WRN inhibitors

Abstract

The present invention provides compounds of formula (I) as WRN inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof, and mixtures thereof. The present invention further provides pharmaceutical compositions containing the compounds and uses of the compounds in the treatment of cancer. JPEG2026502971000217.jpg40170

Description

[Technical Field]

[0001] This application claims priority to Chinese Application No. 202211693494.7 filed on December 30, 2022, Chinese Application No. 202310452664.0 filed on April 25, 2023, Chinese Application No. 202310613550.X filed on May 29, 2023, Chinese Application No. 202310734540.1 filed on June 20, 2023, Chinese Application No. 202310965757.3 filed on August 2, 2023, Chinese Application No. 202311081481.9 filed on August 25, 2023, and Chinese Application No. 202311684693.6 filed on December 8, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present invention is in the field of medicine, and specifically relates to WRN inhibitors. [Background technology]

[0003] Abnormalities in DNA mismatch repair (MMR) lead to frequent mutations (deletions or insertions) in DNA nucleotide repeat regions, called microsatellite instability (MSI). Microsatellite instability-high (MSI-H) is associated with the development of tumors, including colorectal cancer, gastric cancer, endometrial cancer, and ovarian cancer (Nature, 2019, 568, 551-556), with the highest mutation rates in colorectal cancer (15%) and gastric cancer (22%). PD-1 / PD-L1 immunotherapy has demonstrated significant therapeutic benefits for multiple tumors. For example, pembrolizumab significantly improved median progression-free survival (PFS) compared with chemotherapy in patients with late-stage MSI-H colorectal cancer and has been approved by the FDA as first-line therapy (N. Engl. J. Med. 2020, 383, 2207-2218). However, many patients with MSI-H tumors are currently unable to benefit from this treatment. Furthermore, according to a report from the 2022 ASCO meeting, the Phase 2 clinical trial CheckMate 142 (NCT02060188) used the dual immunotherapy PD-1+CTLA-4 (nivolumab+ipilimumab) combination to treat metastatic colorectal cancer patients. Whether patients received first-line or second-line therapy, over half of patients experienced tumor recurrence after four years of follow-up. Therefore, new treatment options are urgently needed.

[0004] Synthetic lethality refers to the fact that inactivation of a single gene in tumor cells has no significant effect on tumor cell survival, but simultaneous inactivation of the two genes can result in tumor cell death (Nat.Rev.DrugDisc.2020,19(1):23-38, CancerDisc.2021,11(7):1626-1635). Synthetic lethal targeted drugs generally can generate a good therapeutic safety margin and improve the development potential of targets with high mutation rates but that are difficult to drug. Currently, the most successful synthetic lethality studies are with PARP1 / 2 inhibitors, such as olaparib, rucaparib, and niraparib. These drugs have demonstrated excellent therapeutic effects in the treatment of BRCA1 / 2-mutated ovarian cancer and breast cancer, and have been approved and marketed one after another (Nat.Rev.DrugDisov.2020,19(10):711-736; Nat.Rev.Clin.Oncol.2020,17(3):136-137). In 2019, Adam J. Bass published two consecutive Nature papers demonstrating that Werner helicase (WRN) is a synthetic lethal target in MSI-H tumors (Nature, 2019,568,551-556; Nature, 2019,586,292-298). Knocking out the entire WRN gene or mutating the WRN helicase (which causes loss of helicase function) to K557M both induces apoptosis and apoptosis in MSI-H tumor cells. Furthermore, Matthew J. Garnett et al. found that even when tumor cells from MSI-H patients had developed drug resistance after chemotherapy and immunotherapy, inhibiting WRN could further inhibit tumor growth (Cancer Discov. 2021, 11, 1923-1937).

[0005] Despite progress in WRN research, no WRN inhibitors have yet entered clinical trials for the treatment of MSI-H-associated cancers. The WRN inhibitors provided by the present invention, which have novel structures, are expected to meet this clinical need. Summary of the Invention [Means for solving the problem]

[0006] In one aspect, the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof: [ka] During the ceremony, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring A is absent or C 3~10 a cycloalkyl group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or C 6~10 aryl groups; R1 is selected from a 5- to 12-membered heteroaryl group or a 5- to 12-membered heterocyclyl group, and R1 is a pyridyl group or [ka] provided that R is not an integer of 1 to 5, and R is optionally 1, 2, 3, 4, or 5 R x is replaced by R x are H, D, halogens, NH2, CN, OH, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NH-R a , -NHC(O)-R a , -(CH2) p -OR a , -(CH2) p -C(O)R a , -P(O)-(R a )2 or -S(O)2-R a where R a is H, C 1~6 Alkyl group, C 1~6haloalkyl group or C 3~6 cycloalkyl groups, and p is selected from 0, 1, 2, 3, or 4; or two R x together form oxo or thio, R2 is H, D, halogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is H, D, halogen, NH2, CN, OH, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group or C 3~6 cycloalkyl groups, or R3 on two different carbon atoms are bonded to form a bridged ring, or two R3 on the same carbon atom are bonded to form a C 3~10 Cycloalkyl groups, 5-10 membered heteroaryl groups, C 3~10 forming a cycloalkyl group or a 3- to 10-membered heterocyclyl group, R4 is H, D, halogen, NH2, CN, OH, SF5, SCF3, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, C 1~6 Alkylthio group, C 3~10 a cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or C 6~10 aryl groups; R5 is H, D, halogen, NH2, CN, OH, C 1~6 Alkyl group, C 1~6 Deuterated alkyl groups, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R1-R5 may optionally be deuterated until fully deuterated.

[0007] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and, optionally, a pharmaceutically acceptable excipient.

[0008] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, and further comprising another therapeutic agent.

[0009] In another aspect, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment and / or prevention of a disease mediated by WRN.

[0010] In another aspect, the present invention provides a method for treating and / or preventing a disease mediated by WRN in a subject, the method comprising administering to the subject a compound of the present invention or a composition of the present invention.

[0011] In another aspect, the present invention provides a compound of the present invention or a composition of the present invention for use in treating and / or preventing a disease mediated by WRN.

[0012] In specific embodiments, the disease treated by the present invention is acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct carcinoma, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kabosi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., , uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia, acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma (CCL). NS) lymphomas, and T-cell non-Hodgkin's lymphomas, for example, precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (e.g., cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma), a mixture of one or more of the above leukemias / lymphomas, multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis,Kidney cancer (e.g., nephroblastoma, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myeloid metaplasia (AMM), The cancers include those selected from chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, and penile cancer.

[0013] Other objects and advantages of the present invention will become apparent to those skilled in the art from the following specific embodiments, examples, and claims. definition

[0014] chemical definition Specific functional groups and chemical term definitions are explained in more detail below.

[0015] When a range of values ​​is listed, it is intended to include each value and subrange within that range. For example, "C 1~6 "Alkyl group" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 Contains an alkyl group.

[0016] "C 1~6An "alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, 1~4 Alkyl groups and C 1~2 Alkyl groups are preferred. 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), t-butyl (C4), s-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-pentyl (C5), and n-hexyl (C6). 1~6 The term "alkyl group" further includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common abbreviations for alkyl groups include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0017] "C 2~6 An "alkenyl group" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2~4 Alkenyl groups are preferred. 2~6 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), and hexenyl (C6). 2~6The term "alkenyl group" further includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkenyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0018] "C 2~6 An "alkynyl group" refers to a straight-chain or branched-chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2~4 Alkynyl groups are preferred. 2~6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. 2~6 The term "alkynyl group" further includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0019] "C 1~6 "Alkylene group" means C 1~6 refers to a divalent group formed by removing one more hydrogen from an alkyl group, which may be substituted or unsubstituted. In some embodiments, C 1~4 Alkylene group, C 2~4 Alkylene group and C 1~3An alkylene group is preferred. The optionally substituted alkylene group includes, but is not limited to, a methylene group (-CH-), an ethylene group (-CHCH-), a propylene group (-CHCHCH-), a butylene group (-CHCHCHCHCH-), a pentylene group (-CHCHCHCHCHCH-), a hexylene group (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl groups (methyl groups), include substituted methylene groups (-CH(CH)-, -C(CH)-), substituted ethylene groups (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), and the like. 2- ), substituted propylene groups (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0020] "C 2~6 The "alkenylene group" is C 2~6 refers to a divalent group formed by removing one more hydrogen from an alkenyl group, which may be substituted or unsubstituted. In some embodiments, C 2~4 An alkenylene group is particularly preferred. Exemplary optionally substituted alkenylene groups include, but are not limited to, an ethenylene group (-CH=CH-) and a propenylene group (e.g., thio-CH=CHCH-, -CH-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl groups (methyl groups), include, but are not limited to, a substituted ethylene group (-C(CH)=CH-, -CH=C(CH)-), a substituted propenylene group (-C(CH)=CHCH-, -CH=C(CH)CH-, -CH=CHCH(CH)-, -CH=CHC(CH)-, -CH(CH)-CH=CH-, -C(CH)-CH=CH-, -CH-C(CH)=CH-, -CH-CH=C(CH)-).

[0021] "C 2~6 The "alkynylene group" is C 2~6 refers to a divalent group formed by removing one more hydrogen from an alkynyl group, which may be substituted or unsubstituted. In some embodiments, C 2~4 Alkynylene groups are particularly preferred. Exemplary alkynylene groups include, but are not limited to, ethynylene groups (-C≡C-), substituted or unsubstituted propynylene groups (-C≡CCH2-), and the like.

[0022] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0023] Therefore, "C 1~6 The term "haloalkyl group" refers to the above "C 1~6 In some embodiments, C refers to an alkyl group substituted with one or more halogen groups. 1~4 Haloalkyl groups are particularly preferred, C 1~2 Haloalkyl groups are more preferred. Exemplary haloalkyl groups include, but are not limited to, -CF, -CHF, -CHFCHF, -CHCHF, -CFCF, -CCl, -CHCl, -CHCl, 2,2,2-trifluoro-1,1-dimethyl-ethyl groups, and the like. Haloalkyl groups may be substituted at any available attachment point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0024] "C 1~6 "Alkoxy" refers to an -OR group, where R is C as defined above. 1~6 It is an alkyl group. 1~4 Alkoxy groups are preferred.

[0025] "C 1~6 Haloalkoxy group means "C 1~6 In some embodiments, C refers to an alkoxy group substituted with one or more halogen groups. 1~4 Haloalkoxyalkyl groups are particularly preferred, C 1~2Haloalkoxyalkyl groups are more preferred.

[0026] "C 3~10 A "cycloalkyl group" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, C 4~10 Cycloalkyl groups, C 5~10 Cycloalkyl groups, C 4~7 Cycloalkyl groups, C 3~7 Cycloalkyl groups, C 3~6 Cycloalkyl groups, C 3~5 Cycloalkyl groups and C 3~4 Cycloalkyl groups are particularly preferred, C 5~6 Cycloalkyl groups are more preferred. Cycloalkyl groups further include ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, and the point of attachment is at the cycloalkyl ring, in which case the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), cycloheptyl (C), cycloheptenyl (C), cycloheptadienyl (C), cycloheptatrienyl (C), and the like. A cycloalkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] A "3- to 12-membered heterocyclyl group" refers to a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, provided that valency allows. In some embodiments, 3- to 10-membered heterocyclyl groups are preferred that are 3- to 10-membered non-aromatic ring systems having ring carbon atoms and 1-3 ring heteroatoms; in some embodiments, 4- to 10-membered heterocyclyl groups are preferred that are 4- to 10-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms; in some embodiments, 5- to 10-membered heterocyclyl groups are preferred that are 5- to 10-membered non-aromatic ring systems having ring carbon atoms and 1-5 ring heteroatoms; in some embodiments, 5- to 8-membered heterocyclyl groups are preferred that are 5- to 8-membered non-aromatic ring systems having ring carbon atoms and 1-5 ring heteroatoms; in some embodiments, 3- to 8-membered heterocyclyl groups are preferred that are 5- to 8-membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. A 3- to 7-membered heterocyclyl group which is a 7-membered non-aromatic ring system is preferred, a 3- to 6-membered heterocyclyl group which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is preferred, a 4- to 7-membered heterocyclyl group which is a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is preferred, a 4- to 6-membered heterocyclyl group which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is preferred, a 5- to 6-membered heterocyclyl group which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is more preferred, and a 3- to 5-membered heterocyclyl group which is a 3- to 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms is more preferred. Heterocyclyl groups further include bicyclic heterocyclyl groups, which refer to ring systems in which the heterocyclyl ring is fused to one or more cycloalkyl groups and the point of attachment is at the cycloalkyl ring, or to ring systems in which the heterocyclyl ring is fused to one or more aryl or heteroaryl groups and the point of attachment is at the heterocyclyl ring, in which case the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system.Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrobenzopyranyl, tetrahydropyranopyridinyl, and the like.A heterocyclyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0028] "C 6~10 An "aryl group" refers to a group of monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and 0 heteroatoms. In some embodiments, an aryl group has 6 ring carbon atoms (a "C6 aryl group," e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (a "C 10 "Aryl groups," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. Aryl groups further include ring systems in which the aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is at the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Aryl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0029] A "5- to 14-membered heteroaryl group" refers to a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π-electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be to a carbon or nitrogen atom, as long as valence allows. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. Heteroaryl groups further include bicyclic heteroaryl groups in which the heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is at the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. In some embodiments, 5- to 12-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms are preferred. In some embodiments, 5- to 10-membered heteroaryl groups are preferred, which are 6- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5- to 9-membered heteroaryl groups are preferred, which are 5- to 9-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5- to 6-membered heteroaryl groups are preferred, which are 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl groups. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl groups. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl groups.Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl groups. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl groups, pyrimidinyl groups, and pyrazinyl groups. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl groups and tetrazinyl groups, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl groups, oxepinyl groups, and thiepinyl groups. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0030] A "cycloalkylene group," "heterocyclylene group," "arylene group," or "heteroarylene group" is a divalent group formed by removing one more hydrogen from the above-defined "cycloalkyl group," "heterocyclyl group," "aryl group," or "heteroaryl group," and may be substituted or unsubstituted. For example, "C 5~7 "Cycloalkylene group" means a C 5~7 A "5- to 8-membered heterocyclylene group" refers to a divalent group formed by removing one more hydrogen from a 5- to 8-membered heterocyclyl group, and "C 6~10 The "arylene group" is C6~10 It refers to a divalent group formed by removing one more hydrogen atom from an aryl group, and a "5- or 6-membered heteroarylene group" refers to a divalent group formed by removing one more hydrogen atom from a 5- or 6-membered heteroaryl group.

[0031] As defined herein, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, etc., are optionally substituted groups.

[0032] Exemplary substituents on carbon atoms are halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NRbb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc), alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently having 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, Alternatively, the two geminal hydrogens on the carbon atom can be =O, =S, or =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc is substituted with a group, R aa are each independently selected from an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, or two R aa groups are linked to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R bb are each independently hydrogen, -OH, or -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SRcc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc ) 2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, or two R bb groups are linked to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc are each independently selected from hydrogen, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R cc groups are linked to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd are each independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NRff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may be linked to form =O or =S; R eeare each independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff are each independently selected from hydrogen, alkyl groups, haloalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, or two R ff groups are linked to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R gg are each independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl group, -ON(C 1~6 alkyl group)2, -N(C 1~6 alkyl group)2, -N(C 1~6 alkyl group)3 + X - , -NH(C 1~6 alkyl group)2 + X - , -NH2(C 1~6 alkyl group) + X - , -NH3 + X - , -N(OC 1~6 alkyl group)(C 1~6 alkyl group), -N(OH)(C 1~6 alkyl group), -NH(OH), -SH, -SC 1~6 Alkyl group, -SS(C 1~6 alkyl group), -C(=O)(C 1~6 alkyl group), -CO2H, -CO2(C 1~6 alkyl group), -OC(=O)(C 1~6 alkyl group), -OCO2(C1~6 alkyl group), -C(=O)NH2, -C(=O)N(C 1~6 alkyl group)2, -OC(=O)NH(C 1~6 alkyl group), -NHC(=O)(C 1~6 alkyl group), -N(C 1~6 alkyl group)C(=O)(C 1~6 alkyl group), -NHCO2(C 1~6 alkyl group), -NHC(=O)N(C 1~6 alkyl group)2, -NHC(=O)NH(C 1~6 alkyl group), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl group), -OC(=NH)(C 1~6 alkyl group), -OC(=NH)OC 1~6 Alkyl group, -C(=NH)N(C 1~6 alkyl group)2, -C(=NH)NH(C 1~6 alkyl group), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl group)2, -OC(NH)NH(C 1~6 alkyl group), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl group), -NHC(=NH)NH, -NHSO(C 1~6 alkyl group), -SO2N(C 1~6 alkyl group)2, -SO2NH(C 1~6 alkyl group), -SO2NH2, -SO2C 1~6 Alkyl group, -SO2OC 1~6 Alkyl group, -OSO2C 1~6 Alkyl group, -SOC 1~6 Alkyl group, -Si(C 1~6 alkyl group)3, -OSi(C 1~6 alkyl group)3, -C(=S)N(C 1~6 alkyl group), C(=S)NH(C 1~6 alkyl group), C(=S)NH2, -C(=O)S(C 1~6 alkyl group), -C(=S)SC 1~6 Alkyl group, -SC(=S)SC 1~6 Alkyl group, -P(=O)2(C 1~6 alkyl group), -P(=O)(C 1~6alkyl group)2, -OP(=O)(C 1~6 alkyl group)2, -OP(=O)(OC 1~6 alkyl group)2, C 1~6 Alkyl group, C 1~6 Haloalkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C7 cycloalkyl groups, C6-C 10 Aryl groups, C3-C7 heterocyclyl groups, C5-C 10 a heteroaryl group, or two geminal R gg The substituents may be linked to form =O or =S, and X - is the counter ion.

[0033] Exemplary nitrogen atom substituents are hydrogen, —OH, —OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, including but not limited to alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, or two R bonded to a nitrogen atom; ccgroups are linked to form a heterocyclyl group or a heteroaryl ring, and each alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as described above.

[0034] Other definitions As used herein, the term "pharmaceutically acceptable salts" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention that are adapted to come into contact with patient tissues within sound medical judgment, do not cause undue toxicity, irritation, allergic response, etc., consistent with a reasonable benefit / risk ratio, and are effective for their anticipated application, including zwitterionic forms of the compounds of the present invention (where possible).

[0035] The "subject" to be administered includes, but is not limited to, a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or older adult)) and / or a non-human animal, e.g., a mammal, e.g., a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. As used herein, the terms "person," "patient," and "subject" are used interchangeably.

[0036] "Disease," "disorder," and "condition" are used interchangeably herein.

[0037] Generally, the "effective amount" of a compound refers to an amount sufficient to produce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on, for example, the biological purpose, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health condition and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.

[0038] "Combination" and related terms refer to the simultaneous or sequential administration of a compound of the present invention and another therapeutic agent. For example, the compound of the present invention may be administered simultaneously or sequentially in separate unit dosage forms with the other therapeutic agent, or may be administered simultaneously with the other therapeutic agent in a single unit dosage form. DETAILED DESCRIPTION OF THE INVENTION

[0039] As used herein, the term "compounds of the invention" refers to compounds of formula (I) below (subgeneric formulas, such as formulas (II), (II-1), (II-2), (III), (IV-2), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-10), (IV-3A), (IV-6A), (V), (VI), (VI-1), (VI-2), etc.), pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates or isotopic variants thereof, and mixtures thereof.

