KR102607237B1 - New triazole substituted indazole derivatives and use thereof - Google Patents

Abstract

The present invention relates to a novel triazole-substituted indazole derivative and its use. The triazole-substituted indazole derivative has excellent TRIB2 inhibitory activity, YAP inhibitory activity, and in vitro and in vivo activity against cancer cells, It can be usefully used as a pharmaceutical composition for preventing or treating cancer metastasis, anticancer drug-resistant cancer, narcolepsy, and fasciitis.

Description

New triazole substituted indazole derivatives and use thereof}

The present invention relates to novel triazole-substituted indazole derivatives and their uses, and more specifically, to triazole-substituted indazole derivatives having TRIB2 inhibitory activity and YAP inhibitory activity, and cancer and cancer cell metastasis inhibitors containing the same. , relates to a pharmaceutical composition for resistance inhibitors, anticancer drug adjuvants, narcolepsy, or fasciitis for cancers showing anticancer drug resistance.

TRIB2 (tribbles pseudokinases 2) is one of the proteins that assists in molecular binding and is involved in several signaling pathways. In particular, TRIB2 is known to play an important role in cancer formation-related properties in various cancers, and through various in vitro and in vivo experiments and tissue studies of cancer patients, it has been found to be effective in androgen-independent prostate cancer, liver cancer, acute myeloid leukemia (AML), It has been reported to be involved in the proliferation/survival of lung cancer, melanoma, and chemotherapy-resistant cancer (Eyers, P. A. et al., Trends Cell Biol., 27(4), 284-298, 2017; Zhang, H. H. et al. ., Oncol Rep., 31(3), 1473-1479, 2014; Wang, P. Y. et al., FEBS Lett., 587(16), 2675-2681, 2013; Bisoffi, M. et al., J Urol. , 172(3), 1145-1150, 2004; Wang, J. et al., Mol Cell., 51(2), 211-225, 2013; Keeshan, K. at al., Cancer Cell., 10(5) ), 401-411, 2006; Keeshan, K. et al., Blood Cells Mol Dis., 40(1), 119-121, 2008; Hill, R. et al., Carcinogenesis, 36(4), 469- 477, 2015).

YAP (Yes-associated protein 1) is an important factor that mediates Hippo signaling. Hippo signaling is involved in cell proliferation and tissue homeostasis, and is known to control cell proliferation and death through contact inhibition. Abnormalities in this regulatory mechanism It is reported to cause cancer when changes occur, so it is considered an important mechanism in cancer treatment (Hyo-won Jeong et al., Study on the efficacy of metastasis inhibition through inhibition of YAP activity in broiler prostate cancer cells, Kor. J. Herbol., 34(3) ), 55-61, 2019; Sudol, M., Yes-associated protein (YAP65) is a prolinerich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product, Oncogene, 9(8), 2145-2152, 1994 ; Pan, D., The hippo signaling pathway in development and cancer, Dev Cell., 19(4), 491-505, 2010; Zhao, B. et al., Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein, Cancer Res., 69(3), 1089-1098, 2009).

In particular, the Hippo tumor suppressor pathway, a downstream effector of YAP, is known to be associated with liver carcinogenesis along with CREB (cAMP response element-binding protein) (Wang, J. et al., Mutual interaction between YAP and CREB promotes tumorigenesis in liver cancer, Hepatology, 58(3), 1011-1020, 2013).

In addition, it can be seen that the higher the level of expression of the intracellular gene LEPRE1, the more the protein kinase AKT is activated, and this activation of AKT is known to promote cancer cell growth, metastasis, anticancer drug resistance, and all diseases related to cancer recurrence. (https://www.sedaily.com/NewsView/263GAIO14H)

Meanwhile, as a prior literature related to pharmaceutical compositions for preventing or treating cancer, narcolepsy, and fasciitis containing indazole derivatives as active ingredients, Korean Patent No. 10-1796781 and Korean Patent Publication No. 2021-0076876 are new. Sol derivatives, their manufacturing methods, and pharmaceutical compositions containing them as active ingredients for the prevention or treatment of cancer diseases are disclosed, and Korean Patent No. 10-1936851 discloses novel pyrazolopyridine derivatives or indazole derivatives, which are protein kinase inhibitors. has been disclosed.

However, there are no previous reports mentioning the triazole-substituted indazole derivatives of formulas 1 and 2 of the present invention and the TRIB2 inhibitory activity or YAP inhibitory activity of these derivatives and their possible treatment of cancer, narcolepsy, and fasciitis. Moreover, There has been no published literature reporting that inhibiting TRIB2 inhibits the metastatic ability of cancer cells or improves sensitivity to anticancer drugs by overcoming anticancer drug resistance.

Accordingly, in the process of researching indazole derivatives, the present inventors completed the present invention by confirming excellent anticancer effects in in vivo animal experiments along with excellent in vitro inhibitory activity against TRIB2 or YAP, and furthermore, conventional chemical The present invention was completed to develop an effective treatment that can suppress the proliferation/survival of drug-resistant cancer and overcome anticancer drug resistance.

Korean Patent No. 1796781, a novel indazole derivative, its manufacturing method, and a pharmaceutical composition for the prevention or treatment of cancer disease containing it as an active ingredient, registered on November 6, 2017. Korean Patent No. 1936851, novel pyrazolopyridine derivative or indazole derivative, a protein kinase inhibitor, registered on January 3, 2019. Korean Patent Publication No. 2021-0076876, novel indazole derivatives, uses thereof, published on June 24, 2021.

Hyowon Jeong et al., study on the efficacy of metastasis inhibition through inhibition of YAP activity in broiler prostate cancer cells, Kor. J. Herbol., 34(3), 55-61, 2019. Bisoffi, M. et al., Expression profiles of androgen independent bone metastatic prostate cancer cells indicate up-regulation of the putative serine-threonine kinase GS3955, J Urol., 172(3), 1145-1150, 2004. Eyers, P. A. et al., Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease, Trends Cell Biol., 27(4), 284-298, 2017. Hill, R. et al., TRIB2 as a biomarker for diagnosis and progression of melanoma, Carcinogenesis, 36(4), 469-477, 2015. Hill, R, et al. “TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT.” Nature communications, 8, 1-9, 2017. Keeshan, K. at al., Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia, Cancer Cell., 10(5), 401-411, 2006. Keeshan, K. et al., Tribbles homolog 2 (Trib2) and HoxA9 cooperate to accelerate acute myelogenous leukemia, Blood Cells Mol Dis., 40(1), 119-121, 2008. Pan, D., The hippo signaling pathway in development and cancer, Dev Cell., 19(4), 491-505, 2010. Sudol, M., Yes-associated protein (YAP65) is a prolinerich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product, Oncogene, 9(8), 2145-2152, 1994. Wang, J. et al., TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPαfunction, Mol Cell., 51(2), 211-225, 2013. Wang, P. Y. et al., Let-7c inhibits A549 cell proliferation through oncogenic TRIB2 related factors, FEBS Lett., 587(16), 2675-2681, 2013. Zhang, H. H. et al., miR-511 induces the apoptosis of radioresistant lung adenocarcinoma cells by triggering BAX, Oncol Rep., 31(3), 1473-1479, 2014. Zhao, B. et al., Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein, Cancer Res., 69(3), 1089-1098, 2009. https://www.sedaily.com/NewsView/263GAIO14H

The object of the present invention relates to novel triazole-substituted indazole derivatives and their uses, and more specifically, to novel triazole-substituted indazole derivatives having TRIB2 inhibitory activity, YAP inhibitory activity, and AKT inhibitory activity, and the same. The aim is to provide an excellent pharmaceutical composition for preventing or treating cancer, a cancer cell metastasis inhibitor, a resistance inhibitor for cancers showing anticancer drug resistance, an anticancer drug adjuvant, narcolepsy, or fasciitis.

The present invention relates to a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

R ₁ is hydrogen, substituted or unsubstituted C ₄ -C ₁₂ aryl, substituted or unsubstituted C ₄ -C ₁₂ heterocycloalkyl, substituted or unsubstituted C ₄ -C ₁₂ cycloalkyl, substituted or unsubstituted C ₄ -C ₁₂ heteroaryl, substituted or unsubstituted C ₁ -C ₄ alkyl C ₄ -C ₁₂ heterocycloalkyl, or substituted or unsubstituted C ₁ -C ₄ alkyl C ₄ -C ₁₂ heteroaryl. And

wherein the substituted C ₄ -C ₁₂ aryl, C ₄ -C ₁₂ heterocycloalkyl, C ₄ -C ₁₂ cycloalkyl, C ₄ -C ₁₂ heteroaryl, C ₁ -C ₄ alkyl C ₄ -C ₁₂ heterocycloalkyl or C ₁ -C ₄ alkyl C ₄ -C ₁₂ heteroaryl is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, halo C ₁ -C ₄ alkyl, amino, hydroxy, tert-part. Toxycarbonyl, phenyl, CONH ₂ , COCH ₃ , COCF ₃ , substituted or unsubstituted C ₄ -C ₁₂ heterocycloalkyl C ₁ -C ₄ alkyl, substituted or unsubstituted C ₄ -C ₁₂ aryl C ₁ -C ₄ alkyl, , , or is substituted with a substituent selected from the group consisting of,

wherein the substituted C ₄ -C ₁₂ heterocycloalkyl C ₁ -C ₄ alkyl or C ₄ -C ₁₂ aryl C ₁ -C ₄ alkyl is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen or halo. is substituted with a substituent selected from the group consisting of C ₁ -C ₄ alkyl;

The R ₇ is hydrogen, amino, mono (or di) C ₁ -C ₆ alkyl amino, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl ketone, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkyl, or halo C ₁ -C ₆ alkoxy;

R ₂ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, halogen, halo C ₁ -C ₆ alkyl, amino, mono (or di) C ₁ -C ₆ alkyl amino, hydroxy, cyano or tetrahydropyranyl;

R ₃ is substituted or unsubstituted C ₄ -C ₁₂ aryl, substituted or unsubstituted C ₄ -C ₁₂ heteroaryl, substituted or unsubstituted C ₄ -C ₁₂ heterocycloalkyl, substituted or unsubstituted pyridine. selected from the group,

wherein the substituted C ₄ -C ₁₂ aryl, C ₄ -C ₁₂ heteroaryl, C ₄ -C ₁₂ heterocycloalkyl, or pyridine is hydrogen, halogen, hydroxy, amino, di (or mono) C ₁ -C ₆ Alkylamino, cyano, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, halo C ₁ -C ₄ alkylketone, C ₁ -C ₆ alkyloxy, tert -butoxycarbonyl, CONH ₂ , formyl , acetyl, C ₁ -C ₆ alkylketone, C ₁ -C ₆ alkylsulfonyl, amino C ₁ -C ₆ alkyl, C ₄ -C ₆ heterocycloalkyl, C ₄ -C ₆ aryl, C ₁ -C ₆ alkyl. is substituted with a substituent selected from the group consisting of C ₄ -C ₆ heterocycloalkyl or C ₁ -C ₄ alkyl C ₄ -C ₆ aryl;

R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen;

X ₁ , X ₂ , X ₃ are independently N, C, or CH;

m is independently 0 or 1;

n is independently an integer from 0 to 3.

Additionally, the present invention relates to a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

R ₁ is hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted piperidine, substituted or unsubstituted pyridine, substituted or unsubstituted tetrahydroisoquinoline, substituted or unsubstituted pyrazole, or substituted or unsubstituted done It is selected from the group consisting of,

wherein the substituted phenyl, piperidine, pyridine, tetrahydroisoquinoline, pyrazole or hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, halo C ₁ -C ₄ alkyl, amino, hydroxy, tert-butoxycarbonyl, phenyl, CONH ₂ , COCH ₃ , COCF ₃ , substituted or unsubstituted piperidine C ₁ -C ₄ alkyl, substituted or unsubstituted phenyl C ₁ -C ₄ alkyl, , , or is substituted with a substituent selected from the group consisting of,

Here, the substituted piperidine C ₁ -C ₄ alkyl or phenyl C ₁ -C ₄ alkyl is selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen or halo C ₁ -C ₄ alkyl. is substituted with a selected substituent;

R ₂ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, halogen, halo C ₁ -C ₆ alkyl, amino, mono (or di) C ₁ -C ₆ alkyl amino, hydroxy, cyano or tetrahydropyranyl;

R ₃ is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazole, substituted or unsubstituted thiophene, substituted or unsubstituted furan, , , , or It is selected from the group consisting of,

wherein the substituted phenyl, pyridine, pyrimidine, pyrazole, thiophene or furan is hydrogen, halogen, hydroxy, amino, di (or mono) C ₁ -C ₄ alkylamino, cyano, C ₁ -C ₄ alkyl , halo C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkyloxy, tert- butoxycarbonyl, CONH ₂ , formyl, acetyl, C ₁ -C ₄ alkylketone, C is substituted with a substituent selected from the group consisting of ₁ -C ₄ alkylsulfonyl, amino C ₁ -C ₄ alkyl, piperidine, phenyl, or benzyl;

R ₇ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkoxy, cyano, amino, amino C ₁ -C ₄ alkyl or is hydroxy;

R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen;

X ₁ , X ₂ , X ₃ are independently N, C, or CH;

m is independently 0 or 1;

n is independently an integer from 0 to 3.

Additionally, the present invention relates to a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

R ₁ is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, or substituted or unsubstituted tetrahydroisoquinoline,

wherein the substituted phenyl, pyridine, tetrahydroisoquinoline is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, halo C ₁ -C ₄ alkyl, phenyl, amino, hydroxy, tert-part Toxycarbonyl, CONH ₂ , COCH ₃ , COCF ₃ , substituted or unsubstituted piperidine C ₁ -C ₄ alkyl, substituted or unsubstituted phenyl C ₁ -C ₄ alkyl, , , or is substituted with a substituent selected from the group consisting of,

Here, the substituted piperidine C ₁ -C ₄ alkyl or phenyl C ₁ -C ₄ alkyl is selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen or halo C ₁ -C ₄ alkyl. is substituted with a selected substituent;

R ₂ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, halogen, halo C ₁ -C ₆ alkyl, amino, mono (or di) C ₁ -C ₆ alkyl amino, hydroxy, cyano or tetrahydropyranyl;

R ₃ is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrazole,

wherein the substituted pyridine or pyrazole is hydrogen, halogen, hydroxy, amino, di (or mono) C ₁ -C ₄ alkylamino, cyano, C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkyloxy, tert- butoxycarbonyl, CONH ₂ , formyl, acetyl, C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkylsulfonyl, amino C is substituted with a substituent selected from the group consisting of ₁ -C ₄ alkyl, piperidine, phenyl, or benzyl;

Here, R ₇ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkoxy, cyano, amino, amino C ₁ -C ₄ alkyl or hydroxy;

R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen;

X ₁ , X ₂ , X ₃ are independently N, C, or CH;

m is independently 0 or 1;

n is independently an integer from 0 to 3.

Additionally, the present invention relates to a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

R ₁ is substituted or unsubstituted pyridine,

wherein the substituted pyridine is substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, halo C ₁ -C ₄ alkyl, phenyl, amino, hydroxy;

R ₂ is hydrogen or tetrahydropyranyl;

R ₃ is substituted or unsubstituted pyridine,

wherein the substituted pyridine is substituted with hydrogen or halogen;

R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen.

Additionally, the present invention relates to a compound represented by the following formula (2), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 2]

In Formula 2,

R ₂ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, halogen, halo C ₁ -C ₆ alkyl, amino, mono (or di) C ₁ -C ₆ alkyl amino, hydroxy, cyano or tetrahydropyranyl;

R ₃ is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazole, substituted or unsubstituted thiophene, substituted or unsubstituted furan, , , , or It is selected from the group consisting of,

wherein the substituted phenyl, pyridine, pyrimidine, pyrazole, thiophene or furan is hydrogen, halogen, hydroxy, amino, di (or mono) C ₁ -C ₄ alkylamino, cyano, C ₁ -C ₄ alkyl , halo C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkyloxy, tert- butoxycarbonyl, CONH ₂ , formyl, acetyl, C ₁ -C ₄ alkylketone, C is substituted with a substituent selected from the group consisting of ₁ -C ₄ alkylsulfonyl, amino C ₁ -C ₄ alkyl, piperidine, phenyl, or benzyl;

R ₇ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, amino, amino C ₁ -C ₄ alkyl or hydroxy;

R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, or halo C ₁ -C ₆ alkyl;

R ₉ is C ₃ -C ₆ cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthalene, substituted or unsubstituted pyridine,

Here, the substituted phenyl, benzyl, naphthalene, pyridine is hydrogen, hydroxy, nitro, amino, halogen, C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₄ is substituted with a substituent selected from the group consisting of alkoxy;

X is C, CH or N;

m is independently 0 or 1;

n is independently an integer from 0 to 3.

In addition, the present invention provides a cancer, cancer cell metastasis inhibitor, a resistance inhibitor against cancer species showing anticancer drug resistance, comprising the compound represented by Formula 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, It relates to a pharmaceutical composition for preventing or treating anticancer drug adjuvants, narcolepsy, or fasciitis,

The above cancers include lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, prostate cancer, triple negative breast cancer, ovarian cancer, cervical cancer, thyroid cancer, melanoma, anticancer drug-resistant melanoma, blood cancer, colon cancer, non-small cell lung cancer, pancreatic cancer, and skin cancer. , head and neck cancer, small intestine cancer, rectal cancer, endometrial cancer, vaginal cancer, testicular cancer, esophageal cancer, biliary tract cancer, lymph node cancer, gallbladder cancer, endocrine cancer, adrenal cancer, lymphoma, multiple myeloma, thymoma, mesothelioma, kidney cancer, brain cancer, and central nervous system tumor. , characterized in that it is selected from the group consisting of brainstem glioma and pituitary adenoma.

In addition, the present invention relates to a pharmaceutical composition for preventing or treating metastatic cancer, comprising the compound represented by Formula 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention relates to a pharmaceutical composition for suppressing anticancer drug-resistant cancer, comprising the compound represented by Formula 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for suppressing anticancer drug-resistant cancer containing the compound represented by Formula 1 or 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and further includes another anticancer agent for concurrent administration. It relates to a pharmaceutical composition for suppressing anticancer drug-resistant cancer, characterized by:

Examples of other anticancer drugs to treat cancer include cell signaling inhibitors (imatinib, gefitinib, voltezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, and panitumumab), mitotic inhibitors (such as paclitaxel, vincristine, and vinblastine) ), alkylating agents (cisplatin, cyclophosphamide, chromabucil and carmustine, etc.), anti-metabolites (methotrexate and 5-FU, etc.), insertional anticancer drugs (doxorubicin, actinomycin, anthracyclines, bleomycin and mitoma) Isin-C, etc.), topoisomerase inhibitors (irinotecan, topotegan, and teniposide, etc.), immunotherapy drugs (interleukin and interferon, etc.), and anti-hormonal drugs (tamoxifen, raloxifene, etc.). It is not limited thereto, and relates to a pharmaceutical composition for suppressing anticancer drug-resistant cancer, characterized by one or more selected from among these.

Another anticancer agent for treating cancer relates to an anticancer agent selected from the group consisting of Doxorubicin (adriamycin), Paclitaxel, and Cisplatin.

The general preparation method and reaction conditions for the synthesis of the triazole compound of the present invention are as follows.

The triazole compound of the present invention was prepared by the method shown in the triazole preparation schemes A to C below.

[Triazole Preparation Scheme A]

[Triazole Preparation Scheme B]

[Triazole Preparation Scheme C]

Additionally, the general procedure for azide synthesis is as follows.

[Azide manufacturing process A]

Dissolve 200 mg (1 equiv.) of amine in a solution of concentrated sulfuric acid (0.25 mL) and water (1.5 mL), cool to 0°C, and stir while adding dropwise a solution of sodium nitrite (1.2 equiv.) dissolved in water (0.5 ml). do. The reaction solution was stirred at 0°C for 1 hour and then left overnight at room temperature. The reaction mixture is alkalized with saturated NaHCO ₃ solution and extracted with dichloromethane (3 x 20 mL). The extracted dichloromethane layer is washed with water, dried with Na ₂ SO ₄ , and the organic solvent is concentrated under reduced pressure to obtain azide without additional purification before proceeding to the next step.

[Azide manufacturing process B]

Dissolve 200 mg (1 equiv.) of aryl halide compound in DMF (3 mL) and add sodium azide (5 equiv.). The reaction mixture was stirred from room temperature to 80° C. for 16 hours. After completion of the reaction, water was added and extracted with EtOAc. The organic layer is dried over sodium sulfate using water and brine. The organic solvent is concentrated under reduced pressure to obtain azide, which proceeds to the next reaction without additional purification.

[Azide manufacturing process C]

Sodium azide (2 equiv.) dissolved in water is added to the aryl halide compound (1 equiv.), and the mixture is heated and refluxed with stirring for 24 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The aqueous solution layer must be confirmed to be slightly alkaline (pH 8-10). If it is not weakly alkaline, add saturated NaHCO ₃ (aq) to adjust and extract. The organic solvent is concentrated under reduced pressure to obtain azide, which proceeds to the next reaction without additional purification.

To illustrate more specifically the compound of Formula 1 or 2 of the present invention,

5-(2-Fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 75 );

5-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole (Compound 76) ;

3-(5-(2-Fluoropyridin-3-yl)-1H-indazol-3-yl)-5-(pyridin-4-yl)-1,2,4-oxadiazole (Compound 77) ;

5-(1-isopropyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-( Tetrahydro-2H-pyran-2-yl)-1H-indazole (Compound 78);

5-(1-isopropyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Sol (Compound 79);

5-(1-propyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetra Hydro-2H-pyran-2-yl)-1H-indazole (Compound 80);

2,2,2-trifluoro-1-(7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- Indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 81);

2,2,2-trifluoro-1-(7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl )-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one ( Compound 82);

2,2,2-trifluoro-1-(7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (compound 83);

7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2 ,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 84);

7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H -1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 85);

7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H- 1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 86);

2,2,2-trifluoro-1-(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3 -Triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 87);

2,2,2-trifluoro-1-(7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1 ,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 88);

2,2,2-trifluoro-1-(7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1, 2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 89);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline (Compound 90);

7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-Tetrahydroisoquinoline (Compound 91);

7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline (Compound 92);

1-(7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl) -1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 93);

1-(7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 94);

7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline (Compound 95);

2,2,2-trifluoro-1-(7-(4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3 -yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one hydrochloride (Compound 96);

7-(4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-tria Zol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 97);

7-(4-(5-phenyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 98);

7-(4-(5-(3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 99);

7-(4-(5-(2-chloropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 100);

7-(4-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 101);

7-(4-(5-(o-tolyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydro Isoquinoline hydrochloride (Compound 102);

7-(4-(5-(4-ethylphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetra Hydroisoquinoline hydrochloride (Compound 103);

7-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indazol-3-yl)-1H-1,2,3- Triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 104);

7-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 105);

4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Benzonitrile hydrochloride (Compound 106);

7-(4-(5-(3-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 107);

7-(4-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 108);

7-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2 ,3,4-Tetrahydroisoquinoline hydrochloride (Compound 109);

3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Benzonitrile hydrochloride (Compound 110);

7-(4-(5-(4-chloro-3-fluorophenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 111);

(3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5 -yl)phenyl)methanamine dihydrochloride (Compound 112);

4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- I)phenol hydrochloride (Compound 113);

3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Benzaldehyde hydrochloride (Compound 114);

1-(4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-yl)phenyl)ethan-1-one hydrochloride (Compound 115);

7-(4-(5-(3-fluoro-5-isopropoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-tetrahydroisoquinoline hydrochloride (Compound 116);

1-(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3 ,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 117);

(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (Compound 118);

(4-chlorophenyl)(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazole-1- 1)-3,4-dihydroisoquinoline-2(1H)-yl)methanone (Compound 119);

(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(4-methoxyphenyl)methanone (Compound 120);

(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(p-tolyl)methanone (Compound 121);

(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(pyridin-4-yl)methanone hydrochloride (Compound 122);

(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(pyridin-3-yl)methanone hydrochloride (Compound 123);

2-benzyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-Tetrahydroisoquinoline (Compound 124);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2-(4 -Methylbenzyl)-1,2,3,4-tetrahydroisoquinoline (Compound 125);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-phenyl- 3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 126);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(o -Tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 127);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(naphthalene -1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 128);

N-cyclopentyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl) -3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 129);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(4 -Methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 130);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(4 -(Trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 131);

7-(4-(5-(furan-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 132);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 133);

7-(4-(5-(4-(methylsulfonyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 134);

7-(4-(5-(6-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 135);

6-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 136);

7-(4-(5-(benzofuran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4 -Tetrahydroisoquinoline hydrochloride (Compound 137);

7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 138);

7-(4-(5-(benzo[b]thiophen-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2 ,3,4-Tetrahydroisoquinoline hydrochloride (Compound 139);

7-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 140);

7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2-(p Peridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (Compound 141);

2-(3-chloro-4-methylbenzyl)-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3 -Triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 142);

7-(4-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4 -Tetrahydroisoquinoline hydrochloride (Compound 143);

1-(5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-yl)thiophen-2-yl)ethan-1-one hydrochloride (Compound 144);

5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) pyridin-2-amine hydrochloride (Compound 145);

7-((4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1 , 2,3,4-tetrahydroisoquinoline hydrochloride (Compound 146);

1-methyl-7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline hydrochloride (Compound 147);

1-methyl-7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline hydrochloride (Compound 148);

3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-5,6, 7,8-Tetrahydro-1,7-naphthyridine hydrochloride (Compound 149);

6-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 150);

6-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 151);

5-(2-Fluoropyridin-3-yl)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 152 );

3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole (Compound 153 );

5-(2-fluoropyridin-3-yl)-3-(1-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 154);

5-(2-fluoropyridin-3-yl)-3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole hydro Chloride (Compound 155);

5-(2-fluoropyridin-3-yl)-3-(1-(2-methoxypyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Sol (Compound 156);

5-(2-fluoropyridin-3-yl)-3-(1-(6-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Sol (Compound 157);

3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)pyridin-2-ol (Compound 158);

3-(1-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)- 1H-indazole (Compound 159);

5-(2-fluoropyridin-3-yl)-3-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 160);

5-(2-Fluoropyridin-3-yl)-3-(1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 161);

3-(1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole (Compound 162);

7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline hydrochloride (Compound 163);

5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Picolinonitrile hydrochloride (Compound 164);

N,N-dimethyl-5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazole-4- 1)-1H-indazol-5-yl)pyridin-2-amine hydrochloride (Compound 165);

7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 -Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 166);

5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Zol-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one hydrochloride (Compound 167);

3-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Zol-5-yl)quinoline hydrochloride (Compound 168);

5-(2-fluoropyridin-3-yl)-3-(1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,3-triazol-4-yl)- 1H-indazole (Compound 169);

7-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 170);

3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)- 1H-indazole (Compound 171);

3-(1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole (Compound 172);

5-(2-Fluoropyridin-3-yl)-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 173 );

5-(2-Fluoropyridin-3-yl)-3-(1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 174 );

3-(1-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl) -1H-indazole (Compound 175);

5-(2-fluoropyridin-3-yl)-3-(1-(6-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 176);

5-(2-fluoropyridin-3-yl)-3-(1-(5-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 177);

6-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 178); and

4-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 179); is selected from the group consisting of.

Additionally, the following terms in the present invention have the following meanings unless otherwise indicated. Any undefined terms have meanings understood in the art.

The term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

The term “alkyl” refers to a straight-chain or branched-chain hydrocarbon group with a single bond. Examples include methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, and 1-methylpropyl.

The terms “cycle” and “ring” refer to a substituted or aromatic group that may or may not be substituted and/or may or may not contain heteroatoms and may be a monocycle, bicycle, polycycle, or spirocycle. It refers to a flag.

The term “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic single bond saturated hydrocarbon group consisting of carbon and hydrogen atoms alone, which may include fused or bridged ring systems. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

The term "heterocycloalkyl" refers to a cyclic, single-bonded saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S. Unless specifically stated otherwise in the specification, the heterocyclyl radical is It may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms, aziridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroisoquinolyl. Including, but not limited to, Neal, etc.

The term “aryl” refers to an aromatic substituent having at least one ring with a shared pi electron system, and examples include, but are not limited to, phenyl, benzyl, naphthalene, etc.

The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic ring compound containing one or more heteroatoms such as N, O, or S, and the number and type of heteroatoms contained in the ring, and pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyranyl, pyrazolyl, thiophenyl, benzofuranyl, benzothiophenyl, quinolinyl, etc., depending on the number of carbon atoms, but is not limited thereto.

Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.

In the present invention, the pharmaceutically acceptable salt refers to a salt or complex of Formula 1 or 2 that possesses desirable biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid. , benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylic acid. Boxylates (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate) and diphenylacetate). The compound of Formula 1 or 2 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving a derivative of Formula 1 or 2 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying the precipitate, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts. Additionally, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The pharmaceutical composition according to the present invention can be formulated in a suitable form with a commonly used pharmaceutically acceptable carrier. “Pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not typically cause allergic or similar reactions such as gastrointestinal upset, dizziness, etc. when administered to humans. In addition, the composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods.

Carriers, excipients, and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, and methyl. It may include, but is not limited to, cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, syrups, etc. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerol, gelatin, etc. can be used. In order to formulate a formulation for parenteral administration, the indazole derivative compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof is sterilized or added with auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts or buffers for osmotic pressure adjustment. , and other therapeutically useful substances can be mixed with water to prepare a solution or suspension, which can be prepared in ampoule or vial unit dosage form.

The pharmaceutical composition containing the compound of Formula 1 or 2 disclosed in the present invention as an active ingredient can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, for example, oral, rectal or by intravenous, intramuscular, subcutaneous, intrathecal or intracerebrovascular injection. The dosage is determined by the age, gender, and weight of the subject to be treated, the specific disease or pathological state to be treated, the severity of the disease or pathological state, administration time, route of administration, absorption, distribution and excretion rate of the drug, types of other drugs used, and the prescriber's It will vary depending on judgment, etc. Dosage determinations based on these factors are within the level of one skilled in the art, and dosages generally range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response regulators for the prevention or treatment of cancer, narcolepsy, and fasciitis.

The present invention relates to novel triazole-substituted indazole derivatives and their uses. The triazole-substituted indazole derivatives have excellent TRIB2, YAP, and AKT inhibitory activities and excellent physiological activity in vivo, preventing cancer and cancer metastasis. , It can be usefully used as a pharmaceutical composition for the prevention or treatment of narcolepsy and fasciitis, including anticancer drug-resistant cancer.

Figure 1 confirms that compounds 75 and 90 of the present invention induce a time-dependent decrease in phosphorylation of TRIB2, YAP, and AKT proteins in breast cancer cells (MDA-MB-231).
Figure 2 shows that compounds 75 and 90 according to the present invention inhibit the survival rate in breast cancer cells (MDA-MB-231) using a clonogenic assay.
Figure 3 confirms the inhibitory activity of compound No. 75 of the present invention in suppressing migration, a characteristic of cancer cells, in a concentration-dependent manner in MDA-MB-231 cancer cells.
Figure 4 confirms that compound No. 75 of the present invention reduces the invasion ability of MDA-MB-231 cancer cells in a concentration-dependent manner.
Figure 5 confirms the results showing that the compounds of the present invention inhibit cell proliferation not only in blood cancer (K562) but also in anticancer drug (doxorubicin)-resistant blood cancer (K562/ADM) cell lines.
Figure 6 confirms that compound No. 90 according to the present invention exhibits an anticancer effect without affecting body weight and organs in the mouse xenograft model of a breast cancer cell line (MDA-MB-231).

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the content introduced herein is provided to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.

<Example 1. Synthesis of novel triazole-substituted indazole derivatives and confirmation of physicochemical properties>

The synthesis process and physicochemical properties of compounds 75 to 179 of the present invention are as follows.

