routinely determined. The method steps for synthesizing the disclosed compounds can be under reaction conditions known per se (including those conditions specifically mentioned), in the absence or conventional presence of a solvent or diluent (including, for example, a solvent or diluent that is inert and soluble to the reagents used), in the absence or presence of a catalyst, a condensing agent or a neutralizing agent (such as an ion exchanger, such as a cation exchanger, such as H +The reaction is carried out at reduced, normal or elevated temperature (e.g., from about -100°C to about 190°C, including, for example, from about -78°C to about 150°C, such as from about 0°C to about 125°C, room temperature, -20 to 40°C or reflux temperature), under atmospheric pressure or in a closed vessel, under pressure when appropriate, and / or under an inert atmosphere, such as an argon or nitrogen atmosphere, depending on the nature of the reaction and / or the reactants.

[0301] Unless otherwise specified, the raw materials and reagents used in the preparation of the compounds are commercially available or known in the literature, or can be prepared by a person skilled in the art by the following methods, methods analogous to those given below, or standard methods known in the art. Unless otherwise specified in the process description, suitable solvents are those conventional solvents well known to a person skilled in the art for the specific type of reaction involved, such as water, esters, ethers, liquid aromatic hydrocarbons, alcohols, nitriles, halogenated hydrocarbons, amides, bases, carboxylic anhydrides, cyclic, linear or branched hydrocarbons, or mixtures of these solvents. Such solvent mixtures can also be used for post-processing, for example, post-processing by chromatography or partitioning.

[0302] If necessary, the raw materials and intermediates in the synthetic reaction scheme can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. If the intermediates and final products are obtained in solid form, purification can also be carried out by recrystallization or aging. The materials can be characterized using conventional methods including physical constants and spectral data. The reaction mixture is post-processed in a conventional manner, for example by mixing with water, separating the phases, and, if appropriate, purifying the crude product by chromatography.

[0303] Those skilled in the art will recognize the presence or absence of stereocenters in the disclosed compounds. At all stages of the reaction, the resulting mixture of isomers can be separated into individual isomers, such as diastereomers or enantiomers, or into any desired mixture of isomers, such as racemates or mixtures of diastereomers, see, for example, E.L. Eliel, S.H. Wilen, and L.N. Mander, "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994).

[0304] In certain specific cases, it may be necessary to protect a particular reactive group with an appropriate protecting group to avoid interference with the reaction of other reactive groups. Suitable protecting groups and methods of protection and deprotection using such suitable protecting groups are well known to those skilled in the art; examples thereof can be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999).

[0305] The following is only an example of a general synthetic scheme for synthesizing the compounds disclosed herein. Other routes and other reactants and intermediates known to those of ordinary skill in the art can also be used to obtain the compounds disclosed herein.

[0306] For the sake of clarity, in the exemplary synthetic schemes described below, unless otherwise specified, X, Y, Z, and R appearing in the structural formula of each intermediate compound are as defined above for the compounds of the present disclosure, wherein PG represents a suitable protecting group that can be determined by those skilled in the art based on knowledge of organic chemistry.

[0307] Synthesis of the Disclosed Compounds

[0308] General synthetic method

[0309] In the following schemes, the variables in the general formula have the same meanings as those given above for the compounds of formula (I) or its various embodiments, unless otherwise indicated.

[0310] Process 1

[0311] Scheme 1 illustrates a general synthetic route that can be used to prepare the compounds of the present disclosure and various embodiments thereof.

[0312] Take 6-tetrazolyl indole as an example:

[0313] Process 2

[0314] Scheme 2 illustrates a synthetic route for compounds of formula A and A' in Scheme 1.

[0315] Process 3

[0316] Scheme 3 illustrates a synthetic route for the intermediate of formula 4 in Scheme 2.

[0317] Process 4

[0318] Scheme 4 illustrates a synthetic route for the intermediate of formula 4 in Scheme 2.

[0319] Process 5

[0320] Scheme 5 illustrates a synthetic route for intermediate 4 in Scheme 2 (when Z is a cyclic amine (such as an alicyclic amine)).

[0321] Process 6

[0322] Scheme 6 illustrates a synthetic route for the intermediate of formula 4 in Scheme 2.

[0323] Process 7

[0324] Scheme 7 illustrates a synthetic route for the intermediate of formula 4 in Scheme 2.

[0325] For non-indole intermediate A Azaindole compounds can be used with commercial azaindole As raw materials, A was synthesized similarly to process 2.

[0326] For non-indole intermediate A Benzofuran compounds can be synthesized similarly to Scheme 2. Scheme 8 illustrates a synthetic route for intermediate 4.

[0327] Process 8

[0328] For non-indole intermediate A Benzothiophene compounds can be synthesized using the benzofuran compound scheme. Scheme 9 illustrates a synthetic route to benzothiophene intermediate 27a (an alternative to intermediate 27).

[0329] Process 9

[0330] For non-indole intermediate A For example, pyrimidine-containing fused ring compounds can be synthesized using a similar method to Scheme 2. Scheme 10 illustrates a synthetic route for intermediate 4.

[0331] Process 10

[0332] For non-6-tetrazolyl indole intermediate A when for When, Scheme 11 illustrates a synthetic route for intermediate A.

[0333] Process 11

[0334] when for When, Scheme 12 illustrates a synthetic route for intermediate A.

[0335] Process 12

[0336] when for When, Scheme 13 illustrates a synthetic route for intermediate A.

[0337] Process 13

[0338] Process 14

[0339] Scheme 14 illustrates a synthetic route for compounds of formula B and B' in Scheme 1 when R is a cyclic amine (particularly an alicyclic amine).

[0340] Process 15

[0341] Scheme 15 illustrates that when R in Scheme 1 is an aryl group (including a heteroaryl group), compounds of formula B and B' can be obtained by any aryl-aryl coupling reaction.

[0342] In the above process, the order of specific unit reactions can be flexibly adjusted according to conventional conditions well known to those skilled in the art.

[0343] Specifically, the present invention provides a method for preparing the above-mentioned compound of the present invention, which comprises:

[0344] 1. Preparation of Intermediates A and A'

[0345] The compound of formula 1

[0346] It reacts with a halogenated compound (such as Y-Br) in the presence of a base (such as cesium carbonate) in a solvent such as DMF to produce compound 2. The compound of formula 2 can also be obtained by reacting the compound of formula 1 with the corresponding organic halide (such as iodide) or organic boronic acid in the presence of a catalyst such as a copper salt (such as copper iodide, copper acetate, etc.).

[0347] The compound of formula 2 reacts with a cyaniding agent (such as copper cyanide or zinc cyanide) in an organic solvent such as NMP to produce a compound of formula 3.

[0348] The compound of formula 3 and a halogenated compound (such as IZ-NHBoc) are reacted in the presence of silver oxide over a catalyst such as palladium / 2-nitrobenzoic acid to introduce a substituent Z to obtain a compound of formula 4. The compound of formula 4 can also be obtained by reacting the compound of formula 3 with an organic boronic acid under the co-catalysis of a catalyst such as a silver salt (such as silver trifluoroacetate) and a rhodium reagent (such as (RhCpCl2)2.

[0349] The cyano group in the compound of formula 4 can also be prepared by the above series of transformations using a carboxylic acid derivative (such as the compound of formula 7) via the intermediate of formula 10.

[0350] The introduction of the substituent Z can also be achieved by reacting an organic boronic acid with an intermediate 14 in the presence of a palladium reagent (such as (Pd(PPh3)2Cl2) for catalysis.

[0351] When Z is an alicyclic amine (eg, piperidine), the compound of formula 2 reacts with the amine in the presence of iodine to produce an intermediate of formula 16.

[0352] The iodine atom can be removed by reduction with zinc powder, and the bromide can be converted to the cyano homolog of formula 4 using a cyanating reagent as shown above.

[0353] Another method for preparing the compound of formula 4 is to activate the phenolic compound 19 to a triflate 20.

[0354] Then, it reacts with terminal alkyne in the presence of a palladium catalyst (e.g., (Pd(PPh3)2Cl2)) to generate benzyne 21.

[0355] Then, under the action of a strong base (such as sodium tert-butoxide) and a palladium catalyst (such as t-Buxphos.PdG3), it directly reacts with Y-NH2 to close the ring to obtain the compound of formula 4.

[0356] The preparation of the compound of formula 4 can also start from nitrobenzene derivative 22, which is reduced to the corresponding aniline 23 using a reducing agent (such as sodium dithionite), and then undergoes reductive amination with ketone Y=O to obtain the intermediate of formula 24.

[0357] Using similar reaction conditions, the intermediate of formula 24 is reacted with a terminal alkyne in the presence of a catalyst such as palladium (e.g., (Pd(PPh3)2Cl2) to generate benzyne 25.

[0358] Then, it is treated with an inorganic strong base (such as potassium hydroxide) to obtain a compound of formula 4. Then, the amino protecting group Boc is removed under standard conditions to obtain intermediate 5.

[0359] Then treat with azide reagent (sodium azide, trimethylsilyl azide, etc.) to prepare intermediate A series compounds.

[0360] Further react with oxalic acid monomethyl chloride to obtain a compound of formula 6,

[0361] The intermediate A' series of compounds can be prepared by treating the product under standard ester hydrolysis conditions.

[0362] Azaindole compounds can be used with commercial azaindole As raw materials, A was synthesized similarly to the above steps.

[0363] Benzofuran compounds can be synthesized using a similar process as Scheme 2. The key intermediate 4 can be prepared by starting with compound 26, which reacts with an acyl chloride under the action of anhydrous aluminum chloride to obtain compound 27.

[0364] Then, under the action of a base (such as sodium hydrogen), it is substituted with a halogenated acetate (such as methyl 2-bromoacetate) to obtain a compound of formula 28.

[0365] After hydrolysis, the compound is treated with a base (such as sodium acetate) and the ring is closed to obtain the compound of formula 30. The bromide is then converted into a cyanide group using a cyaniding reagent (such as zinc cyanide), and then brominated with a brominating reagent (such as N-bromosuccinimide) to obtain the compound of formula 32, which is prepared by introducing the substituent Z in the presence of an organic boronic acid in the presence of a palladium reagent (such as (Pd(PPh3)2Cl2)).

[0366] Benzothiophene compounds can be synthesized using the above-mentioned benzofuran compound process. The key intermediate 27a can be prepared by starting from the above-mentioned compound 27, treating it with dimethylaminomethylthiochloride to obtain the compound of formula 33, heating and rearranging it to obtain the compound of formula 34, and then treating it with a base (such as sodium hydroxide) to obtain 27a.

[0367] Pyrimidine-containing fused ring compounds can be synthesized using a similar process as Scheme 2. The preparation of the key intermediate 4 can start from compound 35, and a substitution reaction occurs under the action of an organic base (such as N,N-diisopropylethylamine) to obtain a compound of formula 36.

[0368] Then, the terminal alkyne is reacted with a catalyst such as palladium (e.g., (Pd(PPh3)2Cl2)) and Cu (e.g., copper iodide) to generate benzyne 37.

[0369] After being treated with tetrabutylammonium fluoride, the chloro compound is converted into the compound of formula 4 using a cyaniding agent (such as zinc cyanide).

[0370] The preparation of the compound of formula 4 can also start from commercial raw material 56, and undergo a substitution reaction under the action of a base (such as cesium carbonate) to obtain a compound of formula 57. The substituent Z is then introduced into the compound of formula 4 by reacting the compound with a halogenated compound (such as IZ-NHBoc) in the presence of silver oxide under the catalytic action of a catalyst such as palladium / 2-nitrobenzoic acid.

[0371] The synthesis of non-tetrazolyl compounds follows a similar process to Scheme 2 to synthesize A after heterocyclic formation. The heterocyclic synthesis process is exemplified below. A triazole compound can be prepared from commercial starting material 2a. Substituent Z can be introduced into compound 39 by reacting with a halide (e.g., IZ-NHBoc) in the presence of silver oxide over a catalyst such as palladium / 2-nitrobenzoic acid. This is then reacted with trimethylethynylsilane over a copper catalyst (e.g., cuprous iodide) and a palladium catalyst (e.g., tetrakistriphenylphosphine palladium) to yield compound 40. This is then deprotected and treated with trimethylsilylazide for further deprotection to produce compound A.

[0372] More non-tetrazolyl acidic heterocyclic intermediates A can be prepared from intermediate 4 by treating it with hydroxylamine hydrochloride to obtain compound 43, which is then treated with a dehydrating agent (such as CDI, trifluoroacetic anhydride, etc.) to obtain compound 44, which is then deprotected to prepare A.

[0373] Intermediate 4 can be treated with an inorganic strong base (such as potassium hydroxide) and hydrogen peroxide in a solvent (such as DMSO) to obtain an amide intermediate 45, which can then react with Lawesson's reagent to generate the corresponding thioamide 46. After treatment with a methylating agent (such as iodomethane), a compound of formula 47 is obtained. The compound further reacts with 2-hydrazino-2-carbonylacetamide and is dehydrated to 48 under the action of trifluoroacetic anhydride. The protecting group is then removed to obtain the cyano-substituted intermediate A.

[0374] If compound 47 is treated with acetylhydrazine, the methyl-substituted intermediate A can be prepared by removing the protecting group.

[0375] 2. Preparation of Intermediates B and B'

[0376] When R is an aryl group (including a heterocyclic aryl group), the intermediate of formula B can be obtained by various aryl-aryl coupling reactions, such as the Suzuki reaction of an arylboronic acid derivative with a corresponding aryl halide in the presence of a palladium catalyst. In the present disclosure, both components of the coupling reaction can bear arylboronic acid derivatives or corresponding aryl halide, such as compounds 53 and 54, which are coupled to form the intermediate of formula B.

[0377] The intermediate of formula B is converted to the intermediate of formula B' through a process similar to the conversion of intermediate A to intermediate A' described above.

[0378] When R is an alicyclic amine, the free amine 50 (or the compound 49 is deprotected to obtain the corresponding free amine)

[0379] and p-nitrobenzene in the presence of a weak base (such as potassium carbonate) to achieve aromatic ring substitution to obtain a compound of formula 51,

[0380] The nitro group can be converted by palladium-carbon or an inorganic reducing agent (such as sodium dithionite) to obtain an aniline derivative of formula B.

[0381] Intermediate B reacts with oxalyl chloride monoester and then hydrolyzes to form a compound of formula B'.

[0382] 3. Preparation of the compounds of the present disclosure

[0383] The compounds of the present disclosure can be prepared by converting the oxalic acid intermediate A' or B' into an active intermediate acid chloride, which is then reacted with B or A, respectively. Alternatively, the compounds can be prepared by reacting the free acid A' or B' with the free amine B or A, respectively, in the presence of an amide condensing agent (e.g., T3P, DCC, PyBOP, etc.). Typically, an organic base (e.g., triethylamine, diisopropylethylamine, etc.) is also used.

[0384] When specific conditions are not specified in the above general synthetic methods, the reaction is usually carried out according to conventional conditions of this type well known to those skilled in the art, or according to the conditions recommended by the manufacturer. DETAILED DESCRIPTION

[0385] The present invention will be further described below with reference to the following examples. It should be noted that the following examples are illustrative only and should not be considered as limiting the scope of protection of the present invention.

[0386] In describing the embodiments and the specific examples that follow, the following abbreviations are used herein:

[0387] ACN (acetonitrile); AcOH (acetic acid); AgO (silver oxide); b / d / t / q (peak shape in nuclear magnetic resonance, b (broad peak) / d (doublet) / t (triplet) / q (quartet)); Boc (tert-butyloxycarbonyl); BSA (bovine serum albumin); t-BuONa (sodium tert-butoxide); Bu2SnO (di-n-butyltin oxide); t-Buxphos-PdG3 (methanesulfonic acid (2-di-tert-butyl) (2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)); CDCl3 (deuterated chloroform); CDI (N',N'-carbonyldiimidazole); CD3OD (deuterated methanol); DiFMUP (6,8-difluoro-4-methyl-7-(phosphonooxy)-2H-1-chromen-2-one); (CF3SO2)2O (trifluoromethane) (sulfonic anhydride); CO2 (carbon dioxide); Cs2CO3 (cesium carbonate); CuI (copper iodide); Cu(OAc)2 (copper acetate); CYP (cytochrome protein, such as CYP1A2 / CYP2B6 / CYP2C8 / CYP2C9 / CYP2C19 / 2D6 / CYP3A4); DCC (dicyclohexylcarbodiimide); DCM (dichloromethane); DIEA or DIPEA (N, N-diisopropylethylamine); DMEM (a cell culture medium); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (hexadeuterated dimethyl sulfoxide); dppf (1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); E (double bond trans isomer); EA (ethyl acetate); EDTA (ethylenediaminetetraacetic acid); hERG (Kv11 encoded by the hERG gene).1 potassium channel conductance); Et (ethyl acetate); EtOH (ethanol); FBC (fed-batch fermentation); FCC (flash column chromatography); g (gram); GLP (Good Laboratory Practice); h (hour); HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HCl (hydrogen chloride); HCl-MeOH (hydrogen chloride-methanol solution); HEPES (4-hydroxyethylpiperazineethanesulfonic acid); HFiPA (hexafluoroisopropanol); HLM (human liver microsomes) ; H2O (water); H3PO4 (phosphoric acid); H2SO4 (sulfuric acid); Hz (hertz); I2 (iodine); IC50 (the concentration of the inhibitor at which 50% of the activity is inhibited); IV (intravenous administration); IMDM (a cell culture medium); J (nuclear magnetic resonance coupling constant); K2CO3 (potassium carbonate); Km (Michaelis constant for enzyme reaction); KOH (sodium hydroxide); L (volume in liters); LCMS (liquid chromatography-mass spectrometry); LC-MS / MS (liquid chromatography-mass spectrometry-mass spectrometry); LDA (lithium diisopropylamide); LiOH ( Lithium hydroxide); LR (Rosen's reagent); Lum (luminescence intensity); MeI (methyl iodide); MEM (a cell culture medium); MeMgBr (methylmagnesium bromide); MeOH (methanol); Methanol-d4 (tetradeuterated methanol); mg (milligram); MHz (megahertz); min (minute); mL (milliliter); mmol (millimolar); MOM (methoxymethyl ether); MS-ESI (electrospray ionization mass spectrometry); MTBE (methyl tert-butyl ether); m / z (mass-to-charge ratio); N2 (nitrogen); N aBH(OAc)3 (sodium triacetate borohydride); NaCl (sodium chloride); NADPH (nicotinamide adenine dinucleotide phosphate); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); Na2SO2O4 (sodium dithionite); Na2SO3 (sodium sulfite); Na2SO4 (sodium sulfate); NBS (bromosuccinimide); NCS (chlorosuccinimide); NH4Cl (ammonium chloride); N2H4-H2O (hydrazine hydrate); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance spectroscopy). 1 H(proton) / 13 C (carbon-13 nucleus) / 19F (fluorine-19 nucleus); pNPP (p-nitrophenylphosphate disodium salt); PdCl2(dtbpf) (1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride); Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride); Pd(OAc) (palladium acetate); Pd(PPh3)4 (tetrakistriphenylphosphine palladium); Pd(PPh3)2Cl2 (tetrakistriphenylphosphine palladium dichloride); PE (petroleum ether); PhSO2Cl (benzenesulfonyl chloride); PO (oral administration); POCl3 (phosphorus oxychloride); PTP (protein tyrosine Phosphohydrolases, such as SHP1 (Src homology region 2 protein tyrosine phosphatase 1) / SHP2 (Src homology region 2 protein tyrosine phosphatase 2) / HePTP (hematopoietic protein tyrosine phosphatase) / Laforin (EPM2A glucan phosphatase) / LMWPTP (low molecular weight protein tyrosine phosphatase) / LYP (lymphoid-specific tyrosine phosphatase) / PTP1B (protein tyrosine phosphatase 1B) / PRL (liver regenerating phosphatase) / SSU72 (SSU72 protein phosphatase) / VHR (dual specificity protein phosphatase 3) / FAP 1 (Streptococcus parasanguinis adhesin) / STEP (striatal-enriched protein tyrosine phosphatase) / CDC14A (cell division cycle protein 14A) / CD45 (type C protein tyrosine phosphatase receptor) / PP5 (protein phosphatase 5)); PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate); RT (room temperature); QT (time required for the complete process of ventricular depolarization and repolarization); SiO2 (silica gel); RFU (fluorescence intensity); rpm (revolutions per minute); T3P (1-propylphosphonic cyclic anhydride); TBAF (tetrabutylammonium fluoride); TE A (triethylamine); Tf (trifluoromethanesulfonyl); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); TIPS (triisopropylsilyl); TLC (thin layer chromatography); TMS (trimethylsilane); TMSN3 (trimethylsilyl azide); TsOH (p-toluenesulfonic acid); TsOH·H2O (p-toluenesulfonic acid monohydrate); Z (double bond cis isomerism); Zn (zinc); Zn(CN)2 (cyanozinc); δ (nuclear magnetic resonance chemical shift); μL (microliter); μM (micromolar concentration); μmol (micromole).

