Androgen Receptor Modulator and its Use

Abstract

The present invention relates to androgen receptor modulators and their uses. Specifically, the present invention relates to compounds having formulas (I) to (VI), pharmaceutical compositions comprising these compounds, and the use of these compounds for the prevention or treatment of diseases, particularly for modulating the activity of androgen receptors and treating diseases including prostate cancer.

Description

[Technical Field]

[0001] This invention relates to compounds used as androgen receptor modulators or pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions comprising these compounds, and methods for using these compounds in the prevention or treatment of androgen receptor-mediated diseases, particularly cancer. [Background technology]

[0002] Prostate cancer is the most common tumor in men and one of the deadliest tumors. Currently, the main treatments for prostate cancer include surgery, radiation therapy, chemotherapy, castration, androgen-targeted therapy, PARP inhibitors, and PD-1 immune checkpoint antibodies. Because most prostate cancer cells depend on androgens for growth, castration and androgen-targeted therapy are common clinical treatments. Androgen-targeted therapy includes androgen synthesis inhibition and androgen receptor inhibition, with drugs such as bicalutamide, abiraterone, and enzalutamide being widely used in clinical practice and effectively extending patient survival. However, most prostate cancer patients eventually develop resistance to castration and androgen-targeted drugs. The mechanisms by which resistance is acquired include 1) reactivation of androgen receptors, 2) activation of the glucocorticoid receptor pathway, and 3) neuroendocrine prostate cancer (Nat Rev Cancer. 2015 Dec;15(12):701-11). Of these, androgen receptor reactivation accounts for more than 60% of resistant patients.

[0003] The androgen receptor (AR) is a transcription factor activated by androgens. In prostate cancer, androgens activate the androgen receptor via its ligand-binding domain, allowing it to enter the cell nucleus from the cell membrane and form a binary complex, activating the transcription and expression of downstream genes. The androgen receptor is divided into three main domains: the N-terminus is a relatively loosely structured region (NTD) that primarily binds to other transcription factors to form complexes; the middle is a DNA-binding domain (DBD) that helps the androgen receptor bind to the DNA of downstream genes; and the C-terminus is a ligand region (LBD) through which it binds to androgens. Existing androgen receptor-targeted drugs primarily target androgen synthesis and the ligand-binding domain of the androgen receptor, inhibiting androgenic activation of the receptor. Mutations in prostate cancer resistant to androgen receptor-targeted therapy mainly occur in the LBD-binding domain. These mutations include a) point mutations in amino acid sites such as F877L and T878A, which can neutralize the effects of androgen receptor antagonists and sometimes induce agonist effects, and b) splice mutations such as AR-V, in which the androgen receptor no longer expresses the complete ligand-binding domain, leaving only the N-terminus and DNA-binding domain. Deletion or mutation of the LBD-binding domain means that existing androgen receptor antagonists cannot effectively inhibit androgen receptor function and are therefore useless in treating patients with drug-resistant prostate.

[0004] In light of the resistance mechanisms caused by the aforementioned androgen receptor LBD-binding domain mutations and deletions, there is a need to develop next-generation androgen receptor-targeted drugs with different mechanisms of action to provide new treatment options for drug-resistant patients. PROTAC molecules that bind to androgen ligands can degrade the androgen receptor and completely block the androgen receptor pathway. Arvinas' ARV-110 has shown early clinical efficacy in prostate patients with androgen receptor mutations such as T878A, but ARV-110 cannot bind to mutations such as AR-Vs that lack the LBD-binding domain and is ineffective in patients expressing these androgen receptor splice mutations. ESSA's EPI-7386, an androgen receptor N-terminal targeting inhibitor, has also entered early clinical trials and shown good tolerability, but its efficacy has not yet been verified.

[0005] Therefore, there remains a high medical need for the development of androgen receptor-targeted drugs with novel mechanisms of action, which could potentially be effective treatments for prostate cancer. Furthermore, while cancer patients have multiple treatment options, there is still a need for effective and safe drugs, as well as the optimal use of these in combination therapies. [Overview of the Initiative]

[0006] The compounds of the present invention are androgen receptor modulators used for the treatment of various diseases and conditions disclosed herein, and are particularly used for regulating androgen receptors having mutations or deletions in the LBD domain. These diseases and conditions include, but are not limited to, prostate cancer, other prostate diseases, breast cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and spinal and bulbar muscular atrophy.

[0007] Specifically, the present invention provides an androgen receptor modulator of formula (I),

[0008] [ka]

[0009] Here, each variable R1, R2, R3, n, X, Y, L0, L1 and ring W are as defined herein and include their stereoisomers, geometric isomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salts. These can be used for the treatment or prevention of androgen receptor-mediated diseases or disorders, particularly cancer.

[0010] The present invention also provides a method for preparing the compound of the present invention, an intermediate for preparing the compound of the present invention, and a method for preparing the intermediate.

[0011] The present invention provides a composition comprising at least one compound of the present invention or a pharmaceutically usable salt thereof.

[0012] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically usable salt thereof, and one or more pharmaceutically usable carriers, diluents, or excipients.

[0013] In certain embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically usable salt thereof.

[0014] In another specific embodiment, the present invention provides compositions, particularly pharmaceutical compositions, comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically usable salt thereof, and one or more other therapeutic agents.

[0015] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other substances, preferably one or two, simultaneously or sequentially.

[0016] The compounds of the present invention are androgen receptor modulators capable of regulating androgen receptors in vivo, and can be used for the treatment or prevention of androgen receptor-mediated diseases or disorders, particularly cancer. Therefore, the present invention can provide inhibition of the transcriptional activation function of the androgen receptor. For example, the compounds of the present invention can be used to enhance androgen-mediated responses in subjects, and methods for regulating immune responses in subjects using the compounds of the present invention can also be provided.

[0017] The compounds of the present invention can be used in therapeutic treatments.

[0018] The compounds of the present invention can be used in the preparation of agents or drugs used for the treatment or prevention of androgen receptor-mediated diseases or disorders, particularly cancer.

[0019] The present invention also provides a method for inhibiting androgen receptor activity in a subject, comprising administering a therapeutically effective amount of an androgen receptor inhibitor, such as the compound of the present invention or a pharmaceutically usable salt thereof, to the subject as needed.

[0020] In certain embodiments of the present invention, the present invention provides a method for treating or preventing an androgen receptor-mediated disorder, comprising administering to a patient in need a first therapeutic agent which is an effective amount of the compound of the present invention or a pharmaceutically usable salt thereof, and a second therapeutic agent which is one or more other optionally selected therapeutic agents.

[0021] In another specific embodiment of the present invention, the present invention relates to a method for treating or preventing an androgen receptor-mediated disorder or disorder, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically usable salt thereof to a subject.

[0022] A particular preferred method of the present invention is to treat androgen receptor-mediated diseases or disorders having LBD domain mutations or deletions, the diseases or disorders including, but not limited to, prostate cancer, other prostate diseases (e.g., benign prostatic hyperplasia, prostatitis, etc.), breast cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and spinal and bulbar muscular atrophy.

[0023] In some embodiments of the present invention, the prostate cancer includes, but is not limited to, metastatic castration-resistant prostate cancer, primary / localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic prostate cancer, and hormone-sensitive prostate cancer.

[0024] In some embodiments of the present invention, the breast cancer includes, but is not limited to, Luminal A (ER+ / PR+, HER-2-), Luminal B (ER+ / PR+, HER-2+), HER-2+ (ER- / PR- / HER-2+), and Basal-like (ER- / PR- / HER-2-) breast cancer.

[0025] Furthermore, the present invention provides combination products or kits for simultaneous, separate, or sequential use in the treatment or prevention of androgen receptor-mediated diseases or disorders, comprising the compound of the present invention as defined above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and one or more other activators, or a pharmaceutical composition containing the activators.

[0026] Embodiment

[0027] In a first embodiment, the present invention provides a compound of formula (I), or its stereoisomers, geometric isomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salts.

[0028] [ka] Here, n is 0 or 1, preferably n is 1. X is either N or CH. Y is NR4 or CHR4, L0 is a bond, O, S, -NR5-, -C(O)-NR5-, -NR5-C(O)-, -NR5-(CH2) m -or-(CH2) m -NR5-, m is 1 or 2, preferably L0 is bond, O, S, -NR5-, -NH-C(O)-, -C(O)-NH-, -NR5-(CH2)2- or -NR5-CH2-, more preferably L0 is bond, O, S, -NR5-, -NHC(O)- or -C(O)-NH-, L1 is a bond, O, S, or -NR5-, preferably L1 is a bond, O, or S. R1 and R2 are each independently selected from H, C1-C6 alkyl groups, halogens, halogenated C1-C6 alkyl groups, CN, C1-C6 alkoxy groups, -C1-C6 alkyl-NR6R7 and -C(O)-NR6R7, preferably R1 and R2 are each independently selected from H, halogens, CF3, CN, C1-C6 alkyl groups, C1-C6 alkoxy groups, -CH2-NH2 and -C(O)NH-CH3. Here, R4, R5, R6, and R7 are each independently selected from H, C1-C6 alkyl groups, and acyl groups, and preferably, R4, R5, R6, and R7 are each independently H or C1-C6 alkyl groups. R3 is a hydroxyl group, C1-C6 alkyl group, C3-C8 cycloalkyl group, C6-C 12 The alkyl group is an aryl group, a 5-12 membered heteroaryl group, or a 4-12 membered heterocycloalkyl group, and each alkyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocycloalkyl group is optionally substituted with one or more halogens or hydroxyl groups, preferably R3 is an optionally substituted C1-C6 alkyl group, C3-C7 cycloalkyl group, or C6-C alkyl group. 10An aryl group, a 5- to 10-member heteroaryl group, or a 5- to 7-member heterocycloalkyl group, more preferably, R3 is a C1-C6 alkyl group optionally substituted by one or more F, Cl or OH, a C3-C7 cycloalkyl group, a C6-C 10 An aryl group, a 5- to 10-member heteroaryl group, or a 5- to 7-member heterocycloalkyl group, W is a C5-C8 cycloalkyl group, a C6-C 12 An aryl group, a 5- to 12-member heteroaryl group, or a 4- to 12-member heterocycloalkyl group, each of which is optionally halogen, CN, oxo, -NR7R8, -OR8, -C(O)-NHR8, R9, -OC(O)-NHR9, -NHC(O)-R 10 , -SO2R9, -SO2NHR8, -NR7SO2R9, -NR7SO2NR8R 10 , a substituted or unsubstituted C3-C8 cycloalkyl group, a 4- to 8-member heterocycloalkyl group, a C6-C 12 An aryl group and a 5- to 10-member heteroaryl group, which are substituted by one or more substituents selected from, wherein the C3-C8 cycloalkyl group, the 4- to 8-member heterocycloalkyl group, the C6-C 12 An aryl group and a 5- to 10-member heteroaryl group are further optionally substituted by one or more halogen, oxo, NH2, hydroxy group, C1-C4 alkyl group or C1-C4 alkoxy group, respectively, wherein R8 is H or a C1-C6 alkyl group optionally substituted by one or more halogen or hydroxy group, preferably, R8 is H or a C1-C6 alkyl group optionally substituted by F or OH, R9 is a C1-C6 alkyl group optionally substituted by one or more halogen, hydroxy group, or NH2, R 10 is a C1-C6 alkyl group or a C1-C6 alkoxy group, Preferably, the heterocycloalkyl group contains 1 to 2 heteroatoms selected from N, NR c , O and S(O) p selected from, and Rc These are, independently, hydrogen and a C1-C4 alkyl group, and p is either 1 or 2.

[0029] In certain preferred embodiments, the present invention provides compounds of formula (I), or stereoisomers, geometric isomers, tautomers, solvates, hydrates or pharmaceutically acceptable salts thereof, where W is a C5-C8 cycloalkyl group, C6-C 12 The group is an aryl group, a 5-12 membered heteroaryl group, or a 4-12 membered heterocycloalkyl group, each of which can be optionally selected from halogens, CN, oxo, NR7R8, OR8, R9, -C(O)-NHR8, -OC(O)-NHR9, -SO2R9, -SO2NHR8, -NR7SO2R9, -NR7SO2NHR 10 ,-NHC(O)-R 10 C3-C8 cycloalkyl groups, 4-8 member heterocycloalkyl groups, C6-C8 cycloalkyl groups, C3 10 The group is an aryl group, a 5-10 membered heteroaryl group, More preferably, these are, respectively, optionally -OH, F, Cl, CN, oxo, -NH2, C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkyl group, halogenated C1-C6 alkoxy group, -(C1-C6alkyl)OH, -(C1-C6alkoxy)OH, -NH(C1-C3alkyl), -NH(C1-C4alkyl)OH, -NHC(O)(C1-C3alkyl), -NHC(O)(C1-C4alkoxy), -OC(O)NH(C1-C3alkyl), -C(O)NH(C1-C3alkyl), -O(C1-C4alkyl)OH, -C (O)NH2, -SO2NH2, -SO2(C1-C4 alkyl), -SO2(C1-C3 alkyl)NH2, -SO2NH(C1-C4 alkyl), -NHSO2(C1-C4 alkyl), -N(CH3)SO2(C1-C3 alkyl), -NHSO2(C1-C3 alkyl)NH2, -NHSO2CF3, and optionally substituted with one or more halogens, OH, NH2, C1-C4 alkyl groups, or C1-C4 alkoxy groups, C3-C7 cycloalkyl groups, 5-8 membered heterocycloalkyl groups, C6-C 10 These are aryl groups and 5- to 10-membered heteroaryl groups.

[0030] In certain preferred embodiments, the present invention provides compounds of formula (I), or stereoisomers, geometric isomers, tautomers, solvates, hydrates or pharmaceutically acceptable salts thereof, where W is a C5-C8 cycloalkyl group, C6-C 12These are aryl groups, 5-12 membered heteroaryl groups, or 4-12 membered heterocycloalkyl groups, each of which can be selected as follows: -OH, F, Cl, CN, oxo, -NH2, -NHCH3, -NH(CH2)2OH, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkyl groups, halogenated C1-C6 alkoxy groups, -NHC(O)CH3, -NHC(O)OCH3, -OC(O)NH-CH3, -C(O)NH-CH3, -C(O)NH2, -O(CH2)2OH, -SO2NH2, -SO2(CH2)2NH2-, -NHSO2CH3, -N(CH3)SO2CH3, -NHSO Substituted with one or more substituents selected from 2CH2CH3, -NHSO2CH(CH3)2, -NHSO2CH2NH2, -NHSO2(CH2)2NH2, -NHSO2CF3, -SO2CH3, -SO2CH(CH3)2, -SO2CH2CH3, cyclopentane, cyclohexane, pyridyl group, phenyl group, morpholinyl group, 1,3-oxazine alkyl group, oxacyclohexane alkyl group, hexahydropyrimidinyl group, piperazinyl group, pyrrole, imidazole, pyrazole, 4-methyl-piperazin-1-yl, piperidinyl group, and 4-hydroxy-piperidine-1-yl.

[0031] In certain preferred embodiments, the present invention provides compounds of formula (I), or stereoisomers, geometric isomers, tautomers, solvates, hydrates or pharmaceutically acceptable salts thereof, where W is cyclopentane, cyclohexane, phenyl group, pyrrolyl, pyrazole, imidazole, thiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazolidine, tetrahydropyran, piperidine, piperazine, hexahydropyrimidine, morpholine, or Kutahydropyrrolo[3,2-b]pyrrolyl, indole, benzopyran, benzimidazole, benzoxazole, benzotriazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, quinoline, isoquinoline, quinazoline, sinnoline, quinoxaline, naphthyl group, indenyl group, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2,3-dihydro Looxazolo[4,5-b]pyridine, isoindoline, indoline, dihydrobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, 2,3-dihydro-1H-indazole, 1,2-dihydroquinoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydronaphthalene, dihydroindene, chroman, isochroman, dihydrobenzofuran, dihydroisobenzofuran, 1,2-dihydro-1,8-naphthyridine, oxazolo[4, 5-b]pyridine, pyridine-2(1H)-one, 2-indolone, 2-benzoxazolone, quinoline-2(1H)-one, 1,4-dihydro-3(2H)-soquinolinone, 1,3-dihydrobenzimidazole-2-one, 2,3-dihydrochromen-4-one, 5,8-dihydro-6H-[1,6]naphthirizine-7-one, 7,8-dihydro-6H-[1,6]naphthirizine-5-one, 1,8-naphthirizine-2(1H)-one, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine, 3a,4,5,6,7,7a-Hexahydro-1H-pyrazolo[3,4-c]pyridine, 2H-chromene, oxazolo[5,4-c]pyridine-2(1H)-one, or oxazolo[4,5-b]pyridine-2(3H)-one, each independently and arbitrarily selected, and are halogen, CN, oxo, -NR7R8, hydroxyl group, C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkyl group, halogenated C1-C6 alkoxy group, hydroxy-C1-C6 alkyl group, hydroxy-C1-C6 alkoxy group, hydroxy-C1-C6 alkyl-NR8-, -C(O)-NHR8, -OC(O)-NHR9, -NHC(O)-R, 10 -SO2R9, -SO2NHR8, -NR7SO2R9, -NR7SO2NHR8, C3-C8 cycloalkyl group, 4-8 member heterocycloalkyl group, C6-C 12 Substituted with one or more substituents selected from aryl groups and 5-10 membered heteroaryl groups, where C3-C8 cycloalkyl groups, 4-8 membered heterocycloalkyl groups, C6-C 12 The aryl group and the 5-10 membered heteroaryl group are each optionally further substituted with one or more halogens, oxo, NH2, hydroxyl groups, C1-C4 alkyl groups, or C1-C4 alkoxy groups. Here, R8 is H, or a C1-C6 alkyl group substituted with one or more halogens or hydroxyl groups of any choice. R9 is a C1-C6 alkyl group that is optionally substituted with one or more halogens or NH2. R 10 This is a C1-C6 alkyl group or a C1-C6 alkoxy group.

[0032] In certain preferred embodiments, the present invention provides compounds of formula (I), where W is cyclopentane, cyclohexane, phenyl group, pyrrolyl, pyrazole, imidazole, thiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazolidine, tetrahydropyran, piperidine, piperazine, hexahydropyrimidine, morpholine, octahydropyrrolo[3,2-b]pyrrolyl, indole, benzopyran, benzimidazole Lu, benzoxazole, benzotriazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, quinoline, isoquinoline, quinazoline, cinnoline, quinoxaline, naphthyl group, indenyl group, imidazole and pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2,3-dihydroxazolo[4,5-b]pyridine, isoindoline, Indoline, dihydrobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, 2,3-dihydro-1H-indazole, 1,2-dihydroquinoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydronaphthalene, dihydroindene, chroman, isochroman, dihydrobenzofuran, dihydroisobenzofuran, 1,2-dihydro-1,8-naphthyridine, oxazolo[4,5-b]pyridine, pyridine-2(1H)-one, 2-Indolone, 2-Benzoxazolone, Quinoline-2(1H)-one, 1,4-Dihydro-3(2H)-Soquinolinone, 1,3-Dihydrobenzimidazole-2-one, 2,3-Dihydrochromen-4-one, 5,8-Dihydro-6H-[1,6]Naphthirizine-7-one, 7,8-Dihydro-6H-[1,6]Naphthirizine-5-one, 1,8-Naphthirizine-2(1H)-one, 3a,4,5,6,7,7a-Hexahydro-1H-Pyrazolo[4,3-c]Pyridine, 3a,4,5,6,7,7a-Hexahydro-1H-Pyrazolo[3,4-c]pyridine, 2H-chromene, oxazolo[5,4-c]pyridine-2(1H)-one, or oxazolo[4,5-b]pyridine-2(3H)-one, which are independently and arbitrarily selected from -OH, F, Cl, CN, oxo, -NH2, -NHCH3, -NH(CH2)2OH, C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkyl group, halogenated C1-C6 alkoxy group, -NHC(O)CH3, -NHC(O)OCH3, -OC(O)NH-CH3, -C(O)NH-CH3, -C(O)NH2, -O(CH2)2OH, -SO2NH2, -SO2(CH2)2NH2-, -NHSO2CH3, - Substituted with one or more substituents selected from N(CH3)SO2CH3, -NHSO2CH2CH3, -NHSO2CH(CH3)2, -NHSO2CH2NH2, -NHSO2(CH2)2NH2, -NHSO2CF3, -SO2CH3, -SO2CH(CH3)2, -SO2CH2CH3, cyclopentane, cyclohexane, pyridyl group, phenyl group, morpholinyl group, 1,3-oxazine alkyl group, oxacyclohexane alkyl group, hexahydropyrimidinyl group, piperazinyl group, pyrrolyl, imidazole, pyrazole, 4-methyl-piperazine-1-yl, piperidinyl group, and 4-hydroxy-piperidine-1-yl.

[0033] In certain preferred embodiments, the present invention provides compounds of formula (I), or stereoisomers, geometric isomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salts thereof, where W is selected from the following:

[0034] [ka] Here, each of the aforementioned groups can be independently and arbitrarily selected as -OH, F, Cl, CN, oxo, -NH2, -NHCH3, -NH(CH2)2OH, C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkyl group, halogenated C1-C6 alkoxy group, -NHC(O)CH3, -NHC(O)OCH3, -OC(O)NH-CH3, -C(O)NH-CH3, -C(O)NH2, -O(CH2)2OH, -SO2NH2, -SO2(CH2)2NH2-, -NHSO2CH3, -N(CH3)SO2CH3, -NHSO2CH2CH3, -NHSO2CH(C Substituted with one or more substituents selected from H3)2, -NHSO2CH2NH2, -NHSO2(CH2)2NH2, -NHSO2CF3, -SO2CH3, -SO2CH(CH3)2, -SO2CH2CH3, cyclopentane, cyclohexane, pyridyl group, phenyl group, morpholinyl group, 1,3-oxazine alkyl group, oxacyclohexane alkyl group, hexahydropyrimidinyl group, pyrrolyl, imidazole, pyrazole, piperazinyl group, 4-methyl-piperazin-1-yl, piperidinyl group, and 4-hydroxy-piperidine-1-yl.

[0035] It should be understood that the W group of the present invention can be linked to the rest of the compound of formula (I) at any possible position (e.g., 1, 2, 3, 4, 5, 6, or 7), and in particular via the linkage positions of the W group shown in the compound of the embodiment.

[0036] In certain more preferred embodiments, the present invention provides compounds of formula (I), or stereoisomers, geometric isomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salts thereof, wherein n is either 0 or 1. X is either N or CH. Y is NR4 or CHR4, where R4 is selected from H and C1-C6 alkyl groups. L0 is a bond, O, S, -NR5-, -C(O)-NH-, -NH-C(O)- or -NR5-(CH2) m - and m is either 1 or 2, L1 is a bond, O, S or -NR5-, Here, R5 is H, an acetyl group, or a C1-C6 alkyl group. R1 and R2 are each independently selected from H, C1-C6 alkyl groups, halogens, CN, -C1-C6 alkyl-NR6R7 and -C(O)-NR6R7, where R6 and R7 are each independently selected from H and C1-C6 alkyl groups. R3 is a C1-C6 alkyl group or a halogenated C1-C6 alkyl group, or R3 is a C3-C8 cycloalkyl group, C6-C, optionally substituted with one or more halogens or hydroxyl groups. 12 The group is an aryl group, a 5- to 12-membered heteroaryl group, or a 5 or 7-membered heterocyclyl group, for example, cyclopropyl, cyclopentane, cyclohexane, phenyl group, pyridyl group, hexahydropyrimidinyl group, piperazinyl group, 4-methylpiperazine-1-yl, piperidinyl group, 1,3-oxazinealkyl group, morpholinyl group, or 4-hydroxy-piperidine-1-yl, which are optionally substituted with one or more halogens or hydroxyl groups.

[0037] In certain preferred embodiments, ring W is optionally and independently a halogen, CN, OH, oxo, NH2, C1-C4 alkyl, C1-C4 alkoxy group, C3-C6 cycloalkyl, C1-C4 halogenated alkyl, C1-C4 halogenated alkoxy group, -NH(C1-C3 alkyl), -NH(C1-C4 alkyl)OH, -NHC(O)(C1-C3 alkyl), -NHC(O)(C1-C3 alkoxy), -OC( O)NH(C1-C3alkyl), -C(O)NH(C1-C3alkyl), -O(C1-C4alkyl)OH, -C(O)NH2, -SO2NH2, -SO2(C1-C4alkyl), -SO2(C1-C3alkyl)NH2-, -NHSO2(C1-C4alkyl), -N(CH3)SO2(C1-C3alkyl), -NHSO2(C1-C3alkyl)NH2, -NHSO2CF3, 5-7 member heterocycloalkyl, C6-C 10It may be substituted once or multiple times with substituents selected from aryl groups and 5- to 7-membered heteroaryl groups, for example, once or twice. More preferably, ring W is optionally and independently F, Cl, CN, OH, (=O), NH2, C1-C3 alkyl group, C1-C3 alkoxy group, C3-C6 cycloalkyl group, C1-C3 halogenated alkyl group, C1-C3 halogenated alkoxy group, -NHCH3, -NH(CH2)2OH, -NHC(O)CH3, -NHC(O)OCH3, -OC(O)NHCH3, -C(O)NHCH3, -C(O)NH2, -O(CH2)2OH, -SO2NH2, -SO2(CH2 ) may be substituted once or multiple times with substituents selected from 2NH2-, -NHSO2CH3, -N(CH3)SO2CH3, -NHSO2CH2CH3, -NHSO2CH(CH3)2, -NHSO2CH2NH2, -NHSO2(CH2)2NH2, -NHSO2CF3, -SO2CH3, -SO2CH(CH3)2, -SO2CH2CH3, 5-7 membered heterocycloalkyl groups, C6-C8 aryl groups, and 5-8 membered heteroaryl groups, for example, once or twice. The heterocycloalkyl group, aryl group, and heteroaryl group are preferably cyclopentane, cyclohexane, phenyl group, pyrrolyl, pyrazole, imidazole, thiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazolidine, tetrahydropyran, piperidine, piperazine, hexahydropyrimidine, and morpholine. Octahydropyrrolo[3,2-b]pyrrolyl, indole, benzopyran, benzimidazole, benzoxazole, benzotriazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, quinoline, isoquinoline, quinazoline, cinnoline, quinoxaline, naphthyl group, indenyl group, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-c] Pyridine, 1H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2,3-dihydrooxazolo[4,5-b]pyridine, isoindoline, indoline, dihydrobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, 2,3-dihydro-1H-indazole, 1,2-dihydroquinoline, tetrahydroquinoline , tetrahydroisoquinoline, tetrahydronaphthalene, dihydroindene, chroman, isochroman, dihydrobenzofuran, dihydroisobenzofuran, 1,2-dihydro-1,8-naphthyridine, oxazolo[4,5-b]pyridine, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine or 2H-chromen, More preferably, the components are cyclopentane, cyclohexane, benzene ring, pyridine ring, piperazine, pyrazine, pyrimidine, oxazolidine, oxazinane, isoxazinane, morpholine, tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, hexahydropyrimidine, pyrrolyl, imidazole, pyrazole, 4-methyl-piperazine-1-yl, or 4-hydroxy-piperidine-1-yl.

[0038] In certain preferred embodiments, ring W is optionally substituted or unsubstituted cyclopentane, cyclohexane, tetrahydrofuran ring, tetrahydropyran ring, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, piperidine ring, morpholine, piperazine ring, piperidine ring, hexahydropyrimidine, oxazinan, octahydropyrrolo[3,2-b]pyrrolyl, pyrrolyl ring, pyrazole ring, imidazole ring, pyrazine ring, pyridazine ring, pyrimidine ring, pyridine ring, benzene ring, indole ring, benzimidazole ring, indazole ring, benzotriazole ring, benzoxazole, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine, 3a,4,5,6,7,7a-hexa Hydro-1H-pyrazolo[3,4-c]pyridine, isoindoline, indoline, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-indazole, oxazolo[4,5-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2,3-dihydrooxazolo[4,5-b]pyridine, tetrahydroquinoline, tetrahydroisoquinoline, dihydrochromene, 1,2-dihydro-1,8-naphthyridine, azaindole, tetrahydronaphthalene, or dihydroindene. More preferably, ring W may be F, Cl, CN, OH, (=O), NH2, C1-C3 alkyl group, C1-C3 alkoxy group, C3-C6 cycloalkyl group, C1-C3 halogenated alkyl group, -NHCH3, -NH(CH2)2OH, NHC(O)CH3, -NHC(O)OCH3, -OC(O)NHCH3, -C(O)NHCH3, -C(O)NH2, -O(CH2)2OH, -SO2NH2, -SO2(CH2)2NH2-, -NHSO2CH3, -N(CH3)SO2CH3, -NHSO2CH2CH3, -NHSO2CH(CH3)2, -NH Selected from SO2CH2NH2, -NHSO2(CH2)2NH2, -NHSO2CF3, -SO2CH3, -SO2CH(CH3)2, -SO2CH2CH3, cyclopentane, cyclohexane, benzene ring, pyridine ring, piperidine, tetrahydropyran, piperazine, pyrazine, pyrimidine, hexahydropyrimidine, oxazinan, isoxazinan, tetrahydrofuran, pyrrolidine, oxazolidine, morpholine, pyrrolyl, imidazole, pyrazole, 4-methylpiperazine-1-yl, or 4-hydroxypiperidine-1-yl Cyclopentane, cyclohexane, tetrahydrofuran ring, tetrahydropyran ring, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, piperidine ring, morpholine, piperazine ring, piperidine ring, hexahydropyrimidine, oxazinane, octahydropyrrolo[3,2-b]pyrrolyl, pyrrolyl ring, pyrazole ring, imidazole ring, pyrazine ring, pyridazine ring, pyrimidine ring, pyridine ring, benzene ring, indole ring, benzimidazole ring, indazole ring, benzotriazole ring, benzox Sazole, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine, isoindorine, indorine, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-indazole, oxazolo[4,5-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,These are [4-b]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2,3-dihydrooxazolo[4,5-b]pyridine, tetrahydroquinoline, tetrahydroisoquinoline, dihydrochromene, 1,2-dihydro-1,8-naphthyridine, azaindole, tetrahydronaphthalene, and dihydroindene.

