7-azabicyclic heteroaryl derivatives as inhibitors of the ectonucleotide pyrophosphatase phosphodiesterase 1

Abstract

The present disclosure provides certain 7-azabicyclic heteroaryl compounds of Formula (Id) that inhibit the ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) enzyme activity and are therefore useful in the treatment of diseases treatable by inhibition of ENPP1. Also provided are pharmaceutical compositions containing such compounds and methods for making such compounds.(Id)

Description

Cross-references to related applications

[0001] This application is based on 35 USC 119(e) claims priority to U.S. Provisional Application No. 63 / 603,798, filed November 29, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0002] This disclosure provides certain 7-azabicyclic heteroaryl compounds that inhibit exonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) enzyme activity and are therefore useful for treating diseases treatable by inhibiting ENPP1. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also provided. Background Technology

[0003] ENPP1 is an enzyme found in a wide range of tissues and cell types, including lymphocytes, macrophages, liver, brain, heart, kidney, vascular smooth muscle cells, and chondrocytes. ENPP1 hydrolyzes ATP and other nucleosides triphosphates, releasing AMP or other nucleosides monophosphates and nucleosides pyrophosphate (PPi) (Kato K et al., 2012 PNAS 109:16876-16881; Hessle L et al., 2002 PNAS 99:9445-9449). This enzyme can also hydrolyze other nucleoside monophosphates (Kato K et al., 2012 PNAS 109:16876-16881). ENPP1 has been identified as a major 2'-3'-cGAMP hydrolase in cultured cells, tissue extracts, and blood (Li L et al., 2014 Nat Chem Biol [Nature Chemical Biology] 10:1043-1048). Tissues and blood from ENPP1 knockout mice lack 2'-3'-cGAMP hydrolase activity. Elevated ENPP1 levels are associated with calcific aortic valve disease (CAVD) and calcium pyrophosphate dihydrate (CPPD) disease (an inflammatory disease caused by the deposition of calcium pyrophosphate dihydrate crystals in joints and surrounding tissues) (Cote N et al., 2012 Eur J Pharmacol 689:139-146; Johnson K et al., 2001 Arthritis Rheum 44:1071). ENPP1 expression is upregulated in certain hepatocellular carcinomas, glioblastomas, melanomas, testicular cancers, pancreatic cancers, thyroid cancers, and breast cancers, and is associated with tolerance to chemotherapy (see Lau WM et al., 2013 PLoSOne 8:5; Bageritz J et al., 2014 Mol Cell Oncology 1:3; Bageritz J et al., 2014 Cell Death, Differentiation 21:929-940; Umar A et al., 2009 Mol Cell Proteomics 8:1278-1294).Upregulation of ENPP1 and its variants are also associated with insulin resistance and type 2 diabetes (Meyre D et al., 2005 Nat Genet 37:863-867; Maddux BA et al., 1995 Nature 373:448-451; Rey D et al., 2012 Mol Biol Rep 39:7687-7693), and it has been reported that the enzyme activity requiring ENPP1 is inhibited by insulin receptor signaling (Chin CN et al., 2009 Eur J Pharmacol 606:17-24).

[0004] Circular GMP-AMP synthase (cGAS) is a pattern recognition receptor that synthesizes the endogenous messenger molecule cGAMP from ATP and GTP in response to the presence of DNA derived from viruses, bacteria, damaged mitochondria, or cancer cells. Then, the cGAMP molecule binds to the interferon gene-stimulating (STING) protein, which initiates the activation of the innate immune signaling response and leads to the production of type I interferon, antiviral agents, and immunostimulatory cytokines (Sun L et al., 2013 Science 339:786-791; Wu J et al., 2013 Science 339:826-830; Gao D et al., 2013 Science 341:903-906; Li X et al., 2013 Science 341:1390-1394; Schoggins JW et al., 2014 Nature 505:691-695; Wassermann R et al., 2015 Cell Host Microbe 17:799-810; Watson RO et al., 2015 Cell Host Microbe). 17:811-819; Collins A et al., 2015 Cell Host Microbe 17:820-828; West A et al., 2015 Nature 520:533-557; Woo SR et al., 2014 Immunity 41:830-842; Deng L et al., 2014 Immunity 41:843-852; Chen Q et al., 2016 Nat Immunol 17:1142-1148). cGAS enzymes, cGAMP messengers, and STING are also involved in host defense against RNA viruses and immune control of tumor development (Aguirre S et al., 2012 PLoS Pathog [PLOS Pathogens] 8:e1002934; Barber GN, 2015 Nat Rev Immunol [Nature Review of Immunology] 15:760-770). ENPP1 has been identified as a naturally occurring enzyme that hydrolyzes cGAMP, and thus counteracts the innate immune response to infectious agents, damaged cells, and cancer cells (Li L et al., 2014 Nat Chem Biol [Nature Chemical Biology] 10:1043-1048).Non-hydrolyzable cGAMP analogues are more effective than naturally hydrolyzable cGAMPs in inducing functional immune responses (Li L et al., 2014 Nat Chem Biol 10:1043-1048; Corrales L et al., 2015 Cell Reports 11:1018-1030). ENPP1 overexpression has been shown to promote viral infection, while ENPP1 silencing has been shown to reduce viral infection (Wang J et al., 2018 Mol Immunol 95:56-63).

[0005] Therefore, cGAMP hydrolysis inhibitors (including ENPP1 inhibition) can be used to enhance the effectiveness of immune responses against cancer cells and tumors, as well as against infections caused by RNA or DNA viruses or bacteria. ENPP1 inhibitors and cGAMP or nucleoside triphosphate hydrolysis inhibitors can also be used to treat inflammatory diseases associated with elevated nucleoside levels, decreased nucleoside triphosphate levels, decreased cGAMP levels, or decreased nucleoside monophosphate levels, or diseases associated with elevated nucleoside or nucleoside monophosphate levels. For these reasons, ENPP1 is an attractive therapeutic target for treating these diseases.

[0006] This disclosure addresses these needs and also provides related advantages. Summary of the Invention

[0007] In a first aspect, a compound having formula (I) or a pharmaceutically acceptable salt thereof is provided: (I), in: X is N, CH, or when attached to R 1 When, it is C; R 1 It is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino, or cyano. R 2 and R 3Independently absent, is alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic, heterocyclic oxy, heterocyclic amino (wherein the heterocyclic group alone or a portion thereof and the heterocyclic oxy group and the heterocyclic amino group may optionally be substituted by one, two or three independently selected from the following substituents: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl). alkyl, and aminoalkyl), heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkylamino (wherein the heterocyclic ring in the heterocyclic alkyl, heterocyclic alkyloxy, and heterocyclic alkylamino is optionally substituted by one, two, or three independent substituents selected from the following: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted by one, two, or three independent substituents selected from the following: alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano); Z is a cyclic imino group, a spirocyclic imino group, a fused cyclic imino group, NH, N (alkyl), O, S, SO, or SO2, wherein: (a) When Z is a cyclic imine, spirocyclic imine, or fused cyclic imine, then Q is -(alk). m -W, where each Z part of (a) is R 4 and R 5 Replace, and R 4 and R 5 Each of these groups does not exist independently; they are alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano groups; and (b) When Z is NH, N (alkyl), O, S, SO, or SO2, then Q is -(alk) 1 ) n -Ar-W, where Ar is a arylene, a 5-membered or a 6-membered heteroarylene, and each Ar is divided by R 6 and R 7 Replace, and R 6 and R 7 It does not exist independently; it is an alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano group. alk and alk 1 Independently, it is an alkylene group that is optionally substituted with one, two, or three halogens; m and n are independently 0 or 1; and W is a group composed of formula (i) or (ii): (i) or (ii); R 8 and R 9 Each of these groups is independently hydrogen, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, heterocyclic, or substituted heterocyclic.

[0008] In some embodiments, a compound having formula (Id) or a pharmaceutically acceptable salt thereof is provided: (Id), in: X is: (a) CH or CR 1 ;or (b) N; R 1 It is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino, or cyano. R 2 and R 3 Independently absent, is alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic, heterocyclic oxy, heterocyclic amino (wherein the heterocyclic group alone or a portion thereof and the heterocyclic oxy group and the heterocyclic amino group may optionally be substituted by one, two or three independently selected from the following substituents: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl). alkyl, and aminoalkyl), heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkylamino (wherein the heterocyclic ring in the heterocyclic alkyl, heterocyclic alkyloxy, and heterocyclic alkylamino is optionally substituted by one, two, or three independent substituents selected from the following: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted by one, two, or three independent substituents selected from the following: alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano); Z is a cyclic imino group, a spirocyclic imino group, a fused cyclic imino group, NH, N (alkyl), O, S, SO, or SO2, wherein: (a) When Z is a cyclic imine group, a spirocyclic imine group, or a fused cyclic imine group, then Q is -(alk). m -W, where each Z part of (a) is R 4 and R 5 Replace, and R 4 and R 5 It does not exist independently; it is an alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, or cyano group; or (b) When Z is NH, N (alkyl), O, S, SO, or SO2, then Q is -(alk) 1 ) n -Ar-W, where Ar is a arylene, a 5-membered or a 6-membered heteroarylene, and each Ar is divided by R 6 and R 7 Replace, and R 6 and R 7 It does not exist independently; it is an alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano group. alk and alk 1 Independently, it is an alkylene group that is optionally substituted with one, two, or three halogens; m and n are independently 0 or 1; and W is a group composed of formula (i) or (ii): (i) or (ii); R 8 and R 9 Each of these groups is independently hydrogen, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, heterocyclic, or substituted heterocyclic.

[0009] In a second aspect, a pharmaceutical composition is provided comprising a compound having (I) (or any of the embodiments described herein) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In a third aspect, a method is provided for treating a disease or condition treatable by inhibiting ENPP1 in a patient, preferably in a patient deemed to require such treatment, the method comprising administering to the patient in a therapeutically effective amount a compound having formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof. In one embodiment, the disease is cancer. In the second embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphoblastic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, low-grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, appendix cancer, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, and bile duct cancer. The cancers include duct cancer, bone cancer, fallopian tube cancer, sarcoma, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, cholangiocarcinoma, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In the third embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.

[0011] In another embodiment, the disease is an inflammatory disease, such as calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment, the disease is a metabolic disease, such as type 2 diabetes, or a viral infection, such as DNA virus infection, HIV, herpes simplex virus infection, human papillomavirus infection, RNA virus infection, and HBV.

[0012] In a fourth aspect, a compound having formula (I) (or any of the embodiments described herein) or a pharmaceutically acceptable salt thereof is provided for use as a pharmaceutical agent. In one embodiment, the pharmaceutical agent is used to treat cancer. In a second embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphoblastic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma. Lymphoma, diffuse large B-cell lymphoma, low-grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, appendix cancer, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcoma, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, bile duct cancer, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In the third embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.

[0013] In another embodiment, the disease is an inflammatory disease, such as calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment, the disease is a metabolic disease, such as type 2 diabetes, or a viral infection, such as DNA virus infection, HIV, herpes simplex virus infection, human papillomavirus infection, RNA virus infection, and HBV.

[0014] In a fifth aspect, the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein) in the manufacture of a medicament for treating a disease in which the activity of ENPP1 promotes the pathology and / or symptoms of the disease in a patient is provided. In one embodiment, the disease is cancer.

[0015] In the second embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphoblastic leukemia, T-cell prolymphoblastic leukemia, prolymphoblastic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Lymphoma, diffuse large B-cell lymphoma, low-grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, appendix cancer, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcoma, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, bile duct cancer, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In the third embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.

[0016] In another embodiment, the disease is an inflammatory disease, such as calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment, the disease is a metabolic disease, such as type 2 diabetes, or a viral infection, such as DNA virus infection, HIV, herpes simplex virus infection, human papillomavirus infection, RNA virus infection, and HBV.

[0017] In a sixth aspect, a method for increasing the activity of immune cells is provided, the method comprising contacting immune cells with a compound having formula (I) or a pharmaceutically acceptable salt thereof (and any of the embodiments disclosed herein).

[0018] In a seventh aspect, a method for increasing the activity of immune cells in a subject is provided, the method comprising administering to a subject in need a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein). In one embodiment of the seventh aspect, the activity of immune cells is increased in a subject suffering from cancer or a viral disease.

[0019] In the second embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphoblastic leukemia, T-cell prolymphoblastic leukemia, prolymphoblastic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Lymphoma, diffuse large B-cell lymphoma, low-grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, appendix cancer, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcoma, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, bile duct cancer, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In the third embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.

[0020] In yet another embodiment, the disease is a viral infection, such as DNA virus infection, HIV, herpes virus infection, papillomavirus infection, RNA virus infection, and HBV.

[0021] In an eighth aspect, a compound having formula (I) or a pharmaceutically acceptable salt thereof (and any examples thereof disclosed herein) is provided for use in the following treatments: 1. Cancer; 2. Inflammatory diseases; 3. Metabolic diseases; or 4. Viral diseases.

[0022] In the first embodiment, the disease is cancer. In the second embodiment, the disease is a cancer selected from the following: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphoblastic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Lymphoma, diffuse large B-cell lymphoma, low-grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, appendix cancer, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcoma, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, bile duct cancer, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer. In the third embodiment, the disease is selected from the following cancers: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, and lung cancer.

[0023] In another embodiment, the disease is an inflammatory disease, such as calcific aortic valve disease, osteoarthritis, and calcium pyrophosphate dihydrate disease. In yet another embodiment, the disease is a metabolic disease, such as type 2 diabetes, or a viral infection, such as DNA virus infection, HIV, herpes simplex virus infection, human papillomavirus infection, RNA virus infection, and HBV.

[0024] In any of the foregoing aspects of cancer treatment, additional embodiments include the administration of a compound having formula (I) or a pharmaceutically acceptable salt thereof (or any of the embodiments disclosed herein) in combination with at least one other anticancer agent. When using combination therapy, these agents may be administered simultaneously or sequentially. Detailed Implementation definition:

[0025] Unless otherwise stated, the following terms used in this specification and claims are defined for the purposes of this application and have the following meanings:

[0026] "Alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having one to six carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc.

[0027] Unless otherwise stated, "alkylene" means a straight-chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched saturated divalent hydrocarbon group having three to six carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

[0028] "Amino" refers to -NH2.

[0029] "alkylamino" refers to the -NHR group (where R is an alkyl group as defined above), such as methylamino, ethylamino, propylamino, or 2-propylamino.

[0030] "Aminoalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms substituted with -NR'R'' (where R' and R'' are independently hydrogen or alkyl as defined above), such as aminomethyl, aminoethyl, methylaminomethyl, etc.

[0031] "Aminoalkylamino" refers to the -NRR group (where R is hydrogen or alkyl and R is an aminoalkyl group as defined above), such as aminoethylamino, dimethylaminoethylamino, diethylaminoethylamino, dimethylaminopropylamino, diethylaminopropylamino, etc.

[0032] "Aminoalkyloxy" or "aminoalkoxy" refers to the -OR group (where R is an aminoalkyl group as defined above), such as aminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, dimethylaminopropyloxy, diethylaminopropyloxy, etc.

[0033] "Amino carbonyl" refers to the -CONH2 group.

[0034] "alkylaminocarbonyl" means -CONHR (where R is an alkyl group as defined above), such as methylaminocarbonyl and propylaminocarbonyl.

[0035] "Alkoxy" refers to the -OR group (where R is an alkyl group as defined above), such as methoxy, ethoxy, propoxy, or 2-propoxy, n-butoxy, isobutoxy, or tert-butoxy, etc.

[0036] "Alkoxyalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms that is substituted by at least one alkoxy group as defined above (such as one or two alkoxy groups), such as 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, or 3-methoxypropyl, 2-ethoxyethyl, etc.

[0037] "Alkoxyalkyloxy" or "alkoxyalkyloxy" refers to an -OR group (where R is an alkoxyalkyl group as defined above), such as methoxyethoxy, ethoxyethoxy, etc.

[0038] "Alkoxyalkylamino" refers to the -NRR' group (where R is hydrogen or alkyl and R' is an alkoxyalkyl group as defined above), such as methoxyethylamino, ethoxyethylamino, propoxypropylamino, ethoxypropylamino, etc.

[0039] "Alkoxycarbonyl" refers to the -C(O)OR group (where R is an alkyl group as defined above), such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.

[0040] "Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 ring atoms, such as phenyl or naphthyl.

[0041] "Areneyl" refers to a divalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, such as 1,3- or 1,4-phenylene or 1,4-naphthylene, etc.

[0042] "Phenyloxy" refers to the -OR group, where R is phenyl.

[0043] "Phenylalkyl" refers to the -(alkylene)-R group, where R is phenyl, such as benzyl.

[0044] "Cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group having three to ten carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0045] "Cycloalkylalkyl" refers to a -(alkylene)-R group (where R is a cycloalkyl group as defined above), such as cyclopropylmethyl.

[0046] "Cycloalkyloxy" refers to the -OR group (where R is a cycloalkyl group as defined above, including specific cycloalkyl rings, such as cyclopropyloxy).

[0047] "Carboxyl group" refers to -COOH.

[0048] "Cyclic amine" refers to a saturated monovalent monocyclic ring with 4 to 8 ring atoms, one of which is nitrogen, and the other ring atoms can be nitrogen, O, or S(O)n (where n is 0, 1, or 2), and the remaining ring atom is carbon. Representative examples of cyclic amines include, but are not limited to, piperidinyl, piperazine, aziridine, and morpholinyl.

[0049] "Biodecanamine" refers to a saturated divalent monocyclic ring with 4 to 8 ring atoms, one of which is nitrogen, and the other ring atoms can be nitrogen, O, or S(O)n (where n is 0, 1, or 2), and the remaining ring atom is carbon. Representative examples of cyclicamines include, but are not limited to, 1,3- or 1,4-piperidinediyl, 1,4-piperazindiyl, 1,3-azacyclobutadiyl, and 1,3-morpholindiyl.

[0050] "Dialkylamino" refers to the -NRR' group (where R and R' are alkyl groups as defined above), such as dimethylamino, methylethylamino, etc.

[0051] "Dialkylaminocarbonyl" means -CONRR', where R and R' are alkyl groups as defined above, such as dimethylaminocarbonyl or diethylaminocarbonyl.

[0052] "Diaminoalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms, which is replaced by two -NR'R'', wherein R' and R'' are independently hydrogen or alkyl as defined above, such as diaminoethyl, 1,3-diaminopropyl, 2-amino-3-methylaminopropyl, etc.

[0053] "Diaminoalkylamino" refers to -NR a R b Group (where R) a It is hydrogen or alkyl and R b It is a diaminoalkyl group as defined above, such as diaminoethylamino, 1,3-diaminopropylamino, 2-amino-3-methylaminopropylamino, etc.

[0054] "Diaminoalkyloxy" refers to -OR a Group (where R) a It is a diaminoalkyl group as defined above, such as 2-diaminoethyloxy, 1,3-diaminopropyloxy, 2-amino-3-methylaminopropyloxy, etc.

[0055] "Fused cyclic imine" refers to a fused divalent bicyclic ring, wherein the first ring is a saturated ring with 4 to 8 ring atoms, one of which is nitrogen, and the other ring atoms can be nitrogen, O, or S(O)n (where n is 0, 1, or 2), and the remaining ring atoms are carbon. Two adjacent ring atoms of the first ring are fused to two adjacent ring atoms of a phenyl, five-membered, or six-membered heteroaryl group as defined herein. Any two suitable ring atoms of the fused cyclic imine can be attachment sites. Non-limiting examples of fused cyclic imines include indoline-2-one-1-yl, indolinel, isoindolinel, etc.

[0056] "Halogen" refers to fluorine, chlorine, bromine, or iodine, with fluorine or chlorine being preferred.

[0057] "Haloalkyl" means an alkyl group as defined above that is substituted with one or more halogen atoms (such as one to five halogen atoms, such as fluorine or chlorine), including those substituted with different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in this application.

[0058] "Haloalkoxy" refers to an -OR group (where R is a haloalkyl group as defined above), such as -OCF3, -OCHF2, etc. When R is a haloalkyl group in which the alkyl group is substituted only by fluorine, it may be referred to as fluoroalkoxy in this application.

[0059] "Hydroxyalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms, substituted with one or two hydroxyl groups, or a branched monovalent hydrocarbon group having three to six carbon atoms, provided that if two hydroxyl groups are present, they are not on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0060] "Hydroxyalkylamino" refers to the -NRR group (where R is hydrogen or alkyl and R is hydroxyalkyl as defined above), such as hydroxyethylamino, hydroxypropylamino, etc.

[0061] "Hydroxyalkyloxy" or "hydroxyalkoxy" refers to the -OR group (where R is a hydroxyalkyl group as defined above), such as hydroxyethyloxy, hydroxypropyloxy, etc.

[0062] "Heterocyclic group" refers to a saturated or unsaturated monocyclic group having 4 to 8 ring atoms, one or two of which are selected from N, O, or S(O). n (where n is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Additionally, one or two ring carbon atoms in the heterocyclic group may optionally be replaced by a -CO- group. More specifically, the term heterocyclic group includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridinyl, morpholinyl, piperazine, tetrahydropyranyl, thiomorpholinyl, etc. When the heterocyclic group ring is unsaturated, it may contain one or two cyclic double bonds, provided that the ring is not aromatic. When the heterocyclic group contains at least one nitrogen atom, it is also referred to herein as a heterocyclic amino and is a subset of heterocyclic groups.

[0063] "Heterocyclic alkyl" or "heterocyclic alkyl" means -(alkylene)-R group (where R is a heterocyclic ring as defined above (including specific heterocyclic rings)), such as tetrahydrofuranylmethyl, piperazineylmethyl, morpholinylethyl, etc.

[0064] "Heterocyclic amino" means -NRR' group, where R is hydrogen or alkyl and R' is a heterocyclic group as defined above (including specific heterocyclic rings).

[0065] "Heterocyclic alkylamino" or "heterocyclic alkylamino" means -NRR' group (where R is hydrogen or alkyl and R' is a heterocyclic alkyl ring as defined above (including specific heterocyclic rings)), such as tetrahydrofuranylmethylamino, piperazinylethylamino, morpholinylethylamino, piperidinylmethylamino, etc.

[0066] "Heterocyclic oxygen group" refers to the -OR group, where R is a heterocyclic group as defined above (including specific heterocyclic rings).

[0067] "Heterocyclic alkyloxy" or "heterocyclic alkyloxy" refers to an -OR group (where R is a heterocyclic alkyl ring as defined above (including specific heterocyclic rings)), such as tetrahydrofuranylmethyloxy, piperazinylethyloxy, morpholinylethyloxy, piperidinylmethyloxy, etc.

[0068] Unless otherwise stated, “heteroaryl” means a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two, or three) of the ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrole, thiophene, thiazolyl, imidazolyl, furanyl, indolyl, isoyindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc. As defined herein, the terms “heteroaryl” and “aryl” are independent of each other. When a heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl.

[0069] Unless otherwise stated, "heteroaryl" means a divalent monocyclic or fused bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two, or three) of the ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolediyl, thiophenediyl, thiazolediyl, imidazolediyl, indolediyl, oxazoldiyl, quinolinediyl, pyridinediyl, pyrimidinediyl, pyrazindiyl, pyridazindiyl, etc. When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl.

[0070] "Heteroaryloxy group" refers to the -OR group, where R is a heteroaryl group as defined above (including a specific heteroaryl ring).

[0071] This disclosure also includes protected derivatives of the compound (I) disclosed herein. For example, when the compounds of this disclosure contain groups such as hydroxyl, carboxyl, thiol, or any group containing one or more nitrogen atoms, these groups may be protected by suitable protecting groups. A comprehensive list of suitable protecting groups can be found at TW Greene,Protective Groups in Organic Synthesis [ Protective Groups in Organic Synthesis The disclosure of the compounds disclosed herein is found in John Wiley & Sons, Inc. (1999), and is incorporated herein by reference in its entirety. Protected derivatives of the compounds disclosed herein can be prepared by methods well known in the art.

[0072] This disclosure also includes polymorphic and deuterated forms of the compounds disclosed herein and / or their pharmaceutically acceptable salts.

[0073] The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalene. Sulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucohepanoic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or salts formed when acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions); or salts formed by coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, etc. N -Methylglucosamine, etc. It should be understood that pharmaceutically acceptable salts are non-toxic. Further information regarding suitable pharmaceutically acceptable salts can be found in [link to relevant information]. Remington's Pharmaceutical Sciences [ Remington's Pharmaceutical Sciences [17th edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.]

[0074] The compounds disclosed herein may have asymmetric centers. Compounds of this disclosure containing asymmetrically substituted atoms may be separated in optical or racemic form. How to prepare the optical form is well known in the art, such as by material resolution. Unless a specific stereochemical or isomeric form is explicitly indicated, all chiral, diastereomeric, mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure. Those skilled in the art will also understand that when a compound is represented as an (R) stereoisomer, it may contain a corresponding (S) stereoisomer as an impurity, i.e., the (S) stereoisomer is less than about 5%, preferably 2%, by weight, and when represented as a mixture of R and S isomers, the amount of R or S isomer in the mixture is greater than about 5%, preferably 2%, w / w.

[0075] Some of the compounds disclosed herein can exist as tautomers and / or geometric isomers. All possible tautomers and... cis and trans Isomers, both individually and in mixtures thereof, are within the scope of this disclosure. Additionally, as used herein, the term alkyl includes all possible isomers of the alkyl group, although only a few examples are listed. Furthermore, when cyclic groups such as aryl, heteroaryl, and heterocyclic are substituted, they include isomers at all positions, although only a few examples are listed. Moreover, all hydrates of the compounds disclosed herein are within the scope of this disclosure.

[0076] The compounds disclosed herein may also contain non-natural amounts of isotopes at one or more atoms constituting such compounds. Non-natural amounts of isotopes can be defined as ranging from amounts found in nature to amounts representing 100% of the atoms considered. This differs only when one or more isotope-enriched atoms are present. Exemplary isotopes that may be incorporated into the compounds of the present invention (such as compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds)) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively as follows: 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I, and 125 1. Isotope-labeled compounds (e.g., those labeled with...)3 H and 14 Those labeled with C can be used in the determination of compound or substrate tissue distribution. Tritium-labeled (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes can be useful due to their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2 Substitution of H) can confer certain therapeutic advantages due to improved metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In some embodiments, in the compounds disclosed herein, including those listed in Table 1 below, one or more hydrogen atoms are... 2 H or 3 H substitution, or one or more carbon atoms being replaced 13 C- or 14 C-enriched carbon substitution. Positron-emitting isotopes (such as...) 15 O、 13 N、 11 C, and 15 F) It can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotope-labeled compounds can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents, following procedures similar to those disclosed in the protocols or examples herein.

[0077] "Oxygenated" or "carbonyl" means (O) group.

[0078] "Optional" or "optionally" means that the event or situation described below may occur but is not required to occur, and means that the description includes both the scenario in which the event or situation occurs and the scenario in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may be present but is not required to be present, and the description includes both the scenario in which the heterocyclic group is substituted with an alkyl group and the scenario in which the heterocyclic group is not substituted with an alkyl group.

[0079] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe and non-toxic, and is neither biologically nor otherwise undesirable for use in the preparation of pharmaceutical compositions, and includes carriers or excipients acceptable for both veterinary and human pharmaceutical use. As used in this specification and claims, "pharmaceuticalally acceptable carrier / excipient" includes both one and more such excipients.

[0080] "Spirocycloimine" refers to a saturated bicyclic divalent ring having 6 to 10 ring atoms, one of which is nitrogen (N), and the other ring atoms can be heteroatoms selected from N, O, and S(O)n (where n is an integer selected from 0 to 2), the remaining ring atoms are carbon (C), and these rings are linked by only one atom, also called a spiro atom, most commonly a quaternary carbon ("spirocarbon"). Unless otherwise stated, the spirocycloimine may optionally be substituted by one or two independent substituents selected from alkyl, halogen, alkoxy, hydroxy, and cyano groups. Representative examples include, but are not limited to, those listed below. wait.

[0081] "Substituted alkyl" means an alkyl group as defined above that is substituted by one or two substituents selected independently from the following: hydroxyl, alkoxy, cyano, amino, alkylamino, and dialkylamino, each of which is defined herein.

[0082] "Substituted cycloalkyl" means a cycloalkyl group as defined above that is substituted by one or two substituents selected independently from the following: alkyl, hydroxy, alkoxy, halogen, cyano, and haloalkyl, each of which is defined herein.

[0083] "Substituted haloalkyl" means a haloalkyl group as defined above that is substituted by one or two substituents selected independently from the following: hydroxyl, alkoxy, cyano, amino, alkylamino, and dialkylamino, each of which is defined herein.

[0084] "Substituted heterocyclic group" means a heterocyclic group as defined above that is substituted by one, two or three substituents independently selected from the following: hydroxyl, alkoxy, cyano, amino, alkylamino, dialkylamino, -COR (where R is alkyl), alkoxycarbonyl, each of which is defined herein.

[0085] Some structures presented in this document are drawn using one or more floating substitution bases. Unless otherwise specified or otherwise derived from the context ( See As is clearly seen in the compounds in Table 1, otherwise the one or more substituents could be present on any atom of the ring through which the substituent is drawn, provided it is chemically feasible and the valence rules permit. Therefore, based on the teachings of this application, the specific compounds in Table 1 are included in the following structures: ,when When C represents CH, R 2 and R 3 It does not exist.

[0086] As used herein, the term “about” is intended to define the numerical value it modifies, indicating that the value is variable within tolerance limits. When no specific tolerance limit is listed (such as the standard deviation of the average given in a chart or data table), the term “about” should be understood to mean a range that includes ±10%, preferably ±5%, of the listed values ​​and ranges.

[0087] As used herein, the term “disease” is intended to be generally synonymous with and interchangeable with the terms “disorder,” “syndrome,” and “symptom” (as in medical conditions), since all of these reflect an abnormal condition of a human or animal body or one of its parts that impairs normal function, typically manifested as distinct signs and symptoms, and resulting in a shortened lifespan or reduced quality of life for the human or animal.

[0088] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans; livestock such as cattle, goats, sheep, pigs, and rabbits; and companion animals such as dogs, cats, and horses. Preferably, a patient is a human.

[0089] The terms “inhibition” and “reduction” regarding ENPP1, or any variations thereof, include any measurable reduction or complete inhibition to achieve the desired result. For example, a reduction in ENPP1 activity compared to normal may be a reduction of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range thereof.

[0090] "Treatment" of diseases includes: (1) Prevention of disease, that is, the prevention of the development of clinical symptoms of disease in mammals that may be exposed to or susceptible to disease but have not yet experienced or shown symptoms of disease; (2) Suppressing the disease, that is, preventing or reducing (stabilizing) the development of the disease or its clinical symptoms; or (3) Relieve disease, that is, the disease or its clinical symptoms subside.

[0091] "Therapeutic effective amount" means the amount of the disclosed compound and / or its pharmaceutically acceptable salts that, when administered to a patient to treat a disease, is sufficient to achieve such treatment of the disease. "Therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0092] Representative compounds having formula (I) are disclosed in Table 1 below: Example: Example A

[0093] In Example A, a compound having formula (I) or a pharmaceutically acceptable salt thereof is as defined in the above description of the invention. Example B

[0094] (B) In Example B, the compound or its pharmaceutically acceptable salt as described in Example A is wherein Z is a cyclic imine group, a spirocyclic imine group, or a fused cyclic imine group, and each Z moiety is R 4 and R 5 replace.

[0095] (Bi) In Example (Bi), the compound or its pharmaceutically acceptable salt as described in Examples A and B is wherein Z is R 4 and R 5 Substituted cyclic imine group.

[0096] (Bii) In Example B of Example (Bii), the compound or its pharmaceutically acceptable salt as described in Examples A and B is wherein Z is R 4 and R 5 Substituted spirocyclic imine group.

[0097] (Biii) In Example B of Example (Biii), the compound or its pharmaceutically acceptable salt as described in Examples A and B is wherein Z is R 4 and R 5 Substituted fused cyclic imine group.

[0098] (Biv) In Example B of Example (Biv), the compound or its pharmaceutically acceptable salt as described in Examples A, B, (Bi), (Bii), or (Biii) is wherein the cyclic imine group and the spirocyclic imine group are attached to the nitrogen ring atom via the nitrogen ring atom. The wavy line represents the attachment point.

[0099] (Bv) In Example (Bv) of Example B, the compound or a pharmaceutically acceptable salt thereof as described in Examples A, B, (Bii), (Biii), or (Biv) is wherein the cyclic imine group, spirocyclic imine group, or fused cyclic imine group of Z is selected from: Each ring is R 4 and R 5 Replace, and among them Is with -(alk) m -W attachment point and Attach to . Example C

[0100] (C) In Example C, the compound or its pharmaceutically acceptable salt as described in Example A is one in which Z is O, N (alkyl), or NH.

[0101] (Ci) In Examples (Ci), the compound or its pharmaceutically acceptable salt as described in Examples A and C is wherein Z is O.

