Its use as a compound and anticancer agent

Abstract

The present invention provides a compound having the structure of formula (I) and that can be used as an SHP2 inhibitor, a pharmaceutical composition containing the compound, a method for preparing the compound, and the use of the compound in the treatment of cancer. TIFF2026523001000265.tif50130

Description

[Technical Field]

[0001] cross reference This application claims priority to Chinese invention patent application No. 2023108367770, filed on July 7, 2023.

[0002] The present invention relates to the field of medicinal chemistry. More specifically, the present invention relates to a class of compounds having novel structures that can be used as SHP2 inhibitors, pharmaceutical compositions comprising such compounds, methods of using such compounds to treat or prevent SHP2-mediated diseases, particularly cancer or tumors, and the use of these compounds in the treatment or prevention of SHP2-mediated diseases, particularly cancer or tumors. [Background technology]

[0003] Abnormal regulation of molecular phosphorylation levels in the body often leads to the development and progression of various diseases, such as cancer. Specifically, the phosphorylation state of tyrosine in signaling proteins plays a crucial role in the initiation, progression, and termination of signaling cascades in many cells. Tyrosine phosphorylation is regulated by protein tyrosine kinase (PTK, phosphorylation) and protein tyrosine phosphatase (PTP, dephosphorylation). Abnormal regulation of these two enzymes leads to abnormal tyrosine phosphorylation, resulting in the development of diseases including diabetes, cancer, and autoimmune diseases.

[0004] Protein tyrosine phosphatase 2 (SHP2), containing Src homology-2, is a full-length 593-amino acid dephosphorylation enzyme encoded by the PTPN11 gene, and is a member of the PTP family. SHP2 consists of two N-terminal SH2 domains, N-SH2 and C-SH2, namely a highly conserved PTP domain and a flexible C-terminal tail. The N-SH2 and C-SH2 domains are primarily used for substrate recognition, regulation of enzyme activity, and downstream signaling protein binding, while the PTP domain binds to phosphorylated tyrosine peptide fragments and catalyzes the hydrolysis of their phosphate ester groups. In the ground state of SHP2, N-SH2 and C-SH2 bind to the PTP, masking its catalytic active site and forming a self-inhibitory, inactive "off" structure. This inhibits the activity of the SHP2 protein and restricts access to the substrate's catalytic site. Under stimulation by appropriate signaling factors such as growth factors or cytokines, or in certain pathogenic mutations, N-SH2 and C-SH2 detach from PTP, opening the PTP active site and exposing the catalytic site. This triggers catalytic dephosphorylation of phosphorylated substrates such as receptors, kinases, and phospholipids, thereby regulating downstream signaling.

[0005] SHP2 is located at the intersection of multiple signaling pathways and is a crucial hub linking various intracellular oncogenic signaling pathways. For example, it is a convergence node in several signaling pathways, such as Ras-Raf-MEK-ERK, JAK-STAT, PI3K-AKT-mTOR, and PD-1 / PD-L1, and is involved in regulating various signaling pathways in the body. Over-activation of SHP2 can stimulate the activation of multiple signaling pathways, thereby promoting the development and progression of various cancers. In other words, the development of many cancers is often closely related to the overactivation of signaling pathways regulated by SHP2. Therefore, inhibiting SHP2 activity can suppress the survival and proliferation of tumor cells.

[0006] However, the development of SHP2 inhibitors has seen little progress over a considerable period, leading to a common understanding within the industry that SHP2 inhibitors are "unpharmaceutically unfeasible." This is because the initial development of small molecule SHP2 inhibitors focused on the catalytic active site. These active site inhibitors exhibit low biological activity. Even the most potent inhibitor to date (salicylic acid-based active site inhibitor 11a-1) only achieved an IC50 of approximately 0.2 μM, and its cellular activity did not exceed an IC50 of 1 μM. Furthermore, their potential for drug development is weak, with an oral bioavailability of only 0.07% (J. Med. Chem. 2014, No. 57, pp. 6594-6609). Moreover, the catalytic domain of SHP2 is highly conserved, and inhibitors at the catalytic site generally exhibit poor selectivity, potentially leading to serious toxic reactions due to off-target effects.

[0007] SHP2 inhibitors are designed to inhibit SHP2 from transitioning to its "open" active structure by stabilizing its ground state (inactive "off" structure), and are called "allosteric inhibitors." Allosteric inhibitors bind to the interaction regions of the three protein modules, rather than the catalytic active site. Currently, nine structurally very similar allosteric inhibitors, pioneered by TNO155, are in clinical trials. However, these allosteric inhibitors have presented many problems in clinical trials, including severe cardiotoxicity, low specificity, susceptibility to off-target toxicity, rapid progression of resistance in solid tumors due to mutations in the N-SH2 and C-SH2 modules affecting PTP module binding in the "off" structure, and ineffectiveness in diseases where SHP2 only exists in the "open" structure, such as NS, LS, and JMML, due to SHP2 mutations.

[0008] On the other hand, despite the aforementioned weaknesses of early and current SHP2 active site inhibitors, overcoming these weaknesses through structural optimization can give SHP2 active site inhibitors significant advantages over allosteric inhibitors in terms of their mechanism of action, resulting in a superior drug option. For example, active site inhibitors have significantly altered structural skeletons and exhibit binding properties consistent with phosphorylated tyrosine peptide fragments. This not only eliminates toxic side effects specific to allosteric inhibitors, such as cardiotoxicity caused by hERG inhibition, but also demonstrates high binding specificity to the protein, reducing the likelihood of unknown off-target effects. Furthermore, the mutation rate of the catalytic active site of SHP2 is low, and its binding site is more distant compared to allosteric inhibitors, resulting in a slower rate of resistance progression and the ability to overcome resistance to allosteric inhibitors. Moreover, they remain effective against diseases that exist only in the "open" structure due to SHP2 mutations, such as NS, LS, and JMML.

[0009] Therefore, there is a great need for more compounds with different structural types that function as SHP2 active site inhibitors. These compounds are expected to offer improved inhibitory activity and other superior properties compared to existing SHP2 active site inhibitors and allosteric inhibitors, overcoming the weaknesses of existing active site inhibitors and allosteric inhibitors while fully leveraging the advantages of SHP2 active site inhibitors, thereby resulting in more potent therapeutics for clinical use.

[0010] The inventors addressed the aforementioned need through meticulous research. This disclosure provides inhibitory compounds with novel structures having SHP2 active site inhibitory activity. These inhibitors, due to their improved structural patterns, exhibit enhanced inhibitory activity specific to the SHP2 protein and against associated tumors compared to existing SHP2 inhibitors, along with favorable pharmacokinetic properties (thus demonstrating good drug viability), excellent selectivity for SHP2 among protein phosphatases, good cardiac safety, such as reduced hERG toxicity, and reduced risk of drug interactions, demonstrating promising inhibitory compounds with high potential for application. [Overview of the project]

[0011] This disclosure relates to compounds having the structural formula (I) as defined herein.

[0012] [ka]

[0013] or to provide pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof. [In the formula,

[0014] [ka]

[0015] This represents a saturated, partially unsaturated, or aromatic ring system.

[0016] [ka]

[0017] This represents an aromatic ring system, A1, A2, A3, A4, and A5 are each independently selected from C, N, O, and S, and do not exist, A6 is selected from C and N, provided that (1) the maximum number of non-existent ones among A1 - A5 is up to 2, and (2) the maximum number of heteroatoms among A1 - A6 is up to 4. 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, and 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 is C-R b and N. A 11 is selected from C-X and N. R b is selected from H, halogen, CN, and -C substituted by halogen. 1~6 alkyl. X is selected from H, halogen, CN, -OH, -OC 1~6 alkyl and -C 1~6 alkyl, and C 1~6 alkyl is optionally substituted. Y is -C 1~6 alkyl, -(CH2) t -3 to 15-member carbocyclic, -(CH2) t -C 6~10 aryl, one or more heteroatoms independently selected from N, O, and S in -(CH2) t -5 to 12-member heteroaryl, and one or more heteroatoms independently selected from N, O, and S in -(CH2) t -3 to 15-member heterocyclic, an optionally substituted group selected from. Z is -C 6~10A divalent group that is optionally substituted, selected from aryl-, -3-10 membered carbocyryl-, -5-12 membered heteroaryls having one or more heteroatoms independently selected from N, O, and S-, and -3-15 membered heterocyclines having one or more heteroatoms independently selected from N, O, and S-. R is -C 6~10 The optionally substituted group is selected from aryls, -3 to 15-membered carbocyclyls, -5 to 12-membered heteroaryls having one or more heteroatoms independently selected from N, O, and S, and -3 to 15-membered heterocyclyls having one or more heteroatoms independently selected from N, O, and S. t is an integer between 0 and 3.

[0018] This disclosure further provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, and optionally a pharmaceutically acceptable excipient or carrier.

[0019] This disclosure further provides, for example, compounds of formula (I), or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof, for use as, for example, SHP2 inhibitors, as pharmaceuticals for the treatment and / or prevention of SHP2-mediated diseases.

[0020] The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, or a pharmaceutical composition containing these, for the treatment and / or prevention of SHP2-mediated diseases, particularly diseases that are expected to be improved by SHP2 inhibition.

[0021] The present invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant or a pharmaceutical composition containing the same in the preparation of a pharmacopoeia for the treatment and / or prevention of SHP2-mediated diseases, particularly diseases that are expected to be improved by inhibition of SHP2.

[0022] The present invention provides a method for treating and / or preventing SHP2-mediated diseases, particularly diseases that are expected to be improved by inhibition of SHP2, and further provides a method comprising administering to a subject in need 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 containing the same.

[0023] The present invention further provides a method for treating a tumor or cancer, comprising administering to a patient in need 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 containing the same.

[0024] The present invention further provides a method for inhibiting SHP2 activity, comprising contacting an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotope variant thereof with a biological sample such as cells.

[0025] The present invention further provides the use of the compound of formula (I) or its pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants as research tool compounds for SHP2 inhibitors in research.

[0026] The present invention further provides pharmaceutical combinations comprising a compound of formula (I) or its pharmaceutically acceptable salts, isomers, solvates, hydrates or stable isotope variants and one or more other pharmaceutically active substances.

[0027] The present invention further provides methods for preparing compounds of formula (I) or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof. [Modes for carrying out the invention]

[0028] definition Unless otherwise noted, each term used in the specification and claims has the meaning set forth below. Where no specific definition exists for a particular term or phrase, it should be interpreted according to its common meaning in the art. In the event of any conflict, the specification of the present invention (including definitions) shall prevail.

[0029] In the event of any inconsistency between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail. 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 part. Other atoms, such as hydrogen atoms or substituents, may be present as needed to satisfy the valence of the atom.

[0030] Where used herein, the terms “comprising,” “including,” and “having,” and their variations, are inclusive or open-ended, meaning “including, but not limited to,” and not intended to exclude other additives, components, integer values, or steps. Where an element is described as containing multiple components, steps, or conditions, the element may also be described as containing any combination of multiple components, steps, or conditions, or as “consisting of multiple components, steps, or conditions, or a combination of components, steps, or conditions,” or “essentially consisting of multiple components, steps, or conditions, or a combination of components, steps, or conditions.”

[0031] As used herein, the term “about” means within ±10%, preferably within ±5%, and more preferably within ±2% of the included number.

[0032] Unless otherwise specified, C n~n+m or C n ~C mIn the definition of a compound in this disclosure, this includes various situations of n to n+m carbon atoms, for example, C 1~6 This includes C1, C2, C3, C4, C5 and C6, and also any range n to n+m, for example, C 1~6 is C 1~2 , C 1~3 , C 1~4 , C 2~6 , C 3~6 This includes, for example, n-membered to n+m-membered rings. Similarly, in the definition of a compound in this disclosure, n-membered to n+m-membered rings means that the number of ring atoms is n to n+m. For example, 3- to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 12-membered rings, etc., and also include any range of n- to n+m-membered rings, such as 3- to 6-membered, 3- to 8-membered, 4- to 7-membered, 4- to 10-membered, 5- to 6-membered, 6- to 8-membered, 6- to 10-membered, 6- to 12-membered, and 8- to 10-membered rings.

[0033] As used herein, the term "SHP2" refers to protein tyrosine phosphatase 2 containing Src homology-2, a full-length 593-amino acid dephosphorylation enzyme encoded by the PTPN11 gene. For the purposes of this disclosure, SHP2 may be wild-type or any mutant or variant of SHP2 containing one or more mutations (e.g., conserved substitutions).

[0034] As used herein, the term “SHP2-mediated disease” refers to a disease in which SHP2 activity promotes the onset and progression of the disease. For the purposes of this disclosure, “SHP2-mediated disease” specifically means a disease in which the incidence of the disease is reduced, or the disease and / or its symptoms are inhibited, improved, alleviated or eliminated by inhibiting SHP2 activity, or a disease in which the disease is sensitive to or responds to SHP2 inhibition, or a disease in which improvement is expected by inhibiting SHP2, and such diseases include, but are not limited to, proliferative disorders, metabolic disorders or hematological disorders, and in particular cancer or neoplasms.

[0035] As used herein, the terms “cancer” or “tumor” refer to any abnormal cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. For all aspects of this disclosure, cancers that can be treated with the compounds of this disclosure include, but are not limited to, the following: 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 tumors, head and neck cancers (e.g., head and neck squamous cell carcinoma), ovarian cancer, prostate cancer, melanoma, melanoma of the skin or eye, soft tissue sarcoma; oral and pharyngeal cancers (lips, tongue, mouth, larynx, nasopharynx), gastric, small intestine, large intestine, colon, rectum, perianal cancer, liver and biliary tract cancers, pancreatic cancer, bone, connective tissue, and skin cancers (including epithelial cell carcinoma), Cancers of the vagina, vulva, cervix, uterus, endometrium, fallopian tubes; cancers of the urethra, penis, testes, bladder, ureters, kidneys, and other tissues of the urinary tract, including elvic carcinoma, renal pelvis carcinoma, and hepatocellular carcinoma; gastroesophageal cancer; as well as cancers of the eye, brain, spinal cord, and the central and peripheral nervous systems and related structures, such as meningeal carcinoma, primary CNS lymphoma, oligodendroglioma, neuroblastoma, spinal cord tumors, brainstem glioma, or pituitary gland tumors. Cancers of the thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin lymphoma, parathyroid carcinoma, adrenal carcinoma, multiple myeloma, neuroblastoma, and hematological malignancies, including chronic or acute lymphoblastic leukemia, chronic or acute myeloid leukemia, chronic myelomonocytic leukemia, and lymphomas, including lymphocytic, granulocytic and monocytic lymphomas, mantle cell lymphoma and histiocytic lymphoma.

[0036] As used herein, the term “treatment” means the administration of one or more of the compounds described herein, or their pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof, to a subject suffering from or having symptoms of the described disease, e.g., a mammal, e.g., a human, for the purpose of curing, alleviating, or reducing the disease or its symptoms. Preferably, the treatment is for the purpose of curing or improving the condition.

[0037] As used herein, the term “prevention” means the administration of one or more of the compounds described herein, or any pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof, to subjects suspected of developing or susceptible to SHP2-mediated diseases, particularly cancer or tumors as defined herein, to mammals or humans, for the purpose of reducing the risk of developing or preventing the onset of a defined disease. The term “prevention” includes the compounds of this disclosure used prior to the diagnosis or identification of any clinical and / or pathological symptoms.

[0038] As used herein, the terms “inhibit” and “reduce,” or any variation thereof, 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 reduction or complete inhibition of the activity of the target of interest. For example, compared to a normal state, the reduction in activity (e.g., SHP2 activity) may be about, at most or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derived from these.

[0039] As used herein, the terms “selective inhibition” or “specific inhibition” refer to the ability of a bioactive agent to preferentially bind to a target of interest in the presence of one or more competing surrogate targets, thereby distinguishing potential targets and preferentially reducing the signaling activity of the target of interest. In some embodiments, the compounds of the Disclosure do not bind to competing surrogate targets at detectable levels when bound to SHP2. In some embodiments, compared to competing surrogate targets, the compounds of the Disclosure bind to SHP2 with a higher binding rate, a lower dissociation rate, increased affinity, decreased dissociation, and / or increased stability. Specifically, the compounds of the Disclosure have the ability to selectively inhibit SHP2 activity compared to other PTP phosphatases, such as SHP1, HePTP, Laforin, LMPTP, LYP, PTP1B, PRL2, SSU72, VHR, FAP1, STEP, CDC14A, CD45, MEG2, PP5, etc. For example, compared to the IC50 of another specific PTP phosphatase, the compounds of this disclosure exhibit an IC50 value that is at least about 1x lower than that of SHP2, for example, about 1 to 1 / 5, 1 / 5 to 1 / 10, 1 / 10 to 1 / 100, and even less than 1 / 100.

[0040] As used herein, the terms “subject,” “individual,” or “patient” refer to vertebrates. In some embodiments, vertebrates are mammals. Mammals include, but are not limited to, domesticated animals (e.g., cattle), sporting animals, pets (e.g., guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In some embodiments, mammals are humans.

[0041] As used herein, the term “therapeutic effective dose” refers to an amount or dose sufficient to induce a beneficial therapeutic response in a patient suffering from a “SHP2-mediated disease,” such as cancer or a tumor. Those skilled in the art can determine an effective dose or amount of the active ingredient of this disclosure by using conventional methods in combination with conventional influencing factors.

[0042] As used herein, the term “pharmaceutically appropriate combination” refers to the ability of a compound of the Disclosure to be combined with other active substances to accomplish the objectives of the present invention. These other active substances may be one or more additional compounds of the Disclosure, or a second or additional (e.g., third) compound compatible with the compound of the Disclosure, where compatible means that they do not adversely affect each other or exhibit complementary activity. For example, these active substances are known to modulate other biological pathways, modulate different components of biological pathways in which the compound of the Disclosure is involved, or even target biological targets that overlap with those of the compound of the Disclosure. The other active substances may be administered co-administered with the compound of the Disclosure in a single pharmaceutical composition, or administered separately in separate units. If administered separately, the administration may be simultaneous or sequential. Sequential administration may be at short intervals or longer intervals.

[0043] As used herein, the term “pharmaceutically acceptable” means molecular entities and compositions that, when administered in appropriate amounts to animals, such as humans, do not produce harmful, allergic, or other undesirable reactions.

[0044] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refer to one or more compatible solid or liquid fillers or gelling agents that are suitable for human use and possess sufficient purity and sufficiently low toxicity. Examples, but not limited to, include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., magnesium stearate), calcium sulfate, vegetable oils, polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tweens), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, and preservatives.

[0045] As used herein, the term “pharmaceutically acceptable salt” means a salt that retains the biological efficacy of the parent compound and is not of a biological or otherwise undesirable nature, and this includes acid addition salts and base addition salts. "Pharmacologically acceptable acidic adducts" can be formed from an acid addition salt having a basic group and an inorganic or organic acid. Inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid. Organic acids can be selected from aliphatic, aromatic, heterocyclic, carboxyl, and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, and others. "Pharmacologically acceptable base addition salts" include, but are not limited to, salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, and salts derived from pharmaceutically acceptable, non-toxic organic bases, including, for example, primary, secondary, and tertiary amines, substituted ammonium compounds, such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-bismethylaminoethanol, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hibamin, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, triethanolamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0046] As used herein, the term “isomer” means any stereoisomer, a mixture of enantiomers including racemates, a mixture of diastereomers, geometric isomers, atropisomers, and / or tautomers that may be present in the structure of a compound. For example, some compounds in this disclosure contain at least one chiral center, which can thus produce stereoisomers. Accordingly, the present invention encompasses all possible isomeric forms of the compounds defined herein, as well as pharmaceutically acceptable salts or solvates thereof, unless otherwise noted. Methods for determining and separating the stereochemistry of such isomers are well known to those skilled in the art (SP. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994).

[0047] The " " used in the structural formulas or structural fragments of the compounds described herein

[0048] [ka]

[0049] "or"

[0050] [ka]

[0051] The letter "" represents the stereocenter, i.e., the absolute configuration of the chiral center. Correspondingly, in the naming of compounds or intermediates provided in this invention, R or S is used to represent the absolute configuration of the relevant chiral center.

[0052] If a person skilled in the art can determine, based on the structure of a compound shown herein, that the compound has one and only one chiral isomer and can be readily divided by conventional methods of the art, then the disclosure of a racemate of the compound herein (whether disclosed in the form of a structural formula or chemical name) should be considered as disclosing each isomer of the compound separately.

[0053] As used herein, the term “isotope variant” refers to a compound in which one or more atoms are replaced with atoms rich in the corresponding isotope. Examples of isotopes that can be incorporated into the compound of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, and iodine, for example, 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 is one example. Such isotopic variants can be used as probes, analytical tools, or therapeutic agents in biological assays. In certain embodiments, the compounds of the Disclosure are provided in an unlabeled form. In certain embodiments, the compounds of the Disclosure are also provided by replacing one or more atoms present in the compound with the corresponding isotopes, for example, one or more hydrogen atoms. 2 H or 3 Replace with H, or one or more carbon atoms 13 C or 14 This includes isotopic variants formed by replacing carbon with carbon-rich carbon atoms.

[0054] As used herein, the term “solvent” refers to the solubilated form of a compound containing a stoichiometric or nonstoichiometric amount of solvent. This includes any solvated form of the compounds of this disclosure, e.g., solvates with water (e.g., hydrates) or organic solvents (e.g., methanol, ethanol, or acetonitrile), which are called methanolates, ethanolates, or acetonitriles, respectively. It also includes solvates in any polymorphic form. It should be understood that such solvates of the compounds of this disclosure also include solvates of pharmaceutically acceptable salts of the compounds of this disclosure.

[0055] As used herein, the terms “halogen” or “halogenated” refer to F, Cl, Br, or I. In addition, as used herein in defining groups, the term “halogen-substituted” group is intended to include monohalogenated or polyhalogenated groups in which one or more identical or different halogens substitute for one or more hydrogen atoms in the corresponding group.

[0056] As used herein, the term "hydroxyl group" refers to an -OH group. As used herein, the term "cyano" refers to the CN group. As used herein, the term "nitro" refers to the -NO2 group.

[0057] As used herein, the term "alkyl" refers to a monovalent saturated hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms. Specifically, alkyl groups have 1 to 10 carbon atoms, for example, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, "C 1~6The term "alkyl" refers to saturated hydrocarbon groups having a linear or branched chain of 1 to 6 carbon atoms. Examples of these 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, and 2-methylpentyl.

[0058] As used herein, the term “alkoxy” refers to an alkyl group as defined herein, which is linked to the rest of the molecule by an oxygen atom. Specifically, an alkoxy group has 1 to 10 carbon atoms, for example, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, “C 1~6 "alkoxy" or "-OC" 1~6 The term "alkyl" refers to saturated hydrocarbon groups having a linear or branched chain of 1 to 6 carbon atoms bonded to the rest of the molecule by oxygen atoms. Examples of these include, but are not limited to, -O-methyl, -O-ethyl, -O-propyl (including -On-propyl and -O-isopropyl), -O-butyl (including -On-butyl, -O-isobutyl, -O-sec-butyl, or -O-tert-butyl), -O-pentyl (including -On-pentyl, -O-isopentyl, and -O-neopentyl), -On-hexyl, 2-methylpentyl-O-, and others.

[0059] As used herein, "C optionally substituted with halogen or CN" 1~6 The term "alkyl" refers to a compound in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are optionally replaced by halogens and / or CNs, as listed above. 1~6 Refers to alkyl. If more than one halogen substituent is present, this halogen may be the same or different, and may be located on the same or different C atoms. "C optionally substituted with halogen or CN" 1~6Examples of alkyl groups, though not limited to these, include -CH2F, -CH2Cl, -CH2CN, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2CH2CN, -CH2CH2CF3, or -CF(CF3)2.

[0060] As used herein, the term "carbocyclyl" refers to a monocyclic, fused polycyclic, bridging polycyclic, or spirocyclic saturated or partially unsaturated non-aromatic hydrocarbon ring structure having a specified number of ring carbon atoms, without a fully conjugated π-electron system. Carbocyclyls have 3 to 15 carbon atoms (i.e., C 3~15 Carbocyclyls may have, 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, or 6 to 15 carbon atoms. Carbocyclyls in the compounds disclosed herein may be unsubstituted or substituted with one or more substituents as defined.

[0061] In some embodiments, the term “carbocykryl” as used herein refers to a “monocyclic saturated or partially unsaturated carbocyclyl” having a specified number of ring carbon atoms. A “monocyclic saturated carbocyclyl” is also called a “monocyclic cycloalkyl,” for example, a 3- to 8-membered monocyclic saturated carbocyclyl or a 3- to 6-membered monocyclic saturated carbocyclyl in the compounds disclosed herein, i.e., C 3~8 Cycloalkyl or C 3~6 These are cycloalkyl compounds, and specific examples, though not limited to these, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Monocyclic partially unsaturated carbocyclyls" are also called "monocyclic cycloalkenyls," for example, 3-8 member monocyclic partially unsaturated carbocyclyls or 3-6 member monocyclic partially unsaturated carbocyclyls, i.e., C 3~8 Cycloalkenyl or C 3~6These are cycloalkenyls, and while not limited to these, specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and cycloheptadienyl.

[0062] In some embodiments, the term “carbocyclyl,” as used herein, refers to a “bridged saturated or partially unsaturated carbocyclyl” having a specified number of ring carbon atoms, meaning a polycyclic carbocycle sharing two indirectly linked carbon atoms (called bridgehead carbons). The two bridgehead carbons may be linked by a carbon chain or a single bond, and this portion is called a bridge. These groups may contain one or more double bonds but do not possess a fully conjugated π-electron system. These rings can be 5 to 14 members, for example 6 to 12 members, more preferably 5 to 10 members. Based on the number of rings, they can be classified as bicyclic, tricyclic, or polycyclic bridged carbocycles, preferably bicyclic or tricyclic. For example, examples of 5- to 10-membered, or 5- to 8-membered, crosslinked saturated or partially unsaturated carbon rings in the compounds disclosed herein 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.

[0063] In some embodiments, the term “carbocyclyl,” as used herein, refers to a “spirocyclic saturated or partially unsaturated carbocyclyl” having a specified number of ring carbon atoms, meaning a polycyclic group sharing a single carbon atom (called a spiro atom) between monocyclic rings. Such groups may contain one or more double bonds but do not have a fully conjugated π-electron system. They may have 6 to 15 members, preferably 7 to 15 members, and more preferably 7 to 11 members. Based on the number of spiro atoms shared between the rings, spirocycloalkyls are classified as monospirocycloalkyls (monospirocarbocyclyls), bispirocycloalkyls (bispirocarbocyclyls), or polyspirocycloalkyls (polyspirocarbocyclyls), preferably monospiro and bispirocarbocyclyls. Monospirocarbocyclyls may also be called bicyclic spirocarbocyclyls. More preferably, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, and 6-membered / 6-membered monospirocarbocycles. The spirocarbocyclyls in the compounds disclosed herein can be 6- to 15-membered monospirocarbocyclyls, i.e., 6- to 15-membered bicyclic spirocarbocycles, preferably 7- to 11-membered bicyclic spirocarbocycles. Non-limiting examples of spirocarbocyclyls include:

[0064] [ka]

[0065] These are some examples. In some embodiments, the term “carbocyclyl,” as used herein, refers to a “condensed saturated or partially unsaturated carbocyclyl” having a specified number of ring carbon atoms, where each ring is a carbocyclyl group sharing a set of adjacent carbon atoms with the other ring, and may contain one or more double bonds but not have a fully conjugated π-electron system. It may be 6-15 membered, e.g., 5-14 membered, 6-12 membered, 7-14 membered, preferably 7-11 membered. Based on the number of rings, it can be classified as a bicyclic, tricyclic, or polycyclic condensed carbocyclyl, preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic condensed carbocyclyl. Non-limiting examples of condensed carbocyclyls include:

[0066] [ka]

[0067] These are some examples. 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, for example, groups having 6 to 10, preferably 6, ring members. Specific aryl groups include phenyl and naphthyl, with phenyl being the most specific aryl. The aryl groups in the compounds disclosed herein may be unsubstituted or substituted with one or more substituents as defined.

[0068] As used herein, the term “heterocyclyl” refers to a cyclic group comprising one or more heteroatoms independently selected from O, N, and S, and a specified number of ring atoms. This cyclic group may be saturated or partially unsaturated, and may have a monocyclic, condensed, spirocyclic, or bridging polycyclic ring structure. The definitions of condensed heterocyclyl, spiroheterocyclyl, or bridging heterocyclyl are similar to those defined above for “condensed carbocyclyl,” “spirocarbocyclyl,” or “bridging carbocyclyl,” except that each contains one or more heteroatoms independently selected from O, N, and S, e.g., 1-4, 1-3, or 1-2 of the aforementioned heteroatoms. In the case of polycyclic heterocyclyl, only the ring structure bonded to the rest of the molecule needs to be a non-aromatic ring. Even if the ring further fused, spirofused, or bridged with this non-aromatic ring is an aromatic ring, the heterocyclic system is still defined as a heterocyclil in this specification. Heterocyclils can have 3 to 15 ring members (called 3 to 15-membered heterocyclils), 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, monocyclic heterocyclils, for example, 3 to 8-membered or 4 to 8-membered monocyclic saturated heterocyclils, or bicyclic or tricyclic heterocyclils, for example, 7- These are 14-membered or 7-11-membered spiroheterocyclils (preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 6-membered monospiroheterocyclils), 5-14-membered, 5-10-membered, or 5-8-membered bridged heterocyclils (preferably bicyclic or tricyclic), or 6-14-membered, 6-10-membered, or 7-11-membered condensed heterocyclils (preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic condensed heterocyclils).Heterocyclines typically contain at least one and up to four (e.g., one, two, three, or four) heteroatoms, such as 3- to 8-membered monocyclic heterocyclines containing 1 to 3 heteroatoms independently selected from N, O, and S, or bicyclic or tricyclic heterocyclines containing 1 to 3 heteroatoms independently selected from N, O, and S, such as 7- to 14-membered or 7- to 11-membered spiroheterocyclines, 5- to 14-membered or 5- to 10-membered or 5- to 8-membered bridged heterocyclines, or 6- to 14-membered, 6- to 10-membered or 7- to 11-membered condensed heterocyclines. Heterocyclines in the compounds disclosed herein may be unsubstituted or substituted with one or more substituents as defined.

[0069] Examples of suitable heterocyclyls, but not limited to these, include azetidinil, oxetanil, thietanil, pyrrolidinil (e.g., 1-pyrrolidinil, 2-pyrrolidinil, and 3-pyrrolidinil), tetrahydrofuryl (e.g., 1-tetrahydrofuryl, 2-tetrahydrofuryl, and 3-tetrahydrofuryl), tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl), piperidinil (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranil (e.g., 4-tetrahydropyranil), and tetrahydrothianil (e.g., 4-tetrahydrothianil). Examples include morpholinyl (e.g., morpholino), thiomorpholinyl, dioxanil, piperazinyl or azepanil, diazepanil, e.g., 1,4-diazepanil, 2-aza-bicyclo[2.2.1]heptyl, 2-aza-bicyclo[2.2.2]octyl, 3,6-diaza-bicyclo[3.1.1]heptyl, 3-aza-bicyclo[3.2.1]octyl, 1,7-dioxa-[4.5]decyl, 2-oxa-7-aza-spiro[4.4]nonyl, 7-oxa-spiro[3.5]nonyl, 5-oxa-spiro[2.4]heptyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, and octahydrobenzo[b][1,4]dioxynyl. The atoms in the heterocycloalkyl bonded to the rest of the compound can be either carbon atoms or heteroatoms, as long as it is chemically possible. Structures with a chiral center encompass their racemic and / or single enantiomer forms, for example,

[0070] [ka]

[0071] teeth,

[0072] [ka]

[0073] Please understand that it is acceptable to represent this. As used herein, the term “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system having 5 to 12 ring atoms, including 1 to 4 heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. This ring system may be bonded to heteroatoms or carbon atoms of the rest of the molecule. Specific embodiments include, for example, 5-6 membered monocyclic or 8-10 membered bicyclic heteroaryls.Examples of heteroaryls, though not limited to these, include 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, and 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, py Lazolo[3,4-b]pyridine, isoindole, purine, indidine, 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, cycloline, quinazoline Examples include quinoxaline, phthalazine, 1,6-naphthidine, 1,7-naphthidine, 1,8-naphthidine, 1,5-naphthidine, 2,6-naphthidine, 2,7-naphthidine, 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, pyrido[5,4-d]pyrimidine, pyrazino[2,3-b]pyrazine, and pyrido[4,5-d]pyrimidine. Heteroaryls in the compounds disclosed herein may be unsubstituted or substituted with one or more substituents as defined.

