Compounds with IRAK4 inhibitory activity, pharmaceutical compositions containing them, and their applications.

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to compounds having IRAK4 inhibitory activity, pharmaceutical compositions comprising the same, and their applications. This invention provides a compound having the structure of formula (I) as an effective inhibitor of IRAK4, capable of being used for the prevention and / or treatment of diseases and / or conditions responding to IRAK4.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a acetamide compound with MyD88 / IRAK4 pathway inhibitory activity, compositions containing the same, and the use of the acetamide compound in medicine, particularly for the prevention and / or treatment of diseases (including various diseases such as tumors, inflammatory diseases, autoimmune diseases, neurodegenerative diseases, metabolic diseases, and genetic diseases) that respond to IRAK4 receptor inhibition. Prior Technology

[0002] Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine / threonine protein kinase that plays a crucial role in inflammatory signaling pathways mediated by the interleukin receptor family (IL-1, IL-18, IL-33) and the Toll-like receptor family (except TLR3) (Clin. Immunol. 2010, 135, 210-222). Animal studies have shown that mice with IRAK4 protein knockout can prevent the transmission of signaling pathways mediated by IL-1R or TLR and the release of related cytokines (Nature 2002, 416, 750-756). Increasing evidence suggests that IRAK4 is a highly attractive target in inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus.

[0003] As a key adaptor in the Toll-like signaling pathway, IRAK4 can form the protein complex Myddosome via its death domain (DD) with myeloid differentiation factor (MyD88) and downstream IRAK1 / 2 (Nature 2010, 465, 885-890). In this complex, IRAK4 is first activated by trans-autophosphorylation, subsequently activating IRAK1 / 2 and downstream NF-κB and MAPK signaling pathways (Mol. Cell 2014, 55, 891-903). Therefore, the kinase activity and scaffold function of IRAK4 play crucial roles in the transmission of inflammatory signals. Increasing experimental evidence demonstrates that inhibiting the kinase activity of IRAK4 through gene editing or small molecule compounds can reduce the expression of inflammatory factors in vitro and in vivo, alleviating symptoms of related inflammatory phenotypes (J. Med. Chem. 2015, 58, 96-110). Furthermore, an increasing number of studies (Am. J. Clin. Pathol. 2013, 140, 387-394.) report that MyD88 has acquired functional mutations in some hematologic malignancies (29% of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), Waldenström macroglobulinemia (WM), etc.), suggesting that regulation of IRAK4 may also have a therapeutic effect on some hematologic cancers.

[0004] Currently, there are no marketed drugs targeting IRAK4, but many pharmaceutical companies are already investing in this area. Pfizer's PF-06650833 is the first IRAK4 inhibitor to enter clinical trials (J. Med. Chem. 2017, 60, 5521-5542), currently in Phase II trials for the treatment of rheumatoid arthritis and hidradenitis suppurativa. In addition, Bayer has launched two IRAK4 inhibitors (BAY-1830839 and BAY-1834845) in recent years, currently in Phase I clinical trials. Rigel's R-835 has also entered Phase I clinical trials. The indications for Bayer and Rigel's IRAK4 inhibitors are mainly in the areas of autoimmune diseases, inflammation, and ABC-DLBCL. It is worth mentioning that Curis's IRAK4 small molecule inhibitor CA4948 has attracted widespread attention due to its positive effects in six patients with relapsed AML / MDS (ACS Med. Chem. Lett. 2020, 11, 2374-2381). In conclusion, the development of IRAK4 small molecule inhibitors is a research direction with great clinical value. Summary of the Invention

[0005] [The problem the invention aims to solve] The purpose of this invention is to provide a compound having IRAK4 inhibitory activity, a pharmaceutical composition comprising the compound, and its application.

[0006] [Solutions for solving the problem] The objective of this invention is achieved through the following technical solution:

[0007] <First Aspect>

[0008] This invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope label, or isomer thereof: in, Ring A is selected from one of the following structures: , , and ; Each n is independently selected from 0, 1, 2, and 3; X 1 is selected from O and S; X 2 is selected from N and CH; If present, R1 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, NH (C1-6 alkyl), N (C1-6 alkyl)2, NH (C3-6 cycloalkyl), N (C3-6 cycloalkyl)2, C1-6 alkyl, 3 to 8-membered heterocyclic, 6 to 10-membered bridged heterobicyclic, 5 to 12-membered spiroheterocyclic, 6 to 12-membered denoted heterobicyclic, C6-10 aryl, and 5 to 10-membered heteroaryl, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, bridged heterobicyclic, spiroheterocyclic, and denoted heterobicyclic is optionally surrounded by 1, 2, or 3 Rs. α-substitution; if present, the heteroatom or heterogroup in the heterocyclic group, bridged heterobicyclic group, spiroheterobicyclic group, fused heterobicyclic group, and heteroaryl group is independently selected from O, S, NH, N, P(=O), S(=O), and S(=O) 2; R2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C3-6 cycloalkyl), N(C3-6 cycloalkyl)2, hydroxyl, OC1-6 alkyl, O-3 to 8-membered heterocyclic, OC3-6 cycloalkyl, 3 to 8-membered heterocyclic, 6 to 10-membered bridged heterobicyclic, 5 to 12-membered spirobicyclic, 6 to 12-membered denoted heterobicyclic, C6-10 aryl, and 5 to 10-membered heteroaryl, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, bridged heterobicyclic, spirobicyclic, and denoted heterobicyclic is optionally surrounded by 1, 2, or 3 Rs. b-substitution; if present, the heteroatom or heterogroup in the heterocyclic group, bridged heterobicyclic group, spirobicyclic group, denoted heterobicyclic group, and heteroaryl group is independently selected from O, S, NH, N, P(=O), S(=O), and S(=O)2; preferably, R2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C3-6 cycloalkyl), N(C3-6 cycloalkyl)2, C1-6 alkyl, 3 to 8-membered heterocyclic group, 6 to 10-membered bridged heterobicyclic group, 5 to 12-membered spirobicyclic group, 6 to 12-membered denoted heterobicyclic group, C 6-10 aryl and 5-10 heteroaryl groups, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, bridged heterobicyclic, spirocyclic, and fused heterobicyclic groups is optionally substituted by 1, 2, or 3 Rb groups; if present, the heteroatom or heterogroup in each of the heterocyclic, bridged, spirocyclic, fused heterobicyclic, and heteroaryl groups is independently selected from O, S, NH, N, P(=O), S(=O), and S(=O) 2; If present, R5 and R6 are each independently selected from hydrogen, deuterium, C1-6 alkyl, C3-6 cycloalkyl, and C1-2 alkylene-C3-6 cycloalkyl, wherein each alkyl group is optionally substituted by 1, 2, or 3 Rc atoms; or, R5 and R6 together with the carbon atoms to which they are attached form a saturated five- or six-membered spiroheterocycle, wherein the heteroatoms in the five- or six-membered spiroheterocycle are each independently selected from oxygen, nitrogen, and sulfur, and each five- or six-membered spiroheterocycle is optionally substituted by 1, 2, or 3 Rc atoms. If present, R7 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, and five- or six-membered heterocyclic groups, wherein each of the alkyl, cycloalkyl, and heterocyclic groups is optionally substituted by one, two, or three Rc; if present, each of the heteroatoms in the five- or six-membered heterocyclic group is independently selected from oxygen, nitrogen, and sulfur; If present, R8 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, and five- or six-membered heterocyclic groups; R9, R10, R11, and R12 are each independently selected from hydrogen, deuterium, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, and five- or six-membered heterocyclic groups, wherein each alkyl, cycloalkyl, and heterocyclic group is optionally substituted by one, two, or three Rc groups; if present, the heteroatoms in the five- or six-membered heterocyclic groups are each independently selected from oxygen, nitrogen, and sulfur; or, R9 and R10 together with the carbon atom to which they are attached form a carbonyl group; The Z1 ring is selected from one of the following groups: 1) Having one to three heteroatoms, each independently selected from nitrogen, oxygen, and sulfur, in a five- or six-membered heteroaryl group; 2) Phenyl; 3) Having one or two partially or fully saturated five- or six-membered heterocyclic groups, each independently selected from oxygen and nitrogen; 4) Having one to three heteroatoms, each independently selected from nitrogen, oxygen, and sulfur, consisting of 7 to 10 fused heterobicyclic groups; 5) Partially or fully saturated C3-6 cycloalkyl groups; The Z2 ring is missing; when missing, Rd replaces the Z2 ring and connects to the Z1 ring; or, the Z2 ring is selected from one of the following groups: 1) Having one to four five- or six-membered heteroaryl groups, each independently selected from nitrogen, oxygen, and sulfur; 2) Phenyl; 3) Having one or two partially or fully saturated five- or six-membered heterocyclic groups, each independently selected from oxygen and nitrogen; 4) Partially or fully saturated C3-6 cycloalkyl groups; If present, each Ra is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, tert-butoxycarbonyl, methylaminomethoxy, C1-2 alkylene-hydroxy, C1-2 alkylene-methoxy, and C1-2 alkylene-deuterated methoxy; If present, each Rb is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, cyano, C1-3 alkyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, C1-2 alkylene-hydroxy, C1-2 alkylene-methoxy, and C1-2 alkylene-deuterated methoxy; or, two Rb from any non-adjacent carbon atoms can form a bridged ring through one or two carbon atoms; or, two Rb from the same carbon atom and the carbon atom to which they are attached together form a carbonyl group; If present, each Rc is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, and deuterated methoxy; If present, each Rd is independently selected from hydrogen, deuterium, methyl, deuterated methyl, ethyl, cyclopropyl, C1-2 alkylene-hydroxy, C1-2 alkylene-methoxy, C1-2 alkylene-deuterated methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, and difluoromethoxy; If present, each R3 and R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, nitro, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and dimethylphosphine.

[0009] Preferably, in the compound, Ring A is selected from and ; Each n is independently selected from 0 and 1; X1 is 0; X 2 is N; If present, R1 is a 3- to 8-membered heterocyclic group, which is optionally substituted by 1, 2, or 3 Ra atoms; if present, the heteroatoms or heterogroups in the heterocyclic group are each independently selected from O, NH, and N; R2 is selected from NH (C 1-6 alkyl), N (C 1-6 alkyl) 2, NH (C 3-6 cycloalkyl), N (C 3-6 cycloalkyl) 2, hydroxyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, O-3 to 8-membered heterocyclic group, 3 to 8-membered heterocyclic group, 6 to 10-membered bridged heterobicyclic group, 5 to 12-membered spiroheterocyclic group, and 6 to 12-membered fused heterobicyclic group, wherein each of the alkyl, cycloalkyl, heterocyclic group, bridged heterobicyclic group, spiroheterocyclic group, and fused heterobicyclic group is optionally substituted by 1, 2, or 3 Rb; if present, the heteroatom or heterogroup in each of the heterocyclic group, bridged heterobicyclic group, spiroheterocyclic group, and fused heterobicyclic group is independently selected from O, NH, and N; If present, R5 and R6 are each independently C1-6 alkyl; The Z1 ring is selected from one of the following groups: 1) Having one to three five- or six-membered heteroaryl groups, each independently selected from nitrogen and oxygen; 2) Phenyl; 3) Having one to three 7- to 10-membered fused heterobicyclic groups, each independently selected from nitrogen and oxygen; The Z2 ring is missing; when missing, Rd replaces the Z2 ring and connects to the Z1 ring; or, the Z2 ring is selected from one of the following groups: 1) Having one to four five- or six-membered heteroaryl groups, each independently selected from nitrogen and oxygen; 2) C3-6 cycloalkyl; If present, each Ra is independently selected from hydrogen, hydroxyl, methyl, ethyl, and C1-2 alkylene-hydroxyl; If present, each Rb is independently selected from hydrogen, fluorine, hydroxyl, amino, methylamino, dimethylamino, C1-3 alkyl, methoxy, cyclopropyl, C1-2 alkylene-hydroxy, and C1-2 alkylene-methoxy; If present, each Rd is independently selected from hydrogen, methyl, ethyl, trifluoromethyl, and difluoromethyl; If present, each R3 and R4 is independently selected from hydrogen, fluorine, cyano, methyl, ethyl, methoxy, and dimethylphosphine.

[0010] More preferably, in the compound, Ring A is selected from and ; Each n is independently selected from 0 and 1; X1 is 0; X 2 is N; If present, R1 is a 6-membered heterocyclic group, which is optionally substituted by one Ra; if present, the heteroatom or heterogroup in the heterocyclic group is independently selected from O, NH and N; R2 is selected from NH (C 1-6 alkyl), N (C 1-6 alkyl) 2, NH (C 3-6 cycloalkyl), N (C 3-6 cycloalkyl) 2, hydroxyl, OC 1-6 alkyl, OC 3-6 cycloalkyl, O-3 to 8-membered heterocyclic group, 3 to 8-membered heterocyclic group, 6 to 10-membered bridged heterobicyclic group, 5 to 12-membered spiroheterocyclic group, and 6 to 12-membered fused heterobicyclic group, wherein each of the alkyl, cycloalkyl, heterocyclic group, bridged heterobicyclic group, spiroheterocyclic group, and fused heterobicyclic group is optionally substituted by 1, 2, or 3 Rb; if present, the heteroatom or heterogroup in each of the heterocyclic group, bridged heterobicyclic group, spiroheterocyclic group, and fused heterobicyclic group is independently selected from O, NH, and N; If present, R5 and R6 are each independently C1-4 alkyl groups; The Z1 ring is a six-membered heteroaryl group having one or two heteroatoms, each independently selected from nitrogen and oxygen, preferably pyridyl; The Z 2 ring is selected from one of the following groups: 1) Having one or two five-membered heteroaryl groups, each independently selected from nitrogen and oxygen, preferably pyrazolyl; 2) C3-6 cycloalkyl, preferably cyclopropyl; If present, each Ra is independently selected from hydrogen, hydroxyl, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, and 2-hydroxyethyl; If present, each Rb is independently selected from hydrogen, fluorine, hydroxyl, amino, methylamino, dimethylamino, methyl, ethyl, methoxy, cyclopropyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-methoxyethyl, and 2-methoxyethyl; If present, each Rd is independently selected from hydrogen, methyl, ethyl, trifluoromethyl, and difluoromethyl; If present, each R3 and R4 is independently selected from hydrogen, fluorine, cyano, methyl, ethyl, methoxy, and dimethylphosphine.

[0011] Preferably, the compound has the structure of formula (IA): Wherein, n, X1, Z1, Z2, R1, R2, R3, and R4 are as defined above; Preferably, it has the structure of formula (I-A1): Wherein, n, Z1, Z2, R1, R2, R3, and R4 are as defined above; More preferably, it has a structure of formula (I-A2): R1 and R2 are defined as above.

[0012] Alternatively, preferably, the compound has the structure of formula (IB): Wherein, n, Z1, Z2, R2, R3, R4, R5, and R6 are as defined above; Preferably, it has the structure of formula (I-B1): Wherein, n, Z1, Z2, R2, R3, and R4 are as defined above; More preferably, it has a structure of formula (I-B2): R2 is defined as above.

[0013] More preferably, in compounds having the structure of formula (I), formula (IA), formula (I-A1), formula (IB), or formula (I-B1), Z1 is selected from five- or six-membered heteroaryl groups, phenyl groups having one to three heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and seven to ten-membered fused heterobicyclic groups having one to three heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

[0014] More preferably, when the Z2 ring exists, Selected from one of the following excerpts: , One of the following segments is preferred: , or, One of the following segments is preferred: , More ; When the Z2 ring is missing, Selected from one of the following excerpts: , One of the following segments is preferred: , More preferably, one of the following segments: .

[0015] More preferably, in compounds having the structure of formula (I), formula (IA), formula (I-A1), formula (IB), or formula (I-B1), When the Z2 ring exists, Selected from one of the following excerpts: , One of the following segments is preferred: , or, One of the following segments is preferred: , More ; When ring Z2 is missing, Rd replaces ring Z2 and connects to ring Z1, as defined above.

[0016] More preferably, in compounds having the structure of formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (IB), formula (I-B1), or formula (I-B2), R1 is selected from one of the following fragments: , One of the following segments is preferred: , More preferably, one of the following segments: , Further select one of the following segments: .

[0017] More preferably, in compounds having the structures of formula (I), formula (IA), formula (I-A1), formula (I-A2), formula (IB), formula (I-B1), or formula (I-B2), R2 is selected from NH (C1-6 alkyl), N (C1-6 alkyl)2, NH (C3-6 cycloalkyl), N (C3-6 cycloalkyl)2, hydroxyl, OC1-6 alkyl, OC3-6 cycloalkyl, O-3 to 8-membered heterocyclic groups, 3 to 8-membered heterocyclic groups, 5 to 12-membered spiroheterocyclic groups, and 6 to 12-membered diacyclic heterocyclic groups, wherein each of the alkyl, cycloalkyl, heterocyclic, spiroheterocyclic, and diacyclic heterocyclic groups is optionally substituted by 1, 2, or 3 Rb, Rb as defined above; preferably, R2 is selected from NH (C1-6 alkyl), N (C1-6 alkyl)2, NH (C3-6 cycloalkyl), N (C3-6 cycloalkyl) 2. OC 1-6 alkyl, 3 to 8 heterocyclic, 5 to 12 spiroheterocyclic and 6 to 12 denominated heterocyclic, wherein each of the alkyl, cycloalkyl, heterocyclic, spiroheterocyclic and denominated heterocyclic is optionally substituted by 1, 2 or 3 Rb as defined above.

[0018] More preferably, R2 is selected from one of the following segments: , One of the following segments is preferred: , or, One of the following segments is preferred: , More preferably, one of the following segments: , Further select one of the following segments: .

[0019] Preferably, the compound has the structure of formula (II): in, Indicates a single or double bond; Y1 is selected from O, S, and CH2; Y2 is selected from CR1 and C(R5)R6; Y3 is selected from N and O; R1, R2, R5 and R6 are defined as above.

[0020] More preferably, in compounds having the structure of formula (II), Selected from one of the following excerpts: , One of the following segments is preferred: .

[0021] More preferably, in compounds having the structure of formula (II), R1 is selected from one of the following fragments: , One of the following segments is preferred: .

[0022] More preferably, in compounds having the structure of formula (II), R2 is selected from one of the following fragments: , One of the following segments is preferred: .

[0023] More preferably, in compounds having the structure of formula (II), R5 and R6 are each independently C1-6 alkyl, preferably methyl.

[0024] <Second aspect>

[0025] This invention provides the following compounds or their pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope-labeled derivatives or isomers: .

[0026] <Third aspect>

[0027] The present invention provides a pharmaceutical composition comprising a compound as described in the first aspect or the second aspect, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope label, or isomer thereof.

[0028] Furthermore, the pharmaceutical composition also comprises at least one pharmaceutically acceptable carrier.

[0029] <Fourth Aspect>

[0030] The present invention provides a pharmaceutical formulation comprising a compound as described in the first aspect or the second aspect, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope label, or isomer thereof, or a pharmaceutical composition as described in the third aspect, wherein the pharmaceutical formulation is any one of tablets, capsules, injections, granules, powders, suppositories, pills, gels, powders, oral solutions, inhalers, suspensions, or dry suspensions.

[0031] <Fifth Aspect>

[0032] The present invention provides a pharmaceutical combination comprising a compound as described in the first or second aspect, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope label, or isomer thereof, or a pharmaceutical composition as described in the third aspect, or a pharmaceutical formulation as described in the fourth aspect.

[0033] <Sixth Aspect>

[0034] The present invention provides the use of compounds as described in the first or second aspect, or pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope-labeled or isomers thereof, or pharmaceutical compositions as described in the third aspect, or pharmaceutical formulations as described in the fourth aspect, or pharmaceutical combinations as described in the fifth aspect, in the preparation of medicaments for the prevention and / or treatment of diseases and / or conditions that are at least partially responsive to IRAK4.

[0035] <Seventh Aspect>

[0036] The present invention provides compounds as described in the first or second aspect, or pharmaceutically acceptable salts, esters, solvates, prodrugs, isotope-labeled or isomers thereof, or pharmaceutical compositions as described in the third aspect, or pharmaceutical formulations as described in the fourth aspect, or pharmaceutical combinations as described in the fifth aspect, for the prevention and / or treatment of diseases and / or conditions that are at least partially responsive to IRAK4.

[0037] <Eighth Aspect>

[0038] This invention provides a method for preventing and / or treating diseases and / or symptoms that are at least partially responsive to IRAK4, comprising the steps of administering a preventive and / or therapeutically effective amount of a compound as described in the first or second aspect, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope label, or isomer thereof, or a pharmaceutical composition as described in the third aspect, or a pharmaceutical formulation as described in the fourth aspect, or a combination of pharmaceuticals as described in the fifth aspect, to a patient in need of it.

[0039] Preferably, the diseases and / or conditions include uveitis, dermatitis, acute lung injury, type II diabetes, arthritis, ulcerative colitis, segmental ileitis, early-onset inflammatory bowel disease, extraintestinal inflammatory bowel disease, prevention of ischemia-reperfusion injury in solid organ transplantation, non-alcoholic fatty liver disease, autoimmune hepatitis, asthma, endometriosis, psoriasis, systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis, pulmonary fibrosis, renal fibrosis, liver fibrosis, myocardial infarction, allergic pneumonia, and interstitial lung disease. Constipation of lung disease, ankylosing spondylitis, multiple sclerosis, systemic sclerosis, polymyositis, rheumatoid arthritis, myasthenia gravis, juvenile-onset diabetes mellitus, glomerulonephritis, autoimmune thyroiditis, graft rejection, Crohn's disease, Brouwer's syndrome, scleroderma, psoriasis, stomatitis, retinitis pigmentosa, proliferative vitreoretinopathy, Best's vitrectomyelitis, eczema, urticaria, vasculitis, eosinophilic fasciitis, wet and dry age-related macular degeneration, diabetes. Diabetic retinopathy, retinopathy of prematurity, diabetic macular erythema, retinal vein occlusion, cystoid macular edema, glaucoma, Parkinson's disease, Alzheimer's disease, Huntington's disease, breast cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, squamous cell carcinoma of the head and neck, thyroid cancer, sarcoma, osteosarcoma, desmoidoma, melanoma, prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, esophageal cancer, gastric cancer, myeloma, lymphoma, mantle cell lymphoma, cutaneous T-cell lymphoma, chronic and non-progressive retinopathy. One or more of the following: anemia, spontaneous or primary thrombocytosis, leukemia, acute leukemia, chronic leukemia, lymphocytic leukemia, myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorders, brain tumor, astrocytoma, medulloblastoma, Schwann cell tumor, primary neuroectodermal tumor, or pituitary tumor; preferably lymphoma, endometriosis, psoriasis, systemic lupus erythematosus, multiple sclerosis, or rheumatoid arthritis; wherein, the lymphoma is preferably a primary central nervous system lymphoma with the MYD88 L265P mutation or a diffuse large B-cell lymphoma.

[0040] [Effects of the Invention] The compounds of the present invention having IRAK4 kinase inhibitory activity can be used as effective inhibitors of IRAK4 and can be used to prevent and / or treat diseases and / or conditions that are at least partially responsive to IRAK4. Simple Explanation of the Diagram

[0041] Other features and effects of the present invention will be clearly presented in the embodiments with reference to the drawings, wherein: Figure 1 shows the compounds synthesized in Examples 4 and 64. [A4] and [B5] Inhibition curve of IRAK4 kinase activity; and Figure 2 shows the compounds synthesized in Examples 4 and 64. [A4] and [B5] Binding ability curve of IRAK4. Implementation

[0042] In order to provide a clearer understanding of the technical features, objectives and beneficial effects of the present invention, the technical solution of the present invention will now be described in detail below, but it should not be construed as limiting the scope of implementation of the present invention.

[0043] To more clearly describe the content of this invention, the terms involved are defined as follows:

[0044] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, alone or in combination, especially fluorine, chlorine, or bromine.

[0045] The term "C1-6 alkyl" alone or in combination refers to a saturated straight-chain or branched alkyl group containing 1 to 6 (particularly 1 to 3) carbon atoms, including (but not limited to) methyl, ethyl, propyl, isopropyl, butyl, dibutyl, isobutyl, tributyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3'-dimethyl-2-butyl, etc. Preferably, "C1-6 alkyl" is any one of methyl, ethyl, n-propyl, isopropyl, and tributyl. Similarly, the term "C1-3 alkyl" alone or in combination refers to a saturated straight-chain or branched alkyl group containing 1 to 3 carbon atoms, including methyl, ethyl, propyl, isopropyl, etc.

[0046] The term “C 1-2 alkylene” alone or in combination refers to a saturated straight-chain or branched alkylene containing one or two carbon atoms, including (but not limited to) methylene, 1,1-ethylene, and 1,2-ethylene.

[0047] The term "OC 1-6 alkyl" alone or in combination represents the "C 1-6 alkyl-O-" group, wherein "C 1-6 alkyl" as defined above includes (but is not limited to) methoxy (-OCH 3), ethoxy (-OCH 2CH 3), n-propoxy (-OCH 2CH 2CH 3), isopropoxy (-OCH(CH 3) 2), n-butoxy (-OCH 2CH 2CH 2CH 3), dibutoxy (-OCH(CH 3)CH 2CH 3), isobutoxy (-OCH 2CH(CH 3) 2), terbutoxy (-OC(CH 3) 3), n-pentoxy (-OCH 2CH 2CH 2CH 2CH 3), and neopentoxy (-OCH 2C(CH 3) 3), etc.

[0048] The term "C 3-6 cycloalkyl" alone or in combination refers to a saturated or partially unsaturated monocyclic or polycyclic cycloalkyl group containing 3 to 6 (especially 3 to 5) carbon atoms, including (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0049] The term "3- to 8-membered heterocyclic group" alone or in combination refers to a saturated or partially unsaturated monocyclic heterocyclic group comprising 3 to 8 (especially 3 to 6, more particularly 5 or 6) carbon atoms and heteroatoms or heteroatom groups for cyclization, wherein the heteroatoms or heteroatom groups are selected from O, S, NH, N, P(=O), S(=O), and S(=O)2. "3- to 8-membered heterocyclic group" includes (but is not limited to) aziridinyl, aziridine, oxo-heterocyclic, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactone, valproic acid, caprolactone, butyrolactone, valproic acid, or caprolactone, etc.

[0050] The term "6- to 10-membered bridged heterobicyclic group" alone or in combination refers to a saturated or partially unsaturated bridged heterobicyclic group comprising 6 to 10 (particularly 6 to 8) carbon atoms and heteroatoms or heteroatom groups for cyclization, wherein the heteroatoms or heteroatom groups are selected from O, S, NH, N, P(=O), S(=O) and S(=O)2. "6- to 10-membered bridged heterobicyclic group" includes (but is not limited to) 3,6-diazabicyclo[3.1.1]hept-1-yl, 3,6-diazabicyclo[3.1.1]hept-3-yl, 3,6-diazabicyclo[3.1.1]hept-6-yl, etc.

[0051] The term "5 to 12-membered spiroheterocyclic bicyclic group" alone or in combination refers to a saturated or partially unsaturated bicyclic group comprising 5 to 12 (especially 6 to 9) carbon atoms and heteroatoms or heteroatom groups for cyclization, the bicyclic groups being interconnected by a single carbon atom, the heteroatoms or heteroatom groups being selected from O, S, NH, N, P(=O), S(=O) and S(=O) 2. "5 to 12-membered spirocyclobicyclic groups" include (but are not limited to) 4,7-diazaspiro[2.5]oct-7-yl, 1-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2,5-diazaspiro[3.4]oct-2-yl, 5-oxa-2-azaspiro[3.4]oct-2-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, etc.