[0040] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof: [ka] During the ceremony, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring A is absent or C 3~10 a cycloalkyl group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or C 6~10 aryl groups; R1 is selected from a 5- to 12-membered heteroaryl group or a 5- to 12-membered heterocyclyl group, and R1 is a pyridyl group or [ka] provided that R1 is not an integer of 1 to 5, and R2 is optionally 1, 2, 3, 4, or 5 R x is replaced by R x are H, D, halogens, NH2, CN, OH, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NH-R a , -NHC(O)-R a , -(CH2) p -OR a , -(CH2) p -C(O)R a , -P(O)-(R a )2 or -S(O)2-R a where R a is H, C 1~6 Alkyl group, C 1~6 haloalkyl group or C 3~6 cycloalkyl groups, and p is selected from 0, 1, 2, 3, or 4; or two R x together form oxo or thio, R2 is H, D, halogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is H, D, halogen, NH2, CN, OH, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group or C 3~6 cycloalkyl groups, or R3 on two different carbon atoms are bonded to form a bridged ring, or two R3 on the same carbon atom are bonded to form a C3~10 Cycloalkyl groups, 5-10 membered heteroaryl groups, C 3~10 forming a cycloalkyl group or a 3- to 10-membered heterocyclyl group, R4 is H, D, halogen, NH2, CN, OH, SF5, SCF3, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkoxy group, C 1~6 Alkylthio group, C 3~10 a cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or C 6~10 aryl groups; R5 is H, D, halogen, NH2, CN, OH, C 1~6 Alkyl group, C 1~6 Deuterated alkyl groups, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R1-R5 may optionally be deuterated until fully deuterated.

[0041] X and Y In one embodiment, X is CH; in another embodiment, X is N.

[0042] In one embodiment, Y is CH; in another embodiment, Y is N.

[0043] In one embodiment, at least one of X and Y is an N atom.

[0044] Ring A In one embodiment, ring A is absent, and in another embodiment, ring A is C 3~10In another embodiment, ring A is a 5- to 10-membered heteroaryl group, for example a 5- to 8-membered heteroaryl group; in another embodiment, ring A is a 5- to 10-membered heterocyclyl group, for example a 5- to 7-membered heterocyclyl group; in another embodiment, ring A is C 6~10 It is an aryl group.

[0045] In one specific embodiment, ring A is a 5- to 6-membered heteroaryl group, and in another embodiment, ring A together with the benzene ring attached thereto is [ka] In another embodiment, ring A together with the benzene ring attached thereto forms [ka] In another embodiment, ring A together with the benzene ring attached thereto forms [ka] Form.

[0046] Ring B In one embodiment, ring B is absent, and in another embodiment, ring B is C 3~10 In another embodiment, Ring B is a 5- to 10-membered heteroaryl group, for example a 5- to 8-membered heteroaryl group; in another embodiment, Ring B is a 5- to 10-membered heterocyclyl group, for example a 5- to 7-membered heterocyclyl group; in another embodiment, Ring B is C 6~10 It is an aryl group.

[0047] In one embodiment, the ring B is optionally selected from the group consisting of halogen, C 1~6 Alkyl group or C 1~6 It is substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl groups.

[0048] R1 In one embodiment, R1 is a 5- to 12-membered heteroaryl group, for example a 5- to 10-membered heteroaryl group, and in another embodiment, R1 is a 5- to 12-membered heterocyclyl group. [ka] It is assumed that this is not the case.

[0049] In one embodiment, R1 is a 5- to 12-membered bicyclic heteroaryl group, for example a 5- to 10-membered bicyclic heteroaryl group, and in another embodiment, R1 is a 5- to 12-membered bicyclic heterocyclyl group, for example a 5- to 10-membered bicyclic heterocyclyl group.

[0050] In one embodiment, R1 optionally comprises 1, 2, 3, 4, or 5 R x is replaced by

[0051] In one specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] and in another specific embodiment, R1 is [ka] is.

[0052] In one preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] In another preferred embodiment, R1 is [ka] is.

[0053] In one embodiment, R1 may be optionally deuterated to full deuteration.

[0054] R2 In one embodiment, R2 is H, in another embodiment, R2 is D, in another embodiment, R2 is halogen, in another embodiment, R2 is C 1~6 Alkyl groups, such as C 1~4 In another embodiment, R is an alkyl group. 1~6 In another embodiment, R is a haloalkyl group. 1~6 In another embodiment, R2 is an alkoxy group. 1~6 In another embodiment, R2 is C 3~6 It is a cycloalkyl group.

[0055] In one specific embodiment, R2 is H; in another specific embodiment, R2 is CH3; in another specific embodiment, R2 is CH2CH3; in another specific embodiment, R2 is a trifluoroethyl group; in another specific embodiment, R2 is a methoxy group; and in another specific embodiment, R2 is a cyclopropyl group.

[0056] In one embodiment, R2 may optionally be deuterated to full deuteration.

[0057] R3 In one embodiment, R3 is H, in another embodiment, R3 is D, in another embodiment, R3 is halogen, in another embodiment, R3 is NH2, in another embodiment, R3 is CN, in another embodiment, R3 is OH, in another embodiment, R3 is C 1~6 In another embodiment, R is an alkyl group. 1~4 In another embodiment, R is an alkyl group. 1~6 In another embodiment, R is a haloalkyl group. 1~6 In another embodiment, R is an alkoxy group. 3~6 In another embodiment, two R3's are bonded to the carbon atoms on which they are located to form a 3-6 membered spiro or bridged ring; in another embodiment, R3's on two different carbon atoms are bonded to form a bridged ring; in another embodiment, two R3's on the same carbon atom are bonded to form a C 3~10 Cycloalkyl groups, such as C 3~7 Cycloalkyl group or C 3~5 In another embodiment, two R3 on the same carbon atom are joined to form a 5-10 membered heteroaryl group; in another embodiment, two R3 on the same carbon atom are joined to form a C 3~10 They form a cycloalkyl group, such as a cyclopropyl group or a cyclobutyl group, and in another embodiment, two R3 on the same carbon atom are joined to form a 3- to 10-membered heterocyclyl group.

[0058] In one specific embodiment, R3 is H; in another specific embodiment, R3 is D; in another embodiment, R3 is a halogen, such as F, Cl, or Br; in another embodiment, R3 is CN; in another embodiment, R3 is a methyl group; in another embodiment, R3 is an ethyl group; in another embodiment, R3 is a trifluoromethyl group; in another embodiment, R3 is a cyclopropyl group; and in another embodiment, two R3 on the same carbon atom are joined to form a cyclopropyl group or a cyclobutyl group.

[0059] In one embodiment, R3 may optionally be deuterated to full deuteration.

[0060] R4 In one embodiment, R4 is H, in another embodiment, R4 is D, in another embodiment, R4 is halogen, such as F, Cl, or Br, in another embodiment, R4 is NH2, in another embodiment, R4 is CN, in another embodiment, R4 is OH, in another embodiment, R4 is SF5, in another embodiment, R4 is SCF3, in another embodiment, R4 is C 1~6 In another embodiment, R is an alkyl group. 1~6 haloalkyl groups, such as methyl and ethyl groups; in another embodiment, R4 is C 1~4 In another embodiment, R is an alkyl group. 1~6 In another embodiment, R4 is a haloalkyl group, such as a trifluoromethyl group, a difluoromethyl group, and in another embodiment, R4 is a C 1~6 In another embodiment, R is an alkoxy group. 1~6 In another embodiment, R is a haloalkoxy group, such as OCF; 1~6 alkylthio groups, such as methylthio and ethylthio groups; in another embodiment, R4 is C 3~10 In another embodiment, R is a cycloalkyl group, such as a cyclopropyl group. 3~6In another embodiment, R4 is a cycloalkyl group; in another embodiment, R4 is a 3-10 membered heterocyclyl group; in another embodiment, R4 is a 4-10 membered heterocyclyl group; in another embodiment, R4 is a 5-10 membered heteroaryl group, such as pyridyl; in another embodiment, R4 is C 6~10 It is an aryl group.

[0061] In one embodiment, R4 may be optionally deuterated to full deuteration.

[0062] R 4a , R 4b and R 4d In one embodiment, R 4a is H, and in another embodiment, R 4a is halogen, for example F, and in another embodiment, R 4a is CN, and in another embodiment, R 4a is C 1~6 In another embodiment, R 4a is C 1~6 In another embodiment, R 4a is C 1~6 It is a haloalkyl group.

[0063] In one embodiment, R 4b is a halogen, e.g., Cl, Br, and in another embodiment, R 4b is CN, and in another embodiment, R 4b is C 1~6 is an alkyl group, preferably C 1~4 alkyl group, for example CH2CH3, and in another embodiment, R 4b is C 1~6 In another embodiment, R 4b is C 1~6 haloalkyl group, preferably C 1~4 A haloalkyl group, for example CF3.

[0064] In one embodiment, R 4d is H, and in another embodiment, R4d is CN, and in another embodiment, R 4d is halogen, e.g., F, Cl, and in another embodiment, R 4d is C 1~6 In another embodiment, R 4d is C 1~4 is an alkyl group, preferably C 1~2 alkyl group, for example CH3, and in another embodiment, R 4d is C 1~6 In another embodiment, R 4d is C 1~6 It is a haloalkyl group.

[0065] R5 In one embodiment, R5 is H, in another embodiment, R5 is D, in another embodiment, R5 is halogen, in another embodiment, R5 is NH2, in another embodiment, R5 is CN, in another embodiment, R5 is OH, in another embodiment, R5 is C 1~6 is an alkyl group, preferably C 1~4 In another embodiment, R5 is C 1~6 In another embodiment, R is a deuterated alkyl group, such as CD; 1~6 In another embodiment, R is a haloalkyl group, such as a trifluoromethyl group. 1~6 In another embodiment, R is an alkoxy group, such as a methoxy group or an ethoxy group. 1~6 In another embodiment, R is an alkylthio group, such as a methylthio group. 3~6 A cycloalkyl group, for example a cyclopropyl group.

[0066] In one embodiment, R5 may be optionally deuterated to full deuteration.

[0067] [ka] In one embodiment, [ka] represents a single bond, and in another embodiment, [ka] represents a double bond, in another embodiment, Q is N and ring B is present, [ka] represents a single bond.

[0068] R x In one embodiment, R x is H, and in another embodiment, R x is D, and in another embodiment, R x is halogen, and in another embodiment, R x is NH, and in another embodiment, R x is CN, and in another embodiment, R x is OH, and in another embodiment, R x is C 1~6 In another embodiment, R x is C 1~4 In another embodiment, R x is C 1~6 In another embodiment, R x is C 1~6 In another embodiment, R x is -C(O)R a and in another embodiment, R x is -C(O)OR a and in another embodiment, R x is -OC(O)R a and in another embodiment, R x is -C(O)NH-R a and in another embodiment, R x is -NHC(O)-R a and in another embodiment, R x is -(CH2) p -ORa and in another embodiment, R x is -(CH2) p -C(O)R a and in another embodiment, R x is -P(O)-(R a )2, and in another embodiment, R x is -S(O)2-R a and in another embodiment, two R x together form an oxo, and in another embodiment, two R x together form thio.

[0069] In one specific embodiment, R x is H, and in another specific embodiment, R x is NH, and in another specific embodiment, R x is CHOH, and in another specific embodiment, R x is CH2OCH3, and in another specific embodiment, R x is C(O)CH3, and in another specific embodiment, R x is —S(O)—CH, and in another specific embodiment, two R x together form an oxo.

[0070] R y In one embodiment, R y is H, and in another embodiment, R y is D, and in another embodiment, R y is halogen, and in another embodiment, R y is C 1~6 In another embodiment, R y is C 1~6 It is a haloalkyl group.

[0071] Q and Q' In one embodiment, Q is CH; in another embodiment, Q is N.

[0072] In one embodiment, Q' is CH; in another embodiment, Q' is N.

[0073] In one embodiment, at most one of Q and Q' is N.

[0074] R a In one embodiment, R a is H, and in another embodiment, R a is C 1~6 alkyl group, for example CH3, and in another embodiment, R a is C 1~6 haloalkyl group, and in another embodiment, R a is C 3~6 It is a cycloalkyl group.

[0075] m, n, k and p In one embodiment, m is selected from 0, 1, 2, 3, 4 or 5.

[0076] In one embodiment, n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0077] In one embodiment, k is selected from 0, 1, 2, 3, 4, or 5.

[0078] In one embodiment, p is selected from 0, 1, 2, 3 or 4.

[0079] Any technical solution of any of the above specific embodiments or any combination thereof can be combined with any technical solution of other specific embodiments or any combination thereof. For example, any technical solution of ring A or any combination thereof can be combined with ring B, X, Y, L, R1, R2, R3, R4, R 4a , R 4b , R 4d , R5, R x , R y , Q, Q', R a, m, n, k and p, or any combination thereof. The present invention is intended to include all combinations of these technical solutions, and is not limited by space limitations and will not be listed one by one.

[0080] In a more specific embodiment, the compound of the present invention represented by the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring A is absent or selected from 5- to 6-membered heteroaryl groups, and the 5- to 6-membered heteroaryl group, together with the benzene ring bonded thereto, [ka] wherein ring A is preferably absent, R1 is a 5- to 10-membered heteroaryl group, and said R1 may optionally be selected from 1, 2, or 3 R x is replaced by R x is preferably H, NH2, CH3, CH2OH, CH2OCH3, or C(O)CH3 or -S(O)2-CH3, or two R on the same carbon atom x together form an oxo, Preferably, R1 is [ka] is selected from Ring B is absent or C 3~10 a cycloalkyl group, a 5- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or C 6~10 aryl groups, wherein ring B is optionally selected from halogen, C 1~6 Alkyl group or C 1~6 substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl groups; Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; R y H, D, halogen, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R2 is C 1~4 alkyl groups, such as CH or CHCH; R3 is H, D or C 1~4 or R on two different carbon atoms are joined to form a bridged ring; or two R on the same carbon atom are joined to form a C 3~5 forming a cycloalkyl group, for example a cyclopropyl group, R4 is selected from H, F, Cl, Br, CH3, CH2CH3, SCF3, OCF3, CF3 or pyridyl; R5 is selected from H, CH3 or CD3, preferably H or CH3; R a is C 1~6 alkyl groups, m is selected from 0, 1, 2 or 3; k is selected from 0, 1, 2, 3, 4 or 5.

[0081] In a more specific embodiment, in the compound of the present invention of the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof, R1 is [ka] is selected from During the ceremony, [ka] represents a single or double bond, and when Q is N and ring B is present, [ka] represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; Ring B is absent or C 3~10 a cycloalkyl group, a 5- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or C 6~10 aryl groups, wherein ring B is optionally selected from halogen, C 1~6 Alkyl group or C 1~6 substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl groups; R x H, NH2, halogen, C 1~6 Alkyl group, C 1~6 Haloalkyl group, -C(O)R a , -C(O)OR a , -OC(O)R a , -C(O)NH-R a , -NHC(O)-R a , -(CH2) p -OR a or -(CH2) p -C(O)R a where R a is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, and p is selected from 1, 2, or 3; R y H, D, halogen, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R a is C 1~6 alkyl groups, m is selected from 0, 1, 2, 3, 4 or 5; k is selected from 0, 1, 2, 3, 4 or 5; Preferably, [ka] represents a single or double bond, and when Q is N and ring B is present, [ka] represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; Ring B is absent or selected from a 5- to 7-membered heterocyclyl group or a 5- to 6-membered heteroaryl group, and said ring B is optionally selected from halogen or C 1~4 substituted with one, two or three substituents selected from alkyl groups; R x are H, NH2, C 1~4 Alkyl group, -C(O)R a or -(CH2) p -OR a where R a is H or C 1~4 alkyl group, p is selected from 1 or 2, R x is preferably H, NH2, CH3, CH2OH, CH2OCH3 or C(O)CH3, R y H, D, halogen, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R a is selected from CH3, m is selected from 0, 1, 2 or 3; k is selected from 0, 1, 2 or 3; More preferably, R1 is [ka] is selected from.

[0082] In a more specific embodiment, the compound of the present invention having the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof, is selected from the following structures: [ka] During the ceremony, Each variable is as defined herein.

[0083] In a more specific embodiment, the present invention provides a compound of formula (IV-6) or (IV-7), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof: [ka] During the ceremony, Ring A is absent or C 3~10 a cycloalkyl group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or C 6~10 aryl groups; X is selected from CH or N; R x H, D, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R2 is H, D, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R3 is H, D, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, or R3 on two different carbon atoms are bonded to form a bridged ring, or two R3 on the same carbon atom are bonded to form a C 3~10 Cycloalkyl groups, 5-10 membered heteroaryl groups, C 3~10 forming a cycloalkyl group or a 3- to 10-membered heterocyclyl group, R4 is H, D, halogen, CN, SCF3, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, C 1~6 Haloalkoxy group, C 3~6 a cycloalkyl group, a 4- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or C 6~10 aryl groups; R5 is H, D, C 1~6 Alkyl group, C 1~6 Deuterated alkyl groups, C 1~6Alkoxy group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0084] In a more specific embodiment, the compound of the present invention represented by the above formula (IV-6) or (IV-7), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a mixture thereof, Ring A is absent or is a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or C 6~10 aryl groups; X is selected from CH or N; R x is H, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R2 is C 1~6 Alkyl group or C 1~6 haloalkyl groups, R3 is H, D, C 1~6 Alkyl group or C 1~6 haloalkyl groups, or R3 on two different carbon atoms are bonded to form a bridged ring, or two R3 on the same carbon atom are bonded to form a C 3~10 forming a cycloalkyl group or a 3- to 10-membered heterocyclyl group, R4 is H, halogen, CN, SCF3, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 haloalkyl group or C 1~6 haloalkoxy groups; R5 is H, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0085] In a more specific embodiment, the compound of the present invention represented by the above formula (IV-6) or (IV-7), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a mixture thereof, Ring A is absent, X is selected from CH or N; R x is H or C 1~6 alkyl groups, R2 is C 1~6 alkyl groups, R3 is H, D or C 1~6 alkyl groups, or R3 on two different carbon atoms are bonded to form a bridged ring, or two R3 on the same carbon atom are bonded to form a C 3~7 forming a cycloalkyl group, R4 is H, halogen, SCF3, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 haloalkyl group or C 1~6 haloalkoxy groups; R5 is H or C 1~6 alkyl groups, m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0086] In a more specific embodiment, the compound of the present invention represented by the above formula (IV-6) or (IV-7), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a mixture thereof, Ring A is selected from 5- to 6-membered heteroaryl groups, and the 5- to 6-membered heteroaryl groups together with the benzene ring bonded thereto are [ka] and X is selected from CH or N, forming a heteroaryl group such as R x is H or C 1~4alkyl groups, preferably H; R2 is C 1~4 alkyl groups, such as CH or CHCH; R3 is H, D or C 1~4 or R on two different carbon atoms are joined to form a bridged ring; or two R on the same carbon atom are joined to form a C 3~5 forming a cycloalkyl group, for example a cyclopropyl group, R4 is H, halogen, SCF3, C 1~4 Alkyl group or C 1~4 haloalkyl groups, such as selected from H, F, Cl, Br, CH3, CH2CH3, CF3, SCF3, OCF3 or OCH3; R5 is H or C 1~4 alkyl groups, such as H or CH3; m is selected from 0, 1, 2 or 3; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0087] In a more specific embodiment, the present invention provides a compound of formula (IV-8) or (IV-9), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof: [ka] During the ceremony, X is selected from N or CH; R4 is H, CN, halogen, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R 4a H, halogen, CN, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R 4b are halogens, CN, C 1~6 Alkyl group, C 1~6 Alkoxy group or C1~6 haloalkyl groups, R 4d H, CN, halogens, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R5 is H, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, preferably C 1~6 Alkyl group or C 1~6 is a haloalkyl group, R x is H, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2, 3, 4 or 5.