Compound 75. 5-(2-Fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

[Scheme 75]

1) 4-azidopyridine synthesis

4-chloropyridine hydrochloride (500 mg, 3.33 mmol) was added to a solution of NaN ₃ (433 mg, 6.67 mmol) dissolved in water (10 ml), and the mixture was refluxed for 24 h while stirring. The reaction mixture is cooled to room temperature and extracted with EtOAc. sat the water layer. The pH was adjusted to slightly alkaline (pH 8-10) with NaHCO ₃ (aq), then extracted, and the extracted organic layer was dried using Na ₂ SO ₄ and concentrated under reduced pressure to obtain compound 75-1 (4-azidopyridine; 260 mg, 2.17 mmol). , 66% yield) is obtained as a yellow liquid.

^1H NMR (300 MHz, Chloroform- d ) δ 8.55 (d, J = 6.3 Hz, 2H), 6.97 (d, J = 6.3 Hz, 2H).

2) Synthesis of 5-bromo-3-iodo-1H-indazole

Add KOH (5.70 g, 102 mmol) and I ₂ (19.3 g, 76.2 mmol) to 5-bromo-1H-indazole (5.00 g, 25.4 mmol) dissolved in DMF (20 mL). The reaction mixture was stirred at room temperature at 35°C for 1 h. The reaction mixture is quenched with water to form a precipitate. The precipitate is filtered, washed with water and reduced pressure. The solid is filtered and compound 75-2 (7.20 g, 22.3 mmol, 88%) is obtained as a white solid.

^1H NMR (400 MHz, DMSO- d6 ) δ 7.61 (s, 1H), 7.55 (s, 2H) _.

3) Synthesis of 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Compound 75-2 (1.00 g, 3.10 mmol) was added to anhydrous THF solution. Add DHP (651 mg, 7.74 mmol) and TsOH monohydrate (118 mg, 0.620 mmol) at room temperature and leave at 60°C overnight. Completion of the reaction was confirmed by TLC. The solvent was removed by concentration under reduced pressure, washed with water, extracted with chloroform and hexane, and concentrated under reduced pressure to obtain compound 75-3 as a brown solid, which was used in the next reaction without purification.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 7.74 (d, J = 9.4 Hz, 1H), 7.66-7.42 (m, 2H), 5.85 (dd, J = 9.7, 2.4 Hz, 1H), 3.92- 3.81 (m, 1H), 3.79-3.66 (m, 2H), 2.40-2.26 (m, 1H), 1.98 (s, 1H), 1.82-1.54 (m, 3H).

4) Synthesis of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole

Compound 75-3 (1.26 g, 3.10 mmol), ethynyltrimethylsilane (457 mg, 4.65 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (43.5 mg, 0.0620 mmol), CuI (23.6 mg, 0.124 mmol) in THF (15 mL) ) and DIPEA (801 mg, 6.20 mmol) to make a mixture. The reaction mixture was stirred at room temperature and stirred at 50° C. for 13 h. The reaction mixture was extracted with EA (2 The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (10% EA/HEX) to obtain compound 75-4 (900 g, 2.38 mmol, 77%) as a yellow oil.

^1H NMR (300 MHz, DMSO- d6 ) δ 7.88 (d, J = 1.4 Hz, 1H), 7.81 (dd, J = 8.9, _0.6 Hz, 1H), 7.63 (dd, J = 8.9, 1.8 Hz, 1H), 5.91 (dd, J = 9.3, 2.5 Hz, 1H), 3.93-3.81 (m, 1H), 3.79-3.57 (m, 1H), 2.41-2.20 (m, 1H), 2.12-1.93 (m, 2H), 1.83-1.66 (m, 1H), 1.65-1.51 (m, 2H), 0.30 (s, 9H).

5) 5-bromo-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole synthesis

Compound 75-1 (4- _{azidopyridine} ; 57.3 mg, 0.477 mmol), sodium ascorbate (31.5 mg, 0.159 mmol), CuSO ₄ (12.69 mg, 0.080 mmol) are added. The reaction mixture was stirred at 70°C and left overnight. After completion of the reaction, the mixture was washed with water, extracted with EA (20 ml x 3), and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure and purified by flash chromatography on silica (10% MeOH/DCM) to obtain compound 75-5 (87 mg, 0.205 mmol, 51.5 % yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 9.64 (s, 1H), 8.90-8.80 (m, 2H), _8.56 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 5.8 Hz, 2H), 7.86 (d, J = 8.9 Hz, 1H), 7.67 (dd, J = 8.9, 1.8 Hz, 1H), 5.99 (dd, J = 9.7, 2.3 Hz, 1H), 4.02-3.91 (m, 1H) ), 3.85-3.62 (m, 1H), 2.70-2.52 (m, 1H), 2.23-1.95 (m, 2H), 1.93-1.71 (m, 1H), 1.70-1.52 (m, 2H).

6) 5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran -2-yl)-1H-indazole synthesis

Na ₂ CO ₃ (31.2 mg, 0.294 mmol) aqueous solution and compound 75-5 (50 mg, 0.118 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (16.50 mg, 0.024 mmol) and (2-fluoropyridin-3-yl) The mixture of boronic acid (19.88 mg, 0.141 mmol) and dioxane suspension was purged with nitrogen for 5 minutes. The reaction mixture is irradiated in a microwave at 120°C for 40 minutes. The reaction mixture was filtered through dioxane, concentrated under reduced pressure, and then purified by MPLC (solvent used: MeOH/DCM) to obtain compound 75-6 (26 mg, 0.059 mmol, 50.1% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 9.64 (s, 1H) _, 8.85 (d, J = 5.4 Hz, 2H), 8.59 (s, 1H), 8.29 (d, J = 4.9 Hz, 1H), 8.27 -8.20 (m, 1H), 8.18 (d, J = 6.4 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H), 7.82-7.72 (m, 1H), 7.59-7.46 (m, 1H), 6.09-6.00 (m, 1H), 4.05-3.91 (m, 1H), 3.87-3.76 (m, 1H), 2.63-2.57 (m, 1H), 2.19-2.02 (m, 2H), 1.90-1.76 (m , 1H), 1.71-1.57 (m, 2H).

7) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

A solution of compound 75-6 (24 mg, 0.054 mmol) dissolved in DCM (1 mL) is added to 4 N HCl/dioxane (0.5 mL, exces amount). The reaction mixture was stirred at room temperature and stirred at 30°C for 13 h. After completion of the reaction, the mixture is concentrated under reduced pressure and washed with ether to obtain compound 75 (18 mg, 0.050 mmol, 93% yield).

LC/MS 356.32 [M-H]

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.78 (s, 1H), 9.11-9.04 (m, 2H), 8.58 (s, 1H), 8.56-8.51 (m, 2H), 8.29 (d, J = 4.6 Hz, 1H), 8.24 (t, J = 9.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.57-7.49 (m, 1H) ).

Compound 76. 5-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole

[Scheme 76]

1) Synthesis of (Z)-N'-hydroxyisonicotinimidamide

Add isonicotinotrile (500 mg, 4.80 mmol) and NH ₂ OH-HCl (500 mg, 7.20 mmol) to distilled water (20 ml), and finally add Na ₂ CO ₃ (770 mg, 7.20 mmol). When the reaction solution is stirred for 2 h, amido oxime is formed. After the reaction is completed, the reaction product is extracted four times with EA (25 mL), dried over Na ₂ SO ₄ , and the organic layer is concentrated under reduced pressure to obtain compound 76-1 (427 mg). , 3.11 mmol, 65%) is obtained as a white solid.

^1H NMR (300 MHz, DMSO- d6 ) δ 10.05 (s, 1H), 8.57 (d, J = 6.2 Hz, 2H), _7.64 (d, J = 6.2 Hz, 2H), 6.02 (s, 2H) .

2) Synthesis of (Z)-N'-((5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonyl)oxy)isonicotinimidamide

A suspension of compound 76-2 (200 mg, 0.615 mmol) in THF (3 mL) was added to DIPEA (239 mg, 1.85 mmol) and HBTU (92.8 mg, 0.677 mmol), and compound 76-1 (199 mg, 1.62 mmol) was added. After addition, the reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was confirmed by the disappearance of the starting material through TLC analysis. The reaction mixture was extracted with EtOAc (20 mL), washed with water, and the organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then recrystallized in EA/Hex to obtain compound 76-3 (254 mg 0.572 mmol, 93%) as a white solid.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.74 (d, J = 4.2 Hz, 2H), 8.25 (dd, J = 1.9, 0.6 Hz, 1H), 7.92 (dd, J = 8.9, 0.7 Hz, 1H), 7.83-7.75 (m, 2H), 7.69 (dd, J = 8.9, 1.9 Hz, 1H), 7.19 (s, 2H), 6.05 (dd, J = 9.5, 2.4 Hz, 1H), 3.97-3.87 (m, 1H), 3.85-3.76 (m, 1H), 2.47-2.33 (m, 1H), 2.18-2.02 (m, 2H), 1.77 (m, J = 11.0, 8.9 Hz, 1H), 1.64 (m) , J = 8.9, 8.2, 4.2 Hz, 2H).

3) Synthesis of 5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole

Compound 76-3 (100 mg, 0.225 mmol) was dissolved in dioxane (4 mL), heated to 110°C, and left overnight to complete the reaction. The solvent is removed and concentrated under reduced pressure to obtain compound 76-4 (60 mg, 0.141 mmol, 62%) as a white solid.

^1H NMR (300 MHz, DMSO- d6 ) δ 8.88 (d, J = 5.5 Hz, 2H), 8.51 (d, J = 1.8 Hz, _1H ), 8.21-8.09 (m, 2H), 8.01 (d, J = 9.0 Hz, 1H), 7.79 (dd, J = 9.0, 1.9 Hz, 1H), 6.14 (dd, J = 9.4, 2.4 Hz, 1H), 3.98-3.89 (m, 1H), 3.88-3.75 (m , 1H), 2.47-2.36 (m, 1H), 2.18-1.96 (m, 2H), 1.87-1.74 (m, 1H), 1.69-1.58 (m, 2H).

4) 5-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3-(pyridin-4-yl)- 1,2,4-oxadiazole synthesis

An aqueous solution of sodium carbonate (31.6 mg, 0.293 mmol) was added to a dioxane suspension of compound 76-4 (50 mg, 0.117 mmol) and (2-fluoropyridin-3-yl)boronic acid (20.0mg, 0.141 mmol) and incubated under nitrogen for 15 minutes. Purge. Add palladium catalyst (8.2 mg, 0.0117 mmol) to the reaction mixture and purge again with nitrogen for 15 minutes. The reaction mixture is irradiated with a microwave at 110°C for 20 minutes. The mixed solution is purified using silica gel column (solvent 10% MeOH/MC) to obtain compound 76-5 (33 mg, 0.0746 mmol, 64%) as a white solid.

5) Synthesis of 5-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole

A solution of compound 76-5 (10.0 mg, 0.0212 mmol) in DCM (1.0 mL) was added to 4 N HCl/dioxane (0.50 ml, exces). The reaction solution was stirred overnight at 30°C. The solvent is concentrated under reduced pressure, MC is added and filtered, and then compound 76 (5.9 mg, 0.0165 mmol, 73%) is obtained as a white solid.

^1H NMR (400 MHz, DMSO- d ₆ ) δ 14.58 (s, 1H), 8.95 (td, J = 4.6, 4.1, 1.5 Hz, 2H), 8.54 (q, J = 1.3 Hz, 1H), 8.35- 8.22 (m, 4H), 7.93 (dd, J = 8.7, 0.8 Hz, 1H), 7.80 (dt, J = 8.6, 1.6 Hz, 1H), 7.56 (ddd, J = 7.0, 4.8, 1.9 Hz, 1H) .

Compound 77. 3-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-5-(pyridin-4-yl)-1,2,4-oxadiazole

[Scheme 77]

1) Synthesis of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbonitrile

Add DHP (474 mg, 5.62 mmol) and TsOH monohydrate (85.6 mg, 0.450 mmol) to an anhydrous THF solution of 5-bromo-1H-indazole-3-carbonitrile (500 mg, 2.25 mmol) at room temperature and incubate overnight at 60°C. Stir. The remaining solvent is removed by concentration under reduced pressure, the mixture is washed with water, and extracted with chloroform and hexane to obtain compound 77-1, which is used in the next reaction without purification.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 8.20 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.76 (dd, J = 9.0, 1.8 Hz, 1H) , 6.08 (dd, J = 9.1, 2.5 Hz, 1H), 3.94-3.70 (m, 2H), 2.43-2.21 (m, 1H), 2.09-1.97 (m, 2H), 1.88-1.69 (m, 1H) , 1.68-1.53 (m, 2H).

2) Synthesis of (Z)-5-bromo-N'-hydroxy-1H-indazole-3-carboximidamide

NH ₂ OH-HCl (235 mg, 3.38 mmol) and Na ₂ CO ₃ (358 mg, 3.38 mmol) were added to a solution of compound 77-1 (689 mg, 2.25 mmol) in MeOH (25 mL). The reactant was refluxed and stirred for 6 h to form amido oxime. After 6 h, the reaction was concentrated under reduced pressure, DCM was added, the formed solid was filtered, and then triturated with CHCl ₃ and hexane to obtain compound 77-2 (648 mg, 1.91 mmol, 85%) as a brown solid. (two step(step 1.~step 2.) yield 85%)

^1H NMR (300 MHz, DMSO- d6 ) δ 9.97 (s, 1H), 8.30 (dd, J = 1.9, 0.6 Hz _, 1H), 7.76 (dd, J = 9.0, 0.7 Hz, 1H), 7.58 ( dd, J = 8.9, 1.9 Hz, 1H), 5.89 (dd, J = 9.6, 2.4 Hz, 1H), 5.72 (s, 2H), 3.95-3.84 (m, 1H), 3.81-3.69 (m, 1H) , 2.47-2.34 (m, 1H), 2.12-1.92 (m, 2H), 1.85-1.68 (m, 1H), 1.63-1.53 (m, 2H).

3) Synthesis of (Z)-5-bromo-N'-(isonicotinoyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboximidamide

Add DIPEA (0.571 mg, 4.41 mmol) and HATU (668 mg, 1.76 mmol) to a suspension of compound 77-2 (500 mg, 1.47 mmol) in THF (10 mL) at room temperature and stir for 15 minutes. Isonicotinic acid (199 mg, 1.62 mmol) was added to the reaction mixture and stirred overnight at room temperature. The reaction mixture was concentrated, extracted with EtOAc (20 mL), and the organic layer was washed with water. The organic layer was concentrated under reduced pressure, and the concentrate was purified by column chromatography (MeOH/MC 7% separation solvent) to obtain compound 77-3 (527 mg, 1.19 mmol, 81%) as a white solid.

^1H NMR (300 MHz, DMSO- d6 ) δ 8.85 (d, J = 5.3 Hz, 2H), _8.45 (d, J = 1.9 Hz, 1H), 8.23-8.09 (m, 2H), 7.85 (d, J = 9.0 Hz, 1H), 7.66 (dd, J = 8.9, 1.9 Hz, 1H), 7.21 (s, 2H), 5.98 (dd, J = 9.7, 2.4 Hz, 1H), 3.99-3.88 (m, 1H) ), 3.84-3.73 (m, 1H), 2.49-2.44 (m, 1H), 2.11-1.98 (m, 2H), 1.88-1.70 (m, 1H), 1.66-1.56 (m, 2H).

4) Synthesis of 3-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-(pyridin-4-yl)-1,2,4-oxadiazole

A solution of compound 77-3 (500 mg, 1.12 mmol) in dioxane (10 mL) is reacted by heating at 110°C overnight. The solvent is removed by concentrating under reduced pressure to obtain compound 77-4 (246 mg, 0.577 mmol, 52%) as a white solid.

^1H NMR (300 MHz, DMSO- d6 ) δ 9.02-8.86 (m, 2H), 8.41 (dd, J ₌ 1.9, 0.7 Hz, 1H), 8.24-8.12 (m, 2H), 7.96 (dd, J) = 9.0, 0.7 Hz, 1H), 7.75 (dd, J = 9.0, 1.9 Hz, 1H), 6.09 (d, J = 8.8 Hz, 1H), 4.02-3.89 (m, 1H), 3.87-3.71 (m, 1H), 2.48-2.37 (m, 1H), 2.14-2.03 (m, 2H), 1.87-1.73 (m, 1H), 1.70-1.57 (m, 2H).

5) 3-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-(pyridin-4-yl)- 1,2,4-oxadiazole synthesis

Na ₂ CO ₃ (31.1 mg, 0.293 mmol) aqueous solution was mixed with compound 77-4 (50.0 mg, 0.117 mmol), palladium catalyst (8.21 mg, 0.0117 mmol) and (2-fluoropyridin-3-yl)boronic acid (20.0 mg, 0.141 mmol) of dioxane suspension and purged with nitrogen for 15 minutes. The reaction mixture is irradiated with a microwave at 110°C for 20 minutes. The crude mixture obtained by filtering the reaction mixture and concentrating the filtrate under reduced pressure was purified by column chromatography (MeOH/MC 10% solvent) to obtain 29.7 mg (mixture) of compound 77-5.

^1H NMR (300 MHz, DMSO- d6 ) δ 8.95 (d, J = 5.0 Hz, 2H), _8.47 (s, 1H), 8.34-8.29 (m, 1H), 8.25 (ddd, J = 10.4, 7.5 , 1.9 Hz, 1H), 8.21-8.15 (m, 2H), 8.09 (dd, J = 8.9, 0.8 Hz, 1H), 7.84 (dt, J = 8.8, 1.7 Hz, 1H), 6.14 (d, 1H) , 4.04-3.91 (m, 1H), 3.90-3.76 (m, 1H), 2.49-2.36 (m, 1H), 2.18-2.05 (m, 2H), 1.92-1.75 (m, 1H), 1.70-1.58 ( m, 2H).

*7.52~7.67 region is impurity

6) Synthesis of 3-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-5-(pyridin-4-yl)-1,2,4-oxadiazole

A solution of compound 77-5 (25 mg, 0.0565 mmol) in DCM (2.0 mL) was added to 4 N HCl/dioxane (1.0 ml, exces). The reaction is carried out overnight at 30°C. Concentrate the reaction mixture under reduced pressure and add DCM. The mixture is filtered to obtain compound 77 (8.6 mg, 0.0240 mmol, 42%) as a yellow solid.

(two step(step 5.~step 6.) yield 21%)

^1H NMR (300 MHz, DMSO- d6 ) δ 14.19 (s, 1H) _, 8.98 (d, J = 5.1 Hz, 2H), 8.50-8.43 (m, 1H), 8.33-8.17 (m, 4H), 7.87 (dd, J = 8.7, 0.9 Hz, 1H), 7.76 (dt, J = 8.8, 1.7 Hz, 1H), 7.54 (ddd, J = 7.2, 4.8, 1.9 Hz, 1H).

Compound 78. 5-(1-isopropyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[Scheme 78]

Na ₂ CO ₃ (18.7 mg, 0.176 mmol) aqueous solution was mixed with compound 78-1 (30.0 mg, 0.0705 mmol), Palladium catalyst (4.95 mg, 0.00705 mmol), 1-isopropyl-4-(4,4,5,5- Add tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0 mg, 0.0846 mmol) to a dioxane suspension and purge with nitrogen for 5 min. The reaction mixture is irradiated with a microwave at 120 °C for 20 mintues. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and purified by chromatography (solvent DCM/MeOH 7%) to obtain Compound 78 (9.31 mg, 0.0204 mmol, 29%) as a white solid.

LC/MS 455.3[M + H] ⁺

^1H NMR (300 MHz, Chloroform- d ) δ 8.88-8.82 (m, 2H), 8.68 (s, 1H), 8.64 (dd, J = 1.5, 0.9 Hz, 1H), 7.89 (d, J = 0.8 Hz) , 1H), 7.86 (dd, J = 4.7, 1.5 Hz, 3H), 7.65 (dd, J = 3.2, 1.2 Hz, 2H), 5.79 (dd, J = 9.7, 2.6 Hz, 1H), 4.58 (p, J = 6.7 Hz, 1H), 4.18-4.11 (m, 1H), 3.88-3.77 (m, 1H), 2.63 (s, 0H), 2.26-2.08 (m, 1H), 1.85 (d, J = 9.8 Hz) , 1H), 1.75 (s, 3H), 1.60 (d, J = 6.7 Hz, 6H).

Compound 79. 5-(1-isopropyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)- 1H-indazole

[Scheme 79]

Add 4 M HCl/dioxane (0.5 ml) to a DCM (1 ml) solution of compound 79-1 (6.3 mg, 0.0139 mmol). The reaction mixture is stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain Compound 79 (4.9 mg, 0.0132 mmol, 95%) as a yellow solid.

LC/MS 371.4[M + H] ⁺

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.68 (s, 1H), 9.03-8.95 (m, 2H), 8.46-8.38 (m, 3H), 8.26 (s, 1H), 7.94 (d, J = 4.5 Hz, 1H), 7.72-7.57 (m, 2H), 4.12 (t, J = 7.0 Hz, 2H), 1.86 (q, J = 7.2 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H) ).

Compound 80. 5-(1-propyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1 -(tetrahydro-2H-pyran-2-yl)-1H-indazole

[Scheme 80]

1) 5-(1-propyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole synthesis

Na ₂ CO ₃ (18.7 mg, 0.176 mmol) aqueous solution was mixed with compound 80-1 (30.0 mg, 0.0705 mmol), Palladium catalyst (4.95 mg, 0.00705 mmol), 1-propyl-4-(4,4,5,5- Add tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0 mg, 0.0846 mmol) to a dioxane suspension and purge with nitrogen for 5 minutes. The reaction mixture was irradiated with microwaves at 110°C for 20 mintues. The reaction mixture was filtered with dioxane and concentrated under reduced pressure to obtain a crude mixture, which was then purified by chromatography (solvent DCM/MeOH 7%) to obtain a white solid of compound 80-2 + impurities (19.3 mg, 0.0425 mmol, 60%).

^1H NMR (300 MHz, Chloroform- d ) δ 8.87-8.81 (m, 2H), 8.68 (s, 1H), 8.64 (t, J = 1.2 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H) ), 7.8 -7.83 (m, 2H), 7.80 (d, J = 0.9 Hz, 1H), 7.64 (d, J = 1.4 Hz, 2H), 5.78 (dd, J = 9.6, 2.6 Hz, 1H), 4.18 -4.13 (m, 2H), 4.09 (d, J = 7.1 Hz, 0H), 3.85 - 3.74 (m, 1H), 2.70-2.57 (m, 1H), 2.15 (s, 2H), 1.97 (q, J = 7.3 Hz, 2H), 1.89-1.81 (m, 3H), 0.99 (t, J = 7.4 Hz, 3H).

2) Synthesis of 5-(1-propyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

A solution of compound 80-2 (8.0 mg, 0.0176 mmol) in DCM (1 ml) was added to 4 M HCl dioxane (0.5 ml). The reaction mixture is stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain Compound 80 (6.4 mg, 0.0173 mmol, 98%) as a yellow solid.

LC/MS 371.2[M + H] ⁺

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.68 (s, 1H), 9.03-8.95 (m, 2H), 8.46-8.38 (m, 3H), 8.26 (s, 1H), 7.94 (d, J = 4.5 Hz, 1H), 7.72-7.57 (m, 2H), 4.12 (t, J = 7.0 Hz, 2H), 1.86 (q, J = 7.2 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H) ).

Compound 81. 2,2,2-trifluoro-1-(7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

[Scheme 81]

1) 1-(7-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1- Synthesis of yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

Compound 81-2 (705 mg, 2.61 mmol) and Sodium ascorbate (172 mg, 0.869 mmol) in t-BuOH/H ₂ O (1:1/8 mL) solution of compound 81-1 (820 mg, 2.17 mmol) , CuSO ₄ (69.4 mg, 0.435 mmol) was added. The reaction mixture was stirred overnight at 70°C. Add water to the reaction mixture, quench it, and extract with EA (100 ml x 3). The organic layer is dried with sodium sulfate and the solvent is concentrated under reduced pressure. The crude mixture is purified by column chromatography (solvent EA/HEX 50%) to obtain compound 81-3 (904 mg, 1.57 mmol, 72%) as a beige solid.

LC/MS 575.1[M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.36 (s, 1H), 8.55 (dt, J = 1.5, 0.7 Hz, 1H), 8.05 (dd, J = _20.5 , 2.3 Hz, 1H), 7.94 ( ddd, J = 10.5, 8.3, 2.3 Hz, 1H), 7.84 (dd, J = 9.0, 0.7 Hz, 1H), 7.66 (dd, J = 8.9, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 3.9 Hz, 1H), 5.97 (dd, J = 9.7, 2.4 Hz, 1H), 4.91 (d, J = 12.7 Hz, 2H), 3.97-3.86 (m, 3H), 3.85-3.74 (m, 1H), 3.06-2.98 (m, 2H), 2.49-2.42 (m, 1H), 2.13-1.99 (m, 2H), 1.86-1.72 (m, 1H), 1.66-1.57 (m, 2H).

2) 2,2,2-trifluoro-1-(7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3 -yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one synthesis

Na ₂ CO ₃ (24.4 mg, 0.230 mmol) aqueous solution was mixed with compound 81-3 (53 mg, 0.0921 mmol), Palladium catalyst (6.46 mg, 0.00921 mmol), (2-fluoropyridin-3-yl)boronic acid (15.6 mg, 0.111 mmol) of dioxane suspension and purge with nitrogen for 5 minutes. The reaction mixture was irradiated with microwaves at 110°C for 20 mintues. The reaction mixture was filtered through dioxane, concentrated under reduced pressure, and purified by chromatography (solvent DCM/MeOH 5%) to obtain Compound 81 (30.4 mg, 0.0514 mmol, 56%) as a white solid.

LC/MS 592.4[M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.37 (s, 1H) _, 8.59 (s, 1H), 8.29 (dt, J = 4.9, 1.5 Hz, 1H), 8.24 (ddd, J = 9.5, 7.3 , 1.9 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.9, 0.8 Hz, 1H), 7.95-7.91 (m, 1H), 7.76 (dt, J = 8.7, 1.7 Hz, 1H), 7.56-7.47 (m, 2H), 6.03 (dd, J = 9.7, 2.4 Hz, 1H), 4.91 (d, J = 11.9 Hz, 2H), 3.99-3.93 (m, 1H), 3.91-3.86 (m, 2H), 3.85-3.77 (m, 1H), 3.07-2.98 (m, 2H), 2.59-2.52 (m, 1H), 2.16-2.02 (m, 2H), 1.88-1.76 (m , 1H), 1.69-1.59 (m, 2H).

Compound 82. 2,2,2-trifluoro-1-(7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1 -on

[Scheme 82]

Na ₂ CO ₃ (46.0 mg, 0.434 mmol) aqueous solution was mixed with compound 82-1 (100 mg, 0.174 mmol), Palladium catalyst (12.2 mg, 0.0174 mmol), 1-isopropyl-4-(4,4,5,5- Add tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (49.3 mg, 0.209 mmol) to a dioxane suspension and purge with nitrogen for 5 minutes. The reaction mixture was irradiated with microwaves at 110°C for 20 mintues. The reaction mixture was filtered with dioxane and concentrated under reduced pressure. The resulting crude mixture was purified by column chromatography (solvent EA/HEX 60%) to obtain Compound 82 (34.5 mg, 0.0571 mmol, 33%) as a white solid.

LC/MS 605.5[M + H] ⁺

^1H NMR (300 MHz, Chloroform- d ) δ 8.64 (s, 1H), 8.55 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 11.9 Hz, 2H), 7.69-7.65 (m, 2H) ), 7.64-7.60 (m, 2H), 7.35 (t, J = 8.4 Hz, 1H), 5.77 (dd, J = 9.6, 2.6 Hz, 1H), 4.87 (d, J = 13.5 Hz, 2H), 4.57 (p, J = 6.7 Hz, 1H), 4.17-4.08 (m, 1H), 3.98-3.87 (m, 2H), 3.8 -3.74 (m, 1H), 3.02 (t, J = 6.2, 4.0 Hz, 2H ), 2.72-2.56 (m, 1H), 2.27-2.04 (m, 2H), 1.93-1.87 (m, 1H), 1.86-1.72 (m, 2H), 1.59 (d, J = 6.7 Hz, 6H).

Compound 83. 2,2,2-trifluoro-1-(7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1- on

[Scheme 83]

As in the preparation method of Scheme 82, compound 83-1 (100 mg, 0.174 mmol) was reacted with 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Reacts with 1H-pyrazole (49.3 mg, 0.209 mmol) to obtain compound 83 (36.8 mg, 0.0609 mmol) as a white solid.

LC/MS 605.2[M + H] ⁺

^1H NMR (300 MHz, Chloroform- d ) δ 8.63 (s, 1H), 8.55 (d, J = 3.2 Hz, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.68-7.63 (m , 2H), 7.62 (s, 2H), 7.34 (t, J = 8.5 Hz, 1H), 5.77 (dd, J = 9.6, 2.5 Hz, 1H), 4.87 (d, J = 12.7 Hz, 2H), 4.14 (t, J = 7.1 Hz, 2H), 4.11-4.02 (m, 1H), 3.95-3.87 (m, 2H), 3.86-3.75 (m, 1H), 3.02 (t, J = 5.6 Hz, 2H), 2.70-2.55 (m, 1H), 2.24-2.05 (m, 2H), 1.96 (h, J = 7.2 Hz, 2H), 1.86-1.75 (m, 2H), 1.75-1.62 (m, 1H), 0.98 ( t, J = 7.4 Hz, 3H).

Compound 84. 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H- 1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

[Scheme 84]

Lithium hydroxide monohydrate (3.96 mg, 0.106 mmol) was added to a solution of compound 84-1 (26.8 mg, 0.0529 mmol) in THF (2 mL), MeOH (1 mL), and H ₂ O (0.5 mL) and stirred at room temperature for 2 hours. do. The reaction mixture was concentrated under reduced pressure, and the crude mixture was purified by column chromatography (solvent DCM/MeOH 10%) to obtain Compound 84 (11.0 mg, 0.0371 mmol, 66%) as a white solid.

LC/MS 496.3[M + H] ⁺

^1H NMR (400 MHz, Chloroform- d ) δ 8.74 (s, 1H), 8.52 (s, 1H), 8.20 (dt, J = 4.8, 1.6 Hz, 1H), 8.03 (ddd, J = 9.6, 7.4, 2.0 Hz, 1H), 7.70 (d, J = 1.4 Hz, 2H), 7.57 (dd, J = 8.2, 2.3 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.33-7.26 (m, 2H), 5.80 (dd, J = 9.5, 2.7 Hz, 1H), 4.17-4.07 (m, 3H), 3.86-3.73 (m, 1H), 3.19 (t, J = 5.9 Hz, 2H), 2.88 (t , J = 5.9 Hz, 2H), 2.70-2.57 (m, 1H), 2.25-2.06 (m, 2H), 1.86-1.75 (m, 2H), 1.73-1.59 (m, 1H).

Compound 85. 7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl )-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

[Scheme 85]

Compound 85-1 (28.6 mg, 0.0473 mmol) is reacted according to the preparation method in Scheme 84 to obtain compound 85 (15.6 mg, 0.0307 mmol, 65%) as a white solid.

LC/MS 509.5[M + H] ⁺

^1H NMR (400 MHz, Chloroform- d ) δ 8.66 (s, 1H), 8.53 (s, 1H), 7.87 (dd, J = 13.3, 0.8 Hz, 2H), 7.67 - 7.57 (m, 3H), 7.53 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 3.3 Hz, 2H), 5.77 (dd, J = 9.6, 2.7 Hz, 1H), 4.58 (hept, J = 6.7 Hz, 1H), 4.17 -4.08 (m, 3H), 3.85-3.76 (m, 1H), 3.21 (t, J = 6.0 Hz, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.70-2.58 (m, 1H), 2.16-2.02 (m, 2H), 1.86-1.77 (m, 2H), 1.73-1.65 (m, 1H), 1.60 (d, J = 6.7 Hz, 6H).

Compound 86. 7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl) -1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

[Scheme 86]

Compound 86-1 (30.0 mg, 0.0496 mmol) is reacted according to the preparation method in Scheme 84 to obtain Compound 86 (11.0 mg, 0.0216 mmol, 44%) as a white solid.