[0102] (Cii) In Examples (Cii), the compound or its pharmaceutically acceptable salt as described in Examples A and C is wherein Z is NH or N (alkyl), preferably NH. Example D

[0103] In Example D, the compound or its pharmaceutically acceptable salt as described in Example A is wherein Z is S or SO2. Example E

[0104] In Example E, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), and D is wherein X is N. Example F

[0105] In Example F, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), and D, is wherein X is CH or CR. 1 .

[0106] It should be understood that X is defined as CH or CR. 1 Implementation F specifies R 1 The carbon at position X and adjacent to X is CH. Therefore, the resulting chemical structure of the compound or its pharmaceutically acceptable salt as described in Example F is based on formula (Id). (Id).

[0107] (Fi) In Example (Fi), the compound having formula (Id) or a pharmaceutically acceptable salt thereof as described in Example F is wherein: R 1 It is cyano; R 2 It does not exist; it is an alkoxy, hydroxyl, cycloalkoxy, or haloalkoxy group. R 3 It is absent or contains alkoxy groups; Z is a cyclic imine group, a spirocyclic imine group, a fused cyclic imine group, NH, or O, wherein: (a) When Z is a cyclic imine group, a spirocyclic imine group, or a fused cyclic imine group, then Q is -(alk). m -W, where each Z part of (a) is R 4 and R 5 Replace, where R 4 It does not exist and R 5 The absence of hydroxyl groups; and (b) When Z is NH or O, then Q is -(alk) 1 ) n -Ar-W, where Ar is the resultant of R. 6 and R 7 Substituted aryl, wherein R 7 It does not exist; and R 6 It is either absent or halogenated; alk and alk 1 It is an alkylene group independently; m and n are independently 0 or 1; W is the formula (i): (i); R 8 It is hydrogen, alkyl, or cycloalkyl; and R 9 It is hydrogen or alkyl.

[0108] (Fii) In Examples (Fii), the compound having formula (Id) or a pharmaceutically acceptable salt thereof as described in Examples F and Fi is wherein X is CH.

[0109] (Fiii) In Example (Fiii), the compound having formula (Id) or a pharmaceutically acceptable salt thereof as described in Examples F, Fi, and Fii is wherein X is a CR 1 .

[0110] (Fiv) In Examples (Fiv), a compound having formula (Id) or a pharmaceutically acceptable salt thereof, as described in Examples F, Fi, Fii, and Fiii, is a compound having formula (Id) according to formula (Id1). (Id1).

[0111] (Fv) In Example (Fv), the compound having formula (Id) or a pharmaceutically acceptable salt thereof as described in Examples F, Fi, Fii, and Fiii is wherein the compound having formula (Id) is according to formula (Id2). (Id2). Example G

[0112] In Example G, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), and (Fiii) is wherein m is 0 and n is 0. Example H

[0113] In Example H, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), and (Fiii) is wherein m is 1 and n is 1. Example I

[0114] (Ii) In Example (Ii), the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), and H, is wherein alk and alk 1 It is methylene, ethylene, or propylene, on its own.

[0115] (Iii) In Example (Iii), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), H, and (Ii) is wherein alk and alk 1 It is methylene. Example J

[0116] In Example J, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), G, H, (Ii), and (Iii) is wherein Ar is R 6 and R 7 Substituted phenylene or 5- or 6-membered heteroaryl groups.

[0117] (Ji). In Example (Ji), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), G, H, (Ii), (Iii), and (J) is wherein Ar is R 6 and R 7 Substituted phenylene.

[0118] (Jii). In Example (Jii), the compound or its pharmaceutically acceptable salt as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), G, H, (Ii), (Iii), (J), and (Ji) is a compound in which Ar is a phenylene ring and W is a carbon attached to the phenylene ring, wherein the carbon is attached to -Z-(alk) 1 ) n -of-(alk) 1 ) n -The meta position of the carbon atom on the phenylene ring.

[0119] (Jiii). In Example (Jiii), the compound or its pharmaceutically acceptable salt as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), G, H, (Ii), (Iii), (J), and (Ji) is a compound in which Ar is a phenylene ring and W is a carbon attached to the phenylene ring, wherein the carbon is attached to -Z-(alk) 1 ) n -of-(alk) 1) n - The para position of the carbon atom on the phenylene ring.

[0120] (Jiv). In Example (Jiv), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fii), (Fiii), G, H, (Ii), (Iii), and (J) is wherein Ar is a heteroaryl group.

[0121] (Jv). In Example (Jv), the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fii), (Fiii), G, H, (Ii), (Iii), (J), and (Jiv), is wherein the 5- or 6-membered heteroaryl group of Ar is selected from divalent pyridinyl, pyrimidinyl, pyridazinyl, thiopheneyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, oxadiazolyl, and imidazolyl.

[0122] (Jvi). In Example (Jvi), the compound or its pharmaceutically acceptable salt as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fii), (Fiii), G, H, (Ii), (Iii), (J), (Jiv), and (Jv) is wherein the heteroaryl group of Ar is a 6-membered ring, such as divalent pyridinyl, pyrimidinyl, or pyridazinyl, wherein W is attached to a carbon on the divalent pyridinyl, pyrimidinyl, or pyridazinyl ring, which attaches the divalent pyridinyl, pyrimidinyl, or pyridazinyl ring to -Z-(alk) 1 ) n -of-(alk) 1 ) n -The meta position of carbon.

[0123] (Jvii). In Example (Jvii), the compound or its pharmaceutically acceptable salt as described in any one of Examples A, C, (Ci), (Cii), D, E, F, (Fii), (Fiii), G, H, (Ii), (Iii), (J), (Jiv), and (Jv) is wherein the heteroaryl group of Ar is a 6-membered ring, such as divalent pyridinyl, pyrimidinyl, or pyridazinyl, wherein W is attached to a carbon on the divalent pyridinyl, pyrimidinyl, or pyridazinyl ring, which attaches the divalent pyridinyl, pyrimidinyl, or pyridazinyl ring to -Z-(alk) 1 ) n -of-(alk) 1 ) n - the para position of carbon. Example K

[0124] (Ki) In Example K, the compound or a pharmaceutically acceptable salt thereof of any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), and (Jvii) is wherein W is: .

[0125] In the first sub-example of embodiment (Ki), W is: .

[0126] In the second sub-example of embodiment (Ki), W is: .

[0127] (Kii) In Example K, the compound or a pharmaceutically acceptable salt thereof of any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fii), (Fiii), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), and (Jvii) is wherein W is: .

[0128] In the first sub-implementation of embodiment (Kii), W is: .

[0129] In the second sub-implementation of embodiment (Kii), W is: . Example L

[0130] (Li) In Examples (Li), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fiii), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), and (Kii) is wherein R 1It is an alkyl, halogen, haloalkyl, haloalkoxy, or cyano group. References to Ki and Kii, as well as the following examples, include sub-examples thereof.

[0131] (Lii) In Examples (Lii), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fiii), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), and (Kii) is wherein R 1 It is methyl, ethyl, isopropyl, cyano, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

[0132] (Liii) In Example (Liii), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fiii), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), and (Kii) is wherein R 1 It is amino, alkylamino, or dialkylamino, or R 1 It is amino, methylamino, or dimethylamino.

[0133] (Liv) In Example (Liv), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fiii), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), and (Kii) is wherein R 1 It is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, or diaminoalkylamino.

[0134] (Lv) In Example (Lv), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fiii), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), and (Kii) is wherein R 1 It is a cyano group. Example M

[0135] In Example M, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (Lv), is wherein R 4 R 5 R 6 and R 7 It does not exist independently and is methyl, ethyl, methoxy, fluorine, trifluoromethyl, trifluoromethoxy, hydroxy, or cyano; or (a) unless otherwise stated, R 4 and R 5 and R 6 and R 7 It is not present independently and is methyl, ethyl, hydroxyl, fluorine, or chlorine. In the sub-examples of Example M, unless otherwise stated, R 4 and R 5 and R 6 and R 7 It is either absent independently or is fluorine. In the sub-examples of Example M, unless otherwise stated, R 4 and R 5 and R 6 and R 7 It is either absent independently or contains hydroxyl groups. In a sub-example of Example M, R 4 and R 5 and R 6 and R 7 It does not exist. Example N

[0136] (Ni) In Examples (Ni), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (M) is wherein, unless otherwise stated, R 2 It does not exist; it is alkyl, hydroxyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.

[0137] (Nii) In sub-example (Nii), the compound or a pharmaceutically acceptable salt thereof as described in any one of examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), and (Ni) is wherein, unless otherwise stated, R 2 It does not exist; it is methyl, hydroxy, methoxy, ethoxy, fluorine, chlorine, trifluoromethyl, cyano, trifluoromethyl, aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl.

[0138] (Niii) In sub-example (Niii), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Ni), and (Nii), wherein, unless otherwise stated, R 2 It does not exist; it is methoxy, ethoxy, aminocarbonyl, or cyano, preferably methoxy. In another sub-example of Example (Niii), R 2 It does not exist; it is either methoxy or ethoxy.

[0139] (Niv) In sub-examples (Niv), the compound or a pharmaceutically acceptable salt thereof as described in any one of examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (M) is wherein R 2 It does not exist; it is an alkoxy group, a haloalkoxy group, or a cycloalkyloxy group.

[0140] (Nv) In sub-example (Nv), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (M) is wherein, unless otherwise stated, R 2 It does not exist; it is methoxy, fluoromethoxy, ethoxy, isopropyloxy, n-propyloxy, aminocarbonyl, cyano, or cyclopropyloxy.

[0141] (Nvi) In Examples (Nvi), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(iv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (M) is wherein R 2 It does not exist; it is methoxy, fluoromethoxy, ethoxy, isopropyloxy, n-propyloxy, or cyclopropyloxy.

[0142] (Nvii) In sub-example (Nvii), the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Ni), (Nii), and (Niii), is a compound having formula (I) that is a compound having formula (Ia), (Ib), or (Ib1): (Ia) (Ib), or (Ib1), Where R 2 R 3 Z, Q, and R 1 It is as defined in this article.

[0143] (Nviii) In sub-example (Nviii), the compound or a pharmaceutically acceptable salt thereof of any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Ni), (Nii), (Niii), (Niv), (Nv), (Nvi), and (Nvii) is wherein R 3 It does not exist.

[0144] (Nix) In Examples (Nix), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), N(vii), and N(viii) is wherein R2 It does not exist; it is a haloalkoxy or cycloalkyloxy group.

[0145] (Nx) In Examples (Nx), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), N(vii), N(viii), and (Nix) is wherein R 2 It does not exist; it is fluoromethoxy, difluoromethoxy, or cycloalkyloxy. Example O

[0146] (Oi) In Examples (Oi), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (M) is wherein, unless otherwise stated, R 2 and R 3 It does not exist independently; it is an alkyl, alkoxy, hydroxyl, halogen, haloalkyl, or haloalkoxy group.

[0147] (Oii). In Example (Oii), the compounds as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), and (Oi) are those whose compounds are: wherein, unless otherwise stated, R 2 and R 3 It is independently alkoxy or halogen, preferably R 2 and R3 Independently, they are methoxy, ethoxy, fluorine, and chlorine.

[0148] (Oiii). In Example (Oiii), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (M) is wherein: Unless otherwise stated, R 2 It does not exist; it is an alkyl, alkoxy, hydroxyl, halogen, haloalkyl, or haloalkoxy group; and R 3 It is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic, heterocyclic oxy, heterocyclic amino (wherein the heterocyclic group alone or a portion thereof and the heterocyclic oxy group and the heterocyclic amino group are optionally substituted by one, two or three independent substituents selected from: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkylamino (wherein the heterocyclic alkyl, halogen ... hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkylamino (wherein the heterocyclic alkyl, halogen, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkylamino, heterocyclic alkyl, hydroxyalkylamino, heterocyclic alkylamino, heterocyclic alkyl, hydroxyalkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic The heterocyclic ring in the heterocyclic alkyloxy group and the heterocyclic alkylamino group may optionally be substituted by one, two or three substituents independently selected from the following: alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl group in the phenyloxy group and the heteroaryl group in the heteroaryloxy group may optionally be substituted by one, two or three substituents, wherein two of these optional substituents are independently selected from alkyl, hydroxyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano).

[0149] (Oiv). In Example (Oiv), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), and (Oii) is wherein, unless otherwise stated, R 2 It does not exist; it is methoxy, ethoxy, or hydroxyl, preferably R. 2 It is methoxy or ethoxy; and R 3 It is 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolylalkyloxy, piperidinyloxy, pyrrolylmethyloxy, piperidinylmethyloxy, pyrrolylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethylamino 2-Ethoxyethylamino, 3-Methoxypropylamino, 3-Ethoxypropylamino, 2-Aminoethylamino, 2-Methylaminoethylamino, 2-Dimethylaminoethylamino, 2-Diethylaminoethylamino, 3-Aminopropylamino, 3-Methylaminopropylamino, 3-Dimethylaminopropylamino, 3-Diethylaminopropylamino, pyrrolylamino, piperidinylamino, pyrrolylmethylamino, piperidinylmethylamino, pyrrolylethylamino, or piperidinylethylamino (wherein the pyrrolyl and piperidinyl groups in each of the above groups, individually or as part of another group, may optionally be substituted by one or two substituents independently selected from methyl, fluorine, hydroxy, or methoxy).

[0150] (Ov). In Examples (Ov), the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), F(iv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), and (M) is one of the following, wherein unless otherwise stated, R 2 and R 3 Independently, it is hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic, heterocyclic oxy, heterocyclic amino (wherein the heterocyclic group alone or a portion thereof and the heterocyclic oxy and heterocyclic amino groups are optionally substituted by one, two or three independent substituents selected from: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkylamino (wherein it is ... The heterocyclic ring in the heterocyclic alkyl, heterocyclic alkyloxy, and heterocyclic alkylamino groups may optionally be substituted by one, two, or three substituents independently selected from the following: alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl group of the phenyloxy group and the heteroaryl group of the heteroaryloxy group may optionally be substituted by one, two, or three substituents independently selected from the following: alkyl, hydroxyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano).

[0151] In the first sub-implementation of embodiment (Ov), R 2 and R 3Independently, 2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethyloxy, 2-ethoxyethyloxy, 3-methoxypropyloxy, 3-ethoxypropyloxy, 2-aminoethyloxy, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, 2-diethylaminoethyloxy, 3-aminopropyloxy, 3-methylaminopropyloxy, 3-dimethylaminopropyloxy, 3-diethylaminopropyloxy, pyrrolylalkyloxy, piperidinyloxy, pyrrolylmethyloxy, piperidinylmethyloxy, pyrrolylethyloxy, piperidinylethyloxy, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-methoxyethyloxy Amino, 2-ethoxyethylamino, 3-methoxypropylamino, 3-ethoxypropylamino, 2-aminoethylamino, 2-methylaminoethylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-aminopropylamino, 3-methylaminopropylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, pyrrolylamino, piperidinylamino, pyrrolylmethylamino, piperidinylmethylamino, pyrrolylethylamino, or piperidinylethylamino (wherein the pyrrolyl and piperidinyl groups in each of the above groups, individually or as part of another group, may optionally be substituted by one or two substituents independently selected from methyl, fluorine, hydroxy, or methoxy).

[0152] (Ovi) In sub-example (Ovi), the compound or a pharmaceutically acceptable salt thereof as described in any one of examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Oi), (Oii), (Oiii), (Oiv), and (Ov) is a compound having formula (I) that is a compound having formula (Ic) or (Ic1): (Ic) or (Ic1). Example P

[0153] (Pi) In sub-example (Pi), the compound or a pharmaceutically acceptable salt thereof as described in any one of examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Oi), (Oii), (Oiii), (Oiv), (Ov), and (Ovi) is wherein each R 8 It is an alkyl group, a substituted alkyl group, a haloalkyl group, a substituted haloalkyl group, a cycloalkyl group, a substituted cycloalkyl group, or a cycloalkylalkyl group.

[0154] (Pii) In sub-example (Pii), the compound or a pharmaceutically acceptable salt thereof as described in any one of examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Oi), (Oii), (Oiii), (Oiv), (Ov), (Ovi), and (Pi) is wherein each R 8 It is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, or cyclobutylmethyl.

[0155] (Piii) In sub-example (Piii), the compound or a pharmaceutically acceptable salt thereof of any one of examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Oi), (Oii), (Oiii), (Oiv), (Ov), (Ovi), and (Pi) is wherein R 8 It is an alkyl or cycloalkyl group.

[0156] (Piv) In sub-examples (Piv), the compound or a pharmaceutically acceptable salt thereof of any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Ki), (Kii), (Li), (Lii), (Liii), (Liv), (M), (Oi), (Oii), (Oiii), (Oiv), (Ov), (Ovi), (Pi), (Pii), and (Piii) is wherein R 8 It is methyl or cyclopropyl.

[0157] (Pv) In sub-examples (Pv), the compound or a pharmaceutically acceptable salt thereof of any one of Examples A, B, (Bi), (Bii), (Biii), (Biv), (Bv), C, (Ci), (Cii), D, E, F, (Fi), (Fii), (Fiii), (Fiv), F(v), G, H, (Ii), (Iii), (Ji), (Jii), (Jiii), (Jiv), (Jv), (Jvi), (Jvii), (Li), (Lii), (Liii), (Liv), (M), (Oi), (Oii), (Oiii), (Oiv), (Ov), (Ovi), (Pi), (Pii), (Piii), (Piv) is wherein R 9 It is hydrogen. Example Q

[0158] In Example (Q), compounds having formula (I) are selected from Table 1 or their pharmaceutically acceptable salts. General synthesis scheme

[0159] The compounds disclosed herein can be prepared by the method described in the reaction scheme shown below.

[0160] The starting materials and reagents used to prepare these compounds may be obtained from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma (St. Louis, Missouri) or prepared by methods known to those skilled in the art following procedures listed in the following references: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–17 (John Willie & Son, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Willie & Son, 1991). References include: March's Advanced Organic Chemistry (John Willie & Son, 4th edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods for synthesizing the compounds disclosed herein, and various modifications can be made to these schemes, as will be apparent to those skilled in the art upon reading this disclosure. If desired, the starting materials and intermediates of the reaction, as well as the final products, can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. Such materials can be characterized using conventional methods, including physical constants and spectroscopic data.

[0161] Unless otherwise specified, the reactions described herein occur at atmospheric pressure in the temperature range of about -78°C to about 150°C, such as about 0°C to about 125°C, and further as at about room temperature (or ambient temperature), such as about 20°C.

[0162] Compounds having formula (I) or (Id) (where Z is a cyclic imine group, spirocyclic imine group, or fused cyclic imine group attached to the core ring via a cyclic nitrogen atom, and Q is -(alk) m-W, where W is a group consisting of formula (i) and other groups are as defined in the compound having formula (I) or (Id) as described in the present invention, can be prepared as illustrated and described in Scheme 1 below (for convenience, only formula (I) is depicted). Option 1

[0163] Compounds having Formula 1 (where hal is a halogen, such as chlorine, and X is CH, N, R) 1 R 4 R 5 and R 6 (as defined in the invention summary) and compounds having Formula 2 (where Z is a cyclic imine group, spirocyclic imine group, or fused cyclic imine group attached to ring 1 via a cyclic nitrogen atom, and (alk) m and R 8 The reaction (as defined in the invention) provides a sulfide of a compound having Formula 3. The reaction is carried out at room temperature or under heating in an aprotic organic solvent (such as NMP, 1,3-dioxolane, TOU (2,5,7,10-tetraoxaundecanane), DMSO, DMPU, HMA, 1,4-dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), etc.) using an organic base (such as DIEA, TEA, etc.). Compounds having Formula 1 (such as 4-chloro-1,7-naphthidine or 4-chloro-8-methoxypyrido[3,4-d]pyrimidine) are commercially available. Compounds having Formula 1 can also be obtained by treating a hydroxyl compound (such as 8-methoxy-1,7-naphthidine-4-ol) with an organic aprotic base in an aprotic solvent under heating or at room temperature with a chlorinating agent (such as P(O)Cl3). The compound having formula 3 was converted into the compound having formula (I) by treating it in methanol with ammonium carbamate and (diacetoxyiodine)benzene.

[0164] Compounds having formula (I) or (Id) (where Z is NH, N (alkyl), O, S, SO, or SO2, and Q is -(alk)). 1 ) n -Ar-W, where W is a group consisting of formula (i) and other groups are as defined in formula (I) or (Id) in the present invention, can be prepared as illustrated and described in the following scheme 2 (for convenience, only formula (I) is depicted). Option 2

[0165] Proceed as described in Scheme 1 above, but replace compound 2 with compound 4 to provide a compound having formula (I), wherein Z is NH, N (alkyl), O, S, SO, or SO2, and Q is -(alk) n -Ar-W, where W is a group composed of formula (I).

[0166] Compounds having formula (I) or (Id) (where Z is a cyclic imine group, spirocyclic imine group, or fused cyclic imine group attached to the core ring via a cyclic nitrogen atom, and Q is -(alk) m -W, where W is a group consisting of formula (ii), and other groups are as defined in formula (I) or (Id) in the present invention, can be prepared as illustrated and described in the following scheme 3 (for convenience, only formula (I) is depicted). Option 3

[0167] In the presence of a base (such as DIEA, CsCO3, or TEA) in a suitable organic solvent (such as DMF or DMP), at room temperature or elevated temperature, a compound having formula 6 (where Z is a cyclic imine group, spirocyclic imine group, or fused cyclic imine group attached to ring 1 via a cyclic nitrogen atom, and (alk) m Treating a compound having Formula 1 (where PG is a suitable amino protecting group) with a suitable organic solvent yields a compound having Formula 7. Treating compound 7 with a mineral acid or Lewis acid (such as TMSOTf, HCl, or TFA) yields an amino compound having Formula 8. Treating a compound having Formula 8 with a formulation of a compound having Formula 9 that has been treated with (diphenylphospho)benzene and oxaloyl chloride and DIEA or another suitable organic base (such as TEA) yields a compound having Formula 10. Treating compound 10 with TFA or another suitable acid yields a compound having Formula (I).

[0168] A chiral sulfoxide imine compound having formula (I) or (Id) (where Z is NH, N (alkyl), O, S, SO, or SO2 (or an embodiment thereof); Q is -(alk) 1 )-Ar-W, wherein W is a group composed of formula (i); X is CH; and the other groups are as defined in formula (I) or (Id) in the summary of the invention (or its embodiments) and can be prepared as illustrated and described in Scheme 4 below (for convenience, only formula (Id) is depicted in Scheme 4). Option 4

[0169] Compounds having formula 4-1 (wherein R) are treated with 2,2-dimethyl-1,3-dioxane-4,6-dione in the presence of trimethoxymethane. 2 and R 3 As defined in the invention description (or embodiments thereof), a compound having formula 4-2 is provided. Compound 4-2 is cyclized in a diphenyl ether at a high temperature (e.g., about 220°C) to provide a compound having formula 4-3.

[0170] (S)-2-methylpropane-2-sulfinamide (compound 4-4) was treated with neopentanoic anhydride, followed by treatment with a compound having formula R in the presence of a deprotonated base (such as sodium hydride). 8 -A halide compound (where R) 8 The process is as defined in the invention (or its embodiments), followed by treatment with an acid (such as trifluoroacetic acid) to provide a compound having formula 4-5.

[0171] Compounds having formulas 4-6 are provided by treating the boric acid of compounds 4-6 in a suitable organic solvent (such as toluene) with compounds having formulas 4-5 (where Ar is as defined in the summary of the invention (or examples thereof), Z is NH, N (alkyl), O, S, SO, or SO2 (or examples thereof), and PG is a suitable amino or oxygen protecting group). The neopentanoyl group and the PG group are removed by methods known in the art, providing benzylmethanol compounds having formulas 4-8. For example, the neopentanoyl group can be removed by treating compounds 4-7 in an organic alcohol solvent (such as methanol, ethanol, etc.) with an inorganic base (such as sodium hydroxide, potassium hydroxide, etc.). For example, if the protecting group is tetrabutyldimethylsilyl, it can be removed by treatment with an acid (such as TBAF) in a suitable organic solvent (such as tetrahydrofuran).

[0172] Under photoelectrophoresis conditions, compounds having formulas 4-8 are coupled with compounds having formulas 4-3 to provide S-sulfonyl imine compounds having formula (Id). It will be apparent to those skilled in the art that R-sulfonyl imines having formula (Id) can be prepared by using (R)-2-methylpropane-2-sulfinamide instead of (S)-2-methylpropane-2-sulfinamide. test

[0173] The following biological examples 1 and 2 can be used. in vitro and in vivo The ENPP1 inhibitory activity of the disclosed compounds was determined. Dosing and Pharmaceutical Composition

[0174] Generally, the compounds disclosed herein will be administered in a therapeutically effective amount via any acceptable mode of administration for agents of similar efficacy. The therapeutically effective amount of the compounds disclosed herein can range from about 0.01 to about 500 mg per kg of patient body weight per day, and can be administered in single or multiple doses. Suitable dose levels can be from about 0.1 to about 250 mg / kg per day; or from about 0.5 to about 100 mg / kg per day. Suitable dose levels can be from about 0.01 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg per day, or from about 0.1 to about 50 mg / kg per day. Within this range, the dose can be from about 0.05 to about 0.5 mg / kg per day, from about 0.5 to about 5 mg / kg per day, or from about 5 to about 50 mg / kg per day. For oral administration, these compositions can be provided in tablet form containing about 1.0 to about 1000 mg of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the active ingredient. The actual amount of the compounds disclosed herein (i.e., the active ingredients) will depend on a variety of factors, such as the severity of the disease to be treated, the patient's age and relative health condition, the potency of the compound used, the route and form of administration, and other factors.

[0175] Generally, the compounds disclosed herein will be administered as pharmaceutical compositions via any of the following routes: oral, systemic (e.g., transdermal, intranasal, or via suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). Preferred administration is oral administration using a convenient daily dosage regimen, which can be adjusted according to the severity of the disease. The compositions may be in the form of tablets, pills, capsules, semi-solid dosage forms, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

[0176] The choice of formulation depends on a variety of factors, such as the mode of drug administration (e.g., for oral administration, formulations in tablet, pill, or capsule form (including enteric-coated or sustained-release tablets, pills, or capsules) are preferred) and the bioavailability of the drug substance. Recently, drug formulations have been developed, particularly for drugs exhibiting poor bioavailability, based on the principle that bioavailability can be increased by increasing surface area (i.e., reducing particle size). For example, U.S. Patent No. 4,107,288 describes a drug formulation having particles in the size range of 10 to 1,000 nm, wherein the active material is loaded on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a drug formulation in which the drug substance is pulverized into nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a drug formulation exhibiting very high bioavailability.

[0177] These compositions typically consist of a combination of the compounds disclosed herein with at least one pharmaceutically acceptable excipient. The acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic benefit of the compounds disclosed herein. Such excipients can be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

[0178] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, and skim milk powder. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and ethylene glycol.

[0179] Compressed gases can be used to disperse the compounds disclosed herein into aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, etc.

[0180] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th edition, 2000).

[0181] The levels of compounds in a formulation can vary within the full range employed by those skilled in the art. Typically, based on the total formulation, the formulation will contain approximately 0.01–99.99 wt.% of the compounds disclosed herein, on a weight percentage (wt.%) basis, with the balance being one or more suitable pharmaceutical excipients. For example, the compounds may be present at a level of approximately 1–80 wt.%.

[0182] The compounds disclosed herein can be combined with one or more other drugs to treat diseases or conditions for which the compounds disclosed herein or other drugs may be effective. Such one or more other drugs may be administered concurrently or sequentially with the compounds disclosed herein via their usual route and in their usual amounts. When the compounds disclosed herein are used concurrently with one or more other drugs, pharmaceutical compositions containing unit dosage forms of such other drugs and the compounds disclosed herein are preferred. However, combination therapies may also include the administration of the compounds disclosed herein and one or more other drugs at different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds disclosed herein and other active ingredients can be administered at lower doses than when used individually. Therefore, the pharmaceutical compositions disclosed herein also include those containing one or more other drugs in addition to the compounds disclosed herein.

[0183] The above combinations include not only combinations of the disclosed compounds with one other drug, but also combinations with two or more other active drugs. Similarly, the disclosed compounds may be used in combination with other drugs used to prevent, treat, control, improve, or reduce the risk of diseases or conditions in which the disclosed compounds are useful. Such other drugs may be administered concurrently or sequentially with the disclosed compounds via their usual route and in their usual amount. When the disclosed compounds are used concurrently with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the disclosed compounds may be used. Therefore, the pharmaceutical compositions disclosed also include those containing one or more other active ingredients in addition to the disclosed compounds. The weight ratio of the disclosed compounds to the second active ingredient may vary and will depend on the effective dose of each ingredient. Typically, the respective effective doses will be used.

[0184] In cases where a subject in need has cancer or is at risk of developing cancer, the disclosed compounds may be used to treat that subject in any combination with one or more other anticancer agents. In some embodiments, one or more anticancer agents are pro-apoptotic agents. Examples of anticancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, chlorhexidine, all-trans retinoic acid (ATRA), lichenin, tumor necrosis factor-associated apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib. TM Gemcitabine, 17-N-allylamino-17-demethoxygerdromycin (17-AAG), flapindole, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, Taxol TM (Also known as "paclitaxel," a well-known anticancer drug that works by enhancing and stabilizing microtubule formation), and Taxol TM Analogs such as Taxotere TM Compounds sharing a basic taxane skeleton as a common structural feature have also shown the ability to arrest cells in the G2-M phase due to stabilized microtubules, and can be combined with the compounds described herein for cancer treatment.

[0185] Further examples of anticancer agents used in combination with the compounds disclosed herein include inhibitors of mitogen-activated protein kinase signaling, such as U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, and BAY. 43-9006, Wollman penicillin, or LY294002; Syk inhibitors; antibodies (e.g., rituxan); MET inhibitors, such as foretinib, cabozantinib, or crizotinib; VEGFR inhibitors, such as sunitinib, sorafenib, regorafenib, lenvatinib, vandetanib, cabozantinib, axitinib; EGFR inhibitors, such as afatinib, brinib, cabozantinib, erlotinib, gefitinib, neratinib, lapatinib; PI3K inhibitors, such as XL147, XL765, BKM120 (buparlisib), GDC-0941, BYL719, IPI145, BAY80-6946, BEX235 (dacrolimus). (dactolisib), CAL101 (idelalisib), GSK2636771, TG100-115; mTOR inhibitors, such as rapamycin (sirolimus), tamsulosin, ileolis, XL388, XL765, AZD2013, PF04691502, PKI-587, BEZ235, GDC0349; MEK inhibitors, such as AZD6244, trametinib, PD184352, pimasertinib, GDC-0973, AZD8330; and proteasome inhibitors, such as carfilzomib, MLN9708, delanzomib, or bortezomib.

[0186] Other anticancer agents that can be used in combination with the compounds disclosed herein include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, axivecin; ararubicin; acodazole hydrochloride; acronin; adorine; interleukin; hexamethylmelamine; ampicillin; ametrine acetate; aminoglutethimide; acridine; anastrozole; atrazomycin; asparaginase; and triamcinolone. Azacitidine; Azatiprine; Azomycin; Balmasta; Benzotiprine; Bicalutamide; Bismuth subsalicylate; Dinefadroxil dimethicone; Bleomycin sulfate; Buquina sodium; Brompirimidine; Busulfan; Actinomycin; Capprotestone; Carbetamide; Carbetin; Carboplatin; Carmustine; Carrubicin hydrochloride; Carzelazin; Sildenafil; Chlormethazine; Claridine; Crizonatol mesylate mesylate); cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dextromethorphan; dezaguanine; dezaguanine mesylate; diazinon; doxorubicin; doxorubicin hydrochloride; droloxifen; droloxifen citrate; drotahistine propionate; dazomycin; edaraxacum; efornithine hydrochloride; ethacridine; enloplatin; enprofen; epirubicin hydrochloride; irbuprofen; isopycin hydrochloride; estradiol; estradiol sodium phosphate; estradiol; Etoposide; Etoposide phosphate; Chlorpheniramine; Fadroxil hydrochloride; Fazalabin; Feniveryl Aamine; Fluorouracil; Fludarabine phosphate; Fluuracil; Flucitabine; Phosphorione; Fostracin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Imofocin; Interleukin II (including recombinant interleukin II or Ril2), Interferon α-2a; Interferon α-2b; Interferon α-n1; Interferon α-n3; Interferon β-1a; Interferon γ-1b; Isopropylplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprorelin acetate; Riazol hydrochloride; Lometraxo sodium; Lomustine; Loxoanthraquinone hydrochloride; Masoronol; Metformin; Nitrogen mustard hydrochloride; Medroxyprogesterone acetate; Meropenem; Minoril; Mercaptopurine; Methotrexate; Methotrexate sodium; Chlorpheniramine; Metformin; Mildolipid; Mitoxin; Mitoxin; Mitoxin; Mitospeptide; Mitoxin; Mitoxin hydrochloride Anthraquinone; Mycophenolic acid; Nocodazole; Nopramine; Omaplatin; Oxysoxime; Pegaspargase; Peribacin; Pendimethicone; Pelosinomycin sulfate; Pephosphonamide; Piperabromide; Piperabromide; Pirroanthraquinone hydrochloride; Procainamide; Promethene; Porphyrom sodium; Methylmitromycin; Prenimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofurane; Lipoadenosine; Rogulam; Safungo; Safungo; Semustine; Citric acid; Sparfosate sodium; Sparmycin; Germanium spiroamine hydrochloride; Spiromustine; Spiroplatin; Streptomycin; Streptozotocin;Sulfochlorpheniramine; Talithromycin; Ticogalane sodium; Tegafur; Tiloanthraquinone hydrochloride; Temopofen; Teniposide; Tiroxicoron; Testrolide; Thiomipril; Thioguanine; Thiotepa; Thiazofuranoline; Tirazamine; Toremifene citrate; Tritoprolone acetate; Tricerebroside phosphate; Trimethotraxa; Trimethotraxa glucuronide; Triptorelin; Tobaccochloride hydrochloride; Uracil nitrogen mustard; Uretoprolone; Vaportide; Vertepofen; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vinpicroline sulfate; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vincristine sulfate; Vorticillium; Zonipram; Netostatin; Zorubicin hydrochloride.