[0052] The term "6- to 12-membered heterocyclic bicyclic group" refers, alone or in combination, to a saturated or partially unsaturated bicyclic group comprising 6 to 12 (particularly 7 to 10) carbon atoms and heteroatoms or heteroatom groups for cyclization, the bicyclic group sharing a single carbon-carbon bond, carbon-hetero-bond, or hetero-hetero-bond, the heteroatom or heteroatom group being selected from O, S, NH, N, P(=O), S(=O), and S(=O)2. "6- to 12-membered heterocyclic bicyclic group" includes (but is not limited to) 3,7-diazabicyclo[3.3.0]oct-3-yl, 3,6-diazabicyclo[3.3.0]oct-3-yl, 2,7-diazabicyclo[3.3.0]oct-2-yl, etc.

[0053] The term "C 6-10 aryl" alone or in combination represents any stable 6- to 10-membered monocyclic or bicyclic aromatic group, including (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindene, or biphenyl.

[0054] The term "5- to 10-membered heteroaryl" alone or in combination refers to any stable 5- to 10-membered monocyclic or bicyclic aromatic group, wherein the carbon atom on the ring is replaced by at least one heteroatom or heteroatom group selected from O, S, NH, N, P(=O), S(=O), and S(=O)2, including (but not limited to) thiophene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridine-2(1H)-keto, pyridin-4(1H)-keto, pyrrolo, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothiophene, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl, etc.

[0055] The term "7- to 10-membered fused heterobicyclic group" refers, alone or in combination, to a fused bicyclic group consisting of one aryl group and one heteroaryl group or two heteroaryl groups, including (but not limited to) benzothiophene, indolyl, benzimidazolyl, pyridiniumimidazolyl, pyraziniumimidazolyl, pyrazolopyrimidinyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl, etc.

[0056] The term "amino group" refers alone or in combination to the first amino group (-NH2), the second amino group (-NH-), or the third amino group (-NH-). ).

[0057] The terms “NH(C 1-6 alkyl)”, “N(C 1-6 alkyl) 2”, “NH(C 3-6 cycloalkyl)”, and “N(C 3-6 cycloalkyl) 2” individually or in combination represent an amino group as defined above, in which the hydrogen atom is replaced by one or two C 1-6 alkyl or C 3-6 cycloalkyl groups, wherein “C 1-6 alkyl” and “C 3-6 cycloalkyl” are as defined above.

[0058] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in SMBerge's description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compounds of the present invention with an organic or inorganic acid, including (but not limited to) hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, and malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of this invention with organic or inorganic bases, including (but not limited to) alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as ammonium salts or N+(C1-6 alkyl)4 salts formed with an organic base containing an N group, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia, triethylamine, or tetrabutylammonium hydroxide, etc. "Pharmaceutically acceptable salts" can be synthesized by conventional chemical methods.

[0059] The term "ester" is used to refer to organic esters, including monoesters, diesters, triesters, and more commonly polyesters.

[0060] The term "solvent" refers to an association formed by one or more solvent molecules with the compounds of this invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0061] The term "prodrug" refers to a chemical derivative of the compound of the present invention, which is converted into the compound represented by general formula I in vivo through a chemical reaction.

[0062] The term "isotope label" indicates that the isotopes include (but are not limited to) 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 32P, 35S, and 36Cl, etc.

[0063] The term "isomer" encompasses all isomeric forms, including enantiomers, diastereomers, tautomers, and geometric isomers (including cis-trans isomers). Therefore, any single stereochemical isomer of the compound designed in this invention, or a mixture of its enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers), is within the scope of this invention.

[0064] The term "independently" means that at least two groups (or ring systems) in a structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0065] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0066] The term “prevention” refers to the complete or near-complete prevention of the occurrence of a disease or condition (e.g., infection, ischemia, or reperfusion injury) when a patient or subject is susceptible to or at risk of disease or condition; prevention may also include suppression, i.e., preventing the development of a condition.

[0067] The term “treatment” means: 1) suppressing the disease; for example, suppressing the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom of the disease (i.e., preventing further development of the pathology and / or symptom); or 2) improving the disease; for example, improving the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom (i.e., reversing the pathology and / or symptom).

[0068] The term "effective amount" refers to the amount of an active compound or agent that researchers, veterinarians, physicians, or other clinicians seek to elicit a biological or medical response in an tissue, system, animal, individual, or human.

[0069] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0070] In the following examples, all solvents and reagents used were of analytical or chemical purity; all solvents were redistilled before use; and all anhydrous solvents were processed according to standard or literature methods.

[0071] The column chromatography silica gel (100-200 mesh) and thin-layer chromatography silica gel (GF254) are products of Qingdao Marine Chemical Plant and Yantai Chemical Plant; unless otherwise specified, petroleum ether (60-90℃) / ethyl acetate (v / v) are used as eluents.

[0072] The colorimetric reagent is an ethanol solution of iodine or phosphomolybdic acid.

[0073] Unless otherwise specified, all extraction solvents were dried over anhydrous Na₂SO₄.

[0074] 1H-NMR was recorded using a Varian-400 nuclear magnetic resonance spectrometer, with TMS as an internal standard.

[0075] LC-MS was recorded using an Agilent Technologies 1100 high-performance liquid chromatography-ion trap mass spectrometry (LC-MSD Trap) system with a diode array detector (DAD) at detection wavelengths of 214 nm and 254 nm, and ion trap mass spectrometry (ESI source).

[0076] The HPLC column was an Agela Durashell C18 (4.6 × 50 mm, 3.5 μm); the mobile phase was 0.1% NH4HCO3 aqueous solution: acetonitrile (from 5:95 to 95:5 within 5 minutes); the flow rate was 1.8 mL / min.

[0077] This invention may use the following abbreviations: NBS (N-bromobutyldiaminoimide); T3P (1-propyl cyclophosphine); DMF (N,N-dimethylformamide); LDA (diisopropylaminolithium); DCE (1,2-dichloroethane); DCM (dichloromethane); TEA (triethylamine); EA (ethyl acetate); THF (tetrahydrofuran); TFA (trifluoroacetic acid); TKB (potassium terbutoxide); DAST (diethylaminosulfur trifluoride); DMEDA (N,N-dimethylethylenediamine); EG (ethylene glycol); Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene); HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea); DIPEA (diisopropylethylamine); Pd(dppf)Cl 2([1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride); Pd(OAc)2(palladium acetate); DPPA(diphenyl azidophosphate).

[0078] [[] [Intermediate]

[10] [The synthesis of] []]

[0079] Synthesis of intermediate 1:

[0080] 2-Chloro-5-hydroxypyridine (12 g, 96 mmol) was dissolved in concentrated sulfuric acid (150 mL), and potassium nitrate (12 g, 116 mmol) was added in portions at 0 °C over 2 hours. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 3 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, and a yellow solid precipitated. The solid was filtered to give yellow intermediate 1 (15.4 g, 91%).

[0081] 1H-NMR (300 MHz, DMSO- d 6): δ 11.94 (s, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H).

[0082] Synthesis of intermediate 2:

[0083] Intermediate 1 (14 g, 83 mmol) was dissolved in a mixed solvent of tetrahydrofuran (300 mL) and water (100 mL). Zinc powder (44 g, 669 mmol) and ammonium chloride (89 g, 1673 mmol) were added in portions at 50 °C. After stirring for 1 hour, the mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), and water (150 mL) was added. After stirring, the mixture was separated, filtered, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give yellow intermediate 2 (11 g, 94%).

[0084] 1H-NMR (300 MHz, DMSO- d 6): δ 9.72 (s, 1H), 6.82 (d, J= 7.8 Hz, 1H), 6.37 (d, J= 7.8 Hz, 1H), 5.88 (s, 2H). LC-MS: m / z 145.1 [M+H] +.

[0085] Synthesis of intermediate 3:

[0086] Intermediate 2 (23 g, 162 mmol) and potassium ethyl xanthate (39 g, 243 mmol) were dissolved in pyridine and refluxed at 120 °C for 4 hours. After cooling to room temperature, the pyridine was removed by rotary evaporation. The residue was added to ice water (100 mL) and the pH was adjusted to 1 with 3 N dilute hydrochloric acid. A grayish-white solid precipitated out. The mixture was stirred for 1 hour and filtered to obtain grayish-white intermediate 3 (29 g, 96%).

[0087] 1H-NMR (300 MHz, DMSO- d 6): δ 7.91 (d, J= 8.4 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H). LC-MS: m / z 187.1 [M+H] +.

[0088] Synthesis of intermediate 4:

[0089] Intermediate 3 (29 g, 155 mmol) was dissolved in ethyl acetate (300 mL), potassium carbonate (43 g, 313 mmol) was added, and iodomethane (20 mL, 311 mmol) was added at room temperature. After stirring for 2 hours, water (200 mL) was added. The mixture was separated, the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain gray solid intermediate 4 (28 g, 91%).

[0090] 1H-NMR (300 MHz, DMSO- d 6): δ 8.14 (d, J= 8.4 Hz, 1H), 7.42 (d, J= 8.4 Hz, 1H), 2.79 (s, 3H).

[0091] Synthesis of intermediate 5:

[0092] Intermediate 4 (28.0 g, 140.2 mmol) was dissolved in tetrahydrofuran (250 mL), morpholine (46 mL) was added, and the mixture was refluxed at 90 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, and tetrahydrofuran was removed by rotary evaporation. The residue was mixed with water (100 mL), slurried, and filtered to obtain gray solid intermediate 5 (32 g, 93%).

[0093] 1H-NMR (300 MHz, CDCl 3): δ 7.37 (d, J= 8.1 Hz, 1H), 6.93 (d, J= 8.1 Hz, 1H), 3.85-3.78 (m, 4H), 3.78-3.72 (m, 4H). LC-MS: m / z 240.0 [M+H] +.

[0094] Synthesis of intermediate 6:

[0095] Intermediate 5 (32 g, 133 mmol) was dissolved in acetonitrile (330 mL), NBS (29 g, 165 mmol) was added in portions at room temperature, diluted with ethyl acetate (1000 mL), washed with 1 N sodium hydroxide aqueous solution (250 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain gray intermediate 6 (28 g, 66%).

[0096] 1H-NMR (300 MHz, DMSO- d 6): δ 8.25 (s, 1H), 3.80-3.69 (m, 4H), 3.70-3.61 (m, 4H). LC-MS: m / z 318.0 [M+H] +.

[0097] Synthesis of intermediate 7:

[0098] Intermediate 6 (11 g, 36 mmol), tris(o-methylphenyl)phosphine (3.3 g, 11 mmol), palladium acetate (0.70 g, 3.6 mmol), and triethylamine (11 g, 107 mmol) were sequentially suspended in dry N,N-dimethylformamide (350 mL). Finally, ethyl acrylate (18.7 mL) was added. Under nitrogen protection, the mixture was heated overnight in an oil bath at 140 °C. After the reaction was complete, the solvent was removed by rotary evaporation, and the mixture was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a white solid intermediate 7 (9.1 g, 76%).

[0099] 1H-NMR (300 MHz, DMSO- d 6): δ 8.39 (s, 1H), 7.88 (d, J= 15.9 Hz, 1H), 6.72 (d, J= 15.9 Hz, 1H), 4.20 (q, J= 6.9 Hz, 2H), 3.77-3.72 (m, 4H), 3.71-3.67 (m, 4H), 1.26 (t, J= 6.9 Hz, 3H). LC-MS: m / z 338.1 [M+H] +.

[0100] Synthesis of intermediate 8:

[0101] Intermediate 7 (4.8 g, 18 mmol) was dissolved in a mixed solvent of dichloromethane (300 mL) and methanol (100 mL), and dried ozone was introduced at -70 °C. After stirring for 3 hours, dimethyl sulfide (2 mL) was added to quench the reaction. The solvent was removed by rotary evaporation to obtain crude intermediate 8 (4.0 g, 83%).

[0102] 1H-NMR (300 MHz, DMSO-d 6): δ 10.22 (s, 1H), 8.04 (s, 1H), 3.77-3.72 (m, 8H).

[0103] Synthesis of intermediate 9:

[0104] Intermediate 8 (5.0 g, 18.7 mmol) was dissolved in terbutanol (250 mL), and then an aqueous solution of 2-methyl-2-butene (13.2 g, 187 mmol), sodium chlorite (6.9 g, 187 mmol), and sodium dihydrogen phosphate dihydrate (17.6 g, 187 mmol) (200 mL) was added sequentially. The mixture was stirred for 2 hours, and the pH was adjusted to 2-3 with 1 N dilute hydrochloric acid. The mixture was extracted with dichloromethane (300 mL × 3), and the organic phase was collected. The solution was concentrated under reduced pressure until dry, and then slurried with diethyl ether (50 mL). The mixture was filtered to obtain a white solid intermediate 9 (4.2 g, 79%).

[0105] 1H-NMR (300 MHz, DMSO- d 6): δ 8.14 (s, 1H), 3.75-3.72 (m, 4H), 3.71-3.68 (m, 4H). LC-MS: m / z 284.0 [M+H] +.

[0106] Synthesis of intermediate 10:

[0107] Intermediate 9 (1.0 g, 3.5 mmol), 2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyridine (615 mg, 3.5 mmol), and triethylamine (1.8 g, 17.7 mmol) were dissolved in 50% T 3P N,N-dimethylformamide solution (2 mL) and reacted with microwave at 110 °C for 2 hours. After the reaction was completed, the reaction solution was slowly added dropwise to water (250 mL), and a solid precipitated. The mixture was stirred overnight and filtered to obtain a grayish-white solid intermediate 10 (510 mg, 33%).

[0108] 1H-NMR (300 MHz, DMSO- d 6): δ 10.94 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 8.00-7.91 (m, 2H), 7.86-7.75 (m, 1H), 7.41 (d, J= 7.5 Hz, 1H), 3.87 (s, 3H), 3.79-3.73 (m, 4H), 3.72-3.67 (m, 4H). LC-MS: m / z 440.0 [M+H] +.

[0109] [Example] [1]

[0110] Compound A1 was synthesized by the following method:

[0111] Intermediate 10 (60 mg, 0.14 mmol) and (R)-3-hydroxypyrrolidine (18 mg, 0.21 mmol) were dissolved in 1,4-dioxane (5 mL), and potassium carbonate (22 mg, 0.16 mmol) was added. The mixture was stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel preparation plate (dichloromethane / methanol = 20 / 1, v / v) to give a white solid A1 (15 mg, 38%).

[0112] [Example] [2]

[0113] Compound A2 was synthesized by the following method:

[0114] Intermediate 10 (32 mg, 0.1 mmol), morpholine (15 mg, 0.2 mmol), and potassium carbonate (50 mg, 0.4 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A2 (8 mg, 22%).

[0115] [Example] [3]

[0116] Compound A3 was synthesized by the following method:

[0117] Intermediate 10 (30 mg, 0.1 mmol), 1-methylpiperazine (68 mg, 0.7 mmol), and potassium carbonate (30 mg, 0.2 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A3 (10 mg, 29%).

[0118] [Example] [4]

[0119] Compound A4 was synthesized by the following method:

[0120] Intermediate 10 (30 mg, 0.1 mmol), piperidine-4-ol (49 mg, 0.5 mmol), and potassium carbonate (20 mg, 0.2 mmol) were suspended in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The mixture was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A4 (9 mg, 26%).

[0121] [Example] [5]

[0122] Compound A5 was synthesized by the following method:

[0123] Intermediate 10 (32 mg, 0.1 mmol), 2-oxa-6-azaspiro[3.3]heptane (15 mg, 0.2 mmol), and potassium carbonate (50 mg, 0.4 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A5 (8 mg, 22%).

[0124] [Example] [6]

[0125] Compound A6 was synthesized by the following method:

[0126] Intermediate 10 (30 mg, 0.1 mmol), (S)-3-hydroxypyrrolidine (42 mg, 0.3 mmol), and potassium carbonate (20 mg, 0.2 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A6 (10 mg, 30%).

[0127] [Example] [7]

[0128] Compound A7 was synthesized by the following method:

[0129] Intermediate 10 (50 mg, 0.11 mmol) and potassium carbonate (30 mg, 0.22 mmol) were dissolved in dry 1,4-dioxane (2 mL), and 20% methylamine methanol solution was added. The mixture was then microwaved at 110 °C for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v). The filtrate was then slurried with diethyl ether, filtered, and dried to give a pale yellow solid A7 (5 mg, 10%).

[0130] [Example] [8]

[0131] Compound A8 was synthesized by the following method:

[0132] Synthesis of intermediate A8-1:

[0133] N-Boc-proline (21.5 g, 100 mmol) was dissolved in N,N-dimethylformamide (150 mL). Potassium carbonate (27.6 g, 200 mmol) was added in portions at 0 °C, followed by dropwise addition of methyl iodoforme (28.4 g, 200 mmol). The reaction mixture was stirred overnight at room temperature and then poured into saturated saline ice water (200 mL). Ethyl acetate (500 mL) was added, followed by washing with saturated saline solution (150 mL × 3), drying over anhydrous sodium sulfate, and concentration to obtain a brown oily product A8-1 (23 g, crude product).

[0134] 1H-NMR (400 MHz, CDCl 3): δ 4.37-4.15 (m, 1H), 3.71 (s, 3H), 3.61-3.28 (m, 2H), 2.30-2.08 (m, 1H), 2.06-1.76 (m, 3H), 1.53-1.33 (m, 9H).

[0135] Synthesis of intermediate A8-2:

[0136] LDA (75 mL, 150 mmol) was added to anhydrous tetrahydrofuran (400 mL) at -78 °C under nitrogen atmosphere. Then, a tetrahydrofuran solution (50 mL) of A8-1 (23 g, 100 mmol) was added dropwise to the reaction system. After stirring at -78 °C for 2 hours, a tetrahydrofuran solution (50 mL) of chloroiodomethane (21 g, 120 mmol) was added dropwise to the reaction system. The mixture was slowly brought to room temperature and stirred overnight. The reaction was quenched by slowly adding a saturated ammonium chloride aqueous solution (100 mL) at -20 °C. The mixture was diluted with 200 mL of saturated saline solution and 200 mL of ethyl acetate. The aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give a pale green oily product A8-2 (15 g, 54%).

[0137] 1H-NMR (300 MHz, CDCl 3): δ 4.56-4.40 (m, 0.4H), 4.27-4.13 (m, 0.6H), 3.99-3.84 (m, 1H), 3.84-3.56 (m, 4H), 3.55-3.36 (m, 1H), 2.50-2.26 (m, 1H), 2.22-1.81 (m, 3H), 1.51-1.33 (m, 9H).

[0138] Synthesis of intermediate A8-3:

[0139] A8-2 (1.8 g, 6.6 mmol) was dissolved in anhydrous ethanol (50 mL), and calcium chloride (1.1 g, 9.9 mmol) was slowly added while stirring at room temperature for 30 minutes. Sodium borohydride (1.0 g, 27 mmol) was added in portions over an ice-water bath, and the mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride aqueous solution (40 mL), filtered, and the filter cake was washed with dichloromethane (20 mL). The aqueous phase was extracted with dichloromethane (40 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily intermediate. The intermediate was dissolved in dichloromethane (50 mL), and Dys-Martin reagent (2.8 g, 6.6 mmol) was added in portions in an ice-water bath. The mixture was stirred at room temperature for 3 hours, and the reaction was quenched by adding saturated sodium sulfite aqueous solution (30 mL). Then, saturated sodium bicarbonate aqueous solution (50 mL) was added. The aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give a colorless oily product A8-3 (1.1 g, 69%).

[0140] Synthesis of intermediate A8-4:

[0141] Intermediate A8-3 (9.7 g, 39 mmol) was dissolved in toluene / methanol (80 mL / 20 mL), and benzylamine (4.8 g, 45 mmol) was added. The reaction mixture was stirred overnight at 40 °C under nitrogen atmosphere. After cooling to room temperature, the solvent was concentrated, and the residue was dissolved in anhydrous methanol (100 mL). Sodium borohydride (5.9 g, 156 mmol) was added in portions, and the mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated ammonium chloride aqueous solution (50 mL), and then diluted with saturated brine (100 mL). The mixture was extracted with dichloromethane (150 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oily product A8-4, which was then directly proceeded to the next step.

[0142] Synthesis of intermediate A8-5:

[0143] The crude intermediate A8-4 was dissolved in N,N-dimethylformamide (50 mL), and triethylamine (7.9 g, 78 mmol) was added. The mixture was stirred overnight at 100 °C under nitrogen atmosphere. After cooling to room temperature, it was diluted with ethyl acetate (200 mL), washed with saturated brine (100 mL × 4), and the organic phase was separated. The product was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a colorless oily product A8-5 (10 g, 85%).

[0144] 1H-NMR (400 MHz, CDCl 3): δ 7.30-7.15 (m, 5H), 4.23-3.61 (m, 4H), 3.51-3.01 (m, 4H), 2.41-2.13 (m, 2H), 1.86-1.50 (m, 11H).

[0145] Synthesis of intermediate A8-6:

[0146] A8-5 (500 mg, 1.6 mmol) was dissolved in anhydrous methanol, and palladium hydroxide (34 mg, 0.25 mmol) was added. The air was replaced with hydrogen, and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain a pale yellow oily A8-6 (300 mg, 86%).

[0147] 1H-NMR (300 MHz, CDCl 3): δ 4.69-4.46 (m, 2H), 4.37 (s, 1H), 3.42-3.14 (m, 4H), 2.45-2.31 (m, 2H), 2.29-2.15 (m, 2H), 1.50 (s, 9H).

[0148] Synthesis of intermediate A8-7:

[0149] Intermediate 10 (50 mg, 0.11 mmol), A8-6 (70 mg, 0.33 mmol), and potassium carbonate (30 mg, 0.22 mmol) were dissolved in dry 1,4-dioxane (4 mL) and stirred at 100 °C for 24 hours. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a pale yellow solid A8-7 (50 mg, 74%).

[0150] 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.38 (s, 1H), 8.21 (s, 1H), 8.03-7.89 (m, 2H), 7.84-7.71 (m, 2H), 7.40-7.33 (m, 1H), 3.88 (s, 3H), 3.76-3.69 (m, 6H), 3.69-3.60 (m, 4H), 3.56 (s, 2H), 3.30-3.21 (m, 2H), 2.32-2.15 (m, 2H), 1.77-1.57 (m, 2H), 1.14 (s, 9H).

[0151] Synthesis of final product A8:

[0152] A8-7 (50 mg, 0.08 mmol) was dissolved in dry dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to dryness, and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate aqueous solution (10 mL). The solution was extracted with dichloromethane (10 mL × 3), concentrated, and a pale yellow solid A8 (5 mg, 12%) was obtained.

[0153] [Example] [9]

[0154] Compound A9 was synthesized by the following method:

[0155] Synthesis of intermediate A9-1:

[0156] A8-5 (2 g, 6.6 mmol) was dissolved in 1.8 N ethyl acetate hydrochloride (15 mL) solution and stirred overnight at room temperature. The mixture was filtered to obtain a white crude solid. The crude solid was dissolved in 1,2-dichloroethane (30 mL), and triethylamine (3.3 g, 33 mmol) and solid formaldehyde (596 mg, 20 mmol) were added. The mixture was stirred at room temperature for 3 hours, and sodium borohydride acetate (7.0 g, 33 mmol) was added. Under nitrogen protection, the mixture was stirred overnight at room temperature. A saturated ammonium chloride aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 × 10 mL). The solution was dried over anhydrous sodium sulfate, and purified by dry loading and silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain a white oily liquid A9-1 (680 mg, 48.5%).

[0157] 1H-NMR (400 MHz, CDCl 3): δ 7.35-7.27 (m, 5H), 3.64 (s, 2H), 3.29 (d, J= 7.6 Hz, 2H), 3.11 (d, J= 7.6 Hz, 2H), 2.66 (t, J= 7.2 Hz, 2H), 2.45 (s, 3H), 2.15-2.04 (m, 2H), 1.79-1.67 (m, 2H).

[0158] Synthesis of final product A9:

[0159] A9-1 (680 mg, 3.2 mmol) was dissolved in methanol (20 mL), palladium hydroxide (68 mg, 0.48 mmol) was added, and a catalytic amount of hydrochloric acid was added. The mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated to obtain crude product (300 mg). The crude product (50 mg, 0.30 mmol) was dissolved in dry 1,4-dioxane (2 mL), intermediate 10 (25 mg, 0.050 mmol) and potassium carbonate (16 mg, 0.11 mmol) were added, and the mixture was stirred at 100 °C for 24 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to obtain pale yellow solid A9 (10 mg, 38%).

[0160] [Example]

[10]

[0161] Compound A10 was synthesized by the following method:

[0162] Intermediate 10 (30 mg, 0.10 mmol), 3-cyclopropyl-1-azacyclobut-3-ol (42 mg, 0.4 mmol), and potassium carbonate (20 mg, 0.2 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A10 (9 mg, 26%).

[0163] [Example]

[11]

[0164] Compound A11 was synthesized by the following method:

[0165] Intermediate 10 (30 mg, 0.10 mmol), 4,4-difluoropiperidine hydrochloride (50 mg, 0.30 mmol), and potassium carbonate (30 mg, 0.30 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A11 (11 mg, 23%).

[0166] [Example]

[12]

[0167] Compound A12 was synthesized by the following method:

[0168] Intermediate 10 (30 mg, 0.10 mmol), 3,3-difluoropyrrolidine hydrochloride (50 mg, 0.30 mmol), and potassium carbonate (30 mg, 0.30 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A12 (5 mg, 11%).

[0169] [Example]

[13]

[0170] Compound A13 was synthesized by the following method:

[0171] Intermediate 10 (40 mg, 0.10 mmol), piperazine (50 mg, 0.30 mmol), and potassium carbonate (30 mg, 0.30 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A13 (10 mg, 23%).

[0172] [Example]

[14]

[0173] Compound A14 was synthesized by the following method:

[0174] Intermediate 10 (30 mg, 0.10 mmol), 3-methyl-1-azacyclobut-3-ol (42 mg, 0.40 mmol), and potassium carbonate (20 mg, 0.20 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A14 (6 mg, 18%).

[0175] [Example]

[15]

[0176] Compound A15 was synthesized by the following method:

[0177] Intermediate 10 (30 mg, 0.10 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane (45 mg, 0.30 mmol), and potassium carbonate (20 mg, 0.20 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A15 (10 mg, 27%).

[0178] [Example]

[16]

[0179] Compound A16 was synthesized by the following method:

[0180] Intermediate 10 (50 mg, 0.10 mmol), piperidine-3-ol (45 mg, 0.30 mmol), and potassium carbonate (40 mg, 0.40 mmol) were dissolved in 1,4-dioxane (4 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to give the final product A16 (10 mg, 17%).

[0181] [Example]

[17]

[0182] Compound A17 was synthesized by the following method:

[0183] Synthesis of intermediate A17-1:

[0184] Tertiary butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid (150 mg, 0.70 mmol) was dissolved in 1,2-dichloroethane (30 mL), and solid formaldehyde (106 mg, 3.5 mmol) was added. The mixture was stirred at room temperature for 3 hours, and sodium borohydride acetate (748 mg, 3.5 mmol) was added. Under nitrogen protection, the mixture was stirred at room temperature overnight. Saturated ammonium chloride aqueous solution (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 × 10 mL). The extract was dried over anhydrous sodium sulfate and concentrated to give a pale yellow oily liquid A17-1 (150 mg, 94%).

[0185] 1H-NMR (300 MHz, CDCl 3): δ 3.64-3.42 (m, 2H), 3.30-3.09 (m, 2H), 2.87-2.75 (m, 2H), 2.69-2.57 (m, 2H), 2.44-2.23 (m, 5H), 1.45 (s, 9H). LC-MS: m / z 227.1 [M+H] +.

[0186] Synthesis of final product A17:

[0187] A17-1 (150 mg, 0.66 mmol) was dissolved in 2.8 N ethyl acetate hydrochloride solution (10 mL) and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to dryness and then dissolved in dry 1,4-dioxane (2 mL). Intermediate 10 (50 mg, 0.11 mmol) and potassium carbonate (76 mg, 0.55 mmol) were added, and the mixture was stirred at 110 °C for 24 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a pale yellow solid A17 (7 mg, 38%).