LC/MS 509.3[M + H] ⁺

^1H NMR (400 MHz, Chloroform- d ) δ 8.66 (s, 1H), 8.53 (s, 1H), 7.85 (dd, J = 33.4, 0.8 Hz, 2H), 7.67-7.56 (m, 3H), 7.54 (d, J = 2.3 Hz, 1H), 7.30 (s, 1H), 5.78 (dd, J = 9.6, 2.7 Hz, 1H), 4.22-4.06 (m, 5H), 3.85-3.77 (m, 1H), 3.22 (s, 2H), 2.90 (t, J = 5.8 Hz, 2H), 2.70-2.58 (m, 1H), 2.26-2.08 (m, 2H), 1.98 (h, J = 7.4 Hz, 2H), 1.86 -1.76 (m, 4H), 1.74-1.65 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H).

Compound 87. 2,2,2-trifluoro-1-(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1, 2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

[Scheme 87]

Add 4 N HCl dioxane (0.5 ml) to a solution of compound 87-1 (46.1 mg, 0.0779 mmol) in DCM (1 ml). The reaction mixture is stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and extracted with EA (2 The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain Compound 87 (36.9 mg, 0.0727 mmol, 93%) as a white solid.

LC/MS 508.2[M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.55 (s, 1H), 9.33 (s, 1H), 8.57 (s, 1H), 8.27 (dt, J = _4.8 , 1.5 Hz, 1H), 8.22 ( ddd, J = 9.5, 7.2, 1.8 Hz, 1H), 8.03 (dd, J = 18.5, 2.3 Hz, 1H), 7.92 (td, J = 8.1, 2.3 Hz, 1H), 7.75 (dd, J = 8.7, 0.9 Hz, 1H), 7.69 (dt, J = 8.8, 1.8 Hz, 1H), 7.66-7.59 (m, 1H), 7.55-7.46 (m, 2H), 4.91 (d, J = 11.7 Hz, 2H), 3.89 (q, J = 5.8 Hz, 2H), 3.06-2.98 (m, 2H).

Compound 88. 2,2,2-trifluoro-1-(7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)- 1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

[Scheme 88]

Compound 88-1 (26.1 mg, 0.0432 mmol) is reacted according to the preparation method in Scheme 87 to obtain compound 88 (19.0 mg, 0.0365, 84%) as a white solid.

LC/MS 521.5[M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.34 (s, 1H), 9.27 (s, 1H), 8.42 (s, _1H ), 8.26 (s, 1H), 8.03 (d, J = 13.9 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.70 (dd, J = 8.7, 1.6 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 4.92 (d, J = 8.3 Hz, 2H), 4.55 (hept, J = 6.7 Hz, 1H), 3.94 - 3.83 (m, 3H), 3.03 (q, J = 6.5 Hz, 3H), 1.48 (d, J = 6.7 Hz, 6H).

Compound 89. 2,2,2-trifluoro-1-(7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H -1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

[Scheme 89]

Compound 89-1 (35.1 mg, 0.0581 mmol) is reacted according to the preparation method in Scheme 87 to obtain compound 89 (25.0 mg, 0.0480, 83%) as a white solid.

LC/MS 521.2[M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.33 (s, 1H), 9.28 (s, 1H), 8.42 (d, J = 1.8 Hz, 1H), 8.24 (d, J = 1.0 Hz, 1H) , 8.04 (dd, J = 17.9, 2.2 Hz, 1H), 7.94-7.91 (m, 2H), 7.68 (dd, J = 8.7, 1.6 Hz, 1H), 7.61 (dd, J = 8.6, 0.8 Hz, 1H) ), 7.50 (dd, J = 8.3, 3.0 Hz, 1H), 4.92 (d, J = 11.3 Hz, 2H), 4.12 (t, J = 7.0 Hz, 2H), 3.92-3.86 (m, 2H), 3.07 .98 (m, 2H), 1.86 (h, J = 7.2 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H).

Compound 90. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline

[Scheme 90]

Compound 90-1 (27.7 mg, 0.0546 mmol) is reacted according to the preparation method in Scheme 84 to obtain compound 90 (12.6 mg, 0.0306 mmol, 56%) as a white solid.

LC/MS 412.1[M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.54 (s, 1H), 9.30 (s, 1H), _8.57 (s, 1H), 8.30-8.16 (m, 2H), 7.81-7.65 (m, 4H) ), 7.52 (ddd, J = 7.1, 4.8, 1.9 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 3.98 (s, 2H), 3.20-3.15 (m, 1H), 3.01 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H).

Compound 91. 7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazole-1- 1)-1,2,3,4-tetrahydroisoquinoline

[Scheme 91]

As in the preparation method of Scheme 84, Compound 91-1 (17.4 mg, 0.0334 mmol) is reacted to obtain Compound 91 (7.10 mg, 0.0167 mmol, 73%) as a white solid.

LC/MS 425.4[M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.32 (s, 1H) _, 9.25 (s, 1H), 8.42 (d, J = 1.5 Hz, 1H), 8.26 (s, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.82-7.72 (m, 2H), 7.71-7.57 (m, 2H), 7.33 (d, J = 8.3 Hz, 1H), 4.55 (h, J = 6.7 Hz, 1H), 3.97 (s, 2H), 3.00 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 1.49 (hept, J = 6.6 Hz, 6H).

Compound 92. 7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-1,2,3,4-tetrahydroisoquinoline

[Scheme 92]

As in the preparation method of Scheme 84, Compound 92-1 (17.4 mg, 0.0334 mmol) is reacted to obtain Compound 92 (7.10 mg, 0.0167 mmol, 73%) as a white solid.

LC/MS 425.3[M + H] ⁺

^1H NMR (300 MHz, DMSO- d ₆ ) δ 13.33 (s, 1H), 9.25 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.81- 7.72 (m, 2H), 7.70-7.58 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 4.12 (t, J = 7.0 Hz, 2H), 3.99 (s, 2H), 3.02 (t , J = 5.8 Hz, 3H), 2.79 (t, J = 5.9 Hz, 3H), 1.85 (h, J = 7.1 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H).

Compound 93. 1-(7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3 -yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-trifluoroethane-1- on

[Scheme 93]

As in the preparation method of Scheme 82, Compound 93-1 (50 mg, 0.174 mmol) is reacted to obtain Compound 93 (16.0 mg, 0.0245, 28%) as a white solid.

LC/MS 653.2[M + H] ⁺

^1H NMR (300 MHz, Chloroform- d ) δ 8.63 (t, J = 1.3 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.80 ( s, 1H), 7.74 - 7.64 (m, 2H), 7.61 (d, J = 1.3 Hz, 2H), 7.43 - 7.29 (m, 6H), 5.77 (dd, J = 9.6, 2.6 Hz, 1H), 5.38 (s, 2H), 4.89 (d, J = 14.2 Hz, 2H), 4.17-4.08 (m, 1H), 3.99-3.88 (m, 2H), 3.86-3.75 (m, 1H), 3.09-3.00 (m) , 2H), 2.72-2.56 (m, 1H), 2.26-2.07 (m, 2H), 1.86-1.80 (m, 1H), 1.78-1.63 (m, 2H).

Compound 94. 1-(7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazole- 1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one

[Scheme 94]

Compound 94-1 (46.1 mg, 0.0779 mmol) is reacted according to the preparation method in Scheme 87 to obtain compound 94 (81.4 mg, 0.143 mmol, 94%) as a white solid.

LC/MS 569.3[M + H] ⁺

^1H NMR (300 MHz, DMSO- d ₆ ) δ 13.35 (s, 1H), 9.28 (s, 1H), 8.44 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 1.6 Hz, 1H) , 8.03 (dd, J = 13.7, 2.3 Hz, 1H), 7.98 (s, 1H), 7.95-7.89 (m, 1H), 7.72-7.59 (m, 2H), 7.49 (dd, J = 8.4, 2.6 Hz) , 1H), 7.42-7.27 (m, 5H), 5.39 (s, 2H), 4.92 (d, J = 8.4 Hz, 2H), 3.94-3.84 (m, 2H), 3.02 (q, J = 6.3 Hz, 2H).

Compound 95. 7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-1,2,3,4-tetrahydroisoquinoline

[Scheme 95]

Compound 95-1 (17.4 mg, 0.0334 mmol) is reacted according to the preparation method in Scheme 84 to obtain compound 95 (43.5 mg, 0.0921 mmol, 76%) as a white solid.

LC/MS 473.5[M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.32 (s, 1H) _, 9.24 (s, 1H), 8.42 (d, J = 1.4 Hz, 1H), 8.36 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.73 (s, 1H), 7.68 (dd, J = 8.7, 1.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.36-7.28 (m, 6H), 5.39 (s, 2H), 3.97 (s, 2H), 3.00 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 5.8 Hz, 2H).

Compound 96. 2,2,2-trifluoro-1-(7-(4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-inda zol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one hydrochloride

[Scheme 96]

1) tert-butyl 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(2-(2,2,2-trifluoroacetyl)-1,2,3,4 -tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate synthesis

As in the preparation method of Scheme 82, tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was added to compound 96-1 (100 mg, 0.174 mmol). )- 1H-pyrazol-1-yl)piperidine-1-carboxylate (78.9 mg, 0.209 mmol) is reacted to obtain compound 96-2 (35 mg).

2) 2,2,2-trifluoro-1-(7-(4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-3-yl)- Synthesis of 1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one hydrochloride

As in the preparation method of Scheme 87, Compound 96-2 (30.0 mg, 0.0402 mmol) is reacted to obtain Compound 96 (15.2 mg, 0.0254 mmol, 2 step yield) as a white solid.

LCMS M+H 562.29

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.49 (br, 1H), 9.39-9.24 (m, 1H), 9.16-9.00 (m, 1H), 8.91-8.69 (m, 1H), 8.59-8.42 (m, 1H), 8.30 (s, 1H), 8.08-7.89 (m, 3H), 7.76-7.54 (m, 2H), 7.53-7.44 (m, 1H), 4.93 (s, 1H), 4.91 (s) , 1H), 4.62-4.48 (m, 1H), 3.98-3.80 (m, 2H), 3.49-3.34 (m, 2H), 3.21-2.94 (m, 4H), 2.56-2.53 (m, 1H), 2.35 -2.13 (m, 3H).

Compound 97. 7-(4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2, 3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

[Scheme 97]

As in the preparation method of Scheme 84, Compound 97-1 (10 mg, 0.0167 mmol) is reacted to obtain Compound 97 (3.5 mg, 0.00767 mmol, 46%) as a yellow solid.

LCMS M+H 466.43

H NMR (300 MHz, DMSO- d ₆ ) δ 13.34 (s, 1H), 9.32-9.21 (m, 1H), 8.56-8.38 (m, 1H), 8.26 (s, 1H), 7.92 (s, 1H) , 7.78 (dt, J = 8.2, 2.2 Hz, 1H), 7.74-7.72 (m, 1H), 7.69 (dd, J = 8.7, 1.6 Hz, 1H), 7.65-7.53 (m, 1H), 7.39-7.28 (m, 1H), 4.31-4.13 (m, 1H), 3.97 (s, 2H), 3.13-3.03 (m, 2H), 3.02-2.92 (m, 2H), 2.84-2.72 (m, 2H), 2.68 -2.55 (m, 2H), 2.06-1.96 (m, 2H), 1.91-1.68 (m, 2H).

Compound 98. 7-(4-(5-phenyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroiso Quinoline hydrochloride

[Scheme 98]

1) 7-(4-(5-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 98-1 (50.0 mg, 0.0870 mmol) was reacted with phenylboronic acid (16.0 mg, 0.130 mmol) to produce compound 98-2 (16 mg, 0.034 mmol, 38.6%) as a white solid. get

LC/MS 477.5 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.31 (d, J = 23.1 Hz, 1H), _8.68-8.30 (m, 1H), 7.99-7.71 (m, 5H), 7.52 (t, J = 7.7) Hz, 2H), 7.45-7.07 (m, 2H), 6.13-5.82 (m, 1H), 3.97 (d, J = 18.0 Hz, 3H), 3.88-3.69 (m, 2H), 3.02 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.20-1.93 (m, 3H), 1.83 (d, J = 14.2 Hz, 1H), 1.71-1.51 (m, 3H).

2) Synthesis of 7-(4-(5-phenyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 98-2 (15.0 mg, 0.0310 mmol) is reacted to obtain Compound 98 (10.2 mg, 0.024 mmol, 76%) as a white solid.

LC/MS 393.4 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d ₆ ) δ 13.45 (d, J = 42.6 Hz, 1H), 9.45-9.29 (m, 3H), 8.70-8.32 (m, 1H), 8.05-7.93 (m, 2H) ), 7.87-7.68 (m, 3H), 7.66-7.43 (m, 3H), 7.42-7.09 (m, 1H), 4.42 (s, 2H), 3.45 (d, J = 6.9 Hz, 2H), 3.11 ( t, J = 6.3 Hz, 2H).

Compound 99. 7-(4-(5-(3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 99]

1) 7-(4-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3- Synthesis of triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

As in the preparation method of Scheme 82, compound 99-1 (50.0 mg, 0.0870 mmol) was reacted with (3-(trifluoromethyl)phenyl)boronic acid (25.0 mg, 0.130 mmol) to obtain compound 99-2 (40 mg, 0.073 mmol). , 85%) to obtain a white solid.

LC/MS 545.6 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.35 (s, 1H) _, 8.62 (d, J = 1.7 Hz, 1H), 8.13-8.07 (m, 1H), 8.04 (s, 1H), 7.96 ( d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.8, 1.7 Hz, 1H), 7.85-7.79 (m, 1H), 7.77 (d, J = 5.1 Hz, 3H), 7.33 (d, J = 8.2 Hz, 1H), 6.02 (dd, J = 9.7, 2.3 Hz, 1H), 3.96 (d, J = 9.1 Hz, 3H), 3.88-3.76 (m, 1H), 3.00 (t, J = 5.9 Hz) , 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.17-1.87 (m, 3H), 1.73 (d, J = 72.8 Hz, 4H).

2) 7-(4-(5-(3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4 -tetrahydroisoquinoline hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 99-2 (30.0 mg, 0.0550 mmol) is reacted to obtain Compound 99 (20 mg, 0.040 mmol, 73.1%) as a white solid.

LC/MS 461.5 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.56 (s, 1H), 9.62-9.44 (m, 2H), _9.37 (d, J = 2.1 Hz, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.13-8.04 (m, 1H), 8.04-7.93 (m, 3H), 7.87-7.80 (m, 1H), 7.80-7.66 (m, 3H), 7.51 (dd, J = 8.4, 2.0 Hz, 1H), 4.40 (d, J = 5.2 Hz, 2H), 3.42 (d, J = 6.1 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H).

Compound 100. 7-(4-(5-(2-chloropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 100]

1) 7-(4-(5-(2-chloropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 100-1 (50.0 mg, 0.0870 mmol) was reacted with (2-chloropyridin-3-yl)boronic acid (20.5 mg, 0.130 mmol) to obtain compound 100-2 (33 mg, 0.064 mmol). mmol, 74.2%) of a yellow solid is obtained.

LC/MS 512.5 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.33 (s, 1H), _8.48 (dd, J = 4.8, 2.0 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.01 (dd, J = 7.6, 1.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.79 (dd, J = 8.2, 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.63 ( dd, J = 8.8, 1.7 Hz, 1H), 7.58 (dd, J = 7.6, 4.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 9.8, 2.3 Hz, 1H) ), 3.96 (d, J = 10.1 Hz, 3H), 3.88-3.75 (m, 1H), 3.01 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.7 Hz, 2H), 2.53 (s) , 2H), 2.08 (d, J = 12.5 Hz, 2H), 1.82 (s, 1H), 1.64 (s, 2H).

2) 7-(4-(5-(2-chloropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 100-2 (25.0 mg, 0.0490 mmol) is reacted to obtain Compound 100 (20 mg, 0.043 mmol, 88%) as a white solid.

LC/MS 428.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.60 (s, 1H), 9.55-9.43 (m, 2H), 9.35 (s, 1H), 8.48 (dd, J = 4.7, 1.9 Hz, 1H), 8.42 (d, J = 1.5 Hz, 1H), 8.04-7.96 (m, 2H), 7.95 (dd, J = 8.2, 2.4 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.61-7.53 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 4.40 (t, J = 4.7 Hz, 2H), 3.43 (d, J = 5.7 Hz, 2H), 3.10 (t, J = 6.2 Hz) , 2H).

Compound 101. 7-(4-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-tetrahydroisoquinoline hydrochloride

[Scheme 101]

1) 7-(4-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol -1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 101-1 (50.0 mg, 0.0870 mmol) was reacted with pyridin-3-ylboronic acid (16.0 mg, 0.130mmol) to obtain compound 101-2 (35 mg, 0.073 mmol, 84%). A white solid is obtained.

LC/MS 478.5 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.37 (s, 1H) _, 9.00 (d, J = 2.4 Hz, 1H), 8.61 (dd, J = 4.6, 1.6 Hz, 2H), 8.18 (dt, J = 8.1, 1.9 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 8.8, 1.8 Hz, 1H), 7.82 (dd, J = 8.2, 2.4 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.0, 4.8 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 9.7, 2.4 Hz, 1H) ), 3.97 (d, J = 22.6 Hz, 3H), 3.87-3.78 (m, 1H), 3.03 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H), 2.57-2.53 (m, 2H), 2.15-2.02 (m, 2H), 1.89-1.76 (m, 1H), 1.64 (s, 2H).

2) 7-(4-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Synthesis of tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 101-2 (25.0 mg, 0.0520 mmol) is reacted to obtain Compound 101 (20 mg, 0.047 mmol, 89%) as a white solid.

LC/MS 394.5 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.71 (s, 1H) _, 9.68 (s, 2H), 9.43 (s, 1H), 9.29 (d, J = 2.2 Hz, 1H), 8.82 (d, J = 5.4 Hz, 1H), 8.78 (d, J = 8.2 Hz, 1H), 8.72 (s, 1H), 8.01 (d, J = 4.3 Hz, 2H), 7.98-7.93 (m, 1H), 7.91 ( d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.39 (d, J = 5.0 Hz, 2H), 3.12 (t, J = 6.3 Hz, 2H), 2.55 (s, 2H).

Compound 102. 7-(4-(5-(o-tolyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4 -Tetrahydroisoquinoline hydrochloride

[Scheme 102]

1) 7-(4-(1-(tetrahydro-2H-pyran-2-yl)-5-(o-tolyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 102-1 (50.0 mg, 0.0870 mmol) was reacted with o-tolylboronic acid (17.7 mg, 0.130 mmol) to obtain white compound 102-2 (25 mg, 0.051 mmol, 58.6%). Obtain a solid.

LC/MS 491.6 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.32 (d, J = 3.0 Hz, 1H), 8.28 (d, J = _2.9 Hz, 1H), 7.92-7.84 (m, 1H), 7.83-7.69 ( m, 2H), 7.53-7.46 (m, 1H), 7.40-7.23 (m, 5H), 6.05-5.94 (m, 1H), 4.03-3.91 (m, 3H), 3.82 (s, 1H), 3.05- 2.94 (m, 2H), 2.82 -2.73 (m, 2H), 2.28 (d, J = 2.9 Hz, 3H), 2.16-2.02 (m, 2H), 1.99 (d, J = 3.2 Hz, 1H), 1.82 (s, 1H), 1.64 (d, J = 6.4 Hz, 2H).

2) 7-(4-(5-(o-tolyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 102-2 (20.0 mg, 0.0410 mmol) is reacted to obtain Compound 102 (14 mg, 0.032 mmol, 78%) as a white solid.

LC/MS 407.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.48 (s, 1H) _, 9.41 (s, 2H), 9.33 (s, 1H), 8.26 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.987.93 (m, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.457.41 (m, 1H), 7.367.26 (m , 4H), 4.40 (t, J = 4.8 Hz, 2H), 3.43 (d, J = 6.2 Hz, 2H), 3.10 (t, J = 6.2 Hz, 2H), 2.28 (s, 3H).

Compound 103. 7-(4-(5-(4-ethylphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, 4-Tetrahydroisoquinoline hydrochloride

[Scheme 103]

1) 7-(4-(5-(4-ethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 103-1 (50.0 mg, 0.0870 mmol) was reacted with (4-ethylphenyl)boronic acid (19.5 mg, 0.130mmol) to produce compound 103-2 (25 mg, 0.050 mmol, 57.0%). ) to obtain a white solid.

LC/MS 505.5 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.33 (s, 1H), 8.55 ₍ d, J = 1.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.86-7.76 (m, 3H), 7.73-7.62 (m, 2H), 7.35 (t, J = 7.5 Hz, 3H), 6.03-5.94 (m, 1H), 3.97 (d, J = 24.8 Hz, 3H), 3.86-3.75 (m) , 1H), 3.04 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.73-2.62 (m, 2H), 2.16-1.97 (m, 3H), 1.80 (d, J = 10.3 Hz, 2H), 1.63 (s, 2H), 1.24 (t, J = 7.6 Hz, 3H).

2) 7-(4-(5-(4-ethylphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 103-2 (25.0 mg, 0.0500 mmol) is reacted to obtain Compound 103 (13 mg, 0.028 mmol, 57.4%) as a white solid.

LC/MS 421.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.45 (s, 1H) _, 9.51 (s, 2H), 9.35 (s, 1H), 8.53 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.99-7.94 (m, 1H), 7.74 (dd, J = 8.8, 1.7 Hz, 1H), 7.72-7.61 (m, 3H), 7.53-7.48 (m, 1H), 7.35 (d, J = 8.1 Hz, 2H), 4.40 (d, J = 5.0 Hz, 2H), 3.43 (d, J = 10.2 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H), 2.68 (q , J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

Compound 104. 7-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indazol-3-yl)-1H-1,2 ,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 104]

1) 7-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3 -yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 104-1 (50.0 mg, 0.0870 mmol) was mixed with (4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (23.4 mg, 0.130 mmol) to obtain a white solid of Compound 104-2 (25 mg, 0.047 mmol, 53.8%).

LC/MS 535.3 [M + H] ⁺

2) 7-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol- Synthesis of 1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 104-2 (25.0 mg, 0.0470 mmol) is reacted to obtain Compound 104 (13 mg, 0.027 mmol, 57.1%) as a white solid.

LC/MS 451.4 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.43 (s, 1H), 9.52 (s, 2H), _9.35 (s, 1H), 8.46 (d, J = 4.5 Hz, 1H), 8.03-7.98 ( m, 2H), 7.96 (d, J = 2.3 Hz, 1H), 7.69-7.66 (m, 1H), 7.53-7.50 (m, 1H), 7.24-7.19 (m, 2H), 7.03-6.94 (m, 1H), 4.41 (s, 2H), 4.31 (s, 4H), 3.42 (s, 2H), 3.11 (t, J = 6.2 Hz, 2H).

Compound 105. 7-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazole-1- 1)-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 105]

1) 7-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1, Synthesis of 2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

As in the preparation method of Scheme 82, compound 105-1 (50.0 mg, 0.0870 mmol) was reacted with (4-chloro-3-(trifluoromethyl)phenyl)boronic acid (29.2 mg, 0.130mmol) to produce compound 105-2 (40 mg, 0.069 mmol, 79%) of a white solid.

LC/MS 579.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.35 (s, 1H), _8.62 (d, J = 1.6 Hz, 1H), 8.16-8.06 (m, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.8, 1.7 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.84-7.74 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 9.7, 2.4 Hz, 1H), 3.96 (d, J = 16.7 Hz, 3H), 3.82 (dt, J = 11.6, 7.1 Hz, 1H), 3.02 (t, J = 5.9 Hz, 2H) ), 2.79 (t, J = 5.9 Hz, 2H), 2.57-2.52 (m, 1H), 2.15-1.57 (m, 6H).

2) 7-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2 ,3,4-tetrahydroisoquinoline hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 105-2 (35.0 mg, 0.0600 mmol) is reacted to obtain Compound 105 (22 mg, 0.041 mmol, 68.5%) as a white solid.

LC/MS 495.3 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d ₆ ) δ 13.58 (s, 1H), 9.38 (s, 3H), 8.61 (d, J = 1.7 Hz, 1H), 8.13-8.05 (m, 2H), 8.03- 7.91 (m, 2H), 7.89-7.80 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.41 (s, 2H), 3.45 (s) , 2H), 3.11 (t, J = 6.1 Hz, 2H).

Compound 106. 4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-day) Benzonitrile hydrochloride

[Scheme 106]

1) 4-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- Synthesis of 4-yl)-1H-indazol-5-yl)benzonitrile

As in the preparation method of Scheme 82, compound 106-1 (50 mg, 0.0870 mmol) was reacted with (4-cyanophenyl)boronic acid (19.1 mg, 0.130 mmol) to obtain compound 106-2 (33 mg, 0.066 mmol, 76%). ) to obtain a white solid.

LC/MS 502.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.36 (s, 1H) _, 8.66 (s, 1H), 7.99 (d, J = 3.1 Hz, 4H), 7.96 (s, 1H), 7.93-7.89 ( m, 1H), 7.83-7.78 (m, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 9.7, 2.4 Hz, 1H) ), 3.96 (d, J = 12.2 Hz, 3H), 3.86-3.77 (m, 1H), 3.01 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.53 (s) , 2H), 2.07 (d, J = 14.4 Hz, 2H), 1.88-1.75 (m, 1H), 1.68-1.58 (m, 2H).

2) 4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)benzonitrile hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 106-2 (25.0 mg, 0.0500 mmol) is reacted to obtain Compound 106 (15 mg, 0.033 mmol, 66.3%) as a white solid.

LC/MS 418.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.60 (s, 1H), 9.53 (s, 2H), _9.38 (s, 1H), 8.65 (d, J = 1.7 Hz, 1H), 8.01-7.97 ( m, 5H), 7.96 (d, J = 2.5 Hz, 1H), 7.87-7.80 (m, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.40 (d, J = 5.0 Hz, 2H), 3.45 (s, 2H), 3.11 (t, J = 6.3 Hz, 2H).

Compound 107. 7-(4-(5-(3-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-tetrahydroisoquinoline hydrochloride

[Scheme 107]

1) 7-(4-(5-(4-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1 -yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 107-1 (50 mg, 0.0870 mmol) was reacted with (4-methoxyphenyl)boronic acid (19.8 mg, 0.130 mmol) to obtain compound 107-2 (25 mg, 0.049 mmol, 56.8%). ) to obtain a white solid.

LC/MS 507.5 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.33 (s, 1H) _, 8.50 (d, J = 1.7 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 7.79-7.74 (m, 2H), 7.72-7.65 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 7.12-7.04 (m, 2H), 5.98 (dd , J = 9.8, 2.3 Hz, 1H), 4.00 (s, 2H), 3.96 (d, J = 11.2 Hz, 1H), 3.82 (s, 4H), 3.03 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.58-2.52 (m, 2H), 2.14-2.01 (m, 2H), 1.80 (d, J = 11.2 Hz, 1H), 1.67-1.58 (m, 2H).

2) 7-(4-(5-(3-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 107-2 (20.0 mg, 0.0500 mmol) is reacted to obtain Compound 107 (14 mg, 0.031 mmol, 77%) as a white solid.

LC/MS 423.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.44 (s, 1H), 9.57 (s, 2H), 9.34 (s, 1H), 8.53-8.45 (m, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.1, 2.4 Hz, 1H), 7.75-7.64 (m, 4H), 7.51 (d, J = 8.3 Hz, 1H), 7.12-7.03 (m, 2H), 4.40 (d, J = 5.1 Hz, 2H), 3.82 (s, 3H), 3.49-3.35 (m, 2H), 3.11 (t, J = 6.3 Hz, 2H).

Compound 108. 7-(4-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-tetrahydroisoquinoline hydrochloride

[Scheme 108]

1) 7-(4-(5-(pyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol -1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 108-1 (50.0 mg, 0.0870 mmol) was reacted with pyridin-4-ylboronic acid (16.0 mg, 0.130mmol) to obtain compound 108-2 (16 mg, 0.034 mmol, 38.6%). A white solid is obtained.

LC/MS 478.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.38 (s, 1H), 8.71 (d, J = 1.5 Hz, 1H), _8.70-8.66 (m, 2H), 7.99 (d, J = 8.8 Hz, 1H), 7.97-7.94 (m, 1H), 7.88-7.84 (m, 1H), 7.84-7.81 (m, 3H), 7.38 (d, J = 8.3 Hz, 1H), 6.06-5.99 (m, 1H) , 4.08 (s, 2H), 4.00-3.92 (m, 1H), 3.87-3.77 (m, 1H), 3.12 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H), 2.57-2.52 (m, 2H), 2.14-2.03 (m, 2H), 1.88-1.74 (m, 1H), 1.68-1.59 (m, 2H).

2) 7-(4-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Synthesis of tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 108-2 (15.0 mg, 0.0310 mmol) is reacted to obtain Compound 108 (9 mg, 0.021 mmol, 66.7%) as a white solid.

LC/MS 394.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.82 (s, 1H), 9.58 (d, J = 7.4 Hz, 2H), 9.45 (s, 1H), 8.93 (dd, J = 7.3, 2.0 Hz, 3H), 8.43 (d, J = 6.1 Hz, 2H), 8.08 (dd, J = 8.9, 1.8 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.2, 2.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 4.40 (d, J = 5.1 Hz, 2H), 3.12 (t, J = 6.2 Hz, 2H).

Compound 109. 7-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 109]

1) 7-(4-(5-(2-fluoro-6-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 109-1 (50 mg, 0.0870 mmol) was reacted with (2-fluoro-6-methoxyphenyl)boronic acid (22.1 mg, 0.130 mmol) to obtain compound 109-2 (30 mg, 0.057 mmol). mmol, 65.8%) of a white solid is obtained.

LC/MS 525.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.30 (s, 1H), 8.32 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.84-7.75 (m, 2H), 7.49- 7.38 (m, 2H), 7.33 (d, J = 8.3 Hz, 1H), 7.06-6.91 (m, 2H), 5.99 (dd, J = 9.7, 2.4 Hz, 1H), 3.98 (d, J = 22.0 Hz) , 3H), 3.82 (dd, J = 9.6, 4.5 Hz, 1H), 3.76 (s, 3H), 3.04 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H), 2.55 (t, J = 9.0 Hz, 2H), 2.15-2.02 (m, 2H), 1.81 (d, J = 8.2 Hz, 1H), 1.64 (dd, J = 7.9, 4.2 Hz, 2H).

2) 7-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 109-2 (25.0 mg, 0.0480 mmol) is reacted to obtain Compound 109 (20 mg, 0.042 mmol, 88%) as a white solid.

LC/MS 441.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.48 (s, 1H) _, 9.46 (s, 2H), 9.32 (s, 1H), 8.29 (s, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 8.3, 2.3 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.46-7.40 (m, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.99-6.90 (m, 1H), 4.39 (d, J = 5.0 Hz, 2H), 3.76 (s, 3H) ), 3.10 (t, J = 6.3 Hz, 2H).

Compound 110. 3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-day) Benzonitrile hydrochloride

[Scheme 110]

1) 3-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- Synthesis of 4-yl)-1H-indazol-5-yl)benzonitrile

As in the preparation method of Scheme 82, compound 110-1 (100 mg, 0.174 mmol) was reacted with (3-cyanophenyl)boronic acid (38.3 mg, 0.261 mmol) to produce compound 110-2 (85 mg, 0.169 mmol, 98%). ) to obtain a white solid.

LC/MS 502.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.37 (s, 1H), _8.61 (d, J = 1.7 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.17-8.08 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 8.8, 1.8 Hz, 1H), 7.88-7.85 (m, 1H), 7.84-7.80 (m, 1H), 7.79 (d , J = 2.3 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.02 (dd, J = 9.7, 2.3 Hz, 1H), 4.02 (s) , 2H), 3.96 (d, J = 11.8 Hz, 1H), 3.87-3.77 (m, 1H), 3.05 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H), 2.58 -2.52 (m, 2H), 2.16-2.02 (m, 2H), 1.80 (d, J = 8.7 Hz, 1H), 1.64 (s, 2H).

2) 3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)benzonitrile hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 110-2 (15.0 mg, 0.0300 mmol) is reacted to obtain Compound 110 (7.7 mg, 0.017 mmol, 56.7%) as a white solid.

