PRMT5 inhibitor

Abstract

There is provided a class of PRMT5 inhibitors represented by formula (X), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. There is further provided a method for preparing the compound, a pharmaceutical composition comprising the compound, and the use of the compound in the prevention and treatment of cancer. [Chemical formula 1] TIFF2025525104000268.tif26156

Description

Technical Field

[0001] This disclosure claims the priority of Chinese applications CN202210898107.7 filed on July 28, 2022, CN202211541013.0 filed on December 2, 2022, CN202310484698.8 filed on April 28, 2023, and CN202310897087.6 filed on July 20, 2023, which are hereby incorporated by reference in their entirety.

[0002] <Technical Field> This disclosure relates to a novel class of PRMT5 inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof. This disclosure also relates to methods for preparing the compounds, pharmaceutical compositions comprising the compounds, and the use of the compounds in the prevention and treatment of PRMT5-mediated diseases such as cancer.

Background Art

[0003] Protein arginine methyltransferase 5 (PRMT5) belongs to type II PRMT and is a type of S-adenosylmethionine (SAM)-dependent methyltransferase. It mainly plays a role in symmetrically transferring the methyl group of SAM to the nitrogen atom of the guanidinium group at the end of the arginine residue of histone or other proteins. In vivo, PRMT5 forms a complex with MEP50 (methylosome protein 50) to recognize and identify the substrate. At the same time, this complex form is also necessary for the activity of PRMT5 that catalyzes the methyl transfer of histone 2A and histone 4. PRMT5 is a universal transcriptional repressor that can regulate the processes of gene transcription and protein modification. At the same time, PRMT5 plays an important role in the proliferation, differentiation, and apoptosis of tumor cells and is a potential target for tumor therapy. However, PRMT5 is also a gene necessary for normal cells. PRMT5 knockout and siRNA knockdown studies have shown that inhibition of PRMT5 activity in normal tissues can cause many toxic side effects such as thrombocytopenia, infertility, skeletal muscle loss, and myocardial hypertrophy.

[0004] In 2016, multiple independent research teams reported that the dependence of MTAP (methylthioadenosine phosphorylase)-deficient tumor cells on PRMT5 activity was increasing. The deficiency of MTAP simultaneously increases the level of intracellular MTA (methylthioadenosine), which is also a natural PRMT5 inhibitor. Therefore, MTAP-deficient tumor cells have an increased dependence on PRMT5 activity, and thus it is possible to target MTAP-null tumor cells without affecting MTAP WT cells, that is, it is possible to target the PRMT5 / MTA complex.

[0005] The mechanisms of action of the developing PRMT5 inhibitors include SAM-competitive inhibitors, substrate-competitive inhibitors, SAM and substrate dual-competitive inhibitors, and MTA synergistic inhibitors. Non-MTA synergistic PRMT5 inhibitors inhibit the activity of PRMT5 indiscriminately, and dose-limiting toxic side effects such as thrombocytopenia, anemia, and neutropenia have been found. Among the inhibitors, MTA synergistic inhibitors target the PRMT5 / MTA complex, inhibit MTAP-deficient tumor cells, and eliminate the effect on MTAP WT cells, thereby improving the therapeutic window.

[0006] Therefore, the development of PRMT5 inhibitors targeting the PRMT5 / MTA complex has important clinical application value, and such inhibitors are required in the art.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] The present disclosure develops a new class of small molecule inhibitors that target the PRMT5 / MTA complex and can be used to treat various cancers.

MEANS FOR SOLVING THE PROBLEMS

[0008] The compounds of the present disclosure target the PRMT5 / MTA complex and are MTA synergistic PRMT5 inhibitors. They have excellent PRMT5 / MTA inhibitory activity and obvious selectivity for the PRMT5 / SAM complex. At the same time, the compounds of the present disclosure have good ADMET (absorption-distribution-metabolism-excretion-toxicity) properties.

[0009] In one aspect, the present disclosure provides a compound of formula (X), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

CHEMICAL FORMULA

[0010] Wherein,

[0011] Ring A is C 6~10 aryl or 5- to 10-membered heteroaryl,

[0012] L1 is NH or CHR x and,

[0013] L2 is CR x R y and,

[0014] L3 is -C(O)-, -S(O)- or -S(O)2-,

[0015] wherein R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0016] or, CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0017] or, when L1 is CHR x and L2 is CR x R y the two R x groups may be bonded to form a chemical bond or C 1~4 alkylene,

[0018] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)(=NRa )R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、P(O)(R a )2、C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, selected from these, which are optionally substituted with 1, 2 or 3 R 1s and are optionally substituted with

[0019] m = 0, 1, 2, 3 or 4,

[0020] R4 is H, D, C 1~6 alkyl and C 1~6 haloalkyl, or

[0021] or, one R1 is bonded to R4 to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S, NH or CH2, q1 = 0, 1 or 2, and q2 = 1, 2 or 3),

[0022] X1 is a C atom or an N atom, which are optionally substituted with R 2b and are optionally substituted with

[0023] X2 is a C atom or an N atom, which are optionally substituted with R 2c and are optionally substituted with

[0024] X3 is a C atom or an N atom, which are optionally substituted with R 2d and are optionally substituted with

[0025] R 2a is H, D, CN, OR a 、NRb R c 、 C(O)OR a and C(O)NR b R c selected from,

[0026] R 2b is H, D, halogen, C(O)OR a 、 C(O)NR b R c 、 C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl,

[0027] R 2c is H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0028] or, X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 [[ID=4〕5]]aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s s,

[0029] R 2d is H, D, halogen, CN, NO2, OR a 、 NR b R c 、 C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0030] R3 is -C 1~6 alkylene-OR a 、 -C 1~6 alkylene-NR b R c 、 C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl,2~6 Alkynyl, -L-C 3~10 Cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 Selected from aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s1 and 1 R 3s2 and are optionally substituted with

[0031] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R

[0032] R 1s and R 2s are independently H, D, halogen, =O, C(O)OR a 、C(O)NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0033] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0034] R 3s2 is H, D, -L-OR a 、-L-NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C6~10 Selected from aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three Rs 3s and

[0035] R and R 3s are, independently, H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, selected from

[0036] R a , R b and R c are, independently, H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl

[0037] Each of the groups in said ring A, L1, L2, R x , R y , R1, R 2a , R 2b , R 2c , R 2d , R3, R4, L, R, R 1s , R 2s , R 3s , R 3s1 , R 3s2 , R a , R b and R c is optionally deuterated until fully deuterated

[0038] Provided that when L2 is CR x R y and L3 is -S(O)- or -S(O)2-, R y and R 2d are joined to form a vinylene

[0039] In another aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chemical formula

[0040] Wherein,

[0041] Ring A is C 6~10 aryl or 5- to 10-membered heteroaryl,

[0042] L1 is NH or CHR x and

[0043] L2 is CR x R y and

[0044] L3 is -C(O)-, -S(O)- or -S(O)2-,

[0045] wherein, R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0046] or, CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0047] or, when L1 is CHR x and L2 is CR x R y the two R x groups may be bonded together to form a chemical bond or C 1~4 alkylene,

[0048] R1 is H, D, halogen, CN, NO2, -L-OR a -L-SR a -L-NRb R c 、 SF5, C(O)R a 、 C(O)OR a 、 C(O)NR b R c 、 OC(O)R a 、 NR b C(O)R c 、 S(O)R a 、 S(O)2R a 、 S(O)OR a 、 S(O)2OR a 、 S(O)NR b R c 、 S(O)2NR b R c 、 P(O)(R a )2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, selected from, these are 1, 2 or 3 R 1s optionally substituted with,

[0049] m = 0, 1, 2, 3 or 4,

[0050] X1 is a C atom or an N atom, these are R 2b optionally substituted with,

[0051] X2 is a C atom or an N atom, these are R 2c optionally substituted with,

[0052] X3 is a C atom or an N atom, these are R 2d optionally substituted with,

[0053] R 2a is H, D, CN, OR a 、 NR b R c 、 C(O)OR a and C(O)NR b R cselected from

[0054] R 2b is selected from H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl,

[0055] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0056] or X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s s,

[0057] R 2d is selected from H, D, halogen, CN, NO2, OR a NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0058] R3 is -C 1~6 alkylene-OR a -C 1~6 alkylene-NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~10 cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10Selected from aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s1 and 1 R 3s2 and are optionally substituted with

[0059] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R

[0060] R 1s and R 2s are independently H, D, halogen, =O, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, selected from

[0061] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, selected from

[0062] R 3s2 is H, D, -L-OR a -L-NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s and are optionally substituted with

[0063] R and R 3s are, independently, H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, and are selected from

[0064] R a , R b and R c are, independently, H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0065] wherein the above ring A, L1, L2, R x , R y , R1, R 2a , R 2b , R 2c , R 2d , R3, L, R, R 1s , R 2s , R 3s , R 3s1 , R 3s2 , R a , R b and R c each of the groups in are optionally deuterated until fully deuterated,

[0066] provided that when L2 is CR x R y and L3 is -S(O)- or -S(O)2-, R y and R 2d are joined to form vinylene.

[0067] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure and optionally a pharmaceutically acceptable excipient, such as a carrier, an adjuvant or a vehicle.

[0068] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, further comprising a selected one from other therapeutic agents, such as CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapeutic agents, radiation therapy, STING agonists, and target drugs / cellular activity regulators such as immune checkpoint inhibitors / modulators.

[0069] In another aspect, the present disclosure provides the use of a compound of the present disclosure in the manufacture of a medicament for treating and / or preventing PRMT5-mediated diseases.

[0070] In another aspect, the present disclosure provides a method for treating and / or preventing PRMT5-mediated diseases in a subject, the method comprising administering to the subject a compound of the present disclosure or a pharmaceutical composition of the present disclosure.

[0071] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutical composition of the present disclosure for use in the treatment and / or prevention of PRMT5-mediated diseases.

[0072] In certain embodiments, the present disclosure is used for the treatment and / or prevention of cancer. In another specific embodiment, the present disclosure relates to the following cancers: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Digestive tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), Stomach (cancer, lymphoma, leiomyosarcoma), Pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), Large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); Genitourinary: Kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), Testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: Osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma exostosis, benign enchondroma, chondroblastoma, fibrochondroma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), Meninges (meningioma, meningiosarcoma, glioma), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), Spinal nerve fibroma, meningioma, glioma, sarcoma; Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, precancerous cervical dysplasia, etc.), Ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma)), Fallopian tube (cancer); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, diffuse large B-cell lymphoma,For the treatment and / or prevention of mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative diseases, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal gland: neuroblastoma.

[0073] In another specific embodiment, the PRMT5-mediated diseases of the present disclosure are selected from the following cancers: malignant peripheral nerve sheath tumors, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer, and thyroid cancer and sarcoma.

[0074] In another specific embodiment, the PRMT5-mediated diseases of the present disclosure are selected from MTAP-related cancers such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0075] Definitions

[0076] Chemical definitions

[0077] The definitions of specific functional groups and chemical terms are described in more detail below.

[0078] When numerical ranges are recited, each numerical value and subrange within that range is intended to be encompassed. For example, "C 1~6 alkyl" includes 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 5~6It is intended to contain alkyl.

[0079] "C 1~6 alkyl" refers to the radical of a straight-chain or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1~4 alkyl and C 1~2 alkyl are options. C 1~6 Examples of alkyl include methyl (C1), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C 1~6 alkyl" also includes heteroalkyl in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are substituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0080] "C 2~6 alkenyl" refers to the radical of a straight-chain 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 is an option. C 2~6 Examples of alkenyl include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. "C 2~6The term "alkenyl" also includes heteroalkenyl in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0081] 「C 2~6 "Alkynyl" refers to a radical of 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 is an option. C 2~6 Examples of alkynyl include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), etc. "C 2~6 The term "alkynyl" also includes heteroalkynyl in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0082] 「C 1~6 "Alkylene" refers to a divalent group formed by removing another hydrogen of C 1~6 alkyl, which may be substituted or unsubstituted. In some embodiments, C 1~4 alkylene, C 2~4 alkylene and C 1~3Alkylene is an option. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Examples of substituted alkylene groups such as those substituted with one or more alkyl (methyl) groups include substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc., but are not limited to these.

[0083] “C 2~6 “Alkenylene” refers to a substituted or unsubstituted C alkenyl group from which another hydrogen has been removed to provide a divalent radical of alkenylene. 2~6 In some embodiments, C 2~4 Alkenylene is a further option. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups such as those substituted with one or more alkyl (methyl) groups include substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc., but are not limited to these.

[0084] “C 2~6"Alkynylene" refers to a divalent radical of alkynylene in which another hydrogen has been removed, which can be substituted or unsubstituted, C 2~6 refers to an alkynyl group. In some embodiments, C 2~4 Alkynylene is a further option. Exemplary alkynylene groups include, but are not limited to, ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), etc.

[0085] "C 0~6 Alkylene" refers to a chemical bond and the above "C 1~6 Alkylene", and "C 0~4 Alkylene" refers to a chemical bond and the above "C 1~4 Alkylene".

[0086] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0087] Therefore, "C 1~6 Haloalkyl" refers to the above "C 1~6 Alkyl" substituted with one or more halogens. In some embodiments, C 1~4 Haloalkyl is a further option, and alternatively C 1~2 Haloalkyl. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Haloalkyl may be substituted at any available bond point, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0088] "C 3~10 Cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms, optionally containing 1, 2, or 3 double bonds or triple bonds. In some embodiments, C 5~10 Cycloalkyl, C 3~7 Cycloalkyl and C3~6 Cycloalkyl is a further option, and alternatively, C 5~7 Cycloalkyl and C 5~6 is cycloalkyl. Cycloalkyl also includes a ring system in which the cycloalkyl described herein is condensed with one or more aryl groups or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbon atoms still represents the number of carbon atoms in the cycloalkyl system. Cycloalkyl also includes those in which, in the above cycloalkyl ring, substituents on any non-adjacent carbon atoms are bonded to form a bridged ring, together forming a polycycloalkane that shares two or more carbon atoms. Cycloalkyl also includes those in which, in the above cycloalkyl ring, substituents on the same carbon atom are bonded to form a ring, together forming a polycycloalkane that shares one carbon atom. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), etc. The cycloalkyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0089] "C 3~10 "Cycloalkylene" refers to a divalent group formed by removing another hydrogen of cycloalkyl, and may be substituted or unsubstituted. In some embodiments, C 3~10 Cycloalkylene and C 3~6 Cycloalkylene are further options, and alternatively, cyclopropylene. 3~4 is cycloalkyl. Cycloalkyl also includes a ring system in which the cycloalkyl described herein is condensed with one or more aryl groups or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbon atoms still represents the number of carbon atoms in the cycloalkyl system. Cycloalkyl also includes those in which, in the above cycloalkyl ring, substituents on any non-adjacent carbon atoms are bonded to form a bridged ring, together forming a polycycloalkane that shares two or more carbon atoms. Cycloalkyl also includes those in which, in the above cycloalkyl ring, substituents on the same carbon atom are bonded to form a ring, together forming a polycycloalkane that shares one carbon atom. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrieneyl (C7), etc. The cycloalkyl group may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0090] "3- to 10-membered heterocyclyl" refers to a saturated or unsaturated radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, each of the heteroatoms being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double bonds or triple bonds. In a heterocyclyl containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as permitted by the valence. In some embodiments, a 5- to 10-membered heterocyclyl, which is a radical of a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, is an option; in some embodiments, a 3- to 7-membered heterocyclyl, which is a radical of a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, is an option; a 5- to 7-membered heterocyclyl, which is a radical of a 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, is an option; a 3- to 6-membered heterocyclyl, which is a radical of a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, is an option; a 4- to 6-membered heterocyclyl, which is a radical of a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, is an option; and a 5- to 6-membered heterocyclyl, which is a radical of a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, is a further option. Heterocyclyl also includes ring systems in which the above-described heterocyclyl is fused with one or more cycloalkyl groups and the point of attachment is on the heterocyclyl ring, or in which the above-described heterocyclyl is fused with one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring. In such cases, the number of ring members still represents the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes those in which, in the above-described heterocyclyl ring, substituents on any non-adjacent carbon atoms or nitrogen atoms are bonded to form a bridged ring, together forming a polycyclic heteroalkane that shares two or more carbon atoms or nitrogen atoms. Heterocyclyl also includes those in which, in the above-described heterocyclyl ring, substituents on the same carbon atom are bonded to form a ring, together forming a polycyclic heteroalkane that shares one carbon atom.Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiirenyl. 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, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three 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, piperidyl, tetrahydropyranyl, dihydropyridyl, 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 three 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 (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.The heterocyclyl also includes a bridged or spiro ring formed by the above heterocyclyl and a cycloalkyl, heterocyclyl, aryl or heteroaryl group sharing one or two atoms, and the shared atoms can be carbon atoms or nitrogen atoms as long as the valence permits. The heterocyclyl also includes the above heterocyclyl and heterocyclyl groups which may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0091] “C 6~10 “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6 to 10 ring carbon atoms and 0 heteroatoms (e.g., having 6 or 10 shared π electrons in a cyclic arrangement). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”, e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C 10 “aryl”, e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). The aryl group also includes a ring system in which the above aryl ring is condensed with one or more cycloalkyl or heterocyclyl groups and the bonding point is on the aryl ring. In this case, the number of carbon atoms still represents the number of carbon atoms in the aryl ring system. The aryl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0092] "5- to 14-membered heteroaryl" has ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently referring to a radical of a 5- to 14-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 shared π electrons in a cyclic arrangement) selected from nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom as valence permits. A heteroaryl bicyclic system can contain one or more heteroatoms in one or two rings. Heteroaryl also includes ring systems in which the above-described heteroaryl ring is fused with one or more cycloalkyl or heterocyclyl groups and the point of attachment is on the heteroaryl ring. In such cases, the number of carbon atoms still represents the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5- to 10-membered heteroaryl group, which is a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, is an option. In other embodiments, a 5- to 6-membered heteroaryl group, which is a radical of a 5- to 6-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, is a further option. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl and pyridonyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. The heteroaryl may be substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0093] The divalent groups formed by removing another hydrogen from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined above are collectively referred to as "-ylene" or "-ylidene". Ring-forming groups such as cycloalkyl, heterocyclyl, aryl, and heteroaryl are collectively referred to as "cyclic groups".

[0094] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl defined herein are optionally substituted groups.

[0095] Exemplary substituents on a carbon atom include, but are not limited to, 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、 -NR bb 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)SRaa 、 -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, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are included, where each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups, or

[0096] or two geminal hydrogens on a carbon atom are replaced with =O, =S, =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 groups,

[0097] R aaEach of which is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two of the R aa groups are joined to form a heterocyclyl or heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups,

[0098] R bb each of which is independently 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 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, selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb groups are joined to form a heterocyclyl or heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups,

[0099] R ccEach of them is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc groups are bonded to form a heterocyclyl or heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups,

[0100] Each of R dd is 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, -NR ff 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 ffSO2R 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,selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be joined to form =O or =S,

[0101] R ee each of which is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups,

[0102] R ff each of which is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ffThe group is bonded to form a heterocyclyl or heteroaryl ring, where each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups,

[0103] each R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6(alkyl), -OC(=NH)(C 1~6 (alkyl), -OC(=NH)OC 1~6 (alkyl, -C(=NH)N(C 1~6 (alkyl)2, -C(=NH)NH(C 1~6 (alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 (alkyl)2, -OC(NH)NH(C 1~6 (alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 (alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 (alkyl), -SO2N(C 1~6 (alkyl)2, -SO2NH(C 1~6 (alkyl), -SO2NH2, -SO2C 1~6 (alkyl, -SO2OC 1~6 (alkyl, -OSO2C 1~6 (alkyl, -SOC 1~6 (alkyl, -Si(C 1~6 (alkyl)3, -OSi(C 1~6 (alkyl)3, -C(=S)N(C 1~6 (alkyl)2, C(=S)NH(C 1~6 (alkyl), C(=S)NH2, -C(=O)S(C 1~6 (alkyl), -C(=S)SC 1~6 (alkyl, -SC(=S)SC 1~6 (alkyl, -P(=O)2(C 1~6 (alkyl), -P(=O)(C 1~6 (alkyl)2, -OP(=O)(C 1~6 (alkyl)2, -OP(=O)(OC 1~6 (alkyl)2, C 1~6 (alkyl, C 1~6 (haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 (aryl, C3-C7 heterocyclyl or C5-C 10 (heteroaryl), or two geminal R gg (substituents) may be bonded to form =O or =S, where X - (is a counterion).

[0104] Exemplary substituents on the nitrogen atom include 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, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are included, but not limited thereto, or two R cc groups bonded to the nitrogen atom are bonded to form a heterocyclyl or heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups, where R aa , R bb , R cc and R dd are as described herein.

[0105] Other definitions

[0106] The term "cancer" includes, but is not limited to, the following: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Digestive tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma exostosis, benign enchondroma, chondroblastoma, fibrochondroma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerve fibroma, meningioma, glioma, sarcoma; Gynecology: uterus (endometrial cancer), cervix (cervical cancer, pre-cancerous cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma)), fallopian tube (cancer); Hematology: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders,Multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and, adrenal gland: neuroblastoma are included.

[0107] In one embodiment, the term "cancer" includes, but is not limited to, the following cancers: malignant peripheral nerve sheath tumor, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer, and thyroid cancer and sarcoma.

[0108] In one embodiment, the term "cancer" includes, but is not limited to, the following cancers: hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0109] As used herein, the term "treat" relates to the reversal, alleviation, or inhibition of the progression of a disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition, or the prevention thereof. As used herein, the noun "treatment" relates to the action of treating, which is a verb and is as defined just now.

[0110] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylate and amino acid addition salts of the compounds of the present disclosure that are suitable for contact with the tissues of a patient within the scope of reliable medical judgment and do not cause undue toxicity, irritation, allergy, etc. They are commensurate with a reasonable benefit / risk ratio and are effective for their intended uses. This term includes, to the extent possible, zwitterionic forms of the compounds of the present disclosure.

[0111] Pharmaceutically acceptable base addition salts are formed using metals or amines such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0112] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form the salt. The free acid can be regenerated by isolating the free acid after contacting the salt form with an acid in a conventional manner. The free acid form has physical properties such as solubility in polar solvents that are somewhat different from those of the respective salt forms. However, for the purposes of the present disclosure, the salts are still equivalent to their respective free acids.

[0113] Salts can be prepared from inorganic acids, and examples include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides. Examples of acids include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include hydrobromides, hydrochlorides, sulfates, bisulfates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates, succinates, tartrates, naphthalates, methanesulfonates, glucoheptanoates, lactobionates, lauryl sulfonates, isethionates, etc. Salts can also be prepared from organic acids, and examples of organic acids include aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, naphthoates, besylates, tosylates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates, etc. Pharmaceutically acceptable salts include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids such as arginine salts, gluconates, galacturonates, etc. are also included (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1~19).

[0114] The "subjects" for which administration is contemplated include humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or the elderly)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats and / or dogs, but are not limited thereto. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" may be used interchangeably herein.

[0115] The terms "disease", "disorder" and "condition" may be used interchangeably herein.

[0116] Unless otherwise specified, as used herein, the term "treatment" refers to an effect on a subject suffering from a particular disease, disorder or condition that reduces the severity of, or delays or slows the progression of, that disease, disorder or condition ("therapeutic treatment"). The term also includes effects that occur before a subject begins to suffer from a particular disease, disorder or condition ("preventive treatment").

[0117] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health status and symptoms of the subject. Effective amounts include therapeutically effective amounts and prophylactically effective amounts.

[0118] Unless otherwise specified, the "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. The therapeutically effective amount of a compound refers to the amount of a therapeutic agent that provides a therapeutic benefit in the treatment of a disease, disorder or condition when used alone or in combination with other therapies. The term "therapeutically effective amount" may include an amount that improves the overall treatment, alleviates or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0119] Unless otherwise specified, the "prophylactically effective amount" of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with the disease, disorder or condition, or to prevent recurrence of the disease, disorder or condition. The prophylactically effective amount of a compound refers to the amount of a therapeutic agent that provides a prophylactic benefit in the prevention of a disease, disorder or condition when used alone or in combination with other agents. The term "prophylactically effective amount" may include an amount that improves the overall prophylaxis, or enhances the prophylactic effect of other prophylactic agents.

[0120] "Combination" and related terms refer to the simultaneous or sequential administration of the compounds of the present disclosure and other therapeutic agents. For example, the compounds of the present disclosure can be administered simultaneously or sequentially in separate unit dosages with other therapeutic agents, or simultaneously in a single unit dosage with other therapeutic agents.

Brief Description of the Drawings

[0121]

Figure 1

Figure 2

Figure 3

Figure 4

BEST MODE FOR CARRYING OUT THE INVENTION

[0122] As used herein, "the compounds disclosed herein" or "the compounds of the present disclosure" refers to the following compounds such as those of formula (I), formula (II), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof.

[0123] In the present disclosure, compounds are named using standard nomenclature. For compounds having asymmetric centers, all optical isomers and mixtures thereof are to be understood as being included unless otherwise specified. Further, unless otherwise specified, all isomeric compounds and carbon-carbon double bonds included in the present disclosure may exist in the Z and E forms. Compounds exist in various tautomeric forms, and one of them is not limited to any particular tautomer, and it is intended to cover all tautomeric forms.

[0124] In one embodiment, the present disclosure relates to a compound of formula (X), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chemical formula

[0125] Wherein,

[0126] Ring A is C 6~10 aryl or a 5- to 10-membered heteroaryl,

[0127] L1 is NH or CHR x and

[0128] L2 is CR x R y and

[0129] L3 is -C(O)-, -S(O)- or -S(O)2-.

[0130] Here, R x and R y are, independently, H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0131] or, CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0132] or, when L1 is CHR x and L2 is CR x R y then the two R x groups may be joined to form a chemical bond or C 1~4 alkylene,

[0133] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)(=NR a )R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , P(O)(R a )2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7Cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 Selected from aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 1s and

[0134] m = 0, 1, 2, 3 or 4,

[0135] R4 is H, D, C 1~6 alkyl and C 1~6 selected from haloalkyl, or

[0136] or, one R1 is bonded to R4 to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2 -(alternatively -(CH2) q1 -X-(CH2) q2 -)(wherein X is O, S, NH or CH2, q1 = 0, 1 or 2, q2 = 1, 2 or 3, and R ss is independently selected from H, D, C 1~6 alkyl and C 1~6 selected from haloalkyl, or two R ss and the carbon atom to which they are attached together form C 3~10 cycloalkyl),

[0137] X1 is a C atom or an N atom, which are optionally substituted with R 2b and

[0138] X2 is a C atom or an N atom, which are optionally substituted with R 2c and

[0139] X3 is a C atom or an N atom, which are optionally substituted with R 2d and

[0140] R 2a is H, D, CN, OR a NR b Rc and C(O)OR a and C(O)NR b R c selected from

[0141] R 2b is H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl,

[0142] R 2c is H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0143] or, X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s groups,

[0144] R 2d is H, D, halogen, CN, NO2, OR a NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0145] R3 is -C 1~6 alkylene-OR a -C 1~6 alkylene-NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6Alkynyl, -L-C 3~10 Cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 Selected from aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s1 And 1 R 3s2 And are optionally substituted with

[0146] L is a chemical bond, C 1~6 Alkylene, C 2~6 Alkenylene or C 2~6 Alkynylene, which are optionally substituted with 1, 2 or 3 R

[0147] R 1s And R 2s Are independently H, D, halogen, CN, =O, C(O)OR a , C(O)NR b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl, or two R 1s And the atoms to which they are attached together form C 3~10 Cycloalkyl or 3- to 10-membered heterocyclyl,

[0148] R 3s1 Is H, D, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl,

[0149] R 3s2 Is H, D, -L-OR a , -L-NR b R c , C1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl, selected from these, which are optionally substituted with one, two or three Rs 3s or, Rs

[0150] or, R 3s1 , R 3s2 and the carbon atom to which they are attached together form a C 3~10 cycloalkyl,

[0151] R and R 3s are independently H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, selected from these,

[0152] R a , R b and R c are independently H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or Rs b , R c and the atom to which they are attached together form a 5- to 10-membered heterocyclyl,

[0153] Each of the groups in the above ring A, L1, L2, R x , R y , R1, R 2a , R 2b , R 2c , R 2d , R3, R4, L, R, R 1s , R 2s , R 3s , R 3s1 , R 3s2 , R a , R b and R c is optionally deuterated until fully deuterated,

[0154] However, when L2 is CR x R y and L3 is -S(O)- or -S(O)2-, R y and R 2d combine to form vinylene.