[0388] In the following examples, the names of the synthesized compounds and their structures are given. Any discrepancies between the names and structures are unintentional; in this case, the structure is decisive.

[0389] In the following examples, the experimental procedures, where specific conditions are not specified, generally followed conditions conventional for such reactions or those recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight, liquid ratios are by volume, and all temperatures are given in degrees Celsius.

[0390] Unless otherwise specified, the experimental materials and reagents used in the following examples were obtained from commercial sources, prepared according to existing methods, or prepared according to methods similar to those disclosed in this application. Unless otherwise specified, all reagents were used without further purification.

[0391] In the following examples, 1 H-NMR spectra were recorded using a Bruker (400 MHz), with chemical shifts expressed as δ (ppm) relative to the deuterated solvent peak (CDCl3: δ = 7.26 ppm; CD3OD: δ = 3.31 ppm; DMSO-d6: δ = 2.50 ppm). Liquid chromatography / mass spectrometry (LC / MS / MS) was performed using an Aglient 1260 liquid chromatograph coupled with an Aglient G6125B mass spectrometer. Gas chromatography / mass spectrometry was performed using a Shimadzu GCMS-QP2010SE.

[0392] 1. Synthesis of intermediates

[0393] Synthesis of Intermediate AA1: 6-Bromo-1-cyclopropyl-5-fluoro-1H-indole

[0394] To a DMF solution (20 mL) of 6-bromo-5-fluoro-1H-indole AA1-1 (1.00 g, 4.67 mmol) and cyclopropylboronic acid (1.20 g, 14.0 mmol) was added 2,2'-bipyridine (2.20 g, 14.0 mmol), copper acetate (1.70 g, 9.34 mmol), and sodium carbonate (0.99 g, 9.34 mmol). The resulting mixture was reacted at 70°C for 8 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain AA1 (0.91 g, 77% yield) as a yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.72-7.71(m,1H),7.31(d,J=9.2Hz,1H),7.15(d,J=3.2Hz, 1H),6.37-6.36(m,1H),3.32-3.29(m,1H),1.11-1.00(m,2H),0.99-0.98(m,2H). MS-ESI[M+H]+ :253.9.

[0395] Synthesis of Intermediate AA2: 2-(4-aminophenyl)-1-cyclobutyl-6-(1H-tetrazol-5-yl)-1H-indol-5-ol

[0396] Step 1: 1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid methyl ester

[0397] To a DMF solution (18 mL) of methyl 5-methoxy-1H-indole-6-carboxylate AA2-1 (2.40 g, 11.7 mmol) and cesium carbonate (13.3 g, 40.9 mmol) was added cyclobutyl bromide (5.05 g, 37.4 mmol). The resulting mixture was heated to 85°C under nitrogen and stirred for 16 hours. After the reaction was complete, the mixture was cooled and filtered. The filtrate was washed with aqueous lithium chloride solution and concentrated. The mixture was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain AA2-2 (2.3 g) as a light green oil. MS-ESI [M+H] + :260.0.

[0398] Step 2: 2-(4-((tert-Butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid methyl ester

[0399] To a DMF solution (25 mL) of methyl 1-cyclobutyl-5-methoxy-1H-indole-6-carboxylate AA2-2 (2.65 g, 10.2 mmol), tert-butyl (4-iodophenyl)carbamate (4.89 g, 15.3 mmol), 2-nitrobenzoic acid (2.56 g, 15.3 mmol), and silver oxide (1.78 g, 7.66 mmol) was added palladium acetate (115 mg, 0.511 mmol). The resulting mixture was heated to 40°C under nitrogen and stirred for 16 hours. After the reaction, the mixture was cooled and filtered. The filtrate was washed with aqueous lithium chloride solution and concentrated. The mixture was purified by silica gel column chromatography (PE / EA = 65 / 35) to give AA2-3 (1.5 g) as a light yellow solid. MS-ESI [M+H] + :451.1.

[0400] Step 3: 2-(4-((tert-Butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid

[0401] To a solution of methyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-methoxy-1H-indole-6-carboxylate AA2-3 (0.6 g, 1.33 mmol) in a mixture of THF / MeOH / H2O = 1 / 1 / 1 (12 mL) was added lithium hydroxide (223.5 mg, 5.33 mmol). The resulting mixture was heated to 60°C and stirred for 2 hours. After the reaction was completed, the mixture was concentrated, adjusted to pH 7 with 1N hydrochloric acid, extracted with ethyl acetate (20 mL), and concentrated to give AA2-4 (580 mg) as a white solid. MS-ESI [M+H] + :437.1.

[0402] Step 4: tert-Butyl (6-carbamoyl-1-cyclobutyl-5-methoxy-1H-indol-2-yl)phenyl)carbamate

[0403] To a DMF solution (5 mL) of 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid AA2-4 (550 mg, 1.26 mmol), ammonium chloride (674.0 mg, 12.6 mmol), and N-ethyl-N-isopropyl-2-propylamine (650.2 mg, 1.57 mmol) was added HATU (598.9 mg, 1.57 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction, ethyl acetate (20 mL) was added, the mixture was washed with aqueous lithium chloride solution, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to give AA2-5 (550 mg) as a light yellow solid. MS-ESI [M+H] + :436.1.

[0404] Step 5: tert-Butyl (4-(6-cyano-1-cyclobutyl-5-methoxy-1H-indol-2-yl)phenyl)carbamate

[0405] To a DCM solution (6 mL) of tert-butyl (6-carbamoyl-1-cyclobutyl-5-methoxy-1H-indol-2-yl)phenyl)carbamate AA2-5 (550 mg, 1.26 mmol) and triethylamine (817.9 mg, 8.08 mmol) was added dropwise trifluoroacetic anhydride (848.8 mg, 4.04 mmol) in an ice-water bath. The mixture was stirred under nitrogen for 1 hour. After the reaction was complete, the mixture was concentrated, ethyl acetate (20 mL) was added, and the mixture was washed with aqueous sodium bicarbonate (10 mL) and concentrated. The mixture was purified by silica gel column chromatography (PE / EA = 7 / 3) to obtain AA2 (250 mg) as a brown solid. MS-ESI [M+H] + :418.1.

[0406] Synthesis of Intermediate AA3: tert-Butyl (4-(6-cyano-1-cyclopropyl-5-fluoro-1H-indol-2-yl)cyclohex-3-en-1-yl)carbamate

[0407] Step 1: 6-Bromo-5-fluoro-1-(phenylsulfonyl)-1H-indole

[0408] To a solution of 6-bromo-5-fluoro-1H-indole AA1-1 (4.00 g, 18.7 mmol) in THF (60 mL) at 0°C was added sodium hydride (0.90 g, 22.4 mmol) and stirred for 20 minutes. Benzenesulfonyl chloride (2.90 mL, 22.4 mmol) was then added to the reaction mixture. The temperature of the reaction mixture was slowly raised to room temperature and stirred for 16 hours. Saturated aqueous ammonium chloride (15 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted three times with ethyl acetate (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford AA3-1 (6.0 g, 90% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.16 (d, J = 8.0 Hz, 1H), 8.04-8.02 (m, 2H), 7.96 (d, J = 4.0 Hz, 1H), 7.75-7.71 (m, 1H), 7.65-7.60 (m, 3H), 6.87 (d, J = 4.0 Hz, 1H).

[0409] Step 2: 6-bromo-5-fluoro-2-iodo-1-(phenylsulfonyl)-1H-indole

[0410] To a solution of 6-bromo-5-fluoro-1-(phenylsulfonyl)-1H-indole AA3-1 (3.0 g, 8.5 mmol) in THF (80 mL) was added LDA (6.0 mL, 12.7 mmol) at -70°C and stirred for 1.5 hours. A solution of elemental iodine (3.2 g, 12.7 mmol) in THF (15 mL) was then added. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. Saturated aqueous ammonium chloride (15 mL) was added to quench the reaction mixture, which was then extracted three times with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford AA3-2 (2.0 g, 49% yield) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.39-8.38 (m, 1H), 7.90-7.87 (m, 2H), 7.75-7.71 (m, 1H), 7.67-7.63 (m, 2H), 7.54 (d, J = 8.0Hz, 1H), 7.22 (s, 1H). MS-ESI[M+H] + :479.8.

[0411] Step 3: 6-Bromo-5-fluoro-2-iodo-1H-indole

[0412] Potassium carbonate (4.0 g, 29.2 mmol) was added to a solution of 6-bromo-5-fluoro-2-iodo-1-(phenylsulfonyl)-1H-indole AA3-2 (1.4 g, 2.9 mmol) in MeOH / H2O (80 mL, V / V = 5 / 3). The resulting mixture was allowed to react overnight at 60°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (100 mL) and washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to afford AA3-3 (0.7 g, 70% yield) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.90 (s, 1H), 7.57-7.55 (m, 1H), 7.44 (d, J = 12.0Hz, 1H), 6.67-6.66 (m, 1H).

[0413] Step 4: 6-Bromo-1-cyclopropyl-5-fluoro-2-iodo-1H-indole

[0414] To a solution of 6-bromo-5-fluoro-2-iodo-1H-indole AA3-3 (700 mg, 2.1 mmol) and cyclopropylboronic acid (525 mg, 6.2 mmol) in DMF (20 mL) were added 2,2'-bipyridine (315 mg, 6.2 mmol), copper acetate (1.1 g, 6.2 mmol), and sodium carbonate (455 mg, 4.1 mmol). The resulting mixture was reacted at 70°C under an oxygen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (60 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to afford AA3-4 (350 mg, 44% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ7.82-7.80(m,1H),7.45(d,J=12.0Hz,1H),6.79(s,1H),3.31-3.24(m,1H),1.30-1.23(m,2H),1.04-1.00(m,2H). MS-ESI[M+H] + :379.9.

[0415] Step 5: tert-Butyl (4-(6-bromo-1-cyclopropyl-5-fluoro-1H-indol-2-yl)cyclohex-3-en-1-yl)carbamate

[0416] To a mixed solution of 6-bromo-1-cyclopropyl-5-fluoro-2-iodo-1H-indole AA3-4 (700 mg, 1.8 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (656 mg, 2.0 mmol) in acetonitrile-water (40 mL, V / V = 3 / 1) were added potassium carbonate (637 mg, 4.6 mmol) and bistriphenylphosphine palladium dichloride (129 mg, 0.18 mmol). The resulting mixture was heated to 85°C in a microwave reactor for 2 hours. The reaction solution was cooled to room temperature and water (10 mL) was added. The mixture was extracted three times with ethyl acetate (60 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to give a brown solid AA3-5 (737 mg, yield 88%). 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),6.89(d,J=8.0Hz,1H),6.31(s,1H),6.05(s,1H),3.58-3.57(m,1H),3.41 -3.38(m,1H),2.49-2.41(m,3H),2.15-2.12(m,1H),1.99-1.90(m,1H) ,1.62-1.59(m,1H),1.41(s,9H),1.19-1.13(m,2H),0.77-0.73(m,2H). MS-ESI[M+H] + :449.1.

[0417] Step 6: tert-Butyl (4-(6-cyano-1-cyclopropyl-5-fluoro-1H-indol-2-yl)cyclohex-3-en-1-yl)carbamate

[0418] To a solution of tert-butyl (4-(6-bromo-1-cyclopropyl-5-fluoro-1H-indol-2-yl)cyclohex-3-en-1-yl)carbamate AA3-5 (700 mg, 1.54 mmol) in DMF (20 mL) were added zinc cyanide (238 mg, 2.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (113 mg, 0.20 mmol), zinc powder (160 mg, 2.46 mmol), and tris(dibenzylideneacetone)dipalladium (186 mg, 0.20 mmol). The resulting mixture was reacted at 110°C for 16 hours. The reaction solution was cooled to room temperature, added with water (20 mL), extracted three times with ethyl acetate (60 mL), and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA=1 / 1) to give AA3 (0.3 g, 49% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.01(d,J=4.0Hz,1H),7.52(d,J=8.0Hz,1H),6.91(d,J=8.0Hz,1H),6.44(s,1H),6.14(s,1H),3.59-3.57(m,1H),3.47 -3.44(m,1H),2.53-2.51(m,3H),2.16-2.12(m,1H),1.99-1.91(m,1H) ,1.62-1.56(m,1H),1.41(s,9H),1.19-1.16(m,2H),0.81-0.78(m,2H). MS-ESI[M+H] + :396.2.

[0419] Synthesis of Intermediate AA4: tert-Butyl (3-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0420] Step 1: 5-amino-4-bromo-2-fluorobenzonitrile

[0421] To a mixed solution of 4-bromo-2-fluoro-5-nitrobenzonitrile AA4-1 (1 g, 4.1 mmol) in tetrahydrofuran (10 mL), ethanol (10 mL), and water (10 mL) was added sodium dithionite (5.68 g, 32.6 mmol). The reaction was stirred at 75°C for 3 hours. Ethyl acetate (50 mL) and water (10 mL) were then added, the layers separated, and the organic phase was dried, concentrated, and purified on a silica gel column (PE / EA = 3 / 1) to afford 5-amino-4-bromo-2-fluorobenzonitrile AA4-2 (540 mg, 61% yield). MS-ESI [M+H] +:215.9.

[0422] Step 2: 4-Bromo-5-(cyclobutylamino)-2-fluorobenzonitrile

[0423] To a solution of 5-amino-4-bromo-2-fluorobenzonitrile AA4-2 (500 mg, 2.32 mmol, 1 eq) and cyclobutanone (1.1 eq) in dichloromethane (15 mL) were added acetic acid (139.6 g, 2.32 mmol) and sodium acetate borohydride (986 mg, 4.65 mmol). The reaction was stirred at room temperature for 16 hours. Dichloromethane (20 mL) and water (10 mL) were then added, the layers separated, and the organic phase dried, concentrated, and purified by column chromatography (PE / EA = 4 / 1) to afford 4-bromo-5-(cyclobutylamino)-2-fluorobenzonitrile AA4-3 (240 mg, 38% yield). MS-ESI [M+H] + :269.0.

[0424] Step 3: tert-butyl (3-((4-cyano-2-(cyclobutylamino)-5-fluorophenyl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0425] To a solution of 4-bromo-5-(cyclobutylamino)-2-fluorobenzonitrile AA4-3 (240 mg, 0.89 mmol) and tert-butyl N-{3-ethynylbicyclo[1.1.1]pentan-1-yl}carbamate (203 mg, 0.98 mmol) in triethylamine (5 mL) was added cuprous iodide (139.6 g, 2.32 mmol) and bis(triphenylphosphine)palladium dichloride (62.6 mg, 0.09 mmol). The reaction was stirred at 80° C. for 3 hours. The mixture was then concentrated and purified on a silica gel column (PE / EA=5 / 2) to give tert-butyl (3-((4-cyano-2-(cyclobutylamino)-5-fluorophenyl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate AA4-4 (210 mg, 60% yield). MS-ESI [M+H] + :396.2.

[0426] Step 4: tert-butyl (3-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0427] To a solution of tert-butyl (3-((4-cyano-2-(cyclobutylamino)-5-fluorophenyl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate AA4-4 (180 mg, 0.46 mmol) in N-methylpyrrolidone (6 mL) was added potassium hydroxide (179 mg, 31.9 mmol). The reaction was stirred at 80°C for 3 hours. Ethyl acetate (20 mL) and water (10 mL) were then added, the layers separated, and the organic phase was dried, concentrated, and purified on a silica gel column (PE / EA = 3 / 1) to afford tert-butyl (3-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate AA4 (140 mg, 78% yield). MS-ESI [M+H] + :396.2.

[0428] Synthesis of Intermediate AA5: tert-Butyl (1-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)piperidin-4-yl)carbamate

[0429] Step 1: tert-Butyl (1-(6-bromo-1-cyclobutyl-5-fluoro-3-iodo-1H-indol-2-yl)piperidin-4-yl)carbamate

[0430] To a mixed solution of 6-bromo-1-cyclobutyl-5-fluoro-1H-indole A1-2 (750 mg, 2.8 mmol) and tert-butyl piperidin-4-ylcarbamate (1.12 g, 5.6 mmol) in methanol (10 mL) and dichloromethane (10 mL) were added cesium carbonate (1.82 g, 5.6 mmol) and iodine (1.4 g, 5.6 mmol), and the reaction was stirred at room temperature for 16 hours. Dichloromethane (30 mL) and water (10 mL) were then added, and the mixture was separated. The organic phase was washed with saturated sodium thiosulfate (10 mL) and saturated brine (10 mL), dried, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain tert-butyl (1-(6-bromo-1-cyclobutyl-5-fluoro-3-iodo-1H-indol-2-yl)piperidin-4-yl)carbamate AA5-1 (400 mg, yield 24%). MS-ESI [M+H] + :592.1.

[0431] Step 2: tert-butyl (1-(6-bromo-1-cyclobutyl-5-fluoro-1H-indol-2-yl)piperidin-4-yl)carbamate

[0432] To a mixture of tert-butyl (1-(6-bromo-1-cyclobutyl-5-fluoro-3-iodo-1H-indol-2-yl)piperidin-4-yl)carbamate AA5-1 (400 mg, 0.67 mmol) and zinc powder (132 mg, 2.03 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added ammonium chloride (108 mg, 2.03 mmol). The reaction was heated under reflux with stirring for 16 hours. Ethyl acetate (20 mL) and water (10 mL) were then added, and the layers were separated. The organic phase was washed with saturated brine, dried, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain tert-butyl (1-(6-bromo-1-cyclobutyl-5-fluoro-1H-indol-2-yl)piperidin-4-yl)carbamate AA5-2 (300 mg, 96% yield). MS-ESI [M+H] + :466.2.