[0074] As used herein, the term “optionally substituted” means that one or more hydrogens in the identified moiety are either unsubstituted or replaced by appropriate substituents. An “optionally substituted” group is one in which stable substituents are present at each substitution site of the group, for example,

[0075] [ka]

[0076] It can hold, at least

[0077] [ka]

[0078] If a group can be retained and one or more positions in any given structure are substituted by one or more substituents selected from the given group, the substituents may be the same or different at each position. The substituent combinations envisioned in the present invention are preferably combinations that result in the formation of a stable or chemically viable compound. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two identical or different substituents. In yet another embodiment, the optionally substituted group has three identical or different substituents. In yet another embodiment, the optionally substituted group has four identical or different substituents.

[0079] Many of the groups defined herein are substituted by choice. The list of substituents provided in this definition section is for illustrative purposes only and is not intended to limit the substituents defined in other parts of the specification and claims.

[0080] Among the cyclic structural fragments discussed herein, for example, -(R1) tWhen substituents are depicted as spanning chemical bonds, such as, this indicates that one or more R1 substituents can occupy any chemically feasible substitution site on the ring, including, for example, position G.

[0081] In the cyclic structural fragments described herein, substituents shown as spanning chemical bonds, such as,

[0082]

Chem.

[0083] refer to one or more R1 substituents that can substitute one or more chemically possible substitution sites within the ring, including G. The "

[0084]

Chem.

[0085] ", for example,

[0086]

Chem.

[0087] among

[0088]

Chem.

[0089] represents that the fragment is attached to the rest of the molecule by any one of the chemically possible ring atoms. Those skilled in the field of organic synthesis will understand that all groups on the structure of the compounds of the present invention, whether unsubstituted or substituted with various defined substituents, are provided to make the compound molecules chemically possible and stable. The type and number of substituents are determined by the number of atoms and chemical valence of the group.

[0090] Technical problems to be solved As described above, SHP2-mediated diseases (e.g., cancer or tumors) can be treated or prevented using compounds capable of inhibiting SHP2 activity. Therefore, various structural types of SHP2 inhibitors have been developed in this field. However, existing SHP2 inhibitors still face challenges that need to be overcome, including insufficient antitumor activity, weak drug resistance due to toxic side effects, insufficient pharmacokinetic properties for convenient administration (i.e., weak "drug viability"), or undesirable drug interactions due to inhibition of the cytochrome P450 enzyme system. Furthermore, even for SHP2 inhibitors with good antitumor activity, there is still a need for further enhancement of their selective inhibitory activity against target proteins in vivo, improvement of their drug resistance (reduced toxicity or improved safety), and optimization of their pharmacokinetic properties through structural optimization, thereby providing more and better therapeutic options for clinical use.

[0091] technical solution Through extensive and meticulous research, the inventors developed a group of compounds exhibiting superior inhibitory activity against SHP2. Through structural modification and activity evaluation, the inventors discovered that modifying specific sites on certain parts of the SHP2 inhibitor structure using specific types of fragmentation modifications resulted in significantly improved inhibitory activity against SHP2 compared to existing inhibitors. These modified compounds can inhibit the proliferation of various tumor cells and exhibit superior selectivity for SHP2 among many PTP phosphatases. These compounds also demonstrate significantly reduced hERG toxicity (i.e., good safety), reduced drug interaction risk, and good or even improved pharmacokinetic properties, enabling convenient administration methods.

[0092] Accordingly, the present invention primarily provides: effective selective SHP2 inhibitors; pharmaceutical compositions containing such compounds as active ingredients; the compounds as pharmaceuticals for treating or preventing diseases, preferably tumors or cancers, that are mediated or expected to be improved by SHP2 inhibition; methods for using the compounds to treat or prevent diseases, preferably tumors or cancers, that are mediated or expected to be improved by SHP2 inhibition; and the use of the compounds in the preparation of pharmaceuticals for treating or preventing diseases, preferably tumors or cancers, that are mediated or expected to be improved by SHP2 inhibition.

[0093] Disclosed Compounds The terms "disclosed compound" and "compound of the present disclosure", when used throughout this application, unless otherwise specified, include the compounds defined in various embodiments of this specification and their preferred or exemplary embodiments, and generally also include compounds formed by any combination or sub - combination of various groups defined preferably, or exemplarily. These include pharmaceutically acceptable salts, isomers (including trans - isomers, enantiomeric mixtures, especially racemates, diastereomeric mixtures, geometric isomers, tautomers), solvates, or isotopic variants of such compounds. However, these are preferably the compounds of the present disclosure and / or their pharmaceutically acceptable salts or solvates.

[0094] The present disclosure also includes N - oxides of these compounds, provided that the compounds disclosed herein contain a basic nitrogen atom, such as a nitrogen atom present in a nitrogen - containing heterocyclic ring, and are chemically and biologically feasible. Certain compounds of the present disclosure may exist in polymorphic or amorphous forms, and thus these are also included 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]

Chemical formula

[0097] or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotopic variant thereof. [wherein,

[0098]

Chemical formula

[0099] represents a saturated, partially unsaturated, or aromatic ring system,

[0100] [ka]

[0101] This represents an aromatic ring system, A1, A2, A3, A4, and A5 are each independently selected from the non-existent C, N, O, and S atoms, and A6 is selected from C and N, provided that (1) a maximum of two of A1-A5 are non-existent, and (2) a maximum of four of A1-A6 are heteroatoms. R a -C is optionally substituted with -H, =O, =S, =N-OH, -OH, -NH2, halogen, -CN and halogen. 1~6 Selected from alkyl groups, A7, A8, and 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 CR b and selected from N, A 11 It is selected from CX and N, R b -C is substituted with H, halogen, CN, and halogen. 1~6 Selected from alkyl groups, X is H, halogen, CN, -OH, -OC 1~6 Alkyl and -C 1~6 Selected from alkyl groups, C 1~6 Alkyl is optionally substituted, Y is -C 1~6 Alkyl, -(CH2) t -3-15 member carbocyclyl, -(CH2) t -C 6~10 -(CH2) having one or more heteroatoms independently selected from aryl, N, O, and S t -5- to 12-membered heteroaryls, and -(CH2) having one or more heteroatoms independently selected from N, O, and S t- A group that is optionally substituted, selected from 3- to 15-membered heterocyclines. Z is -C 6~10 A divalent group that is optionally substituted, selected from aryl-, -3-10 membered carbocyryl-, -5-12 membered heteroaryls having one or more heteroatoms independently selected from N, O, and S-, and -3-15 membered heterocyclines having one or more heteroatoms independently selected from N, O, and S-. R is -C 6~10 The optionally substituted group is selected from aryls, -3 to 15-membered carbocyclyls, -5 to 12-membered heteroaryls having one or more heteroatoms independently selected from N, O, and S, and -3 to 15-membered heterocyclyls having one or more heteroatoms independently selected from N, O, and S. Each of t is an integer between 0 and 3, independently of the others. In further embodiments of this disclosure, in a compound of formula (I), Y is -C 1~6 Alkyl, -(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon rings, -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon rings, -(CH2) t -6-15 member spirotype or condensed saturated or partially unsaturated carbon rings, -(CH2) t -C 6~10 Ariel, -(CH2) has 1 to 4 heteroatoms independently selected from N, O, and S. t -5-12 member heteroaryl, -(CH2) has 1 to 3 heteroatoms independently selected from N, O, and S. t -3 to 8-membered monocyclic saturated or partially unsaturated heterocyclic rings, -(CH2) has 1 to 3 heteroatoms independently selected from N, O, and S. t -5 to 10-membered bridging saturated or partially unsaturated heterocycles, -(CH2) has 1 to 4 heteroatoms independently selected from N, O, and S. t -6 to 15-membered spirotype or condensed saturated or partially unsaturated heterocycle It is a base that is selected from and substituted by arbitrary choice.

[0102] In further embodiments of this disclosure, in a compound of formula (I), Z is -C 6~10 Ariel- -3- to 8-membered monocyclic saturated or partially unsaturated carbon rings- -5-10 membered cross-linked saturated or partially unsaturated carbon rings- A 5-12 member heteroaryl having 1-4 heteroatoms independently selected from N, O, and S-, -3 to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S-, -5 to 10 membered bridged saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S-, -6 to 15 member spirotype or condensed saturated or partially unsaturated heterocycles having 1 to 4 heteroatoms independently selected from N, O, and S- It is a divalent group that is arbitrarily substituted, selected from among the others.

[0103] In further embodiments of this disclosure, in a compound of formula (I), R is -C 6~10 Ariel, -3- to 8-membered monocyclic saturated or partially unsaturated carbon rings, -5-10 membered bridged saturated or partially unsaturated carbon rings, -6-15 member spirotype or condensed saturated or partially unsaturated carbon rings, -5-12 member heteroaryls having 1-4 heteroatoms independently selected from N, O, and S, -3 to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S, A -5- to 10-membered bridged saturated or partially unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O, and S A -6- to 15-membered spiro or fused saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from N, O, and S A group, optionally substituted, selected from the above

[0104] In some embodiments of the compound of formula (I), the cyclic heteroatom

[0105]

Chemical formula

[0106] has 1 to 4 cyclic heteroatoms selected from N, O, and S, and is a 5- or 6-membered saturated, partially unsaturated or aromatic group optionally substituted by 0 to 3 R a Preferably, it has 2 to 4 cyclic heteroatoms selected from N, O, and S, and is a 5-membered partially unsaturated or aromatic group optionally substituted by 0 to 3 R a More preferably, it has 3 to 4 cyclic heteroatoms selected from N, O, and S, and is a 5-membered partially unsaturated or aromatic group optionally substituted by 0 to 1 R a Most preferably, it is a 5-membered aromatic group having 3 to 4 nitrogen heteroatoms optionally substituted by 0 to 1 R a a

[0107] In some embodiments of the compound of formula (I), A6 is C In some embodiments of the compound of formula (I), R a is H. In some embodiments, R a is =O or =S. In some embodiments, R a is -OH or -NH2. In some embodiments, R a is halogen, -CN, or -C optionally substituted by halogen 1~6is alkyl. In some embodiments, R a is selected from -H, =O, =S, -OH, -NH2, -CN, and -C 1~6 alkyl optionally substituted by halogen, and further selected from -H, -CN, halogen, =O, and -C 1~6 alkyl substituted by halogen. In some embodiments, R a is substituted on a ring carbon atom.

[0108] In some embodiments of the compound of formula (I), the ring formed by A1 - A6 is triazolyl, A6 is C, for example, substituted by one R a and is

[0109]

Chemical formula

[0110] wherein the R a is selected from H, halogen, CN, and -C 1~6 alkyl optionally substituted by halogen, preferably selected from halogen, CN, and -C 1~6 alkyl optionally substituted by halogen, most preferably -C 1~6 alkyl substituted by halogen, such as -CF3.

[0111] In some embodiments of the compound of formula (I), the ring formed by A1 - A6 is tetrazolyl

[0112]

Chemical formula

[0113] and is In some embodiments of the compound of formula (I), the ring formed by A1 - A6 is a 5 - membered partially unsaturated ring having 3 - 4 cyclic heteroatoms selected from N, O, and S, for example, but not limited to,

[0114] [ka]

[0115] Preferably,

[0116] [ka]

[0117] That is the case. In this embodiment,

[0118] [ka]

[0119] These are not limited to these,

[0120] [ka]

[0121] It includes, preferably

[0122] [ka]

[0123] and, more

[0124] [ka]

[0125] That is the case. In some embodiments of the compound of formula (I),

[0126] [ka]

[0127] It is a condensed aromatic heterocycle that is substituted with Y and has 1 to 3 heterocyclic atoms selected from N, O, and S. In some embodiments, A 10 CR b A 11 is CX. In some embodiments, A 10 and A 11 One of them is a nitrogen heteroatom, and the other is a carbon atom, for example, A 10 is N, and A 11 is CX. In some embodiments, A 10 and A 11 Both are nitrogen atoms.

[0128] 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, only one of A7 and A9 is a heteroatom, and A8 is a carbon atom. Even more preferably, Y is bonded to the ring atom of A7.

[0129] In this embodiment,

[0130] [ka]

[0131] These are not limited to these, however

[0132] [ka]

[0133] It includes, preferably

[0134] [ka]

[0135] and, more

[0136] [ka]

[0137] That is the case. In some embodiments of the compound of formula (I), R b is H. In some embodiments, R b is a halogen, preferably F. In some embodiments, R b is CN. In some embodiments, R b C is optionally replaced by a halogen. 1~6 It is an alkyl group, for example -CH2F, -CH2Cl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -C2F5, -CF(CF3)2, preferably -CF3.

[0138] In some embodiments of the compound of formula (I), X is H. In some embodiments of the compound of formula (I), X is a halogen selected from F, Cl, Br, and I, preferably F.

[0139] In some embodiments of the compound of formula (I), X is CN. In some embodiments of the compound of formula (I), X is -OH. In some embodiments of the compound of formula (I), X is optionally substituted with a halogen or CN -OC 1~6 These are alkyl groups, and are not limited to these, but include, for example, -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, and -O-CH2CH2CN.

[0140] In some embodiments of the compounds of formula (I), X is optionally substituted with a halogen or CN. 1~6 These are alkyl groups, and are not limited to these, but include, for example, -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, and -CF(CF3)2.

[0141] In preferred embodiments, X is selected from H, halogens, and -OH, and more preferably F. In some embodiments of the compounds of formula (I), Y is optionally substituted with a halogen or CN. 1~6 It is an alkyl group in which any carbon atom is optionally substituted with NR', O, or S, preferably a halogen or CN-substituted -C 1~6 Alkyl, more preferably halogen-substituted -C 1~6 These are alkyl groups, and are not limited to these, but include, for example, -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(C F3)2, -CH2-OCH3, -CH2-O-CH2CH3, -CH2CH2-O-CH3, -CH2CH2-O-CH2CH3, -CH2-SCH3, -CH2-S-CH2CH3, -CH2CH2-S-CH3, -CH2CH2-S- CH2CH3, -CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-NH-CH2CH3, -CH2CH2-NH-CH3, -CH2CH2-NH-CH2CH3, -CH2CH2-N(CH3)-CH2CH3.

[0142] In some embodiments of the compound of formula (I), Y is -(CH2) t -3-15 member carbocyclyl, specifically -(CH2) t -3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, more specifically, -C 1~6 Alkyl, -OH, or -OC 1~6 -(CH2) is optionally substituted with alkyl. t -3 to 6-membered monocyclic saturated carbocyclic ring (wherein t is preferably 0 or 1), -C 1~6 The alkyl group is optionally substituted with a halogen or CN, for example, but not limited to these.

[0143] [ka]

[0144] Preferably

[0145] [ka]

[0146] That is the case. In some embodiments of the compound of formula (I), Y is -(CH2) t -3-15 member carbocyclyl, specifically -(CH2) t -5 to 10-membered bridged saturated or partially unsaturated carbon rings, more specifically, -C 1~6 Alkyl, -OH, or -OC 1~6 -(CH2) is optionally substituted with alkyl. t -5 to 8 membered bicyclic bridged saturated carbon ring (wherein t is preferably 0 or 1), -C 1~6 The alkyl group is optionally substituted with a halogen or CN, and the crosslinked carbon ring is, for example, not limited to these,

[0147] [ka]

[0148] That is the case. In some embodiments of the compound of formula (I), Y is -(CH2) t -3-15 member carbocyclyl, specifically -(CH2) t -6-15 membered spiro-type or condensed saturated or partially unsaturated carbon rings, more specifically, -C 1~6 Alkyl, -OH, or -OC 1~6 -(CH2) is optionally substituted with alkyl. t -7 to 11 membered bicyclic, spirocyclic, or condensed saturated carbocyclic (wherein t is preferably 0 or 1), -C 1~6 The alkyl group is optionally substituted with a halogen or CN, and this group is also

[0149] [ka]

[0150] It may also be expressed as [wherein k is an integer from 0 to 2, m and n are independently integers from 1 to 3, l is an integer from 1 to 4, r and p are independently integers from 0 to 3, and q is an integer from 1 to 4], and optionally contains one or more double bonds (non-aromatic), -C 1~6 Alkyl, -OH, or -OC 1~6 It is optionally substituted with an alkyl group. In this embodiment, the carbocyclic Y is more specifically a -7 to 11-membered bicyclic spiro-type saturated carbocyclic ring (wherein k is 0 to 2, m and n are independently integers 1 to 2, and l is an integer 1 to 3) or a -7 to 11-membered bicyclic condensed-type saturated carbocyclic ring (wherein r is an integer 0 to 1, p is an integer 0 to 2, and q is an integer 1 to 3), and the spiro-type and condensed-type carbocyclic rings are, for example, not limited to these,

[0151] [ka]

[0152] It is either a carbon-carbon double bond or an exemplary group having one or two carbon-carbon double bonds. In some embodiments of the compound of formula (I), Y is -(CH2) t -C 6~10 It is an aryl, specifically -C 1~6 Alkyl, -OH, or -OC 1~6 -(CH2) is optionally substituted with alkyl. t -phenyl (wherein t is preferably 0 or 1), -C 1~6 The alkyl group is optionally substituted with a halogen or CN, for example, but not limited to these.

[0153] [ka]

[0154] Preferably

[0155] [ka]

[0156] That is the case. In some embodiments of the compound of formula (I), Y has one or more heteroatoms independently selected from N, O, and S -(CH2) t -5- to 12-membered heteroaryl compounds, specifically -(CH2) having 1 to 4 heteroatoms independently selected from N, O, and S. t -5-12 member monocyclic or bicyclic heteroaryls, more specifically having 1-4 heteroatoms independently selected from N, O, and S, and -C 1~6 Alkyl, -OH, or -OC 1~6 -(CH2) is optionally substituted with alkyl. t -5-6 member monocyclic or bicyclic heteroaryl (wherein t is preferably 0 or 1), -C 1~6Alkyl is optionally substituted with halogen or CN, and as heteroaryl, it is not limited to these, but includes furanyl, pyridinyl, pyridadinyl, 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, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

[0157] [ka]

[0158] Examples include the heteroaryl group, which may be bonded to the rest of the molecule at the heteroatom or carbon atom of the heteroaryl group. In some embodiments of the compounds of formula (I), Y is a 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S; more specifically, a 3- to 8-membered monocyclic saturated or partially unsaturated heterocycline having one to three heteroatoms independently selected from N, O, and S; more specifically, having one to two heteroatoms independently selected from N, O, and S, and -C 1~6 Alkyl, -OH, or -OC 1~6 A 4- to 7-membered monocyclic saturated or partially unsaturated heterocycline (wherein t is preferably 0 or 1) optionally substituted with an alkyl group, and -C 1~6Alkyls are optionally substituted with halogens or CN, and heterocyclyls include, for example, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuryl (e.g., 1-tetrahydrofuryl, 2-tetrahydrofuryl, and 3-tetrahydrofuryl), and tetrahydrothienyl (e.g., 1-tetrahydrothienyl, 2-tetrahydrothienyl). (e.g., 1-piperidinyl and 3-tetrahydrothienyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranil (e.g., 4-tetrahydropyranil), tetrahydrothianil (e.g., 4-tetrahydrothianil), morpholinil (e.g., morpholinyl), thiomorpholinil, dioxanil, piperadinyl or azepanil, diazepanil, e.g., 1,4-diazepanil, and pyrrololinil (py (e.g., 1-pyrrololinyl, 2-pyrrolylyl, 3-pyrrololinyl, 4-pyrrololinyl, or 5-pyrrololinyl), dihydrofuranyl (e.g., 1-dihydrofuranyl, 2-dihydrofuranyl, 3-dihydrofuranyl, 4-dihydrofuranyl, or 5-dihydrofuranyl), dihydrothienyl (e.g., 1-dihydrothienyl, 2-dihydrothienyl, 3-dihydrothienyl, or 4-dihydrothienyl), tetra The substituents are tetrahydropyridyl (e.g., 1-, 2-, 3-, 4-, 5-, or 6-tetrahydropyridyl), oxacyclohexenyl, dihydropyranyl (e.g., 4-dihydropyranyl), or dihydrothiopyranyl (e.g., 4-dihydrothiopyranyl), where the heterocyclyl may be bonded to the rest of the molecule at a heteroatom or carbon atom of the heterocycle, and substituents may be substituted at a ring carbon atom or ring heteroatom only if chemically feasible.

[0159] In some embodiments of the compound of formula (I), Y has one or more heteroatoms independently selected from N, O, and S -(CH2) tA 3- to 15-membered heterocycline, specifically having 1 to 3 heteroatoms independently selected from N, O, and S -(CH2) t -5 to 10 membered bridged saturated or partially unsaturated heterocycles, more specifically having 1 to 2 heteroatoms independently selected from N, O, and S, and -C 1~6 Alkyl, -OH, or -OC 1~6 -(CH2) is optionally substituted with alkyl. t -5 to 8-membered bridged saturated or partially unsaturated heterocycle (wherein t is preferably 0 or 1), -C 1~6 The alkyl group is optionally substituted with a halogen or CN, and the bridging heterocycle is, for example, not limited to these,

[0160] [ka]

[0161] The heterocyclyl may have the rest of the molecule bonded to a heteroatom or carbon atom of the heterocycle, and its substituents may substitute for a ring carbon atom or ring heteroatom, provided that it is chemically feasible.

[0162] In some embodiments of the compound of formula (I), Y has one or more heteroatoms independently selected from N, O, and S -(CH2) t A 3- to 15-membered heterocycline, specifically having 1 to 4 heteroatoms independently selected from N, O, and S -(CH2) t -6-15 membered spiro-type or condensed saturated or partially unsaturated heterocycle, more specifically having 1-3 heteroatoms independently selected from N, O, and S, and -C 1~6 Alkyl, -OH, or -OC 1~6 -(CH2) is optionally substituted with alkyl. t -7 to 11 membered bicyclic spirotype or condensed saturated heterocycle (wherein t is preferably 0 or 1), -C 1~6The alkyl group is optionally substituted with a halogen or CN, and the group is also

[0163] [ka]

[0164] [In the formula, 1 to 4 ring atoms, preferably 1 to 3, more preferably 1 to 2 ring atoms may be replaced by heteroatoms independently selected from N, O, and S, where k is an integer from 0 to 2, m and n are integers from 1 to 3, l is an integer from 1 to 4, r and p are each independently integers from 0 to 3, and q is an integer from 1 to 4] may be expressed as having one or more double bonds (non-aromatic) of any choice, and -C 1~6 Alkyl, -OH, or -OC 1~6 It is optionally substituted with alkyl, -C 1~6 The alkyl group is optionally substituted with a halogen or CN, and in this embodiment, the heterocycle of Y is more specifically a -7 to 11-membered bicyclic spiro-type saturated heterocycle (wherein k is 0 to 2, m and n are integers 1 to 2, and l is an integer 1 to 3) or a -7 to 11-membered bicyclic condensed-type saturated heterocycle (wherein r is an integer 0 to 1, p is an integer 0 to 2, and q is an integer 1 to 3) (wherein t is preferably 0 or 1), and the spiro-type heterocycle and the condensed-type heterocycle are, for example, not limited to these,

[0165] [ka]

[0166] [ka]

[0167] The heterocyclyl may be bonded to the rest of the molecule at any feasible heteroatom or carbon atom of the entire heterocycle, and its substituents may substitute for ring carbon atoms or ring heteroatoms only if chemically feasible.

[0168] In embodiments of the compound of formula (I), Y is -C 1~6 Alkyl, -(CH2) t -3-15 membered carbon rings and -(CH2) t -C 6~10 A group that is optionally substituted, selected from aryl groups, and more preferably Y is -C 1~6 Alkyl, -(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -5-10 membered bridged saturated or partially unsaturated carbon rings and -(CH2) t -C 6~10 A group that is optionally substituted, selected from aryl groups, and more preferably, Y is -C 1~6 Alkyl, -(CH2) t -3- to 6-membered monocyclic saturated carbon ring, -(CH2) t -5-8 membered bicyclic bridged saturated carbon ring and -(CH2) t - A group that is optionally substituted, selected from phenyl.

[0169] In embodiments of the compound of formula (I), t for Y is preferably 0 to 2, and more preferably 0 to 1. In embodiments of the compound of formula (I), each cyclic group of Y is -C 1~6 Alkyl, -OH, or -OC 1~6 Y is optionally substituted with one or more groups independently selected from alkyl, and the -C is present in Y and its substituents. 1~6 Alkyl or -(CH2) t - is optionally substituted with a halogen or CN, and any carbon chain atom is optionally substituted with NR', O or S, and R' is H or -C 1~6 Selected from alkyl groups, preferably Y-C 1~6 The alkyl group is optionally substituted with a halogen or CN, and the cyclic group of Y is -C 1~6 Alkyl and -OC 1~6It is optionally substituted with 1 to 3 groups selected from alkyl groups, preferably 1 or 2, more preferably 1 group, and -C 1~6 Alkyl and -OC 1~6 Non-restrictive examples of alkyl groups are defined above, corresponding to each substituent X. Y is -(CH2) t -In embodiments where t is 0 and the 3-15 membered carbocyclyl is a 3-6 membered monocyclic saturated carbocyclyl, the carbocyclyl is a substituent C 1~6 It optionally contains an alkyl group, preferably C 1~6 If present, alkyl groups are bonded to the ring carbon atoms of the carbon ring that are bonded to the rest of the molecule.

[0170] In some embodiments of the compound of formula (I), Z is a halogen, -C 1~6 Alkyl or -OC 1~6 -C is optionally substituted with alkyl. 6~10 It is aryl- and -C 1~6 The alkyl group is optionally substituted with a halogen or CN, for example, but not limited to these.

[0171] [ka]

[0172] Preferably

[0173] [ka]

[0174] That is the case. In some embodiments of the compound of formula (I), Z is a -3 to 10-membered carbocyclyl, specifically a -3 to 8-membered monocyclic saturated or partially unsaturated carbon ring, more specifically a -3 to 6-membered monocyclic saturated or partially unsaturated carbon ring, and a halogen, -C 1~6 Alkyl or -OC 1~6 It is optionally substituted with alkyl, -C 1~6The alkyl group is optionally substituted with a halogen or CN, for example, but not limited to these.

[0175] [ka]

[0176] Note that the divalent bond points of these carbocyclic rings to the rest of the molecule are merely illustrative, and the carbocyclic rings may be bonded to the rest of the molecule at any chemically feasible group.

[0177] In some embodiments of the compound of formula (I), Z is a -3 to 10-membered carbocyclyl, specifically a -5 to 10-membered bridged saturated or partially unsaturated carbon ring, more specifically a -5 to 8-membered bicyclic bridged saturated carbon ring, and a halogen, -C 1~6 Alkyl or -OC 1~6 It is optionally substituted with alkyl, -C 1~6 The alkyl group is optionally substituted with a halogen or CN, and the crosslinked carbon ring is, for example, not limited to these,

[0178] [ka]

[0179] That is the case. In some embodiments of the compounds of formula (I), Z is a 5- to 12-membered heteroaryl having one or more heteroatoms independently selected from N, O, and S-, more specifically a 5- to 12-membered monocyclic or bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, more specifically having 1 to 4 heteroatoms independently selected from N, O, and S, and containing halogens, -C 1~6 Alkyl, or -OC 1~6 A 5-6 member monocyclic or bicyclic heteroaryl that is optionally substituted with alkyl, and -C 1~6Alkyl groups are optionally substituted with halogens or CN, and examples of heteroaryls are shown above as "5-6 membered monocyclic or 8-10 membered bicyclic heteroaryls having 1-4 heteroatoms independently selected from N, O, and S" for Y. The difference is that the above are divalent groups, and the heteroaryl and the rest of the molecule may be bonded to the heteroatoms or carbon atoms of the heteroaryl, and the substituents thereon may be substituted to the ring carbon atoms or ring heteroatoms, only if chemically feasible.

[0180] In some embodiments of the compounds of formula (I), Z is a divalent 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S, more specifically a -3- to 8-membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S-, more specifically a -4- to 7-membered monocyclic saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from N, O, and S-, and a halogen, -C 1~6 Alkyl, or -OC 1~6 It is optionally substituted with alkyl, -C 1~6 Alkyl groups are optionally substituted with halogens or CN, and examples of heterocycles are shown above for Y as "3- to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from N, O, and S." The difference is that the above are divalent groups, and the heterocyclyl and the rest of the molecule may be bonded at heteroatoms or carbon atoms of the heterocycle, where substitution is possible at ring carbon atoms or ring heteroatoms, only if chemically feasible.

[0181] In some embodiments of the compound of formula (I), Z is a 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S, more specifically a 5- to 10-membered bridged saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S, more specifically a 5- to 8-membered bridged saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, and a halogen, -C 1~6 Alkyl, or -OC 1~6 It is optionally substituted with alkyl, -C 1~6 Alkyl groups are optionally substituted with halogens or CN, and examples of bridging heterocycles are shown above for Y as "5-10 membered bridging saturated or partially unsaturated heterocycles having 1-3 heteroatoms independently selected from N, O, and S." The difference is that the above are divalent groups, and the heterocyclyl and the rest of the molecule may be bonded at heteroatoms or carbon atoms of the heterocycle, and substituents thereon may be substituted at ring carbon atoms or ring heteroatoms only if chemically feasible.

[0182] In some embodiments of the compound of formula (I), Z is a 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S; more specifically, a 6- to 15-membered spirotype or condensed saturated or partially unsaturated heterocycle having 1 to 4 heteroatoms independently selected from N, O, and S; more specifically, a 7- to 11-membered bicyclic spirotype or condensed saturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S, and a halogen, -C 1~6 Alkyl, or -OC 1~6 It is optionally substituted with alkyl, -C 1~6Alkyl groups are optionally substituted with halogens or CN, and examples of spiro-type and condensed heterocycles are shown above for Y as "6-15 membered spiro-type or condensed heterocycles having 1-4 heteroatoms independently selected from N, O, and S." The difference is that the above are divalent groups, and the heterocyclyl and the rest of the molecule may be bonded at heteroatoms or carbon atoms of the heterocycle, and substituents thereon may be substituted at ring carbon atoms or ring heteroatoms only if chemically feasible.

[0183] In some embodiments of the compound of formula (I), Z is -C 6~10 Preferably selected from aryl-, -3-10 membered carbocyryl-, and 3-15 membered heterocyclines having one or more heteroatoms independently selected from N, O, and S, and optionally substituted, more preferably Z is -C 6~10 Z is selected from aryl-, -3- to 8-membered monocyclic saturated or partially unsaturated carbocyclyl-, -5- to 10-membered bridged saturated or partially unsaturated carbocyclyl-, and -3- to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S, and is optionally substituted, and more preferably Z is optionally substituted, phenyl, -3- to 6-membered monocyclic saturated or partially unsaturated carbocyclyl-, -5- to 8-membered bridged saturated carbocycle-, and -4- to 7-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from N, O, and S, and most preferably Z is phenyl.

[0184] In one embodiment of the compound of formula (I), Z is a halogen, -C 1~6 Alkyl or -OC 1~6 It is optionally substituted with one or more groups independently selected from the alkyl group, and -C 1~6 Alkyl groups are optionally substituted with halogens or CN, for example, Z is a halogen, -C 1~6 Alkyl and -OC 1~6It is optionally substituted with one or two groups selected from alkyl groups, preferably one group, and in one embodiment, Z is not substituted.