[0155] In another embodiment, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. [Chemical formula]

[0156] Wherein,

[0157] Ring A is C 6~10 aryl or 5- to 10-membered heteroaryl,

[0158] L1 is NH or CHR x and

[0159] L2 is CR x R y and

[0160] L3 is -C(O)-, -S(O)- or -S(O)2-,

[0161] wherein R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0162] or CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0163] or L1 is CHR x and L2 is CR x R yWhen this is the case, the two Rs x groups may be bonded to form a chemical bond or a C 1~4 alkylene,

[0164] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , P(O)(R a )2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, and these are optionally substituted with one, two or three Rs 1s ,

[0165] m = 0, 1, 2, 3 or 4,

[0166] X1 is a C atom or an N atom, and these are optionally substituted with R 2b ,

[0167] X2 is a C atom or an N atom, and these are optionally substituted with R 2c ,

[0168] X3 is a C atom or an N atom, and these are optionally substituted with R 2dis optionally substituted,

[0169] R 2a is H, D, CN, OR a 、NR b R c 、C(O)OR a and C(O)NR b R c selected from

[0170] R 2b is H, D, halogen, C(O)OR a 、C(O)NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl selected from

[0171] R 2c is H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl selected from or

[0172] or, X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s is optionally substituted,

[0173] R 2d is H, D, halogen, CN, NO2, OR a 、NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl selected from

[0174] R3 is -C 1~6 alkylene-OR a 、-C 1~6Alkylene-NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~10 cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, selected from these, which are optionally substituted with 1, 2 or 3 R 3s1 and 1 R 3s2 and are optionally substituted with,

[0175] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R,

[0176] R 1s and R 2s are independently H, D, halogen, =O, C(O)OR a 、C(O)NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, selected from,

[0177] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, selected from,

[0178] R 3s2 is H, D, -L-OR a 、-L-NRb R c 、 C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, selected from these, and these are optionally substituted with 1, 2 or 3 Rs 3s and,

[0179] R and R 3s are, independently, H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, selected from these,

[0180] R a 、 R b and R c are, independently, H, D, C 1~6 alkyl and C 1~6 haloalkyl, selected from these, or R b 、 R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0181] each of the groups in the above ring A, L1, L2, R x 、 R y 、 R1, R 2a 、 R 2b 、 R 2c 、 R 2d 、 R3, L, R, R 1s 、 R 2s 、 R 3s 、 R 3s1 、 R 3s2 、 R a 、 R b and R c is optionally deuterated until fully deuterated,

[0182] provided that when L2 is CR x R y and L3 is -S(O)- or -S(O)2-, R y and R 2d are joined to form a vinylene.

[0183] Ring A

[0184] In one embodiment, Ring A is C 6~10 aryl, alternatively phenyl, and in another embodiment, Ring A is a 5- to 10-membered heteroaryl, alternatively a 5- to 10-membered heteroaryl, for example, phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, alternatively pyridyl or pyridazinyl.

[0185] L1, L2, and L3

[0186] In one embodiment, L1 is NH, and in another embodiment, L1 is CHR x and in another embodiment, L1 is NH, L2 is CR x R y and -L1-L2- is alternatively

Chemical formula

Chemical formula

Chemical formula

[0187] R x and R y

[0188] In one embodiment, R x and R y are H, and in another embodiment, R x and R y are D, and in another embodiment, R x and R y are C1~6 is alkyl, and in another embodiment, R x and R y is C 1~6 haloalkyl, alternatively CF3, and in another embodiment, CR x R y together form C=O, and in another embodiment, CR x R y together form C=S, and in another embodiment, CR x R y together form C 3~6 cycloalkylene, alternatively cyclopropylene, and in another embodiment, L1 is CHR x and L2 is CR x R y and the two R x groups are bonded to form a chemical bond, and in another embodiment, L1 is CHR x and L2 is CR x R y and the two R x groups are bonded to form C 1~4 alkylene, alternatively cyclopropylene.

[0189] R1

[0190] In one embodiment, R1 is H, in another embodiment, R1 is D, in another embodiment, R1 is halogen, in another embodiment, R1 is CN, in another embodiment, R1 is NO2, in another embodiment, R1 is -L-OR a and in another embodiment, R1 is, -L-SR a and in another embodiment, R1 is -L-NR b R c and in another embodiment, R1 is SF5, in another embodiment, R1 is C(O)R a and in another embodiment, R1 is C(O)OR a and in another embodiment, R1 is C(O)NR b R c and in another embodiment, R1 is OC(O)R a and in another embodiment, R1 is NR bC(O)R c In another embodiment, R1 is S(O)R a In another embodiment, R1 is S(O)2R a In another embodiment, R1 is S(O)(=NR a )R a In another embodiment, R1 is S(O)OR a In another embodiment, R1 is S(O)2OR a In another embodiment, R1 is S(O)NR b R c In another embodiment, R1 is S(O)2NR b R c In another embodiment, R1 is P(O)(R a )2, and in another embodiment, R1 is C 1~6 alkyl, and in another embodiment, R1 is C 1~6 haloalkyl, and in another embodiment, R1 is C 2~6 alkenyl, and in another embodiment, R1 is C 2~6 alkynyl, and in another embodiment, R1 is -L-C 3~7 cycloalkyl, and in another embodiment, R1 is -L-3- to 7-membered heterocyclyl, and in another embodiment, R1 is -L-C 6~10 aryl, and in another embodiment, R1 is -L-5- to 10-membered heteroaryl, and in another embodiment, R1 is optionally substituted with one, two, or three R 1s .

[0191] In a more specific embodiment, R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10Selected from aryl and -L-5- to 10-membered heteroaryl. In another more specific embodiment, R1 is H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 Selected from aryl and -L-5- to 10-membered heteroaryl. In another more specific embodiment, R1 is H, D, halogen, CN, OR a 、SR a 、NR b R c 、SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 3~7 Selected from cycloalkyl and 3- to 7-membered heterocyclyl. In another more specific embodiment, R1 is H, D, halogen, CN, OR a 、SR a 、NR b R c 、SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 Selected from cycloalkyl and 5- to 7-membered heterocyclyl. In another more specific embodiment, R1 is H, D, halogen, CN, OR a 、NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 Selected from cycloalkyl and 4- to 6-membered heterocyclyl. In another more specific embodiment, R1 is H, D, halogen, CN, OR a 、NR b R c 、C 1~6 alkyl, C 1~6 Selected from haloalkyl and 5- to 6-membered heterocyclyl. In another more specific embodiment, R1 is H, D, CN, OR a 、C1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Selected from cycloalkyl and 5- to 6-membered heterocyclyl. In another more specific embodiment, R1 is H, D, CN, OR a , C 1~6 Alkyl, C 1~6 Selected from haloalkyl and 5- to 6-membered heterocyclyl. In another more specific embodiment, R1 is CF3, CN, OCF3, OCH2CH3,

Chemical formula

Chemical formula

[0192] m

[0193] In one embodiment, m = 0; in another embodiment, m = 1; in another embodiment, m = 2; in another embodiment, m = 3; in another embodiment, m = 4.

[0194] R4

[0195] In one embodiment, R4 is H; in another embodiment, R4 is D; in another embodiment, R4 is C 1~6 Alkyl; in another embodiment, R4 is C 1~6 Haloalkyl; in another embodiment, R1 and R4 are joined to form -(CR ss R ss ) q1 -X-(CR ss R ss ) q2 -(wherein X is O, S, NH or CH2; q1 = 0, 1 or 2; q2 = 1, 2 or 3; and R ss is independently H, D, C 1~6 Alkyl and C 1~6Selected from haloalkyl or two Rs ss and the carbon atoms to which they are attached together form a C 3~10 cycloalkyl, such as C 3~6 cycloalkyl (to form), and in another embodiment, R1 and R4 are joined to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S, NH or CH2, q1 = 0, 1 or 2, and q2 = 1, 2 or 3), and in another embodiment, R1 and R4 are joined to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S, NH or CH2, q1 = 0 or 1, and q2 = 1 or 2), and in another embodiment, R1 and R4 are joined to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S or NH2, q1 = 0 or 1, and q2 = 1 or 2) is formed.

[0196] X1, X2 and X3

[0197] In one embodiment, X1 is a C atom, in another embodiment, X1 is an N atom, in another embodiment, X1 is CR 2b and in another embodiment, X1 is NR 2b and in one embodiment, X2 is a C atom, in another embodiment, X2 is an N atom, in another embodiment, X2 is CR 2c and in another embodiment, X2 is NR 2c and in one embodiment, X3 is a C atom, in another embodiment, X3 is an N atom, in another embodiment, X3 is CR 2d and in another embodiment, X3 is NR 2d is.

[0198] In a more specific embodiment,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0199] In a more specific embodiment, X1, X2 and their substituents together form a C 5~10 cycloalkyl, and in another more specific embodiment, X1, X2 and their substituents together form a 5- to 10-membered heterocyclyl, and in another more specific embodiment, X1, X2 and their substituents together form a C 6~10 aryl, and in another more specific embodiment, X1, X2 and their substituents together form a 5- to 10-membered heteroaryl, and in another more specific embodiment, X1, X2 and their substituents together form a C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, and in another more specific embodiment, X1, X2 and their substituents together form

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0200] R 2a

[0201] In one embodiment, R 2a is H, and in another embodiment, R 2a is D, and in another embodiment, R 2a is CN, and in another embodiment, R 2a is OR a and in another embodiment, R 2a is NR b R c and in another embodiment, R 2a is C(O)OR aand in another embodiment, R 2a is C(O)NR b R c .

[0202] In a more specific embodiment, R 2a is selected from H, D, CN, OR a and NR b R c and in another more specific embodiment, R 2a is selected from OR a and NR b R c and in another more specific embodiment, R 2a is selected from OMe and NH2, and alternatively is NH2.

[0203] R 2b

[0204] In one embodiment, R 2b is H, and in another embodiment, R 2b is D, and in another embodiment, R 2b is halogen, and in another embodiment, R 2b is C(O)OR a and in another embodiment, R 2b is C(O)NR b R c and in another embodiment, R 2b is C 1~6 alkyl, and in another embodiment, R 2b is C 1~6 haloalkyl, and in another embodiment, R 2b is C 3~10 cycloalkyl, and in another embodiment, R 2b is a 3- to 10-membered heterocyclyl.

[0205] In a more specific embodiment, R 2b is selected from H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10Selected from cycloalkyl and 3- to 10-membered heterocyclyl, and in another more specific embodiment, R 2b is H, D, halogen, C(O)NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl and 4- to 6-membered heterocyclyl, and in another more specific embodiment, R 2b is H, D, halogen, C(O)NR b R c 、C 1~6 alkyl and C 1~6 haloalkyl, and in another more specific embodiment, R 2b is H, D, halogen, C(O)NR b R c and C 1~6 alkyl, and in another more specific embodiment, R 2b is H, F, Cl, Br, Me, CH2CH3, C(O)NH2 and

Chemical formula

[0206] R 2c

[0207] In one embodiment, R 2c is H, and in another embodiment, R 2c is D, and in another embodiment, R 2c is halogen, and in another embodiment, R 2c is C 1~6 alkyl, and in another embodiment, R 2c is C 1~6 haloalkyl.

[0208] In a more specific embodiment, R 2c is selected from H, halogen and Me, or alternatively selected from H and Me.

[0209] R 2d

[0210] In one embodiment, R 2d is H, and in another embodiment, R 2d is D, and in another embodiment, R 2d is halogen, and in another embodiment, R 2d is CN, and in another embodiment, R 2d is NO2, and in another embodiment, R 2d is OR a and in another embodiment, R 2d is NR b R c and in another embodiment, R 2d is C 1~6 alkyl, and in another embodiment, R 2d is C 1~6 haloalkyl, and in another embodiment, R 2d is C 5~10 cycloalkyl, and in another embodiment, R 2d is a 5- to 10-membered heterocyclyl, and in another embodiment, R 2d is C 6~10 aryl, and in another embodiment, R 2d is a 5- to 10-membered heteroaryl.

[0211] In a more specific embodiment, R 2d is selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, and in another more specific embodiment, R 2d is selected from H and D.

[0212] R3

[0213] In one embodiment, R3 is -C 1~6 alkylene-OR a and in another embodiment, R3 is -C 1~6 alkylene-NR b R c and in another embodiment, R3 is C 1~6is alkyl, and in another embodiment, R3 is C 1~6 is haloalkyl, and in another embodiment, R3 is C 2~6 is alkenyl, and in another embodiment, R3 is C 2~6 is alkynyl, and in another embodiment, R3 is -L-C 3~10 is cycloalkyl, and in another embodiment, R3 is -L-3- to 10-membered heterocyclyl, and in another embodiment, R3 is -L-C 6~10 is aryl, and in another embodiment, R3 is -L-5- to 10-membered heteroaryl, and in another embodiment, R3 is one, two or three Rs 3s1 and one R 3s2 and is optionally substituted with.

[0214] In a more specific embodiment, R3 is C 1~6 alkyl, C 1~6 haloalkyl, -L-C 3~10 cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, and in another more specific embodiment, R3 is C 1~6 alkyl, C 1~6 haloalkyl, C 5~6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, and in another more specific embodiment, R3 is Me, Et, iPr, cyclopropyl, cyclobutyl,

Chemical formula

[0215] L

[0216] In one embodiment, L is a chemical bond, and in another embodiment, L is C 1~6 alkylene, and in another embodiment, L is C 2~6 alkenylene, and in another embodiment, L is C 2~6 alkynylene, and in another embodiment, L is optionally substituted with one, two or three Rs.

[0217] R 1s

[0218] In one embodiment, R 1s is H, and in another embodiment, R 1s is D, and in another embodiment, R 1s is halogen, and in another embodiment, R 1s is CN, and in another embodiment, R 1s is =O, and in another embodiment, R 1s is C(O)OR a and in another embodiment, R 1s is C(O)NR b R c and in another embodiment, R 1s is C 1~6 alkyl, and in another embodiment, R 1s is C 1~6 haloalkyl, and in another embodiment, R 1s is C 2~6 alkenyl, and in another embodiment, R 1s is C 2~6 alkynyl, and in another embodiment, R 1s is C 3~10 cycloalkyl, and in another embodiment, R 1s is a 3- to 10-membered heterocyclyl, and in another embodiment, R 1s is C 6~10 aryl, and in another embodiment, R 1s is a 5- to 10-membered heteroaryl, and in another embodiment, two Rs 1s and the atoms to which they are attached together form a C 3~10 cycloalkyl, and in another embodiment, two Rs 1s and the atoms to which they are attached together form a 3- to 10-membered heterocyclyl.

[0219] In one embodiment, R 2s is H, and in another embodiment, R 2s is D, and in another embodiment, R 2s is halogen, and in another embodiment, R 2s is =O, and in another embodiment, R2s is C(O)OR a and in another embodiment, R 2s is C(O)NR b R c and in another embodiment, R 2s is C 1~6 alkyl, and in another embodiment, R 2s is C 1~6 haloalkyl, and in another embodiment, R 2s is C 2~6 alkenyl, and in another embodiment, R 2s is C 2~6 alkynyl, and in another embodiment, R 2s is C 3~10 cycloalkyl, and in another embodiment, R 2s is a 3- to 10-membered heterocyclyl, and in another embodiment, R 2s is C 6~10 aryl, and in another embodiment, R 2s is a 5- to 10-membered heteroaryl.

[0220] In a more specific embodiment, R 1s is H, D, halogen, =O, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, a 3- to 10-membered heterocyclyl, C 6~10 aryl and a 5- to 10-membered heteroaryl, and in another more specific embodiment, R 1s is H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl and a 5- to 7-membered heterocyclyl, and in another more specific embodiment, R 1s is H, D, halogen, C(O)OR a , C(O)NR bR c 、 and C 1~6 are selected from alkyl and C 1~6 haloalkyl. In another more specific embodiment, R 1s is H, D, halogen, C(O)OR a , C 1~6 alkyl and C 1~6 haloalkyl. In another more specific embodiment, R 1s is selected from halogen and C(O)OCH3.

[0221] In a more specific embodiment, R 2s is H, D, halogen, =O, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl. In another more specific embodiment, R 2s is H, D, halogen, =O, C 1~6 alkyl and C 1~6 haloalkyl. In another more specific embodiment, R 2s is H, D, =O, C 1~6 alkyl and C 1~6 haloalkyl. In another more specific embodiment, R 2s is selected from H, D, =O, and Me.

[0222] R 3s1

[0223] In one embodiment, R 3s1 is H, in another embodiment, R 3s1 is D, in another embodiment, R 3s1 is halogen, in another embodiment, R 3s1 is C 1~6 alkyl, and in another embodiment, R 3s1 is C 1~6is haloalkyl, and in another embodiment, R 3s1 is C 2~6 is alkenyl, and in another embodiment, R 3s1 is C 2~6 is alkynyl, and in another embodiment, R 3s1 is C 3~10 is cycloalkyl, and in another embodiment, R 3s1 is 3- to 10-membered heterocyclyl, and in another embodiment, R 3s1 is C 6~10 is aryl, and in another embodiment, R 3s1 is 5- to 10-membered heteroaryl.

[0224] In a more specific embodiment, R 3s1 is selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, and in another more specific embodiment, R 3s1 is selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl, and in another more specific embodiment, R 3s1 is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl, and in another more specific embodiment, R 3s1 is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl and C 3~6 cycloalkyl, and in another more specific embodiment, R 3s1 is selected from H, Me and cyclopropyl, or alternatively selected from H and Me.

[0225] R 3s2

[0226] In one embodiment, R 3s2 is H, and in another embodiment, R 3s2 is D, and in another embodiment, R 3s2 is -L-OR a and in another embodiment, R 3s2 is -L-NR b R c and in another embodiment, R 3s2 is C 1~6 alkyl, and in another embodiment, R 3s2 is C 1~6 haloalkyl, and in another embodiment, R 3s2 is C 3~10 cycloalkyl, and in another embodiment, R 3s2 is a 5- to 10-membered heterocyclyl, and in another embodiment, R 3s2 is C 6~10 aryl, and in another embodiment, R 3s2 is a 5- to 10-membered heteroaryl, and in another embodiment, R 3s2 is optionally substituted with one, two, or three R 3s .

[0227] In a more specific embodiment, R 3s2 is selected from H, D, -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, a 5- to 10-membered heterocyclyl, C 6~10 aryl, and a 5- to 10-membered heteroaryl, and in another more specific embodiment, R 3s2 is selected from H, D, -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl, a 5- to 7-membered heterocyclyl, C 6~10 aryl, and a 5- to 10-membered heteroaryl, and in another more specific embodiment, R 3s2 is H, D, -L-OR a , C1~6 Alkyl, C 1~6 Haloalkyl, C 5~7 Selected from cycloalkyl, phenyl and 5- to 10-membered heteroaryl. In another more specific embodiment, R 3s2 is H, D, Me, CF3, CH2OCH3, cyclopropyl, [Chemical formula] Selected from, and alternatively, C 5~7 Selected from cycloalkyl, 5- to 7-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl, and alternatively a C such as cyclopropyl 5~7 Cycloalkyl, and alternatively Et.

[0228] In another more specific embodiment, R 3s1 , R 3s2 and the carbon atom to which they are attached together form a C 3~10 Cycloalkyl, for example C 3~6 Cycloalkyl.

[0229] R

[0230] In one embodiment, R is H, in another embodiment, R is D, in another embodiment, R is a halogen, and in another embodiment, R is C 1~6 Alkyl, and in another embodiment, R is C 1~6 Haloalkyl.

[0231] R 3s

[0232] In one embodiment, R 3s is H, in another embodiment, R 3s is D, in another embodiment, R 3s is a halogen, and in another embodiment, R 3s is C 1~6 Alkyl, and in another embodiment, R 3s is C 1~6 Haloalkyl.

[0233] R a 、R b and R c

[0234] In one embodiment, R a 、R b and R c are independently H. In another embodiment, R a 、R b and R c are independently D. In another embodiment, R a 、R b and R c are independently C 1~6 alkyl. In another embodiment, R a 、R b and R c are independently C 1~6 haloalkyl. In another embodiment, R a 、R b and R c are independently C 3~10 cycloalkyl. In another embodiment, R a 、R b and R c are independently 3- to 10-membered heterocyclyl. In another embodiment, R a 、R b and R c are independently C 6~10 aryl. In another embodiment, R a 、R b and R c are independently 5- to 10-membered heteroaryl. In another embodiment, R b 、R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, alternatively a 5- to 6-membered heterocyclyl.

[0235] Any technical solution in any one or any combination of the above-described specific embodiments can be combined with any technical solution in any other specific embodiment or any combination thereof. For example, any technical solution of ring A or any combination thereof can be combined with L1, L2, L3, R x 、Ry , R1, m, X1, X2, X3, R 2a , R 2b , R 2c , R 2d , R3, L, R, R 1s , R 2s , R 3s , R 3s1 , R 3s2 , R a , R b and R c and can be combined with any technical solution of these or any combination thereof. The present disclosure is intended to include all combinations of such technical solutions and is not enumerated comprehensively here to save space.

[0236] In a more specific embodiment, the present disclosure provides a compound of formula (X), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chemical formula

[0237] In the formula,

[0238] ring A is C 6~10 aryl or 5- to 10-membered heteroaryl,

[0239] L1 is NH or CHR x wherein,

[0240] L2 is CR x R y wherein,

[0241] L3 is -C(O)-, -S(O)- or -S(O)2-,

[0242] Here, R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0243] or CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0244] or L1 is CHR x and L2 is CR x R y in which case the two R x groups may be joined to form a chemical bond or C 1~4 alkylene,

[0245] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)(=NR a )R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , P(O)(R a )2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, selected from these, which are optionally substituted with 1, 2 or 3 R 1s groups,

[0246] m = 0, 1, 2, 3 or 4,

[0247] R4 is H, D, C 1~6 alkyl and C 1~6 is selected from haloalkyl, or

[0248] or, one R1 is bonded to R4 to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S, NH or CH2, q1 = 0, 1 or 2, and q2 = 1, 2 or 3).

[0249] X1 is a C atom or an N atom, which is optionally substituted with R 2b

[0250] X2 is a C atom or an N atom, which is optionally substituted with R 2c

[0251] X3 is a C atom or an N atom, which is optionally substituted with R 2d

[0252] R 2a is selected from H, D, CN, OR a NR b R c C(O)OR a and C(O)NR b R c

[0253] R 2b is selected from H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl

[0254] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0255] ​​​​ or, X1, X2 and their substituents together form a C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s and

[0256] R 2d is H, D, halogen, CN, NO2, OR a , NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, selected from

[0257] R3 is -C 1~6 alkylene-OR a , -C 1~6 alkylene-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~10 cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, selected from, which are optionally substituted with 1, 2 or 3 R 3s1 and one R 3s2 and are optionally substituted

[0258] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R

[0259] R 1s and R 2s are independently H, D, halogen, =O, C(O)OR a , C(O)NR b Rc and C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 selected from aryl and 5- to 10-membered heteroaryl,

[0260] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 selected from aryl and 5- to 10-membered heteroaryl,

[0261] R 3s2 is H, D, -L-OR a or -L-NR b R c and C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 selected from aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s groups,

[0262] R and R 3s are independently H, D, halogen, C 1~6 alkyl and C 1~6 selected from haloalkyl,

[0263] R a R b and R c are independently H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 selected from aryl and 5- to 10-membered heteroaryl, or R b R, Rc and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0264] the above ring A, L1, L2, R x , R y , R1, R 2a , R 2b , R 2c , R 2d , R3, R4, L, R, R 1s , R 2s , R 3s , R 3s1 , R 3s2 , R a , R b and R c each of the groups in is optionally deuterated until fully deuterated,

[0265] provided that when L2 is CR x R y and L3 is -S(O)- or -S(O)2-, R y and R 2d are joined to form a vinylene.

[0266] In a more specific embodiment, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chemical formula

[0267] wherein,

[0268] ring A is C 6~10 aryl or 5- to 10-membered heteroaryl,

[0269] L1 is NH or CHR x and

[0270] L2 is CR x R y and

[0271] L3 is -C(O)-, -S(O)- or -S(O)2-,

[0272] wherein R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0273] or CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0274] or when L1 is CHR x and L2 is CR x R y the two R x groups may be joined to form a chemical bond or C 1~4 alkylene,

[0275] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , P(O)(R a ), C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C6~10 Selected from aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 Rs 1s and

[0276] m = 0, 1, 2, 3 or 4,

[0277] X1 is a C atom or an N atom, which are optionally substituted with Rs 2b and

[0278] X2 is a C atom or an N atom, which are optionally substituted with Rs 2c and

[0279] X3 is a C atom or an N atom, which are optionally substituted with Rs 2d and

[0280] R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a and C(O)NR b R c and

[0281] R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl,

[0282] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0283] or, X1, X2 and their substituents together form a C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10Form an aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s and are optionally substituted with

[0284] R 2d is H, D, halogen, CN, NO2, OR a , NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, selected from

[0285] R3 is -C 1~6 alkylene-OR a , -C 1~6 alkylene-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~10 cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, selected from these, which are optionally substituted with 1, 2 or 3 R 3s1 and 1 R 3s2 and are optionally substituted with

[0286] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R,

[0287] R 1s and R 2s are independently H, D, halogen, =O, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 Selected from aryl and 5- to 10-membered heteroaryl,

[0288] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 ed Selected from aryl and 5- to 10-membered heteroaryl,

[0289] R 3s2 is H, D, -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 Selected from aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R 3s s,

[0290] R and R 3s are independently H, D, halogen, C 1~6 alkyl and C 1~6 Selected from haloalkyl,

[0291] R a , R b and R c are independently H, D, C 1~6 alkyl and C 1~6 Selected from haloalkyl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0292] The above ring A, L1, L2, R x , R y , R1, R 2a , R2b , R 2c , R 2d , R3, L, R, R 1s , R 2s , R 3s , R 3s1 , R 3s2 , R a , R b and R c Each of the groups in and R is optionally deuterated until fully deuterated,

[0293] provided that when L2 is CR x R y and L3 is -S(O)- or -S(O)2-, R y and R 2d are joined to form vinylene.

[0294] In a more specific embodiment, the present disclosure provides the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein ring A is phenyl or a 5- to 6-membered heteroaryl, alternatively phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

[0295] In a more specific embodiment, the present disclosure provides the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is NH, L2 is CR x R y and -L1-L2- is alternatively

Chemical formula

Chemical formula

[0296] In a more specific embodiment, the present disclosure provides the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L1 is CHR x and L2 is CR x R y and -L1-L2- is alternatively​ [Chemical formula] There is provided the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0297] In a more specific embodiment, the present disclosure provides the above compound wherein L3 is -C(O)-, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0298] In a more specific embodiment, the present disclosure provides that R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, alternatively selected from H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, alternatively selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 3~7Selected from cycloalkyl and 3- to 7-membered heterocyclyl, alternatively H, D, halogen, CN, OR a 、SR a 、NR b R c 、SF5、C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 Selected from cycloalkyl and 5- to 7-membered heterocyclyl, alternatively H, D, halogen, CN, OR a 、NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 Selected from cycloalkyl and 4- to 6-membered heterocyclyl, alternatively H, D, halogen, CN, OR a 、NR b R c 、C 1~6 alkyl, C 1~6 Selected from haloalkyl and 5- to 6-membered heterocyclyl, alternatively H, D, CN, OR a 、C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 Selected from cycloalkyl and 5- to 6-membered heterocyclyl, alternatively H, D, CN, OR a 、C 1~6 alkyl, C 1~6 Selected from haloalkyl and 5- to 6-membered heterocyclyl, alternatively CF3, CN, OCF3, OCH2CH3,

Chem.