[0433] Step 3: tert-butyl (1-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)piperidin-4-yl)carbamate

[0434] To a solution of tert-butyl (1-(6-bromo-1-cyclobutyl-5-fluoro-1H-indol-2-yl)piperidin-4-yl)carbamate AA5-2 (300 mg, 0.64 mmol) and zinc cyanide (45 mg, 0.38 mmol) in N-methylpyrrolidone (10 mL) were added tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (14 mg, 0.026 mmol) under nitrogen protection, and the reaction was stirred at 150 ° C. under microwave for 16 hours. Ethyl acetate (20 mL) and water (10 mL) were then added, the mixture was separated, and the organic phase was washed with saturated brine (10 mL), dried, concentrated, and chromatographed on a silica gel column (PE / EA = 3 / 2) to obtain tert-butyl (1-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)piperidin-4-yl)carbamate AA5 (150 mg, yield 57%). MS-ESI [M+H] + :413.2.

[0435] Synthesis of intermediate AA6: tert-butyl 2-bromo-4-cyano-5-fluorophenyl-4-(alkynylphenyl)carbamate

[0436] Step 1: 2-Bromo-4-cyano-5-fluorophenyl trifluoromethanesulfonic acid

[0437] To a solution of 5-bromo-2-fluoro-4-hydroxybenzonitrile AA6-1 (5.4 g, 25 mmol) and trifluoromethanesulfonic anhydride (10.6 g, 37.5 mmol) in DCM (100 mL) was slowly added dropwise TEA (5.05 g, 50 mmol) under ice bath, followed by stirring at room temperature for 3 hours. The reaction mixture was poured into water (200 mL) and extracted twice with DCM (200 mL each). The organic phases were combined, washed twice with saturated brine (200 mL each), and dried over anhydrous sodium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (PE / EA=4 / 1) to obtain AA6-2 (8.17 g) as a yellow oil.

[0438] Step 2: tert-Butyl 2-bromo-4-cyano-5-fluorophenyl-4-(alkynylphenyl)carbamate

[0439] To a solution of compound AA6-2 (8.17 g, 23.5 mmol) and tert-butyl 4-(alkynylphenyl)carbamate (5.35 g, 24.65 mmol) in DMF (100 mL) were added bis(triphenylphosphine)palladium dichloride (825 mg, 1.2 mmol), cuprous iodide (890 mg, 4.7 mmol), and triethylamine (9.5 g, 94 mmol). The reaction was stirred at room temperature under nitrogen for 2 hours. Ethyl acetate (200 mL) and water (50 mL) were then added, and the layers were separated. The organic phase was dried, concentrated, and purified on a silica gel column (DCM / PE = 1 / 1) to yield tert-butyl 2-bromo-4-cyano-5-fluorophenyl-4-(alkynylphenyl)carbamate AA6 (8 g). MS-ESI[M-55] + :360.3.

[0440] Synthesis of Intermediate AA7: 2-(4-tert-Butyloxycarbonylaminophenyl)-5-fluoro-1-(1-methylcyclobutyl)-1H-indole-6-carbonitrile

[0441] To a solution of tert-butyl 2-bromo-4-cyano-5-fluorophenyl-4-(alkynylphenyl)carbamate AA6 (5 g, 12 mmol) and 1-methylcyclobutane-1-amine hydrochloride (1.75 g, 14.45 mmol) in N,N-dimethylformamide (50 mL) was added methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (480 mg, 0.6 mmol) and sodium tert-butoxide (3.45 g, 36 mmol). Under nitrogen protection, the mixture was heated to 65 ° C and stirred for 5 hours. The reaction mixture was filtered, and ethyl acetate (100 mL) and water (20 mL) were added for separation. The organic phase was dried, concentrated, and purified on a silica gel column (PE / EA = 10 / 1) to give 2-(4-tert-butoxycarbonylaminophenyl)-5-fluoro-1-(1-methylcyclobutyl)-1H-indole-6-carbonitrile AA7 (2.2 g). MS-ESI [M-55] + :364.1.

[0442] The following intermediates AA8 and AA9 were prepared using the synthetic method of intermediate AA7.

[0443] Synthesis of Intermediate AA10: tert-Butyl (4-(6-cyano-5-fluoro-1-(1-methylcyclopropyl)-1H-indol-2-yl)phenyl)carbamate

[0444] Step 1: tert-Butyl (4-((4-cyano-5-fluoro-2-((1-methylcyclopropyl)amino)phenyl)ethynyl)carbamate

[0445] To a solution of tert-butyl (4-((2-bromo-4-cyano-5-fluorophenyl)ethynyl)phenyl)carbamate AA9 (4 g, 9.6 mmol) and 1-methylcyclopropylamine hydrochloride (1.55 g, 14.4 mmol) in 1,4-dioxane (10 mL) were added tris(dibenzylideneacetone)dipalladium (176 mg, 0.20 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (223 mg, 0.38 mmol) and sodium tert-butoxide (2.8 g, 28.9 mmol). Under nitrogen protection, the reaction was heated at reflux with stirring for 16 hours. Ethyl acetate (20 mL) and water (10 mL) were then added, the layers were separated, and the organic phase was washed with saturated brine (10 mL), dried, concentrated, and purified by silica gel column chromatography (PE / EA = 8 / 1) to give tert-butyl (4-((4-cyano-5-fluoro-2-((1-methylcyclopropyl)amino)phenyl)ethynyl)carbamate AA10-1 (1.01 g, yield 26%). MS-ESI [M+H] + :406.2.

[0446] Step 2: tert-Butyl (4-(6-cyano-5-fluoro-1-(1-methylcyclopropyl)-1H-indol-2-yl)phenyl)carbamate

[0447] To a solution of tert-butyl (4-((4-cyano-5-fluoro-2-((1-methylcyclopropyl)amino)phenyl)ethynyl)carbamate AA10-1 (1.01 g, 0.25 mmol) in N-methylpyrrolidone (10 mL) was added potassium hydroxide (700 mg, 12.5 mmol), and the reaction was stirred at 80° C. for 2 hours. Ethyl acetate (20 mL) and water (10 mL) were then added, and the layers were separated; the organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA=10 / 1) to afford tert-butyl (4-(6-cyano-5-fluoro-1-(1-methylcyclopropyl)-1H-indol-2-yl)phenyl)carbamate AA10 (840 mg, 83% yield). MS-ESI [M+H] + :406.2.

[0448] Synthesis of Intermediate AA11: tert-Butyl (4-(2-cyano-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[0449] Step 1: 5-Bromo-2-chloro-N-cyclobutylpyrimidin-4-amine

[0450] To a dichloromethane solution (25 mL) of 5-bromo-2,4-dichloropyrimidine AA11-1 (2.50 g, 11.0 mmol) and N,N-diisopropylethylamine (2.83 g, 22.0 mmol) was added dropwise a dichloromethane solution (5 mL) of cyclobutylamine (780 mg, 11.0 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. After the reaction, the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 85 / 15) to give AA11-2 (2.5 g, 89% yield) as a white solid. MS-ESI [M+H] + :263.1.

[0451] Step 2: tert-Butyl (4-((2-chloro-4-(cyclobutylamino)pyrimidin-5-yl)ethynyl)phenyl)carbamate

[0452] To a DMF solution (15 mL) of 5-bromo-2-chloro-N-cyclobutylpyrimidin-4-amine AA11-2 (511 mg, 1.95 mmol), tert-butyl (4-ethynylphenyl)carbamate (507 mg, 2.33 mmol), cuprous iodide (74 mg, 0.39 mmol), and triethylamine (788 mg, 7.78 mmol) was added bistriphenylphosphine palladium dichloride (68.3 mg, 0.097 mmol). The resulting mixture was heated to 80°C and stirred under nitrogen for 4 hours. After the reaction, ethyl acetate (50 mL) and water (50 mL) were added. The organic phase was washed with brine (10 mL) and concentrated. The product was purified by silica gel column chromatography (PE / THF = 5 / 1) to afford AA11-3 as a yellow solid (650 mg, 83% yield). MS-ESI [M+H] + :399.1.

[0453] Step 3: tert-Butyl (4-(2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[0454] To a solution of tert-butyl (4-((2-chloro-4-(cyclobutylamino)pyrimidin-5-yl)ethynyl)phenyl)carbamate AA11-3 (550 mg, 1.38 mmol) in tetrahydrofuran (8 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.03 mL, 3.03 mmol). The resulting mixture was heated to 75°C and stirred for 6 hours. After the reaction was completed, the mixture was cooled, ethyl acetate (30 mL) and water (30 mL) were added, and the organic phase was washed with brine (10 mL) and concentrated. The organic phase was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain AA11-4 as a yellow solid (230 mg, 41% yield). MS-ESI [M+H] + :399.1.

[0455] Step 4: tert-Butyl (4-(2-cyano-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate

[0456] To a solution of tert-butyl (4-(2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)carbamate AA11-4 (0.40 g, 1.0 mmol), zinc cyanide (71 mg, 0.6 mmol), zinc powder (7.8 mg, 0.12 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (22 mg, 0.04 mmol) in N-methylpyrrolidone (10 mL) was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol). The resulting mixture was heated to 180°C and stirred for 1 hour. After the reaction was completed, the mixture was cooled, and ethyl acetate (30 mL) and water (20 mL) were added. The organic phase was washed with brine (10 mL) and concentrated. The product was purified by silica gel column chromatography (PE / THF = 50 / 50) to afford AA11 as a yellow solid (180 mg, 62% yield). MS-ESI [M+H] + :390.1.

[0457] Synthesis of Intermediate AA12: tert-Butyl (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0458] Step 1: 1-cyclobutyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile

[0459] To a DMF solution (6 mL) of 5-fluoro-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile AA12-1 (500 mg, 3.10 mmol) and cesium carbonate (3.03 g, 9.31 mmol) was added cyclobutyl bromide (1.26 g, 9.31 mmol). The resulting mixture was heated to 90°C and stirred under nitrogen for 16 hours. After the reaction, the mixture was cooled and filtered. The filtrate was washed three times with aqueous lithium chloride (10 mL) and then concentrated. Purification by silica gel column chromatography (PE / EA = 85 / 15) afforded AA12-2 (600 mg, 89% yield) as a light green solid. MS-ESI [M+H] + :216.1.

[0460] Step 2: tert-Butyl (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)carbamate

[0461] To a DMF solution (8 mL) of 1-cyclobutyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile AA12-2 (560 mg, 1.49 mmol), tert-butyl (4-iodophenyl)carbamate (711.7 mg, 2.23 mmol), 2-nitrobenzoic acid (372.7 mg, 2.23 mmol), and silver oxide (258.4 mg, 1.12 mmol) was added palladium acetate (23.4 mg, 0.104 mmol). The resulting mixture was heated to 90°C in a microwave oven under nitrogen and stirred for 3 hours. After the reaction, the mixture was cooled and filtered. The filtrate was washed three times with aqueous lithium chloride (10 mL) and then concentrated. Purification by silica gel column chromatography (PE / DCM = 1 / 3) afforded AA12 as a light yellow solid (380 mg, 62% yield). MS-ESI [M+H] + :407.2.

[0462] The following intermediates AA13 to AA15 were prepared using the synthetic method of intermediate AA12.

[0463] Synthesis of Intermediate AA16: tert-Butyl (4-(1-cyclobutyl-5-fluoro-6-(N'-hydroxyaminocarbamoyl)-1H-indol-2-yl)phenyl)carbamate

[0464] To a solution of tert-butyl 4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate AA16-1 (500 mg, 1.23 mmol) and hydroxylamine hydrochloride (514 mg, 7.4 mmol) in ethanol (20 mL) was added triethylamine (747 mg, 7.38 mmol). The resulting mixture was heated to 80°C and stirred under nitrogen for 16 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was performed three times with ethyl acetate (60 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the product AA16 as a yellow solid (450 mg, 83% yield). MS-ESI [M+H] + :439.1.

[0465] Synthesis of Intermediate AA17: tert-Butyl (4-(5-cyano-3-cyclobutyl-6-fluorobenzofuran-2-yl)phenyl)carbamate

[0466] Step 1: (5-Bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)ketone

[0467] To a solution of 4-bromo-3-fluorophenol AA17-1 (1.0 g, 5.2 mmol) and anhydrous aluminum chloride (1.05 g, 7.9 mmol) in 1,2-dichloroethane (20 mL) was added cyclobutanecarbonyl chloride (0.68 g, 5.7 mmol) dropwise. The resulting mixture was heated to 75°C and stirred for 3 hours under nitrogen. After the reaction was completed, the mixture was cooled and poured into a dilute aqueous hydrochloric acid solution (15 mL) in an ice-water bath. The mixture was filtered, and the filtrate was washed with brine (10 mL) and concentrated. The product was purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain AA17-2 as a colorless oil (1.2 g, 84% yield). MS-ESI [M+H] + :274.1.

[0468] Step 2: Methyl 2-(4-bromo-2-(cyclobutanecarbonyl)-5-fluorophenoxy)acetate

[0469] To a DMF solution (15 mL) of (5-bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)methanone AA17-2 (4.0 g, 14.6 mmol) was added 60% sodium hydroxide (0.878 g, 22 mmol). The resulting mixture was stirred at room temperature for 0.5 hours, followed by the addition of methyl 2-bromoacetate (2.91 g, 19.0 mmol). The resulting mixture was stirred at room temperature for 3 hours. After the reaction, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL), concentrated, and purified by silica gel column chromatography (PE / EA = 85 / 15) to obtain AA17-3 as a yellow solid (3.5 g, 69% yield). MS-ESI [M+H] + :346.1.

[0470] Step 3: 2-(4-bromo-2-(cyclobutanecarbonyl)-5-fluorophenoxy)acetic acid

[0471] To a solution of methyl 2-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenoxy)acetate AA17-3 (3.3 g, 9.56 mmol) in a mixture of THF / H2O = 3 / 1 (20 mL) was added sodium hydroxide (573 mg, 14.3 mmol). The resulting mixture was stirred at room temperature for 6 hours. After the reaction, ethyl acetate (30 mL) and water (30 mL) were added, and the pH was adjusted to 4.0 with 1N hydrochloric acid (50 mL). The organic phase was concentrated to dryness to give AA17-4 (3.0 g, 94% yield) as a yellow solid. MS-ESI [M+H] + :332.1.

[0472] Step 4: 5-Bromo-3-cyclobutyl-6-fluorobenzofuran

[0473] To a solution of 2-(4-bromo-2-(cyclobutanecarbonyl)-5-fluorophenoxy)acetic acid AA17-4 (3.16 g, 9.54 mmol) in acetic anhydride (25 mL) was added sodium acetate (1.57 g, 19.1 mmol). The resulting mixture was heated to 140°C and stirred for 16 hours. After the reaction was completed, the mixture was concentrated, ethyl acetate (30 mL) and water (30 mL) were added, and the pH was adjusted to 9.0 with 1N aqueous sodium hydroxide solution (50 mL). The organic phase was concentrated to dryness and purified by silica gel column chromatography (PE / EA = 50 / 50) to give AA17-5 (2.0 g, 77% yield). MS-ESI [M+H] + :270.1.

[0474] Step 5: 3-cyclobutyl-6-fluorobenzofuran-5-carbonitrile

[0475] To a solution of 5-bromo-3-cyclobutyl-6-fluorobenzofuran AA17-5 (2.0 g, 7.43 mmol), zinc cyanide (0.524 g, 4.46 mmol), zinc powder (58 mg, 0.89 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (165 mg, 0.297 mmol) in DMF (20 mL) was added tris(dibenzylideneacetone)dipalladium (136 mg, 0.148 mmol). The resulting mixture was heated to 120°C under nitrogen for 16 hours. After the reaction, the mixture was cooled, ethyl acetate (40 mL) and water (40 mL) were added, and the mixture was filtered. The filtrate was washed with brine (15 mL), concentrated to dryness, and purified by silica gel column chromatography (PE / EA = 60 / 40) to afford AA17-6 (1.2 g, 75% yield). MS-ESI [M+H] + :216.1.

[0476] Step 6: 2-Bromo-3-cyclobutyl-6-fluorobenzofuran-5-carbonitrile

[0477] To a solution of 3-cyclobutyl-6-fluorobenzofuran-5-carbonitrile AA17-6 (1.28 g, 5.95 mmol) in DMF (15 mL) was added N-bromosuccinimide (1.27 g, 7.13 mmol). The resulting mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, ethyl acetate (20 mL) and water (30 mL) were added. The organic phase was washed with brine (15 mL), concentrated to dryness, and purified by silica gel column chromatography (PE / EA = 85 / 15) to afford AA17-7 (1.31 g, 74% yield). MS-ESI [M+H] + :294.1.

[0478] Step 7: tert-Butyl (4-(5-cyano-3-cyclobutyl-6-fluorobenzofuran-2-yl)phenyl)carbamate

[0479] To a solution of 2-bromo-3-cyclobutyl-6-fluorobenzofuran-5-carbonitrile AA17-7 (1.31 g, 4.45 mmol), (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (1.58 g, 6.68 mmol), and sodium bicarbonate (1.12 g, 13.36 mmol) in DME / H2O = 3 / 1 (20 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (325 mg, 0.445 mmol). The resulting mixture was heated to 100°C under nitrogen for 3 hours. After completion of the reaction, the mixture was cooled, and ethyl acetate (50 mL) and water (50 mL) were added. The organic phase was washed with saturated brine (15 mL), concentrated to dryness, and purified by silica gel column chromatography (PE / EA = 70 / 30) to afford AA17 (1.34 g, 74% yield). MS-ESI [M+H] + :407.1.

[0480] Synthesis of Intermediate AA18: 2-(4-((tert-Butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbamidyl methyl sulfate

[0481] Step 1: tert-Butyl (4-(6-carbamoyl-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate

[0482] To a solution of tert-butyl (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate AA18-1 (200 mg, 0.5 mmol) and potassium carbonate (103 mg, 0.7 mmol) in dimethyl sulfoxide (10 mL) was added hydrogen peroxide (2 mL). The resulting mixture was stirred under nitrogen for 2 hours. After the reaction was completed, ice water (80 mL) was added to precipitate the solution, which was filtered to obtain AA18-2 (200 mg, 97% yield) as a white solid. MS-ESI [M+H] + :424.2.

[0483] Step 2: tert-Butyl (4-(6-carbamoyl-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate

[0484] To a toluene solution (5 mL) of tert-butyl (4-(6-carbamoyl-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate AA18-2 (200 mg, 0.47 mmol) was added Lawesson's reagent (400 mg, 1 mmol). The resulting mixture was heated to 100°C and stirred under nitrogen for 16 hours. After the reaction, the product was directly dried and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain the product AA18-3 as a yellow solid (200 mg, 96% yield). MS-ESI [M+H]+ :440.1.