[0039] In a particular embodiment, X is N.

[0040] In a particular embodiment, X is CH.

[0041] In certain embodiments, Y is NR4 or CHR4, and R4 is selected from H, C1-C3 alkyl groups, and acetyl groups.

[0042] In certain preferred embodiments, Y is NR4, and preferably R4 is selected from H, C1-C3 alkyl groups, and acetyl groups.

[0043] In another preferred embodiment, Y is CHR4, preferably R4 is selected from H, C1-C3 alkyl groups, and more preferably R4 is H.

[0044] In certain preferred embodiments, R1 and R2 are each independently selected from H, C1-C6 alkyl groups, halogens, halogenated C1-C4 alkyl groups, CN, C1-C4 alkoxy groups, -CH2-NH2, and -C(O)NH-CH3, preferably R1 and R2 are each independently selected from H, halogens, CN, CF3, C1-C4 alkyl groups, and C1-C4 alkoxy groups, and more preferably R1 and R2 are each independently selected from H, C1-C6 alkyl groups, halogens, and CN. In certain preferred embodiments, R1 and R2 are each independently selected from H, halogen, CN, -CH2-NH2, and -C(O)NH-CH3, and more preferably, R1 and R2 are each independently selected from H, halogen, and CN.

[0045] In certain preferred embodiments, the present invention provides compounds of formula (I), or stereoisomers, geometric isomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salts thereof. Here, n is either 0 or 1. X is either N or CH. Y is NR4 or CHR4, L0 is a bond, O, -NR5-, -C(O)-NR5- or -NR5-C(O)-, L1 is a bond or O, R1 and R2 are each independently selected from H, C1-C6 alkyl groups, halogens, CN, -C1-C6 alkyl-NR6R7, and -C(O)-NR6R7, where R4, R5, R6, and R7 are each independently selected from H and C1-C6 alkyl groups. R3 is either a C1-C6 alkyl group or a halogenated C1-C6 alkyl group, or R3 is a 5 or 6-membered heterocycloalkyl group optionally substituted with one or more halogen or hydroxyl groups, such as a piperazinyl group, 4-methylpiperazine-1-yl, piperidinyl group, or 4-hydroxypiperidine-1-yl.

[0046] In certain specific embodiments, the present invention provides compounds of the following formula (II):

[0047] [ka] The other variables R1, R2, R3, n, Y, L0, L1, and the ring W are given by equation (I).

[0048] In certain preferred embodiments, Y in the compound of formula (II) is CHR4, and R4 is selected from H, C1-C3 alkyl groups.

[0049] In certain preferred embodiments, L0 in the compound of formula (II) is a bond.

[0050] In a particular preferred embodiment, Y in the compound of formula (II) is CHR4 and L0 is a bond.

[0051] In certain specific embodiments, the present invention provides compounds of the following formula (III):

[0052] [ka] The other variables R1, R2, R3, n, Y, L0, L1, and the ring W are given by equation (I).

[0053] In certain preferred embodiments, L0 in the compound of formula (III) is a bond, O, S, -NH- or -NH(C=O)-.

[0054] In certain specific embodiments, the present invention provides compounds of the following formulas (IV), (V), and (VI):

[0055] [ka] The variables R1, R2, R3, R4, L0, L1, and the ring W are given by equation (I).

[0056] In certain preferred embodiments, in the compounds of formulas (IV), (V), and (VI), R1 and R2 are independently selected from H, C1-C6 alkyl groups, halogens, CN,-halogenated C1-C6 alkyl groups, and C1-C6 alkoxy groups, respectively.

[0057] In certain preferred embodiments, in the compounds of formulas (IV), (V), and (VI), R1 and R2 are independently selected from H, C1-C3 alkyl groups, halogens, and CN.

[0058] In a particular embodiment of the present invention, the compound of formula (I) is selected from the compounds of the following embodiments: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0059] In another embodiment, the present invention provides a method for preparing the compound of the present invention.

[0060] In certain embodiments, the present invention also provides intermediates for preparing the compounds of the present invention and methods for preparing them.

[0061] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention or a pharmaceutically usable salt thereof.

[0062] In certain embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically usable salt thereof, and at least one pharmaceutically usable carrier, diluent, or excipient.

[0063] In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0064] In another embodiment, the present invention provides a pharmaceutical combination product comprising at least one compound of the present invention or a pharmaceutically usable salt thereof, and one or more other activators.

[0065] In another embodiment, the present invention provides the use of the compound of formula (I), or its stereoisomers, geometric isomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salts, in the preparation of agents for preventing, treating, or alleviating disorders or diseases caused by abnormal androgenic activity in patients.

[0066] In certain embodiments, the abnormal androgenic activity is caused by an androgen receptor containing LBD domain mutations or deletions.

[0067] In another embodiment, the present invention provides a method for preventing, treating, or alleviating one or more abnormal androgen activity-mediated disorders or diseases, comprising administering to a subject in need of treatment an effective amount of a compound represented by formula I, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0068] In some embodiments of the present invention, the disorders or diseases include, but are not limited to, tumors, for example, prostate cancer, breast cancer, other prostate diseases, breast cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, spinal and bulbar muscular atrophy, and the like.

[0069] In some embodiments of the present invention, the prostate cancer includes, but is not limited to, metastatic castration-resistant prostate cancer, primary / localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic prostate cancer, and hormone-sensitive prostate cancer.

[0070] The aforementioned breast cancers include, but are not limited to, Luminal A type (ER+ / PR+, HER-2-), Luminal B type (ER+ / PR+, HER-2+), HER-2+ type (ER- / PR- / HER-2+), and Basal-like type (ER- / PR- / HER-2-) breast cancers.

[0071] In specific embodiments, when the Envision disclosed herein is used in combination with GraphPad Prism(6.0) and / or GraphPad Prism(6.0) two-way ANOVA and Dunnett and Tukey tests, the compounds of the present invention exhibit IC50 of 2 μM or less. 50 The IC value is preferably 1.5 μM or less. 50 The value, more preferably, is 1 μM or less for ICs. 50 The IC value is more preferably 0.5 μM or less, and most preferably 0.2 μM or less. 50 It has a value.

[0072] Within the scope of this invention, it should be understood that the technical features defined in each technical solution of the present invention and the technical features specifically described below (for example, in the examples) can be combined to form new or preferred technical solutions. Due to space limitations, each will not be explained in detail here. It should also be understood that each element of the embodiments is an independent embodiment. Explanation of terms

[0073] In this invention, unless otherwise specified, terms used herein have the meanings defined below. Terms not explicitly defined herein have the ordinary meanings generally understood by those skilled in the art.

[0074] The base is a wavy line [ka] If marked with a dash, the dash indicates the bond point of the group to the rest of the molecule.

[0075] This website states, [ka] " indicates a single or double bond. A person skilled in the art can determine, based on the compound value of the relevant ring atoms and the status of the connected base group, [ka] It is possible to determine whether a single or double bond is present, and this is within the capabilities of those skilled in the art. Those skilled in the art should understand that the ring in question may be saturated, partially saturated, or aromatic.

[0076] In this specification, the term “heteroatom” means a nitrogen (N), oxygen (O), or sulfur (S) atom, particularly nitrogen or oxygen, each of which may be substituted or unsubstituted, and includes its oxidized form. Examples of heteroatoms include, but are not limited to, -O-, -N=, -NR-, -S-, -S(O)-, and -S(O)2-, where R is hydrogen, a C1-C4 alkyl group, or a nitrogen protecting group (such as benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, p-methoxyphenyl, 3,4-dimethoxybenzyl). Unless otherwise specified, a heteroatom whose valence is not satisfied is considered to have enough hydrogen atoms to satisfy its valence.

[0077] In this specification, the terms “halogen” or “halogenated” refer to fluorine, chlorine, bromine, and iodine. Preferably, the halogens as substituents are fluorine and chlorine.

[0078] In this specification, the term “alkyl group” refers to a fully saturated linear or branched hydrocarbon group. Alkyl groups preferably contain 1 to 20, more preferably 1 to 16, 1 to 10, 1 to 6, or 1 to 4 carbon atoms. The term “C1-C6 alkyl group” refers to an alkyl group having 1 to 6 carbon atoms. The term “C1-C3 alkyl group” refers to an alkyl group having 1 to 3 carbon atoms. Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl groups.

[0079] In this specification, the term "alkoxy group" refers to an alkyl-O-yl group, where the alkyl group is as defined above. The term "C1-C6 alkoxy group" refers to an alkoxy group having 1 to 6 carbon atoms. Typical examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, and cyclohexyloxy groups. Preferably, the alkoxy group contains 1 to 6 or 1 to 4 carbon atoms.

[0080] In this specification, the term "halogenated C1-C6 alkyl group" refers to the C1-C6 alkyl group as defined above, substituted with one or more halogens, such as fluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, and trichloroethyl groups.

[0081] In this specification, the term "halogenated C1-C6 alkoxy group" refers to the C1-C6 alkoxy group defined above that is substituted with one or more halogens, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, chloroethoxy, dichloroethoxy, and trichloroethoxy.

[0082] In this specification, the term "cycloalkyl group" refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon group consisting of 3 to 12 carbon atoms. Cycloalkyl groups preferably contain 3 to 8 ring carbon atoms, for example, 3 to 8, 3 to 7, or 4 to 7 ring carbon atoms. Examples of monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl groups. Examples of bicyclic hydrocarbon groups include bornyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, and bicyclo[2.2.2]octyl. Examples of tricyclic hydrocarbon groups include the adamantyl group.

[0083] In this specification, the term "aryl group" refers to an aromatic hydrocarbon ring group having 6 to 18 carbon atoms in its ring portion and at least one aromatic ring. Preferably, the aryl group is C6-C 12 Aryl group or C6-C 10 It is an aryl group. Non-restrictive examples of aryl groups include phenyl, biphenyl, naphthyl, or anthracenyl groups.

[0084] In this specification, the term "aralkyl group" refers to the alkyl group substituted with the aryl group. Preferably, the aralkyl group is C6-C12 It is an aryl-C1-C6 alkyl group. Non-restrictive examples of aralkyl groups include the benzyl group and the naphthylmethyl group.

[0085] In this specification, the term “heteroaryl group” refers to a 5-14 member monocyclic, bicyclic, or fused polycyclic aromatic ring containing 1-6 heteroatoms selected from N, O, and S. Preferably, the heteroaryl group contains 1-3, 1-4, or 1-5 heteroatoms selected from N, O, and S. The heteroaryl group is preferably a 5-12 member heteroaryl group or a 5-10 member heteroaryl group, and more preferably a 5-6 member heteroaryl group. Preferably, heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, indolyl, benzotriazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, sinnolinyl, quinazolinyl, quinoxalinyl, tetrahydroquinolinyl, oxazolopyridinyl, imidazopyridinyl, 7-azaindryl, 6-azaindryl, 5-azaindryl, 4-azaindryl, and azaindazolyl.

[0086] In this specification, the term “heterocyclic” means fully saturated or partially saturated aromatic or non-aromatic cyclic groups, e.g., 4- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered tricyclic cyclic systems, preferably 4- to 12-membered monocyclic or bicyclic heterocyclics, the cyclic system comprising at least one heteroatom in a ring comprising at least one carbon atom. Each ring of the heterocyclic containing heteroatoms may contain 1-3, 1-4, 1-5, or 1-6 heteroatoms, preferably 1, 2, or 3, the heteroatoms selected from nitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfur heteroatoms may be further optionally oxidized, for example, the sulfur heteroatom may form a -S(O)- or -S(O)2- structure.

[0087] Examples of monocyclic heterocycles include fully saturated, partially saturated, or aromatic pyrrolidines, pyrroles, pyrazoles, oxetanes, oxolanes, oxhexanes, pyrazolines, imidazoles, imidazolines, imidazolidines, triazoles, thiazoles, thiadiazoles, thiazolidins, isothiazols, isothiazolidins, furans, tetrahydrofurans, thiophenes, piperidines, piperazines, 2-oxopiperazines, 2-oxopiperidines, 2-oxopyrrolidines, 4-piperidones, pyridines, pyrazines, pyrimidines, pyridazines, tetrahydropyrans, morpholines, thiomorpholines, thiomorpholine sulfoxides, thiomorpholine sulfones, 1,3-dioxolanes, and tetrahydro-1,1-dioxothiophenes. Other examples include 1,1,4-trioxo-1,2,5-thiadiazolidine-2-yl.

[0088] Examples of bicyclic heterocycles include fully saturated, partially saturated, or aromatic indole, dihydroindole, indazole, benzothiazole, benzoxazole, benzimidazole, benzopyrazole, benzotriazole, quinoline, isoquinoline, tetrahydroisoquinoline, pyridoxazole, pyridoimidazole, pyridopyridine, and pyridopyrazole.

[0089] The term "heterocycloalkyl group" refers to a group formed by the loss of one or more hydrogen atoms from the heterocycle defined above. Heterocycloalkyl groups can be bonded to the rest of the molecule at the heteroatom or carbon atom. Preferably, the heterocycloalkyl group is a 4- to 12-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, for example, a 5- to 7-membered heterocycloalkyl group.

[0090] In this specification, the term "acyl group" refers to the group R'-C(O)-, where R' is a C1-C6 alkyl group or C6-C as defined above. 12It is an aryl-C1-C6 alkyl group. Typical examples of acyls include, but are not limited to, the formyl group, acetyl group, propionyl group, butyryl group, valeryl group, hexanoyl group, and benzoyl group. In this specification, the term "oxo" refers to a group (=O).

[0091] In this specification, the terms “optional,” “optional,” or “optionally” mean that the substitution patterns, events, or situations described below may or may not occur, and that both the cases in which the substitution patterns described occur and the cases in which they do not occur are included herein. For example, the term “optionally substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined herein. Those skilled in the art will understand that for groups containing one or more substituents, the group does not contain substitution patterns that are sterically impractical, chemically inaccurate, unsynthetic, and / or inherently unstable.

[0092] In this specification, the terms “substituted” or “substituted by” mean that one or more hydrogen atoms on a particular atom or group are substituted by one or more substituents selected from a particular group of substituents, provided that the valence does not exceed the normal valence of that atom. When the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are substituted by oxygen. Combinations of substituents and / or variables are permitted only if they result in a chemically correct and stable compound. A chemically correct and stable compound is one that is stable enough to be isolated from a reaction mixture, have its chemical structure determined, and subsequently prepared into at least a practically useful formulation. For example, in this specification, the terms “substituted” or “substituted by” mean that one or more hydrogen atoms on a particular atom or group are independently substituted by one or more (e.g., one, two, three, or four) substituents, unless substituents are explicitly enumerated. When an atom or group is substituted by multiple substituents, those substituents may be identical or different. In this specification, groups such as alkyl groups, alkenyl groups, alkoxy groups, cycloalkyl groups, heteroaryl groups, heterocyclyl groups, heterocycloalkyl groups, carbonyl groups, sulfonyl groups, and sulfinyl groups may be substituted with substituents. Examples of substituents include, but are not limited to, OH, Boc, halogens, cyano groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkoxy groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, NRR', C(O)R, C(O)NRR', or C(O)OR. Furthermore, each R and b' is independently selected from H and a substituted or unsubstituted alkyl group.

[0093] In this specification, the term “pharmaceutically acceptable salt” includes acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as hydrochlorides, hydrobroms, sulfates, nitrates, phosphates, methanesulfons, oxalates, maleates, succinates, citrates, formates, benzoates, fumarates, tartrates, salicylates, mandelates, and carbonates. Those skilled in the art will understand that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid by any of the many known methods.

[0094] In this specification, the term “pharmaceutically acceptable excipient” includes any solvent, dispersion medium, coating agent, surfactant, antioxidant, preservative (e.g., antimicrobial, antifungal), isotonic agent, absorption retardant, salt, preservative, drug, drug stabilizer, binder, excipient, disintegrant, lubricant, sweetener, flavoring agent, dye, and similar substances, as well as combinations thereof.

[0095] The compounds of the present invention or their pharmaceutically usable salts may contain one or more chiral centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers, the stereoisomer forms of which may be defined from the viewpoint of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids, (D)- or (L)-. All such possible isomers, whether or not they are specifically described herein, as well as their racemic and optically pure forms, are encompassed in the present invention. Optically active (+)- and (-)-, (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthesis or chiral reagents, or separated using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemics (or racemics of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC).

[0096] The term "stereoisomer" refers to a compound that is composed of the same atoms bonded together by the same bonds, but has a different, incompatible three-dimensional structure. This invention considers various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed.

[0097] The term "tautomerism" refers to the transfer of a proton from one atom in a molecule to another atom in the same molecule. The present invention includes tautomers of any of the aforementioned compounds.

[0098] In this specification, the term “solvate” refers to substances including stoichiometric or non-stoichiometric solvent addition forms. When the solvent is water, the solvate formed is a hydrate; when the solvent is ethanol, the solvate formed is an ethanolate. A hydrate is formed by one or more molecules of water and one molecule of the substance, where water maintains the molecular form of H2O. Such bonding can form one or more hydrates, such as hemihydrate, monohydrate, and dihydrate.

[0099] In this specification, the term “therapeutic dose” refers to the amount of the compound of the present invention that can induce a biological or medical response in a subject, improve symptoms, slow the progression of a disease, or prevent a disease.

[0100] In this specification, the terms “subject” or “patient” refer to an animal. Preferably, the animal is a primate (e.g., human), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain preferred embodiments, the subject refers to a human.

[0101] In this specification, the term "inhibition" refers to the reduction or suppression of a particular disease, symptom, condition, or illness, or a significant decrease in the baseline activity of a biological activity or process.

[0102] In this specification, in certain embodiments, the term “to treat” any disease or condition means to improve the disease or condition (i.e., to stop or delay the progression of the disease or at least one clinical symptom). In another particular embodiment, the term “treatment” means to improve at least one physical parameter that may not be noticed by the patient. In yet another particular embodiment, the term “treatment” means to regulate the disease or condition physically (e.g., stabilizing observable symptoms), physiologically (e.g., stabilizing physical parameters), or both. Beneficial effects

[0103] The compounds of the present invention are inhibitors that target the N-terminus of the androgen receptor and exhibit high selectivity for the AR receptor. They show excellent growth inhibitory effects in cells expressing AR splice mutants (AR-V) lacking the ligand-binding domain (LBD) of the androgen receptor, particularly in cells expressing AR-vs androgen receptor splice mutants that are resistant to second-generation androgen receptor antagonists.

[0104] General synthesis pathway:

[0105] In certain embodiments, the compounds of the present invention can be synthesized by the following general synthesis route, where each variable is as defined herein, and the specific reaction conditions are as shown in the examples.

[0106] [ka]

[0107] Starting with 6-hydroxy-1-tetralone, 5,7-disubstituted alkoxynaphthalenone is obtained via halogenation, coupling, and alkylation reactions. This is then reacted with Tf2O to convert it to the important common intermediate INT-1 / 2. Next, this intermediate is reacted with various boronic acids or boron esters via the Suzuki reaction and subjected to hydrogenation reduction to obtain the initial target product TM1. Alternatively, starting with alkoxynaphthalenone, the carbonyl group is reduced to an alcohol and reacted with PBr3 to obtain the important common intermediate INT-3. Next, INT-3 is reacted with ammonia to convert Br to an amino group. The resulting benzylamine is then subjected to Buchwald coupling and amide condensation reactions to obtain TM2 and TM3. Furthermore, TM4 is obtained by directly substituting INT-3 with a heterocycloalkylamino.

[0108] [ka]

[0109] Alternatively, 6-hydroxy-1,2,3,4-tetrahydroquinoline can be used as a starting material and subjected to Boc protection, halogenation, alkylation, acidification, and deprotection reactions to obtain the 5,7-disubstituted tetrahydroquinoline intermediate INT-4. INT-4 can then be coupled with various halogenated aromatic rings via the Buchwald reaction to obtain TM5. [Modes for carrying out the invention]

[0110] In this application, if there is a contradiction between the chemical name and the structural formula, the structural formula shall take precedence unless the context indicates that the chemical name is correct rather than the structural formula.

[0111] The present invention will be described in more detail below with reference to specific examples. It should be understood that these examples are used solely to illustrate the present invention and do not limit its scope. Experimental methods in the following examples that do not specify particular experimental conditions will follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts refer to weight percentages and parts by weight.

[0112] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial sources.

[0113] In each example, the experimental apparatus will be described as follows (for example, 1 ¹H NMR was recorded using a Varian Mercury-300 or Varian Mercury-400 nuclear magnetic resonance spectrometer. 13 ¹³C NMR is recorded using a Varian Mercury-400, Varian Mercury-500, or Varian Mercury-600 nuclear magnetic resonance spectrometer, with chemical shifts expressed in δ (ppm). Mass spectra are recorded using Finnigan / MAT-95 (EI) and Finnigan LCQ / DECA and Micromass Ultra Q-TOF (ESI) mass spectrometers (silica gel for reversed-phase preparative HPLC separation is 200-300 mesh). SFC purification method (Column: Chiralpak IG 250mm*4.6mm 5um, mobile phase: Hex-EtOH, 30℃).

[0114] The Japanese names for reagents represented by chemical formulas or English abbreviations are as follows:

[0115] DCM: Dichloromethane; DCE: 1,2-Dichloroethane; THF: Tetrahydrofuran; MeCN: Acetonitrile; DMF: N,N-Dimethylformamide; Tol: Toluene; TFA: Trifluoroacetic acid; PE: Petroleum ether; EA: Ethyl acetate; TEA: Triethylamine; DIEA: N,N-Diisopropylethylamine; HEPES: 4-Hydroxyethylpiperazine ethanesulfonic acid; Tf2O: Trifluoromethanesulfonic anhydride; DBAD: Dibenzyl azodicarboxylate; Trt-Cl: TosCl: p-Toluene sulfonyl chloride; Triphenylmethane; A CN: Acetonitrile; (Bpin)2: Pinacol diboronate; AcOK: Potassium acetate; AcOH: Acetic acid; Pybop: 1H-Benzotriazole-1-yloxytripyrrolidinoylhexafluorophosphate; DHP: Dihydropyran; BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-Binaphthyl; PTSA: p-Toluene sulfonic acid; NMP: N-Methylpyrrolidone; EGTA: Glycol ether diaminetetraacetic acid; DTT: Dithiothreitol; EDTA: Ethylenediaminetetraacetic acid; DIPEA: N,N-Diisopropylethylamine; Raney Ni: Raney nickel; Boc2O: di-tert-butyl dicarbonate; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; NIS: N-iodosuccinimide; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(OAC)2: Fumaronitrile; P(nBu)3: tri-n-butylphosphino LDA: Lithium diisopropylamide; HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexachloride fluorophosphate; HBTU: O-benzotriazole-tetramethyluronium hexafluorophosphate; Xphos: 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;tBuBrettphos-Pd-G3:[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonic acid; TLC: Thin-layer chromatography; RT: Retention time; LCMS: Liquid chromatography-mass spectrometry.

[0116] Synthesis of major intermediates

[0117] Intermediate INT-1

[0118] [ka]

[0119] Step 1: Synthesis of 5,7-dichloro-6-hydroxy-3,4-dihydronaphthalene-1(2H)-one

[0120] Compound S1 (10 g, 61.7 mmol) was added to chloroform (650 mL), and S2 (16.2 mL, 142 mmol) was added at 0°C. The mixture was stirred overnight at room temperature and concentrated to obtain a yellow solid INT-1-1 (9.5 g, yield: 66.9%). LC-MS (ESI): m / z = 231.0 [M + H] + .

[0121] Step 2: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalene-1(2H)-one

[0122] Compounds INT-1-1 (5g, 21.7 mmol) and S3 (13.6g, 95.5 mmol) were dissolved in DMF (80 mL), potassium carbonate (3.3g, 23.8 mmol) was added, and the mixture was reacted at 35°C for 26 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a yellow solid INT-1-2 (4.65 g, yield: 72.6%). LC-MS (ESI): m / z = 293.0 [M + H] + .

[0123] Step 3: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate

[0124] Compound INT-1-2 (4.65 g, 15.9 mmol) and TEA (5.12 g, 50.7 mmol) were dissolved in a three-necked flask containing DCM (100 mL). Under nitrogen gas protection, Tf2O (22. g, 79.5 mmol) was added at 0 °C, and the reaction was carried out overnight at room temperature. The reaction solution was extracted with DCM, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column to obtain yellow oily substance INT-1 (6.2 g, yield: 95.3%). LCMS (ESI): m / z = 424.9 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 6.08 (t, J = 4.8 Hz, 1H), 4.28 (t, J = 6.3 Hz, 2H), 3.88 (t, J = 6.2 Hz, 2H), 2.98 (t, J = 8.3 Hz, 2H), 2.56 (td, J = 8.4, 4.8 Hz, 2H).

[0125] Intermediate INT-2

[0126]

Chemical Structure

[0127] Step 1: Synthesis of 5-chloro-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one

[0128] Compound S1 (20 g, 125 mmol) was added to chloroform (300 mL), S2 (12 g, 110 mmol) was added at 0 °C, and the mixture was stirred overnight at room temperature and concentrated to obtain solid INT-2-1 (18 g, yield: 75%). LCMS (ESI): m / z = 197.0 [M+H][[ID=?]] + [[ID=?]]。

[0129] Step 2: Synthesis of 5-chloro-6-hydroxy-7-iodo-3,4-dihydronaphthalene-1(2H)-one

[0130] Compound INT-2-1 (18 g, 91.8 mmol) and NIS (26 g, 115 mmol) were dissolved in DCE (300 mL) and reacted at 60°C for 4 hours. After cooling, the reaction mixture was filtered and concentrated under reduced pressure to obtain a brown solid INT-2-2 (20 g, yield: 77%). LC-MS (ESI): m / z = 322.9 [M + H] + .

[0131] Step 3: Synthesis of 5-chloro-6-(2-chloroethoxy)-7-iodo-3,4-dihydronaphthalene-1(2H)-one

[0132] Compounds INT-2-2 (20 g, 62 mmol), S4 (15 g, 186 mmol), DBAD (14 g, 61 mmol), and PPh3 (16 g, 61 mmol) were dissolved in 300 mL of water and reacted at 110°C for 8 hours under nitrogen gas protection. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a white solid INT-2-3 (15 g, yield: 85%). LC-MS (ESI): m / z = 384.9 [M + H] + .

[0133] Step 4: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0134] Compound INT-2-3 (5g, 13 mmol), CuCN (2.4g, 26 mmol), and NMP (80 mL) were placed in a sealed tube and reacted at 120°C for 8 hours under nitrogen gas protection. After cooling, the reaction mixture was extracted by EA, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a white solid INT-2-4 (3.2g, yield: 86%). LC-MS (ESI): m / z = 284.0 [M + H] +.

[0135] Step 5: Synthesis of 5-chloro-6-(2-chloroethoxy)-7-cyano-3,4-dihydronaphthalene-1-yltrifluoromethanesulfonic acid

[0136] INT-2-4 (3.2g, 11.3 mmol) and TEA (3.4g, 33.9 mmol) were dissolved in a three-necked flask containing DCM (100 mL). Under nitrogen gas protection and at 0°C, Tf2O (16g, 56.5 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction mixture was extracted with DCM, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a yellow solid INT-2 (3.5g, yield: 66%). LC-MS (ESI): m / z = 416.0 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ7.46(s,1H),6.15(t,J=4.8Hz,1H),4.48(t,J=6.0Hz,2H),3.90(t,J=6.0Hz,2H),3.08(t,J=8.3Hz,2H),2.66-2.56(m,2H).

[0137] Intermediates INT-3, INT-5

[0138] [ka]

[0139] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0140] Compound INT-2-4 (800 mg, 2.8 mmol) was added to methanol (10 mL), and NaBH4 (430 mg, 11.3 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, the residue was extracted with EA, the organic phase was dried and concentrated to obtain solid INT-3-1 (700 mg, yield: 87%). LCMS (ESI): m / z = 286.0 [M+H] + .

[0141] Step 2: Synthesis of 8-bromo-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0142] Compound INT-3-1 (700 mg, 2.4 mmol) was added to DCM (10 mL), and PBr3 (1.3 g, 4.8 mmol) was added at 0 °C. The mixture was stirred at room temperature for 5 hours. The reaction solution was extracted with DCM, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid INT-3 (500 mg, yield: 59%). LCMS (ESI): m / z = 347.9 [M+H] + ; 1 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 5.45 (t, J = 3.7 Hz, 1H), 4.42 (td, J = 6.1, 1.7 Hz, 2H), 3.88 (t, J = 6.1 Hz, 2H), 3.18 - 3.05 (m, 1H), 2.82 - 2.65 (m, 1H), 2.43 - 2.32 (m, 1H), 2.29 - 2.18 (m, 1H), 2.12 - 1.96 (m, 2H).