[0188] [Example]

[18]

[0189] Compound A18 was synthesized by the following method:

[0190] Synthesis of intermediate A18-1:

[0191] Tetrahydrofuran-3-carboxylic acid (500 mg, 4.3 mmol) was dissolved in dry dichloromethane (10 mL), and a catalytic amount of N,N-dimethylformamide was added dropwise. Oxalic chloride (1.65 g, 13 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to dryness to obtain a pale yellow oily crude oxalic chloride, which was set aside for use. 1,3,5-Tribenzylhexahydro-1,3,5-triazine (500 mg, 1.4 mmol) was dissolved in dry dichloromethane under nitrogen protection, and boron trifluoride diethyl ether solution (610 mg, 4.3 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. Crude acetal chloride was dissolved in dry dichloromethane. Under nitrogen protection at -78°C, dry triethylamine (1.3 g, 13 mmol) was added dropwise to the reaction system. The above reaction solution was then slowly added dropwise to the reaction system. After stirring for 10 minutes, the mixture was transferred to an ice-water bath and stirred overnight. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and dry-loaded. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a pale yellow oily liquid A18-1 (558 mg, 60%).

[0192] 1H-NMR (400 MHz, CDCl 3): δ 7.33 (dd, J= 14.8, 6.4 Hz, 3H), 7.23 (d, J= 7.0 Hz, 2H), 4.40 (q, J= 14.8 Hz, 2H), 3.99 (q, J= 9.2 Hz, 2H), 3.88 (dd, J= 14.0, 7.2 Hz, 2H), 3.29-3.15 (m, 2H), 2.50-2.35 (m, 1H), 2.11 (dt, J= 12.4, 6.4 Hz, 1H). LC-MS: m / z 217.9 [M+H] +.

[0193] Synthesis of intermediate A18-2:

[0194] Aluminum trichloride (366 mg, 2.8 mmol) was dissolved in 20 mL of dry tetrahydrofuran. Lithium aluminum hydride (322 mg, 8.48 mmol) was slowly added in portions at 0 °C. After stirring briefly, a dry tetrahydrofuran solution of A18-1 (460 mg, 2.1 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 2.5 hours under nitrogen protection. Water (0.32 mL) was added dropwise to the reaction mixture, followed by 10% sodium hydroxide aqueous solution (0.64 mL), and finally water (0.96 mL). The mixture was stirred in an ice-water bath for 10 minutes, filtered, and the residue was washed with tetrahydrofuran. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily liquid, A18-2 (350 mg, 81%).

[0195] 1H-NMR (400 MHz, CDCl 3): δ 7.39-7.27 (m, 4H), 7.26-7.20 (m, 1H), 3.83 (s, 2H), 3.76 (t, J= 6.8 Hz, 2H), 3.61 (s, 2H), 3.24 (s, 4H), 2.09 (t, J= 6.8 Hz, 2H). LC-MS: m / z 204.0 [M+H] +.

[0196] Synthesis of final product A18:

[0197] A18-2 (200 mg, 0.10 mmol) was dissolved in dry ethanol (10 mL), 10% palladium on carbon (50 mg) was added, and the air was replaced with hydrogen. The mixture was stirred overnight at room temperature, filtered, and the filtrate was concentrated. The crude product was dissolved in dry 1,4-dioxane (2 mL), intermediate 10 (50 mg, 0.11 mmol) and potassium carbonate (45 mg, 0.33 mmol) were added, and the mixture was stirred overnight at 100 °C. The mixture was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a pale yellow solid A18 (27 mg, 48%).

[0198] [Example]

[19]

[0199] Compound A19 was synthesized by the following method:

[0200] Synthesis of intermediate A19-1:

[0201] Intermediate 10 (70 mg, 0.16 mmol), hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylic acid tert-butyl ester (170 mg, 0.80 mmol), and potassium carbonate (109 mg, 0.8 mmol) were dissolved in dry 1,4-dioxane (4 mL) and stirred overnight at 110 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a pale yellow solid A19-1 (50 mg, 74%).

[0202] 1H-NMR (300 MHz, CDCl 3): δ 10.68 (s, 1H), 8.22-8.05 (m, 2H), 7.94-7.81 (m, 2H), 7.70 (s, 1H), 7.24-7.16 (m, 1H), 3.97 (s, 3H), 3.90-3.75 (m, 8H), 3.75-3.49 (m, 4H), 3.45-3.26 (m, 3H), 3.13-2.95 (m, 2H), 2.17 (m, 1H), 1.39 (s, 9H).

[0203] Synthesis of final product A19:

[0204] Dissolve A19-1 (50 mg, 0.080 mmol) in dry dichloromethane (5 mL), add trifluoroacetic acid (0.5 mL), and stir overnight at room temperature. Concentrate the reaction solution under reduced pressure to dryness, adjust the pH to 8-9 with saturated sodium bicarbonate aqueous solution (10 mL), extract with dichloromethane (10 mL × 3), concentrate, and obtain a pale yellow solid A19 (27 mg, 65%).

[0205] [Example]

[20]

[0206] Compound A20 was synthesized by the following method:

[0207] Intermediate 10 (50 mg, 0.10 mmol), hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tributyl ester (200 mg, 0.90 mmol), and potassium carbonate (140 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. After purification by preparative plate, the mixture was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred for 1 hour, and the trifluoroacetic acid was removed by rotary evaporation. The mixture was then dissolved in dichloromethane (25 mL), washed with saturated sodium bicarbonate (25 mL × 1), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The mixture was then slurried in diethyl ether (2 mL), filtered, and the final product A20 (11 mg, 19%) was obtained.

[0208] [Example] [twenty one]

[0209] Compound A21 was synthesized by the following method:

[0210] Intermediate 10 (50 mg, 0.10 mmol), (R)-octahydropyrrolo[1,2-a]pyrazine (200 mg, 0.9 mmol), and potassium carbonate (140 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v), and slurried with diethyl ether (2 mL) to give the final product A21 (10 mg, 17%).

[0211] [Example] [twenty two]

[0212] Compound A22 was synthesized by the following method:

[0213] Intermediate 10 (50 mg, 0.10 mmol), 2-azaspiro[3.3]hepta-6-ol (200 mg, 1.2 mmol), and potassium carbonate (140 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v), and slurried with diethyl ether (2 mL) to obtain the final product A22 (10 mg, 17%).

[0214] [Example] [twenty three]

[0215] Compound A23 was synthesized by the following method:

[0216] Intermediate 10 (60 mg, 0.16 mmol), 4-dimethylaminopiperidine (87 mg, 0.80 mmol), and potassium carbonate (109 mg, 0.80 mmol) were dissolved in dry 1,4-dioxane (4 mL) and stirred overnight at 110 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a pale yellow solid A23 (27 mg, 37%).

[0217] [Example] [twenty four]

[0218] Compound A24 was synthesized by the following method:

[0219] Intermediate 10 (50 mg, 0.11 mmol), 4-methoxypiperidine (126 mg, 1.1 mmol), and potassium carbonate (76 mg, 0.55 mmol) were dissolved in dry 1,4-dioxane (4 mL) and stirred overnight at 110 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid A24 (16 mg, 28%).

[0220] [Example]

[25]

[0221] Compound A25 was synthesized by the following method:

[0222] Synthesis of intermediate A25-1:

[0223] N-Benzylpiperidin-4-one (1.0 g, 5.3 mmol) was dissolved in dry tetrahydrofuran (20 mL) under nitrogen protection and stirred at -20 °C. A solution of 3N-methylmagnesium chloride tetrahydrofuran (3.3 mL, 10 mmol) was slowly added dropwise, and the reaction was stirred for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give a crude yellow liquid. The crude product was dissolved in dry methanol (20 mL), 10% palladium on carbon (100 mg) was added, and the air was replaced with hydrogen. The mixture was stirred overnight at room temperature. The reaction solution was filtered and concentrated to give A25-1 (500 mg, 83%).

[0224] 1H-NMR (300 MHz, CDCl 3): δ 3.51-3.40 (m, 1H), 2.98-2.87 (m, 2H), 2.84-2.73 (m, 2H), 2.28 (s, 1H), 1.76-1.59 (m, 4H), 1.24 (s, 3H).

[0225] Synthesis of final product A25:

[0226] Intermediate 10 (50 mg, 0.11 mmol), A25-1 (164 mg, 1.4 mmol), and potassium carbonate (76 mg, 0.55 mmol) were dissolved in dry 1,4-dioxane (4 mL) and stirred overnight at 110 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid A25 (10 mg, 17%).

[0227] [Example]

[26]

[0228] Compound A26 was synthesized by the following method:

[0229] Synthesis of intermediate A26-1:

[0230] Trimethylsulfonium iodide (2.0 g, 10 mmol) was suspended in terbutanol (70 mL), potassium terbutoxide (2.8 g, 25 mmol) was added, and the mixture was stirred at 50 °C for 1.5 h. N-terbutoxycarbonylpiperidin-4-one (5.5 g, 25 mmol) was added, and the mixture was stirred at 50 °C for 48 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (150 mL), washed with saturated brine (50 mL × 3), the organic phase was separated, dried, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give a colorless oily liquid product A26-1 (1.5 g, 66%).

[0231] 1H-NMR (300 MHz, CDCl 3): δ 4.68-4.39 (m, 2H), 3.41 (s, 4H), 2.54-2.26 (m, 2H), 1.98-1.67 (m, 4H), 1.45 (s, 9H).

[0232] Synthesis of final product A26:

[0233] Intermediate A26-1 (227 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was concentrated, and the residue was dispersed in methanol. Sodium methoxide (108 mg, 2.0 mmol) was added to adjust the compound to a free state. Diethyl ether (10 mL) was added, and the mixture was stirred for 10 minutes. The mixture was filtered, and the filtrate was concentrated to obtain a yellow oily liquid. Intermediate 10 (62 mg, 0.14 mmol) was dissolved in 1,4-dioxane (10 mL), and the freshly prepared yellow oily liquid was added. Potassium carbonate (193 mg, 1.4 mmol) was then added, and the mixture was stirred at 110 °C for 24 hours. Cool to room temperature, concentrate the solvent, add saturated saline (20 mL) to the residue, extract with ethyl acetate (15 mL × 3), separate the organic phase, dry, concentrate, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to obtain a yellow solid, which is then slurried with ethyl acetate / diethyl ether (5 mL / 5 mL) to obtain a pale yellow solid product A26 (20 mg, 27%).

[0234] [Example]

[27]

[0235] Compound A27 was synthesized by the following method:

[0236] Intermediate 10 (30 mg, 0.070 mmol), (S)-octahydropyrrolo[1,2-a]pyrazine (85 mg, 0.68 mmol), and potassium carbonate (47 mg, 0.34 mmol) were dissolved in dry 1,4-dioxane (3 mL) and stirred at 110 °C for 24 hours. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid A27 (14 mg, 38%).

[0237] [Example]

[28]

[0238] Compound A28 was synthesized by the following method:

[0239] Intermediate 10 (50 mg, 0.1 mmol), tropine (80 mg, 0.6 mmol), and potassium carbonate (150 mg, 1.1 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurryed with diethyl ether (2 mL) to obtain the final product A28 (18 mg, 30%).

[0240] [Example]

[29]

[0241] Compound A29 was synthesized by the following method:

[0242] Intermediate 10 (50 mg, 0.10 mmol), tributyl (piperidin-3-yl)aminocarbamate (113 mg, 0.6 mmol), and potassium carbonate (152 mg, 1.1 mmol) were dissolved in 1,4-dioxane (8 mL). The mixture was heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The mixture was purified by preparative plate (dichloromethane / methanol = 20 / 1, v / v) to give a white solid. Then, ethyl acetate hydrochloride solution (5 mL) was added, and the mixture was stirred for half an hour. The solution was then concentrated under reduced pressure to dryness. Diethyl ether (5 mL) was added, and the mixture was concentrated under reduced pressure to dryness to give a yellow solid, A29 hydrochloride (8 mg, 13%).

[0243] [Example]

[30]

[0244] Compound A30 was synthesized by the following method:

[0245] Intermediate 10 (50 mg, 0.11 mmol), 1,2-dimethylpiperazine (63 mg, 0.55 mmol), and potassium carbonate (76 mg, 0.55 mmol) were dissolved in dry 1,4-dioxane (2 mL) and stirred overnight at 105 °C. The reaction mixture was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a yellow solid product. The product was dissolved in 2.8 N ethyl acetate hydrochloride solution (5 mL), stirred overnight at room temperature, filtered, and dried to give a pale yellow solid A30 hydrochloride (15 mg, 27%).

[0246] [Example]

[31]

[0247] Compound A31 was synthesized by the following method:

[0248] Intermediate 10 (50 mg, 0.11 mmol), (S)-1,2-dimethylpiperazine (63 mg, 0.55 mmol), and potassium carbonate (76 mg, 0.55 mmol) were dissolved in dry 1,4-dioxane (2 mL) and stirred overnight at 105 °C. The reaction mixture was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a yellow solid product. The product was dissolved in 2.8 N ethyl hydrochloride solution (5 mL), stirred overnight at room temperature, filtered, and dried to give a pale yellow solid, A31 hydrochloride (19 mg, 32%).

[0249] [Example]

[32] [and]

[33]

[0250] Compound A32 was synthesized by the following method:

[0251] Synthesis of final product A32:

[0252] Intermediate 10 (50 mg, 0.11 mmol), 2,6-dimethylpiperazine (63 mg, 0.55 mmol), and potassium carbonate (76 mg, 0.55 mmol) were dissolved in dry 1,4-dioxane (2 mL) and stirred overnight at 100 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a white solid product A32 (30 mg, 53%).

[0253] Synthesis of final product A33:

[0254] A32 (120 mg, 0.23 mmol) and paraformaldehyde (70 mg, 2.3 mmol) were added to 1,2-dichloroethane (10 mL), and the mixture was stirred at room temperature for 3 hours under nitrogen protection. Sodium borohydride acetate (487 mg, 2.3 mmol) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid A32 (65 mg, 53%).

[0255] [Example]

[34]

[0256] Compound A34 was synthesized by the following method:

[0257] Intermediate 10 (100 mg, 0.2 mmol), 1-(2-methoxyethyl)piperazine (532 mg, 4.6 mmol), and potassium carbonate (639 mg, 4.6 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred for 24 hours, filtered, and the solvent was removed by rotary evaporation. The mixture was purified by thick-plate chromatography, and then 3 N ethyl hydrochloride solution (4 mL) was added. The mixture was stirred overnight, and the ethyl hydrochloride was removed by rotary evaporation. Then, diethyl ether (2 mL) was added and the mixture was stirred and filtered to obtain the final product A34 hydrochloride (10 mg, 8%).

[0258] [Example]

[35]

[0259] Compound A35 was synthesized by the following method:

[0260] Intermediate 10 (50 mg, 0.11 mmol), N-cyclopropylpiperazine (142 mg, 1.1 mmol), and potassium carbonate (78 mg, 0.56 mmol) were dissolved in dry 1,4-dioxane (2 mL) and stirred overnight at 110 °C. The reaction mixture was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a yellow solid product. The product was dissolved in 2.8 N ethyl acetate hydrochloride solution (5 mL), stirred overnight at room temperature, filtered, and dried to give a pale yellow solid, A35 hydrochloride (30 mg, 48%).

[0261] [Example]

[36]

[0262] Compound A36 was synthesized by the following method:

[0263] Intermediate 10 (100 mg, 0.2 mmol), 1-(2-hydroxyethyl)piperazine (520 mg, 4.5 mmol), and potassium carbonate (639 mg, 4.6 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v). Then, 3 N ethyl hydrochloride solution (4 mL) was added, stirred overnight, and ethyl hydrochloride was removed by rotary evaporation. Then, diethyl ether (2 mL) was added and stirred, filtered, to obtain the final product A36 hydrochloride (8 mg, 7%).

[0264] [Example]

[37]

[0265] Compound A37 was synthesized by the following method:

[0266] Intermediate 10 (100 mg, 0.2 mmol), (1-methylpiperazin-2-yl)methanol (580 mg, 4.7 mmol), and potassium carbonate (600 mg, 4.4 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v). Then, 3 N ethyl hydrochloride solution (4 mL) was added, stirred overnight, and ethyl hydrochloride was removed by rotary evaporation. Then, diethyl ether (2 mL) was added and stirred, filtered, to obtain the final product A37 hydrochloride (10 mg, 7%).

[0267] [Example]

[38]

[0268] Compound A38 was synthesized by the following method:

[0269] Synthesis of intermediate A38-1:

[0270] 6-Bromopyridine-2-carboxaldehyde (3.7 g, 20 mmol) was dissolved in dichloromethane (30 mL), and DAST (3.9 g, 24 mmol) was added dropwise at room temperature with stirring overnight. The reaction was quenched by adding sodium bicarbonate aqueous solution (20 mL) in an ice-water bath. The organic phase was washed with saturated brine (20 mL × 3), dried, and concentrated to obtain a brown oily crude product A38-1, which was directly used for the next step.

[0271] Synthesis of intermediate A38-2:

[0272] A38-1 (828 mg, 4.0 mmol), Cu₂O (29 mg, 0.2 mmol), potassium carbonate (110 mg, 0.80 mmol), and N,N-dimethylethylenediamine (35 mg, 0.40 mmol) were suspended in ammonia / ethylene glycol (10 mL / 8 mL) and stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL), filtered, and the filtrate was extracted with saturated saline (20 mL) using dichloromethane (20 mL × 3). The organic phases were combined, dried, concentrated, and the residue was purified by silica gel column chromatography to obtain A38-2 (300 mg, 52%).

[0273] 1H-NMR (300 MHz, CDCl 3): δ 7.58-7.48 (m, 1H), 6.94 (d, J= 7.2 Hz, 1H), 6.57 (d, J= 8.4 Hz, 1H), 6.42 (t, J= 55.8 Hz, 1H), 4.58 (br s, 2H). LC-MS: m / z 145.1 [M+H] +.

[0274] Synthesis of intermediate A38-3:

[0275] A38-2 (144 mg, 1.0 mmol), intermediate 9 (283 mg, 1.0 mmol), and triethylamine (500 mg, 5.0 mmol) were dissolved sequentially in 3 mL of 50% T3P N,N-dimethylformamide solution and reacted in a microwave-assisted reaction at 120 °C for 1 hour. After cooling to room temperature, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution (20 mL), followed by the addition of ethyl acetate (40 mL). The organic phase was washed with saturated brine (20 mL × 4), and the organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid product A38-3 (25 mg, 6.1%).

[0276] 1H-NMR (300 MHz, CDCl 3): δ 9.18 (s, 1H), 8.45 (d, J= 8.1 Hz, 1H), 8.04-7.81 (m, 2H), 7.42 (d, J= 7.5 Hz, 1H), 6.52 (t, J= 55.8 Hz, 1H), 3.83 (s, 8H).

[0277] Synthesis of final product A38:

[0278] A38-3 (30 mg, 0.07 mmol) and (R)-3-hydroxypyrrolidine (18 mg, 0.21 mmol) were dissolved in 1,4-dioxane (5 mL), and potassium carbonate (22 mg, 0.16 mmol) was added. The mixture was stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel preparative chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid product A38 (20 mg, 63%).

[0279] [Example]

[39]

[0280] Compound A39 was synthesized by the following method:

[0281] Synthesis of intermediate A39-1:

[0282] Intermediate 9 (528 mg, 1.2 mmol), 3-aminopyrazolo[1,5-a]pyrimidine (245 mg, 1.4 mmol), and triethylamine (360 mg, 3.6 mmol) were dissolved in 2 mL of 50% T3P N,N-dimethylformamide solution and reacted with microwave at 110 °C for 2 hours. After the reaction was complete, the reaction solution was slowly added dropwise to 250 mL of water. A solid precipitated, was stirred overnight, and filtered to obtain a grayish-white solid intermediate A39-1 (510 mg, 33%).

[0283] 1H-NMR (300 MHz, DMSO- d 6): δ 10.81 (s, 1H), 9.05 (d, J= 6.0 Hz, 1H), 8.65 (s, 1H), 8.53 (d, J= 3.9 Hz, 1H), 8.03 (s, 1H), 7.04 (dd, J= 6.9, 4.2 Hz, 1H), 3.80-3.72 (m, 4H), 3.71-3.64 (m, 4H).

[0284] Synthesis of final product A39:

[0285] A39-1 (90 mg, 0.20 mmol), (R)-3-hydroxypyrrolidine (200 mg, 2.3 mmol), and potassium carbonate (100 mg, 1.0 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to obtain the final product A39 (53 mg, 53%).

[0286] [Example]

[40]

[0287] Compound A40 was synthesized by the following method:

[0288] Synthesis of intermediate A40-1:

[0289] Intermediate 9 (500 mg, 1.8 mmol), 1-methyl-1H-pyrazole-4-amine (257 mg, 1.8 mmol), and triethylamine (880 mg, 8.8 mmol) were dissolved in 2 mL of 50% T3P N,N-dimethylformamide solution and reacted with microwave at 110 °C for 2 hours. After the reaction was complete, the reaction solution was slowly added dropwise to 25 mL of water. A solid precipitated, was stirred overnight, and filtered to obtain a grayish-white solid intermediate A40-1 (240 mg, 35%).

[0290] Synthesis of final product A40:

[0291] A40-1 (90 mg, 0.25 mmol), (R)-3-hydroxypyrrolidine (200 mg, 2.3 mmol), and potassium carbonate (140 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v) and slurried with diethyl ether (2 mL) to obtain the final product A40 (50 mg, 51%).

[0292] [Example]

[41]

[0293] Compound A41 was synthesized by the following method:

[0294] Synthesis of intermediate A41-1:

[0295] Intermediate 9 (100 mg, 0.38 mmol), 6-methylpyridin-2-amine (62 mg, 0.56 mmol), and triethylamine (192 mg, 1.9 mmol) were dissolved sequentially in 50% T 3P N,N-dimethylformamide solution (1 mL), and the mixture was microwaved at 100 °C for 2.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove N,N-dimethylformamide, washed with saturated brine (10 mL × 3), the organic phases were combined, concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a gray solid A41-1 (40 mg, 28%).

[0296] 1H-NMR (300 MHz, DMSO- d 6): δ 10.98 (s, 1H), 8.08-7.94 (m, 2H), 7.79-7.66 (m, 1H), 7.04 (d, J= 6.6 Hz, 1H), 3.86-3.72 (m, 4H), 3.72-3.62 (m, 4H), 2.48-2.31 (m, 3H). LC-MS: m / z 374.1 [M+H] +.

[0297] Synthesis of final product A41:

[0298] A41-1 (40 mg, 0.11 mmol), piperidine-4-ol (168 mg, 1.6 mmol), and potassium carbonate (46 mg, 0.33 mmol) were dissolved sequentially in 1,4-dioxane (2 mL) and reacted at 100 °C for 24 hours. After the reaction was completed, dichloromethane (3 mL) was added for dilution, the mixture was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 40 / 1, v / v) to obtain a white crude product. The crude product was then slurried with diethyl ether to obtain a white solid A41 (29 mg, 60%).

[0299] [Example]

[42]

[0300] Compound A42 was synthesized by the following method:

[0301] Synthesis of intermediate A42-1:

[0302] Intermediate 9 (50 mg, 0.19 mmol), 6-cyanopyridin-2-amine (33 mg, 0.28 mmol), triethylamine (96 mg, 0.95 mmol), and a 50% T 3P solution of N,N-dimethylformamide (0.5 mL) were dissolved sequentially in a 0.5 mL solution of N,N-dimethylformamide. The mixture was then microwaved at 100 °C for 2.5 hours. After the reaction was complete, water (3 mL) was added to the reaction solution, and the mixture was filtered to obtain a brown crude product. This product was then slurried with diethyl ether to obtain a brown solid A42-1 (46 mg, 63%).

[0303] Synthesis of final product A42:

[0304] A42-1 (46 mg, 0.12 mmol), piperidine-4-ol (121 mg, 1.2 mmol), and potassium carbonate (50 mg, 0.36 mmol) were dissolved sequentially in 1,4-dioxane (2 mL) and reacted at 100 °C for 24 hours. After the reaction was completed, dichloromethane (3 mL) was added for dilution, the mixture was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to obtain a white crude product. The crude product was then slurried with diethyl ether to obtain a white solid A42 (11 mg, 60%).

[0305] [Example]

[43]

[0306] Compound A43 was synthesized by the following method:

[0307] Synthesis of intermediate A43-1:

[0308] Intermediate 9 (200 mg, 0.76 mmol), 6-methoxypyridine-2-amine (141 mg, 1.1 mmol), and triethylamine (384 mg, 3.8 mmol) were dissolved sequentially in 50% T 3P N,N-dimethylformamide solution (2 mL), and the mixture was microwaved at 100 °C for 2.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove N,N-dimethylformamide, washed with saturated brine (10 mL × 3), the organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a yellow solid A43-1 (94 mg, 32%).

[0309] 1H-NMR (300 MHz, DMSO- d 6): δ 10.90 (s, 1H), 8.08 (s, 1H), 7.85-7.68 (m, 2H), 6.65-6.53 (m, 1H), 3.83 (s, 3H), 3.79-3.74 (m, 4H), 3.74-3.68 (m, 4H). LC-MS: m / z 390.1 [M+H] +.

[0310] Synthesis of final product A43:

[0311] A43-1 (50 mg, 0.13 mmol), piperidine-4-ol (130 mg, 1.3 mmol), and potassium carbonate (53 mg, 0.38 mmol) were dissolved sequentially in 1,4-dioxane (2 mL) and reacted at 100 °C for 24 hours. After the reaction was completed, dichloromethane (3 mL) was added for dilution, the mixture was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to obtain a white crude product. The crude product was then slurried with diethyl ether to obtain a white solid A43 (28 mg, 48%).

[0312] [Example]

[44]

[0313] Compound A44 was synthesized by the following method:

[0314] Synthesis of intermediate A44-1:

[0315] m-Bromoaniline (200 mg, 1.2 mmol), dimethylphosphine oxide (136 mg, 1.7 mmol), palladium acetate (25 mg, 0.11 mmol), Xantphos (63 mg, 0.11 mmol), and potassium phosphate (371 mg, 1.7 mmol) were suspended in dry 1,4-dioxane (10 mL) and stirred overnight at 120 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a white solid product A44-1 (80 mg, 41%).

[0316] 1H-NMR (300 MHz, CDCl 3): δ 7.22 (s, 1H), 7.11 (d, J= 12.6 Hz, 1H), 7.02-6.90 (m, 1H), 6.80 (d, J= 8.4 Hz, 1H), 3.72 (s, 2H), 1.69 (d, J= 12.6 Hz, 6H) ). LC-MS: m / z 170.1 [M+H] +.

[0317] Synthesis of intermediate A44-2:

[0318] A44-1 (179 mg, 1.1 mmol) was dissolved in dry N,N-dimethylformamide (2 mL), and triethylamine (490 mg, 3.5 mmol) and intermediate 9 (200 mg, 0.71 mmol) were added. A 50% T3P solution (1.1 g, 3.5 mmol) in N,N-dimethylformamide was added with stirring, and the mixture was microwaved at 115 °C for 2 hours. The reaction mixture was poured into ice water (10 mL), and the product precipitated. After stirring for 30 minutes, the mixture was filtered, washed with water, and dried to obtain a gray solid A44-2 (120 mg, 26%).

[0319] 1H-NMR (300 MHz, CDCl 3): δ 10.16-10.11 (m, 1H), 8.24 (s, 1H), 8.04 (d, J= 13.3 Hz, 1H), 7.85 (s, 1H), 7.53-7.43 (m, 1H), 7.29 (s, 1H), 3.93-3.69 (m, 8H), 1.61 (d, J= 12.8 Hz, 6H). LC-MS: m / z 435.0 [M+H] +.

