PD-L1 antagonist compounds

Abstract

The present invention provides compounds of formula (I), pharmaceutical compositions thereof, and methods of using compounds of formula (I) to prevent and / or treat immune-related conditions. JPEG2022552693000241.jpg3985

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 201911368320.1, filed with the China Patent Office on December 26, 2019, entitled "PD-L1 Antagonist Compound," the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates to PD-L1 antagonist compounds and methods of using same to treat / prevent immune-related conditions. [Background technology]

[0003] Due to its remarkable efficacy and novelty, tumor immunotherapy was recognized as the most important scientific breakthrough of the year by Science magazine in 2013. Tumor immunotherapy is expected to revolutionize the field of tumor treatment, following surgery, chemotherapy, radiation therapy, and targeted therapy. Tumor immunotherapy uses immunological principles and methods to enhance the immunogenicity of tumor cells and the susceptibility of effector cells to damage, stimulating and enhancing the body's anti-tumor immune response. It also uses immune cells and effector molecules injected into the host to cooperate with the host's immune system to damage tumors and inhibit tumor growth. Tumor immunotherapy has recently attracted much attention and become a focal point in the field of tumor treatment. In recent years, there has been a flurry of good news regarding tumor immunotherapy. To date, it has demonstrated excellent anti-tumor activity in the treatment of some tumors, including melanoma and non-small cell lung cancer, and some tumor immunotherapy drugs have been approved for clinical use by the U.S. Food and Drug Administration (FDA).

[0004] PD-1 (programmed cell death 1 receptor) is a member of the CD28 superfamily. Immunomodulation targeting PD-1 plays an important role in anti-tumor, anti-infection, anti-autoimmune disease, and transplant organ survival. Its ligand, PD-L1, is also targeted, and its corresponding antibody plays the same role. PD-L1 (programmed cell death receptor-ligand 1) is a type 1 transmembrane protein with a size of 40 kDa. Normally, the immune system responds to foreign antigens accumulated in lymph nodes or the spleen by promoting the proliferation of antigen-specific T cells. When PD-1 and PD-L1 bind to each other, an inhibitory signal is transmitted, reducing T cell proliferation.

[0005] One way tumor cells evade T cell destruction is by producing PD-L1 on their surface. When PD-1 on the surface of immune T cells recognizes PD-L1 and transmits an inhibitory signal, the T cells are unable to detect tumor cells and issue an attack signal to them. PD-1 is a novel immunotherapy that prevents tumor cells from evading the immune system. The mechanism of action of PD-1 immunotherapy is to engineer specific protein antibodies against PD-1 or PD-L1, block the process of PD-1 and PD-L1 recognition, and restore some T cell function, allowing T cells to kill tumor cells.

[0006] PD-1 is expressed on activated T cells, B cells, and myeloid cells and has two ligands, PD-L1 and PD-L2. Both PD-L1 and PD-L2 are expressed on antigen-presenting cells, and PD-L1 is also expressed in many tissues. The binding of PD-1 and PD-L1 mediates a co-inhibitory signal for T cell activation, regulating T cell activation and proliferation and acting as a negative regulator of CTLA-4. Chinese scientist Chen Lieping first discovered in the laboratory that PD-L1 is highly expressed in tumor tissue and regulates the function of tumor-infiltrating CD8 T cells. Therefore, immune modulation targeting PD-1 / PD-L1 plays an important role in anti-tumor therapy.

[0007] Many therapeutic monoclonal antibodies (mAbs) targeting the interaction between PD-1 and PD-L1 have been approved by the US Food and Drug Administration and are now commercially available. In addition to the development of related monoclonal antibodies, another cutting-edge area of ​​tumor immunotherapy is the identification of small molecule compounds that are easily administered orally to cancer patients to target and inhibit immune checkpoints. Small molecule compounds are widely available because they can penetrate cell membranes and act on intracellular targets. Furthermore, chemical modifications of small molecules generally provide excellent bioavailability and good compliance, effectively preventing degradation and inactivation by intestinal enzymes. Furthermore, active research is being conducted on small molecules, including their manufacturing processes, formulation design, and administration methods.

[0008] Most monoclonal antibodies (mAbs) are administered by intravenous injection at high doses. Small molecule drugs are more suitable for oral administration and reduce serious immune-related adverse events. Compared with monoclonal antibodies, small molecule inhibitors have many other advantages, such as lower production costs, greater stability, and better organ and tumor penetration. The many advantageous pharmacokinetic properties of small molecule drugs may allow greater flexibility in dosing in monotherapy or combination therapy. The small molecule compounds of the present invention represent an attractive therapeutic option for patients and physicians. Summary of the Invention

[0009] The present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, prodrug, isotopic derivative, hydrate, isomer, solvate, or metabolite thereof.

[0010] [ka]

[0011] L1 is -CR A R B -, -C(O)-, L2 and L3 are -(CR C R D ) p , -(CR C RD ) p -NR a -(CR C R D ) q -, -(CR C R D ) p -O-(CR C R D ) q -, -C(O)-, W1 and W2 are independent CR L or N, R 1 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, or -NR a R b , or a C1-C6 alkyl group, a C3-C6 cycloalkyl group, -O(C1-C6 alkyl group), -O(C0-C6 alkylene)(C5-C 10 aryl group), -O(C0-C6 alkylene)(5-10 membered heteroaryl group), -O(C0-C6 alkylene)(C3-C6 cycloalkyl group), or -O(C0-C6 alkylene)(3-6 membered heterocycloalkyl group), wherein the substituent is -OR a , cyano group, oxo, halogen, C1-C6 alkyl group, -(C1-C6 alkylene)OR a , cyano group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C8 cycloalkyl group, -C(O)R a , -(C1-C6 alkylene)C(O)R a , -C(O)OR a , -(C1-C6 alkyl group)C(O)OR a , -NR a R b , -(C1-C6 alkylene)NR a R b , -C(O)NR a R b , -SO2R a , -C(O)NR a SO2R b , -NR a C(O)R b Selected from R 2 , R 3, R 4 , R 5 are each independently hydrogen, halogen, a nitro group, a cyano group, or -NR a R b , -SO2R a , -S(O)R a , -P(O)R a R b , a C1-C6 alkyl group, -O(C1-C6 alkyl group), -O(C3-C6 cycloalkyl group), halo(C1-C6 alkyl group) or C3-C6 cycloalkyl group, Cy is 0, 1, 2, or 3 R 6 wherein the six-membered heteroaryl group optionally contains one or two nitrogen atoms, and the R 6 is hydrogen, halogen, nitro group, cyano group, -NR a R b , -SO2R a , -S(O)R a Or-P(O)R a R b , or a C1-C6 alkyl group, a C3-C6 cycloalkyl group, -O(C1-C6 alkyl group), -O(C0-C6 alkylene)(C5-C 10 aryl group), -O(C0-C6 alkylene)(5-10 membered heteroaryl group), -O(C0-C6 alkylene)(C3-C6 cycloalkyl group), or -O(C0-C6 alkylene)(3-6 membered heterocycloalkyl group), wherein the substituent is -OR a , cyano group, oxo, halogen, C1-C6 alkyl group, -(C1-C6 alkylene)OR a , cyano group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C8 cycloalkyl group, -C(O)R a , -(C1-C6 alkylene)C(O)R a , -C(O)OR a , -(C1-C6 alkylene)C(O)OR a , -NR a R b , -(C1-C6 alkylene)NR a R b , -C(O)NR a Rb , -SO2R a , -C(O)NR a SO2R b , -NR a C(O)R b Selected from R L is hydrogen, C1-C6 alkyl group, -O(C1-C6 alkyl group), -O(C3-C6 cycloalkyl group), halogen, nitro group, cyano group, -NR a R b , halo(C1-C6 alkyl group) or C3-C6 cycloalkyl group; T and A each independently represent a -(C1-C6 alkyl group), -(C0-C6 alkylene)-(C3-C 12 cycloalkyl group), -(C0-C6 alkylene)-(3-12 membered heterocycloalkyl group), -(C0-C6 alkylene)-(C6-C 10 -(C0-C6 alkylene)-(5-10 membered heteroaryl group), and the substituents are cyano, oxo, halogen, C1-C6 alkyl group, -(C0-C6 alkylene)OR a , cyano group, C1-C6 alkyl group, halo(C1-C6 alkyl group), C3-C8 cycloalkyl group, -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkenyl)C(O)OR a , (C0-C6 alkylene)NR a R b , -C(O)NR a R b , -NR a SO2R b , -C(O)NR a SO2R b , -NR a C(O)R b Selected from R A , R B are each independently hydrogen, a C1-C6 alkyl group, -(C0-C3 alkylene)(C3-C 12-(C0-C3 alkylene) (3-12 membered heterocycloalkyl group), halo (C1-C6 alkyl group) or halogen, or R A and R B form a 3- to 6-membered ring together with their co-bonded carbon atoms, R C , R D are each independently hydrogen, a C1-C6 alkyl group, -(C0-C3 alkylene)(C3-C 12 represents a -(C0-C3 alkylene) (3-12 membered heterocycloalkyl group), halo (C1-C6 alkyl group) or halogen, or represents R C and R D form a 3- to 6-membered ring together with their co-bonding atoms, R a , R b are each independently hydrogen, a C1-C6 alkyl group, a halo(C1-C6 alkyl group), -(C0-C6 alkylene)OH, -(C0-C3 alkylene)(C3-C 12 cycloalkyl group), -(C0-C3 alkylene)(3-12 membered heterocycloalkyl group), -(C0-C3 alkylene)(C6-C 10 -(C0-C3 alkylene)(5-10 membered heteroaromatic ring) or halo(C1-C6 alkyl group), or R a and R b form a 3- to 6-membered ring together with their co-bonding atoms, m and o each independently represent 0, 1, or 2; p and q each independently represent 0, 1, 2 or 3.

[0012] Preferably, the compound of formula (I) has the structure of formula (II):

[0013] [ka]

[0014] R 1 , R 2 , R 3 , R4 , R 5 , R 6 , L1, L2, L3, T, A, W1, W2, m, and o are defined as in formula (I), r represents 0, 1, 2 or 3.

[0015] Preferably, the compound of formula (I) has the structure of formula (III):

[0016] [ka]

[0017] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L1, L2, L3, T, A, W1, W2, m, and o are defined as in formula (I), W3 is CR M or N, R M is hydrogen, C1-C6 alkyl group, -O(C1-C6 alkyl group), -O(C3-C6 cycloalkyl group), halogen, nitro group, cyano group, -NR a R b , halo(C1-C6 alkyl group) or C3-C6 cycloalkyl group, r represents 0, 1 or 2.

[0018] Preferably, the compound of formula (I) has the structure of formula (IV):

[0019] [ka]

[0020] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L1, L2, L3, T, A, W1, W2, m, and o are defined as in formula (I), W4 is CRN or N, R N is hydrogen, C1-C6 alkyl group, -O(C1-C6 alkyl group), -O(C3-C6 cycloalkyl group), halogen, nitro group, cyano group, -NR a R b , halo(C1-C6 alkyl group) or C3-C6 cycloalkyl group; r represents 0, 1 or 2.

[0021] In the compounds of the present invention, L1 is preferably -CR A R B -Selected from R A , R B are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a halo(C1-C6 alkyl group), and are preferably hydrogen.

[0022] In the compounds of the present invention, L2 and L3 are each preferably independently -CR C R D -, -CR C R D -NR a - (CR C R D ) q -, q is selected from 0, 1 or 2, and R C , R D are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a halo(C1-C6 alkyl group), and are preferably hydrogen. a are each independently hydrogen, a C1-C6 alkyl group, a halo(C1-C6 alkyl group), -(C0-C3 alkylene)C3-C 12 It is selected from cycloalkyl groups.

[0023] In the compounds of the present invention, W1 and W2 each preferably independently represent CH or N. In the compounds of the invention, W3 preferably represents CH or N. In the compounds of the invention, W4 preferably represents CH or N.

[0024] In the compounds of the present invention, T and A are each independently substituted with 0, 1, 2, or 3 substituents: -(C1-C6 alkyl group), -(C0-C6 alkylene)-(C3-C 12 -(C0-C6 alkylene)-(3-12 membered heterocycloalkyl group), wherein the substituents are cyano, oxo, halogen, C1-C6 alkyl group, -(C0-C6 alkylene)OR a , cyano group, C1-C6 alkyl group, halo(C1-C6 alkyl group), C3-C8 cycloalkyl group, -(C0-C6 alkylene)C(O)R a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkenyl)C(O)OR a , -(C0-C6 alkylene)NR a R b , -C(O)NR a R b , -NR a SO2R b , -C(O)NR a SO2R b , -NR a C(O)R b Selected from R a , R b each independently represents hydrogen, a C1-C6 alkyl group, or a halo(C1-C6 alkyl group).

[0025] In the compounds of the present invention, T and A are each independently a C1-C6 alkyl group substituted with 0, 1 or 2 substituents, a C3-C 12 represents a cycloalkyl group or a 3- to 12-membered heterocycloalkyl group, and the substituent is a cyano group, an oxo group, an -OR a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkenyl)C(O)OR a , -NR a SO2R b , -C(O)NR a SO2R b W-NR a C(O)R b Selected from R a , R beach independently represents hydrogen, a C1-C6 alkyl group, or a halo(C1-C6 alkyl group).

[0026] In the compounds of the present invention, T and A are each preferably independently optionally substituted with 0, 1 or 2 substituents.

[0027] [ka]

[0028] wherein the substituent is selected from a C1-C6 alkyl group, -OR a , -(C0-C6 alkylene)C(O)OR a , -(C0-C6 alkenyl)C(O)OR a Selected from R a represents hydrogen or a C1-C6 alkyl group, preferably hydrogen; and α represents 1, 2, or 3.

[0029] In the compound of the present invention, T and A each preferably independently represent the following group:

[0030] [ka]

[0031] In the compounds of the present invention, T and A are each preferably independently optionally substituted with 0, 1 or 2 substituents.

[0032] [ka]

[0033] wherein the substituent is selected from a C1-C6 alkyl group, -OR a , halogen, R e , R a each independently represents hydrogen or a C1-C6 alkyl group, and α represents 1, 2, 3, or 4. In the compound of the present invention, T and A are each preferably independently

[0034] [ka]

[0035] represents R e represents hydrogen or a C1-C6 alkyl group, and α represents 1, 2, 3, or 4. In the compound of the present invention, T and A each preferably independently represent the following group:

[0036] [ka]

[0037] In the compounds of the present invention, R 1 is preferably —O(C1-C6 alkyl), —O(C0-C6 alkylene)(C5-C 10 -C-C alkylene) (5-10 membered heteroaryl group), -C-C alkylene) (C-C cycloalkyl group), or -C-C alkylene) (3-6 membered heterocycloalkyl group), wherein the substituents are selected from cyano, oxo, halogen, cyano, C-C alkyl group, and C-C haloalkyl group.

[0038] In the compounds of the present invention, R 2 is preferably hydrogen, halogen, a nitro group, a cyano group, -SO2R a , a C1-C6 alkyl group, a halo(C1-C6 alkyl group) or a C3-C6 cycloalkyl group, R a represents hydrogen, a C1-C6 alkyl group, or a halo(C1-C6 alkyl group).

[0039] In the compounds of the present invention, R 3 , R 4 preferably each independently represents hydrogen, halogen, a nitro group or a cyano group. In the compounds of the present invention, R 5preferably represents hydrogen, halogen, a nitro group, a cyano group, a C1-C6 alkyl group, a halo(C1-C6 alkyl group) or a C3-C6 cycloalkyl group.

[0040] In the compounds of the present invention, R 6 is preferably hydrogen, halogen, a nitro group, a cyano group, -SO2R a , C1-C6 alkyl group, halo(C1-C6 alkyl group) or C3-C6 cycloalkyl group or —O(C1-C6 alkyl group), —O(C0-C6 alkylene)(C5-C 10 -C-C alkylene) (5-10 membered heteroaryl group), -C-C alkylene) (C-C cycloalkyl group), or -C-C alkylene) (3-6 membered heterocycloalkyl group), wherein the substituents are selected from cyano, oxo, halogen, cyano, C-C alkyl group, and C-C haloalkyl group.

[0041] In the compounds of the present invention, R L preferably represents hydrogen or halogen. In the compounds of the present invention, R M , R N preferably each independently represents hydrogen. Detailed Description Specifically, the present invention provides compounds of the following structure:

[0042] [Table 1-1]

[0043] [Table 1-2]

[0044] [Table 1-3]

[0045]

Table 1-4

[0046]

Table 1-5

[0047]

Table 1-6

[0048]

Table 1-7

[0049]

Table 1-8

[0050]

Table 1-9

[0051]

Table 1-10

[0052]

Table 1-11

[0053]

Table 1-12

[0054]

Table 1-13

[0055]

Table 1-14

[0056] The present invention further provides pharmaceutical compositions comprising a compound according to the present invention, and optionally further comprising other therapeutic agents and / or immune checkpoint inhibitors. The pharmaceutical compositions of the present invention may also comprise a pharmaceutical carrier.

[0057] The present invention further provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for treating a disease or condition treatable by inhibiting the binding of PD-L1 to PD-1, preferably the disease is selected from tumors, cancers, viral infections, inflammation-related diseases, and autoimmune diseases.

[0058] The present invention further provides the use of a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, in the manufacture of a medicament for the treatment of a disease or condition responsive to inhibition of the binding of PD-L1 to PD-1, preferably wherein the disease or condition is selected from tumors, cancer, viral infections, inflammation-related diseases, and autoimmune diseases.

[0059] The present invention also provides a method for treating a disease or condition that can be treated by inhibiting the binding of PD-L1 to PD-1 (preferably tumor, cancer, viral infection, inflammatory disease, or autoimmune disease), which comprises administering a compound of the present invention or a pharmaceutical composition of the present invention to an applicable mammal.

[0060] The present invention also provides a method for treating a disease or condition responsive to inhibition of the binding of PD-L1 to PD-1, comprising administering a compound of the present invention or a pharmaceutical composition of the present invention to an applicable mammal. The term "disease or condition responsive to inhibition of the binding of PD-L1 to PD-1" refers to a disease or condition in which inhibition of the binding of PD-L1 to PD-1 can alter the course of the disease, or alleviate, inhibit, eliminate, improve, or prevent the disease, symptom, disorder, etc. Preferably, the disease or condition responsive to inhibition of the binding of PD-L1 to PD-1 is selected from tumors, cancers, viral infections, inflammation-related diseases, and autoimmune diseases.

[0061] The present invention also provides a method for inhibiting the binding of PD-L1 to PD-1, which method comprises exposing PD-L1 and / or PD-1 to a compound of the invention or a pharmaceutical composition of the invention.

[0062] In the above embodiments relating to the compounds of the invention, pharmaceutical compositions, uses and methods using the compounds or pharmaceutical compositions of the invention, the compounds of the invention particularly include pharmaceutically acceptable salt forms thereof.

[0063] Representative examples of inflammatory, autoimmune, and immune-mediated diseases include arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, pulmonary inflammation, adult acute respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia-reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis, and the like. These include, but are not limited to, sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic sinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndromes (MDS), myelodysplastic neoplasms (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0064] Representative examples of cancers or tumors include skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary system cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, primitive neuroectomy), These include, but are not limited to, myeloid leukemia (MYC), Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0065] When the compound of the present invention or a pharmaceutical salt thereof is administered in combination with other therapeutic agents or immune checkpoint inhibitors for treating cancer or tumors, the compound of the present invention or a pharmaceutical salt thereof exhibits an enhanced anti-cancer effect.

[0066] Representative examples of therapeutic agents for treating cancer or tumors include cell signaling inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trametinib, thiazolinone ... Bectedin, dactinomycin, doxorubicin, epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib , cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib ), motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, telatinib, tivantinib, tivozanib, tofacitinib,These include, but are not limited to, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panituzumab, rituximab, tositumomab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, LAG3 antibodies, TIM-3 antibodies, anti-CTLA-4 antibodies, or any combination thereof.

[0067] When the compounds of the present invention or pharmaceutical salts thereof are administered in combination with other therapeutic agents for treating inflammatory diseases, autoimmune diseases or immune-mediated diseases, the compounds of the present invention or pharmaceutical salts thereof exhibit enhanced therapeutic effects.

[0068] Representative examples of therapeutic agents for inflammatory diseases, autoimmune diseases, or immune-mediated diseases include, but are not limited to, steroid drugs (e.g., prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNFα drugs (e.g., etanercept, infliximab, adalizumab, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from these may be contained in the pharmaceutical composition of the present invention.

[0069] The compound of the present invention or a pharmaceutical salt thereof may be administered orally or parenterally as an active ingredient. The effective dose range for mammals, including humans (body weight: about 70 kg), is 0.1 to 2000 mg / kg body weight / day, preferably 1 to 1000 mg / kg body weight / day, and may be administered once or four times a day, or at a predetermined time or at any time. The dose of the active ingredient may be adjusted based on several relevant factors (e.g., the condition of the subject being treated, the type and severity of the disease, the frequency of administration, and the doctor's opinion). In some cases, a lower dose than the above may be appropriate. As long as no adverse side effects occur, a higher dose than the above may be administered in several divided doses per day.

[0070] The present invention also provides a method for inhibiting PD-L1, the method comprising exposing PD-L1 to a compound described in the present invention, a pharmaceutically acceptable salt thereof, or a drug combination described in the present invention.

[0071] "Definition of Terms" It should be noted that, when a "compound" having a particular structural formula is referred to herein, it generally includes its stereoisomers, diastereomers, enantiomers, racemic mixtures, isotopic derivatives, and alternative forms such as pharmaceutical salts, solvates, and hydrates. As is well known to those skilled in the art, salts, solvates, and hydrates of a compound are alternative forms of the compound that can be converted to the compound under certain conditions. Therefore, when a compound of interest is referred to herein, it generally includes its pharmaceutical salts, solvates, and hydrates.

[0072] Similarly, when a subject compound is referred to herein, it generally includes its prodrugs, metabolites, and nitroxides. The medicinal salts or pharmaceutically acceptable salts described in the present invention may be formed with inorganic or organic acids, and the term "medicinal salts" or "pharmaceutically acceptable salts" refers to salts that, in the reasonable medical judgment, are suitable for use in contact with the tissues of humans and lower animals, do not produce undesirable toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio. During the final isolation and purification of the compounds of the present invention, the salts may be formed in situ, or they may be prepared by reacting the free base or free acid with a suitable reagent, as described below. For example, the free base can be reacted with a suitable acid. Furthermore, when the compounds of the present invention contain an acidic moiety, suitable medicinal salts include metal salts, such as alkali metal salts (e.g., sodium salt or potassium salt) and alkaline earth metal salts (e.g., calcium salt or magnesium salt). Examples of pharmaceutically acceptable non-toxic acid addition salts include salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid), or salts formed by other methods known in the art, such as ion exchange. Other pharmaceutical salts include adipate, sodium alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. These include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, etc. Other pharmaceutical salts include (where appropriate) non-toxic ammonium salts, quaternary ammonium salts, ammonium cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, aryl sulfonates.

[0073] The pharmaceutical salts of the present invention may be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, acetonitrile), then adding an excess amount of an aqueous solution of an organic or inorganic acid to precipitate the salt from the mixture, removing the solvent and excess free acid, and separating the precipitated salt.

[0074] The precursors or metabolites described in the present invention may be precursors or metabolites known in the art, as long as they are converted into compounds by metabolism in the body. For example, a "prodrug" refers to a prodrug of a compound of the present invention that, in reasonable medical judgment, is suitable for use in contact with the tissues of humans and lower animals, does not produce undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit / risk ratio, and is effective for the desired application. The term "prodrug" refers to a compound that is rapidly converted in the body to produce the parent compound shown in the formula above, for example, by metabolism in the body or N-demethylation of the compound of the present invention.

[0075] According to the present invention, a "solvate" refers to a compound of the present invention physically associated with one or more solvent molecules (which may be organic or inorganic). Such physical associations include hydrogen bonds. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate may be arranged in an ordered and / or disordered manner. A solvate may contain solvent molecules in a stoichiometric or non-stoichiometric manner. "Solvate" includes solution-phase and isolable solvates. Examples of solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates.

[0076] "Stereoisomerism" as used herein can be divided into conformational isomerism and configurational isomerism, and configurational isomerism can be divided into cis-trans isomerism and optical isomerism. Conformational isomerism refers to the phenomenon of stereoisomerism in which the spatial arrangement of each atom or group of atoms in an organic molecule with a specific configuration changes due to rotation or twisting of a carbon-carbon single bond. This is commonly seen in the structures of alkane and cycloalkane compounds, and examples of this include the chair and boat conformations of the cyclohexane structure. "Stereoisomer" refers to the fact that the compounds of the present invention contain one or more asymmetric centers and therefore may be racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. The compounds of the present invention may contain asymmetric centers, and each asymmetric center has two optical isomers. The present invention encompasses optical isomers, diastereomeric mixtures, and pure or partially pure compounds. The compounds of the present invention may also exist as tautomers, which have different hydrogen connection sites due to displacement of one or more double bonds. For example, a ketone form and an enol form are ketone-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the present invention. The compounds of formula (I) include enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epi isomers, and mixtures thereof.

[0077] In the present invention, the term "isotope derivative" refers to a molecule of the compound of the present application that is labeled with an isotope. The isotope generally used for isotope labeling is a hydrogen isotope ( 2 H, 3 H), carbon isotopes ( 11 C. 13 C. 14 C), chlorine isotopes ( 35 Cl, 37 Cl), fluorine isotopes ( 18 F), iodine isotopes ( 123 I, 125 I), nitrogen isotopes ( 13 N, 15 N), oxygen isotopes ( 15 O. 17 O. 18 O), sulfur isotopes ( 35 These isotope-labeled compounds can be used to study the distribution of drug molecules in tissues. 2 H and carbon 13 C is widely used because it is easy to label and detect. Certain heavy isotopes (e.g., deuterium ( 2 When substituted with H), metabolic stability is improved and half-life is extended, allowing for dose reduction while ensuring efficacy. Isotopically labeled compounds can generally be synthesized from labeled starting materials using conventional synthetic techniques, similar to the synthesis of non-isotopically labeled compounds.

[0078] The compounds or pharmaceutical compositions of the present invention can be formulated in any conventional manner into dosage forms for oral or parenteral administration (including intramuscular, intravenous, subcutaneous, and intratumoral injection), such as tablets, granules, powders, capsules, syrups, emulsions, microemulsions, solutions, or suspensions.

[0079] The pharmaceutical compositions of the present invention for oral administration may be prepared by mixing the active ingredient with a carrier such as cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Examples of carriers used in the injectable compositions of the present invention include water, salt solutions, glucose solutions, glucose-like solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, and emulsifiers.

[0080] Other features of the present invention will become apparent from the description of exemplary embodiments, which are merely illustrative of the present invention and are prepared, isolated, and characterized using the methods disclosed in the following examples.

[0081] Unless otherwise indicated, the terms used in the specification and claims of this application are defined as follows: In the specification and claims, the singular "a" or "an" includes the plural unless otherwise indicated. Conventional methods in the fields of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used unless otherwise indicated. In this application, "or" or "and" means "and / or" unless otherwise indicated.

[0082] In the specification and claims, a given chemical formula or name includes all stereoisomers, optical isomers, and racemates in which such isomers exist. Unless otherwise specified, all chiral molecules (enantiomers and diastereomers) and racemates are within the scope of the present invention. The compounds may exist in various geometric isomers, such as C=C double bonds, C=N double bonds, and ring systems, and such stable isomers are also included in the present invention. The present invention discloses cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, which can be isolated as mixtures of isomers or as individual isomers. The compounds of the present invention can be separated by optical activity or racemization. The present invention also encompasses methods for preparing the compounds of the present invention and intermediates thereto. When enantiomeric or diastereomeric products are desired, they can be separated by conventional methods (e.g., chromatography or fractional crystallization). Depending on the process conditions, the final products of the present invention may be obtained in free (neutral) form or as salts. These final products, both in free form and as salts, are also within the scope of the present invention. If necessary, a compound may be converted from one form to another. A free base or acid may be converted to a salt, or a salt may be converted to the free compound or another salt, and a mixture of isomers of a compound of the present invention may be separated into individual isomers. The compounds of the present invention, both in their free form and salts, exist as various tautomers in which hydrogen atoms are transferred to other parts of the molecule, thereby rearranging the chemical bonds between the atoms of the molecule. All existing tautomeric forms are included in the present invention.

[0083] Unless otherwise defined, the substituents of the present invention are not related to each other and are defined independently of each other, for example, R a (or R b ) are each independently defined as different substituents. Specifically, R a (or R b ) is already defined for a particular substituent, the same R a (or R b ) does not necessarily mean that it has that definition. More specifically, for example (although illustrative), NR a R b So, Ra (or R b ) is defined as hydrogen, a R b So, R a (or R b ) does not necessarily mean hydrogen.

[0084] Unless otherwise defined, when a substituent is described as being "optionally substituted with...", the substituent includes, for example, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group, a halogen atom, a hydroxy group, an alkoxy group, an oxo group, an alkanoyl group, an aryloxy group, an alkanoyloxy group, an amino group, an alkylamino group, an arylamino group, an arylalkylamino group, a disubstituted amino group (wherein the two amino group substituents are selected from an alkyl group, an aryl group, and an arylalkyl group), an alkanoylamino group, an aroylamino group, an aralkanoylamino group, a substituted alkanoylamino group, a substituted arylamino group, a substituted aralkanoylamino group, a thio group, an alkylthio group, an arylthio group, an arylalkylthio group, an arylthiocarbonyl group, an arylalkylthiocarbonyl group, an alkylsulfonyl group, an alkylamino group, an arylthio group, an arylalkylthio group, an alkylsulfonyl group, an alkylamino group, an arylthio group, an arylalkylthio group, an aryl ...alkylthio group, an alkylsulfonyl group, an alkylamino group, an arylalkylthio group, an arylthiocarbonyl group, an alkylsulfonyl group, an alkylamino group, an arylalkylthio group, an alkylsulfonyl group, an alkylamino group, an arylalkylthio group, an arylthiocarbonyl group, an alkylsulfonyl group, an alkylamino group, an arylalkylthio group, an alkylamino group, an arylalkylthio group, an alkylthio group, an alkylsulfonyl group, an alkylamino group, an arylalkylthio group, an and the like. The aryl group is selected from a methyl group, an arylsulfonyl group, an arylalkylsulfonyl group, a sulfonylamino group (e.g., -SO2NH2), a substituted sulfonylamino group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group (e.g., -CONH2), a substituted carbamoyl group (e.g., a -CONH alkyl group, a -CONH aryl group, a -CONH arylalkyl group, or a group having two substituents at the nitrogen atom selected from an alkyl group, an aryl group, and an arylalkyl group), an alkoxycarbonyl group, an aryl group, a substituted aryl group, a guanidino group, a heterocyclic group (e.g., an indolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, a pyrrolidinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group, a homopiperazinyl group, etc.), and a substituted heterocyclic group.

[0085] As used herein, the term "alkyl group" or "alkylene group" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, a "C1-C6 alkyl group" refers to an alkyl group having from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and neopentyl groups.

[0086] The term "alkenyl group" refers to a straight or branched chain hydrocarbon group having one or more double bonds and generally having 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl group" has 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0087] The term "alkynyl group" refers to a straight or branched chain hydrocarbon group having one or more triple bonds and generally having 2 to 20 carbon atoms. For example, a "C2-C6 alkynyl group" has 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.

[0088] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. A "C1-C6 alkoxy (or alkyloxy)" is intended to include C1, C2, C3, C4, C5, and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy, isopropoxy), and t-butoxy. Similarly, an "alkylthio" or "thioalkoxy" refers to an alkyl group as defined above with the specified number of carbon atoms connected via a sulfur bridge, e.g., methyl-S-, ethyl-S-.

[0089] The term "carbonyl group" refers to an organic functional group in which two atoms, carbon and oxygen, are connected by a double bond (C=O). The term "aryl group," by itself or as part of, for example, an "aralkyl group," "aralkoxy group," or "aryloxyalkyl group," refers to a monocyclic, bicyclic, or tricyclic ring system consisting of a total of 5 to 12 ring atoms, provided that at least one ring in the ring system is aromatic and each ring in the ring system has 3 to 7 ring atoms. In some embodiments of the present invention, "aryl group" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl groups. The term "aralkyl group" or "arylalkyl group" refers to an alkyl residue attached to an aromatic ring. Non-limiting examples include benzyl, phenethyl, and the like. Fused aryl groups may be attached to other groups at any suitable position on the cycloalkyl or aromatic ring. For example, a dashed line drawn through a ring system indicates that the bond may be attached to any suitable ring atom.

[0090] The term "cycloalkyl group" refers to a monocyclic or bicyclic alkyl group. Monocyclic alkyl groups refer to C3-C8 cyclic alkyl groups, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornanyl groups. Branched cycloalkyl groups, such as 1-methylcyclopropyl and 2-methylcyclopropyl, are also included within the definition of "cycloalkyl group." Bicyclic alkyl groups include bridged, spiro, or fused cycloalkyl groups.