[0088] In a more specific embodiment, the compound of the present invention represented by the above formula (IV-8) or (IV-9), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a mixture thereof, X is selected from N or CH; R4 is H, halogen, C 1~4 Alkyl group or C 1~4 haloalkyl groups, R 4a is selected from H or halogen; R 4b is a halogen, C 1~4 Alkyl group or C 1~4 haloalkyl groups, R 4d is H, halogen or C 1~4 alkyl groups, R5 is H, C 1~4 Alkyl group or C 1~4 haloalkyl groups, preferably C 1~4 Alkyl group or C 1~4 is a haloalkyl group, R x is H, C 1~4Alkyl group or C 1~4 haloalkyl groups, m is selected from 0, 1, 2, 3 or 4; Preferably, X is selected from N or CH; R4 is H, halogen, C 1~2 Alkyl group or C 1~2 haloalkyl groups, such as H, Cl, Br, CH3, CH2CH3, or CF3; R 4a is selected from H or halogen, preferably H or F, R 4b is a halogen, C 1~2 Alkyl group or C 1~2 haloalkyl groups, preferably Cl, Br, CF or CHCH; R 4d is H, halogen or C 1~2 alkyl groups, preferably H, F, Cl or CH3; R5 is H or C 1~2 alkyl groups, preferably CH3; R x is H or C 1~2 alkyl groups, preferably H; m is selected from 0, 1, 2 or 3.

[0089] In a more specific embodiment, the present invention provides a compound of formula (IV-10), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and mixtures thereof: [ka] During the ceremony, R 4b is a halogen or C 1~6 haloalkyl groups, R 4d is a halogen or C 1~6 alkyl groups, R5 is C 1~6 Alkyl group or C1~6 haloalkyl groups, R x is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, m is 0 or 1; Preferably, R 4b is a halogen or C 1~4 haloalkyl groups, R 4d is a halogen or C 1~4 alkyl groups, R5 is C 1~4 Alkyl group or C 1~4 haloalkyl groups, R x is H, C 1~4 Alkyl group or C 1~4 haloalkyl groups, m is 0 or 1; More preferably, R 4b is a halogen or C 1~2 haloalkyl groups, preferably Cl, Br or CF; R 4d is a halogen or C 1~2 alkyl groups, preferably F, Cl or CH; R5 is C 1~2 is an alkyl group, preferably CH3; R x is H or C 1~2 is an alkyl group, preferably H, m is 0 or 1.

[0090] In a more specific embodiment, the present invention provides a compound of formula (II) or (II-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and mixtures thereof: [ka] During the ceremony, [ka] represents a single or double bond, and when Q is N and ring B is present, [ka] represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; X and Y are each independently selected from CH or N, and X and Y contain at least one N atom; Ring A is absent or C 3~10 a cycloalkyl group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or C 6~10 aryl groups, and ring A is preferably absent; Ring B is absent or C 3~10 a cycloalkyl group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or C 6~10 aryl groups, wherein ring B is optionally selected from C 1~6 Alkyl group or C 1~6 substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl groups; R x are H, NH2, CN, OH, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 Haloalkyl group, -C(O)R a , -OC(O)R a , -C(O)OR a , -C(O)NH-R a , -NHC(O)R a or -(CH2) p -OR a where R a is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, and p is selected from 0, 1, 2, 3, or 4; R2 is H, D, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6haloalkyl groups, R3 is H, D, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 haloalkyl groups, R4 is H, D, halogen, CN, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R5 is H, D, halogen, CN, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1 or 2.

[0091] In a more specific embodiment, the compound of the present invention represented by the above formula (II) or (II-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and a mixture thereof, [ka] represents a single or double bond, and when Q is N and ring B is present, [ka] represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; X and Y are each independently selected from CH or N, and X and Y contain at least one N atom; Ring A is absent or a 5- to 10-membered heteroaryl group or C 6~10 aryl groups, and ring A is preferably absent; Ring B is absent or is a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or C 6~10 aryl groups, wherein ring B is optionally selected from C 1~6 Alkyl group or C1~6 substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl groups; R x are H, NH2, CN, and C 1~6 Alkyl group, C 1~6 Haloalkyl group, -C(O)R a , -OC(O)R a , -C(O)OR a or -(CH2) p -OR a where R a is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, and p is selected from 0, 1, 2, 3, or 4; R2 is C 1~6 Alkyl group or C 1~6 haloalkyl groups, R3 is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R4 is H, halogen, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R5 is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1 or 2.

[0092] In a more specific embodiment, the compound of the present invention represented by the above formula (II) or (II-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and a mixture thereof, [ka] represents a single or double bond, and when Q is N and ring B is present, [ka] represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; X and Y are each independently selected from CH or N, and X and Y contain at least one N atom; Ring A is absent or selected from 5- to 8-membered heteroaryl groups, and Ring A is preferably absent; Ring B is absent or selected from a 5- to 8-membered heteroaryl group or a 5- to 8-membered heterocyclyl group, and said ring B is optionally selected from C 1~6 substituted with one, two or three substituents selected from alkyl groups; R x are H, NH2, C 1~6 Alkyl group, -C(O)R a or -(CH2) p -OR a where R a is H or C 1~6 alkyl groups, and p is selected from 0, 1, 2, or 3; R2 is C 1~6 alkyl groups, R3 is H or C 1~6 alkyl groups, R4 is H, halogen, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R5 is H or C 1~6 alkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2.

[0093] In a more specific embodiment, the compound of the present invention represented by the above formula (II) or (II-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and a mixture thereof, [ka] represents a single or double bond, and when Q is N and ring B is present, [ka] represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; X and Y are each independently selected from CH or N, and X and Y contain at least one N atom; Ring A is absent or a 5- to 6-membered heteroaryl group, for example [ka] wherein ring A is preferably absent; Ring B is absent or selected from a 5- to 6-membered heterocyclyl group or a 5- to 6-membered heteroaryl group, and said ring B is optionally selected from C 1~4 and preferably, ring B is absent or [ka] is selected from R x are H, NH2, C 1~4 Alkyl group, -C(O)R a or -(CH2) p -OR a where R a is H or C 1~4 alkyl groups, and p is selected from 1 or 2; R x is preferably H, NH2, CH3, CH2OH, CH2OCH3 or C(O)CH3, R2 is C 1~4 alkyl groups, such as CH or CHCH; R3 is H or C 1~4 alkyl groups, preferably H; R4 is H, halogen, C 1~4 Alkyl group or C 1~4 haloalkyl groups, such as H, F, Cl, CH or CF; R5 is H or C1~4 alkyl groups, such as H or CH3; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2.

[0094] In a more specific embodiment, the present invention provides a compound of formula (II-2) or (II-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and mixtures thereof: [ka] During the ceremony, X is selected from CH or N; Q is selected from CH or N; Ring B is absent or a 5- to 10-membered heteroaryl group or C 6~10 aryl groups, and the 5- to 10-membered heteroaryl groups or C 6~10 The aryl group is optionally selected from C 1~6 Alkyl group or C 1~6 substituted with 1, 2, 3, 4 or 5 substituents selected from haloalkyl groups; R x are H, NH2, C 1~6 Alkyl group, C 1~6 Haloalkyl group, -C(O)R a , -C(O)OR a , -OC(O)R a or -(CH2) p -OR a where R a is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, and p is selected from 0, 1, 2, 3, or 4; R5 is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2, 3 or 4; Preferably, X is selected from CH or N; Q is selected from CH or N; Ring B is absent or selected from a 5- to 8-membered heteroaryl group, and the 5- to 8-membered heteroaryl group is optionally selected from C 1~6 substituted with one, two or three substituents selected from alkyl groups; R x are H, NH2, C 1~6 Alkyl group, -C(O)R a or -(CH2) p -OR a where R a is H or C 1~6 alkyl groups, and p is selected from 0, 1, 2, or 3; R5 is H or C 1~6 alkyl groups, m is selected from 0, 1, 2 or 3; More preferably, X is selected from CH or N; Q is selected from CH or N; Ring B is absent or selected from a 5- to 6-membered heteroaryl group, and the 5- to 6-membered heteroaryl group is optionally selected from C 1~4 and preferably, ring B is absent or [ka] is selected from R x are H, NH2, C 1~4 Alkyl group, -C(O)R a or -(CH2) p -OR a where R a is H or C 1~4 alkyl groups, and p is selected from 1 or 2; R x is preferably H, NH2, CH3, CH2OH, CH2OCH3 or C(O)CH3, R5 is H or C 1~4 alkyl groups, such as H or CH3; m is selected from 0, 1 or 2.

[0095] In a more specific embodiment, the present invention provides a compound of formula (VI-1) or (VI-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and mixtures thereof: [ka] X is selected from CH or N; R x is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R2 is H, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R3 is H, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R4 is H, CN, halogen, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, R5 is H, C 1~6 Alkyl group, C 1~6 Alkoxy group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2 or 3; Preferably, X is selected from CH or N; R x is H or C 1~6 alkyl groups, R2 is H or C 1~6 alkyl groups, R3 is H or C 1~6 alkyl groups, R4 is H, halogen, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R5 is H or C 1~6 alkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; More preferably, X is selected from CH or N; R x is H or C 1~4 alkyl groups, preferably H; R2 is H or C 1~4 alkyl groups, preferably CH2CH3; R3 is H or C 1~4 alkyl groups, preferably H; R4 is H, halogen, C 1~4 Alkyl group or C 1~4 haloalkyl groups, such as H, F, Cl, CH or CF; R5 is H or C 1~4 alkyl groups, preferably CH3; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2.

[0096] In a more specific embodiment, the present invention provides a compound of formula (VI-3) or (VI-4), having the structure (VI-3) or (VI-4), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate, or hydrate thereof, and mixtures thereof. [ka] During the ceremony, R x is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R2 is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, R5 is H, C 1~6 Alkyl group or C 1~6 haloalkyl groups, m is selected from 0, 1, 2 or 3; Preferably, R x is H or C 1~4 alkyl groups, preferably H; R2 is H or C 1~4 alkyl groups, preferably CH2CH3; R5 is H or C 1~4 alkyl groups, preferably CH3; m is selected from 0, 1, 2 or 3.

[0097] In one embodiment, the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: [ka] During the ceremony, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; R1 is selected from a 5- to 12-membered heteroaryl group or a 5- to 12-membered heterocyclyl group, and R1 is selected from one, two, or three R x may be substituted with With the proviso that when R1 is selected from 5- to 12-membered monocyclic heterocyclyl groups, [ka] and [ka] represents a single bond or a double bond, With the proviso that when R1 is selected from 5- to 12-membered heteroaryl groups, it is not a pyridyl group; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently H, halogen, CN, C 1~6 Alkyl group, C 1~6 haloalkyl group or C 3~6 cycloalkyl groups, or two R3 are joined to the carbon atoms to form a 3- to 6-membered spiro or bridged ring; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0098] In one embodiment, the compound of the present invention represented by the above formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a mixture thereof, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring B is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocyclyl group; X1 and X2 are each independently selected from CH or N; [ka] represents a single bond or a double bond, Q is selected from CH or N; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently selected from H, halogen, CN, methyl, ethyl, trifluoromethyl, or cyclopropyl; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is selected from H, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methylthio or cyclopropyl; R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H or C 1~6 alkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0099] In one embodiment, the present invention provides a compound of formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (VI-1) or (VI-2), having the structure of the following general formula: [ka] During the ceremony, X is selected from CH or N; [ka] represents a single bond or a double bond, Q is selected from CH or N; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently H, halogen, CN, C 1~6 Alkyl group, C 1~6 haloalkyl group or C 3~6 cycloalkyl groups, or two R3 are joined to the carbon atoms to form a 3- to 6-membered spiro or bridged ring; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0100] In another embodiment, the present invention relates to a compound of Formula (II), Formula (III) or Formula (VI), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof. [ka] During the ceremony, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring B is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocyclyl group; Z is selected from O or NH; [ka] represents a single bond or a double bond, X1 and X2 are each independently selected from CH or N; [ka] represents a single bond or a double bond, Q is selected from CH or N; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently H, halogen, CN, C 1~6 Alkyl group, C 1~6 haloalkyl group or C 3~6 cycloalkyl groups, or two R3 are joined to the carbon atoms to form a 3- to 6-membered spiro or bridged ring; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a)2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0101] In another more specific embodiment, in the compound of formula (II), formula (III) or formula (VI) according to the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring B is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocyclyl group; Z is selected from O or NH; [ka] represents a single bond or a double bond, X1 and X2 are each independently selected from CH or N; [ka] represents a single bond or a double bond, Q is selected from CH or N; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently selected from H, halogen, CN, methyl, ethyl, trifluoromethyl, or cyclopropyl; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is selected from H, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methylthio or cyclopropyl; R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H or C 1~6 alkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0102] In another embodiment, the present invention relates to a compound of Formula (IV-1), Formula (IV-2), Formula (IV-3), Formula (IV-4), Formula (IV-5), Formula (IV-6), or Formula (V-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. [ka] During the ceremony, X is selected from CH or N; Z is selected from O or NH; [ka] represents a single bond or a double bond, Q is selected from CH or N; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently H, halogen, CN, C 1~6 Alkyl group, C 1~6 haloalkyl group or C 3~6 cycloalkyl groups, or two R3 are joined to the carbon atoms to form a 3- to 6-membered spiro or bridged ring; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0103] In another more specific embodiment, in the compound of the present invention, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, X is selected from CH or N; Z is selected from O or NH; [ka] represents a single bond or a double bond, Q is selected from CH or N; R2 is selected from H, methyl, ethyl, trifluoroethyl, methoxy or cyclopropyl; R3 is independently selected from H, F, CN, a methyl group, an ethyl group, a trifluoromethyl group, or a cycloalkyl group, or two R3 are joined to the carbon atoms at which they are located to form a cycloalkyl group or a cyclobutyl group; R4 is independently selected from H, F, Cl, Br, CN, SF5, methyl, ethyl, trifluoromethyl, difluoromethyl, methylthio, ethylthio, or cyclopropyl; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is selected from H, methyl, ethyl, trifluoromethyl, methoxy, methylthio or cyclopropyl; R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0104] In another more specific embodiment, the invention relates to a compound of formula (IV-3A) or formula (IV-6A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: [ka] During the ceremony, X is selected from CH or N; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently H, halogen, CN, C 1~6 Alkyl group, C 1~6 haloalkyl group or C 3~6 cycloalkyl groups, or two R3 are joined to the carbon atoms to form a 3- to 6-membered spiro or bridged ring; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; R5 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R x is H, C 1~6 Alkyl group, C1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0105] In another more specific embodiment, the compound of the present invention represented by the above formula (IV-3A) or (IV-6A), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and a mixture thereof, X is selected from CH or N; R2 is selected from H, methyl, ethyl, trifluoroethyl, methoxy or cyclopropyl; R3 is independently selected from H, F, CN, a methyl group, an ethyl group, a trifluoromethyl group, or a cycloalkyl group, or two R3 are joined to the carbon atoms at which they are located to form a cycloalkyl group or a cyclobutyl group; R4 is independently selected from H, F, Cl, Br, CN, SF5, methyl, ethyl, trifluoromethyl, difluoromethyl, methylthio, ethylthio, or cyclopropyl; R5 is selected from H, methyl, ethyl, trifluoromethyl, methoxy, methylthio or cyclopropyl; R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)ORa , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0106] In another specific embodiment, the present invention relates to a compound of formula (VI-1) or formula (VI-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: [ka] X is selected from CH or N; R2 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6 Alkylthio group or C 3~6 cycloalkyl groups, R3 is independently H, halogen, CN, C 1~6 Alkyl group, C 1~6 haloalkyl group or C 3~6 cycloalkyl groups, or two R3 are joined to the carbon atoms to form a 3- to 6-membered spiro or bridged ring; R4 is independently H, halogen, CN, SF5, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkylthio group, C 3~6 selected from a cycloalkyl group or a 4- to 10-membered heterocyclyl group; R5 is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy group, C 1~6Alkylthio group or C 3~6 cycloalkyl groups, R x is H, C 1~6 Alkyl group, C 1~6 Haloalkyl group, C 1~6 Alkoxy groups, CN, NH2, -C(O)R a , -C(O)OR a , -(CH2) p -OR a , -P(O)-(R a )2 or -S(O)2-R a is selected from R a is H, C 1~6 Alkyl group or C 3~6 cycloalkyl groups, m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1 or 2.

[0107] In another embodiment, the present invention relates to a compound selected from the following: [ka] JPEG2026502971000102.jpg245170 JPEG2026502971000103.jpg243170 JPEG2026502971000104.jpg153170

[0108] In another embodiment, the present invention relates to a compound selected from the following: [ka]

[0109] The compounds of the present invention may contain one or more asymmetric centers and therefore may exist in multiple stereoisomeric forms, e.g., enantiomeric and / or diastereomeric forms. For example, the compounds of the present invention may be in the form of a single enantiomer, diastereomer, or geometric isomer (e.g., cis and trans isomers), or a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis.

[0110] The compounds of the present invention may also exist as tautomers. For compounds that exist in different tautomeric forms, one reference to a compound is not limited to any particular tautomer, but is intended to cover all tautomeric forms.

[0111] The present invention also includes isotopically labeled compounds (isotopic variants), which are the same as the compounds of formula (A), except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number common in nature. Illustrative examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the above isotopes and / or other isotopes of other atoms are all within the scope of the present invention. Some isotopically labeled compounds of the present invention, such as compounds containing radioactive isotopes (e.g., 3 H and 14The compound of the present invention into which C) is introduced can be used to measure the distribution of drugs and / or substrate tissues. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to produce and detect. Additionally, deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may be preferable in some cases because their greater metabolic stability can provide therapeutic benefits, such as increased half-life in the body or reduced dosage requirements. Isotopically labeled compounds of formula (A) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when carrying out the procedures described below and / or the steps disclosed in the Examples and Preparations.

[0112] Pharmaceutical compositions and kits In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.

[0113] The pharmaceutically acceptable excipient of the present invention refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum albumin (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0114] The present invention further includes kits (e.g., drug packages). Such kits may include a compound of the present invention and another therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispensable or other suitable containers) containing the compound of the present invention and the other therapeutic agent. In some embodiments, such kits may optionally further include a third container containing a pharmaceutical excipient for diluting or suspending the compound of the present invention and / or the other therapeutic agent. In some embodiments, the compound of the present invention and the other therapeutic agent provided in the first and second containers combine to form a single unit dosage form.

[0115] Administration The pharmaceutical compositions of the present invention may be administered by a number of routes, including, but not limited to, oral, parenteral, inhalation, topical, rectal, intranasal, buccal, vaginal, implant, or other modes of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0116] Typically, an effective amount of the compound according to the present invention is administered. The amount of the compound actually administered may be determined by a physician depending on the condition to be treated, the selected route of administration, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and other factors.

[0117] In preventing the conditions described in the present invention, a subject at risk of developing the condition is administered a compound described herein, typically under the supervision of a physician on the advice of a physician, at a dosage level as described above. Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or subjects identified by genetic testing or selection as being particularly susceptible to developing the condition.

[0118] Additionally, the pharmaceutical compositions provided herein may be administered over an extended period of time ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or indefinitely, for example, for the remainder of the subject's life. In some embodiments, chronic administration aims to provide a constant level of the compound in the blood, e.g., in the therapeutic range, for an extended period of time.

[0119] Various administration methods may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., to raise the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient in the body; for example, an intramuscular or subcutaneous bolus dose may provide a gradual release of the active ingredient, while a direct bolus delivered intravenously (e.g., an IV infusion) may provide a more rapid delivery, thereby quickly raising the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, e.g., an IV intravenous infusion, to provide a steady-state concentration of the active ingredient in the subject's body. In other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.

[0120] Oral compositions can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, the compositions are provided in unit dosage form to facilitate administration of precise dosages. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human patients and other mammals, each unit containing a predetermined number of active agents and appropriate pharmaceutical excipients appropriate for producing a desired therapeutic effect. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound is typically the minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various carriers or excipients and processing aids useful for forming the desired dosage form.