[0320] Synthesis of final product A44:

[0321] A44-2 (60 mg, 0.14 mmol), p-methoxypiperidine (158 mg, 1.4 mmol), and potassium carbonate (97 mg, 0.75 mmol) were dissolved in dry 1,4-dioxane (2 mL) and stirred overnight at 110 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a white solid A44 (40 mg, 57%).

[0322] [Example]

[45]

[0323] Compound A45 was synthesized by the following method:

[0324] Synthesis of intermediate A45-1:

[0325] Intermediate 9 (100 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of HATU (201 mg, 0.53 mmol) and N,N-diisopropylethylamine (91 mg, 0.71 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, 2-methoxypyridine-3-amine (66 mg, 0.53 mmol) was added, and the mixture was stirred overnight at 80 °C. The reaction mixture was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a yellow oily intermediate A45-1 (30 mg, 22%).

[0326] 1H-NMR (300 MHz, CDCl 3): δ 9.22 (s, 1H), 8.73 (d, J= 6.6 Hz, 1H), 8.08 (s, 1H), 7.91 (d, J= 3.3 Hz, 1H), 7.00-6.90 (m, 1H), 4.05 (s, 3H), 3.83 (s, 8H). LC-MS: m / z 390.1 [M+H] +.

[0327] Synthesis of final product A45:

[0328] Intermediate A45-1 (25 mg, 0.060 mmol) was dissolved in 1,4-dioxane (3 mL), followed by the addition of potassium carbonate (26 mg, 0.19 mmol) and piperidine-4-ol (65 mg, 0.64 mmol). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was then concentrated under reduced pressure to dryness and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid A45 (17 mg, 58%).

[0329] [Example]

[46]

[0330] Compound A46 was synthesized by the following method:

[0331] A43-1 (44 mg, 0.11 mmol), 4-methoxypiperidine (130 mg, 1.1 mmol), and potassium carbonate (47 mg, 0.34 mmol) were sequentially suspended in 1,4-dioxane (2 mL) and reacted at 100 °C for 24 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to obtain a white crude product. The crude product was then slurried with diethyl ether to obtain a white solid A46 (25 mg, 48%).

[0332] [Example]

[47]

[0333] Compound A47 was synthesized by the following method:

[0334] Synthesis of intermediate A47-1:

[0335] 3-Bromo-2-methoxyaniline (500 mg, 2.4 mmol), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (603 mg, 2.9 mmol), potassium carbonate (684 mg, 4.9 mmol), and Pd(dppf)Cl₂ (183 mg, 0.25 mmol) were suspended in a mixed solvent (20 mL / 2 mL) of 1,4-dioxane and water under nitrogen protection and reacted overnight at 100 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1, v / v) to give a pale yellow oil A47-1 (380 mg, 70%).

[0336] Synthesis of intermediate A47-2:

[0337] Intermediate 9 (50 mg, 0.17 mmol) was dissolved in dry N,N-dimethylformamide (2 mL), and triethylamine (121 mg, 0.88 mmol) and A47-1 (76 mg, 0.35 mmol) were added. While stirring, a 50% T3P (280 mg, 0.88 mmol) solution of N,N-dimethylformamide was added, and the mixture was microwave-stirred at 100 °C for 2 hours. The reaction mixture was poured into ice water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine, concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v). The mixture was then slurried with diethyl ether, filtered, and dried to obtain a white solid A47-2 (60 mg, 73%).

[0338] 1H-NMR (300 MHz, CDCl 3): δ 9.49 (s, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.22-7.12 (m, 2H), 3.98 (s, 3H), 3.90-3.80 (m, 8H), 3.67 (s, 3H).

[0339] Synthesis of final product A47:

[0340] A47-2 (60 mg, 0.13 mmol), 4-methoxypiperazine (150 mg, 1.3 mmol), and potassium carbonate (88 mg, 0.64 mmol) were dissolved in dry 1,4-dioxane (2 mL) and stirred overnight at 110 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a white solid product A47 (13 mg, 18%).

[0341] [Example]

[48]

[0342] Compound A48 was synthesized by the following method:

[0343] Synthesis of intermediate A48-1:

[0344] m-Nitrobenzonitrile (1.0 g, 6.8 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium azide (2.6 g, 39.9 mmol) and ammonium chloride (2.2 g, 39.9 mmol) were added. The mixture was reacted overnight in an oil bath at 120 °C. After the reaction was complete, water (25 mL) was added, and the mixture was extracted with dichloromethane (25 mL × 3). The extract was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to give a white solid intermediate A48-1 (620 mg, 50%).

[0345] 1H-NMR (300 MHz, CDCl 3): δ 8.12 (s, 1H), 7.79-7.66 (m, 2H), 7.23-7.16 (m, 1H).

[0346] Synthesis of intermediate A48-2:

[0347] A48-1 (620 mg, 3.2 mmol) was dissolved in methanol (10 mL), and 10% palladium on carbon (300 mg) was added. The reaction was carried out overnight under hydrogen atmosphere. After the reaction was completed, the mixture was filtered and the solvent was removed by rotary evaporation to obtain a green solid intermediate A48-2 (430 mg, 82%).

[0348] 1H-NMR (300 MHz, CDCl 3): δ 7.95 (s, 1H), 7.26 (s, 1H), 7.19 (d, J= 7.2 Hz, 1H), 7.15-7.09 (m, 1H), 6.73 (d, J= 7.2 Hz, 1H), 4.97 (s, 2H).

[0349] Synthesis of intermediate A48-3:

[0350] Intermediate 9 (100 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (10 mL), and HATU (66 mg, 0.5 mmol) and DIPEA (90 mg, 0.7 mmol) were added. After stirring at room temperature for 1 hour, A48-2 (85 mg, 0.5 mmol) was added, and the mixture was stirred overnight at 80 °C. After the reaction was complete, water (25 mL) was added, and the mixture was extracted with dichloromethane (25 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 5), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give a brown solid intermediate A48-3 (51 mg, 19%).

[0351] 1H-NMR (300 MHz, DMSO- d 6): δ 10.82 (s, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.82 (d, J= 6.9 Hz, 1H), 7.77 (d, J= 6.9 Hz, 1H), 7.68-7.54 (m, 1H), 3.85-3.71 (m, 8H).

[0352] Synthesis of final product A48:

[0353] A48-3 (51 mg, 0.1 mmol), 4-methoxypiperidine (80 mg, 0.6 mmol), and potassium carbonate (150 mg, 1.1 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 30 / 1, v / v), slurried with diethyl ether (2 mL), filtered, and the final product A48 (7 mg, 12%) was obtained.

[0354] [Example]

[49]

[0355] Compound A49 was synthesized by the following method:

[0356] Synthesis of intermediate A49-1:

[0357] 4-Bromo-2-methylpyridine (7.5 g, 44 mmol), ethyl oxazolium-4-carboxylate (6.2 g, 44 mmol), and tris(o-methylphenyl)phosphine (2.6 g, 8.7 mmol) were suspended in N,N-dimethylformamide (200 mL), followed by the addition of palladium acetate (500 mg, 4.4 mmol) and cesium carbonate (15.6 g, 48 mmol). The reaction mixture was then subjected to nitrogen protection and reacted overnight at 70 °C. The reaction system was subsequently cooled, filtered, and concentrated to obtain a yellow solid crude product, A49-1, which was directly added to the next reaction step.

[0358] Synthesis of intermediate A49-2:

[0359] The crude intermediate A49-1 was dissolved in tetrahydrofuran (50 mL), followed by the dissolution of lithium hydroxide (2.1 g, 87 mmol) in water (10 mL). The aqueous solution of lithium hydroxide was then added dropwise to the tetrahydrofuran solution, and the mixture was stirred overnight at room temperature. The reaction mixture was then filtered, and the filter cake was dissolved in water (20 mL). The pH was adjusted to 4, and a solid precipitated. This solid was filtered, dried, and yielded a yellow solid product, A49-2 (2.3 g, 25%).

[0360] 1H-NMR (300 MHz, DMSO- d 6 ): δ 8.93 (s, 1H), 8.64 (d, J= 5.1 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J= 4.8 Hz, 1H), 2.57 (s, 3H). LC-MS: m / z 205.1 [M+H] +.

[0361] Synthesis of intermediate A49-3:

[0362] A49-2 (510 mg, 2.5 mmol) was dissolved in terbutanol (20 mL), and triethylamine (505 mg, 5.0 mmol) was added. DPPA (756 mg, 2.8 mmol) was added under nitrogen atmosphere, and the mixture was stirred overnight at 100 °C. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a white solid product A49-3 (230 mg, 33%).

[0363] 1H-NMR (300 MHz, CDCl 3): δ 8.60 (d, J= 5.1 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.61 (d, J= 4.8 Hz, 1H), 6.94 (s, 1H), 2.63 (s, 3H), 1.52 (s, 9H). LC-MS: m / z 276.0 [M+H] +.

[0364] Synthesis of intermediate A49-4:

[0365] Intermediate 10 (223 mg, 0.79 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of oxalichlor (2 mL) and a catalytic amount of N,N-dimethylmethamide (5 mg). The mixture was stirred at 50 °C for 1 hour and concentrated to obtain a yellow solid crude oxalichlor. Separately, 60% sodium hydride (142 mg, 3.6 mmol) was suspended in dry tetrahydrofuran (25 mL). Under ice-water bath and nitrogen protection, a tetrahydrofuran solution (2 mL) of A49-3 (195 mg, 0.71 mmol) was added dropwise, and the mixture was stirred for 10 minutes. Then, a tetrahydrofuran solution (2 mL) of the freshly prepared crude oxalichlor was added dropwise. After stirring at room temperature for 1 hour, the mixture was placed in a -10°C environment and quenched with glacial acetic acid (1 mL). The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a white solid product A49-4 (150 mg, 39%).

[0366] 1H-NMR (300 MHz, DMSO- d 6 ): δ 8.68-8.55 (m, 2H), 8.14 (s, 1H), 7.80 (s, 1H), 7.73-7.68 (m, 1H), 3.79-3.65 (m, 8H), 2.58 (s, 3H), 1.20 (s, 9H).

[0367] Synthesis of intermediate A49-5:

[0368] A49-4 (150 mg, 0.28 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the pH of the residue was adjusted to 8 with saturated sodium bicarbonate. A white solid precipitated out. The mixture was filtered, and the filter cake was dried to give a white solid product A49-5 (90 mg, 73%).

[0369] 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.57 (s, 1H), 8.67 (d, J= 5.1 Hz, 1H), 8.53 (s, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.77 (d, J= 4.8 Hz, 1H), 3.80-3.65 (m, 8H), 2.61 (s, 3H).

[0370] Synthesis of final product A49:

[0371] A49-5 (35 mg, 0.08 mmol) and (R)-3-hydroxypyrrolidine (28 mg, 0.32 mmol) were dissolved in 1,4-dioxane (5 mL), and potassium carbonate (22 mg, 0.16 mmol) was added. The mixture was stirred at 100 °C for 24 hours. After cooling to room temperature, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel preparative chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid product A49 (15 mg, 38%).

[0372] [Example]

[50]

[0373] Compound A50 was synthesized by the following method:

[0374] A45-1 (90 mg, 0.2 mmol), 4-methoxypiperidine (532 mg, 4.6 mmol), and potassium carbonate (639 mg, 4.6 mmol) were dissolved in 1,4-dioxane (5 mL), heated and stirred at 100 °C for 24 hours, filtered, and the solvent was removed by rotary evaporation. The solution was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v), and then slurried with diethyl ether (2 mL) to obtain the final product A50 (23 mg, 21%).

[0375] [Example]

[51]

[0376] Compound A51 was synthesized by the following method:

[0377] Synthesis of intermediate A51-1:

[0378] Intermediate 4 (2.0 g, 10 mmol) and piperazine-1-carboxylic acid tributyl ester (5.0 g, 50 mmol) were dissolved in tetrahydrofuran (70 mL) and stirred overnight at 80 °C. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to give a white solid product A51-1 (3.0 g, 72%).

[0379] 1H-NMR (300 MHz, CDCl 3): δ 7.37 (d, J= 8.1 Hz, 1H), 6.93 (d, J= 8.1 Hz, 1H), 3.77-3.67 (m, 4H), 3.64-3.51 (m, 4H), 1.48 (s, 9H).

[0380] Synthesis of intermediate A51-2:

[0381] Dissolve A51-1 (3.0 g, 8.8 mmol) in dry acetonitrile (100 mL), slowly add NBS (2.2 g, 12.3 mmol) in portions under an ice-water bath, stir at room temperature for 5 hours, dilute with ethyl acetate (200 mL), wash with 1 N sodium hydroxide (50 mL × 4) aqueous solution, dry with anhydrous sodium sulfate, concentrate, and obtain brown solid A51-2 (3.0 g, 83%).

[0382] 1H-NMR (300 MHz, CDCl 3): δ 7.68 (s, 1H), 3.77-3.71 (m, 4H), 3.62-3.55 (m, 4H), 1.49 (s, 9H).

[0383] Synthesis of intermediate A51-3:

[0384] A51-2 (1 g, 2.4 mmol), ethyl acrylate (4.2 g, 48 mmol), palladium acetate (54 mg, 0.24 mmol), tris(o-methylphenyl)phosphine (220 mg, 0.72 mmol), and triethylamine (726 mg, 7.2 mmol) were suspended in dry N,N-dimethylformamide (5 mL) under nitrogen protection and reacted in a microwave oven at 140 °C for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid product A51-3 (460 mg, 46%).

[0385] 1H-NMR (300 MHz, CDCl 3): δ 8.07 (d, J= 15.9 Hz, 1H), 7.64 (s, 1H), 6.30 (d, J= 15.9 Hz, 1H), 4.33-4.22 (m, 2H), 3.82-3.71 (m, 4H), 3.64-3.52 (m, 4H), 1.49 (s, 9H), 1.35 (t, J= 5.7 Hz, 3H). LC-MS: m / z 437.1 [M+H] +.

[0386] Synthesis of intermediate A51-4:

[0387] A51-3 (450 mg, 1.0 mmol) was dissolved in a dichloromethane / methanol mixture (30 mL / 3 mL), ozone was bubbled through at -78 °C for 5 minutes, then quenched with dimethyl sulfide (0.5 mL), brought to room temperature, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give a pale yellow solid product A51-4 (250 mg, 68%).

[0388] 1H-NMR (300 MHz, CDCl 3): δ 10.37 (s, 1H), 7.91 (s, 1H), 3.88-3.73 (m, 4H), 3.66-3.52 (m, 4H), 1.48 (s, 9H). LC-MS: m / z 367.1 [M+H] +.

[0389] Synthesis of intermediate A51-5:

[0390] Dissolve A51-4 (50 mg, 0.13 mmol) in terbutanol / water (5 mL / 5 mL), add 2-methyl-2-butene (91 mg, 1.3 mmol) at room temperature, then slowly add an aqueous solution of sodium dihydrogen phosphate dihydrate (202 mg, 1.3 mmol) and sodium chlorite (59 mg, 0.65 mmol) (5 mL), stir at room temperature for 1 hour, dilute with water (30 mL), adjust pH to 3-4 with 1 N dilute hydrochloric acid, extract with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL × 3), concentrate to obtain white solid A51-5 (40 mg, 77%).

[0391] 1H-NMR (300 MHz, DMSO- d 6 ): δ 8.14 (s, 1H), 3.78-3.63 (m, 4H), 3.60-3.46 (m, 4H), 1.44 (s, 9H). LC-MS: m / z 383.1 [M+H] +.

[0392] Synthesis of intermediate A51-6:

[0393] Dissolve A51-5 (40 mg, 0.1 mmol) in dry N,N-dimethylformamide (2 mL), add triethylamine (69 mg, 0.5 mmol), 2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyridine (34 mg, 0.2 mmol), and add 50% T3P (159 mg, 0.5 mmol) N,N-dimethylformamide solution while stirring. Microwave stirring at 100 °C for 2 hours. Pour the reaction solution into ice water (10 mL), the product precipitates, stir for 30 minutes, filter, wash with water, and dry to obtain a pale yellow solid A51-6 (10 mg, 18%).

[0394] 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.92 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.98-7.91 (m, 2H), 7.85-7.75 (m, 1H), 7.46-7.35 (m, 1H), 3.87 (s, 3H), 3.75-3.63 (m, 4H), 3.57-3.48 (m, 4H), 1.43 (s, 9H).

[0395] Synthesis of intermediate A51-7:

[0396] A51-6 (80 mg, 0.15 mmol), p-methoxypiperidine (172 mg, 1.5 mmol), and potassium carbonate (103 mg, 0.75 mmol) were dissolved in dry 1,4-dioxane (5 mL) and stirred at 110 °C for 24 hours. The reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid A51-7 (45 mg, 49%).

[0397] 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.46-13.31 (m, 1H), 8.35-8.20 (m, 2H), 8.10-7.99 (m, 2H), 7.78 (s, 1H), 7.39 (s, 1H), 3.87 (s, 3H), 3.76-3.63 (m, 9H), 3.25-3.13 (m, 5H), 3.10-2.93 (m, 2H), 2.25-1.98 (m, 4H), 1.43 (s, 9H). LC-MS: m / z 618.3 [M+H] +.

[0398] Synthesis of final product A51:

[0399] A51-7 (30 mg, 0.05 mmol) was dissolved in 2.8 N ethyl hydrochloride solution (5 mL), stirred overnight at room temperature, the reaction solution was concentrated, ethyl acetate / ethyl ether (2 mL / 2 mL) was slurryed, filtered, and dried to obtain a pale yellow solid A51 dihydrochloride (25 mg, 86%).

[0400] [Example]

[52]

[0401] Compound A52 was synthesized by the following method:

[0402] A51 (30 mg, 0.058 mmol) and solid formaldehyde (18 mg, 0.58 mmol) were dissolved in 1,2-dichloroethane (2 mL) and reacted at room temperature for 4 hours. Sodium borohydride acetate (124 mg, 0.58 mmol) was added, and the reaction was allowed to proceed overnight. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL), extracted with dichloromethane (10 mL × 3), and the organic phases were combined, concentrated, and subjected to preparative plate chromatography to obtain a white crude product. The product was then slurried with diethyl ether to obtain a white solid A52 (6 mg, 20%).

[0403] [Example]

[53]

[0404] Compound A53 was synthesized by the following method:

[0405] Intermediate 10 (50 mg, 0.11 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and potassium carbonate (121 mg, 0.88 mmol) was added at room temperature. The mixture was stirred in a microwave reactor at 125 °C for 1 hour. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL × 3), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by alkaline alumina column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid product. The product was then slurried in ethyl acetate / diethyl ether (5 mL / 5 mL), filtered, and a white solid product A53 (20 mg, 37%) was obtained.

[0406] [Example]

[54]

[0407] Compound A54 was synthesized by the following method:

[0408] Synthesis of intermediate A54-1:

[0409] 5-Hydroxy-2-methoxypyridine (4.8 g, 38 mmol) was dissolved in concentrated sulfuric acid (20 mL), and potassium nitrate (4.6 g, 46 mmol) was slowly added in portions at -10 °C while stirring at low temperature for 2 hours. The reaction solution was poured into ice water, filtered, and dried to obtain a yellow solid A54-1 (5.0 g, 77%).

[0410] 1H-NMR (300 MHz, CDCl 3): δ 10.18 (s, 1H), 7.54 (d, J= 9.0 Hz, 1H), 7.11 (d, J= 9.0 Hz, 1H), 3.98 (s, 3H).

[0411] Synthesis of intermediate A54-2:

[0412] Dissolve A54-1 (4.0 g, 24 mmol) and ammonium chloride (24 g, 470 mmol) in a tetrahydrofuran / water mixture (80 mL / 30 mL). Slowly add zinc powder (12 g, 188 mmol) at 50 °C and stir for 5 hours. Filter the reaction mixture, dilute the filtrate with saturated sodium bicarbonate aqueous solution (30 mL), extract with ethyl acetate (20 mL × 3), dry to anhydrous sodium sulfate, concentrate, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give black solid A54-2 (2.7 g, 82%).

[0413] 1H-NMR (300 MHz, DMSO- d 6 ): δ 8.69 (s, 1H), 6.95-6.70 (m, 1H), 5.87-5.66 (m, 1H), 5.35 (s, 2H), 3.65 (s, 3H).

[0414] Synthesis of intermediate A54-3:

[0415] Dissolve A54-2 (1.0 g, 7.1 mmol) in pyridine (20 mL), add potassium ethyl xanthate (1.7 g, 11 mmol), and reflux at 120 °C overnight with stirring. Pour the reaction solution into ice water, adjust the pH to 4 with 3 N dilute hydrochloric acid, filter, and wash with water to obtain a yellow solid A54-3 (1.0 g, 77%).

[0416] 1H-NMR (300 MHz, CDCl 3): δ 7.49 (d, J= 8.8 Hz, 1H), 6.60 (d, J= 9.3 Hz, 1H), 3.92 (s, 3H). LC-MS: m / z 183.1 [M+H] +.

[0417] Synthesis of intermediate A54-4:

[0418] A54-3 (1.1 g, 6.0 mmol) was dissolved in ethyl acetate (20 mL), and potassium carbonate (1.6 g, 12 mmol) and methyl iodoform (1.7 g, 12 mmol) were added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to dryness, diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give a yellow solid A54-4 (1.8 g, 81%).

[0419] 1H-NMR (300 MHz, CDCl 3): δ 7.81 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.5 Hz, 1H), 4.19 (s, 3H), 2.98 (s, 3H).

[0420] Synthesis of intermediate A54-5:

[0421] A54-4 (1.0 g, 5.1 mmol) and morpholine (2.5 g, 28 mmol) were dissolved in tetrahydrofuran (5 mL), stirred overnight at 90 °C, concentrated, mixed with water (20 mL), filtered, and dried to obtain brown solid A54-5 (700 mg, 58%).

[0422] 1H-NMR (300 MHz, CDCl 3): δ 7.39 (d, J= 8.4 Hz, 1H), 6.37 (d, J= 8.4 Hz, 1H), 3.96 (s, 3H), 3.84-3.79 (m, 4H), 3.74-3.68 (m, 4H).

[0423] Synthesis of intermediate A54-6:

[0424] Dissolve A54-5 (100 mg, 0.42 mmol) in dry acetonitrile (15 mL), slowly add NBS (91 mg, 0.51 mmol) in portions at room temperature, stir at room temperature for 2 hours, dilute with ethyl acetate (20 mL), wash with 1 N sodium hydroxide (20 mL × 3) aqueous solution, dry with anhydrous sodium sulfate, concentrate to obtain white solid A54-6 (90 mg, 68%).

[0425] 1H-NMR (300 MHz, CDCl 3): δ 7.65 (s, 1H), 4.04 (s, 3H), 3.85-3.78 (m, 4H), 3.76-3.69 (m, 4H). LC-MS: m / z 313.9 [M+H] +.

[0426] Synthesis of intermediate A54-7:

[0427] A54-6 (500 mg, 1.6 mmol), ethyl acrylate (3.2 g, 32 mmol), palladium acetate (72 mg, 0.32 mmol), tris(o-methylphenyl)phosphine (146 mg, 0.48 mmol), and triethylamine (485 mg, 4.8 mmol) were suspended in dry N,N-dimethylformamide (20 mL) under nitrogen protection and reacted overnight at 140 °C. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give a pale yellow oily product A54-7 (400 mg, 75%).

[0428] 1H-NMR (300 MHz, CDCl 3): δ 7.91 (d, J= 15.9 Hz, 1H), 7.57 (s, 1H), 6.42 (d, J= 16.2 Hz, 1H), 4.26 (q, 7.2 Hz, 2H), 4.05 (s, 3H), 3.86-3.70 (m, 8H), 1.33 (t, J= 7.2 Hz, 3H).

[0429] Synthesis of intermediate A54-8:

[0430] A54-7 (150 mg, 0.45 mmol) was dissolved in a dichloromethane / methanol mixture (30 mL / 3 mL), and ozone was bubbled through at -78 °C for 5 minutes. Then, dimethyl sulfide (0.5 mL) was added to quench the reaction, and the mixture was brought to room temperature. The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give a pale yellow solid product A54-8 (100 mg, 84%).

[0431] 1H-NMR (300 MHz, CDCl 3): δ 10.29 (s, 1H), 7.87 (s, 1H), 4.09 (s, 3H), 3.82 (s, 8H).

[0432] Synthesis of intermediate A54-9:

[0433] Dissolve A54-8 (90 mg, 0.34 mmol) in terbutanol / water (10 mL / 10 mL), add 2-methyl-2-butene (238 mg, 3.4 mmol) at room temperature, then slowly add an aqueous solution (10 mL) of sodium dihydrogen phosphate dihydrate (530 mg, 3.4 mmol) and sodium chlorite (192 mg, 0.34 mmol). Stir at room temperature for 2 hours, dilute with water (30 mL), adjust pH to 3-4 with 1 N dilute hydrochloric acid, extract with dichloromethane (20 mL × 3), wash with saturated brine, concentrate, and obtain a white solid A54-9 (70 mg, 74%).

[0434] 1H-NMR (300 MHz, DMSO- d 6 ): δ 8.05 (s, 1H), 3.89 (s, 3H), 3.77-3.70 (m, 4H), 3.70-3.62 (m, 4H).

[0435] Synthesis of final product A54:

[0436] A54-9 (40 mg, 0.14 mmol) was dissolved in dry N,N-dimethylformamide (2 mL), and triethylamine (97 mg, 0.70 mmol) and 2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyridine (49 mg, 0.28 mmol) were added. While stirring, a solution of T 3P (222 mg, 0.7 mmol) in N,N-dimethylformamide was added, and the mixture was microwaved at 100 °C for 2 hours. The reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (20 mL × 3), washed with saturated brine, concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v). The mixture was then slurried with diethyl ether (3 mL), filtered, and dried to obtain a white solid A54 (16 mg, 26%).

[0437] [Example]

[55]

[0438] Compound A55 was synthesized by the following method:

[0439] Synthesis of intermediate A55-1:

[0440] A26-1 (500 mg, 2.2 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (2 mL) was added dropwise. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in methanol (3 mL). A saturated sodium bicarbonate solution (8 mL) was added, and the mixture was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure until dry, and anhydrous sodium sulfate (500 mg) and a mixed solvent of dichloromethane and methanol (15:1, 30 mL) were added. The mixture was filtered, and the filtrate was concentrated to obtain a green oily substance A55-1 (110 mg, 43%).

[0441] 1H-NMR (300 MHz, CDCl 3): δ 5.55 (s, 1H), 3.69 (t, J= 6.0 Hz, 2H), 3.37-3.30 (m, 2H), 2.97 (t, J= 5.7 Hz, 2H), 2.24 (t, J= 5.7 Hz, 2H), 2.06-2.00 (m, 2H), 1.98-1.95 (m, 2H).

[0442] Synthesis of intermediate A55-2:

[0443] A51-6 (100 mg, 0.18 mmol), A55-1 (200 mg, 1.5 mmol), and potassium carbonate (125 mg, 0.9 mmol) were sequentially suspended in 1,4-dioxane (3 mL) and reacted at 105 °C for 36 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a yellow solid intermediate A55-2 (40 mg, 54%).

[0444] 1H-NMR (300 MHz, DMSO- d 6): δ 12.40 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 8.05 (d, J= 7.8 Hz, 1H), 7.92 (s, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.37 (d, J= 7.5 Hz, 1H), 5.65-5.56 (m, 1H), 4.52-4.43 (m, 1H), 3.89 (s, 3H), 3.80-3.61 (m, 6H), 3.58-3.44 (m, 6H), 3.26-3.18 (m, 2H), 2.45-2.35 (m, 2H), 2.27-2.15 (m, 2H), 1.41 (s, 9H).LC-MS: m / z 629.9 [M+H] +.

[0445] Synthesis of final product A55:

[0446] A55-2 (90 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate solution (5 mL). Dichloromethane (6 mL × 3) was added for extraction. The organic phases were combined, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1, v / v) to obtain a white crude product. The crude product was then slurried with diethyl ether to obtain a white solid A55 (50 mg, 65%).