[0485] Step 3: 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbamidyl methyl sulfate

[0486] To a solution of tert-butyl (4-(6-carbamoyl-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate AA18-3 (200 mg, 0.4 mmol) in tetrahydrofuran (5 mL) was added iodomethane (130 mg, 0.1 mmol). The resulting mixture was reacted for 3 hours. The mixture was directly concentrated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain the product AA18 as a yellow solid (100 mg, 55% yield). MS-ESI [M+H] + :454.2.

[0487] Synthesis of Intermediate AA19: tert-Butyl (4-(5-cyano-3-cyclobutyl-6-fluorobenzo[b]thiophen-2-yl)phenyl)carbamate

[0488] Step 1: (5-Bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)ketone

[0489] To a solution of 4-bromo-3-fluorophenol AA19-1 (5 g, 26.18 mmol) and anhydrous aluminum chloride (5.24 g, 39.27 mmol) in 1,2-dichloroethane (40 mL) was added cyclobutanecarbonyl chloride (3.42 g, 28.8 mmol). The resulting mixture was heated to 85°C and stirred under nitrogen for 4 hours. The reaction solution was cooled to room temperature and added with water (100 mL). The mixture was extracted three times with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain the product AA19-2 (5 g, 70% yield). MS-ESI [M+H] + :273.2.

[0490] Step 2: O-(4-bromo-2-(cyclobutanecarbonyl)-5-fluorophenyl)dimethylaminomethanesulfate

[0491] To a DMF solution (40 mL) of (5-bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)methanone AA19-2 (5 g, 18 mmol) were added 1,4-diazabicyclo[2,2,2]octane (4.11 g, 37 mmol) and dimethylaminomethylthiochloride (4.53 g, 37 mmol). The resulting mixture was stirred under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted three times with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the product AA19-3 (6.2 g, 96% yield). MS-ESI [M+H] + :360.2.

[0492] Step 3: S-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)dimethylaminomethanesulfate

[0493] O-(4-Bromo-2-(cyclobutanecarbonyl)-5-fluorophenyl)dimethylaminomethanesulfate AA19-3 (100 mg, 0.28 mmol) was heated to 210°C for 2 hours. The reaction solution was used directly in the next reaction.

[0494] Step 4: (5-Bromo-4-fluoro-2-mercaptophenyl)(cyclobutyl)ketone

[0495] Potassium hydroxide (93 mg, 1.7 mmol) was added to a methanol solution (3 mL) of S-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)dimethylaminomethanesulfate AA19-4 (100 mg, 0.28 mmol). The resulting mixture was heated to 70°C and stirred for 3 hours under nitrogen. The reaction solution was cooled to room temperature and water (100 mL) and hydrochloric acid (1N, 1.8 mL) were added. The mixture was extracted three times with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain the product AA19-5 (65 mg, 96% yield). MS-ESI [M+H] + :289.2.

[0496] Step 5: 2-((4-bromo-2-(cyclobutanecarbonyl)-5-fluorophenyl)thio)acetic acid

[0497] To a solution of (5-bromo-4-fluoro-2-mercaptophenyl)(cyclobutyl)methanone AA19-5 (65 mg, 0.23 mmol) in acetonitrile (4 mL) were added 2-bromoacetic acid (38 mg, 0.28 mmol) and potassium carbonate (62 mg, 0.45 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was added to water (15 mL) and extracted three times with ethyl acetate (15 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the product AA19-6 (70 mg, 85% yield). MS-ESI [M+H] + :346.2.

[0498] Step 6: 5-Bromo-3-cyclobutyl-6-fluorobenzo[b]thiophene

[0499] To a solution of 2-((4-bromo-2-(cyclobutanecarbonyl)-5-fluorophenyl)thio)acetic acid AA19-6 (74 mg, 0.21 mmol) in acetic acid (3 mL) was added sodium acetate (87 mg, 0.64 mmol), and the resulting mixture was heated to 140°C and stirred for 2 hours. The reaction solution was cooled to room temperature, and water (20 mL) and sodium hydroxide solution (1N, 2 mL) were added. The product was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 20 / 1) to obtain the product AA19-7 (34 mg, 57% yield). MS-ESI [M+H] + :285.2.

[0500] Step 7: 3-cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile

[0501] To a DMF solution (1 mL) of 5-bromo-3-cyclobutyl-6-fluorobenzo[b]thiophene AA19-7 (20 mg, 0.07 mmol) were added zinc cyanide (5 mg, 0.04 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.5 mg, 0.002 mmol), zinc (0.6 mg, 0.008 mmol), and tris(dibenzylideneacetone)dipalladium (1.3 mg, 0.02 mmol). The resulting mixture was heated to 120°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 20 / 1) to afford the product AA19-8 (15 mg, 80% yield). MS-ESI [M+H] + :232.2.

[0502] Step 8: 2-Bromo-3-cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile

[0503] To a solution of 3-cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile AA19-8 (300 mg, 1.3 mmol) in acetic acid (6 mL) was added bromine (829 mg, 5.2 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was cooled to room temperature, and water (20 mL) and sodium thiosulfate (15 mL) were added. The product was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 6 / 1) to obtain the product AA19-9 (320 mg, 80% yield). MS-ESI [M+H] + :310.2.

[0504] Step 9: 3-cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile

[0505] To a solution of 5-bromo-3-cyclobutyl-6-fluorobenzo[b]thiophene AA19-9 (320 mg, 1.03 mmol) in DME (8 mL) and water (2 mL) were added (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (366 mg, 1.55 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (75 mg, 0.1 mmol), and sodium bicarbonate (260 mg, 3.1 mmol). The resulting mixture was heated to 100°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 20 / 1) to afford the product AA19 (260 mg, 61% yield). MS-ESI [M+H] + :423.2.

[0506] Synthesis of Intermediate A1: 4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline

[0507] Step 1: 6-Bromo-1-cyclobutyl-5-fluoro-1H-indole

[0508] To a solution of 6-bromo-5-fluoro-1H-indole A1-1 (1.5 g, 7.0 mmol) and bromocyclobutane (2.17 g, 16.0 mmol) in N,N-dimethylformamide (35 mL) was added cesium carbonate (6.85 g, 21.0 mmol). The mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was filtered, and ethyl acetate (50 mL) and water (10 mL) were added for separation. The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to afford 6-bromo-1-cyclobutyl-5-fluoro-1H-indole A1-2 (1.7 g, 91% yield). MS-ESI [M+H] + :267.9.

[0509] Step 2: 1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile

[0510] To a solution of 6-bromo-1-cyclobutyl-5-fluoro-1H-indole A1-2 (1.7 g, 6.3 mmol) in N-methylpyrrolidone (15 mL) was added cuprous cyanide (1.13 g, 12.7 mmol). The mixture was heated to 180°C under a nitrogen atmosphere and stirred for 3 hours in a microwave oven. The reaction mixture was filtered, and ethyl acetate (30 mL) and water (10 mL) were added for separation. The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA = 8 / 1) to afford 1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile A1-3 (1.1 g, 81% yield). MS-ESI [M+H] + :215.0.

[0511] Step 3: tert-Butyl (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate

[0512] To a solution of 1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile A1-3 (1.1 g, 5.1 mmol), o-nitrobenzoic acid (1.29 g, 7.7 mmol), and tert-butyl (4-iodophenyl)carbamate (2.46 g, 7.7 mmol) in N,N-dimethylformamide (40 mL) were added palladium acetate (57.6 mg, 0.26 mmol) and silver oxide (892 mg, 3.85 mmol). The mixture was heated to 50°C and stirred under nitrogen for 16 hours. The reaction mixture was filtered, and ethyl acetate (60 mL) and water (10 mL) were added. The organic phase was separated, dried, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to afford tert-butyl (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate A1-4 (950 mg, 46% yield). MS-ESI[M+H] + :406.1.

[0513] Step 4: 2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile

[0514] To a solution of tert-butyl (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate A1-4 (950 mg, 2.34 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and ethyl acetate (30 mL) and water (10 mL) were added. Saturated sodium bicarbonate was then added to neutralize the trifluoroacetic acid, and the layers were separated. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford 2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile A1-5 (700 mg, 98% yield). MS-ESI [M+H] + :306.0.

[0515] Step 5: 4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline

[0516] To a mixed solution of 2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile A1-5 (200 mg, 0.65 mmol) in toluene (6 mL) and tetrahydrofuran (1.5 mL) were added trimethylsilyl azide (226 mg, 1.96 mmol) and dibutyltin oxide (16.2 mg, 0.065 mmol). The mixture was sealed and heated to 120°C with stirring for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (MeOH / DCM = 1 / 15) to afford 4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline A1 (100 mg, 44% yield). 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=5.8Hz,1H),7.55(d,J=11.4Hz,1H),7.16(d,J=8.4Hz,2H),6.69(d,J=8.5Hz,2H ), 6.41 (d, J = 0.7Hz, 1H), 5.12-5.03 (m, 1H), 3.34 (s, 2H), 2.79-2.71 (m, 2H), 2.41-2.34 (m, 2H), 1.92-1.75 (m, 2H). MS-ESI[M+H] + :349.1.

[0517] The following intermediates A2 to A8 were prepared using the synthetic method of intermediate A1.

[0518] Synthesis of Intermediate A9: 2-(4-aminophenyl)-1-cyclobutyl-6-(1H-tetrazol-5-yl)-1H-indol-5-ol

[0519] Step 1: 2-(4-aminophenyl)-1-cyclobutyl-5-hydroxy-1H-indole-6-carbonitrile

[0520] To a solution of tert-butyl (4-(6-cyano-1-cyclobutyl-5-methoxy-1H-indol-2-yl)phenyl)carbamate AA2 (160 mg, 0.504 mmol) in 1,2-dichloroethane (4 mL) was added dropwise boron tribromide (624 mg, 2.49 mmol) under ice-water bath. The mixture was heated to 50°C and stirred under nitrogen for 5 hours. After the reaction was completed, the ice-water bath was lowered to 0°C, methanol was added dropwise, and the reaction was quenched. The mixture was then concentrated, ethyl acetate (15 mL) was added, and the mixture was washed with aqueous sodium bicarbonate (5 mL) and concentrated. Purification by silica gel column chromatography (PE / EA = 1 / 1) afforded A9-1 (60 mg) as a light yellow solid. MS-ESI [M+H] + :304.0.

[0521] Step 2: 2-(4-aminophenyl)-1-cyclobutyl-6-(1H-tetrazol-5-yl)-1H-indol-5-ol

[0522] To a toluene solution (1.5 mL) of 2-(4-aminophenyl)-1-cyclobutyl-5-hydroxy-1H-indole-6-carbonitrile A9-1 (60 mg, 197.8 μmol) and tetrabutylammonium fluoride in tetrahydrofuran (0.79 mL, 791 μmol) was added trimethylsilylazide (91.2 mg, 791 μmol). The mixture was heated to 120°C and stirred for 48 hours. After the reaction, the mixture was concentrated and purified by silica gel column chromatography (DCM / MeOH = 92 / 8) to obtain A9 (65 mg) as a light yellow solid. MS-ESI [M+H] + :347.0.

[0523] Synthesis of Intermediate A10: 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetic acid

[0524] Step 1: 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetic acid methyl ester

[0525] To a solution of 4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline A1 (100 mg, 0.29 mmol) and triethylamine (58 mg, 0.57 mmol) in tetrahydrofuran (5 mL) was added dropwise methyl oxalyl chloride (37 mg, 0.30 mmol) under ice-cooling. The mixture was then stirred at room temperature for 1 hour, quenched with saturated ammonium chloride (10 mL), and extracted with ethyl acetate (20 mL). The organic phase was dried, filtered, and concentrated to afford methyl 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetate A10-1 (110 mg, 88% yield). MS-ESI [M+H] + :435.1.

[0526] Step 2: 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetic acid

[0527] To a mixture of methyl 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetate A10-1 (99 mg, 0.23 mmol) in tetrahydrofuran (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (11.5 mg, 0.27 mmol), and the reaction was stirred at room temperature for 1 hour. 1N hydrochloric acid was then added to adjust the pH of the reaction mixture to 5-6, and ethyl acetate (15 mL) was added. The layers were separated, and the organic phase was dried and concentrated to afford 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetic acid A10 (80 mg, 82% yield). 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),8.34(d,J=5.8Hz,1H),7.95(d,J=8.7Hz,2H),7.63(d,J=11.3Hz,1H),7. 53(d,J=8.6Hz,2H),6.58(s,1H),5.13-5.04(m,1H),2.75-2.64(m,2H),2.43-2.36(m,2H),1.87-1.73(m,2H). MS-ESI[M+H] + :421.1.

[0528] The following intermediates A11 to A13 were prepared using the synthetic method of intermediate A10.

[0529] Synthesis of Intermediate A14: 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetic acid

[0530] Step 1: 6-Bromo-1-(cyclopropylmethyl)-5-fluoro-1H-indole

[0531] To a solution of 6-bromo-5-fluoro-1H-indole A1-1 (3.0 g, 14.0 mmol) and cesium carbonate (13.7 g, 42.0 mmol) in DMF (70 mL) was added bromomethylcyclopropane (3.78 g, 28.0 mmol). The mixture was heated to 85°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled and filtered. The filtrate was washed with aqueous lithium chloride (10 mL) and concentrated. The product was purified by silica gel column chromatography (PE / EA = 4 / 1) to give A14-1 (3.1 g) as a colorless oil. MS-ESI [M+H] + :268.0.

[0532] Step 2: 1-(Cyclopropylmethyl)-5-fluoro-1H-indole-6-carbonitrile

[0533] To a solution of methyl 1-cyclobutyl-5-methoxy-1H-indole-6-carboxylate A14-1 (3.1 g, 11.56 mmol) in NMP (60 mL) was added cuprous cyanide (3.62 g, 40.5 mmol). The mixture was heated to 200°C and stirred for 3 hours. After the reaction was complete, the mixture was cooled and filtered. The filtrate was washed with aqueous lithium chloride (10 mL) and concentrated. The mixture was purified on a silica gel column (PE / EA = 1 / 1) to give A14-2 (2.0 g) as a light green solid. MS-ESI [M+H] + :215.1.

[0534] Step 3: tert-Butyl (4-(6-cyano-1-(cyclopropylmethyl)-5-fluoro-1H-indol-2-yl)phenyl)carbamate

[0535] To a solution of 1-(cyclopropylmethyl)-5-fluoro-1H-indole-6-carbonitrile A14-2 (2.0 g, 9.34 mmol), tert-butyl (4-iodophenyl)carbamate (4.47 g, 14.0 mmol), 2-nitrobenzoic acid (2.34 g, 14.0 mmol), and silver oxide (1.62 g, 7.0 mmol) in DMF (70 mL) was added palladium acetate (104.8 mg, 0.467 mmol). The mixture was heated to 100°C under nitrogen and stirred for 16 hours. After the reaction, the mixture was cooled and filtered. The filtrate was washed with aqueous lithium chloride (10 mL) and concentrated. The product was purified by silica gel column chromatography (PE / DCM = 1 / 1) to give A14-3 (1.0 g) as a light yellow solid. MS-ESI [M+H] + :406.2.

[0536] Step 4: 2-(4-aminophenyl)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-6-carbonitrile

[0537] To a solution of tert-butyl (4-(6-cyano-1-(cyclopropylmethyl)-5-fluoro-1H-indol-2-yl)phenyl)carbamate A14-3 (900 mg, 2.22 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated to dryness, and dichloromethane (50 mL) was added. The mixture was washed twice with aqueous sodium bicarbonate solution (10 mL), dried, and concentrated to give the crude product A14-4. MS-ESI [M+H] + :306.1.

[0538] Step 5: 4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline

[0539] To a 25 mL solution of 2-(4-aminophenyl)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-6-carbonitrile A14-4 (720 mg, 2.36 mmol) and dibutyltin oxide (88.1 mg, 0.354 mmol) in a 5 / 2 mixture of toluene / tetrahydrofuran was added trimethylsilane (1.63 g, 14.2 mmol). The mixture was heated to 120°C and stirred for 16 hours. After the reaction, the mixture was concentrated and purified by silica gel column chromatography (DCM / MeOH = 95 / 5) to give A14-5 (630 mg) as a light yellow solid. MS-ESI [M+H] + :349.1.

[0540] Step 6: 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetic acid methyl ester

[0541] To a solution of 4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline A14-5 (300 mg, 0.861 mmol) and triethylamine (261.4 mg, 2.58 mmol) in dichloromethane (25 mL) was added methyl oxalyl chloride (158.2 mg, 1.29 mmol) and stirred at room temperature for 2 hours. After the reaction, the mixture was washed with brine (10 mL), dried, and concentrated to give crude product A14-6 (300 mg). MS-ESI [M+H] + :435.1.

[0542] Step 7: 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetic acid

[0543] To a mixed solution of methyl 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)phenyl)amino)-2-oxoacetate A14-6 (0.3 g, 0.691 mmol) in THF / MeOH / H2O=1 / 1 / 1 (12 mL) was added lithium hydroxide (58.0 mg, 1.38 mmol), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated, adjusted to pH 7 with 1N hydrochloric acid, extracted with a mixed solvent of DCM / MeOH=10 / 1 (50 mL), and concentrated to give A14 (230 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.28(d,J=5.6Hz,1H),7.96(d,J=8.4Hz,2H),7.58-7.51(m, 3H), 6.60 (s, 1H), 4.22 (d, J = 6.8Hz, 2H), 0.98-0.89 (m, 1H), 0.33-0.27 (m, 2H), 0.10-0.04 (m, 2H). MS-ESI[M+H] + :421.1.

[0544] The following intermediates A15 to A17 were prepared using the synthetic method of intermediate A14.

[0545] Synthesis of Intermediate A18: 4-(1-cyclobutyl-6-(1H-1,2,3-triazol-5-yl)-1H-indol-2-yl)aniline

[0546] Step 1: tert-Butyl (4-(1-cyclobutyl-6-((trimethylsilyl)ethynyl)-1H-indol-2-yl)phenyl)carbamate

[0547] To a solution of tert-butyl (4-(6-bromo-1-cyclobutyl-1H-indol-2-yl)phenyl)carbamate AA15 (441 mg, 1 mmol) in THF (30 mL) and TEA (20 mL) were added cuprous iodide (19 mg, 0.1 mmol), tetrakistriphenylphosphine palladium (116 mg, 0.1 mmol), and trimethylethynylsilane (295 mg, 0.45 mmol). The resulting mixture was heated to 100°C for 24 hours. The residue was concentrated and purified by silica gel column chromatography (PE / EA = 10 / 1) to afford the product A18-1 as a yellow solid (445 mg, 81% yield). MS-ESI [M+H] + :459.1.

[0548] Step 2: tert-Butyl (4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-2-yl)phenyl)carbamate

[0549] Potassium carbonate (265 mg, 1.92 mmol) was added to a solution of tert-butyl (4-(1-cyclobutyl-6-((trimethylsilyl)ethynyl)-1H-indol-2-yl)phenyl)carbamate A18-1 (440 mg, 0.96 mmol) in THF (60 mL) and methanol (60 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction solution was concentrated and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain the product A18-2 as a yellow oily liquid (245 mg, 61% yield). MS-ESI [M+H] + :387.1.