[0091] The term "cycloalkenyl group" refers to a monocyclic or bicyclic alkenyl group. Monocyclic alkenyl groups refer to C3-C8 cyclic alkenyl groups, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Branched cycloalkenyl groups, such as 1-methylcyclopropenyl and 2-methylcyclopropenyl, are also included in the definition of "cycloalkenyl group." Bicyclic alkenyl groups include bridged, spiro, and fused cyclic alkenyl groups.

[0092] The term "halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl group" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl groups. Haloalkyl groups further include, by way of example, "fluoroalkyl groups," which are intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more fluorine atoms.

[0093] The term "haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group, as defined above, having the specified number of carbon atoms connected via an oxygen bridge. For example, a "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, and C6 haloalkoxy groups. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, the term "haloalkylthio" or "thiohaloalkoxy" refers to a haloalkyl group, as defined above, having the specified number of carbon atoms connected via a sulfur bridge, such as trifluoromethyl-S- or pentafluoroethyl-S-.

[0094] In this disclosure, the term "C" is used to describe some of the substituents. x1 -C x2" represents that the number of carbon atoms in the substituent is x1 to x2. For example, C0-C8 represents that the group has 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C1-C8 represents that the group has 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C2-C8 represents that the group has 2, 3, 4, 5, 6, 7, or 8 carbon atoms, C3-C8 represents that the group has 3, 4, 5, 6, 7, or 8 carbon atoms, and C4-C8 represents that the group has C0-C6 means that the group has 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 means that the group has 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 means that the group has 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 means that the group has 3, 4, 5, or 6 carbon atoms.

[0095] In the present disclosure, the expression "x1-x2-membered ring" used to describe a cyclic group (e.g., an aryl group, a heteroaryl group, a cycloalkyl group, or a heterocycloalkyl group) indicates that the number of ring atoms in the group is x1 to x2. For example, in the case of a 3-12-membered cyclic group, this indicates that the ring is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring and has 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms. In the case of a 3-6-membered ring, this indicates that the cyclic group is a 3-, 4-, 5-, or 6-membered ring and has 3, 4, 5, or 6 ring atoms. In the case of a 3-8-membered ring, this indicates that the cyclic group is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring and has 3, 4, 5, 6, 7, or 8 ring atoms. When it is a 3-9 membered ring, it means that the cyclic group is a 3-, 4-, 5-, 6-, 7-, 8-, or 9-membered ring and has 3, 4, 5, 6, 7, 8, or 9 ring atoms. When it is a 4-, 5-, 6-, or 7-membered ring, it means that the cyclic group is a 4-, 5-, 6-, or 7-membered ring and has 4, 5, 6, or 7 ring atoms. When it is a 5-, 8-, or 5-membered ring, it means that the cyclic group is a 5-, 6-, 7-, or 8-membered ring and has 5, 6, 7, or 8 ring atoms. When it is a 5-, 12-, or 12-membered ring, it means that the cyclic group is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring and has 5, 6, 7, 8, 9-, 10-, 11-, or 12 ring atoms. When the ring is a 6- to 12-membered ring, the cyclic group is a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the number of ring atoms is 6, 7, 8, 9, 10, 11, or 12. The ring atoms are carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocyclic ring, the heterocyclic ring may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more heteroatoms, for example, heteroatoms selected from N, O, and S.

[0096] In the present invention, the one or more halogens are each independently selected from fluorine, chlorine, bromine, and iodine. The term "heteroaryl group" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic or bicyclic ring, or a 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic polyheterocyclic ring, fully unsaturated or partially unsaturated, containing carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, including polycyclic groups formed by condensing any of the heterocyclic rings defined above with a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent, as defined). The heterocyclic ring may be attached to a pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein may be substituted at carbon or nitrogen atoms if the resulting compound is stable. The nitrogen atom in the heterocyclic ring may optionally be quaternized. It is preferred that when the total number of S and O atoms in a heterocycle exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in a heterocycle is 1 or less. When the term "heterocycle" is used, it is intended to include aromatic heterocycles. Examples of aromatic heterocycles include acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuryl, benzothiofuryl, benzothienyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]Tetrahydrofuryl group, furyl group, furazanyl group, imidazolidinyl group, imidazolinyl group, imidazolyl group, 1H-indazolyl group, imidazopyridyl group, indolenyl group, dihydroindolyl group, indazinyl group, indolyl group, 3H-indolyl group, isatinoyl group, isobenzofuryl group, isochromanyl group, isoindazolyl group, isodihydroindolyl group, isoindolyl group, isoquinolinyl group, isothiazolyl group, isothiazolopyridyl group, isoxazolyl group, isoxazolopyridyl group Lysyl group, methylenedioxyphenyl group, morpholinyl group, phthalazinyl group, octahydroisoquinolinyl group, oxadiazolyl group, 1,2,3-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, oxazolidinyl group, oxazolyl group, oxazopyridyl group, oxazolidinyl group, perimidinyl group, indoxyl group, pyrimidinyl group, phenanthridinyl group, phenanthrolinyl group, phenazinyl group, phenothiazinyl group, phenoxathiinyl group, phenoxazin ... Talazinyl group, piperazinyl group, piperidinyl group, piperidonyl group, 4-piperidonyl group, piperonyl group, pteridinyl group, purinyl group, pyranyl group, pyrazinyl group, pyrazolidinyl group, pyrazolinyl group, pyrazolopyridyl group, pyrazolyl group, pyridazinyl group, pyridooxazolyl group, pyridoimidazolyl group, pyridothiazolyl group, pyridyl group, pyrimidinyl group, pyrrolidinyl group, pyrrolinyl group, 2-pyrrolidonyl group, 2H-pyrrolyl group, pyrrolyl group, quinazolinyl group, quinolinyl group, 4H-quinolizidinyl group, quinoxalyl group, quinuclidinyl group, tetrahydrofuran ... tolazolyl group, tetrahydrofuryl group, tetrahydroisoquinolinyl group, tetrahydroquinolinyl group, 6H-1,2,5-thiadiazinyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, thianthrenyl group, thiazolyl group, thienyl group, thiazolopyridyl group, thienothiazolyl group, thienoxazolyl group, thienoimidazolyl group, thienyl group, triazinyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, 1,2,5-triazolyl group, 1,3,These include, but are not limited to, 4-triazolyl, xanthenyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydrobenzofuryl, chromanyl, 1,2,3,4-tetrahydroquinoxalyl, and 1,2,3,4-tetrahydroquinazolinyl. The term "heteroaryl group" may further include biaryl group structures formed by the above-defined "aryl group" and a monocyclic "heteroaryl group" (e.g., -phenylbipyridyl-, -phenylbipyrimidinyl-, -pyridylbiphenyl-, -pyridylbipyrimidinyl-, -pyrimidinylbiphenyl-), and the present invention further includes, for example, fused ring compounds and spiro ring compounds having the above heterocycles.

[0097] As used herein, the term "heterocycloalkyl group" or "heterocycle" refers to a monocyclic heterocycloalkyl system or a bicyclic heterocycloalkyl system, further including spiroheterocycloalkyl groups and bridged heterocycloalkyl groups. A monocyclic heterocycloalkyl group refers to a saturated or unsaturated non-aromatic cyclic alkyl system having 3 to 8 members and containing at least one heteroatom selected from O, N, S, and P. A bicyclic heterocycloalkyl group refers to a heterocycloalkyl group fused to a phenyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, or heteroaryl group. Preferably, a "heterocycloalkyl group" or "heterocycle" contains at least one or two heteroatoms selected from O, N, and S.

[0098] The term "bridged cycloalkyl group" as used herein refers to a polycyclic compound that shares two or more carbon atoms. It is divided into bicyclic bridged cyclic hydrocarbons and polycyclic bridged cyclic hydrocarbons. The former is composed of two aliphatic rings that share two or more carbon atoms, while the latter is a bridged cyclic hydrocarbon consisting of three or more rings.

[0099] As used herein, the term "spirocycloalkyl group" refers to a polycyclic hydrocarbon group in which two or more monocyclic rings share one carbon atom (spiro atom). The term "bridged heterocyclic group" as used herein means a polycyclic compound formed by the sharing of two or more carbon atoms, and the ring contains at least one atom selected from O, N, and S. They are divided into bicyclic bridged heterocycles and polycyclic bridged heterocycles.

[0100] As used herein, the term "heterospirocyclic group" refers to a polycyclic hydrocarbon group in which two or more monocyclic rings share one carbon atom (spiroatom), and the ring contains at least one heteroatom selected from O, N, and S.

[0101] As used herein, the term "substituted" means that at least one hydrogen atom has been replaced with a non-hydrogen group, provided that the correct valences are maintained and the substitution results in a stable compound. As used herein, a "ring double bond" means a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0102] Where nitrogen atoms are present in the compounds of the invention (e.g., amines), these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the invention. Thus, where a nitrogen atom is desired to be represented or protected, both the nitrogen and its N-oxide are included to provide derivatives of the invention.

[0103] When a variable occurs more than once in any compound or formula, each occurrence is independently defined. Thus, for example, a description of a group substituted with 0-3 R refers to that group being optionally substituted with up to three R groups, and each occurrence of R is independently selected from the definitions of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0104] As used herein, the term "patient" refers to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably are humans.

[0105] As used herein, the term "effective amount" refers to an amount of a drug or pharmaceutical agent (a compound of the present invention) that can elicit the biological or medical response desired by a researcher or clinician in a tissue, system, animal, or human. The term "therapeutically effective amount" refers to an amount that results in an improved therapeutic, curative, or preventative effect, or a reduction in the disease, symptom, or side effect, or a reduction in the rate of progression of a disease or symptom, compared to a subject not receiving that amount. An effective amount is not limited to a particular formulation or route of administration, and may be administered in one or more divided doses or in one or more doses. The term also encompasses an amount effective in the sense of a range capable of enhancing normal physiological function.

[0106] The term "treatment" as used herein is used broadly to include therapeutic and / or prophylactic treatment of a subject. Specifically, "treatment" includes any treatment that alleviates, inhibits, eliminates, improves, and / or prevents a symptom, disease, disorder, etc., such as alleviating, reducing, regulating, improving, eliminating, preventing, preventing, or ameliorating a symptom. Therapeutic treatment includes alleviating, inhibiting, or improving a symptom or condition of a disease, inhibiting the development of a complication, improving underlying metabolic syndrome, inhibiting the development of a disease or condition, for example, controlling the progression of a disease or condition, alleviating a disease or condition, reducing a disease or condition, reducing complications caused by a disease or condition, or treating symptoms associated with a disease or condition. Prophylactic treatment includes prior treatment to prevent, block, delay, or alleviate the development or progression of a disease or condition, or reduce the severity of a disease or condition.

[0107] Similarly, a "therapeutic agent" includes a drug or reagent that has therapeutic and / or prophylactic effects on a subject. As used herein, the terms "medicinal" or "pharmaceutically acceptable" mean compounds, substances, compositions and / or dosage forms that, in the reasonable medical judgment, are suitable for use in contact with the tissues of human beings and animals and are free from excessive toxicity, irritation, allergic response and / or other problem or complication and are commensurate with a reasonable benefit / risk ratio.

[0108] "Certain Pharmaceutical and Medical Terms" The term "cancer," as used herein, refers to the abnormal growth of cells that is uncontrolled and can metastasize (spread) under certain conditions. Cancer includes, but is not limited to, solid tumors (e.g., bladder, intestine, brain, breast, uterus, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas, other endocrine organs (e.g., thyroid), prostate, skin (melanoma)) or blood tumors (e.g., non-leukemic leukemia).

[0109] As used herein, the term "administration in combination" or similar terms means that two or more specified therapeutic agents are administered to the same patient at the same or different times using the same or different modes of administration.

[0110] As used herein, the term "enhance" or "potentiable" means that the expected result is increased efficacy or extended duration. Thus, when used in the context of enhancing the therapeutic effect of a drug, the term "potentiable" means that the drug has the ability to provide increased efficacy or extended duration to the subject to which it is administered. As used herein, the term "synergy" refers to the ability to maximize the effect of another therapeutic drug under ideal circumstances.

[0111] The term "immune disease" refers to a disease or condition in which an unwanted or harmful response occurs to an endogenous or exogenous antigen, generally resulting in dysfunction, destruction or dysfunction of cells, or destruction of organs or tissues that trigger the immune response.

[0112] The terms "kit" and "product packaging" are synonymous. The terms "subject," "test subject," or "patient" include mammals and non-mammals. Mammals include, but are not limited to, mammals (humans, non-human primates, e.g., orangutans, monkeys), farm animals (e.g., cows, horses, goats, sheep, pigs), livestock (rabbits, dogs), and laboratory animals (rodents, e.g., rats, mice, guinea pigs, etc.). Non-mammals include, but are not limited to, birds, fish, etc. In a preferred example, the mammal is a human.

[0113] Certain compounds or pharmaceutical compositions described herein, after administration, result in an improvement in a particular disease, symptom, or condition, particularly a reduction in the severity, delay in onset, slowing of disease progression, or shortening of disease duration, whether administered as a fixed dose or punctually, whether administered continuously or intermittently.

[0114] "Route of Administration" Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, intra-aural, nasal, and topical administration, and illustrative parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary, ventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0115] The compounds of the present invention may be administered locally. In certain embodiments, long-acting formulations are administered by infusion (e.g., subcutaneous or intramuscular) or intramuscular injection. In another particular embodiment, the drug is administered via a targeted drug delivery system, e.g., a liposome encapsulated with an organ-specific antibody. In such embodiments, the liposome is selectively targeted to and absorbed by a specific organ.

[0116] Pharmaceutical Compositions and Dosages As used herein, the term "pharmaceutical carrier" refers to a medicinal substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, various auxiliary substances (e.g., lubricants, talc, magnesium stearate, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulating substance that functions to carry and transport the compound of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.

[0117] The term "pharmaceutical composition" refers to a composition comprising a compound of the present invention and, optionally, other pharmaceutical carriers. "Pharmaceutical carrier" refers to a vehicle generally accepted in the art for delivering a biologically active agent to an animal (particularly a mammal), and includes adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants, and dispersing agents, depending on the method of administration and the characteristics of the dosage form.

[0118] Pharmaceutical compositions of the present invention may comprise a therapeutically effective amount of one or more compounds of the present invention, optionally combined with one or more pharmaceutical carriers (excipients) and / or diluents, and optionally one or more other therapeutic agents. For any of the above uses, the compounds of the present invention can be administered in any suitable manner, for example, orally (e.g., tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, and spray-dried dispersions), syrups, emulsions, sublingually, buccally, parenterally (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., sterile aqueous or non-aqueous solutions or suspensions for injection)), nasally (e.g., administration to the nasal membranes (e.g., inhalation spray)), topically (e.g., creams or ointments), rectally (e.g., suppositories), or intratumoral injection. Compounds of the present invention may also be administered alone, generally with a pharmaceutical carrier selected based on the intended route of administration and standard pharmaceutical experimentation.

[0119] Pharmaceutical carriers are prepared taking into consideration a variety of factors within the knowledge of one skilled in the art, including, but not limited to, the type and characteristics of the active agent being incorporated, the intended recipient of the composition having the active agent, the intended route of administration of the composition, and the target indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms.

[0120] The above-mentioned carriers may contain various ingredients and additives in addition to the active agent, and the other ingredients, such as stabilizers, adhesives, etc., are used in the formulation based on various factors known to those skilled in the art. Many references are available for explanations of suitable pharmaceutical carriers and factors involved in the selection of carriers (e.g., Allen LVJr. et al. Remington: The Science and Practice of Pharmacy (2 volumes), 22nd Edition (2012), Pharmaceutical Press).

[0121] The dosing regimen for the compounds of the present invention varies depending on known factors, such as the pharmacodynamic properties of the drug, the frequency and route of administration, the target organism, age, sex, health status, disease state and weight, characteristics and severity of symptoms, type and frequency of concurrent treatment, route of administration, the patient's renal and hepatic function, and the desired effect. Generally, to achieve the desired effect, the daily oral dose of each active ingredient is about 0.001 mg / day to about 10-5000 mg / day, preferably about 0.01 mg / day to about 1000 mg / day, and most preferably about 0.1 mg / day to about 250 mg / day. When administered by constant rate infusion, the intravenous dose is most preferably about 0.01 mg / kg / min to about 10 mg / kg / min. The compounds of the present invention may be administered in a single daily dose, or in two, three, or four divided doses throughout the day.

[0122] The compounds are generally administered in admixture with pharmaceutical diluents, excipients, and carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected depending on the desired route of administration (e.g., oral tablets, capsules, elixirs, syrups) and on the basis of conventional pharmaceutical experience.

[0123] The dosage form (pharmaceutical composition) for administration has an active ingredient per dosage unit of about 1 mg to about 2000 mg, and in such pharmaceutical compositions, the active ingredient is generally present in an amount of about 0.1 to 95% by weight based on the total weight of the composition.

[0124] A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is screened through a 60 mesh screen and then filled into a #1 gelatin capsule.

[0125] A typical method for producing an injectable formulation is as follows: At least one compound of the present invention (250 mg) is placed in a bottle under sterile conditions, which is then freeze-dried under sterile conditions and sealed. At the time of use, the contents of the bottle are mixed with 2 mL of saline to obtain an injectable formulation.

[0126] The present invention includes pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the present invention as an active ingredient (alone or in combination with a pharmaceutical carrier), optionally used alone or in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances).

[0127] Regardless of the route of administration selected, the compounds of the present invention (including appropriate hydrates) and / or pharmaceutical compositions of the present invention are formulated in pharmaceutical dosages by conventional methods known to those skilled in the art. The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is adjusted to obtain an amount of the active ingredient that can effectively achieve the desired therapeutic response in a particular patient, composition and mode of administration, and that is not toxic to the patient.

[0128] The selected dose level will be determined by many factors known in the medical field, such as the activity of the compound of the present invention, its ester, salt or amide used, the route of administration, the duration of administration, the rate of metabolism of the compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or substances administered in combination with the compound used, the age, sex, weight, condition, underlying health and medical history of the patient being treated, etc.

[0129] A physician or veterinarian skilled in the art can easily determine and prescribe an effective amount of the pharmaceutical composition. For example, to achieve a desired therapeutic effect, a physician or veterinarian can start with a pharmaceutical composition containing a compound of the present invention at a lower amount than the target level and gradually increase the dosage until the desired effect is achieved. In general, an appropriate daily dose of a compound of the present invention is the lowest dose of the compound necessary to achieve a therapeutic effect. The effective dose is generally determined by the factors described above. In general, oral, intravenous, intracerebroventricular, or subcutaneous doses of a compound of the present invention for a patient range from about 0.01 to about 50 mg / kg body weight / day. If necessary, an effective daily dose of the active compound may be administered in two, three, four, five, six, or more divided doses at appropriate intervals throughout the day, or, if desired, in a unit dosage form. In some embodiments of the present invention, the drug is administered once daily.

[0130] While a compound of the present invention may be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition). Kit / Product Packaging Kits / product packaging for use in treating the above-mentioned indications are now described. These kits consist of a shipping device, drug pack, or container box, which can be divided into sections to house one or more containers (e.g., vials, test tubes, etc.), each containing one component of the method. Suitable containers include bottles, vials, syringes, test tubes, etc. The containers can be made from acceptable materials such as glass or plastic.

[0131] For example, the container may contain one or more of the compounds, and the compound may be present as a component of a drug or may be present in a mixture with other components described herein. The container may be provided with a single sterile delivery port (e.g., the container may be an intravenous drug bag or bottle with a stopper that can be pierced by the needle tip of a hypodermic syringe). Such product packaging may include the compound and instructions, labels, or manuals for use as described herein.

[0132] A typical product package contains one or more containers, each containing one or more materials (e.g., reagents, concentrated mother liquors, and / or equipment) to meet the marketing and use requirements of the compound. These materials, e.g., buffers, diluents, filters, needle tips, syringes, transfer devices, bags, containers, bottles, and / or test tubes, are provided with a list of contents and / or instructions, and instructions are also provided on the inner packaging. All information provided as instructions must be provided in its entirety.

[0133] A label may be affixed to or associated with a container. When a label is affixed to a container, it may have letters, numbers, or other features affixed, molded, or imprinted onto the container. A label may also be placed inside a container box or shipping box containing multiple containers, for example, as a product description. A label may indicate a specific therapeutic use of the contents. A label may also indicate how to use the contents, as described in the methods above.

[0134] All features described in this specification (including all claims, abstracts, and drawings), and / or all steps associated with any method or procedure, may be present in any combination, unless some features or steps in a combination are mutually exclusive.

[0135] The above-described features of the present invention or the features of the embodiments thereof can be arbitrarily combined. All features described in this specification can be provided in the form of a suitable composition, and each feature described in the specification may be replaced with an alternative feature that can achieve the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the described feature is merely an example of an equivalent or similar feature.

[0136] The present invention will now be further described in connection with specific examples. It should be noted that these examples are merely illustrative and do not limit the scope of the present invention. Experimental methods not specifically described in the following examples are carried out under standard conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages, ratios, proportions, and parts are all by weight.

[0137] In the present invention, the units used to indicate weight-volume percentages are known to those skilled in the art, for example, the weight of a solute in 100 mL of solution. Unless otherwise defined, all technical and scientific terms used herein have the ordinary meanings understood by those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are merely illustrative. [Example]

[0138] Where no preparative route is mentioned, the relevant intermediates are commercially available (eg from Sigma Aldrich, Alfa). General Process Commercially available reagents were used without further purification. 1H-NMR spectra were recorded on a Bruker instrument at 500 MHz. Chemical shift values ​​were expressed in parts per million, or δ values. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, brs = broad, d = doublet, t = triplet, and m = multiplet. Coupling constants are listed as J values ​​and measured in Hz. NMR and mass spectral results were corrected for background peaks. Chromatography refers to column chromatography (flash chromatography) performed under nitrogen pressure using 100-mesh silica gel. TLC for reaction monitoring refers to TLC performed using the specified mobile phase and silica gel F254 (from Merck) as the stationary phase.

[0139] The LC-MS experiments were performed under the following conditions: Instrument: Thermo U3000, ALLtech ELSD, MSQ, UV detector combined with ELSD and MSD (flow ratio 4:1). Column: Waters X-Bridge C-18, 3.5 μm, 4.6 x 50 mm. Column temperature: 30 o C. Gradient [time (min) / solvent B in A (%)]: 0.00 / 5.0, 0.70 / 95, 1.40 / 95, 1.41 / 5, 1.50 / 5. (Solvent A = 0.01% trifluoroacetic acid in water, solvent B = 0.01% trifluoroacetic acid in acetonitrile). UV detection: 214 / 254 / 280 / 300 nm. DAD detection: 200-400 nm. Flow rate: 4 mL / min. MS: ESI, 100-1500 m / z. Preparative HPLC typically uses a basic method (acetonitrile and water gradient with 10 mM ammonium bicarbonate in water). Thermo U3000 AFC-3000. Column: Globalsil C-18 12 nm, 250 x 20 mm, 10 μm, or equivalent. Flow rate: 20 mL / min for separation.

[0140] Synthesis of intermediates Preparation of compound INT-1

[0141] [ka]

[0142] 2-Chloro-5-hydroxybenzoic acid (29.0 g, 168 mmol) was dissolved in tetrahydrofuran (100 mL) and borane (1.0 M tetrahydrofuran solution, 336 mL) was added dropwise under a nitrogen atmosphere and ice bath. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. TLC confirmed that the starting material had been completely consumed. The reaction was quenched by adding methanol dropwise to the reaction mixture in an ice bath until no more bubbles were observed. The solvent was concentrated to give a pale yellow solid, INT-1a (26.6 g, yield: 99.8%).

[0143] Compound INT-1a (26.6 g, 168 mmol) and imidazole (11.5 g, 169 mmol) were dissolved in dichloromethane (300 mL), and tert-butyldimethylsilyl chloride (25.5 g, 169 mmol) predissolved in dichloromethane (100 mL) was added in batches at 0 °C. The mixture was warmed to 30 °C and stirred for 16 h. The reaction was quenched with water (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a pale yellow liquid, INT-1b (33.4 g, yield: 73%).

[0144] Compound INT-1b (8.0 g, 29.3 mmol) was dissolved in acetonitrile (100 mL) and, sequentially, triethylamine (14.8 g, 147 mmol), magnesium chloride (5.58 g, 58.6 mmol), and paraformaldehyde (8.80 g, 293 mmol) were added. The mixture was heated to 90 °C under a nitrogen atmosphere and vigorously stirred for 20 h. The reaction mixture was diluted with water (100 mL) and adjusted to pH 3-4 with saturated aqueous citric acid, followed by extraction with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a white solid, INT-1c (5.0 g, yield: 56.7%). 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.23 (s, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 4.72 (s, 2H), 0.96 (s, 9H), 0.14 (s, 6H). 5-Chloromethyl-3-cyanopyridine hydrochloride (3.20 g, 17.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (5.48 g, 42.4 mmol) and potassium carbonate (5.86 g, 42.4 mmol) were added in an ice bath. After stirring for 10 minutes, INT-1c (4.25 g, 14.1 mmol) and potassium iodide (234 mg, 1.41 mmol) were added to the reaction mixture. The reaction mixture was stirred in an ice bath for 30 minutes. The temperature was then raised to 50 °C and stirred for 16 hours. The reaction mixture was cooled in an ice bath, and 100 mL of water was added. A solid precipitated. The solid was filtered, washed with water, and dried. The crude solid product was then purified by silica gel column chromatography to give INT-1d (5.00 g, yield: 84.9%) as a white solid. MS (ESI): m / z 417.2 (M+H) + . Compound INT-1d (5.0 g, 12.0 mmol) was dissolved in toluene (10 mL), and ethylene glycol (14.9 g, 240 mmol) and p-toluenesulfonic acid (228 mg, 1.20 mmol) were added. Trimethyl orthoformate (2.55 g, 24.0 mmol) was then added dropwise. The mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 16 h. The reaction mixture was cooled in an ice bath and quenched with saturated aqueous sodium bicarbonate (50 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a white solid, INT-1e (5.50 g, yield: 99.5%). MS (ESI): m / z 461.2 (M+H). + . Compound INT-1e (2.20 g, 4.77 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 7.16 mL) was added. The reaction mixture was stirred at 30 °C for 0.5 hours. The mixture was diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried in a mixture of ethyl acetate and petroleum ether (v / v = 3 / 100, 20 mL) and filtered to give a pale yellow solid, INT-1f (1.58 g, yield: 95.5%). MS (ESI): m / z 347.2 (M+H). + . Compound INT-1f (1.50 g, 4.33 mmol) was dissolved in dichloromethane (30 mL), N,N-diisopropylethylamine (1.68 g, 13.0 mmol) was added, and methanesulfonic anhydride (1.51 g, 8.65 mmol) was added at 0 °C under a nitrogen atmosphere. A mixture of N,N-diisopropylethylamine (1.68 g, 13.0 mmol) and HCl in dioxane (4 M, 1.62 mL) in dichloromethane (10 mL) was then added. The reaction was stirred at 25 °C for 16 h. The reaction was quenched with water (30 mL), and the aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to give a pale yellow solid INT-1g (1.40 g, yield: 88.6%). MS (ESI): m / z 365.2 (M+H) + . Compound INT-1g (1.36 g, 3.72 mmol), 4-bromo-1H-indazole (734 mg, 3.72 mmol), and potassium carbonate (1.03 g, 7.45 mmol) were dissolved in N,N-dimethylformamide (10 mL). The mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled in an ice bath, and 100 mL of water was added to precipitate a solid. The solid was filtered, washed with water, and dried. The resulting crude solid was purified by silica gel column chromatography to give a pale yellow solid, INT-1h (1.08 g, yield: 55.2%). 1H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 2.0 Hz, 1H), 8.82 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 6.91 (s, 1H), 6.04 (s, 1H), 5.71 (s, 2H), 5.16 (s, 2H), 4.04 - 4.01 (m, 2H), 3.97 - 3.89 (m, 2H); MS (ESI): m / z 525.0 (M+H) + . Compound INT-1h (1.00 g, 1.90 mmol) was dissolved in tetrahydrofuran (20 mL) and hydrochloric acid (4.0 M aqueous solution, 5.0 mL) was added. The reaction mixture was stirred at 30°C for 1 hour. It was then neutralized with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid, INT-1i (900 mg, yield: 98.2%). MS (ESI): m / z 481.0 (M+H) + . Compound INT-1i (840 mg, 1.74 mmol) was dissolved in N,N-dimethylformamide (5 mL), and o-tert-butyl-L-serine (418 mg, 1.92 mmol) and acetic acid (209 mg, 3.48 mmol) were added. The reaction mixture was stirred at 30 °C for 1 h. Sodium triacetoxyborohydride (1.48 g, 6.96 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at 30 °C for 1 h. Water (50 mL) was then added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a pale yellow solid, INT-1j (720 mg, yield: 60.5%). MS (ESI): m / z 682.1 (M+H) + . Intermediate INT-1j (1.00 g, 1.46 mmol), pinaol biborate (558 mg, 2.20 mmol), potassium acetate (431 mg, 4.39 mmol), and Pd(dppf)Cl2 (107 mg, 0.15 mmol) were dissolved in dioxane (15 mL). The reaction mixture was heated to 90 °C under a nitrogen atmosphere and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through diatomaceous earth, and washed with 100 mL of ethyl acetate. The filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol, v / v = 20 / 1) to give a pale yellow solid, INT-1 (600 mg, yield: 56.1%). MS (ESI): m / z 730.7 (M+H). + . Preparation of compound INT-2

[0145] [ka]

[0146] (S)-5-Hydroxymethyl-2-pyrrolidone (10.0 g, 86.9 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and phthalimide (12.8 g, 86.9 mmol) and triphenylphosphine (34.2 g, 130 mmol) were added. Diisopropyl azodicarboxylate (26.4 g, 130 mmol) was slowly added dropwise to the reaction mixture under ice bath conditions and nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting precipitate was filtered and dried to give INT-2a (11.4 g, 53.7% yield) as a white solid. MS (ESI): m / z 245.1 (M+H) + . Compound INT-2a (1.0 g, 4.09 mmol) was dissolved in ethanol (20 mL) and 80% hydrazine hydrate (512 mg, 8.19 mmol) was added. The reaction mixture was heated to 85°C and stirred for 2 hours. After cooling to room temperature, the resulting precipitate was removed by filtration. The filtrate was concentrated, and dichloromethane (50 mL) was added. The filtrate was further concentrated in vacuo to give INT-2 (430 mg, yield: 92.0%) as a yellow oily liquid. 1 H NMR (500 MHz, DMSO-d6) δ 7.65 (s, 1H), 3.43 - 3.37 (m, 1H), 2.47 - 2.42 (m, 2H), 2.12 - 2.04 (m, 2H), 2.03 - 1.96 (m, 1H), 1.66 - 1.60 (m, 1H), 1.58 (s, 2H). Preparation of compound INT-3

[0147] [ka]

[0148] Pinarole 4-formylphenylborate (4.50 g, 19.4 mmol) and 1,3-dibromo-2-chlorobenzene (10.5 g, 38.8 mmol) were dissolved in a mixture of dioxane and water (60 mL, v / v = 5 / 1), and potassium carbonate (8.04 g, 58.2 mmol) and Pd(dppf)Cl (1.42 g, 1.94 mmol) were added. The reaction mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 3 h. The reaction was quenched with water (100 mL), and the aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 4 / 1) to give a white solid INT-3a (3.7 g, yield: 64.6%).