[0447] [Example]

[56]

[0448] Compound A56 was synthesized by the following method:

[0449] Synthesis of intermediate A56-1:

[0450] A51-6 (150 mg, 0.28 mmol), A25-1 (320 mg, 2.8 mmol), and potassium carbonate (192 mg, 1.4 mmol) were sequentially suspended in 1,4-dioxane (3 mL) and reacted at 105 °C for 36 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid intermediate A56-1 (96 mg, 55%).

[0451] Synthesis of final product A56:

[0452] A56-1 (94 mg, 0.15 mmol) was dissolved in ethyl acetate (2 mL), and 3.6 N ethyl acetate hydrochloride solution (3 mL) was added. The reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate solution (5 mL). Dichloromethane (6 mL × 3) was added for extraction. The organic phases were combined, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1, v / v) to obtain a white crude product. The product was then slurried with diethyl ether to obtain a white solid A56 (38 mg, 49%).

[0453] [Example]

[57]

[0454] Compound A57 was synthesized by the following method:

[0455] Synthesis of final product A57:

[0456] A51 (30 mg, 0.058 mmol), 2-bromoethanol (10.8 mg, 0.087 mmol), and potassium carbonate (16 mg, 0.12 mmol) were dissolved in dry DMF (2 ml) and stirred overnight at 100 °C. The solution was diluted with water (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 50 / 1, v / v). The solution was then slurried in diethyl ether, filtered, and dried to give a white solid A57 (5 mg, 15%).

[0457] [Example]

[58]

[0458] Compound A58 was synthesized by the following method:

[0459] A55 (15 mg, 0.028 mmol), paraformaldehyde (10 mg, 0.028 mmol), sodium acetate (4 mg, 0.042 mmol), and sodium cyanoborohydride (6 mg, 0.042 mmol) were sequentially suspended in methanol (3 mL) and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 10 / 1, v / v) to obtain a white solid A58 (12 mg, 80%).

[0460] [Example]

[59]

[0461] Compound A59 was synthesized by the following method:

[0462] A56 (15 mg, 0.028 mmol), paraformaldehyde (10 mg, 0.028 mmol), sodium acetate (4 mg, 0.042 mmol), and sodium cyanoborohydride (6 mg, 0.042 mmol) were sequentially suspended in methanol (3 mL) and stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 10 / 1, v / v) to obtain a white solid A59 (6 mg, 40%).

[0463] [Example]

[60]

[0464] Compound B1 was synthesized by the following method:

[0465] Synthesis of intermediate B1-1

[0466] 2,6-Difluoro-3-bromopyridine (200 mg, 1.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen protection. Butyllithium (0.44 mL, 1.1 mmol) was slowly added at -78 °C, and the mixture was stirred for 30 minutes. Then, 2,2-dimethylethylene oxide (86 mg, 1.2 mmol) and boron trifluoride diethyl ether solution (0.15 mL, 1.2 mmol) were slowly added, and the reaction was carried out at -78 °C for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to give a yellow oily intermediate B1-1 (50 mg, 27%).

[0467] 1H-NMR (300 MHz, CDCl 3): δ 7.82 (dd, J= 16.5, 8.1 Hz, 1H), 6.79 (d, J= 8.1 Hz, 1H), 2.78 (s, 2H), 1.26 (s, 6H).

[0468] Synthesis of intermediate B1-2

[0469] Intermediate B1-1 (40 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran (10 mL), and potassium terbutoxide (47 mg, 0.42 mmol) was slowly added in portions at room temperature. The mixture was stirred and refluxed overnight at 50 °C. The reaction solution was diluted with ethyl acetate (10 mL), washed three times with water (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give colorless oily intermediate B1-2 (10 mg, 28%).

[0470] 1H-NMR (300 MHz, CDCl 3): δ 7.52-7.38 (m, 1H), 6.35 (d, J= 6.9 Hz, 1H), 2.99 (s, 2H), 1.51 (s, 6H).

[0471] Synthesis of intermediate B1-3

[0472] B1-2 (1.0 g, 6.0 mmol) was dissolved in dry acetonitrile (100 mL), and NBS (1.6 g, 9.0 mmol) was slowly added. The reaction was carried out under nitrogen protection at room temperature for 24 hours. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL × 3), the organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give yellow solid B1-3 (300 mg, 21%).

[0473] 1H-NMR (300 MHz, CDCl 3): δ 7.60 (d, J= 8.3 Hz, 1H), 3.01 (s, 2H), 1.51 (s, 6H).

[0474] Synthesis of intermediate B1-4

[0475] B1-3 (100 mg, 0.41 mmol), tris(o-methylphenyl)phosphine (36 mg, 0.12 mmol), palladium acetate (9.0 mg, 0.04 mmol), and triethylamine (121 mg, 1.2 mmol) were dissolved sequentially in dry DMF (2 mL). Finally, ethyl acrylate (810 mg, 8.1 mmol) was added. Under nitrogen protection, the mixture was microwaved at 140 °C for 2 hours. After the reaction was complete, the solvent was removed by rotary evaporation, and the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a pale yellow intermediate B1-4 (50 mg, 46%).

[0476] 1H-NMR (300 MHz, CDCl 3): δ 7.68 (d, J= 16.5 Hz, 1H), 7.68 (s, 1H), 6.33 (d, J= 16.2 Hz, 1H), 4.24 (q, J= 7.2 Hz, 2H), 3.03 (s, 2H), 1.53 (s, 6H), 1.32 (t, J= 7.2 Hz, 3H).

[0477] Synthesis of intermediate B1-5

[0478] B1-4 (50 mg, 0.18 mmol) was dissolved in a dichloromethane / methanol mixed solvent (30 mL / 3 mL), ozone was introduced at -78 °C for 10 minutes, then dimethyl sulfide (0.5 mL) was added to quench the reaction, the mixture was brought to room temperature, and concentrated to obtain a pale yellow solid product B1-5 (40 mg).

[0479] 1H-NMR (300 MHz, CDCl 3): δ 10.14 (s, 1H), 8.01 (d, J= 8.7 Hz, 1H), 3.06 (s, 2H), 1.57 (s, 6H).

[0480] Synthesis of intermediate B1-6

[0481] Dissolve B1-5 (50 mg, 0.25 mmol) in terbutanol / water (5 mL / 5 mL), add 2-methyl-2-butene (175 mg, 2.5 mmol) at room temperature, then slowly add an aqueous solution of sodium dihydrogen phosphate dihydrate (390 mg, 2.5 mmol) and sodium chlorite (112 mg, 1.2 mmol), stir at room temperature for 2 hours, dilute with water (10 mL), adjust the pH to 3-4 with 1 N dilute hydrochloric acid, extract with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated brine, concentrate, and give white solid B1-6 (40 mg, 77%).

[0482] 1H-NMR (300 MHz, DMSO- d 6 ): δ 8.13 (d, J= 9.3 Hz, 1H), 3.07 (s, 2H), 1.48 (s, 6H).

[0483] Synthesis of intermediate B1-7

[0484] B1-6 (40 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of HATU (106 mg, 0.28 mmol) and N,N-diisopropylethylamine (49 mg, 0.38 mmol). The mixture was stirred at room temperature for 5 minutes, and then 2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyridine (49 mg, 0.28 mmol) was added. The mixture was stirred overnight at 80 °C. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow oily intermediate B1-7 (10 mg, 14%).

[0485] 1H-NMR (300 MHz, CDCl 3): δ 9.01 (d, J= 13.8 Hz, 1H), 8.32 (d, J= 9.6 Hz, 1H), 8.12 (d, J= 8.1 Hz, 1H), 7.92 (d, J= 3.6 Hz, 1H), 7.70 (t, J= 7.8 Hz, 1H), 7.23 (d, J= 7.8 Hz, 1H), 3.96 (s, 3H), 3.09 (s, 2H), 1.57 (s, 6H).

[0486] Synthesis of final product B1

[0487] Intermediate B1-7 (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), followed by the addition of potassium carbonate (207 mg, 1.5 mmol) and 4-methoxypiperidine hydrochloride (226 mg, 1.5 mmol). The mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a white solid product B1 (14 mg, 20%).

[0488] [Example]

[61]

[0489] Compound B2 was synthesized by the following method:

[0490] Intermediate B1-7 (30 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of N-methylpiperazine (41 mg, 0.41 mmol) and potassium carbonate (56 mg, 0.41 mmol). The mixture was heated at 100 °C for approximately 5 hours. The reaction solution was cooled to room temperature, washed with ethyl acetate (30 mL) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid B2 (22 mg, 61%).

[0491] [Example]

[62]

[0492] Compound B3 was synthesized by the following method:

[0493] Intermediate B1-7 (30 mg, 0.08 mmol), 1-(2-hydroxyethyl)piperazine (53 mg, 0.41 mmol), and potassium carbonate (57 mg, 0.41 mmol) were dissolved in dry DMF (3 ml) and stirred at 100 °C for 5 hours. The solution was diluted with water (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 40 / 1, v / v). The solution was then slurried in diethyl ether, filtered, and dried to give a white solid B3 (21 mg, 54%).

[0494] [Example]

[63]

[0495] Compound B4 was synthesized by the following method:

[0496] Intermediate B1-7 (50 mg, 0.14 mmol) was dissolved in DMF (5 mL), followed by the addition of potassium carbonate (94 mg, 0.68 mmol) and N-cyclopropylpiperazine (86 mg, 0.68 mmol). The mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (10 mL), slurried, filtered, and dried to obtain a white solid B4 (24 mg, 37%).

[0497] [Example]

[64]

[0498] Compound B5 was synthesized by the following method:

[0499] Intermediate B1-7 (30 mg, 0.08 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of piperidine-4-ol (41 mg, 0.41 mmol) and potassium carbonate (56 mg, 0.41 mmol). The mixture was heated at 100 °C for approximately 5 hours. The reaction solution was cooled to room temperature, washed with ethyl acetate (30 mL) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid B5 (22 mg, 61%).

[0500] [Example]

[65]

[0501] Compound B6 was synthesized by the following method:

[0502] Intermediate B1-7 (35 mg, 0.096 mmol), 1-oxa-7-azaspiro[3.5]nonane (60 mg, 0.48 mmol), and potassium carbonate (68 mg, 0.48 mmol) were sequentially suspended in DMF (2 mL) and reacted overnight at 100 °C. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to obtain a white solid crude product. The crude product was then slurried with diethyl ether to obtain a white solid B6 (17 mg, 38%).

[0503] [Example]

[66]

[0504] Compound B7 was synthesized by the following method:

[0505] Intermediate B1-7 (35 mg, 0.096 mmol), 4-methylpiperidin-4-ol (55 mg, 0.48 mmol), and potassium carbonate (65 mg, 0.48 mmol) were sequentially suspended in DMF (2 mL) and reacted overnight at 100 °C. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by preparative plate chromatography (dichloromethane / methanol = 20 / 1, v / v) to obtain a white crude solid. This crude solid was then slurried with diethyl ether to obtain a white solid B7 (23 mg, 52%).

[0506] [Example]

[67]

[0507] Compound B8 was synthesized by the following method:

[0508] Intermediate B1-7 (35 mg, 0.09 mmol) and 4,7-diazaspiro[2.5]octane (51 mg, 0.45 mmol) were dissolved in 1,4-dioxane (8 mL), and potassium carbonate (62 mg, 0.45 mmol) was added. The mixture was reacted overnight at 110 °C. After the reaction was complete, the solvent was removed by rotary evaporation, and the mixture was purified by thick-plate chromatography (dichloromethane / methanol = 20 / 1, v / v). The mixture was then slurried in diethyl ether / ethyl acetate (4 mL / 2 mL), filtered, and a white solid B8 (29 mg, 69%) was obtained.

[0509] [Example]

[68]

[0510] Compound B9 was synthesized by the following method:

[0511] Synthesis of intermediate B9-1:

[0512] (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (2.8 g, 27 mmol), DPPA (8.1 g, 30 mmol), and triethylamine (8.1 g, 81 mmol) were dissolved sequentially in terbutanol (120 mL) under nitrogen protection and reacted at 90 °C for 72 hours. A saturated sodium bicarbonate solution (50 mL) was added, followed by extraction with ethyl acetate (60 mL × 2). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give a green oily substance B9-1 (3.4 g, 72%).

[0513] 1H-NMR (300 MHz, CDCl 3): δ 4.83 (s, 1H), 4.58 (d, J= 63.6 Hz, 1H), 2.62-2.52 (m, 1H), 1.45 (s, 9H), 1.10-0.82 (m, 2H).

[0514] Synthesis of intermediate B9-2:

[0515] B9-1 (2.1 g, 12 mmol) was dissolved in ethyl acetate (10 mL), and 3 N ethyl acetate hydrochloride solution (24 mL) was added. The reaction was allowed to proceed overnight. The reaction solution was concentrated and slurryed with diethyl ether to give a white solid B9-2 (1.3 g, 98%).

[0516] 1H-NMR (300 MHz, DMSO- d 6 ): δ 8.69 (s, 2H), 4.88 (d, J= 63.9 Hz, 1H), 2.69-2.54 (m, 1H), 1.27-1.01 (m, 2H).

[0517] Synthesis of intermediate B9-3:

[0518] B9-2 (777 mg, 7.0 mmol), dimethyl (E)-2-(3-methoxyallyl)malonate (2.1 g, 10 mmol), and triethylamine (2.1 g, 21 mmol) were dissolved sequentially in dry methanol (12 mL) and reacted at room temperature for 3 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid B9-3 (1.1 g, 65%).

[0519] 1H-NMR (300 MHz, CDCl 3): δ 7.64 (d, J= 12.3 Hz, 1H), 7.10-6.99 (m, 1H), 6.39 (t, J= 12.9 Hz, 1H), 5.09 (s, 1H), 4.72 (d, J= 64.2 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 2.60 (s, 1H), 1.27-1.16 (m, 1H), 1.07-0.91 (m, 1H).

[0520] Synthesis of intermediate B9-4:

[0521] B9-3 (960 mg, 4 mmol) and potassium hydroxide (360 mg, 6.4 mmol) were dissolved in dry ethanol (15 mL). After reacting at room temperature for 1 hour, the reaction was transferred to 90 °C and reacted for 3 hours. The reaction solution was concentrated, and the residue was diluted with water (10 mL). The pH was adjusted to 1-2 with 2 N dilute hydrochloric acid, and a large amount of yellow solid precipitated. The solid was extracted with ethyl acetate (30 mL × 2). The organic phases were combined and concentrated to obtain yellow solid B9-4 (760 mg, 96%).

[0522] 1H-NMR (300 MHz, CDCl 3): δ 14.07 (s, 1H), 8.53 (d, J= 7.2 Hz, 1H), 7.70 (d, J= 6.9 Hz, 1H), 6.57 (t, J= 6.9 Hz, 1H), 4.97 (d, J= 60.0 Hz, 1H), 3.47-3.32 (m, 1H), 1.71-1.53​​ (m, 2H).

[0523] Synthesis of intermediate B9-5:

[0524] B9-4 (760 mg, 3.9 mmol), DPPA (1.3 g, 4.6 mmol), and triethylamine (600 mg, 5.9 mmol) were dissolved sequentially in terbutanol (25 mL) and reacted at 90 °C for 4 hours under nitrogen protection. The reaction was quenched with saturated brine (15 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a yellow solid B9-5 (480 mg, 48%).

[0525] 1H-NMR (300 MHz, CDCl 3): δ 8.01-7.92 (m, 1H), 7.65 (s, 1H), 6.96 (d, J= 6.3 Hz, 1H), 6.21 (t, J= 7.2 Hz, 1H), 4.91 (d, J= 64.5 Hz, 1H), 3.34-3.23 (m, 1H), 1.39-1.20 (m, 2H), 1.50 (s, 9H).

[0526] Synthesis of intermediate B9-6:

[0527] B9-5 (450 mg, 1.6 mmol) was dissolved in ethyl acetate (2 mL), and 3 N hydrochloric acid ethyl acetate solution (12 mL) was added. The reaction mixture was reacted for 3 hours. The reaction solution was concentrated, and the residue was adjusted to pH 7-8 with saturated sodium bicarbonate solution. Ethyl acetate (20 mL × 2) was added for extraction. The organic phases were combined and concentrated to give a yellow oil (255 mg, 95%).

[0528] 1H-NMR (300 MHz, CDCl 3): δ 6.77 (d, J= 6.9 Hz, 1H), 6.52 (d, J= 6.0 Hz, 1H), 6.06 (t, J= 6.9 Hz, 1H), 4.89 (d, J= 60.0 Hz, 1H), 4.21 (s, 2H), 3.34-3.21 (m, 1H), 1.50-1.35 (m, 2H).

[0529] Synthesis of intermediate B9-7:

[0530] B1-6 (104 mg, 0.49 mmol) was dissolved in 10 mL of dry dichloromethane. Xylene chloride (1.2 g, 9.8 mmol) was added, followed by a catalytic amount of DMF (0.05 mL). The reaction was carried out at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to dryness to obtain crude xylene chloride. B9-6 was dissolved in 10 mL of dry dichloromethane. DIPEA (126 mg, 0.98 mmol) was added, followed by a slow addition of the crude xylene chloride solution in dichloromethane. The reaction was carried out at room temperature for 5 hours. The reaction was quenched with 5 mL of saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined and concentrated to obtain a pale yellow solid, B9-7 (100 mg, 56%).

[0531] 1H-NMR (300 MHz, CDCl 3): δ 9.72 (s, 1H), 8.49 (s, 1H), 8.37-8.13 (m, 1H), 7.15-7.01 (m, 1H), 6.37-6.19 (m, 1H), 4.91 (d, J= 60.3 Hz, 1H), 3.40-3.21 (m, 1H), 3.06 (s, 2H), 1.46-1.35 (m, 2H), 1.23 (s, 6H).

[0532] Synthesis of final product B9:

[0533] Intermediate B9-7 (100 mg, 0.27 mmol) was dissolved in dry 1,4-dioxane (10 mL), and potassium carbonate (190 mg, 1.4 mmol) and piperidine-4-ol (139 mg, 1.4 mmol) were added. The mixture was stirred overnight at 100 °C. The reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a yellow solid B9 (69 mg, 58%).

[0534] [Example]

[69]

[0535] Compound B10 was synthesized by the following method:

[0536] Synthesis of intermediate B10-1:

[0537] 2-Hydroxy-3-aminopyridine (1.2 g, 11 mmol) was dissolved in water (150 mL), followed by the addition of sodium carbonate (2.6 g, 24 mmol) and sodium bicarbonate (1.0 g, 12 mmol) to adjust the pH to 7-8. Acetone (20 mL) was then added, and the mixture was stirred in an ice bath until the solution cooled to 0°C. Benzyl chloroformate (2.1 g, 12 mmol) was then slowly added dropwise, and the mixture was slowly heated to room temperature. After stirring for 4 hours, ethyl acetate (100 mL) was added to dilute the reaction solution. The mixture was filtered, and the filtrate was washed three times with water (100 mL), dried over anhydrous sodium sulfate, and concentrated to give a white solid crude product. Ethyl acetate (20 mL) was then added, and the mixture was stirred for 3 hours, filtered, to give a white solid intermediate B10-1 (2 g, 74%).

[0538] 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.92 (s, 1H), 8.31 (s, 1H), 7.83 (d, J= 8.7 Hz, 1H), 7.47-7.25 (m, 5H), 7.07 (d, J= 6.6 Hz, 1H), 6.23 (t, J= 6.6 Hz, 1H), 5.15 (s, 2H). LC-MS: m / z 244.9 [M+H] +.

[0539] Synthesis of intermediate B10-2:

[0540] Intermediate B10-1 (1.4 g, 5.7 mmol), potassium cyclopropyltrifluoroborate (1.7 g, 11.5 mmol), copper acetate (1.2 g, 6.0 mmol), 2,2′-bipyridine (0.94 g, 6.0 mmol), and sodium carbonate (1.3 g, 13 mmol) were dissolved in 1,2-dichloroethane (35 mL) and heated in air at 70 °C for 15 hours. The solution was diluted with ethyl acetate (40 mL), filtered, and the filtrate was further diluted with ethyl acetate (100 mL). The solution was washed successively with water (80 mL), 0.5 N dilute hydrochloric acid (80 mL), water (80 mL), and saturated brine (80 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a black oily intermediate B10-2 (327 mg, 20%).

[0541] 1H-NMR (300 MHz, CDCl 3): δ 7.97 (s, 1H), 7.93-7.87 (m, 1H), 7.43-7.31 (m, 4H), 7.28-7.20 (m, 1H), 7.02-6.87 (m, 1H), 6.26-6.08 (m, 1H), 5.19 (s, 2H), 3.50-3.14 (m, 1H), 1.16-1.08 (m, 2H), 0.97-0.79 (m, 2H). LC-MS: m / z 284.9 [M+H] +.

[0542] Synthesis of intermediate B10-3:

[0543] Intermediate B10-2 (320 mg, 1.1 mmol) and 5% palladium on carbon (90 mg, 0.040 mmol) were dissolved in a methanol / tetrahydrofuran mixed solvent (45 mL / 15 mL), stirred overnight in a hydrogen atmosphere, filtered through diatomaceous earth, and the filtrate was concentrated to obtain a gray oily intermediate B10-3 (150 mg, 88%).

[0544] 1H-NMR (300 MHz, CDCl 3): δ 6.73 (d, J= 6.3 Hz, 1H), 6.50 (d, J= 7.5 Hz, 1H), 6.02 (t, J= 6.3 Hz, 1H), 4.20 (s, 2H), 2.73-2.52 (m, 1H), 1.21-1.02 (m, 2H), 0.89-0.80 (m, 2H). LC-MS: m / z 151.0 [M+H] +.

[0545] Synthesis of intermediate B10-4:

[0546] Intermediate B1-6 (100 mg, 0.47 mmol) was dissolved in dry dichloromethane (5 mL), and oxalic acid (895 mg, 7.0 mmol) was added. Then, one drop of DMF was added dropwise to catalyze the reaction. After approximately 6 hours, the reaction was complete, and the mixture was concentrated to dryness under reduced pressure to obtain oxalic acid for later use. Intermediate B10-3 (66 mg, 0.44 mmol) was dissolved in dry dichloromethane (5 mL), and oxalic acid was dissolved in dry dichloromethane (5 mL). The solutions were slowly added dropwise to the reaction system under an ice-water bath. Then, N,N-diisopropylethylamine (68 mg, 0.53 mmol) was added, the reaction temperature was raised to room temperature, and stirring continued overnight. The mixture was concentrated, and the residue was precipitated by silica gel column chromatography (dichloromethane / methanol = 50 / 1, v / v) to obtain a gray oily intermediate B10-4 (60 mg, 39%).

[0547] 1H-NMR (300 MHz, CDCl 3): δ 9.77 (s, 1H), 8.44 (s, 1H), 8.26 (d, J= 7.5 Hz, 1H), 7.04 (d, J= 10.2 Hz, 1H), 6.39-6.12 (m, 1H), 3.53-3.24 (m, 1H), 3.05 (s, 2H), 1.54 (s, 6H), 1.21-1.01 (m, 2H), 0.97-0.83 (m, 2H). LC-MS: m / z 344.1 [M+H] +.

[0548] Synthesis of final product B10:

[0549] Intermediate B10-4 (60 mg, 0.17 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of piperidine-4-ol (88 mg, 0.87 mmol) and potassium carbonate (121 mg, 0.96 mmol). The mixture was stirred overnight at 100 °C. The reaction solution was cooled to room temperature and concentrated under reduced pressure until dry. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid crude product. Diethyl ether (10 mL) was added and the mixture was stirred for 3 hours. After filtration, a white solid B10 (16 mg, 19%) was obtained.

[0550] [Example]

[70]

[0551] Compound B11 was synthesized by the following method:

[0552] Anhydrous methanol (87 mg, 2.7 mmol) was dissolved in dry DMF (5 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour, and B1-7 (50 mg, 0.14 mmol) was added. The mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1, v / v) to give white solid B11 (20 mg, 39%).

[0553] [Example]

[71]

[0554] Compound B12 was synthesized by the following method:

[0555] Ethanol (150 mg, 3.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 60% sodium hydride (131 mg, 3.3 mmol) was added. The mixture was stirred at room temperature for 1 hour. Intermediate B1-7 (60 mg, 0.16 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, and ethyl acetate (20 mL) was added. The mixture was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and then slurried with diethyl ether (10 mL) for 3 hours. The mixture was filtered to give a white solid B12 (26 mg, 48%).

[0556] [Example]

[72]

[0557] Compound B13 was synthesized by the following method:

[0558] Isopropanol (163 mg, 2.7 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, and ethyl acetate (20 mL) was added. The mixture was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and then slurried with diethyl ether (10 mL) for 3 hours. The mixture was filtered to give a white solid B13 (26 mg, 47%).

[0559] [Example]

[73]

[0560] Compound B14 was synthesized by the following method:

[0561] Cyclobutanol (19 mg, 0.27 mmol) was dissolved in dry THF (5 mL), and 60% sodium hydride (16 mg, 0.39 mmol) was added. The mixture was stirred at room temperature for 1 hour, and B1-7 (50 mg, 0.13 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried with ethanol / ether (10 / 1, v / v). The mixture was filtered, dried, and a white solid B14 (28 mg, 52%) was obtained.

[0562] [Example]

[74]

[0563] Compound B15 was synthesized by the following method:

[0564] Cyclopentanol (232 mg, 2.7 mmol) was dissolved in dry DMF (5 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (8 mL), filtered, slurried, and dried to obtain a white solid B15 (16 mg, 27%).

[0565] [Example]

[75]

[0566] Compound B16 was synthesized by the following method:

[0567] Oxalide-3-ol (201 mg, 2.7 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, ethyl acetate (20 mL), washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and then slurried with diethyl ether (10 mL) for 3 hours. The mixture was filtered to give a white solid B16 (20 mg, 35%).

[0568] [Example]

[76]

[0569] Compound B17 was synthesized by the following method:

[0570] (S)-Tetrahydrofuran-3-ol (238 mg, 2.7 mmol) was dissolved in dry DMF (5 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (8 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed three times (15 mL × 3) with saturated sodium chloride solution (45 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by preparative plate chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a white solid B17 (12 mg, 20%).

[0571] [Example]

[77]

[0572] Compound B18 was synthesized by the following method:

[0573] Ethylene glycol (169 mg, 2.7 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, ethyl acetate (20 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid B18 (8 mg, 14%).

[0574] [Example]

[78]

[0575] Compound B19 was synthesized by the following method:

[0576] 2-Methoxyethanol (207 mg, 2.7 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, ethyl acetate (20 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid B19 (23 mg, 40%).

[0577] [Example]

[79]

[0578] Compounds B34 and B20 were synthesized by the following method:

[0579] Synthesis of final product B34:

[0580] Intermediate B1-7 (350 mg, 0.95 mmol) was dissolved in a 1,4-dioxane / water mixed solvent (45 mL / 45 mL), followed by the addition of potassium carbonate (1.3 g, 9.4 mmol), and stirred at 72 °C for 4 hours. The mixture was then concentrated under reduced pressure to dryness and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1, v / v) to give a yellow solid B34 (170 mg, 49%).

[0581] Synthesis of final product B20:

[0582] B34 (60 mg, 0.16 mmol) was dissolved in N-methylpyrrolidone (9 mL), followed by the addition of sodium difluorochloroacetate (63 mg, 0.41 mmol) and potassium carbonate (57 mg, 0.41 mmol). The mixture was stirred at 70 °C for 15 hours. The reaction was then quenched with water (15 mL), extracted with ethyl acetate (20 mL), washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, and concentrated to give a white solid crude product. This crude product was then stirred with ethanol / ethanol (0.5 mL / 3 mL) for 3 hours, filtered, and yielded a white solid B20 (10 mg, 15%).