[0121] For oral administration, a typical scheme is 1 to 5 oral doses daily, particularly 2 to 4 oral doses, typically 3 oral doses. In these dosage regimens, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0122] A transdermal dose is typically selected to provide blood levels similar to or lower than an injected dose, and is about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0123] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for about 1 hour to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve adequate steady-state levels. For a 40-80 kg human patient, the maximum total dose should not exceed about 2 g / day.

[0124] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, adhesives such as microcrystalline cellulose, gum tragacanth or gelatin, excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel or corn starch, lubricants such as magnesium stearate, flow aids such as colloidal silica, sweeteners such as sucrose or saccharin, or flavorings such as peppermint, methyl salicylate or orange flavoring, or any ingredient of such compounds of a similar nature.

[0125] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As noted above, in such compositions, the active compound is typically the minor component, always about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0126] Typically, transdermal compositions are formulated as topical ointments or creams containing the active ingredient. When formulating an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and usually contain other ingredients to enhance the consistent skin penetration of the active ingredient or formulation. Such known transdermal formulations and ingredients are within the scope of the present invention.

[0127] The compounds of the present invention may also be administered by a transdermal device. Thus, transdermal administration can be accomplished using a patch of the reservoir or porous membrane type or of a multiple solid base.

[0128] The above components of compositions administered orally, by injection, or topically are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0129] The compounds of the invention can also be administered in sustained release forms or from sustained release delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0130] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, and eight α-1,4-linked glucose units, respectively. The linked sugar moieties may optionally contain one or more substituents, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol. See, e.g., US5,376,645. In some embodiments, the formulation contains hexapropyl-β-cyclodextrin (e.g., 10-50% in water). [Example]

[0131] The reagents used in the present invention are either directly purchased commercially or synthesized by common methods well known in the art.

[0132] Notes on common abbreviations: PE = petroleum ether, EA = ethyl acetate, MeOH = methanol, DCM = dichloromethane, DCE = dichloroethane, CH3CN = acetonitrile, 1,4-dioxane = 1,4-dioxane, DMSO = dimethyl sulfoxide, HFIP = hexafluoroisopropanol, DMF = N,N-dimethylformamide, DME = ethylene glycol dimethyl ether, Hex = n-hexane, IPA = isopropyl alcohol, NMP = N-methylpyrrolidone, NMO = N-methylmorpholine-N-oxide, TEA = triethylamine, DIEA = diisopropylethylamine, CuI = cuprous iodide, CuC N = cuprous cyanide, triphosgene = triphosgene, p-TsOH = p-toluenesulfonic acid, T3P = 1-propylphosphoric acid cyclic anhydride, TsN3 = p-toluenesulfonyl azide, PPA = polyphosphoric acid, SEM-Cl = 2-(trimethylsilyl)ethoxymethyl chloride, DMC = diethyl carbonate, NBS = N-bromosuccinimide, TBS-Cl = t-butyldimethylchlorosilane, LDA = diisopropylaminolithium, HMPA = hexamethylphosphortriamide, HATU = 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. MSI-H = microsatellite instability-high, MSI-L = microsatellite instability-low, MSS = microsatellite stable.

[0133] Example 1: Manufacturing of key intermediates Preparation of intermediate a1 [ka]

[0134] Step 1: Ethyl acetoacetate a1-1 (9.0 g, 69.2 mmol) and 5-bromo-1-H-3-amino-1,2,4-triazole a1-2 (11.3 g, 69.2 mmol) were dissolved in 90 mL of ethanol, and polyphosphate (PPA) (8.0 g, 69.2 mmol) was slowly added. After the dropwise addition was complete, the mixture was heated to 80 °C and reacted for 12 hours. The mixture was then cooled to room temperature, and the solvent was evaporated under reduced pressure. The reaction mixture was poured into 100 mL of ice water, the pH was adjusted to approximately 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a white solid a1 (7.5 g). The yield was 45%. LCMS ESI-MS m / z: 243 [M+H] + .

[0135] Preparation of intermediates a5, a7 to a13 [ka]

[0136] Step 1: The starting material a5-1 (24.0 g, 134 mmol) and piperazine-1-carboxylic acid t-butyl ester (25.0 g, 134 mmol) were dissolved in 240 mL of acetonitrile, and TEA (40.8 g, 403 mmol) was slowly added. After the dropwise addition was complete, the mixture was heated to 60 °C and reacted for 16 h. The mixture was then cooled to room temperature, and the solvent was evaporated under reduced pressure. The reaction mixture was poured into 100 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 9 / 1) to give a yellow oil a5-2 (24 g). The yield was 54%. LCMS ESI-MS m / z: 329 [M+H] + .

[0137] Step 2: Intermediate a5-2 (22.2 g, 67.6 mmol) from the previous step and 5-bromo-1-H-3-amino-1,2,4-triazole a1-2 (11.0 g, 67.6 mmol) were dissolved in 200 mL of ethanol, and polyphosphate (PPA) (7.8 g, 67.6 mmol) was slowly added. After the addition was complete, the mixture was heated to 80 °C and reacted for 12 h. The mixture was then cooled to room temperature and the solvent was evaporated under reduced pressure. The reaction mixture was poured into 100 mL of ice water, the pH was adjusted to approximately 8 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 3 / 1) to give a yellow solid a5 (4.4 g). The yield was 15%. LCMS ESI-MS m / z: 427 [M+H] + .

[0138] The following target intermediates were synthesized using similar starting materials / analogs by referring to the synthetic route of intermediate a1 or a5.

[0139] [Table 1]

[0140] Preparation of intermediates a2, a6, a14 to a32 [ka]

[0141] Step 1: Intermediate a1 (7.5 g, 30.9 mmol) and starting material a2-1 (10.1 g, 37.0 mmol) were dissolved in 75 mL of NMP, and DIEA (12.0 g, 92.6 mmol) was slowly added. After the addition was complete, the mixture was heated to 50 °C and reacted for 16 hours. The mixture was then cooled to room temperature to terminate the reaction. The reaction mixture was poured into 100 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: XSelect Prep OBD C18 Column, 30 x 150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 90 mL / min, retention time: 3 min) to give yellow solid a2 (5.2 g). Yield: 35%. LCMS ESI-MS m / z: 478 [M+H] + .

[0142] [ka]

[0143] Step 1: Intermediate a5 (1.1 g, 2.57 mmol) and starting material a2-1 (1.1 g, 3.86 mmol) were dissolved in 11 mL of NMP, and DIEA (1.0 g, 7.72 mmol) was slowly added. After the dropwise addition was complete, the mixture was heated to 70 °C and reacted for 12 hours. The mixture was then cooled to room temperature to terminate the reaction. The reaction mixture was poured into 50 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O = 5 / 1) to give a yellow solid a6 (996 mg). The yield was 58%. LCMS ESI-MS m / z: 662 [M+H] + .

[0144] The following target intermediates were synthesized using similar starting materials / analogs by referring to the synthetic route of intermediate a2 or a6.

[0145] [The analogue a2-1 was synthesized by reacting the analogous heteroaryl group NH2 with acetyl chloride.] [Table 2A] [Table 2B] [Table 2C]

[0146] Preparation of intermediate a3 [ka]

[0147] Step: Under nitrogen gas protection, intermediate a2 (5.0 g, 10.4 mmol), raw material a3-1 (2.9 g, 13.6 mmol), and sodium carbonate (3.3 g, 31.3 mmol) were dissolved in 50 mL of a mixture of 1,4-dioxane and water (v / v, 4 / 1). Catalyst Pd(dppf)Cl2 (900 mg, 1.0 mmol) was added, and the mixture was heated to 100 °C and reacted for 2 h. The reaction was then stopped and filtered. The reaction mixture was added with 100 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: WelFlash C18-I, 20-40 μm, 330 g, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 80 mL / min, retention time: 12 min) to give a yellow solid a3 (2.6 g). The yield was 52%. LCMS ESI-MS m / z: 482 [M+H] + .

[0148] Preparation of intermediate a4 [ka]

[0149] Step 1: Intermediate a3 (2.4 g, 5.0 mmol) was dissolved in 25 mL of DMF, and NBS (1.8 g, 10.0 mmol) was added. The mixture was reacted at room temperature for 2 hours, then quenched and filtered. 100 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: WelFlash C18-I, 20-40 μm, 330 g, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 90 mL / min, retention time: 11 min) to give a white solid a4 (1.6 g). The yield was 57%. LCMS ESI-MS m / z: 560 [M+H] + .

[0150] Preparation of intermediate b1 [ka]

[0151] Step 1: Under nitrogen gas protection, 4,6-dichloro-5-methoxypyrimidine b1-1 (20.0 g, 111 mmol), methyl boronic acid (7.0 g, 117 mmol), and potassium phosphate (59.2 g, 279 mmol) were dissolved in 120 mL of DME. Catalyst Pd(dppf)Cl2 (4.6 g, 5.6 mmol) was added, and the mixture was heated to 85 °C for 12 h. The reaction was then stopped and filtered. 100 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to give a white solid b1-2 (6.0 g). The yield was 34%. LCMS ESI-MS m / z: 159 [M+H] + .

[0152] Step 2: Under a carbon monoxide atmosphere, intermediate b1-2 (6.0 g, 37.0 mmol) from the previous step and TEA (7.66 g, 75.0 mmol) were dissolved in 90 mL of methanol. Catalyst Pd(dppf)Cl2 (1.85 g, 2.3 mmol) was added, and the mixture was heated to 100 °C under CO2 (20 atm) for 12 h. The reaction was then quenched and filtered. The solvent was removed by evaporation under reduced pressure, and the crude product was separated by HPLC preparative chromatography (column: WelFlash C18-I, 20-40 μm, 120 g, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 60 mL / min) to give white solid b1-3 (5.0 g). The yield was 73%. LCMS ESI-MS m / z: 183 [M+H] + .

[0153] Step 3: Intermediate b1-3 (3.0 g, 16.5 mmol) from the previous step was dissolved in 15 mL of aqueous HBr (40%) and heated to 40 °C for 10 h. The reaction was then stopped. HI (15 mL) was added to the reaction mixture, and the reaction was continued at 40 °C for 6 h. The solvent was then removed by evaporation under reduced pressure. The crude product was adjusted to pH 8 with aqueous NaOH (1N), then adjusted to pH 3 with concentrated hydrochloric acid, and the solvent was removed by evaporation under reduced pressure. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 1 / 1) to give b1 (1.5 g), a yellow solid. The yield was 59%. LCMS ESI-MS m / z: 155 [M+H] + .

[0154] Preparation of intermediate b2 [ka]

[0155] Step 1: In an ice bath and under nitrogen gas protection, the raw material b2-1 (500 mg, 3.81 mmol) was dissolved in 10 mL of tetrahydrofuran, NBS (679 mg, 3.81 mmol) was added, and the mixture was reacted at room temperature for 0.5 hours. The reaction was then stopped and filtered. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to give b2-2 (540 mg) as a yellow oil. The yield was 63%. LCMS ESI-MS m / z: 224 [M+H] + .

[0156] Step 2: Under nitrogen gas protection, the intermediate b2-2 (510 mg, 2.28 mmol) from the previous step was dissolved in 3 mL of diethyl carbonate (DMC), and CHONa (185 mg, 3.42 mmol) was added. The mixture was heated to 125 °C and reacted for 0.5 h, then cooled to room temperature. 20 mL of ice water was added to the reaction mixture, which was then extracted with methyl t-butyl ether, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to give yellow oil b2-3 (300 mg). The yield was 64%. LCMS ESI-MS m / z: 205 [M+H] + .

[0157] Step 3: At −78° C. under the protection of nitrogen gas, the intermediate b2-3 (300 mg, 1.46 mmol) from the previous step was dissolved in 6 mL of anhydrous tetrahydrofuran. n BuLi (2.5M, 1.47mL) was added dropwise, and after the addition was completed, the mixture was stirred for 1 hour. Isopropoxyboronic acid pinacol ester (327mg, 1.75mmol) was added to the reaction mixture, and the mixture was allowed to react for 1 hour at -78°C. The mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give yellow oil b2 (300mg). The yield was 81%. LCMS ESI-MS m / z: 253 [M+H] + .

[0158] Preparation of intermediate b3 [ka]

[0159] Step 1: Under a carbon monoxide atmosphere (30 atm), the starting material 4-chloro-5-methoxypyrimidine b3-1 (5.0 g, 34.6 mmol) and TEA (7.0 g, 69.2 mmol) were dissolved in 100 mL of methanol. Catalyst Pd(dppf)Cl2 (1.5 g, 2.07 mmol) was added. The mixture was then heated to 100 °C under carbon monoxide protection for 12 h. The reaction was then quenched and filtered. The solvent was removed by evaporation under reduced pressure, and the crude product was separated by column chromatography (PE / EA, 1 / 1) to give yellow oil b3-2 (4.0 g). The yield was 69%. LCMS ESI-MS m / z: 275 [M+H] + .

[0160] Step 2: Intermediate b3-2 (1.0 g, 5.94 mmol) from the previous step was dissolved in 20 mL of water, and NaOH (0.5 g, 11.9 mmol) was added. The temperature was raised to 40 °C and the reaction was continued for 10 h. The reaction was then quenched. The pH of the reaction mixture was adjusted to approximately 5 with dilute hydrochloric acid, and the solvent was removed by evaporation under reduced pressure. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 1 / 10) to give white solid b3 (400 mg). The yield was 44%. LCMS ESI-MS m / z: 155 [M+H] + .

[0161] Preparation of intermediate b4 [ka]

[0162] Step 1: In an ice bath under nitrogen gas protection, the starting material 4,6-dichloro-5-methoxypyrimidine b1-1 (11.0 g, 61.5 mmol) was dissolved in 220 mL of anhydrous tetrahydrofuran, and an ethereal solution of CD3MgI (1 M, 62 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 12 hours, after which the reaction was quenched. 100 mL of water was added to the reaction mixture, and the organic solvent was removed by evaporation under reduced pressure. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to give b4-1 (4.0 g) as a yellow oil. The yield was 40%. LCMS ESI-MS m / z: 161 [M+H] + .

[0163] Step 2: Under a carbon monoxide atmosphere, the intermediate b4-1 (5.0 g, 30.9 mmol) from the previous step and TEA (9.3 g, 92.8 mmol) were dissolved in 50 mL of deuterated methanol (CD3OD). Catalyst Pd(dppf)Cl2 (0.7 g, 0.93 mmol) was added, and the mixture was heated to 100 °C under CO (30 atm) for 12 h. The reaction was then quenched and filtered. 300 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to give b4-2 (2.0 g) as a yellow oil. The yield was 35%. LCMS ESI-MS m / z: 186 [M+H] + .

[0164] Step 3: Intermediate b4-2 (1.0 g, 5.4 mmol) from the previous step was dissolved in 20 mL of deuterium oxide (DO). NaOH (0.4 g, 10.8 mmol) was added to the reaction mixture and the mixture was allowed to react at room temperature for 6 hours. The solvent was then removed by evaporation under reduced pressure. The crude product was adjusted to pH 5 with dilute HCl (2 M), and the solvent was removed by evaporation under reduced pressure. The crude product was separated by reverse-phase flash column chromatography (column: C18, CHCN / HO, 1 / 20) to give b4 (920 mg) as a white solid. The yield was 99%. LCMS ESI-MS m / z: 172 [M+H] + .

[0165] Preparation of intermediates c1 to c4 [ka]

[0166] Step 1: Under nitrogen gas protection, intermediate a4 (210 mg, 0.3 mmol) and TEA (114 mg, 1.1 mmol) were dissolved in 2 mL of DMSO, and starting material c1-1 (371 mg, 1.9 mmol) was added. The mixture was heated to 85 °C and reacted for 12 h. The reaction was then quenched. 100 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (column: WelFlash C18-I, 20-40 μm, 180 g, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 70 mL / min, retention time: 12 min) to give white solid c1-2 (120 mg). The yield was 47%. LCMS ESI-MS m / z: 678 [M+H] + .

[0167] Step 2: Intermediate c1-1 (120 mg, 0.2 mmol) from the previous step and trifluoroacetic acid (0.5 mL) were dissolved in 2 mL of dichloromethane and reacted at room temperature for 2 hours. The reaction was then quenched. The solvent was removed by evaporation under reduced pressure, and the crude product was separated by HPLC preparative chromatography (column: WelFlash C18-I, 20-40 μm, 40 g, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 50 mL / min, retention time: 9 min) to give a white solid c1 (80 mg). Yield: 78%. LCMS ESI-MS m / z: 578 [M+H] + .

[0168] The following target intermediates were synthesized using similar raw materials / analogs by referring to the synthetic route of intermediate c1. [Table 3]

[0169] Production of intermediates c5~c6, c12~c17 [ka]

[0170] Step 1: Intermediate a6 (996 mg, 1.5 mmol) was dissolved in 10 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added dropwise. The mixture was allowed to react at room temperature for 1 hour, after which the reaction was quenched. 20 mL of water was added to the reaction mixture, and the pH was adjusted to approximately 9 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid, c5-2 (694 mg). The yield was 82%. LCMS ESI-MS m / z: 562 [M+H] + .

[0171] Step 2: The intermediate c5-2 (494 mg, 0.88 mmol) from the previous step and DIEA (567 mg, 4.4 mmol) were dissolved in 5 mL of dichloromethane, and the starting material 3-hydroxy-2-pyridinecarboxylic acid chloride c5-1 (277 mg, 1.76 mmol) was added. The reaction was allowed to proceed at room temperature for 2 hours, after which the reaction was quenched. The solvent was removed by evaporation under reduced pressure, and the crude product was separated by flash column chromatography (column: WelFlash C18-I, 20-40 μm, 130 g, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 60 mL / min, retention time: 14 min) to give a yellow solid c5 (360 mg). Yield: 60%. LCMS ESI-MS m / z: 683 [M+H] + .

[0172] [ka]

[0173] Step 1: Under the protection of nitrogen gas and ice bath, intermediate b1 (49 mg, 0.32 mmol) and 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (43 mg, 0.32 mmol) were dissolved in 2 mL of dichloromethane and stirred for 1 hour in an ice bath. DIEA (138 mg, 1.06 mmol) and intermediate c5-2 (120 mg, 0.21 mmol) were added to the reaction mixture, and the mixture was allowed to react at room temperature for 1 hour. The reaction was then quenched by adding 15 mL of water, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 4 / 5) to give pale yellow solid c6 (45 mg). Yield: 30%. LCMS ESI-MS m / z: 698 [M+H] + .

[0174] The following target intermediates were synthesized using similar starting materials / analogs by referring to the synthetic route of intermediate c5 or c6. [Table 4]

[0175] Preparation of intermediates c7 to c11 [ka]

[0176] Step 1: Under nitrogen gas protection, intermediate a5 (2.5 g, 5.85 mmol), raw material a3-1 (1.2 g, 5.85 mmol), and sodium carbonate (1.9 g, 17.5 mmol) were dissolved in 50 mL of a mixture of 1,4-dioxane and water (v / v, 1 / 1). Catalyst Pd(dppf)Cl2 (400 mg, 0.59 mmol) was added, and the mixture was heated to 100 °C and reacted for 12 h. The reaction was then stopped and filtered. The reaction mixture was added with 100 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: WelFlash C18-I, 20-40 μm, 330 g, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 40 mL / min, retention time: 16 min) to give yellow oil c7-1 (1.5 g). The yield was 58%. LCMS ESI-MS m / z: 431 [M+H] + .

[0177] Step 2: Intermediate c7-1 (1.5 g, 3.48 mmol) from the previous step and starting ethyl bromoacetate c7-2 (0.8 g, 4.88 mmol) were dissolved in 25 mL of 1,4-dioxane. DIEA (1.4 g, 10.5 mmol) was slowly added. After the addition was complete, the mixture was heated to 80 °C and reacted for 4 hours. The mixture was then cooled to room temperature to quench the reaction. The reaction mixture was poured into 100 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (XSelect Prep OBD C18 Column, 30 x 150 mm, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: acetonitrile; flow rate: 40 mL / min; retention time: 16 min) to afford c7-3 (1.4 g, 78% yield). LCMS ESI-MS m / z: 517 [M+H] + .