LC/MS 418.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.56 (s, 1H), 9.41-9.33 (m, 3H), _8.60 (d, J = 1.7 Hz, 1H), 8.23 (d, J = 1.9 Hz, 1H), 8.14-8.09 (m, 1H), 8.02-7.95 (m, 2H), 7.88-7.81 (m, 2H), 7.77-7.69 (m, 2H), 7.53 (d, J = 8.3 Hz, 1H) , 4.41 (d, J = 5.0 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 2.53 (s, 2H).

Compound 111. 7-(4-(5-(4-chloro-3-fluorophenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 111]

1) 7-(4-(5-(4-chloro-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 111-1 (50 mg, 0.0870 mmol) was reacted with (4-chloro-3-fluorophenyl)boronic acid (22.7 mg, 0.130 mmol) to obtain compound 111-2 (30 mg, 0.057 mmol). mmol, 65.3%) of a white solid is obtained.

LC/MS 529.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.36 (s, 1H), _8.59 (d, J = 1.7 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.81 (dd, J = 8.2, 2.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 8.4, 2.1 Hz, 1H) ), 7.34 (d, J = 8.3 Hz, 1H), 6.05-5.96 (m, 1H), 4.16-4.07 (m, 2H), 3.96 (d, J = 17.2 Hz, 3H), 3.87-3.76 (m, 1H), 3.02 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.07 (d, J = 14.9 Hz, 2H), 1.80 (d, J = 10.2 Hz, 1H) , 1.64 (s, 2H).

2) 7-(4-(5-(4-chloro-3-fluorophenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 111-2 (30.0 mg, 0.0570 mmol) is reacted to obtain Compound 111 (22 mg, 0.046 mmol, 81%) as a white solid.

LC/MS 4145.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.55 (s, 1H) _, 9.39 (d, J = 10.1 Hz, 3H), 8.58 (d, J = 1.7 Hz, 1H), 8.05-7.94 (m, 2H), 7.86-7.78 (m, 2H), 7.76-7.69 (m, 2H), 7.67-7.60 (m, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.42 (t, J = 4.7 Hz) , 2H), 3.46-3.38 (m, 2H), 3.11 (t, J = 6.3 Hz, 2H).

Compound 112. (3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Zol-5-yl)phenyl)methanamine dihydrochloride

[Scheme 112]

1) (3-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol -4-yl)-1H-indazol-5-yl)phenyl)methanamine synthesis

As in the preparation method of Scheme 82, compound 112-1 (50 mg, 0.0870 mmol) was reacted with (3-(aminomethyl)phenyl)boronic acid (19.6 mg, 0.130 mmol) to obtain compound 112-2 (19 mg, 0.038 mmol). , 43.2%) of a white solid is obtained.

LC/MS 506.4 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d6 ) δ 9.34 (d, J = 2.8 Hz, 1H), 8.59 (s _, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 16.1, 8.5 Hz, 2H), 7.77 (s, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.35 (dd, J = 23.4, 8.0 Hz, 2H), 6.01 (d, J = 9.7 Hz, 1H), 3.97 (s, 3H), 3.89 (s, 2H), 3.83 (d, J = 10.8 Hz, 1H), 3.18 (s, 1H), 2.99 ( d, J = 5.9 Hz, 2H), 2.78 (d, J = 6.1 Hz, 2H), 2.18-1.73 (m, 4H), 1.64 (s, 2H).

2) (3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl) Synthesis of phenyl)methanamine dihydrochloride

As in the preparation method of Scheme 87, Compound 112-2 (18.0 mg, 0.0360 mmol) is reacted to obtain Compound 112 (12 mg, 0.024 mmol, 68.2%) as a white solid.

LC/MS 422.3 [M + H] ⁺

^1H NMR (500 MHz, DMSO-d6) δ 13.59 (s, 1H), 9.84-9.69 (m, 2H), 9.43 (d, J = 2.7 Hz, 1H), 8.63 (s, 1H), 8.56 (s) , 3H), 8.06 (s, 1H), 8.00 (d, J = 5.8 Hz, 2H), 7.84-7.71 (m, 3H), 7.56 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 4.40 (s, 2H), 4.15 (d, J = 6.0 Hz, 2H), 3.47-3.38 (m, 2H), 3.13 (d, J = 6.3 Hz, 2H).

Compound 113. 4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-day) Phenol hydrochloride

[Scheme 113]

1) 4-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- Synthesis of 4-yl)-1H-indazol-5-yl)phenol

As in the preparation method of Scheme 82, compound 113-1 (50 mg, 0.0870 mmol) was reacted with (4-hydroxyphenyl)boronic acid (17.9 mg, 0.130 mmol) to obtain compound 113-2 (20 mg, 0.041 mmol, 46.7%). ) to obtain a white solid.

LC/MS 493.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.32 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 7.89-7.80 (m, 2H), 7.79-7.72 (m, 2H), 7.60-7.54 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 6.93-6.86 (m, 2H), 5.97 (dd, J = 9.8, 2.4 Hz, 1H), 4.00 (s, 2H), 3.96 (d, J = 11.5 Hz, 1H), 3.86-3.74 (m, 1H), 3.04 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.9 Hz, 2H) ), 2.48 (s, 2H), 2.12-2.03 (m, 2H), 1.80 (d, J = 11.1 Hz, 1H), 1.67-1.59 (m, 2H).

2) 4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)phenol hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 113-2 (20.0 mg, 0.0410 mmol) is reacted to obtain Compound 113 (12 mg, 0.027 mmol, 66.4%) as a white solid.

LC/MS 409.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 9.55 (s, 3H), 9.33 (s, 1H), 8.45 (s, 1H), 8.00 (d, J = 2.3 Hz, 1H ), 7.97 (dd, J = 8.3, 2.5 Hz, 1H), 7.71-7.63 (m, 2H), 7.59-7.53 (m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 6.94-6.88 ( m, 2H), 4.40 (d, J = 5.0 Hz, 2H), 3.47-3.40 (m, 2H), 3.11 (t, J = 6.3 Hz, 2H).

Compound 114. 3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-day) Benzaldehyde hydrochloride

[Scheme 114]

1) 3-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- Synthesis of 4-yl)-1H-indazol-5-yl)benzaldehyde

As in the preparation method of Scheme 82, compound 114-1 (50 mg, 0.0870 mmol) was reacted with (3-formylphenyl)boronic acid (19.5 mg, 0.130 mmol) to obtain compound 114-2 (35 mg, 0.069 mmol, 80%). ) to obtain a white solid.

LC/MS 505.4 [M + H] ⁺

2) 3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)benzaldehyde hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 114-2 (30.0 mg, 0.0590 mmol) is reacted to obtain Compound 114 (22 mg, 0.048 mmol, 81%) as a white solid.

LC/MS 421.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 10.16 (s, 1H), 9.47 (s, 2H), 9.38 (s, 1H), 8.65 (d, J = 1.7 Hz, 1H ), 8.28 (t, J = 1.8 Hz, 1H), 8.16-8.08 (m, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.99-7.96 (m, 1H), 7.95-7.91 (m, 1H), 7.85 (dd, J = 8.7, 1.7 Hz, 1H), 7.80-7.71 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 4.41 (t, J = 4.7 Hz, 2H), 3.44 (d, J = 7.0 Hz, 2H), 3.11 (t, J = 6.2 Hz, 2H).

Compound 115. 1-(4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H -indazol-5-yl)phenyl)ethan-1-one hydrochloride

[Scheme 115]

1) 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3 -triazol-4-yl)-1H-indazol-5-yl)phenyl)ethan-1-one synthesis

As in the preparation method of Scheme 82, compound 115-1 (50 mg, 0.0870 mmol) was reacted with (4-acetylphenyl)boronic acid (21.3 mg, 0.130 mmol) to obtain compound 115-2 (35 mg, 0.067 mmol, 78%). ) to obtain a white solid.

LC/MS 519.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.67 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.00 - 7.92 (m, 2H) ), 7.95-7.88 (m, 2H), 7.82 (dd, J = 8.1, 2.4 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 9.8, 2.3 Hz, 1H), 3.97 (d, J = 17.0 Hz, 3H), 3.82 (dt, J = 11.6, 7.0 Hz, 1H), 3.02 (t, J = 5.8 Hz, 2H) , 2.79 (t, J = 5.9 Hz, 2H), 2.64 (s, 3H), 2.53 (d, J = 7.8 Hz, 2H), 2.07 (d, J = 12.3 Hz, 2H), 1.86 (d, J = 37.9 Hz, 1H), 1.64 (s, 2H).

2) 1-(4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- Synthesis of yl)phenyl)ethan-1-one hydrochloride

As in the preparation method of Scheme 87, Compound 115-2 (30.0 mg, 0.0580 mmol) is reacted to obtain Compound 115 (23 mg, 0.0490 mmol, 84%) as a white solid.

LC/MS 435.3 [M + H] ⁺

^1H NMR (500 MHz, DMSO-d6) δ 13.59 (s, 1H), 9.52 (s, 2H), 9.39 (d, J = 2.6 Hz, 1H), 8.67 (s, 1H), 8.10 (d, J = 7.9 Hz, 2H), 8.03-7.97 (m, 2H), 7.96-7.91 (m, 2H), 7.89-7.81 (m, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.41 (s, 2H), 3.45 (q, J = 5.3, 4.8 Hz, 2H), 3.12 (d, J = 6.5 Hz, 2H), 2.64 (d, J = 2.6 Hz, 3H).

Compound 116. 7-(4-(5-(3-fluoro-5-isopropoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 116]

1) 7-(4-(5-(3-fluoro-5-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 116-1 (50 mg, 0.0870 mmol) was reacted with (3-fluoro-5-isopropoxyphenyl)boronic acid (21.3 mg, 0.130 mmol) to obtain compound 116-2 (30 mg, 0.054 mmol). mmol, 62.5%) of a white solid is obtained.

LC/MS 553.4 [M + H] ⁺

2) 7-(4-(5-(3-fluoro-5-isopropoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 116-2 (30.0 mg, 0.0540 mmol) is reacted to obtain Compound 116 (18 mg, 0.036 mmol, 65.7%) as a white solid.

LC/MS 469.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.57 (s, 2H), 9.38 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.02-7.94 (m , 2H), 7.80-7.74 (m, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.16-7.05 (m, 2H), 6.88-6.80 ( m, 1H), 4.82-4.72 (m, 1H), 4.40 (t, J = 4.6 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 1.32 (d, J = 6.0 Hz, 6H).

Compound 117. 1-(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

[Scheme 117]

1) 1-(7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1, Synthesis of 2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

Add acetic anhydride (4.29 ul, 0.045 mmol) and TEA (8.46 ul, 0.061 mmol) to the DCM solution of compound 117-1 (15 mg, 0.030 mmol). Stir the reaction mixture at room temperature for 4 h. Add water to the reaction mixture. After quenching, EA was extracted and the organic layer was washed with water and brine. The organic layer was dried with sodim sulfate, concentrated, and purified by MPLC (solvent MC MeOH 10%) to obtain compound 117-2 (7.2 mg 0.013 mmol, 44%). ) to get

^1H NMR (300 MHz, DMSO- d6 ) δ 9.37 (d, J = 2.3 Hz, 1H), 8.59 ( _s , 1H), 8.34-8.17 (m, 2H), 8.04-7.91 (m, 2H), 7.89 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.60-7.50 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.03 (d, J = 9.0 Hz, 1H), 4.79 (s, 1H), 4.73 (s, 1H), 4.05-3.91 (m, 1H), 3.89-3.78 (m, 1H), 3.72 (t, J = 5.9 Hz, 2H) , 3.05-2.80 (m, 2H), 2.61-2.56 (m, 1H), 2.27-2.01 (m, 5H), 2.02-1.75 (m, 1H), 1.71-1.47 (m, 2H).

2) 1-(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)ethan-1-one synthesis

As in the preparation method of Scheme 87, compound 117-2 (6.3 mg) is reacted to obtain compound 117 (4 mg, 75%).

^1H NMR (400 MHz, DMSO- d6 ) δ 13.55 (s, 1H), _9.32 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.27 (d, J = 5.0 Hz, 1H) , 8.22 (ddd, J = 9.7, 7.3, 1.9 Hz, 1H), 7.98 - 7.83 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 (dt, J = 8.6, 1.8 Hz, 1H) ), 7.52 (ddd, J = 7.1, 4.9, 1.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 4.79 (s, 0.7H), 4.73 (s, 1.3H), 3.72 (td, J = 6.0, 2.0 Hz, 2H), 2.97 (t, J = 5.9 Hz, 1.3H), 2.85 (t, J = 6.0 Hz, 0.7H), 2.13 (s, 1H), 2.12 (s, 2H).

LC/MS 454.3 [m+H]

Compound 118. (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone

[Scheme 118]

1) (7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2, Synthesis of 3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone

Add benzoyl chloride (5.27 ul, 0.045 mmol) and TEA (8.46 ul, 0.061 mmol) to the DCM solution of compound 118-1 (15 mg, 0.030 mmol). The reaction mixture was stirred at room temperature for 4 h. Add water to the reaction mixture and mix well. Next, it is extracted with EA, and the organic layer is washed with water and brine, then dried and concentrated with sodim sulfate. The crude mixture was purified by MPLC (solvent MC MeOH 10%) to obtain compound 118-2 (9.2 mg 0.015 mmol, 51%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.45-9.28 (m, 1H), 8.59 (s, 1H), 8.37-8.18 (m, 2H), 8.12-7.87 (m, 3H), 7.84-7.70 (m, 1H), 7.62-7.28 (m, 7H), 6.02 (d, J = 9.5 Hz, 1H), 4.92 (s, 1H), 4.72 (s, 1H), 4.08-3.91 (m, 1H), 3.90-3.76 (m, 1H), 3.62 (s, 1H), 3.30 (s, 1H), 2.96 (s, 2H), 2.63-2.55 (m, 1H), 2.18-2.02 (m, 2H), 1.90- 1.74 (m, 1H), 1.69-1.54 (m, 2H).

2) (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin -2(1H)-yl)(phenyl)methanone synthesis

As in the preparation method of Scheme 87, compound 118-2 (7.5 mg) is reacted to obtain compound 118 (5 mg, 78%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.55 (s, 1H), 9.46-9.16 (m, 1H), 8.57 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.25- 8.13 (m, 1H), 8.04-7.94 (m, 1H), 7.91-7.85 (m, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 11.6 Hz, 7H), 4.92 (s, 1H), 4.72 (s, 1H), 4.03-3.82 (m, 1H), 3.70-3.57 (m, 1H), 3.06-2.85 (m, 2H) ).

LC/MS 515.3 [m+H]

Compound 119. (4-Chlorophenyl)(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazole -1-yl)-3,4-dihydroisoquinoline-2(1H)-yl)methanone

[Scheme 119]

1) (4-chlorophenyl)(7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H -1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone synthesis

As in the preparation method of Scheme 118, compound 119-1 (30 mg, 0.061 mmol) is reacted with 4-chloro benzoyl chloride (11.64 ul, 0.091 mmol) to obtain compound 119-2 (16.9 mg 0.027 mmol, 44%). .

^1H NMR (500 MHz, DMSO- d6 ) δ 9.35 (d, J = 41.2 Hz _, 1H), 8.59 (s, 1H), 8.31 (d, J = 17.7 Hz, 1H), 8.24 (s, 1H) , 8.07 - 7.70 (m, 4H), 7.55 (d, J = 9.5 Hz, 5H), 7.47 (d, J = 8.5 Hz, 1H), 6.03 (s, 1H), 4.91 (s, 1H), 4.71 ( s, 1H), 3.95 (s, 2H), 3.83 (s, 1H), 3.62 (s, 1H), 2.97 (s, 2H), 2.58 - 2.53 (m, 1H), 2.10 (s, 2H), 1.82 (s, 1H), 1.64 (s, 2H).

2) (4-chlorophenyl)(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- Synthesis of 3,4-dihydroisoquinolin-2(1H)-yl)methanone

As in the preparation method of Scheme 87, compound 119-2 (15 mg) is reacted to obtain compound 119 (11 mg, 85%).

^1H NMR (400 MHz, DMSO- d6 ) δ 13.55 (s, 1H), _9.30 (d, J = 25.6 Hz, 1H), 8.57 (s, 1H), 8.27 (d, J = 4.5 Hz, 1H) , 8.22 (t, J = 9.3 Hz, 1H), 8.08-7.94 (m, 1H), 7.89 (dd, J = 8.1, 2.3 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 ( d, J = 8.7 Hz, 1H), 7.55 (q, J = 8.1, 7.7 Hz, 5H), 7.46 (d, J = 8.4 Hz, 1H), 4.91 (s, 1H), 4.70 (s, 1H), 3.96-3.87 (m, 1H), 3.68-3.59 (m, 1H), 3.05-2.87 (m, 2H).

LC/MS 550.3 [m+H]

Compound 120. (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 3,4-dihydroisoquinolin-2(1H)-yl)(4-methoxyphenyl)methanone

[Scheme 120]

1) ((7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2 ,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(4-methoxyphenyl)methanone synthesis

As in the preparation method of Scheme 118, compound 120-1 (30 mg, 0.061 mmol) is reacted with 4-methoxy benzoyl chloride (12.29 ul, 0.091 mmol) to obtain compound 120-2 (15.2 mg 0.024 mmol, 40%). .

^1H NMR (400 MHz, DMSO- d6 ) δ 9.35 (s, 1H), 8.58 (s, 1H), _8.30-8.27 (m, 1H), 8.26-8.19 (m, 1H), 8.04-7.85 (m) , 3H), 7.76 (d, J = 8.7 Hz, 1H), 7.57-7.50 (m, 1H), 7.50-7.36 (m, 3H), 7.03 (d, J = 8.7 Hz, 2H), 6.02 (d, J = 9.5 Hz, 1H), 4.83 (s, 2H), 4.05-3.90 (m, 1H), 3.87-3.75 (m, 4H), 3.56-3.47 (m, 2H), 3.03-2.92 (m, 2H) , 2.65-2.57 (m, 1H), 2.19-2.02 (m, 2H), 1.92-1.76 (m, 1H), 1.68-1.56 (m, 2H).

2) (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin -2(1H)-yl)(4-methoxyphenyl)methanone synthesis

As in the preparation method of Scheme 87, compound 120-2 (14 mg) is reacted to obtain compound 120 (10 mg, 75%).

^1H NMR (400 MHz, DMSO- d6 ) δ 13.55 (s, 1H), 9.31 (s, 1H), 8.56 (s, 1H), 8.27 (dd, J = _4.9 , 1.5 Hz, 1H), 8.22 ( ddd, J = 9.7, 7.4, 1.9 Hz, 1H), 8.00-7.80 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 (dt, J = 8.6, 1.8 Hz, 1H), 7.52 (ddd, J = 7.0, 4.8, 1.8 Hz, 1H), 7.49-7.37 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H), 4.84 (s, 2H), 3.82 (s, 3H), 3.78-3.64 (m, 2H), 3.11-2.85 (m, 2H).

LC/MS 556.3 [m+H]

Compound 121. (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 3,4-dihydroisoquinolin-2(1H)-yl)(p-tolyl)methanone

[Scheme 121]

1) (7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2, Synthesis of 3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(p-tolyl)methanone

As in the preparation method of Scheme 118, compound 121-1 (30 mg, 0.061 mmol) is reacted with 4-methyl benzoyl chloride (12.01 ul, 0.091 mmol) to obtain compound 121-2 (16.9 mg 0.027 mmol, 46%). .

^1H NMR (400 MHz, DMSO- d6 ) δ 9.36 (s, 1H) _, 8.58 (s, 1H), 8.28 (dd, J = 4.8, 1.5 Hz, 1H), 8.23 (t, J = 9.0 Hz, 1H), 8.07-7.82 (m, 3H), 7.76 (d, J = 8.7 Hz, 1H), 7.53 (t, J = 5.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39 ( d, J = 7.8 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.02 (d, J = 9.6 Hz, 1H), 5.01-4.63 (m, 2H), 4.04-3.74 (m, 3H) ), 3.63 (s, 1H), 2.96 (s, 2H), 2.65-2.58 (m, 1H), 2.37 (s, 3H), 2.19-2.00 (m, 2H), 1.89-1.77 (m, 1H), 1.69-1.62 (m, 2H).

2) (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin -2(1H)-yl)(p-tolyl)methanone synthesis

As in the preparation method of Scheme 87, compound 121-2 (15 mg) is reacted to obtain compound 121 (11 mg, 85%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.55 (s, 1H), 9.32 (s, 1H), 8.56 (s, 1H), 8.33-8.22 (m, 1H), 8.22 (t, J = 9.2 Hz, 1H), 7.99 (s, 1H), 7.88 (dd, J = 8.3, 2.3 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.57-7.48 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 5.05-4.54 (m , 2H), 4.02-3.80 (m, 1H), 3.73-3.61 (m, 1H), 2.99-2.91 (m, 2H), 2.37 (s, 3H).

LC/MS 530.3 [m+H]

Compound 122. (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-4-yl)methanone hydrochloride

[Scheme 122]

1) (7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2, Synthesis of 3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-4-yl)methanone

Add isonicotinic acid (7.45 mg, 0.061 mmol), HATU (30.7 mg, 0.081 mmol), and DIPEA (21.09 μl, 0.121 mmol) to a DMF solution of compound 122-1 (20 mg, 0.040 mmol) and stir at 30°C for 13 h. do. Water was added to the reaction mixture, quenched, extracted with EA, washed with water and brine, dried with sodium sulfate, concentrated, and the crude mixture obtained was purified by MPLC (solvent MC MeOH 10%) to obtain compound 122-2 (6.9 mg, 0.011 mmol, 28.5% yield).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.61 - 9.20 (m, 1H), 8.72 (d, J = 5.9 Hz, 2H), 8.64-8.52 (m, 1H), 8.34-8.15 (m, 2H) ), 8.06-7.70 (m, 4H), 7.60-7.39 (m, 4H), 6.07-5.83 (m, 1H), 4.94 (s, 1H), 4.65 (s, 1H), 4.05-3.88 (m, 2H) ), 3.87-3.78 (m, 1H), 3.66-3.51 (m, 1H), 3.10-2.87 (m, 2H), 2.65-2.52 (m, 1H), 2.20-1.99 (m, 2H), 1.91-1.72 (m, 1H), 1.68-1.41 (m, 2H).

2) (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin -2(1H)-yl)(pyridin-4-yl)methanone hydrochloride synthesis

As in the preparation method of Scheme 87, compound 122-2 (5 mg) is reacted to obtain compound 122 (4 mg, 87%).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 13.60 (s, 1H), 9.36 (s, 0.6H), 9.27 (s, 0.4H), 9.02-8.82 (m, 2H), 8.56 (d, J = 15.6 Hz, 1H), 8.36-8.12 (m, 2H), 8.04 (s, 1H), 7.90 (dd, J = 9.8, 5.8 Hz, 3H), 7.72 (ddd, J = 22.6, 8.5, 5.0 Hz, 3H), 7.58-7.32 (m, 2H), 4.96 (s, 1.2H), 4.64 (s, 0.8H), 3.99-3.88 (m, 0.8H), 3.62-3.51 (m, 1.2H), 3.06- 2.99 (m, 0.8H), 2.98-2.91 (m, 1.2H).

LC/MS 533.3 [m+H]

Compound 123. (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-3-yl)methanone hydrochloride

[Scheme 123]

1) (7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2, Synthesis of 3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)(pyridin-3-yl)methanone

As in the preparation method of Scheme 122, compound 123-1 (20 mg, 0.040 mmol) is reacted with nicotinic acid (7.45 mg, 0.061 mmol) to obtain compound 123-2 (9.3 mg, 0.015 mmol, 38.4% yield).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.54-9.20 (m, 1H), 8.86-8.65 (m, 2H), 8.62-8.45 (m, 1H), 8.35-8.17 (m, 2H), 8.11 -7.67 (m, 5H), 7.65-7.25 (m, 3H), 6.03 (d, J = 9.4 Hz, 1H), 4.84 (d, J = 58.5 Hz, 2H), 4.08-3.89 (m, 2H), 3.86-3.74 (m, 1H), 3.68-3.56 (m, 1H), 3.06-2.91 (m, 2H), 2.63-2.53 (m, 1H), 2.20-1.91 (m, 2H), 1.89-1.74 (m) , 1H), 1.69-1.57 (m, 2H).

2) (7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin Synthesis of -2(1H)-yl)(pyridin-3-yl)methanone hydrochloride

As in the preparation method of Scheme 87, compound 123-2 (7 mg) is reacted to obtain compound 123 (5.5 mg, 85%).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 13.60 (s, 1H), 9.49-9.20 (m, 1H), 8.83 (d, J = 2.1 Hz, 1H), 8.79 (dd, J = 5.1, 1.6 Hz, 1H), 8.63-8.49 (m, 1H), 8.40-8.08 (m, 4H), 8.08-7.84 (m, 2H), 7.83-7.62 (m, 3H), 7.60-7.40 (m, 2H), 4.95 (s, 1H), 4.75 (s, 1H), 4.04-3.90 (m, 1H), 3.83-3.76 (m, 1H), 3.08-2.86 (m, 2H).

LC/MS 533.3 [m+H]

Compound 124. 2-Benzyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazole-1- 1)-1,2,3,4-tetrahydroisoquinoline

[Scheme 124]

1) 2-benzyl-7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1 ,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

Add benzaldehyde (4.28 mg, 0.040 mmol) and acetic acid (1 drop, catalytic amount) to a solution of compound 124-1 (20 mg, 0.010 mmol) in MeOH (1 mL) and stir overnight. Add NaBH ₃ CN (3.80 mg, 0.061 mmol) to the reaction mixture, stir for 1 h, and completely distill off the solvent. The residue was dissolved in MC, washed with water and brine, and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting concentrate was purified by MPLC (solvent 10% MeOH/MC) to obtain compound 124-2 (14 mg, 0.024 mmol, 59%) as a yellow solid.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.33 (s, 1H), 8.57 (s, 1H), 8.31-8.27 (m, 1H), 8.26-8.17 (m, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 8.1, 2.3 Hz, 1H), 7.80-7.69 (m, 2H), 7.53 (ddd, J = 7.1, 4.9, 1.9 Hz, 1H), 7.45-7.32 ( m, 5H), 7.32-7.25 (m, 1H), 6.01 (d, J = 8.9 Hz, 1H), 4.01-3.91 (m, 1H), 3.87-3.76 (m, 1H), 3.71 (s, 2H) , 3.66 (s, 2H), 3.00-2.85 (m, 2H), 2.83-2.63 (m, 2H), 2.64-2.55 (m, 1H), 2.18-1.99 (m, 2H), 1.89-1.75 (m, 1H), 1.68-1.51 (m, 2H).

2) 2-benzyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 87, compound 124-2 (12 mg, 0.020 mmol) is reacted to obtain compound 124 (9.2 mg, 0.018 mmol, 90%).

^1H NMR (500 MHz, DMSO- d6 ) δ 11.41 (s, 1H) _, 9.35 (s, 1H), 8.56 (s, 1H), 8.31-8.26 (m, 1H), 8.22 (t, J = 9.1 Hz, 1H), 8.04-7.89 (m, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.73-7.64 (m, 3H), 7.63-7.39 (m, 5H), 4.61-4.52 (m, 1H), 4.52-4.46 (m, 1H), 4.46-4.33 (m, 2H), 3.68-3.62 (m, 1H), 3.45-3.29 (m, 2H), 3.26-3.11 (m, 1H).

LC/MS 502.4 [M+H]

Compound 125. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2 -(4-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline

[Scheme 125]

1) 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-2-(4-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 124, Compound 125-1 (20 mg, 0.010 mmol) and 4-methylbenzaldehyde (4.85 mg, 0.040 mmol) were reacted to produce Compound 125-2 (13 mg, 0.022 mmol, 54%) as a yellow solid. get

^1H NMR (300 MHz, DMSO- d6 ) δ 9.33 (s, 1H) _, 8.57 (s, 1H), 8.28 (d, J = 4.9 Hz, 1H), 8.26-8.17 (m, 1H), 7.96 ( d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.79-7.69 (m, 2H), 7.53 (ddd, J = 7.0, 4.8, 1.8 Hz, 1H), 7.36 (d , J = 8.4 Hz, 1H), 7.27 (d, J = 7.7 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H), 6.01 (d, J = 9.0 Hz, 1H), 4.00-3.90 (m , 1H), 3.86-3.76 (m, 1H), 3.65 (s, 2H), 3.63 (s, 2H), 2.97-2.85 (m, 2H), 2.79-2.64 (m, 2H), 2.62-2.56 (m , 1H), 2.30 (s, 3H), 2.17-1.97 (m, 2H), 1.90-1.74 (m, 1H), 1.72-1.58 (m, 2H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2-(4-methylbenzyl )-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 87, compound 125-2 (12 mg, 0.020 mmol) is reacted to obtain compound 125 (8.7 mg, 0.017 mmol, 84%).

^1H NMR (500 MHz, DMSO- d6 ) δ 10.93 (s, 1H) _, 9.36 (s, 1H), 8.56 (s, 1H), 8.28 (s, 1H), 8.22 (t, J = 9.0 Hz, 1H), 8.05-7.96 (m, 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.59-7.44 (m, 4H), 7.33 (d, J = 7.5 Hz, 2H), 4.58-4.32 (m, 4H), 3.85-3.71 (m, 1H), 3.41-3.25 (m, 2H), 3.21-3.08 (m, 1H), 2.37 (s, 3H).

LC/MS 516.4 [M+H]

Compound 126. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N -Phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide

[Scheme 126]

1) 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-N-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

Add isocyanatobenzene (7.21 mg, 0.061 mmol) and TEA (8.17 mg, 0.081 mmol) to a solution of compound 126-1 (20 mg, 0.040 mmol) in DCM (1 ml) and stir at room temperature for 4 h. Water was added to the reaction mixture, extracted with EA, and the organic layer was washed with water and brine, dried with sodim sulfate, concentrated under reduced pressure, and purified by MPLC (solvent MC MeOH 10%) to obtain compound 126-2 (16 mg 0.026 mmol). , 65%) is obtained.

^1H NMR (500 MHz, DMSO- d6 ) δ 9.41 (s, 1H) _, 8.69 (s, 1H), 8.60 (s, 1H), 8.29 (d, J = 4.0 Hz, 1H), 8.25 (t, J = 9.4 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.94 (s, 1H), 7.92-7.83 (m, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.62- 7.41 (m, 4H), 7.31-7.17 (m, 2H), 7.02-6.90 (m, 1H), 6.03 (d, J = 9.6 Hz, 1H), 4.78 (s, 2H), 4.04-3.93 (m, 1H), 3.87-3.71 (m, 3H), 3.05-2.88 (m, 2H), 2.61-2.54 (m, 1H), 2.19-2.03 (m, 2H), 1.89-1.77 (m, 1H), 1.70- 1.58 (m, 2H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-phenyl-3, Synthesis of 4-dihydroisoquinoline-2(1H)-carboxamide

As in the preparation method of Scheme 87, compound 126-2 (15 mg, 0.024 mmol) is reacted to obtain compound 126 (10 mg, 0.019 mmol, 77%).

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.37 (s, 1H), 8.70 (s, 1H), 8.58 (s, 1H), 8.29-8.27 (m, 1H), 8.26-8.19 (m, 1H) ), 7.92 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.58-7.42 (m , 4H), 7.29-7.18 (m, 2H), 6.99-6.92 (m, 1H), 4.79 (s, 2H), 3.87-3.68 (m, 2H), 3.08-2.90 (m, 2H).

LC/MS 531.3 [M+H]

Compound 127. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N -(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[Scheme 127]

1) 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-N-(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 126, compound 127-1 (20 mg, 0.040 mmol) was reacted with 1-isocyanato-2-methylbenzene (6.05 mg, 0.061 mmol) to obtain compound 127-2 (11.8 mg 0.019 mmol, 62%). get

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.40 (s, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 8.27-8.17 (m, 2H), 7.98 (d, J = 8.9 Hz, 1H), 7.95-7.83 (m, 2H), 7.77 (d, J = 8.7 Hz, 1H), 7.54 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.32-7.17 (m , 2H), 7.18-7.12 (m, 1H), 7.10-6.92 (m, 1H), 6.03 (d, J = 9.6 Hz, 1H), 4.78 (s, 2H), 4.13-3.91 (m, 1H), 3.88-3.75 (m, 3H), 3.03-2.90 (m, 2H), 2.68-2.55 (m, 1H), 2.19 (s, 3H), 2.15-2.01 (m, 2H), 1.90-1.75 (m, 1H) ), 1.74-1.48 (m, 2H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(o-tolyl )-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 87, Compound 127-2 (10 mg, 0.016 mmol) is reacted to obtain Compound 127 (7 mg, 0.013 mmol, 81%) as a white solid.