[0550] Step 3: tert-Butyl (4-(1-cyclobutyl-6-(1H-1,2,3-triazol-5-yl)-1H-indol-2-yl)phenyl)carbamate

[0551] To a mixed solution of tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-2-yl)phenyl)carbamate A18-2 (240 mg, 0.62 mmol) in DMF (0.9 mL) and methanol (0.1 mL) were added cuprous iodide (6 mg, 0.03 mmol) and trimethylsilylazide (107 mg, 0.9 mmol). The resulting mixture was heated to 100°C for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (PE / EA = 3 / 1) to afford the product A18-3 as a yellow solid (150 mg, 62% yield). MS-ESI [M+H] + :430.1.

[0552] Step 4: 4-(1-cyclobutyl-6-(1H-1,2,3-triazol-5-yl)-1H-indol-2-yl)aniline

[0553] To a solution of tert-butyl (4-(1-cyclobutyl-6-(1H-1,2,3-triazol-5-yl)-1H-indol-2-yl)phenyl)carbamate (150 mg, 0.35 mmol) in DCM (5 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was reacted at room temperature for 3 hours. The reaction solution was cooled to room temperature, and aqueous sodium bicarbonate (50 mL) was added. The mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the product A18 (93 mg, 80% yield) as a yellow solid. MS-ESI [M+H] + :330.1.

[0554] Synthesis of Intermediate A19: 3-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indol-6-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride

[0555] Step 1: tert-Butyl (4-(1-cyclobutyl-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl)phenyl)carbamate

[0556] To a solution of tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(N'-hydroxyaminocarbamoyl)-1H-indol-2-yl)phenyl)carbamate AA16 (200 mg, 0.46 mmol) in 1,4-dioxane (10 mL) was added CDI (148 mg, 0.96 mmol) and TEA (138 mg, 1.37 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain the product A19-1 as a yellow solid (200 mg, 93% yield). MS-ESI [M+H] + : 465.2.

[0557] Step 2: 3-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indol-6-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride

[0558] To a solution of tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl)phenyl)carbamate A19-1 (200 mg, 0.43 mmol) in dichloromethane (10 mL) was added a 4 M dioxane solution (2 mL, 8 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product A19 (100 mg) as a yellow solid. MS-ESI [M+H] + :365.1.

[0559] Synthesis of Intermediate A20: 4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-2-yl)aniline

[0560] Step 1: tert-Butyl (4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl)phenyl)carbamate

[0561] To a solution of tert-butyl (Z)-(4-(1-cyclobutyl-5-fluoro-6-(N'-hydroxyaminocarbamoyl)-1H-indol-2-yl)phenyl)carbamate AA16 (200 mg, 0.45 mmol) in tetrahydrofuran (5 mL) was added trifluoroacetic anhydride (115 mg, 0.55 mmol). The resulting mixture was reacted at room temperature for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (PE / EA = 4 / 1) to afford the product A20-1 (120 mg, 51% yield) as a yellow solid. MS-ESI [M+H] + :517.2.

[0562] Step 2: tert-Butyl (4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-2-yl)phenyl)carbamate

[0563] To a DMF solution (3 mL) of tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl)phenyl)carbamate A20-1 (120 mg, 0.23 mmol) was added hydrazine hydrate (2 mL), and the resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction solution was added with water (10 mL) and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain the product A20-2 as a yellow solid (100 mg, 83% yield). MS-ESI [M+H]+ :516.2.

[0564] Step 3: 4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indol-2-yl)aniline

[0565] To a solution of hexafluoroisopropanol (5 mL) was added tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)-1H-indol-2-yl)phenyl)carbamate (100 mg, 0.19 mmol). The resulting mixture was heated to 120°C in a microwave oven for 12 hours. The product was concentrated directly to afford the crude product A20 (80 mg) as a yellow solid. MS-ESI [M+H] + :416.1.

[0566] Synthesis of Intermediate A21: 5-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indol-6-yl)-4H-1,2,4-triazole-3-carbonitrile

[0567] Step 1: tert-Butyl (4-(6-(5-carbamoyl-4H-1,2,4-triazol-3-yl)-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate

[0568] To a mixed solution of 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbamidylsulfate AA18 (320 mg, 0.7 mmol) in DMF (5 mL) were added 2-hydrazino-2-carboacetamide (95 mg, 0.92 mmol) and acetic acid (1 drop). The resulting mixture was heated to 65°C for 3 hours. The reaction solution was cooled to room temperature and added with water (10 mL). The mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / EA = 2 / 1) to obtain the product A21-1 as a white solid (220 mg, 89% yield). MS-ESI [M+H] + :491.2.

[0569] Step 2: tert-Butyl (4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl)phenyl)carbamate

[0570] To a mixed solution of tert-butyl (4-(6-(5-carbamoyl-4H-1,2,4-triazol-3-yl)-1-cyclobutyl-5-fluoro-1H-indol-2-yl)phenyl)carbamate A21-1 (220 mg, 0.45 mmol) in dichloromethane (5 mL) were added trifluoroacetic anhydride (141 mg, 0.67 mmol) and triethylamine (91 mg, 0.89 mmol). The resulting mixture was reacted at room temperature for 2 hours. The mixture was concentrated and purified by silica gel column chromatography (DCM / EA = 3 / 1) to obtain the product A20-2 (110 mg, 50% yield) as a yellow solid. MS-ESI [M+H] + :472.2.

[0571] Step 3: 5-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indol-6-yl)-4H-1,2,4-triazole-3-carbonitrile

[0572] To a solution of tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indol-2-yl)phenyl)carbamate (90 mg, 0.2 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). The resulting mixture was reacted at room temperature for 3 hours. Direct concentration gave the crude product A21 (60 mg) as a yellow solid. MS-ESI [M+H] + :373.1.

[0573] Synthesis of Intermediate A22: 4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indol-2-yl)aniline

[0574] Step 1: tert-Butyl (4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indol-2-yl)phenyl)carbamate

[0575] To a solution of 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbamidylsulfate AA18 (100 mg, 0.2 mmol) in DMF (5 mL) were added acetic acid (25 mg, 0.3 mmol) and acetic acid (2 drops). The resulting mixture was heated to 90°C and reacted for 36 hours. The reaction solution was cooled to room temperature and added with water (10 mL). The mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on a silica gel column (PE / EA = 4 / 1) to obtain the product A22-1 as a yellow solid (90 mg, 89% yield). MS-ESI [M+H] + :462.2.

[0576] Step 2: 4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indol-2-yl)aniline

[0577] To a solution of hexafluoroisopropanol (5 mL) was added tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indol-2-yl)phenyl)carbamate (90 mg, 0.2 mmol). The resulting mixture was heated to 120°C in a microwave oven for 12 hours. The product was concentrated directly to afford the crude product A22 (60 mg) as a yellow solid. MS-ESI [M+H] + :362.1.

[0578] Synthesis of Intermediate A23: 4-(1-cyclobutyl-5,7-difluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline

[0579] Step 1: 3-(cyclobutylamino)-2,6-difluorobenzonitrile

[0580] To a solution of 3-amino-2,6-difluorobenzonitrile A23-1 (2.0 g, 7.14 mmol) and cyclobutanone (4.51 g, 64.28 mmol) in 1,2-dichloroethane (20 mL) was added tetraisopropyl titanate (13.2 g, 37.4 mmol). The resulting mixture was heated to 100°C under microwave conditions and stirred for 10 hours. After the reaction was completed, the mixture was cooled to room temperature and sodium cyanoborohydride (12.1 g, 57.1 mmol) was added portionwise with stirring. The mixture was heated to 90°C and stirred for 8 hours. After the reaction was completed, the mixture was cooled and poured into a saturated aqueous sodium bicarbonate solution (50 mL) and filtered. The filtrate was washed with a saturated aqueous sodium bicarbonate solution and concentrated. The product was purified by silica gel column chromatography (PE / EA = 80 / 20) to obtain A23-2 as a colorless oil (1.2 g, 80% yield). MS-ESI [M+H] + :209.1.

[0581] Step 2: 4-Bromo-3-(cyclobutylamino)-2,6-difluorobenzonitrile

[0582] To a solution of 3-(cyclobutylamino)-2,6-difluorobenzonitrile A23-2 (1.5 g, 7.20 mmol) in AcOH (15 mL) was added N-bromosuccinimide (2.05 g, 11.5 mmol). The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reactant was poured into a saturated aqueous sodium bicarbonate solution (50 mL) in an ice-water bath, extracted three times with ethyl acetate (50 mL), concentrated, and purified by silica gel column chromatography (PE / EtOAc = 85 / 15) to afford A23-3 as a colorless oil (1.2 g, 58% yield). MS-ESI [M+H] + :289.0.

[0583] Step 3: tert-Butyl (4-(4-cyano-2-(cyclobutylamino)-3,5-difluorophenyl)ethynyl)carbamate

[0584] To a solution of 4-bromo-3-(cyclobutylamino)-2,6-difluorobenzonitrile A23-3 (0.6 g, 2.09 mmol), tert-butyl (4-ethynylphenyl)carbamate (0.454 g, 2.09 mmol), triethylamine (0.423 g, 4.18 mmol), and cuprous iodide (27.9 mg, 146 μmol) in acetonitrile (10 mL) was added bistriphenylphosphine palladium dichloride (103 mg, 146 μmol). The resulting mixture was heated to 100°C in a microwave oven under nitrogen and stirred for 2 hours. After the reaction, the mixture was cooled, filtered, and the filtrate was concentrated to dryness. The mixture was purified by silica gel column chromatography (PE / DCM = 70 / 30) to afford A23-4 as a colorless oil (280 mg, 41% yield). MS-ESI [M+H] + :424.1.

[0585] Step 4: 2-(4-aminophenyl)-1-cyclobutyl-5,7-difluoro-1H-indole-6-carbonitrile

[0586] To a solution of tert-butyl (4-(4-cyano-2-(cyclobutylamino)-3,5-difluorophenyl)ethynyl)carbamate A23-4 (0.36 g, 0.85 mmol) in tetrahydrofuran (8 mL) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (4.25 mL, 4.25 mmol). The resulting mixture was heated to 80°C and stirred for 12 hours. After the reaction was completed, the mixture was cooled and ethyl acetate (50 mL) was added. The organic phase was washed three times with 1N aqueous hydrochloric acid (10 mL) and then concentrated. Purification by silica gel column chromatography (PE / EA = 70 / 30) afforded A23-5 as a colorless oil (230 mg, 83% yield). MS-ESI [M+H] + :324.1.

[0587] Step 5: 4-(1-cyclobutyl-5,7-difluoro-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline

[0588] To a solution of 2-(4-aminophenyl)-1-cyclobutyl-5,7-difluoro-1H-indole-6-carbonitrile A23-5 (200 mg, 0.619 mmol) and triethylamine hydrochloride (1.28 g, 9.28 mmol) in DMF (15 mL) was added sodium azide (402 mg, 6.19 mmol). The resulting mixture was heated to 110°C for 16 hours. After completion of the reaction, the mixture was cooled, filtered, and the filtrate was isolated by alkaline preparative separation to afford the product A23 as an off-white solid (18 mg, 7% yield). 1 H NMR (400MHz, DMSO-d6) δ7.24(d,J=9.6Hz,1H),7.16-7.12(m,2H),6.69(d,J=8.4Hz,2H),6.41(d,J=2.4Hz,1H), 5.00(q,J=9.2Hz,1H),2.69-2.64(m,1H),2.34-2.32(m,2H),2.02-1.95(m,2H),1.77-1.66(m,2H).MS-ESI[M+H] + :367.1.

[0589] Synthesis of Intermediate A24: 4-(1-cyclobutyl-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline

[0590] Step 1: 2-(4-aminophenyl)-1-cyclobutyl-1H-indole-6-carbonitrile

[0591] To a solution of tert-butyl (4-(6-cyano-1-cyclobutyl-1H-indol-2-yl)phenyl)carbamate AA13 (700 mg, 1.8 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction, it was concentrated to dryness, and dichloromethane (30 mL) was added. The pH was adjusted to 9.0 with saturated aqueous sodium bicarbonate (5 mL). The organic phase was concentrated to dryness to give A24-1 as an off-white solid (310 mg, 59% yield). MS-ESI [M+H] + :288.0.

[0592] Step 2: 4-(1-cyclobutyl-6-(1H-tetrazol-5-yl)-1H-indol-2-yl)aniline

[0593] To a toluene solution (8 mL) of 2-(4-aminophenyl)-1-cyclobutyl-1H-indole-6-carbonitrile A24-2 (287 mg, 1.0 mmol) and trimethylsilyl cyanide (230 mg, 2.0 mmol) was added 1N tetrabutylammonium fluoride in tetrahydrofuran (0.5 mL, 0.5 mmol). The resulting mixture was heated to 110°C and stirred for 17 hours. After completion of the reaction, the mixture was concentrated to dryness and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford A24 as an off-white solid (130 mg, 39% yield). MS-ESI [M+H] + :331.1.

[0594] The following intermediates A25 to A29 were prepared using the synthetic method of intermediate A24.

[0595] Synthesis of intermediate BB1: 2-(pyrrolidin-3-yl)ethan-1-ol hydrochloride

[0596] To a solution of tert-butyl 3-(2-hydroxyethyl)pyrrolidine-1-carboxylate BB1-1 (200 mg, 0.93 mmol) in dichloromethane (10 mL) was added a dioxane hydrochloride solution (4 M, 2 mL, 8 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined and dried to give the crude product BB1 (100 mg), which was used directly in the next reaction. MS-ESI [M+H] + :116.1.

[0597] The following intermediates BB2 to BB15 were obtained by the synthetic method of intermediate BB1.

[0598] Synthesis of Intermediate BB16: (3-Methylpiperidin-4-yl)methanol hydrochloride

[0599] Step 1: Methyl-3-methylpiperidine-4-carboxylate

[0600] To a solution of methyl-3-methylisonicotinate BB16-1 (400 mg, 2.64 mmol) in acetic acid (4 mL) was added platinum dioxide (150 mg, 12.5 mmol). The reaction was stirred at room temperature under a hydrogen balloon for 16 hours. Concentration afforded crude methyl 3-methylpiperidine-4-carboxylate BB16-2. MS-ESI [M+H] + :158.1.

[0601] Step 2: 1-(tert-butyl)-4-methyl-3-methylpiperidine-1,4-dicarboxylate

[0602] To a mixture of DCM (15 mL) and water (10 mL) of the crude product from the previous step, methyl-3-methylpiperidine-4-carboxylate BB16-2 was added sodium bicarbonate (444 mg, 5.29 mmol). The reaction was stirred at room temperature for 2 hours. The organic phase was then separated, washed with saturated brine (10 mL), dried, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to afford 1-(tert-butyl)-4-methyl-3-methylpiperidine-1,4-dicarboxylate BB16-3 (600 mg, 88% yield). MS-ESI [M+H] + :258.1.

[0603] Step 3: tert-Butyl 4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate

[0604] To a solution of 1-(tert-butyl)-4-methyl-3-methylpiperidine-1,4-dicarboxylate BB16-3 (600 mg, 2.33 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum tetrahydride (124 mg, 3.27 mmol) under ice-cooling. The reaction was stirred at room temperature for 1 hour. Saturated ammonium chloride (5 mL) was then added to quench the reaction. Ethyl acetate (30 mL) and water (10 mL) were then added and the layers separated. The organic phase was dried, concentrated, and purified on a silica gel column (PE / EA = 2 / 1) to afford tert-butyl 4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate BB16-4 (500 mg, 94% yield). MS-ESI [M+H] + :230.1.

[0605] Step 4: (3-Methylpiperidin-4-yl)methanol hydrochloride

[0606] To a solution of tert-butyl 4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate BB16-4 (500 mg, 2.33 mmol) in dichloromethane (6 mL) was added a dioxane hydrochloride solution (4 M, 2.2 mL, 8.8 mmol) under ice-cooling. The reaction was stirred at room temperature for 3 hours. The mixture was then concentrated to give (3-methylpiperidin-4-yl)methanol hydrochloride BB16 (384 mg). MS-ESI [M+H] + :130.1.

[0607] Synthesis of Intermediate BB17: (4-(Methoxymethyl)piperidin-4-yl)methanol hydrochloride

[0608] Step 1: 1-(tert-Butyl)-4-methyl-4-(methoxymethyl)piperidine-1,4-dicarboxylate

[0609] Under nitrogen, to a tetrahydrofuran solution (15 mL) of 1-(tert-butyl)-4-methylpiperidine-1,4-dicarboxylate BB17-1 (1.0 g, 4.11 mmol) was added a tetrahydrofuran solution of lithium diisopropylamide (1 M, 2.98 mL, 5.96 mmol). Bromomethyl methyl ether (770.4 mg, 6.17 mmol) was then added dropwise at -70°C (in a dry ice ethanol bath). The mixture was stirred at room temperature for 2 hours. After completion, the reaction was quenched with water (5 mL), concentrated, and extracted with ethyl acetate (30 mL). The mixture was washed with saturated brine (10 mL) and concentrated. Purification on a silica gel column (PE / EA = 7 / 3) afforded BB17-2 (920 mg) as a light brown oil. MS-ESI [M-Boc] + :188.1.

[0610] Step 2: tert-Butyl 4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate

[0611] Under nitrogen protection, lithium aluminum tetrahydride (59.4 mg, 1.57 mmol) was added in portions to a tetrahydrofuran solution (10 mL) of 1-(tert-butyl)-4-methyl-4-(methoxymethyl)piperidine-1,4-dicarboxylate BB17-2 (0.50 g, 1.74 mmol) at 0°C (ice-water bath) and stirred at room temperature for 2 hours. After the reaction was completed, water (5 mL) was added dropwise at 0°C to quench the reaction. Ethyl acetate (20 mL) was added for extraction, and the mixture was dried over anhydrous sodium sulfate. The filter cake was washed with ethyl acetate (10 mL). The combined filtrates were concentrated to dryness to give the crude product BB17-3 (500 mg). MS-ESI[M-55] + :204.1.

[0612] Step 3: (4-(Methoxymethyl)piperidin-4-yl)methanol hydrochloride

[0613] To a methanol solution (5 mL) of 1-(tert-butyl)-4-methyl-4-(methoxymethyl)piperidine-1,4-dicarboxylate BB17-3 (0.40 g, 1.54 mmol) was added a dioxane hydrochloride solution (4 M, 2 mL, 8 mmol) and stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated to dryness to give the crude product BB17 (350 mg).

[0614] Synthesis of Intermediate BB18: 5-Methyloctahydrocyclopenta[c]pyrrol-5-ol Hydrochloride

[0615] Step 1: tert-Butyl 5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0616] To a solution of tert-butyl 5-carbonylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate BB18-1 (400 mg, 2.33 mmol) in tetrahydrofuran (6 mL) was added methylmagnesium bromide in tetrahydrofuran (1 M, 2.3 mL, 2.3 mmol) under ice-cooling. The reaction was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride (5 mL) was then added to quench the reaction. Ethyl acetate (30 mL) and water (10 mL) were then added for separation. The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA = 2 / 1) to afford tert-butyl 5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate BB18-2 (360 mg, 64% yield). MS-ESI [M+H] + :242.1.