[0178] Step 3: Intermediate c7-3 (1.2 g, 2.32 mmol) from the previous step was dissolved in 18 mL of a 2 / 1 tetrahydrofuran / water mixture. NaOH (3.5 mL, 1 M) was slowly added. After the dropwise addition, the mixture was allowed to react at room temperature for 1 hour, after which the reaction was quenched. The pH of the reaction mixture was adjusted to approximately 4 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: XSelect Prep OBD C18 Column, 30 x 150 mm, 5 μm, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 40 mL / min, retention time: 16 min) to give c7 (900 mg) as a yellow solid. The yield was 92%. LCMS ESI-MS m / z: 489 [M+H] + .

[0179] The following target intermediates were synthesized using similar starting materials / analogs by referring to the synthetic route of intermediate c7. [Table 5]

[0180] Preparation of intermediate c18 [ka]

[0181] Step 1: Under nitrogen gas protection, intermediate a1 (1.42 g, 5.85 mmol), raw material b2 (1.47 g, 5.85 mmol), and sodium carbonate (1.9 g, 17.5 mmol) were dissolved in 30 mL of a 1,4-dioxane / water mixture (v / v, 1 / 1). Catalyst Pd(dppf)Cl2 (400 mg, 0.59 mmol) was added, and the mixture was heated to 100 °C for 2 h. The reaction was then quenched and filtered. 80 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 1 / 1) to give a yellow solid c18-1 (1.0 g). The yield was 60%. LCMS ESI-MS m / z: 289 [M+H] +.

[0182] Step 2: The intermediate c18-1 (1.0 g, 3.47 mmol) from the previous step and the starting ethyl bromoacetate c7-2 (0.8 g, 4.88 mmol) were dissolved in 25 mL of 1,4-dioxane, and DIEA (1.4 g, 10.5 mmol) was slowly added. After the dropwise addition was complete, the mixture was heated to 80 °C and reacted for 4 hours. The mixture was then cooled to room temperature to terminate the reaction. The reaction mixture was poured into 100 mL of ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO = 3 / 1) to give c18-2 (1.1 g) as a pale yellow solid. The yield was 85%. LCMS ESI-MS m / z: 375 [M+H] + .

[0183] Step 3: Intermediate c18-2 (1.1 g, 2.94 mmol) from the previous step was dissolved in 30 mL of a 2 / 1 mixture of tetrahydrofuran and water. NaOH solution (5.0 mL, 1 M) was slowly added. After the dropwise addition, the mixture was allowed to react at room temperature for 1 hour, after which the reaction was quenched. The pH of the reaction mixture was adjusted to approximately 4 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (XSelect Prep OBD C18 Column, 30 x 150 mm, 5 μm, mobile phase A: water, mobile phase B: acetonitrile, flow rate: 60 mL / min) to give c18 (730 mg) as a yellow solid. The yield was 72%. LCMS ESI-MS m / z: 347 [M+H] + .

[0184] Preparation of intermediates d1 to d7 [ka]

[0185] Step 1: Under nitrogen gas protection, the raw material d1-1 (2.0 g, 7.40 mmol) and methylhydrazine sulfate (1.1 g, 7.40 mmol) were dissolved in 40 mL of ethanol, and acetic acid (100 mg, 0.14 mmol) was added. The mixture was heated to 80 °C and reacted for 2 h. The reaction was stopped, and the solvent was evaporated under reduced pressure. The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give yellow oil d1-2 (2.5 g). The yield was 89%. LCMS ESI-MS m / z: 297 [M+H] + .

[0186] Step 2: Under nitrogen gas protection, the intermediate d1-2 (2.5 g, 8.38 mmol) from the previous step and potassium phosphate (1.78 g, 8.39 mmol) were dissolved in 38 mL of DMSO, and catalyst CuI (160 mg, 0.83 mmol) was added. The mixture was heated to 100 °C and reacted for 3 h. The reaction was then quenched and filtered. 100 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: WelFlash C18-I, 20-40 μm, 330 g, mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile, flow rate: 40 mL / min, retention time: 12 min) to give a white solid d1-3 (130 mg). The yield was 7%. LCMS ESI-MS m / z: 217 [M+H] + .

[0187] Step 3: At -78 °C under nitrogen gas protection, intermediate d1-3 (130 mg, 0.59 mmol) from the previous step was dissolved in 2.5 mL of anhydrous tetrahydrofuran, and n-BuLi (0.28 mL, 2.5 M) was slowly added. After the dropwise addition was completed, the mixture was stirred at -78 °C for 1 hour. 2-Isopropoxyboronic acid pinacol ester (134 mg, 1.23 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes to quench the reaction. 10 mL of saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, which was then dried over anhydrous sodium sulfate and concentrated to give yellow oil d1 (110 mg). The yield was 70%. LCMS ESI-MS m / z: 265 [M+H] + .

[0188] The following target intermediates were synthesized using similar raw materials / analogs by referring to the synthetic route of intermediate d1. [Table 6]

[0189] Preparation of intermediates d8 and d15 [ka]

[0190] Step 1: Under nitrogen gas protection, the starting material 1-bromo-2-fluoro-4-iodobenzene d8-1 (1.95 g, 6.5 mmol) and the starting material d8-2 (2.32 g, 7.8 mmol) were dissolved in 40 mL of acetonitrile. Potassium t-butoxide (2.2 g, 19.4 mmol) was added, and the mixture was heated to 50 °C and reacted for 6 h. The reaction was then quenched and filtered. 100 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE / EA, 20 / 1) to give 2.22 g of yellow oil d8-3 in 79% yield.

[0191] Step 2: Intermediate d8-3 (2.22 g, 5.15 mmol) from the previous step was dissolved in 133 mL of chlorobenzene, and polyphosphate PPA (2.37 g, 20.6 mmol) was added. The mixture was heated to 130 °C and reacted for 5 h. The reaction was then stopped and cooled to room temperature. 100 mL of ice water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CHCN / HO, 9 / 10) to give yellow oil d8-4 (1.05 g). Yield: 60%.

[0192] Step 3: Under nitrogen gas protection, the intermediate d8-4 (1.05 g, 3.1 mmol) from the previous step and the starting material d8-5 (1.95 g, 9.3 mmol) were dissolved in 21 mL of DMF. Catalyst CuI (290 mg, 1.55 mmol) and HMPA (2.39 g, 13.3 mmol) were added. The mixture was heated to 100 °C for 2 h, then quenched and filtered. The reaction mixture was added with 60 mL of water, extracted with methyl t-butyl ether, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE / EA, 100 / 1) to give 0.8 g of a yellow solid, d8-6, in a 92% yield.

[0193] Step 4: Under nitrogen gas protection, intermediate d8-6 (0.8 g, 2.85 mmol) from the previous step and the starting diphenylketone imine (1.03 g, 5.69 mmol) were dissolved in 16 mL of toluene. The catalyst Pd(OAc)2 (60 mg, 0.28 mmol), the ligand BINAP (0.35 g, 0.57 mmol), and cesium carbonate (1.85 g, 5.69 mmol) were added. The mixture was heated to 110 °C and reacted for 2 h. The reaction was then quenched and filtered. The reaction mixture was added with 60 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a crude product mixture. The mixture was dissolved in 4 mL of tetrahydrofuran, and a 2 M solution of hydrogen chloride in tetrahydrofuran (16 mL) was added. The reaction was allowed to proceed at room temperature for 1 h. The reaction was then quenched. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CHCN / H2O, 10 / 7) to give yellow solid d8 (0.5 g). The yield was 81%. LCMS ESI-MS m / z: 218 [M+H] + .

[0194] The following target intermediates were synthesized using similar starting materials / analogs by referring to the synthetic route of intermediate d8. [Table 7]

[0195] Preparation of intermediate d9 [ka]

[0196] Step 1: Under nitrogen gas protection, raw materials d9-1 (3.5 g, 27.3 mmol) and d9-2 (4.1 g, 32.8 mmol) were dissolved in 70 mL of dichloromethane, and DIEA (10.6 g, 81.9 mmol) was added. The mixture was reacted at room temperature for 3 hours, and then quenched. 100 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give yellow oil d9-3 (3.3 g).

[0197] Step 2: Intermediate d9-3 (1.7 g, 7.86 mmol) from the previous step was dissolved in 17 mL of acetonitrile, and InCl (0.35 g, 1.57 mmol) was added. The mixture was heated to 80 °C and reacted for 5 h. The reaction was then stopped and cooled to room temperature. 100 mL of ice water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give yellow oil d9-4 (1.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 4.9 Hz, 1H), 6.87 (d, J = 5.0 Hz, 1H), 4.73 (s, 2H), 3.84 (t, J = 5.6 Hz, 2H), 2.66 (d, J = 11.3 Hz, 2H).

[0198] Step 3: Under nitrogen gas protection, the intermediate d9-4 (1.5 g, 7.56 mmol) from the previous step was dissolved in 30 mL of toluene, and NBS (1.3 g, 7.56 mmol) was added. The mixture was reacted at room temperature for 12 hours, then quenched and filtered. 60 mL of water was added to the reaction mixture, which was then extracted with methyl t-butyl ether, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 100 / 1) to give d9-5 (500 mg) as a yellow oil in a 17% yield. 1 H NMR (300 MHz, DMSO-d6) δ 6.99 (s, 1H), 4.62 (s, 2H), 3.83 (t, J = 5.6 Hz, 2H), 2.61 (tt, J = 5.7, 1.9 Hz, 2H).

[0199] Step 4: At -78 °C under nitrogen gas protection, intermediate d9-5 (0.5 g, 2.28 mmol) from the previous step was dissolved in 10 mL of anhydrous tetrahydrofuran, and a hexane solution of n-BuLi (1.4 mL, 2 M) was added dropwise. After the addition was complete, the mixture was stirred for 30 min. Isopropoxyboronic acid pinacol ester iPrOBpin (0.51 g, 2.74 mmol) was added to the mixture, and the mixture was reacted at room temperature for 1 h. The reaction was then quenched. 60 mL of saturated aqueous NH4Cl was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give yellow solid d9 (550 mg). The yield was 91%. LCMS ESI-MS m / z: 267 [M+H] + .

[0200] Preparation of intermediates d10 to d11 [ka]

[0201] Step 1: Under nitrogen gas protection, starting material d10-1 (50 mg, 0.23 mmol) and bis(pinacolato)diboron B2Pin2 (89 mg, 0.35 mmol) were dissolved in 1 mL of 1,4-dioxane. Catalysts Pd(dppf)Cl2 (17 mg, 0.02 mmol) and KOAc (57 mg, 0.58 mmol) were added. The mixture was heated to 80 °C and reacted for 2 h. The reaction was then quenched and filtered. 5 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give yellow solid d10 (20 mg). The yield was 33%. LCMS ESI-MS m / z: 263 [M+H] + .

[0202] The following target intermediates were synthesized using similar raw materials / analogs by referring to the synthetic route of intermediate d10. [Table 8]

[0203] Preparation of intermediate d12 [ka]

[0204] Step 1: Under nitrogen gas protection, the raw material d12-1 (2.5 g, 12.88 mmol) and imidazole (1.8 g, 25.77 mmol) were dissolved in 40 mL of dichloromethane. TBS-Cl (2.1 g, 14.2 mmol) was added, and the mixture was reacted at room temperature for 1 hour to quench the reaction. 100 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE / EA, 10 / 1) to give yellow oil d12-2 (3.0 g). The yield was 76%. LCMS ESI-MS m / z: 308 [M+H] + .

[0205] Step 2: At -78 °C under nitrogen gas protection, intermediate d12-2 (1.0 g, 3.24 mmol) from the previous step was dissolved in 23 mL of anhydrous tetrahydrofuran. A hexane solution of n-BuLi (1.3 mL, 2.5 M) was added dropwise, and the mixture was stirred for 30 minutes. A pre-prepared tetrahydrofuran solution of ZnCl (10.7 mL, 1 M) was added to the reaction mixture, followed by an additional hour of reaction. The reaction was then quenched and used directly in the next step.

[0206] Preparation of intermediate d13 [ka]

[0207] Step 1: At -78 °C under nitrogen gas protection, starting material d13-1 (1.1 g, 4.24 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and LDA (4.24 mL, 2 M) in hexane was added dropwise. After the addition was complete, a solution of pre-formulated I2 (1.62 g, 6.36 mmol, 1 mL) in tetrahydrofuran was added, and the mixture was reacted at 78 °C for 1 h to quench the reaction. 50 mL of saturated aqueous sodium thiosulfate (NaSO) was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CHCN / H2O, 7 / 10) to give yellow solid d13-2 (310 mg). The yield was 18%. LCMS ESI-MS m / z: 386 [M+H] + .

[0208] Step 2: The intermediate d13-2 (386 mg, 1.0 mmol) from the previous step was dissolved in 4 mL of methanol, and aqueous NaOH (3.9 mL, 2.5 N) was added. The mixture was allowed to react at room temperature for 1 hour. 30 mL of ice water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid d13-3 (200 mg). The yield was 81%. LCMS ESI-MS m / z: 246 [M+H] + .

[0209] Step 3: In an ice bath, the intermediate d13-3 (0.2 g, 0.81 mmol) from the previous step was dissolved in 4 mL of DMF, and NaH (30 mg, 1.22 mmol, 60%) was slowly added. After stirring for 1 h, SEM-Cl (0.2 g, 1.22 mmol) was added to the reaction mixture, and the mixture was allowed to warm to room temperature and react for 1 h to quench the reaction. 50 mL of ice water was added to the reaction mixture, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 1 / 1) to give yellow solid d13-4 (200 mg). The yield was 65%. LCMS ESI-MS m / z: 376 [M+H] + .

[0210] Step 4: At -78 °C under nitrogen gas protection, intermediate d13-4 (170 mg, 0.45 mmol) from the previous step was dissolved in 4 mL of anhydrous tetrahydrofuran, and a hexane solution of n-BuLi (0.22 mL, 2.5 M) was added dropwise. After the addition was complete, the mixture was stirred for 30 min. Isopropoxyboronic acid pinacol ester iPrOBpin (101 mg, 0.54 mmol) was added to the mixture, and the mixture was reacted at room temperature for 1 h. The reaction was then quenched by adding 60 mL of saturated aqueous NH4Cl. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give yellow solid d13 (80 mg). The yield was 48%. LCMS ESI-MS m / z: 376 [M+H] + .

[0211] Preparation of intermediate d14 [ka]

[0212] Step 1: The raw material d14-1 (2.4 g, 9.1 mmol) and TEA (2.75 g, 27.2 mmol) were dissolved in 24 mL of anhydrous dichloromethane, and p-toluenesulfonyl chloride TsCl (3.1 g, 54.3 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 12 hours, after which the reaction was quenched. 50 mL of ice water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 3 / 1) to give d14-2 (3.1 g), a pale pink solid. The yield was 81%. LCMS ESI-MS m / z: 420 [M+H] + .

[0213] Step 2: In an ice bath and under nitrogen gas protection, the intermediate d14-2 (3.1 g, 7.39 mmol) from the previous step was dissolved in 31 mL of ethanol, NaBH4 (0.28 g, 7.39 mmol) was added, and the mixture was allowed to react at room temperature for 1 hour. 30 mL of ice water was added to the reaction mixture, and the pH was adjusted to approximately 6 with trifluoroacetic acid. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid d14-3 (1.3 g). The yield was 41%. LCMS ESI-MS m / z: 422 [M+H] + .

[0214] Step 3: The intermediate d14-3 (1.3 g, 3.09 mmol) from the previous step was dissolved in 12 mL of anhydrous tetrahydrofuran, and NaH (123 mg, 3.09 mmol, 60%) was slowly added. The mixture was reacted at room temperature for 12 hours to quench the reaction. 40 mL of ice water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (PE / EA, 50 / 1) to give a yellow solid d14-4 (440 mg). The yield was 57%. LCMS ESI-MS m / z: 250 [M+H] + .

[0215] Step 4: At -78 °C under nitrogen gas protection, intermediate d14-4 (170 mg, 0.68 mmol) from the previous step was dissolved in 2 mL of anhydrous tetrahydrofuran, and a hexane solution of n-BuLi (0.27 mL, 2.5 M) was added dropwise. After the addition was complete, the mixture was stirred for 30 min. Isopropoxyboronic acid pinacol ester iPrOBpin (152 mg, 0.82 mmol) was added to the mixture, and the mixture was reacted at room temperature for 1 h. The reaction was then quenched by adding 10 mL of saturated aqueous NH4Cl. The reaction mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give yellow solid d14 (120 mg). The yield was 71%. LCMS ESI-MS m / z: 376 [M+H] + .

[0216] Preparation of intermediates d16 to d17 [ka]

[0217] Step 1: Under nitrogen gas protection, TMSCF3 (490 mg, 3.44 mmol) and KF (200 mg, 3.44 mmol) were dissolved in 12 mL of a mixture of DMF and NMP (v / v, 1 / 1). Catalyst CuI (657 mg, 3.44 mmol) was added and stirred at room temperature for 3 h. The starting material d16-1 (600 mg, 2.29 mmol) was added to the reaction mixture, and the mixture was heated to 70 °C and reacted for 12 h. The reaction was then stopped and filtered. 60 mL of water was added to the reaction mixture, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 1 / 1) to give d16 (150 mg) as a brown oil. The yield was 32%. LCMS ESI-MS m / z: 204 [M+H] + .

[0218] The following target intermediates were synthesized using similar raw materials / analogs by referring to the synthetic route of intermediate d16. [Table 9]

[0219] Preparation of intermediates d18 to d19 [ka]

[0220] Step 1: Under nitrogen gas protection, the raw material 2-bromo-5-trifluoromethylphenol d18-1 (5.0 g, 20.75 mmol) and potassium carbonate (8.6 g, 62.2 mmol) were dissolved in 100 mL of DMF. The raw material d18-2 (12.3 g, 62.2 mmol) was added dropwise. The mixture was heated to 80 °C and reacted for 12 h. The reaction was then stopped and filtered. 250 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE / EA, 20 / 1) to give d18-3 (6.0 g) as a yellow oil in 81% yield.

[0221] Step 2: The intermediate d18-3 (6.0 g, 16.8 mmol) from the previous step and polyphosphoric acid (30 g, 261 mmol) were dissolved in 72 mL of toluene, and the mixture was heated to 120 °C and reacted for 5 h. The reaction was then quenched. 100 mL of water was added to the reaction mixture, and the pH was adjusted to approximately 8 with aqueous ammonia. The mixture was extracted with methyl t-butyl ether, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE / EA, 20 / 1) to give d18-4 (1.0 g) as a yellow oil in a 23% yield.

[0222] Step 3: Under nitrogen gas protection, intermediate d18-4 (1.0 g, 3.77 mmol) from the previous step and the starting diphenylketone imine (1.4 g, 7.55 mmol) were dissolved in 20 mL of toluene. Catalyst Pd(OAc)2 (80 mg, 0.38 mmol), ligand BINAP (0.5 g, 0.8 mmol), and cesium carbonate (2.5 g, 7.55 mmol) were added. The mixture was heated to 110 °C and reacted for 2 h. The reaction was then quenched and filtered. 100 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give the crude product mixture. The mixture was dissolved in 5 mL of tetrahydrofuran, and a 2 M solution of hydrogen chloride in tetrahydrofuran (20 mL) was added. The reaction was allowed to proceed at room temperature for 1 h. The reaction was then quenched. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CHCN / H2O, 1 / 1) to give yellow solid d18 (150 mg). The yield was 20%. LCMS ESI-MS m / z: 202 [M+H] + .