[0149] Compound INT-3a (1.00 g, 3.38 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound INT-2 (541 mg, 4.74 mmol) and acetic acid (203 mg, 3.38 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (2.87 g, 13.5 mmol) was then added. The resulting reaction mixture was further stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid, INT-3b (1.41 g, yield: 99.5%). MS (ESI): m / z 393.3 (M+H). + . Compound INT-3b (1.41 g, 3.58 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (725 mg, 7.16 mmol) and di-tert-butyl dicarbonate (860 mg, 3.94 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours and then diluted with 200 mL of dichloromethane. The resulting organic phase was washed sequentially with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol, v / v = 20 / 1) to give a white solid, INT-3 (1.55 g, yield: 87.6%). 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (dd, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.44 - 7.25 (m, 6H), 4.53 - 4.39 (m, 2H), 3.80 - 3.70 (m, 1H), 3.26 - 3.10 (m, 2H), 2.17 - 1.99 (m, 3H), 1.76 - 1.66 (m, 1H), 1.38 (s, 9H); MS (ESI): m / z 493.3 (M+H) + . Preparation of compound INT-4

[0150] [ka]

[0151] A white solid INT-4 was obtained from 1,3-dibromo-2-toluene according to the synthesis method of compound INT-3. 1H NMR (500 MHz, Chloroform-d) δ 7.76 (d, J = 7.2 Hz, 1H), 7.28 - 7.22 (m, 7H), 4.53 (s, 2H), 4.05 - 3.67 (m, 1H), 3.42 - 3.20 (m, 2H), 2.40 (s, 3H), 2.01 - 1.90 (m, 3H), 1.82 - 1.71 (m, 1H), 1.36 (s, 9H); MS (ESI): m / z 473.4 (M+H) + . Preparation of compound INT-5

[0152] [ka]

[0153] Compound INT-3a (1.50 g, 5.08 mmol) was dissolved in N,N-dimethylformamide (20 mL), and (R)-3-hydroxypyrrolidine hydrochloride (1.88 g, 15.2 mmol) and anhydrous sodium acetate (1.25 g, 15.2 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature. Sodium triacetoxyborohydride (4.31 g, 20.3 mmol) was then added. The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (dichloromethane / methanol, v / v = 20 / 1) to obtain a pale yellow solid INT-5 (1.60 g, yield: 80.6%). 1H NMR (500 MHz, Methanol-d4) δ 7.71 - 7.67 (m, 1H), 7.46 - 7.41 (m, 2H), 7.38 - 7.33 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 4.41 - 4.31 (m, 1H), 3.81 - 3.66 (m, 2H), 2.88 - 2.83 (m, 1H), 2.83 - 2.76 (m, 1H), 2.64 - 2.58 (m, 1H), 2.56 - 2.51 (m, 1H), 2.22 - 2.12 (m, 1H), 1.79 - 1.70 (m, 1H); MS (ESI): m / z 366.1 (M+H) + . Preparation of compound INT-6

[0154] [ka]

[0155] Compound INT-6a was obtained from 4-bromo-2-methoxybenzaldehyde by the Suzuki boron esterification reaction of compound INT-1. Compound INT-6 was obtained from compound INT-6a by referring to the synthesis method of compound INT-3. 1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.42 - 7.38 (m, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.11 - 7.03 (m, 1H), 7.02 - 7.00 (m, 1H), 6.98 - 6.93 (m, 1H), 4.47-4.34 (m, 2H), 3.81 (s, 3H), 3.77 - 3.71 (m, 1H), 3.26 - 3.17 (m, 2H), 2.18 - 2.10 (m, 1H), 2.09 - 2.00 (m, 2H), 1.74 - 1.64 (m, 1H), 1.47 - 1.26 (m, 9H). MS (ESI): m / z 523.2 (M+H) + . Preparation of compound INT-7

[0156] [ka]

[0157] Intermediate INT-1i (1.00 g, 2.08 mmol), bis(pinacolato)diboron (635 mg, 2.50 mmol), potassium acetate (612 mg, 6.24 mmol), and Pd(dppf)Cl2 (152 mg, 0.21 mmol) were dissolved in dioxane (20 mL). The reaction mixture was heated to 90 °C under a nitrogen atmosphere and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 1 / 1) to give a pale yellow solid, INT-7a (940 mg, yield: 85.5%). MS (ESI): m / z 529.2 (M+H). + . Compound INT-7a (96.4 mg, 0.18 mmol) and compound INT-3 (75.0 mg, 0.15 mmol) were dissolved in a mixture of dioxane and water (11 mL, v / v = 10 / 1). Potassium carbonate (63.0 mg, 0.46 mmol) and Pd(dppf)Cl2 (11.1 mg, 0.015 mmol) were added, and the mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 3 h. The reaction was then quenched with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative thin-layer chromatography (dichloromethane / methanol, v / v = 95 / 5) to give a pale yellow solid, INT-7 (120 mg, yield: 96.9%). MS (ESI): m / z 815.2 (M+H) + . Preparation of compound INT-8

[0158] [ka]

[0159] Compound INT-8b was obtained from compound INT-1c and iodine methane according to the synthesis of INT-1i. MS (ESI): m / z 379.1 (M+H) + . From compound INT-8b, compound INT-8c and compound INT-8 were obtained by referring to the synthesis of compound INT-7. The spectral information of these compounds is as follows:

[0160] INT-8c: 1H NMR (500 MHz, Chloroform-d) δ 10.31 (s, 1H), 8.50 (s, 1H), 7.83 (s, 1H), 7.69 (d, J = 7.0 Hz, 1H),7.47 (d, J = 8.5 Hz, 1H), 7.44 - 7.37 (m, MS (ESI): m / z 427.3 (M+H) + . INT-8: MS (ESI): m / z 713.5 (M+H) + . Preparation of compound INT-9

[0161] [ka]

[0162] Compound INT-9 was obtained from compound INT-8c and compound INT-6 by referring to the synthesis of compound INT-8. MS (ESI): m / z 743.6 (M+H) + . Preparation of compound INT-10

[0163] [ka]

[0164] Compound INT-10a was obtained from 3-bromo-2-chlorophenol according to the synthesis method of compound INT-7a. MS (ESI): m / z 253.3 (MH) - . Compound INT-10b was obtained from compound INT-10a and 6-chloro-2-methoxy-3-pyridineformaldehyde according to the synthesis method of compound INT-3a. MS (ESI): m / z 262.0 (MH) - . Compound INT-10b (500 mg, 1.90 mmol) was dissolved in anhydrous dichloromethane (10 mL), N,N-diisopropylethylamine (490 mg, 3.80 mmol) was added, and the mixture was cooled to 0 °C in an ice bath. Trifluoromethanesulfonic anhydride (804 mg, 2.85 mmol) was then slowly added dropwise. The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The reaction was quenched with 50 mL of saturated aqueous ammonium chloride, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give INT-10 (482 mg, yield: 64.2%) as an orange oil. MS (ESI): m / z 396.2 (M+H) + . Preparation of compound INT-11

[0165] [ka]

[0166] twenty five o Under C conditions, a solution of (R)-1-Boc-3-carboxypyrrolidine (1.00 g, 4.65 mmol), iodine methane (1.00 g, 7.05 mmol), and potassium carbonate (2.00 g, 14.5 mmol) in N,N-dimethylformamide (3 mL) was stirred for 3 h. Water (50 mL) was then added and diluted. The mixture was then extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give yellow oil INT-11a (1.00 g, yield: 93.9%).

[0167] To a solution of compound INT-11a (1.00 g, 4.36 mmol) in dichloromethane (2 mL) was added hydrochloric acid (4 M solution in 1,4-dioxane, 5 mL). oThe mixture was stirred for 3 hours under the conditions of C. The resulting reaction mixture was concentrated to give a yellow solid, INT-11 (700 mg, yield: 96.9%). 1 H NMR (500 MHz, DMSO-d6) δ 9.70 (brs, 2H), 3.66 (s, 3H), 3.42 - 3.35 (m, 1H), 3.30 - 3.22 (m, 2H), 3.19 - 3.13 (m, 2H), 2.22 - 2.14 (m, 1H), 2.06 - 1.99 (m, 1H). Preparation of compound INT-12

[0168] [ka]

[0169] Compound INT-12 was obtained from compound INT-8c and compound INT-5 by referring to the synthesis of compound INT-8. MS (ESI): m / z 586.4 (M+H) + . Preparation of compound INT-13

[0170] [ka]

[0171] Thionyl chloride (11.7 g, 98.6 mmol) was added to a solution of 2-hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol) in methanol (20 mL) under ice bath conditions. o The mixture was stirred under C conditions for 16 hours. The reaction mixture was concentrated, and ethyl acetate (100 mL) and water (100 mL) were added to the residue. The organic phase was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give yellow oil INT-13a (5.25 g, yield: 96.1%).

[0172] Compound INT-13a (5.25 g, 31.6 mmol) was dissolved in N,N-dimethylformamide (30 mL) and iodine methane (5.83 g, 41.1 mmol) and potassium carbonate (8.73 g, 63.2 mmol) were added. o The mixture was stirred under C conditions for 6 hours. The reaction mixture was concentrated, and ethyl acetate (100 mL) and water (100 mL) were added to the residue. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil, INT-13b (5.6 g, yield: 98.4%).

[0173] To a solution of compound INT-13b (1.0 g, 5.55 mmol) in methanol (15 mL) was added silver trifluoromethanesulfonate (1.57 g, 6.10 mmol) and iodine (1.55 g, 6.10 mmol). o The mixture was stirred under C conditions for 2 hours, filtered, and the filtrate was diluted with ethyl acetate (50 mL), washed with aqueous sodium sulfite solution (5% w / w, 50 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give an orange solid, INT-13 (1.6 g, yield: 94.2%). 1 H NMR (500 MHz, Chloroform-d) δ 8.20 (s, 1H), 6.86 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.45 (s, 3H); MS (ESI): m / z 306.9 (M+H) + . Preparation of compound INT-14

[0174] [ka]

[0175] Thionyl chloride (185 mg, 1.55 mol) was added to a solution of trans-(N-Boc-4-aminocyclohexyl)acetic acid (100 mg, 0.39 mmol) in methanol (3 mL). o The mixture was stirred for 3 hours under C conditions. After concentrating the reaction mixture, a white solid INT-14 (70 mg, yield: 86.7%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 8.15 - 7.92 (m, 3H), 3.56 (s, 3H), 2.87 (s, 1H), 2.21 - 2.15 (m, 2H), 1.95 - 1.87 (m, 2H), 1.74 - 1.66 (m, 2H), 1.63 - 1.53 (m, 1H), 1.35 - 1.25 (m, 2H), 1.06 - 0.95 (m, 2H). Preparation of compound INT-15

[0176] [ka]

[0177] Sodium methoxide (5.4 M methanol solution, 1.11 mL) was added dropwise to a solution of 4-bromo-2,6-difluorobenzeneformaldehyde (1.10 g, 4.98 mmol) in methanol (10 mL) under ice bath conditions. The reaction mixture was stirred under the same conditions for 3 hours. The reaction mixture was quenched with hydrochloric acid (1 M aqueous solution, 12 mL) and stirred for 10 minutes. The resulting solution was further diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give a white solid INT-15a (660 mg, yield: 56.9%) and a white solid INT-15b (204 mg, yield: 16.7%).

[0178] Compound INT-15a:1 H NMR (500 MHz, Chloroform-d) δ 10.36 (s, 1H), 6.97 - 6.93 (m, 2H), 3.94 (s, 3H). Compound INT-15b: 1 H NMR (500 MHz, Chloroform-d) δ 10.42 (s, 1H), 6.76 (s, 2H), 3.90 (s, 6H). The synthesis method of compound INT-15a is as follows, the synthesis method of compound INT-6 is as reference, and the compound INT-15 is as obtained. 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.90 - 6.86 (m, 2H), 4.54 - 4.50 (m, 2H), 3.84 (s, 3H), 3.77 - 3.73 (m, 1H), 3.17 (d, J = 5.3 Hz, 2H), 2.12 - 2.02 (m, 3H), 1.71 - 1.65 (m, 1H), 1.40 - 1.32 (m, 9H); MS (ESI): m / z 541.5 (M+H) + . Preparation of compound INT-16

[0179]

change

[0180] Compound INT-8c is the reference for compound INT-15, compound INT-8 is the synthesis reference, and compound INT-16 is the result. MS (ESI): m / z 761.7 (M+H) + . Preparation of compound INT-17

[0181]

change

[0182] 110 o Under C conditions, a solution of S-2-aminoadipic acid (5 g, 31 mmol) in acetic acid and water (25 mL, v / v = 1 / 4) was stirred for 16 hours. The reaction mixture was concentrated, and the resulting residue was dissolved in ethanol. Unreacted starting material was not dissolved in ethanol. The ethanol filtrate was concentrated to give a white solid, INT-17a (3 g, yield: 67.6%). MS (ESI): m / z 142.1 (MH) - A colorless oily substance INT-17b was obtained from compound INT-17a by referring to the synthesis method of compound INT-13a.

[0183] 0 o Under C conditions, sodium borohydride (433 mg, 11.5 mmol) was added to a solution of compound INT-17b (450 mg, 2.9 mmol) in ethanol (10 mL). The resulting mixture was stirred at room temperature for 16 hours. A small amount of acetic acid was added to quench the reaction, and the resulting reaction mixture was concentrated. The resulting residue was dissolved in dichloromethane. The organic phase was washed with a small amount of saturated brine, dried over anhydrous sodium sulfate, and concentrated to give colorless oil INT-17c (369 mg, yield: 99.8%). MS (ESI): m / z 130.2 (M+H) + . A pale yellow oily substance, INT-17, was obtained from compound INT-17c by referring to the synthesis method of compound INT-2. 1 H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 3.22 - 3.06 (m, 1H), 2.59 - 2.42 (m, 2H), 2.18 - 1.98 (m, 2H), 1.75 (brs, 2H), 1.64 - 1.50 (m, 2H), 1.37 - 1.18 (m, 2H).

[0184] Preparation of compound INT-18

[0185] [ka]

[0186] Compound INT-18a was obtained from compound INT-15a by the final step of Suzuki boron esterification of compound INT-1 and the synthesis method of compound INT-3a. 1 H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.91 - 7.87 (m, 1H), 7.52 - 7.48 (m, 1H), 7.44 - 7.38 (m, 1H), 7.13 - 7.10 (m, 1H), 7.04 - 7.00 (m, 1H), 3.96 (s, 3H). From compound INT-18a, compound INT-18 was obtained by the final step Suzuki boron esterification reaction of compound INT-1. 1 H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 7.68 - 7.64 (m, 1H), 7.55 - 7.51 (m, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.05 (s, 1H), 6.97 - 6.89 (m, 1H), 3.93 (s, 3H), 1.31 (s, 12H); MS (ESI): m / z 391.7 (M+H) + . Synthesis of Example Compounds Example 1

[0187] [ka]

[0188] Compound 1a was obtained from Compound INT-1 and Compound INT-5 by referring to the synthesis of Compound INT-7. MS (ESI): m / z 889.9 (M+H) + . Compound 1a (20 mg, 0.022 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. oThe mixture was stirred for 6 hours under C conditions. The reaction mixture was concentrated, and the residue was purified by preparative high performance liquid chromatography to give a white solid 1 (6.5 mg, yield: 37.4%). 1 H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.72 - 7.67 (m, 1H), 7.55 - 7.45 (m, 7H), 7.40 (d, J = 8.0 Hz, 2H), 7.18 - 7.15 (m, 1H), 6.83 (s, 1H), 5.74 - 5.69 (m, 2H), 5.11 - 5.05 (m, 2H), 4.24 - 4.18 (m, 1H), 3.93 (d, J = 14.5 Hz, 1H), 3.85 (d, J = 14.5 Hz, 1H), 3.65 (d, J = 13.0 Hz, 1H), 3.61 - 3.55 (m, 2H), 3.12 - 3.07 (m, 1H), 2.72 - 2.68 (m, 1H), 2.65 - 2.58 (m, 2H), 2.38 - 2.32 (m, 2H), 2.05 - 1.97 (m, 1H), 1.59 - 1.52 (m, 1H); MS (ESI): m / z 777.8 (M+H) + . Example 2

[0189] [ka]

[0190] Compound 2 was obtained from compound INT-1 and compound INT-4 by referring to the synthesis of compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 (t, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.71 - 7.64 (m, 2H), 7.55 (s, 1H), 7.46 - 7.37 (m, 6H), 7.34 - 7.31 (m, 1H), 7.28 (d, J = 7.5, 1H), 7.09 (d, J = 7.0 Hz, 1H), 6.86 (s, 1H), 5.71 (s, 2H), 5.14 - 5.08 (m, 2H), 3.96 - 3.84 (m, 2H), 3.79 - 3.74 (m, 2H), 3.64 - 3.57 (m, 3H), 3.13 - 3.09 (m, 1H), 2.55 (d, J = 6.0 Hz, 2H), 2.15 - 2.05 (m, 3H), 1.99 (s, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 784.3 (M+H) + . Example 3

[0191] [ka]

[0192] Compound 3a was obtained from compound INT-1 and compound INT-3a by referring to the synthesis of compound INT-7. MS (ESI): m / z 818.4 (M+H) + . Compound 3b was obtained from compound 3a and morpholine by the reductive amination step in the synthesis of compound INT-3b. MS (ESI): m / z 889.9 (M+H) + . Compound 3 was obtained from compound 3b by following the final step, the de-Boc protection step, in the synthesis of compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.33 (s, 1H), 7.86 (s, 1H), 7.72-7.67 (m, 1H), 7.56-7.45 (m, 7H), 7.41 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.13 - 5.05 (m, 2H), 3.92 (d, J = 14.0 Hz, 1H), 3.85 (d, J = 14.0 Hz, 1H), 3.63-3.56 (m, 6H), 3.52 (s, 2H), 3.13-3.06 (m, 1H), 2.40 (s, 4H); MS (ESI): m / z 777.6 (M+H) + . Example 4

[0193] [ka]

[0194] Compound 4 was obtained from compound 3a and N-methylethanolamine according to the synthesis of compound 3. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.55 - 7.46 (m, 6H), 7.41 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 6.84 (s, 1H), 5.72 (s, 2H), 5.14 - 5.06 (m, 2H), 3.96 (d, J = 14.0 Hz, 1H), 3.88 (d, J = 14.0 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.61 - 3.58 (m, 1H), 3.57 (s, 2H), 3.54 (t, J = 6.5 Hz, 2H), 3.18 - 3.14 (m, 1H), 2.55 - 2.53 (m, 2H), 2.20 (s, 3H); MS (ESI): m / z 765.7 (M+H) + . Example 5

[0195] [ka]

[0196] Compound 5 was obtained from compound 3a and ethanolamine by following the synthesis of compound 3. 1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.83 (s, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.49 - 7.43 (m, 6H), 7.17 (d, J = 7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.13 - 5.05 (m, 2H), 3.90 (d, J = 14.0 Hz, 1H), 3.86 - 3.80 (m, 3H), 3.60 - 3.54 (m, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.10 - 3.05 (m, 1H), 2.65 (t, J = 6.0 Hz, 2H); MS (ESI): m / z 751.4 (M+H) + . Example 6

[0197] [ka]

[0198] Compound INT-3a and N-methylethanolamine were reacted in the reductive amination step in the synthesis of compound INT-3b to give compound 6a. MS (ESI): m / z 354.2 (M+H) + . In an ice bath, N,N-diisopropylethylamine (226 mg, 1.75 mmol) and methanesulfonic anhydride (203 mg, 1.17 mmol) were added to a solution of compound 6a (207 mg, 0.58 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for half an hour in an ice bath, and then cooled to 25°C. oThe temperature was raised to 0°C. The mixture was stirred at the same temperature for 2 hours. Water (20 mL) was added to the reaction mixture to dilute it, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6b. Under ice bath conditions and a nitrogen atmosphere, sodium hydride (60% w / w in kerosene, 46.8 mg) was added to a solution of (R)-(-)-3-hydroxytetrahydrofuran (103 mg, 1.17 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred in an ice bath for half an hour. Then, compound 6b obtained above was added. The resulting reaction mixture was diluted with 50 mL of o The temperature was raised to 0°C and stirred overnight. After cooling to room temperature, the reaction mixture was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative thin-layer chromatography (dichloromethane / methanol, v / v = 15 / 1) to give yellow oil 6c (110 mg, yield: 44.4%). MS (ESI): m / z 424.3 (M+H) + . Compound 6 was obtained from compound INT-1 and compound 6c by referring to the synthesis of compound 1. 11H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 - 8.32 (m, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.55 - 7.45 (m, 7H), 7.40 (d, J = 8.0 Hz, 2H), 7.20 - 7.15 (m, 1H), 6.81 (s, 1H), 5.72 (s, 2H), 5.12 - 5.05 (m, 2H), 4.12 - 4.08 (m, 1H), 3.89 - 3.77 (m, 2H), 3.73 - 3.68 (m, 1H), 3.67 - 3.62 (m, 3H), 3.57 (s, 2H), 3.55 - 3.48 (m, 4H), 3.02 - 2.94 (m, 1H), 2.55 (t, J = 6.0 Hz, 2H), 2.20 (s, 3H), 1.94 - 1.83 (m, 2H); MS (ESI): m / z 835.7 (M+H) + . Example 7

[0199]

Chem.

[0200] Sodium hydride (60% w / w in kerosene, 32.4 mg) was added to compound INT-3 (200 mg, 0.40 mmol) dissolved in tetrahydrofuran (2 mL) under ice bath conditions. The reaction mixture was stirred for half an hour under ice bath conditions. Then, iodomethane (86 mg, 0.61 mmol) was added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol, v / v = 10 / 1) to give yellow oil 7a (200 mg, yield: 97%). MS (ESI): m / z 507.4 (M+H) + . Compound 7 was obtained from compound INT-1 and compound 7a by referring to the synthesis of compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.99 - 8.90 (m, 1H), 8.90 - 8.79 (m, 1H), 8.32 (s, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.57 - 7.43 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.15 - 5.05 (m, 2H), 3.97 - 3.91 (m, 1H), 3.89 - 3.83 (m, 1H), 3.78 (s, 2H), 3.68 - 3.52 (m, 3H), 3.18 - 3.10 (m, 1H), 2.73 - 2.63 (m, 5H), 2.33 - 2.22 (m, 1H), 2.18 - 2.08 (m, 1H), 2.06 - 1.98 (m, 1H), 1.87 - 1.77 (m, 1H); MS (ESI): m / z 818.6 (M+H) + . Example 8

[0201] [ka]

[0202] Compound 8 was obtained from compound INT-1 and compound INT-6 by referring to the synthesis of compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.74 - 7.68 (m, 2H), 7.57 - 7.49 (m, 4H), 7.48 - 7.45 (m, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.19 - 7.15 (m, 1H), 7.11 - 7.04 (m, 2H), 6.85 (s, 1H), 5.72 (s, 2H), 5.15 - 5.06 (m, 2H), 3.95 (d, J = 14.5 Hz, 1H), 3.87 (d, J = 14.5 Hz, 1H), 3.83 (s, 3H), 3.76 - 3.73 (m, 2H), 3.66 - 3.62 (m, 2H), 3.61 - 3.55 (m, MS (ESI): m / z 834.7 (M+H) + . Example 9

[0203] [ka]

[0204] Compound 9a was obtained from compound INT-1 and 1,3-dibromo-2-chlorobenzene by the Suzuki reaction, which is the final step in the synthesis of compound INT-7. MS (ESI): m / z 792.6 (M+H) + . Compound 9b was obtained from compound 9a by referring to the synthesis of compound INT-7a. MS (ESI): m / z 840.6 (M+H) + . Compound 9b and 2-bromo-5-aldehyde pyridine were subjected to the Suzuki reaction, the final step in the synthesis of compound INT-7, to give compound 9c. MS (ESI): m / z 819.4 (M+H) + . Compound 9d was obtained from compound 9c and compound INT-2 by the reductive amination step in the synthesis of compound INT-3b. MS (ESI): m / z 917.8 (M+H) + . Compound 9 was obtained from compound 9d by following the final step, the Boc deprotection step, in the synthesis of compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.33 (s, 1H), 7.92 - 7.83 (m, 2H), 7.75 - 7.66 (m, 3H), 7.65 - 7.55 (m, 3H), 7.52 - 7.44 (m, 1H), 7.21 - 7.14 (m, 1H), 6.86 (s, 1H), 5.73 (s, 2H), 5.15 - 5.05 (m, 2H), 3.99 - 3.73 (m, 4H), 3.69 - 3.55 (m, 3H), 3.21 - 3.15 (m, 1H), 2.58 - 2.52 (m, 2H), 2.18 - 2.03 (m, 3H), 1.75 - 1.64 (m, 1H); MS (ESI): m / z 805.8 (M+H) + . Example 10

[0205] [ka]

[0206] Compound 10 was obtained from compound 9b and 5-bromo-2-pyridineformaldehyde according to the synthesis of compound 9. 1 H NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.74 - 7.69 (m, 2H), 7.62 - 7.44 (m, 6H), 7.18 (d, J = 7.0 Hz, 1H), 6.83 (s, 1H), 5.72 (s, 2H), 5.14 - 5.05 (m, 2H), 3.93 - 3.73 (m, 4H), 3.68 - 3.50 (m, 3H), 3.03 - 2.94 (m, 1H), 2.58 (d, J = 6.2 Hz, 2H), 2.16 - 2.05 (m, 3H), 1.75 - 1.66 (m, 1H); MS (ESI): m / z 805.3 (M+H) + . Example 11

[0207] [ka]

[0208] Compound 11 was obtained from compound 9b and 4-bromo-3-methoxybenzaldehyde according to the synthesis of compound 9. 1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.73 (s, 1H), 7.66 - 7.59 (m, 2H), 7.47 (s, 1H), 7.45 - 7.37 (m, 3H), 7.32 - 7.28 (m, 1H), 7.15 - 7.08 (m, 2H), 7.05 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.78 (s, 1H), 5.64 (s, 2H), 5.06 - 5.00 (m, 2H), 3.87 - 3.82 (m, 1H), 3.80 - 3.75 (m, 1H), 3.74 - 3.67 (m, 6H), 3.58 - 3.56 (m, 1H), 3.51 - 3.50 (m, 1H), 3.04 - 2.99 (m, MS (ESI): m / z 834.7 (M+H) + . Example 12

[0209] [ka]

[0210] Compound 12a was obtained from 4-formylphenyl pinarol borate and 1,3-dibromo-2-fluorobenzene according to the synthesis of compound INT-3a. 1 H NMR (500 MHz, Chloroform-d) δ 10.08 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 7.0 Hz, 1H), 7.40 (t, J = 7.0 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H). Compound 12a was synthesized from compound INT-2 and compound INT-1 by referring to the synthesis of compound INT-3 and compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 - 8.32 (m, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.64 - 7.57 (m, 4H), 7.53 (s, 1H), 7.51 - 7.42 (m, 4H), 7.30 - 7.26 (m, 1H), 6.85 (s, 1H), 5.72 (s, 2H), 5.15 - 5.07 (m, 2H), 3.90 (d, J = 14.5 Hz, 1H), 3.85 - 3.72 (m, 3H), 3.65 - 3.60 (m, 1H), 3.56 (d, J = 5.5 Hz, 2H), 3.07 - 2.99 (m, 1H), 2.54 - 2.52 (m, 2H), 2.14 - 2.05 (m, 3H), 1.73 - 1.64 (m, 1H); MS (ESI): m / z 788.3 (M+H) + . Example 13

[0211] [ka]

[0212] Compound 13a was obtained from 4-formylphenyl pinarol borate and 2,6-dibromobenzonitrile by referring to the synthesis of compound INT-3a. 1 H NMR (500 MHz, Chloroform-d) δ 10.11 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H). Compound 13a was synthesized from compound INT-2 and compound INT-1 by referring to the synthesis of compound INT-3 and compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.31 - 8.29 (m, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.93-7.87 (m, 1H), 7.80 - 7.72 (m, 2H), 7.70 - 7.63 (m, 4H), 7.56 - 7.45 (m, 4H), 7.37 - 7.33 (m, 1H), 6.70 (s, 1H), 5.78 - 5.73 (m, 2H), 5.06 - 4.99 (m, 2H), 3.90 (d, J = 15.0 Hz, 1H), 3.84 - 3.75 (m, 3H), 3.71 (d, J = 15.0 Hz, 1H), 3.66 - 3.61 (m, 1H), 3.58 - 3.54 (m, 1H), 3.09 - 3.02 (m, 1H), 2.56 - 2.53 (m, 2H), 2.14 - 2.05 (m, 3H), 1.73 - 1.65 (m, 1H); MS (ESI): m / z 795.7 (M+H) + . Example 14

[0213] [ka]

[0214] Compound 14a was obtained from 4-formylphenyl pinarol borate and 1-bromo-3-iodobenzene by referring to the synthesis of compound INT-3a. Compound 14a was synthesized from compound INT-2 and compound INT-1 by referring to the synthesis of compound INT-3 and compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.91 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.32 - 8.30 (m, 1H), 8.21 - 8.18 (m, 1H), 7.96 - 7.94 (m, 1H), 7.76 - 7.71 (m, 4H), 7.69 - 7.62 (m, 3H), 7.55 (s, 1H), 7.51 - 7.44 (m, 3H), 7.38 (d, J = 7.0 Hz, 1H), 6.83 (s, 1H), 5.76 - 5.70 (m, 2H), 5.16 - 5.08 (m, 2H), 3.94 (d, J = 14.0 Hz, 1H), 3.87 (d, J = 14.0 Hz, 1H), 3.79 (d, J = 14.0 Hz, 1H), 3.75 (d, J = 14.0 Hz, 1H), 3.66 - 3.61 (m, 2H), 3.61 - 3.55 (m, 1H), 3.15 - 3.12 (m, 1H), 2.54 - 2.52 (m, 2H), 2.13 - 2.04 (m, 3H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 770.7 (M+H) + . Example 15

[0215] [ka]

[0216] 3-Bromo-4-chloroaniline (2.06 g, 9.98 mmol) was dissolved in sulfuric acid (25% w / w aqueous solution, 40 mL) at room temperature and stirred for half an hour. o The mixture was cooled to -5°C. A solution of sodium nitrite (826 mg, 12.0 mmol) in water (10 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was cooled to -5°C. oThe mixture was stirred for another hour under the conditions of C. Then, a mixture of ethyl acetate and water (50 mL, v / v = 3 / 2) containing potassium iodide (3.31 g, 20.0 mmol) was added dropwise. o The reaction mixture was confirmed to be below C. The aqueous phase was further extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed successively with saturated sodium thiosulfate solution (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a pale yellow solid 15a (2.05 g, yield: 64.7%). 1 H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 2.0 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H). 4-Formylphenyl pinarole borate (439 mg, 1.89 mmol) and compound 15a (500 mg, 1.58 mmol) were dissolved in a mixture of dioxane and water (10 mL, v / v = 4 / 1), and sodium bicarbonate (397 mg, 4.73 mmol) and Pd(dppf)Cl2 (58 mg, 0.079 mmol) were added. The reaction mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 3 h. The reaction was quenched with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give yellow oil 15b (271 mg, yield: 58.2%).

[0217] Compound 15b: Compound 15 was obtained from Compound INT-2 and Compound INT-1 by referring to the synthesis of Compound INT-3 and Compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 7.85 (s, 1H), 7.81 - 7.76 (m, 2H), 7.74 - 7.65 (m, 5H), 7.55 - 7.40 (m, 4H), 7.25 - 7.19 (m, 1H), 6.81 (s, 1H), 5.72 (s, 2H), 5.13 - 5.04 (m, 2H), 3.90 - 3.83 (m, 1H), 3.78 - 3.69 (m, 3H), 3.63 - 3.53 (m, 3H), 3.06 - 2.97 (m, 1H), 2.57 - 2.55 (m, 2H), 2.13 - 2.03 (m, 3H), 1.70 - 1.63 (m, 1H); MS (ESI): m / z 804.7 (M+H) + . Example 16

[0218] [ka]

[0219] N-chlorosuccinimide (419 mg, 3.14 mmol) was added to a solution of 3-bromo-4-methylaniline (584 mg, 3.14 mmol) in N,N-dimethylformamide (3 mL) at room temperature. o The temperature was raised to 1°C and stirred at the same temperature for 1 h. The reaction was quenched with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give a white solid 16a (292 mg, yield: 42.2%). 1H NMR (500 MHz, DMSO-d6) δ 6.97 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.41 (s, 2H), 2.22 (s, 3H). Compound 16b was obtained from 4-formylphenyl pinarol borate and compound 16a by referring to the synthesis of compound INT-3a.