[0185] In some embodiments of the compounds of formula (I), R is optionally substituted with -C. 6~10 It is aryl, preferably

[0186] [ka]

[0187] That is the case. In some embodiments of the compound of formula (I), R is optionally substituted -3 to 15 membered carbocyclyl, specifically -3 to 8 membered monocyclic saturated or partially unsaturated carbocyclic rings, and more specifically -(CH2) t -3- to 6-membered monocyclic saturated carbon rings, and 3- to 8-membered monocyclic saturated or partially unsaturated carbon rings, for example, are not limited to these,

[0188] [ka]

[0189] That is the case. In some embodiments of the compounds of formula (I), R is optionally substituted with a -3 to 15 membered carbon ring, specifically a -5 to 10 membered bridged saturated or partially unsaturated carbon ring, more specifically a -5 to 8 membered bicyclic bridged saturated carbon ring, and a -5 to 10 membered bridged saturated or partially unsaturated carbon ring is, for example, not limited to these,

[0190] [ka]

[0191] That is the case. In some embodiments of the compounds of formula (I), R is optionally substituted with a -3 to 15 membered carbocyclyl, specifically a -6 to 15 membered spirotype or condensed saturated or partially unsaturated carbon ring, more specifically a -7 to 11 membered bicyclic spirotype or condensed saturated carbon ring, and a 6 to 15 membered spirotype or condensed saturated or partially unsaturated carbon ring is also,

[0192] [ka]

[0193] It may also be expressed as [wherein k is an integer from 0 to 2, m and n are independently integers from 1 to 3, l is an integer from 1 to 4, r and p are independently integers from 0 to 3, and q is an integer from 1 to 4], and optionally contains one or more double bonds (non-aromatic), and in this embodiment R is more specifically an optionally substituted -7 to 11 membered bicyclic spiro-type saturated carbon ring (wherein k is from 0 to 2, m and n are independently integers from 1 to 2, and l is an integer from 1 to 3) or a -7 to 11 membered bicyclic condensed-type saturated carbon ring (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), and the spiro-type carbon ring and condensed-type carbon ring are, for example, but not limited to these, the groups exemplified above for the "6 to 15 spiro-type or condensed-type saturated or partially unsaturated carbon ring" of Y.

[0194] In some embodiments of the compounds of formula (I), R is an optionally substituted 5- to 12-membered heteroaryl having one or more heteroatoms independently selected from N, O, and S, specifically a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, more specifically a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the heteroaryl may be bonded to the rest of the molecule by a ring carbon atom or a ring heteroatom, specific examples of which are illustrated above for the heteroaryl of Y, such as thienyl and pyrazolyl.

[0195] In some embodiments of the compounds of formula (I), R is an optionally substituted 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S, more specifically a 3- to 8-membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, more specifically a 4- to 7-membered monocyclic saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from N, O, and S, where the heterocycle is, for example, but not limited to, the group exemplified above as "a 3- to 8-membered monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S" for Y, such as oxetanyl, tetrahydropyranyl, morpholinyl, oxocyclopentenyl, oxocyclohexenyl, piperidinyl, pyrrolidinyl, azetidinyl, etc.

[0196] In some embodiments of the compounds of formula (I), R is an optionally substituted 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S, more specifically a 5- to 10-membered bridged saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S, more specifically a 5- to 8-membered bicyclic bridged saturated heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, and an example of a bridged heterocycle is shown above for Y as "a 5- to 10-membered bridged saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S", for example

[0197] [ka]

[0198] That is the case. In further embodiments, the bridging heterocycle is bonded to the rest of the molecule by a nitrogen heteroatom. In further embodiments, the bridging heterocycle is unsubstituted. In further embodiments, the bridging heterocycle is halogen, CN, -C 1~6 Substituted with 1 to 3 substituents independently selected from a 4- to 7-membered monocyclic saturated heterocycle having 1 to 3 heteroatoms independently selected from alkyl, N, O, and S, and C among the substituents 1~6 Alkyls are halogens, -OH, or -OC 1~6 It is further optionally substituted with alkyl groups.

[0199] In some embodiments of the compound of formula (I), R is an optionally substituted 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S, more specifically a 6- to 15-membered spirotype or condensed saturated or partially unsaturated heterocycline having 1 to 4 heteroatoms independently selected from N, O, and S, more specifically a 7- to 11-membered bicyclic spirotype or condensed saturated heterocycline having 1 to 3 heteroatoms independently selected from N, O, and S, where the spirotype and condensed heterocyclines are, for example, but not limited to these, "a 6- to 15-membered spirotype or condensed saturated or partially unsaturated heterocycline having 1 to 4 heteroatoms independently selected from N, O, and S" as shown above for Y.

[0200] In some embodiments of the compounds of formula (I), R is a 3- to 15-membered heterocycline having one or more heteroatoms independently selected from N, O, and S, and is bonded to the rest of the molecule by a ring heteroatom, as in the various embodiments described above.

[0201] In embodiments of the compound of formula (I), R is preferably an optionally substituted group selected from -5-12 member heteroaryls having one or more heteroatoms independently selected from N, O, and S, and -3-15 member heterocyclils having one or more heteroatoms independently selected from N, O, and S; more preferably, R is a -5-6 member monocyclic heteroaryl or 8-10 member bicyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, a -3-8 member monocyclic saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S, or a -5-10 member bridging saturated or partially unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, and S. R is an optionally substituted group selected from heterocycles, -6 to 15-membered spirotype or condensed saturated or partially unsaturated heterocycles having 1 to 4 heteroatoms independently selected from N, O, and S, and more preferably R is an optionally substituted group selected from -5 to 6-membered monocyclic heteroaryls having 1 to 4 heteroatoms independently selected from N, O, and S, -4 to 7-membered monocyclic saturated or unsaturated heterocycles having 1 to 2 heteroatoms independently selected from N, O, and S, 5 to 8-membered bicyclic bridging saturated heterocycles having 1 to 2 heteroatoms independently selected from N, O, and S, and 7 to 11-membered spirotype or condensed saturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S.

[0202] In embodiments of the compound of formula (I), each type of R group is a halogen, CN, -OH, -NH2, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkinyl, -OC 1~6 Alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t-(CH2) - A 5- to 8-membered bridged saturated or partially unsaturated carbon ring having 1 to 3 heteroatoms independently selected from N, O, and S t -3- to 8-membered monocyclic saturated or partially unsaturated heterocycle, having 1 to 3 heteroatoms independently selected from N, O, and S -(CH2) t -Having 0 to 4, preferably 0 to 3, more preferably 0 to 2, optional substituents independently selected from a -5 to 8-membered bridged saturated or partially unsaturated heterocycle, two substituents bonded to the same ring carbon atom may, together with the carbon atom to which they are bonded, form a -3 to 8-membered saturated spirocarbocyclic ring, and -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 The alkynyl or cyclic groups are, independently and optionally, halogens, CN, -OH, or -OC. 1~6 Substituted with alkyl, preferably halogen, CN, -OH, -C 1~6 Alkyl, -OC 1~6 -(CH2) has 1-2 heteroatoms independently selected from alkyl, N, O, and S. t -Selected from a 4- to 7-membered monocyclic saturated heterocycle, two substituents bonded to the same carbon atom may, together with the carbon atom to which they are bonded, form a 3- to 6-membered saturated spirocarbocycle. 1~6 Alkyls are halogens, CN, -OH, or -OC 1~6 The substituents are optionally substituted with alkyl groups, and are not limited to these, but include, for example, -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,

[0203] [ka]

[0204] The substituents on R can be substituted on a ring carbon atom or ring heteroatom only if it is chemically feasible. In embodiments of the compound of formula (I), the value of t in the R substituent is preferably 0 to 2, and more preferably 0 to 1.

[0205] In some embodiments of the compound of formula (I), R is of formula (A)

[0206] [ka]

[0207] [In the formula, f is selected from integers 0 to 3, preferably from integers 0 to 2. t is selected from integers 0 to 3, preferably from integers 0 to 1. G is selected from O, N-R2, and CR3R4, preferably O and CR3R4, and most preferably CR3R4. R1 is H, and halogens, CN, -OH, or -OC 1~6 -C is optionally substituted with alkyl. 1~6 Two R1 atoms, selected from alkyl groups and bonded to the same ring carbon atom within the ring, may together with the carbon atom to which they are bonded to form a -3 to 8-membered saturated spirocarbocyclic ring; preferably, R1 atoms are H and -OH or -OC. 1~6 -C is optionally substituted with alkyl. 1~6 Selected from alkyl groups; most preferably, R1 is H and -C 1~6 Selected from alkyl groups, R3 and R4 are independently H, halogen, CN, -OH, -NH2, and -C, respectively. 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkinyl, -OC1~6 Alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -(CH) - a 5- to 8-membered bridged saturated or partially unsaturated carbon ring having 1 to 3 heteroatoms independently selected from N, O, and S 2) -(CH2) -3- to 8-membered monocyclic saturated or partially unsaturated heterocycle, having 1 to 3 heteroatoms independently selected from N, O, and S t -Selected from a 5- to 8-membered bridged saturated or partially unsaturated heterocycle, or R3 and R4, together with the ring carbon atoms to which they are bonded, form a 3- to 8-membered saturated spirocarbon ring, with -C in the substituent. 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 The alkynyl or cyclic group can be a halogen, CN, -OH, or -OC, independently and optionally. 1~6 Substituted with alkyl groups; preferably R3 and R4 are H, halogen, CN, -OH, -C 1~6 Alkyl, -OC 1~6 -(CH2) has 1-2 heteroatoms independently selected from alkyl, N, O, and S. t -Selected from a 4- to 7-membered monocyclic saturated heterocycle, or R3 and R4, together with the ring carbon atoms to which they are bonded, form a 3- to 6-membered saturated spirocarbon ring, with C in the substituent 1~6 Alkyls are halogens, CN, -OH, or -OC 1~6 They are optionally substituted with alkyl groups; more preferably R3 and R4 are H, halogen, CN, -C 1~6 Selected from a 4- to 7-membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from alkyl, N, O, and S, with C among the substituents. 1~6 Alkyls are halogens, -OH, or -OC 1~6 It is optionally further substituted with alkyl groups. R2 is H, -C 1~6 Alkyl, -(CH2)t -3- to 8-membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -(CH2) - A 5- to 8-membered bridged saturated or partially unsaturated carbon ring having 1 to 3 heteroatoms independently selected from N, O, and S t -3- to 8-membered monocyclic saturated or partially unsaturated heterocycles, and -(CH2) having 1 to 3 heteroatoms independently selected from N, O, and S t - Selected from 5- to 8-membered bridged saturated or partially unsaturated heterocycles, with C in the substituent. 1~6 Alkyl or cyclic groups include halogens, CN, -OH, or -OC. 1~6 It is optionally substituted with alkyl; preferably, R2 is H, -C 1~6 -(CH2) has 1-2 heteroatoms independently selected from alkyl, N, O, and S. t - Selected from 4- to 7-membered monocyclic saturated heterocycles, with C among the substituents 1~6 Alkyl or cyclic groups include halogens, CN, -OH, or -OC. 1~6 Optionally substituted with alkyl; more preferably, R2 is H, -C 1~6 Selected from a 4- to 7-membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from alkyl, N, O, and S, with C among the substituents. 1~6 Alkyls are halogens, -OH, or -OC 1~6 It is optionally substituted with alkyl, If f is 0, then G is -CH2-.

[0208] In some embodiments of formula (A), when G is CR3R4, one of R3 and R4 is H, halogen, and -C. 1~6 Selected from alkyl groups, the other being substituted with OH or further substituted with halogens -C 1~6 Selected from alkyl groups. In some embodiments of formula (A), one of R3 and R4 is H and -C. 1~6One is selected from 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- to 7-membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from N, O, and S.

[0209] In further such embodiments, R is

[0210] [ka]

[0211] Selected from these, these are optionally substituted by R1~R4 defined above, preferably substituted by 1~3 of the preferred R1~R4 above, the exemplary groups of R1~R4 are as shown above with respect to substituents on R, preferably the exemplary groups of R1~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,

[0212] [ka]

[0213] And more preferably -CN, F, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH(OH)CH3,

[0214] [ka]

[0215] , -CH2C(CH3)(OH)CH3, -CH2CH2C(CH3)(OH)CH3, -CH(OH)CH2CH3, -CH(OH)(CF3)-, -C(CH3)(OH)(CH3), -CH2-OCH3.

[0216] In further such embodiments, exemplary groups of R include, but are not limited to,

[0217] [ka]

[0218] These are some examples. In some embodiments of the compound of formula (I), R is given by the following formula:

[0219] [ka]

[0220] [In the formula, k is an integer between 0 and 2, m and n are independently integers between 1 and 3, and l is an integer between 1 and 4. Preferably, k is an integer between 0 and 2, m and n are independently integers between 1 and 2, and l is an integer between 1 and 3. r and p are each independent integers from 0 to 3, and 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. t is selected from integers 0 to 3, preferably from integers 0 to 1. G is selected from O, N-R2, and CR3R4, preferably O and CR3R4. R1 is H, and halogens, CN, -OH, or -OC 1~6 -C is optionally substituted with alkyl. 1~6 Two R1 atoms, selected from alkyl groups and bonded to the same ring carbon atom, may together with the carbon atom to which they are bonded to form a -3 to 8-membered saturated spirocarbocyclic ring; preferably, R1 is H and -OH or -OC 1~6-C is optionally substituted with alkyl. 1~6 Selected from alkyl groups; more preferably, R1 is H. R3 and R4 are independently H, halogen, CN, -OH, -NH2, and -C, respectively. 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkinyl, -OC 1~6 Alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -(CH2) - A 5- to 8-membered bridged saturated or partially unsaturated carbon ring having 1 to 3 heteroatoms independently selected from N, O, and S t -3- to 8-membered monocyclic saturated or partially unsaturated heterocycle, having 1 to 3 heteroatoms independently selected from N, O, and S -(CH2) t -Selected from a 5- to 8-membered bridged saturated or partially unsaturated heterocycle, or R3 and R4, together with the ring carbon atoms to which they are bonded, form a 3- to 8-membered saturated spirocarbon ring, with -C in the substituent. 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 The alkynyl or cyclic group can be a halogen, CN, -OH, or -OC, independently and optionally. 1~6 Substituted with alkyl groups; preferably R3 and R4 are H, halogen, CN, -OH, -C 1~6 Alkyl, -OC 1~6 -(CH2) has 1-2 heteroatoms independently selected from alkyl, N, O, and S. t -Selected from a 4- to 7-membered monocyclic saturated heterocycle, or R3 and R4, together with the ring carbon atoms to which they are bonded, form a 3- to 6-membered saturated spirocarbon ring, with C in the substituent 1~6 Alkyls are halogens, CN, -OH, or -OC 1~6 They are optionally substituted with alkyl groups; more preferably R3 and R4 are H, -OH, -C 1~6Selected from alkyl groups, C in the substituent 1~6 Alkyls are halogens, -OH, or -OC 1~6 It is optionally further substituted with alkyl groups. R2 is H, -C 1~6 Alkyl, -(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -(CH2) - A 5- to 8-membered bridged saturated or partially unsaturated carbon ring having 1 to 3 heteroatoms independently selected from N, O, and S t -3- to 8-membered monocyclic saturated or partially unsaturated heterocycles, and -(CH2) having 1 to 3 heteroatoms independently selected from N, O, and S t - Selected from 5- to 8-membered bridged saturated or partially unsaturated heterocycles, with C in the substituent. 1~6 Alkyl or cyclic groups include halogens, CN, -OH, or -OC. 1~6 It is optionally substituted with alkyl; preferably, R2 is H, -C 1~6 -(CH2) has 1-2 heteroatoms independently selected from alkyl, N, O, and S. t - Selected from 4- to 7-membered monocyclic saturated heterocycles, with C among the substituents 1~6 Alkyl or cyclic groups include halogens, CN, -OH, or -OC. 1~6 Optionally substituted with alkyl; more preferably, R2 is H, -C 1~6 Selected from alkyl groups, C 1~6 Alkyls are halogens, -OH, or -OC 1~6 [It has further optionally substituted alkyl groups.]

[0221] In some embodiments of formulas (B) and (C), when G is O, R1 is H. In some embodiments of formulas (B) and (C), when G is CR3R4, one of R3 and R4 is replaced with -OH and -OH -C 1~6 One atom is selected from alkyl groups, and the other is optionally substituted with H and halogens -C 1~6 Selected from alkyl groups.

[0222] In further such embodiments, R is

[0223] [ka]

[0224] [ka]

[0225] Selected from, preferably

[0226] [ka]

[0227] These are optionally substituted by R1 to R4 as defined above, preferably substituted by 1 to 3 of the preferred R1 to R4 above, and exemplary groups of R1 to R4 are as shown above with respect to substituents on R, and preferably exemplary groups of R1 to R4 include, but are not limited to, H, -OH, -CH3, -CF3, -CH2OH, and -C(CH3)(OH)(CH3).

[0228] In further such embodiments, exemplary groups of R include, but are not limited to:

[0229] [ka]

[0230] These are some examples. Further embodiments of the compound of formula (I) include the compound of formula (I), or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotope variant thereof [wherein,

[0231] [ka]

[0232] R is 0 to 1 a It is optionally substituted by and has 3 to 4 cyclic heteroatoms selected from N, O, and S, preferably 0 to 1 R a It is optionally substituted by a 5-membered aromatic group having 3 to 4 nitrogen heterocyclic atoms, most preferably 0 to 1 R a It is optionally substituted by and is a 5-membered aromatic group having 4 nitrogen heterocyclic atoms. R a -H, -CN, halogen, =O, and -C substituted with halogen 1~6 Selected from alkyl groups, preferably H, A7 and A9 are heteroatoms selected from N, O, and S, and 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. A 10 CR b and selected from N, A 11 is selected from CX and N, preferably A 10 CR b A 11 CX is, R b -C is substituted with H, halogen, CN, and halogen. 1~6 Selected from alkyl groups, preferably H, X is selected from H, halogens, and -OH, and is preferably a halogen. Y is -C 1~6 Alkyl, -(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon rings, -(CH2) t -5-10 membered cross-linked saturated or partially unsaturated carbon rings- -(CH2) t -C 6~10 Ariel A base that is selected from and substituted by choice, Z is -C 6~10 Ariel- -3- to 8-membered monocyclic saturated or partially unsaturated carbon rings- -5-10 membered cross-linked saturated or partially unsaturated carbon rings- -3 to 8-membered monocyclic saturated or partially unsaturated heterocyclic rings having 1 to 3 heteroatoms independently selected from N, O, and S. A divalent base that is arbitrarily substituted, selected from the following: R is -5-12 member heteroaryls having 1-4 heteroatoms independently selected from N, O, and S, -3 to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S. -5 to 10-membered bridging saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S, -6 to 15 member spirotype or condensed saturated or partially unsaturated heterocycles having 1 to 4 heteroatoms independently selected from N, O, and S. A base that is selected from and substituted by choice, [t is an integer between 0 and 3] is provided.

[0233] In these further embodiments, each cyclic group of Y is independently and optionally has 1 to 3 -C 1~6 Alkyl, OH, or -OC 1~6 Substituting with alkyl, Y and its substituents have -C 1~6 Alkyl or -(CH2) t - is optionally substituted with a halogen or CN, any carbon chain atom is optionally substituted with NR', O, or S, and R' is H or -C 1~6 Selected from alkyl groups, these substituents are as generally or specifically illustrated above with respect to the substituents of Y, preferably each cyclic group of Y is independently and optionally, one or two, more preferably one-C1~6 Alkyl or -OC 1~6 It is alkyl-substituted, and -C is present in Y and its substituents. 1~6 Alkyl or -(CH2) t - is optionally replaced by a halogen. Y is -(CH2) t -In embodiments where it is a carbocykyl, preferably t is 0, and the carbon ring is a 3-6 membered monocyclic saturated carbon ring, C 1~6 The alkyl substituent is optionally retained, and more preferably, if present, C 1~6 The alkyl group is substituted on the ring carbon atoms of the carbon ring bonded to the rest of the molecule.

[0234] In these further embodiments, each cyclic group of Z is optionally and independently a halogen, -C 1~6 Alkyl, or -OC 1~6 Substituted with one or more groups independently selected from alkyl, -C 1~6 The alkyl group is optionally substituted with a halogen or CN, and these substituents are as generally or specifically exemplified above with respect to the substituent of Z, preferably Z is a halogen, -C 1~6 Alkyl and -OC 1~6 It is optionally substituted with one or two, more preferably one, groups selected from alkyl groups. In one embodiment, Z is not substituted.

[0235] In these further embodiments, the R group is a halogen, CN, -OH, -NH2, -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkinyl, -OC 1~6 Alkyl, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-(CH2) t -3- to 8-membered monocyclic saturated or partially unsaturated carbon ring, -(CH2) t -(CH2) - A 5- to 8-membered bridged saturated or partially unsaturated carbon ring having 1 to 3 heteroatoms independently selected from N, O, and S t-3- to 8-membered monocyclic saturated or partially unsaturated heterocycle, having 1 to 3 heteroatoms independently selected from N, O, and S -(CH2) t -Having 0 to 4, preferably 0 to 3, more preferably 0 to 2, optional substituents independently selected from a -5 to 8-membered bridged saturated or partially unsaturated heterocycle, two substituents bonded to the same ring carbon atom may, together with the carbon atom to which they are bonded, form a -3 to 8-membered saturated spirocarbocyclic ring, and -C 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 The alkynyl or cyclic groups are, independently and optionally, halogens, CN, -OH, or -OC. 1~6 The substituents are alkyl groups, and these substituents are generally or specifically as exemplified above for the substituents of R, preferably halogens, CN, -OH, and -C 1~6 Alkyl, -OC 1~6 -(CH2) has 1-2 heteroatoms independently selected from alkyl, N, O, and S. t -Selected from a 4- to 7-membered monocyclic saturated heterocycle, two substituents bonded to the same carbon atom may, together with the carbon atom to which they are bonded, form a 3- to 6-membered saturated spirocarbocyclic ring, and among the substituents C 1~6 Alkyls are halogens, CN, -OH, or -OC 1~6 Optionally substituted with alkyl groups, and examples of substituents are not limited to the general and specific definitions of substituents that retain R, but rather include, for example, -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,

[0236] [ka]

[0237] These include, more preferably, -CN, F, -OH, -CH3, -CF3, -CH2CH3, -CH2CF3, -CH2OH, -CH2CH2OH, -CH(OH)CH3,

[0238] [ka]

[0239] -CH2C(CH3)(OH)CH3, -CH2CH2C(CH3)(OH)CH3, -CH(OH)CH2CH3, -CH(OH)(CF3)-, -C(CH3)(OH)(CH3), -CH2-OCH3.

[0240] This disclosure further provides compounds of general formula (I-1), or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof.

[0241] [ka]

[0242] [In the formula, A1~A 11 , R a Y, R, and t are defined above in correspondence to the general and specific embodiments of the compound of formula (I), respectively.

[0243] [ka]

[0244] Preferably, it has 3 to 4 cyclic heteroatoms selected from N, O, and S, and 0 to 1 R a A 5-membered unsaturated or aromatic group optionally substituted by, more preferably having 3-4 nitrogen heterocyclic atoms and 0-1 R aA 5-membered aromatic group that is optionally substituted by, most preferably a 5-membered aromatic group having 4 nitrogen heterocyclic atoms, A 11 It is preferably CX, A 10 N and CR b Selected from, A8 is C, R b [where is preferably H, 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 a compound of the following formula:

[0245] [Table 1]

[0246] Here, X, Y, R b And R are as defined above, corresponding to the general and specific embodiments of the compound of formula (I), respectively. The present invention further provides compounds of general formula (I-2), or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof.

[0247] [ka]

[0248] [In the formula, A1~A 11 , R a Y, G, R1, t, and f are defined above in correspondence to the general and specific embodiments of the compound of formula (I), respectively.

[0249] [ka]

[0250] Preferably, it has 3 to 4 cyclic heteroatoms selected from N, O, and S, and 0 to 1 R aA 5-membered unsaturated or aromatic group optionally substituted by, more preferably having 3-4 nitrogen heterocyclic atoms and 0-1 R a A 5-membered aromatic group that is optionally substituted by, most preferably a 5-membered aromatic group having 4 nitrogen heterocyclic atoms, A 11 It is preferably CX, A 10 N and CR b Selected from, A8 is C, R b [wherein is preferably H, 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 a compound of the following formula:

[0251] [Table 2]

[0252] Here, X, Y, and R b These are defined above, corresponding to the general and specific embodiments of the compound of formula (I),

[0253] [ka]

[0254] This is as defined above, corresponding to the general and specific embodiments of the structural fragment of formula (A). The present invention further provides compounds of general formula (I-3), or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof.

[0255] [ka]

[0256] [In the formula, A1~A 11 , R aY, G, R1, t, m, k, n, and l are defined above in correspondence to the general and specific embodiments of the compound of formula (I),

[0257] [ka]

[0258] Preferably, it has 3 to 4 cyclic heteroatoms selected from N, O, and S, and 0 to 1 R a A 5-membered unsaturated or aromatic group optionally substituted by, more preferably having 3-4 nitrogen heterocyclic atoms and 0-1 R a A 5-membered aromatic group that is optionally substituted by, most preferably a 5-membered aromatic group having 4 nitrogen heterocyclic atoms, A 11 It is preferably CX, A 10 N and CR b Selected from, A8 is C, R b [where is preferably H, 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 a compound of the following formula:

[0259] [Table 3]

[0260] Here, X, Y, and R b These are defined above, corresponding to the general and specific embodiments of the compound of formula (I),

[0261] [ka]

[0262] This is as defined above, corresponding to the general and specific embodiments of the structural fragment of formula (B). The present invention further provides compounds of general formula (I-4), or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof.

[0263] [ka]

[0264] [In the formula, A1~A 11 , R a Y, G, R1, t, r, p, and q are defined above in correspondence to the general and specific embodiments of the compound of formula (I),

[0265] [ka]

[0266] Preferably, it has 3 to 4 cyclic heteroatoms selected from N, O, and S, and 0 to 1 R a A 5-membered unsaturated or aromatic group optionally substituted by, more preferably having 3-4 nitrogen heterocyclic atoms and 0-1 R a A 5-membered aromatic group that is optionally substituted by, most preferably a 5-membered aromatic group having 4 nitrogen heterocyclic atoms, A 11 It is preferably CX, A 10 N and CR b [Selected from, 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 a compound of the following formula:

[0267] [Table 4]

[0268] Here, X, Y, and R bThese are defined above, corresponding to the general and specific embodiments of the compound of formula (I),

[0269] [ka]

[0270] This is as defined above, corresponding to the general and specific embodiments of the structural fragment of formula (C). In certain embodiments, the present disclosure provides the compounds of Examples 1 to 134 below, or pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants thereof.

[0271] It should be noted that the compounds disclosed herein encompass each of the individual or specific embodiments described above, as well as embodiments consisting of any combination or subcommittal combination of the embodiments or specific embodiments described above, and embodiments consisting of any combination of any of the preferred or exemplary embodiments described above.

[0272] Advantageous effects of the present invention As previously described, SHP2 is known to play a crucial role in tumorigenesis and various other diseases. Surprisingly, the inventors have discovered that by introducing a low-ionization "conditional" acidic group into the molecular structure to avoid highly ionized, strongly acidic groups, the compounds of this disclosure not only overcome the permeability / transportation problems of existing active-site inhibitors but also exhibit potent inhibitory activity by strongly binding to the catalytic domain of the active site of the SHP2 enzyme. Furthermore, these compounds demonstrate highly selective inhibition of SHP2 and thus have potential value as antiproliferative and / or anti-invasive substances in the prevention, suppression, and / or treatment of related diseases, particularly cancer. In particular, the compounds of this disclosure are expected to be used for the prevention or treatment of SHP2-mediated diseases or diseases in which improvement is expected by inhibition of SHP2, such as cancer or tumors, as defined below.

[0273] Specifically, studies have shown that the compounds disclosed herein can achieve one or more of the following technical effects: • Highly potent SHP2 inhibitory activity: The compounds disclosed herein, in particular those specifically exemplified in the context, exhibit generally enhanced inhibitory activity compared to the prior art inhibitor 11a-1 in SHP2 enzyme inhibition assays, with IC50 values ​​for the SHP2 catalytic domain in the range of 0.001 to 1 μM, for example, in the range of 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 in the range of 0.01 to 0.5 μM, more preferably in the range of 0.01 to 0.2 μM, as generally verified in Activity Test Example 1, and / or • Potent tumor cell proliferation inhibitory activity: The compounds disclosed herein, in particular the compounds specifically exemplified in the context, exhibit significantly enhanced proliferation inhibitory activity compared to the conventional inhibitor 11a-1 in various SHP2-dependent tumor cell lines, with IC50 values ​​generally in the range of 0.001 to 1 μM, for example, in the range of 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, and 0.05 to 0.1 μM, preferably in the range of 0.01 to 0.5 μM, more preferably in the range of 0.01 to 0.1 μM, as verified in Activity Test Example 2, and / or • Broad-spectrum tumor cell inhibitory activity: The compounds disclosed herein, in particular those specifically exemplified in this context, exhibit cell proliferation inhibitory activity across a variety of tumor cell lines, including solid tumors and hematological malignancies, with IC50 values ​​generally in the range of 0.001 to 1 μM, for example, in the range of 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 in the range of 0.01 to 0.5 μM, more preferably in the range of 0.01 to 0.1 μM, as verified in Activity Test Example 3, and / or • Favorable pharmacokinetic properties, for example, compared to conventional inhibitors 11a-1 1 / 2 This allows for longer dosing intervals and better patient compliance. Oral AUC 0-t It increased significantly 、 This may result in higher bioavailability, as demonstrated in Activity Test Example 4, and / or • Excellent selective inhibitory activity against SHP2 in the tyrosine phosphatase group, as demonstrated in Activity Test Example 5, and / or • Satisfactory cardiac safety, no inhibitory activity against hERG at a concentration of 10 μM, low risk of drug interaction, and no significant inhibitory effect on major CYP subtypes of drug metabolism, as verified in activity test examples 6-7.

[0274] Based on the advantageous effects of the compounds of the present invention, the present invention also provides technical solutions in the following embodiments. The compounds disclosed herein are for therapeutic or medicinal purposes.

[0275] In one embodiment, the present disclosure provides the compounds described above, preferably pharmaceutically acceptable salts or solvates thereof, for use as pharmaceuticals, specifically as SHP2 inhibitors.

[0276] In another aspect, the disclosure provides compounds disclosed herein, preferably pharmaceutically acceptable salts or solvates thereof, for the treatment and / or prevention of SHP2-mediated diseases or diseases that are expected to be improved by inhibition of SHP2.

[0277] In certain embodiments, the disclosure provides compounds for treating and / or preventing diseases in which abnormal SHP2 activity promotes the onset and progression of the disease, or where inhibiting SHP2 activity reduces the incidence of the disease, or reduces or eliminates disease symptoms. Diseases are selected from, but are not limited to, cancer or tumors, cardiovascular diseases, immunodeficiencies, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes mellitus, neutropenia, or combinations thereof. Preferably, diseases are selected from Noonan syndrome (NS), Leopard syndrome (LS), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, pancreatic cancer, and combinations thereof.

[0278] Pharmaceutical compositions and their administration In one embodiment, 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 compositions of the present disclosure can be used to treat or prevent SHP2-mediated diseases, such as tumors or cancer.

[0279] The pharmaceutical compositions disclosed herein can be formulated using techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20th edition. For example, these pharmaceutical compositions can be formulated as tablets, powders, capsules, lozenges, granules, liquids, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. The compositions may contain conventional components found in pharmaceutical preparations, such as diluents (e.g., glucose, lactose, or mannitol), carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, flavoring agents, tasters, other known additives, and other active substances. Suitable carriers and excipients are well known to those skilled in the art, and are described in detail, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004.

[0280] The administration and delivery of the pharmaceutical compositions disclosed herein are consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the individual patient's condition, the cause of the disorder, the location of drug delivery, the method of administration, the administration schedule, and other factors well known to medical practitioners. The optimal dose level and frequency of administration of the compounds or pharmaceutical compositions disclosed herein can be determined by those skilled in the art through standard experiments in the field of pharmaceutical research.