[0223] The following target intermediates were synthesized using similar raw materials / analogs by referring to the synthetic route of intermediate d18. [Table 10]

[0224] Preparation of intermediate d20 [ka]

[0225] Step 1: At -78 °C under nitrogen gas protection, the starting material 7-aminobenzofuran d20-1 (600 mg, 4.13 mmol) was dissolved in 14 mL of anhydrous dichloromethane. A pre-prepared Br2 solution (0.7 g, 4.13 mmol, 11 mL of DCM) was added, and the mixture was reacted at -78 °C for 1 h to quench the reaction. 20 mL of saturated aqueous sodium thiosulfate was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 1 / 1) to give d20 (200 mg) as a yellow oil. The yield was 23%. LCMS ESI-MS m / z: 212 [M+H] + .

[0226] Preparation of intermediate d21 [ka]

[0227] Step 1: Under nitrogen gas protection, 2-chloro-4-bromoaniline P23-1 (1.1 g, 5.32 mmol) and starting pyridine-3-boric acid d21-1 (1.0 g, 7.99 mmol) were dissolved in 20 mL of a mixture of DMF and water (v / v, 4 / 1). Catalyst Pd(dppf)Cl2 (400 mg, 0.53 mmol) and potassium carbonate (1.5 g, 10.65 mmol) were added. The mixture was heated to 110 °C for 1 h, then quenched and filtered. The reaction mixture was added with 50 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to give the crude product mixture. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 1 / 1) to give d21 (900 mg) as a yellow solid in 83% yield. LCMS ESI-MS m / z: 205 [M+H] + .

[0228] Preparation of intermediate d22 [ka]

[0229] Step 1: Under nitrogen gas protection in an ice bath, the raw material 4-iodo-2,3-dimethylaniline d22-1 (5.1 g, 20.6 mmol) and TEA (4.1 g, 40.5 mmol) were dissolved in 10 mL of dichloromethane. Acetyl chloride (1.9 g, 24.7 mmol) was added and the mixture was reacted in an ice bath for 2 hours to quench the reaction. 50 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 10 / 7) to give 5.5 g of white solid d22-2. The yield was 92%. LCMS ESI-MS m / z: 290 [M+H] + .

[0230] Step 2: Under nitrogen gas protection, the intermediate d22-2 (1.5 g, 5.18 mmol) from the previous step and the starting methyl 2,2-difluoro-2-(fluorosulfonyl)acetate d8-5 (4.9 g, 25.9 mmol) were dissolved in 15 mL of DMF. Catalyst CuI (1.4 g, 7.78 mmol) and HMPA (4.6 g, 25.9 mmol) were added. The mixture was heated to 80 °C for 12 h, then quenched and filtered. The reaction mixture was added with 60 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CHCN / HO, 10 / 7) to give yellow solid d22-3 (950 mg). The yield was 79%. LCMS ESI-MS m / z: 232 [M+H] + .

[0231] Step 3: The intermediate d22-3 (950 mg, 4.10 mmol) from the previous step was dissolved in 15 mL of ethanol, diluted hydrochloric acid (7.6 mL, 6 M) was added, and the mixture was heated to 80 °C for 2 h to quench the reaction. The solvent was removed by evaporation under reduced pressure to give a yellow solid d22 (750 mg). The yield was 96%. LCMS ESI-MS m / z: 190 [M+H] + .

[0232] Preparation of intermediate d23 [ka]

[0233] Step 1: At -78 °C under nitrogen gas protection, the starting material 4-bromo-2-fluoro-trifluoromethylbenzene d23-1 (2.1 g, 8.64 mmol) was dissolved in 21 mL of anhydrous tetrahydrofuran, and a hexane solution of LDA (6.5 mL, 2 M) was added dropwise. The mixture was stirred at this temperature for 1 hour. Mel (1.4 g, 9.51 mmol) was added to the reaction mixture, and the mixture was allowed to warm to room temperature and react for 2 hours. The reaction mixture was then quenched by adding 50 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give yellow oil d23-2 (1.5 g). The yield was 68%. LCMS ESI-MS m / z: 257 [M+H] + .

[0234] Step 2: Under nitrogen gas protection, the intermediate d23-2 (550 mg, 2.14 mmol), Cs2CO3 (1.4 g, 4.28 mmol), and starting BocNH2 (275.8 mg, 2.35 mmol) from the previous step were dissolved in 9 mL of 1,4-dioxane. The catalyst Pd2(dba)3 (58.8 mg, 0.064 mmol) and the ligand XantPhos (49.5 mg, 0.086 mmol) were added. The mixture was heated to 80 °C for 1 h, quenched, and filtered. The reaction mixture was added with 60 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (C18 column, CH3CN / HO, 5 / 4) to give d23-3 (700 mg) as a yellow solid in 95% yield. LCMS ESI-MS m / z: 294 [M+H] + .

[0235] Step 3: Intermediate d23-3 (700 mg, 4.10 mmol) from the previous step was dissolved in 15 mL of HCl in 1,4-dioxane (2 M). The mixture was allowed to react at room temperature for 1 h and then quenched. The solvent was removed by evaporation under reduced pressure, and the reaction mixture was adjusted to pH 8 with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 10 / 7) to give yellow solid d23 (300 mg). The yield was 65%. LCMS ESI-MS m / z: 194 [M+H] + .

[0236] Preparation of intermediate d24 [ka]

[0237] Step 1: Under nitrogen gas protection, the starting material, 3-fluoro-4-trifluoromethylaniline d24-1 (2.0 g, 11.2 mmol) was dissolved in 21 mL of acetic acid, and N-iodosuccinimide (NIS) (2.5 g, 11.2 mmol) was slowly added. The mixture was allowed to react at room temperature for 3 hours. 50 mL of saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 5 / 4) to give yellow solid d24-2 (1.5 g). The yield was 44%. LCMS ESI-MS m / z: 306 [M+H] + .

[0238] Step 2: Under nitrogen gas protection, the intermediate d24-2 (1.5 g, 4.92 mmol), K2CO3 (2.0 g, 14.8 mmol), and starting trimethylboroxine d24-3 (930 mg, 7.38 mmol) from the previous step were dissolved in 15 mL of DME. Catalyst Pd(PPh3)4 (0.28 g, 0.25 mmol) was added, and the mixture was heated to 100 °C for 1 h. The reaction was then quenched and filtered. The reaction mixture was added with 60 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 5 / 3) to give d24 (300 mg) as a yellow oil in 32% yield. LCMS ESI-MS m / z: 194 [M+H] + .

[0239] Example 2: Production of target molecules P1 to P3 [ka]

[0240] Step 1: Under nitrogen gas protection, intermediate b1 (16 mg, 0.1 mmol) and 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (13.9 mg, 0.1 mmol) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 1 hour. Intermediate c2 (51 mg, 0.1 mmol) and DIEA (56 mg, 0.4 mmol) were added to the reaction mixture, and the mixture was reacted at room temperature for 1 hour to quench the reaction. The reaction mixture was added with 10 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (Column: XSelect Prep OBD C18 Column, 30*150 mm, 5 μm, Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile, Flow Rate: 60 mL / min, Retention Time: 3 min) to obtain a white solid, P1 (7.3 mg). The yield was 11%. LCMS ESI-MS m / z: 714 [M+H] + .

[0241] The following target molecules were synthesized using similar raw materials / intermediates with reference to the synthetic route of compound P1. [Table 11]

[0242] Example 3: Production of target molecules P4 to P21, P33 to P51, and A3 [ka]

[0243] Step: Under nitrogen gas protection, intermediate c5 (55 mg, 0.08 mmol), raw material thiophene 2-carboxylic acid P4-1 (11 mg, 0.08 mmol), and potassium phosphate (51 mg, 0.24 mmol) were dissolved in 1 mL of a mixed solution of DMF and water (v / v, 4 / 1). The catalyst Pd(dppf)Cl2.CH2Cl2 (6.6 mg, 0.01 mmol) was added, the mixture was heated to 90 °C, and the reaction was continued for 1 h, after which the reaction was stopped. 5 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (column: Xbridge Prep phenyl OBD column, 30*150 nm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 60 mL / min, retention time: 8.7 min) to give white solid P4 (10.1 mg). The yield was 18%. LCMS ESI-MS m / z: 687 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 13.0, 6.5 Hz, 3H), 7.30 (s, 2H), 7.21 (t, J = 4.3 Hz, 1H), 5.37 (s, 2H), 4.57 (d, J = 12.1 Hz, 1H), 3.48 (s, 3H), 3.42 (d, J = 13.3 Hz, 1H), 3.26 (d, J = 13.2 Hz, 3H), 2.99 (d, J = 12.7 Hz, 1H), 2.82 (d, J = 11.3 Hz, 1H), 2.62 (d, J = 28.8 Hz, 1H), 1.21 (t, J = 7.7 Hz, 4H).

[0244] Compound P4 was synthesized using reference materials and similar raw materials / intermediates (eg, intermediates c6, c12-c13, c16-c17, b2, d1-d7, d9-d11, d13-d14) and the following target molecules. Table 12A Table 12B Table 12C

Table 12D

Table 12E

Table 12G

[0245] Example 4: Production of target molecule P22 [ka]

[0246] Step 1: Under nitrogen gas protection, intermediate c5 (50 mg, 0.07 mmol), starting material P22-1 (45 mg, 0.37 mmol), and potassium acetate (72 mg, 0.73 mmol) were dissolved in 1 mL of DMSO, heated to 120 °C, and reacted for 12 hours. The reaction was then quenched. 5 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (Column: XBridge Prep Shield RP18 OBD Column, 30 x 150 mm, 5 μm, Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: acetonitrile, Flow Rate: 60 mL / min, Retention Time: 10.9 min) to give white solid P22 (13.2 mg). Yield: 24%. LCMS ESI-MS m / z: 726 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 2H), 8.11 - 7.92 (m, 3H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 3.0 Hz, 2H), 6.16 (d, J = 1.9 Hz, 1H), 5.24 (s, 2H), 4.72 (s, 2H), 4.54 (d, J = 12.5 Hz, 1H), 4.17 (t, J = 5.4 Hz, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.57 - 3.41 (m, 3H), 3.23 (d, J = 12.3 Hz, 1H), 2.96 (d, J = 11.0 Hz, 3H), 2.82 - 2.71 (m, 1H), 2.59 (d, J = 11.2 Hz, 1H), 1.16 (t, J = 7.3 Hz, 3H).

[0247] Example 5: Production of target molecules P23-P32, P56-P62 [ka]

[0248] Step 1: Under nitrogen gas protection, intermediate c8 (110 mg, 0.21 mmol), the starting material 4-bromo-2-aniline P23-1 (86 mg, 0.42 mmol), and DMAP (76 mg, 0.63 mmol) were dissolved in 3 mL of dichloromethane. DIEA (161 mg, 1.3 mmol) and T3P (528 mg, 0.84 mmol) were added and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was then quenched by adding 15 mL of water, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 1 / 1) to give brown solid P23-2 (80 mg). The yield was 54%. LCMS ESI-MS m / z: 718 [M+H] + .

[0249] Step 2: The intermediate P23-2 (80 mg, 0.11 mmol) from the previous step was dissolved in 2 mL of 1,4-dioxane, and 0.5 mL of 4 M diluted hydrochloric acid was added. The reaction was allowed to proceed at room temperature for 1 hour, after which the reaction was quenched. 15 mL of water was added to the reaction mixture, and the pH was adjusted to approximately 9 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give brown solid P23-3 (50 mg). The yield was 73%. LCMS ESI-MS m / z: 618 [M+H] + .

[0250] Step 3: Under nitrogen gas protection in an ice bath, the intermediate P23-3 (50 mg, 0.08 mmol) from the previous step, the raw material C5-1 (38 mg, 0.24 mmol), and TEA (41 mg, 0.40 mmol) were dissolved in 1 mL of dichloromethane and reacted for 1 hour in an ice bath to quench the reaction. 5 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (column: Xselect CSH Prep C18 OBD Column, 19*250 nm, 5 μm; mobile phase A: water (0.1% TFA); mobile phase B: acetonitrile; flow rate: 25 mL / min; retention time: 11.5 min) to give a white solid, P23 (10.3 mg). The yield was 17%. LCMS ESI-MS m / z: 739 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 2H), 8.06 (dd, J = 3.8, 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.58 - 7.49 (m, 2H), 7.35 - 7.23 (m, 2H), 5.27 (s, 2H), 5.02 (q, J = 6.5, 4.9 Hz, 2H), 4.89 (t, J = 3.5 Hz, 2H), 4.55 (d, J = 12.3 Hz, 1H), 3.54 - 3.41 (m, 2H), 3.39 (s, 1H), 3.21 (d, J = 11.8 Hz, 1H), 3.06 - 2.91 (m, 3H), 2.81 (d, J = 11.2 Hz, 1H), 2.63 (d, J = 10.9 Hz, 1H), 1.25 - 1.16 (m, 3H).

[0251] [ka]

[0252] Step 1: Under nitrogen gas protection, intermediate b1 (37 mg, 0.24 mmol) and 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (65 mg, 0.48 mmol) were dissolved in 2 mL of dichloromethane and stirred at room temperature for 1 hour. DIEA (104 mg, 0.8 mmol) and intermediate P23-3 (100 mg, 0.16 mmol) were added to the reaction mixture, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then quenched by adding 15 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 5 / 3) to give white solid P24 (29 mg). The yield was 23%. LCMS ESI-MS m / z: 754 [M+H] + .

[0253] The following target molecules were synthesized using similar raw materials / intermediates (e.g., intermediates d8, d15, d18-d24, etc.) by referring to the synthetic route of compound P23 or P24.

[0254] [Table 13A] [Table 13B] [Table 13C] [Table 13D]

[0255] Example 6: Production of target molecules P52 to P55 [ka]

[0256] Step 1: Intermediate a26 (388 mg, 0.59 mmol) was dissolved in 4 mL of HCl in 1,4-dioxane (4 M) and reacted at room temperature for 1 h. The reaction was then quenched. The solvent was removed by evaporation under reduced pressure to give brown solid P52-1 (333 mg). LCMS ESI-MS m / z: 556 [M+H] + .

[0257] Step 2: Under nitrogen gas protection, intermediate b1 (62 mg, 0.40 mmol) and 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (108 mg, 0.81 mmol) were dissolved in 3 mL of dichloromethane and stirred at room temperature for 1 hour. DIEA (348 mg, 2.70 mmol) and intermediate P52-1 (150 mg, 0.07 mmol) were added to the reaction mixture, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then quenched by adding 15 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 4 / 5) to give white solid P52-2 (144 mg). The yield was 77%. LCMS ESI-MS m / z: 692 [M+H] + .

[0258] Step 3: Under nitrogen gas protection, intermediate P52-2 (144 mg, 0.20 mmol) from the previous step, intermediate b2 (61 mg, 0.24 mmol), and KPO (441 mg, 2.08 mmol) were dissolved in 3 mL of a mixed solution of DMF and water (v / v, 5 / 1). Catalyst Pd(dppf)Cl (91.3 mg, 0.12 mmol) was added, and the temperature was raised to 80 °C for 1 h, after which the reaction was quenched. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (column: YMC-Actus Triart C18 ExRS30*150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O), mobile phase B: acetonitrile, flow rate: 60 mL / min, retention time: 7.0 min) to give white solid P52 (31 mg). The yield was 20%. LCMS ESI-MS m / z: 738 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.55 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.65 - 7.48 (m, 3H), 5.28 (q, J = 17.6 Hz, 2H), 5.02 (d, J = 3.6 Hz, 2H), 4.90 (d, J = 3.9 Hz, 2H), 4.52 (s, 1H), 3.64 (s, 2H), 3.48 (s, 3H), 2.98 - 2.79 (m, 3H), 2.44 (d, J = 3.5 Hz, 3H), 2.37 (s, 3H), 1.31 - 1.13 (m, 3H), 0.82 (dd, J = 54.2, 6.2 Hz, 3H).

[0259] The following target molecules were synthesized using similar raw materials / intermediates (e.g., intermediates a25, a27 to a28, etc.) with reference to the synthetic route for compound P52. [Table 14]

[0260] Example 7: Production of target molecules P63-P64 [ka]

[0261] Step 1: The starting material P63-1 (2.4 g, 8.72 mmol) was dissolved in 24 mL of methanol and stirred for 5 minutes. After that, aqueous KOH (96 mL, 2 M) was added and the reaction was allowed to proceed at room temperature for 12 hours. The reaction was then quenched. The solvent was removed by evaporation under reduced pressure, and the reaction mixture was adjusted to pH 5 with dilute hydrochloric acid to precipitate a solid. The solid was washed with water and dried to obtain a white solid, P63-2 (1.4 g). The yield was 65%. LCMS ESI-MS m / z: 247 [M+H] + .

[0262] Step 2: Compound P63-2 (1.4 g, 5.66 mmol) from the previous step was dissolved in 25 mL of a mixed solution of acetic acid and water (v / v, 3 / 2). After stirring for 5 minutes, concentrated hydrochloric acid (1.0 mL) was added and the mixture was heated to 105 °C for 12 hours to quench the reaction. The solvent was removed by evaporation under reduced pressure, and the reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO = 10 / 7) to give white solid P63-3 (0.6 g). The yield was 52%. LCMS ESI-MS m / z: 203 [M+H] + .

[0263] Step 3: In an ice bath and under nitrogen gas protection, compound P63-3 (420 mg, 2.06 mmol) from the previous step was dissolved in 13 mL of anhydrous tetrahydrofuran, and a solution of iPrMgCl (255 mg, 2.48 mmol, 1.0 mL) in tetrahydrofuran was added dropwise. After the addition was complete, the mixture was stirred for 1 hour in an ice bath. Tributyltin chloride Bu3SnCl (1.3 g, 4.13 mmol) was added to the reaction mixture, and the mixture was allowed to react for another hour before quenching. 30 mL of saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give yellow solid P63-4 (116 mg). The yield was 14%. LCMS ESI-MS m / z: 415 [M+H] + .

[0264] Step 4: Under nitrogen gas protection, compound P63-4 (55 mg, 0.13 mmol) from the previous step and intermediate c6 (93 mg, 0.13 mmol) were dissolved in 3 mL of DMF, and catalyst Pd(dppf)Cl2 (19.4 mg, 0.027 mmol) was added. The mixture was heated to 100 °C for 2 h to quench the reaction. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC (column: Xselect CSH Prep C18 OBD Column, 19*250 nm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: acetonitrile; flow rate: 25 mL / min; retention time: 10.2 min) to give white solid P63 (4.0 mg). The yield was 4%. LCMS ESI-MS m / z:742[M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.57 (d, J = 32.2 Hz, 2H), 8.25 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.11 (s, 1H), 5.36 (s, 2H), 4.53 (d, J = 12.6 Hz, 2H), 3.50 (d, J = 10.7 Hz, 4H), 3.02 (s, 3H), 2.83 (d, J = 11.2 Hz, 1H), 2.66 (d, J = 11.2 Hz, 1H), 2.43 (s, 3H), 1.21 (dd, J = 12.7, 5.9 Hz, 3H).

[0265] The following target molecules were synthesized using similar raw materials / intermediates (e.g., intermediate c16) with reference to the synthetic route for compound P63. [Table 15]

[0266] Example 8: Production of target molecules P65-P66 [ka]

[0267] Step 1: Intermediate a29 (350 mg, 0.54 mmol) was dissolved in 4 mL of dichloromethane, and 1.7 mL of trifluoroacetic acid was added dropwise. The reaction was allowed to proceed at room temperature for 1 hour to quench the reaction. The solvent was evaporated under reduced pressure to give a yellow solid, P65-1 (290 mg). LCMS ESI-MS m / z: 548 [M+H] + .