[0143] Step 3: Synthesis of 8-amino-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0144] Compound INT-3 (200 mg, 0.56 mmol) was dissolved in dioxane (510 mL), aqueous ammonia (5 mL) was added, and the mixture was placed in a sealed tube at 40°C and stirred for 12 hours. The solution was filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain INT-5 (110 mg, yield: 69%). LC-MS (ESI): m / z = 285.1 [M + H] + ; 1 HNMR(400MHz,DMSO)δ7.92(s,1H),4.37(t,J=5.2Hz,2H),3.96(t,J=4.8Hz,2H),3.80(dd,J=7.2,4.8H z,1H),2.73(t,J=8.0Hz,2H),2.22(brs,2H),1.97-1.82(m,2H),1.74-1.67(m,1H),1.56-1.48(m,1H).

[0145] Intermediate INT-4

[0146] [ka]

[0147] Step 1: Synthesis of tert-butyl 6-hydroxy-3,4-dihydroquinoline-1(2H)-carboxylate

[0148] Compound S5 (2 g, 13.4 mmol) was added to dioxane (40 mL), followed by Boc anhydride (4.5 g, 20.7 mmol) and NaOH (40 mL, 1 M) aqueous solution. The mixture was reacted at room temperature for 5 hours. The concentrate was extracted with glacial ammonium chloride and EA, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the crude white solid INT-4-1 (2.3 g, yield: 69.6%). LC-MS (ESI): m / z = 250.1 [M + H] + .

[0149] Step 2: Synthesis of tert-butyl 5,7-dichloro-6-hydroxy-3,4-dihydroquinoline-1(2H)-carboxylate

[0150] Compound INT-4-1 (4.8 g, 19.2 mmol) was added to DCE (120 mL), followed by NCS (5.9 g, 44.2 mmol) and acetic acid (24 mL). The mixture was reacted at room temperature for 8 hours. The concentrate was extracted with ice-cold sodium bicarbonate and DCM, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the crude product, a white solid INT-4-2 (3.6 g, yield: 59%). LCMS (ESI): m / z = 318.1 [M + H] + .

[0151] Step 3: Synthesis of tert-butyl 5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydroquinoline-1(2H)-carboxylate

[0152] Compounds INT-4-2 (3.6 g, 11.3 mmol) and S3 (3.25 g, 22.7 mmol) were dissolved in DMF (30 mL), and cesium carbonate (4.4 g, 13.5 mmol) was added. The mixture was reacted at 35°C for 16 hours. Extraction was performed with ammonium chloride and EA, and the mixture was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a colorless oily compound, INT-4-3 (1.35 g, yield: 31.3%). LC-MS (ESI): m / z = 380.1 [M + H] + .

[0153] Step 4: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydroquinoline

[0154] Compound INT-4-3 (1.35 g, 3.5 mmol) was dissolved in a necked flask containing DCM (20 mL), TFA (8 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was adjusted to approximately pH=7 with sodium bicarbonate under ice bath conditions, extracted with DCM, and the organic phase was concentrated under reduced pressure to obtain a white solid INT-4 (890 mg, yield: 89.5%). LC-MS (ESI): m / z = 280.0 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ6.41(s,1H),4.16(t,J=6.4Hz,2H),3.84(t,J=6.4Hz,2H),3.25-3.21(m,2H),2.73(t,J=6.6Hz,2H),1.96-1.91(m,2H).

[0155] Example 1

[0156] [ka]

[0157] Step 1: 5-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalene-1-yl)-1H-indazole

[0158] Compound INT-1 (500 mg, 1.18 mmol), compound S1 (430 mg, 1.76 mmol), Pd(dppf)Cl2 (86 mg, 0.18 mmol), and sodium carbonate (312 mg, 2.95 mmol) were sequentially added to a dry flask, dissolved in dioxane / water (10 / 2 ml), and reacted at 100°C for 6 hours under nitrogen gas protection. Extraction was performed with EA, washed with saturated ammonium chloride aqueous solution, the organic phase was dried over anhydrous sodium carbonate, filtered, concentrated, and purified by silica gel column (DCM / MeOH = 25:1) to obtain a white solid H100-1 (250 mg, yield: 63%). LCMS (ESI): m / z = 393.1 [M + H] + .

[0159] Step 2: 5-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-1H-indazole

[0160] Compound H100-1 (250 mg, 0.6 mmol), PtO2 (50 mg, 20 wt%), and MeOH (10 mL) were sequentially added to a dry flask and reacted under a hydrogen gas atmosphere at room temperature for 5 hours. The mixture was filtered, concentrated, and purified by Prep-HPLC to obtain HANT-100 (40 mg, yield: 16%). LC-MS (ESI): m / z = 395.2 [M + H] + . 1 HNMR(400MHz,CDCl3):δ8.02(s,1H),7.44(d,J=8.4Hz,1H),7.39(s,1H),7.12(d,J=8.4Hz,1H),6.82(s,1H),4.26(t, J=6.4Hz,2H),4.15(t,J=6.8Hz,1H),3.88(t,J=6.4Hz,2H),2.88-2.84(m,2H),2.16-2.11(m,1H),1.96-1.70(m,3H).

[0161] Example 2

[0162] [ka]

[0163] The synthesis method was the same as in Example 1, yielding compound HANT-101 (4.4 mg, white solid, yield: 14.6%). LCMS(ESI): m / z = 372.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.40-7.35(m,1H),7.10(d,J=2.6Hz,1H),6.93(s,1H),6.53(d,J=9.4Hz,1H) ,4.23(t,J=5.8Hz,2H),3.96(s,1H),3.88(t,J=5.8Hz,2H),2.83(s,2H),2.03(s,1H),1.80(s,3H).

[0164] Example 3

[0165] [ka]

[0166] Step 1: 2-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalene-1-yl)-5-methoxypyridine

[0167] Compounds S2 (1.0 g, 5.3 mmol), S3 (1.76 g, 6.9 mmol), potassium acetate (1.04 g, 10.6 mmol), and Pd(dppf)Cl2 (0.39 g, 0.53 mmol) were sequentially added to a dry flask, dissolved in dioxane (30 mL), and stirred at 100°C for 2 hours under nitrogen gas protection. Further, INT-1 (300 mg, 5.3 mmol), sodium carbonate (150 mg, 10.6 mmol), and water (2 mL) were added to the reaction mixture and stirred at 100°C for 2 hours under nitrogen gas protection. After cooling, the mixture was extracted with saturated ammonium chloride solution and EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column to obtain the gray oily compound H102-1 (90 mg, yield: 33.2%). LCMS(ESI): m / z = 384[M+H] + .

[0168] Step 2: 2-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-5-methoxypyridine

[0169] Compound H102-1 (90 mg, 0.23 mmol) was dissolved in MeOH / THF (6 mL / 3 mL), PtO2 (26.7 mg, 0.12 mmol) was added, and the reaction was carried out under a hydrogen gas atmosphere at room temperature for 3 hours. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow oily compound H102-2 (86 mg, yield: 95.0%). LC-MS (ESI): m / z = 386 [M + H] + .

[0170] Step 3: 6-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)pyridine-3-ol

[0171] Compound H102-2 (30 mg, 0.078 mmol) was added to BBr3 (0.9 mL, 0.78 mmol) at 0°C. The bottle was sealed, and the temperature was allowed to rise naturally from 0°C to room temperature for 2 hours. The reaction mixture was extracted with saturated saline and DCM. The organic phase was backwashed with saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and purified by neutral reverse phase preparative fractionation to obtain a white solid HANT-102 (5.9 mg, yield: 20.4%). LC-MS (ESI): m / z = 372 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ8.18(d,J=2.0Hz,1H),7.15(dd,J=8.4,2.5Hz,1H),6.89(d,J=8.5Hz,1H),6.77(s,1H),4.21(t,J=6.3Hz,3H) ,3.85(t,J=6.4Hz,2H),2.83(t,J=6.3Hz,2H),2.12-2.06(m,1H),2.00-1.96(m,1H),1.89(dd,J=7.9,5.8Hz,1H),1.80-1.76(m,1H).

[0172] Example 4

[0173] [ka]

[0174] Step 1: Synthesis of 1,3-difluoro-4-iodo-2-methoxybenzene

[0175] Compound S1 (5.0 g, 34.7 mmol) was dissolved in a three-necked flask containing THF (100 mL), and n-BuLi (15.5 mL) was added at -78 °C, followed by stirring for 1 hour. I2 (9.3 g, 36.6 mmol) was then added, and the mixture was stirred at -78 °C for 1 hour. The reaction mixture was extracted by DCM, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H103-1 (8.4 g, yield: 89%). LC-MS (ESI): m / z = 270.9 [M + H] + .

[0176] Step 2: Synthesis of 4-(2,4-difluoro-3-methoxyphenyl)buta-3-in-1-ol

[0177] Compound H103-1 (8.4g, 31.1 mmol), S2 (4.4g, 62 mmol), Pd(PPh3)2Cl2 (112mg, 0.15 mmol), CuI (1.2g, 6.2 mmol), and TEA (31.5g, 311 mmol) were added to DMF (100 mL) and stirred at 50°C for 3 hours. The reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H103-2 (4.1 mg, yield: 62%). LCMS (ESI): m / z = 213.1 [M + H] + .

[0178] Step 3: Synthesis of 4-(2,4-difluoro-3-methoxyphenyl)butanol

[0179] Compound H103-2 (4.5 g, 21.2 mmol), Pd / C (900 mg), and methanol (10 mL) were stirred overnight at room temperature. The reaction mixture was filtered and concentrated to obtain compound H103-3 (4.1 g, yield: 85%). LC-MS (ESI): m / z = 217.1 [M + H] + .

[0180] Step 4: Synthesis of 4-(2,4-difluoro-3-methoxyphenyl)butanoic acid

[0181] Compound H103-3 (2.0 g, 8.7 mmol), TEMPO (400 mg, 2.6 mmol), and DAIB (7.0 g, 21.7 mmol) were added to DCM / water (20 mL / 4 mL) and stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain solid H103-4 (1.4 g, yield: 75%). LC-MS (ESI): m / z = 229.1 [M + H] + .

[0182] Step 5: Synthesis of 5,7-difluoro-6-methoxy-3,4-dihydronaphthalene-1(2H)-one

[0183] Compound H103-4 (1.4 g, 6.1 mmol) was added to PPA (20 mL) and stirred at 80°C for 1 hour. The reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H103-5 (900 mg, yield: 69.7%). LC-MS (ESI): m / z = 213.1 [M + H] + .

[0184] Step 6: Synthesis of 5,7-difluoro-6-hydroxy-3,4-dihydronaphthalene-1(2H)-one

[0185] Compound H103-5 (850 mg, 4.0 mmol) and NaSEt (1.2 g, 20.0 mmol) were added to DMF (20 mL) and stirred at 120°C for 3 hours. The reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H103-6 (476 mg, yield: 60%). LC-MS (ESI): m / z = 199.0 [M + H] + .

[0186] Step 7: Synthesis of 6-(2-chloroethoxy)-5,7-difluoro-3,4-dihydronaphthalene-1(2H)-one

[0187] Compound H103-6 (476 mg, 2.4 mmol), S3 (1.03 mg, 7.2 mmol), and potassium carbonate (1.0 mg, 7.2 mmol) were added to DMF (10 mL) and stirred overnight at room temperature. The reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H103-7 (300 mg, yield: 49%). LC-MS (ESI): m / z = 261.0 [M + H] + .

[0188] Step 8: Synthesis of 6-(2-chloroethoxy)-5,7-difluoro-3,4-dihydronaphthalene-1-yltrifluoromethanesulfonic acid

[0189] Compound H103-7 (300 mg, 1.15 mmol) and TEA (350 mg, 3.5 mmol) were dissolved in a three-necked flask containing DCM (10 mL). Tf2O (1.63 g, 5.8 mmol) was added at 0°C, and the mixture was reacted overnight at room temperature. The reaction mixture was extracted with DCM, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H103-8 (350 mg, yield: 77%). LC-MS (ESI): m / z = 393.0 [M + H] + .

[0190] Step 9: Synthesis of 5-(6-(2-chloroethoxy)-5,7-difluoro-3,4-dihydronaphthalene-1-yl)-1H-indazole

[0191] Compound H103-8 (300 mg, 0.77 mmol), S4 (186 mg, 1.15 mmol), Pd(dppf)Cl2 (112 mg, 0.15 mmol), and Na2CO3 (163 mg, 1.53 mmol) were added to dioxane / water (5 mL / 1 mL) and stirred at 80°C for 4 hours. The reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H103-9 (150 mg, yield: 54%). LCMS (ESI): m / z = 361.1 [M + H] + .

[0192] Step 10: Synthesis of 5-(6-(2-chloroethoxy)-5,7-difluoro-1,2,3,4-tetrahydronaphthalene-1-yl)-1H-indazole

[0193] Compound H103-9 (150 mg, 0.42 mmol) and PtO2 (50 mg) were added to MeOH / THF (3 mL / 1 mL) and reacted under a hydrogen gas atmosphere at room temperature for 2 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain a white solid HANT-103 (61.3 mg, yield: 61%). LC-MS (ESI): m / z = 363.1 [M + H] + ; 1 HNMR(300MHz,DMSO-d6)δ12.89(s,1H),8.01(s,1H),7.56-7.40(m,2H),7.13(d,J=9.3Hz,1H),6.45(d,J=11.5Hz,1H),4.36(t,J=5. 2Hz,2H),4.20(t,J=6.5Hz,1H),3.90(t,J=5.2Hz,2H),2.84-2.73(m,2H),2.17-2.04(m,1H),1.98-1.82(m,2H),1.83-1.66(m,1H).

[0194] Example 5

[0195] [ka]

[0196] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(4-hydroxyphenyl)-5,6-dihydronaphthalene-2-carbonitrile

[0197] Compounds INT-2 (170 mg, 0.41 mmol), S2 (85 mg, 0.61 mmol), Pd(dppf)Cl2 (60 mg, 0.08 mmol), and Na2CO3 (87 mg, 0.82 mmol) were added to dioxane / water (3 mL / 0.5 mL) and stirred at 80°C for 4 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain the yellow oily compound H105-1 (130 mg, yield: 88%). LCMS (ESI): m / z = 360.0 [M + H] + .

[0198] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0199] Compounds H105-1 (100 mg, 0.28 mmol) and S3 (65 mg, 0.56 mmol) were dissolved in TFA (5 mL) and reacted under a nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was adjusted to pH=8 with aqueous sodium bicarbonate solution, extracted with EA, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a white solid HANT-105 (58.7 mg, yield: 58%). LC-MS (ESI): m / z = 362.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.30(s,1H),7.11(s,1H),6.86(d,J=8.2Hz,2H),6.70(d,J=8.4Hz,2H),4.39(t,J=5.1 Hz,2H),4.05(t,J=5.8Hz,1H),3.97(t,J=5.2Hz,2H),2.89-2.80(m,2H),2.03-1.89(m,1H),1.84-1.66(m,3H).

[0200] Example 6

[0201] [ka]

[0202] Step 1: Synthesis of 3-chloro-2-(2-chloroethoxy)-5-(4-hydroxyphenyl)-7,8-dihydronaphthalene-1-carbonitrile

[0203] Compound INT-2' (100 mg, 0.24 mmol, synthesized using the same method as compound INT-2), S2 (50 mg, 0.36 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol), and Na2CO3 (52 mg, 0.5 mmol) were added to dioxane / water (3 mL / 0.5 mL) and stirred at 80°C for 4 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain the yellow oily compound H106-1 (80 mg, yield: 93%). LCMS (ESI): m / z = 360.0 [M + H] + .

[0204] Step 2: Synthesis of 3-chloro-2-(2-chloroethoxy)-5-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile

[0205] Compounds H106-1 (80 mg, 0.23 mmol) and S3 (53 mg, 0.45 mmol) were dissolved in TFA (3 mL) and reacted under a nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was adjusted to pH=8 with aqueous sodium bicarbonate solution, extracted with EA, and the organic phase was concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain a white solid HANT-106 (49.8 mg, yield: 82%). LC-MS (ESI): m / z = 362.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.30(s,1H),7.10(s,1H),6.88(d,J=8.5Hz,2H),6.70(d,J=8.4Hz,2H),4.43-4. 35(m,2H),4.06-3.98(m,1H),3.99-3.91(m,2H),2.98-2.82(m,2H),2.04-1.93(m,1H),1.87-1.62(m,3H).

[0206] Example 7

[0207] [ka]

[0208] Step 1: Synthesis of 6-chloro-5-hydroxy-2,3-dihydro-1H-inden-1-one

[0209] Compound S1 (800 mg, 4.08 mmol) was dissolved in toluene (10 mL), and aluminum trichloride (1.63 g, 12.2 mmol) was added. The reaction was carried out under N2 at 75°C for 6 hours. After cooling, the reaction mixture was extracted with ammonium chloride solution and EA. The organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. Purification by column chromatography yielded compound H107-1 (530 mg, yield: 70.9%). LCMS(ESI): m / z = 183.0 [M + H] + .

[0210] Step 2: Synthesis of 6-chloro-5-(2-chloroethoxy)-2,3-dihydro-1H-inden-1-one

[0211] Compound H107-1 (500 mg, 2.7 mmol) was dissolved in DMF (15 mL), and 1-bromo-2-chloroethane (985 mg, 6.89 mmol) and potassium carbonate (454 mg, 3.29 mmol) were added. The mixture was reacted at 35°C for 15 hours. Extraction was performed with ammonium chloride solution and EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to obtain compound H107-2 (490 mg, yellow solid, yield: 72.8%). LCMS (ESI): m / z = 245.0 [M + H] + .

[0212] Step 3: Synthesis of 5-chloro-6-(2-chloroethoxy)-1H-indene-3-yltrifluoromethanesulfonate

[0213] Compound H107-2 (400 mg, 1.63 mmol) and triethylamine (480 mg, 4.75 mmol) were dissolved in DCM (10 mL), and Tf2O (1.2 mL) was added at 0°C. The reaction was carried out under a nitrogen atmosphere at room temperature for 3 hours. After cooling the reaction mixture, it was extracted with ammonium chloride solution and DCM. The organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. Purification by column chromatography yielded compound H107-3 (390 mg, yellow oily, yield: 63.4%). LCMS (ESI): m / z = 376.9 [M + H] + .

[0214] Step 4: Synthesis of 4-(5-chloro-6-(2-chloroethoxy)-1H-inden-3-yl)phenol

[0215] Compound H107-3 (300 mg, 0.80 mmol) and compound S2 (165 mg, 1.20 mmol) were dissolved in a mixed solution of dioxane and water (5.5 mL, 10:1). Pd(dppf)Cl2 (88 mg, 0.12 mmol) and sodium carbonate (168 mg, 1.56 mmol) were then added, and the mixture was heated to 105°C and reacted for 6 hours. After cooling the reaction mixture, it was extracted with ammonium chloride solution and EA. The organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. After purification by column chromatography, compound H107-4 (66 mg, yellow solid, yield: 25.7%) was obtained. LCMS(ESI): m / z = 321.0 [M + H] + .

[0216] Step 5: Synthesis of 4-(6-chloro-5-(2-chloroethoxy)-2,3-dihydro-1H-inden-1-yl)phenol

[0217] Compound H107-4 (66 mg, 0.20 mmol) was dissolved in a mixed solution of methanol and THF (1.5 mL, 2:1). Under a hydrogen gas atmosphere, PtO2 (13 mg, 0.2 eq) was added, and the reaction was carried out at room temperature for 3 hours. It was extracted with ammonium chloride solution and DCM. The organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. It was purified by prep-HPLC to obtain compound HANT-107 (4.1 mg, white solid, yield: 6.6%). LCMS (ESI): m / z = 323.0 [M+H] + ; 1 HNMR (400 MHz, CD3OD) δ 7.00 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 6.73 (d, J = 8.4 Hz, 2H), 4.28 (t, J = 5.6 Hz, 2H), 4.18 (t, J = 8.2 Hz, 1H), 3.87 (t, J = 5.6 Hz, 2H), 2.96 (d, J = 5.4 Hz, 1H), 2.88 (dt, J = 16.2, 8.4 Hz, 1H), 2.53 (d, J = 8.4 Hz, 1H), 1.99 (dd, J = 12.6, 9.0 Hz, 1H).

[0218] Example 8

[0219]

Chemical Structure

[0220] Step 1: Synthesis of 4-chloro-5-hydroxy-2,3-dihydro-1H-inden-1-one

[0221] Compound S1 (2.0 g, 13.5 mmol) was dissolved in chloroform (100 mL). At 0 °C, tert-butyl hypochlorite (2.2 g, 20.2 mmol) was added, and the reaction was carried out overnight at room temperature. The reaction solution was extracted with ammonium chloride solution and DCM. The organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. After purification by column chromatography, compound H108-1 (1.75 g, yellow solid, yield: 71%) was obtained. LCMS (ESI): m / z = 183.0 [M+H] + 。

[0222] Step 2: Synthesis of 4-chloro-5-(2-chloroethoxy)-2,3-dihydro-1H-inden-1-one

[0223] Compound H108-1 (1.5 g, 8.2 mmol) was dissolved in DMF (25 mL), and 1-bromo-2-chloroethane (2.95 g, 20.6 mmol) and potassium carbonate (1.37 g, 9.9 mmol) were added. The mixture was reacted overnight at 35°C. Extraction was performed with ammonium chloride solution and EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to obtain compound H108-2 (1.37 g, white solid, yield: 68.5%). LCMS (ESI): m / z = 245.0 [M + H] + .

[0224] Step 3: Synthesis of 7-chloro-6-(2-chloroethoxy)-1H-indene-3-yltrifluoromethanesulfonate

[0225] Compound H108-2 (1.0 g, 4.08 mmol) and triethylamine (1.2 g, 11.8 mmol) were dissolved in DCM (15 mL), and Tf2O (3 mL) was added at 0°C. The reaction was carried out under a nitrogen atmosphere for 3 hours. The reaction mixture was extracted with ammonium chloride solution and DCM, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. Purification by column chromatography yielded compound H108-3 (1.1 g, yellow oily, yield: 71.8%). LCMS (ESI): m / z = 376.9 [M + H] + .

[0226] Step 4: Synthesis of 4-(7-chloro-6-(2-chloroethoxy)-1H-inden-3-yl)phenol

[0227] Compound H108-3 (500 mg, 1.33 mmol) and compound S2 (275 mg, 1.99 mmol) were dissolved in a mixed solution of dioxane and water (11 mL, 10:1). Pd(dppf)Cl2 (195 mg, 0.27 mmol) and sodium carbonate (280 mg, 2.64 mmol) were then added, and the mixture was reacted under N2 protection at 105°C for 6 hours. After cooling, the reaction mixture was extracted with ammonium chloride solution and EA. The organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. After purification by column chromatography, compound H108-4 (173 mg, yellow solid, yield: 40.5%) was obtained. LCMS(ESI): m / z = 321.0 [M + H] + .

[0228] Step 5: Synthesis of 4-(4-chloro-5-(2-chloroethoxy)-2,3-dihydro-1H-inden-1-yl)phenol

[0229] Compound H108-4 (173 mg, 0.54 mmol) was dissolved in a mixture of methanol and THF (3 mL, 2:1), and PtO2 (34 mg, 0.2 eq) was added under H2 conditions. The mixture was reacted at room temperature for 3 hours. Extraction was performed with ammonium chloride solution and DCM, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC yielded compound HANT-108 (9.3 mg, white solid, yield: 5.3%). LCMS(ESI): m / z = 323.1 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ6.97(d,J=8.4Hz,2H),6.84(d,J=8.2Hz,1H),6.72(t,J=7.8Hz,3H),4.31-4.20(m,3H),3.86 (t,J=5.4Hz,2H),3.17-3.02(m,1H),2.91(dd,J=16.4,8.2Hz,1H),2.62-2.48(m,1H),2.00(dd,J=12.6,9.0Hz,1H).

[0230] Example 9

[0231] [ka]

[0232] The synthesis method was the same as that in Example 1, and compound HANT-109 (10.3 mg, white solid, yield: 25.6%) was obtained. LCMS (ESI): m / z = 389.0 [M+H] + ; 1 HNMR (400 MHz, CD3OD) δ 6.84 (dd, J = 14.4, 5.6 Hz, 2H), 6.76 - 6.63 (m, 2H), 4.23 (t, J = 5.8 Hz, 2H), 4.00 (t, J = 6.4 Hz, 1H), 3.88 (t, J = 5.8 Hz, 2H), 2.83 (t, J = 5.6 Hz, 2H), 2.06 - 2.02 (m, 1H), 1.95 - 1.69 (m, 3H).

[0233] Example 10

[0234]

Chemical Structure

[0235] Step 1: Synthesis of 4-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalen-1-yl)-3-fluorophenol

[0236] In a sealed tube, compound INT-1 (50 mg, 0.12 mmol) and S2 (28 mg, 0.18 mmol) were dissolved in a mixed solution of dioxane / water (1 mL / 0.2 mL), sodium carbonate (25 mg, 0.24 mmol) and Pd(dppf)Cl2 (17.2 mg, 0.024 mmol) were added, and the mixture was stirred at 100 °C for 6 hours under nitrogen gas protection. After cooling, it was extracted with saturated ammonium chloride solution and EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column to obtain a colorless solid H110-1 (33 mg, yield: 72.7%). LCMS (ESI): m / z = 387 [M-H] + 。

[0237] Step 2: Synthesis of 4-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-3-fluorophenol

[0238] Compound H110-1 (33 mg, 0.085 mmol) was dissolved in MeOH (2 mL) / THF (1 mL), and PtO2 (10 mg, 0.0425 mmol) was added. The mixture was reacted under a hydrogen gas atmosphere at room temperature for 2 hours. After filtration, the mixture was concentrated under reduced pressure and purified by neutral preparative separation to obtain gray solid HANT-110 (11.8 mg, yield: 35.5%). LC-MS (ESI): m / z = 389 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ6.82(s,1H),6.67(t,J=8.5Hz,1H),6.59(dd,J=11.3,2.3Hz,1H),6.52(dd,J=8.4,2.3Hz,1H),4.94 (s,1H),4.26(dd,J=14.0,7.5Hz,3H),3.87(t,J=6.4Hz,2H),2.81(t,J=6.3Hz,2H),2.03-1.99(m,1H),1.92-1.75(m,3H).

[0239] Example 11

[0240] [ka]

[0241] The synthesis method was the same as in Example 1, but Pd-C was used instead of PtO2 in the hydrogenation reaction to obtain HANT-112 (6 mg, white solid, yield: 19.9%). LCMS(ESI): m / z = 395.0 [M + H] + . 1HNMR(400MHz,CDCl3)δ8.06(s,1H),7.60(d,J=7.6Hz,1H),7.25(s,1H),7.04(d,J=8.4Hz,1H),6.83(s,1H),4.26(t,J=6.4Hz ,2H),4.17(t,J=6.4Hz,1H),3.88(t,J=6.4Hz,2H),2.84(t,J=5.6Hz,2H),1.91-1.79(m,1H),1.79-1.77(m,2H),1.25(s,1H).

[0242] Example 12

[0243] [ka]

[0244] Step 1: Synthesis of 5-bromo-1-triphenyl-1H-benzo[d][1,2,3]triazole

[0245] Compound S1 (1.0 g, 5.05 mmol), Trt-Cl (2.1 g, 7.6 mmol), and TEA (1.53 g, 15.2 mmol) were added to ACN (20 mL) and stirred overnight at room temperature. The reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H113-1 (2.0 g, yield: 90%). LC-MS (ESI): m / z = 440.1 [M + H] + .

[0246] Step 2: Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-1-trimethyl-1H-benzo[d][1,2,3]triazole

[0247] Compound H113-1 (2.0 g, 4.6 mmol), (Bpin)2 (1.74 g, 6.8 mmol), Pd(dppf)Cl2 (333 mg, 0.46 mmol), and AcOK (1.34 g, 13.7 mmol) were added to dioxane (30 mL) and stirred at 80°C for 3 hours. After cooling, the reaction mixture was extracted by EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H113-2 (800 mg, yield: 36%). LCMS (ESI): m / z = 488.2 [M + H] + .

[0248] Step 3: Synthesis of 5-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalene-1-yl)-1-triphenyl-1H-benzo[d][1,2,3]triazole

[0249] Compounds H113-2 (100 mg, 0.24 mmol), INT-1 (176 mg, 0.36 mmol), Pd(dppf)Cl2 (35 mg, 0.05 mmol), and Na2CO3 (51 mg, 0.48 mmol) were added to dioxane / water (3 mL / 0.5 mL) and stirred at 80°C under nitrogen gas protection for 3 hours. After cooling, the reaction mixture was extracted by EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H113-3 (150 mg crude, yield: 98%). LCMS (ESI): m / z = 636.1 [M + H] + .

[0250] Step 4: Synthesis of 5-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalene-1-yl)-1H-benzo[d][1,2,3]triazole

[0251] Compound H113-3 (150 mg, 0.24 mmol) and TFA (2 mL) were dissolved in DCM (2 mL) and reacted at room temperature for 1 hour. The reaction mixture was purified by direct prep-HPLC to obtain a white solid H113-4 (35 mg, yield: 38%). LC-MS (ESI): m / z = 394.0 [M + H] + .

[0252] Step 5: Synthesis of 5-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-1H-benzo[d][1,2,3]triazole

[0253] Compound H113-4 (35 mg, 0.09 mmol) and PtO2 (15 mg) were dissolved in MeOH / THF (3 mL / 1 mL) and stirred at room temperature for 1 hour. The mixture was filtered, the organic phase was dried, concentrated, and the residue was purified by prep-HPLC to obtain solid HANT-113 (5.4 mg, yield: 17%). LC-MS (ESI): m / z = 396.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.82(d,J=8.7Hz,1H),7.50(s,1H),7.24(d,J=8.6Hz,1H),6.81(d,J=0.8Hz,1H),4.33(t,J=6.7Hz,1H) ,4.25(t,J=5.8Hz,2H),3.89(t,J=5.8Hz,2H),2.89(t,J=6.4Hz,2H),2.23-2.11(m,1H),1.98-1.89(m,2H),1.85-1.79(m,1H).