[0281] The compositions disclosed herein can be administered by any suitable method, including oral, topical (including oral buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhalation, epidural, and intranasal administration, and may also be administered to the lesion if topical treatment is required. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. In preferred embodiments, the pharmaceutical compositions of this disclosure are administered orally.

[0282] When the compounds disclosed herein are administered to human subjects, the daily dose is usually determined by the prescribing physician based on the individual patient's age, weight, sex, and the severity of the disease. Generally, dose levels of approximately 0.1 mg / kg to approximately 150 mg / kg body weight are used to treat the aforementioned diseases. For a human subject weighing 70 kg, an appropriate dose range of the compounds disclosed herein can be conventionally determined by those skilled in the art, for example, the dose range may be 1 to 1000 mg / day.

[0283] Where this document specifies a dosage of a drug or a pharmaceutically acceptable salt thereof, please understand that the dosage is based on the weight of the free base, excluding either the hydrate or solvate, unless the package insert suggests that the dosage is based on the weight of the salt, hydrate, or solvate.

[0284] Treatment methods and use As demonstrated above and further verified in the following examples, the compounds of the present disclosure and the compounds of various specific embodiments, in particular the compounds specifically 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 oncogenic function of the RAS-RAF-ERK pathway.

[0285] Accordingly, in another aspect, the present disclosure provides medical uses of the compounds of the present disclosure, preferably pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions containing them, or pharmaceutically acceptable combinations of the compounds of the present disclosure described below, for inhibiting the abnormal activity of SHP2 in cells, in particular for inhibiting abnormal cell proliferation in mammals, or for treating and / or preventing SHP2-mediated diseases, in particular diseases that are expected to be improved by SHP2 inhibition.

[0286] In another aspect, the Disclosure also provides a method for inhibiting abnormal cell proliferation in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of the Disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition comprising the same.

[0287] In another embodiment, the present disclosure provides a method for treating and / or preventing SHP2-mediated diseases, particularly diseases that are expected to be improved by inhibition of SHP2, the method comprising the step of administering to a subject in need 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 pharmaceutically acceptable combination of the present disclosure as described below.

[0288] In another aspect, the disclosure provides the use of the compounds disclosed herein, preferably pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions comprising them, in the preparation of pharmaceuticals for treating and / or preventing SHP2-mediated diseases, particularly diseases that are expected to be improved by inhibition of SHP2.

[0289] Based on the same properties, the Disclosure also provides methods for inhibiting SHP2 activity, particularly in vitro methods, comprising the steps of contacting or applying a compound of the Disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, to a sample (e.g., a biological sample), specifically including the use of cells, cell extracts or organelle extracts, and / or biomolecules in an artificial environment. Specifically, the Disclosure also provides the in vitro use of the compounds of the Disclosure, preferably a pharmaceutically acceptable salt or solvate thereof, as SHP2 inhibitors in research, particularly as research tool compounds for inhibiting SHP2.

[0290] With regard to the various methods and uses provided in this disclosure, the SHP2-mediated disease is selected from cancer or tumors, cardiovascular disease, immunodeficiency, fibrosis, ocular disorders, systemic lupus erythematosus, diabetes mellitus, 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, gastric cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof. Preferably, any of the cancers is primary or metastatic.

[0291] SHP2-mediated diseases specifically refer to diseases caused by abnormal cell proliferation, whether malignant or benign, as well as all precancerous cells and cancer cells and tissues, particularly cancer or tumors. Cancer or tumors may be solid tumors or hematological malignancies, and may be hormone-dependent or hormone-resistant. In some embodiments, cancer may be a drug-resistant phenotype of cancer disclosed herein or known in the art, and may be primary or metastatic. Accordingly, the compounds, compositions, combinations, and methods disclosed herein can be used to treat precancerous tumorigenesis, tumor growth, tumor invasion, tumor metastasis, and angiogenesis.

[0292] Cancers that can be treated with the compounds disclosed herein include, 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 tumors, head and neck cancers (e.g., head and neck squamous cell carcinoma), ovarian cancer, prostate cancer, melanoma, melanoma of the skin or eye, soft tissue sarcoma; oral cavity and pharynx (lips, tongue, mouth, larynx, nasopharynx). Cancers of the following sites: stomach, small intestine, large intestine, colon, rectum, perianal area, liver and bile ducts, pancreas, bone, connective tissue, skin (including epithelial cell carcinoma), vagina, vulva, cervix, uterus, endometrium, fallopian tubes, urethra, penis, testes, bladder, ureters, kidneys, and other urinary tract tissues, including elvic carcinoma, renal pelvis carcinoma, and hepatocellular carcinoma; gastroesophageal cancer, as well as cancers of the eyes, brain, spinal cord, and the central and peripheral nervous systems and related structures, including meningeal carcinoma, primary CNS lymphoma, and hypochondriacal cancer. dendroglioma, neuroblastoma, spinal cord tumor, brainstem glioma, or pituitary adenoma; cancers of the thyroid and other endocrine glands, Hodgkin's disease, non-Hodgkin lymphoma, parathyroid carcinoma, adrenal carcinoma, multiple myeloma, neuroblastoma, and hematological malignancies, including, for example, chronic or acute lymphoblastic leukemia, chronic or acute myeloid leukemia, chronic myelomonocytic leukemia, and lymphomas, including, for example, lymphocytic, granulocytic, and monocytic lymphoma, mantle cell lymphoma, and histiocytic lymphoma.

[0293] Accordingly, in preferred embodiments of this aspect, the Disclosure provides methods and uses for treating or preventing cancer or tumors by inhibiting SHP2 activity. In further preferred embodiments, the Disclosure provides methods and uses for treating or preventing Noonan syndrome (NS), Leopard syndrome (LS), juvenile myelomonocytic leukemia (JMML), myelodysplastic syndrome (MDS), neuroblastoma, melanoma, squamous cell carcinoma of the head and neck, acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, gastric cancer, pancreatic cancer, and combinations thereof by inhibiting SHP2 activity.

[0294] Drug combination The compounds disclosed herein may be administered as sole active ingredients or in combination with other drugs or therapies.

[0295] Accordingly, in another embodiment, the present disclosure provides pharmaceutically acceptable combinations comprising the compounds disclosed herein, preferably pharmaceutically acceptable salts or solvates thereof, and other active substances, or both. These pharmaceutically acceptable combinations are used to treat and / or prevent SHP2-mediated diseases.

[0296] Other active substances may be one or more other compounds disclosed herein, or second or other (e.g., third) compounds that are compatible with the compounds disclosed herein, i.e., do not adversely affect each other, or have complementary activity. For example, these active substances may be compounds known to modulate other biological activity pathways, or compounds that modulate different components in the biological activity pathways in which the compounds disclosed herein are involved.

[0297] In some embodiments of this disclosure, other active substances that can be used in combination with the compounds of this 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, and tyrosine kinase inhibitors.

[0298] The compounds disclosed herein can also be used in combination with antitumor therapies, including, but not limited to, surgery, radiotherapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), tumor immunotherapy, and chemotherapy.

[0299] Other active substances used in combination with the compounds of the Disclosure may be administered simultaneously, separately, or sequentially with the compounds of the Disclosure via the same or different routes of administration. These other active substances may be administered together with the compounds of the Disclosure in a single pharmaceutical composition, or separately in the form of different separate units, e.g., combination products, preferably kits, and if administered separately, they may be administered simultaneously or sequentially, with sequential administrations occurring in close proximity or at intervals. These active substances may be prepared and / or formulated by the same or different manufacturers. Furthermore, these combinations of the compounds of the Disclosure and other active substances may be made by (i) before delivery to a physician (e.g., in the case of a kit containing the compounds of the Disclosure and other drugs); (ii) by the physician himself (or under the guidance of a physician) before administration; or (iii) by the patient himself, for example, between sequential administrations of the compounds of the Disclosure and other active substances in combination therapy.

[0300] Accordingly, in another embodiment, the Disclosure also provides a kit comprising two or more distinct pharmaceutical compositions (at least one of which contains a compound of the Disclosure or a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotope variant thereof) and means for containing the compositions, such as a container, dispensing vial, or individual foil package, which includes instructions for use. The kits of the Disclosure are particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, or different compositions at different dose intervals.

[0301] With respect to the technical solutions of the pharmaceutical compositions, pharmaceutically acceptable combinations, or kits disclosed above, the relevant SHP2-mediated diseases are as defined above for the methods and uses of this disclosure.

[0302] With regard to the compounds, pharmaceutical compositions, methods, uses, pharmaceutical combinations, and kits disclosed herein, the compounds of the embodiments herein are preferred. Method for preparing the compound of the present invention In another aspect, the disclosure also provides a method for preparing a defined compound.

[0303] The compounds disclosed herein can be prepared in a variety of ways, including the general methods given below, the methods disclosed in the examples, or similar methods.

[0304] Standard synthetic methods and procedures for the preparation of organic compounds and the transformation and manipulation of functional groups are known in the art and can be found in standard textbooks, e.g., Smith MB, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," 7th edition, Wiley, 2013. For each reaction step of each general synthetic scheme, appropriate reaction conditions are known to those skilled in the art or can be determined by custom. Method steps for synthesizing the disclosed compounds are performed under reaction conditions that are inherently known (including those specifically described), i.e., in the absence or generally in the presence of a catalyst, condensing agent or neutralizing agent (e.g., ion exchanger, e.g., cation exchanger, e.g., H) depending on the nature of the reaction and / or reactants. + This can be done in the absence or presence of (form), at low temperatures, room temperature or high temperatures (e.g., including about -100°C to about 190°C, e.g., about -78°C to about 150°C, e.g., about 0°C to about 125°C, room temperature, -20 to 40°C or reflux temperature), at atmospheric pressure or in a sealed container, under pressurized conditions where appropriate, and / or in an inert atmosphere, e.g., argon or nitrogen.

[0305] Unless otherwise specified, the starting materials and reagents used in the preparation of the compounds are commercially available, known in the literature, or can be prepared by those skilled in the art using the methods described below, similar methods, or standard methods known in the art. Unless otherwise specified in the description of the method, the applicable solvents are conventional solvents well known to those skilled in the art, suitable for the specific type of reaction involved, such as water, esters, ethers, liquid aromatic hydrocarbons, alcohols, nitriles, halogenated hydrocarbons, amides, bases, carboxylic acid anhydrides, cyclic, linear or branched hydrocarbons, or mixtures of these solvents. Such solvent mixtures can also be used for work-up, such as by chromatography or resolution.

[0306] If necessary, the starting materials and intermediates of the synthetic reaction scheme can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. 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-treated in conventional ways, e.g., by mixing with water, phase separation, etc., and the crude product is purified by chromatography where appropriate.

[0307] Those skilled in the art will recognize the presence of stereocenters in the compounds disclosed herein. At all steps of the reaction, the mixture of isomers formed can be separated into individual isomers, e.g., diastereomers or enantiomers, or into any desired mixture of isomers, e.g., a racemate or a mixture of diastereomers; see, for example, "Stereochemistry of Organic Compounds" by ELEliel, SHWilen, and LNMander (Wiley-Interscience, 1994).

[0308] In certain circumstances, it may be necessary to use an appropriate protecting group to protect a particular reactive group in order to avoid interference with the reactions of other reactive groups. Suitable protecting groups and methods for protection and deprotection using such appropriate protecting groups are well known to those skilled in the art, and examples can be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd edition), John Wiley & Sons, NY (1999).

[0309] The following description merely illustrates a general synthetic scheme for synthesizing the compounds disclosed herein. The compounds disclosed herein can also be obtained using other routes and other reactants and intermediates known to those skilled in the art.

[0310] For clarity, in the exemplary synthesis schemes described below, unless otherwise specified, X, Y, Z, and R appearing in the structural formulas of various intermediate compounds are as defined above for the compounds disclosed herein, and PG represents an appropriate protecting group, which can be determined by those skilled in the art based on their knowledge of organic chemistry.

[0311] Synthesis of the disclosed compound General synthesis methods In the following scheme, each variable element of the general formula has the same meaning as the corresponding variable element in formula (I) or in the various specific embodiments thereof provided above, unless otherwise specified.

[0312] [ka]

[0313] Scheme 1 illustrates a general synthetic route that can be used to prepare the compounds of this disclosure and various specific embodiments thereof. Taking 6-tetrazole indole as an example,

[0314] [ka]

[0315] Scheme 2 illustrates the synthetic routes for compounds of formulas A and A' in Scheme 1.

[0316] [ka]

[0317] Scheme 3 illustrates a synthesis route for the intermediate in Equation 4 of Scheme 2.

[0318] [ka]

[0319] Scheme 4 illustrates a synthesis route for the intermediate in Equation 4 of Scheme 2.

[0320] [ka]

[0321] Scheme 5 illustrates the synthetic route for intermediate 4 in Scheme 2 (when Z is a cyclic amine (e.g., an alicyclic amine)).

[0322] [ka]

[0323] Scheme 6 illustrates a synthesis route for the intermediate in Equation 4 of Scheme 2.

[0324] [ka]

[0325] Scheme 7 illustrates a synthesis route for the intermediate in Equation 4 of Scheme 2. Non-indole intermediate A

[0326] [ka]

[0327] In contrast, the azaindole compound, similar to Scheme 2, uses commercially available azaindole as a raw material.

[0328] [ka]

[0329] It can be synthesized from. Non-indole intermediate A

[0330] [ka]

[0331] In contrast, benzofuran compounds can be synthesized using a scheme similar to Scheme 2. Scheme 8 illustrates one synthetic route for intermediate 4.

[0332] [ka]

[0333] Non-indole intermediate A

[0334] [ka]

[0335] In contrast, benzothiophene compounds can be synthesized using the scheme for benzofuran compounds. Scheme 9 illustrates one synthetic route for benzothiophene intermediate 27a (substitution of intermediate 27).

[0336] [ka]

[0337] Non-indole intermediate A

[0338] [ka]

[0339] For example, with respect to pyrimidine-containing condensed ring compounds, A can be synthesized using a scheme similar to Scheme 2. Scheme 10 illustrates one synthetic route for intermediate 4.

[0340] [ka]

[0341] Non-6-tetrazazole indole intermediate A

[0342] [ka]

[0343] In contrast,

[0344] [ka]

[0345] but,

[0346] [ka]

[0347] In this case, scheme 11 illustrates a synthesis route for intermediate A.

[0348] [ka]

[0349] [ka]

[0350] but,

[0351] [ka]

[0352] In this case, scheme 12 illustrates a synthesis route for intermediate A.

[0353] [ka]

[0354] [ka]

[0355] but,

[0356] [ka]

[0357] In this case, scheme 13 illustrates a synthesis route for intermediate A.

[0358] [ka]

[0359] [ka]

[0360] Scheme 14 illustrates synthetic routes for compounds of formulas B and B' when R in Scheme 1 is a cyclic amine (particularly an alicyclic amine).

[0361] [ka]

[0362] Scheme 15 illustrates that when R in Scheme 1 is an aryl group (including a heteroaryl group), compounds B and B' can be obtained by any aryl-aryl coupling reaction.

[0363] In the above scheme, the order of specific unit reactions can be flexibly adjusted according to conventional conditions known to those skilled in the art. Specifically, the present invention provides a method for preparing the compounds described above, the method comprising: 1. Preparation of intermediates A and A' Compound of formula 1

[0364] [ka]

[0365] Compound 2 is produced by reacting the compound of formula 1 with a halogenated compound (e.g., Y-Br) in a solvent such as DMF in the presence of a base (e.g., cesium carbonate). Compound 2 can also be obtained by reacting the compound of formula 1 with the corresponding organohalide (e.g., iodide) or organoboronic acid in the presence of a catalyst such as a copper salt (e.g., copper iodide, copper acetate).

[0366] [ka]

[0367] Compound 2 is reacted with a cyanidating agent (e.g., copper cyanide or zinc cyanide) in an organic solvent such as NMP to produce compound 3.

[0368] [ka]

[0369] The compound of formula 3 and its halogenated compound (e.g., IZ-NHBoc) are reacted catalytically in the presence of silver oxide using a catalyst such as palladium / 2-nitrobenzoic acid to introduce substituent Z and produce the compound of formula 4. The compound of formula 4 can also be obtained by reacting the compound of formula 3 with an organoboronic acid under the cocatalytic action of a silver salt (e.g., silver trifluoroacetate) and a rhodium reagent (e.g., (RhCpCl2)2) or other catalyst.

[0370] [ka]

[0371] The cyano group of the compound of formula 4 can also be prepared by a series of transformations of a carboxylic acid derivative (e.g., the compound of formula 7) via the intermediate of formula 10.

[0372] [ka]

[0373] The introduction of substituent Z can also be achieved by reacting the organoboronic acid with intermediate 14 under the catalytic action of a palladium reagent (e.g., (Pd(PPh3)2Cl2)).

[0374] [ka]

[0375] When Z is an alicyclic amine (e.g., piperidine), the compound of formula 2 reacts with the amine in the presence of iodine to produce the intermediate of formula 16.

[0376] [ka]

[0377] The iodine atom can be removed by reduction with zinc powder. The bromide is converted to the cyano homolog of formula 4 by using a cyanidating reagent, as shown above.

[0378] [ka]

[0379] Another method for preparing compound 4 is to activate phenolic compound 19 to trifluoromethanesulfonate 20.

[0380] [ka]

[0381] Next, this is reacted with a terminal alkyne in the presence of a catalyst such as palladium (e.g., Pd(PPh3)2Cl2) to produce phenylacetylene 21.

[0382] [ka]

[0383] Next, under the action of a strong base (e.g., sodium Tert-butoxide) and a palladium catalyst (e.g., t-Buxphos.PdG3), this is directly reacted with Y-NH2 to form a cyclized compound, thereby obtaining the compound of formula 4.

[0384] The preparation of the compound of formula 4 can also be started from the nitrobenzene derivative 22. The nitrobenzene derivative 22 is reduced to the corresponding aniline 23 with a reducing agent (e.g., sodium dithionite), and then reductive amination is performed using the ketone Y=O to obtain the intermediate of formula 24.

[0385] [ka]

[0386] 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 produce phenylacetylene 25.

[0387] [ka]

[0388] Next, phenylacetylene 25 is treated with a strong inorganic base (e.g., potassium hydroxide) to obtain the compound of formula 4. Then, under standard conditions, the amino protecting group Boc is removed to obtain intermediate 5.

[0389] [ka]

[0390] Further treatment with azide reagents (such as sodium azide or trimethylsilane azide) generates the intermediate A series compounds.

[0391] [ka]

[0392] Further reaction with monomethyloxalate chloride yields the compound of formula 6.

[0393] [ka]

[0394] When the compound of formula 6 is treated under standard ester hydrolysis conditions, the intermediate A' series compounds can be prepared.

[0395] [ka]

[0396] Azaindole compounds can be obtained using a procedure similar to the one described above, or commercially available azaindole

[0397] [ka]

[0398] It can be synthesized from. Benzofuran compounds can be synthesized using a scheme similar to Scheme 2. The preparation of the main intermediate 4 can be started with compound 26. Compound 26 is reacted with acyl chloride in the presence of anhydrous aluminum trichloride to produce compound 27.

[0399] [ka]

[0400] Next, under the action of a base (e.g., sodium hydride), a substitution reaction with a haloacetate (e.g., methyl 2-bromoacetate) is carried out to obtain the compound of formula 28.

[0401] [ka]

[0402] The compound of formula 28 is hydrolyzed again and treated with an alkali (e.g., sodium acetate) to cyclize it and obtain compound 30. Then, using a cyanidating reagent (e.g., zinc cyanide), the bromide compound 30 is converted to a cyano compound, and then brominated using a brominating reagent (e.g., N-bromosuccinimide) to obtain compound 32. Next, compound 32 is treated with an organoboronic acid to introduce substituent Z under the catalytic action of a palladium reagent (e.g., (Pd(PPh3)2Cl2)).

[0403] [ka]

[0404] For benzothiophene compounds, A can be synthesized using the scheme for benzofuran compounds. The preparation of its main intermediate 27a can begin with compound 27. Compound 33 is obtained by treating compound 27 with dimethylthiocarbamoyl chloride. Compound 34 is obtained by rearranging compound 33 by heating. This is then treated with alkali (e.g., sodium hydroxide) to obtain 27a.

[0405] [ka]

[0406] For pyrimidine-containing condensed ring compounds, A can be synthesized using a scheme similar to Scheme 2. The preparation of its main intermediate 4 can be started from compound 35. Compound 36 is obtained by a substitution reaction of compound 35 in the presence of an organic base (e.g., N,N-diisopropylethylamine).

[0407] [ka]

[0408] Next, this is reacted with terminal alkynes under the catalytic action of catalysts such as palladium (e.g., Pd(PPh3)2Cl2) and Cu (e.g., cuprous iodide) to produce phenylacetylene 37.

[0409] [ka]

[0410] After treatment with tetrabutylammonium fluoride, a cyanidating agent (e.g., zinc cyanide) is used to convert the chlorinated compound to the compound of formula 4. The compound of formula 4 can also be prepared starting from a commercially available starting material 56. By subjecting this to a substitution reaction in the presence of a base (e.g., cesium carbonate), the compound of formula 57 is obtained. This is then reacted with a halogenated compound (e.g., IZ-NHBoc) in the presence of silver oxide and catalyzed with a catalyst such as palladium / 2-nitrobenzoic acid to introduce substituent Z, thereby obtaining the compound of formula 4.

[0411] [ka]

[0412] For the synthesis of non-tetrazole compounds, A is synthesized using a scheme similar to Scheme 2, following heterocycle formation. The heterocycle synthesis process is illustrated below. Triazole compounds can be synthesized from commercially available starting material 2a. This starting material 2a is reacted with a halide (e.g., IZ-NHBoc) in the presence of silver oxide, and catalytically reacted with a catalyst such as palladium / 2-nitrobenzoic acid to introduce substituent Z and produce compound 39. Compound 39 is then reacted with trimethylethynylsilane in the presence of a copper catalyst (e.g., cuprous iodide) and a palladium catalyst (e.g., tetrakis(triphenylphosphine)-palladium) to produce 40. Further deprotection, followed by treatment with azido-trimethylsilane and further deprotection, prepares A.

[0413] [ka]

[0414] Further non-tetrazole acidic heterocyclic intermediate A can be obtained starting from intermediate 4. Intermediate 4 is treated with hydroxylamine hydrochloride to produce compound 43, which is then dehydrated with a dehydrating agent (e.g., CDI, trifluoroacetic anhydride, etc.) to produce compound 44, which is then deprotected to prepare A.

[0415] [ka]

[0416] Intermediate 4 is reacted with an inorganic strong base (e.g., potassium hydroxide) and hydrogen peroxide in a solvent (e.g., DMSO) to produce amide intermediate 45. This intermediate is then reacted with Lawson's reagent to produce the corresponding thioamide 46. After treatment with a methylating agent (e.g., iodomethane), compound 47 is obtained. This compound is then reacted with 2-hydrazino-2-carbonylacetamide and dehydrated in the presence of trifluoroacetic anhydride to form 48. Finally, the protecting group is removed to obtain cyano-substituted intermediate A.

[0417] [ka]

[0418] When compound 47 is treated with acetylhydrazine, a methyl-substituted intermediate A can be prepared by removing the protecting group. 2. Preparation of intermediates B and B' When R is an aryl (including heterocyclic aryl), the intermediate of formula B can be obtained by various aryl-aryl coupling reactions, such as the Suzuki reaction of arylboronic acid derivatives with their corresponding haloaryls in the presence of a palladium catalyst. In this disclosure, both components of the coupling reaction can be arylboronic acid derivatives or their corresponding haloaryls, for example, compounds 53 and 54, which couple to form the intermediate of formula B.

[0419] [ka]

[0420] Intermediate B is transformed into intermediate B' via a transformation process from intermediate A to intermediate A', similar to the process described above. If R is an alicyclic amine, then free amine 50 (or compound 49 is deprotected to obtain the corresponding free amine) and p-nitrobenzene

[0421] [ka]

[0422] Compound 51 is then produced by aromatic ring substitution in the presence of a weak base (e.g., potassium carbonate).

[0423] [ka]

[0424] The nitro group can be converted with palladium-carbon or an inorganic reducing agent (e.g., sodium dithionite) to obtain the aniline derivative of formula B.

[0425] [ka]

[0426] Intermediate B is reacted with oxaloyl chloride monoester, followed by hydrolysis to form the compound of formula B'.

[0427] [ka]

[0428] 3. Preparation of Exemplary Compounds of the Disclosure The exemplary compounds of this disclosure can be prepared by converting oxalic acid intermediate A' or B' to an active intermediate acyl chloride, and then reacting it with B or A, respectively. Alternatively, the exemplary compounds can be obtained by reacting free acid A' or B' with free amine B or A, respectively, in the presence of an amide condenser (e.g., T3P, DCC, PyBOP, etc.). Generally, an organic base (e.g., triethylamine, diisopropylethylamine, etc.) is used concurrently.

[0429] [ka]

[0430] Unless otherwise specified, the reactions in the above general synthesis methods are usually carried out under conventional conditions known to those skilled in the art, or under conditions recommended by the manufacturer. [Examples]

[0431] Specific Embodiments The present invention is further described below with reference to embodiments. It should be noted that the following embodiments are illustrative and should not be considered to limit the scope of protection of the present invention.

[0432] In subsequent descriptions of the embodiments, the following abbreviations are used: ACN (acetonitrile); AcOH (acetic acid); AgO (silver oxide); b / d / t / q (NMR peaks, b (broad peak) / d (double line) / t (triple line) / q (quadruplicate line); Boc (tert-butoxycarbonyl); BSA (bovine serum albumin); t-BuONa (tert-butoxide sodium); Bu2SnO (di-n-butyltin oxide); t-Buxphos-PdG3 (methanesulfonic acid (2-di-tert-butyl) Phosphine-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-(phosphoryloxy)-2H-1-benzopyran-2-one); (CF3SO2)2O (tri Fluoromethanesulfonic anhydride); CO2 (carbon dioxide); Cs2CO3 (cesium carbonate); CuI (cuprous iodide); Cu(OAc)2 (copper acetate); CYP (cytochrome proteins, e.g., CYP1A2 / CYP2B6 / CYP2C8 / CYP2C9 / CYP2C19 / 2D6 / CYP3A4); DCC (dicyclohexylcarbodiimide); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropyl alcohol) Tylamine); DMEM (cell culture medium); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DMSO-d6 (hexatetrahydrogenated dimethyl sulfoxide); dppf (1,1'-bis(diphenylphosphine)ferrocene); DTT (dithiothreitol); E (double bond trans isomer); EA (ethyl acetate); EDTA (ethylenediaminetetraacetic acid); hERG (Kv11 encoded in the hERG gene).1. Potassium ion channel conduction); Et (ethyl); EtOH (ethanol); FBC (Fed batch fermentation); FCC (high-performance column chromatography); g (grams); GLP (Good Practice for Non-clinical Testing); h (hours); HATU (2-(7-azobenzotriazole)-N,N,N',N'-tetramethylureahexafluorophosphate); HCl (hydrogen chloride); HCl-MeOH (hydrogen chloride in methanol); HEPES (4-hydroxyethylpiperazine ethanesulfonic acid); HFiPA (hexafluoroisopropanol); HLM (human liver microsomes); H2O (water); H3PO4 (phosphate); H2SO4 (sulfuric acid); Hz (Hertz); I2 (iodine); IC50 (inhibitory concentration at 50% inhibition); IV (intravenous administration); IMDM (cell culture medium); J (nuclear magnetic resonance coupling constant); K2CO3 (potassium carbonate). ; Km (Michaelis constant for enzymatic reactions); KOH (sodium hydroxide); L (liters); LC-MS (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 (methane iodide); MEM (cell culture medium); MeMgBr (methylmagnesium bromide); MeOH (methanol); methanol-d4 (tetradeuterated methanol); mg (milligrams); MHz (megahertz); min (minute); mL (milliliters); mmol (millimoles); MOM (methoxymethyl ether); MS-ESI (electrospray ionization mass spectrometry); MTBE (methyl tert-butyl ether); m / z (mass-charge ratio); N2 (nitrogen); NaBH(OAc)3 (sodium triacetoxyborohydride); 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) 1 H (proton) / 13 C(carbon - 13) / 19 F (Fluorine-19)); pNPP (p-nitrophenyl phosphate disodium); PdCl2 (dtbpf) (1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride); Pd(dppf)Cl2 (1,1'-bis(diphenylphosphine)ferrocene palladium dichloride); Pd(OAc) (palladium acetate); Pd(PPh3)4 (tetraphenylphosphine palladium); Pd(PPh3)2Cl2 (tetraphenylphosphine palladium dichloride); PE (petroleum ether); PhSO2Cl (benzenesulfonyl chloride); PO (oral administration); POCl3 (phosphorus oxychloride); PTP (protein tyrosine phosphatase, e.g., SHP1 (Src homologous region 2 protein tyrosine phosphatase 1) / SHP2 (Src homologous region 2 protein tyrosine phosphatase 2) / HePTP (hematopoietic protein tyrosine Phosphatase) / Laforin (EPM2A dextran phosphatase) / LMWPTP (low molecular weight protein tyrosine phosphatase) / LYP (lymphatic tyrosine phosphatase) / PTP1B (protein tyrosine phosphatase 1B) / PRL (liver regeneration phosphatase) / SSU72 (SSU72 protein phosphatase) / VHR (bispecific protein phosphatase 3) / FAP1 (S. parasanguinis adhesin) / STEP (striatal-dominantly expressed protein tyrosine phosphatase) / CDC14A (cyclin 14A) / CD45 (C-type protein tyrosine phosphatase receptor) / PP5 (protein phosphatase 5)); PyBOP (benzotriazole-1-yl-oxytripyrrolidine phosphonium); RT (room temperature); QT (time required for ventricular depolarization and repolarization); SiO 2(Silica gel); RFU (fluorescence intensity); rpm (revolutions per minute); T3P (1-propylphosphonic acid cyclic anhydride); TBAF (tetrabutylammonium fluoride); TEA (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 (Cis isomer of double bond); Zn (zinc); Zn(CN)2 (zinc cyanide); δ (nuclear magnetic resonance chemical shift); μL (microliter); μM (micromolar concentration); μmol (micromoles).

[0433] In the following examples, the synthesized compounds are given names and structures. Any discrepancies between the names and structures are unintentional. In these cases, the structure takes precedence. The experimental procedures in the following examples, where conditions are not specified, are generally carried out under standard conditions for such reactions or as recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight, liquid ratios are by volume, and all temperatures mentioned are given in Celsius.

[0434] Unless otherwise specified, all experimental materials and reagents used in the following examples are commercially available, prepared using conventional methods, or prepared using methods similar to those disclosed in this application. Unless otherwise stated, all reagents are used without further purification.

[0435] In the following examples, 1¹H-NMR spectra were recorded using a Bruker (400 MHz) instrument. Chemical shifts are expressed as δ(ppm) relative to the deuterated solvent peaks (CDCl3:δ=7.26 ppm; CD3OD:δ=3.31 ppm; DMSO-d6:δ=2.50 ppm). Liquid chromatography-mass spectrometry (LC-MS) was performed using an Aglient 1260LC-MS instrument equipped with an Aglient G6125B mass spectrometer. Gas chromatography-mass spectrometry (GC-MS) was performed using a Shimadzu GCMS-QP2010SE.

[0436] 1. Synthesis of intermediates Synthesis of intermediate AA1: 6-bromo-1-cyclopropyl-5-fluoro-1H-indole

[0437] [ka]

[0438] To a 20 mL DMF solution of 6-bromo-5-fluoro-1H-indole AA1-1 (1.00 g, 4.67 mmol) and cyclopropylboronic acid (1.20 g, 14.0 mmol), 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) were added, and the 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 subjected to silica gel column chromatography (PE / EA = 5 / 1) to obtain a yellow liquid AA1 (0.91 g, yield 77%). 1H NMR (400 MHz, CDCl3) δ 7.72-7.71 (m, 1H), 7.31 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 3.2 Hz, 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.