[0583] [Example]

[80]

[0584] Compound B21 was synthesized by the following method:

[0585] 1-Methylpyrrolidine-3-ol (131 mg, 1.3 mmol) was dissolved in dry DMF (5 mL), and 60% sodium hydride (52 mg, 1.3 mmol) was added. The mixture was stirred at room temperature for 1 hour, and B1-7 (50 mg, 0.14 mmol) was added. The mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give white solid B21 (17 mg, 29%).

[0586] [Example]

[81]

[0587] Compound B22 was synthesized by the following method:

[0588] Synthesis of intermediate B22-1:

[0589] 3-hydroxypyrrolidine-1-carboxylic acid tributyl ester (252 mg, 1.3 mmol) was dissolved in dry DMF (10 mL), 60% sodium hydride (54 mg, 1.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. B1-7 (100 mg, 0.27 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give white solid B22-1 (140 mg, 97%).

[0590] Synthesis of final product B22:

[0591] B22-1 (140 mg, 0.27 mmol) was dissolved in ethyl acetate (2 mL), and 3 N ethyl acetate hydrochloride solution (0.4 mL) was added. The mixture was reacted overnight at room temperature. After the reaction was completed, the reaction solution was concentrated, and the pH was adjusted to 7-8 by adding saturated sodium bicarbonate solution (5 mL). The solution was then extracted with ethyl acetate (6 mL × 3). The organic phases were combined, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to obtain a white crude product. The crude product was then slurried with diethyl ether to obtain a white solid B22 (37 mg, 32%).

[0592] [Example]

[82]

[0593] Compound B23 was synthesized by the following method:

[0594] Tetrahydropyran-4-ol (138 mg, 1.4 mmol) was dissolved in dry DMF (5 mL), and 60% sodium hydride (55 mg, 1.4 mmol) was added. The mixture was stirred at room temperature for 1 hour, and B1-7 (50 mg, 0.14 mmol) was added. The mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1, v / v) to give white solid B23 (24 mg, 39%).

[0595] [Example]

[83]

[0596] Compound B24 was synthesized by the following method:

[0597] Cyclopropylmethanol (196 mg, 2.7 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, ethyl acetate (20 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid B24 (30 mg, 52%).

[0598] [Example]

[84]

[0599] Compound B25 was synthesized by the following method:

[0600] Synthesis of intermediate B25-1:

[0601] 2-(N-Boc-N-methylamino)ethanol (73 mg, 0.41 mmol) was dissolved in dry DMF (5 mL), and anhydrous sodium carbonate (44 mg, 0.41 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (8 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by preparative plate chromatography (dichloromethane / methanol = 50 / 1, v / v) to give crude product B25-1 (35 mg, 49%).

[0602] 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.21 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 8.02-7.93 (m, 2H), 7.77 (t, J= 8.4 Hz, 1H), 7.38 (d, J= 8.4 Hz, 1H), 4.67 (t, J= 4.8 Hz, 2H), 3.89 (s, 3H), 3.68 (t, J= 4.8 Hz, 2H), 3.06 (s, 2H), 1.99 (s, 3H), 1.48 (s, 6H), 1.17 (s, 9H). LC-MS: m / z 522.9 [M+H] +.

[0603] Synthesis of final product B25:

[0604] B25-1 (35 mg, 0.07 mmol) was dissolved in dry DCM (25 mL), and trifluoroacetic acid (1 mL) was added at 0 °C. The mixture was then heated to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by thick silica gel chromatography (dichloromethane / methanol = 25 / 1, v / v) to give pure B25 (2 mg, 7%).

[0605] [Example]

[85]

[0606] Compound B26 was synthesized by the following method:

[0607] 1-Cyclopropylethanol (234 mg, 2.7 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, ethyl acetate (20 mL), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1, v / v) to give a white solid B26 (7 mg, 12%).

[0608] [Example]

[86]

[0609] Compound B27 was synthesized by the following method:

[0610] Synthesis of intermediate B27-1:

[0611] 3-(benzyloxy)-1-cyclobutanone (500 mg, 2.8 mmol) was dissolved in ethanol (10 mL), and sodium borohydride (173 mg, 4.6 mmol) was slowly added in portions at 0 °C. The reaction was carried out at 0 °C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give B27-1 (450 mg, 89%).

[0612] 1H-NMR (300 MHz, DMSO- d 6 ): δ 7.37-7.24 (m, 5H), 5.02 (d, J= 6.9 Hz, 1H), 4.33 (s, 2H), 3.74-3.61 (m, 1H), 3.59-3.47 (m, 1H), 3.39-3.38 (m, 2H), 1.79-1.64 (m, 2H). LC-MS: m / z 201.0 [M+Na] +.

[0613] Synthesis of intermediate B27-2:

[0614] Intermediate B27-1 (100 mg, 0.54 mmol) was dissolved in dry THF (5 mL), and 60% sodium hydride (33 mg, 0.82 mmol) was added in portions at 0 °C, with stirring at room temperature for 0.5 hours. Then, intermediate B1-7 (100 mg, 0.27 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a colorless oily crude product B27-2 (180 mg).

[0615] 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.52 (s, 1H), 8.29-8.16 (m, 2H), 8.06-7.93 (m, 2H), 7.80 (t, J= 8.1 Hz, 1H), 7.46-7.21 (m, 6H), 5.07-4.99 (m, 1H), 4.47 (s, 2H), 3.93-3.87 (m, 1H), 3.82 (s, 3H), 3.05 (s, 2H), 3.01-2.90 (m, 2H), 2.34-2.19 (m, 2H), 1.47 (s, 6H). LC-MS: m / z 525.8 [M+H] +.

[0616] Synthesis of final product B27:

[0617] Intermediate B27-2 (180 mg, 0.34 mmol) was dissolved in methanol (25 mL), and 5% palladium on carbon (30 mg) was added. The air was then replaced three times with hydrogen, followed by stirring overnight at room temperature. After filtering off the palladium on carbon, the solution was concentrated under reduced pressure to dryness, purified by column chromatography (dichloromethane / methanol = 30 / 1, v / v), slurryed, and dried to give a white solid B27 (30 mg, 25%).

[0618] [Example]

[87]

[0619] Compound B28 was synthesized by the following method:

[0620] 3-hydroxyazacyclobutane-1-carboxylic acid tributyl ester (467 mg, 2.7 mmol) was dissolved in dry DMF (5 mL), and 60% sodium hydride (108 mg, 2.7 mmol) was added. The mixture was stirred at room temperature for 1 hour, and B1-7 (100 mg, 0.27 mmol) was added. The mixture was stirred overnight at 100 °C. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a white oily intermediate. The intermediate was dissolved in 3 N hydrochloric acid-ethyl acetate solution to give B28 (20 mg, 16%).

[0621] [Example]

[88]

[0622] Compound B29 was synthesized by the following method:

[0623] Cyclopropanol (16 mg, 0.27 mmol) was dissolved in dry THF (5 mL), and 60% sodium hydride (16 mg, 0.39 mmol) was added. The mixture was stirred at room temperature for 1 hour, and B1-7 (50 mg, 0.13 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, slurried with diethyl ether, filtered, and dried to obtain white solid B29 (27 mg, 39%).

[0624] [Example]

[89]

[0625] Compound B30 was synthesized by the following method:

[0626] Synthesis of intermediate B30-1:

[0627] Azacyclobutane-3-ol (1.0 g, 9.2 mmol) was dissolved in tetrahydrofuran / water (20 mL / 10 mL), potassium carbonate was added and stirred for 30 minutes, and Cbz-Cl (1.7 g, 10 mmol) was slowly added dropwise under an ice-water bath, and the mixture was heated to room temperature and stirred overnight. The solution was diluted with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give colorless liquid B30-1 (560 mg, 31%).

[0628] 1H-NMR (300 MHz, CDCl 3): δ 7.37-7.31 (m, 5H), 5.08 (s, 2H), 4.66-4.55 (m, 1H), 4.27-4.18 (m, 2H), 3.94-3.83 (m, 2H), 2.78 (d, J= 4.5 Hz, 1H).

[0629] Synthesis of intermediate B30-2:

[0630] B30-1 (112 mg, 0.54 mmol) was dissolved in dry THF (5 mL), and 60% sodium hydride (32 mg, 0.81 mmol) was added. The mixture was stirred at room temperature for 1 hour, and B1-7 (100 mg, 0.27 mmol) was added. The mixture was stirred at room temperature overnight, diluted with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give white solid B30-2 (140 mg, 39%).

[0631] 1H-NMR (300 MHz, CDCl 3): δ 10.31 (s, 1H), 8.35 (s, 1H), 8.12 (d, J= 8.1 Hz, 1H), 7.93-7.89 (m, 2H), 7.69 (t, J= 7.5 Hz, 1H), 7.39-7.28 (m, 5H), 7.22 (d, J= 7.5 Hz, 1H), 5.65-5.45 (m, 1H), 5.13 (s, 2H), 4.65-4.51 (m, 2H), 4.42-4.17 (m, 2H), 3.90 (s, 3H), 3.04 (s, 2H), 1.55 (s, 6H).

[0632] Synthesis of final product B30:

[0633] B30-2 (140 mg, 0.25 mmol) was dissolved in methanol (20 mL), and 5% palladium on carbon (20 mg) was added. The air was replaced with hydrogen, and the mixture was stirred overnight at room temperature. The reaction solution was filtered, the filtrate was concentrated, and the solution was slurried with diethyl ether to obtain a gray solid B30 (75 mg, 71%).

[0634] [Example]

[90]

[0635] Compound B31 was synthesized by the following method:

[0636] B30 (55 mg, 0.13 mmol) and solid formaldehyde (8.0 mg, 0.26 mmol) were dissolved in 1,2-dichloroethane (10 mL), and sodium borohydride acetate (41 mg, 0.20 mmol) was added. The reaction was allowed to proceed overnight. The reaction was quenched with saturated ammonium chloride aqueous solution (5 mL), and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, concentrated, and purified by preparative plate chromatography to obtain a white crude product. The product was then slurried with diethyl ether to obtain a pale yellow solid B31 (8 mg, 14%).

[0637] [Example]

[91]

[0638] Compound B32 was synthesized by the following method:

[0639] 2-Dimethylaminoethanol (242 mg, 2.7 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 60% sodium hydride (131 mg, 3.3 mmol) was added. The mixture was stirred at room temperature for 1 hour. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, and ethyl acetate (20 mL) was added. The mixture was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, concentrated, and then slurried with diethyl ether (10 mL) for 3 hours. The mixture was filtered to give a white solid B32 (16 mg, 27%).

[0640] [Example]

[92]

[0641] Compound B33 was synthesized by the following method:

[0642] (R)-tetrahydrofuran-3-ol (24 mg, 0.27 mmol) was dissolved in dry THF (5 mL), and 60% sodium hydride (16 mg, 0.41 mmol) was added in portions at 0 °C, with stirring at room temperature for 0.5 h. Then, intermediate B1-7 (50 mg, 0.14 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by thick silica gel chromatography (dichloromethane / methanol = 30 / 1, v / v). The mixture was pulped, dried, and a white solid B33 (29 mg, 49%) was obtained.

[0643] [Example]

[93]

[0644] Compound B35 was synthesized by the following method:

[0645] Synthesis of intermediate B35-1:

[0646] 3-(benzyloxy)-1-cyclobutanone (500 mg, 2.8 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Under nitrogen protection at -78 °C, 3N-methylmagnesium chloride reagent (2.8 mL, 8.5 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was quenched by adding methanol (5 mL) at 0 °C, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a yellow oily intermediate B35-1 (400 mg, 73%).

[0647] 1H-NMR (300 MHz, DMSO- d 6 ): δ 7.31-7.20 (m, 5H), 5.00 (s, 1H), 4.33 (s, 2H), 3.69-3.61 (m, 1H), 2.30-2.20 (m, 2H), 1.98-1.88 (m, 2H), 1.14 (s, 3H). LC-MS: m / z 214.9 [M+Na] +.

[0648] Synthesis of intermediate B35-2:

[0649] Intermediate B35-1 (400 mg, 2.1 mmol) was dissolved in methanol (20 mL), and 5% Pd / C (40 mg) was added. The air was then purged three times with hydrogen, followed by stirring overnight at room temperature. After filtering off palladium on carbon, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1, v / v) to give colorless oily intermediate B35-2 (110 mg, 52%).

[0650] 1H-NMR (300 MHz, DMSO- d 6 ): δ 4.89 (d, J= 5.4 Hz, 1H), 4.83 (s, 1H), 3.74-3.64 (m, 1H), 2.23-2.13 (m, 2H), 1.90-1.79 (m, 2H), 1.12 (s, 3H).

[0651] Synthesis of final product B35:

[0652] Intermediate B35-2 (83 mg, 0.82 mmol) was dissolved in dry tetrahydrofuran (20 mL), and 60% sodium hydride (49 mg, 1.23 mmol) was added in portions at 0 °C, with stirring for 0.5 hours. Then, intermediate B1-7 (150 mg, 0.41 mmol) was added, and the mixture was stirred overnight at 0 °C. The reaction mixture was diluted with water (10 mL), extracted three times with ethyl acetate (15 mL × 3), the organic phases were combined, washed three times with saturated NaCl solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v), slurryed, and dried to give white solid B35 (84 mg, 46%).

[0653] [Example]

[94]

[0654] Compound B36 was synthesized by the following method:

[0655] Synthesis of intermediate B36-1:

[0656] B27-1 (100 mg, 0.56 mmol), 4-nitrobenzoic acid (187 mg, 1.12 mmol), and triphenylphosphine (440 mg, 1.68 mmol) were dissolved in dry tetrahydrofuran (10 mL). Under an ice-water bath and nitrogen protection, DIAD (339 mg, 1.68 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give a yellow solid B36-1 (168 mg, 91%).

[0657] 1H-NMR (300 MHz, CDCl 3): δ 8.29 (d, J= 8.7 Hz, 2H), 8.20 (d, J= 8.4 Hz, 2H), 7.43-7.29 (m, 5H), 5.57-5.35 (m, 1H), 4.46 (s, 2H), 4.40-4.29 (m, 1H), 2.68-2.56 (m, 2H), 2.54-2.44 (m, 2H).

[0658] Synthesis of intermediate B36-2:

[0659] B36-1 (168 mg, 0.51 mmol) was dissolved in 1,4-dioxane (5 mL), and 0.4 N sodium hydroxide aqueous solution (40 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 1 hour, acidified with acetic acid (0.3 mL), concentrated, diluted with ethyl acetate (20 mL), washed with saturated NaHCO3 aqueous solution (15 mL × 3), dried the organic phase, and concentrated to obtain yellow oily B36-2 (80 mg, 89%).

[0660] 1H-NMR (300 MHz, CDCl 3): δ 7.40-7.28 (m, 5H), 4.64-4.50 (m, 1H), 4.41 (s, 2H), 4.35-4.23 (m, 1H), 2.50-2.30 (m, 2H), 2.24-2.11 (m, 2H), 1.75 (s, 1H).

[0661] Synthesis of intermediate B36-3:

[0662] Intermediate B36-2 (153 mg, 0.86 mmol) was dissolved in dry THF (5 mL), and 60% sodium hydride (52 mg, 1.29 mmol) was added in portions at 0 °C, with stirring at room temperature for 0.5 hours. Then, intermediate B1-7 (160 mg, 0.43 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and purified by column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a colorless oily crude product B36-3 (100 mg, 44%).

[0663] 1H-NMR (300 MHz, CDCl 3): δ 10.55 (s, 1H), 8.35 (s, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.70 (t, J= 8.1 Hz, 1H), 7.38-7.31 (m, 5H), 7.21 (d, J= 7.5 Hz, 1H), 5.70-5.57 (m, 1H), 4.61-4.52 (m, 1H), 4.47 (s, 2H), 3.93 (s, 3H), 3.05 (s, 2H), 2.82-2.61 (m, 4H), 1.59 (s, 6H).

[0664] Synthesis of final product B36:

[0665] Intermediate B36-3 (100 mg, 0.19 mmol) was dissolved in methanol (25 mL), and 5% palladium on carbon (30 mg) was added. The air was then purged three times with hydrogen, followed by stirring overnight at room temperature. After filtering off the palladium on carbon, the solution was concentrated under reduced pressure to dryness, purified by column chromatography (dichloromethane / methanol = 30 / 1, v / v), slurryed, and dried to give a white solid B36 (40 mg, 48%).