[0187] Compounds disclosed herein, such as 8-(3-(4-acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido(2,3-d)pyrimidin-7(8H)-one, can be used to determine HGS and RT4 tumor models (Example 4 below: In the HGS model, the mediator dose group reached a tumor size of 645 on day 42 post-inoculation, while for animals treated with 20 / kg of the compound, the tumor size was 55). Other anticancer agents with antitumor activity (such as mm3, which showed significant antitumor activity and induced tumor regression) include: 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; ararubicin; acylfulvene; adenosylcyclopentanol; adorexin; adeleukin; ALL-TK antagonists; hexamethylmelamine; amimastatin; amidox; amifostine; aminolevulinic acid; and ararubicin. Acridine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis Inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-dorsal Morphogenetic Protein-1; Anti-androgen, Prostate Cancer; Anti-estrogen; Anti-tumor; Antisense Oligonucleotide; Glycine Afenidimycin; Apoptosis Gene Regulator; Apoptosis Regulator; Depurine Nucleic Acid; ara-CDP-DL-PTBA; Arginine Deaminase; Asulacrine; Atamitan; Amostain; Anestain 1; Anestain 2; Anestain 3; Azasetron; Azatoxin; Diazotyrosine; Baccatin III Derivative; Balanol; Balamastia; BCR / ABL Antagonist; Benzodihydroporphyrin; Benzoylstaurosporine; β-Lactam Derivative; Beta-alethine; Subacram Betulinum toxin B; betulinic acid; Bfgf inhibitor; bicalutamide; bisaccharin; diazinon; bistratene A; bizole; breflate; bromipridine; budotitanol; sulfoxide imine; calcipotriol; carfastatin C; camptothecin derivatives; canarypox IL-2; capecitabine; formamide-amino-triazole; carboxymethylamino-triazole; CaRest M3; CARN 700; Cartilage-derived inhibitors; Capelin; Casein kinase inhibitors (ICOS); Prunella vulgaris; Cetropine B; Cetrolec; Chlorin; Chloroquinoxaline sulfonamide; Cicalprost; Cisporphyrin; Cladribine; Clomiphene analogs; Clotrimazole; Collosimycin A; Collosimycin B; Cobustatin A4; Cobustatin analogs; Conagenin; Crambescidin 816; Crinator; Nostoc cyclopeptide 8;Nostoc cyclopeptide A derivative; Curacin A; Cyclopentafenone; Cycloplatam; Cypemycin; Cytarabine octadecyl phosphate; Cytolysin; Hexestrol phosphate; Dacizumab; Decitabine; Dehydroepiandrone B; Diloxacin; Dexamethasone; Dextromethorphan; Dextromethorphan; Dextromethorphan; Dextromethorphan; Dextromethorphan B; Didox; Diethylnorspermide; Dihydro-5-azacytidine; 9-dioxamycin; Bifenromustine; Twenty-two Alcohol; Dolastron; Deoxyfluorouridine; Droloxifene; Drolbinafine; Betamethasone SA; Ebuseline; Ecomustine; Edifosine; Ezocurumab; Eflunomide; Elimexene; Ethiributyrol; Epirubicin; Iridasteride; Estrogen-mustine analogs; Estrogen agonists; Estrogen antagonists; Ethidazole; Etoposide phosphate; Exemestane; Faldroxil; Fazalabin; Fenivel Aamine; Filgrass; Finasteride; Vrapin; Flucalester; Fludarabine Fludorphine hydrochloride; Folicol; Formestan; Fostracin; Formustin; Gadolinium texaphyrin; Gallium nitrate; Galotetabine; Ganirelix; Gelatinase inhibitor; Gemcitabine; Glutathione inhibitor; Hepsulfam; Modulin; Hexamethylacetamide; Hypericin; Ibandronic acid; Idarubicin; Edoxifen; Igamonone; Imofocin; Ilomasta; Imidazolidine; Imiquimod; Immunostimulatory peptides; Insulin-like growth factor-1 Receptor inhibitors; interferon agonists; interferon; interleukin; iodobenzylguanidine; doxorubicin; ipomeanol, 4-; iroplact; isolaridine; isobengazole; ishomohalicondrin B; istasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate); lanreotide; leinamycin; levofloxacin; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; lirozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; earthworm phospholipids; lometroxoline; chlordamine; loxoanthraquinone; lovastatin; loxoribin; letopecan; tersavorin; lissotheline; cleavage peptide; metansin;Mannostatin A; Malimastastatin; Masoroxyfen; Mammary serine; Matrix dissolving factor inhibitor; Matrix metalloproteinase inhibitor; Menolidin; Meparon; Metraterelin; Methionin; Metoclopramide; MIF inhibitor; Mifepristone; Mitefosine; Milistatin; Mismatched double-stranded RNA; Mitoguanidine hydrazone; Dibromoceramide; Mitomycin analogue; Mitonaphthylamine; Mitotoxin fibroblast growth factor-saponin; Mitoxanthrene Quinones; Mofarotin; Moraxetin; Monoclonal antibodies; Human chorionic gonadotropin; Monophospholipid A; Diethylstilbestrol; Moparinol; Multidrug resistance gene inhibitors; Therapies based on multiple tumor suppressor factor 1; Nitrogen mustard anticancer agents; Indian Ocean sponge (mycaperoxide) B; Mycobacterium cell wall extract; Myriaporone; N-acetyl-binarin; N-substituted benzamide; Nafarelin; Naretepen; Naloxone+ Pentazocine; Napavin; Naphterpin; Natostin; Nedaplatin; Nemorubicin; Neridronate; Neutral endopeptidase; Nilumet; Nisamycin; Nitric oxide regulator; Nitrogen oxide antioxidant; Nitrullyn; O6-benzylguanine; Octreotide; Ocicenone; Oligonucleotide; Ondansetron; Ondansetron; Oracin; Oral cytokine inducer; Omaplatin; Oxatabolone; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylrhizoxin; Pamidronate; Ginsenoside Triol; Panomiphen; Paracoccin; Pazepril; Pegaspargase; Pedesine; Sodium lignosulfonate; Pentostat Ding; Pantozole; Perfluorobromide; Pesophosphatamide; Perillyl alcohol; Benzodiazecin; Phenylacetyl acetate; Phosphatase inhibitors; Sapelelin; Pilocarpine hydrochloride; Pirarubicin; Pyritoxine; Placetin A; Placetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complexes; Porphyrin sodium; Methylmitomycin; Prednisone; Propylbis-Acridinone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immunomodulators; Protein kinase C inhibitors, Microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Hydroxyalkaloid; Pyrazoline acridine; Pyridoxal-modified hemoglobin polyoxyethylene conjugates; RAF antagonists; Raltitrexed; Ramosetron; RAS farnesyltransferase inhibitors; RAS inhibitors; RAS-GAP inhibitors; Demethylated retepritin; Rhenium etidronate Re 186; Rhizomycin; Ribozyme; R.sub.11 Retinoamide; Roguliamine; Roxithromycin; Romotide; Roquimetac; Rubiginone B1;Examples include: ruboxyl; safingo; saintopin; SarCNU; muscle chlorophyll A; saxaglastine; Sdi 1 mimic; semustine; senescence-derived 1; positive oligonucleotides; signal transduction inhibitors; signal transduction modulators; single-chain antigen-binding proteins; cizonan; sobuzosen; boric acid sodium; sodium phenylacetate; solverol; somatostatin-binding proteins; sonaringin; phosphatidylcholine; spiramycin D; spiromonastine; spleen pentapeptide; spongin inhibitor 1; squalamine; stem cell inhibitors; stem cell division inhibitors; stipiamide; matrix-degrading inhibitors; sulfinosine; potent vasoactive intestinal peptide antagonists; suratista. adista); suramin; sorghum extract; synthetic glycosaminoglycans; tamustine; tamoxifen methyl iodide; tauromustine; tazarotene; tecogallan sodium; tegafur; telurimilium; telomerase inhibitors; temopofol; temozolomide; teniposide; tetrachlorodecoxide; tetrazomine; thaliblastine; thiazolinone; thrombopoietin; thrombopoietin mimics; thymosin; thymopoietin receptor agonists; thymic trehalone; thyroid-stimulating hormone; tin Ethyl etiopurpurin); terazamine; dichenol dichloride; topsentin; toremifene; pluripotent stem cell factor; translation inhibitor; retinoic acid; triacetyluridine; trimethoprim; trimethoprim; triptorelin; tropisetron; tolostaniel; tyrosine kinase inhibitor; tyrosine phosphorylation inhibitor; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; vaporpeptide; variolin B; vector system, erythrocyte gene therapy; verarate; veratrine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorazole; zanoteron; zeniplatin; zilascorb; and fenestrated statin ester.

[0188] Another type of anticancer agent that can be used in combination with the compounds disclosed herein includes alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustard (e.g., nitrogen mustard hydrochloride, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazines (dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0189] Examples of natural products that may be useful in combination with the compounds disclosed herein include, but are not limited to, vinca alkaloids (e.g., vincristine), epipodophyllotoxin (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon α).

[0190] Examples of alkylating agents that can be used in combination with the compounds disclosed herein include, but are not limited to, nitrogen mustard (e.g., nitrogen mustard hydrochloride, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin, etc.), or triazines (dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, fluorouracil, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0191] Examples of hormones and antagonists useful in combination with the compounds disclosed herein include, but are not limited to, corticosteroids (e.g., prednisone), progesters (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinylestradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, flumethasone), antiandrogens (e.g., flutamide), and gonadotropin-releasing hormone analogs (e.g., leuprolide). Other agents for the treatment or prevention of cancer that may be used in the methods and compositions described herein include platinum coordination complexes (e.g., cisplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), and adrenocortical inhibitors (e.g., mitotane, aminoglutethimide).

[0192] Examples of anticancer agents that arrest cells in the G2-M phase through stabilized microtubules and can be used in combination with irreversible Btk inhibitor compounds include, but are not limited to, the following marketed and developing drugs: irbuprozil (also known as R-55104), dolastatin 10 (also known as DLS-10 and NSC-376128), mivobulin isethionate (also known as CI-980), vincristine, NSC-639829, discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), altorhyrtin (such as altorhyrtin A and altorhyrtin C), and spongistatin (such as spongistatin 1, spongistatin 2, and spongistatin 3). Spongistatin 4, 5, 6, 7, 8, and 9), cimadolic acid hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (such as epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA), epothilone D (also known as KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, and epothilone B). N-oxide, epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as deoxyepothilone F and dEpoF), 26-fluoroepothilone), auratestatin PE (also known as NSC-654663), solidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia) The following companies are listed: LS-477-P, LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine Sulfuric Acid, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), and BSF-223651 (BASF).Also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Nostocin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS... -39-L-Ser.HCl, and RPR-258062A), Vitivalamide, Tubulysin A, Canadensol, Cyanobacterium cyanide (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute) Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mount Sinai School of Medicine). Medicine), also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (AstaMedica), A-105972 (Abbott Laboratories), Hammetrin, 3-BAABU (Cytoskeleton Company / Mount Sinai School of Medicine),Also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Duraric Company), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mount Sinai School of Medicine), A-204197 (Abbott Laboratories), T-607 (Duraric Company, also known as T-900607), RPR-115781 (Annette), Eleutherobin (e.g., demethylated Eleutherobin) smethyleleutherobin), desaetyleleutherobin, isoeleutherobin A, and Z-Isrobin), Caribaeolin, Halichondrin B, D-64131 (Astar Pharmaceuticals), D-68144 (Astar Pharmaceuticals), Diazonamide A A-293620 (Abbott Laboratories), NPI-2350 (Nereus), Root meadone lactone A, TUB-245 (Annette), A-259754 (Abbott Laboratories), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Astar Pharmaceuticals), D-68836 (Astar Pharmaceuticals), Matrix protein B, D-43411 (Sentari) Zentaris (also known as D-81862), A-289099 (Abbott Laboratories), A-318315 (Abbott Laboratories), HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0193] Further examples of anticancer agents used in combination with the compounds disclosed herein include immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologics) targeting immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is selected from the following stimulating checkpoint molecules: CD27, CD28, CD40, ICOS, OX40, GITR, CD137, and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from the following: B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from CTLA-4. In some embodiments, the compounds provided herein can be used in combination with one or more reagents selected from the following: KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFRβ inhibitors.

[0194] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab, or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0195] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atelizumab) or MEDI4736 (dulvarubb).

[0196] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or trimemumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383. General Methods

[0197] All solvents used were commercially available and ready for use without further purification. Reactions were typically carried out using anhydrous solvents under a nitrogen inert atmosphere.

[0198] Protons were recorded at 400 MHz or 300 MHz on a Bruker 400 NMR spectrometer equipped with a Bruker 400 BBO probe or a Bruker BBFO ULTRASHIELD™ 300 AVANCE III. 1 H-spectroscopy. All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal ( 1 H and 13 C. Both are set to d0.00).

[0199] LCMS analysis was performed on a SHIMADZU LCMS consisting of a UFLC 20-AD and an LCMS 2020 MS detector. The diode array detector was scanned from 190–400 nm. The mass spectrometer was equipped with an electrospray ionization (ESI) source operating in either positive or negative mode. The mass spectrometer was scanned between m / z 90–900 with scan times ranging from 0.5 to 3.0 s.

[0200] HPLC analysis was performed on a SHIMADZU UFLC equipped with two LC20 AD pumps and an SPD-M20A photodiode array detector. An XBridge C18 column, 3.5 µm, 4.6 × 100 mm, was used. A linear gradient was applied, starting with 90% A (A: 0.05% TFA in water) and ending within 10 min with 95% B (B: 0.05% TFA in MeCN), for a total run time of 15 min. The column temperature was 40 °C, and the flow rate was 1.5 mL / min. The photodiode array detector was scanned from 200–400 nm.

[0201] Thin-layer chromatography (TLC) was performed on Alugram® (silica gel 60 F254) from Manchery-Nagel, typically using UV to visualize the spots. In some cases, alternative visualization methods were employed. In these cases, iodine (prepared by adding approximately 1 g of I₂ to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (prepared by thoroughly mixing 25 g of (NH₄)₆Mo₇O₇ in 450 mL of water and 50 mL of concentrated H₂SO₄) was used. 24 TLC plates were developed to visualize the compounds using 4H₂O and 5 g of (NH₄)₂Ce(IV)(NO₃)₆. Rapid chromatography was performed using 40–63 µm (230–400 mesh) silica gel from Silicycle, following techniques similar to those disclosed in Still, WC; Kahn, M. and Mitra, M., *Journal of Organic Chemistry*, 1978, 43, 2923. Typical solvents used for rapid chromatography or thin-layer chromatography are mixtures of chloroform / methanol, dichloromethane / methanol, ethyl acetate / methanol, and hexane / ethyl acetate. Synthesis Examples Example 1 Synthesis of imino(methyl)[[2-(1,7-naphthidin-4-yl)-2-azaspiro[3.3]hept-6-yl]methyl]-λ6-thione Step 1: 6-[(methanesulfonyloxy)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0202] At 0 °C, TEA (890 mg, 8.79 mmol, 2 equivalents) and MsCl (604 mg, 5.27 mmol, 1.2 equivalents) were added to a stirred solution of 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.00 g, 4.39 mmol, 1 equivalent) in DCM (12 mL). After stirring at room temperature for 2 h, the resulting mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-[(methanesulfonyloxy)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.34 g, 99%) as a yellow solid. Step 2: 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0203] At room temperature, sodium methanethiol (6.68 mL, 20% in H2O) was added to a stirred solution of 6-[(methanesulfonyloxy)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.34 g, 4.38 mmol, 1 equivalent) in EtOH (10 mL). After stirring for 2 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with EA / PE (18:82) to give 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (894 mg, 79%) as a yellow solid. Step 3: 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane

[0204] At room temperature, tert-butyl 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.16 mmol, 1 equivalent) was added to a solution of 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (10 mL) in DCM, along with 2,6-dimethylpyridine (0.12 g, 1.16 mmol, 1 equivalent) and TMSOTf (0.78 g, 3.498 mmol, 3 equivalent). After stirring for 2 h, the reaction mixture was concentrated under reduced pressure to give 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane (380 mg, crude) as a pale yellow oil, which was used directly in the next step without further purification. Step 4: 4-[6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]hept-2-yl]-1,7-naphthidine

[0205] DIEA (314 mg, 2.43 mmol, 4 equivalents) and 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane (191 mg, crude) were added to a solution of 4-chloro-1,7-naphthidine (100 mg, 0.608 mmol, 1 equivalent) in NMP (4 mL). The resulting mixture was stirred at 110 °C for 3 h. After cooling to room temperature, the crude product was purified by elution with ACN / H2O (45:55) using a reverse-phase CombiFlash method to give 4-[6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]hept-2-yl]-1,7-naphthidine (68 mg, 39%) as a brown solid. Step 5: Imino(methyl)[[2-(1,7-naphthid-4-yl)-2-azaspiro[3.3]hept-6-yl]methyl]-λ6-thione

[0206] Add (acetoxy)(phenyl)-λ3-iodoalkyl acetate (179 mg, 0.558 mmol, 3 equivalents) and ammonium carbamate (58 mg, 0.744 mmol, 4 equivalents) to a solution of 4-[6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]hept-2-yl]-1,7-naphthidine (53 mg, 0.186 mmol, 1 equivalent) in MeOH (3 mL ... 150 mm, 5 µm; mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 24% B over 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.07), to obtain imino(methyl)[[2-(1,7-naphthid-4-yl)-2-azaspiro[3.3]hept-6-yl]methyl]-λ6-thione (20.3 mg, 32%) as a grayish-white solid. MS (ESI, positive ion) m / z: 317.1 (M+1). 1 H NMR (300 MHz, DMSO- d 6 +D2O, ppm ) δ 9.08 (s, 1H), 8.43 (d, J = 5.4 Hz, 1H), 8.34 (d, J = 5.8 Hz, 1H), 7.83(d,J = 5.9 Hz, 1H), 6.38 (d, J = 5.4 Hz, 1H), 4.43 (s, 2H), 4.28 (s, 2H), 3.21(d, J = 7.2 Hz, 2H), 2.85 (s, 3H), 2.70-2.62 (m, 1H), 2.50-2.41 (m, 2H), 2.18-2.10 (m, 2H). Example 2 Synthesis of imino((2-(8-methoxypyridano[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(methyl)-λ6-thione (2a) and ((2-(8-hydroxypyridano[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(imino)(methyl)-λ6-thione (2b) Step 1: 2-[8-methoxypyrido[3,4-d]pyrimidin-4-yl]-6-[(methylthioalkyl)methyl]-2-azaspiro[3,3]heptane

[0207] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxypyrido[3,4-d]pyrimidine (100 mg, 0.51 mmol) was used and the mixture was stirred at 90 °C for 2 h. 2-[8-methoxypyrido[3,4-d]pyrimidin-4-yl]-6-[(methylthioalkyl)methyl]-2-azaspiro[3,3]heptane (105 mg, 64%) was obtained as a brown solid. Step 2: Imino((2-(8-methoxypyridano[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(methyl)-λ6-thione and ((2-(8-hydroxypyridano[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(imino)(methyl)-λ6-thione

[0208] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 2-[8-methoxypyridano[3,4-d]pyrimidin-4-yl]-6-[(methylthioalkyl)methyl]-2-azaspiro[3,3]heptane (95 mg, 0.30 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: YMC-ActusTriart C18 ExRS column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 28% B over 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 7.12. Fractions containing the desired product were combined and lyophilized to obtain:

[0209] Fraction 1: Imino((2-(8-methoxypyridano[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(methyl)-λ6-thione (2a, 21.1 mg, 20%) as a white solid. MS (ESI, positive ion) m / z: 348.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.50 (s, 1H), 8.01 (d, J = 5.8 Hz, 1H), 7.30(d, J = 5.9 Hz, 1H), 4.45 (s, 4H), 3.99 (s, 3H), 3.56 (s, 1H), 3.24-3.12 (m,2H), 2.85 (s, 3H), 2.69-2.63 (m, 1H), 2.48-2.45 (m 1H), 2.15 (q, J = 11.4, 10.9Hz, 2H).

[0210] Fraction 2: White solid ((2-(8-hydroxypyridino[3,4-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(imino)(methyl)-λ6-thione (2b, 12.6 mg, 12%). MS (ESI, positive ion) m / z: 334.2 (M+1). 1 H NMR (300 MHz, DMSO- d 6 , ppm) δ 11.65 (s, 1H), 8.46 (s, 1H), 7.17 (d, J =7.2 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H), 4.47 (s, 2H), 4.31 (s, 2H), 3.55 (s,1H), 3.21-3.14 (m, 2H), 2.84 (s, 3H), 2.67-2.63 (m, 1H), 2.48-2.43 (m, 2H),2.12 (q, J = 10.7 Hz, 2H). Example 3 Synthesis of imino(3-(1-(8-methoxy-1,7-naphthidin-4-yl)azacyclobutane-3-yl)propyl)(methyl)-λ6-thione Step 1: 3-(3-((methanesulfonyl)oxy)propyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0211] The title compound was synthesized in a manner similar to that described in Step 1 of Example 1, except that tert-butyl 3-(3-hydroxypropyl)azacyclobutane-1-carboxylate (1.00 g, 4.64 mmol) was used. tert-butyl 3-(3-((methanesulfonyl)oxy)propyl)azacyclobutane-1-carboxylate (1.40 g, crude) was obtained as a pale yellow oil and used directly in the next step without further purification. Step 2: tert-butyl 3-[3-(methylthioalkyl)propyl]azacyclobutane-1-carboxylate

[0212] The title compound was synthesized in a manner similar to that described in Example 1, step 2, except that tert-butyl 3-(3-((methanesulfonyl)oxy)propyl)azacyclobutane-1-carboxylate (1.40 g, 4.77 mmol) was used. 3-[3-(methylthioalkyl)propyl]azacyclobutane-1-carboxylate tert-butyl ester (1.00 g, 85%) was obtained as a colorless oil. Step 3: 3-(3-(methylthio)propyl)azacyclobutane

[0213] The title compound was synthesized in a manner similar to that described in Example 1, step 3, except that tert-butyl 3-[3-(methylthio)propyl]azacyclobutane-1-carboxylate (450 mg, 1.83 mmol) was used. 3-(3-(methylthio)propyl)azacyclobutane (0.80 g, crude) was obtained as a colorless oil. Step 4: 4-Chloro-8-methoxy-1,7-naphthidine

[0214] At room temperature, DIEA (2.35 g, 18.16 mmol, 2 equivalents) and POCl3 (1.67 g, 10.89 mmol, 1.2 equivalents) were added to a stirred solution of 8-methoxy-1,7-naphthidine-4-ol (1.60 g, 9.08 mmol, 1 equivalent) in toluene (32 mL). After stirring overnight at 70 °C, the resulting mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography with elution of ACN / H2O (35:65) to give 4-chloro-8-methoxy-1,7-naphthidine (1.11 g, 62%) as a yellow solid. Step 5: 8-Methoxy-4-[3-[3-(methylthioalkyl)propyl]azacyclobutane-1-yl]-1,7-naphthidine

[0215] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (150 mg, 0.77 mmol) and 3-[3-(methylthioalkyl)-propyl]azacyclobutane (1.05 g, crude) were used and the mixture was stirred at 130 °C for 2 h. 8-methoxy-4-[3-[3-(methylthioalkyl)-propyl]azacyclobutane-1-yl]-1,7-naphthidine (42 mg, 18%) was obtained as a grayish-white solid. Step 6: Imino(3-(1-(8-methoxy-1,7-naphthidin-4-yl)azacyclobutane-3-yl)propyl)(methyl)-λ6-thione

[0216] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 8-methoxy-4-[3-[3-(methylthioalkyl)propyl]azacyclobutane-1-yl]-1,7-naphthidine (32 mg, 0.10 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...). 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 27% B over 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.9). Fractions containing the desired product were combined and lyophilized to give imino(3-(1-(8-methoxy-1,7-naphthidin-4-yl)azacyclobutane-3-yl)propyl)(methyl)-λ6-thione (4.1 mg, 10%) as a brown solid. MS (ESI, positive ion) m / z: 335.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.41 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 6.0Hz, 1H), 7.39 (d, J = 6.1 Hz, 1H), 6.43 (d, J = 5.3 Hz, 1H), 4.45 (t, J = 8.2 Hz,2H), 3.99 (s, 5H), 3.64 (s, 1H), 3.07 (t, J = 7.5 Hz, 2H), 2.90 (s, 3H), 2.80-2.78 (m, 1H), 1.82-1.66 (m, 4H). Example 4 Synthesis of cyclopropyl((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)-methyl)(imino)-λ6-thione Step 1: 4-Hydroxy-4-(thioalkylmethyl)piperidine-1-carboxylic acid tert-butyl ester

[0217] A mixture of sodium sulfide nonahydrate (5.63 g, 23.44 mmol, 2.5 equivalents) and sodium sulfide nonahydrate (5.63 g, 23.44 mmol, 2.5 equivalents) in MeOH (80 mL) was stirred at 0 °C under N2 atmosphere for 15 min. Tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2.00 g, 9.37 mmol, 1 equivalent) was added to MeOH (80 mL), and the mixture was stirred at 0 °C under N2 atmosphere for 1 h, then warmed to room temperature over 1 h. A saturated sodium bicarbonate solution was then slowly added at 0 °C. The resulting mixture was concentrated to remove MeOH and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (1:8) to give tert-butyl 4-hydroxy-4-(thioalkylmethyl)piperidine-1-carboxylate (1.50 g, 64%) as a colorless oil. Step 2: 4-[(cyclopropylthioalkyl)methyl]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0218] Potassium tert-butoxide (816 mg, 7.27 mmol, 3 equivalents) was added to a mixture of tert-butyl 4-hydroxy-4-(thioalkylmethyl)piperidine-1-carboxylate (600 mg, 2.42 mmol, 1 equivalent) and bromocyclopropane (293 mg, 2.42 mmol, 1 equivalent) in DMSO (6 mL). The resulting mixture was stirred overnight at 120 °C under N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EA / PE (1:9) elution to give tert-butyl 4-[(cyclopropylthioalkyl)methyl]-4-hydroxypiperidine-1-carboxylate (410 mg, 58%) as a colorless oil. Step 3: 4-((cyclopropylthio)methyl)piperidine-4-ol hydrochloride

[0219] A solution of tert-butyl 4-[(cyclopropylthio)methyl]-4-hydroxypiperidine-1-carboxylate (410 mg, 1.42 mmol) in 3 mL of HCl (g, 4 M in dioxane) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 4-((cyclopropylthio)methyl)piperidine-4-ol hydrochloride (380 mg crude), which was used directly in the next step without further purification. Step 4: 4-[(cyclopropylthioalkyl)methyl]-1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-ol

[0220] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthylidine (125 mg, 0.64 mmol) and 4-((cyclopropylthio)methyl)piperidin-4-ol hydrochloride (359 mg, 1.60 mmol) were used and the mixture was stirred overnight at 130 °C. A brownish-yellow solid of 4-[(cyclopropylthio)methyl]-1-(8-methoxy-1,7-naphthyl-4-yl)piperidin-4-ol (165 mg, 74%) was obtained. Step 5: Cyclopropyl((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(imino)-λ6-thione

[0221] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-[(cyclopropylthioalkyl)methyl]-1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-ol (150 mg, 0.43 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 36% B over 20 min; Wavelength: 254 nm / 220 nm; RT1 (min): 19.65. Fractions containing the desired product were combined and lyophilized to give a grayish-white solid of cyclopropyl((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(imino)-λ6-thione (68.3 mg, 41%). MS (ESI, positive ion) m / z: 377.2 (M+1). 1 HNMR (400 MHz, DMSO- d 6 , ppm ) δ 8.67 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 5.9 Hz, 1H), 7.34 (d, J = 6.0 Hz, 1H), 7.18 (d, J= 5.0 Hz, 1H), 5.89 (s, 1H), 4.03 (s, 3H), 3.99 (t, J = 2.7 Hz, 1H), 3.40 (d, J = 14.1 Hz, 1H), 3.34 (d, J = 1.7 Hz, 1H), 3.31(s, 2H), 3.24-3.13 (m, 2H), 2.77-2.74 (m, 1H), 2.20-2.06 (m, 2H), 2.06-1.96(m, 1H), 1.90 (d, J = 13.3 Hz, 1H), 1.17-1.04 (m, 1H), 1.02-0.85 (m, 3H). Example 5 Synthesis of (4-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)(methyl)-λ6-thione Step 1: 1,7-Naphthidine-2,4-diol

[0222] Under a nitrogen atmosphere, potassium tert-butoxide (77.44 g, 690.10 mmol, 2.1 equivalents) was added to a solution of methyl 3-aminopyridine-4-carboxylate (50.00 g, 328.62 mmol, 1 equivalent) in ethyl acetate (400 mL). The reaction mixture was heated to 75 °C and stirred overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water was added. The organic phase was separated and the aqueous phase was extracted with EtOAc and tert-butyl methyl ether. The aqueous phase was acidified to pH = 6 with 2 N HCl. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give 1,7-naphthyl-2,4-diol (15.00 g, 28%) as a brown solid. Step 2: 2,4-Dichloro-1,7-Naphthylidine

[0223] A solution of 1,7-naphthidine-2,4-diol (3.80 g, 23.44 mmol, 1 equivalent) in POCl3 (40 mL) was stirred at 110 °C for 40 min. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution and extracted with EtOAc and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution using MeOH / DCM (12 / 88) to give 2,4-dichloro-1,7-naphthidine (2.80 g, 60%), which was concentrated under reduced pressure to give a yellow solid, which was used without further purification. Step 3: 4-Chloro-1,7-Naphthyl

[0224] At room temperature, propyl formate (18.37 g, 208.51 mmol, 5 equivalents) and PdCl2(PPh3)2 (585 mg, 0.83 mmol, 0.02 equivalents) were added to a stirred solution of 2,4-dichloro-1,7-naphthidine (8.30 g, 41.70 mmol, 1 equivalent) in DMF (120 mL) and H2O (60 mL). After stirring at 80 °C under a nitrogen atmosphere for 3 days, the resulting mixture was cooled to room temperature. Water was added and the mixture was extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EA / PE (28 / 72) elution to give 4-chloro-1,7-naphthidine (2.66 g, 38%) as a yellow solid. Step 4: 4-[[4-(methylthioalkyl)phenyl]methoxy]-1,7-naphthidine

[0225] At 0 °C, NaH (126 mg, 3.16 mmol, 2 equivalents, 60%) was added to a solution of [4-(methylthioalkyl)phenyl]methanol (365 mg, 2.37 mmol, 1.5 equivalents) in DMF (4 mL). After stirring at 0 °C for 20 min, 4-chloro-1,7-naphthidine (260 mg, 1.58 mmol, 1 equivalent) was added. The resulting mixture was stirred at 80 °C for 2 h. After cooling to 0 °C, water was added, followed by extraction with EtOAc and washing with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EA / PE (87 / 13) elution to give 4-[[4-(methylthioalkyl)phenyl]methoxy]-1,7-naphthidine (120 mg, 24%) as an orange solid. Step 5: (4-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)(methyl)-λ6-thione

[0226] The title compound was synthesized similarly to that described in Example 1, step 5, except that 4-[[4-(methylthioalkyl)phenyl]methoxy]-1,7-naphthidine (100 mg, 0.35 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 28% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.5). Fractions containing the desired product were combined and lyophilized to give (4-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)-(imino)(methyl)-λ6-thione (38.3 mg, 33%) as a white solid. MS (ESI, positive ion) m / z: 314.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.35 (d, J =1.0 Hz, 1H), 8.91 (d, J = 5.2 Hz, 1H), 8.62 (d, J = 5.6 Hz, 1H), 8.09-8.03 (m,1H), 8.03-7.97 (m, 2H), 7.83-7.76 (m, 2H), 7.36 (d, J = 5.2 Hz, 1H), 5.57 (s,2H), 4.26 (s, 1H), 3.09 (d, J = 0.8 Hz, 3H). Example 6 Synthesis of (3-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(cyclopropyl)(imino)-λ6-thione Step 1: 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-1,7-naphthidine