[0439] Synthesis of intermediate AA2: 2-(4-aminophenyl)-1-cyclobutyl-6-(1H-tetrazole-5-yl)-1H-indole-5-ol

[0440] [ka]

[0441] Step 1: Methyl 1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid Cyclobutyl bromide (5.05 g, 37.4 mmol) was added 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). The resulting mixture was heated to 85°C under nitrogen atmosphere and stirred for 16 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was washed with an aqueous lithium chloride solution and concentrated. The filtrate was purified by silica gel column chromatography (PE / EA=4 / 1) to obtain a pale green oily substance AA2-2 (2.3 g). MS-ESI[M+H] + :260.0. Step 2: 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-methoxy-1H-indole-6-carboxylate methyl ester Palladium acetate (115 mg, 0.511 mmol) was added to a 25 mL DMF solution of methyl 1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid 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). The resulting mixture was heated to 40°C under nitrogen atmosphere and stirred for 16 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was washed with an aqueous lithium chloride solution and concentrated. The filtrate was purified by silica gel column chromatography (PE / EA = 65 / 35) to obtain a pale yellow solid AA2-3 (1.5 g). MS-ESI[M+H] + :451.1. Step 3: 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid Lithium hydroxide (223.5 mg, 5.33 mmol) was added to a mixture of methyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-methoxy-1H-indole-6-carboxylic acid ester AA2-3 (0.6 g, 1.33 mmol) in THF / MeOH / H2O=1 / 1 / 1 (12 mL). The resulting mixture was heated to 60°C and stirred for 2 hours. After this reaction was complete, the mixture was concentrated, the pH was adjusted to 7 with 1N hydrochloric acid, extracted with ethyl acetate (20 mL), and concentrated to obtain a white solid AA2-4 (580 mg). MS-ESI[M+H] + :437.1. Step 4: (6-Carbamoyl-1-cyclobutyl-5-methoxy-1H-indole-2-yl)phenyl)tert-butylcarbamate HATU (598.9 mg, 1.57 mmol) was added to a 5 mL solution of DMF containing 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-propanamine (650.2 mg, 1.57 mmol). The mixture was stirred at room temperature for 2 hours. After this reaction was complete, 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 obtain a pale yellow solid AA2-5 (550 mg). MS-ESI[M+H] + :436.1. Step 5: tert-butyl(4-(6-cyano-1-cyclobutyl-5-methoxy-1H-indole-2-yl)phenyl)carbamate (6-Carbamoyl-1-cyclobutyl-5-methoxy-1H-indole-2-yl)phenyl)carbamate tert-butyl ester AA2-5 (550 mg, 1.26 mmol) and triethylamine (817.9 mg, 8.08 mmol) were mixed in a DCM solution (6 mL) with trifluoroacetic anhydride (848.8 mg, 4.04 mmol) added dropwise under an ice-cold water bath. The mixture was stirred for 1 hour under nitrogen protection. After the reaction was complete, the solution was concentrated, ethyl acetate (20 mL) was added, the mixture was washed with aqueous sodium bicarbonate solution (10 mL), concentrated again, and purified by silica gel column chromatography (PE / EA = 7 / 3) to obtain a brown solid AA2 (250 mg). MS-ESI[M+H] + :418.1. Synthesis of intermediate AA3: tert-butyl(4-(6-cyano-1-cyclopropyl-5-fluoro-1H-indole-2-yl)cyclohexa-3-en-1-yl)carbamate

[0442] [ka]

[0443] Step 1: 6-bromo-5-fluoro-1-(benzenesulfonyl)-1H-indole Sodium hydride (0.90 g, 22.4 mmol) was added at 0°C to a solution of 6-bromo-5-fluoro-1H-indole AA1-1 (4.00 g, 18.7 mmol) in THF (60 mL) and stirred for 20 minutes. Then, benzenesulfonyl chloride (2.90 mL, 22.4 mmol) was added to the reaction mixture. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. The reaction was quenched by adding saturated aqueous solution of ammonium chloride (15 mL), and the mixture was extracted three times with ethyl acetate (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (PE / EA = 5 / 1) to obtain a white solid AA3-1 (6.0 g, yield 90%). 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (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). Step 2: 6-Bromo-5-fluoro-2-iodo-1-(benzenesulfonyl)-1H-indole To a solution of 6-bromo-5-fluoro-1-(phenylsulfonyl)-1H-indole AA3-1 (3.0 g, 8.5 mmol) in THF (80 mL), LDA (6.0 mL, 12.7 mmol) was added at -70 °C, and the mixture was stirred for 1.5 hours. Then, a solution of iodine (3.2 g, 12.7 mmol) in THF (15 mL) was added to the reaction mixture. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. The reaction was quenched by adding saturated aqueous solution of ammonium chloride (15 mL), and the mixture was extracted three times with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (PE / EA = 5 / 1) to obtain a pale yellow solid AA3-2 (2.0 g, yield 49%). 1H NMR (400 MHz, 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 = 8.0 Hz, 1H), 7.22(s, 1H). Step 3: 6-bromo-5-fluoro-2-iodo-1H-indole Potassium carbonate (4.0 g, 29.2 mmol) was added to a MeOH / H2O solution (80 mL, V / V=5 / 3) of 6-bromo-5-fluoro-2-iodo-1-(benzenesulfonyl)-1H-indole AA3-2 (1.4 g, 2.9 mmol). The resulting mixture was reacted overnight at 60°C. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (100 mL), washed with water (20 mL), and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (PE / EA=3 / 1) to obtain a pale yellow solid AA3-3 (0.7 g, yield 70%). 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.57-7.55 (m, 1H), 7.44 (d, J = 12.0 Hz, 1H), 6.67-6.66 (m, 1H). Step 4: 6-bromo-1-cyclopropyl-5-fluoro-2-iodo-1H-indole 6-bromo-5-fluoro-2-iodide-1H-indole AA3-3 (700 mg, 2.1 mmol) and cyclopropylboronic acid (525 mg, 6.2 mmol) were dissolved in DMF (20 mL) and then 2,2'-bipyridine (315 mg, 6.2 mmol), copper acetate (1.1 g, 6.2 mmol), and sodium carbonate (455 mg, 4.1 mmol) were added. The resulting mixture was reacted under oxygen atmosphere at 70°C for 16 hours. The reaction solution 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 subjected to silica gel column chromatography (PE / EA = 5 / 1) to obtain a white solid AA3-4 (350 mg, yield 44%). 1 H NMR (400 MHz, DMSO-d6) δ 7.82-7.80 (m, 1H), 7.45 (d, J = 12.0 Hz, 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. Step 5: tert-butyl(4-(6-bromo-1-cyclopropyl-5-fluoro-1H-indole-2-yl)cyclohexa-3-en-1-yl)carbamate Potassium carbonate (637 mg, 4.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (129 mg, 0.18 mmol) were added to an aqueous acetonitrile solution (40 mL, V / V=3 / 1) mixed with 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-1,3,2-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-yl) carbamate (656 mg, 2.0 mmol). The resulting mixture was heated in a microwave reactor at 85°C for 2 hours. The reaction mixture was cooled to room temperature, water (10 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 subjected to silica gel column chromatography (PE / EA = 1 / 1) to obtain a brownish-yellow solid AA3-5 (737 mg, yield 88%). 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 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. Step 6: tert-butyl(4-(6-cyano-1-cyclopropyl-5-fluoro-1H-indole-2-yl)cyclohexa-3-en-1-yl)carbamate To a solution of tert-butyl(4-(6-bromo-1-cyclopropyl-5-fluoro-1H-indole-2-yl)cyclohexa-3-en-1-yl)carbamate AA3-5 (700 mg, 1.54 mmol) in DMF (20 mL), zinc cyanide (238 mg, 2.03 mmol), 1,1'-bis(diphenylphosphine)ferrocene (113 mg, 0.20 mmol), zinc powder (160 mg, 2.46 mmol), and tris(dibenzylideneacetone)dipalladium (186 mg, 0.20 mmol) were added. The resulting mixture was reacted at 110 °C for 16 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (60 mL). It was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography (PE / EA=1 / 1) to obtain a pale yellow solid AA3 (0.3 g, yield 49%). 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 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. Synthesis of intermediate AA4: tert-butyl(3-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0444] [ka]

[0445] Step 1: 5-amino-4-bromo-2-fluorobenzonitrile Sodium dithionite (5.68 g, 32.6 mmol) was added to a mixed solution of 4-bromo-2-fluoro-5-nitrobenzene AA4-1 (1 g, 4.1 mmol) in tetrahydrofuran (10 mL), ethanol (10 mL), and water (10 mL). The reaction mixture was stirred at 75°C for 3 hours. Then, ethyl acetate (50 mL) and water (10 mL) were added, the mixture was separated, the organic phase was dried and concentrated, and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain 5-amino-4-bromo-2-fluorobenzonitrile AA4-2 (540 mg, yield 61%). MS-ESI[M+H] + :215.9. Step 2: 4-Bromo-5-(cyclobutylamino)-2-fluorobenzonitrile To a solution of 5-amino-4-bromo-2-fluorobenzonitrile AA4-2 (500 mg, 2.32 mmol, 1 equivalent) and cyclobutanone (1.1 equivalents) in dichloromethane (15 mL), acetic acid (139.6 g, 2.32 mmol) and sodium borohydride acetate (986 mg, 4.65 mmol) were added, and the reaction mixture was stirred at room temperature for 16 hours. Then, dichloromethane (20 mL) and water (10 mL) were added, the mixture was separated, the organic phase was dried, concentrated, and purified by column chromatography (PE / EA=4 / 1) to obtain 4-bromo-5-(cyclobutylamino)-2-fluorobenzonitrile AA4-3 (240 mg, yield 38%). MS-ESI[M+H] + :269.0. Step 3: tert-butyl(3-((4-cyano-2-(cyclobutylamino)-5-fluorophenyl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate To a solution of 4-bromo-5-(cyclobutylamino)-2-fluorobenzonitrile AA4-3 (240 mg, 0.89 mmol) and N-{3-ethynylbicyclo[1.1.1]pentan-1-yl}carbamate tert-butyl ester (203 mg, 0.98 mmol) in triethylamine (5 mL), cuprous iodide (139.6 g, 2.32 mmol) and bis(triphenylphosphine)palladium dichloride (62.6 mg, 0.09 mmol) were added, and the reaction mixture was stirred at 80°C for 3 hours. The mixture was then concentrated and purified by silica gel column chromatography (PE / EA=5 / 2) to obtain (3-((4-cyano-2-(cyclobutylamino)-5-fluorophenyl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester AA4-4 (210 mg, yield 60%). MS-ESI[M+H] + :396.2. Step 4: tert-butyl(3-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate Potassium hydroxide (179 mg, 31.9 mmol) was added to a solution of (3-((4-cyano-2-(cyclobutylamino)-5-fluorophenyl)ethynyl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester AA4-4 (180 mg, 0.46 mmol) in N-methylpyrrolidone (6 mL), and the reaction was stirred at 80°C for 3 hours. Then, ethyl acetate (20 mL) and water (10 mL) were added, the mixture was separated, the organic phase was dried and concentrated, and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain (3-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate tert-butyl ester AA4 (140 mg, yield 78%). MS-ESI[M+H] + :396.2. Synthesis of intermediate AA5:tert-butyl(1-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)piperidine-4-yl)carbamate

[0446] [ka]

[0447] Step 1: tert-butyl(1-(6-bromo-1-cyclobutyl-5-fluoro-3-iodo-1H-indole-2-yl)piperidine-4-yl)carbamate Cesium carbonate (1.82 g, 5.6 mmol) and iodine (1.4 g, 5.6 mmol) were added to a mixture of 6-bromo-1-cyclobutyl-5-fluoro-1H-indole A1-2 (750 mg, 2.8 mmol) and tert-butylpiperidine-4-ylcarbamate (1.12 g, 5.6 mmol) in methanol (10 mL) and dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 16 hours. Then, dichloromethane (30 mL) and water (10 mL) were added, and the mixture was separated. The organic phase was washed with saturated sodium thiosulfate (10 mL) and saturated brine (10 mL), respectively, dried, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain (1-(6-bromo-1-cyclobutyl-5-fluoro-3-iodo-1H-indole-2-yl)piperidine-4-yl)carbamate tert-butyl ester AA5-1 (400 mg, yield 24%). MS-ESI[M+H] + :592.1. Step 2: tert-butyl(1-(6-bromo-1-cyclobutyl-5-fluoro-1H-indole-2-yl)piperidine-4-yl)carbamate A mixture of tert-butyl 1-(6-bromo-1-cyclobutyl-5-fluoro-1H-indole-2-yl)piperidine-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 mixed with ammonium chloride (108 mg, 2.03 mmol). The reaction was heated under reflux and stirred for 16 hours. Then, ethyl acetate (20 mL) and water (10 mL) were added, the mixture was separated, the organic phase was washed with saturated brine, dried, concentrated, and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain 300 mg (96% yield) of tert-butyl 1-(6-bromo-1-cyclobutyl-5-fluoro-1H-indole-2-yl)piperidine-4-yl)carbamate AA5-2. MS-ESI[M+H] + :466.2. Step 3: tert-butyl(1-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)piperidine-4-yl)carbamate To a solution of tert-butyl 1-(6-bromo-1-cyclobutyl-5-fluoro-1H-indole-2-yl)piperidine-4-yl)carbamate AA5-2 (300 mg, 0.64 mmol) and zinc cyanide (45 mg, 0.38 mmol) in N-methylpyrrolidone (10 mL), tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) and 1,1'-bis(diphenylphosphine)ferrocene (14 mg, 0.026 mmol) were added, and the reaction was carried out under nitrogen protection, stirred in a microwave at 150 °C for 16 hours. Next, ethyl acetate (20 mL) and water (10 mL) were added, the mixture was separated, the organic phase was washed with saturated brine (10 mL), dried, concentrated, and subjected to silica gel column chromatography (PE / EA = 3 / 2) to obtain (1-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)piperidine-4-yl)carbamate tert-butyl ester AA5 (150 mg, yield 57%). MS-ESI[M+H] + :413.2. Synthesis of intermediate AA6:tert-butyl 2-bromo-4-cyano-5-fluorophenyl-4-(ethynylphenyl)carbamate

[0448] [ka]

[0449] Step 1: 2-Bromo-4-cyano-5-fluorophenyltrifluoromethanesulfonic acid To a solution of 5-bromo-2-fluoro-4-hydroxybenzonitrile AA6-1 (5.4 g, 25 mmol) and trifluoromethanesulfonic acid anhydride (10.6 g, 37.5 mmol) in DCM (100 mL), TEA (5.05 g, 50 mmol) was slowly added dropwise under an ice bath. The mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into water (200 mL) and extracted twice with DCM (200 mL each time). The organic phases were combined, washed twice with saturated brine (200 mL each time), 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 a yellow oily substance AA6-2 (8.17 g). Step 2: 2-Bromo-4-cyano-5-fluorophenyl-4-(ethynylbenzene)carbamate tert-butyl ester To a solution of compound AA6-2 (8.17 g, 23.5 mmol) and tert-butyl 4-(ethynylphenyl)carbamate (5.35 g, 24.65 mmol) in DMF (100 mL), bis(triphenylphosphine)palladium dichloride (825 mg, 1.2 mmol), cuprous iodide (890 mg, 4.7 mmol), and triethylamine (9.5 g, 94 mmol) were added, and the reaction was stirred at room temperature for 2 hours under nitrogen protection. Then, ethyl acetate (200 mL) and water (50 mL) were added, and the mixture was separated. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM / PE=1 / 1) to produce tert-butyl 2-bromo-4-cyano-5-fluorophenyl-4-(ynynebenzene))carbamate AA6 (8 g). MS-ESI[M-55] + :360.3. Synthesis of intermediate AA7: 2-(4-tert-butoxycarbonylaminophenyl)-5-fluoro-1-(1-methylcyclobutyl)-1H-indole-6-carbonitrile

[0450] [ka]

[0451] To a solution of tert-butyl 2-bromo-4-cyano-5-fluorophenyl-4-(ethynylbenzene)carbamate AA6 (5 g, 12 mmol) and 1-methylcyclobutan-1-amine hydrochloride (1.75 g, 14.45 mmol) in N,N-dimethylformamide (50 mL), 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 tert-butoxide sodium (3.45 g, 36 mmol) were added. The mixture was heated to 65°C and stirred under nitrogen protection for 5 hours. The reaction mixture was filtered and ethyl acetate (100 mL) and water (20 mL) were added. The mixture was separated, the organic phase was dried and concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 2-(4-tert-butoxycarbonylaminophenyl)-5-fluoro-1-(1-methylcyclobutyl)-1H-indole-6-carbonitrile AA7 (2.2 g). MS-ESI[M-55] + :364.1.

[0452] Using the same method as for intermediate AA7, the following intermediates AA8 and AA9 were prepared.

[0453] [Table 5]

[0454] Synthesis of intermediate AA10: tert-butyl(4-(6-cyano-5-fluoro-1-(1-methylcyclopropyl)-1H-indole-2-yl)phenyl)carbamate

[0455] [ka]

[0456] Step 1: tert-butyl(4-((4-cyano-5-fluoro-2-((1-methylcyclopropyl)amino)phenyl)ethynyl)carbamate A solution of tert-butyl(4-((2-bromo-4-cyano-5-fluorophenyl)ethynyl)carbamate AA9 (4g, 9.6 mmol) and 1-methylcyclopropylamine hydrochloride (1.55g, 14.4 mmol) in 1,4-dioxane (10 mL) contains tris(dibenzylideneacetone)dipalladium (176 mg, 0.20 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanethracene) (223 mg, 0.38 mmol), and tert-butoxide sodium (2.8 g, 28 0.9 mmol) was added. The reaction mixture was heated and stirred under reflux and nitrogen protection for 16 hours. Then, ethyl acetate (20 mL) and water (10 mL) were added, the mixture was separated, the organic phase was washed with saturated brine (10 mL), dried, concentrated, and purified by silica gel column chromatography (PE / EA=8 / 1) to obtain 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. Step 2: tert-butyl(4-(6-cyano-5-fluoro-1-(1-methylcyclopropyl)-1H-indole-2-yl)phenyl)carbamate To 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), potassium hydroxide (700 mg, 12.5 mmol) was added, and the reaction mixture was stirred at 80°C for 2 hours. Then, ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was separated. The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain tert-butyl(4-(6-cyano-5-fluoro-1-(1-methylcyclopropyl)-1H-indole-2-yl)phenyl)carbamate AA10 (840 mg, yield 83%). MS-ESI[M+H] + :406.2. Synthesis of intermediate AA11: tert-butyl(4-(2-cyano-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl) carbamate

[0457] [ka]

[0458] Step 1: 5-Bromo-2-chloro-N-cyclobutylpyrimidine-4-amine A solution of cyclobutylamine (780 mg, 11.0 mmol) in dichloromethane (5 mL) was added dropwise at 0°C to a solution of 5-bromo-2,4-dichloropyrimidine AA11-1 (2.50 g, 11.0 mmol) and N,N-diisopropylethylamine (2.83 g, 22.0 mmol) in dichloromethane (2.55 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 85 / 15) to obtain a white solid AA11-2 (2.5 g, yield 89%). MS-ESI[M+H] + :263.1. Step 2: tert-butyl(4-((2-chloro-4-(cyclobutylamino)pyrimidine-5-yl)ethynyl)phenyl)carbamate 5-Bromo-2-chloro-N-cyclobutylpyrimidine-4-amine AA11-2 (511 mg, 1.95 mmol), (4-ethynylphenyl)carbamate tert-butyl ester (507 mg, 2.33 mmol), cuprous iodide (74 mg, 0.39 mmol), and triethylamine (788 mg, 7.78 mmol) were dissolved in DMF (15 mL) and bis(triphenylphosphine)palladium(II) dichloride (68.3 mg, 0.097 mmol) were added. The resulting mixture was heated to 80°C and stirred under nitrogen atmosphere for 4 hours. After the reaction was complete, 50 mL of ethyl acetate and 50 mL of water were added. The organic phase was washed with 10 mL of brine, concentrated, and purified by silica gel column chromatography (PE / THF = 5 / 1) to obtain a yellow solid AA11-3 (650 mg, yield 83%). MS-ESI[M+H] + :399.1. Step 3: tert-butyl(4-(2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)carbamate 1M tetrabutylammonium fluoride in tetrahydrofuran (3.03 mL, 3.03 mmol) was added to a solution of tert-butyl 4-(2-chloro-4-(cyclobutylamino)pyrimidine-5-yl)ethynyl)phenyl)carbamate (550 mg, 1.38 mmol) in tetrahydrofuran (8 mL). The resulting mixture was heated to 75°C and stirred for 6 hours. After the reaction was complete, the mixture was cooled and ethyl acetate (30 mL) and water (30 mL) were added. The organic phase was washed with brine (10 mL), concentrated, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain a yellow solid AA11-4 (230 mg, yield 41%). MS-ESI[M+H] + :399.1. Step 4: tert-butyl(4-(2-cyano-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-6-yl)phenyl)carbamate To a solution of tert-butyl(4-(2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine-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(diphenylphosphine)ferrocene (22 mg, 0.04 mmol) in N-methylpyrrolidone (10 mL), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) was added. The resulting mixture was heated to 180 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled and ethyl acetate (30 mL) and water (20 mL) were added. The organic phase was washed with brine (10 mL), concentrated, and purified by silica gel column chromatography (PE / THF=5) (0 / 50) to produce a yellow solid AA11 (180 mg, yield 62%). MS-ESI[M+H] + :390.1. Synthesis of intermediate AA12: tert-butyl(4-(6-cyano-1-cyclobutyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-yl)carbamate

[0459] [ka]

[0460] Step 1: 1-Cyclobutyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile To a solution 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) in DMF (6 mL), cyclobutyl bromide (1.26 g, 9.31 mmol) was added. The resulting mixture was heated to 90°C and stirred under nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was washed three times with aqueous lithium chloride (10 mL). The filtrate was concentrated and purified by silica gel column chromatography (PE / EA = 85 / 15) to obtain a pale green solid AA12-2 (600 mg, yield 89%). MS-ESI[M+H] +:216.1. Step 2: tert-butyl(4-(6-cyano-1-cyclobutyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-yl)carbamate Palladium acetate (23.4 mg, 0.104 mmol) was added 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). The resulting mixture was microwave-heated to 90°C and stirred under nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was washed three times with aqueous lithium chloride solution (10 mL). The filtrate was concentrated and purified by silica gel column chromatography (PE / DCM = 1 / 3) to obtain a pale yellow solid AA12 (380 mg, yield 62%). MS-ESI[M+H] + :407.2.

[0461] Using the synthesis method for intermediate AA12, the following intermediates AA13 to AA15 were prepared.

[0462] [Table 6]

[0463] Synthesis of intermediate AA16: tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(N'-hydroxyaminomethyliminoyl)-1H-indole-2-yl)phenyl) carbamate

[0464] [ka]

[0465] Triethylamine (747 mg, 7.38 mmol) was added to an ethanol solution (20 mL) of 4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate tert-butyl ester AA16-1 (500 mg, 1.23 mmol) and hydroxylamine hydrochloride (514 mg, 7.4 mmol). The resulting mixture was heated to 80°C and stirred under nitrogen for 16 hours. The reaction mixture 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, concentrated, and purified by silica gel column chromatography (PE / EA=1 / 1) to obtain product AA16 (450 mg, yield 83%) as a yellow solid. MS-ESI[M+H] + :439.1.

[0466] Synthesis of intermediate AA17: tert-butyl(4-(5-cyano-3-cyclobutyl-6-fluorobenzofuran-2-yl)phenyl)carbamate

[0467] [ka]

[0468] Step 1: (5-bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)methyl ketone To a 1,2-dichloroethane solution (20 mL) of 4-bromo-3-fluorophenol AA17-1 (1.0 g, 5.2 mmol) and anhydrous aluminum trichloride (1.05 g, 7.9 mmol), cyclobutaneacyl chloride (0.68 g, 5.7 mmol) was added dropwise. The resulting mixture was heated to 75°C and stirred under nitrogen atmosphere for 3 hours. After the reaction was complete, the mixture was cooled and poured into a diluted aqueous hydrochloric acid solution (15 mL) under an ice bath. The mixture was filtered, the filtrate was washed with brine (10 mL), concentrated, and purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain a colorless oily substance AA17-2 (1.2 g, yield 84%). MS-ESI[M+H] + :274.1. Step 2: Methyl 2-(4-bromo-2-(cyclobutoxycarbonyl)-5-fluorophenoxy)acetate (5-bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)ketone AA17-2 (4.0 g, 14.6 mmol) was dissolved in DMF (15 mL) and 60% sodium hydride (0.878 g, 22 mmol) was added. 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 mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted twice with ethyl acetate (30 mL). The mixture was concentrated and purified by silica gel column chromatography (PE / EA = 85 / 15) to obtain a yellow solid AA17-3 (3.5 g, yield 69%). MS-ESI[M+H] + :346.1. Step 3: 2-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenoxy)acetic acid Sodium hydroxide (573 mg, 17.7 mmol) was added to a solution of methyl 2-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenoxy) acetate AA17-3 (3.3 g, 9.56 mmol) in THF / H2O=3 / 1. The mixture was stirred at room temperature for 6 hours. After the reaction was complete, 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 and dried to obtain a yellow solid AA17-4 (3.0 g, 94% yield). MS-ESI[M+H] + :332.1. Step 4: 5-bromo-3-cyclobutyl-6-fluorobenzofuran Sodium acetate (1.57 g, 19.1 mmol) was added to a solution of 2-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenoxy)acetic acid AA17-4 (3.16 g, 9.54 mmol) in acetic anhydride (25 mL). The resulting mixture was heated to 140 °C and stirred for 16 hours. After the reaction was complete, the mixture was concentrated and ethyl acetate (30 mL) and water (30 mL) were added. The pH was adjusted to 9.0 with 1 N sodium hydroxide aqueous solution (50 mL). The organic phase was concentrated and dried, and purified by silica gel column chromatography (PE / EA = 50 / 50) to obtain AA17-5 (2.0 g, yield 77%). MS-ESI[M+H] + :270.1. Step 5: 3-Cyclobutyl-6-Fluorobenzofuran-5-Carbonitrile 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(diphenylphosphine)ferrocene (165 mg, 0.297 mmol) and tris(dibenzylideneacetone)dipalladium (136 mg, 0.148 mmol) were added. The resulting mixture was heated at 120°C for 16 hours under nitrogen atmosphere. After the reaction was complete, the mixture was cooled and ethyl acetate (40 mL) and water (40 mL) were added. The mixture was filtered, the filtrate was washed with brine (15 mL), concentrated and dried, and purified by silica gel column chromatography (PE / EA = 60 / 40) to obtain AA17-6 (1.2 g, yield 75%). MS-ESI[M+H] + :216.1. Step 6: 2-Bromo-3-cyclobutyl-6-fluorobenzofuran-5-carbonitrile N-bromosuccinimide (1.27 g, 7.13 mmol) was added to a solution of 3-cyclobutyl-6-fluorobenzofuran-5-carbonitrile (AA17-6) (1.28 g, 5.95 mmol) in DMF (15 mL). The resulting mixture was reacted at room temperature for 16 hours. After the reaction was complete, ethyl acetate (20 mL) and water (30 mL) were added, the organic phase was washed with brine (15 mL), concentrated and dried, and purified by silica gel column chromatography (PE / EA = 85 / 15) to obtain AA17-7 (1.31 g, yield 74%). MS-ESI[M+H] + :294.1. Step 7: tert-butyl(4-(5-cyano-3-cyclobutyl-6-fluorobenzofuran-2-yl)phenyl)carbamate 1,1'-bis(diphenylphosphine)ferrocene)palladium dichloride (325 mg, 0.445 mmol) was added 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). The resulting mixture was heated at 100 °C for 3 hours under nitrogen atmosphere. After the reaction was complete, 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 and dried, and purified by silica gel column chromatography (PE / EA = 70 / 30) to obtain AA17 (1.34 g, yield 74%). MS-ESI[M+H] + :407.1.

[0469] Synthesis of intermediate AA18: 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbazidoimidothiomethyl ester

[0470] [ka]

[0471] Step 1: tert-butyl(4-(6-carbamoyl-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate Hydrogen peroxide (2 mL) was added to a solution of tert-butyl(4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl) carbamate AA18-1 (200 mg, 0.5 mmol) and potassium carbonate (103 mg, 0.7 mmol) in dimethyl sulfoxide (10 mL). The resulting mixture was stirred under nitrogen atmosphere for 2 hours. After the reaction was complete, ice water (80 mL) was added to precipitate the solid, which was then filtered to obtain a white solid AA18-2 (200 mg, 97% yield). MS-ESI[M+H] + :424.2. Step 2: tert-butyl(4-(6-thiocarbamoyl-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate Lawson's reagent (400 mg, 1 mmol) was added to a toluene solution (5 mL) of tert-butyl (4-(6-carbamoyl-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl) carbamate AA18-2 (200 mg, 0.47 mmol). The resulting mixture was heated to 100°C and stirred under nitrogen for 16 hours. After the reaction was complete, the mixture was directly evaporated to dryness and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain product AA18-3 (200 mg, 96% yield) as a yellow solid. MS-ESI[M+H] + :440.1. Step 3: Methyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbamimidothioate Methyl iodide (130 mg, 0.1 mmol) was added to a mixed solution of tert-butyl 4-(4-(6-carbamoyl-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate AA18-3 (200 mg, 0.4 mmol) in tetrahydrofuran (5 mL). The resulting mixture was reacted for 3 hours. The mixture was then concentrated directly and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain product AA18 (100 mg, yield 55%) as a yellow solid. MS-ESI[M+H] + :454.2.

[0472] Synthesis of intermediate AA19: tert-butyl(4-(5-cyano-3-cyclobutyl-6-fluorobenzo[b]thiophen-2-yl)phenyl) carbamate

[0473] [ka]

[0474] Step 1: (5-bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)ketone To a 1,2-dichloroethane solution (40 mL) of 4-bromo-3-fluorophenol AA19-1 (5 g, 26.18 mmol) and anhydrous aluminum trichloride (5.24 g, 39.27 mmol), cyclobutyl acyl chloride (3.42 g, 28.8 mmol) was added. The resulting mixture was heated to 85°C and stirred under nitrogen for 4 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, and 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 product AA19-2 (5 g, 70% yield). MS-ESI[M+H] + :273.2. Step 2: O-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)dimethylaminothioformate (5-bromo-4-fluoro-2-hydroxyphenyl)(cyclobutyl)ketone AA19-2 (5 g, 18 mmol) was dissolved in DMF (40 mL) and 1,4-diazabicyclo[2,2,2]octane (4.11 g, 37 mmol) and dimethylaminothiocarbamoyl chloride (4.53 g, 37 mmol) were added. 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 product AA19-3 (6.2 g, 96% yield). MS-ESI[M+H] + :360.2. Step 3: S-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)dimethylaminothioformate O-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)dimethylaminothioformate AA19-3 (100 mg, 0.28 mmol) was heated to 210°C and reacted for 2 hours. This reaction solution was used directly in the next reaction. Step 4: (5-bromo-4-fluoro-2-mercaptophenyl)(cyclobutyl)ketone Potassium hydroxide (93 mg, 1.7 mmol) was added to a methanol solution (3 mL) of S-(4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)dimethylaminothioformate AA19-4 (100 mg, 0.28 mmol). The resulting mixture was heated to 70°C and stirred under nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, water (100 mL) and hydrochloric acid (1 N, 1.8 mL) were added, and 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 product AA19-5 (65 mg, yield 96%). MS-ESI[M+H] + :289.2. Step 5: 2-((4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)thio)acetic acid (5-bromo-4-fluoro-2-mercaptophenyl)(cyclobutyl)ketone AA19-5 (65 mg, 0.23 mmol) was dissolved in acetonitrile (4 mL), to which 2-bromoacetic acid (38 mg, 0.28 mmol) and potassium carbonate (62 mg, 0.45 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (15 mL) was added to the reaction mixture, and it was 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 product AA19-6 (70 mg, yield 85%). MS-ESI[M+H] + :346.2. Step 6: 5-bromo-3-cyclobutyl-6-fluorobenzo[b]thiophene Sodium acetate (87 mg, 0.64 mmol) was added to a 3 mL acetic acid solution of 2-((4-bromo-2-(cyclobutylcarbonyl)-5-fluorophenyl)thio)acetic acid AA19-6 (74 mg, 0.21 mmol). The resulting mixture was heated to 140°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, then water (20 mL) and sodium hydroxide solution (1 N, 2 mL) were 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 obtain product AA19-7 (34 mg, yield 57%). MS-ESI[M+H] + :285.2. Step 7: 3-Cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile To a 1 mL DMF solution of 5-bromo-3-cyclobutyl-6-fluorobenzo[b]thiophene AA19-7 (20 mg, 0.07 mmol), zinc cyanide (5 mg, 0.04 mmol), 1,1'-bis(diphenylphosphine)ferrocene (1.5 mg, 0.002 mmol), zinc (0.6 mg, 0.008 mmol), and tris(dibenzylideneacetone)dipalladium (1.3 mg, 0.02 mmol) were added. 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 obtain product AA19-8 (15 mg, yield 80%). MS-ESI[M+H] + :232.2. Step 8: 2-Bromo-3-cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile 3-Cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile AA19-8 (300 mg, 1.3 mmol) was dissolved in acetic acid (6 mL), to which brine (829 mg, 5.2 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to room temperature, then water (20 mL) and sodium thiosulfate (15 mL) were 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=6 / 1) to obtain product AA19-9 (320 mg, yield 80%). MS-ESI[M+H] + :310.2. Step 9: 3-Cyclobutyl-6-fluorobenzo[b]thiophene-5-carbonitrile To a mixed 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), (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (366 mg, 1.55 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (75 mg, 0.1 mmol), and sodium bicarbonate (260 mg, 3.1 mmol) were added. 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 obtain product AA19 (260 mg, yield 61%). MS-ESI[M+H] + :423.2.