^1H NMR (500 MHz, DMSO- d6 ) δ 9.37 (s, 1H), 8.58 (s, 1H), _8.35-8.26 (m, 1H), 8.26-8.18 (m, 2H), 8.02-7.84 (m) , 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.56-7.50 (m, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.27 -7.18 (m, 2H), 7.15 (t, J = 7.7 Hz, 1H), 7.10-7.01 (m, 1H), 4.78 (s, 2H), 3.86-3.68 (m, 2H), 3.03-2.82 (m , 2H), 2.19 (s, 3H).

LC/MS 545.3 [M+H]

Compound 128. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N -(naphthalen-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[Scheme 128]

1) 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-N-(naphthalen-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 126, compound 128-1 (10 mg, 0.020 mmol) is reacted with 1-isocyanatonaphthalene (5.12 mg, 0.030 mmol) to obtain compound 128-2 (10 mg 0.015 mmol, 75%).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.43 (s, 1H), 8.81 (s, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 8.28-8.18 (m, 1H), 8.02-7.95 (m, 3H), 7.95-7.90 (m, 2H), 7.78-7.70 (m, 2H), 7.61-7.42 (m, 6H), 6.03 (d, J = 9.7 Hz, 1H), 4.87 ( s, 2H), 4.07-3.94 (m, 1H), 3.92-3.86 (m, 2H), 3.84-3.75 (m, 1H), 3.14-2.98 (m, 2H), 2.66-2.55 (m, 1H), 2.17-2.01 (m, 2H), 1.92-1.73 (m, 1H), 1.72-1.62 (m, 2H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(naphthalen-1 -yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 87, Compound 128-2 (8 mg, 0.012 mmol) is reacted to obtain Compound 128 (5 mg, 0.012 mmol, 72%) as a white solid.

^1H NMR (300 MHz, DMSO- d6 ) δ 13.57 (s, 1H) _, 9.37 (s, 1H), 8.80 (s, 1H), 8.58 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.24-8.17 (m, 1H), 8.04-7.87 (m, 4H), 7.80-7.73 (m, 2H), 7.71-7.65 (m, 1H), 7.59-7.45 (m, 6H), 4.87 ( s, 2H), 3.88 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 5.8 Hz, 2H).

LC/MS 581.3 [M+H]

Compound 129. N-Cyclopentyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazole-1 -1)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[Scheme 129]

1) N-cyclopentyl-7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1 ,2,3-triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 126, compound 129-1 (10 mg, 0.020 mmol) is reacted with isocyanatocyclopentane (3.36 mg, 0.030 mmol) to obtain compound 129-2 (8.4 mg 0.015 mmol, 69%).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.39 (s, 1H), 8.59 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H), 8.24 (ddd, J = 9.8, 7.3, 1.9 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.92 - 7.83 (m, 2H), 7.81-7.71 (m, 1H), 7.53 (ddd, J = 7.0, 4.8, 1.8 Hz, 1H) , 7.42 (d, J = 8.9 Hz, 1H), 6.40 (d, J = 6.9 Hz, 1H), 6.03 (dd, J = 9.7, 2.4 Hz, 1H), 4.62 (s, 2H), 4.06-3.91 ( m, 2H), 3.87-3.76 (m, 1H), 3.60 (t, J = 5.8 Hz, 2H), 2.85 (t, J = 5.8 Hz, 2H), 2.65-2.57 (m, 1H), 2.17-2.02 (m, 2H), 1.88-1.74 (m, 3H), 1.67-1.57 (m, 4H), 1.54-1.33 (m, 4H).

2) N-cyclopentyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-carboxamide

As in the preparation method of Scheme 87, Compound 129-2 (6 mg, 0.0099 mmol) is reacted to obtain Compound 129 (4 mg, 0.0077 mmol, 77%) as a white solid.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 13.59 (s, 1H), 9.34 (s, 1H), 8.57 (s, 1H), 8.31-8.25 (m, 1H), 8.24-8.17 (m, 1H) ), 7.92-7.81 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.68 (dt, J = 8.7, 1.8 Hz, 1H), 7.53 (ddd, J = 7.1, 4.8, 1.9 Hz, 1H), 7.45-7.38 (m, 1H), 6.39 (s, 1H), 4.62 (s, 2H), 3.73-3.65 (m, 1H), 3.61 (t, J = 5.8 Hz, 2H), 2.85 (t , J = 5.8 Hz, 2H), 1.89-1.73 (m, 2H), 1.72-1.57 (m, 2H), 1.53-1.34 (m, 4H).

LC/MS 523.3 [M+H]

Compound 130. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N -(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[Scheme 130]

1) 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-N-(4-methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 126, compound 130-1 (10 mg, 0.020 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (4.94 mg, 0.030 mmol) were reacted to produce compound 130-2 (9.1 mg 0.020 mmol, 69 %) is obtained.

^1H NMR (300 MHz, DMSO- d6 ) δ 9.39 (s, 1H) _, 8.59 (s, 1H), 8.36-8.17 (m, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.87 ( s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.60-7.45 (m, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.29-7.10 (m, 3H), 6.86 (d) , J = 8.6 Hz, 2H), 6.29 (s, 1H), 6.03 (d, J = 9.4 Hz, 1H), 4.66 (s, 2H), 4.40-4.08 (m, 2H), 4.05-3.91 (m, 1H), 3.87-3.76 (m, 1H), 3.72 (s, 3H), 3.65 (t, J = 5.9 Hz, 2H), 2.88 (d, J = 5.9 Hz, 2H), 2.64-2.57 (m, 1H) ), 2.17-2.01 (m, 2H), 1.92-1.73 (m, 1H), 1.69-1.53 (m, 2H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxybenzyl )-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 87, Compound 130-2 (7 mg, 0.010 mmol) is reacted to obtain Compound 130 (4 mg, 0.0070 mmol, 66%).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.34 (s, 1H), 8.57 (s, 1H), 8.41-8.16 (m, 2H), 7.94-7.80 (m, 2H), 7.75 (d, J = 8.7 Hz, 1H), 7.72-7.63 (m, 1H), 7.52 (ddd, J = 7.0, 4.8, 1.9 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.27-7.08 (m, 3H), 6.95-6.80 (m, 2H), 4.66 (s, 2H), 4.32-4.13 (m, 2H), 3.72 (s, 3H), 3.65 (t, J = 5.9 Hz, 2H), 2.88 (t , J = 5.7 Hz, 2H).

LC/MS 575.3 [M+H]

Compound 131. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N -(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

[Scheme 131]

1) 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-N-(4-(trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide synthesis

As in the preparation method of Scheme 126, compound 131-1 (10 mg, 0.020 mmol) was reacted with 1-isocyanato-4-(trifluoromethoxy)benzene (6.15 mg, 0.030 mmol) to obtain compound 131-2 (7.9 mg, 0.011 mmol, 56%).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.40 (s, 1H), 8.88 (s, 1H), 8.59 (s, 1H), 8.33-8.18 (m, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.94 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.81-7.72 (m, 1H), 7.61 (d, J = 9.1 Hz, 2H), 7.57-7.50 (m , 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 6.09-5.94 (m, 1H), 4.79 (s, 2H), 4.10-3.92 (m, 1H), 3.89-3.68 (m, 3H), 3.06-2.89 (m, 2H), 2.65-2.54 (m, 1H), 2.20-2.01 (m, 2H), 1.94-1.76 (m, 1H), 1.71- 1.56 (m, 2H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(4-( Synthesis of trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

To a solution of compound 131-2 (6 mg, 0.0086 mmol) in DCM (1 ml) was added 4 N HCl in dioxane (0.5 mL) at room temperature. The mixture was stirred for 13 hours. After completion of the reaction, the solvent was evaporated to obtain compound 131 (4 mg, 0.0065 mmol, 76%).

^1H NMR (300 MHz, DMSO- d6 ) δ 13.56 (s, 1H), 9.36 (s, 1H), 8.88 (s, _1H ), 8.58 (s, 1H), 8.30-8.17 (m, 2H), 7.97-7.84 (m, 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (dt, J = 8.8, 1.8 Hz, 1H), 7.61 (d, J = 9.1 Hz, 2H), 7.53 (ddd , J = 7.1, 4.9, 1.9 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 4.79 (s, 2H), 3.78 (t, J = 5.8 Hz, 2H), 2.97 (t, J = 5.7 Hz, 2H).

LC/MS 615.3 [M+H]

Compound 132. 7-(4-(5-(furan-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-tetrahydroisoquinoline hydrochloride

[Scheme 132]

1) 7-(4-(5-(furan-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol -1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 132-1 (50 mg, 0.0870 mmol) was reacted with furan-3-ylboronic acid (14.5 mg, 0.130 mmol) to obtain compound 132-2 (28 mg, 0.060 mmol, 69.1%). A white solid is obtained.

LC/MS 467.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.29-8.23 (m, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.83-7.76 (m, 4H), 7.34 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 1.8 Hz, 1H), 6.00-5.95 (m, 1H), 4.02-3.91 (m , 3H), 3.85-3.77 (m, 1H), 3.02 (t, J = 5.9 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.61-2.52 (m, 2H), 2.13-2.01 ( m, 2H), 1.79 (d, J = 10.9 Hz, 1H), 1.63 (dt, J = 8.6, 4.9 Hz, 2H).

2) 7-(4-(5-(furan-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Synthesis of tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 132-2 (27.0 mg, 0.0580 mmol) is reacted to obtain Compound 132 (15 mg, 0.036 mmol, 61.9%) as a beige solid.

LC/MS 383.3 [M + H] ⁺

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.57 (s, 2H), 9.35 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.98 ( d, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 4.41 (s, 2H), 3.44 (d, J = 6.9 Hz, 2H), 3.11 (d, J = 6.6 Hz, 2H).

Compound 133. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 -Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 133]

1) 1-(7-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1- Synthesis of yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

Compound 133-2 (425 mg, 1.49 mmol) and Sodium ascorbate (118 mg, 0.598 mmol) in t-BuOH/H ₂ O (1:1/6 mL) solution of Compound 133-1 (508 mg, 1.34 mmol) , CuSO ₄ (47.7 mg, 0.299 mmol) was added. The reaction mixture was stirred at 70°C for 14 h. Water was added to the reaction mixture, quenched, extracted with EA (20 ml 298 mg, 0.506 mmol, 33.8 %) of a beige solid is obtained.

LC/MS 589.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 - 9.27 (m, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.13-8.03 (m, 1H), 7.98-7.90 (m, 1H) ), 7.85 (d, J = 8.9 Hz, 1H), 7.70-7.63 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 6.02-5.94 (m, 1H), 5.64-5.53 (m, 1H), 4.07-3.89 (m, 2H), 3.86-3.66 (m, 2H), 3.07-2.92 (m, 2H), 2.48-2.41 (m, 1H), 2.13-2.00 (m, 2H), 1.86- 1.73 (m, 1H), 1.72-1.57 (m, 5H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 133-3 (50 mg, 0.0850 mmol) was reacted with (2-fluoropyridin-3-yl)boronic acid (17.9 mg, 0.127 mmol) to obtain compound 133-4 (22 mg, 0.043 mmol, 50.9%) of a beige solid is obtained.

LC/MS 510.4 [M + H] ⁺

3) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1-methyl-1, Synthesis of 2,3,4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 133-4 (20.0 mg, 0.0390 mmol) is reacted to obtain Compound 133 (10 mg, 0.022 mmol, 55.2%) as a beige solid.

LC/MS 426.3 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d6 ) δ 13.62 (s, 1H) _, 9.66 (s, 1H), 9.44 (d, J = 2.6 Hz, 1H), 9.27 (s, 1H), 8.59 (s, 1H), 8.28 (d, J = 4.7 Hz, 1H), 8.23 (t, J = 9.1 Hz, 1H), 8.03 (s, 1H), 8.02-7.96 (m, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 4.71 (s, 1H), 3.51 (d, J = 5.9 Hz, 2H), 3.21- 3.03 (m, 2H), 1.72 (d, J = 6.8 Hz, 3H).

Compound 134. 7-(4-(5-(4-(methylsulfonyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 134]

1) 7-(4-(5-(4-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3- Synthesis of triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

As in the preparation method of Scheme 82, compound 134-1 (50 mg, 0.0870 mmol) was reacted with (4-(methylsulfonyl)phenyl)boronic acid (26.1 mg, 0.130 mmol) to obtain compound 134-2 (45.2 mg, 0.081 mmol). , 94%) to obtain a white solid.

LC/MS 555.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.37 (s, 1H), 8.67 (d, J = 1.7 Hz, 1H), 8.05 (s, 4H), 7.99 (d, J = 8.8 Hz, 1H) , 7.95-7.90 (m, 1H), 7.89-7.84 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 6.07-5.96 (m, 1H), 4.14 (s, 2H), 3.96 (d) , J = 11.6 Hz, 1H), 3.88-3.75 (m, 1H), 3.28 (s, 3H), 3.17 (t, J = 6.0 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.60 -2.52 (m, 2H), 2.16-2.04 (m, 2H), 1.81 (d, J = 9.8 Hz, 1H), 1.70-1.60 (m, 2H).

2) 7-(4-(5-(4-(methylsulfonyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4 -tetrahydroisoquinoline hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 134-2 (40.0 mg, 0.0720 mmol) is reacted to obtain Compound 134 (22 mg, 0.043 mmol, 60.2%) as a white solid.

LC/MS 471.3 [M + H] ⁺

^1H NMR (300 MHz, DMSO-d ₆ ) δ 13.60 (s, 1H), 9.39 (s, 3H), 8.67 (d, J = 1.5 Hz, 1H), 8.15-7.94 (m, 6H), 7.91- 7.81 (m, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.42 (s, 2H), 3.44 (s, 2H), 3.28 (s, 3H) ), 3.11 (t, J = 6.3 Hz, 2H).

Compound 135. 7-(4-(5-(6-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 135]

1) 7-(4-(5-(6-methoxypyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 135-1 (50 mg, 0.0870 mmol) was reacted with (6-methoxypyridin-3-yl)boronic acid (19.9 mg, 0.130 mmol) to obtain compound 135-2 (32 mg, 0.063 mg). mmol, 72.5%) of a white solid is obtained.

LC/MS 508.4 [M + H] ⁺

2) 7-(4-(5-(6-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 135-2 (30.0 mg, 0.0590 mmol) is reacted to obtain Compound 135 (21 mg, 0.046 mmol, 77%) as a white solid.

LC/MS 424.2 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d6 ) δ 9.57 (s, 2H), 9.39 (s, 1H), 8.57 (s, _1H ), 8.51 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 8.01 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.52 (d, J = 8.6 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.41 (s, 2H), 3.93 (d, J = 2.7 Hz, 3H), 3.44 (s, 2H), 3.12 (d, J = 6.7 Hz, 2H).

Compound 136. 6-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 136]

1) 1-(6-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1- Synthesis of yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

Compound 136-2 (81.0 mg, 0.301 mmol), Sodium ascorbate (23.8 mg, 0.120 mmol) in t-BuOH/H ₂ O (1:1/ 4 mL) solution of Compound 136-1 (102 mg, 0.271 mmol) , CuSO ₄ (9.60 mg, 0.0600 mmol) was added and stirred at 70°C for 14 h. Water was added to the reaction mixture, quenched, extracted with EA (20 ml 3 (94 mg, 0.164 mmol, 54.4%) of a beige solid is obtained.

LC/MS 575.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.40 (s, 1H), _8.56 (d, J = 1.8 Hz, 1H), 8.02-7.91 (m, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.9, 1.9 Hz, 1H), 7.56 (dd, J = 12.4, 8.3 Hz, 1H), 5.98 (dd, J = 9.7, 2.3 Hz, 1H), 4.87 (d, J = 11.9 Hz, 2H), 3.91 (dd, J = 16.7, 9.3 Hz, 3H), 3.84-3.73 (m, 1H), 3.08 (t, J = 6.7 Hz, 2H), 2.44 (dd, J = 12.8, 3.5 Hz, 1H), 2.05 (d, J = 14.3 Hz, 2H), 1.78 (d, J = 9.7 Hz, 1H), 1.62 (s, 2H).

2) 6-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 136-3 (50.0 mg, 0.0870 mmol) was reacted with (2-fluoropyridin-3-yl)boronic acid (18.3 mg, 0.130 mmol) to obtain compound 136-4 (31 mg, 0.063). mmol, 72.0%) of a beige solid is obtained.

LC/MS 496.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.36 (s, 1H), 8.59 (s, 1H), 8.31-8.27 (m, 1H), 8.27-8.19 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 7.0 Hz, 2H), 7.78-7.72 (m, 1H), 7.58-7.49 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.02 (dd, J = 9.7, 2.4 Hz, 1H), 3.96 (d, J = 12.3 Hz, 3H), 3.86-3.78 (m, 1H), 3.05 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.55 (d, J = 9.0 Hz, 1H), 2.48-2.46 (m, 1H), 2.15-2.02 (m, 2H), 1.89-1.75 (m, 1H), 1.69-1.59 (m, 2H).

3) 6-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 136-4 (30.0 mg, 0.0610 mmol) is reacted to obtain Compound 136 (21 mg, 0.047 mmol, 77%) as a white solid.

LC/MS 412.3 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d6 ) δ 13.61 (s, 1H) _, 9.40 (s, 3H), 8.58 (s, 1H), 8.28 (d, J = 4.3 Hz, 1H), 8.23 (t, J = 9.0 Hz, 1H), 8.06-7.90 (m, 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 4.37 (s, 2H), 3.16 (t, J = 6.3 Hz, 2H), 2.65 (s, 2H).

Compound 137. 7-(4-(5-(benzofuran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 137]

1) 7-(4-(5-(benzofuran-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol -1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 137-1 (50 mg, 0.0870 mmol) was reacted with (benzofuran-2-yl)boronic acid (19.9 mg, 0.130 mmol) to obtain compound 137-2 (39 mg, 0.075 mmol, 87%) to obtain a white solid.

LC/MS 517.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.35 (s, 1H), 8.90 ₍ d, J = 1.6 Hz, 1H), 8.15-8.06 (m, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 8.2, 2.4 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.71-7.67 (m, 1H), 7.52 (s, 1H), 7.37-7.32 (m, 2H), 7.29 (t, J = 7.3 Hz, 1H), 6.02 (dd, J = 9.8, 2.4 Hz, 1H), 3.97 (d, J = 11.6 Hz) , 3H), 3.87-3.79 (m, 1H), 3.01 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.55-2.52 (m, 1H), 2.49-2.45 ( m, 1H), 2.15-2.02 (m, 2H), 1.80 (d, J = 10.3 Hz, 1H), 1.68-1.59 (m, 2H).

2) 7-(4-(5-(benzofuran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- tetrahydroisoquinoline hydrochloride hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 137-2 (35.0 mg, 0.0680 mmol) is reacted to obtain Compound 137 (25 mg, 0.053 mmol, 79%) as a white solid.

LC/MS 433.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.64 (s, 1H), 9.53 (s, 2H), 9.38 (s, 1H), 8.90 (d, J = 1.6 Hz, 1H), 8.07-8.01 ( m, 2H), 8.01-7.97 (m, 1H), 7.74 (t, J = 8.8 Hz, 2H), 7.70-7.66 (m, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.48 (s) , 1H), 7.36-7.31 (m, 1H), 7.31-7.25 (m, 1H), 4.41 (d, J = 5.0 Hz, 2H), 3.48-3.41 (m, 2H), 3.12 (t, J = 6.3 Hz, 2H).

Compound 138. 7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 138]

1) 7-(4-(5-(5-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 138-1 (50 mg, 0.0870 mmol) was reacted with (5-methylpyridin-3-yl)boronic acid (17.8 mg, 0.130 mmol) to obtain compound 138-2 (40 mg, 0.081 mmol). mmol, 94%) of a white solid is obtained.

LC/MS 492.4 [M + H] ⁺

2) 7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 138-2 (35.0 mg, 0.0710 mmol) is reacted to obtain Compound 138 (21 mg, 0.047 mmol, 66.4%) as a white solid.

LC/MS 408.2 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d6 ) δ 9.71-9.60 (m, 2H), 9.47 (d, J = 3.0 Hz, 1H), 9.22 (s, 1H), 8.84 ₍ s, 1H), 8.77 ( d, J = 12.9 Hz, 2H), 8.03 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 4.41 (s, 2H), 3.44 (s, 2H), 3.13 (d, J = 7.3 Hz, 2H), 2.60 (s, 3H).

Compound 139. 7-(4-(5-(benzo[b]thiophen-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 139]

1) 7-(4-(5-(benzo[b]thiophen-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2 ,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 139-1 (50 mg, 0.0870 mmol) was reacted with (benzo[b]thiophen-2-yl)boronic acid (22.7 mg, 0.130 mmol) to obtain compound 139-2 (30 mg). , 0.057 mmol, 65.3%) of a white solid is obtained.

LC/MS 529.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.36 (s, 1H), _8.59 (d, J = 1.7 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.81 (dd, J = 8.2, 2.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 8.4, 2.1 Hz, 1H) ), 7.34 (d, J = 8.3 Hz, 1H), 6.05-5.96 (m, 1H), 4.16-4.07 (m, 2H), 3.96 (d, J = 17.2 Hz, 3H), 3.87-3.76 (m, 1H), 3.02 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H), 2.07 (d, J = 14.9 Hz, 2H), 1.80 (d, J = 10.2 Hz, 1H) , 1.64 (s, 2H).

2) 7-(4-(5-(benzo[b]thiophen-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, Synthesis of 3,4-tetrahydroisoquinoline hydrochloride

To a solution of compound 139-2 (30.0 mg, 0.0560 mmol) in DCM (5 ml) was added 4N HCl (3.67 mg, 0.113 mmol) in dioxane. The reaction mixture was stirred at room temperature overnight. The crude material was concentrated in vacuo and the resulting solid was washed with ether and filtered to give compound 139 (13 mg, 0.027 mmol, 47.6%) as a beige solid.

LC/MS 449.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.63 (s, 1H), 9.54-9.44 (m, 2H), 9.38 (s, 1H), 8.71 (d, J = 1.7 Hz, 1H), 8.04- 7.98 (m, 3H), 7.97-7.91 (m, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H) ), 7.45-7.33 (m, 2H), 4.41 (d, J = 5.0 Hz, 2H), 3.50-3.39 (m, 2H), 3.11 (t, J = 6.2 Hz, 2H).

Compound 140. 7-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 140]

1) 7-(4-(5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3 -triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 140-1 (50 mg, 0.0870 mmol) was reacted with (4-methylpyridin-3-yl)boronic acid (17.8 mg, 0.130 mmol) to produce compound 140-2 (38 mg, 0.077 mmol). mmol, 89%) of a white solid is obtained.

LC/MS 492.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.36 (s, 1H) _, 8.48 (d, J = 4.2 Hz, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.56 (dd, J = 8.8, 1.6 Hz, 1H), 7.44-7.30 (m, 2H), 6.02 (dd, J = 9.7, 2.4 Hz, 1H), 4.16 (s, 2H), 3.97 (d, J = 11.5 Hz, 1H), 3.89-3.76 (m, 1H), 3.22-3.13 (m, 3H), 2.91 (t, J = 6.1 Hz, 2H), 2.59-2.52 (m, 2H) , 2.32 (s, 3H), 2.19-2.00 (m, 2H), 1.81 (d, J = 9.6 Hz, 1H), 1.71-1.58 (m, 2H).

2) 7-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 140-2 (35.0 mg, 0.0710 mmol) is reacted to obtain Compound 140 (15 mg, 0.034 mmol, 47.5%) as a white solid.

LC/MS 408.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.69 (s, 1H) _, 9.63 (s, 2H), 9.36 (s, 1H), 8.88 (s, 1H), 8.80 (d, J = 5.9 Hz, 1H), 8.44 (s, 1H), 8.02 (d, J = 5.9 Hz, 1H), 8.00-7.91 (m, 2H), 7.79 (d, J = 8.7 Hz, 1H), 7.61-7.54 (m, 1H) ), 7.50 (d, J = 8.4 Hz, 1H), 4.39 (t, J = 4.8 Hz, 2H), 3.43 (d, J = 6.8 Hz, 2H), 3.11 (t, J = 6.3 Hz, 2H), 2.55 (s, 3H).

Compound 141. 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2 -(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

[Scheme 141]

1) tert-butyl 4-((7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)- Synthesis of 1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carboxylate

To a solution of compound 141-1 (10.0 mg, 0.0201 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (4.30 mg, 0.0201 mmol) in MeOH (5 mL) was added acetic acid (1 drop) at room temperature. was added and the reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.20 mg, 0.100 mmol) was added to the reaction mixture and stirred at room temperature for 15 hours. The crude reaction mixture was concentrated under vacuum and purified by column chromatography using DCM/MeOH 5% to give compound 141-2 (11.0 mg, 0.0158 mmol, 78%) as a white solid.

LC/MS [M+H]+

^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.58 (s, 1H), 8.30-8.27 (m, 1H), 8.26-8.20 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.84-7.73 (m, 3H), 7.53 (ddd, J = 7.0, 4.8, 1.8 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 6.05-5.99 (m, 1H), 3.95 (s, 4H), 3.86-3.76 (m, 1H), 3.66 (s, 2H), 2.89 (d, J = 6.2 Hz, 2H), 2.16-2.02 (m, 2H), 1.89-1.58 (m, 7H), 1.39 (d, J = 3.2 Hz, 9H), 1.20 (d, J = 38.0 Hz, 3H), 1.07-0.83 (m, 4H).

2) 7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2-(piperidin-4 -ylmethyl)-1,2,3,4-tetrahydroisoquinoline synthesis

To a solution of compound 141-2 (11.0 mg, 0.015 mmol) in DCM (2 ml) was added 4 N HCl/dioxane (0.2 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was diluted with water and washed with DCM, the aqueous layer was basified with saturated NaHCO ₃ (aq), the aqueous layer was extracted with DCM (20 mL Concentrated under evaporation to obtain the compound (6.0 mg, 0.011 mmol, 78%) as a white solid.

LC/MS 509.5 [M+H]+

^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.54 (s, 1H), 9.29 (s, 1H), 8.57 (s, 1H), 8.29-8.26 (m, 1H), 8.25-8.19 (m, 1H) ), 7.82-7.73 (m, 3H), 7.70-7.66 (m, 1H), 7.55-7.50 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H), 3.65 (s, 2H), 2.97- 2.85 (m, 4H), 1.67 (d, J = 12.6 Hz, 4H), 1.32-1.20 (m, 4H), 1.09-0.95 (m, 2H), 0.89-0.83 (m, 2H).

Compound 142. 2-(3-chloro-4-methylbenzyl)-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1, 2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

[Scheme 142]

1) 2-(3-chloro-4-methylbenzyl)-7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- Synthesis of 3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline

To a solution of compound 142-1 (20.0 mg, 0.0403 mmol) and 3-chloro-4-methylbenzaldehyde (6.24 mg, 0.0403 mmol) in MeOH (5 mL) was added acetic acid (1 drop) at room temperature and the reaction mixture was cooled to room temperature. It was stirred for 1 hour. Sodium cyanoborohydride (6.34 mg, 0.100 mmol) was added to the reaction mixture and stirred at room temperature for 15 hours. The crude reaction mixture was concentrated in vacuo and purified by column chromatography using DCM/MeOH 5% to give compound 142-2 (10.0 mg, 0.0157 mmol, 40%) as a white solid.

^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 8.42 (d, J = 91.8 Hz, 3H), 8.05-7.68 (m, 4H), 7.39 (s, 5H), 6.01 ( s, 1H), 4.02- 3.52 (m, 5H), 2.83 (d, J = 48.0 Hz, 3H), 2.40 (s, 3H), 2.00 (d, J = 50.6 Hz, 2H), 1.64 (s, 2H) ), 1.24 (s, 3H), 0.85 (s, 1H).

2) 2-(3-chloro-4-methylbenzyl)-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol -1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

To a solution of compound 142-2 (9.0 mg, 0.014 mmol) in DCM (1 ml) was added 4 N HCl/dioxane (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction solvent was completely evaporated and the crude material was dissolved in water and washed with DCM (10 mL), then the aqueous layer was basified using sodium bicarbonate and the aqueous layer was extracted with DCM (20 mL), and the collected organic layers were evaporated under vacuum. After drying, compound 142 (3.0 mg, 0.0054 mmol, 38%) was obtained as a white solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 13.57 (s, 1H), 9.34 (s, 1H), 8.56 (s, 1H), 8.28 (d, J = 4.8 Hz, 1H), 8.25-8.18 ( m, 1H), 8.00 (d, J = 4.5 Hz, 2H), 7.78-7.71 (m, 2H), 7.71-7.67 (m, 1H), 7.57-7.48 (m, 4H), 4.58-4.41 (m, 4H), 3.21 (s, 2H), 2.54 (d, J = 6.3 Hz, 2H), 2.39 (s, 3H).

Compound 143. 7-(4-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 143]

1) 7-(4-(5-(pyrimidin-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol -1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 143-1 (50 mg, 0.0870 mmol) was reacted with pyrimidin-5-ylboronic acid (16.1 mg, 0.130 mmol) to obtain compound 143-2 (37 mg, 0.077 mmol, 89%). A white solid is obtained.

LC/MS 479.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.41 (s, 1H), _9.26 (s, 2H), 9.23 (s, 1H), 8.65 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.96 (dd, J = 8.9, 1.7 Hz, 1H), 7.90-7.83 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 6.04 (dd, J = 9.7, 2.4 Hz, 1H) ), 4.15 (s, 2H), 3.96 (d, J = 11.4 Hz, 1H), 3.89-3.77 (m, 1H), 3.18 (t, J = 6.0 Hz, 2H), 2.90 (t, J = 6.0 Hz) , 2H), 2.54 (s, 2H), 2.16-2.02 (m, 2H), 1.81 (d, J = 9.6 Hz, 1H), 1.66 (d, J = 9.0 Hz, 2H).

2) 7-(4-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Synthesis of tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 143-2 (35.0 mg, 0.0710 mmol) is reacted to obtain Compound 143 (29 mg, 0.067 mmol, 92%) as a white solid.

LC/MS 395.2 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 9.55 (s, 2H), _9.44 (d, J = 11.4 Hz, 1H), 9.30-9.16 (m, 3H), 8.65 (d, J = 3.9 Hz, 1H), 8.09-7.93 (m, 3H), 7.90-7.75 (m, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.41 (s, 2H), 3.51-3.35 (m, 2H), 3.12 (t, J = 6.2 Hz, 2H).

Compound 144. 1-(5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H -indazol-5-yl)thiophen-2-yl)ethan-1-one hydrochloride

[Scheme 144]

1) 1-(5-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3 -triazol-4-yl)-1H-indazol-5-yl)thiophen-2-yl)ethan-1-one synthesis

As in the preparation method of Scheme 82, compound 144-1 (50 mg, 0.0870 mmol) was reacted with (5-acetylthiophen-2-yl)boronic acid (22.1 mg, 0.130 mmol) to obtain compound 144-2 (29 mg, 0.055 mg). mmol, 63.6%) of a beige solid is obtained.

LC/MS 525.3[M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 9.36 (s, 1H) _, 8.69 (d, J = 1.3 Hz, 1H), 7.99 (d, J = 4.0 Hz, 1H), 7.94 (d, J = 1.5 Hz, 2H), 7.87-7.74 (m, 2H), 7.73 (d, J = 4.0 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 6.00 (dd, J = 9.8, 2.3 Hz, 1H), 3.97 (d, J = 17.9 Hz, 3H), 3.81 (dt, J = 11.6, 6.5 Hz, 1H), 3.17 (s, 1H), 3.03 (t, J = 5.8 Hz, 2H), 2.79 ( t, J = 5.9 Hz, 2H), 2.57 (s, 3H), 2.48 (s, 1H), 2.06 (d, J = 12.5 Hz, 2H), 1.80 (s, 1H), 1.63 (s, 2H).