[0220] At room temperature, tert-butyl nitrite (50 mg, 0.49 mmol) and cuprous bromide (91 mg, 0.63 mmol) were added to a solution of compound 16b (100 mg, 0.41 mmol) in acetonitrile (1 mL). o The temperature was raised to 1°C and stirred at the same temperature for 1 hour. The reaction was quenched with water (20 mL), and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give a white solid 16c (28 mg, yield: 22.2%). 1 H NMR (500 MHz, Chloroform-d) δ 10.09 (s, 1H), 8.02 - 7.95 (m, 2H), 7.56 (d, J= 8.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 2.01 (s, 3H). Compound 16c: Compound 16 was obtained from Compound INT-2 and Compound INT-1 by referring to the synthesis of Compound INT-3 and Compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.98 - 8.88 (m, 1H), 8.85 - 8.77 (m, 1H), 8.32 - 8.23 ​​(m, 1H), 7.81 (s, 1H), 7.67 - 7.63 (m, 2H), 7.53 (s, 1H), 7.47 - 7.42 (m, 3H), 7.42 - 7.39 (m, 2H), 7.27 - 7.21 (m, 2H), 7.14 - 7.09 (m, 1H), 6.82 (s, 1H), 5.69 (s, 2H), 5.11 - 5.04 (m, 2H), 3.95 - 3.82 (m, 2H), 3.82 - 3.75 (m, 2H), 3.66 - 3.61 (m, 2H), 3.59 - 3.55 (m, 1H), 3.17 - 3.13 (m, 1H), 2.62 - 2.56 (m, 2H), 2.14 - 2.10 (m, MS (ESI): m / z 818.5 (M+H) + . Example 17

[0221] [ka]

[0222] Compound 17 was obtained from 3-bromo-4-chloroaniline according to the synthesis of compound 16. 1H NMR (500 MHz, DMSO-d6) δ 8.95 - 8.88 (m, 1H), 8.85 - 8.76 (m, 1H), 8.34 - 8.27 (m, 1H), 7.90 - 7.84 (m, 1H), 7.72 - 7.64 (m, 3H), 7.54 (d, J = 8.3 Hz, 1H), 7.49 - 7.40 (m, 4H), 7.29 (d, J = 7.7 Hz, 2H), 7.14 (d, J = 7.0 Hz, 1H), 6.73 (s, 1H), 5.68 (s, 2H), 5.09 - 4.99 (m, 2H), 3.80 - 3.71 (m, 2H), 3.66 (s, 2H), 3.63 - 3.57 (m, 1H), 3.42 - 3.34 (m, 2H), 3.21 - 3.16 (m, 1H), 2.56 - 2.52 (m, 2H), 2.13 - 2.04 (m, 3H), 1.70 - 1.64 (m, 1H); MS (ESI): m / z 838.2 (M+H) + . Example 18

[0223] [ka]

[0224] Compound 18a was obtained from 4-bromophenylethanol according to the synthesis of compound INT-7a. MS (ESI): m / z 249.1 (M+H) + . Compound 18b was obtained from compound 18a and 1,3-dibromo-2-toluene according to the synthesis of compound INT-3a. MS (ESI): m / z 311.0 (M+H) + . Compound 18c was obtained from compound 18b by following the synthesis of compound 6b. MS (ESI): m / z 389.0 (M+H) + . 50 oA solution of compound 18c (290 mg, 0.74 mmol), (R)-3-hydroxypyrrolidine hydrochloride (138 mg, 1.12 mmol), and cesium carbonate (727 mg, 2.23 mmol) in acetonitrile (10 mL) was stirred for 16 h under C conditions. The reaction was quenched with water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol, v / v = 10 / 1) to give 18d (140 mg, yield: 49.0%) as a yellow oil. MS (ESI): m / z 380.2 (M+H) + . Compound 18 was obtained from compound 18d and compound INT-1 by referring to the synthesis of compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.33 - 8.31 (m, 1H), 7.86 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.53 - 7.51 (m, 2H), 7.48 - 7.45 (m, 2H), 7.44 - 7.41 (m, 2H), 7.34 - 7.32 (m, 3H), 7.16 (d, J = 7.0 Hz, 1H), 6.79 (s, 1H), 5.71 (s, 2H), 5.08 (d, J = 3.0 Hz, 2H), 4.20 - 4.18 (m, 1H), 3.86 - 3.81 (m, 2H), 3.53 - 3.51 (m, 2H), 2.97 (t, J = 6.0 Hz, 1H), 2.80 - 2.76 (m, 4H), 2.68 - 2.63 (m, 4H), 2.00 - 1.96 (m, 1H), 1.57 - 1.53 (m, 1H); MS (ESI): m / z 791.5 (M+H) + . Example 19

[0225]

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[0226] Compound 19 was obtained by referring to the synthesis of 4-ブロモフェニルプロパノールから and compound 18. 1 H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.54 (s, 1H), 8.35 - 8.33 (m, 1H), 7.86 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.49 - 7.42 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.0 Hz, 1H), 6.75 (s, 1H), 5.70 (s, 2H), 5.13 - 4.98 (m, 2H), 4.22 - 4.15 (m, 2H), 3.71 - 3.64 (m, 2H), 3.24 - 3.17 (m, 3H), 2.71 - 2.63 (m, 3H), 2.56 - 2.53 (m, 1H), 2.42 - 2.38 (m, 3H), 2.30 - 2.27 (m, 1H), 2.01 - 1.93 (m, 1H), 1.79 - 1.73 (m, 2H), 1.56 - 1.50 (m, 1H); MS (ESI): m / z 805.7 (M+H) + . Example 20

[0227]

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[0228] 25 oUnder C conditions, N-chlorosuccinimide (639 mg, 4.78 mmol) was added batchwise to a solution of 2,6-dibromoaniline (1.00 g, 3.99 mmol) in acetonitrile (20 mL). The resulting reaction mixture was stirred at the same temperature for 16 h. Water was added to the reaction mixture to precipitate a solid. The resulting solid was washed with water and dried to give a white solid 20a (1.10 g, yield: 96.7%). 1 H NMR (500 MHz, DMSO-d6) δ 7.53 (s, 2H), 5.48 (s, 2H). Compound 20a was synthesized by replacing copper bromide with copper chloride using the synthesis of compound 16c. 1 H NMR (500 MHz, DMSO-d6) δ 8.00 (s, 2H). Compound 20 was obtained from compound 20b by following the synthesis of compound 12. 1 H NMR (500 MHz, DMSO-d6) δ 8.95 - 8.88 (m, 1H), 8.83 - 8.76 (m, 1H), 8.32 - 8.23 ​​(m, 1H), 7.90 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.61 - 7.58 (m, 1H), 7.56 - 7.41 (m, 7H), 7.21 - 7.14 (m, 1H), 6.79 - 6.66 (m, 1H), 5.70 (s, 2H), 5.13 - 5.01 (m, 2H), 3.83 - 3.70 (m, 4H), 3.61 (t, J = 6.5 Hz, 1H), 3.51 - 3.47 (m, 1H), 3.44 - 3.41 (m, 1H), 2.86 (s, 1H), 2.53 - 2.52 (m, 2H), 2.16 - 2.00 (m, 3H), 1.73 - 1.63 (m, 1H); MS (ESI): m / z 838.3 (M+H) + . Example 21

[0229] [ka]

[0230] twenty five o Under C conditions, N-bromosuccinimide (6.28 g, 35.3 mmol) was added batchwise to a solution of 5-chloro-2-methylaniline (2.00 g, 14.1 mmol) in acetonitrile (30 mL). The resulting reaction mixture was stirred at the same temperature for 16 h. The reaction was quenched with water (100 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 21a (4.00 g, yield: 94.6%) as a deep red solid. 1 H NMR (500 MHz, Chloroform-d) δ 7.27 (s, 1H), 4.25 (s, 2H), 2.18 (s, 3H). twenty five o Under C conditions and a nitrogen atmosphere, tert-butyl nitrite (3.91 g, 33.4 mmol) was slowly added dropwise to a solution of compound 21a (4.00 g, 13.4 mmol) in ethanol (30 mL). The reaction mixture was stirred at 50°C for 2 hours. After cooling, the reaction mixture was concentrated, and the resulting residue was separated by silica gel column chromatography to give a white solid, 21b (2.1 g, yield: 55.3%). 1 H NMR (500 MHz, Chloroform-d) δ 7.41 (s, 2H), 2.29 (s, 3H). Compound 21 was obtained from compound 21b by following the synthesis of compound 12. 1H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.31 - 8.29 (m, 1H), 7.84 (s, 1H), 7.72 - 7.63 (m, 2H), 7.53 (s, 1H), 7.48 - 7.39 (m, 5H), 7.33 - 7.25 (m, 2H), 7.13 (d, J = 7.0 Hz, 1H), 6.82 (s, 1H), 5.70 (s, 2H), 5.14 - 5.04 (m, 2H), 3.93 (d, J = 14.5 Hz, 1H), 3.85 (d, J = 14.5 Hz, 1H), 3.80 - 3.73 (m, 2H), 3.67 - 3.54 (m, 3H), 3.14 (t, J = 5.5 Hz, 1H), 2.54 - 2.53 (m, 2H), 2.38 (s, 3H), 2.12 - 2.04 (m, 3H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 818.8 (M+H) + . Example 22

[0231]

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[0232] Compound INT-7 was decontaminated, and compound INT-1j was synthesized by reduction and merization. In the synthesis of compound 1, the Boc-protecting group was removed and compound 22 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.34 - 8.32 (m, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.46 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H), 6.86 (s, 1H), 5.73 (s, 2H), 5.11 (s, 2H), 3.93 (s, 2H), 3.90 - 3.82 (m, 2H), 3.71 - 3.67 (m, MS (ESI): m / z 774.7 (M+H) + . Example 23

[0233] [ka]

[0234] Compound 23 was obtained from compound INT-7 and serine isopropyl according to the synthesis of compound 22. 1H NMR (500 MHz, DMSO-d6) δ 8.97 (d, J = 1.9 Hz, 1H), 8.83 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 7.87 (s, 1H), 7.74 - 7.68 (m, 2H), 7.55 - 7.43 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H), 6.85 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.86 - 4.80 (m, 1H), 3.81 - 3.72 (m, 3H), 3.66 - 3.60 (m, 2H), 3.54 (d, J = 5.0 Hz, 2H), 3.19 (t, J = 5.0 Hz, 1H), 2.56 - 2.54 (m, 2H), 2.14 - 2.07 (m, 3H), 1.74 - 1.65 (m, 1H), 1.11 (d, J = 6.0 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H); MS (ESI): m / z 846.7 (M+H) + . Example 24

[0235]

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[0236] Compound INT-7 was synthesized as a reference, compound 22 was synthesized as a reference, and compound 24 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 7.87 (s, 1H), 7.71 (d, J = 9.5 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.52 - 7.43 (m, 8H), 7.17 (d, J = 7.0 Hz, 1H), 6.84 (s, 1H), 5.72 (s, 2H), 5.09 (s, 2H), 3.79 (d, J = 13.5 Hz, 1H), 3.77 - 3.73 (m, 3H), 3.66 - 3.61 (m, 1H), 3.47 (t, J = 5.5 Hz, 2H), 2.59 (t, J = 5.5 Hz, 2H), 2.57 - 2.54 (m, 2H), 2.15 - 2.06 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 760.6 (M+H) + . Example 25

[0237]

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[0238] Compound INT-7 was synthesized as a reference, compound 22 was synthesized as a reference, and compound 25 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.95 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.35 - 8.33 (m, 1H), 7.88 (s, 1H), 7.72 - 7.68 (m, 2H), 7.55 - 7.44 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H), 6.82 (s, 1H), 5.72 (s, 2H), 5.14 - 5.06 (m, 2H), 3.98 (d, J = 14.0 Hz, 1H), 3.82 (d, J = 14.0 Hz, 1H), 3.77 (d, J = 7.5 Hz, 2H), 3.65 - 3.62 (m, 1H), 3.05 - 3.02 (m, 1H), 2.56 - 2.54 (m, 2H), 2.15 - 2.03 (m, 5H), 1.90 - 1.84 (m, 1H), 1.81 - 1.65 (m, 4H); MS (ESI): m / z 814.8 (M+H) + . Example 26

[0239] [ka]

[0240] Compound 26b was obtained from compound INT-1j by the reductive amination step in the synthesis of compound INT-1j and the boron esterification step in the synthesis of compound INT-1. MS (ESI): m / z 744.6 (M+H) + . Compound 26 was obtained from compound 26b and compound INT-3 by referring to the synthesis of compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.94 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.87 (s, 1H), 7.72 - 7.68 (m, 2H), 7.57 - 7.43 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H), 6.80 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 3.82 - 3.69 (m, 6H), 3.66 - 3.58 (m, 2H), 2.55 (d, J = 6.0 Hz, 2H), 2.28 (s, 3H), 2.14 - 2.07 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 818.8 (M+H) + . Example 27

[0241] [ka]

[0242] Compound 27a was obtained from compound INT-7 by following the Boc protecting group removal step in the synthesis of compound 1. MS (ESI): m / z 715.5 (M+H) + . twenty five o Under C conditions, (R)-3-hydroxypyrrolidine hydrochloride (21 mg, 0.14 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol) were added to compound 27a (45 mg, 0.054 mmol) dissolved in N,N-dimethylformamide (2 mL). The resulting reaction mixture was stirred at the same temperature for 1 h. Sodium borohydride triacetate (58 mg, 0.27 mmol) was then added, and the reaction mixture was further stirred for 25 h. o The mixture was stirred under C conditions for 16 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phase was concentrated, and the residue was purified by preparative high-performance liquid chromatography to give 27 (10 mg, yield: 22.6%) as a white solid.1 H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J = 2.0 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.26 - 8.24 (m, 1H), 7.85 (s, 1H), 7.71 - 7.65 (m, 2H), 7.52 - 7.40 (m, 9H), 7.15 (d, J = 6.9 Hz, 1H), 6.80 (s, 1H), 5.69 (s, 2H), 5.07 (s, 2H), 3.77 (d, J = 12.5 Hz, 1H), 3.74 (d, J = 12.5 Hz, 1H), 3.62 - 3.56 (m, 3H), MS (ESI): m / z 814.8 (M+H) + . Example 28

[0243] [ka]

[0244] Compound 28 was obtained from compound INT-7a, compound INT-6, and serine isopropyl, with reference to the synthesis of compound INT-7 and compound 23. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.30 - 8.28 (m, 1H), 7.88 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.56 - 7.47 (m, 4H), 7.46 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.84 (s, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.87 - 4.81 (m, 1H), 4.78 (t, J = 5.8 Hz, 1H), 3.83 (s, 3H), 3.77 (d, J = 14.7 Hz, 1H), 3.75 - 3.73 (m, 1H), 3.66 - 3.60 (m, 2H), 3.54 (t, J = 5.6 Hz, 2H), 3.30 - 3.28 (m, 1H), 3.19 (t, J = 5.3 Hz, 1H), 2.56 (d, J = 6.0 Hz, 2H), 2.16 - 2.05 (m, 3H), 1.75 - 1.64 (m, 1H), 1.11 (d, J = 6.2 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H); MS (ESI): m / z 876.2 (M+H) + . Example 29

[0245]

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[0246] Compound INT-10, compound INT-2, compound INT-7a, compound INT-7a, compound INT-3, compound INT-7, reference for the synthesis of compound 23, and compound 29 were obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.97 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.33 - 8.31 (m, 1H), 7.85 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.72 (s, 1H), 7.69 - 7.65 (m, 1H), 7.60 - 7.54 (m, 2H), 7.52 - 7.47 (m, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 7.0 Hz, 1H), 6.87 (s, 1H), 5.72 (s, 2H), 5.11 (s, 2H), 3.92 (s, 3H), 3.80 (s, 2H), 3.72 (d, J = 4.0 Hz, 2H), 3.66 - 3.62 (m, 1H), 3.48 (t, J = 5.5 Hz, 2H), 2.64 (t, J = 5.5 Hz, 2H), 2.56 (d, J = 6.0 Hz, 2H), 2.14 - 2.07 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 791.6 (M+H) + . Example 30

[0247]

change

[0248] Compound INT-8 and O-tert-ブチル-L-セリン-t-ブチルから, compound 22 was synthesized as a reference, and compound 30 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.56 - 7.44 (m, 9H), 7.17 (d, J = 7.0 Hz, 1H), 6.72 (s, 1H), 5.75 (s, 2H), 3.89 (d, J = 14.5 Hz, 1H), 3.83 - 3.75 (m, 3H), 3.68 - 3.63 (m, 2H), 3.61 (s, 3H), 3.60 - 3.57 (m, 1H), 3.14 (t, J = 5.5 Hz, 1H), 2.57 (d, J = 6.5 Hz, 2H), 2.16 - 2.07 (m, 3H), 1.74 - 1.67 (m, 1H); MS (ESI): m / z 702.5 (M+H) + . Example 31

[0249] [ka]

[0250] Compound 31 was obtained from compound INT-8 and (R)-(-)-4-amino-3-hydroxybutyric acid according to the synthesis of compound 27. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.43 (m, 7H), 7.17 (d, J = 7.0 Hz, 1H), 6.69 (s, 1H), 5.74 (s, 2H), 3.94 - 3.90 (m, 1H), 3.80 - 3.77 (m, 2H), 3.69 - 3.68 (m, 2H), 3.65 - 3.63 (m, 1H), 3.60 (s, 3H), 2.57 - 2.53 (m, 4H), 2.45 - 2.39 (m, 1H), 2.28 - 2.22 (m, 1H), 2.13 - 2.05 (m, 3H), 1.75 - 1.65 (m, 1H); MS (ESI): m / z 716.7 (M+H) + . Example 32

[0251]

change

[0252] Compound INT-8 was synthesized as a reference, compound 22 was synthesized as a reference, and compound 32 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.42 (m, 7H), 7.17 (d, J = 7.0 Hz, 1H), 6.70 (s, 1H), 5.74 (s, 2H), 3.80 - 3.72 (m, 4H), 3.65 - 3.62 (m, 1H), 3.60 (s, 3H), 3.07 (s, 2H), 2.55 - 2.53 (m, 2H), 2.14 - 2.07 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 672.6 (M+H) + . Example 33

[0253] [ka]

[0254] Compound 33a was obtained from compound INT-8 and compound INT-11 by referring to the synthesis of compound INT-5. MS (ESI): m / z 826.7 (M+H) + . twenty five o Under C conditions, lithium hydroxide (10 mg, 0.42 mmol) was added to a solution of compound 33a (90 mg, 0.11 mmol) in a mixture of methanol and water (9 mL, v / v=8 / 1). The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated and then diluted with saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was concentrated. The residue was dissolved in a mixture of dichloromethane and trifluoroacetic acid (4 mL, v / v=3 / 1) and 25 o The reaction was continued for another 2 hours under C conditions. After concentrating the reaction mixture, the residue was purified by preparative high performance liquid chromatography to give a white solid 33 (10.3 mg, yield: 23.5%). 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.43 (m, 6H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83 - 3.74 (m, 2H), 3.67 - 3.62 (m, 1H), 3.58 (s, 3H), 3.56 - 3.48 (m, 2H), 2.95 - 2.88 (m, 1H), 2.68 - 2.64 (m, 2H), 2.59 - 2.54 (m, 2H), 2.54 - 2.51 (m, 1H), 2.15 - 2.06 (m, 3H), 1.98 - 1.90 (m, 2H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 712.7 (M+H) + . Example 34

[0255] [ka]

[0256] Compound 34a was obtained from (R)-1-Boc-3-carboxypyrrolidine according to the synthesis of compound INT-11. Compound 34 was obtained from compound 34a and compound INT-8 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.43 (m, 8H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 3.81 - 3.73 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 (s, 3H), 3.56 - 3.47 (m, 2H), 2.92 - 2.86 (m, 1H), 2.69 - 2.62 (m, 2H), 2.56 - 2.53 (m, 2H), 2.49 - 2.46 (m, 1H), 2.14 - 2.07 (m, 3H), 1.96 - 1.90 (m, 2H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 712.7 (M+H) + . Example 35

[0257] [ka]

[0258] Compound 35a was obtained by following the synthesis of N-Boc-(R)-3-piperidinecarboxylic acid, compound INT-11. Compound 35 was obtained from compound 35a and compound INT-8 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.42 (m, 8H), 7.39 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.80 - 3.73 (m, 2H), 3.65 - 3.61 (m, 1H), 3.58 (s, 3H), 3.41 (s, 2H), 2.78 - 2.72 (m, 1H), 2.59 - 2.53 (m, 3H), 2.44 - 2.40 (m, 1H), 2.24 - 2.18 (m, 1H), 2.13 - 2.04 (m, 4H), 1.79 - 1.73 (m, 1H), 1.72 - 1.67 (m, 1H), 1.64 - 1.59 (m, 1H), 1.50 - 1.42 (m, 1H), 1.40 - 1.33 (m, 1H); MS (ESI): m / z 726.7 (M+H) + . Example 36

[0259] [ka]

[0260] Compound 36a was obtained by following the synthesis of N-Boc-(S)-3-piperidinecarboxylic acid, compound INT-11. Compound 36 was obtained from compound 36a and compound INT-8 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.43 (m, 6H), 7.39 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83 - 3.74 (m, 2H), 3.66 - 3.63 (m, 1H), 3.58 (s, 3H), 3.42 (s, 2H), 2.77 - 2.73 (m, 1H), 2.56 (m, 3H), 2.45 - 2.39 (m, 1H), 2.23 - 2.16 (m, 1H), 2.15 - 2.04 (m, 4H), 1.79 - 1.73 (m, 1H), 1.72 - 1.66 (m, 1H), 1.64 - 1.59 (m, 1H), 1.50 - 1.42 (m, 1H), 1.41 - 1.33 (m, 1H); MS (ESI): m / z 726.7 (M+H) + . Example 37

[0261] [ka]

[0262] Compound 37 was obtained from methyl 4-piperidinecarboxylate and compound INT-8 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.78 - 7.76 (m, 1H), 7.67 (s, 1H), 7.53 - 7.46 (m, 7H), 7.35 (s, 1H), 7.32 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.81 - 3.73 (m, 2H), 3.65 - 3.62 (m, 1H), 3.58 (s, 3H), 3.52 - 3.50 (m, 2H), 2.80 - 2.77 (m, 1H), 2.74 - 2.70 (m, 1H), 2.20 - 2.15 (m, 1H), 2.13 - 2.08 (m, 3H), 2.02 - 1.98 (m, 4H), 1.78 - 1.74 (m, 2H), 1.72 - 1.67 (m, 1H), 1.56 - 1.52 (m, 2H); MS (ESI): m / z 726.7 (M+H) + . Example 38

[0263] [ka]

[0264] Compound 38 was obtained from 3-methylazetidine carboxylate hydrochloride and compound INT-8 according to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.44 (m, 8H), 7.27 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.72 (s, 2H), 3.84 - 3.77 (m, 2H), 3.68 - 3.63 (m, 1H), 3.58 (s, 3H), 3.47 (s, 2H), 3.42 - 3.38 (m, 2H), 3.23 - 3.17 (m, 3H), 2.58 (d, J = 6.0 Hz, 2H), 2.16 - 2.06 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 698.7 (M+H) + . Example 39

[0265]

change

[0266] The compound INT-8 was synthesized as a hemostatic acid, compound 33 was synthesized as a reference, and compound 39 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 - 7.50 (m, 2H), 7.48 - 7.41 (m, 7H), 7.17 (d, J = 7.0 Hz, 1H), 6.70 (s, 1H), 5.74 (s, 2H), 3.83 - 3.75 (m, 2H), 3.68 (s, 2H), 3.67 - 3.62 (m, 1H), 3.60 (s, 3H), 2.57 (d, J = 6.0 Hz, 2H), 2.40 (d, J = 6.5 Hz, 2H), 2.15 - 2.06 (m, 4H), 1.88 (d, J = 11.0 Hz, 2H), 1.80 (d, J = 11.0 Hz, 2H), 1.74 - 1.67 (m, 1H), 1.43 - 1.37 (m, 1H), 1.32 - 1.22 (m, 2H), 0.94 - 0.84 (m, 2H); MS (ESI): m / z 754.8 (M+H) + . Example 40

[0267] [ka]

[0268] Compound 40 was obtained from methyl trans-4-aminocyclohexanecarboxylate hydrochloride and compound INT-8 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.51 (m, 3H), 7.50 - 7.45 (m, 6H), 7.18 (d, J = 7.0 Hz, 1H), 6.78 (s, 1H), 5.76 (s, 2H), 3.95 (s, 2H), 3.88 - 3.80 (m, 2H), 3.69 - 3.65 (m, 1H), 3.64 (s, 3H), 2.81 (s, 1H), 2.62 (d, J = 6.5 Hz, 2H), 2.18 - 2.09 (m, 4H), 2.04 (d, J = 11.0 Hz, 2H), 1.94 (d, J = 11.0 Hz, 2H), 1.75 - 1.67 (m, 1H), 1.37 - 1.22 (m, 4H); MS (ESI): m / z 740.7 (M+H) + . Example 41

[0269] [ka]

[0270] Compound 41 was obtained from cis-4-aminocyclohexanecarboxylate hydrochloride and compound INT-8 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.51 (m, 3H), 7.50 - 7.45 (m, 6H), 7.18 (d, J = 7.0 Hz, 1H), 6.76 (s, 1H), 5.76 (s, 2H), 3.92 - 3.78 (m, 4H), 3.69 - 3.66 (m, 1H), 3.63 (s, 3H), 2.87 - 2.83 (m, 1H), 2.61 (d, J = 6.0 Hz, 2H), 2.46 - 2.44 (m, MS (ESI): m / z 740.7 (M+H) + . Example 42

[0271] [ka]

[0272] Compound 42 was obtained from trans-4-hydroxy-L-proline methyl ester hydrochloride and compound INT-8 according to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.43 (m, 7H), 7.17 (d, J = 7.0 Hz, 1H), 6.69 (d, J = 7.0 Hz, 1H), 5.74 (s, 2H), 4.21 - 4.15 (m, 1H), 3.87 - 3.82 (m, 1H), 3.80 - 3.76 (m, 2H), 3.67 - 3.62 (m, 2H), 3.61 - 3.57 (m, 3H), 3.50 - 3.45 (m, 1H), 3.21 - 3.19 (m, 1H), 2.58 - 2.53 (m, 3H), 2.13 - 2.07 (m, 3H), 2.02 - 1.90 (m, 1H), 1.81 - 1.75 (m, 1H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 728.7 (M+H) + . Example 43

[0273] [ka]

[0274] Compound 43 was obtained from L-proline methyl ester hydrochloride and compound INT-8 according to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 - 7.43 (m, 10H), 7.17 (d, J = 7.0 Hz, 1H), 6.70 (s, 1H), 5.75 (s, 2H), 3.93 (d, J = 14.0 Hz, 1H), 3.84 - 3.77 (m, 3H), 3.67 - 3.62 (m, 1H), 3.60 (s, 3H), 3.37 - 3.33 (m, 1H), 3.10 - 3.04 (m, 1H), 2.59 - 2.52 (m, 3H), 2.14 - 2.05 (m, 4H), 1.90 - 1.83 (m, 1H), 1.80 - 1.74 (m, 1H), 1.73 - 1.66 (m, 2H); MS (ESI): m / z 712.7 (M+H) + . Example 44

[0275] [ka]

[0276] Compound 44a was obtained from compound INT-8 and methyl 4-aminomethylbenzoate hydrochloride according to the synthesis of compound INT-5. MS (ESI): m / z 862.7 (M+H) + . Compound 44a was subjected to the reductive amination step in the synthesis of compound INT-1j to give compound 44b. MS (ESI): m / z 876.8 (M+H) + . Compound 44 was obtained from compound 44b by following the last two steps in the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.44 (m, 7H), 7.40 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.74 (s, 2H), 3.81 - 3.73 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 - 3.53 (m, 2H), 3.57 (s, 3H), 3.45 (s, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.07 (m, 6H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 762.7 (M+H) + . Example 45

[0277] [ka]

[0278] Compound 45 was obtained from compound INT-8 and methyl p-aminobenzeneacetate according to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.43 (m, 6H), 7.17 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.75 (s, 1H), 6.55 (d, J = 8.0 Hz, 2H), 5.72 (s, 2H), 4.41 (s, 2H), 3.81 - 3.73 (m, 2H), 3.66 - 3.61 (m, 4H), 3.35 (s, 2H), 2.98 (s, 3H), 2.58 - 2.53 (m, 2H), 2.14 - 2.06 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 762.7 (M+H) + . Example 46

[0279]

change

[0280] Compound INT-8 was synthesized as a chemical compound of benzoic acid, compound 44 was synthesized as a reference, and compound 46 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.74 - 7.70 (m, 2H), 7.64 - 7.60 (m, 5H), 7.59 - 7.50 (m, 3H), 7.50 - 7.46 (m, 1H), 7.17 (d, J = 7.1 Hz, 1H), 6.87 (s, 1H), 6.85 - 6.81 (m, 1H), 6.68 - 6.63 (m, 2H), 5.72 (s, 2H), 4.53 (s, 2H), 4.25 (s, 2H), 3.91 - 3.85 (m, 1H), 3.68 (s, 3H), 3.09 (s, 3H), 2.57 - 2.53 (m, 2H), 2.23 - 2.14 (m, 3H), 1.83 - 1.77 (m, 1H); MS (ESI): m / z 748.7 (M+H) + . Example 47

[0281]

change

[0282] Compound INT-8 was synthesized as a tourniquet acid, compound 44 was synthesized as a reference, and compound 47 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.40 (m, 8H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.78 - 3.71 (m, 2H), 3.64 - 3.60 (m, 1H), 3.55 (s, 3H), 3.35 - 3.31 (m, 2H), 2.53 - 2.51 (m, 2H), 2.13 - 2.07 (m, 4H), 2.07 (s, 3H), 2.01 - 1.96 (m, 1H), 1.85 - 1.76 (m, 4H), 1.71 - 1.65 (m, 1H), 1.46 - 1.39 (m, 1H), 1.28 - 1.17 (m, 3H), 0.82 - 0.73 (m, 2H); MS (ESI): m / z 768.4 (M+H) + . Example 48

[0283] [ka]

[0284] Compound 48a was obtained from 4-bromo-2-methylbenzaldehyde by following the boron esterification synthesis step of compound INT-7a. 1 H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.60 (s, 1H), 2.61 (s, 3H), 1.29 (s, 12H). Compound 48b was obtained from compound 48a and 1,3-dibromo-2-chlorobenzene according to the synthesis of compound INT-3a. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 - 7.81 (m, 1H), 7.48 - 7.34 (m, 4H), 2.66 (s, 3H). Compound 48 was obtained from Compound 48b, Compound INT-2, Compound INT-8c, and Compound INT-11 by referring to the synthesis of Compound INT-3, Compound INT-8, and Compound 33. 1 H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.38 (m, 5H), 7.35 (s, 1H), 7.30 - 7.23 (m, 2H), 7.14 (d, J = 7.0 Hz, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.74 - 3.67 (m, 2H), 3.65 - 3.61 (m, 1H), 3.56 (s, 3H), 3.52 - 3.48 (m, 2H), 2.92 - 2.85 (m, 1H), 2.64 MS (ESI): m / z 726.2 (M+H) + . Example 49

[0285] [ka]

[0286] Compound 49 was obtained from 4-bromo-2-chlorobenzeneformaldehyde according to the synthesis of compound 48. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 7.57 - 7.45 (m, 5H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.90 - 3.80 (m, 2H), 3.70 - 3.61 (m, 1H), 3.58 (s, 3H), 3.56 - 3.49 (m, 2H), 2.96 - 2.86 (m, 1H), 2.69 - 2.63 (m, 2H), 2.61 - 2.56 (m, 2H), 2.53 - 2.50 (m, 2H), 2.17 - 2.06 (m, 3H), 1.97 - 1.90 (m, 2H), 1.75 - 1.66 (m, 1H); MS (ESI): m / z 746.6 (M+H) + . Example 50

[0287] [ka]

[0288] Compound 50 was obtained from 4-bromo-3-chlorobenzaldehyde according to the synthesis of compound 48. 1H NMR (500 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.57 - 7.47 (m, 4H), 7.39 - 7.38 (m, 3H), 7.34 (s, 1H), 7.16 (d, J = 7.0 Hz, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.80 - 3.72 (m, 2H), 3.63 - 3.60 (m, 1H), 3.56 (s, 3H), 3.53 - 3.47 (m, 2H), 2.90 - 2.83 (m, 1H), 2.65 - 2.59 (m, 2H), 2.55 - 2.51 (m, 2H), 2.47 - 2.45 (m, 2H), 2.14 - 2.03 (m, 3H), 1.95 - 1.87 (m, 2H), 1.72 - 1.63 (m, 1H); MS (ESI): m / z 746.5 (M+H) + . Example 51

[0289] [ka]

[0290] Compound 51 was obtained from 4-bromo-2-(trifluoromethoxy)benzaldehyde according to the synthesis of compound 48. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.82 - 7.73 (m, 2H), 7.69 (s, 1H), 7.61 - 7.50 (m, 5H), 7.51 - 7.48 (m, 1H), 7.38 (s, 1H), 7.19 (d, J = 7.0 Hz, 1H), 6.69 (s, 1H), 5.75 (s, 2H), 3.88-3.80 (m, 2H), 3.65 (t, J = 6.5 Hz, 1H), 3.59 (s, 3H), 3.57 - 3.49 (m, 2H), 2.85 - 2.75 (m, 1H), 2.70 - 2.60 (m, 2H), 2.60 - 2.55 (m, 2H), 2.56 - 2.53 (m, 1H), 2.50 - 2.43 (m, 1H), 2.18 - 2.08 (m, 3H), 1.98 - 1.85 (m, 2H), 1.77 - 1.67 (m, 1H); MS (ESI): m / z 796.7 (M+H) + . Example 52

[0291]

change

[0292] Compound INT-9 and compound INT-11 were synthesized as a reference, compound 33 was synthesized as a reference, and compound 52 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.57 - 7.47 (m, 4H), 7.42 (d, J = 7.7 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.75 - 3.72 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.55 - 3.50 (m, 2H), 2.95 - 2.87 (m, 1H), 2.70 - 2.62 (m, 2H), 2.60 - 2.54 (m, 2H), 2.53 - 2.51 (m, 2H), 2.17 - 2.04 (m, 3H), 1.97 - 1.90 (m, 2H), 1.75 - 1.65 (m, 1H); MS (ESI): m / z 742.2 (M+H) + . Example 53

[0293]

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[0294] Compound INT-9 and O-tert-ブチル-L-セリン-t-ブチルから, compound 22 was synthesized as a reference, and compound 53 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.48 (m, 5H), 7.42 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.10 (s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 5.74 (s, 2H), 3.88 (d, J = 14.6 Hz, 1H), 3.84 (s, 3H), 3.81 - 3.74 (m, 3H), 3.68 - 3.63 (m, 2H), 3.61 (s, 3H), 3.60 - 3.57 (m, 1H), 3.14 (t, J = 5.4 Hz, 1H), 2.62 - 2.57 (m, 2H), 2.18 - 2.04 (m, 3H), 1.76 - 1.66 (m, 1H); MS (ESI): m / z 732.6 (M+H) + . Example 54

[0295]