[0617] Step 2: 5-Methyloctahydrocyclopenta[c]pyrrol-5-ol hydrochloride

[0618] 5-Methyloctahydrocyclopenta[c]pyrrol-5-ol hydrochloride BB18 is prepared from tert-butyl 5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrol-2(1H)-carboxylate BB18-2 using the fourth step of the synthesis of intermediate BB15. MS-ESI[M+H] + :142.1.

[0619] The following intermediates BB19 to BB23 were prepared using the synthetic method of intermediate BB18.

[0620] Synthesis of intermediate BB24: 2-(tert-butyl)-7-methyl-2-azaspiro[3.5]nonane-2,7-dicarboxylate

[0621] To a solution of 2-(tert-butyloxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid BB24-1 (250 mg, 0.93 mmol) and iodomethane (171 mg, 1.2 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (256 mg, 1.85 mmol), and the reaction was stirred at room temperature for 16 hours. Ethyl acetate (20 mL) and water (10 mL) were added for separation, and the organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to afford 2-(tert-butyl)-7-methyl-2-azaspiro[3.5]nonane-2,7-dicarboxylate BB24 (260 mg, 99% yield). MS-ESI [M+H-56] + :228.1.

[0622] The following intermediate BB25 was prepared using the synthetic method of intermediate BB24.

[0623] Synthesis of intermediate BB26: 2-methyl-1-(piperidin-4-yl)propan-2-ol hydrochloride

[0624] Step 1: tert-Butyl 4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate

[0625] To a solution of tert-butyl 4-(2-methoxy-2-carbonylethyl)piperidine-1-carboxylate BB26-1 (1000 mg, 3.89 mmol) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1 M, 12 mL, 12 mmol) under ice-cooling. The resulting mixture was stirred at room temperature overnight under nitrogen. The reaction was quenched with water (5 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, dried, and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain the product BB26-2 (920 mg, 92% yield). MS-ESI [M-55] + :202.1.

[0626] Step 2: 2-Methyl-1-(piperidin-4-yl)propan-2-ol hydrochloride

[0627] To a solution of tert-butyl 4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate BB26-2 (500 mg, 1.93 mmol) in dichloromethane (10 mL) was added a solution of dioxane hydrochloride (4 M, 2 mL, 8 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted three times with dichloromethane (30 mL). The organic phases were combined and dried to give the crude product BB26 (300 mg), which was used directly in the next reaction. MS-ESI [M+H] + :158.1.

[0628] The following intermediates BB27 to B29 were prepared using the synthetic method of intermediate BB26.

[0629] Synthesis of Intermediate B1: 4-(Thiophen-3-yl)aniline

[0630] To a mixed solution of 3-thiopheneboronic acid B1-1 (1.75 g, 13.7 mmol) and 4-iodoaniline (2 g, 9.1 mmol) in ethylene glycol dimethyl ether (30 mL) and water (3 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (67 mg, 0.09 mmol) and sodium carbonate (1.93 g, 18.2 mmol). Under nitrogen, the reaction was heated at 90°C with stirring for 3 hours. Ethyl acetate (20 mL) and water (10 mL) were then added, and the layers separated. The organic phase was washed with saturated sodium chloride (10 mL), dried, concentrated, and purified on a silica gel column (PE / EA = 4 / 1) to afford 4-(thiophen-3-yl)aniline B1 (1.4 g, 88% yield). MS-ESI [M+H] + :176.2.

[0631] The following intermediates B2 to B5 were prepared using the synthetic method of intermediate B1.

[0632] Synthesis of Intermediate B6: (4-(4-aminophenyl)thiophen-2-yl)methanol

[0633] Step 1: tert-Butyl (4-(5-(hydroxymethyl)thiophen-3-yl)phenyl)carbamate

[0634] To a solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methanol B6-1 (200 mg, 0.83 mmol) and tert-butyl (4-iodophenyl)carbamate (319 mg, 1 mmol) in ethylene glycol dimethyl ether / water (2 mL / 0.5 mL) were added 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (61 mg, 0.083 mmol) and sodium carbonate (265 mg, 2.5 mmol). The resulting mixture was stirred at 120°C under nitrogen overnight. The mixture was spin-dried and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain product B6-2 (120 mg, 47% yield).

[0635] Step 2: (4-(4-aminophenyl)thiophen-2-yl)methanol

[0636] Tert-butyl (4-(5-(hydroxymethyl)thiophen-3-yl)phenyl)carbamate B6-2 (100 mg, 0.33 mmol) was added to hexafluoroisopropanol (4 mL), and the resulting mixture was stirred in a microwave oven at 120°C for 8 hours. The mixture was spin-dried and purified by silica gel column chromatography (PE / EA = 1 / 2) to obtain (4-(4-aminophenyl)thiophen-2-yl)methanol B6 (40 mg, 67% yield). MS-ESI [M+H]: 206.0.

[0637] Synthesis of Intermediate B7: 2-(4-(4-aminophenyl)thiophen-2-yl)acetonitrile

[0638] Step 1: 2-(4-bromothiophen-2-yl)acetonitrile

[0639] To a solution of 4-bromo-2-(chloromethyl)thiophene B7-1 (500 mg, 2.38 mmol) in acetonitrile (10 mL) was added sodium cyanide (210 mg, 4.3 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then at 85°C overnight. The mixture was spin-dried and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 2-(4-(4-aminophenyl)thiophen-2-yl)acetonitrile B7-2 (300 mg, 63% yield). MS-ESI [M+H] + :201.9.

[0640] Step 2: tert-Butyl (4-(5-(cyanomethyl)thiophen-3-yl)phenyl)carbamate

[0641] To a solution of 2-(4-bromothiophen-2-yl)acetonitrile B7-2 (100 mg, 0.49 mmol) in dioxane / water (2 mL / 0.5 mL) were added 4-(tert-butoxycarbonyl)aminophenylboronic acid (236 mg, 1 mmol), 1,1-bis(diphenylphosphino)diboronium palladium chloride (36 mg, 0.05 mmol), and potassium phosphate (317 mg, 1.5 mmol). The resulting mixture was stirred at 90°C overnight. The mixture was dried and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain the product B7-3 (107 mg, 69% yield). MS-ESI [M+H] + :315.

[0642] Step 3: 2-(4-(4-aminophenyl)thiophen-2-yl)acetonitrile

[0643] To a solution of tert-butyl (4-(5-(cyanomethyl)thiophen-3-yl)phenyl)carbamate B7-3 (100 mg, 0.32 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL), and the resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane (10 mL). The organic phases were combined and dried to give the crude product B7 (107 mg), which was used directly in the next reaction. MS-ESI [M+H] + :215.1.

[0644] Synthesis of Intermediate B8: 4-(2-ethylmorpholino)aniline

[0645] Step 1: 2-ethyl-4-(4-nitrophenyl)morpholine

[0646] To a solution of 2-ethylmorpholine B8-1 (500 mg, 2.2 mmol) in DMF (5 mL) were added p-fluoronitrobenzene (613 mg, 4.3 mmol) and potassium carbonate (901 mg, 6.5 mmol). The resulting mixture was stirred at 80°C for 3 hours. The mixture was dried and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain the yellow solid product B8-2 (500 mg, 49% yield). MS-ESI [M+H] + :237.1.

[0647] Step 2: 4-(2-ethylmorpholino)aniline

[0648] Palladium on carbon (10%, 50 mg) was added to a solution of 2-ethyl-4-(4-nitrophenyl)morpholine B8-2 (500 mg, 2.1 mmol) in methanol (5 mL). The resulting mixture was stirred at room temperature under hydrogen for 3 hours. The reaction solution was filtered through celite and the filtrate was dried to give the crude product B8 (300 mg), which was used directly in the next reaction. MS-ESI [M+H] + :207.1.

[0649] The following intermediates B9 to B74 were prepared using the synthetic method of intermediate B8.

[0650] Synthesis of Intermediate B75: (1-(4-aminophenyl)-4,4-dimethylpyrrolidin-3-yl)methanol

[0651] Step 1: 4,4-Dimethyl-1-(4-nitrophenyl)pyrrolidine-3-carboxylic acid ethyl ester

[0652] To a DMF solution (10 mL) of ethyl 4,4-dimethylpyrrolidine-3-carboxylate hydrochloride B75-1 (250 mg, 1.20 mmol) and potassium carbonate (582.2 g, 4.21 mmol) was added 1-fluoro-4-nitrobenzene (424.6 mg, 3.01 mmol). The resulting mixture was heated to 80°C and stirred for 2 hours, then cooled and filtered. Ethyl acetate (50 mL) was added to the filtrate, which was washed with aqueous lithium chloride (10 mL) and concentrated. The mixture was purified by silica gel column chromatography (PE / EA = 3 / 2) to obtain B75-2 (290 mg, 82% yield) as a light yellow solid. MS-ESI [M+H] + :293.2.

[0653] Step 2: (4,4-Dimethyl-1-(4-nitrophenyl)pyrrolidin-3-yl)methanol

[0654] To a solution of ethyl 4,4-dimethyl-1-(4-nitrophenyl)pyrrolidine-3-carboxylate B75-2 (290 mg, 0.992 mmol) in THF (20 mL) was added portionwise with lithium aluminum tetrahydride (49.0 mg, 1.29 mmol) in an ice-water bath. The mixture was warmed to room temperature under nitrogen and stirred for 2 hours. After the reaction was complete, the temperature was lowered to 0°C and water (10 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The mixture was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain B75-3 as a brown oil (190 mg, 77% yield). MS-ESI [M+H] + :251.1.

[0655] Step 3: (1-(4-aminophenyl)-4,4-dimethylpyrrolidin-3-yl)methanol

[0656] To a solution of (4,4-dimethyl-1-(4-nitrophenyl)pyrrolidin-3-yl)methanol B75-3 (100 mg, 0.454 mmol) in EtOH / H2O = 1 / 1 (15 mL) was added sodium dithionite (632.6 mg, 3.63 mmol). The mixture was heated to 80°C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with a DCM / MeOH = 10 / 1 solvent mixture (30 mL). The mixture was washed with brine (5 mL), dried, concentrated, and purified on a silica gel column (DCM / MeOH = 10 / 1) to obtain B75 as a light yellow solid (45 mg, yield 88%). MS-ESI [M+H] + :191.1.

[0657] Synthesis of Intermediate B76: 2-((4-(2-oxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)-2-oxoacetic acid

[0658] Step 1: 2-((4-(2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-2-oxoacetic acid methyl ester

[0659] To a solution of 4-(2-oxa-8-azaspiro[4.5]decane-8-yl)aniline B42 (3 g, 12.9 mmol) in tetrahydrofuran (50 mL) was added triethylamine (2.6 g, 25.8 mmol). Methyl oxalyl chloride (2.37 g, 19.35 mmol) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 1 hour, quenched with saturated aqueous ammonium chloride (10 mL), and extracted with ethyl acetate (60 mL). The organic phase was dried, filtered, and concentrated to give the product B76-1 (3.9 g). MS-ESI [M+H] + :319.3.

[0660] Step 2: 2-((4-(2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-2-oxoacetic acid

[0661] To a solution of methyl 2-((4-(2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-2-oxoacetate B76-1 (3.9 g, 12.2 mmol) in tetrahydrofuran (50 mL) was added a monohydrated aqueous solution of lithium hydroxide (12.5 mL, 1.02 g, 24.4 mmol), and the reaction was stirred at room temperature for 1 hour. 1N hydrochloric acid was then added to adjust the pH of the reaction solution to 3-4. A solid precipitated and was extracted twice with ethyl acetate (150 mL each). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give B76 (3.7 g, 99% yield) as a pale yellow solid. MS-ESI [M+H] + :305.3.

[0662] The following intermediates B77 and B78 were prepared using the synthetic method of intermediate B76.

[0663] 2. Synthesis of Examples

[0664] Method C:

[0665] To a solution of intermediate A (0.05 mmol, 1 eq) and intermediate B (1.5 eq) in N,N-dimethylformamide (2 mL) were added a solution of 1-propylphosphoric anhydride in N,N-dimethylformamide (50%, 2.0 eq) and N,N-diisopropylethylamine (3.0 eq). The mixture was stirred at room temperature for 3 hours and separated and purified by preparative HPLC to obtain the target product.

[0666] Method D:

[0667] To a solution of Intermediate B (0.05 mmol, 1 eq) in dichloromethane (3 mL) was added dropwise oxalyl chloride (4.0 eq) under an ice bath, followed by the addition of 1 drop of DMF. The reaction was stirred at room temperature for 0.5 hour and concentrated to yield the crude product. The crude product was then dissolved in N,N-dimethylformamide (3 mL), followed by the addition of Intermediate A1 (1.0 eq) and N,N-diisopropylethylamine (2.0 eq), and the reaction was stirred at room temperature for 0.5 hour. The desired product was isolated and purified by preparative HPLC.

[0668] According to the above synthesis method, the following example compounds were prepared using the corresponding intermediates:

[0669] 3. Active Examples

[0670] It should be understood that when describing the compounds of the present invention, pharmaceutical compositions, pharmaceutical combinations, kits and related uses and methods herein, the dosages referred to are based on the weight of the free form and do not include any salts, hydrates or solvates thereof, unless otherwise stated.

[0671] Example 1: Inhibitory effect of the compounds of the present invention on SHP2 enzyme

[0672] This experiment evaluates the inhibitory effect of the test compound on SHP2 enzyme activity by detecting the reaction between human recombinant protein SHP2 enzyme and substrate.

[0673] The stock solutions of the components of the reaction buffer were taken out, melted and mixed at room temperature to prepare the reaction buffer (55 mM HEPES pH = 7.2 (Sigma, Catalog No. PHR1428), 100 mM NaCl (Biyuntian, Catalog No. ST374, 5 M solution), 0.5 mM EDTA (Biyuntian, Catalog No. ST066), 1 mM DL-Dithiothreitol (DTT) (Sigma, Catalog No. D9779), 0.002% BSA (Solarbio, Catalog No. A8010), 0.001% Brij35 ( L23 solution (Brij35) (Sigma, catalog #B4184). SHP2 enzyme (catalytic domain, amino acid sequence 224–528, expressed and purified by GenScript) was removed and slowly thawed on ice. 1 μL of this solution (1.37 mg / mL) was added to 386 μL of reaction buffer to dilute to 100 nM. 120 μL of the 100 nM SHP2 enzyme solution was then added to 2880 μL of reaction buffer to prepare a 4 nM SHP2 enzyme working solution. Test compounds and a specific SHP2 inhibitor (11a-1, used as a positive control; Zeng, L. et al., J. Med. Chem. 2014, 57, 6594-6609) were prepared as 10 mM solutions in DMSO. 10 μL of the 10 mM compound solution was mixed with 20 μL of DMSO and diluted three-fold to a total of 10 concentrations. Take 1 μL of the gradient dilution solution and mix it with 99 μL of reaction buffer to obtain a 10x compound working solution.

[0674] To a 96-well black half-area microplate (Greiner, Catalog #675076), add 25 μL of 4 nM SHP2 enzyme working solution and 5 μL of 10x compound working solution to each well and incubate at room temperature for 30 minutes. Add 15 μL of DiFMUP substrate (Thermo Fisher Scientific, Catalog #D6567) to 2985 μL of reaction buffer to prepare a 50 μM substrate working solution. After incubation of compound and SHP2 enzyme, add 20 μL of 50 μM substrate working solution to each well and incubate at room temperature for 5 minutes. Read the plate on a multi-function microplate reader (BioTek, Synergy H1 Multi-function Microplate Reader) and read fluorescence at 340 nm / 450 nm.

[0675] Positive control compound (11a-1)

[0676] The data were analyzed using GraphPad Prism 9.0 software. The dose-response-inhibition equation was used to fit the data using a nonlinear S-curve regression model to obtain a dose-effect curve, and the IC50 value was calculated based on the following equation: SHP2 enzyme inhibition rate (%) = 1-(RFU 待测药 -RFU 缓冲液对照 ) / (RFU DMSO对照 -RFU 缓冲液对照 )×100%.

[0677] Representative compounds of the present disclosure showed excellent inhibitory properties against the SHP2 enzyme, as shown in the table below.

[0678] The above results show that the compounds disclosed herein exhibit excellent SHP2 enzyme inhibitory activity, with IC50 values ​​of <1 μM, preferably 1-100 nM, and more preferably 1-50 nM. For example, the IC50 values ​​of Examples 4, 11, 20, 22, 58, 63, 67, 75, 77, 80, 82, 94, 101, 108 and 115 are 3-4 times lower than those of the most active active center inhibitor in the prior art (control compound 11a-1, IC50 = 0.108 μM), that is, the inhibitory activity is increased by 3-4 times.

[0679] Example 2: Inhibitory activity of the disclosed compounds on proliferation of three tumor cells: KYSE520, MeWo, and MV4-11

[0680] This experiment used Promega The Luminescent Cell Viability Assay kit was used to evaluate the inhibitory effects of the disclosed compounds on the proliferation of cell lines KYSE520 (a human esophageal squamous cell carcinoma cell line that depends on SHP2 for growth), MeWo (a human malignant melanoma cell line), and MV4-11 (a human acute monocytic leukemia cell line with RTK mutations).

[0681] To thaw KYSE520 cells (Nanjing Kebai Biotechnology Co., Ltd., catalog number #CBP60658), rapidly shake the cell cryovial in a 37°C water bath to thaw within 1 minute. Mix the thawed cell suspension with RPMI 1640 medium (HyClone, catalog number #SH30027.01) containing 10% FBS (ExCell, catalog number #FND500), centrifuge at 1000 rpm for 5 minutes, and discard the supernatant. Resuspend the cell pellet in 5 mL of complete medium (RPMI 1640 medium containing 10% FBS) and place it in a 25 cm bottom container. 2Place the cells in a cell culture flask at 37°C, 95% humidity and 5% CO2 and culture in a cell culture incubator. When the cell confluence reaches about 80%, cell passage is performed. When cell passage occurs, discard the old culture medium, wash the cells once with DPBS (Thermo Fisher, catalog number #14190-144), and add 1 mL of trypsin (Thermo Fisher, catalog number #25200072) to digest the cells. When the cells are dispersed into single cells and fall off from the bottom of the cell culture flask, add 3 mL of new complete culture medium to stop digestion. After pipetting the cell suspension evenly, retain 1 / 5 of the cell suspension, add 5 mL of new complete culture medium, pipet evenly, and place the cells in a cell culture flask for continued culture. When the cell confluence reaches about 80% again, cell plating is performed. When plating cells, refer to the cell passaging method, retain 1 / 5 of the cell suspension for continued culture, and place the remaining 4 / 5 of the cell suspension in a 15 mL centrifuge tube. Cell viability is detected by trypan blue exclusion to ensure that the cell viability is above 90%. Complete medium was used to prepare a density of 2.22 × 10 4 Add 135 μL of cell suspension at a concentration of 10 cells / mL to a 96-well transparent flat-bottom black-walled cell culture plate (Greiner, catalog number #655090) to a cell density of 3000 viable cells / well in the cell culture plate. Set up a control group containing no cells, no compounds, and only complete culture medium (i.e., culture medium control), and set up a control group containing no compounds and cells (i.e., cell control). Place the cell plate in a cell culture incubator and culture overnight. First, use DMSO (damas-beta, catalog number #75927R) to continuously dilute the DMSO stock solution of 10 mM compound (example compound and positive control compound 11a-1) with a dilution factor of 3 to the 9th concentration, and set up a DMSO control without compound at the 10th concentration. Then use complete culture medium to dilute the DMSO solution containing different concentrations of compound with a dilution factor of 100 times so that the DMSO content in the compound solution of each concentration is 1%. Finally, 15 μL of the above solution was added to the corresponding cell culture plate, so that the initial concentration of the compound was 10 μM, the adjacent concentrations were diluted 3 times, and the DMSO content in the cell culture plate was 0.1%. The cell plate was placed in a cell culture incubator and cultured for 120 hours.