[0268] Step 2: Under nitrogen gas protection, the intermediate 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid b1 (122 mg, 0.79 mmol) and 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (212 mg, 1.58 mmol) were dissolved in 3 mL of dichloromethane and stirred at room temperature for 1 h. DIEA (683 mg, 5.28 mmol) and the compound P65-1 (290 mg, 0.53 mmol) from the previous step were added to the reaction mixture and the mixture was stirred at room temperature for 1 h. The reaction was then quenched by adding 15 mL of water, followed by extraction with dichloromethane, drying over anhydrous sodium sulfate, and concentration. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 10 / 7) to give P65-2 (239 mg) as a white solid. The yield was 66%. LCMS ESI-MS m / z: 684 [M+H] + .

[0269] Step 3: Under nitrogen gas protection, intermediate P65-2 (239 mg, 0.35 mmol) from the previous step, intermediate b2 (132 mg, 0.52 mmol), and KPO (741 mg, 3.49 mmol) were dissolved in 5 mL of a mixture of DMF and water (v / v, 4 / 1). Catalyst Pd(dppf)Cl (153.2 mg, 0.21 mmol) was added, and the mixture was heated to 80 °C for 1 h, after which the reaction was quenched. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O), mobile phase B: acetonitrile, flow rate: 60 mL / min, retention time: 8.82 min) to give white solid P65 (15.5 mg). The yield was 6%. LCMS ESI-MS m / z: 730 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.97 (s, 1H), 7.76 - 7.66 (m, 1H), 7.56 (s, 1H), 5.37 (s, 2H), 5.02 (s, 2H), 4.89 (s, 2H), 4.51 (d, J = 13.2 Hz, 1H), 3.48 (t, J = 11.1 Hz, 2H), 3.20-3.30 (s, 2H), 3.00 (s, 1H), 2.81 (d, J = 10.6 Hz, 1H), 2.61 (s, 4H), 2.43 (s, 3H).

[0270] The following target molecules were synthesized using similar raw materials / intermediates (e.g., intermediate a30) with reference to the synthetic route for compound P65. [Table 16]

[0271] Example 9: Production of target molecules P67~P68, A2 [ka]

[0272] Step 1: Under nitrogen gas protection, intermediate 5-methoxy-pyrimidine-4-carboxylic acid b3 (123 mg, 0.80 mmol) and intermediate c5-2 (300 mg, 0.53 mmol) were dissolved in 6 mL of DMF and stirred at room temperature for 5 minutes. DIEA (344 mg, 2.66 mmol) and HATU (304 mg, 0.80 mmol) were added to the reaction mixture, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then quenched with 20 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CHCN / HO, 10 / 7) to give yellow solid P67-1 (200 mg). The yield was 54%. LCMS ESI-MS m / z: 698 [M+H] + .

[0273] Step 2: Under nitrogen gas protection, compound P67-1 (180 mg, 0.25 mmol) from the previous step was dissolved in 2 mL of DMF, LiCl (44 mg, 1.03 mmol) was added, and the mixture was heated to 150 °C for 4 hours to quench the reaction. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / H2O, 3 / 5) to give white solid P67-2 (140 mg). The yield was 79%. LCMS ESI-MS m / z: 684 [M+H] + .

[0274] Step 3: Under nitrogen gas protection, compound P67-2 (50 mg, 0.073 mmol) from the previous step, intermediate b2 (100 mg, 0.39 mmol), and K3PO4 (155 mg, 0.73 mmol) were dissolved in 2 mL of a mixed solution of DMF and water (v / v, 4 / 1). Catalyst Pd(dppf)Cl2 (32 mg, 0.044 mmol) was added, and the temperature was raised to 80 °C for 1 h, after which the reaction was quenched. The reaction mixture was added with 10 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC chromatography (column: XBridge Prep C18 OBD Column, 30*150 nm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile, flow rate: 60 mL / min, retention time: 11.0 min) to give white solid P67 (4.5 mg). The yield was 8%. LCMS ESI-MS m / z: 730 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.36 (s, 1H), 8.08 - 7.92 (m, 2H), 7.78 - 7.68 (m, 1H), 7.55 (s, 1H), 5.34 (s, 2H), 5.09 - 4.84 (m, 4H), 4.52 (d, J = 12.4 Hz, 1H), 3.49 (d, J = 9.7 Hz, 4H), 3.00 (d, J = 9.7 Hz, 3H), 2.82 (d, J = 11.1 Hz, 1H), 2.66 (d, J = 10.9 Hz, 1H), 1.25 - 1.16 (m, 3H).

[0275] The following target molecules were synthesized using similar raw materials / intermediates (e.g., intermediate b4) with reference to the synthetic route for compound P67. [Table 17]

[0276] Example 10: Production of target molecules P69-P70 [ka]

[0277] Step 1: Under nitrogen gas protection, intermediate a2 (3.0 g, 6.26 mmol), intermediate b2 (4.5 g, 17.86 mmol), and K3PO4 (13.3 g, 62.6 mmol) were dissolved in 30 mL of a mixed solution of DMF and water (v / v, 6 / 1). Catalyst Pd(dppf)Cl2 (2.7 g, 3.76 mmol) was added, and the mixture was heated to 80 °C for 1 h. The reaction was then quenched. 200 mL of water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was washed with tetrahydrofuran to give white solid P69-1 (240 mg). The yield was 7%. LCMS ESI-MS m / z: 524 [M+H] + .

[0278] Step 2: Under nitrogen gas protection, compound P69-1 (240 mg, 0.45 mmol) from the previous step was dissolved in 5 mL of DMF, N-bromosuccinimide (NBS) (163 mg, 0.91 mmol) was added, and the mixture was heated to 60 °C for 1 hour to quench the reaction. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give white solid P69-2 (180 mg). The yield was 65%. LCMS ESI-MS m / z: 602 [M+H] + .

[0279] Step 3: Under nitrogen gas protection, compound P69-2 (105 mg, 0.17 mmol), TEA (53 mg, 0.52 mmol), and deuterated starting material P69-3 (169 mg, 0.87 mmol) were dissolved in 1 mL of DMSO. The mixture was heated to 120 °C and reacted for 12 hours, after which the reaction was quenched. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (column: C18, CHCN / HO, 4 / 5) to give white solid P69-3 (20 mg). The yield was 16%. LCMS ESI-MS m / z: 716 [M+H] + .

[0280] Step 4: Compound P69-3 (20 mg, 0.03 mmol) from the previous step was dissolved in 1 mL of hydrogen chloride in 1,4-dioxane (2 M) and reacted at room temperature for 1 h. The reaction was then quenched. The solvent was removed by evaporation under reduced pressure to give white solid P69-4 (18 mg). The yield was 98%. LCMS ESI-MS m / z: 616 [M+H] + .

[0281] Step 5: Under nitrogen gas protection, the intermediate 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid b1 (8 mg, 0.05 mmol) and 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (13 mg, 0.10 mmol) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 1 hour. DIEA (39 mg, 0.30 mmol) and the compound P69-4 (18 mg, 0.29 mmol) from the previous step were added to the reaction mixture, and the mixture was allowed to react at room temperature for 1 hour. The reaction was then quenched. The reaction mixture was mixed with 15 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: Xbridge Prep OBD C18 Column, 30*150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O, mobile phase B: acetonitrile, flow rate: 60 mL / min, retention time: 7.03 min) to give white solid P69 (5.3 mg). The yield was 22%. LCMS ESI-MS m / z: 752 [M+H] + [Deuteration rate: 99%] 1 H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.71 (dd, J = 8.7, 2.2 Hz, 1H), 7.55 (s, 1H), 5.34 (s, 2H), 5.02 (t, J = 3.3 Hz, 2H), 4.88 (t, J = 3.3 Hz, 2H), 3.01 (s, 2H), 2.41 (s, 3H), 1.23 - 1.14 (m, 3H).

[0282] The following target molecules were synthesized using similar raw materials / intermediates (e.g., intermediate a31) with reference to the synthetic route of compound P69. [Table 18]

[0283] Example 11: Production of target molecule P71 [ka]

[0284] Step 1: Under nitrogen gas protection, intermediate c18 (500 mg, 1.44 mmol), starting material 2-chloro-4-bromoaniline P23-1 (450 mg, 2.17 mmol), and DMAP (530 mg, 4.33 mmol) were dissolved in 10 mL of dichloromethane. DIEA (930 mg, 7.22 mmol) and T3P (2.3 g, 7.22 mmol) were added and the mixture was allowed to react at room temperature for 2 hours. The reaction was then quenched. 40 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 5 / 3) to give P71-1 (280 mg), a yellow solid. The yield was 36%. LCMS ESI-MS m / z: 534 [M+H] + .

[0285] Step 2: Under nitrogen gas protection, compound P71-1 (280 mg, 0.52 mmol) from the previous step was dissolved in 6 mL of DMF, N-bromosuccinimide (NBS) (190 mg, 1.05 mmol) was added, and the mixture was heated to 60 °C for 1 hour to quench the reaction. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by reverse-phase flash column chromatography (column: C18, CH3CN / HO, 1 / 1) to give white solid P71-2 (140 mg). The yield was 44%. LCMS ESI-MS m / z: 612 [M+H] + .

[0286] Step 3: Under nitrogen gas protection, compound P71-2 (140 mg, 0.23 mmol), TEA (70 mg, 0.68 mmol), and deuterated starting material P69-3 (222 mg, 1.14 mmol) from the previous step were dissolved in 3 mL of DMSO, heated to 120 °C, and reacted for 12 hours. The reaction was then quenched. 20 mL of water was added to the reaction mixture, which was then extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by flash column chromatography (column: C18, CH3CN / HO, 5 / 3) to give yellow solid P71-3 (50 mg). The yield was 30%. LCMS ESI-MS m / z: 726 [M+H] + .

[0287] Step 4: Compound P71-3 (50 mg, 0.07 mmol) from the previous step was dissolved in 1 mL of hydrogen chloride in 1,4-dioxane (2 M) and reacted at room temperature for 1 h. The reaction was then quenched. The solvent was removed by evaporation under reduced pressure to give crude yellow solid P71-4 (45 mg). LCMS ESI-MS m / z: 626 [M+H] + .

[0288] Step 5: Under nitrogen gas protection, the intermediate 5-hydroxy-6-methyl-pyrimidine-4-carboxylic acid b1 (17 mg, 0.11 mmol) and 1-chloro-N,N,2-trimethylpropyl-1-en-1-amine (29 mg, 0.22 mmol) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 1 hour. DIEA (93 mg, 0.72 mmol) and compound P71-4 (45 mg, 0.07 mmol) from the previous step were added to the reaction mixture, and the mixture was allowed to react at room temperature for 1 hour. The reaction was then quenched. The reaction mixture was mixed with 15 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by HPLC preparative chromatography (column: Xbridge Prep OBD C18 Column, 30*150 mm, 5 μm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O, mobile phase B: acetonitrile, flow rate: 60 mL / min, retention time: 7.67 min) to give white solid P71 (16.5 mg). The yield was 31%. LCMS ESI-MS m / z: 762 [M+H] + [Deuteration rate: 99%] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.53 (s, 1H), 7.92-7.50 (m, 4H), 5.27 (s, 2H), 5.15 (s, 2H), 4.89 (s, 2H), 3.00 (s, 2H), 2.63 (s, 3H), 1.20 (q, J = 8.3, 7.8 Hz, 4H).

[0289] Example 12: The activity of the molecules of the invention on WRN helicase dissociating DNA duplexes was tested (Table 1).

[0290] The working solution and buffer solution to be tested were prepared, and the test compound was diluted 4-fold with DMSO (starting at a final concentration of 10 μM). 0.2 μL of the test compound solution was added to a 384-well plate, followed by 10 μL (2X) of WRN enzyme solution. After incubation in the dark for 30 minutes, 10 μL of substrate detection solution containing double-stranded DNA was added (19 bp in length, labeled with TAMRA and BHQ2 at the 3' and 5' ends, respectively) to initiate the reaction. The reaction was then incubated at room temperature for 60 minutes. The inhibitory activity (IC) against WRN enzyme was determined from the change in fluorescence Ex530 / Em590 between the blank group (DMSO) and the compound group. 50 ) was calculated. Calculation formula: Y = bottom signal + (top signal - bottom signal) / (1 + 10^((LogIC 50 -X) × Hill slope) X: logarithmic value of compound concentration Y: Inhibition rate (%)

[0291] [Table 19]

[0292] As is clear from the above results, the molecules of the present invention have a good inhibitory effect on WRN unwinding DNA, and are expected to achieve a good tumor-inhibiting effect by inhibiting the activity of WRN helicase.

[0293] Example 13: The antiproliferative activity of the molecules of the invention against MSI-H tumor cells was tested.

[0294] Microsatellite-unstable MSI-H tumor cells show a growth sensitivity to WRN inhibitors, whereas microsatellite-stable MSS tumor cells show a growth sensitivity insensitive to WRN inhibitors. By testing the activity of both tumor cells, we demonstrate the inhibitory and synthetic lethal effects of the molecules of the present invention on WRN at the cellular level.

[0295] MSI-unstable SW48 colorectal cancer cells were cultured in RMI1640 medium containing 10% FBS and 1% penicillin-streptomycin and incubated at 37°C in a 5% CO2 incubator. 40 μL of the cell suspension was added to each well of a 384-well microplate. Using an Echo™ system, 40 nL of different concentrations of compounds were added to each well and incubated at 37°C in a 5% CO2 incubator for 5 days. 40 μL of CTG solution (Promega, Cat. No. G7573) was added to each well and incubated at 37°C in a 5% CO2 incubator in the dark for 30 minutes. Luminescence readings were read using an Envision multifunction microplate reader (Perkin Elmer, Cat. No. Envision 2104). The light signal was proportional to the amount of ATP in the system, which directly characterizes the number of viable cells in the system.

[0296] I C 50 Calculating the value: Y = bottom signal + (top signal - bottom signal) / (1 + 10^((LogIC 50 -X) × Hill slope) X: logarithmic value of compound concentration Y: Inhibition rate (%)

[0297] [Table 20]

[0298] The following control molecule A1 was synthesized with reference to WO2022249060. [ka]

[0299] [Table 21]

[0300] [Table 22]

[0301] [Table 23]

[0302] [Table 24]

[0303] [Table 25]

[0304] As is clear from the above results, the molecules of the present invention have a good anti-proliferative effect on MSI-H tumor cells and are expected to achieve a good tumor-inhibiting effect by inhibiting the activity of WRN helicase.

[0305] Furthermore, as is clear from the above results, the control molecule A1 has no inhibitory effect on SW48 cells at a concentration of 156 nM, whereas the molecules of the present invention, such as P7, P19, and P29, have a significant inhibitory effect (>95%) even at 156 nM, and furthermore, have high inhibitory activity even at 39 nM. From the above, it can be seen that the molecules of the present invention have a significantly enhanced inhibitory effect on SW48 cells compared to the control molecules A3 and A1.

[0306] Example 14: The antiproliferative activity of the molecules of the invention against MSS tumor cells was tested.

[0307] HT-29 colorectal cancer cells from MSS were cultured in McCoy's 5A medium containing 10% FBS and 1% penicillin-streptomycin and incubated at 37°C in a 5% CO2 incubator. 40 μL of the cell suspension was added to each well of a 384-well microplate. Using an Echo™ system, 40 nL of different concentrations of compounds were added to each well and incubated at 37°C in a 5% CO2 incubator for 5 days. 40 μL of CTG solution (Promega, Cat. No. G7573) was added to each well and incubated at 37°C in a 5% CO2 incubator in the dark for 30 minutes. Luminescence readings were obtained using an Envision multifunction microplate reader (Perkin Elmer, Cat. No. Envision 2104). The light signal was proportional to the amount of ATP in the system, which directly characterizes the number of viable cells in the system.

[0308] I C 50 Calculating the value: Y = bottom signal + (top signal - bottom signal) / (1 + 10^((LogIC 50 -X) × Hill slope) X: logarithmic value of compound concentration Y: Inhibition rate (%)

[0309] [Table 26]

[0310] As is clear from the above results, the molecules of the present invention have no inhibitory effect on MSS tumor cells, demonstrating the high selectivity of the molecules of the present invention for selective inhibition of WRN.

[0311] Example 15: Liver microsome stability test of compounds: Specifically, the test was carried out as follows.

[0312] Liver microsome stability test studies were conducted on the compounds of the present invention, in which the compounds under test were co-incubated with different species of liver microsomes with or without the addition of NADPH, and the final concentration of the compounds under test in the test system was 1 μM, the final concentration of NADPH was 1 mM, and the final concentration of liver microsomes was 0.5 mg / mL. The concentration of the compounds in the supernatant was detected at different time points over 60 minutes, and the pharmacokinetic parameters were calculated (e.g., clearance Cl int ).

[0313] As is clear from these results, the molecules of the present invention have good metabolic stability (particularly in the human body).

[0314] [Table 27]

[0315] Example 16: Membrane permeability evaluation experiments: Caco-2 assays

[0316] The membrane permeability of the molecules of the present invention was evaluated. Samples were analyzed by LC-MS to determine the apparent permeability coefficient (P) of the compounds in Caco-2 monolayer cells. app The pH of the apical compartment is estimated to be 6.5, while that of the basolateral compartment is 7.4. P-gp efflux transporter, BCRP, and MRP2 inhibitors (50 μM quinidine, 30 μM benzbromarone, and 20 μM sulfasalazine) can block active efflux transport of compounds. The data are used to express the permeability (Papp). P app =(V A ×[drug] acceptor ) / (Area×Time×[drug] initial,donor ) where V Ais the volume of the receptor pore (unit: mL), and Area is the surface area of ​​the membrane (0.143 cm for Transwell-96 well permeable supports). 2 ), time is the total transport time (in seconds). Efflux Ratio=P app ( B-A ) / P app ( A-B )

[0317] [Table 28] As is clear from the above results, the molecules of the present invention have good membrane permeability and are expected to have good pharmacokinetic properties in the body and to achieve good tumor-inhibiting effects.

[0318] Example 17: Pharmacokinetic evaluation experiments in mice

[0319] CD1 female mice were used as test animals, and the compound was administered orally / intravenously (oral dose was 10 mg / kg, and intravenous dose was 2 mg / kg).

[0320] Experimental scheme: Three mice were administered orally (solvent: 10% Hβ-CD, pH 7.4) in each group, and three mice were administered intravenously. For oral administration, plasma samples were collected before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, and 24 h). For intravenous administration, plasma samples were collected before (0 h) and after (0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h). Plasma concentrations in mice after oral and intravenous administration were measured using LC / MS / MS. The collected data were analyzed using AB Sciex QTRAP 6500 software. The experimental results are shown below.

[0321] [Table 29]

[0322] [Table 30]

[0323] [Table 31]

[0324] As is clear from the above experimental results, the compounds of the present invention have good oral absorption effects, and compared to the control molecule A1, they have better oral absorption, higher body exposure, and better activity and selectivity, and are therefore expected to provide better therapeutic effects.

[0325] Furthermore, as is clear from the above experimental results, thiophene ring molecules P7, P24, P32, and P29 are more orally absorbable than P9, which is substituted with a single thiophene ring, and have a higher oral absorption effect.

[0326] Example 18: The specifics of the in vivo drug efficacy experiment in BALB / c nude mice are as follows.

[0327] SW48 (MSI-H) colorectal cancer tumor cells were cultured in L15 medium containing 10% fetal bovine serum and then subcutaneously inoculated into 6-8 week-old female BALB / c nude mice (weighing approximately 20 g). All mice were cultured in an SPF-level experimental environment and had free access to a commercially certified standard diet. The average tumor volume of the mice was 160 mm. 3 Once the tumors reached a growth stage, the test compound was administered orally daily. The blank group received the solvent (10% HP-β-CD aqueous solution, pH 7). The treatment groups received 50 mg / kg or 120 mg / kg once daily. Tumor volume was measured three times a week using a two-dimensional caliper, and the animals were weighed daily. After 21 consecutive days of administration, the inhibition rate (TGI / 100%) was calculated from the final tumor volume. The volume calculation formula was V=1 / 2a*b. 2 where a represents the long diameter of the tumor and b represents the short diameter of the tumor.