Chem.

[0299] In a more specific embodiment, the present disclosure provides that R1 and R4 are joined to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S, NH or CH2, q1 = 0 or 1, and q2 = 1 or 2), or alternatively, R1 and R4 are joined to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S or NH, q1 = 0 or 1, and q2 = 1 or 2), and provides the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0300] In a more specific embodiment, the present disclosure provides that

Chemical formula

Chemical formula

Chemical formula

[0301] In a more specific embodiment, the present disclosure provides that R 2a is selected from H, D, CN, OR a and NR b R c alternatively, OR a and NR b R c alternatively, selected from OMe and NH2, and alternatively NH2, and provides the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0302] In a more specific embodiment, the present disclosure provides that R 2bis H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl, alternatively H, D, halogen, C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl and 4- to 6-membered heterocyclyl, alternatively H, D, halogen, C(O)NR b R c C 1~6 alkyl and C 1~6 haloalkyl, alternatively H, D, halogen, C(O)NR b R c and C 1~6 alkyl, alternatively H, F, Cl, Br, Me, CH2CH3, C(O)NH2 and

Chemical formula

[0303] In a more specific embodiment, the present disclosure provides a compound of formula (I) wherein R 2c is selected from H and Me, or a pharmaceutically acceptable salt, isotopomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0304] In a more specific embodiment, the present disclosure provides that X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, alternatively C 5~7Forming cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, or alternatively, [Chemical formula] Forming, or alternatively, [Chemical formula] Forming, or alternatively, [Chemical formula] Forming, or alternatively, [Chemical formula] Provided is the above compound that forms, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0305] In a more specific embodiment, the present disclosure provides that R 2d is selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or alternatively, is selected from H and D, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0306] In a more specific embodiment, the present disclosure provides that R3 is selected from C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~10 cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, or alternatively, is selected from C 1~6 alkyl, C 1~6 haloalkyl, -L-C 3~10 cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, or alternatively, is selected from C1~6 Alkyl, C 1~6 Haloalkyl, C 5~6 Selected from cycloalkyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, alternatively, Me, Et, iPr, cyclopropyl, cyclobutyl, [Chemical formula] Provided is the above compound selected from the group consisting of, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

[0307] In a more specific embodiment, the present disclosure provides a compound wherein R 1s is H, D, halogen, =O, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 selected from cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, alternatively, H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 selected from cycloalkyl and 5- to 7-membered heterocyclyl, alternatively, H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, and C 1~6 haloalkyl, alternatively, selected from H, D, halogen, C(O)OR a , C 1~6 alkyl, and C 1~6 haloalkyl, alternatively, selected from halogen and C(O)OCH3, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

[0308] In a more specific embodiment, the present disclosure provides that R 2s is selected from H, D, halogen, =O, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or alternatively is selected from H, D, halogen, =O, C 1~6 alkyl, and C 1~6 haloalkyl, or alternatively is selected from H, D, =O, C 1~6 alkyl, and C 1~6 haloalkyl, or alternatively is selected from H, D, =O, and Me, and provides the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate, or solvate thereof.

[0309] In a more specific embodiment, the present disclosure provides that R 3s1 is selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or alternatively is selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl, and 3- to 6-membered heterocyclyl, or alternatively is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl, and 3- to 6-membered heterocyclyl, or alternatively is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, and C 3~6Provided is the above compound selected from cycloalkyl, alternatively selected from H, Me and cyclopropyl, alternatively selected from H and Me, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0310] In a more specific embodiment, the present disclosure relates to R 3s2 which is selected from H, D, -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, alternatively selected from H, D, -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, alternatively selected from H, D, -L-OR a , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl, phenyl and 5- to 10-membered heteroaryl, alternatively selected from H, D, Me, CF3, CH2OCH3, cyclopropyl, [Chemical formula] selected from, alternatively C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, alternatively a C 5~7 cycloalkyl such as cyclopropyl, alternatively Et, of the above compound, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

[0311] In a more specific embodiment, the present disclosure provides the above compound having the following structural formula, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chemical formula

[0312] In the formula, each group is as defined above.

[0313] In a more specific embodiment, the present disclosure provides the above compound which is a compound of formula (II), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0314] L1 is NH or CHR x and

[0315] L2 is CR x R y and

[0316] wherein R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0317] or CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0318] or when L1 is CHR x and L2 is CR x R y the two R x groups may be bonded together to form a chemical bond or C 1~4 alkylene,

[0319] Z1 is CH or N,

[0320] R1 is H, D, halogen, CN, OR a , SR a , NR b R c , SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl or 5- to 7-membered heterocyclyl, which are optionally substituted with one, two or three R 1s s,

[0321] m = 0, 1, 2 or 3, alternatively m = 0,

[0322] X1 is a C atom or an N atom, which are optionally substituted with R 2b s,

[0323] X2 is a C atom or an N atom, which are optionally substituted with R 2c s,

[0324] X3 is a C atom or an N atom, which are optionally substituted with R 2d s,

[0325] R 2a is selected from H, D, OR a and NR b R c s,

[0326] R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl,

[0327] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0328] Or, X1, X2 and their substituents together form a C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with one, two or three R 2s and

[0329] R 2d is H, D, halogen, CN, NO2, OR a , NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0330] R 1s is H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl and 5- to 7-membered heterocyclyl,

[0331] R 2s is H, D, halogen, =O, C 1~6 alkyl and C 1~6 haloalkyl,

[0332] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl,

[0333] R 3s2 is H, D, -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, C6~10 Selected from aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s and are optionally substituted with

[0334] L is a chemical bond or C 1~6 alkylene, which are optionally substituted with 1, 2 or 3 R and

[0335] R and R 3s are independently selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl,

[0336] R a 、R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b 、R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0337] wherein L1, L2, R x 、R y 、Z1、R1、R 2a 、R 2b 、R 2c 、R 2d 、R 1s 、R 2s 、R 3s1 、R 3s2 、L、R、R 3s 、R a 、R b and R c each of the groups in is optionally deuterated until fully deuterated.

[0338] In a more specific embodiment, the disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0339] L1 is NH or CHR xand

[0340] L2 is CR x R y and

[0341] wherein R x and R y are, independently, H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0342] or CR x R y together form C=O, C=S or C 3~4 cycloalkylene, or

[0343] or when L1 is CHR x and L2 is CR x R y the two R x groups may be bonded to form a chemical bond or C 1~3 alkylene,

[0344] Z1 is CH or N,

[0345] R1 is selected from H, D, halogen, CN, OR a NR b R c C 1~6 alkyl, C 1~6 haloalkyl and 5-6 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with 1, 2 or 3 R 1s groups,

[0346] m = 0, 1, 2 or 3, alternatively m = 0,

[0347] X1 is a C atom or an N atom, which are optionally substituted with R 2b groups,

[0348] X2 is a C atom or an N atom, which are optionally substituted with R 2c groups,

[0349] X3 is a C atom or an N atom, which are optionally substituted with R 2d and

[0350] R 2a is NH2,

[0351] R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl,

[0352] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0353] alternatively, X1, X2 and their substituents together form a C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s groups,

[0354] R 2d is selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl,

[0355] R 1s is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl and C 1~6 haloalkyl,

[0356] R 2s is selected from H, D, =O, C 1~6 alkyl and C 1~6 haloalkyl,

[0357] R 3s1 is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl, and

[0358] R 3s2 is H, D, -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three Rs 3s , and

[0359] L is a chemical bond or C 1~3 alkylene, which are optionally substituted with one, two or three Rs, and

[0360] R and R 3s are independently selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, and

[0361] R a , R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl.

[0362] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0363] L1 is NH or CHR x , and

[0364] L2 is CR xR y is,

[0365] wherein R x and R y are independently H, D, C 1~3 alkyl or C 1~3 haloalkyl, or

[0366] or, CR x R y together form C=O or cyclopropylene, or

[0367] or, when L1 is CHR x and L2 is CR x R y the two R x groups may be joined to form a chemical bond or C 1~2 alkylene,

[0368] Z1 is CH or N,

[0369] R1 is H, D, CN, OR a C 1~6 alkyl, C 1~6 haloalkyl and 5- to 6-membered heterocyclyl, which are optionally substituted with one, two or three R 1s groups,

[0370] m = 0, 1, 2 or 3, alternatively m = 0,

[0371] X1 is a C atom or an N atom, which are optionally substituted with R 2b groups,

[0372] X2 is a C atom or an N atom, which are optionally substituted with R 2c groups,

[0373] X3 is a C atom or an N atom, which are optionally substituted with R 2d groups,

[0374] R 2ais NH2,

[0375] R 2b is selected from H, D, halogen, C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl and 4-6 membered heterocyclyl,

[0376] R 2c is selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or

[0377] alternatively, X1, X2 and their substituents together form C 5~7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s alternatively, X1, X2 and their substituents together form

Chemical formula

[0378] R 2d is selected from H and D,

[0379] R 1s is selected from H, D, halogen, C(O)OR a , C 1~6 alkyl and C 1~6 haloalkyl, alternatively halogen or C(O)OCH3,

[0380] R 2s is selected from H, D, =O and Me,

[0381] R 3s1 is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl and C 3~6 cycloalkyl,

[0382] R3s2 is H, D, -L-OR a , C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl, phenyl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s and, alternatively, R 3s2 is H, D, Me, CF3, CH2OCH3, cyclopropyl,

Chemical formula

[0383] L is a chemical bond or C 1~3 alkylene, alternatively methylene, which are optionally substituted with 1, 2 or 3 R,

[0384] R and R 3s are independently selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl,

[0385] R a 、R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl.

[0386] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0387] L1 is NH,

[0388] L2 is CR x R y and where CR x R y together form C=O or C=S,

[0389] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , P(O)(R a )2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 1s s,

[0390] m = 0, 1, 2, 3 or 4,

[0391] X1 is a C atom, which is substituted with R 2b s,

[0392] X2 is a C atom or an N atom, which are optionally substituted with R 2c s,

[0393] X3 is a C atom, which is substituted with R 2d s,

[0394] R 2a is H, D, CN, OR a , NR b R c , C(O)ORa and C(O)NR b R c is selected from

[0395] R 2b is H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl,

[0396] R 2c is H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0397] or, X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s 's,

[0398] R 2d is H, D, halogen, CN, NO2, OR a , NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0399] Z1 is CH,

[0400] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R's,

[0401] R1s and R 2s is independently selected from H, D, halogen, =O, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0402] R 3s1 is independently selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0403] R 3s2 is -L-OR a , -L-NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R 3s s,

[0404] R and R 3s are independently selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl,

[0405] R a , R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or Rb , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0406] wherein each of the above groups is optionally deuterated until fully deuterated.

[0407] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0408] L1 is NH,

[0409] L2 is CR x R y and wherein CR x R y together form C=O or C=S,

[0410] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10Aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2, or 3 R 1s and m = 0, 1, 2, 3, or 4,

[0411] wherein X1 is a C atom which is substituted with R

[0412] and X2 is a C atom or an N atom, which are optionally substituted with R 2b and X3 is a C atom which is substituted with R

[0413] wherein R is selected from H, D, CN, OR 2c and NR

[0414] wherein R is selected from H, D, halogen, C(O)OR 2d and C(O)NR

[0415] wherein R is selected from H, D, halogen, C 2a alkyl and C a haloalkyl, b wherein R is selected from H, D, halogen, C c alkyl and C

[0416] haloalkyl, or X1, X2 and their substituents together form C 2b cycloalkyl, 5- to 10-membered heterocyclyl, C a aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2, or 3 R b wherein R is selected from H, D, halogen, CN, NO2, OR c and NR 1~6 R 1~6 R

[0417] R 2c wherein R is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0418] or, X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2, or 3 R 2s and m = 0, 1, 2, 3, or 4,

[0419] wherein R is selected from H, D, halogen, CN, NO2, OR 2d and NRa 、 NR b R c 、 C 1~6 alkyl and C 1~6 selected from haloalkyl,

[0420] Z1 is CH,

[0421] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene,

[0422] R 1s and R 2s are independently H, D, halogen, =O, C(O)OR a 、 C(O)NR b R c 、 C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 selected from alkynyl,

[0423] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 selected from alkynyl,

[0424] R 3s2 is -L-OR a 、 -L-NR b R c 、 C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 3s s,

[0425] R 3s are independently H, D, halogen, C 1~6 alkyl and C 1~6Selected from haloalkyl,

[0426] R a 、R b and R c are independently H, D, C 1~6 alkyl and C 1~6 selected from haloalkyl, or R b 、R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0427] wherein each of the above groups is optionally deuterated until fully deuterated.

[0428] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0429] L1 is NH,

[0430] L2 is CR x R y where CR x R y together form C=O or C=S,

[0431] R1 is H, D, halogen, CN, NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、SF5、C(O)R a 、C(O)OR a 、C(O)NR b R c 、S(O)R a 、S(O)2R a 、S(O)OR a 、S(O)2OR a 、S(O)NR b R c 、S(O)2NR b R c 、C 1~6 alkyl, C 1~6Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -L-C 3~7 Cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 Selected from aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 1s and

[0432] m = 0, 1, 2, 3 or 4,

[0433] X1 is a C atom, which is substituted with R 2b and

[0434] X2 is a C atom or an N atom, which are optionally substituted with R 2c and

[0435] X3 is a C atom, which is substituted with R 2d and

[0436] R 2a is selected from H, D, CN, OR a and NR b R c and

[0437] R 2b is selected from H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl and C 1~6 haloalkyl,

[0438] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl or

[0439] or, X1, X2 and their substituents together form a C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10Form an aryl or 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three Rs 2s and are optionally substituted with

[0440] R 2d is selected from H, D, halogen, CN, NO2, C 1~6 alkyl and C 1~6 haloalkyl,

[0441] Z1 is CH,

[0442] L is a chemical bond or C 1~6 alkylene,

[0443] R 1s and R 2s are independently selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 alkynyl,

[0444] R 3s1 is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl,

[0445] R 3s2 is -L-OR a -L-NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three Rs 3s and are optionally substituted with

[0446] R 3s are independently selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl,

[0447] Ra , R b and R c are each independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0448] wherein each of the above groups is optionally deuterated until fully deuterated.

[0449] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0450] L1 is NH,

[0451] L2 is CR x R y where CR x R y together form C=O or C=S,

[0452] R1 is H, D, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , P(O)(R a )2, C 1~6 alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -L-C 3~7 Selected from cycloalkyl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 1s and

[0453] m = 0, 1, 2, 3 or 4,

[0454] X1 is a C atom, which is substituted with R 2b and

[0455] X2 is a C atom, which is substituted with R 2c and

[0456] X3 is a C atom, which is substituted with R 2d and

[0457] R 2a is selected from H, D, CN, OR a , NR b R c , C(O)OR a and C(O)NR b R c and

[0458] R 2b is selected from C(O)OR a , C(O)NR b R c , C 1~6 alkyl and C 1~6 haloalkyl,

[0459] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0460] or, X1, X2 and their substituents together form a 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2sis arbitrarily substituted,

[0461] R 2d is H, D, halogen, CN, NO2, OR a 、NR b R c 、C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, and is selected from

[0462] Z1 is CH,

[0463] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, and these are arbitrarily substituted with 1, 2 or 3 R's,

[0464] R 1s and R 2s are independently selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, and is selected from

[0465] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, and is selected from

[0466] R 3s2 is -L-OR a 、-L-NR b R c 、C 1~6Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl, selected from these, and these are optionally substituted with 1, 2 or 3 R 3s and

[0467] R and R 3s are, independently, H, D, C 1~6 alkyl and C 1~6 haloalkyl, selected from

[0468] R a , R b and R c are, independently, H, D, C 1~6 alkyl and C 1~6 haloalkyl, selected from, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl

[0469] wherein each of the above groups is optionally deuterated until fully deuterated.

[0470] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0471] L1 is NH

[0472] L2 is CR x R y and where CR x R y together form C=O or C=S

[0473] R1 is H, D, -L-OR a , -L-SR a , -L-NR b R c , C(O)R a , C(O)ORa , C(O)NR b R c , S(O)R a , S(O)2R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , C 1~6 , alkyl, C 1~6 , haloalkyl, C 2~6 , alkenyl, C 2~6 , alkynyl, -L-C 3~7 , cycloalkyl, and -L-5- to 10-membered heteroaryl, selected from these, and these are optionally substituted with 1, 2, or 3 R 1s and are optionally substituted with

[0474] m = 0, 1, 2, 3, or 4,

[0475] X1 is a C atom, which is substituted with R 2b and is optionally substituted with

[0476] X2 is a C atom, which is substituted with R 2c and is optionally substituted with

[0477] X3 is a C atom, which is substituted with R 2d and is optionally substituted with

[0478] R 2a is selected from H, D, CN, OR a and NR b R c and is selected from

[0479] R 2b is C(O)OR a , C(O)NR b R c , C 1~6 , alkyl and C 1~6 is selected from haloalkyl,

[0480] R 2c is H, D, halogen, C 1~6 , alkyl and C1~6 selected from haloalkyl,

[0481] or X1, X2 and their substituents together form a 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s groups,

[0482] R 2d is selected from H, D, halogen and CN,

[0483] Z1 is CH,

[0484] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene,

[0485] R 1s and R 2s are independently selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 alkynyl,

[0486] R 3s1 is selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 alkynyl,

[0487] R 3s2 is -L-OR a or -L-NR b R c and is selected from C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0488] Ra , R b and R c are each independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0489] wherein each of the above groups is optionally deuterated until fully deuterated.

[0490] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0491] L1 is NH,

[0492] L2 is CR x R y where CR x R y together form C=O or C=S,

[0493] R1 is H, D, OR a , SR a , NR b R c , C(O)R a , S(O)R a , S(O)2R a , C 1~6 alkyl, C 1~6 haloalkyl, C 3~7 cycloalkyl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 1s groups,

[0494] m = 0, 1, 2, 3 or 4,

[0495] X1 is a C atom, which is substituted with R 2b groups,

[0496] X2 is a C atom, which is substituted with R 2c and

[0497] X3 is a C atom, which is substituted with R 2d and

[0498] R 2a is selected from OR a and NR b R c and

[0499] R 2b is selected from C(O)OR a C(O)NR b R c C 1~6 alkyl and C 1~6 haloalkyl

[0500] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0501] alternatively, X1, X2 and their substituents together form a 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R 2s and

[0502] R 2d is selected from H, D, halogen and CN

[0503] Z1 is CH

[0504] L is a chemical bond or C 1~6 alkylene

[0505] R 1s and R 2s are independently selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6Selected from alkynyl,

[0506] R 3s1 is H, D, halogen, C 1~4 alkyl and C 1~4 selected from haloalkyl,

[0507] R 3s2 is -L-OR a -L-NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 selected from aryl and 5- to 10-membered heteroaryl,

[0508] R a R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 selected from haloalkyl, or R b R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0509] wherein each of the above groups is optionally deuterated until fully deuterated.

[0510] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0511] L1 is NH,

[0512] L2 is CR x R y wherein CR x R y together form C=O or C=S,

[0513] R1 is H, D, ORa , SR a , NR b R c , C(O)R a , S(O)R a , S(O)2R a , C 1~6 alkyl, C 1~6 haloalkyl, C 3~7 selected from cycloalkyl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 1s and,

[0514] m = 0, 1, 2, 3 or 4,

[0515] X1 is a C atom, which is substituted with R 2b and,

[0516] X2 is a C atom, which is substituted with R 2c and,

[0517] X3 is a C atom, which is substituted with R 2d and,

[0518] R 2a is selected from OR a and NR b R c and,

[0519] R 2b is selected from C(O)OR a , C(O)NR b R c and C 1~6 alkyl,

[0520] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0521] or, X1, X2 and their substituents together form a 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R2s is optionally replaced with,

[0522] R 2d is selected from H, D, halogen and CN,

[0523] Z1 is CH,

[0524] L is a chemical bond or C 1~6 alkylene,

[0525] R 1s and R 2s are independently selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 alkynyl,

[0526] R 3s1 is Me,

[0527] R 3s2 is Et,

[0528] R a , R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0529] wherein each of the above groups is optionally deuterated until fully deuterated.

[0530] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0531] L1 is NH,

[0532] L2 is CR x R y and here, CR x R y together form C=O or C=S,

[0533] R1 is H, D, OR a , SR a , NR b R c , C(O)R a , S(O)R a , S(O)2R a , C 1~6 alkyl, C 1~6 haloalkyl, C 3~7 cycloalkyl and 5- to 6-membered heteroaryl, selected from which are optionally substituted with 1, 2 or 3 Rs 1s and,

[0534] m = 0, 1, 2, 3 or 4,

[0535] X3 is a C atom which is substituted with R 2d and,

[0536] R 2a is OR a and NR b R c selected from,

[0537] X1, X2 and their substituents together form a 5- to 6-membered heteroaryl which is optionally substituted with 1, 2 or 3 Rs 2s and,

[0538] R 2d is selected from H, D, halogen and CN,

[0539] Z1 is CH,

[0540] R 1s and R 2s are independently H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6Alkenyl and C 2~6 selected from alkynyl,

[0541] R 3s1 is selected from H and D,

[0542] R 3s2 is C 3~6 selected from cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl,

[0543] R a , R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0544] wherein each of the above groups is optionally deuterated until fully deuterated.

[0545] In a more specific embodiment, the present disclosure provides a compound of formula (II) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0546] L1 is NH,

[0547] L2 is CR x R y where CR x R y together form C=O or C=S,

[0548] R1 is H, D, OR a , SR a , NR b R c , C(O)R a , S(O)R a , S(O)2R a , C 1~6 alkyl, C1~6 Haloalkyl, C 3~7 Selected from cycloalkyl and 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 Rs 1s and

[0549] m = 0, 1, 2, 3 or 4,

[0550] X3 is a C atom, which is substituted with R 2d and

[0551] R 2a is selected from OR a and NR b R c and

[0552] X1, X2 and their substituents together form a 5- to 6-membered heteroaryl, which is optionally substituted with 1, 2 or 3 Rs 2s and

[0553] R 2d is selected from H, D, halogen and CN,

[0554] Z1 is CH,

[0555] L is a chemical bond or C 1~6 alkylene,

[0556] R 1s and R 2s are independently selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 alkynyl,

[0557] R 3s1 is selected from C 1~4 alkyl and C 1~4 haloalkyl,

[0558] R 3s2 is -L-OR a or -L-NR bR c 、 C 1~6 alkyl and C 1~6 haloalkyl, selected from

[0559] R a 、 R b and R c are independently H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b 、 R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl

[0560] wherein each of the above groups is optionally deuterated until fully deuterated

[0561] In a more specific embodiment, the present disclosure provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0562] L1 is NH or CHR x and

[0563] L2 is CR x R y and

[0564] wherein R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0565] or, CR x R y together form C=O, C=S or C 3~6 cycloalkylene, or

[0566] or, when L1 is CHR x and L2 is CR x R y in which case the two R xThe base is bonded to form a chemical bond or C 1~4 It may form an alkylene,

[0567] Z1 is CH or N,

[0568] R1 is selected from H, D, halogen, CN, OR a , SR a , NR b R c , SF5, C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl and 5- to 7-membered heterocyclyl, which are optionally substituted with 1, 2 or 3 R 1s s,

[0569] m = 0, 1, 2 or 3, alternatively m = 0,

[0570] X1 is a C atom or an N atom, which are optionally substituted with R 2b s,

[0571] X2 is a C atom or an N atom, which are optionally substituted with R 2c s,

[0572] X3 is a C atom or an N atom, which are optionally substituted with R 2d s,

[0573] R 2b is selected from H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl,

[0574] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0575] or X1, X2, and their substituents together form a C 5~7 cycloalkyl, 5- to 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2, or 3 R 2s and

[0576] R 2d is selected from H and D,

[0577] R 1s is selected from H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 5~7 cycloalkyl, and 5- to 7-membered heterocyclyl,

[0578] R 2s is selected from H, D, halogen, =O, C 1~6 alkyl, and C 1~6 haloalkyl,

[0579] R 3s1 is selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl, and 3- to 6-membered heterocyclyl,

[0580] R 3s is selected from H, D, halogen, C 1~6 alkyl, and C 1~6 haloalkyl,

[0581] p = 0, 1, 2, or 3, or alternatively p = 0,

[0582] R a R b and R c are independently selected from H, D, C 1~6 alkyl, and C 1~6 haloalkyl, or R b Rc and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0583] the above L1, L2, R x , R y , Z1, R1, R 2b , R 2c , R 1s , R 2s , R 3s1 , R 3s , R a , R b and R c each of the groups in is optionally deuterated until fully deuterated.

[0584] In a more specific embodiment, the present disclosure provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0585] L1 is NH or CHR x ,

[0586] L2 is CR x R y ,

[0587] wherein R x and R y are independently H, D, C 1~6 alkyl or C 1~6 haloalkyl, or

[0588] or, CR x R y together form C=O, C=S or C 3~4 cycloalkylene, or

[0589] or, when L1 is CHR x and L2 is CR x R y the two R x groups may be joined to form a chemical bond or C 1~3 alkylene,

[0590] Z1 is CH or N,

[0591] R1 is H, D, halogen, CN, OR a , NR b R c , C 1~6 alkyl, C 1~6 haloalkyl and 5- to 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with 1, 2 or 3 R 1s s,

[0592] m = 0, 1, 2 or 3, alternatively m = 0,

[0593] X1 is a C atom or an N atom, which are optionally substituted with R 2b s,

[0594] X2 is a C atom or an N atom, which are optionally substituted with R 2c s,

[0595] X3 is a C atom or an N atom, which are optionally substituted with R 2d s,

[0596] R 2b is H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3- to 6-membered heterocyclyl,

[0597] R 2c is H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0598] or, X1, X2 and their substituents together form a C 5~7forming a cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted with one, two or three R 2s and are optionally substituted with

[0599] R 2d is selected from H and D,

[0600] R 1s is selected from H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl and C 1~6 haloalkyl;

[0601] R 2s is selected from H, D, =O, C 1~6 alkyl and C 1~6 haloalkyl;

[0602] R 3s1 is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl and 3-6 membered heterocyclyl;

[0603] R 3s is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl;

[0604] p = 0, 1, 2 or 3, alternatively p = 0,

[0605] R a R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl.

[0606] In a more specific embodiment, the present disclosure provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0607] L1 is NH or CHR x and

[0608] L2 is CR x R y and

[0609] wherein R x and R y are independently H, D, C 1~3 alkyl or C 1~3 haloalkyl, or

[0610] or CR x R y together form C=O or cyclopropylene, or

[0611] or when L1 is CHR x and L2 is CR x R y then the two R x groups may be joined to form a chemical bond or C 1~2 alkylene,

[0612] Z1 is CH or N,

[0613] R1 is selected from H, D, CN, OR a , C 1~6 alkyl, C 1~6 haloalkyl and 5- to 6-membered heterocyclyl, which are optionally substituted with one, two or three R 1s groups,

[0614] m = 0, 1, 2 or 3, alternatively m = 0,

[0615] X1 is a C atom or an N atom, which are optionally substituted with R 2b groups,

[0616] X2 is a C atom or an N atom, which is optionally substituted with R 2c and

[0617] X3 is a C atom or an N atom, which is optionally substituted with R 2d and

[0618] R 2b is selected from H, D, halogen, C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl and 4-6 membered heterocyclyl,

[0619] R 2c is selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or

[0620] alternatively, X1, X2 and their substituents together form a C 5~7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s and

[0621] R 2d is selected from H and D,

[0622] R 1s is selected from H, D, halogen, C(O)OR a , C 1~6 alkyl and C 1~6 haloalkyl, alternatively, halogen or C(O)OCH3,

[0623] R 2s is selected from H, D, =O and Me,

[0624] R 3s1 is selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl and C 3~6Selected from cycloalkyl,

[0625] R 3s is H, D, halogen, C 1~6 alkyl and C 1~6 selected from haloalkyl,

[0626] p = 0, 1, 2 or 3, alternatively p = 0,

[0627] R a 、R b and R c are independently H, D, C 1~6 alkyl and C 1~6 selected from haloalkyl.