[0227] The title compound was synthesized in a manner similar to that described in step 4 of Example 5, except that [3-(cyclopropylthioalkyl)phenyl]methanol (98 mg, 0.55 mmol) was used. 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-1,7-naphthidine (133 mg, 65%) was obtained as a yellow oil. Step 2: (3-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(cyclopropyl)(imino)-λ6-thione

[0228] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-1,7-naphthidine (110 mg, 0.36 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 35% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.5). Fractions containing the desired product were combined and lyophilized to give (3-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)-(cyclopropyl)(imino)-λ6-thione (44.7 mg, 36%) as a white solid. MS (ESI, positive ion) m / z: 340.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.35 (d, J =1.0 Hz, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.62 (d, J = 5.6 Hz, 1H), 8.12-8.07 (m,1H), 8.05-7.99 (m, 1H), 7.95-7.83 (m, 2H), 7.72-7.64 (m, 1H), 7.38 (d, J = 5.2Hz, 1H), 5.57 (s, 2H), 4.29 (s, 1H), 2.74-2.62 (m, 1H), 1.19-1.06 (m, 1H), 1.04-0.75 (m, 3H). Example 7 Synthesis of (3-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)(methyl)-λ6-thione Step 1: [3-(methylthioalkyl)phenyl]methanol

[0229] Under a nitrogen atmosphere at 0 °C, LiAlH4 (14.2 mL, 2 M in THF) was slowly added to a solution of 3-(methylthioalkyl)benzoic acid (4.00 g, 23.78 mmol, 1 equivalent) in 40 mL of THF. After stirring at room temperature for 2 h, the mixture was quenched by adding saturated ammonium chloride solution (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (43:57) to give [3.08 g, 84%) as a colorless oil. Step 2: 4-[[3-(methylthioalkyl)phenyl]methoxy]-1,7-naphthidine

[0230] The title compound was synthesized in a manner similar to that described in step 4 of Example 5, except that [3-(methylthioalkyl)phenyl]methanol (187 mg, 1.215 mmol) was used. 4-[[3-(methylthioalkyl)phenyl]methoxy]-1,7-naphthidine (300 mg, 87%) was obtained as a yellow oil. Step 3: (3-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)(methyl)-λ6-thione

[0231] The title compound was synthesized in a manner similar to that described in Example 1, step 5, except that 4-[[3-(methylthioalkyl)phenyl]methoxy]-1,7-naphthidine (150 mg, 0.531 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: Xselect CSH Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 25% B over 8 min; Wavelength: 254 / 220 nm; RT1 (min): 7.65). Fractions containing the desired product were combined and lyophilized to give (3-(((1,7-naphthid-4-yl)oxy)methyl)-phenyl)(imino)(methyl)-λ6-thione (17.5 mg, 10%) as a white solid. MS (ESI, positive ion) m / z: 314.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.35 (s, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 8.03 (d, J =5.6 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.7Hz, 1H), 7.39 (d, J = 5.2 Hz, 1H), 5.56 (s, 2H), 4.30 (s, 1H), 3.10 (s, 3H). Example 8 Synthesis of ((1-(1,7-naphthid-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione Step 1: (1-(1,7-naphthid-4-yl)piperidin-4-yl)methanol

[0232] A mixture of 4-chloro-1,7-naphthidine (480 mg, 2.93 mmol, 1 equivalent), piperidin-4-ylmethanol (336 mg, 2.92 mmol, 1.50 equivalent), X-Phos (279 mg, 0.58 mmol, 0.2 equivalent), Pd2(dba)3 (268 mg, 0.29 mmol, 0.1 equivalent), and Cs2CO3 (2.86 g, 8.7 mmol, 3 equivalent) in 1,4-dioxane (10 ml) was stirred at 100 °C under a nitrogen atmosphere for 2 h. After cooling to room temperature, the resulting mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (60:40) to give (1-(1,7-naphthid-4-yl)piperidin-4-yl)methanol (180 mg, 22%) as a yellow solid. Step 2: Methanesulfonic acid (1-(1,7-naphthid-4-yl)piperidin-4-yl)methyl ester

[0233] At 0 °C, MsCl (78.7 mg, 0.69 mmol, 1.2 equivalent) was added to a mixture of (1-(1,7-naphthid-4-yl)piperidin-4-yl)methanol (160 mg, 0.57 mmol, 1 equivalent) and TEA (174 mg, 1.72 mmol, 3 equivalent) in DCM (10 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (70:30) to give methyl methanesulfonic acid (1-(1,7-naphthid-4-yl)piperidin-4-yl) ester (100 mg, 54%) as a yellow solid. Step 3: 4-(4-((methylthio)methyl)piperidin-1-yl)-1,7-naphthylidine

[0234] At 0 °C, a solution of methyl methanesulfonic acid (1-(1,7-naphthyl-4-yl)piperidin-4-yl)methyl ester (90 mg, 0.28 mmol, 1 equivalent) in EtOH (3 mL) was added with 20% NaSMe in water (590 mg, 1.68 mmol, 6 equivalents). The resulting solution was stirred at room temperature for another 4 h and then concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution using ACN / H2O (45 / 55). The fraction was concentrated to give 4-(4-((methylthio)methyl)piperidin-1-yl)-1,7-naphthylidine (23 mg, 30%) as a white solid. Step 4: ((1-(1,7-naphthid-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione

[0235] The title compound was synthesized in a manner similar to that described in Example 1, step 5, except that 4-(4-((methylthio)methyl)piperidin-1-yl)-1,7-naphthidine (23 mg, 0.08 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep Phenyl OBD C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 24% B over 13 min; wavelength: 254 / 220 nm). Fractions containing the desired product were combined and lyophilized to give a yellow solid ((1-(1,7-naphthid-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (3.1 mg, 12%). MS (ESI, positive ion) m / z: 305.0 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.28 (s, 1H), 8.78 (d, J = 5.0 Hz, 1H), 8.54 (d, J = 5.8 Hz, 1H), 7.80 (d, J = 5.8 Hz, 1H), 7.14 (d, J = 5.1Hz, 1H), 3.74 (s, 1H), 3.59 (d, J = 12.3 Hz, 2H), 3.15 (d, J = 6.3 Hz, 2H), 2.97(s, 3H), 2.94-2.91 (m, 2H), 2.23 (d, J = 12.6 Hz, 1H), 2.13-2.01 (m, 2H), 1.70-1.61 (m, 2H). Example 9 Synthesis of (4-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(cyclopropyl)(imino)-λ6-thione Step 1: 4-(cyclopropylthioalkyl)benzoic acid

[0236] At room temperature, potassium tert-butoxide (3.64 g, 32.43 mmol, 2.5 equivalents) and bromocyclopropane (1.6 mL) were added to a stirred solution of 4-mercaptobenzoic acid (2.00 g, 12.97 mmol, 1 equivalent) in DMSO (20 mL). After stirring overnight at 120 °C, the resulting mixture was dissolved in water and acidified to pH = 5 with 1 M HCl (aqueous). The precipitated solid was collected by filtration, washed with water (150 mL), and dried under reduced pressure to give 4-(cyclopropylthioalkyl)benzoic acid (1.69 g, 67%) as a white solid. Step 2: [4-(cyclopropylthioalkyl)phenyl]methanol

[0237] The title compound was synthesized in a manner similar to that described in step 1 of Example 7, except that 4-(cyclopropylthioalkyl)benzoic acid (500 mg, 2.57 mmol) was used. [4-(cyclopropylthioalkyl)phenyl]methanol (292 mg, 62%) was obtained as a colorless oil. Step 3: 4-((4-(cyclopropylthio)benzyl)oxy)-1,7-naphthylidine

[0238] The title compound was synthesized in a manner similar to that described in step 4 of Example 5, except that [4-(cyclopropylthio)phenyl]methanol (246 mg, 1.36 mmol) was used. 4-((4-(cyclopropylthio)benzyl)oxy)-1,7-naphthidine (198 mg, 70%) was obtained as a yellow solid. Step 4: (4-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)(cyclopropyl)(imino)-λ6-thione

[0239] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-((4-(cyclopropylthio)benzyl)oxy)-1,7-naphthidine (178 mg, 0.57 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: Xselect CSH Prep OBD C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 35% B over 8 min; wavelength: 254 / 220 nm; RT1 (min): 6.97). Fractions containing the desired product were combined and lyophilized to give (4-(((1,7-naphthid-4-yl)oxy)methyl)phenyl)-(cyclopropyl)(imino)-λ6-thione (70.4 mg, 35%) as a white solid. MS (ESI, positive ion) m / z: 340.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.36 (s, 1H), 8.92 (d, J = 5.1 Hz, 1H), 8.62 (d, J = 5.7 Hz, 1H), 8.07 (d, J = 5.6 Hz, 1H), 8.00-7.93(m, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 5.2 Hz, 1H), 5.57 (s, 2H), 4.25 (s, 1H), 2.70-2.67 (m, 1H), 1.18-1.08 (m, 1H), 1.03-0.85 (m, 3H). Example 10 Synthesis of ((4-hydroxy-1-(1,7-naphthid-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione Step 1: 4-((methylthio)methyl)-1-(1,7-naphthid-4-yl)piperidin-4-ol

[0240] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-((methylthio)methyl)piperidin-4-ol hydrochloride (551 mg, 2.80 mmol) was used and the mixture was stirred overnight at 90 °C. 4-((methylthio)methyl)-1-(1,7-naphthidin-4-yl)piperidin-4-ol (320 mg, 70%) was obtained as a yellow solid. Step 2: ((4-hydroxy-1-(1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione

[0241] The title compound was synthesized in a similar manner to that described in Example 1, step 5, except that 4-((methylthio)methyl)-1-(1,7-naphthid-4-yl)piperidin-4-ol (220 mg, 0.76 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 19...) 250 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: MEOH; Flow rate: 25 mL / min; Gradient: 3% B to 33% B over 15 min; Wavelength: 254 / 220 nm; RT1 (min): 14.42). Fractions containing the desired product were combined and lyophilized to give a brown semi-solid ((4-hydroxy-1-(1,7-naphthid-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (23.4 mg, 10%). MS (ESI, positive ion) m / z: 321.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ9.28 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.81 (d, J = 5.6Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 5.64 (s, 1H), 4.03 (s, 1H), 3.47-3.43 (m,2H), 3.39-3.32 (m, 2H), 3.25-3.19 (m, 2H), 3.06 (s, 3H), 2.08-1.99 (m, 4H). Example 11 Synthesis of (2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione Step 1: 2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethanol-1-ol

[0242] At room temperature under a nitrogen atmosphere, Cs₂CO₃ (2.97 g, 9.11 mmol, 3 equivalents), 4-piperidineethanol (588 mg, 4.55 mmol, 1.5 equivalents), Pd(OAc)₂ (136 mg, 0.61 mmol, 0.2 equivalents), and Xantphos (351 mg, 0.61 mmol, 0.2 equivalents) were added to a stirred solution of 4-chloro-1,7-naphthyl (500 mg, 3.03 mmol, 1 equivalent) in DMF (15 mL). After stirring at 80 °C for 2 h, the resulting mixture was diluted with DCM and washed with H₂O and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of MeOH / DCM (10:90) and concentrated under reduced pressure to give 2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl-1-ol (302 mg, 38%) as a yellow solid. Step 2: 2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl methanesulfonate

[0243] At 0 °C, TEA (202 mg, 2.17 mmol, 0.1 equivalent), methanesulfonyl methanesulfonate (284 mg, 1.63 mmol, 1.5 equivalent), and DMAP (13 mg, 0.11 mmol, 0.1 equivalent) were added to a stirred solution of 2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl methanesulfonate (280 mg, 1.63 mmol, 1.5 equivalent) in DCM (6 mL). After stirring at room temperature for 1 h, the resulting mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution using MeOH / DCM (6:94) to give 2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl methanesulfonate (200 mg, 54%) as a yellow solid. Step 3: 4-[4-[2-(methylthioalkyl)ethyl]piperidin-1-yl]-1,7-naphthidine

[0244] The title compound was synthesized in a manner similar to that described in Example 1, step 2, except that 2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl methanesulfonic acid (180 mg, 0.537 mmol) was used. 4-[4-[2-(methylthioalkyl)ethyl]piperidin-1-yl]-1,7-naphthidine (111 mg, 72%) was obtained as a yellow solid. Step 4: (2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione

[0245] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-[4-[2-(methylthioalkyl)ethyl]piperidin-1-yl]-1,7-naphthidine (95 mg, 0.33 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 30% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.38). Fractions containing the desired product were combined and lyophilized to give a yellow semi-solid (2-(1-(1,7-naphthid-4-yl)piperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione (29.4 mg, 27%). MS (ESI, positive ion) m / z: 319.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ9.28 (s, 1H), 8.77 (d, J = 5.0 Hz, 1H), 8.53 (d, J = 5.8 Hz, 1H), 7.81-7.78 (m,1H), 7.13 (d, J = 5.1 Hz, 1H), 3.61 (d, J = 12.6 Hz, 3H), 3.16-3.08 (m, 2H), 2.91(s, 3H), 2.86-2.83 (m, 2H), 1.89-1.86 (m, 2H), 1.83-1.71 (m, 2H), 1.64-1.61(m, 1H), 1.53-1.50 (m, 2H). Example 12 Synthesis of imino(4-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione Step 1: 5-(((2-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0246] A solution of 2-methoxypyridin-3-amine (3.00 g, 24.2 mmol, 1 equivalent), 2,2-dimethyl-1,3-dioxane-4,6-dione (4.50 g, 31.46 mmol, 1.3 equivalent), and trimethoxymethane (3.60 g, 33.8 mmol, 1.4 equivalent) in acetonitrile (30 mL) was stirred at 80 °C under nitrogen atmosphere for 2 h. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EA / PE (25:75) elution. Fractions containing the desired product were combined and concentrated under reduced pressure to give 5-(((2-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.50 g, 97%) as a yellow solid. Step 2: 8-Methoxy-1,7-Naphthyl-4-ol

[0247] A mixture of 5-(((2-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.50 g, 5.4 mmol) in diphenyl ether (38 mL) was stirred at 225 °C for 1.5 h. After cooling to room temperature, 100 mL of PE was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with PE (100 mL). The crude product was purified by reversed-phase rapid chromatography with elution using ACN / H2O (23:77) to give 8-methoxy-1,7-naphthidine-4-ol (600 mg, 63%) as a white solid. Step 3: 8-Methoxy-4-((4-(methylthio)benzyl)oxy)-1,7-naphthidine

[0248] Add (4-(methylthio)phenyl)methanol (912 mg, 5.92 mmol, 2 equivalents) and 2-(tributylphosphine)acetonitrile (1.40 g, 5.92 mmol, 2 equivalents) to a mixture of 8-methoxy-1,7-naphthyl-4-ol (550 mg, 2.96 mmol, 1 equivalent) in toluene (8 mL). Stir the resulting mixture at 130 °C for 2 h. After cooling to room temperature, concentrate the mixture under reduced pressure. Purify the residue by silica gel chromatography with MeOH / DCM (9:91) to give 650 mg of crude product, which was further purified by reversed-phase rapid chromatography with ACN / H2O (45:55) to give 8-methoxy-4-((4-(methylthio)benzyl)oxy)-1,7-naphthylidine (470 mg, 44%) as a white solid. Step 4: Imino(4-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione

[0249] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 8-methoxy-4-((4-(methylthio)benzyl)oxy)-1,7-naphthidine (110 mg, 0.35 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.6). Fractions containing the desired product were combined and lyophilized to give imino(4-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione (75.4 mg, 62%) as a white solid. MS (ESI, positive ion) m / z: 344.0 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.78 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4Hz, 2H), 7.58 (d,J = 6.0 Hz, 1H), 7.36 (d, J = 5.2 Hz, 1H), 5.53 (s, 2H), 4.26 (s, 1H), 4.05 (s, 3H), 3.09 (s, 3H). Example 13 Synthesis of cyclopropyl(imino)(4-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione Step 1: 4-((4-(cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthidine

[0250] The title compound was synthesized in a manner similar to that described in step 4 of Example 5, except that 4-chloro-8-methoxy-1,7-naphthidine (200 mg, 1.02 mmol) and [4-(cyclopropylthio)phenyl]methanol (370 mg, 2.05 mmol) were used. 4-((4-(cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthidine (121 mg, 34%) was obtained as a yellow solid. Step 2: Cyclopropyl(imino)(4-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione

[0251] The title compound was synthesized in a manner similar to that described in Example 1, step 5, except that 4-((4-(cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthidine (100 mg, 0.295 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (Column: XBridge Prep Shield RP C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 14% B to 35% B over 7 min; Wavelength: 254 / 220 nm; RT1 (min): 7). Fractions containing the desired product were combined and lyophilized to give cyclopropyl(imino)(4-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione (42.0 mg, 38%) as a white solid. MS (ESI, positive ion) m / z: 370.1 (M+1). 1H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.79 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 5.8 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 5.8 Hz, 1H), 7.37 (d, J = 5.3 Hz, 1H), 5.53 (s, 2H), 4.26 (s, 1H), 4.05 (s, 3H), 2.69-2.66 (m, 1H) 1.14-1.11 (m,1H), 1.03-0.84 (m, 3H). Example 14 Synthesis of cyclopropyl(imino)(3-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)-phenyl)-λ6-thione Step 1: 3-(cyclopropylthioalkyl)benzoic acid

[0252] The title compound was synthesized in a manner similar to that described in step 1 of Example 9, except that 3-thioalkylbenzoic acid (5.00 g, 30.80 mmol) was used. 3-(cyclopropylthioalkyl)benzoic acid (3.99 g, 61%) was obtained as a colorless oil. Step 2: [3-(cyclopropylthioalkyl)phenyl]methanol

[0253] The title compound was synthesized in a manner similar to that described in step 1 of Example 7, except that 3-(cyclopropylthioalkyl)benzoic acid (24.00 g, 117.37 mmol) was used. [3-(cyclopropylthioalkyl)phenyl]methanol (20.00 g, 86%) was obtained as a yellow oil. Step 3: 8-Methoxy-3H-pyrido[3,4-d]pyrimidin-4-one

[0254] Formamidinium acetate (5.99 g, 57.56 mmol, 2 equivalents) was added to a stirred solution of 3-amino-2-methoxypyridin-4-carboxylic acid (4.84 g, 28.783 mmol, 1 equivalent) in 2-methoxyethanol (90 mL) at room temperature. After stirring at 120 °C for 24 h, the resulting mixture was cooled to room temperature and poured into water. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give 8-methoxy-3H-pyrido[3,4-d]pyrimidin-4-one (4.60 g, 90%) as a gray solid. Step 4: 4-Chloro-8-methoxypyrido[3,4-d]pyrimidine

[0255] At 0 °C, DIEA (2.92 g, 22.57 mmol, 1 equivalent) and POCl3 (8.65 g, 56.44 mmol, 5 equivalent) were added to a stirred solution of 8-methoxy-3H-pyrido[3,4-d]pyrimidin-4-one (2.00 g, 11.28 mmol, 1 equivalent) in toluene (40 mL). After stirring overnight at 90 °C, the resulting mixture was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc, and washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-chloro-8-methoxypyrido[3,4-d]pyrimidinyl (2.08 g, 94%) as a yellow solid. Step 5: 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-methoxypyrido[3,4-d]pyrimidine

[0256] At room temperature, Cs₂CO₃ (999 mg, 3.06 mmol, 2 equivalents) and [3-(cyclopropylthioalkyl)phenyl]methanol (331 mg, 1.84 mmol, 1.2 equivalents) were added to a stirred solution of 4-chloro-8-methoxypyrido[3,4-d]pyrimidine (300 mg, 1.53 mmol, 1 equivalent) in DMF (5 mL). After stirring at 80 °C for 2 h, the resulting mixture was cooled to room temperature, diluted with DCM, and washed with H₂O and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with EA / PE (44:56) elution to give 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-methoxypyrido[3,4-d]pyrimidine (261 mg, 50%) as a yellow solid. Step 6: Cyclopropyl(imino)(3-(((8-methoxypyridano[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione

[0257] The title compound was synthesized in a manner similar to that described in Example 1, step 5, except that 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-methoxypyrido[3,4-d]pyrimidine (241 mg, 0.71 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 38% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.68). Fractions containing the desired product were combined and lyophilized to give cyclopropyl(imino)(3-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione (87.7 mg, 33%) as a white solid. MS (ESI, positive ion) m / z: 371.2 (M+1). 1 HNMR (400 MHz, DMSO- d 6, ppm ) δ 8.93 (s, 1H), 8.24 (d, J = 5.7 Hz, 1H), 8.08 (t, J =1.8 Hz, 1H), 7.93-7.86 (m, 1H), 7.85-7.79 (m, 1H), 7.65 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 5.7 Hz, 1H), 5.76 (s, 2H), 4.27 (s, 1H), 4.07 (s, 3H), 2.82-2.63(m, 1H), 1.17-1.06 (m, 1H), 1.03-0.82 (m, 3H). Example 15 Synthesis of cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione Step 1: 4-((3-(cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthidine

[0258] The title compound was synthesized in a manner similar to that described in step 3 of Example 12, except that (3-(cyclopropylthio)phenyl)methanol (511 mg, 2.84 mmol) was used. 4-((3-(cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthidine (169 mg, 35%) was obtained as a yellow solid. Step 2: Cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione

[0259] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-((3-(cyclopropylthio)benzyl)oxy)-8-methoxy-1,7-naphthidine (154 mg, 0.46 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.6). Fractions containing the desired product were combined and lyophilized to give cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione (74.4 mg, 44%) as a white solid. MS (ESI, positive ion) m / z: 370.1 (M+1). 1 H NMR (400 MHz, DMSO-d 6, ppm )δ 8.79 (d, J = 5.2 Hz, 1H), 8.09-8.07 (m, 2H), 7.91 (d, J = 8 Hz, 1H), 7.84 (d, J =7.6 Hz, 1H), 7.70-7.67 (m, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.37 (d, J= 5.2 Hz,1H), 5.53 (s, 2H), 4.29 (s, 1H), 4.05 (s, 3H), 2.69-2.66 (m, 1H), 1.15-1.09(m, 1H), 1.01-0.97 (m, 3H).

[0260] Following the procedure described in the above paragraphs, another racemic cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione was prepared and purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IH 3). 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: IPA (1%-2 M-NH3-IPA); Flow rate: 90 mL / min; Gradient: isocratic 46% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; Sample solvent: MEOH; Injection volume: 4 mL; Runs: 45, to obtain a grayish-white solid ( R )-Cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thionone (RT1: 7.03 min) and a grayish-white solid ( S )-Cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione (RT2: 10.23 min).

[0261] Fraction 1: (R)-cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione. MS (ESI, positive ion) m / z: 370.0 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) 1 H NMR (400 MHz, DMSO-) d 6) δ 8.79 (d, J = 5.2 Hz, 1H), 8.09 - 8.07 (m, 2H), 7.92 - 7.82(m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 5.8 Hz, 1H), 7.38 (d, J= 5.3 Hz,1H), 5.53 (s, 2H), 4.28 (s, 1H), 4.05 (s, 3H), 2.70 - 2.64 (m, 1H), 1.23 -1.11 (m, 1H), 1.09 - 0.85 (m, 3H).

[0262] Fraction 2: (S)-cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione. MS (ESI, positive ion) m / z: 370.0 (M+1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.79 (d, J =5.2 Hz, 1H), 8.09 - 8.07 (m, 2H), 7.92 - 7.82 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 5.8 Hz, 1H), 7.38 (d, J = 5.3 Hz, 1H), 5.53 (s, 2H), 4.28 (s,1H), 4.05 (s, 3H), 2.70 - 2.64 (m, 1H), 1.23 - 1.11 (m, 1H), 1.09 - 0.85 (m,3H). Example 16 Synthesis of imino(4-(((8-methoxypyrido[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione Step 1: 8-Methoxy-4-[[4-(methylthioalkyl)phenyl]methoxy]pyrido[3,4-d]pyrimidine

[0263] The title compound was synthesized in a manner similar to that described in step 5 of Example 14, except that [4-(methylthioalkyl)phenyl]methanol (283 mg, 1.84 mmol) was used. 8-Methoxy-4-[[4-(methylthioalkyl)phenyl]methoxy]pyrido[3,4-d]pyrimidine (261 mg, 54%) was obtained as a white oil. Step 2: Imino(4-(((8-methoxypyrido[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione

[0264] The title compound was synthesized in a manner similar to that described in Example 1, step 5, except that 8-methoxy-4-[[4-(methylthioalkyl)phenyl]methoxy]-pyrido[3,4-d]pyrimidine (180 mg, 0.574 mmol). The crude product was purified by filtration, washed with MeCN, and lyophilized to give imino(4-(((8-methoxypyrido[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione (76.5 mg, 38%) as a white solid. MS (ESI, positive ion) m / z: 345.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.91 (s, 1H), 8.24 (d, J = 5.7 Hz, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.57 (d, J =5.7 Hz, 1H), 5.75 (s, 2H), 4.25 (s, 1H), 4.07 (s, 3H), 3.08 (s, 3H). Example 17 Synthesis of cyclopropyl(imino)(4-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione Step 1: 4-((4-(cyclopropylthio)benzyl)oxy)-8-methoxypyrido[3,4-d]pyrimidine

[0265] The title compound was synthesized in a manner similar to that described in step 5 of Example 14, except that [4-(cyclopropylthio)phenyl]methanol (332 mg, 1.8 mmol, 1.2 equivalents) was used. 4-((4-(cyclopropylthio)benzyl)oxy)-8-methoxypyrido[3,4-d]pyrimidine (60 mg, 11%) was obtained as a yellow oil. Step 2: Cyclopropyl(imino)(4-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione

[0266] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-((4-(cyclopropylthio)benzyl)oxy)-8-methoxypyridino[3,4-d]pyrimidine (50 mg, 0.15 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18 ExRS column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 7% B to 37% B over 7 min; Wavelength: 254 / 220 nm; RT1 (min): 6.82. The fractions containing the desired product were combined and lyophilized to give cyclopropyl(imino)(4-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione (21.4 mg, 39%) as a white solid. MS (ESI, positive ion) m / z: 371.1 (M+1). 1 H NMR (400 MHz, DMSO-) d 6 , ) δ 8.68 (s, 1H), 8.21-8.17 (m, 1H), 7.89-7.82 (m, 2H), 7.57-7.49 (m, 3H), 5.31 (s, 2H), 4.19 (s, 1H), 4.02 (s, 3H), 2.66-2.59 (m,1H), 1.11-1.05 (m, 1H), 0.99-0.79 (m, 3H). Example 18 Synthesis of cyclopropyl(imino)(3-(((6-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione Step 1: 4-((3-(cyclopropylthio)benzyl)oxy)-6-methoxypyrido[3,4-d]pyrimidine

[0267] The title compound was synthesized in a manner similar to that described in step 5 of Example 14, except that 4-chloro-6-methoxypyridano[3,4-d]pyrimidine (300 mg, 1.53 mmol) was used. 4-((3-(cyclopropylthio)benzyl)oxy)-6-methoxypyridano[3,4-d]pyrimidine (314 mg, 60%) was obtained as a yellow oil. Step 2: Cyclopropyl(imino)(3-(((6-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione

[0268] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-((3-(cyclopropylthio)benzyl)oxy)-6-methoxypyridino[3,4-d]pyrimidine (294 mg, 0.87 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 45% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.6). Fractions containing the desired product were combined and lyophilized to give cyclopropyl(imino)(3-(((6-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione (131.8 mg, 40%) as a white solid. MS (ESI, positive ion) m / z: 371.1 (M+1). 1 H NMR (400MHz, DMSO- d 6 , ppm ) δ 9.12 (s, 1H), 8.79 (s, 1H), 8.15-8.06 (m, 1H), 7.90-7.83(m, 2H), 7.67-7.61 (m, 1H), 7.29-7.28 (m, 1H), 5.77 (s, 2H), 4.27 (s, 1H), 4.00 (s, 3H), 2.70-2.64 (m, 1H), 1.17-1.06 (m, 1H), 1.03-0.82 (m, 3H). Example 19 Synthesis of imino(4-(((6-methoxypyrido[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione Step 1: 6-Methoxy-4-((4-(methylthio)benzyl)oxy)pyrido[3,4-d]pyrimidine

[0269] The title compound was synthesized in a manner similar to that described in step 5 of Example 14, except that 4-chloro-6-methoxypyridano[3,4-d]pyrimidine (200 mg, 1.02 mmol) and [4-(methylthioalkyl)phenyl]methanol (189 mg, 1.23 mmol) were used. A white solid 6-methoxy-4-((4-(methylthio)benzyl)oxy)pyridano[3,4-d]pyrimidine (184 mg, 57%) was obtained. Step 2: Imino(4-(((6-methoxypyridano[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione

[0270] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 6-methoxy-4-((4-(methylthio)benzyl)oxy)pyrido[3,4-d]pyrimidine (160 mg, 0.51 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B over 7 min; Wavelength: 254 / 220 nm; RT1 (min): 6.65. The fractions containing the desired product were combined and lyophilized to give imino(4-(((6-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione (28.1 mg, 15%) as a white solid. MS (ESI, positive ion) m / z: 345.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 9.12 (d, J = 1.0 Hz, 1H), 8.77 (s, 1H), 8.0 (d, J = 7.96 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 1.0 Hz, 1H), 5.77 (s, 2H), 4.24 (s, 1H), 4.00(s, 3H), 3.07 (d, J = 1.1 Hz, 3H). Example 20 Synthesis of ((4-hydroxy-1-(8-methoxypyridino[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-(imino)(methyl)-λ6-thione Step 1: 1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-4-((methylthio)methyl)piperidin-4-ol

[0271] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxypyrido[3,4-d]pyrimidine (300 mg, 1.53 mmol) and 4-[(methylthio)methyl]piperidin-4-ol hydrochloride (364 mg, 1.84 mmol) were used and the mixture was stirred at 90 °C for 2 h. A white solid 1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-4-((methylthio)methyl)piperidin-4-ol (366 mg, 74%) was obtained. Step 2: ((4-hydroxy-1-(8-methoxypyridino[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-(imino)(methyl)-λ6-thione

[0272] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 1-(8-methoxypyridano[3,4-d]pyrimidin-4-yl)-4-((methylthio)methyl)piperidin-4-ol (200 mg, 0.62 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 23% B over 7 min; Wavelength: 254 / 220 nm; RT1 (min): 6.03). Fractions containing the desired product were combined and lyophilized to give ((4-hydroxy-1-(8-methoxypyridino[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-(imino)(methyl)-λ6-thione (130.1 mg, 58%) as a white solid. MS (ESI, positive ion) m / z: 352.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm) δ 8.64 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.34(d, J = 5.6 Hz, 1H), 6.05 (s, 1H), 4.09 (d, J = 13.6 Hz, 2H), 4.02 (s, 4H), 3.58-3.52 (m, 2H), 3.42-3.38 (m, 1H), 3.29-3.25(m, 1H), 3.02 (s, 3H), 2.02-1.80(m, 4H). Example 21 Synthesis of 4-((3-(cyclopropanesulfonylimide)benzyl)oxy)-8-methoxy-1,7-naphthidine-3-carboxynitrile Step 1: Methyl 3-[(E)-[(dimethylamino)methylethylene]amino]-2-methoxypyridine-4-carboxylic acid

[0273] A solution of methyl 3-amino-2-methoxypyridine-4-carboxylate (2.10 g, 11.52 mmol, 1.0 equivalent) in DMF-DMA (1.37 g, 11.52 mmol, 1.0 equivalent) was stirred at 110 °C for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give methyl 3-[(E)-[(dimethylamino)methylethylene]amino]-2-methoxypyridine-4-carboxylate (1.80 g, 65.8%) as a pale yellow oil. Step 2: 4-Hydroxy-8-methoxy-1,7-naphthyl-3-carboxynitrile

[0274] Under a nitrogen atmosphere, at -70 °C, n-BuLi (10.7 mL, 26.97 mmol, 2.0 equivalent, 2.5 M in n-hexane) was slowly added to a solution of MeCN (1.11 g, 26.97 mmol, 2.0 equivalent) in THF (30 mL). After stirring at -70 °C for 0.5 h, methyl 3-[(E)-[(dimethylamino)methylethylene]amino]-2-methoxypyridine-4-carboxylate (3.20 g, 13.48 mmol, 1.0 equivalent) in THF (30 mL) was added to the reaction mixture and stirred at -70 °C for another 1.5 h. AcOH (2.4 mL) was added and the reaction mixture was poured into water. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography with elution of ACN / H2O (10:90) to obtain 4-hydroxy-8-methoxy-1,7-naphthidine-3-carboxynitrile (1.80 g, 66%) as a light yellow solid. Step 3: 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-methoxy-1,7-naphthidine-3-carboxynitrile