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[0296] Compound INT-9 was synthesized as a tourniquet acid, compound 33 was synthesized as a reference, and compound 54 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.57 - 7.45 (m, 5H), 7.45 - 7.39 (m, 2H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.70 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.75 - 3.73 (m, 2H), 3.66 - 3.62 (m, 3H), 3.60 (s, 3H), 2.59 - 2.54 (m, 2H), 2.37 - 2.33 (m, 2H), 2.18 - 2.05 (m, 4H), 1.90 - 1.84 (m, 2H), 1.82 - 1.76 (m, 2H), 1.72 - 1.68 (m, 1H), 1.42 - 1.32 (m, 1H), 1.32 - 1.20 (m, 3H), 0.95 - 0.82 (m, 2H); MS (ESI): m / z 784.7 (M+H) + . Example 55

[0297]

change

[0298] Compound INT-9 was synthesized as a tourniquet acid, compound 44 was synthesized as a reference, and compound 55 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.46 (m, 4H), 7.42 (d, J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.79 - 3.71 (m, 2H), 3.66 - 3.62 (m, 1H), 3.58 (s, 3H), 3.36 (s, 2H), 2.58 - 2.56 (m, 2H), 2.15 - 2.06 (m, 9H), 1.89 - 1.80 (m, 4H), 1.74 - 1.66 (m, 1H), 1.51 - 1.42 (m, 1H), 1.33 - 1.23 (m, 2H), 0.88 - 0.76 (m, 2H); MS (ESI): m / z 798.7 (M+H) + . Example 56

[0299] [ka]

[0300] Compound 56 was obtained from methyl trans-4-aminocyclohexanecarboxylate hydrochloride and compound INT-9 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.43 (m, 4H), 7.42 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.05-7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75-3.68 (m,2H), 3.65-3.59 (m, 3H), 3.58 (s, 3H), 2.56 - 2.52 (m, 2H), 2.32 - 2.24 (m, 1H), 2.14 - 2.03 (m, 4H), 1.92 - 1.80 (m, 4H), 1.72 - 1.63 (m, 1H), 130 - 1.18 (m, 2H), 1.05 -0.95 (m, 2H); MS (ESI): m / z 770.7 (M+H) + . Example 57

[0301] [ka]

[0302] Compound 57 was obtained from methyl trans-4-aminocyclohexanecarboxylate hydrochloride and compound INT-9 by referring to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.43 (m, 4H), 7.39 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.44 (s, 2H), 2.56 - 2.52 (m, 2H), 2.39 - 2.31 (m, 1H), 2.14 - 2.10 (m, 7H), 1.95 - 1.86 (m, 2H), 1.81 - 1.74 (m, 2H), 1.71 - 1.65 (m, 1H), 1.31 - 1.23 (m, 4H); MS (ESI): m / z 784.8 (M+H) + . Example 58

[0303]

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[0304] Compound INT-9 and compound INT-2 were synthesized as a reference, compound 22 was synthesized as a reference, and compound 58 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.53 - 7.44 (m, 4H), 7.41 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.06 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.76 - 3.68 (m, 2H), 3.66 - 3.59 MS (ESI): m / z 741.8 (M+H) + . Example 59

[0305] [ka]

[0306] Compound 59 was obtained from cis-methyl 4-aminocyclohexanecarboxylate hydrochloride and compound INT-9 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.45 (m, 4H), 7.43 (s, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.62 - 3.60 (m, 3H), 3.58 (s, 3H), 2.55 - 2.52 (m, 3H), 2.31 - 2.25 (m, 1H), 2.13 - 2.04 (m, 3H), 1.87 - 1.79 (m, 2H), 1.72 - 1.63 (m, 1H), 1.57 - 1.48 (m, 2H), 1.46 - 1.37 (m, 4H); MS (ESI): m / z 770.7 (M+H) + . Example 60

[0307] [ka]

[0308] Compound 60 was obtained from cis-methyl 4-aminocyclohexanecarboxylate hydrochloride and compound INT-9 by referring to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.53 - 7.44 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.60 (m, 1H), 3.56 (s, 2H), 3.42 - 3.35 (m, 3H), 2.57 - 2.52 (m, 2H), 2.45 - 2.40 (m, 1H), 2.38 - 2.31 (m, 1H), 2.14 - 2.07 (m, 3H), 2.06 (s, 3H), 2.01 - 1.93 (m, 2H), 1.72 - 1.63 (m, 1H), 1.60 - 1.52 (m, 2H), 1.50 - 1.37 (m, 4H); MS (ESI): m / z 784.7 (M+H) + . Example 61

[0309]

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[0310] Compound INT-11 and compound INT-12 were synthesized as a reference, compound 33 was synthesized as a reference, and compound 61 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s,1H), 7.75 (d, J = 8.5 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.48 - 7.43 (m, 4H), 7.41 - 7.36 (m, 2H), 7.35 (s,1H), 7.15 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 4.21 - 4.16 (m, 1H), 3.70 - 3.45 (m, 4H), 3.56 (s, 3H), 2.92 - 2.85 (m, 1H), 2.72 - 2.66 (m, 1H), MS (ESI): m / z 685.8 (M+H) + . Example 62

[0311]

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[0312] Compound INT-12 and compound 35a were synthesized as a reference, compound 33 was synthesized as a reference, and compound 62 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.45 (m, 4H), 7.42 - 7.37 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 4.24 - 4.19 (m, 1H), 3.66 - 3.58 (m, 2H), 3.57 (s, 3H), 3.41 (s, 2H), 2.80 - 2.72 (m, 1H), 2.73 - 2.67 (m, 1H), 2.64 - 2.55 (m, 2H), 2.46 - 2.43 (m, 1H), 2.42 - 2.38 (m, 1H), 2.37 - 2.34 (m, 1H), 2.22 - 2.12 (m, 1H), 2.08 - 1.98 (m, 2H), 1.80 - 1.71 (m, 1H), 1.65 - 1.53 (m, 2H), 1.50 - 1.42 (m, 1H), 1.40 - 1.31 (m, 1H); MS (ESI): m / z 699.7 (M+H) + . Example 63

[0313]

change

[0314] Compound INT-12 was synthesized as a tourniquet acid, compound 33 was synthesized as a reference, and compound 63 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.49 - 7.45 (m, 4H), 7.42 - 7.38 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 4.24 - 4.18 (m, 1H), 3.64 (d, J = 13.0 Hz, 1H), 3.60 - 3.56 (m, 6H), 2.73 - 2.67 (m, 1H), 2.64 - 2.60 (m, 1H), 2.46 - 2.42 (m, 1H), 2.37 - 2.34 (m, 1H), 2.31 (d, J = 6.5 Hz, 2H), 2.12 - 2.06 (m, 1H), 2.04 - 1.98 (m, 1H), 1.89 - 1.84 (m, 2H), 1.82 - 1.77 (m, 2H), 1.59 - 1.52 (m, 1H), 1.39 - 1.32 (m, 1H), 1.31 - 1.21 (m, 2H), 0.93 - 0.83 (m, 2H); MS (ESI): m / z 727.5 (M+H) + . Example 64

[0315] [ka]

[0316] Compound 64a was obtained from (S)-3-hydroxypyrrolidine hydrochloride and compound INT-3a by referring to the synthesis of compounds INT-5 and INT-8. MS (ESI): m / z 586.4 (M+H) + . Compound 64 was obtained from compound 64a and compound INT-11 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.47 - 7.42 (m, 4H), 7.39 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 4.22 - 4.15 (m, 1H), 3.64 - 3.57 (m, 2H), 3.56 (s, 3H), 3.52 - 3.45 (m, 2H), 2.90 - 2.82 (m, 1H), 2.70 - 2.56 (m, 4H), 2.45 - 2.38 (m, 3H), 2.35 - 2.30 (m, 1H), 2.02 - 1.95 (m, 1H), 1.94 - 1.86 (m, 2H), 1.62 - 1.50 (m, 1H); MS (ESI): m / z 685.5 (M+H) + . Example 65

[0317] [ka]

[0318] Compound 65 was obtained from 3-hydroxyazetidine hydrochloride according to the synthesis of compound 64. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.49 - 7.44 (m, 4H), 7.38 - 7.33 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 5.34 - 5.26 (m, 1H), 4.23 - 4.19 (m, 1H), 3.61 (s, 2H), 3.58 (s, 3H), 3.56 - 3.46 (m, 6H), 2.94 - 2.88 (m, MS (ESI): m / z 671.6 (M+H) + . Example 66

[0319] [ka]

[0320] Compound 66a was obtained from N-acetylethylenediamine and compound INT-3a according to the synthesis of compound INT-3. MS (ESI): m / z 481.2 (M+H) + . Compound 66 was obtained from Compound 66a, Compound INT-8c, and Compound INT-11 by referring to the synthesis of Compound INT-8 and Compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.82 - 7.77 (m, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.40 (m, 6H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.73 (s, 2H), 3.56 (s, 3H), 3.52 - 3.47 (m, 2H), 3.16 - 3.12 (m, 2H), 2.93 - 2.84 (m, 1H), 2.67 - 2.61 (m, 2H), 2.57 (t, J = 6.5 Hz, 2H), 2.45 - 2.42 (m, 2H), 1.96 - 1.87 (m, 2H), 1.77 (s, 3H); MS (ESI): m / z 700.2 (M+H) + . Example 67

[0321] [ka]

[0322] Compound 67a was obtained from (R)-5-hydroxymethyl-2-pyrrolidone and compound INT-3a by referring to the synthesis of compounds INT-2 and INT-3. MS (ESI): m / z 493.2 (M+H) + . Compound 67 was obtained from Compound 67a, Compound INT-8c, and Compound INT-11 by referring to the synthesis of Compound INT-8 and Compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.39 (m, 6H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.77 - 3.71 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.52 - 3.48 (m, 2H), 2.91 - 2.83 (m, 1H), 2.66 - 2.60 (m, 2H), 2.55 - 2.51 (m, 2H), 2.47 - 2.45 (m, 2H), 2.15 - 2.04 (m, 3H), 1.95 - 1.88 (m, 2H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 712.6 (M+H) + . Example 68

[0323] [ka]

[0324] Methanesulfonic anhydride (135 mg, 0.77 mmol) and triethylamine (102 mg, 1.01 mmol) were added sequentially to a solution of N-tert-butoxycarbonyl-1,2-ethylenediamine (99 mg, 0.62 mmol) in dichloromethane (3 mL) under ice bath conditions. The reaction mixture was stirred under the same conditions for 1 h. Saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated to give a white solid 68a (160 mg, yield: 86.6%).

[0325] To a solution of compound 68a (160 mg, 0.67 mmol) in dichloromethane (2 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 1.7 mL). o The mixture was stirred for 16 hours under C conditions. The reaction mixture was concentrated to give yellow oil 68b (90 mg, yield: 76.8%). 1 H NMR (500 MHz, DMSO-d6) δ8.14 (s, 3H), 7.36 (t, J = 6.0 Hz, 1H), 3.27 - 3.16 (m, 2H), 2.94 (s, 3H), 2.92 - 2.84 (m, 2H). Compound 68 was obtained from compound 68b by following the synthesis of compound 64. 1 H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.47 - 7.43 (m, 4H), 7.43 - 7.40 (m, 2H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.94 (s, 1H), 6.65 (s, 1H), 5.71 (s, 2H), 3.74 (s, 2H), 3.56 (s, 3H), 3.54 - 3.52 (m, 2H), 3.05 (t, J = 6.5 Hz, 2H), 2.92 - 2.89 (m, 1H), 2.88 (s, 3H), 2.67 - 2.60 (m, 4H), 2.47 - 2.45 (m, 2H), 1.95 - 1.87 (m, 2H); MS (ESI): m / z 736.9 (M+H) + . Example 69

[0326] [ka]

[0327] Compound 69a was obtained from compound INT-11, compound INT-3a, and compound INT-8c by referring to the synthesis of compound INT-5 and compound INT-8. MS (ESI): m / z 628.5 (M+H) + . Compound 69 was obtained from compound 69a and (R)-3-hydroxypyrrolidine hydrochloride according to the synthesis of compound 33. 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.50 - 7.45 (m, 4H), 7.40 (d, J = 8.0 Hz, 2H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 4.20 - 4.15 (m, 1H), 3.66 - 3.59 (m, 2H), 3.58 (s, 3H), 3.53 (d, J = 14.5 Hz, 1H), 3.48 (d, J = 14.5 Hz, 1H), 2.96 - 2.91 (m, 1H), 2.74 (t, J = 8.5 Hz, 1H), 2.66 - 2.62 (m, 2H), 2.61 - 2.58 (m, 1H), 2.42 - 2.32 (m, 4H), 2.01 - 1.94 (m, 3H), 1.56 - 1.49 (m, 1H); MS (ESI): m / z 685.3 (M+H) + . Example 70

[0328] [ka]

[0329] Compound 70a was obtained from compound INT-11, 4-bromo-2-methoxybenzaldehyde, and compound INT-8c, following the synthesis of compounds INT-5 and INT-8. MS (ESI): m / z 658.4 (M+H) + . Compound 70 was obtained from compound 70a and compound INT-2 by following the synthesis of compound 33. 1 H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.53 - 7.44 (m, 4H), 7.41 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.06 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H), 3.62 - 3.59 (m, 4H), 3.58 - 3.56 (m, 4H), 2.95 - 2.89 (m, 1H), 2.77 - 2.71 (m, 1H), 2.70 - 2.65 (m, 1H), 2.58 - 2.52 (m, 2H), 2.47 - 2.43 (m, 2H), 2.11 - 2.02 (m, 3H), 1.98 - 1.92 (m, 2H), 1.67 - 1.60 (m, 1H); MS (ESI): m / z 742.7 (M+H) + . Example 71

[0330] [ka]

[0331] Compound 71 was obtained from compound 70a and (R)-3-hydroxypyrrolidine hydrochloride according to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.52 - 7.44 (m, 4H), 7.36 (d, J = 7.5Hz, 1H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.06 - 7.02 (m, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 4.18 - 4.11 (m, 1H), 3.80 (s, 3H), 3.61 - 3.59 (m, 2H), 3.56 (s, 3H), 3.53 - 3.46 (m, 2H), 2.95 - 2.87 (m, 1H), 2.78 - 2.71 (m, 1H), 2.69 - 2.64 (m, 1H), 2.64 - 2.53 (m, 4H), 2.41 - 2.35 (m, 1H), 2.34 - 2.29 (m, 1H), 1.99 - 1.92 (m, 3H), 1.55 - 1.48 (m, 1H); MS (ESI): m / z 715.8 (M+H) + . Example 72

[0332] [ka]

[0333] Potassium carbonate (231 mg, 1.67 mmol) was added to a solution of methyl 4-(bromomethyl)-3-chlorobenzoate (200 mg, 0.76 mmol) and 4-bromoindazole (150 mg, 0.76 mmol) in acetonitrile (6 mL). o The mixture was stirred under C conditions for 10 hours. The reaction mixture was cooled to room temperature, and the filtrate was concentrated. The residue was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 30) to give 72a as a white solid (150 mg, yield: 52.1%). MS (ESI): m / z 379.2 (M+H) +. -65 o Under C conditions, diisobutylaluminum hydride (1.5 M toluene solution, 0.79 mL) was slowly added dropwise to a solution of compound 72a (150 mg, 0.40 mmol) in dichloromethane (10 mL). The resulting reaction mixture was stirred at the same temperature for 0.5 hours. The reaction mixture was then quenched with methanol (2 mL) and allowed to warm to room temperature. Potassium sodium tartrate (10% w / w aqueous solution, 10 mL) was added, followed by vigorous stirring for 2 hours. Dichloromethane (20 mL) was then added to the resulting mixture. The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated to give colorless oil 72b (130 mg, yield: 93.6%). MS (ESI): m / z 351.1 (M+H). + . To a solution of compound 72b (130 mg, 0.37 mmol) in dichloromethane (6 mL) was added Dess-Martin oxidant (157 mg, 0.37 mmol). o The mixture was stirred for 1 hour under C conditions. Saturated sodium bicarbonate solution (20 mL) and dichloromethane (20 mL) were added to the reaction mixture. The resulting organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 - 100 / 30) to give colorless oil 72c (120 mg, yield: 92.8%). MS (ESI): m / z 349.1 (M+H) + . Compound 72c, O-tert-butyl-L-serine-t-butyl and compound INT-3 were synthesized by referring to the synthesis of compound INT-1 and compound 1. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.52 - 7.44 (m, 8H), 7.29 - 7.25 (m, 1H), 7.18 (d, J = 7.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 3.90 (d, J = 14.0 Hz, 1H), 3.81 - 3.76 (m, 3H), 3.65 - 3.63 (m, 1H), 3.62 - 3.56 MS (ESI): m / z 672.5 (M+H) + . Example 73

[0334] [ka]

[0335] Azobisisobutyronitrile (9.4 mg, 0.17 mmol) was added to a solution of methyl 2-methoxy-4-methylbenzoate (250 mg, 1.39 mmol) and N-bromosuccinimide (296 mg, 1.66 mmol) in carbon tetrachloride (8 mL). o The mixture was stirred for 16 hours under C conditions. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 to 100 / 25) to give a white solid 73a (204 mg, yield: 34.0%).

[0336] Compound 73 was obtained from compound 73a, 4-bromoindazole, O-tert-butyl-L-serine-t-butyl and compound INT-3 by referring to the synthesis of compound INT-1 and compound 1. 1H NMR (500 MHz, DMSO-d6) δ 8.18 - 8.16 (m, 2H), 7.87 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 7.52 - 7.49 (m, 1H), 7.48 - 7.25 (m, 5H), 7.13 (d, J = 7.0 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J = 7.6 Hz, 1H), 5.68 (s, 2H), 3.96-3.92 (m, 1H), 3.78 (d, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.69 - 3.61 MS (ESI): m / z 668.7 (M+H) + . Example 74

[0337] [ka]

[0338] To a solution of methyl 6-hydroxymethylnicotinate (470 mg, 2.81 mmol) in dichloromethane (10 mL) was added thionyl chloride (1.67 g, 14.1 mmol). o The mixture was stirred under C conditions for 3 hours. The reaction mixture was concentrated, and the residue was layered on a silica gel column (ethyl acetate / petroleum ether = 0 / 100 - 40 / 100) to give a white solid 74a (420 mg, yield: 80.5%). MS (ESI): m / z 186.0 (M+H). + . Compound 74 was obtained from compound 74a by following the synthesis of compound 73. 1H NMR (500 MHz, DMSO-d6) δ 8.49 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.77 - 7.69 (m, 2H), 7.67 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.48 - 7.44 (m, 6H), 7.15 (d, J = 7.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 3.91 (d, J = 13.5 Hz, 1H), 3.82 - 3.73 (m, 3H), 3.66 - 3.60 (m, 1H), 3.60 - 3.53 (m, 2H), 3.09 (t, J = 5.5 Hz, 1H), 2.55 (d, J = 6.0 Hz, 2H), 2.16 - 2.03 (m, 3H), 1.78 - 1.61 (m, 1H); MS (ESI): m / z 639.5 (M+H) + . Example 75

[0339] [ka]

[0340] Copper(I) cyanide (322 mg, 3.59 mmol) was added to a solution of compound INT-13 (550 mg, 1.80 mmol) in N,N-dimethylformamide (5 mL). o C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 to 100 / 30) to give a white solid 75a (210 mg, yield: 57.0%).

[0341] Compound 75 was obtained from compound 75a by following the synthesis of compound 73. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.84-7.82 (m, 2H), 7.67 (s, 1H), 7.54 - 7.50 (m, 2H), 7.50 - 7.42 (m, 6H), 7.18 (d, J = 6.9 Hz, 1H), 6.92 (s, 1H), 5.82 (s, 2H), 3.85 (d, J = 14.9 Hz, 1H), 3.80 - 3.73 (m, 3H), 3.71 (s, 3H), 3.64-3.60 (m, 2H), 3.60 - 3.54 (m, 1H), 3.15-3.11 (m, 1H), 2.55 - 2.54 (m, 2H), 2.13 - 2.06 (m, 3H), 1.71 - 1.67 (m, 1H); MS (ESI): m / z 693.2 (M+H) + . Example 76

[0342] [ka]

[0343] Under ice bath conditions, a solution of potassium nitrate (56.1 mg, 0.55 mmol) in concentrated sulfuric acid (0.5 mL) was added dropwise to compound INT-13b (100 mg, 0.55 mmol) in concentrated sulfuric acid (2 mL). The reaction mixture was stirred under the same conditions for 0.5 hours. A large amount of ice water was added to the reaction mixture. The precipitated solid was washed with ice water and then dried to obtain white solid 76a (115 mg, yield: 92.0%). 1 H NMR (500 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.29 (s, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 2.64 (s, 3H). Compound 76 was obtained from compound 76a by following the synthesis of compound 73. 1H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.51-7.49 (m, 3H), 7.47 - 7.43 (m, 4H), 7.19 (d, J = 7.0 Hz, 1H), 6.13 (s, 1H), 6.11 (s, 1H), 3.87 (d, J = 15.4 Hz, 1H), 3.81 - 3.72 (m, 3H), 3.67 - 3.57 (m, 3H), 3.51 (s, MS (ESI): m / z 713.8 (M+H) + . Example 77

[0344] [ka]

[0345] Compound INT-13b (300 mg, 1.66 mmol) was dissolved in concentrated sulfuric acid (3 mL) and N-chlorosuccinimide (467 mg, 3.50 mmol) was added. o The mixture was stirred at C for 2 hours. Ice water (25 mL) and ethyl acetate (25 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium bicarbonate solution (30 mL) and saturated brine (30 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated to give a yellow solid 77a (360 mg, yield: 86.8%). 1 H NMR (500 MHz, DMSO-d6) δ 7.74 (s, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.45 (s, 3H); MS (ESI): m / z 249.7 (M+H) + . Compound 77 was obtained from compound 77a by following the synthesis of compound 73. 1 H NMR (500 MHz, DMSO-d6) δ 7.86 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.56 - 7.50 (m, 2H), 7.48 - 7.43 (m, 6H), 7.17 (d, J = 7.0 Hz, 1H), 5.81 (s, 2H), 3.95 (d, J = 14.5 Hz, 1H), 3.82-3.79 (m, 3H), 3.77 (s, 3H), 3.66 - 3.59 (m, 3H), 3.20 (t, J = 5.1 Hz, 1H), 2.57 - 2.58 (m, 2H), 2.13 - 2.07 (m, 3H), 1.74-1.66 (m, 1H); MS (ESI): m / z 736.7 (M+H) + . Example 78

[0346] [ka]

[0347] Under ice bath conditions, N-iodosuccinimide (731 mg, 3.25 mmol) was added to a solution of methyl 3-chloro-4-methylbenzoate (500 mg, 2.71 mmol) in concentrated sulfuric acid (2 mL). o The mixture was stirred under C conditions for 2 hours. Ice water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 100 / 15) to give a white solid 78a (820 mg, yield: 97.5%).

[0348] Nitrogen atmosphere and 100 oA solution of compound 78a (1.00 g, 3.22 mmol), copper(I) iodide (61.3 mg, 0.32 mmol), 1,10-phenanthroline (116 mg, 0.64 mmol), and cesium carbonate (2.10 g, 6.44 mmol) in methanol (5 mL) was stirred for 24 hours under C conditions. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in methanol (5 mL), and then thionyl chloride (1.4 mL) was added. The resulting reaction mixture was 60 o The mixture was stirred at C for 2 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 to 100 / 5) to give 78b (480 mg, yield: 69.4%) as a white solid. 1 H NMR (500 MHz, Chloroform-d) δ 7.67 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.31 (s, 3H). Compound 78 was obtained from compound 78b by following the synthesis of compound 73. 1H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.52 - 7.48 (m, 2H), 7.46 - 7.43 (m, 5H), 7.14 - 7.11 (m, 3H), 5.67 (s, 2H), 3.94 (d, J = 14.2 Hz, 1H), 3.81 - 3.78 (m, 2H), 3.77 (s, 3H), 3.65 - 3.61 (m, 4H), 3.15 - 3.09 (m, 1H), 2.57 - 2.55 (d, J = 6.0 Hz, 2H), 2.13 - 2.07 (m, 3H), 1.73 - 1.66 (m, 1H); MS (ESI): m / z 702.7 (M+H) + . Example 79

[0349]

change

[0350] Compound 78a was obtained, compound 75a was synthesized according to the reference method, and compound 79a was obtained. Compound 79a was synthesized, compound 73 was synthesized as a reference, and compound 79 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.90 - 7.85 (m, 2H), 7.83 (s, 1H), 7.67 (s, 1H), 7.58 - 7.54 (m, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.48 - 7.42 (m, 5H), 7.18 (d, J = 7.1 Hz, 1H), 5.82 (s, 2H), 3.95 (d, J = 14.8 Hz, 1H), 3.81 - 3.74 (m, 3H), 3.65-3.62 (m, 1H), 3.61 - 3.56 (m, 2H), 3.12 (t, J = 5.3 Hz, 1H), 2.56 (d, J = 6.1 Hz, 2H), 2.13 - 2.07 (m, 3H), 1.72 - 1.66 (m, 1H); MS (ESI): m / z 697.5 (M+H) + . Example 80

[0351] [ka]

[0352] To a solution of 2-hydroxy-6-methylnicotinic acid (1.00 g, 6.53 mmol) in chloroform (35 mL) was added iodine methane (3.24 g, 22.9 mmol) and silver carbonate (1.81 g, 6.55 mmol). o The mixture was stirred for 16 hours under C conditions. The reaction mixture was filtered, and the filtrate was concentrated to give a colorless oil 80a (390 mg, yield: 33.0%). 1 H NMR (500 MHz, Chloroform-d) δ 8.06 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 2.48 (s, 3H); MS (ESI): m / z 182.0 (M+H) + . N-chlorosuccinimide (321 mg, 2.40 mmol) was added to a solution of compound 80a (363 mg, 2.00 mmol) in acetonitrile (10 mL). o The mixture was stirred for 10 hours under C conditions. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 to 100 / 20) to give a colorless oily substance 80b (420 mg, yield: 97.2%). 1 H NMR (500 MHz, DMSO-d6) δ 8.09 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.51 (s, 3H). Compound 80 was obtained from compound 80b by following the synthesis of compound 73. 1 H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.51 (m, 1H), 7.48 - 7.44 (m, 7H), 7.14 (d, J = 7.0 Hz, 1H), 5.82 (s, 2H), 3.79 - 3.76 (m, 2H), 3.66 - 3.55 (m, 5H), 3.38 (s, 3H), 3.13 - 3.08 (m, 1H), 2.58 - 2.54 (m, 2H), 2.13 - 2.08 (m, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 703.2 (M+H) + . Example 81

[0353] [ka]

[0354] Compound 81a was obtained from 3-methoxy-4-methylbenzoic acid according to the synthesis of compound 80b. 1H NMR (500 MHz, DMSO-d6) δ 13.25 (s, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 3.82 (s, 3H), 2.17 (s, 3H). To a solution of compound 81a (300 mg, 1.50 mmol) in dichloromethane (8 mL) was added oxalyl chloride (345 mg, 2.72 mmol) and one drop of N,N-dimethylformamide. o The mixture was stirred at 3°C ​​for 3 hours. The reaction mixture was then concentrated. The resulting residue was redissolved in dichloromethane (3 mL) and added to a solution of 4-bromoindazole (265 mg, 1.35 mmol), 4-dimethylaminopyridine (18.3 mg, 0.15 mmol), and triethylamine (302 mg, 2.99 mmol) in dichloromethane (8 mL). The reaction mixture was stirred for 25 minutes. o The mixture was stirred for 16 hours under C conditions. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 100 / 0 to 100 / 20) to give a white solid 81b (410 mg, yield: 72.2%).

[0355] From compound 81b, compound 81c was obtained by referring to the synthesis of compound 73a. Compound 81c (120 mg, 0.26 mmol) and O-tert-butyl-L-serine-t-butyl (171 mg, 0.78 mmol) were dissolved in N'N-dimethylformamide (2 mL) and potassium carbonate (72 mg, 0.52 mmol) was added. o The mixture was stirred under C conditions for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture. The organic phase was further washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The residue was separated on a silica gel thin-layer chromatography plate (petroleum ether / ethyl acetate, v / v = 4 / 1) to give a white solid 81d (70 mg, yield: 45.0%). MS (ESI): m / z 594.4 (M+H) + . Compound 81d was converted to compound 81e by the boron esterification step in the synthesis of INT-1. MS (ESI): m / z 642.8 (M+H) + . 90 o A solution of compound 81e (35 mg, 0.038 mmol), compound INT-3 (18.9 mg, 0.038 mmol), Pd(dppf)Cl2 (2.8 mg, 0.0038 mmol), and potassium fluoride (6.7 mg, 0.11 mmol) in 1,4-dioxane (4 mL) was stirred for 16 hours under C conditions and a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was separated by silica gel thin-layer chromatography (dichloromethane / methanol, v / v = 20 / 1) to give colorless oily product 81f (20 mg, yield: 36.7%). MS (ESI): m / z 928.2 (M+H). + . Compound 81 was obtained from compound 81f by following the final step of the synthesis of compound 1, the Boc protecting group removal step. 1 H NMR (500 MHz, DMSO-d6) δ 8.49 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.55 - 7.53 (m, 1H), 7.52 - 7.49 (m, 3H), 7.47 - 7.40 (m, 5H), 3.79 (s, 3H), 3.76 - 3.74 (m, 2H), 3.62 - 3.59 (m, 3H), 3.50 - 3.48 (m, 2H), 3.12 - 3.11 (m, 1H), 2.53 - 2.52 (m, 2H), 2.10 - 2.06 (m, 3H), 1.69 - 1.65 (m, 1H); MS (ESI): m / z 716.0 (M+H) + . Example 82

[0356] [ka]

[0357] Compound 82a was obtained from compound 80b by the bromination step of compound 73a, the substitution step of compound 72a, and the ester hydrolysis and acid-amine condensation steps in the synthesis of compound INT-11d. MS (ESI): m / z 595.4 (M+H) + . Compound 82 was obtained from compound 82a and compound INT-3 by following the last two steps in the synthesis of compound 81. 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 7.0 Hz, 1H), 8.23 ​​(s, 1H), 7.88 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.45 (m, 7H), 7.15 (d, J = 7.0 Hz, 1H), 5.93 (s, 2H), 4.28 - 4.26 (m, 1H), 3.85 - 3.75 (m, 3H), 3.67 - 3.60 (m, 2H), 3.39 (s, 3H), 2.59 (d, J = 6.2 Hz, 2H), 2.14 - 2.07 (m, 3H), 1.72-1.69 (m, 1H); MS (ESI): m / z 717.2 (M+H) + . Example 83

[0358] [ka]

[0359] 80 oA solution of 4-bromoindazole (500 mg, 2.54 mmol) and 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate (4.49 g, 12.7 mmol) in acetonitrile (20 mL) was stirred for 15 hours under C conditions. Ethyl acetate (100 mL) was added to the reaction mixture, which was then washed with water (100 mL) and saturated brine (100 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography to give 83a (231 mg, yield: 42.3%) as a white solid. MS (ESI): m / z 215.1 (M+H). + . Compound 83a, O-tert-butyl-L-serine-t-butyl and compound INT-3 were synthesized by referring to the synthesis of compound INT-8 and compound 1. 1 H NMR (500 MHz, DMSO-d6) δ 7.84 - 7.79 (m, 1H), 7.66 (s, 1H), 7.62 - 7.58 (m, 1H), 7.52 - 7.43 (m, 8H), 7.17 (d, J = 7.0 Hz, 1H), 6.84 (s, 1H), 5.62 (s, 2H), 3.91 - 3.79 (m, 4H), 3.67 (s, 3H), 3.65 - 3.56 (m, 3H), 3.17 - 3.15 (m, 1H), 2.60 - 2.55 (m, 2H), 2.14 - 2.09 (m, 3H), 1.73 - 1.67 (m, 1H); MS (ESI): m / z 720.6 (M+H) + . Example 84

[0360] [ka]

[0361] twenty five oA solution of 4-bromoindazole (200 mg, 1.02 mmol) and N-chlorosuccinimide (149 mg, 1.12 mmol) in N,N-dimethylformamide (3 mL) was stirred for 15 hours under C conditions. Ethyl acetate (50 mL) was added to the reaction mixture, which was then washed with water (50 mL) and saturated brine (50 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography to give 84a as a white solid (122 mg, yield: 51.9%). MS (ESI): m / z 231.3 (M+H). + . Compound 84 was obtained from compound 84a by following the synthesis of compound 83. 1 H NMR (500 MHz, DMSO-d6) δ 7.85 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.59 - 7.55 (m, 1H), 7.50 - 7.47 (m, 2H), 7.45 - 7.39 (m, 6H), 7.11 (d, J = 7.0 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 5.75 - 5.68 (m, 1H), 5.70 (s, 1H), 3.89 - 3.86 (m, 1H), 3.79 - 3.75 (m, 3H), 3.65 (s, 3H), 3.62 - 3.59 (m, 3H), 3.14 - 3.12 (m, 1H), 2.54 (d, J = 6.0 Hz, 2H), 2.11 - 2.06 (m, 3H), 1.70 - 1.65 (m, 1H); MS (ESI): m / z 736.5 (M+H) + . Example 85

[0362] [ka]