[0628] In a more specific embodiment, the present disclosure provides a compound of formula (III) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0629] L1-L2 is,

Chemical formula

[0630] Z1 is CH or N,

[0631] R1 is CF3, CN, OCF3, OCH2CH3,

Chemical formula

[0632] m = 0,

[0633] X1 is a C atom or an N atom, which are optionally substituted with R 2b and,

[0634] X2 is a C atom or an N atom, which are optionally substituted with R 2c and,

[0635] X3 is a C atom or an N atom, which is optionally substituted with R 2d and

[0636] R 2b is H, F, Cl, Br, Me, CH2CH3, C(O)NH2 or

Chemical formula

[0637] R 2c is H or Me, or

[0638] alternatively, X1, X2 and their substituents together form

Chemical formula

[0639] R 2d is H,

[0640] R 3s1 is H, Me or cyclopropyl,

[0641] R 3s is H,

[0642] p = 0.

[0643] In a more specific embodiment, the present disclosure provides a compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b) above, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein

[0644] R1 is H, D, halogen, CN, NO2, -L-OR a , -L-SR a , -L-NR b R c , SF5, C(O)Ra 、 C(O)OR a 、 C(O)NR b R c 、 OC(O)R a 、 NR b C(O)R c 、 S(O)R a 、 S(O)2R a 、 S(O)OR a 、 S(O)2OR a 、 S(O)NR b R c 、 S(O)2NR b R c 、 P(O)(R a )2、 C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, -L-C 3~7 cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C 6~10 aryl and -L-5- to 10-membered heteroaryl, selected from, these are optionally substituted with 1, 2 or 3 R 1s and,

[0645] m = 0, 1 or 2,

[0646] R4 is selected from H and D,

[0647] X1 is a C atom, which is substituted with R 2b and,

[0648] X2 is a C atom or an N atom, which are optionally substituted with R 2c and,

[0649] X3 is a C atom, which is substituted with R 2d and,

[0650] R 2a is H, D, CN, OR a 、 NR b R c 、 C(O)OR a and C(O)NR b R cselected from

[0651] R 2b is H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl and 3- to 10-membered heterocyclyl,

[0652] R 2c is H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0653] or X1, X2 and their substituents together form C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s s,

[0654] R 2d is H, D, halogen, CN, NO2, OR a NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0655] Z1 is CH,

[0656] Z2 is CR1 or N,

[0657] Z3 is CR1 or N,

[0658] when Z2 is CR1, R1 and R4 are joined to form -(CH2) q1 -X-(CH2) q2-(wherein X is O, S, NH or CH2, q1 = 0, 1 or 2, and q2 = 1, 2 or 3) is formed,

[0659] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R's,

[0660] R 1s and R 2s are independently H, D, halogen, CN, =O, OR a , NR b R c , C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R 1s and the atoms to which they are attached together form C 3~10 cycloalkyl or 3- to 10-membered heterocyclyl, alternatively, R 1s and R 2s are independently H, D, halogen, CN, =O, C(O)OR a , C(O)NR b R c , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, and are selected from

[0661] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 Selected from aryl and 5- to 10-membered heteroaryl,

[0662] R 3s2 is H, D, -L-OR a , -L-NR b R c , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 Aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three Rs 3s and,

[0663] R and R 3s are independently selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl,

[0664] R a , R b and R c are independently selected from H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl,

[0665] wherein each of the above groups is optionally deuterated until fully deuterated.

[0666] In a more specific embodiment, the present disclosure provides a compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0667] R1 is H, D, halogen, CN, NO2, OR a , SR a , NR b R c , SF5, C(O)R a , C(O)OR a , C(O)NR b R c , OC(O)R a , NR b C(O)R c , S(O)R a , S(O)2R a , S(O)OR a , S(O)2OR a , S(O)NR b R c , S(O)2NR b R c , P(O)(R a )2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 1s s,

[0668] m = 0, 1 or 2,

[0669] R4 is selected from H and D,

[0670] X1 is a C atom, which is substituted with R 2b s,

[0671] X2 is a C atom or an N atom, which are R2c is arbitrarily substituted with

[0672] X3 is a C atom, which is R 2d substituted with

[0673] R 2a is H, D, CN, OR a and NR b R c selected from

[0674] R 2b is H, D, halogen, C(O)OR a , C(O)NR b R c , C 1~6 alkyl and C 1~6 haloalkyl selected from

[0675] R 2c is H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl selected from, or

[0676] or, X1, X2 and their substituents together form C 5~6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R 2s

[0677] R 2d is H, D, halogen, CN, NO2, OR a , NR b R c , C 1~6 alkyl and C 1~6 haloalkyl selected from

[0678] Z1 is CH,

[0679] Z2 is CR1, and R1 and R4 are bonded to form -(CH2) q1 -X-(CH2) q2 ​-(wherein X is O, S, NH or CH2, q1 = 0 or 1, and q2 = 1 or 2) is formed,

[0680] Z3 is CR1 or N,

[0681] L is a chemical bond, C 1~6 alkylene, C 2~6 alkenylene or C 2~6 alkynylene, which are optionally substituted with 1, 2 or 3 R's,

[0682] R 1s and R 2s are independently H, D, halogen, =O, C(O)OR a C(O)NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0683] R 3s1 is H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl,

[0684] R 3s2 is H, D, -L-OR a -L-NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R's3s is optionally substituted with,

[0685] R and R 3s are, independently, H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, selected from,

[0686] R a , R b and R c are, independently, H, D, C 1~6 alkyl, C 1~6 haloalkyl, C 3~10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or R b , R c and the atom to which they are attached together form a 5- to 10-membered heterocyclyl,

[0687] wherein each of the above groups is optionally deuterated until fully deuterated.

[0688] In a more specific embodiment, the disclosure provides a compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,

[0689] R1 is H, D, halogen, CN, NO2, OR a , SR a , NR b R c , SF5, C(O)R a , S(O)R a , S(O)2R a , C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 4~6Selected from cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, which are optionally substituted with one, two or three R 1s and

[0690] m = 0, 1 or 2,

[0691] R4 is selected from H and D,

[0692] X1 is a C atom, which is substituted with R 2b and

[0693] X2 is a C atom or an N atom, which are optionally substituted with R 2c and

[0694] X3 is a C atom, which is substituted with R 2d and

[0695] R 2a is selected from OR a and NR b R c and

[0696] R 2b is selected from H, D, halogen, C(O)OR a C(O)NR b R c C 1~6 alkyl and C 1~6 haloalkyl,

[0697] R 2c is selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, or

[0698] or, X1, X2 and their substituents together form a C 5~6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with one, two or three R 2s and

[0699] R 2d is selected from H, D, halogen, CN, NO2, C 1~6 alkyl and C 1~6 haloalkyl,

[0700] Z1 is CH,

[0701] Z2 is CR1, and R1 and R4 are joined to form -(CH2) q1 -X-(CH2) q2 -(wherein X is O, S or NH, q1 = 0 or 1, and q2 = 1 or 2),

[0702] Z3 is CR1 or N,

[0703] L is a chemical bond or C 1~6 alkylene,

[0704] R 1s and R 2s are independently selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 alkynyl,

[0705] R 3s1 is selected from H, D, halogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl and C 2~6 alkynyl,

[0706] R 3s2 is selected from H, D, -L-OR a ,-L-NR b R c C 1~6 alkyl, C 1~6 haloalkyl, C 3~6 cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, which are optionally substituted with one, two or three R 3s s,

[0707] R 3s is independently selected from H, D, halogen, C 1~6 alkyl and C 1~6 haloalkyl, provided that

[0708] R a , R b and R c are independently selected from H, D, C 1~6 alkyl and C 1~6 haloalkyl, or R b , R c and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, provided that

[0709] each of the above groups is optionally deuterated until fully deuterated.

[0710] In the most specific embodiments, the disclosure provides a compound of formula (X) selected from the following, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0711] In the most specific embodiments, the disclosure provides a compound of formula (X) selected from the following, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0712] In the most specific embodiments, the present disclosure provides a compound of formula (X) selected from the following, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0713] In the most specific embodiments, the present disclosure provides a compound of formula (X) selected from the following, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry]

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0714] The compounds of the present disclosure may contain one or more asymmetric centers and may exist, for example, in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of the present disclosure may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or in the form of mixtures of stereoisomers such as racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, such as chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or alternatively, the alternative isomers can be prepared by asymmetric synthesis.

[0715] The compounds of the present disclosure may exist in tautomeric forms. Tautomers are functional group isomers generated by the rapid movement of atoms within a molecule between two positions. Tautomers are a special type of functional group isomers. A pair of tautomers can be converted into each other, but usually the relatively stable isomer is the main form of existence. The most important examples are enol and keto tautomers.

[0716] Those skilled in the art will understand that organic compounds can form complexes with the solvents in which their reactions or precipitation or crystallization occur. These complexes are known as "solvates". When the solvent is water, the complex is known as a "hydrate". The present disclosure encompasses all solvates of the compounds of the present disclosure.

[0717] The term "solvate" generally refers to the form of a compound or its salt that is combined with a solvent through a solvolysis reaction. This physical bond may include hydrogen bonds. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described in this specification can be prepared, for example, in crystalline form and can form solvates. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0718] The term "hydrate" refers to a compound that is combined with water. Generally, the number of water molecules contained in a hydrate of a compound is in a certain ratio to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound can form multiple types of hydrates, such as monohydrates (x = 1), lower hydrates (x is a number greater than 0 and less than 1, for example, hemihydrates (R·0.5H2O)), and polyhydrates (x is a number greater than 1, for example, dihydrates (R·2H2O) and hexahydrates (R·6H2O)).

[0719] The compounds of the present disclosure may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present disclosure may exist in one or more crystalline forms. Thus, the present disclosure includes within its scope all amorphous or crystalline forms of the compounds of the present disclosure. The term "polymorph" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0720] The present disclosure also includes compounds labeled with isotopes (isotopic variants) equivalent to those described in formula (I), but in which one or more atoms are replaced by atoms with a different mass or mass number than atoms common in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as: 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 Compounds of the present disclosure, prodrugs thereof, 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 disclosure. Certain isotopically labeled compounds of the present disclosure, for example, those that contain radioactive isotopes (e.g., 3 H and 14 C) can be used to measure drug and / or substrate distribution within tissues. 3 H isotopes tritium and 14 The C isotope carbon-14 is a further alternative due to its ease of preparation and detection.2 When replaced with a heavier isotope such as deuterium which is H, a therapeutic benefit due to higher metabolic stability such as an extended half-life in vivo or a reduced required dose may be obtained, and thus may be an option in some cases. The isotope-labeled compounds of formula (A) of the present disclosure and their prodrugs can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents in the following schemes and / or the procedures disclosed in the examples and preparation examples.

[0721] Furthermore, prodrugs are also included within the context of the present disclosure. As used herein, the term "prodrug" refers to a compound that is converted in vivo to an active form having a medical effect, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2) 115 - 130, each of which is incorporated herein by reference.

[0722] A prodrug is any covalent compound of the present disclosure that releases the parent compound in vivo when the prodrug is administered to a patient. Prodrugs are typically prepared by modifying a functional group such that the modification can be cleaved by routine manipulations or can decompose in vivo to generate the parent compound. Examples of prodrugs include, but are not limited to, compounds of the present disclosure in which a hydroxyl, amino, or sulfhydryl group is attached to any group that is cleaved when administered to a patient to form a hydroxyl, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate / acetamide, formate / formamide, and benzoate / benzamide derivatives of the hydroxyl, sulfhydryl, or amino functional groups of the compounds of formula (A). In the case of a carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, etc. can be employed. The ester itself may be active per se and / or may be hydrolyzable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include groups that can be easily decomposed in the human body to release the parent acid or its salt.

[0723] The present disclosure also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (A) or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. All of these forms belong to the present disclosure.

[0724] Pharmaceutical Compositions and Kits

[0725] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present disclosure.

[0726] A pharmaceutically acceptable excipient for use in the present disclosure refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present disclosure include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin, but are not limited thereto.

[0727] Suitable formulations for administering the compounds of the present disclosure will be apparent to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (especially injection solutions (subcutaneous, intravenous, intramuscular) and infusions (injections)), elixirs, syrups, cachets, emulsions, inhalants and dispersible powders. The content of one or more pharmaceutically active compounds should be in the range of 0.1 to 90% by weight, alternatively 0.5 to 50% by weight, of the total composition, i.e., an amount sufficient to achieve the dosage ranges specified below. If necessary, a specific dosage can be administered several times a day.

[0728] The present disclosure also includes kits (e.g., pharmaceutical packs). The kits provided may include the compounds disclosed herein, other therapeutic agents, and first and second containers (e.g., vials, ampules, bottles, syringes, and / or dispersible packages or other suitable containers) containing the compounds or other therapeutic agents disclosed herein. In some embodiments, the kits provided may optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compounds and / or other therapeutic agents disclosed herein. In some embodiments, the compounds disclosed herein prepared in the first container and the other therapeutic agents prepared in the second container are combined to form a unit dosage form.

[0729] Administration

[0730] The pharmaceutical compositions provided by the present disclosure can be administered by various routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant, or other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intra-sternal administration, intraventricular administration, intralesional administration, and intracranial injection or infusion techniques.

[0731] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of relevant circumstances including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0732] When used to prevent the disorders disclosed herein, the compounds provided herein are typically administered at the dosage levels described above to subjects at risk of developing the condition, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as particularly prone to developing the condition.

[0733] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to the administration of a compound or its pharmaceutical composition over an extended period of time, e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continued indefinitely, e.g., over the lifetime of the subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic range.

[0734] The pharmaceutical compositions of the disclosure can further be delivered using a variety of administration methods. For example, in certain 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 desired systemic level of the active ingredient in the body. For example, an intramuscular or subcutaneous bolus dose allows for slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV infusion) allows for a much faster delivery that rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, e.g., by IV infusion, to maintain a steady-state concentration of the active ingredient in the subject's body. Further, in still other embodiments, the pharmaceutical composition may be administered first as a bolus dose followed by a continuous infusion.

[0735] Compositions for oral administration can be in the form of a bulk liquid solution or suspension, or a bulk powder. However, more commonly, the compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or alternatively from about 1 to about 40% by weight), and the remainder consists of various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0736] For oral administration, oral administration 1 to 5 times a day, particularly 2 to 4 times a day, typically 3 times a day is a typical regimen. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of the compounds provided herein, with alternative doses providing from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg.

[0737] Transdermal dosages are generally selected in amounts in the range of about 0.01 to about 20% by weight, alternatively about 0.1 to about 20% by weight, alternatively about 0.1 to about 10% by weight, and further alternatively about 0.5 to about 15% by weight, so as to provide blood levels similar to or lower than those generally achieved using injection dosages.

[0738] Injection dosage levels are all in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A bolus of from about 0.1 mg / kg to about 10 mg / kg or more can also be pre-administered to achieve sufficient steady-state levels. The maximum total dose should not exceed about 2 g / day for a human patient weighing 40 kg to 80 kg.

[0739] Liquid forms suitable for oral administration may contain a suitable aqueous or non-aqueous vehicle, including buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may contain, for example, the following components or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, primogel or corn starch, lubricants such as magnesium stearate, flow promoters such as colloidal silicon dioxide, sweetening agents such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate or orange flavoring.

[0740] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable excipients known in the art. As described above, the active compounds in such compositions are typically minor components, often about 0.05 - 10% by weight, with the remainder being injectable excipients and the like.

[0741] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with either a paraffin-based ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain the active ingredient or additional components to enhance the stable skin penetration of the formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0742] The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be achieved using a patch of either the reservoir or porous membrane type, or of the solid matrix type.

[0743] The above-described ingredients for an orally administrable composition, an injectable composition, or a topically administrable composition are merely representative. Other materials as well as processing techniques, etc. are described in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is hereby incorporated by reference into this specification.

[0744] The compounds of the present disclosure can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0745] The present disclosure also relates to pharmaceutically acceptable formulations of the compounds of the present disclosure. 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 consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, and optionally contain on the linked sugar moiety one or more substituents such as, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin also known as Captisol. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the formulation contains hexapropyl-β-cyclodextrin (e.g., 10 - 50% in water).

[0746] Indications

[0747] In the case of MTAP-deficient tumors, the development of MTA synergistic PRMT5 inhibitors can provide therapeutic benefits to a large number of cancer patients. The compounds of the present disclosure exert a therapeutic effect by negatively regulating MTA-bound PRMT5 activity in tumor cells, particularly MTAP-deficient cells or various MTAP-related tumor cells.

[0748] In some embodiments, the MTA synergistic PRMT5 inhibitors of the present disclosure can treat various cancers including, but not limited to, malignant peripheral nerve sheath tumors, mesotheliomas, glioblastomas, pancreatic cancers, cholangiocarcinomas, prostate cancers, breast cancers, brain cancers, skin cancers, cervical cancers, bladder cancers, astrocytomas, colorectal cancers, endometrial cancers, esophageal cancers, gastric cancers, thymomas, head and neck cancers, hepatocellular carcinomas, laryngeal cancers, squamous cell carcinomas of the lung, lung adenocarcinomas, oral cancers, ovarian cancers, kidney cancers, and thyroid cancers and sarcomas.

[0749] More specifically, the compound is effective against tumors in the following organs: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma, adenocarcinoma, etc.), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Digestive tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, etc.), Stomach (cancer, lymphoma, leiomyosarcoma, etc.), Pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma, etc.), Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, etc.), Large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma, etc.); Genitourinary system: Kidney (adenocarcinoma, nephroblastoma, etc.), Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, etc.), Prostate (adenocarcinoma, sarcoma, etc.), Testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma, etc.); Liver: Liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder cancer, ampullary cancer, cholangiocarcinoma, etc.; Bone: Osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma, etc.), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor of bone; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease, etc.), Meninges (meningioma, meningiosarcoma, glioma, etc.), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor, etc.), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, etc.), Spinal cord neurofibroma, meningioma, glioma, sarcoma, etc.; Gynecology: Uterus (endometrial cancer, etc.), Cervix (cervical cancer, cervical intraepithelial neoplasia, etc.), Ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, etc.), Granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma, etc.), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, etc.), Vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma, etc.), fallopian tube cancer, etc.); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL),Useful for the treatment of follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, etc., Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), etc., skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc., adrenal gland: neuroblastoma, etc.

[0750] Combination therapy

[0751] The MTA synergistic PRMT5 inhibitor of the present disclosure can be combined with other drugs for treating cancer, and the other drugs include at least one of targeted drugs / cellular activity regulators such as CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapeutic drugs, radiotherapy, STING agonists, and immune checkpoint inhibitors / modulators.

[0752]

Example

[0753] The materials or reagents used in this specification are commercially available or prepared by synthetic methods generally known in the art.

[0754] 1. Synthesis of Example 1

Chemical formula

[0755] 1.1 Synthesis of Intermediate 1-1

[0756] A solution of 2-amino-3-methyl-5-nitropyridine (5 g) in dichloromethane (50 mL) was added with di-tert-butyl dicarbonate (18 g), triethylamine (13 g), and 4-dimethylaminopyridine (0.8 g), and the mixture was stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate (100 * 3 mL). The organic phase was washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1) to obtain white solid 1-1 (10 g, yield 82%). LC-MS: M+Na + = 376.1.

[0757] 1.2 Synthesis of Intermediate 1-2

[0758] To a solution of compound 1-1 (10 g) in methanol (100 mL) was added 10% palladium on carbon (2 g), and the mixture was stirred at room temperature for 2 hours under hydrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain pale yellow solid 1-2 (9.2 g). LC-MS: M+H + = 324.2.

[0759] 1.3 Synthesis of Intermediate 1-3

[0760] Ethyl 2-chloro-2-oxoacetate (830 mg) and triethylamine (620 mg) were added to a solution of 1-2 (2 g) in dichloromethane (20 mL) under nitrogen at 0 °C. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (10 * 3 mL). The organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 2 / 1) to obtain white solid 1-3 (2.5 g, yield 80%). LC-MS: M+H + = 424.0.

[0761] 1.4 Synthesis of Intermediate 1-4

[0762] A solution of 1-3 (3 g) dissolved in methanol (10 mL) and water (10 mL) was added with lithium hydroxide (240 mg), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and diluted by adding water (20 mL). The pH was adjusted to 6 with 1N hydrochloric acid solution, and the mixture was filtered. The filter cake was dried to obtain white solid 1-4 (1 g). LC-MS: M+H + = 396.2.

[0763] 1.5 Synthesis of Intermediate 1-5

[0764] Triethylamine (1080 mg) was added to a solution of (R)-1-(pyrimidin-2-yl)ethanamine hydrochloride (2 g) dissolved in 1,2-dichloroethane (100 mL). The mixture was stirred at room temperature for 1 hour. 5-(Trifluoromethyl)pyridine-2-carboxaldehyde (1.8 g) was added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (3.2 g) was added, and the mixture was stirred at room temperature for 1 hour. Dichloromethane (50 mL) was added, and the mixture was successively washed with a saturated aqueous solution of sodium hydrogen carbonate (50 mL), water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / methanol = 100 / 0 to 100 / 3) to obtain pale yellow oil 1-5 (1.8 g, yield 64%). LC-MS: M+H + = 283.1.

[0765] 1.6 Synthesis of Intermediate 1-6

[0766] Phosphorus oxychloride (38 mg) was added dropwise to a solution of 1-4 (50 mg) and 1-5 (36 mg) dissolved in pyridine (2 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution (10 mL) and water (20 mL) were added to the residue. The mixture was extracted with ethyl acetate (10 * 3 mL). The organic phase was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / methanol = 10 / 1) to obtain a yellow solid 1-6 (20 mg, yield 32%). LC-MS: M+H + = 660.0.

[0767] 1.7 Synthesis of Compound 1

[0768] Trifluoroacetic acid (2 mL) was added to a solution of 1-6 (20 mg) dissolved in dichloromethane (6 mL), and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: [H2O(NH3)-ACN], B%: 2% - 10%, 6 minutes) to obtain a white solid 1 (5 mg, yield 20%). LC-MS: M+H + = 460.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.52 - 10.35 (m, 1H), 8.82 - 8.73 (m, 2H), 8.14 - 7.32 (m, 6H), 5.73 - 5.60 (m, 3H), 5.20 - 4.57 (m, 2H), 2.03 - 1.96 (m, 3H), 1.66 - 1.52 (m, 3H).

[0769] 2. Synthesis of Example 2

Chemical Structure

[0770] 2.1 Synthesis of Intermediate 2-1

[0771] Di-tert-butyl dicarbonate (565 mg) was added to a solution of 4-dimethylaminopyridine (6.8 mg), triethylamine (112.9 mg) and 7-bromo-1,3-dihydrofuro[3,4-c]pyridin-4-amine (120 mg) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours. The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1 - 2 / 1) to obtain white solid 2-1 (160 mg, yield 65.6%). LC-MS: M+Na + = 437.1, 439.1.

[0772] 2.2 Synthesis of Compound 2-2

[0773] To a solution of trifluoroacetamide (71.7 mg) and 2-1 (100 mg) in dioxane (5 mL), copper(I) iodide (18.1 mg), cesium carbonate (200 mg) and trans-(1R,2R)-N,N’-dimethyl-1,2-cyclohexanediamine (110.2 mg) were added. The mixture was stirred at 110 °C for 16 hours under nitrogen and cooled to room temperature. Water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, dichloromethane / ethyl acetate = 5 / 1 - 1 / 1) to obtain white solid 2-2 (34 mg, yield 38.7%). LC-MS: M+H + = 352.0.

[0774] 2.3 Synthesis of Compound 2-3

[0775] Ethyl 2-chloro-2-oxoacetate (139.8 mg) was added to a solution of triethylamine (121.2 mg) and 2-2 (240 mg) dissolved in dichloromethane (5 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour. The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1 - 2 / 1) to obtain white solid 2-3 (230 mg, yield 74.6%). LC-MS: M+H + = 451.9.

[0776] 2.4 Synthesis of Compound 2-4

[0777] Lithium hydroxide (38.2 mg) was added to a solution of 2-3 (230 mg) dissolved in methanol (5 mL) and water (1 mL). The mixture was stirred at room temperature for 1 hour, and the pH was adjusted to 6 with 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and lyophilized to obtain white solid 2-4 (170 mg, yield 71.9%). LC-MS: M+H + = 424.2.

[0778] 2.5 Synthesis of Compound 2-5

[0779] Phosphorus oxychloride (36.2 mg) was added to a solution of 1-5 (40 mg) and 2-4 (50 mg) dissolved in pyridine (2 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (1 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 3 / 1 - 1 / 1) to obtain brown solid 2-5 (22 mg, yield 30.6%). LC-MS: M+H + = 688.2.

[0780] 2.6 Synthesis of Compound 2

[0781] Trifluoroacetic acid (0.5 mL) was added to a solution of 2-5 (22 mg) dissolved in dichloromethane (1.5 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5 um, mobile phase: ACN-H2O (0.05% NH3), B%: 5% - 10%, 20 minutes) to obtain white solid 2 (3.6 mg, yield 23.2%). LC-MS: M+H + = 488.0. 1 H NMR (400 MHz, CD3OD) δ ppm 8.69 - 8.62 (m, 2H), 8.59 (d, J = 4.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.79 - 7.63 (m, 1H), 7.52 - 7.39 (m, 1H), 7.24 -7.15 (m, 1H), 5.78 - 5.66 (m, 1H), 5.23 - 5.04 (m, 1H), 4.94 - 4.92 (m, 1H), 4.86 - 4.79 (m, 3H), 4.71 - 4.63 (m, 1H), 1.64-1.49 (m, 3H).

[0782] 3. Synthesis of Example 3

Chemical Structure

[0783] 3.1 Synthesis of Intermediate 3-1

[0784] A solution of methylamine (70.9 mg) in 1,2-dichloroethane (5 mL) was added to 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) and acetic acid (102.0 mg), and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (484.2 mg) was added, and the mixture was stirred at room temperature for 0.5 hour. Saturated sodium carbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain white solid 3-1 (150.0 mg, yield 72.0%). LC-MS m / z (ESI): 191.1 [M+H] + .

[0785] 3.2 Synthesis of Intermediate 3-2

[0786] To a solution of 1-4 (62.2 mg) and 3-1 (36.0 mg) in N,N-dimethylformamide (5 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (120.2 mg) and N,N-diisopropylethylamine (40.8 mg), and the mixture was stirred at room temperature for 5 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain black oil 3-2 (21.0 mg, yield 22.3%). LC-MS m / z (ESI): 568.0 [M+H] + .

[0787] 3.3 Synthesis of Compound 3

[0788] Trifluoroacetic acid (2 mL) was added to a solution of 3-2 (21.0 mg) dissolved in dichloromethane (2 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 10%, 20 minutes) to obtain the formate salt of 3 (2.3 mg, yield 16.9%) as a white solid. LC-MS m / z (ESI): 368.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.14 - 8.01 (m, 2H), 7.62 - 7.55 (m, 2H), 4.84 (s, 1H), 4.59 (s, 1H), 3.28 - 3.05 (m, 3H), 2.15 - 2.11 (m, 3H).

[0789] 4. Synthesis of Example 4

Chemical Structure

[0790] 4.1 Synthesis of Intermediate 4-1

[0791] 30-7 (30.0 mg), propylphosphonic anhydride (45.0 mg) and N,N-diisopropylethylamine (15.0 mg) were added to a solution of 16-1 (35.0 mg) dissolved in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 12 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL×3). The organic phase was washed with a saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 - 1 / 1) to obtain pale yellow solid 4-1 (30.0 mg, yield 65.8%). LC-MS m / z (ESI): 662.3 [M+H] + .