[0275] The title compound was synthesized in a manner similar to that described in step 3 of Example 12, except that 4-hydroxy-8-methoxy-1,7-naphthyl-3-carboxynitrile (400 mg, 1.98 mmol) and [3-(cyclopropylthioalkyl)phenyl]methanol (716 mg, 3.97 mmol) were used. 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-methoxy-1,7-naphthyl-3-carboxynitrile (38 mg, 5%) was obtained as a brown solid. Step 4: 4-((3-(cyclopropanesulfonylimide)benzyl)oxy)-8-methoxy-1,7-naphthidine-3-carboxynitrile

[0276] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-methoxy-1,7-naphthyl-3-carboxynitrile (35 mg, 0.096 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep Shield RPC18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 19% B to 40% B over 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.57, to obtain 12.8 mg, 31%, as a grayish-white solid of 4-((3-(cyclopropanesulfonylimide)benzyl)oxy)-8-methoxy-1,7-naphthyl-3-carboxynitrile (ESI, positive ion) m / z: 395.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ9.03 (d, J = 1.6 Hz 1H), 8.24 -8.17 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.95 (d, J =7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.74 -7.66 (m, 1H), 7.53-7.51 (m, 1H), 5.99 (s, 2H), 4.29 (s, 1H), 4.08 (s, 3H), 1.15-0.90 (m, 5H). Example 22 Synthesis of imino((2-(8-methoxy-1,7-naphthidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(methyl)-λ6-thione Step 1: 8-Methoxy-4-[6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]hept-2-yl]-1,7-naphthidine

[0277] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (130 mg, 0.66 mmol) and 6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]heptane (315 mg, 2.00 mmol) were used. 8-methoxy-4-[6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]hept-2-yl]-1,7-naphthidine (120 mg, 56%) was obtained as a brownish-yellow solid. Step 2: Imino((2-(8-methoxy-1,7-naphthidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)-(methyl)-λ6-thione

[0278] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 8-methoxy-4-[6-[(methylthioalkyl)methyl]-2-azaspiro[3.3]hept-2-yl]-1,7-naphthidine (100 mg, 0.31 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBDC18 column, 50...) 250 mm, 10 µm; mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 33% B over 20 min; wavelength: 254 / 220 nm; RT1 (min): 20.77). Fractions containing the desired product were combined and lyophilized to give imino((2-(8-methoxy-1,7-naphthidin-4-yl)-2-azaspiro[3.3]hept-6-yl)methyl)(methyl)-λ6-thione (42.3 mg, 36%) as a pale yellow semi-solid. MS (ESI, positive ion) m / z: 347.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6， ppm ) δ 8.40 (d, J = 5.2 Hz, 1H), 7.87 (d, J =6.0 Hz, 1H), 7.35 (d, J = 6.0 Hz, 1H), 6.41 (d, J = 5.2 Hz, 1H), 4.38 (s, 2H),4.23 (s, 2H), 3.98 (s, 3H), 3.57 (s, 1H), 3.19-3.18 (m, 2H), 2.84 (s, 3H),2.68-2.64 (m, 1H), 2.46-2.43 (m, 2H), 2.17-2.09 (m, 2H). Example 23 Synthesis of ((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)-(imino)(methyl)-λ6-thione Step 1: 1-(8-methoxy-1,7-naphthidin-4-yl)-4-[(methylthioalkyl)methyl]piperidin-4-ol

[0279] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (150 mg, 0.77 mmol) and 4-[(methylthioalkyl)methyl]piperidin-4-ol hydrochloride (457 mg, 2.31 mmol) were used and the mixture was stirred overnight at 130 °C. 1-(8-methoxy-1,7-naphthidine-4-yl)-4-[(methylthioalkyl)methyl]piperidin-4-ol (161 mg, 65%) was obtained as a brown oil. Step 2: ((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(imino)-(methyl)-λ6-thione

[0280] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 1-(8-methoxy-1,7-naphthid-4-yl)-4-[(methylthioalkyl)methyl]piperidin-4-ol (140 mg, 0.44 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: Xbridge Prep OBD C18 column, 19...) 250 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MEOH; flow rate: 25 mL / min; gradient: 13% B to 33% B over 13.5 min; wavelength: 254 / 220 nm; RT1 (min): 12.53), to obtain a white solid ((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (50.7 mg, 32%). MS (ESI, positive ion) m / z: 351.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.66 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 6.0 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 7.17 (d, J=5.2 Hz, 1H), 5.61 (s, 1H), 4.02 (d, J = 4.4 Hz, 4H), 3.44 (d, J = 14.4 Hz, 1H), 3.33 (s, 1H), 3.32 (d, J = 14.6 Hz, 2H), 3.22-3.11 (m, 2H), 3.05 (s, 3H), 2.09-1.88 (m, 4H). Example 24 Synthesis of imino((1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(methyl)-λ6-thione Step 1: [1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-yl]methanol

[0281] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (300 mg, 1.54 mmol) and piperidin-4-ylmethanol (355 mg, 3.08 mmol) were used and the mixture was stirred at 130 °C for 2 h. A yellow solid of [1-(8-methoxy-1,7-naphthidine-4-yl)piperidin-4-yl]methanol (272 mg, 45%) was obtained. Step 2: Methyl methanesulfonate [1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl] ester

[0282] At 0 °C, TEA (296 mg, 2.926 mmol, 2 equivalents), DMAP (17 mg, 0.14 mmol, 0.1 equivalents), and methanesulfonyl methanesulfonate (382 mg, 2.19 mmol, 1.5 equivalents) were added to a stirred solution of [1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-yl]methanesulfonate in DCM (8 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with MeOH / DCM (12:88) to give methyl methanesulfonate [1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-yl]methanesulfonate (1.10 g, crude) as a yellow solid. Step 3: 8-Methoxy-4-[4-[(methylthioalkyl)methyl]piperidin-1-yl]-1,7-naphthidine

[0283] The title compound was synthesized in a manner similar to that described in Example 1, step 2, except that methyl methanesulfonate [1-(8-methoxy-1,7-naphthyl-4-yl)piperidin-4-yl] ester (1.00 g, 2.84 mmol) was used. 8-methoxy-4-[4-[(methylthioalkyl)-methyl]piperidin-1-yl]-1,7-naphthylidine (323 mg, 37%) was obtained as a yellow solid. Step 4: Imino((1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(methyl)-λ6-thione

[0284] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 8-methoxy-4-[4-[(methylthioalkyl)methyl]piperidin-1-yl]-1,7-naphthidine (150 mg, 0.42 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...). 150 mm, 5 µm; Mobile phase A: water (10 nmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 27% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.83), to obtain imino((1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(methyl)-λ6-thione (56.3 mg, 39%) as a yellow solid. MS (ESI, positive ion) m / z: 335.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.67 (d, J = 5.0 Hz, 1H), 8.02(d, J = 5.9 Hz, 1H), 7.32 (d, J = 6.0 Hz, 1H), 7.15 (d, J = 5.0 Hz, 1H), 4.03 (s,3H), 3.73 (s, 1H), 3.52 (d, J = 12.1 Hz, 2H), 3.14 (d, J= 6.3 Hz, 2H), 2.97 (s,3H), 2.88-2.85 (m, 2H), 2.21 (d, J = 10.9 Hz, 1H), 2.08-2.05 (m, 2H), 1.64-1.61 (m, 2H). Example 25 Synthesis of imino(2-(1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)ethyl)(methyl)-λ6-thione) Step 1: 2-[1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl]ethanol

[0285] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (350 mg, 1.79 mmol) and 4-piperidinol (697 mg, 5.39 mmol) were used. 2-[1-(8-methoxy-1,7-naphthidine-4-yl)piperidin-4-yl]ethanol (350 mg, 67%) was obtained as a brown solid. Step 2: 2-[1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl]ethyl methanesulfonate

[0286] The title compound was synthesized in a manner similar to that described in step 2 of Example 24, except that 2-[1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-yl]ethanol (330 mg, 1.14 mmol). 2-[1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-yl]ethyl methanesulfonate (300 mg, 71%) was obtained as a brown oil. Step 3: 8-Methoxy-4-[4-[2-(methylthioalkyl)ethyl]piperidin-1-yl]-1,7-naphthidine

[0287] The title compound was synthesized in a manner similar to that described in Example 1, step 2, except that 2-[1-(8-methoxy-1,7-naphthyl-4-yl)piperidin-4-yl]ethyl methanesulfonate (280 mg, 0.76 mmol). 8-Methoxy-4-[4-[2-(methylthioalkyl)-ethyl]piperidin-1-yl]-1,7-naphthylidine (200 mg, 82 mmol) was obtained as a grayish-white solid. Step 4: Imino(2-(1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)ethyl)(methyl)-λ6-thione

[0288] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 8-methoxy-4-[4-[2-(methylthioalkyl)ethyl]piperidin-1-yl]-1,7-naphthidine (180 mg, 0.56 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18 ExRS column, 30...). 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 28% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 7.07), to obtain imino(2-(1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)ethyl)(methyl)-λ6-thione (90.5 mg, 45%) as a pale yellow solid. MS (ESI, positive ion) m / z: 349.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.66 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 7.14 (d, J = 4.8 Hz, 1H), 4.03(s, 3H), 3.63 (s, 1H), 3.54-3.51 (m, 2H), 3.13-3.09 (m, 2H), 2.92 (s, 3H),2.84-2.76 (m, 2H), 1.87-1.84 (m, 2H), 1.78-1.72 (m, 2H), 1.65-1.56 (m, 1H), 1.51-1.49 (m, 2H). Example 26 Synthesis of cyclopropyl(imino)((1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)-λ6-thione Step 1: 4-[(cyclopropylthio)methyl]piperidine-1-carboxylic acid tert-butyl ester

[0289] The title compound was synthesized in a manner similar to that described in Step 1 of Example 9, except that tert-butyl 4-(thioalkylmethyl)piperidine-1-carboxylate (200 mg, 0.86 mmol) was used and the mixture was stirred at 120 °C for 3 days. 4-[(cyclopropylthioalkyl)methyl]piperidine-1-carboxylate tert-butyl ester (163 mg, 69%) was obtained as a yellow oil. Step 2: 4-[(cyclopropylthio)methyl]piperidine hydrochloride

[0290] A solution of tert-butyl 4-[(cyclopropylthioalkyl)methyl]piperidine-1-carboxylate (163 mg, 0.60 mmol) in 1,4-dioxane (2 mL) in 4 M HCl was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 4-[(cyclopropylthioalkyl)methyl]piperidine hydrochloride (140 mg, crude) as a white solid. Step 3: 4-[4-[(cyclopropylthio)methyl]piperidin-1-yl]-8-methoxy-1,7-naphthyl

[0291] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-[(cyclopropylthioalkyl)methyl]piperidine hydrochloride (344 mg, 1.65 mmol) and 4-chloro-8-methoxy-1,7-naphthidine (100 mg, 0.51 mmol) were used and the mixture was stirred at 130 °C for 2 h. 4-[4-[(cyclopropylthioalkyl)methyl]piperidin-1-yl]-8-methoxy-1,7-naphthidine (73 mg, 43%) was obtained as a yellow solid. Step 4: Cyclopropyl(imino)((1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)-λ6-thione

[0292] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-[4-[(cyclopropylthioalkyl)methyl]piperidin-1-yl]-1,7-naphthidine (63 mg, 0.21 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep Shield RP C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 8% B to 29% B over 8 min; wavelength: 254 / 220 nm; RT1 (min): 8), to obtain a yellow solid cyclopropyl(imino)((1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)-λ6-thione (28.1 mg, 36%). MS (ESI, positive ion) m / z: 361.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.67 (d, J = 5.0 Hz, 1H), 8.02 (d, J =5.9 Hz, 1H), 7.32 (d, J = 6.0 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 4.03 (s, 3H), 3.54-3.50 (m, 3H), 3.11 (d, J = 6.3 Hz, 2H), 2.87 (t, J = 12.0 Hz, 2H), 2.69-2.60(m, 1H), 2.27 (s, 1H), 2.16-2.10 (m, 2H), 1.65 (q, J = 12.3 Hz, 2H), 1.13-0.76(m, 4H). Example 27 Synthesis of imino(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione Step 1: 8-Methoxy-4-[[3-(methylthioalkyl)phenyl]methoxy]-1,7-naphthidine

[0293] The title compound was synthesized in a manner similar to that described in step 3 of Example 11, except that 8-methoxy-1,7-naphthyl-4-ol (300 mg, 1.70 mmol) and [3-(methylthioalkyl)phenyl]methanol (525 mg, 3.41 mmol) were used. A mixture of 8-methoxy-4-[[3-(methylthioalkyl)phenyl]methoxy]-1,7-naphthylidine and 8-methoxy-1-(3-(methylthio)benzyl)-1,7-naphthyl-4(1H)-one (102 mg, 19%) was obtained as a yellow solid. Step 2: Imino(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione

[0294] The title compound was synthesized in a manner similar to that described in Example 1, step 5, except that a mixture of 8-methoxy-4-[[3-(methylthioalkyl)-phenyl]methoxy]-1,7-naphthidine and 8-methoxy-1-(3-(methylthio)benzyl)-1,7-naphthidine-4(1H)-one (90 mg, 0.29 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18 ExRS column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 38% B over 7 min; Wavelength: 254 / 220 nm; RT (min): 5.48, 6.63. The fractions containing the desired product were combined and lyophilized to give: imino(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione (29.8 mg, 30%) as a white solid. MS (ESI, positive ion) m / z: 344.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.79 (d, J =5.2 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1H), 7.99-7.92 (m,1H), 7.88-7.81 (m, 1H), 7.73-7.64 (m, 1H), 7.55 (d, J= 5.8 Hz, 1H), 7.38 (d, J =5.2 Hz, 1H), 5.52 (s, 2H), 4.29 (s, 1H), 4.05 (s, 3H), 3.10 (d, J = 1.1 Hz, 3H). Example 28 Synthesis of cyclopropyl(3-(((8-ethoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione Step 1: 5-[[(2-ethoxypyridin-3-yl)amino]methyl methyl alkyl]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0295] The title compound was synthesized in a manner similar to that described in step 1 of Example 12, except that 2-ethoxypyridin-3-amine (2.00 g, 14.47 mmol) was used. A black solid, 5-[[(2-ethoxypyridin-3-yl)amino]methylethylenedimethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (4.20 g, 99%), was obtained. Step 2: 8-ethoxy-1,7-naphthidine-4-ol

[0296] The title compound was synthesized in a manner similar to that described in step 2 of Example 12, except that 5-[[(2-ethoxypyridin-3-yl)amino]methylethylenediyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (4.10 g, 14.03 mmol) was used. 8-ethoxy-1,7-naphthyl-4-ol (552 mg, 20%) was obtained as a brown solid. Step 3: 4-Chloro-8-ethoxy-1,7-naphthidine

[0297] The title compound was synthesized in a manner similar to that described in Example 3, step 4, except that 8-ethoxy-1,7-naphthidine-4-ol (200 mg, 1.05 mmol) was used. 4-Chloro-8-ethoxy-1,7-naphthidine (100 mg, 45%) was obtained as a yellow solid. Step 4: 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-ethoxy-1,7-naphthidine

[0298] The title compound was synthesized in a manner similar to that described in step 4 of Example 5, except that [3-(cyclopropylthioalkyl)phenyl]methanol (98 mg, 0.55 mmol) and 4-chloro-8-ethoxy-1,7-naphthidine (80 mg, 0.42 mmol) were used. 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-ethoxy-1,7-naphthidine (78 mg, 52%) was obtained as a brown oil. Step 5: Cyclopropyl(3-(((8-ethoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione

[0299] The title compound was synthesized in a manner similar to that described in Example 1, step 5, except that 4-[[3-(cyclopropylthioalkyl)phenyl]methoxy]-8-ethoxy-1,7-naphthidine (68 mg, 0.19 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 41% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.27), to obtain cyclopropyl(3-(((8-ethoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione (30.6 mg, 40%) as a white solid. MS (ESI, positive ion) m / z: 384.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.79 (d, J = 5.2 Hz, 1H), 8.10-8.03 (m, 2H), 7.94-7.87 (m, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.72-7.64 (m, 1H),7.53 (d, J = 5.8 Hz, 1H), 7.37 (d, J= 5.3 Hz, 1H), 5.53 (s, 2H), 4.56-4.46 (m,2H), 4.28 (s, 1H), 2.72-2.61 (m, 1H), 1.47-1.39 (m, 3H), 1.16-1.06 (m, 1H),1.03-0.82 (m, 3H). Example 29 Synthesis of imino(3-(((8-methoxypyrido[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione Step 1: 8-Methoxy-4-[[3-(methylthioalkyl)phenyl]methoxy]pyrido[3,4-d]pyrimidine

[0300] The title compound was synthesized in a manner similar to that described in step 5 of Example 14, except that [3-(methylthioalkyl)phenyl]methanol (300 mg, 1.94 mmol) and 4-chloro-8-methoxypyridano[3,4-d]pyrimidine (570 mg, 2.91 mmol) were used. 8-Methoxy-4-[[3-(methylthioalkyl)phenyl]methoxy]pyridano[3,4-d]pyrimidine (250 mg, 41%) was obtained as a grayish-white solid. Step 2: Imino(3-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione

[0301] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 8-methoxy-4-[[3-(methylthioalkyl)phenyl]-methoxy]pyridino[3,4-d]pyrimidine (230 mg, 0.73 mmol). The crude product was purified by preparative HPLC under the following conditions: (Column: XBridge Prep Shield RPC18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 11% B to 32% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.95), to obtain imino(3-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methyl)-λ6-thione (115.0 mg, 45%) as a grayish-white solid. MS (ESI, positive ion) m / z: 345.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm δ8.94 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.94 (dt, J =8.0, 1.6 Hz, 1H), 7.85 (dt, J = 7.6, 1.2 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 5.76 (s, 2H), 4.28 (s, 1H), 4.08 (s, 3H), 3.09 (d, J = 1.2Hz, 3H). Example 30 Synthesis of (4-((1,7-naphthid-4-yl)oxy)phenyl)(cyclopropyl)(imino)-λ6-thione Step 1: 4-[4-(cyclopropylthio)phenoxy]-1,7-naphthidine

[0302] 4-(cyclopropylthioalkyl)phenol (151 mg, 0.91 mmol, 1 equivalent) and Cs₂CO₃ (297 mg, 0.91 mmol, 1.5 equivalent) were added to a solution of 4-chloro-1,7-naphthylidine (100 mg, 0.61 mmol, 1 equivalent) in DMSO (2 mL). The resulting mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the resulting mixture was diluted with H₂O (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give 4-[4-(cyclopropylthioalkyl)phenoxy]-1,7-naphthylidine (208 mg, 90%) as a gray solid. Step 2: (4-((1,7-naphthid-4-yl)oxy)phenyl)(cyclopropyl)(imino)-λ6-thione

[0303] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 4-[4-(cyclopropylthioalkyl)phenoxy]-1,7-naphthidine (188 mg, 0.64 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: Xselect CSH Prep OBD C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13% B to 43% B over 8 min; wavelength: 254 / 220 nm; RT1 (min): 7.7), to obtain (4-((1,7-naphthid-4-yl)oxy)phenyl)(cyclopropyl)(imino)-λ6-thione (59.2 mg, 28%) as a brown solid. MS (ESI, positive ion) m / z: 326.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.46 (d, J = 0.9 Hz, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.70 (d, J = 5.6Hz, 1H), 8.14-8.11 (m, 1H), 8.07-7.99 (m, 2H), 7.57-7.49 (m, 2H), 7.06 (d, J=5.2 Hz, 1H), 4.31 (s, 1H), 2.78-2.67 (m, 1H), 1.20-1.10 (m, 1H), 1.06-0.87 (m, 3H). Example 31 Synthesis of 4-[4-[imino(methyl)oxo-λ6-thioalkyl]phenoxy]-8-methoxy-1,7-naphthidine-3-carboxynitrile Step 1: 8-Methoxy-4-[4-(methylthioalkyl)phenoxy]-1,7-naphthidine-3-carboxynitrile

[0304] The title compound was synthesized in a manner similar to that described in step 1 of Example 30, except that 4-chloro-8-methoxy-1,7-naphthyl-3-carboxylonitrile (300 mg, 1.36 mmol) and 4-(methylthio)-phenol (287 mg, 2.04 mmol) were used and the mixture was stirred at 80 °C for 3 h. 8-methoxy-4-[4-(methylthio)phenoxy]-1,7-naphthyl-3-carboxylonitrile (100 mg, 22%) was obtained as a pale yellow solid. Step 2: 4-[4-[imino(methyl)oxo-λ6-thioalkyl]phenoxy]-8-methoxy-1,7-naphthidine-3-carboxynitrile

[0305] The title compound was synthesized in a manner similar to that described in step 5 of Example 1, except that 8-methoxy-4-[4-(methylthioalkyl)phenoxy]-1,7-naphthyl-3-carboxynitrile (80 mg, 0.24 mmol) was used. The crude product was purified by preparative HPLC under the following conditions: (column: Xselect CSH Prep C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 35% B over 10 min; Wavelength: 254 / 220 nm; RT1 (min): 8.68), to obtain 4-[4-[imino(methyl)oxo-λ6-thioalkyl]phenoxy]-8-methoxy-1,7-naphthidine-3-carboxynitrile (9.4 mg, 10.64%) as a grayish-white solid. MS (ESI, positive ion) m / z: 355.0 (M+1). 1 H NMR (400 MHz, DMSO- d 6,ppm ) δ 9.28 (s, 1H), 8.23 ​​(d, J = 5.9 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.39-9.35 (m, 3H), 4.29 (s, 1H), 4.13 (s, 3H), 3.08 (s, 3H). Example 32 Synthesis of 2-(S-methylsulfonylimino)-8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane Step 1: tert-butyl 8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0306] The title compound was synthesized in a manner similar to that described in step 1 of Example 8, except that 4-chloro-1,7-naphthidine (450 mg, 2.73 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.31 g, 5.47 mmol) were used. 8-(1,7-naphthidine-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (836 mg, 72%) was obtained as an orange solid. Step 2: 8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane hydrochloride

[0307] A solution of tert-butyl 8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (800 mg, 2.17 mmol) in 14 mL HCl (g, 4 M in EtOAc) was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure to give 8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane hydrochloride (1.00 g, crude) as a yellow solid. Step 3: 2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane

[0308] Oxalate dichloro(1.20 g, 9.45 mmol, 3.2 equivalents) was added to a mixture of (diphenylphospho)benzene (2.46 g, 8.86 mmol, 3 equivalents) in DCM (24 mL) at 0 °C under N2. After stirring at 0 °C for 30 min, DIEA (3.82 g, 29.53 mmol, 10 equivalents) was added and stirred at the same temperature for 15 min. N-(tert-butyldimethylsilyl)methanesulfonamide (927 mg, 4.43 mmol, 1.5 equivalents) was added, and the resulting mixture was stirred at 0 °C for 20 min, then added to a solution of 8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane hydrochloride (900 mg, 2.95 mmol, 1 equivalent) and DIEA (1.14 g, 8.86 mmol, 3 equivalents) in DCM (10 mL). After stirring at 0°C under N2 atmosphere for 30 min, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with elution of ACN / H2O (84:16) to give 2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (454 mg, 25%), which was a brown oil. Step 4: 2-(S-methylsulfonylimino)-8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane

[0309] Add 25% formic acid (0.4 mL, v / v) to a solution of 2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (165 mg, 0.36 mmol) in DMF (2 mL). Stir the resulting mixture at room temperature for 10 min. Concentrate the resulting mixture under reduced pressure. Purify the crude product by preparative HPLC under the following conditions (column: Xselect CSH Prep Fluoro-Phenyl column, 19). 250 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 11% B to 32% B over 8 min; wavelength: 254 / 220 nm; RT1 (min): 12.57), to obtain 2-(S-methylsulfonylimino)-8-(1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (54.4 mg, 43%) as a white solid. MS (ESI, positive ion) m / z: 346.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.29 (d, J = 0.7 Hz, 1H), 8.79 (d, J =4.8 Hz, 1H), 8.54 (d, J = 5.6 Hz, 1H), 7.85-7.78 (m, 1H), 7.16 (d, J = 5.2 Hz,1H), 3.63 (s, 1H), 3.43-3.29 (m, 3H), 3.28-3.19 (m, 3H), 3.14 (d, J = 4.3 Hz, 2H), 2.81 (s, 3H), 1.91-1.73 (m, 6H). Example 33 Synthesis of 4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine Step 1: tert-butyl 7-(1,7-naphthid-4-yl)-3,4-dihydroisoquinoline-2(1H)-formate

[0310] To a mixture of 4-chloro-1,7-naphthidine (570 mg, 3.5 mmol, 1 equivalent) in 1,4-dioxane (15 mL) and water (5 mL), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,4-dihydroisoquinoline-2(1H)-formate (1.85 g, 4.94 mmol, 1.5 equivalent), Pd(dppf)Cl2.CH2Cl2 (284 mg, 0.35 mmol, 0.1 equivalent), and K2CO3 (1.45 g, 10.5 mmol, 3 equivalent) were added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EA / PE (50:50) elution. Fractions containing the desired product were combined and concentrated under reduced pressure to give tert-butyl 7-(1,7-naphthid-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (910 mg, 73%) as a yellow solid. Step 2: 4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthylidine hydrochloride

[0311] A mixture of tert-butyl 7-(1,7-naphthid-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (890 mg, 2.47 mmol, 1 equivalent) in 14 mL HCl (g, 4 M in EtOAc) was stirred at room temperature for 2 h. The resulting mixture was then concentrated under reduced pressure to give 4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidium hydrochloride (1.02 g, crude product) as a yellow solid. Step 3: 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine

[0312] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine hydrochloride (902 mg, crude) was used. 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine (200 mg, 18% (two steps)) was obtained as a yellow solid. Step 4: 4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine

[0313] The title compound was synthesized in a manner similar to that described in step 4 of Example 34, except that 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine (180 mg, 0.40 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XB ridge Prep OBD C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 40% B over 10 min; wavelength: 254 / 220 nm). The fraction containing the desired product was concentrated under reduced pressure and lyophilized to give 4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine (67.1 mg, 50%) as a grayish-white solid. MS (ESI, positive ion) m / z: 339.2 (M+1). 1 H NMR (400 MHz, DMSO-) d 6, ppm ) δ 9.47 (s, 1H), 9.10 (d, J = 4.4 Hz, 1H), 8.61 (d, J = 5.6Hz, 1H), 7.80 (d, J = 6 Hz, 1H), 7.73(d, J = 4.4 Hz, 1H), 7.42 (d, J = 6.4 Hz, 3H), 4.46 (s, 2H), 3.79 (s, 1H), 3.57-3.51 (m, 2H), 3.03-3.00 (m, 2H), 2.84 (s, 3H). Example 34 Synthesis of 6-methoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine Step 1: 6-Methoxypyrido[3,4-d]pyrimidin-4(3H)-one

[0314] The title compound was synthesized in a manner similar to that described in step 3 of Example 14, except that 5-amino-2-methoxypyridin-4-carboxylic acid (5.00 g, 29.74 mmol) was used. 6-methoxypyrido[3,4-d]pyrimidine-4(3H)-one (5.00 g, 95%) was obtained as a white solid. Step 2: 4-Chloro-6-methoxypyrido[3,4-d]pyrimidine

[0315] The title compound was synthesized in a manner similar to that described in step 4 of Example 14, except that 6-methoxypyrido[3,4-d]pyrimidin-4(3H)-one (2.00 g, 11.28 mmol) was used in CHCl3 (30 mL) and stirred overnight at 80 °C. 4-Chloro-6-methoxypyrido[3,4-d]pyrimidinyl (2.00 g, 85%) was presented as a yellow solid. Step 3: tert-butyl 8-[6-methoxypyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4,5]decane-2-carboxylate

[0316] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-6-methoxypyrido[3,4-d]pyrimidine (500 mg, 2.56 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.23 g, 5.11 mmol) were used and the mixture was stirred at 100 °C for 2 h. A yellow solid of tert-butyl 8-[6-methoxypyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (1.00 g, 95%) was obtained. Step 4: 6-Methoxy-4-(2,8-diazaspiro[4,5]dec-8-yl)pyrido[3,4-d]pyrimidine

[0317] A solution of tert-butyl 8-[6-methoxypyridano[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (1.00 g, 2.50 mmol) in 15 mL HCl (g, 4 M in EtOAc) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, water (NH4HCO3) in ACN, gradient from 5% to 40% over 20 min; detector, UV 254 / 220 nm. The fraction containing the desired product was concentrated under reduced pressure to give 6-methoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)pyridano[3,4-d]pyrimidinyl (271 mg, 32%) as a yellow solid. Step 5: 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)-6-methoxypyrido[3,4-d]pyrimidine

[0318] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 6-methoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine (217 mg, 0.72 mmol). 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)-6-methoxypyrido[3,4-d]pyrimidine (122 mg, 34%) was obtained as a yellow oil. Step 6: 6-Methoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine

[0319] The title compound was synthesized in a manner similar to that described in step 4 of Example 32, except that 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)-6-methoxypyridino[3,4-d]pyrimidine (112 mg, 0.23 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep OBD C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 nmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 35% B over 10 min; wavelength: 254 / 220 nm; RT1 (min): 8.82), to obtain 6-methoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine (29.3 mg, 33%) as a white solid. MS (ESI, positive ion) m / z: 377.3 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.93 (s, 1H), 8.53 (s, 1H), 7.10 (s, 1H), 3.97 (s, 3H), 3.85-3.71 (m, 4H), 3.63 (s, 1H), 3.32-3.23 (m, 2H), 3.18-3.07(m, 2H), 2.80 (d, J = 1.2 Hz, 3H), 1.90-1.80 (m, 2H), 1.80-1.64 (m, 4H). Example 35 Synthesis of 8-methoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine Step 1: tert-butyl 8-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4,5]decane-2-carboxylate

[0320] The title compound was synthesized in a manner similar to that described in step 1 of Example 30, except that 4-chloro-8-methoxypyrido[3,4-d]pyrimidine (500 mg, 2.56 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.23 g, 5.11 mmol) were used in DMF (5 mL) and stirred at 80 °C for 2 h. 8-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (759 mg, 74%) was obtained as a grayish-white solid. Step 2: 8-Methoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine

[0321] To a solution of tert-butyl 8-[8-methoxypyridano[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, 0.50 mmol, 1 equivalent) in dichloromethane (2 mL), 2,4-dimethylpyridine (53 mg, 0.50 mmol, 1 equivalent) and trimethylsilyl trifluoromethanesulfonate (333 mg, 1.50 mmol, 3 equivalent) were added. The resulting mixture was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure to give 8-methoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)pyridano[3,4-d]pyrimidinidine (495 mg, crude) as a white solid. Step 3: 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)-8-methoxypyrido[3,4-d]pyrimidine

[0322] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 8-methoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine (459 mg, crude) was used. 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)-8-methoxypyrido[3,4-d]pyrimidine (174 mg, 23%) was obtained as a yellow oil. Step 4: 8-Methoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine

[0323] The title compound was synthesized in a manner similar to that described in step 4 of Example 32, except that 4-(2-(N-(tert-butyldimethylsilyl)-S-methyl-sulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)-8-methoxypyrido[3,4-d]pyrimidine (140 mg, 0.28 mmol). The crude product was purified by preparative HPLC under the following conditions: (Column: XBridge Prep Shield RP C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 4% B to 34% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.62), to obtain 8-methoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)pyrido[3,4-d]pyrimidine (30.9 mg, 28%) as a white solid. MS (ESI, positive ion) m / z: 377.2 (M+1). 1 H NMR (400 MHz, DMSO-d 6 , ppm ) δ 8.65 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.32 (d, J = 6.0 Hz, 1H), 4.02 (s, 3H), 3.82-3.68 (m, 4H), 3.63 (s, 1H), 3.35-3.21 (m, 2H), 3.18-3.07 (m, 2H), 2.80 (s, 3H), 1.88-1.80 (m, 2H), 1.80-1.64 (m, 4H). Example 36 Synthesis of 8-(8-methoxy-1,7-naphthid-4-yl)-2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]decane Step 1: tert-butyl 8-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0324] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (400 mg, 2.055 mmol, 1 equivalent) was used and the mixture was stirred at 130 °C for 2 h. A yellow solid of tert-butyl 8-(8-methoxy-1,7-naphthidine-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (692 mg, 84%) was obtained. Step 2: 8-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane

[0325] The title compound was synthesized in a manner similar to that described in step 2 of Example 35, except that tert-butyl 8-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, 0.50 mmol) was used. 8-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (285 mg, crude) was obtained as a colorless oil. Step 3: (tert-butyldimethylsilyl)([[8-(8-methoxy-1,7-naphthidin-4-yl)-2,8-diazaspiro-[4,5]dec-2-yl](methyl)oxo-λ6-thionyl])amine

[0326] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 8-(8-methoxy-1,7-naphthidin-4-yl)-2,8-diazaspiro[4.5]decane (149 mg, crude). (tert-butyldimethylsilyl)([[8-(8-methoxy-1,7-naphthidin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl](methyl)oxo-λ6-thionyl])amine (83 mg, 37%) was presented as a yellow solid. Step 4: 8-(8-methoxy-1,7-naphthid-4-yl)-2-(S-methylsulfonylimino)-2,8-diaza-spiro[4.5]decane

[0327] The title compound was synthesized in a manner similar to that described in step 4 of Example 32, except that (tert-butyldimethylsilyl)([[8-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]dec-2-yl](methyl)oxo-λ 6 [-Thionyl]amine (73 mg, 0.149 mmol). The crude product was purified by preparative HPLC under the following conditions: (Column: XBridge Prep Shield RP C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 31% B over 7 min; Wavelength: 254 / 220 nm; RT1 (min): 6.35). Fractions containing the desired product were combined and lyophilized to give 8-(8-methoxy-1,7-naphthid-4-yl)-2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]decane (20.2 mg, 36%) as a white solid. MS (ESI, positive ion) m / z: 376.1 (M+1). 1 H NMR (400 MHz, DMSO-d6, ppm ) δ8.68 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 5.9 Hz, 1H), 7.35 (d, J = 5.9 Hz, 1H), 7.18(d, J = 5.1 Hz, 1H), 4.03 (s, 3H), 3.63 (s, 1H), 3.29 (t, J = 7.0 Hz, 2H), 3.17-3.14 (m, 6H), 2.81 (d, J = 1.6 Hz, 3H), 1.84-1.81 (m, 6H). Example 37 Synthesis of 2-(8-methoxy-1,7-naphthid-4-yl)-8-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]decane Step 1: 2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[0328] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (230 mg, 1.18 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (568 mg, 2.36 mmol) were used and the mixture was stirred at 130 °C for 2 h. A yellow solid of tert-butyl 2-(8-methoxy-1,7-naphthidine-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (486 mg, 90%) was obtained. Step 2: 2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane

[0329] The title compound was synthesized in a manner similar to that described in step 2 of Example 35, except that tert-butyl 2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (240 mg, 0.60 mmol) was used. 2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (527 mg, crude) was obtained as a brown oil. Step 3: 8-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimide)-2-(8-methoxy-1,7-naphthidin-4-yl)-2,8-diazaspiro[4.5]decane

[0330] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (527 mg, 1.76 mmol). 8-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (168 mg, 19%) was obtained as a brown solid. Step 4: 2-(8-methoxy-1,7-naphthid-4-yl)-8-(S-methylsulfonylimino)-2,8-diaza-spiro[4.5]decane

[0331] The title compound was synthesized in a manner similar to that described in step 4 of Example 32, except that 8-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane (168 mg, 0.34 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: XBridge Prep Shield RP C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 61% B to 31% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 7.17), to obtain 2-(8-methoxy-1,7-naphthid-4-yl)-8-(S-methyl-sulfonylimino)-2,8-diazaspiro[4.5]decane (44.7 mg, 33%) as a white solid. MS (ESI, positive ion) m / z: 376.2 (M+1). 1 HNMR (400 MHz, DMSO- d 6, ppm ) δ 8.42 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 6.4 Hz, 1H), 7.69 (d, J = 6.4 Hz, 1H), 6.71 (d, J = 5.2 Hz, 1H), 4.00 (s, 3H), 3.79-3.71 (m,2H), 3.51 (d, J = 10.8 Hz, 3H), 3.27-3.07 (m, 4H), 2.75 (d, J = 1.6 Hz, 3H), 1.95-1.87 (m, 2H), 1.73-1.60 (m, 4H). Example 38 Synthesis of 8-methoxy-4-(7-(S-methylsulfonylimino)-2,7-diazaspiro[4.4]non-2-yl)-1,7-naphthidine Step 1: tert-butyl 8-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate

[0332] The title compound was synthesized in a manner similar to that described in Example 1, step 4, except that 4-chloro-8-methoxy-1,7-naphthidine (250 mg, 1.285 mmol) and tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (436 mg, 1.92 mmol) were used and the mixture was stirred overnight at 130 °C. 7-(8-methoxy-1,7-naphthidine-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (423 mg, 85%) was obtained as a yellow oil. Step 2: 4-[2,7-diazaspiro[4.4]non-2-yl]-8-methoxy-1,7-naphthidine

[0333] The title compound was synthesized in a manner similar to that described in step 2 of Example 35, except that tert-butyl 7-(8-methoxy-1,7-naphthodin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (220 mg, 0.57 mmol) was used. 4-[2,7-diazaspiro[4.4]non-2-yl]-8-methoxy-1,7-naphthodinium (380 mg, crude) was obtained as a yellow solid. Step 3: (tert-butyldimethylsilyl)(([8-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro-[4,5]dec-2-yl](methyl)oxo-λ6-thionyl))amine

[0334] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 4-[2,7-diazaspiro[4.4]non-2-yl]-8-methoxy-1,7-naphthidine (155 mg, 0.545 mmol). A yellow solid (tert-butyldimethylsilyl)([[7-(8-methoxy-1,7-naphthidine-4-yl)-2,7-diazaspiro[4.4]non-2-yl](methyl)oxo-λ6-thionyl])amine (82 mg, 31%) was obtained. Step 4: 8-Methoxy-4-(7-(S-methylsulfonylimino)-2,7-diazaspiro[4.4]non-2-yl)-1,7-naphthidine

[0335] The title compound was synthesized in a manner similar to that described in step 4 of Example 32, except that (tert-butyldimethylsilyl)([[7-(8-methoxy-1,7-naphthidin-4-yl)-2,7-diazaspiro[4.4]non-2-yl](methyl)oxo-λ6-thionyl])amine (77 mg, 0.16 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18 ExRS column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 3% B to 33% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.97). Fractions containing the desired product were combined and lyophilized to give 8-methoxy-4-(7-(S-methylsulfonylimino)-2,7-diazaspiro[4.4]non-2-yl)-1,7-naphthidine (22.1 mg, 37%) as a white solid. MS (ESI, positive ion) m / z: 362.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.43 (d, J =5.4 Hz, 1H), 7.87 (d, J = 6.1 Hz, 1H), 7.67 (dd, J = 6.3, 2.5 Hz, 1H), 6.71 (d, J =5.5 Hz, 1H), 4.00 (s, 3H), 3.79-3.60 (m, 5H), 3.29-3.16 (m, 4H), 2.81 (d, J =1.6 Hz, 3H), 2.11-1.89 (m, 4H). Example 39 Synthesis of 8-methoxy-4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine Step 1: tert-butyl 7-(8-methoxy-1,7-naphthid-4-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0336] The title compound was synthesized in a manner similar to that described in step 1 of Example 33, except that 4-chloro-8-methoxy-1,7-naphthidine (300 mg, 1.54 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (664 mg, 1.85 mmol) were used. 7-(8-methoxy-1,7-naphthidine-4-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (793 mg, crude) was obtained as a yellow oil. Step 2: 8-Methoxy-4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine

[0337] The title compound was synthesized in a manner similar to that described in step 2 of Example 35, except that tert-butyl 7-(8-methoxy-1,7-naphthidin-4-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (760 mg, crude) was used. 8-Methoxy-4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidium (1.69 g, crude) was obtained as a yellow oil. Step 3: 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-1,2,3,4-tetrahydro-isoquinoline-7-yl)-8-methoxy-1,7-naphthidine

[0338] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 8-methoxy-4-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine (1.59 g, crude) was used. 4-(2-(N-(tert-butyldimethylsilyl)-S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-8-methoxy-1,7-naphthidine (422 mg, 16%) was obtained as a brown solid. Step 4: 8-Methoxy-4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine

[0339] The title compound was synthesized in a manner similar to that described in step 4 of Example 32, except that 4-(2-(N-(tert-butyldimethylsilyl)-S-methyl-sulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-8-methoxy-1,7-naphthidine (150 mg, 0.31 mmol). The crude product was purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18 ExRS column, 30...) 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 39% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.6), to obtain 8-methoxy-4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-1,7-naphthidine (38.7 mg, 33%) as a white solid. MS (ESI, positive ion) m / z: 369.1 (M+1). 1 H NMR (400 MHz, DMSO-) d 6, ppm ) δ 8.98 (d, J = 4.4 Hz, 1H), 8.12-8.05 (m, 1H), 7.72-7.66(m, 1H), 7.41-7.35 (m, 3H), 7.31 (d, J = 6.1 Hz, 1H), 4.46 (d, J = 2.4 Hz, 2H), 4.10 (s, 3H), 3.77 (d, J = 1.9 Hz, 1H), 3.59-3.42 (m, 2H), 3.05-2.97 (m, 2H), 2.84 (d, J = 1.6 Hz, 3H). Example 40 Synthesis of 8-methoxy-4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-pyrido[3,4-d]pyrimidine Step 1: tert-butyl 7-[8-methoxypyrido[3,4-d]pyrimidin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate

[0340] The title compound was synthesized in a manner similar to that described in step 1 of Example 33, except that 4-chloro-8-methoxypyrido[3,4-d]pyrimidine (300 mg, 1.53 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (664 mg, 1.85 mmol) were used. A yellow solid of 7-[8-methoxypyrido[3,4-d]pyrimidine-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (407 mg, 67%) was obtained. Step 2: 7-[8-methoxypyrido[3,4-d]pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline

[0341] The title compound was synthesized in a manner similar to that described in step 2 of Example 35, except that tert-butyl 7-[8-methoxypyridano[3,4-d]pyrimidin-4-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (387 mg, 0.98 mmol) was used. 7-[8-methoxypyridano[3,4-d]pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline (1.00 g, crude) was obtained as a yellow solid. Step 3: (tert-butyldimethylsilyl)[(7-[8-methoxypyridino[3,4-d]pyrimidin-4-yl]-3,4-dihydro-1H-isoquinoline-2-yl)(methyl)oxo-λ6-thionyl]amine

[0342] The title compound was synthesized in a manner similar to that described in step 3 of Example 32, except that 7-[8-methoxypyridano[3,4-d]pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline (500 mg, crude) was used. A yellow solid (tert-butyldimethylsilyl)[(7-[8-methoxy-pyridano[3,4-d]pyrimidin-4-yl]-3,4-dihydro-1H-isoquinoline-2-yl)(methyl)oxo-λ6-thionyl]amine (79 mg, 9%) was obtained. Step 4: 8-Methoxy-4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)-pyrido[3,4-d]pyrimidine

[0343] The title compound was synthesized in a manner similar to that described in step 4 of Example 32, except that (tert-butyldimethylsilyl)[(7-[8-methoxypyridino[3,4-d]pyrimidin-4-yl]-3,4-dihydro-1H-isoquinoline-2-yl)(methyl)oxo-λ 6 [-Thionylamine] (69 mg, 0.143 mmol). The crude product was purified by preparative HPLC under the following conditions: (Column: XBridge Prep Shield RP C18 column, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9% B to 39% B over 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.7). Fractions containing the desired product were combined and lyophilized to give 8-methoxy-4-(2-(S-methylsulfonylimino)-1,2,3,4-tetrahydroisoquinoline-7-yl)pyrido[3,4-d]pyrimidine (46.4 mg, 85%) as a white solid. MS (ESI, positive ion) m / z: 370.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 9.45 (s, 1H), 8.24 (d, J = 6.0 Hz, 1H), 7.68-7.61 (m, 2H), 7.52 (d, J =6.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 4.49 (d, J = 2.1 Hz, 2H), 4.13 (s, 3H), 3.78 (d, J = 1.8 Hz, 1H), 3.58 - 3.42 (m, 2H), 3.04 (t, J = 6.0 Hz, 2H), 2.85 (d, J = 1.7 Hz, 3H). Examples 41, 42 and 43 Synthesis of cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)phenyl)-(imino)-λ6-thione, (R)-cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione, and (S)-cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione) Step 1: 3-(cyclopropylthioalkyl)benzoic acid

[0344] A mixture of 3-thioalkylbenzoic acid (20.00 g, 129.72 mmol, 1.0 equivalent) in DMSO (200 mL) was supplemented with bromocyclopropane (23.54 g, 194.57 mmol, 1.5 equivalent) and potassium tert-butoxide (36.39 g, 324.29 mmol, 2.5 equivalent). The reaction mixture was stirred at 80 °C for 24 h. After cooling to room temperature, the reaction mixture was diluted with water, the pH was adjusted to 5 with 1 NHCl (aqueous), and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (40:60) elution to give 3-(cyclopropylthioalkyl)benzoic acid (20.00 g, 69%) as a colorless oil. Step 2: (3-(cyclopropylthio)phenyl)methanol

[0345] At 0 °C, lithium aluminum hydride (110 mL, 2 equivalents, 2 M in THF) was added to a solution of 3-(cyclopropylthioalkyl)benzoic acid (24.0 g, 117.37 mmol, 1 equivalent) in 250 mL of THF. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. At 0 °C, the reaction mixture was quenched with saturated ammonium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (10:90) elution to give (3-(cyclopropylthioalkyl)-phenyl)methanol (20.0 g, 86%) as a yellow oil. Step 3: 2-(fluoromethoxy)-3-nitropyridine

[0346] DIEA (242 mL, 1.39 mol, 3.0 equivalent) and bromofluoromethane (104.80 g, 927.92 mmol, 2.0 equivalent) were added to a solution of 3-nitropyridin-2-ol (65.00 g, 463.96 mmol, 1.0 equivalent) in DMF (650 mL). The resulting mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with EtOAc / PE (1:4) to give 2-(fluoromethoxy)-3-nitropyridine (16.31 g, 16%) as a yellow oil. Step 4: 2-(fluoromethoxy)pyridine-3-amine

[0347] Pd / C (4.20 g, 11.15 mmol, 0.2 equivalent) was added to a solution of 2-(fluoromethoxy)-3-nitropyridine (16.31 g, 92.96 mmol, 1.0 equivalent) in MeOH (200 mL). After stirring overnight at room temperature under a hydrogen atmosphere achieved by using a hydrogen balloon, the reaction mixture was filtered through a diatomaceous earth pad and concentrated under reduced pressure to give 2-(fluoromethoxy)pyridine-3-amine (12.30 g, crude) as a yellow oil, which was used directly in the next step without further purification. Step 5: 5-(((2-(fluoromethoxy)pyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0348] To a solution of 2-(fluoromethoxy)pyridin-3-amine (12.00 g, 84.42 mmol, 1.0 equivalent) in ACN (150 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (15.82 g, 109.75 mmol, 1.3 equivalent) and trimethoxymethane (12.54 g, 118.20 mmol, 1.4 equivalent) were added. The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the resulting mixture was diluted with PE. The precipitate was collected by filtration and washed with PE to give 5-(((2-(fluoromethoxy)pyridin-3-yl)amino)methylethylenediyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.21 g, 87%) as a brown solid. Step 6: 8-(fluoromethoxy)-1,7-naphthidine-4-ol

[0349] A mixture of 5-(((2-(fluoromethoxy)pyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.00 g, 54.01 mmol, 1.0 equivalent) in diphenyl ether (200 mL) was stirred at 225 °C for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with PE. The precipitate was collected by filtration, washed with PE, and purified by silica gel column chromatography with MeOH / DCM (7:93) to give 8-(fluoromethoxy)-1,7-naphthidine-4-ol (1.81 g, 17%) as a brown solid. Step 7: 4-((3-(cyclopropylthio)phenyl)methoxy)-8-(fluoromethoxy)-1,7-naphthidine

[0350] To a solution of 8-(fluoromethoxy)-1,7-naphthyl-4-ol (1.00 g, 5.15 mmol, 1.0 equivalent) in toluene (10 mL), 2-(tributyl-λ5-phosphono)acetonitrile (2.49 g, 10.30 mmol, 2.0 equivalent) and (3-(cyclopropylthioalkyl)phenyl)methanol (1.39 g, 7.72 mmol, 1.5 equivalent) were added. The resulting mixture was stirred at 130 °C under a nitrogen atmosphere for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with EtOAc / PE (53:47) to obtain a crude product, which was further purified by reversed-phase CombiFlash with ACN / H2O (67:33) to obtain 4-((3-(cyclopropylthioalkyl)phenyl)methoxy)-8-(fluoromethoxy)-1,7-naphthidine (550 mg, 29%) as a yellow solid. Step 8: Cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-(imino)-λ6-thione

[0351] To a solution of 4-((3-(cyclopropylthioalkyl)phenyl)methoxy)-8-(fluoromethoxy)-1,7-naphthidine (550 mg, 1.53 mmol, 1.0 equivalent) in MeOH (10 mL), (acetoxy)(phenyl)-λ3-iodoalkyl acetate (1.49 g, 4.62 mmol, 3.0 equivalent) and ammonium carbamate (481 mg, 6.17 mmol, 4.0 equivalent) were added. After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (43:57) to give cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione (450 mg, 75%) as a brown solid. MS (ESI, positive ion) m / z: 388.1 (M+1); 1 H NMR (400 MHz, DMSO- d 6 ppm ) δ 8.88 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 5.6 Hz, 1H), 8.09 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.69(t, J = 7.6 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 5.57(s, 2H), 4.29 (s, 1H), 2.73 - 2.63 (m, 1H), 1.15 - 1.03 (m, 1H), 1.04 - 0.83(m, 3H).

[0352] 19 F NMR (376 MHz, DMSO- d 6 , ppm ) δ -155.95 (s, 1 F). Step 9: ( R )-Cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)-phenyl)(imino)-λ6-thione and ( S)-Cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione

[0353] Racemic cyclopropyl (3-(((8-(fluoromethoxy)-1,7-naphthyl-4-yl)oxy)methyl)phenyl)imino-λ6-thione (498 mg, 1.28 mmol) was purified by chiral SFC under the following conditions (column: CHIRAL ARTAmylose-C NEO 3). 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: IPA (1%-2 M-NH3-MeOH); Flow rate: 100 mL / min; Gradient: isocratic 48% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; Sample solvent: MeOH; Injection volume: 3 mL), to obtain two fractions.

[0354] Grade 1: Grayish-white solid ( R )-Cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)-phenyl)(imino)-λ6-thione (180 mg, 35%). RT1: 7.12 min, MS (ESI, positive ion) m / z: 388.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.88 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 5.6Hz, 1H), 8.09 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 6.38 (s,1H), 6.25 (s, 1H), 5.57 (s, 2H), 4.29 (s, 1H), 2.73 - 2.63 (m, 1H), 1.15 -1.03 (m, 1H), 1.04 - 0.83 (m, 3H).

[0355] 19 F NMR (377 MHz, DMSO- d 6 , ppm ) δ -155.94 (s, 1 F).

[0356] Grade 2: Yellow solid ( S )-Cyclopropyl(3-(((8-(fluoromethoxy)-1,7-naphthid-4-yl)oxy)methyl)-phenyl)(imino)-λ6-thione (178 mg, 35%). RT2: 10.18 min, MS (ESI, positive ion) m / z: 388.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.88 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 5.6Hz, 1H), 8.09 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 5.2 Hz, 1H), 6.38 (s,1H), 6.25 (s, 1H), 5.57 (s, 2H), 4.29 (s, 1H), 2.73 - 2.63 (m, 1H), 1.15 -1.03 (m, 1H), 1.04 - 0.83 (m, 3H).

[0357] 19 F NMR (377 MHz, DMSO- d 6 , ppm ) δ -155.95 (s, 1 F). Example 44 Synthesis of 8-methoxy-4-(2-(S-methylsulfonylimino)-2,6-diazaspiro(3,4)oct-6-yl)-1,7-naphthidine Step 1: tert-butyl 6-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)octane-2-carboxylate

[0358] DIEA (498 mg, 3.85 mmol, 3.0 equivalent) and tert-butyl 2,6-diazaspiro-(3,4)octane-2-carboxylate (409 mg, 1.92 mmol, 1.5 equivalent) were added to a solution of 4-chloro-8-methoxy-1,7-naphthidine (250 mg, 1.28 mmol, 1.0 equivalent) in NMP (5 mL). The reaction mixture was stirred at 130 °C for 2 h. After cooling to room temperature, the resulting mixture was purified by reversed-phase column chromatography with elution of ACN / H2O (45:55) to give tert-butyl 6-(8-methoxy-1,7-naphthidine-4-yl)-2,6-diazaspiro(3,4)octane-2-carboxylate (420 mg, 88%) as a brown solid. Step 2: 4-(2,6-diazaspiro(3,4)oct-6-yl)-8-methoxy-1,7-naphthidine

[0359] Dimethylpyridine (115 mg, 1.08 mmol, 1.0 equivalent) and TMSOTf (719 mg, 3.24 mmol, 3.0 equivalent) were added to a solution of 6-(8-methoxy-1,7-naphtho-4-yl)-2,6-diazaspiro(3,4)octane-2-carboxylic acid tert-butyl ester (400 mg, 1.08 mmol, 1.0 equivalent) in DCM (10 mL). After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure to give 4-(2,6-diazaspiro(3,4)octane-6-yl)-8-methoxy-1,7-naphtho-4-yl ester (400 mg, crude) as a brown solid, which was used directly in the next step without further purification. Step 3: (tert-butyldimethylsilyl)(((6-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)-oct-2-yl)(methyl)oxo-λ6-thionyl))amine

[0360] Add (COCl)₂ (450 mg, 3.55 mmol, 3.2 equivalents) to a solution of Ph₃PO (926 mg, 3.33 mmol, 3.0 equivalents) in DCM (10 mL). Stir the reaction mixture at 0 °C under a nitrogen atmosphere for 0.5 h. Add DIEA (1.43 g, 11.10 mmol, 10.0 equivalents), and stir the resulting mixture at 0 °C for 10 min. N-(tert-butyldimethylsilyl)methanesulfonamide (348 mg, 1.66 mmol, 1.5 equivalents) was added and the mixture was stirred at 0 °C for 20 min. Then, under a nitrogen atmosphere at 0 °C, it was added to a mixture of 4-(2,6-diazaspiro(3,4)oct-6-yl)-8-methoxy-1,7-naphthidine (300 mg, 1.11 mmol, 1.0 equivalents) and DIEA (1.43 mg, 11.10 mmol, 10.0 equivalents) in DCM (10 mL). After stirring at room temperature under a nitrogen atmosphere for 0.5 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (72:28) to give a brown oily substance (tert-butyldimethylsilyl)(((6-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)oct-2-yl)(methyl)oxo-λ6-thionyl))amine (350 mg, 40%). Step 4: 8-Methoxy-4-(2-(S-methylsulfonylimino)-2,6-diazaspiro(3,4)oct-6-yl)-1,7-naphthidine

[0361] Formic acid (0.2 mL, 25% (v / v)) was added to a solution of (tert-butyldimethylsilyl)(((6-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)oct-2-yl)(methyl)oxo-λ6-thionyl))amine (300 mg, 0.39 mmol, 1.0 equivalent) in DMF (5 mL). After stirring at room temperature for 10 min, the resulting mixture was concentrated under reduced pressure to give a crude product, which was further purified by preparative HPLC under the following conditions (column: YMC-ActusTriart C18 ExRS column, 30). 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 3% B to 26% B over 7 min; wavelength: 254 nm / 220 nm; RT: 6.95 min), to obtain 8-methoxy-4-(2-(S-methylsulfonylimino)-2,6-diazaspiro(3,4)oct-6-yl)-1,7-naphthidine (50 mg, 37%) as a grayish-white solid. MS (ESI, positive ion) m / z: 348.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, , ppm )δ8.43 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 6.0 Hz, 1H), 7.65 (d, J = 6.4, 1H), 6.73 -6.67 (m, 1H), 4.00 (s, 3H), 3.91 - 3.80 (m, 4H), 3.75 - 3.71 (m, 2H), 3.66(s, 2H), 3.57 (d, J = 2.0 Hz, 1H), 2.89 (d, J = 1.6 Hz, 3H), 2.21 (t, J = 6.7 Hz, 2H). Example 45 Synthesis of 8-methoxy-4-(6-(S-methylsulfonylimino)-2,6-diazaspiro(3,4)oct-2-yl)-1,7-naphthidine Step 1: 2-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)octane-6-carboxylic acid tert-butyl ester

[0362] DIEA (498 mg, 3.85 mmol, 3.0 equivalent) and tert-butyl 2,6-diazaspiro(3,4)octane-6-carboxylate (409 mg, 1.92 mmol, 1.5 equivalent) were added to a solution of 4-chloro-8-methoxy-1,7-naphthidine (250 mg, 1.28 mmol, 1.0 equivalent) in NMP (5 mL). The reaction mixture was stirred at 130 °C for 2 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (60:40) to give tert-butyl 2-(8-methoxy-1,7-naphthidine-4-yl)-2,6-diazaspiro(3,4)octane-6-carboxylate (400 mg, 84%) as a brown solid. Step 2: 8-Methoxy-4-(2,6-diazaspiro(3,4)oct-2-yl)-1,7-naphthidine

[0363] Dimethylpyridine (115 mg, 1.08 mmol, 1.0 equivalent) and TMSOTf (720 mg, 3.24 mmol, 3.0 equivalent) were added to a solution of 2-(8-methoxy-1,7-naphtho-4-yl)-2,6-diazaspiro(3,4)octane-6-carboxylic acid tert-butyl ester (400 mg, 1.08 mmol, 1.0 equivalent) in DCM (10 mL). After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure to give 8-methoxy-4-(2,6-diazaspiro(3,4)octane-2-yl)-1,7-naphtho-1 (350 mg, crude), which was used directly in the next step without further purification. Step 3: (tert-butyldimethylsilyl)(((2-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)-oct-6-yl)(methyl)oxo-λ6-thionyl))amine

[0364] (COCl)₂ (450 mg, 3.55 mmol, 3.2 equivalence) was added to a solution of Ph₃PO (926 mg, 3.33 mmol, 3.0 equivalence) in DCM (5 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min. DIEA (1.43 mg, 11.10 mmol, 10.0 equivalence) was added and the resulting mixture was stirred at 0 °C for 15 min. N-(tert-butyldimethylsilyl)methanesulfonamide (348 mg, 1.66 mmol, 1.5 equivalents) was added and the mixture was stirred at 0 °C for 20 min. Then, under a nitrogen atmosphere at 0 °C, it was added to a mixture of 8-methoxy-4-(2,6-diazaspiro(3,4)oct-2-yl)-1,7-naphthidine (300 mg, 1.11 mmol, 1.0 equivalents) and DIEA (1.43 g, 11.10 mmol, 10.0 equivalents) in DCM (5 mL). After stirring at room temperature under a nitrogen atmosphere for 30 min, the resulting mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (65:35) to obtain a brown oily substance (tert-butyldimethylsilyl)(((2-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)oct-6-yl)(methyl)oxo-λ6-thionyl))amine (350 mg, 40%). Step 4: 8-Methoxy-4-(6-(S-methylsulfonylimino)-2,6-diazaspiro(3,4)oct-2-yl)-1,7-naphthidine

[0365] Formic acid (0.2 mL, 25% (v / v)) was added to a solution of (tert-butyldimethylsilyl)(((2-(8-methoxy-1,7-naphthid-4-yl)-2,6-diazaspiro(3,4)oct-6-yl)(methyl)oxo-λ6-thionyl))amine (300 mg, 0.65 mmol, 1.0 equivalent) in DMF (5 mL). After stirring at room temperature for 10 min, the resulting mixture was concentrated under reduced pressure to give a crude product, which was further purified by preparative HPLC under the following conditions: (column: XBridgePrep OBD C18 column, 50 250 mm, 10 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 8% B to 32% B over 20 min; wavelength: 254 nm / 220 nm; RT: 20.33 min), to obtain 8-methoxy-4-(6-(S-methylsulfonylimino)-2,6-diazaspiro(3,4)oct-2-yl)-1,7-naphthidine (96 mg, 42%) as a grayish-white solid. MS (ESI, positive ion) m / z: 348.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ8.44 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H), 7.38 (d, J = 6.0 Hz, 1H), 6.47(d, J = 5.2 Hz, 1H), 4.35 - 4.32 (m, 2H), 4.27 (d, J = 8.0 Hz, 2H), 4.00 (s, 3H), 3.66 (s, 1H), 3.50 - 3.42 (m, 2H), 3.32 - 3.20 (m, 2H), 2.82 (d, J = 1.6 Hz, 3H), 2.20 (t, J = 6.8 Hz, 2H). Example 46 Synthesis of ((1-(8-ethoxy-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)-(methyl)-λ6-thione Step 1: 4-Hydroxy-4-((methylthio)methyl)piperidine-1-carboxylic acid tert-butyl ester

[0366] At 0 °C, sodium methanethiol (85.84 g, 244.99 mmol, 10.0 equivalent, 20%) was added to a solution of 1-oxa-6-azaspiro(2.5)octane-6-carboxylate (5.50 g, 24.49 mmol, 1.0 equivalent) in EtOH (50 mL). After stirring at room temperature for 2 h, the resulting solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc / PE (25:75) to give tert-butyl 4-hydroxy-4-((methylthioalkyl)methyl)piperidine-1-carboxylate (6.47 g, 95%) as a colorless oil. Step 2: 4-((methylthioalkyl)methyl)piperidine-4-ol hydrochloride

[0367] A solution of tert-butyl 4-hydroxy-4-((methylthioalkyl)methyl)piperidine-1-carboxylate (24.00 g, 91.82 mmol, 1.0 equivalent) in 1,4-dioxane (200 mL) in 4 M HCl was stirred at room temperature for 2 h and concentrated under reduced pressure to give 4-((methylthioalkyl)methyl)piperidine-4-ol hydrochloride (19.00 g, crude) as a white solid. 1 H NMR (400 MHz, DMSO-) d 6 ppm ) δ 3.12 - 2.94 (m, 4H), 2.60 (s, 2H), 2.12 (s, 3H), 1.83 - 1.65 (m, 4H). Step 3: 5-(((2-ethoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0368] A solution of 2-ethoxypyridin-3-amine (2.00 g, 14.47 mmol, 1 equivalent), 2,2-dimethyl-1,3-dioxane-4,6-dione (2.71 g, 18.82 mmol, 1.3 equivalent), and trimethoxymethane (2.15 g, 20.26 mmol, 1.4 equivalent) in ACN (30 mL) was stirred at 80 °C under a nitrogen atmosphere for 2 h. After cooling to room temperature, the mixture was diluted with PE. The resulting precipitate was filtered and washed with PE to give 5-(((2-ethoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.20 g, 99%) as a black solid. Step 4: 8-Ethoxy-1,7-Naphthyl-4-ol

[0369] A solution of 5-(((2-ethoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (4.10 g, 14.03 mmol) in diphenyl ether (40 mL) was stirred at 225 °C for 1.5 h. After cooling to room temperature, the mixture was diluted with PE. The precipitate was collected by filtration, washed with PE (200 mL), and purified by reversed-phase rapid chromatography with elution of ACN / H2O (32:68) to give 8-ethoxy-1,7-naphthidine-4-ol (552 mg, 20%) as a brown solid. Step 5: 4-Chloro-8-ethoxy-1,7-naphthidine

[0370] DIEA (271 mg, 2.10 mmol, 2.0 equivalent) and POCl3 (241.83 mg, 1.57 mmol, 1.5 equivalent) were added dropwise to a solution of 8-ethoxy-1,7-naphthyl-4-ol (200 mg, 1.05 mmol, 1.0 equivalent) in toluene (5 mL). The resulting mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (41:59) to give 4-chloro-8-ethoxy-1,7-naphthylidine (100 mg, 45%) as a yellow solid. Step 6: 1-(8-ethoxy-1,7-naphthidin-4-yl)-4-((methylthioalkyl)methyl)piperidin-4-ol

[0371] At room temperature, DIEA (247 mg, 1.91 mmol, 2.0 equivalent) and 4-((methylthioalkyl)methyl)piperidin-4-ol hydrochloride (284 mg, 1.43 mmol, 1.5 equivalent, from step 2) were added to a stirred solution of 4-chloro-8-ethoxy-1,7-naphthyl (200 mg, 0.95 mmol, 1.0 equivalent) in NMP (4 mL). The reaction mixture was stirred overnight at 130 °C. After cooling to room temperature, the resulting mixture was purified by reversed-phase rapid chromatography with elution of ACN / H2O (3:2) to give 1-(8-ethoxy-1,7-naphthyl)-4-((methylthioalkyl)methyl)piperidin-4-ol (180 mg, 56%) as a white solid. Step 7: ((1-(8-ethoxy-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)-(methyl)-λ6-thione

[0372] At room temperature, (acetoxy)(phenyl)-λ3-iodoalkyl acetate (463 mg, 1.44 mmol, 3.0 equivalent) and ammonium carbamate (149 mg, 1.92 mmol, 4.0 equivalent) were added to a stirred solution of 1-(8-ethoxy-1,7-naphthid-4-yl)-4-((methylthioalkyl)-methyl)piperidin-4-ol (160 mg, 0.48 mmol, 1.0 equivalent) in MeOH (3 mL). After stirring at the same temperature for 2 h, the resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (UV 254 nm / 220 nm, Xbridge Prep OBD C18 column, 19...). 250 mm, 5 µm; water (10 mmol / L NH4HCO3), MeOH; 25 mL / min; 20% B to 40% B over 13 min; wavelength: 254 nm / 220 nm; RT: 12.3 min). Fractions containing the desired product were combined and lyophilized to give (1-(8-ethoxy-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (54.1 mg, 30%) as a yellow solid. MS (ESI, positive ion) m / z: 365.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.67 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 5.62 (s, 1H), 4.53 -4.44 (m, 2H), 4.03 (s, 1H), 3.46 - 3.43 (m, 1H), 3.35 - 3.25 (m, 3H), 3.22 -3.11 (m, 2H), 3.05 (s, 3H), 2.08 - 1.96 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H). Examples 47, 48 and 49 ((1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione and ( R )-((1-(8-(fluoromethoxy)-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thionone and ( S Synthesis of )-((1-(8-(fluoromethoxy)-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione Step 1: 4-Chloro-8-(fluoromethoxy)-1,7-naphthidine

[0373] DIEA (2.93 g, 22.66 mmol, 2.0 equivalent) and POCl3 (2.08 g, 13.59 mmol, 1.2 equivalent) were added dropwise to a solution of 8-(fluoromethoxy)-1,7-naphthidine-4-ol (2.20 g, 11.33 mmol, 1.0 equivalent) in toluene (10 mL). The resulting mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with EtOAc / PE (18:82) to give 4-chloro-8-(fluoromethoxy)-1,7-naphthidine (900 mg, 35%) as a brown solid. Step 2: 1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-((methylthioalkyl)methyl)-piperidin-4-ol

[0374] DIEA (1.09 g, 8.46 mmol, 2.0 equivalent) and 4-((methylthio)methyl)piperidin-4-ol hydrochloride (1.02 g, 6.34 mmol, 1.5 equivalent) were added to a solution of 4-chloro-8-(fluoromethoxy)-1,7-naphthyl (900 mg, 4.23 mmol, 1.0 equivalent) in NMP (10 mL). The resulting mixture was stirred at 130 °C for 2 h. After cooling to room temperature, the reaction mixture was purified by reversed-phase rapid chromatography with elution using ACN / H2O (65:35) to give 1-(8-(fluoromethoxy)-1,7-naphthyl)-4-((methylthio)methyl)piperidin-4-ol (1.02 g, 63%) as a brown solid. Step 3: ((1-(8-(fluoromethoxy)-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)-(imino)(methyl)-λ6-thione

[0375] To a solution of 1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-((methylthioalkyl)-methyl)piperidin-4-ol (1.00 g, 2.96 mmol, 1.0 equivalent) in MeOH (10 mL), (acetoxy)(phenyl)-λ3-iodoalkyl acetate (2.86 g, 8.89 mmol, 3.0 equivalent) and ammonium carbamate (0.93 g, 11.85 mmol, 4.0 equivalent) were added. After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography with elution of ACN / H2O (35:65) to give (1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (800 mg, 73%) as a brown solid. MS (ESI, positive ion) m / z: 369.1 (M+1). 1 HNMR (400 MHz, DMSO- d 6, , ppm ) δ 8.73 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 6.36 (s, 1H), 6.23 (s, 1H), 5.63 (s, 1H), 4.03 (s, 1H), 3.48 - 3.46 (m, 1H), 3.45 - 3.41 (m, 2H), 3.34 -3.31 (m, 1H), 3.26 - 3.14 (m, 2H), 3.06 (s, 3H), 2.10 - 2.02 (m, 2H), 2.02 -1.92 (m, 2H). 19 F NMR (376 MHz, DMSO- d 6, ppm ) δ -155.74 (s, 1 F). Step 4: ( R)-((1-(8-(fluoromethoxy)-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)-(imino)(methyl)-λ6-thionone and ( S )-((1-(8-(fluoromethoxy)-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione

[0376] Racemic ((1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (800 mg, 2.17 mmol) was purified by Chrial-SFC under the following conditions (column: Lux5um Cellulose-4 30). 250 mm, 5.0 μm; Mobile phase A: CO2, Mobile phase B: MeOH (1%-2 M-NH3-MeOH); Flow rate: 90 mL / min; Gradient: isocratic 44% B; Column temperature (°C): 35; Back pressure (bar): 100; Wavelength: 220 nm; Sample solvent: MEOH; Injection volume: 3 mL; Number of runs: 10, to obtain two fractions.