[0363] Compound 85 was obtained from compound INT-8 and 5-aminoethyltetrazolium according to the synthesis of compound 22. 1H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.55 - 7.38 (m, 9H), 7.14 (d, J = 7.0 Hz, 1H), 6.71 (s, 1H), 5.72 (s, 2H), 3.95 - 3.91 (m, 2H), 3.79 - 3.71 (m, 4H), 3.65 - 3.62 (m, 1H), 3.57 (s, 3H), 2.55 (d, J = 6.0 Hz, 2H), 2.15 - 2.04 (m, 3H), 1.72 - 1.61 (m, 1H); MS (ESI): m / z 696.1 (M+H) + . Example 86

[0364] [ka]

[0365] Compound 86a was obtained from compound INT-1c, tert-butyl bromoacetate, and 4-bromoindazole according to the synthesis of compound INT-1i. MS (ESI): m / z 479.4 (M+H) + . Compound 86a: Compound 86 was obtained from compound INT-3 and ethanolamine by referring to the synthesis of compound INT-7 and compound 22. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.41 (m, 9H), 7.15 (d, J = 6.9 Hz, 1H), 6.94 (s, 1H), 5.70 (s, 2H), 4.26 (s, 2H), 4.01 (s, 2H), 3.81 - 3.72 (m, 2H), 3.67 - 3.58 (m, 3H), 2.86 (t, J = 5.4 Hz, 2H), 2.57 - 2.50 (m, 2H), 2.13 - 2.04 (m, 3H), 1.72 - 1.64 (m, 1H); MS (ESI): m / z 702.4 (M+H) + . Example 87

[0366] [ka]

[0367] Compound 87a was obtained from (R)-3-hydroxypyrrolidine hydrochloride, 4-bromo-2-methoxybenzaldehyde, and compound INT-8c, following the synthesis of compounds INT-5 and INT-8. MS (ESI): m / z 616.4 (M+H) + . Compound 87 was obtained from compound 87a and compound INT-11 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.55 - 7.47 (m, 4H), 7.39 (d, J = 7.5 Hz, 1H), 7.36 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 4.23 - 4.17 (m, 1H), 3.82 (s, 3H), 3.64 - 3.56 (m, 5H), 3.55 - 3.47 (m, 2H), 2.88 - 2.82 (m, 1H), 2.75 - 2.69 (m, 1H), 2.67 - 2.61 (m, 3H), 2.47 - 2.43 (m, 2H), 2.41 - 2.36 (m, 2H), 2.05 - 1.97 (m, 1H), 1.95 - 1.89 (m, 2H), 1.58 - 1.52 (m, 1H); MS (ESI): m / z 715.7 (M+H) + . Example 88

[0368] [ka]

[0369] Compound 88a was obtained from ethanolamine, 4-bromo-2-methoxybenzaldehyde, and compound INT-8c, following the synthesis of compounds INT-3 and INT-8. MS (ESI): m / z 690.4 (M+H) + . Compound 88 was obtained from compound 88a and compound INT-11 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.55 - 7.47 (m, 4H), 7.41 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.11 (s, 1H), 7.09 - 7.04 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.84 (s, 3H), 3.79 (d, J = 3.5 Hz, 2H), 3.58 (s, 3H), 3.56 - 3.47 (m, 4H), 2.94 - 2.85 (m, 1H), 2.70 - 2.62 (m, 4H), 2.50 - 2.48 (m, 2H), 1.96 - 1.90 (m, 2H); MS (ESI): m / z 689.6 (M+H) + . Example 89

[0370] [ka]

[0371] Compound 89a was obtained from compound 76a by following the synthesis of compound 73. MS (ESI): m / z 925.5 (M+H) + . Zinc powder (32 mg, 0.49 mmol) was added to a solution of compound 89a (150 mg, 0.16 mmol) in acetic acid (3 mL). o The mixture was stirred under C conditions for half an hour. The reaction mixture was concentrated, and the residue was separated by preparative thin-layer chromatography (dichloromethane / methanol, v / v = 20 / 1) to give yellow oil 89b (30 mg, yield: 20.7%). MS (ESI): m / z 895.9 (M+H) + . Compound 89 was obtained from compound 89b by following the final step in the synthesis of compound 1, the Boc protecting group removal step. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.54 - 7.42 (m, 8H), 7.14 (d, J = 6.9 Hz, 1H), 6.80 (s, 1H), 6.68 (s, 1H), 5.55 (s, 2H), 5.00 - 4.95 (m, 1H), 3.84 - 3.73 (m, 4H), 3.63 (s, 3H), 3.60 - 3.51 (m, 3H), 3.04 - 3.02 (m, 1H), 2.56 - 2.52 (m, 2H), 2.13 - 2.06 (m, 3H), 1.73-1.66 (m, 1H); MS (ESI): m / z 683.1 (M+H) + . Example 90

[0372] [ka]

[0373] Compound 90a was obtained from 1,3-dibromo-2-toluene, 4-bromo-2-methoxybenzaldehyde, compound INT-2, and compound INT-8c, following the synthesis of compounds INT-3 and INT-8. MS (ESI): m / z 723.5 (M+H) + . Compound 90 was obtained from compound 90a and compound INT-11 by referring to the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.43 - 7.36 (m, 3H), 7.34 - 7.30 (m, 2H), 7.10 (d, J = 7.0 Hz, 1H), 7.03 (s, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.73 (s, 2H), 3.84 (s, 3H), 3.82 - 3.77 (m, 2H), 3.70 - 3.65 (m, 1H), 3.58 (s, 3H), 3.53 (d, J = 9.0 Hz, 2H), 2.95 - 2.88 (m, 1H), 2.68 - 2.62 (m, 4H), 2.53 - 2.52 (m, 2H), 2.16 - 2.08 (m, 3H), 2.00 (s, 3H), 1.97 - 1.91 (m, 2H), 1.75 - 1.68 (m, 1H); MS (ESI): m / z 722.3 (M+H) + . Example 91

[0374]

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[0375] Compound INT-10, compound INT-2, compound INT-8c, hemolytic acid hydrochloric acid, compound INT-3, compound INT-8 and compound 44 were synthesized as a reference, and compound 91 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.59 - 7.49 (m, 3H), 7.43 - 7.32 (m, 2H), 7.18 (d, J = 7.0 Hz, 1H), 6.71 (s, 1H), 5.74 (s, 2H), 3.94 (s, 3H), 3.91 - 3.77 (m, 2H), 3.73 - 3.67 (m, 1H), 3.59 (s, 3H), 3.41 - 3.35 (m, 2H), 2.72 - 2.65 (m, 1H), 2.53 - 2.52 (m, 1H), 2.19 - 2.01 (m, 9H), 1.91 - 1.79 (m, 4H), 1.77 - 1.68 (m, 1H), 1.53 - 1.40 (m, 1H), 1.34 - 1.21 (m, 2H), 0.88 - 0.78 (m, 2H); MS (ESI): m / z 799.7 (M+H) + . Example 92

[0376] [ka]

[0377] Compound 92a was obtained from compound 76a, 4-bromoindazole, and compound INT-6 by referring to the synthesis of compound 73a, compound 82a, and compound INT-8. MS (ESI): m / z 754.5 (M+H) + . Compound 92 was obtained from compound 92a and methyl trans-4-aminocyclohexanecarboxylate hydrochloride according to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.96 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.54 - 7.48 (m, 4H), 7.41 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.11 - 6.08 (m, 3H), 3.82 (s, 3H), 3.78 - 3.72 (m, 2H), 3.66 - 3.62 (m, 1H), 3.51 - 3.49 (m, 2H), 3.48 (s, 3H), 2.57 (d, J = 6.0 Hz, 2H), 2.46 - 2.36 (m, 2H), 2.13 (s, 3H), 2.11 - 2.07 (m, 3H), 1.94 - 1.89 (m, MS (ESI): m / z 795.7 (M+H) + . Example 93

[0378] [ka]

[0379] Compound 93 was obtained from trans-4-aminocyclobutylmethyl formate hydrochloride and compound INT-9 by referring to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.30 - 3.24 (m, 2H), 3.04 - 2.98 (m, 1H), 2.84 - 2.79 (m, 1H), 2.55 - 2.50 (m, 2H), 2.20 - 2.12 (m, 2H), 2.12 - 2.03 (m, 5H), 1.91 (s, 3H), 1.70 - 1.64 (m, 1H); MS (ESI): m / z 756.6 (M+H) + . Example 94

[0380] [ka]

[0381] Compound 94 was obtained from methyl (4-piperidine)acetate and compound INT-9 according to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.06 (m, 1H), 7.05 - 7.01 (m, 1H), 6.68 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.74 - 3.68 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 2.76 - 2.69 (m, 2H), 2.56 - 2.51 (m, 2H), 2.14 - 2.03 (m, 5H), 1.96 - 1.87 (m, 2H), 1.77 - 1.64 (m, 2H), 1.63 - 1.54 (m, 2H), 1.22 - 1.14 (m, 2H); MS (ESI): m / z 770.6 (M+H) + . Example 95

[0382]

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[0383] Compound INT-9 and compound INT-14 were synthesized, compound 44 was synthesized as a reference, and compound 95 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.53 - 7.44 (m, 4H), 7.39 (d, J = 7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.05 (m, 1H), 7.05 - 7.01 (m, 1H), 6.67 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.72 - 3.69 (m, 2H), 3.64 - 3.58 (m, 1H), 3.56 (s, 3H), 3.44 - 3.35 (m, 2H), 2.54 - 2.51 (m, 2H), 2.35 - 2.29 (m, 1H), 2.12 - 2.10 (m, 1H), 2.09 (s, 3H), 2.07 - 2.05 (m, 1H), 2.04 (d, J = 7.0 Hz, 2H), 1.76 - 1.71 (m, 4H), 1.69 - 1.63 (m, 1H), 1.59 - 1.51 (m, 1H), 1.29 - 1.20 (m, 2H), 0.99 - 0.86 (m, 2H); MS (ESI): m / z 798.7 (M+H) + . Example 96

[0384] [ka]

[0385] Compound 96 was obtained by referring to the synthesis of compound 92, substituting methyl trans-4-aminocyclohexanecarboxylate hydrochloride for methyl hemocytate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.98 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.56 - 7.48 (m, 4H), 7.44 - 7.43 (m, 1H), 7.19 (d, J = 6.9 Hz, 1H), 7.13 - 7.11 (m, 1H), 7.09 - 7.07 (m, 1H), 6.13 - 6.11 (m, 3H), 3.85 (s, 3H), 3.80-3.79 (m, 2H), 3.71 - 3.64 (m, 1H), 3.49 (s, 3H), 3.41 (s, 2H), 2.64 - 2.62 (m, 2H), 2.59-2.51 (m, 2H), 2.14 (s, 3H), 2.13 - 2.07 (m, 4H), 1.89 - 1.81 (m, 4H), 1.73 - 1.68 (m, MS (ESI): m / z 809.8 (M+H). Example 97

[0386] [ka]

[0387] Compound 97a was obtained from compound 4-bromo-2-hydroxybenzformaldehyde by the boron esterification of compound INT-7a and the synthesis of compound INT-3a. Compound 97b was obtained from compound 97a by following the alkylation reaction step of compound INT-8a. 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.86 - 7.82 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 7.10 - 7.06 (m, 1H), 4.23 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H). Compound 97b, compound INT-2, compound INT-8c, and hemostatic acid hydrochloride were synthesized as a reference, and compound 97 was synthesized as a reference. 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.55 - 7.44 (m, 4H), 7.39 (d, J = 7.7 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.74 - 3.68 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.55 - 2.53 (m, 2H), 2.13 - 2.03 (m, 9H), 1.86 - 1.75 (m, 4H), 1.72 - 1.66 (m, 1H), 1.46 - 1.40 (m, 1H), 1.33 (t, J = 6.9 Hz, 3H), 1.27 - 1.21 (m, 2H), 0.84 - 0.75 (m, 2H); MS (ESI): m / z 812.8 (M+H). Example 98

[0388]

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[0389] Compound 98 was obtained by following the synthesis of compound 97, substituting 2-iodopropane for ethyl iodide. 1 H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.55 - 7.43 (m, 4H), 7.39 (d, J = 7.7 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 7.01 - 6.97 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 4.70 - 4.62 (m, 1H), 3.74 - 3.66 (m, 2H), 3.64 - 3.60 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.54 - 2.52 (m, 2H), 2.13 - 2.03 (m, 9H), 1.89 - 1.78 (m, 4H), 1.71 - 1.65 (m, 1H), 1.48 - 1.39 (m, 1H), 1.29 - 1.26 (m, 6H), 1.26 - 1.20 (m, 2H), 0.86 - 0.74 (m, 2H); MS (ESI): m / z 826.7 (M+H). Example 99

[0390] [ka]

[0391] Compound 99a was obtained from (R)-N-Boc-3-tetrahydropyrrole acetic acid according to the synthesis of compound INT-14. 1H NMR (500 MHz, DMSO-d6) δ 9.27 - 8.91 (m, 2H), 3.59 (s, 3H), 3.32 - 3.26 (m, 1H), 3.23 - 3.15 (m, 1H), 3.13 - 3.02 (m, 1H), 2.80 - 2.71 (m, 1H), 2.55 - 2.49 (m, 3H), 2.10 - 2.02 (m, 1H), 1.55 - 1.48 (m, 1H). Compound 99a and compound INT-9 were synthesized, compound 44 was synthesized as a reference, and compound 99 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.45 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.68 (m, 2H), 3.64 - 3.60 (m, 1H), 3.56 (s, 3H), 3.48 (s, 2H), 2.68 - 2.62 (m, 1H), 2.55 - 2.51 (m, 2H), 2.47 - 2.42 (m, 2H), 2.40 - 2.34 (m, 1H), 2.28 - 2.23 (m, 2H), 2.15 - 2.05 (m, 4H), 1.97 - 1.89 (m, 1H), 1.72 - 1.64 (m, 1H), 1.37 - 1.29 (m, 1H); MS (ESI): m / z 756.7 (M+H). Example 100

[0392]

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[0393] Compound 100a was obtained from compound INT-9 and methyl hemostatic acid hydrochloride by the synthesis of compound INT-5 and the final step in the synthesis of compound 1, i.e., the removal of the Boc protecting group. MS (ESI): m / z 798.7 (M+H). Compound 100a (40 mg, 0.050 mmol) was dissolved in N,N-dimethylformamide (2 mL) and formaldehyde (34% aqueous solution, 0.10 mL), acetic acid (6.0 mg, 0.10 mmol), and sodium borohydride triacetate (42 mg, 0.20 mmol) were added. o The mixture was stirred under C conditions for 2 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 100b (35 mg, yield: 84.5%) as a light brown oil. MS (ESI): m / z 826.7 (M+H). Compound 100 was obtained from compound 100b by following the ester hydrolysis step in the synthesis of compound 33. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.55 - 7.45 (m, 5H), 7.44 (d, J = 7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.06 - 7.03 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.80 (s, 3H), 3.74 - 3.68 (m, 1H), 3.56 (s, 3H), 3.53 - 3.49 (m, 2H), 3.36 (s, 2H), 2.44 - 2.39 (m, 1H), 2.36 - 2.30 (m, 1H), 2.17 (s, 3H), 2.11 - 2.05 (m, 9H), 1.87 - 1.78 (m, 4H), 1.70 - 1.64 (m, 1H), 1.48 - 1.40 (m, 1H), 1.32 - 1.21 (m, 2H), 0.86 - 0.76 (m, 2H); MS (ESI): m / z 812.7 (M+H). Example 101

[0394]

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[0395] Compound INT-16 was synthesized as a tourniquet acid, compound 44 was synthesized as a reference, and compound 101 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.57 - 7.49 (m, 4H), 7.38 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.69 (s, 1H), 5.73 (s, 2H), 3.87 (s, 3H), 3.79 - 3.71 (m, 2H), 3.61 - 3.59 (m, 1H), 3.58 (s, 3H), 3.36 (s, 2H), 2.53 - 2.51 (m, 2H), 2.13 - 2.03 (m, 6H), 2.09 (s, 3H), 1.88 - 1.78 (m, 4H), 1.70 - 1.62 (m, 1H), 1.49 - 1.41 (m, 1H), 1.32 - 1.22 (m, 2H), 0.87 - 0.76 (m, 2H); MS (ESI): m / z 816.3 (M+H). Example 102

[0396]

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[0397] Compound INT-15b was synthesized, compound INT-3 was synthesized as a reference, and compound 102a was obtained. MS (ESI): m / z 553.6 (M+H). Compound 102a, compound INT-8c, and acetonitrile acid were synthesized as reference materials, and compound INT-8 and compound 44 were synthesized as a reference, and compound 102 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.48 (m, 4H), 7.38 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.77 (s, 2H), 6.70 (s, 1H), 5.73 (s, 2H), 3.82 (s, 6H), 3.76 - 3.70 (m, 2H), 3.60 - 3.56 (m, 4H), 3.36 (s, 2H), 2.53 - 2.52 (m, 2H), 2.13 - 2.04 (m, MS (ESI): m / z 828.5 (M+H). Example 103

[0398] [ka]

[0399] twenty five o A solution of L-proline (132 mg, 1.14 mmol) and sodium hydroxide (46 mg, 1.14 mmol) in dimethyl sulfoxide (5 mL) was stirred for 1 h under C conditions. Compound INT-13 (350 mg, 1.14 mmol), sodium methanesulfinate (1.17 g, 11.4 mmol), and copper(I) iodide (218 mg, 1.14 mmol) were then added. The resulting reaction mixture was flushed with nitrogen three times, then cooled to 120°C. oThe mixture was stirred under C conditions for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 1 / 1) to give white solid 103a (232 mg, yield: 94.5%). 1 H NMR (500 MHz, Chloroform-d) δ 8.48 (s, 1H), 6.89 (s, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.07 (s, 3H), 2.74 (s, 3H); MS (ESI): m / z 259.1 (M+H). Compound 103 was obtained from compound 103a by following the synthesis of compound 92. 1 H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.96 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.56 - 7.47 (m, 4H), 7.40 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.31 (s, 1H), 6.14 (s, 2H), 3.82 (s, 3H), 3.76 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.48 (s, 2H), 3.47 (s, 3H), 3.21 (s, 3H), 2.56 - 2.52 (m, 2H), 2.39 - 2.33 (m, 1H), 2.11 (s, 3H), 2.11 - 2.07 (m, 3H), 2.07 - 2.04 (m, 1H), 1.94 - 1.87 (m, 2H), 1.82 - 1.76 (m, 2H), 1.71 - 1.64 (m, 1H), 1.32 - 1.23 (m, 4H); MS (ESI): m / z 828.2 (M+H). Example 104

[0400] [ka]

[0401] Compound 104 was obtained from compound INT-9 and methyl cis-3-aminocyclobutanecarboxylate hydrochloride according to the synthesis of compound 44. 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H),7.52 - 7.47 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.81 (s, 3H), 3.75 - 3.68 (m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.26 (s, 2H), 2.82 - 2.75 (m, 1H), 2.67 - 2.60 (m, 1H), 2.57 - 2.52 (m, 2H), 2.23 - 2.17 (m, 2H), 2.14 - 2.04 (m, 3H), 1.94 - 1.87 (m, 2H), 1.92 (s, 3H), 1.71 - 1.64 (m, 1H); MS (ESI): m / z 755.9 (M+H). Example 105

[0402] [ka]

[0403] Compound 105 was obtained from compound INT-9 and 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride according to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.43 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.38 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.05 - 7.02 (m, 1H), 6.66 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.74 - 3.68 (m, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.56 - 2.52 (m, 2H), 2.14 - 2.04 (m, 3H), 1.99 (s, 3H), 1.75 - 1.66 (m, 7H), 1.60 - 1.49 (m, 6H); MS (ESI): m / z 810.2 (M+H). Example 106

[0404] [ka]

[0405] Compound 106 was obtained from compound INT-9 and methyl 6-aminospiro[3.3]heptane-2-carboxylate hydrochloride according to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.54 - 7.44 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.64 - 3.59 (m, 1H), 3.56 (s, 3H), 3.21 (s, 2H), 2.93 - 2.86 (m, 1H), 2.74 - 2.68 (m, 1H), 2.55 - 2.52 (m, 2H), 2.20 - 1.98 (m, 9H), 1.88 (s, 3H), 1.80 - 1.74 (m, 1H), 1.72 - 1.65 (m, 2H); MS (ESI): m / z 796.2 (M+H). Example 107

[0406]

change

[0407] Compound 75a was synthesized, compound 92 was synthesized as a reference, and compound 107 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.53 - 7.46 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.90 (s, 1H), 5.80 (s, 2H), 3.81 (s, 3H), 3.71 (d, J = 3.0 Hz, 2H), 3.69 (s, 3H), 3.63 - 3.60 (m, 1H), 3.47 (s, 2H), 2.54 - 2.52 (m, 2H), 2.39 - 2.36 (m, 1H), 2.12 - 2.06 (m, 4H), 2.10 (s, 3H), 1.93 - 1.88 (m, MS (ESI): m / z 775.3 (M+H). Example 108

[0408] [ka]

[0409] Compound 108 was obtained by referring to the synthesis of compound 107, substituting compound INT-14 for methyl trans-4-aminocyclohexanecarboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H), 7.54 - 7.46 (m, 4H), 7.42 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.92 (s, 1H), 5.80 (s, 2H), 3.87 - 3.78 (m, 2H), 3.83 (s, 3H), 3.71 - 3.66 (m, 1H), 3.70 (s, 3H), 3.51 - 3.45 (m, 2H), 2.54 - 2.52 (m, 2H), 2.14 - 2.04 (m, 8H), 1.78 - 1.68 (m, 5H), 1.59 - 1.53 (m, 1H), 1.31 - 1.21 (m, 2H), 0.98 - 0.90 (m, 2H); MS (ESI): m / z 789.1 (M+H). Example 109

[0410] [ka]

[0411] Compound 109a was obtained from cis-(N-BOC-4-aminocyclohexyl)acetic acid according to the synthesis of compound INT-14. 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (brs, 3H), 3.57 (s, 3H), 3.18 - 3.08 (m, 1H), 2.27 (d, J = 7.5 Hz, 2H), 1.95 - 1.86 (m, 1H), 1.69 - 1.56 (m, 4H), 1.54 - 1.38 (m, 4H). Compound 109 was obtained from compound 109a and compound INT-9 by referring to the synthesis of compound 44. 11H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.54 - 7.46 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.71 (d, J = 3.0 Hz, 2H), 3.64 - 3.59 (m, 1H), 3.57 (s, 3H), 3.43 (s, 2H), 2.56 - 2.52 (m, 2H), 2.36 - 2.31 (m, 1H), 2.21 - 2.16 (m, 2H), 2.13 - 2.04 (m, 3H), 2.07 (s, 3H), 1.98 - 1.91 (m, 1H), 1.72 - 1.66 (m, 1H), 1.61 - 1.53 (m, 2H), 1.51 - 1.39 (m, 6H); MS (ESI): m / z 798.3 (M+H). Example 110

[0412] [Chemical Formula]

[0413] To a solution of compound INT-8b (500 mg, 1.32 mmol) in dichloromethane (10 mL) was added boron tribromide (1 M dichloromethane solution, 3.95 mL) dropwise under ice bath conditions. The reaction mixture was stirred under the same conditions for 1 hour. The reaction mixture was quenched by adding ice water (30 mL). The resulting mixture was stirred for another half hour. The aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give a white solid, 110a (370 mg, yield: 76.8%). MS (ESI): m / z 365.2 (M+H). Compound 110b was obtained from compound 110a by following the alkylation reaction step of compound INT-8a. 1 H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.13 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.48 - 7.24 (m, 2H), 6.80 (s, 1H), 5.78 (s, 2H), 4.55 - 4.32 (m, 1H), 1.19 (d, J = 6.0 Hz, 6H). Compound 110b: Compound 110 was obtained from compound INT-6 and methyl hemostatic acid hydrochloride by referring to the synthesis of compound INT-8 and compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.54 - 7.45 (m, 4H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.41 (s, 1H), 5.72 (s, 2H), 4.20 - 4.12 (m, 1H), 3.86 - 3.82 (m, 2H), 3.84 (s, 3H), 3.71 - 3.66 (m, 1H), 3.33 (s, 2H), 2.73 - 2.63 (m, 2H), 2.14 - 2.06 (m, 9H), 1.87 - 1.77 (m, 4H), 1.72 - 1.68 (m, 1H), 1.48 - 1.39 (m, MS (ESI): m / z 826.3 (M+H). Example 111

[0414] [ka]

[0415] Compound 111a was obtained from 2-fluoro-5-hydroxybenzoic acid according to the synthesis of compounds INT-1c and INT-8b. MS (ESI): m / z 363.1 (M+H). Compound 111a: Compound INT-2 and methyl hemostatic acid hydrochloride were synthesized by referring to the synthesis of Compound INT-8 and Compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 - 7.49 (m, 2H), 7.48 - 7.42 (m, 6H), 7.18 - 7.12 (m, 2H), 6.88 (d, J = 6.0 Hz, 1H), 5.69 (s, 2H), 3.80 - 3.72 (m, 2H), 3.66 - 3.60 (m, 1H), 3.65 (s, 3H), 3.36 (s, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.07 (m, MS (ESI): m / z 752.3 (M+H). Example 112

[0416] [ka]

[0417] Compound 112a was obtained from 5-hydroxy-2-methylbenzoic acid according to the synthesis of compounds INT-1c and INT-8b. MS (ESI): m / z 359.2 (M+H). Compound 112a: Compound 112 was obtained from compound INT-6 and methyl hemostatic acid hydrochloride by referring to the synthesis of compound INT-8 and compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.46 (m, 4H), 7.44 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.12 (s, 2H), 7.09 (d, J = 7.5 Hz, 1H), 6.60 (s, 1H), 5.66 (s, 2H), 3.88 - 3.82 (m, 2H), 3.85 (s, 3H), 3.72 - 3.67 (m, 1H), 3.57 (s, 3H), 3.43 - 3.40 (m, 2H), 2.67 (d, J = 6.0 Hz, 2H), 2.25 (s, 3H), 2.18 - 2.04 (m, 9H), 1.89 - 1.80 (m, 4H), 1.76 - 1.68 (m, 1H), 1.55 - 1.45 (m, 1H), 1.32 - 1.23 (m, 2H), 0.86 - 0.75 (m, 2H); MS (ESI): m / z 778.4 (M+H). Example 113

[0418] [ka]

[0419] Compound 113 was obtained from compound INT-16 and methyl trans-4-aminocyclobutanecarboxylate hydrochloride by referring to the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.56 - 7.45 (m, 4H), 7.34 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.02 - 6.93 (m, 2H), 6.68 (s, 1H), 5.72 (s, 2H), 3.86 (s, 3H), 3.83 - 3.72 (m, 2H), 3.62- 3.58 (m. 1H), 3.57 (s, 3H), 3.27 - 3.25 (m, 2H), 3.06 - 2.97 MS (ESI): m / z 774.2 (M+H). Example 114

[0420] [ka]

[0421] Compound 114 was obtained from compound INT-16 and methyl trans-4-aminocyclohexanecarboxylate hydrochloride by referring to the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.98 - 6.93 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.60 - 3.56 (m,1 H), 3.57 (s, 3H), 3.45 (brs, 2H), 2.52 - 2.50 (m, 2H), 2.40 - 2.35 (m, 1H), 2.12 - 2.03 (m, 7H), 1.94 - 1.87 (m, 2H), 1.81 - 1.75 (m, 2H), 1.69 - 1.60 (m, 1H), 1.32 - 1.23 (m, 4H); MS (ESI): m / z 802.2 (M+H). Example 115

[0422]

change

[0423] Compound INT-16 and compound 109a were synthesized as a reference, compound 101 was synthesized as a reference, and compound 115 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.45 (m, 4H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 3.86 (s, 3H), 3.78 - 3.69 (m, 2H), 3.60 - 3.58 (m, 1H), 3.57 (s, 3H), 3.45 (s, 2H), 2.53 - 2.50 (m, 2H), 2.36 - 2.31 (m, 1H), 2.09 (s, 3H), 2.07 - 2.02 (m, 5H), 1.78 - 1.70 (m, 4H), 1.68 - 1.60 (m, 1H), 1.59 - 1.50 (m, 1H), 1.31 - 1.18 (m, 2H), 0.98 - 0.86 (m, 2H); MS (ESI): m / z 816.2 (M+H). Example 116

[0424] [ka]

[0425] Compound 116 was obtained from compound INT-16 and 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride according to the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.97 - 7.88 (m, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.38 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.66 (s, 1H), 5.70 (s, 2H), 3.85 (s, 3H), 3.77 - 3.69 (m, 2H), 3.65 - 3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.60 - 2.54 (m, 2H), 2.14 - 2.03 (m, 3H), 1.99 (s, 3H), 1.76 - 1.69 (m, 6H), 1.67 - 1.61 (m, 1H), 1.58 - 1.52 (m, 6H); MS (ESI): m / z 828.1 (M+H). Example 117

[0426]

change

[0427] Compound INT-8 and Compound 30 were synthesized as reference and Compound 117 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.93 (s, 1H), 7.66 (s, 1H), 7.55 - 7.44 (m, 8H), 7.24 (s, 1H), 6.78 (s, 1H), 5.74 (brs, 2H), 3.91 - 3.85 (m, 1H), 3.79 - 3.76 (m, 2H), 3.69 - 3.57 (m, 7H), 3.15 - 3.08 (m, 1H), 2.57 - 2.55 (m, 2H), 2.15 - 2.07 (m, 3H), 1.74 - 1.66 (m, 1H); MS (ESI): m / z 736.0 (M+H). Example 118

[0428]

change

[0429] Compound 118a was synthesized, compound INT-14 was synthesized as a reference, and compound 118b was obtained. Compound 118b and compound INT-9 were synthesized, compound 44 was synthesized as a reference, and compound 118 was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.45 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.81 (s, 3H), 3.75 - 3.67 (m, 2H), 3.65 - 3.59 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.56 - 2.52 (m, 2H), 2.14 - 2.03 (m, 10H), 1.80 - 1.73 (m, 2H), 1.72 - 1.65 (m, 3H), 1.58 - 1.53 (m, 1H), 1.44 - 1.36 (m, 1H), 0.97 - 0.86 (m, 2H), 0.83 - 0.75 (m, 2H); MS (ESI): m / z 812.2 (M+H). Example 119

[0430]

change

[0431] Under a nitrogen atmosphere, a solution of tert-butyl (3-oxocyclobutyl)carbamate (1.0 g, 5.4 mmol) and ethoxyformylmethylenetriphenylphosphine (2.1 g, 5.9 mmol) in toluene (15 mL) was heated to 110 o The mixture was stirred under C conditions for 6 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. The aqueous phase was further extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 119a (1.1 g, yield: 79.8%) as a white solid. MS (ESI): m / z 256.3 (M+H).

[0432] A solution of compound 119a (1.1 g, 4.3 mmol) and palladium (10% w / w adsorbed on activated carbon, 150 mg) in methanol (15 mL) was heated for 25 min under a hydrogen atmosphere. o The mixture was stirred overnight under C conditions. The reaction mixture was filtered, and the filtrate was concentrated to give a white solid 119b (1.1 g, yield: 99.8%). MS (ESI): m / z 258.3 (M+H).

[0433] To a solution of compound 119b (1.1 g, 4.3 mmol) in dichloromethane (15 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 5.4 mL). The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give colorless oil 119c (0.83 g, yield: 99.5%).

[0434] Compound 119 was obtained from compound 119c and compound INT-9 by referring to the synthesis of compound 44. (Based on nuclear magnetic analysis, this compound should be a mixture of anti- and anti-isomers in a ratio of 6:4.) 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.47 (m, 4H), 7.42 (d, J = 7.0 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.06 (dd, J = 7.5, 1.5 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 (s, 3H), 3.25 (s, 2H), 3.03 - 2.95 (m, 0.4H), 2.74 - 2.69 (m, 0.6H), 2.58 - 2.54 (m, 2H), 2.43 - 2.35 (m, 1H), 2.31 - 2.27 (m, 1.2H), 2.23 - 2.06 (m, 5H), 2.04 - 1.97 (m, 0.8H), 1.91 (s, 3H), 1.80 - 1.73 (m, 0.8H), 1.72 - 1.64 (m, 1H), 1.51 - 1.41 (m, 1.2H); MS (ESI): m / z 770.0 (M+H).

[0435] Example 120

[0436] [ka]

[0437] Compound 120b was obtained from trans-4-(Boc-amino)cyclohexylformaldehyde according to the synthesis of compounds 119a and 119c. MS (ESI): m / z 198.6 (M+H). Compound 120 was obtained from compound 120b and compound INT-9 by following the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.56 - 7.47 (m, 4H), 7.42 (d, J = 7.7 Hz, 1H), 7.39 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.10 (s, 1H), 7.09 - 7.05 (m, 1H), 6.77 - 6.71 (m, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 5.72 - 5.66 (m, 1H), 3.84 (s, 3H), 3.82 - 3.73 (m, 2H), 3.68 - 3.63 (m, 1H), 3.59 (s, 3H), 3.53 - 3.42 (m, 2H), 2.61 - 2.56 (m, 2H), 2.44 - 2.36 (m, 1H), 2.17 - 2.06 (m, 7H), 1.86 - 1.75 (m, 4H), 1.75 - 1.66 (m, 1H), 1.40 - 1.27 (m, 2H), 1.18 - 1.08 (m, 2H); MS (ESI): m / z 810.2 (M+H).