[0792] 4.2 Synthesis of Compound 4

[0793] Trifluoroacetic acid (0.5 mL) was added to a solution of 4-1 (30.0 mg) dissolved in dichloromethane (1 mL) under an ice bath. The mixture was stirred at room temperature for 2 hours, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (5 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150 × 19 mm, 5 μm, mobile phase: ACN-H2O (0.05% NH3), B%: 5% - 10%, 20 minutes) to obtain white solid 4 (6.40 mg, yield 30.6%). LC-MS m / z (ESI): 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (s, 1H), 8.96 - 8.91 (m, 1H), 8.29 - 8.20 (m, 1H), 7.92 -7.84 (m, 1H), 7.66 (d, J = 4Hz, 1H), 7.53 (d, J = 8Hz, 1H), 6.24 - 6.18 (m, 2H), 4.91 - 4.75 (m, 2H), 4.28 - 4.23 (m, 3H), 3.57 - 3.45 (m, 2H), 2.67 - 2.57 (m, 1H), 1.97 - 1.84 (m, 2H), 1.83 - 1.66 (m, 4H).

[0794] 5. Synthesis of Example 5

Chemical Structure

[0795] 5.1 Synthesis of Intermediate 5-1

[0796] Propylphosphonic anhydride (260.0 mg) and N,N-diisopropylethylamine (84.1 mg) were added to a solution of 25-5 (100.0 mg) and 8-1 (77.0 mg) dissolved in N,N-dimethylformamide (3 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour, and saturated ammonium chloride solution (10 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5um, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 60%, 20 minutes) to obtain white solid 5-1 (20.8 mg, yield 10.8%). LC-MS m / z (ESI): 454.0 [M+H] + .

[0797] 5.2 Synthesis of Compound 5

[0798] Compound 5-1 (20.8 mg) was purified by SFC (column: CHIRALPAK AD-H 250×20 mm, 5um, mobile phase: 40% IPA (0.2% NH4OH)) to obtain white solid 5-P1 (5.8 mg, yield 36.8%). LC-MS m / z (ESI): 454.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.04 - 10.79 (m, 1H), 8.92 - 8.83 (m, 1H), 8.58 - 8.49 (m, 1H), 8.40 - 8.37 (m, 1H), 8.24 - 8.14 (m, 1H), 7.78 - 7.69 (m, 2H), 7.59 - 7.57 (m, 1H), 4.75 - 4.58 (m, 2H), 3.99 - 3.92 (m, 4H), 1.67 - 1.43 (m, 2H), 1.19 - 1.03 (m, 3H), 0.85 - 0.78 (m, 3H);

[0799] A white solid 5-P2 (4.5 mg, yield 42.1%) was obtained. LC-MS m / z (ESI): 454.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.04 - 10.80 (m, 1H), 8.93 - 8.83 (m, 1H), 8.58 - 8.49 (m, 1H), 8.40 - 8.15 (m, 2H), 7.79 - 7.57 (m, 3H), 4.75 - 4.57 (m, 2H), 4.01 - 3.92 (m, 4H), 1.68 - 1.45 (m, 2H), 1.19 - 1.04 (m, 3H), 0.84 - 0.78 (m, 3H).

[0800] 6. Synthesis of Example 6

Chemical Structure

[0801] 6.1 Synthesis of Intermediate 6-1

[0802] To a solution of compound 2-amino-5-bromo-3-methylpyridine (5.0 g) dissolved in acetic acid (40 mL), acetic anhydride (5.4 g) was added, and the mixture was stirred at 120 °C for 4 hours. The mixture was cooled to 50 °C and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), and the mixture was washed successively with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain a white solid 6-1 (4.5 g, yield 73%). LC-MS m / z (ESI): 229.0, 231.1 [M+H] + .

[0803] 6.2 Synthesis of Intermediate 6-2

[0804] To a solution of compound 6-1 (2.0 g) dissolved in N,N-dimethylformamide (40 mL), methyl acrylate (1.1 g), N,N-diisopropylethylamine (2.2 g), palladium(II) acetate (0.2 g), and tri(o-tolyl)phosphine (0.5 g) were added, and the mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, and the reaction solution was slowly poured into ice water (200 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain pale yellow solid 6-2 (1.6 g, yield 80%). LC-MS m / z (ESI): 235.0 [M+H] + .

[0805] 6.3 Synthesis of Intermediate 6-3

[0806] To a solution of 6-2 (0.2 g) dissolved in methanol (5 mL) and water (5 mL), sodium hydroxide (70.0 mg) was added at 0 °C, and the mixture was stirred at 70 °C for 5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain white solid 6-3 (100.0 mg), and the crude product was used directly in the reaction of the next step. LC-MS m / z (ESI): 179.0 [M+H] + .

[0807] 6.4 Synthesis of Compound 6

[0808] To a solution of 1-5 (50.0 mg) dissolved in N,N-dimethylacetamide (2 mL), 6-3 (38.0 mg), bromotripyrrolidinophosphonium hexafluorophosphate (103.0 mg) and triethylamine (46.0 mg) were added. The mixture was stirred at room temperature for 16 hours and vacuum filtered. The filtrate was purified by high performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: [water (FA)-ACN], B%: 2% - 10%, 10 minutes) to obtain the formate salt of 6 (10 mg, yield 12%) as a white solid. LC-MS m / z (ESI): 443.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.89 - 8.71 (m, 3H), 8.15 - 8.05 (m, 1H), 8.00 - 7.73 (m, 2H), 7.54 - 7.31 (m, 3H), 7.25 - 6.74 (m, 1H), 6.25 - 6.22 (m, 2H), 5.59 - 5.88 (m, 1H), 5.19 - 4.88 (m, 1H), 4.85 - 4.42 (m, 1H), 2.06 - 1.98 (m, 3H), 1.63 - 1.42 (m, 3H).

[0809] 7. Synthesis of Example 7

Chemical formula

[0810] 7.1 Synthesis of Intermediate 7-1

[0811] A solution of 2-amino-5-bromo-3-methylpyridine (5.0 g) dissolved in dichloromethane (50 mL) was added with di-tert-butyl dicarbonate (14.6 g), triethylamine (10.8 g), and 4-dimethylaminopyridine (0.7 g), and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain white solid 7-1 (9.3 g, yield 85.5%). LC-MS m / z (ESI): 796.9 [2M+H] + .

[0812] 7.2 Synthesis of Intermediate 7-2

[0813] To a solution of compound 7-1 (2.0 g) dissolved in N,N-dimethylformamide (20 mL) were added methyl acrylate (0.7 g), N,N-diisopropylethylamine (1.3 g), and palladium(II) acetate (0.1 g). The mixture was stirred at 100 °C for 16 hours under nitrogen. The mixture was cooled to room temperature, and the reaction solution was slowly added to ice water (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain white solid 7-2 (1.4 g, yield 63.6%). LC-MS m / z (ESI): 393.1 [M+H] + .

[0814] 7.3 Synthesis of Intermediate 7-3

[0815] A solution prepared by dissolving trimethylsulfoxonium iodide (1.3 g) in dimethyl sulfoxide (5 mL) was added with sodium hydride (1.5 g, 60%) at 0 °C under nitrogen, and the mixture was stirred for 1 hour. Compound 7-2 (1.4 g) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. 1 M hydrochloric acid (20 mL) was added to adjust the pH to 6. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain white solid 7-3 (400.0 mg, yield 52.1%). LC-MS m / z (ESI): 393.1 [M+H] + .

[0816] 7.4 Synthesis of Intermediate 7-4

[0817] Lithium hydroxide (14.1 mg) was added to a mixed solution prepared by dissolving compound 7-3 (90.0 mg) in methanol (5 mL) and water (5 mL), and the mixture was stirred at 50 °C for 2 hours. The mixture was cooled to room temperature, and the pH was adjusted to 6 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain white solid 7-4 (50 mg, yield 34.4%), and the crude product was used directly in the reaction of the next step. LC-MS m / z (ESI): 293.1 [M+H] + .

[0818] 7.5 Synthesis of Intermediate 7-5

[0819] To a solution of 1-5 (45.0 mg) dissolved in N,N-dimethylformamide (2 mL), 7-4 (50.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (101.0 mg), and N,N-diisopropylethylamine (46.5 mg) were added. The mixture was stirred at room temperature for 2 hours. Ice water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain yellow solid 7-5 (20.0 mg, yield 32.3%). LC-MS m / z (ESI): 557.2 [M+H] + .

[0820] 7.6 Synthesis of Compound 7

[0821] To a solution of 7-5 (20.0 mg) dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: [water (TFA)-ACN], B%: 2% - 10%, 8 minutes) to obtain the trifluoroacetate salt of 7 (8.0 mg, yield 57.4%) as a white solid. LC-MS m / z (ESI): 457.0 [M+H] + . 11H NMR (400 MHz, MeOD-d4) δ ppm 8.76 (d, J = 4.8 Hz, 1H), 8.68 (d, J = 4.8 Hz, 2H), 8.01 - 7.91 (m, 1H), 7.66 - 7.57 (m, 1H), 7.42 - 7.41 (m, 1H), 7.38 - 7.26 (m, 2H), 6.05 - 5.83 (m, 1H), 5.25 - 4.69 (m, 2H), 2.57 - 2.28 (m, 1H), 2.26 - 1.98 (m, 4H), 1.71 - 1.60 (m, 4H), 1.41 - 1.16 (m, 1H).

[0822] 8. Synthesis of Example 8

Chemical Structure

[0823] 8.1 Synthesis of Intermediate 8-1

[0824] To a solution of 2-aminobutane (166.0 mg) dissolved in 1,2-dichloroethane (5 mL), 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 8-1 (200.0 mg, yield 75.5%). LC-MS m / z (ESI): 233.1 [M+H] + .

[0825] 8.2 Synthesis of Intermediate 8-2

[0826] Compound 8-1 (90.0 mg), propylphosphonic anhydride (50% ethyl acetate solution, 244.0 mg), and N,N-diisopropylethylamine (66.0 mg) were added to a solution of Compound 1-4 (50.0 mg) dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 8-2 (50.0 mg, yield 64.9%). LC-MS m / z (ESI): 610.0 [M+H] + .

[0827] 8.3 Synthesis of Compound 8

[0828] Trifluoroacetic acid (2 mL) was added to a solution of Compound 8-2 (50.0 mg) dissolved in dichloromethane (4 mL) under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under pressure, and water (10 mL) was added. The pH was adjusted to weakly alkaline with a saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), B%: 2% - 30%, 12 minutes) to obtain the formate salt of 8 (6.0 mg, yield 17.8%) as a white solid. LC-MS m / z (ESI): 410.0 [M+H] + . 11H NMR (400 MHz, MeOD-d4) δ ppm 8.82 (s, 1H), 8.12 - 7.96 (m, 2H), 7.67 - 7.46 (m, 2H), 5.14 - 4.62 (m, 2H), 4.51 - 4.13 (m, 1H), 2.17 - 2.11 (m, 3H), 1.74 - 1.54 (m, 2H), 1.26 - 1.19 (m, 3H), 0.93 - 0.88 (m, 3H).

[0829] 9. Synthesis of Example 9

Chemical Structure

[0830] 9.1 Synthesis of Intermediate 9-1

[0831] A solution of (R)-1-methoxy-2-propylamine hydrochloride (166.0 mg) in 1,2-dichloroethane (5 mL) was added with 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg), and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 9-1 (20.0 mg, yield 7.1%). LC-MS m / z (ESI): 249.1 [M+H] + .

[0832] 9.2 Synthesis of Intermediate 9-2

[0833] To a solution of compound 9-1 (20.0 mg) dissolved in N,N-dimethylformamide (3 mL), compound 1-4 (50.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50.0 mg) and N,N-diisopropylethylamine (20.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 9-2 (15.0 mg, yield 30.2%). LC-MS m / z (ESI): 626.3 [M+H] + .

[0834] 9.3 Synthesis of Compound 9

[0835] To a solution of compound 9-2 (15.0 mg) dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added under an ice bath, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under pressure, and water (10 mL) was added. The pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), B%: 2% - 40%, 12 minutes) to obtain the formate salt of 9 (3.0 mg, yield 29.4%) as a white solid. LC-MS m / z (ESI): 426.2 [M+H] + . 11H NMR (400 MHz, MeOD-d4) δ ppm 8.71 (s, 1H), 8.02 - 7.84 (m, 2H), 7.62 - 7.51 (m, 2H), 4.95 (s, 1H), 4.69 (d, J = 8.0 Hz, 1H), 4.53 - 4.43 (m, 1H), 3.36 - 3.25 (m, 2H), 3.09 (d, J = 3.6 Hz, 3H), 2.03 (d, J = 224.8 Hz, 3H), 1.18 - 1.07 (m, 3H).

[0836] 10. Synthesis of Example 10

Chemical Structure

[0837] 10.1 Synthesis of Intermediate 10-1

[0838] Tributyl(1-ethoxyvinyl)tin (13.2 g) was added to a solution of 3-bromo-2-chloro-4-methylpyridine (5.0 g), potassium carbonate (6.7 g) and bis(triphenylphosphine)palladium(II) dichloride (850.0 mg) dissolved in a mixed solvent of tetrahydrofuran and water (50 mL, V / V = 3:1). The mixture was stirred at 90 °C for 16 h under nitrogen. The reaction solution was cooled to room temperature, and saturated potassium fluoride solution (100 mL) and ethyl acetate (100 mL) were added to the reaction solution. The mixture was filtered. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL), and hydrochloric acid (6 M, 10 mL) was added to the above solution. The mixture was stirred at room temperature for 16 h under nitrogen. The reaction solution was concentrated under reduced pressure, and saturated sodium hydrogen carbonate solution (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 - 20 / 1) to obtain a yellow liquid 10-1 (2.2 g, yield 53.7%). LC-MS m / z (ESI): 170.0 [M+H] + .

[0839] 10.2 Synthesis of Intermediate 10-2

[0840] Sodium borohydride (980.0 mg) was added to a solution of 10-1 (2.2 g) dissolved in methanol (20 mL). The mixture was stirred at 25 °C for 1 h under nitrogen. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate = 10 / 1 - 5 / 1) to obtain a colorless liquid 10-2 (2.0 g, yield 80.8%). LC-MS m / z (ESI): 172.1 [M+H] + .

[0841] 10.3 Synthesis of Intermediate 10-3

[0842] tert-Butyl(dichloro)phenylsilane (3.9 g) was added to a solution of 10-2 (2.0 g) and imidazole (1.2 g) dissolved in dichloromethane (20 mL). The mixture was stirred at 25 °C for 16 h under nitrogen. Water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain colorless oil 79-3 (4.5 g, yield 93.2%). LC-MS m / z (ESI): 410.0 [M+H] + .

[0843] 10.4 Synthesis of Intermediate 10-4

[0844] N-Bromosuccinimide (2.4 g) was added to a solution of 10-3 (5.0 g) and azobisisobutyronitrile (0.1 g) dissolved in carbon tetrachloride (50 mL). The mixture was stirred at 90 °C for 2 h under nitrogen. The reaction solution was cooled to room temperature, and water (100 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to obtain colorless oil 10-4 (4.5 g, yield 59.8%). LC-MS m / z (ESI): 488.2 [M+H] + .

[0845] 10.5 Synthesis of Intermediate 10-5

[0846] A solution of tetrabutylammonium fluoride (1 M, 18.4 mL) in tetrahydrofuran was added to a solution of 10-4 (4.5 g) in tetrahydrofuran (50 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain a colorless oil 10-5 (600.0 mg, yield 38.0%). LC-MS m / z (ESI): 170.1 [M+H] + .

[0847] 10.6 Synthesis of Intermediate 10-6

[0848] 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl (418.5 mg), tris(dibenzylideneacetone)dipalladium(0) (193.2 mg), and sodium tert-butoxide (645.9 mg) were added to a solution of 10-5 (570.0 mg) and 2,4-dimethoxybenzylamine (842.9 mg) in toluene (1 mL). The mixture was stirred at 100 °C for 16 hours under nitrogen. The reaction solution was cooled to room temperature, and water (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to obtain a white solid 10-6 (410 mg, yield 40.6%). LC-MS m / z (ESI): 301.1 [M+H] + .

[0849] 10.7 Synthesis of Intermediate 10-7

[0850] 10-6 (410 mg) was added to a solution of trifluoroacetic acid (3 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 10) to obtain white solid 10-7 (150.0 mg, yield 73.2%). LC-MS m / z (ESI): 151.0 [M+H] + .

[0851] 10.8 Synthesis of Intermediate 10-8

[0852] N-Bromosuccinimide (213.3 mg) was added to a solution of 10-7 (150.0 mg) dissolved in acetonitrile (5 mL). The mixture was stirred at 25 °C for 2 hours under nitrogen. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain white solid 10-8 (130.0 mg, yield 56.8%). LC-MS m / z (ESI): 229.0 [M+H] + .

[0853] 10.9 Synthesis of Intermediate 10-9

[0854] Di-tert-butyl dicarbonate (309.6 mg) was added to a solution of 10-8 (130.0 mg), 4-dimethylaminopyridine (6.9 mg) and triethylamine (172.3 mg) dissolved in dichloromethane (5 mL). Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain white solid 10-9 (150.0 mg, yield 61.3%). LC-MS m / z (ESI): 451 [M+Na] + .

[0855] 10.10 Synthesis of Intermediate 10-10

[0856] Tris(dibenzylideneacetone)dipalladium(0) (66.2 mg), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (67.5 mg) and cesium carbonate (176.5 mg) were added to a solution of benzophenone imine (98.2 mg) and 10-9 (150.0 mg) dissolved in dioxane (5 mL). The mixture was stirred at 100 °C for 8 hours under nitrogen. The reaction solution was cooled to room temperature, and water (30 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain white solid 10-10 (60.0 mg, yield 32.2%). LC-MS m / z (ESI): 530.1 [M+H] + .

[0857] 10.11 Synthesis of Intermediate 10-11

[0858] A solution of HCl in dioxane (0.6 mL, 4 M) was added to a solution of 10-10 (60.0 mg) dissolved in tetrahydrofuran (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour under nitrogen. A saturated aqueous sodium carbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to obtain a white solid 10-11 (25.0 mg, yield 60.4%). LC-MS m / z (ESI): 366.2 [M+H] + .

[0859] 10.12 Synthesis of Intermediate 10-12

[0860] Ethyl 2-chloro-2-oxoacetate (70.6 mg) was added to a solution of 10-11 (100.0 mg) and triethylamine (87.1 mg) dissolved in dichloromethane (3 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 2 / 1) to obtain a brown oil 10-12 (140 mg, yield 97.8%). LC-MS m / z (ESI): 333.2 [M+H] + .

[0861] 10.13 Synthesis of Intermediate 10-13

[0862] Lithium hydroxide monohydrate (94.7 mg) was added to a solution of 10-12 (150.0 mg) dissolved in a mixed solvent of methanol and water (6 mL, V / V = 5:1). The mixture was stirred at 25 °C for 1 hour under nitrogen. Water (10 mL) was added to the reaction solution, and 1 M hydrochloric acid was added dropwise until the pH of the reaction solution reached 5-6. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 1 to 5 / 1) to obtain 10-13 as a brown solid (80.0 mg, yield 58.2%). LC-MS m / z (ESI): 305.2 [M+H] + .

[0863] 10.14 Synthesis of Intermediate 10-14

[0864] Chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate (22.9 mg) was added to a solution of 10-13 (33.1 mg), 10-11 (20.0 mg) and methylimidazole (8.9 mg) dissolved in N,N-dimethylformamide (1 mL). The mixture was stirred at 25 °C for 1 hour under nitrogen. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain 10-14 as a white solid (10.0 mg, yield 28.1%). LC-MS m / z (ESI): 652.2 [M+H] + .

[0865] 10.15 Synthesis of Compound 10

[0866] A solution of HCl in dioxane (0.2 mL, 4 M) was added to a solution of 10-14 (10 mg) dissolved in dichloromethane (1 mL). The mixture was stirred at 25 °C for 3 hours under nitrogen. The reaction solution was concentrated under reduced pressure. The residue was purified by thin layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain white solid 10 (5.4 mg, yield 78.4%). LC-MS m / z (ESI): 452.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, 80 o C) δ 10.50 - 10.25 (m, 1H), 8.87 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.70 - 7.60 (m, 1H), 5.72 (s, 2H), 5.25 - 5.20 (m, 1H), 5.05 - 4.93 (m, 1H), 4.85 (m, 1H), 4.72 (m, 1H), 4.62 - 4.52 (m, 1H), 4.10 - 3.87 (m, 1H), 1.67 - 1.48 (m, 2H), 1.39 (d, J = 6.4 Hz, 2H), 1.34 - 1.31 (m, 1H), 1.20 (d, J = 6.5 Hz, 2H), 1.07 (d, J = 6.8 Hz, 1H), 0.84 (t, J = 7.4 Hz, 3H).

[0867] 11. Synthesis of Example 11

Chemical Structure

[0868] 11.1 Synthesis of Intermediate 11-1

[0869] Cyclopentylamine (486.3 mg) was added to a solution of 5-(trifluoromethyl)pyridine-2-carboxaldehyde (500.0 mg) and acetic acid (343.0 mg) dissolved in 1,2-dichloroethane (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (1210.0 mg) was added. The mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1 to 8 / 1) to obtain yellow oil 11-1 (540.0 mg, yield 69.7%). LC-MS m / z (ESI): 245.1 [M+H] + .

[0870] 11.2 Synthesis of Intermediate 11-2

[0871] Propylphosphonic anhydride (483.0 mg, 50% ethyl acetate solution) was added to a solution of N,N-diisopropylethylamine (130.7 mg), 11-1 (148.3 mg), and 1-4 (200.0 mg) dissolved in dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hours. Ice water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain white solid 11-2 (150.0 mg, yield 43.0%). LC-MS m / z (ESI): 622.3 [M+H] + .

[0872] 11.3 Synthesis of Compound 11

[0873] A solution of HCl in 1,4-dioxane (4 mL, 4 M) was added to 11-2 (140.0 mg) under an ice bath. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), B%: 10% - 40%, 20 min) to obtain the formate salt of 11 (15.1 mg, yield 15.8%) as a white solid. LC-MS m / z (ESI): 422.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.52 - 10.30 (m, 1H), 8.93 - 8.88 (m, 1H), 8.28 - 8.05 (m, 2H), 7.87 - 7.30 (m, 2H), 5.67 - 5.60 (m, 2H), 4.88 - 4.66 (m, 2H), 4.38 - 4.34 (m, 1H), 2.06 - 1.95 (m, 3H), 1.84 - 1.73 (m, 2H), 1.63 - 1.49 (m, 6H).

[0874] 12. Synthesis of Example 12

Chemical formula

[0875] 12.1 Synthesis of Intermediate 12-1

[0876] Cyclopropylamine (131.0 mg) was added to a solution of 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) in 1,2-dichloroethane (2 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 1 hour under nitrogen, and then sodium triacetoxyborohydride (485.0 mg) was added. The mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a pale yellow liquid crude product 12-1 (10.0 mg). LC-MS m / z (ESI): 217.1 [M+H] + .

[0877] 12.2 Synthesis of Intermediate 12-2

[0878] To a solution of 12-1 (10.0 mg) dissolved in N,N-dimethylformamide (1 mL), 1-4 (20.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (35.0 mg), and N,N-diisopropylethylamine (10.0 mg) were added. The mixture was stirred at room temperature for 2 hours under nitrogen. Water (1 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a pale yellow liquid crude product 12-2 (15.0 mg). LC-MS m / z (ESI): 594.0 [M+H] + .

[0879] 12.3 Synthesis of Compound 12

[0880] Trifluoroacetic acid (0.5 mL) was added to a solution of 12-2 (15.0 mg) dissolved in dichloromethane (1 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (5 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5 um, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 10%, 20 minutes) to obtain the formate salt of 12 (3.47 mg, yield 34.9%) as a yellow solid. LC-MS m / z (ESI): 394.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ ppm 8.87 (s, 1H), 8.14 - 8.13 (m, 1H), 8.10 - 8.09 (m, 1H), 7.63 - 7.61 (m, 2H), 4.87 (s, 2H), 3.13 - 3.03 (m, 1H), 2.18 (s, 3H), 0.91 - 0.83 (m, 4H).

[0881] 13. Synthesis of Example 13

Chemical Structure

[0882] 13.1 Synthesis of Intermediate 13-1

[0883] A solution of cyclobutylamine (162.0 mg) dissolved in 1,2-dichloroethane (5 mL) was added with 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg), and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 13-1 (250.0 mg, yield 95.0%). LC-MS m / z (ESI): 230.9 [M+H] + .

[0884] 13.2 Synthesis of Intermediate 13-2

[0885] Compound 13-1 (100.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (216.0 mg) and N,N-diisopropylethylamine (98.0 mg) were added to a solution of compound 1-4 (150.0 mg) dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 13-2 (40.0 mg, yield 17.4%). LC-MS m / z (ESI): 608.2 [M+H] + .

[0886] 13.3 Synthesis of Compound 13

[0887] Trifluoroacetic acid (2 mL) was added to a solution of compound 13-2 (40.0 mg) dissolved in dichloromethane (4 mL) under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain pale yellow solid 13 (10.0 mg, yield 37.3%). LC-MS m / z (ESI): 408.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ ppm 8.84 - 8.82 (m, 1H), 8.11 - 7.95 (m, 2H), 7.64 - 7.47 (m, 2H), 5.10 - 4.93 (m, 2H), 4.75 - 4.65 (m, 1H), 2.27 - 2.06 (m, 7H), 1.72 - 1.63 (m, 2H).

[0888] 14. Synthesis of Example 14-P1 and Example 14-P2

Chemical Structure

[0889] 14.1 Synthesis of Intermediate 14-1

[0890] A solution of 3-aminotetrahydropyran (229.7 mg) in 1,2-dichloroethane (5 mL) was added with 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) and acetic acid (102.0 mg), and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (418.6 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain yellow oil 14-1 (210.0 mg, yield 67.9%). LC-MS m / z (ESI): 261.0 [M+H] + .

[0891] 14.2 Synthesis of Intermediate 14-2

[0892] A solution of compound 14-1 (100.0 mg) and 1-4 (150.0 mg) in N,N-dimethylformamide (5 mL) was added with propylphosphonic anhydride (216.0 mg) and N,N-diisopropylethylamine (98.0 mg), and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain yellow solid 14-2 (210.0 mg, yield 85.6%). LC-MS m / z (ESI): 638.1 [M+H] + .

[0893] 14.3 Synthesis of Compound 14-P1 and Compound 14-P2

[0894] A solution of compound 14-2 (210.0 mg) in dichloromethane (6 mL) was added with trifluoroacetic acid (2 mL) under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and water (30 mL) was added. The pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: [water (FA)-ACN], B%: 2% - 10%, 16 minutes) to obtain the formate salt of 14-3 (82.0 mg, yield 67.3%) as a white solid. The product was separated by SFC (column: CHIRALPAK IC 250 mm × 20 mm, 5 μm, mobile phase: ETOH (NH4OH 0.2%), B%: 40% EtOH, 15 minutes) to obtain a white solid 14-P1 (30.0 mg). LC-MS m / z (ESI): 438.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ ppm 8.83 (s, 1H), 8.13 - 7.90 (m, 2H), 7.68 - 7.40 (m, 2H), 5.11 - 4.83 (m, 2H), 4.43 - 4.12 (m, 2H), 4.03 - 3.75 (m, 2H), 3.45 - 3.41 (m, 1H), 2.16 - 2.09 (m, 3H), 2.04 - 1.79 (m, 2H), 1.75 - 1.65 (m, 2H);

[0895] A white solid 14-P2 (37.0 mg) was obtained. LC-MS m / z (ESI): 438.0 [M+H] + . 11H NMR (400 MHz, MeOD-d4) δ ppm 8.83 (s, 1H), 8.11 - 7.90 (m, 2H), 7.68 - 7.39 (m, 2H), 5.12 - 4.81 (m, 2H), 4.43 - 4.09 (m, 2H), 4.03 - 3.74 (m, 2H), 3.50 - 3.39 (m, 1H), 2.18 - 2.06 (m, 3H), 2.03 - 1.80 (m, 2H), 1.75 - 1.65 (m, 2H).