[0254] Example 13

[0255] [ka]

[0256] The synthesis method was the same as in Example 1, but Pd-C was used instead of PtO2 in the hydrogenation reaction to obtain a white solid HANT-114 (36.7 mg, yield: 28%). LCMS(ESI): m / z = 412.0 [M + H] + ; 1HNMR(400MHz,DMSO-d6)δ11.58(s,1H),7.05(d,J=1.6Hz,1H),7.02(d,J=8.0Hz,1H),6.85(dd,J=8.1,1.6Hz,1H),6.81(d,J=0.9Hz,1H),4.21(d d,J=5.8,4.5Hz,2H),4.15(t,J=6.5Hz,1H),3.99-3.92(m,2H),2.79(t, J=6.4Hz,2H),2.04-1.94(m,1H),1.86-1.75(m,2H),1.76-1.67(m,1H).

[0257] Example 14

[0258] [ka]

[0259] Step 1: Synthesis of tert-butyl 5,7-dichloro-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0260] Compound S1 (3g, 12 mmol) was added to chloroform (300 mL), and compound S2 (3.3g, 30 mmol) was slowly added in an ice bath. The mixture was reacted overnight at room temperature. The mixture was concentrated under reduced pressure to obtain the crude yellow solid H115-1 (2g, yield: 52.6%). LC-MS (ESI): m / z = 318.1 [M + H] + .

[0261] Step 2: Synthesis of tert-butyl 5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0262] Compound H115-1 (2.1 g, 6.6 mmol) and 1-bromo-2-chloroethane (2.37 g, 16.5 mmol) were dissolved in DMF (30 mL), and cesium carbonate (4.3 g, 13.2 mmol) was added. The mixture was reacted at 70°C for 16 hours. Extraction was performed with ammonium chloride and EA, and the mixture was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20:1) to obtain a white solid H115-2 (2 g, yield: 80%). LCMS (ESI): m / z = 380.1 [M + H] + .

[0263] Step 3: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydroisoquinoline

[0264] Compound H115-2 (2 g, 5.2 mmol) was dissolved in a necked flask containing DCM (20 mL), TFA (15 mL) was added, and the mixture was reacted overnight at room temperature. The pH was adjusted to approximately 9 with sodium bicarbonate under an ice bath, and the mixture was extracted with DCM. The organic phase was concentrated under reduced pressure to obtain a white solid H115-3 (1.45 g, yield: 98.6%). LC-MS (ESI): m / z = 280.0 [M + H] + .

[0265] Step 4: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydroisoquinoline

[0266] Compound H115-3 (1.17 g, 4.1 mmol) was added to DCM (35 mL), followed by manganese dioxide (4.36 g, 50 mmol). The mixture was stirred overnight at room temperature. The mixture was filtered and concentrated to obtain a yellow solid H115-4 (1.0 g, yield: 86.2%). LC-MS (ESI): m / z = 278.0 [M + H] + .

[0267] Step 5: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-2-methyl-3,4-dihydroisoquinoline-2-iodine

[0268] Compound H115-4 (250 mg, 0.9 mmol) was dissolved in acetone (12 mL), and iodomethane (1.3 g, 9 mmol) was added at 0°C. The reaction was allowed to proceed for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a yellow solid H115-5 (376 mg, yield: 100%). LC-MS (ESI): m / z = 292.0 [M] + .

[0269] Step 6: 5,7-Dichloro-6-(2-chloroethoxy)-1-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0270] In a three-necked flask, compound H115-5 (150 mg, 0.51 mmol) was dissolved in THF (18 mL), cooled to -70°C under N2, and S3 (3.2 mL, 3.08 mmol, 1 mol / LINTHF) was added. The mixture was reacted for 6 hours. Extraction was performed with glacial ammonium chloride solution and EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to obtain a yellow oily compound H115-6 (60 mg, yield: 29.2%). LCMS (ESI): m / z = 400.0 [M + H] + .

[0271] Step 7: 4-(5,7-dichloro-6-(2-chloroethoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)phenol

[0272] In a three-necked flask, compound H115-6 (45 mg, 0.11 mmol) was dissolved in DCM (5 mL), and boron tribromide (0.34 mL, 0.34 mmol) was added under N2 protection at 0°C. The reaction was allowed to proceed for 16 hours. The reaction mixture was extracted with glacial ammonium chloride solution and DCM, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain a white solid HANT-115 (4.4 mg, yield: 10.1%). LC-MS (ESI): m / z = 386.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.03(d,J=8.6Hz,2H),6.78(d,J=8.6Hz,2H),6.61(s,1H),4.23(d,J=5.4Hz) ,3H),3.87(t,J=5.8Hz,2H),3.20-3.11(m,1H),3.04-2.89(m,2H),2.71-2.53(m,1H),2.21(s,3H).

[0273] Example 15

[0274] [ka]

[0275] The synthesis method was the same as in Example 1, yielding compound HANT-117 (15.1 mg, white solid, yield: 37.5%). LCMS(ESI): m / z = 425.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.00(d,J=8.0Hz,1H),6.86(d,J=1.4Hz,1H),6.81-6.75(m,2H),4.23(t,J=5.8Hz,2H),4.1 6-4.09(m,1H),3.88(t,J=5.8Hz,2H),3.34(s,3H),2.87(dd,J=16.1,6.2Hz,2H),2.11(s,1H),2.03-1.76(m,3H).

[0276] Example 16

[0277] [ka]

[0278] INT-3 (100 mg, 0.28 mmol), S2 (56 mg, 0.56 mmol), and potassium carbonate (77 mg, 0.56 mmol) were dissolved in DMF (3 mL) and reacted at room temperature for 3 hours. The reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain a white solid HANT-123 (78.7 mg, yield: 74%). LC-MS (ESI): m / z = 378.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.69(s,1H),4.52(d,J=4.2Hz,1H),4.24-4.16(m,2H),3.95 (dd,J=6.1,4.4Hz,2H),3.78-3.67(m,1H),3.48-3.38(m,1H),2.79-2.65(m,2H),2.60 -2.51(m,1H),2.48-2.39(m,2H),2.11(t,J=10.5Hz,1H),2.04-1.96(m,1H),1.92-1.8 5(m,1H),1.79-1.67(m,2H),1.65-1.53(m,1H),1.54-1.41(m,2H),1.39-1.22(m,1H).

[0279] Example 17 [ka]

[0280] Step 1: Synthesis of 2-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-6-methoxy-1,2,3,4tetrahydroisoquinoline

[0281] Compounds INT-3 (200 mg, 0.56 mmol) and S2 (279.3 mg, 1.4 mmol) were dissolved in DMF (12 mL), and potassium carbonate (154.2 mg, 1.12 mmol) was added. The mixture was reacted overnight at room temperature. Extraction was performed with saturated ammonium chloride solution and EA. The organic phase was backwashed with saturated ammonium chloride solution and saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a colorless oily compound H124-1 (90 mg, yield: 36.6%). LCMS (ESI): m / z = 440 [M + H] + .

[0282] Step 2: Synthesis of 2-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-1,2,3,4-tetrahydroisoquinoline-6-ol

[0283] Compound H124-1 (90 mg, 0.20 mmol) was dissolved in DCM (8 mL), BBr3 (2.0 mL, 2.0 mmol) was added at 0°C, the bottle was sealed, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was extracted with saturated saline and DCM, the organic phase was backwashed with saturated saline, dried over sodium sulfate, concentrated under reduced pressure, and purified by neutral reverse phase fractionation to obtain a yellow solid HANT-124 (41.0 mg, yield: 51.7%). LC-MS (ESI): m / z = 426 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ7.79(s,1H),6.89(d,J=8.2Hz,1H),6.65-6.60(m,2H),4.63(s,1H),4.25(t,J=6.3Hz,2H),3.87(t,J=6.4Hz,3H) ,3.81(d,J=14.2Hz,1H),3.67(d,J=13.7Hz,1H),2.92-2.73(m,4H),2.65-2.55(m,2H),2.16-2.02(m,2H),1.64(dd,J=15.2,6.0Hz,2H).

[0284] Example 18

[0285] [ka]

[0286] Compounds INT-3 (150 mg, 0.42 mmol), S2 (164 mg, 0.84 mmol), and cesium carbonate (273 mg, 0.84 mmol) were dissolved in acetonitrile (5 mL) and reacted at room temperature for 3 hours. The reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain a white solid HANT-125 (99.5 mg, yield: 59.6%). LC-MS (ESI): m / z = 400.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.34(s,1H),7.69(s,1H),7.30(s,1H),4.22(dd,J=6.0,4.4Hz,2H),3.96(dd,J =5.9,4.5Hz,3H),3.60-3.49(m,2H),2.84-2.53(m,6H),2.10-1.91(m,2H),1.64(dt,J=21.9,11.7Hz,2H).

[0287] Example 19

[0288] [ka]

[0289] Step 1: Synthesis of 3a,4,5,6,7,7a-Hexahydro-1H-pyrazolo[3,4-c]pyridine

[0290] Compound S1 (230 mg, 1.03 mmol) and TFA (1 mL) were dissolved in DCM (3 mL) and reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a yellow oily compound H126-1 (110 mg, yield: 91%). LC-MS (ESI): m / z = 126.1 [M + H] + .

[0291] Step 2: Synthesis of 6-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine

[0292] Compound H126-1 (110 mg, 1.06 mmol), INT-3 (370 mg, 1.06 mmol), and cesium carbonate (690 mg, 2.12 mmol) were dissolved in acetonitrile (5 mL) and reacted at room temperature for 3 hours. The reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain a white solid HANT-126 (73.6 mg, yield: 18%). LC-MS (ESI): m / z = 402.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.33(s,1H),7.69(s,1H),7.41(s,1H),4.22(t,J=5.2Hz,2H),3.96(dd,J=6.0,4. 5Hz,3H),3.61(s,2H),2.79(d,J=17.4Hz,1H),2.70-2.52(m,5H),2.01(d,J=13.2Hz,2H),1.70-1.52(m,2H).

[0293] Example 20

[0294] [ka]

[0295] Step 1: Synthesis of tert-butyl 5-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydroquinoline-1(2H)-yl)-1H-indazole-1-carboxylate

[0296] Compounds INT-4 (150 mg, 0.54 mmol), S2 (191 mg, 0.65 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), Xphos (51.3 mg, 0.1 mmol), and Cs2CO3 (350 mg, 1.1 mmol) were added to 5 mL of water and stirred overnight at 110 °C. After cooling, the reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain solid H127-1 (130 mg, yield: 49%). LC-MS (ESI): m / z = 496.1 [M + H] + .

[0297] Step 2: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1H-indazole-5-yl)-1,2,3,4-tetrahydroquinoline

[0298] Compound H127-1 (130 mg, 0.26 mmol) and TFA (1 mL) were dissolved in DCM (3 mL) and reacted at room temperature for 2 hours. The reaction mixture was adjusted to pH=8 with aqueous sodium bicarbonate solution, extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain a white solid HANT-127 (17.1 mg, yield: 58%). LC-MS (ESI): m / z = 396.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.04(d,J=0.9Hz,1H),7.65-7.56(m,2H),7.25(dd,J=8.9,1.9Hz,1H),6.24(s,1H), 4.13(t,J=5.8Hz,2H),3.83(t,J=5.8Hz,2H),3.61-3.55(m,2H),2.89(t,J=6.6Hz,2H),2.14-2.05(m,2H).

[0299] Example 21

[0300] [ka]

[0301] The synthesis method was the same as in Example 10, yielding compound HANT-131 (4.2 mg, white solid, yield: 16.7%). LCMS(ESI): m / z=409[M+H] + ; 1 HNMR(400MHz,CD3OD)δ7.92(d,J=1.0Hz,1H),7.49(dt,J=8.8,1.0Hz,1H),7.40(dt,J=1.6,0.8Hz,1H),7.17(dd,J=8.8,1.6Hz,1H),6.78(d ,J=1.0Hz,1H),4.22(dt,J=11.4,6.4Hz,3H),4.05(s,3H),3.88(t,J=5.8Hz,2H),2.96-2.78(m,2H),2.23-2.11(m,1H),2.05-1.80(m,3H).

[0302] Example 22

[0303] [ka]

[0304] Step 1: Synthesis of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-1H-indazole-3carboxamide

[0305] Compounds S1 (540 mg, 2.13 mmol), (Bpin)2 (705 mg, 2.77 mmol), potassium acetate (418 mg, 4.26 mmol), and Pd(dppf)Cl2 (625 mg, 0.852 mmol) were sequentially added to a dry flask, dissolved in dioxane (30 mL), and reacted overnight at 110°C under nitrogen gas protection. After the reaction was complete, the mixture was cooled, extracted with saturated ammonium chloride solution and EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, a black solid H132-1 (730 mg, purity: 62%). LCMS(ESI): m / z=302[M+H] + .

[0306] Step 2: Synthesis of 5-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalene-1-yl)-N-methyl-1H-indazole-3carboxamide

[0307] Crude products H132-1 (330 mg, 1.1 mmol) and INT-1 (289 mg, 1.1 mmol) were dissolved in a mixed solution of dioxane / water (30 mL / 6 mL). Sodium carbonate (144.4 mg, 2.2 mmol) and Pd(dppf)Cl2 (99.7 mg, 0.22 mmol) were added, and the mixture was stirred at 100°C for 4 hours under nitrogen gas protection. After the reaction was complete, the mixture was cooled, extracted with saturated ammonium chloride solution and EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column to obtain a yellow solid H132-2 (100 mg, yield: 32.6%). LCMS(ESI): m / z=450[M+H] + .

[0308] Step 3: Synthesis of 5-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-N-methyl-1H-indazole-3carboxamide

[0309] H132-2 (112 mg, 0.25 mmol) was dissolved in MeOH (10 mL) / THF (5 mL), and PtO2 (28.2 mg, 0.125 mmol) was added. The mixture was stirred under a hydrogen gas atmosphere at room temperature for 4 hours. After filtration, the mixture was concentrated under reduced pressure and purified by neutral reverse-phase preparative fractionation to obtain a white solid HANT-132 (59.3 mg, yield: 57.8%). LC-MS (ESI): m / z = 452 [M + H] + ; 1HNMR(400MHz,CD3OD)δ7.91(s,1H),7.52(d,J=8.7Hz,1H),7.17(d,J=8.7Hz,1H),6.81(s,1H),4.24(t,J=5.7Hz,3H),3.89(t,J =5.7Hz,2H),2.94(s,3H),2.88(d,J=3.5Hz,2H),2.13(dd,J=13.8,7.0Hz,1H),1.93(dd,J=22.2,9.6Hz,2H),1.86-1.75(m,1H).

[0310] Example 23

[0311] [ka]

[0312] Step 1: Synthesis of tert-butyl3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-1H-indazole-1-carboxylate

[0313] Compounds S1 (300 mg, 0.96 mmol), (Bpin)2 (366.3 mg, 1.44 mmol), potassium acetate (228.4 mg, 2.4 mmol), and Pd(dppf)Cl2 (70.4 mg, 0.096 mmol) were sequentially dissolved in dioxane (30 mL) in a dry flask and reacted overnight at 95°C under nitrogen gas protection. After cooling, the mixture was extracted with saturated ammonium chloride solution and EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a yellow solid H133-1 (317 mg, yield: 91.9%). LCMS(ESI): m / z=360[M+H] + .

[0314] Step 2: Synthesis of tert-butyl3-amino-5-(5,7-dichloro-6-(2-chloroethoxy)-3,4-dihydronaphthalene-1-yl)-1H-indazole-1-carboxylate

[0315] Compound H133-1 (317 mg, 0.88 mmol) and compound INT-1 (375.3 mg, 0.88 mmol) were dissolved in a mixed solution of dioxane / water (30 mL / 6 mL). Sodium carbonate (187.2 mg, 1.76 mmol) and Pd(dppf)Cl2 (129.3 mg, 0.176 mmol) were added, and the mixture was stirred at 100°C for 4 hours under nitrogen gas protection. After cooling, the mixture was extracted with saturated ammonium chloride solution and EA. The organic phase was washed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a brown oily compound H133-2 (200 mg, yield: 44.6%). LCMS(ESI): m / z=452[M-56] + .

[0316] Step 3: Synthesis of tert-butyl3-amino-5-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-1H-indazole-1-carboxylate

[0317] Compound H133-2 (200 mg, 0.39 mmol) was dissolved in MeOH (10 mL) / THF (5 mL), and PtO2 (44.8 mg, 0.195 mmol) was added. The reaction was carried out under a hydrogen gas atmosphere at room temperature for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, a yellow oily compound H133-3 (160 mg, yield: 63.7%). LC-MS (ESI): m / z = 454 [M-56] + .

[0318] Step 4: Synthesis of 5-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)-1H-indazole-3-amine

[0319] The crude compound H133-3 (160 mg, 0.31 mmol) was dissolved in DCM (12 mL), and TFA (3 mL) was added at 0°C. The mixture was reacted at room temperature for 1 hour. After filtration and concentration under reduced pressure, the mixture was purified by neutral reverse-phase fractionation to obtain a white solid HANT-133 (32.0 mg, yield: 32.6%). LC-MS (ESI): m / z = 410 [M + H]+ ; 1 HNMR(400MHz,CD3OD)δ7.34(s,1H),7.25(d,J=8.6Hz,1H),7.09(dd,J=8.7,1.6Hz,1H),6.83(s,1H),4.23(t,J=5.8Hz ,2H),4.17(t,J=6.7Hz,1H),3.88(t,J=5.8Hz,2H),2.87(dd,J=9.6,4.0Hz,2H),2.15-2.07(m,1H),1.99-1.77(m,3H).

[0320] Example 24

[0321] [ka]

[0322] The synthesis method was the same as in Example 1, yielding HANT-134 (22.5 mg, yield: 13%). LCMS(ESI): m / z = 395.2 [M + H] + . 1 HNMR(400MHz,CD3OD)δ7.99(s,1H),7.71-7.69(m,1H),7.17(s,1H),6.93-6.90(m,1H),6.83(s,1H),4.26-4. 23(m,3H),3.89(t,J=5.6Hz,2H),2.89-2.86(m,2H),2.16-2.11(m,1H),1.99-1.83(m,2H),1.82-1.79(m,1H).

[0323] Example 25

[0324] [ka]

[0325] The synthesis method was the same as in Example 1, yielding HANT-135 (16.5 mg, yield: 11%). LCMS(ESI): m / z = 410.2 [M + H] + . 1HNMR(400MHz,CD3OD)δ6.96(s,1H),6.93(d,J=8.0Hz,1H),6.84-6.81(m,2H),4.23(t,J=5.6Hz,2H),4.06-4.03(m,1 H),3.88(t,J=6.0Hz,2H),3.49(s,2H),2.86-2.82(m,2H),2.09-2.04(m,1H),1.96-1.85(m,1H),1.84-1.75(m,2H).

[0326] Example 26

[0327] [ka]

[0328] The synthesis method was the same as in Example 1, yielding a white solid HANT-137 (123.5 mg, yield: 41%). LCMS (ESI): m / z = 401.0 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.33(s,1H),6.76(s,1H),6.49-6.37(m,2H),6.26(dd,J=8.2,2.3Hz,1H),4.29(t, J=6.1Hz,1H),4.24-4.16(m,2H),3.95(t,J=5.2Hz,2H),3.74(s,3H),2.79-2.68(m,2H),1.85-1.64(m,4H).

[0329] Example 27

[0330] [ka]

[0331] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1H-indazole-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0332] Compounds INT-2 (200 mg, 0.48 mmol), S2 (117 mg, 0.72 mmol), Pd(dppf)Cl2 (71 mg, 0.1 mmol), and Na2CO3 (102 mg, 1.0 mmol) were added to dioxane / water (5 mL / 1 mL) and stirred at 80°C under nitrogen gas protection for 3 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H144-1 (220 mg, yield: 80%). LCMS (ESI): m / z = 384.1 [M + H] + .

[0333] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1H-indazole-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0334] Compound H144-1 (100 mg, 0.26 mmol), Pd / C (100 mg), and AcOH (0.2 mL) were dissolved in MeOH (5 mL) and reacted under a hydrogen gas atmosphere at room temperature for 6 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain the crude product, a white solid HANT-144. LCMS (ESI): m / z = 386.1 [M + H] + . It was separated and purified by SFC method (mobile phase: Hex-EtOH-70-30-20MIN) to obtain optically active compounds HANT-144A (17.1 mg, retention time 6.528) and HANT-144B (15.7 mg, retention time 9.085).

[0335] HANT-144A: 1 H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.99(s,1H),7.49(d,J=8.6Hz,1H),7.38(d,J=1.6Hz,1H),7.18-7.06(m,2H),4 .44-4.37(m,2H),4.29(t,J=6.2Hz,1H),4.02-3.93(m,2H),2.95-2.85(m,2H),2.11-1.97(m,1H),1.94-1.73(m,3H).

[0336] HANT-144B: 1 H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.99(s,1H),7.49(d,J=8.6Hz,1H),7.38(s,1H),7.19-7.06(m,2H),4.45- 4.36(m,2H),4.28(t,J=6.4Hz,1H),4.02-3.91(m,2H),2.95-2.86(m,2H),2.10-1.99(m,1H),1.93-1.70(m,3H).

[0337] Example 28

[0338] [ka]

[0339] Step 1: Synthesis of N-(3-methoxyphenethyl)-3-methyl-4-nitrobenzamide

[0340] Compounds S1 (5.2g, 28.7 mmol), S2 (4.34g, 28.7 mmol), DMF (57 mL), EDCI (8.2g, 43.1 mmol), HOBT (5.81g, 43.1 mmol), and TEA (8.7g, 86.1 mmol) were sequentially added to a dry flask, and the mixture was stirred at room temperature under nitrogen gas protection for 4 hours. The solution was diluted with 400 mL of water, extracted with EA (100 mL x 3), the organic phase was dried over anhydrous sodium carbonate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (DCM:EA = 1:1) to obtain a yellow solid H146-1 (7.35 g, yield: 82%). LCMS (ESI): m / z = 315.1 [M + H] + .

[0341] Step 2: Synthesis of 6-methoxy-1-(3-methyl-4-nitrophenyl)-3,4-dihydroisoquinoline

[0342] In a dry flask, H146-1 (7.35 g, 2.34 mmol), acetonitrile (100 mL), phosphorus oxychloride (7.16 g, 46.8 mmol), and TEA (8.7 g, 86.1 mmol) were sequentially added and stirred overnight at 85°C under nitrogen gas protection. After cooling, the mixture was concentrated under reduced pressure, quenched with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography (DCM:EA=1:1) to obtain a yellow solid H146-2 (4.4 g, yield: 63%). LCMS(ESI): m / z=297.1[M+H] + .

[0343] Step 3: Synthesis of 6-methoxy-1-(3-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline

[0344] Compound H146-2 (4.4 g, 14.8 mmol), methanol (60 mL), and sodium borohydride (1.69 g, 44.6 mmol) were sequentially added to a dry flask. The mixture was stirred at room temperature for 1 hour under nitrogen gas protection. Water was added to quench the mixture, and it was concentrated under reduced pressure. Extraction was performed using EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed to obtain a yellow solid H146-3 (4.4 g, yield: 99%). LC-MS (ESI): m / z = 299.1 [M + H] + .

[0345] Step 4: Synthesis of 6-methoxy-2-methyl-1-(3-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline

[0346] Compound H146-3 (4.4 g, 14.8 mmol), methanol (100 mL), aqueous formaldehyde solution (4.75 g, 147.7 mmol), and acetic acid (1 drop) were sequentially added to a dry flask. After stirring for 30 minutes, sodium borohydride cyanohydride (1.86 g, 29.5 mmol) was added. The mixture was stirred overnight at room temperature under nitrogen gas protection. Water was added to quench the mixture, and it was concentrated under reduced pressure. Extraction was performed using EA, the organic phase was dried over sodium sulfate, filtered, and concentrated to obtain a yellow solid H146-4 (4.4 g, yield: 95%). LCMS(ESI): m / z = 313.1 [M + H] + .

[0347] Step 5: Synthesis of 2-methyl-1-(3-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-6-ol

[0348] Compound H146-4 (4.4 g, 14.1 mmol) and DCM (20 mL) were sequentially added to a dry flask, and boron tribromide (40 mL, 17% in DCM) was added at 0°C. The mixture was stirred at room temperature for 4 hours under nitrogen gas protection. Methanol was added to quench the mixture, and it was concentrated under reduced pressure. The pH was adjusted to basic with sodium bicarbonate solution, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown solid H146-5 (4.0 g, yield: 95%). LCMS(ESI): m / z = 299.1 [M + H] + .

[0349] Step 6: Synthesis of 5,7-dichloro-2-methyl-1-(3-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-6-ol

[0350] Compound H146-5 (4.0 g, 13.4 mmol) and chloroform (60 mL) were sequentially added to a dry flask, followed by the addition of S3 (2.9 g, 26.84 mmol) at 0°C. The mixture was stirred overnight at room temperature under nitrogen gas protection. The solution was diluted with water, extracted by DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash column chromatography (DCM:EA=30:1) to obtain a yellow solid H146-6 (520 mg, yield: 10%). LCMS(ESI): m / z=367.1[M+H] + .

[0351] Step 7: Synthesis of 5,7-dichloro-2-methyl-1-(3-methyl-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-6-ol

[0352] Compound H146-6 (520 mg, 1.41 mmol), DMF (15 mL), 1-bromo-2-chloroethane (304 mg, 2.12 mmol), and cesium carbonate (914 mg, 2.84 mmol) were sequentially added to a dry flask and stirred overnight at 30°C under nitrogen gas protection. The mixture was diluted with water, extracted with EA, the organic phase was dried over sodium sulfate, filtered, and concentrated to obtain a brown oily substance H146-7 (600 mg, yield: 98%). LC-MS (ESI): m / z = 429.0 [M + H] + .

[0353] Step 8: Synthesis of 4-(5,7-dichloro-6-(2-chloroethoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-2-methylaniline

[0354] Compound H146-7 (600 mg, 1.4 mmol), methanol / water (40 mL, 1 / 1), iron powder (468 mg, 8.4 mmol), and ammonium chloride (450 mg, 8.4 mmol) were sequentially added to a dry flask, and the mixture was stirred at 30°C for 2 hours. The mixture was filtered, concentrated under reduced pressure, extracted with EA, the organic phase was dried over sodium sulfate, filtered, and concentrated to obtain a yellow solid H146-8 (520 mg, yield: 93%). LCMS (ESI): m / z = 399.1 [M + H]+ .

[0355] Step 9: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1H-indazole-5-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline

[0356] Compound H146-8 (350 mg, 0.88 mmol) and tetrafluoroboric acid (6 mL, 50% in H2O) were sequentially added to a dry flask. Sodium nitrite (75 mg, 1.1 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. Then, chloroform (6 mL), water (6 mL), potassium acetate (515 mg, 5.3 mmol), and 18-crown-6-ether (116 mg, 0.44 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Extraction was performed using DCM, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by flash column chromatography to obtain a white solid crude product, HANT-146 (yield: 29%). LCMS (ESI): m / z = 410.1 [M + H] + The compound was purified using SFC (Hex:EtOH=70:30-15min) to obtain the optically active compound HANT-146A (53.6mg, retention time 5.214min) and the yellow solid HANT-146B (50.8mg, retention time 6.642min).

[0357] HANT-146A: 1 HNMR(400MHz,CD3OD)δ8.06(s,1H),7.72(s,1H),7.52(d,J=8.8Hz,1H),7.19(dd,J=8.8,1.6Hz,1H),6.59(s,1H),4.40(s ,1H),4.22(t,J=5.8Hz,2H),3.86(t,J=5.8Hz,2H),3.25-3.19(m,1H),3.13-2.94(m,2H),2.71-2.63(m,1H),2.23(s,3H).

[0358] HANT-146B: 1HNMR(400MHz,CD3OD)δ8.06(d,J=1.1Hz,1H),7.72(s,1H),7.52(d,J=8.8Hz,1H),7.19(dd,J=8.8,1.6Hz,1H),6.58(s,1H),4. 39(s,1H),4.22(t,J=5.8Hz,2H),3.86(t,J=5.8Hz,2H),3.25-3.19(m,1H),3.13-2.93(m,2H),2.70-2.62(m,1H),2.22(s,3H).

[0359] Example 29

[0360] [ka]

[0361] Step 1: Synthesis of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine

[0362] S1 (500 mg, 2.52 mmol), DHP (427 mg, 5.05 mmol), and PTSA (242 mg, 1.26 mmol) were dissolved in DCM (15 mL) and reacted overnight at room temperature under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound H148-1 (520 mg, colorless oil, yield: 73.0%). LCMS (ESI): m / z = 282.0 [M + H] + .

[0363] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0364] Compound H148-1 (200 mg, 0.71 mmol), S2 (360 mg, 1.42 mmol), Pd(dppf)Cl2 (104 mg, 0.14 mmol), and potassium acetate (208 mg, 2.13 mmol) were dissolved in dioxane (10 mL) and reacted at 100°C for 4 hours under nitrogen gas protection. After cooling, INT-2 (148 mg, 0.35 mmol), sodium carbonate (150 mg, 1.42 mmol), and water (1 mL) were added to the reaction mixture. The reaction was reacted at 100°C for 1 hour under nitrogen gas protection. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound H148-2 (90 mg, colorless oily substance, yield: 27.1%). LCMS(ESI): m / z = 469.1 [M + H] + .