[0377] Grade 1: Grayish-white solid ( R )-((1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (335.1 mg, 40%). RT1: 9.47 min, MS (ESI, positive ion) m / z: 369.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.73 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.22 (d, J= 5.2 Hz, 1H), 6.36 (s, 1H), 6.23 (s, 1H), 5.63 (s, 1H), 4.03 (s, 1H), 3.48 - 3.46 (m, 1H), 3.45 - 3.41(m, 2H), 3.34 - 3.31 (m, 1H), 3.26 - 3.14 (m, 2H), 3.06 (s, 3H), 2.10 - 2.02(m, 2H), 2.02 - 1.92 (m, 2H).

[0378] 19 F NMR (376 MHz, DMSO- d 6, ppm ) δ -155.74 (s, 1 F).

[0379] Grade 2: Grayish-white solid ( S )-((1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (360.5 mg, 43%). RT2: 12.08 min, MS (ESI, positive ion) m / z: 369.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.73 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 6.36 (s, 1H), 6.23 (s, 1H), 5.63 (s, 1H), 4.03 (s, 1H), 3.48 - 3.46 (m, 1H), 3.45 - 3.41(m, 2H), 3.34 - 3.31 (m, 1H), 3.26 - 3.14 (m, 2H), 3.06 (s, 3H), 2.10 - 2.02(m, 2H), 2.02 - 1.92 (m, 2H).

[0380] 19 F NMR (377 MHz, DMSO- d 6, ppm ) δ -155.74 (s, 1 F). Example 50 Synthesis of imino(4-((8-methoxy-1,7-naphthidin-4-yl)oxy)phenyl)(methyl)-λ6-thione Step 1: 8-Methoxy-4-(4-(methylthio)phenoxy)-1,7-naphthidine

[0381] Cs₂CO₃ (502 mg, 1.54 mmol, 2.0 equivalent) and 4-(methylthio)phenol (216 mg, 1.54 mmol, 2.0 equivalent) were added to a solution of 4-chloro-8-methoxy-1,7-naphthidine (150 mg, 0.77 mmol, 1.0 equivalent) in DMSO (3 mL). The resulting mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by elution with EtOAc / PE (3:7) to give 8-methoxy-4-(4-(methylthio)phenoxy)-1,7-naphthidine (200 mg, 86%) as a pale yellow solid. Step 2: Imino(4-((8-methoxy-1,7-naphthidin-4-yl)oxy)phenyl)(methyl)-λ6-thione

[0382] Add (acetoxy)(phenyl)-λ3-iodoalkyl acetate (582 mg, 1.80 mmol, 3.0 equivalent) and ammonium carbamate (188 mg, 2.41 mmol, 4.0 equivalent) to a solution of 8-methoxy-4-(4-(methylthio)phenoxy)-1,7-naphthidine (180 mg, 0.60 mmol, 1.0 equivalent) in MeOH (3 mL) to a solution of 8-methoxy-4-(4-(methylthio)phenoxy)-1,7-naphthidine (180 mg, 0.60 mmol, 1.0 equivalent) in MeOH (3 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the resulting mixture under reduced pressure. Purify the crude product by preparative HPLC using the following conditions (column: XBridgePrep OBD C18 column, 50 mL). 250 mm, 10 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 42% B over 20 min; wavelength: 254 nm / 220 nm; RT: 21.07 min), to obtain imino(4-((8-methoxy-1,7-naphthidin-4-yl)oxy)phenyl)(methyl)-λ6-thione (85.8 mg, 43%) as a grayish-white solid. MS (ESI, positive ion) m / z: 330.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.81 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 5.6 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.61 (d, J = 6.0Hz, 1H), 7.53 - 7.45 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 4.30 (s, 1H), 4.09 (s, 3H), 3.12 (d, J = 1.2 Hz, 3H). Example 51 Synthesis of imino(3-((8-methoxy-1,7-naphthidin-4-yl)oxy)phenyl)(methyl)-λ6-thione Step 1: 3-(methylthio)phenol

[0383] At 0 °C, BBr3 (9.73 mL, 9.72 mmol, 3.0 equivalent, 1 M in DCM) was added to a solution of 1-methoxy-3-(methylthioalkyl)benzene (500 mg, 3.24 mmol, 1.0 equivalent) in DCM (10 mL). After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure. The residue was quenched with H2O (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 3-(methylthio)phenol (400 mg, 88%) as a green oil. Step 2: 8-Methoxy-4-(3-(methylthio)phenoxy)-1,7-naphthidine

[0384] Cs₂CO₃ (502 mg, 1.54 mmol, 2.0 equivalent) and 4-chloro-8-methoxy-1,7-naphthidine (150 mg, 0.77 mmol, 1.0 equivalent) were added to a solution of 3-(methylthio)phenol (108 mg, 0.77 mmol, 1.0 equivalent) in DMSO (3 mL). The reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with H₂O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (44:56) as elution to give 8-methoxy-4-(3-(methylthio)phenoxy)-1,7-naphthidine (200 mg, 86%) as a brown solid. Step 3: Imino(3-((8-methoxy-1,7-naphthidin-4-yl)oxy)phenyl)(methyl)-λ6-thione

[0385] Add (acetoxy)(phenyl)-λ3-iodoalkyl acetate (647 mg, 2.01 mmol, 3.0 equivalent) and ammonium carbamate (209 mg, 2.68 mmol, 4.0 equivalent) to a solution of 8-methoxy-4-(3-(methylthio)phenoxy)-1,7-naphthidine (200 mg, 0.67 mmol, 1.0 equivalent) in MeOH (5 mL) to a solution of 8-methoxy-4-(3-(methylthio)phenoxy)-1,7-naphthidine (200 mg, 0.67 mmol, 1.0 equivalent). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC under the following conditions (column: XBridgePrep Shield RP C18 column, 30 °C). 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 32% B over 7 min; wavelength: 254 nm / 220 nm; RT: 7.0 min), to obtain imino(3-((8-methoxy-1,7-naphthidin-4-yl)oxy)phenyl)(methyl)-λ6-thione (82.0 mg, 37%) as a grayish-white solid. MS (ESI, positive ion) m / z: 330.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ8.78 (d, J = 5.2 Hz, 1H), 8.18 (d, J= 5.6 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.83 -7.75 (m, 2H), 7.68 (d, J = 5.6 Hz, 1H), 7.65 - 7.59 (m, 1H), 6.99 (d, J = 5.2 Hz,1H), 4.37 (s, 1H), 4.10 (s, 3H), 3.17 - 3.12 (m, 3H). Example 52 Synthesis of ((1-(8-cyclopropoxy-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione Step 1: 2-Cyclopropoxy-3-nitropyridine

[0386] At 0 °C, NaH (2.11 g, 52.78 mmol, 1.5 equivalents, 60%) was added to a cooled solution of cyclopropanol (3.07 g, 52.78 mmol, 1.5 equivalents, 50 mL) in THF (50 mL), followed by the addition of 2-fluoro-3-nitropyridine (5.00 g, 35.18 mmol, 1.0 equivalents). The resulting mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (8:92) to give 2-cyclopropoxy-3-nitropyridine (5.50 g, 86%) as a colorless oil. Step 2: 2-Cyclopropoxypyridine-3-amine

[0387] Under a nitrogen atmosphere, Pd / C (3.07 g, 2.88 mmol, 0.1 equivalent, 10%) was added to a solution of 2-cyclopropoxy-3-nitropyridine (5.20 g, 28.86 mmol, 1.0 equivalent) in MeOH (80 mL). The mixture was stirred overnight at room temperature under a hydrogen atmosphere achieved by using a hydrogen balloon, then filtered through a diatomaceous earth pad and concentrated under reduced pressure to give 2-cyclopropoxypyridine-3-amine (3.80 g, 87%) as a gray oil. Step 3: 5-(((2-Cyclopropoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0388] At room temperature, 2,2-dimethyl-1,3-dioxane-4,6-dione (5.11 g, 35.42 mmol, 1.0 equivalent) and trimethoxymethane (3.76 g, 35.42 mmol, 1.4 equivalent) were added to a stirred mixture of 2-cyclopropoxypyridin-3-amine (3.80 g, 25.30 mmol, 1.0 equivalent) in ACN (50 mL). After stirring at 80 °C for 2 h, the resulting mixture was cooled to 0 °C. The precipitate was collected by filtration and washed with PE (50 mL) to give 5-(((2-cyclopropoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.10 g, 79%) as a grayish-white solid. Step 4: 8-Cyclopropoxy-1,7-Naphthyl-4-ol

[0389] A solution of 5-(((2-cyclopropoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.50 g, 11.50 mmol, 1.0 equivalent) in diphenyl ether (35 mL) was stirred at 225 °C under a nitrogen atmosphere for 1.5 h. After cooling to room temperature, PE was added to the reaction mixture. The precipitate was collected by filtration, washed with PE, and purified by reversed-phase rapid chromatography with elution using ACN / H2O (23:77) to give 8-cyclopropoxy-1,7-naphthidine-4-ol (400 mg, 17%) as a white solid. Step 5: 4-Chloro-8-cyclopropoxy-1,7-naphthidine

[0390] At room temperature, DIEA (485 mg, 3.75 mmol, 2.0 equivalent) and POCl3 (432 mg, 2.81 mmol, 1.5 equivalent) were added to a stirred solution of 8-cyclopropoxy-1,7-naphthyl-4-ol (380 mg, 1.87 mmol, 1.0 equivalent) in toluene (8 mL). After stirring at 70 °C for 2 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (42:58) to give 4-chloro-8-cyclopropoxy-1,7-naphthylidine (280 mg, 67%) as a yellow solid. Step 6: 1-(8-cyclopropoxy-1,7-naphthidin-4-yl)-4-((methylthioalkyl)methyl)piperidin-4-ol

[0391] At room temperature, DIEA (304 mg, 2.35 mmol, 2.0 equivalent) and 4-((methylthioalkyl)methyl)piperidin-4-ol hydrochloride (349 mg, 1.76 mmol, 1.5 equivalent, prepared as described in steps 1 and 2 of Example 46) were added to a stirred solution of 4-chloro-8-cyclopropoxy-1,7-naphthyl)idine (260 mg, 1.17 mmol, 1.0 equivalent) in NMP (5 mL). After stirring overnight at 130 °C, the resulting solution was purified by reversed-phase rapid chromatography with elution using ACN / H2O (51:49) to give 1-(8-cyclopropoxy-1,7-naphthyl)-4-((methylthioalkyl)methyl)piperidin-4-ol (301 mg, 73%) as a yellow solid. Step 7: ((1-(8-cyclopropoxy-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)-(methyl)-λ6-thione

[0392] At room temperature, (acetoxy)(phenyl)-λ3-iodoalkyl acetate (419 mg, 1.30 mmol, 3.0 equivalent) and ammonium carbamate (135 mg, 1.73 mmol, 4.0 equivalent) were added to a stirred solution of 1-(8-cyclopropoxy-1,7-naphthyl-4-yl)-4-((methylthioalkyl)-methyl)piperidin-4-ol (150 mg, 0.43 mmol, 1.0 equivalent) in MeOH (3 mL). After stirring at the same temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 50). 250 mm, 10 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 34% B over 20 min; Wavelength: 254 nm / 220 nm; RT: 21.17 min). Fractions containing the desired product were combined and lyophilized to give (1-(8-cyclopropoxy-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (72.7 mg, 42%) as a white solid. MS (ESI, positive ion) m / z: 377.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ppm ) δ 8.64 (d, J= 5.2Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.36 (d, J = 6.0 Hz, 1H), 7.17 (d, J = 5.2 Hz,1H), 5.61 (s, 1H), 4.51 - 4.42 (m, 1H), 4.02 (s, 1H), 3.44 (d, J = 12.0 Hz,1H), 3.32 - 3.27 (m, 3H), 3.24 - 3.13 (m, 2H), 3.05 (s, 3H), 2.10 -1.92 (m,4H), 0.88 - 0.81 (m, 2H), 0.79 - 0.73 (m, 2H). Example 53 Synthesis of ((2-(8-methoxy-1,7-naphthid-4-yl)-2,8-diazaspiro(4,5)dec-8-yl)(methyl)oxo-λ6-thionyl)(methyl)amine

[0393] At 0 °C, NaH (42 mg, 1.06 mmol, 5.0 equivalent, 60%) was added to a solution of 2-(8-methoxy-1,7-naphthid-4-yl)-8-(S-methylsulfonylimino)-2,8-diazaspiro(4,5)decane (80 mg, 0.21 mmol, 1.0 equivalent) in DMF (2 mL). After stirring at 0 °C for 0.5 h, MeI (60 mg, 0.42 mmol, 2.0 equivalent) was added. After stirring at room temperature for 1 h, the resulting mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30...). 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7% B to 37% B over 10 min; wavelength: 254 nm / 220 nm; RT: 9.1 min), to obtain ((2-(8-methoxy-1,7-naphthidin-4-yl)-2,8-diazaspiro(4,5)dec-8-yl)(methyl)oxo-λ6-thionyl)(methyl)amine (22.0 mg, 26%) as a grayish-white solid. MS (ESI, positive ion) m / z: 390.2 (M+1).1 H NMR (400 MHz, DMSO- d 6, , ppm ) δ 8.42 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 6.4 Hz, 1H), 7.69 (d, J = 6.4 Hz, 1H), 6.71 (d, J = 5.6 Hz, 1H), 3.99 (s, 3H), 3.79 -3.71 (m, 2H), 3.53 (s, 2H), 3.17 - 3.03 (m, 4H), 2.77 (s, 3H), 2.46 (s, 3H),1.96 - 1.88 (m, 2H), 1.71 - 1.67 (m, 4H). Example 54 Synthesis of ((7-(8-methoxy-1,7-naphthid-4-yl)-2,7-diazaspiro(4,4)non-2-yl)(methyl)oxo-λ6-thionyl)(methyl)amine

[0394] At 0 °C, NaH (8 mg, 0.34 mmol, 3.0 equivalent) was added to a stirred solution of 8-methoxy-4-(7-(S-methylsulfonylimino)-2,7-diazaspiro(4,4)-non-2-yl)-1,7-naphthidine (42 mg, 0.11 mmol, 1.0 equivalent) in DMF (2 mL). After stirring for 30 min, MeI (32 mg, 0.23 mmol, 2.0 equivalent) was added and the mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: (Column: XBridge Prep RP OBD C18 column, 30...) 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 32% B over 10 min; wavelength: 254 nm / 220 nm; RT: 8.9 min). Fractions containing the desired product were combined and lyophilized to give ((7-(8-methoxy-1,7-naphthidin-4-yl)-2,7-diazaspiro(4,4)non-2-yl)(methyl)oxo-λ6-thionyl)(methyl)amine (3.9 mg, 8%) as a white solid. MS (ESI, positive ion) m / z: 376.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ppm ) δ8.42 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.66 (d, J = 6.0 Hz, 1H), 6.71(d, J = 5.6 Hz, 1H), 3.99 (s, 3H), 3.75 (s, 2H), 3.72 - 3.59 (m, 2H), 3.31 -3.25 (m, 3H), 3.19 (s, 2H), 2.83 (d, J = 2.0 Hz, 3H), 2.50 (s, 1H), 2.48 (s,1H), 2.11 - 1.90 (m, 4H). Example 55 Synthesis of cyclopropyl(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-(methylimino)-λ6-thione

[0395] At 0 °C, NaH (19 mg, 0.48 mmol, 1.5 equivalence, 60%) was added to a solution of cyclopropyl(imino)(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)-methyl)phenyl)-λ6-thione (120 mg, 0.32 mmol, 1.0 equivalence) in DMF (5 mL), and the mixture was stirred at 0 °C for 30 min. MeI (92 mg, 0.65 mmol, 2.0 equivalence) was added. After stirring at room temperature for 1 h, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30...). 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13% B to 43% B over 10 min; wavelength: 254 nm / 220 nm; RT: 8.5 min), to obtain cyclopropyl(3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(methylimino)-λ6-thione (63.2 mg, 50%) as a grayish-white solid. MS (ESI, positive ion) m / z: 384.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, , ppm ) δ 8.80 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.84 - 7.77 (m, 1H), 7.76 -7.67 (m, 1H), 7.56 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 5.55 (s, 2H), 4.06 (s, 3H), 2.79 - 2.68 (m, 1H), 2.53 (s, 3H), 1.26 - 1.13 (m, 1H), 1.12 -1.00 (m, 1H), 0.97 - 0.78 (m, 2H). Example 56 Synthesis of cyclopropyl(3-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-(methylimino)-λ6-thione

[0396] At room temperature, Cs₂CO₃ (175 mg, 0.54 mmol, 2.0 equivalent) and MeI (76 mg, 0.54 mmol, 2.0 equivalent) were added to a stirred solution of cyclopropyl(imino)(3-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)-λ6-thione (100 mg, 0.27 mmol, 1.0 equivalent) in DMF (2 mL). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the resulting mixture was quenched with water at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep RP OBD C18 column, 30). 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 50% B over 7 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.4). Fractions containing the desired product were combined and lyophilized to give cyclopropyl(3-(((8-methoxypyridino[3,4-d]pyrimidin-4-yl)oxy)methyl)phenyl)(methylimino)-λ6-thione (1.6 mg, 1%) as a white solid. MS (ESI, positive ion) m / z: 385.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6, ppm ) δ 8.92 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H),7.81 - 7.77 (m, 1H), 7.69 (t, J= 7.6 Hz, 1H), 7.55 - 7.51 (m, 1H), 5.76 (s,2H), 4.07 (s, 3H), 2.75 - 2.68 (m, 1H), 2.51 (s, 3H), 1.25 - 1.13 (m, 1H),1.10 - 1.00 (m, 1H), 0.96 - 0.77 (m, 2H). Example 57 Synthesis of ((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)(methyl)-(methylimino)-λ6-thione

[0397] At 0 °C, NaH (30 mg, 0.74 mmol, 1.5 equivalent, 60%) was added to a stirred solution of ((4-hydroxy-1-(8-methoxy-1,7-naphthid-4-yl)piperidin-4-yl)methyl)(imino)(methyl)-λ6-thione (175 mg, 0.49 mmol, 1 equivalent) in DMF (5 mL). The resulting mixture was stirred at 0 °C for 30 min. Then MeI (77 mg, 0.54 mmol, 1.5 equivalent) was added. After stirring at room temperature for 1 h, the reaction mixture was quenched with water at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: (column: YMC-Actus Triart C18ExRs, 30...) 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 23% B over 10 min; Wavelength: 254 nm / 220 nm; RT: 8.6 min). Fractions containing the desired product were combined and lyophilized to give ((4-hydroxy-1-(8-methoxy-1,7-naphthidin-4-yl)piperidin-4-yl)methyl)-(methyl)(methylimino)-λ6-thione (32 mg, 17%) as a grayish-white solid. MS (ESI, positive ion) m / z: 365.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ppm ) δ 8.66 (d, J = 5.2 Hz, 1H), 8.02 (d, J= 6.0 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 5.76 (s, 1H), 4.03 (s,3H), 3.55 - 3.51 (m, 1H), 3.32 - 3.28 (m, 1H), 3.20 - 3.18 (m, 2H), 3.17 -3.12 (m, 2H), 3.07 (s, 3H), 2.66 (s, 3H), 2.03 - 1.95 (m, 4H). Example 58 Synthesis of ((2-(8-methoxy-1,7-naphthidin-4-yl)-2-azaspiro(3,3)hept-6-yl)methyl-methyl)(methylimino)-λ6-thione

[0398] At 0 °C, NaH (41 mg, 1.03 mmol, 3.0 equivalence, 60%) was added to a solution of imino((2-(8-methoxy-1,7-naphthidin-4-yl)-2-azaspiro(3,3)hept-6-yl)methyl)(methyl)-λ6-thione (120 mg, 0.34 mmol, 1.0 equivalence) in DMF (2 mL). After stirring at 0 °C for 30 min, MeI (98 mg, 0.69 mmol, 2.0 equivalence) was added. The resulting mixture was stirred at room temperature for 1 h, then quenched with water (50 mL) at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18ExRs, 30). 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min gradient: 14% B to 24% B over 10 min; wavelength: 254 nm / 220 nm; RT: 8.9 min), to obtain ((2-(8-methoxy-1,7-naphthidin-4-yl)-2-azaspiro(3,3)hept-6-yl)methyl)(methyl)(methylimino)-λ6-thione (26.9 mg, 21.41%) as a grayish-white solid. MS (ESI, positive ion) m / z: 361.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6, , ppm) δ 8.41 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 6.0 Hz, 1H), 7.35 (d, J = 6.0 Hz, 1H), 6.41 (d, J = 5.2 Hz, 1H),4.39 (s, 2H), 4.23 (s, 2H), 3.98 (s, 3H), 3.32 - 3.17 (m, 2H), 2.84 (s, 3H),2.69 - 2.62 (m, 1H), 2.60 (s, 3H), 2.50 - 2.40 (m, 2H), 2.18 - 2.07 (m, 2H). Example 59 Synthesis of cyclopropyl(4-fluoro-3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)-phenyl)(imino)-λ6-thione Step 1: 5-(chlorosulfonyl)-2-fluorobenzoic acid

[0399] Chlorosulfonic acid (4.29 g, 7.37 mmol, 5.0 equivalent) was added dropwise to 2-fluorobenzoic acid (1.00 g, 1.43 mmol, 1.0 equivalent) over 5 min. The reaction mixture was stirred at room temperature for 30 min and then heated to 90 °C for 4.5 h. After cooling to room temperature, the resulting mixture was quenched with water. The precipitate was collected by filtration, washed with water, and dried under vacuum to give 5-(chlorosulfonyl)-2-fluorobenzoic acid (1.10 g, 65%) as a grayish-white solid. Step 2: 2-Fluoro-5-thioalkylbenzoic acid

[0400] SnCl₂·2H₂O (3.15 g, 13.83 mmol, 3.0 equivalent) was added to a solution of 5-(chlorosulfonyl)-2-fluorobenzoic acid (1.10 g, 4.61 mmol, 1.0 equivalent) in concentrated HCl (10 mL). The reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with water and basified with saturated sodium bicarbonate. The inorganic material was filtered off, and the filtrate was acidified with 1 N HCl and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 2-fluoro-5-thioalkylbenzoic acid (550 mg, 69%) as a pale yellow oil. Step 3: 5-(cyclopropylthio)-2-fluorobenzoic acid

[0401] Add bromocyclopropane (579 mg, 4.79 mmol, 1.5 equivalent) and potassium tert-butoxide (716 mg, 6.39 mmol, 2.0 equivalent) to a solution of 2-fluoro-5-thioalkylbenzoic acid (550 mg, 3.19 mmol, 1.0 equivalent) in DMSO (10 mL). Stir the reaction mixture overnight at 80 °C under nitrogen atmosphere. After cooling to room temperature, dilute the resulting mixture with water (100 mL) and acidify to pH 4–5 with 1 N HCl. Extract the resulting mixture with EtOAc. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by reversed-phase rapid chromatography with elution of ACN / H₂O (45:55) to give 5-(cyclopropylthioalkyl)-2-fluorobenzoic acid (460 mg, 54%) as a pale yellow solid. Step 4: (5-(cyclopropylthio)-2-fluorophenyl)methanol

[0402] At 0 °C, LiAlH4 (2.1 mL, 4.14 mmol, 2.0 M in THF) was added dropwise to a solution of 5-(cyclopropylthioalkyl)-2-fluorobenzoic acid (440 mg, 2.07 mmol, 1.0 equivalent) in 10 mL of THF. After stirring overnight at room temperature under nitrogen atmosphere, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution using MeOH / DCM (14:86) to give (5-(cyclopropylthioalkyl)-2-fluorophenyl)methanol (210 mg, 51%) as a brown oil. Step 5: 4-((5-(cyclopropylthioalkyl)-2-fluorophenyl)methoxy)-8-methoxy-1,7-naphthidine

[0403] Cs₂CO₃ (624 mg, 1.91 mmol, 2.0 equivalence) and 4-chloro-8-methoxy-1,7-naphthidine (279 mg, 1.43 mmol, 1.5 equivalence) were added to a solution of (5-(cyclopropylthioalkyl)-2-fluorophenyl)methanol (190 mg, 0.95 mmol, 1.0 equivalence) in DMF (5 mL). The reaction mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (80:20) as elution to give 4-((5-(cyclopropylthioalkyl)-2-fluorophenyl)methoxy)-8-methoxy-1,7-naphthidine (150 mg, 43%) as a pale yellow solid. Step 6: Cyclopropyl(4-fluoro-3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-(imino)-λ6-thione

[0404] Add (acetoxy)(phenyl)-λ3-iodoalkyl acetate (352 mg, 1.09 mmol, 3.0 equivalent) and ammonium carbamate (113 mg, 1.46 mmol, 4.0 equivalent) to a solution of 4-((5-(cyclopropylthioalkyl)-2-fluorophenyl)methoxy)-8-methoxy-1,7-naphthidine (130 mg, 0.36 mmol, 1.0 equivalent) in MeOH (3 mL) to a solution of 4-((5-(cyclopropylthioalkyl)-2-fluorophenyl)methoxy)-8-methoxy-1,7-naphthidine (130 mg, 0.36 mmol, 1.0 equivalent) in MeOH (3 mL) to a solution of 4-((5-(cyclopropylthioalkyl)-2-fluorophenyl)methoxy)-8-methoxy-1,7-naphthidine (130 mg, 1.46 mmol, 4.0 equivalent) in MeOH (3 mL) to a solution of 4-((5-(cyclopropylthioalkyl)-2-fluorophenyl)methoxy)-8-methoxy-1,7-naphthidine (130 mg, 0.36 mmol, 1 ... 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 40% B over 10 min; wavelength: 254 nm / 220 nm; RT: 9.3 min), to obtain cyclopropyl(4-fluoro-3-(((8-methoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(imino)-λ6-thione (57.1 mg, 40%) as a grayish-white solid. MS (ESI, positive ion) m / z: 388.0 (M+1). 1H NMR (400 MHz, DMSO-) d 6 ppm ) δ 8.82 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 6.8 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1H), 8.08 - 8.00 (m, 1H), 7.60 - 7.51 (m, 1H), 7.47 (d, J =6.8, 2H), 5.56 (s, 2H), 4.38 (s, 1H), 4.06 (s, 3H), 2.71 (d, J = 8.6 Hz, 1H), 1.17 - 1.07 (m, 1H), 1.04 - 0.76 (m, 3H).