[0475] Synthesis of intermediate A1: 4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)aniline

[0476] [ka]

[0477] Step 1: 6-bromo-1-cyclobutyl-5-fluoro-1H-indole Cesium carbonate (6.85 g, 21.0 mmol) was added 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). 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. The mixture was separated. The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 6-bromo-1-cyclobutyl-5-fluoro-1H-indole A1-2 (1.7 g, 91% yield). MS-ESI[M+H]+ :267.9. Step 2: 1-Cyclobutyl-5-fluoro-1H-indole-6-carbonitrile 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), cuprous cyanide (1.13 g, 12.7 mmol) was added. The mixture was heated to 180 °C and stirred for 3 hours under nitrogen protection and microwave irradiation. The reaction mixture was filtered and ethyl acetate (30 mL) and water (10 mL) were added. The mixture was separated. The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA=8 / 1) to obtain 1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile A1-3 (1.1 g, yield 81%). MS-ESI[M+H] + :215.0. Step 3: tert-butyl(4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate 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), palladium acetate (57.6 mg, 0.26 mmol) was added, followed by silver oxide (892 mg, 3.85 mmol). The mixture was heated to 50°C and stirred under nitrogen protection for 16 hours. The reaction mixture was filtered, and ethyl acetate (60 mL) and water (10 mL) were added. The mixture was separated, the organic phase was dried and concentrated, and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate tert-butyl ester A1-4 (950 mg, yield 46%). MS-ESI[M+H] + :406.1. Step 4: 2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile (4-(6-cyano-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate tert-butyl ester A1-4 (950 mg, 2.34 mmol) was dissolved in dichloromethane (10 mL), to which trifluoroacetic acid (2 mL) was added, 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. Trifluoroacetic acid was then neutralized with saturated sodium bicarbonate. The mixture was separated from the organic phase. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbonitrile A1-5 (700 mg, 98% yield). MS-ESI[M+H] + :306.0. Step 5: 4-(1-Cyclobutyl-5-Fluoro-6-(1H-Tetrazole-5-yl)-1H-Indole-2-yl)Aniline 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), azidotrimethylsilane (226 mg, 1.96 mmol) and dibutyltin oxide (16.2 mg, 0.065 mmol) were added. The tube was sealed and heated to 120°C, and stirred for 16 hours. The reaction product was concentrated and purified by silica gel column chromatography (MeOH / DCM = 1 / 15) to obtain 4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)aniline A1 (100 mg, yield 44%). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 5.8 Hz, 1H), 7.55 (d, J = 11.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.5 Hz, 2H), 6.41 (d, J MS-ESI[M+H] + :349.1.

[0478] Using the synthesis method for intermediate A1, the following intermediates A2 to A8 were prepared.

[0479] [Table 7]

[0480] Synthesis of intermediate A9: 2-(4-aminophenyl)-1-cyclobutyl-6-(1H-tetrazole-5-yl)-1H-indole-5-ol

[0481] [ka]

[0482] Step 1: 2-(4-aminophenyl)-1-cyclobutyl-5-hydroxy-1H-indole-6-carbonitrile (4-(6-cyano-1-cyclobutyl-5-methoxy-1H-indole-2-yl)phenyl)carbamate tert-butyl ester AA2 (160 mg, 0.504 mmol) was dissolved in 1,2-dichloroethane (4 mL), to which boron tribromide (624 mg, 2.49 mmol) was added dropwise in an ice bath. The mixture was heated to 50°C and stirred under nitrogen protection for 5 hours. After the reaction was complete, the temperature was lowered to 0°C in an ice bath, and the mixture was quenched and concentrated by adding methanol dropwise, followed by the addition of ethyl acetate (15 mL). The mixture was washed with aqueous sodium bicarbonate (5 mL) and concentrated. The solution was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain a pale yellow solid A9-1 (60 mg). MS-ESI[M+H] + :304.0. Step 2: 2-(4-aminophenyl)-1-cyclobutyl-6-(1H-tetrazol-5-yl)-1H-indole-5-ol 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) solution (1.5 mL) were combined with azidotrimethylsilane (91.2 mg, 791 μmol). The mixture was heated to 120 °C and stirred for 48 hours. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (DCM / MeOH = 92 / 8) to obtain a pale yellow solid A9 (65 mg). MS-ESI[M+H] + :347.0.

[0483] Synthesis of intermediate A10: 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonylacetic acid

[0484] [ka]

[0485] Step 1: 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonyl acetate methyl ester 4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)aniline A1 (100 mg, 0.29 mmol) and triethylamine (58 mg, 0.57 mmol) were dissolved in tetrahydrofuran (5 mL), to which monomethyl oxaloyl chloride (37 mg, 0.30 mmol) was added dropwise under ice bath conditions. The mixture was 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 obtain 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonyl acetate methyl ester A10-1 (110 mg, yield 88%). MS-ESI[M+H] + :435.1. Step 2: 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonylacetic acid To a mixed solution of 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonylacetic acid methyl ester A10-1 (99 mg, 0.23 mmol) in tetrahydrofuran (2 mL) and water (0.5 mL), lithium hydroxide monohydrate (11.5 mg, 0.27 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, 1N hydrochloric acid was added to adjust the pH of the reaction mixture to 5-6, and ethyl acetate (15 mL) was added to separate the mixture. The organic phase was dried and concentrated to obtain 2-((4-(1-cyclobutyl-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonylacetic acid A10 (80 mg, yield 82%). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.34 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 11.3 Hz, 1H), 7.53 (d, J = 8.6 Hz, MS-ESI[M+H] + :421.1.

[0486] Using the synthesis method for intermediate A10, the following intermediates A11 to A13 were prepared.

[0487] [Table 8]

[0488] Synthesis of intermediate A14: 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonylacetic acid

[0489] [ka]

[0490] Step 1: 6-bromo-1-(cyclopropylmethyl)-5-fluoro-1H-indole Bromomethylcyclopropane (3.78 g, 28.0 mmol) was added 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). The mixture was heated to 85 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was washed with an aqueous lithium chloride solution (10 mL) and concentrated. The filtrate was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain a colorless oily substance A14-1 (3.1 g). MS-ESI[M+H] + :268.0. Step 2: 1-(cyclopropylmethyl)-5-fluoro-1H-indole-6-carbonitrile Cuprous cyanide (3.62 g, 40.5 mmol) was added to a 60 mL NMP solution of 1-cyclobutyl-5-methoxy-1H-indole-6-carboxylate methyl ester A14-1 (3.1 g, 11.56 mmol). The mixture was heated to 200 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was washed with an aqueous lithium chloride solution (10 mL) and concentrated. The filtrate was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain a pale green solid A14-2 (2.0 g). MS-ESI[M+H] + :215.1. Step 3: tert-butyl(4-(6-cyano-1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-yl)phenyl)carbamate Palladium acetate (104.8 mg, 0.467 mmol) was added to a solution of 1-(cyclopropylmethyl)-5-fluoro-1H-indole-6-carbonitrile A14-2 (2.0 g, 9.34 mmol), (4-iodophenyl)carbamate tert-butyl ester (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). The mixture was heated to 100 °C and stirred under nitrogen for 16 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was washed with aqueous lithium chloride (10 mL) and concentrated. The filtrate was purified by silica gel column chromatography (PE / DCM = 1 / 1) to obtain a pale yellow solid A14-3 (1.0 g). MS-ESI[M+H] + :406.2. Step 4: 2-(4-aminophenyl)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-6-carbonitrile Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (4-(6-cyano-1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-yl)phenyl) carbamate A14-3 (900 mg, 2.22 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated and dried, and dichloromethane (50 mL) was added. The solution was washed twice with aqueous sodium bicarbonate (10 mL), dried, and concentrated to obtain crude product A14-4. MS-ESI[M+H] + :306.1. Step 5: 4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)aniline To 25 mL of a mixed 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 toluene / tetrahydrofuran (5 / 2), azidotrimethylsilane (1.63 g, 14.2 mmol) was added. The mixture was heated to 120°C and stirred for 16 hours. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (DCM / MeOH = 95 / 5) to obtain a pale yellow solid A14-5 (630 mg). MS-ESI[M+H] + :349.1. Step 6: 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonyl acetate methyl ester Oxaloyl chloride monomethyl ester (158.2 mg, 1.29 mmol) was added to a solution of 4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)aniline A14-5 (300 mg, 0.861 mmol) and triethylamine (261.4 mg, 2.58 mmol) in dichloromethane (25 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was washed with brine (10 mL), dried, and concentrated to obtain crude product A14-6 (300 mg). MS-ESI[M+H] + :435.1. Step 7: 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonylacetic acid Lithium hydroxide (58.0 mg, 1.38 mmol) was added to a 12 mL THF / MeOH / H2O=1 / 1 / 1 mixed solution of 2-((4-(1-(cyclopropylmethyl)-5-fluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)phenyl)amino)-2-carbonyl methyl acetate A14-6 (0.3 g, 0.691 mmol). The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated, the pH was adjusted to 7 with 1N hydrochloric acid, extracted with a DCM / MeOH=10 / 1 mixture (50 mL), and then concentrated to obtain a white solid A14 (230 mg). 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.28 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.58-7.51 (m, 3H), 6.60 (s, 1H), 4.22 (d, J = 6.8 Hz, 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. Using the synthesis method for intermediate A14, the following intermediates A15 to A17 were prepared.

[0491] [Table 9]

[0492] Synthesis of intermediate A18: 4-(1-cyclobutyl-6-(1H-1,2,3-triazole-5-yl)-1H-indole-2-yl)aniline

[0493] [ka]

[0494] Step 1: tert-butyl(4-(1-cyclobutyl-6-((trimethylsilyl)ethynyl)-1H-indole-2-yl)phenyl)carbamate To a solution of tert-butyl(4-(6-bromo-1-cyclobutyl-1H-indole-2yl)phenyl)carbamate AA15 (441 mg, 1 mmol) in a mixture of THF (30 mL) and TEA (20 mL), cuprous iodide (19 mg, 0.1 mmol), tetrakis(triphenylphosphine)-palladium (116 mg, 0.1 mmol), and trimethylethynylsilane (295 mg, 0.45 mmol) were added. The resulting mixture was heated at 100°C for 24 hours. The mixture was concentrated and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain a yellow solid product A18-1 (445 mg, yield 81%). MS-ESI[M+H] + :459.1. Step 2: tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl)carbamate Potassium carbonate (265 mg, 1.92 mmol) was added to a THF solution (60 mL) of tert-butyl (4-(1-cyclobutyl-6-((trimethylsilyl)ethynyl)-1H-indole-2-yl)phenyl) carbamate A18-1 (440 mg, 0.96 mmol) and methanol (60 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain a yellow oily liquid product A18-2 (245 mg, yield 61%). MS-ESI[M+H] + :387.1. Step 3: tert-butyl(4-(1-cyclobutyl-6-(1H-1,2,3-triazole-5-yl)-1H-indole-2-yl)phenyl)carbamate To a solution of tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl)carbamate A18-2 (240 mg, 0.62 mmol) in a mixture of DMF (0.9 mL) and methanol (0.1 mL), cuprous iodide (6 mg, 0.03 mmol) and azidotrimethylsilane (107 mg, 0.9 mmol) were added. The resulting mixture was heated at 100°C for 16 hours. The mixture was concentrated and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain a yellow solid product A18-3 (150 mg, yield 62%). MS-ESI[M+H] + :430.1. Step 4: 4-(1-Cyclobutyl-6-(1H-1,2,3-Triazole-5-yl)-1H-Indole-2-yl)Aniline (4-(1-cyclobutyl-6-(1H-1,2,3-triazole-5-yl)-1H-indole-2-yl)phenyl)carbamate tert-butyl ester (150 mg, 0.35 mmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (1 mL) was added. The resulting mixture was reacted at room temperature for 3 hours. The reaction solution was cooled to room temperature, sodium bicarbonate aqueous solution (50 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 = 1 / 1) to obtain a yellow solid product A18 (93 mg, yield 80%). MS-ESI[M+H] + :330.1. Synthesis of intermediate A19: 3-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-yl)-1,2,4-oxadiazole-5(4H)-one hydrochloride

[0495] [ka]

[0496] Step 1: tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)-1H-indole-2-yl)phenyl)carbamate CDI (148 mg, 0.96 mmol) and TEA (138 mg, 1.37 mmol) were added to a 1,4-dioxane solution (10 mL) of tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(N'-hydroxyaminoformimidoyl)-1H-indole-2-yl)phenyl) carbamate AA16 (200 mg, 0.46 mmol). The resulting mixture was stirred under nitrogen at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain a yellow solid product A19-1 (200 mg, 93% yield). MS-ESI[M+H] + :465.2. Step 2: 3-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-yl)-1,2,4-oxadiazole-5(4H)-one hydrochloride A solution of (4-(1-cyclobutyl-5-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)-1H-indole-2-yl)phenyl) carbamate tert-butyl ester A19-1 (200 mg, 0.43 mmol) in dichloromethane (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a yellow solid crude product A19 (100 mg). MS-ESI[M+H] + :365.1.

[0497] Synthesis of intermediate A20: 4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)-1H-indole-2-yl)aniline

[0498] [ka]

[0499] Step 1: tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)-1H-indole-2-yl)phenyl)carbamate Trifluoroacetic anhydride (115 mg, 0.55 mmol) was added to a solution of (Z)-(4-(1-cyclobutyl-5-fluoro-6-(N'-hydroxyaminoformimidoyl)-1H-indole-2-yl)phenyl)carbamate tert-butyl ester AA16 (200 mg, 0.45 mmol) and tetrahydrofuran (5 mL). 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 obtain a yellow solid product A20-1 (120 mg, yield 51%). MS-ESI[M+H] + :517.2. Step 2: tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl)carbamate Hydrazine hydrate (2 mL) was added to a DMF solution (3 mL) of tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl) carbamate A20-1 (120 mg, 0.23 mmol). The mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture 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 a yellow solid product A20-2 (100 mg, yield 83%). MS-ESI[M+H] + :516.2. Step 3: 4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indole-2-yl)aniline To a solution of hexafluoroisopropanol (5 mL), tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1H-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl)carbamate (100 mg, 0.19 mmol) was added. The resulting mixture was heated in a microwave tube at 120°C for 12 hours. Direct concentration yielded a yellow solid crude product A20 (80 mg). MS-ESI[M+H] + :416.1.

[0500] Synthesis of intermediate A21: 5-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-yl)-4H-1,2,4-triazole-3-carbonitrile

[0501] [ka]

[0502] Step 1: tert-butyl(4-(6-(5-carbamoyl-4H-1,2,4-triazole-3-yl)-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate A mixture of methyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbamimidothioate AA18 (320 mg, 0.7 mmol) and DMF (5 mL) was mixed with 2-hydrazino-2-carbonylacetamide (95 mg, 0.92 mmol) and acetic acid (1 drop). The resulting mixture was heated at 65°C for 3 hours. The reaction mixture was cooled to room temperature and water (10 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 (DCM / EA=2 / 1) to obtain a white solid product A21-1 (220 mg, yield 89%). MS-ESI[M+H] + :491.2. Step 2: tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl)-1H-indole-2-yl)phenyl)carbamate To a solution of tert-butyl(4-(6-(5-carbamoyl-4H-1,2,4-triazole-3-yl)-1-cyclobutyl-5-fluoro-1H-indole-2-yl)phenyl)carbamate A21-1 (220 mg, 0.45 mmol) in dichloromethane (5 mL), trifluoroacetic anhydride (141 mg, 0.67 mmol) and triethylamine (91 mg, 0.89 mmol) were added. The mixture was reacted at room temperature for 2 hours. The product was concentrated and purified by silica gel column chromatography (DCM / EA=3 / 1) to obtain a yellow solid product A20-2 (110 mg, 50% yield). MS-ESI[M+H] + :472.2. Step 3: 5-(2-(4-aminophenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-yl)-4H-1,2,4-triazole-3-carbonitrile Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl) carbamate (90 mg, 0.2 mmol) in dichloromethane (2 mL). The resulting mixture was reacted at room temperature for 3 hours. Direct concentration yielded a yellow solid crude product A21 (60 mg). MS-ESI[M+H] + :373.1.

[0503] Synthesis of intermediate A22: 4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazole-3-yl)-1H-indole-2-yl)aniline

[0504] [ka]

[0505] Step 1: tert-butyl(4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl)carbamate To a solution of methyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)-1-cyclobutyl-5-fluoro-1H-indole-6-carbamimidothioate AA18 (100 mg, 0.2 mmol) in DMF (5 mL), acetylhydrazine (25 mg, 0.3 mmol) and acetic acid (2 drops) were added. The resulting mixture was heated to 90°C and reacted for 36 hours. The reaction mixture was cooled to room temperature, water (10 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 subjected to silica gel column chromatography (PE / EA=4 / 1) to obtain a yellow solid product A22-1 (90 mg, yield 89%). MS-ESI[M+H] + :462.2. Step 2: 4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazol-3-yl)-1H-indole-2-yl)aniline To a solution of hexafluoroisopropanol (5 mL), tert-butyl 4-(1-cyclobutyl-5-fluoro-6-(5-methyl-4H-1,2,4-triazole-3-yl)-1H-indole-2-yl)phenyl)carbamate (90 mg, 0.2 mmol) was added. The resulting mixture was heated in a microwave tube at 120°C for 12 hours. Direct concentration yielded a yellow solid crude product A22 (60 mg). MS-ESI[M+H] + :362.1.

[0506] Synthesis of intermediate A23: 4-(1-cyclobutyl-5,7-difluoro-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)aniline

[0507] [ka]

[0508] Step 1: 3-(cyclobutylamino)-2,6-difluorobenzonitrile 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), tetraisopropyl titanate (13.2 g, 37.4 mmol) was added. The resulting mixture was heated to 100 °C and stirred under microwave conditions for 10 hours. After the reaction was complete, the mixture was cooled to room temperature, and sodium borohydride cyanohydride (12.1 g, 57.1 mmol) was added gradually while stirring. The mixture was heated to 90 °C and stirred for 8 hours. After the reaction was complete, the mixture was cooled, and the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (50 mL). The mixture was filtered, the filtrate was washed with a saturated aqueous solution of sodium bicarbonate, and the mixture was concentrated. The filtrate was purified by silica gel column chromatography (PE / EA = 80 / 20) to obtain a colorless oily substance A23-2 (1.2 g, yield 80%). MS-ESI[M+H] + :209.1. Step 2: 4-Bromo-3-(cyclobutylamino)-2,6-difluorobenzonitrile N-bromosuccinimide (2.05 g, 11.5 mmol) was added to a 15 mL AcOH solution of 3-(cyclobutylamino)-2,6-difluorobenzonitrile A23-2 (1.5 g, 7.20 mmol). The resulting mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reactants were poured into 50 mL of saturated sodium bicarbonate solution under ice water conditions. The mixture was extracted three times with ethyl acetate (50 mL), concentrated, and then purified by silica gel column chromatography (PE / Â=85 / 15) to obtain a colorless oily substance A23-3 (1.2 g, yield 58%). MS-ESI[M+H] + :289.0. Step 3: tert-butyl(4-(4-cyano-2-(cyclobutylamino)-3,5-difluorophenyl)ethynyl)carbamate 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 copper(I) iodide (27.9 mg, 146 μmol) were dissolved in acetonitrile (10 mL), to which bis(triphenylphosphine)palladium(II) dichloride (103 mg, 146 μmol) was added. The resulting mixture was microwaved to 100 °C and stirred under nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was cooled, filtered, concentrated and dried, and purified by silica gel column chromatography (PE / DCM = 70 / 30) to obtain colorless oil A23-4 (280 mg, yield 41%). MS-ESI[M+H] + :424.1. Step 4: 2-(4-aminophenyl)-1-cyclobutyl-5,7-difluoro-1H-indole-6-carbonitrile 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 to a 1 M 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 complete, the mixture was cooled and ethyl acetate (50 mL) was added. The organic phase was washed three times with 1 N aqueous hydrochloric acid (10 mL), concentrated, and purified by silica gel column chromatography (PE / EA = 70 / 30) to obtain a colorless oily substance A23-5 (230 mg, yield 83%). MS-ESI[M+H] + :324.1. Step 5: 4-(1-Cyclobutyl-5,7-Difluoro-6-(1H-Tetrazole-5-yl)-1H-Indole-2-yl)Aniline Sodium azide (402 mg, 6.19 mmol) was added 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). The resulting mixture was heated to 110 °C and reacted for 16 hours. After the reaction was complete, the mixture was cooled, filtered, and the filtrate was separated by an alkaline method to obtain an off-white solid product A23 (18 mg, yield 7%). 1 H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 9.6 Hz, 1H), 7.16-7.12 (m, 2H), 6.69 (d, J = 8.4 Hz, 2H), 6.41 (d, J = 2.4 Hz, 1H), 5.00 (q, J = 9.2 MS-ESI[M+H] + :367.1.

[0509] Synthesis of intermediate A24: 4-(1-cyclobutyl-6-(1H-tetrazole-5-yl)-1H-indole-2-yl)aniline

[0510] [ka]

[0511] Step 1: 2-(4-aminophenyl)-1-cyclobutyl-1H-indole-6-carbonitrile Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl 4-(6-cyano-1-cyclobutyl-1H-indole-2-yl)phenyl)carbamate AA13 (700 mg, 1.8 mmol) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated and dried, and dichloromethane (30 mL) was added. The pH was adjusted to 9.0 with saturated sodium bicarbonate solution (5 mL). The organic phase was concentrated and dried to obtain off-white solid A24-1 (310 mg, yield 59%). MS-ESI[M+H] + :288.0. Step 2: 4-(1-Cyclobutyl-6-(1H-Tetrazole-5-yl)-1H-Indole-2-yl)Aniline A solution of 1N tetrabutylammonium fluoride in tetrahydrofuran (0.5 mL, 0.5 mmol) was added to a toluene solution (8 mL) of 2-(4-aminophenyl)-1-cyclobutyl-1H-indole-6-carbonitrile A24-2 (287 mg, 1.0 mmol) and trimethylcyanosilane (230 mg, 2.0 mmol). The resulting mixture was heated to 110°C and stirred for 17 hours. After the reaction was complete, the mixture was concentrated and dried, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain off-white solid A24 (130 mg, yield 39%). MS-ESI[M+H] + :331.1.

[0512] Intermediate A24 was prepared using the same method as A25 to A29.

[0513] [Table 10]

[0514] Synthesis of intermediate BB1: 2-(pyrrolidine-3-yl)ethane-1-ol hydrochloride

[0515] [ka]

[0516] To a solution of 3-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester BB1-1 (200 mg, 0.93 mmol) in dichloromethane (10 mL), dioxane hydrochloride solution (4 M, 2 mL, 8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction product was quenched with saturated aqueous sodium bicarbonate solution (10 mL), and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined and evaporated to dryness to obtain crude product BB1 (100 mg). This was used directly in the next step. MS-ESI[M+H] + :116.1.

[0517] Using the synthesis method for intermediate BB1, the following intermediates BB2 to BB15 were obtained.

[0518] [Table 11]

[0519] Synthesis of intermediate BB16: (3-methylpiperidine-4-yl)methanol hydrochloride

[0520] [ka]

[0521] Step 1: Methyl-3-methylpiperidine-4-carboxylate Platinum dioxide (150 mg, 12.5 mmol) was added to a 4 mL acetic acid solution of methyl-3-methyl isonicotinate BB16-1 (400 mg, 2.64 mmol). The reaction mixture was stirred at room temperature under hydrogen balloon pressure for 16 hours. The solution was concentrated to obtain crude methyl-3-methylpiperidine-4-carboxylate BB16-2. MS-ESI[M+H] + :158.1. Step 2: 1-(tert-butyl)-4-methyl-3-methylpiperidine-1,4-dicarbonoxylate To a mixture of crude methyl 3-methylpiperidine-4-carboxylate BB16-2 in DCM (15 mL) and water (10 mL), sodium bicarbonate (444 mg, 5.29 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The layers were then separated, the organic phase was washed with saturated brine (10 mL), dried, concentrated, and purified by silica gel column chromatography (PE / EA=3 / 1) to produce 1-(tert-butyl)-4-methyl-3-methylpiperidine-1,4-dicarboxylate BB16-3 (600 mg, yield 88%). MS-ESI[M+H] + :258.1. Step 3: 4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate tert-butyl ester To a solution of 1-(tert-butyl)-4-methyl-3-methylpiperidine-1,4-dicarbonoxylate BB16-3 (600 mg, 2.33 mmol) in tetrahydrofuran (10 mL), lithium aluminum hydride (124 mg, 3.27 mmol) was added under ice bath conditions, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was then quenched with saturated ammonium chloride (5 mL), followed by the addition of ethyl acetate (30 mL) and water (10 mL). The mixture was separated, the organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain 4-(hydroxymethyl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester BB16-4 (500 mg, yield 94%). MS-ESI[M+H] + :230.1. Step 4: (3-Methylpiperidine-4-yl)methanol hydrochloride To a solution of tert-butyl 4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate BB16-4 (500 mg, 2.33 mmol) in dichloromethane (6 mL), a solution of hydrogen chloride in dioxane (4 M, 2.2 mL, 8.8 mmol) was added under ice bath cooling. The reaction mixture was stirred at room temperature for 3 hours and then concentrated to obtain (3-methylpiperidine-4-yl)methanol hydrochloride BB16 (384 mg). MS-ESI[M+H] + :130.1.

[0522] Synthesis of intermediate BB17: (4-(methoxymethyl)piperidine-4-yl)methanol hydrochloride

[0523] [ka]

[0524] Step 1: 1-(tert-butyl)-4-methyl-4-(methoxymethyl)piperidine-1,4-dicarbonoxylate Under a nitrogen atmosphere, a solution of 1-(tert-butyl)-4-methylpiperidine-1,4-dicarbonoxylate BB17-1 (1.0 g, 4.11 mmol) in tetrahydrofuran (15 mL) was added to a solution of lithium diisopropylamide in tetrahydrofuran (1 M, 2.98 mL, 5.96 mmol). Bromomethylmethyl ether (770.4 mg, 6.17 mmol) was then added dropwise at -70°C (dry ice-ethanol bath). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (5 mL) was added to quench the reaction. The mixture was concentrated, extracted with ethyl acetate (30 mL), washed with saturated brine (10 mL), concentrated again, and then purified by silica gel column chromatography (PE / EA = 7 / 3) to obtain a light brown oily substance BB17-2 (920 mg). MS-ESI[M-Boc]+: 188.1 Step 2: 4-(hydroxymethyl)-4-(methoxymethyl)piperidine-1-carboxylate tert-butyl ester Under a nitrogen atmosphere, lithium aluminum hydride (59.4 mg, 1.57 mmol) was gradually added at 0°C (ice bath) to a solution of 1-(tert-butyl)-4-methyl-4-(methoxymethyl)piperidine-1,4-dicarbonoxylate BB17-2 (0.50 g, 1.74 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (5 mL) was added dropwise at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, and the filter cake was washed with ethyl acetate (10 mL). The combined filtrate was concentrated and dried to obtain the crude product BB17-3 (500 mg). MS-ESI[M-55]+: 204.1. Step 3: (4-(methoxymethyl)piperidine-4-yl)methanol hydrochloride A solution of 1-(tert-butyl)-4-methyl-4-(methoxymethyl)piperidine-1,4-dicarbonoxylate BB17-3 (0.40 g, 1.54 mmol) in methanol (5 mL) was added to a solution of hydrogen chloride in dioxane (4 M, 2 mL, 8 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated and dried to obtain the crude product BB17 (350 mg).

[0525] Synthesis of intermediate BB18: 5-methyloxooctahydrocyclopenta[c]pyrrole-5-phenol hydrochloride

[0526] [ka]

[0527] Step 1: 5-Hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester A solution of 5-carbonylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester BB18-1 (400 mg, 2.33 mmol) in tetrahydrofuran (6 mL) was added under ice bath conditions, and the reaction mixture was stirred at room temperature for 1 hour. The reaction was then quenched with a saturated aqueous solution of ammonium chloride (5 mL), followed by the addition of ethyl acetate (30 mL) and water (10 mL), and the mixture was separated. The organic phase was dried, concentrated, and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain 5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester BB18-2 (360 mg, yield 64%). MS-ESI[M+H] + :242.1. Step 2: 5-Methyloctahydrocyclopenta[c]pyrrole-5-phenol hydrochloride 5-methyloctahydrocyclopenta[c]pyrrole-5-phenol hydrochloride BB18 was prepared from 5-hydroxy-5-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate tert-butyl ester BB18-2 using the synthesis method of intermediate BB15 in step 4. MS-ESI[M+H] + :142.1.

[0528] Using the same method as for intermediate BB18, the following intermediates BB19 to BB23 were prepared.

[0529] [Table 12]

[0530] Synthesis of intermediate BB24: 2-(tert-butyl)-7-methyl-2-azaspiro[3.5]nonane-2,7-dicarbonoxylate

[0531] [ka]

[0532] Potassium carbonate (256 mg, 1.85 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-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), and the reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (20 mL) and water (10 mL) were added, the mixture was separated, the organic phase was dried and concentrated, and purified by silica gel column chromatography (PE / EA=3 / 1) to obtain 2-(tert-butyl)-7-methyl-2-azaspiro[3.5]nonane-2,7-dicarbonoxylate BB24 (260 mg, 99% yield). MS-ESI[M+H-56] + :228.1.

[0533] Using the same method as for intermediate BB24, the following intermediate BB25 was prepared.