[0682] MeWo cells (ATCC, catalog #HTB-65) were treated similarly using essentially the same experimental materials: To thaw cells, rapidly shake the cryovial in a 37°C water bath to thaw within 1 minute. The thawed cell suspension was mixed with MEM / EBSS medium (HyClone, catalog #SH30024.01) containing 10% FBS, centrifuged at 1000 rpm for 5 minutes, and the supernatant discarded. The cell pellet was resuspended in 5 mL of complete medium (MEM / EBSS containing 10% FBS) and placed in a 25 cm 2 Place the cell culture flask in a cell culture incubator at 37°C, 95% humidity and 5% CO2 for culture. When the cell confluence reaches about 80%, cell passage is performed. When cell passage occurs, discard the old culture medium, wash the cells once with DPBS, and add 1 mL of trypsin to digest the cells. When the cells are dispersed into single cells and fall off from the bottom of the cell culture flask, add 3 mL of new complete culture medium to terminate the digestion. After blowing the cell suspension evenly, retain 1 / 5 of the cell suspension, add 5 mL of new complete culture medium, blow evenly, and place the cells in a cell culture flask for continued culture. When the cell confluence reaches about 80% again, cell plating is performed. When plating cells, refer to the cell passaging method, retain 1 / 5 of the cell suspension for continued culture, and place the remaining 4 / 5 of the cell suspension in a 15 mL centrifuge tube. Use the trypan blue exclusion method to detect cell viability to ensure that the cell viability is above 90%. Use 5% FBS MEM / EBSS culture medium to prepare a density of 2.22×10 4 90 μL of cell suspension of cells / mL was added to a 96-well cell culture plate to a cell density of 2000 viable cells / well in the cell culture plate. A control group containing no cells, no compound, and only complete culture medium (i.e., culture medium control) was set, and a control group containing no compound and cells (i.e., cell control) was set. The cell plate was placed in a cell culture incubator and cultured overnight. First, a DMSO stock solution of 10 mM compound (example compound and positive control compound 11a-1) was serially diluted using DMSO, with a dilution factor of 3 times, diluted to the 9th concentration, and a DMSO control without compound was set for the 10th concentration. The DMSO solution containing different concentrations of compound was then diluted with complete culture medium, with a dilution factor of 100 times, so that the DMSO content in the compound solution of each concentration was 1%. Finally, 10 μL of the above solution was added to the corresponding cell culture plate, so that the compound starting concentration was 10 μM, the adjacent concentration dilution factor was 3 times, and the DMSO content in the cell culture plate was 0.1%. The cell plate was placed in a cell culture incubator and continued to be cultured for 72 hours.

[0683] Using essentially the same experimental materials, MV4-11 cells (Nanjing Kebai Biotechnology Co., Ltd., catalog number #CBP60522) were treated similarly: To thaw cells, the cryopreserved tubes were rapidly shaken in a 37°C water bath to thaw within 1 minute. The thawed cell suspension was mixed with IMDM medium containing 10% FBS (HyClone, catalog number #SH30228.01), centrifuged at 1000 rpm for 7 minutes, and the supernatant discarded. The cell pellet was resuspended in 5 mL of complete medium (IMDM medium containing 10% FBS) and placed in a 25 cm bottom container. 2 The cells were cultured in a cell culture flask at 37°C, 95% humidity and 5% CO2. 6 When the cell number reaches about 10 cells / mL, the cells are passaged. When the cell number reaches about 10 cells / mL, the old cell suspension is directly blown evenly, and 1 / 5 of the cell suspension is retained. 4 mL of new complete culture medium is added and the cells are placed in a cell culture incubator for further culture. 6 When the cell suspension is about 1 / 5 of the cell suspension, continue culturing and place the remaining 4 / 5 of the cell suspension in a 15 mL centrifuge tube. Use the trypan blue exclusion method to detect cell viability and ensure that the cell viability is above 90%. Use complete culture medium to prepare a density of 1.11 × 10 5 90 μL of cell suspension with a viable cell / mL was added to a 96-well cell culture plate to a cell density of 10,000 viable cells / well in the cell culture plate. A control group containing no cells, no compound, and only complete culture medium (i.e., culture medium control) was set, and a control group containing no compound and cells (i.e., cell control) was set. The cell plate was placed in a cell culture incubator and cultured overnight. First, DMSO was used to serially dilute the DMSO stock solution of 10 mM compound (example compound and positive control compound 11a-1) with a dilution factor of 3 times to the 9th concentration, and a DMSO control without compound was set for the 10th concentration. Then, DMSO solutions containing different concentrations of compound were diluted with complete culture medium with a dilution factor of 100 times to make the DMSO content in each concentration compound solution 1%. Finally, 10 μL of the above solution was added to the corresponding cell culture plate to make the compound starting concentration 10 μM, the adjacent concentration dilution factor 3 times, and the DMSO content in the cell culture plate 0.1%. The cell plate was placed in a cell culture incubator and continued to be cultured for 72 hours.

[0684] For endpoint detection, melt CellTiter-Glo reagent (Promega, catalog number #G7573, Luminescent Cell Viability Assay Kit) was used and each cell plate was moved to room temperature for equilibration for 30 minutes. 75 μL (KYSE520 cells) or 50 μL (MeWo cells and MV4-11 cells) of CellTiter-Glo was added to each well of the corresponding cell plate and shaken on an orbital shaker for 2 minutes to fully lyse the cells. The cell plate was left at room temperature for 8 minutes to stabilize the luminescence signal, and the luminescence value of each well was scanned at all wavelengths using a multi-function microplate reader (PerkinElmer, Envision 2105 Multimode Plate Reader).

[0685] The following formula was used to calculate the cell survival rate under the action of each concentration of compound: Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum 细胞对照 -Lum 培养液对照 )×100%

[0686] The data were analyzed using GmphPad Prism 8.0 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated based on this.

[0687] The inhibitory activity of the example compounds on cell proliferation is shown in the following table:

[0688] The above results show that the compounds disclosed herein exhibit excellent proliferation inhibitory activity against KYSE-520 and / or Mewo and / or MV4-11 cell lines, with IC50 values ​​of <1 μM, preferably <200 nM, more preferably 50-100 nM, and even more preferably <50 nM, and are significantly superior to the active site inhibitor reference compound 11a-1. For example, the IC50 value of the representative example compound tested for KYSE-520 cells was reduced by at least 6 times compared with the IC50 value of 11a-1 (1.23 μM), and even reduced by 34 times (0.036 μM, Ex#20); the IC50 value for Mewo cells was reduced by at least 15 times compared with the IC50 value of 11a-1 (3.10 μM), and even reduced by 100 times (0.060 μM, Ex#68); the IC50 value for MV4-11 cells was generally significantly reduced compared with the IC50 value of 11a-1 (5.13 μM), and even reduced by 85 times (0.060 μM, Ex#68).

[0689] Example 3: Inhibitory activity of representative compounds of the present disclosure on proliferation of various tumor cells

[0690] This experiment used Promega Luminescent Cell Viability Assay Kit was used to evaluate the inhibitory activity of the disclosed compounds on the proliferation of the following cells: 4T1 (mouse breast cancer cell line), A20 (mouse B cell lymphoma cell line), A2780 (human ovarian cancer cell line), AsPC-1 (pancreatic cancer cell line), B16F10 (mouse melanoma cell line), BT549 (human breast cancer cell line), CT26 (mouse colorectal cancer cell line), EMT6 (mouse breast cancer cell line), HCT116 (colorectal cancer cell line), Jurket (acute leukemia cell line), KP-4 (pancreatic cancer cell line), LL / 2 (mouse lung cancer cell line), MCF7 (breast cancer cell line), MKN45 (mouse B cell lymphoma cell line), NCI-H358 (lung cancer cell line), NCI-H727 (gastric cancer cell line), NCI-1944 (lung cancer cell line), Pan 04.03 (pancreatic cancer cell line), SK-BR- 3 (breast cancer cell line), THP-1 (leukemia cell line), TOV21G (ovarian cancer cell line), U87MG (glioma cell line), UM-UC-a (bladder cancer cell line).

[0691] All cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd. The following materials were also used in the experiment: RPMI-1640 media (HyClone, catalog number #SH30022.01), McCoy's 5A media (Thermo Fisher, catalog number #16600-082), MCDB 105 media (Sigma, catalog number #117-500), Medium 199 (Thermo Fisher, catalog number #11150-059), MEM media (Thermo Fisher, catalog number #11095-080), DMEM media (HyClone, catalog number #SH30027.01), fetal bovine serum (FBS) (ExCell, catalog number #M4530), Sodium Pyruvate (100 mM) (Thermo Fisher, catalog number #11360-070), MEM NEAA (100X) (Thermo Fisher, catalog number #11140-050), insulin-transferrin-selenium (ITS-G) (100X) (Thermo Fisher, catalog number #41400045), DPBS (Thermo Fisher, catalog number #14190-144), trypsin (Thermo Fisher, catalog number #25200072).

[0692] Cells were cultured according to the instructions provided by the cell supplier (Nanjing Kebai Biotechnology Co., Ltd.). The recovery and passage of adherent and suspension cells were performed according to the method described in Activity Example 2 above. Suspension or adherent cells were collected and cell viability was tested by trypan blue exclusion to ensure that the cell viability was above 90%. For adherent cells, complete medium was used to prepare a density of 3.75×10 4 Add 80 μL of cell suspension to a 96-well clear flat-bottom black-walled cell culture plate (Greiner, catalog number #655090) to a cell density of 3000 viable cells / well. For suspension cells, use complete medium to prepare a density of 1.25×10 5 Add 80 μL of cell suspension of 10 cells / mL to a 96-well cell culture plate to make the cell density in the cell culture plate 10,000 viable cells / well, set up a control group containing no cells, no compounds, and only complete culture medium (i.e., culture medium control), and set up a control group containing no compounds and cells (i.e., cell control). The cell plate was placed in a cell culture incubator and cultured overnight. First, DMSO (damas-beta, product number #75927R) was used to continuously dilute the DMSO stock solution of 2 mM compound (example compound and positive control compound 11a-1) with a dilution factor of 3 times to the 9th concentration, and a DMSO control without compound was set at the 10th concentration. Then, complete culture medium was used to dilute the DMSO solution containing different concentrations of compound with a dilution factor of 40 times so that the DMSO content in the compound solution of each concentration was 2.5%. Finally, add 20 μL of the above solution to the corresponding cell culture plate, so that the initial concentration of the compound is 10 μM, the adjacent concentration dilution factor is 3 times, and the DMSO content in the cell culture plate is 0.5%. The cell plate is placed in a cell culture incubator and cultured for 72 hours. At the end point of the test, melt the CellTiter-Glo reagent ( Luminescent Cell Viability Assay Kit (Promega, catalog number G7573) was used and the cell plate was moved to room temperature for equilibration for 30 minutes. 50 μL of CellTiter-Glo was added to each well of the cell plate and shaken on an orbital shaker for 2 minutes to fully lyse the cells. The cell plate was placed at room temperature for 8 minutes to stabilize the luminescence signal. The luminescence value of each well was scanned at full wavelength using a multifunctional microplate reader (PerkinElmer Envision 2105 Multimode Plate Reader).

[0693] The following formula was used to calculate the cell survival rate under the action of each concentration of compound: Cell survival rate (%) = (Lum 待测药 -Lum 培养液对照 ) / (Lum细胞对照 -Lum 培养液对照 )×100%

[0694] The data were analyzed using GmphPad Prism 8.0 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated based on this.

[0695] The inhibitory activity results of representative compounds of the present disclosure in various cell lines are shown in the table below:

[0696] The above results show that the compounds disclosed herein exhibit broad-spectrum anti-tumor cell proliferation activity.

[0697] Example 4: Rat PK results of representative compounds of the present disclosure

[0698] According to the standard method of rat PK study conventional in the art, rat PK test of representative compounds of the present disclosure and positive control compound (11a-1) was performed as follows.

[0699] Specifically, six male SD rats (6 to 8 weeks old, weighing 200±20 g, purchased from Vital River) were randomly divided into two groups, 3 rats in each group, for intravenous injection (IV) and oral gavage (PO) administration, respectively.

[0700] For the intravenous injection group: weigh the test compound according to the dosage (1 mpk), dissolve it in the solvent in the table below, and finally obtain a 1 mg / mL clear solution. Inject it into the tail vein of rats at a dose of 1 mg / kg.

[0701] For the oral administration group: Weigh the test compound according to the administration dose (5 mpk), prepare and dissolve it using the solvent in the following table, with a formulation concentration of 1 mg / mL and a dosing volume of 5 mL / kg for oral administration.

[0702] Blood was collected by jugular vein puncture at time points of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. 0.2 mL of whole blood was collected each time and placed in a 1.5 mL anticoagulant tube containing EDTA. The tube was placed on a sample plate containing wet ice and waited for centrifugation. The tube was centrifuged for 10 minutes at 4°C and 8000 rpm. 0.1 mL of plasma samples were collected and stored in 81-well cryoboxes at -20°C until analysis.

[0703] Preparation of test compound stock solution: Accurately weigh 1 mg of the test compound and dissolve it in 1 mL of DMSO to prepare a 1 mg / mL stock solution S1, which was stored in a refrigerator at 4°C until use.

[0704] Preparation of internal standard working solution: Pipette 0.1 mL of tolbutamide (2 mg / mL) internal standard stock solution into 1000 mL of acetonitrile to prepare a 200 ng / mL internal standard working solution. This solution will be used as a protein precipitation agent during sample pretreatment. Store this solution at 4°C and it is valid for 12 months.

[0705] Preparation of test sample standard curve and quality control sample working solutions: 50 μL of the 1 mg / mL DMSO stock solution S1 of the test compound was diluted with 950 μL of 100% methanol to obtain a 50,000 ng / mL working solution. This 50,000 ng / mL working solution was then serially diluted with 100% methanol to obtain a series of standard curve working solutions with concentrations of 10, 20, 50, 100, 500, 1,000, 5,000, 10,000, 20,000, and 50,000 ng / mL. 40 μL of the 1 mg / mL DMSO stock solution S1 of the test compound was diluted with 960 μL of 100% methanol to obtain a 40,000 ng / mL quality control sample working solution. Appropriate amounts of this working solution were then diluted to prepare quality control sample working solutions at concentrations of 8,000 and 16,000 ng / mL. Take 60 μL of DMSO standard curve working solution of the test compound with a concentration of 50 ng / mL, and dilute it with 40 μL of 100% methanol solution to make a quality control sample working solution with a concentration of 30 ng / mL.

[0706] Plasma sample processing: Preparation of plasma sample standard curves and quality control samples of the test compounds: Dilute 5 μL of the standard curve working solution of the test compounds at different concentrations and the quality control sample working solution into 45 μL of blank rat plasma to obtain standard curves with final concentrations of 1, 2, 5, 10, 50, 100, 500, 1000, 2000 and 5000 ng / mL and quality control samples with final concentrations of 3, 800, 1600 and 4000 ng / mL.

[0707] Plasma sample pretreatment: 50 μL of plasma sample was transferred to a 96-well plate, and protein precipitation was performed by adding 500 μL of acetonitrile containing 200 ng / mL tolbutamide as internal standard. The sample was centrifuged at 4000 rpm for 20 minutes at 2-8°C. 300 μL of supernatant was added to a new labeled 96-well plate and mixed with 300 μL of 0.1% formic acid water. 10 μL of the sample was injected into the LC-MS / MS (API-4000Qtrap-Shimadzu) Controller-CBM20A); phase A: 0.1% formic acid in water, phase B: 100% methanol, gradient: 0-0.3 min, 98% A + 2% B, 0.3-0.6 min, B from 98% to 2% / A from 2% to 98%, hold until 1.5 min, 1.50-1.51 min, to 98% B / 2% A, 1.51-2.00 min, hold 98% B / 2% A; chromatographic column: Waters Xbridge C18 3.5 μm 2.1×50 mm, injection volume: 10 μL; flow rate 0.5 mL / min).

[0708] Sample analysis was performed using the internal standard method. Data were collected and analyzed using Analyst 1.6.3. The theoretical concentration of the standard curve was used as the abscissa, and the peak area ratio of the test compound to the internal standard was used as the ordinate. Linear regression was performed using the least squares method to fit the standard curve equation (weighted 1 / X²), with an R² > 0.9900. The results are shown in the table below:

[0709] The results in the above table show that the oral pharmacokinetic properties of the representative compounds of the present disclosure are greatly improved.

[0710] Example 5: Study on the selectivity of the compounds of the present invention for tyrosine phosphatase

[0711] This experiment evaluated the selectivity of the disclosed compounds against tyrosine phosphatases. The tyrosine phosphatases tested included SHP1, HePTP, Laforin, LMWPTP, LYP, PTP1B, PRL2, SSU72, VHR, FAP1, STEP, CDC14A, CD45, MEG2, and PP5, all of which were expressed and purified from Escherichia coli.

[0712] Phosphatase activity was determined using p-nitrophenyl phosphate (pNPP) (Fisher Scientific) as a substrate in 50 mM 3,3-dimethylglutaric acid buffer (pH 7.0, containing 1 mM EDTA). The ionic strength was adjusted to 0.15 M with NaCl. In a 384-well plate, 20 μL of each enzyme solution in the 3,3-dimethylglutaric acid buffer was added to a 30 μL reaction mixture containing 5 μM of the compound (example compound and positive control compound 11a-1) and a specific concentration of pNPP (the pNPP concentration used corresponds to the Km value of the enzyme being studied). The reaction was initiated and quenched by adding 20 μL of 5N NaOH after 10-60 minutes. Wells without enzyme served as controls for correction. Absorbance at 405 nm was measured using a Spectra MAX340 microplate spectrophotometer (Molecular Devices). The molar extinction coefficient was 18,000 M. -1 cm -1 , determine the amount of product p-nitrophenol.

[0713] The data were analyzed using GraphPad Prism software, and the dose-response-inhibition equation was fitted to the data using nonlinear S-curve regression to obtain the dose-effect curve, from which the IC50 value was calculated.

[0714] The selectivity of representative compounds of the present disclosure for tyrosine phosphatase is shown in the following table:

[0715] The above results show that the representative compounds of the present disclosure exhibit good selectivity against SHP2 on the PTP phosphatase panel.

[0716] Example 6: hERG activity of representative compounds

[0717] This experiment was a non-GLP study conducted with reference to GLP guidelines and in accordance with the following technical guidelines: National Medical Products Administration: Technical Guidelines for Nonclinical Studies of Drugs with Potential for QT Interval Prolongation (2014) and ICH S7B Guidelines for Nonclinical Evaluation of Potential Drugs to Induce Delayed Ventricular Repolarization (QT Interval Prolongation) in Humans (2005).