[0365] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole[4,3-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0366] Compound H148-2 (80 mg) and tris(triphenylphosphine)rhodium chloride (40 mg, 50% wt) were dissolved in methanol (5 mL), and the system was reacted under a hydrogen gas atmosphere at room temperature for 2 hours. The reaction product was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound H148-3 (24 mg, colorless oil, yield: 29.9%). LCMS(ESI): m / z = 471.1 [M + H] + .

[0367] Step 4: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1H-pyrazolo[4,3-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0368] Compound H148-3 (24 mg) was dissolved in DCM (2 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise to the reaction mixture. The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound HANT-148 (2.5 mg, white solid, yield: 12.7%). LCMS (ESI): m / z = 387.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.14(s,1H),8.00(d,J=8.8Hz,1H),7.26(d,J=8.8Hz,1H),7.04(s,1H),4.52-4.45(m,1H),4.4 1(t,J=5.8Hz,2H),3.91(t,J=5.6Hz,2H),3.07-2.91(m,2H),2.24-2.15(m,1H),2.11-1.96(m,2H),1.91-1.83(m,1H).

[0369] Example 30

[0370] [ka]

[0371] The synthesis method was the same as in Example 29, yielding compound HANT-149 (white solid, yield: 39.3%). LCMS(ESI): m / z = 387.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.93(s,1H),8.12(s,1H),7.51(s,1H),7.04(s,1H),4.48-4.34(m,3H),3. 91(t,J=5.6Hz,2H),3.06-2.91(m,2H),2.23-2.07(m,2H),2.03-1.92(m,1H),1.88-1.78(m,1H).

[0372] Example 31

[0373] [ka]

[0374] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0375] Compounds INT-2 (500 mg, 1.2 mmol), S2 (595 mg, 1.8 mmol), Pd(dppf)Cl2 (176 mg, 0.24 mmol), and Na2CO3 (255 mg, 2.4 mmol) were added to dioxane / water (10 mL / 2 mL) and stirred at 80°C under nitrogen gas protection for 4 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H150-1 (520 mg, yield: 92%). LCMS (ESI): m / z = 469.1 [M + H] + .

[0376] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0377] Compound H150-1 (520 mg, 1.1 mmol) and Pd / C (300 mg) were dissolved in MeOH (10 mL) and reacted under a hydrogen gas atmosphere at room temperature for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain compound H150-2 (500 mg, white solid, yield: 96%). LC-MS (ESI): m / z = 471.1 [M + H] + .

[0378] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0379] Compound H150-2 (200 mg, 0.5 mmol) and TFA (5 mL) were added to DCM (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH=8 with aqueous sodium bicarbonate solution, extracted with EA, the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain the crude product HANT-150. LCMS (ESI): m / z = 387.1 [M + H] + Furthermore, the compounds were separated and purified using the SFC method (Hex-EtOH-70-30-30MIN) to obtain the optically active compounds HANT-150A (37.4 mg, RT=8.159 min) and HANT-150B (39 mg, RT=10.662 min).

[0380] HANT-150A: 1 HNMR(400MHz,DMSO-d6)δ13.60(s,1H),8.38(d,J=2.2Hz,1H),8.06(s,1H),7.80(d,J=2.2Hz,1H),7.24(s ,1H),4.41(t,J=5.2Hz,3H),4.07-3.89(m,2H),3.03-2.80(m,2H),2.18-2.03(m,1H),1.98-1.74(m,3H).

[0381] HANT-150B: 1 HNMR(400MHz,DMSO-d6)δ13.60(s,1H),8.38(d,J=2.2Hz,1H),8.06(s,1H),7.80(d,J=2.2Hz,1H),7.24 (s,1H),4.49-4.34(m,3H),4.04-3.92(m,2H),3.01-2.78(m,2H),2.11-2.03(m,1H),1.97-1.74(m,3H).

[0382] Example 32

[0383] [ka]

[0384] Step 1: Synthesis of 5-bromo-1-tosyl-1H-pyrazolo[3,4-c]pyridine

[0385] Compound S1 (500 mg, 2.5 mmol), TsCl (675 mg, 3.5 mmol), and NaH (131 mg, 3.3 mmol) were added to a round-bottom flask containing DMF (20 mL) and reacted under ice bath for 1 hour. The reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a pink solid H164-1 (650 mg, yield: 68%). LCMS (ESI): m / z = 351.1 [M + H] + .

[0386] Step 2: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1-tosyl-1H-pyrazolo[3,4-c]pyridine-5-yl)-1,2,3,4-tetrahydroquinoline

[0387] H164-1 (230 mg, 0.66 mmol), INT-4 (92 mg, 0.33 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), Xantphos (115 mg, 0.2 mmol), and Cs2CO3 (215 mg, 0.65 mmol) were dissolved in toluene (5 mL) and reacted under a nitrogen gas atmosphere at 110 °C for 12 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a yellow oily compound H164-2 (180 mg, yield: 98%). LCMS (ESI): m / z = 551.1 [M + H] + .

[0388] Step 3: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1H-pyrazolo[3,4-c]pyridine-5-yl)-1,2,3,4-tetrahydroquinoline

[0389] H164-2 (170 mg, 0.31 mmol) and K2CO3 (214 mg, 1.55 mmol) were dissolved in MeOH (30 mL) and reacted at 110°C for 3 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white solid HANT-164 (12 mg, yield: 12%). LCMS (ESI): m / z = 397.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.88(s,1H),8.14(s,1H),7.56(s,1H),6.53(s,1H),4.16-3 .87(m,2H),3.85-3.71(m,2H),3.70-3.30(m,2H),2.89-2.87(m,2H),2.07(m,2H).

[0390] Example 33

[0391] [ka]

[0392] Step 1: Synthesis of 5-bromo-1-tosyl-1H-pyrazolo[4,3-b]pyridine

[0393] Compound S1 (500 mg, 2.53 mmol) and DMF (25 mL) were sequentially added to a dry flask. Sodium hydride (131 mg, 3.28 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. Then TosCl (674 mg, 3.54 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water was added to quench the mixture, and it was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain a white solid H165-1 (600 mg, yield: 67%). LCMS(ESI): m / z = 352.0 [M + H] + .

[0394] Step 2: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1-tosyl-1H-pyrazolo[4,3-b]pyridine-5-yl)-1,2,3,4-tetrahydroquinoline

[0395] Compound H165-1 (253 mg, 0.72 mmol), dioxane (10 mL), INT-4 (100 mg, 0.36 mmol), cesium carbonate (234 mg, 0.72 mmol), Xant-phos (83 mg, 0.14 mmol), and Pd2(dba)3 (66 mg, 0.072 mmol) were sequentially added to a dry flask and stirred overnight at 110°C under nitrogen gas protection. After cooling, the mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain a yellow solid H165-2 (78 mg, yield: 39%). LCMS(ESI): m / z = 551.0 [M + H] + .

[0396] Step 3: Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1H-pyrazolo[4,3-b]pyridine-5-yl)-1,2,3,4-tetrahydroquinoline

[0397] H165-2 (60 mg, 0.11 mmol), methanol (3 mL), and saturated potassium carbonate aqueous solution (1 mL) were sequentially added to a dry flask. The mixture was stirred at 70°C under a nitrogen atmosphere for 2 hours. After cooling, the mixture was concentrated under reduced pressure, diluted with water, extracted with EA, the organic phase was dried over sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC to obtain a white solid HANT-165 (10.7 mg, yield: 24.5%). LC-MS (ESI): m / z = 397.0 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ13.19(s,1H),8.08(s,1H),7.96(d,J=9.0Hz,1H),7.25(d,J=9.0Hz,1H),7.08(s,1H) ),4.18(t,J=5.2Hz,2H),3.95(t,J=5.2Hz,2H),3.84-3.77(m,2H),2.80(t,J=6.8Hz,2H),1.99-1.89(m,2H).

[0398] Example 34

[0399] [ka]

[0400] Step 1: Synthesis of 5-bromo-1-tosyl-1H-pyrazolo[3,4-b]pyridine

[0401] Compound S3 (4.0 g, 20.2 mmol) was dissolved in DMF (50 mL), NaH (1.0 g, 26.3 mmol) was added under nitrogen gas protection, and the mixture was stirred in an ice bath for 30 minutes. TosCl (5.4 g, 28.3 mmol) was then added, and the mixture was stirred at room temperature for 12 hours. Extraction was performed with EA, washed with saturated ammonium chloride aqueous solution, the organic phase was dried over anhydrous sodium carbonate, filtered, concentrated, homogenized with PE, and purified to obtain a red solid H166-1 (4.4 g, yield: 62%). LCMS (ESI): m / z = 352.1 [M + H] + .

[0402] Step 2. Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1-tosyl-1H-pyrazolo[3,4-b]pyridine-5-yl)-1,2,3,4-tetrahydroquinoline

[0403] Compounds H166-1 (100 mg, 0.36 mmol), INT-4 (190 mg, 0.54 mmol), Pd(OAC)2 (16 mg, 0.072 mmol), X-Phos (68 mg, 0.15 mmol), and cesium carbonate (350 mg, 1.44 mmol) were sequentially added to a dry flask, dissolved in 15 mL of water, and reacted at 110°C for 12 hours. After cooling, filtration, and concentration, the mixture was purified by silica gel column chromatography (PE:EA = 2:1) to obtain H166-2 (40 mg, yield: 21%). LC-MS (ESI): m / z = 551.2 [M + H] + .

[0404] Step 3. Synthesis of 5,7-dichloro-6-(2-chloroethoxy)-1-(1H-pyrazolo[3,4-b]pyridine-5-yl)-1,2,3,4-tetrahydroquinoline

[0405] H166-2 (40 mg, 0.07 mmol), potassium carbonate (50 mg, 0.35 mmol), and methanol / water (5 mL / 2 mL) were sequentially added to a dry flask, and the mixture was reacted at 50°C for 12 hours. After cooling, filtration, and concentration, the mixture was purified by Prep-HPLC to obtain HANT-166 (4.5 mg, yield: 15%). LC-MS (ESI): m / z = 397.2 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ8.47(d,J=2.0Hz,1H),8.09(s,1H),7.93(d,J=2.4Hz,1H),6.30(s,1H),4.18(t ,J=6.4Hz,2H),3.85(t,J=6.0Hz,2H),3.59(t,J=6.4Hz,2H),2.91(t,J=6.8Hz,2H),2.14-2.11(m,2H).

[0406] Example 35

[0407] [ka]

[0408] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0409] Compound H150-2 (100 mg, 0.21 mmol), AcOH (4 mL), and HCl (2 mL) were stirred at 100°C for 36 hours. After cooling, the pH was adjusted to 8 with aqueous sodium bicarbonate solution, and the mixture was extracted using EA. The organic phase was dried, concentrated, and the residue was purified by silica gel column chromatography to obtain the oily compound H183-1 (60 mg, yield: 70%). LC-MS (ESI): m / z = 406.1 [M + H] + .

[0410] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-N-methyl-8-(1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2carboxamide

[0411] H183-1 (60 mg, 0.15 mmol), S2 (0.1 mL), HATU (113 mg, 0.3 mmol), and DIEA (38 mg, 0.3 mmol) were dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. Extraction with EA was performed, the organic phase was dried and concentrated, and the residue was purified by prep-HPLC to obtain compound HANT-183 (10.4 mg, white solid, yield: 17%). LC-MS (ESI): m / z = 419.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.39(d,J=2.2Hz,1H),8.05(s,1H),7.89(d,J=2.2Hz,1H),7.23(d,J=1.0Hz,1H),4.43(t,J=6.6H) z,1H),4.33-4.24(m,2H),3.98-3.89(m,2H),3.00(t,J=6.4Hz,2H),2.87(s,3H),2.27-2.18(m,1H),2.04-1.84(m,3H).

[0412] Example 36

[0413] [ka]

[0414] Step 1: Synthesis of tert-butyl((4-chloro-3-(2-chloroethoxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-methyl)carbamate

[0415] Compound H150-2 (100 mg, 0.21 mmol), Ni (50 mg), and (Boc)2O (93 mg, 0.4 mmol) were added to methanol (3 mL) and stirred at room temperature for 24 hours. The reaction mixture was filtered, the organic phase was dried, and concentrated to obtain the oily compound H184-1 (100 mg, yield: 82%). LC-MS (ESI): m / z = 575.2 [M + H] + .

[0416] Step 2: Synthesis of (4-chloro-3-(2-chloroethoxy)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-ylcarboxamide

[0417] H184-1 (30 mg, 0.05 mmol) was dissolved in DCM (3 mL), and TFA (1 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain a white solid HANT-184 (14.3 mg, yield: 56%). LC-MS (ESI): m / z = 391.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.36(d,J=2.2Hz,1H),8.03(s,1H),7.87(d,J=2.2Hz,1H),6.89(s,1H), 4.42-4.34(m,3H),4.13-4.02(m,2H),4.00-3.91(m,2H),3.00-2.91(m,2H),2.06-1.82(m,4H).

[0418] Example 37

[0419] [ka]

[0420] Compounds INT-5 (40 mg, 0.14 mmol), 1H-indazole-5-carboxylic acid (33 mg, 0.16 mmol), Pybop (110 mg, 0.21 mmol), and TEA (28 mg, 0.28 mmol) were sequentially added to a dry flask, dissolved in DCM (10 mL), and reacted at room temperature for 12 hours. The mixture was filtered, concentrated, and purified by Prep-HPLC to obtain HANT-186 (21.3 mg, yield: 36%). LC-MS (ESI): m / z = 429.2 [M + H] + . 1 HNMR(400MHz,CD3OD):δ8.36(d,J=0.8Hz,1H),8.16(s,1H),7.93-7.90(m,1H),7.62-7.58(m,2H),5.34(d,J=3. 2Hz,1H),4.42(t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),2.92-2.91(m,2H),2.11-2.08(m,2H),1.96-1.92(m,2H).

[0421] Example 38

[0422] [ka]

[0423] Compounds INT-5 (15 mg, 0.13 mmol), EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.18 mmol), and DIEA (54 mg, 0.42 mmol) were sequentially added to a dry flask, dissolved in DMF (5 mL), and stirred at room temperature for 30 minutes. Compound S1 (40 mg, 0.14 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction mixture was poured into EA, washed with aqueous ammonium chloride solution, the organic phases were combined, concentrated under reduced pressure, and purified by reverse phase fractionation to obtain a white solid HANT-187 (37.8 mg, yield: 73%). LCMS (ESI): m / z = 379.1 [M + H] + ; 1HNMR(400MHz,DMSO-d6)δ13.14(brs,1H),8.37(d,J=8.3Hz,1H),8.08(brs,2H),7.56(s,1H),5 .18-5.14(m,1H),4.40-4.37(m,2H),3.99-3.96(m,2H),2.83-2.80(m,2H),2.00-1.77(m,4H).

[0424] Example 39

[0425] [ka]

[0426] Compounds INT-5 (12 mg, 0.1 mmol), EDCI (29 mg, 0.15 mmol), HOBt (20 mg, 0.15 mmol), and DIEA (39 mg, 0.3 mmol) were sequentially added to a dry flask, dissolved in DMF (5 mL), and stirred at room temperature for 30 minutes. Compound S1 (30 mg, 0.1 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction mixture was poured into EA, washed with aqueous ammonium chloride, the organic phases were combined, concentrated under reduced pressure, and purified by reverse phase fractionation to obtain a white solid HANT-188 (29.7 mg, yield: 74%). LCMS (ESI): m / z = 379.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ13.26(s,1H),8.47(d,J=8.7Hz,1H),7.84(s,1H),7.51(s,1H),6.71(s,1H), 5.19-5.14(m,1H),4.39(t,J=4.8Hz2H),3.97(t,J=5.0Hz,2H),2.85-2.75(m,2H),2.07-1.67(m,4H).

[0427] Example 40

[0428] [ka]

[0429] Step 1: Synthesis of 5-bromo-1-tosyl-1H-pyrazolo[4,3-b]pyridine

[0430] Compound S1 (1 g, 5.05 mmol), TosCl (1.38 g, 7.07 mmol), and NaH (262 mg, 6.56 mmol) were added to a round-bottom flask containing DMF (30 mL) and reacted at room temperature for 1 hour. The reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a yellow oily compound H191-1 (1.13 g, yield: 64%). LCMS (ESI): m / z = 352.1 [M + H] + .

[0431] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1-tosyl-1H-pyrazole[4,3-b]pyridine-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0432] H191-1 (360 mg, 1.02 mmol), INT-5 (100 mg, 0.34 mmol), Pd2(dba)3 (94 mg, 0.1 mmol), Xantphos (119 mg, 0.2 mmol), and Cs2CO3 (223 mg, 0.68 mmol) were dissolved in 5 mL of solution and reacted under a nitrogen atmosphere at 130°C for 12 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a yellow oily compound H191-2 (30 mg, yield: 16%). LCMS (ESI): m / z = 556.1 [M + H] + .

[0433] Step 3: Synthesis of 8-((1H-pyrazolo[4,3-b]pyridine-5-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0434] Compound H191-2 (30 mg, 0.31 mmol) and K2CO3 were dissolved in MeOH (30 mL) and reacted at 70°C for 3 hours. The reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the crude white solid HANT-191 (20 mg, yield: 90%). LCMS (ESI): m / z = 402.1 [M + H] + . 1 HNMR(400MHz,CD3OD)δ7.81(s,1H),7.70(d,J=9.2Hz,1H),7.61(s,1H),6.71(d,J=9.2Hz,1H),5.27(d,J=6.4H) z,1H),4.40(t,J=5.6Hz,2H),3.90(t,J=5.6Hz,2H),2.92-2.88(m,2H),2.07-2.01(m,2H),1.93-1.87(m,2H).

[0435] Example 41

[0436] [ka]

[0437] Step 1: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-amine

[0438] Compound S1 (1.25 g, 5.05 mmol) and Pd / C (625 mg) were added to MeOH (10 mL) and hydrogenated at room temperature for 2 hours. The reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a yellow oily compound S2 (1.0 g, yield: 90%). LCMS (ESI): m / z = 219.1 [M + H] + .

[0439] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0440] Compounds S2 (754 mg, 3.45 mmol), INT-3 (600 mg, 1.75 mmol), and DIEA (1128 mg, 8.75 mmol) were dissolved in DMF (20 mL) and reacted overnight at 60°C. After cooling, the reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white solid H192-1 (530 mg, yield: 16%). LCMS (ESI): m / z = 486.1 [M + H] + .

[0441] Step 3: Synthesis of 8-((1H-pyrazolo[3,4-b]pyridine-5-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0442] Compound H192-1 (530 mg) and TFA (1 mL) were dissolved in DCM (30 mL) and reacted at room temperature for 2 hours. The reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was separated and purified to obtain a white solid crude product HANT-192 (51 mg, yield: 23%). LCMS (ESI): m / z = 402.1 [M + H] + The compounds were separated and purified using the SFC method (mobile phase: Hex-EtOH-30-70-0.2-30 min) to obtain the optically active compounds HANT-192A (retention time 6.635 min) and HANT-192B (retention time 8.971 min).

[0443] HANT-192A: 1 HNMR(400MHz,CD3OD)δ8.17(d,J=2.6Hz,1H),7.89(s,1H),7.72(d,J=1.8Hz,1H),7.39(d,J=2.6Hz, 1H),4.67-4.68(m,1H),4.40-4.43(m,2H),3.90-3.93(m,2H),3.04-2.72(m,2H),2.12-1.77(m,4H).

[0444] HANT-192B:1 HNMR(400MHz,CD3OD)δ8.17(d,J=2.6Hz,1H),7.89(s,1H),7.72(d,J=1.8Hz,1H),7.39(d,J=2.6Hz, 1H),4.67-4.68(m,1H),4.40-4.43(m,2H),3.90-3.93(m,2H),3.04-2.72(m,2H),2.12-1.77(m,4H).

[0445] Example 42

[0446] [ka]

[0447] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1H-indazole-7-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0448] Compounds INT-2 (150 mg, 0.36 mmol), S2 (132 mg, 0.54 mmol), Pd(dppf)Cl2 (53 mg, 0.07 mmol), and Na2CO3 (77 mg, 0.73 mmol) were added to dioxane / water (3 mL / 0.5 mL) and stirred at 80°C for 4 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H193-1 (120 mg, yield: 87%). LCMS (ESI): m / z = 384.1 [M + H] + .

[0449] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1H-indazole-7-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0450] Compound H193-1 (120 mg, 0.31 mmol), Pd / C (50 mg), and AcOH (0.1 mL) were dissolved in MeOH (5 mL) and reacted at room temperature under a hydrogen gas atmosphere for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain compound HANT-193 (21.1 mg, white solid, yield: 18%). LC-MS (ESI): m / z = 386.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ13.11(s,1H),7.90(d,J=1.4Hz,1H),7.42(d,J=8.4Hz,1H),7.26(dd,J=8.4,7.0Hz,1H),7.13(d,J=0.8Hz,1H),6.61(d ,J=7.0Hz,1H),4.63(t,J=6.6Hz,1H),4.45-4.37(m,2H),3.97(dd,J=6. 0,4.4Hz,2H),3.03-2.85(m,2H),2.13-1.98(m,2H),1.84-1.75(m,2H).

[0451] Example 43

[0452] [ka]

[0453] The synthesis method was the same as in Example 42, yielding a white solid HANT-194 (18.7 mg, yield: 19%). LCMS(ESI): m / z = 386.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.08(s,1H),7.68(dd,J=8.2,1.0Hz,1H),7.12-7.03(m,2H),6.77(d,J=7.0Hz,1H),4.65(t,J =6.2Hz,1H),4.42(t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),3.11-2.91(m,2H),2.19-2.04(m,2H),1.96-1.84(m,2H).

[0454] Example 44

[0455] [ka]

[0456] Step 1: Synthesis of 5-chloro-7-iodo-6-propoxy-3,4-dihydronaphthalene-1(2H)-one

[0457] Compounds H195-2 (2.0 g, 6.2 mmol), S1 (740 mg, 12.4 mmol), DBAD (2.1 g, 9.3 mmol), and PPh3 (2.4 g, 9.3 mmol) were sequentially added to a dry flask, dissolved in toluene (30 mL), and stirred at 60°C for 6 hours. After cooling, the mixture was concentrated under reduced pressure, the solvent toluene was removed, and the resulting crude product was poured into an EA (organic aqueous solution), washed three times with saturated brine, combined with the organic phases, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the yellow oily compound H196-1 (850 mg, yield: 38%). LC-MS (ESI): m / z = 295.0 [M + H] + .

[0458] Step 2: Synthesis of 4-chloro-8-oxo-3-propoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0459] Compound H196-1 (850 mg, 2.34 mmol) and CuCN (1 g, 11.7 mmol) were sequentially added to a dry, sealed tube, dissolved in NMP (15 mL), and reacted with stirring at 160°C for 3 hours. After cooling, the reaction mixture was poured into EA, washed three times with ammonium chloride solution, the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid H196-2 (260 mg, yield: 43%). LC-MS (ESI): m / z = 264.1 [M + H] + .

[0460] Step 3: Synthesis of 5-chloro-7-cyano-6-propoxy-3,4-dihydronaphthalene-1-yltrifluoromethanesulfonate

[0461] Compound H196-2 (200 mg, 0.76 mmol) and TEA (230 mg, 2.3 mmol) were sequentially added to a dry flask, dissolved in DCM (10 mL), and Tf2O (0.7 mL, 3.8 mmol) was added under an ice bath. The reaction was allowed to proceed overnight at room temperature. The reaction mixture was poured into saturated saline solution, extracted with DCM, the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the yellow oily compound H196-3 (200 mg, yield: 67%). LCMS (ESI): m / z = 396.0 [M + H] + .

[0462] Step 4: Synthesis of 4-chloro-3-propoxy-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0463] Compound H196-3 (100 mg, 0.25 mmol), S2 (125 mg, 0.38 mmol), Pd(dppf)Cl2 (18 mg, 0.025 mmol), and sodium carbonate (54 mg, 0.5 mmol) were sequentially added to a dry flask. The mixture was dissolved in dioxane / water (8 / 2 mL) and stirred at 80°C under nitrogen protection for 6 hours. After cooling, the reaction mixture was poured into saturated saline solution, extracted with EA, and the organic phases were combined. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white solid H196-4 (100 mg, yield: 74%). LC-MS (ESI): m / z = 449.1 [M + H] + .

[0464] Step 5: Synthesis of 4-chloro-3-propoxy-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0465] In a dry flask, H196-4 (90 mg, 0.2 mmol) was added, dissolved in methanol (10 mL), and palladium-carbon (9 mg, 10% wt) and AcOH (5 drops) were added. The mixture was reacted overnight at room temperature under a hydrogen gas atmosphere. After filtration, the filtrates were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid H196-5 (65 mg, yield: 72%). LC-MS (ESI): m / z = 451.1 [M + H] + .

[0466] Step 6: Synthesis of 4-chloro-3-propoxy-8-(1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0467] Compound H196-5 (65 mg, 0.14 mmol) was added to a dry flask, dissolved in DCM (5 mL), and compound TFA (2 mL) was added. The reaction was allowed to proceed overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase fractionation to obtain a white solid HANT-196 (19.7 mg, yield: 37%). LC-MS (ESI): m / z = 367.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ13.59(s,1H),8.37(d,J=2.2Hz,1H),8.05(s,1H),7.79(d,J=2.1Hz,1H),7.21(s,1H),4.41 -4.37(m,1H),4.09(t,J=6.5Hz,2H),3.00-2.78(m,2H),2.08-2.05(m,1H),1.91-1.75(m,5H),1.03(t,J=7.4Hz,3H).

[0468] Example 45

[0469] [ka]

[0470] The synthesis method was the same as in Example 31, yielding HANT-200 (7.5 mg, yield: 31%). LCMS(ESI): m / z = 336.2 [M + H] + .1 HNMR(400MHz,CD3OD)δ7.35(s,2H),7.26(s,1H),4.39(t,J=5.6Hz,2H),4.16(t,J=5.6H z,1H),3.91(t,J=6.0Hz,2H),2.92-2.87(m,2H),2.04-2.03(m,1H),1.93-1.86(m,3H).

[0471] Example 46

[0472] [ka]

[0473] The synthesis method was the same as in Example 42, yielding HANT-202 (1.2 mg, yield: 1.5%). LCMS(ESI): m / z = 414.2 [M + H] + . 1 HNMR(400MHz,CDCl3)δ9.95(s,1H),8.37(d,J=2.0Hz,1H),7.64(d,J=10Hz,1H),7.47(d,J=2.0Hz,1H),7.00(s,1H),6.73(d,J=9. 6Hz,1H),4.43(t,J=6.8Hz,2H),4.20(s,1H),3.90(t,J=6.4Hz,2H),2.96(d,J=4.0Hz,2H),2.22-2.20(m,1H),1.31-1.26(m,3H).

[0474] Example 47

[0475] [ka]

[0476] The synthesis method was the same as in Example 42, yielding a white solid HANT-203 (11 mg, yield: 44%). LCMS(ESI): m / z = 362.1 [M + H] + ; 1HNMR(400MHz,CD3OD)δ7.64(d,J=2.4Hz,1H),7.18(dd,J=8.6,2.5Hz,1H),7.10(d,J=1.0Hz,1H),6.58(dd,J=8.6,0.8Hz,1H),4.41(t ,J=5.6Hz,2H),4.01-4.05(m,1H),3.91(t,J=5.6Hz,2H),2.92-2.95(m,2H),2.12-2.01(m,1H),2.01-1.90(m,1H),1.79-1.86(m,2H).

[0477] Example 48

[0478]

change

[0479] The synthesis method was the same as in Example 42, and compound HANT-204 (14.2 mg, white solid, yield: 36%) was obtained. LCMS(ESI):m / z=363.1[M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.00(s,2H),7.17(d,J=0.9Hz,1H),4.41(t,J=5.6Hz,2H),4.07(t,J= 6.2Hz,1H),3.91(t,J=5.6Hz,2H),3.00-2.88(m,2H),2.14-2.02(m,1H),1.97-1.76(m,3H).

[0480] Compound HANT-204 was separated and purified by SFC method (Hex-EtOH-DEA-60-40-0.2-30MIN), and optically active compounds HANT-204A (16.8mg, RT=8.103min) and HANT-204B (14.6mg, RT=10.902min) were obtained.

[0481] HANT-204A: 1HNMR(400MHz,DMSO-d6)δ7.96(s,2H),7.28(d,J=0.9Hz,1H),6.52(s,2H),4.46-4.33 (m,2H),4.07-3.91(m,3H),2.93-2.76(m,2H),2.03-1.88(m,1H),1.86-1.72(m,3H).

[0482] HANT-204B: 1 HNMR(400MHz,DMSO-d6)δ7.96(s,2H),7.29(s,1H),6.55(s,2H),4.46-4.31(m,2 H),4.06-3.92(m,3H),2.97-2.77(m,2H),2.03-1.89(m,1H),1.88-1.66(m,3H).

[0483] Example 49

[0484]

change

[0485] The synthesis method was the same as in Example 42, and white solid HANT-205 (13.9 mg, yield: 9%) was obtained. LCMS(ESI):m / z=404.1[M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.08-7.97(m,2H),7.44-7.47(m,1H),7.09(s,1H),4.41(t,J=5.5Hz,2H),4.20(t,J= 6.3Hz,1H),3.91(t,J=5.6Hz,2H),2.96(t,J=6.1Hz,2H),2.16(s,3H),2.11-2.13(m,1H),1.84-1.94(m,3H).