[0405] 19 F NMR (376 MHz, DMSO- d 6 , ppm ) δ -111.88 (s, 1 F). Example 60 Synthesis of (3-(((8-cyclopropoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-(cyclopropyl)(imino)-λ6-thione Step 1: 8-Cyclopropoxy-4-((3-(cyclopropylthio)phenyl)methoxy)-1,7-naphthidine

[0406] At 0 °C, NaH (45 mg, 1.90 mmol, 3.0 equivalent) was added to a stirred solution of (3-(cyclopropylthioalkyl)phenyl)methanol (114 mg, 0.63 mmol, 1.0 equivalent) in DMF (3 mL). After stirring for 10 min, 4-chloro-8-cyclopropoxy-1,7-naphthidine (140 mg, 0.63 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the resulting mixture was quenched with water at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (45:55) to give 8-cyclopropoxy-4-((3-(cyclopropylthioalkyl)phenyl)methoxy)-1,7-naphthidine (58 mg, 25%) as a yellow solid. Step 2: (3-(((8-cyclopropoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(cyclopropyl)-(imino)-λ6-thione

[0407] At room temperature, (acetoxy)(phenyl)-λ3-iodoalkyl acetate (127 mg, 0.39 mmol, 3.0 equivalent) and ammonium carbamate (41 mg, 0.52 mmol, 4.0 equivalent) were added to a stirred solution of 8-cyclopropoxy-4-((3-(cyclopropylthio)phenyl)methoxy)-1,7-naphthidine (48 mg, 0.13 mmol, 1.0 equivalent) in MeOH (2 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge Prep OBD C18 column, 30). 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 43% B over 10 min; Wavelength: 254 nm / 220 nm; RT: 8.68 min). Fractions containing the desired product were combined and lyophilized to give (3-(((8-cyclopropoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)(cyclopropyl)(imino)-λ6-thione (26.8 mg, 50%) as a white solid. MS (ESI, positive ion) m / z: 396.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.77 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.6 Hz, 1H), 8.08 (t, J = 1.6 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.87 -7.82 (m, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.37 (d, J= 5.2Hz, 1H), 5.54 (s, 2H), 4.54 - 4.45 (m, 1H), 4.29 (s, 1H), 2.72 - 2.64 (m,1H), 1.16 - 1.07 (m, 1H), 1.02 - 0.83 (m, 5H), 0.82 - 0.75 (m, 2H). Example 61 Synthesis of cyclopropyl(imino)(3-(((8-isopropoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione Step 1: 2-Isopropoxy-3-nitropyridine

[0408] At 0 °C, NaH (2.52 g, 63.07 mmol, 2.0 equivalent, 60%) was added to a solution of isopropanol (17 mL) in THF (50 mL). After stirring at 0 °C for 30 min, 2-chloro-3-nitropyridine (5.00 g, 31.54 mmol, 1.0 equivalent) was added. After stirring at room temperature for 2 h, the reaction mixture was quenched with water at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography with EtOAc / PE (10:90) to give 2-isopropoxy-3-nitropyridine (3.83 g, 66%) as an orange oil. Step 2: 2-Isopropoxypyridine-3-amine

[0409] Pd / C (220 mg, 2.10 mmol, 0.1 equivalent) was added to a solution of 2-isopropoxy-3-nitropyridine (3.83 g, 21.02 mmol, 1.0 equivalent) in MeOH (100 mL). The resulting mixture was stirred at room temperature under a H2 atmosphere for 2 h. The reaction mixture was filtered through a diatomaceous earth pad, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give 2-isopropoxypyridine-3-amine (3.12 g, 92%) as a yellow oil. Step 3: 5-(((2-isopropoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0410] 2,2-Dimethyl-1,3-dioxane-4,6-dione (3.69 g, 25.62 mmol, 1.0 equivalent) and trimethoxymethane (2.93 g, 27.59 mmol, 1.4 equivalent) were added to a solution of 2-isopropoxypyridin-3-amine (3.00 g, 19.71 mmol, 1.0 equivalent) in ACN (30 mL). The resulting mixture was stirred at 80 °C under N2 atmosphere for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and filtered. The filter cake was washed with water and dried under vacuum to give 5-(((2-isopropoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.02 g, 99%) as a green solid. Step 4: 8-Isopropoxy-1,7-Naphthyl-4-ol

[0411] Add to a solution of 5-(((2-isopropoxypyridin-3-yl)amino)methylethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.00 g, 9.79 mmol, 1.0 equivalent) diphenyl ether (30 mL). Stir the resulting mixture at 225 °C for 1.5 h. After cooling to room temperature, filter the mixture and wash the filter cake with PE. Purify the crude product by reversed-phase rapid chromatography with elution of ACN / H₂O (63:37) to give 8-isopropoxy-1,7-naphthyl-4-ol (518 mg, 25%) as a white solid. MS (ESI, positive ion) m / z: 205.1 (M+1). Step 5: 4-Chloro-8-isopropoxy-1,7-naphthidine

[0412] DIEA (605 mg, 4.68 mmol, 2.0 equivalent) and POCl3 (430 mg, 2.81 mmol, 1.2 equivalent) were added to a solution of 8-isopropoxy-1,7-naphthyl-4-ol (478 mg, 2.34 mmol, 1.0 equivalent) in toluene (6 mL). The resulting mixture was stirred overnight at 70 °C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by reversed-phase rapid chromatography with elution of ACN / H2O (31:69) to give 4-chloro-8-isopropoxy-1,7-naphthylidine (352 mg, 67%) as a grayish-white solid. Step 6: 4-((3-(cyclopropylthio)benzyl)oxy)-8-isopropoxy-1,7-naphthylidine

[0413] At 0 °C, NaH (118 mg, 2.96 mmol, 2.0 equivalent, 60%) was added to a solution of (3-(cyclopropylthioalkyl)phenyl)methanol (267 mg, 1.48 mmol, 1.0 equivalent) in DMF (5 mL). After stirring at 0 °C for 10 min, 4-chloro-8-isopropoxy-1,7-naphthidine (330 mg, 1.48 mmol, 1.0 equivalent) was added. The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water at 0 °C and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (100:0) to obtain 4-((3-(cyclopropylthio)benzyl)oxy)-8-isopropoxy-1,7-naphthidine (472 mg, 84%) as a colorless oil. Step 7: Cyclopropyl(imino)(3-(((8-isopropoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione

[0414] Add (acetoxy)(phenyl)-λ3-iodoalkyl acetate (527 mg, 1.64 mmol, 3.0 equivalent) and ammonium carbamate (170 mg, 2.18 mmol, 4.0 equivalent) to a solution of 4-((3-(cyclopropylthio)benzyl)oxy)-8-isopropoxy-1,7-naphthidine (200 mg, 0.54 mmol, 1.0 equivalent) in MeOH (3 mL ... 250 mm, 10 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 29% B to 59% B over 20 min; wavelength: 254 nm / 220 nm; RT: 18.17 min), to obtain cyclopropyl(imino)(3-(((8-isopropoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione (78.2 mg, 35%) as a white solid. MS (ESI, positive ion) m / z: 398.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6, , ppm )δ 8.77 (d, J= 5.2 Hz, 1H), 8.10 - 8.02 (m, 2H), 7.94 - 7.87 (m, 1H), 7.86 -7.79 (m, 1H), 7.71 - 7.63 (m, 1H), 7.50 (d, J = 6.0 Hz, 1H), 7.36 (d, J = 5.2 Hz,1H), 5.59 - 5.46 (m, 3H), 4.28 (s, 1H), 2.72 - 2.61 (m, 1H), 1.40 (d, J = 6.4Hz, 6H), 1.16 - 1.06 (m, 1H), 1.03 - 0.83 (m, 3H). Example 62 Synthesis of cyclopropyl(imino)(3-(((8-propoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione Step 1: 3-Nitro-2-propoxypyridine

[0415] At 0 °C, NaH (2.27 g, 94.61 mmol, 3.0 equivalent) was added to a solution of propanol (16.6 mL, 222.97 mmol, 7.0 equivalent) in THF (100 mL). After stirring at 0 °C for 0.5 h, 2-chloro-3-nitropyridine (5.00 g, 31.53 mmol, 1.0 equivalent) was added. After stirring at room temperature for 2 h, the reaction mixture was quenched with water at 0 °C and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography with EtOAc / PE (12:88) to give 3-nitro-2-propoxypyridine (5.22 g, 90%) as a brown oil. Step 2: 2-Propoxypyridine-3-amine

[0416] Pd / C (2.61 g, 24.54 mmol) was added to a solution of 3-nitro-2-propoxypyridine (5.20 g, 28.54 mmol, 1.0 equivalent) in MeOH (80 mL). The mixture was stirred at room temperature under a hydrogen atmosphere achieved by using a hydrogen balloon for 2 h, and then filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure to give 2-propoxypyridine-3-amine (5.10 g, crude product) as a brown oil. Step 3: 2,2-Dimethyl-5-(((2-propoxypyridin-3-yl)amino)methylethylene)-1,3-dioxane-4,6-dione

[0417] Under a nitrogen atmosphere, 2,2-dimethyl-1,3-dioxane-4,6-dione (6.16 g, 42.70 mmol, 1.3 equivalents) and trimethoxymethane (4.88 g, 45.99 mmol, 1.4 equivalents) were added to a solution of 2-propoxypyridin-3-amine (5.00 g, 32.85 mmol, 1.0 equivalents) in 50 mL of ACN. The reaction mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with PE. The precipitate was collected by filtration and washed with PE to give 2,2-dimethyl-5-(((2-propoxypyridin-3-yl)amino)methylethylene)-1,3-dioxane-4,6-dione (7.00 g, 69%) as a pale yellow solid. Step 4: 8-Propoxy-1,7-Naphthyl-4-ol

[0418] A mixture of 2,2-dimethyl-5-(((2-propoxypyridin-3-yl)amino)methylethylene)-1,3-dioxane-4,6-dione (3.50 g, 11.42 mmol, 1.0 equivalent) in diphenyl ether (50 mL) was stirred at 225 °C for 1.5 h. After cooling to room temperature, the resulting mixture was diluted with PE. The precipitate was collected by filtration and washed with PE. The crude product was purified by reversed-phase rapid chromatography with elution of ACN / H2O (60:40) to give 8-propoxy-1,7-naphthidine-4-ol (570 mg, 24%) as a yellow solid. Step 5: 4-((3-(cyclopropylthio)phenyl)methoxy)-8-propoxy-1,7-naphthidine

[0419] To a solution of 8-propoxy-1,7-naphthyl-4-ol (300 mg, 1.46 mmol, 1.0 equivalent) in toluene (5 mL), (3-(cyclopropylthioalkyl)phenyl)methanol (397 mg, 2.20 mmol, 1.5 equivalent) and 2-(tributyl-λ5-phosphono)acetonitrile (709 mg, 2.93 mmol, 2.0 equivalent) were added. The reaction mixture was stirred at 130 °C under a nitrogen atmosphere for 2 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution of ACN / H2O (70:30) to give 4-((3-(cyclopropylthioalkyl)phenyl)methoxy)-8-propoxy-1,7-naphthylidine (300 mg, 55%) as a brown solid. Step 6: Cyclopropyl(imino)(3-(((8-propoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione

[0420] Add (acetoxy)(phenyl)-λ3-iodoalkyl acetate (474 ​​mg, 1.47 mmol, 3.0 equivalent) and ammonium carbamate (153 mg, 1.96 mmol, 4.0 equivalent) to a solution of 4-((3-(cyclopropylthio)phenyl)methoxy)-8-propoxy-1,7-naphthidine (180 mg, 0.49 mmol, 1.0 equivalent) in MeOH (4 mL ...methoxy)-8-propoxy-1,7-naphthidine)methoxy)-1.49 mmol, 1.0 equivalent) in MeOH (4 mL) to a solution of 4-((3-(cyclopropylthio)methoxy)-8-propoxy-1,7-naphthidine (180 mg, 0.49 mmol, 1.0 equivalent) in MeOH (4 mL) to a solution of 4-((3-(cyclopropylthio)methoxy)-8-propoxy-1,7-naphthidine (180 mg, 0.49 mmol, 1.0 equivalent) in MeOH (4 mL) to a solution of 4-((3-(cyclopropylth 250 mm, 10 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 31% B to 61% B over 20 min; wavelength: 254 nm / 220 nm; RT: 17.65 min), to obtain a grayish-white solid of cyclopropyl(imino)(3-(((8-propoxy-1,7-naphthidin-4-yl)oxy)methyl)phenyl)-λ6-thione (70.3 mg, 35%). MS (ESI, positive ion) m / z: 398.1 (M+1). 1 H NMR (400 MHz, DMSO- d 6 ppm ) δ 8.80 (d, J = 5.2 Hz, 1H), 8.10 - 8.03 (m, 2H), 7.94 - 7.87 (m,1H), 7.84 (d, J= 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 5.53 (s, 2H), 4.43 - 4.39 (m, 2H), 4.28 (s, 1H), 2.69- 2.66 (m, 1H), 1.91 - 1.78 (m, 2H), 1.19 - 1.07 (m, 1H), 1.06 - 1.00 (m,3H), 1.00 - 0.95 (m, 1H), 0.95 - 0.82 (m, 2H). Example 63 Synthesis of (2-(1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-hydroxypiperidin-4-yl)ethyl)-(imino)(methyl)-λ6-thione Step 1: 4-Hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester

[0421] Under a nitrogen atmosphere at 0 °C, a borane-tetrahydrofuran complex (77.1 mL, 77.13 mmol, 4.0 equivalents, 1.0 M in THF) was added dropwise to a solution of 2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)acetic acid (5.00 g, 19.28 mmol, 1.0 equivalent) in THF (50 mL). After stirring at room temperature for 16 h, the reaction mixture was quenched with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (60:40) elution to give tert-butyl 4-hydroxy-4-(2-hydroxyethyl)piperidin-1-carboxylate (3.12 g, crude) as a colorless oil. Step 2: 4-Hydroxy-4-(2-(methanesulfonyloxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester

[0422] MsCl (1.60 g, 13.90 mmol, 1.1 equivalent) was added dropwise to a solution of tert-butyl 4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylate (3.10 g, 12.63 mmol, 1.0 equivalent) and Et3N (2.56 g, 25.27 mmol, 2.0 equivalent) in DCM (30 mL) at 0 °C. After stirring at 0 °C for 10 min, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with EtOAc / PE (56:44) to give tert-butyl 4-hydroxy-4-(2-(methanesulfonyloxy)ethyl)piperidine-1-carboxylate (3.30 g, crude) as a pale yellow oil. Step 3: 4-Hydroxy-4-(2-(methylthio)ethyl)piperidine-1-carboxylic acid tert-butyl ester

[0423] To a solution of tert-butyl 4-hydroxy-4-(2-(methanesulfonyloxy)ethyl)piperidine-1-carboxylate (3.30 g, 10.20 mmol, 1.0 equivalent) in EtOH (30 mL), sodium methanethiol (17.81 g, 51.02 mmol, 5.0 equivalent, 20%) was added. After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc / PE (28:72) to give tert-butyl 4-hydroxy-4-(2-(methylthioalkyl)ethyl)piperidine-1-carboxylate (900 mg, 25%) as a brown oil. Step 4: 4-(2-(methylthio)ethyl)piperidine-4-ol hydrochloride

[0424] A solution of tert-butyl 4-hydroxy-4-(2-(methylthio)ethyl)piperidine-1-carboxylate (900 mg, 3.26 mmol, 1.0 equivalent) in 1,4-dioxane (10 mL) in 4 M HCl (g) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 4-(2-(methylthio)ethyl)piperidine-4-ol hydrochloride (1.03 g, crude product) as a grayish-white solid. Step 5: 1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-(2-(methylthioalkyl)ethyl)piperidin-4-ol

[0425] To a solution of 4-chloro-8-(fluoromethoxy)-1,7-naphthylidine (250 mg, 1.17 mmol, 1.0 equivalent) in NMP (5 mL), 4-(2-(methylthio)ethyl)piperidin-4-ol hydrochloride (298 mg, 1.41 mmol, 1.2 equivalent) and DIEA (759 mg, 5.88 mmol, 5.0 equivalent) were added. The reaction mixture was stirred at 130 °C for 3 h. After cooling to room temperature, the reaction solution was purified by reversed-phase rapid chromatography with elution using ACN / H2O (47:53) to give 1-(8-(fluoromethoxy)-1,7-naphthyl)-4-(2-(methylthio)ethyl)piperidin-4-ol (300 mg, 72%) as a pale yellow solid. Step 6: 4-(4-((tert-butyldimethylsilyl)oxy)-4-(2-(methylthio)ethyl)piperidin-1-yl)-8-(fluoromethoxy)-1,7-naphthidine

[0426] To a solution of 1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-(2-(methylthioalkyl)ethyl)-piperidin-4-ol (280 mg, 0.79 mmol, 1.0 equivalent) in THF (5 mL), 2,6-dimethylpyridine (128 mg, 1.19 mmol, 1.5 equivalent) and tert-butyldimethylsilyl trifluoromethanesulfonate (421 mg, 1.59 mmol, 2.0 equivalent) were added. After stirring overnight at room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with MeOH / DCM (6:94) elution to give 4-(4-((tert-butyldimethylsilyl)oxy)-4-(2-(methylthioalkyl)-ethyl)piperidin-1-yl)-8-(fluoromethoxy)-1,7-naphthidine (200 mg, 53%) as a brown semi-solid. Step 7: (2-(4-((tert-butyldimethylsilyl)oxy)-1-(8-(fluoromethoxy)-1,7-naphthidin-4-yl)piperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione

[0427] At -15 °C, ammonium hydroxide (225 mg, 25% (v / v)) was added to a solution of 4-(4-((tert-butyldimethylsilyl)oxy)-4-(2-(methylthio)ethyl)piperidin-1-yl)-8-(fluoromethoxy)-1,7-naphthylidine (150 mg, 0.32 mmol, 1.0 equivalent) in ACN (5 mL). The reaction mixture was stirred at -15 °C for 1 h. Tert-butyl hypochlorite (174 mg, 1.61 mmol, 5.0 equivalent) was added, and the reaction mixture was then stirred at -15 °C for another 1 h. Additional ammonium hydroxide (225 mg, 25% (v / v)) was added. The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography with MeOH / DCM (18:82) to give a grayish-white solid (2-(4-((tert-butyldimethylsilyl)oxy)-1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)piperidin-4-yl)ethyl)(methyl)-λ6-thione diimine (50 mg, 31%) MS (ESI, positive ion) m / z: 496.1 (M+1) and a grayish-white solid (2-(4-((tert-butyldimethylsilyl)oxy)-1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)piperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione (20 mg, 20%) MS (ESI, positive ion) m / z: 497.1 (M+1). Step 8: (2-(1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)-4-hydroxypiperidin-4-yl)ethyl)-(imino)(methyl)-λ6-thione

[0428] TBAF (0.1 mL, 0.10 mmol, 2.5 equivalents, 1.0 M in THF) was added to a solution of (2-(4-((tert-butyldimethylsilyl)oxy)-1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)piperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione (20 mg, 0.04 mmol, 1.0 equivalent) in THF (1 mL). After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC with MeOH / DCM (5:95) to give a crude product, which was further purified by preparative HPLC under the following conditions (column: Xbridge Prep OBD C18 column, 30). 150 mm, 5 µm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2% B to 29% B over 10 min; wavelength: 254 nm / 220 nm; RT: 8.68 min), to obtain (2-(1-(8-(fluoromethoxy)-1,7-naphthidin-4-yl)-4-hydroxypiperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione (3.8 mg, 24%) as a grayish-white solid. MS (ESI, positive ion) m / z: 383.2 (M+1). 1 H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.73(d, J = 5.2 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 6.0 Hz, 1H), 7.23 (d, J =5.2 Hz, 1H), 6.36 (s, 1H), 6.23 (s, 1H), 4.64 (s, 1H), 3.66 (s, 1H), 3.35 (s,2H), 3.24 - 3.11 (m, 4H), 2.93 (s, 3H), 1.99 - 1.89 (m, 2H), 1.89 - 1.78 (m, 2H), 1.71 (d, J = 11.6 Hz, 2H).

[0429] 19 F NMR (376 MHz, DMSO- d 6 , ppm ) δ -155.73 (s, 1 F). Example 64 Synthesis of imino(2-(1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethyl)(methyl)-λ6-thione Step 1: 1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-4-[2-(methylthioalkyl)ethyl]piperidine

[0430] DIEA (991 mg, 7.67 mmol, 5 equivalents) and 4-[2-(methylthioalkyl)ethyl]piperidine hydrochloride (450 mg, 2.30 mmol, 1.5 equivalents) were added to a solution of 4-chloro-8-methoxypyrido[3,4-d]pyrimidinidine (300 mg, 1.5 mmol, 1.5 equivalents) in NMP (6 mL). The resulting mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the crude product was purified by reversed-phase rapid chromatography with elution of ACN / H2O (60:40) to give 1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-4-[2-(methylthioalkyl)ethyl]piperidine (330 mg, 67%) as a yellow solid. MS (ESI, positive ion) m / z: 319.1 (M+1). Step 2: Imino(2-(1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethyl)(methyl)-λ6-thione

[0431] Ammonium hydroxide (1.19 g, 25% (v / v)) was added to a mixture of 1-(8-methoxypyrido[3,4-d]pyrimidin-4-yl)-4-(2-(methylthioalkyl)-ethyl)piperidine (280 mg, 0.87 mmol, 1.0 equivalent) in ACN (8 mL) at -15 °C under a N2 atmosphere. The mixture was stirred at -15 °C for 1 h. Tert-butyl hypochlorite (477 mg, 4.39 mmol, 5.0 equivalent) was added, and the mixture was stirred at -15 °C for 1 h. Additional ammonium hydroxide (1.19 g, 25% (v / v)) was added at -15 °C, and the mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography with elution using ACN / H2O (20:80) and concentrated under reduced pressure. The crude product was further purified by preparative HPLC (column: Xbridge Prep OBD C18 column, 30). 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 29% B over 10 min; Wavelength: 254 nm / 220 nm; RT: 8.68 min). Fractions containing the desired product were combined and lyophilized to give imino(2-(1-(8-methoxypyridino[3,4-d]pyrimidin-4-yl)piperidin-4-yl)ethyl)(methyl)-λ6-thione (17.0 mg, 5%) as a yellow solid. MS (ESI, positive ion) m / z: 350.1 (M+1). 1H NMR (400 MHz, DMSO- d 6 , ppm ) δ 8.64 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 4.34 - 4.31 (m, 2H), 4.02 (s, 3H), 3.61 (s, 1H), 3.21 - 3.05 (m, 4H), 2.89 (s, 3H), 1.84 (d, J =12.0 Hz, 2H), 1.75 - 1.64 (m, 3H), 1.44 - 1.26 (m, 2H). Example 65 Synthesis of (2-(1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)piperidin-4-yl)ethyl)-(imino)(methyl)-λ6-thione Step 1: 4-(2-((methanesulfonyl)oxy)ethyl)piperidine-1-carboxylic acid tert-butyl ester

[0432] At 0 °C, TEA (11.91 g, 117.73 mmol, 3 equivalents), DMAP (0.48 g, 3.925 mmol, 0.1 equivalents), and methanesulfonic anhydride (20.51 g, 117.74 mmol, 3 equivalents) were added to a solution of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (9.00 g, 39.24 mmol, 1 equivalent) in DCM (150 mL). After stirring at room temperature for 2 h, the reaction mixture was diluted with water (500 mL) and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 4-[2-(methanesulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (10.00 g, crude) as a pale yellow oil, which was used directly in the next step without further purification. Step 2: 4-[2-(methylthioalkyl)ethyl]piperidine-1-carboxylic acid tert-butyl ester

[0433] Sodium methanethiol (113.98 g, 325.30 mmol, 1 equivalent) was added to a solution of 4-[2-(methanesulfonyloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (10.00 g, 32.53 mmol, 1 equivalent) in EtOH (150 mL). After stirring at room temperature for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with EA / PE (20:80) elution to give 4-[2-(methylthioalkyl)ethyl]piperidine-1-carboxylic acid tert-butyl ester (7.00 g, 69% (two steps)) as a colorless oil. Step 3: 4-(2-(methylthio)ethyl)piperidine hydrochloride

[0434] A solution of tert-butyl 4-(2-(methylthio)ethyl)piperidine-1-carboxylate (851 mg, 3.28 mmol) in HCl (10 mL, gas, 4 M in 4-dioxane) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 4-(2-(methylthio)ethyl)-piperidine hydrochloride (716 mg, crude) as a white solid. Step 4: 8-(fluoromethoxy)-4-(4-(2-(methylthio)ethyl)piperidin-1-yl)-1,7-naphthidine

[0435] DIEA (600 mg, 4.64 mmol, 4.9 equivalents) was added to a stirred mixture of 4-chloro-8-(fluoromethoxy)-1,7-naphthylidine (200 mg, 0.94 mmol, 1.0 equivalent) and 4-(2-(methylthio)ethyl)piperidine hydrochloride (320 mg, 1.63 mmol, 1.7 equivalent) in NMP (4 mL). The resulting mixture was stirred at 130 °C for 4 h. After cooling to room temperature, the reaction solution was purified by reversed-phase rapid chromatography with elution using ACN / H2O (57:33) to give 8-(fluoromethoxy)-4-(4-(2-(methylthio)ethyl)piperidin-1-yl)-1,7-naphthylidine (220 mg, 69%) as a brown solid. MS Step 5: (2-(1-(8-(fluoromethoxy)-1,7-naphthid-4-yl)piperidin-4-yl)ethyl)(imino)(methyl)-λ6-thione

[0436] A solution of 8-(fluoromethoxy)-4-(4-(2-(methylthioalkyl)ethyl)piperidin-1-yl)-1,7-naphthidine (220 mg, 0.66 mmol, 1.0 equivalent) in ACN (8 mL) was treated with ammonium hydroxide (880 mg, 25% (v / v)) for 1 h at -15 °C under a nitrogen atmosphere, followed by dropwise addition of tert-butyl hypochlorite (356 mg, 3.28 mmol, 5.0 equivalent) at -15 °C for 1 h. Ammonium hydroxide (880 mg, 25% (v / v)) was then added dropwise to the mixture at -15 °C for 1 h. The resulting mixture was stirred overnight ...

Claims

1. A compound having the formula (Id) or a pharmaceutically acceptable salt thereof: (Id), in: X is: (a) CH or CR 1 ;or (b) N; R 1 It is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, diaminoalkyl, diaminoalkoxy, diaminoalkylamino, or cyano. R 2 and R 3 Independently absent, is alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkoxy, hydroxyalkylamino, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heterocyclic, heterocyclic oxy, heterocyclic amino (wherein the heterocyclic group alone or a portion thereof and the heterocyclic oxy group and the heterocyclic amino group may optionally be substituted by one, two or three independently selected from the following substituents: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl). alkyl, and aminoalkyl), heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkylamino (wherein the heterocyclic ring in the heterocyclic alkyl, heterocyclic alkyloxy, and heterocyclic alkylamino is optionally substituted by one, two, or three independent substituents selected from the following: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, and aminoalkyl), cycloalkyloxy, phenyloxy, or heteroaryloxy (wherein the phenyl in the phenyloxy and the heteroaryl in the heteroaryloxy are optionally substituted by one, two, or three independent substituents selected from the following: alkyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano); Z is a cyclic imino group, a spirocyclic imino group, a fused cyclic imino group, NH, N (alkyl), O, S, SO, or SO2, wherein: (a) When Z is a cyclic imine group, a spirocyclic imine group, or a fused cyclic imine group, then Q is -(alk). m -W, where each Z part of (a) is R 4 and R 5 Replace, and R 4 and R 5 It does not exist independently; it is an alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, or cyano group; and (b) When Z is NH, N (alkyl), O, S, SO, or SO2, then Q is -(alk) 1 ) n -Ar-W, where Ar is a arylene, a 5-membered or a 6-membered heteroarylene, and each Ar is divided by R 6 and R 7 Replace, and R 6 and R 7 It does not exist independently; it is an alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, or cyano group. alk and alk 1 Independently, it is an alkylene group that is optionally substituted with one, two, or three halogens; m and n are independently 0 or 1; and W is a group composed of formula (i) or (ii): (i) or (ii); R 8 and R 9 Each of these groups is independently hydrogen, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, heterocyclic, or substituted heterocyclic.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, X is CH or CR 1 .

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, X is CH.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, X is CR 1 .

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, X is N.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein, Z is a cyclic imine group, a spirocyclic imine group, or a fused cyclic imine group, wherein each Z moiety is divided by R. 4 and R 5 replace.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein, Z was R 4 and R 5 Substituted cyclic imine group.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein, Z was R 4 and R 5 Substituted spirocyclic imine group.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein, The cycloimine or spirocycloimine group is attached to the nitrogen ring atom via attachment. The wavy line represents the attachment point.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein, The cyclic imine group, spirocyclic imine group, or fused cyclic imine group of Z is selected from: Each ring is R 4 and R 5 Replace, and among them Is with -(alk) m -W attachment point and Attach to .

11. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein, Z is O, N (alkyl), or NH.

12. The compound of any one of claims 1 to 4 or 11, or a pharmaceutically acceptable salt thereof, wherein, Z is O.

13. The compound of any one of claims 1 to 4 or 11, or a pharmaceutically acceptable salt thereof, wherein, Z is NH or N (alkyl).

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein, m is 0 and n is 0.

15. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein, m is 1 and n is 1.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein, alk and alk 1 It is methylene, ethylene, or propylene, on its own.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein, alk and alk 1 It is methylene.

18. The compound of any one of claims 1 to 4 and 11 to 17, or a pharmaceutically acceptable salt thereof, wherein, Ar was R 6 and R 7 Substituted phenylene or 5- or 6-membered heteroaryl groups.

19. The compound of any one of claims 1 to 4 and 11 to 18, or a pharmaceutically acceptable salt thereof, wherein, Ar was R 6 and R 7 Substituted phenylene.

20. The compound of any one of claims 1 to 4 and 11 to 19, or a pharmaceutically acceptable salt thereof, wherein, Ar is a phenylene ring and W is a carbon atom attached to the phenylene ring, which is attached to -Z-(alk) 1 ) n -of-(alk) 1 ) n - The para position of the carbon atom on the phenylene ring.

21. The compound of any one of claims 1 to 4 and 11 to 19, or a pharmaceutically acceptable salt thereof, wherein, Ar is a phenylene ring and W is a carbon atom attached to the phenylene ring, which is attached to -Z-(alk) 1 ) n -of-(alk) 1 ) n -The meta position of the carbon atom on the phenylene ring.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein, W is: 。 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein, W is: 。 24. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein, W is: 。 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is an alkyl group, halogen, haloalkyl group, haloalkoxy group, or cyano group.

26. The compound of any one of claims 1, 2, and 4 to 24, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is methyl, ethyl, isopropyl, cyano, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

27. The compound of any one of claims 1, 2, and 4 to 24, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is an amino, alkylamino, or dialkylamino.

28. The compound of any one of claims 1, 2, and 4 to 24, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is a cyano group.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein, R 4 R 5 R 6 and R 7 It does not exist independently; it is methyl, ethyl, hydroxyl, fluorine, or chlorine.

30. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein, R 4 R 5 R 6 and R 7 It does not exist independently, or it is fluorine.

31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein, R 4 R 5 R 6 and R 7 It does not exist independently, or it is a hydroxyl group.

32. The compound of any one of claims 1, 2, 3, 11, 12, 15 to 19, 22 to 24, and 29 to 31, or a pharmaceutically acceptable salt thereof, having the formula (Id1): (Id1)。 33. The compound of any one of claims 1, 2, 3, 11, 12, 15 to 19, 22 to 24, and 29 to 31, or a pharmaceutically acceptable salt thereof, having the formula (Id2): (Id2)。 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein, R 2 It does not exist; it is alkyl, hydroxyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.

35. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein, R 2 It does not exist; it is an alkoxy group, a haloalkoxy group, or a cycloalkyloxy group.

36. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein, R 2 It does not exist; it is methyl, hydroxy, methoxy, ethoxy, fluorine, chlorine, trifluoromethyl, cyano, trifluoromethyl, aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl.

37. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein, R 2 It does not exist; it is methoxy, fluoromethoxy, ethoxy, isopropyloxy, n-propyloxy, aminocarbonyl, cyano, or cyclopropyloxy.

38. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein, R 2 It does not exist; it is methoxy, fluoromethoxy, ethoxy, isopropyloxy, n-propyloxy, or cyclopropyloxy.

39. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein, R 2 It does not exist; it is either methoxy or ethoxy.

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein, R 3 It does not exist.

41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein, R 8 It is an alkyl group, a substituted alkyl group, a haloalkyl group, a substituted haloalkyl group, a cycloalkyl group, a substituted cycloalkyl group, or a cycloalkylalkyl group.

42. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein, R 8 It is independently methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, or cyclobutylmethyl.

43. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein, R 8 It is an alkyl or cycloalkyl group.

44. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein, R 8 It is methyl or cyclopropyl.

45. The compound of any one of claims 1 to 21 and 25 to 44, or a pharmaceutically acceptable salt thereof, wherein, R 9 It is hydrogen.

46. ​​The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the list in Table 1.

47. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

48. A method of treating a disease or condition in a patient that is at least partially regulated by ENPP1, the method comprising administering to the patient a compound as described in any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 47.

49. The method of claim 48, wherein, The disease or condition is cancer, an inflammatory disease, a metabolic disease, or a viral disease.

50. The method of claim 49, wherein, The disease or condition is cancer.

51. The method of claim 49 or 50, wherein, The disease or condition is selected from: hepatocellular carcinoma, glioblastoma, melanoma, testicular cancer, pancreatic cancer, thyroid cancer, cervical cancer, ovarian cancer, bladder cancer, colon cancer, lung cancer, breast cancer, multiple myeloma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, large granular lymphoblastic leukemia, T-cell prolymphocytic leukemia, prolymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse lymphoma. Large B-cell lymphoma, low-grade glioma, colorectal cancer, gastric and gastrointestinal cancer, esophageal cancer, anal cancer, appendix cancer, kidney cancer, skin cancer, uterine cancer, brain cancer, adrenal cancer, bile duct cancer, bone cancer, fallopian tube cancer, sarcoma, germ cell tumors, head and neck cancer, neuroblastoma, pheochromocytoma and paraganglioma, bile duct cancer, peritoneal cancer, retinoblastoma, liver cancer, thymoma, urethral cancer, prostate cancer, uveal melanoma, adenoid cystic carcinoma, and vaginal and vulvar cancer.

52. The method of any one of claims 48 to 51, further comprising administering an additional anticancer agent.

53. The method of claim 52, wherein, The other anticancer agent is an immune checkpoint inhibitor.

54. The method of claim 53, wherein, This immune checkpoint inhibitor targets immune checkpoint molecules selected from the following group: CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1, and PD-L2.

Images