[0328] [Table 32]

[0329] These results clearly show that the molecules of the present invention have good in vivo efficacy against MSI-H microsatellite unstable tumor cells and low toxicity in mice (none of the dose groups caused a weight loss of more than 5%).Compared to the control molecule A1, the molecules of the present invention have significantly improved in vivo tumor-inhibiting effects.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof. 【Chemistry 1】 (In the formula, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring A is absent or selected from a C3-10 cycloalkyl group, a 5-10 membered heteroaryl group, a 5-10 membered heterocyclyl group, or a C6-10 aryl group; R1 is selected from a 5- to 12-membered heteroaryl group or a 5- to 12-membered heterocyclyl group, and R1 is a pyridyl group or 【Chemistry 2】 wherein R is optionally substituted with 1, 2, 3, 4 or 5 R; Rx is selected from H, D, halogen, NH2, CN, OH, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —C(O)NH-Ra, —NHC(O)-Ra, —(CH2)p-ORa, —(CH2)p-C(O)Ra, —P(O)-(Ra)2 or —S(O)2-Ra, wherein Ra is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group or a C3-6 cycloalkyl group, and p is selected from 0, 1, 2, 3 or 4, or two Rx on the same atom together form oxo or thio; R2 is selected from H, D, halogen, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; R3 is selected from H, D, halogen, NH2, CN, OH, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, or a C3-6 cycloalkyl group; or R3 on two different carbon atoms are bonded to form a bridged ring; or two R3 on the same carbon atom are bonded to form a C3-10 cycloalkyl group, a 5-10 membered heteroaryl group, a C3-10 cycloalkyl group, or a 3-10 membered heterocyclyl group; R4 is selected from H, D, halogen, NH2, CN, OH, SF5, SCF3, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a C1-6 alkylthio group, a C3-10 cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a C6-10 aryl group; R5 is selected from H, D, halogen, NH2, CN, OH, a C1-6 alkyl group, a C1-6 deuterated alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; m is selected from 0, 1, 2, 3, 4 or 5; n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R1-R5 may optionally be deuterated until fully deuterated.

2. X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring A is absent or selected from a 5- to 6-membered heteroaryl group, and the 5- to 6-membered heteroaryl group together with the benzene ring attached thereto 【Transformation 3】 wherein ring A is preferably absent, R1 is a 5- to 10-membered heteroaryl group or a 5- to 12-membered heterocyclyl group, preferably a 5- to 10-membered bicyclic heteroaryl group, wherein R1 is optionally substituted with 1, 2, or 3 Rx; Rx is preferably H, NH2, CH3, CH2OH, CH2OCH3, C(O)CH3 or -S(O)2-CH3, or two Rx on the same carbon atom together form oxo; Preferably, R1 is 【Chemistry 4】 is selected from Ring B is absent or selected from a C3-10 cycloalkyl group, a 5-10 membered heterocyclyl group, a 5-10 membered heteroaryl group, or a C6-10 aryl group, said Ring B being optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, a C1-6 alkyl group, or a C1-6 haloalkyl group; Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; Ry is selected from H, D, halogen, a C1-6 alkyl group or a C1-6 haloalkyl group; R2 is selected from C1-4 alkyl groups, such as CH3 or CH2CH3; R3 is selected from H, D, or a C1-4 alkyl group, for example H, D, or CH3; or R3 on two different carbon atoms are joined to form a bridged ring; or two R3 on the same carbon atom are joined to form a C3-5 cycloalkyl group, for example a cyclopropyl group; R4 is selected from H, F, Cl, Br, CH3, CH2CH3, SCF3, OCF3, CF3 or pyridyl; R5 is selected from H, CH3 or CD3, preferably H or CH3; Ra is selected from a C1-6 alkyl group and m is selected from 0, 1, 2 or 3; 2. The compound of claim 1, wherein k is selected from 0, 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and mixtures thereof.

3. R1 is 【Transformation 5】 is selected from During the ceremony, 【Transformation 6】 represents a single bond or a double bond, and when Q is N and ring B is present, 【Transformation 7】 represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; Ring B is absent or selected from a C3-10 cycloalkyl group, a 5-10 membered heterocyclyl group, a 5-10 membered heteroaryl group, or a C6-10 aryl group, said Ring B being optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halogen, a C1-6 alkyl group, or a C1-6 haloalkyl group; Rx is selected from H, NH2, halogen, a C1-6 alkyl group, a C1-6 haloalkyl group, —C(O)Ra, —C(O)ORa, —OC(O)Ra, —C(O)NH-Ra, —NHC(O)-Ra, —(CH2)p-ORa or —(CH2)p-C(O)Ra, where Ra is selected from H, a C1-6 alkyl group or a C1-6 haloalkyl group and p is selected from 1, 2 or 3; Ry is selected from H, D, halogen, a C1-6 alkyl group or a C1-6 haloalkyl group; Ra is selected from C1-6 alkyl groups; m is selected from 0, 1, 2, 3, 4 or 5; k is selected from 0, 1, 2, 3, 4 or 5; Preferably, 【Transformation 8】 represents a single bond or a double bond, and when Q is N and ring B is present, 【Chemistry 9】 represents a single bond, Q and Q' are independently selected from CH or N, and at most one of Q and Q' is N; Ring B is absent or selected from a 5- to 7-membered heterocyclyl group or a 5- to 6-membered heteroaryl group, said Ring B being optionally substituted with 1, 2, or 3 substituents selected from halogen or a C1-4 alkyl group; Rx is selected from H, NH2, a C1-4 alkyl group, -C(O)Ra or -(CH2)p-ORa, where Ra is selected from H or a C1-4 alkyl group and p is selected from 1 or 2, and Rx is preferably H, NH2, CH3, CH2OH, CHOCH3 or C(O)CH3; Ry is selected from H, D, halogen, a C1-6 alkyl group or a C1-6 haloalkyl group; Ra is selected from CH3; m is selected from 0, 1, 2 or 3; k is selected from 0, 1, 2 or 3; More preferably, R1 is 【Chemistry 10】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof, selected from:

4. selected from the following structures: 【Chemistry 11】 During the ceremony, 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof, wherein each variable is as defined in any one of claims 1 to 3.

5. It has the structure of (IV-6) or (IV-7), 【Chemistry 12】 During the ceremony, Ring A is absent or selected from a C3-10 cycloalkyl group, a 5-10 membered heteroaryl group, a 5-10 membered heterocyclyl group, or a C6-10 aryl group; X is selected from CH or N; Rx is selected from H, D, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; R2 is selected from H, D, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; R3 is selected from H, D, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; or R3 on two different carbon atoms are joined to form a bridged ring; or two R3 on the same carbon atom are joined to form a C3-10 cycloalkyl group, a 5-10 membered heteroaryl group, a C3-10 cycloalkyl group, or a 3-10 membered heterocyclyl group; R4 is selected from H, D, halogen, CN, SCF3, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, a C3-6 cycloalkyl group, a 4-10 membered heterocyclyl group, a 5-10 membered heteroaryl group, or a C6-10 aryl group; R5 is selected from H, D, a C1-6 alkyl group, a C1-6 deuterated alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; m is selected from 0, 1, 2, 3, 4 or 5; 5. The compound according to any one of claims 1 to 4, wherein n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and mixtures thereof.

6. Ring A is absent or selected from a 5- to 10-membered heteroaryl group, a 5- to 10-membered heterocyclyl group, or a C6-10 aryl group; X is selected from CH or N; Rx is selected from H, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; R2 is selected from a C1-6 alkyl group or a C1-6 haloalkyl group; R3 is selected from H, D, a C1-6 alkyl group or a C1-6 haloalkyl group, or R3 on two different carbon atoms are joined to form a bridged ring, or two R3 on the same carbon atom are joined to form a C3-10 cycloalkyl group or a 3-10 membered heterocyclyl group; R4 is selected from H, halogen, CN, SCF3, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; R5 is selected from H, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; m is selected from 0, 1, 2, 3, 4 or 5; 6. The compound of claim 5, wherein n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and mixtures thereof.

7. Ring A is absent, X is selected from CH or N; Rx is selected from H or a C1-6 alkyl group; R2 is selected from a C1-6 alkyl group; R3 is selected from H, D, or a C1-6 alkyl group, or R3 on two different carbon atoms are joined to form a bridged ring, or two R3 on the same carbon atom are joined to form a C3-7 cycloalkyl group; R4 is selected from H, halogen, SCF3, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; R5 is selected from H or a C1-6 alkyl group; m is selected from 0, 1, 2, 3 or 4; 7. The compound of claim 5 or 6, wherein n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof.

8. Ring A is selected from 5- to 6-membered heteroaryl groups, and said 5- to 6-membered heteroaryl groups together with the benzene ring attached thereto form 【Chemistry 13】 and X is selected from CH or N, forming a heteroaryl group such as Rx is selected from H or a C1-4 alkyl group, preferably H; R2 is selected from C1-4 alkyl groups, such as CH3 or CH2CH3; R3 is selected from H, D, or a C1-4 alkyl group, for example H, D, or CH3; or R3 on two different carbon atoms are joined to form a bridged ring; or two R3 on the same carbon atom are joined to form a C3-5 cycloalkyl group, for example a cyclopropyl group; R4 is selected from H, halogen, SCF3, a C1-4 alkyl group or a C1-4 haloalkyl group, such as H, F, Cl, Br, CH3, CH2CH3, CF3, SCF3, OCF3 or OCH3; R5 is selected from H or a C1-4 alkyl group, for example H or CH3; m is selected from 0, 1, 2 or 3; The compound according to any one of claims 5 to 7, wherein n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and mixtures thereof.

9. The compound has the structure (IV-8) or (IV-9): 【Chemistry 14】 During the ceremony, X is selected from N or CH; R4 is selected from H, CN, halogen, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; R4a is selected from H, halogen, CN, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; R4b is selected from halogen, CN, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; R4d is selected from H, CN, halogen, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; R5 is selected from H, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group, preferably a C1-6 alkyl group or a C1-6 haloalkyl group; Rx is selected from H, a C1-6 alkyl group, a C1-6 alkoxy group, or a C1-6 haloalkyl group; 9. The compound according to any one of claims 5 to 8, wherein m is selected from 0, 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and mixtures thereof.

10. X is selected from N or CH; R4 is selected from H, halogen, a C1-4 alkyl group or a C1-4 haloalkyl group; R4a is selected from H or halogen; R4b is selected from halogen, a C1-4 alkyl group, or a C1-4 haloalkyl group; R4d is selected from H, halogen, or a C1-4 alkyl group; R5 is selected from H, a C1-4 alkyl group or a C1-4 haloalkyl group, preferably a C1-4 alkyl group or a C1-4 haloalkyl group; Rx is selected from H, a C1-4 alkyl group, or a C1-4 haloalkyl group; m is selected from 0, 1, 2, 3 or 4; Preferably, X is selected from N or CH; R4 is selected from H, halogen, a C1-2 alkyl group or a C1-2 haloalkyl group, such as H, Cl, Br, CH3, CH2CH3 or CF3; R4a is selected from H or halogen, preferably H or F; R4b is selected from halogen, a C1-2 alkyl group or a C1-2 haloalkyl group, preferably Cl, Br, CF3 or CH2CH3; R4d is selected from H, halogen or a C1-2 alkyl group, preferably H, F, Cl or CH3; R5 is selected from H or a C1-2 alkyl group, preferably CH3; Rx is selected from H or a C1-2 alkyl group, preferably H; 10. The compound of claim 9, wherein m is selected from 0, 1, 2, or 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and mixtures thereof.

11. The compound has the structure (IV-10): 【Chemistry 15】 During the ceremony, R4b is selected from halogen or a C1-6 haloalkyl group; R4d is selected from halogen or a C1-6 alkyl group; R5 is selected from a C1-6 alkyl group or a C1-6 haloalkyl group; Rx is selected from H, a C1-6 alkyl group, or a C1-6 haloalkyl group; m is 0 or 1; Preferably, R4b is selected from halogen or a C1-4 haloalkyl group; R4d is selected from halogen or a C1-4 alkyl group; R5 is selected from a C1-4 alkyl group or a C1-4 haloalkyl group; Rx is selected from H, a C1-4 alkyl group, or a C1-4 haloalkyl group; m is 0 or 1; More preferably, R4b is selected from halogen or C1-2 haloalkyl groups, preferably Cl, Br or CF3; R4d is selected from halogen or a C1-2 alkyl group, preferably F, Cl or CH3; R5 is a C1-2 alkyl group, preferably CH3; Rx is H or a C1-2 alkyl group, preferably H; The compound according to any one of claims 5 to 10, wherein m is 0 or 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and mixtures thereof.

12. A compound of formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof. 【Chemistry 16】 (In the formula, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; R1 is selected from a 5- to 12-membered heteroaryl group or a 5- to 12-membered heterocyclyl group, and said R1 is optionally substituted with 1, 2 or 3 Rx; with the proviso that when R1 is selected from 5- to 12-membered heteroaryl groups, it is not a pyridyl group; R2 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; R3 is independently selected from H, halogen, CN, a C1-6 alkyl group, a C1-6 haloalkyl group, or a C3-6 cycloalkyl group, or two R3 are joined to the carbon atoms at which they are located to form a 3-6 membered spiro or bridged ring; R4 is independently selected from H, halogen, CN, SF5, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkylthio group, a C3-6 cycloalkyl group, or a 4-10 membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; Rx is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, CN, NH2, —C(O)Ra, —C(O)ORa, —(CH2)p-ORa, —P(O)—(Ra)2, or —S(O)2-Ra; Ra is selected from H, a C1-6 alkyl group, or a C3-6 cycloalkyl group; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; p is selected from 0, 1, or 2.

13. A compound of formula (II) or formula (VI), 【Chemistry 17】 During the ceremony, X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring B is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocyclyl group; X1 and X2 are each independently selected from CH or N; [Chemistry 18] represents a single bond or a double bond, Q is selected from CH or N; R2 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; R3 is independently selected from H, halogen, CN, a C1-6 alkyl group, a C1-6 haloalkyl group, or a C3-6 cycloalkyl group, or two R3 are joined to the carbon atoms at which they are located to form a 3-6 membered spiro or bridged ring; R4 is independently selected from H, halogen, CN, SF5, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkylthio group, a C3-6 cycloalkyl group, or a 4-10 membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; Rx is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, CN, NH2, —C(O)Ra, —C(O)ORa, —(CH2)p-ORa, —P(O)—(Ra)2, or —S(O)2-Ra; Ra is selected from H, a C1-6 alkyl group, or a C3-6 cycloalkyl group; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; 13. The compound of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof, wherein p is selected from 0, 1 or 2.

14. X and Y are each independently selected from CH or N, and at least one of X and Y is an N atom; Ring B is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocyclyl group; X1 and X2 are each independently selected from CH or N; 【Chemistry 19】 represents a single bond or a double bond, Q is selected from CH or N; R2 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; R3 is independently selected from H, halogen, CN, methyl, ethyl, trifluoromethyl, or cyclopropyl; R4 is independently selected from H, halogen, CN, SF5, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkylthio group, a C3-6 cycloalkyl group, or a 4-10 membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is selected from H, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methylthio, and cyclopropyl; Rx is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, CN, NH2, —C(O)Ra, —C(O)ORa, —(CH2)p-ORa, —P(O)—(Ra)2, or —S(O)2-Ra; Ra is selected from H or a C1-6 alkyl group; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; 14. The compound of claim 13, wherein p is selected from 0, 1, or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and mixtures thereof.

15. having a structure of the general formula: 【Chemistry 20】 During the ceremony, X is selected from CH or N; 【Chemistry 21】 represents a single bond or a double bond, Q is selected from CH or N; R2 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; R3 is independently selected from H, halogen, CN, a C1-6 alkyl group, a C1-6 haloalkyl group, or a C3-6 cycloalkyl group, or two R3 are joined to the carbon atoms at which they are located to form a 3-6 membered spiro or bridged ring; R4 is independently selected from H, halogen, CN, SF5, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkylthio group, a C3-6 cycloalkyl group, or a 4-10 membered heterocyclyl group; Ring A is present or absent and is selected from a 5- to 6-membered heteroaryl group or a 5- to 7-membered heterocyclyl group; R5 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; Rx is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, CN, NH2, —C(O)Ra, —C(O)ORa, —(CH2)p-ORa, —P(O)—(Ra)2, or —S(O)2-Ra; Ra is selected from H, a C1-6 alkyl group, or a C3-6 cycloalkyl group; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; 15. The compound according to any one of claims 12 to 14, wherein p is selected from 0, 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof.

16. having a structure of the general formula: 【Chemistry 22】 During the ceremony, X is selected from CH or N; R2 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; R3 is independently selected from H, halogen, CN, a C1-6 alkyl group, a C1-6 haloalkyl group, or a C3-6 cycloalkyl group, or two R3 are joined to the carbon atoms at which they are located to form a 3-6 membered spiro or bridged ring; R4 is independently selected from H, halogen, CN, SF5, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkylthio group, a C3-6 cycloalkyl group, or a 4-10 membered heterocyclyl group; R5 is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, or a C3-6 cycloalkyl group; Rx is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, CN, NH2, —C(O)Ra, —C(O)ORa, —(CH2)p-ORa, —P(O)—(Ra)2, or —S(O)2-Ra; Ra is selected from H, a C1-6 alkyl group, or a C3-6 cycloalkyl group; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; 16. The compound of claim 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and mixtures thereof, wherein p is selected from 0, 1 or 2.

17. X is selected from CH or N; R2 is selected from H, methyl, ethyl, trifluoroethyl, methoxy or cyclopropyl; R3 is independently selected from H, F, CN, a methyl group, an ethyl group, a trifluoromethyl group, or a cycloalkyl group, or two R3 are joined to the carbon atoms at which they are located to form a cycloalkyl group or a cyclobutyl group; R4 is independently selected from H, F, Cl, Br, CN, SF5, methyl, ethyl, trifluoromethyl, difluoromethyl, methylthio, ethylthio, or cyclopropyl; R5 is selected from H, methyl, ethyl, trifluoromethyl, methoxy, methylthio, or cyclopropyl; Rx is selected from H, a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, CN, NH2, —C(O)Ra, —C(O)ORa, —(CH2)p-ORa, —P(O)—(Ra)2, or —S(O)2-Ra; Ra is selected from H, a C1-6 alkyl group, or a C3-6 cycloalkyl group; m is selected from 0, 1, 2 or 3; n is selected from 0, 1 or 2; 17. The compound of claim 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, solvate or hydrate thereof, and mixtures thereof, wherein p is selected from 0, 1 or 2.

18. A compound selected from the following: or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】

19. A compound selected from the following: or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof: 【Chemistry 27】

20. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient, preferably containing another therapeutic agent.

21. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 20, in the manufacture of a medicament for treating and / or preventing a disease mediated by WRN.

22. 21. A method for treating and / or preventing a disease mediated by WRN in a subject, comprising administering to the subject a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 20.

23. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition according to claim 20, for use in treating and / or preventing a disease mediated by WRN.

24. The disease mediated by WRN is cancer, and examples of the cancer include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangioma), appendix cancer, benign monoclonal gamma disease, bile duct cancer, bladder cancer, brain cancer (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kabosi's sarcoma, multiple idiopathic hemorrhagic sarcoma), uterine cancer, and uterine cancer. endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemia, acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML) , chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and and primary central nervous system (CNS) lymphomas, and T-cell non-Hodgkin's lymphomas, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (e.g., cutaneous T-cell lymphomas (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma), mixtures of one or more of the above leukemias / lymphomas, multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor,immune cell amyloidosis, kidney cancer (e.g., nephroblastoma, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma, malignant hepatocellular carcinoma), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myelofibrosis, The use according to claim 21, the method according to claim 22, or the compound or composition according to claim 23, wherein the cancer is selected from myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, and penile cancer.

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