[0896] 15. Synthesis of Example 15

Chemical Structure

[0897] 15.1 Synthesis of Intermediate 15-1

[0898] To a solution of cyclopropylmethylamine (41.0 mg) dissolved in anhydrous dichloroethane (2 mL), 5-(trifluoromethyl)pyridine-2-carboxaldehyde (100.0 mg) and acetic acid (65.0 mg) were added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (363.0 mg) was added, and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution (30 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain yellow oil 15-1 (20.0 mg, yield 15.2%). LC-MS m / z (ESI): 231.1 [M+H] + .

[0899] 15.2 Synthesis of Intermediate 15-2

[0900] To a solution of 15-1 dissolved in N,N-dimethylformamide (2 mL), 1-4 (34.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (66.0 mg), and N,N-diisopropylethylamine (23.0 mg) were added. The mixture was stirred at room temperature for 3 hours. Ice water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 15-2 (20.0 mg), and the crude product was used directly in the reaction of the next step. LC-MS m / z (ESI): 608.3 [M+H] + .

[0901] 15.3 Synthesis of Compound 15

[0902] To a solution of 15-2 (20.0 mg) dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain white solid 15 (4.4 mg, yield 32.8%). LC-MS m / z (ESI): 408.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ ppm 8.61 (s, 1H), 8.00 - 7.92 (m, 2H), 7.54 - 7.44 (m, 2H), 5.04 - 4.85 (m, 2H), 3.41 - 3.28 (m, 2H), 2.09 - 2.03 (m, 3H), 1.00 - 0.82 (m, 1H), 0.26 - 0.21 (m, 2H), 0.13 - 0.11 (m, 2H).

[0903] 16. Synthesis of Example 16

Chemical Structure

[0904] 16.1 Synthesis of Intermediate 16-1

[0905] Cyclobutylmethylamine (300.0 mg) was added to a solution of 5-(trifluoromethyl)pyridine-2-carboxaldehyde (300.0 mg) dissolved in 1,2-dichloroethane (2 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 1 hour under nitrogen. Then, sodium triacetoxyborohydride (727.0 mg) was added and the mixture was stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain pale yellow oil 16-1 (300.0 mg, yield 71.7%). LC-MS m / z (ESI): 245.0 [M+H] + .

[0906] 16.2 Synthesis of Intermediate 16-2

[0907] 1-4 (453.0 mg), propylphosphonic anhydride (782.1 mg), and N,N-diisopropylethylamine (318.0 mg) were added to a solution of 16-1 (280.0 mg) dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 12 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain white solid 16-2 (240.0 mg, yield 33.7%). LC-MS m / z (ESI): 622.0 [M+H] + .

[0908] 16.3 Synthesis of Compound 16

[0909] Trifluoroacetic acid (1 mL) was added to a solution of 16-2 (240.0 mg) dissolved in dichloromethane (2 mL) under an ice bath. The mixture was stirred at room temperature for 2 hours, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (5 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150 × ɸ9 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 10%, 20 min) to obtain the formate salt of 16 (145.6 mg, yield 89.5%) as a white solid. LC-MS m / z (ESI): 422.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.54 - 10.39 (m, 1H), 8.95 - 8.90 (m, 1H), 8.25 - 8.21 (m, 1H), 8.06 - 7.95 (m, 1H), 7.62 - 7.42 (m, 2H), 5.86 - 5.66 (m, 2H), 4.91 - 4.73 (m, 2H), 3.57 - 3.34 (m, 2H), 2.61 - 2.56 (m, 1H), 2.05 - 1.99 (m, 3H), 1.95 - 1.63 (m, 6H).

[0910] 17. Synthesis of Example 17

Chemical Structure

[0911] 17.1 Synthesis of Intermediate 17-1

[0912] A solution of cyclopentylmethylamine (225.0 mg) dissolved in 1,2-dichloroethane (5 mL) was added with 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) and acetic acid (137.0 mg), and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (485.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 17-1 (200.0 mg, yield 67.8%). LC-MS m / z (ESI): 259.2 [M+H] + .

[0913] 17.2 Synthesis of Intermediate 17-2

[0914] To a solution of compound 1-4 (50.0 mg) dissolved in N,N-dimethylformamide (3 mL) were added compound 17-1 (100.0 mg), propylphosphonic anhydride (244.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (66.0 mg), and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 17-2 (55.0 mg, yield 68.4%). LC-MS m / z (ESI): 636.1 [M+H] + .

[0915] 17.3 Synthesis of Compound 17

[0916] A solution of compound 17-2 (40.0 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) in an ice bath, and the mixture was warmed to room temperature and stirred for 2 hours. Water (10 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), B%: 2% - 40%, 12 minutes) to obtain the formate salt of 17 (18.0 mg, yield 27.5%) as a white solid. LC-MS m / z (ESI): 436.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ ppm 8.84 (s, 1H), 8.13 - 8.0 (m, 2H), 7.63 - 7.52 (m, 2H), 5.08 - 4.86 (m, 2H), 3.62 - 3.43 (m, 2H), 2.31 - 2.29 (m, 1H), 2.16 - 2.11 (m, 3H), 1.75 - 1.55 (m, 6H), 1.29 - 1.25 (m, 2H).

[0917] 18. Synthesis of Example 18

Chemical Structure

[0918] 18.1 Synthesis of Intermediate 18-1

[0919] 1-Methyl-1H-pyrazol-4-amine (270.0 mg) was added to a solution of 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 hour under nitrogen, and then triethylsilane (1 mL) was added. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain yellow liquid 18-1 (240.0 mg, yield 82.0%). LC-MS m / z (ESI): 257.2 [M+H] + .

[0920] 18.2 Synthesis of Intermediate 18-2

[0921] To a solution of 18-1 (40.0 mg) dissolved in N,N-dimethylformamide (1 mL), 1-4 (53.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (120.0 mg) and N,N-diisopropylethylamine (40.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain pale yellow oil 18-2 (50.0 mg). The crude product was used directly in the reaction of the next step without purification. LC-MS m / z (ESI): 634.0 [M+H] + .

[0922] 18.3 Synthesis of Compound 18

[0923] To a solution of 18-2 (50.0 mg) dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added under an ice bath, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5um, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 10%, 20 minutes) to obtain the formate salt of 18 (9.4 mg, yield 27.5%) as a yellow solid. LC-MS m / z (ESI): 434.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.77 - 10.59 (m, 1H), 8.94 - 8.90 (m, 1H), 8.26 - 8.23 (m, 1H), 8.06 - 8.04 (m, 1H), 7.78 (s, 1H), 7.64 - 7.57 (m, 2H), 7.41 - 7.38 (m, 1H), 6.21 (s, 2H), 5.29 - 5.02 (m, 2H), 3.79 - 3.71 (m, 3H), 2.05 (s, 3H).

[0924] 19. Synthesis of Example 19-P1 and Example 19-P2 [Chemical formula]

[0925] 19.1 Synthesis of Intermediate 19-1

[0926] A solution of (5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (334.0 mg) in 1,2-dichloroethane (5 mL) was added with triethylamine (239.0 mg), and the mixture was stirred at room temperature for 3 hours. 4-Acetylthiazole (200.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (667.0 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 19-1 (150.0 mg, yield 33.2%). LC-MS m / z (ESI): 288.0 [M+H] + .

[0927] 19.2 Synthesis of Intermediate 19-2

[0928] Compound 19-1 (130.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (258.0 mg), and N,N-diisopropylethylamine (117.0 mg) were added to a solution of Compound 1-4 (180.0 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 19-2 (75.0 mg, yield 24.9%). LC-MS m / z (ESI): 665.2 [M+H] + .

[0929] 19.3 Synthesis of Compound 19-P1 and Compound 19-P2

[0930] To a solution of compound 19-2 (75 mg) dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under pressure. Water (10 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain pale yellow solid 19-3 (30.0 mg, yield 57.3%). Compound 19-3 was purified by high performance liquid chromatography (column: SFC Thar prep 80, CHIRALPAK AD-H 250 mm × 20 mm, 5 μm, mobile phase: 40% IPA (NH4OH 0.2%)) to obtain white solid 19-P1 (12.0 mg, yield 40%). LC-MS m / z (ESI): 464.9 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ ppm 8.88 - 8.87 (m, 1H), 8.70 - 8.68 (m, 1H), 8.14 - 7.89 (m, 2H), 7.68 - 7.60 (m, 1H), 7.54 - 7.36 (m, 2H), 6.09 - 5.81 (m, 1H), 5.01 - 4.60 (m, 2H), 2.16 - 2.09 (m, 3H), 1.75 - 1.61 (m, 3H);

[0931] White solid 19-P2 (11.8 mg, yield 39.3%) was obtained. LC-MS m / z (ESI): 465.0 [M+H] + . 11H NMR (400 MHz, MeOD-d4) δ ppm 8.88 - 8.87 (m, 1H), 8.70 - 8.68 (m, 1H), 8.14 - 7.89 (m, 2H), 7.68 - 7.60 (m, 1H), 7.55 - 7.36 (m, 2H), 6.09 - 5.81 (m, 1H), 5.01 - 4.60 (m, 2H), 2.16 - 2.10 (m, 3H), 1.75 - 1.61 (m, 3H).

[0932] 20. Synthesis of Example 20 [Chemical Structure Diagram]

[0933] 20.1 Synthesis of Intermediate 20-1

[0934] To a solution of 4-aminomethyl-7-azaindole (167.0 mg) and acetic acid (136.0 mg) dissolved in 1,2-dichloroethane (5 mL), 5-(trifluoromethyl)pyridine-2-carboxaldehyde (200.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (481.0 mg) was added, and the mixture was stirred for 30 minutes. Water (20 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 20-1 (250.0 mg, yield 71.4%). LC-MS m / z (ESI): 307.1 [M+H] + .

[0935] 20.2 Synthesis of Intermediate 20-2

[0936] Compound 20-1 (36.5 mg), propylphosphonic anhydride (121.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (33.0 mg) were added to a solution of Compound 1-4 (50.0 mg) dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 16 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain yellow solid 20-2 (40.0 mg, yield 46.3%). LC-MS m / z (ESI): 684.0 [M+H] + .

[0937] 20.3 Synthesis of Compound 20

[0938] To a solution of Compound 20-2 (40.0 mg) dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added under an ice bath. The mixture was warmed to room temperature and stirred for 2 h. The reaction solution was concentrated under pressure. Water (10 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain white solid 20 (10.0 mg, yield 35.3%). LC-MS m / z (ESI): 484.0 [M+H] + . 11H NMR (400 MHz, MeOD-d4) δ ppm 8.76 (s, 1H), 8.16 - 8.11 (m, 1H), 8.05 - 7.93 (m, 2H), 7.58 - 7.47 (m, 2H), 7.39 - 7.38(m, 1H), 7.13 - 7.03 (m, 1H), 6.58 - 6.57 (m, 1H), 5.32 - 5.06(m, 2H), 5.04 - 4.8 (m, 2H), 2.12 - 2.16 (m, 3H).

[0939] 21. Synthesis of Example 21 [Chemical formula]

[0940] 21.1 Synthesis of Intermediate 21-1

[0941] To a solution of 3-bromo-5-nitropyridin-2-amine (5.0 g) dissolved in dichloromethane (50 mL), di-tert-butyl dicarbonate (12.5 g), 4-dimethylaminopyridine (1.4 g), and triethylamine (4.7 g) were added, and the mixture was stirred at room temperature for 12 hours. The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain pale yellow solid 21-1 (8.0 g, yield 83.3%). LC-MS m / z (ESI): 440.1, 442.1 [M+Na] + .

[0942] 21.2 Synthesis of Intermediate 21-2

[0943] To a mixed solution of 1,4-dioxane (12 mL) and water (4 mL), potassium vinyltrifluoroborate (540.0 mg), potassium carbonate (1.3 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (150.0 mg) and 21-1 (1.0 g) were added, and the mixture was stirred at 100 °C for 12 h under nitrogen. The mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain a pale yellow solid 21-2 (500.0 mg, yield 57.1%). LC-MS m / z (ESI): 753.0 [2M+Na] + .

[0944] 21.3 Synthesis of Intermediate 21-3

[0945] Palladium carbon (500.0 mg) was added under nitrogen to a solution of 21-2 (500.0 mg) dissolved in methanol (10 mL). Hydrogen was introduced to purge the system three times. The mixture was stirred at room temperature for 2 h under hydrogen. The mixture was vacuum filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain a pale yellow solid 21-3 (400.0 mg, yield 86.6%). LC-MS m / z (ESI): 338.1 [M+H] + .

[0946] 21.4 Synthesis of Intermediate 21-4

[0947] Ethyl 2-chloro-2-oxoacetate (410.0 mg) was added to a solution of 21-3 (1.0 g) and N,N-diisopropylethylamine (390.0 mg) in dichloromethane (14 mL) under an ice bath, and the mixture was stirred at room temperature for 3 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain a pale yellow solid 21-4 (1.0 g, yield 76.9%). LC-MS m / z (ESI): 438.1 [M+H] + .

[0948] 21.5 Synthesis of Intermediate 21-5

[0949] Lithium hydroxide (110.0 mg) was added to a solution of 21-4 (1.0 g) in methanol (9 mL) and water (3 mL). The mixture was stirred at room temperature for 2 hours. 2M hydrochloric acid was added to adjust the pH to 6, and the mixture was vacuum filtered to obtain a pale yellow solid 21-5 (800.0 mg, yield 85.5%). LC-MS m / z (ESI): 410.0 [M+H] + .

[0950] 21.6 Synthesis of Intermediate 21-6

[0951] To a solution of 21-5 (87.2 mg) and 1-5 (50.0 mg) dissolved in N,N-dimethylformamide (5 mL), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (134.2 mg) and N,N-diisopropylethylamine (45.6 mg) were added, and the mixture was stirred at room temperature for 5 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain 21-6 (40.0 mg, 40.7%) as a yellow oil. LC-MS m / z (ESI): 674.0 [M+H] + .

[0952] 21.7 Synthesis of Compound 21

[0953] Trifluoroacetic acid (2 mL) was added to a solution of 21-6 (40.0 mg) dissolved in dichloromethane (2 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5um, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 10%, 20 minutes) to obtain the formate salt of 21 (2.0 mg, yield 7.1%) as a white solid. LC-MS m / z (ESI): 474.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.71 - 8.68 (m, 3H), 8.02 - 7.95 (m, 2H), 7.65 - 7.63 (m, 1H), 7.54 - 7.46 (m, 1H), 7.31 - 7.28 (m, 1H), 5.88 - 5.80 (m, 1H), 4.59 (s, 2H), 2.51 - 2.44 (m, 2H), 1.75 - 1.61 (m, 3H), 1.26 - 1.17 (m, 3H).

[0954] 22. Synthesis of Example 22 [Chemical formula]

[0955] 22.1 Synthesis of Intermediate 22-1

[0956] To a solution of 5-bromo-3-fluoropyridin-2-amine (5.0 g) dissolved in dichloromethane (50 mL), di-tert-butyl dicarbonate (14.3 g), triethylamine (10.6 g), and 4-dimethylaminopyridine (0.6 g) were added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain white solid 22-1 (8.8 g, yield 95.3%). LC-MS m / z (ESI): 804.9 [2M+Na] + .

[0957] 22.2 Synthesis of Intermediate 22-2

[0958] To a solution of compound 22-1 (300 mg) dissolved in 1,4-dioxane (5 mL), ethyl oxamate (134.1 mg), copper(I) iodide (15.0 mg), cesium carbonate (497.0 mg), and N,N'-dimethylethylenediamine (19.4 mg) were added, and the mixture was stirred at 100 °C for 2 hours under nitrogen. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain yellow solid 22-2 (200.0 mg, yield 49.4%). LC-MS m / z (ESI): 677.3 [2M+Na] + .

[0959] 22.3 Synthesis of Intermediate 22-3

[0960] To a solution of triethylamine (61.4 mg) and compound 22-2 (200.0 mg) dissolved in dichloromethane (5 mL), ethyl 2-chloro-2-oxoacetate (82.9 mg) was added under nitrogen and in an ice bath, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 40 / 1) to obtain yellow oily substance 22-3 (200.0 mg, yield 71.4%). LC-MS m / z (ESI): 877.0 [2M+Na] + .

[0961] 22.4 Synthesis of Intermediate 22-4

[0962] To a solution of compound 22-3 (200.0 mg) dissolved in 1,2-dichloroethane (5 mL), trimethylstannyl hydroxide (252.6 mg) was added, and the mixture was stirred at 70 °C for 2 hours. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude yellow solid product 22-4 (180 mg). LC-MS m / z (ESI): 821.0 [2M+Na] + .

[0963] 22.5 Synthesis of Intermediate 22-5

[0964] To a solution of compound 22-4 (180.0 mg) dissolved in N,N-dimethylformamide (3 mL), 1-5 (140.6 mg), propylphosphonic anhydride (317.6 mg) and N,N-diisopropylethylamine (128.8 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 30 / 1) to obtain yellow oil 22-5 (80.0 mg, yield 23.2%). LC-MS m / z (ESI): 664.0 [M+H] + .

[0965] 22.6 Synthesis of Intermediate 22

[0966] To a solution of compound 22-5 (80.0 mg) dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain pale yellow solid 22 (30.0 mg, yield 53.7%). LC-MS m / z (ESI): 464.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ ppm 10.77 - 10.69 (m, 1H), 8.86 - 8.71 (m, 3H), 8.17 - 8.10 (m, 1H), 8.09 - 7.92 (m, 1H), 7.75 - 7.64 (m, 1H), 7.50 - 7.39 (m, 1H), 7.41 - 7.34 (m, 1H), 6.12 - 6.10 (m, 2H), 5.75 - 5.72 (m, 1H), 5.17 - 4.56 (m, 2H), 1.67 - 1.52 (m, 3H).

[0967] 23. Synthesis of Example 23

Chemical Structure

[0968] 23.1 Synthesis of Intermediate 23-1

[0969] To a solution of 4-dimethylaminopyridine (140.0 mg) and triethylamine (2.4 g) dissolved in dichloromethane (20 mL), 2-amino-3-chloro-5-nitropyridine (1.0 g) and di-tert-butyl dicarbonate (3.2 g) were added, and the mixture was stirred at room temperature for 3 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 5 / 1) to obtain white solid 23-1 (1.5 g, yield 69.4%). LC-MS m / z (ESI): 396.0 [M+Na] + .

[0970] 23.2 Synthesis of Intermediate 23-2

[0971] To a mixed solution prepared by dissolving 23-1 (500.0 mg) in ethanol (10 mL) and water (10 mL), iron powder (743.2 mg) and ammonium chloride (711.2 mg) were added, and the mixture was stirred at 0 °C for 16 hours. The mixture was filtered, and water (50 mL) was added to the filtrate. The resulting mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain white solid 23-2 (220.0 mg, yield 47.8%). LC-MS m / z (ESI): 244.0 [M-100+H] + .

[0972] 23.3 Synthesis of Intermediate 23-3

[0973] To a solution prepared by dissolving triethylamine (40.0 mg) and 23-2 (100.0 mg) in dichloromethane (5 mL), ethyl 2-chloro-2-oxoacetate (48.0 mg) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated sodium chloride solution (3 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to obtain white solid 23-3 (100.0 mg, yield 77.4%). LC-MS m / z (ESI): 288.0 [M-156+H] + .

[0974] 23.4 Synthesis of Intermediate 23-4

[0975] To a solution prepared by dissolving 23-3 (100.0 mg) in methanol (3 mL) and water (1 mL), lithium hydroxide (20.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to acidic with 1 M hydrochloric acid and filtered to obtain crude white solid 23-4 (100.0 mg). The crude product was used directly in the reaction of the next step without purification. LC-MS m / z (ESI): 437.9 [M+Na] + .

[0976] Synthesis of Intermediate 23-5

[0977] To a solution of 23-4 (100.0 mg) dissolved in N,N-dimethylformamide (1 mL), 1-5 (70.0 mg), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (142.0 mg), and N,N-diisopropylethylamine (65.0 mg) were added. The mixture was stirred at room temperature for 12 hours under nitrogen. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (1 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product of yellow solid, Intermediate 23-5 (50.0 mg). LC-MS m / z (ESI): 680.0 [M+H] + .

[0978] Synthesis of Intermediate 23

[0979] Trifluoroacetic acid (1 mL) was added to a solution of 23-5 (50.0 mg) dissolved in dioxymethane (2 mL) under an ice bath. The mixture was stirred at room temperature for 2 hours, and the pH was adjusted to 8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (10 mL × 3), and the organic phase was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19mm, 5um, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 10%, 20 minutes) to obtain the formate salt of 23 (19.0 mg, yield 53.8%) as a yellow solid. LC-MS m / z (ESI): 480.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ ppm 10.77 - 10.60 (m, 1H), 8.83 - 8.74 (m, 3H), 8.20 - 8.06 (m, 2H), 7.92 - 7.34 (m, 3H), 6.24 - 6.18 (m, 2H), 5.77 - 5.70 (m, 1H), 5.21 - 4.56 (m, 2H), 1.65 - 1.47 (m, 3H).

[0980] 24. Synthesis of Example 24 [Chemical Structure Diagram]

[0981] 24.1 Synthesis of Intermediate 24-1

[0982] To a solution of 2-amino-3-bromo-5-nitropyridine (5 g) dissolved in dichloromethane (50 mL), di-tert-butyl dicarbonate (12.5 g), triethylamine (9.3 g), and 4-dimethylaminopyridine (0.6 g) were added. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain white solid 24-1 (9.0 g, yield 97%). LC-MS m / z (ESI): 859.0 [2M+Na] + .

[0983] 24.2 Synthesis of Intermediate 24-2

[0984] To a solution of compound 24-1 (500 mg) dissolved in ethanol (5 mL), iron powder (664.5 mg) and ammonium chloride (636.4 mg) were added, and the mixture was stirred at 50 °C for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 24-2 (360.0 mg, yield 72.4%). LC-MS m / z (ESI): 799.0 [2M+Na] + .

[0985] 24.3 Synthesis of Intermediate 24-3

[0986] To a solution of compound 24-2 (200.0 mg) dissolved in dichloromethane (5 mL), ethyl 2-chloro-2-oxoacetate (82.9 mg) and triethylamine (61.4 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 24-3 (240 mg, yield 81.4%). LC-MS m / z (ESI): 998.8 [2M+Na] + .

[0987] 24.4 Synthesis of Intermediate 24-4

[0988] To a solution of compound 24-3 (240 mg) dissolved in 1,2-dichloroethane (5 mL), trimethylstannyl hydroxide (276.6 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a yellow solid 24-4 (100 mg, yield 76.2%). LC-MS m / z (ESI): 942.8 [2M+Na] + .

[0989] 24.5 Synthesis of Intermediate 24-5

[0990] To a solution of compound 24-4 (100 mg) dissolved in N,N-dimethylformamide (3 mL), 1-5 (62.6 mg), propylphosphonic anhydride (55.9 mg), and N,N-diisopropylethylamine (55.8 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain a yellow oil 24-5 (80 mg, yield 23.2%). LC-MS m / z (ESI): 723.9 [M+H] + .

[0991] 24.6 Synthesis of Compound 24

[0992] To a solution of Compound 24-5 (80.0 mg) dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Water (10 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium hydrogen carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain pale yellow solid 24 (9.0 mg, yield 22.3%). LC-MS m / z (ESI): 524.0, 526.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.75 -10.25 (m, 1H), 8.86 - 8.73 (m, 3H), 8.15 - 8.10 (m, 2H), 7.68 - 7.35 (m, 3H), 6.17 - 6.11 (m, 2H), 5.71 - 5.70 (m, 1H), 5.19 - 4.56 (s, 2H), 1.59-1.52 (m, 3H).

[0993] 25. Synthesis of Example 25

Chemical Structure

[0994] 25.1 Synthesis of Intermediate 25-1

[0995] To a solution of sodium methoxide (4.3 g) dissolved in methanol (40 mL), 2-chloro-5-nitronicotinic acid (3.2 g) was added, and the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was diluted by adding water (20 mL). The pH was adjusted to 7 with 1M hydrochloric acid, and the mixture was filtered to obtain pale yellow solid 25-1 (1.8 g). The crude product was used directly in the reaction of the next step without purification. LC-MS m / z (ESI): 197.0 [M-H] + .

[0996] 25.2 Synthesis of Intermediate 25-2

[0997] 25-1 (1.8 g) was added to a thionyl chloride solution (20 mL), and the mixture was stirred at 80 °C for 4 hours. The mixture was concentrated under reduced pressure. Tetrahydrofuran (20 mL) was added to the residue, and the mixture was added dropwise to an ammonia solution (9 mL) in an ice bath. The mixture was stirred at 0 °C for 1 hour. The mixture was warmed to room temperature, and water (50 mL) was added to dilute the mixture. The mixture was filtered to obtain a crude white solid product 25-2 (1.1 g). The crude product was used directly in the reaction of the next step without purification. LC-MS m / z (ESI): 198.1 [M+H] + .

[0998] 25.3 Synthesis of Intermediate 25-3

[0999] Palladium carbon (0.1 g) was added to a solution of 25-2 (1.0 g) dissolved in methanol (12 mL) under nitrogen. Hydrogen was introduced to purge the system three times, and the mixture was stirred at 25 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain an off-white solid crude product 25-3 (0.8 g). The crude product was used directly in the reaction of the next step without purification. LC-MS m / z (ESI): 168.1 [M+H] + .

[1000] 25.4 Synthesis of Intermediate 25-4

[1001] 2-Chloro-2-oxoethyl acetate (270.0 mg) was added dropwise to a solution of the crude product 25-3 (300.0 mg) and triethylamine (272.0 mg) dissolved in dichloromethane (8 mL) in an ice bath. The mixture was stirred at room temperature for 1 hour. Dichloromethane (30 mL) was added. The organic phase was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 - 4 / 1) to obtain a white solid 25-4 (340.0 mg, yield 63.8%). LC-MS m / z (ESI): 268.0 [M+H]+ .

[1002] Synthesis of Intermediate 25-5 in 25.5

[1003] Lithium hydroxide (34.4 mg) was added to a mixed solution of 25-5 (320.0 mg) dissolved in methanol and water (8 mL, V / V = 3:1). The mixture was stirred at room temperature for 1 hour. 1M hydrochloric acid was added to adjust the pH to 7, and the mixture was vacuum filtered to obtain a crude white solid product 25-5 (200.0 mg). The crude product was used directly in the reaction of the next step without purification. LC-MS m / z (ESI): 239.9 [M+H] + .

[1004] Synthesis of Compound 25 in 25.6

[1005] O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (254.4 mg) was added to a solution of N,N-diisopropylethylamine (108.1 mg), 25-5 (80.0 mg) and 1-5 (113.3 mg) dissolved in N,N-dimethylformamide (4 mL). The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5um, mobile phase: ACN-H2O (0.1% FA), B%: 10% - 60%, 20 minutes) to obtain the formate salt of 25 (27.8 mg, yield 15.7%) as a white solid. LC-MS m / z (ESI): 504.0 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ ppm 11.10 - 10.82 (m, 1H), 8.87 - 8.71 (m, 3H), 8.54 (dd, J = 14.8, 2.6 Hz, 1H), 8.48 - 8.39 (m, 1H), 8.21 - 8.07 (m, 1H), 7.80 - 7.45 (m, 3H), 7.45 - 7.34 (m, 1H), 5.78 - 5.66 (m, 1H), 5.22 - 4.91 (m, 1H), 4.90 - 4.49 (m, 1H), 3.97 - 3.91 (m, 3H), 1.67 - 1.52 (m, 3H).