[0486] Example 50

[0487]

change

[0488] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(4-hydroxyphenyl)-5,6-dihydronaphthalene-2-carbonitrile

[0489] Compounds INT-2 (200 mg, 0.5 mmol), S2 (100 mg, 0.72 mmol), Pd(dppf)Cl2 (70 mg, 0.1 mmol), and Na2CO3 (102 mg, 1.0 mmol) were added to dioxane / water (10 mL / 2 mL) and stirred at 80°C for 4 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H2O6-1 (130 mg, yield: 75%). LCMS (ESI): m / z = 360.0 [M + H] + .

[0490] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0491] Compound H2O6-1 (130 mg, 0.36 mmol) and S3 (84 mg, 0.72 mmol) were dissolved in TFA (5 mL) and reacted under a nitrogen atmosphere at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound H2O6-2 (100 mg, yellow oily, yield: 77%). LC-MS (ESI): m / z = 362.1 [M + H] + .

[0492] Step 3: Synthesis of 4-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)phenylcarbamate

[0493] H2O6-2 (100 mg, 0.28 mmol) was added to THF (5 mL), and NaH (22.2 mg, 0.56 mmol) was added at 0°C, and the mixture was stirred for 1 hour. S4 (39 mg, 0.42 mmol) was then added, and the mixture was reacted at room temperature for 3 hours. The reaction mixture was extracted by DCM, the organic phase was dried and concentrated, and the residue was purified by prep-HPLC to obtain solid HANT-206 (15.0 mg, yield: 13%). LC-MS (ESI): m / z = 419.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.59(d,J=4.8Hz,1H),7.17(s,1H),7.09-6.99(m,4H),4.40(t,J=5.2Hz,2H),4.21(t,J= 6.2Hz,1H),3.97(t,J=5.2Hz,2H),2.95-2.79(m,2H),2.65(d,J=4.6Hz,3H),2.14-1.96(m,1H),1.88-1.70(m,3H).

[0494] Example 51

[0495] [ka]

[0496] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)oxazolo[4,5-b]pyridine-2(3H)-one

[0497] Compounds S1 (500 mg, 2.3 mmol), S2 (890 mg, 3.5 mmol), Pd2(dba)3 (211 mg, 0.23 mmol), xphos (219 mg, 0.46 mmol), and potassium acetate (676 mg, 6.9 mmol) were dissolved in 15 mL of solution and reacted at 100°C under a nitrogen atmosphere for 7 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound H2O7-1 (100 mg, white solid, yield: 16%). LC-MS (ESI): m / z = 263.1 [M + H]+ .

[0498] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0499] Compounds H2O7-1 (100 mg, 0.38 mmol), INT-2 (237 mg, 0.57 mmol), Pd(dppf)Cl2 (56 mg, 0.08 mmol), and Na2CO3 (81 mg, 0.8 mmol) were added to dioxane / water (3 mL / 0.5 mL) and stirred at 80°C under nitrogen gas protection for 4 hours. After cooling, the reaction mixture was extracted by EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H2O7-2 (50 mg, yield: 33%). LCMS (ESI): m / z = 402.0 [M + H] + .

[0500] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0501] Compound H207-2 (30 mg, 0.07 mmol), Pd(OH)2 / C (20 mg), and AcOH (20 mg) were dissolved in MeOH (3 mL) and reacted at room temperature under a hydrogen gas atmosphere for 3 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain compound HANT-207 (2.5 mg, white solid, yield: 8%). LC-MS (ESI): m / z = 404.0 [M + H] + ; 1HNMR(400MHz,CD3OD)δ7.82(s,1H),7.26(s,1H),7.11(s,1H),4.41(t,J=5.6Hz,2H),4.25(t,J= 6.4Hz,1H),3.91(t,J=5.6Hz,2H),2.97(t,J=6.2Hz,2H),2.23-2.11(m,1H),1.99-1.81(m,3H).

[0502] Example 52

[0503]

change

[0504] The synthesis method was the same as in Example 27, and white solid HANT-208 (24.4 mg, yield: 33%) was obtained. LCMS(ESI):m / z=403.0[M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.22-7.19(m,1H),7.15(s,1H),6.79-6.76(m,2H),4.41-4.38(m,2H),4. 21-4.19(m,1H),3.97(dd,J=6.2,4.0Hz,2H),2.88(brs,2H),2.04-1.98(m,1H),1.85-1.72(m,3H).

[0505] Example 53

[0506]

change

[0507] In a dry flask, compounds INT-5 (30 mg, 0.103 mmol), H2O9-2 (16 mg, 0.124 mmol), and HATU (51 mg, 0.134 mmol) were dissolved in DMF (5 mL) solution, and DIEA (40 mg, 0.31 mmol) was added. The reaction mixture was stirred overnight at room temperature. Extraction with water and EA was performed, the organic phase was dried over anhydrous sodium carbonate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product HANT-209 (13.7 mg, white solid, yield: 32.9%). LCMS (ESI): m / z = 395.1 [M + H] + . 1 HNMR(400MHz,DMSO-d6)δ8.11(d,J=8.4Hz,1H),7.46(s,1H),4.92(dd,J=12.8,8.0Hz,1H),4.43-4.34 (m,2H),4.01-3.93(m,2H),2.77(t,J=6.2Hz,2H),2.15(m,1H),1.86-1.58(m,8H),1.45-1.13(m,6H).

[0508] Example 54

[0509] [ka]

[0510] In a dry flask, compounds INT-5 (30 mg, 0.105 mmol), S2 (15 mg, 0.115 mmol), and HATU (51 mg, 0.134 mmol) were sequentially dissolved in DMF (5 mL) solution, and then DIEA (0.054 mL, 0.31 mmol) was added. The reaction mixture was stirred overnight at room temperature. Extraction with water and EA was performed, the organic phase was dried over anhydrous sodium carbonate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by perp-HPLC (NH4HCO3) yielded compound HANT-210 (14.8 mg, white solid, yield: 47%). LCMS (ESI): m / z = 397.2 [M + H] + ; 1HNMR(400MHz,DMSO-d6)δ8.20(d,J=8.4Hz,1H),7.50(s,1H),4.96-4.91(m,1H),4.38(t,J=4.8Hz,2H),3.97(t,J=5.2Hz,2H),3.89-3.85(m, 2H),3.29(s,1H),3.27(d,J=9.6Hz,1H),2.77(t,J=6.4Hz,2H),2.45-2.37(m,1H),1.91-1.88(m,1H),1.84-1.76(m,2H),1.70-1.58(m,5H).

[0511] Example 55

[0512] [ka]

[0513] Step 1: Synthesis of tert-butyl 4-((5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)carbamoyl)piperidine-1-carboxylate

[0514] In a dry flask, compounds INT-5 (42 mg, 0.18 mmol), HATU (70 mg, 0.18 mmol), and S1 (40 mg, 0.14 mmol) were sequentially dissolved in DMF (5 mL) solution, and then DIEA (55 mg, 0.43 mmol) was added. The reaction mixture was stirred overnight at 100°C. After cooling, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted with EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product H211-1 (50 mg, yellow oily substance, yield: 64%). LCMS (ESI): m / z = 440.1 [M-56+H] + .

[0515] Step 2: Synthesis of 4-((5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)carbamoyl)piperidine

[0516] In a dry flask, compound H211-1 (45 mg, 0.09 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (1.5 mL) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to obtain the crude product. Purification by prep-HPLC (NH4HCO3) yielded HANT-211 (23.1 mg, white solid, yield: 63%). LC-MS (ESI): m / z = 396.1 [M + H] + . 1 HNMR(400MHz,DMSO-d6)δ8.52(s,1H),7.48(s,1H),5.07-5.04(m,1H),4.41(t,J=5.6Hz,2H),3.90(t,J=6.0Hz,2H) ,3.49-3.42(m,2H),3.04-2.97(m,2H),2.89-2.85(m,2H),2.60-2.52(m,1H),2.07-1.84(m,8H),1.84-1.75(m,1H).

[0517] Example 56

[0518] [ka]

[0519] Compound INT-5 (20 mg, 0.07 mmol), benzoyl chloride (12 mg, 0.09 mmol), and triethylamine (14 mg, 0.14 mmol) were dissolved in DCM (3 mL) and stirred at room temperature for 2 hours. The mixture was concentrated and purified by Prep-HPLC to obtain HANT-212 (15.1 mg, yield: 56%). LC-MS (ESI): m / z = 389.2 [M + H] + . 1 HNMR(400MHz,CD3OD)δ7-86-7.84(m,2H),7.57-7.53(m,2H),7.49-7.45(m,2H),5.31(d,J=4.0Hz,1HH) ,4.41(t,J=4.2Hz,2H),3.90(t,J=4.2Hz,2H),2.92-2.90(m,2H),2.09-2.05(m,2H),1.94-1.89(m,2H).

[0520] Example 57

[0521] [ka]

[0522] Compound S1 (30 mg, 0.25 mmol) and HATU (145 mg, 0.38 mmol) were dissolved in DMF (5 mL), stirred for 10 minutes, and compound INT-5 (70 mg, 0.25 mmol) and DIEA (96 mg, 0.75 mmol) were added. The mixture was reacted overnight at room temperature. The reaction mixture was poured into EA and washed with saturated ammonium chloride aqueous solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative separation to obtain a white solid HANT-213 (42.6 mg, yield: 47%). LCMS (ESI): m / z = 390.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.04(dd,J=2.3,0.9Hz,1H),8.97(d,J=8.0Hz,1H),8.71(dd,J=4.8,1.7Hz,1H),8.23(dt,J=8.0,1.9Hz,1H),7.70(s,1H),7.51 (ddd,J=7.9,4.8,0.9Hz,1H),5.24-5.21(m,1H),4.40(t,J=5.0Hz,2H),3.9 8(t,J=5.0Hz,2H),2.94-2.76(m,2H),2.04-1.91(m,2H),1.91-1.79(m,2H).

[0523] Example 58

[0524] [ka]

[0525] Compounds INT-5 (30 mg, 0.11 mmol), S2 (13 mg, 0.11 mmol), HATU (60 mg, 0.16 mmol), and DIEA (20.5 mg, 0.16 mmol) were added to DMF (3 mL) and stirred at room temperature for 2 hours. The reaction mixture was extracted with EA, the organic phase was dried and concentrated, and the residue was purified by prep-HPLC to obtain solid HANT-214 (19.8 mg, yield: 48%). LC-MS (ESI): m / z = 390.1 [M + H] +;1 HNMR(400MHz,DMSO-d6)δ9.07(d,J=8.2Hz,1H),8.73(d,J=5.2Hz,2H),7.84-7.77(m,2H),7.68(d,J=0.8 Hz,1H),5.24-5.15(m,1H),4.43-4.35(m,2H),4.01-3.95(m,2H),2.86-2.79(m,2H),2.03-1.80(m,4H).

[0526] Example 59

[0527] [ka]

[0528] Compound INT-5 (20 mg, 0.07 mmol), picolinic acid (11 mg, 0.09 mmol), HATU (35 mg, 0.09 mmol), DIEA (23 mg, 0.18 mmol), and DMF (5 mL) were stirred at room temperature for 12 hours. Extraction with EA, washing with saturated ammonium chloride, drying of the organic phase, concentration, and purification by Prep-HPLC were performed to obtain HANT-215 (10.1 mg, yield: 37%). LC-MS (ESI): m / z = 390.2 [M + H] + . 1 HNMR(400MHz,CD3OD)δ8.62(d,J=4.0Hz,1H),8.15(d,J=4.0Hz,1H),8.01-7.97(m,1H),7.58-7.53(m,2H),5.30(d,J =3.6Hz,1H),4.41(t,J=5.6Hz,2H),3.90(t,J=5.6Hz,2H),2.94-2.91(m,2H),2.10-2.06(m,2H),1.97-1.92(m,2H).

[0529] Example 60

[0530] [ka]

[0531] Step 1: Synthesis of N-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)-1H-pyrazole-4 carboxamide

[0532] Compounds S1 (67 mg, 0.6 mmol), EDCI (171 mg, 0.9 mmol), HOBT (121 mg, 0.9 mmol), and DIEA (230 mg, 1.8 mmol) were added to DMF (5 mL) and stirred at room temperature for 30 minutes. INT-5 (170 mg, 0.6 mmol) was then added to the reaction system and stirred at room temperature for 2 hours. Extraction with EA was performed, the mixture was washed with saturated ammonium chloride, the organic phase was dried, and the mixture was concentrated to obtain H216-1 (160 mg, yield: 71%). LC-MS (ESI): m / z = 379.2 [M + H] + .

[0533] Step 2. Synthesis of N-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4 carboxamide

[0534] Compound H216-1 (160 mg, 0.4 mmol), DHP (71 mg, 0.8 mmol), and PTSA (40 mg, 0.2 mmol) were added to DCM (5 mL) and stirred at room temperature for 12 hours. The organic phase was concentrated and purified by silica gel column (PE:EA = 2:1) to obtain H216-2 (160 mg, yield: 71%). LCMS (ESI): m / z = 463.2 [M + H] + .

[0535] Step 3. Synthesis of N-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4 carboxamide

[0536] Compound H216-2 (100 mg, 0.22 mmol) was added to DMF (5 mL), NaH (17 mg, 0.43 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Iodomethane (46 mg, 0.32 mmol) was added to the reaction system, and the mixture was stirred at room temperature for 2 hours. Extraction was performed with EA, washed with saturated ammonium chloride, the organic phase was dried, concentrated, and purified by silica gel column (PE:EA = 1:1) to obtain H216-3 (40 mg, yield: 39%). LCMS (ESI): m / z = 477.2 [M + H] + .

[0537] Step 4. Synthesis of N-(5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)-N-methyl-1H-pyrazole-4 carboxamide

[0538] Compound H216-3 (40 mg, 0.08 mmol) was added to DCM (5 mL), TFA (0.5 mL) was added at 0°C, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified by Prep-HPLC to obtain HANT-216 (18 mg, yield: 55%). LC-MS (ESI): m / z = 393.2 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.01(d,J=63.5Hz,2H),7.38(d,J=29.2Hz,1H),5.59(d,J=201.0Hz,1H),4.42(t,J =5.6Hz,2H),3.89(dd,J=22.4,16.8Hz,2H),3.10-2.90(m,3H),2.76(d,J=11.4Hz,2H),2.23-1.81(m,4H).

[0539] Example 61

[0540] [ka]

[0541] Step 1: Synthesis of 8-(3-bromo-1H-pyrazolo[3,4-b]pyridine-5-yl)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0542] HANT-150 (180 mg, 0.47 mmol), NBS (100 mg, 0.56 mmol), and DMF (3 mL) were sequentially added to a 10 mL flask and reacted under nitrogen gas protection at room temperature for 5 hours. After cooling, the mixture was extracted with EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to obtain compound H218-1 (150 mg, yield: 69%). LC-MS (ESI): m / z = 465.0 [M + H] + .

[0543] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(3-(pyridine-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0544] In a 10 mL three-necked flask, H218-1 (50 mg, 0.1 mmol), S2 (133 mg, 1.08 mmol), Pd(dppf)Cl2 (27.6 mg, 0.038 mmol), sodium carbonate (40 mg, 0.38 mmol), dioxane, and water (3 mL, 5:1) were sequentially added, and the mixture was reacted at 80°C for 12 hours under nitrogen gas protection. After cooling, the mixture was extracted with ammonium chloride solution and EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain compound HANT-218 (3.5 mg, white solid, yield: 7.0%). LC-MS (ESI): m / z = 464.1 [M + H] + ; 1HNMR(400MHz,CD3OD)δ8.67(d,J=6.2Hz,2H),8.41(d,J=2.0Hz,1H),8.38(d,J=2.0Hz,1H),8.08(dd,J=4.8, 1.6Hz,2H),7.14(s,1H),4.51-4.41(m,3H),3.95(t,J=5.6Hz,2H),3.07(d,J=9.6Hz,2H),2.35-2.01(m,4H).

[0545] Example 62

[0546] [ka]

[0547] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(3-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0548] Compounds H218-1 (100 mg, 0.1 mmol), S2 (91 mg, 0.2 mmol), Pd(dppf)Cl2 (32 mg, 0.04 mmol), and Na2CO3 (46 mg, 0.4 mmol) were added to dioxane / water (5 mL / 1 mL) and stirred at 90°C under nitrogen gas protection for 6 hours. After cooling, the reaction mixture was extracted by EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H220-1 (50 mg, yield: 50%). LCMS (ESI): m / z = 469.1 [M + H] + .

[0549] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0550] Compound H220-1 (20 mg, 0.04 mmol), Pd / C (20 mg), and AcOH (0.1 mL) were dissolved in MeOH (3 mL) and reacted at room temperature under a hydrogen gas atmosphere for 5 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain compound HANT-220 (4.8 mg, white solid, yield: 24%). LC-MS (ESI): m / z = 471.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.27(s,1H),8.00(d,J=2.0Hz,1H),7.08(s,1H),4.43(t,J=5.6Hz,2H),4.38(t,J=6.8Hz,1H),4. 08-4.01(m,2H),3.91(t,J=5.6Hz,2H),3.66-3.56(m,2H),3.01(t,J=6.4Hz,2H),2.23-2.16(m,1H),2.06-1.87(m,8H).

[0551] Example 63

[0552] [ka]

[0553] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(1-tosyl-1H-pyrazole[3,4-c]pyridine-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0554] INT-5 (50 mg, 0.18 mmol), S2 (93 mg, 0.26 mmol), Pd2(dba)3 (48 mg, 0.05 mmol), Xantphos (61 mg, 0.105 mmol), and Cs2CO3 (58 mg, 0.36 mmol) were added to toluene (3 mL), placed in a sealed tube at 110 °C, and reacted overnight under nitrogen protection. After cooling, the reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a yellow solid H224-1 (80 mg, yield: 78%). LCMS (ESI): m / z = 556.1 [M + H]+ .

[0555] Step 2: Synthesis of 8-(1H-pyrazolo[3,4-c]pyridine-5-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0556] Compound H224-1 (80 mg, 0.14 mmol) and K2CO3 (96 mg, 0.7 mmol) were dissolved in methanol (3 mL) and reacted under a nitrogen atmosphere at 70°C for 3 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the yellow oily compound HANT-224 (13.7 mg, yield: 23%). LCMS (ESI): m / z = 402.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.60(s,1H),7.89(s,1H),7.69(s,1H),6.82(s,1H),5.04-5.05(m,1H),4.4 0(t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),3.01-2.69(m,2H),2.01-2.05(m,2H),1.97-1.80(m,2H).

[0557] Example 64

[0558] [ka]

[0559] Step 1: Synthesis of 5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0560] S1 (1.0 g, 6.1 mmol), DCM (20 mL), DHP (1.03 g, 12.3 mmol), and PTSA (582 mg, 3.07 mmol) were sequentially added to a dry flask. The mixture was stirred overnight at room temperature under nitrogen gas protection. The solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography to obtain orange solid H225-1 (1.2 g, yield: 80%). LCMS (ESI): m / z = 248.1 [M + H] + .

[0561] Step 2: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-amine

[0562] Compound H225-1 (500 mg, 2.0 mmol), methanol / water (20 mL), iron powder (680 mg, 12.0 mmol), and ammonium chloride (642 mg, 12.0 mmol) were sequentially added to a dry flask, and the mixture was stirred at 50°C for 2 hours. After cooling and filtering, the mixture was concentrated under reduced pressure, diluted with water, extracted with EA, the organic phase was dried over sodium sulfate, filtered, and concentrated to obtain an orange solid H225-2 (430 mg, yield: 99%). LCMS(ESI): m / z = 218.1 [M + H] + .

[0563] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0564] Compounds H225-2 (54 mg, 0.25 mmol), DMF (4 mL), INT-3 (175 mg, 0.5 mmol), and DIEA (97 mg, 0.75 mmol) were sequentially added to a dry flask. The mixture was stirred overnight at 60°C under nitrogen gas protection. After cooling, the solution was diluted with water, extracted with EA, the organic phase was dried over sodium sulfate, filtered, concentrated, and the residue was purified by flash column chromatography to obtain a yellow solid (100 mg, yield: 82%). LCMS (ESI): m / z = 485.1 [M + H] + .

[0565] Step 4: Synthesis of 8-((1H-indazole-5-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0566] H225-3 (90 mg, 0.19 mmol) and hydrochloric acid / dioxane (4 M, 7 mL) were sequentially added to a dry flask and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, adjusted to basicity with saturated sodium bicarbonate solution, extracted by DCM, the organic phase was dried over sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC to obtain a white solid HANT-225 (20.1 mg, yield: 27%). LC-MS (ESI): m / z = 401.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.80(s,1H),7.71(s,1H),7.36(d,J=9.0Hz,1H),6.98(dd,J=9.0,2.2Hz,1H),6.93(s,1H),4.6 6-4.63(m,1H),4.41(t,J=6.0Hz,2H),3.91(t,J=6.0Hz,2H),3.00-2.92(m,1H),2.86-2.78(m,1H),2.07-1.79(m,4H).

[0567] Example 65

[0568] [ka]

[0569] INT-3 (50 mg, 0.14 mmol), S2 (27 mg, 0.27 mmol), and DIEA (93 mg, 0.72 mmol) were added to DMF (2 mL) and reacted overnight at 60°C under nitrogen protection. After cooling, the reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white solid HANT-226 (9.0 mg, yield: 17%). LCMS (ESI): m / z = 362.1 [M + H] + ; 1HNMR(400MHz,CD3OD)δ7.64(d,J=0.8Hz,1H),7.16-7.03(m,2H),6.73-6.66(m,2H),6.61-6.65(m,1H),4.60-4.6 3(m,1H),4.39(t,J=5.6Hz,2H),3.90(t,J=5.6Hz,2H),2.99-2.73(m,2H),1.93-1.99(m,2H),1.91-1.77(m,2H).

[0570] Example 66

[0571]

change

[0572] The synthesis method was the same as in Example 65, and HANT-227 (11.9 mg, yield: 10%) was obtained. LCMS(ESI):m / z=362.2[M+H] + . 1 HNMR(400MHz,CD3OD)δ8.00(s,1H),7.80(s,1H),7.64(s,1H),7.21-7.13(m,2H),4.69(s ,1H),4.41(t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),2.98-2.80(m,2H),2.03-1.88(m,4H).

[0573] Example 67

[0574]

change

[0575] INT-5 (50 mg, 0.177 mmol), S2 (48 mg, 0.212 mmol), Pd2(dba)3 (48 mg, 0.053 mmol), Xantphos (61.5 mg, 0.106 mmol), and Cs2CO3 (115 mg, 0.354 mmol) were dissolved in 4 mL of toluene. The sealed tube system was heated to 100°C and stirred overnight. After cooling, the mixture was quenched with ammonium chloride solution, extracted with DCM, washed the organic phase with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative fractionation to obtain compound HANT-228 (13.5 mg, white solid, yield: 21.1%). LCMS(ESI): m / z = 362.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ8.04(d,J=5.8Hz,2H),7.56(s,1H),7.52-7.31(m,1H),6.74-6.65(m,2H),4.80(d,J=5.4Hz,1H),4.42(td,J= 5.6,1.2Hz,2H),3.91(t,J=5.6Hz,2H),3.00-2.91(m,1H),2.86(s,1H),1.94(ddt,J=25.2,8.6,6.0Hz,3H),1.31(d,J=16.4Hz,1H).

[0576] Example 68

[0577] [ka]

[0578] Step 1: Synthesis of 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0579] Compound S1 (1 g, 6.1 mmol), DHP (1.03 g, 12.26 mmol), and PTSA (582 mg, 3.0 mmol) were dissolved in DCM (10 mL) solution and reacted at room temperature under nitrogen gas protection for 12 hours. Extraction was performed with DCM and ammonium chloride solution, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound H229-2 (1.1 g, yellow oily substance, yield: 73.3%). LCMS (ESI): m / z = 248 [M + H] + .

[0580] Step 2: Synthesis of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-amine

[0581] H229-2 (500 mg, 2.0 mmol), Fe powder (680 mg, 12.0 mmol), and NH4Cl (642 mg, 12.0 mmol) were dissolved in methanol / water (100 mL / 10 mL) solution. The mixture was reacted at 50°C for 2 hours. After cooling, the Fe powder was removed by filtration, the mixture was concentrated under reduced pressure, and the methanol solvent was removed. The reaction mixture was extracted with EA and ammonium chloride solution, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain H229-3 (430 mg, crude product, brown oily substance, yield: 98%). LCMS(ESI): m / z = 218 [M + H] + .

[0582] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-((1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0583] H229-3 (50 mg, 0.23 mmol, crude product) and compound INT-3 (160 mg, 0.46 mmol) were dissolved in DMF (5 mL), DIEA (89.2 mg, 0.69 mmol) was added dropwise, and the mixture was reacted overnight at 60°C. After cooling, the reaction mixture was quenched over ice ammonium chloride solution, extracted with EA, the organic phase was backwashed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography to obtain compound H229-4 (60 mg, yellow oily substance, yield: 49.6%). LCMS (ESI): m / z = 485 [M + H] + .

[0584] Step 4: Synthesis of 8-((1H-indazole-6-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0585] H229-4 (60 mg, 0.124 mmol, crude product) was dissolved in dioxane (5 mL) passed through hydrochloric acid gas and reacted at room temperature for 1 hour. The pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution, extracted with EA, the organic phase was backwashed with water and saturated brine, dried with sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by neutral preparative fractionation to obtain compound HANT-229 (12.2 mg, white solid, yield: 24.6%). LCMS(ESI): m / z=401[M+H] + ; 1 HNMR(400MHz,CD3OD)δ7.78(s,1H),7.67(s,1H),7.47(d,J=8.8Hz,1H),6.68-6.59(m,2H),4.69(s,1H),4.41( t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),2.93(d,J=6.0Hz,1H),2.84(d,J=18.6Hz,1H),2.01(d,J=17.8Hz,4H).

[0586] Example 69

[0587] [ka]

[0588] In a dry flask, compounds INT-5 (30 mg, 0.106 mmol), S1 (20 mg, 0.127 mmol), and HATU (52 mg, 0.137 mmol) were dissolved in DMF (5 mL) solution, and DIEA (41 mg, 0.317 mmol) was added. The mixture was stirred overnight at room temperature. Extraction was performed with water and EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography to obtain compound HANT-232 (23 mg, white solid, yield: 51.1%). LCMS (ESI): m / z = 424.0 [M + H] + . 1 HNMR(400MHz,DMSO-d6)δ8.86(d,J=8.2Hz,1H),7.96-7.89(m,2H),7.63(s,1H),7.58-7.51(m,2H),5.25 -5.14(m,1H),4.45-4.35(m,2H),3.98(dd,J=5.8,4.6Hz,2H),2.82(t,J=5.6Hz,2H),2.04-1.77(m,4H).

[0589] Example 70

[0590] [ka]

[0591] Compound S1 (30 mg, 0.19 mmol), compound INT-5 (54 mg, 0.19 mmol), and HATU (110 mg, 0.29 mmol) were dissolved in DMF (5 mL), DIEA (74 mg, 0.57 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction mixture was poured into EA and washed with saturated ammonium chloride aqueous solution. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative separation to obtain a white solid HANT-233 (31.3 mg, yield: 39%). LCMS (ESI): m / z = 423.0 [M + H] + ; 1HNMR(400MHz,DMSO-d6)δ8.91(d,J=8.0Hz,1H),7.94(brs,1H),7.86(d,J=7.8Hz,1H),7.66(s,1H),7.63-7.61(m,1H),7 .53-7.49(m,1H),5.19-5.18(m,1H),4.44-4.32(m,2H),3.98(dd,J=5.9,4.3Hz,2H),2.81(brs,2H),2.07-1.64(m,4H).

[0592] Example 71

[0593] [ka]

[0594] In a dry flask, compounds INT-5 (30 mg, 0.106 mmol), S1 (19 mg, 0.127 mmol), and HATU (52 mg, 0.137 mmol) were dissolved in DMF (5 mL) solution, and DIEA (41 mg, 0.317 mmol) was added. The mixture was stirred overnight at room temperature. Extraction was performed with water and EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography to obtain compound HANT-234 (20.3 mg, white solid, yield: 46.14%). LCMS (ESI): m / z = 414.1 [M + H] + . 1 HNMR(400MHz,DMSO-d6)δ9.03(d,J=8.0Hz,1H),8.05(d,J=8.6Hz,2H),7.97(d,J=8.6Hz,2H),7.68(s,1H) ),5.20(d,J=5.4Hz,1H),4.47-4.32(m,2H),4.06-3.92(m,2H),2.81(d,J=5.6Hz,2H),2.07-1.75(m,4H).

[0595] Example 72

[0596] [ka]

[0597] INT-5 (19.3 mg, 0.12 mmol), HATU (48.2 mg, 0.12 mmol), and DIEA (34.2 mg, 0.26 mmol) were dissolved in DMF (3 mL), and S1 (30 mg, 0.1 mmol) was added. The mixture was reacted at room temperature for 3 hours. Extraction was performed with ammonium chloride and EA, the organic phase was dried over anhydrous sodium carbonate, concentrated, and purified by prep-HPLC to obtain compound HANT-235 (20.1 mg, white solid, yield: 45.5%). LC-MS (ESI): m / z = 419.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.84(d,J=9.0Hz,2H),7.52(s,1H),6.99(d,J=9.0Hz,2H),5.28(s,1H),4.41(t ,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),3.85(s,3H),2.91(s,2H),2.13-1.99(m,2H),1.95-1.83(m,2H).