2) 1-(5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- Synthesis of yl)thiophen-2-yl)ethan-1-one hydrochloride

As in the preparation method of Scheme 87, Compound 144-2 (25.0 mg, 0.0480 mmol) is reacted to obtain Compound 144 (15 mg, 0.031 mmol, 66.0%) as a yellow solid.

LC/MS 441.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.63 (s, 1H) _, 9.52 (s, 2H), 9.37 (s, 1H), 8.68 (d, J = 1.7 Hz, 1H), 8.03-7.98 ( m, 2H), 7.98-7.93 (m, 1H), 7.90-7.82 (m, 1H), 7.77-7.65 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 4.41 (t, J = 4.7 Hz, 2H), 3.50-3.39 (m, 2H), 3.12 (t, J = 6.3 Hz, 2H), 2.57 (s, 3H).

Compound 145. 5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-day) pyridin-2-amine hydrochloride

[Scheme 145]

1) 5-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- Synthesis of 4-yl)-1H-indazol-5-yl)pyridin-2-amine

As in the preparation method of Scheme 82, compound 145-1 (50 mg, 0.0870 mmol) was reacted with (6-aminopyridin-3-yl)boronic acid (17.9 mg, 0.130 mmol) to obtain compound 145-2 (34 mg, 0.069 mmol). mmol, 79%) of a beige solid is obtained.

LC/MS 493.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.35 (s, 1H) _, 8.42 (d, J = 1.7 Hz, 1H), 8.33 (d, J = 2.6 Hz, 1H), 7.93-7.83 (m, 3H), 7.79 (dd, J = 8.6, 2.6 Hz, 1H), 7.74 (dd, J = 8.8, 1.7 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.59 (d, J = 8.6) Hz, 1H), 6.08 (s, 2H), 5.97 (dd, J = 9.9, 2.4 Hz, 1H), 4.15 (d, J = 25.2 Hz, 4H), 3.95 (d, J = 11.4 Hz, 1H), 3.85-3.74 (m, 1H), 3.22 (t, J = 6.1 Hz, 2H), 2.94 (t, J = 6.1 Hz, 2H), 2.14-2.00 (m, 2H), 1.80 (d, J = 10.4 Hz) , 1H), 1.69-1.57 (m, 2H).

2) 5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)pyridin -2-amine hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 145-2 (30.0 mg, 0.0480 mmol) is reacted to obtain Compound 145 (19 mg, 0.039 mmol, 64.8%) as a beige solid.

LC/MS 409.3 [M + H] ⁺

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.91 (s, 2H), 9.40 (s, 1H), 8.53 (s, 1H), 8.47-8.37 (m, 2H), 8.26 (s, 2H), 8.02 (d, J = 2.3 Hz, 1H), 7.98-7.93 (m, 1H), 7.74 (s, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.23-7.14 (m, 1H), 4.38 (d, J = 5.2 Hz, 2H), 3.45-3.36 (m, 2H), 3.18-3.05 (m, 2H).

Compound 146. 7-((4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)methyl )-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 146]

1) 1-(7-((4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1 Synthesis of -yl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one

As in the preparation method of Scheme 136, compound 146-1 (71.7 mg, 0.190 mmol), compound 146-2 (60.0 mg, 0.211 mmol), Sodium ascorbate (16.7 mg, 0.0840 mmol), CuSO4 (6.74 mg, 0.0420 mmol) React to obtain a white solid of compound 146-3 (34 mg, 0.058 mmol, 27.3%).

LC/MS 589.1 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.77 (d, J = 2.3 Hz, 1H), 8.47 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.9, 1.9 Hz, 1H), 7.39-7.33 (m, 1H), 7.32-7.20 (m, 2H), 5.92 (dd, J = 9.8, 2.4 Hz, 1H), 5.66 (s, 2H) ), 4.76 (d, J = 8.7 Hz, 2H), 3.90 (d, J = 11.6 Hz, 1H), 3.85-3.70 (m, 3H), 2.90 (dt, J = 10.6, 5.9 Hz, 2H), 2.45 -2.35 (m, 1H), 2.11-1.95 (m, 2H), 1.75 (d, J = 10.8 Hz, 1H), 1.59 (dd, J = 8.9, 4.8 Hz, 2H).

2) 7-((4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2, Synthesis of 3-triazol-1-yl)methyl)-1,2,3,4-tetrahydroisoquinoline

As in the preparation method of Scheme 82, compound 146-3 (30 mg, 0.0510 mmol) was reacted with (2-fluoropyridin-3-yl)boronic acid (10.7 mg, 0.0760 mmol) to obtain compound 146-4 (23 mg, 0.045 mmol). mmol, 89%) to obtain a beige solid.

LC/MS 510.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 8.75 (s, 1H) _, 8.51 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.23-8.14 (m, 1H), 7.93 ( d, J = 8.8 Hz, 1H), 7.78-7.67 (m, 1H), 7.56-7.45 (m, 1H), 7.26-7.19 (m, 1H), 7.18-7.09 (m, 2H), 5.97 (dd, J = 9.7, 2.3 Hz, 1H), 5.64 (s, 2H), 3.94 (d, J = 22.0 Hz, 3H), 3.86-3.72 (m, 1H), 3.06 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.49-2.38 (m, 2H), 2.14-1.90 (m, 2H), 1.78 (d, J = 9.0 Hz, 1H), 1.61 (dd, J = 8.5, 4.5 Hz, 2H).

3) 7-((4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1,2 ,3,4-tetrahydroisoquinoline hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 146-4 (20.0 mg, 0.0390 mmol) is reacted to obtain Compound 146 (12 mg, 0.026 mmol, 66.2%) as a beige solid.

LC/MS 426.2 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.46 (s, 1H), 9.23 (s, 2H), _8.73 (s, 1H), 8.50 (s, 1H), 8.30-8.22 (m, 1H), 8.25-8.12 (m, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.70-7.60 (m, 1H), 7.56-7.45 (m, 1H), 7.39-7.30 (m, 1H), 7.26 ( d, J = 7.9 Hz, 2H), 5.68 (s, 2H), 4.26 (s, 2H), 3.39 (s, 2H), 2.99 (t, J = 6.3 Hz, 2H).

Compound 147. 1-Methyl-7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 147]

1) 1-methyl-7-(4-(5-(5-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1 ,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 147-1 (50 mg, 0.0850 mmol) was reacted with (5-methylpyridin-3-yl)boronic acid (17.4 mg, 0.127 mmol) to obtain compound 147-2 (21 mg, 0.042 mg). mmol, 49.0%) of a beige solid is obtained.

LC/MS 506.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.42 (s, 1H) _, 8.79 (d, J = 2.2 Hz, 1H), 8.61 (d, J = 1.7 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.03-7.94 (m, 2H), 7.93-7.84 (m, 3H), 7.38 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 9.8, 2.4 Hz, 1H), 4.34-4.02 (m, 2H), 3.97 (d, J = 11.5 Hz, 1H), 3.87-3.78 (m, 1H), 3.11-2.77 (m, 4H), 2.56 (d, J = 9.2 Hz, 1H) , 2.42 (s, 3H), 2.18-2.01 (m, 2H), 1.87-1.74 (m, 1H), 1.69 -1.59 (m, 2H), 1.54 (d, J = 6.7 Hz, 3H).

2) 1-methyl-7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, Synthesis of 2,3,4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 147-2 (15.0 mg, 0.0300 mmol) is reacted to obtain Compound 147 (5 mg, 10.92 μmol, 36.8%) as a beige solid.

LC/MS 422.2 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.75 (s, 1H), 10.02 (s, 1H), 9.53 (s, 2H), 9.20 (d, J = _2.0 Hz, 1H), 8.91-8.71 ( m, 3H), 8.06 (d, J = 2.2 Hz, 1H), 8.03-7.90 (m, 2H), 7.82 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.69 (s, 1H), 3.24-3.01 (m, 4H), 2.59 (s, 3H), 1.75 (d, J = 6.8 Hz, 3H).

Compound 148. 1-Methyl-7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 148]

1) 2,2,2-trifluoro-1-(1-methyl-7-(4-(5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H Synthesis of -indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one

As in the preparation method of Scheme 82, compound 148-1 (50 mg, 0.0850 mmol) was reacted with (4-methylpyridin-3-yl)boronic acid (17.4 mg, 0.127 mmol) to obtain compound 148-2 (37 mg, 0.061 mmol). mmol, 72.5%) of a beige solid is obtained.

LC/MS 602.8 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.43-9.33 (m, 1H), 8.48 (s, 1H), 8.36 -8.29 (m, 1H), 8.06 (d, J = 15.8 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.58-7.53 (m, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 5.1 Hz, 1H), 6.02 (d, J = 9.5 Hz, 1H), 5.58 (d, J = 7.0 Hz, 1H), 3.97 (d, J = 10.4 Hz, 2H), 3.87-3.62 (m, 2H), 3.00 (s, 2H), 2.32 (s, 3H), 2.10 (s, 2H), 1.82 (s, 2H), 1.72-1.55 (m, 5H) .

2) 1-methyl-7-(4-(5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1 ,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 84, compound 148-2 (35.0 mg, 0.0580 mmol) was reacted with lithium hydroxide monohydrate (6.10 mg, 0.0145 mmol) to obtain beige color of compound 148-3 (24 mg, 0.047 mmol, 82%). Obtain a solid.

3) 1-methyl-7-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, Synthesis of 2,3,4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 148-3 (20.0 mg, 0.0400 mmol) is reacted to obtain Compound 148 (13 mg, 0.028 mmol, 71.8%) as a beige solid.

LC/MS 422.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.68 (s, 1H), 9.91 (s, 1H), 9.44 (s, _2H ), 8.83 (s, 1H), 8.76 (d, J = 5.7 Hz, 1H), 8.44 (d, J = 7.1 Hz, 1H), 8.06 - 7.88 (m, 3H), 7.79 (d, J = 8.6 Hz, 1H), 7.57 (dd, J = 8.6, 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.68 (s, 1H), 3.41-3.30 (m, 3H), 3.25-3.01 (m, 4H), 1.72 (d, J = 6.9 Hz, 3H).

Compound 149. 3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-5 ,6,7,8-tetrahydro-1,7-naphthyridine hydrochloride

[Scheme 149]

1) tert-butyl 3-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1- Synthesis of yl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

As in the preparation method of Scheme 136, compound 149-1 (234 mg, 0.621 mmol), compound 149-2 (190 mg, 0.690 mmol), Sodium ascorbate (54.7 mg, 0.276 mmol), CuSO4 (22.0 mg, 0.138 mmol) React to obtain compound 149-3 (93 mg, 0.160 mmol, 23.21%) as a beige solid.

LC/MS 582.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.56-9.37 (m, 1H), 9.10 (d, J = 18.1 Hz _, 1H), 8.60-8.46 (m, 1H), 8.40-8.22 (m, 1H) ), 7.94-7.77 (m, 1H), 7.73-7.51 (m, 1H), 6.07-5.84 (m, 1H), 4.63 (d, J = 17.1 Hz, 2H), 3.90 (d, J = 15.8 Hz, 1H), 3.80 (d, J = 13.9 Hz, 1H), 3.71-3.57 (m, 2H), 3.04-2.86 (m, 2H), 2.16-1.92 (m, 3H), 1.77 (s, 1H), 1.66 -1.53 (m, 2H), 1.50-1.33 (m, 9H).

2) tert-butyl 3-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1, Synthesis of 2,3-triazol-1-yl)-5,8-dihydro-1,7-naphthyridine-7(6H)-carboxylate

As in the preparation method of Scheme 82, compound 149-3 (40.0 mg, 0.0690 mmol) was reacted with (2-fluoropyridin-3-yl)boronic acid (14.5 mg, 0.103 mmol) to obtain compound 149-4 (37 mg, 0.062 mmol). mmol, 90%) to obtain a beige solid.

LC/MS 597.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.49 (s, 1H) _, 9.11 (d, J = 2.4 Hz, 1H), 8.59 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H) , 8.33-8.17 (m, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 12.1, 7.3 Hz, 2H), 7.59- 7.49 (m, 2H), 6.09-5.97 (m, 1H), 4.64 (s, 2H), 3.96 (d, J = 11.5 Hz, 1H), 3.82 (dt, J = 11.9, 6.7 Hz, 1H), 3.67 (t, J = 5.9 Hz, 2H), 2.97 (t, J = 5.9 Hz, 2H), 2.08 (d, J = 12.8 Hz, 2H), 1.81 (d, J = 9.0 Hz, 1H), 1.64 (s) , 2H), 1.46 (s, 9H), 1.27 (d, J = 24.9 Hz, 1H).

3) 3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-5,6,7, Synthesis of 8-tetrahydro-1,7-naphthyridine hydrochloride

As in the preparation method of Scheme 87, Compound 149-4 (35.0 mg, 0.0590 mmol) is reacted to obtain Compound 149 (18 mg, 0.040 mmol, 68.4%) as a beige solid.

LC/MS 413.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.64 (s, 1H), 9.86-9.64 (m, 2H), 9.49 (d, J = 3.0 Hz, 1H), 9.17 (t, J = 2.6 Hz, 1H), 8.57 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.33-8.16 (m, 2H), 7.80-7.73 (m, 1H), 7.69 (d, J = 8.9 Hz, 1H) ), 7.52 (t, J = 6.0 Hz, 1H), 4.40 (t, J = 4.5 Hz, 2H), 3.48 (d, J = 6.6 Hz, 2H), 3.21 (t, J = 6.2 Hz, 2H).

Compound 150. 6-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 150]

1) tert-butyl 6-(4-(5-(5-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1, Synthesis of 2,3-triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

As in the preparation method of Scheme 82, compound 150-1 (50 mg, 0.0860 mmol) was reacted with (5-methylpyridin-3-yl)boronic acid (17.7 mg, 0.129 mmol) to obtain compound 150-2 (43 mg, 0.073 mmol). mmol, 84%) to obtain a beige solid.

LC/MS 592.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.40 (s, 1H), _8.59 (d, J = 1.6 Hz, 1H), 8.03-7.94 (m, 2H), 7.93-7.83 (m, 3H), 7.68-7.59 (m, 1H), 7.60-7.52 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 6.01 (dd, J = 9.7, 2.3 Hz, 1H), 4.60 (s, 2H) , 3.96 (d, J = 11.4 Hz, 1H), 3.86-3.77 (m, 1H), 3.62 (t, J = 5.9 Hz, 2H), 2.92 (t, J = 5.9 Hz, 2H), 2.54 (s, 1H), 2.42 (s, 3H), 2.15-2.00 (m, 2H), 1.80 (d, J = 10.1 Hz, 1H), 1.69-1.58 (m, 2H), 1.45 (s, 9H).

2) 6-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, Synthesis of 4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 150-2 (40.0 mg, 0.0680 mmol) is reacted to obtain Compound 150 (13 mg, 0.029 mmol, 43.3%) as a beige solid.

LC/MS 408.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.70 (s, 1H), 9.63 (s, 2H), 9.45 (s, 1H), 9.15 (s, 1H), 8.74 (s, 3H), 8.05- 7.88 (m, 3H), 7.82 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 4.9 Hz, 2H), 3.49-3.38 (m, 2H) ), 3.17 (t, J = 6.3 Hz, 2H), 2.57 (s, 3H).

Compound 151. 6-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-Tetrahydroisoquinoline hydrochloride

[Scheme 151]

1) tert-butyl 6-(4-(5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1, Synthesis of 2,3-triazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

As in the preparation method of Scheme 82, compound 151-1 (50 mg, 0.0860 mmol) was reacted with (4-methylpyridin-3-yl)boronic acid (17.7 mg, 0.129 mmol) to obtain compound 151-2 (40 mg, 0.068 mmol). mmol, 78%) of a beige solid is obtained.

LC/MS 592.8 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.38 (s, 1H) _, 8.48 (d, J = 4.9 Hz, 2H), 7.99-7.84 (m, 3H), 7.68-7.52 (m, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 5.0 Hz, 1H), 6.02 (dd, J = 9.8, 2.3 Hz, 1H), 4.59 (s, 2H), 3.97 (d, J = 11.4 Hz, 1H), 3.88-3.77 (m, 1H), 3.61 (t, J = 5.8 Hz, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.55 (s, 1H), 2.31 (s , 3H), 2.17-2.02 (m, 2H), 1.81 (d, J = 9.7 Hz, 1H), 1.64 (s, 2H), 1.45 (s, 9H).

2) 6-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3, 4-tetrahydroisoquinoline hydrochloride) synthesis

As in the preparation method of Scheme 87, Compound 151-2 (40.0 mg, 0.0680 mmol) is reacted to obtain Compound 151 (22 mg, 0.050 mmol, 73.3%) as a white solid.

LC/MS 408.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.71 (s, 1H) _, 9.67 (s, 2H), 9.39 (s, 1H), 8.89 (s, 1H), 8.81 (d, J = 5.9 Hz, 1H), 8.44 (s, 1H), 8.04 (d, J = 5.9 Hz, 1H), 7.99-7.90 (m, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 8.5 , 1.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.34 (d, J = 5.0 Hz, 2H), 3.41 (t, J = 7.3 Hz, 2H), 3.15 (t, J = 6.4 Hz, 2H), 2.55 (s, 3H).

Compound 152. 5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

[Scheme 152]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran -2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 152-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- indazole; 13.6 mg, 0.035 mmol), 3-azidopyridine (4.98 mg, 0.041 mmol), sodium ascorbate (2.74 mg, 0.014 mmol), CuSO4 (1.103 mg, 6.91 μmol) react to produce compound 152-2 (7 mg, 0.016 mmol) , 45.9%).

^1H NMR (300 MHz, DMSO- d6 ) δ 9.53 (s, 1H), _9.32 (d, J = 2.6 Hz, 1H), 8.75 (dd, J = 4.7, 1.4 Hz, 1H), 8.60 (s, 1H), 8.55-8.47 (m, 1H), 8.33-8.26 (m, 1H), 8.27-8.18 (m, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.82-7.75 (m, 1H) , 7.74-7.67 (m, 1H), 7.59-7.50 (m, 1H), 6.19-5.96 (m, 1H), 4.05-3.92 (m, 1H), 3.89-3.76 (m, 1H), 2.64-2.54 ( m, 1H), 2.20-2.02 (m, 2H), 1.91-1.75 (m, 1H), 1.71-1.58 (m, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, Compound 152-2 (5 mg, 0.011 mmol) is reacted to obtain Compound 152 (3 mg, 8.40 μmol, 74.1%).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.51 (s, 1H), 9.42-9.32 (m, 1H), 8.78 (d, J = 4.8 Hz, 1H), 8.64-8.52 (m, 2H), 8.35-8.25 (m, 1H), 8.24-8.16 (m, 1H), 7.78 (t, J = 4.2 Hz, 1H), 7.75 (s, 1H), 7.73-7.66 (m, 1H), 7.56-7.49 ( m, 1H).

Compound 153. 3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole

[Scheme 153]

1) 3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 153-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Indazole; 15 mg, 0.038 mmol), 1-azido-4-fluorobenzene (6.27 mg, 0.046 mmol), sodium ascorbate (3.02 mg, 0.015 mmol) and CuSO ₄ (1.217 mg, 7.62 μmol) were reacted to obtain compound 153-2. (3 mg, 6.54 μmol, 17.17% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 9.42 (s, 1H), 8.59 (s, 1H), _8.32-8.26 (m, 1H), 8.26-8.19 (m, 1H), 8.17-8.08 (m) , 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.81-7.69 (m, 1H), 7.60-7.46 (m, 3H), 6.03 (d, J = 9.6 Hz, 1H), 4.05-3.88 ( m, 1H), 3.88-3.73 (m, 1H), 2.68-2.56 (m, 1H), 2.21-2.01 (m, 2H), 1.96-1.78 (m, 1H), 1.71-1.61 (m, 2H).

2) Synthesis of 3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 153-2 (3 mg, 6.54 μmol) is reacted to obtain compound 153 (1.5 mg, 4.01 μmol, 61.2% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 9.38 (s, 1H), 8.58 (s, 1H), _8.30-8.25 (m, 1H), 8.25-8.18 (m, 1H), 8.16-8.08 (m) , 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.72-7.65 (m, 1H), 7.57-7.45 (m, 3H).

Compound 154. 5-(2-fluoropyridin-3-yl)-3-(1-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H -Indazole

[Scheme 154]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H -pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 154-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Indazole; 30 mg, 0.076 mmol), 3-azido-2-methylpyridine (20.45 mg, 0.152 mmol) sodium ascorbate (6.04 mg, 0.030 mmol), CuSO ₄ (2.433 mg, 0.015 mmol) were reacted to obtain compound 154-2 ( 12 mg, 0.026 mmol, 34.6% yield).

H NMR (300 MHz, DMSO- d ₆ ) δ 9.20 (s, 1H), 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 8.59 (s, 1H), 8.33-8.19 (m, 2H), 8.07 (dd, J = 7.9, 1.6 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.81-7.73 (m, 1H), 7.63-7.49 (m, 2H), 6.02 (d, J = 9.4 Hz, 1H), 4.05-3.92 (m, 1H), 3.89-3.73 (m, 1H), 2.62-2.55 (m, 1H), 2.47 (s, 3H), 2.24-2.01 (m, 2H), 1.89- 1.74 (m, 1H), 1.69-1.58 (m, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 154-2 (10 mg, 0.022 mmol) is reacted to obtain compound 154 (6 mg, 0.016 mmol, 73.6% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 9.19 (s, 1H) _, 8.75 (s, 1H), 8.58 (s, 1H), 8.28 (d, J = 4.2 Hz, 1H), 8.25-8.20 ( m, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.68-7.60 (m, 2H), 7.55-7.50 (m, 1H), 2.54 (s, 3H).

Compound 155. 5-(2-fluoropyridin-3-yl)-3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H- Indazole hydrochloride

[Scheme 155]

1) tert-butyl 4-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1, Synthesis of 2,3-triazol-1-yl)piperidine-1-carboxylate

As in the preparation method of Scheme 136, compound 155-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Compound 155 was obtained by reacting indazole; 30 mg, 0.076 mmol), tert-butyl 4-azidopiperidine-1-carboxylate (17.25 mg, 0.076 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), and CuSO ₄ (2.433 mg, 0.015 mmol). -2 (14.8 mg, 0.027 mmol, 35.5% yield) is obtained.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 8.83 (s, 1H), 8.53 (s, 1H), 8.27 (d, J = 5.0 Hz, 1H), 8.21 (ddd, J = 9.7, 7.4, 1.9 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.77-7.69 (m, 1H), 7.59-.46 (m, 1H), 5.98 (d, J = 9.5 Hz, 1H), 4.96- 4.75 (m, 1H), 4.25-4.04 (m, 2H), 3.97-3.88 (m, 1H), 3.87-3.75 (m, 1H), 3.14-2.90 (m, 2H), 2.49-2.41 (m, 1H) ), 2.26-1.90 (m, 6H), 1.88-1.72 (m, 1H), 1.68-1.55 (m, 2H), 1.44 (s, 9H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole hydrochloride

As in the preparation method of Scheme 87, compound 155-2 (10 mg, 0.018 mmol) is reacted to obtain compound 155 (6 mg, 0.015 mmol, 82% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 9.09-8.96 (m, 1H), 8.84-8.77 (m, 1H), 8.74 (s, 1H), _8.53 (s, 1H), 8.32-8.25 (m) , 1H), 8.23-8.15 (m, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.58-7.48 (m, 1H), 5.06-4.88 ( m, 1H), 3.52-3.41 (m, 2H), 3.26-3.06 (m, 2H), 2.45-2.39 (m, 2H), 2.36-2.24 (m, 2H).

Compound 156. 5-(2-fluoropyridin-3-yl)-3-(1-(2-methoxypyridin-4-yl)-1H-1,2,3-triazol-4-yl)- 1H-indazole

[Scheme 156]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(2-methoxypyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H -pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 156-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Compound 156-2 was obtained by reacting indazole; 30 mg, 0.076 mmol), 4-azido-2-methoxypyridine (22.89 mg, 0.152 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), and CuSO ₄ (2.433 mg, 0.015 mmol). (26 mg, 0.055 mmol, 72.3% yield).

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 8.59 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.30 (d, J = 4.6 Hz, 1H) , 8.24 (t, J = 9.1 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.85-7.71 (m, 2H), 7.60 (s, 1H), 7.54 (t, J = 6.4 Hz, 1H), 6.04 (d, J = 9.6 Hz, 1H), 3.97 (s, 3H), 3.97-3.73 (m, 1H), 3.90-3.78 (m, 1H), 2.68-2.56 (m, 1H), 2.21 -2.01 (m, 2H), 1.90-1.76 (m, 1H), 1.68-1.62 (m, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(2-methoxypyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 156-2 (20 mg, 0.042 mmol) is reacted to obtain compound 156 (6 mg, 0.015 mmol, 36.5% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 13.63 (s, 1H) _, 9.58 (s, 1H), 8.57 (s, 1H), 8.42 (d, J = 5.7 Hz, 1H), 8.28 (d, J = 4.8 Hz, 1H), 8.25-8.18 (m, 1H), 7.82-7.75 (m, 2H), 7.69 (d, J = 8.9 Hz, 1H), 7.61-7.56 (m, 1H), 7.56-7.48 (m, 1H), 3.97 (s, 3H).

Compound 157. 5-(2-fluoropyridin-3-yl)-3-(1-(6-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)- 1H-indazole

[Scheme 157]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(6-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H -pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 157-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Compound 157-2 was obtained by reacting indazole; 30 mg, 0.076 mmol), 5-azido-2-methoxypyridine (22.89 mg, 0.152 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), and CuSO ₄ (2.433 mg, 0.015 mmol). (11.1 mg, 0.024 mmol, 30.9% yield) is obtained.

^1H NMR (500 MHz, DMSO- d6 ) δ 9.39 (s, 1H), _8.87 (d, J = 2.7 Hz, 1H), 8.60 (s, 1H), 8.38 (dd, J = 8.9, 2.6 Hz, 1H), 8.29 (d, J = 4.5 Hz, 1H), 8.24 (t, J = 8.7 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H) , 7.54 (t, J = 6.0 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 6.03 (d, J = 9.8 Hz, 1H), 3.99-3.97 (m, 1H), 3.97 (s, 3H), 3.88-3.75 (m, 1H), 2.62-2.53 (m, 1H), 2.21-2.02 (m, 2H), 1.89-1.76 (m, 1H), 1.68-1.56 (m, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(6-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 157-2 (10 mg, 0.021 mmol) is reacted to obtain compound 157 (7 mg, 0.018 mmol, 85% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 13.56 (s, 1H) _, 9.35 (s, 1H), 8.85 (d, J = 2.8 Hz, 1H), 8.58 (s, 1H), 8.36 (dd, J = 8.9, 2.8 Hz, 1H), 8.27 (d, J = 5.1 Hz, 1H), 8.25-8.15 (m, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.57-7.49 (m, 1H), 7.11 (d, J = 8.9 Hz, 1H), 3.96 (s, 3H).

Compound 158. 3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)pyridine- 2-all

[Scheme 158]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(2-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H -pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 158-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Compound 158-2 was obtained by reacting indazole; 30 mg, 0.076 mmol), 3-azido-2-methoxypyridine (22.89 mg, 0.152 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), and CuSO ₄ (2.433 mg, 0.015 mmol). (13.6 mg, 0.029 mmol, 37.8% yield) is obtained.

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.09 (s, 1H), 8.58 (s, 1H), 8.46-8.37 (m, 1H), 8.32-8.19 (m, 3H), 7.98 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.58-7.48 (m, 1H), 7.36-7.27 (m, 1H), 6.02 (d, J = 9.4 Hz, 1H), 4.02 (s, 3H), 3.99-3.94 (m, 1H), 3.89-3.72 (m, 1H), 2.67-2.54 (m, 1H), 2.17-2.00 (m, 2H), 1.88-1.74 (m, 1H) , 1.70-1.56 (m, 2H).

2) Synthesis of 3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)pyridin-2-ol

As in the preparation method of Scheme 87, compound 158-2 (10 mg, 0.021 mmol) is reacted to obtain compound 158 (7 mg, 0.019 mmol, 88% yield).

LC/MS: 374.41 M+H

^1H NMR (300 MHz, DMSO- d6 ) δ 13.51 (s, 1H) _, 12.62 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 8.31-8.14 (m, 3H), 7.75 (d, J = 8.7 Hz, 1H), 7.71-7.64 (m, 2H), 7.55-7.46 (m, 1H), 6.50 (t, J = 6.9 Hz, 1H).

Compound 159. 3-(1-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3- 1)-1H-indazole

[Scheme 159]

1) 3-(1-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 159-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- indazole; 30 mg, 0.076 mmol), 1-azido-3,5-bis(trifluoromethyl)benzene (38.9 mg, 0.152 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), CuSO ₄ (2.433 mg, 0.015 mmol) By reaction, compound 159-2 (12.7 mg, 0.022 mmol, 28.9% yield) is obtained.

^1H NMR (300 MHz, DMSO- d6 ) δ 9.78 (s, 1H) _, 8.83 (s, 2H), 8.59 (s, 1H), 8.33 (s, 1H), 8.29 (d, J = 4.9 Hz, 1H), 8.27 - 8.18 (m, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.59 - 7.50 (m, 1H), 6.05 (d, J = 9.2 Hz, 1H), 4.02-3.93 (m, 1H), 3.87-3.73 (m, 1H), 2.66-2.51 (m, 1H), 2.22-2.03 (m, 2H), 1.91-1.74 (m, 1H) ), 1.76-1.61 (m, 2H).

2) Synthesis of 3-(1-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 159-2 (10 mg, 0.017 mmol) is reacted to obtain compound 159 (8 mg, 0.016 mmol, 94% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 13.63 (s, 1H), 9.74 (s, 1H), 8.81 (s, 2H), 8.57 (s, 1H), 8.32 ₍ s, 1H), 8.28 ( d, J = 4.8 Hz, 1H), 8.29-8.16 (m, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.59-7.48 (m, 1H) ).

Compound 160. 5-(2-fluoropyridin-3-yl)-3-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl) -1H-indazole

[Scheme 160]

1) 5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3 -triazol-4-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 160-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- indazole; 30 mg, 0.076 mmol), 5-azido-1,2,3-trimethoxybenzene (31.9 mg, 0.152 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), CuSO ₄ (2.433 mg, 0.015 mmol) Compound 160-2 (30 mg, 0.057 mmol, 74.2% yield) was obtained.

^1H NMR (300 MHz, DMSO- d6 ) δ 9.45 (s, 1H) _, 8.62 (s, 1H), 8.28 (d, J = 5.1 Hz, 1H), 8.27-8.19 (m, 1H), 7.98 ( d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.59-7.49 (m, 1H), 7.40 (s, 2H), 6.02 (d, J = 9.6 Hz, 1H), 4.05-3.95 (m, 1H), 3.93 (s, 6H), 3.87-3.78 (m, 1H), 3.74 (s, 3H), 2.62-2.54 (m, 1H), 2.16-2.00 (m, 2H), 1.89-1.74 (m, 1H), 1.74-1.58 (m, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, Compound 160-2 (25 mg, 0.047 mmol) is reacted to obtain Compound 160 (12 mg, 0.027 mmol, 57.0% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 13.57 (s, 1H), 9.43 (s, 1H), 8.59 (s, 1H), 8.27 (d, J = 4.8 Hz _, 1H), 8.25-8.17 ( m, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.57-7.47 (m, 1H), 7.38 (s, 2H), 3.92 (s, 6H) ), 3.74 (s, 3H).

Compound 161. 5-(2-fluoropyridin-3-yl)-3-(1H-1,2,3-triazol-4-yl)-1H-indazole

[Scheme 161]

1) Synthesis of 5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-(1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 136, compound 161-1 (100 mg, 0.254 mmol) in t-BuOH/H ₂ O (1:1/ 3 mL), Sodium azide (18.1 mg, 0.280 mmol), Sodium ascorbate (20.1 mg, 0.102 mmol) and CuSO ₄ (8.11 mg, 0.0510 mmol) to obtain a beige solid of compound 161-2 (40 mg, 0.110 mmol, 43.2%).