[0534] [Table 13]

[0535] Synthesis of intermediate BB26: 2-methyl-1-(piperidine-4-yl)propan-2-ol hydrochloride

[0536] [ka]

[0537] Step 1: 4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate tert-butyl ester 4-(2-methoxy-2-carbonylethyl)piperidine-1-carboxylic acid tert-butyl ester BB26-1 (1000 mg, 3.89 mmol) was dissolved in tetrahydrofuran (10 mL), to which methylmagnesium bromide (1 M, 12 mL, 12 mmol) was added under ice bath. The resulting mixture was stirred overnight under nitrogen at room temperature. The reaction was quenched with water (5 mL), and the mixture was extracted three times with dichloromethane (20 mL). The combined organic phase was evaporated to dryness and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain product BB26-2 (920 mg, yield 92%). MS-ESI[M-55] + :202.1. Step 2: 2-Methyl-1-(piperidine-4-yl)propan-2-ol hydrochloride 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 mixed with a solution of dioxane hydrochloride (4 M, 2 mL, 8 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction product was quenched with 10 mL of saturated sodium bicarbonate aqueous solution and extracted three times with dichloromethane (30 mL). The organic phases were combined and evaporated to dryness to obtain the crude product BB26 (300 mg). This was used directly in the next step. MS-ESI[M+H] + :158.1.

[0538] Using the same method as for intermediate BB26, the following intermediates BB27 to B29 were prepared.

[0539] [Table 14]

[0540] Synthesis of intermediate B1: 4-(chain-3-yl)aniline

[0541] [ka]

[0542] 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), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (67 mg, 0.09 mmol) and sodium carbonate (1.93 g, 18.2 mmol) were added. Under nitrogen protection, the reaction mixture was heated to 90°C and stirred for 3 hours. Then, ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was separated. The organic phase was washed with saturated physiological saline (10 mL), dried, concentrated, and purified by silica gel column chromatography (PE / EA=4 / 1) to obtain 4-(thiophen-3-yl)aniline B1 (1.4 g, yield 88%). MS-ESI[M+H] + :176.2.

[0543] Using the same method as for intermediate B1, the following intermediates B2 to B5 were prepared.

[0544] [Table 15]

[0545] Intermediate B6: Synthesis of (4-(4-aminophenyl)thiophen-2-yl)methanol

[0546] [ka]

[0547] Step 1: tert-butyl(4-(5-(hydroxymethyl)thiophen-3-yl)phenyl)carbamate (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-yl)methanol B6-1 (200 mg, 0.83 mmol) and (4-iodophenyl)carbamate tert-butyl ester (319 mg, 1 mmol) were dissolved in ethylene glycol dimethyl ether / water (2 mL / 0.5 mL), to which 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (61 mg, 0.083 mmol) and sodium carbonate (265 mg, 2.5 mmol) were added. The resulting mixture was stirred overnight at 120°C under nitrogen protection. The mixture was evaporated to dryness and purified by silica gel column chromatography (PE / EA=2 / 1) to obtain product B6-2 (120 mg, yield 47%). Step 2: (4-(4-aminophenyl)thiophen-2-yl) methanol (4-(5-(hydroxymethyl)thiophen-3-yl)phenyl)carbamate tert-butyl ester 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 evaporated to dryness using a rotary evaporator and purified by silica gel column chromatography (PE / EA = 1 / 2) to obtain (4-(4-aminophenyl)thiophen-2-yl)methanol B6 (40 mg, yield 67%). MS-ESI[M+H]: 206.0.

[0548] Intermediate B7: Synthesis of 2-(4-(4-aminophenyl)thiophen-2-yl)acetonitrile

[0549] [ka]

[0550] Step 1: 2-(4-bromothiophene-2-yl)acetonitrile 4-bromo-2-(chloromethyl)thiophene B7-1 (500 mg, 2.38 mmol) was dissolved in acetonitrile (10 mL) and sodium cyanide (210 mg, 4.3 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes, then stirred overnight at 85 °C. The mixture was evaporated to dryness using a rotary evaporator and purified by silica gel column chromatography (PE / EA = 4 / 1) to produce 2-(4-(4-aminophenyl)thiophene-2-yl)acetonitrile B7-2 (300 mg, 63% yield). MS-ESI[M+H]+: 201.9. Step 2: tert-butyl(4-(5-(cyanomethyl)thiophen-3-yl)phenyl)carbamate 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), 4-(tert-butoxycarbonyl)aminophenylboronic acid (236 mg, 1 mmol), 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (36 mg, 0.05 mmol), and potassium phosphate (317 mg, 1.5 mmol) were added. The resulting mixture was stirred overnight at 90°C. After evaporation to dryness using a rotary evaporator, the mixture was purified by silica gel column chromatography (PE / EA=4 / 1) to obtain product B7-3 (107 mg, yield 69%). MS-ESI[M+H] + :315. Step 3: 2-(4-(4-aminophenyl)thiophen-2-yl)acetonitrile 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), trifluoroacetic acid (2 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction product was quenched with saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane (10 mL). The combined organic phase was evaporated to dryness using a rotary evaporator to obtain crude product B7 (107 mg). This was used directly in the next step. MS-ESI[M+H]+: 215.1.

[0551] Synthesis of intermediate B8: 4-(2-ethylmorpholino)aniline

[0552] [ka]

[0553] Step 1: 2-Ethyl-4-(4-nitrophenyl)morpholine To a solution of 2-ethylmorpholine B8-1 (500 mg, 2.2 mmol) in DMF (5 mL), p-fluoronitrobenzene (613 mg, 4.3 mmol) and potassium carbonate (901 mg, 6.5 mmol) were added. The resulting mixture was stirred at 80°C for 3 hours. The mixture was then evaporated to dryness using a rotary evaporator and purified by silica gel column chromatography (PE / EA=5 / 1) to produce a yellow solid product B8-2 (500 mg, yield 49%). MS-ESI[M+H]+:237.1.1. Step 2: 4-(2-ethylmorpholino)aniline Palladium-supported 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), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated to dryness to obtain crude product B8 (300 mg). This was used directly in the next reaction: MS-ESI[M+H] + :207.1.

[0554] The following intermediates B9 to B74 were prepared using the same method as intermediate B8.

[0555] [Table 16-1]

[0556] [Table 16-2]

[0557] [Table 16-3]

[0558] [Table 16-4]

[0559] [Table 16-5]

[0560] Synthesis of intermediate B75: (1-(4-aminophenyl)-4,4-dimethylpyrrolidine-3-yl)methanol

[0561] [ka]

[0562] Step 1: 4,4-dimethyl-1-(4-nitrophenyl)pyrrolidine-3-carboxylate ethyl ester 4,4-dimethylpyrrolidine-3-carboxylate ethyl ester hydrochloride B75-1 (250 mg, 1.20 mmol) and potassium carbonate (582.2 g, 4.21 mmol) were dissolved in DMF (10 mL) and 1-fluoro-4-nitrobenzene (424.6 mg, 3.01 mmol) was added. The resulting mixture was heated to 80°C, stirred for 2 hours, then cooled, filtered, and ethyl acetate (50 mL) was added to the filtrate. The mixture was washed with aqueous lithium chloride (10 mL), concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 2) to obtain a pale yellow solid B75-2 (290 mg, yield 82%). MS-ESI[M+H] + :293.2. Step 2: (4,4-dimethyl-1-(4-nitrophenyl)pyrrolidine-3-yl)methanol To a solution of 4,4-dimethyl-1-(4-nitrophenyl)pyrrolidine-3-carboxylate ethyl ester B75-2 (290 mg, 0.992 mmol) in THF (20 mL), lithium aluminum hydride (49.0 mg, 1.29 mmol) was gradually added under ice bath conditions. The mixture was then warmed to room temperature under nitrogen protection and stirred for 2 hours. After the reaction was complete, the temperature was lowered to 0°C, the reaction was quenched by slow dropwise addition of water (10 mL), extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated and dried, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain a brown oily substance B75-3 (190 mg, yield 77%). MS-ESI[M+H] + :251.1. Step 3: (1-(4-aminophenyl)-4,4-dimethylpyrrolidine-3-yl)methanol (4,4-dimethyl-1-(4-nitrophenyl)pyrrolidine-3-yl)methanol B75-3 (100 mg, 0.454 mmol) EtOH / H2O = Sodium dithionite (632.6 mg, 3.63 mmol) was added to a 1 / 1 (15 mL) solution. The mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, extracted with a mixed solvent of DCM / MeOH=10 / 1 (30 mL), washed with brine (5 mL), dried, concentrated, and purified by silica gel column chromatography (DCM / MeOH=10 / 1) to obtain a pale yellow solid B75 (45 mg, yield 88%). MS-ESI[M+H] + :191.1.

[0563] Synthesis of intermediate B76: 2-((4-(2-oxa-8-azaspiro[4,5]decane-8-yl)phenyl)amino)-2-carbonylacetic acid

[0564] [ka]

[0565] Step 1: 2-((4-(2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-2-carbonylacetate methyl ester 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), triethylamine (2.6 g, 25.8 mmol) was added, followed by the dropwise addition of monomethyloxaloyl chloride (2.37 g, 19.35 mmol) under ice bath conditions. The mixture was stirred at room temperature for 1 hour, quenched with saturated aqueous solution of ammonium chloride (10 mL), and extracted with ethyl acetate (60 mL). The organic phase was dried, filtered, and concentrated to obtain product B76-1 (3.9 g). MS-ESI[M+H] + :319.3. Step 2: 2-((4-(2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-2-carbonylacetic acid To a solution of 2-((4-(2-oxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)-2-carbonylacetic acid methyl ester B76-1 (3.9 g, 12.2 mmol) in tetrahydrofuran (50 mL), an aqueous solution of lithium hydroxide monohydrate (12.5 mL, 1.02 g, 24.4 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, 1N hydrochloric acid was added to adjust the pH of the reaction mixture to 3-4. The solid was precipitated and extracted twice with ethyl acetate (150 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow solid B76 (3.7 g, yield 99%). MS-ESI[M+H] + :305.3.

[0566] Using the same method as for intermediate B76, the following intermediates B77 and B78 were prepared.

[0567] [Table 17]

[0568] 2. Synthesis of Examples Method C: To a solution of intermediate A (0.05 mmol, 1 equivalent) and intermediate B (1.5 equivalents) in N,N-dimethylformamide (2 mL), solutions of 1-propyl phosphonate anhydride in N,N-dimethylformamide (50%, 2.0 equivalents) and N,N-diisopropylethylamine (3.0 equivalents) were added. The mixture was stirred at room temperature for 3 hours, and the target product was obtained by preparative HPLC separation and purification.

[0569] Method D: To a solution of intermediate B (0.05 mmol, 1 equivalent) in dichloromethane (3 mL), oxalyl chloride (4.0 equivalents) was added dropwise under ice bath conditions, followed by the addition of 1 drop of DMF. The reaction mixture was stirred at room temperature for 0.5 hours and then concentrated to obtain the crude product. The crude product was then dissolved in N,N-dimethylformamide (3 mL), followed by the addition of intermediate A1 (1.0 equivalent) and N,N-diisopropylethylamine (2.0 equivalents). The reaction mixture was stirred at room temperature for 0.5 hours. The target product was obtained by preparative HPLC separation and purification.

[0570] The compounds described in the examples were prepared using the above synthesis method and corresponding intermediates:

[0571] [Table 18-1]

[0572] [Table 18-2]

[0573] [Table 18-3]

[0574] [Table 18-4]

[0575] [Table 18-5]

[0576] Table 18-6

[0577] Table 18-7

[0578] Table 18-8

[0579] Table 18-9

[0580] Table 18-10

[0581] Table 18-11

[0582] Table 18-12

[0583] Table 18-13

[0584] Table 18-14

[0585] Table 18-15

[0586] Table 18-16

[0587] Table 18-17

[0588] Table 18-18

[0589] Table 18-19

[0590] Table 18-20

[0591] Table 18-21

[0592] Table 18-22

[0593] Table 18-23

[0594] Table 18-24

[0595] Table 18-25

[0596] Table 18-26

[0597] Table 18-27

[0598] Table 18-28

[0599] Table 18-29

[0600] Table 18-30

[0601] Table 18-31

[0602] Table 18-32

[0603] Table 18-33

[0604] Table 18-34

[0605] Table 18-35

[0606] Table 18-36

[0607] Table 18-37

[0608] Table 18-38

[0609] Table 18-39

[0610] Table 18-40

[0611] Table 18-41

[0612] Table 18-42

[0613] Table 18-43

[0614] Table 18-44

[0615] Table 18-45

[0616] [Table 18-46]

[0617] [Table 18-47]

[0618] [Table 18-48]

[0619] 3. Examples of activity tests It should be understood that the doses referenced herein, where describing the compounds of the present invention, pharmaceutical compositions containing them, pharmaceutical combinations, cassettes, and related uses and methods, are based on the weight of the free form and do not include any salts, hydrates, or solvates thereof, unless otherwise specified.

[0620] Example 1 Inhibitory effect of the compound of the present invention on the SHP2 enzyme This experiment evaluates the inhibitory effect of the test compound on SHP2 enzyme activity by detecting the reaction between the human recombinant protein SHP2 enzyme and its substrate.

[0621] Thaw the stock solutions of the reaction buffer components and mix them uniformly at room temperature. The reaction buffer consists of (55mM HEPES pH=7.2 (Sigma, Cat.No.#PHR1428), 100mM NaCl (Beyotime, Cat.No.#ST374, 5M solution), and 0.5mM EDTA (Beyotime, Cat. No. #ST066), 1 mM DL-Dithiothreitol (DTT) (Sigma, Cat. No. #D9779), 0.002% BSA (Solarbio, Cat. No. #A8010), and 0.001% Brij35 (Bri(registered trademark) L23 solution (Brij35) (Sigma, Cat. No. #B4184)) were prepared. The SHP2 enzyme (catalytic domain, amino acid sequence 224-528, expressed and purified by GenScript) was slowly thawed on ice. 1 μL of this solution (1.37 mg / mL) was added to 386 μL of reaction buffer and diluted to 100 nM. Then, 120 μL of the 100 nM SHP2 enzyme solution was added to 2880 μL of reaction buffer and diluted to 4 nM. SHP2 enzyme working solutions were prepared. The test compound and a specific inhibitor of SHP2 (11a-1, used as a positive control, Zeng, L. et al., J. Med. Chem., 2014, Vol. 57, pp. 6594-6609) were prepared as 10 mM DMSO solutions. 10 μL of the 10 mM compound solution was mixed with 20 μL of DMSO solution, and then sequentially diluted threefold to obtain 10 different concentrations. 1 μL of each serially diluted solution was mixed with 99 μL of reaction buffer to obtain 10-fold diluted compound working solutions.

[0622] A 96-well black half-area microplate (Greiner, catalog #675076) was used. 25 μL of 4 nM SHP2 enzyme working solution and 5 μL of 10 × compound working solution were added to each well and incubated at room temperature for 30 minutes. 15 μL of DiFMUP substrate (Thermo Fisher Scientific, catalog #D6567) was added to 2985 μL of reaction buffer to prepare a 50 μM substrate working solution. After incubation of the compound and SHP2 enzyme, 20 μL of the 50 μM substrate working solution was added to each well and incubated at room temperature for 5 minutes. The plate was then read using a multimode microplate reader (BioTek, Synergy H1) at 340 nm / 450 nm fluorescence.

[0623] Positive control compound (11a-1)

[0624] [ka]

[0625] The data was analyzed using GraphPad Prism 9.0 software. A dose-response-inhibition model equation for nonlinear S-shaped regression was used to fit the data and create dose-response curves. From these, the IC (Indicative Concentration) was calculated. 50 The value was calculated. SHP2 enzyme inhibition rate (%) = 1 - (RFU 試験薬物 )-RFU 緩衝液対照 ) / (RFU DMSO対照 )-RFU 緩衝液対照 ) × 100%.

[0626] The representative compounds disclosed herein exhibited excellent inhibitory properties against the SHP2 enzyme, as shown in the table below.

[0627] [Table 19]

[0628] The above results indicate that the compounds disclosed herein exhibit excellent SHP2 enzyme inhibitory activity, with an IC50 value of <1 μM, preferably 1 to 100 nM, and more preferably 1 to 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 to 4 times lower than the most active active-site inhibitor in the prior art (control compound 11a-1, IC50 = 0.108 μM), which means that the inhibitory activity is 3 to 4 times higher.

[0629] Example 2 Inhibitory activity of the disclosed compounds against the proliferation of three tumor cell lines: KYSE520, MeWo, and MV4-11.

[0630] In this experiment, the inhibitory effects of the disclosed compounds on the proliferation of the cell lines KYSE520 (a human esophageal squamous cell carcinoma cell line dependent on SHP2 for growth), MeWo (a human malignant melanoma cell line), and MV4-11 (a human acute monocytic leukemia cell line with RTK mutations) were evaluated using the CellTiter-Glo® Luminescent Cell Viability Assay Kit, manufactured by Promega.

[0631] KYSE520 cells (Nanjing Kebaio Biotechnology Co., Ltd., Catalog #CBP60658) were thawed by rapidly shaking the frozen vial in a 37°C water bath for less than 1 minute. The thawed cell suspension was homogeneously mixed with RPMI 1640 medium (HyClone, Catalog #SH30027.01) containing 10% FBS (ExCell, Catalog #FND500), centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cell pellet was resuspended in 5 mL of complete medium (RPMI 1640 medium containing 10% FBS) and incubated at 25 cm³. 2The cells were placed in a cell culture flask with a certain bottom area and then cultured in a cell culture incubator at 37°C, 95% humidity, and 5% CO2. Subculturing was performed when cell confluence reached approximately 80%. During subculturing, the old medium was discarded, the cells were washed once with DPBS (Thermo Fisher, Catalog #14190-144), and 1 mL of trypsin (Thermo Fisher, Catalog #25200072) was added to digest the cells. Once the cells had dispersed into single cells and separated from the bottom of the culture flask, 3 mL of fresh complete medium was added to stop digestion. After gently pipetting the cell suspension, 1 / 5 of the cell suspension was retained, 5 mL of fresh complete medium was added and mixed, and the cells were placed in a cell culture flask and cultured further. Cell plating was performed when cell confluence again reached approximately 80%. During cell plating, following the subculture method, 1 / 5 of the cell suspension was retained for continued culture, and the remaining 4 / 5 of the cell suspension was placed in a 15 mL centrifuge tube. Cell viability was determined using the trypan blue exclusion method to ensure that cell viability exceeded 90%. Complete medium was used, at a density of 2.22 × 10⁶. 4Cell suspensions were prepared at a cell / mL concentration, and 135 μL of the cell suspension was added to 96-well transparent flat-bottom black-walled cell culture plates (Greiner, catalog #655090) to a cell density of 3000 viable cells per well. A control group containing only complete medium without cells or compounds (i.e., medium control) and a control group containing cells but no compounds (i.e., cell control) were placed. The cell plates were incubated overnight in a cell culture incubator. First, 10 mM stock solutions of the compounds (example compounds and positive control compound 11a-1) in DMSO (Damas-beta, catalog #75927R) were serially diluted 3-fold to the 9th concentration, and a 10th concentration (no compound) containing only DMSO was also prepared as a control. Next, the DMSO solutions containing different concentrations of the compounds were diluted 100-fold with complete medium to a 1% DMSO concentration in each solution. Finally, 15 μL of each solution was added to the corresponding wells of the cell culture plate, resulting in a starting compound concentration of 10 μM, a 3-fold dilution between adjacent concentrations, and a final DMSO concentration of 0.1% in the cell culture plate. The cell plate was then incubated in a cell culture incubator for a further 120 hours.

[0632] Using essentially the same experimental materials, MeWo cells (ATCC, catalog #HTB-65) were processed in the same manner. When thawing the cells, the frozen vials were rapidly shaken in a 37°C water bath, thawing the cells within 1 minute. The thawed cell suspension was mixed with MEM / EBSS medium containing 10% FBS (HyClone, catalog #SH30024.01), centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cell pellet was resuspended in 5 mL of complete medium (MEM / EBSS medium containing 10% FBS) and refrigerated for 25 cm. 2The cells were placed in a cell culture flask with a certain bottom area and cultured in a cell culture incubator at 37°C, 95% humidity, and 5% CO2. Subculturing was performed when cell confluence reached approximately 80%. During subculturing, the old medium was discarded, the cells were washed once with DPBS, and 1 mL of trypsin was added to digest the cells. Once the cells had dispersed into single cells and separated from the bottom of the cell culture flask, 3 mL of fresh complete medium was added to stop digestion. After thoroughly mixing the cell suspension, 1 / 5 of the cell suspension was retained, 5 mL of fresh complete medium was added, and after thorough mixing, the cells were placed in the cell culture flask and cultured further. Cell plating was performed when cell confluence again reached approximately 80%. During cell plating, following the subculturing procedure, 1 / 5 of the cell suspension was retained for further culture, and the remaining 4 / 5 of the cell suspension was placed in a 15 mL centrifuge tube. Cell viability was determined using the trypan blue exclusion method to ensure that cell viability exceeded 90%. MEM / EBSS medium containing 5% FBS was used, with a density of 2.22 × 10⁶. 4 Cell suspensions were prepared at a concentration of cells / mL. 90 μL of the cell suspension was added to a 96-well cell culture plate to achieve a cell density of 2000 viable cells / well. A control group containing only complete medium (i.e., medium control), without cells or compounds, and a control group containing cells but no compounds (i.e., cell control) were placed in the cell plates. The cell plates were cultured overnight in a cell culture incubator. First, 10 mM stock solutions of the compounds (example compounds and positive control compound 11a-1) in DMSO were progressively diluted down to the 9th concentration by 3-fold dilution using DMSO. A 10th concentration (no compound) containing only DMSO was also prepared as a control. Next, DMSO solutions containing different concentrations of the compounds were diluted 100-fold with complete medium to a 1% DMSO concentration in each solution. Finally, 10 μL of each solution was added to the corresponding wells of the cell culture plate, setting the starting compound concentration to 10 μM, the adjacent concentration to a 3-fold dilution, and the DMSO concentration in the cell culture plate to 0.1%. The cell plate was then incubated in a cell culture incubator for 72 hours.

[0633] Using essentially the same experimental materials, MV4-11 cells (Nanjing Cobio Biotechnology Co., Ltd., catalog #CBP60522) were processed in the same manner. When thawing the cells, the frozen vials were rapidly shaken in a 37°C water bath until thawed within 1 minute. The thawed cell suspension was mixed with IMDM medium containing 10% FBS (HyClone, catalog #SH30228.01), centrifuged at 1000 rpm for 7 minutes, and the supernatant was discarded. The cell pellet was resuspended in 5 mL of complete medium (IMDM medium containing 10% FBS) and refrigerated for 25 cm. 2 The cells were placed in a cell culture flask with a base area of ​​10 and cultured in a cell culture incubator at 37°C, 95% humidity, and 5% CO2. The cell density was approximately 10 6 Subculturing was performed when the cell density reached approximately 10 / mL. During subculturing, the old cell suspension was thoroughly mixed, retaining 1 / 5 of the cell suspension, and 4 mL of fresh complete medium was added. After thorough mixing, the cells were returned to the cell culture incubator and cultured further. The cell density was again approximately 10 / mL. 6 Cell plating was performed when the cell density reached 1.11 × 10⁶ cells / mL. During cell plating, following the subculture method, 1 / 5 of the cell suspension was retained for continued culture, and the remaining 4 / 5 of the cell suspension was placed in a 15 mL centrifuge tube. Cell viability was determined using the trypan blue exclusion method to ensure that cell viability exceeded 90%. Complete medium was used, with a density of 1.11 × 10⁶ cells. 5A cell suspension containing 10,000 viable cells / mL was prepared. 90 μL of the cell suspension was added to a 96-well cell culture plate to achieve a cell density of 10,000 viable cells / well. A control group containing only complete medium (i.e., medium control), without cells or compounds, and a control group containing cells but no compounds (i.e., cell control) were placed. The cell plates were incubated overnight in a cell culture incubator. First, a 10 mM stock solution of the compounds (example compound and positive control compound 11a-1) in DMSO was progressively diluted down to the 9th concentration by 3-fold dilution with DMSO. A 10th concentration (no compound) containing only DMSO was also prepared as a control. Next, the DMSO solutions containing different concentrations of the compounds were diluted 100-fold with complete medium to a 1% DMSO concentration in each solution. Finally, 10 μL of each solution was added to the corresponding wells of the cell culture plate, setting the initial compound concentration to 10 μM, the adjacent concentrations to a 3-fold dilution, and the DMSO concentration in the cell culture plate to 0.1%. The cell plate was then incubated in a cell culture incubator for 72 hours.

[0634] To detect the endpoint, CellTiter-Glo reagent (Promega, catalog number #G7573, CellTiter-Glo® Luminescent Cell Viability Assay Kit) was thawed, and each cell plate was allowed to rise to room temperature for 30 minutes to equilibrate. 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. The plates were shaken in a tracked shaker for 2 minutes to completely lyse the cells. The cell plates were held at room temperature for 8 minutes to stabilize the luminescence signal. A full wavelength scan of the luminescence values ​​in each well was performed using a multi-mode microplate reader (PerkinEImer, Envision 2105 Multimode plate Read).

[0635] Use the following formula to calculate cell viability under the action of each concentration of the compound: Cell viability (%)=(Lum 試験薬物 )-Lum培地対照 ) / (Lum 細胞対照 )-Lum 培地対照 ) × 100% The data was analyzed using GmphPad Prism 8.0 software. Nonlinear S-curve regression was used to fit the data and obtain dose-response curves, from which the IC50 value was calculated.

[0636] The inhibitory activity of the example compounds on cell proliferation is shown in the table below:

[0637] [Table 20]

[0638] The above results indicate that the disclosed compounds exhibit excellent growth inhibitory activity against KYSE-520 and / or Mewo and / or MV4-11 cell lines, with an IC50 value of <1 μM, preferably <200 nM, more preferably 50-100 nM, and even more preferably <50 nM, which is significantly superior to the reference compound 11a-1 for active site inhibition. For example, the IC50 value of a representative example compound tested against KYSE-520 cells was less than one-sixth, and even less than one-thirtieth, of the IC50 value for 11a-1 (1.23 μM) (0.036 μM, Ex#20); the IC50 value for Mewo cells was less than one-fifteenth, and even less than one-hundredth, of the IC50 value for 11a-1 (3.10 μM) (0.060 μM, Ex#68). The IC50 values ​​for MV4-11 cells were generally significantly lower than those for 11a-1 cells (5.13 μM), and were even lower, down to 1 / 85th (0.060 μM, Ex#68).

[0639] Example 3 Representative inhibitory activity of the compounds disclosed herein against the proliferation of various tumor cells. This experiment used the CellTiter-Glo® Luminescent Cell Viability Assay Kit, manufactured by Promega, to evaluate the inhibitory activity of the disclosed compounds on the proliferation of the following cell lines: 4T1 (mouse mammary 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 mammary cancer cell line), CT26 (mouse colon cancer cell line), EMT6 (mouse mammary cancer cell line), HCT116 (rectal colon cancer cell line), and 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), Pan04.03 (pancreatic cancer cell line), SK-BR-3 (breast cancer cell line), THP-1 (leukemia cell line), TOV21G (ovarian cancer cell line), U87MG (glioblastoma cell line), and UM-UC-a (bladder cancer cell line).

[0640] All cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd. The following materials were also used in the experiment: RPMI-1640 medium (HyClone, catalog number #SH30022.01), McCoy's 5A medium (Thermo Fisher, catalog number #16600-082), MCDB 105 medium (Sigma, catalog number #117-500), Medium 199 (Thermo Fisher, catalog number #11150-059), MEM medium (Thermo Fisher, catalog number #11095-080), DMEM medium (HyClone, catalog number #SH30027.01), fetal bovine serum (FBS) (ExCell, catalog number #M4530), sodium pyruvate (100Mm) (Thermo Fisher, catalog number #11360-070), and MEM NEAA (100X) (Thermo Fisher). Fisher Scientific, catalog number #11140-050), Insulin-Transferrin-Selenium (ITS-G) (100X) (Thermo Fisher Scientific, catalog number #41400045), DPBS (Thermo Fisher Scientific, catalog number #14190-144), Trypsin (Thermo Fisher Scientific, catalog number #25200072).

[0641] The cells were cultured according to the instructions provided by the cell manufacturer (Nanjing Kebai Biotechnology Co., Ltd.). Thawing and subculturing of adherent and suspended cells were performed in accordance with Activity Test Example 2 above. Suspended or adherent cells were collected, and cell viability was determined using the trypan blue exclusion method, ensuring that cell viability exceeded 90%. For adherent cells, complete medium was used to subculture them at a density of 3.75 × 10⁶. 4A cell suspension was prepared at a concentration of 10⁴ cells / mL. 80 μL of the cell suspension was added to a 96-well transparent flat-bottom black-walled cell culture plate (Greiner, catalog #655090) to a cell density of 3000 viable cells / well. The suspended cells were cultured in complete medium at a density of 1.25 × 10⁴. 5 Cell suspensions at 10,000 cells / mL were prepared. 80 μL of the cell suspension was added to a 96-well cell culture plate to achieve a cell density of 10,000 viable cells / well. A control group containing only complete medium, without cells or compounds (i.e., medium control), and a control group containing cells but without compounds (i.e., cell control) were placed. The cell plates were incubated overnight in a cell culture incubator. First, 2 mM DMSO stock solutions of the compounds (example compounds and positive control compound 11a-1) were progressively diluted down to the 9th concentration by 3-fold dilution using DMSO (Damas-beta, catalog #75927R), and a 10th concentration DMSO control without the compounds was placed. Next, DMSO solutions containing different concentrations of the compounds were diluted 40-fold with complete medium so that the DMSO content of each concentration of compound solution was 2.5%. Finally, 20 μL of the above solution was added to the corresponding cell culture plate, setting the starting compound concentration to 10 μM, the inter-concentration dilution to 3-fold, and the DMSO content in the cell culture plate to 0.5%. The cell plate was incubated for a further 72 hours in a cell culture incubator. For endpoint detection, the CellTiter-Glo reagent (CellTiter-Glo® Luminescent Cell Viability Assay Kit, Promega, Catalog #G7573) was thawed, and the cell plate was transferred to room temperature for 30 minutes to equilibrate. 50 μL of CellTiter-Glo was added to each well of the cell plate, and the plate was shaken on an orbital shaker for 2 minutes to ensure complete cell lysis. The cell plate was then allowed to stand at room temperature for 8 minutes to stabilize the luminescence signal. The luminescence value of each well was measured using a multimode plate reader (PerkinElmer Envision 2105 Multimode Plate Reader) at all wavelengths.

[0642] The cell viability at each compound concentration was calculated using the following formula: Cell viability (%)=(Lum 試験薬物 )-Lum 培地対照 ) / (Lum 細胞対照 )-Lum 培地対照 ) × 100% The data was analyzed using GmphPad Prism 8.0 software. Nonlinear S-curve regression was used to fit the data, obtain dose-response curves, and calculate the IC50 value from these curves.

[0643] The inhibitory activity of representative compounds disclosed herein in various cell lines is shown in the following table:

[0644] [Table 21]

[0645] The above results demonstrate that the compounds disclosed herein exhibit broad-spectrum antitumor cell proliferation activity. Example 4 Representative compound rat PK results from this disclosure In accordance with standard methods for rat PK experiments in this field, rat PK tests were performed on representative compounds and a positive control compound (11a-1) of this disclosure as follows.

[0646] Specifically, six male SD rats (6-8 weeks old, 200±20g body weight, purchased from Vital River Laboratories) were randomly divided into two groups of three rats each, and administered intravenously (IV) and orally (PO) to the respective groups.

[0647] Intravenous injection group: The test compound was weighed according to the administration dose (1 mg / kg), dissolved using the solvents listed in the table below to obtain a clear solution of 1 mg / mL, and administered to rats at a dose of 1 mg / kg via tail vein injection.

[0648] Oral administration group: The test compound was weighed according to the administration dose (5 mg / kg), dissolved using the solvents listed in the table below, and administered orally at a final concentration of 1 mg / mL and an administration volume of 5 mL / kg.

[0649] Blood was collected via jugular vein puncture at various time points: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. At each time point, 0.2 mL of whole blood was collected and placed in a 1.5 mL anticoagulant tube containing EDTA, and then placed on a sample plate containing moist ice until centrifugation. After centrifugation at 8000 rpm at 4°C for 10 minutes, 0.1 mL of plasma sample was collected and stored at -20°C in an 81-well frozen vial until analysis.