[0598] Example 73

[0599] [ka]

[0600] Step 1: Synthesis of tert-butyl 4-((5-chloro-6-(2-chloroethoxy)-7-cyano-1,2,3,4-tetrahydronaphthalene-1-yl)amino)-1H-pyrazole-1-carboxylate

[0601] Compounds INT-3 (50 mg, 0.14 mmol), S2 (53 mg, 0.28 mmol), and DIEA (93 mg, 0.72 mmol) were added to DMF (3 mL) and reacted overnight at 60°C. After cooling, the reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a yellow solid H239-1 (50 mg, yield: 78%). LCMS (ESI): m / z = 451.1 [M + H] + .

[0602] Step 2: Synthesis of 8-((1H-pyrazole-4-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0603] Compound H239-1 (50 mg) and TFA (0.05 mL) were dissolved in DCM (3 mL) and reacted under a nitrogen atmosphere at room temperature for 3 hours. The reaction mixture was extracted with EA, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white solid HANT-239 (19.8 mg, yield: 62%). LCMS (ESI): m / z = 351.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.76(s,1H),7.11(s,2H),4.68(d,J=8.8Hz,1H),4.43-4.31(m,2H),4 .21-4.12(m,1H),3.96-3.98(m,2H),2.86-2.67(m,2H),1.90-1.94(m,1H),1.87-1.62(m,3H).

[0604] Example 74

[0605] [ka]

[0606] Step 1: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-((6-nitropyridine-3-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0607] Compound S1 (47 mg, 0.23 mmol) and compound INT-5 (50 mg, 0.177 mmol) were dissolved in 4 mL of water. Pd2(dba)3 (48.6 mg, 0.053 mmol), Xantphos (61 mg, 0.106 mmol), and Cs2CO3 (57.6 mg, 0.353 mmol) were added to each, and the reaction mixture was allowed to react in a sealed tube at 110°C for 12 hours under nitrogen gas protection. After cooling, the reaction mixture was quenched over ice ammonium chloride solution, extracted with EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound H240-1 (50 mg, yellow oily substance, yield: 69.7%). LCMS(ESI): m / z=407[M+H] + .

[0608] Step 2: Synthesis of 8-((6-aminopyridine-3-yl)amino)-4-chloro-3-(2-chloroethoxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0609] Compound H240-1 (40 mg, 0.099 mmol), Fe powder (33 mg, 0.591 mmol), and NH4Cl (32 mg, 0.591 mmol) were dissolved in MeOH / H2O (3 mL / 1 mL) and stirred at 50°C for 6 hours. After cooling and filtering, the solvent was removed, and the mixture was extracted with EA and ammonium chloride. The organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound HANT-240 (3.2 mg, gray solid, yield: 8.6%). LCMS(ESI): m / z=377[M+H] + ; 1 HNMR(400MHz,CD3OD)δ7.68(s,1H),7.34(d,J=3.0Hz,1H),7.30(dd,J=9.0,2.8Hz,1H),6.71(d,J=9.0Hz,1H),4.52-4.45( m,1H),4.41(t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),3.00-2.88(m,1H),2.86-2.74(m,1H),1.91(s,3H),2.02-1.81(m,1H).

[0610] Example 75

[0611] [ka]

[0612] The synthesis method was the same as in Example 65, yielding a pink solid HANT-241 (15.8 mg, yield: 28%). LCMS(ESI): m / z = 392.1 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.68(s,1H),7.57(d,J=2.9Hz,1H),7.21(dd,J=8.9,3.0Hz,1H),6.69(d,J=2.9Hz,1H),4.55-4.56(m,1H),4. 41(t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),3.82(s,3H),2.90-2.93(m,1H),2.82-2.85(m,1H),2.07-1.91(m,2H),1.90-1.79(m,2H).

[0613] Example 76

[0614] [ka]

[0615] The synthesis method was the same as in Example 42, yielding a white solid HANT-246 (20.7 mg, yield: 30%). LCMS(ESI): m / z = 348.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.08(s,1H),8.56(s,2H),7.32(s,1H),4.41(t,J=5.2Hz,2H),4.30(t ,J=6.2Hz,1H),3.97(t,J=5.2Hz,2H),2.98-2.79(m,2H),2.12-2.00(m,1H),1.90-1.71(m,3H).

[0616] Example 77

[0617] [ka]

[0618] Step 1: Synthesis of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)pyrimidine-2-amine

[0619] S1 (200 mg, 1.06 mmol), (Bpin)2 (320 mg, 1.27 mmol), Pd(dppf)Cl2 (40 mg, 0.05 mmol), and potassium acetate (311 mg, 3.18 mmol) were sequentially added to a dry flask, dissolved in DMF (10 mL), and stirred at 80°C for 3 hours. After cooling, the reaction mixture was poured into EA, washed with saturated brine, combined the organic phases, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid H247-1 (120 mg, yield: 48%). LCMS (ESI): m / z = 236.1 [M + H] + .

[0620] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(methylamino)pyrimidine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0621] Compounds H247-1 (100 mg, 0.43 mmol), INT-2 (136 mg, 0.33 mmol), Pd(dppf)Cl2 (24 mg, 0.033 mmol), and sodium carbonate (70 mg, 0.66 mmol) were sequentially added to a dry flask. The mixture was dissolved in dioxane / water (8 / 2 mL) and stirred at 80°C under a nitrogen atmosphere for 6 hours. After cooling, the reaction mixture was poured into saturated brine, extracted with EA, and the organic phases were combined. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a white solid H247-2 (50 mg, yield: 32%). LC-MS (ESI): m / z = 375.0 [M + H] + .

[0622] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-(methylamino)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0623] Compound H247-2 (50 mg, 0.13 mmol) was added to a dry flask and dissolved in EA (10 mL) and palladium-carbon (10 mg, 10% wt). The mixture was reacted overnight at room temperature under a hydrogen gas atmosphere. After filtration, the filtrates were combined, concentrated under reduced pressure, and purified by reverse-phase preparative fractionation to obtain a white solid HANT-247 (8.1 mg, yield: 16%). LC-MS (ESI): m / z = 377.0 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ8.01(s,2H),7.28(s,1H),7.00(q,J=4.8Hz,1H),4.39(t,J=5.2Hz,2H),4.04-3.99( m,1H),3.99-3.93(m,2H),2.86(q,J=6.8Hz,2H),2.77(d,J=4.7Hz,3H),2.08-1.95(m,1H),1.80-1.76(m,3H).

[0624] Example 78

[0625] [ka]

[0626] Step 1: Synthesis of 2-((5-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)pyrimidine-2-amino)ethane-1-ol

[0627] Compounds S1 (200 mg, 0.83 mmol), S2 (76 mg, 1.25 mmol), and TEA (252 mg, 2.5 mmol) were added to ethanol (5 mL) and reacted at 78°C for 1.5 hours. After cooling, the reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white solid H248-1 (200 mg, yield: 91%). LCMS (ESI): m / z = 266.2 [M + H] + .

[0628] Step 2: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-((2-hydroxyethyl)amino)pyrimidine-5-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0629] Compounds H248-1 (66 mg, 0.36 mmol), INT-2 (100 mg, 0.24 mmol), Pd(dppf)Cl2 (35 mg, 0.05 mmol), and Na2CO3 (51 mg, 0.48 mmol) were added to dioxane / water (3 mL / 0.5 mL) and stirred at 80°C for 3 hours. After cooling, the reaction mixture was extracted by EA, the organic phase was dried and concentrated, and the residue was purified by silica gel column to obtain solid H248-2 (45 mg, yield: 46%). LCMS (ESI): m / z = 405.1 [M + H] + .

[0630] Step 3: Synthesis of 4-chloro-3-(2-chloroethoxy)-8-(2-((2-hydroxyethyl)amino)pyrimidine-5-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0631] Compound H248-2 (45 mg, 0.11 mmol) and Pd / C (90 mg) were dissolved in MeOH (3 mL) and reacted under a hydrogen gas atmosphere at 30°C for 5 hours. The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by prep-HPLC to obtain a white solid HANT-248 (5.2 mg, yield: 12%). LC-MS (ESI): m / z = 407.1 [M + H]+ ; 1 HNMR(400MHz,CD3OD)δ8.01(s,2H),7.17(s,1H),4.41(t,J=5.6Hz,2H),4.06(d,J=6.8Hz,1H),3.91(t,J=5.6Hz ,2H),3.69(t,J=5.7Hz,2H),3.49(t,J=5.7Hz,2H),2.94(t,J=6.2Hz,2H),2.14-1.99(m,1H),1.98-1.75(m,3H).

[0632] Example 79

[0633]

change

[0634] The synthesis method was the same as in Example 51, and white solid HANT-249 (4.9 mg, yield: 31%) was obtained. LCMS(ESI):m / z=363.0[M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.80(s,1H),7.72(s,1H),7.22(s,1H),6.29(s,2H),4.50-4.29(m,2H),4.13(t ,J=6.2Hz,1H),3.96(dd,J=6.0,4.3Hz,2H),2.84(t,J=6.2Hz,2H),1.93-1.86(m,3H),1.82-1.64(m,1H).

[0635] Example 80

[0636]

change

[0637] The synthesis method was the same as in Example 65, and compound HANT-250 (3.3 mg, white solid, yield: 6.3%) was obtained. LCMS(ESI):m / z=363.0[M+H] + ; 1HNMR(400MHz,CD3OD)δ8.42(s,1H),8.23(s,2H),7.66(s,1H),4.76(s,1H),4.42(t,J=5.6Hz,2H),3 .92(t,J=5.6Hz,2H),2.97(d,J=18.4Hz,1H),2.83(d,J=18.4Hz,1H),1.95(dd,J=14.6,7.4Hz,4H).

[0638] Example 81

[0639]

change

[0640] The synthesis method was the same as in Example 65, and compound HANT-251 (17.6 mg, white solid, yield: 33%) was obtained. LCMS(ESI):m / z=378.1[M+H] + ;1HNMR(400MHz,DMSO-d6)δ7.89(s,2H),7.79(s,1H),5.82(s,2H),5.19(d,J=9.4Hz,1H),4.55-4.43(m,1H),4.42-4.31(m,2 H),4.01-3.87(m,2H),2.92-2.78(m,1H),2.70(dd,J=18.6,7.0Hz,1H),1.87(d,J=5.2Hz,1H),1.75(dt,J=17.8,10.4Hz,3H).

[0641] Example 82

[0642]

change

[0643] Compounds INT-5 (50 mg, 0.18 mmol), S2 (54 mg, 0.26 mmol), Pd(OAc)2 (8 mg, 0.03 mmol), BINAP (22 mg, 0.03 mmol), and NaOtBu (35 mg, 0.36 mmol) were added to toluene (3 mL) in a sealed tube and reacted overnight at 100°C. After cooling, the reaction mixture was extracted with EA, the organic phase was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white solid HANT-252 (3.3 mg, yield: 4%). LCMS (ESI): m / z = 362.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ8.04-7.97(m,1H),7.62(s,1H),7.40(td,J=8.3,7.7,2.0Hz,1H),6.92(d,J=8.3Hz,1H), 6.51-6.54(m,2H),5.29-5.09(m,1H),4.45-4.32(m,2H),4.03-3.92(m,2H),2.77-2.83(m,2H),1.75-1.93(m,4H).

[0644] Example 83

[0645] [ka]

[0646] The synthesis method was the same as in Example 65, yielding compound HANT-254 (2.1 mg, white solid, yield: 5%). LCMS(ESI): m / z = 380 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.85(s,1H),7.69-7.61(m,2H),6.94(dt,J=11.8,2.6Hz,1H),4.69(d,J=4.4Hz,1H),4.42( t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),3.01-2.90(m,1H),2.84(s,1H),2.19(t,J=7.8Hz,1H),1.99-1.86(m,3H).

[0647] Example 84

[0648] [ka]

[0649] The synthesis method was the same as in Example 27, yielding HANT-255 (10.4 mg, yield: 26%). LCMS(ESI): m / z = 347.2 [M + H] + . 1 HNMR(400MHz,CD3OD)δ8.43(dd,J=4.8,1.4Hz,1H),8.34(d,J=2.0Hz,1H),7.53(d,J=8.0Hz,1H),7.39(dd,J=8.0,5.0Hz,1H),7.07(s, 1H),4.42(t,J=5.6Hz,2H),4.28(t,J=6.2Hz,1H),3.91(t,J=5.6Hz,2H),2.97(t,J=6.2Hz,2H),2.27-2.08(m,1H),1.96-1.77(m,3H).

[0650] Example 85

[0651] [ka]

[0652] The synthesis method was the same as in Example 42, yielding compound HANT-256 (2.3 mg, white solid, yield: 8%). LCMS(ESI): m / z = 362.0 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.84(d,J=2.6Hz,1H),7.59(d,J=2.2Hz,1H),7.10(s,1H),6.71(t,J=2.2Hz,1H),4.41(t,J=5 .6Hz,2H),4.12(t,J=6.4Hz,1H),3.91(t,J=5.6Hz,2H),2.95(t,J=6.2Hz,2H),2.17-2.02(m,1H),1.96-1.78(m,3H).

[0653] Example 86

[0654] [ka]

[0655] INT-5 (20 mg, 0.07 mmol), 4-bromo-1-methylpyridine-2-one (19 mg, 0.1 mmol), tert-butoxide sodium (20 mg, 0.21 mmol), Pd(OAC)2 (3 mg, 0.015 mmol), and BINAP (17 mg, 0.03 mmol) were added to a flask, dissolved in toluene (10 mL), and refluxed overnight at 110°C under N2 protection. After cooling, the mixture was quenched with NH4Cl(aq), extracted with EA, washed the organic phase with saturated saline, dried over anhydrous sodium carbonate, filtered, concentrated under reduced pressure, and purified the residue by reverse phase preparative fractionation to obtain a yellow solid HANT-261 (5 mg, yield 19%). LCMS(ESI): m / z = 392 [M + H] + ; 1 HNMR(400MHz,CD3OD)δ7.53(s,1H),7.32(d,J=7.6Hz,1H),5.95(dd,J=7.4,2.4Hz,1H),5.63(d,J=2.6Hz,1H),4.66(s,1H),4 .41(t,J=5.6Hz,2H),3.91(t,J=5.6Hz,2H),3.43(s,3H),2.92(dd,J=15.2,9.4Hz,1H),2.88-2.80(m,1H),1.99-1.84(m,4H).

[0656] Example 87

[0657] [ka]

[0658] Compound S2 (25 mg, 0.22 mmol) was added to a dry flask, dissolved in DMF (3 mL), cooled to 0°C, NaH (5 mg, 0.22 mmol) was added, and the mixture was reacted at 0°C for 30 minutes. INT-3 (50 mg, 0.14 mmol) was slowly added dropwise to DMF (1 mL), the mixture was heated to room temperature, and the mixture was reacted overnight with stirring. Extraction was performed with EA (20 mL x 3), the organic phase was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified to obtain a pale yellow solid HANT-262 (7 mg, yield: 13%). LC-MS (ESI): m / z = 387.0 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ8.16(d,J=2.8Hz,1H),7.77(s,1H),7.72(d,J=8.6Hz,1H),7.36(d,J=8.0Hz,1H),7.20-7.13(m, 1H),4.87(s,1H),4.45-4.40(m,2H),4.03-3.99(m,2H),2.90-2.75(m,2H),2.02(d,J=7.2Hz,1H),1.87(d,J=7.0Hz,3H).

[0659] Example 88

[0660] [ka]

[0661] Compound INT-5 (30 mg, 0.105 mmol) and compound S2 (34 mg, 0.157 mmol) were dissolved in toluene (8 mL). Pd2(dba)3 (29 mg, 0.032 mmol), Xant-phos (37 mg, 0.063 mmol), and cesium carbonate (103 mg, 0.316 mmol) were added, and the mixture was reacted overnight at 110°C under nitrogen gas protection. After cooling, the reaction mixture was concentrated to room temperature, extracted with water and EA, the organic phase was dried over anhydrous sodium carbonate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified and fractionated by column chromatography to obtain compound HANT-263 (4.4 mg, white solid, yield: 10%). LCMS(ESI): m / z = 419.0 [M + H] + ;1 HNMR(400MHz,DMSO-d6)δ8.29(q,J=4.8Hz,1H),8.03(d,J=2.8Hz,1H),7.78( d,J=8.6Hz,1H),7.72(s,1H),7.14(dd,J=8.8,2.8Hz,1H),6.81(d,J=8.6Hz, 1H),4.78(d,J=7.4Hz,1H),4.45-4.34(m,2H),3.98(dd,J=5.8,4.4Hz,2H),2 .92-2.81(m,1H),2.77(d,J=4.8Hz,4H),1.84(td,J=12.0,10.6,5.8Hz,4H).

[0662] Example 89

[0663]

change

[0664] The synthesis method was the same as in Example 65, and HANT-264 (5.5 mg, white solid, yield 4.7%) was obtained. LCMS(ESI):m / z=369[M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.26(brs,1H),7.75(d,J=5.4Hz,1H),4.43(td,J=5.6,2.4Hz,2H) ,4.10(dd,J=18.6,11.4Hz,1H),3.91(t,J=5.6Hz,3H),3.81(d,J=11.4Hz,1H),3.48(t,J= 9.2Hz,1H),3.35(dd,J=12.0,6.0Hz,1H),3.07-2.93(m,2H),2.78(d,J=18.8Hz,1H),2.0 9-1.84(m,5H),1.78(s,1H),1.66(dt,J=27.0,16.4Hz,1H),1.54(dd,J=19.4,9.2Hz,1H).

[0665] Example 90

[0666]

change

[0667] The substrates INT-3 (20 mg, 0.07 mmol), 5-aminonicotinonitrile (26 mg, 0.14 mmol), tert-butoxide sodium (21 mg, 0.21 mmol), and tBuBrettphos-Pd-G3 (7 mg, 0.21 mmol) were added to a flask, dissolved with THF (5 mL), and reacted overnight at 60°C under nitrogen gas protection. After cooling, the mixture was quenched with NH4Cl(aq), extracted with EA, the organic phase was washed with saturated saline solution, dried over anhydrous sodium carbonate, filtered, concentrated under reduced pressure, and the residue was purified by reverse phase preparative fractionation to obtain HANT-265 (5.5 mg, white solid yield 20.3%). LCMS(ESI): m / z=387[M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.22(d,J=2.8Hz,1H),8.08(d,J=1.2Hz,1H),7.63(s,1H),7.41(d,J=1.6Hz,1H ),4.73(brs,1H),4.42(t,J=5.6Hz,2H),3.92(t,J=5.6Hz,2H),2.95-2.84(m,2H),1.97-1.88(m,4H).

[0668] Example 91

[0669] [ka]

[0670] The synthesis method was the same as in Example 65, yielding HANT-266 (4 mg, white solid, yield 9.8%). LCMS(ESI): m / z = 392 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.69(d,J=4.0Hz,2H),7.54(d,J=2.4Hz,1H),6.55(t,J=2.0Hz,1H),6.24(d,J=8.8Hz,1H ),5.33(brs,1H),4.71(t,J=8.8Hz,2H),4.41(t,J=4.8Hz,2H),3.96(s,3H),3.10-2.72(m,2H),2.03-1.78(m,4H).

[0671] Example 92

[0672] [ka]

[0673] Compound INT-3 (50 mg, 0.143 mmol) and compound S2 (18 mg, 0.186 mmol) were dissolved in acetonitrile (20 mL), cesium carbonate (140 mg, 0.430 mmol) was added, and the mixture was refluxed for 4 hours. The mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography and fractionated to obtain compound HANT-267 (16.1 mg, white solid, 31% yield). LC-MS (ESI): m / z = 363.0 [M + H] + ; 1 HNMR(400MHz,CDCl3)δ8.32(s,1H),8.24(s,1H),7.51(s,1H),7.23(q,J=3.2,2.8Hz2H),5.32-5.23(m,1H),4. 37(t,J=6.2Hz,2H),3.83(t,J=6.2Hz,2H),2.95(dt,J=19.0,5.8Hz,1H),2.79-2.64(m,1H),2.12-1.82(m,4H).

[0674] Example 93

[0675] [ka]

[0676] Step 1: Synthesis of 5-chloro-7-iodo-6-propoxy-3,4-dihydronaphthalene-1(2H)-one

[0677] S1 (1 g, 3.1 mmol), S2 (370 mg, 6.2 mmol), DBAD (1.05 g, 4.6 mmol), and PPh3 (1.2 g, 4.6 mmol) were sequentially added to a dry flask, dissolved in toluene (15 mL), and stirred at 60°C for 6 hours. After cooling, the mixture was concentrated under reduced pressure, the solvent was removed, the crude product was poured into EA, washed with saturated brine, the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the yellow oily compound H268-1 (270 mg, yield: 25%). LCMS (ESI): m / z = 365.0 [M + H] + .

[0678] Step 2: Synthesis of 4-chloro-8-oxo-3-propoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0679] H268-1 (220 mg, 0.6 mmol) and CuCN (270 mg, 3.0 mmol) were sequentially added to a dry, sealed tube, dissolved in NMP (8 mL), and reacted in the sealed tube at 160°C for 3 hours with stirring. After cooling, the mixture was quenched with aqueous ammonia, the reaction mixture was poured into EA, washed with aqueous ammonium chloride solution, the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid H268-2 (100 mg, yield: 63%). LCMS (ESI): m / z = 264.1 [M + H] + .

[0680] Step 3: Synthesis of 4-chloro-8-hydroxy-3-propoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0681] Compound H268-2 (100 mg, 0.38 mmol) was added to a dry flask, dissolved in MeOH (10 mL), and NaBH4 (58 mg, 3.8 mmol) was added under ice bath. The mixture was reacted at room temperature for 8 hours. The mixture was quenched with water, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid H268-3 (80 mg, yield: 66%). LC-MS (ESI): m / z = 266.0 [M + H] + .

[0682] Step 4: Synthesis of 8-bromo-4-chloro-3-propoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0683] Compound H268-3 (70 mg, 0.26 mmol) was added to a dry flask, dissolved in DMF (8 mL), and PBr3 (350 mg, 1.3 mmol) was added at 0°C. The reaction was carried out with stirring for 8 hours. The mixture was quenched with NH4Cl aqueous solution, the reaction mixture was poured into EA, washed with saturated brine, the organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid H268-4 (50 mg, yield: 51%). LCMS (ESI): m / z = 328.0 [M + H] + .

[0684] Step 5: Synthesis of 4-chloro-3-propoxy-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0685] Compounds H268-4 (40 mg, 0.12 mmol) and S3 (52 mg, 0.24 mmol) were added to a dry flask, dissolved in DMF (5 mL), and DIEA (77 mg, 0.6 mmol) was added. The reaction was allowed to proceed overnight at 60°C. After cooling, the reaction mixture was poured into DIEA, washed with saturated brine, the organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid H268-5 (35 mg, yield: 63%). LC-MS (ESI): m / z = 465.2 [M + H] + .

[0686] Step 6: Synthesis of 8-((1H-indazole-5-yl)amino)-4-chloro-3-propoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0687] Compound H268-5 (35 mg, 0.075 mmol) was added to a dry flask, dissolved in DCM (5 mL), and TFA (2 mL) was added. The reaction was allowed to proceed at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase fractionation to obtain a white solid HANT-268 (7.4 mg, yield: 26%). LC-MS (ESI): m / z = 381.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.63(s,1H),7.78(s,1H),7.71(s,1H),7.31(d,J=8.8Hz,1H),6.91(dd,J=8.9,2.1Hz,1H),6.85(s,1H),5.68(d, J=8.9Hz,1H),4.62(t,J=4.9Hz,1H),4.08(t,J=6.4Hz,2H),2.91-2.85(m,1H),2.78-2.71(m,1H),1.96-1.69(m,6H),1.04(t,J=7.4Hz,3H).

[0688] Example 94

[0689] [ka]

[0690] Step 1: Synthesis of 5-chloro-6-ethoxy-7-iodo-3,4-dihydronaphthalene-1(2H)-one

[0691] Compounds S1 (1 g, 3.1 mmol) and S2 (960 mg, 6.2 mmol) were sequentially added to a dry flask, dissolved in DMF (15 mL), and potassium carbonate (1.3 g, 9.3 mmol) was added. The mixture was stirred at 60°C for 6 hours. After cooling, the reaction mixture was poured into EA, washed three times with saturated brine, and the organic phases were combined. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain a yellow solid H269-1 (370 mg, yield: 34%). LC-MS (ESI): m / z = 351.0 [M + H] + .

[0692] Step 2: Synthesis of 4-chloro-3-ethoxy-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0693] Compounds H269-1 (320 mg, 0.91 mmol) and CuCN (410 mg, 4.6 mmol) were sequentially added to a dry, sealed tube, dissolved in NMP (15 mL), and stirred at 160°C for 5 hours. After cooling, the mixture was quenched with aqueous ammonia, the reaction mixture was poured into EA, washed three times with aqueous ammonium chloride, the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid H269-2 (140 mg, yield: 54%). LC-MS (ESI): m / z = 250.1 [M + H] + .

[0694] Step 3: Synthesis of 4-chloro-3-ethoxy-8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0695] Compound H269-2 (140 mg, 0.56 mmol) was added to a dry flask, dissolved in MeOH (10 mL), and NaBH4 (85 mg, 2.2 mmol) was added under ice bath. The mixture was reacted overnight at room temperature. The mixture was quenched with water, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid H269-3 (110 mg, yield: 78%). LC-MS (ESI): m / z = 251.1 [M + H] + .

[0696] Step 4: Synthesis of 8-bromo-4-chloro-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0697] Adding compound H269-3 (110 mg, 0.44 mmol) to a dry flask, dissolving it in DMF (10 mL), adding PBr3 (590 mg, 2.2 mmol) at 0°C, and stirring at room temperature for 6 hours. Quenching with aqueous NH4Cl solution, pouring the reaction mixture into EA, washing three times with saturated brine, combining the organic phases, drying, concentrating under reduced pressure, and purifying by silica gel column chromatography to obtain a white solid H269-4 (80 mg, yield: 51%). LC-MS (ESI): m / z = 314.0 [M + H] + .

[0698] Step 5: Synthesis of 4-chloro-3-ethoxy-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0699] Compounds H269-4 (70 mg, 0.22 mmol) and S3 (95 mg, 0.44 mmol) were added to a dry flask, dissolved in DMF (5 mL), and DIEA (143 mg, 1.1 mmol) was added. The reaction was allowed to proceed overnight at 60°C. After cooling, the reaction mixture was poured into DIEA, washed with saturated brine, the organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid H269-5 (80 mg, yield: 70%). LC-MS (ESI): m / z = 451.1 [M + H] + .

[0700] Step 6: Synthesis of 8-((1H-indazole-5-yl)amino)-4-chloro-3-ethoxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0701] Compound H269-5 (80 mg, 0.18 mmol) was added to a dry flask, dissolved in DCM (5 mL), and TFA (2 mL) was added. The reaction was allowed to proceed at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by reverse-phase fractionation to obtain a white solid HANT-269 (12.8 mg, yield: 20%). LC-MS (ESI): m / z = 367.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.66(s,1H),7.78(s,1H),7.72(s,1H),7.31(d,J=8.9Hz,1H),6.90(dd,J=8.8,2.0Hz,1H),6.85(s,1H), 5.72-5.69(d,J=8.9Hz,1H),4.64-4.62(m,1H),4.17(q,J=7.0Hz,2H),2.84-2.73(m,2H),2.07-1.83(m,4H),1.39(t,J=7.0Hz,3H).

[0702] Example 95

[0703] [ka]

[0704] The synthesis method was the same as in Example 27, yielding compound HANT-334 (8.5 mg, colorless oil, yield: 33.8%). LCMS: m / z = 393.2 [M + NH3 + H] + ; 1 HNMR(400MHz,CD3OD)δ7.01(s,1H),6.99-6.94(m,2H),6.88-6.82(m,2H),4.38(t,J=5.6Hz,2H),4.06(t,J=6.4Hz,1 H),3.89(t,J=5.6Hz,2H),3.76(s,3H),3.00-2.81(m,2H),2.10-2.01(m,1H),1.97-1.88(m,1H),1.87-1.74(m,2H).

[0705] Example 96

[0706] [ka]

[0707] The synthesis method was the same as in Example 27, yielding HANT-335 (21 mg, white solid, yield 41.8%). LCMS(ESI): m / z = 377 [M + H] + ; 1 HNMR(400MHz,MeOD)δ7.87(d,J=1.8Hz,1H),7.37(dd,J=8.6,2.2Hz,1H),7.05(s,1H),6.76(d,J=8.6Hz,1H),4.40(t,J=5.6Hz,2H),4. 14(t,J=6.2Hz,1H),3.92-3.88(m,5H),2.95(d,J=4.8Hz,2H),2.09(t,J=11.8Hz,1H),1.98-1.90(m,1H),1.84(dd,J=9.8,6.4Hz,2H).

[0708] Example 97

[0709] [ka]

[0710] Step 1: Synthesis of 4-(5,7-dichloro-6-(2-chloroethoxy)-1,2,3,4-tetrahydronaphthalene-1-yl)phenol

[0711] Compound S1 (400 mg, 1.08 mmol) was dissolved in a mixed solution of methanol and THF (4.5 mL, 2:1), platinum dioxide (40 mg, 0.1 eq) was added, and the mixture was reacted under a hydrogen gas atmosphere at room temperature for 2.5 hours. The solution was filtered and concentrated under reduced pressure to obtain the crude product HANT-336 (150 mg, yield: 40.9%). LC-MS: m / z = 371.0 [M + H] + The compounds were separated and purified using the SFC method (mobile phase: Hex-EtOH-95-5-20MIN) to obtain the optically active compounds HANT-336A (36 mg, retention time 8.810 min) and HANT-336B (46.4 mg, retention time 10.433 min).