LC/MS 365.2 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 15.23 (s, 1H), 8.47 (s, 1H), _8.33-8.13 (m, 3H), 7.95 (d, J = 8.8 Hz, 1H), 7.74 ( d, J = 8.8 Hz, 1H), 7.63-7.42 (m, 1H), 5.99 (d, J = 9.2 Hz, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.82 (t, J = 7.1 Hz, 1H), 2.07 (s, 3H), 1.81 (s, 1H), 1.64 (s, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, Compound 161-2 (35.0 mg, 0.0960 mmol) is reacted to obtain Compound 161 (11 mg, 0.039 mmol, 40.9%) as a beige solid.

LC/MS 281.1 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 13.45 (s, 1H), 8.43 (d, J = _16.5 Hz, 2H), 8.32-8.11 (m, 2H), 7.85-7.59 (m, 2H), 7.56-7.38 (m, 1H).

Compound 162. 3-(1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H -Indazole

[Scheme 162]

1) Synthesis of 2-(azidomethyl)-1,3-difluorobenzene

Add sodium azide (94.0 mg, 1.44 mmol) to a solution of 2-(bromomethyl)-1,3-difluorobenzene (200 mg, 0.966 mmol) in DMF (3 mL) while stirring at room temperature, then stir at 80°C for 1 hour. Stir at room temperature for 3 hours. Water was added to the reaction mixture and extracted with Et ₂ O. The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain a colorless oil of compound 162-1 (117 mg, 0.692 mmol, 71.6 %).

LC/MS 171.1 [M + H] ⁺

^1H NMR (400 MHz, Chloroform- d ) δ 7.50-7.29 (m, 1H), 7.14-6.84 (m, 2H), 4.46 (s, 2H).

2) 3-(1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran -2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, Compound 162-2 (30.0 mg, 0.0760 mmol) in t-BuOH/H ₂ O (1:1/ 2 mL), Compound 162-1 (19.3 mg, 0.114 mmol), Sodium ascorbate (6.04 mg, 0.0300 mmol) and CuSO ₄ (2.43 mg, 0.0150 mmol) are reacted to obtain compound 162-3 (36 mg, 0.073 mmol, 96%) as a beige solid.

LC/MS 491.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.73 (s, 1H), 8.50 (s, 1H), 8.26 (d, J = 4.7 Hz, 1H), 8.19 (ddd, J = 9.7, 7.5, 1.9 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.52 (dt, J = 11.9, 6.4 Hz, 2H), 7.22 (t, J = 8.1 Hz, 2H), 6.03-5.92 (m, 1H), 5.80 (s, 2H), 3.94 (d, J = 11.6 Hz, 1H), 3.84-3.72 (m, 1H), 2.46 (s, 1H), 2.14 -1.95 (m, 2H), 1.78 (d, J = 10.4 Hz, 1H), 1.62 (s, 2H).

3) Synthesis of 3-(1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole

As in the preparation method of Scheme 87, Compound 162-3 (30.0 mg, 0.0610 mmol) is reacted to obtain Compound 162 (18 mg, 0.044 mmoll, 72.4%) as a gray solid.

LC/MS 407.2 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d6 ) δ 13.45 (s, 1H) _, 8.69 (s, 1H), 8.49 (s, 1H), 8.26 (d, J = 4.7 Hz, 1H), 8.22-8.13 ( m, 1H), 7.76-7.61 (m, 2H), 7.59-7.43 (m, 2H), 7.22 (t, J = 8.2 Hz, 2H), 5.80 (s, 2H).

Compound 163. 7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 163]

1) 5-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- Synthesis of 4-yl)-1H-indazol-5-yl)pyridin-2-amine

As in the preparation method of Scheme 82, compound 163-1 (50 mg, 0.0870 mmol) was reacted with (2,6-difluoropyridin-3-yl)boronic acid (20.7 mg, 0.130 mmol) to obtain compound 163-2 (38 mg). , 0.074 mmol, 85%) of a beige solid is obtained.

LC/MS 514.3 M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.35 (s, 1H), 8.57 (s, 1H), 8.50-8.38 (m, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.86 ( d, J = 10.1 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.48-7.30 (m, 2H), 6.07-5.94 (m, 1H), 4.13 (s, 1H), 3.96 (d , J = 11.7 Hz, 1H), 3.82 (d, J = 9.7 Hz, 1H), 3.67 (d, J = 3.5 Hz, 1H), 3.16 (t, J = 6.0 Hz, 2H), 2.90 (d, J = 6.0 Hz, 2H), 2.54 (s, 1H), 2.07 (d, J = 14.2 Hz, 2H), 1.82 (s, 2H), 1.64 (s, 2H).

2) 7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, Synthesis of 3,4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 163-2 (35.0 mg, 0.0680 mmol) is reacted to obtain Compound 163 (11 mg, 0.024 mmol, 34.6%) as a gray solid.

LC/MS 430.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.60 (s, 1H), 9.69-9.20 (m, 3H), _8.55 (s, 1H), 8.49-8.37 (m, 1H), 8.06-7.83 (m) , 2H), 7.76 (dd, J = 8.8, 3.4 Hz, 1H), 7.70-7.61 (m, 1H), 7.56-7.42 (m, 1H), 7.41-7.27 (m, 1H), 4.40 (d, J = 5.5 Hz, 2H), 3.53-3.31 (m, 2H), 3.20-2.91 (m, 2H).

Compound 164. 5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-day) Picolinonitrile hydrochloride

[Scheme 164]

1) 5-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol- Synthesis of 4-yl)-1H-indazol-5-yl)picolinonitrile

As in the preparation method of Scheme 82, compound 164-1 (50 mg, 0.0870 mmol) was reacted with (6-cyanopyridin-3-yl)boronic acid (19.2 mg, 0.130 mmol) to obtain compound 164-2 (33 mg, 0.066 mmol, 76%) of a beige solid is obtained.

LC/MS 503.3 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d6 ) δ 9.40 (s, 1H) _, 9.23 (d, J = 2.3 Hz, 1H), 8.70 (s, 1H), 8.47 (dd, J = 8.2, 2.3 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.07-7.94 (m, 2H), 7.86-7.75 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H), 6.04 (d, J = 9.4 Hz, 1H), 3.98 (d, J = 22.3 Hz, 3H), 3.89-3.77 (m, 1H), 3.04 (s, 2H), 2.81 (s, 2H), 2.56 (d, J = 8.6 Hz) , 1H), 2.09 (s, 3H), 1.82 (s, 1H), 1.64 (s, 2H).

2) 5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5-yl)picolinonitrile hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 164-2 (30.0 mg, 0.0600 mmol) is reacted to obtain Compound 164 (12 mg, 0.026 mmol, 44.2% of a gray solid).

LC/MS 419.2 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.63 (s, 1H), 9.71-9.46 (m, 2H), 9.41 (d, J = 4.7 Hz, 1H), 9.29-8.98 (m, 1H), 8.68 (d, J = 11.7 Hz, 1H), 8.53-8.29 (m, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.09-7.92 (m, 2H), 7.90 (t, J = 9.1 Hz) , 1H), 7.79 (dd, J = 8.8, 4.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.40 (d, J = 4.9 Hz, 2H), 3.43 (t, J = 6.8 Hz) , 2H), 3.11 (d, J = 6.4 Hz, 2H).

Compound 165. N,N-dimethyl-5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazole -4-yl)-1H-indazol-5-yl)pyridin-2-amine hydrochloride

[Scheme 165]

1) N,N-dimethyl-5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl) -1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-2-amine synthesis

As in the preparation method of Scheme 82, compound 165-1 (25.0 mg, 0.0420 mmol) was reacted with (6-(dimethylamino)pyridin-3-yl)boronic acid (10.5 mg, 0.127 mmol) to produce compound 165-2 (14 mg, 0.026 mmol, 61.7%) of a beige solid.

LC/MS 535.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.37 (s, 1H) _, 8.51 (d, J = 2.6 Hz, 1H), 8.47 (s, 1H), 7.96-7.73 (m, 6H), 7.33 ( d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.06-5.91 (m, 1H), 4.11 (d, J = 7.2 Hz, 1H), 3.96 (d, J = 11.3 Hz, 1H), 3.81 (s, 1H), 3.10 (d, J = 2.1 Hz, 6H), 2.97-2.81 (m, 2H), 2.75 (d, J = 13.9 Hz, 1H), 2.55 (s, 2H) ), 2.06 (d, J = 16.4 Hz, 2H), 1.81 (s, 1H), 1.64 (s, 2H), 1.48 (d, J = 6.6 Hz, 3H).

2) N,N-dimethyl-5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl) -1H-indazol-5-yl)pyridin-2-amine hydrochloride synthesis

As in the preparation method of Scheme 87, Compound 165-2 (13.0 mg, 0.0240 mmol) is reacted to obtain Compound 165 (7.2 mg, 0.015 mmol, 60.8%) as a gray solid.

LC/MS 451.4 [M + H] ⁺

^1H NMR (300 MHz, DMSO- d ₆ ) δ 13.61 (s, 1H), 9.95 (s, 1H), 9.49 (d, J = 14.4 Hz, 2H), 8.60-8.51 (m, 1H), 8.41 ( d, J = 9.3 Hz, 1H), 8.33-8.22 (m, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 8.3, 2.3 Hz, 1H), 7.76 (d, J = 1.6 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 9.5 Hz, 1H), 4.69 (s, 1H), 3.38 (t, J = 6.1 Hz, 2H), 3.30 (s, 6H), 3.14 (dd, J = 12.7, 6.3 Hz, 2H), 1.74 (d, J = 6.8 Hz, 3H).

Compound 166. 7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

[Scheme 166]

1) 7-(4-(5-(2,6-difluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2 ,3-triazol-1-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline synthesis

As in the preparation method of Scheme 82, compound 166-1 (50.0 mg, 0.0850 mmol) was reacted with (2,6-difluoropyridin-3-yl)boronic acid (20.2 mg, 0.127 mmol) to obtain compound 166-2 (19 mg). , 0.036 mmol, 42.5%) of a beige solid is obtained.

LC/MS 528.4 [M + H] ⁺

2) 7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1-methyl- Synthesis of 1,2,3,4-tetrahydroisoquinoline hydrochloride

As in the preparation method of Scheme 87, Compound 166-2 (15.0 mg, 0.0280 mmol) is reacted to obtain Compound 166 (4.7 mg, 9.79 μmol, 34.4%) as a gray solid.

LC/MS 444.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.60 (s, 1H), 9.76 (s, 1H), 9.38 (d _, J = 31.3 Hz, 2H), 8.56 (s, 1H), 8.49-8.35 ( m, 1H), 8.08-7.89 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 8.0, 2.8 Hz, 1H), 4.69 (s, 1H), 3.51 (d, J = 14.6 Hz, 1H), 3.39 (d, J = 10.9 Hz, 1H), 3.23-2.98 (m , 2H), 1.73 (d, J = 6.7 Hz, 3H).

Compound 167. 5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)- 1H-indazol-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one hydrochloride

[Scheme 167]

1) 5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro- Synthesis of 2H-pyran-2-yl)-1H-indazol-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

As in the preparation method of Scheme 82, compound 167-1 (50.0 mg, 0.0850 mmol) was mixed with (2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid ( 22.6 mg, 0.127 mmol) to obtain a beige solid of Compound 167-2 (29 mg, 0.053 mmol, 62.5%).

LC/MS 547.4 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 11.11 (s, 1H), 9.45 (s, 1H), _8.53 (s, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.11-7.99 ( m, 2H), 7.94 (dd, J = 12.3, 3.0 Hz, 2H), 7.82 (t, J = 7.5 Hz, 2H), 7.47 (dd, J = 39.4, 8.4 Hz, 1H), 6.00 (d, J) = 9.7 Hz, 1H), 4.72 (d, J = 7.5 Hz, 1H), 4.40-4.19 (m, 1H), 3.96 (d, J = 11.6 Hz, 1H), 3.83 (s, 1H), 3.68 (d) , J = 3.6 Hz, 2H), 3.60-3.49 (m, 1H), 3.47-3.38 (m, 2H), 3.17 (d, J = 4.6 Hz, 1H), 3.16-3.06 (m, 1H), 2.17- 2.02 (m, 2H), 1.82 (s, 1H), 1.72 (d, J = 6.9 Hz, 2H), 1.64 (s, 2H).

2) 5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5 Synthesis of -yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one hydrochloride

As in the preparation method of Scheme 87, Compound 167-2 (25.0 mg, 0.0460 mmol) is reacted to obtain Compound 167 (15 mg, 0.030 mmol, 65.7%) as a beige solid.

LC/MS 463.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 13.51 (s, 1H), 11.12 (s, 1H), 9.84 (s, 1H), 9.42 (s, 1H), 8.52 ( _s , 1H), 8.44 ( d, J = 9.4 Hz, 1H), 8.05-8.00 (m, 1H), 8.00-7.93 (m, 2H), 7.90-7.78 (m, 1H), 7.73 (d, J = 3.5 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H), 4.69 (s, 1H), 3.67 (s, 2H), 3.57-3.44 (m, 1H), 3.43-3.32 (m, 1H), 3.23-3.0

Compound 168. 3-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)- 1H-indazol-5-yl)quinoline hydrochloride

[Scheme 168]

1) 3-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro- Synthesis of 2H-pyran-2-yl)-1H-indazol-5-yl)quinoline

As in the preparation method of Scheme 82, compound 168-1 (50.0 mg, 0.0850 mmol) was reacted with quinolin-3-ylboronic acid (22.0 mg, 0.127 mmol) to obtain compound 168-2 (33 mg, 0.061 mmol, 71.8%). A beige solid is obtained.

LC/MS 542.2 [M + H] ⁺

2) 3-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5 -yl)quinoline hydrochloride) synthesis

As in the preparation method of Scheme 87, Compound 168-2 (30.0 mg, 0.0550 mmol) is reacted to obtain Compound 168 (14 mg, 0.028 mmol, 51.2%) as a beige solid.

LC/MS 458.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.70 (s, 1H), 9.89 (s, 1H), 9.69-9.35 (m, 2H), 9.24 (d, J = 9.3 Hz, 1H), 8.86 ( d, J = 6.8 Hz, 1H), 8.40-8.20 (m, 2H), 8.21-7.69 (m, 7H), 7.47 (dd, J = 34.0, 8.2 Hz, 1H), 4.70 (s, 1H), 3.62 -3.25 (m, 2H), 3.23-3.01 (m, 1H), 2.89 (s, 1H), 1.74 (d, J = 7.0 Hz, 2H), 1.51 (d, J = 6.9 Hz, 1H).

Compound 169. 5-(2-fluoropyridin-3-yl)-3-(1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,3-triazole-4- 1)-1H-indazole

[Scheme 169]

1) Synthesis of 3-azido-1-methyl-1H-pyrazole

Add H2SO4 (0.5 mL) to a suspension of 1-methyl-1H-pyrazol-3-amine (200 mg, 2.05 mmol) in water (1.0 mL) at room temperature. Cool to 0°C using an ice bath, add NaNO ₂ (170 mg, 2.47 mmol) dissolved in 0.5 mL of water, and stir at 0°C for 20-30 minutes. An aqueous solution of sodium azide (201 mg, 3.09 mmol) was slowly added and stirred for 3 h. When the reaction was completed, extraction was performed with diethyl ether (3 x 40 mL). _The organic layer was washed with saturated NaHCO ₃ solution ( ₂ Obtained as a yellow liquid.

^1H NMR (400 MHz, Chloroform- d ) δ 7.25 (d, J = 2.6 Hz, 1H), 5.87 (t, J = 2.2 Hz, 1H), 3.83 (s, 3H).

2) 5-(2-fluoropyridin-3-yl)-3-(1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,3-triazol-4-yl)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 169-2 (30.0 mg, 0.0760 mmol), compound 169-1 (11.2 mg, 0.0910 mmol), Sodium ascorbate (6.04 mg, 0.0300 mmol), CuSO ₄ (2.43 mg, 0.0150 mmol) ) to obtain a beige solid of compound 169-3 (30 mg, 0.067 mmol, 89%).

LC/MS 445.3 [M + H] ⁺

^1H NMR (400 MHz, DMSO- d6 ) δ 9.08 (d, J = 1.5 Hz, 1H), 8.55 (s, 1H), _8.33-8.13 (m, 2H), 8.03-7.85 (m, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.52 (t, J = 6.3 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 6.01 (d, J = 9.5 Hz, 1H), 3.96 ( s, 4H), 3.90-3.71 (m, 1H), 2.07 (d, J = 14.2 Hz, 3H), 1.81 (s, 1H), 1.64 (s, 2H).

3) 5-(2-fluoropyridin-3-yl)-3-(1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,3-triazol-4-yl)-1H- indazole synthesis

As in the preparation method of Scheme 87, Compound 169-3 (30.0 mg, 0.0670 mmol) is reacted to obtain Compound 169 (22 mg, 0.061 mmol, 90%) as a beige solid.

LC/MS 361.3 [M + H] ⁺

^1H NMR (500 MHz, DMSO- d6 ) δ 13.59 (s, 1H), _9.05 (d, J = 6.1 Hz, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.33-8.14 (m, 2H), 8.05-7.90 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.53 (d, J = 6.7 Hz, 1H), 6.80 ( dd, J = 6.4, 3.0 Hz, 1H), 3.97 (d, J = 6.0 Hz, 3H).

Compound 170. 7-Fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl) -1H-indazole

[Scheme 170]

1) Synthesis of 5-bromo-7-fluoro-3-iodo-1H-indazole

KOH (1.30 g, 23.2 mmol) and I ₂ (3.54 g, 13.9 mmol) were added to a solution of compound 170-1 (5-bromo-7-fluoro-1H-indazole; 1.00 g, 4.65 mmol) in DMF (10 ml). Add and stir at room temperature for 1 hour. When water is added to the reaction mixture and quenched, a precipitate is formed. The precipitate is filtered, washed with water, and dried under reduced pressure to obtain compound 170-2 (1.5 g, 4.40 mmol, 95%) as a beige solid.

2) Synthesis of 5-bromo-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Add DHP (0.925 g, 11.0 mmol) and TsOH monohydrate (0.167 g, 0.880 mmol) to a solution of compound 170-2 (1.50 g, 4.40 mmol) in THF anhydrous (20 mL) and stir at 60°C for 16 h. The residual solvent was removed under reduced pressure to obtain compound 170-3 (1.2 g, 2.82 mmol, 64.2%) as a sticky solid.

^1H NMR (500 MHz, DMSO- d ₆ ) δ 7.70 (dd, J = 11.0, 1.9 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 5.91 - 5.59 (m, 1H), 3.90 ( d, J = 11.5 Hz, 1H), 3.73 - 3.54 (m, 1H), 2.41 - 2.24 (m, 1H), 2.05 (t, J = 16.3 Hz, 2H), 1.74 (s, 1H), 1.56 (d) , J = 5.0 Hz, 2H).

3) Synthesis of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole

Compound 170-3 (1.20 g, 2.82 mmol), ethynyltrimethylsilane (416 mg, 4.23 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (40.0 mg, 0.0560 mmol), CuI (22.0 mg, 0.113 mmol), DIPEA (730 mg , 5.65 mmol) in THF (15 mL) and stirred at 30 °C for 14 h. The reaction mixture was concentrated under reduced pressure and extracted with EA ( ₂ (1 g, 2.53 mmol, 90%) of a yellow oil is obtained.

^1H NMR (500 MHz, DMSO- d6 ) δ 7.76-7.70 (m, 1H), 7.69-7.63 (m, 1H), 5.83 (dd, J = 9.5, 2.4 Hz _, 1H), 3.89 (d, J) = 11.3 Hz, 1H), 3.71-3.61 (m, 1H), 2.39-2.26 (m, 1H), 2.10-1.99 (m, 2H), 1.78-1.68 (m, 1H), 1.57 (dd, J = 8.9 , 4.2 Hz, 2H), 0.31 (d, J = 2.0 Hz, 9H).

4) 5-bromo-7-fluoro-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl )-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 170-4 (150 mg, 0.0379 mmol) in t-BuOH/H2O (1:1/ 2 mL), 4-azidopyridine (68.4 mg, 0.569 mmol), Sodium ascorbate (30.1 mg) , 0.152 mmol) and CuSO ₄ (12.1 mg, 0.0760 mmol) to obtain compound 170-5 (118 mg, 0.266 mmol, 70.2%) as a beige solid.

^1H NMR (400 MHz, DMSO) δ 9.64 (s, 1H), 8.85 (s, 2H), 8.40 (d, J = 1.7 Hz, 1H), 8.16 (d, J = 5.0 Hz, 2H), 7.69 ( dd, J = 11.3, 1.7 Hz, 1H), 6.01-5.82 (m, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.84-3.57 (m, 1H), 2.47 (d, J = 9.6 Hz) , 1H), 2.12 (t, J = 14.5 Hz, 2H), 1.79 (s, 1H), 1.60 (d, J = 8.2 Hz, 2H).

5) 7-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 82, compound 170-5 (50.0 mg, 0.113 mmol) was reacted with (2-fluoropyridin-3-yl)boronic acid (23.8 mg, 0.169 mmol) to obtain compound 170-6 (40 mg, 0.087 mmol). mmol, 77%) of a beige solid is obtained.

^1H NMR (400 MHz, DMSO) δ 9.67 (s, 1H), 8.85 (d, J = 5.3 Hz, 2H), 8.46 (s, 1H), 8.35 -8.23 (m, 2H), 8.17 (d, J = 5.3 Hz, 2H), 7.72 (d, J = 13.0 Hz, 1H), 7.68-7.49 (m, 4H), 5.99 (d, J = 9.7 Hz, 1H), 3.98 (d, J = 11.4 Hz, 1H) ), 3.86-3.58 (m, 1H), 2.56 (s, 1H), 2.16 (t, J = 16.8 Hz, 2H), 1.82 (s, 1H), 1.62 (s, 2H).

6) Synthesis of 7-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, Compound 170-6 (40.0 mg, 0.0870 mmol) is reacted to obtain Compound 170 (25 mg, 0.067 mmol, 77%) as a beige solid.

^1H NMR (300 MHz, DMSO) δ 14.31 (s, 1H), 9.78 (s, 1H), 9.11-8.86 (m, 2H), 8.57-8.36 (m, 3H), 8.37-8.14 (m, 2H) , 7.74-7.59 (m, 1H), 7.58-7.38 (m, 1H).

Compound 171. 3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3- 1)-1H-indazole

[Scheme 171]

1) 3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 171-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- indazole; 30 mg, 0.076 mmol), 1-(azidomethyl)-3,5-bis(trifluoromethyl)benzene (20.52 mg, 0.076 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), CuSO ₄ (2.433 mg, 0.015 mmol) ) to obtain compound 171-2 (28.8 mg, 0.049 mmol, 64.0% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 8.95 (s, 1H), 8.52 (s, 1H), _8.29-8.25 (m, 1H), 8.23-8.14 (m, 4H), 7.98-7.92 (m) , 1H), 7.77-7.71 (m, 1H), 7.53-7.48 (m, 1H), 6.03-5.89 (m, 3H), 4.02-3.88 (m, 1H), 3.83-3.72 (m, 1H), 2.50 -2.33 (m, 1H), 2.14-1.97 (m, 2H), 1.83-1.75 (m, 1H), 1.64-1.53 (m, 2H).

2) Synthesis of 3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 171-2 (25 mg, 0.042 mmol) is reacted to obtain compound 171 (6.5 mg, 0.013 mmol, 30.3% yield).

^1H NMR (500 MHz, DMSO- d ₆ ) δ 8.91 (s, 1H), 8.50 (s, 1H), 8.29-8.23 (m, 2H), 8.22-8.12 (m, 4H), 7.72 (d, J = 8.9 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 5.96 (s, 2H).

Compound 172. 3-(1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H -Indazole

[Scheme 172]

1) 3-(1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1-(tetrahydro- Synthesis of 2H-pyran-2-yl)-1H-indazole

As in the preparation method of Scheme 136, compound 172-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- indazole; 30 mg, 0.076 mmol), 1-azido-4-(tert-butyl)benzene (13.36 mg, 0.076 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), CuSO ₄ (2.433 mg, 0.015 mmol) Compound 172-2 (29.6 mg, 0.060 mmol, 78% yield) is obtained.

^1H NMR (500 MHz, DMSO- d6 ) δ 9.38 (s, 1H) _, 8.61 (s, 1H), 8.29 (s, 1H), 8.24 (t, J = 9.2 Hz, 1H), 8.08-7.95 ( m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.56-7.53 (m, 1H), 6.02 (d, J = 9.7 Hz, 1H), 4.03-3.92 (m, 1H), 3.87-3.77 (m, 1H), 2.59-2.54 (m, 1H), 2.17-2.03 (m, 2H), 1.89-1.74 (m, 1H), 1.70-1.61 (m) , 2H), 1.36 (s, 9H).

2) Synthesis of 3-(1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 172-2 (25 mg, 0.050 mmol) in DCM (1 ml) is reacted to obtain compound 172 (12.1 mg, 0.029 mmol, 58.3% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 9.36 (s, 1H), 8.59 (s, 1H), 8.28 ( _s , 1H), 8.23 (t, J = 9.1 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.52 (t, J = 6.5 Hz, 1H), 1.36 (s, 9H).

Compound 173. 5-(2-fluoropyridin-3-yl)-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole

[Scheme 173]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 173-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Compound 173-2 was obtained by reacting indazole; 30 mg, 0.076 mmol), 1-azido-4-methoxybenzene (11.37 mg, 0.076 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), and CuSO ₄ (2.433 mg, 0.015 mmol). (28 mg, 0.060 mmol, 78% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 9.33 (s, 1H), 8.60 (s, 1H), 8.29 (s, 1H), 8.27-8.17 (m, 1H), 8.04-7.91 (m, 3H ₎ ), 7.77-7.73 (m, 1H), 7.61-7.51 (m, 1H), 7.24-7.13 (m, 2H), 6.02 (d, J = 9.7 Hz, 1H), 4.01-3.92 (m, 1H), 3.85 (s, 3H), 3.83-3.79 (m, 1H), 2.61-2.53 (m, 1H), 2.17-2.04 (m, 2H), 1.86-1.77 (m, 1H), 1.68-1.60 (m, 2H) ).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 173-2 (25 mg, 0.053 mmol) is reacted to obtain compound 173 (11.7 mg, 0.030 mmol, 57.0% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 9.28 (s, 1H) _, 8.57 (s, 1H), 8.27 (d, J = 4.7 Hz, 1H), 8.25-8.17 (m, 1H), 7.96 ( d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.54-7.49 (m, 1H), 7.18 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H).

Compound 174. 5-(2-fluoropyridin-3-yl)-3-(1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole

[Scheme 174]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2 -yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 174-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Compound 174-2 was obtained by reacting indazole; 30 mg, 0.076 mmol), 1-azido-3-methoxybenzene (11.37 mg, 0.076 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), and CuSO ₄ (2.433 mg, 0.015 mmol). (28.8 mg, 0.061 mmol, 80% yield) is obtained.

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.46 (s, 1H), 8.61 (s, 1H), 8.29 (s, 1H), 8.26-8.20 (m, 1H), 8.01-7.97 (m, 1H) ), 7.83-7.76 (m, 1H), 7.69-7.65 (m, 2H), 7.60-7.50 (m, 2H), 7.12-7.05 (m, 1H), 6.03 (d, J = 9.7 Hz, 1H), 4.02-3.94 (m, 1H), 3.90 (s, 3H), 3.87-3.79 (m, 1H), 2.62-2.57 (m, 1H), 2.15-2.04 (m, 2H), 1.92-1.78 (m, 1H) ), 1.68-1.58 (m, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 174-2 (25 mg, 0.053 mmol) is reacted to obtain compound 174 (16.2 mg, 0.042 mmol, 79% yield).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.42 (s, 1H), 8.58 (s, 1H), 8.27 (d, J = 4.5 Hz, 1H), 8.22 (t, J = 6.2 Hz, 1H) , 7.75 (d, J = 8.8 Hz, 1H), 7.71-7.61 (m, 3H), 7.58-7.50 (m, 2H), 7.14-7.08 (m, 1H), 3.89 (s, 3H).

Compound 175. 3-(1-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3 -1)-1H-indazole

[Scheme 175]

1) 3-(1-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1 -(tetrahydro-2H-pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 175-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- indazole; 30 mg, 0.076 mmol), 4-azido-1,1'-biphenyl (14.88 mg, 0.076 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), CuSO ₄ (2.433 mg, 0.015 mmol) to form a compound Obtain 175-2 (6 mg, 0.012 mmol, 15.24% yield).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.49 (s, 1H), 8.62 (s, 1H), 8.31-8.28 (m, 1H), 8.27-8.22 (m, 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.02-7.93 (m, 3H), 7.83-7.75 (m, 3H), 7.57-7.49 (m, 3H), 7.47-7.40 (m, 1H), 6.10-5.97 (m, 1H) ), 4.08-3.93 (m, 1H), 3.87-3.73 (m, 1H), 2.61-2.53 (m, 1H), 2.17-2.05 (m, 2H), 1.90-1.76 (m, 1H), 1.78-1.60 (m, 2H).

2) 3-(1-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H -indazole synthesis

As in the preparation method of Scheme 87, compound 175-2 (5 mg, 9.68 μmol) is reacted to obtain compound 175 (3.4 mg, 7.86 μmol, 81% yield).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.56 (s, 1H), 9.45 (s, 1H), 8.60 (s, 1H), 8.29-8.26 (m, 1H), 8.26-8.20 (m, 1H) ), 8.17 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H), 7.78-7.75 (m, 1H), 7.72-7.67 (m, 1H), 7.58-7.49 (m, 3H), 7.47-7.41 (m, 1H).

Compound 176. 5-(2-fluoropyridin-3-yl)-3-(1-(6-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H -Indazole

[Scheme 176]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(6-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H -pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 176-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Indazole; 30 mg, 0.076 mmol), 5-azido-2-phenylpyridine (17.95 mg, 0.091 mmol), sodium ascorbate (6.04 mg, 0.030 mmol, CuSO ₄ (2.433 mg, 0.015 mmol) were reacted to obtain compound 176-2 ( 32 mg, 0.062 mmol, 81% yield).

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.57 (s, 1H), 9.40 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.36-8.16 ( m, 5H), 7.99 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.61 - 7.46 (m, 4H), 6.04 (d, J = 9.5 Hz, 1H), 4.04-3.94 (m, 1H), 3.92-3.79 (m, 1H), 2.67-2.53 (m, 1H), 2.22-2.00 (m, 2H), 1.89-1.78 (m, 1H), 1.68-1.56 (m) , 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(6-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 176-2 (30 mg, 0.058 mmol) is reacted to obtain compound 176 (20 mg, 0.046 mmol, 80% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 9.54 (s, 1H) _, 9.39 (s, 1H), 8.60 (s, 1H), 8.57 (d, J = 8.9 Hz, 1H), 8.32-8.26 ( m, 2H), 8.27-8.23 (m, 1H), 8.22-8.18 (m, 2H), 7.77 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.61-7.48 (m, 4H).

Compound 177. 5-(2-fluoropyridin-3-yl)-3-(1-(5-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H -Indazole

[Scheme 177]

1) 5-(2-fluoropyridin-3-yl)-3-(1-(5-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H -pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 177-1 (5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H- Indazole; 30 mg, 0.076 mmol), 3-azido-5-phenylpyridine (17.95 mg, 0.091 mmol), sodium ascorbate (6.04 mg, 0.030 mmol), and CuSO ₄ (2.433 mg, 0.015 mmol) were reacted to obtain compound 177-2. (27 mg, 0.052 mmol, 68.4% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 9.65 (s, 1H), 8.80 (s, 1H), _8.61 (s, 1H), 8.34-8.16 (m, 2H), 8.04-7.85 (m, 3H) ), 7.83-7.72 (m, 2H), 7.63-7.35 (m, 5H), 6.03 (d, J = 9.3 Hz, 1H), 4.02-3.89 (m, 1H), 3.87-3.74 (m, 1H), 2.67-2.55 (m, 1H), 2.18-2.01 (m, 2H), 1.87-1.73 (m, 1H), 1.70-1.56 (m, 2H).