[0666] Table 1. Compounds [A1]- [A59] and Structural formulas and spectral data of [B1-B36] serial number structural 1H-NMR & LC-MS A1 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.67 (s, 1H), 8.20 (s, 1H), 8.00-7.88 (m, 2H), 7.82-7.71 (m, 2H), 7.40-7.30 (m, 1H), 4.93-4.83 (m, 1H), 4.36-4.24 (m, 1H), 3.88 (s, 3H), 3.79-3.68 (m, 4H), 3.68-3.59 (m, 4H), 3.58-3.45 (m, 2H), 3.12-3.02 (m, 1H), 2.04-1.70 (m, 3H). LC-MS: m / z 491.2 [M+H] +. A2 1H-NMR (300 MHz, DMSO- d 6): δ 12.83 (s, 1H), 8.25 (s, 1H), 8.24 (s, 1H), 8.05 (d, J= 7.5 Hz, 1H), 7.96 (s, 1H), 7.85-7.77 (m, 1H), 7.39 (d, J= 7.2 Hz, 1H), 4.06-3.94 (m, 4H), 3.94 (s, 3H), 3.80-3.72 (m, 4H), 3.73-3.67 (m, 4H), 3.18-3.08 (m, 4H). LC-MS: m / z 491.2 [M+H] +. A3 1H-NMR (300 MHz, DMSO- d 6): δ 12.65 (s, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 8.11-8.05 (m, 2H), 7.79 (d, J= 8.4 Hz, 1H), 7.39 (d, J= 7.5 Hz, 1H), 3.91 (s, 3H), 3.76-3.73 (m, 4H), 3.72-3.68 (m, 4H), 3.18-3.09 (m, 4H), 2.77-2.70 (m, 4H), 2.33-2.27 (m, 3H). LC-MS: m / z 504.2 [M+H] +. A4 1H-NMR (300 MHz, DMSO- d 6): δ 13.50 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.83-7.74 (m, 1H), 7.39 (d, J= 7.5 Hz, 1H), 5.16 (s, 1H), 4.08-3.98 (m, 1H), 3.86 (s, 3H), 3.77-3.71 (m, 4H), 3.71-3.66 (m, 4H), 3.25-3.14 (m, 2H), 3.06-2.94 (m, 2H), 2.13-1.96 (m, 4H). LC-MS: m / z 505.2 [M+H] +. A5 1H-NMR (300 MHz, DMSO- d 6): δ 10.45 (s, 1H), 8.21 (s, 1H), 7.99-7.92 (m, 2H), 7.83-7.75 (m, 2H), 7.39 (d, J= 7.5 Hz, 1H), 4.71-4.63 (m, 4H), 4.10-4.03 (m, 4H), 3.88 (s, 3H), 3.74-3.69 (m, 4H), 3.65-3.61 (m, 4H). LC-MS: m / z 503.2 [M+H] +. A6 1H-NMR (300 MHz, DMSO- d 6): δ 10.67 (s, 1H), 8.20 (s, 1H), 8.02-7.90 (m, 2H), 7.82-7.70 (m, 2H), 7.36 (d, J= 7.5 Hz, 1H), 4.93 (s, 1H), 4.34-4.27 (m, 1H), 3.88 (s, 3H), 3.75-3.68 (m, 4H), 3.66-3.59 (m, 4H), 3.57-3.53 (m, 2H), 3.14-2.99 (m, 2H), 1.93-1.75 (m, 2H). LC-MS: m / z 491.1 [M+H] +. A7 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.14 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 7.99 (s, 1H), 7.80-7.72 (m, 2H), 7.40-7.32 (m, 1H), 3.89 (s, 3H), 3.78-3.71 (m, 4H), 3.70-3.62 (m, 4H), 2.92 (d, J= 4.2 Hz, 3H). LC-MS: m / z 435.1 [M+H] +. A8 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 8.23 (s, 1H), 7.99-7.85 (m, 3H), 7.83-7.71 (m, 1H), 7.43-7.32 (m, 1H), 4.27-4.12 (m, 2H), 3.99-3.91 (m, 2H), 3.88 (s, 3H), 3.76-3.69 (m, 4H), 3.67-3.57 (m, 4H), 3.16-3.01 (m, 2H), 2.16-2.05 (m, 2H), 1.90-1.76 (m, 2H). LC-MS: m / z 516.2 [M+H] +. A9 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.39 (s, 1H), 8.20 (s, 1H), 7.99-7.91 (m, 2H), 7.85 (s, 1H), 7.82-7.72 (m, 1H), 7.42-7.33 (m, 1H), 4.13-3.99 (m, 2H), 3.88 (s, 3H), 3.79-3.69 (m, 6H), 3.69-3.57 (m, 4H), 2.56 (s, 2H), 2.36 (s, 3H), 2.13-1.93 (m, 2H), 1.71-1.54 (m, 2H). LC-MS: m / z 530.2 [M+H] +. A10 1H-NMR (300 MHz, DMSO- d 6): δ 10.40 (s, 1H), 8.20 (s, 1H), 8.00-7.90 (m, 2H), 7.85-7.75 (m, 2H), 7.38 (d, J= 7.2 Hz, 1H), 5.42 (s, 1H), 3.88 (s, 3H), 3.80-3.69 (m, 8H), 3.68-3.59 (m, 4H), 1.27-1.15 (m, 1H), 0.40-0.25 (m, 4H). LC-MS: m / z 517.2 [M+H] +. A11 1H-NMR (300 MHz, DMSO- d 6): δ 12.83 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 8.06 (d, J= 7.5 Hz, 1H), 7.93 (s, 1H), 7.86-7.78 (m, 1H), 7.41 (d, J= 7.2 Hz, 1H), 3.87 (s, 3H), 3.78-3.73 (m, 4H), 3.72-3.68 (m, 4H), 3.27-3.23 (m, 4H), 2.47-2.37 (m, 4H). LC-MS: m / z 525.2 [M+H] +. A12 1H-NMR (300 MHz, DMSO- d 6): δ 10.92 (s, 1H), 8.20 (s, 1H), 7.99-7.89 (m, 3H), 7.82-7.75 (m, 1H), 7.38 (d, J= 7.5 Hz, 1H), 3.88 (s, 3H), 3.75-3.70 (m, 4H), 3.69-3.62 (m, 4H), 3.60-3.54 (m, 2H), 3.26-3.23 (m, 2H), 2.45-2.41 (m, 2H). LC-MS: m / z 511.1 [M+H] +. A13 1H-NMR (300 MHz, DMSO- d 6): δ 12.65 (s, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 8.06 (d, J= 9.0 Hz, 1H), 8.00 (s, 1H), 7.85-7.77 (m, 1H), 7.41 (d, J= 7.2 Hz, 1H), 3.92 (s, 3H), 3.77-3.72 (m, 4H), 3.72-3.66 (m, 4H), 3.30-3.25 (m, 4H), 3.23-3.15 (m, 4H). LC-MS: m / z 490.2 [M+H] +. A14 1H-NMR (300 MHz, DMSO- d 6): δ 10.50 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.96-7.92 (m, 1H), 7.83 (s, 1H), 7.81-7.75 (m, 1H), 7.38 (d, J= 7.2 Hz, 1H), 5.48 (s, 1H), 3.88 (s, 3H), 3.83-3.75 (m, 4H), 3.76-3.70 (m, 4H), 3.68-3.62 (m, 4H), 1.42 (s, 3H). LC-MS: m / z 491.1 [M+H] +. A15 1H-NMR (300 MHz, DMSO- d 6): δ 10.50 (s, 1H), 8.25 (s, 1H), 8.03-7.95 (m, 2H), 7.87 (s, 1H), 7.84-7.78 (m, 1H), 7.42 (d, J= 7.2 Hz, 1H), 4.10-4.01 (m, 4H), 3.93 (s, 3H), 3.81-3.73 (m, 4H), 3.71-3.62 (m, 4H), 2.91-2.80 (m, 4H). LC-MS: m / z 537.2 [M+H] +. A16 1H-NMR (300 MHz, DMSO- d 6): δ 12.98 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.05 (d, J= 9.3 Hz, 1H), 7.95 (s, 1H), 7.83-7.75 (m, 1H), 7.38 (d, J= 7.8 Hz, 1H), 5.07-4.99 (m, 1H), 4.14-4.06 (m, 1H), 3.90 (s, 3H), 3.82-3.73 (m, 4H), 3.73-3.66 (m, 4H), 3.13-3.06 (m, 1H), 2.92-2.83 (m, 1H), 2.80-2.65 (m, 2H), 2.05-1.88 (m, 3H), 1.43-1.33 (m, 1H). LC-MS: m / z 505.2 [M+H] +. A17 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.30 (s, 1H), 8.21 (s, 1H), 8.01-7.88 (m, 2H), 7.84-7.73 (m, 2H), 7.43-7.31 (m, 1H), 3.88 (s, 3H), 3.78-3.70 (m, 4H), 3.69-3.62 (m, 4H), 3.26-3.11 (m,4H), 3.00-2.85 (m, 2H), 2.81-2.57 (m, 4H), 2.29 (s, 3H). LC-MS: m / z 530.2 [M+H] +. A18 1H-NMR (300 MHz, CDCl 3): δ 10.20 (s, 1H), 8.23-8.10 (m, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.76-7.65 (m, 1H), 7.24-7.17 (m, 1H), 4.10 (s, 3H), 4.02-3.93 (m, 5H), 3.89-3.76 (m, 11H), 2.22 (t, J= 7.1 Hz, 2H). LC-MS: m / z 517.2 [M+H] +. A19 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.88 (s, 1H), 8.22 (s, 1H), 7.99-7.94 (m, 2H), 7.90 (s, 1H), 7.84-7.73 (m, 1H), 7.41-7.36 (m, 1H), 3.89 (s, 3H), 3.77-3.70 (m, 4H), 3.69-3.61 (m, 4H), 3.56-3.44 (m, 4H), 3.34-3.27 (m, 2H), 3.10-2.99 (m, 4H). LC-MS: m / z 516.2 [M+H] +. A20 1H-NMR (300 MHz, DMSO- d 6): δ 12.09 (s, 1H), 8.21 (s, 1H), 8.08-8.01 (m, 2H), 8.00-7.94 (m, 1H), 7.83-7.76 (m, 1H), 7.38 (d, J= 6.9 Hz, 1H), 4.57-4.52 (m, 1H), 3.89 (s, 3H), 3.76-3.71 (m, 4H), 3.70-3.65 (m, 4H), 3.09-3.01 (m, 2H), 2.84-2.74 (m, 4H), 2.64-2.55 (m, 2H), 2.12-2.07 (m, 1H), 1.77-1.70 (m, 1H). LC-MS: m / z 516.3 [M+H] +. A21 1H-NMR (300 MHz, DMSO- d 6): δ 12.63 (s, 1H), 8.28-8.19 (m, 2H), 8.05 (d, J= 8.4 Hz, 1H), 8.00 (s, 1H), 7.83-7.75 (m, 1H), 7.38 (d, J= 7.8 Hz, 1H), 3.89 (s, 3H), 3.78-3.72 (m, 4H), 3.71-3.66 (m, 4H), 3.23-3.10 (m, 4H), 3.04-2.75 (m, 4H), 1.88-1.71 (m, 3H), 1.61-1.37 (m, 2H). LC-MS: m / z 530.3 [M+H] +. A22 1H-NMR (300 MHz, DMSO- d 6): δ 10.42 (s, 1H), 8.21 (s, 1H), 7.99-7.89 (m, 2H), 7.85-7.75 (m, 2H), 7.38 (d, J= 7.2 Hz, 1H), 5.03-4.98 (m, 1H), 3.90-3.87 (m, 4H), 3.86-3.81 (m, 4H), 3.74-3.71 (m, 4H), 3.65-3.62 (m, 4H), 2.46-2.35 (m, 2H), 2.02-1.91 (m, 2H). LC-MS: m / z 517.2 [M+H] +. A23 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.61-12.38 (m, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 8.13 (d, J= 8.4 Hz, 1H), 8.07 (s, 1H), 7.90-7.80 (m, 1H), 7.44 (d, J= 7.6 Hz, 1H), 3.92 (s, 3H), 3.83-3.70 (m, 8H), 3.38-3.29 (m, 3H), 3.14-2.94 (m, 2H), 2.55 (s, 6H), 2.20-2.10 (m, 2H), 2.06-1.94 (m, 2H). LC-MS: m / z 532.2 [M+H] +. A24 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.50-13.36 (m, 1H), 8.29-8.25 (m, 2H), 8.07-8.02 (m, 2H), 7.83-7.75 (m, 1H), 7.39 (d, J= 7.2 Hz, 1H), 3.87 (s, 3H), 3.76-3.65 (m, 8H), 3.38 (s, 3H), 3.26-3.15 (m, 3H), 3.06-2.93 (m, 2H), 2.23-2.12 (m, 2H), 2.09-1.98 (m, 2H). LC-MS: m / z 519.3 [M+H] +. A25 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.20-13.12 (m, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.12-8.05 (m, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.38 (d, J= 7.2 Hz, 1H), 4.61 (s, 1H), 3.87 (s, 3H), 3.79-3.67 (m, 8H), 3.28-3.20 (m, 2H), 3.04-2.93 (m, 2H), 1.95-1.82 (m, 4H), 1.26 (s, 3H). LC-MS: m / z 519.2 [M+H] +. A26 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.42 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 8.09-7.98 (m, 1H), 7.92 (s, 1H), 7.84-7.70 (m, 1H), 7.42-7.31 (m, 1H), 5.67-5.52 (m, 1H), 4.59-4.41 (m, 1H), 3.89 (s, 3H), 3.80-3.63 (m, 8H), 3.61-3.49 (m, 4H), 3.25-3.14 (m, 2H), 2.43-2.32 (m, 2H), 2.27-2.13 (m, 2H). A27 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.76 (s, 1H), 8.28-8.23 (m, 2H), 8.07 (d, J= 8.1 Hz, 1H), 8.01 (s, 1H), 7.80 (t, J= 7.8 Hz, 1H), 7.41-7.35 (m, 1H), 3.89 (s, 3H), 3.78-3.67 (m, 8H), 3.19-3.03 (m, 4H), 2.98-2.85 (m, 2H), 2.83-2.61 (m, 2H), 2.32-2.17 (m, 1H), 1.90-1.65 (m, 3H), 1.46-1.31 (m, 1H). LC-MS: m / z 530.3 [M+H] +. A28 1H-NMR (300 MHz, DMSO- d 6): δ 11.52 (s, 1H), 8.18 (s, 1H), 8.11-8.01 (m, 2H), 7.88 (s, 1H), 7.81-7.75 (m, 1H), 7.36 (d, J= 6.6 Hz, 1H), 4.58-4.52 (m, 1H), 4.04-3.93 (m, 2H), 3.88 (s, 3H), 3.78-3.70 (m, 4H), 3.70-3.62 (m, 4H), 2.45-2.37 (m, 2H), 2.21-2.13 (m, 2H), 1.95-1.85 (m, 2H), 1.81-1.72 (m, 2H). LC-MS: m / z 531.2 [M+H] +. A29 1H-NMR (300 MHz, DMSO- d 6): δ 12.57 (s, 1H), 8.34-8.28 (m, 2H), 8.26 (s, 1H), 8.20 (s, 1H), 8.06 (d, J= 7.5 Hz, 1H), 7.95 (s, 1H), 7.87-7.79 (m, 1H), 7.41 (d, J= 7.5 Hz, 1H), 3.93 (s, 3H), 3.80-3.67 (m, 8H), 3.24-3.17 (m, 1H), 3.07-3.00 (m, 1H), 2.85-2.69 (m, 2H), 2.31-2.23 (m, 1H), 2.15-2.05 (m, 1H), 2.02-1.95 (m, 2H), 1.62-1.55 (m, 1H). A30 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.81 (s, 1H), 11.57 (s, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.08-7.97 (m, 2H), 7.87 (t, J= 7.8 Hz, 1H), 7.45 (d, J= 7.5 Hz, 1H), 3.96 (s, 1H), 3.92 (s, 3H), 3.73-3.65 (m, 8H), 3.60-3.46 (m, 4H), 3.43-3.26 (m, 2H), 2.78 (s, 3H), 1.38 (d, J= 5.4 Hz, 3H). A31 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.80 (s, 1H), 11.43 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 8.09-7.98 (m, 2H), 7.87 (t, J= 7.8 Hz, 1H), 7.45 (d, J= 7.5 Hz, 1H), 3.95 (s, 1H), 3.92 (s, 3H), 3.84-3.81 (m, 8H), 3.60-3.47 (m, 4H), 3.41-3.27 (m, 2H), 2.79 (s, 3H), 1.38 (d, J= 5.4 Hz, 3H). A32 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.10 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.94 (s, 1H), 7.79 (t, J= 7.8 Hz, 1H), 7.38 (d, J= 7.8 Hz, 1H), 3.91 (s, 3H), 3.80-3.62 (m, 8H), 3.53-3.42 (m, 2H), 3.06 (d, J= 11.1 Hz, 2H), 2.60-2.52 (m, 2H), 1.01 (d, J= 6.0 Hz, 6H). A33 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.34 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.06 (d, J= 7.8 Hz, 1H), 8.02 (s, 1H), 7.81 (t, J= 7.8 Hz, 1H), 7.40 (d, J= 7.5 Hz, 1H), 3.90 (s, 3H), 3.79-3.68 (m, 8H), 3.54-3.46 (m, 4H), 3.23 (s, 3H), 3.08-2.89 (m, 2H), 1.16 (s, 6H). A34 1H-NMR (300 MHz, DMSO- d 6): δ 11.74 (s, 1H), 11.28 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 8.11-7.98 (m, 2H), 7.91-7.80 (m, 1H), 7.44 (d, J= 7.5 Hz, 1H), 4.26-4.09 (m, 11H), 3.93-3.88 (m, 2H), 3.81-3.72 (m, 4H), 3.72-3.62 (m, 4H), 3.52 (s, 3H), 3.38-3.27 (m, 2H). A35 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.68 (s, 1H), 11.50 (s, 1H), 8.38 (s, 1H), 8.17 (s, 1H), 8.11-7.97 (m, 2H), 7.93-7.77 (m, 1H), 7.51-7.39 (m, 1H), 3.89 (s, 3H), 3.82-3.66 (m, 8H), 3.64-3.38 (m, 8H), 2.77-2.65 (m, 1H), 1.32-1.15 (m, 2H), 0.85-0.70 (m, 2H). A36 1H-NMR (300 MHz, DMSO- d 6): δ 11.77 (s, 1H), 10.89 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.11-7.94 (m, 2H), 7.93-7.80 (m, 1H), 7.43 (d, J= 7.5 Hz, 1H), 3.91 (s, 3H), 3.86-3.78 (m, 8H), 3.69-3.60 (m, 4H), 3.58-3.46 (m, 4H), 3.42-3.29 (m, 2H), 3.25-3.13 (m, 2H). A37 1H-NMR (300 MHz, DMSO- d 6): δ 11.83 (s, 1H), 10.50 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 8.15-7.98 (m, 2H), 7.90-7.80 (m, 1H), 7.52-7.39 (m, 1H), 3.93 (s, 3H), 3.72-3.63 (m, 16H), 3.47-3.36 (m, 3H), 2.91-2.83 (m, 2H). A38 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.07 (s, 1H), 8.32 (d, J= 7.8 Hz, 1H), 8.07-7.93 (m, 1H), 7.75 (s, 1H), 7.41 (d, J= 7.2 Hz, 1H), 6.89 (t, J= 55.2 Hz, 1H), 4.92-4.80 (m, 1H), 4.33-4.22 (m, 1H), 3.79-3.67 (m, 4H), 3.67-3.59 (m, 4H), 3.59-3.51 (m, 1H), 3.50-3.42 (m, 1H), 3.06-2.97 (m, 1H), 2.00-1.68 (m, 3H). LC-MS: m / z 461.4 [M+H] +. A39 1H-NMR (300 MHz, DMSO- d 6): δ 10.48 (s, 1H), 9.04 (d, J= 3.9 Hz, 1H), 8.60 (s, 1H), 8.54-8.48 (m, 1H), 7.75 (s, 1H), 7.06-6.99 (m, 1H), 4.88 (s, 1H), 4.33-4.25 (m, 1H), 3.77-3.69 (m, 4H), 3.68-3.61 (m, 4H), 3.58-3.54 (m, 2H), 3.18-3.03 (m, 2H), 1.99-1.72 (m, 2H). LC-MS: m / z 451.1 [M+H] +. A40 1H-NMR (300 MHz, DMSO- d 6): δ 10.65 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 6.53 (s, 1H), 4.89 (s, 1H), 4.31-4.23 (m, 1H), 3.75 (s, 3H), 3.73-3.67 (m, 4H), 3.65-3.58 (m, 4H), 3.54-3.49 (m, 2H), 3.06-2.99 (m, 2H), 1.90-1.74 (m, 2H). LC-MS: m / z 414.2 [M+H] +. A41 1H-NMR (300 MHz, DMSO- d 6): δ 12.82 (s, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 6.99 (s, 1H), 4.78 (s, 1H), 3.75-3.68 (m, 9H), 3.25-3.12 (m, 2H), 3.00-2.88 (m, 2H), 2.44-2.34 (m, 3H), 2.02-1.73 (m, 4H). LC-MS: m / z 439.2 [M+H] +. A42 1H-NMR (300 MHz, DMSO- d 6): δ 13.14 (s, 1H), 8.55 (d, J= 8.7 Hz, 1H), 8.18 (s, 1H), 8.13-8.02 (m, 1H), 7.76 (d, J= 7.2 Hz, 1H), 4.81 (s, 1H), 3.82-3.62 (m, 10H), 3.26-3.18 (m, 1H), 3.05-2.83 (m, 2H), 2.05-1.82 (m, 2H), 1.81-1.58 (m, 2H). LC-MS: m / z 450.1 [M+H] +. A43 1H-NMR (300 MHz, DMSO- d 6): δ 13.22 (s, 1H), 8.25 (s, 1H), 7.85 (d, J= 7.5 Hz, 1H), 7.77-7.69 (m, 1H), 6.55 (d, J= 7.2 Hz, 1H), 4.84 (s, 1H), 3.87 (s, 3H), 3.78-3.64 (m, 8H), 3.25-3.13 (m, 3H), 3.04-2.86 (m, 2H), 2.06-1.79 (m, 4H). LC-MS: m / z 455.2 [M+H] +. A44 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.52 (s, 1H), 8.17 (d, J= 11.4 Hz, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.54-7.39 (m, 2H), 3.78-3.71 (m, 4H), 3.69-3.64 (m, 4H), 3.28-3.19 (m, 6H), 3.03-2.89 (m, 2H), 2.04-1.86 (m, 2H), 1.65 (d, J= 13.2 Hz, 6H), 1.60-1.53 (m, 2H). LC-MS: m / z 514.2 [M+H] +. A45 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.09 (s, 1H), 8.83 (d, J= 7.7 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J= 4.5 Hz, 1H), 7.12-6.95 (m, 1H), 4.86 (s, 1H), 4.03 (s, 3H), 3.81-3.63 (m, 8H), 3.25-3.10 (m, 3H), 3.06-2.86 (m, 2H), 1.94-1.86 (m, 2H), 1.81-1.66 (m, 2H).LC-MS: m / z 455.1 [M+H] +. A46 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.21 (s, 1H), 8.26 (s, 1H), 7.84 (d, J= 7.9 Hz, 1H), 7.73 (t, J= 7.5 Hz, 1H), 6.55 (d, J= 8.1 Hz, 1H), 3.84 (s, 3H), 3.76-3.68 (m, 9H), 3.28 (s, 3H), 3.23-3.16 (m, 2H), 3.02-2.93 (m, 2H), 2.11 (s, 2H), 2.02-1.85 (m, 2H). LC-MS: m / z 469.2 [M+H] +. A47 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.11 (s, 1H), 8.30 (d, J= 7.7 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.32 (d, J= 8.9 Hz, 1H), 7.20-7.10 (m, 1H), 3.91 (s, 3H), 3.79-3.64 (m, 8H), 3.57 (s, 3H), 3.45-3.40 (m, 3H), 3.27 (s, 3H), 3.09-2.94 (m, 2H), 2.06-1.94 (m, 2H), 1.85-1.68 (m, 2H). A48 1H-NMR (300 MHz, DMSO- d 6): δ 11.43 (s, 1H), 8.54 (s, 1H), 8.04 (s, 1H), 7.81-7.61 (m, 2H), 7.51-7.42 (m, 1H), 3.82-3.63 (m, 8H), 3.51-3.45 (m, 2H), 3.40-3.31 (m, 4H), 3.04-2.92 (m, 2H), 1.95 (s, 2H), 1.62 (s, 2H). A49 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.21 (s, 1H), 8.62 (d, J= 5.1 Hz, 1H), 8.41 (s, 1H), 7.75-7.67 (m, 2H), 7.67-7.60 (m, 1H), 4.86 (s, 1H), 4.31-4.20 (m, 1H), 3.80-3.66 (m, 4H), 3.66-3.57 (m, 4H), 3.57-3.50 (m, 1H), 3.49-3.41 (m, 1H), 3.05-2.89 (m, 1H), 2.56 (s, 3H), 2.00-1.67 (m, 3H). LC-MS: m / z 490.4 [M-H] -. A50 1H-NMR (300 MHz, DMSO- d 6): δ 12.09 (s, 1H), 8.84 (d, J= 7.8 Hz, 1H), 8.22 (s, 1H), 7.91-7.85 (m, 1H), 7.09-6.97 (m, 1H), 4.00 (s, 3H), 3.77-3.72 (m, 4H), 3.71-3.66 (m, 4H), 3.30 (s, 3H), 3.25-3.22 (m, 1H), 3.21-3.14 (m, 2H), 3.00-2.89 (m, 2H), 2.11-1.98 (m, 2H), 1.85-1.70 (m, 2H). A51 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.37 (s, 1H), 9.69-9.44 (m, 2H), 8.46-8.21 (m, 2H), 8.11-7.93 (m, 2H), 7.80 (s, 1H), 7.41 (s, 1H), 4.00-3.92 (m, 4H), 3.88 (s, 3H), 3.38 (s, 3H), 3.31-3.17 (m, 7H), 3.05-2.89 (m, 2H), 2.23-1.96 (m, 4H). A52 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.42 (s, 1H), 8.41-8.18 (m, 2H), 8.09-7.99 (m, 2H), 7.86-7.72 (m, 1H), 7.40 (d, J= 6.9 Hz, 1H), 3.88 (s, 3H), 3.75-3.66 (m, 7H), 3.23-3.18 (m, 4H), 3.06-2.94 (m, 5H), 2.25 (s, 3H), 2.17-2.01 (m, 4H). A53 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.65 (s, 1H), 8.20 (s, 1H), 8.11-7.86 (m, 2H), 7.86-7.61 (m, 2H), 7.49-7.23 (m, 1H), 5.16 (s, 1H), 4.89 (s, 1H), 4.52-4.41 (m, 2H), 3.88 (s, 3H), 3.78-3.40 (m, 8H), 3.17-2.94 (m, 1H), 2.17-1.70 (m, 3H). LC-MS: m / z 491.2 [M+H] +. A54 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.38 (s, 1H), 8.32-8.17 (m, 2H), 8.10-7.92 (m, 2H), 7.79 (s, 1H), 7.41 (s, 1H), 4.15 (s, 3H), 3.90 (s, 3H), 3.79-3.64 (m, 8H). LC-MS: m / z 436.1 [M+H] +. A55 1H-NMR (300 MHz, DMSO- d 6): δ 12.45 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 8.06 (d, J= 7.8 Hz, 1H), 7.92 (s, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.37 (d, J= 7.2 Hz, 1H), 5.66-5.56 (m, 1H), 4.55-4.43 (m, 1H), 3.89 (s, 3H), 3.72-3.62 (m, 6H), 3.57-3.49 (m, 2H), 3.24-3.17 (m, 3H), 2.93-2.84 (m, 4H), δ 2.43-2.35 (m, 2H), 2.25-2.17 (m, 2H). LC-MS: m / z 529.8 [M+H] +. A56 1H-NMR (300 MHz, DMSO- d 6): δ 13.19 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 8.08 (d, J= 7.8 Hz, 1H), 8.00 (s, 1H), 7.79 (t, J= 7.5 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 4.62 (s, 1H), 3.87 (s, 3H), 3.76-3.68 (m, 4H), 3.19-3.13 (m, 2H), 3.05-2.93 (m, 7H), 1.96-1.82 (m, 4H), 1.26 (s, 3H). LC-MS: m / z 517.8 [M+H] +. A57 1H-NMR (300 MHz, DMSO- d 6 ): δ 13.42 (s, 1H), 8.29-8.16 (m, 2H), 8.08-7.96 (m, 2H), 7.82-7.75 (m, 1H), 7.39 (d, J= 7.8 Hz, 1H), 4.49 (s, 1H), 3.88 (s, 3H), 3.72-3.65 (m, 4H), 3.57-3.50 (m, 5H), 3.45 (s, 3H), 3.24-3.18 (m, 2H), 3.06-2.96 (m, 2H), 2.61-2.54 (m, 4H), 2.25-2.01 (m, 4H). LC-MS: m / z 561.8 [M+H] +. A58 1H-NMR (300 MHz, DMSO- d 6): δ 12.43 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 8.09-7.98 (m, 1H), 7.92 (s, 1H), 7.83-7.71 (m, 1H), 7.37 (d, J= 7.5 Hz, 1H), 5.67-5.54 (m, 1H), 4.58-4.44 (m, 1H), 3.89 (s, 3H), 3.81-3.63 (m, 6H), 3.60-3.47 (m, 4H), 3.25-3.18 (m, 2H), 2.61-2.54 (m, 2H), 2.43-2.36 (m, 2H), 2.30 (s, 3H), 2.24-2.14 (m, 2H).LC-MS: m / z 543.8 [M+H] +. A59 1H-NMR (300 MHz, DMSO- d 6): δ 13.18 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 8.08 (d, J= 8.3 Hz, 1H), 8.00 (s, 1H), 7.84-7.73 (m, 1H), 7.38 (d, J= 7.8 Hz, 1H), 4.60 (s, 1H), 3.87 (s, 3H), 3.77-3.58 (m, 4H), 3.51-3.41 (m, 2H), 3.25-3.18 (m, 2H), 3.11-2.91 (m, 4H), 2.29 (s, 3H), 1.96-1.79 (m, 4H), 1.25 (s, 3H). LC-MS: m / z 531.8 [M+H] +. B1 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.71 (s, 1H), 8.23 (d, J= 9.3 Hz, 2H), 8.07-7.97 (m, 2H), 7.78 (t, J= 7.5 Hz, 1H), 7.44-7.27 (m, 1H), 3.87 (s, 3H), 3.55-3.47 (m, 4H), 3.26-3.16 (m, 2H), 3.08 (s, 2H), 2.99-2.87 (m, 2H), 2.19-2.08 (m, 2H), 2.06-1.94 (m, 2H), 1.47 (s, 6H). B2 1H-NMR (300 MHz, DMSO- d 6): δ 11.96 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.70-7.95 (m, 2H), 7.82-7.75 (t, J= 7.5 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 3.89 (s, 3H), 3.73 (s, 2H), 3.15-2.95 (m, 4H), 2.75-2.55 (m, 4H), 2.27 (s, 3H), 1.47 (s, 6H). LC-MS: m / z 447.8 [M+H] +. B3 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.01 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), δ 8.10-7.99 (m, 2H), 7.85-7.74 (m, 1H), 7.44-7.35 (m, 1H), 4.48 (s, 1H), 3.89 (s, 3H), 3.61-3.45 (m, 4H), 3.21-2.99 (m, 6H), 2.87-2.70 (m, 4H), 1.57-1.38 (m, 6H). LC-MS: m / z 477.8 [M+H] +. B4 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.99 (s, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.08-7.98 (m, 2H), 7.79 (s, 1H), 7.46-7.28 (m, 1H), 3.87 (s, 3H), 3.11-2.95 (m, 6H), 2.93-2.80 (m, 4H), 1.72-1.60 (m, 1H), 1.46 (s, 6H), 0.54-0.42 (m, 2H), 0.38-0.28 (m, 2H). LC-MS: m / z 473.9 [M+H] +. B5 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.80 (s, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 8.02 (d, J= 7.8 Hz, 1H), 7.78 (t, J= 8.1 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 5.11-5.06 (m, 1H), 3.86 (s, 3H), 3.74 (s, 2H), 3.25-3.15(m, 2H), 3.08 (s, 1H), 3.02-2.85 (m, 2H), 2.05-1.85 (m, 4H), 1.47 (s, 6H). LC-MS: m / z 448.8 [M+H] +. B6 1H-NMR (300 MHz, DMSO- d 6): δ 11.46 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 8.01 (d, J= 8.4 Hz, 1H), 7.92 (s, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.36 (d, J= 7.5 Hz, 1H), 5.60-5.50 (m, 1H), 4.48-4.36 (m, 1H), 3.89 (s, 3H), 3.70-3.60 (m, 2H), 3.59-3.45 (m, 2H), 3.25-3.20 (m, 2H), 3.04 (s, 2H), 2.35-2.25 (m, 2H), 2.23-2.12 (m, 2H), 1.52-1.38 (m, 6H).LC-MS: m / z 474.9 [M+H] +. B7 1H-NMR (300 MHz, DMSO- d 6): δ 12.44 (s, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 8.04 (d, J= 8.4 Hz, 1H), 7.99 (s, 1H), 7.78 (t, J= 7.5 Hz, 1H), 7.37 (d, J= 7.5 Hz, 1H), 4.54 (s, 1H), 3.87 (s, 3H), 3.26-3.13 (m, 2H), 3.07 (s, 2H), 3.03-2.93 (m, 2H), 1.92-1.72 (m, 4H), 1.53-1.40 (m, 6H), 1.22 (s, 3H). LC-MS: m / z 462.9 [M+H] +. B8 1H-NMR (300 MHz, DMSO-d 6): δ 12.11 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.06 (d, J= 6.6 Hz, 1H), 7.98 (s, 1H), 7.81-7.72 (m, 1H), 7.37 (d, J= 6.6 Hz, 1H), 3.89 (s, 3H), 3.21-3.07 (m, 6H), 3.01 (s, 2H), 1.57-1.39 (m, 6H), 0.67-0.48 (m, 4H). LC-MS: m / z 459.8 [M+H] +. B9 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.49 (s, 1H), 8.45 (d, J= 6.0 Hz, 1H), 8.05 (s, 1H), 7.37 (d, J= 6.6 Hz, 1H), 6.33-6.26 (m, 1H), 5.01 (d, J= 64.8 Hz, 1H), 4.67-4.57 (m, 1H), 3.76-3.62 (m, 1H), 3.25-3.16 (m, 3H), 3.03 (s, 2H), 2.95-2.81 (m, 2H), 1.93-1.84 (m, 2H), 1.78-1.60 (m, 2H), 1.45 (s, 6H), 1.28-1.14 (m, 2H). LC-MS: m / z 442.8 [M+H] +. B10 1H-NMR (300 MHz, DMSO- d 6 ): δ 11.44 (s, 1H), 8.41 (d, J= 6.6 Hz, 1H), 8.04 (s, 1H), 7.26 (d, J= 6.0 Hz, 1H), 6.39-6.15 (m, 1H), 4.70-4.55(m, 1H), 3.73-3.61 (m, 1H), 3.49-3.42 (m, 1H), 3.28-3.14 (m, 2H), 3.03 (s, 2H), 2.94-2.82 (m, 2H), 2.01-1.79 (m, 2H), 1.77-1.62 (m, 2H), 1.45 (s, 6H), 1.11-0.93 (m, 2H), 0.96-0.83 (m, 2H). LC-MS: m / z 424.9 [M+H] +. B11 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.20 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 8.07-7.96 (m, 2H), 7.79 (t, J= 7.8 Hz, 1H), 7.40 (d, J= 7.2 Hz, 1H), 4.09 (s, 3H), 3.90 (s, 3H), 3.06 (s, 2H), 1.48 (s, 6H). LC-MS: m / z 379.9 [M+H] +. B12 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.45 (s, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.94 (s, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 4.51 (q, J= 6.6 Hz, 2H), 3.89 (s, 3H), 3.06 (s, 2H), 1.55 (t, J= 6.6 Hz, 3H), 1.48 (s, 6H). LC-MS: m / z 393.8 [M+H] +. B13 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.56 (s, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 8.02 (d, J= 6.3 Hz, 1H), 7.93 (s, 1H), 7.79 (t, J= 4.8 Hz, 1H), 7.38 (d, J= 7.8 Hz, 1H), 5.46-5.29 (m, 1H), 3.90 (s, 3H), 3.05 (s, 2H), 1.66-1.34 (m, 12H). LC-MS: m / z 407.9 [M+H] +. B14 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.51 (s, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.93 (s, 1H), 7.80 (t, J= 7.8 Hz, 1H), 7.42-7.36 (m, 1H), 5.35-5.22 (m, 1H), 3.89 (s, 3H), 3.04 (s, 2H), 2.63-2.53 (m, 2H), 2.36-2.26 (m, 2H), 1.99-1.86 (m, 1H), 1.82-1.68 (m, 1H), 1.47 (s, 6H). LC-MS: m / z 419.9 [M+H] +. B15 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.43 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 8.04 (d, J= 8.1 Hz, 1H), 7.92 (s, 1H), 7.79 (t, J= 8.1 Hz, 1H), 7.38 (d, J= 6.9 Hz, 1H), 5.67-5.61 (m, 1H), 3.89 (s, 3H), 3.05 (s, 2H), 2.09-1.88 (m, 6H), 1.78-1.63 (m, 2H), 1.48 (s, 6H). LC-MS: m / z 433.9 [M+H] +. B16 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.36 (s, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 8.02 (d, J= 7.5 Hz, 1H), 7.94 (s, 1H), 7.81 (t, J= 4.8 Hz, 1H), 7.40 (d, J= 7.8 Hz, 1H), 5.77-5.61 (m, 1H), 5.10-4.91 (m, 2H), 4.82-4.69 (m, 2H), 3.89 (s, 3H), 3.06 (s, 2H), 1.47 (s, 6H). LC-MS: m / z 421.8 [M+H] +. B17 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.39 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.95 (s, 1H), 7.79 (t, J= 8.1 Hz, 1H), 7.38 (d, J= 7.8 Hz, 1H), 5.78-5.70 (m, 1H), 4.17-3.92 (m, 4H), 3.89 (s, 3H), 3.06 (s, 2H), 2.39-2.19 (m, 2H), 1.48 (s, 6H). LC-MS: m / z 435.8 [M+H] +. B18 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.46 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 8.01 (d, J= 6.0 Hz, 1H), 7.78 (t, J= 7.8 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 5.04-4.91 (m, 1H), 4.55-4.45 (m, 2H), 4.12-3.74 (m, 5H), 3.06 (s, 2H), 1.48 (s, 6H). LC-MS: m / z 409.8 [M+H] +. B19 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.32 (s, 1H), 8.24 (s, 1H), 8.23 (s, 1H), 8.02 (d, J= 5.7 Hz, 1H), 7.99 (s, 1H), 7.79 (t, J= 7.8 Hz, 1H), 7.38 (d, J= 7.8 Hz, 1H), 4.63-4.54 (m, 2H), 3.92-3.81 (m, 5H), 3.30 (s, 3H), 3.06 (s, 2H), 1.48 (s, 6H). LC-MS: m / z 423.9 [M+H] +. B20 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.22 (s, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.99-7.93 (m, 1H), 7.93 (s, 1H), 7.80 (t, J= 8.1 Hz, 1H), 7.75 (d, J= 71.7 Hz, 1H), 7.40 (d, J= 7.8 Hz, 1H), 3.89 (s, 3H), 3.09 (s, 2H), 1.49 (s, 6H). LC-MS: m / z 415.8 [M+H] +. B21 1H-NMR (300 MHz, CDCl 3): δ 9.93 (s, 1H), 8.31 (s, 1H), 8.15 (d, J= 8.1 Hz, 1H), 7.85 (s, 1H), 7.70 (t, J= 7.8 Hz, 1H), 7.24 (s, 1H), 7.22-7.18 (m, 1H), 5.93-5.85 (m, 1H), 3.99 (s, 3H), 3.06 (s, 2H), 2.91 (s, 3H), 2.75-2.62 (m, 2H), 2.18-2.15 (m, 2H), 1.86-1.75 (m, 2H), 1.56 (s, 6H). LC-MS: m / z 448.9 [M+H] +. B22 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.20 (s, 1H), 8.27-8.17 (m, 2H), 8.02 (d, J= 7.5 Hz, 1H), 7.95 (s, 1H), 7.88-7.75 (m, 1H), 7.40 (d, J= 6.9 Hz, 1H), 5.68-5.52 (m, 1H), 3.91 (s, 3H), 3.28-3.18 (m, 5H), 3.07 (s, 2H), 2.43-2.36 (m, 2H), 1.49 (s, 6H). LC-MS: m / z 434.9 [M+H] +. B23 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.46 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 8.05 (d, J= 8.1 Hz, 1H), 7.95 (s, 1H), 7.87-7.72 (m, 1H), 7.40 (d, J= 7.5 Hz, 1H), 5.63-5.46 (m, 1H), 4.15-3.97 (m, 2H), 3.88 (s, 3H), 3.76-3.62 (m, 2H), 3.06 (s, 2H), 2.18-2.05 (m, 2H), 1.94-1.77 (m, 2H), 1.48 (s, 6H). LC-MS: m / z 449.8 [M+H] +. B24 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.47 (s, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 8.05 (d, J= 8.1 Hz, 1H), 7.94 (s, 1H), 7.79 (t, J= 7.8 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 4.34 (d, J= 4.2 Hz, 2H), 3.88 (s, 3H), 3.05 (s, 2H), 1.47 (s, 6H), 1.45-1.37 (m, 1H), 0.75-0.60 (m, 2H), 0.59-0.47 (m, 2H). LC-MS: m / z 419.8 [M+H] +. B25 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.31 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 8.06-7.93 (m, 2H), 7.79 (t, J= 8.4 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 4.63 (t, J= 4.5 Hz, 2H), 3.89 (s, 3H), 3.58 (t, J= 4.5 Hz, 2H), 3.06 (s, 2H), 2.54 (s, 3H), 1.48 (s, 6H). LC-MS: m / z 422.9 [M+H] +. B26 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.57 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (d, J= 7.8 Hz, 1H), 7.91 (s, 1H), 7.79 (t, J= 7.8 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 5.00-4.79 (m, 1H), 3.89 (s, 3H), 3.05 (s, 2H), 1.51-1.47 (m, 9H), 1.40-1.30 (m, 1H), 0.75-0.32 (m, 4H). LC-MS: m / z 433.8 [M+H] +. B27 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 8.08-7.91 (m, 2H), 7.81 (t, J= 7.8 Hz, 1H), 7.40 (d, J= 7.5 Hz, 1H), 5.45-5.35 (m, 1H), 4.96-4.86 (m, 1H), 4.04-3.94 (m, 1H), 3.88 (s, 3H), 3.05 (s, 2H), 2.99-2.87 (m, 2H), 2.26-2.12 (m, 2H), 1.47 (s, 6H). LC-MS: m / z 435.8 [M+H] +. B28 1H-NMR (300 MHz, DMSO- d 6 ): δ 12.10 (s, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.08 (d, J= 8.1 Hz, 1H), 7.95 (s, 1H), 7.75 (t, J= 7.8 Hz, 1H), 7.65 (s, 1H), 7.35 (s, 1H), 5.00-4.84 (m, 1H), 4.29-4.20 (m, 2H), 3.89 (s, 3H), 3.74-3.45 (m, 2H), 3.07 (s, 2H), 1.56 (s, 6H). B29 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.14 (s, 1H), 8.29-8.17 (m, 2H), 7.99 (d, J= 8.4 Hz, 1H), 7.94 (s, 1H), 7.85-7.73 (m, 1H), 7.38 (d, J= 7.1 Hz, 1H), 4.56-4.45 (m, 1H), 3.91 (s, 3H), 3.07 (s, 2H), 1.49 (s, 6H), 1.03-0.86 (m, 4H). LC-MS: m / z 405.8 [M+H] +. B30 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.36 (s, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.95-7.87 (m, 2H), 7.72 (t, J= 8.1 Hz, 1H), 7.30 (d, J= 7.8 Hz, 1H), 5.38-5.23 (m, 1H), 3.90-3.81 (m, 2H), 3.78 (s, 3H), 3.56-3.43 (m, 2H), 3.41-3.38 (m, 1H), 3.03 (s, 2H), 1.47 (s, 6H). LC-MS: m / z 420.9 [M+H] +. B31 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.41 (s, 1H), 8.25-8.19 (m, 2H), 8.01 (d, J= 6.6 Hz, 1H), 7.96 (s, 1H), 7.81 (t, J= 7.1 Hz, 1H), 7.40 (d, J= 7.1 Hz, 1H), 5.33-5.23 (m, 1H), 3.89 (s, 3H), 3.83-3.73 (m, 2H), 3.25-3.15 (m, 2H), 3.05 (s, 2H), 2.35 (s, 3H), 1.47 (s, 6H). LC-MS: m / z 434.9 [M+H] +. B32 1H-NMR (300 MHz, CDCl 3): δ 10.43 (s, 1H), 8.33 (s, 1H), 8.15 (d, J= 8.7 Hz, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.68 (t, J= 7.5 Hz, 1H), 7.18 (d, J= 7.8 Hz, 1H), 4.66 (s, 2H), 3.96 (s, 3H), 3.11-3.02 (m, 2H), 3.02-2.92 (m, 2H), 2.39 (s, 6H), 1.58 (s, 6H). B33 1H-NMR (300 MHz, DMSO- d 6 ): δ 10.38 (s, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 8.00 (d, J= 8.4 Hz, 1H), 7.95 (s, 1H), 7.79 (t, J= 7.5 Hz, 1H), 7.38 (d, J= 6.9 Hz, 1H), 5.78-5.69 (m, 1H), 4.22-3.91 (m, 4H), 3.89 (s, 3H), 3.06 (s, 2H), 2.33-2.17 (m, 2H), 1.48 (s, 6H). LC-MS: m / z 435.8 [M+H] +. B34 1H-NMR (300 MHz, DMSO-d6): δ 12.16 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 5.1 Hz, 1H), 7.94 (s, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 3.88 (s, 3H), 2.96 (s, 2H), 1.51 (s, 6H). B35 1H-NMR (300 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 8.06 - 7.94 (m, 2H), 7.80 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 5.35 (s, 1H), 5.04 - 4.95 (m, 1H), 3.89 (s, 3H), 3.05 (s, 2H), 2.69 - 2.57 (m, 2H), 2.42 - 2.31 (m, 2H), 1.47 (s, 6H), 1.33 (s, 3H). LC-MS: m / z 449.8 [M+H]+. B36 1H-NMR (300 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.26 - 8.16 (m, 2H), 8.05 - 7.98 (m, 1H), 7.94 (s, 1H), 7.84 - 7.76 (m, 1H), 7.44 - 7.34 (m, 1H), 5.51 - 5.42 (m, 1H), 5.38 - 5.28 (m, 1H), 4.67 - 4.56 (m, 1H), 3.88 (s, 3H), 3.05 (s, 2H), 2.68 - 2.55 (m, 4H), 1.47 (s, 6H).