[0438] Example 121

[0439]

change

[0440] Compound 120a was synthesized, compound 119 was synthesized as a reference, and compound 121 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.46 (m, 4H), 7.41 (d, J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.08 (d, J = 1.7 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.83 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 - 3.61 (m, 1H), 3.58 (s, 3H), 3.46 (brs, 2H), 2.57 - 2.54 (m, 2H), 2.38 - 2.30 (m, 1H), 2.18 (t, J = 7.5 Hz, 2H), 2.15 - 2.05 (m, 6H), 1.81 - 1.65 (m, 5H), 1.38 (t, J = 7.5 Hz, 2H), 1.29 - 1.17 (m, 2H), 1.17 - 1.08 (m, 1H), 0.92 - 0.82 (m, 2H); MS (ESI): m / z 812.2 (M+H).

[0441] Examples 122 and 123

[0442] [ka]

[0443] Compounds 122 and 123 were obtained from compound INT-9, cyclopropylamine, and methyl 4-oxocyclohexanecarboxylate by referring to the synthesis of compound 44. Compound 122: 11H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.55 - 7.45 (m, 4H), 7.41 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 - 7.07 (m, 1H), 7.07 - 7.03 (m, 1H), 6.66 (s, 1H), 5.71 (s, 2H), 3.83 (s, 3H), 3.73 - 3.72 (m, 2H), 3.68 (s, 2H), 3.65 - 3.60 (m, 1H), 3.59 (s, 3H), 2.56 - 2.53 (m, 2H), 2.46 - 2.42 (m, 1H), 2.14 - 2.03 (m, 5H), 1.93 - 1.87 (m, 2H), 1.83 - 1.78 (m, 2H), 1.72 - 1.67 (m, 1H), 1.38 - 1.30 (m, 2H), 1.26 - 1.20 (m, 2H), 0.40 - 0.35 (m, 2H), 0.26 - 0.17 (m, 2H); MS (ESI): m / z 810.2 (M+H).

[0444] Compound 123: 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.52 - 7.45 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.29 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 - 7.06 (m, 1H), 7.05 - 7.02 (m, 1H), 6.63 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.72 - 3.70 (m, 2H), 3.68 - 3.66 (m, 1H), 3.64 (s, 2H), 3.57 (s, 3H), 2.55 - 2.52 (m, 2H), 2.45 - 2.42 (m, 1H), 2.13 - 2.03 (m, 5H), 1.70 - 1.65 (m, 1H), 1.60 - 1.55 (m, MS (ESI): m / z 810.2 (M+H).

[0445] Example 124

[0446] [ka]

[0447] Compound 124 was obtained by following the synthesis of compound 110, substituting ethyl iodide for isopropyl iodide. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.55 - 7.47 (m, 4H), 7.42 (d, J = 7.7 Hz, 1H), 7.37 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 7.08 - 7.05 (m, 1H), 6.59 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.78 (q, J = 7.0 Hz, 2H), 3.75 - 3.71 (m, 2H), 3.65 - 3.61 (m, 1H), 3.36 (brs, 2H), 2.56 - 2.53 (m, 2H), 2.14 - 2.03 (m, 6H), 2.08 (s, 3H), 1.89 - 1.80 (m, 4H), 1.72 - 1.66 (m, 1H), 1.50 - 1.42 (m, 1H), 1.29 - 1.24 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H), 0.85 - 0.79 (m, 2H); MS (ESI): m / z 812.2 (M+H).

[0448] Example 125

[0449] [ka]

[0450] Compound 125 was obtained from compound INT-9, methyl trans-4-aminocyclohexanecarboxylate hydrochloride, and benzaldehyde by referring to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.53 - 7.43 (m, 4H), 7.44 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.30 - 7.23 (m, 4H), 7.22- 7.13 (m, 2H), 7.08 - 7.06 (m, 1H), 7.05- 7.02 (m, 1H), 6.62 (s, 1H), 5.68 (s, 2H), 3.81 (s, 3H), 3.77 - 3.70 (m, 2H), 3.66 - 3.61 (m, 1H), 3.57 (s, 2H), 3.54 (s, 3H), 3.51 (s, 2H), 2.59 - 2.54 (m, 2H), 2.41 - 2.36 (m, 1H), 2.14 - 2.04 (m, 4H), 1.94 - 1.87 (m, 2H), 1.84 - 1.79 (m, 2H), 1.71 - 1.65 (m, 1H), 1.41 - 1.32 (m, 2H), 1.20 - 1.11 (m, 2H); MS (ESI): m / z 860.1 (M+H).

[0451] Example 126

[0452] [ka]

[0453] Compound 126 was obtained from compound INT-9, methyl trans-4-aminocyclohexanecarboxylate hydrochloride, and cyclopropanecarboxaldehyde by referring to the synthesis of compound 44. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.55 - 7.46 (m, 4H), 7.41 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.10 - 7.08 (m, 1H), 7.08- 7.03 (m, 1H), 6.67 (s, 1H), 5.72 (s, 3H), 3.83 (s, 3H), 3.76 - 7.68 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, 3H), 3.55 (s, 2H), 2.56 - 2.53 (m, 2H), 2.32 (d, J = 6.0 Hz, 2H), 2.15 - 2.05 (m, 4H), 1.93 - 1.88 (m, 2H), 1.80 - 1.73 MS (ESI): m / z 824.1 (M+H).

[0454] Example 127

[0455] [ka]

[0456] Compound 127 was obtained by referring to the synthesis of compound 110, substituting 2-bromoacetamide for isopropyl iodide. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J = 1.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.54 (s, 1H), 7.51 - 7.47 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.06 - 7.02 (m, 1H), 6.79 (s, 1H), 5.68 (s, 2H), 4.28 (s, 2H), 3.81 (s, 3H), 3.72 (d, J = 3.0 Hz, 2H), 3.64 - 3.61 (m, 1H), 3.43 (s, 2H), 2.58 - 2.55 (m, 2H), 2.15 - 2.09 (m, 6H), 2.08 (s, MS (ESI): m / z 841.2 (M+H).

[0457] Example 128

[0458] [ka]

[0459] Compound 128 was obtained by referring to the synthesis of compound 110, substituting tert-butyl 2-bromoacetate for isopropyl iodine. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.51 - 7.46 (m, 4H), 7.42 - 7.37 (m, 2H), 7.14 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.79 (s, 1H), 5.65 (s, 2H), 4.09 (brs, 2H), 3.81 (s, 3H), 3.73 - 3.69 (m, 2H), 3.63 - 3.60 (m, 1H), 3.41 (s, 2H), 2.54 - 2.52 (m, 2H), 2.33 - 2.28 (m, 1H), 2.20 (s, 3H), 2.12 - 2.05 (m, 5H), 1.86 - 1.80 (m, 4H), 1.71 - 1.66 (m, MS (ESI): m / z 843.2 (M+H).

[0460] Example 129

[0461] [ka]

[0462] Compound 129a was obtained from compound INT-9 and methyl trans-4-aminocyclohexanecarboxylate hydrochloride according to the synthesis of compound 44 (without the final step of de-Bocation). MS (ESI): m / z 883.6 (M+H).

[0463] Compound 129a and methanesulfonamide were synthesized using the acid-amine condensation conditions used in the synthesis of compound 82a and the final step of Boc deprotection of compound 1, to obtain compound 129. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.56 - 7.47 (m, 4H), 7.44 (d, J = 7.5 Hz, 1H), 7.41 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.70 (s, 1H), 5.73 (s, 2H), 3.85 (s, 3H), 3.84 - 3.79 (m, 2H), 3.71 - 3.65 (m, 1H), 3.59 (s, 3H), 3.53 (s, 2H), 3.05 (s, 3H), 2.65 (d, J = 6.0 Hz, 2H), 2.46 - 2.40 (m, 1H), 2.15 (s, 3H), 2.14 - 2.05 (m, 4H), 1.88 - 1.78 (m, 4H), 1.75 - 1.68 (m, 1H), 1.35 - 1.22 (m, 4H); MS (ESI): m / z 861.3 (M+H).

[0464] Example 130

[0465]

change

[0466] Compound INT-16 and compound 118b were synthesized as a reference, compound 101 was synthesized as a reference, and compound 130 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.63 (s, 1H), 7.54 - 7.48 (m, 4H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 3.85 (s, 3H), 3.76 - 3.70 (m, 2H), 3.60 - 3.57 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.53 - 2.50 (m, 2H), 2.11 - 2.02 (m, 10H), 1.79 - 1.74 (m, 2H), 1.71 - 1.66 (m, 2H), 1.65 - 1.60 (m, 1H), 1.58 - 1.51 (m, 1H), 1.44 - 1.36 (m, 1H), 0.95 - 0.87 (m, 2H), 0.83 - 0.74 (m, 2H); MS (ESI): m / z 830.1 (M+H).

[0467] Example 131

[0468]

change

[0469] Compound INT-16 and compound 121a were synthesized, compound 101 was synthesized as a reference, and compound 131 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.36 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.66 (s, 1H), 5.71 (s, 2H), 3.85 (s, 3H), 3.77 - 3.69 (m, 2H), 3.62 - 3.59 (m, 1H), 3.56 (s, 3H), 3.44 (s, 2H), 2.55 - 2.52 (m, 2H), 2.36 - 2.31 (m, 1H), 2.19 - 2.14 (m, 2H), 2.09 (s, 3H), 2.07 - 2.02 (m, 3H), 1.77 - 1.69 (m, 4H), 1.66 - 1.60 (m, 1H), 1.39 - 1.33 (m, 2H), 1.24 - 1.17 (m, 2H), 1.13 - 1.08 (m, 1H), 0.89 - 0.82 (m, 2H); MS (ESI): m / z 830.1 (M+H).

[0470] Example 132

[0471]

change

[0472] Compound INT-16 and compound 120b were synthesized as a reference, compound 101 was synthesized as a reference, and compound 132 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.54 - 7.47 (m, 4H), 7.37 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.76 - 6.69 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 5.69 - 5.64 (m, 1H), 3.86 (s, 3H), 3.77 - 3.71 (m, 2H), 3.61 - 3.58 (m, 1H), 3.57 (s, 3H), 3.46 (s, 2H), 2.52 - 2.50 (m, 2H), 2.14 - 2.02 (m, 8H), 1.84 - 1.74 (m, 4H), 1.69 - 1.60 (m, 1H), 1.34 - 1.24 (m, 2H), 1.16 - 1.07 (m, 2H); MS (ESI): m / z 828.1 (M+H).

[0473] Example 133

[0474] [ka]

[0475] Compound 133 was obtained by referring to the synthesis of compound 91, substituting methyl hemostatic acid hydrochloride with 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.68 - 7.64 (m, 2H), 7.58 - 7.49 (m, 3H), 7.40 (s, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.69 (s, 1H), 5.72 (s, 2H), 3.92 (s, 3H), 3.76 - 3.68 (m, 2H), 3.66 - 3.62 (m, 1H), 3.59 (s, MS (ESI): m / z 811.1 (M+H).

[0476] Example 134

[0477] [ka]

[0478] Compound 134 was obtained by referring to the synthesis of compound 110, substituting (S)-5-bromomethyl-2-pyrrolidone for isopropyl iodide. 1H NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.78 - 7.73 (m, 2H), 7.66 (s, 1H), 7.52 - 7.46 (m, 4H), 7.40 (d, J = 7.5 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.72 (s, 1H), 5.70 (s, 2H), 3.81 (s, 3H), 3.80 - 3.76 (m, 1H), 3.75 - 3.72 (m, 1H), 3.72 - 3.70 (m, 2H), 3.66 - 3.60 (m, 2H), 3.40 - 3.35 (m, 2H), 2.57 - 2.52 (m, 2H), 2.17 (d, J = 11.0 Hz, 1H), 2.12 - 2.08 (m, 6H), 2.08 (s, 3H), 2.06 - 2.04 (m, 1H), 1.87 - 1.75 (m, 5H), 1.70 - 1.64 (m, 1H), 1.47 - 1.40 (m, 1H), 1.30 - 1.20 (m, 3H), 0.85 - 0.77 (m, 2H); MS (ESI): m / z 881.2 (M+H).

[0479] Example 135

[0480] [ka]

[0481] Compound 80b, 4-bromoindazole and compound INT-15 were synthesized according to the synthesis of compound 73a and compound INT-16 to give compound 135a. MS (ESI): m / z 661.4 (M+H). Compound 135 was obtained from compound 135a and 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride according to the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.57 - 7.43 (m, 4H), 7.12 (d, J = 7.0 Hz, 1H), 6.96 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.78 (s, 2H), 3.85 (s, 3H), 3.74 - 3.73 (m, 2H), 3.58 - 3.56 (m, 3H), 3.37 (s, 3H), 2.51-2.50 (m, 2H), 2.10 - 2.03 (m, 3H), 1.99 (s, 3H), 1.70 - 1.67 (m, 6H), 1.64 - 1.62 (m, 1H), 1.54 - 1.51 (m, 6H); MS (ESI): m / z 829.2 (M+H).

[0482] Example 136

[0483] [ka]

[0484] Compound 136 was obtained from compound INT-16 and methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride according to the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.46 (m, 4H), 7.33 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.00 - 6.94 (m, 2H), 6.67 (s, 1H), 5.72 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.57 (s, 3H), 3.56 - 3.52 (m, 1H), 3.40 (s, 2H), 2.55 - 2.52 (m, MS (ESI): m / z 786.0 (M+H).

[0485] Example 137

[0486] [ka]

[0487] Compound 137a was obtained from Compound INT-10, Compound INT-2, Compound 80b and 4-bromoindazole according to the synthesis of Compound INT-3, Compound 73a and Compound 16. MS (ESI): m / z 644.3 (M+H). Compound 137 was obtained from compound 137a and 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride according to the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.83 - 7.80 (m, 3H), 7.70 - 7.65 (m, 3H), 7.55 (t, J = 7.5 Hz, 1H), 7.50 - 7.47 (m, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.0 Hz, 1H), 5.80 (s, 2H), 3.92 (s, 3H), 3.73 - 3.71 (m, 2H), 3.65 - 3.63 (m, 1H), 3.39 (s, 3H), 3.36 (brs, 2H), 2.56 (d, J = 6.0 Hz, 2H), 2.14 - 2.07 (m, 3H), 2.00 (s, 3H), 1.72-1.68 (m, 7H), 1.56-1.52 (m, 6H); MS (ESI): m / z 812.1 (M+H).

[0488] Example 138

[0489]

change

[0490] Compound 107 was synthesized as a reference, compound INT-6 was substituted for compound INT-15, and compound 138 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.56 - 7.50 (m, 4H), 7.18 (d, J = 7.0 Hz, 1H), 6.99 - 6.97 (m, 2H), 6.92 (s, 1H), 5.82 (s, 2H), 3.87 (s, 3H), 3.76 - 3.73 (m, 2H), 3.71 (s, 3H), 3.62 - 3.58 (m, 1H), 3.49 (s, 2H), 2.60-2.55 (m, 2H), 2.45 - 2.35 (m, 1H), 2.12 (s, 3H), 2.10 - 2.04 (m, 3H), 1.94 - 1.92 (m, 2H), 1.81 - 1.79 (m, 2H), 1.69 - 1.62 (m, 1H), 1.34-1.23 (m, 5H); MS (ESI): m / z 793.0 (M+H).

[0491] Example 139

[0492] [ka]

[0493] Compound 139 was obtained by referring to the synthesis of compound 138, substituting methyl trans-4-aminocyclohexanecarboxylate hydrochloride with methyl trans-4-aminocyclobutylformate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.55 - 7.48 (m, 4H), 7.17 (d, J = 7.1 Hz, 1H), 6.99 - 6.95 (m, 2H), 6.91 (s, 1H), 5.80 (s, 2H), 3.85 (s, 3H), 3.73 (d, J = 4.2 Hz, 2H), 3.69 (s, 3H), 3.58 - 3.56 (m, 1H), 3.26 (brs, 2H), 3.03 - 3.01 MS (ESI): m / z 765.1 (M+H).

[0494] Example 140

[0495] [ka]

[0496] Compound 140 was obtained by referring to the synthesis of compound 138, substituting methyl trans-4-aminocyclohexanecarboxylate hydrochloride with methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.56 - 7.49 (m, 4H), 7.18 (d, J = 7.0 Hz, 1H), 7.00 - 6.97 (m, 2H), 6.91 (s, 1H), 5.81 (s, 2H), 3.87 (s, 3H), 3.75 (d, J = 4.5 Hz, 2H), 3.70 (s, 3H), 3.62 - 3.56 (m, 1H), 3.45 (s, 2H), 2.54 - 2.52 (m, MS (ESI): m / z 819.0 (M+H).

[0497] Example 141

[0498] [ka]

[0499] Compound 141 was obtained by referring to the synthesis of compound 138, substituting compound INT-14 for methyl trans-4-aminocyclohexanecarboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.56 - 7.48 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 6.97 - 6.95 (m, 2H), 6.90 (s, 1H), 5.80 (s, 2H), 3.85 (s, 3H), 3.73 (d, J = 4.1 Hz, 2H), 3.69 (s, 3H), 3.58 - 3.55 (m, 1H), 3.46 (s, 2H), 2.52 - 2.49 (m, 2H), 2.36 - 2.33 (m, 1H), 2.10 (s, 3H), 2.08 - 2.01 (m, 5H), 1.77 - 1.70 (m, 4H), 1.66 - 1.61 (m, 1H), 1.58 -1.52 (m, 1H), 1.29 - 1.22 (m, 2H), 0.96 - 0.89 (m, 2H); MS (ESI): m / z 807.1 (M+H).

[0500] Example 142

[0501]

change

[0502] Compound 92 was synthesized as a reference, compound INT-6 was substituted for compound INT-15, and compound 142 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.99 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.57 - 7.46 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.10 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.73 (d, J = 4.5 Hz, 2H), 3.59 - 3.55 (m, 1H), 3.49 (s, 2H), 3.48 (s, 3H), 2.53 - 2.51 (m, 2H), 2.43 - 2.37 (m, 1H), 2.13 (s, 3H), 2.11 - 2.01 (m, 4H), 1.95 - 1.86 (m, 2H), 1.84 - 1.75 (m, 2H), 1.68 - 1.59 (m, 1H), 1.33 - 1.23 (m, 4H); MS (ESI): m / z 813.3 (M+H).

[0503] Example 143

[0504] [ka]

[0505] Compound 143 was obtained by referring to the synthesis of compound 142, substituting methyl trans-4-aminocyclohexanecarboxylate hydrochloride with methyl trans-4-aminocyclobutylformate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.99 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.48 (m, 4H), 7.17 (d, J = 6.5 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.12 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.48 (s, 3H), 3.32 - 3.30 (m, 2H), 3.09 - 3.02 MS (ESI): m / z 785.3 (M+H).

[0506] Example 144

[0507] [ka]

[0508] Compound 144 was obtained by referring to the synthesis of compound 142, substituting compound INT-14 for methyl trans-4-aminocyclohexanecarboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.98 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.57 - 7.47 (m, 4H), 7.17 (d, J = 6.5 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.09 (s, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.49 (s, 2H), 3.48 (s, 3H), 2.54 - 2.50 (m, 2H), 2.36 - 2.33 (m, 1H), 2.13 (s, 3H), 2.10 - 2.02 (m, 5H), 1.78 - 1.70 (m, 4H), 1.67 - 1.64 (m, 1H), 1.57 - 1.52 (m, 1H), 1.32 - 1.21 (m, 2H), 0.98 - 0.88 (m, 2H); MS (ESI): m / z 827.1 (M+H).

[0509] Example 145

[0510] [ka]

[0511] Compound 145 was obtained by referring to the synthesis of compound 142, substituting 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride for trans-4-aminocyclohexanecarboxylate methyl ester hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.98 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.56 - 7.47 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.09 (s, 1H), 6.08 (s, 2H), 3.86 (s, 3H), 3.77 - 3.70 (m, 2H), 3.59 - 3.55 (m, 1H), 3.48 (s, 3H), 3.45 (s, 2H), 2.54 - 2.50 (m, MS (ESI): m / z 839.1 (M+H).

[0512] Example 146

[0513] [ka]

[0514] Copper(I) iodide (156 mg, 0.82 mmol) was added to a solution of compound INT-13 (50 mg, 0.16 mmol) and methyl fluorosulfonyldifluoroacetate (314 mg, 1.6 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at 150°C for 4 hours. After filtering the reaction mixture, a mixture of ethyl acetate and water (100 mL, v / v=1 / 1) was added to the filtrate. The resulting organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give a white solid 146a (40 mg, yield: 98.7%). 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.27 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H); MS (ESI): m / z 249.0 (M+H).

[0515] Compound 146 was obtained from Compound 146a by referring to the synthesis of Compound 92, substituting Compound INT-14 for methyl trans-4-aminocyclohexanecarboxylate hydrochloride. 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.70 (s, 1H), 7.67 - 7.62 (m, 2H), 7.54 - 7.46 (m, 4H), 7.40 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 7.04 (dd, J = 7.5, 1.6 Hz, 1H), 6.32 (s, 1H), 5.82 (s, 2H), 3.82 (s, 3H), 3.71 (d, J = 3.0 Hz, 2H), 3.65 - 3.59 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.55 - 2.53 (m, 2H), 2.37 - 2.33 (m, 1H), 2.12 - 2.06 (m, 6H), 2.02 (d, J = 7.1 Hz, 2H), 1.76 - 1.67 (m, 5H), 1.58 - 1.51 (m, 1H), 1.29 - 1.21 (m, 2H), 0.97 - 0.87 (m, 2H); MS (ESI): m / z 832.2 (M+H).

[0516] Example 147

[0517] [ka]

[0518] Compound 147 was obtained by replacing compound INT-6 with compound INT-15 in accordance with the synthesis of compound 146.1 H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.70 (s, 1H), 7.68 - 7.61 (m, 2H), 7.57 - 7.47 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 7.01 - 6.94 (m, 2H), 6.33 (s, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.62 - 3.54 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.55 - 2.50 (m, 2H), 2.36 - 2.31 (m, 1H), 2.10 (s, 3H), 2.09 - 2.01 (m, 5H), 1.77 - 1.69 (m, 4H), 1.67 - 1.61 (m, 1H), 1.59 - 1.52 (m, 1H), 1.31 - 1.24 (m, 2H), 0.97 - 0.88 (m, 2H); MS (ESI): m / z 850.1 (M+H).

[0519] Example 148

[0520] [ka]

[0521] Compound 148 was obtained by referring to the synthesis of compound 147, substituting compound INT-14 with methyl trans-4-aminocyclohexanecarboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.70 (s, 1H), 7.69 - 7.61 (m, 2H), 7.57 - 7.46 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.33 (s, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 3.78 - 3.68 (m, 2H), 3.61 - 3.55 (m, 1H), 3.48 (s, 2H), 3.46 (s, 3H), 2.56 - 2.50 (m, 2H), 2.39 - 2.33 (m, MS (ESI): m / z 836.1 (M+H).

[0522] Example 149

[0523] [ka]

[0524] Compound 149 was obtained by referring to the synthesis of compound 147, substituting compound INT-14 with methyl trans-4-aminocyclohexanecarboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.69 - 7.62 (m, 3H), 7.57 - 7.47 (m, 4H), 7.17 (d, J = 6.9 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.34 (s, 1H), 5.83 (s, 2H), 3.86 (s, 3H), 3.79 - 3.70 (m, 2H), 3.61 - 3.54 (m, 1H), 3.46 (s, 3H), 3.29 (s, 2H), 3.06 - 2.97 (m, 1H), 2.83 - 2.75 (m, 1H), 2.56 - 2.52 (m, 2H), 2.19 - 2.14 (m, 2H), 2.11 - 2.01 (m, 5H), 1.91 (s, 3H), 1.68 - 1.61 (m, 1H); MS (ESI): m / z 808.1 (M+H).

[0525] Example 150

[0526] [ka]

[0527] Compound 150 was obtained by referring to the synthesis of compound 147, substituting 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride for compound INT-14. 1H NMR (500 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.72 (s, 1H), 7.67 - 7.61 (m, 2H), 7.58 - 7.47 (m, 4H), 7.17 (d, J = 7.0 Hz, 1H), 7.05 - 6.94 (m, 2H), 6.32 (s, 1H), 5.82 (s, 2H), 3.86 (s, 3H), 3.78 - 3.70 (m, 2H), 3.61 - 3.55 (m, 1H), 3.46 (s, 3H), 3.44 (s, 2H), 2.60 - 2.54 (m, 2H), 2.10 - 2.02 (m, MS (ESI): m / z 862.1 (M+H).

[0528] Example 151

[0529] [ka]

[0530] Compound 151 was obtained by referring to the synthesis of compound 137, substituting methyl trans-4-aminocyclohexanecarboxylate hydrochloride for methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.83 - 7.78 (m, 3H), 7.72 - 7.63 (m, 3H), 7.54 (t, J = 7.5 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.30 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 5.80 (s, 2H), 3.90 (s, 3H), 3.70 (d, J = 3.5 Hz, 2H), 3.65 - 3.60 (m, 1H), 3.39 (s, 2H), 3.37 (s, 3H), 2.55 - 2.53 (m, 2H), 2.37 - 2.33 (m, 1H), 2.12 - 2.05 (m, 4H), 2.08 (s, 3H), 1.93 - 1.87 (m, 2H), 1.78 - 1.73 (m, 2H), 1.71 - 1.66 (m, 1H), 1.29 - 1.23 (m, 4H); MS (ESI): m / z 786.0 (M+H).

[0531] Example 152

[0532] [ka]

[0533] Compound 152 was obtained by referring to the synthesis of compound 91, substituting methyl trans-4-aminocyclohexanecarboxylate hydrochloride for methyl hemostatic acid hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.59 - 7.49 (m, 3H), 7.38 (s, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.18 (d, J = 7.0 Hz, 1H), 6.69 (s, 1H), 5.73 (s, 2H), 3.92 (s, 3H), 3.76 - 3.70 (m, 2H), 3.66 - 3.61 (m, 1H), 3.59 (s, 3H), 3.46 (s, 2H), 2.56 - 2.55 (m, 2H), 2.42 - 2.35 (m, 1H), 2.16 - 2.06 (m, 4H), 2.12 (s, 3H), 1.96 - 1.88 (m, 2H), 1.83 - 1.76 (m, 2H), 1.74 - 1.66 (m, 1H), 1.34 - 1.23 (m, 4H); MS (ESI): m / z 784.8 (M+H).

[0534] Example 153

[0535]

change

[0536] Compound 57 was synthesized as a reference, compound INT-2 was substituted for compound INT-17, and compound 153 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.54 - 7.48 (m, 4H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.19 - 7.14 (m, 2H), 7.10 (brs, 1H), 7.07 - 7.03 (m, 1H), 6.68 (s, 1H), 5.73 (s, 2H), 3.83 (s, 3H), 3.76 - 3.66 (m, 2H), 3.58 (s, 3H), 3.46 (s, 2H), 3.41 - 3.36 (m, 1H), 2.61 - 2.58 (m, 2H), 2.16 - 2.05 (m, 3H), 2.13 (s, 3H), 1.95 - 1.89 (m, 2H), 1.83 - 1.74 (m, 4H), 1.63 - 1.54 (m, 1H), 1.36 - 1.23 (m, 6H); MS (ESI): m / z 799.1 (M+H).

[0537] Example 154

[0538] [ka]

[0539] -78 o Under C conditions, lithium diisopropylamide (2.0 M in tetrahydrofuran, 2.6 mL) was added to a solution of 1-chloro-2-bromo-4-fluorobenzene (1.0 g, 4.8 mmol) in tetrahydrofuran (6 mL). The resulting reaction mixture was stirred at the same temperature for 1 hour. N,N-dimethylformamide (1.7 g, 24 mmol) was then added to the reaction mixture. The resulting mixture was further heated to -78 oThe mixture was stirred under C conditions for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride (40 mL, 5% w / w), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 1) to give 154a (830 mg, yield: 73.2%) as a white solid. MS (ESI): m / z 237.1 (M+H).

[0540] 90 o Compound 154a (830 mg, 3.5 mmol), hydrazine hydrate (2.0 mL, 85% analytical purity) and ethylene glycol dimethyl ether (5 mL) were stirred for 3 hours under C conditions. After the reaction was cooled, ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 1) to give a pale yellow solid 154b (725 mg, yield: 89.6%). MS (ESI): m / z 231.0 (M+H).

[0541] Compound 154 was obtained from compound 154b by referring to the synthesis of compound INT-9 and compound 30. 1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J = 9.0 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.55 - 7.53 (m, 2H), 7.48 (s, 1H), 7.43 - 7.39 (m, 2H), 7.07 - 7.02 (m, 2H), 6.75 (s, 1H), 5.73 (s, 2H), 3.88 - 3.84 (m, 1H), 3.82 (s, 3H), 3.79 - 3.73 (m, 3H), 3.65 - 3.64 (m, 1H), 3.62 MS (ESI): m / z 765.9 (M+H).

[0542] Example 155

[0543] [ka]

[0544] N-Chlorosuccinimide (843 mg, 6.3 mmol) was added batchwise to a solution of 4-bromo-2-fluoroaniline (1.0 g, 5.3 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at reflux for 2 hours. After cooling, 5% aqueous potassium carbonate (50 mL) was added. The resulting aqueous phase was extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether as eluent) to give 155a (1.0 g, yield: 84.6%) as a white solid. 1H NMR (500 MHz, Chloroform-d) δ 7.21 (t, J = 2.0 Hz, 1H), 7.09 (dd, J = 10.0, 2.0 Hz, 1H), 4.04 (brs, 2H).

[0545] Compound 155a (1.0 g, 4.5 mmol) dissolved in aqueous sulfuric acid (25% w / w) was stirred at room temperature for half an hour. o After cooling to -5°C, a solution of sodium nitrite (369 mg, 5.4 mmol) in water (5 mL) was slowly added dropwise. o The mixture was stirred for another 1 hour under C conditions, and a solution of potassium iodide (1.5 g, 8.9 mmol) in ethyl acetate and water (50 mL, v / v = 3 / 2) was slowly added dropwise at the same temperature. The resulting reaction mixture was reacted at room temperature for 1 hour. After layering the reaction mixture, the aqueous phase was further extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether as an eluent) to give colorless oil 155b (800 mg, yield: 53.6%). 1 H NMR (500 MHz, Chloroform-d) δ 7.45 (t, J = 2.0 Hz, 1H), 7.13 (dd, J = 7.0, 2.0 Hz, 1H).

[0546] Nitrogen atmosphere and 80 oUnder the conditions described in C, a mixture of compound 155b (1.0 g, 3.0 mmol), vinyl pinacol borate (1.4 g, 9.0 mmol), Pd(dppf)Cl2 (109 mg, 0.15 mmol), and sodium bicarbonate (504 mg, 6.0 mmol) in 1,4-dioxane and water (11 mL, v / v = 10 / 1) was stirred for 16 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether as eluent) to give 155c (550 mg, 58.7% yield) as a colorless oil.

[0547] Compound 155c (520 mg, 2.2 mmol) was mixed in a 1,4-dioxane / water mixture (6 mL, v / v = 1 / 1) at room temperature, and potassium osmate dihydrate (8.1 mg, 0.02 mmol) and sodium periodate (1.4 g, 6.6 mmol) were added. The reaction mixture was stirred at the same temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 10 / 1) to give colorless oil 155d (400 mg, yield: 76.3%). 1 H NMR (500 MHz, Chloroform-d) δ 10.40 (brs, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.33 - 7.29 (m, 1H).

[0548] Compound 155 was obtained from compound 155d by referring to the synthesis of compound INT-16 and compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.48 (m, 4H), 7.36 (s, 1H), 7.19 - 7.17 (m, 1H), 7.15 (d, J = 7.0 Hz, 1H), 7.11 - 7.09 (m, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 3.85 (s, 3H), 3.85 - 3.83 (m, 2H), 3.62 - 3.57 (m, 1H), 3.56 (s, 3H), 3.34 (s, 2H), 2.54 - 2.51 (m, 2H), 2.11 - 2.04 (m, 8H), 1.86 - 1.77 (m, 4H), 1.67 - 1.61 (m, 1H), 1.48 - 1.39 (m, 1H), 1.27 - 1.19 (m, 3H), 0.85 - 0.75 (m, 2H); MS (ESI): m / z 832.2 (M+H).

[0549] Example 156

[0550] [ka]

[0551] Sodium methoxide (1.8 g, 33.5 mmol) was added to a solution of methyl 4,6-dichloronicotinate (4.6 g, 22.3 mmol) in tetrahydrofuran (40 mL). o The mixture was stirred under C conditions for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 156a (2.8 g, yield: 62.2%) as a white solid. MS (ESI): m / z 202.1 (M+H).

[0552] Compound 156b was obtained from compound 156a according to the synthesis of compound 72c. MS (ESI): m / z 172.1 (M+H). Compound 156 was obtained from compound 156b by referring to the synthesis of compound INT-10 and compound 133. 1 H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J = 1.7 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.61 - 7.48 (m, 5H), 7.40 (s, 1H), 7.18 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 3.88 (s, 3H), 3.86 (s, 2H), 3.65 - 3.60 (m, 1H), 3.58 (s, 3H), 3.43 (s, 2H), 2.66 - 2.56 (m, 2H), 2.15 - 2.05 (m, 3H), 2.00 (s, 3H), 1.77 - 1.67 (m, 7H), 1.61 - 1.52 (m, 6H); MS (ESI): m / z 811.1 (M+H).