[0718] Test sample preparation: Weigh the test substance into DMSO to prepare a 5 mM or 10 mM stock solution. Dilute the solution with DMSO to a 3.33 mM solution. Then, dilute the solution with extracellular fluid to a 10 μM working solution, ensuring a DMSO concentration of 0.3%. Sonicate for 20 minutes. Visually inspect the solubility of the test sample; all concentrations dissolve completely without visible precipitation.

[0719] Positive control preparation: 3.99 mg of cisapride (positive control) was prepared with 807.96 μL of DMSO to a 10 mM stock solution. This was then diluted sequentially with DMSO to 1000, 333.33, 33.33, 3.33, and 0.33 μM dilutions. Prior to testing, 30 μL of each of the last four dilutions was added to 10 mL of extracellular fluid, ensuring a DMSO concentration of 0.3%. Final working concentrations of cisapride were 1000, 100, 10, and 1 nM. Visual inspection of cisapride solubility revealed complete dissolution at all concentrations with no visible precipitation.

[0720] The blank control stock solution (DMSO) was stored at room temperature. The blank control working solution was prepared on the same day and stored at room temperature. The test substance and positive control stock solutions were stored at -20°C. The test substance working solution was prepared on the same day and stored at room temperature. The positive control working solution was prepared on the same day and stored at room temperature.

[0721] HEK-293 cells stably expressing the hERG potassium channel were used (purchased from Creacell, catalog number #A-0320). Specifically, the HEK-293 cells stably expressing the hERG potassium channel were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 (37°C, 5% CO2). The old medium was removed and the cells were washed once with PBS, and then 1 mL of TrypLE was added. TM Express solution (Gibco, catalog number #12604-021), incubate at 37°C for about 0.5 min. When the cells detach from the bottom of the dish, add about 5 mL of the above-mentioned DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, inoculate the cells in a 6 cm cell culture dish with a cell inoculation capacity of 2.5×10 5 Cells (final volume: 5 mL) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0722] Before the patch clamp test, cells were treated with TrypLE TM Express separation, 4×10 3 The cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, patch clamp analysis was performed.

[0723] The hERG activity of the representative compounds of the present disclosure was detected using conventional manual patch clamp techniques in the art (Patch-Clamp Methods and Protocols, 2014, 2nd edition, Humana Press, editors: Marzia Martina, Stefano Taverna.) as follows:

[0724] The above results show that the representative compounds of the present disclosure have no inhibitory activity against hERG at a concentration of 10 μM.

[0725] Example 7: CYP450 Inhibitory Activity of Representative Compounds

[0726] According to the standard methods for studying cytochrome P450 enzyme systems conventional in the art, such as the methods described in Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization (2008) by Kerns, Edward H. and Di Li et al., San Diego, Academic Press, and In Vitro Assessment of Cytochrome P450 Inhibition: Strategies for Increasing LC / MS-Based Assay Throughput Using a One-Point IC50 Method and Multiplexing High-Performance Liquid Chromatography (J. Pharm. Sci. 2007, 96(9), 2485), the inhibitory effects of the compounds of the present disclosure on the cytochrome P450 enzyme system were similarly investigated as follows.

[0727] Human liver microsomes were purchased from Corning or Xenotech. The test compounds were evaluated by detecting the metabolism of substrates of different Cyp450 isoforms by human liver microsomes.

[0728] The specific inhibitor solution, substrate solution and internal standard information are shown in the following table:

[0729] Preheat 0.1 M potassium phosphate buffer (potassium buffer, pH 7.4).

[0730] 100 mM K-buffer was prepared by mixing 9.5 mL of stock solution A (1 M potassium dihydrogen phosphate, prepared by dissolving 136.5 g potassium dihydrogen phosphate in 1 L Milli-Q water) into 40.5 mL of stock solution B (1 M potassium dihydrogen phosphate, prepared by dissolving 174.2 g potassium dihydrogen phosphate in 1 L Milli-Q water), making the total to 500 mL with Milli-Q water, and titrating the buffer to pH 7.4 with KOH or H3PO4.

[0731] Prepare test compounds and specific inhibitor solutions (400-fold dilution) in a 96-well plate: transfer 8 μL of 10 mM test compound to 12 μL of ACN; mix 12 μL of 1 mM α-naphthoflavone + 10 μL of 40 mM sulfaphenazole + 10 μL of 10 mM quinidine + 8 μL of dimethyl sulfoxide to prepare specific inhibitor solutions for CYP1A2, CYP2C9 and CYP2D6; add 8 μL of dimethyl sulfoxide stock solution to 12 μL of ACN to prepare specific inhibitor solutions for CYP3A4, CYP2B6, CYP2C8 and CYP2C19, respectively.

[0732] Dissolve 66.7 mg of NADPH in 10 mL of 0.1 M potassium buffer, pH 7.4, to prepare a 4-fold diluted NADPH solution. Prepare a human liver microsomal solution in potassium buffer, where the concentrations of 1A2, 2C9, 2D6, 3A4, and 2B6 are all 0.1 mg / mL, the concentration of 2C19 is 0.5 mg / mL, and the concentration of 2C8 is 0.2 mg / mL. Prepare a 4-fold diluted substrate solution (2 mL of each isomer) in potassium buffer (add HLM on ice if necessary), with concentrations of 120 μM (1A2), 40 μM (2C9), 140 μM 1.6 mg / mL HLM (2C19), 40 μM (2D6), 320 μM (3A4), 20 μM (3A4), 280 μM (2B6), and 40 μM 0.4 mg / mL HLM (2C8).

[0733] Prepare a 0.2 mg / mL HLM solution on ice (10 μL of 20 mg / mL to 990 μL of 0.1 M potassium buffer). Add 400 μL of 0.2 mg / mL HLM to the assay wells, then add 2 μL of a 400-fold diluted test compound to the designated wells on ice. Add 200 μL of 0.2 mg / mL HLM to the assay wells, then add 1 μL of a specific inhibitor solution to the designated wells on ice. Add the following solutions (in duplicate) to a 96-well assay plate on ice: add 30 μL of a 2-fold diluted test compound solution and a specific inhibitor solution to a 0.2 mg / mL HLM solution; add 15 μL of a 4-fold diluted substrate solution. Pre-incubate the 96-well assay plate and NADPH solution at 37°C for 5 minutes, add 15 μL of a preheated 8 mM NADPH solution to the assay plate, and the reaction begins. The reaction times for the different P450 isoforms were as follows: 5 minutes for 3A4, 10 minutes for 1A2, 2B6, 2C8, 2C9, and 2D6, and 45 minutes for 2C19 at 37°C. The reactions were terminated by adding 120 μL of ACN containing internal standards (final internal standard concentrations: 0.1 μM for 2C19, 1A2, 3A4 (midazolam), 2D6), 200 ng / mL for 3A4 (testosterone), 0.31 μM for 2C9, 0.36 μM (100 ng / mL) for 2B6, and 40 ng / mL for 2C8).

[0734] After the reaction was quenched, the mixture was shaken on a shaker (IKA, MTS2 / 4) for 10 minutes (600 rpm) and then centrifuged at 5594 g for 15 minutes (Thermo Multifuge×3R). 50 μL of the supernatant was transferred from each well to a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01) for LC / MS analysis (column model ACQUITY UPLC BEH_C18 (2.1×50 mm, 1.7 μm), mobile phase A was H2O-0.025% FA-1 mM NH4OAC, mobile phase B was MeOH-0.025% FA-1 mM NH4OAC, and the flow rate was 0.6 mL / min).

[0735] The CYP inhibition results of the representative compounds of the present invention are shown in the following table:

[0736] The above results show that the representative compounds of the present disclosure have no significant inhibitory effect on major P450 enzymes, which indicates that the risk of drug interactions is greatly reduced, which will greatly facilitate the combined use of the compounds of the present disclosure with other active agents.

[0737] While the invention has been described with reference to particular embodiments thereof, it will be understood that the invention is capable of further modifications, and this application is intended to cover any changes, uses, or modifications of the invention that generally follow the principles of the invention and include such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains, which departures may be applied to the basic characteristics herein above described and which fall within the scope of the appended claims.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, in: represents a saturated, partially unsaturated, or aromatic ring system; represents an aromatic ring system; A1, A2, A3, A4, A5 are each independently selected from absent, C, N, O and S, and A6 is selected from C and N, provided that (1) at most two of A1-A5 are absent, and (2) at most four of A1-A6 are heteroatoms; R a is selected from -H, =O, =S, =N-OH, -OH, -NH2, halogen, -CN and -C optionally substituted by halogen 1-6 alkyl; A7, A8, A9 are each independently selected from C, N, O and S, provided that at least one of A7, A8 and A9 is not C; A 10 Selected from CR b and N; A 11 Selected from CX and N; R b is selected from H, halogen, CN and halogen-substituted -C 1-6 alkyl; X is selected from H, halogen, CN, -OH, -OC 1-6 Alkyl and -C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted; Y is selected from the following groups which are optionally substituted: -C 1-6 Alkyl, -(CH2) t -3-15 membered carbocyclic group, -(CH2) t -C 6-10 Aryl, -(CH2) t -5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S, -(CH2) t - a 3-15 membered heterocyclic group having 1 or more heteroatoms independently selected from N, O and S; Z is selected from the following optionally substituted divalent groups: -C 6-10 Aryl-, -3-10 membered carbocyclyl-, -5-12 membered heteroaryl- having 1 or more heteroatoms independently selected from N, O and S, -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S; R is selected from the following groups which are optionally substituted: -C 6-10 aryl, -3-15 membered carbocyclyl, -5-12 membered heteroaryl having 1 or more heteroatoms independently selected from N, O and S, -3-15 membered heterocyclyl having 1 or more heteroatoms independently selected from N, O and S; and t is optionally an integer of 0 to 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Y is selected from the following groups which are optionally substituted: -C 1-6 alkyl, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t -6-15 membered spiro ring or fused saturated or partially unsaturated carbon ring, -(CH2) t -C 6-10 Aryl, -(CH2) t - a 5-12 membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, and -(CH2) t - a 6-15 membered spirocyclic or fused saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O and S; Z is selected from the following divalent groups which are optionally substituted: -C 6-10 Aryl-, -3-8 membered monocyclic saturated or partially unsaturated carbon ring-, -5-10 membered bridged saturated or partially unsaturated carbon ring-, -5-12 membered heteroaryl having 1-4 heteroatoms independently selected from N, O and S-, - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S-, - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S-, and - a 6-15 membered spirocyclic ring or a fused saturated or partially unsaturated ring having 1-4 heteroatoms independently selected from N, O and S Heterocyclic ring; R is selected from the following groups which are optionally substituted: -C 6-10 Aryl, -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -5-10 membered bridged saturated or partially unsaturated carbon ring, -6-15 membered spiro ring or fused saturated or partially unsaturated carbocyclic ring, - a 5-12 membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S, - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, - a 5-10 membered bridged saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S, and - a 6- to 15-membered spirocyclic or fused saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from N, O and S.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: 0-1 R is optional a A substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S, preferably a five-membered aromatic group containing 4 nitrogen heteroatoms, A6 is C; R a is selected from -H, -CN, halogen, =O and -C substituted by halogen 1-6 alkyl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: One of A7 and A9 is a heteroatom selected from N, O and S, the other is C, and A8 is a carbon atom; preferably, A7 is selected from CY and NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom, and A8 is a carbon atom.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: A 10 CR b And A 11 CX; R b is selected from H, and X is selected from halogen and -OH.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Y is selected from the following groups which are optionally substituted: -C 1-6 Alkyl, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t -C 6-10 Aryl; preferably optionally substituted with the following groups: -C 1-6 Alkyl, -(CH2) t -3-6 membered monocyclic saturated carbocyclic ring, -(CH2) t -5-8 membered bicyclic bridged saturated carbocyclic ring and -(CH2) t -phenyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Y-C 1-6 The alkyl group is optionally substituted by halogen or CN, and the cyclic group of Y is optionally substituted by 1-3, preferably 1 or 2, more preferably 1 selected from -C 1-6 Alkyl and -OC 1-6 Alkyl radicals are substituted.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Z is selected from optionally substituted -C 6-10 Aryl-, -3-8 membered monocyclic saturated or partially unsaturated carbocyclic ring-, -5-10 membered bridged saturated or partially unsaturated carbocyclic ring- and -3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from N, O and S; preferably Z is selected from optionally substituted phenyl, -3-6 membered monocyclic saturated or partially unsaturated carbocyclic ring-, -5-8 membered bridged saturated carbocyclic ring- and -4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O and S.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: Z is optionally replaced by one or more independently selected from halogen, -C 1-6 Alkyl or -OC 1-6 Alkyl radical substitution, where -C 1-6 Alkyl is optionally substituted by halogen or CN; preferably Z is unsubstituted.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R is selected from the following groups which are optionally substituted: - a 5-6 membered monocyclic heteroaryl or 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, - a 3-8 membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S, - a 5-10 membered bridged saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O and S, and - a 6-15 membered spiro or fused heterocycle having 1-4 heteroatoms independently selected from N, O and S. Saturated or partially unsaturated heterocycle; preferably selected from the following groups which are optionally substituted: - a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O and S, - a 4-7 membered monocyclic saturated or unsaturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, - a 5-8 membered bicyclic bridged saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, - and - a 7-11 membered spiro or fused saturated heterocycle having 1-3 heteroatoms independently selected from N, O and S.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R is 0 to 4, preferably 0 to 3, more preferably 0-2, independently selected from the following groups: halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein two substituents attached to the same ring carbon atom can form a 3-8 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached, and the -C in the substituent is 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The alkynyl or cyclic groups are each independently optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably substituted by a group selected from the following: halogen, CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein two substituents attached to the same carbon atom can form a 3-6 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached, and the C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substitution.

12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R has the formula (A) in, f is selected from an integer from 0 to 3, preferably an integer from 0 to 2; t is selected from an integer from 0 to 3, preferably an integer from 0 to 1; G is selected from O, N-R2 and CR3R4; preferably O and CR3R4, most preferably CR3R4; R1 is selected from H and optionally halogen, CN, -OH or -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, wherein two R1 attached to the same ring carbon atom can form a 3-8 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached; preferably R1 is selected from H and optionally substituted by -OH or -OC 1-6 Alkyl-substituted-C 1-6 Alkyl; most preferably R1 is selected from H and -C 1-6 alkyl; R3 and R4 are each independently selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atoms to which they are attached form a 3-8 membered saturated spirocarbocyclic ring, and the -C in the substituent is 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The alkynyl or cyclic groups are each independently optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, halogen, CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atoms to which they are attached form a 3-6 membered saturated spirocarbocyclic ring, and the C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably selected from H, halogen, CN, -C 1-6 Alkyl, -4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl group is optionally further substituted with halogen, -OH or -OC 1-6 Alkyl substitution; R2 is selected from H, -C 1-6 Alkyl, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein the C 1-6 The alkyl or cyclic group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, -C 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably a group selected from the following: H, -C 1-6 Alkyl, -4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, -OH or -OC 1-6 Alkyl substitution; When f is 0, G is -CH2-.

13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, wherein: R has the following formula: in: k is an integer of 0-2, m and n are each independently an integer of 1-3, and l is an integer of 1-4, preferably k is an integer of 0-2, m and n are each independently an integer of 1-2, and l is an integer of 1-3; r and p are each independently an integer of 0-3, q is an integer of 1-4, preferably r is an integer of 0-1, p is an integer of 0-2 and q is an integer of 1 to 3; t is selected from an integer from 0 to 3, preferably an integer from 0 to 1; G is selected from O, N-R2 and CR3R4, preferably O and CR3R4; R1 is selected from H and optionally halogen, CN, -OH or -OC 1-6 Alkyl-substituted-C 1-6 Alkyl, wherein two R1 attached to the same ring carbon atom can form a 3-8 membered saturated spirocarbocyclic ring together with the carbon atom to which they are attached; preferably R1 is selected from H and optionally substituted by -OH or -OC 1-6 Alkyl-substituted-C 1-6 Alkyl; more preferably R1 is H; R3 and R4 are each independently selected from H, halogen, CN, -OH, -NH2, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -OC 1-6 Alkyl, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atoms to which they are attached form a 3-8 membered saturated spirocarbocyclic ring, and the -C in the substituent is 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 The alkynyl or cyclic groups are each independently optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, halogen, CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, or R3 and R4 together with the ring carbon atoms to which they are attached form a 3-6 membered saturated spirocarbocyclic ring, and the C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably selected from H, -OH, -C 1-6 Alkyl, where the C 1-6 The alkyl group is optionally further substituted with halogen, -OH or -OC 1-6 Alkyl substitution; R2 is selected from H, -C 1-6 Alkyl, -(CH2) t -3-8 membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-8 membered bridged saturated or partially unsaturated carbon ring, -(CH2) t - a 3-8 membered monocyclic saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, -(CH2) t - a 5-8 membered bridged saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from N, O and S, wherein the C 1-6 The alkyl or cyclic group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; preferably a group selected from the following: H, -C 1-6 Alkyl, -(CH2) t - a 4-7 membered monocyclic saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S, wherein C in the substituent is 1-6 The alkyl group is optionally substituted with halogen, CN, -OH or -OC 1-6 Alkyl substituted; more preferably a group selected from the following: selected from H, -C 1-6 Alkyl, where C 1-6 The alkyl group is optionally further substituted with halogen, -OH or -OC 1-6 Alkyl substitution.

14. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, having the formula: Among them, A1~A 11 , R a , R b , Y, G, R1, t, f, m, k, n, l, r, p and q are each as defined in the preceding claims for the compound of formula (I), formula (A), formula (B) and formula (C) structural fragment; wherein Preferably, 0-1 R a A substituted, five-membered partially unsaturated or aromatic group containing 3-4 ring heteroatoms selected from N, O and S; more preferably optionally substituted with 0-1 R a A substituted five-membered aromatic group containing 3-4 nitrogen heterocyclic atoms; most preferably a five-membered aromatic group containing 4 nitrogen heterocyclic atoms; A 11 Preferably CX, A 10 Selected from N and CR b , A8 is C, R b Preferably, A7 is selected from CY or NY, A9 is selected from C, O and S, and only one of A7 and A9 is a heteroatom; Preferably it has the following formula:

15. A compound, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, which is a compound of Examples 1-134.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, and a pharmaceutically acceptable excipient.

17. A compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutical composition according to claim 16, for use as a medicament for the treatment and / or prevention of a disease mediated by SHP2.

18. Use of a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutical composition according to claim 16 for the preparation of a medicament for preventing or treating a disease mediated by SHP2.

19. A method for treating and / or preventing a disease mediated by SHP2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotopic variant thereof, or a pharmaceutical composition according to claim 16.

20. The compound of claim 17, the use of claim 18 and the method of claim 19, wherein the disease mediated by SHP2 is cancer or a tumor, cardiovascular disease, immune disorder, fibrosis, eye disorder, systemic lupus erythematosus, diabetes, neutropenia or a combination thereof, preferably selected from Noonan syndrome (NS), Leopard syndrome (LS), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer and a combination thereof.

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