[0667] [Examples]

[95] [Kinetic activity test]

[0668] The compounds prepared in the above examples were subjected to kinase function inhibition experiments with IRAK4 kinase, and the inhibition capacity IC50 was obtained.

[0669] 1. Experimental steps:

[0670] 1.1 Prepare a 1x kinase base solution and a stop solution: 1x kinase base solution: 50 mM HEPES (pH 7.5); 0.0015% Brij-35; Termination solution: 100 mM HEPES (pH 7.5); 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA.

[0671] 1.2 Preparation of the test compound: 1) Dilute the analyte with 100% DMSO to 50 times the final maximum inhibitor concentration required for the reaction; 2) Transfer 100 µL of the diluted analyte solution to the wells of the 96-well disk; 3) The compound was serially diluted 3-fold at 10 different locations; 4) Add 100 μL of 100% DMSO to two empty wells in the same 96-well plate for a compound-free control and an enzyme-free control; this plate is the source plate. 5) Transfer 10 μL of the compound from the source disk to a new 96-well disk as an intermediate disk. Add 90 μL of 1-fold kinase base solution to each well of the intermediate disk and mix the compound in the intermediate disk on a shaker for 10 minutes.

[0672] 1.3 Transfer 5 μL per well from the 96-well intermediate disk to the 384-well disk in duplicate.

[0673] 1.4 Kinase response: 1) Add IRAK4 kinase to a 1x kinase base solution to form a 2.5x enzyme solution; 2) Add the FAM-labeled peptide substrate and ATP (final ATP concentration 10 μM) to a 1-fold kinase substrate solution to form a 2.5-fold substrate solution; 3) Add 10 µL of 2.5-fold enzyme solution (final enzyme concentration of 6 nM) to each well of the 384-well plate and incubate at room temperature for 10 minutes; then add 10 µL of 2.5-fold substrate solution (final substrate concentration of 3 μM) to each well of the 384-well plate and incubate at 28°C for a period of time before adding 30 µL of stop solution to terminate the reaction.

[0674] 1.5 Collect data and plot curves on Caliper to obtain IC 50.

[0675] 2. Experimental Results:

[0676] Table 2. Results of the inhibitory activity test of the compounds against IRAK4 kinase serial number IC 50(nM) (10 μM ATP) serial number IC 50(nM) (10 μM ATP) serial number IC 50(nM) (10 μM ATP) serial number IC 50(nM) (10 μM ATP) [A1] 405 [A2] 45 [A3] 43 [A4] 11 [A6] 194 [A10] 122 [A11] twenty two [A12] 33 [A13] 304 [A14] 164 [A15] 244 [A16] 31 [A18] 221 [A21] 26 [A22] 188 [A23] 425 [A24] 4.1 [A25] 8.6 [A26] 4.2 [A27] 81 [A28] 80 [A30] 125 [A34] 40 [A35] 8.9 [A36] 17 [A37] 462 [A42] 87 [A43] 137 [A45] 131 [A46] 179 [A49] >6000 [A50] 98 [A51] 7.0 [A52] 5.1 [A54] 21 [A55] 5.9 [A56] 7.8 [A57] 5.1 [A58] 4.9 [A59] 6.6 [B1] 4.5 [B2] 54 [B3] 31 [B4] 7.5 [B5] 7.6 [B6] 5.9 [B7] 11 [B8] 224 [B9] 69 [B10] 479 [B11] 50 [B12] 9.2 [B13] 6.2 [B14] 6.1 [B15] 5.6 [B16] 11 [B17] 6.5 [B18] 22 [B19] 18 [B20] 27 [B21] 75 [B22] 354 [B23] 11 [B24] 11 [B26] 13 [B27] 7.3 [B28] 248 [B29] 6.2 [B30] 170 [B31] 176 [B32] 236 [B33] 8.9 [B34] 243 [B35] 6.8 [B36] 4.5 [CA4948] 115 CA4948

[0677] Enzyme activity assays showed that all compounds of the present invention exhibited inhibitory activity against IRAK4 kinase, and unexpectedly, the compounds... [A24] [A26] [B1] [、] The activity of [B36] was more than 25 times higher than that of the positive control compound CA4948 (ACS Med. Chem. Lett. 2020, 11, 2374-2381). [A4] [A25] [A35] [A51]- [A52] [A55]- [A59] [B4]- [B7]、 [B12]- [B17]、 [B23]- [B24] [B26]- [B27] [B29]、 [B33]、 The activity of [B35] was more than 10 times higher than that of CA4948, while the compound [A11]、 [A36] [A54] The activity of [B18-B19] is also more than 5 times higher than that of CA4948.

[0678] [Example]

[96] [Combined with ability test]

[0679] The compounds prepared in Examples 1, 4, and 64 [A1]、 [A4] [、] [B5] Binding ability with IRAK4 kinase was tested separately.

[0680] In the experiments, kinase-labeled T7 phage strains were prepared from E. coli hosts derived from strain BL21. E. coli were cultured to the logarithmic phase, infected with T7 phage, and cultured at 32°C with shaking until lysis. The lysate was centrifuged and filtered to remove cell debris; the remaining kinases were produced in HEK-293 cells and subsequently detected by qPCR using DNA labeling. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands at room temperature for 30 minutes to generate affinity resins for kinase analysis. The ligand-blocking beads were washed with excess biotin to remove unbound ligands and reduce nonspecific binding using blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, and 1 mM DTT). The binding reaction was assembled by conjugating the kinase, ligand affinity beads, and testing the compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111× stock solutions in 100% DMSO. Kds were determined using an 11 concentration point 3-fold compound dilution series and 3 DMSO control points. All compounds used for Kd measurements were distributed in 100% DMSO via acoustic transfer (non-contact distribution). The compounds were then diluted directly into the analytes to a final concentration of 0.9%. All reactions were performed on 384-well polypropylene discs in 0.02 mL volumes. The discs were incubated with shaking at room temperature for 1 hour, and the affinity beads were washed with washing buffer (1x PBS, 0.05% Tween 20). The affinity beads were then resuspended in elution buffer (1x PBS, 0.05% gradient for 20 days, 0.5 µM non-biotinylated affinity ligand) and incubated with shaking at room temperature for 30 minutes. The kinase concentration in the elution buffer was determined by qPCR.

[0681] The standard dose-response curve for the compound was calculated using the Hill equation with the constant (Kds). [A1]、 [A4] [、] [B5] The binding ability test results of IRAK4 are shown in Table 3.

[0682] Table 3. Results of the test on the binding ability of the compounds to IRAK4 serial number Kd (nM) A1 29 A4 0.59 B5 0.69

[0683] Based on the experimental results, the compound [A1] [、] [A4] [、] [B5] all have high binding activity with IRAK4, and the Kd of A4, B5 and IRAK4 is less than 1 nM.

[0684] [Example]

[97] [Liver microsomal metabolic stability test]

[0685] 1. Experimental steps:

[0686] 1.1. Preparation of buffer solution: Buffer A: 1.0 L of 0.1 M monobasic potassium phosphate buffer containing 1.0 mM EDTA. Buffer B: 1.0 L of 0.1 M dipotassium hydrogen phosphate buffer containing 1.0 mM EDTA. Buffer C: A 0.1 M potassium phosphate buffer, 1.0 mM EDTA, pH 7.4 was obtained by titrating 700 mL of buffer B with buffer A while monitoring with a pH meter.

[0687] 1.2. Preparation of stock solutions for test compounds and reference compounds: Testosterone, Diclofenac, and Propafenone were selected as reference compounds, and these three compounds and the test compound were prepared into 10 mM DMSO stock solutions.

[0688] 1.3. Prepare spiking solutions for the reference compound and the test compound: 100 µM spiked solution: Add 5 µL of 10 mM DMSO stock solution to 495 µL of acetonitrile.

[0689] 1.4. Preparation of NADPH stock solution: Dissolve NADPH in a 10 mM magnesium chloride solution (working concentration 10 mM, final concentration of the reaction system 1 mM).

[0690] 1.5. Preparation of quenching solution: Cold (4°C) acetonitrile (ACN) containing 200 ng / mL tosylate and 200 ng / mL labetalol as internal standards (IS) was used as the quenching solution.

[0691] 1.6. Operating Procedures: (1) Preheat the empty “cultivation” trays T60 and NCF60 for 10 minutes. (2) Dilute liver microsomes to 0.56 mg / mL in 100 mM phosphate buffer (i.e., buffer C). (3) Transfer 445 µL of microsomal working solution (0.56 mg / mL) to preheated “incubation” trays T60 and NCF60, and then pre-incubate the “incubation” trays T60 and NCF60 for 10 minutes with continuous shaking at 37°C. Transfer 54 µL of liver microsomes to a blank tray, then add 6 µL of NAPDH cofactor to the blank tray, and then add 180 µL of quenching solution to the blank tray. (4) Add 5 µL of the compound working solution (100 μM) to the “culture” trays (T60 and NCF60) containing microparticles and mix thoroughly 3 times. (5) For NCF60 discs, add 50 µL of buffer C and mix thoroughly three times. Start timing and incubate the discs at 37°C for 60 minutes while shaking. (6) In the quenching pan T0, add 180 µL of quenching solution and 6 µL of NAPDH cofactor. Ensure the pan is cooled to prevent evaporation. (7) For the T60 plate, mix thoroughly 3 times and immediately transfer 54 µL of the mixture to the "quench" plate within 0 minutes. Then add 44 µL of NAPDH cofactor to the culture plate (T60). Start timing and incubate the plate at 37°C for 60 minutes while shaking. (8) At 5, 15, 30, 45 and 60 minutes, add 180 µL of quenching solution to the “quenching” pan, mix once, and then transfer 60 µL of sample from the T60 pan to the “quenching” pan sequentially at each time point. (9) For NCF60: Mix once and at the 60-minute time point, transfer 60 µL of sample from the NCF60 culture to the “quench” dish containing the quench solution. (10) Shake all the sampling trays for 10 minutes, and then centrifuge at 4000 rpm for 20 minutes at 4°C. (11) Transfer 80 µL of supernatant to 240 µL of HPLC water and mix with a flat plate shaker for 10 minutes. (12) Seal each bioanalytical disc and shake for 10 minutes before performing LC-MS / MS analysis.

[0692] 2. Experimental Results:

[0693] Table 4. Metabolic half-life of the tested compounds in liver microsomes of various species serial number Human liver microsomes (t 1 / 2) rat liver microsomes (t 1 / 2) Mouse liver microsomes (t 1 / 2) Canine liver microsomes (t 1 / 2) [A1] >145 min >145 min >145 min >145 min [A4] >145 min 92 min >145 min 102 min [A24] 117 min 76 min 89 min 68 min [B5] >145 min >145 min 71 min >145 min

[0694] The results of the metabolic stability experiment showed that the compound [A1] and [A4] The compound exhibits good metabolic stability in the liver microsomes of humans, rats, mice, and dogs. [A24] It exhibits good metabolic stability in the liver microsomes of humans and mice, and moderate metabolic stability in the liver microsomes of rats and dogs; Compound B5 exhibits good metabolic stability in the liver microsomes of humans, rats and dogs, and moderate metabolic stability in mice.

[0695] [Example]

[98] [:] [ICR] [Pharmacokinetic assay in mice]

[0696] The pharmacokinetic characteristics of the compounds after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, candidate compounds were prepared into clear solutions and administered to mice via single intravenous injection, while suspensions were used for oral administration. Both intravenous and oral solvents were 10% DMSO + 10% Solutol + 80% (20% Hp-β-CD). This project used six male ICR mice. Three mice received intravenous administration at a dose of 2 mg / kg, and plasma samples were collected at 0 h (before administration) and at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. The other three mice received oral gavage at a dose of 10 mg / kg, and plasma samples were collected at 0 h (before administration) and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. The collected samples were then analyzed by LC / MS / MS, and data were collected. AUC represents the area under the plasma concentration-time curve from time zero to 24 hours. Cmax represents peak concentration; Tmax represents time to peak concentration; T1 / 2 represents half-life; Cl represents clearance; Vd represents apparent volume of distribution; F represents bioavailability; po represents oral administration; iv represents intravenous administration.

[0697] Table 5. Pharmacokinetic results of the compound in mice. Compound numbering [A4] [B5] [iv: , , ]2 mg / kg Cl (mL / kg / min) 8.1 13.6 Vd (L / kg) 0.98 3.6 AUC (ng·h / mL) 4051 2452 T 1 / 2(h) 1.4 3.1 [po: , , ]10 mg / kg Cmax (ng / mL) 8584 1457 Tmax (h) 1.17 2.0 AUC (ng·h / mL) 26417 9992 F(%) 130 91

[0698] In vivo pharmacokinetic results showed that intravenous administration of the compound to mice... [A4] [B5] exhibited a low clearance rate and a good half-life, indicating that the compound... [A4] [B5] was well metabolized in mice; oral administration showed extremely high oral exposure and bioavailability, indicating that the compound... [A4] [B5] is well absorbed orally in mice.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, or isotopic label thereof: wherein, Ring A is selected from one of the following structures: and; each n is independently selected from 0, 1, 2, and 3; X1 is O; X2 is selected from N and CH; if present, R1 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C3-6 cycloalkyl), N(C3-6 cycloalkyl)2, OC1-6 alkyl, 3 to 8-membered heterocyclic group, 6 to 10-membered bridged heterobicyclic group, 5 to 12-membered spiroheterocyclic group, 6 to 12-membered denoted heterobicyclic group, C6-10 The alkyl group and 5 to 10-membered heteroaryl group, wherein the alkyl group, cycloalkyl group, aryl group, heteroaryl group, heterocyclic group, bridged heterobicyclic group, spirobicyclic group and fused heterobicyclic group are each optionally substituted by 1, 2 or 3 Ra groups; if present, the heteroatom or heterogroup in the heterocyclic group, bridged heterobicyclic group, spirobicyclic group, fused heterobicyclic group and heteroaryl group are each independently selected from O, S, NH, N, P(=O), S(=O) and S(=O)2; R2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C1-2 alkylene-C3-6 cycloalkyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, NH(C3-6 cycloalkyl), N(C3-6 cycloalkyl)2, hydroxyl, OC1-6 alkyl, OC3-6 cycloalkyl, O-3 to 8-membered heterocyclic group, 3 to 8-membered heterocyclic group, 6 to 10-membered bridged heterobicyclic group, 5 to 12-membered spirobicyclic group, 6 to 12-membered fused heterobicyclic group. Bicyclic, C6-10 aryl, and 5- to 10-membered heteroaryl groups, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, bridged heterobicyclic, spiroheterocyclic, and fused heterobicyclic groups is optionally substituted with 1, 2, or 3 Rb atoms; if present, the heteroatoms or heterogroups in the heterocyclic, bridged heterobicyclic, spiroheterocyclic, fused heterobicyclic, and heteroaryl groups are each independently selected from O, S, NH, N, P(=O), S(=O), and S(=O)2; If present, R5 and R6 are each independently selected from hydrogen, deuterium, C1-6 alkyl, C3-6 cycloalkyl, and C1-2 alkylene-C3-6 cycloalkyl, wherein each alkyl group is optionally substituted by 1, 2, or 3 Rc atoms; or, R5 and R6 together with the carbon atoms to which they are attached form a saturated five- or six-membered spirocyclic ring, wherein the heteroatoms in the five- or six-membered spirocyclic ring are each independently selected from oxygen, nitrogen, and sulfur, and each five- or six-membered spirocyclic ring is optionally substituted by 1, 2, or 3 Rc atoms; the Z1 ring is selected from one of the following groups: 1) a five- or six-membered heteroaryl group having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; 2) phenyl; 3) a partially or fully saturated five- or six-membered heterocyclic group having 1 to 2 heteroatoms each independently selected from oxygen and nitrogen; 4) a 7- to 10-membered fused heterobicyclic group having 1 to 3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; 5) Partially or fully saturated C3-6 cycloalkyl groups; Z2 ring missing, in which case Rd replaces Z2 ring and connects to Z1 ring;Alternatively, the Z2 ring is selected from one of the following groups: 1) a five- or six-membered heteroaryl group having one to four heteroatoms each independently selected from nitrogen, oxygen, and sulfur; 2) a phenyl group; 3) a partially or fully saturated five- or six-membered heterocyclic group having one to two heteroatoms each independently selected from oxygen and nitrogen; 4) a partially or fully saturated C3-6 cycloalkyl group; if present, each Ra is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, tert-butoxycarbonyl, methylaminomethyl, C1-2 alkylene-hydroxy, C1-2 alkylene-methoxy, and C1-2 alkylene-deuterated methoxy. If present, each Rb is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, cyano, C1-3 alkyl, deuterated methyl, methoxy, deuterated methoxy, cyclopropyl, C1-2 alkylene-hydroxy, C1-2 alkylene-methoxy, and C1-2 alkylene-deuterated methoxy; or, two Rb from any non-adjacent carbon atoms can form a bridged ring through one or two carbon atoms; or, two Rb from the same carbon atom and the carbon atom to which they are attached together form a carbonyl group; if present, each Rc is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, and deuterated methoxy; If present, each Rd is independently selected from hydrogen, deuterium, methyl, deuterated methyl, ethyl, cyclopropyl, C1-2 alkylene-hydroxy, C1-2 alkylene-methoxy, C1-2 alkylene-deuterated methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, and difluoromethoxy; if present, each R3 and R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, methylamino, dimethylamino, nitro, cyano, methyl, deuterated methyl, methoxy, deuterated methoxy, ethyl, cyclopropyl, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, and dimethylphosphineoxy.

2. The compound as claimed in claim 1, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, wherein the compound has the structure of formula (IA): where, n, X1, Z1, Z2, R1, R2, R3, and R4 are as defined in request item 1.

3. The compound as claimed in claim 1, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, wherein the compound has the structure of formula (IB): where, n, Z1, Z2, R2, R3, R4, R5 and R6 are as defined in request item 1.

4. The compound as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, or isotope label thereof, wherein: Z1 is selected from five- or six-membered heteroaryl groups, phenyl groups having one to three heteroatoms each independently selected from nitrogen, oxygen, and sulfur, and seven to ten-membered fused heterobicyclic groups having one to three heteroatoms each independently selected from nitrogen, oxygen, and sulfur.

5. The compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, wherein: When the Z2 ring exists, select one of the following fragments: , When the Z2 ring is missing, select one of the following fragments: .

6. The compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, wherein: R1 is selected from one of the following fragments:

7. The compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, wherein: When the Z2 ring exists, it is selected from one of the following fragments: When the Z2 ring is missing, Rd replaces the Z2 ring and connects to the Z1 ring, Rd as defined in request item 1.

8. The compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, wherein: R2 is selected from NH (C1-6 alkyl), N (C1-6 alkyl)2, NH (C3-6 cycloalkyl), N (C3-6 cycloalkyl)2, hydroxyl, OC1-6 alkyl, OC3-6 cycloalkyl, O-3 to 8-membered heterocyclic group, 3 to 8-membered heterocyclic group, 5 to 12-membered spiroheterocyclic group and 6 to 12-membered diacyclic group, wherein each of the alkyl, cycloalkyl, heterocyclic, spiroheterocyclic and diacyclic groups is optionally substituted by 1, 2 or 3 Rb, Rb as defined in claim 1.

9. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, wherein: R2 is selected from one of the following passages:

10. A compound having the structure of formula (II) or a pharmaceutically acceptable salt, ester, or isotopic label thereof: wherein, R1 is selected from one of the following fragments: ; R2 is selected from one of the following fragments: ; R5 and R6 are each independently C1-6 alkyl.

11. A compound such as the following or a pharmaceutically acceptable salt, ester, or isotopic label thereof: .

12. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, or isotopic label thereof.

13. Use of a compound as described in any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, or isotopic label thereof, or a pharmaceutical composition as described in claim 12, in the preparation of a medicament for the prevention and / or treatment of diseases and / or conditions that are at least partially responsive to IRAK4.

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