[0712] HANT-336A: 1 HNMR(400MHz,CDCl3)δ6.93-6.90(m,2H),6.82(s,1H),6.78-6.74(m,2H),4.73(s,1H),4.25(t,J=6.4Hz,2H),3.99-3. 94(m,1H),3.87(t,J=6.4Hz,2H),2.82(td,J=6.1,2.5Hz,2H),2.09-1.99(m,1H),1.94-1.85(m,1H),1.82-1.71(m,2H).

[0713] HANT-336B: 1 HNMR(400MHz,CDCl3)δ6.93-6.89(m,2H),6.82(s,1H),6.79-6.75(m,2H),4.75(s,1H),4.25(t,J=6.4Hz,2H),3.96(t,J= 6.2Hz,1H),3.87(t,J=6.4Hz,2H),2.82(dt,J=6.4,2.9Hz,2H),2.08-1.99(m,1H),1.94-1.85(m,1H),1.82-1.71(m,2H).

[0714] Example 98

[0715] [ka]

[0716] The synthesis method was the same as in Example 42, yielding a white solid compound HANT-948 (46.6 mg, yield: 26.7%) with an RT of 1.32 min (1.80 min). LC-MS (ESI): m / z = 401.0 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ8.56(s,1H),7.52(d,J=7.8Hz,1H),7.38-7.31(m,2H),7.15(s,1H),4.41(t,J=4.8 Hz,2H),4.35-4.32(m,3H),3.97(t,J=4.8Hz,2H),2.96-2.84(m,2H),2.07-2.01(m,1H),1.89-1.76(m,3H).

[0717] Example 99

[0718] [ka]

[0719] The synthesis method was the same as in Example 42, yielding compound HANT-949 (46.3 mg, white solid, yield: 57.9%). LCMS(ESI): m / z = 402.1[M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.60(d,J=8.5Hz,1H),7.49(d,J=8.2Hz,1H),7.43-7.33(m,1H),7.19(s,1H),7.07-7.05(m,1H), 4.66(t,J=6.4Hz,1H),4.40(t,J=4.8Hz,2H),3.98-3.95(m,5H),2.95-2.91(m,2H),2.10-2.05(m,2H),1.94-1.82(m,2H).

[0720] Example 100

[0721] [ka]

[0722] Step 1: tert-butyl 2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

[0723] Compound S1 (5 g, 23.9 mmol) and iodomethane (4.4 g, 31.1 mmol) were dissolved in DMF (30 mL) and cesium carbonate (15.5 g, 47.8 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was recovered and dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to obtain the crude product, which was further purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the white solid compound H950-1 (2 g, yield: 37.7%). LCMS (ESI): m / z = 224.1 [M + H] + RT=1.313min (1.80min).

[0724] Step 2: 2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

[0725] Compound H950-1 (2 g, 8.9 mmol) was dissolved in dioxane (10 mL), and HCl / dioxane (11 mL, 44.5 mmol, 4.0 M) was added. The mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain crude product H950-2 (1 g, yield: 100%), which was directly added to the next reaction. LC-MS (ESI): m / z = 124.1 [M + H] + RT=0.195min(1.80min).

[0726] Step 3: 4-Chloro-3-(2-chloroethoxy)-8-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0727] Compound INT-3 (70 mg, 0.2005 mmol) was dissolved in DMF (5 mL), and H950-2 (49 mg, 0.401 mmol) and DIEA (77 mg, 0.6015 mmol) were added. The mixture was reacted at 90°C for 3 hours. The organic phase was extracted with ethyl acetate, washed with saturated saline solution, dried over sodium sulfate, and purified by preparative separation to obtain compound HANT-950 (6 mg, white solid, yield: 7.3%). LC-MS (ESI): m / z = 391.1 [M + H] + RT=1.11min (1.80min). 1 HNMR(400MHz,DMSO-d6)δ7.87(s,1H),7.35(s,1H),4.50-4.35(m,2H),4.03-3.91(m,3H),3. 78-3.75(m,5H),3.59-3.57(m,2H),2.87-2.69(m,2H),2.10-2.06(m1H),1.86-1.71(m,3H).

[0728] Example 101

[0729] [ka]

[0730] The synthesis method was the same as in Example 51, yielding compound HANT-977 (11.4 mg, white solid, yield: 14.2%). LCMS(ESI): m / z = 415.0 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ11.28(s,1H),7.77(d,J=7.6Hz,1H),7.54-7.52(m,2H),7.18(s,1H),4. 46-4.29(m,3H),3.97(t,J=5.2Hz,2H),3.01-2.78(m,2H),2.08-2.05(m,1H),1.93-1.54(m,3H).

[0731] Example 102

[0732] [ka]

[0733] The synthesis method was the same as in Example 51, yielding compound HANT-978 (12.1 mg, white solid, yield: 13.11%). LCMS(ESI): m / z = 403.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.00(s,1H),7.48(s,1H),7.40(s,1H),7.17(d,J=9.7Hz,1H),6.92(dd,J=9.7,1.5H z,1H),4.40(t,J=4.8Hz,2H),4.18-4.04(m,1H),3.97(t,J=5.2Hz,2H),3.00-2.75(m,2H),2.03-1.65(m,4H).

[0734] Example 103

[0735] [ka]

[0736] Step 1: 5-Bromo-1,3-Dioxo-1H-Benzo[de]Isoquinoline-2(3H)-4-Methylbenzenesulfonate

[0737] Compound S1 (2 g, 7.2 mmol) and hydroxylamine hydrochloride (500 mg, 7.2 mmol) were dissolved in pyridine (15 mL), refluxed at 115°C for 5 hours, cooled to 80°C, TosCl (2.75 g, 14.4 mmol) was added, and refluxed at 115°C for 5 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was stirred until a solid precipitated at room temperature. The mixture was filtered, the resulting filter cake was washed with water, and dried to obtain H979-1 (brown solid), which was used directly in the next reaction. LCMS(ESI): m / z = 446.0 [M + H] + .

[0738] Step 2: tert-butyl 4-bromo-2-oxobenzo[cd]indole-1(2H)-carboxylate

[0739] To a mixture of H979-1 (2g, 4.5 mmol) and ethanol / water (6 mL / 8 mL), an aqueous solution of NaOH (1.34 g, 33.6 mmol) (24 mL) was slowly added dropwise, refluxed at 100°C for 3 hours, cooled to room temperature, concentrated hydrochloric acid (36%, 4 mL) was added, and the mixture was stirred for 1 hour until a solid precipitate formed. The mixture was filtered, the resulting filter cake was washed with water, and dried. The filter cake was dissolved in dichloromethane (30 mL), and Boc2O (2.2 g, 10.1 mmol), TEA (2.04 g, 20.2 mmol), and DMAP (60 mg, 0.5 mmol) were added sequentially, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain the yellow solid compound H979-2 (1.3 g, total yield: 52%). LCMS(ESI): m / z = 292.0[M+H-56] + .

[0740] Step 3: 4-Bromobenze[cd]Indole-2(1H)-On

[0741] Compound H979-2 (1.3 g, 3.7 mmol) was dissolved in dioxane (15 mL), and HCl / dioxane (3.7 mL, 14.8 mmol, 4.0 M) was added. The mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the resulting crude product H979-3 (800 mg, yield: 73%) was directly added to the next reaction. LC-MS (ESI): m / z = 248.0 [M + H] + .

[0742] Step 4: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[cd]indole-2(1H)-one

[0743] Compound H979-3 (330 mg, 1.33 mmol) and (Bpin)2 (675 mg, 2.66 mmol) were dissolved in dioxane (20 mL), and Pd(dppf)Cl2 (97 mg, 0.133 mmol) and potassium acetate (392 mg, 3.99 mmol) were added. The mixture was heated to 90°C and reacted for 3 hours. After filtration, the resulting filtered cake was concentrated under reduced pressure to obtain crude product H979-4 (black oily), which was used directly in the next reaction. LCMS(ESI): m / z = 296.2 [M + H] + .

[0744] Step 5: 4-Chloro-3-(2-chloroethoxy)-8-(2-oxo-1,2-dihydrobenzo[cd]indole-4-yl)-5,6-dihydronaphthalene-2-carbonitrile

[0745] INT-2 (300 mg, 0.721 mmol) and crude product H979-4 (319 mg, 1.08 mmol) were dissolved in a mixed solvent of dioxane (20 mL) and water (4 mL). Sodium carbonate (229 mg, 2.16 mmol) and Pd(dppf)Cl2 (53 mg, 0.0721 mmol) were added to the reaction system, and the mixture was heated to 90°C under a nitrogen atmosphere and reacted for 3 hours. After cooling, water was added to the reaction mixture, and ethyl acetate was added for extraction. The organic phase was backwashed with saturated brine and dried over sodium sulfate. The organic phase was then filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE / EA=1 / 1) to obtain compound H979-5 (120 mg, yellow solid, yield: 36.3%). LCMS(ESI): m / z=435.2[M+H] + .

[0746] Step 6: 4-Chloro-3-(2-chloroethoxy)-8-(2-oxo-1,2-dihydrobenzo[cd]indole-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile

[0747] Compound H979-5 (100 mg, 0.230 mmol) was dissolved in methanol (15 mL), Pd(OH)2 / C (50 mg, 50% wt) was added, and the mixture was reacted overnight under a hydrogen gas atmosphere at atmospheric pressure and room temperature. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative fractionation to obtain compound HANT-979 (8.6 mg, white solid, yield: 8.14%). LC-MS (ESI): m / z = 437.1 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ10.74(s,1H),7.86(s,1H),7.76(s,1H),7.56-7.42(m,2H),7.20(s,1H),6.94(d,J=6.5Hz,1H) ,4.53(t,J=6.6Hz,1H),4.47-4.37(m,2H),4.01-3.93(m,2H),3.05-2.87(m,2H),2.19-2.07(m,1H),2.01-1.72(m,3H).

[0748] Example 104

[0749] [ka]

[0750] The synthesis method was the same as in Example 51, yielding compound HANT-982 (12.8 mg, white solid, yield: 18.61%). LC-MS (ESI): m / z = 429.0 [M + H] + ; 1 HNMR(400MHz,DMSO-d6)δ7.80(d,J=7.7Hz,1H),7.59(s,1H),7.53(dd,J=7.7,1.4Hz,1H),7.15(s,1H),4. 50-4.35(m,3H),4.02-3.92(m,2H),3.02(s,3H),2.98-2.85(m,2H),2.13-2.01(m,1H),1.94-1.68(m,3H).

[0751] Example 105

[0752] [ka]

[0753] The synthesis method was the same as in Example 42, yielding a white solid compound HANT-983 (24.1 mg, yield: 23.9%). LCMS(ESI): m / z = 415.1 [M + H] + RT=1.33min (1.80min). 1 HNMR(400MHz,DMSO-d6)δ7.53(d,J=8.3Hz,1H),7.35-7.32(m,2H),7.11(s,1H),4.43(s,2H),4.41(t,J=4.8Hz,2H), 4.33(t,J=6.0Hz,1H),3.97(t,J=5.2Hz,2H),3.06(s,3H),2.93-2.88(m,2H),2.10-2.01(m,1H),1.87-1.75(m,3H).

[0754] Biological tests:

[0755] Androgen receptor (AR) reporter gene experiment

[0756] Experimental reagents: 11-Ketodihydrotestosterone (11-KDHT) was purchased from MCE (cat.HY-135794), enzalutamide (MDV3100) was purchased from Selleck (cat.S1250), and the Bright-Lite luciferase measurement system kit was purchased from Vazyme (cat.DD1204-01).

[0757] Test method:

[0758] 1. The compound was dissolved in 100% DMSO to a final concentration of 10 mM. Using an Echo, 100 nL each of the 400X experimental compound and 400X 11-KDHT (40 nM) were added to a 384-well assay plate. 20 μL of complete medium was added, the mixture was centrifuged at 1000 rpm for 1 minute, and then shaken at room temperature for 20-30 minutes.

[0759] 2. 20 μL of AR+ARE / Luc HEK293T cells (10,000 cells / well) were inoculated into an assay plate containing the compound and 11-KDHT, and the plate was centrifuged at 1000 rpm for 1 minute. The assay plate was incubated in a 37°C CO2 incubator for 24 hours.

[0760] 3. Transfer 40 μL of Bright-Lite assay reagent to each well of the assay plate, centrifuge at 1000 rpm for 1 minute, shield from light, and shake at room temperature for 2 minutes. The luminescence value (RLU) was measured using Envision. IC of the compound was measured. 50 The values ​​were calculated based on these results.

[0761] [Table 2-1] [Table 2-2] [Table 2-3]

Claims

1. A compound of formula (I), or its stereoisomers, geometric isomers, tautomers, solvates, hydrates, or pharmaceutically acceptable salts, 【Chemistry 1】 Here, n is either 0 or 1, X is N or CH, Y is NR ４ or CHR ４ And, L ０ is a bond, O, S, -NR ５ -, -C(O)-NR ５ -, -NR ５ -C(O)- or -NR ５ -(CH ２ ) ｍ -, and m is 1 or 2, preferably, L ０ is a bond, O, S, -NR ５ -, -NH-C(O)-, -C(O)-NH-, -NR ５ -(CH ２ ) ２ - or -NR ５ -CH ２ -, and more preferably, L ０ is a bond, O, S, -NR ５ -, -NHC(O)- or -C(O)-NH- L １ is a bond, O, S or -NR ５ - and preferably, L １ It is a bond, O or S, R １ , R ２ These are H and C, which are independent of each other. １ -C ６ Alkyl alkyl groups, halogens, halogenated C １ -C ６ alkyl, CN, C １ -C ６ Alkoxy group, -C １ -C ６ Alkyl-NR ６ R ７ and -C(O)-NR ６ R ７ Selected from, preferably R １ , R ２ These are H, halogen, and CF, respectively, independently. ３ , CN, C １ -C ６ alkyl group, C １ -C ６ Alkoxy group, -CH ２ -NH ２ and -C(O)NH-CH ３ Selected from, Here, R ４ , R ５ , R ６ , R ７ These are H and C, which are independent of each other. １ -C ６ Selected from alkyl groups and acyl groups, R ３ C １ -C ６ alkyl group, C ３ -C ８ Cycloalkyl groups, C ６ -C １２ The alkyl group is an aryl group, a 5-12 membered heteroaryl group, or a 4-12 membered heterocycloalkyl group, and each alkyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocycloalkyl group is optionally substituted with one or more halogens or hydroxyl groups, preferably R ３ C is optionally substituted with one or more halogens or hydroxyl groups. １ -C ６ alkyl group, C ３ -C ７ Cycloalkyl groups, C ６ -C １０ An aryl group, a 5-10 membered heteroaryl group, or a 5-7 membered heterocycloalkyl group, more preferably R ３ C is optionally substituted with one or more F, Cl or OH groups. １ -C ６ alkyl group, C ３ -C ７ Cycloalkyl groups, C ６ -C １０ The group is an aryl group, a 5-10 membered heteroaryl group, or a 5-7 membered heterocycloalkyl group. W is C ５ -C ８ a cycloalkyl group, C ６ -C １２ an aryl group, a 5- to 12-member heteroaryl group, or a 4- to 12-member heterocycloalkyl group, which are each optionally halogen, CN, oxo, -NR ７ R ８ , -OR ８ , -C(O)-NHR ８ , R ９ , -OC(O)-NHR ９ , -NHC(O)-R １０ , -SO ２ R ９ , -SO ２ NHR ８ , -NR ７ SO ２ R ９ , -NR ７ SO ２ NR ８ R １０ , a substituted or unsubstituted C ３ -C ８ cycloalkyl group, a 4- to 8-member heterocycloalkyl group, C ６ -C １２ an aryl group and a 5- to 10-member heteroaryl group, which are substituted by one or more substituents selected from, and wherein the C ３ -C ８ cycloalkyl group, a 4- to 8-member heterocycloalkyl group, C ６ -C １２ an aryl group and a 5- to 10-member heteroaryl group are each further optionally one or more halogen, oxo, NH ２ , hydroxy group, C １ -C ４ alkyl group or C １ -C ４ alkoxy group, Here, R ８ C is substituted with H or optionally one or more halogens or hydroxyl groups. １ -C ６ It is an alkyl group, preferably R ８ C is replaced by H or optionally by F or OH. １ -C ６ It is an alkyl group, R ９ This may optionally contain one or more halogens, hydroxyl groups, and NH ２ C is replaced by １ -C ６ It is an alkyl group, R １０ C １ -C ６ Alkyl or C １ -C ６ It is an alkoxy group, Preferably, the heterocycloalkyl group is N, NR ｃ , O and S(O) ｐ It contains one or two heteroatoms selected from and R ｃ These are, independently, hydrogen and C １ -C ４ A compound of formula (I), wherein p is an alkyl group and p is 1 or 2, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

2. W is C ５ -C ８ Cycloalkyl groups, C ６ -C １２ The group is an aryl group, a 5-10 membered heteroaryl group, or a 4-12 membered heterocycloalkyl group, which can be optionally -OH, F, Cl, CN, oxo, or -NH. ２ , C １ -C ６ alkyl group, C １ -C ６ Alkoxy group, halogenated C １ -C ６ Alkyl alkyl groups, halogenated C １ -C ６ Alkoxy group, -(C １ -C ６ Alkyl)OH, -(C １ -C ６ Alkoxy)OH, -NH(C １ -C ３ Alkyl), -NH(C １ -C ４ Alkyl)OH,-NHC(O)(C １ -C ３ Alkyl), -NHC(O)(C １ -C ４ Alkoxy), -OC(O)NH(C １ -C ３ Alkyl), -C(O)NH(C １ -C ３ Alkyl), -O (C １ -C ４ Alkyl)OH, -C(O)NH ２ , -SO ２ NH ２ , -SO ２ (C １ -C ４ Alkyl), -SO ２ (C １ -C ３ Alkyl)NH ２ , -SO ２ NH(C) １ -C ４ Alkyl), -NHSO ２ (C １ -C ４ Alkyl), -N (CH ３ ) SO ２ (C １ -C ３ Alkyl), -NHSO ２ (C １ -C ３ Alkyl)NH ２ , - NHSO ２ CF ３ , and optionally independently one or more halogens, OH, NH ２ , C １ -C ４ Alkyl or C １ -C ４ C substituted with an alkoxy group ３ -C ７ Cycloalkyl groups, 5-8 member heterocycloalkyl groups, C ６ -C １０ The compound according to claim 1, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, characterized by being substituted with one or more substituents selected from an aryl group or a 5- to 10-membered heteroaryl group.

3. W is C ５ -C ８ Cycloalkyl groups, C ６ -C １２ The group is an aryl group, a 5-10 membered heteroaryl group, or a 4-12 membered heterocycloalkyl group, which can be optionally and independently -OH, F, Cl, CN, oxo, or -NH ２ , - NHCH ３ ,-NH(CH ２ ) ２ OH, C １ -C ６ alkyl group, C １ -C ６ Alkoxy group, halogenated C １ -C ６ Alkyl alkyl groups, halogenated C １ -C ６ Alkoxy group, -NHC(O)CH ３ , -NHC(O)OCH ３ , -OC(O)NH-CH ３ , -C(O)NH-CH ３ , -C(O)NH ２ , -O(CH ２ ) ２ OH, -SO ２ NH ２ , -SO ２ (CH ２ ) ２ NH ２ -, -NHSO ２ CH ３ , -N(CH ３ ) SO ２ CH ３ , - NHSO ２ CH ２ CH ３ , - NHSO ２ CH (CH ３ ) ２ , - NHSO ２ CH ２ NH ２ , - NHSO ２ (CH ２ ) ２ NH ２ , - NHSO ２ CF ３ , -SO ２ CH ３ , -SO ２ CH (CH ３ ) ２ , -SO ２ CH ２ CH ３ The compound according to claim 1, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof, characterized by being substituted with one or more substituents selected from cyclopentane, cyclohexane, pyridyl group, phenyl group, morpholinyl group, 1,3-oxazine alkyl group, oxacyclohexane alkyl group, hexahydropyrimidinyl group, piperazinyl group, pyrrole, imidazole, pyrazole, 4-methylpiperazine-1-yl, piperidinyl group and 4-hydroxypiperidine-1-yl.

4. W stands for cyclopentane, cyclohexane, phenyl group, pyrrole, pyrazole, imidazole, thiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazolidine, tetrahydropyran, piperidine, piperazine, hexahydropyrimidine, morpholine, octahydropyrrolo[3,2-b]pyrrole, indole, benzopyran, benzimidazole, benzoxazole, benzotriazole, 4-azaindole, 5-azai Dol, 6-azaindole, 7-azaindole, quinoline, isoquinoline, quinazoline, cinnoline, quinoxaline, naphthyl group, indenyl group, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2,3-dihydrooxazolo[4,5-b]pyridine, isoindoline, indoline, dihydrobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobe Nzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, 2,3-dihydro-1H-indazole, 1,2-dihydroquinoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydronaphthalene, dihydroindene, chroman, isochroman, dihydrobenzofuran, dihydroisobenzofuran, 1,2-dihydro-1,8-naphthyridine, oxazolo[4,5-b]pyridine, pyridine-2(1H)-one, 2-indolone, 2-benzoxazolone, quinoline-2(1H)-one, 1,4-dihydro-3(2H)-soquinolone Linone, 1,3-dihydrobenzimidazole-2-one, 2,3-dihydrochromene-4-one, 5,8-dihydro-6H-[1,6]naphthirizine-7-one, 7,8-dihydro-6H-[1,6]naphthirizine-5-one, 1,8-naphthirizine-2(1H)-one, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine, 2H-chromene, oxazolo[5,4-c]pyridine-2(1H)-one or oxazolo[4,5-b]pyridine-2(3H)-one, which can be optionally and independently halogen, CN, oxo, -NR, ７ R ８ , hydroxyl group, C １ -C ６ alkyl group, C １ -C ６ Alkoxy group, halogenated C １ -C ６ Alkyl alkyl groups, halogenated C １ -C ６ Alkoxy group, hydroxy-C １ -C ６ Alkyl alkyl, hydroxy-C １ -C ６ Alkoxy group, hydroxy-C １ -C ６ Alkyl-NR ８ -, -C(O)-NHR ８ , -OC(O)-NHR ９ , -NHC(O)-R １０ , -SO ２ R ９ , -SO ２ NHR ８ , -NR ７ SO ２ R ９ , -NR ７ SO ２ NHR ８ , C ３ -C ８ Cycloalkyl groups, 4-8 member heterocycloalkyl groups, C ６ -C １２ Substituted with one or more substituents selected from aryl groups and 5- to 10-membered heteroaryl groups, where the C ３ -C ８ Cycloalkyl groups, 4-8 member heterocycloalkyl groups, C ６ -C １２ The aryl group and the 5-10 membered heteroaryl group may each be optionally further varied with one or more halogens, oxos, or NH4. ２ , hydroxyl group, C １ -C ４ Alkyl or C １ -C ４ Substituted with an alkoxy group, Here, R ８ C is substituted with H, and optionally one or more halogens or hydroxyl groups. １ -C ６ It is an alkyl group, R ９ This may optionally contain one or more halogens or NH ２ C is replaced by １ -C ６ It is an alkyl group, R １０ C １ -C ６ Alkyl or C １ -C ６ The compound according to claim 1, characterized by being an alkoxy group, or its stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt.

5. W stands for cyclopentane, cyclohexane, phenyl group, pyrrole, pyrazole, imidazole, thiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazolidine, tetrahydropyran, piperidine, piperazine, hexahydropyrimidine, morpholine, octahydropyrrolo[3,2-b]pyrrole, indole, benzopyran, benzimidazole, benzoxazole, benzotriazole, 4-azaindole, 5-azaindole , 6-azaindole, 7-azaindole, quinoline, isoquinoline, quinazoline, cinnoline, quinoxaline, naphthyl group, indenyl group, imidazole and pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2,3-dihydrooxazolo[4,5-b]pyridine, isoindoline, indoline, dihydrobenzofuran, 2,3-dihydro-1H-benzo[d]imidazole, 2,3 -dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, 2,3-dihydro-1H-indazole, 1,2-dihydroquinoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydronaphthalene, dihydroindene, chroman, isochroman, dihydrobenzofuran, dihydroisobenzofuran, 1,2-dihydro-1,8-naphthyridine, oxazolo[4,5-b]pyridine, pyridine-2(1H)-one, 2-indolone, 2-benzoxazolone, quinoline-2(1H)-one, 1,4-dihydro-3(2H)- Soquinolinone, 1,3-dihydrobenzimidazole-2-one, 2,3-dihydrochromene-4-one, 5,8-dihydro-6H-[1,6]naphthirizine-7-one, 7,8-dihydro-6H-[1,6]naphthirizine-5-one, 1,8-naphthirizine-2(1H)-one, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[4,3-c]pyridine, 3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine, 2H-chromene, oxazolo[5,4-c]pyridine-2(1H)-one or oxazolo[4,5-b]pyridine-2(3H)-one, which can be selected independently as -OH, F, Cl, CN, oxo, -NH, ２ , - NHCH ３ ,-NH(CH ２ ) ２ OH, C １ -C ６ alkyl group, C １ -C ６ Alkoxy group, halogenated C １ -C ６ Alkyl alkyl groups, halogenated C １ -C ６ Alkoxy group, -NHC(O)CH ３ , -NHC(O)OCH ３ , -OC(O)NH-CH ３ , -C(O)NH-CH ３ , -C(O)NH ２ , -O(CH ２ ) ２ OH, -SO ２ NH ２ , -SO ２ (CH ２ ) ２ NH ２ -, -NHSO ２ CH ３ , -N(CH ３ ) SO ２ CH ３ , - NHSO ２ CH ２ CH ３ , - NHSO ２ CH (CH ３ ) ２ , - NHSO ２ CH ２ NH ２ , - NHSO ２ (CH ２ ) ２ NH ２ , - NHSO ２ CF ３ , -SO ２ CH ３ , -SO ２ CH (CH ３ ) ２ , -SO ２ CH ２ CH ３ The compound according to claim 1, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof, characterized by being substituted with one or more substituents selected from cyclopentane, cyclohexane, pyridyl group, phenyl group, morpholinyl group, 1,3-oxazine alkyl group, oxacyclohexane alkyl group, hexahydropyrimidinyl group, piperazinyl group, pyrrole, imidazole, pyrazole, 4-methylpiperazine-1-yl, piperidinyl group and 4-hydroxypiperidine-1-yl.

6. n is either 0 or 1, X is N or CH, Y is NR ４ or CHR ４ And here, R ４ H and C １ -C ６ Selected from alkyl groups, L ０ is bond, O, -NR ５ -, -C(O)-NR ５ -, or -NR ５ -C(O)-, where R ５ is H or C １ -C ６ It is an alkyl group, L １ is a bond or O, R １ , R ２ These are H and C, which are independent of each other. １ -C ６ Alkyl alkyl, halogen, CN, -C １ -C ６ Alkyl-NR ６ R ７ and -C(O)-NR ６ R ７ Selected from, here, R ６ , R ７ These are H and C, respectively, independently. １ -C ６ Selected from alkyl groups, R ３ C １ -C ６ Alkyl or halogenated C １ -C ６ It is an alkyl group, or R ３ The compound according to any one of claims 1 to 5, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof, characterized in that is a 5 or 6-membered heterocycloalkyl group optionally substituted with one or more halogens or hydroxyl groups, for example, a piperazinyl group, 4-methyl-piperazine-1-yl, a piperidinyl group, or 4-hydroxy-piperidine-1-yl, wherein is a stereoisomer, geometric isomer, tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof.

7. The aforementioned compound, Table 1-1 Table 1-2 Table 1-3 Table 1-4 A compound according to claim 1, characterized by being selected from the above, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. A compound according to any one of claims 1 to 7, or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, used in a pharmaceutical.

10. Use of a compound according to any one of claims 1 to 7 or a stereoisomer, geometric isomer, tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof in the preparation of a drug for preventing, treating or alleviating a disorder or disease caused by a patient's androgen receptor.

11. The use according to claim 10, characterized in that the disorder or disease is selected from prostate cancer, other prostate diseases (e.g., benign prostatic hyperplasia, prostatitis, etc.), breast cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and spinal and bulbar muscular atrophy.

12. A method for treating or preventing androgen receptor-mediated diseases or disorders, comprising administering an effective amount of the compound described in any one of claims 1 to 7 or a stereoisomer, geometric isomer, tautomer, solvate, hydrate, or pharmaceutically acceptable salt thereof to a patient in need.

13. A method for treating or preventing an androgen receptor-mediated disorder, comprising administering to a patient in need an effective amount of the compound or any stereoisomer, geometric isomer, tautomer, solvate, hydrate or pharmaceutically acceptable salt thereof described in any one of claims 1 to 7, and one or more other therapeutic agents.

14. The method according to claim 12 or 13, characterized in that the disorder or disease is selected from prostate cancer, other prostate diseases (e.g., benign prostatic hyperplasia, prostatitis, etc.), breast cancer, acne, hirsutism, hidradenitis suppurativa, male pattern baldness, undescended testicles, androgen insensitivity syndrome, and spinal and bulbar muscular atrophy.

15. A combination product or kit for simultaneous, separate, or sequential use in the treatment or prevention of androgen receptor-mediated diseases or disorders, comprising a compound according to any one of claims 1 to 7 or its stereoisomer, geometric isomer, tautomer, solvate, hydrate or pharmaceutically acceptable salt, and one or more other activators, or a pharmaceutical composition containing the activator.

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