[0650] [Table 22]

[0651] Preparation of stock solution of test compound: 1 mg of the test compound was accurately weighed and dissolved 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.

[0652] Preparation of internal standard working solution: 0.1 mL of tolbutamide (2 mg / mL) internal standard stock solution was pipetted into 1000 mL of acetonitrile to prepare a 200 ng / mL internal standard working solution. This is used as a protein precipitant in sample preparation. The prepared internal standard working solution should be stored at 4°C and will remain effective for 12 months.

[0653] Preparation of calibration curve and quality control sample working solutions: 50 μL of 1 mg / mL test compound DMSO stock solution S1 was diluted with 950 μL of 100% methanol solution to obtain a working solution with a concentration of 50,000 ng / mL. The 50,000 ng / mL working solution was then serially diluted with 100% methanol solution to obtain a series of calibration curve working solutions with concentrations of 10, 20, 50, 100, 500, 1000, 5000, 10000, 20000, and 50000 ng / mL. 40 μL of 1 mg / mL test compound DMSO stock solution S1 was diluted with 960 μL of 100% methanol solution to obtain a quality control sample working solution with a concentration of 40,000 ng / mL. Appropriate amounts of this working solution were appropriately diluted to prepare quality control sample working solutions with concentrations of 8000 ng / mL and 16000 ng / mL. 60 μL of a DMSO calibration curve working solution containing 50 ng / mL of the test compound was diluted with 40 μL of 100% methanol solution to obtain a quality control sample working solution with a concentration of 30 ng / mL.

[0654] Processing of plasma samples: Calibration curves and quality control samples for the test compound in plasma were prepared by diluting 5 μL of working solution of the test compound at different concentrations for the calibration curve and quality control samples with 45 μL of blank rat plasma. The final concentrations for the calibration curve were 1, 2, 5, 10, 50, 100, 500, 1000, 2000, and 5000 ng / mL, and the final concentrations for the quality control samples were 3,800, 1600, and 4000 ng / mL.

[0655] Plasma sample pretreatment: 50 μL of plasma sample was transferred to a 96-well plate, 500 μL of acetonitrile containing 200 ng / mL tolbutamide as an internal standard for protein precipitation was added, and the plate was centrifuged at 4000 rpm for 20 minutes at 2-8°C. 300 μL of the supernatant was transferred to a newly labeled 96-well plate, thoroughly mixed with 300 μL of 0.1% formic acid in water, and 10 μL of the mixture was injected into an LC-MS / MS (API-4000 Qtrap-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 98%-2% / A 2%-98%, maintained until 1.5 min, 1.50-1.51 min, to 98% B / 2% A, 1.51-2.00 min, maintained at 98% B / 2% A; Column: Waters Xbridge C18 3.5 μm 2.1 × 50 mm, Injection volume: 10 μL; Flow rate: 0.5 mL / min.

[0656] The internal standard method was used for sample analysis. Data acquisition and analysis were performed using Analyst 1.6.3. The theoretical concentration of the calibration curve was used as the x-axis, and the ratio of the peak area of ​​the analyte to the peak area of ​​the internal standard was used as the y-axis. Linear regression was performed using the least squares method to obtain the calibration curve equation (weighted 1 / X). 2 The simulation was performed using the fitted model, with R2 > 0.9900. The results are shown in the table below:

[0657] [Table 23]

[0658] The results in the table above show that the oral pharmacokinetic properties of the representative compounds disclosed herein have been significantly improved. Example 5 Selectivity experiment of the compound of the present invention against tyrosine phosphatase This experiment evaluates the selectivity of the disclosed compounds for tyrosine phosphatases including SHP1, HePTP, Laforin, LMWPTP, LYP, PTP1B, PRL2, SSU72, VHR, FAP1, STEP, CDC14A, CD45, MEG2, and PP5, all of which were expressed and purified from E. coli.

[0659] Phosphatase activity was measured using p-nitrophenyl phosphate (pNPP) (Fisher Scientific) as the substrate in 50 mM 3,3-dimethylglutarate buffer (pH 7.0, containing 1 mM EDTA), and the ionic strength was adjusted to 0.15 M with NaCl. In a 384-well plate, 20 μL of each enzyme solution in the aforementioned 3,3-dimethylglutarate buffer was added to 30 μL of a reaction mixture containing 5 μM of the compound (example compound and positive control compound 11a-1) and a specific concentration of pNPP (using the pNPP concentration corresponding to the Km value of each enzyme being tested) to initiate the reaction. After 10–60 minutes, the reaction was quenched by adding 20 μL of 5N NaOH. Wells without enzymes were used as corrective controls. The amount of the product, p-nitrophenol, was measured using a molar extinction coefficient of 18000 M. -1 cm -1 The absorbance was determined by measuring it at 405 nm using a Spectra MAX340 microplate spectrophotometer (Molecular Devices).

[0660] The data was analyzed using GraphPad Prism software. A dose-response-inhibition model equation for nonlinear S-shaped regression was used to fit the data, obtain dose-response curves, and calculate IC50 values.

[0661] The selectivity of representative compounds disclosed herein for tyrosine phosphatases is shown in the following table:

[0662] [Table 24]

[0663] The above results demonstrate that the representative compounds of this disclosure exhibit good selectivity for SHP2 on a PTP phosphatase panel. Example 6 hERG activity of representative compounds This experiment was conducted as a non-GLP trial, referring to GLP guidelines and following the following technical guidelines: National Medical Products Administration: Technical Guidelines for Non-Clinical Studies of Potential Effects of Drugs on QT Interval Prolongation (2014), and ICH S7B Guidelines for Non-Clinical Evaluation of Potential Drug-Induced Delayed Ventricular Repolarization (QT Interval Prolongation) in Humans (2005).

[0664] Sample preparation: The weighed test substance was prepared into a 5 mM or 10 mM stock solution using DMSO, and then diluted with DMSO to a 3.33 mM dilution. Next, the stock solution was diluted with extracellular fluid to prepare a 10 μM working solution, ensuring that the DMSO concentration was 0.3%. The solution was sonicated for 20 minutes. The solubility of the test sample was visually inspected. At all concentrations, no precipitate was visible, indicating complete dissolution.

[0665] Preparation of positive control: 3.99 mg of cisapride (positive control) was prepared into a 10 mM stock solution using 807.96 μL of DMSO. This stock solution was then sequentially diluted with DMSO to 1000, 333.33, 33.33, 3.33, and 0.33 μM dilutions. Before testing, 30 μL of each of the last four dilutions was added to 10 mL of extracellular solution to ensure a DMSO concentration of 0.3%. The final working solution concentrations of cisapride were 1000, 100, 10, and 1 nM. The solubility of cisapride was visually inspected. At all concentrations, it was completely dissolved without any visible precipitate.

[0666] Store the blank control stock solution (DMSO) at room temperature. Prepare the blank control working solution on the same day and store it at room temperature. Store the test substance and positive control stock solution at -20°C. Prepare the test substance working solution on the same day and store it at room temperature. Prepare the positive control working solution on the same day and store it at room temperature.

[0667] We used the HEK-293 cell line (purchased from Creacell, catalog number #A-0320) which stably expresses the hERG potassium channel. Specifically, the HEK-293 cell line, which stably expresses the hERG potassium channel, was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL of G418 (37°C, 5% CO2). The old medium was removed, the cells were washed once with PBS, and then 1 mL of TrypLE® Express solution (Gibco, catalog number #12604-021) was added, and the cells were incubated at 37°C for 0.5 min. Once the cells separated from the bottom of the petri dish, approximately 5 mL of DMEM medium, preheated to 37°C and containing 10% fetal bovine serum and 0.8 mg / mL of G418, was added. The cell suspension was gently pipetteed, and the aggregated cells were separated. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to collect the cells. For expanding or maintaining the culture, the cells were placed in 6 cm cell culture dishes, 2.5 × 10⁶ cells per dish. 5Cells were seeded at a seeding density of 1 cell (final volume: 5 mL). To maintain cellular electrophysiological activity, the cell density should not exceed 80%.

[0668] Prior to the patch clamp assay, cells were isolated using TrypLE® Express and 4 × 10 3 The cells were seeded onto coverslips and cultured in a 24-well plate (final volume: 500 μL). A patch-clamp assay was performed within 18 hours.

[0669] The hERG activity of representative compounds in this disclosure was detected using conventional manual patch-clamp techniques in the art (Patch-Clamp Methods and Protocols, 2014, 2nd edition, Humana Press, edited by Marzia Martina and Stefano Taverna).

[0670] [Table 25]

[0671] The above results indicate that the representative compounds disclosed herein do not exhibit inhibitory activity against hERG at a concentration of 10 μM. Example 7 CYP450 inhibitory activity of representative compounds The inhibitory effects of the disclosed compounds on the cytochrome P450 enzyme system were similarly tested below, following the standard methods in this field for experiments on the cytochrome P450 enzyme system, for example, Kerns, Edward H., and Di Li et al., Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization (2008), San Diego, Academic Press, and Lin, Tong et al., 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, Vol. 96 (No. 9), p. 2485).

[0672] Human liver microsomes were purchased from Corning or Xenotech. Test compounds were evaluated by detecting the metabolism of substrates against different Cyp450 isoforms by human liver microsomes.

[0673] The following table shows specific inhibitor solutions, substrate solutions, and internal standard information:

[0674] [Table 26]

[0675] 0.1M potassium phosphate buffer (K-buffer, pH 7.4) was preheated. A 100 mM K-buffer solution was prepared by mixing 9.5 mL of stock solution A (prepared by dissolving 136.5 g of 1 M potassium dihydrogen phosphate in 1 L of Milli-Q water) with 40.5 mL of stock solution B (prepared by dissolving 174.2 g of 1 M potassium hydrogen phosphate in 1 L of Milli-Q water). The total volume was adjusted to 500 mL using Milli-Q water, and the buffer solution was titrated to pH 7.4 using KOH or H3PO4.

[0676] Test compound solutions and specific inhibitor solutions (400× dilutions) were prepared in 96-well plates. For the test compound, 8 μL of 10 mM test compound was transferred to 12 μL of ACN. For inhibitors specific to CYP1A2, CYP2C9, and CYP2D6, 12 μL of 1 mM α-naphthoflavone, 10 μL of 40 mM sulfafenazole, 10 μL of 10 mM quinidine, and 8 μL of DMSO were mixed. For inhibitors specific to CYP3A4, CYP2B6, CYP2C8, and CYP2C19, 8 μL of DMSO stock solution was added to 12 μL of ACN.

[0677] A 4x diluted NADPH solution was prepared by dissolving 66.7 mg of NADPH in 10 mL of 0.1 MK-buffer (pH 7.4). Human liver microsome (HLM) solutions were prepared in potassium buffer, with concentrations of 0.1 mg / mL for CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP2B6, 0.5 mg / mL for CYP2C19, and 0.2 mg / mL for CYP2C8. Four-fold diluted substrate solutions (2 mL per isozyme) were prepared in potassium buffer (with HLM added on ice if necessary) at the following concentrations: 120 μM for CYP1A2, 40 μM for CYP2C9, 140 μM and 1.6 mg / mL HLM for CYP2C19, 40 μM for CYP2D6, 320 μM and 20 μM (two concentrations) for CYP3A4, 280 μM for CYP2B6, and 40 μM and 0.4 mg / mL HLM for CYP2C8.

[0678] A 0.2 mg / mL HLM solution was prepared on ice (10 μL of 20 mg / mL stock solution was added to 990 μL of 0.1 MK buffer). 400 μL of 0.2 mg / mL HLM solution was added to the assay well, followed by 2 μL of 400× diluted test compound solution, and this was added to the designated well on ice. 200 μL of 0.2 mg / mL HLM solution was added to the assay well, followed by 1 μL of specific inhibitor solution, and this was added to the designated well on ice. The following solutions were added to a 96-well analysis plate in two repeated steps and kept on ice. 30 μL of 2× diluted test compound solution and specific inhibitor solution were added to the 0.2 mg / mL HLM solution, followed by 15 μL of 4× diluted substrate solution. The 96-well assay plate and NADPH solution were pre-incubated at 37°C for 5 minutes. The reaction was initiated by adding 15 μL of pre-warmed 8 mM NADPH solution to the assay plate. The reaction was carried out at 37°C for the following durations according to the P450 isoform: 5 min for CYP3A4, 10 min for CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6, and 45 min for CYP2C19. The reaction was stopped by adding 120 μL of ACN containing the internal standard. The final internal standard concentrations were 0.1 μM for CYP2C19, CYP1A2, CYP3A4 (midazolam), and CYP2D6; 200 ng / mL for CYP3A4 (testosterone); 0.31 μM for CYP2C9; 0.36 μM (100 ng / mL) for CYP2B6; and 40 ng / mL for CYP2C8.

[0679] After quenching, the plate was shaken at 600 rpm for 10 minutes on a vibrating shaker (IKA, MTS2 / 4), and then centrifuged at 5594 g for 15 minutes (Thermo Multifuge × 3R). 50 μL of supernatant from each well was transferred to a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01), and LC / MS analysis was performed (column: ACQUITY UPLC BEHC18 (2.1 × 50 mm, 1.7 μm), mobile phase A: H2O-0.025% FA-1 mM NH4OAc, mobile phase B: MeOH-0.025% FA-1 mM NH4OAc, flow rate: 0.6 mL / min).

[0680] The following table shows the CYP inhibition results of representative compounds of the present invention:

[0681] [Table 27]

[0682] The results described above indicate that the representative compounds of this disclosure do not exhibit significant inhibitory activity against major P450 enzymes. This suggests a significant reduction in the risk of drug interactions and greatly facilitates the combined use of the compounds of this disclosure with other active substances.

[0683] While the present invention is described in relation to its particular embodiments, it should be understood that the invention is subject to further modifications. This application is intended to cover all variations, uses, or modifications to the principles generally followed by the invention, including deviations from this disclosure that are known or customary in the art to which the invention is associated, and that are applicable to the basic features described above and to the claims.

Claims

1. Compounds of formula (I), their pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants. 【Chemistry 1】 or its pharmaceutically acceptable salts, isomers, solvates, hydrates, or stable isotope variants. [In the formula, 【Chemistry 2】 This represents a saturated, partially unsaturated, or aromatic ring system. 【Transformation 3】 This represents an aromatic ring system, A １ 、 A ２ 、 A ３ 、 A ４ 、 A ５ is, independently of each other, selected from C, N, O, and S and does not exist, A ６ is selected from C and N, provided that (1) A １ to A ５ that do not exist are up to a maximum of two, and (2) A １ to A ６ that are heteroatoms are up to a maximum of four, R ａ is -H, =O, =S, =N-OH, -OH, -NH ２ , halogen, -CN and -C optionally substituted with halogen １～６ Selected from alkyl groups, A ７ A ８ and A ９ Each is independently selected from C, N, O, and S, however A ７ A ８ and A ９ At least one of them is not C, A １０ CR ｂ and selected from N, A １１ It is selected from C-X and N, R ｂ -C is substituted with H, halogen, CN, and halogen. １～６ Selected from alkyl groups, X is H, halogen, CN, -OH, -OC １～６ Alkyl and -C １～６ Selected from alkyl groups, C １～６ Alkyl is optionally substituted, Y is -C １～６ Alkyl, -(CH ２ ) ｔ -3-15 member carbocyclyl, -(CH ２ ) ｔ -C ６～１０ (CH) having one or more heteroatoms independently selected from aryl, N, O, and S ２ ) ｔ -Having 5- to 12-membered heteroaryls, and one or more heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - A group that is optionally substituted, selected from 3- to 15-membered heterocyclines. Z is -C ６～１０ A divalent group that is optionally substituted, selected from aryl-, -3 to 10-membered carbocyrill-, -5 to 12-membered heteroaryls having one or more heteroatoms independently selected from N, O, and S, and -3 to 15-membered heterocyclines having one or more heteroatoms independently selected from N, O, and S. R is -C ６～１０ The optionally substituted group is selected from aryls, -3 to 15-membered carbocyrills, -5 to 12-membered heteroaryls having one or more heteroatoms independently selected from N, O, and S, and 3 to 15-membered heterocyclines having one or more heteroatoms independently selected from N, O, and S. t is an integer of any choice between 0 and 3.

2. Y, -C １～６ Alkyl, - (CH ２ ) ｔ - 3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, - (CH ２ ) ｔ - 5-10 membered cross-linked saturated or partially unsaturated carbon rings, - (CH ２ ) ｔ -6 to 15 member spirotype or condensed saturated or partially unsaturated carbon rings, - (CH ２ ) ｔ -C ６～１０ Ariel, (CH) has 1 to 4 heteroatoms independently selected from N, O, and S. ２ ) ｔ - 5 to 12 member heteroaryls, (CH) has 1 to 3 heteroatoms independently selected from N, O, and S. ２ ) ｔ -3 to 8-membered monocyclic saturated or partially unsaturated heterocyclic rings, (CH) has 1 to 3 heteroatoms independently selected from N, O, and S. ２ ) ｔ - 5 to 10-membered bridged saturated or partially unsaturated heterocycles, and (CH) has 1 to 4 heteroatoms independently selected from N, O, and S. ２ ) ｔ -6 to 15 member spirotype or condensed saturated or partially unsaturated heterocycles A base that is selected from and substituted by choice, Z is -C ６～１０ Ariel, - 3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, - 5-10 membered cross-linked saturated or partially unsaturated carbon rings, -5 to 12-membered heteroaryls having 1 to 4 heteroatoms independently selected from N, O, and S, -3 to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S, -5 to 10-membered bridged saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S, and -6 to 15 member spirotype or condensed saturated or partially unsaturated heterocycles having 1 to 4 heteroatoms independently selected from N, O, and S. A divalent base that is arbitrarily substituted, selected from the following: R is, -C ６～１０ Ariel, - 3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, - 5-10 membered cross-linked saturated or partially unsaturated carbon rings, -6 to 15 spiro-type or condensed saturated or partially unsaturated carbon rings, -5 to 12-membered heteroaryls having 1 to 4 heteroatoms independently selected from N, O, and S, -3 to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S, -5 to 10 membered bridging saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S, -6 to 15 membered spirotype or condensed saturated or partially unsaturated heterocycles having 1 to 4 heteroatoms independently selected from N, O, and S. The compound according to claim 1, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, wherein the group is optionally substituted, selected from the above. 【Request Item 3】 【Chemistry 4】 However, 0 to 1 R ａ A is a five-membered partially unsaturated or aromatic group having 3 to 4 cyclic heteroatoms selected from N, O, and S, which are optionally substituted by A. ６ C is R ａ However, -H, -CN, halogen, =O, and -C substituted with halogen １～６ A compound according to claim 1 or 2, selected from alkyl groups, a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotope variant thereof.

4. A ７ and A ９ One of them is a heteroatom selected from N, O, and S, and the other is C, A ８ is a carbon atom; preferably A ７ However, it is selected from C-Y and N-Y, A ９ However, selected from C, O, and S, A ７ and A ９ Only one of them is a heteroatom, A ８ A compound according to any one of claims 1 to 3, wherein is a carbon atom, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof.

5. A １０ CR ｂ A １１ C-X is R ｂ A compound according to any one of claims 1 to 4, wherein is selected from H and X is selected from halogens and -OH, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof.

6. Y is -C １～６ alkyl, -(CH ２ ) ｔ -3 to 8-membered monocyclic saturated or partially unsaturated carbocyclic ring, -(CH ２ ) ｔ -5 to 10-membered bridged saturated or partially unsaturated carbocyclic ring, -(CH ２ ) ｔ -C ６～１０ aryl, a group optionally selected and optionally substituted, preferably -C １～６ alkyl, -(CH ２ ) ｔ -3 to 6-membered monocyclic saturated carbocyclic ring, -(CH ２ ) ｔ -5 to 8-membered bicyclic bridged saturated carbocyclic ring, and -(CH ２ ) ｔ -phenyl, a group optionally selected and optionally substituted, the compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant.

7. Y's -C １～６ The alkyl group is optionally substituted with a halogen or CN, and the cyclic group of Y is -C １～６ Alkyl and -OC １～６ A compound according to any one of claims 1 to 6, optionally substituted with one to three, preferably one or two, more preferably one, groups selected from alkyl groups, a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotope variant thereof.

8. Z is -C ６～１０ A compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, selected from aryl-, -3 to 8-membered monocyclic saturated or partially unsaturated carbocyclics-, -5 to 10-membered bridged saturated or partially unsaturated carbocyclics-, and optionally substituted -3 to 8-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S; preferably Z is selected from phenyl, -3 to 6-membered monocyclic saturated or partially unsaturated carbocyclics-, -5 to 8-membered bridged saturated carbocyclics-, and optionally substituted -4 to 7-membered monocyclic saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from N, O, and S, the compound, is a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof.

9. Z is optionally substituted by one or more groups independently selected from halogen, -C １～６ alkyl or -OC １～６ alkyl, and -C １～６ alkyl is optionally substituted by halogen or CN; preferably Z is unsubstituted, the compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant.

10. R is an optionally substituted group selected from a range of heteroaryl or bicyclic heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S; monocyclic saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S; bridging saturated or partially unsaturated heterocycles having 1 to 3 heteroatoms independently selected from N, O, and S; and spirotype or condensed saturated or partially unsaturated heterocycles having 1 to 4 heteroatoms independently selected from N, O, and S, preferably N, O, and A compound according to any one of claims 1 to 9, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, wherein the optionally substituted group is selected from a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from S, a 4-7 member monocyclic saturated or unsaturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, a 5-8 member bicyclic bridged saturated heterocycle having 1-2 heteroatoms independently selected from N, O and S, and a 7-11 member spirotype or condensed saturated heterocycle having 1-3 heteroatoms independently selected from N, O and S.

11. R is halogen, CN, -OH, -NH ２ , -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkinyl, -OC １～６ Alkyl, -NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ ,-(CH ２ ) ｔ -3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, -(CH ２ ) ｔ -Having a 5- to 8-membered bridged saturated or partially unsaturated carbon ring, and 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - A 3- to 8-membered monocyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - Substituted with 0 to 4, preferably 0 to 3, more preferably 0 to 2 groups independently selected from 5 to 8-membered bridged saturated or partially unsaturated heterocycles, wherein two substituents bonded to the same ring carbon atom may, together with the carbon atom to which they are bonded, form a 3 to 8-membered saturated spirocarbocyclic ring, and the substituent's -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ The alkynyl or cyclic group can be, independently and optionally, a halogen, CN, -OH, or -OC. １～６ It is substituted with alkyl; preferably, R is halogen, CN, -OH, -C １～６ Alkyl, -OC １～６ Alkyl 、 (CH) has one or two heteroatoms independently selected from N, O, and S. ２ ) ｔ - Substituted with a group selected from 4- to 7-membered monocyclic saturated heterocycles, two substituents bonded to the same carbon atom may form a 3- to 6-membered saturated spirocarbocycle together with the carbon atom to which they are bonded, and the substituent C １～６ Alkyl is halogen, CN, -OH, or -OC １～６ A compound according to any one of claims 1 to 10, optionally substituted with an alkyl group, a pharmaceutically acceptable salt, isomer, solvate, hydrate, or stable isotope variant thereof.

12. R is given by equation (A) 【Transformation 5】 [In the formula, f is selected from integers 0 to 3, preferably integers 0 to 2. t is selected from integers 0 to 3, preferably integers 0 to 1. G is O, N-R ２ and CR ３ R ４ Selected from, preferably O and CR ３ R ４ And most preferably CR ３ R ４ And, R １ H, and halogens, CN, -OH or -OC １～６ -C is optionally substituted with alkyl. １～６ Two R's selected from alkyl groups and bonded to the same ring carbon atom. １ These may also form a 3- to 8-membered saturated spirocarbon ring together with the carbon atoms to which they are bonded; preferably, R １ H and -OH or -OC １～６ -C is optionally substituted with alkyl. １～６ Selected from alkyl groups; most preferably, R １ H and -C １～６ Selected from alkyl groups, R ３ and R ４ These are H, halogen, CN, -OH, and -NH, respectively, independently. ２ , -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkinyl, -OC １～６ Alkyl, -NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ ,-(CH ２ ) ｔ -3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, -(CH ２ ) ｔ -Having a 5- to 8-membered bridged saturated or partially unsaturated carbon ring, and 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - A 3- to 8-membered monocyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - Selected from 5- to 8-membered bridging saturated or partially unsaturated heterocycles, or R ３ and R ４ These, together with the ring carbon atoms to which they are bonded, form a 3- to 8-membered saturated spirocarbon ring, and among the substituents -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ The alkynyl or cyclic group can be a halogen, CN, -OH, or -OC, independently and optionally. １～６ Substituted with alkyl; preferably R ３ and R ４ H, halogen, CN, -OH, -C １～６ Alkyl, -OC １～６ (CH) has one or two heteroatoms independently selected from alkyl, N, O, and S. ２ ) ｔ - Selected from 4- to 7-membered monocyclic saturated heterocycles, or R ３ and R ４ These, together with the ring carbon atoms to which they are bonded, form a 3-6 member saturated spirocarbon ring, and the C in the substituent １～６ Alkyls are halogens, CN, -OH, or -OC １～６ Optionally substituted with alkyl; more preferably R ３ and R ４ H, halogen, CN, -C １～６ A 4- to 7-membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from alkyl, N, O, and S, with C among the substituents. １～６ Alkyls are halogens, -OH, or -OC １～６ It is optionally further substituted with alkyl groups. R ２ H, -C １～６ Alkyl, -(CH ２ ) ｔ -3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, -(CH ２ ) ｔ -Having a 5- to 8-membered bridged saturated or partially unsaturated carbon ring, and 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ -3- to 8-membered monocyclic saturated or partially unsaturated heterocycles, and having 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - Selected from 5- to 8-membered bridged saturated or partially unsaturated heterocycles, with C in the substituent. １～６ Alkyl or cyclic groups include halogens, CN, -OH, or -OC １～６ It is optionally substituted with alkyl; preferably, R ２ H, -C １～６ - (CH) having one or two heteroatoms independently selected from alkyl, N, O, and S ２ ) ｔ - Selected from 4- to 7-membered monocyclic saturated heterocycles, with C in the substituent １～６ Alkyls are halogens, CN, -OH, or -OC １～６ Optionally substituted with alkyl; more preferably R ２ H, -C １～６ A 4- to 7-membered monocyclic saturated heterocycle having 1-2 heteroatoms independently selected from alkyl, N, O, and S, with C among the substituents. １～６ Alkyls are halogens, -OH or -OC １～６ It is optionally substituted with alkyl, If f is 0, then G is -CH ２ -is] A compound according to any one of claims 1 to 10, having a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof.

13. R is given by the following formula: 【Transformation 6】 [In the formula, k is an integer from 0 to 2, m and n are independently integers from 1 to 3, and l is an integer from 1 to 4, preferably k is an integer from 0 to 2, m and n are independently integers from 1 to 2, and l is an integer from 1 to 3. r and p are each independently integers from 0 to 3, and 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. t is selected from integers 0 to 3, preferably from integers 0 to 1. G is O, N-R ２ and CR ３ R ４ Selected from, preferably O and CR ３ R ４ Selected from, R １ H, and halogens, CN, -OH or -OC １～６ -C is optionally substituted with alkyl. １～６ Two R's selected from alkyl groups and bonded to the same ring carbon atom. １ These may also form a 3- to 8-membered saturated spirocarbon ring together with the carbon atoms to which they are bonded; preferably, R １ H and -OH or -OC １～６ -C is optionally substituted with alkyl. １～６ Selected from alkyl groups; more preferably R １ H is, R ３ and R ４ These are H, halogen, CN, -OH, and -NH, respectively, independently. ２ , -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkinyl, -OC １～６ Alkyl, -NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ ,-(CH ２ ) ｔ -3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, -(CH ２ ) ｔ -Having a 5- to 8-membered bridged saturated or partially unsaturated carbon ring, and 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - A 3- to 8-membered monocyclic saturated or partially unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - Selected from 5- to 8-membered bridging saturated or partially unsaturated heterocycles, or R ３ and R ４ These, together with the ring carbon atoms to which they are bonded, form a 3- to 8-membered saturated spirocarbon ring, and among the substituents -C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ The alkynyl or cyclic group can be a halogen, CN, -OH, or -OC, independently and optionally. １～６ Substituted with alkyl; preferably R ３ and R ４ H, halogen, CN, -OH, -C １～６ Alkyl, -OC １～６ (CH) has one or two heteroatoms independently selected from alkyl, N, O, and S. ２ ) ｔ - Selected from 4- to 7-membered monocyclic saturated heterocycles, or R ３ and R ４ These, together with the ring carbon atoms to which they are bonded, form a 3-6 member saturated spirocarbon ring, and the C in the substituent １～６ Alkyls are halogens, CN, -OH, or -OC １～６ Optionally substituted with alkyl; more preferably R ３ and R ４ H, -OH, -C １～６ Selected from alkyl groups, C in the substituent １～６ Alkyls are halogens, -OH, or -OC １～６ It is optionally further substituted with alkyl groups. R ２ H, -C １～６ Alkyl, -(CH ２ ) ｔ -3 to 8-membered monocyclic saturated or partially unsaturated carbon rings, -(CH ２ ) ｔ -Having a 5- to 8-membered bridged saturated or partially unsaturated carbon ring, and 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ -3- to 8-membered monocyclic saturated or partially unsaturated heterocycles, and having 1 to 3 heteroatoms independently selected from N, O, and S - (CH ２ ) ｔ - Selected from 5- to 8-membered bridged saturated or partially unsaturated heterocycles, with C in the substituent. １～６ Alkyl or cyclic groups include halogens, CN, -OH, or -OC １～６ It is optionally substituted with alkyl; preferably, R ２ H, -C １～６ - (CH) having one or two heteroatoms independently selected from alkyl, N, O, and S ２ ) ｔ - Selected from 4- to 7-membered monocyclic saturated heterocycles, with C in the substituent １～６ Alkyl or cyclic groups include halogens, CN, -OH, or -OC １～６ Optionally substituted with alkyl; more preferably, R ２ H, -C １～６ Selected from alkyl groups, C １～６ Alkyls are halogens, -OH or -OC １～６ [Further substitution with alkyl groups is optional.] A compound according to any one of claims 1 to 10, having a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof.

14. The following formula: 【Transformation 7】 [In the formula, A １ ~A １１ , R ａ , R ｂ Y, G, R １ t, f, m, k, n, l, r, p and q are as defined in claims 1 to 13, respectively, for the compound of formula (I), and the structural fragments of formula (A), formula (B), and formula (C). 【Transformation 8】 It preferably has 3 to 4 ring heteroatoms selected from N, O, and S, and 0 to 1 R ａ A five-membered partially unsaturated or aromatic group optionally substituted by, more preferably having 3 to 4 nitrogen heteroatoms and 0 to 1 R ａ A five-membered aromatic group that is optionally substituted by, most preferably a five-membered aromatic group having four nitrogen heteroatoms; A １１ Preferably C-X, A １０ is N and CR ｂ Selected from, A ８ C is R ｂ H is preferred, A ７ is selected from C-Y or N-Y, A ９ is selected from C, O, and S, A ７ and A ９ [Only one of them is a heteroatom] Having; Preferably, the following formula: 【Chemistry 9】 A compound according to claim 1, having the above, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof.

15. Compounds of Examples 1 to 134, including compounds, pharmaceutically acceptable salts thereof, isomers, solvates, hydrates, or stable isotope variants.

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 isotope 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 isotope variant thereof, or a pharmaceutical composition according to claim 16, for use as a pharmacopoeia for the treatment and / or prevention of SHP2-mediated diseases.

18. Use of a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, isomer, solvate, hydrate or stable isotope variant thereof, or the pharmaceutical composition according to claim 16 in the preparation of a pharmaceutical for the prevention or treatment of SHP2-mediated diseases.

19. A method for treating and / or preventing an SHP2-mediated disease, comprising the step of administering to a subject in need 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 isotope variant thereof, or a pharmaceutical composition according to claim 16.

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

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