[0553] Example 157

[0554] [ka]

[0555] Compound 157a was obtained from compound INT-15a according to the synthesis of compound INT-1e. MS (ESI): m / z 276.8 (M+H). Compound 157c was obtained from compound 157a by following the synthesis of 155c. 1 H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.31 (d, J = 1.5 Hz, 1H), 6.19 (d, J = 1.5 Hz, 1H), 4.11 - 4.07 (m, 2H), 3.96 - 3.92 (m, 2H), 3.90 (s, 3H).

[0556] 0 o Under C conditions, sodium borohydride (29 mg, 0.77 mmol) was added to a solution of compound 157c (400 mg, 1.53 mmol) in tetrahydrofuran (20 mL). The reaction mixture was then stirred at room temperature for 0.5 hours. Saturated sodium bicarbonate (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid, 157d (400 mg, yield: 99.2%). MS (ESI): m / z 263.3 (M+H).

[0557] Compound 157d was synthesized by synthesis of compounds INT-8c and INT-1i, and compound 157e was obtained. MS (ESI): m / z 445.5 (M+H). Compound 157 was obtained from compound 157e by following the synthesis of compound 133. 1 H NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.56 - 7.49 (m, 3H), 7.30 (d, J = 7.5 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.58 (s, 1H), 5.76 (s, 2H), 3.90 (s, 3H), 3.70 (d, J = 3.5 Hz, 2H), 3.64 - 3.61 (m, 1H), 3.60 (s, 3H), 3.45 (s, MS (ESI): m / z 829.3 (M+H).

[0558] Example 158

[0559] [ka]

[0560] Compound 158 was obtained from 1-chloro-2-fluoro-4-bromobenzene according to the synthesis of compound 154. 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.66 (s, 1H), 7.56 - 7.49 (m, 4H), 7.45 - 7.39 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 7.6, 1.6 Hz, 1H), 6.04 - 6.00 (m, 3H), 3.81 (s, 3H), 3.73 - 3.69 (m, 2H), 3.66 - 3.56 (m, 3H), 3.45 - 3.41 (m, 2H), 3.38 (s, 3H), 3.25 - 3.22 (m, 1H), 2.55 - 2.50 (m, 2H), 2.11 - 2.05 (m, 3H), 1.71 - 1.65 (m, 1H); MS (ESI): m / z 766.0 (M+H).

[0561] Example 159

[0562] [ka]

[0563] Compound 159 was obtained by following the synthesis of compound 116 and substituting acetaldehyde for formaldehyde in the reductive amination step. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.54 - 7.47 (m, 4H), 7.15 (d, J = 7.0 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.64 (s, 1H), 5.70 (s, 2H), 3.86 (s, 3H), 3.77 - 3.71 (m, 2H), 3.62 - 3.57 (m, 1H), 3.60 (s, 3H), 3.56 (s, 2H), 2.57 - 2.50 (m, MS (ESI): m / z 842.1 (M+H).

[0564] Example 160

[0565] [ka]

[0566] 60 o A solution of 4-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (150 mg, 0.49 mmol) in thionyl chloride (2 mL) was stirred for 2 hours under C conditions. After concentrating the reaction mixture, the residue was dissolved in acetonitrile (3 mL), and trimethylsilylated diazomethane (2 M in n-hexane, 0.24 mL) was added. The resulting reaction mixture was stirred at room temperature for 2 hours. oUnder conditions C, triethylamine (0.13 mL), silver trifluoroacetate (154 mg, 0.70 mmol), and methanol (1 mL) were added to the above solution. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain a white solid 160a (50 mg, yield: 32.4%). 1 H NMR (500 MHz, DMSO-d6) δ 7.37 - 7.26 (m, 5H), 6.87 (s, 1H), 4.92 (s, 2H), 3.53 (s, 3H), 2.05 (s, 2H), 1.75 - 1.66 (m, 6H), 1.55 - 1.42 (m, 6H); MS (ESI): m / z 332.4 (M+H).

[0567] A solution of compound 160a (100 mg, 0.30 mmol) and palladium hydroxide (10% w / w adsorbed on activated carbon, 20 mg) in methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated, and the residue was dissolved in dichloromethane (2 mL), and hydrochloric acid (4 M in ethyl acetate, 0.15 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for half an hour. The reaction mixture was concentrated, and the resulting solid residue was washed with ethyl acetate to give a white solid, 160b (60 mg, yield: 85.1%). MS (ESI): m / z 198.5 (M+H).

[0568] Compound 160 was obtained from compound INT-16 and compound 160b by following the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.47 (m, 4H), 7.40 (s, 1H), 7.16 (d, J = 7.0 Hz, 1H), 6.98 - 6.95 (m, 2H), 6.67 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.79 - 3.71 (m, 2H), 3.65 - 3.59 (m, 1H), 3.58 (s, 3H), 3.41 (s, 2H), 2.60 - 2.54 (m, MS (ESI): m / z 842.3 (M+H).

[0569] Example 161

[0570] [ka]

[0571] Compound 161 was obtained by referring to the synthesis of compound 116, substituting 2-methyl-1,3-dibromobenzene for 2-chloro-1,3-dibromobenzene. 1H NMR (500 MHz, DMSO-d6) δ 7.92 (d, J = 1.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.52 - 7.47 (m, 1H), 7.40 - 7.36 (m, 2H), 7.35 - 7.31 (m, 2H), 7.09 (d, J = 7.0 Hz, 1H), 6.93 - 6.88 (m, 2H), 6.65 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.78 - 3.71 (m, 2H), 3.64 - 3.60 (m, 1H), 3.57 (s, 3H), 3.42 (s, 2H), 2.56 - 2.53 (m, 2H), 2.13 - 2.06 (m, 3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.76 - 1.68 (m, 6H), 1.69 - 1.63 (m, 1H), 1.60 - 1.53 (m, 6H); MS (ESI): m / z 808.1 (M+H).

[0572] Example 162

[0573] [ka]

[0574] Compound 162 was obtained from compound INT-16 and trans-4-aminocyclohexanol according to the synthesis of compound 101. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H), 7.54 - 7.48 (m, 4H), 7.35 (s, 1H), 7.15 (d, J = 7.0 Hz, 1H), 6.98 - 6.94 (m, 2H), 6.67 (s, 1H), 5.71 (s, 2H), 4.43 (d, J = 4.5 Hz, 1H), 3.85 (s, 3H), 3.77 - 3.70 (m, 2H), 3.62 - 3.60 (m, 1H), 3.56 (s, 3H), 3.42 (s, 2H), 3.35 - 3.32 (m, 1H), 2.55 - 2.52 (m, 1H), 2.36 - 2.33 (m, 1H), 2.10 - 2.04 (m, 6H), 1.84 - 1.78 (m, 2H), 1.72 - 1.67 (m, 2H), 1.65 - 1.59 (m, 1H), 1.31 - 1.20 (m, 2H), 1.14 - 1.06 (m, 2H); MS (ESI): m / z 774.1 (M+H).

[0575] Example 163

[0576] [ka]

[0577] Compound 163 was obtained by referring to the synthesis of compound 135, substituting methyl trans-4-aminocyclohexanecarboxylate hydrochloride for methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride. 1H NMR (500 MHz, DMSO-d6) δ 7.88 - 7.83 (m, 1H), 7.81 - 7.75 (m, 1H), 7.71 - 7.61 (m, 2H), 7.55 - 7.44 (m, 4H), 7.15 - 7.09 (m, 1H), 6.99 - 6.92 (m, 2H), 5.83 - 5.76 (m, 2H), 3.88 - 3.83 (m, 3H), 3.76 - 3.70 (m, 2H), 3.59 - 3.54 (m, 1H), 3.40 - 3.38 (m, 2H), 3.37 - 3.36 (m, 3H), 2.51 - 2.50 (m, 2H), 2.35 - 2.30 (m, 1H), 2.10 - 2.03 (m, 6H), 1.90 - 1.81 (m, 3H), 1.76 - 1.69 (m, 2H), 1.68 - 1.61 (m, 1H), 1.24 - 1.16 (m, 4H); MS (ESI): m / z 803.1 (M+H).

[0578] Example 164

[0579] [ka]

[0580] Compound 164 was obtained by referring to the synthesis of compound 133, substituting 2-methyl-1,3-dibromobenzene for 2-chloro-1,3-dibromobenzene. 11H NMR (500 MHz, DMSO-d6) δ 7.81 - 7.77 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.50 - 7.44 (m, 2H), 7.40 - 7.35 (m, 2H), 7.34 - 7.30 (m, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 7.0 Hz, 1H), 6.65 (s, 1H), 5.70 (s, 2H), 3.88 (s, 3H), 3.75 - 3.68 (m, 2H), 3.66 - 3.59 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.54 (d, J = 6.0 Hz, 2H), 2.15 - 2.05 (m, 3H), 2.09 (s, 3H), 1.99 (s, 3H), 1.75 - 1.69 (m, 6H), 1.69 - 1.65 (m, 1H), 1.59 - 1.52 (m, 6H); MS (ESI): m / z 791.0 (M+H).

[0581] Example 165

[0582]

Chem.

[0583] -78 oUnder C conditions and a nitrogen atmosphere, diisobutylaluminum hydride (1 M in toluene, 30.6 mL) was slowly added dropwise to a solution of 5-bromo-3-fluoro-2-pyridinenitrile (4.1 g, 20.4 mmol) in tetrahydrofuran (40 mL). The reaction mixture was then stirred at the same temperature for 2 hours. Water (50 mL) was then added to the reaction mixture and filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give 165a (2.7 g, yield: 64.9%) as a white solid. MS (ESI): m / z 204.0 (M+H).

[0584] Compound 165b was obtained from compound 165a according to the synthesis of compound 156a. MS (ESI): m / z 216.3 (M+H). Compound 165 was obtained from Compound 165b and 3-bromo-2-methylphenol by referring to the synthesis of Compound INT-10 and Compound 133. 1H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.52 - 7.48 (m, 1H), 7.46 - 7.43 (m, 1H), 7.42 - 7.38 (m, 2H), 7.37 - 7.33 (m, 1H), 7.19 (s, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.66 (s, 1H), 5.72 (s, 2H), 3.92 (s, 3H), 3.78 - 3.69 (m, 2H), 3.67 - 3.60 (m, 1H), 3.58 (s, 3H), 3.43 - 3.38 (m, 2H), 2.55 (d, J = 6.0 Hz, 2H), 2.15 - 2.06 (m, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.77 - 1.71 (m, 6H), 1.71 - 1.65 (m, 1H), 1.61 - 1.54 (m, 6H); MS (ESI): m / z 791.0 (M+H).

[0585] Example 166

[0586] [ka]

[0587] Compound 166 was obtained by referring to the synthesis of compound 135, substituting 2-methyl-1,3-dibromobenzene for 2-chloro-1,3-dibromobenzene. 1H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J = 1.0 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.72 (s, 1H), 7.67 (s, 1H), 7.50 - 7.46 (m, 1H), 7.41 - 7.37 (m, 1H), 7.36 - 7.29 (m, 2H), 7.09 - 7.05 (m, 1H), 6.95 - 6.89 (m, 2H), 5.82 (s, 2H), 3.88 (s, 3H), 3.80 - 3.72 (m, 2H), 3.65 - 3.55 (m, 1H), 3.38 (s, 3H), 3.35 - 3.30 (m, 2H), 2.54 - 2.50 (m, 2H), 2.13 - 2.05 (m, 3H), 2.02 (s, 6H), 1.76 - 1.70 (m, 6H), 1.69 - 1.64 (m, 1H), 1.60 - 1.53 (m, 6H); MS (ESI): m / z 809.1 (M+H).

[0588] Example 167

[0589]

change

[0590] Compound 133 was synthesized as a reference, compound INT-2 was substituted for compound 67a, and compound 167 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.57 - 7.49 (m, 4H), 7.39 (s, 1H), 7.16 (d, J = 7.0 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.69 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.78 - 3.71 (m, 2H), 3.59 - 3.53 (m, 1H), 3.58 (s, 3H), 3.42 (s, 2H), 2.54 - 2.53 (m, 2H), 2.11 - 2.04 (m, 3H), 2.00 (s, 3H), 1.75 - 1.70 (m, 6H), 1.67 - 1.63 (m, 1H), 1.60 - 1.54 (m, 6H); MS (ESI): m / z 828.1 (M+H).

[0591] Example 168

[0592]

change

[0593] Compound 133 was synthesized as a reference, compound INT-2 was substituted for compound INT-18, and compound 168 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.55 - 7.50 (m, 4H), 7.39 (s, 1H), 7.19 - 7.11 (m, 2H), 7.01 - 6.97 (m, 2H), 6.69 (s, 1H), 5.72 (s, 2H), 3.87 (s, 3H), 3.75 - 3.70 (m, 2H), 3.58 (s, 3H), 3.42 (s, 2H), 3.36 - 3.35 (m, 1H), 2.53 - 2.52 (m, 2H), 2.12 - 2.07 (m, MS (ESI): m / z 842.1 (M+H).

[0594] Example 169

[0595] [ka]

[0596] Compound 169 was obtained by referring to the synthesis of compound 137, substituting 2-methyl-1,3-dibromobenzene for 2-chloro-1,3-dibromobenzene. 1H NMR (500 MHz, DMSO-d6) δ 7.81 (d, J = 7.5 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.73 - 7.69 (m, 2H), 7.51 - 7.44 (m, 2H), 7.42 - 7.37 (m, 1H), 7.35 - 7.29 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 5.81 (s, 2H), 3.90 (s, 3H), 3.75 - 3.67 (m, 2H), 3.66 - 3.59 (m, 1H), 3.37 (s, 3H), MS (ESI): m / z 792.2 (M+H).

[0597] Example 170

[0598] [ka]

[0599] 0 o Under C conditions, a solution of sodium nitrite (10 g, 147 mmol) in water (50 mL) was slowly added dropwise to a mixture of acetonitrile and water (250 mL, v / v = 3 / 2) containing 2-amino-5-bromo-3-methoxypyrazine (2 g, 9.8 mmol) and hydroiodic acid (57% w / w, 50 mL). The reaction mixture was stirred and heated to 50°C. oThe temperature rose to C and the mixture was allowed to react under these conditions for 16 hours. The reaction mixture was neutralized with 20% aqueous sodium hydroxide and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated sodium thiosulfate solution and saturated brine (150 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a brown solid 170a (1.55 g, yield: 50.2%).

[0600] Nitrogen atmosphere and -40 o Under the conditions of C, isopropylmagnesium chloride-lithium chloride (1.3 M in tetrahydrofuran, 1.83 mL) was slowly added dropwise to a solution of compound 170a (500 mg, 1.6 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred for another half hour under the same conditions. o After the temperature was raised to 15°C, N,N-dimethylformamide (1.2 mL) was slowly added. o The mixture was stirred for an additional 2 hours under C conditions. The reaction mixture was neutralized with citric acid and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to give a pale yellow solid 170b (300 mg, yield: 87.1%). MS (ESI): m / z 217.0 (M+H).

[0601] Compound 170 was obtained from compound 165b and 3-bromo-2-methylphenol by referring to the synthesis of compound INT-10 and compound 133. 1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.81 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.44 - 7.37 (m, 3H), 7.09 (d, J = 7.0 Hz, 1H), 6.66 (s, 1H), 5.70 (s, 2H), 3.95 (s, 3H), 3.87 (s, 2H), 3.63 - 3.60 (m, 1H), 3.57 (s, 3H), 3.41 (s, 2H), 2.60 - 2.57 (m, 2H), 2.11 (s, 3H), 2.10 - 2.02 (m, 3H), 1.99 (s, 3H), 1.73 - 1.67 (m, 7H), 1.58 - 1.53 (m, 6H); MS (ESI): m / z 792.1 (M+H).

[0602] Example 171

[0603] [ka]

[0604] Compound 171 was obtained from compound INT-16, methyl trans-4-aminocyclohexanecarboxylate hydrochloride, and tert-butyldimethylsiloxaneacetaldehyde, following the synthesis of compound 125. 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.60 - 7.50 (m, 5H), 7.17 (d, J = 7.1 Hz, 1H), 7.09 - 6.99 (m, 2H), 6.69 (s, 1H), 5.73 (s, 2H), 3.89 (s, 3H), 3.85 - 3.80 (m, 2H), 3.78 - 3.47 (m, 5H), 3.60 (s, 3H), 2.56 - 2.53 (m, 2H), 2.16 - 2.04 (m, 5H), 1.94 - 1.87 (m, 2H), 1.81 - 1.65 (m, 4H), 1.63 - 1.53 (m, 1H), 1.31 - 1.20 (m, 4H); MS (ESI): m / z 832.0 (M+H).

[0605] Example 172

[0606]

change

[0607] Compound 135 was synthesized as a reference, compound INT-2 was substituted for compound INT-18, and compound 172 was obtained. 1H NMR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.57 - 7.47 (m, 4H), 7.17 - 7.12 (m, 2H), 7.01 - 6.96 (m, 2H), 5.81 (s, 2H), 3.88 (s, 3H), 3.76 - 3.69 (m, 2H), 3.38 (s, 3H), 3.36 - 3.29 (m, 3H), 2.57 - 2.53 (m, 2H), 2.15 - 2.05 (m, 2H), 2.00 (s, 3H), 1.79 - 1.68 (m, 8H), 1.60 - 1.52 (m, 7H), 1.35 - 1.28 (m, 1H); MS (ESI): m / z 843.1 (M+H).

[0608] Example 173

[0609] [ka]

[0610] Methyl 3-chloro-4-methylbenzoate (100 mg, 0.54 mmol) was dissolved in concentrated sulfuric acid (2 mL) and 0 o Under C conditions, potassium nitrate (55 mg, 0.54 mmol) dissolved in concentrated sulfuric acid (1 mL) was added dropwise. The reaction mixture was stirred under the same conditions for 30 minutes. The mixture was then poured into ice water and extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give colorless oil 173a (100 mg, yield: 80.4%). 1 H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.93 (s, 1H), 3.83 (s, 3H), 2.44 (s, 3H). Compound 173a and methyl trans-4-aminocyclohexanecarboxylate hydrochloride were subjected to the synthesis of compound 72c and the reductive amination described in compound 44 to give compound 173c. MS (ESI): m / z 549.0 (M+H).

[0611] Zinc powder (44 mg, 0.67 mmol) was added to a solution of compound 173c (74 mg, 0.13 mmol) in acetic acid (4 mL). o The mixture was heated under C conditions and stirred for 2 hours. The reaction mixture was concentrated, and then ethyl acetate (20 mL) and saturated sodium bicarbonate solution (20 mL) were added. The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 173d. MS (ESI): m / z 519.0 (M+H).

[0612] Compound 173d was obtained from compound INT-18 and compound INT-2, in the order of Suzuki reaction of compound INT-7, reductive amination reaction of compound INT-3b, and ester hydrolysis reaction of compound 33. 1 H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.64 (s, 1H), 7.55 - 7.46 (m, 4H), 7.15 (d, J = 7.0 Hz, 1H), 7.04 (s, 1H), 6.98 - 6.96 (m, 2H), 6.23 (s, 1H), 5.60 (s, 2H), 5.38 (s, 2H), 3.86 (s, 3H), 3.73 (d, J = 4.3 Hz, 2H), 3.58 - 3.56 (m, 1H), 3.42 (s, 2H), 2.53 - 2.50 (m, 2H), 2.34 - 2.30 (m, 1H), 2.23 (brs, 1H), 2.10 - 1.95 (m, 3H), 2.03 (s, 3H), 1.92 - 1.86 (m, 2H), 1.77 -1.71 (m, 2H), 1.66 - 1.61 (m, 1H), 1.32 - 1.18 (m, 4H); MS (ESI): m / z 787.8 (M+H).

[0613] Test Example Detection of the biological activity of PD-1 / PD-L1 signaling inhibition at the cellular level This detection method is used to evaluate the biological activity of the compounds described in the present invention at the cellular level.

[0614] Experimental principle: This detection method uses a luciferase reporter gene assay to detect the biological activity of compounds inhibiting PD-1 / PD-L1 signaling at the cellular level. PD-1 / NFAT-reporter-Jurkat cells stably express human PD-1 and a luciferase reporter gene regulated by NFAT elements. TCR activator / PD-L1-CHO cells stably express human PD-L1 and TCR activator. When the two cell lines are co-cultured, PD-1 / PD-L1 binding inhibits the TCR signaling pathway and inhibits downstream NFAT-controlled luciferase reporter gene expression. Addition of a PD-1 / PD-L1 antibody or inhibitor reverses this inhibition, resulting in luciferase expression, allowing the effect of PD-1 / PD-L1 inhibitors on luciferase activity to be detected.

[0615] Experimental materials and equipment PD-1 / NFAT-reporter-Jurkat cells (catalog no. 60535) and TCR activator / PD-L1-CHO cells (catalog no. 60536) were purchased from BPS Biosciences. PD-L1 antibody (atezolizumab, catalog no. A2004) was purchased from Selleck. Luciferase detection reagent (ONE-Glo® Luciferase Assay System, catalog no. E6120) was purchased from Promega. A multipurpose microplate reader (model SpectraMax i3x) was purchased from Molecular Devices.

[0616] Main experimental procedures PD-1 / NFAT-reporter-Jurkat cells and TCR activator / PD-L1-CHO cells were cultured according to standard cell culture procedures.

[0617] TCR activator / PD-L1-CHO cells were harvested and seeded at 35,000 cells / well into a 96-well culture plate in 100 μL of medium and incubated overnight at 37°C. The next day, the medium was discarded, and compounds were added and incubated for 30 minutes. Simultaneously, a solvent control (dimethyl sulfoxide (DMSO), final concentration 0.1%) and a PD-L1 antibody (atezolizumab, final concentration approximately 10 nM) positive control were also used. PD-1 / NFAT-reporter-Jurkat cells were added. After a further 6 hours of incubation, luciferase activity was detected according to the luciferase detection reagent instructions.

[0618] Using PD-L1 antibody as a positive control, the PD-1 / PD-L1 binding inhibition rate (%) of test compounds was calculated as follows: (chemiluminescence value of compound-treated wells / mean chemiluminescence value of solvent control wells - 1) / (mean chemiluminescence value of PD-L1 antibody wells / mean chemiluminescence value of solvent control wells - 1) × 100%.

[0619] The biological activity of the compounds described in the present invention at the cellular level was evaluated using the above detection method. The activity results are shown in the table below.

[0620] [Table 2-1]

[0621] [Table 2-2]

[0622] [Table 2-3]

[0623] These results demonstrate that the developed compound is effective in suppressing PD-1 / PD-L1 and has good PD-1 / PD-L1 inhibitory activity.

Claims

【Request 1】 【Chemistry 1】 L １ Ha-CR Ａ R Ｂ -, -C(O)-, L ２ , L ３ Ha- (CR Ｃ R Ｄ ) ｐ , -(CR Ｃ R Ｄ ) ｐ -NR ａ - (CR Ｃ R Ｄ ) ｑ -, - (CR Ｃ R Ｄ ) ｐ -O-(CR Ｃ R Ｄ ) ｑ -, -C(O)-, W １ , W ２ are each independently CR Ｌ or N, R １ are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, or -NR ａ R ｂ or C substituted by 0, 1, 2 or 3 substituents １ -C ６ Alkyl group, -O(C １ -C ６ alkyl group), or -O(C ０ -C ６ alkylene)(3-6 membered heterocycloalkyl group), the substituent being -OR ａ , cyano group, oxo, halogen, C １ -C ６ Alkyl group, -(C １ -C ６ Alkylene) OR ａ , cyano group C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ３ -C ８ Cycloalkyl group, —C(O)R ａ , -(C １ -C ６ alkylene)C(O)R ａ , -C(O)OR ａ , -(C １ -C ６ alkyl group)C(O)OR ａ , -NR ａ R ｂ , -(C １ -C ６ Alkylene)NR ａ R ｂ , -C(O)NR ａ R ｂ , -SO ２ R ａ , -C(O)NR ａ SO ２ R ｂ , -NR ａ C(O)R ｂ Selected from R ２ , R ３ , R ４ , R ５ are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, or -NR ａ R ｂ , -SO ２ R ａ , C １ -C ６ Alkyl group, -O(C １ -C ６ alkyl group), or halo(C １ -C ６ alkyl group), Cy is 0, 1, 2, or 3 R ６ wherein the six-membered heteroaryl group optionally contains one or two nitrogen atoms, and the R ６ is hydrogen, halogen, nitro group, cyano group, -NR ａ R ｂ , -SO ２ R ａ , -S(O)R ａ Or -P(O)R ａ R ｂ or C substituted by 0, 1, 2 or 3 substituents １ -C ６ Alkyl group, C ３ -C ６ Cycloalkyl groups, -O(C １ -C ６ alkyl group), -O(C ０ -C ６ Alkylene) (C ３ -C ６ cycloalkyl group) or -O(C ０ -C ６ alkylene)(3-6 membered heterocycloalkyl group), the substituent being -OR ａ , cyano group, oxo, halogen, C １ -C ６ Alkyl group, -(C １ -C ６ Alkylene) OR ａ , cyano group C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C ３ -C ８ Cycloalkyl group, —C(O)R ａ , -(C １ -C ６ alkylene)C(O)R ａ , -C(O)OR ａ , -(C １ -C ６ alkylene)C(O)OR ａ , -NR ａ R ｂ , -(C １ -C ６ Alkylene)NR ａ R ｂ , -C(O)NR ａ R ｂ , -SO ２ R ａ , -C(O)NR ａ SO ２ R ｂ , -NR ａ C(O)R ｂ Selected from R Ｌ is hydrogen, C １ -C ６ Alkyl group, -O(C １ -C ６ alkyl group), -O(C ３ -C ６ cycloalkyl group), halogen, nitro group, cyano group, -NR ａ R ｂ , Haro (C １ -C ６ Alkyl group) or C ３ -C ６ represents a cycloalkyl group, T is optionally substituted with 0, 1 or 2 substituents. 【Chemistry 2】 wherein the substituents are selected from C 1 -C 6 alkyl groups, -OR a , -(C 0 -C 6 alkylene)C(O)OR a , and -(C 0 -C 6 alkenyl)C(O)OR a , and α represents 1, 2, or 3; or T is optionally substituted with 0, 1 or 2 substituents. 【Chemistry 3】 wherein said substituents are selected from C 1 -C 6 alkyl groups, -OR a and halogen, R e represents hydrogen or a C 1 -C 6 alkyl group, α represents 1, 2, 3 or 4, or T is 【Chemistry 4】 represents A is optionally substituted with 0, 1 or 2 substituents. 【Chemistry 5】 wherein the substituents are selected from C 1 -C 6 alkyl groups, -OR a , -(C 0 -C 6 alkylene)C(O)OR a , and -(C 0 -C 6 alkenyl)C(O)OR a , and α represents 1, 2, or 3; or A is optionally substituted with 0, 1 or 2 substituents. 【Chemistry 6】 wherein said substituents are selected from C 1 -C 6 alkyl groups, -OR a and halogen, R e represents hydrogen or a C 1 -C 6 alkyl group, α represents 1, 2, 3 or 4, or A is 【Chemistry 7】 represents R Ａ , R Ｂ are each independently hydrogen, C １ -C ６ Alkyl group, halo(C １ -C ６ alkyl group) or halogen; R Ｃ , R Ｄ are each independently hydrogen, C １ -C ６ Alkyl group, halo(C １ -C ６ alkyl group) or halogen; R ａ , R ｂ are each independently hydrogen, C １ -C ６ Alkyl group, halo(C １ -C ６ Alkyl group), -(C ０ -C ６ alkylene)OH, -(C ０ -C ３ Alkylene) (C ３ -C １２ Cycloalkyl group), -(C ０ -C ３ alkylene)(3- to 12-membered heterocycloalkyl group), -(C ０ -C ３ Alkylene) (C ６ -C １０ member aromatic ring), -(C ０ -C ３ alkylene) (5-10 membered heteroaromatic ring) or halo (C １ -C ６ alkyl group), or R ａ and R ｂ form a 3- to 6-membered ring together with their co-bonding atoms, m and o each independently represent 0, 1 or 2; p and q each independently represent 0, 1, 2 or 3; A compound of formula (I) or a pharma- ceutically acceptable salt, isotopic derivative, or solvate thereof.

2. The compound of formula (I) has the structure of formula (III): 【Chemistry 8】 R １ , R ２ , R ３ , R ４ , R ５ , R ６ , L １ , L ２ , L ３ ,T.A.,W. １ , W ２ , m, o are defined as in claim 1; r represents 0, 1, 2 or 3; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt, isotopic derivative, or solvate thereof.

3. The compound of formula (I) has the structure of formula (IV): 【Chemistry 9】 R １ , R ２ , R ３ , R ４ , R ５ , R ６ , L １ , L ２ , L ３ ,T.A.,W. １ , W ２ , m, o are defined as in claim 1; W ３ is CR Ｍ or N, R Ｍ is hydrogen, C １ -C ６ Alkyl group, -O(C １ -C ６ alkyl group), -O(C ３ -C ６ cycloalkyl group), halogen, nitro group, cyano group, -NR ａ R ｂ , Haro (C １ -C ６ Alkyl group) or C ３ -C ６ represents a cycloalkyl group, r represents 0, 1 or 2; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt, isotopic derivative, or solvate thereof.

4. The compound of formula (I) has the structure of formula (V): 【Chemistry 10】 R １ , R ２ , R ３ , R ４ , R ５ , R ６ , L １ , L ２ , L ３ ,T.A.,W. １ , W ２ , m, o are defined as in claim 1; W ４ is CR Ｎ or N, R Ｎ is hydrogen, C １ -C ６ Alkyl group, -O(C １ -C ６ alkyl group), -O(C ３ -C ６ cycloalkyl group), halogen, nitro group, cyano group, -NR ａ R ｂ , Haro (C １ -C ６ Alkyl group) or C ３ -C ６ represents a cycloalkyl group, r represents 0, 1 or 2; 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt, isotopic derivative, or solvate thereof.

5. L １ But -CR Ａ R Ｂ -, R Ａ and R Ｂ 2. The compound of claim 1, wherein each is independently selected from hydrogen, halogen, C1-C6 alkyl, and halo(C1-C6 alkyl).

6. L ２ and L ３ Each independently represents -CR Ｃ R Ｄ --and--CR Ｃ R Ｄ -NR ａ - (CR Ｃ R Ｄ ) ｑ -, q is selected from 0, 1 or 2, R Ｃ and R Ｄ are each independently hydrogen, halogen, or C １ -C ６ Alkyl groups and halo(C １ -C ６ alkyl group), R ａ are each independently hydrogen, C １ -C ６ Alkyl group, halo(C １ -C ６ Alkyl group), -(C ０ -C ３ Alkylene) C ３ -C １２ The compound according to any one of claims 1 to 3, which is selected from cycloalkyl groups.

7. W １ , W ２ Each independently represents CH or N.

8. W ３ The compound according to claim 3, wherein represents CH or N.

9. T and A are independent of each other. 【Chemistry 11】 2. The compound according to claim 1 , wherein

10. T and A are independent of each other. 【Chemistry 12】 represents R ｅ is hydrogen or C １ -C ６ 2. The compound according to claim 1, wherein:

11. R １ HA -O(C １ -C ６ The compound according to any one of claims 1 to 10, wherein R is an alkyl group.

12. R ２ is hydrogen, halogen, nitro group, cyano group, -SO ２ R ａ , C １ -C ６ Alkyl group, halo(C １ -C ６ Alkyl group) or C ３ -C ６ A compound according to any one of claims 1 to 10, which represents a cycloalkyl group.

13. R ３ and R ４ The compound according to any one of claims 1 to 10, wherein each independently represents hydrogen or halogen.

14. R ５ is hydrogen, halogen, cyano group, C １ -C ６ Alkyl group, halo(C １ -C ６ Alkyl group) or C ３ -C ６ A compound according to any one of claims 1 to 10, which represents a cycloalkyl group.

15. R ６ is hydrogen, halogen, C １ -C ６ Alkyl group, halo(C １ -C ６ alkyl group) or C ３ -C ６ -O(C) substituted with 0, 1, 2, or 3 substituents or １ -C ６ alkyl group) or -O(C ０ -C ６ Alkylene) (C ３ -C ６ 11. The compound according to claim 1, wherein the substituents are selected from halogen.

16. R Ｌ The compound according to any one of claims 1 to 10, wherein represents hydrogen or halogen.

17. R Ｍ The compound of claim 3 , wherein represents hydrogen.

18. R Ｎ The compound of claim 4 , wherein represents hydrogen.

19. A compound having any of the following structures: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and optionally a pharma- ceutically acceptable carrier.

21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 in the manufacture of a medicament for the prevention or treatment of a disease or condition responsive to inhibition of binding between PD-L1 and PD-1.

22. 22. The use according to claim 21, wherein the disease or condition is selected from the group consisting of a tumor, a cancer, a viral infection, an inflammation-related disease, and an autoimmune disease.

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