2) Synthesis of 5-(2-fluoropyridin-3-yl)-3-(1-(5-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 89-1 (35.1 mg, 0.0581 mmol) is reacted to obtain compound 177 (9 mg, 0.021 mmol, 43.0% yield).

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 8.79 (s, 1H), 8.60 (s, 1H), 8.31-8.27 (m, 1H), 8.26-8.20 (m, 1H) ), 7.98-7.92 (m, 2H), 7.82-7.79 (m, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63-7.56 (m, 3H), 7.55-7.48 (m, 2H).

Compound 178. 6-Fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl) -1H-indazole

[Scheme 178]

1) Synthesis of 5-bromo-6-fluoro-3-iodo-1H-indazole

As in the preparation method of Scheme 170, compound 178-1 (5-bromo-6-fluoro-1H-indazole; 1 g, 4.65 mmol), KOH (1.305 g, 23.25 mmol), I ₂ (3.54 g, 13.95 mmol) React to obtain compound 178-2 (1.5 g, 4.40 mmol, 95% yield).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.66 (d, J = 6.6 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H).

2) Synthesis of 5-bromo-6-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

As in the preparation method of Scheme 170, compound 178-2 (1.5 g, 4.40 mmol), 3,4-dihydro-2H-pyran (1.004 ml, 11.00 mmol), PTSA·H ₂ O (0.167 g, 0.880 mmol) React to obtain compound 178-3 and proceed to the next reaction without purification.

3) Synthesis of 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole

As in the preparation method of Scheme 170, compound 178-3 (1.8 g, 4.23 mmol), ethynyltrimethylsilane (0.713 ml, 5.08 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.059 g, 0.085 mmol), CuI (0.032 g, 0.169 mmol) and TEA (1.182 ml, 8.47 mmol) to obtain a yellow oil of compound 178-4 (250 mg, 0.632 mmol, 14.93% yield).

^1H NMR (500 MHz, DMSO- d ₆ ) δ 8.09-8.04 (m, 1H), 8.00-7.89 (m, 1H), 5.87 (d, J = 9.4 Hz, 1H), 3.91-3.83 (m, 1H) ), 3.80-3.70 (m, 1H), 2.37-2.24 (m, 1H), 2.07-1.94 (m, 2H), 1.89-1.80 (m, 1H), 1.76-1.68 (m, 2H), 0.31 (s) , 9H).

4) 5-bromo-6-fluoro-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl )-1H-indazole

As in the preparation method of Scheme 136, compound 178-4 (100 mg, 0.253 mmol), 4-azidopyridine (36.5 mg, 0.304 mmol), sodium ascorbate (20.04 mg, 0.101 mmol), CuSO ₄ (8.07 mg, 0.051 mmol) React to obtain compound 178-5 (25 mg, 0.056 mmol, 22.30% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 9.66 (d, J = 3.1 Hz, 1H), _8.98-8.82 (m, 2H), 8.71-8.55 (m, 1H), 8.19 (s, 2H), 8.01 (dd, J = 9.6, 3.2 Hz, 1H), 5.95 (d, J = 9.6 Hz, 1H), 4.04-3.90 (m, 1H), 3.87-3.75 (m, 1H), 2.49-2.38 (m, 1H), 2.19-1.96 (m, 2H), 1.90-1.71 (m, 1H), 1.73-1.53 (m, 2H).

5) 6-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 82, compound 178-5 (23 mg, 0.052 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (7.28 mg, 10.38 μmol) and (2-fluoropyridin-3-yl)boronic acid (8.77 mg) , 0.062 mmol) to obtain a yellow solid of compound 178-6 (6 mg, 0.013 mmol, 25.2% yield).

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.65 (s, 1H), 8.93-8.79 (m, 2H), 8.52-8.42 (m, 1H), 8.41-8.34 (m, 1H), 8.24-8.10 (m, 3H), 8.03-7.90 (m, 1H), 7.66-7.53 (m, 1H), 6.00 (d, J = 9.4 Hz, 1H), 4.02-3.94 (m, 1H), 3.88-3.78 (m , 1H), 2.50-2.39 (m, 1H), 2.17-2.05 (m, 2H), 1.90-1.75 (m, 1H), 1.71-1.60 (m, 2H).

6) Synthesis of 6-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 178-6 (5 mg, 10.88 μmol) is reacted to obtain compound 178 (3.5 mg, 9.32 μmol, 86% yield).

^1H NMR (300 MHz, DMSO- d ₆ ) δ 9.71 (s, 1H), 9.10-8.91 (m, 2H), 8.56-8.31 (m, 4H), 8.23-8.11 (m, 1H), 7.64 (d) , J = 10.4 Hz, 1H), 7.59-7.51 (m, 1H).

Compound 179. 4-Fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl) -1H-indazole

[Scheme 179]

1) Synthesis of 5-bromo-4-fluoro-3-iodo-1H-indazole

As in the preparation method of Scheme 170, compound 179-1 (5-bromo-4-fluoro-1H-indazole; 1 g, 4.65 mmol), KOH (1.305 g, 23.25 mmol), I ₂ (2.95 g, 11.63 mmol) React to obtain compound 179-2 (1.48 g, 4.34 mmol, 93% yield).

^1H NMR (500 MHz, DMSO- d6 ) δ 13.92 (s, 1H), _7.61-7.54 (m, 1H), 7.44-7.40 (m, 1H).

2) Synthesis of 5-bromo-4-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

As in the preparation method of Scheme 170, compound 179-2 (1.48 g, 4.34 mmol) in THF anhydrous solution, 3,4-dihydro-2H-pyran (0.990 ml, 10.85 mmol), PTSA·H ₂ O (0.165 g, 0.868 mmol) to obtain compound 179-3 and proceed with the next reaction without purification.

3) Synthesis of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H-indazole

As in the preparation method of Scheme 170, compound 179-3 (1.8 g, 4.23 mmol), ethynyltrimethylsilane (0.891 ml, 6.35 mmol), Pd(PPh3)2Cl2 (0.059 g, 0.085 mmol), CuI (0.032 g, 0.169 mmol) , DIPEA (1.475 ml, 8.47 mmol) was reacted to give compound 179-4 (1.07 g, 2.71 mmol, 63.9% yield) as a yellow oil.

^1H NMR (300 MHz, DMSO- d6 ) δ 8.04-7.28 (m, 2H), 5.92 (dd, J = _9.3 , 2.5 Hz, 1H), 3.95-3.79 (m, 1H), 3.78 - 3.68 (m) , 1H), 2.40-2.20 (m, 1H), 2.09-1.92 (m, 2H), 1.81-1.69 (m, 1H), 1.62-1.52 (m, 2H), 0.28 (s, 9H).

4) 5-bromo-6-fluoro-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl )-1H-indazole synthesis

As in the preparation method of Scheme 136, compound 179-4 (100 mg, 0.253 mmol), 4-azidopyridine (36.5 mg, 0.304 mmol), sodium ascorbate (20.04 mg, 0.101 mmol), CuSO ₄ (8.07 mg, 0.051 mmol) React to obtain compound 179-5 (50 mg, 0.113 mmol, 44.6% yield).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 9.46 (s, 1H), 8.90-8.60 (m, 2H), 8.31-8.01 (m, 2H), 7.87-7.54 (m, 2H), 6.01 (d) , J = 9.4 Hz, 1H), 4.10-3.88 (m, 1H), 3.86-3.69 (m, 1H), 2.48-2.34 (m, 1H), 2.19-2.00 (m, 2H), 1.78 (d, J = 8.7 Hz, 1H), 1.62 (s, 2H).

5) 4-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro -2H-pyran-2-yl)-1H-indazole synthesis

As in the preparation method of Scheme 82, compound 179-5 (30 mg, 0.068 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (9.50 mg, 0.014 mmol), (2-fluoropyridin-3-yl)boronic acid (11.44 mg) , 0.081 mmol) to obtain a yellow solid of compound 179-6 (19 mg, 0.041 mmol, 61.1% yield).

^1H NMR (300 MHz, DMSO- d6 ) δ 9.45 (s, 1H) _, 8.83 (d, J = 6.3 Hz, 2H), 8.44-8.26 (m, 1H), 8.28-8.06 (m, 2H), 7.85 (d, J = 8.7 Hz, 1H), 7.74-7.47 (m, 3H), 6.07 (dd, J = 9.6, 2.1 Hz, 1H), 4.05-3.89 (m, 1H), 3.88-3.74 (m, 1H), 2.48-2.42 (m, 1H), 2.18- 2.03 (m, 2H), 1.92-1.72 (m, 1H), 1.70-1.48 (m, 2H).

6) Synthesis of 4-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole

As in the preparation method of Scheme 87, compound 179-6 (15 mg, 0.033 mmol) is reacted to obtain compound 179 (9.7 mg, 0.026 mmol, 79% yield).

^1H NMR (500 MHz, DMSO- d ₆ ) δ 9.51 (s, 1H), 9.01-8.91 (m, 2H), 8.44-8.32 (m, 3H), 8.16 (t, J = 8.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.59-7.51 (m, 2H).

<Example 2. Confirmation of TRIB2 or YAP, AKT inhibition and cancer cell proliferation inhibition activity>

TRIB2 kinase inhibitory activity and cancer cell proliferation inhibitory activity were confirmed using compounds 75 to 179 of the present invention synthesized in Example 1, and are shown in Table 1 below. TRIB2 protein, YAP, and AKT inhibitory activities are shown in Figure 1. .

TRIB2 kinase activity assay was conducted by requesting Eurofins, and the simple method is as follows. Human TRIB2 enzyme was first mixed with 8mM MOPS pH 7.0, 0.2mM EDTA, and 250μM substrate (RRRFRPASPLRGPPK), then treated with 10mM Magnesium acetate, 15μM gamma-33P-ATP, and test drugs at different concentrations, and reacted at room temperature for 120 minutes. I order it. Afterwards, the reaction is stopped by treatment with 0.5% phosphoric acid, and 10 μl of the reaction solution is dropped onto the P30 filter. After washing with 0.425% phosphoric acid four times for 4 minutes, it was treated with methanol, dried, and the results were measured.

The method of testing for inhibition of proliferation of cancer cells is as follows. The cancer cell line was spread at 4,000 cells per 96 well plate and stabilized for 24 hours. Afterwards, the drug was treated at 1 μM, and after 3 days, cell viability was measured using Dojindo's Cell Counting Kit-8.

As shown in Table 1, the indazole compound linked to a triazole in the structure of Chemical Formula 1 of the present invention is better than the comparative material (prior literature, Korean Patent Publication 2021-0076876, Compound 55), which is an indazole compound linked to an amide in the structure of Chemical Formula 1 of the present invention. It showed excellent TRIB2 kinase inhibitory activity, YAP kinase inhibitory activity, and activity against cancer cells in vitro and in vivo .

The compound of the present invention is a compound having a pyridine or tetrahydroisoquinoline substituent at the R ₁ position in a triazole-linked indazole structure, and a pyridine or pyrazole substituent at the R ₃ position, showing excellent TRIB2 inhibitory activity, YAP inhibitory activity and It showed in vitro and in vivo activity against cancer cells.

Characteristically, compounds substituted with tetrahydroisoquinoline at the R ₁ position showed increased in vivo activity compared to compounds with pyridine substitution.

As shown in Figure 1, it was confirmed that compounds Nos. 75 and 90 of the present invention inhibited the phosphorylation of TRIB2 protein, YAP, and AKT in a time-dependent manner in a breast cancer cell line (MDA-MB-231). To analyze the inhibitory effect of compounds 75 and 90 on cancer cell colony forming ability (clonogenic assay), MDA-MB-231 cell line was distributed at 3,000 cells/well in a 6-well plate, and each compound, including the control group, was treated for 2 weeks. The remaining cells were stained using 0.5% crystal violet solution. Referring to Figure 2, it can be seen that compounds Nos. 75 and 90 of the present invention inhibit colony formation of breast cancer cell line (MDA-MB-231).

As a result of confirming the TRIB2 kinase inhibitory activity and the proliferation inhibitory activity of cancer cells, the triazole-substituted indazole derivative of the present invention had an IC ₅₀ value of 0.0001 to 1 μM, showing very excellent inhibitory activity.

<Example 3. Confirmation of cancer cell metastasis inhibition activity>

In order to analyze the control of metastatic ability of the MDA-MB-231 breast cancer cell line of the present invention compound No. 75 synthesized in Example 1, a 6-well plate was filled with cells to close to 100%, then scratched using a 200 μl tip and the compound was added. After treatment at different concentrations, the scratch recovery ability was observed under a microscope and compared with the control group. In addition, Corning BioCoat Matrigel Invasion Chambers were used to analyze the invasion ability of cancer cell lines (Invasion assay). The cell line suspended with compound No. 75 in serum-free medium was placed in the upper well, and medium containing serum was added to the lower well, cultured for 24 hours, and the attached cells passed through the filter, fixed and stained with H&E, and then used as a control group under a microscope. was observed in comparison with .

Referring to Figures 3 and 4, it was confirmed that migration and invasion, which are characteristics of cancer cell metastasis, were inhibited in a concentration-dependent manner in breast cancer cell line (MDA-MB-231) by compound No. 75 according to the present invention. did.

<Example 4. Inhibition of proliferation of anticancer drug resistant cell lines and in vivo Confirmation of anti-cancer efficacy>

In order to analyze whether the compound of the present invention is active in overcoming anticancer drug resistance, 4,000 cells each of the blood cancer cell line K562 and the doxorubicin-resistant cell line K562/ADM were spread on a 96 well plate, stabilized for 24 hours, and then injected with the corresponding drug. was treated with 1 μM and after 3 days, cell viability was measured using Dojindo's Cell Counting Kit-8. In addition, in order to confirm the in vivo anticancer efficacy of the compound of the present invention, the MDA-MB-231 cell line was planted in the fat pad of female BALB/c nude mice to form tumors, and then the compound administration group and the test group were divided. did. Compound No. 90 was injected intraperitoneally every day at a dose of 10 mg/kg for 28 days, and the animal's body weight and tumor volume were checked twice a week (tumor diameter) ² was measured and compared with the control group.

Also, referring to Figures 5 and 6, in particular, the triazole-substituted indazole compounds of the present invention significantly inhibit the proliferation of cancer cells not only in blood cancer (K562) but also in anticancer drug (doxorubicin)-resistant blood cancer (K562/ADM) cell lines. It was confirmed that compounds 75 and 90 have excellent anticancer effects in in vivo animal experiments.

From this, the triazole-substituted indazole derivatives of the present invention are not only excellent for preventing or treating TRIB2-related diseases such as cancer, narcolepsy, and fasciitis, but are also used as pharmaceutical agents for cancer cell metastasis and anticancer drug-resistant carcinomas as resistance inhibitors or as adjuvants for anticancer drugs. It was found that the composition could be usefully used.

Meanwhile, the compound according to the present invention can be formulated in various forms depending on the purpose. The following illustrates several formulation methods containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

<Formulation example 1. Preparation of powder>

A powder was prepared by mixing 2 g of Compound 90 of the present invention and 1 g of lactose and filling it in an airtight envelope.

<Formulation Example 2. Preparation of tablets>

Tablets were prepared by mixing 100 mg of Compound 90 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate and tableting according to a conventional tablet manufacturing method. .

<Formulation example 3. Preparation of capsule>

Mix 100 mg of Compound 90 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, and then mix the above ingredients according to a typical capsule manufacturing method. Capsules were prepared by filling gelatin capsules.

<Formulation example 4. Preparation of pills>

After mixing 90 mg of Compound 90 of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and a small amount of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as an additive that inhibits hygroscopicity, 100 mg of pills are added according to a conventional method. made.

<Formulation example 5. Preparation of injection>

After mixing 10 mg of Compound 90 of the present invention, an appropriate amount of sterilized distilled water for injection, and an appropriate amount of a pH adjuster, the mixture was prepared at the above ingredient content per ampoule (2 ml) according to a conventional preparation method for injections.

Claims (13)

A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof;
[Formula 1]

In Formula 1,
R ₁ is substituted or unsubstituted phenyl, substituted or unsubstituted piperidine, substituted or unsubstituted pyridine, substituted or unsubstituted tetrahydroisoquinoline, substituted or unsubstituted pyrazole, substituted or unsubstituted It is a substituent selected from the group consisting of,
wherein the substituted phenyl, piperidine, pyridine, tetrahydroisoquinoline, pyrazole, hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, halo C ₁ -C ₄ alkyl, amino, hydroxy, tert-butoxycarbonyl, phenyl, CONH ₂ , COCH ₃ , COCF ₃ , substituted or unsubstituted piperidine C ₁ -C ₄ alkyl, substituted or unsubstituted phenyl C ₁ -C ₄ alkyl, , , or It is a substituent selected from the group consisting of;
Here, the substituted piperidine C ₁ -C ₄ alkyl or phenyl C ₁ -C ₄ alkyl is selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen or halo C ₁ -C ₄ alkyl. is substituted with a selected substituent;
The R ₇ is hydrogen, amino, mono (or di) C ₁ -C ₆ alkyl amino, halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl ketone, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkyl, or halo C ₁ -C ₆ alkoxy;
R ₂ is hydrogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or tetrahydropyranyl;
R ₃ is a group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazole, substituted or unsubstituted thiophene, and substituted or unsubstituted furan. It is a substituent selected from,
wherein the substituted phenyl, pyridine, pyrimidine, pyrazole, thiophene or furan is hydrogen, halogen, hydroxy, amino, di (or mono) C ₁ -C ₄ alkylamino, cyano, C ₁ -C ₄ alkyl , halo C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkyloxy, tert-butoxycarbonyl, CONH ₂ , formyl, acetyl, C ₁ -C ₄ alkylketone, C is substituted with a substituent selected from the group consisting of ₁ -C ₄ alkylsulfonyl, amino C ₁ -C ₄ alkyl, piperidine, phenyl, or benzyl;
R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen;
X ₁ , X ₂ , X ₃ are independently N, C, or CH;
m is independently 0 or 1;
n is independently an integer from 0 to 3. delete According to paragraph 1,
R ₁ is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, or substituted or unsubstituted tetrahydroisoquinoline,
wherein the substituted phenyl, pyridine, tetrahydroisoquinoline is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, halo C ₁ -C ₄ alkyl, phenyl, amino, hydroxy, tert-part Toxycarbonyl, CONH ₂ , COCH ₃ , COCF ₃ , substituted or unsubstituted piperidine C ₁ -C ₄ alkyl, substituted or unsubstituted phenyl C ₁ -C ₄ alkyl, , , or is substituted with a substituent selected from the group consisting of,
Here, the substituted piperidine C ₁ -C ₄ alkyl or phenyl C ₁ -C ₄ alkyl is selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen or halo C ₁ -C ₄ alkyl. is substituted with a selected substituent;
R ₂ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, halo C ₁ -C ₆ alkyl, or tetrahydropyranyl;
R ₃ is substituted or unsubstituted pyridine, or substituted or unsubstituted pyrazole,
wherein the substituted pyridine or pyrazole is hydrogen, halogen, hydroxy, amino, di (or mono) C ₁ -C ₄ alkylamino, cyano, C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkyloxy, tert- butoxycarbonyl, CONH ₂ , formyl, acetyl, C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkylsulfonyl, amino C is substituted with a substituent selected from the group consisting of ₁ -C ₄ alkyl, piperidine, phenyl, or benzyl;
Here, R ₇ is hydrogen, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkoxy, cyano, amino, amino C ₁ -C ₄ alkyl or hydroxy;
R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen;
X ₁ , X ₂ , X ₃ are independently N, C, or CH;
m is independently 0 or 1;
n is independently an integer from 0 to 3. According to paragraph 3,
R ₁ is substituted or unsubstituted pyridine,
wherein the substituted pyridine is substituted with a substituent selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, halogen, halo C ₁ -C ₄ alkyl, phenyl, amino, hydroxy;
R ₂ is hydrogen or tetrahydropyranyl;
R ₃ is substituted or unsubstituted pyridine,
wherein the substituted pyridine is substituted with hydrogen or halogen;
R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen. A compound represented by the following formula (2), an optical isomer thereof, or a pharmaceutically acceptable salt thereof;
[Formula 2]

In Formula 2,
R ₂ is hydrogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl or tetrahydropyranyl;
R ₃ is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazole, substituted or unsubstituted thiophene, substituted or unsubstituted furan, , , , or It is selected from the group consisting of,
wherein the substituted phenyl, pyridine, pyrimidine, pyrazole, thiophene or furan is hydrogen, halogen, hydroxy, amino, di (or mono) C ₁ -C ₄ alkylamino, cyano, C ₁ -C ₄ alkyl , halo C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkylketone, C ₁ -C ₄ alkyloxy, tert- butoxycarbonyl, CONH ₂ , formyl, acetyl, C ₁ -C ₄ alkylketone, C is substituted with a substituent selected from the group consisting of ₁ -C ₄ alkylsulfonyl, amino C ₁ -C ₄ alkyl, piperidine, phenyl, or benzyl;
R ₇ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, cyano, amino, amino C ₁ -C ₄ alkyl or hydroxy;
R ₄ , R ₅ , and R ₆ are independently hydrogen or halogen;
R ₈ is hydrogen, C ₁ -C ₆ alkyl, or halo C ₁ -C ₆ alkyl;
R ₉ is C ₃ -C ₆ cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted naphthalene, substituted or unsubstituted pyridine,
Here, the substituted phenyl, benzyl, naphthalene, pyridine is hydrogen, hydroxy, nitro, amino, halogen, C ₁ -C ₄ alkyl, halo C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halo C ₁ -C ₄ is substituted with a substituent selected from the group consisting of alkoxy;
X is C, CH or N;
m is independently 0 or 1;
n is independently an integer from 0 to 3. A compound selected from the group consisting of the following formula or a pharmaceutically acceptable salt thereof.
5-(2-Fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 75 );
5-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-3-(pyridin-4-yl)-1,2,4-oxadiazole (Compound 76) ;
3-(5-(2-Fluoropyridin-3-yl)-1H-indazol-3-yl)-5-(pyridin-4-yl)-1,2,4-oxadiazole (Compound 77) ;
5-(1-isopropyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-( Tetrahydro-2H-pyran-2-yl)-1H-indazole (Compound 78);
5-(1-isopropyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Sol (Compound 79);
5-(1-propyl-1H-pyrazol-4-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1-(tetra Hydro-2H-pyran-2-yl)-1H-indazole (Compound 80);
2,2,2-trifluoro-1-(7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H- Indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 81);
2,2,2-trifluoro-1-(7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl )-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one ( Compound 82);
2,2,2-trifluoro-1-(7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (compound 83);
7-(4-(5-(2-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H-1,2 ,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 84);
7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H -1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 85);
7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-1H- 1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 86);
2,2,2-trifluoro-1-(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3 -Triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 87);
2,2,2-trifluoro-1-(7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1 ,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 88);
2,2,2-trifluoro-1-(7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1, 2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 89);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline (Compound 90);
7-(4-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-Tetrahydroisoquinoline (Compound 91);
7-(4-(5-(1-propyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline (Compound 92);
1-(7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl) -1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (compound 93);
1-(7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl )-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 94);
7-(4-(5-(1-benzyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline (Compound 95);
2,2,2-trifluoro-1-(7-(4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazole-3 -yl)-1H-1,2,3-triazol-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one hydrochloride (Compound 96);
7-(4-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indazol-3-yl)-1H-1,2,3-tria Zol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 97);
7-(4-(5-phenyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 98);
7-(4-(5-(3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 99);
7-(4-(5-(2-chloropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 100);
7-(4-(5-(pyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 101);
7-(4-(5-(o-tolyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetrahydro Isoquinoline hydrochloride (Compound 102);
7-(4-(5-(4-ethylphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4-tetra Hydroisoquinoline hydrochloride (Compound 103);
7-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indazol-3-yl)-1H-1,2,3- Triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 104);
7-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 105);
4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Benzonitrile hydrochloride (Compound 106);
7-(4-(5-(3-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 107);
7-(4-(5-(pyridin-4-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 108);
7-(4-(5-(2-fluoro-6-methoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2 ,3,4-Tetrahydroisoquinoline hydrochloride (Compound 109);
3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Benzonitrile hydrochloride (Compound 110);
7-(4-(5-(4-chloro-3-fluorophenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 111);
(3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5 -yl)phenyl)methanamine dihydrochloride (Compound 112);
4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- I)phenol hydrochloride (Compound 113);
3-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Benzaldehyde hydrochloride (Compound 114);
1-(4-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-yl)phenyl)ethan-1-one hydrochloride (Compound 115);
7-(4-(5-(3-fluoro-5-isopropoxyphenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1, 2,3,4-tetrahydroisoquinoline hydrochloride (Compound 116);
1-(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3 ,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 117);
(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (Compound 118);
(4-chlorophenyl)(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazole-1- 1)-3,4-dihydroisoquinoline-2(1H)-yl)methanone (Compound 119);
(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(4-methoxyphenyl)methanone (Compound 120);
(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(p-tolyl)methanone (Compound 121);
(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(pyridin-4-yl)methanone hydrochloride (Compound 122);
(7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-3,4 -dihydroisoquinolin-2(1H)-yl)(pyridin-3-yl)methanone hydrochloride (Compound 123);
2-benzyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)- 1,2,3,4-Tetrahydroisoquinoline (Compound 124);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2-(4 -Methylbenzyl)-1,2,3,4-tetrahydroisoquinoline (Compound 125);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-phenyl- 3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 126);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(o -Tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 127);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(naphthalene -1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 128);
N-cyclopentyl-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl) -3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 129);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(4 -Methoxybenzyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 130);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-N-(4 -(Trifluoromethoxy)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 131);
7-(4-(5-(furan-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4- Tetrahydroisoquinoline hydrochloride (Compound 132);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 133);
7-(4-(5-(4-(methylsulfonyl)phenyl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 134);
7-(4-(5-(6-methoxypyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 135);
6-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2, 3,4-Tetrahydroisoquinoline hydrochloride (Compound 136);
7-(4-(5-(benzofuran-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4 -Tetrahydroisoquinoline hydrochloride (Compound 137);
7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 138);
7-(4-(5-(benzo[b]thiophen-2-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2 ,3,4-Tetrahydroisoquinoline hydrochloride (Compound 139);
7-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 140);
7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-2-(p Peridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (Compound 141);
2-(3-chloro-4-methylbenzyl)-7-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3 -Triazol-1-yl)-1,2,3,4-tetrahydroisoquinoline (Compound 142);
7-(4-(5-(pyrimidin-5-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3,4 -Tetrahydroisoquinoline hydrochloride (Compound 143);
1-(5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole -5-yl)thiophen-2-yl)ethan-1-one hydrochloride (Compound 144);
5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) pyridin-2-amine hydrochloride (Compound 145);
7-((4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1 , 2,3,4-tetrahydroisoquinoline hydrochloride (Compound 146);
1-methyl-7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline hydrochloride (Compound 147);
1-methyl-7-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline hydrochloride (Compound 148);
3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-5,6, 7,8-Tetrahydro-1,7-naphthyridine hydrochloride (Compound 149);
6-(4-(5-(5-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 150);
6-(4-(5-(4-methylpyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1,2,3 ,4-Tetrahydroisoquinoline hydrochloride (Compound 151);
5-(2-Fluoropyridin-3-yl)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 152 );
3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole (Compound 153 );
5-(2-fluoropyridin-3-yl)-3-(1-(2-methylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 154);
5-(2-fluoropyridin-3-yl)-3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole hydro Chloride (Compound 155);
5-(2-fluoropyridin-3-yl)-3-(1-(2-methoxypyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Sol (Compound 156);
5-(2-fluoropyridin-3-yl)-3-(1-(6-methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Sol (Compound 157);
3-(4-(5-(2-fluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)pyridin-2-ol (Compound 158);
3-(1-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)- 1H-indazole (Compound 159);
5-(2-fluoropyridin-3-yl)-3-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 160);
5-(2-Fluoropyridin-3-yl)-3-(1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 161);
3-(1-(2,6-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole (Compound 162);
7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 ,2,3,4-Tetrahydroisoquinoline hydrochloride (Compound 163);
5-(3-(1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-indazol-5- 1) Picolinonitrile hydrochloride (Compound 164);
N,N-dimethyl-5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazole-4- 1)-1H-indazol-5-yl)pyridin-2-amine hydrochloride (Compound 165);
7-(4-(5-(2,6-difluoropyridin-3-yl)-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl)-1 -Methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (Compound 166);
5-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Zol-5-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one hydrochloride (Compound 167);
3-(3-(1-(1-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,3-triazol-4-yl)-1H-inda Zol-5-yl)quinoline hydrochloride (Compound 168);
5-(2-fluoropyridin-3-yl)-3-(1-(1-methyl-1H-pyrazol-3-yl)-1H-1,2,3-triazol-4-yl)- 1H-indazole (Compound 169);
7-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 170);
3-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)- 1H-indazole (Compound 171);
3-(1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl)-1H-indazole (Compound 172);
5-(2-Fluoropyridin-3-yl)-3-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 173 );
5-(2-Fluoropyridin-3-yl)-3-(1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 174 );
3-(1-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)-5-(2-fluoropyridin-3-yl) -1H-indazole (Compound 175);
5-(2-fluoropyridin-3-yl)-3-(1-(6-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 176);
5-(2-fluoropyridin-3-yl)-3-(1-(5-phenylpyridin-3-yl)-1H-1,2,3-triazol-4-yl)-1H-indazole (Compound 177);
6-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 178); and
4-fluoro-5-(2-fluoropyridin-3-yl)-3-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1H- Indazole (Compound 179). Prevention or treatment of cancer, narcolepsy, and fasciitis comprising a compound represented by Formula 1 or 2 of any one of claims 1 and 3 to 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. For pharmaceutical compositions. In clause 7,
The above cancers include lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, prostate cancer, triple negative breast cancer, ovarian cancer, cervical cancer, thyroid cancer, melanoma, anticancer drug-resistant melanoma, blood cancer, colon cancer, non-small cell lung cancer, pancreatic cancer, and skin cancer. , head and neck cancer, small intestine cancer, rectal cancer, endometrial cancer, vaginal cancer, testicular cancer, esophageal cancer, biliary tract cancer, lymph node cancer, gallbladder cancer, endocrine cancer, adrenal cancer, lymphoma, multiple myeloma, thymoma, mesothelioma, kidney cancer, brain cancer, and central nervous system tumor. , A pharmaceutical composition for preventing or treating cancer, characterized in that it is selected from the group consisting of brainstem glioma and pituitary adenoma. A pharmaceutical composition for preventing or treating metastatic cancer comprising the compound represented by Formula 1 or 2 of any one of claims 1 and 3 to 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. . A pharmaceutical composition for suppressing anticancer drug-resistant cancer, comprising the compound represented by Formula 1 or 2 of any one of claims 1 and 3 to 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. According to clause 10,
The pharmaceutical composition for suppressing anticancer drug-resistant cancer further comprises an anticancer chemotherapy agent. According to clause 11,
The anticancer chemotherapy agents include cell signaling inhibitors (imatinib, gefitinib, voltezomib, erlotinib, sorafenib, sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib, Everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab, pegaptanib, or panitumumab), mitotic inhibitors (paclitaxel, vincristine, or vinblastine), alkylating agents (cisplatin, cyclophosphamide, chromabucil or carmustine), anti-metabolites (methotrexate or 5-FU), implantable anticancer drugs (doxorubicin, actinomycin, anthracyclines, bleomycin or mitomycin-C), topoisomeres. A pharmaceutical composition for suppressing anticancer drug-resistant cancer, characterized in that one or more types selected from the group consisting of inhibitors (irinotecan, topotegan or teniposide), immunotherapy agents (interleukin or interferon), and anti-hormonal agents (tamoxifen or raloxifene). According to clause 11,
A pharmaceutical composition for suppressing anticancer drug resistance, wherein the anticancer chemotherapy agent is selected from the group consisting of doxorubicin (adriamycin), paclitaxel, and cisplatin.