[1006] 26. Synthesis of Example 26

Chemical Structure

[1007] 26.1 Synthesis of Intermediate 26-1

[1008] To a solution of Compound 1-5 (2.0 g) and triethylamine (0.9 g) dissolved in dichloromethane (20 mL), ethyl 2-chloro-2-oxoacetate (1.1 g) was slowly added dropwise under an ice bath. The mixture was warmed to room temperature and stirred for 16 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain yellow oil 26-1 (1.9 g, yield 70.1%). LC-MS m / z (ESI): 393.1 [M+H] + .

[1009] 26.2 Synthesis of Intermediate 26-2

[1010] To a mixed solution of compound 26-1 (1.9 g) dissolved in ethanol and water (100 mL, V / V = 1:1), lithium hydroxide (238.0 mg) was added under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure. Water (10 mL) was added, and the pH was adjusted to weakly acidic with 2M hydrochloric acid. The mixture was extracted with dichloromethane (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 26-2 (1.5 g, 85.2%). LC-MS m / z (ESI): 355.1 [M+H] + .

[1011] 26.3 Synthesis of Intermediate 26-3

[1012] Sodium hydride (200.0 mg) was added to a solution of 2-amino-5-nitro-4-methylpyridine (500.0 mg) dissolved in tetrahydrofuran (20 mL). The mixture was stirred at room temperature for 0.5 hour. Di-tert-butyl dicarbonate (900.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to obtain yellow solid 26-3 (800.0 mg, yield 96.9%). LC-MS m / z (ESI): 198.1 [M-56+H] + .

[1013] 26.4 Synthesis of Intermediate 26-4

[1014] To a solution of palladium carbon (200.0 mg) dissolved in ethanol (20 mL), 26-3 (800.0 mg) was added under nitrogen. Hydrogen was introduced to purge the system three times, and the mixture was stirred at room temperature for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain a yellow solid 26-4 (300.0 mg, yield 40.8%). LC-MS m / z (ESI): 224.1 [M+H] + .

[1015] 26.5 Synthesis of Intermediate 26-5

[1016] To a solution of 26-2 (250.0 mg) dissolved in N,N-dimethylformamide (5 mL), 26-4 (100.0 mg), N,N-diisopropylethylamine (173.5 mg), and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (300.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2) to obtain a yellow solid 26-5 (35.0 mg, yield 14.8%). LC-MS m / z (ESI): 560.1 [M+H] + .

[1017] 26.6 Synthesis of Compound 26

[1018] Trifluoroacetic acid (1 mL) was added to a solution of 26-5 (35.0 mg) dissolved in dichloromethane (3 mL) under an ice bath. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5 um, mobile phase: ACN-H2O (0.1% FA), B%: 5% - 10%, 20 minutes) to obtain the formate salt of 26 (12.0 mg, yield 41.8%) as a white solid. LC-MS m / z (ESI): 460.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.10 - 9.96 (m, 1H), 8.83 - 8.74 (m, 3H), 8.14 - 8.10 (m, 1H), 7.70 - 7.63 (m, 1H), 7.46 - 7.35 (m, 2H), 6.32 - 6.25 (m, 1H), 5.95 - 5.88 (m, 3H), 5.25 - 4.97 (m, 1H), 4.92 - 4.59 (m, 1H), 2.01 - 1.82 (m, 3H), 1.66 - 1.52 (m, 3H).

[1019] 27. Synthesis of Example 27

Chemical Structure

[1020] 27.1 Synthesis of Intermediate 27-1

[1021] A solution of 4-dimethylaminopyridine (0.1 g), triethylamine (1.6 g) and 2-amino-5-bromo-3-methylpyrazine (1.0 g) in dichloromethane (20 mL) was added with di-tert-butyl dicarbonate (2.9 g), and the mixture was stirred at room temperature for 1 hour. The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 8 / 1 - 6 / 1) to obtain white solid 27-1 (1.9 g, yield 83.0%). LC-MS m / z (ESI): 410.0, 411.9 [M+Na] + .

[1022] 27.2 Synthesis of Intermediate 27-2

[1023] Copper(I) iodide (0.1 g) was added to a solution of 27-1 (1.0 g), ethyl oxamate (0.5 g), N,N'-dimethylethylenediamine (0.1 g) and cesium carbonate (2.5 g) in 1,4-dioxane (10 mL). The mixture was stirred at 100 °C for 3 hours under nitrogen. The mixture was cooled to room temperature and water (20 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 - 2 / 3) to obtain white solid 27-2 (600.0 mg, yield 65.4%). LC-MS m / z (ESI): 325.0 [M+H] + .

[1024] 27.3 Synthesis of Intermediate 27-3

[1025] A solution of 27-2 (580.0 mg) and triethylamine (271.0 mg) dissolved in dichloromethane (8 mL) was added dropwise with ethyl 2-chloro-2-oxoacetate (269.0 mg) under an ice bath. The mixture was stirred at room temperature for 1 hour. Dichloromethane (10 mL) was added. The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 to 3 / 1) to obtain white solid 27-3 (520.0 mg, yield 61.7%). LC-MS m / z (ESI): 425.0 [M+H] + .

[1026] 27.4 Synthesis of Intermediate 27-4

[1027] Lithium hydroxide (33.9 mg) was added to a mixed solution of 27-3 (500.0 mg) dissolved in methanol and water (5 mL, V / V = 3:1). The mixture was stirred at room temperature for 1 hour. Water (8 mL) was added and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was vacuum filtered to obtain crude white solid 27-4 (240.0 mg). The crude product was used directly in the next step reaction without purification. LC-MS m / z (ESI): 397.0 [M+H] + .

[1028] 27.5 Synthesis of Intermediate 27-5

[1029] Propylphosphonic anhydride (722.0 mg, 50% ethyl acetate solution) was added to a solution of N,N-diisopropylethylamine (244.5 mg), 27-4 (150.0 mg), and 1-5 (128.2 mg) dissolved in dichloromethane (4 mL). The mixture was stirred at room temperature for 2 hours. Ice water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1 to 10 / 1) to obtain white solid 27-5 (80.0 mg, yield 28.8%). LC-MS m / z (ESI): 661.0 [M+H] + .

[1030] 27.6 Synthesis of Compound 27

[1031] To a solution of 27-5 (70.0 mg) dissolved in dioxane (1 mL), a solution of HCl dissolved in dioxane (2 mL, 4 M) was added under an ice bath, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5um, mobile phase: ACN-H2O (0.1% FA), B%: 10% - 50%, 20 minutes) to obtain the formate salt of 27 (25.4 mg, yield 51.6%) as a white solid. LC-MS m / z (ESI): 461.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.03 - 10.58 (m, 1H), 8.80 - 8.71 (m, 3H), 8.41 - 8.06 (m, 2H), 7.69 - 7.54 (m, 1H), 7.39 - 7.33 (m, 1H), 6.15 - 6.11 (m, 2H), 5.71 - 5.47 (m, 1H), 5.12 - 4.65 (m, 2H), 2.28 - 2.22 (m, 3H), 1.64 - 1.53 (m, 3H).

[1032] 28. Synthesis of Example 28

Chemical Formula

[1033] 28.1 Synthesis of Intermediate 28-1

[1034] To a mixed solution of (R)-1-(pyrimidin-2-yl)ethanamine hydrochloride (146.0 mg) dissolved in 1,2-dichloroethane / methanol (5 mL, V / V = 1:1), triethylamine (153.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Acetic acid (91.0 mg) and 5-cyanopyridine-2-carboxaldehyde (100.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (321.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 28-1 (70.0 mg, yield 38.7%). LC-MS m / z (ESI): 240.0 [M+H] + .

[1035] 28.2 Synthesis of Intermediate 28-2

[1036] Compound 28-1 (45.0 mg), propylphosphonic anhydride (121.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (33.0 mg) were added to a solution of Compound 1-4 (50.0 mg) dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1) to obtain yellow solid 28-2 (30.0 mg, yield 38.2%). LC-MS m / z (ESI): 617.3 [M+H] + .

[1037] 28.3 Synthesis of Compound 28

[1038] Trifluoroacetic acid (1 mL) was added to a solution of Compound 28-2 (30.0 mg) dissolved in dichloromethane (4 mL) under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. Water (10 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), B%: 2% - 35%, 14 minutes) to obtain the formate salt of 28 (1.9 mg, yield 9.3%) as a white solid. LC-MS m / z (ESI): 417.2 [M+H] + . 11H NMR (400 MHz, MeOD-d4) δ ppm 8.75 - 8.69 (m, 3H), 8.08 - 8.03 (m, 2H), 7.65 - 7.61 (m, 1H), 7.51 - 7.49 (m, 1H), 7.34 - 7.30 (m, 1H), 5.86 - 5.81 (m, 1H), 5.33 - 4.69 (m, 2H), 2.16 - 2.12 (m, 3H), 1.74 - 1.59 (m, 3H).

[1039] 29. Synthesis of Example 29 [Chemical Structure Diagram]

[1040] 29.1 Synthesis of Intermediate 29-1

[1041] To a solution of (R)-1-(pyrimidin-2-yl)ethanamine hydrochloride (558.0 mg) in 1,2-dichloroethane (10 mL), triethylamine (367.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Acetic acid (323.0 mg) and 5-bromopyridine-2-carbaldehyde (500.0 mg) were added, and the mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (1140.0 mg) was added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added, and the pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 29-1 (250.0 mg, yield 31.7%). LC-MS m / z (ESI): 293.1, 295.1 [M+H] + .

[1042] 29.2 Synthesis of Intermediate 29-2

[1043] A solution of compound 29-1 (250.0 mg) and triethylamine (175.0 mg) in dichloromethane (5 mL) was added with di-tert-butyl dicarbonate (280.0 mg), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain yellow solid 29-2 (240 mg, yield 71.6%). LC-MS m / z (ESI): 392.9, 394.9 [M+H] + .

[1044] 29.3 Synthesis of Intermediate 29-3

[1045] 3,3-Difluoropyrrolidine hydrochloride (168.0 mg), methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-amino-1,1’-biphenyl-2-yl)palladium(II) (98.0 mg), 2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl (109.0 mg) and cesium carbonate (760.0 mg) were added to a solution of compound 29-2 (230.0 mg) in 1,4-dioxane (10 mL), and the mixture was stirred at 90 °C for 16 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain yellow oil 29-3 (150.0 mg, yield 56.2%). LC-MS m / z (ESI): 420.0 [M+H] + .

[1046] 29.4 Synthesis of Intermediate 29-4

[1047] A solution of compound 29-3 (150.0 mg) in dichloromethane (5 mL) was added with trifluoroacetic acid (2 mL) under an ice bath, and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and water (20 mL) was added. The pH was adjusted to weakly alkaline with saturated sodium carbonate solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow oil 29-4 (90.0 mg, yield 78.9%). LC-MS m / z (ESI): 320.2 [M+H] + .

[1048] 29.5 Synthesis of Intermediate 29-5

[1049] Compound 29-4 (90.0 mg), propylphosphonic anhydride (359.0 mg, 50% ethyl acetate solution), and N,N-diisopropylethylamine (110.0 mg) were added to a solution of compound 1-4 (167.0 mg) dissolved in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to obtain yellow solid 29-5 (90.0 mg, yield 45.9%). LC-MS m / z (ESI): 697.3 [M+H] + .

[1050] 29.6 Synthesis of Compound 29

[1051] A solution of compound 29-5 (90.0 mg) in dichloromethane (3 mL) was added with trifluoroacetic acid (1 mL) under an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to weakly alkaline with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini 5u C18 150×21.2 mm, mobile phase: ACN-H2O (0.1% FA), B%: 2% - 30%, 15 minutes) to obtain the formate salt of 29 (11.0 mg, yield 17.2%) as a white solid. LC-MS m / z (ESI): 497.2 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ ppm 8.71 - 8.69 (m, 2H), 8.08 - 7.96 (m, 1H), 7.82 - 7.72 (m, 1H), 7.62 - 7.52 (m, 1H), 7.34 - 7.21 (m, 2H), 7.00 - 6.94 (m, 1H), 5.72 - 5.62 (m, 1H), 4.96 - 4.49 (m, 2H), 3.71 - 3.63 (m, 2H), 3.55 - 3.50 (m, 2H), 2.54 - 2.49 (m, 2H), 2.14 - 2.11 (m, 3H), 1.68 - 1.60 (m, 3H).

[1052] 30. Synthesis of Example 30

Chemical Structure

[1053] 30.1 Synthesis of Intermediate 30-1

[1054] A solution of 4-bromo-7-chloro-1H-pyrazolo[3,4-c]pyridine (3.0 g) in N,N-dimethylformamide (30 mL) was added with sodium hydride (2.0 g, 60%) at 0 °C under nitrogen, and the mixture was stirred for 1 hour. Iodomethane (375.0 mg) was added dropwise to the reaction solution, and the mixture was heated to room temperature and stirred for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain white solid 30-1 (1.9 g, yield 61.9%). LC-MS m / z (ESI): 245.9, 247.8 [M+H] + .

[1055] 30.2 Synthesis of Intermediate 30-2

[1056] To a solution of 30-1 (1.9 g) in N-methylpyrrolidone (20 mL) were added sodium carbonate (1.6 g) and p-anisidine (1.6 g) under nitrogen, and the mixture was stirred at 130 °C for 2 hours. Water (60 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain white solid 30-2 (1.6 g, yield 60.4%). LC-MS m / z (ESI): 346.9, 348.9 [M+H] + .

[1057] 30.3 Synthesis of Intermediate 30-3

[1058] Under nitrogen, 30-2 (1.6 g) was added to trifluoroacetic acid (20 mL), and the mixture was stirred at 60 °C for 16 hours. Saturated sodium bicarbonate solution (60 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain white solid 30-3 (800.0 mg, yield 76.9%). LC-MS m / z (ESI): 227.0, 229.1 [M+H] + .

[1059] 30.4 Synthesis of Intermediate 30-4

[1060] To a solution of 30-3 (800 mg) dissolved in dichloromethane (20 mL), triethylamine (1.5 g), 4-dimethylaminopyridine (80.0 mg) and di-tert-butyl dicarbonate (1.9 g) were added under nitrogen, and the mixture was stirred at room temperature for 2 hours. Water (60 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1) to obtain white solid 30-4 (900.0 mg, yield 59.6%). LC-MS m / z (ESI): 449.0, 451.0 [M+Na] + .

[1061] 30.5 Synthesis of Intermediate 30-5

[1062] To a solution of 30-4 (50.0 mg) dissolved in anhydrous dioxane (8 mL), trifluoroacetamide (250.0 mg), cesium carbonate (380.0 mg), copper(I) iodide (30.0 mg), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (16.0 mg) were added. The mixture was stirred at 100 °C for 16 h under nitrogen. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1) to obtain yellow solid 30-5 (120.0 mg, yield 56.3%). LC-MS m / z (ESI): 364.2 [M+H] + .

[1063] 30.6 Synthesis of Intermediate 30-6

[1064] To a solution of triethylamine (35.0 mg) and 30-5 (110.0 mg) dissolved in anhydrous dichloromethane (5 mL), ethyl 2-chloro-2-oxoacetate (45.0 mg) was added dropwise at 0 °C under nitrogen, and the mixture was stirred at 0 °C for 1 h. The mixture was warmed to room temperature and water (20 mL) was added. The mixture was extracted with dichloromethane (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1) to obtain yellow solid 30-6 (110 mg, yield 72.3%). LC-MS m / z (ESI): 464.0 [M+H] + .

[1065] 30.7 Synthesis of Intermediate 30-7

[1066] A solution of 30-6 (40.0 mg) dissolved in 1,2-dichloroethane (6 mL) was added with trimethylstannyl hydroxide (78.0 mg) at room temperature, and the mixture was stirred at 50 °C for 2 hours. The mixture was cooled to room temperature. Dichloromethane (20 mL) and water (20 mL) were added, and the pH was adjusted to 4 - 5 with 1 M hydrochloric acid. The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain an off-white solid crude product 30-7 (40.0 mg). The crude product was used directly in the reaction of the next step. LC-MS m / z (ESI): 436.2 [M+H] + .

[1067] 30.8 Synthesis of Intermediate 30-8

[1068] To a solution of triethylamine (32.0 mg), 1-5 (27.0 mg) and 30-7 (35.0 mg) dissolved in N,N-dimethylformamide (2 mL), propylphosphonic anhydride (102.0 mg, 50% ethyl acetate solution) was added under nitrogen at room temperature, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (30 mL) was added to dilute the mixture, and the mixture was washed with saturated sodium chloride solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 1 - 30 / 1) to obtain an off-white solid 30-8 (30.0 mg, yield 53.5%). LC-MS m / z (ESI): 700.0 [M+H] + .

[1069] 30.9 Synthesis of Compound 30

[1070] Trifluoroacetic acid (1 mL) was added to a solution of 30 - 8 (30.0 mg) dissolved in dichloromethane (2 mL) under nitrogen and in an ice bath. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Xbridge-C18 150×19 mm, 5 um, mobile phase: ACN-H2O (0.05% NH4OH), B%: 20% - 50%, 15 minutes) to obtain a white solid 30 (4.0 mg, yield 18.7%). LC-MS m / z (ESI): 500.0 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ ppm 8.73 - 8.69 (m, 3H), 8.05 - 7.82 (m, 2H), 7.75 - 7.66 (m, 1H), 7.64 - 7.55 (m, 1H), 7.33 - 7.29 (m, 1H), 5.91 - 5.82 (m, 1H), 5.35 - 5.12 (m, 1H), 5.05 - 4.78 (m, 1H), 4.34 - 4.30 (m, 3H), 1.76 - 1.63 (m, 3H).

[1071] 31. Synthesis of Example 31

Chemical Structure

[1072] 31.1 Synthesis of Intermediate 31-1

[1073] A solution of 4-dimethylaminopyridine (64.6 mg), triethylamine (802.4 mg) and 4-nitroisoquinolin-1-amine (500.0 mg) in dichloromethane (8 mL) was added with di-tert-butyl dicarbonate (1442.1 mg), and the mixture was stirred at room temperature for 1 hour. The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 - 2 / 3) to obtain white solid 31-1 (830.0 mg, yield 72.5%). LC-MS m / z (ESI): 412.0 [M+Na] + . 【107...

Claims

1. A compound of formula (X), or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. 【Chemical 1】 (wherein, Ring A is C ６～１０ aryl or 5- to 10-membered heteroaryl, L １ is NH or CHR ｘ and L ２ is CR ｘ R ｙ and L ３ is -C(O)-, -S(O)- or -S(O) ２ - and Here, R ｘ and R ｙ are, independently, H, D, C １～６ alkyl or C １～６ haloalkyl, or Or, CR ｘ R ｙ come together to form C=O, C=S or C ３～６ cycloalkylene, or or L １ is CHR ｘ and L ２ is CR ｘ R ｙ in the case where, the two R ｘ groups may be bonded to form a chemical bond or C １～４ alkylene, R １ is selected from H, D, halogen, CN, NO ２ , -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , SF ５ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , OC(O)R ａ , NR ｂ C(O)R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)(=NR ａ )R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , P(O)(R ａ ) ２ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～７ cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R １ｓ s, m = 0, 1, 2, 3 or 4, R ４ is selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or or, one R １ is R ４ bonded to, -(CR ｓｓ R ｓｓ ) ｑ１ -X-(CR ｓｓ R ｓｓ ) ｑ２ -(alternatively -(CH ２ ) ｑ１ -X-(CH ２ ) ｑ２ -)(wherein X is O, S, NH or CH ２ , q1 = 0, 1 or 2, q2 = 1, 2 or 3, and R ｓｓ is independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or two R ｓｓ and the carbon atom to which they are attached together form C ３～１０ cycloalkyl) is formed, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ , NR ｂ R ｃ , C(O)OR ａ and C(O)NR ｂ R ｃ and is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl and 3- to 10-membered heterocyclyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or X １ X ２ and their substituents together form C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ２ｓ and R ２ｄ is selected from H, D, halogen, CN, NO ２ , OR ａ , NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R ３ is selected from -C １～６ alkylene - OR ａ , -C １～６ alkylene - NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～１０ cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, and these are optionally substituted with 1, 2 or 3 R ３ｓ１ and 1 R ３ｓ２ and are optionally substituted, L is a chemical bond, C １～６ alkylene, C ２～６ alkenylene or C ２～６ alkynylene, and these are optionally substituted with one, two or three Rs, R １ｓ and R ２ｓ are, independently, H, D, halogen, CN, =O, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, or two Rs １ｓ and the atoms to which they are attached together form a C ３～１０ cycloalkyl or 3- to 10-membered heterocyclyl, R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R ３ｓ２ is selected from H, D, -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, and these are optionally substituted with 1, 2 or 3 R ３ｓ or or, R ３ｓ１ , R ３ｓ２ and the carbon atoms to which they are attached together form a C ３～１０ cycloalkyl, R and R ３ｓ are each independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, The above-mentioned rings A and L １ and L ２ and R ｘ and R ｙ and R １ and R ２ａ and R ２ｂ and R ２ｃ and R ２ｄ and R ３ and R ４ and L, R, R[[ID=A]] １ｓ and R ２ｓ and R ３ｓ and R ３ｓ１ and R ３ｓ２ and R ａ and R ｂ and R ｃ Each of the groups in and R is optionally deuterated until it is completely deuterated. It should be noted that there seems to be a repeated tag [[ID=A]] in your original text which might be an error. This has been left as is in the translation. If this is incorrect, please check and correct the original text for a more accurate translation. However, L ２ is CR ｘ R ｙ and when L ３ is -S(O)- or -S(O) ２ -, R ｙ and R ２ｄ combine to form vinylene.)

2. The compound according to claim 1, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the above ring A is phenyl or a 5- to 6-membered heteroaryl, alternatively, phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

3. L １ is NH, and L ２ is CR ｘ R ｙ and -L １ -L ２ - is alternatively [Chemical 2] and -L １ -L ２ - is alternatively [Chemical Formula 3] The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is

4. L ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein L is -C(O)-.

5. R １ and R ４ are joined to form -(CH ２ ｑ１ -X-(CH ２ ｑ２ -(wherein X is O, S, NH or CH ２ and q1 = 0 or 1, q2 = 1 or 2), or alternatively, R １ and R ４ are joined to form -(CH ２ ｑ１ -X-(CH ２ ｑ２ -(wherein X is O, S or NH and q1 = 0 or 1, q2 = 1 or 2), a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.​​​​

6. 【Fig. 4】 is 【Chemical Formula 5】 selected from, alternatively 【Chemical Formula 6】 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is

7. R ２ａ is H, D, CN, OR ａ and NR ｂ R ｃ selected from, alternatively OR ａ and NR ｂ R ｃ selected from, alternatively OMe and NH ２ selected from, alternatively NH ２ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

8. X １ , X ２ and their substituents together form a C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl, or alternatively, C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, or alternatively, 【Chemical Formula 7】 forms, alternatively, [Chemical Formula 8] forms, alternatively, 【Chemical Formula 9】 forms, alternatively, 【Chemical Formula 10】 forms. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

9. R ３ is C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～１０ cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, alternatively C １～６ alkyl, C １～６ haloalkyl, -L-C ３～１０ cycloalkyl, -L-3- to 10-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, alternatively C １～６ alkyl, C １～６ haloalkyl, C ５～６ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, alternatively Me, Et, iPr, cyclopropyl, cyclobutyl, 【Chemical 11】 selected from. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

10. The above compound has the following structural formula: 【Chemical 12】 wherein, each group is as defined in claims 1 to 9. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

11. A compound of formula (II), wherein, L １ is NH or CHR ｘ and L ２ is CR ｘ R ｙ and is Here, R ｘ and R ｙ are each independently H, D, C １～６ alkyl or C １～６ haloalkyl, or or CR ｘ R ｙ together form C=O, C=S or C ３～６ cycloalkylene, or or L １ is CHR ｘ and L ２ is CR ｘ R ｙ in the case where, the two R ｘ groups may be bonded to form a chemical bond or C １～４ alkylene Z １ is CH or N, R １ is selected from H, D, halogen, CN, OR ａ , SR ａ , NR ｂ R ｃ , SF ５ , C １～６ alkyl, C １～６ haloalkyl, C ５～７ cycloalkyl and 5- to 7-membered heterocyclyl, which are optionally substituted with one, two or three R １ｓ ; m = 0, 1, 2 or 3, alternatively m = 0, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ａ is selected from H, D, OR ａ and NR ｂ R ｃ and is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or X １ , X ２ and their substituents together form C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , OR ａ , NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R １ｓ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～７ cycloalkyl and 5- to 7-membered heterocyclyl, R ２ｓ is selected from H, D, halogen, =O, C １～６ alkyl and C １～６ haloalkyl, and R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ３ｓ２ is selected from H, D, -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R ３ｓ ; L is a chemical bond or C １～６ alkylene, which are optionally substituted with one, two or three Rs, R and R ３ｓ are each independently selected from H, D, halogen, C １～６ alkyl, and C １～６ haloalkyl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, the above L １ , L ２ R ｘ R ｙ Z １ R １ R ２ａ R ２ｂ R ２ｃ R ２ｄ R １ｓ R ２ｓ R ３ｓ１ R ３ｓ２ L, R, R ３ｓ R ａ R ｂ and R ｃ Each of the groups in L, L, R, R, Z, R, R, R, R, R, R, R, R, R, R, R, R, L, R, R, R, R, and R is optionally deuterated until fully deuterated, a compound according to claim 10, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

12. L １ is NH or CHR ｘ and L ２ is CR ｘ R ｙ and Here, R ｘ and R ｙ are, independently, H, D, C １～６ alkyl or C １～６ haloalkyl, or or, CR ｘ R ｙ are combined together to form C=O, C=S or C ３～４ cycloalkylene, or or L １ is CHR ｘ and L ２ is CR ｘ R ｙ when it is, the two R ｘ groups may be bonded to form a chemical bond or C １～３ alkylene Z １ is CH or N, R １ is selected from H, D, halogen, CN, OR ａ , NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl and 5- to 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with 1, 2 or 3 R １ｓ and m = 0, 1, 2 or 3, alternatively m = 0, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ａ is NH ２ and R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or X １ X ２ and their substituents together form C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, C １～６ alkyl and C １～６ haloalkyl, and R １ｓ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, R ２ｓ is selected from H, D, =O, C １～６ alkyl and C １～６ haloalkyl, R ３ｓ１ is selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ３ｓ２ is selected from H, D, -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ３ｓ and L is a chemical bond or C １～３ alkylene, which are optionally substituted with one, two or three Rs, R and R ３ｓ are each independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ 、 R ｂ and R ｃ are independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, the compound according to claim 11, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

13. L １ is NH or CHR ｘ and L ２ is CR ｘ R ｙ and Here, R ｘ and R ｙ are, independently, H, D, C １～３ alkyl or C １～３ haloalkyl, or or, CR ｘ R ｙ combine to form C=O or cyclopropylene, or or L １ is CHR ｘ and L ２ is CR ｘ R ｙ in the case where, the two R ｘ groups are bonded to form a chemical bond or C １～２ alkylene may be formed Z １ is CH or N, R １ is selected from H, D, CN, OR ａ , C １～６ alkyl, C １～６ haloalkyl and 5- to 6-membered heterocyclyl, which are optionally substituted with 1, 2 or 3 R １ｓ and are optionally substituted with m = 0, 1, 2 or 3, alternatively m = 0, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ａ is NH ２ and R ２ｂ is selected from H, D, halogen, C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl and 4- to 6-membered heterocyclyl, R ２ｃ is selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or or X １ X ２ and their substituents together form C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ２ｓ alternatively, X １ X ２ and their substituents together form 【Chemical Formula 13】 forms, R ２ｄ is selected from H and D, R １ｓ is selected from H, D, halogen, C(O)OR ａ , C １～６ alkyl and C １～６ haloalkyl, or alternatively is halogen or C(O)OCH ３ and R ２ｓ is selected from H, D, =O and Me, R ３ｓ１ is selected from H, D, C １～６ alkyl, C １～６ haloalkyl and C ３～６ cycloalkyl, and R ３ｓ２ is H, D, -L-OR ａ , C １～６ alkyl, C １～６ haloalkyl, C ５～７ cycloalkyl, phenyl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ３ｓ alternatively, R ３ｓ２ is H, D, Me, CF ３ , CH ２ OCH ３ , cyclopropyl, 【Chemical 14】 selected from, L is a chemical bond or C １～３ alkylene, alternatively methylene, which are optionally substituted with one, two or three Rs, R and R ３ｓ are each independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ 、R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, the compound according to claim 11, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

14. A compound of formula (II), wherein, L １ is NH, L ２ is CR ｘ R ｙ wherein CR ｘ R ｙ together form C=O or C=S, R １ is H, D, halogen, CN, NO ２ , -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , SF ５ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , OC(O)R ａ , NR ｂ C(O)R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , P(O)(R ａ ) ２ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～７ cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ 's, m = 0, 1, 2, 3 or 4, X １ is a C atom, which is substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom, which is substituted with R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ , NR ｂ R ｃ , C(O)OR ａ and C(O)NR ｂ R ｃ and is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl and 3- to 10-membered heterocyclyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or, X １ , X ２ and their substituents together form C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical Formula 15】 ), which are formed, and these are optionally substituted with one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , OR ａ , NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, Z １ is CH, L is a chemical bond, C １～６ alkylene, C ２～６ alkenylene or C ２～６ alkynylene, and these are optionally substituted with one, two or three Rs, R １ｓ and R ２ｓ are each independently H, D, halogen, =O, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, and are selected from R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R ３ｓ２ is -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5 - to 10 - membered heterocyclyl, C ６～１０ aryl and 5 - to 10 - membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ３ｓ s, R and R ３ｓ are each independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ 、 R ｂ and R ｃ are independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, or alternatively H, D, C １～６ alkyl or C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, Here, each of the above groups is optionally deuterated until fully deuterated, the compound according to claim 10, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

15. L １ is NH, L ２ is CR ｘ R ｙ and here, CR ｘ R ｙ together form C=O or C=S, R １ is H, D, halogen, CN, NO ２ , -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , SF ５ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , OC(O)R ａ , NR ｂ C(O)R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～７ cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ and m = 0, 1, 2, 3 or 4, X １ is a C atom, which is substituted by R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom, which is substituted by R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ and NR ｂ R ｃ and is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or Or, X １ , X ２ and their substituents together form C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical 16】 ), which are formed and these are optionally substituted by one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , OR ａ , NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, and Z １ is CH, L is a chemical bond, C １～６ alkylene, C ２～６ alkenylene or C ２～６ alkynylene, and R １ｓ and R ２ｓ are independently selected from H, D, halogen, =O, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, and R ３ｓ２ is -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5 - to 10 - membered heterocyclyl, C ６～１０ aryl and 5 - to 10 - membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ３ｓ 's, R ３ｓ is independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl, 3- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, or alternatively H, D, C １～６ alkyl or C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, wherein each of the above groups is optionally deuterated until fully deuterated, the compound according to claim 14, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

16. L １ is NH, L ２ is CR ｘ R ｙ and here, CR ｘ R ｙ together form C=O or C=S, R １ is selected from H, D, halogen, CN, NO ２ , -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , SF ５ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～７ cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, and these are optionally substituted with 1, 2 or 3 R １ｓ 's, m = 0, 1, 2, 3 or 4, X １ is a C atom, which is substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom, which is substituted with R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ and NR ｂ R ｃ and is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, and R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or, X １ , X ２ and their substituents together form C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical 17】 ) are formed, and these are optionally substituted with one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , C １～６ alkyl and C １～６ haloalkyl, and Z １ is CH, L is a chemical bond or C １～６ alkylene, R １ｓ and R ２ｓ are each independently selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, and R ３ｓ２ is -L-OR ａ ,-L-NR ｂ R ｃ ,C １～６ alkyl,C １～６ haloalkyl,C ３～１０ cycloalkyl,a 5 - to 10 - membered heterocyclyl,C ６～１０ aryl and a 5 - to 10 - membered heteroaryl,selected from these,and these are optionally substituted with 1,2 or 3 R ３ｓ 's,and R ３ｓ is independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ , R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3-6 membered heterocyclyl, or alternatively H, D, C １～６ alkyl or C １～６ haloalkyl, or R ｂ , R ｃ and the atoms to which they are attached together form a 5-10 membered heterocyclyl, wherein each of the above groups is optionally deuterated until fully deuterated, the compound according to claim 14, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

17. L １ is NH, L ２ is CR ｘ R ｙ and here, CR ｘ R ｙ together form C=O or C=S, R １ is H, D, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , SF ５ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , OC(O)R ａ , NR ｂ C(O)R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , P(O)(R ａ ) ２ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～７ cycloalkyl and -L-5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R １ｓ 's, m = 0, 1, 2, 3 or 4, X １ is a C atom, which is substituted by R ２ｂ and X ２ is a C atom, which is substituted by R ２ｃ and X ３ is a C atom, which is substituted by R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ , NR ｂ R ｃ , C(O)OR ａ and C(O)NR ｂ R ｃ and is selected from R ２ｂ is C(O)OR ａ C(O)NR ｂ R ｃ C １～６ alkyl and C １～６ selected from haloalkyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or X １ , X ２ and their substituents together form a 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical Formula 18】 ), which are formed, and these are optionally substituted with one, two or three Rs ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , OR ａ , NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, Z １ is CH, L is a chemical bond, C １～６ alkylene, C ２～６ alkenylene or C ２～６ alkynylene, and these are optionally substituted with one, two or three Rs, R １ｓ and R ２ｓ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R ３ｓ２ is -L-OR ａ -L-NR ｂ R ｃ C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5 - to 10 - membered heterocyclyl, C ６～１０ aryl and 5 - to 10 - membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ３ｓ and, R and R ３ｓ are, independently, H, D, C １～６ alkyl and C １～６ selected from haloalkyl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, or alternatively H, D, C １～６ alkyl or C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, wherein each of the above groups is optionally deuterated until fully deuterated, the compound according to claim 14, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

18. L １ is NH, L ２ is CR ｘ R ｙ and here, CR ｘ R ｙ together form C=O or C=S, R １ is H, D, -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～７ cycloalkyl and -L-5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ and m = 0, 1, 2, 3 or 4, X １ is a C atom, which is substituted with R ２ｂ and X ２ is a C atom, which is substituted with R ２ｃ and X ３ is a C atom, which is substituted by R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ and NR ｂ R ｃ and is selected from R ２ｂ is C(O)OR ａ C(O)NR ｂ R ｃ C １～６ alkyl and C １～６ selected from haloalkyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or Or, X １ , X ２ and their substituents together form a 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical Formula 19】 ), which are formed, and these are optionally substituted with one, two or three Rs ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen and CN, Z １ is CH, L is a chemical bond, C １～６ alkylene, C ２～６ alkenylene or C ２～６ alkynylene, and R １ｓ and R ２ｓ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, and R ３ｓ２ is -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ is selected from aryl and 5- to 10-membered heteroaryl, R ａ 、 R ｂ and R ｃ each independently is selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, or alternatively is H, D, C １～６ alkyl or C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, wherein each of the above groups is optionally deuterated until fully deuterated, the compound according to claim 17, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

19. L １ is NH, L ２ is CR ｘ R ｙ and here, CR ｘ R ｙ together form C=O or C=S, R １ is H, D, OR ａ , SR ａ , NR ｂ R ｃ , C(O)R ａ , S(O)R ａ , S(O) ２ R ａ , C １～６ alkyl, C １～６ haloalkyl, C ３～７ selected from cycloalkyl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ s, m = 0, 1, 2, 3 or 4, X １ is a C atom, which is substituted by R ２ｂ and X ２ is a C atom, which is substituted with R ２ｃ and X ３ is a C atom, which is substituted by R ２ｄ and R ２ａ is OR ａ and NR ｂ R ｃ is selected from R ２ｂ is C(O)OR ａ C(O)NR ｂ R ｃ C １～６ alkyl and C １～６ selected from haloalkyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or Or, X １ , X ２ and their substituents together form a 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical 20】 ), which are formed and these are optionally substituted with one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, and CN, Z １ is CH, L is a chemical bond or C １～６ is alkylene, R １ｓ and R ２ｓ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, R ３ｓ１ is selected from H, D, halogen, C １～４ alkyl and C １～４ haloalkyl, and R ３ｓ２ is -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ is selected from aryl and 5- to 10-membered heteroaryl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, or alternatively H, D, C １～６ alkyl or C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, wherein each of the above groups is optionally deuterated until fully deuterated, the compound according to claim 17, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

20. L １ is NH, L ２ is CR ｘ R ｙ and here, CR ｘ R ｙ together form C=O or C=S, R １ is H, D, OR ａ , SR ａ , NR ｂ R ｃ , C(O)R ａ , S(O)R ａ , S(O) ２ R ａ , C １～６ alkyl, C １～６ haloalkyl, C ３～７ cycloalkyl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ and m = 0, 1, 2, 3 or 4, X １ is a C atom, which is substituted with R ２ｂ and X ２ is a C atom, which is substituted with R ２ｃ and X ３ is a C atom, which is substituted with R ２ｄ and R ２ａ is OR ａ and NR ｂ R ｃ is selected from R ２ｂ is selected from COOR ａ , CONR ｂ R ｃ and C １～６ selected from alkyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or, X １ , X ２ and their substituents together form a 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical 21】 ), which are optionally substituted with one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen and CN, Z １ is CH, L is a chemical bond or C １～６ is alkylene, R １ｓ and R ２ｓ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, R ３ｓ１ is Me, R ３ｓ２ is Et, R ａ 、 R ｂ and R ｃ are independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3-6 membered heterocyclyl, or alternatively H, D, C １～６ alkyl or C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5-10 membered heterocyclyl, wherein each of the above groups is optionally deuterated until fully deuterated, the compound according to claim 17, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

21. L １ is NH, L ２ is CR ｘ R ｙ where CR ｘ R ｙ together form C=O or C=S, R １ is H, D, OR ａ , SR ａ , NR ｂ R ｃ , C(O)R ａ , S(O)R ａ , S(O) ２ R ａ , C １～６ alkyl, C １～６ haloalkyl, C ３～７ cycloalkyl and 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ and m = 0, 1, 2, 3 or 4, X ３ is a C atom, which is substituted by R ２ｄ and R ２ａ is OR ａ and NR ｂ R ｃ is selected from X １ , X ２ and their substituents together form a 5- or 6-membered heteroaryl (alternatively 【Chemical 22】 ) to form, which is optionally substituted with one, two or three R ２ｓ and is optionally substituted with R ２ｄ is selected from H, D, halogen and CN, Z １ is CH, R １ｓ and R ２ｓ are independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, R ３ｓ１ is selected from H and D, R ３ｓ２ is selected from C ３～６ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, Here, each of the above groups is optionally deuterated until fully deuterated, a compound according to claim 17, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

22. L １ is NH, L ２ is CR ｘ R ｙ and here, CR ｘ R ｙ together form C=O or C=S, R １ is H, D, OR ａ , SR ａ , NR ｂ R ｃ , C(O)R ａ , S(O)R ａ , S(O) ２ R ａ , C １～６ alkyl, C １～６ haloalkyl, C ３～７ selected from cycloalkyl and 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ and m = 0, 1, 2, 3 or 4, X ３ is a C atom, which is substituted with R ２ｄ and R ２ａ is OR ａ and NR ｂ R ｃ is selected from X １ , X ２ and their substituents together form a 5- to 6-membered heteroaryl (alternatively 【Chemical 23】 ), which is formed with one, two or three Rs ２ｓ optionally substituted with R ２ｄ is selected from H, D, halogen and CN, Z １ is CH, L is a chemical bond or C １～６ alkylene, and R １ｓ and R ２ｓ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, R ３ｓ１ is selected from C １～４ alkyl and C １～４ haloalkyl, R ３ｓ２ is -L-OR ａ or -L-NR ｂ R ｃ or C １～６ alkyl and C １～６ selected from haloalkyl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, Here, each of the above groups is optionally deuterated until fully deuterated, a compound according to claim 17, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

23. A compound of formula (III), wherein L １ is NH or CHR ｘ and L ２ is CR ｘ R ｙ and is Here, R ｘ and R ｙ are, independently, H, D, C １～６ alkyl or C １～６ haloalkyl, or or, CR ｘ R ｙ are combined to form C=O, C=S or C ３～６ cycloalkylene, or or L １ is CHR ｘ and L ２ is CR ｘ R ｙ in the case where, the two R ｘ groups are bonded to form a chemical bond or C １～４ alkylene may be formed, Z １ is CH or N, R １ is selected from H, D, halogen, CN, OR ａ , SR ａ , NR ｂ R ｃ , SF ５ , C １～６ alkyl, C １～６ haloalkyl, C ５～７ cycloalkyl and 5- to 7-membered heterocyclyl, which are optionally substituted with one, two or three R １ｓ 's, m = 0, 1, 2 or 3, alternatively m = 0, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or Or, X １ , X ２ and their substituents together form C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ２ｓ and R ２ｄ is selected from H and D, R １ｓ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～７ cycloalkyl and 5- to 7-membered heterocyclyl, R ２ｓ is selected from H, D, halogen, =O, C １～６ alkyl and C １～６ haloalkyl, and R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ３ｓ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, and p = 0, 1, 2 or 3, alternatively p = 0, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, the above-mentioned L １ 、L ２ 、R ｘ 、R ｙ 、Z １ 、R １ 、R ２ｂ 、R ２ｃ 、R １ｓ 、R ２ｓ 、R ３ｓ１ 、R ３ｓ 、R ａ 、R ｂ and R ｃ Each of the groups in, is optionally deuterated until fully deuterated, the compound according to claim 10, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

24. L １ is NH or CHR ｘ and L ２ is CR ｘ R ｙ and Here, R ｘ and R ｙ are, independently, H, D, C １～６ alkyl or C １～６ haloalkyl, or Or, CR ｘ R ｙ are combined to form C=O, C=S or C ３～４ cycloalkylene, or or L １ is CHR ｘ and L ２ is CR ｘ R ｙ when it is, the two R ｘ groups may be bonded to form a chemical bond or C １～３ alkylene Z １ is CH or N, R １ is selected from H, D, halogen, CN, OR ａ , NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl and 5- to 6-membered heterocyclyl, where the heterocyclyl is optionally substituted with 1, 2 or 3 R １ｓ s, m = 0, 1, 2 or 3, alternatively m = 0, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or or X １ , X ２ and their substituents together form C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with one, two or three R ２ｓ and R ２ｄ is selected from H and D, R １ｓ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, and R ２ｓ is selected from H, D, =O, C １～６ alkyl and C １～６ haloalkyl, and R ３ｓ１ is selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl and 3- to 6-membered heterocyclyl, R ３ｓ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, and p = 0, 1, 2 or 3, alternatively p = 0, R ａ 、 R ｂ and R ｃ are each independently H, D, C １～６ alkyl and C １～６ haloalkyl, the compound according to claim 23, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

25. L １ is NH or CHR ｘ and L ２ is CR ｘ R ｙ and Here, R ｘ and R ｙ are each independently H, D, C １～３ alkyl or C １～３ haloalkyl, or or, CR ｘ R ｙ combine to form C=O or cyclopropylene, or or L １ is CHR ｘ and L ２ is CR ｘ R ｙ in the case where, the two R ｘ groups may be bonded to form a chemical bond or C １～２ alkylene, Z １ is CH or N, R １ is selected from H, D, CN, OR ａ , C １～６ alkyl, C １～６ haloalkyl and 5- to 6-membered heterocyclyl, which are optionally substituted with 1, 2 or 3 R １ｓ and are optionally substituted with m = 0, 1, 2 or 3, alternatively m = 0, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which may be optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ｂ is selected from H, D, halogen, C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl and 4- to 6-membered heterocyclyl, R ２ｃ is selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or or X １ , X ２ and their substituents together form C ５～７ cycloalkyl, 5- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ２ｓ and are optionally substituted with R ２ｄ is selected from H and D, R １ｓ is selected from H, D, halogen, C(O)OR ａ , C １～６ alkyl and C １～６ haloalkyl, alternatively halogen or C(O)OCH ３ and R ２ｓ is selected from H, D, =O and Me, R ３ｓ１ is selected from H, D, C １～６ alkyl, C １～６ haloalkyl and C ３～６ cycloalkyl, and R ３ｓ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, and p = 0, 1, 2 or 3, alternatively p = 0, R ａ 、 R ｂ and R ｃ are, independently, H, D, C １～６ alkyl and C １～６ alkyl selected from haloalkyl, the compound according to claim 23, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

26. L １ -L ２ is 【Chemical 24】 wherein Z １ is CH or N, R １ is CF ３ , CN, OCF ３ , OCH ２ CH ３ , 【Chemical 25】 and alternatively CF ３ and m = 0, X １ is a C atom or an N atom, which are optionally substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom or an N atom, which are optionally substituted with R ２ｄ and R ２ｂ is H, F, Cl, Br, Me, CH ２ CH ３ , C(O)NH ２ or ​ wherein R ２ｃ is H or Me, or Or, X １ , X ２ and their substituents together form 【Chemical 27】 forms R ２ｄ is H, R ３ｓ１ is H, Me or cyclopropyl, R ３ｓ is H, p = 0, a compound according to claim 23, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

27. A compound of formula (IV), (IV-1), (IV-1a), (IV-1b), (IV-2), (IV-2a) or (IV-2b), wherein R １ is H, D, halogen, CN, NO ２ , -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , SF ５ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , OC(O)R ａ , NR ｂ C(O)R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , P(O)(R ａ ) ２ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, -L-C ３～７ cycloalkyl, -L-3- to 7-membered heterocyclyl, -L-C ６～１０ aryl and -L-5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R １ｓ s, m = 0, 1 or 2, R ４ is selected from H and D, X １ is a C atom, which is substituted by R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom, which is substituted with R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ , NR ｂ R ｃ , C(O)OR ａ and C(O)NR ｂ R ｃ and is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl and 3- to 10-membered heterocyclyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or Or, X １ , X ２ and their substituents together form C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl or 5- to 10-membered heteroaryl (alternatively 【Chemical Formula 28】 ), which are formed and these may be optionally substituted with one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , OR ａ , NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ５～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, and Z １ is CH, Z ２ is either CR １ or N, and Z ３ is CR １ or N, and Z ２ or Z ３ is CR １ in which case any R １ is R ４ is bonded to R ｓｓ R ｓｓ to form -(CR ｑ１ R ｓｓ R ｓｓ )) ｑ２ - (alternatively -(CH ２ )) ｑ１ -X-(CH ２ )) ｑ２ -)(wherein X is O, S, NH or CH ２ , q1 = 0, 1 or 2, q2 = 1, 2 or 3, and R ｓｓ is independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or two R ｓｓ and the carbon atoms to which they are attached together form C ３～１０ cycloalkyl). L is a chemical bond, C １～６ alkylene, C ２～６ alkenylene or C ２～６ alkynylene, and these are optionally substituted with one, two or three Rs, R １ｓ and R ２ｓ are each independently H, D, halogen, CN, =O, OR ａ , NR ｂ R ｃ , C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, or two Rs １ｓ and the atoms to which they are attached together form C ３～１０ cycloalkyl or 3- to 10-membered heterocyclyl, or alternatively, R １ｓ and R ２ｓ are each independently H, D, halogen, CN, =O, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, and are selected from R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R ３ｓ２ is selected from H, D, -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, which are optionally substituted with one, two or three R ３ｓ s, or or R ３ｓ１ , R ３ｓ２ and the carbon atoms to which they are attached together form a C ３～１０ cycloalkyl, R and R ３ｓ are, independently, H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, and are selected from R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, Here, each of the above groups is optionally deuterated until fully deuterated, a compound according to claim 10, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

28. R １ is H, D, halogen, CN, NO ２ , OR ａ , SR ａ , NR ｂ R ｃ , SF ５ , C(O)R ａ , C(O)OR ａ , C(O)NR ｂ R ｃ , OC(O)R ａ , NR ｂ C(O)R ｃ , S(O)R ａ , S(O) ２ R ａ , S(O)OR ａ , S(O) ２ OR ａ , S(O)NR ｂ R ｃ , S(O) ２ NR ｂ R ｃ , P(O)(R ａ ) ２ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R １ｓ 's, m = 0, 1 or 2, R ４ is selected from H and D, X １ is a C atom, which is substituted by R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom, which is substituted with R ２ｄ and R ２ａ is selected from H, D, CN, OR ａ and NR ｂ R ｃ and is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or Or, X １ , X ２ and their substituents together form C ５～６ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl (alternatively ​ ), which are formed and these are optionally substituted with one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , OR ａ , NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, and Z １ is CH, Z ２ is CR １ and the above R １ and R ４ are combined to form -(CR ｓｓ R ｓｓ ) ｑ１ -X-(CR ｓｓ R ｓｓ ) ｑ２ -(alternatively -(CH ２ ) ｑ１ -X-(CH ２ ) ｑ２ -)(wherein X is O, S, NH or CH ２ , q1 = 0 or 1, q2 = 1 or 2, and R ｓｓ is independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or two R ｓｓ and the carbon atom to which they are attached together form C ３～１０ cycloalkyl). Z ３ is CR １ or N, and L is a chemical bond, C １～６ alkylene, C ２～６ alkenylene or C ２～６ alkynylene, and these are optionally substituted with 1, 2 or 3 R's, R １ｓ and R ２ｓ each independently is H, D, halogen, =O, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, or two Rs １ｓ and the atoms to which they are attached together form a C ３～６ cycloalkyl or 3- to 6-membered heterocyclyl, R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, R ３ｓ２ is selected from H, D, -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 5- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, which may be optionally substituted with one, two or three R ３ｓ groups, or or R ３ｓ１ , R ３ｓ２ and the carbon atoms to which they are attached together form a C ３～１０ cycloalkyl, R and R ３ｓ are each independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ , R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl, C １～６ haloalkyl, C ３～１０ cycloalkyl, 3- to 10-membered heterocyclyl, C ６～１０ aryl and 5- to 10-membered heteroaryl, or R ｂ , R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, Here, each of the above groups is optionally deuterated until fully deuterated, a compound according to claim 27, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

29. R １ is H, D, halogen, CN, NO ２ , OR ａ , SR ａ , NR ｂ R ｃ , SF ５ , C(O)R ａ , S(O)R ａ , S(O) ２ R ａ , C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ４～６ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, which are optionally substituted with one, two or three R １ｓ and are optionally substituted with one, two or three R m = 0, 1 or 2, R ４ is selected from H and D, X １ is a C atom, which is substituted with R ２ｂ and X ２ is a C atom or an N atom, which are optionally substituted with R ２ｃ and X ３ is a C atom, which is substituted by R ２ｄ and R ２ａ is OR ａ and NR ｂ R ｃ is selected from R ２ｂ is selected from H, D, halogen, C(O)OR ａ , C(O)NR ｂ R ｃ , C １～６ alkyl and C １～６ haloalkyl, R ２ｃ is selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, or Or, X １ , X ２ and their substituents together form C ５～６ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl (alternatively 【Chemical Formula 30】 ), which are formed and these are optionally substituted with one, two or three R ２ｓ and are optionally substituted with R ２ｄ is selected from H, D, halogen, CN, NO ２ , C １～６ alkyl and C １～６ haloalkyl, and Z １ is CH, Z ２ is CR １ and the above R １ and R ４ are combined to form -(CR ｓｓ R ｓｓ ) ｑ１ -X-(CR ｓｓ R ｓｓ ) ｑ２ -(alternatively -(CH ２ ) ｑ１ -X-(CH ２ ) ｑ２ -)(wherein X is O, S or NH, q1 = 0 or 1, q2 = 1 or 2, and R ｓｓ is independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or two R ｓｓ and the carbon atom to which they are attached together form C ３～６ cycloalkyl). Z ３ is CR １ or N, and L is a chemical bond or C １～６ alkylene, R １ｓ and R ２ｓ each independently is H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, or two Rs １ｓ and the atoms to which they are attached together form a C ３～６ cycloalkyl or 3- to 6-membered heterocyclyl, R ３ｓ１ is selected from H, D, halogen, C １～６ alkyl, C １～６ haloalkyl, C ２～６ alkenyl and C ２～６ alkynyl, and R ３ｓ２ is selected from H, D, -L-OR ａ , -L-NR ｂ R ｃ , C １～６ alkyl, C １～６ haloalkyl, C ３～６ cycloalkyl, 5- to 6-membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl, which are optionally substituted with 1, 2 or 3 R ３ｓ groups, or or R ３ｓ１ , R ３ｓ２ and the carbon atoms to which they are attached together form a C ３～６ cycloalkyl, R ３ｓ is independently selected from H, D, halogen, C １～６ alkyl and C １～６ haloalkyl, R ａ 、 R ｂ and R ｃ are each independently selected from H, D, C １～６ alkyl and C １～６ haloalkyl, or R ｂ 、 R ｃ and the atoms to which they are attached together form a 5- to 10-membered heterocyclyl, Here, each of the above groups is optionally deuterated until fully deuterated, a compound according to claim 27, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

30. The compound according to claim 1, wherein the above compound is selected from Compounds 1 to 245, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof.

31. A pharmaceutical composition comprising the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, a pharmaceutically acceptable carrier, adjuvant or vehicle, and optionally another therapeutic agent.

32. The above other therapeutic agent is selected from CDK4 / 6 inhibitors, MAT2A inhibitors, MAPK1 / MAPK3 inhibitors, type I PRMT inhibitors, EGFR inhibitors, SHP2 inhibitors, pan-KRAS inhibitors, KRASG12C inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, Bcl-2 inhibitors, SOS1 inhibitors, PARP inhibitors, MALT1 inhibitors, MALT2 inhibitors, BTK inhibitors, PI3K inhibitors, AKT inhibitors, FGFR inhibitors, DNA methyltransferase (DNMT) inhibitors, EZH1 / 2 inhibitors, EZH2 inhibitors, Menin-MLL inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1 / 2 inhibitors, chemotherapeutic agents, radiotherapy, STING agonists and immune checkpoint inhibitors / modulators, etc. The pharmaceutical composition according to claim 31.

33. Use of the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in the manufacture of a medicament for treating or preventing PRMT5-mediated diseases.

34. A method for treating or preventing PRMT5-mediated diseases in a subject, comprising administering to the subject the compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or the pharmaceutical composition according to claim 31 or 32.

35. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, isotope variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or the pharmaceutical composition according to claim 31 or 32, for use in the treatment or prevention of PRMT5-mediated diseases.

36. The use according to claim 33, or the method according to claim 34, or the compound or pharmaceutical composition according to claim 35, wherein the disease is cancer.

37. The PRMT5-mediated diseases are the following cancers: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Digestive tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); Genitourinary: kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondromatosis, benign enchondroma, chondroblastoma, fibrochondroma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerve fibroma, meningioma, glioma, sarcoma; Gynecology: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma)), fallopian tube (cancer); Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma,Myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma), skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and, adrenal gland: neuroblastoma, the use according to claim 33, or the method according to claim 34, or the compound or pharmaceutical composition according to claim 35.,

38. The use according to claim 33, or the method according to claim 34, or the compound or pharmaceutical composition according to claim 35, wherein the PRMT5-mediated disease is selected from the following cancers: malignant peripheral nerve sheath tumor, mesothelioma, glioblastoma multiforme, pancreatic cancer, cholangiocarcinoma, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, bladder cancer, astrocytoma, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, thymoma, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, squamous cell carcinoma of the lung, lung adenocarcinoma, oral cancer, ovarian cancer, kidney cancer, and thyroid cancer and sarcoma.

39. The use according to claim 33, or the method according to claim 34, or the compound or pharmaceutical composition according to claim 35, wherein the PRMT5-mediated disease is selected from MTAP-related cancers such as hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer and head and neck cancer.

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